| Text | Predicted type |
| Taken together, these results make it clear that CHEMICAL-bound forms of GENE and Cdc6p are likely to be required for productive interactions and pre-RC formation. | BINDING-INTERACTION |
| Taken together, these results make it clear that CHEMICAL-bound forms of ORC and GENE are likely to be required for productive interactions and pre-RC formation. | BINDING-INTERACTION |
| Additional experiments were therefore performed to clarify whether the GENE cd could in fact bind to human GENE and GGA2. | NO-RELATIONSHIP |
| Additional experiments were therefore performed to clarify whether the GENE cd could in fact bind to human GGA1 and GENE. | NO-RELATIONSHIP |
| We conclude that the GENE subunit of dynactin binds directly to GENE. | BINDING-INTERACTION |
| We conclude that the Arp1 subunit of GENE binds directly to GENE. | BINDING-INTERACTION |
| We show that GENE and activin bind to the same type II receptors, GENE and IIB, but recruit distinct type I receptors into heteromeric receptor complexes. | BINDING-INTERACTION |
| We show that GENE and activin bind to the same type II receptors, ActRII and IIB, but recruit distinct type I receptors into heteromeric receptor complexes. | BINDING-INTERACTION |
| We show that BMP7 and GENE bind to the same type II receptors, GENE and IIB, but recruit distinct type I receptors into heteromeric receptor complexes. | BINDING-INTERACTION |
| We show that BMP7 and GENE bind to the same type II receptors, ActRII and IIB, but recruit distinct type I receptors into heteromeric receptor complexes. | BINDING-INTERACTION |
| The results suggest unanticipated roles for this region in GENE binding to GENE, tropomyosin, and possibly troponin. | BINDING-INTERACTION |
| The results suggest unanticipated roles for this region in GENE binding to myosin, GENE, and possibly troponin. | BINDING-INTERACTION |
| The results suggest unanticipated roles for this region in GENE binding to myosin, tropomyosin, and possibly GENE. | BINDING-INTERACTION |
| C, disruption of Ca -dependent phospholipid binding does not inhibit Ca -dependent GENE binding to GENE. | BINDING-INTERACTION |
| C, disruption of Ca -dependent CHEMICAL binding does not inhibit Ca -dependent GENE binding to synaptotagmin. | NO-RELATIONSHIP |
| Binding of GENE to GENE is regulated by ordered phosphorylation of critical proline-directed Ser/ Thr residues on 4E-BP1 [15, 16] . | BINDING-INTERACTION |
| It is interesting to note that deletion of coding exon 3 or 4 did not significantly affect GENE binding to GENE proteins, even though both exons encode conserved sequences. | BINDING-INTERACTION |
| Since paralog members exhibit relatively conserved amino acid sequences, these data make it likely that all 39 GENE proteins bind GENE. | BINDING-INTERACTION |
| H2A-H2B stabilizes binding of GENE to GENE. | BINDING-INTERACTION |
| A cadherin mutant unable to bind PS1 is not cleaved by the GENE activity To examine whether PS1 binding to GENE is necessary for the GENE cleavage, we used GENE mutant GGG759-761AAA ( Thoreson et al., 2000). | PART-OF |
| Binding of GENE to GENE has been shown to reduce the ability of CBP to catalyze this reaction, perhaps by steric interference [ 97]. | BINDING-INTERACTION |
| Clearly, the demonstration that GENE predominantly binds mature GENE additionally questions the existence of the spatial paradox. | BINDING-INTERACTION |
| Interaction between the GENE and GENE was previously shown by genetic analysis (18). | BINDING-INTERACTION |
| Therefore, we examined the binding of GENE to GENE in the Spry cell lines ( 28). | BINDING-INTERACTION |
| Both GENE and TFIIE can bind to GENE, pointing to a direct effect of these proteins on GENE CTD kinase activity [ 24]. | BINDING-INTERACTION |
| Both Gal11p and GENE can bind to GENE, pointing to a direct effect of these proteins on GENE CTD kinase activity [ 24]. | BINDING-INTERACTION |
| A similar C-tail release is induced by GENE binding to GENE ( 16, 27), i.e. by the normal process of wild type GENE's transition into its active state. | BINDING-INTERACTION |
| A similar C-tail release is induced by GENE binding to P-GENE* ( 16, 27), i.e. by the normal process of wild type GENE's transition into its active state. | BINDING-INTERACTION |
| SMAD-induced transcriptional stimulation is inhibited by an GENE protein that binds GENE but not by an GENE protein unable to bind GENE in two different cell lines treated with TGF-beta. | BINDING-INTERACTION |
| As expected, GENE specifically bound to the GENE tail peptide methylated at K9 (Fig. 5B). | BINDING-INTERACTION |
| A and B show that GENE was bound to the GENE in both the undiluted (100 nM GENE + 100 nM GENE) and the 10-fold diluted samples, respectively. | BINDING-INTERACTION |
| The results demonstrated that GENE bound to GENE with the highest recovery ( Figure 6A). | BINDING-INTERACTION |
| The effect was specific to rapamycin, as CHEMICAL, an immunosuppressant that also binds GENE but does not target mTOR, had no effect on the interaction, nor did ethanol, the vehicle used for both drugs. | DIRECT-REGULATOR |
| C, double-reciprocal plot for the adducin-dependent binding of GENE to GENE data shown in panels A and B. | BINDING-INTERACTION |
| GENE binds GENE directly via the MH domain | BINDING-INTERACTION |
| To further define the interaction domain for GENE binding to GENE, we constructed a deletion mutant of GENE (GENE-deltaN125) in which the distal 125 amino acids of the amino terminus were removed. | BINDING-INTERACTION |
| The intracellular concentration of Ubc2 is consistently within the micromolar range, which is saturating with respect to the Km of 102 ± 13 nM for uncharged GENE binding to GENE and theKm of 54 ± 18 nM for GENE-ubiquitin thiolester binding to E3α. | BINDING-INTERACTION |
| The intracellular concentration of Ubc2 is consistently within the micromolar range, which is saturating with respect to the Km of 102 ± 13 nM for uncharged HsUbc2b binding to E1 and theKm of 54 ± 18 nM for GENE binding to GENE. | BINDING-INTERACTION |
| (D) Binding of GENE to GENE deletion mutants. | BINDING-INTERACTION |
| In contrast, CC2, GENE CT (COOH-terminal 75 aa of GENE, which binds to GENE and GM130) and GM130 NT (NH2-terminal 73 aa of GM130, which binds GENE) had no effect ( Fig. 2, E and F). | BINDING-INTERACTION |
| In contrast, CC2, GENE CT (COOH-terminal 75 aa of GENE, which binds to Giantin and GENE) and GENE NT (NH2-terminal 73 aa of GENE, which binds GENE) had no effect ( Fig. 2, E and F). | BINDING-INTERACTION |
| GENE binding to GENE can prevent the inhibitory effects of transcriptional repressors, Dr1/DRAP1, HMG1, DSP1, MOT1, and TAFII250 ( 8-14). | BINDING-INTERACTION |
| TFIIA binding to TBP can prevent the inhibitory effects of transcriptional repressors, GENE/GENE, HMG1, DSP1, MOT1, and TAFII250 ( 8-14). | BINDING-INTERACTION |
| A phosphoprotein of 62-64 kDa was clearly seen in association with GENE upon ephrin-B1 stimulation, demonstrating that GENE not only binds to GENE, but also interacts with other proteins in ephrin-B1-stimulated cells. | BINDING-INTERACTION |
| Specifically, we have determined that GENE binds to GENE kinase both in vivo (Figs. 1, 6, 8, and 9) and in vitro (Fig. 2). | BINDING-INTERACTION |
| The mutation in the APPKPPR sequence (mPR) abolished the binding of GENE to GENE SH3 (Fig. 3B, lanes 1, 2), strongly suggesting that this sequence was the binding site for GENE SH3. | BINDING-INTERACTION |
| As expected, the affinity of [3H]LY341495 in rat brain shown here is much higher than that observed for GENE binding with CHEMICAL (Kd= 187 nM). | BINDING-INTERACTION |
| Moreover, concentrations of tamoxifen as low as 0.25 muM substantially increased the binding of GENE to the GENE. | BINDING-INTERACTION |
| Moreover, we showed that the binding regions of GENE and GENE were the region containing the first and second SH3 domains and the proline-rich region, respectively. | BINDING-INTERACTION |
| ( Table II), suggesting that the inhibitory role of intracellular Na+ is not mediated by directly affecting the binding of GENE to GENE. | BINDING-INTERACTION |
| ( B) The GENE AD binds GENE and Sug2/Rpt4 directly. | BINDING-INTERACTION |
| ( B) The GENE AD binds Sug1/Rpt6 and GENE directly. | BINDING-INTERACTION |
| Our results suggest a mechanism by which GENE binding to GENE molecules translates into peptide release via disturbance of key interactions between the peptide and GENE molecule near the P1 pocket. | BINDING-INTERACTION |
| Functional consequences of phosphorylation reported here include modulation of adducin interactions with spectrin and actin by GENE and inhibition of GENE binding by GENE and PKC. | BINDING-INTERACTION |
| Functional consequences of phosphorylation reported here include modulation of adducin interactions with spectrin and actin by PKA and inhibition of GENE binding by PKA and GENE. | BINDING-INTERACTION |
| It has been suggested that GENE binding to GENE affects the GENE conformation, resulting in a block in MEKK binding ( 36). | BINDING-INTERACTION |
| It has been suggested that GSK-3beta binding to GENE affects the GENE conformation, resulting in a block in GENE binding ( 36). | BINDING-INTERACTION |
| Although the GENE binding domain of the GENE has not been identified, these apparently discrepant data can be interpreted in the context of recently solved crystal structures ( 38). | BINDING-INTERACTION |
| This effect was dose-dependent in that increasing concentrations of Slit led to more binding of GENE with GENE (Figure 4D). | BINDING-INTERACTION |
| Interestingly, it has been described that GENE can bind GENE to phosphorylate it, which would result in a tighter interaction with - catenin [ 20]. | BINDING-INTERACTION |
| Interestingly, it has been described that GSK-3 can bind GENE to phosphorylate it, which would result in a tighter interaction with - GENE [ 20]. | BINDING-INTERACTION |
| It has been found that GENE is bound directly to GENE in the cytoplasm of quiescent cells; upon activation of the MAPK pathway by growth factors or activated RAS, GENE is relocalized to the plasma membrane in a complex containing RAF, GENE, and MAPK (Michaudet al. 1997; Denouel-Galyet al. 1998; Yuet al. 1998; Stewartet al. 1999). | BINDING-INTERACTION |
| In sum, the binding of GENE to GENE cytoplasmic domains is crucial for integrin function and is involved in the regulation of integrin activation and clustering. | BINDING-INTERACTION |
| GENE binding to GENE - expressing COS-7 cells is indistinguishable from NP-1-expressing COS-7 cells at saturating concentrations of ligand (3 nM). | BINDING-INTERACTION |
| Sema3A binding to GENE/GENE - expressing COS-7 cells is indistinguishable from GENE-expressing COS-7 cells at saturating concentrations of ligand (3 nM). | BINDING-INTERACTION |
| K d for CHEMICAL binding to GENE at pH 7.5 and 6.5 calculated using Equation 1 for the F obsdata in Fig. 10 A were, at pH 7.5, K d = 6.8 ± 0.6 μM, N o = 0.51 ± 0.02 mol of CHEMICAL/mol of protein and, at pH 6.5,K d = 1.4 ± 0.1 μM. | DIRECT-REGULATOR |
| Inhibition of Actin Binding by PhosphorylationWe examined the effects of phosphorylation on GENE-GENE binding and found that phosphorylation by PKC inhibits GENE binding of GENE. | BINDING-INTERACTION |
| This experiment showed that Bcr increased the binding of GENE to activated GENE in a reaction that requires binding of its C terminus to the PDZ domain of GENE. | BINDING-INTERACTION |
| Thus, a straightforward interpretation of our results might be that overexpression of the GTP-bound form of Rab3a inhibits CHEMICAL-induced exocytosis by sequestering CHEMICAL/GENE. | BINDING-INTERACTION |
| Thus, a straightforward interpretation of our results might be that overexpression of the CHEMICAL-bound form of GENE inhibits Ca2+-induced exocytosis by sequestering Ca2+/CaM. | BINDING-INTERACTION |
| Therefore, it is possible that the amino-terminal and SH3 domains of GENE can bind simultaneously to GENE or Grb2 and Abl, respectively. | BINDING-INTERACTION |
| Therefore, it is possible that the amino-terminal and SH3 domains of GENE can bind simultaneously to Sos or GENE and Abl, respectively. | BINDING-INTERACTION |
| Therefore, it is possible that the amino-terminal and SH3 domains of GENE can bind simultaneously to Sos or Grb2 and GENE, respectively. | BINDING-INTERACTION |
| It is intriguing that our observation that GENE directly binds to the TPR domain of GENE and that GENE binding to GENE is inhibited by the GENE-All antibody, which binds specifically to the TPR domain of GENE ( Stenoien and Brady 1997 ), is similar to recent work on the SYD protein. | BINDING-INTERACTION |
| These Tcf-binding proteins appear to suppress the complex formation of GENE, Tcf, and DNA. GENE is a nuclear protein that binds to GENE, but the physiological significance is not known ( 33). | BINDING-INTERACTION |
| The general transcription factors GENE and TFIIB bind directly to GENE, stabilize its association with the promoter, and form the core of the RNA polymerase II preinitiation complex ( 18, 36, 48). | BINDING-INTERACTION |
| The general transcription factors TFIIA and GENE bind directly to GENE, stabilize its association with the promoter, and form the core of the RNA polymerase II preinitiation complex ( 18, 36, 48). | BINDING-INTERACTION |
| (vii) Overexpression of a GENE mutant lacking the SH2 domain impairs IGF-I-mediated ubiquitination of the IGF-IR in both p6 and p6/GENE cells, suggesting that binding between GENE and GENE is critical for ubiquitination of the receptor. | BINDING-INTERACTION |
| B, the COOH terminus of p65 is required for binding of GENE and GENE. | BINDING-INTERACTION |
| Phosphorylation of GENE at Ser142 has been shown in vitro to disrupt the binding of GENE to the KIX domain of GENE (Parker et al., 1998 ; Kornhauser et al., 2002 ). | BINDING-INTERACTION |
| 2 This raised the possibility that, as is the case with the other well characterized class B scavenger receptor SR-BI, CHEMICAL might bind directly to GENE. | BINDING-INTERACTION |
| Likewise, we found no change in the distance between Cys and Cys of RLC when the GENE was bound to GENE. | BINDING-INTERACTION |
| Instead, we find that GENE binds to the second PDZ repeat of GENE, and a related protein PSD-93. | BINDING-INTERACTION |
| Instead, we find that GENE binds to the second GENE of PSD-95, and a related protein PSD-93. | BINDING-INTERACTION |
| Instead, we find that GENE binds to the second PDZ repeat of PSD-95, and a related protein GENE. | BINDING-INTERACTION |
| Various quantities of GST-GENE were incubated with GENE (10 pmol) on nitrocellulose membranes for 2 hr. Syntaxin-1a bound to GENE was detected. | BINDING-INTERACTION |
| These findings are consistent with the results in CAT assay ( Fig 5, a - f) and support the idea that the nuclear translocation of QM/Jif-1 is promoted by normal PS1 thereby inhibiting the binding of GENE homodimer to TRE. | BINDING-INTERACTION |
| For example, GENE binds the basic region of the bipartite GENE of the androgen receptor (38). | BINDING-INTERACTION |
| For example, GENE binds the basic region of the bipartite NLS of the GENE (38). | BINDING-INTERACTION |
| GENE binds to GENE and inhibits its function (Goppelt and Meisterernst, 1996 ; Goppelt et al., 1996 ). | BINDING-INTERACTION |
| Next we investigated the nucleotide specificity and effect of Mg2+ on CHEMICAL binding to GENE. | BINDING-INTERACTION |
| The activity of GENE is negatively regulated by interaction with GENE, but GENE is released from this inhibitory association when GTP binds to GENE. | BINDING-INTERACTION |
| The activity of PLCdelta1 is negatively regulated by interaction with GENE, but PLCdelta1 is released from this inhibitory association when CHEMICAL binds to GENE. | BINDING-INTERACTION |
| These investigators propose that GENE binding to GENE may induce a conformational change in GENE that alters the nuclear export/import balance by inactivating the NES, thus favoring nuclear import. | BINDING-INTERACTION |
| To further explore the role of the C-terminal domain in the CHEMICAL binding of GENE, we used GENE (1-260), a C-terminal truncated variant that is monomeric rather than tetrameric in aqueous solution ( 21). | BINDING-INTERACTION |
| Direct SH2-mediated binding of GENE to GENE occurs after FN stimulation (Schlaepfer and Hunter, 1997 ) and GENE can directly phosphorylate GENE at Tyr317 to promote Grb2 binding and signaling to ERK2 (Schlaepfer et al., 1998 ). | BINDING-INTERACTION |
| Direct SH2-mediated binding of Shc to FAK occurs after FN stimulation (Schlaepfer and Hunter, 1997 ) and FAK can directly phosphorylate Shc at Tyr317 to promote GENE binding and signaling to GENE (Schlaepfer et al., 1998 ). | BINDING-INTERACTION |
| To investigate this, we isolated the GENE binding part of human plasma gelsolin comprising segment 2 and 3 (S2–3) and performed competition experiments under conditions (pH 6.8) where GENE is known to efficiently bind to GENE and only causes limited depolymerization (14). | BINDING-INTERACTION |
| To investigate this, we isolated the GENE binding part of human plasma GENE comprising segment 2 and 3 (S2–3) and performed competition experiments under conditions (pH 6.8) where cofilin is known to efficiently bind to GENE and only causes limited depolymerization (14). | BINDING-INTERACTION |
| To investigate this, we isolated the F-GENE binding part of human plasma gelsolin comprising segment 2 and 3 (S2–3) and performed competition experiments under conditions (pH 6.8) where GENE is known to efficiently bind to F-GENE and only causes limited depolymerization (14). | BINDING-INTERACTION |
| To investigate this, we isolated the F-GENE binding part of human plasma GENE comprising segment 2 and 3 (S2–3) and performed competition experiments under conditions (pH 6.8) where cofilin is known to efficiently bind to F-GENE and only causes limited depolymerization (14). | BINDING-INTERACTION |
| In the absence of GENE signals, LEF1 binds to transcriptional co-repressors GENE, CtBP, and HDACs to inhibit gene expression ( 22). | BINDING-INTERACTION |
| In the absence of GENE signals, LEF1 binds to transcriptional co-repressors TLE, GENE, and HDACs to inhibit gene expression ( 22). | BINDING-INTERACTION |
| In the absence of GENE signals, LEF1 binds to transcriptional co-repressors TLE, CtBP, and GENE to inhibit gene expression ( 22). | BINDING-INTERACTION |
| dTCF/GENE is the cofactor necessary for GENE-dependent transcriptional activitation, and a dominant-negative form of dTCF that no longer binds GENE inhibits the ability of GENE to activate transcription 36, 37. | BINDING-INTERACTION |
| This sequence shows marked homology to the amino-terminal sequence determined here for processed GENE bound to GENE, AVPIAQ; GENE has been processed here to remove the first 55 amino acids. | BINDING-INTERACTION |
| As shown in Figure 6A, addition of poly-l-proline, even in large excess, had no significant effect on the binding of GENE to GENE, although in corresponding ELISAs we could demonstrate the successful masking of the polyproline binding site on GENE by poly-l-proline incubation (data not shown). | BINDING-INTERACTION |
| At early time points after activation, newly synthesized GENE is also quantitatively bound to GENE (see 8 and 12 h after activation of Myc); taken together, both observations suggest that there is not enough p130 in these cells to inhibit quantitatively newly formed GENE-GENE complexes. | BINDING-INTERACTION |
| Because GENE binds to the GENE, we wished to determine whether HPC2 also binds to the GENE. | NO-RELATIONSHIP |
| Because GENE binds to the GENE repression domain, we wished to determine whether HPC2 also binds to the GENE repression domain. | NO-RELATIONSHIP |
| Because CtBP binds to the GENE repression domain, we wished to determine whether GENE also binds to the GENE repression domain. | NO-RELATIONSHIP |
| Because CtBP binds to the GENE, we wished to determine whether GENE also binds to the GENE. | NO-RELATIONSHIP |
| In this study, we found that binding of GENE to GENE did not preclude binding of phospho-CREB to GENE, indicating that GENE may interfere instead with recruitment of a general transcription factor to GENE. | BINDING-INTERACTION |
| In this study, we found that binding of pp90RSK to GENE did not preclude binding of GENE to GENE, indicating that pp90RSK may interfere instead with recruitment of a general transcription factor to GENE. | BINDING-INTERACTION |
| In this study, we found that binding of pp90RSK to GENE did not preclude binding of phospho-GENE to GENE, indicating that pp90RSK may interfere instead with recruitment of a general transcription factor to GENE. | BINDING-INTERACTION |
| A similar mechanism involving heparin sulfate facilitation of GENE binding to GENE has been postulated (31), but a more complex role in inducing conformational changes in the GENE complex has become apparent with crystallographic analysis (32). | BINDING-INTERACTION |
| We determined the binding affinities of GENE for GENE, BAF, and lamin A and analyzed their oligomeric interactions. | BINDING-INTERACTION |
| We determined the binding affinities of GENE for GCL, GENE, and lamin A and analyzed their oligomeric interactions. | BINDING-INTERACTION |
| We determined the binding affinities of GENE for GCL, BAF, and GENE and analyzed their oligomeric interactions. | BINDING-INTERACTION |
| The anti-FGF Ab showed that GENE was bound to a similar extent to GENE and CD44vRA, whereas CD44s did not bind GENE. | BINDING-INTERACTION |
| The anti-FGF Ab showed that GENE was bound to a similar extent to CD44v3-v10 and CD44vRA, whereas CD44s did not bind GENE. | BINDING-INTERACTION |
| Such ATP-dependent binding of GENE to GENE is consistent with previously published work utilizing other assay systems (Holstein et al., 1996 ; Jiang et al., 1997 ). | BINDING-INTERACTION |
| The binding of GENE to GENE is essential for the ability of GENE to ventralize Xenopus embryos ( 23). | BINDING-INTERACTION |
| Because the Kd value for GENE binding with GENE is in the submicromolar range, GENE-mediated ubiquitination reactions would be expected to be nearly saturated by 10 muM GENE (Haas and Siepmann, 1997 ). | BINDING-INTERACTION |
| For example, a high-affinity form of GENE (bound to GENE) may promote initial 40S interactions with capped mRNA but subsequently convert to the low-affinity form after a rearrangement of the preinitiation complex (Fig. 8) ( 449). | BINDING-INTERACTION |
| Previous biochemical studies on the binding of CHEMICAL and PI to GENE provided evidence for the presence of separate binding sites for the phosphorylinositol and phosphorylcholine head group [ 3. | DIRECT-REGULATOR |
| Previous biochemical studies on the binding of PC and CHEMICAL to CHEMICAL provided evidence for the presence of separate binding sites for the phosphorylinositol and phosphorylcholine head group [ 3. | DIRECT-REGULATOR |
| The binding of GENE-CTD to GENE but not to FKBP12 underscores the selective nature of immunophilin interactions in vivo. | BINDING-INTERACTION |
| Previous studies have demonstrated that both antibodies and peptides directed at this site interfere with GENE binding to GENE (Mayer et al., 1993a ). | BINDING-INTERACTION |
| However, it has recently been reported that the tumor suppressor GENE (adenomatous polyposis coli protein) is able to bind to the GENE of axin (1, 11, 25), suggesting that the binding of GENE to this region may be important for normal axis formation. | BINDING-INTERACTION |
| However, it has recently been reported that the tumor suppressor GENE (adenomatous polyposis coli protein) is able to bind to the RGS domain of GENE (1, 11, 25), suggesting that the binding of GENE to this region may be important for normal axis formation. | BINDING-INTERACTION |
| Deletion of the UIM sharply reduced the efficiency with which GENE bound GENE ( Fig. 1 E). | BINDING-INTERACTION |
| Specific binding of GENE to GENE. | BINDING-INTERACTION |
| Nir2 was also shown to preferentially bind the inactive GENE (Fig. 6A). | BINDING-INTERACTION |
| GENE was also shown to preferentially bind the inactive GENE (Fig. 6A). | BINDING-INTERACTION |
| If the binding of GENE to endogenous GENE inhibits the function of GENE, leading to the formation of an ectopic axis, it should be possible to overcome the effects of GENE by ectopically expressing additional GENE. | BINDING-INTERACTION |
| Inhibition of cell adhesion induced by soluble GENE is further complicated in view of the fact that GENE can also bind soluble GENE present in the serum. | BINDING-INTERACTION |
| The hyperphosphorylation of Cla4 can be induced experimentally by expression of Clb2 and the CHEMICAL-bound form of GENE ( 44). | BINDING-INTERACTION |
| We also present evidence that TIM alone cannot repress GENE-GENE-mediated transcription of an E-box reporter in S2 cells, despite a report that TIM disrupts the DNA-binding ability of GENE and GENE in vitro (Lee et al., 1999 ). | BINDING-INTERACTION |
| It has been shown that GENE binds to PP1 in addition to GENE (29). | BINDING-INTERACTION |
| It has been shown that GENE binds to GENE in addition to PKA (29). | BINDING-INTERACTION |
| GENE binds to GENE in cells. | BINDING-INTERACTION |
| A structural superposition of PP1 onto the adenine moeity of CHEMICAL bound to GENE suggests why PP1 does not inhibit GENE ( Figure 6B). | BINDING-INTERACTION |
| Once GENE is bound to CHEMICAL, it binds and activates these RalGEFs, which in turn activate Ral proteins. | BINDING-INTERACTION |
| Once GENE is bound to GTP, it binds and activates these GENE, which in turn activate Ral proteins. | BINDING-INTERACTION |
| The areas of proteolytic cleavage sites that become accessible in mu2 when GENE binds GENE and forms coats are indicated (red). | BINDING-INTERACTION |
| The GENE bind the F box protein GENE, a subunit of the SCF-type E3 ubiquitin ligase complex, resulting in ubiquitination of β-catenin and its destruction by the proteasome Jiang and Struhl 1998, Winston et al. 1999, Hart et al. 1999, Kitagawa et al. 1999, Polakis 2001. | BINDING-INTERACTION |
| The phosphorylated forms of GENE bind the F box protein GENE, a subunit of the SCF-type E3 ubiquitin ligase complex, resulting in ubiquitination of GENE and its destruction by the proteasome Jiang and Struhl 1998, Winston et al. 1999, Hart et al. 1999, Kitagawa et al. 1999, Polakis 2001. | BINDING-INTERACTION |
| Thus, binding of GENE and PKC to GENE are inversely correlated. | BINDING-INTERACTION |
| Thus, binding of BAD and GENE to GENE are inversely correlated. | BINDING-INTERACTION |
| This protein family is characterized by a GENE, a highly conserved tetrahelical domain that binds to GENE chaperones and activates their ATPase activity. | BINDING-INTERACTION |
| Binding of soluble GENE proteins to GENE on the cell surface. | BINDING-INTERACTION |
| GENE binds to both GENE and RhoA, and mediates Wnt-induced GENE-RhoA complex formation. | BINDING-INTERACTION |
| GENE binds to both Dsh and GENE, and mediates Wnt-induced Dsh-GENE complex formation. | BINDING-INTERACTION |
| Daam1 binds to both GENE and GENE, and mediates Wnt-induced GENE-GENE complex formation. | BINDING-INTERACTION |
| Using P19 cells, we show that GENE and activin bind to the common type II receptors, GENE and IIB, but recruit different type I receptors into the ligand-receptor complex and activate distinct Smad signaling pathways. | BINDING-INTERACTION |
| Using P19 cells, we show that GENE and activin bind to the common type II receptors, ActRII and GENE, but recruit different type I receptors into the ligand-receptor complex and activate distinct Smad signaling pathways. | BINDING-INTERACTION |
| Using P19 cells, we show that BMP7 and GENE bind to the common type II receptors, GENE and IIB, but recruit different type I receptors into the ligand-receptor complex and activate distinct Smad signaling pathways. | BINDING-INTERACTION |
| Using P19 cells, we show that BMP7 and GENE bind to the common type II receptors, ActRII and GENE, but recruit different type I receptors into the ligand-receptor complex and activate distinct Smad signaling pathways. | BINDING-INTERACTION |
| The cytoplasmic domain of GENE binds to GENE, and this complex is linked to the actin cytoskeleton by alpha-catenin. | BINDING-INTERACTION |
| We have also determined that the carboxyl-terminal domain of GENE is necessary and sufficient for the direct binding of GENE to GENE. | BINDING-INTERACTION |
| We found that the GENE selectively retained GENE and H4, whereas binding to H2A and H2B was significantly weaker. | BINDING-INTERACTION |
| We found that the GENE selectively retained histones H3 and GENE, whereas binding to H2A and H2B was significantly weaker. | BINDING-INTERACTION |
| We found that the GENE selectively retained histones H3 and H4, whereas binding to GENE and H2B was significantly weaker. | BINDING-INTERACTION |
| We found that the GENE selectively retained histones H3 and H4, whereas binding to H2A and GENE was significantly weaker. | BINDING-INTERACTION |
| Measurement of the Binding of GENE to GENE by Surface Plasmon Resonance | BINDING-INTERACTION |
| In particular, pairwise binding of GENE and GENE to either site appears to be essentially noncooperative when evaluated from GENE titrations. | BINDING-INTERACTION |
| This most likely occurs through the interaction between GENE bound to the pre-mRNA and a protein of the GENE or another factor that would bridge GENE and U7snRNP. | BINDING-INTERACTION |
| In Aplysia, as in mammals, the regulation of gene transcription by cAMP is mediated by GENE CREB. | BINDING-INTERACTION |
| CYFIP1 (or p140Sra-1, specifically GENE-associated protein) or CYFIP2 (or PIR121 or pop), which presents 94.5% of sequence similarities with CYFIP1, have been shown to be specific targets of GENE, binding only to the CHEMICAL-bound form of GENE. | BINDING-INTERACTION |
| CYFIP1 (or p140Sra-1, GENE) or CYFIP2 (or PIR121 or pop), which presents 94.5% of sequence similarities with CYFIP1, have been shown to be specific targets of Rac1, binding only to the GENE. | BINDING-INTERACTION |
| CYFIP1 (or p140Sra-1, specifically Rac1-associated protein) or CYFIP2 (or GENE or pop), which presents 94.5% of sequence similarities with CYFIP1, have been shown to be specific targets of Rac1, binding only to the GENE. | BINDING-INTERACTION |
| The activity of GENE on GENE may also regulate the actin cytoskeleton, as prevention of GENE binding to GENE inhibited GENE from inducing filopodia formation, where inhibition of secretion with BFA had no effect (Sugihara et al., 2002 ). | BINDING-INTERACTION |
| While we do not discount the possibility that the first two explanations may be valid for some of the confusion in the literature, in this report we show evidence that GENE can phosphorylate the GENE on novel sites in vitro, that GENE and P85α preferentially associate with the GENE after it has been phosphorylated by GENE, that these GENE-phosphorylated sites (including consensus binding sites for GENE and P85α) are phosphorylated in cells in response to EGF, that P85α and GENE bind to the GENE in these cells in an EGF-dependent manner, and that Csk-inactivated GENE is reactivated upon binding to the GENE phosphorylated GENE. | BINDING-INTERACTION |
| While we do not discount the possibility that the first two explanations may be valid for some of the confusion in the literature, in this report we show evidence that Src can phosphorylate the GENE on novel sites in vitro, that Src and GENE preferentially associate with the GENE after it has been phosphorylated by Src, that these Src-phosphorylated sites (including consensus binding sites for Src and GENE) are phosphorylated in cells in response to EGF, that GENE and Src bind to the GENE in these cells in an EGF-dependent manner, and that Csk-inactivated Src is reactivated upon binding to the Src phosphorylated GENE. | BINDING-INTERACTION |
| Phosphorylation of Y1176 prevents GENE binding to GENE, an adaptor required for clathrin-mediated internalization of GENE. | BINDING-INTERACTION |
| In contrast, while binding of GENE to GENE was increased at 10 muM Ca2+ it was also detectable at 0 Ca2+. | BINDING-INTERACTION |
| Perhaps it is another region of GENE, not the KIX domain, which is bound to the GENE after depolarization, or perhaps GENE binds to another nearby factor, though a stimulatory role for such GENE binding remains unproven. | BINDING-INTERACTION |
| The experiments of Fig. 5 were performed to determine if GENE also binds directly to GENE. | NO-RELATIONSHIP |
| The first is that the strength of the GENE-GENE interaction partly overrides the coiled-coil interaction within the kinesin dimer, forcing the heads to come apart so that the individual kinesin molecules can bind to different GENE heterodimers, relieving the constraints imposed by the coiled-coil necks (Thormählen et al., 1998b). | BINDING-INTERACTION |
| The first is that the strength of the GENE-motor interaction partly overrides the coiled-coil interaction within the GENE dimer, forcing the heads to come apart so that the individual GENE molecules can bind to different GENE heterodimers, relieving the constraints imposed by the coiled-coil necks (Thormählen et al., 1998b). | BINDING-INTERACTION |
| The first is that the strength of the tubulin-motor interaction partly overrides the coiled-coil interaction within the GENE dimer, forcing the heads to come apart so that the individual GENE molecules can bind to different GENE, relieving the constraints imposed by the coiled-coil necks (Thormählen et al., 1998b). | BINDING-INTERACTION |
| The first is that the strength of the GENE-motor interaction partly overrides the coiled-coil interaction within the kinesin dimer, forcing the heads to come apart so that the individual kinesin molecules can bind to different GENE heterodimers, relieving the constraints imposed by the coiled-coil necks (Thormählen et al., 1998b). | BINDING-INTERACTION |
| The 3′ UTR of GENE contributes a function in addition to GENE binding (Figure 2E). | BINDING-INTERACTION |
| The FN region of GENE that binds to GENE was chosen originally for expression in flies because we predicted, using the method of Woolfson and Alber (1995), that almost half of FN (amino acids 96-172) would form a two‐stranded, α‐helical, coiled‐coil structure (Figure 11). | BINDING-INTERACTION |
| To rule out the possibility that the IVT-GENE is homodimerizing in this assay through GENE's basic helix-loop-helix domain with one of the GENE subunits binding to GST-dCtBP and the other binding to GENE, we repeated the assay with a truncated form of IVT-GENE. | BINDING-INTERACTION |
| We have shown that GENE directly binds to the GENE of beta-catenin ( 45, 51). | BINDING-INTERACTION |
| We have shown that GENE directly binds to the armadillo repeats of GENE ( 45, 51). | BINDING-INTERACTION |
| E and F, Mg2+ dependence of the 22C11 action on the turnover number of GTPase activity (E) or CHEMICAL binding activity (F) of GENE vesicles. | BINDING-INTERACTION |
| A point mutation or a small deletion in the basic region of GENE renders it unable to bind to the GENE site, and consequently inactivates the transcriptional activity of GENE and its ability to synergize with Smad3. | BINDING-INTERACTION |
| These results suggest that GENE and vinculin bind to GENE in a competitive manner, and that GENE, GENE, and vinculin hardly form a ternary complex. | BINDING-INTERACTION |
| These results suggest that l-afadin and GENE bind to GENE in a competitive manner, and that l-afadin, GENE, and GENE hardly form a ternary complex. | BINDING-INTERACTION |
| These results suggest that l-GENE and vinculin bind to GENE in a competitive manner, and that l-GENE, GENE, and vinculin hardly form a ternary complex. | BINDING-INTERACTION |
| Since removal of these two residues destroys the ability of the GENE to bind the GENE ( 18), the most likely interpretation is that the GENE inhibits the binding of EBP50 to Ez-(1-296). | BINDING-INTERACTION |
| Another GENE, different from CBF/NF-Y, was also reported to recognize the CCAAT sequence around -90 (13), and GENE and p53 competitively bind to the GENE to stimulate or repress the hsp70 promoter activity, respectively (22, 23). | BINDING-INTERACTION |
| Another GENE, different from CBF/NF-Y, was also reported to recognize the CCAAT sequence around -90 (13), and E1A and GENE competitively bind to the GENE to stimulate or repress the hsp70 promoter activity, respectively (22, 23). | BINDING-INTERACTION |
| The binding of GENE to GENE is mediated through the p105 subunit of GENE. | BINDING-INTERACTION |
| The binding of GENE to dCAF-1 is mediated through the GENE subunit of dCAF-1. | BINDING-INTERACTION |
| To evaluate whether both CREB and GENE occupy CRE2 and the overlapping NF-E2 binding sites, DNase I footprinting was performed with CREB and GENE/GENE synthesized by in vitro transcription and translation. | BINDING-INTERACTION |
| Differential binding of GENE and filamin to GENE. | BINDING-INTERACTION |
| Differential binding of talin and GENE to GENE. | BINDING-INTERACTION |
| Furthermore, GENE binding to the tumor suppressor gene product APC (GENE ( 45, 46)) and GSK3beta binding to the APC. | BINDING-INTERACTION |
| Furthermore, beta-catenin binding to the tumor suppressor gene product APC (GENE ( 45, 46)) and GENE binding to the APC. | BINDING-INTERACTION |
| On the basis of the previous findings that GENE binds to GENE through this region, we speculate that this activation occurred through the interaction of GENE with GENE. | BINDING-INTERACTION |
| This suggests that binding of GENE and GSK3beta to GENE promotes the phosphorylation of GENE in vivo, presumably by GSK3beta (Rubinfeld et al., 1996 ). | BINDING-INTERACTION |
| This suggests that binding of APC and GENE to GENE promotes the phosphorylation of APC in vivo, presumably by GENE (Rubinfeld et al., 1996 ). | BINDING-INTERACTION |
| Collagen peptides I and II effectively inhibited the binding of both GENE and alpha2I to GENE in a dose-dependent manner (Fig. 9). | BINDING-INTERACTION |
| Collagen peptides I and II effectively inhibited the binding of both alpha1I and GENE to GENE in a dose-dependent manner (Fig. 9). | BINDING-INTERACTION |
| GENE binds GENE/TRF1 in vitro and in vivo. | BINDING-INTERACTION |
| Binding of CHEMICAL to GENE may be required for it to adopt an active conformation. | BINDING-INTERACTION |
| Also, like GENE and APC, MUC1 binds directly to GENE ( 61). | BINDING-INTERACTION |
| Also, like E-cadherin and GENE, MUC1 binds directly to GENE ( 61). | BINDING-INTERACTION |
| Also, like E-cadherin and APC, GENE binds directly to GENE ( 61). | BINDING-INTERACTION |
| CHEMICAL-associated DISEASE. A series of six cases. CHEMICAL is a histamine H2-receptor antagonist used in inpatient settings for prevention of stress ulcers and is showing increasing popularity because of its low cost. Although all of the currently available H2-receptor antagonists have shown the propensity to cause DISEASE, only two previously reported cases have been associated with CHEMICAL. The authors report on six cases of CHEMICAL-associated DISEASE in hospitalized patients who cleared completely upon removal of CHEMICAL. The pharmacokinetics of CHEMICAL are reviewed, with no change in its metabolism in the elderly population seen. The implications of using CHEMICAL in elderly persons are discussed. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL induced DISEASE in sodium and volume depleted rats. After a single oral dose of 4 mg/kg CHEMICAL (CHEMICAL) to sodium and volume depleted rats plasma renin activity (PRA) and systolic blood pressure fell significantly within four hours. In sodium repleted animals CHEMICAL did not change systolic blood pressure (BP) although plasma renin activity was decreased. Thus, CHEMICAL by inhibition of prostaglandin synthesis may diminish the blood pressure maintaining effect of the stimulated renin-angiotensin system in sodium and volume depletion. | CHEMICAL-INDUCED-DISEASE |
| Late-onset scleroderma renal crisis induced by tacrolimus and prednisolone: a case report. Scleroderma renal crisis (SRC) is a rare complication of systemic sclerosis (SSc) but can be severe enough to require temporary or permanent renal replacement therapy. Moderate to high dose corticosteroid use is recognized as a major risk factor for SRC. Furthermore, there have been reports of DISEASE precipitated by CHEMICAL in patients with SSc. In this article, we report a patient with SRC induced by tacrolimus and corticosteroids. The aim of this work is to call attention to the risk of tacrolimus use in patients with SSc. | NO-RELATIONSHIP |
| Late-onset scleroderma renal crisis induced by tacrolimus and prednisolone: a case report. Scleroderma renal crisis (SRC) is a rare complication of DISEASE (DISEASE) but can be severe enough to require temporary or permanent renal replacement therapy. Moderate to high dose CHEMICAL use is recognized as a major risk factor for SRC. Furthermore, there have been reports of thrombotic microangiopathy precipitated by cyclosporine in patients with DISEASE. In this article, we report a patient with SRC induced by tacrolimus and CHEMICAL. The aim of this work is to call attention to the risk of tacrolimus use in patients with DISEASE. | NO-RELATIONSHIP |
| Late-onset scleroderma renal crisis induced by CHEMICAL and prednisolone: a case report. Scleroderma renal crisis (SRC) is a rare complication of DISEASE (DISEASE) but can be severe enough to require temporary or permanent renal replacement therapy. Moderate to high dose corticosteroid use is recognized as a major risk factor for SRC. Furthermore, there have been reports of thrombotic microangiopathy precipitated by cyclosporine in patients with DISEASE. In this article, we report a patient with SRC induced by CHEMICAL and corticosteroids. The aim of this work is to call attention to the risk of CHEMICAL use in patients with DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Late-onset DISEASE induced by tacrolimus and CHEMICAL: a case report. DISEASE (DISEASE) is a rare complication of systemic sclerosis (SSc) but can be severe enough to require temporary or permanent renal replacement therapy. Moderate to high dose corticosteroid use is recognized as a major risk factor for DISEASE. Furthermore, there have been reports of thrombotic microangiopathy precipitated by cyclosporine in patients with SSc. In this article, we report a patient with DISEASE induced by tacrolimus and corticosteroids. The aim of this work is to call attention to the risk of tacrolimus use in patients with SSc. | CHEMICAL-INDUCED-DISEASE |
| The risk and associated factors of CHEMICAL DISEASE in CHEMICAL-dependent patients in Malaysia. OBJECTIVE: The objective of this study was to determine the risk of lifetime and current CHEMICAL-induced DISEASE in patients with CHEMICAL dependence. The association between psychiatric co-morbidity and CHEMICAL-induced DISEASE was also studied. METHODS: This was a cross-sectional study conducted concurrently at a teaching hospital and a drug rehabilitation center in Malaysia. Patients with the diagnosis of CHEMICAL based on DSM-IV were interviewed using the Mini International Neuropsychiatric Interview (M.I.N.I.) for CHEMICAL-induced DISEASE and other Axis I psychiatric disorders. The information on sociodemographic background and drug use history was obtained from interview or medical records. RESULTS: Of 292 subjects, 47.9% of the subjects had a past history of DISEASE and 13.0% of the patients were having current DISEASE. Co-morbid major depressive disorder (OR=7.18, 95 CI=2.612-19.708), bipolar disorder (OR=13.807, 95 CI=5.194-36.706), antisocial personality disorder (OR=12.619, 95 CI=6.702-23.759) and heavy CHEMICAL uses were significantly associated with lifetime CHEMICAL-induced DISEASE after adjusted for other factors. Major depressive disorder (OR=2.870, CI=1.154-7.142) and antisocial personality disorder (OR=3.299, 95 CI=1.375-7.914) were the only factors associated with current DISEASE. CONCLUSION: There was a high risk of DISEASE in patients with CHEMICAL dependence. It was associated with co-morbid affective disorder, antisocial personality, and heavy CHEMICAL use. It is recommended that all cases of CHEMICAL dependence should be screened for DISEASE. | CHEMICAL-INDUCED-DISEASE |
| The risk and associated factors of CHEMICAL psychosis in CHEMICAL-dependent patients in Malaysia. OBJECTIVE: The objective of this study was to determine the risk of lifetime and current CHEMICAL-induced psychosis in patients with CHEMICAL dependence. The association between psychiatric co-morbidity and CHEMICAL-induced psychosis was also studied. METHODS: This was a cross-sectional study conducted concurrently at a teaching hospital and a drug rehabilitation center in Malaysia. Patients with the diagnosis of CHEMICAL based on DSM-IV were interviewed using the Mini International Neuropsychiatric Interview (M.I.N.I.) for CHEMICAL-induced psychosis and other Axis I psychiatric disorders. The information on sociodemographic background and drug use history was obtained from interview or medical records. RESULTS: Of 292 subjects, 47.9% of the subjects had a past history of psychotic symptoms and 13.0% of the patients were having current psychotic symptoms. Co-morbid major depressive disorder (OR=7.18, 95 CI=2.612-19.708), DISEASE (OR=13.807, 95 CI=5.194-36.706), antisocial personality disorder (OR=12.619, 95 CI=6.702-23.759) and heavy CHEMICAL uses were significantly associated with lifetime CHEMICAL-induced psychosis after adjusted for other factors. Major depressive disorder (OR=2.870, CI=1.154-7.142) and antisocial personality disorder (OR=3.299, 95 CI=1.375-7.914) were the only factors associated with current psychosis. CONCLUSION: There was a high risk of psychosis in patients with CHEMICAL dependence. It was associated with co-morbid affective disorder, antisocial personality, and heavy CHEMICAL use. It is recommended that all cases of CHEMICAL dependence should be screened for psychotic symptoms. | CHEMICAL-INDUCED-DISEASE |
| The risk and associated factors of CHEMICAL psychosis in CHEMICAL-dependent patients in Malaysia. OBJECTIVE: The objective of this study was to determine the risk of lifetime and current CHEMICAL-induced psychosis in patients with CHEMICAL dependence. The association between psychiatric co-morbidity and CHEMICAL-induced psychosis was also studied. METHODS: This was a cross-sectional study conducted concurrently at a teaching hospital and a drug rehabilitation center in Malaysia. Patients with the diagnosis of CHEMICAL based on DSM-IV were interviewed using the Mini International Neuropsychiatric Interview (M.I.N.I.) for CHEMICAL-induced psychosis and other Axis I psychiatric disorders. The information on sociodemographic background and drug use history was obtained from interview or medical records. RESULTS: Of 292 subjects, 47.9% of the subjects had a past history of psychotic symptoms and 13.0% of the patients were having current psychotic symptoms. Co-morbid major depressive disorder (OR=7.18, 95 CI=2.612-19.708), bipolar disorder (OR=13.807, 95 CI=5.194-36.706), DISEASE (OR=12.619, 95 CI=6.702-23.759) and heavy CHEMICAL uses were significantly associated with lifetime CHEMICAL-induced psychosis after adjusted for other factors. Major depressive disorder (OR=2.870, CI=1.154-7.142) and DISEASE (OR=3.299, 95 CI=1.375-7.914) were the only factors associated with current psychosis. CONCLUSION: There was a high risk of psychosis in patients with CHEMICAL dependence. It was associated with co-morbid affective disorder, DISEASE, and heavy CHEMICAL use. It is recommended that all cases of CHEMICAL dependence should be screened for psychotic symptoms. | CHEMICAL-INDUCED-DISEASE |
| Cerebellar sensory processing alterations impact motor cortical plasticity in Parkinson's disease: clues from DISEASE patients. The plasticity of primary motor cortex (M1) in patients with Parkinson's disease (PD) and CHEMICAL-induced DISEASE (DISEASE) is severely impaired. We recently reported in young healthy subjects that inhibitory cerebellar stimulation enhanced the sensorimotor plasticity of M1 that was induced by paired associative stimulation (PAS). This study demonstrates that the deficient sensorimotor M1 plasticity in 16 patients with DISEASE could be reinstated by a single session of real inhibitory cerebellar stimulation but not sham stimulation. This was evident only when a sensory component was involved in the induction of plasticity, indicating that cerebellar sensory processing function is involved in the resurgence of M1 plasticity. The benefit of inhibitory cerebellar stimulation on DISEASE is known. To explore whether this benefit is linked to the restoration of sensorimotor plasticity of M1, we conducted an additional study looking at changes in DISEASE and PAS-induced plasticity after 10 sessions of either bilateral, real inhibitory cerebellar stimulation or sham stimulation. Only real and not sham stimulation had an antidyskinetic effect and it was paralleled by a resurgence in the sensorimotor plasticity of M1. These results suggest that alterations in cerebellar sensory processing function, occurring secondary to abnormal basal ganglia signals reaching it, may be an important element contributing to the maladaptive sensorimotor plasticity of M1 and the emergence of DISEASE. | CHEMICAL-INDUCED-DISEASE |
| The function of P2X3 receptor and NK1 receptor antagonists on CHEMICAL-induced DISEASE in rats. PURPOSE: The purpose of the study is to explore the function of P2X3 and NK1 receptors antagonists on CHEMICAL (CHEMICAL)-induced DISEASE in rats. METHODS: Sixty female Sprague-Dawley (SD) rats were randomly divided into three groups. The rats in the control group were intraperitoneally (i.p.) injected with 0.9% saline (4 ml/kg); the rats in the model group were i.p. injected with CHEMICAL (150 mg/kg); and the rats in the intervention group were i.p. injected with CHEMICAL with subsequently perfusion of bladder with P2X3 and NK1 receptors' antagonists, Suramin and GR 82334. Spontaneous pain behaviors following the administration of CHEMICAL were observed. Urodynamic parameters, bladder pressure-volume curve, maximum voiding pressure (MVP), and maximum cystometric capacity (MCC), were recorded. Pathological changes in bladder tissue were observed. Immunofluorescence was used to detect the expression of P2X3 and NK1 receptors in bladder. RESULTS: CHEMICAL treatment increased the spontaneous pain behaviors scores. The incidence of bladder instability during urine storage period of model group was significantly higher than intervention group (X(2) = 7.619, P = 0.007) and control group (X(2) = 13.755, P = 0.000). MCC in the model group was lower than the control and intervention groups (P < 0.01). Histological changes evident in model and intervention groups rats' bladder included edema, vasodilation, and infiltration of inflammatory cells. In model group, the expression of P2X3 receptor increased in urothelium and suburothelium, and NK1 receptor increased in suburothelium, while the expression of them in intervention group was lower. CONCLUSIONS: In CHEMICAL-induced DISEASE, the expression of P2X3 and NK1 receptors increased in urothelium and/or suburothelium. Perfusion of bladder with P2X3 and NK1 receptors antagonists ameliorated the bladder function. | CHEMICAL-INDUCED-DISEASE |
| The function of P2X3 receptor and NK1 receptor antagonists on CHEMICAL-induced cystitis in rats. PURPOSE: The purpose of the study is to explore the function of P2X3 and NK1 receptors antagonists on CHEMICAL (CHEMICAL)-induced cystitis in rats. METHODS: Sixty female Sprague-Dawley (SD) rats were randomly divided into three groups. The rats in the control group were intraperitoneally (i.p.) injected with 0.9% saline (4 ml/kg); the rats in the model group were i.p. injected with CHEMICAL (150 mg/kg); and the rats in the intervention group were i.p. injected with CHEMICAL with subsequently perfusion of bladder with P2X3 and NK1 receptors' antagonists, Suramin and GR 82334. Spontaneous DISEASE behaviors following the administration of CHEMICAL were observed. Urodynamic parameters, bladder pressure-volume curve, maximum voiding pressure (MVP), and maximum cystometric capacity (MCC), were recorded. Pathological changes in bladder tissue were observed. Immunofluorescence was used to detect the expression of P2X3 and NK1 receptors in bladder. RESULTS: CHEMICAL treatment increased the spontaneous DISEASE behaviors scores. The incidence of bladder instability during urine storage period of model group was significantly higher than intervention group (X(2) = 7.619, P = 0.007) and control group (X(2) = 13.755, P = 0.000). MCC in the model group was lower than the control and intervention groups (P < 0.01). Histological changes evident in model and intervention groups rats' bladder included edema, vasodilation, and infiltration of inflammatory cells. In model group, the expression of P2X3 receptor increased in urothelium and suburothelium, and NK1 receptor increased in suburothelium, while the expression of them in intervention group was lower. CONCLUSIONS: In CHEMICAL-induced cystitis, the expression of P2X3 and NK1 receptors increased in urothelium and/or suburothelium. Perfusion of bladder with P2X3 and NK1 receptors antagonists ameliorated the bladder function. | CHEMICAL-INDUCED-DISEASE |
| The function of P2X3 receptor and NK1 receptor antagonists on CHEMICAL-induced cystitis in rats. PURPOSE: The purpose of the study is to explore the function of P2X3 and NK1 receptors antagonists on CHEMICAL (CHEMICAL)-induced cystitis in rats. METHODS: Sixty female Sprague-Dawley (SD) rats were randomly divided into three groups. The rats in the control group were intraperitoneally (i.p.) injected with 0.9% saline (4 ml/kg); the rats in the model group were i.p. injected with CHEMICAL (150 mg/kg); and the rats in the intervention group were i.p. injected with CHEMICAL with subsequently perfusion of bladder with P2X3 and NK1 receptors' antagonists, Suramin and GR 82334. Spontaneous pain behaviors following the administration of CHEMICAL were observed. Urodynamic parameters, bladder pressure-volume curve, maximum voiding pressure (MVP), and maximum cystometric capacity (MCC), were recorded. Pathological changes in bladder tissue were observed. Immunofluorescence was used to detect the expression of P2X3 and NK1 receptors in bladder. RESULTS: CHEMICAL treatment increased the spontaneous pain behaviors scores. The incidence of bladder instability during urine storage period of model group was significantly higher than intervention group (X(2) = 7.619, P = 0.007) and control group (X(2) = 13.755, P = 0.000). MCC in the model group was lower than the control and intervention groups (P < 0.01). Histological changes evident in model and intervention groups rats' bladder included DISEASE, vasodilation, and infiltration of inflammatory cells. In model group, the expression of P2X3 receptor increased in urothelium and suburothelium, and NK1 receptor increased in suburothelium, while the expression of them in intervention group was lower. CONCLUSIONS: In CHEMICAL-induced cystitis, the expression of P2X3 and NK1 receptors increased in urothelium and/or suburothelium. Perfusion of bladder with P2X3 and NK1 receptors antagonists ameliorated the bladder function. | CHEMICAL-INDUCED-DISEASE |
| Acute DISEASE associated with CHEMICAL: a case report and review of the literature. Drug-induced DISEASE is a common cause of acute DISEASE, and the recognition of the responsible drug may be difficult. We describe a case of CHEMICAL-related acute DISEASE. The diagnosis is strongly suggested by an accurate medical history and liver biopsy. Reports about cases of DISEASE due to CHEMICAL are increasing in the last few years, after the increased use of this drug. In conclusion, we believe that physicians should carefully consider the risk of drug-induced DISEASE when CHEMICAL is prescribed. | CHEMICAL-INDUCED-DISEASE |
| Bortezomib and CHEMICAL as salvage therapy in patients with relapsed/refractory multiple myeloma: analysis of long-term clinical outcomes. Bortezomib (bort)-CHEMICAL (CHEMICAL) is an effective therapy for relapsed/refractory (R/R) multiple myeloma (MM). This retrospective study investigated the combination of bort (1.3 mg/m(2) on days 1, 4, 8, and 11 every 3 weeks) and CHEMICAL (20 mg on the day of and the day after bort) as salvage treatment in 85 patients with R/R MM after prior autologous stem cell transplantation or conventional chemotherapy. The median number of prior lines of therapy was 2. Eighty-seven percent of the patients had received immunomodulatory drugs included in some line of therapy before bort-CHEMICAL. The median number of bort-CHEMICAL cycles was 6, up to a maximum of 12 cycles. On an intention-to-treat basis, 55 % of the patients achieved at least partial response, including 19 % CR and 35 % achieved at least very good partial response. Median durations of response, time to next therapy and treatment-free interval were 8, 11.2, and 5.1 months, respectively. The most relevant adverse event was DISEASE, which occurred in 78 % of the patients (grade II, 38 %; grade III, 21 %) and led to treatment discontinuation in 6 %. With a median follow up of 22 months, median time to progression, progression-free survival (PFS) and overall survival (OS) were 8.9, 8.7, and 22 months, respectively. Prolonged PFS and OS were observed in patients achieving CR and receiving bort-CHEMICAL a single line of prior therapy. Bort-CHEMICAL was an effective salvage treatment for MM patients, particularly for those in first relapse. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL and dexamethasone as salvage therapy in patients with relapsed/refractory multiple myeloma: analysis of long-term clinical outcomes. CHEMICAL (CHEMICAL)-dexamethasone (dex) is an effective therapy for relapsed/refractory (R/R) multiple myeloma (MM). This retrospective study investigated the combination of CHEMICAL (1.3 mg/m(2) on days 1, 4, 8, and 11 every 3 weeks) and dex (20 mg on the day of and the day after CHEMICAL) as salvage treatment in 85 patients with R/R MM after prior autologous stem cell transplantation or conventional chemotherapy. The median number of prior lines of therapy was 2. Eighty-seven percent of the patients had received immunomodulatory drugs included in some line of therapy before CHEMICAL-dex. The median number of CHEMICAL-dex cycles was 6, up to a maximum of 12 cycles. On an intention-to-treat basis, 55 % of the patients achieved at least partial response, including 19 % CR and 35 % achieved at least very good partial response. Median durations of response, time to next therapy and treatment-free interval were 8, 11.2, and 5.1 months, respectively. The most relevant adverse event was DISEASE, which occurred in 78 % of the patients (grade II, 38 %; grade III, 21 %) and led to treatment discontinuation in 6 %. With a median follow up of 22 months, median time to progression, progression-free survival (PFS) and overall survival (OS) were 8.9, 8.7, and 22 months, respectively. Prolonged PFS and OS were observed in patients achieving CR and receiving CHEMICAL-dex a single line of prior therapy. CHEMICAL-dex was an effective salvage treatment for MM patients, particularly for those in first relapse. | CHEMICAL-INDUCED-DISEASE |
| Pubertal exposure to CHEMICAL increases DISEASE-like behavior and decreases acetylcholinesterase activity of hippocampus in adult male mice. The negative effects of CHEMICAL (CHEMICAL) on neurodevelopment and behaviors have been well established. Acetylcholinesterase (AChE) is a regulatory enzyme which is involved in DISEASE-like behavior. This study investigated behavioral phenotypes and AChE activity in male mice following CHEMICAL exposure during puberty. On postnatal day (PND) 35, male mice were exposed to 50mg CHEMICAL/kg diet per day for a period of 35 days. On PND71, a behavioral assay was performed using the elevated plus maze (EPM) and the light/dark test. In addition, AChE activity was measured in the prefrontal cortex, hypothalamus, cerebellum and hippocampus. Results from our behavioral phenotyping indicated that DISEASE-like behavior was increased in mice exposed to CHEMICAL. AChE activity was significantly decreased in the hippocampus of mice with CHEMICAL compared to control mice, whereas no difference was found in the prefrontal cortex, hypothalamus and cerebellum. Our findings showed that pubertal CHEMICAL exposure increased DISEASE-like behavior, which may be associated with decreased AChE activity of the hippocampus in adult male mice. Further studies are necessary to investigate the cholinergic signaling of the hippocampus in PBE induced DISEASE-like behaviors. | CHEMICAL-INDUCED-DISEASE |
| Biochemical effects of Solidago virgaurea extract on experimental DISEASE. Cardiovascular diseases (CVDs) are the major health problem of advanced as well as developing countries of the world. The aim of the present study was to investigate the protective effect of the Solidago virgaurea extract on CHEMICAL-induced DISEASE in rats. The subcutaneous injection of CHEMICAL (30 mg/kg) into rats twice at an interval of 24 h, for two consecutive days, led to a significant increase in serum lactate dehydrogenase, creatine phosphokinase, alanine transaminase, aspartate transaminase, and angiotensin-converting enzyme activities, total cholesterol, triglycerides, free serum fatty acid, cardiac tissue malondialdehyde (MDA), and nitric oxide levels and a significant decrease in levels of glutathione and superoxide dismutase in cardiac tissue as compared to the normal control group (P < 0.05). Pretreatment with S. virgaurea extract for 5 weeks at a dose of 250 mg/kg followed by CHEMICAL injection significantly prevented the observed alterations. Captopril (50 mg/kg/day, given orally), an inhibitor of angiotensin-converting enzyme used as a standard cardioprotective drug, was used as a positive control in this study. The data of the present study suggest that S. virgaurea extract exerts its protective effect by decreasing MDA level and increasing the antioxidant status in CHEMICAL-treated rats. The study emphasizes the beneficial action of S. virgaurea extract as a cardioprotective agent. | CHEMICAL-INDUCED-DISEASE |
| Biochemical effects of Solidago virgaurea extract on experimental cardiotoxicity. DISEASE (DISEASE) are the major health problem of advanced as well as developing countries of the world. The aim of the present study was to investigate the protective effect of the Solidago virgaurea extract on isoproterenol-induced cardiotoxicity in rats. The subcutaneous injection of isoproterenol (30 mg/kg) into rats twice at an interval of 24 h, for two consecutive days, led to a significant increase in serum lactate dehydrogenase, creatine phosphokinase, CHEMICAL transaminase, aspartate transaminase, and angiotensin-converting enzyme activities, total cholesterol, triglycerides, free serum fatty acid, cardiac tissue malondialdehyde (MDA), and nitric oxide levels and a significant decrease in levels of glutathione and superoxide dismutase in cardiac tissue as compared to the normal control group (P < 0.05). Pretreatment with S. virgaurea extract for 5 weeks at a dose of 250 mg/kg followed by isoproterenol injection significantly prevented the observed alterations. Captopril (50 mg/kg/day, given orally), an inhibitor of angiotensin-converting enzyme used as a standard cardioprotective drug, was used as a positive control in this study. The data of the present study suggest that S. virgaurea extract exerts its protective effect by decreasing MDA level and increasing the antioxidant status in isoproterenol-treated rats. The study emphasizes the beneficial action of S. virgaurea extract as a cardioprotective agent. | NO-RELATIONSHIP |
| Biochemical effects of Solidago virgaurea extract on experimental cardiotoxicity. DISEASE (DISEASE) are the major health problem of advanced as well as developing countries of the world. The aim of the present study was to investigate the protective effect of the Solidago virgaurea extract on isoproterenol-induced cardiotoxicity in rats. The subcutaneous injection of isoproterenol (30 mg/kg) into rats twice at an interval of 24 h, for two consecutive days, led to a significant increase in serum CHEMICAL dehydrogenase, creatine phosphokinase, alanine transaminase, aspartate transaminase, and angiotensin-converting enzyme activities, total cholesterol, triglycerides, free serum fatty acid, cardiac tissue malondialdehyde (MDA), and nitric oxide levels and a significant decrease in levels of glutathione and superoxide dismutase in cardiac tissue as compared to the normal control group (P < 0.05). Pretreatment with S. virgaurea extract for 5 weeks at a dose of 250 mg/kg followed by isoproterenol injection significantly prevented the observed alterations. Captopril (50 mg/kg/day, given orally), an inhibitor of angiotensin-converting enzyme used as a standard cardioprotective drug, was used as a positive control in this study. The data of the present study suggest that S. virgaurea extract exerts its protective effect by decreasing MDA level and increasing the antioxidant status in isoproterenol-treated rats. The study emphasizes the beneficial action of S. virgaurea extract as a cardioprotective agent. | NO-RELATIONSHIP |
| Biochemical effects of Solidago virgaurea extract on experimental cardiotoxicity. DISEASE (DISEASE) are the major health problem of advanced as well as developing countries of the world. The aim of the present study was to investigate the protective effect of the Solidago virgaurea extract on isoproterenol-induced cardiotoxicity in rats. The subcutaneous injection of isoproterenol (30 mg/kg) into rats twice at an interval of 24 h, for two consecutive days, led to a significant increase in serum lactate dehydrogenase, creatine phosphokinase, alanine transaminase, aspartate transaminase, and angiotensin-converting enzyme activities, total cholesterol, triglycerides, free serum fatty acid, cardiac tissue malondialdehyde (MDA), and nitric oxide levels and a significant decrease in levels of CHEMICAL and superoxide dismutase in cardiac tissue as compared to the normal control group (P < 0.05). Pretreatment with S. virgaurea extract for 5 weeks at a dose of 250 mg/kg followed by isoproterenol injection significantly prevented the observed alterations. Captopril (50 mg/kg/day, given orally), an inhibitor of angiotensin-converting enzyme used as a standard cardioprotective drug, was used as a positive control in this study. The data of the present study suggest that S. virgaurea extract exerts its protective effect by decreasing MDA level and increasing the antioxidant status in isoproterenol-treated rats. The study emphasizes the beneficial action of S. virgaurea extract as a cardioprotective agent. | NO-RELATIONSHIP |
| Biochemical effects of Solidago virgaurea extract on experimental cardiotoxicity. DISEASE (DISEASE) are the major health problem of advanced as well as developing countries of the world. The aim of the present study was to investigate the protective effect of the Solidago virgaurea extract on isoproterenol-induced cardiotoxicity in rats. The subcutaneous injection of isoproterenol (30 mg/kg) into rats twice at an interval of 24 h, for two consecutive days, led to a significant increase in serum lactate dehydrogenase, creatine phosphokinase, alanine transaminase, aspartate transaminase, and angiotensin-converting enzyme activities, total cholesterol, triglycerides, free serum fatty acid, cardiac tissue malondialdehyde (MDA), and nitric oxide levels and a significant decrease in levels of glutathione and CHEMICAL dismutase in cardiac tissue as compared to the normal control group (P < 0.05). Pretreatment with S. virgaurea extract for 5 weeks at a dose of 250 mg/kg followed by isoproterenol injection significantly prevented the observed alterations. Captopril (50 mg/kg/day, given orally), an inhibitor of angiotensin-converting enzyme used as a standard cardioprotective drug, was used as a positive control in this study. The data of the present study suggest that S. virgaurea extract exerts its protective effect by decreasing MDA level and increasing the antioxidant status in isoproterenol-treated rats. The study emphasizes the beneficial action of S. virgaurea extract as a cardioprotective agent. | NO-RELATIONSHIP |
| Biochemical effects of Solidago virgaurea extract on experimental cardiotoxicity. DISEASE (DISEASE) are the major health problem of advanced as well as developing countries of the world. The aim of the present study was to investigate the protective effect of the Solidago virgaurea extract on isoproterenol-induced cardiotoxicity in rats. The subcutaneous injection of isoproterenol (30 mg/kg) into rats twice at an interval of 24 h, for two consecutive days, led to a significant increase in serum lactate dehydrogenase, creatine phosphokinase, alanine transaminase, aspartate transaminase, and CHEMICAL-converting enzyme activities, total cholesterol, triglycerides, free serum fatty acid, cardiac tissue malondialdehyde (MDA), and nitric oxide levels and a significant decrease in levels of glutathione and superoxide dismutase in cardiac tissue as compared to the normal control group (P < 0.05). Pretreatment with S. virgaurea extract for 5 weeks at a dose of 250 mg/kg followed by isoproterenol injection significantly prevented the observed alterations. Captopril (50 mg/kg/day, given orally), an inhibitor of CHEMICAL-converting enzyme used as a standard cardioprotective drug, was used as a positive control in this study. The data of the present study suggest that S. virgaurea extract exerts its protective effect by decreasing MDA level and increasing the antioxidant status in isoproterenol-treated rats. The study emphasizes the beneficial action of S. virgaurea extract as a cardioprotective agent. | NO-RELATIONSHIP |
| Biochemical effects of Solidago virgaurea extract on experimental cardiotoxicity. DISEASE (DISEASE) are the major health problem of advanced as well as developing countries of the world. The aim of the present study was to investigate the protective effect of the Solidago virgaurea extract on isoproterenol-induced cardiotoxicity in rats. The subcutaneous injection of isoproterenol (30 mg/kg) into rats twice at an interval of 24 h, for two consecutive days, led to a significant increase in serum lactate dehydrogenase, creatine phosphokinase, alanine transaminase, CHEMICAL transaminase, and angiotensin-converting enzyme activities, total cholesterol, triglycerides, free serum fatty acid, cardiac tissue malondialdehyde (MDA), and nitric oxide levels and a significant decrease in levels of glutathione and superoxide dismutase in cardiac tissue as compared to the normal control group (P < 0.05). Pretreatment with S. virgaurea extract for 5 weeks at a dose of 250 mg/kg followed by isoproterenol injection significantly prevented the observed alterations. Captopril (50 mg/kg/day, given orally), an inhibitor of angiotensin-converting enzyme used as a standard cardioprotective drug, was used as a positive control in this study. The data of the present study suggest that S. virgaurea extract exerts its protective effect by decreasing MDA level and increasing the antioxidant status in isoproterenol-treated rats. The study emphasizes the beneficial action of S. virgaurea extract as a cardioprotective agent. | NO-RELATIONSHIP |
| Biochemical effects of Solidago virgaurea extract on experimental cardiotoxicity. DISEASE (DISEASE) are the major health problem of advanced as well as developing countries of the world. The aim of the present study was to investigate the protective effect of the Solidago virgaurea extract on isoproterenol-induced cardiotoxicity in rats. The subcutaneous injection of isoproterenol (30 mg/kg) into rats twice at an interval of 24 h, for two consecutive days, led to a significant increase in serum lactate dehydrogenase, CHEMICAL phosphokinase, alanine transaminase, aspartate transaminase, and angiotensin-converting enzyme activities, total cholesterol, triglycerides, free serum fatty acid, cardiac tissue malondialdehyde (MDA), and nitric oxide levels and a significant decrease in levels of glutathione and superoxide dismutase in cardiac tissue as compared to the normal control group (P < 0.05). Pretreatment with S. virgaurea extract for 5 weeks at a dose of 250 mg/kg followed by isoproterenol injection significantly prevented the observed alterations. Captopril (50 mg/kg/day, given orally), an inhibitor of angiotensin-converting enzyme used as a standard cardioprotective drug, was used as a positive control in this study. The data of the present study suggest that S. virgaurea extract exerts its protective effect by decreasing MDA level and increasing the antioxidant status in isoproterenol-treated rats. The study emphasizes the beneficial action of S. virgaurea extract as a cardioprotective agent. | NO-RELATIONSHIP |
| Biochemical effects of Solidago virgaurea extract on experimental cardiotoxicity. DISEASE (DISEASE) are the major health problem of advanced as well as developing countries of the world. The aim of the present study was to investigate the protective effect of the Solidago virgaurea extract on isoproterenol-induced cardiotoxicity in rats. The subcutaneous injection of isoproterenol (30 mg/kg) into rats twice at an interval of 24 h, for two consecutive days, led to a significant increase in serum lactate dehydrogenase, creatine phosphokinase, alanine transaminase, aspartate transaminase, and angiotensin-converting enzyme activities, total cholesterol, triglycerides, free serum fatty acid, cardiac tissue malondialdehyde (MDA), and CHEMICAL levels and a significant decrease in levels of glutathione and superoxide dismutase in cardiac tissue as compared to the normal control group (P < 0.05). Pretreatment with S. virgaurea extract for 5 weeks at a dose of 250 mg/kg followed by isoproterenol injection significantly prevented the observed alterations. Captopril (50 mg/kg/day, given orally), an inhibitor of angiotensin-converting enzyme used as a standard cardioprotective drug, was used as a positive control in this study. The data of the present study suggest that S. virgaurea extract exerts its protective effect by decreasing MDA level and increasing the antioxidant status in isoproterenol-treated rats. The study emphasizes the beneficial action of S. virgaurea extract as a cardioprotective agent. | NO-RELATIONSHIP |
| Biochemical effects of Solidago virgaurea extract on experimental cardiotoxicity. DISEASE (DISEASE) are the major health problem of advanced as well as developing countries of the world. The aim of the present study was to investigate the protective effect of the Solidago virgaurea extract on isoproterenol-induced cardiotoxicity in rats. The subcutaneous injection of isoproterenol (30 mg/kg) into rats twice at an interval of 24 h, for two consecutive days, led to a significant increase in serum lactate dehydrogenase, creatine phosphokinase, alanine transaminase, aspartate transaminase, and angiotensin-converting enzyme activities, total CHEMICAL, triglycerides, free serum fatty acid, cardiac tissue malondialdehyde (MDA), and nitric oxide levels and a significant decrease in levels of glutathione and superoxide dismutase in cardiac tissue as compared to the normal control group (P < 0.05). Pretreatment with S. virgaurea extract for 5 weeks at a dose of 250 mg/kg followed by isoproterenol injection significantly prevented the observed alterations. Captopril (50 mg/kg/day, given orally), an inhibitor of angiotensin-converting enzyme used as a standard cardioprotective drug, was used as a positive control in this study. The data of the present study suggest that S. virgaurea extract exerts its protective effect by decreasing MDA level and increasing the antioxidant status in isoproterenol-treated rats. The study emphasizes the beneficial action of S. virgaurea extract as a cardioprotective agent. | NO-RELATIONSHIP |
| Biochemical effects of Solidago virgaurea extract on experimental cardiotoxicity. DISEASE (DISEASE) are the major health problem of advanced as well as developing countries of the world. The aim of the present study was to investigate the protective effect of the Solidago virgaurea extract on isoproterenol-induced cardiotoxicity in rats. The subcutaneous injection of isoproterenol (30 mg/kg) into rats twice at an interval of 24 h, for two consecutive days, led to a significant increase in serum lactate dehydrogenase, creatine phosphokinase, alanine transaminase, aspartate transaminase, and angiotensin-converting enzyme activities, total cholesterol, triglycerides, free serum fatty acid, cardiac tissue CHEMICAL (CHEMICAL), and nitric oxide levels and a significant decrease in levels of glutathione and superoxide dismutase in cardiac tissue as compared to the normal control group (P < 0.05). Pretreatment with S. virgaurea extract for 5 weeks at a dose of 250 mg/kg followed by isoproterenol injection significantly prevented the observed alterations. Captopril (50 mg/kg/day, given orally), an inhibitor of angiotensin-converting enzyme used as a standard cardioprotective drug, was used as a positive control in this study. The data of the present study suggest that S. virgaurea extract exerts its protective effect by decreasing CHEMICAL level and increasing the antioxidant status in isoproterenol-treated rats. The study emphasizes the beneficial action of S. virgaurea extract as a cardioprotective agent. | NO-RELATIONSHIP |
| Biochemical effects of Solidago virgaurea extract on experimental cardiotoxicity. DISEASE (DISEASE) are the major health problem of advanced as well as developing countries of the world. The aim of the present study was to investigate the protective effect of the Solidago virgaurea extract on isoproterenol-induced cardiotoxicity in rats. The subcutaneous injection of isoproterenol (30 mg/kg) into rats twice at an interval of 24 h, for two consecutive days, led to a significant increase in serum lactate dehydrogenase, creatine phosphokinase, alanine transaminase, aspartate transaminase, and angiotensin-converting enzyme activities, total cholesterol, triglycerides, free serum fatty acid, cardiac tissue malondialdehyde (MDA), and nitric oxide levels and a significant decrease in levels of glutathione and superoxide dismutase in cardiac tissue as compared to the normal control group (P < 0.05). Pretreatment with S. virgaurea extract for 5 weeks at a dose of 250 mg/kg followed by isoproterenol injection significantly prevented the observed alterations. CHEMICAL (50 mg/kg/day, given orally), an inhibitor of angiotensin-converting enzyme used as a standard cardioprotective drug, was used as a positive control in this study. The data of the present study suggest that S. virgaurea extract exerts its protective effect by decreasing MDA level and increasing the antioxidant status in isoproterenol-treated rats. The study emphasizes the beneficial action of S. virgaurea extract as a cardioprotective agent. | NO-RELATIONSHIP |
| Biochemical effects of Solidago virgaurea extract on experimental cardiotoxicity. DISEASE (DISEASE) are the major health problem of advanced as well as developing countries of the world. The aim of the present study was to investigate the protective effect of the Solidago virgaurea extract on isoproterenol-induced cardiotoxicity in rats. The subcutaneous injection of isoproterenol (30 mg/kg) into rats twice at an interval of 24 h, for two consecutive days, led to a significant increase in serum lactate dehydrogenase, creatine phosphokinase, alanine transaminase, aspartate transaminase, and angiotensin-converting enzyme activities, total cholesterol, CHEMICAL, free serum fatty acid, cardiac tissue malondialdehyde (MDA), and nitric oxide levels and a significant decrease in levels of glutathione and superoxide dismutase in cardiac tissue as compared to the normal control group (P < 0.05). Pretreatment with S. virgaurea extract for 5 weeks at a dose of 250 mg/kg followed by isoproterenol injection significantly prevented the observed alterations. Captopril (50 mg/kg/day, given orally), an inhibitor of angiotensin-converting enzyme used as a standard cardioprotective drug, was used as a positive control in this study. The data of the present study suggest that S. virgaurea extract exerts its protective effect by decreasing MDA level and increasing the antioxidant status in isoproterenol-treated rats. The study emphasizes the beneficial action of S. virgaurea extract as a cardioprotective agent. | NO-RELATIONSHIP |
| Biochemical effects of Solidago virgaurea extract on experimental cardiotoxicity. DISEASE (DISEASE) are the major health problem of advanced as well as developing countries of the world. The aim of the present study was to investigate the protective effect of the Solidago virgaurea extract on isoproterenol-induced cardiotoxicity in rats. The subcutaneous injection of isoproterenol (30 mg/kg) into rats twice at an interval of 24 h, for two consecutive days, led to a significant increase in serum lactate dehydrogenase, creatine phosphokinase, alanine transaminase, aspartate transaminase, and angiotensin-converting enzyme activities, total cholesterol, triglycerides, free serum CHEMICAL, cardiac tissue malondialdehyde (MDA), and nitric oxide levels and a significant decrease in levels of glutathione and superoxide dismutase in cardiac tissue as compared to the normal control group (P < 0.05). Pretreatment with S. virgaurea extract for 5 weeks at a dose of 250 mg/kg followed by isoproterenol injection significantly prevented the observed alterations. Captopril (50 mg/kg/day, given orally), an inhibitor of angiotensin-converting enzyme used as a standard cardioprotective drug, was used as a positive control in this study. The data of the present study suggest that S. virgaurea extract exerts its protective effect by decreasing MDA level and increasing the antioxidant status in isoproterenol-treated rats. The study emphasizes the beneficial action of S. virgaurea extract as a cardioprotective agent. | NO-RELATIONSHIP |
| "Real-world" data on the efficacy and safety of lenalidomide and CHEMICAL in patients with relapsed/refractory multiple myeloma who were treated according to the standard clinical practice: a study of the Greek Myeloma Study Group. Lenalidomide and CHEMICAL (RD) is a standard of care for relapsed/refractory multiple myeloma (RRMM), but there is limited published data on its efficacy and safety in the "real world" (RW), according to the International Society of Pharmacoeconomics and Outcomes Research definition. We studied 212 RRMM patients who received RD in RW. Objective response (>PR (partial response)) rate was 77.4 % (complete response (CR), 20.2 %). Median time to first and best response was 2 and 5 months, respectively. Median time to CR when RD was given as 2nd or >2(nd)-line treatment at 4 and 11 months, respectively. Quality of response was independent of previous lines of therapies or previous exposure to thalidomide or bortezomib. Median duration of response was 34.4 months, and it was higher in patients who received RD until progression (not reached versus 19 months, p < 0.001). Improvement of humoral immunity occurred in 60 % of responders (p < 0.001) and in the majority of patients who achieved stable disease. Adverse events were reported in 68.9 % of patients (myelosuppression in 49.4 %) and 12.7 % of patients needed hospitalization. DISEASE was observed only in 2.5 % of patients and deep vein thrombosis in 5.7 %. Dose reductions were needed in 31 % of patients and permanent discontinuation in 38.9 %. Median time to treatment discontinuation was 16.8 months. Performance status (PS) and initial lenalidomide dose predicted for treatment discontinuation. Extra-medullary relapses occurred in 3.8 % of patients. Our study confirms that RD is effective and safe in RRMM in the RW; it produces durable responses especially in patients who continue on treatment till progression and improves humoral immunity even in patients with stable disease. | CHEMICAL-INDUCED-DISEASE |
| "Real-world" data on the efficacy and safety of lenalidomide and CHEMICAL in patients with relapsed/refractory multiple myeloma who were treated according to the standard clinical practice: a study of the Greek Myeloma Study Group. Lenalidomide and CHEMICAL (RD) is a standard of care for relapsed/refractory multiple myeloma (RRMM), but there is limited published data on its efficacy and safety in the "real world" (RW), according to the International Society of Pharmacoeconomics and Outcomes Research definition. We studied 212 RRMM patients who received RD in RW. Objective response (>PR (partial response)) rate was 77.4 % (complete response (CR), 20.2 %). Median time to first and best response was 2 and 5 months, respectively. Median time to CR when RD was given as 2nd or >2(nd)-line treatment at 4 and 11 months, respectively. Quality of response was independent of previous lines of therapies or previous exposure to thalidomide or bortezomib. Median duration of response was 34.4 months, and it was higher in patients who received RD until progression (not reached versus 19 months, p < 0.001). Improvement of humoral immunity occurred in 60 % of responders (p < 0.001) and in the majority of patients who achieved stable disease. Adverse events were reported in 68.9 % of patients (DISEASE in 49.4 %) and 12.7 % of patients needed hospitalization. Peripheral neuropathy was observed only in 2.5 % of patients and deep vein thrombosis in 5.7 %. Dose reductions were needed in 31 % of patients and permanent discontinuation in 38.9 %. Median time to treatment discontinuation was 16.8 months. Performance status (PS) and initial lenalidomide dose predicted for treatment discontinuation. Extra-medullary relapses occurred in 3.8 % of patients. Our study confirms that RD is effective and safe in RRMM in the RW; it produces durable responses especially in patients who continue on treatment till progression and improves humoral immunity even in patients with stable disease. | CHEMICAL-INDUCED-DISEASE |
| "Real-world" data on the efficacy and safety of lenalidomide and CHEMICAL in patients with relapsed/refractory multiple myeloma who were treated according to the standard clinical practice: a study of the Greek Myeloma Study Group. Lenalidomide and CHEMICAL (RD) is a standard of care for relapsed/refractory multiple myeloma (RRMM), but there is limited published data on its efficacy and safety in the "real world" (RW), according to the International Society of Pharmacoeconomics and Outcomes Research definition. We studied 212 RRMM patients who received RD in RW. Objective response (>PR (partial response)) rate was 77.4 % (complete response (CR), 20.2 %). Median time to first and best response was 2 and 5 months, respectively. Median time to CR when RD was given as 2nd or >2(nd)-line treatment at 4 and 11 months, respectively. Quality of response was independent of previous lines of therapies or previous exposure to thalidomide or bortezomib. Median duration of response was 34.4 months, and it was higher in patients who received RD until progression (not reached versus 19 months, p < 0.001). Improvement of humoral immunity occurred in 60 % of responders (p < 0.001) and in the majority of patients who achieved stable disease. Adverse events were reported in 68.9 % of patients (myelosuppression in 49.4 %) and 12.7 % of patients needed hospitalization. Peripheral neuropathy was observed only in 2.5 % of patients and DISEASE in 5.7 %. Dose reductions were needed in 31 % of patients and permanent discontinuation in 38.9 %. Median time to treatment discontinuation was 16.8 months. Performance status (PS) and initial lenalidomide dose predicted for treatment discontinuation. Extra-medullary relapses occurred in 3.8 % of patients. Our study confirms that RD is effective and safe in RRMM in the RW; it produces durable responses especially in patients who continue on treatment till progression and improves humoral immunity even in patients with stable disease. | CHEMICAL-INDUCED-DISEASE |
| "Real-world" data on the efficacy and safety of CHEMICAL and dexamethasone in patients with relapsed/refractory multiple myeloma who were treated according to the standard clinical practice: a study of the Greek Myeloma Study Group. CHEMICAL and dexamethasone (RD) is a standard of care for relapsed/refractory multiple myeloma (RRMM), but there is limited published data on its efficacy and safety in the "real world" (RW), according to the International Society of Pharmacoeconomics and Outcomes Research definition. We studied 212 RRMM patients who received RD in RW. Objective response (>PR (partial response)) rate was 77.4 % (complete response (CR), 20.2 %). Median time to first and best response was 2 and 5 months, respectively. Median time to CR when RD was given as 2nd or >2(nd)-line treatment at 4 and 11 months, respectively. Quality of response was independent of previous lines of therapies or previous exposure to thalidomide or bortezomib. Median duration of response was 34.4 months, and it was higher in patients who received RD until progression (not reached versus 19 months, p < 0.001). Improvement of humoral immunity occurred in 60 % of responders (p < 0.001) and in the majority of patients who achieved stable disease. Adverse events were reported in 68.9 % of patients (DISEASE in 49.4 %) and 12.7 % of patients needed hospitalization. Peripheral neuropathy was observed only in 2.5 % of patients and deep vein thrombosis in 5.7 %. Dose reductions were needed in 31 % of patients and permanent discontinuation in 38.9 %. Median time to treatment discontinuation was 16.8 months. Performance status (PS) and initial CHEMICAL dose predicted for treatment discontinuation. Extra-medullary relapses occurred in 3.8 % of patients. Our study confirms that RD is effective and safe in RRMM in the RW; it produces durable responses especially in patients who continue on treatment till progression and improves humoral immunity even in patients with stable disease. | CHEMICAL-INDUCED-DISEASE |
| "Real-world" data on the efficacy and safety of CHEMICAL and dexamethasone in patients with relapsed/refractory multiple myeloma who were treated according to the standard clinical practice: a study of the Greek Myeloma Study Group. CHEMICAL and dexamethasone (RD) is a standard of care for relapsed/refractory multiple myeloma (RRMM), but there is limited published data on its efficacy and safety in the "real world" (RW), according to the International Society of Pharmacoeconomics and Outcomes Research definition. We studied 212 RRMM patients who received RD in RW. Objective response (>PR (partial response)) rate was 77.4 % (complete response (CR), 20.2 %). Median time to first and best response was 2 and 5 months, respectively. Median time to CR when RD was given as 2nd or >2(nd)-line treatment at 4 and 11 months, respectively. Quality of response was independent of previous lines of therapies or previous exposure to thalidomide or bortezomib. Median duration of response was 34.4 months, and it was higher in patients who received RD until progression (not reached versus 19 months, p < 0.001). Improvement of humoral immunity occurred in 60 % of responders (p < 0.001) and in the majority of patients who achieved stable disease. Adverse events were reported in 68.9 % of patients (myelosuppression in 49.4 %) and 12.7 % of patients needed hospitalization. DISEASE was observed only in 2.5 % of patients and deep vein thrombosis in 5.7 %. Dose reductions were needed in 31 % of patients and permanent discontinuation in 38.9 %. Median time to treatment discontinuation was 16.8 months. Performance status (PS) and initial CHEMICAL dose predicted for treatment discontinuation. Extra-medullary relapses occurred in 3.8 % of patients. Our study confirms that RD is effective and safe in RRMM in the RW; it produces durable responses especially in patients who continue on treatment till progression and improves humoral immunity even in patients with stable disease. | CHEMICAL-INDUCED-DISEASE |
| "Real-world" data on the efficacy and safety of CHEMICAL and dexamethasone in patients with relapsed/refractory multiple myeloma who were treated according to the standard clinical practice: a study of the Greek Myeloma Study Group. CHEMICAL and dexamethasone (RD) is a standard of care for relapsed/refractory multiple myeloma (RRMM), but there is limited published data on its efficacy and safety in the "real world" (RW), according to the International Society of Pharmacoeconomics and Outcomes Research definition. We studied 212 RRMM patients who received RD in RW. Objective response (>PR (partial response)) rate was 77.4 % (complete response (CR), 20.2 %). Median time to first and best response was 2 and 5 months, respectively. Median time to CR when RD was given as 2nd or >2(nd)-line treatment at 4 and 11 months, respectively. Quality of response was independent of previous lines of therapies or previous exposure to thalidomide or bortezomib. Median duration of response was 34.4 months, and it was higher in patients who received RD until progression (not reached versus 19 months, p < 0.001). Improvement of humoral immunity occurred in 60 % of responders (p < 0.001) and in the majority of patients who achieved stable disease. Adverse events were reported in 68.9 % of patients (myelosuppression in 49.4 %) and 12.7 % of patients needed hospitalization. Peripheral neuropathy was observed only in 2.5 % of patients and DISEASE in 5.7 %. Dose reductions were needed in 31 % of patients and permanent discontinuation in 38.9 %. Median time to treatment discontinuation was 16.8 months. Performance status (PS) and initial CHEMICAL dose predicted for treatment discontinuation. Extra-medullary relapses occurred in 3.8 % of patients. Our study confirms that RD is effective and safe in RRMM in the RW; it produces durable responses especially in patients who continue on treatment till progression and improves humoral immunity even in patients with stable disease. | CHEMICAL-INDUCED-DISEASE |
| "Real-world" data on the efficacy and safety of lenalidomide and dexamethasone in patients with relapsed/refractory DISEASE who were treated according to the standard clinical practice: a study of the Greek DISEASE Study Group. Lenalidomide and dexamethasone (RD) is a standard of care for relapsed/refractory DISEASE (DISEASE), but there is limited published data on its efficacy and safety in the "real world" (RW), according to the International Society of Pharmacoeconomics and Outcomes Research definition. We studied 212 DISEASE patients who received RD in RW. Objective response (>PR (partial response)) rate was 77.4 % (complete response (CR), 20.2 %). Median time to first and best response was 2 and 5 months, respectively. Median time to CR when RD was given as 2nd or >2(nd)-line treatment at 4 and 11 months, respectively. Quality of response was independent of previous lines of therapies or previous exposure to thalidomide or CHEMICAL. Median duration of response was 34.4 months, and it was higher in patients who received RD until progression (not reached versus 19 months, p < 0.001). Improvement of humoral immunity occurred in 60 % of responders (p < 0.001) and in the majority of patients who achieved stable disease. Adverse events were reported in 68.9 % of patients (myelosuppression in 49.4 %) and 12.7 % of patients needed hospitalization. Peripheral neuropathy was observed only in 2.5 % of patients and deep vein thrombosis in 5.7 %. Dose reductions were needed in 31 % of patients and permanent discontinuation in 38.9 %. Median time to treatment discontinuation was 16.8 months. Performance status (PS) and initial lenalidomide dose predicted for treatment discontinuation. Extra-medullary relapses occurred in 3.8 % of patients. Our study confirms that RD is effective and safe in DISEASE in the RW; it produces durable responses especially in patients who continue on treatment till progression and improves humoral immunity even in patients with stable disease. | NO-RELATIONSHIP |
| "Real-world" data on the efficacy and safety of lenalidomide and dexamethasone in patients with relapsed/refractory DISEASE who were treated according to the standard clinical practice: a study of the Greek DISEASE Study Group. Lenalidomide and dexamethasone (CHEMICAL) is a standard of care for relapsed/refractory DISEASE (DISEASE), but there is limited published data on its efficacy and safety in the "real world" (RW), according to the International Society of Pharmacoeconomics and Outcomes Research definition. We studied 212 DISEASE patients who received CHEMICAL in RW. Objective response (>PR (partial response)) rate was 77.4 % (complete response (CR), 20.2 %). Median time to first and best response was 2 and 5 months, respectively. Median time to CR when CHEMICAL was given as 2nd or >2(nd)-line treatment at 4 and 11 months, respectively. Quality of response was independent of previous lines of therapies or previous exposure to thalidomide or bortezomib. Median duration of response was 34.4 months, and it was higher in patients who received CHEMICAL until progression (not reached versus 19 months, p < 0.001). Improvement of humoral immunity occurred in 60 % of responders (p < 0.001) and in the majority of patients who achieved stable disease. Adverse events were reported in 68.9 % of patients (myelosuppression in 49.4 %) and 12.7 % of patients needed hospitalization. Peripheral neuropathy was observed only in 2.5 % of patients and deep vein thrombosis in 5.7 %. Dose reductions were needed in 31 % of patients and permanent discontinuation in 38.9 %. Median time to treatment discontinuation was 16.8 months. Performance status (PS) and initial lenalidomide dose predicted for treatment discontinuation. Extra-medullary relapses occurred in 3.8 % of patients. Our study confirms that CHEMICAL is effective and safe in DISEASE in the RW; it produces durable responses especially in patients who continue on treatment till progression and improves humoral immunity even in patients with stable disease. | NO-RELATIONSHIP |
| "Real-world" data on the efficacy and safety of lenalidomide and dexamethasone in patients with relapsed/refractory DISEASE who were treated according to the standard clinical practice: a study of the Greek DISEASE Study Group. Lenalidomide and dexamethasone (RD) is a standard of care for relapsed/refractory DISEASE (DISEASE), but there is limited published data on its efficacy and safety in the "real world" (RW), according to the International Society of Pharmacoeconomics and Outcomes Research definition. We studied 212 DISEASE patients who received RD in RW. Objective response (>PR (partial response)) rate was 77.4 % (complete response (CR), 20.2 %). Median time to first and best response was 2 and 5 months, respectively. Median time to CR when RD was given as 2nd or >2(nd)-line treatment at 4 and 11 months, respectively. Quality of response was independent of previous lines of therapies or previous exposure to CHEMICAL or bortezomib. Median duration of response was 34.4 months, and it was higher in patients who received RD until progression (not reached versus 19 months, p < 0.001). Improvement of humoral immunity occurred in 60 % of responders (p < 0.001) and in the majority of patients who achieved stable disease. Adverse events were reported in 68.9 % of patients (myelosuppression in 49.4 %) and 12.7 % of patients needed hospitalization. Peripheral neuropathy was observed only in 2.5 % of patients and deep vein thrombosis in 5.7 %. Dose reductions were needed in 31 % of patients and permanent discontinuation in 38.9 %. Median time to treatment discontinuation was 16.8 months. Performance status (PS) and initial lenalidomide dose predicted for treatment discontinuation. Extra-medullary relapses occurred in 3.8 % of patients. Our study confirms that RD is effective and safe in DISEASE in the RW; it produces durable responses especially in patients who continue on treatment till progression and improves humoral immunity even in patients with stable disease. | NO-RELATIONSHIP |
| The cytogenetic action of ifosfamide, mesna, and their combination on peripheral rabbit lymphocytes: an in vivo/in vitro cytogenetic study. Ifosfamide (IFO) is an alkylating CHEMICAL mustard, administrated as an antineoplasmic agent. It is characterized by its intense urotoxic action, leading to hemorrhagic cystitis. This side effect of IFO raises the requirement for the co-administration with sodium 2-sulfanylethanesulfonate (Mesna) aiming to avoid or minimize this effect. IFO and Mesna were administrated separately on rabbit's lymphocytes in vivo, which were later developed in vitro. Cytogenetic markers for sister chromatid exchanges (SCEs), proliferation rate index (PRI) and Mitotic Index were recorded. Mesna's action, in conjunction with IFO reduces the frequency of SCEs, in comparison with the SCEs recordings obtained when IFO is administered alone. In addition to this, when high concentrations of Mesna were administered alone significant reductions of the PRI were noted, than with IFO acting at the same concentration on the lymphocytes. Mesna significantly reduces IFO's DISEASE, while when administered in high concentrations it acts in an inhibitory fashion on the cytostatic action of the drug. | NO-RELATIONSHIP |
| The cytogenetic action of ifosfamide, CHEMICAL, and their combination on peripheral rabbit lymphocytes: an in vivo/in vitro cytogenetic study. Ifosfamide (IFO) is an alkylating nitrogen mustard, administrated as an antineoplasmic agent. It is characterized by its intense urotoxic action, leading to hemorrhagic cystitis. This side effect of IFO raises the requirement for the co-administration with CHEMICAL (CHEMICAL) aiming to avoid or minimize this effect. IFO and CHEMICAL were administrated separately on rabbit's lymphocytes in vivo, which were later developed in vitro. Cytogenetic markers for sister chromatid exchanges (SCEs), proliferation rate index (PRI) and Mitotic Index were recorded. CHEMICAL's action, in conjunction with IFO reduces the frequency of SCEs, in comparison with the SCEs recordings obtained when IFO is administered alone. In addition to this, when high concentrations of CHEMICAL were administered alone significant reductions of the PRI were noted, than with IFO acting at the same concentration on the lymphocytes. CHEMICAL significantly reduces IFO's DISEASE, while when administered in high concentrations it acts in an inhibitory fashion on the cytostatic action of the drug. | NO-RELATIONSHIP |
| The cytogenetic action of ifosfamide, CHEMICAL, and their combination on peripheral rabbit lymphocytes: an in vivo/in vitro cytogenetic study. Ifosfamide (IFO) is an alkylating nitrogen mustard, administrated as an antineoplasmic agent. It is characterized by its intense urotoxic action, leading to DISEASE. This side effect of IFO raises the requirement for the co-administration with CHEMICAL (CHEMICAL) aiming to avoid or minimize this effect. IFO and CHEMICAL were administrated separately on rabbit's lymphocytes in vivo, which were later developed in vitro. Cytogenetic markers for sister chromatid exchanges (SCEs), proliferation rate index (PRI) and Mitotic Index were recorded. CHEMICAL's action, in conjunction with IFO reduces the frequency of SCEs, in comparison with the SCEs recordings obtained when IFO is administered alone. In addition to this, when high concentrations of CHEMICAL were administered alone significant reductions of the PRI were noted, than with IFO acting at the same concentration on the lymphocytes. CHEMICAL significantly reduces IFO's genotoxicity, while when administered in high concentrations it acts in an inhibitory fashion on the cytostatic action of the drug. | NO-RELATIONSHIP |
| The cytogenetic action of ifosfamide, mesna, and their combination on peripheral rabbit lymphocytes: an in vivo/in vitro cytogenetic study. Ifosfamide (IFO) is an alkylating CHEMICAL mustard, administrated as an antineoplasmic agent. It is characterized by its intense urotoxic action, leading to DISEASE. This side effect of IFO raises the requirement for the co-administration with sodium 2-sulfanylethanesulfonate (Mesna) aiming to avoid or minimize this effect. IFO and Mesna were administrated separately on rabbit's lymphocytes in vivo, which were later developed in vitro. Cytogenetic markers for sister chromatid exchanges (SCEs), proliferation rate index (PRI) and Mitotic Index were recorded. Mesna's action, in conjunction with IFO reduces the frequency of SCEs, in comparison with the SCEs recordings obtained when IFO is administered alone. In addition to this, when high concentrations of Mesna were administered alone significant reductions of the PRI were noted, than with IFO acting at the same concentration on the lymphocytes. Mesna significantly reduces IFO's genotoxicity, while when administered in high concentrations it acts in an inhibitory fashion on the cytostatic action of the drug. | NO-RELATIONSHIP |
| Risk factors and predictors of CHEMICAL-induced DISEASE among multiethnic Malaysians with Parkinson's disease. Chronic pulsatile CHEMICAL therapy for Parkinson's disease (PD) leads to the development of motor fluctuations and DISEASE. We studied the prevalence and predictors of CHEMICAL-induced DISEASE among multiethnic Malaysian patients with PD. METHODS: This is a cross-sectional study involving 95 patients with PD on uninterrupted CHEMICAL therapy for at least 6 months. The instrument used was the UPDRS questionnaires. The predictors of DISEASE were determined using multivariate logistic regression analysis. RESULTS: The mean age was 65.6 + 8.5 years. The mean onset age was 58.5 + 9.8 years. The median disease duration was 6 (7) years. DISEASE was present in 44% (n = 42) with median CHEMICAL therapy of 3 years. There were 64.3% Chinese, 31% Malays, and 3.7% Indians and other ethnic groups. Eighty-one percent of patients with DISEASE had clinical fluctuations. Patients with DISEASE had lower onset age ( p < 0.001), longer duration of CHEMICAL therapy ( p < 0.001), longer disease duration ( p < 0.001), higher total daily CHEMICAL dose ( p < 0.001), and higher total UPDRS scores ( p = 0.005) than patients without DISEASE. The three significant predictors of DISEASE were duration of CHEMICAL therapy, onset age, and total daily CHEMICAL dose. CONCLUSIONS: The prevalence of CHEMICAL-induced DISEASE in our patients was 44%. The most significant predictors were duration of CHEMICAL therapy, total daily CHEMICAL dose, and onset age. | CHEMICAL-INDUCED-DISEASE |
| An unexpected diagnosis in a renal-transplant patient with proteinuria treated with CHEMICAL: DISEASE DISEASE. Proteinuria is an expected complication in transplant patients treated with mammalian target of rapamycin inhibitors (mTOR-i). However, clinical suspicion should always be supported by histological evidence in order to investigate potential alternate diagnoses such as acute or chronic rejection, interstitial fibrosis and tubular atrophy, or recurrent or de novo glomerulopathy. In this case we report the unexpected diagnosis of DISEASE in a renal-transplant patient with pre-transplant monoclonal gammapathy of undetermined significance who developed proteinuria after conversion from tacrolimus to CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| An unexpected diagnosis in a renal-transplant patient with DISEASE treated with CHEMICAL: AL amyloidosis. DISEASE is an expected complication in transplant patients treated with mammalian target of rapamycin inhibitors (mTOR-i). However, clinical suspicion should always be supported by histological evidence in order to investigate potential alternate diagnoses such as acute or chronic rejection, interstitial fibrosis and tubular atrophy, or recurrent or de novo glomerulopathy. In this case we report the unexpected diagnosis of amyloidosis in a renal-transplant patient with pre-transplant monoclonal gammapathy of undetermined significance who developed DISEASE after conversion from tacrolimus to CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| An unexpected diagnosis in a renal-transplant patient with proteinuria treated with everolimus: AL amyloidosis. Proteinuria is an expected complication in transplant patients treated with mammalian target of CHEMICAL inhibitors (mTOR-i). However, clinical suspicion should always be supported by histological evidence in order to investigate potential alternate diagnoses such as acute or chronic rejection, interstitial DISEASE and tubular atrophy, or recurrent or de novo glomerulopathy. In this case we report the unexpected diagnosis of amyloidosis in a renal-transplant patient with pre-transplant monoclonal gammapathy of undetermined significance who developed proteinuria after conversion from tacrolimus to everolimus. | NO-RELATIONSHIP |
| An unexpected diagnosis in a renal-transplant patient with proteinuria treated with everolimus: AL amyloidosis. Proteinuria is an expected complication in transplant patients treated with mammalian target of rapamycin inhibitors (mTOR-i). However, clinical suspicion should always be supported by histological evidence in order to investigate potential alternate diagnoses such as acute or chronic rejection, interstitial DISEASE and tubular atrophy, or recurrent or de novo glomerulopathy. In this case we report the unexpected diagnosis of amyloidosis in a renal-transplant patient with pre-transplant monoclonal gammapathy of undetermined significance who developed proteinuria after conversion from CHEMICAL to everolimus. | NO-RELATIONSHIP |
| An unexpected diagnosis in a renal-transplant patient with proteinuria treated with everolimus: AL amyloidosis. Proteinuria is an expected complication in transplant patients treated with mammalian target of CHEMICAL inhibitors (mTOR-i). However, clinical suspicion should always be supported by histological evidence in order to investigate potential alternate diagnoses such as acute or chronic rejection, interstitial fibrosis and tubular atrophy, or recurrent or de novo DISEASE. In this case we report the unexpected diagnosis of amyloidosis in a renal-transplant patient with pre-transplant monoclonal gammapathy of undetermined significance who developed proteinuria after conversion from tacrolimus to everolimus. | NO-RELATIONSHIP |
| An unexpected diagnosis in a renal-transplant patient with proteinuria treated with everolimus: AL amyloidosis. Proteinuria is an expected complication in transplant patients treated with mammalian target of rapamycin inhibitors (mTOR-i). However, clinical suspicion should always be supported by histological evidence in order to investigate potential alternate diagnoses such as acute or chronic rejection, interstitial fibrosis and tubular atrophy, or recurrent or de novo DISEASE. In this case we report the unexpected diagnosis of amyloidosis in a renal-transplant patient with pre-transplant monoclonal gammapathy of undetermined significance who developed proteinuria after conversion from CHEMICAL to everolimus. | NO-RELATIONSHIP |
| An unexpected diagnosis in a renal-transplant patient with proteinuria treated with everolimus: AL amyloidosis. Proteinuria is an expected complication in transplant patients treated with mammalian target of rapamycin inhibitors (mTOR-i). However, clinical suspicion should always be supported by histological evidence in order to investigate potential alternate diagnoses such as acute or chronic rejection, interstitial fibrosis and tubular DISEASE, or recurrent or de novo glomerulopathy. In this case we report the unexpected diagnosis of amyloidosis in a renal-transplant patient with pre-transplant monoclonal gammapathy of undetermined significance who developed proteinuria after conversion from CHEMICAL to everolimus. | NO-RELATIONSHIP |
| An unexpected diagnosis in a renal-transplant patient with proteinuria treated with everolimus: AL amyloidosis. Proteinuria is an expected complication in transplant patients treated with mammalian target of CHEMICAL inhibitors (mTOR-i). However, clinical suspicion should always be supported by histological evidence in order to investigate potential alternate diagnoses such as acute or chronic rejection, interstitial fibrosis and tubular DISEASE, or recurrent or de novo glomerulopathy. In this case we report the unexpected diagnosis of amyloidosis in a renal-transplant patient with pre-transplant monoclonal gammapathy of undetermined significance who developed proteinuria after conversion from tacrolimus to everolimus. | NO-RELATIONSHIP |
| An investigation of the pattern of kidney injury in HIV-positive persons exposed to CHEMICAL: an examination of a large population database (MHRA database). The potential for tenofovir to cause a range of kidney syndromes has been established from mechanistic and randomised clinical trials. However, the exact pattern of kidney involvement is still uncertain. We undertook a descriptive analysis of Yellow Card records of 407 HIV-positive persons taking CHEMICAL (CHEMICAL) as part of their antiretroviral therapy regimen and submitted to the Medicines and Healthcare Products Regulatory Agency (MHRA) with suspected kidney adverse effects. Reports that satisfy defined criteria were classified as DISEASE, kidney tubular dysfunction and Fanconi syndrome. Of the 407 Yellow Card records analysed, 106 satisfied criteria for CHEMICAL-related kidney disease, of which 53 (50%) had features of kidney tubular dysfunction, 35 (33%) were found to have features of glomerular dysfunction and 18 (17%) had Fanconi syndrome. The median CHEMICAL exposure was 316 days (interquartile range 120-740). The incidence of hospitalisation for CHEMICAL kidney adverse effects was high, particularly amongst patients with features of Fanconi syndrome. The pattern of kidney syndromes in this population series mirrors that reported in randomised clinical trials. Cessation of CHEMICAL was associated with complete restoration of kidney function in up half of the patients in this report. | CHEMICAL-INDUCED-DISEASE |
| An investigation of the pattern of kidney injury in HIV-positive persons exposed to CHEMICAL: an examination of a large population database (MHRA database). The potential for tenofovir to cause a range of kidney syndromes has been established from mechanistic and randomised clinical trials. However, the exact pattern of kidney involvement is still uncertain. We undertook a descriptive analysis of Yellow Card records of 407 HIV-positive persons taking CHEMICAL (CHEMICAL) as part of their antiretroviral therapy regimen and submitted to the Medicines and Healthcare Products Regulatory Agency (MHRA) with suspected kidney adverse effects. Reports that satisfy defined criteria were classified as acute kidney injury, kidney tubular dysfunction and DISEASE. Of the 407 Yellow Card records analysed, 106 satisfied criteria for CHEMICAL-related kidney disease, of which 53 (50%) had features of kidney tubular dysfunction, 35 (33%) were found to have features of glomerular dysfunction and 18 (17%) had DISEASE. The median CHEMICAL exposure was 316 days (interquartile range 120-740). The incidence of hospitalisation for CHEMICAL kidney adverse effects was high, particularly amongst patients with features of DISEASE. The pattern of kidney syndromes in this population series mirrors that reported in randomised clinical trials. Cessation of CHEMICAL was associated with complete restoration of kidney function in up half of the patients in this report. | CHEMICAL-INDUCED-DISEASE |
| An investigation of the pattern of DISEASE in HIV-positive persons exposed to tenofovir disoproxil fumarate: an examination of a large population database (MHRA database). The potential for CHEMICAL to cause a range of kidney syndromes has been established from mechanistic and randomised clinical trials. However, the exact pattern of kidney involvement is still uncertain. We undertook a descriptive analysis of Yellow Card records of 407 HIV-positive persons taking tenofovir disoproxil fumarate (TDF) as part of their antiretroviral therapy regimen and submitted to the Medicines and Healthcare Products Regulatory Agency (MHRA) with suspected kidney adverse effects. Reports that satisfy defined criteria were classified as acute kidney injury, DISEASE and Fanconi syndrome. Of the 407 Yellow Card records analysed, 106 satisfied criteria for TDF-related DISEASE, of which 53 (50%) had features of DISEASE, 35 (33%) were found to have features of DISEASE and 18 (17%) had Fanconi syndrome. The median TDF exposure was 316 days (interquartile range 120-740). The incidence of hospitalisation for TDF kidney adverse effects was high, particularly amongst patients with features of Fanconi syndrome. The pattern of kidney syndromes in this population series mirrors that reported in randomised clinical trials. Cessation of TDF was associated with complete restoration of kidney function in up half of the patients in this report. | NO-RELATIONSHIP |
| Incidence of DISEASE is high even in a population without known risk factors. PURPOSE: DISEASE is a recognized complication in populations at risk. The aim of this study is to assess the prevalence of early DISEASE in a population without known risk factors admitted to the ICU for postoperative monitoring after elective major surgery. The secondary outcome investigated is to identify eventual independent risk factors among demographic data and anesthetic drugs used. METHODS: An observational, prospective study was conducted on a consecutive cohort of patients admitted to our ICU within and for at least 24 h after major surgical procedures. Exclusion criteria were any preexisting predisposing factor for delirium or other potentially confounding neurological dysfunctions. Patients were assessed daily using the confusion assessment method for the ICU scale for 3 days after the surgical procedure. Early DISEASE incidence risk factors were then assessed through three different multiple regression models. RESULTS: According to the confusion assessment method for the ICU scale, 28 % of patients were diagnosed with early DISEASE. The use of CHEMICAL was significantly associated with an eight-fold-higher risk for delirium compared to propofol (57.1% vs. 7.1%, RR = 8.0, X2 = 4.256; df = 1; 0.05 < p < 0.02). CONCLUSION: In this study early DISEASE was found to be a very common complication after major surgery, even in a population without known risk factors. CHEMICAL was independently associated with an increase in its relative risk. | CHEMICAL-INDUCED-DISEASE |
| Incidence of postoperative delirium is high even in a population without known risk factors. PURPOSE: Postoperative delirium is a recognized complication in populations at risk. The aim of this study is to assess the prevalence of early postoperative delirium in a population without known risk factors admitted to the ICU for postoperative monitoring after elective major surgery. The secondary outcome investigated is to identify eventual independent risk factors among demographic data and anesthetic drugs used. METHODS: An observational, prospective study was conducted on a consecutive cohort of patients admitted to our ICU within and for at least 24 h after major surgical procedures. Exclusion criteria were any preexisting predisposing factor for DISEASE or other potentially confounding neurological dysfunctions. Patients were assessed daily using the confusion assessment method for the ICU scale for 3 days after the surgical procedure. Early postoperative delirium incidence risk factors were then assessed through three different multiple regression models. RESULTS: According to the confusion assessment method for the ICU scale, 28 % of patients were diagnosed with early postoperative delirium. The use of CHEMICAL was significantly associated with an eight-fold-higher risk for DISEASE compared to propofol (57.1% vs. 7.1%, RR = 8.0, X2 = 4.256; df = 1; 0.05 < p < 0.02). CONCLUSION: In this study early postoperative delirium was found to be a very common complication after major surgery, even in a population without known risk factors. CHEMICAL was independently associated with an increase in its relative risk. | CHEMICAL-INDUCED-DISEASE |
| Incidence of postoperative delirium is high even in a population without known risk factors. PURPOSE: Postoperative delirium is a recognized complication in populations at risk. The aim of this study is to assess the prevalence of early postoperative delirium in a population without known risk factors admitted to the ICU for postoperative monitoring after elective major surgery. The secondary outcome investigated is to identify eventual independent risk factors among demographic data and anesthetic drugs used. METHODS: An observational, prospective study was conducted on a consecutive cohort of patients admitted to our ICU within and for at least 24 h after major surgical procedures. Exclusion criteria were any preexisting predisposing factor for delirium or other potentially confounding neurological dysfunctions. Patients were assessed daily using the DISEASE assessment method for the ICU scale for 3 days after the surgical procedure. Early postoperative delirium incidence risk factors were then assessed through three different multiple regression models. RESULTS: According to the confusion assessment method for the ICU scale, 28 % of patients were diagnosed with early postoperative delirium. The use of thiopentone was significantly associated with an eight-fold-higher risk for delirium compared to CHEMICAL (57.1% vs. 7.1%, RR = 8.0, X2 = 4.256; df = 1; 0.05 < p < 0.02). CONCLUSION: In this study early postoperative delirium was found to be a very common complication after major surgery, even in a population without known risk factors. Thiopentone was independently associated with an increase in its relative risk. | NO-RELATIONSHIP |
| Incidence of postoperative delirium is high even in a population without known risk factors. PURPOSE: Postoperative delirium is a recognized complication in populations at risk. The aim of this study is to assess the prevalence of early postoperative delirium in a population without known risk factors admitted to the ICU for postoperative monitoring after elective major surgery. The secondary outcome investigated is to identify eventual independent risk factors among demographic data and anesthetic drugs used. METHODS: An observational, prospective study was conducted on a consecutive cohort of patients admitted to our ICU within and for at least 24 h after major surgical procedures. Exclusion criteria were any preexisting predisposing factor for delirium or other potentially confounding DISEASE. Patients were assessed daily using the confusion assessment method for the ICU scale for 3 days after the surgical procedure. Early postoperative delirium incidence risk factors were then assessed through three different multiple regression models. RESULTS: According to the confusion assessment method for the ICU scale, 28 % of patients were diagnosed with early postoperative delirium. The use of thiopentone was significantly associated with an eight-fold-higher risk for delirium compared to CHEMICAL (57.1% vs. 7.1%, RR = 8.0, X2 = 4.256; df = 1; 0.05 < p < 0.02). CONCLUSION: In this study early postoperative delirium was found to be a very common complication after major surgery, even in a population without known risk factors. Thiopentone was independently associated with an increase in its relative risk. | NO-RELATIONSHIP |
| A single neurotoxic dose of CHEMICAL induces a long-lasting DISEASE-like behaviour in mice. CHEMICAL (CHEMICAL) triggers a disruption of the monoaminergic system and CHEMICAL abuse leads to negative emotional states including DISEASE during drug withdrawal. However, it is currently unknown if the acute toxic dosage of CHEMICAL also causes a long-lasting DISEASE phenotype and persistent monoaminergic deficits. Thus, we now assessed the DISEASE-like behaviour in mice at early and long-term periods following a single high CHEMICAL dose (30 mg/kg, i.p.). CHEMICAL did not alter the motor function and procedural memory of mice as assessed by swimming speed and escape latency to find the platform in a cued version of the water maze task. However, CHEMICAL significantly increased the immobility time in the tail suspension test at 3 and 49 days post-administration. This DISEASE-like profile induced by CHEMICAL was accompanied by a marked depletion of frontostriatal dopaminergic and serotonergic neurotransmission, indicated by a reduction in the levels of dopamine, DOPAC and HVA, tyrosine hydroxylase and serotonin, observed at both 3 and 49 days post-administration. In parallel, another neurochemical feature of DISEASE--astroglial dysfunction--was unaffected in the cortex and the striatal levels of the astrocytic protein marker, glial fibrillary acidic protein, were only transiently increased at 3 days. These findings demonstrate for the first time that a single high dose of CHEMICAL induces long-lasting DISEASE-like behaviour in mice associated with a persistent disruption of frontostriatal dopaminergic and serotonergic homoeostasis. | CHEMICAL-INDUCED-DISEASE |
| A single DISEASE dose of methamphetamine induces a long-lasting depressive-like behaviour in mice. Methamphetamine (METH) triggers a disruption of the monoaminergic system and METH abuse leads to negative emotional states including depressive symptoms during drug withdrawal. However, it is currently unknown if the acute toxic dosage of METH also causes a long-lasting depressive phenotype and persistent monoaminergic deficits. Thus, we now assessed the depressive-like behaviour in mice at early and long-term periods following a single high METH dose (30 mg/kg, i.p.). METH did not alter the motor function and procedural memory of mice as assessed by swimming speed and escape latency to find the platform in a cued version of the water maze task. However, METH significantly increased the immobility time in the tail suspension test at 3 and 49 days post-administration. This depressive-like profile induced by METH was accompanied by a marked depletion of frontostriatal dopaminergic and serotonergic neurotransmission, indicated by a reduction in the levels of dopamine, DOPAC and HVA, CHEMICAL hydroxylase and serotonin, observed at both 3 and 49 days post-administration. In parallel, another neurochemical feature of depression--astroglial dysfunction--was unaffected in the cortex and the striatal levels of the astrocytic protein marker, glial fibrillary acidic protein, were only transiently increased at 3 days. These findings demonstrate for the first time that a single high dose of METH induces long-lasting depressive-like behaviour in mice associated with a persistent disruption of frontostriatal dopaminergic and serotonergic homoeostasis. | NO-RELATIONSHIP |
| A single DISEASE dose of methamphetamine induces a long-lasting depressive-like behaviour in mice. Methamphetamine (METH) triggers a disruption of the monoaminergic system and METH abuse leads to negative emotional states including depressive symptoms during drug withdrawal. However, it is currently unknown if the acute toxic dosage of METH also causes a long-lasting depressive phenotype and persistent monoaminergic deficits. Thus, we now assessed the depressive-like behaviour in mice at early and long-term periods following a single high METH dose (30 mg/kg, i.p.). METH did not alter the motor function and procedural memory of mice as assessed by swimming speed and escape latency to find the platform in a cued version of the water maze task. However, METH significantly increased the immobility time in the tail suspension test at 3 and 49 days post-administration. This depressive-like profile induced by METH was accompanied by a marked depletion of frontostriatal dopaminergic and serotonergic neurotransmission, indicated by a reduction in the levels of dopamine, DOPAC and CHEMICAL, tyrosine hydroxylase and serotonin, observed at both 3 and 49 days post-administration. In parallel, another neurochemical feature of depression--astroglial dysfunction--was unaffected in the cortex and the striatal levels of the astrocytic protein marker, glial fibrillary acidic protein, were only transiently increased at 3 days. These findings demonstrate for the first time that a single high dose of METH induces long-lasting depressive-like behaviour in mice associated with a persistent disruption of frontostriatal dopaminergic and serotonergic homoeostasis. | NO-RELATIONSHIP |
| A single DISEASE dose of methamphetamine induces a long-lasting depressive-like behaviour in mice. Methamphetamine (METH) triggers a disruption of the monoaminergic system and METH abuse leads to negative emotional states including depressive symptoms during drug withdrawal. However, it is currently unknown if the acute toxic dosage of METH also causes a long-lasting depressive phenotype and persistent monoaminergic deficits. Thus, we now assessed the depressive-like behaviour in mice at early and long-term periods following a single high METH dose (30 mg/kg, i.p.). METH did not alter the motor function and procedural memory of mice as assessed by swimming speed and escape latency to find the platform in a cued version of the water maze task. However, METH significantly increased the immobility time in the tail suspension test at 3 and 49 days post-administration. This depressive-like profile induced by METH was accompanied by a marked depletion of frontostriatal dopaminergic and serotonergic neurotransmission, indicated by a reduction in the levels of dopamine, DOPAC and HVA, tyrosine hydroxylase and CHEMICAL, observed at both 3 and 49 days post-administration. In parallel, another neurochemical feature of depression--astroglial dysfunction--was unaffected in the cortex and the striatal levels of the astrocytic protein marker, glial fibrillary acidic protein, were only transiently increased at 3 days. These findings demonstrate for the first time that a single high dose of METH induces long-lasting depressive-like behaviour in mice associated with a persistent disruption of frontostriatal dopaminergic and serotonergic homoeostasis. | NO-RELATIONSHIP |
| A single DISEASE dose of methamphetamine induces a long-lasting depressive-like behaviour in mice. Methamphetamine (METH) triggers a disruption of the monoaminergic system and METH abuse leads to negative emotional states including depressive symptoms during drug withdrawal. However, it is currently unknown if the acute toxic dosage of METH also causes a long-lasting depressive phenotype and persistent monoaminergic deficits. Thus, we now assessed the depressive-like behaviour in mice at early and long-term periods following a single high METH dose (30 mg/kg, i.p.). METH did not alter the motor function and procedural memory of mice as assessed by swimming speed and escape latency to find the platform in a cued version of the water maze task. However, METH significantly increased the immobility time in the tail suspension test at 3 and 49 days post-administration. This depressive-like profile induced by METH was accompanied by a marked depletion of frontostriatal dopaminergic and serotonergic neurotransmission, indicated by a reduction in the levels of dopamine, CHEMICAL and HVA, tyrosine hydroxylase and serotonin, observed at both 3 and 49 days post-administration. In parallel, another neurochemical feature of depression--astroglial dysfunction--was unaffected in the cortex and the striatal levels of the astrocytic protein marker, glial fibrillary acidic protein, were only transiently increased at 3 days. These findings demonstrate for the first time that a single high dose of METH induces long-lasting depressive-like behaviour in mice associated with a persistent disruption of frontostriatal dopaminergic and serotonergic homoeostasis. | NO-RELATIONSHIP |
| A single DISEASE dose of methamphetamine induces a long-lasting depressive-like behaviour in mice. Methamphetamine (METH) triggers a disruption of the monoaminergic system and METH abuse leads to negative emotional states including depressive symptoms during drug withdrawal. However, it is currently unknown if the acute toxic dosage of METH also causes a long-lasting depressive phenotype and persistent monoaminergic deficits. Thus, we now assessed the depressive-like behaviour in mice at early and long-term periods following a single high METH dose (30 mg/kg, i.p.). METH did not alter the motor function and procedural memory of mice as assessed by swimming speed and escape latency to find the platform in a cued version of the water maze task. However, METH significantly increased the immobility time in the tail suspension test at 3 and 49 days post-administration. This depressive-like profile induced by METH was accompanied by a marked depletion of frontostriatal dopaminergic and serotonergic neurotransmission, indicated by a reduction in the levels of CHEMICAL, DOPAC and HVA, tyrosine hydroxylase and serotonin, observed at both 3 and 49 days post-administration. In parallel, another neurochemical feature of depression--astroglial dysfunction--was unaffected in the cortex and the striatal levels of the astrocytic protein marker, glial fibrillary acidic protein, were only transiently increased at 3 days. These findings demonstrate for the first time that a single high dose of METH induces long-lasting depressive-like behaviour in mice associated with a persistent disruption of frontostriatal dopaminergic and serotonergic homoeostasis. | NO-RELATIONSHIP |
| CHEMICAL-induced DISEASE. Many systemic antimicrobials have been implicated to cause ocular adverse effects. This is especially relevant in multidrug therapy where more than one drug can cause a similar ocular adverse effect. We describe a case of progressive loss of vision associated with CHEMICAL therapy. A 45-year-old male patient who was on treatment with multiple second-line anti-tuberculous drugs including CHEMICAL and ethambutol for extensively drug-resistant tuberculosis (XDR-TB) presented to us with painless progressive loss of vision in both eyes. Color vision was defective and fundus examination revealed optic disc edema in both eyes. Ethambutol-induced DISEASE was suspected and tablet ethambutol was withdrawn. Deterioration of vision occurred despite withdrawal of ethambutol. Discontinuation of CHEMICAL resulted in marked improvement of vision. Our report emphasizes the need for monitoring of visual function in patients on long-term CHEMICAL treatment. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced optic neuropathy. Many systemic antimicrobials have been implicated to cause ocular adverse effects. This is especially relevant in multidrug therapy where more than one drug can cause a similar ocular adverse effect. We describe a case of progressive loss of vision associated with CHEMICAL therapy. A 45-year-old male patient who was on treatment with multiple second-line anti-tuberculous drugs including CHEMICAL and ethambutol for extensively drug-resistant tuberculosis (XDR-TB) presented to us with painless progressive loss of vision in both eyes. Color vision was defective and fundus examination revealed DISEASE in both eyes. Ethambutol-induced toxic optic neuropathy was suspected and tablet ethambutol was withdrawn. Deterioration of vision occurred despite withdrawal of ethambutol. Discontinuation of CHEMICAL resulted in marked improvement of vision. Our report emphasizes the need for monitoring of visual function in patients on long-term CHEMICAL treatment. | CHEMICAL-INDUCED-DISEASE |
| Linezolid-induced optic neuropathy. Many systemic antimicrobials have been implicated to cause ocular adverse effects. This is especially relevant in multidrug therapy where more than one drug can cause a similar ocular adverse effect. We describe a case of progressive DISEASE associated with linezolid therapy. A 45-year-old male patient who was on treatment with multiple second-line anti-tuberculous drugs including linezolid and CHEMICAL for extensively drug-resistant tuberculosis (XDR-TB) presented to us with painless progressive DISEASE in both eyes. Color vision was defective and fundus examination revealed optic disc edema in both eyes. CHEMICAL-induced toxic optic neuropathy was suspected and tablet CHEMICAL was withdrawn. Deterioration of vision occurred despite withdrawal of CHEMICAL. Discontinuation of linezolid resulted in marked improvement of vision. Our report emphasizes the need for monitoring of visual function in patients on long-term linezolid treatment. | CHEMICAL-INDUCED-DISEASE |
| Linezolid-induced optic neuropathy. Many systemic antimicrobials have been implicated to cause ocular adverse effects. This is especially relevant in multidrug therapy where more than one drug can cause a similar ocular adverse effect. We describe a case of progressive loss of vision associated with linezolid therapy. A 45-year-old male patient who was on treatment with multiple second-line anti-tuberculous drugs including linezolid and CHEMICAL for DISEASE (DISEASE) presented to us with painless progressive loss of vision in both eyes. Color vision was defective and fundus examination revealed optic disc edema in both eyes. CHEMICAL-induced toxic optic neuropathy was suspected and tablet CHEMICAL was withdrawn. Deterioration of vision occurred despite withdrawal of CHEMICAL. Discontinuation of linezolid resulted in marked improvement of vision. Our report emphasizes the need for monitoring of visual function in patients on long-term linezolid treatment. | NO-RELATIONSHIP |
| Linezolid-induced optic neuropathy. Many systemic antimicrobials have been implicated to cause ocular adverse effects. This is especially relevant in multidrug therapy where more than one drug can cause a similar ocular adverse effect. We describe a case of progressive loss of vision associated with linezolid therapy. A 45-year-old male patient who was on treatment with multiple second-line anti-tuberculous drugs including linezolid and CHEMICAL for extensively drug-resistant tuberculosis (XDR-TB) presented to us with painless progressive loss of vision in both eyes. Color vision was defective and fundus examination revealed optic disc edema in both eyes. CHEMICAL-induced toxic optic neuropathy was suspected and tablet CHEMICAL was withdrawn. DISEASE occurred despite withdrawal of CHEMICAL. Discontinuation of linezolid resulted in marked improvement of vision. Our report emphasizes the need for monitoring of visual function in patients on long-term linezolid treatment. | CHEMICAL-INDUCED-DISEASE |
| Resuscitation with lipid, epinephrine, or both in CHEMICAL-induced cardiac toxicity in newborn piglets. BACKGROUND: The optimal dosing regimens of lipid emulsion, epinephrine, or both are not yet determined in neonates in cases of local anaesthetic systemic toxicity (LAST). METHODS: Newborn piglets received CHEMICAL until DISEASE occurred. Standard cardiopulmonary resuscitation was started and electrocardiogram (ECG) was monitored for ventricular tachycardia, fibrillation, or QRS prolongation. Piglets were then randomly allocated to four groups: control (saline), Intralipid( ) alone, epinephrine alone, or a combination of Intralipd plus epinephrine. Resuscitation continued for 30 min or until there was a return of spontaneous circulation (ROSC) accompanied by a mean arterial pressure at or superior to the baseline pressure and normal sinus rhythm for a period of 30 min. RESULTS: ROSC was achieved in only one of the control piglets compared with most of the treated piglets. Mortality was not significantly different between the three treatment groups, but was significantly lower in all the treatment groups compared with control. The number of ECG abnormalities was zero in the Intralipid only group, but 14 and 17, respectively, in the epinephrine and epinephrine plus lipid groups (P<0.05). CONCLUSIONS: Lipid emulsion with or without epinephrine, or epinephrine alone were equally effective in achieving a return to spontaneous circulation in this model of LAST. Epinephrine alone or in combination with lipid was associated with an increased number of ECG abnormalities compared with lipid emulsion alone. | CHEMICAL-INDUCED-DISEASE |
| Resuscitation with lipid, CHEMICAL, or both in levobupivacaine-induced cardiac toxicity in newborn piglets. BACKGROUND: The optimal dosing regimens of lipid emulsion, CHEMICAL, or both are not yet determined in neonates in cases of local anaesthetic systemic toxicity (LAST). METHODS: Newborn piglets received levobupivacaine until cardiovascular collapse occurred. Standard cardiopulmonary resuscitation was started and electrocardiogram (ECG) was monitored for ventricular tachycardia, DISEASE, or QRS prolongation. Piglets were then randomly allocated to four groups: control (saline), Intralipid( ) alone, CHEMICAL alone, or a combination of Intralipd plus CHEMICAL. Resuscitation continued for 30 min or until there was a return of spontaneous circulation (ROSC) accompanied by a mean arterial pressure at or superior to the baseline pressure and normal sinus rhythm for a period of 30 min. RESULTS: ROSC was achieved in only one of the control piglets compared with most of the treated piglets. Mortality was not significantly different between the three treatment groups, but was significantly lower in all the treatment groups compared with control. The number of ECG abnormalities was zero in the Intralipid only group, but 14 and 17, respectively, in the CHEMICAL and CHEMICAL plus lipid groups (P<0.05). CONCLUSIONS: Lipid emulsion with or without CHEMICAL, or CHEMICAL alone were equally effective in achieving a return to spontaneous circulation in this model of LAST. CHEMICAL alone or in combination with lipid was associated with an increased number of ECG abnormalities compared with lipid emulsion alone. | NO-RELATIONSHIP |
| Resuscitation with lipid, CHEMICAL, or both in levobupivacaine-induced cardiac toxicity in newborn piglets. BACKGROUND: The optimal dosing regimens of lipid emulsion, CHEMICAL, or both are not yet determined in neonates in cases of local anaesthetic systemic toxicity (LAST). METHODS: Newborn piglets received levobupivacaine until cardiovascular collapse occurred. Standard cardiopulmonary resuscitation was started and electrocardiogram (ECG) was monitored for DISEASE, fibrillation, or QRS prolongation. Piglets were then randomly allocated to four groups: control (saline), Intralipid( ) alone, CHEMICAL alone, or a combination of Intralipd plus CHEMICAL. Resuscitation continued for 30 min or until there was a return of spontaneous circulation (ROSC) accompanied by a mean arterial pressure at or superior to the baseline pressure and normal sinus rhythm for a period of 30 min. RESULTS: ROSC was achieved in only one of the control piglets compared with most of the treated piglets. Mortality was not significantly different between the three treatment groups, but was significantly lower in all the treatment groups compared with control. The number of ECG abnormalities was zero in the Intralipid only group, but 14 and 17, respectively, in the CHEMICAL and CHEMICAL plus lipid groups (P<0.05). CONCLUSIONS: Lipid emulsion with or without CHEMICAL, or CHEMICAL alone were equally effective in achieving a return to spontaneous circulation in this model of LAST. CHEMICAL alone or in combination with lipid was associated with an increased number of ECG abnormalities compared with lipid emulsion alone. | NO-RELATIONSHIP |
| Resuscitation with lipid, CHEMICAL, or both in levobupivacaine-induced DISEASE in newborn piglets. BACKGROUND: The optimal dosing regimens of lipid emulsion, CHEMICAL, or both are not yet determined in neonates in cases of local anaesthetic systemic toxicity (LAST). METHODS: Newborn piglets received levobupivacaine until cardiovascular collapse occurred. Standard cardiopulmonary resuscitation was started and electrocardiogram (ECG) was monitored for ventricular tachycardia, fibrillation, or QRS prolongation. Piglets were then randomly allocated to four groups: control (saline), Intralipid( ) alone, CHEMICAL alone, or a combination of Intralipd plus CHEMICAL. Resuscitation continued for 30 min or until there was a return of spontaneous circulation (ROSC) accompanied by a mean arterial pressure at or superior to the baseline pressure and normal sinus rhythm for a period of 30 min. RESULTS: ROSC was achieved in only one of the control piglets compared with most of the treated piglets. Mortality was not significantly different between the three treatment groups, but was significantly lower in all the treatment groups compared with control. The number of ECG abnormalities was zero in the Intralipid only group, but 14 and 17, respectively, in the CHEMICAL and CHEMICAL plus lipid groups (P<0.05). CONCLUSIONS: Lipid emulsion with or without CHEMICAL, or CHEMICAL alone were equally effective in achieving a return to spontaneous circulation in this model of LAST. CHEMICAL alone or in combination with lipid was associated with an increased number of ECG abnormalities compared with lipid emulsion alone. | NO-RELATIONSHIP |
| Resuscitation with lipid, CHEMICAL, or both in levobupivacaine-induced cardiac toxicity in newborn piglets. BACKGROUND: The optimal dosing regimens of lipid emulsion, CHEMICAL, or both are not yet determined in neonates in cases of local anaesthetic systemic DISEASE (LAST). METHODS: Newborn piglets received levobupivacaine until cardiovascular collapse occurred. Standard cardiopulmonary resuscitation was started and electrocardiogram (ECG) was monitored for ventricular tachycardia, fibrillation, or QRS prolongation. Piglets were then randomly allocated to four groups: control (saline), Intralipid( ) alone, CHEMICAL alone, or a combination of Intralipd plus CHEMICAL. Resuscitation continued for 30 min or until there was a return of spontaneous circulation (ROSC) accompanied by a mean arterial pressure at or superior to the baseline pressure and normal sinus rhythm for a period of 30 min. RESULTS: ROSC was achieved in only one of the control piglets compared with most of the treated piglets. Mortality was not significantly different between the three treatment groups, but was significantly lower in all the treatment groups compared with control. The number of ECG abnormalities was zero in the Intralipid only group, but 14 and 17, respectively, in the CHEMICAL and CHEMICAL plus lipid groups (P<0.05). CONCLUSIONS: Lipid emulsion with or without CHEMICAL, or CHEMICAL alone were equally effective in achieving a return to spontaneous circulation in this model of LAST. CHEMICAL alone or in combination with lipid was associated with an increased number of ECG abnormalities compared with lipid emulsion alone. | NO-RELATIONSHIP |
| Incidence of CHEMICAL-induced DISEASE and postoperative recovery of platelet count in liver graft recipients: a retrospective cohort analysis. BACKGROUND: DISEASE in patients with end-stage liver disease is a common disorder caused mainly by portal hypertension, low levels of thrombopoetin, and endotoxemia. The impact of immune-mediated CHEMICAL-induced DISEASE (DISEASE) as a cause of DISEASE after liver transplantation is not yet understood, with few literature citations reporting contradictory results. The aim of our study was to demonstrate the perioperative course of DISEASE after liver transplantation and determine the occurrence of clinical DISEASE. METHOD: We retrospectively evaluated the medical records of 205 consecutive adult patients who underwent full-size liver transplantation between January 2006 and December 2010 due to end-stage or malignant liver disease. Preoperative platelet count, postoperative course of platelets, and clinical signs of DISEASE were analyzed. RESULTS: A total of 155 (75.6%) of 205 patients had DISEASE before transplantation, significantly influenced by Model of End-Stage Liver Disease score and liver cirrhosis. The platelet count exceeded 100,000/uL in most of the patients (n = 193) at a medium of 7 d. Regarding DISEASE, there were four (1.95%) patients with a background of DISEASE. CONCLUSIONS: The incidence of DISEASE in patients with end-stage hepatic failure is, with about 1.95%, rare. For further reduction of DISEASE, the use of intravenous CHEMICAL should be avoided and the prophylactic anticoagulation should be performed with low-molecular-weight CHEMICAL after normalization of platelet count. | CHEMICAL-INDUCED-DISEASE |
| Takotsubo syndrome (or apical ballooning syndrome) secondary to CHEMICAL. Takotsubo syndrome (TS), also known as broken heart syndrome, is characterized by left ventricle apical ballooning with elevated cardiac biomarkers and electrocardiographic changes suggestive of an acute coronary syndrome (ie, ST-segment elevation, T wave inversions, and pathologic Q waves). We report a case of 54-year-old woman with medical history of mitral valve prolapse and migraines, who was admitted to the hospital for substernal chest pain and electrocardiogram demonstrated 1/2 mm ST-segment elevation in leads II, III, aVF, V5, and V6 and positive troponin I. Emergent coronary angiogram revealed normal coronary arteries with moderately reduced left ventricular ejection fraction with wall motion abnormalities consistent with TS. Detailed history obtained retrospectively revealed that the patient took CHEMICAL sparingly only when she had migraines. But before this event, she was taking CHEMICAL 2-3 times daily for several days because of a persistent migraine headache. She otherwise reported that she is quite active, rides horses, and does show jumping without any limitations in her physical activity. There was no evidence of any recent stress or status migrainosus. Extensive literature search revealed multiple cases of DISEASE secondary to CHEMICAL, but none of the cases were associated with TS. | CHEMICAL-INDUCED-DISEASE |
| DISEASE (or DISEASE) secondary to CHEMICAL. DISEASE (DISEASE), also known as DISEASE, is characterized by left ventricle apical ballooning with elevated cardiac biomarkers and electrocardiographic changes suggestive of an acute coronary syndrome (ie, ST-segment elevation, T wave inversions, and pathologic Q waves). We report a case of 54-year-old woman with medical history of mitral valve prolapse and migraines, who was admitted to the hospital for substernal chest pain and electrocardiogram demonstrated 1/2 mm ST-segment elevation in leads II, III, aVF, V5, and V6 and positive troponin I. Emergent coronary angiogram revealed normal coronary arteries with moderately reduced left ventricular ejection fraction with wall motion abnormalities consistent with DISEASE. Detailed history obtained retrospectively revealed that the patient took CHEMICAL sparingly only when she had migraines. But before this event, she was taking CHEMICAL 2-3 times daily for several days because of a persistent migraine headache. She otherwise reported that she is quite active, rides horses, and does show jumping without any limitations in her physical activity. There was no evidence of any recent stress or status migrainosus. Extensive literature search revealed multiple cases of coronary artery vasospasm secondary to CHEMICAL, but none of the cases were associated with DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Depression, impulsiveness, sleep, and memory in past and present polydrug users of CHEMICAL (CHEMICAL, CHEMICAL). RATIONALE: CHEMICAL (CHEMICAL, CHEMICAL) is a worldwide recreational drug of abuse. Unfortunately, the results from human research investigating its psychological effects have been inconsistent. OBJECTIVES: The present study aimed to be the largest to date in sample size and 5HT-related behaviors; the first to compare present CHEMICAL users with past users after an abstinence of 4 or more years, and the first to include robust controls for other recreational substances. METHODS: A sample of 997 participants (52 % male) was recruited to four control groups (non-drug (ND), alcohol/nicotine (AN), cannabis/alcohol/nicotine (CAN), non-CHEMICAL polydrug (PD)), and two CHEMICAL polydrug groups (present (CHEMICAL) and past users (EX-CHEMICAL). Participants completed a drug history questionnaire, Beck Depression Inventory, Barratt Impulsiveness Scale, Pittsburgh Sleep Quality Index, and Wechsler Memory Scale-Revised which, in total, provided 13 psychometric measures. RESULTS: While the CAN and PD groups tended to record greater deficits than the non-drug controls, the CHEMICAL and EX-CHEMICAL groups recorded greater deficits than all the control groups on ten of the 13 psychometric measures. Strikingly, despite prolonged abstinence (mean, 4.98; range, 4-9 years), past CHEMICAL users showed few signs of recovery. Compared with present CHEMICAL users, the past users showed no change for ten measures, increased impairment for two measures, and improvement on just one measure. CONCLUSIONS: Given this record of impaired memory and clinically significant levels of depression, impulsiveness, and DISEASE, the prognosis for the current generation of CHEMICAL users is a major cause for concern. | CHEMICAL-INDUCED-DISEASE |
| Depression, DISEASE, sleep, and memory in past and present polydrug users of CHEMICAL (CHEMICAL, CHEMICAL). RATIONALE: CHEMICAL (CHEMICAL, CHEMICAL) is a worldwide recreational drug of abuse. Unfortunately, the results from human research investigating its psychological effects have been inconsistent. OBJECTIVES: The present study aimed to be the largest to date in sample size and 5HT-related behaviors; the first to compare present CHEMICAL users with past users after an abstinence of 4 or more years, and the first to include robust controls for other recreational substances. METHODS: A sample of 997 participants (52 % male) was recruited to four control groups (non-drug (ND), alcohol/nicotine (AN), cannabis/alcohol/nicotine (CAN), non-CHEMICAL polydrug (PD)), and two CHEMICAL polydrug groups (present (CHEMICAL) and past users (EX-CHEMICAL). Participants completed a drug history questionnaire, Beck Depression Inventory, Barratt DISEASE Scale, Pittsburgh Sleep Quality Index, and Wechsler Memory Scale-Revised which, in total, provided 13 psychometric measures. RESULTS: While the CAN and PD groups tended to record greater deficits than the non-drug controls, the CHEMICAL and EX-CHEMICAL groups recorded greater deficits than all the control groups on ten of the 13 psychometric measures. Strikingly, despite prolonged abstinence (mean, 4.98; range, 4-9 years), past CHEMICAL users showed few signs of recovery. Compared with present CHEMICAL users, the past users showed no change for ten measures, increased impairment for two measures, and improvement on just one measure. CONCLUSIONS: Given this record of impaired memory and clinically significant levels of depression, DISEASE, and sleep disturbance, the prognosis for the current generation of CHEMICAL users is a major cause for concern. | CHEMICAL-INDUCED-DISEASE |
| DISEASE, impulsiveness, sleep, and memory in past and present polydrug users of CHEMICAL (CHEMICAL, CHEMICAL). RATIONALE: CHEMICAL (CHEMICAL, CHEMICAL) is a worldwide recreational drug of abuse. Unfortunately, the results from human research investigating its psychological effects have been inconsistent. OBJECTIVES: The present study aimed to be the largest to date in sample size and 5HT-related behaviors; the first to compare present CHEMICAL users with past users after an abstinence of 4 or more years, and the first to include robust controls for other recreational substances. METHODS: A sample of 997 participants (52 % male) was recruited to four control groups (non-drug (ND), alcohol/nicotine (AN), cannabis/alcohol/nicotine (CAN), non-CHEMICAL polydrug (PD)), and two CHEMICAL polydrug groups (present (CHEMICAL) and past users (EX-CHEMICAL). Participants completed a drug history questionnaire, Beck DISEASE Inventory, Barratt Impulsiveness Scale, Pittsburgh Sleep Quality Index, and Wechsler Memory Scale-Revised which, in total, provided 13 psychometric measures. RESULTS: While the CAN and PD groups tended to record greater deficits than the non-drug controls, the CHEMICAL and EX-CHEMICAL groups recorded greater deficits than all the control groups on ten of the 13 psychometric measures. Strikingly, despite prolonged abstinence (mean, 4.98; range, 4-9 years), past CHEMICAL users showed few signs of recovery. Compared with present CHEMICAL users, the past users showed no change for ten measures, increased impairment for two measures, and improvement on just one measure. CONCLUSIONS: Given this record of impaired memory and clinically significant levels of DISEASE, impulsiveness, and sleep disturbance, the prognosis for the current generation of CHEMICAL users is a major cause for concern. | CHEMICAL-INDUCED-DISEASE |
| Depression, impulsiveness, sleep, and memory in past and present polydrug users of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). RATIONALE: Ecstasy (3,4-methylenedioxymethamphetamine, MDMA) is a worldwide recreational drug of abuse. Unfortunately, the results from human research investigating its psychological effects have been inconsistent. OBJECTIVES: The present study aimed to be the largest to date in sample size and 5HT-related behaviors; the first to compare present ecstasy users with past users after an abstinence of 4 or more years, and the first to include robust controls for other recreational substances. METHODS: A sample of 997 participants (52 % male) was recruited to four control groups (non-drug (ND), alcohol/nicotine (CHEMICAL), cannabis/alcohol/nicotine (CAN), non-ecstasy polydrug (PD)), and two ecstasy polydrug groups (present (MDMA) and past users (EX-MDMA). Participants completed a drug history questionnaire, Beck Depression Inventory, Barratt Impulsiveness Scale, Pittsburgh Sleep Quality Index, and Wechsler Memory Scale-Revised which, in total, provided 13 psychometric measures. RESULTS: While the CAN and PD groups tended to record greater deficits than the non-drug controls, the MDMA and EX-MDMA groups recorded greater deficits than all the control groups on ten of the 13 psychometric measures. Strikingly, despite prolonged abstinence (mean, 4.98; range, 4-9 years), past ecstasy users showed few signs of recovery. Compared with present ecstasy users, the past users showed no change for ten measures, increased impairment for two measures, and improvement on just one measure. CONCLUSIONS: Given this record of DISEASE and clinically significant levels of depression, impulsiveness, and sleep disturbance, the prognosis for the current generation of ecstasy users is a major cause for concern. | NO-RELATIONSHIP |
| Depression, impulsiveness, sleep, and memory in past and present polydrug users of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). RATIONALE: Ecstasy (3,4-methylenedioxymethamphetamine, MDMA) is a worldwide recreational drug of abuse. Unfortunately, the results from human research investigating its psychological effects have been inconsistent. OBJECTIVES: The present study aimed to be the largest to date in sample size and 5HT-related behaviors; the first to compare present ecstasy users with past users after an abstinence of 4 or more years, and the first to include robust controls for other recreational substances. METHODS: A sample of 997 participants (52 % male) was recruited to four control groups (non-drug (ND), alcohol/nicotine (AN), CHEMICAL/alcohol/nicotine (CAN), non-ecstasy polydrug (PD)), and two ecstasy polydrug groups (present (MDMA) and past users (EX-MDMA). Participants completed a drug history questionnaire, Beck Depression Inventory, Barratt Impulsiveness Scale, Pittsburgh Sleep Quality Index, and Wechsler Memory Scale-Revised which, in total, provided 13 psychometric measures. RESULTS: While the CAN and PD groups tended to record greater deficits than the non-drug controls, the MDMA and EX-MDMA groups recorded greater deficits than all the control groups on ten of the 13 psychometric measures. Strikingly, despite prolonged abstinence (mean, 4.98; range, 4-9 years), past ecstasy users showed few signs of recovery. Compared with present ecstasy users, the past users showed no change for ten measures, increased impairment for two measures, and improvement on just one measure. CONCLUSIONS: Given this record of DISEASE and clinically significant levels of depression, impulsiveness, and sleep disturbance, the prognosis for the current generation of ecstasy users is a major cause for concern. | NO-RELATIONSHIP |
| Depression, impulsiveness, sleep, and memory in past and present polydrug users of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). RATIONALE: Ecstasy (3,4-methylenedioxymethamphetamine, MDMA) is a worldwide recreational drug of abuse. Unfortunately, the results from human research investigating its psychological effects have been inconsistent. OBJECTIVES: The present study aimed to be the largest to date in sample size and 5HT-related behaviors; the first to compare present ecstasy users with past users after an abstinence of 4 or more years, and the first to include robust controls for other recreational substances. METHODS: A sample of 997 participants (52 % male) was recruited to four control groups (non-drug (ND), CHEMICAL/nicotine (AN), cannabis/CHEMICAL/nicotine (CAN), non-ecstasy polydrug (PD)), and two ecstasy polydrug groups (present (MDMA) and past users (EX-MDMA). Participants completed a drug history questionnaire, Beck Depression Inventory, Barratt Impulsiveness Scale, Pittsburgh Sleep Quality Index, and Wechsler Memory Scale-Revised which, in total, provided 13 psychometric measures. RESULTS: While the CAN and PD groups tended to record greater deficits than the non-drug controls, the MDMA and EX-MDMA groups recorded greater deficits than all the control groups on ten of the 13 psychometric measures. Strikingly, despite prolonged abstinence (mean, 4.98; range, 4-9 years), past ecstasy users showed few signs of recovery. Compared with present ecstasy users, the past users showed no change for ten measures, increased impairment for two measures, and improvement on just one measure. CONCLUSIONS: Given this record of DISEASE and clinically significant levels of depression, impulsiveness, and sleep disturbance, the prognosis for the current generation of ecstasy users is a major cause for concern. | NO-RELATIONSHIP |
| Depression, impulsiveness, sleep, and memory in past and present polydrug users of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). RATIONALE: Ecstasy (3,4-methylenedioxymethamphetamine, MDMA) is a worldwide recreational drug of abuse. Unfortunately, the results from human research investigating its psychological effects have been inconsistent. OBJECTIVES: The present study aimed to be the largest to date in sample size and 5HT-related behaviors; the first to compare present ecstasy users with past users after an abstinence of 4 or more years, and the first to include robust controls for other recreational substances. METHODS: A sample of 997 participants (52 % male) was recruited to four control groups (non-drug (ND), alcohol/CHEMICAL (AN), cannabis/alcohol/CHEMICAL (CAN), non-ecstasy polydrug (PD)), and two ecstasy polydrug groups (present (MDMA) and past users (EX-MDMA). Participants completed a drug history questionnaire, Beck Depression Inventory, Barratt Impulsiveness Scale, Pittsburgh Sleep Quality Index, and Wechsler Memory Scale-Revised which, in total, provided 13 psychometric measures. RESULTS: While the CAN and PD groups tended to record greater deficits than the non-drug controls, the MDMA and EX-MDMA groups recorded greater deficits than all the control groups on ten of the 13 psychometric measures. Strikingly, despite prolonged abstinence (mean, 4.98; range, 4-9 years), past ecstasy users showed few signs of recovery. Compared with present ecstasy users, the past users showed no change for ten measures, increased impairment for two measures, and improvement on just one measure. CONCLUSIONS: Given this record of DISEASE and clinically significant levels of depression, impulsiveness, and sleep disturbance, the prognosis for the current generation of ecstasy users is a major cause for concern. | NO-RELATIONSHIP |
| Depression, impulsiveness, sleep, and memory in past and present polydrug users of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). RATIONALE: Ecstasy (3,4-methylenedioxymethamphetamine, MDMA) is a worldwide recreational drug of abuse. Unfortunately, the results from human research investigating its psychological effects have been inconsistent. OBJECTIVES: The present study aimed to be the largest to date in sample size and 5HT-related behaviors; the first to compare present ecstasy users with past users after an abstinence of 4 or more years, and the first to include robust controls for other recreational substances. METHODS: A sample of 997 participants (52 % male) was recruited to four control groups (non-drug (ND), alcohol/nicotine (AN), cannabis/alcohol/nicotine (CHEMICAL), non-ecstasy polydrug (PD)), and two ecstasy polydrug groups (present (MDMA) and past users (EX-MDMA). Participants completed a drug history questionnaire, Beck Depression Inventory, Barratt Impulsiveness Scale, Pittsburgh Sleep Quality Index, and Wechsler Memory Scale-Revised which, in total, provided 13 psychometric measures. RESULTS: While the CHEMICAL and PD groups tended to record greater deficits than the non-drug controls, the MDMA and EX-MDMA groups recorded greater deficits than all the control groups on ten of the 13 psychometric measures. Strikingly, despite prolonged abstinence (mean, 4.98; range, 4-9 years), past ecstasy users showed few signs of recovery. Compared with present ecstasy users, the past users showed no change for ten measures, increased impairment for two measures, and improvement on just one measure. CONCLUSIONS: Given this record of DISEASE and clinically significant levels of depression, impulsiveness, and sleep disturbance, the prognosis for the current generation of ecstasy users is a major cause for concern. | NO-RELATIONSHIP |
| Association of common genetic variants of HOMER1 gene with CHEMICAL adverse effects in Parkinson's disease patients. CHEMICAL is the most effective symptomatic therapy for Parkinson's disease, but its chronic use could lead to chronic adverse outcomes, such as motor fluctuations, dyskinesia and DISEASE. HOMER1 is a protein with pivotal function in glutamate transmission, which has been related to the pathogenesis of these complications. This study investigates whether polymorphisms in the HOMER1 gene promoter region are associated with the occurrence of the chronic complications of CHEMICAL therapy. A total of 205 patients with idiopathic Parkinson's disease were investigated. Patients were genotyped for rs4704559, rs10942891 and rs4704560 by allelic discrimination with Taqman assays. The rs4704559 G allele was associated with a lower prevalence of dyskinesia (prevalence ratio (PR)=0.615, 95% confidence interval (CI) 0.426-0.887, P=0.009) and DISEASE (PR=0.515, 95% CI 0.295-0.899, P=0.020). Our data suggest that HOMER1 rs4704559 G allele has a protective role for the development of CHEMICAL adverse effects. | CHEMICAL-INDUCED-DISEASE |
| Association of common genetic variants of HOMER1 gene with CHEMICAL adverse effects in Parkinson's disease patients. CHEMICAL is the most effective symptomatic therapy for Parkinson's disease, but its chronic use could lead to chronic adverse outcomes, such as motor fluctuations, DISEASE and visual hallucinations. HOMER1 is a protein with pivotal function in glutamate transmission, which has been related to the pathogenesis of these complications. This study investigates whether polymorphisms in the HOMER1 gene promoter region are associated with the occurrence of the chronic complications of CHEMICAL therapy. A total of 205 patients with idiopathic Parkinson's disease were investigated. Patients were genotyped for rs4704559, rs10942891 and rs4704560 by allelic discrimination with Taqman assays. The rs4704559 G allele was associated with a lower prevalence of DISEASE (prevalence ratio (PR)=0.615, 95% confidence interval (CI) 0.426-0.887, P=0.009) and visual hallucinations (PR=0.515, 95% CI 0.295-0.899, P=0.020). Our data suggest that HOMER1 rs4704559 G allele has a protective role for the development of CHEMICAL adverse effects. | CHEMICAL-INDUCED-DISEASE |
| Association of common genetic variants of HOMER1 gene with levodopa adverse effects in DISEASE patients. Levodopa is the most effective symptomatic therapy for DISEASE, but its chronic use could lead to chronic adverse outcomes, such as motor fluctuations, dyskinesia and visual hallucinations. HOMER1 is a protein with pivotal function in CHEMICAL transmission, which has been related to the pathogenesis of these complications. This study investigates whether polymorphisms in the HOMER1 gene promoter region are associated with the occurrence of the chronic complications of levodopa therapy. A total of 205 patients with DISEASE were investigated. Patients were genotyped for rs4704559, rs10942891 and rs4704560 by allelic discrimination with Taqman assays. The rs4704559 G allele was associated with a lower prevalence of dyskinesia (prevalence ratio (PR)=0.615, 95% confidence interval (CI) 0.426-0.887, P=0.009) and visual hallucinations (PR=0.515, 95% CI 0.295-0.899, P=0.020). Our data suggest that HOMER1 rs4704559 G allele has a protective role for the development of levodopa adverse effects. | NO-RELATIONSHIP |
| Crocin improves lipid dysregulation in subacute CHEMICAL exposure through ERK1/2 pathway in rat liver. INTRODUCTION: CHEMICAL Yis one of the most broadly used organophosphorus insecticides in agriculture. It has been shown that exposure to CHEMICAL may interfere with lipid metabolism. Moreover, the hypolipidemic effect of crocin has been established. Earlier studies revealed the major role of Extracellular signal-regulated kinase (ERK) pathways in low-density lipoprotein receptor (LDLr) expression. The aim of this study was to evaluate changes in the regulation of lipid metabolism, ERK and LDLr expression in the liver of rats exposed to subacute CHEMICAL. Furthermore ameliorating effect of crocin on CHEMICAL induced disturbed cholesterol homeostasis was studied. METHODS: 24 Rats were divided into 4 groups and received following treatments for 4 weeks; Corn oil (control), CHEMICAL (15mg/kg per day, orally) and crocin (12.5 and 25mg/kg per day, intraperitoneally) in combination with CHEMICAL (15 mg/kg). The levels of cholesterol, triglyceride and LDL in blood of rats were analyzed. Moreover mRNA levels of LDLr and ERK1/2 as well as protein levels of total and activated forms of ERK1/2 in rat liver were evaluated by Western blotting and quantitative real time polymerase chain reaction analysis. RESULTS: Our data showed that subacute exposure to CHEMICAL significantly increased concentrations of cholesterol, triglyceride and LDL. Moreover CHEMICAL decreased ERK1/2 protein phosphorylation and LDLr transcript. Crocin reduced inhibition of ERK activation and CHEMICAL-induced DISEASE and increased levels of LDLr transcript. CONCLUSIONS: Crocin may be considered as a novel protective agent in CHEMICAL-induced DISEASE through modulating of ERK pathway and increase of LDLr expression. | CHEMICAL-INDUCED-DISEASE |
| GEM-P chemotherapy is active in the treatment of relapsed Hodgkin lymphoma. Hodgkin lymphoma (HL) is a relatively chemosensitive malignancy. However, for those who relapse, high-dose chemotherapy with autologous stem cell transplant is the treatment of choice which relies on adequate disease control with salvage chemotherapy. Regimens commonly used often require inpatient administration and can be difficult to deliver due to toxicity. Gemcitabine and cisplatin have activity in HL, non-overlapping toxicity with first-line chemotherapeutics, and may be delivered in an outpatient setting. In this retrospective single-centre analysis, patients with relapsed or refractory HL treated with gemcitabine 1,000 mg/m(2) day (D)1, D8 and D15; CHEMICAL 1,000 mg D1-5; and cisplatin 100 mg/m(2) D15, every 28 days (GEM-P) were included. Demographic, survival, response and toxicity data were recorded. Forty-one eligible patients were identified: median age 27. One hundred and twenty-two cycles of GEM-P were administered in total (median 3 cycles; range 1-6). Twenty of 41 (48 %) patients received GEM-P as second-line treatment and 11/41 (27 %) as third-line therapy. Overall response rate (ORR) to GEM-P in the entire cohort was 80 % (complete response (CR) 37 %, partial response 44 %) with 14/15 CR confirmed as a metabolic CR on PET and ORR of 85 % in the 20 second-line patients. The most common grade 3/4 toxicities were haematological: DISEASE 54 % and thrombocytopenia 51 %. Median follow-up from the start of GEM-P was 4.5 years. Following GEM-P, 5-year progression-free survival was 46 % (95 % confidence interval (CI), 30-62 %) and 5-year overall survival was 59 % (95 % CI, 43-74 %). Fourteen of 41 patients proceeded directly to autologous transplant. GEM-P is a salvage chemotherapy with relatively high response rates, leading to successful transplantation in appropriate patients, in the treatment of relapsed or refractory HL. | NO-RELATIONSHIP |
| CHEMICAL-P chemotherapy is active in the treatment of relapsed Hodgkin lymphoma. Hodgkin lymphoma (HL) is a relatively chemosensitive malignancy. However, for those who relapse, high-dose chemotherapy with autologous stem cell transplant is the treatment of choice which relies on adequate disease control with salvage chemotherapy. Regimens commonly used often require inpatient administration and can be difficult to deliver due to toxicity. CHEMICAL and cisplatin have activity in HL, non-overlapping toxicity with first-line chemotherapeutics, and may be delivered in an outpatient setting. In this retrospective single-centre analysis, patients with relapsed or refractory HL treated with CHEMICAL 1,000 mg/m(2) day (D)1, D8 and D15; methylprednisolone 1,000 mg D1-5; and cisplatin 100 mg/m(2) D15, every 28 days (CHEMICAL-P) were included. Demographic, survival, response and toxicity data were recorded. Forty-one eligible patients were identified: median age 27. One hundred and twenty-two cycles of CHEMICAL-P were administered in total (median 3 cycles; range 1-6). Twenty of 41 (48 %) patients received CHEMICAL-P as second-line treatment and 11/41 (27 %) as third-line therapy. Overall response rate (ORR) to CHEMICAL-P in the entire cohort was 80 % (complete response (CR) 37 %, partial response 44 %) with 14/15 CR confirmed as a metabolic CR on PET and ORR of 85 % in the 20 second-line patients. The most common grade 3/4 toxicities were haematological: neutropenia 54 % and DISEASE 51 %. Median follow-up from the start of CHEMICAL-P was 4.5 years. Following CHEMICAL-P, 5-year progression-free survival was 46 % (95 % confidence interval (CI), 30-62 %) and 5-year overall survival was 59 % (95 % CI, 43-74 %). Fourteen of 41 patients proceeded directly to autologous transplant. CHEMICAL-P is a salvage chemotherapy with relatively high response rates, leading to successful transplantation in appropriate patients, in the treatment of relapsed or refractory HL. | CHEMICAL-INDUCED-DISEASE |
| GEM-P chemotherapy is active in the treatment of relapsed Hodgkin lymphoma. Hodgkin lymphoma (HL) is a relatively chemosensitive malignancy. However, for those who relapse, high-dose chemotherapy with autologous stem cell transplant is the treatment of choice which relies on adequate disease control with salvage chemotherapy. Regimens commonly used often require inpatient administration and can be difficult to deliver due to toxicity. Gemcitabine and cisplatin have activity in HL, non-overlapping toxicity with first-line chemotherapeutics, and may be delivered in an outpatient setting. In this retrospective single-centre analysis, patients with relapsed or refractory HL treated with gemcitabine 1,000 mg/m(2) day (D)1, D8 and D15; CHEMICAL 1,000 mg D1-5; and cisplatin 100 mg/m(2) D15, every 28 days (GEM-P) were included. Demographic, survival, response and toxicity data were recorded. Forty-one eligible patients were identified: median age 27. One hundred and twenty-two cycles of GEM-P were administered in total (median 3 cycles; range 1-6). Twenty of 41 (48 %) patients received GEM-P as second-line treatment and 11/41 (27 %) as third-line therapy. Overall response rate (ORR) to GEM-P in the entire cohort was 80 % (complete response (CR) 37 %, partial response 44 %) with 14/15 CR confirmed as a metabolic CR on PET and ORR of 85 % in the 20 second-line patients. The most common grade 3/4 toxicities were haematological: neutropenia 54 % and DISEASE 51 %. Median follow-up from the start of GEM-P was 4.5 years. Following GEM-P, 5-year progression-free survival was 46 % (95 % confidence interval (CI), 30-62 %) and 5-year overall survival was 59 % (95 % CI, 43-74 %). Fourteen of 41 patients proceeded directly to autologous transplant. GEM-P is a salvage chemotherapy with relatively high response rates, leading to successful transplantation in appropriate patients, in the treatment of relapsed or refractory HL. | NO-RELATIONSHIP |
| CHEMICAL-P chemotherapy is active in the treatment of relapsed Hodgkin lymphoma. Hodgkin lymphoma (HL) is a relatively chemosensitive malignancy. However, for those who relapse, high-dose chemotherapy with autologous stem cell transplant is the treatment of choice which relies on adequate disease control with salvage chemotherapy. Regimens commonly used often require inpatient administration and can be difficult to deliver due to toxicity. CHEMICAL and cisplatin have activity in HL, non-overlapping toxicity with first-line chemotherapeutics, and may be delivered in an outpatient setting. In this retrospective single-centre analysis, patients with relapsed or refractory HL treated with CHEMICAL 1,000 mg/m(2) day (D)1, D8 and D15; methylprednisolone 1,000 mg D1-5; and cisplatin 100 mg/m(2) D15, every 28 days (CHEMICAL-P) were included. Demographic, survival, response and toxicity data were recorded. Forty-one eligible patients were identified: median age 27. One hundred and twenty-two cycles of CHEMICAL-P were administered in total (median 3 cycles; range 1-6). Twenty of 41 (48 %) patients received CHEMICAL-P as second-line treatment and 11/41 (27 %) as third-line therapy. Overall response rate (ORR) to CHEMICAL-P in the entire cohort was 80 % (complete response (CR) 37 %, partial response 44 %) with 14/15 CR confirmed as a metabolic CR on PET and ORR of 85 % in the 20 second-line patients. The most common grade 3/4 toxicities were haematological: DISEASE 54 % and thrombocytopenia 51 %. Median follow-up from the start of CHEMICAL-P was 4.5 years. Following CHEMICAL-P, 5-year progression-free survival was 46 % (95 % confidence interval (CI), 30-62 %) and 5-year overall survival was 59 % (95 % CI, 43-74 %). Fourteen of 41 patients proceeded directly to autologous transplant. CHEMICAL-P is a salvage chemotherapy with relatively high response rates, leading to successful transplantation in appropriate patients, in the treatment of relapsed or refractory HL. | CHEMICAL-INDUCED-DISEASE |
| GEM-P chemotherapy is active in the treatment of relapsed DISEASE. DISEASE (DISEASE) is a relatively chemosensitive malignancy. However, for those who relapse, high-dose chemotherapy with autologous stem cell transplant is the treatment of choice which relies on adequate disease control with salvage chemotherapy. Regimens commonly used often require inpatient administration and can be difficult to deliver due to toxicity. Gemcitabine and CHEMICAL have activity in DISEASE, non-overlapping toxicity with first-line chemotherapeutics, and may be delivered in an outpatient setting. In this retrospective single-centre analysis, patients with relapsed or refractory DISEASE treated with gemcitabine 1,000 mg/m(2) day (D)1, D8 and D15; methylprednisolone 1,000 mg D1-5; and CHEMICAL 100 mg/m(2) D15, every 28 days (GEM-P) were included. Demographic, survival, response and toxicity data were recorded. Forty-one eligible patients were identified: median age 27. One hundred and twenty-two cycles of GEM-P were administered in total (median 3 cycles; range 1-6). Twenty of 41 (48 %) patients received GEM-P as second-line treatment and 11/41 (27 %) as third-line therapy. Overall response rate (ORR) to GEM-P in the entire cohort was 80 % (complete response (CR) 37 %, partial response 44 %) with 14/15 CR confirmed as a metabolic CR on PET and ORR of 85 % in the 20 second-line patients. The most common grade 3/4 toxicities were haematological: neutropenia 54 % and thrombocytopenia 51 %. Median follow-up from the start of GEM-P was 4.5 years. Following GEM-P, 5-year progression-free survival was 46 % (95 % confidence interval (CI), 30-62 %) and 5-year overall survival was 59 % (95 % CI, 43-74 %). Fourteen of 41 patients proceeded directly to autologous transplant. GEM-P is a salvage chemotherapy with relatively high response rates, leading to successful transplantation in appropriate patients, in the treatment of relapsed or refractory DISEASE. | NO-RELATIONSHIP |
| GEM-P chemotherapy is active in the treatment of relapsed Hodgkin lymphoma. Hodgkin lymphoma (HL) is a relatively chemosensitive malignancy. However, for those who relapse, high-dose chemotherapy with autologous stem cell transplant is the treatment of choice which relies on adequate disease control with salvage chemotherapy. Regimens commonly used often require inpatient administration and can be difficult to deliver due to DISEASE. Gemcitabine and CHEMICAL have activity in HL, non-overlapping DISEASE with first-line chemotherapeutics, and may be delivered in an outpatient setting. In this retrospective single-centre analysis, patients with relapsed or refractory HL treated with gemcitabine 1,000 mg/m(2) day (D)1, D8 and D15; methylprednisolone 1,000 mg D1-5; and CHEMICAL 100 mg/m(2) D15, every 28 days (GEM-P) were included. Demographic, survival, response and DISEASE data were recorded. Forty-one eligible patients were identified: median age 27. One hundred and twenty-two cycles of GEM-P were administered in total (median 3 cycles; range 1-6). Twenty of 41 (48 %) patients received GEM-P as second-line treatment and 11/41 (27 %) as third-line therapy. Overall response rate (ORR) to GEM-P in the entire cohort was 80 % (complete response (CR) 37 %, partial response 44 %) with 14/15 CR confirmed as a metabolic CR on PET and ORR of 85 % in the 20 second-line patients. The most common grade 3/4 DISEASE were haematological: neutropenia 54 % and thrombocytopenia 51 %. Median follow-up from the start of GEM-P was 4.5 years. Following GEM-P, 5-year progression-free survival was 46 % (95 % confidence interval (CI), 30-62 %) and 5-year overall survival was 59 % (95 % CI, 43-74 %). Fourteen of 41 patients proceeded directly to autologous transplant. GEM-P is a salvage chemotherapy with relatively high response rates, leading to successful transplantation in appropriate patients, in the treatment of relapsed or refractory HL. | NO-RELATIONSHIP |
| GEM-P chemotherapy is active in the treatment of relapsed Hodgkin lymphoma. Hodgkin lymphoma (HL) is a relatively chemosensitive DISEASE. However, for those who relapse, high-dose chemotherapy with autologous stem cell transplant is the treatment of choice which relies on adequate disease control with salvage chemotherapy. Regimens commonly used often require inpatient administration and can be difficult to deliver due to toxicity. Gemcitabine and CHEMICAL have activity in HL, non-overlapping toxicity with first-line chemotherapeutics, and may be delivered in an outpatient setting. In this retrospective single-centre analysis, patients with relapsed or refractory HL treated with gemcitabine 1,000 mg/m(2) day (D)1, D8 and D15; methylprednisolone 1,000 mg D1-5; and CHEMICAL 100 mg/m(2) D15, every 28 days (GEM-P) were included. Demographic, survival, response and toxicity data were recorded. Forty-one eligible patients were identified: median age 27. One hundred and twenty-two cycles of GEM-P were administered in total (median 3 cycles; range 1-6). Twenty of 41 (48 %) patients received GEM-P as second-line treatment and 11/41 (27 %) as third-line therapy. Overall response rate (ORR) to GEM-P in the entire cohort was 80 % (complete response (CR) 37 %, partial response 44 %) with 14/15 CR confirmed as a metabolic CR on PET and ORR of 85 % in the 20 second-line patients. The most common grade 3/4 toxicities were haematological: neutropenia 54 % and thrombocytopenia 51 %. Median follow-up from the start of GEM-P was 4.5 years. Following GEM-P, 5-year progression-free survival was 46 % (95 % confidence interval (CI), 30-62 %) and 5-year overall survival was 59 % (95 % CI, 43-74 %). Fourteen of 41 patients proceeded directly to autologous transplant. GEM-P is a salvage chemotherapy with relatively high response rates, leading to successful transplantation in appropriate patients, in the treatment of relapsed or refractory HL. | NO-RELATIONSHIP |
| Basal functioning of the hypothalamic-pituitary-adrenal (HPA) axis and psychological distress in recreational CHEMICAL polydrug users. RATIONALE: CHEMICAL (CHEMICAL) is a psychostimulant drug which is increasingly associated with psychobiological dysfunction. While some recent studies suggest acute changes in neuroendocrine function, less is known about long-term changes in HPA functionality in recreational users. OBJECTIVES: The current study is the first to explore the effects of CHEMICAL-polydrug use on psychological distress and basal functioning of the HPA axis through assessing the secretion of cortisol across the diurnal period. METHOD: Seventy-six participants (21 nonusers, 29 light CHEMICAL-polydrug users, 26 heavy CHEMICAL-polydrug users) completed a substance use inventory and measures of psychological distress at baseline, then two consecutive days of cortisol sampling (on awakening, 30 min post awakening, between 1400 and 1600 hours and pre bedtime). On day 2, participants also attended the laboratory to complete a 20-min multitasking stressor. RESULTS: Both user groups exhibited significantly greater levels of anxiety and DISEASE than nonusers. On day 1, all participants exhibited a typical cortisol profile, though light users had significantly elevated levels pre-bed. On day 2, heavy users demonstrated elevated levels upon awakening and all CHEMICAL-polydrug users demonstrated elevated pre-bed levels compared to non-users. Significant between group differences were also observed in afternoon cortisol levels and in overall cortisol secretion across the day. CONCLUSIONS: The increases in anxiety and DISEASE are in line with previous observations in recreational CHEMICAL-polydrug users. Dysregulated diurnal cortisol may be indicative of inappropriate anticipation of forthcoming demands and hypersecretion may lead to the increased psychological and physical morbidity associated with heavy recreational use of CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Basal functioning of the hypothalamic-pituitary-adrenal (HPA) axis and psychological distress in recreational ecstasy polydrug users. RATIONALE: Ecstasy (MDMA) is a psychostimulant drug which is increasingly associated with psychobiological dysfunction. While some recent studies suggest acute changes in neuroendocrine function, less is known about long-term changes in HPA functionality in recreational users. OBJECTIVES: The current study is the first to explore the effects of ecstasy-polydrug use on psychological distress and basal functioning of the HPA axis through assessing the secretion of CHEMICAL across the diurnal period. METHOD: Seventy-six participants (21 nonusers, 29 light ecstasy-polydrug users, 26 heavy ecstasy-polydrug users) completed a substance use inventory and measures of psychological distress at baseline, then two consecutive days of CHEMICAL sampling (on awakening, 30 min post awakening, between 1400 and 1600 hours and pre bedtime). On day 2, participants also attended the laboratory to complete a 20-min multitasking stressor. RESULTS: Both user groups exhibited significantly greater levels of DISEASE and depression than nonusers. On day 1, all participants exhibited a typical CHEMICAL profile, though light users had significantly elevated levels pre-bed. On day 2, heavy users demonstrated elevated levels upon awakening and all ecstasy-polydrug users demonstrated elevated pre-bed levels compared to non-users. Significant between group differences were also observed in afternoon CHEMICAL levels and in overall CHEMICAL secretion across the day. CONCLUSIONS: The increases in DISEASE and depression are in line with previous observations in recreational ecstasy-polydrug users. Dysregulated diurnal CHEMICAL may be indicative of inappropriate anticipation of forthcoming demands and hypersecretion may lead to the increased psychological and physical morbidity associated with heavy recreational use of ecstasy. | NO-RELATIONSHIP |
| Basal functioning of the hypothalamic-pituitary-adrenal (HPA) axis and psychological distress in recreational ecstasy polydrug users. RATIONALE: Ecstasy (MDMA) is a psychostimulant drug which is increasingly associated with DISEASE. While some recent studies suggest acute changes in neuroendocrine function, less is known about long-term changes in HPA functionality in recreational users. OBJECTIVES: The current study is the first to explore the effects of ecstasy-polydrug use on psychological distress and basal functioning of the HPA axis through assessing the secretion of CHEMICAL across the diurnal period. METHOD: Seventy-six participants (21 nonusers, 29 light ecstasy-polydrug users, 26 heavy ecstasy-polydrug users) completed a substance use inventory and measures of psychological distress at baseline, then two consecutive days of CHEMICAL sampling (on awakening, 30 min post awakening, between 1400 and 1600 hours and pre bedtime). On day 2, participants also attended the laboratory to complete a 20-min multitasking stressor. RESULTS: Both user groups exhibited significantly greater levels of anxiety and depression than nonusers. On day 1, all participants exhibited a typical CHEMICAL profile, though light users had significantly elevated levels pre-bed. On day 2, heavy users demonstrated elevated levels upon awakening and all ecstasy-polydrug users demonstrated elevated pre-bed levels compared to non-users. Significant between group differences were also observed in afternoon CHEMICAL levels and in overall CHEMICAL secretion across the day. CONCLUSIONS: The increases in anxiety and depression are in line with previous observations in recreational ecstasy-polydrug users. Dysregulated diurnal CHEMICAL may be indicative of inappropriate anticipation of forthcoming demands and hypersecretion may lead to the increased psychological and physical morbidity associated with heavy recreational use of ecstasy. | NO-RELATIONSHIP |
| CHEMICAL related encephalopathy: the need for a timely EEG evaluation. BACKGROUND: CHEMICAL is an alkylating agent useful in the treatment of a wide range of cancers including sarcomas, lymphoma, gynecologic and testicular cancers. Encephalopathy has been reported in 10-40% of patients receiving high-dose IV CHEMICAL. OBJECTIVE: To highlight the role of electroencephalogram (EEG) in the early detection and management of CHEMICAL related encephalopathy. METHODS: Retrospective chart review including clinical data and EEG recordings was done on five patients, admitted to MD Anderson Cancer Center between years 2009 and 2012, who developed CHEMICAL related acute encephalopathy. RESULTS: All five patients experienced symptoms of encephalopathy soon after (within 12 h-2 days) receiving CHEMICAL. Two patients developed generalized DISEASE while one patient developed continuous non-convulsive status epilepticus (NCSE) that required ICU admission and intubation. Initial EEG showed epileptiform discharges in three patients; run of triphasic waves in one patient and moderate degree diffuse generalized slowing. Mixed pattern with the presence of both sharps and triphasic waves were also noted. Repeat EEGs within 24_h of symptom onset showed marked improvement that was correlated with clinical improvement. CONCLUSIONS: Severity of CHEMICAL related encephalopathy correlates with EEG changes. We suggest a timely EEG evaluation for patients receiving CHEMICAL who develop features of encephalopathy. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL related encephalopathy: the need for a timely EEG evaluation. BACKGROUND: CHEMICAL is an alkylating agent useful in the treatment of a wide range of cancers including sarcomas, lymphoma, gynecologic and testicular cancers. Encephalopathy has been reported in 10-40% of patients receiving high-dose IV CHEMICAL. OBJECTIVE: To highlight the role of electroencephalogram (EEG) in the early detection and management of CHEMICAL related encephalopathy. METHODS: Retrospective chart review including clinical data and EEG recordings was done on five patients, admitted to MD Anderson Cancer Center between years 2009 and 2012, who developed CHEMICAL related acute encephalopathy. RESULTS: All five patients experienced symptoms of encephalopathy soon after (within 12 h-2 days) receiving CHEMICAL. Two patients developed generalized convulsions while one patient developed continuous DISEASE (DISEASE) that required ICU admission and intubation. Initial EEG showed epileptiform discharges in three patients; run of triphasic waves in one patient and moderate degree diffuse generalized slowing. Mixed pattern with the presence of both sharps and triphasic waves were also noted. Repeat EEGs within 24_h of symptom onset showed marked improvement that was correlated with clinical improvement. CONCLUSIONS: Severity of CHEMICAL related encephalopathy correlates with EEG changes. We suggest a timely EEG evaluation for patients receiving CHEMICAL who develop features of encephalopathy. | CHEMICAL-INDUCED-DISEASE |
| Incidence of CHEMICAL-induced DISEASE in hospitalised patients with cancer. OBJECTIVES: To determine the frequency of and possible factors related to CHEMICAL-induced DISEASE (CIN) in hospitalised patients with cancer. METHODS: Ninety adult patients were enrolled. Patients with risk factors for acute renal failure were excluded. Blood samples were examined the day before CHEMICAL-enhanced computed tomography (CT) and serially for 3 days thereafter. CIN was defined as an increase in serum creatinine (Cr) of 0.5 mg/dl or more, or elevation of Cr to 25 % over baseline. Relationships between CIN and possible risk factors were investigated. RESULTS: CIN was detected in 18/90 (20 %) patients. CIN developed in 25.5 % patients who underwent chemotherapy and in 11 % patients who did not (P = 0.1). CIN more frequently developed in patients who had undergone CT within 45 days after the last chemotherapy (P = 0.005); it was also an independent risk factor (P = 0.017). CIN was significantly more after treatment with bevacizumab/irinotecan (P = 0.021) and in patients with hypertension (P = 0.044). CONCLUSIONS: The incidence of CIN after CT in hospitalised oncological patients was 20 %. CIN developed 4.5-times more frequently in patients with cancer who had undergone recent chemotherapy. Hypertension and the combination of bevacizumab/irinotecan may be additional risk factors for CIN development. KEY POINTS: . CHEMICAL-induced DISEASE (CIN) is a concern for oncological patients undergoing CT. . CIN occurs more often when CT is performed <45 days after chemotherapy. . Hypertension and treatment with bevacizumab appear to be additional risk factors. | CHEMICAL-INDUCED-DISEASE |
| Incidence of contrast-induced DISEASE in hospitalised patients with cancer. OBJECTIVES: To determine the frequency of and possible factors related to contrast-induced DISEASE (CIN) in hospitalised patients with cancer. METHODS: Ninety adult patients were enrolled. Patients with risk factors for acute renal failure were excluded. Blood samples were examined the day before contrast-enhanced computed tomography (CT) and serially for 3 days thereafter. CIN was defined as an increase in serum creatinine (Cr) of 0.5 mg/dl or more, or elevation of Cr to 25 % over baseline. Relationships between CIN and possible risk factors were investigated. RESULTS: CIN was detected in 18/90 (20 %) patients. CIN developed in 25.5 % patients who underwent chemotherapy and in 11 % patients who did not (P = 0.1). CIN more frequently developed in patients who had undergone CT within 45 days after the last chemotherapy (P = 0.005); it was also an independent risk factor (P = 0.017). CIN was significantly more after treatment with bevacizumab/CHEMICAL (P = 0.021) and in patients with hypertension (P = 0.044). CONCLUSIONS: The incidence of CIN after CT in hospitalised oncological patients was 20 %. CIN developed 4.5-times more frequently in patients with cancer who had undergone recent chemotherapy. Hypertension and the combination of bevacizumab/CHEMICAL may be additional risk factors for CIN development. KEY POINTS: . Contrast-induced DISEASE (CIN) is a concern for oncological patients undergoing CT. . CIN occurs more often when CT is performed <45 days after chemotherapy. . Hypertension and treatment with bevacizumab appear to be additional risk factors. | CHEMICAL-INDUCED-DISEASE |
| Incidence of contrast-induced nephropathy in hospitalised patients with cancer. OBJECTIVES: To determine the frequency of and possible factors related to contrast-induced nephropathy (CIN) in hospitalised patients with cancer. METHODS: Ninety adult patients were enrolled. Patients with risk factors for DISEASE were excluded. Blood samples were examined the day before contrast-enhanced computed tomography (CT) and serially for 3 days thereafter. CIN was defined as an increase in serum CHEMICAL (Cr) of 0.5 mg/dl or more, or elevation of Cr to 25 % over baseline. Relationships between CIN and possible risk factors were investigated. RESULTS: CIN was detected in 18/90 (20 %) patients. CIN developed in 25.5 % patients who underwent chemotherapy and in 11 % patients who did not (P = 0.1). CIN more frequently developed in patients who had undergone CT within 45 days after the last chemotherapy (P = 0.005); it was also an independent risk factor (P = 0.017). CIN was significantly more after treatment with bevacizumab/irinotecan (P = 0.021) and in patients with hypertension (P = 0.044). CONCLUSIONS: The incidence of CIN after CT in hospitalised oncological patients was 20 %. CIN developed 4.5-times more frequently in patients with cancer who had undergone recent chemotherapy. Hypertension and the combination of bevacizumab/irinotecan may be additional risk factors for CIN development. KEY POINTS: . Contrast-induced nephropathy (CIN) is a concern for oncological patients undergoing CT. . CIN occurs more often when CT is performed <45 days after chemotherapy. . Hypertension and treatment with bevacizumab appear to be additional risk factors. | NO-RELATIONSHIP |
| Incidence of contrast-induced nephropathy in hospitalised patients with cancer. OBJECTIVES: To determine the frequency of and possible factors related to contrast-induced nephropathy (CIN) in hospitalised patients with cancer. METHODS: Ninety adult patients were enrolled. Patients with risk factors for DISEASE were excluded. Blood samples were examined the day before contrast-enhanced computed tomography (CT) and serially for 3 days thereafter. CIN was defined as an increase in serum creatinine (Cr) of 0.5 mg/dl or more, or elevation of Cr to 25 % over baseline. Relationships between CIN and possible risk factors were investigated. RESULTS: CIN was detected in 18/90 (20 %) patients. CIN developed in 25.5 % patients who underwent chemotherapy and in 11 % patients who did not (P = 0.1). CIN more frequently developed in patients who had undergone CT within 45 days after the last chemotherapy (P = 0.005); it was also an independent risk factor (P = 0.017). CIN was significantly more after treatment with CHEMICAL/irinotecan (P = 0.021) and in patients with hypertension (P = 0.044). CONCLUSIONS: The incidence of CIN after CT in hospitalised oncological patients was 20 %. CIN developed 4.5-times more frequently in patients with cancer who had undergone recent chemotherapy. Hypertension and the combination of CHEMICAL/irinotecan may be additional risk factors for CIN development. KEY POINTS: . Contrast-induced nephropathy (CIN) is a concern for oncological patients undergoing CT. . CIN occurs more often when CT is performed <45 days after chemotherapy. . Hypertension and treatment with CHEMICAL appear to be additional risk factors. | CHEMICAL-INDUCED-DISEASE |
| Incidence of contrast-induced nephropathy in hospitalised patients with DISEASE. OBJECTIVES: To determine the frequency of and possible factors related to contrast-induced nephropathy (CIN) in hospitalised patients with DISEASE. METHODS: Ninety adult patients were enrolled. Patients with risk factors for acute renal failure were excluded. Blood samples were examined the day before contrast-enhanced computed tomography (CT) and serially for 3 days thereafter. CIN was defined as an increase in serum creatinine (Cr) of 0.5 mg/dl or more, or elevation of Cr to 25 % over baseline. Relationships between CIN and possible risk factors were investigated. RESULTS: CIN was detected in 18/90 (20 %) patients. CIN developed in 25.5 % patients who underwent chemotherapy and in 11 % patients who did not (P = 0.1). CIN more frequently developed in patients who had undergone CT within 45 days after the last chemotherapy (P = 0.005); it was also an independent risk factor (P = 0.017). CIN was significantly more after treatment with CHEMICAL/irinotecan (P = 0.021) and in patients with hypertension (P = 0.044). CONCLUSIONS: The incidence of CIN after CT in hospitalised oncological patients was 20 %. CIN developed 4.5-times more frequently in patients with DISEASE who had undergone recent chemotherapy. Hypertension and the combination of CHEMICAL/irinotecan may be additional risk factors for CIN development. KEY POINTS: . Contrast-induced nephropathy (CIN) is a concern for oncological patients undergoing CT. . CIN occurs more often when CT is performed <45 days after chemotherapy. . Hypertension and treatment with CHEMICAL appear to be additional risk factors. | NO-RELATIONSHIP |
| Incidence of contrast-induced nephropathy in hospitalised patients with DISEASE. OBJECTIVES: To determine the frequency of and possible factors related to contrast-induced nephropathy (CIN) in hospitalised patients with DISEASE. METHODS: Ninety adult patients were enrolled. Patients with risk factors for acute renal failure were excluded. Blood samples were examined the day before contrast-enhanced computed tomography (CT) and serially for 3 days thereafter. CIN was defined as an increase in serum CHEMICAL (Cr) of 0.5 mg/dl or more, or elevation of Cr to 25 % over baseline. Relationships between CIN and possible risk factors were investigated. RESULTS: CIN was detected in 18/90 (20 %) patients. CIN developed in 25.5 % patients who underwent chemotherapy and in 11 % patients who did not (P = 0.1). CIN more frequently developed in patients who had undergone CT within 45 days after the last chemotherapy (P = 0.005); it was also an independent risk factor (P = 0.017). CIN was significantly more after treatment with bevacizumab/irinotecan (P = 0.021) and in patients with hypertension (P = 0.044). CONCLUSIONS: The incidence of CIN after CT in hospitalised oncological patients was 20 %. CIN developed 4.5-times more frequently in patients with DISEASE who had undergone recent chemotherapy. Hypertension and the combination of bevacizumab/irinotecan may be additional risk factors for CIN development. KEY POINTS: . Contrast-induced nephropathy (CIN) is a concern for oncological patients undergoing CT. . CIN occurs more often when CT is performed <45 days after chemotherapy. . Hypertension and treatment with bevacizumab appear to be additional risk factors. | NO-RELATIONSHIP |
| Incidence of contrast-induced nephropathy in hospitalised patients with cancer. OBJECTIVES: To determine the frequency of and possible factors related to contrast-induced nephropathy (CIN) in hospitalised patients with cancer. METHODS: Ninety adult patients were enrolled. Patients with risk factors for acute renal failure were excluded. Blood samples were examined the day before contrast-enhanced computed tomography (CT) and serially for 3 days thereafter. CIN was defined as an increase in serum CHEMICAL (Cr) of 0.5 mg/dl or more, or elevation of Cr to 25 % over baseline. Relationships between CIN and possible risk factors were investigated. RESULTS: CIN was detected in 18/90 (20 %) patients. CIN developed in 25.5 % patients who underwent chemotherapy and in 11 % patients who did not (P = 0.1). CIN more frequently developed in patients who had undergone CT within 45 days after the last chemotherapy (P = 0.005); it was also an independent risk factor (P = 0.017). CIN was significantly more after treatment with bevacizumab/irinotecan (P = 0.021) and in patients with DISEASE (P = 0.044). CONCLUSIONS: The incidence of CIN after CT in hospitalised oncological patients was 20 %. CIN developed 4.5-times more frequently in patients with cancer who had undergone recent chemotherapy. DISEASE and the combination of bevacizumab/irinotecan may be additional risk factors for CIN development. KEY POINTS: . Contrast-induced nephropathy (CIN) is a concern for oncological patients undergoing CT. . CIN occurs more often when CT is performed <45 days after chemotherapy. . DISEASE and treatment with bevacizumab appear to be additional risk factors. | NO-RELATIONSHIP |
| Incidence of contrast-induced nephropathy in hospitalised patients with DISEASE. OBJECTIVES: To determine the frequency of and possible factors related to contrast-induced nephropathy (CIN) in hospitalised patients with DISEASE. METHODS: Ninety adult patients were enrolled. Patients with risk factors for acute renal failure were excluded. Blood samples were examined the day before contrast-enhanced computed tomography (CT) and serially for 3 days thereafter. CIN was defined as an increase in serum creatinine (CHEMICAL) of 0.5 mg/dl or more, or elevation of CHEMICAL to 25 % over baseline. Relationships between CIN and possible risk factors were investigated. RESULTS: CIN was detected in 18/90 (20 %) patients. CIN developed in 25.5 % patients who underwent chemotherapy and in 11 % patients who did not (P = 0.1). CIN more frequently developed in patients who had undergone CT within 45 days after the last chemotherapy (P = 0.005); it was also an independent risk factor (P = 0.017). CIN was significantly more after treatment with bevacizumab/irinotecan (P = 0.021) and in patients with hypertension (P = 0.044). CONCLUSIONS: The incidence of CIN after CT in hospitalised oncological patients was 20 %. CIN developed 4.5-times more frequently in patients with DISEASE who had undergone recent chemotherapy. Hypertension and the combination of bevacizumab/irinotecan may be additional risk factors for CIN development. KEY POINTS: . Contrast-induced nephropathy (CIN) is a concern for oncological patients undergoing CT. . CIN occurs more often when CT is performed <45 days after chemotherapy. . Hypertension and treatment with bevacizumab appear to be additional risk factors. | NO-RELATIONSHIP |
| Incidence of contrast-induced nephropathy in hospitalised patients with cancer. OBJECTIVES: To determine the frequency of and possible factors related to contrast-induced nephropathy (CIN) in hospitalised patients with cancer. METHODS: Ninety adult patients were enrolled. Patients with risk factors for DISEASE were excluded. Blood samples were examined the day before contrast-enhanced computed tomography (CT) and serially for 3 days thereafter. CIN was defined as an increase in serum creatinine (CHEMICAL) of 0.5 mg/dl or more, or elevation of CHEMICAL to 25 % over baseline. Relationships between CIN and possible risk factors were investigated. RESULTS: CIN was detected in 18/90 (20 %) patients. CIN developed in 25.5 % patients who underwent chemotherapy and in 11 % patients who did not (P = 0.1). CIN more frequently developed in patients who had undergone CT within 45 days after the last chemotherapy (P = 0.005); it was also an independent risk factor (P = 0.017). CIN was significantly more after treatment with bevacizumab/irinotecan (P = 0.021) and in patients with hypertension (P = 0.044). CONCLUSIONS: The incidence of CIN after CT in hospitalised oncological patients was 20 %. CIN developed 4.5-times more frequently in patients with cancer who had undergone recent chemotherapy. Hypertension and the combination of bevacizumab/irinotecan may be additional risk factors for CIN development. KEY POINTS: . Contrast-induced nephropathy (CIN) is a concern for oncological patients undergoing CT. . CIN occurs more often when CT is performed <45 days after chemotherapy. . Hypertension and treatment with bevacizumab appear to be additional risk factors. | NO-RELATIONSHIP |
| Incidence of contrast-induced nephropathy in hospitalised patients with cancer. OBJECTIVES: To determine the frequency of and possible factors related to contrast-induced nephropathy (CIN) in hospitalised patients with cancer. METHODS: Ninety adult patients were enrolled. Patients with risk factors for acute renal failure were excluded. Blood samples were examined the day before contrast-enhanced computed tomography (CT) and serially for 3 days thereafter. CIN was defined as an increase in serum creatinine (CHEMICAL) of 0.5 mg/dl or more, or elevation of CHEMICAL to 25 % over baseline. Relationships between CIN and possible risk factors were investigated. RESULTS: CIN was detected in 18/90 (20 %) patients. CIN developed in 25.5 % patients who underwent chemotherapy and in 11 % patients who did not (P = 0.1). CIN more frequently developed in patients who had undergone CT within 45 days after the last chemotherapy (P = 0.005); it was also an independent risk factor (P = 0.017). CIN was significantly more after treatment with bevacizumab/irinotecan (P = 0.021) and in patients with DISEASE (P = 0.044). CONCLUSIONS: The incidence of CIN after CT in hospitalised oncological patients was 20 %. CIN developed 4.5-times more frequently in patients with cancer who had undergone recent chemotherapy. DISEASE and the combination of bevacizumab/irinotecan may be additional risk factors for CIN development. KEY POINTS: . Contrast-induced nephropathy (CIN) is a concern for oncological patients undergoing CT. . CIN occurs more often when CT is performed <45 days after chemotherapy. . DISEASE and treatment with bevacizumab appear to be additional risk factors. | NO-RELATIONSHIP |
| Incidence of contrast-induced nephropathy in hospitalised patients with cancer. OBJECTIVES: To determine the frequency of and possible factors related to contrast-induced nephropathy (CIN) in hospitalised patients with cancer. METHODS: Ninety adult patients were enrolled. Patients with risk factors for acute renal failure were excluded. Blood samples were examined the day before contrast-enhanced computed tomography (CT) and serially for 3 days thereafter. CIN was defined as an increase in serum creatinine (Cr) of 0.5 mg/dl or more, or elevation of Cr to 25 % over baseline. Relationships between CIN and possible risk factors were investigated. RESULTS: CIN was detected in 18/90 (20 %) patients. CIN developed in 25.5 % patients who underwent chemotherapy and in 11 % patients who did not (P = 0.1). CIN more frequently developed in patients who had undergone CT within 45 days after the last chemotherapy (P = 0.005); it was also an independent risk factor (P = 0.017). CIN was significantly more after treatment with CHEMICAL/irinotecan (P = 0.021) and in patients with DISEASE (P = 0.044). CONCLUSIONS: The incidence of CIN after CT in hospitalised oncological patients was 20 %. CIN developed 4.5-times more frequently in patients with cancer who had undergone recent chemotherapy. DISEASE and the combination of CHEMICAL/irinotecan may be additional risk factors for CIN development. KEY POINTS: . Contrast-induced nephropathy (CIN) is a concern for oncological patients undergoing CT. . CIN occurs more often when CT is performed <45 days after chemotherapy. . DISEASE and treatment with CHEMICAL appear to be additional risk factors. | CHEMICAL-INDUCED-DISEASE |
| DISEASE secretion associated with CHEMICAL. OBJECTIVE: To report a case of DISEASE (DISEASE) secretion associated with CHEMICAL. CASE SUMMARY: A 57-year old female with hyponatraemia. Her medications included CHEMICAL, and symptoms included nausea, anxiety and confusion. The serum sodium at this time was 120 mmol/L, serum osmolality was 263 mosmol/kg, urine osmolality 410 mosmol/kg and urine sodium 63 mmol/L, consistent with a diagnosis of DISEASE. CHEMICAL was ceased and fluid restriction implemented. After 4 days the sodium increased to 128 mmol/L and fluid restriction was relaxed. During her further 3 weeks inpatient admission the serum sodium ranged from 134 to 137 mmol/L during treatment with mirtazapine. DISCUSSION: DISEASE has been widely reported with a range of antidepressants. This case report suggests that CHEMICAL might cause clinically significant hyponatremia. CONCLUSIONS: Clinicians should be aware of the potential for antidepressants to cause hyponatremia,and take appropriate corrective action where necessary. | CHEMICAL-INDUCED-DISEASE |
| Syndrome of inappropriate antidiuretic hormone secretion associated with CHEMICAL. OBJECTIVE: To report a case of syndrome of inappropriate anti-diuretic hormone (SIADH) secretion associated with CHEMICAL. CASE SUMMARY: A 57-year old female with hyponatraemia. Her medications included CHEMICAL, and symptoms included nausea, DISEASE and confusion. The serum sodium at this time was 120 mmol/L, serum osmolality was 263 mosmol/kg, urine osmolality 410 mosmol/kg and urine sodium 63 mmol/L, consistent with a diagnosis of SIADH. CHEMICAL was ceased and fluid restriction implemented. After 4 days the sodium increased to 128 mmol/L and fluid restriction was relaxed. During her further 3 weeks inpatient admission the serum sodium ranged from 134 to 137 mmol/L during treatment with mirtazapine. DISCUSSION: SIADH has been widely reported with a range of antidepressants. This case report suggests that CHEMICAL might cause clinically significant hyponatremia. CONCLUSIONS: Clinicians should be aware of the potential for antidepressants to cause hyponatremia,and take appropriate corrective action where necessary. | CHEMICAL-INDUCED-DISEASE |
| Syndrome of inappropriate antidiuretic hormone secretion associated with CHEMICAL. OBJECTIVE: To report a case of syndrome of inappropriate anti-diuretic hormone (SIADH) secretion associated with CHEMICAL. CASE SUMMARY: A 57-year old female with DISEASE. Her medications included CHEMICAL, and symptoms included nausea, anxiety and confusion. The serum sodium at this time was 120 mmol/L, serum osmolality was 263 mosmol/kg, urine osmolality 410 mosmol/kg and urine sodium 63 mmol/L, consistent with a diagnosis of SIADH. CHEMICAL was ceased and fluid restriction implemented. After 4 days the sodium increased to 128 mmol/L and fluid restriction was relaxed. During her further 3 weeks inpatient admission the serum sodium ranged from 134 to 137 mmol/L during treatment with mirtazapine. DISCUSSION: SIADH has been widely reported with a range of antidepressants. This case report suggests that CHEMICAL might cause clinically significant DISEASE. CONCLUSIONS: Clinicians should be aware of the potential for antidepressants to cause DISEASE,and take appropriate corrective action where necessary. | CHEMICAL-INDUCED-DISEASE |
| Syndrome of inappropriate antidiuretic hormone secretion associated with CHEMICAL. OBJECTIVE: To report a case of syndrome of inappropriate anti-diuretic hormone (SIADH) secretion associated with CHEMICAL. CASE SUMMARY: A 57-year old female with hyponatraemia. Her medications included CHEMICAL, and symptoms included nausea, anxiety and DISEASE. The serum sodium at this time was 120 mmol/L, serum osmolality was 263 mosmol/kg, urine osmolality 410 mosmol/kg and urine sodium 63 mmol/L, consistent with a diagnosis of SIADH. CHEMICAL was ceased and fluid restriction implemented. After 4 days the sodium increased to 128 mmol/L and fluid restriction was relaxed. During her further 3 weeks inpatient admission the serum sodium ranged from 134 to 137 mmol/L during treatment with mirtazapine. DISCUSSION: SIADH has been widely reported with a range of antidepressants. This case report suggests that CHEMICAL might cause clinically significant hyponatremia. CONCLUSIONS: Clinicians should be aware of the potential for antidepressants to cause hyponatremia,and take appropriate corrective action where necessary. | CHEMICAL-INDUCED-DISEASE |
| Syndrome of inappropriate antidiuretic hormone secretion associated with CHEMICAL. OBJECTIVE: To report a case of syndrome of inappropriate anti-diuretic hormone (SIADH) secretion associated with CHEMICAL. CASE SUMMARY: A 57-year old female with hyponatraemia. Her medications included CHEMICAL, and symptoms included DISEASE, anxiety and confusion. The serum sodium at this time was 120 mmol/L, serum osmolality was 263 mosmol/kg, urine osmolality 410 mosmol/kg and urine sodium 63 mmol/L, consistent with a diagnosis of SIADH. CHEMICAL was ceased and fluid restriction implemented. After 4 days the sodium increased to 128 mmol/L and fluid restriction was relaxed. During her further 3 weeks inpatient admission the serum sodium ranged from 134 to 137 mmol/L during treatment with mirtazapine. DISCUSSION: SIADH has been widely reported with a range of antidepressants. This case report suggests that CHEMICAL might cause clinically significant hyponatremia. CONCLUSIONS: Clinicians should be aware of the potential for antidepressants to cause hyponatremia,and take appropriate corrective action where necessary. | CHEMICAL-INDUCED-DISEASE |
| Oxidative stress on DISEASE after treatment with single and multiple doses of CHEMICAL. The mechanism of CHEMICAL (CHEMICAL)-induced DISEASE remains controversial. Wistar rats (n = 66) received CHEMICAL injections intraperitoneally and were randomly assigned to 2 experimental protocols: (1) rats were killed before (-24 h, n = 8) and 24 h after (+24 h, n = 8) a single dose of CHEMICAL (4 mg/kg body weight) to determine the CHEMICAL acute effect and (2) rats (n = 58) received 4 injections of CHEMICAL (4 mg/kg body weight/week) and were killed before the first injection (M0) and 1 week after each injection (M1, M2, M3, and M4) to determine the chronological effects. Animals used at M0 (n = 8) were also used at moment -24 h of acute study. Cardiac total antioxidant performance (TAP), DNA damage, and morphology analyses were carried out at each time point. Single dose of CHEMICAL was associated with increased cardiac disarrangement, necrosis, and DNA damage (strand breaks (SBs) and oxidized pyrimidines) and decreased TAP. The chronological study showed an effect of a cumulative dose on body weight (R = -0.99, p = 0.011), necrosis (R = 1.00, p = 0.004), TAP (R = 0.95, p = 0.049), and DNA SBs (R = -0.95, p = 0.049). DNA SBs damage was negatively associated with TAP (R = -0.98, p = 0.018), and necrosis (R = -0.97, p = 0.027). Our results suggest that oxidative damage is associated with acute DISEASE induced by a single dose of CHEMICAL only. Increased resistance to the oxidative stress is plausible for the multiple dose of CHEMICAL. Thus, different mechanisms may be involved in acute toxicity versus chronic toxicity. | CHEMICAL-INDUCED-DISEASE |
| Oxidative stress on cardiotoxicity after treatment with single and multiple doses of CHEMICAL. The mechanism of CHEMICAL (CHEMICAL)-induced cardiotoxicity remains controversial. Wistar rats (n = 66) received CHEMICAL injections intraperitoneally and were randomly assigned to 2 experimental protocols: (1) rats were killed before (-24 h, n = 8) and 24 h after (+24 h, n = 8) a single dose of CHEMICAL (4 mg/kg body weight) to determine the CHEMICAL acute effect and (2) rats (n = 58) received 4 injections of CHEMICAL (4 mg/kg body weight/week) and were killed before the first injection (M0) and 1 week after each injection (M1, M2, M3, and M4) to determine the chronological effects. Animals used at M0 (n = 8) were also used at moment -24 h of acute study. Cardiac total antioxidant performance (TAP), DNA damage, and morphology analyses were carried out at each time point. Single dose of CHEMICAL was associated with increased cardiac disarrangement, DISEASE, and DNA damage (strand breaks (SBs) and oxidized pyrimidines) and decreased TAP. The chronological study showed an effect of a cumulative dose on body weight (R = -0.99, p = 0.011), DISEASE (R = 1.00, p = 0.004), TAP (R = 0.95, p = 0.049), and DNA SBs (R = -0.95, p = 0.049). DNA SBs damage was negatively associated with TAP (R = -0.98, p = 0.018), and DISEASE (R = -0.97, p = 0.027). Our results suggest that oxidative damage is associated with acute cardiotoxicity induced by a single dose of CHEMICAL only. Increased resistance to the oxidative stress is plausible for the multiple dose of CHEMICAL. Thus, different mechanisms may be involved in acute toxicity versus chronic toxicity. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-related DISEASE after pediatric liver transplantation--a single-center experience. To identify the risk factors for new-onset DISEASE after pediatric LT and to assess their clinical implications and long-term prognosis. The clinical and laboratory data of 27 consecutive children who underwent LT from January 2007 to December 2010 in our center were analyzed retrospectively. Patients were divided into DISEASE group and a non-DISEASE group. Pre-operative, intra-operative, and post-operative data were collected. DISEASE occurred in four children, an incidence of 14.8%. All exhibited generalized tonic-clonic seizures within the first two wk after LT. Univariate analysis showed that the risk factors associated with DISEASE after pediatric LT included gender, pediatric end-stage liver disease score before surgery, Child-Pugh score before surgery, serum total bilirubin after surgery, and trough CHEMICAL level. Multivariate analysis showed that trough CHEMICAL level was the only independent risk factor associated with the DISEASE. All children who experienced DISEASE survived with good graft function and remained DISEASE-free without anti-epileptic drugs over a mean follow-up period of 33.7 + 14.6 months. High trough CHEMICAL level was the predominant factor that contributed to DISEASE in the early post-operative period after pediatric LT. High PELD and Child-Pugh scores before LT and high post-operative serum Tbil may be contributory risk factors for CHEMICAL-related DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Tacrolimus-related seizure after pediatric liver transplantation--a single-center experience. To identify the risk factors for new-onset seizures after pediatric LT and to assess their clinical implications and long-term prognosis. The clinical and laboratory data of 27 consecutive children who underwent LT from January 2007 to December 2010 in our center were analyzed retrospectively. Patients were divided into seizures group and a non-seizures group. Pre-operative, intra-operative, and post-operative data were collected. Seizures occurred in four children, an incidence of 14.8%. All exhibited generalized tonic-clonic seizures within the first two wk after LT. Univariate analysis showed that the risk factors associated with seizures after pediatric LT included gender, pediatric end-stage liver disease score before surgery, Child-Pugh score before surgery, serum total CHEMICAL after surgery, and trough TAC level. Multivariate analysis showed that trough TAC level was the only independent risk factor associated with the seizures. All children who experienced seizures survived with good graft function and remained seizure-free without anti-DISEASE drugs over a mean follow-up period of 33.7 + 14.6 months. High trough TAC level was the predominant factor that contributed to seizures in the early post-operative period after pediatric LT. High PELD and Child-Pugh scores before LT and high post-operative serum Tbil may be contributory risk factors for TAC-related seizures. | NO-RELATIONSHIP |
| Tacrolimus-related seizure after pediatric liver transplantation--a single-center experience. To identify the risk factors for new-onset seizures after pediatric LT and to assess their clinical implications and long-term prognosis. The clinical and laboratory data of 27 consecutive children who underwent LT from January 2007 to December 2010 in our center were analyzed retrospectively. Patients were divided into seizures group and a non-seizures group. Pre-operative, intra-operative, and post-operative data were collected. Seizures occurred in four children, an incidence of 14.8%. All exhibited generalized tonic-clonic seizures within the first two wk after LT. Univariate analysis showed that the risk factors associated with seizures after pediatric LT included gender, pediatric DISEASE score before surgery, Child-Pugh score before surgery, serum total CHEMICAL after surgery, and trough TAC level. Multivariate analysis showed that trough TAC level was the only independent risk factor associated with the seizures. All children who experienced seizures survived with good graft function and remained seizure-free without anti-epileptic drugs over a mean follow-up period of 33.7 + 14.6 months. High trough TAC level was the predominant factor that contributed to seizures in the early post-operative period after pediatric LT. High PELD and Child-Pugh scores before LT and high post-operative serum Tbil may be contributory risk factors for TAC-related seizures. | NO-RELATIONSHIP |
| Tacrolimus-related seizure after pediatric liver transplantation--a single-center experience. To identify the risk factors for new-onset seizures after pediatric LT and to assess their clinical implications and long-term prognosis. The clinical and laboratory data of 27 consecutive children who underwent LT from January 2007 to December 2010 in our center were analyzed retrospectively. Patients were divided into seizures group and a non-seizures group. Pre-operative, intra-operative, and post-operative data were collected. Seizures occurred in four children, an incidence of 14.8%. All exhibited generalized DISEASE within the first two wk after LT. Univariate analysis showed that the risk factors associated with seizures after pediatric LT included gender, pediatric end-stage liver disease score before surgery, Child-Pugh score before surgery, serum total CHEMICAL after surgery, and trough TAC level. Multivariate analysis showed that trough TAC level was the only independent risk factor associated with the seizures. All children who experienced seizures survived with good graft function and remained seizure-free without anti-epileptic drugs over a mean follow-up period of 33.7 + 14.6 months. High trough TAC level was the predominant factor that contributed to seizures in the early post-operative period after pediatric LT. High PELD and Child-Pugh scores before LT and high post-operative serum Tbil may be contributory risk factors for TAC-related seizures. | NO-RELATIONSHIP |
| The flavonoid apigenin delays forgetting of passive avoidance conditioning in rats. The present experiments were performed to study the effect of the flavonoid apigenin (20 mg/kg intraperitoneally (i.p.), 1 h before acquisition), on 24 h retention performance and forgetting of a step-through passive avoidance task, in young male Wistar rats. There were no differences between saline- and apigenin-treated groups in the 24 h retention trial. Furthermore, apigenin did not prevent the DISEASE induced by CHEMICAL (1mg/kg, i.p., 30 min before the acquisition). The saline- and apigenin-treated rats that did not step through into the dark compartment during the cut-off time (540 s) were retested weekly for up to eight weeks. In the saline treated group, the first significant decline in passive avoidance response was observed at four weeks, and complete memory loss was found five weeks after the acquisition of the passive avoidance task. At the end of the experimental period, 60% of the animals treated with apigenin still did not step through. These data suggest that 1) apigenin delays the long-term forgetting but did not modulate the 24 h retention of fear memory and 2) the obtained beneficial effect of apigenin on the passive avoidance conditioning is mediated by mechanisms that do not implicate its action on the muscarinic cholinergic system. | CHEMICAL-INDUCED-DISEASE |
| The flavonoid CHEMICAL delays forgetting of passive avoidance conditioning in rats. The present experiments were performed to study the effect of the flavonoid CHEMICAL (20 mg/kg intraperitoneally (i.p.), 1 h before acquisition), on 24 h retention performance and forgetting of a step-through passive avoidance task, in young male Wistar rats. There were no differences between saline- and CHEMICAL-treated groups in the 24 h retention trial. Furthermore, CHEMICAL did not prevent the amnesia induced by scopolamine (1mg/kg, i.p., 30 min before the acquisition). The saline- and CHEMICAL-treated rats that did not step through into the dark compartment during the cut-off time (540 s) were retested weekly for up to eight weeks. In the saline treated group, the first significant decline in passive avoidance response was observed at four weeks, and complete DISEASE was found five weeks after the acquisition of the passive avoidance task. At the end of the experimental period, 60% of the animals treated with CHEMICAL still did not step through. These data suggest that 1) CHEMICAL delays the long-term forgetting but did not modulate the 24 h retention of fear memory and 2) the obtained beneficial effect of CHEMICAL on the passive avoidance conditioning is mediated by mechanisms that do not implicate its action on the muscarinic cholinergic system. | NO-RELATIONSHIP |
| The CHEMICAL apigenin delays forgetting of passive avoidance conditioning in rats. The present experiments were performed to study the effect of the CHEMICAL apigenin (20 mg/kg intraperitoneally (i.p.), 1 h before acquisition), on 24 h retention performance and forgetting of a step-through passive avoidance task, in young male Wistar rats. There were no differences between saline- and apigenin-treated groups in the 24 h retention trial. Furthermore, apigenin did not prevent the amnesia induced by scopolamine (1mg/kg, i.p., 30 min before the acquisition). The saline- and apigenin-treated rats that did not step through into the dark compartment during the cut-off time (540 s) were retested weekly for up to eight weeks. In the saline treated group, the first significant decline in passive avoidance response was observed at four weeks, and complete DISEASE was found five weeks after the acquisition of the passive avoidance task. At the end of the experimental period, 60% of the animals treated with apigenin still did not step through. These data suggest that 1) apigenin delays the long-term forgetting but did not modulate the 24 h retention of fear memory and 2) the obtained beneficial effect of apigenin on the passive avoidance conditioning is mediated by mechanisms that do not implicate its action on the muscarinic cholinergic system. | NO-RELATIONSHIP |
| Cholecystokinin-octapeptide restored CHEMICAL-induced hippocampal long-term potentiation impairment in rats. Cholecystokinin-octapeptide (CCK-8), which is a typical brain-gut peptide, exerts a wide range of biological activities on the central nervous system. We have previously reported that CCK-8 significantly alleviated CHEMICAL-induced DISEASE and reversed spine density decreases in the CA1 region of the hippocampus in CHEMICAL-treated animals. Here, we investigated the effects of CCK-8 on long-term potentiation (LTP) in the lateral perforant path (LPP)-granule cell synapse of rat dentate gyrus (DG) in acute saline or CHEMICAL-treated rats. Population spikes (PS), which were evoked by stimulation of the LPP, were recorded in the DG region. Acute CHEMICAL (30mg/kg, s.c.) treatment significantly attenuated hippocampal LTP and CCK-8 (1ug, i.c.v.) restored the amplitude of PS that was attenuated by CHEMICAL injection. Furthermore, microinjection of CCK-8 (0.1 and 1ug, i.c.v.) also significantly augmented hippocampal LTP in saline-treated (1ml/kg, s.c.) rats. Pre-treatment of the CCK2 receptor antagonist L-365,260 (10ug, i.c.v) reversed the effects of CCK-8, but the CCK1 receptor antagonist L-364,718 (10ug, i.c.v) did not. The present results demonstrate that CCK-8 attenuates the effect of CHEMICAL on hippocampal LTP through CCK2 receptors and suggest an ameliorative function of CCK-8 on CHEMICAL-induced memory impairment. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL restored morphine-induced hippocampal long-term potentiation impairment in rats. CHEMICAL (CHEMICAL), which is a typical brain-gut peptide, exerts a wide range of biological activities on the central nervous system. We have previously reported that CHEMICAL significantly alleviated morphine-induced amnesia and reversed spine density decreases in the CA1 region of the hippocampus in morphine-treated animals. Here, we investigated the effects of CHEMICAL on long-term potentiation (LTP) in the lateral perforant path (LPP)-granule cell synapse of rat dentate gyrus (DG) in acute saline or morphine-treated rats. Population spikes (PS), which were evoked by stimulation of the LPP, were recorded in the DG region. Acute morphine (30mg/kg, s.c.) treatment significantly attenuated hippocampal LTP and CHEMICAL (1ug, i.c.v.) restored the amplitude of PS that was attenuated by morphine injection. Furthermore, microinjection of CHEMICAL (0.1 and 1ug, i.c.v.) also significantly augmented hippocampal LTP in saline-treated (1ml/kg, s.c.) rats. Pre-treatment of the CCK2 receptor antagonist L-365,260 (10ug, i.c.v) reversed the effects of CHEMICAL, but the CCK1 receptor antagonist L-364,718 (10ug, i.c.v) did not. The present results demonstrate that CHEMICAL attenuates the effect of morphine on hippocampal LTP through CCK2 receptors and suggest an ameliorative function of CHEMICAL on morphine-induced DISEASE. | NO-RELATIONSHIP |
| Glial activation and post-synaptic neurotoxicity: the key events in CHEMICAL (ICV) induced memory impairment in rats. In the present study the role of glial activation and post synaptic toxicity in ICV CHEMICAL (CHEMICAL) induced memory impaired rats was explored. In experiment set up 1: Memory deficit was found in Morris water maze test on 14-16 days after CHEMICAL (ICV; 3mg/Kg) administration. CHEMICAL causes increased expression of GFAP, CD11b and TNF-a indicating glial activation and DISEASE. CHEMICAL also significantly increased the level of ROS, nitrite, Ca(2+) and reduced the mitochondrial activity in synaptosomal preparation illustrating free radical generation and excitotoxicity. Increased expression and activity of Caspase-3 was also observed in CHEMICAL treated rat which specify apoptotic cell death in hippocampus and cortex. CHEMICAL treatment showed decrease expression of post synaptic markers CaMKIIa and PSD-95, while, expression of pre synaptic markers (synaptophysin and SNAP-25) remains unaltered indicating selective post synaptic neurotoxicity. Oral treatment with Memantine (10mg/kg) and Ibuprofen (50 mg/kg) daily for 13 days attenuated CHEMICAL induced glial activation, apoptotic cell death and post synaptic neurotoxicity in rat brain. Further, in experiment set up 2: where memory function was not affected i.e. 7-9 days after CHEMICAL treatment. The level of GFAP, CD11b, TNF-a, ROS and nitrite levels were increased. On the other hand, apoptotic marker, synaptic markers, mitochondrial activity and Ca(2+) levels remained unaffected. Collective data indicates that DISEASE process and oxidative stress occurs earlier to apoptosis and does not affect memory function. Present study clearly suggests that glial activation and post synaptic neurotoxicity are the key factors in CHEMICAL induced memory impairment and neuronal cell death. | CHEMICAL-INDUCED-DISEASE |
| Glial activation and post-synaptic neurotoxicity: the key events in CHEMICAL (ICV) induced DISEASE in rats. In the present study the role of glial activation and post synaptic toxicity in ICV CHEMICAL (CHEMICAL) induced DISEASE rats was explored. In experiment set up 1: DISEASE was found in Morris water maze test on 14-16 days after CHEMICAL (ICV; 3mg/Kg) administration. CHEMICAL causes increased expression of GFAP, CD11b and TNF-a indicating glial activation and neuroinflammation. CHEMICAL also significantly increased the level of ROS, nitrite, Ca(2+) and reduced the mitochondrial activity in synaptosomal preparation illustrating free radical generation and excitotoxicity. Increased expression and activity of Caspase-3 was also observed in CHEMICAL treated rat which specify apoptotic cell death in hippocampus and cortex. CHEMICAL treatment showed decrease expression of post synaptic markers CaMKIIa and PSD-95, while, expression of pre synaptic markers (synaptophysin and SNAP-25) remains unaltered indicating selective post synaptic neurotoxicity. Oral treatment with Memantine (10mg/kg) and Ibuprofen (50 mg/kg) daily for 13 days attenuated CHEMICAL induced glial activation, apoptotic cell death and post synaptic neurotoxicity in rat brain. Further, in experiment set up 2: where memory function was not affected i.e. 7-9 days after CHEMICAL treatment. The level of GFAP, CD11b, TNF-a, ROS and nitrite levels were increased. On the other hand, apoptotic marker, synaptic markers, mitochondrial activity and Ca(2+) levels remained unaffected. Collective data indicates that neuroinflammatory process and oxidative stress occurs earlier to apoptosis and does not affect memory function. Present study clearly suggests that glial activation and post synaptic neurotoxicity are the key factors in CHEMICAL induced DISEASE and neuronal cell death. | CHEMICAL-INDUCED-DISEASE |
| Glial activation and post-synaptic neurotoxicity: the key events in Streptozotocin (ICV) induced memory impairment in rats. In the present study the role of glial activation and post synaptic DISEASE in ICV Streptozotocin (STZ) induced memory impaired rats was explored. In experiment set up 1: Memory deficit was found in Morris water maze test on 14-16 days after STZ (ICV; 3mg/Kg) administration. STZ causes increased expression of GFAP, CD11b and TNF-a indicating glial activation and neuroinflammation. STZ also significantly increased the level of ROS, nitrite, Ca(2+) and reduced the mitochondrial activity in synaptosomal preparation illustrating free radical generation and DISEASE. Increased expression and activity of Caspase-3 was also observed in STZ treated rat which specify apoptotic cell death in hippocampus and cortex. STZ treatment showed decrease expression of post synaptic markers CaMKIIa and PSD-95, while, expression of pre synaptic markers (synaptophysin and SNAP-25) remains unaltered indicating selective post synaptic neurotoxicity. Oral treatment with Memantine (10mg/kg) and CHEMICAL (50 mg/kg) daily for 13 days attenuated STZ induced glial activation, apoptotic cell death and post synaptic neurotoxicity in rat brain. Further, in experiment set up 2: where memory function was not affected i.e. 7-9 days after STZ treatment. The level of GFAP, CD11b, TNF-a, ROS and nitrite levels were increased. On the other hand, apoptotic marker, synaptic markers, mitochondrial activity and Ca(2+) levels remained unaffected. Collective data indicates that neuroinflammatory process and oxidative stress occurs earlier to apoptosis and does not affect memory function. Present study clearly suggests that glial activation and post synaptic neurotoxicity are the key factors in STZ induced memory impairment and neuronal cell death. | NO-RELATIONSHIP |
| Glial activation and post-synaptic DISEASE: the key events in Streptozotocin (ICV) induced memory impairment in rats. In the present study the role of glial activation and post synaptic toxicity in ICV Streptozotocin (STZ) induced memory impaired rats was explored. In experiment set up 1: Memory deficit was found in Morris water maze test on 14-16 days after STZ (ICV; 3mg/Kg) administration. STZ causes increased expression of GFAP, CD11b and TNF-a indicating glial activation and neuroinflammation. STZ also significantly increased the level of ROS, nitrite, Ca(2+) and reduced the mitochondrial activity in synaptosomal preparation illustrating free radical generation and excitotoxicity. Increased expression and activity of Caspase-3 was also observed in STZ treated rat which specify apoptotic cell death in hippocampus and cortex. STZ treatment showed decrease expression of post synaptic markers CaMKIIa and PSD-95, while, expression of pre synaptic markers (synaptophysin and SNAP-25) remains unaltered indicating selective post synaptic DISEASE. Oral treatment with Memantine (10mg/kg) and CHEMICAL (50 mg/kg) daily for 13 days attenuated STZ induced glial activation, apoptotic cell death and post synaptic DISEASE in rat brain. Further, in experiment set up 2: where memory function was not affected i.e. 7-9 days after STZ treatment. The level of GFAP, CD11b, TNF-a, ROS and nitrite levels were increased. On the other hand, apoptotic marker, synaptic markers, mitochondrial activity and Ca(2+) levels remained unaffected. Collective data indicates that neuroinflammatory process and oxidative stress occurs earlier to apoptosis and does not affect memory function. Present study clearly suggests that glial activation and post synaptic DISEASE are the key factors in STZ induced memory impairment and neuronal cell death. | NO-RELATIONSHIP |
| Glial activation and post-synaptic DISEASE: the key events in Streptozotocin (ICV) induced memory impairment in rats. In the present study the role of glial activation and post synaptic toxicity in ICV Streptozotocin (STZ) induced memory impaired rats was explored. In experiment set up 1: Memory deficit was found in Morris water maze test on 14-16 days after STZ (ICV; 3mg/Kg) administration. STZ causes increased expression of GFAP, CD11b and TNF-a indicating glial activation and neuroinflammation. STZ also significantly increased the level of ROS, nitrite, CHEMICAL(2+) and reduced the mitochondrial activity in synaptosomal preparation illustrating free radical generation and excitotoxicity. Increased expression and activity of Caspase-3 was also observed in STZ treated rat which specify apoptotic cell death in hippocampus and cortex. STZ treatment showed decrease expression of post synaptic markers CaMKIIa and PSD-95, while, expression of pre synaptic markers (synaptophysin and SNAP-25) remains unaltered indicating selective post synaptic DISEASE. Oral treatment with Memantine (10mg/kg) and Ibuprofen (50 mg/kg) daily for 13 days attenuated STZ induced glial activation, apoptotic cell death and post synaptic DISEASE in rat brain. Further, in experiment set up 2: where memory function was not affected i.e. 7-9 days after STZ treatment. The level of GFAP, CD11b, TNF-a, ROS and nitrite levels were increased. On the other hand, apoptotic marker, synaptic markers, mitochondrial activity and CHEMICAL(2+) levels remained unaffected. Collective data indicates that neuroinflammatory process and oxidative stress occurs earlier to apoptosis and does not affect memory function. Present study clearly suggests that glial activation and post synaptic DISEASE are the key factors in STZ induced memory impairment and neuronal cell death. | NO-RELATIONSHIP |
| Glial activation and post-synaptic neurotoxicity: the key events in Streptozotocin (ICV) induced memory impairment in rats. In the present study the role of glial activation and post synaptic DISEASE in ICV Streptozotocin (STZ) induced memory impaired rats was explored. In experiment set up 1: Memory deficit was found in Morris water maze test on 14-16 days after STZ (ICV; 3mg/Kg) administration. STZ causes increased expression of GFAP, CD11b and TNF-a indicating glial activation and neuroinflammation. STZ also significantly increased the level of ROS, nitrite, Ca(2+) and reduced the mitochondrial activity in synaptosomal preparation illustrating free radical generation and DISEASE. Increased expression and activity of Caspase-3 was also observed in STZ treated rat which specify apoptotic cell death in hippocampus and cortex. STZ treatment showed decrease expression of post synaptic markers CaMKIIa and PSD-95, while, expression of pre synaptic markers (synaptophysin and SNAP-25) remains unaltered indicating selective post synaptic neurotoxicity. Oral treatment with CHEMICAL (10mg/kg) and Ibuprofen (50 mg/kg) daily for 13 days attenuated STZ induced glial activation, apoptotic cell death and post synaptic neurotoxicity in rat brain. Further, in experiment set up 2: where memory function was not affected i.e. 7-9 days after STZ treatment. The level of GFAP, CD11b, TNF-a, ROS and nitrite levels were increased. On the other hand, apoptotic marker, synaptic markers, mitochondrial activity and Ca(2+) levels remained unaffected. Collective data indicates that neuroinflammatory process and oxidative stress occurs earlier to apoptosis and does not affect memory function. Present study clearly suggests that glial activation and post synaptic neurotoxicity are the key factors in STZ induced memory impairment and neuronal cell death. | NO-RELATIONSHIP |
| Glial activation and post-synaptic DISEASE: the key events in Streptozotocin (ICV) induced memory impairment in rats. In the present study the role of glial activation and post synaptic toxicity in ICV Streptozotocin (STZ) induced memory impaired rats was explored. In experiment set up 1: Memory deficit was found in Morris water maze test on 14-16 days after STZ (ICV; 3mg/Kg) administration. STZ causes increased expression of GFAP, CD11b and TNF-a indicating glial activation and neuroinflammation. STZ also significantly increased the level of ROS, nitrite, Ca(2+) and reduced the mitochondrial activity in synaptosomal preparation illustrating free radical generation and excitotoxicity. Increased expression and activity of Caspase-3 was also observed in STZ treated rat which specify apoptotic cell death in hippocampus and cortex. STZ treatment showed decrease expression of post synaptic markers CaMKIIa and PSD-95, while, expression of pre synaptic markers (synaptophysin and SNAP-25) remains unaltered indicating selective post synaptic DISEASE. Oral treatment with CHEMICAL (10mg/kg) and Ibuprofen (50 mg/kg) daily for 13 days attenuated STZ induced glial activation, apoptotic cell death and post synaptic DISEASE in rat brain. Further, in experiment set up 2: where memory function was not affected i.e. 7-9 days after STZ treatment. The level of GFAP, CD11b, TNF-a, ROS and nitrite levels were increased. On the other hand, apoptotic marker, synaptic markers, mitochondrial activity and Ca(2+) levels remained unaffected. Collective data indicates that neuroinflammatory process and oxidative stress occurs earlier to apoptosis and does not affect memory function. Present study clearly suggests that glial activation and post synaptic DISEASE are the key factors in STZ induced memory impairment and neuronal cell death. | NO-RELATIONSHIP |
| Glial activation and post-synaptic DISEASE: the key events in Streptozotocin (ICV) induced memory impairment in rats. In the present study the role of glial activation and post synaptic toxicity in ICV Streptozotocin (STZ) induced memory impaired rats was explored. In experiment set up 1: Memory deficit was found in Morris water maze test on 14-16 days after STZ (ICV; 3mg/Kg) administration. STZ causes increased expression of GFAP, CD11b and TNF-a indicating glial activation and neuroinflammation. STZ also significantly increased the level of ROS, CHEMICAL, Ca(2+) and reduced the mitochondrial activity in synaptosomal preparation illustrating free radical generation and excitotoxicity. Increased expression and activity of Caspase-3 was also observed in STZ treated rat which specify apoptotic cell death in hippocampus and cortex. STZ treatment showed decrease expression of post synaptic markers CaMKIIa and PSD-95, while, expression of pre synaptic markers (synaptophysin and SNAP-25) remains unaltered indicating selective post synaptic DISEASE. Oral treatment with Memantine (10mg/kg) and Ibuprofen (50 mg/kg) daily for 13 days attenuated STZ induced glial activation, apoptotic cell death and post synaptic DISEASE in rat brain. Further, in experiment set up 2: where memory function was not affected i.e. 7-9 days after STZ treatment. The level of GFAP, CD11b, TNF-a, ROS and CHEMICAL levels were increased. On the other hand, apoptotic marker, synaptic markers, mitochondrial activity and Ca(2+) levels remained unaffected. Collective data indicates that neuroinflammatory process and oxidative stress occurs earlier to apoptosis and does not affect memory function. Present study clearly suggests that glial activation and post synaptic DISEASE are the key factors in STZ induced memory impairment and neuronal cell death. | NO-RELATIONSHIP |
| Glial activation and post-synaptic neurotoxicity: the key events in Streptozotocin (ICV) induced memory impairment in rats. In the present study the role of glial activation and post synaptic DISEASE in ICV Streptozotocin (STZ) induced memory impaired rats was explored. In experiment set up 1: Memory deficit was found in Morris water maze test on 14-16 days after STZ (ICV; 3mg/Kg) administration. STZ causes increased expression of GFAP, CD11b and TNF-a indicating glial activation and neuroinflammation. STZ also significantly increased the level of ROS, nitrite, CHEMICAL(2+) and reduced the mitochondrial activity in synaptosomal preparation illustrating free radical generation and DISEASE. Increased expression and activity of Caspase-3 was also observed in STZ treated rat which specify apoptotic cell death in hippocampus and cortex. STZ treatment showed decrease expression of post synaptic markers CaMKIIa and PSD-95, while, expression of pre synaptic markers (synaptophysin and SNAP-25) remains unaltered indicating selective post synaptic neurotoxicity. Oral treatment with Memantine (10mg/kg) and Ibuprofen (50 mg/kg) daily for 13 days attenuated STZ induced glial activation, apoptotic cell death and post synaptic neurotoxicity in rat brain. Further, in experiment set up 2: where memory function was not affected i.e. 7-9 days after STZ treatment. The level of GFAP, CD11b, TNF-a, ROS and nitrite levels were increased. On the other hand, apoptotic marker, synaptic markers, mitochondrial activity and CHEMICAL(2+) levels remained unaffected. Collective data indicates that neuroinflammatory process and oxidative stress occurs earlier to apoptosis and does not affect memory function. Present study clearly suggests that glial activation and post synaptic neurotoxicity are the key factors in STZ induced memory impairment and neuronal cell death. | NO-RELATIONSHIP |
| Glial activation and post-synaptic neurotoxicity: the key events in Streptozotocin (ICV) induced memory impairment in rats. In the present study the role of glial activation and post synaptic DISEASE in ICV Streptozotocin (STZ) induced memory impaired rats was explored. In experiment set up 1: Memory deficit was found in Morris water maze test on 14-16 days after STZ (ICV; 3mg/Kg) administration. STZ causes increased expression of GFAP, CD11b and TNF-a indicating glial activation and neuroinflammation. STZ also significantly increased the level of ROS, CHEMICAL, Ca(2+) and reduced the mitochondrial activity in synaptosomal preparation illustrating free radical generation and DISEASE. Increased expression and activity of Caspase-3 was also observed in STZ treated rat which specify apoptotic cell death in hippocampus and cortex. STZ treatment showed decrease expression of post synaptic markers CaMKIIa and PSD-95, while, expression of pre synaptic markers (synaptophysin and SNAP-25) remains unaltered indicating selective post synaptic neurotoxicity. Oral treatment with Memantine (10mg/kg) and Ibuprofen (50 mg/kg) daily for 13 days attenuated STZ induced glial activation, apoptotic cell death and post synaptic neurotoxicity in rat brain. Further, in experiment set up 2: where memory function was not affected i.e. 7-9 days after STZ treatment. The level of GFAP, CD11b, TNF-a, ROS and CHEMICAL levels were increased. On the other hand, apoptotic marker, synaptic markers, mitochondrial activity and Ca(2+) levels remained unaffected. Collective data indicates that neuroinflammatory process and oxidative stress occurs earlier to apoptosis and does not affect memory function. Present study clearly suggests that glial activation and post synaptic neurotoxicity are the key factors in STZ induced memory impairment and neuronal cell death. | NO-RELATIONSHIP |
| Comparison of effects of isotonic sodium chloride with diltiazem in prevention of CHEMICAL-induced nephropathy. INTRODUCTION AND OBJECTIVE: CHEMICAL-induced nephropathy (CIN) significantly increases the morbidity and mortality of patients. The aim of this study is to investigate and compare the protective effects of isotonic sodium chloride with sodium bicarbonate infusion and isotonic sodium chloride infusion with diltiazem, a calcium channel blocker, in preventing CIN. MATERIALS AND METHODS: Our study included patients who were administered 30-60 mL of iodinated CHEMICAL agent for percutaneous coronary angiography (PCAG), all with creatinine values between 1.1 and 3.1 mg/dL. Patients were divided into three groups and each group had 20 patients. The first group of patients was administered isotonic sodium chloride; the second group was administered a solution that of 5% dextrose and sodium bicarbonate, while the third group was administered isotonic sodium chloride before and after the CHEMICAL injection. The third group received an additional injection of diltiazem the day before and first 2 days after the CHEMICAL injection. All of the patients' plasma blood urea nitrogen (BUN) and creatinine levels were measured on the second and seventh day after the administration of intravenous CHEMICAL material. RESULTS: The basal creatinine levels were similar for all three groups (p > 0.05). Among a total of 60 patients included in the study, 16 patients developed DISEASE (DISEASE) on the second day after CHEMICAL material was injected (26.6%). The number of patients who developed DISEASE on the second day after the injection in the first group was five (25%), in the second group was six (30%) and the third group was five (25%) (p > 0.05). CONCLUSION: There was no significant difference between isotonic sodium chloride, sodium bicarbonate and isotonic sodium chloride with diltiazem application in prevention of CIN. | CHEMICAL-INDUCED-DISEASE |
| Comparison of effects of isotonic sodium chloride with diltiazem in prevention of contrast-induced DISEASE. INTRODUCTION AND OBJECTIVE: Contrast-induced DISEASE (CIN) significantly increases the morbidity and mortality of patients. The aim of this study is to investigate and compare the protective effects of isotonic sodium chloride with CHEMICAL infusion and isotonic sodium chloride infusion with diltiazem, a calcium channel blocker, in preventing CIN. MATERIALS AND METHODS: Our study included patients who were administered 30-60 mL of iodinated contrast agent for percutaneous coronary angiography (PCAG), all with creatinine values between 1.1 and 3.1 mg/dL. Patients were divided into three groups and each group had 20 patients. The first group of patients was administered isotonic sodium chloride; the second group was administered a solution that of 5% dextrose and CHEMICAL, while the third group was administered isotonic sodium chloride before and after the contrast injection. The third group received an additional injection of diltiazem the day before and first 2 days after the contrast injection. All of the patients' plasma blood urea nitrogen (BUN) and creatinine levels were measured on the second and seventh day after the administration of intravenous contrast material. RESULTS: The basal creatinine levels were similar for all three groups (p > 0.05). Among a total of 60 patients included in the study, 16 patients developed acute renal failure (ARF) on the second day after contrast material was injected (26.6%). The number of patients who developed ARF on the second day after the injection in the first group was five (25%), in the second group was six (30%) and the third group was five (25%) (p > 0.05). CONCLUSION: There was no significant difference between isotonic sodium chloride, CHEMICAL and isotonic sodium chloride with diltiazem application in prevention of CIN. | CHEMICAL-INDUCED-DISEASE |
| Comparison of effects of isotonic sodium chloride with CHEMICAL in prevention of contrast-induced DISEASE. INTRODUCTION AND OBJECTIVE: Contrast-induced DISEASE (CIN) significantly increases the morbidity and mortality of patients. The aim of this study is to investigate and compare the protective effects of isotonic sodium chloride with sodium bicarbonate infusion and isotonic sodium chloride infusion with CHEMICAL, a calcium channel blocker, in preventing CIN. MATERIALS AND METHODS: Our study included patients who were administered 30-60 mL of iodinated contrast agent for percutaneous coronary angiography (PCAG), all with creatinine values between 1.1 and 3.1 mg/dL. Patients were divided into three groups and each group had 20 patients. The first group of patients was administered isotonic sodium chloride; the second group was administered a solution that of 5% dextrose and sodium bicarbonate, while the third group was administered isotonic sodium chloride before and after the contrast injection. The third group received an additional injection of CHEMICAL the day before and first 2 days after the contrast injection. All of the patients' plasma blood urea nitrogen (BUN) and creatinine levels were measured on the second and seventh day after the administration of intravenous contrast material. RESULTS: The basal creatinine levels were similar for all three groups (p > 0.05). Among a total of 60 patients included in the study, 16 patients developed acute renal failure (ARF) on the second day after contrast material was injected (26.6%). The number of patients who developed ARF on the second day after the injection in the first group was five (25%), in the second group was six (30%) and the third group was five (25%) (p > 0.05). CONCLUSION: There was no significant difference between isotonic sodium chloride, sodium bicarbonate and isotonic sodium chloride with CHEMICAL application in prevention of CIN. | CHEMICAL-INDUCED-DISEASE |
| Comparison of effects of isotonic sodium chloride with diltiazem in prevention of contrast-induced DISEASE. INTRODUCTION AND OBJECTIVE: Contrast-induced DISEASE (CIN) significantly increases the morbidity and mortality of patients. The aim of this study is to investigate and compare the protective effects of isotonic sodium chloride with sodium bicarbonate infusion and isotonic sodium chloride infusion with diltiazem, a CHEMICAL channel blocker, in preventing CIN. MATERIALS AND METHODS: Our study included patients who were administered 30-60 mL of iodinated contrast agent for percutaneous coronary angiography (PCAG), all with creatinine values between 1.1 and 3.1 mg/dL. Patients were divided into three groups and each group had 20 patients. The first group of patients was administered isotonic sodium chloride; the second group was administered a solution that of 5% dextrose and sodium bicarbonate, while the third group was administered isotonic sodium chloride before and after the contrast injection. The third group received an additional injection of diltiazem the day before and first 2 days after the contrast injection. All of the patients' plasma blood urea nitrogen (BUN) and creatinine levels were measured on the second and seventh day after the administration of intravenous contrast material. RESULTS: The basal creatinine levels were similar for all three groups (p > 0.05). Among a total of 60 patients included in the study, 16 patients developed acute renal failure (ARF) on the second day after contrast material was injected (26.6%). The number of patients who developed ARF on the second day after the injection in the first group was five (25%), in the second group was six (30%) and the third group was five (25%) (p > 0.05). CONCLUSION: There was no significant difference between isotonic sodium chloride, sodium bicarbonate and isotonic sodium chloride with diltiazem application in prevention of CIN. | CHEMICAL-INDUCED-DISEASE |
| Comparison of effects of isotonic CHEMICAL with diltiazem in prevention of contrast-induced DISEASE. INTRODUCTION AND OBJECTIVE: Contrast-induced DISEASE (CIN) significantly increases the morbidity and mortality of patients. The aim of this study is to investigate and compare the protective effects of isotonic CHEMICAL with sodium bicarbonate infusion and isotonic CHEMICAL infusion with diltiazem, a calcium channel blocker, in preventing CIN. MATERIALS AND METHODS: Our study included patients who were administered 30-60 mL of iodinated contrast agent for percutaneous coronary angiography (PCAG), all with creatinine values between 1.1 and 3.1 mg/dL. Patients were divided into three groups and each group had 20 patients. The first group of patients was administered isotonic CHEMICAL; the second group was administered a solution that of 5% dextrose and sodium bicarbonate, while the third group was administered isotonic CHEMICAL before and after the contrast injection. The third group received an additional injection of diltiazem the day before and first 2 days after the contrast injection. All of the patients' plasma blood urea nitrogen (BUN) and creatinine levels were measured on the second and seventh day after the administration of intravenous contrast material. RESULTS: The basal creatinine levels were similar for all three groups (p > 0.05). Among a total of 60 patients included in the study, 16 patients developed acute renal failure (ARF) on the second day after contrast material was injected (26.6%). The number of patients who developed ARF on the second day after the injection in the first group was five (25%), in the second group was six (30%) and the third group was five (25%) (p > 0.05). CONCLUSION: There was no significant difference between isotonic CHEMICAL, sodium bicarbonate and isotonic CHEMICAL with diltiazem application in prevention of CIN. | CHEMICAL-INDUCED-DISEASE |
| Comparison of effects of isotonic sodium chloride with diltiazem in prevention of contrast-induced DISEASE. INTRODUCTION AND OBJECTIVE: Contrast-induced DISEASE (CIN) significantly increases the morbidity and mortality of patients. The aim of this study is to investigate and compare the protective effects of isotonic sodium chloride with sodium bicarbonate infusion and isotonic sodium chloride infusion with diltiazem, a calcium channel blocker, in preventing CIN. MATERIALS AND METHODS: Our study included patients who were administered 30-60 mL of iodinated contrast agent for percutaneous coronary angiography (PCAG), all with creatinine values between 1.1 and 3.1 mg/dL. Patients were divided into three groups and each group had 20 patients. The first group of patients was administered isotonic sodium chloride; the second group was administered a solution that of 5% dextrose and sodium bicarbonate, while the third group was administered isotonic sodium chloride before and after the contrast injection. The third group received an additional injection of diltiazem the day before and first 2 days after the contrast injection. All of the patients' plasma CHEMICAL (CHEMICAL) and creatinine levels were measured on the second and seventh day after the administration of intravenous contrast material. RESULTS: The basal creatinine levels were similar for all three groups (p > 0.05). Among a total of 60 patients included in the study, 16 patients developed acute renal failure (ARF) on the second day after contrast material was injected (26.6%). The number of patients who developed ARF on the second day after the injection in the first group was five (25%), in the second group was six (30%) and the third group was five (25%) (p > 0.05). CONCLUSION: There was no significant difference between isotonic sodium chloride, sodium bicarbonate and isotonic sodium chloride with diltiazem application in prevention of CIN. | CHEMICAL-INDUCED-DISEASE |
| Comparison of effects of isotonic sodium chloride with diltiazem in prevention of contrast-induced DISEASE. INTRODUCTION AND OBJECTIVE: Contrast-induced DISEASE (CIN) significantly increases the morbidity and mortality of patients. The aim of this study is to investigate and compare the protective effects of isotonic sodium chloride with sodium bicarbonate infusion and isotonic sodium chloride infusion with diltiazem, a calcium channel blocker, in preventing CIN. MATERIALS AND METHODS: Our study included patients who were administered 30-60 mL of iodinated contrast agent for percutaneous coronary angiography (PCAG), all with creatinine values between 1.1 and 3.1 mg/dL. Patients were divided into three groups and each group had 20 patients. The first group of patients was administered isotonic sodium chloride; the second group was administered a solution that of 5% CHEMICAL and sodium bicarbonate, while the third group was administered isotonic sodium chloride before and after the contrast injection. The third group received an additional injection of diltiazem the day before and first 2 days after the contrast injection. All of the patients' plasma blood urea nitrogen (BUN) and creatinine levels were measured on the second and seventh day after the administration of intravenous contrast material. RESULTS: The basal creatinine levels were similar for all three groups (p > 0.05). Among a total of 60 patients included in the study, 16 patients developed acute renal failure (ARF) on the second day after contrast material was injected (26.6%). The number of patients who developed ARF on the second day after the injection in the first group was five (25%), in the second group was six (30%) and the third group was five (25%) (p > 0.05). CONCLUSION: There was no significant difference between isotonic sodium chloride, sodium bicarbonate and isotonic sodium chloride with diltiazem application in prevention of CIN. | CHEMICAL-INDUCED-DISEASE |
| Comparison of effects of isotonic sodium chloride with diltiazem in prevention of contrast-induced DISEASE. INTRODUCTION AND OBJECTIVE: Contrast-induced DISEASE (CIN) significantly increases the morbidity and mortality of patients. The aim of this study is to investigate and compare the protective effects of isotonic sodium chloride with sodium bicarbonate infusion and isotonic sodium chloride infusion with diltiazem, a calcium channel blocker, in preventing CIN. MATERIALS AND METHODS: Our study included patients who were administered 30-60 mL of iodinated contrast agent for percutaneous coronary angiography (PCAG), all with CHEMICAL values between 1.1 and 3.1 mg/dL. Patients were divided into three groups and each group had 20 patients. The first group of patients was administered isotonic sodium chloride; the second group was administered a solution that of 5% dextrose and sodium bicarbonate, while the third group was administered isotonic sodium chloride before and after the contrast injection. The third group received an additional injection of diltiazem the day before and first 2 days after the contrast injection. All of the patients' plasma blood urea nitrogen (BUN) and CHEMICAL levels were measured on the second and seventh day after the administration of intravenous contrast material. RESULTS: The basal CHEMICAL levels were similar for all three groups (p > 0.05). Among a total of 60 patients included in the study, 16 patients developed acute renal failure (ARF) on the second day after contrast material was injected (26.6%). The number of patients who developed ARF on the second day after the injection in the first group was five (25%), in the second group was six (30%) and the third group was five (25%) (p > 0.05). CONCLUSION: There was no significant difference between isotonic sodium chloride, sodium bicarbonate and isotonic sodium chloride with diltiazem application in prevention of CIN. | CHEMICAL-INDUCED-DISEASE |
| Neurocognitive and neuroradiologic central nervous system late effects in children treated on Pediatric Oncology Group (POG) P9605 (standard risk) and P9201 (lesser risk) acute lymphoblastic leukemia protocols (ACCL0131): a CHEMICAL consequence? A report from the Children's Oncology Group. Concerns about long-term CHEMICAL (CHEMICAL) neurotoxicity in the 1990s led to modifications in intrathecal (IT) therapy, leucovorin rescue, and frequency of systemic CHEMICAL administration in children with acute lymphoblastic leukemia. In this study, neurocognitive outcomes and neuroradiologic evidence of leukoencephalopathy were compared in children treated with intense central nervous system (CNS)-directed therapy (P9605) versus those receiving fewer CNS-directed treatment days during intensive consolidation (P9201). A total of 66 children from 16 Pediatric Oncology Group institutions with "standard-risk" acute lymphoblastic leukemia, 1.00 to 9.99 years at diagnosis, without evidence of CNS leukemia at diagnosis were enrolled on ACCL0131: 28 from P9201 and 38 from P9605. Magnetic resonance imaging scans and standard neuropsychological tests were performed >2.6 years after the end of treatment. Significantly more P9605 patients developed leukoencephalopathy compared with P9201 patients (68%, 95% confidence interval 49%-83% vs. 22%, 95% confidence interval 5%-44%; P=0.001) identified as late as 7.7 years after the end of treatment. Overall, 40% of patients scored <85 on either Verbal or Performance IQ. Children on both studies had significant DISEASE, but P9605 children scored below average on more neurocognitive measures than those treated on P9201 (82%, 14/17 measures vs. 24%, 4/17 measures). This supports ongoing concerns about intensive CHEMICAL exposure as a major contributor to CNS late effects. | CHEMICAL-INDUCED-DISEASE |
| Neurocognitive and neuroradiologic central nervous system late effects in children treated on Pediatric Oncology Group (POG) P9605 (standard risk) and P9201 (lesser risk) acute lymphoblastic leukemia protocols (ACCL0131): a CHEMICAL consequence? A report from the Children's Oncology Group. Concerns about long-term CHEMICAL (CHEMICAL) neurotoxicity in the 1990s led to modifications in intrathecal (IT) therapy, leucovorin rescue, and frequency of systemic CHEMICAL administration in children with acute lymphoblastic leukemia. In this study, neurocognitive outcomes and neuroradiologic evidence of DISEASE were compared in children treated with intense central nervous system (CNS)-directed therapy (P9605) versus those receiving fewer CNS-directed treatment days during intensive consolidation (P9201). A total of 66 children from 16 Pediatric Oncology Group institutions with "standard-risk" acute lymphoblastic leukemia, 1.00 to 9.99 years at diagnosis, without evidence of CNS leukemia at diagnosis were enrolled on ACCL0131: 28 from P9201 and 38 from P9605. Magnetic resonance imaging scans and standard neuropsychological tests were performed >2.6 years after the end of treatment. Significantly more P9605 patients developed DISEASE compared with P9201 patients (68%, 95% confidence interval 49%-83% vs. 22%, 95% confidence interval 5%-44%; P=0.001) identified as late as 7.7 years after the end of treatment. Overall, 40% of patients scored <85 on either Verbal or Performance IQ. Children on both studies had significant attention problems, but P9605 children scored below average on more neurocognitive measures than those treated on P9201 (82%, 14/17 measures vs. 24%, 4/17 measures). This supports ongoing concerns about intensive CHEMICAL exposure as a major contributor to CNS late effects. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL overdosage-induced generalized seizure in renal failure. We report a 45-year-old lady with chronic kidney disease stage 4 due to chronic tubulointerstial disease. She was admitted to our center for severe anemia due to menorrhagia and deterioration of renal function. She was infused three units of packed cells during a session of hemodialysis. CHEMICAL (CHEMICAL) 1 g 8-hourly was administered to her to control bleeding per vaginum. Two hours after the sixth dose of CHEMICAL, she had an episode of generalized DISEASE. CHEMICAL was discontinued. Investigations of the patient revealed no biochemical or structural central nervous system abnormalities that could have provoked the convulsions. She did not require any further dialytic support. She had no further episodes of convulsion till dis-charge and during the two months of follow-up. Thus, the precipitating cause of convulsions was believed to be an overdose of CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Pre-treatment of CHEMICAL-induced cardiovascular depression using different lipid formulations of propofol. BACKGROUND: Pre-treatment with lipid emulsions has been shown to increase lethal doses of CHEMICAL, and the lipid content of propofol may alleviate CHEMICAL-induced cardiotoxicity. The aim of this study is to investigate the effects of propofol in intralipid or medialipid emulsions on CHEMICAL-induced cardiotoxicity. METHODS: Rats were anaesthetised with ketamine and were given 0.5 mg/kg/min propofol in intralipid (Group P), propofol in medialipid (Group L), or saline (Group C) over 20 min. Thereafter, 2 mg/kg/min CHEMICAL 0.5% was infused. We recorded time to first dysrhythmia occurrence, respective times to 25% and 50% reduction of the heart rate (HR) and mean arterial pressure, and time to DISEASE and total amount of CHEMICAL consumption. Blood and tissue samples were collected following DISEASE. RESULTS: The time to first dysrhythmia occurrence, time to 25% and 50% reductions in HR, and time to DISEASE were longer in Group P than the other groups. The cumulative CHEMICAL dose given at those time points was higher in Group P. Plasma CHEMICAL levels were significantly lower in Group P than in Group C. CHEMICAL levels in the brain and heart were significantly lower in Group P and Group L than in Group C. CONCLUSION: We conclude that pre-treatment with propofol in intralipid, compared with propofol in medialipid or saline, delayed the onset of CHEMICAL-induced cardiotoxic effects as well as reduced plasma CHEMICAL levels. Further studies are needed to explore tissue CHEMICAL levels of propofol in medialipid and adapt these results to clinical practice. | CHEMICAL-INDUCED-DISEASE |
| Pre-treatment of CHEMICAL-induced cardiovascular depression using different lipid formulations of propofol. BACKGROUND: Pre-treatment with lipid emulsions has been shown to increase lethal doses of CHEMICAL, and the lipid content of propofol may alleviate CHEMICAL-induced DISEASE. The aim of this study is to investigate the effects of propofol in intralipid or medialipid emulsions on CHEMICAL-induced DISEASE. METHODS: Rats were anaesthetised with ketamine and were given 0.5 mg/kg/min propofol in intralipid (Group P), propofol in medialipid (Group L), or saline (Group C) over 20 min. Thereafter, 2 mg/kg/min CHEMICAL 0.5% was infused. We recorded time to first dysrhythmia occurrence, respective times to 25% and 50% reduction of the heart rate (HR) and mean arterial pressure, and time to asystole and total amount of CHEMICAL consumption. Blood and tissue samples were collected following asystole. RESULTS: The time to first dysrhythmia occurrence, time to 25% and 50% reductions in HR, and time to asystole were longer in Group P than the other groups. The cumulative CHEMICAL dose given at those time points was higher in Group P. Plasma CHEMICAL levels were significantly lower in Group P than in Group C. CHEMICAL levels in the brain and heart were significantly lower in Group P and Group L than in Group C. CONCLUSION: We conclude that pre-treatment with propofol in intralipid, compared with propofol in medialipid or saline, delayed the onset of CHEMICAL-induced DISEASE effects as well as reduced plasma CHEMICAL levels. Further studies are needed to explore tissue CHEMICAL levels of propofol in medialipid and adapt these results to clinical practice. | CHEMICAL-INDUCED-DISEASE |
| Pre-treatment of bupivacaine-induced cardiovascular depression using different lipid formulations of CHEMICAL. BACKGROUND: Pre-treatment with lipid emulsions has been shown to increase lethal doses of bupivacaine, and the lipid content of CHEMICAL may alleviate bupivacaine-induced cardiotoxicity. The aim of this study is to investigate the effects of CHEMICAL in intralipid or medialipid emulsions on bupivacaine-induced cardiotoxicity. METHODS: Rats were anaesthetised with ketamine and were given 0.5 mg/kg/min CHEMICAL in intralipid (Group P), CHEMICAL in medialipid (Group L), or saline (Group C) over 20 min. Thereafter, 2 mg/kg/min bupivacaine 0.5% was infused. We recorded time to first DISEASE occurrence, respective times to 25% and 50% reduction of the heart rate (HR) and mean arterial pressure, and time to asystole and total amount of bupivacaine consumption. Blood and tissue samples were collected following asystole. RESULTS: The time to first DISEASE occurrence, time to 25% and 50% reductions in HR, and time to asystole were longer in Group P than the other groups. The cumulative bupivacaine dose given at those time points was higher in Group P. Plasma bupivacaine levels were significantly lower in Group P than in Group C. Bupivacaine levels in the brain and heart were significantly lower in Group P and Group L than in Group C. CONCLUSION: We conclude that pre-treatment with CHEMICAL in intralipid, compared with CHEMICAL in medialipid or saline, delayed the onset of bupivacaine-induced cardiotoxic effects as well as reduced plasma bupivacaine levels. Further studies are needed to explore tissue bupivacaine levels of CHEMICAL in medialipid and adapt these results to clinical practice. | NO-RELATIONSHIP |
| Pre-treatment of bupivacaine-induced DISEASE using different lipid formulations of propofol. BACKGROUND: Pre-treatment with lipid emulsions has been shown to increase lethal doses of bupivacaine, and the lipid content of propofol may alleviate bupivacaine-induced cardiotoxicity. The aim of this study is to investigate the effects of propofol in intralipid or medialipid emulsions on bupivacaine-induced cardiotoxicity. METHODS: Rats were anaesthetised with CHEMICAL and were given 0.5 mg/kg/min propofol in intralipid (Group P), propofol in medialipid (Group L), or saline (Group C) over 20 min. Thereafter, 2 mg/kg/min bupivacaine 0.5% was infused. We recorded time to first dysrhythmia occurrence, respective times to 25% and 50% reduction of the heart rate (HR) and mean arterial pressure, and time to asystole and total amount of bupivacaine consumption. Blood and tissue samples were collected following asystole. RESULTS: The time to first dysrhythmia occurrence, time to 25% and 50% reductions in HR, and time to asystole were longer in Group P than the other groups. The cumulative bupivacaine dose given at those time points was higher in Group P. Plasma bupivacaine levels were significantly lower in Group P than in Group C. Bupivacaine levels in the brain and heart were significantly lower in Group P and Group L than in Group C. CONCLUSION: We conclude that pre-treatment with propofol in intralipid, compared with propofol in medialipid or saline, delayed the onset of bupivacaine-induced cardiotoxic effects as well as reduced plasma bupivacaine levels. Further studies are needed to explore tissue bupivacaine levels of propofol in medialipid and adapt these results to clinical practice. | NO-RELATIONSHIP |
| Pre-treatment of bupivacaine-induced DISEASE using different lipid formulations of CHEMICAL. BACKGROUND: Pre-treatment with lipid emulsions has been shown to increase lethal doses of bupivacaine, and the lipid content of CHEMICAL may alleviate bupivacaine-induced cardiotoxicity. The aim of this study is to investigate the effects of CHEMICAL in intralipid or medialipid emulsions on bupivacaine-induced cardiotoxicity. METHODS: Rats were anaesthetised with ketamine and were given 0.5 mg/kg/min CHEMICAL in intralipid (Group P), CHEMICAL in medialipid (Group L), or saline (Group C) over 20 min. Thereafter, 2 mg/kg/min bupivacaine 0.5% was infused. We recorded time to first dysrhythmia occurrence, respective times to 25% and 50% reduction of the heart rate (HR) and mean arterial pressure, and time to asystole and total amount of bupivacaine consumption. Blood and tissue samples were collected following asystole. RESULTS: The time to first dysrhythmia occurrence, time to 25% and 50% reductions in HR, and time to asystole were longer in Group P than the other groups. The cumulative bupivacaine dose given at those time points was higher in Group P. Plasma bupivacaine levels were significantly lower in Group P than in Group C. Bupivacaine levels in the brain and heart were significantly lower in Group P and Group L than in Group C. CONCLUSION: We conclude that pre-treatment with CHEMICAL in intralipid, compared with CHEMICAL in medialipid or saline, delayed the onset of bupivacaine-induced cardiotoxic effects as well as reduced plasma bupivacaine levels. Further studies are needed to explore tissue bupivacaine levels of CHEMICAL in medialipid and adapt these results to clinical practice. | NO-RELATIONSHIP |
| Pre-treatment of bupivacaine-induced cardiovascular depression using different lipid formulations of propofol. BACKGROUND: Pre-treatment with lipid emulsions has been shown to increase lethal doses of bupivacaine, and the lipid content of propofol may alleviate bupivacaine-induced cardiotoxicity. The aim of this study is to investigate the effects of propofol in intralipid or medialipid emulsions on bupivacaine-induced cardiotoxicity. METHODS: Rats were anaesthetised with CHEMICAL and were given 0.5 mg/kg/min propofol in intralipid (Group P), propofol in medialipid (Group L), or saline (Group C) over 20 min. Thereafter, 2 mg/kg/min bupivacaine 0.5% was infused. We recorded time to first DISEASE occurrence, respective times to 25% and 50% reduction of the heart rate (HR) and mean arterial pressure, and time to asystole and total amount of bupivacaine consumption. Blood and tissue samples were collected following asystole. RESULTS: The time to first DISEASE occurrence, time to 25% and 50% reductions in HR, and time to asystole were longer in Group P than the other groups. The cumulative bupivacaine dose given at those time points was higher in Group P. Plasma bupivacaine levels were significantly lower in Group P than in Group C. Bupivacaine levels in the brain and heart were significantly lower in Group P and Group L than in Group C. CONCLUSION: We conclude that pre-treatment with propofol in intralipid, compared with propofol in medialipid or saline, delayed the onset of bupivacaine-induced cardiotoxic effects as well as reduced plasma bupivacaine levels. Further studies are needed to explore tissue bupivacaine levels of propofol in medialipid and adapt these results to clinical practice. | NO-RELATIONSHIP |
| Drug-Induced Acute Liver Injury Within 12 Hours After CHEMICAL Therapy. Although statins are generally well-tolerated drugs, recent cases of drug-induced liver injury associated with their use have been reported. A 52-year-old Chinese man reported with liver damage, which appeared 12 hours after beginning treatment with CHEMICAL. Patient presented with complaints of increasing nausea, anorexia, and upper DISEASE. His laboratory values showed elevated creatine kinase and transaminases. Testing for autoantibodies was also negative. The liver biochemistries eventually normalized within 3 weeks of stopping the CHEMICAL. Therefore, when prescribing statins, the possibility of hepatic damage should be taken into account. | CHEMICAL-INDUCED-DISEASE |
| DISEASE Within 12 Hours After CHEMICAL Therapy. Although statins are generally well-tolerated drugs, recent cases of DISEASE associated with their use have been reported. A 52-year-old Chinese man reported with DISEASE, which appeared 12 hours after beginning treatment with CHEMICAL. Patient presented with complaints of increasing nausea, anorexia, and upper abdominal pain. His laboratory values showed elevated creatine kinase and transaminases. Testing for autoantibodies was also negative. The liver biochemistries eventually normalized within 3 weeks of stopping the CHEMICAL. Therefore, when prescribing statins, the possibility of DISEASE should be taken into account. | CHEMICAL-INDUCED-DISEASE |
| Drug-Induced Acute Liver Injury Within 12 Hours After CHEMICAL Therapy. Although statins are generally well-tolerated drugs, recent cases of drug-induced liver injury associated with their use have been reported. A 52-year-old Chinese man reported with liver damage, which appeared 12 hours after beginning treatment with CHEMICAL. Patient presented with complaints of increasing nausea, DISEASE, and upper abdominal pain. His laboratory values showed elevated creatine kinase and transaminases. Testing for autoantibodies was also negative. The liver biochemistries eventually normalized within 3 weeks of stopping the CHEMICAL. Therefore, when prescribing statins, the possibility of hepatic damage should be taken into account. | CHEMICAL-INDUCED-DISEASE |
| Drug-Induced Acute Liver Injury Within 12 Hours After CHEMICAL Therapy. Although statins are generally well-tolerated drugs, recent cases of drug-induced liver injury associated with their use have been reported. A 52-year-old Chinese man reported with liver damage, which appeared 12 hours after beginning treatment with CHEMICAL. Patient presented with complaints of increasing DISEASE, anorexia, and upper abdominal pain. His laboratory values showed elevated creatine kinase and transaminases. Testing for autoantibodies was also negative. The liver biochemistries eventually normalized within 3 weeks of stopping the CHEMICAL. Therefore, when prescribing statins, the possibility of hepatic damage should be taken into account. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL associated DISEASE and thrombocytopenia. CASE: We describe a second case of CHEMICAL associated DISEASE with thrombocytopenia and recovery upon discontinuation of therapy. The patient began to have changes in white blood cells and platelets within 48 h of administration of CHEMICAL and began to recover with 48 h of discontinuation. This case highlights that drug-induced blood dyscrasias can occur unexpectedly as a result of treatment with a commonly used drug thought to be "safe". CONCLUSION: According to Naranjo's algorithm the likelihood that our patient's DISEASE and thrombocytopenia occurred as a result of therapy with CHEMICAL is probable, with a total of six points. We feel that the weight of the overall evidence of this evidence is strong. In particular the temporal relationship of bone marrow suppression to the initiation of CHEMICAL and the abatement of symptoms that rapidly reversed immediately following discontinuation. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL associated agranulocytosis and DISEASE. CASE: We describe a second case of CHEMICAL associated agranulocytosis with DISEASE and recovery upon discontinuation of therapy. The patient began to have changes in white blood cells and platelets within 48 h of administration of CHEMICAL and began to recover with 48 h of discontinuation. This case highlights that drug-induced blood dyscrasias can occur unexpectedly as a result of treatment with a commonly used drug thought to be "safe". CONCLUSION: According to Naranjo's algorithm the likelihood that our patient's agranulocytosis and DISEASE occurred as a result of therapy with CHEMICAL is probable, with a total of six points. We feel that the weight of the overall evidence of this evidence is strong. In particular the temporal relationship of bone marrow suppression to the initiation of CHEMICAL and the abatement of symptoms that rapidly reversed immediately following discontinuation. | CHEMICAL-INDUCED-DISEASE |
| Two-dimensional speckle tracking echocardiography combined with high-sensitive cardiac troponin T in early detection and prediction of DISEASE during CHEMICAL-based chemotherapy. AIMS: To investigate whether alterations of myocardial strain and high-sensitive cardiac troponin T (cTnT) could predict future cardiac dysfunction in patients after CHEMICAL exposure. METHODS: Seventy-five patients with non-Hodgkin lymphoma treated with CHEMICAL were studied. Blood collection and echocardiography were performed at baseline, 1 day after the third cycle, and 1 day after completion of chemotherapy. Patients were studied using echocardiography during follow-up. Global longitudinal (GLS), circumferential (GCS), and radial strain (GRS) were calculated using speckle tracking echocardiography. Left ventricular ejection fraction was analysed by real-time 3D echocardiography. DISEASE was defined as a reduction of the LVEF of >5% to <55% with symptoms of heart failure or an asymptomatic reduction of the LVEF of >10% to <55%. RESULTS: Fourteen patients (18.67%) developed DISEASE after treatment. GLS (-18.48 + 1.72% vs. -15.96 + 1.6%), GCS (-20.93 + 2.86% vs. -19.20 + 3.21%), and GRS (39.23 + 6.44% vs. 34.98 + 6.2%) were markedly reduced and cTnT was elevated from 0.0010 + 0.0020 to 0.0073 + 0.0038 ng/mL (P all < 0.01) at the completion of chemotherapy compared with baseline values. A >15.9% decrease in GLS [sensitivity, 86%; specificity, 75%; area under the curve (AUC) = 0.815; P = 0.001] and a >0.004 ng/mL elevation in cTnT (sensitivity, 79%; specificity, 64%; AUC = 0.757; P = 0.005) from baseline to the third cycle of chemotherapy predicted later DISEASE. The decrease in GLS remained the only independent predictor of DISEASE (P = 0.000). CONCLUSIONS: GLS combined with cTnT may provide a reliable and non-invasive method to predict cardiac dysfunction in patients receiving anthracycline-based chemotherapy. | CHEMICAL-INDUCED-DISEASE |
| Two-dimensional speckle tracking echocardiography combined with high-sensitive cardiac troponin T in early detection and prediction of cardiotoxicity during CHEMICAL-based chemotherapy. AIMS: To investigate whether alterations of myocardial strain and high-sensitive cardiac troponin T (cTnT) could predict future cardiac dysfunction in patients after CHEMICAL exposure. METHODS: Seventy-five patients with non-Hodgkin lymphoma treated with CHEMICAL were studied. Blood collection and echocardiography were performed at baseline, 1 day after the third cycle, and 1 day after completion of chemotherapy. Patients were studied using echocardiography during follow-up. Global longitudinal (GLS), circumferential (GCS), and radial strain (GRS) were calculated using speckle tracking echocardiography. Left ventricular ejection fraction was analysed by real-time 3D echocardiography. Cardiotoxicity was defined as a reduction of the LVEF of >5% to <55% with symptoms of DISEASE or an asymptomatic reduction of the LVEF of >10% to <55%. RESULTS: Fourteen patients (18.67%) developed cardiotoxicity after treatment. GLS (-18.48 + 1.72% vs. -15.96 + 1.6%), GCS (-20.93 + 2.86% vs. -19.20 + 3.21%), and GRS (39.23 + 6.44% vs. 34.98 + 6.2%) were markedly reduced and cTnT was elevated from 0.0010 + 0.0020 to 0.0073 + 0.0038 ng/mL (P all < 0.01) at the completion of chemotherapy compared with baseline values. A >15.9% decrease in GLS [sensitivity, 86%; specificity, 75%; area under the curve (AUC) = 0.815; P = 0.001] and a >0.004 ng/mL elevation in cTnT (sensitivity, 79%; specificity, 64%; AUC = 0.757; P = 0.005) from baseline to the third cycle of chemotherapy predicted later cardiotoxicity. The decrease in GLS remained the only independent predictor of cardiotoxicity (P = 0.000). CONCLUSIONS: GLS combined with cTnT may provide a reliable and non-invasive method to predict cardiac dysfunction in patients receiving anthracycline-based chemotherapy. | CHEMICAL-INDUCED-DISEASE |
| Two-dimensional speckle tracking echocardiography combined with high-sensitive cardiac troponin T in early detection and prediction of cardiotoxicity during epirubicine-based chemotherapy. AIMS: To investigate whether alterations of DISEASE and high-sensitive cardiac troponin T (cTnT) could predict future cardiac dysfunction in patients after epirubicin exposure. METHODS: Seventy-five patients with non-Hodgkin lymphoma treated with epirubicin were studied. Blood collection and echocardiography were performed at baseline, 1 day after the third cycle, and 1 day after completion of chemotherapy. Patients were studied using echocardiography during follow-up. Global longitudinal (GLS), circumferential (GCS), and radial strain (GRS) were calculated using speckle tracking echocardiography. Left ventricular ejection fraction was analysed by real-time 3D echocardiography. Cardiotoxicity was defined as a reduction of the LVEF of >5% to <55% with symptoms of heart failure or an asymptomatic reduction of the LVEF of >10% to <55%. RESULTS: Fourteen patients (18.67%) developed cardiotoxicity after treatment. GLS (-18.48 + 1.72% vs. -15.96 + 1.6%), GCS (-20.93 + 2.86% vs. -19.20 + 3.21%), and GRS (39.23 + 6.44% vs. 34.98 + 6.2%) were markedly reduced and cTnT was elevated from 0.0010 + 0.0020 to 0.0073 + 0.0038 ng/mL (P all < 0.01) at the completion of chemotherapy compared with baseline values. A >15.9% decrease in GLS [sensitivity, 86%; specificity, 75%; area under the curve (AUC) = 0.815; P = 0.001] and a >0.004 ng/mL elevation in cTnT (sensitivity, 79%; specificity, 64%; AUC = 0.757; P = 0.005) from baseline to the third cycle of chemotherapy predicted later cardiotoxicity. The decrease in GLS remained the only independent predictor of cardiotoxicity (P = 0.000). CONCLUSIONS: GLS combined with cTnT may provide a reliable and non-invasive method to predict cardiac dysfunction in patients receiving CHEMICAL-based chemotherapy. | NO-RELATIONSHIP |
| Two-dimensional speckle tracking echocardiography combined with high-sensitive cardiac troponin T in early detection and prediction of cardiotoxicity during epirubicine-based chemotherapy. AIMS: To investigate whether alterations of myocardial strain and high-sensitive cardiac troponin T (cTnT) could predict future DISEASE in patients after epirubicin exposure. METHODS: Seventy-five patients with non-Hodgkin lymphoma treated with epirubicin were studied. Blood collection and echocardiography were performed at baseline, 1 day after the third cycle, and 1 day after completion of chemotherapy. Patients were studied using echocardiography during follow-up. Global longitudinal (GLS), circumferential (GCS), and radial strain (GRS) were calculated using speckle tracking echocardiography. Left ventricular ejection fraction was analysed by real-time 3D echocardiography. Cardiotoxicity was defined as a reduction of the LVEF of >5% to <55% with symptoms of heart failure or an asymptomatic reduction of the LVEF of >10% to <55%. RESULTS: Fourteen patients (18.67%) developed cardiotoxicity after treatment. GLS (-18.48 + 1.72% vs. -15.96 + 1.6%), GCS (-20.93 + 2.86% vs. -19.20 + 3.21%), and GRS (39.23 + 6.44% vs. 34.98 + 6.2%) were markedly reduced and cTnT was elevated from 0.0010 + 0.0020 to 0.0073 + 0.0038 ng/mL (P all < 0.01) at the completion of chemotherapy compared with baseline values. A >15.9% decrease in GLS [sensitivity, 86%; specificity, 75%; area under the curve (AUC) = 0.815; P = 0.001] and a >0.004 ng/mL elevation in cTnT (sensitivity, 79%; specificity, 64%; AUC = 0.757; P = 0.005) from baseline to the third cycle of chemotherapy predicted later cardiotoxicity. The decrease in GLS remained the only independent predictor of cardiotoxicity (P = 0.000). CONCLUSIONS: GLS combined with cTnT may provide a reliable and non-invasive method to predict DISEASE in patients receiving CHEMICAL-based chemotherapy. | NO-RELATIONSHIP |
| Two-dimensional speckle tracking echocardiography combined with high-sensitive cardiac troponin T in early detection and prediction of cardiotoxicity during epirubicine-based chemotherapy. AIMS: To investigate whether alterations of myocardial strain and high-sensitive cardiac troponin T (cTnT) could predict future cardiac dysfunction in patients after epirubicin exposure. METHODS: Seventy-five patients with DISEASE treated with epirubicin were studied. Blood collection and echocardiography were performed at baseline, 1 day after the third cycle, and 1 day after completion of chemotherapy. Patients were studied using echocardiography during follow-up. Global longitudinal (GLS), circumferential (GCS), and radial strain (GRS) were calculated using speckle tracking echocardiography. Left ventricular ejection fraction was analysed by real-time 3D echocardiography. Cardiotoxicity was defined as a reduction of the LVEF of >5% to <55% with symptoms of heart failure or an asymptomatic reduction of the LVEF of >10% to <55%. RESULTS: Fourteen patients (18.67%) developed cardiotoxicity after treatment. GLS (-18.48 + 1.72% vs. -15.96 + 1.6%), GCS (-20.93 + 2.86% vs. -19.20 + 3.21%), and GRS (39.23 + 6.44% vs. 34.98 + 6.2%) were markedly reduced and cTnT was elevated from 0.0010 + 0.0020 to 0.0073 + 0.0038 ng/mL (P all < 0.01) at the completion of chemotherapy compared with baseline values. A >15.9% decrease in GLS [sensitivity, 86%; specificity, 75%; area under the curve (AUC) = 0.815; P = 0.001] and a >0.004 ng/mL elevation in cTnT (sensitivity, 79%; specificity, 64%; AUC = 0.757; P = 0.005) from baseline to the third cycle of chemotherapy predicted later cardiotoxicity. The decrease in GLS remained the only independent predictor of cardiotoxicity (P = 0.000). CONCLUSIONS: GLS combined with cTnT may provide a reliable and non-invasive method to predict cardiac dysfunction in patients receiving CHEMICAL-based chemotherapy. | NO-RELATIONSHIP |
| Prevention of CHEMICAL-induced DISEASE: which is superior: Fentanyl, midazolam, or a combination? A Retrospective comparative study. BACKGROUND: In this retrospective comparative study, we aimed to compare the effectiveness of fentanyl, midazolam, and a combination of fentanyl and midazolam to prevent CHEMICAL-induced DISEASE. MATERIAL AND METHODS: This study was performed based on anesthesia records. Depending on the drugs that would be given before the induction of anesthesia with CHEMICAL, the patients were separated into 4 groups: no pretreatment (Group NP), fentanyl 1 ug.kg-1 (Group F), midazolam 0.03 mg.kg-1 (Group M), and midazolam 0.015 mg.kg-1 + fentanyl 0.5 ug.kg-1 (Group FM). Patients who received the same anesthetic procedure were selected: 2 minutes after intravenous injections of the pretreatment drugs, anesthesia is induced with 0.3 mg.kg-1 CHEMICAL injected intravenously over a period of 20-30 seconds. Myoclonic movements are evaluated, which were observed and graded according to clinical severity during the 2 minutes after CHEMICAL injection. The severity of pain due to CHEMICAL injection, mean arterial pressure, heart rate, and adverse effects were also evaluated. RESULTS: Study results showed that DISEASE incidence was 85%, 40%, 70%, and 25% in Group NP, Group F, Group M, and Group FM, respectively, and were significantly lower in Group F and Group FM. CONCLUSIONS: We conclude that pretreatment with fentanyl or combination of fentanyl and midazolam was effective in preventing CHEMICAL-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Prevention of etomidate-induced myoclonus: which is superior: CHEMICAL, midazolam, or a combination? A Retrospective comparative study. BACKGROUND: In this retrospective comparative study, we aimed to compare the effectiveness of CHEMICAL, midazolam, and a combination of CHEMICAL and midazolam to prevent etomidate-induced myoclonus. MATERIAL AND METHODS: This study was performed based on anesthesia records. Depending on the drugs that would be given before the induction of anesthesia with etomidate, the patients were separated into 4 groups: no pretreatment (Group NP), CHEMICAL 1 ug.kg-1 (Group F), midazolam 0.03 mg.kg-1 (Group M), and midazolam 0.015 mg.kg-1 + CHEMICAL 0.5 ug.kg-1 (Group FM). Patients who received the same anesthetic procedure were selected: 2 minutes after intravenous injections of the pretreatment drugs, anesthesia is induced with 0.3 mg.kg-1 etomidate injected intravenously over a period of 20-30 seconds. DISEASE are evaluated, which were observed and graded according to clinical severity during the 2 minutes after etomidate injection. The severity of pain due to etomidate injection, mean arterial pressure, heart rate, and adverse effects were also evaluated. RESULTS: Study results showed that myoclonus incidence was 85%, 40%, 70%, and 25% in Group NP, Group F, Group M, and Group FM, respectively, and were significantly lower in Group F and Group FM. CONCLUSIONS: We conclude that pretreatment with CHEMICAL or combination of CHEMICAL and midazolam was effective in preventing etomidate-induced myoclonus. | NO-RELATIONSHIP |
| Prevention of etomidate-induced myoclonus: which is superior: Fentanyl, CHEMICAL, or a combination? A Retrospective comparative study. BACKGROUND: In this retrospective comparative study, we aimed to compare the effectiveness of fentanyl, CHEMICAL, and a combination of fentanyl and CHEMICAL to prevent etomidate-induced myoclonus. MATERIAL AND METHODS: This study was performed based on anesthesia records. Depending on the drugs that would be given before the induction of anesthesia with etomidate, the patients were separated into 4 groups: no pretreatment (Group NP), fentanyl 1 ug.kg-1 (Group F), CHEMICAL 0.03 mg.kg-1 (Group M), and CHEMICAL 0.015 mg.kg-1 + fentanyl 0.5 ug.kg-1 (Group FM). Patients who received the same anesthetic procedure were selected: 2 minutes after intravenous injections of the pretreatment drugs, anesthesia is induced with 0.3 mg.kg-1 etomidate injected intravenously over a period of 20-30 seconds. Myoclonic movements are evaluated, which were observed and graded according to clinical severity during the 2 minutes after etomidate injection. The severity of DISEASE due to etomidate injection, mean arterial pressure, heart rate, and adverse effects were also evaluated. RESULTS: Study results showed that myoclonus incidence was 85%, 40%, 70%, and 25% in Group NP, Group F, Group M, and Group FM, respectively, and were significantly lower in Group F and Group FM. CONCLUSIONS: We conclude that pretreatment with fentanyl or combination of fentanyl and CHEMICAL was effective in preventing etomidate-induced myoclonus. | NO-RELATIONSHIP |
| Prevention of etomidate-induced myoclonus: which is superior: CHEMICAL, midazolam, or a combination? A Retrospective comparative study. BACKGROUND: In this retrospective comparative study, we aimed to compare the effectiveness of CHEMICAL, midazolam, and a combination of CHEMICAL and midazolam to prevent etomidate-induced myoclonus. MATERIAL AND METHODS: This study was performed based on anesthesia records. Depending on the drugs that would be given before the induction of anesthesia with etomidate, the patients were separated into 4 groups: no pretreatment (Group NP), CHEMICAL 1 ug.kg-1 (Group F), midazolam 0.03 mg.kg-1 (Group M), and midazolam 0.015 mg.kg-1 + CHEMICAL 0.5 ug.kg-1 (Group FM). Patients who received the same anesthetic procedure were selected: 2 minutes after intravenous injections of the pretreatment drugs, anesthesia is induced with 0.3 mg.kg-1 etomidate injected intravenously over a period of 20-30 seconds. Myoclonic movements are evaluated, which were observed and graded according to clinical severity during the 2 minutes after etomidate injection. The severity of DISEASE due to etomidate injection, mean arterial pressure, heart rate, and adverse effects were also evaluated. RESULTS: Study results showed that myoclonus incidence was 85%, 40%, 70%, and 25% in Group NP, Group F, Group M, and Group FM, respectively, and were significantly lower in Group F and Group FM. CONCLUSIONS: We conclude that pretreatment with CHEMICAL or combination of CHEMICAL and midazolam was effective in preventing etomidate-induced myoclonus. | NO-RELATIONSHIP |
| Prevention of etomidate-induced myoclonus: which is superior: Fentanyl, CHEMICAL, or a combination? A Retrospective comparative study. BACKGROUND: In this retrospective comparative study, we aimed to compare the effectiveness of fentanyl, CHEMICAL, and a combination of fentanyl and CHEMICAL to prevent etomidate-induced myoclonus. MATERIAL AND METHODS: This study was performed based on anesthesia records. Depending on the drugs that would be given before the induction of anesthesia with etomidate, the patients were separated into 4 groups: no pretreatment (Group NP), fentanyl 1 ug.kg-1 (Group F), CHEMICAL 0.03 mg.kg-1 (Group M), and CHEMICAL 0.015 mg.kg-1 + fentanyl 0.5 ug.kg-1 (Group FM). Patients who received the same anesthetic procedure were selected: 2 minutes after intravenous injections of the pretreatment drugs, anesthesia is induced with 0.3 mg.kg-1 etomidate injected intravenously over a period of 20-30 seconds. DISEASE are evaluated, which were observed and graded according to clinical severity during the 2 minutes after etomidate injection. The severity of pain due to etomidate injection, mean arterial pressure, heart rate, and adverse effects were also evaluated. RESULTS: Study results showed that myoclonus incidence was 85%, 40%, 70%, and 25% in Group NP, Group F, Group M, and Group FM, respectively, and were significantly lower in Group F and Group FM. CONCLUSIONS: We conclude that pretreatment with fentanyl or combination of fentanyl and CHEMICAL was effective in preventing etomidate-induced myoclonus. | NO-RELATIONSHIP |
| Cholestatic presentation of yellow CHEMICAL poisoning. Yellow CHEMICAL, a component of certain pesticide pastes and fireworks, is well known to cause hepatotoxicity. Poisoning with yellow CHEMICAL classically manifests with DISEASE leading to acute liver failure which may need liver transplantation. We present a case of yellow CHEMICAL poisoning in which a patient presented with florid clinical features of cholestasis highlighting the fact that cholestasis can rarely be a presenting feature of yellow CHEMICAL hepatotoxicity. | CHEMICAL-INDUCED-DISEASE |
| DISEASE presentation of yellow CHEMICAL poisoning. Yellow CHEMICAL, a component of certain pesticide pastes and fireworks, is well known to cause hepatotoxicity. Poisoning with yellow CHEMICAL classically manifests with acute hepatitis leading to acute liver failure which may need liver transplantation. We present a case of yellow CHEMICAL poisoning in which a patient presented with florid clinical features of DISEASE highlighting the fact that DISEASE can rarely be a presenting feature of yellow CHEMICAL hepatotoxicity. | CHEMICAL-INDUCED-DISEASE |
| Cholestatic presentation of yellow CHEMICAL poisoning. Yellow CHEMICAL, a component of certain pesticide pastes and fireworks, is well known to cause hepatotoxicity. Poisoning with yellow CHEMICAL classically manifests with acute hepatitis leading to DISEASE which may need liver transplantation. We present a case of yellow CHEMICAL poisoning in which a patient presented with florid clinical features of cholestasis highlighting the fact that cholestasis can rarely be a presenting feature of yellow CHEMICAL hepatotoxicity. | CHEMICAL-INDUCED-DISEASE |
| Vasovagal syncope and severe DISEASE following intranasal CHEMICAL for pediatric procedural sedation. We report syncope and DISEASE in an 11-year-old girl following administration of intranasal CHEMICAL for sedation for a voiding cystourethrogram. Following successful completion of VCUG and a 60-min recovery period, the patient's level of consciousness and vital signs returned to presedation levels. Upon leaving the sedation area, the patient collapsed, with no apparent inciting event. The patient quickly regained consciousness and no injury occurred. The primary abnormality found was persistent DISEASE, and she was admitted to the hospital for telemetric observation. The DISEASE lasted ~2 h, and further cardiac workup revealed no underlying abnormality. Unanticipated and previously unreported outcomes may be witnessed as we expand the use of certain sedatives to alternative routes of administration. | CHEMICAL-INDUCED-DISEASE |
| DISEASE and severe bradycardia following intranasal CHEMICAL for pediatric procedural sedation. We report syncope and bradycardia in an 11-year-old girl following administration of intranasal CHEMICAL for sedation for a voiding cystourethrogram. Following successful completion of VCUG and a 60-min recovery period, the patient's level of consciousness and vital signs returned to presedation levels. Upon leaving the sedation area, the patient collapsed, with no apparent inciting event. The patient quickly regained consciousness and no injury occurred. The primary abnormality found was persistent bradycardia, and she was admitted to the hospital for telemetric observation. The bradycardia lasted ~2 h, and further cardiac workup revealed no underlying abnormality. Unanticipated and previously unreported outcomes may be witnessed as we expand the use of certain sedatives to alternative routes of administration. | CHEMICAL-INDUCED-DISEASE |
| Paradoxical severe DISEASE induced by add-on high-doses CHEMICAL in schizo-affective disorder. We report the case of a 35-year-old patient suffering from schizo-affective disorder since the age of 19 years, treated by a combination of first-generation antipsychotics, zuclopenthixol (100 mg/day) and lithium (1200 mg/day) (serum lithium=0.85 mEq/l). This patient had no associated personality disorder (particularly no antisocial disorder) and no substance abuse disorder. Within the 48 h following the gradual introduction of CHEMICAL (up to 600 mg/day), the patient presented severe DISEASE without an environmental explanation, contrasting with the absence of a history of aggressiveness or personality disorder. The diagnoses of manic shift and akathisia were dismissed. The withdrawal and the gradual reintroduction of CHEMICAL 2 weeks later, which led to another severe DISEASE, enabled us to attribute the DISEASE specifically to CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Paradoxical severe agitation induced by add-on high-doses quetiapine in schizo-affective disorder. We report the case of a 35-year-old patient suffering from schizo-affective disorder since the age of 19 years, treated by a combination of first-generation antipsychotics, CHEMICAL (100 mg/day) and lithium (1200 mg/day) (serum lithium=0.85 mEq/l). This patient had no associated personality disorder (particularly no antisocial disorder) and no DISEASE. Within the 48 h following the gradual introduction of quetiapine (up to 600 mg/day), the patient presented severe agitation without an environmental explanation, contrasting with the absence of a history of aggressiveness or personality disorder. The diagnoses of manic shift and akathisia were dismissed. The withdrawal and the gradual reintroduction of quetiapine 2 weeks later, which led to another severe agitation, enabled us to attribute the agitation specifically to quetiapine. | NO-RELATIONSHIP |
| Paradoxical severe agitation induced by add-on high-doses quetiapine in DISEASE. We report the case of a 35-year-old patient suffering from DISEASE since the age of 19 years, treated by a combination of first-generation antipsychotics, zuclopenthixol (100 mg/day) and CHEMICAL (1200 mg/day) (serum CHEMICAL=0.85 mEq/l). This patient had no associated personality disorder (particularly no antisocial disorder) and no substance abuse disorder. Within the 48 h following the gradual introduction of quetiapine (up to 600 mg/day), the patient presented severe agitation without an environmental explanation, contrasting with the absence of a history of aggressiveness or personality disorder. The diagnoses of manic shift and akathisia were dismissed. The withdrawal and the gradual reintroduction of quetiapine 2 weeks later, which led to another severe agitation, enabled us to attribute the agitation specifically to quetiapine. | NO-RELATIONSHIP |
| Paradoxical severe agitation induced by add-on high-doses quetiapine in schizo-affective disorder. We report the case of a 35-year-old patient suffering from schizo-affective disorder since the age of 19 years, treated by a combination of first-generation antipsychotics, zuclopenthixol (100 mg/day) and CHEMICAL (1200 mg/day) (serum CHEMICAL=0.85 mEq/l). This patient had no associated personality disorder (particularly no antisocial disorder) and no substance abuse disorder. Within the 48 h following the gradual introduction of quetiapine (up to 600 mg/day), the patient presented severe agitation without an environmental explanation, contrasting with the absence of a history of aggressiveness or personality disorder. The diagnoses of DISEASE shift and akathisia were dismissed. The withdrawal and the gradual reintroduction of quetiapine 2 weeks later, which led to another severe agitation, enabled us to attribute the agitation specifically to quetiapine. | NO-RELATIONSHIP |
| Paradoxical severe agitation induced by add-on high-doses quetiapine in schizo-affective disorder. We report the case of a 35-year-old patient suffering from schizo-affective disorder since the age of 19 years, treated by a combination of first-generation antipsychotics, zuclopenthixol (100 mg/day) and CHEMICAL (1200 mg/day) (serum CHEMICAL=0.85 mEq/l). This patient had no associated personality disorder (particularly no DISEASE) and no substance abuse disorder. Within the 48 h following the gradual introduction of quetiapine (up to 600 mg/day), the patient presented severe agitation without an environmental explanation, contrasting with the absence of a history of aggressiveness or personality disorder. The diagnoses of manic shift and akathisia were dismissed. The withdrawal and the gradual reintroduction of quetiapine 2 weeks later, which led to another severe agitation, enabled us to attribute the agitation specifically to quetiapine. | NO-RELATIONSHIP |
| Paradoxical severe agitation induced by add-on high-doses quetiapine in DISEASE. We report the case of a 35-year-old patient suffering from DISEASE since the age of 19 years, treated by a combination of first-generation antipsychotics, CHEMICAL (100 mg/day) and lithium (1200 mg/day) (serum lithium=0.85 mEq/l). This patient had no associated personality disorder (particularly no antisocial disorder) and no substance abuse disorder. Within the 48 h following the gradual introduction of quetiapine (up to 600 mg/day), the patient presented severe agitation without an environmental explanation, contrasting with the absence of a history of aggressiveness or personality disorder. The diagnoses of manic shift and akathisia were dismissed. The withdrawal and the gradual reintroduction of quetiapine 2 weeks later, which led to another severe agitation, enabled us to attribute the agitation specifically to quetiapine. | NO-RELATIONSHIP |
| Paradoxical severe agitation induced by add-on high-doses quetiapine in schizo-affective disorder. We report the case of a 35-year-old patient suffering from schizo-affective disorder since the age of 19 years, treated by a combination of first-generation antipsychotics, zuclopenthixol (100 mg/day) and CHEMICAL (1200 mg/day) (serum CHEMICAL=0.85 mEq/l). This patient had no associated personality disorder (particularly no antisocial disorder) and no substance abuse disorder. Within the 48 h following the gradual introduction of quetiapine (up to 600 mg/day), the patient presented severe agitation without an environmental explanation, contrasting with the absence of a history of aggressiveness or personality disorder. The diagnoses of manic shift and DISEASE were dismissed. The withdrawal and the gradual reintroduction of quetiapine 2 weeks later, which led to another severe agitation, enabled us to attribute the agitation specifically to quetiapine. | NO-RELATIONSHIP |
| Paradoxical severe agitation induced by add-on high-doses quetiapine in schizo-affective disorder. We report the case of a 35-year-old patient suffering from schizo-affective disorder since the age of 19 years, treated by a combination of first-generation antipsychotics, zuclopenthixol (100 mg/day) and CHEMICAL (1200 mg/day) (serum CHEMICAL=0.85 mEq/l). This patient had no associated personality disorder (particularly no antisocial disorder) and no DISEASE. Within the 48 h following the gradual introduction of quetiapine (up to 600 mg/day), the patient presented severe agitation without an environmental explanation, contrasting with the absence of a history of aggressiveness or personality disorder. The diagnoses of manic shift and akathisia were dismissed. The withdrawal and the gradual reintroduction of quetiapine 2 weeks later, which led to another severe agitation, enabled us to attribute the agitation specifically to quetiapine. | NO-RELATIONSHIP |
| Paradoxical severe agitation induced by add-on high-doses quetiapine in schizo-affective disorder. We report the case of a 35-year-old patient suffering from schizo-affective disorder since the age of 19 years, treated by a combination of first-generation antipsychotics, CHEMICAL (100 mg/day) and lithium (1200 mg/day) (serum lithium=0.85 mEq/l). This patient had no associated personality disorder (particularly no DISEASE) and no substance abuse disorder. Within the 48 h following the gradual introduction of quetiapine (up to 600 mg/day), the patient presented severe agitation without an environmental explanation, contrasting with the absence of a history of aggressiveness or personality disorder. The diagnoses of manic shift and akathisia were dismissed. The withdrawal and the gradual reintroduction of quetiapine 2 weeks later, which led to another severe agitation, enabled us to attribute the agitation specifically to quetiapine. | NO-RELATIONSHIP |
| Paradoxical severe agitation induced by add-on high-doses quetiapine in schizo-affective disorder. We report the case of a 35-year-old patient suffering from schizo-affective disorder since the age of 19 years, treated by a combination of first-generation antipsychotics, zuclopenthixol (100 mg/day) and CHEMICAL (1200 mg/day) (serum CHEMICAL=0.85 mEq/l). This patient had no associated DISEASE (particularly no antisocial disorder) and no substance abuse disorder. Within the 48 h following the gradual introduction of quetiapine (up to 600 mg/day), the patient presented severe agitation without an environmental explanation, contrasting with the absence of a history of DISEASE or DISEASE. The diagnoses of manic shift and akathisia were dismissed. The withdrawal and the gradual reintroduction of quetiapine 2 weeks later, which led to another severe agitation, enabled us to attribute the agitation specifically to quetiapine. | CHEMICAL-INDUCED-DISEASE |
| Paradoxical severe agitation induced by add-on high-doses quetiapine in schizo-affective disorder. We report the case of a 35-year-old patient suffering from schizo-affective disorder since the age of 19 years, treated by a combination of first-generation antipsychotics, CHEMICAL (100 mg/day) and lithium (1200 mg/day) (serum lithium=0.85 mEq/l). This patient had no associated personality disorder (particularly no antisocial disorder) and no substance abuse disorder. Within the 48 h following the gradual introduction of quetiapine (up to 600 mg/day), the patient presented severe agitation without an environmental explanation, contrasting with the absence of a history of aggressiveness or personality disorder. The diagnoses of manic shift and DISEASE were dismissed. The withdrawal and the gradual reintroduction of quetiapine 2 weeks later, which led to another severe agitation, enabled us to attribute the agitation specifically to quetiapine. | NO-RELATIONSHIP |
| Paradoxical severe agitation induced by add-on high-doses quetiapine in schizo-affective disorder. We report the case of a 35-year-old patient suffering from schizo-affective disorder since the age of 19 years, treated by a combination of first-generation antipsychotics, CHEMICAL (100 mg/day) and lithium (1200 mg/day) (serum lithium=0.85 mEq/l). This patient had no associated DISEASE (particularly no antisocial disorder) and no substance abuse disorder. Within the 48 h following the gradual introduction of quetiapine (up to 600 mg/day), the patient presented severe agitation without an environmental explanation, contrasting with the absence of a history of DISEASE or DISEASE. The diagnoses of manic shift and akathisia were dismissed. The withdrawal and the gradual reintroduction of quetiapine 2 weeks later, which led to another severe agitation, enabled us to attribute the agitation specifically to quetiapine. | CHEMICAL-INDUCED-DISEASE |
| Paradoxical severe agitation induced by add-on high-doses quetiapine in schizo-affective disorder. We report the case of a 35-year-old patient suffering from schizo-affective disorder since the age of 19 years, treated by a combination of first-generation antipsychotics, CHEMICAL (100 mg/day) and lithium (1200 mg/day) (serum lithium=0.85 mEq/l). This patient had no associated personality disorder (particularly no antisocial disorder) and no substance abuse disorder. Within the 48 h following the gradual introduction of quetiapine (up to 600 mg/day), the patient presented severe agitation without an environmental explanation, contrasting with the absence of a history of aggressiveness or personality disorder. The diagnoses of DISEASE shift and akathisia were dismissed. The withdrawal and the gradual reintroduction of quetiapine 2 weeks later, which led to another severe agitation, enabled us to attribute the agitation specifically to quetiapine. | CHEMICAL-INDUCED-DISEASE |
| Antioxidant effects of bovine lactoferrin on CHEMICAL-induced DISEASE in rat. CHEMICAL- (CHEMICAL-) induced DISEASE is associated with enhanced oxidative stress. Lactoferrin (LF) is an iron-binding glycoprotein with antihypertensive properties. In this study, we investigated the effect of chronic administration of LF on oxidative stress and DISEASE upon CHEMICAL administration. Male Wistar rats were treated by CHEMICAL (30 u g/kg/day subcutaneously) or saline for 14 days. Oral bovine LF (30, 100, 300 mg/kg) was given from day 8 to 14 in a reversal study. In a prevention study, rats received 4 days of LF treatment followed by CHEMICAL and continued during the test period. Systolic blood pressure (SBP) was measured using tail-cuff method. Thymus weight was used as a marker of glucocorticoid activity. Plasma hydrogen peroxide (H2O2) concentration and ferric reducing antioxidant power (FRAP) value were determined. CHEMICAL significantly increased SBP and plasma H2O2 level and decreased thymus and body weights. LF lowered (P < 0.01) and dose dependently prevented (P < 0.001) CHEMICAL-induced DISEASE. LF prevented body weight loss and significantly reduced the elevated plasma H2O2 and increased FRAP values. Chronic administration of LF strongly reduced the blood pressure and production of ROS and improved antioxidant capacity in CHEMICAL-induced DISEASE, suggesting the role of inhibition of oxidative stress as another mechanism of antihypertensive action of LF. | CHEMICAL-INDUCED-DISEASE |
| Antioxidant effects of bovine lactoferrin on CHEMICAL-induced hypertension in rat. CHEMICAL- (CHEMICAL-) induced hypertension is associated with enhanced oxidative stress. Lactoferrin (LF) is an iron-binding glycoprotein with antihypertensive properties. In this study, we investigated the effect of chronic administration of LF on oxidative stress and hypertension upon CHEMICAL administration. Male Wistar rats were treated by CHEMICAL (30 u g/kg/day subcutaneously) or saline for 14 days. Oral bovine LF (30, 100, 300 mg/kg) was given from day 8 to 14 in a reversal study. In a prevention study, rats received 4 days of LF treatment followed by CHEMICAL and continued during the test period. Systolic blood pressure (SBP) was measured using tail-cuff method. Thymus weight was used as a marker of glucocorticoid activity. Plasma hydrogen peroxide (H2O2) concentration and ferric reducing antioxidant power (FRAP) value were determined. CHEMICAL significantly increased SBP and plasma H2O2 level and decreased thymus and body weights. LF lowered (P < 0.01) and dose dependently prevented (P < 0.001) CHEMICAL-induced hypertension. LF prevented body DISEASE and significantly reduced the elevated plasma H2O2 and increased FRAP values. Chronic administration of LF strongly reduced the blood pressure and production of ROS and improved antioxidant capacity in CHEMICAL-induced hypertension, suggesting the role of inhibition of oxidative stress as another mechanism of antihypertensive action of LF. | CHEMICAL-INDUCED-DISEASE |
| The association between CHEMICAL and DISEASE DISEASE after cardiac surgery: a multivariate analysis in 11 529 patients. Because of a lack of contemporary data regarding DISEASE after cardiac surgery, we undertook a retrospective analysis of prospectively collected data from 11 529 patients in whom cardiopulmonary bypass was used from January 2004 to December 2010. A DISEASE DISEASE was defined as a transient episode of disturbed brain function characterised by abnormal involuntary motor movements. Multivariate regression analysis was performed to identify independent predictors of postoperative DISEASE. A total of 100 (0.9%) patients developed postoperative DISEASE DISEASE. DISEASE were identified in 68 and 32 patients, respectively. The median (IQR [range]) time after surgery when the DISEASE occurred was 7 (6-12 [1-216]) h and 8 (6-11 [4-18]) h, respectively. Epileptiform findings on electroencephalography were seen in 19 patients. Independent predictors of postoperative DISEASE included age, female sex, redo cardiac surgery, calcification of ascending aorta, congestive heart failure, deep hypothermic circulatory arrest, duration of aortic cross-clamp and CHEMICAL. When tested in a multivariate regression analysis, CHEMICAL was a strong independent predictor of DISEASE (OR 14.3, 95% CI 5.5-36.7; p < 0.001). Patients with DISEASE DISEASE had 2.5 times higher in-hospital mortality rates and twice the length of hospital stay compared with patients without DISEASE DISEASE. Mean (IQR [range]) length of stay in the intensive care unit was 115 (49-228 [32-481]) h in patients with DISEASE DISEASE compared with 26 (22-69 [14-1080]) h in patients without DISEASE (p < 0.001). DISEASE DISEASE are a serious postoperative complication after cardiac surgery. As CHEMICAL is the only modifiable factor, its administration, particularly in doses exceeding 80 mg.kg(-1), should be weighed against the risk of postoperative DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Dysfunctional overnight memory consolidation in CHEMICAL users. Sleep plays an important role in the consolidation and integration of memory in a process called overnight memory consolidation. Previous studies indicate that CHEMICAL users have marked and persistent neurocognitive and DISEASE. We extend past research by examining overnight memory consolidation among regular CHEMICAL users (n=12) and drug naive healthy controls (n=26). Memory recall of word pairs was evaluated before and after a period of sleep, with and without interference prior to testing. In addition, we assessed neurocognitive performances across tasks of learning, memory and executive functioning. CHEMICAL users demonstrated impaired overnight memory consolidation, a finding that was more pronounced following associative interference. Additionally, CHEMICAL users demonstrated impairments on tasks recruiting frontostriatal and hippocampal neural circuitry, in the domains of proactive interference memory, long-term memory, encoding, working memory and complex planning. We suggest that CHEMICAL-associated dysfunction in fronto-temporal circuitry may underlie overnight consolidation memory impairments in regular CHEMICAL users. | CHEMICAL-INDUCED-DISEASE |
| DISEASE consolidation in CHEMICAL users. Sleep plays an important role in the consolidation and integration of memory in a process called overnight memory consolidation. Previous studies indicate that CHEMICAL users have marked and persistent neurocognitive and sleep-related impairments. We extend past research by examining overnight memory consolidation among regular CHEMICAL users (n=12) and drug naive healthy controls (n=26). Memory recall of word pairs was evaluated before and after a period of sleep, with and without interference prior to testing. In addition, we assessed neurocognitive performances across tasks of learning, memory and executive functioning. CHEMICAL users demonstrated DISEASE consolidation, a finding that was more pronounced following associative interference. Additionally, CHEMICAL users demonstrated impairments on tasks recruiting frontostriatal and hippocampal neural circuitry, in the domains of proactive interference memory, long-term memory, encoding, working memory and complex planning. We suggest that CHEMICAL-associated dysfunction in fronto-temporal circuitry may underlie overnight consolidation DISEASE in regular CHEMICAL users. | CHEMICAL-INDUCED-DISEASE |
| Normoammonemic encephalopathy: solely CHEMICAL induced or multiple mechanisms? A 77-year-old woman presented with subacute onset progressive confusion, aggression, auditory hallucinations and DISEASE. In the preceding months, the patient had a number of admissions with transient unilateral hemiparesis with facial droop, and had been started on CHEMICAL for presumed hemiplegic migraine. CHEMICAL was withdrawn soon after admission and her cognitive abilities have gradually improved over 3 months of follow-up. CHEMICAL levels taken prior to withdrawal were subtherapeutic and the patient was normoammonaemic. EEG undertaken during inpatient stay showed changes consistent with encephalopathy, and low titre N-methyl-D-aspartate (NMDA) receptor antibodies were present in this patient. The possible aetiologies of CHEMICAL-induced encephalopathy and NMDA receptor-associated encephalitis present a diagnostic dilemma. We present a putative combinatorial hypothesis to explain this patient's symptoms. | CHEMICAL-INDUCED-DISEASE |
| Normoammonemic encephalopathy: solely CHEMICAL induced or multiple mechanisms? A 77-year-old woman presented with subacute onset progressive DISEASE, aggression, auditory hallucinations and delusions. In the preceding months, the patient had a number of admissions with transient unilateral hemiparesis with facial droop, and had been started on CHEMICAL for presumed hemiplegic migraine. CHEMICAL was withdrawn soon after admission and her cognitive abilities have gradually improved over 3 months of follow-up. CHEMICAL levels taken prior to withdrawal were subtherapeutic and the patient was normoammonaemic. EEG undertaken during inpatient stay showed changes consistent with encephalopathy, and low titre N-methyl-D-aspartate (NMDA) receptor antibodies were present in this patient. The possible aetiologies of CHEMICAL-induced encephalopathy and NMDA receptor-associated encephalitis present a diagnostic dilemma. We present a putative combinatorial hypothesis to explain this patient's symptoms. | CHEMICAL-INDUCED-DISEASE |
| Normoammonemic encephalopathy: solely CHEMICAL induced or multiple mechanisms? A 77-year-old woman presented with subacute onset progressive confusion, aggression, DISEASE and delusions. In the preceding months, the patient had a number of admissions with transient unilateral hemiparesis with facial droop, and had been started on CHEMICAL for presumed hemiplegic migraine. CHEMICAL was withdrawn soon after admission and her cognitive abilities have gradually improved over 3 months of follow-up. CHEMICAL levels taken prior to withdrawal were subtherapeutic and the patient was normoammonaemic. EEG undertaken during inpatient stay showed changes consistent with encephalopathy, and low titre N-methyl-D-aspartate (NMDA) receptor antibodies were present in this patient. The possible aetiologies of CHEMICAL-induced encephalopathy and NMDA receptor-associated encephalitis present a diagnostic dilemma. We present a putative combinatorial hypothesis to explain this patient's symptoms. | CHEMICAL-INDUCED-DISEASE |
| Normoammonemic encephalopathy: solely valproate induced or multiple mechanisms? A 77-year-old woman presented with subacute onset progressive confusion, aggression, auditory hallucinations and delusions. In the preceding months, the patient had a number of admissions with transient unilateral DISEASE with facial droop, and had been started on valproate for presumed hemiplegic migraine. Valproate was withdrawn soon after admission and her cognitive abilities have gradually improved over 3 months of follow-up. Valproate levels taken prior to withdrawal were subtherapeutic and the patient was normoammonaemic. EEG undertaken during inpatient stay showed changes consistent with encephalopathy, and low titre CHEMICAL (CHEMICAL) receptor antibodies were present in this patient. The possible aetiologies of valproate-induced encephalopathy and CHEMICAL receptor-associated encephalitis present a diagnostic dilemma. We present a putative combinatorial hypothesis to explain this patient's symptoms. | NO-RELATIONSHIP |
| Normoammonemic encephalopathy: solely valproate induced or multiple mechanisms? A 77-year-old woman presented with subacute onset progressive confusion, aggression, auditory hallucinations and delusions. In the preceding months, the patient had a number of admissions with transient unilateral hemiparesis with facial droop, and had been started on valproate for presumed hemiplegic migraine. Valproate was withdrawn soon after admission and her cognitive abilities have gradually improved over 3 months of follow-up. Valproate levels taken prior to withdrawal were subtherapeutic and the patient was normoammonaemic. EEG undertaken during inpatient stay showed changes consistent with encephalopathy, and low titre CHEMICAL (CHEMICAL) receptor antibodies were present in this patient. The possible aetiologies of valproate-induced encephalopathy and CHEMICAL receptor-associated DISEASE present a diagnostic dilemma. We present a putative combinatorial hypothesis to explain this patient's symptoms. | NO-RELATIONSHIP |
| Normoammonemic encephalopathy: solely valproate induced or multiple mechanisms? A 77-year-old woman presented with subacute onset progressive confusion, DISEASE, auditory hallucinations and delusions. In the preceding months, the patient had a number of admissions with transient unilateral hemiparesis with facial droop, and had been started on valproate for presumed hemiplegic migraine. Valproate was withdrawn soon after admission and her cognitive abilities have gradually improved over 3 months of follow-up. Valproate levels taken prior to withdrawal were subtherapeutic and the patient was normoammonaemic. EEG undertaken during inpatient stay showed changes consistent with encephalopathy, and low titre CHEMICAL (CHEMICAL) receptor antibodies were present in this patient. The possible aetiologies of valproate-induced encephalopathy and CHEMICAL receptor-associated encephalitis present a diagnostic dilemma. We present a putative combinatorial hypothesis to explain this patient's symptoms. | NO-RELATIONSHIP |
| Normoammonemic DISEASE: solely valproate induced or multiple mechanisms? A 77-year-old woman presented with subacute onset progressive confusion, aggression, auditory hallucinations and delusions. In the preceding months, the patient had a number of admissions with transient unilateral hemiparesis with facial droop, and had been started on valproate for presumed hemiplegic migraine. Valproate was withdrawn soon after admission and her cognitive abilities have gradually improved over 3 months of follow-up. Valproate levels taken prior to withdrawal were subtherapeutic and the patient was normoammonaemic. EEG undertaken during inpatient stay showed changes consistent with DISEASE, and low titre CHEMICAL (CHEMICAL) receptor antibodies were present in this patient. The possible aetiologies of valproate-induced DISEASE and CHEMICAL receptor-associated encephalitis present a diagnostic dilemma. We present a putative combinatorial hypothesis to explain this patient's symptoms. | NO-RELATIONSHIP |
| Normoammonemic encephalopathy: solely valproate induced or multiple mechanisms? A 77-year-old woman presented with subacute onset progressive confusion, aggression, auditory hallucinations and delusions. In the preceding months, the patient had a number of admissions with transient unilateral hemiparesis with facial droop, and had been started on valproate for presumed DISEASE. Valproate was withdrawn soon after admission and her cognitive abilities have gradually improved over 3 months of follow-up. Valproate levels taken prior to withdrawal were subtherapeutic and the patient was normoammonaemic. EEG undertaken during inpatient stay showed changes consistent with encephalopathy, and low titre CHEMICAL (CHEMICAL) receptor antibodies were present in this patient. The possible aetiologies of valproate-induced encephalopathy and CHEMICAL receptor-associated encephalitis present a diagnostic dilemma. We present a putative combinatorial hypothesis to explain this patient's symptoms. | NO-RELATIONSHIP |
| Cerebellar and oculomotor dysfunction induced by rapid infusion of CHEMICAL. CHEMICAL is an opioid that gains its popularity for the effective pain control through acting on the opioid-receptors. However, rapid pain relief sometimes brings about unfavourable side effects that largely limit its clinical utility. Common side effects include nausea, vomiting and hypotension. In patients with impaired renal and liver function, and those who need long-term pain control, CHEMICAL may cause excitatory central nervous system (CNS) effects through its neurotoxic metabolite, norpethidine, resulting in irritability and seizure attack. On the contrary, though not clinically apparent, CHEMICAL potentially causes inhibitory impacts on the CNS and impairs normal cerebellar and oculomotor function in the short term. In this case report, we highlight opioid's inhibitory side effects on the cerebellar structure that causes DISEASE, dysarthria, reduced smooth pursuit gain and decreased saccadic velocity. | CHEMICAL-INDUCED-DISEASE |
| Cerebellar and oculomotor dysfunction induced by rapid infusion of CHEMICAL. CHEMICAL is an opioid that gains its popularity for the effective pain control through acting on the opioid-receptors. However, rapid pain relief sometimes brings about unfavourable side effects that largely limit its clinical utility. Common side effects include DISEASE, vomiting and hypotension. In patients with impaired renal and liver function, and those who need long-term pain control, CHEMICAL may cause excitatory central nervous system (CNS) effects through its neurotoxic metabolite, norpethidine, resulting in irritability and seizure attack. On the contrary, though not clinically apparent, CHEMICAL potentially causes inhibitory impacts on the CNS and impairs normal cerebellar and oculomotor function in the short term. In this case report, we highlight opioid's inhibitory side effects on the cerebellar structure that causes dysmetria, dysarthria, reduced smooth pursuit gain and decreased saccadic velocity. | CHEMICAL-INDUCED-DISEASE |
| Cerebellar and oculomotor dysfunction induced by rapid infusion of pethidine. Pethidine is an opioid that gains its popularity for the effective pain control through acting on the opioid-receptors. However, rapid pain relief sometimes brings about unfavourable side effects that largely limit its clinical utility. Common side effects include nausea, vomiting and hypotension. In patients with impaired renal and liver function, and those who need long-term pain control, pethidine may cause excitatory central nervous system (CNS) effects through its neurotoxic metabolite, CHEMICAL, resulting in irritability and DISEASE attack. On the contrary, though not clinically apparent, pethidine potentially causes inhibitory impacts on the CNS and impairs normal cerebellar and oculomotor function in the short term. In this case report, we highlight opioid's inhibitory side effects on the cerebellar structure that causes dysmetria, dysarthria, reduced smooth pursuit gain and decreased saccadic velocity. | NO-RELATIONSHIP |
| Cerebellar and oculomotor dysfunction induced by rapid infusion of CHEMICAL. CHEMICAL is an opioid that gains its popularity for the effective pain control through acting on the opioid-receptors. However, rapid pain relief sometimes brings about unfavourable side effects that largely limit its clinical utility. Common side effects include nausea, vomiting and hypotension. In patients with impaired renal and liver function, and those who need long-term pain control, CHEMICAL may cause excitatory central nervous system (CNS) effects through its neurotoxic metabolite, norpethidine, resulting in irritability and seizure attack. On the contrary, though not clinically apparent, CHEMICAL potentially causes inhibitory impacts on the CNS and impairs normal cerebellar and oculomotor function in the short term. In this case report, we highlight opioid's inhibitory side effects on the cerebellar structure that causes dysmetria, DISEASE, reduced smooth pursuit gain and decreased saccadic velocity. | CHEMICAL-INDUCED-DISEASE |
| Cerebellar and oculomotor dysfunction induced by rapid infusion of CHEMICAL. CHEMICAL is an opioid that gains its popularity for the effective pain control through acting on the opioid-receptors. However, rapid pain relief sometimes brings about unfavourable side effects that largely limit its clinical utility. Common side effects include nausea, DISEASE and hypotension. In patients with impaired renal and liver function, and those who need long-term pain control, CHEMICAL may cause excitatory central nervous system (CNS) effects through its neurotoxic metabolite, norpethidine, resulting in irritability and seizure attack. On the contrary, though not clinically apparent, CHEMICAL potentially causes inhibitory impacts on the CNS and impairs normal cerebellar and oculomotor function in the short term. In this case report, we highlight opioid's inhibitory side effects on the cerebellar structure that causes dysmetria, dysarthria, reduced smooth pursuit gain and decreased saccadic velocity. | CHEMICAL-INDUCED-DISEASE |
| Cerebellar and oculomotor dysfunction induced by rapid infusion of CHEMICAL. CHEMICAL is an opioid that gains its popularity for the effective pain control through acting on the opioid-receptors. However, rapid pain relief sometimes brings about unfavourable side effects that largely limit its clinical utility. Common side effects include nausea, vomiting and DISEASE. In patients with impaired renal and liver function, and those who need long-term pain control, CHEMICAL may cause excitatory central nervous system (CNS) effects through its neurotoxic metabolite, norpethidine, resulting in irritability and seizure attack. On the contrary, though not clinically apparent, CHEMICAL potentially causes inhibitory impacts on the CNS and impairs normal cerebellar and oculomotor function in the short term. In this case report, we highlight opioid's inhibitory side effects on the cerebellar structure that causes dysmetria, dysarthria, reduced smooth pursuit gain and decreased saccadic velocity. | CHEMICAL-INDUCED-DISEASE |
| Baboon syndrome induced by CHEMICAL. A 27-year-old male patient presented with a DISEASE on the flexural areas and buttocks after using oral CHEMICAL. The patient was diagnosed with drug-induced baboon syndrome based on his history, which included prior sensitivity to topical CHEMICAL, a physical examination, and histopathological findings. Baboon syndrome is a drug- or contact allergen-related DISEASE that typically involves the flexural and gluteal areas. To the best of our knowledge, this is the first reported case of CHEMICAL-induced baboon syndrome in the English literature. | CHEMICAL-INDUCED-DISEASE |
| A Case of Sudden Cardiac Death due to CHEMICAL-Induced DISEASE. An 84-year-old male received oral CHEMICAL, a pure sodium channel blocker with slow recovery kinetics, to convert his paroxysmal atrial fibrillation to a sinus rhythm; the patient developed sudden cardiac death two days later. The Holter electrocardiogram, which was worn by chance, revealed DISEASE with gradually prolonged QT intervals. This drug is rapidly absorbed from the gastrointestinal tract, and most of it is excreted from the kidney. Although the patient's renal function was not highly impaired and the dose of CHEMICAL was low, the plasma concentration of CHEMICAL may have been high, which can produce DISEASE in the octogenarian. Although the oral administration of class IC drugs, including CHEMICAL, is effective to terminate atrial fibrillation, careful consideration must be taken before giving these drugs to octogenarians. | CHEMICAL-INDUCED-DISEASE |
| A Case of DISEASE due to CHEMICAL-Induced Torsades de Pointes. An 84-year-old male received oral CHEMICAL, a pure sodium channel blocker with slow recovery kinetics, to convert his paroxysmal atrial fibrillation to a sinus rhythm; the patient developed DISEASE two days later. The Holter electrocardiogram, which was worn by chance, revealed torsade de pointes with gradually prolonged QT intervals. This drug is rapidly absorbed from the gastrointestinal tract, and most of it is excreted from the kidney. Although the patient's renal function was not highly impaired and the dose of CHEMICAL was low, the plasma concentration of CHEMICAL may have been high, which can produce torsades de pointes in the octogenarian. Although the oral administration of class IC drugs, including CHEMICAL, is effective to terminate atrial fibrillation, careful consideration must be taken before giving these drugs to octogenarians. | CHEMICAL-INDUCED-DISEASE |
| A Case of Sudden Cardiac Death due to Pilsicainide-Induced Torsades de Pointes. An 84-year-old male received oral pilsicainide, a pure CHEMICAL channel blocker with slow recovery kinetics, to convert his paroxysmal DISEASE to a sinus rhythm; the patient developed sudden cardiac death two days later. The Holter electrocardiogram, which was worn by chance, revealed torsade de pointes with gradually prolonged QT intervals. This drug is rapidly absorbed from the gastrointestinal tract, and most of it is excreted from the kidney. Although the patient's renal function was not highly impaired and the dose of pilsicainide was low, the plasma concentration of pilsicainide may have been high, which can produce torsades de pointes in the octogenarian. Although the oral administration of class IC drugs, including pilsicainide, is effective to terminate DISEASE, careful consideration must be taken before giving these drugs to octogenarians. | NO-RELATIONSHIP |
| CHEMICAL-induced inflammatory DISEASE in a patient with acute promyelocytic leukemia. CHEMICAL (CHEMICAL), a component of standard therapy for acute promyelocytic leukemia (APL), is associated with potentially serious but treatable adverse effects involving numerous organ systems, including rare skeletal muscle involvement. Only a handful of cases of CHEMICAL-induced DISEASE in children have been reported, and none in the radiology literature. We present such a case in a 15-year-old boy with APL, where recognition of imaging findings played a crucial role in making the diagnosis and facilitated prompt, effective treatment. | CHEMICAL-INDUCED-DISEASE |
| Tolerability of lomustine in combination with CHEMICAL in dogs with lymphoma. This retrospective study describes toxicity associated with a protocol of lomustine (CCNU) and CHEMICAL (CHEMICAL) in dogs with lymphoma. CCNU was administered per os (PO) at a targeted dosage of 60 mg/m(2) body surface area on day 0, CHEMICAL was administered PO at a targeted dosage of 250 mg/m(2) divided over days 0 through 4, and all dogs received prophylactic antibiotics. Ninety treatments were given to the 57 dogs included in the study. DISEASE was the principal toxic effect, and the overall frequency of grade 4 DISEASE after the first treatment of CCNU/CHEMICAL was 30% (95% confidence interval, 19-43%). The mean body weight of dogs with grade 4 DISEASE (19.7 kg + 13.4 kg) was significantly less than the mean body weight of dogs that did not develop grade 4 DISEASE (31.7 kg + 12.4 kg; P = .005). One dog (3%) developed hematologic changes suggestive of hepatotoxicity. No dogs had evidence of either renal toxicity or hemorrhagic cystitis. Adverse gastrointestinal effects were uncommon. On the basis of the findings reported herein, a dose of 60 mg/m(2) of CCNU combined with 250 mg/m(2) of CHEMICAL (divided over 5 days) q 4 wk is tolerable in tumor-bearing dogs. | CHEMICAL-INDUCED-DISEASE |
| Tolerability of CHEMICAL in combination with cyclophosphamide in dogs with lymphoma. This retrospective study describes toxicity associated with a protocol of CHEMICAL (CHEMICAL) and cyclophosphamide (CTX) in dogs with lymphoma. CHEMICAL was administered per os (PO) at a targeted dosage of 60 mg/m(2) body surface area on day 0, CTX was administered PO at a targeted dosage of 250 mg/m(2) divided over days 0 through 4, and all dogs received prophylactic antibiotics. Ninety treatments were given to the 57 dogs included in the study. DISEASE was the principal toxic effect, and the overall frequency of grade 4 DISEASE after the first treatment of CHEMICAL/CTX was 30% (95% confidence interval, 19-43%). The mean body weight of dogs with grade 4 DISEASE (19.7 kg + 13.4 kg) was significantly less than the mean body weight of dogs that did not develop grade 4 DISEASE (31.7 kg + 12.4 kg; P = .005). One dog (3%) developed hematologic changes suggestive of hepatotoxicity. No dogs had evidence of either renal toxicity or hemorrhagic cystitis. Adverse gastrointestinal effects were uncommon. On the basis of the findings reported herein, a dose of 60 mg/m(2) of CHEMICAL combined with 250 mg/m(2) of CTX (divided over 5 days) q 4 wk is tolerable in tumor-bearing dogs. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL neurotoxicity with concurrent intrathecal chemotherapy: Case report and review of literature. Severe CHEMICAL neurotoxicity in a patient who received concurrent intrathecal (IT) chemotherapy is reported. A 37-year-old Caucasian woman with a history of T-cell lymphoblastic lymphoma was admitted for relapsed disease. She was originally treated with induction chemotherapy followed by an autologous transplant. She developed relapsed disease 10 months later with leukemic involvement. She was re-induced with CHEMICAL 1500 mg/m(2) on days 1, 3, and 5 with 1 dose of IT cytarabine 100 mg on day 2 as central nervous system (CNS) prophylaxis. At the time of treatment, she was on continuous renal replacement therapy due to sequelae of tumor lysis syndrome (TLS). She tolerated therapy well, entered a complete remission, and recovered her renal function. She received a second cycle of CHEMICAL without additional IT prophylaxis one month later. A week after this second cycle, she noted numbness in her lower extremities. Predominantly sensory, though also motor and autonomic, DISEASE started in her feet, ascended proximally to the mid-thoracic region, and eventually included her distal upper extremities. A magnetic resonance imaging (MRI) of her spine demonstrated changes from C2 to C6 consistent with subacute combined degeneration. CHEMICAL was felt to be the cause of her symptoms. Her neuropathy stabilized and showed slight improvement and ultimately received an unrelated, reduced-intensity allogeneic transplant while in complete remission, but relapsed disease 10 weeks later. She is currently being treated with best supportive care. To our knowledge, this is the first published case report of severe neurotoxicity caused by CHEMICAL in a patient who received concurrent IT chemotherapy. | CHEMICAL-INDUCED-DISEASE |
| Nelarabine DISEASE with concurrent intrathecal chemotherapy: Case report and review of literature. Severe nelarabine DISEASE in a patient who received concurrent intrathecal (IT) chemotherapy is reported. A 37-year-old Caucasian woman with a history of T-cell lymphoblastic lymphoma was admitted for relapsed disease. She was originally treated with induction chemotherapy followed by an autologous transplant. She developed relapsed disease 10 months later with leukemic involvement. She was re-induced with nelarabine 1500 mg/m(2) on days 1, 3, and 5 with 1 dose of IT CHEMICAL 100 mg on day 2 as central nervous system (CNS) prophylaxis. At the time of treatment, she was on continuous renal replacement therapy due to sequelae of tumor lysis syndrome (TLS). She tolerated therapy well, entered a complete remission, and recovered her renal function. She received a second cycle of nelarabine without additional IT prophylaxis one month later. A week after this second cycle, she noted numbness in her lower extremities. Predominantly sensory, though also motor and autonomic, peripheral neuropathy started in her feet, ascended proximally to the mid-thoracic region, and eventually included her distal upper extremities. A magnetic resonance imaging (MRI) of her spine demonstrated changes from C2 to C6 consistent with subacute combined degeneration. Nelarabine was felt to be the cause of her symptoms. Her neuropathy stabilized and showed slight improvement and ultimately received an unrelated, reduced-intensity allogeneic transplant while in complete remission, but relapsed disease 10 weeks later. She is currently being treated with best supportive care. To our knowledge, this is the first published case report of severe DISEASE caused by nelarabine in a patient who received concurrent IT chemotherapy. | NO-RELATIONSHIP |
| Nelarabine neurotoxicity with concurrent intrathecal chemotherapy: Case report and review of literature. Severe nelarabine neurotoxicity in a patient who received concurrent intrathecal (IT) chemotherapy is reported. A 37-year-old Caucasian woman with a history of T-cell lymphoblastic lymphoma was admitted for relapsed disease. She was originally treated with induction chemotherapy followed by an autologous transplant. She developed relapsed disease 10 months later with leukemic involvement. She was re-induced with nelarabine 1500 mg/m(2) on days 1, 3, and 5 with 1 dose of IT CHEMICAL 100 mg on day 2 as central nervous system (CNS) prophylaxis. At the time of treatment, she was on continuous renal replacement therapy due to sequelae of DISEASE (DISEASE). She tolerated therapy well, entered a complete remission, and recovered her renal function. She received a second cycle of nelarabine without additional IT prophylaxis one month later. A week after this second cycle, she noted numbness in her lower extremities. Predominantly sensory, though also motor and autonomic, peripheral neuropathy started in her feet, ascended proximally to the mid-thoracic region, and eventually included her distal upper extremities. A magnetic resonance imaging (MRI) of her spine demonstrated changes from C2 to C6 consistent with subacute combined degeneration. Nelarabine was felt to be the cause of her symptoms. Her neuropathy stabilized and showed slight improvement and ultimately received an unrelated, reduced-intensity allogeneic transplant while in complete remission, but relapsed disease 10 weeks later. She is currently being treated with best supportive care. To our knowledge, this is the first published case report of severe neurotoxicity caused by nelarabine in a patient who received concurrent IT chemotherapy. | NO-RELATIONSHIP |
| Nelarabine neurotoxicity with concurrent intrathecal chemotherapy: Case report and review of literature. Severe nelarabine neurotoxicity in a patient who received concurrent intrathecal (IT) chemotherapy is reported. A 37-year-old Caucasian woman with a history of DISEASE was admitted for relapsed disease. She was originally treated with induction chemotherapy followed by an autologous transplant. She developed relapsed disease 10 months later with leukemic involvement. She was re-induced with nelarabine 1500 mg/m(2) on days 1, 3, and 5 with 1 dose of IT CHEMICAL 100 mg on day 2 as central nervous system (CNS) prophylaxis. At the time of treatment, she was on continuous renal replacement therapy due to sequelae of tumor lysis syndrome (TLS). She tolerated therapy well, entered a complete remission, and recovered her renal function. She received a second cycle of nelarabine without additional IT prophylaxis one month later. A week after this second cycle, she noted numbness in her lower extremities. Predominantly sensory, though also motor and autonomic, peripheral neuropathy started in her feet, ascended proximally to the mid-thoracic region, and eventually included her distal upper extremities. A magnetic resonance imaging (MRI) of her spine demonstrated changes from C2 to C6 consistent with subacute combined degeneration. Nelarabine was felt to be the cause of her symptoms. Her neuropathy stabilized and showed slight improvement and ultimately received an unrelated, reduced-intensity allogeneic transplant while in complete remission, but relapsed disease 10 weeks later. She is currently being treated with best supportive care. To our knowledge, this is the first published case report of severe neurotoxicity caused by nelarabine in a patient who received concurrent IT chemotherapy. | NO-RELATIONSHIP |
| Nelarabine neurotoxicity with concurrent intrathecal chemotherapy: Case report and review of literature. Severe nelarabine neurotoxicity in a patient who received concurrent intrathecal (IT) chemotherapy is reported. A 37-year-old Caucasian woman with a history of T-cell lymphoblastic lymphoma was admitted for relapsed disease. She was originally treated with induction chemotherapy followed by an autologous transplant. She developed relapsed disease 10 months later with DISEASE involvement. She was re-induced with nelarabine 1500 mg/m(2) on days 1, 3, and 5 with 1 dose of IT CHEMICAL 100 mg on day 2 as central nervous system (CNS) prophylaxis. At the time of treatment, she was on continuous renal replacement therapy due to sequelae of tumor lysis syndrome (TLS). She tolerated therapy well, entered a complete remission, and recovered her renal function. She received a second cycle of nelarabine without additional IT prophylaxis one month later. A week after this second cycle, she noted numbness in her lower extremities. Predominantly sensory, though also motor and autonomic, peripheral neuropathy started in her feet, ascended proximally to the mid-thoracic region, and eventually included her distal upper extremities. A magnetic resonance imaging (MRI) of her spine demonstrated changes from C2 to C6 consistent with subacute combined degeneration. Nelarabine was felt to be the cause of her symptoms. Her neuropathy stabilized and showed slight improvement and ultimately received an unrelated, reduced-intensity allogeneic transplant while in complete remission, but relapsed disease 10 weeks later. She is currently being treated with best supportive care. To our knowledge, this is the first published case report of severe neurotoxicity caused by nelarabine in a patient who received concurrent IT chemotherapy. | NO-RELATIONSHIP |
| Nelarabine neurotoxicity with concurrent intrathecal chemotherapy: Case report and review of literature. Severe nelarabine neurotoxicity in a patient who received concurrent intrathecal (IT) chemotherapy is reported. A 37-year-old Caucasian woman with a history of T-cell lymphoblastic lymphoma was admitted for relapsed disease. She was originally treated with induction chemotherapy followed by an autologous transplant. She developed relapsed disease 10 months later with leukemic involvement. She was re-induced with nelarabine 1500 mg/m(2) on days 1, 3, and 5 with 1 dose of IT CHEMICAL 100 mg on day 2 as central nervous system (CNS) prophylaxis. At the time of treatment, she was on continuous renal replacement therapy due to sequelae of tumor lysis syndrome (TLS). She tolerated therapy well, entered a complete remission, and recovered her renal function. She received a second cycle of nelarabine without additional IT prophylaxis one month later. A week after this second cycle, she noted numbness in her lower extremities. Predominantly sensory, though also motor and autonomic, peripheral neuropathy started in her feet, ascended proximally to the mid-thoracic region, and eventually included her distal upper extremities. A magnetic resonance imaging (MRI) of her spine demonstrated changes from C2 to C6 consistent with subacute combined degeneration. Nelarabine was felt to be the cause of her symptoms. Her DISEASE stabilized and showed slight improvement and ultimately received an unrelated, reduced-intensity allogeneic transplant while in complete remission, but relapsed disease 10 weeks later. She is currently being treated with best supportive care. To our knowledge, this is the first published case report of severe neurotoxicity caused by nelarabine in a patient who received concurrent IT chemotherapy. | NO-RELATIONSHIP |
| CHEMICAL-induced hyperammonemic encephalopathy in a renal transplanted patient. Neurological complications after renal transplantation constitute an important cause of morbidity and mortality. Their differential diagnosis is difficult and essential for subsequent patient's management. CHEMICAL-induced hyperammonemic encephalopathy is an uncommon but serious effect of CHEMICAL treatment. Here, we describe the case of a 15-year-old girl who was on a long-term therapy with CHEMICAL due to epilepsy and revealed DISEASE with hyperammonemia 12 days after renal transplantation. After withdraw of CHEMICAL, patients' symptoms resolved within 24 h. Clinicians should increase their awareness for potential complication of CHEMICAL, especially in transplanted patients. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced DISEASE encephalopathy in a renal transplanted patient. Neurological complications after renal transplantation constitute an important cause of morbidity and mortality. Their differential diagnosis is difficult and essential for subsequent patient's management. CHEMICAL-induced DISEASE encephalopathy is an uncommon but serious effect of CHEMICAL treatment. Here, we describe the case of a 15-year-old girl who was on a long-term therapy with CHEMICAL due to epilepsy and revealed impaired consciousness with DISEASE 12 days after renal transplantation. After withdraw of CHEMICAL, patients' symptoms resolved within 24 h. Clinicians should increase their awareness for potential complication of CHEMICAL, especially in transplanted patients. | CHEMICAL-INDUCED-DISEASE |
| DISEASE after bortezomib and CHEMICAL-containing regimen in an elderly patient of Waldenstrom macroglobulinaemia. Bortezomib and high-dose CHEMICAL-containing regimens are considered to be generally tolerable with few severe bacterial infections in patients with B-cell malignancies. However, information is limited concerning the safety of the regimen in elderly patients. We report a case of a 76-year-old man with Waldenstrom macroglobulinaemia who suffered DISEASE without neutropenia after the combination treatment with bortezomib, high-dose CHEMICAL and rituximab. Despite immediate intravenous antimicrobial therapy, he succumbed 23 h after the onset. Physicians should recognise the possibility of fatal bacterial infections related to bortezomib plus high-dose CHEMICAL in elderly patients, and we believe this case warrants further investigation. | CHEMICAL-INDUCED-DISEASE |
| DISEASE after CHEMICAL and dexamethasone-containing regimen in an elderly patient of Waldenstrom macroglobulinaemia. CHEMICAL and high-dose dexamethasone-containing regimens are considered to be generally tolerable with few severe bacterial infections in patients with B-cell malignancies. However, information is limited concerning the safety of the regimen in elderly patients. We report a case of a 76-year-old man with Waldenstrom macroglobulinaemia who suffered DISEASE without neutropenia after the combination treatment with CHEMICAL, high-dose dexamethasone and rituximab. Despite immediate intravenous antimicrobial therapy, he succumbed 23 h after the onset. Physicians should recognise the possibility of fatal bacterial infections related to CHEMICAL plus high-dose dexamethasone in elderly patients, and we believe this case warrants further investigation. | CHEMICAL-INDUCED-DISEASE |
| An integrated characterization of serological, pathological, and functional events in CHEMICAL-induced cardiotoxicity. Many efficacious cancer treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study, we have utilized a rat model of progressive CHEMICAL (CHEMICAL)-induced cardiomyopathy, applying multiple approaches, including cardiac magnetic resonance imaging (MRI), to provide the most comprehensive characterization to date of the timecourse of serological, pathological, and functional events underlying this toxicity. Hannover Wistar rats were dosed with 1.25 mg/kg CHEMICAL weekly for 8 weeks followed by a 4 week off-dosing "recovery" period. Electron microscopy of the myocardium revealed subcellular degeneration and marked mitochondrial changes after a single dose. Histopathological analysis revealed progressive cardiomyocyte degeneration, hypertrophy/cytomegaly, and extensive vacuolation after two doses. Extensive replacement DISEASE (quantified by Sirius red staining) developed during the off-dosing period. Functional indices assessed by cardiac MRI (including left ventricular ejection fraction (LVEF), cardiac output, and E/A ratio) declined progressively, reaching statistical significance after two doses and culminating in "clinical" LV dysfunction by 12 weeks. Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I (cTnI) emerged after eight doses, importantly preceding the LVEF decline to <50%. Troponin I levels positively correlated with delayed and peak gadolinium contrast enhancement, histopathological grading, and diastolic dysfunction. In summary, subcellular cardiomyocyte degeneration was the earliest marker, followed by progressive functional decline and histopathological manifestations. Myocardial contrast enhancement and elevations in cTnI occurred later. However, all indices predated "clinical" LV dysfunction and thus warrant further evaluation as predictive biomarkers. | CHEMICAL-INDUCED-DISEASE |
| An integrated characterization of serological, pathological, and functional events in CHEMICAL-induced cardiotoxicity. Many efficacious cancer treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study, we have utilized a rat model of progressive CHEMICAL (CHEMICAL)-induced DISEASE, applying multiple approaches, including cardiac magnetic resonance imaging (MRI), to provide the most comprehensive characterization to date of the timecourse of serological, pathological, and functional events underlying this toxicity. Hannover Wistar rats were dosed with 1.25 mg/kg CHEMICAL weekly for 8 weeks followed by a 4 week off-dosing "recovery" period. Electron microscopy of the myocardium revealed subcellular degeneration and marked mitochondrial changes after a single dose. Histopathological analysis revealed progressive cardiomyocyte degeneration, hypertrophy/cytomegaly, and extensive vacuolation after two doses. Extensive replacement fibrosis (quantified by Sirius red staining) developed during the off-dosing period. Functional indices assessed by cardiac MRI (including left ventricular ejection fraction (LVEF), cardiac output, and E/A ratio) declined progressively, reaching statistical significance after two doses and culminating in "clinical" LV dysfunction by 12 weeks. Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I (cTnI) emerged after eight doses, importantly preceding the LVEF decline to <50%. Troponin I levels positively correlated with delayed and peak gadolinium contrast enhancement, histopathological grading, and diastolic dysfunction. In summary, subcellular cardiomyocyte degeneration was the earliest marker, followed by progressive functional decline and histopathological manifestations. Myocardial contrast enhancement and elevations in cTnI occurred later. However, all indices predated "clinical" LV dysfunction and thus warrant further evaluation as predictive biomarkers. | CHEMICAL-INDUCED-DISEASE |
| An integrated characterization of serological, pathological, and functional events in CHEMICAL-induced cardiotoxicity. Many efficacious cancer treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study, we have utilized a rat model of progressive CHEMICAL (CHEMICAL)-induced cardiomyopathy, applying multiple approaches, including cardiac magnetic resonance imaging (MRI), to provide the most comprehensive characterization to date of the timecourse of serological, pathological, and functional events underlying this toxicity. Hannover Wistar rats were dosed with 1.25 mg/kg CHEMICAL weekly for 8 weeks followed by a 4 week off-dosing "recovery" period. Electron microscopy of the myocardium revealed subcellular degeneration and marked mitochondrial changes after a single dose. Histopathological analysis revealed progressive cardiomyocyte degeneration, hypertrophy/cytomegaly, and extensive vacuolation after two doses. Extensive replacement fibrosis (quantified by Sirius red staining) developed during the off-dosing period. Functional indices assessed by cardiac MRI (including left ventricular ejection fraction (LVEF), cardiac output, and E/A ratio) declined progressively, reaching statistical significance after two doses and culminating in "clinical" DISEASE by 12 weeks. Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I (cTnI) emerged after eight doses, importantly preceding the LVEF decline to <50%. Troponin I levels positively correlated with delayed and peak gadolinium contrast enhancement, histopathological grading, and diastolic dysfunction. In summary, subcellular cardiomyocyte degeneration was the earliest marker, followed by progressive functional decline and histopathological manifestations. Myocardial contrast enhancement and elevations in cTnI occurred later. However, all indices predated "clinical" DISEASE and thus warrant further evaluation as predictive biomarkers. | CHEMICAL-INDUCED-DISEASE |
| An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity. Many efficacious cancer treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study, we have utilized a rat model of progressive doxorubicin (DOX)-induced cardiomyopathy, applying multiple approaches, including cardiac magnetic resonance imaging (MRI), to provide the most comprehensive characterization to date of the timecourse of serological, pathological, and functional events underlying this DISEASE. Hannover Wistar rats were dosed with 1.25 mg/kg DOX weekly for 8 weeks followed by a 4 week off-dosing "recovery" period. Electron microscopy of the myocardium revealed subcellular degeneration and marked mitochondrial changes after a single dose. Histopathological analysis revealed progressive cardiomyocyte degeneration, hypertrophy/cytomegaly, and extensive vacuolation after two doses. Extensive replacement fibrosis (quantified by Sirius red staining) developed during the off-dosing period. Functional indices assessed by cardiac MRI (including left ventricular ejection fraction (LVEF), cardiac output, and E/A ratio) declined progressively, reaching statistical significance after two doses and culminating in "clinical" LV dysfunction by 12 weeks. Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I (cTnI) emerged after eight doses, importantly preceding the LVEF decline to <50%. Troponin I levels positively correlated with delayed and peak CHEMICAL contrast enhancement, histopathological grading, and diastolic dysfunction. In summary, subcellular cardiomyocyte degeneration was the earliest marker, followed by progressive functional decline and histopathological manifestations. Myocardial contrast enhancement and elevations in cTnI occurred later. However, all indices predated "clinical" LV dysfunction and thus warrant further evaluation as predictive biomarkers. | NO-RELATIONSHIP |
| An integrated characterization of serological, pathological, and functional events in doxorubicin-induced DISEASE. Many efficacious cancer treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study, we have utilized a rat model of progressive doxorubicin (DOX)-induced cardiomyopathy, applying multiple approaches, including cardiac magnetic resonance imaging (MRI), to provide the most comprehensive characterization to date of the timecourse of serological, pathological, and functional events underlying this toxicity. Hannover Wistar rats were dosed with 1.25 mg/kg DOX weekly for 8 weeks followed by a 4 week off-dosing "recovery" period. Electron microscopy of the myocardium revealed subcellular degeneration and marked mitochondrial changes after a single dose. Histopathological analysis revealed progressive cardiomyocyte degeneration, hypertrophy/cytomegaly, and extensive vacuolation after two doses. Extensive replacement fibrosis (quantified by Sirius red staining) developed during the off-dosing period. Functional indices assessed by cardiac MRI (including left ventricular ejection fraction (LVEF), cardiac output, and E/A ratio) declined progressively, reaching statistical significance after two doses and culminating in "clinical" LV dysfunction by 12 weeks. Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I (cTnI) emerged after eight doses, importantly preceding the LVEF decline to <50%. Troponin I levels positively correlated with delayed and peak CHEMICAL contrast enhancement, histopathological grading, and diastolic dysfunction. In summary, subcellular cardiomyocyte degeneration was the earliest marker, followed by progressive functional decline and histopathological manifestations. Myocardial contrast enhancement and elevations in cTnI occurred later. However, all indices predated "clinical" LV dysfunction and thus warrant further evaluation as predictive biomarkers. | NO-RELATIONSHIP |
| An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity. Many efficacious cancer treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study, we have utilized a rat model of progressive doxorubicin (DOX)-induced cardiomyopathy, applying multiple approaches, including cardiac magnetic resonance imaging (MRI), to provide the most comprehensive characterization to date of the timecourse of serological, pathological, and functional events underlying this toxicity. Hannover Wistar rats were dosed with 1.25 mg/kg DOX weekly for 8 weeks followed by a 4 week off-dosing "recovery" period. Electron microscopy of the myocardium revealed subcellular degeneration and marked mitochondrial changes after a single dose. Histopathological analysis revealed progressive cardiomyocyte degeneration, DISEASE/cytomegaly, and extensive vacuolation after two doses. Extensive replacement fibrosis (quantified by Sirius red staining) developed during the off-dosing period. Functional indices assessed by cardiac MRI (including left ventricular ejection fraction (LVEF), cardiac output, and E/A ratio) declined progressively, reaching statistical significance after two doses and culminating in "clinical" LV dysfunction by 12 weeks. Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I (cTnI) emerged after eight doses, importantly preceding the LVEF decline to <50%. Troponin I levels positively correlated with delayed and peak CHEMICAL contrast enhancement, histopathological grading, and diastolic dysfunction. In summary, subcellular cardiomyocyte degeneration was the earliest marker, followed by progressive functional decline and histopathological manifestations. Myocardial contrast enhancement and elevations in cTnI occurred later. However, all indices predated "clinical" LV dysfunction and thus warrant further evaluation as predictive biomarkers. | NO-RELATIONSHIP |
| An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity. Many efficacious cancer treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study, we have utilized a rat model of progressive doxorubicin (DOX)-induced cardiomyopathy, applying multiple approaches, including cardiac magnetic resonance imaging (MRI), to provide the most comprehensive characterization to date of the timecourse of serological, pathological, and functional events underlying this toxicity. Hannover Wistar rats were dosed with 1.25 mg/kg DOX weekly for 8 weeks followed by a 4 week off-dosing "recovery" period. Electron microscopy of the myocardium revealed DISEASE and marked mitochondrial changes after a single dose. Histopathological analysis revealed progressive DISEASE, hypertrophy/cytomegaly, and extensive vacuolation after two doses. Extensive replacement fibrosis (quantified by Sirius red staining) developed during the off-dosing period. Functional indices assessed by cardiac MRI (including left ventricular ejection fraction (LVEF), cardiac output, and E/A ratio) declined progressively, reaching statistical significance after two doses and culminating in "clinical" LV dysfunction by 12 weeks. Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I (cTnI) emerged after eight doses, importantly preceding the LVEF decline to <50%. Troponin I levels positively correlated with delayed and peak CHEMICAL contrast enhancement, histopathological grading, and diastolic dysfunction. In summary, subcellular DISEASE was the earliest marker, followed by progressive functional decline and histopathological manifestations. Myocardial contrast enhancement and elevations in cTnI occurred later. However, all indices predated "clinical" LV dysfunction and thus warrant further evaluation as predictive biomarkers. | NO-RELATIONSHIP |
| An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity. Many efficacious DISEASE treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study, we have utilized a rat model of progressive doxorubicin (DOX)-induced cardiomyopathy, applying multiple approaches, including cardiac magnetic resonance imaging (MRI), to provide the most comprehensive characterization to date of the timecourse of serological, pathological, and functional events underlying this toxicity. Hannover Wistar rats were dosed with 1.25 mg/kg DOX weekly for 8 weeks followed by a 4 week off-dosing "recovery" period. Electron microscopy of the myocardium revealed subcellular degeneration and marked mitochondrial changes after a single dose. Histopathological analysis revealed progressive cardiomyocyte degeneration, hypertrophy/cytomegaly, and extensive vacuolation after two doses. Extensive replacement fibrosis (quantified by Sirius red staining) developed during the off-dosing period. Functional indices assessed by cardiac MRI (including left ventricular ejection fraction (LVEF), cardiac output, and E/A ratio) declined progressively, reaching statistical significance after two doses and culminating in "clinical" LV dysfunction by 12 weeks. Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I (cTnI) emerged after eight doses, importantly preceding the LVEF decline to <50%. Troponin I levels positively correlated with delayed and peak CHEMICAL contrast enhancement, histopathological grading, and diastolic dysfunction. In summary, subcellular cardiomyocyte degeneration was the earliest marker, followed by progressive functional decline and histopathological manifestations. Myocardial contrast enhancement and elevations in cTnI occurred later. However, all indices predated "clinical" LV dysfunction and thus warrant further evaluation as predictive biomarkers. | NO-RELATIONSHIP |
| An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity. Many efficacious cancer treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study, we have utilized a rat model of progressive doxorubicin (DOX)-induced cardiomyopathy, applying multiple approaches, including cardiac magnetic resonance imaging (MRI), to provide the most comprehensive characterization to date of the timecourse of serological, pathological, and functional events underlying this toxicity. Hannover Wistar rats were dosed with 1.25 mg/kg DOX weekly for 8 weeks followed by a 4 week off-dosing "recovery" period. Electron microscopy of the myocardium revealed subcellular degeneration and marked mitochondrial changes after a single dose. Histopathological analysis revealed progressive cardiomyocyte degeneration, hypertrophy/cytomegaly, and extensive vacuolation after two doses. Extensive replacement fibrosis (quantified by Sirius red staining) developed during the off-dosing period. Functional indices assessed by cardiac MRI (including left ventricular ejection fraction (LVEF), cardiac output, and E/A ratio) declined progressively, reaching statistical significance after two doses and culminating in "clinical" LV dysfunction by 12 weeks. Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I (cTnI) emerged after eight doses, importantly preceding the LVEF decline to <50%. Troponin I levels positively correlated with delayed and peak CHEMICAL contrast enhancement, histopathological grading, and DISEASE. In summary, subcellular cardiomyocyte degeneration was the earliest marker, followed by progressive functional decline and histopathological manifestations. Myocardial contrast enhancement and elevations in cTnI occurred later. However, all indices predated "clinical" LV dysfunction and thus warrant further evaluation as predictive biomarkers. | NO-RELATIONSHIP |
| Intradermal glutamate and CHEMICAL injections: intra- and interindividual variability of provoked DISEASE and DISEASE. Intradermal injections of glutamate and CHEMICAL are attractive to use in human experimental pain models because DISEASE and DISEASE mimic isolated aspects of clinical pain disorders. The aim of the present study was to investigate the reproducibility of these models. Twenty healthy male volunteers (mean age 24 years; range 18-38 years) received intradermal injections of glutamate and CHEMICAL in the volar forearm. Magnitudes of secondary pinprick DISEASE and brush-evoked DISEASE were investigated using von Frey filaments (gauges 10, 15, 60 and 100 g) and brush strokes. Areas of DISEASE and DISEASE were quantified immediately after injection and after 15, 30 and 60 min. Two identical experiments separated by at least 7 days were performed. Reproducibility across and within volunteers (inter- and intra-individual variation, respectively) was assessed using intraclass correlation coefficient (ICC) and coefficient of variation (CV). Secondary pinprick DISEASE was observed as a marked increase in the visual analogue scale (VAS) response to von Frey gauges 60 and 100 g (P < 0.001) after glutamate injection. For CHEMICAL, secondary pinprick DISEASE was detected with all von Frey gauges (P < 0.001). Glutamate evoked reproducible VAS response to all von Frey gauges (ICC > 0.60) and brush strokes (ICC > 0.83). CHEMICAL injection was reproducible for DISEASE (ICC > 0.70) and DISEASE (ICC > 0.71). Intra-individual variability was generally lower for the VAS response to von Frey and brush compared with areas of DISEASE and DISEASE. In conclusion, glutamate and CHEMICAL yield reproducible DISEASE and DISEASE responses, and the present model is well suited for basic research, as well as for assessing the modulation of central phenomena. | CHEMICAL-INDUCED-DISEASE |
| Intradermal CHEMICAL and capsaicin injections: intra- and interindividual variability of provoked hyperalgesia and allodynia. Intradermal injections of CHEMICAL and capsaicin are attractive to use in human experimental pain models because hyperalgesia and allodynia mimic isolated aspects of clinical DISEASE. The aim of the present study was to investigate the reproducibility of these models. Twenty healthy male volunteers (mean age 24 years; range 18-38 years) received intradermal injections of CHEMICAL and capsaicin in the volar forearm. Magnitudes of secondary pinprick hyperalgesia and brush-evoked allodynia were investigated using von Frey filaments (gauges 10, 15, 60 and 100 g) and brush strokes. Areas of secondary hyperalgesia and allodynia were quantified immediately after injection and after 15, 30 and 60 min. Two identical experiments separated by at least 7 days were performed. Reproducibility across and within volunteers (inter- and intra-individual variation, respectively) was assessed using intraclass correlation coefficient (ICC) and coefficient of variation (CV). Secondary pinprick hyperalgesia was observed as a marked increase in the visual analogue scale (VAS) response to von Frey gauges 60 and 100 g (P < 0.001) after CHEMICAL injection. For capsaicin, secondary pinprick hyperalgesia was detected with all von Frey gauges (P < 0.001). CHEMICAL evoked reproducible VAS response to all von Frey gauges (ICC > 0.60) and brush strokes (ICC > 0.83). Capsaicin injection was reproducible for secondary hyperalgesia (ICC > 0.70) and allodynia (ICC > 0.71). Intra-individual variability was generally lower for the VAS response to von Frey and brush compared with areas of secondary hyperalgesia and allodynia. In conclusion, CHEMICAL and capsaicin yield reproducible hyperalgesic and allodynic responses, and the present model is well suited for basic research, as well as for assessing the modulation of central phenomena. | CHEMICAL-INDUCED-DISEASE |
| Intradermal CHEMICAL and capsaicin injections: intra- and interindividual variability of provoked hyperalgesia and allodynia. Intradermal injections of CHEMICAL and capsaicin are attractive to use in human experimental DISEASE models because hyperalgesia and allodynia mimic isolated aspects of clinical pain disorders. The aim of the present study was to investigate the reproducibility of these models. Twenty healthy male volunteers (mean age 24 years; range 18-38 years) received intradermal injections of CHEMICAL and capsaicin in the volar forearm. Magnitudes of secondary pinprick hyperalgesia and brush-evoked allodynia were investigated using von Frey filaments (gauges 10, 15, 60 and 100 g) and brush strokes. Areas of secondary hyperalgesia and allodynia were quantified immediately after injection and after 15, 30 and 60 min. Two identical experiments separated by at least 7 days were performed. Reproducibility across and within volunteers (inter- and intra-individual variation, respectively) was assessed using intraclass correlation coefficient (ICC) and coefficient of variation (CV). Secondary pinprick hyperalgesia was observed as a marked increase in the visual analogue scale (VAS) response to von Frey gauges 60 and 100 g (P < 0.001) after CHEMICAL injection. For capsaicin, secondary pinprick hyperalgesia was detected with all von Frey gauges (P < 0.001). CHEMICAL evoked reproducible VAS response to all von Frey gauges (ICC > 0.60) and brush strokes (ICC > 0.83). Capsaicin injection was reproducible for secondary hyperalgesia (ICC > 0.70) and allodynia (ICC > 0.71). Intra-individual variability was generally lower for the VAS response to von Frey and brush compared with areas of secondary hyperalgesia and allodynia. In conclusion, CHEMICAL and capsaicin yield reproducible hyperalgesic and allodynic responses, and the present model is well suited for basic research, as well as for assessing the modulation of central phenomena. | CHEMICAL-INDUCED-DISEASE |
| Ocular-specific ER stress reduction rescues DISEASE in murine glucocorticoid-induced DISEASE. Administration of glucocorticoids induces ocular hypertension in some patients. If untreated, these patients can develop a secondary DISEASE that resembles primary open-angle glaucoma (POAG). The underlying pathology of glucocorticoid-induced DISEASE is not fully understood, due in part to lack of an appropriate animal model. Here, we developed a murine model of glucocorticoid-induced DISEASE that exhibits DISEASE features that are observed in patients. Treatment of WT mice with topical ocular 0.1% CHEMICAL led to elevation of intraocular pressure (IOP), functional and structural loss of retinal ganglion cells, and axonal degeneration, resembling glucocorticoid-induced DISEASE in human patients. Furthermore, CHEMICAL-induced ocular hypertension was associated with chronic ER stress of the trabecular meshwork (TM). Similar to patients, withdrawal of CHEMICAL treatment reduced elevated IOP and ER stress in this animal model. CHEMICAL induced the transcriptional factor CHOP, a marker for chronic ER stress, in the anterior segment tissues, and Chop deletion reduced ER stress in these tissues and prevented CHEMICAL-induced ocular hypertension. Furthermore, reduction of ER stress in the TM with sodium 4-phenylbutyrate prevented CHEMICAL-induced ocular hypertension in WT mice. Our data indicate that ER stress contributes to glucocorticoid-induced ocular hypertension and suggest that reducing ER stress has potential as a therapeutic strategy for treating glucocorticoid-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Ocular-specific ER stress reduction rescues glaucoma in murine glucocorticoid-induced glaucoma. Administration of glucocorticoids induces ocular hypertension in some patients. If untreated, these patients can develop a secondary glaucoma that resembles primary open-angle glaucoma (POAG). The underlying pathology of glucocorticoid-induced glaucoma is not fully understood, due in part to lack of an appropriate animal model. Here, we developed a murine model of glucocorticoid-induced glaucoma that exhibits glaucoma features that are observed in patients. Treatment of WT mice with topical ocular 0.1% CHEMICAL led to elevation of intraocular pressure (IOP), functional and structural loss of retinal ganglion cells, and DISEASE, resembling glucocorticoid-induced glaucoma in human patients. Furthermore, CHEMICAL-induced ocular hypertension was associated with chronic ER stress of the trabecular meshwork (TM). Similar to patients, withdrawal of CHEMICAL treatment reduced elevated IOP and ER stress in this animal model. CHEMICAL induced the transcriptional factor CHOP, a marker for chronic ER stress, in the anterior segment tissues, and Chop deletion reduced ER stress in these tissues and prevented CHEMICAL-induced ocular hypertension. Furthermore, reduction of ER stress in the TM with sodium 4-phenylbutyrate prevented CHEMICAL-induced ocular hypertension in WT mice. Our data indicate that ER stress contributes to glucocorticoid-induced ocular hypertension and suggest that reducing ER stress has potential as a therapeutic strategy for treating glucocorticoid-induced glaucoma. | CHEMICAL-INDUCED-DISEASE |
| Ocular-specific ER stress reduction rescues glaucoma in murine glucocorticoid-induced glaucoma. Administration of glucocorticoids induces DISEASE in some patients. If untreated, these patients can develop a secondary glaucoma that resembles primary open-angle glaucoma (POAG). The underlying pathology of glucocorticoid-induced glaucoma is not fully understood, due in part to lack of an appropriate animal model. Here, we developed a murine model of glucocorticoid-induced glaucoma that exhibits glaucoma features that are observed in patients. Treatment of WT mice with topical ocular 0.1% CHEMICAL led to elevation of intraocular pressure (IOP), functional and structural loss of retinal ganglion cells, and axonal degeneration, resembling glucocorticoid-induced glaucoma in human patients. Furthermore, CHEMICAL-induced DISEASE was associated with chronic ER stress of the trabecular meshwork (TM). Similar to patients, withdrawal of CHEMICAL treatment reduced elevated IOP and ER stress in this animal model. CHEMICAL induced the transcriptional factor CHOP, a marker for chronic ER stress, in the anterior segment tissues, and Chop deletion reduced ER stress in these tissues and prevented CHEMICAL-induced DISEASE. Furthermore, reduction of ER stress in the TM with sodium 4-phenylbutyrate prevented CHEMICAL-induced DISEASE in WT mice. Our data indicate that ER stress contributes to glucocorticoid-induced DISEASE and suggest that reducing ER stress has potential as a therapeutic strategy for treating glucocorticoid-induced glaucoma. | CHEMICAL-INDUCED-DISEASE |
| Ocular-specific ER stress reduction rescues glaucoma in murine glucocorticoid-induced glaucoma. Administration of glucocorticoids induces ocular hypertension in some patients. If untreated, these patients can develop a secondary glaucoma that resembles primary open-angle glaucoma (POAG). The underlying pathology of glucocorticoid-induced glaucoma is not fully understood, due in part to lack of an appropriate animal model. Here, we developed a murine model of glucocorticoid-induced glaucoma that exhibits glaucoma features that are observed in patients. Treatment of WT mice with topical ocular 0.1% dexamethasone led to elevation of intraocular pressure (IOP), functional and structural loss of DISEASE cells, and axonal degeneration, resembling glucocorticoid-induced glaucoma in human patients. Furthermore, dexamethasone-induced ocular hypertension was associated with chronic ER stress of the trabecular meshwork (TM). Similar to patients, withdrawal of dexamethasone treatment reduced elevated IOP and ER stress in this animal model. Dexamethasone induced the transcriptional factor CHOP, a marker for chronic ER stress, in the anterior segment tissues, and Chop deletion reduced ER stress in these tissues and prevented dexamethasone-induced ocular hypertension. Furthermore, reduction of ER stress in the TM with CHEMICAL prevented dexamethasone-induced ocular hypertension in WT mice. Our data indicate that ER stress contributes to glucocorticoid-induced ocular hypertension and suggest that reducing ER stress has potential as a therapeutic strategy for treating glucocorticoid-induced glaucoma. | NO-RELATIONSHIP |
| Ocular-specific ER stress reduction rescues glaucoma in murine glucocorticoid-induced glaucoma. Administration of glucocorticoids induces ocular hypertension in some patients. If untreated, these patients can develop a secondary glaucoma that resembles DISEASE (DISEASE). The underlying pathology of glucocorticoid-induced glaucoma is not fully understood, due in part to lack of an appropriate animal model. Here, we developed a murine model of glucocorticoid-induced glaucoma that exhibits glaucoma features that are observed in patients. Treatment of WT mice with topical ocular 0.1% dexamethasone led to elevation of intraocular pressure (IOP), functional and structural loss of retinal ganglion cells, and axonal degeneration, resembling glucocorticoid-induced glaucoma in human patients. Furthermore, dexamethasone-induced ocular hypertension was associated with chronic ER stress of the trabecular meshwork (TM). Similar to patients, withdrawal of dexamethasone treatment reduced elevated IOP and ER stress in this animal model. Dexamethasone induced the transcriptional factor CHOP, a marker for chronic ER stress, in the anterior segment tissues, and Chop deletion reduced ER stress in these tissues and prevented dexamethasone-induced ocular hypertension. Furthermore, reduction of ER stress in the TM with CHEMICAL prevented dexamethasone-induced ocular hypertension in WT mice. Our data indicate that ER stress contributes to glucocorticoid-induced ocular hypertension and suggest that reducing ER stress has potential as a therapeutic strategy for treating glucocorticoid-induced glaucoma. | NO-RELATIONSHIP |
| Effects of ginsenosides on opioid-induced DISEASE in mice. Opioid-induced DISEASE (DISEASE) is characterized by nociceptive sensitization caused by the cessation of chronic opioid use. DISEASE can limit the clinical use of opioid analgesics and complicate withdrawal from opioid addiction. In this study, we investigated the effects of Re, Rg1, and Rb1 ginsenosides, the bioactive components of ginseng, on DISEASE. DISEASE was achieved in mice after subcutaneous administration of CHEMICAL for 7 consecutive days three times per day. During withdrawal (days 8 and 9), these mice were administered Re, Rg1, or Rb1 intragastrically two times per day. On the test day (day 10), mice were subjected to the thermal sensitivity test and the acetic acid-induced writhing test. Re (300 mg/kg) inhibited DISEASE in both the thermal sensitivity test and the acetic acid-induced writhing test. However, the Rg1 and Rb1 ginsenosides failed to prevent DISEASE in either test. Furthermore, Rg1 showed a tendency to aggravate DISEASE in the acetic acid-induced writhing test. Our data suggested that the ginsenoside Re, but not Rg1 or Rb1, may contribute toward reversal of DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Effects of ginsenosides on opioid-induced hyperalgesia in mice. Opioid-induced hyperalgesia (OIH) is characterized by nociceptive sensitization caused by the cessation of chronic opioid use. OIH can limit the clinical use of opioid analgesics and complicate withdrawal from DISEASE. In this study, we investigated the effects of Re, Rg1, and Rb1 ginsenosides, the bioactive components of ginseng, on OIH. OIH was achieved in mice after subcutaneous administration of morphine for 7 consecutive days three times per day. During withdrawal (days 8 and 9), these mice were administered CHEMICAL, Rg1, or Rb1 intragastrically two times per day. On the test day (day 10), mice were subjected to the thermal sensitivity test and the acetic acid-induced writhing test. CHEMICAL (300 mg/kg) inhibited OIH in both the thermal sensitivity test and the acetic acid-induced writhing test. However, the Rg1 and Rb1 ginsenosides failed to prevent OIH in either test. Furthermore, Rg1 showed a tendency to aggravate OIH in the acetic acid-induced writhing test. Our data suggested that the CHEMICAL, but not Rg1 or Rb1, may contribute toward reversal of OIH. | NO-RELATIONSHIP |
| Effects of ginsenosides on opioid-induced hyperalgesia in mice. Opioid-induced hyperalgesia (OIH) is characterized by nociceptive sensitization caused by the cessation of chronic opioid use. OIH can limit the clinical use of opioid analgesics and complicate withdrawal from DISEASE. In this study, we investigated the effects of Re, Rg1, and Rb1 ginsenosides, the bioactive components of ginseng, on OIH. OIH was achieved in mice after subcutaneous administration of morphine for 7 consecutive days three times per day. During withdrawal (days 8 and 9), these mice were administered Re, Rg1, or Rb1 intragastrically two times per day. On the test day (day 10), mice were subjected to the thermal sensitivity test and the CHEMICAL-induced writhing test. Re (300 mg/kg) inhibited OIH in both the thermal sensitivity test and the CHEMICAL-induced writhing test. However, the Rg1 and Rb1 ginsenosides failed to prevent OIH in either test. Furthermore, Rg1 showed a tendency to aggravate OIH in the CHEMICAL-induced writhing test. Our data suggested that the ginsenoside Re, but not Rg1 or Rb1, may contribute toward reversal of OIH. | NO-RELATIONSHIP |
| Effects of ginsenosides on opioid-induced hyperalgesia in mice. Opioid-induced hyperalgesia (OIH) is characterized by nociceptive sensitization caused by the cessation of chronic opioid use. OIH can limit the clinical use of opioid analgesics and complicate withdrawal from DISEASE. In this study, we investigated the effects of Re, Rg1, and Rb1 ginsenosides, the bioactive components of ginseng, on OIH. OIH was achieved in mice after subcutaneous administration of morphine for 7 consecutive days three times per day. During withdrawal (days 8 and 9), these mice were administered Re, Rg1, or CHEMICAL intragastrically two times per day. On the test day (day 10), mice were subjected to the thermal sensitivity test and the acetic acid-induced writhing test. Re (300 mg/kg) inhibited OIH in both the thermal sensitivity test and the acetic acid-induced writhing test. However, the Rg1 and Rb1 ginsenosides failed to prevent OIH in either test. Furthermore, Rg1 showed a tendency to aggravate OIH in the acetic acid-induced writhing test. Our data suggested that the ginsenoside Re, but not Rg1 or CHEMICAL, may contribute toward reversal of OIH. | NO-RELATIONSHIP |
| Effects of ginsenosides on opioid-induced hyperalgesia in mice. Opioid-induced hyperalgesia (OIH) is characterized by nociceptive sensitization caused by the cessation of chronic opioid use. OIH can limit the clinical use of opioid analgesics and complicate withdrawal from DISEASE. In this study, we investigated the effects of Re, Rg1, and Rb1 ginsenosides, the bioactive components of ginseng, on OIH. OIH was achieved in mice after subcutaneous administration of morphine for 7 consecutive days three times per day. During withdrawal (days 8 and 9), these mice were administered Re, Rg1, or Rb1 intragastrically two times per day. On the test day (day 10), mice were subjected to the thermal sensitivity test and the acetic acid-induced writhing test. Re (300 mg/kg) inhibited OIH in both the thermal sensitivity test and the acetic acid-induced writhing test. However, the CHEMICAL failed to prevent OIH in either test. Furthermore, Rg1 showed a tendency to aggravate OIH in the acetic acid-induced writhing test. Our data suggested that the ginsenoside Re, but not Rg1 or Rb1, may contribute toward reversal of OIH. | NO-RELATIONSHIP |
| Effects of ginsenosides on opioid-induced hyperalgesia in mice. Opioid-induced hyperalgesia (OIH) is characterized by nociceptive sensitization caused by the cessation of chronic opioid use. OIH can limit the clinical use of opioid analgesics and complicate withdrawal from DISEASE. In this study, we investigated the effects of CHEMICAL, the bioactive components of ginseng, on OIH. OIH was achieved in mice after subcutaneous administration of morphine for 7 consecutive days three times per day. During withdrawal (days 8 and 9), these mice were administered Re, Rg1, or Rb1 intragastrically two times per day. On the test day (day 10), mice were subjected to the thermal sensitivity test and the acetic acid-induced writhing test. Re (300 mg/kg) inhibited OIH in both the thermal sensitivity test and the acetic acid-induced writhing test. However, the Rg1 and Rb1 ginsenosides failed to prevent OIH in either test. Furthermore, Rg1 showed a tendency to aggravate OIH in the acetic acid-induced writhing test. Our data suggested that the ginsenoside Re, but not Rg1 or Rb1, may contribute toward reversal of OIH. | NO-RELATIONSHIP |
| Effects of CHEMICAL on opioid-induced hyperalgesia in mice. Opioid-induced hyperalgesia (OIH) is characterized by nociceptive sensitization caused by the cessation of chronic opioid use. OIH can limit the clinical use of opioid analgesics and complicate withdrawal from DISEASE. In this study, we investigated the effects of Re, Rg1, and Rb1 ginsenosides, the bioactive components of ginseng, on OIH. OIH was achieved in mice after subcutaneous administration of morphine for 7 consecutive days three times per day. During withdrawal (days 8 and 9), these mice were administered Re, Rg1, or Rb1 intragastrically two times per day. On the test day (day 10), mice were subjected to the thermal sensitivity test and the acetic acid-induced writhing test. Re (300 mg/kg) inhibited OIH in both the thermal sensitivity test and the acetic acid-induced writhing test. However, the Rg1 and Rb1 ginsenosides failed to prevent OIH in either test. Furthermore, Rg1 showed a tendency to aggravate OIH in the acetic acid-induced writhing test. Our data suggested that the ginsenoside Re, but not Rg1 or Rb1, may contribute toward reversal of OIH. | NO-RELATIONSHIP |
| Effects of ginsenosides on opioid-induced hyperalgesia in mice. Opioid-induced hyperalgesia (OIH) is characterized by nociceptive sensitization caused by the cessation of chronic opioid use. OIH can limit the clinical use of opioid analgesics and complicate withdrawal from DISEASE. In this study, we investigated the effects of Re, Rg1, and Rb1 ginsenosides, the bioactive components of ginseng, on OIH. OIH was achieved in mice after subcutaneous administration of morphine for 7 consecutive days three times per day. During withdrawal (days 8 and 9), these mice were administered Re, CHEMICAL, or Rb1 intragastrically two times per day. On the test day (day 10), mice were subjected to the thermal sensitivity test and the acetic acid-induced writhing test. Re (300 mg/kg) inhibited OIH in both the thermal sensitivity test and the acetic acid-induced writhing test. However, the Rg1 and Rb1 ginsenosides failed to prevent OIH in either test. Furthermore, CHEMICAL showed a tendency to aggravate OIH in the acetic acid-induced writhing test. Our data suggested that the ginsenoside Re, but not CHEMICAL or Rb1, may contribute toward reversal of OIH. | NO-RELATIONSHIP |
| A comparison of severe hemodynamic disturbances between dexmedetomidine and CHEMICAL for sedation in neurocritical care patients. OBJECTIVE: Dexmedetomidine and CHEMICAL are commonly used sedatives in neurocritical care as they allow for frequent neurologic examinations. However, both agents are associated with significant hemodynamic side effects. The primary objective of this study is to compare the prevalence of severe hemodynamic effects in neurocritical care patients receiving dexmedetomidine and CHEMICAL. DESIGN: Multicenter, retrospective, propensity-matched cohort study. SETTING: Neurocritical care units at two academic medical centers with dedicated neurocritical care teams and board-certified neurointensivists. PATIENTS: Neurocritical care patients admitted between July 2009 and September 2012 were evaluated and then matched 1:1 based on propensity scoring of baseline characteristics. INTERVENTIONS: Continuous sedation with dexmedetomidine or CHEMICAL. MEASUREMENTS AND MAIN RESULTS: A total of 342 patients (105 dexmedetomidine and 237 CHEMICAL) were included in the analysis, with 190 matched (95 in each group) by propensity score. The primary outcome of this study was a composite of severe hypotension (mean arterial pressure < 60 mm Hg) and DISEASE (heart rate < 50 beats/min) during sedative infusion. No difference in the primary composite outcome in both the unmatched (30% vs 30%, p = 0.94) or matched cohorts (28% vs 34%, p = 0.35) could be found. When analyzed separately, no differences could be found in the prevalence of severe hypotension or DISEASE in either the unmatched or matched cohorts. CONCLUSIONS: Severe hypotension and DISEASE occur at similar prevalence in neurocritical care patients who receive dexmedetomidine or CHEMICAL. Providers should similarly consider the likelihood of hypotension or DISEASE before starting either sedative. | CHEMICAL-INDUCED-DISEASE |
| A comparison of severe hemodynamic disturbances between CHEMICAL and propofol for sedation in neurocritical care patients. OBJECTIVE: CHEMICAL and propofol are commonly used sedatives in neurocritical care as they allow for frequent neurologic examinations. However, both agents are associated with significant hemodynamic side effects. The primary objective of this study is to compare the prevalence of severe hemodynamic effects in neurocritical care patients receiving CHEMICAL and propofol. DESIGN: Multicenter, retrospective, propensity-matched cohort study. SETTING: Neurocritical care units at two academic medical centers with dedicated neurocritical care teams and board-certified neurointensivists. PATIENTS: Neurocritical care patients admitted between July 2009 and September 2012 were evaluated and then matched 1:1 based on propensity scoring of baseline characteristics. INTERVENTIONS: Continuous sedation with CHEMICAL or propofol. MEASUREMENTS AND MAIN RESULTS: A total of 342 patients (105 CHEMICAL and 237 propofol) were included in the analysis, with 190 matched (95 in each group) by propensity score. The primary outcome of this study was a composite of severe DISEASE (mean arterial pressure < 60 mm Hg) and bradycardia (heart rate < 50 beats/min) during sedative infusion. No difference in the primary composite outcome in both the unmatched (30% vs 30%, p = 0.94) or matched cohorts (28% vs 34%, p = 0.35) could be found. When analyzed separately, no differences could be found in the prevalence of severe DISEASE or bradycardia in either the unmatched or matched cohorts. CONCLUSIONS: Severe DISEASE and bradycardia occur at similar prevalence in neurocritical care patients who receive CHEMICAL or propofol. Providers should similarly consider the likelihood of DISEASE or bradycardia before starting either sedative. | CHEMICAL-INDUCED-DISEASE |
| A comparison of severe hemodynamic disturbances between CHEMICAL and propofol for sedation in neurocritical care patients. OBJECTIVE: CHEMICAL and propofol are commonly used sedatives in neurocritical care as they allow for frequent neurologic examinations. However, both agents are associated with significant hemodynamic side effects. The primary objective of this study is to compare the prevalence of severe hemodynamic effects in neurocritical care patients receiving CHEMICAL and propofol. DESIGN: Multicenter, retrospective, propensity-matched cohort study. SETTING: Neurocritical care units at two academic medical centers with dedicated neurocritical care teams and board-certified neurointensivists. PATIENTS: Neurocritical care patients admitted between July 2009 and September 2012 were evaluated and then matched 1:1 based on propensity scoring of baseline characteristics. INTERVENTIONS: Continuous sedation with CHEMICAL or propofol. MEASUREMENTS AND MAIN RESULTS: A total of 342 patients (105 CHEMICAL and 237 propofol) were included in the analysis, with 190 matched (95 in each group) by propensity score. The primary outcome of this study was a composite of severe hypotension (mean arterial pressure < 60 mm Hg) and DISEASE (heart rate < 50 beats/min) during sedative infusion. No difference in the primary composite outcome in both the unmatched (30% vs 30%, p = 0.94) or matched cohorts (28% vs 34%, p = 0.35) could be found. When analyzed separately, no differences could be found in the prevalence of severe hypotension or DISEASE in either the unmatched or matched cohorts. CONCLUSIONS: Severe hypotension and DISEASE occur at similar prevalence in neurocritical care patients who receive CHEMICAL or propofol. Providers should similarly consider the likelihood of hypotension or DISEASE before starting either sedative. | CHEMICAL-INDUCED-DISEASE |
| A comparison of severe hemodynamic disturbances between dexmedetomidine and CHEMICAL for sedation in neurocritical care patients. OBJECTIVE: Dexmedetomidine and CHEMICAL are commonly used sedatives in neurocritical care as they allow for frequent neurologic examinations. However, both agents are associated with significant hemodynamic side effects. The primary objective of this study is to compare the prevalence of severe hemodynamic effects in neurocritical care patients receiving dexmedetomidine and CHEMICAL. DESIGN: Multicenter, retrospective, propensity-matched cohort study. SETTING: Neurocritical care units at two academic medical centers with dedicated neurocritical care teams and board-certified neurointensivists. PATIENTS: Neurocritical care patients admitted between July 2009 and September 2012 were evaluated and then matched 1:1 based on propensity scoring of baseline characteristics. INTERVENTIONS: Continuous sedation with dexmedetomidine or CHEMICAL. MEASUREMENTS AND MAIN RESULTS: A total of 342 patients (105 dexmedetomidine and 237 CHEMICAL) were included in the analysis, with 190 matched (95 in each group) by propensity score. The primary outcome of this study was a composite of severe DISEASE (mean arterial pressure < 60 mm Hg) and bradycardia (heart rate < 50 beats/min) during sedative infusion. No difference in the primary composite outcome in both the unmatched (30% vs 30%, p = 0.94) or matched cohorts (28% vs 34%, p = 0.35) could be found. When analyzed separately, no differences could be found in the prevalence of severe DISEASE or bradycardia in either the unmatched or matched cohorts. CONCLUSIONS: Severe DISEASE and bradycardia occur at similar prevalence in neurocritical care patients who receive dexmedetomidine or CHEMICAL. Providers should similarly consider the likelihood of DISEASE or bradycardia before starting either sedative. | CHEMICAL-INDUCED-DISEASE |
| Hydroxytyrosol ameliorates oxidative stress and mitochondrial dysfunction in CHEMICAL-induced cardiotoxicity in rats with breast cancer. Oxidative stress is involved in several processes including cancer, aging and cardiovascular disease, and has been shown to potentiate the therapeutic effect of drugs such as CHEMICAL. CHEMICAL causes significant cardiotoxicity characterized by marked increases in oxidative stress and mitochondrial dysfunction. Herein, we investigate whether CHEMICAL-associated chronic cardiac toxicity can be ameliorated with the antioxidant hydroxytyrosol in rats with breast cancer. Thirty-six rats bearing breast tumors induced chemically were divided into 4 groups: control, hydroxytyrosol (0.5mg/kg, 5days/week), CHEMICAL (1mg/kg/week), and CHEMICAL plus hydroxytyrosol. DISEASE at the cellular and mitochondrial level, mitochondrial electron transport chain complexes I-IV and apoptosis-inducing factor, and oxidative stress markers have been analyzed. Hydroxytyrosol improved the DISEASE enhanced by CHEMICAL by significantly reducing the percentage of altered mitochondria and oxidative damage. These results suggest that hydroxytyrosol improve the mitochondrial electron transport chain. This study demonstrates that hydroxytyrosol protect rat DISEASE provoked by CHEMICAL decreasing oxidative damage and mitochondrial alterations. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with DISEASE. Oxidative stress is involved in several processes including cancer, aging and cardiovascular disease, and has been shown to potentiate the therapeutic effect of drugs such as doxorubicin. Doxorubicin causes significant cardiotoxicity characterized by marked increases in oxidative stress and mitochondrial dysfunction. Herein, we investigate whether doxorubicin-associated chronic cardiac toxicity can be ameliorated with the antioxidant CHEMICAL in rats with DISEASE. Thirty-six rats bearing DISEASE induced chemically were divided into 4 groups: control, CHEMICAL (0.5mg/kg, 5days/week), doxorubicin (1mg/kg/week), and doxorubicin plus CHEMICAL. Cardiac disturbances at the cellular and mitochondrial level, mitochondrial electron transport chain complexes I-IV and apoptosis-inducing factor, and oxidative stress markers have been analyzed. CHEMICAL improved the cardiac disturbances enhanced by doxorubicin by significantly reducing the percentage of altered mitochondria and oxidative damage. These results suggest that CHEMICAL improve the mitochondrial electron transport chain. This study demonstrates that CHEMICAL protect rat heart damage provoked by doxorubicin decreasing oxidative damage and mitochondrial alterations. | NO-RELATIONSHIP |
| CHEMICAL ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with breast cancer. Oxidative stress is involved in several processes including cancer, aging and DISEASE, and has been shown to potentiate the therapeutic effect of drugs such as doxorubicin. Doxorubicin causes significant cardiotoxicity characterized by marked increases in oxidative stress and mitochondrial dysfunction. Herein, we investigate whether doxorubicin-associated chronic cardiac toxicity can be ameliorated with the antioxidant CHEMICAL in rats with breast cancer. Thirty-six rats bearing breast tumors induced chemically were divided into 4 groups: control, CHEMICAL (0.5mg/kg, 5days/week), doxorubicin (1mg/kg/week), and doxorubicin plus CHEMICAL. Cardiac disturbances at the cellular and mitochondrial level, mitochondrial electron transport chain complexes I-IV and apoptosis-inducing factor, and oxidative stress markers have been analyzed. CHEMICAL improved the cardiac disturbances enhanced by doxorubicin by significantly reducing the percentage of altered mitochondria and oxidative damage. These results suggest that CHEMICAL improve the mitochondrial electron transport chain. This study demonstrates that CHEMICAL protect rat heart damage provoked by doxorubicin decreasing oxidative damage and mitochondrial alterations. | NO-RELATIONSHIP |
| CHEMICAL ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced DISEASE in rats with breast cancer. Oxidative stress is involved in several processes including cancer, aging and cardiovascular disease, and has been shown to potentiate the therapeutic effect of drugs such as doxorubicin. Doxorubicin causes significant DISEASE characterized by marked increases in oxidative stress and mitochondrial dysfunction. Herein, we investigate whether doxorubicin-associated chronic DISEASE can be ameliorated with the antioxidant CHEMICAL in rats with breast cancer. Thirty-six rats bearing breast tumors induced chemically were divided into 4 groups: control, CHEMICAL (0.5mg/kg, 5days/week), doxorubicin (1mg/kg/week), and doxorubicin plus CHEMICAL. Cardiac disturbances at the cellular and mitochondrial level, mitochondrial electron transport chain complexes I-IV and apoptosis-inducing factor, and oxidative stress markers have been analyzed. CHEMICAL improved the cardiac disturbances enhanced by doxorubicin by significantly reducing the percentage of altered mitochondria and oxidative damage. These results suggest that CHEMICAL improve the mitochondrial electron transport chain. This study demonstrates that CHEMICAL protect rat heart damage provoked by doxorubicin decreasing oxidative damage and mitochondrial alterations. | NO-RELATIONSHIP |
| CHEMICAL ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with breast cancer. Oxidative stress is involved in several processes including DISEASE, aging and cardiovascular disease, and has been shown to potentiate the therapeutic effect of drugs such as doxorubicin. Doxorubicin causes significant cardiotoxicity characterized by marked increases in oxidative stress and mitochondrial dysfunction. Herein, we investigate whether doxorubicin-associated chronic cardiac toxicity can be ameliorated with the antioxidant CHEMICAL in rats with breast cancer. Thirty-six rats bearing breast tumors induced chemically were divided into 4 groups: control, CHEMICAL (0.5mg/kg, 5days/week), doxorubicin (1mg/kg/week), and doxorubicin plus CHEMICAL. Cardiac disturbances at the cellular and mitochondrial level, mitochondrial electron transport chain complexes I-IV and apoptosis-inducing factor, and oxidative stress markers have been analyzed. CHEMICAL improved the cardiac disturbances enhanced by doxorubicin by significantly reducing the percentage of altered mitochondria and oxidative damage. These results suggest that CHEMICAL improve the mitochondrial electron transport chain. This study demonstrates that CHEMICAL protect rat heart damage provoked by doxorubicin decreasing oxidative damage and mitochondrial alterations. | NO-RELATIONSHIP |
| CHEMICAL ameliorates oxidative stress and DISEASE in doxorubicin-induced cardiotoxicity in rats with breast cancer. Oxidative stress is involved in several processes including cancer, aging and cardiovascular disease, and has been shown to potentiate the therapeutic effect of drugs such as doxorubicin. Doxorubicin causes significant cardiotoxicity characterized by marked increases in oxidative stress and DISEASE. Herein, we investigate whether doxorubicin-associated chronic cardiac toxicity can be ameliorated with the antioxidant CHEMICAL in rats with breast cancer. Thirty-six rats bearing breast tumors induced chemically were divided into 4 groups: control, CHEMICAL (0.5mg/kg, 5days/week), doxorubicin (1mg/kg/week), and doxorubicin plus CHEMICAL. Cardiac disturbances at the cellular and mitochondrial level, mitochondrial electron transport chain complexes I-IV and apoptosis-inducing factor, and oxidative stress markers have been analyzed. CHEMICAL improved the cardiac disturbances enhanced by doxorubicin by significantly reducing the percentage of altered mitochondria and oxidative damage. These results suggest that CHEMICAL improve the mitochondrial electron transport chain. This study demonstrates that CHEMICAL protect rat heart damage provoked by doxorubicin decreasing oxidative damage and mitochondrial alterations. | NO-RELATIONSHIP |
| CHEMICAL-induced myxoedema coma. A 62-year-old man was found to have DISEASE, hypothermia and respiratory failure 3 weeks after initiation of CHEMICAL therapy for atrial fibrillation. Thyroid-stimulating hormone was found to be 168 uIU/mL (nl. 0.3-5 uIU/mL) and free thyroxine (FT4) was <0.2 ng/dL (nl. 0.8-1.8 ng/dL). He received intravenous fluids, vasopressor therapy and stress dose steroids; he was intubated and admitted to the intensive care unit. He received 500 ug of intravenous levothyroxine in the first 18 h of therapy, and 150 ug intravenous daily thereafter. Haemodynamic improvement, along with complete recovery of mental status, occurred after 48 h. Twelve hours after the initiation of therapy, FT4 was 0.96 ng/dL. The patient was maintained on levothyroxine 175 (g POorally daily. A thyroid ultrasound showed diffuse heterogeneity. The 24 hour excretion of iodine was 3657 (mcg (25-756 ( mcg). The only two cases of CHEMICAL-induced myxoedema coma in the literature report patient death despite supportive therapy and thyroid hormone replacement. This case represents the most thoroughly investigated case of CHEMICAL-induced myxoedema coma with a history significant for subclinical thyroid disease. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced myxoedema coma. A 62-year-old man was found to have bradycardia, DISEASE and respiratory failure 3 weeks after initiation of CHEMICAL therapy for atrial fibrillation. Thyroid-stimulating hormone was found to be 168 uIU/mL (nl. 0.3-5 uIU/mL) and free thyroxine (FT4) was <0.2 ng/dL (nl. 0.8-1.8 ng/dL). He received intravenous fluids, vasopressor therapy and stress dose steroids; he was intubated and admitted to the intensive care unit. He received 500 ug of intravenous levothyroxine in the first 18 h of therapy, and 150 ug intravenous daily thereafter. Haemodynamic improvement, along with complete recovery of mental status, occurred after 48 h. Twelve hours after the initiation of therapy, FT4 was 0.96 ng/dL. The patient was maintained on levothyroxine 175 (g POorally daily. A thyroid ultrasound showed diffuse heterogeneity. The 24 hour excretion of iodine was 3657 (mcg (25-756 ( mcg). The only two cases of CHEMICAL-induced myxoedema coma in the literature report patient death despite supportive therapy and thyroid hormone replacement. This case represents the most thoroughly investigated case of CHEMICAL-induced myxoedema coma with a history significant for subclinical thyroid disease. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced myxoedema coma. A 62-year-old man was found to have bradycardia, hypothermia and DISEASE 3 weeks after initiation of CHEMICAL therapy for atrial fibrillation. Thyroid-stimulating hormone was found to be 168 uIU/mL (nl. 0.3-5 uIU/mL) and free thyroxine (FT4) was <0.2 ng/dL (nl. 0.8-1.8 ng/dL). He received intravenous fluids, vasopressor therapy and stress dose steroids; he was intubated and admitted to the intensive care unit. He received 500 ug of intravenous levothyroxine in the first 18 h of therapy, and 150 ug intravenous daily thereafter. Haemodynamic improvement, along with complete recovery of mental status, occurred after 48 h. Twelve hours after the initiation of therapy, FT4 was 0.96 ng/dL. The patient was maintained on levothyroxine 175 (g POorally daily. A thyroid ultrasound showed diffuse heterogeneity. The 24 hour excretion of iodine was 3657 (mcg (25-756 ( mcg). The only two cases of CHEMICAL-induced myxoedema coma in the literature report patient death despite supportive therapy and thyroid hormone replacement. This case represents the most thoroughly investigated case of CHEMICAL-induced myxoedema coma with a history significant for subclinical thyroid disease. | CHEMICAL-INDUCED-DISEASE |
| Amiodarone-induced DISEASE. A 62-year-old man was found to have bradycardia, hypothermia and respiratory failure 3 weeks after initiation of amiodarone therapy for atrial fibrillation. Thyroid-stimulating hormone was found to be 168 uIU/mL (nl. 0.3-5 uIU/mL) and free thyroxine (FT4) was <0.2 ng/dL (nl. 0.8-1.8 ng/dL). He received intravenous fluids, vasopressor therapy and stress dose CHEMICAL; he was intubated and admitted to the intensive care unit. He received 500 ug of intravenous levothyroxine in the first 18 h of therapy, and 150 ug intravenous daily thereafter. Haemodynamic improvement, along with complete recovery of mental status, occurred after 48 h. Twelve hours after the initiation of therapy, FT4 was 0.96 ng/dL. The patient was maintained on levothyroxine 175 (g POorally daily. A thyroid ultrasound showed diffuse heterogeneity. The 24 hour excretion of iodine was 3657 (mcg (25-756 ( mcg). The only two cases of amiodarone-induced DISEASE in the literature report patient death despite supportive therapy and thyroid hormone replacement. This case represents the most thoroughly investigated case of amiodarone-induced DISEASE with a history significant for subclinical thyroid disease. | NO-RELATIONSHIP |
| Amiodarone-induced myxoedema coma. A 62-year-old man was found to have bradycardia, hypothermia and respiratory failure 3 weeks after initiation of amiodarone therapy for DISEASE. Thyroid-stimulating hormone was found to be 168 uIU/mL (nl. 0.3-5 uIU/mL) and free thyroxine (FT4) was <0.2 ng/dL (nl. 0.8-1.8 ng/dL). He received intravenous fluids, vasopressor therapy and stress dose CHEMICAL; he was intubated and admitted to the intensive care unit. He received 500 ug of intravenous levothyroxine in the first 18 h of therapy, and 150 ug intravenous daily thereafter. Haemodynamic improvement, along with complete recovery of mental status, occurred after 48 h. Twelve hours after the initiation of therapy, FT4 was 0.96 ng/dL. The patient was maintained on levothyroxine 175 (g POorally daily. A thyroid ultrasound showed diffuse heterogeneity. The 24 hour excretion of iodine was 3657 (mcg (25-756 ( mcg). The only two cases of amiodarone-induced myxoedema coma in the literature report patient death despite supportive therapy and thyroid hormone replacement. This case represents the most thoroughly investigated case of amiodarone-induced myxoedema coma with a history significant for subclinical thyroid disease. | NO-RELATIONSHIP |
| Amiodarone-induced myxoedema coma. A 62-year-old man was found to have bradycardia, hypothermia and respiratory failure 3 weeks after initiation of amiodarone therapy for atrial fibrillation. Thyroid-stimulating hormone was found to be 168 uIU/mL (nl. 0.3-5 uIU/mL) and free thyroxine (FT4) was <0.2 ng/dL (nl. 0.8-1.8 ng/dL). He received intravenous fluids, vasopressor therapy and stress dose steroids; he was intubated and admitted to the intensive care unit. He received 500 ug of intravenous levothyroxine in the first 18 h of therapy, and 150 ug intravenous daily thereafter. Haemodynamic improvement, along with complete recovery of mental status, occurred after 48 h. Twelve hours after the initiation of therapy, FT4 was 0.96 ng/dL. The patient was maintained on levothyroxine 175 (g POorally daily. A thyroid ultrasound showed diffuse heterogeneity. The 24 hour excretion of CHEMICAL was 3657 (mcg (25-756 ( mcg). The only two cases of amiodarone-induced myxoedema coma in the literature report patient death despite supportive therapy and thyroid hormone replacement. This case represents the most thoroughly investigated case of amiodarone-induced myxoedema coma with a history significant for subclinical DISEASE. | NO-RELATIONSHIP |
| Amiodarone-induced myxoedema coma. A 62-year-old man was found to have bradycardia, hypothermia and respiratory failure 3 weeks after initiation of amiodarone therapy for atrial fibrillation. Thyroid-stimulating hormone was found to be 168 uIU/mL (nl. 0.3-5 uIU/mL) and free thyroxine (FT4) was <0.2 ng/dL (nl. 0.8-1.8 ng/dL). He received intravenous fluids, vasopressor therapy and stress dose CHEMICAL; he was intubated and admitted to the intensive care unit. He received 500 ug of intravenous levothyroxine in the first 18 h of therapy, and 150 ug intravenous daily thereafter. Haemodynamic improvement, along with complete recovery of mental status, occurred after 48 h. Twelve hours after the initiation of therapy, FT4 was 0.96 ng/dL. The patient was maintained on levothyroxine 175 (g POorally daily. A thyroid ultrasound showed diffuse heterogeneity. The 24 hour excretion of iodine was 3657 (mcg (25-756 ( mcg). The only two cases of amiodarone-induced myxoedema coma in the literature report patient death despite supportive therapy and thyroid hormone replacement. This case represents the most thoroughly investigated case of amiodarone-induced myxoedema coma with a history significant for subclinical DISEASE. | NO-RELATIONSHIP |
| Amiodarone-induced DISEASE. A 62-year-old man was found to have bradycardia, hypothermia and respiratory failure 3 weeks after initiation of amiodarone therapy for atrial fibrillation. Thyroid-stimulating hormone was found to be 168 uIU/mL (nl. 0.3-5 uIU/mL) and free thyroxine (FT4) was <0.2 ng/dL (nl. 0.8-1.8 ng/dL). He received intravenous fluids, vasopressor therapy and stress dose steroids; he was intubated and admitted to the intensive care unit. He received 500 ug of intravenous levothyroxine in the first 18 h of therapy, and 150 ug intravenous daily thereafter. Haemodynamic improvement, along with complete recovery of mental status, occurred after 48 h. Twelve hours after the initiation of therapy, FT4 was 0.96 ng/dL. The patient was maintained on levothyroxine 175 (g POorally daily. A thyroid ultrasound showed diffuse heterogeneity. The 24 hour excretion of CHEMICAL was 3657 (mcg (25-756 ( mcg). The only two cases of amiodarone-induced DISEASE in the literature report patient death despite supportive therapy and thyroid hormone replacement. This case represents the most thoroughly investigated case of amiodarone-induced DISEASE with a history significant for subclinical thyroid disease. | NO-RELATIONSHIP |
| Amiodarone-induced myxoedema coma. A 62-year-old man was found to have bradycardia, hypothermia and respiratory failure 3 weeks after initiation of amiodarone therapy for DISEASE. Thyroid-stimulating hormone was found to be 168 uIU/mL (nl. 0.3-5 uIU/mL) and free CHEMICAL (FT4) was <0.2 ng/dL (nl. 0.8-1.8 ng/dL). He received intravenous fluids, vasopressor therapy and stress dose steroids; he was intubated and admitted to the intensive care unit. He received 500 ug of intravenous CHEMICAL in the first 18 h of therapy, and 150 ug intravenous daily thereafter. Haemodynamic improvement, along with complete recovery of mental status, occurred after 48 h. Twelve hours after the initiation of therapy, FT4 was 0.96 ng/dL. The patient was maintained on CHEMICAL 175 (g POorally daily. A thyroid ultrasound showed diffuse heterogeneity. The 24 hour excretion of iodine was 3657 (mcg (25-756 ( mcg). The only two cases of amiodarone-induced myxoedema coma in the literature report patient death despite supportive therapy and thyroid hormone replacement. This case represents the most thoroughly investigated case of amiodarone-induced myxoedema coma with a history significant for subclinical thyroid disease. | NO-RELATIONSHIP |
| Amiodarone-induced myxoedema coma. A 62-year-old man was found to have bradycardia, hypothermia and respiratory failure 3 weeks after initiation of amiodarone therapy for DISEASE. Thyroid-stimulating hormone was found to be 168 uIU/mL (nl. 0.3-5 uIU/mL) and free thyroxine (FT4) was <0.2 ng/dL (nl. 0.8-1.8 ng/dL). He received intravenous fluids, vasopressor therapy and stress dose steroids; he was intubated and admitted to the intensive care unit. He received 500 ug of intravenous levothyroxine in the first 18 h of therapy, and 150 ug intravenous daily thereafter. Haemodynamic improvement, along with complete recovery of mental status, occurred after 48 h. Twelve hours after the initiation of therapy, FT4 was 0.96 ng/dL. The patient was maintained on levothyroxine 175 (g POorally daily. A thyroid ultrasound showed diffuse heterogeneity. The 24 hour excretion of CHEMICAL was 3657 (mcg (25-756 ( mcg). The only two cases of amiodarone-induced myxoedema coma in the literature report patient death despite supportive therapy and thyroid hormone replacement. This case represents the most thoroughly investigated case of amiodarone-induced myxoedema coma with a history significant for subclinical thyroid disease. | NO-RELATIONSHIP |
| Amiodarone-induced DISEASE. A 62-year-old man was found to have bradycardia, hypothermia and respiratory failure 3 weeks after initiation of amiodarone therapy for atrial fibrillation. Thyroid-stimulating hormone was found to be 168 uIU/mL (nl. 0.3-5 uIU/mL) and free CHEMICAL (FT4) was <0.2 ng/dL (nl. 0.8-1.8 ng/dL). He received intravenous fluids, vasopressor therapy and stress dose steroids; he was intubated and admitted to the intensive care unit. He received 500 ug of intravenous CHEMICAL in the first 18 h of therapy, and 150 ug intravenous daily thereafter. Haemodynamic improvement, along with complete recovery of mental status, occurred after 48 h. Twelve hours after the initiation of therapy, FT4 was 0.96 ng/dL. The patient was maintained on CHEMICAL 175 (g POorally daily. A thyroid ultrasound showed diffuse heterogeneity. The 24 hour excretion of iodine was 3657 (mcg (25-756 ( mcg). The only two cases of amiodarone-induced DISEASE in the literature report patient death despite supportive therapy and thyroid hormone replacement. This case represents the most thoroughly investigated case of amiodarone-induced DISEASE with a history significant for subclinical thyroid disease. | NO-RELATIONSHIP |
| Amiodarone-induced myxoedema coma. A 62-year-old man was found to have bradycardia, hypothermia and respiratory failure 3 weeks after initiation of amiodarone therapy for atrial fibrillation. Thyroid-stimulating hormone was found to be 168 uIU/mL (nl. 0.3-5 uIU/mL) and free CHEMICAL (FT4) was <0.2 ng/dL (nl. 0.8-1.8 ng/dL). He received intravenous fluids, vasopressor therapy and stress dose steroids; he was intubated and admitted to the intensive care unit. He received 500 ug of intravenous CHEMICAL in the first 18 h of therapy, and 150 ug intravenous daily thereafter. Haemodynamic improvement, along with complete recovery of mental status, occurred after 48 h. Twelve hours after the initiation of therapy, FT4 was 0.96 ng/dL. The patient was maintained on CHEMICAL 175 (g POorally daily. A thyroid ultrasound showed diffuse heterogeneity. The 24 hour excretion of iodine was 3657 (mcg (25-756 ( mcg). The only two cases of amiodarone-induced myxoedema coma in the literature report patient death despite supportive therapy and thyroid hormone replacement. This case represents the most thoroughly investigated case of amiodarone-induced myxoedema coma with a history significant for subclinical DISEASE. | NO-RELATIONSHIP |
| Use of argatroban and catheter-directed thrombolysis with alteplase in an oncology patient with CHEMICAL-induced DISEASE with thrombosis. PURPOSE: The case of an oncology patient who developed CHEMICAL-induced DISEASE with thrombosis (HITT) and was treated with argatroban plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to CHEMICAL-induced DISEASE. A continuous i.v. infusion of argatroban was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on argatroban. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while argatroban was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on argatroban; ultimately, he was transitioned to warfarin for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with argatroban and CDT with alteplase. | CHEMICAL-INDUCED-DISEASE |
| Use of argatroban and catheter-directed thrombolysis with alteplase in an oncology patient with CHEMICAL-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed CHEMICAL-induced thrombocytopenia with thrombosis (HITT) and was treated with argatroban plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and DISEASE secondary to CHEMICAL-induced thrombocytopenia. A continuous i.v. infusion of argatroban was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on argatroban. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while argatroban was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on argatroban; ultimately, he was transitioned to warfarin for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with argatroban and CDT with alteplase. | CHEMICAL-INDUCED-DISEASE |
| Use of argatroban and catheter-directed thrombolysis with alteplase in an oncology patient with CHEMICAL-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed CHEMICAL-induced thrombocytopenia with thrombosis (HITT) and was treated with argatroban plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DISEASE) and pulmonary embolism secondary to CHEMICAL-induced thrombocytopenia. A continuous i.v. infusion of argatroban was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on argatroban. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while argatroban was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on argatroban; ultimately, he was transitioned to warfarin for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with argatroban and CDT with alteplase. | NO-RELATIONSHIP |
| Use of CHEMICAL and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (HITT) and was treated with CHEMICAL plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral DISEASE (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of CHEMICAL was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on CHEMICAL. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while CHEMICAL was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on CHEMICAL; ultimately, he was transitioned to warfarin for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with CHEMICAL and CDT with alteplase. | CHEMICAL-INDUCED-DISEASE |
| Use of argatroban and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with DISEASE. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with DISEASE (HITT) and was treated with argatroban plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of argatroban was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on argatroban. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while argatroban was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on argatroban; ultimately, he was transitioned to CHEMICAL for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with argatroban and CDT with alteplase. | NO-RELATIONSHIP |
| Use of CHEMICAL and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (DISEASE) and was treated with CHEMICAL plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of CHEMICAL was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on CHEMICAL. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while CHEMICAL was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on CHEMICAL; ultimately, he was transitioned to warfarin for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to DISEASE was successfully treated with CHEMICAL and CDT with alteplase. | NO-RELATIONSHIP |
| Use of argatroban and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (HITT) and was treated with argatroban plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of argatroban was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on argatroban. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while argatroban was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on argatroban; ultimately, he was transitioned to CHEMICAL for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as DISEASE. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with argatroban and CDT with alteplase. | NO-RELATIONSHIP |
| Use of CHEMICAL and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (HITT) and was treated with CHEMICAL plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of CHEMICAL was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to DISEASE. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on CHEMICAL. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while CHEMICAL was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on CHEMICAL; ultimately, he was transitioned to warfarin for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and DISEASE secondary to HITT was successfully treated with CHEMICAL and CDT with alteplase. | NO-RELATIONSHIP |
| Use of CHEMICAL and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with DISEASE. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with DISEASE (HITT) and was treated with CHEMICAL plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of CHEMICAL was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on CHEMICAL. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while CHEMICAL was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on CHEMICAL; ultimately, he was transitioned to warfarin for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with CHEMICAL and CDT with alteplase. | NO-RELATIONSHIP |
| Use of CHEMICAL and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (HITT) and was treated with CHEMICAL plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of CHEMICAL was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on CHEMICAL. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while CHEMICAL was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on CHEMICAL; ultimately, he was transitioned to warfarin for long-term anticoagulation. Although the patient recovered, he experienced permanent DISEASE, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with CHEMICAL and CDT with alteplase. | CHEMICAL-INDUCED-DISEASE |
| Use of argatroban and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (HITT) and was treated with argatroban plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of argatroban was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to DISEASE. The DISEASE resolved the next day, and the patient was restarted on argatroban. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while argatroban was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on argatroban; ultimately, he was transitioned to CHEMICAL for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with argatroban and CDT with alteplase. | NO-RELATIONSHIP |
| Use of CHEMICAL and catheter-directed DISEASE with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (HITT) and was treated with CHEMICAL plus catheter-directed DISEASE (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of CHEMICAL was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on CHEMICAL. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while CHEMICAL was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on CHEMICAL; ultimately, he was transitioned to warfarin for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with CHEMICAL and CDT with alteplase. | NO-RELATIONSHIP |
| Use of argatroban and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (DISEASE) and was treated with argatroban plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of argatroban was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on argatroban. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while argatroban was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on argatroban; ultimately, he was transitioned to CHEMICAL for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to DISEASE was successfully treated with argatroban and CDT with alteplase. | NO-RELATIONSHIP |
| Use of CHEMICAL and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (HITT) and was treated with CHEMICAL plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal DISEASE undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of CHEMICAL was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on CHEMICAL. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while CHEMICAL was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on CHEMICAL; ultimately, he was transitioned to warfarin for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal DISEASE and SVC syndrome secondary to HITT was successfully treated with CHEMICAL and CDT with alteplase. | NO-RELATIONSHIP |
| Use of argatroban and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (HITT) and was treated with argatroban plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of argatroban was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to DISEASE. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on argatroban. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while argatroban was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on argatroban; ultimately, he was transitioned to CHEMICAL for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and DISEASE secondary to HITT was successfully treated with argatroban and CDT with alteplase. | NO-RELATIONSHIP |
| Use of argatroban and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (HITT) and was treated with argatroban plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of argatroban was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on argatroban. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while argatroban was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on argatroban; ultimately, he was transitioned to CHEMICAL for long-term anticoagulation. Although the patient recovered, he experienced permanent DISEASE, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with argatroban and CDT with alteplase. | NO-RELATIONSHIP |
| Use of argatroban and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (HITT) and was treated with argatroban plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral DISEASE (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of argatroban was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on argatroban. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while argatroban was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on argatroban; ultimately, he was transitioned to CHEMICAL for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with argatroban and CDT with alteplase. | NO-RELATIONSHIP |
| Use of CHEMICAL and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (HITT) and was treated with CHEMICAL plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of CHEMICAL was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on CHEMICAL. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while CHEMICAL was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on CHEMICAL; ultimately, he was transitioned to warfarin for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as DISEASE. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with CHEMICAL and CDT with alteplase. | CHEMICAL-INDUCED-DISEASE |
| Use of argatroban and catheter-directed DISEASE with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (HITT) and was treated with argatroban plus catheter-directed DISEASE (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of argatroban was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on argatroban. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while argatroban was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on argatroban; ultimately, he was transitioned to CHEMICAL for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with argatroban and CDT with alteplase. | NO-RELATIONSHIP |
| Use of argatroban and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (HITT) and was treated with argatroban plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal DISEASE undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of argatroban was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to epistaxis. The epistaxis resolved the next day, and the patient was restarted on argatroban. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while argatroban was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on argatroban; ultimately, he was transitioned to CHEMICAL for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal DISEASE and SVC syndrome secondary to HITT was successfully treated with argatroban and CDT with alteplase. | NO-RELATIONSHIP |
| Use of CHEMICAL and catheter-directed thrombolysis with alteplase in an oncology patient with heparin-induced thrombocytopenia with thrombosis. PURPOSE: The case of an oncology patient who developed heparin-induced thrombocytopenia with thrombosis (HITT) and was treated with CHEMICAL plus catheter-directed thrombolysis (CDT) with alteplase is presented. SUMMARY: A 63-year-old Caucasian man with renal amyloidosis undergoing peripheral blood stem cell collection for an autologous stem cell transplant developed extensive bilateral upper-extremity deep venous thrombosis (DVT) and pulmonary embolism secondary to heparin-induced thrombocytopenia. A continuous i.v. infusion of CHEMICAL was initiated, and the patient was managed on the general medical floor. After one week of therapy, he was transferred to the intensive care unit with cardiopulmonary compromise related to superior vena cava (SVC) syndrome. A percutaneous mechanical thrombectomy and CDT with alteplase were attempted, but the procedure was aborted due to DISEASE. The DISEASE resolved the next day, and the patient was restarted on CHEMICAL. A second percutaneous mechanical thrombectomy was performed six days later and resulted in partial revascularization of the SVC and central veins. Postthrombectomy continuous CDT with alteplase was commenced while CHEMICAL was withheld, and complete patency of the SVC and central veins was achieved after three days of therapy. Alteplase was discontinued, and the patient was reinitiated on CHEMICAL; ultimately, he was transitioned to warfarin for long-term anticoagulation. Although the patient recovered, he experienced permanent vision and hearing loss, as well as end-stage renal disease. CONCLUSION: A 63-year-old man with renal amyloidosis and SVC syndrome secondary to HITT was successfully treated with CHEMICAL and CDT with alteplase. | CHEMICAL-INDUCED-DISEASE |
| Effects of dehydroepiandrosterone in amphetamine-induced DISEASE models in mice. OBJECTIVE: To examine the effects of dehydroepiandrosterone (DHEA) on animal models of DISEASE. METHODS: Seventy Swiss albino female mice (25-35 g) were divided into 4 groups: amphetamine-free (control), amphetamine, 50, and 100 mg/kg DHEA. The DHEA was administered intraperitoneally (ip) for 5 days. Amphetamine (3 mg/kg ip) induced hyper locomotion, CHEMICAL (1.5 mg/kg subcutaneously [sc]) induced climbing, and haloperidol (1.5 mg/kg sc) induced catalepsy tests were used as animal models of DISEASE. The study was conducted at the Animal Experiment Laboratories, Department of Pharmacology, Medical School, Eskisehir Osmangazi University, Eskisehir, Turkey between March and May 2012. Statistical analysis was carried out using Kruskal-Wallis test for hyper locomotion, and one-way ANOVA for climbing and catalepsy tests. RESULTS: In the amphetamine-induced locomotion test, there were significant increases in all movements compared with the amphetamine-free group. Both DHEA 50 mg/kg (p<0.05), and 100 mg/kg (p<0.01) significantly decreased all movements compared with the amphetamine-induced locomotion group. There was a significant difference between groups in the haloperidol-induced catalepsy test (p<0.05). There was no significant difference between groups in terms of total climbing time in the CHEMICAL-induced climbing test (p>0.05). CONCLUSION: We observed that DHEA reduced locomotor activity and increased catalepsy at both doses, while it had no effect on climbing behavior. We suggest that DHEA displays typical neuroleptic-like effects, and may be used in the treatment of DISEASE. | NO-RELATIONSHIP |
| Effects of dehydroepiandrosterone in CHEMICAL-induced DISEASE models in mice. OBJECTIVE: To examine the effects of dehydroepiandrosterone (DHEA) on animal models of DISEASE. METHODS: Seventy Swiss albino female mice (25-35 g) were divided into 4 groups: CHEMICAL-free (control), CHEMICAL, 50, and 100 mg/kg DHEA. The DHEA was administered intraperitoneally (ip) for 5 days. CHEMICAL (3 mg/kg ip) induced hyper locomotion, apomorphine (1.5 mg/kg subcutaneously [sc]) induced climbing, and haloperidol (1.5 mg/kg sc) induced catalepsy tests were used as animal models of DISEASE. The study was conducted at the Animal Experiment Laboratories, Department of Pharmacology, Medical School, Eskisehir Osmangazi University, Eskisehir, Turkey between March and May 2012. Statistical analysis was carried out using Kruskal-Wallis test for hyper locomotion, and one-way ANOVA for climbing and catalepsy tests. RESULTS: In the CHEMICAL-induced locomotion test, there were significant increases in all movements compared with the CHEMICAL-free group. Both DHEA 50 mg/kg (p<0.05), and 100 mg/kg (p<0.01) significantly decreased all movements compared with the CHEMICAL-induced locomotion group. There was a significant difference between groups in the haloperidol-induced catalepsy test (p<0.05). There was no significant difference between groups in terms of total climbing time in the apomorphine-induced climbing test (p>0.05). CONCLUSION: We observed that DHEA reduced locomotor activity and increased catalepsy at both doses, while it had no effect on climbing behavior. We suggest that DHEA displays typical neuroleptic-like effects, and may be used in the treatment of DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Effects of dehydroepiandrosterone in amphetamine-induced schizophrenia models in mice. OBJECTIVE: To examine the effects of dehydroepiandrosterone (DHEA) on animal models of schizophrenia. METHODS: Seventy Swiss albino female mice (25-35 g) were divided into 4 groups: amphetamine-free (control), amphetamine, 50, and 100 mg/kg DHEA. The DHEA was administered intraperitoneally (ip) for 5 days. Amphetamine (3 mg/kg ip) induced hyper locomotion, apomorphine (1.5 mg/kg subcutaneously [sc]) induced climbing, and CHEMICAL (1.5 mg/kg sc) induced DISEASE tests were used as animal models of schizophrenia. The study was conducted at the Animal Experiment Laboratories, Department of Pharmacology, Medical School, Eskisehir Osmangazi University, Eskisehir, Turkey between March and May 2012. Statistical analysis was carried out using Kruskal-Wallis test for hyper locomotion, and one-way ANOVA for climbing and DISEASE tests. RESULTS: In the amphetamine-induced locomotion test, there were significant increases in all movements compared with the amphetamine-free group. Both DHEA 50 mg/kg (p<0.05), and 100 mg/kg (p<0.01) significantly decreased all movements compared with the amphetamine-induced locomotion group. There was a significant difference between groups in the CHEMICAL-induced DISEASE test (p<0.05). There was no significant difference between groups in terms of total climbing time in the apomorphine-induced climbing test (p>0.05). CONCLUSION: We observed that DHEA reduced locomotor activity and increased DISEASE at both doses, while it had no effect on climbing behavior. We suggest that DHEA displays typical neuroleptic-like effects, and may be used in the treatment of schizophrenia. | CHEMICAL-INDUCED-DISEASE |
| Effects of dehydroepiandrosterone in amphetamine-induced DISEASE models in mice. OBJECTIVE: To examine the effects of dehydroepiandrosterone (DHEA) on animal models of DISEASE. METHODS: Seventy Swiss albino female mice (25-35 g) were divided into 4 groups: amphetamine-free (control), amphetamine, 50, and 100 mg/kg DHEA. The DHEA was administered intraperitoneally (ip) for 5 days. Amphetamine (3 mg/kg ip) induced hyper locomotion, apomorphine (1.5 mg/kg subcutaneously [sc]) induced climbing, and CHEMICAL (1.5 mg/kg sc) induced catalepsy tests were used as animal models of DISEASE. The study was conducted at the Animal Experiment Laboratories, Department of Pharmacology, Medical School, Eskisehir Osmangazi University, Eskisehir, Turkey between March and May 2012. Statistical analysis was carried out using Kruskal-Wallis test for hyper locomotion, and one-way ANOVA for climbing and catalepsy tests. RESULTS: In the amphetamine-induced locomotion test, there were significant increases in all movements compared with the amphetamine-free group. Both DHEA 50 mg/kg (p<0.05), and 100 mg/kg (p<0.01) significantly decreased all movements compared with the amphetamine-induced locomotion group. There was a significant difference between groups in the CHEMICAL-induced catalepsy test (p<0.05). There was no significant difference between groups in terms of total climbing time in the apomorphine-induced climbing test (p>0.05). CONCLUSION: We observed that DHEA reduced locomotor activity and increased catalepsy at both doses, while it had no effect on climbing behavior. We suggest that DHEA displays typical neuroleptic-like effects, and may be used in the treatment of DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Effects of CHEMICAL in amphetamine-induced schizophrenia models in mice. OBJECTIVE: To examine the effects of CHEMICAL (CHEMICAL) on animal models of schizophrenia. METHODS: Seventy Swiss albino female mice (25-35 g) were divided into 4 groups: amphetamine-free (control), amphetamine, 50, and 100 mg/kg CHEMICAL. The CHEMICAL was administered intraperitoneally (ip) for 5 days. Amphetamine (3 mg/kg ip) induced DISEASE locomotion, apomorphine (1.5 mg/kg subcutaneously [sc]) induced climbing, and haloperidol (1.5 mg/kg sc) induced catalepsy tests were used as animal models of schizophrenia. The study was conducted at the Animal Experiment Laboratories, Department of Pharmacology, Medical School, Eskisehir Osmangazi University, Eskisehir, Turkey between March and May 2012. Statistical analysis was carried out using Kruskal-Wallis test for DISEASE locomotion, and one-way ANOVA for climbing and catalepsy tests. RESULTS: In the amphetamine-induced locomotion test, there were significant increases in all movements compared with the amphetamine-free group. Both CHEMICAL 50 mg/kg (p<0.05), and 100 mg/kg (p<0.01) significantly decreased all movements compared with the amphetamine-induced locomotion group. There was a significant difference between groups in the haloperidol-induced catalepsy test (p<0.05). There was no significant difference between groups in terms of total climbing time in the apomorphine-induced climbing test (p>0.05). CONCLUSION: We observed that CHEMICAL reduced locomotor activity and increased catalepsy at both doses, while it had no effect on climbing behavior. We suggest that CHEMICAL displays typical neuroleptic-like effects, and may be used in the treatment of schizophrenia. | NO-RELATIONSHIP |
| Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for DISEASE. Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict CHEMICAL(+) channel and Ca(2+) channel blocker effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers. hiPS-CMs were seeded onto MEA and FPD was measured for 2min every 10min for 30min after drug exposure for the vehicle and each drug concentration. IKr and IKs blockers concentration-dependently prolonged corrected FPD (FPDc), whereas Ca(2+) channel blockers concentration-dependently shortened FPDc. Also, the multichannel blockers Amiodarone, Paroxetine, Terfenadine and Citalopram prolonged FPDc in a concentration dependent manner. Finally, the IKr blockers, Terfenadine and Citalopram, which are reported to cause Torsade de Pointes (TdP) in clinical practice, produced early afterdepolarization (EAD). hiPS-CMs using MEA system and FPDc can predict the effects of drug candidates on QT interval. This study also shows that this assay can help detect EAD for drugs with TdP potential. | NO-RELATIONSHIP |
| Dermal developmental toxicity of N-phenylimide herbicides in rats. BACKGROUND: CHEMICAL and S-23121 are N-phenylimide herbicides and produced embryolethality, teratogenicity (mainly ventricular septal defects and wavy ribs), and DISEASE in rats in conventional oral developmental toxicity studies. Our objective in this study was to investigate whether the compounds induce developmental toxicity via the dermal route, which is more relevant to occupational exposure, hence better addressing human health risks. METHODS: CHEMICAL was administered dermally to rats at 30, 100, and 300 mg/kg during organogenesis, and S-23121 was administered at 200, 400, and 800 mg/kg (the maximum applicable dose level). Fetuses were obtained by a Cesarean section and examined for external, visceral, and skeletal alterations. RESULTS: Dermal exposure of rats to CHEMICAL at 300 mg/kg produced patterns of developmental toxicity similar to those resulting from oral exposure. Toxicity included embryolethality, teratogenicity, and DISEASE. Dermal administration of S-23121 at 800 mg/kg resulted in an increased incidence of embryonic death and ventricular septal defect, but retarded fetal growth was not observed as it was following oral exposure to S-23121. CONCLUSIONS: Based on the results, CHEMICAL and S-23121 were teratogenic when administered dermally to pregnant rats as were the compounds administered orally. Thus, investigation of the mechanism and its human relevancy become more important. | CHEMICAL-INDUCED-DISEASE |
| Dermal developmental toxicity of N-phenylimide herbicides in rats. BACKGROUND: S-53482 and CHEMICAL are N-phenylimide herbicides and produced embryolethality, teratogenicity (mainly ventricular septal defects and wavy ribs), and DISEASE in rats in conventional oral developmental toxicity studies. Our objective in this study was to investigate whether the compounds induce developmental toxicity via the dermal route, which is more relevant to occupational exposure, hence better addressing human health risks. METHODS: S-53482 was administered dermally to rats at 30, 100, and 300 mg/kg during organogenesis, and CHEMICAL was administered at 200, 400, and 800 mg/kg (the maximum applicable dose level). Fetuses were obtained by a Cesarean section and examined for external, visceral, and skeletal alterations. RESULTS: Dermal exposure of rats to S-53482 at 300 mg/kg produced patterns of developmental toxicity similar to those resulting from oral exposure. Toxicity included embryolethality, teratogenicity, and DISEASE. Dermal administration of CHEMICAL at 800 mg/kg resulted in an increased incidence of embryonic death and ventricular septal defect, but retarded fetal growth was not observed as it was following oral exposure to CHEMICAL. CONCLUSIONS: Based on the results, S-53482 and CHEMICAL were teratogenic when administered dermally to pregnant rats as were the compounds administered orally. Thus, investigation of the mechanism and its human relevancy become more important. | CHEMICAL-INDUCED-DISEASE |
| Dermal developmental toxicity of N-phenylimide herbicides in rats. BACKGROUND: S-53482 and CHEMICAL are N-phenylimide herbicides and produced embryolethality, DISEASE (mainly ventricular septal defects and wavy ribs), and growth retardation in rats in conventional oral developmental toxicity studies. Our objective in this study was to investigate whether the compounds induce developmental toxicity via the dermal route, which is more relevant to occupational exposure, hence better addressing human health risks. METHODS: S-53482 was administered dermally to rats at 30, 100, and 300 mg/kg during organogenesis, and CHEMICAL was administered at 200, 400, and 800 mg/kg (the maximum applicable dose level). Fetuses were obtained by a Cesarean section and examined for external, visceral, and skeletal alterations. RESULTS: Dermal exposure of rats to S-53482 at 300 mg/kg produced patterns of developmental toxicity similar to those resulting from oral exposure. Toxicity included embryolethality, DISEASE, and growth retardation. Dermal administration of CHEMICAL at 800 mg/kg resulted in an increased incidence of embryonic death and ventricular septal defect, but retarded fetal growth was not observed as it was following oral exposure to CHEMICAL. CONCLUSIONS: Based on the results, S-53482 and CHEMICAL were DISEASE when administered dermally to pregnant rats as were the compounds administered orally. Thus, investigation of the mechanism and its human relevancy become more important. | CHEMICAL-INDUCED-DISEASE |
| Dermal developmental toxicity of N-phenylimide herbicides in rats. BACKGROUND: S-53482 and CHEMICAL are N-phenylimide herbicides and produced DISEASE, teratogenicity (mainly ventricular septal defects and wavy ribs), and growth retardation in rats in conventional oral developmental toxicity studies. Our objective in this study was to investigate whether the compounds induce developmental toxicity via the dermal route, which is more relevant to occupational exposure, hence better addressing human health risks. METHODS: S-53482 was administered dermally to rats at 30, 100, and 300 mg/kg during organogenesis, and CHEMICAL was administered at 200, 400, and 800 mg/kg (the maximum applicable dose level). Fetuses were obtained by a Cesarean section and examined for external, visceral, and skeletal alterations. RESULTS: Dermal exposure of rats to S-53482 at 300 mg/kg produced patterns of developmental toxicity similar to those resulting from oral exposure. Toxicity included DISEASE, teratogenicity, and growth retardation. Dermal administration of CHEMICAL at 800 mg/kg resulted in an increased incidence of DISEASE and ventricular septal defect, but retarded fetal growth was not observed as it was following oral exposure to CHEMICAL. CONCLUSIONS: Based on the results, S-53482 and CHEMICAL were teratogenic when administered dermally to pregnant rats as were the compounds administered orally. Thus, investigation of the mechanism and its human relevancy become more important. | CHEMICAL-INDUCED-DISEASE |
| Dermal developmental toxicity of N-phenylimide herbicides in rats. BACKGROUND: CHEMICAL and S-23121 are N-phenylimide herbicides and produced DISEASE, teratogenicity (mainly ventricular septal defects and wavy ribs), and growth retardation in rats in conventional oral developmental toxicity studies. Our objective in this study was to investigate whether the compounds induce developmental toxicity via the dermal route, which is more relevant to occupational exposure, hence better addressing human health risks. METHODS: CHEMICAL was administered dermally to rats at 30, 100, and 300 mg/kg during organogenesis, and S-23121 was administered at 200, 400, and 800 mg/kg (the maximum applicable dose level). Fetuses were obtained by a Cesarean section and examined for external, visceral, and skeletal alterations. RESULTS: Dermal exposure of rats to CHEMICAL at 300 mg/kg produced patterns of developmental toxicity similar to those resulting from oral exposure. Toxicity included DISEASE, teratogenicity, and growth retardation. Dermal administration of S-23121 at 800 mg/kg resulted in an increased incidence of DISEASE and ventricular septal defect, but retarded fetal growth was not observed as it was following oral exposure to S-23121. CONCLUSIONS: Based on the results, CHEMICAL and S-23121 were teratogenic when administered dermally to pregnant rats as were the compounds administered orally. Thus, investigation of the mechanism and its human relevancy become more important. | CHEMICAL-INDUCED-DISEASE |
| Dermal developmental toxicity of N-phenylimide herbicides in rats. BACKGROUND: CHEMICAL and S-23121 are N-phenylimide herbicides and produced embryolethality, DISEASE (mainly ventricular septal defects and wavy ribs), and growth retardation in rats in conventional oral developmental toxicity studies. Our objective in this study was to investigate whether the compounds induce developmental toxicity via the dermal route, which is more relevant to occupational exposure, hence better addressing human health risks. METHODS: CHEMICAL was administered dermally to rats at 30, 100, and 300 mg/kg during organogenesis, and S-23121 was administered at 200, 400, and 800 mg/kg (the maximum applicable dose level). Fetuses were obtained by a Cesarean section and examined for external, visceral, and skeletal alterations. RESULTS: Dermal exposure of rats to CHEMICAL at 300 mg/kg produced patterns of developmental toxicity similar to those resulting from oral exposure. Toxicity included embryolethality, DISEASE, and growth retardation. Dermal administration of S-23121 at 800 mg/kg resulted in an increased incidence of embryonic death and ventricular septal defect, but retarded fetal growth was not observed as it was following oral exposure to S-23121. CONCLUSIONS: Based on the results, CHEMICAL and S-23121 were DISEASE when administered dermally to pregnant rats as were the compounds administered orally. Thus, investigation of the mechanism and its human relevancy become more important. | CHEMICAL-INDUCED-DISEASE |
| Dermal developmental toxicity of N-phenylimide herbicides in rats. BACKGROUND: S-53482 and CHEMICAL are N-phenylimide herbicides and produced embryolethality, teratogenicity (mainly DISEASE and wavy ribs), and growth retardation in rats in conventional oral developmental toxicity studies. Our objective in this study was to investigate whether the compounds induce developmental toxicity via the dermal route, which is more relevant to occupational exposure, hence better addressing human health risks. METHODS: S-53482 was administered dermally to rats at 30, 100, and 300 mg/kg during organogenesis, and CHEMICAL was administered at 200, 400, and 800 mg/kg (the maximum applicable dose level). Fetuses were obtained by a Cesarean section and examined for external, visceral, and skeletal alterations. RESULTS: Dermal exposure of rats to S-53482 at 300 mg/kg produced patterns of developmental toxicity similar to those resulting from oral exposure. Toxicity included embryolethality, teratogenicity, and growth retardation. Dermal administration of CHEMICAL at 800 mg/kg resulted in an increased incidence of embryonic death and DISEASE, but retarded fetal growth was not observed as it was following oral exposure to CHEMICAL. CONCLUSIONS: Based on the results, S-53482 and CHEMICAL were teratogenic when administered dermally to pregnant rats as were the compounds administered orally. Thus, investigation of the mechanism and its human relevancy become more important. | CHEMICAL-INDUCED-DISEASE |
| Dermal developmental toxicity of N-phenylimide herbicides in rats. BACKGROUND: CHEMICAL and S-23121 are N-phenylimide herbicides and produced embryolethality, teratogenicity (mainly DISEASE and wavy ribs), and growth retardation in rats in conventional oral developmental toxicity studies. Our objective in this study was to investigate whether the compounds induce developmental toxicity via the dermal route, which is more relevant to occupational exposure, hence better addressing human health risks. METHODS: CHEMICAL was administered dermally to rats at 30, 100, and 300 mg/kg during organogenesis, and S-23121 was administered at 200, 400, and 800 mg/kg (the maximum applicable dose level). Fetuses were obtained by a Cesarean section and examined for external, visceral, and skeletal alterations. RESULTS: Dermal exposure of rats to CHEMICAL at 300 mg/kg produced patterns of developmental toxicity similar to those resulting from oral exposure. Toxicity included embryolethality, teratogenicity, and growth retardation. Dermal administration of S-23121 at 800 mg/kg resulted in an increased incidence of embryonic death and DISEASE, but retarded fetal growth was not observed as it was following oral exposure to S-23121. CONCLUSIONS: Based on the results, CHEMICAL and S-23121 were teratogenic when administered dermally to pregnant rats as were the compounds administered orally. Thus, investigation of the mechanism and its human relevancy become more important. | CHEMICAL-INDUCED-DISEASE |
| Rates of Renal Toxicity in Cancer Patients Receiving CHEMICAL With and Without Mannitol. BACKGROUND: CHEMICAL is a widely used antineoplastic. One of the major complications of CHEMICAL use is dose-limiting nephrotoxicity. There are many strategies to prevent this toxicity, including the use of mannitol as a nephroprotectant in combination with hydration. OBJECTIVE: We aimed to evaluate the rates of CHEMICAL-induced nephrotoxicity in cancer patients receiving single-agent CHEMICAL with and without mannitol. METHODS: This single-center retrospective analysis was a quasi experiment created by the national mannitol shortage. Data were collected on adult cancer patients receiving single-agent CHEMICAL as an outpatient from January 2011 to September 2012. The primary outcome was DISEASE (DISEASE). RESULTS: We evaluated 143 patients who received single-agent CHEMICAL; 97.2% of patients had head and neck cancer as their primary malignancy. Patients who did not receive mannitol were more likely to develop nephrotoxicity: odds ratio [OR] = 2.646 (95% CI = 1.008, 6.944; P = 0.048). Patients who received the 100 mg/m(2) dosing and patients who had a history of hypertension also had a higher likelihood of developing nephrotoxicity: OR = 11.494 (95% CI = 4.149, 32.258; P < 0.0001) and OR = 3.219 (95% CI = 1.228, 8.439; P = 0.017), respectively. CONCLUSIONS: When limited quantities of mannitol are available, it should preferentially be given to patients at particularly high risk of nephrotoxicity. Our analysis suggests that those patients receiving the dosing schedule of 100 mg/m(2) CHEMICAL every 3 weeks and those with hypertension are at the greatest risk of nephrotoxicity and would benefit from the addition of mannitol. | CHEMICAL-INDUCED-DISEASE |
| Rates of Renal Toxicity in Cancer Patients Receiving Cisplatin With and Without CHEMICAL. BACKGROUND: Cisplatin is a widely used antineoplastic. One of the major complications of cisplatin use is dose-limiting nephrotoxicity. There are many strategies to prevent this DISEASE, including the use of CHEMICAL as a nephroprotectant in combination with hydration. OBJECTIVE: We aimed to evaluate the rates of cisplatin-induced nephrotoxicity in cancer patients receiving single-agent cisplatin with and without CHEMICAL. METHODS: This single-center retrospective analysis was a quasi experiment created by the national CHEMICAL shortage. Data were collected on adult cancer patients receiving single-agent cisplatin as an outpatient from January 2011 to September 2012. The primary outcome was acute kidney injury (AKI). RESULTS: We evaluated 143 patients who received single-agent cisplatin; 97.2% of patients had head and neck cancer as their primary malignancy. Patients who did not receive CHEMICAL were more likely to develop nephrotoxicity: odds ratio [OR] = 2.646 (95% CI = 1.008, 6.944; P = 0.048). Patients who received the 100 mg/m(2) dosing and patients who had a history of hypertension also had a higher likelihood of developing nephrotoxicity: OR = 11.494 (95% CI = 4.149, 32.258; P < 0.0001) and OR = 3.219 (95% CI = 1.228, 8.439; P = 0.017), respectively. CONCLUSIONS: When limited quantities of CHEMICAL are available, it should preferentially be given to patients at particularly high risk of nephrotoxicity. Our analysis suggests that those patients receiving the dosing schedule of 100 mg/m(2) cisplatin every 3 weeks and those with hypertension are at the greatest risk of nephrotoxicity and would benefit from the addition of CHEMICAL. | NO-RELATIONSHIP |
| Rates of Renal Toxicity in DISEASE Patients Receiving Cisplatin With and Without CHEMICAL. BACKGROUND: Cisplatin is a widely used antineoplastic. One of the major complications of cisplatin use is dose-limiting nephrotoxicity. There are many strategies to prevent this toxicity, including the use of CHEMICAL as a nephroprotectant in combination with hydration. OBJECTIVE: We aimed to evaluate the rates of cisplatin-induced nephrotoxicity in DISEASE patients receiving single-agent cisplatin with and without CHEMICAL. METHODS: This single-center retrospective analysis was a quasi experiment created by the national CHEMICAL shortage. Data were collected on adult DISEASE patients receiving single-agent cisplatin as an outpatient from January 2011 to September 2012. The primary outcome was acute kidney injury (AKI). RESULTS: We evaluated 143 patients who received single-agent cisplatin; 97.2% of patients had head and neck cancer as their primary DISEASE. Patients who did not receive CHEMICAL were more likely to develop nephrotoxicity: odds ratio [OR] = 2.646 (95% CI = 1.008, 6.944; P = 0.048). Patients who received the 100 mg/m(2) dosing and patients who had a history of hypertension also had a higher likelihood of developing nephrotoxicity: OR = 11.494 (95% CI = 4.149, 32.258; P < 0.0001) and OR = 3.219 (95% CI = 1.228, 8.439; P = 0.017), respectively. CONCLUSIONS: When limited quantities of CHEMICAL are available, it should preferentially be given to patients at particularly high risk of nephrotoxicity. Our analysis suggests that those patients receiving the dosing schedule of 100 mg/m(2) cisplatin every 3 weeks and those with hypertension are at the greatest risk of nephrotoxicity and would benefit from the addition of CHEMICAL. | NO-RELATIONSHIP |
| Rates of Renal Toxicity in Cancer Patients Receiving Cisplatin With and Without CHEMICAL. BACKGROUND: Cisplatin is a widely used antineoplastic. One of the major complications of cisplatin use is dose-limiting nephrotoxicity. There are many strategies to prevent this toxicity, including the use of CHEMICAL as a nephroprotectant in combination with hydration. OBJECTIVE: We aimed to evaluate the rates of cisplatin-induced nephrotoxicity in cancer patients receiving single-agent cisplatin with and without CHEMICAL. METHODS: This single-center retrospective analysis was a quasi experiment created by the national CHEMICAL shortage. Data were collected on adult cancer patients receiving single-agent cisplatin as an outpatient from January 2011 to September 2012. The primary outcome was acute kidney injury (AKI). RESULTS: We evaluated 143 patients who received single-agent cisplatin; 97.2% of patients had DISEASE as their primary malignancy. Patients who did not receive CHEMICAL were more likely to develop nephrotoxicity: odds ratio [OR] = 2.646 (95% CI = 1.008, 6.944; P = 0.048). Patients who received the 100 mg/m(2) dosing and patients who had a history of hypertension also had a higher likelihood of developing nephrotoxicity: OR = 11.494 (95% CI = 4.149, 32.258; P < 0.0001) and OR = 3.219 (95% CI = 1.228, 8.439; P = 0.017), respectively. CONCLUSIONS: When limited quantities of CHEMICAL are available, it should preferentially be given to patients at particularly high risk of nephrotoxicity. Our analysis suggests that those patients receiving the dosing schedule of 100 mg/m(2) cisplatin every 3 weeks and those with hypertension are at the greatest risk of nephrotoxicity and would benefit from the addition of CHEMICAL. | NO-RELATIONSHIP |
| Rates of DISEASE in Cancer Patients Receiving Cisplatin With and Without CHEMICAL. BACKGROUND: Cisplatin is a widely used antineoplastic. One of the major complications of cisplatin use is dose-limiting DISEASE. There are many strategies to prevent this toxicity, including the use of CHEMICAL as a nephroprotectant in combination with hydration. OBJECTIVE: We aimed to evaluate the rates of cisplatin-induced DISEASE in cancer patients receiving single-agent cisplatin with and without CHEMICAL. METHODS: This single-center retrospective analysis was a quasi experiment created by the national CHEMICAL shortage. Data were collected on adult cancer patients receiving single-agent cisplatin as an outpatient from January 2011 to September 2012. The primary outcome was acute kidney injury (AKI). RESULTS: We evaluated 143 patients who received single-agent cisplatin; 97.2% of patients had head and neck cancer as their primary malignancy. Patients who did not receive CHEMICAL were more likely to develop DISEASE: odds ratio [OR] = 2.646 (95% CI = 1.008, 6.944; P = 0.048). Patients who received the 100 mg/m(2) dosing and patients who had a history of hypertension also had a higher likelihood of developing DISEASE: OR = 11.494 (95% CI = 4.149, 32.258; P < 0.0001) and OR = 3.219 (95% CI = 1.228, 8.439; P = 0.017), respectively. CONCLUSIONS: When limited quantities of CHEMICAL are available, it should preferentially be given to patients at particularly high risk of DISEASE. Our analysis suggests that those patients receiving the dosing schedule of 100 mg/m(2) cisplatin every 3 weeks and those with hypertension are at the greatest risk of DISEASE and would benefit from the addition of CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Rates of Renal Toxicity in Cancer Patients Receiving Cisplatin With and Without CHEMICAL. BACKGROUND: Cisplatin is a widely used antineoplastic. One of the major complications of cisplatin use is dose-limiting nephrotoxicity. There are many strategies to prevent this toxicity, including the use of CHEMICAL as a nephroprotectant in combination with hydration. OBJECTIVE: We aimed to evaluate the rates of cisplatin-induced nephrotoxicity in cancer patients receiving single-agent cisplatin with and without CHEMICAL. METHODS: This single-center retrospective analysis was a quasi experiment created by the national CHEMICAL shortage. Data were collected on adult cancer patients receiving single-agent cisplatin as an outpatient from January 2011 to September 2012. The primary outcome was acute kidney injury (AKI). RESULTS: We evaluated 143 patients who received single-agent cisplatin; 97.2% of patients had head and neck cancer as their primary malignancy. Patients who did not receive CHEMICAL were more likely to develop nephrotoxicity: odds ratio [OR] = 2.646 (95% CI = 1.008, 6.944; P = 0.048). Patients who received the 100 mg/m(2) dosing and patients who had a history of DISEASE also had a higher likelihood of developing nephrotoxicity: OR = 11.494 (95% CI = 4.149, 32.258; P < 0.0001) and OR = 3.219 (95% CI = 1.228, 8.439; P = 0.017), respectively. CONCLUSIONS: When limited quantities of CHEMICAL are available, it should preferentially be given to patients at particularly high risk of nephrotoxicity. Our analysis suggests that those patients receiving the dosing schedule of 100 mg/m(2) cisplatin every 3 weeks and those with DISEASE are at the greatest risk of nephrotoxicity and would benefit from the addition of CHEMICAL. | NO-RELATIONSHIP |
| Metformin protects against seizures, learning and memory impairments and oxidative damage induced by CHEMICAL-induced kindling in mice. DISEASE, the most common and severe comorbidity of epilepsy, greatly diminishes the quality of life. However, current therapeutic interventions for epilepsy can also cause untoward cognitive effects. Thus, there is an urgent need for new kinds of agents targeting both seizures and DISEASE. Oxidative stress is considered to play an important role in epileptogenesis and DISEASE, and antioxidants have a putative antiepileptic potential. Metformin, the most commonly prescribed antidiabetic oral drug, has antioxidant properties. This study was designed to evaluate the ameliorative effects of metformin on seizures, DISEASE and brain oxidative stress markers observed in CHEMICAL-induced kindling animals. Male C57BL/6 mice were administered with subconvulsive dose of CHEMICAL (37 mg/kg, i.p.) every other day for 14 injections. Metformin was injected intraperitoneally in dose of 200mg/kg along with alternate-day CHEMICAL. We found that metformin suppressed the progression of kindling, ameliorated the DISEASE and decreased brain oxidative stress. Thus the present study concluded that metformin may be a potential agent for the treatment of epilepsy as well as a protective medicine against DISEASE induced by seizures. | CHEMICAL-INDUCED-DISEASE |
| Metformin protects against DISEASE, learning and memory impairments and oxidative damage induced by CHEMICAL-induced kindling in mice. Cognitive impairment, the most common and severe comorbidity of epilepsy, greatly diminishes the quality of life. However, current therapeutic interventions for epilepsy can also cause untoward cognitive effects. Thus, there is an urgent need for new kinds of agents targeting both DISEASE and cognition deficits. Oxidative stress is considered to play an important role in epileptogenesis and cognitive deficits, and antioxidants have a putative antiepileptic potential. Metformin, the most commonly prescribed antidiabetic oral drug, has antioxidant properties. This study was designed to evaluate the ameliorative effects of metformin on DISEASE, cognitive impairment and brain oxidative stress markers observed in CHEMICAL-induced kindling animals. Male C57BL/6 mice were administered with subconvulsive dose of CHEMICAL (37 mg/kg, i.p.) every other day for 14 injections. Metformin was injected intraperitoneally in dose of 200mg/kg along with alternate-day CHEMICAL. We found that metformin suppressed the progression of kindling, ameliorated the cognitive impairment and decreased brain oxidative stress. Thus the present study concluded that metformin may be a potential agent for the treatment of epilepsy as well as a protective medicine against cognitive impairment induced by DISEASE. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL protects against seizures, learning and memory impairments and oxidative damage induced by pentylenetetrazole-induced kindling in mice. Cognitive impairment, the most common and severe comorbidity of DISEASE, greatly diminishes the quality of life. However, current therapeutic interventions for DISEASE can also cause untoward cognitive effects. Thus, there is an urgent need for new kinds of agents targeting both seizures and cognition deficits. Oxidative stress is considered to play an important role in epileptogenesis and cognitive deficits, and antioxidants have a putative antiepileptic potential. CHEMICAL, the most commonly prescribed antidiabetic oral drug, has antioxidant properties. This study was designed to evaluate the ameliorative effects of CHEMICAL on seizures, cognitive impairment and brain oxidative stress markers observed in pentylenetetrazole-induced kindling animals. Male C57BL/6 mice were administered with subconvulsive dose of pentylenetetrazole (37 mg/kg, i.p.) every other day for 14 injections. CHEMICAL was injected intraperitoneally in dose of 200mg/kg along with alternate-day PTZ. We found that CHEMICAL suppressed the progression of kindling, ameliorated the cognitive impairment and decreased brain oxidative stress. Thus the present study concluded that CHEMICAL may be a potential agent for the treatment of DISEASE as well as a protective medicine against cognitive impairment induced by seizures. | NO-RELATIONSHIP |
| CHEMICAL protects against seizures, DISEASE and oxidative damage induced by pentylenetetrazole-induced kindling in mice. Cognitive impairment, the most common and severe comorbidity of epilepsy, greatly diminishes the quality of life. However, current therapeutic interventions for epilepsy can also cause untoward cognitive effects. Thus, there is an urgent need for new kinds of agents targeting both seizures and cognition deficits. Oxidative stress is considered to play an important role in epileptogenesis and cognitive deficits, and antioxidants have a putative antiepileptic potential. CHEMICAL, the most commonly prescribed antidiabetic oral drug, has antioxidant properties. This study was designed to evaluate the ameliorative effects of CHEMICAL on seizures, cognitive impairment and brain oxidative stress markers observed in pentylenetetrazole-induced kindling animals. Male C57BL/6 mice were administered with subconvulsive dose of pentylenetetrazole (37 mg/kg, i.p.) every other day for 14 injections. CHEMICAL was injected intraperitoneally in dose of 200mg/kg along with alternate-day PTZ. We found that CHEMICAL suppressed the progression of kindling, ameliorated the cognitive impairment and decreased brain oxidative stress. Thus the present study concluded that CHEMICAL may be a potential agent for the treatment of epilepsy as well as a protective medicine against cognitive impairment induced by seizures. | NO-RELATIONSHIP |
| P53 inhibition exacerbates late-stage anthracycline cardiotoxicity. AIMS: CHEMICAL (CHEMICAL) is an effective anti-cancer therapeutic, but is associated with both acute and late-stage cardiotoxicity. Children are particularly sensitive to CHEMICAL-induced DISEASE. Here, the impact of p53 inhibition on acute vs. late-stage CHEMICAL cardiotoxicity was examined in a juvenile model. METHODS AND RESULTS: Two-week-old MHC-CB7 mice (which express dominant-interfering p53 in cardiomyocytes) and their non-transgenic (NON-TXG) littermates received weekly CHEMICAL injections for 5 weeks (25 mg/kg cumulative dose). One week after the last CHEMICAL treatment (acute stage), MHC-CB7 mice exhibited improved cardiac function and lower levels of cardiomyocyte apoptosis when compared with the NON-TXG mice. Surprisingly, by 13 weeks following the last CHEMICAL treatment (late stage), MHC-CB7 exhibited a progressive decrease in cardiac function and higher rates of cardiomyocyte apoptosis when compared with NON-TXG mice. p53 inhibition blocked transient CHEMICAL-induced STAT3 activation in MHC-CB7 mice, which was associated with enhanced induction of the DNA repair proteins Ku70 and Ku80. Mice with cardiomyocyte-restricted deletion of STAT3 exhibited worse cardiac function, higher levels of cardiomyocyte apoptosis, and a greater induction of Ku70 and Ku80 in response to CHEMICAL treatment during the acute stage when compared with control animals. CONCLUSION: These data support a model wherein a p53-dependent cardioprotective pathway, mediated via STAT3 activation, mitigates CHEMICAL-induced myocardial stress during drug delivery. Furthermore, these data suggest an explanation as to how p53 inhibition can result in cardioprotection during drug treatment and, paradoxically, enhanced cardiotoxicity long after the cessation of drug treatment. | CHEMICAL-INDUCED-DISEASE |
| P53 inhibition exacerbates late-stage CHEMICAL cardiotoxicity. AIMS: Doxorubicin (DOX) is an effective anti-DISEASE therapeutic, but is associated with both acute and late-stage cardiotoxicity. Children are particularly sensitive to DOX-induced heart failure. Here, the impact of p53 inhibition on acute vs. late-stage DOX cardiotoxicity was examined in a juvenile model. METHODS AND RESULTS: Two-week-old MHC-CB7 mice (which express dominant-interfering p53 in cardiomyocytes) and their non-transgenic (NON-TXG) littermates received weekly DOX injections for 5 weeks (25 mg/kg cumulative dose). One week after the last DOX treatment (acute stage), MHC-CB7 mice exhibited improved cardiac function and lower levels of cardiomyocyte apoptosis when compared with the NON-TXG mice. Surprisingly, by 13 weeks following the last DOX treatment (late stage), MHC-CB7 exhibited a progressive decrease in cardiac function and higher rates of cardiomyocyte apoptosis when compared with NON-TXG mice. p53 inhibition blocked transient DOX-induced STAT3 activation in MHC-CB7 mice, which was associated with enhanced induction of the DNA repair proteins Ku70 and Ku80. Mice with cardiomyocyte-restricted deletion of STAT3 exhibited worse cardiac function, higher levels of cardiomyocyte apoptosis, and a greater induction of Ku70 and Ku80 in response to DOX treatment during the acute stage when compared with control animals. CONCLUSION: These data support a model wherein a p53-dependent cardioprotective pathway, mediated via STAT3 activation, mitigates DOX-induced myocardial stress during drug delivery. Furthermore, these data suggest an explanation as to how p53 inhibition can result in cardioprotection during drug treatment and, paradoxically, enhanced cardiotoxicity long after the cessation of drug treatment. | NO-RELATIONSHIP |
| P53 inhibition exacerbates late-stage CHEMICAL DISEASE. AIMS: Doxorubicin (DOX) is an effective anti-cancer therapeutic, but is associated with both acute and late-stage DISEASE. Children are particularly sensitive to DOX-induced heart failure. Here, the impact of p53 inhibition on acute vs. late-stage DOX DISEASE was examined in a juvenile model. METHODS AND RESULTS: Two-week-old MHC-CB7 mice (which express dominant-interfering p53 in cardiomyocytes) and their non-transgenic (NON-TXG) littermates received weekly DOX injections for 5 weeks (25 mg/kg cumulative dose). One week after the last DOX treatment (acute stage), MHC-CB7 mice exhibited improved cardiac function and lower levels of cardiomyocyte apoptosis when compared with the NON-TXG mice. Surprisingly, by 13 weeks following the last DOX treatment (late stage), MHC-CB7 exhibited a progressive decrease in cardiac function and higher rates of cardiomyocyte apoptosis when compared with NON-TXG mice. p53 inhibition blocked transient DOX-induced STAT3 activation in MHC-CB7 mice, which was associated with enhanced induction of the DNA repair proteins Ku70 and Ku80. Mice with cardiomyocyte-restricted deletion of STAT3 exhibited worse cardiac function, higher levels of cardiomyocyte apoptosis, and a greater induction of Ku70 and Ku80 in response to DOX treatment during the acute stage when compared with control animals. CONCLUSION: These data support a model wherein a p53-dependent cardioprotective pathway, mediated via STAT3 activation, mitigates DOX-induced myocardial stress during drug delivery. Furthermore, these data suggest an explanation as to how p53 inhibition can result in cardioprotection during drug treatment and, paradoxically, enhanced DISEASE long after the cessation of drug treatment. | NO-RELATIONSHIP |
| CHEMICAL-induced DISEASE: an uncommon scenario. CHEMICAL can produce neurological complications although it is not a common scenario. We present a case where a patient developed features of DISEASE following prolonged CHEMICAL intake. Magnetic resonance imaging (MRI) brain showed abnormal signal intensity involving both dentate nuclei of cerebellum and splenium of corpus callosum. The diagnosis of CHEMICAL toxicity was made by the MRI findings and supported clinically. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced Ca2+ overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats. CHEMICAL is a major bioactive diterpenoid alkaloid with high content derived from herbal aconitum plants. Emerging evidence indicates that voltage-dependent Na(+) channels have pivotal roles in the cardiotoxicity of CHEMICAL. However, no reports are available on the role of Ca(2+) in CHEMICAL DISEASE. In this study, we explored the importance of pathological Ca(2+) signaling in CHEMICAL DISEASE in vitro and in vivo. We found that Ca(2+) overload lead to accelerated beating rhythm in adult rat ventricular myocytes and caused arrhythmia in conscious freely moving rats. To investigate effects of CHEMICAL on myocardial injury, we performed cytotoxicity assay in neonatal rat ventricular myocytes (NRVMs), as well as measured lactate dehydrogenase level in the culture medium of NRVMs and activities of serum cardiac enzymes in rats. The results showed that CHEMICAL resulted in myocardial injury and reduced NRVMs viability dose-dependently. To confirm the pro-apoptotic effects, we performed flow cytometric detection, cardiac histology, transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. The results showed that CHEMICAL stimulated apoptosis time-dependently. The expression analysis of Ca(2+) handling proteins demonstrated that CHEMICAL promoted Ca(2+) overload through the expression regulation of Ca(2+) handling proteins. The expression analysis of apoptosis-related proteins revealed that pro-apoptotic protein expression was upregulated, and anti-apoptotic protein BCL-2 expression was downregulated. Furthermore, increased phosphorylation of MAPK family members, especially the P-P38/P38 ratio was found in cardiac tissues. Hence, our results suggest that CHEMICAL significantly aggravates Ca(2+) overload and causes arrhythmia and finally promotes apoptotic development via phosphorylation of P38 mitogen-activated protein kinase. | NO-RELATIONSHIP |
| CHEMICAL-induced Ca2+ overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats. CHEMICAL is a major bioactive diterpenoid alkaloid with high content derived from herbal aconitum plants. Emerging evidence indicates that voltage-dependent Na(+) channels have pivotal roles in the DISEASE of CHEMICAL. However, no reports are available on the role of Ca(2+) in CHEMICAL poisoning. In this study, we explored the importance of pathological Ca(2+) signaling in CHEMICAL poisoning in vitro and in vivo. We found that Ca(2+) overload lead to accelerated beating rhythm in adult rat ventricular myocytes and caused arrhythmia in conscious freely moving rats. To investigate effects of CHEMICAL on myocardial injury, we performed cytotoxicity assay in neonatal rat ventricular myocytes (NRVMs), as well as measured lactate dehydrogenase level in the culture medium of NRVMs and activities of serum cardiac enzymes in rats. The results showed that CHEMICAL resulted in myocardial injury and reduced NRVMs viability dose-dependently. To confirm the pro-apoptotic effects, we performed flow cytometric detection, cardiac histology, transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. The results showed that CHEMICAL stimulated apoptosis time-dependently. The expression analysis of Ca(2+) handling proteins demonstrated that CHEMICAL promoted Ca(2+) overload through the expression regulation of Ca(2+) handling proteins. The expression analysis of apoptosis-related proteins revealed that pro-apoptotic protein expression was upregulated, and anti-apoptotic protein BCL-2 expression was downregulated. Furthermore, increased phosphorylation of MAPK family members, especially the P-P38/P38 ratio was found in cardiac tissues. Hence, our results suggest that CHEMICAL significantly aggravates Ca(2+) overload and causes arrhythmia and finally promotes apoptotic development via phosphorylation of P38 mitogen-activated protein kinase. | NO-RELATIONSHIP |
| CHEMICAL-induced Ca2+ overload causes DISEASE and triggers apoptosis through p38 MAPK signaling pathway in rats. CHEMICAL is a major bioactive diterpenoid alkaloid with high content derived from herbal aconitum plants. Emerging evidence indicates that voltage-dependent Na(+) channels have pivotal roles in the cardiotoxicity of CHEMICAL. However, no reports are available on the role of Ca(2+) in CHEMICAL poisoning. In this study, we explored the importance of pathological Ca(2+) signaling in CHEMICAL poisoning in vitro and in vivo. We found that Ca(2+) overload lead to accelerated beating rhythm in adult rat ventricular myocytes and caused DISEASE in conscious freely moving rats. To investigate effects of CHEMICAL on myocardial injury, we performed cytotoxicity assay in neonatal rat ventricular myocytes (NRVMs), as well as measured lactate dehydrogenase level in the culture medium of NRVMs and activities of serum cardiac enzymes in rats. The results showed that CHEMICAL resulted in myocardial injury and reduced NRVMs viability dose-dependently. To confirm the pro-apoptotic effects, we performed flow cytometric detection, cardiac histology, transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. The results showed that CHEMICAL stimulated apoptosis time-dependently. The expression analysis of Ca(2+) handling proteins demonstrated that CHEMICAL promoted Ca(2+) overload through the expression regulation of Ca(2+) handling proteins. The expression analysis of apoptosis-related proteins revealed that pro-apoptotic protein expression was upregulated, and anti-apoptotic protein BCL-2 expression was downregulated. Furthermore, increased phosphorylation of MAPK family members, especially the P-P38/P38 ratio was found in cardiac tissues. Hence, our results suggest that CHEMICAL significantly aggravates Ca(2+) overload and causes DISEASE and finally promotes apoptotic development via phosphorylation of P38 mitogen-activated protein kinase. | CHEMICAL-INDUCED-DISEASE |
| Aconitine-induced CHEMICAL2+ overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats. Aconitine is a major bioactive diterpenoid alkaloid with high content derived from herbal aconitum plants. Emerging evidence indicates that voltage-dependent Na(+) channels have pivotal roles in the cardiotoxicity of aconitine. However, no reports are available on the role of CHEMICAL(2+) in aconitine poisoning. In this study, we explored the importance of pathological CHEMICAL(2+) signaling in aconitine poisoning in vitro and in vivo. We found that CHEMICAL(2+) overload lead to accelerated beating rhythm in adult rat ventricular myocytes and caused arrhythmia in conscious freely moving rats. To investigate effects of aconitine on DISEASE, we performed cytotoxicity assay in neonatal rat ventricular myocytes (NRVMs), as well as measured lactate dehydrogenase level in the culture medium of NRVMs and activities of serum cardiac enzymes in rats. The results showed that aconitine resulted in DISEASE and reduced NRVMs viability dose-dependently. To confirm the pro-apoptotic effects, we performed flow cytometric detection, cardiac histology, transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. The results showed that aconitine stimulated apoptosis time-dependently. The expression analysis of CHEMICAL(2+) handling proteins demonstrated that aconitine promoted CHEMICAL(2+) overload through the expression regulation of CHEMICAL(2+) handling proteins. The expression analysis of apoptosis-related proteins revealed that pro-apoptotic protein expression was upregulated, and anti-apoptotic protein BCL-2 expression was downregulated. Furthermore, increased phosphorylation of MAPK family members, especially the P-P38/P38 ratio was found in cardiac tissues. Hence, our results suggest that aconitine significantly aggravates CHEMICAL(2+) overload and causes arrhythmia and finally promotes apoptotic development via phosphorylation of P38 mitogen-activated protein kinase. | NO-RELATIONSHIP |
| Aconitine-induced Ca2+ overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats. Aconitine is a major bioactive diterpenoid alkaloid with high content derived from herbal aconitum plants. Emerging evidence indicates that voltage-dependent CHEMICAL(+) channels have pivotal roles in the cardiotoxicity of aconitine. However, no reports are available on the role of Ca(2+) in aconitine poisoning. In this study, we explored the importance of pathological Ca(2+) signaling in aconitine poisoning in vitro and in vivo. We found that Ca(2+) overload lead to accelerated beating rhythm in adult rat ventricular myocytes and caused arrhythmia in conscious freely moving rats. To investigate effects of aconitine on DISEASE, we performed cytotoxicity assay in neonatal rat ventricular myocytes (NRVMs), as well as measured lactate dehydrogenase level in the culture medium of NRVMs and activities of serum cardiac enzymes in rats. The results showed that aconitine resulted in DISEASE and reduced NRVMs viability dose-dependently. To confirm the pro-apoptotic effects, we performed flow cytometric detection, cardiac histology, transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. The results showed that aconitine stimulated apoptosis time-dependently. The expression analysis of Ca(2+) handling proteins demonstrated that aconitine promoted Ca(2+) overload through the expression regulation of Ca(2+) handling proteins. The expression analysis of apoptosis-related proteins revealed that pro-apoptotic protein expression was upregulated, and anti-apoptotic protein BCL-2 expression was downregulated. Furthermore, increased phosphorylation of MAPK family members, especially the P-P38/P38 ratio was found in cardiac tissues. Hence, our results suggest that aconitine significantly aggravates Ca(2+) overload and causes arrhythmia and finally promotes apoptotic development via phosphorylation of P38 mitogen-activated protein kinase. | NO-RELATIONSHIP |
| Aconitine-induced Ca2+ overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats. Aconitine is a major bioactive diterpenoid alkaloid with high content derived from herbal aconitum plants. Emerging evidence indicates that voltage-dependent Na(+) channels have pivotal roles in the cardiotoxicity of aconitine. However, no reports are available on the role of Ca(2+) in aconitine poisoning. In this study, we explored the importance of pathological Ca(2+) signaling in aconitine poisoning in vitro and in vivo. We found that Ca(2+) overload lead to accelerated beating rhythm in adult rat ventricular myocytes and caused arrhythmia in conscious freely moving rats. To investigate effects of aconitine on DISEASE, we performed cytotoxicity assay in neonatal rat ventricular myocytes (NRVMs), as well as measured CHEMICAL dehydrogenase level in the culture medium of NRVMs and activities of serum cardiac enzymes in rats. The results showed that aconitine resulted in DISEASE and reduced NRVMs viability dose-dependently. To confirm the pro-apoptotic effects, we performed flow cytometric detection, cardiac histology, transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. The results showed that aconitine stimulated apoptosis time-dependently. The expression analysis of Ca(2+) handling proteins demonstrated that aconitine promoted Ca(2+) overload through the expression regulation of Ca(2+) handling proteins. The expression analysis of apoptosis-related proteins revealed that pro-apoptotic protein expression was upregulated, and anti-apoptotic protein BCL-2 expression was downregulated. Furthermore, increased phosphorylation of MAPK family members, especially the P-P38/P38 ratio was found in cardiac tissues. Hence, our results suggest that aconitine significantly aggravates Ca(2+) overload and causes arrhythmia and finally promotes apoptotic development via phosphorylation of P38 mitogen-activated protein kinase. | NO-RELATIONSHIP |
| Aconitine-induced CHEMICAL2+ overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats. Aconitine is a major bioactive diterpenoid alkaloid with high content derived from herbal aconitum plants. Emerging evidence indicates that voltage-dependent Na(+) channels have pivotal roles in the cardiotoxicity of aconitine. However, no reports are available on the role of CHEMICAL(2+) in aconitine poisoning. In this study, we explored the importance of pathological CHEMICAL(2+) signaling in aconitine poisoning in vitro and in vivo. We found that CHEMICAL(2+) overload lead to accelerated beating rhythm in adult rat ventricular myocytes and caused arrhythmia in conscious freely moving rats. To investigate effects of aconitine on myocardial injury, we performed DISEASE assay in neonatal rat ventricular myocytes (NRVMs), as well as measured lactate dehydrogenase level in the culture medium of NRVMs and activities of serum cardiac enzymes in rats. The results showed that aconitine resulted in myocardial injury and reduced NRVMs viability dose-dependently. To confirm the pro-apoptotic effects, we performed flow cytometric detection, cardiac histology, transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. The results showed that aconitine stimulated apoptosis time-dependently. The expression analysis of CHEMICAL(2+) handling proteins demonstrated that aconitine promoted CHEMICAL(2+) overload through the expression regulation of CHEMICAL(2+) handling proteins. The expression analysis of apoptosis-related proteins revealed that pro-apoptotic protein expression was upregulated, and anti-apoptotic protein BCL-2 expression was downregulated. Furthermore, increased phosphorylation of MAPK family members, especially the P-P38/P38 ratio was found in cardiac tissues. Hence, our results suggest that aconitine significantly aggravates CHEMICAL(2+) overload and causes arrhythmia and finally promotes apoptotic development via phosphorylation of P38 mitogen-activated protein kinase. | NO-RELATIONSHIP |
| Aconitine-induced Ca2+ overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats. Aconitine is a major bioactive diterpenoid alkaloid with high content derived from herbal aconitum plants. Emerging evidence indicates that voltage-dependent Na(+) channels have pivotal roles in the cardiotoxicity of aconitine. However, no reports are available on the role of Ca(2+) in aconitine poisoning. In this study, we explored the importance of pathological Ca(2+) signaling in aconitine poisoning in vitro and in vivo. We found that Ca(2+) overload lead to accelerated beating rhythm in adult rat ventricular myocytes and caused arrhythmia in conscious freely moving rats. To investigate effects of aconitine on DISEASE, we performed cytotoxicity assay in neonatal rat ventricular myocytes (NRVMs), as well as measured lactate dehydrogenase level in the culture medium of NRVMs and activities of serum cardiac enzymes in rats. The results showed that aconitine resulted in DISEASE and reduced NRVMs viability dose-dependently. To confirm the pro-apoptotic effects, we performed flow cytometric detection, cardiac histology, transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-CHEMICAL nick end labeling assay. The results showed that aconitine stimulated apoptosis time-dependently. The expression analysis of Ca(2+) handling proteins demonstrated that aconitine promoted Ca(2+) overload through the expression regulation of Ca(2+) handling proteins. The expression analysis of apoptosis-related proteins revealed that pro-apoptotic protein expression was upregulated, and anti-apoptotic protein BCL-2 expression was downregulated. Furthermore, increased phosphorylation of MAPK family members, especially the P-P38/P38 ratio was found in cardiac tissues. Hence, our results suggest that aconitine significantly aggravates Ca(2+) overload and causes arrhythmia and finally promotes apoptotic development via phosphorylation of P38 mitogen-activated protein kinase. | NO-RELATIONSHIP |
| Aconitine-induced Ca2+ overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats. Aconitine is a major bioactive diterpenoid alkaloid with high content derived from herbal aconitum plants. Emerging evidence indicates that voltage-dependent Na(+) channels have pivotal roles in the cardiotoxicity of aconitine. However, no reports are available on the role of Ca(2+) in aconitine poisoning. In this study, we explored the importance of pathological Ca(2+) signaling in aconitine poisoning in vitro and in vivo. We found that Ca(2+) overload lead to accelerated beating rhythm in adult rat ventricular myocytes and caused arrhythmia in conscious freely moving rats. To investigate effects of aconitine on myocardial injury, we performed DISEASE assay in neonatal rat ventricular myocytes (NRVMs), as well as measured lactate dehydrogenase level in the culture medium of NRVMs and activities of serum cardiac enzymes in rats. The results showed that aconitine resulted in myocardial injury and reduced NRVMs viability dose-dependently. To confirm the pro-apoptotic effects, we performed flow cytometric detection, cardiac histology, transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated CHEMICAL-biotin nick end labeling assay. The results showed that aconitine stimulated apoptosis time-dependently. The expression analysis of Ca(2+) handling proteins demonstrated that aconitine promoted Ca(2+) overload through the expression regulation of Ca(2+) handling proteins. The expression analysis of apoptosis-related proteins revealed that pro-apoptotic protein expression was upregulated, and anti-apoptotic protein BCL-2 expression was downregulated. Furthermore, increased phosphorylation of MAPK family members, especially the P-P38/P38 ratio was found in cardiac tissues. Hence, our results suggest that aconitine significantly aggravates Ca(2+) overload and causes arrhythmia and finally promotes apoptotic development via phosphorylation of P38 mitogen-activated protein kinase. | NO-RELATIONSHIP |
| Aconitine-induced Ca2+ overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats. Aconitine is a major bioactive diterpenoid alkaloid with high content derived from herbal aconitum plants. Emerging evidence indicates that voltage-dependent Na(+) channels have pivotal roles in the cardiotoxicity of aconitine. However, no reports are available on the role of Ca(2+) in aconitine poisoning. In this study, we explored the importance of pathological Ca(2+) signaling in aconitine poisoning in vitro and in vivo. We found that Ca(2+) overload lead to accelerated beating rhythm in adult rat ventricular myocytes and caused arrhythmia in conscious freely moving rats. To investigate effects of aconitine on myocardial injury, we performed DISEASE assay in neonatal rat ventricular myocytes (NRVMs), as well as measured lactate dehydrogenase level in the culture medium of NRVMs and activities of serum cardiac enzymes in rats. The results showed that aconitine resulted in myocardial injury and reduced NRVMs viability dose-dependently. To confirm the pro-apoptotic effects, we performed flow cytometric detection, cardiac histology, transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-CHEMICAL nick end labeling assay. The results showed that aconitine stimulated apoptosis time-dependently. The expression analysis of Ca(2+) handling proteins demonstrated that aconitine promoted Ca(2+) overload through the expression regulation of Ca(2+) handling proteins. The expression analysis of apoptosis-related proteins revealed that pro-apoptotic protein expression was upregulated, and anti-apoptotic protein BCL-2 expression was downregulated. Furthermore, increased phosphorylation of MAPK family members, especially the P-P38/P38 ratio was found in cardiac tissues. Hence, our results suggest that aconitine significantly aggravates Ca(2+) overload and causes arrhythmia and finally promotes apoptotic development via phosphorylation of P38 mitogen-activated protein kinase. | NO-RELATIONSHIP |
| Aconitine-induced Ca2+ overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats. Aconitine is a major bioactive diterpenoid alkaloid with high content derived from herbal aconitum plants. Emerging evidence indicates that voltage-dependent Na(+) channels have pivotal roles in the cardiotoxicity of aconitine. However, no reports are available on the role of Ca(2+) in aconitine poisoning. In this study, we explored the importance of pathological Ca(2+) signaling in aconitine poisoning in vitro and in vivo. We found that Ca(2+) overload lead to accelerated beating rhythm in adult rat ventricular myocytes and caused arrhythmia in conscious freely moving rats. To investigate effects of aconitine on myocardial injury, we performed DISEASE assay in neonatal rat ventricular myocytes (NRVMs), as well as measured CHEMICAL dehydrogenase level in the culture medium of NRVMs and activities of serum cardiac enzymes in rats. The results showed that aconitine resulted in myocardial injury and reduced NRVMs viability dose-dependently. To confirm the pro-apoptotic effects, we performed flow cytometric detection, cardiac histology, transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. The results showed that aconitine stimulated apoptosis time-dependently. The expression analysis of Ca(2+) handling proteins demonstrated that aconitine promoted Ca(2+) overload through the expression regulation of Ca(2+) handling proteins. The expression analysis of apoptosis-related proteins revealed that pro-apoptotic protein expression was upregulated, and anti-apoptotic protein BCL-2 expression was downregulated. Furthermore, increased phosphorylation of MAPK family members, especially the P-P38/P38 ratio was found in cardiac tissues. Hence, our results suggest that aconitine significantly aggravates Ca(2+) overload and causes arrhythmia and finally promotes apoptotic development via phosphorylation of P38 mitogen-activated protein kinase. | NO-RELATIONSHIP |
| Aconitine-induced Ca2+ overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats. Aconitine is a major bioactive diterpenoid alkaloid with high content derived from herbal aconitum plants. Emerging evidence indicates that voltage-dependent CHEMICAL(+) channels have pivotal roles in the cardiotoxicity of aconitine. However, no reports are available on the role of Ca(2+) in aconitine poisoning. In this study, we explored the importance of pathological Ca(2+) signaling in aconitine poisoning in vitro and in vivo. We found that Ca(2+) overload lead to accelerated beating rhythm in adult rat ventricular myocytes and caused arrhythmia in conscious freely moving rats. To investigate effects of aconitine on myocardial injury, we performed DISEASE assay in neonatal rat ventricular myocytes (NRVMs), as well as measured lactate dehydrogenase level in the culture medium of NRVMs and activities of serum cardiac enzymes in rats. The results showed that aconitine resulted in myocardial injury and reduced NRVMs viability dose-dependently. To confirm the pro-apoptotic effects, we performed flow cytometric detection, cardiac histology, transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. The results showed that aconitine stimulated apoptosis time-dependently. The expression analysis of Ca(2+) handling proteins demonstrated that aconitine promoted Ca(2+) overload through the expression regulation of Ca(2+) handling proteins. The expression analysis of apoptosis-related proteins revealed that pro-apoptotic protein expression was upregulated, and anti-apoptotic protein BCL-2 expression was downregulated. Furthermore, increased phosphorylation of MAPK family members, especially the P-P38/P38 ratio was found in cardiac tissues. Hence, our results suggest that aconitine significantly aggravates Ca(2+) overload and causes arrhythmia and finally promotes apoptotic development via phosphorylation of P38 mitogen-activated protein kinase. | NO-RELATIONSHIP |
| Aconitine-induced Ca2+ overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats. Aconitine is a major bioactive diterpenoid alkaloid with high content derived from herbal aconitum plants. Emerging evidence indicates that voltage-dependent Na(+) channels have pivotal roles in the cardiotoxicity of aconitine. However, no reports are available on the role of Ca(2+) in aconitine poisoning. In this study, we explored the importance of pathological Ca(2+) signaling in aconitine poisoning in vitro and in vivo. We found that Ca(2+) overload lead to accelerated beating rhythm in adult rat ventricular myocytes and caused arrhythmia in conscious freely moving rats. To investigate effects of aconitine on DISEASE, we performed cytotoxicity assay in neonatal rat ventricular myocytes (NRVMs), as well as measured lactate dehydrogenase level in the culture medium of NRVMs and activities of serum cardiac enzymes in rats. The results showed that aconitine resulted in DISEASE and reduced NRVMs viability dose-dependently. To confirm the pro-apoptotic effects, we performed flow cytometric detection, cardiac histology, transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated CHEMICAL-biotin nick end labeling assay. The results showed that aconitine stimulated apoptosis time-dependently. The expression analysis of Ca(2+) handling proteins demonstrated that aconitine promoted Ca(2+) overload through the expression regulation of Ca(2+) handling proteins. The expression analysis of apoptosis-related proteins revealed that pro-apoptotic protein expression was upregulated, and anti-apoptotic protein BCL-2 expression was downregulated. Furthermore, increased phosphorylation of MAPK family members, especially the P-P38/P38 ratio was found in cardiac tissues. Hence, our results suggest that aconitine significantly aggravates Ca(2+) overload and causes arrhythmia and finally promotes apoptotic development via phosphorylation of P38 mitogen-activated protein kinase. | NO-RELATIONSHIP |
| Chronic treatment with metformin suppresses toll-like receptor 4 signaling and attenuates left ventricular dysfunction following DISEASE. Acute treatment with metformin has a protective effect in DISEASE by suppression of inflammatory responses due to activation of AMP-activated protein kinase (AMPK). In the present study, the effect of chronic pre-treatment with metformin on cardiac dysfunction and toll-like receptor 4 (TLR4) activities following DISEASE and their relation with AMPK were assessed. Male Wistar rats were randomly assigned to one of 5 groups (n=6): normal control and groups were injected CHEMICAL after chronic pre-treatment with 0, 25, 50, or 100mg/kg of metformin twice daily for 14 days. CHEMICAL (100mg/kg) was injected subcutaneously on the 13th and 14th days to induce DISEASE. CHEMICAL alone decreased left ventricular systolic pressure and myocardial contractility indexed as LVdp/dtmax and LVdp/dtmin. The left ventricular dysfunction was significantly lower in the groups treated with 25 and 50mg/kg of metformin. Metfromin markedly lowered CHEMICAL-induced elevation in the levels of TLR4 mRNA, myeloid differentiation protein 88 (MyD88), tumor necrosis factor-alpha (TNF-a), and interleukin 6 (IL-6) in the heart tissues. Similar changes were also seen in the serum levels of TNF-a and IL-6. However, the lower doses of 25 and 50mg/kg were more effective than 100mg/kg. Phosphorylated AMPKa (p-AMPK) in the myocardium was significantly elevated by 25mg/kg of metformin, slightly by 50mg/kg, but not by 100mg/kg. Chronic pre-treatment with metformin reduces post-DISEASE cardiac dysfunction and suppresses inflammatory responses, possibly through inhibition of TLR4 activities. This mechanism can be considered as a target to protect infarcted myocardium. | CHEMICAL-INDUCED-DISEASE |
| Chronic treatment with metformin suppresses toll-like receptor 4 signaling and attenuates DISEASE following myocardial infarction. Acute treatment with metformin has a protective effect in myocardial infarction by suppression of inflammatory responses due to activation of AMP-activated protein kinase (AMPK). In the present study, the effect of chronic pre-treatment with metformin on cardiac dysfunction and toll-like receptor 4 (TLR4) activities following myocardial infarction and their relation with AMPK were assessed. Male Wistar rats were randomly assigned to one of 5 groups (n=6): normal control and groups were injected CHEMICAL after chronic pre-treatment with 0, 25, 50, or 100mg/kg of metformin twice daily for 14 days. CHEMICAL (100mg/kg) was injected subcutaneously on the 13th and 14th days to induce acute myocardial infarction. CHEMICAL alone decreased left ventricular systolic pressure and myocardial contractility indexed as LVdp/dtmax and LVdp/dtmin. The DISEASE was significantly lower in the groups treated with 25 and 50mg/kg of metformin. Metfromin markedly lowered CHEMICAL-induced elevation in the levels of TLR4 mRNA, myeloid differentiation protein 88 (MyD88), tumor necrosis factor-alpha (TNF-a), and interleukin 6 (IL-6) in the heart tissues. Similar changes were also seen in the serum levels of TNF-a and IL-6. However, the lower doses of 25 and 50mg/kg were more effective than 100mg/kg. Phosphorylated AMPKa (p-AMPK) in the myocardium was significantly elevated by 25mg/kg of metformin, slightly by 50mg/kg, but not by 100mg/kg. Chronic pre-treatment with metformin reduces post-myocardial infarction cardiac dysfunction and suppresses inflammatory responses, possibly through inhibition of TLR4 activities. This mechanism can be considered as a target to protect infarcted myocardium. | CHEMICAL-INDUCED-DISEASE |
| Chronic treatment with CHEMICAL suppresses toll-like receptor 4 signaling and attenuates left ventricular dysfunction following myocardial infarction. Acute treatment with CHEMICAL has a protective effect in myocardial infarction by suppression of inflammatory responses due to activation of AMP-activated protein kinase (AMPK). In the present study, the effect of chronic pre-treatment with CHEMICAL on cardiac dysfunction and toll-like receptor 4 (TLR4) activities following myocardial infarction and their relation with AMPK were assessed. Male Wistar rats were randomly assigned to one of 5 groups (n=6): normal control and groups were injected isoproterenol after chronic pre-treatment with 0, 25, 50, or 100mg/kg of CHEMICAL twice daily for 14 days. Isoproterenol (100mg/kg) was injected subcutaneously on the 13th and 14th days to induce acute myocardial infarction. Isoproterenol alone decreased left ventricular systolic pressure and myocardial contractility indexed as LVdp/dtmax and LVdp/dtmin. The left ventricular dysfunction was significantly lower in the groups treated with 25 and 50mg/kg of CHEMICAL. Metfromin markedly lowered isoproterenol-induced elevation in the levels of TLR4 mRNA, myeloid differentiation protein 88 (MyD88), tumor DISEASE factor-alpha (TNF-a), and interleukin 6 (IL-6) in the heart tissues. Similar changes were also seen in the serum levels of TNF-a and IL-6. However, the lower doses of 25 and 50mg/kg were more effective than 100mg/kg. Phosphorylated AMPKa (p-AMPK) in the myocardium was significantly elevated by 25mg/kg of CHEMICAL, slightly by 50mg/kg, but not by 100mg/kg. Chronic pre-treatment with CHEMICAL reduces post-myocardial infarction cardiac dysfunction and suppresses inflammatory responses, possibly through inhibition of TLR4 activities. This mechanism can be considered as a target to protect infarcted myocardium. | NO-RELATIONSHIP |
| Chronic treatment with CHEMICAL suppresses toll-like receptor 4 signaling and attenuates left ventricular dysfunction following myocardial infarction. Acute treatment with CHEMICAL has a protective effect in myocardial infarction by suppression of inflammatory responses due to activation of AMP-activated protein kinase (AMPK). In the present study, the effect of chronic pre-treatment with CHEMICAL on cardiac dysfunction and toll-like receptor 4 (TLR4) activities following myocardial infarction and their relation with AMPK were assessed. Male Wistar rats were randomly assigned to one of 5 groups (n=6): normal control and groups were injected isoproterenol after chronic pre-treatment with 0, 25, 50, or 100mg/kg of CHEMICAL twice daily for 14 days. Isoproterenol (100mg/kg) was injected subcutaneously on the 13th and 14th days to induce acute myocardial infarction. Isoproterenol alone decreased left ventricular systolic pressure and myocardial contractility indexed as LVdp/dtmax and LVdp/dtmin. The left ventricular dysfunction was significantly lower in the groups treated with 25 and 50mg/kg of CHEMICAL. Metfromin markedly lowered isoproterenol-induced elevation in the levels of TLR4 mRNA, myeloid differentiation protein 88 (MyD88), DISEASE necrosis factor-alpha (TNF-a), and interleukin 6 (IL-6) in the heart tissues. Similar changes were also seen in the serum levels of TNF-a and IL-6. However, the lower doses of 25 and 50mg/kg were more effective than 100mg/kg. Phosphorylated AMPKa (p-AMPK) in the myocardium was significantly elevated by 25mg/kg of CHEMICAL, slightly by 50mg/kg, but not by 100mg/kg. Chronic pre-treatment with CHEMICAL reduces post-myocardial infarction cardiac dysfunction and suppresses inflammatory responses, possibly through inhibition of TLR4 activities. This mechanism can be considered as a target to protect infarcted myocardium. | NO-RELATIONSHIP |
| Chronic treatment with metformin suppresses toll-like receptor 4 signaling and attenuates left ventricular dysfunction following myocardial infarction. Acute treatment with metformin has a protective effect in myocardial infarction by suppression of inflammatory responses due to activation of CHEMICAL-activated protein kinase (AMPK). In the present study, the effect of chronic pre-treatment with metformin on cardiac dysfunction and toll-like receptor 4 (TLR4) activities following myocardial infarction and their relation with AMPK were assessed. Male Wistar rats were randomly assigned to one of 5 groups (n=6): normal control and groups were injected isoproterenol after chronic pre-treatment with 0, 25, 50, or 100mg/kg of metformin twice daily for 14 days. Isoproterenol (100mg/kg) was injected subcutaneously on the 13th and 14th days to induce acute myocardial infarction. Isoproterenol alone decreased left ventricular systolic pressure and myocardial contractility indexed as LVdp/dtmax and LVdp/dtmin. The left ventricular dysfunction was significantly lower in the groups treated with 25 and 50mg/kg of metformin. Metfromin markedly lowered isoproterenol-induced elevation in the levels of TLR4 mRNA, myeloid differentiation protein 88 (MyD88), tumor DISEASE factor-alpha (TNF-a), and interleukin 6 (IL-6) in the heart tissues. Similar changes were also seen in the serum levels of TNF-a and IL-6. However, the lower doses of 25 and 50mg/kg were more effective than 100mg/kg. Phosphorylated AMPKa (p-AMPK) in the myocardium was significantly elevated by 25mg/kg of metformin, slightly by 50mg/kg, but not by 100mg/kg. Chronic pre-treatment with metformin reduces post-myocardial infarction cardiac dysfunction and suppresses inflammatory responses, possibly through inhibition of TLR4 activities. This mechanism can be considered as a target to protect infarcted myocardium. | ACTIVATOR |
| Chronic treatment with CHEMICAL suppresses toll-like receptor 4 signaling and attenuates left ventricular dysfunction following myocardial infarction. Acute treatment with CHEMICAL has a protective effect in myocardial infarction by suppression of inflammatory responses due to activation of AMP-activated protein kinase (AMPK). In the present study, the effect of chronic pre-treatment with CHEMICAL on DISEASE and toll-like receptor 4 (TLR4) activities following myocardial infarction and their relation with AMPK were assessed. Male Wistar rats were randomly assigned to one of 5 groups (n=6): normal control and groups were injected isoproterenol after chronic pre-treatment with 0, 25, 50, or 100mg/kg of CHEMICAL twice daily for 14 days. Isoproterenol (100mg/kg) was injected subcutaneously on the 13th and 14th days to induce acute myocardial infarction. Isoproterenol alone decreased left ventricular systolic pressure and myocardial contractility indexed as LVdp/dtmax and LVdp/dtmin. The left ventricular dysfunction was significantly lower in the groups treated with 25 and 50mg/kg of CHEMICAL. Metfromin markedly lowered isoproterenol-induced elevation in the levels of TLR4 mRNA, myeloid differentiation protein 88 (MyD88), tumor necrosis factor-alpha (TNF-a), and interleukin 6 (IL-6) in the heart tissues. Similar changes were also seen in the serum levels of TNF-a and IL-6. However, the lower doses of 25 and 50mg/kg were more effective than 100mg/kg. Phosphorylated AMPKa (p-AMPK) in the myocardium was significantly elevated by 25mg/kg of CHEMICAL, slightly by 50mg/kg, but not by 100mg/kg. Chronic pre-treatment with CHEMICAL reduces post-myocardial infarction cardiac dysfunction and suppresses inflammatory responses, possibly through inhibition of TLR4 activities. This mechanism can be considered as a target to protect infarcted myocardium. | NO-RELATIONSHIP |
| Chronic treatment with metformin suppresses toll-like receptor 4 signaling and attenuates left ventricular dysfunction following myocardial infarction. Acute treatment with metformin has a protective effect in myocardial infarction by suppression of inflammatory responses due to activation of CHEMICAL-activated protein kinase (AMPK). In the present study, the effect of chronic pre-treatment with metformin on cardiac dysfunction and toll-like receptor 4 (TLR4) activities following myocardial infarction and their relation with AMPK were assessed. Male Wistar rats were randomly assigned to one of 5 groups (n=6): normal control and groups were injected isoproterenol after chronic pre-treatment with 0, 25, 50, or 100mg/kg of metformin twice daily for 14 days. Isoproterenol (100mg/kg) was injected subcutaneously on the 13th and 14th days to induce acute myocardial infarction. Isoproterenol alone decreased left ventricular systolic pressure and myocardial contractility indexed as LVdp/dtmax and LVdp/dtmin. The left ventricular dysfunction was significantly lower in the groups treated with 25 and 50mg/kg of metformin. Metfromin markedly lowered isoproterenol-induced elevation in the levels of TLR4 mRNA, myeloid differentiation protein 88 (MyD88), DISEASE necrosis factor-alpha (TNF-a), and interleukin 6 (IL-6) in the heart tissues. Similar changes were also seen in the serum levels of TNF-a and IL-6. However, the lower doses of 25 and 50mg/kg were more effective than 100mg/kg. Phosphorylated AMPKa (p-AMPK) in the myocardium was significantly elevated by 25mg/kg of metformin, slightly by 50mg/kg, but not by 100mg/kg. Chronic pre-treatment with metformin reduces post-myocardial infarction cardiac dysfunction and suppresses inflammatory responses, possibly through inhibition of TLR4 activities. This mechanism can be considered as a target to protect infarcted myocardium. | ACTIVATOR |
| Chronic treatment with metformin suppresses toll-like receptor 4 signaling and attenuates left ventricular dysfunction following myocardial infarction. Acute treatment with metformin has a protective effect in myocardial infarction by suppression of inflammatory responses due to activation of CHEMICAL-activated protein kinase (AMPK). In the present study, the effect of chronic pre-treatment with metformin on DISEASE and toll-like receptor 4 (TLR4) activities following myocardial infarction and their relation with AMPK were assessed. Male Wistar rats were randomly assigned to one of 5 groups (n=6): normal control and groups were injected isoproterenol after chronic pre-treatment with 0, 25, 50, or 100mg/kg of metformin twice daily for 14 days. Isoproterenol (100mg/kg) was injected subcutaneously on the 13th and 14th days to induce acute myocardial infarction. Isoproterenol alone decreased left ventricular systolic pressure and myocardial contractility indexed as LVdp/dtmax and LVdp/dtmin. The left ventricular dysfunction was significantly lower in the groups treated with 25 and 50mg/kg of metformin. Metfromin markedly lowered isoproterenol-induced elevation in the levels of TLR4 mRNA, myeloid differentiation protein 88 (MyD88), tumor necrosis factor-alpha (TNF-a), and interleukin 6 (IL-6) in the heart tissues. Similar changes were also seen in the serum levels of TNF-a and IL-6. However, the lower doses of 25 and 50mg/kg were more effective than 100mg/kg. Phosphorylated AMPKa (p-AMPK) in the myocardium was significantly elevated by 25mg/kg of metformin, slightly by 50mg/kg, but not by 100mg/kg. Chronic pre-treatment with metformin reduces post-myocardial infarction cardiac dysfunction and suppresses inflammatory responses, possibly through inhibition of TLR4 activities. This mechanism can be considered as a target to protect infarcted myocardium. | NO-RELATIONSHIP |
| DISEASE induced by combination therapy with CHEMICAL and tiapride in a Japanese patient with Huntington's disease at the terminal stage of recurrent breast cancer. We herein describe the case of an 81-year-old Japanese woman with DISEASE that occurred 36 days after the initiation of combination therapy with tiapride (75 mg/day) and CHEMICAL (12.5 mg/day) for Huntington's disease. The patient had been treated with tiapride or CHEMICAL alone without any adverse effects before the administration of the combination therapy. She also had advanced breast cancer when the combination therapy was initiated. To the best of our knowledge, the occurrence of DISEASE due to combination therapy with CHEMICAL and tiapride has not been previously reported. CHEMICAL should be administered very carefully in combination with other neuroleptic drugs, particularly in patients with a worsening general condition. | CHEMICAL-INDUCED-DISEASE |
| DISEASE induced by combination therapy with tetrabenazine and CHEMICAL in a Japanese patient with Huntington's disease at the terminal stage of recurrent breast cancer. We herein describe the case of an 81-year-old Japanese woman with DISEASE that occurred 36 days after the initiation of combination therapy with CHEMICAL (75 mg/day) and tetrabenazine (12.5 mg/day) for Huntington's disease. The patient had been treated with CHEMICAL or tetrabenazine alone without any adverse effects before the administration of the combination therapy. She also had advanced breast cancer when the combination therapy was initiated. To the best of our knowledge, the occurrence of DISEASE due to combination therapy with tetrabenazine and CHEMICAL has not been previously reported. Tetrabenazine should be administered very carefully in combination with other neuroleptic drugs, particularly in patients with a worsening general condition. | CHEMICAL-INDUCED-DISEASE |
| Neuroleptic malignant syndrome induced by combination therapy with tetrabenazine and tiapride in a Japanese patient with Huntington's disease at the terminal stage of recurrent DISEASE. We herein describe the case of an 81-year-old Japanese woman with neuroleptic malignant syndrome that occurred 36 days after the initiation of combination therapy with tiapride (75 mg/day) and tetrabenazine (12.5 mg/day) for Huntington's disease. The patient had been treated with tiapride or tetrabenazine alone without any adverse effects before the administration of the combination therapy. She also had advanced DISEASE when the combination therapy was initiated. To the best of our knowledge, the occurrence of neuroleptic malignant syndrome due to combination therapy with tetrabenazine and tiapride has not been previously reported. Tetrabenazine should be administered very carefully in combination with other CHEMICAL, particularly in patients with a worsening general condition. | NO-RELATIONSHIP |
| Neuroleptic malignant syndrome induced by combination therapy with tetrabenazine and tiapride in a Japanese patient with DISEASE at the terminal stage of recurrent breast cancer. We herein describe the case of an 81-year-old Japanese woman with neuroleptic malignant syndrome that occurred 36 days after the initiation of combination therapy with tiapride (75 mg/day) and tetrabenazine (12.5 mg/day) for DISEASE. The patient had been treated with tiapride or tetrabenazine alone without any adverse effects before the administration of the combination therapy. She also had advanced breast cancer when the combination therapy was initiated. To the best of our knowledge, the occurrence of neuroleptic malignant syndrome due to combination therapy with tetrabenazine and tiapride has not been previously reported. Tetrabenazine should be administered very carefully in combination with other CHEMICAL, particularly in patients with a worsening general condition. | NO-RELATIONSHIP |
| A CHEMICAL-terbinafine combination induced DISEASE. To report a sinus bradycardia induced by CHEMICAL and terbinafine drug-drug interaction and its management. A 63 year-old Caucasian man on CHEMICAL 200 mg/day for stable coronary artery disease was prescribed a 90-day course of oral terbinafine 250 mg/day for onychomycosis. On the 49th day of terbinafine therapy, he was brought to the emergency room for a decrease of his global health status, confusion and falls. The electrocardiogram revealed a 37 beats/min sinus bradycardia. A score of 7 on the Naranjo adverse drug reaction probability scale indicates a probable relationship between the patient's sinus bradycardia and the drug interaction between CHEMICAL and terbinafine. The heart rate ameliorated first with a decrease in the dose of CHEMICAL. It was subsequently changed to bisoprolol and the heart rate remained normal. By inhibiting the cytochrome P450 2D6, terbinafine had decreased CHEMICAL's clearance, leading in CHEMICAL accumulation which has resulted in clinically significant sinus bradycardia. | CHEMICAL-INDUCED-DISEASE |
| A metoprolol-CHEMICAL combination induced DISEASE. To report a sinus bradycardia induced by metoprolol and CHEMICAL drug-drug interaction and its management. A 63 year-old Caucasian man on metoprolol 200 mg/day for stable coronary artery disease was prescribed a 90-day course of oral CHEMICAL 250 mg/day for onychomycosis. On the 49th day of CHEMICAL therapy, he was brought to the emergency room for a decrease of his global health status, confusion and falls. The electrocardiogram revealed a 37 beats/min sinus bradycardia. A score of 7 on the Naranjo adverse drug reaction probability scale indicates a probable relationship between the patient's sinus bradycardia and the drug interaction between metoprolol and CHEMICAL. The heart rate ameliorated first with a decrease in the dose of metoprolol. It was subsequently changed to bisoprolol and the heart rate remained normal. By inhibiting the cytochrome P450 2D6, CHEMICAL had decreased metoprolol's clearance, leading in metoprolol accumulation which has resulted in clinically significant sinus bradycardia. | CHEMICAL-INDUCED-DISEASE |
| A metoprolol-terbinafine combination induced bradycardia. To report a sinus bradycardia induced by metoprolol and terbinafine drug-drug interaction and its management. A 63 year-old Caucasian man on metoprolol 200 mg/day for stable coronary artery disease was prescribed a 90-day course of oral terbinafine 250 mg/day for onychomycosis. On the 49th day of terbinafine therapy, he was brought to the emergency room for a decrease of his global health status, confusion and falls. The electrocardiogram revealed a 37 beats/min sinus bradycardia. A score of 7 on the Naranjo DISEASE probability scale indicates a probable relationship between the patient's sinus bradycardia and the drug interaction between metoprolol and terbinafine. The heart rate ameliorated first with a decrease in the dose of metoprolol. It was subsequently changed to CHEMICAL and the heart rate remained normal. By inhibiting the cytochrome P450 2D6, terbinafine had decreased metoprolol's clearance, leading in metoprolol accumulation which has resulted in clinically significant sinus bradycardia. | NO-RELATIONSHIP |
| A metoprolol-terbinafine combination induced bradycardia. To report a sinus bradycardia induced by metoprolol and terbinafine drug-drug interaction and its management. A 63 year-old Caucasian man on metoprolol 200 mg/day for stable coronary artery disease was prescribed a 90-day course of oral terbinafine 250 mg/day for DISEASE. On the 49th day of terbinafine therapy, he was brought to the emergency room for a decrease of his global health status, confusion and falls. The electrocardiogram revealed a 37 beats/min sinus bradycardia. A score of 7 on the Naranjo adverse drug reaction probability scale indicates a probable relationship between the patient's sinus bradycardia and the drug interaction between metoprolol and terbinafine. The heart rate ameliorated first with a decrease in the dose of metoprolol. It was subsequently changed to CHEMICAL and the heart rate remained normal. By inhibiting the cytochrome P450 2D6, terbinafine had decreased metoprolol's clearance, leading in metoprolol accumulation which has resulted in clinically significant sinus bradycardia. | NO-RELATIONSHIP |
| A metoprolol-terbinafine combination induced bradycardia. To report a sinus bradycardia induced by metoprolol and terbinafine drug-drug interaction and its management. A 63 year-old Caucasian man on metoprolol 200 mg/day for stable DISEASE was prescribed a 90-day course of oral terbinafine 250 mg/day for onychomycosis. On the 49th day of terbinafine therapy, he was brought to the emergency room for a decrease of his global health status, confusion and falls. The electrocardiogram revealed a 37 beats/min sinus bradycardia. A score of 7 on the Naranjo adverse drug reaction probability scale indicates a probable relationship between the patient's sinus bradycardia and the drug interaction between metoprolol and terbinafine. The heart rate ameliorated first with a decrease in the dose of metoprolol. It was subsequently changed to CHEMICAL and the heart rate remained normal. By inhibiting the cytochrome P450 2D6, terbinafine had decreased metoprolol's clearance, leading in metoprolol accumulation which has resulted in clinically significant sinus bradycardia. | NO-RELATIONSHIP |
| A metoprolol-terbinafine combination induced bradycardia. To report a sinus bradycardia induced by metoprolol and terbinafine drug-drug interaction and its management. A 63 year-old Caucasian man on metoprolol 200 mg/day for stable coronary artery disease was prescribed a 90-day course of oral terbinafine 250 mg/day for onychomycosis. On the 49th day of terbinafine therapy, he was brought to the emergency room for a decrease of his global health status, DISEASE and falls. The electrocardiogram revealed a 37 beats/min sinus bradycardia. A score of 7 on the Naranjo adverse drug reaction probability scale indicates a probable relationship between the patient's sinus bradycardia and the drug interaction between metoprolol and terbinafine. The heart rate ameliorated first with a decrease in the dose of metoprolol. It was subsequently changed to CHEMICAL and the heart rate remained normal. By inhibiting the cytochrome P450 2D6, terbinafine had decreased metoprolol's clearance, leading in metoprolol accumulation which has resulted in clinically significant sinus bradycardia. | NO-RELATIONSHIP |
| A metoprolol-terbinafine combination induced bradycardia. To report a DISEASE induced by metoprolol and terbinafine drug-drug interaction and its management. A 63 year-old Caucasian man on metoprolol 200 mg/day for stable coronary artery disease was prescribed a 90-day course of oral terbinafine 250 mg/day for onychomycosis. On the 49th day of terbinafine therapy, he was brought to the emergency room for a decrease of his global health status, confusion and falls. The electrocardiogram revealed a 37 beats/min DISEASE. A score of 7 on the Naranjo adverse drug reaction probability scale indicates a probable relationship between the patient's DISEASE and the drug interaction between metoprolol and terbinafine. The heart rate ameliorated first with a decrease in the dose of metoprolol. It was subsequently changed to CHEMICAL and the heart rate remained normal. By inhibiting the cytochrome P450 2D6, terbinafine had decreased metoprolol's clearance, leading in metoprolol accumulation which has resulted in clinically significant DISEASE. | NO-RELATIONSHIP |
| Optochiasmatic and peripheral neuropathy due to CHEMICAL overtreatment. CHEMICAL is known to cause optic neuropathy and, more rarely, axonal DISEASE. We characterize the clinical, neurophysiological, and neuroimaging findings in a 72-year-old man who developed visual loss and paresthesias after 11 weeks of exposure to a supratherapeutic dose of CHEMICAL. This case demonstrates the selective vulnerability of the anterior visual pathways and peripheral nerves to CHEMICAL toxicity. | CHEMICAL-INDUCED-DISEASE |
| Optochiasmatic and peripheral neuropathy due to CHEMICAL overtreatment. CHEMICAL is known to cause optic neuropathy and, more rarely, axonal polyneuropathy. We characterize the clinical, neurophysiological, and neuroimaging findings in a 72-year-old man who developed DISEASE and paresthesias after 11 weeks of exposure to a supratherapeutic dose of CHEMICAL. This case demonstrates the selective vulnerability of the anterior visual pathways and peripheral nerves to CHEMICAL toxicity. | CHEMICAL-INDUCED-DISEASE |
| Optochiasmatic and peripheral neuropathy due to CHEMICAL overtreatment. CHEMICAL is known to cause DISEASE and, more rarely, axonal polyneuropathy. We characterize the clinical, neurophysiological, and neuroimaging findings in a 72-year-old man who developed visual loss and paresthesias after 11 weeks of exposure to a supratherapeutic dose of CHEMICAL. This case demonstrates the selective vulnerability of the anterior visual pathways and peripheral nerves to CHEMICAL toxicity. | CHEMICAL-INDUCED-DISEASE |
| Optochiasmatic and peripheral neuropathy due to CHEMICAL overtreatment. CHEMICAL is known to cause optic neuropathy and, more rarely, axonal polyneuropathy. We characterize the clinical, neurophysiological, and neuroimaging findings in a 72-year-old man who developed visual loss and DISEASE after 11 weeks of exposure to a supratherapeutic dose of CHEMICAL. This case demonstrates the selective vulnerability of the anterior visual pathways and peripheral nerves to CHEMICAL toxicity. | CHEMICAL-INDUCED-DISEASE |
| Testosterone ameliorates CHEMICAL-induced DISEASE in male rats. AIM: To study the effects of testosterone on CHEMICAL (CHEMICAL)-induced DISEASE in male rats. METHODS: Adult male Wistar rats were intracerebroventricularly (icv) infused with CHEMICAL (750 ug) on d 1 and d 3, and a passive avoidance task was assessed 2 weeks after the first injection of CHEMICAL. Castration surgery was performed in another group of rats, and the passive avoidance task was assessed 4 weeks after the operation. Testosterone (1 mg.kg(-1).d(-1), sc), the androgen receptor antagonist flutamide (10 mg.kg(-1).d(-1), ip), the estrogen receptor antagonist tamoxifen (1 mg.kg(-1).d(-1), ip) or the aromatase inhibitor letrozole (4 mg.kg(-1).d(-1), ip) were administered for 6 d after the first injection of CHEMICAL. RESULTS: CHEMICAL administration and castration markedly decreased both STL1 (the short memory) and STL2 (the long memory) in passive avoidance tests. Testosterone replacement almost restored the STL1 and STL2 in castrated rats, and significantly prolonged the STL1 and STL2 in CHEMICAL-treated rats. Administration of flutamide, letrozole or tamoxifen significantly DISEASE in intact rats, and significantly attenuated the testosterone replacement in improving CHEMICAL- and castration-induced DISEASE. CONCLUSION: Testosterone administration ameliorates CHEMICAL- and castration-induced DISEASE in male Wistar rats. | CHEMICAL-INDUCED-DISEASE |
| Testosterone ameliorates streptozotocin-induced DISEASE in male rats. AIM: To study the effects of testosterone on streptozotocin (STZ)-induced DISEASE in male rats. METHODS: Adult male Wistar rats were intracerebroventricularly (icv) infused with STZ (750 ug) on d 1 and d 3, and a passive avoidance task was assessed 2 weeks after the first injection of STZ. Castration surgery was performed in another group of rats, and the passive avoidance task was assessed 4 weeks after the operation. Testosterone (1 mg.kg(-1).d(-1), sc), the androgen receptor antagonist CHEMICAL (10 mg.kg(-1).d(-1), ip), the estrogen receptor antagonist tamoxifen (1 mg.kg(-1).d(-1), ip) or the aromatase inhibitor letrozole (4 mg.kg(-1).d(-1), ip) were administered for 6 d after the first injection of STZ. RESULTS: STZ administration and castration markedly decreased both STL1 (the short memory) and STL2 (the long memory) in passive avoidance tests. Testosterone replacement almost restored the STL1 and STL2 in castrated rats, and significantly prolonged the STL1 and STL2 in STZ-treated rats. Administration of CHEMICAL, letrozole or tamoxifen significantly DISEASE in intact rats, and significantly attenuated the testosterone replacement in improving STZ- and castration-induced DISEASE. CONCLUSION: Testosterone administration ameliorates STZ- and castration-induced DISEASE in male Wistar rats. | NO-RELATIONSHIP |
| Testosterone ameliorates streptozotocin-induced DISEASE in male rats. AIM: To study the effects of testosterone on streptozotocin (STZ)-induced DISEASE in male rats. METHODS: Adult male Wistar rats were intracerebroventricularly (icv) infused with STZ (750 ug) on d 1 and d 3, and a passive avoidance task was assessed 2 weeks after the first injection of STZ. Castration surgery was performed in another group of rats, and the passive avoidance task was assessed 4 weeks after the operation. Testosterone (1 mg.kg(-1).d(-1), sc), the androgen receptor antagonist flutamide (10 mg.kg(-1).d(-1), ip), the estrogen receptor antagonist tamoxifen (1 mg.kg(-1).d(-1), ip) or the aromatase inhibitor CHEMICAL (4 mg.kg(-1).d(-1), ip) were administered for 6 d after the first injection of STZ. RESULTS: STZ administration and castration markedly decreased both STL1 (the short memory) and STL2 (the long memory) in passive avoidance tests. Testosterone replacement almost restored the STL1 and STL2 in castrated rats, and significantly prolonged the STL1 and STL2 in STZ-treated rats. Administration of flutamide, CHEMICAL or tamoxifen significantly DISEASE in intact rats, and significantly attenuated the testosterone replacement in improving STZ- and castration-induced DISEASE. CONCLUSION: Testosterone administration ameliorates STZ- and castration-induced DISEASE in male Wistar rats. | NO-RELATIONSHIP |
| Testosterone ameliorates streptozotocin-induced DISEASE in male rats. AIM: To study the effects of testosterone on streptozotocin (STZ)-induced DISEASE in male rats. METHODS: Adult male Wistar rats were intracerebroventricularly (icv) infused with STZ (750 ug) on d 1 and d 3, and a passive avoidance task was assessed 2 weeks after the first injection of STZ. Castration surgery was performed in another group of rats, and the passive avoidance task was assessed 4 weeks after the operation. Testosterone (1 mg.kg(-1).d(-1), sc), the androgen receptor antagonist flutamide (10 mg.kg(-1).d(-1), ip), the estrogen receptor antagonist CHEMICAL (1 mg.kg(-1).d(-1), ip) or the aromatase inhibitor letrozole (4 mg.kg(-1).d(-1), ip) were administered for 6 d after the first injection of STZ. RESULTS: STZ administration and castration markedly decreased both STL1 (the short memory) and STL2 (the long memory) in passive avoidance tests. Testosterone replacement almost restored the STL1 and STL2 in castrated rats, and significantly prolonged the STL1 and STL2 in STZ-treated rats. Administration of flutamide, letrozole or CHEMICAL significantly DISEASE in intact rats, and significantly attenuated the testosterone replacement in improving STZ- and castration-induced DISEASE. CONCLUSION: Testosterone administration ameliorates STZ- and castration-induced DISEASE in male Wistar rats. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in CHEMICAL-induced DISEASE. Garcinielliptone FC (GFC) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat skin diseases in both humans and animals as well as the seed decoction has been used to treat diarrheas and inflammatory diseases. However, there is no research on GFC effects in the central nervous system of rodents. The present study aimed to evaluate the GFC effects at doses of 25, 50 or 75 mg/kg on DISEASE parameters to determine their anticonvulsant activity and its effects on amino acid (r-aminobutyric acid (GABA), glutamine, aspartate and glutathione) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after DISEASE. GFC produced an increased latency to first DISEASE, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In aspartate, glutamine and glutamate levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of CHEMICAL-induced status epilepticus, as demonstrated by increase in latency to first DISEASE and decrease in mortality rate of animals. In conclusion, our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in CHEMICAL model by modulating the GABA and glutamate contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | CHEMICAL-INDUCED-DISEASE |
| Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in CHEMICAL-induced seizures. Garcinielliptone FC (GFC) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat skin diseases in both humans and animals as well as the seed decoction has been used to treat diarrheas and inflammatory diseases. However, there is no research on GFC effects in the central nervous system of rodents. The present study aimed to evaluate the GFC effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on amino acid (r-aminobutyric acid (GABA), glutamine, aspartate and glutathione) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. GFC produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In aspartate, glutamine and glutamate levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of CHEMICAL-induced DISEASE, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in CHEMICAL model by modulating the GABA and glutamate contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | CHEMICAL-INDUCED-DISEASE |
| Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine-induced seizures. Garcinielliptone FC (GFC) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat skin diseases in both humans and animals as well as the seed decoction has been used to treat DISEASE and inflammatory diseases. However, there is no research on GFC effects in the central nervous system of rodents. The present study aimed to evaluate the GFC effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on amino acid (CHEMICAL (CHEMICAL), glutamine, aspartate and glutathione) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. GFC produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, CHEMICAL content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In aspartate, glutamine and glutamate levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the CHEMICAL and glutamate contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine-induced seizures. Garcinielliptone FC (GFC) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat DISEASE in both humans and animals as well as the seed decoction has been used to treat diarrheas and inflammatory diseases. However, there is no research on GFC effects in the central nervous system of rodents. The present study aimed to evaluate the GFC effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on amino acid (r-aminobutyric acid (GABA), CHEMICAL, aspartate and glutathione) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. GFC produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In aspartate, CHEMICAL and CHEMICAL levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the GABA and CHEMICAL contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine-induced seizures. Garcinielliptone FC (GFC) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat skin diseases in both humans and animals as well as the seed decoction has been used to treat diarrheas and DISEASE. However, there is no research on GFC effects in the central nervous system of rodents. The present study aimed to evaluate the GFC effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on amino acid (CHEMICAL (CHEMICAL), glutamine, aspartate and glutathione) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. GFC produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, CHEMICAL content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In aspartate, glutamine and glutamate levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the CHEMICAL and glutamate contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with CHEMICAL in pilocarpine-induced seizures. CHEMICAL (CHEMICAL) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat skin diseases in both humans and animals as well as the seed decoction has been used to treat diarrheas and DISEASE. However, there is no research on CHEMICAL effects in the central nervous system of rodents. The present study aimed to evaluate the CHEMICAL effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on amino acid (r-aminobutyric acid (GABA), glutamine, aspartate and glutathione) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. CHEMICAL produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In aspartate, glutamine and glutamate levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that CHEMICAL can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that CHEMICAL may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the GABA and glutamate contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine-induced seizures. Garcinielliptone FC (GFC) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat skin diseases in both humans and animals as well as the seed decoction has been used to treat DISEASE and inflammatory diseases. However, there is no research on GFC effects in the central nervous system of rodents. The present study aimed to evaluate the GFC effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on amino acid (r-aminobutyric acid (GABA), glutamine, CHEMICAL and glutathione) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. GFC produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In CHEMICAL, glutamine and glutamate levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the GABA and glutamate contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with CHEMICAL in pilocarpine-induced seizures. CHEMICAL (CHEMICAL) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat skin diseases in both humans and animals as well as the seed decoction has been used to treat DISEASE and inflammatory diseases. However, there is no research on CHEMICAL effects in the central nervous system of rodents. The present study aimed to evaluate the CHEMICAL effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on amino acid (r-aminobutyric acid (GABA), glutamine, aspartate and glutathione) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. CHEMICAL produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In aspartate, glutamine and glutamate levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that CHEMICAL can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that CHEMICAL may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the GABA and glutamate contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine-induced seizures. Garcinielliptone FC (GFC) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat skin diseases in both humans and animals as well as the seed decoction has been used to treat DISEASE and inflammatory diseases. However, there is no research on GFC effects in the central nervous system of rodents. The present study aimed to evaluate the GFC effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on amino acid (r-aminobutyric acid (GABA), CHEMICAL, aspartate and glutathione) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. GFC produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In aspartate, CHEMICAL and CHEMICAL levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the GABA and CHEMICAL contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine-induced seizures. Garcinielliptone FC (GFC) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat skin diseases in both humans and animals as well as the seed decoction has been used to treat DISEASE and inflammatory diseases. However, there is no research on GFC effects in the central nervous system of rodents. The present study aimed to evaluate the GFC effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on CHEMICAL (r-aminobutyric acid (GABA), glutamine, aspartate and glutathione) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. GFC produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In aspartate, glutamine and glutamate levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the GABA and glutamate contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine-induced seizures. Garcinielliptone FC (GFC) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat DISEASE in both humans and animals as well as the seed decoction has been used to treat diarrheas and inflammatory diseases. However, there is no research on GFC effects in the central nervous system of rodents. The present study aimed to evaluate the GFC effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on CHEMICAL (r-aminobutyric acid (GABA), glutamine, aspartate and glutathione) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. GFC produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In aspartate, glutamine and glutamate levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the GABA and glutamate contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine-induced seizures. Garcinielliptone FC (GFC) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat skin diseases in both humans and animals as well as the seed decoction has been used to treat diarrheas and DISEASE. However, there is no research on GFC effects in the central nervous system of rodents. The present study aimed to evaluate the GFC effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on amino acid (r-aminobutyric acid (GABA), CHEMICAL, aspartate and glutathione) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. GFC produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In aspartate, CHEMICAL and CHEMICAL levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the GABA and CHEMICAL contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine-induced seizures. Garcinielliptone FC (GFC) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat DISEASE in both humans and animals as well as the seed decoction has been used to treat diarrheas and inflammatory diseases. However, there is no research on GFC effects in the central nervous system of rodents. The present study aimed to evaluate the GFC effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on amino acid (r-aminobutyric acid (GABA), glutamine, aspartate and CHEMICAL) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. GFC produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In aspartate, glutamine and glutamate levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the GABA and glutamate contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine-induced seizures. Garcinielliptone FC (GFC) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat skin diseases in both humans and animals as well as the seed decoction has been used to treat DISEASE and inflammatory diseases. However, there is no research on GFC effects in the central nervous system of rodents. The present study aimed to evaluate the GFC effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on amino acid (r-aminobutyric acid (GABA), glutamine, aspartate and CHEMICAL) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. GFC produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In aspartate, glutamine and glutamate levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the GABA and glutamate contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine-induced seizures. Garcinielliptone FC (GFC) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat skin diseases in both humans and animals as well as the seed decoction has been used to treat diarrheas and DISEASE. However, there is no research on GFC effects in the central nervous system of rodents. The present study aimed to evaluate the GFC effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on CHEMICAL (r-aminobutyric acid (GABA), glutamine, aspartate and glutathione) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. GFC produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In aspartate, glutamine and glutamate levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the GABA and glutamate contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine-induced seizures. Garcinielliptone FC (GFC) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat skin diseases in both humans and animals as well as the seed decoction has been used to treat diarrheas and DISEASE. However, there is no research on GFC effects in the central nervous system of rodents. The present study aimed to evaluate the GFC effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on amino acid (r-aminobutyric acid (GABA), glutamine, CHEMICAL and glutathione) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. GFC produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In CHEMICAL, glutamine and glutamate levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the GABA and glutamate contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine-induced seizures. Garcinielliptone FC (GFC) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat DISEASE in both humans and animals as well as the seed decoction has been used to treat diarrheas and inflammatory diseases. However, there is no research on GFC effects in the central nervous system of rodents. The present study aimed to evaluate the GFC effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on amino acid (r-aminobutyric acid (GABA), glutamine, CHEMICAL and glutathione) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. GFC produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In CHEMICAL, glutamine and glutamate levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the GABA and glutamate contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine-induced seizures. Garcinielliptone FC (GFC) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat skin diseases in both humans and animals as well as the seed decoction has been used to treat diarrheas and DISEASE. However, there is no research on GFC effects in the central nervous system of rodents. The present study aimed to evaluate the GFC effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on amino acid (r-aminobutyric acid (GABA), glutamine, aspartate and CHEMICAL) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. GFC produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In aspartate, glutamine and glutamate levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the GABA and glutamate contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with garcinielliptone FC in pilocarpine-induced seizures. Garcinielliptone FC (GFC) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat DISEASE in both humans and animals as well as the seed decoction has been used to treat diarrheas and inflammatory diseases. However, there is no research on GFC effects in the central nervous system of rodents. The present study aimed to evaluate the GFC effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on amino acid (CHEMICAL (CHEMICAL), glutamine, aspartate and glutathione) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. GFC produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, CHEMICAL content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In aspartate, glutamine and glutamate levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that GFC can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that GFC may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the CHEMICAL and glutamate contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Behavioral and neurochemical studies in mice pretreated with CHEMICAL in pilocarpine-induced seizures. CHEMICAL (CHEMICAL) isolated from hexanic fraction seed extract of species Platonia insignis Mart. It is widely used in folk medicine to treat DISEASE in both humans and animals as well as the seed decoction has been used to treat diarrheas and inflammatory diseases. However, there is no research on CHEMICAL effects in the central nervous system of rodents. The present study aimed to evaluate the CHEMICAL effects at doses of 25, 50 or 75 mg/kg on seizure parameters to determine their anticonvulsant activity and its effects on amino acid (r-aminobutyric acid (GABA), glutamine, aspartate and glutathione) levels as well as on acetylcholinesterase (AChE) activity in mice hippocampus after seizures. CHEMICAL produced an increased latency to first seizure, at doses 25mg/kg (20.12 + 2.20 min), 50mg/kg (20.95 + 2.21 min) or 75 mg/kg (23.43 + 1.99 min) when compared with seized mice. In addition, GABA content of mice hippocampus treated with GFC75 plus P400 showed an increase of 46.90% when compared with seized mice. In aspartate, glutamine and glutamate levels detected a decrease of 5.21%, 13.55% and 21.80%, respectively in mice hippocampus treated with GFC75 plus P400 when compared with seized mice. Hippocampus mice treated with GFC75 plus P400 showed an increase in AChE activity (63.30%) when compared with seized mice. The results indicate that CHEMICAL can exert anticonvulsant activity and reduce the frequency of installation of pilocarpine-induced status epilepticus, as demonstrated by increase in latency to first seizure and decrease in mortality rate of animals. In conclusion, our data suggest that CHEMICAL may influence in epileptogenesis and promote anticonvulsant actions in pilocarpine model by modulating the GABA and glutamate contents and of AChE activity in seized mice hippocampus. This compound may be useful to produce neuronal protection and it can be considered as an anticonvulsant agent. | NO-RELATIONSHIP |
| Standard operating procedures for antibiotic therapy and the occurrence of DISEASE: a prospective, clinical, non-interventional, observational study. INTRODUCTION: DISEASE (DISEASE) occurs in 7% of hospitalized and 66% of Intensive Care Unit (ICU) patients. It increases mortality, hospital length of stay, and costs. The aim of this study was to investigate, whether there is an association between adherence to guidelines (standard operating procedures (SOP)) for potentially nephrotoxic antibiotics and the occurrence of DISEASE. METHODS: This study was carried out as a prospective, clinical, non-interventional, observational study. Data collection was performed over a total of 170 days in three ICUs at Charite - Universitaetsmedizin Berlin. A total of 675 patients were included; 163 of these had therapy with vancomycin, gentamicin, or CHEMICAL; were >18 years; and treated in the ICU for >24 hours. Patients with an adherence to SOP >70% were classified into the high adherence group (HAG) and patients with an adherence of <70% into the low adherence group (LAG). DISEASE was defined according to RIFLE criteria. Adherence to SOPs was evaluated by retrospective expert audit. Development of DISEASE was compared between groups with exact Chi2-test and multivariate logistic regression analysis (two-sided P <0.05). RESULTS: LAG consisted of 75 patients (46%) versus 88 HAG patients (54%). DISEASE occurred significantly more often in LAG with 36% versus 21% in HAG (P = 0.035). Basic characteristics were comparable, except an increased rate of soft tissue infections in LAG. Multivariate analysis revealed an odds ratio of 2.5-fold for LAG to develop DISEASE compared with HAG (95% confidence interval 1.195 to 5.124, P = 0.039). CONCLUSION: Low adherence to SOPs for potentially nephrotoxic antibiotics was associated with a higher occurrence of DISEASE. TRIAL REGISTRATION: Current Controlled Trials ISRCTN54598675. Registered 17 August 2007. | CHEMICAL-INDUCED-DISEASE |
| Standard operating procedures for antibiotic therapy and the occurrence of DISEASE: a prospective, clinical, non-interventional, observational study. INTRODUCTION: DISEASE (DISEASE) occurs in 7% of hospitalized and 66% of Intensive Care Unit (ICU) patients. It increases mortality, hospital length of stay, and costs. The aim of this study was to investigate, whether there is an association between adherence to guidelines (standard operating procedures (SOP)) for potentially nephrotoxic antibiotics and the occurrence of DISEASE. METHODS: This study was carried out as a prospective, clinical, non-interventional, observational study. Data collection was performed over a total of 170 days in three ICUs at Charite - Universitaetsmedizin Berlin. A total of 675 patients were included; 163 of these had therapy with CHEMICAL, gentamicin, or tobramycin; were >18 years; and treated in the ICU for >24 hours. Patients with an adherence to SOP >70% were classified into the high adherence group (HAG) and patients with an adherence of <70% into the low adherence group (LAG). DISEASE was defined according to RIFLE criteria. Adherence to SOPs was evaluated by retrospective expert audit. Development of DISEASE was compared between groups with exact Chi2-test and multivariate logistic regression analysis (two-sided P <0.05). RESULTS: LAG consisted of 75 patients (46%) versus 88 HAG patients (54%). DISEASE occurred significantly more often in LAG with 36% versus 21% in HAG (P = 0.035). Basic characteristics were comparable, except an increased rate of soft tissue infections in LAG. Multivariate analysis revealed an odds ratio of 2.5-fold for LAG to develop DISEASE compared with HAG (95% confidence interval 1.195 to 5.124, P = 0.039). CONCLUSION: Low adherence to SOPs for potentially nephrotoxic antibiotics was associated with a higher occurrence of DISEASE. TRIAL REGISTRATION: Current Controlled Trials ISRCTN54598675. Registered 17 August 2007. | CHEMICAL-INDUCED-DISEASE |
| Standard operating procedures for antibiotic therapy and the occurrence of DISEASE: a prospective, clinical, non-interventional, observational study. INTRODUCTION: DISEASE (DISEASE) occurs in 7% of hospitalized and 66% of Intensive Care Unit (ICU) patients. It increases mortality, hospital length of stay, and costs. The aim of this study was to investigate, whether there is an association between adherence to guidelines (standard operating procedures (SOP)) for potentially nephrotoxic antibiotics and the occurrence of DISEASE. METHODS: This study was carried out as a prospective, clinical, non-interventional, observational study. Data collection was performed over a total of 170 days in three ICUs at Charite - Universitaetsmedizin Berlin. A total of 675 patients were included; 163 of these had therapy with vancomycin, CHEMICAL, or tobramycin; were >18 years; and treated in the ICU for >24 hours. Patients with an adherence to SOP >70% were classified into the high adherence group (HAG) and patients with an adherence of <70% into the low adherence group (LAG). DISEASE was defined according to RIFLE criteria. Adherence to SOPs was evaluated by retrospective expert audit. Development of DISEASE was compared between groups with exact Chi2-test and multivariate logistic regression analysis (two-sided P <0.05). RESULTS: LAG consisted of 75 patients (46%) versus 88 HAG patients (54%). DISEASE occurred significantly more often in LAG with 36% versus 21% in HAG (P = 0.035). Basic characteristics were comparable, except an increased rate of soft tissue infections in LAG. Multivariate analysis revealed an odds ratio of 2.5-fold for LAG to develop DISEASE compared with HAG (95% confidence interval 1.195 to 5.124, P = 0.039). CONCLUSION: Low adherence to SOPs for potentially nephrotoxic antibiotics was associated with a higher occurrence of DISEASE. TRIAL REGISTRATION: Current Controlled Trials ISRCTN54598675. Registered 17 August 2007. | CHEMICAL-INDUCED-DISEASE |
| DISEASE in a hepatitis C virus infected patient treated with CHEMICAL and simvastatin. A 46-year old man with a chronic hepatitis C virus infection received triple therapy with ribavirin, pegylated interferon and CHEMICAL. The patient also received simvastatin. One month after starting the antiviral therapy, the patient was admitted to the hospital because he developed DISEASE. At admission simvastatin and all antiviral drugs were discontinued because toxicity due to a drug-drug interaction was suspected. The creatine kinase peaked at 62,246 IU/L and the patient was treated with intravenous normal saline. The patient's renal function remained unaffected. Fourteen days after hospitalization, creatine kinase level had returned to 230 IU/L and the patient was discharged. CHEMICAL was considered the probable causative agent of an interaction with simvastatin according to the Drug Interaction Probability Scale. The interaction is due to inhibition of CYP3A4-mediated simvastatin clearance. Simvastatin plasma concentration increased 30 times in this patient and statin induced muscle toxicity is related to the concentration of the statin in blood. In conclusion, with this case we illustrate that CHEMICAL as well as statins are susceptible to clinical relevant drug-drug interactions. | CHEMICAL-INDUCED-DISEASE |
| DISEASE in a hepatitis C virus infected patient treated with telaprevir and CHEMICAL. A 46-year old man with a chronic hepatitis C virus infection received triple therapy with ribavirin, pegylated interferon and telaprevir. The patient also received CHEMICAL. One month after starting the antiviral therapy, the patient was admitted to the hospital because he developed DISEASE. At admission CHEMICAL and all antiviral drugs were discontinued because toxicity due to a drug-drug interaction was suspected. The creatine kinase peaked at 62,246 IU/L and the patient was treated with intravenous normal saline. The patient's renal function remained unaffected. Fourteen days after hospitalization, creatine kinase level had returned to 230 IU/L and the patient was discharged. Telaprevir was considered the probable causative agent of an interaction with CHEMICAL according to the Drug Interaction Probability Scale. The interaction is due to inhibition of CYP3A4-mediated CHEMICAL clearance. CHEMICAL plasma concentration increased 30 times in this patient and CHEMICAL induced muscle toxicity is related to the concentration of the CHEMICAL in blood. In conclusion, with this case we illustrate that telaprevir as well as CHEMICAL are susceptible to clinical relevant drug-drug interactions. | CHEMICAL-INDUCED-DISEASE |
| Rhabdomyolysis in a hepatitis C virus infected patient treated with telaprevir and CHEMICAL. A 46-year old man with a chronic hepatitis C virus infection received triple therapy with ribavirin, pegylated interferon and telaprevir. The patient also received CHEMICAL. One month after starting the antiviral therapy, the patient was admitted to the hospital because he developed rhabdomyolysis. At admission CHEMICAL and all antiviral drugs were discontinued because toxicity due to a drug-drug interaction was suspected. The creatine kinase peaked at 62,246 IU/L and the patient was treated with intravenous normal saline. The patient's renal function remained unaffected. Fourteen days after hospitalization, creatine kinase level had returned to 230 IU/L and the patient was discharged. Telaprevir was considered the probable causative agent of an interaction with CHEMICAL according to the Drug Interaction Probability Scale. The interaction is due to inhibition of CYP3A4-mediated CHEMICAL clearance. CHEMICAL plasma concentration increased 30 times in this patient and CHEMICAL induced DISEASE is related to the concentration of the CHEMICAL in blood. In conclusion, with this case we illustrate that telaprevir as well as CHEMICAL are susceptible to clinical relevant drug-drug interactions. | CHEMICAL-INDUCED-DISEASE |
| Rhabdomyolysis in a hepatitis C virus infected patient treated with telaprevir and simvastatin. A 46-year old man with a chronic hepatitis C virus infection received triple therapy with ribavirin, pegylated interferon and telaprevir. The patient also received simvastatin. One month after starting the antiviral therapy, the patient was admitted to the hospital because he developed rhabdomyolysis. At admission simvastatin and all antiviral drugs were discontinued because DISEASE due to a drug-drug interaction was suspected. The CHEMICAL kinase peaked at 62,246 IU/L and the patient was treated with intravenous normal saline. The patient's renal function remained unaffected. Fourteen days after hospitalization, CHEMICAL kinase level had returned to 230 IU/L and the patient was discharged. Telaprevir was considered the probable causative agent of an interaction with simvastatin according to the Drug Interaction Probability Scale. The interaction is due to inhibition of CYP3A4-mediated simvastatin clearance. Simvastatin plasma concentration increased 30 times in this patient and statin induced muscle toxicity is related to the concentration of the statin in blood. In conclusion, with this case we illustrate that telaprevir as well as statins are susceptible to clinical relevant drug-drug interactions. | NO-RELATIONSHIP |
| Rhabdomyolysis in a DISEASE patient treated with telaprevir and simvastatin. A 46-year old man with a chronic DISEASE received triple therapy with CHEMICAL, pegylated interferon and telaprevir. The patient also received simvastatin. One month after starting the antiviral therapy, the patient was admitted to the hospital because he developed rhabdomyolysis. At admission simvastatin and all antiviral drugs were discontinued because toxicity due to a drug-drug interaction was suspected. The creatine kinase peaked at 62,246 IU/L and the patient was treated with intravenous normal saline. The patient's renal function remained unaffected. Fourteen days after hospitalization, creatine kinase level had returned to 230 IU/L and the patient was discharged. Telaprevir was considered the probable causative agent of an interaction with simvastatin according to the Drug Interaction Probability Scale. The interaction is due to inhibition of CYP3A4-mediated simvastatin clearance. Simvastatin plasma concentration increased 30 times in this patient and statin induced muscle toxicity is related to the concentration of the statin in blood. In conclusion, with this case we illustrate that telaprevir as well as statins are susceptible to clinical relevant drug-drug interactions. | NO-RELATIONSHIP |
| Rhabdomyolysis in a DISEASE patient treated with telaprevir and simvastatin. A 46-year old man with a chronic DISEASE received triple therapy with ribavirin, pegylated interferon and telaprevir. The patient also received simvastatin. One month after starting the antiviral therapy, the patient was admitted to the hospital because he developed rhabdomyolysis. At admission simvastatin and all antiviral drugs were discontinued because toxicity due to a drug-drug interaction was suspected. The CHEMICAL kinase peaked at 62,246 IU/L and the patient was treated with intravenous normal saline. The patient's renal function remained unaffected. Fourteen days after hospitalization, CHEMICAL kinase level had returned to 230 IU/L and the patient was discharged. Telaprevir was considered the probable causative agent of an interaction with simvastatin according to the Drug Interaction Probability Scale. The interaction is due to inhibition of CYP3A4-mediated simvastatin clearance. Simvastatin plasma concentration increased 30 times in this patient and statin induced muscle toxicity is related to the concentration of the statin in blood. In conclusion, with this case we illustrate that telaprevir as well as statins are susceptible to clinical relevant drug-drug interactions. | NO-RELATIONSHIP |
| Rhabdomyolysis in a DISEASE patient treated with telaprevir and simvastatin. A 46-year old man with a chronic DISEASE received triple therapy with ribavirin, CHEMICAL and telaprevir. The patient also received simvastatin. One month after starting the antiviral therapy, the patient was admitted to the hospital because he developed rhabdomyolysis. At admission simvastatin and all antiviral drugs were discontinued because toxicity due to a drug-drug interaction was suspected. The creatine kinase peaked at 62,246 IU/L and the patient was treated with intravenous normal saline. The patient's renal function remained unaffected. Fourteen days after hospitalization, creatine kinase level had returned to 230 IU/L and the patient was discharged. Telaprevir was considered the probable causative agent of an interaction with simvastatin according to the Drug Interaction Probability Scale. The interaction is due to inhibition of CYP3A4-mediated simvastatin clearance. Simvastatin plasma concentration increased 30 times in this patient and statin induced muscle toxicity is related to the concentration of the statin in blood. In conclusion, with this case we illustrate that telaprevir as well as statins are susceptible to clinical relevant drug-drug interactions. | NO-RELATIONSHIP |
| Rhabdomyolysis in a hepatitis C virus infected patient treated with telaprevir and simvastatin. A 46-year old man with a chronic hepatitis C virus infection received triple therapy with CHEMICAL, pegylated interferon and telaprevir. The patient also received simvastatin. One month after starting the antiviral therapy, the patient was admitted to the hospital because he developed rhabdomyolysis. At admission simvastatin and all antiviral drugs were discontinued because DISEASE due to a drug-drug interaction was suspected. The creatine kinase peaked at 62,246 IU/L and the patient was treated with intravenous normal saline. The patient's renal function remained unaffected. Fourteen days after hospitalization, creatine kinase level had returned to 230 IU/L and the patient was discharged. Telaprevir was considered the probable causative agent of an interaction with simvastatin according to the Drug Interaction Probability Scale. The interaction is due to inhibition of CYP3A4-mediated simvastatin clearance. Simvastatin plasma concentration increased 30 times in this patient and statin induced muscle toxicity is related to the concentration of the statin in blood. In conclusion, with this case we illustrate that telaprevir as well as statins are susceptible to clinical relevant drug-drug interactions. | NO-RELATIONSHIP |
| Rhabdomyolysis in a hepatitis C virus infected patient treated with telaprevir and simvastatin. A 46-year old man with a chronic hepatitis C virus infection received triple therapy with ribavirin, CHEMICAL and telaprevir. The patient also received simvastatin. One month after starting the antiviral therapy, the patient was admitted to the hospital because he developed rhabdomyolysis. At admission simvastatin and all antiviral drugs were discontinued because DISEASE due to a drug-drug interaction was suspected. The creatine kinase peaked at 62,246 IU/L and the patient was treated with intravenous normal saline. The patient's renal function remained unaffected. Fourteen days after hospitalization, creatine kinase level had returned to 230 IU/L and the patient was discharged. Telaprevir was considered the probable causative agent of an interaction with simvastatin according to the Drug Interaction Probability Scale. The interaction is due to inhibition of CYP3A4-mediated simvastatin clearance. Simvastatin plasma concentration increased 30 times in this patient and statin induced muscle toxicity is related to the concentration of the statin in blood. In conclusion, with this case we illustrate that telaprevir as well as statins are susceptible to clinical relevant drug-drug interactions. | NO-RELATIONSHIP |
| Combination of bortezomib, thalidomide, and CHEMICAL (VTD) as a consolidation therapy after autologous stem cell transplantation for symptomatic multiple myeloma in Japanese patients. Consolidation therapy for patients with multiple myeloma (MM) has been widely adopted to improve treatment response following autologous stem cell transplantation. In this study, we retrospectively analyzed the safety and efficacy of combination regimen of bortezomib, thalidomide, and CHEMICAL (VTD) as consolidation therapy in 24 Japanese patients with newly diagnosed MM. VTD consisted of bortezomib at a dose of 1.3 mg/m(2) and CHEMICAL at a dose of 40 mg/day on days 1, 8, 15, and 22 of a 35-day cycle, with daily oral thalidomide at a dose of 100 mg/day. Grade 3-4 neutropenia and thrombocytopenia were documented in four and three patients (17 and 13 %), respectively, but drug dose reduction due to cytopenia was not required in any case. DISEASE was common (63 %), but severe grade 3-4 DISEASE was not observed. Very good partial response or better response (>VGPR) rates before and after consolidation therapy were 54 and 79 %, respectively. Patients had a significant probability of improving from | CHEMICAL-INDUCED-DISEASE |
| Combination of bortezomib, CHEMICAL, and dexamethasone (VTD) as a consolidation therapy after autologous stem cell transplantation for symptomatic multiple myeloma in Japanese patients. Consolidation therapy for patients with multiple myeloma (MM) has been widely adopted to improve treatment response following autologous stem cell transplantation. In this study, we retrospectively analyzed the safety and efficacy of combination regimen of bortezomib, CHEMICAL, and dexamethasone (VTD) as consolidation therapy in 24 Japanese patients with newly diagnosed MM. VTD consisted of bortezomib at a dose of 1.3 mg/m(2) and dexamethasone at a dose of 40 mg/day on days 1, 8, 15, and 22 of a 35-day cycle, with daily oral CHEMICAL at a dose of 100 mg/day. Grade 3-4 neutropenia and thrombocytopenia were documented in four and three patients (17 and 13 %), respectively, but drug dose reduction due to cytopenia was not required in any case. DISEASE was common (63 %), but severe grade 3-4 DISEASE was not observed. Very good partial response or better response (>VGPR) rates before and after consolidation therapy were 54 and 79 %, respectively. Patients had a significant probability of improving from | CHEMICAL-INDUCED-DISEASE |
| Combination of CHEMICAL, thalidomide, and dexamethasone (VTD) as a consolidation therapy after autologous stem cell transplantation for symptomatic multiple myeloma in Japanese patients. Consolidation therapy for patients with multiple myeloma (MM) has been widely adopted to improve treatment response following autologous stem cell transplantation. In this study, we retrospectively analyzed the safety and efficacy of combination regimen of CHEMICAL, thalidomide, and dexamethasone (VTD) as consolidation therapy in 24 Japanese patients with newly diagnosed MM. VTD consisted of CHEMICAL at a dose of 1.3 mg/m(2) and dexamethasone at a dose of 40 mg/day on days 1, 8, 15, and 22 of a 35-day cycle, with daily oral thalidomide at a dose of 100 mg/day. Grade 3-4 DISEASE and thrombocytopenia were documented in four and three patients (17 and 13 %), respectively, but drug dose reduction due to cytopenia was not required in any case. Peripheral neuropathy was common (63 %), but severe grade 3-4 peripheral neuropathy was not observed. Very good partial response or better response (>VGPR) rates before and after consolidation therapy were 54 and 79 %, respectively. Patients had a significant probability of improving from | CHEMICAL-INDUCED-DISEASE |
| Combination of bortezomib, CHEMICAL, and dexamethasone (VTD) as a consolidation therapy after autologous stem cell transplantation for symptomatic multiple myeloma in Japanese patients. Consolidation therapy for patients with multiple myeloma (MM) has been widely adopted to improve treatment response following autologous stem cell transplantation. In this study, we retrospectively analyzed the safety and efficacy of combination regimen of bortezomib, CHEMICAL, and dexamethasone (VTD) as consolidation therapy in 24 Japanese patients with newly diagnosed MM. VTD consisted of bortezomib at a dose of 1.3 mg/m(2) and dexamethasone at a dose of 40 mg/day on days 1, 8, 15, and 22 of a 35-day cycle, with daily oral CHEMICAL at a dose of 100 mg/day. Grade 3-4 neutropenia and DISEASE were documented in four and three patients (17 and 13 %), respectively, but drug dose reduction due to cytopenia was not required in any case. Peripheral neuropathy was common (63 %), but severe grade 3-4 peripheral neuropathy was not observed. Very good partial response or better response (>VGPR) rates before and after consolidation therapy were 54 and 79 %, respectively. Patients had a significant probability of improving from | CHEMICAL-INDUCED-DISEASE |
| Combination of CHEMICAL, thalidomide, and dexamethasone (VTD) as a consolidation therapy after autologous stem cell transplantation for symptomatic multiple myeloma in Japanese patients. Consolidation therapy for patients with multiple myeloma (MM) has been widely adopted to improve treatment response following autologous stem cell transplantation. In this study, we retrospectively analyzed the safety and efficacy of combination regimen of CHEMICAL, thalidomide, and dexamethasone (VTD) as consolidation therapy in 24 Japanese patients with newly diagnosed MM. VTD consisted of CHEMICAL at a dose of 1.3 mg/m(2) and dexamethasone at a dose of 40 mg/day on days 1, 8, 15, and 22 of a 35-day cycle, with daily oral thalidomide at a dose of 100 mg/day. Grade 3-4 neutropenia and DISEASE were documented in four and three patients (17 and 13 %), respectively, but drug dose reduction due to cytopenia was not required in any case. Peripheral neuropathy was common (63 %), but severe grade 3-4 peripheral neuropathy was not observed. Very good partial response or better response (>VGPR) rates before and after consolidation therapy were 54 and 79 %, respectively. Patients had a significant probability of improving from | CHEMICAL-INDUCED-DISEASE |
| Combination of bortezomib, CHEMICAL, and dexamethasone (VTD) as a consolidation therapy after autologous stem cell transplantation for symptomatic multiple myeloma in Japanese patients. Consolidation therapy for patients with multiple myeloma (MM) has been widely adopted to improve treatment response following autologous stem cell transplantation. In this study, we retrospectively analyzed the safety and efficacy of combination regimen of bortezomib, CHEMICAL, and dexamethasone (VTD) as consolidation therapy in 24 Japanese patients with newly diagnosed MM. VTD consisted of bortezomib at a dose of 1.3 mg/m(2) and dexamethasone at a dose of 40 mg/day on days 1, 8, 15, and 22 of a 35-day cycle, with daily oral CHEMICAL at a dose of 100 mg/day. Grade 3-4 DISEASE and thrombocytopenia were documented in four and three patients (17 and 13 %), respectively, but drug dose reduction due to cytopenia was not required in any case. Peripheral neuropathy was common (63 %), but severe grade 3-4 peripheral neuropathy was not observed. Very good partial response or better response (>VGPR) rates before and after consolidation therapy were 54 and 79 %, respectively. Patients had a significant probability of improving from | CHEMICAL-INDUCED-DISEASE |
| Combination of CHEMICAL, thalidomide, and dexamethasone (VTD) as a consolidation therapy after autologous stem cell transplantation for symptomatic multiple myeloma in Japanese patients. Consolidation therapy for patients with multiple myeloma (MM) has been widely adopted to improve treatment response following autologous stem cell transplantation. In this study, we retrospectively analyzed the safety and efficacy of combination regimen of CHEMICAL, thalidomide, and dexamethasone (VTD) as consolidation therapy in 24 Japanese patients with newly diagnosed MM. VTD consisted of CHEMICAL at a dose of 1.3 mg/m(2) and dexamethasone at a dose of 40 mg/day on days 1, 8, 15, and 22 of a 35-day cycle, with daily oral thalidomide at a dose of 100 mg/day. Grade 3-4 neutropenia and thrombocytopenia were documented in four and three patients (17 and 13 %), respectively, but drug dose reduction due to cytopenia was not required in any case. DISEASE was common (63 %), but severe grade 3-4 DISEASE was not observed. Very good partial response or better response (>VGPR) rates before and after consolidation therapy were 54 and 79 %, respectively. Patients had a significant probability of improving from | CHEMICAL-INDUCED-DISEASE |
| Combination of bortezomib, thalidomide, and CHEMICAL (VTD) as a consolidation therapy after autologous stem cell transplantation for symptomatic multiple myeloma in Japanese patients. Consolidation therapy for patients with multiple myeloma (MM) has been widely adopted to improve treatment response following autologous stem cell transplantation. In this study, we retrospectively analyzed the safety and efficacy of combination regimen of bortezomib, thalidomide, and CHEMICAL (VTD) as consolidation therapy in 24 Japanese patients with newly diagnosed MM. VTD consisted of bortezomib at a dose of 1.3 mg/m(2) and CHEMICAL at a dose of 40 mg/day on days 1, 8, 15, and 22 of a 35-day cycle, with daily oral thalidomide at a dose of 100 mg/day. Grade 3-4 neutropenia and DISEASE were documented in four and three patients (17 and 13 %), respectively, but drug dose reduction due to cytopenia was not required in any case. Peripheral neuropathy was common (63 %), but severe grade 3-4 peripheral neuropathy was not observed. Very good partial response or better response (>VGPR) rates before and after consolidation therapy were 54 and 79 %, respectively. Patients had a significant probability of improving from | CHEMICAL-INDUCED-DISEASE |
| Combination of bortezomib, thalidomide, and CHEMICAL (VTD) as a consolidation therapy after autologous stem cell transplantation for symptomatic multiple myeloma in Japanese patients. Consolidation therapy for patients with multiple myeloma (MM) has been widely adopted to improve treatment response following autologous stem cell transplantation. In this study, we retrospectively analyzed the safety and efficacy of combination regimen of bortezomib, thalidomide, and CHEMICAL (VTD) as consolidation therapy in 24 Japanese patients with newly diagnosed MM. VTD consisted of bortezomib at a dose of 1.3 mg/m(2) and CHEMICAL at a dose of 40 mg/day on days 1, 8, 15, and 22 of a 35-day cycle, with daily oral thalidomide at a dose of 100 mg/day. Grade 3-4 DISEASE and thrombocytopenia were documented in four and three patients (17 and 13 %), respectively, but drug dose reduction due to cytopenia was not required in any case. Peripheral neuropathy was common (63 %), but severe grade 3-4 peripheral neuropathy was not observed. Very good partial response or better response (>VGPR) rates before and after consolidation therapy were 54 and 79 %, respectively. Patients had a significant probability of improving from | CHEMICAL-INDUCED-DISEASE |
| Conversion to sirolimus ameliorates CHEMICAL-induced DISEASE in the rat: focus on serum, urine, gene, and protein renal expression biomarkers. Protocols of conversion from CHEMICAL (CHEMICAL) to sirolimus (SRL) have been widely used in immunotherapy after transplantation to prevent CHEMICAL-induced DISEASE, but the molecular mechanisms underlying these protocols remain nuclear. This study aimed to identify the molecular pathways and putative biomarkers of CHEMICAL-to-SRL conversion in a rat model. Four animal groups (n = 6) were tested during 9 weeks: control, CHEMICAL, SRL, and conversion (CHEMICAL for 3 weeks followed by SRL for 6 weeks). Classical and emergent serum, urinary, and kidney tissue (gene and protein expression) markers were assessed. DISEASE were analyzed in hematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome stains. SRL-treated rats presented proteinuria and NGAL (serum and urinary) as the best markers of DISEASE. Short CHEMICAL treatment presented slight or even absent DISEASE and TGF-b, NF- kb, mTOR, PCNA, TP53, KIM-1, and CTGF as relevant gene and protein changes. Prolonged CHEMICAL exposure aggravated DISEASE, without clear changes on the traditional markers, but with changes in serums TGF- b and IL-7, TBARs clearance, and kidney TGF-b and mTOR. Conversion to SRL prevented CHEMICAL-induced DISEASE evolution (absent/mild grade lesions), while NGAL (serum versus urine) seems to be a feasible biomarker of CHEMICAL replacement to SRL. | CHEMICAL-INDUCED-DISEASE |
| Conversion to CHEMICAL ameliorates cyclosporine-induced nephropathy in the rat: focus on serum, urine, gene, and protein renal expression biomarkers. Protocols of conversion from cyclosporin A (CsA) to CHEMICAL (CHEMICAL) have been widely used in immunotherapy after transplantation to prevent CsA-induced nephropathy, but the molecular mechanisms underlying these protocols remain nuclear. This study aimed to identify the molecular pathways and putative biomarkers of CsA-to-CHEMICAL conversion in a rat model. Four animal groups (n = 6) were tested during 9 weeks: control, CsA, CHEMICAL, and conversion (CsA for 3 weeks followed by CHEMICAL for 6 weeks). Classical and emergent serum, urinary, and kidney tissue (gene and protein expression) markers were assessed. Renal lesions were analyzed in hematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome stains. CHEMICAL-treated rats presented DISEASE and NGAL (serum and urinary) as the best markers of renal impairment. Short CsA treatment presented slight or even absent kidney lesions and TGF-b, NF- kb, mTOR, PCNA, TP53, KIM-1, and CTGF as relevant gene and protein changes. Prolonged CsA exposure aggravated renal damage, without clear changes on the traditional markers, but with changes in serums TGF- b and IL-7, TBARs clearance, and kidney TGF-b and mTOR. Conversion to CHEMICAL prevented CsA-induced renal damage evolution (absent/mild grade lesions), while NGAL (serum versus urine) seems to be a feasible biomarker of CsA replacement to CHEMICAL. | NO-RELATIONSHIP |
| Kinin B2 receptor deletion and blockage ameliorates CHEMICAL-induced acute renal injury. CHEMICAL treatment has been adopted in some chemotherapies; however, this drug can induce acute kidney injury due its ability to negatively affect renal function, augment serum levels of creatinine and urea, increase the DISEASE score and up-regulate cytokines (e.g., IL-1b and TNF-a). The kinin B2 receptor has been associated with the inflammation process, as well as the regulation of cytokine expression, and its deletion resulted in an improvement in the diabetic nephropathy status. To examine the role of the kinin B2 receptor in CHEMICAL-induced acute kidney injury, kinin B2 receptor knockout mice were challenged with CHEMICAL. Additionally, WT mice were treated with a B2 receptor antagonist after CHEMICAL administration. B2 receptor-deficient mice were less sensitive to this drug than the WT mice, as shown by reduced weight loss, better preservation of kidney function, down regulation of inflammatory cytokines and less DISEASE. Moreover, treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum creatinine and blood urea after CHEMICAL administration. Thus, our data suggest that the kinin B2 receptor is involved in CHEMICAL-induced acute kidney injury by mediating the necrotic process and the expression of inflammatory cytokines, thus resulting in declined renal function. These results highlight the kinin B2 receptor antagonist treatment in amelioration of nephrotoxicity induced by CHEMICAL therapy. | CHEMICAL-INDUCED-DISEASE |
| Kinin B2 receptor deletion and blockage ameliorates CHEMICAL-induced DISEASE. CHEMICAL treatment has been adopted in some chemotherapies; however, this drug can induce DISEASE due its ability to negatively affect renal function, augment serum levels of creatinine and urea, increase the acute tubular necrosis score and up-regulate cytokines (e.g., IL-1b and TNF-a). The kinin B2 receptor has been associated with the inflammation process, as well as the regulation of cytokine expression, and its deletion resulted in an improvement in the diabetic nephropathy status. To examine the role of the kinin B2 receptor in CHEMICAL-induced DISEASE, kinin B2 receptor knockout mice were challenged with CHEMICAL. Additionally, WT mice were treated with a B2 receptor antagonist after CHEMICAL administration. B2 receptor-deficient mice were less sensitive to this drug than the WT mice, as shown by reduced weight loss, better preservation of kidney function, down regulation of inflammatory cytokines and less acute tubular necrosis. Moreover, treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum creatinine and blood urea after CHEMICAL administration. Thus, our data suggest that the kinin B2 receptor is involved in CHEMICAL-induced DISEASE by mediating the necrotic process and the expression of inflammatory cytokines, thus resulting in declined renal function. These results highlight the kinin B2 receptor antagonist treatment in amelioration of nephrotoxicity induced by CHEMICAL therapy. | CHEMICAL-INDUCED-DISEASE |
| Kinin B2 receptor deletion and blockage ameliorates CHEMICAL-induced acute renal injury. CHEMICAL treatment has been adopted in some chemotherapies; however, this drug can induce acute kidney injury due its ability to negatively affect renal function, augment serum levels of creatinine and urea, increase the acute tubular necrosis score and up-regulate cytokines (e.g., IL-1b and TNF-a). The kinin B2 receptor has been associated with the inflammation process, as well as the regulation of cytokine expression, and its deletion resulted in an improvement in the diabetic nephropathy status. To examine the role of the kinin B2 receptor in CHEMICAL-induced acute kidney injury, kinin B2 receptor knockout mice were challenged with CHEMICAL. Additionally, WT mice were treated with a B2 receptor antagonist after CHEMICAL administration. B2 receptor-deficient mice were less sensitive to this drug than the WT mice, as shown by reduced DISEASE, better preservation of kidney function, down regulation of inflammatory cytokines and less acute tubular necrosis. Moreover, treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum creatinine and blood urea after CHEMICAL administration. Thus, our data suggest that the kinin B2 receptor is involved in CHEMICAL-induced acute kidney injury by mediating the necrotic process and the expression of inflammatory cytokines, thus resulting in declined renal function. These results highlight the kinin B2 receptor antagonist treatment in amelioration of nephrotoxicity induced by CHEMICAL therapy. | CHEMICAL-INDUCED-DISEASE |
| Kinin B2 receptor deletion and blockage ameliorates cisplatin-induced acute renal injury. Cisplatin treatment has been adopted in some chemotherapies; however, this drug can induce acute kidney injury due its ability to negatively affect renal function, augment serum levels of CHEMICAL and urea, increase the acute tubular necrosis score and up-regulate cytokines (e.g., IL-1b and TNF-a). The kinin B2 receptor has been associated with the inflammation process, as well as the regulation of cytokine expression, and its deletion resulted in an improvement in the DISEASE status. To examine the role of the kinin B2 receptor in cisplatin-induced acute kidney injury, kinin B2 receptor knockout mice were challenged with cisplatin. Additionally, WT mice were treated with a B2 receptor antagonist after cisplatin administration. B2 receptor-deficient mice were less sensitive to this drug than the WT mice, as shown by reduced weight loss, better preservation of kidney function, down regulation of inflammatory cytokines and less acute tubular necrosis. Moreover, treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum CHEMICAL and blood urea after cisplatin administration. Thus, our data suggest that the kinin B2 receptor is involved in cisplatin-induced acute kidney injury by mediating the necrotic process and the expression of inflammatory cytokines, thus resulting in declined renal function. These results highlight the kinin B2 receptor antagonist treatment in amelioration of nephrotoxicity induced by cisplatin therapy. | NO-RELATIONSHIP |
| Kinin B2 receptor deletion and blockage ameliorates cisplatin-induced acute renal injury. Cisplatin treatment has been adopted in some chemotherapies; however, this drug can induce acute kidney injury due its ability to negatively affect renal function, augment serum levels of creatinine and CHEMICAL, increase the acute tubular necrosis score and up-regulate cytokines (e.g., IL-1b and TNF-a). The kinin B2 receptor has been associated with the inflammation process, as well as the regulation of cytokine expression, and its deletion resulted in an improvement in the DISEASE status. To examine the role of the kinin B2 receptor in cisplatin-induced acute kidney injury, kinin B2 receptor knockout mice were challenged with cisplatin. Additionally, WT mice were treated with a B2 receptor antagonist after cisplatin administration. B2 receptor-deficient mice were less sensitive to this drug than the WT mice, as shown by reduced weight loss, better preservation of kidney function, down regulation of inflammatory cytokines and less acute tubular necrosis. Moreover, treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum creatinine and blood CHEMICAL after cisplatin administration. Thus, our data suggest that the kinin B2 receptor is involved in cisplatin-induced acute kidney injury by mediating the necrotic process and the expression of inflammatory cytokines, thus resulting in declined renal function. These results highlight the kinin B2 receptor antagonist treatment in amelioration of nephrotoxicity induced by cisplatin therapy. | NO-RELATIONSHIP |
| Kinin B2 receptor deletion and blockage ameliorates cisplatin-induced acute renal injury. Cisplatin treatment has been adopted in some chemotherapies; however, this drug can induce acute kidney injury due its ability to negatively affect renal function, augment serum levels of creatinine and CHEMICAL, increase the acute tubular necrosis score and up-regulate cytokines (e.g., IL-1b and TNF-a). The kinin B2 receptor has been associated with the inflammation process, as well as the regulation of cytokine expression, and its deletion resulted in an improvement in the diabetic nephropathy status. To examine the role of the kinin B2 receptor in cisplatin-induced acute kidney injury, kinin B2 receptor knockout mice were challenged with cisplatin. Additionally, WT mice were treated with a B2 receptor antagonist after cisplatin administration. B2 receptor-deficient mice were less sensitive to this drug than the WT mice, as shown by reduced weight loss, better preservation of kidney function, down regulation of inflammatory cytokines and less acute tubular necrosis. Moreover, treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum creatinine and blood CHEMICAL after cisplatin administration. Thus, our data suggest that the kinin B2 receptor is involved in cisplatin-induced acute kidney injury by mediating the DISEASE process and the expression of inflammatory cytokines, thus resulting in declined renal function. These results highlight the kinin B2 receptor antagonist treatment in amelioration of nephrotoxicity induced by cisplatin therapy. | NO-RELATIONSHIP |
| Kinin B2 receptor deletion and blockage ameliorates cisplatin-induced acute renal injury. Cisplatin treatment has been adopted in some chemotherapies; however, this drug can induce acute kidney injury due its ability to negatively affect renal function, augment serum levels of creatinine and CHEMICAL, increase the acute tubular necrosis score and up-regulate cytokines (e.g., IL-1b and TNF-a). The kinin B2 receptor has been associated with the inflammation process, as well as the regulation of cytokine expression, and its deletion resulted in an improvement in the diabetic nephropathy status. To examine the role of the kinin B2 receptor in cisplatin-induced acute kidney injury, kinin B2 receptor knockout mice were challenged with cisplatin. Additionally, WT mice were treated with a B2 receptor antagonist after cisplatin administration. B2 receptor-deficient mice were less sensitive to this drug than the WT mice, as shown by reduced weight loss, better preservation of kidney function, down regulation of inflammatory cytokines and less acute tubular necrosis. Moreover, treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum creatinine and blood CHEMICAL after cisplatin administration. Thus, our data suggest that the kinin B2 receptor is involved in cisplatin-induced acute kidney injury by mediating the necrotic process and the expression of inflammatory cytokines, thus resulting in declined renal function. These results highlight the kinin B2 receptor antagonist treatment in amelioration of DISEASE induced by cisplatin therapy. | NO-RELATIONSHIP |
| Kinin B2 receptor deletion and blockage ameliorates cisplatin-induced acute renal injury. Cisplatin treatment has been adopted in some chemotherapies; however, this drug can induce acute kidney injury due its ability to negatively affect renal function, augment serum levels of creatinine and CHEMICAL, increase the acute tubular necrosis score and up-regulate cytokines (e.g., IL-1b and TNF-a). The kinin B2 receptor has been associated with the DISEASE process, as well as the regulation of cytokine expression, and its deletion resulted in an improvement in the diabetic nephropathy status. To examine the role of the kinin B2 receptor in cisplatin-induced acute kidney injury, kinin B2 receptor knockout mice were challenged with cisplatin. Additionally, WT mice were treated with a B2 receptor antagonist after cisplatin administration. B2 receptor-deficient mice were less sensitive to this drug than the WT mice, as shown by reduced weight loss, better preservation of kidney function, down regulation of inflammatory cytokines and less acute tubular necrosis. Moreover, treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum creatinine and blood CHEMICAL after cisplatin administration. Thus, our data suggest that the kinin B2 receptor is involved in cisplatin-induced acute kidney injury by mediating the necrotic process and the expression of inflammatory cytokines, thus resulting in declined renal function. These results highlight the kinin B2 receptor antagonist treatment in amelioration of nephrotoxicity induced by cisplatin therapy. | NO-RELATIONSHIP |
| Kinin B2 receptor deletion and blockage ameliorates cisplatin-induced acute renal injury. Cisplatin treatment has been adopted in some chemotherapies; however, this drug can induce acute kidney injury due its ability to negatively affect renal function, augment serum levels of CHEMICAL and urea, increase the acute tubular necrosis score and up-regulate cytokines (e.g., IL-1b and TNF-a). The kinin B2 receptor has been associated with the DISEASE process, as well as the regulation of cytokine expression, and its deletion resulted in an improvement in the diabetic nephropathy status. To examine the role of the kinin B2 receptor in cisplatin-induced acute kidney injury, kinin B2 receptor knockout mice were challenged with cisplatin. Additionally, WT mice were treated with a B2 receptor antagonist after cisplatin administration. B2 receptor-deficient mice were less sensitive to this drug than the WT mice, as shown by reduced weight loss, better preservation of kidney function, down regulation of inflammatory cytokines and less acute tubular necrosis. Moreover, treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum CHEMICAL and blood urea after cisplatin administration. Thus, our data suggest that the kinin B2 receptor is involved in cisplatin-induced acute kidney injury by mediating the necrotic process and the expression of inflammatory cytokines, thus resulting in declined renal function. These results highlight the kinin B2 receptor antagonist treatment in amelioration of nephrotoxicity induced by cisplatin therapy. | NO-RELATIONSHIP |
| Kinin B2 receptor deletion and blockage ameliorates cisplatin-induced acute renal injury. Cisplatin treatment has been adopted in some chemotherapies; however, this drug can induce acute kidney injury due its ability to negatively affect renal function, augment serum levels of CHEMICAL and urea, increase the acute tubular necrosis score and up-regulate cytokines (e.g., IL-1b and TNF-a). The kinin B2 receptor has been associated with the inflammation process, as well as the regulation of cytokine expression, and its deletion resulted in an improvement in the diabetic nephropathy status. To examine the role of the kinin B2 receptor in cisplatin-induced acute kidney injury, kinin B2 receptor knockout mice were challenged with cisplatin. Additionally, WT mice were treated with a B2 receptor antagonist after cisplatin administration. B2 receptor-deficient mice were less sensitive to this drug than the WT mice, as shown by reduced weight loss, better preservation of kidney function, down regulation of inflammatory cytokines and less acute tubular necrosis. Moreover, treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum CHEMICAL and blood urea after cisplatin administration. Thus, our data suggest that the kinin B2 receptor is involved in cisplatin-induced acute kidney injury by mediating the DISEASE process and the expression of inflammatory cytokines, thus resulting in declined renal function. These results highlight the kinin B2 receptor antagonist treatment in amelioration of nephrotoxicity induced by cisplatin therapy. | NO-RELATIONSHIP |
| Kinin B2 receptor deletion and blockage ameliorates cisplatin-induced acute renal injury. Cisplatin treatment has been adopted in some chemotherapies; however, this drug can induce acute kidney injury due its ability to negatively affect renal function, augment serum levels of CHEMICAL and urea, increase the acute tubular necrosis score and up-regulate cytokines (e.g., IL-1b and TNF-a). The kinin B2 receptor has been associated with the inflammation process, as well as the regulation of cytokine expression, and its deletion resulted in an improvement in the diabetic nephropathy status. To examine the role of the kinin B2 receptor in cisplatin-induced acute kidney injury, kinin B2 receptor knockout mice were challenged with cisplatin. Additionally, WT mice were treated with a B2 receptor antagonist after cisplatin administration. B2 receptor-deficient mice were less sensitive to this drug than the WT mice, as shown by reduced weight loss, better preservation of kidney function, down regulation of inflammatory cytokines and less acute tubular necrosis. Moreover, treatment with the kinin B2 receptor antagonist effectively reduced the levels of serum CHEMICAL and blood urea after cisplatin administration. Thus, our data suggest that the kinin B2 receptor is involved in cisplatin-induced acute kidney injury by mediating the necrotic process and the expression of inflammatory cytokines, thus resulting in declined renal function. These results highlight the kinin B2 receptor antagonist treatment in amelioration of DISEASE induced by cisplatin therapy. | NO-RELATIONSHIP |
| Safety and efficacy of CHEMICAL intravitreal implant (0.59 mg) in birdshot retinochoroidopathy. PURPOSE: To report the treatment outcomes of the CHEMICAL intravitreal implant (0.59 mg) in patients with birdshot retinochoroidopathy whose disease is refractory or intolerant to conventional immunomodulatory therapy. METHODS: A retrospective case series involving 11 birdshot retinochoroidopathy patients (11 eyes). Eleven patients (11 eyes) underwent surgery for CHEMICAL implant (0.59 mg). Treatment outcomes of interest were noted at baseline, before CHEMICAL implant, and then at 6 months, 1 year, 2 years, 3 years, and beyond 3 years. Disease activity markers, including signs of ocular inflammation, evidence of retinal vasculitis, Swedish interactive threshold algorithm-short wavelength automated perimetry Humphrey visual field analysis, electroretinographic parameters, and optical coherence tomography were recorded. Data on occurrence of cataract and DISEASE were collected in all eyes. RESULTS: Intraocular inflammation was present in 54.5, 9.9, 11.1, and 0% of patients at baseline, 6 months, 1 year, 2 years, 3 years, and beyond 3 years after receiving the implant, respectively. Active vasculitis was noted in 36.3% patients at baseline and 0% at 3 years of follow-up. More than 20% (47.61-67.2%) reduction in central retinal thickness was noted in all patients with cystoid macular edema at 6 months, 1 year, 2 years, and 3 years postimplant. At baseline, 54.5% patients were on immunomodulatory agents. This percentage decreased to 45.45, 44.4, and 14.28% at 1 year, 2 years, and 3 years postimplant, respectively. Adverse events included DISEASE (54.5%) and cataract formation (100%). CONCLUSION: The data suggest that CHEMICAL implant (0.59 mg) helps to control inflammation in otherwise treatment-refractory cases of birdshot retinochoroidopathy. It is associated with significant side effects of cataract and DISEASE requiring treatment. | CHEMICAL-INDUCED-DISEASE |
| Safety and efficacy of CHEMICAL intravitreal implant (0.59 mg) in birdshot retinochoroidopathy. PURPOSE: To report the treatment outcomes of the CHEMICAL intravitreal implant (0.59 mg) in patients with birdshot retinochoroidopathy whose disease is refractory or intolerant to conventional immunomodulatory therapy. METHODS: A retrospective case series involving 11 birdshot retinochoroidopathy patients (11 eyes). Eleven patients (11 eyes) underwent surgery for CHEMICAL implant (0.59 mg). Treatment outcomes of interest were noted at baseline, before CHEMICAL implant, and then at 6 months, 1 year, 2 years, 3 years, and beyond 3 years. Disease activity markers, including signs of ocular inflammation, evidence of retinal vasculitis, Swedish interactive threshold algorithm-short wavelength automated perimetry Humphrey visual field analysis, electroretinographic parameters, and optical coherence tomography were recorded. Data on occurrence of DISEASE and raised intraocular pressure were collected in all eyes. RESULTS: Intraocular inflammation was present in 54.5, 9.9, 11.1, and 0% of patients at baseline, 6 months, 1 year, 2 years, 3 years, and beyond 3 years after receiving the implant, respectively. Active vasculitis was noted in 36.3% patients at baseline and 0% at 3 years of follow-up. More than 20% (47.61-67.2%) reduction in central retinal thickness was noted in all patients with cystoid macular edema at 6 months, 1 year, 2 years, and 3 years postimplant. At baseline, 54.5% patients were on immunomodulatory agents. This percentage decreased to 45.45, 44.4, and 14.28% at 1 year, 2 years, and 3 years postimplant, respectively. Adverse events included increased intraocular pressure (54.5%) and DISEASE formation (100%). CONCLUSION: The data suggest that CHEMICAL implant (0.59 mg) helps to control inflammation in otherwise treatment-refractory cases of birdshot retinochoroidopathy. It is associated with significant side effects of DISEASE and ocular hypertension requiring treatment. | CHEMICAL-INDUCED-DISEASE |
| Optimal precurarizing dose of rocuronium to decrease DISEASE and myalgia following CHEMICAL administration. BACKGROUND: CHEMICAL commonly produces frequent adverse effects, including DISEASE and myalgia. The current study identified the optimal dose of rocuronium to prevent CHEMICAL-induced DISEASE and myalgia and evaluated the influence of rocuronium on the speed of onset produced by CHEMICAL. METHODS: This randomized, double-blinded study was conducted in 100 patients randomly allocated into five groups of 20 patients each. Patients were randomized to receive 0.02, 0.03, 0.04, 0.05 and 0.06 mg/kg rocuronium as a precurarizing dose. Neuromuscular monitoring after each precurarizing dose was recorded from the adductor pollicis muscle using acceleromyography with train-of-four stimulation of the ulnar nerve. All patients received CHEMICAL 1.5 mg/kg at 2 minutes after the precurarization, and were assessed the incidence and severity of DISEASE, while myalgia was assessed at 24 hours after surgery. RESULTS: The incidence and severity of visible DISEASE was significantly less with increasing the amount of precurarizing dose of rocuronium (P < 0.001). Those of myalgia tend to decrease according to increasing the amount of precurarizing dose of rocuronium, but there was no significance (P = 0.072). The onset time of CHEMICAL was significantly longer with increasing the amount of precurarizing dose of rocuronium (P < 0.001). CONCLUSIONS: Precurarization with 0.04 mg/kg rocuronium was the optimal dose considering the reduction in the incidence and severity of DISEASE and myalgia with acceptable onset time, and the safe and effective precurarization. | CHEMICAL-INDUCED-DISEASE |
| Optimal precurarizing dose of rocuronium to decrease fasciculation and DISEASE following CHEMICAL administration. BACKGROUND: CHEMICAL commonly produces frequent adverse effects, including muscle fasciculation and DISEASE. The current study identified the optimal dose of rocuronium to prevent CHEMICAL-induced fasciculation and DISEASE and evaluated the influence of rocuronium on the speed of onset produced by CHEMICAL. METHODS: This randomized, double-blinded study was conducted in 100 patients randomly allocated into five groups of 20 patients each. Patients were randomized to receive 0.02, 0.03, 0.04, 0.05 and 0.06 mg/kg rocuronium as a precurarizing dose. Neuromuscular monitoring after each precurarizing dose was recorded from the adductor pollicis muscle using acceleromyography with train-of-four stimulation of the ulnar nerve. All patients received CHEMICAL 1.5 mg/kg at 2 minutes after the precurarization, and were assessed the incidence and severity of fasciculations, while DISEASE was assessed at 24 hours after surgery. RESULTS: The incidence and severity of visible muscle fasciculation was significantly less with increasing the amount of precurarizing dose of rocuronium (P < 0.001). Those of DISEASE tend to decrease according to increasing the amount of precurarizing dose of rocuronium, but there was no significance (P = 0.072). The onset time of CHEMICAL was significantly longer with increasing the amount of precurarizing dose of rocuronium (P < 0.001). CONCLUSIONS: Precurarization with 0.04 mg/kg rocuronium was the optimal dose considering the reduction in the incidence and severity of fasciculation and DISEASE with acceptable onset time, and the safe and effective precurarization. | CHEMICAL-INDUCED-DISEASE |
| Absence of PKC-alpha attenuates CHEMICAL-induced nephrogenic diabetes insipidus. CHEMICAL, an effective antipsychotic, induces nephrogenic diabetes insipidus (NDI) in 40% of patients. The decreased capacity to concentrate urine is likely due to CHEMICAL acutely disrupting the cAMP pathway and chronically reducing urea transporter (UT-A1) and water channel (AQP2) expression in the inner medulla. Targeting an alternative signaling pathway, such as PKC-mediated signaling, may be an effective method of treating CHEMICAL-induced DISEASE. PKC-alpha null mice (PKCa KO) and strain-matched wild type (WT) controls were treated with CHEMICAL for 0, 3 or 5 days. WT mice had increased urine output and lowered urine osmolality after 3 and 5 days of treatment whereas PKCa KO mice had no change in urine output or concentration. Western blot analysis revealed that AQP2 expression in medullary tissues was lowered after 3 and 5 days in WT mice; however, AQP2 was unchanged in PKCa KO. Similar results were observed with UT-A1 expression. Animals were also treated with CHEMICAL for 6 weeks. CHEMICAL-treated WT mice had 19-fold increased urine output whereas treated PKCa KO animals had a 4-fold increase in output. AQP2 and UT-A1 expression was lowered in 6 week CHEMICAL-treated WT animals whereas in treated PKCa KO mice, AQP2 was only reduced by 2-fold and UT-A1 expression was unaffected. Urinary sodium, potassium and calcium were elevated in CHEMICAL-fed WT but not in CHEMICAL-fed PKCa KO mice. Our data show that ablation of PKCa preserves AQP2 and UT-A1 protein expression and localization in CHEMICAL-induced NDI, and prevents the development of the severe DISEASE associated with CHEMICAL therapy. | CHEMICAL-INDUCED-DISEASE |
| Absence of PKC-alpha attenuates CHEMICAL-induced DISEASE. CHEMICAL, an effective antipsychotic, induces DISEASE (DISEASE) in 40% of patients. The decreased capacity to concentrate urine is likely due to CHEMICAL acutely disrupting the cAMP pathway and chronically reducing urea transporter (UT-A1) and water channel (AQP2) expression in the inner medulla. Targeting an alternative signaling pathway, such as PKC-mediated signaling, may be an effective method of treating CHEMICAL-induced polyuria. PKC-alpha null mice (PKCa KO) and strain-matched wild type (WT) controls were treated with CHEMICAL for 0, 3 or 5 days. WT mice had increased urine output and lowered urine osmolality after 3 and 5 days of treatment whereas PKCa KO mice had no change in urine output or concentration. Western blot analysis revealed that AQP2 expression in medullary tissues was lowered after 3 and 5 days in WT mice; however, AQP2 was unchanged in PKCa KO. Similar results were observed with UT-A1 expression. Animals were also treated with CHEMICAL for 6 weeks. CHEMICAL-treated WT mice had 19-fold increased urine output whereas treated PKCa KO animals had a 4-fold increase in output. AQP2 and UT-A1 expression was lowered in 6 week CHEMICAL-treated WT animals whereas in treated PKCa KO mice, AQP2 was only reduced by 2-fold and UT-A1 expression was unaffected. Urinary sodium, potassium and calcium were elevated in CHEMICAL-fed WT but not in CHEMICAL-fed PKCa KO mice. Our data show that ablation of PKCa preserves AQP2 and UT-A1 protein expression and localization in CHEMICAL-induced DISEASE, and prevents the development of the severe polyuria associated with CHEMICAL therapy. | CHEMICAL-INDUCED-DISEASE |
| Is DISEASE Going to be a Rare or a Common Side-effect of CHEMICAL? A very rare side-effect of CHEMICAL is DISEASE. A review of the literature produced only one case. We report a case about a female with essential hypertension on drug treatment with CHEMICAL developed loss of taste sensation. Condition moderately improved on stoppage of the drug for 25 days. We conclude that CHEMICAL can cause DISEASE. Here, we describe the clinical presentation and review the relevant literature on CHEMICAL and DISEASE. | CHEMICAL-INDUCED-DISEASE |
| DISEASE in association with simvastatin and dosage increment in CHEMICAL. CHEMICAL is the most documented cytochrome P450 3A4 (CYP3A4) inhibitor to cause an adverse interaction with simvastatin. This particular case is of interest as DISEASE only occurred after an increase in the dose of CHEMICAL. The patient developed raised cardiac biomarkers without any obvious cardiac issues, a phenomenon that has been linked to DISEASE previously. To date, there has been no reported effect of DISEASE on the structure and function of cardiac muscle. Clinicians need to be aware of prescribing concomitant medications that increase the risk of myopathy or inhibit the CYP3A4 enzyme. Our case suggests that troponin elevation could be associated with statin induced DISEASE, which may warrant further studies. | CHEMICAL-INDUCED-DISEASE |
| DISEASE in association with CHEMICAL and dosage increment in clarithromycin. Clarithromycin is the most documented cytochrome P450 3A4 (CYP3A4) inhibitor to cause an adverse interaction with CHEMICAL. This particular case is of interest as DISEASE only occurred after an increase in the dose of clarithromycin. The patient developed raised cardiac biomarkers without any obvious cardiac issues, a phenomenon that has been linked to DISEASE previously. To date, there has been no reported effect of DISEASE on the structure and function of cardiac muscle. Clinicians need to be aware of prescribing concomitant medications that increase the risk of myopathy or inhibit the CYP3A4 enzyme. Our case suggests that troponin elevation could be associated with CHEMICAL induced DISEASE, which may warrant further studies. | CHEMICAL-INDUCED-DISEASE |
| Characterization of a novel BCHE "silent" allele: point mutation (p.Val204Asp) causes loss of activity and prolonged DISEASE with suxamethonium. Butyrylcholinesterase deficiency is characterized by prolonged DISEASE after the use of muscle relaxants (suxamethonium or CHEMICAL) in patients who have mutations in the BCHE gene. Here, we report a case of prolonged neuromuscular block after administration of suxamethonium leading to the discovery of a novel BCHE variant (c.695T>A, p.Val204Asp). Inhibition studies, kinetic analysis and molecular dynamics were undertaken to understand how this mutation disrupts the catalytic triad and determines a "silent" phenotype. Low activity of patient plasma butyrylcholinesterase with butyrylthiocholine (BTC) and benzoylcholine, and values of dibucaine and fluoride numbers fit with heterozygous atypical silent genotype. Electrophoretic analysis of plasma BChE of the proband and his mother showed that patient has a reduced amount of tetrameric enzyme in plasma and that minor fast-moving BChE components: monomer, dimer, and monomer-albumin conjugate are missing. Kinetic analysis showed that the p.Val204Asp/p.Asp70Gly-p.Ala539Thr BChE displays a pure Michaelian behavior with BTC as the substrate. Both catalytic parameters Km = 265 uM for BTC, two times higher than that of the atypical enzyme, and a low Vmax are consistent with the absence of activity against suxamethonium. Molecular dynamic (MD) simulations showed that the overall effect of the mutation p.Val204Asp is disruption of hydrogen bonding between Gln223 and Glu441, leading Ser198 and His438 to move away from each other with subsequent disruption of the catalytic triad functionality regardless of the type of substrate. MD also showed that the enzyme volume is increased, suggesting a pre-denaturation state. This fits with the reduced concentration of p.Ala204Asp/p.Asp70Gly-p.Ala539Thr tetrameric enzyme in the plasma and non-detectable fast moving-bands on electrophoresis gels. | CHEMICAL-INDUCED-DISEASE |
| Characterization of a novel BCHE "silent" allele: point mutation (p.Val204Asp) causes loss of activity and prolonged DISEASE with CHEMICAL. Butyrylcholinesterase deficiency is characterized by prolonged DISEASE after the use of muscle relaxants (CHEMICAL or mivacurium) in patients who have mutations in the BCHE gene. Here, we report a case of prolonged neuromuscular block after administration of CHEMICAL leading to the discovery of a novel BCHE variant (c.695T>A, p.Val204Asp). Inhibition studies, kinetic analysis and molecular dynamics were undertaken to understand how this mutation disrupts the catalytic triad and determines a "silent" phenotype. Low activity of patient plasma butyrylcholinesterase with butyrylthiocholine (BTC) and benzoylcholine, and values of dibucaine and fluoride numbers fit with heterozygous atypical silent genotype. Electrophoretic analysis of plasma BChE of the proband and his mother showed that patient has a reduced amount of tetrameric enzyme in plasma and that minor fast-moving BChE components: monomer, dimer, and monomer-albumin conjugate are missing. Kinetic analysis showed that the p.Val204Asp/p.Asp70Gly-p.Ala539Thr BChE displays a pure Michaelian behavior with BTC as the substrate. Both catalytic parameters Km = 265 uM for BTC, two times higher than that of the atypical enzyme, and a low Vmax are consistent with the absence of activity against CHEMICAL. Molecular dynamic (MD) simulations showed that the overall effect of the mutation p.Val204Asp is disruption of hydrogen bonding between Gln223 and Glu441, leading Ser198 and His438 to move away from each other with subsequent disruption of the catalytic triad functionality regardless of the type of substrate. MD also showed that the enzyme volume is increased, suggesting a pre-denaturation state. This fits with the reduced concentration of p.Ala204Asp/p.Asp70Gly-p.Ala539Thr tetrameric enzyme in the plasma and non-detectable fast moving-bands on electrophoresis gels. | CHEMICAL-INDUCED-DISEASE |
| Characterization of a novel BCHE "silent" allele: point mutation (p.Val204Asp) causes loss of activity and prolonged apnea with suxamethonium. DISEASE is characterized by prolonged apnea after the use of muscle relaxants (suxamethonium or CHEMICAL) in patients who have mutations in the BCHE gene. Here, we report a case of prolonged neuromuscular block after administration of suxamethonium leading to the discovery of a novel BCHE variant (c.695T>A, p.Val204Asp). Inhibition studies, kinetic analysis and molecular dynamics were undertaken to understand how this mutation disrupts the catalytic triad and determines a "silent" phenotype. Low activity of patient plasma butyrylcholinesterase with butyrylthiocholine (BTC) and benzoylcholine, and values of dibucaine and fluoride numbers fit with heterozygous atypical silent genotype. Electrophoretic analysis of plasma BChE of the proband and his mother showed that patient has a reduced amount of tetrameric enzyme in plasma and that minor fast-moving BChE components: monomer, dimer, and monomer-albumin conjugate are missing. Kinetic analysis showed that the p.Val204Asp/p.Asp70Gly-p.Ala539Thr BChE displays a pure Michaelian behavior with BTC as the substrate. Both catalytic parameters Km = 265 uM for BTC, two times higher than that of the atypical enzyme, and a low Vmax are consistent with the absence of activity against suxamethonium. Molecular dynamic (MD) simulations showed that the overall effect of the mutation p.Val204Asp is disruption of hydrogen bonding between Gln223 and Glu441, leading Ser198 and His438 to move away from each other with subsequent disruption of the catalytic triad functionality regardless of the type of substrate. MD also showed that the enzyme volume is increased, suggesting a pre-denaturation state. This fits with the reduced concentration of p.Ala204Asp/p.Asp70Gly-p.Ala539Thr tetrameric enzyme in the plasma and non-detectable fast moving-bands on electrophoresis gels. | NO-RELATIONSHIP |
| Characterization of a novel BCHE "silent" allele: point mutation (p.Val204Asp) causes loss of activity and prolonged apnea with CHEMICAL. DISEASE is characterized by prolonged apnea after the use of muscle relaxants (CHEMICAL or mivacurium) in patients who have mutations in the BCHE gene. Here, we report a case of prolonged neuromuscular block after administration of CHEMICAL leading to the discovery of a novel BCHE variant (c.695T>A, p.Val204Asp). Inhibition studies, kinetic analysis and molecular dynamics were undertaken to understand how this mutation disrupts the catalytic triad and determines a "silent" phenotype. Low activity of patient plasma butyrylcholinesterase with butyrylthiocholine (BTC) and benzoylcholine, and values of dibucaine and fluoride numbers fit with heterozygous atypical silent genotype. Electrophoretic analysis of plasma BChE of the proband and his mother showed that patient has a reduced amount of tetrameric enzyme in plasma and that minor fast-moving BChE components: monomer, dimer, and monomer-albumin conjugate are missing. Kinetic analysis showed that the p.Val204Asp/p.Asp70Gly-p.Ala539Thr BChE displays a pure Michaelian behavior with BTC as the substrate. Both catalytic parameters Km = 265 uM for BTC, two times higher than that of the atypical enzyme, and a low Vmax are consistent with the absence of activity against CHEMICAL. Molecular dynamic (MD) simulations showed that the overall effect of the mutation p.Val204Asp is disruption of hydrogen bonding between Gln223 and Glu441, leading Ser198 and His438 to move away from each other with subsequent disruption of the catalytic triad functionality regardless of the type of substrate. MD also showed that the enzyme volume is increased, suggesting a pre-denaturation state. This fits with the reduced concentration of p.Ala204Asp/p.Asp70Gly-p.Ala539Thr tetrameric enzyme in the plasma and non-detectable fast moving-bands on electrophoresis gels. | CHEMICAL-INDUCED-DISEASE |
| Delayed anemia after treatment with injectable CHEMICAL in the Democratic Republic of the Congo: a manageable issue. Cases of delayed DISEASE have been described after treatment with injectable CHEMICAL, the current World Health Organization (WHO)-recommended first-line drug for the treatment of severe malaria. A total of 350 patients (215 [61.4%] < 5 years of age and 135 [38.6%] > 5 years of age) were followed-up after treatment with injectable CHEMICAL for severe malaria in hospitals and health centers of the Democratic Republic of the Congo. Complete series of hemoglobin (Hb) measurements were available for 201 patients. A decrease in Hb levels between 2 and 5 g/dL was detected in 23 (11.4%) patients during the follow-up period. For five patients, Hb levels decreased below 5 g/dL during at least one follow-up visit. All cases of delayed anemia were clinically manageable and resolved within one month. | CHEMICAL-INDUCED-DISEASE |
| Regulation of signal transducer and activator of transcription 3 and apoptotic pathways by betaine attenuates CHEMICAL-induced acute myocardial injury in rats. The present study was designed to investigate the cardioprotective effects of betaine on acute DISEASE induced experimentally in rats focusing on regulation of signal transducer and activator of transcription 3 (STAT3) and apoptotic pathways as the potential mechanism underlying the drug effect. Male Sprague Dawley rats were treated with betaine (100, 200, and 400 mg/kg) orally for 40 days. Acute DISEASE was induced in rats by subcutaneous injection of CHEMICAL (85 mg/kg), for two consecutive days. Serum cardiac marker enzyme, histopathological variables and expression of protein levels were analyzed. Oral administration of betaine (200 and 400 mg/kg) significantly reduced the level of cardiac marker enzyme in the serum and prevented left ventricular remodeling. Western blot analysis showed that CHEMICAL-induced phosphorylation of STAT3 was maintained or further enhanced by betaine treatment in myocardium. Furthermore, betaine (200 and 400 mg/kg) treatment increased the ventricular expression of Bcl-2 and reduced the level of Bax, therefore causing a significant increase in the ratio of Bcl-2/Bax. The protective role of betaine on myocardial damage was further confirmed by histopathological examination. In summary, our results showed that betaine pretreatment attenuated CHEMICAL-induced acute DISEASE via the regulation of STAT3 and apoptotic pathways. | CHEMICAL-INDUCED-DISEASE |
| Regulation of signal transducer and activator of transcription 3 and apoptotic pathways by betaine attenuates CHEMICAL-induced acute myocardial injury in rats. The present study was designed to investigate the cardioprotective effects of betaine on acute myocardial ischemia induced experimentally in rats focusing on regulation of signal transducer and activator of transcription 3 (STAT3) and apoptotic pathways as the potential mechanism underlying the drug effect. Male Sprague Dawley rats were treated with betaine (100, 200, and 400 mg/kg) orally for 40 days. Acute myocardial ischemic injury was induced in rats by subcutaneous injection of CHEMICAL (85 mg/kg), for two consecutive days. Serum cardiac marker enzyme, histopathological variables and expression of protein levels were analyzed. Oral administration of betaine (200 and 400 mg/kg) significantly reduced the level of cardiac marker enzyme in the serum and prevented left DISEASE. Western blot analysis showed that CHEMICAL-induced phosphorylation of STAT3 was maintained or further enhanced by betaine treatment in myocardium. Furthermore, betaine (200 and 400 mg/kg) treatment increased the ventricular expression of Bcl-2 and reduced the level of Bax, therefore causing a significant increase in the ratio of Bcl-2/Bax. The protective role of betaine on myocardial damage was further confirmed by histopathological examination. In summary, our results showed that betaine pretreatment attenuated CHEMICAL-induced acute myocardial ischemia via the regulation of STAT3 and apoptotic pathways. | CHEMICAL-INDUCED-DISEASE |
| Regulation of signal transducer and activator of transcription 3 and apoptotic pathways by CHEMICAL attenuates isoproterenol-induced acute DISEASE in rats. The present study was designed to investigate the cardioprotective effects of CHEMICAL on acute myocardial ischemia induced experimentally in rats focusing on regulation of signal transducer and activator of transcription 3 (STAT3) and apoptotic pathways as the potential mechanism underlying the drug effect. Male Sprague Dawley rats were treated with CHEMICAL (100, 200, and 400 mg/kg) orally for 40 days. Acute myocardial ischemic injury was induced in rats by subcutaneous injection of isoproterenol (85 mg/kg), for two consecutive days. Serum cardiac marker enzyme, histopathological variables and expression of protein levels were analyzed. Oral administration of CHEMICAL (200 and 400 mg/kg) significantly reduced the level of cardiac marker enzyme in the serum and prevented left ventricular remodeling. Western blot analysis showed that isoproterenol-induced phosphorylation of STAT3 was maintained or further enhanced by CHEMICAL treatment in myocardium. Furthermore, CHEMICAL (200 and 400 mg/kg) treatment increased the ventricular expression of Bcl-2 and reduced the level of Bax, therefore causing a significant increase in the ratio of Bcl-2/Bax. The protective role of CHEMICAL on DISEASE was further confirmed by histopathological examination. In summary, our results showed that CHEMICAL pretreatment attenuated isoproterenol-induced acute myocardial ischemia via the regulation of STAT3 and apoptotic pathways. | NO-RELATIONSHIP |
| CHEMICAL-induced DISEASE in a bipolar patient with hepatocellular carcinoma. OBJECTIVE: CHEMICAL is a dibenzothiazepine derivative, similar to clozapine, which has the highest risk of causing blood dyscrasias, especially DISEASE. There are some case reports about this side effect of CHEMICAL, but possible risk factors are seldom discussed and identified. A case of a patient with hepatocellular carcinoma that developed DISEASE after treatment with CHEMICAL is described here. CASE REPORT: A 62-year-old Taiwanese widow with bipolar disorder was diagnosed with hepatocellular carcinoma at age 60. She developed leucopenia after being treated with CHEMICAL. After CHEMICAL was discontinued, her white blood cell count returned to normal. CONCLUSIONS: Although DISEASE is not a common side effect of CHEMICAL, physicians should be cautious about its presentation and associated risk factors. Hepatic dysfunction may be one of the possible risk factors, and concomitant fever may be a diagnostic marker for adverse reaction to CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced neutropenia in a bipolar patient with hepatocellular carcinoma. OBJECTIVE: CHEMICAL is a dibenzothiazepine derivative, similar to clozapine, which has the highest risk of causing blood dyscrasias, especially neutropenia. There are some case reports about this side effect of CHEMICAL, but possible risk factors are seldom discussed and identified. A case of a patient with hepatocellular carcinoma that developed neutropenia after treatment with CHEMICAL is described here. CASE REPORT: A 62-year-old Taiwanese widow with bipolar disorder was diagnosed with hepatocellular carcinoma at age 60. She developed DISEASE after being treated with CHEMICAL. After CHEMICAL was discontinued, her white blood cell count returned to normal. CONCLUSIONS: Although neutropenia is not a common side effect of CHEMICAL, physicians should be cautious about its presentation and associated risk factors. Hepatic dysfunction may be one of the possible risk factors, and concomitant fever may be a diagnostic marker for adverse reaction to CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced neutropenia in a bipolar patient with hepatocellular carcinoma. OBJECTIVE: CHEMICAL is a dibenzothiazepine derivative, similar to clozapine, which has the highest risk of causing blood dyscrasias, especially neutropenia. There are some case reports about this side effect of CHEMICAL, but possible risk factors are seldom discussed and identified. A case of a patient with hepatocellular carcinoma that developed neutropenia after treatment with CHEMICAL is described here. CASE REPORT: A 62-year-old Taiwanese widow with bipolar disorder was diagnosed with hepatocellular carcinoma at age 60. She developed leucopenia after being treated with CHEMICAL. After CHEMICAL was discontinued, her white blood cell count returned to normal. CONCLUSIONS: Although neutropenia is not a common side effect of CHEMICAL, physicians should be cautious about its presentation and associated risk factors. Hepatic dysfunction may be one of the possible risk factors, and concomitant DISEASE may be a diagnostic marker for adverse reaction to CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Quetiapine-induced neutropenia in a bipolar patient with DISEASE. OBJECTIVE: Quetiapine is a dibenzothiazepine derivative, similar to CHEMICAL, which has the highest risk of causing blood dyscrasias, especially neutropenia. There are some case reports about this side effect of quetiapine, but possible risk factors are seldom discussed and identified. A case of a patient with DISEASE that developed neutropenia after treatment with quetiapine is described here. CASE REPORT: A 62-year-old Taiwanese widow with bipolar disorder was diagnosed with DISEASE at age 60. She developed leucopenia after being treated with quetiapine. After quetiapine was discontinued, her white blood cell count returned to normal. CONCLUSIONS: Although neutropenia is not a common side effect of quetiapine, physicians should be cautious about its presentation and associated risk factors. Hepatic dysfunction may be one of the possible risk factors, and concomitant fever may be a diagnostic marker for adverse reaction to quetiapine. | NO-RELATIONSHIP |
| Quetiapine-induced neutropenia in a bipolar patient with hepatocellular carcinoma. OBJECTIVE: Quetiapine is a dibenzothiazepine derivative, similar to CHEMICAL, which has the highest risk of causing blood dyscrasias, especially neutropenia. There are some case reports about this side effect of quetiapine, but possible risk factors are seldom discussed and identified. A case of a patient with hepatocellular carcinoma that developed neutropenia after treatment with quetiapine is described here. CASE REPORT: A 62-year-old Taiwanese widow with bipolar disorder was diagnosed with hepatocellular carcinoma at age 60. She developed leucopenia after being treated with quetiapine. After quetiapine was discontinued, her white blood cell count returned to normal. CONCLUSIONS: Although neutropenia is not a common side effect of quetiapine, physicians should be cautious about its presentation and associated risk factors. DISEASE may be one of the possible risk factors, and concomitant fever may be a diagnostic marker for adverse reaction to quetiapine. | NO-RELATIONSHIP |
| Quetiapine-induced neutropenia in a DISEASE patient with hepatocellular carcinoma. OBJECTIVE: Quetiapine is a dibenzothiazepine derivative, similar to CHEMICAL, which has the highest risk of causing blood dyscrasias, especially neutropenia. There are some case reports about this side effect of quetiapine, but possible risk factors are seldom discussed and identified. A case of a patient with hepatocellular carcinoma that developed neutropenia after treatment with quetiapine is described here. CASE REPORT: A 62-year-old Taiwanese widow with DISEASE was diagnosed with hepatocellular carcinoma at age 60. She developed leucopenia after being treated with quetiapine. After quetiapine was discontinued, her white blood cell count returned to normal. CONCLUSIONS: Although neutropenia is not a common side effect of quetiapine, physicians should be cautious about its presentation and associated risk factors. Hepatic dysfunction may be one of the possible risk factors, and concomitant fever may be a diagnostic marker for adverse reaction to quetiapine. | NO-RELATIONSHIP |
| Quetiapine-induced neutropenia in a bipolar patient with hepatocellular carcinoma. OBJECTIVE: Quetiapine is a dibenzothiazepine derivative, similar to CHEMICAL, which has the highest risk of causing DISEASE, especially neutropenia. There are some case reports about this side effect of quetiapine, but possible risk factors are seldom discussed and identified. A case of a patient with hepatocellular carcinoma that developed neutropenia after treatment with quetiapine is described here. CASE REPORT: A 62-year-old Taiwanese widow with bipolar disorder was diagnosed with hepatocellular carcinoma at age 60. She developed leucopenia after being treated with quetiapine. After quetiapine was discontinued, her white blood cell count returned to normal. CONCLUSIONS: Although neutropenia is not a common side effect of quetiapine, physicians should be cautious about its presentation and associated risk factors. Hepatic dysfunction may be one of the possible risk factors, and concomitant fever may be a diagnostic marker for adverse reaction to quetiapine. | CHEMICAL-INDUCED-DISEASE |
| Lateral antebrachial cutaneous neuropathy after CHEMICAL injection at lateral epicondyle. BACKGROUND AND OBJECTIVES: This report aimed to present a case of lateral antebrachial cutaneous neuropathy (LACNP) that occurred after a CHEMICAL injection in the lateral epicondyle to treat lateral epicondylitis in a 40-year-old woman. MATERIAL AND METHOD: A 40-year-old woman presented with decreased sensation and DISEASE over her right lateral forearm; the DISEASE had occurred after a CHEMICAL injection in the right lateral epicondyle 3 months before. Her sensation of light touch and pain was diminished over the lateral side of the right forearm and wrist area. RESULTS: The sensory action potential amplitude of the right lateral antebrachial cutaneous nerve (LACN) (6.2 uV) was lower than that of the left (13.1 uV). The difference of amplitude between both sides was significant because there was more than a 50% reduction. She was diagnosed with right LACNP (mainly axonal involvement) on the basis of the clinical manifestation and the electrodiagnostic findings. Her symptoms improved through physical therapy but persisted to some degree. CONCLUSION: This report describes the case of a woman with LACNP that developed after a CHEMICAL injection for the treatment of lateral epicondylitis. An electrodiagnostic study, including a nerve conduction study of the LACN, was helpful to diagnose right LACNP and to find the passage of the LACN on the lateral epicondyle. | CHEMICAL-INDUCED-DISEASE |
| Curcumin prevents CHEMICAL-induced nephrotoxicity: relation to hemodynamic alterations, oxidative stress, mitochondrial oxygen consumption and activity of respiratory complex I. The potential protective effect of the dietary antioxidant curcumin (120 mg/Kg/day for 6 days) against the renal injury induced by CHEMICAL was evaluated. Tubular DISEASE and oxidative stress were induced by a single injection of CHEMICAL (400 mg/kg) in rats. CHEMICAL-induced renal injury included increase in renal vascular resistance and in the urinary excretion of total protein, glucose, sodium, neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl b-D-glucosaminidase (NAG), upregulation of kidney injury molecule (KIM)-1, decrease in renal blood flow and claudin-2 expression besides of necrosis and apoptosis of tubular cells on 24 h. Oxidative stress was determined by measuring the oxidation of lipids and proteins and diminution in renal Nrf2 levels. Studies were also conducted in renal epithelial LLC-PK1 cells and in mitochondria isolated from kidneys of all the experimental groups. CHEMICAL induced cell damage and reactive oxygen species (ROS) production in LLC-PK1 cells in culture. In addition, CHEMICAL treatment reduced oxygen consumption in ADP-stimulated mitochondria and diminished respiratory control index when using malate/glutamate as substrate. The activities of both complex I and aconitase were also diminished. All the above-described alterations were prevented by curcumin. It is concluded that curcumin is able to attenuate in vivo CHEMICAL-induced nephropathy and in vitro cell damage. The in vivo protection was associated to the prevention of oxidative stress and preservation of mitochondrial oxygen consumption and activity of respiratory complex I, and the in vitro protection was associated to the prevention of ROS production. | CHEMICAL-INDUCED-DISEASE |
| Curcumin prevents CHEMICAL-induced nephrotoxicity: relation to hemodynamic alterations, oxidative stress, mitochondrial oxygen consumption and activity of respiratory complex I. The potential protective effect of the dietary antioxidant curcumin (120 mg/Kg/day for 6 days) against the renal injury induced by CHEMICAL was evaluated. Tubular proteinuria and oxidative stress were induced by a single injection of CHEMICAL (400 mg/kg) in rats. CHEMICAL-induced renal injury included increase in renal vascular resistance and in the urinary excretion of total protein, glucose, sodium, neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl b-D-glucosaminidase (NAG), upregulation of kidney injury molecule (KIM)-1, decrease in renal blood flow and claudin-2 expression besides of DISEASE and apoptosis of tubular cells on 24 h. Oxidative stress was determined by measuring the oxidation of lipids and proteins and diminution in renal Nrf2 levels. Studies were also conducted in renal epithelial LLC-PK1 cells and in mitochondria isolated from kidneys of all the experimental groups. CHEMICAL induced cell damage and reactive oxygen species (ROS) production in LLC-PK1 cells in culture. In addition, CHEMICAL treatment reduced oxygen consumption in ADP-stimulated mitochondria and diminished respiratory control index when using malate/glutamate as substrate. The activities of both complex I and aconitase were also diminished. All the above-described alterations were prevented by curcumin. It is concluded that curcumin is able to attenuate in vivo CHEMICAL-induced nephropathy and in vitro cell damage. The in vivo protection was associated to the prevention of oxidative stress and preservation of mitochondrial oxygen consumption and activity of respiratory complex I, and the in vitro protection was associated to the prevention of ROS production. | CHEMICAL-INDUCED-DISEASE |
| Curcumin prevents CHEMICAL-induced DISEASE: relation to hemodynamic alterations, oxidative stress, mitochondrial oxygen consumption and activity of respiratory complex I. The potential protective effect of the dietary antioxidant curcumin (120 mg/Kg/day for 6 days) against the DISEASE induced by CHEMICAL was evaluated. Tubular proteinuria and oxidative stress were induced by a single injection of CHEMICAL (400 mg/kg) in rats. CHEMICAL-induced DISEASE included increase in renal vascular resistance and in the urinary excretion of total protein, glucose, sodium, neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl b-D-glucosaminidase (NAG), upregulation of DISEASE molecule (KIM)-1, decrease in renal blood flow and claudin-2 expression besides of necrosis and apoptosis of tubular cells on 24 h. Oxidative stress was determined by measuring the oxidation of lipids and proteins and diminution in renal Nrf2 levels. Studies were also conducted in renal epithelial LLC-PK1 cells and in mitochondria isolated from kidneys of all the experimental groups. CHEMICAL induced cell damage and reactive oxygen species (ROS) production in LLC-PK1 cells in culture. In addition, CHEMICAL treatment reduced oxygen consumption in ADP-stimulated mitochondria and diminished respiratory control index when using malate/glutamate as substrate. The activities of both complex I and aconitase were also diminished. All the above-described alterations were prevented by curcumin. It is concluded that curcumin is able to attenuate in vivo CHEMICAL-induced DISEASE and in vitro cell damage. The in vivo protection was associated to the prevention of oxidative stress and preservation of mitochondrial oxygen consumption and activity of respiratory complex I, and the in vitro protection was associated to the prevention of ROS production. | CHEMICAL-INDUCED-DISEASE |
| Incidence of solid tumours among pesticide applicators exposed to the organophosphate insecticide CHEMICAL in the Agricultural Health Study: an updated analysis. OBJECTIVE: CHEMICAL, a common organophosphate insecticide with genotoxic properties, was previously associated with DISEASE in the Agricultural Health Study (AHS) cohort, but few other epidemiological studies have examined CHEMICAL-associated cancer risk. We used updated CHEMICAL exposure and cancer incidence information to evaluate solid tumour risk in the AHS. METHODS: Male pesticide applicators in Iowa and North Carolina reported lifetime CHEMICAL use at enrolment (1993-1997) and follow-up (1998-2005); cancer incidence was assessed through 2010(North Carolina)/2011(Iowa). Among applicators with usage information sufficient to evaluate exposure-response patterns, we used Poisson regression to estimate adjusted rate ratios (RRs) and 95% CI for cancer sites with >10 exposed cases for both lifetime (LT) exposure days and intensity-weighted (IW) lifetime exposure days (accounting for factors impacting exposure). RESULTS: We observed elevated DISEASE risks (N=283) among applicators with the greatest number of LT (RR=1.60; 95% CI 1.11 to 2.31; Ptrend=0.02) and IW days of CHEMICAL use (RR=1.41; 95% CI 0.98 to 2.04; Ptrend=0.08). Kidney cancer (N=94) risks were non-significantly elevated (RRLT days=1.77; 95% CI 0.90 to 3.51; Ptrend=0.09; RRIW days 1.37; 95% CI 0.64 to 2.92; Ptrend=0.50), as were risks for aggressive prostate cancer (N=656). CONCLUSIONS: Our updated evaluation of CHEMICAL provides additional evidence of an association with DISEASE risk. Newly identified links to kidney cancer and associations with aggressive prostate cancer require further evaluation. | CHEMICAL-INDUCED-DISEASE |
| Incidence of solid DISEASE among pesticide applicators exposed to the CHEMICAL insecticide diazinon in the Agricultural Health Study: an updated analysis. OBJECTIVE: Diazinon, a common CHEMICAL insecticide with genotoxic properties, was previously associated with lung cancer in the Agricultural Health Study (AHS) cohort, but few other epidemiological studies have examined diazinon-associated DISEASE risk. We used updated diazinon exposure and DISEASE incidence information to evaluate solid DISEASE risk in the AHS. METHODS: Male pesticide applicators in Iowa and North Carolina reported lifetime diazinon use at enrolment (1993-1997) and follow-up (1998-2005); DISEASE incidence was assessed through 2010(North Carolina)/2011(Iowa). Among applicators with usage information sufficient to evaluate exposure-response patterns, we used Poisson regression to estimate adjusted rate ratios (RRs) and 95% CI for DISEASE sites with >10 exposed cases for both lifetime (LT) exposure days and intensity-weighted (IW) lifetime exposure days (accounting for factors impacting exposure). RESULTS: We observed elevated lung cancer risks (N=283) among applicators with the greatest number of LT (RR=1.60; 95% CI 1.11 to 2.31; Ptrend=0.02) and IW days of diazinon use (RR=1.41; 95% CI 0.98 to 2.04; Ptrend=0.08). Kidney cancer (N=94) risks were non-significantly elevated (RRLT days=1.77; 95% CI 0.90 to 3.51; Ptrend=0.09; RRIW days 1.37; 95% CI 0.64 to 2.92; Ptrend=0.50), as were risks for aggressive prostate cancer (N=656). CONCLUSIONS: Our updated evaluation of diazinon provides additional evidence of an association with lung cancer risk. Newly identified links to kidney cancer and associations with aggressive prostate cancer require further evaluation. | NO-RELATIONSHIP |
| Incidence of solid tumours among pesticide applicators exposed to the CHEMICAL insecticide diazinon in the Agricultural Health Study: an updated analysis. OBJECTIVE: Diazinon, a common CHEMICAL insecticide with genotoxic properties, was previously associated with lung cancer in the Agricultural Health Study (AHS) cohort, but few other epidemiological studies have examined diazinon-associated cancer risk. We used updated diazinon exposure and cancer incidence information to evaluate solid tumour risk in the AHS. METHODS: Male pesticide applicators in Iowa and North Carolina reported lifetime diazinon use at enrolment (1993-1997) and follow-up (1998-2005); cancer incidence was assessed through 2010(North Carolina)/2011(Iowa). Among applicators with usage information sufficient to evaluate exposure-response patterns, we used Poisson regression to estimate adjusted rate ratios (RRs) and 95% CI for cancer sites with >10 exposed cases for both lifetime (LT) exposure days and intensity-weighted (IW) lifetime exposure days (accounting for factors impacting exposure). RESULTS: We observed elevated lung cancer risks (N=283) among applicators with the greatest number of LT (RR=1.60; 95% CI 1.11 to 2.31; Ptrend=0.02) and IW days of diazinon use (RR=1.41; 95% CI 0.98 to 2.04; Ptrend=0.08). Kidney cancer (N=94) risks were non-significantly elevated (RRLT days=1.77; 95% CI 0.90 to 3.51; Ptrend=0.09; RRIW days 1.37; 95% CI 0.64 to 2.92; Ptrend=0.50), as were risks for aggressive DISEASE (N=656). CONCLUSIONS: Our updated evaluation of diazinon provides additional evidence of an association with lung cancer risk. Newly identified links to kidney cancer and associations with aggressive DISEASE require further evaluation. | NO-RELATIONSHIP |
| Incidence of solid tumours among pesticide applicators exposed to the CHEMICAL insecticide diazinon in the Agricultural Health Study: an updated analysis. OBJECTIVE: Diazinon, a common CHEMICAL insecticide with genotoxic properties, was previously associated with lung cancer in the Agricultural Health Study (AHS) cohort, but few other epidemiological studies have examined diazinon-associated cancer risk. We used updated diazinon exposure and cancer incidence information to evaluate solid tumour risk in the AHS. METHODS: Male pesticide applicators in Iowa and North Carolina reported lifetime diazinon use at enrolment (1993-1997) and follow-up (1998-2005); cancer incidence was assessed through 2010(North Carolina)/2011(Iowa). Among applicators with usage information sufficient to evaluate exposure-response patterns, we used Poisson regression to estimate adjusted rate ratios (RRs) and 95% CI for cancer sites with >10 exposed cases for both lifetime (LT) exposure days and intensity-weighted (IW) lifetime exposure days (accounting for factors impacting exposure). RESULTS: We observed elevated lung cancer risks (N=283) among applicators with the greatest number of LT (RR=1.60; 95% CI 1.11 to 2.31; Ptrend=0.02) and IW days of diazinon use (RR=1.41; 95% CI 0.98 to 2.04; Ptrend=0.08). DISEASE (N=94) risks were non-significantly elevated (RRLT days=1.77; 95% CI 0.90 to 3.51; Ptrend=0.09; RRIW days 1.37; 95% CI 0.64 to 2.92; Ptrend=0.50), as were risks for aggressive prostate cancer (N=656). CONCLUSIONS: Our updated evaluation of diazinon provides additional evidence of an association with lung cancer risk. Newly identified links to DISEASE and associations with aggressive prostate cancer require further evaluation. | NO-RELATIONSHIP |
| Associations of Ozone and PM2.5 Concentrations With DISEASE Among Participants in the Agricultural Health Study. OBJECTIVE: This study describes associations of ozone and fine CHEMICAL with DISEASE observed among farmers in North Carolina and Iowa. METHODS: We used logistic regression to determine the associations of these pollutants with self-reported, doctor-diagnosed DISEASE. Daily predicted pollutant concentrations were used to derive surrogates of long-term exposure and link them to study participants' geocoded addresses. RESULTS: We observed positive associations of DISEASE with ozone (odds ratio = 1.39; 95% CI: 0.98 to 1.98) and fine CHEMICAL (odds ratio = 1.34; 95% CI: 0.93 to 1.93) in North Carolina but not in Iowa. CONCLUSIONS: The plausibility of an effect of ambient concentrations of these pollutants on DISEASE risk is supported by experimental data demonstrating damage to dopaminergic neurons at relevant concentrations. Additional studies are needed to address uncertainties related to confounding and to examine temporal aspects of the associations we observed. | CHEMICAL-INDUCED-DISEASE |
| Associations of CHEMICAL and PM2.5 Concentrations With DISEASE Among Participants in the Agricultural Health Study. OBJECTIVE: This study describes associations of CHEMICAL and fine particulate matter with DISEASE observed among farmers in North Carolina and Iowa. METHODS: We used logistic regression to determine the associations of these pollutants with self-reported, doctor-diagnosed DISEASE. Daily predicted pollutant concentrations were used to derive surrogates of long-term exposure and link them to study participants' geocoded addresses. RESULTS: We observed positive associations of DISEASE with CHEMICAL (odds ratio = 1.39; 95% CI: 0.98 to 1.98) and fine particulate matter (odds ratio = 1.34; 95% CI: 0.93 to 1.93) in North Carolina but not in Iowa. CONCLUSIONS: The plausibility of an effect of ambient concentrations of these pollutants on DISEASE risk is supported by experimental data demonstrating damage to dopaminergic neurons at relevant concentrations. Additional studies are needed to address uncertainties related to confounding and to examine temporal aspects of the associations we observed. | CHEMICAL-INDUCED-DISEASE |
| Low functional programming of renal AT2R mediates the developmental origin of glomerulosclerosis in adult offspring induced by prenatal CHEMICAL exposure. UNASSIGNED: Our previous study has indicated that prenatal CHEMICAL exposure (PCE) could induce intrauterine growth retardation (IUGR) of offspring. Recent research suggested that IUGR is a risk factor for glomerulosclerosis. However, whether PCE could induce glomerulosclerosis and its underlying mechanisms remain unknown. This study aimed to demonstrate the induction to glomerulosclerosis in adult offspring by PCE and its intrauterine programming mechanisms. A rat model of IUGR was established by PCE, male fetuses and adult offspring at the age of postnatal week 24 were euthanized. The results revealed that the adult offspring kidneys in the PCE group exhibited glomerulosclerosis as well as interstitial fibrosis, accompanied by elevated levels of serum creatinine and urine protein. Renal angiotensin II receptor type 2 (AT2R) gene expression in adult offspring was reduced by PCE, whereas the renal angiotensin II receptor type 1a (AT1aR)/AT2R expression ratio was increased. The fetal kidneys in the PCE group displayed an enlarged Bowman's space and a shrunken glomerular tuft, accompanied by a reduced cortex width and an increase in the nephrogenic zone/cortical zone ratio. Observation by electronic microscope revealed structural damage of podocytes; the reduced expression level of podocyte marker genes, nephrin and podocin, was also detected by q-PCR. Moreover, AT2R gene and protein expressions in fetal kidneys were inhibited by PCE, associated with the repression of the gene expression of glial-cell-line-derived neurotrophic factor (GDNF)/tyrosine kinase receptor (c-Ret) signaling pathway. These results demonstrated that PCE could induce DISEASE as well as glomerulosclerosis of adult offspring, and the low functional programming of renal AT2R might mediate the developmental origin of adult glomerulosclerosis. | CHEMICAL-INDUCED-DISEASE |
| Low functional programming of renal AT2R mediates the developmental origin of glomerulosclerosis in adult offspring induced by prenatal CHEMICAL exposure. UNASSIGNED: Our previous study has indicated that prenatal CHEMICAL exposure (PCE) could induce intrauterine growth retardation (IUGR) of offspring. Recent research suggested that IUGR is a risk factor for glomerulosclerosis. However, whether PCE could induce glomerulosclerosis and its underlying mechanisms remain unknown. This study aimed to demonstrate the induction to glomerulosclerosis in adult offspring by PCE and its intrauterine programming mechanisms. A rat model of IUGR was established by PCE, male fetuses and adult offspring at the age of postnatal week 24 were euthanized. The results revealed that the adult offspring kidneys in the PCE group exhibited glomerulosclerosis as well as DISEASE, accompanied by elevated levels of serum creatinine and urine protein. Renal angiotensin II receptor type 2 (AT2R) gene expression in adult offspring was reduced by PCE, whereas the renal angiotensin II receptor type 1a (AT1aR)/AT2R expression ratio was increased. The fetal kidneys in the PCE group displayed an enlarged Bowman's space and a shrunken glomerular tuft, accompanied by a reduced cortex width and an increase in the nephrogenic zone/cortical zone ratio. Observation by electronic microscope revealed structural damage of podocytes; the reduced expression level of podocyte marker genes, nephrin and podocin, was also detected by q-PCR. Moreover, AT2R gene and protein expressions in fetal kidneys were inhibited by PCE, associated with the repression of the gene expression of glial-cell-line-derived neurotrophic factor (GDNF)/tyrosine kinase receptor (c-Ret) signaling pathway. These results demonstrated that PCE could induce dysplasia of fetal kidneys as well as glomerulosclerosis of adult offspring, and the low functional programming of renal AT2R might mediate the developmental origin of adult glomerulosclerosis. | CHEMICAL-INDUCED-DISEASE |
| Low functional programming of renal AT2R mediates the developmental origin of glomerulosclerosis in adult offspring induced by prenatal CHEMICAL exposure. UNASSIGNED: Our previous study has indicated that prenatal CHEMICAL exposure (PCE) could induce DISEASE (DISEASE) of offspring. Recent research suggested that DISEASE is a risk factor for glomerulosclerosis. However, whether PCE could induce glomerulosclerosis and its underlying mechanisms remain unknown. This study aimed to demonstrate the induction to glomerulosclerosis in adult offspring by PCE and its intrauterine programming mechanisms. A rat model of DISEASE was established by PCE, male fetuses and adult offspring at the age of postnatal week 24 were euthanized. The results revealed that the adult offspring kidneys in the PCE group exhibited glomerulosclerosis as well as interstitial fibrosis, accompanied by elevated levels of serum creatinine and urine protein. Renal angiotensin II receptor type 2 (AT2R) gene expression in adult offspring was reduced by PCE, whereas the renal angiotensin II receptor type 1a (AT1aR)/AT2R expression ratio was increased. The fetal kidneys in the PCE group displayed an enlarged Bowman's space and a shrunken glomerular tuft, accompanied by a reduced cortex width and an increase in the nephrogenic zone/cortical zone ratio. Observation by electronic microscope revealed structural damage of podocytes; the reduced expression level of podocyte marker genes, nephrin and podocin, was also detected by q-PCR. Moreover, AT2R gene and protein expressions in fetal kidneys were inhibited by PCE, associated with the repression of the gene expression of glial-cell-line-derived neurotrophic factor (GDNF)/tyrosine kinase receptor (c-Ret) signaling pathway. These results demonstrated that PCE could induce dysplasia of fetal kidneys as well as glomerulosclerosis of adult offspring, and the low functional programming of renal AT2R might mediate the developmental origin of adult glomerulosclerosis. | CHEMICAL-INDUCED-DISEASE |
| Low functional programming of renal AT2R mediates the developmental origin of DISEASE in adult offspring induced by prenatal caffeine exposure. UNASSIGNED: Our previous study has indicated that prenatal caffeine exposure (PCE) could induce intrauterine growth retardation (IUGR) of offspring. Recent research suggested that IUGR is a risk factor for DISEASE. However, whether PCE could induce DISEASE and its underlying mechanisms remain unknown. This study aimed to demonstrate the induction to DISEASE in adult offspring by PCE and its intrauterine programming mechanisms. A rat model of IUGR was established by PCE, male fetuses and adult offspring at the age of postnatal week 24 were euthanized. The results revealed that the adult offspring kidneys in the PCE group exhibited DISEASE as well as interstitial fibrosis, accompanied by elevated levels of serum creatinine and urine protein. Renal CHEMICAL receptor type 2 (AT2R) gene expression in adult offspring was reduced by PCE, whereas the renal CHEMICAL receptor type 1a (AT1aR)/AT2R expression ratio was increased. The fetal kidneys in the PCE group displayed an enlarged Bowman's space and a shrunken glomerular tuft, accompanied by a reduced cortex width and an increase in the nephrogenic zone/cortical zone ratio. Observation by electronic microscope revealed structural damage of podocytes; the reduced expression level of podocyte marker genes, nephrin and podocin, was also detected by q-PCR. Moreover, AT2R gene and protein expressions in fetal kidneys were inhibited by PCE, associated with the repression of the gene expression of glial-cell-line-derived neurotrophic factor (GDNF)/tyrosine kinase receptor (c-Ret) signaling pathway. These results demonstrated that PCE could induce dysplasia of fetal kidneys as well as DISEASE of adult offspring, and the low functional programming of renal AT2R might mediate the developmental origin of adult DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Low functional programming of renal AT2R mediates the developmental origin of DISEASE in adult offspring induced by prenatal caffeine exposure. UNASSIGNED: Our previous study has indicated that prenatal caffeine exposure (PCE) could induce intrauterine growth retardation (IUGR) of offspring. Recent research suggested that IUGR is a risk factor for DISEASE. However, whether PCE could induce DISEASE and its underlying mechanisms remain unknown. This study aimed to demonstrate the induction to DISEASE in adult offspring by PCE and its intrauterine programming mechanisms. A rat model of IUGR was established by PCE, male fetuses and adult offspring at the age of postnatal week 24 were euthanized. The results revealed that the adult offspring kidneys in the PCE group exhibited DISEASE as well as interstitial fibrosis, accompanied by elevated levels of serum CHEMICAL and urine protein. Renal angiotensin II receptor type 2 (AT2R) gene expression in adult offspring was reduced by PCE, whereas the renal angiotensin II receptor type 1a (AT1aR)/AT2R expression ratio was increased. The fetal kidneys in the PCE group displayed an enlarged Bowman's space and a shrunken glomerular tuft, accompanied by a reduced cortex width and an increase in the nephrogenic zone/cortical zone ratio. Observation by electronic microscope revealed structural damage of podocytes; the reduced expression level of podocyte marker genes, nephrin and podocin, was also detected by q-PCR. Moreover, AT2R gene and protein expressions in fetal kidneys were inhibited by PCE, associated with the repression of the gene expression of glial-cell-line-derived neurotrophic factor (GDNF)/tyrosine kinase receptor (c-Ret) signaling pathway. These results demonstrated that PCE could induce dysplasia of fetal kidneys as well as DISEASE of adult offspring, and the low functional programming of renal AT2R might mediate the developmental origin of adult DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Low functional programming of renal AT2R mediates the developmental origin of DISEASE in adult offspring induced by prenatal caffeine exposure. UNASSIGNED: Our previous study has indicated that prenatal caffeine exposure (PCE) could induce intrauterine growth retardation (IUGR) of offspring. Recent research suggested that IUGR is a risk factor for DISEASE. However, whether PCE could induce DISEASE and its underlying mechanisms remain unknown. This study aimed to demonstrate the induction to DISEASE in adult offspring by PCE and its intrauterine programming mechanisms. A rat model of IUGR was established by PCE, male fetuses and adult offspring at the age of postnatal week 24 were euthanized. The results revealed that the adult offspring kidneys in the PCE group exhibited DISEASE as well as interstitial fibrosis, accompanied by elevated levels of serum creatinine and urine protein. Renal angiotensin II receptor type 2 (AT2R) gene expression in adult offspring was reduced by PCE, whereas the renal angiotensin II receptor type 1a (AT1aR)/AT2R expression ratio was increased. The fetal kidneys in the PCE group displayed an enlarged Bowman's space and a shrunken glomerular tuft, accompanied by a reduced cortex width and an increase in the nephrogenic zone/cortical zone ratio. Observation by electronic microscope revealed structural damage of podocytes; the reduced expression level of podocyte marker genes, nephrin and podocin, was also detected by q-PCR. Moreover, AT2R gene and protein expressions in fetal kidneys were inhibited by PCE, associated with the repression of the gene expression of glial-cell-line-derived neurotrophic factor (GDNF)/CHEMICAL kinase receptor (c-Ret) signaling pathway. These results demonstrated that PCE could induce dysplasia of fetal kidneys as well as DISEASE of adult offspring, and the low functional programming of renal AT2R might mediate the developmental origin of adult DISEASE. | GENE-CHEMICAL |
| CHEMICAL, CML and the t(9:22) translocation: A reality check. UNASSIGNED: Epidemiological studies of CHEMICAL have suggest that exposures to humans are associated with chronic myeloid leukemia (CML). CML has a well-documented association with ionizing radiation, but reports of associations with chemical exposures have been questioned. Ionizing radiation is capable of inducing the requisite CML-associated t(9:22) translocation (DISEASE) in appropriate cells in vitro but, thus far, chemicals have not shown this capacity. We have proposed that CHEMICAL metabolites be so tested as a reality check on the epidemiological reports. In order to conduct reliable testing in this regard, it is essential that a positive control for induction be available. We have used ionizing radiation to develop such a control. Results described here demonstrate that this agent does in fact induce pathogenic t(9:22) translocations in a human myeloid cell line in vitro, but does so at low frequencies. Conditions that will be required for studies of CHEMICAL are discussed. | CHEMICAL-INDUCED-DISEASE |
| Cancer incidence and CHEMICAL use in the Agricultural Health Study: An update. UNASSIGNED: CHEMICAL, a widely used herbicide, is classified as a Group C carcinogen by the U.S. Environmental Protection Agency based on increased liver neoplasms in female rats. Epidemiologic studies of the health effects of CHEMICAL have been limited. The Agricultural Health Study (AHS) is a prospective cohort study including licensed private and commercial pesticide applicators in Iowa and North Carolina enrolled 1993-1997. We evaluated cancer incidence through 2010/2011 (NC/IA) for 49,616 applicators, 53% of whom reported ever using CHEMICAL. We used Poisson regression to evaluate relations between two metrics of CHEMICAL use (lifetime days, intensity-weighted lifetime days) and cancer incidence. We saw no association between CHEMICAL use and incidence of all cancers combined (n = 5,701 with a 5-year lag) or most site-specific cancers. For liver cancer, in analyses restricted to exposed workers, elevations observed at higher categories of use were not statistically significant. However, trends for both lifetime and intensity-weighted lifetime days of CHEMICAL use were positive and statistically significant with an unexposed reference group. A similar pattern was observed for DISEASE, but no other lymphoma subtypes. An earlier suggestion of increased lung cancer risk at high levels of CHEMICAL use in this cohort was not confirmed in this update. This suggestion of an association between CHEMICAL and liver cancer among pesticide applicators is a novel finding and echoes observation of increased liver neoplasms in some animal studies. However, our findings for both liver cancer and follicular cell lymphoma warrant follow-up to better differentiate effects of CHEMICAL use from other factors. | CHEMICAL-INDUCED-DISEASE |
| Cancer incidence and CHEMICAL use in the Agricultural Health Study: An update. UNASSIGNED: CHEMICAL, a widely used herbicide, is classified as a Group C carcinogen by the U.S. Environmental Protection Agency based on increased DISEASE in female rats. Epidemiologic studies of the health effects of CHEMICAL have been limited. The Agricultural Health Study (AHS) is a prospective cohort study including licensed private and commercial pesticide applicators in Iowa and North Carolina enrolled 1993-1997. We evaluated cancer incidence through 2010/2011 (NC/IA) for 49,616 applicators, 53% of whom reported ever using CHEMICAL. We used Poisson regression to evaluate relations between two metrics of CHEMICAL use (lifetime days, intensity-weighted lifetime days) and cancer incidence. We saw no association between CHEMICAL use and incidence of all cancers combined (n = 5,701 with a 5-year lag) or most site-specific cancers. For DISEASE, in analyses restricted to exposed workers, elevations observed at higher categories of use were not statistically significant. However, trends for both lifetime and intensity-weighted lifetime days of CHEMICAL use were positive and statistically significant with an unexposed reference group. A similar pattern was observed for follicular cell lymphoma, but no other lymphoma subtypes. An earlier suggestion of increased lung cancer risk at high levels of CHEMICAL use in this cohort was not confirmed in this update. This suggestion of an association between CHEMICAL and DISEASE among pesticide applicators is a novel finding and echoes observation of increased DISEASE in some animal studies. However, our findings for both DISEASE and follicular cell lymphoma warrant follow-up to better differentiate effects of CHEMICAL use from other factors. | CHEMICAL-INDUCED-DISEASE |
| Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Research Trends and Scientific Gaps. BACKGROUND: Millions of individuals worldwide, particularly those living in rural and developing areas, are exposed to harmful levels of CHEMICAL (CHEMICAL) in their drinking water. CHEMICAL exposure during key developmental periods is associated with a variety of adverse health effects including those that are evident in adulthood. There is considerable interest in identifying the molecular mechanisms that relate early-life CHEMICAL exposure to the development of these latent diseases, particularly in relationship to DISEASE. OBJECTIVES: This work summarizes research on the molecular mechanisms that underlie the increased risk of DISEASE development in adulthood that is associated with early-life CHEMICAL exposure. DISCUSSION: Epigenetic reprogramming that imparts functional changes in gene expression, the development of DISEASE stem cells, and immunomodulation are plausible underlying mechanisms by which early-life CHEMICAL exposure elicits latent carcinogenic effects. CONCLUSIONS: Evidence is mounting that relates early-life CHEMICAL exposure and DISEASE development later in life. Future research should include animal studies that address mechanistic hypotheses and studies of human populations that integrate early-life exposure, molecular alterations, and latent disease outcomes. | CHEMICAL-INDUCED-DISEASE |
| On the antiarrhythmic activity of one N-substituted piperazine derivative of trans-2-amino-3-hydroxy-1, 2, 3, 4-tetrahydroanaphthalene. The antiarrhythmic activity of the compound N-(trans-3-hydroxy-1,2,3,4-tetrahydro-2-naphthyl)-N-(3-oxo-3-phenyl-2-methylpropyl)-piperazine hydrochloride, referred to as P11, is studied on anaesthesized cats and Wistar albino rats, as well as on non-anaesthesized rabbits. Four types of experimental DISEASE are used--with BaCl2, with CHEMICAL-adrenaline, with strophantine G and with aconitine. The compound P11 is introduced in doses of 0.25 and 0.50 mg/kg intravenously and 10 mg/kg orally. The compound manifests antiarrhythmic activity in all models of experimental DISEASE used, causing greatest inhibition on the DISEASE induced by CHEMICAL-adrenaline (in 90 per cent) and with BaCl2 (in 84 per cent). The results obtained are associated with the beta-adrenoblocking and with the membrane-stabilizing action of the compound. | CHEMICAL-INDUCED-DISEASE |
| On the antiarrhythmic activity of one N-substituted piperazine derivative of trans-2-amino-3-hydroxy-1, 2, 3, 4-tetrahydroanaphthalene. The antiarrhythmic activity of the compound N-(trans-3-hydroxy-1,2,3,4-tetrahydro-2-naphthyl)-N-(3-oxo-3-phenyl-2-methylpropyl)-piperazine hydrochloride, referred to as P11, is studied on anaesthesized cats and Wistar albino rats, as well as on non-anaesthesized rabbits. Four types of experimental DISEASE are used--with CHEMICAL, with chloroform-adrenaline, with strophantine G and with aconitine. The compound P11 is introduced in doses of 0.25 and 0.50 mg/kg intravenously and 10 mg/kg orally. The compound manifests antiarrhythmic activity in all models of experimental DISEASE used, causing greatest inhibition on the DISEASE induced by chloroform-adrenaline (in 90 per cent) and with CHEMICAL (in 84 per cent). The results obtained are associated with the beta-adrenoblocking and with the membrane-stabilizing action of the compound. | CHEMICAL-INDUCED-DISEASE |
| On the antiarrhythmic activity of one N-substituted piperazine derivative of trans-2-amino-3-hydroxy-1, 2, 3, 4-tetrahydroanaphthalene. The antiarrhythmic activity of the compound N-(trans-3-hydroxy-1,2,3,4-tetrahydro-2-naphthyl)-N-(3-oxo-3-phenyl-2-methylpropyl)-piperazine hydrochloride, referred to as P11, is studied on anaesthesized cats and Wistar albino rats, as well as on non-anaesthesized rabbits. Four types of experimental DISEASE are used--with BaCl2, with chloroform-adrenaline, with strophantine G and with CHEMICAL. The compound P11 is introduced in doses of 0.25 and 0.50 mg/kg intravenously and 10 mg/kg orally. The compound manifests antiarrhythmic activity in all models of experimental DISEASE used, causing greatest inhibition on the DISEASE induced by chloroform-adrenaline (in 90 per cent) and with BaCl2 (in 84 per cent). The results obtained are associated with the beta-adrenoblocking and with the membrane-stabilizing action of the compound. | CHEMICAL-INDUCED-DISEASE |
| On the antiarrhythmic activity of one N-substituted piperazine derivative of trans-2-amino-3-hydroxy-1, 2, 3, 4-tetrahydroanaphthalene. The antiarrhythmic activity of the compound N-(trans-3-hydroxy-1,2,3,4-tetrahydro-2-naphthyl)-N-(3-oxo-3-phenyl-2-methylpropyl)-piperazine hydrochloride, referred to as P11, is studied on anaesthesized cats and Wistar albino rats, as well as on non-anaesthesized rabbits. Four types of experimental DISEASE are used--with BaCl2, with chloroform-CHEMICAL, with strophantine G and with aconitine. The compound P11 is introduced in doses of 0.25 and 0.50 mg/kg intravenously and 10 mg/kg orally. The compound manifests antiarrhythmic activity in all models of experimental DISEASE used, causing greatest inhibition on the DISEASE induced by chloroform-CHEMICAL (in 90 per cent) and with BaCl2 (in 84 per cent). The results obtained are associated with the beta-adrenoblocking and with the membrane-stabilizing action of the compound. | CHEMICAL-INDUCED-DISEASE |
| On the antiarrhythmic activity of one N-substituted piperazine derivative of trans-2-amino-3-hydroxy-1, 2, 3, 4-tetrahydroanaphthalene. The antiarrhythmic activity of the compound N-(trans-3-hydroxy-1,2,3,4-tetrahydro-2-naphthyl)-N-(3-oxo-3-phenyl-2-methylpropyl)-piperazine hydrochloride, referred to as P11, is studied on anaesthesized cats and Wistar albino rats, as well as on non-anaesthesized rabbits. Four types of experimental DISEASE are used--with BaCl2, with chloroform-adrenaline, with CHEMICAL and with aconitine. The compound P11 is introduced in doses of 0.25 and 0.50 mg/kg intravenously and 10 mg/kg orally. The compound manifests antiarrhythmic activity in all models of experimental DISEASE used, causing greatest inhibition on the DISEASE induced by chloroform-adrenaline (in 90 per cent) and with BaCl2 (in 84 per cent). The results obtained are associated with the beta-adrenoblocking and with the membrane-stabilizing action of the compound. | CHEMICAL-INDUCED-DISEASE |
| Experimental progressive DISEASE and its treatment with high doses anabolizing agents. We are still a long way from discovering an unequivocal pathogenetic interpretation of progressive DISEASE in man. Noteworthy efforts have been made in the experimental field; a recessive autosomic form found in the mouse seems to bear the closest resemblance to the human form from the genetic point of view. Myopathy due to lack of vitamin E and myopathy induced by certain viruses have much in common anatomically and pathologically with the human form. The authors induced DISEASE in the rat by giving it a diet lacking in vitamin E. The pharmacological characteristics of vitamin E and the degenerative changes brought about by its deficiency, especially in the muscles, are illustrated. It is thus confirmed that the histological characteristics of myopathic rat muscle induced experimentally are extraordinarily similar to those of human myopathy as confirmed during biopsies performed at the Orthopaedic Traumatological Centre, Florence. The encouraging results obtained in various authoratative departments in myopathic patients by using anabolizing steroids have encouraged the authors to investigate the beneficial effects of one anabolizing agent (CHEMICAL, CIBA) at high doses in rats rendered myopathic by a diet deficient in vitamin E. In this way they obtained appreciable changes in body weight (increased from 50 to 70 g after forty days at a dose of 5 mg per day of anabolizing agent), but most of all they found histological changes due to "regenerative" changes in the muscle tissue, which however maintained its myopathic characteristics in the control animals that were not treated with the anabolizing agent. The authors conclude by affirming the undoubted efficacy of the anabolizing steroids in experimental myopathic disease, but they have reservations as to the transfer of the results into the human field, where high dosage cannot be carried out continuously because of the effects of the drug on virility; because the tissue injury too often occurs at an irreversible stage vis-a-vis the "regeneration" of the muscle tissue; and finally because the dystrophic injurious agent is certainly not the lack of vitamin E but something as yet unknown. | CHEMICAL-INDUCED-DISEASE |
| Experimental progressive DISEASE and its treatment with high doses anabolizing agents. We are still a long way from discovering an unequivocal pathogenetic interpretation of progressive DISEASE in man. Noteworthy efforts have been made in the experimental field; a recessive autosomic form found in the mouse seems to bear the closest resemblance to the human form from the genetic point of view. Myopathy due to lack of CHEMICAL and myopathy induced by certain viruses have much in common anatomically and pathologically with the human form. The authors induced DISEASE in the rat by giving it a diet lacking in CHEMICAL. The pharmacological characteristics of CHEMICAL and the degenerative changes brought about by its deficiency, especially in the muscles, are illustrated. It is thus confirmed that the histological characteristics of myopathic rat muscle induced experimentally are extraordinarily similar to those of human myopathy as confirmed during biopsies performed at the Orthopaedic Traumatological Centre, Florence. The encouraging results obtained in various authoratative departments in myopathic patients by using anabolizing steroids have encouraged the authors to investigate the beneficial effects of one anabolizing agent (Dianabol, CIBA) at high doses in rats rendered myopathic by a diet deficient in CHEMICAL. In this way they obtained appreciable changes in body weight (increased from 50 to 70 g after forty days at a dose of 5 mg per day of anabolizing agent), but most of all they found histological changes due to "regenerative" changes in the muscle tissue, which however maintained its myopathic characteristics in the control animals that were not treated with the anabolizing agent. The authors conclude by affirming the undoubted efficacy of the anabolizing steroids in experimental myopathic disease, but they have reservations as to the transfer of the results into the human field, where high dosage cannot be carried out continuously because of the effects of the drug on virility; because the tissue injury too often occurs at an irreversible stage vis-a-vis the "regeneration" of the muscle tissue; and finally because the dystrophic injurious agent is certainly not the lack of CHEMICAL but something as yet unknown. | CHEMICAL-INDUCED-DISEASE |
| Experimental progressive muscular dystrophy and its treatment with high doses anabolizing agents. We are still a long way from discovering an unequivocal pathogenetic interpretation of progressive muscular dystrophy in man. Noteworthy efforts have been made in the experimental field; a recessive autosomic form found in the mouse seems to bear the closest resemblance to the human form from the genetic point of view. DISEASE due to lack of vitamin E and DISEASE induced by certain viruses have much in common anatomically and pathologically with the human form. The authors induced myodystrophy in the rat by giving it a diet lacking in vitamin E. The pharmacological characteristics of vitamin E and the degenerative changes brought about by its deficiency, especially in the muscles, are illustrated. It is thus confirmed that the histological characteristics of DISEASE rat muscle induced experimentally are extraordinarily similar to those of human DISEASE as confirmed during biopsies performed at the Orthopaedic Traumatological Centre, Florence. The encouraging results obtained in various authoratative departments in DISEASE patients by using anabolizing steroids have encouraged the authors to investigate the beneficial effects of one anabolizing agent (Dianabol, CHEMICAL) at high doses in rats rendered DISEASE by a diet deficient in vitamin E. In this way they obtained appreciable changes in body weight (increased from 50 to 70 g after forty days at a dose of 5 mg per day of anabolizing agent), but most of all they found histological changes due to "regenerative" changes in the muscle tissue, which however maintained its DISEASE characteristics in the control animals that were not treated with the anabolizing agent. The authors conclude by affirming the undoubted efficacy of the anabolizing steroids in experimental DISEASE, but they have reservations as to the transfer of the results into the human field, where high dosage cannot be carried out continuously because of the effects of the drug on virility; because the tissue injury too often occurs at an irreversible stage vis-a-vis the "regeneration" of the muscle tissue; and finally because the dystrophic injurious agent is certainly not the lack of vitamin E but something as yet unknown. | CHEMICAL-INDUCED-DISEASE |
| Experimental progressive muscular dystrophy and its treatment with high doses anabolizing agents. We are still a long way from discovering an unequivocal pathogenetic interpretation of progressive muscular dystrophy in man. Noteworthy efforts have been made in the experimental field; a recessive autosomic form found in the mouse seems to bear the closest resemblance to the human form from the genetic point of view. DISEASE due to lack of vitamin E and DISEASE induced by certain viruses have much in common anatomically and pathologically with the human form. The authors induced myodystrophy in the rat by giving it a diet lacking in vitamin E. The pharmacological characteristics of vitamin E and the degenerative changes brought about by its deficiency, especially in the muscles, are illustrated. It is thus confirmed that the histological characteristics of DISEASE rat muscle induced experimentally are extraordinarily similar to those of human DISEASE as confirmed during biopsies performed at the Orthopaedic Traumatological Centre, Florence. The encouraging results obtained in various authoratative departments in DISEASE patients by using anabolizing CHEMICAL have encouraged the authors to investigate the beneficial effects of one anabolizing agent (Dianabol, CIBA) at high doses in rats rendered DISEASE by a diet deficient in vitamin E. In this way they obtained appreciable changes in body weight (increased from 50 to 70 g after forty days at a dose of 5 mg per day of anabolizing agent), but most of all they found histological changes due to "regenerative" changes in the muscle tissue, which however maintained its DISEASE characteristics in the control animals that were not treated with the anabolizing agent. The authors conclude by affirming the undoubted efficacy of the anabolizing CHEMICAL in experimental DISEASE, but they have reservations as to the transfer of the results into the human field, where high dosage cannot be carried out continuously because of the effects of the drug on virility; because the tissue injury too often occurs at an irreversible stage vis-a-vis the "regeneration" of the muscle tissue; and finally because the dystrophic injurious agent is certainly not the lack of vitamin E but something as yet unknown. | CHEMICAL-INDUCED-DISEASE |
| Fetal risks due to CHEMICAL therapy during pregnancy. Two mothers with heart valve prosthesis were treated with CHEMICAL during pregnancy. In the first case a caesarean section was done one week after replacement of CHEMICAL with heparin. The baby died of cerebral and pulmonary hemorrhage. The second mother had a male infant by caesarean section. The baby showed CHEMICAL-induced embryopathy with nasal hypoplasia and DISEASE (DISEASE). Nasal hypoplasia with or without DISEASE has now been reported in 11 infants born to mothers treated with CHEMICAL during the first trimester, and a causal association is probable. In view of the risks to both mother and fetus in women with prosthetic cardiac valves it is recommended that therapeutic abortion be advised as the first alternative. | CHEMICAL-INDUCED-DISEASE |
| Fetal risks due to warfarin therapy during pregnancy. Two mothers with heart valve prosthesis were treated with warfarin during pregnancy. In the first case a caesarean section was done one week after replacement of warfarin with CHEMICAL. The baby died of cerebral and pulmonary hemorrhage. The second mother had a male infant by caesarean section. The baby showed warfarin-induced embryopathy with DISEASE and stippled epiphyses (chondrodysplasia punctata). DISEASE with or without stippled epiphyses has now been reported in 11 infants born to mothers treated with warfarin during the first trimester, and a causal association is probable. In view of the risks to both mother and fetus in women with prosthetic cardiac valves it is recommended that therapeutic abortion be advised as the first alternative. | NO-RELATIONSHIP |
| Fetal risks due to warfarin therapy during pregnancy. Two mothers with heart valve prosthesis were treated with warfarin during pregnancy. In the first case a caesarean section was done one week after replacement of warfarin with CHEMICAL. The baby died of DISEASE. The second mother had a male infant by caesarean section. The baby showed warfarin-induced embryopathy with nasal hypoplasia and stippled epiphyses (chondrodysplasia punctata). Nasal hypoplasia with or without stippled epiphyses has now been reported in 11 infants born to mothers treated with warfarin during the first trimester, and a causal association is probable. In view of the risks to both mother and fetus in women with prosthetic cardiac valves it is recommended that therapeutic abortion be advised as the first alternative. | NO-RELATIONSHIP |
| Fetal risks due to warfarin therapy during pregnancy. Two mothers with heart valve prosthesis were treated with warfarin during pregnancy. In the first case a caesarean section was done one week after replacement of warfarin with CHEMICAL. The baby died of cerebral and pulmonary hemorrhage. The second mother had a male infant by caesarean section. The baby showed warfarin-induced DISEASE with nasal hypoplasia and stippled epiphyses (chondrodysplasia punctata). Nasal hypoplasia with or without stippled epiphyses has now been reported in 11 infants born to mothers treated with warfarin during the first trimester, and a causal association is probable. In view of the risks to both mother and fetus in women with prosthetic cardiac valves it is recommended that therapeutic abortion be advised as the first alternative. | NO-RELATIONSHIP |
| CHEMICAL treatment for hypertension in general practice in Hong Kong. A 6-week open study of the introduction of CHEMICAL treatment was conducted in general practice in Hong Kong. 303 Chinese patients with mild to moderate hypertension entered the study. Side effects were reported in 21% of patients and caused withdrawal from the study in 3 patients. The main side-effects were DISEASE, dizziness, palpitation and flushing and these were not more frequent than reported in other studies with CHEMICAL or with placebo. Supine blood pressure was reduced (P less than 0.01) from 170 +/- 20/102 +/- 6 mmHg to 153 +/- 19/92 +/- 8, 147 +/- 18/88 +/- 7 and 144 +/- 14/87 +/- 6 mmHg at 2, 4 and 6 weeks respectively in evaluable patients. Similar reductions occurred in standing blood pressure and there was no evidence of postural hypotension. Normalization and responder rates at 6 weeks were 86% and 69% respectively. Dosage was increased from 2.5 mg b.d. to 5 mg b.d. at 4 weeks in patients with diastolic blood pressure greater than 90 mmHg and their further response was greater than those remaining on 2.5 mg b.d. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL treatment for hypertension in general practice in Hong Kong. A 6-week open study of the introduction of CHEMICAL treatment was conducted in general practice in Hong Kong. 303 Chinese patients with mild to moderate hypertension entered the study. Side effects were reported in 21% of patients and caused withdrawal from the study in 3 patients. The main side-effects were headache, DISEASE, palpitation and flushing and these were not more frequent than reported in other studies with CHEMICAL or with placebo. Supine blood pressure was reduced (P less than 0.01) from 170 +/- 20/102 +/- 6 mmHg to 153 +/- 19/92 +/- 8, 147 +/- 18/88 +/- 7 and 144 +/- 14/87 +/- 6 mmHg at 2, 4 and 6 weeks respectively in evaluable patients. Similar reductions occurred in standing blood pressure and there was no evidence of postural hypotension. Normalization and responder rates at 6 weeks were 86% and 69% respectively. Dosage was increased from 2.5 mg b.d. to 5 mg b.d. at 4 weeks in patients with diastolic blood pressure greater than 90 mmHg and their further response was greater than those remaining on 2.5 mg b.d. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL treatment for hypertension in general practice in Hong Kong. A 6-week open study of the introduction of CHEMICAL treatment was conducted in general practice in Hong Kong. 303 Chinese patients with mild to moderate hypertension entered the study. Side effects were reported in 21% of patients and caused withdrawal from the study in 3 patients. The main side-effects were headache, dizziness, palpitation and DISEASE and these were not more frequent than reported in other studies with CHEMICAL or with placebo. Supine blood pressure was reduced (P less than 0.01) from 170 +/- 20/102 +/- 6 mmHg to 153 +/- 19/92 +/- 8, 147 +/- 18/88 +/- 7 and 144 +/- 14/87 +/- 6 mmHg at 2, 4 and 6 weeks respectively in evaluable patients. Similar reductions occurred in standing blood pressure and there was no evidence of postural hypotension. Normalization and responder rates at 6 weeks were 86% and 69% respectively. Dosage was increased from 2.5 mg b.d. to 5 mg b.d. at 4 weeks in patients with diastolic blood pressure greater than 90 mmHg and their further response was greater than those remaining on 2.5 mg b.d. | CHEMICAL-INDUCED-DISEASE |
| Tachyphylaxis to systemic but not to airway responses during prolonged therapy with high dose inhaled CHEMICAL in asthmatics. High doses of inhaled CHEMICAL produce substantial improvements in airway response in patients with asthma, and are associated with dose-dependent systemic beta-adrenoceptor responses. The purpose of the present study was to investigate whether tachyphylaxis occurs during prolonged treatment with high dose inhaled CHEMICAL. Twelve asthmatic patients (FEV1, 81 +/- 4% predicted), requiring only occasional inhaled beta-agonists as their sole therapy, were given a 14-day treatment with high dose inhaled CHEMICAL (HDS), 4,000 micrograms daily, low dose inhaled CHEMICAL (LDS), 800 micrograms daily, or placebo (PI) by metered-dose inhaler in a double-blind, randomized crossover design. During the 14-day run-in and during washout periods, inhaled beta-agonists were withheld and ipratropium bromide was substituted for rescue purposes. At the end of each 14-day treatment, a dose-response curve (DRC) was performed, and airway (FEV1, FEF25-75) chronotropic (HR), DISEASE, and metabolic (K, Glu) responses were measured at each step (from 100 to 4,000 micrograms). Treatment had no significant effect on baseline values. There were dose-dependent increases in FEV1 and FEF25-75 (p less than 0.001), and pretreatment with HDS did not displace the DRC to the right. DRC for HR (p less than 0.001), K (p less than 0.001), and Glu (p less than 0.005) were attenuated after treatment with HDS compared with PI. There were also differences between HDS and LDS for HR (p less than 0.001) and Glu (p less than 0.05) responses. Frequency and severity of subjective adverse effects were also reduced after HDS: tremor (p less than 0.001), palpitations (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) | CHEMICAL-INDUCED-DISEASE |
| Tachyphylaxis to systemic but not to airway responses during prolonged therapy with high dose inhaled salbutamol in DISEASE. High doses of inhaled salbutamol produce substantial improvements in airway response in patients with DISEASE, and are associated with dose-dependent systemic beta-adrenoceptor responses. The purpose of the present study was to investigate whether tachyphylaxis occurs during prolonged treatment with high dose inhaled salbutamol. Twelve DISEASE patients (FEV1, 81 +/- 4% predicted), requiring only occasional inhaled beta-agonists as their sole therapy, were given a 14-day treatment with high dose inhaled salbutamol (HDS), 4,000 micrograms daily, low dose inhaled salbutamol (LDS), 800 micrograms daily, or placebo (PI) by metered-dose inhaler in a double-blind, randomized crossover design. During the 14-day run-in and during washout periods, inhaled beta-agonists were withheld and CHEMICAL was substituted for rescue purposes. At the end of each 14-day treatment, a dose-response curve (DRC) was performed, and airway (FEV1, FEF25-75) chronotropic (HR), tremor, and metabolic (K, Glu) responses were measured at each step (from 100 to 4,000 micrograms). Treatment had no significant effect on baseline values. There were dose-dependent increases in FEV1 and FEF25-75 (p less than 0.001), and pretreatment with HDS did not displace the DRC to the right. DRC for HR (p less than 0.001), K (p less than 0.001), and Glu (p less than 0.005) were attenuated after treatment with HDS compared with PI. There were also differences between HDS and LDS for HR (p less than 0.001) and Glu (p less than 0.05) responses. Frequency and severity of subjective adverse effects were also reduced after HDS: tremor (p less than 0.001), palpitations (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Tachyphylaxis to systemic but not to airway responses during prolonged therapy with high dose inhaled salbutamol in DISEASE. High doses of inhaled salbutamol produce substantial improvements in airway response in patients with DISEASE, and are associated with dose-dependent systemic beta-adrenoceptor responses. The purpose of the present study was to investigate whether tachyphylaxis occurs during prolonged treatment with high dose inhaled salbutamol. Twelve DISEASE patients (FEV1, 81 +/- 4% predicted), requiring only occasional inhaled beta-agonists as their sole therapy, were given a 14-day treatment with high dose inhaled salbutamol (HDS), 4,000 micrograms daily, low dose inhaled salbutamol (LDS), 800 micrograms daily, or placebo (PI) by metered-dose inhaler in a double-blind, randomized crossover design. During the 14-day run-in and during washout periods, inhaled beta-agonists were withheld and ipratropium bromide was substituted for rescue purposes. At the end of each 14-day treatment, a dose-response curve (DRC) was performed, and airway (FEV1, FEF25-75) chronotropic (HR), tremor, and metabolic (CHEMICAL, Glu) responses were measured at each step (from 100 to 4,000 micrograms). Treatment had no significant effect on baseline values. There were dose-dependent increases in FEV1 and FEF25-75 (p less than 0.001), and pretreatment with HDS did not displace the DRC to the right. DRC for HR (p less than 0.001), K (p less than 0.001), and Glu (p less than 0.005) were attenuated after treatment with HDS compared with PI. There were also differences between HDS and LDS for HR (p less than 0.001) and Glu (p less than 0.05) responses. Frequency and severity of subjective adverse effects were also reduced after HDS: tremor (p less than 0.001), palpitations (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Increased anxiogenic effects of CHEMICAL in panic disorders. The effects of oral administration of CHEMICAL (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder. CHEMICAL produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, restlessness, and DISEASE in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma CHEMICAL levels. Seventy-one percent of the patients reported that the behavioral effects of CHEMICAL were similar to those experienced during panic attacks. CHEMICAL did not alter plasma MHPG levels in either the healthy subjects or patients. CHEMICAL increased plasma cortisol levels equally in the patient and healthy groups. Because CHEMICAL is an adenosine receptor antagonist, these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving adenosine. Patients with anxiety disorders may benefit by avoiding CHEMICAL-containing foods and beverages. | CHEMICAL-INDUCED-DISEASE |
| Increased anxiogenic effects of CHEMICAL in panic disorders. The effects of oral administration of CHEMICAL (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder. CHEMICAL produced significantly greater increases in subject-rated anxiety, nervousness, fear, DISEASE, palpitations, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma CHEMICAL levels. Seventy-one percent of the patients reported that the behavioral effects of CHEMICAL were similar to those experienced during panic attacks. CHEMICAL did not alter plasma MHPG levels in either the healthy subjects or patients. CHEMICAL increased plasma cortisol levels equally in the patient and healthy groups. Because CHEMICAL is an adenosine receptor antagonist, these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving adenosine. Patients with anxiety disorders may benefit by avoiding CHEMICAL-containing foods and beverages. | CHEMICAL-INDUCED-DISEASE |
| Increased anxiogenic effects of CHEMICAL in panic disorders. The effects of oral administration of CHEMICAL (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder. CHEMICAL produced significantly greater increases in subject-rated DISEASE, nervousness, fear, nausea, palpitations, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma CHEMICAL levels. Seventy-one percent of the patients reported that the behavioral effects of CHEMICAL were similar to those experienced during panic attacks. CHEMICAL did not alter plasma MHPG levels in either the healthy subjects or patients. CHEMICAL increased plasma cortisol levels equally in the patient and healthy groups. Because CHEMICAL is an adenosine receptor antagonist, these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving adenosine. Patients with DISEASE may benefit by avoiding CHEMICAL-containing foods and beverages. | CHEMICAL-INDUCED-DISEASE |
| Increased anxiogenic effects of caffeine in panic disorders. The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of CHEMICAL (CHEMICAL) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, DISEASE, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks. Caffeine did not alter plasma CHEMICAL levels in either the healthy subjects or patients. Caffeine increased plasma cortisol levels equally in the patient and healthy groups. Because caffeine is an adenosine receptor antagonist, these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving adenosine. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages. | NO-RELATIONSHIP |
| Increased anxiogenic effects of caffeine in panic disorders. The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and CHEMICAL were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, DISEASE, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks. Caffeine did not alter plasma MHPG levels in either the healthy subjects or patients. Caffeine increased plasma CHEMICAL levels equally in the patient and healthy groups. Because caffeine is an adenosine receptor antagonist, these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving adenosine. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages. | NO-RELATIONSHIP |
| Increased anxiogenic effects of caffeine in panic disorders. The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and CHEMICAL were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks. Caffeine did not alter plasma MHPG levels in either the healthy subjects or patients. Caffeine increased plasma CHEMICAL levels equally in the patient and healthy groups. Because caffeine is an adenosine receptor antagonist, these results suggest that some panic disorder patients may have DISEASE involving adenosine. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages. | NO-RELATIONSHIP |
| Increased anxiogenic effects of caffeine in panic disorders. The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, DISEASE, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks. Caffeine did not alter plasma MHPG levels in either the healthy subjects or patients. Caffeine increased plasma cortisol levels equally in the patient and healthy groups. Because caffeine is an CHEMICAL receptor antagonist, these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving CHEMICAL. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages. | NO-RELATIONSHIP |
| Increased anxiogenic effects of caffeine in panic disorders. The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of CHEMICAL (CHEMICAL) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, DISEASE, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks. Caffeine did not alter plasma CHEMICAL levels in either the healthy subjects or patients. Caffeine increased plasma cortisol levels equally in the patient and healthy groups. Because caffeine is an adenosine receptor antagonist, these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving adenosine. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages. | NO-RELATIONSHIP |
| Increased anxiogenic effects of caffeine in panic disorders. The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for DISEASE with panic attacks or panic disorder. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks. Caffeine did not alter plasma MHPG levels in either the healthy subjects or patients. Caffeine increased plasma cortisol levels equally in the patient and healthy groups. Because caffeine is an CHEMICAL receptor antagonist, these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving CHEMICAL. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages. | NO-RELATIONSHIP |
| Increased anxiogenic effects of caffeine in panic disorders. The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of CHEMICAL (CHEMICAL) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for DISEASE with panic attacks or panic disorder. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks. Caffeine did not alter plasma CHEMICAL levels in either the healthy subjects or patients. Caffeine increased plasma cortisol levels equally in the patient and healthy groups. Because caffeine is an adenosine receptor antagonist, these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving adenosine. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages. | NO-RELATIONSHIP |
| Increased anxiogenic effects of caffeine in panic disorders. The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of CHEMICAL (CHEMICAL) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks. Caffeine did not alter plasma CHEMICAL levels in either the healthy subjects or patients. Caffeine increased plasma cortisol levels equally in the patient and healthy groups. Because caffeine is an adenosine receptor antagonist, these results suggest that some panic disorder patients may have DISEASE involving adenosine. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages. | NO-RELATIONSHIP |
| Increased anxiogenic effects of caffeine in DISEASE. The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with DISEASE or DISEASE. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during DISEASE. Caffeine did not alter plasma MHPG levels in either the healthy subjects or patients. Caffeine increased plasma cortisol levels equally in the patient and healthy groups. Because caffeine is an CHEMICAL receptor antagonist, these results suggest that some DISEASE patients may have abnormalities in neuronal systems involving CHEMICAL. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages. | NO-RELATIONSHIP |
| Increased anxiogenic effects of caffeine in DISEASE. The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of CHEMICAL (CHEMICAL) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with DISEASE or DISEASE. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during DISEASE. Caffeine did not alter plasma CHEMICAL levels in either the healthy subjects or patients. Caffeine increased plasma cortisol levels equally in the patient and healthy groups. Because caffeine is an adenosine receptor antagonist, these results suggest that some DISEASE patients may have abnormalities in neuronal systems involving adenosine. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages. | NO-RELATIONSHIP |
| Increased anxiogenic effects of caffeine in DISEASE. The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and CHEMICAL were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with DISEASE or DISEASE. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during DISEASE. Caffeine did not alter plasma MHPG levels in either the healthy subjects or patients. Caffeine increased plasma CHEMICAL levels equally in the patient and healthy groups. Because caffeine is an adenosine receptor antagonist, these results suggest that some DISEASE patients may have abnormalities in neuronal systems involving adenosine. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages. | NO-RELATIONSHIP |
| Increased anxiogenic effects of caffeine in panic disorders. The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and CHEMICAL were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, DISEASE, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks. Caffeine did not alter plasma MHPG levels in either the healthy subjects or patients. Caffeine increased plasma CHEMICAL levels equally in the patient and healthy groups. Because caffeine is an adenosine receptor antagonist, these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving adenosine. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages. | NO-RELATIONSHIP |
| Increased anxiogenic effects of caffeine in panic disorders. The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and CHEMICAL were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for DISEASE with panic attacks or panic disorder. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks. Caffeine did not alter plasma MHPG levels in either the healthy subjects or patients. Caffeine increased plasma CHEMICAL levels equally in the patient and healthy groups. Because caffeine is an adenosine receptor antagonist, these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving adenosine. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages. | NO-RELATIONSHIP |
| Increased anxiogenic effects of caffeine in panic disorders. The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, DISEASE, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks. Caffeine did not alter plasma MHPG levels in either the healthy subjects or patients. Caffeine increased plasma cortisol levels equally in the patient and healthy groups. Because caffeine is an CHEMICAL receptor antagonist, these results suggest that some panic disorder patients may have abnormalities in neuronal systems involving CHEMICAL. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages. | NO-RELATIONSHIP |
| Increased anxiogenic effects of caffeine in panic disorders. The effects of oral administration of caffeine (10 mg/kg) on behavioral ratings, somatic symptoms, blood pressure and plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and cortisol were determined in 17 healthy subjects and 21 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder. Caffeine produced significantly greater increases in subject-rated anxiety, nervousness, fear, nausea, palpitations, restlessness, and tremors in the patients compared with healthy subjects. In the patients, but not the healthy subjects, these symptoms were significantly correlated with plasma caffeine levels. Seventy-one percent of the patients reported that the behavioral effects of caffeine were similar to those experienced during panic attacks. Caffeine did not alter plasma MHPG levels in either the healthy subjects or patients. Caffeine increased plasma cortisol levels equally in the patient and healthy groups. Because caffeine is an CHEMICAL receptor antagonist, these results suggest that some panic disorder patients may have DISEASE involving CHEMICAL. Patients with anxiety disorders may benefit by avoiding caffeine-containing foods and beverages. | NO-RELATIONSHIP |
| Human and canine ventricular vasoactive intestinal polypeptide: decrease with DISEASE. Vasoactive intestinal polypeptide (VIP) is a systemic and coronary vasodilator that may have positive inotropic properties. Myocardial levels of VIP were assayed before and after the development of DISEASE in two canine models. In the first, cobalt cardiomyopathy was induced in eight dogs; VIP (by radioimmunoassay) decreased from 35 +/- 11 pg/mg protein (mean +/- SD) to 5 +/- 4 pg/mg protein (P less than 0.05). In six dogs with CHEMICAL-induced DISEASE, VIP decreased from 31 +/- 7 to 11 +/- 4 pg/mg protein (P less than 0.05). In addition, VIP content of left ventricular muscle of resected failing hearts in 10 patients receiving a heart transplant was compared with the papillary muscles in 14 patients (five with rheumatic disease, nine with myxomatous degeneration) receiving mitral valve prostheses. The lowest myocardial VIP concentration was found in the hearts of patients with coronary disease (one patient receiving a transplant and three receiving mitral prostheses) (6.3 +/- 1.9 pg/mg protein). The other patients undergoing transplantation had an average ejection fraction of 17% +/- 6% and a VIP level of 8.8 +/- 3.9 pg/mg protein. The hearts without coronary artery disease (average ejection fraction of this group 62% +/- 10%) had a VIP concentration of 14.1 +/- 7.9 pg/mg protein, and this was greater than in hearts of the patients with coronary disease and the hearts of patients receiving a transplant (P less than 0.05). Myocardial catecholamines were also determined in 14 subjects; a weak correlation (r = 0.57, P less than 0.05) between the tissue concentrations of VIP and norepinephrine was noted.(ABSTRACT TRUNCATED AT 250 WORDS) | CHEMICAL-INDUCED-DISEASE |
| Human and canine ventricular vasoactive intestinal polypeptide: decrease with heart failure. Vasoactive intestinal polypeptide (VIP) is a systemic and coronary vasodilator that may have positive inotropic properties. Myocardial levels of VIP were assayed before and after the development of heart failure in two canine models. In the first, CHEMICAL DISEASE was induced in eight dogs; VIP (by radioimmunoassay) decreased from 35 +/- 11 pg/mg protein (mean +/- SD) to 5 +/- 4 pg/mg protein (P less than 0.05). In six dogs with doxorubicin-induced heart failure, VIP decreased from 31 +/- 7 to 11 +/- 4 pg/mg protein (P less than 0.05). In addition, VIP content of left ventricular muscle of resected failing hearts in 10 patients receiving a heart transplant was compared with the papillary muscles in 14 patients (five with rheumatic disease, nine with myxomatous degeneration) receiving mitral valve prostheses. The lowest myocardial VIP concentration was found in the hearts of patients with coronary disease (one patient receiving a transplant and three receiving mitral prostheses) (6.3 +/- 1.9 pg/mg protein). The other patients undergoing transplantation had an average ejection fraction of 17% +/- 6% and a VIP level of 8.8 +/- 3.9 pg/mg protein. The hearts without coronary artery disease (average ejection fraction of this group 62% +/- 10%) had a VIP concentration of 14.1 +/- 7.9 pg/mg protein, and this was greater than in hearts of the patients with coronary disease and the hearts of patients receiving a transplant (P less than 0.05). Myocardial catecholamines were also determined in 14 subjects; a weak correlation (r = 0.57, P less than 0.05) between the tissue concentrations of VIP and norepinephrine was noted.(ABSTRACT TRUNCATED AT 250 WORDS) | CHEMICAL-INDUCED-DISEASE |
| Human and canine ventricular vasoactive intestinal polypeptide: decrease with heart failure. Vasoactive intestinal polypeptide (VIP) is a systemic and coronary vasodilator that may have positive inotropic properties. Myocardial levels of VIP were assayed before and after the development of heart failure in two canine models. In the first, cobalt cardiomyopathy was induced in eight dogs; VIP (by radioimmunoassay) decreased from 35 +/- 11 pg/mg protein (mean +/- SD) to 5 +/- 4 pg/mg protein (P less than 0.05). In six dogs with doxorubicin-induced heart failure, VIP decreased from 31 +/- 7 to 11 +/- 4 pg/mg protein (P less than 0.05). In addition, VIP content of left ventricular muscle of resected failing hearts in 10 patients receiving a heart transplant was compared with the papillary muscles in 14 patients (five with DISEASE, nine with myxomatous degeneration) receiving mitral valve prostheses. The lowest myocardial VIP concentration was found in the hearts of patients with coronary disease (one patient receiving a transplant and three receiving mitral prostheses) (6.3 +/- 1.9 pg/mg protein). The other patients undergoing transplantation had an average ejection fraction of 17% +/- 6% and a VIP level of 8.8 +/- 3.9 pg/mg protein. The hearts without coronary artery disease (average ejection fraction of this group 62% +/- 10%) had a VIP concentration of 14.1 +/- 7.9 pg/mg protein, and this was greater than in hearts of the patients with coronary disease and the hearts of patients receiving a transplant (P less than 0.05). Myocardial CHEMICAL were also determined in 14 subjects; a weak correlation (r = 0.57, P less than 0.05) between the tissue concentrations of VIP and norepinephrine was noted.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Human and canine ventricular vasoactive intestinal polypeptide: decrease with heart failure. Vasoactive intestinal polypeptide (VIP) is a systemic and coronary vasodilator that may have positive inotropic properties. Myocardial levels of VIP were assayed before and after the development of heart failure in two canine models. In the first, cobalt cardiomyopathy was induced in eight dogs; VIP (by radioimmunoassay) decreased from 35 +/- 11 pg/mg protein (mean +/- SD) to 5 +/- 4 pg/mg protein (P less than 0.05). In six dogs with doxorubicin-induced heart failure, VIP decreased from 31 +/- 7 to 11 +/- 4 pg/mg protein (P less than 0.05). In addition, VIP content of left ventricular muscle of resected failing hearts in 10 patients receiving a heart transplant was compared with the papillary muscles in 14 patients (five with rheumatic disease, nine with myxomatous degeneration) receiving mitral valve prostheses. The lowest myocardial VIP concentration was found in the hearts of patients with DISEASE (one patient receiving a transplant and three receiving mitral prostheses) (6.3 +/- 1.9 pg/mg protein). The other patients undergoing transplantation had an average ejection fraction of 17% +/- 6% and a VIP level of 8.8 +/- 3.9 pg/mg protein. The hearts without coronary artery disease (average ejection fraction of this group 62% +/- 10%) had a VIP concentration of 14.1 +/- 7.9 pg/mg protein, and this was greater than in hearts of the patients with DISEASE and the hearts of patients receiving a transplant (P less than 0.05). Myocardial catecholamines were also determined in 14 subjects; a weak correlation (r = 0.57, P less than 0.05) between the tissue concentrations of VIP and CHEMICAL was noted.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Human and canine ventricular vasoactive intestinal polypeptide: decrease with heart failure. Vasoactive intestinal polypeptide (VIP) is a systemic and coronary vasodilator that may have positive inotropic properties. Myocardial levels of VIP were assayed before and after the development of heart failure in two canine models. In the first, cobalt cardiomyopathy was induced in eight dogs; VIP (by radioimmunoassay) decreased from 35 +/- 11 pg/mg protein (mean +/- SD) to 5 +/- 4 pg/mg protein (P less than 0.05). In six dogs with doxorubicin-induced heart failure, VIP decreased from 31 +/- 7 to 11 +/- 4 pg/mg protein (P less than 0.05). In addition, VIP content of left ventricular muscle of resected failing hearts in 10 patients receiving a heart transplant was compared with the papillary muscles in 14 patients (five with rheumatic disease, nine with DISEASE) receiving mitral valve prostheses. The lowest myocardial VIP concentration was found in the hearts of patients with coronary disease (one patient receiving a transplant and three receiving mitral prostheses) (6.3 +/- 1.9 pg/mg protein). The other patients undergoing transplantation had an average ejection fraction of 17% +/- 6% and a VIP level of 8.8 +/- 3.9 pg/mg protein. The hearts without coronary artery disease (average ejection fraction of this group 62% +/- 10%) had a VIP concentration of 14.1 +/- 7.9 pg/mg protein, and this was greater than in hearts of the patients with coronary disease and the hearts of patients receiving a transplant (P less than 0.05). Myocardial CHEMICAL were also determined in 14 subjects; a weak correlation (r = 0.57, P less than 0.05) between the tissue concentrations of VIP and norepinephrine was noted.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Human and canine ventricular vasoactive intestinal polypeptide: decrease with heart failure. Vasoactive intestinal polypeptide (VIP) is a systemic and coronary vasodilator that may have positive inotropic properties. Myocardial levels of VIP were assayed before and after the development of heart failure in two canine models. In the first, cobalt cardiomyopathy was induced in eight dogs; VIP (by radioimmunoassay) decreased from 35 +/- 11 pg/mg protein (mean +/- SD) to 5 +/- 4 pg/mg protein (P less than 0.05). In six dogs with doxorubicin-induced heart failure, VIP decreased from 31 +/- 7 to 11 +/- 4 pg/mg protein (P less than 0.05). In addition, VIP content of left ventricular muscle of resected failing hearts in 10 patients receiving a heart transplant was compared with the papillary muscles in 14 patients (five with DISEASE, nine with myxomatous degeneration) receiving mitral valve prostheses. The lowest myocardial VIP concentration was found in the hearts of patients with coronary disease (one patient receiving a transplant and three receiving mitral prostheses) (6.3 +/- 1.9 pg/mg protein). The other patients undergoing transplantation had an average ejection fraction of 17% +/- 6% and a VIP level of 8.8 +/- 3.9 pg/mg protein. The hearts without coronary artery disease (average ejection fraction of this group 62% +/- 10%) had a VIP concentration of 14.1 +/- 7.9 pg/mg protein, and this was greater than in hearts of the patients with coronary disease and the hearts of patients receiving a transplant (P less than 0.05). Myocardial catecholamines were also determined in 14 subjects; a weak correlation (r = 0.57, P less than 0.05) between the tissue concentrations of VIP and CHEMICAL was noted.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Human and canine ventricular vasoactive intestinal polypeptide: decrease with heart failure. Vasoactive intestinal polypeptide (VIP) is a systemic and coronary vasodilator that may have positive inotropic properties. Myocardial levels of VIP were assayed before and after the development of heart failure in two canine models. In the first, cobalt cardiomyopathy was induced in eight dogs; VIP (by radioimmunoassay) decreased from 35 +/- 11 pg/mg protein (mean +/- SD) to 5 +/- 4 pg/mg protein (P less than 0.05). In six dogs with doxorubicin-induced heart failure, VIP decreased from 31 +/- 7 to 11 +/- 4 pg/mg protein (P less than 0.05). In addition, VIP content of left ventricular muscle of resected failing hearts in 10 patients receiving a heart transplant was compared with the papillary muscles in 14 patients (five with rheumatic disease, nine with myxomatous degeneration) receiving mitral valve prostheses. The lowest myocardial VIP concentration was found in the hearts of patients with coronary disease (one patient receiving a transplant and three receiving mitral prostheses) (6.3 +/- 1.9 pg/mg protein). The other patients undergoing transplantation had an average ejection fraction of 17% +/- 6% and a VIP level of 8.8 +/- 3.9 pg/mg protein. The hearts without DISEASE (average ejection fraction of this group 62% +/- 10%) had a VIP concentration of 14.1 +/- 7.9 pg/mg protein, and this was greater than in hearts of the patients with coronary disease and the hearts of patients receiving a transplant (P less than 0.05). Myocardial catecholamines were also determined in 14 subjects; a weak correlation (r = 0.57, P less than 0.05) between the tissue concentrations of VIP and CHEMICAL was noted.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Human and canine ventricular vasoactive intestinal polypeptide: decrease with heart failure. Vasoactive intestinal polypeptide (VIP) is a systemic and coronary vasodilator that may have positive inotropic properties. Myocardial levels of VIP were assayed before and after the development of heart failure in two canine models. In the first, cobalt cardiomyopathy was induced in eight dogs; VIP (by radioimmunoassay) decreased from 35 +/- 11 pg/mg protein (mean +/- SD) to 5 +/- 4 pg/mg protein (P less than 0.05). In six dogs with doxorubicin-induced heart failure, VIP decreased from 31 +/- 7 to 11 +/- 4 pg/mg protein (P less than 0.05). In addition, VIP content of left ventricular muscle of resected failing hearts in 10 patients receiving a heart transplant was compared with the papillary muscles in 14 patients (five with rheumatic disease, nine with myxomatous degeneration) receiving mitral valve prostheses. The lowest myocardial VIP concentration was found in the hearts of patients with coronary disease (one patient receiving a transplant and three receiving mitral prostheses) (6.3 +/- 1.9 pg/mg protein). The other patients undergoing transplantation had an average ejection fraction of 17% +/- 6% and a VIP level of 8.8 +/- 3.9 pg/mg protein. The hearts without DISEASE (average ejection fraction of this group 62% +/- 10%) had a VIP concentration of 14.1 +/- 7.9 pg/mg protein, and this was greater than in hearts of the patients with coronary disease and the hearts of patients receiving a transplant (P less than 0.05). Myocardial CHEMICAL were also determined in 14 subjects; a weak correlation (r = 0.57, P less than 0.05) between the tissue concentrations of VIP and norepinephrine was noted.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Human and canine ventricular vasoactive intestinal polypeptide: decrease with heart failure. Vasoactive intestinal polypeptide (VIP) is a systemic and coronary vasodilator that may have positive inotropic properties. Myocardial levels of VIP were assayed before and after the development of heart failure in two canine models. In the first, cobalt cardiomyopathy was induced in eight dogs; VIP (by radioimmunoassay) decreased from 35 +/- 11 pg/mg protein (mean +/- SD) to 5 +/- 4 pg/mg protein (P less than 0.05). In six dogs with doxorubicin-induced heart failure, VIP decreased from 31 +/- 7 to 11 +/- 4 pg/mg protein (P less than 0.05). In addition, VIP content of left ventricular muscle of resected failing hearts in 10 patients receiving a heart transplant was compared with the papillary muscles in 14 patients (five with rheumatic disease, nine with myxomatous degeneration) receiving mitral valve prostheses. The lowest myocardial VIP concentration was found in the hearts of patients with DISEASE (one patient receiving a transplant and three receiving mitral prostheses) (6.3 +/- 1.9 pg/mg protein). The other patients undergoing transplantation had an average ejection fraction of 17% +/- 6% and a VIP level of 8.8 +/- 3.9 pg/mg protein. The hearts without coronary artery disease (average ejection fraction of this group 62% +/- 10%) had a VIP concentration of 14.1 +/- 7.9 pg/mg protein, and this was greater than in hearts of the patients with DISEASE and the hearts of patients receiving a transplant (P less than 0.05). Myocardial CHEMICAL were also determined in 14 subjects; a weak correlation (r = 0.57, P less than 0.05) between the tissue concentrations of VIP and norepinephrine was noted.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Human and canine ventricular vasoactive intestinal polypeptide: decrease with heart failure. Vasoactive intestinal polypeptide (VIP) is a systemic and coronary vasodilator that may have positive inotropic properties. Myocardial levels of VIP were assayed before and after the development of heart failure in two canine models. In the first, cobalt cardiomyopathy was induced in eight dogs; VIP (by radioimmunoassay) decreased from 35 +/- 11 pg/mg protein (mean +/- SD) to 5 +/- 4 pg/mg protein (P less than 0.05). In six dogs with doxorubicin-induced heart failure, VIP decreased from 31 +/- 7 to 11 +/- 4 pg/mg protein (P less than 0.05). In addition, VIP content of left ventricular muscle of resected failing hearts in 10 patients receiving a heart transplant was compared with the papillary muscles in 14 patients (five with rheumatic disease, nine with DISEASE) receiving mitral valve prostheses. The lowest myocardial VIP concentration was found in the hearts of patients with coronary disease (one patient receiving a transplant and three receiving mitral prostheses) (6.3 +/- 1.9 pg/mg protein). The other patients undergoing transplantation had an average ejection fraction of 17% +/- 6% and a VIP level of 8.8 +/- 3.9 pg/mg protein. The hearts without coronary artery disease (average ejection fraction of this group 62% +/- 10%) had a VIP concentration of 14.1 +/- 7.9 pg/mg protein, and this was greater than in hearts of the patients with coronary disease and the hearts of patients receiving a transplant (P less than 0.05). Myocardial catecholamines were also determined in 14 subjects; a weak correlation (r = 0.57, P less than 0.05) between the tissue concentrations of VIP and CHEMICAL was noted.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Interstrain variation in acute toxic response to CHEMICAL among inbred mice. Acute toxic dosage-dependent behavioral effects of CHEMICAL were compared in adult males from seven inbred mouse strains (A/J, BALB/cJ, CBA/J, C3H/HeJ, C57BL/6J, DBA/2J, SWR/J). C57BL/6J, chosen as a "prototypic" mouse strain, was used to determine behavioral responses to a broad range (5-500 mg/kg) of CHEMICAL doses. Five phenotypic characteristics--locomotor activity, righting ability, DISEASE induction, stress-induced lethality, death without external stress--were scored at various CHEMICAL doses in drug-naive animals under empirically optimized, rigidly constant experimental conditions. Mice (n = 12 for each point) received single IP injections of a fixed volume/g body weight of physiological saline carrier with or without CHEMICAL in doses ranging from 125-500 mg/kg. Loss of righting ability was scored at 1, 3, 5 min post dosing and at 5 min intervals thereafter for 20 min. In the same animals the occurrence of DISEASE was scored as to time of onset and severity for 20 min after drug administration. When these proceeded to DISEASE, death occurred in less than 20 min. Animals surviving for 20 min were immediately stressed by a swim test in 25 degrees C water, and death-producing DISEASE were scored for 2 min. In other animals locomotor activity was measured 15 or 60 min after CHEMICAL administration. By any single behavioral criterion or a combination of these criteria, marked differences in response to toxic CHEMICAL doses were observed between strains. These results indicate that behavioral toxicity testing of alkylxanthines in a single mouse strain may be misleading and suggest that toxic responses of the central nervous system to this class of compounds are genetically influenced in mammals. | CHEMICAL-INDUCED-DISEASE |
| Interstrain variation in acute toxic response to caffeine among inbred mice. Acute toxic dosage-dependent behavioral effects of caffeine were compared in adult males from seven inbred mouse strains (A/J, BALB/cJ, CBA/J, C3H/HeJ, C57BL/6J, DBA/2J, SWR/J). C57BL/6J, chosen as a "prototypic" mouse strain, was used to determine behavioral responses to a broad range (5-500 mg/kg) of caffeine doses. Five phenotypic characteristics--locomotor activity, righting ability, clonic seizure induction, stress-induced lethality, death without external stress--were scored at various caffeine doses in drug-naive animals under empirically optimized, rigidly constant experimental conditions. Mice (n = 12 for each point) received single IP injections of a fixed volume/g body weight of physiological saline carrier with or without caffeine in doses ranging from 125-500 mg/kg. Loss of righting ability was scored at 1, 3, 5 min post dosing and at 5 min intervals thereafter for 20 min. In the same animals the occurrence of clonic seizures was scored as to time of onset and severity for 20 min after drug administration. When these proceeded to tonic seizures, death occurred in less than 20 min. Animals surviving for 20 min were immediately stressed by a swim test in 25 degrees C water, and death-producing tonic seizures were scored for 2 min. In other animals locomotor activity was measured 15 or 60 min after caffeine administration. By any single behavioral criterion or a combination of these criteria, marked differences in response to toxic caffeine doses were observed between strains. These results indicate that behavioral DISEASE testing of CHEMICAL in a single mouse strain may be misleading and suggest that toxic responses of the central nervous system to this class of compounds are genetically influenced in mammals. | NO-RELATIONSHIP |
| Invasive carcinoma of the renal pelvis following CHEMICAL therapy for nonmalignant disease. A 47-year-old woman with right hydroureteronephrosis due to ureterovesical junction obstruction had gross DISEASE after being treated for five years wtih CHEMICAL for cerebral vasculitis. A right nephroureterectomy was required for control of bleeding. The pathology specimen contained clinically occult invasive carcinoma of the renal pelvis. Although the ability of CHEMICAL to cause hemorrhagic cystitis and urine cytologic abnormalities indistinguishable from high grade carcinoma is well known, it is less widely appreciated that it is also associated with carcinoma of the urinary tract. Twenty carcinomas of the urinary bladder and one carcinoma of the prostate have been reported in association with its use. The present case is the first carcinoma of the renal pelvis reported in association with CHEMICAL treatment. It is the third urinary tract cancer reported in association with CHEMICAL treatment for nonmalignant disease. The association of the tumor with preexisting hydroureteronephrosis suggests that stasis prolonged and intensified exposure of upper urinary tract epithelium to CHEMICAL. Patients who are candidates for long-term CHEMICAL treatment should be routinely evaluated for obstructive uropathy. | CHEMICAL-INDUCED-DISEASE |
| Invasive carcinoma of the renal pelvis following CHEMICAL therapy for nonmalignant disease. A 47-year-old woman with right hydroureteronephrosis due to ureterovesical junction obstruction had gross hematuria after being treated for five years wtih CHEMICAL for cerebral vasculitis. A right nephroureterectomy was required for control of bleeding. The pathology specimen contained clinically occult invasive carcinoma of the renal pelvis. Although the ability of CHEMICAL to cause hemorrhagic cystitis and urine cytologic abnormalities indistinguishable from high grade DISEASE is well known, it is less widely appreciated that it is also associated with carcinoma of the urinary tract. Twenty carcinomas of the urinary bladder and one carcinoma of the prostate have been reported in association with its use. The present case is the first carcinoma of the renal pelvis reported in association with CHEMICAL treatment. It is the third urinary tract cancer reported in association with CHEMICAL treatment for nonmalignant disease. The association of the tumor with preexisting hydroureteronephrosis suggests that stasis prolonged and intensified exposure of upper urinary tract epithelium to CHEMICAL. Patients who are candidates for long-term CHEMICAL treatment should be routinely evaluated for obstructive uropathy. | CHEMICAL-INDUCED-DISEASE |
| Invasive carcinoma of the renal pelvis following CHEMICAL therapy for nonmalignant disease. A 47-year-old woman with right hydroureteronephrosis due to ureterovesical junction obstruction had gross hematuria after being treated for five years wtih CHEMICAL for cerebral vasculitis. A right nephroureterectomy was required for control of bleeding. The pathology specimen contained clinically occult invasive carcinoma of the renal pelvis. Although the ability of CHEMICAL to cause hemorrhagic cystitis and urine cytologic abnormalities indistinguishable from high grade carcinoma is well known, it is less widely appreciated that it is also associated with carcinoma of the urinary tract. Twenty DISEASE and one carcinoma of the prostate have been reported in association with its use. The present case is the first carcinoma of the renal pelvis reported in association with CHEMICAL treatment. It is the third urinary tract cancer reported in association with CHEMICAL treatment for nonmalignant disease. The association of the tumor with preexisting hydroureteronephrosis suggests that stasis prolonged and intensified exposure of upper urinary tract epithelium to CHEMICAL. Patients who are candidates for long-term CHEMICAL treatment should be routinely evaluated for obstructive uropathy. | CHEMICAL-INDUCED-DISEASE |
| Ascending dose tolerance study of intramuscular CHEMICAL administered after normal vaginal birth. OBJECTIVE: To determine the maximum tolerated dose (MTD) of CHEMICAL (a long-acting synthetic analogue of oxytocin), when administered immediately after vaginal delivery at term. MATERIALS AND METHODS: CHEMICAL was given as an intramuscular injection immediately after the birth of the infant in 45 healthy women with normal singleton pregnancies who delivered vaginally at term. Dosage groups of 15, 30, 50, 75, 100, 125, 150, 175 or 200 microg CHEMICAL were assigned to blocks of three women according to the continual reassessment method (CRM). RESULTS: All dosage groups consisted of three women, except those with 100 microg (n=6) and 200 microg (n=18). Recorded were dose-limiting adverse events: hyper- or hypotension (three), severe abdominal pain (0), vomiting (0) and DISEASE (four). Serious adverse events occurred in seven women: six cases with blood loss > or = 1000 ml, four cases of manual placenta removal, five cases of additional oxytocics administration and five cases of blood transfusion. Maximum blood loss was greatest at the upper and lower dose levels, and lowest in the 70-125 microg dose range. Four out of six cases with blood loss > or = 1000 ml occurred in the 200 microg group. The majority of additional administration of oxytocics (4/5) and blood transfusion (3/5) occurred in the dose groups of 200 microg. All retained placentae were found in the group of 200 microg. CONCLUSION: The MTD was calculated to be at 200 microg CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Ascending dose tolerance study of intramuscular CHEMICAL administered after normal vaginal birth. OBJECTIVE: To determine the maximum tolerated dose (MTD) of CHEMICAL (a long-acting synthetic analogue of oxytocin), when administered immediately after vaginal delivery at term. MATERIALS AND METHODS: CHEMICAL was given as an intramuscular injection immediately after the birth of the infant in 45 healthy women with normal singleton pregnancies who delivered vaginally at term. Dosage groups of 15, 30, 50, 75, 100, 125, 150, 175 or 200 microg CHEMICAL were assigned to blocks of three women according to the continual reassessment method (CRM). RESULTS: All dosage groups consisted of three women, except those with 100 microg (n=6) and 200 microg (n=18). Recorded were dose-limiting adverse events: hyper- or hypotension (three), severe abdominal pain (0), DISEASE (0) and retained placenta (four). Serious adverse events occurred in seven women: six cases with blood loss > or = 1000 ml, four cases of manual placenta removal, five cases of additional oxytocics administration and five cases of blood transfusion. Maximum blood loss was greatest at the upper and lower dose levels, and lowest in the 70-125 microg dose range. Four out of six cases with blood loss > or = 1000 ml occurred in the 200 microg group. The majority of additional administration of oxytocics (4/5) and blood transfusion (3/5) occurred in the dose groups of 200 microg. All retained placentae were found in the group of 200 microg. CONCLUSION: The MTD was calculated to be at 200 microg CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Ascending dose tolerance study of intramuscular CHEMICAL administered after normal vaginal birth. OBJECTIVE: To determine the maximum tolerated dose (MTD) of CHEMICAL (a long-acting synthetic analogue of oxytocin), when administered immediately after vaginal delivery at term. MATERIALS AND METHODS: CHEMICAL was given as an intramuscular injection immediately after the birth of the infant in 45 healthy women with normal singleton pregnancies who delivered vaginally at term. Dosage groups of 15, 30, 50, 75, 100, 125, 150, 175 or 200 microg CHEMICAL were assigned to blocks of three women according to the continual reassessment method (CRM). RESULTS: All dosage groups consisted of three women, except those with 100 microg (n=6) and 200 microg (n=18). Recorded were dose-limiting adverse events: hyper- or hypotension (three), severe abdominal pain (0), vomiting (0) and retained placenta (four). Serious adverse events occurred in seven women: six cases with DISEASE > or = 1000 ml, four cases of manual placenta removal, five cases of additional oxytocics administration and five cases of blood transfusion. Maximum DISEASE was greatest at the upper and lower dose levels, and lowest in the 70-125 microg dose range. Four out of six cases with DISEASE > or = 1000 ml occurred in the 200 microg group. The majority of additional administration of oxytocics (4/5) and blood transfusion (3/5) occurred in the dose groups of 200 microg. All retained placentae were found in the group of 200 microg. CONCLUSION: The MTD was calculated to be at 200 microg CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Ascending dose tolerance study of intramuscular CHEMICAL administered after normal vaginal birth. OBJECTIVE: To determine the maximum tolerated dose (MTD) of CHEMICAL (a long-acting synthetic analogue of oxytocin), when administered immediately after vaginal delivery at term. MATERIALS AND METHODS: CHEMICAL was given as an intramuscular injection immediately after the birth of the infant in 45 healthy women with normal singleton pregnancies who delivered vaginally at term. Dosage groups of 15, 30, 50, 75, 100, 125, 150, 175 or 200 microg CHEMICAL were assigned to blocks of three women according to the continual reassessment method (CRM). RESULTS: All dosage groups consisted of three women, except those with 100 microg (n=6) and 200 microg (n=18). Recorded were dose-limiting adverse events: hyper- or hypotension (three), severe DISEASE (0), vomiting (0) and retained placenta (four). Serious adverse events occurred in seven women: six cases with blood loss > or = 1000 ml, four cases of manual placenta removal, five cases of additional oxytocics administration and five cases of blood transfusion. Maximum blood loss was greatest at the upper and lower dose levels, and lowest in the 70-125 microg dose range. Four out of six cases with blood loss > or = 1000 ml occurred in the 200 microg group. The majority of additional administration of oxytocics (4/5) and blood transfusion (3/5) occurred in the dose groups of 200 microg. All retained placentae were found in the group of 200 microg. CONCLUSION: The MTD was calculated to be at 200 microg CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Ascending dose tolerance study of intramuscular carbetocin administered after normal vaginal birth. OBJECTIVE: To determine the maximum tolerated dose (MTD) of carbetocin (a long-acting synthetic analogue of CHEMICAL), when administered immediately after vaginal delivery at term. MATERIALS AND METHODS: Carbetocin was given as an intramuscular injection immediately after the birth of the infant in 45 healthy women with normal singleton pregnancies who delivered vaginally at term. Dosage groups of 15, 30, 50, 75, 100, 125, 150, 175 or 200 microg carbetocin were assigned to blocks of three women according to the continual reassessment method (CRM). RESULTS: All dosage groups consisted of three women, except those with 100 microg (n=6) and 200 microg (n=18). Recorded were dose-limiting adverse events: DISEASE (three), severe abdominal pain (0), vomiting (0) and retained placenta (four). Serious adverse events occurred in seven women: six cases with blood loss > or = 1000 ml, four cases of manual placenta removal, five cases of additional oxytocics administration and five cases of blood transfusion. Maximum blood loss was greatest at the upper and lower dose levels, and lowest in the 70-125 microg dose range. Four out of six cases with blood loss > or = 1000 ml occurred in the 200 microg group. The majority of additional administration of oxytocics (4/5) and blood transfusion (3/5) occurred in the dose groups of 200 microg. All retained placentae were found in the group of 200 microg. CONCLUSION: The MTD was calculated to be at 200 microg carbetocin. | NO-RELATIONSHIP |
| A pilot study to assess the safety of dobutamine stress echocardiography in the emergency department evaluation of CHEMICAL-associated DISEASE. STUDY OBJECTIVE: DISEASE in the setting of CHEMICAL use poses a diagnostic dilemma. Dobutamine stress echocardiography (DSE) is a widely available and sensitive test for evaluating cardiac ischemia. Because of the theoretical concern regarding administration of dobutamine in the setting of CHEMICAL use, we conducted a pilot study to assess the safety of DSE in emergency department patients with CHEMICAL-associated DISEASE. METHODS: A prospective case series was conducted in the intensive diagnostic and treatment unit in the ED of an urban tertiary-care teaching hospital. Patients were eligible for DSE if they had used CHEMICAL within 24 hours preceding the onset of DISEASE and had a normal ECG and tropinin I level. Patients exhibiting signs of continuing CHEMICAL toxicity were excluded from the study. All patients were admitted to the hospital for serial testing after the DSE testing in the intensive diagnostic and treatment unit. RESULTS: Twenty-four patients were enrolled. Two patients had inadequate resting images, one DSE was terminated because of inferior hypokinesis, another DSE was terminated because of a rate-related atrial conduction deficit, and 1 patient did not reach the target heart rate. Thus, 19 patients completed a DSE and reached their target heart rates. None of the patients experienced signs of exaggerated adrenergic response, which was defined as a systolic blood pressure of greater than 200 mm Hg or the occurrence of tachydysrhythmias (excluding sinus tachycardia). Further suggesting lack of exaggerated adrenergic response, 13 (65%) of 20 patients required supplemental atropine to reach their target heart rates. CONCLUSION: No exaggerated adrenergic response was detected when dobutamine was administered to patients with CHEMICAL-related DISEASE. | CHEMICAL-INDUCED-DISEASE |
| A pilot study to assess the safety of dobutamine stress echocardiography in the emergency department evaluation of cocaine-associated chest pain. STUDY OBJECTIVE: Chest pain in the setting of cocaine use poses a diagnostic dilemma. Dobutamine stress echocardiography (DSE) is a widely available and sensitive test for evaluating cardiac ischemia. Because of the theoretical concern regarding administration of dobutamine in the setting of cocaine use, we conducted a pilot study to assess the safety of DSE in emergency department patients with cocaine-associated chest pain. METHODS: A prospective case series was conducted in the intensive diagnostic and treatment unit in the ED of an urban tertiary-care teaching hospital. Patients were eligible for DSE if they had used cocaine within 24 hours preceding the onset of chest pain and had a normal ECG and tropinin I level. Patients exhibiting signs of continuing cocaine DISEASE were excluded from the study. All patients were admitted to the hospital for serial testing after the DSE testing in the intensive diagnostic and treatment unit. RESULTS: Twenty-four patients were enrolled. Two patients had inadequate resting images, one DSE was terminated because of inferior hypokinesis, another DSE was terminated because of a rate-related atrial conduction deficit, and 1 patient did not reach the target heart rate. Thus, 19 patients completed a DSE and reached their target heart rates. None of the patients experienced signs of exaggerated adrenergic response, which was defined as a systolic blood pressure of greater than 200 mm Hg or the occurrence of tachydysrhythmias (excluding sinus tachycardia). Further suggesting lack of exaggerated adrenergic response, 13 (65%) of 20 patients required supplemental CHEMICAL to reach their target heart rates. CONCLUSION: No exaggerated adrenergic response was detected when dobutamine was administered to patients with cocaine-related chest pain. | NO-RELATIONSHIP |
| A pilot study to assess the safety of CHEMICAL stress echocardiography in the emergency department evaluation of cocaine-associated chest pain. STUDY OBJECTIVE: Chest pain in the setting of cocaine use poses a diagnostic dilemma. CHEMICAL stress echocardiography (DSE) is a widely available and sensitive test for evaluating cardiac DISEASE. Because of the theoretical concern regarding administration of CHEMICAL in the setting of cocaine use, we conducted a pilot study to assess the safety of DSE in emergency department patients with cocaine-associated chest pain. METHODS: A prospective case series was conducted in the intensive diagnostic and treatment unit in the ED of an urban tertiary-care teaching hospital. Patients were eligible for DSE if they had used cocaine within 24 hours preceding the onset of chest pain and had a normal ECG and tropinin I level. Patients exhibiting signs of continuing cocaine toxicity were excluded from the study. All patients were admitted to the hospital for serial testing after the DSE testing in the intensive diagnostic and treatment unit. RESULTS: Twenty-four patients were enrolled. Two patients had inadequate resting images, one DSE was terminated because of inferior hypokinesis, another DSE was terminated because of a rate-related atrial conduction deficit, and 1 patient did not reach the target heart rate. Thus, 19 patients completed a DSE and reached their target heart rates. None of the patients experienced signs of exaggerated adrenergic response, which was defined as a systolic blood pressure of greater than 200 mm Hg or the occurrence of tachydysrhythmias (excluding sinus tachycardia). Further suggesting lack of exaggerated adrenergic response, 13 (65%) of 20 patients required supplemental atropine to reach their target heart rates. CONCLUSION: No exaggerated adrenergic response was detected when CHEMICAL was administered to patients with cocaine-related chest pain. | NO-RELATIONSHIP |
| A pilot study to assess the safety of CHEMICAL stress echocardiography in the emergency department evaluation of cocaine-associated chest pain. STUDY OBJECTIVE: Chest pain in the setting of cocaine use poses a diagnostic dilemma. CHEMICAL stress echocardiography (DSE) is a widely available and sensitive test for evaluating cardiac ischemia. Because of the theoretical concern regarding administration of CHEMICAL in the setting of cocaine use, we conducted a pilot study to assess the safety of DSE in emergency department patients with cocaine-associated chest pain. METHODS: A prospective case series was conducted in the intensive diagnostic and treatment unit in the ED of an urban tertiary-care teaching hospital. Patients were eligible for DSE if they had used cocaine within 24 hours preceding the onset of chest pain and had a normal ECG and tropinin I level. Patients exhibiting signs of continuing cocaine toxicity were excluded from the study. All patients were admitted to the hospital for serial testing after the DSE testing in the intensive diagnostic and treatment unit. RESULTS: Twenty-four patients were enrolled. Two patients had inadequate resting images, one DSE was terminated because of inferior DISEASE, another DSE was terminated because of a rate-related atrial conduction deficit, and 1 patient did not reach the target heart rate. Thus, 19 patients completed a DSE and reached their target heart rates. None of the patients experienced signs of exaggerated adrenergic response, which was defined as a systolic blood pressure of greater than 200 mm Hg or the occurrence of tachydysrhythmias (excluding sinus tachycardia). Further suggesting lack of exaggerated adrenergic response, 13 (65%) of 20 patients required supplemental atropine to reach their target heart rates. CONCLUSION: No exaggerated adrenergic response was detected when CHEMICAL was administered to patients with cocaine-related chest pain. | NO-RELATIONSHIP |
| A pilot study to assess the safety of dobutamine stress echocardiography in the emergency department evaluation of cocaine-associated chest pain. STUDY OBJECTIVE: Chest pain in the setting of cocaine use poses a diagnostic dilemma. Dobutamine stress echocardiography (DSE) is a widely available and sensitive test for evaluating cardiac ischemia. Because of the theoretical concern regarding administration of dobutamine in the setting of cocaine use, we conducted a pilot study to assess the safety of DSE in emergency department patients with cocaine-associated chest pain. METHODS: A prospective case series was conducted in the intensive diagnostic and treatment unit in the ED of an urban tertiary-care teaching hospital. Patients were eligible for DSE if they had used cocaine within 24 hours preceding the onset of chest pain and had a normal ECG and tropinin I level. Patients exhibiting signs of continuing cocaine toxicity were excluded from the study. All patients were admitted to the hospital for serial testing after the DSE testing in the intensive diagnostic and treatment unit. RESULTS: Twenty-four patients were enrolled. Two patients had inadequate resting images, one DSE was terminated because of inferior DISEASE, another DSE was terminated because of a rate-related atrial conduction deficit, and 1 patient did not reach the target heart rate. Thus, 19 patients completed a DSE and reached their target heart rates. None of the patients experienced signs of exaggerated adrenergic response, which was defined as a systolic blood pressure of greater than 200 mm Hg or the occurrence of tachydysrhythmias (excluding sinus tachycardia). Further suggesting lack of exaggerated adrenergic response, 13 (65%) of 20 patients required supplemental CHEMICAL to reach their target heart rates. CONCLUSION: No exaggerated adrenergic response was detected when dobutamine was administered to patients with cocaine-related chest pain. | NO-RELATIONSHIP |
| A pilot study to assess the safety of dobutamine stress echocardiography in the emergency department evaluation of cocaine-associated chest pain. STUDY OBJECTIVE: Chest pain in the setting of cocaine use poses a diagnostic dilemma. Dobutamine stress echocardiography (DSE) is a widely available and sensitive test for evaluating cardiac DISEASE. Because of the theoretical concern regarding administration of dobutamine in the setting of cocaine use, we conducted a pilot study to assess the safety of DSE in emergency department patients with cocaine-associated chest pain. METHODS: A prospective case series was conducted in the intensive diagnostic and treatment unit in the ED of an urban tertiary-care teaching hospital. Patients were eligible for DSE if they had used cocaine within 24 hours preceding the onset of chest pain and had a normal ECG and tropinin I level. Patients exhibiting signs of continuing cocaine toxicity were excluded from the study. All patients were admitted to the hospital for serial testing after the DSE testing in the intensive diagnostic and treatment unit. RESULTS: Twenty-four patients were enrolled. Two patients had inadequate resting images, one DSE was terminated because of inferior hypokinesis, another DSE was terminated because of a rate-related atrial conduction deficit, and 1 patient did not reach the target heart rate. Thus, 19 patients completed a DSE and reached their target heart rates. None of the patients experienced signs of exaggerated adrenergic response, which was defined as a systolic blood pressure of greater than 200 mm Hg or the occurrence of tachydysrhythmias (excluding sinus tachycardia). Further suggesting lack of exaggerated adrenergic response, 13 (65%) of 20 patients required supplemental CHEMICAL to reach their target heart rates. CONCLUSION: No exaggerated adrenergic response was detected when dobutamine was administered to patients with cocaine-related chest pain. | NO-RELATIONSHIP |
| A pilot study to assess the safety of CHEMICAL stress echocardiography in the emergency department evaluation of cocaine-associated chest pain. STUDY OBJECTIVE: Chest pain in the setting of cocaine use poses a diagnostic dilemma. CHEMICAL stress echocardiography (DSE) is a widely available and sensitive test for evaluating cardiac ischemia. Because of the theoretical concern regarding administration of CHEMICAL in the setting of cocaine use, we conducted a pilot study to assess the safety of DSE in emergency department patients with cocaine-associated chest pain. METHODS: A prospective case series was conducted in the intensive diagnostic and treatment unit in the ED of an urban tertiary-care teaching hospital. Patients were eligible for DSE if they had used cocaine within 24 hours preceding the onset of chest pain and had a normal ECG and tropinin I level. Patients exhibiting signs of continuing cocaine toxicity were excluded from the study. All patients were admitted to the hospital for serial testing after the DSE testing in the intensive diagnostic and treatment unit. RESULTS: Twenty-four patients were enrolled. Two patients had inadequate resting images, one DSE was terminated because of inferior hypokinesis, another DSE was terminated because of a rate-related atrial conduction deficit, and 1 patient did not reach the target heart rate. Thus, 19 patients completed a DSE and reached their target heart rates. None of the patients experienced signs of exaggerated adrenergic response, which was defined as a systolic blood pressure of greater than 200 mm Hg or the occurrence of tachydysrhythmias (excluding DISEASE). Further suggesting lack of exaggerated adrenergic response, 13 (65%) of 20 patients required supplemental atropine to reach their target heart rates. CONCLUSION: No exaggerated adrenergic response was detected when CHEMICAL was administered to patients with cocaine-related chest pain. | NO-RELATIONSHIP |
| A pilot study to assess the safety of CHEMICAL stress echocardiography in the emergency department evaluation of cocaine-associated chest pain. STUDY OBJECTIVE: Chest pain in the setting of cocaine use poses a diagnostic dilemma. CHEMICAL stress echocardiography (DSE) is a widely available and sensitive test for evaluating cardiac ischemia. Because of the theoretical concern regarding administration of CHEMICAL in the setting of cocaine use, we conducted a pilot study to assess the safety of DSE in emergency department patients with cocaine-associated chest pain. METHODS: A prospective case series was conducted in the intensive diagnostic and treatment unit in the ED of an urban tertiary-care teaching hospital. Patients were eligible for DSE if they had used cocaine within 24 hours preceding the onset of chest pain and had a normal ECG and tropinin I level. Patients exhibiting signs of continuing cocaine DISEASE were excluded from the study. All patients were admitted to the hospital for serial testing after the DSE testing in the intensive diagnostic and treatment unit. RESULTS: Twenty-four patients were enrolled. Two patients had inadequate resting images, one DSE was terminated because of inferior hypokinesis, another DSE was terminated because of a rate-related atrial conduction deficit, and 1 patient did not reach the target heart rate. Thus, 19 patients completed a DSE and reached their target heart rates. None of the patients experienced signs of exaggerated adrenergic response, which was defined as a systolic blood pressure of greater than 200 mm Hg or the occurrence of tachydysrhythmias (excluding sinus tachycardia). Further suggesting lack of exaggerated adrenergic response, 13 (65%) of 20 patients required supplemental atropine to reach their target heart rates. CONCLUSION: No exaggerated adrenergic response was detected when CHEMICAL was administered to patients with cocaine-related chest pain. | NO-RELATIONSHIP |
| A pilot study to assess the safety of dobutamine stress echocardiography in the emergency department evaluation of cocaine-associated chest pain. STUDY OBJECTIVE: Chest pain in the setting of cocaine use poses a diagnostic dilemma. Dobutamine stress echocardiography (DSE) is a widely available and sensitive test for evaluating cardiac ischemia. Because of the theoretical concern regarding administration of dobutamine in the setting of cocaine use, we conducted a pilot study to assess the safety of DSE in emergency department patients with cocaine-associated chest pain. METHODS: A prospective case series was conducted in the intensive diagnostic and treatment unit in the ED of an urban tertiary-care teaching hospital. Patients were eligible for DSE if they had used cocaine within 24 hours preceding the onset of chest pain and had a normal ECG and tropinin I level. Patients exhibiting signs of continuing cocaine toxicity were excluded from the study. All patients were admitted to the hospital for serial testing after the DSE testing in the intensive diagnostic and treatment unit. RESULTS: Twenty-four patients were enrolled. Two patients had inadequate resting images, one DSE was terminated because of inferior hypokinesis, another DSE was terminated because of a rate-related atrial conduction deficit, and 1 patient did not reach the target heart rate. Thus, 19 patients completed a DSE and reached their target heart rates. None of the patients experienced signs of exaggerated adrenergic response, which was defined as a systolic blood pressure of greater than 200 mm Hg or the occurrence of DISEASE (excluding sinus tachycardia). Further suggesting lack of exaggerated adrenergic response, 13 (65%) of 20 patients required supplemental CHEMICAL to reach their target heart rates. CONCLUSION: No exaggerated adrenergic response was detected when dobutamine was administered to patients with cocaine-related chest pain. | NO-RELATIONSHIP |
| A pilot study to assess the safety of dobutamine stress echocardiography in the emergency department evaluation of cocaine-associated chest pain. STUDY OBJECTIVE: Chest pain in the setting of cocaine use poses a diagnostic dilemma. Dobutamine stress echocardiography (DSE) is a widely available and sensitive test for evaluating cardiac ischemia. Because of the theoretical concern regarding administration of dobutamine in the setting of cocaine use, we conducted a pilot study to assess the safety of DSE in emergency department patients with cocaine-associated chest pain. METHODS: A prospective case series was conducted in the intensive diagnostic and treatment unit in the ED of an urban tertiary-care teaching hospital. Patients were eligible for DSE if they had used cocaine within 24 hours preceding the onset of chest pain and had a normal ECG and tropinin I level. Patients exhibiting signs of continuing cocaine toxicity were excluded from the study. All patients were admitted to the hospital for serial testing after the DSE testing in the intensive diagnostic and treatment unit. RESULTS: Twenty-four patients were enrolled. Two patients had inadequate resting images, one DSE was terminated because of inferior hypokinesis, another DSE was terminated because of a rate-related atrial conduction deficit, and 1 patient did not reach the target heart rate. Thus, 19 patients completed a DSE and reached their target heart rates. None of the patients experienced signs of exaggerated adrenergic response, which was defined as a systolic blood pressure of greater than 200 mm Hg or the occurrence of tachydysrhythmias (excluding DISEASE). Further suggesting lack of exaggerated adrenergic response, 13 (65%) of 20 patients required supplemental CHEMICAL to reach their target heart rates. CONCLUSION: No exaggerated adrenergic response was detected when dobutamine was administered to patients with cocaine-related chest pain. | NO-RELATIONSHIP |
| A pilot study to assess the safety of CHEMICAL stress echocardiography in the emergency department evaluation of cocaine-associated chest pain. STUDY OBJECTIVE: Chest pain in the setting of cocaine use poses a diagnostic dilemma. CHEMICAL stress echocardiography (DSE) is a widely available and sensitive test for evaluating cardiac ischemia. Because of the theoretical concern regarding administration of CHEMICAL in the setting of cocaine use, we conducted a pilot study to assess the safety of DSE in emergency department patients with cocaine-associated chest pain. METHODS: A prospective case series was conducted in the intensive diagnostic and treatment unit in the ED of an urban tertiary-care teaching hospital. Patients were eligible for DSE if they had used cocaine within 24 hours preceding the onset of chest pain and had a normal ECG and tropinin I level. Patients exhibiting signs of continuing cocaine toxicity were excluded from the study. All patients were admitted to the hospital for serial testing after the DSE testing in the intensive diagnostic and treatment unit. RESULTS: Twenty-four patients were enrolled. Two patients had inadequate resting images, one DSE was terminated because of inferior hypokinesis, another DSE was terminated because of a rate-related atrial conduction deficit, and 1 patient did not reach the target heart rate. Thus, 19 patients completed a DSE and reached their target heart rates. None of the patients experienced signs of exaggerated adrenergic response, which was defined as a systolic blood pressure of greater than 200 mm Hg or the occurrence of DISEASE (excluding sinus tachycardia). Further suggesting lack of exaggerated adrenergic response, 13 (65%) of 20 patients required supplemental atropine to reach their target heart rates. CONCLUSION: No exaggerated adrenergic response was detected when CHEMICAL was administered to patients with cocaine-related chest pain. | NO-RELATIONSHIP |
| CHEMICAL-induced DISEASE during bladder irrigation: an unusual presentation--a case report. The authors present a case of early (within 4 days) development of DISEASE (DISEASE) associated with oral CHEMICAL therapy. Consistent with other reports this case of DISEASE occurred in the context of multiple exacerbating factors including hypokalemia and digoxin excess. Transient prolongation of the QT during bladder irrigation prompted the episode of DISEASE. It is well known that bradycardia exacerbates acquired DISEASE. The authors speculate that the increased vagal tone during bladder irrigation, a vagal maneuver, in the context of CHEMICAL therapy resulted in CHEMICAL-induced proarrhythmia. In the absence of CHEMICAL therapy, a second bladder irrigation did not induce DISEASE despite hypokalemia and hypomagnesemia. | CHEMICAL-INDUCED-DISEASE |
| Amiodarone-induced torsade de pointes during bladder irrigation: an unusual presentation--a case report. The authors present a case of early (within 4 days) development of torsade de pointes (TdP) associated with oral amiodarone therapy. Consistent with other reports this case of TdP occurred in the context of multiple exacerbating factors including hypokalemia and CHEMICAL excess. Transient prolongation of the QT during bladder irrigation prompted the episode of TdP. It is well known that bradycardia exacerbates acquired TdP. The authors speculate that the increased vagal tone during bladder irrigation, a vagal maneuver, in the context of amiodarone therapy resulted in amiodarone-induced DISEASE. In the absence of amiodarone therapy, a second bladder irrigation did not induce TdP despite hypokalemia and hypomagnesemia. | NO-RELATIONSHIP |
| Amiodarone-induced torsade de pointes during bladder irrigation: an unusual presentation--a case report. The authors present a case of early (within 4 days) development of torsade de pointes (TdP) associated with oral amiodarone therapy. Consistent with other reports this case of TdP occurred in the context of multiple exacerbating factors including DISEASE and CHEMICAL excess. Transient prolongation of the QT during bladder irrigation prompted the episode of TdP. It is well known that bradycardia exacerbates acquired TdP. The authors speculate that the increased vagal tone during bladder irrigation, a vagal maneuver, in the context of amiodarone therapy resulted in amiodarone-induced proarrhythmia. In the absence of amiodarone therapy, a second bladder irrigation did not induce TdP despite DISEASE and hypomagnesemia. | NO-RELATIONSHIP |
| Amiodarone-induced torsade de pointes during bladder irrigation: an unusual presentation--a case report. The authors present a case of early (within 4 days) development of torsade de pointes (TdP) associated with oral amiodarone therapy. Consistent with other reports this case of TdP occurred in the context of multiple exacerbating factors including hypokalemia and CHEMICAL excess. Transient prolongation of the QT during bladder irrigation prompted the episode of TdP. It is well known that bradycardia exacerbates acquired TdP. The authors speculate that the increased vagal tone during bladder irrigation, a vagal maneuver, in the context of amiodarone therapy resulted in amiodarone-induced proarrhythmia. In the absence of amiodarone therapy, a second bladder irrigation did not induce TdP despite hypokalemia and DISEASE. | NO-RELATIONSHIP |
| Amiodarone-induced torsade de pointes during bladder irrigation: an unusual presentation--a case report. The authors present a case of early (within 4 days) development of torsade de pointes (TdP) associated with oral amiodarone therapy. Consistent with other reports this case of TdP occurred in the context of multiple exacerbating factors including hypokalemia and CHEMICAL excess. Transient prolongation of the QT during bladder irrigation prompted the episode of TdP. It is well known that DISEASE exacerbates acquired TdP. The authors speculate that the increased vagal tone during bladder irrigation, a vagal maneuver, in the context of amiodarone therapy resulted in amiodarone-induced proarrhythmia. In the absence of amiodarone therapy, a second bladder irrigation did not induce TdP despite hypokalemia and hypomagnesemia. | NO-RELATIONSHIP |
| DISEASE after high-dose CHEMICAL in patients with primary systemic amyloidosis during stem cell transplantation. BACKGROUND: Patients with primary systemic amyloidosis (AL) have a poor prognosis. Median survival time from standard treatments is only 17 months. High-dose intravenous CHEMICAL followed by peripheral blood stem cell transplant (PBSCT) appears to be the most promising therapy, but treatment mortality can be high. The authors have noted the development of DISEASE immediately after CHEMICAL conditioning. This study was undertaken to further examine its risk factors and impact on posttransplant mortality. METHODS: Consecutive AL patients who underwent PBSCT were studied retrospectively. DISEASE (DISEASE) after high-dose CHEMICAL was defined by a minimum increase of 0.5 mg/dL (44 micromol/L) in the serum creatinine level that is greater than 50% of baseline immediately after conditioning. Urine sediment score was the sum of the individual types of sediment identified on urine microscopy. RESULTS: Of the 80 patients studied, DISEASE developed in 18.8% of the patients after high-dose CHEMICAL. Univariate analysis identified age, hypoalbuminemia, heavy proteinuria, diuretic use, and urine sediment score (>3) as risk factors. Age and urine sediment score remained independently significant risk factors in the multivariate analysis. Patients who had DISEASE after high-dose CHEMICAL underwent dialysis more often (P = 0.007), and had a worse 1-year survival (P = 0.03). CONCLUSION: The timing of DISEASE strongly suggests CHEMICAL as the causative agent. Ongoing tubular injury may be a prerequisite for DISEASE by CHEMICAL as evidenced by the active urinary sediment. Development of DISEASE adversely affected the outcome after PBSCT. Effective preventive measures may help decrease the treatment mortality of PBSCT in AL patients. | CHEMICAL-INDUCED-DISEASE |
| Acute renal insufficiency after high-dose melphalan in patients with primary systemic amyloidosis during stem cell transplantation. BACKGROUND: Patients with primary systemic amyloidosis (DISEASE) have a poor prognosis. Median survival time from standard treatments is only 17 months. High-dose intravenous melphalan followed by peripheral blood stem cell transplant (PBSCT) appears to be the most promising therapy, but treatment mortality can be high. The authors have noted the development of acute renal insufficiency immediately after melphalan conditioning. This study was undertaken to further examine its risk factors and impact on posttransplant mortality. METHODS: Consecutive DISEASE patients who underwent PBSCT were studied retrospectively. Acute renal insufficiency (ARI) after high-dose melphalan was defined by a minimum increase of 0.5 mg/dL (44 micromol/L) in the serum CHEMICAL level that is greater than 50% of baseline immediately after conditioning. Urine sediment score was the sum of the individual types of sediment identified on urine microscopy. RESULTS: Of the 80 patients studied, ARI developed in 18.8% of the patients after high-dose melphalan. Univariate analysis identified age, hypoalbuminemia, heavy proteinuria, diuretic use, and urine sediment score (>3) as risk factors. Age and urine sediment score remained independently significant risk factors in the multivariate analysis. Patients who had ARI after high-dose melphalan underwent dialysis more often (P = 0.007), and had a worse 1-year survival (P = 0.03). CONCLUSION: The timing of renal injury strongly suggests melphalan as the causative agent. Ongoing tubular injury may be a prerequisite for renal injury by melphalan as evidenced by the active urinary sediment. Development of ARI adversely affected the outcome after PBSCT. Effective preventive measures may help decrease the treatment mortality of PBSCT in DISEASE patients. | NO-RELATIONSHIP |
| Acute renal insufficiency after high-dose melphalan in patients with DISEASE during stem cell transplantation. BACKGROUND: Patients with DISEASE (AL) have a poor prognosis. Median survival time from standard treatments is only 17 months. High-dose intravenous melphalan followed by peripheral blood stem cell transplant (PBSCT) appears to be the most promising therapy, but treatment mortality can be high. The authors have noted the development of acute renal insufficiency immediately after melphalan conditioning. This study was undertaken to further examine its risk factors and impact on posttransplant mortality. METHODS: Consecutive AL patients who underwent PBSCT were studied retrospectively. Acute renal insufficiency (ARI) after high-dose melphalan was defined by a minimum increase of 0.5 mg/dL (44 micromol/L) in the serum CHEMICAL level that is greater than 50% of baseline immediately after conditioning. Urine sediment score was the sum of the individual types of sediment identified on urine microscopy. RESULTS: Of the 80 patients studied, ARI developed in 18.8% of the patients after high-dose melphalan. Univariate analysis identified age, hypoalbuminemia, heavy proteinuria, diuretic use, and urine sediment score (>3) as risk factors. Age and urine sediment score remained independently significant risk factors in the multivariate analysis. Patients who had ARI after high-dose melphalan underwent dialysis more often (P = 0.007), and had a worse 1-year survival (P = 0.03). CONCLUSION: The timing of renal injury strongly suggests melphalan as the causative agent. Ongoing tubular injury may be a prerequisite for renal injury by melphalan as evidenced by the active urinary sediment. Development of ARI adversely affected the outcome after PBSCT. Effective preventive measures may help decrease the treatment mortality of PBSCT in AL patients. | NO-RELATIONSHIP |
| Acute renal insufficiency after high-dose melphalan in patients with primary systemic amyloidosis during stem cell transplantation. BACKGROUND: Patients with primary systemic amyloidosis (AL) have a poor prognosis. Median survival time from standard treatments is only 17 months. High-dose intravenous melphalan followed by peripheral blood stem cell transplant (PBSCT) appears to be the most promising therapy, but treatment mortality can be high. The authors have noted the development of acute renal insufficiency immediately after melphalan conditioning. This study was undertaken to further examine its risk factors and impact on posttransplant mortality. METHODS: Consecutive AL patients who underwent PBSCT were studied retrospectively. Acute renal insufficiency (ARI) after high-dose melphalan was defined by a minimum increase of 0.5 mg/dL (44 micromol/L) in the serum CHEMICAL level that is greater than 50% of baseline immediately after conditioning. Urine sediment score was the sum of the individual types of sediment identified on urine microscopy. RESULTS: Of the 80 patients studied, ARI developed in 18.8% of the patients after high-dose melphalan. Univariate analysis identified age, DISEASE, heavy proteinuria, diuretic use, and urine sediment score (>3) as risk factors. Age and urine sediment score remained independently significant risk factors in the multivariate analysis. Patients who had ARI after high-dose melphalan underwent dialysis more often (P = 0.007), and had a worse 1-year survival (P = 0.03). CONCLUSION: The timing of renal injury strongly suggests melphalan as the causative agent. Ongoing tubular injury may be a prerequisite for renal injury by melphalan as evidenced by the active urinary sediment. Development of ARI adversely affected the outcome after PBSCT. Effective preventive measures may help decrease the treatment mortality of PBSCT in AL patients. | NO-RELATIONSHIP |
| Acute renal insufficiency after high-dose melphalan in patients with primary systemic amyloidosis during stem cell transplantation. BACKGROUND: Patients with primary systemic amyloidosis (AL) have a poor prognosis. Median survival time from standard treatments is only 17 months. High-dose intravenous melphalan followed by peripheral blood stem cell transplant (PBSCT) appears to be the most promising therapy, but treatment mortality can be high. The authors have noted the development of acute renal insufficiency immediately after melphalan conditioning. This study was undertaken to further examine its risk factors and impact on posttransplant mortality. METHODS: Consecutive AL patients who underwent PBSCT were studied retrospectively. Acute renal insufficiency (ARI) after high-dose melphalan was defined by a minimum increase of 0.5 mg/dL (44 micromol/L) in the serum CHEMICAL level that is greater than 50% of baseline immediately after conditioning. Urine sediment score was the sum of the individual types of sediment identified on urine microscopy. RESULTS: Of the 80 patients studied, ARI developed in 18.8% of the patients after high-dose melphalan. Univariate analysis identified age, hypoalbuminemia, heavy proteinuria, diuretic use, and urine sediment score (>3) as risk factors. Age and urine sediment score remained independently significant risk factors in the multivariate analysis. Patients who had ARI after high-dose melphalan underwent dialysis more often (P = 0.007), and had a worse 1-year survival (P = 0.03). CONCLUSION: The timing of renal injury strongly suggests melphalan as the causative agent. Ongoing DISEASE may be a prerequisite for renal injury by melphalan as evidenced by the active urinary sediment. Development of ARI adversely affected the outcome after PBSCT. Effective preventive measures may help decrease the treatment mortality of PBSCT in AL patients. | NO-RELATIONSHIP |
| Acute renal insufficiency after high-dose melphalan in patients with primary systemic amyloidosis during stem cell transplantation. BACKGROUND: Patients with primary systemic amyloidosis (AL) have a poor prognosis. Median survival time from standard treatments is only 17 months. High-dose intravenous melphalan followed by peripheral blood stem cell transplant (PBSCT) appears to be the most promising therapy, but treatment mortality can be high. The authors have noted the development of acute renal insufficiency immediately after melphalan conditioning. This study was undertaken to further examine its risk factors and impact on posttransplant mortality. METHODS: Consecutive AL patients who underwent PBSCT were studied retrospectively. Acute renal insufficiency (ARI) after high-dose melphalan was defined by a minimum increase of 0.5 mg/dL (44 micromol/L) in the serum CHEMICAL level that is greater than 50% of baseline immediately after conditioning. Urine sediment score was the sum of the individual types of sediment identified on urine microscopy. RESULTS: Of the 80 patients studied, ARI developed in 18.8% of the patients after high-dose melphalan. Univariate analysis identified age, hypoalbuminemia, heavy DISEASE, diuretic use, and urine sediment score (>3) as risk factors. Age and urine sediment score remained independently significant risk factors in the multivariate analysis. Patients who had ARI after high-dose melphalan underwent dialysis more often (P = 0.007), and had a worse 1-year survival (P = 0.03). CONCLUSION: The timing of renal injury strongly suggests melphalan as the causative agent. Ongoing tubular injury may be a prerequisite for renal injury by melphalan as evidenced by the active urinary sediment. Development of ARI adversely affected the outcome after PBSCT. Effective preventive measures may help decrease the treatment mortality of PBSCT in AL patients. | NO-RELATIONSHIP |
| DISEASE in regular recreational CHEMICAL users. INTRODUCTION: The ability to read facial expressions is essential for normal human social interaction. The aim of the present study was to conduct the first investigation of facial expression recognition performance in recreational CHEMICAL users. MATERIALS AND METHODS: Three groups, comprised of 21 CHEMICAL naive participants (CN), 30 occasional CHEMICAL (OC), and 48 regular recreational CHEMICAL (RC) users, were compared. An emotional facial expression (EFE) task consisting of a male and female face expressing six basic emotions (happiness, surprise, sadness, anger, fear, and disgust) was administered. Mean percent accuracy and latencies for correct responses across eight presentations of each basic emotion were derived. Participants were also assessed with the "Eyes task" to investigate their ability to recognize more complex emotional states and the Symptom CheckList-90-Revised to measure psychopathology. RESULTS: There were no group differences in psychopathology or "eyes task" performance, but the RC group, who otherwise had similar illicit substance use histories to the OC group, exhibited DISEASE accuracy compared to the OC and CN groups. The RC group also correctly identified anger, fear, happiness, and surprise, more slowly than CN, but not OC participants. The OC group was slower than CN when correctly identifying disgust. The selective DISEASE accuracy manifested by the RC group cannot be explained by the subacute effects of CHEMICAL, or ecstasy, because recent and less recent users of these drugs within this group were similarly impaired. Possible parallels between RC users and psychopaths with respect to DISEASE, amygdala dysfunction, and etiology are discussed. | CHEMICAL-INDUCED-DISEASE |
| Impaired fear recognition in regular recreational cocaine users. INTRODUCTION: The ability to read facial expressions is essential for normal human social interaction. The aim of the present study was to conduct the first investigation of facial expression recognition performance in recreational cocaine users. MATERIALS AND METHODS: Three groups, comprised of 21 cocaine naive participants (CN), 30 occasional cocaine (OC), and 48 regular recreational cocaine (RC) users, were compared. An emotional facial expression (EFE) task consisting of a male and female face expressing six basic emotions (happiness, surprise, sadness, anger, fear, and disgust) was administered. Mean percent accuracy and latencies for correct responses across eight presentations of each basic emotion were derived. Participants were also assessed with the "Eyes task" to investigate their ability to recognize more complex emotional states and the Symptom CheckList-90-Revised to measure psychopathology. RESULTS: There were no group differences in psychopathology or "eyes task" performance, but the RC group, who otherwise had similar illicit substance use histories to the OC group, exhibited impaired fear recognition accuracy compared to the OC and CN groups. The RC group also correctly identified anger, fear, happiness, and surprise, more slowly than CN, but not OC participants. The OC group was slower than CN when correctly identifying disgust. The selective deficit in fear recognition accuracy manifested by the RC group cannot be explained by the subacute effects of cocaine, or CHEMICAL, because recent and less recent users of these drugs within this group were similarly impaired. Possible parallels between RC users and psychopaths with respect to impaired fear recognition, DISEASE, and etiology are discussed. | NO-RELATIONSHIP |
| Impaired fear recognition in regular recreational cocaine users. INTRODUCTION: The ability to read facial expressions is essential for normal human social interaction. The aim of the present study was to conduct the first investigation of facial expression recognition performance in recreational cocaine users. MATERIALS AND METHODS: Three groups, comprised of 21 cocaine naive participants (CN), 30 occasional cocaine (OC), and 48 regular recreational cocaine (RC) users, were compared. An emotional facial expression (EFE) task consisting of a male and female face expressing six basic emotions (happiness, surprise, sadness, anger, fear, and disgust) was administered. Mean percent accuracy and latencies for correct responses across eight presentations of each basic emotion were derived. Participants were also assessed with the "Eyes task" to investigate their ability to recognize more complex emotional states and the Symptom CheckList-90-Revised to measure psychopathology. RESULTS: There were no group differences in psychopathology or "eyes task" performance, but the RC group, who otherwise had similar illicit substance use histories to the OC group, exhibited impaired fear recognition accuracy compared to the OC and CN groups. The RC group also correctly identified anger, fear, happiness, and surprise, more slowly than CN, but not OC participants. The OC group was slower than CN when correctly identifying disgust. The selective deficit in fear recognition accuracy manifested by the RC group cannot be explained by the subacute effects of cocaine, or CHEMICAL, because recent and less recent users of these drugs within this group were similarly impaired. Possible parallels between RC users and DISEASE with respect to impaired fear recognition, amygdala dysfunction, and etiology are discussed. | NO-RELATIONSHIP |
| DISEASE associated with aerosolized CHEMICAL use. PURPOSE: We report 4 cases of DISEASE associated with drug abuse. The pathogenesis of these ulcers and management of these patients are also reviewed. METHODS: Review of all cases of DISEASE associated with drug abuse seen at our institution from July 2006 to December 2006. RESULTS: Four patients with DISEASE associated with CHEMICAL use were reviewed. All DISEASE were cultured, and the patients were admitted to the hospital for intensive topical antibiotic treatment. Each patient received comprehensive health care, including medical and substance abuse consultations. Streptococcal organisms were found in 3 cases and Capnocytophaga and Brevibacterium casei in 1 patient. The infections responded to antibiotic treatment. Two patients needed a lateral tarsorrhaphy for persistent epithelial defects. CONCLUSIONS: Aerosolized CHEMICAL use can be associated with the development of DISEASE. Drug abuse provides additional challenges for management. Not only treatment of their infections but also the overall poor health of the patients and increased risk of noncompliance need to be addressed. Comprehensive care may provide the patient the opportunity to discontinue their substance abuse, improve their overall health, and prevent future corneal complications. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL as an adjunct to phenobarbital treatment in cats with suspected idiopathic epilepsy. OBJECTIVE: To assess pharmacokinetics, efficacy, and tolerability of oral CHEMICAL administered as an adjunct to phenobarbital treatment in cats with poorly controlled suspected idiopathic epilepsy. DESIGN-Open-label, noncomparative clinical trial. ANIMALS: 12 cats suspected to have idiopathic epilepsy that was poorly controlled with phenobarbital or that had unacceptable adverse effects when treated with phenobarbital. PROCEDURES: Cats were treated with CHEMICAL (20 mg/kg [9.1 mg/lb], PO, q 8 h). After a minimum of 1 week of treatment, serum CHEMICAL concentrations were measured before and 2, 4, and 6 hours after drug administration, and maximum and minimum serum concentrations and elimination half-life were calculated. Seizure frequencies before and after initiation of CHEMICAL treatment were compared, and adverse effects were recorded. RESULTS: Median maximum serum CHEMICAL concentration was 25.5 microg/mL, median minimum serum CHEMICAL concentration was 8.3 microg/mL, and median elimination half-life was 2.9 hours. Median seizure frequency prior to treatment with CHEMICAL (2.1 seizures/mo) was significantly higher than median seizure frequency after initiation of CHEMICAL treatment (0.42 seizures/mo), and 7 of 10 cats were classified as having responded to CHEMICAL treatment (ie, reduction in seizure frequency of >or=50%). Two cats had transient DISEASE and inappetence. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that CHEMICAL is well tolerated in cats and may be useful as an adjunct to phenobarbital treatment in cats with idiopathic epilepsy. | CHEMICAL-INDUCED-DISEASE |
| Levetiracetam as an adjunct to CHEMICAL treatment in cats with suspected DISEASE. OBJECTIVE: To assess pharmacokinetics, efficacy, and tolerability of oral levetiracetam administered as an adjunct to CHEMICAL treatment in cats with poorly controlled suspected DISEASE. DESIGN-Open-label, noncomparative clinical trial. ANIMALS: 12 cats suspected to have DISEASE that was poorly controlled with CHEMICAL or that had unacceptable adverse effects when treated with CHEMICAL. PROCEDURES: Cats were treated with levetiracetam (20 mg/kg [9.1 mg/lb], PO, q 8 h). After a minimum of 1 week of treatment, serum levetiracetam concentrations were measured before and 2, 4, and 6 hours after drug administration, and maximum and minimum serum concentrations and elimination half-life were calculated. Seizure frequencies before and after initiation of levetiracetam treatment were compared, and adverse effects were recorded. RESULTS: Median maximum serum levetiracetam concentration was 25.5 microg/mL, median minimum serum levetiracetam concentration was 8.3 microg/mL, and median elimination half-life was 2.9 hours. Median seizure frequency prior to treatment with levetiracetam (2.1 seizures/mo) was significantly higher than median seizure frequency after initiation of levetiracetam treatment (0.42 seizures/mo), and 7 of 10 cats were classified as having responded to levetiracetam treatment (ie, reduction in seizure frequency of >or=50%). Two cats had transient lethargy and inappetence. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that levetiracetam is well tolerated in cats and may be useful as an adjunct to CHEMICAL treatment in cats with DISEASE. | NO-RELATIONSHIP |
| Levetiracetam as an adjunct to CHEMICAL treatment in cats with suspected idiopathic epilepsy. OBJECTIVE: To assess pharmacokinetics, efficacy, and tolerability of oral levetiracetam administered as an adjunct to CHEMICAL treatment in cats with poorly controlled suspected idiopathic epilepsy. DESIGN-Open-label, noncomparative clinical trial. ANIMALS: 12 cats suspected to have idiopathic epilepsy that was poorly controlled with CHEMICAL or that had unacceptable adverse effects when treated with CHEMICAL. PROCEDURES: Cats were treated with levetiracetam (20 mg/kg [9.1 mg/lb], PO, q 8 h). After a minimum of 1 week of treatment, serum levetiracetam concentrations were measured before and 2, 4, and 6 hours after drug administration, and maximum and minimum serum concentrations and elimination half-life were calculated. Seizure frequencies before and after initiation of levetiracetam treatment were compared, and adverse effects were recorded. RESULTS: Median maximum serum levetiracetam concentration was 25.5 microg/mL, median minimum serum levetiracetam concentration was 8.3 microg/mL, and median elimination half-life was 2.9 hours. Median seizure frequency prior to treatment with levetiracetam (2.1 seizures/mo) was significantly higher than median seizure frequency after initiation of levetiracetam treatment (0.42 seizures/mo), and 7 of 10 cats were classified as having responded to levetiracetam treatment (ie, reduction in seizure frequency of >or=50%). Two cats had transient lethargy and DISEASE. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that levetiracetam is well tolerated in cats and may be useful as an adjunct to CHEMICAL treatment in cats with idiopathic epilepsy. | CHEMICAL-INDUCED-DISEASE |
| Levetiracetam as an adjunct to CHEMICAL treatment in cats with suspected idiopathic epilepsy. OBJECTIVE: To assess pharmacokinetics, efficacy, and tolerability of oral levetiracetam administered as an adjunct to CHEMICAL treatment in cats with poorly controlled suspected idiopathic epilepsy. DESIGN-Open-label, noncomparative clinical trial. ANIMALS: 12 cats suspected to have idiopathic epilepsy that was poorly controlled with CHEMICAL or that had unacceptable adverse effects when treated with CHEMICAL. PROCEDURES: Cats were treated with levetiracetam (20 mg/kg [9.1 mg/lb], PO, q 8 h). After a minimum of 1 week of treatment, serum levetiracetam concentrations were measured before and 2, 4, and 6 hours after drug administration, and maximum and minimum serum concentrations and elimination half-life were calculated. DISEASE frequencies before and after initiation of levetiracetam treatment were compared, and adverse effects were recorded. RESULTS: Median maximum serum levetiracetam concentration was 25.5 microg/mL, median minimum serum levetiracetam concentration was 8.3 microg/mL, and median elimination half-life was 2.9 hours. Median DISEASE frequency prior to treatment with levetiracetam (2.1 DISEASE/mo) was significantly higher than median DISEASE frequency after initiation of levetiracetam treatment (0.42 DISEASE/mo), and 7 of 10 cats were classified as having responded to levetiracetam treatment (ie, reduction in DISEASE frequency of >or=50%). Two cats had transient lethargy and inappetence. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that levetiracetam is well tolerated in cats and may be useful as an adjunct to CHEMICAL treatment in cats with idiopathic epilepsy. | CHEMICAL-INDUCED-DISEASE |
| Bilateral haemorrhagic infarction of the globus pallidus after cocaine and alcohol intoxication. Cocaine is a risk factor for both ischemic and haemorrhagic stroke. We present the case of a 31-year-old man with bilateral ischemia of the globus pallidus after excessive alcohol and intranasal cocaine use. Drug-related DISEASE are most often associated with CHEMICAL. Bilateral DISEASE after the use of cocaine, without concurrent CHEMICAL use, have never been reported. In our patient, transient cardiac arrhythmia or respiratory dysfunction related to cocaine and/or ethanol use were the most likely causes of cerebral hypoperfusion. | CHEMICAL-INDUCED-DISEASE |
| Bilateral haemorrhagic infarction of the globus pallidus after CHEMICAL and alcohol intoxication. CHEMICAL is a risk factor for both ischemic and haemorrhagic stroke. We present the case of a 31-year-old man with bilateral DISEASE after excessive alcohol and intranasal CHEMICAL use. Drug-related globus pallidus infarctions are most often associated with heroin. Bilateral basal ganglia infarcts after the use of CHEMICAL, without concurrent heroin use, have never been reported. In our patient, transient cardiac arrhythmia or respiratory dysfunction related to CHEMICAL and/or ethanol use were the most likely causes of cerebral hypoperfusion. | CHEMICAL-INDUCED-DISEASE |
| DISEASE after high-dose CHEMICAL therapy in a patient with ileostomy. High-dose CHEMICAL (HD-CHEMICAL) is an important treatment for Burkitt lymphoma, but can cause hepatic and renal toxicity when its clearance is delayed. We report a case of DISEASE after HD-CHEMICAL therapy in a patient with ileostomy, The patient was a 3-year-old boy who had received a living-related liver transplantation for congenital biliary atresia. At day 833 after the transplantation, he was diagnosed with PTLD (post-transplantation lymphoproliferative disorder, Burkitt-type malignant lymphoma). During induction therapy, he suffered ileal perforation and ileostomy was performed. Subsequent HD-CHEMICAL therapy caused DISEASE that required continuous hemodialysis. We supposed that intravascular hypovolemia due to substantial drainage from the ileostoma caused acute prerenal failure. After recovery of his renal function, we could safely treat the patient with HD-CHEMICAL therapy by controlling drainage from ileostoma with total parenteral nutrition. | CHEMICAL-INDUCED-DISEASE |
| Antithrombotic drug use, cerebral microbleeds, and DISEASE: a systematic review of published and unpublished studies. BACKGROUND AND PURPOSE: Cerebral microbleeds (MB) are potential risk factors for DISEASE (DISEASE), but it is unclear if they are a contraindication to using antithrombotic drugs. Insights could be gained by pooling data on MB frequency stratified by antithrombotic use in cohorts with DISEASE and ischemic stroke (IS)/transient ischemic attack (TIA). METHODS: We performed a systematic review of published and unpublished data from cohorts with stroke or TIA to compare the presence of MB in: (1) antithrombotic users vs nonantithrombotic users with DISEASE; (2) antithrombotic users vs nonusers with IS/TIA; and (3) DISEASE vs ischemic events stratified by antithrombotic use. We also analyzed published and unpublished follow-up data to determine the risk of DISEASE in antithrombotic users with MB. RESULTS: In a pooled analysis of 1460 DISEASE and 3817 IS/TIA, MB were more frequent in DISEASE vs IS/TIA in all treatment groups, but the excess increased from 2.8 (odds ratio; range, 2.3-3.5) in nonantithrombotic users to 5.7 (range, 3.4-9.7) in antiplatelet users and 8.0 (range, 3.5-17.8) in CHEMICAL users (P difference=0.01). There was also an excess of MB in CHEMICAL users vs nonusers with DISEASE (OR, 2.7; 95% CI, 1.6-4.4; P<0.001) but none in CHEMICAL users with IS/TIA (OR, 1.3; 95% CI, 0.9-1.7; P=0.33; P difference=0.01). There was a smaller excess of MB in antiplatelet users vs nonusers with DISEASE (OR, 1.7; 95% CI, 1.3-2.3; P<0.001), but findings were similar for antiplatelet users with IS/TIA (OR, 1.4; 95% CI, 1.2-1.7; P<0.001; P difference=0.25). In pooled follow-up data for 768 antithrombotic users, presence of MB at baseline was associated with a substantially increased risk of subsequent DISEASE (OR, 12.1; 95% CI, 3.4-42.5; P<0.001). CONCLUSIONS: The excess of MB in CHEMICAL users with DISEASE compared to other groups suggests that MB increase the risk of CHEMICAL-associated DISEASE. Limited prospective data corroborate these findings, but larger prospective studies are urgently required. | CHEMICAL-INDUCED-DISEASE |
| Verapamil stimulation test in DISEASE: loss of prolactin response in anatomic or functional stalk effect. AIM: Verapamil stimulation test was previously investigated as a tool for differential diagnosis of DISEASE, but with conflicting results. Macroprolactinemia was never considered in those previous studies. Here, we aimed to re-investigate the diagnostic value of verapamil in a population who were all screened for macroprolactinemia. Prolactin responses to verapamil in 65 female patients (age: 29.9 +/- 8.1 years) with DISEASE were tested in a descriptive, matched case-control study. METHODS: Verapamil 80 mg, p.o. was administered, and then PRL levels were measured at 8th and 16th hours, by immunometric chemiluminescence. Verapamil responsiveness was determined by peak percent change in basal prolactin levels (PRL). RESULTS: Verapamil significantly increased PRL levels in healthy controls (N. 8, PRL: 183%), macroprolactinoma (N. 8, PRL: 7%), microprolactinoma (N. 19, PRL: 21%), macroprolactinemia (N. 23, PRL: 126%), but not in pseudoprolactinoma (N. 8, PRL: 0.8%), and CHEMICAL-induced DISEASE (N. 7, PRL: 3%). ROC curve analysis revealed that unresponsiveness to verapamil defined as PRL <7%, discriminated anatomical or functional stalk effect (sensitivity: 74%, specificity: 73%, AUC: 0.855+/-0.04, P <0.001, CI: 0.768-0.942) associated with pseudoprolactinoma or CHEMICAL-induced DISEASE, respectively. CONCLUSION: Verapamil responsiveness is not a reliable finding for the differential diagnosis of DISEASE. However, verapamil unresponsiveness discriminates stalk effect (i.e., anatomically or functionally inhibited dopaminergic tonus) from other causes of DISEASE with varying degrees of responsiveness. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL stimulation test in hyperprolactinemia: loss of prolactin response in anatomic or functional stalk effect. AIM: CHEMICAL stimulation test was previously investigated as a tool for differential diagnosis of hyperprolactinemia, but with conflicting results. Macroprolactinemia was never considered in those previous studies. Here, we aimed to re-investigate the diagnostic value of CHEMICAL in a population who were all screened for macroprolactinemia. Prolactin responses to CHEMICAL in 65 female patients (age: 29.9 +/- 8.1 years) with hyperprolactinemia were tested in a descriptive, matched case-control study. METHODS: CHEMICAL 80 mg, p.o. was administered, and then PRL levels were measured at 8th and 16th hours, by immunometric chemiluminescence. CHEMICAL responsiveness was determined by peak percent change in basal prolactin levels (PRL). RESULTS: CHEMICAL significantly increased PRL levels in healthy controls (N. 8, PRL: 183%), macroprolactinoma (N. 8, PRL: 7%), microprolactinoma (N. 19, PRL: 21%), macroprolactinemia (N. 23, PRL: 126%), but not in DISEASE (N. 8, PRL: 0.8%), and risperidone-induced hyperprolactinemia (N. 7, PRL: 3%). ROC curve analysis revealed that unresponsiveness to CHEMICAL defined as PRL <7%, discriminated anatomical or functional stalk effect (sensitivity: 74%, specificity: 73%, AUC: 0.855+/-0.04, P <0.001, CI: 0.768-0.942) associated with DISEASE or risperidone-induced hyperprolactinemia, respectively. CONCLUSION: CHEMICAL responsiveness is not a reliable finding for the differential diagnosis of hyperprolactinemia. However, CHEMICAL unresponsiveness discriminates stalk effect (i.e., anatomically or functionally inhibited dopaminergic tonus) from other causes of hyperprolactinemia with varying degrees of responsiveness. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL stimulation test in hyperprolactinemia: loss of prolactin response in anatomic or functional stalk effect. AIM: CHEMICAL stimulation test was previously investigated as a tool for differential diagnosis of hyperprolactinemia, but with conflicting results. DISEASE was never considered in those previous studies. Here, we aimed to re-investigate the diagnostic value of CHEMICAL in a population who were all screened for DISEASE. Prolactin responses to CHEMICAL in 65 female patients (age: 29.9 +/- 8.1 years) with hyperprolactinemia were tested in a descriptive, matched case-control study. METHODS: CHEMICAL 80 mg, p.o. was administered, and then PRL levels were measured at 8th and 16th hours, by immunometric chemiluminescence. CHEMICAL responsiveness was determined by peak percent change in basal prolactin levels (PRL). RESULTS: CHEMICAL significantly increased PRL levels in healthy controls (N. 8, PRL: 183%), DISEASE (N. 8, PRL: 7%), DISEASE (N. 19, PRL: 21%), DISEASE (N. 23, PRL: 126%), but not in pseudoprolactinoma (N. 8, PRL: 0.8%), and risperidone-induced hyperprolactinemia (N. 7, PRL: 3%). ROC curve analysis revealed that unresponsiveness to CHEMICAL defined as PRL <7%, discriminated anatomical or functional stalk effect (sensitivity: 74%, specificity: 73%, AUC: 0.855+/-0.04, P <0.001, CI: 0.768-0.942) associated with pseudoprolactinoma or risperidone-induced hyperprolactinemia, respectively. CONCLUSION: CHEMICAL responsiveness is not a reliable finding for the differential diagnosis of hyperprolactinemia. However, CHEMICAL unresponsiveness discriminates stalk effect (i.e., anatomically or functionally inhibited dopaminergic tonus) from other causes of hyperprolactinemia with varying degrees of responsiveness. | CHEMICAL-INDUCED-DISEASE |
| Central action of narcotic analgesics. Part IV. Noradrenergic influences on the activity of analgesics in rats. The effect of CHEMICAL, naphazoline and xylometazoline on analgesia induced by morphine, codeine, fentanyl and pentazocine, and on DISEASE effect of morphine, codine and fentanyl was studied in rats. The biochemical assays on the influence of four analgesics on the brain concentration and turnover of noradrenaline (NA) were also performed. It was found that three drugs stimulating central NA receptors failed to affect the analgesic ED50 of all antinociceptive agents and they enhanced DISEASE induced by morphine and fentanyl. Codeine DISEASE was increased by CHEMICAL and decreased by naphazoline and xylometazoline. The brain concentration of NA was not changed by morphine and fentanyl, but one of the doses of codeine (45 mg/kg) slightly enhanced it. Pentazocine dose-dependently decreased the brain level of NA. The rate of NA turnover was not altered by analgesics except for the higher dose of fentanyl (0.2 mg/kg) following which the disappearance of NA from the brain was diminished. The results are discussed in the light of various and non-uniform data from the literature. It is suggested that in rats the brain NA plays a less important function than the other monoamines in the behavioural activity of potent analgesics. | CHEMICAL-INDUCED-DISEASE |
| Central action of narcotic analgesics. Part IV. Noradrenergic influences on the activity of analgesics in rats. The effect of clonidine, naphazoline and xylometazoline on analgesia induced by morphine, codeine, CHEMICAL and pentazocine, and on DISEASE effect of morphine, codine and CHEMICAL was studied in rats. The biochemical assays on the influence of four analgesics on the brain concentration and turnover of noradrenaline (NA) were also performed. It was found that three drugs stimulating central NA receptors failed to affect the analgesic ED50 of all antinociceptive agents and they enhanced DISEASE induced by morphine and CHEMICAL. Codeine DISEASE was increased by clonidine and decreased by naphazoline and xylometazoline. The brain concentration of NA was not changed by morphine and CHEMICAL, but one of the doses of codeine (45 mg/kg) slightly enhanced it. Pentazocine dose-dependently decreased the brain level of NA. The rate of NA turnover was not altered by analgesics except for the higher dose of CHEMICAL (0.2 mg/kg) following which the disappearance of NA from the brain was diminished. The results are discussed in the light of various and non-uniform data from the literature. It is suggested that in rats the brain NA plays a less important function than the other monoamines in the behavioural activity of potent analgesics. | CHEMICAL-INDUCED-DISEASE |
| Central action of narcotic analgesics. Part IV. Noradrenergic influences on the activity of analgesics in rats. The effect of clonidine, CHEMICAL and xylometazoline on analgesia induced by morphine, codeine, fentanyl and pentazocine, and on DISEASE effect of morphine, codine and fentanyl was studied in rats. The biochemical assays on the influence of four analgesics on the brain concentration and turnover of noradrenaline (NA) were also performed. It was found that three drugs stimulating central NA receptors failed to affect the analgesic ED50 of all antinociceptive agents and they enhanced DISEASE induced by morphine and fentanyl. Codeine DISEASE was increased by clonidine and decreased by CHEMICAL and xylometazoline. The brain concentration of NA was not changed by morphine and fentanyl, but one of the doses of codeine (45 mg/kg) slightly enhanced it. Pentazocine dose-dependently decreased the brain level of NA. The rate of NA turnover was not altered by analgesics except for the higher dose of fentanyl (0.2 mg/kg) following which the disappearance of NA from the brain was diminished. The results are discussed in the light of various and non-uniform data from the literature. It is suggested that in rats the brain NA plays a less important function than the other monoamines in the behavioural activity of potent analgesics. | CHEMICAL-INDUCED-DISEASE |
| Central action of narcotic analgesics. Part IV. Noradrenergic influences on the activity of analgesics in rats. The effect of clonidine, naphazoline and xylometazoline on analgesia induced by morphine, CHEMICAL, fentanyl and pentazocine, and on DISEASE effect of morphine, CHEMICAL and fentanyl was studied in rats. The biochemical assays on the influence of four analgesics on the brain concentration and turnover of noradrenaline (NA) were also performed. It was found that three drugs stimulating central NA receptors failed to affect the analgesic ED50 of all antinociceptive agents and they enhanced DISEASE induced by morphine and fentanyl. CHEMICAL DISEASE was increased by clonidine and decreased by naphazoline and xylometazoline. The brain concentration of NA was not changed by morphine and fentanyl, but one of the doses of CHEMICAL (45 mg/kg) slightly enhanced it. Pentazocine dose-dependently decreased the brain level of NA. The rate of NA turnover was not altered by analgesics except for the higher dose of fentanyl (0.2 mg/kg) following which the disappearance of NA from the brain was diminished. The results are discussed in the light of various and non-uniform data from the literature. It is suggested that in rats the brain NA plays a less important function than the other monoamines in the behavioural activity of potent analgesics. | CHEMICAL-INDUCED-DISEASE |
| Central action of narcotic analgesics. Part IV. Noradrenergic influences on the activity of analgesics in rats. The effect of clonidine, naphazoline and CHEMICAL on analgesia induced by morphine, codeine, fentanyl and pentazocine, and on DISEASE effect of morphine, codine and fentanyl was studied in rats. The biochemical assays on the influence of four analgesics on the brain concentration and turnover of noradrenaline (NA) were also performed. It was found that three drugs stimulating central NA receptors failed to affect the analgesic ED50 of all antinociceptive agents and they enhanced DISEASE induced by morphine and fentanyl. Codeine DISEASE was increased by clonidine and decreased by naphazoline and CHEMICAL. The brain concentration of NA was not changed by morphine and fentanyl, but one of the doses of codeine (45 mg/kg) slightly enhanced it. Pentazocine dose-dependently decreased the brain level of NA. The rate of NA turnover was not altered by analgesics except for the higher dose of fentanyl (0.2 mg/kg) following which the disappearance of NA from the brain was diminished. The results are discussed in the light of various and non-uniform data from the literature. It is suggested that in rats the brain NA plays a less important function than the other monoamines in the behavioural activity of potent analgesics. | NO-RELATIONSHIP |
| Central action of narcotic analgesics. Part IV. Noradrenergic influences on the activity of analgesics in rats. The effect of clonidine, naphazoline and xylometazoline on analgesia induced by CHEMICAL, codeine, fentanyl and pentazocine, and on DISEASE effect of CHEMICAL, codine and fentanyl was studied in rats. The biochemical assays on the influence of four analgesics on the brain concentration and turnover of noradrenaline (NA) were also performed. It was found that three drugs stimulating central NA receptors failed to affect the analgesic ED50 of all antinociceptive agents and they enhanced DISEASE induced by CHEMICAL and fentanyl. Codeine DISEASE was increased by clonidine and decreased by naphazoline and xylometazoline. The brain concentration of NA was not changed by CHEMICAL and fentanyl, but one of the doses of codeine (45 mg/kg) slightly enhanced it. Pentazocine dose-dependently decreased the brain level of NA. The rate of NA turnover was not altered by analgesics except for the higher dose of fentanyl (0.2 mg/kg) following which the disappearance of NA from the brain was diminished. The results are discussed in the light of various and non-uniform data from the literature. It is suggested that in rats the brain NA plays a less important function than the other monoamines in the behavioural activity of potent analgesics. | CHEMICAL-INDUCED-DISEASE |
| Modification by CHEMICAL of cardiovascular effects of induced hypoglycaemia. The cardiovascular effects of hypoglycaemia, with and without beta-blockade, were compared in fourteen healthy men. Eight received insulin alone, and eight, including two of the original insulin-only group, were given CHEMICAL and insulin. In the insulin-group the period of hypoglycaemia was associated with an increase in heart-rate and a fall in diastolic blood-pressure. In the CHEMICAL-insulin group there was a significant fall in heart-rate in most subjects and an increase in diastolic pressure. Typical S-T/T changes occurred in the insulin-group but in none of the CHEMICAL-insulin group. DISEASE in diabetics prone to hypoglycaemia attacks should not be treated with beta-blockers because these drugs may cause a sharp rise in blood-pressure in such patients. | NO-RELATIONSHIP |
| Prevention and treatment of endometrial disease in climacteric women receiving CHEMICAL therapy. The treatment regimens are described in 74 patients with endometrial disease among 850 climacteric women receiving CHEMICAL therapy. Cystic DISEASE was associated with unopposed CHEMICAL therapy without progestagen. Two courses of 21 days of 5 mg norethisterone daily caused reversion to normal in all 57 cases of cystic DISEASE and 6 of the 8 cases of atypical DISEASE. 4 cases of endometrial carcinoma referred from elsewhere demonstrated the problems of inappropriate and unsupervised unopposed CHEMICAL therapy and the difficulty in distinguishing severe DISEASE from malignancy. Cyclical low-dose CHEMICAL therapy with 7--13 days of progestagen does not seem to increase the risk of endometrial hyperplasia or carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Prevention and treatment of DISEASE in climacteric women receiving oestrogen therapy. The treatment regimens are described in 74 patients with DISEASE among 850 climacteric women receiving oestrogen therapy. Cystic hyperplasia was associated with unopposed oestrogen therapy without CHEMICAL. Two courses of 21 days of 5 mg norethisterone daily caused reversion to normal in all 57 cases of cystic hyperplasia and 6 of the 8 cases of atypical hyperplasia. 4 cases of endometrial carcinoma referred from elsewhere demonstrated the problems of inappropriate and unsupervised unopposed oestrogen therapy and the difficulty in distinguishing severe hyperplasia from malignancy. Cyclical low-dose oestrogen therapy with 7--13 days of CHEMICAL does not seem to increase the risk of endometrial hyperplasia or carcinoma. | NO-RELATIONSHIP |
| Prevention and treatment of endometrial disease in climacteric women receiving oestrogen therapy. The treatment regimens are described in 74 patients with endometrial disease among 850 climacteric women receiving oestrogen therapy. Cystic hyperplasia was associated with unopposed oestrogen therapy without progestagen. Two courses of 21 days of 5 mg CHEMICAL daily caused reversion to normal in all 57 cases of cystic hyperplasia and 6 of the 8 cases of atypical hyperplasia. 4 cases of endometrial carcinoma referred from elsewhere demonstrated the problems of inappropriate and unsupervised unopposed oestrogen therapy and the difficulty in distinguishing severe hyperplasia from malignancy. Cyclical low-dose oestrogen therapy with 7--13 days of progestagen does not seem to increase the risk of endometrial hyperplasia or DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Prevention and treatment of endometrial disease in climacteric women receiving oestrogen therapy. The treatment regimens are described in 74 patients with endometrial disease among 850 climacteric women receiving oestrogen therapy. Cystic hyperplasia was associated with unopposed oestrogen therapy without CHEMICAL. Two courses of 21 days of 5 mg norethisterone daily caused reversion to normal in all 57 cases of cystic hyperplasia and 6 of the 8 cases of atypical hyperplasia. 4 cases of endometrial carcinoma referred from elsewhere demonstrated the problems of inappropriate and unsupervised unopposed oestrogen therapy and the difficulty in distinguishing severe hyperplasia from malignancy. Cyclical low-dose oestrogen therapy with 7--13 days of CHEMICAL does not seem to increase the risk of DISEASE or carcinoma. | NO-RELATIONSHIP |
| Prevention and treatment of endometrial disease in climacteric women receiving oestrogen therapy. The treatment regimens are described in 74 patients with endometrial disease among 850 climacteric women receiving oestrogen therapy. Cystic hyperplasia was associated with unopposed oestrogen therapy without CHEMICAL. Two courses of 21 days of 5 mg norethisterone daily caused reversion to normal in all 57 cases of cystic hyperplasia and 6 of the 8 cases of atypical hyperplasia. 4 cases of DISEASE referred from elsewhere demonstrated the problems of inappropriate and unsupervised unopposed oestrogen therapy and the difficulty in distinguishing severe hyperplasia from malignancy. Cyclical low-dose oestrogen therapy with 7--13 days of CHEMICAL does not seem to increase the risk of endometrial hyperplasia or carcinoma. | NO-RELATIONSHIP |
| Prevention and treatment of endometrial disease in climacteric women receiving oestrogen therapy. The treatment regimens are described in 74 patients with endometrial disease among 850 climacteric women receiving oestrogen therapy. Cystic hyperplasia was associated with unopposed oestrogen therapy without progestagen. Two courses of 21 days of 5 mg CHEMICAL daily caused reversion to normal in all 57 cases of cystic hyperplasia and 6 of the 8 cases of atypical hyperplasia. 4 cases of endometrial carcinoma referred from elsewhere demonstrated the problems of inappropriate and unsupervised unopposed oestrogen therapy and the difficulty in distinguishing severe hyperplasia from malignancy. Cyclical low-dose oestrogen therapy with 7--13 days of progestagen does not seem to increase the risk of DISEASE or carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Prevention and treatment of DISEASE in climacteric women receiving oestrogen therapy. The treatment regimens are described in 74 patients with DISEASE among 850 climacteric women receiving oestrogen therapy. Cystic hyperplasia was associated with unopposed oestrogen therapy without progestagen. Two courses of 21 days of 5 mg CHEMICAL daily caused reversion to normal in all 57 cases of cystic hyperplasia and 6 of the 8 cases of atypical hyperplasia. 4 cases of endometrial carcinoma referred from elsewhere demonstrated the problems of inappropriate and unsupervised unopposed oestrogen therapy and the difficulty in distinguishing severe hyperplasia from malignancy. Cyclical low-dose oestrogen therapy with 7--13 days of progestagen does not seem to increase the risk of endometrial hyperplasia or carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Prevention and treatment of endometrial disease in climacteric women receiving oestrogen therapy. The treatment regimens are described in 74 patients with endometrial disease among 850 climacteric women receiving oestrogen therapy. Cystic hyperplasia was associated with unopposed oestrogen therapy without progestagen. Two courses of 21 days of 5 mg CHEMICAL daily caused reversion to normal in all 57 cases of cystic hyperplasia and 6 of the 8 cases of atypical hyperplasia. 4 cases of endometrial carcinoma referred from elsewhere demonstrated the problems of inappropriate and unsupervised unopposed oestrogen therapy and the difficulty in distinguishing severe hyperplasia from DISEASE. Cyclical low-dose oestrogen therapy with 7--13 days of progestagen does not seem to increase the risk of endometrial hyperplasia or carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Prevention and treatment of endometrial disease in climacteric women receiving oestrogen therapy. The treatment regimens are described in 74 patients with endometrial disease among 850 climacteric women receiving oestrogen therapy. Cystic hyperplasia was associated with unopposed oestrogen therapy without progestagen. Two courses of 21 days of 5 mg CHEMICAL daily caused reversion to normal in all 57 cases of cystic hyperplasia and 6 of the 8 cases of atypical hyperplasia. 4 cases of DISEASE referred from elsewhere demonstrated the problems of inappropriate and unsupervised unopposed oestrogen therapy and the difficulty in distinguishing severe hyperplasia from malignancy. Cyclical low-dose oestrogen therapy with 7--13 days of progestagen does not seem to increase the risk of endometrial hyperplasia or carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Prevention and treatment of endometrial disease in climacteric women receiving oestrogen therapy. The treatment regimens are described in 74 patients with endometrial disease among 850 climacteric women receiving oestrogen therapy. Cystic hyperplasia was associated with unopposed oestrogen therapy without CHEMICAL. Two courses of 21 days of 5 mg norethisterone daily caused reversion to normal in all 57 cases of cystic hyperplasia and 6 of the 8 cases of atypical hyperplasia. 4 cases of endometrial carcinoma referred from elsewhere demonstrated the problems of inappropriate and unsupervised unopposed oestrogen therapy and the difficulty in distinguishing severe hyperplasia from malignancy. Cyclical low-dose oestrogen therapy with 7--13 days of CHEMICAL does not seem to increase the risk of endometrial hyperplasia or DISEASE. | NO-RELATIONSHIP |
| Prevention and treatment of endometrial disease in climacteric women receiving oestrogen therapy. The treatment regimens are described in 74 patients with endometrial disease among 850 climacteric women receiving oestrogen therapy. Cystic hyperplasia was associated with unopposed oestrogen therapy without CHEMICAL. Two courses of 21 days of 5 mg norethisterone daily caused reversion to normal in all 57 cases of cystic hyperplasia and 6 of the 8 cases of atypical hyperplasia. 4 cases of endometrial carcinoma referred from elsewhere demonstrated the problems of inappropriate and unsupervised unopposed oestrogen therapy and the difficulty in distinguishing severe hyperplasia from DISEASE. Cyclical low-dose oestrogen therapy with 7--13 days of CHEMICAL does not seem to increase the risk of endometrial hyperplasia or carcinoma. | NO-RELATIONSHIP |
| Pure red cell aplasia, DISEASE and lymphadenopathy in a patient taking CHEMICAL. A patient taking CHEMICAL for 3 weeks developed a generalized skin rash, lymphadenopathy and pure red cell aplasia. After withdrawal of the pharmacon all symptoms disappeared spontaneously. Skin rash is a well-known complication of CHEMICAL treatment as is benign and malignant lymphadenopathy. Pure red cell aplasia associated with CHEMICAL medication has been reported in 3 patients. The exact mechanism by which CHEMICAL exerts its toxic effects is not known. In this patient the time relation between the ingestion of CHEMICAL and the occurrence of the skin rash, lymphadenopathy and pure red cell aplasia is very suggestive of a direct connection. | CHEMICAL-INDUCED-DISEASE |
| Pure red cell aplasia, toxic dermatitis and DISEASE in a patient taking CHEMICAL. A patient taking CHEMICAL for 3 weeks developed a generalized skin rash, DISEASE and pure red cell aplasia. After withdrawal of the pharmacon all symptoms disappeared spontaneously. Skin rash is a well-known complication of CHEMICAL treatment as is benign and malignant DISEASE. Pure red cell aplasia associated with CHEMICAL medication has been reported in 3 patients. The exact mechanism by which CHEMICAL exerts its toxic effects is not known. In this patient the time relation between the ingestion of CHEMICAL and the occurrence of the skin rash, DISEASE and pure red cell aplasia is very suggestive of a direct connection. | CHEMICAL-INDUCED-DISEASE |
| DISEASE, toxic dermatitis and lymphadenopathy in a patient taking CHEMICAL. A patient taking CHEMICAL for 3 weeks developed a generalized skin rash, lymphadenopathy and DISEASE. After withdrawal of the pharmacon all symptoms disappeared spontaneously. Skin rash is a well-known complication of CHEMICAL treatment as is benign and malignant lymphadenopathy. DISEASE associated with CHEMICAL medication has been reported in 3 patients. The exact mechanism by which CHEMICAL exerts its toxic effects is not known. In this patient the time relation between the ingestion of CHEMICAL and the occurrence of the skin rash, lymphadenopathy and DISEASE is very suggestive of a direct connection. | CHEMICAL-INDUCED-DISEASE |
| Continuous infusion CHEMICAL combined with carbenicillin for infections in cancer patients. The cure rate of infections in cancer patients is adversely affected by neutropenia (less than 1,000/mm3). In particular, patients with severe neutropenia (less than 100/mm3) have shown a poor response to antibiotics. To overcome the adverse effects of neutropenia, CHEMICAL was given by continuous infusion and combined with intermittent carbenicillin. CHEMICAL was given to a total daily dose of 300 mg/m2 and carbenicillin was given at a dose of 5 gm every four hours. There were 125 infectious episodes in 116 cancer patients receiving myelosuppressive chemotherapy. The overall cure rate was 70%. Pneumonia was the most common infection and 61% of 59 episodes were cured. Gram-negative bacilli were the most common causative organisms and 69% of these infections were cured. The most common pathogen was Klebsiella pneumoniae and this, together with Escherichia coli and Pseudomonas aeruginosa, accounted for 74% of all gram-negative bacillary infections. Response was not influenced by the initial neutrophil count, with a 62% cure rate for 39 episodes associated with severe neutropenia. However, failure of the neutrophil count to increase during therapy adversely affected response. DISEASE was the major side effect recognized, and it occurred in 11% of episodes. Major DISEASE (serum creatinine greater than 2.5 mg/dl or BUN greater than 50 mg/dl) occurred in only 2%. DISEASE was not related to duration of therapy or serum CHEMICAL concentration. This antibiotic regimen showed both therapeutic efficacy and acceptable renal toxicity for these patients. | CHEMICAL-INDUCED-DISEASE |
| Continuous infusion tobramycin combined with CHEMICAL for infections in cancer patients. The cure rate of infections in cancer patients is adversely affected by neutropenia (less than 1,000/mm3). In particular, patients with severe neutropenia (less than 100/mm3) have shown a poor response to antibiotics. To overcome the adverse effects of neutropenia, tobramycin was given by continuous infusion and combined with intermittent CHEMICAL. Tobramycin was given to a total daily dose of 300 mg/m2 and CHEMICAL was given at a dose of 5 gm every four hours. There were 125 infectious episodes in 116 cancer patients receiving myelosuppressive chemotherapy. The overall cure rate was 70%. Pneumonia was the most common infection and 61% of 59 episodes were cured. Gram-negative bacilli were the most common causative organisms and 69% of these infections were cured. The most common pathogen was Klebsiella pneumoniae and this, together with Escherichia coli and Pseudomonas aeruginosa, accounted for 74% of all gram-negative bacillary infections. Response was not influenced by the initial neutrophil count, with a 62% cure rate for 39 episodes associated with severe neutropenia. However, failure of the neutrophil count to increase during therapy adversely affected response. DISEASE was the major side effect recognized, and it occurred in 11% of episodes. Major DISEASE (serum creatinine greater than 2.5 mg/dl or BUN greater than 50 mg/dl) occurred in only 2%. DISEASE was not related to duration of therapy or serum tobramycin concentration. This antibiotic regimen showed both therapeutic efficacy and acceptable renal toxicity for these patients. | CHEMICAL-INDUCED-DISEASE |
| Continuous infusion tobramycin combined with carbenicillin for infections in cancer patients. The cure rate of infections in cancer patients is adversely affected by neutropenia (less than 1,000/mm3). In particular, patients with severe neutropenia (less than 100/mm3) have shown a poor response to antibiotics. To overcome the adverse effects of neutropenia, tobramycin was given by continuous infusion and combined with intermittent carbenicillin. Tobramycin was given to a total daily dose of 300 mg/m2 and carbenicillin was given at a dose of 5 gm every four hours. There were 125 infectious episodes in 116 cancer patients receiving myelosuppressive chemotherapy. The overall cure rate was 70%. Pneumonia was the most common infection and 61% of 59 episodes were cured. Gram-negative bacilli were the most common causative organisms and 69% of these infections were cured. The most common pathogen was Klebsiella pneumoniae and this, together with Escherichia coli and Pseudomonas aeruginosa, accounted for 74% of all gram-negative bacillary infections. Response was not influenced by the initial neutrophil count, with a 62% cure rate for 39 episodes associated with severe neutropenia. However, failure of the neutrophil count to increase during therapy adversely affected response. Azotemia was the major side effect recognized, and it occurred in 11% of episodes. Major azotemia (serum CHEMICAL greater than 2.5 mg/dl or BUN greater than 50 mg/dl) occurred in only 2%. Azotemia was not related to duration of therapy or serum tobramycin concentration. This antibiotic regimen showed both therapeutic efficacy and acceptable DISEASE for these patients. | NO-RELATIONSHIP |
| Continuous infusion tobramycin combined with carbenicillin for infections in cancer patients. The cure rate of infections in cancer patients is adversely affected by neutropenia (less than 1,000/mm3). In particular, patients with severe neutropenia (less than 100/mm3) have shown a poor response to antibiotics. To overcome the adverse effects of neutropenia, tobramycin was given by continuous infusion and combined with intermittent carbenicillin. Tobramycin was given to a total daily dose of 300 mg/m2 and carbenicillin was given at a dose of 5 gm every four hours. There were 125 infectious episodes in 116 cancer patients receiving myelosuppressive chemotherapy. The overall cure rate was 70%. DISEASE was the most common infection and 61% of 59 episodes were cured. Gram-negative bacilli were the most common causative organisms and 69% of these infections were cured. The most common pathogen was Klebsiella DISEASE and this, together with Escherichia coli and Pseudomonas aeruginosa, accounted for 74% of all gram-negative bacillary infections. Response was not influenced by the initial neutrophil count, with a 62% cure rate for 39 episodes associated with severe neutropenia. However, failure of the neutrophil count to increase during therapy adversely affected response. Azotemia was the major side effect recognized, and it occurred in 11% of episodes. Major azotemia (serum CHEMICAL greater than 2.5 mg/dl or BUN greater than 50 mg/dl) occurred in only 2%. Azotemia was not related to duration of therapy or serum tobramycin concentration. This antibiotic regimen showed both therapeutic efficacy and acceptable renal toxicity for these patients. | NO-RELATIONSHIP |
| Continuous infusion tobramycin combined with carbenicillin for infections in DISEASE patients. The cure rate of infections in DISEASE patients is adversely affected by neutropenia (less than 1,000/mm3). In particular, patients with severe neutropenia (less than 100/mm3) have shown a poor response to antibiotics. To overcome the adverse effects of neutropenia, tobramycin was given by continuous infusion and combined with intermittent carbenicillin. Tobramycin was given to a total daily dose of 300 mg/m2 and carbenicillin was given at a dose of 5 gm every four hours. There were 125 infectious episodes in 116 DISEASE patients receiving myelosuppressive chemotherapy. The overall cure rate was 70%. Pneumonia was the most common infection and 61% of 59 episodes were cured. Gram-negative bacilli were the most common causative organisms and 69% of these infections were cured. The most common pathogen was Klebsiella pneumoniae and this, together with Escherichia coli and Pseudomonas aeruginosa, accounted for 74% of all gram-negative bacillary infections. Response was not influenced by the initial neutrophil count, with a 62% cure rate for 39 episodes associated with severe neutropenia. However, failure of the neutrophil count to increase during therapy adversely affected response. Azotemia was the major side effect recognized, and it occurred in 11% of episodes. Major azotemia (serum CHEMICAL greater than 2.5 mg/dl or BUN greater than 50 mg/dl) occurred in only 2%. Azotemia was not related to duration of therapy or serum tobramycin concentration. This antibiotic regimen showed both therapeutic efficacy and acceptable renal toxicity for these patients. | NO-RELATIONSHIP |
| Continuous infusion tobramycin combined with carbenicillin for infections in cancer patients. The cure rate of infections in cancer patients is adversely affected by neutropenia (less than 1,000/mm3). In particular, patients with severe neutropenia (less than 100/mm3) have shown a poor response to antibiotics. To overcome the adverse effects of neutropenia, tobramycin was given by continuous infusion and combined with intermittent carbenicillin. Tobramycin was given to a total daily dose of 300 mg/m2 and carbenicillin was given at a dose of 5 gm every four hours. There were 125 infectious episodes in 116 cancer patients receiving myelosuppressive chemotherapy. The overall cure rate was 70%. Pneumonia was the most common infection and 61% of 59 episodes were cured. Gram-negative bacilli were the most common causative organisms and 69% of these infections were cured. The most common pathogen was Klebsiella pneumoniae and this, together with Escherichia coli and Pseudomonas aeruginosa, accounted for 74% of all DISEASE. Response was not influenced by the initial neutrophil count, with a 62% cure rate for 39 episodes associated with severe neutropenia. However, failure of the neutrophil count to increase during therapy adversely affected response. Azotemia was the major side effect recognized, and it occurred in 11% of episodes. Major azotemia (serum CHEMICAL greater than 2.5 mg/dl or BUN greater than 50 mg/dl) occurred in only 2%. Azotemia was not related to duration of therapy or serum tobramycin concentration. This antibiotic regimen showed both therapeutic efficacy and acceptable renal toxicity for these patients. | NO-RELATIONSHIP |
| Continuous infusion tobramycin combined with carbenicillin for infections in cancer patients. The cure rate of infections in cancer patients is adversely affected by DISEASE (less than 1,000/mm3). In particular, patients with severe DISEASE (less than 100/mm3) have shown a poor response to antibiotics. To overcome the adverse effects of DISEASE, tobramycin was given by continuous infusion and combined with intermittent carbenicillin. Tobramycin was given to a total daily dose of 300 mg/m2 and carbenicillin was given at a dose of 5 gm every four hours. There were 125 infectious episodes in 116 cancer patients receiving myelosuppressive chemotherapy. The overall cure rate was 70%. Pneumonia was the most common infection and 61% of 59 episodes were cured. Gram-negative bacilli were the most common causative organisms and 69% of these infections were cured. The most common pathogen was Klebsiella pneumoniae and this, together with Escherichia coli and Pseudomonas aeruginosa, accounted for 74% of all gram-negative bacillary infections. Response was not influenced by the initial neutrophil count, with a 62% cure rate for 39 episodes associated with severe DISEASE. However, failure of the neutrophil count to increase during therapy adversely affected response. Azotemia was the major side effect recognized, and it occurred in 11% of episodes. Major azotemia (serum CHEMICAL greater than 2.5 mg/dl or BUN greater than 50 mg/dl) occurred in only 2%. Azotemia was not related to duration of therapy or serum tobramycin concentration. This antibiotic regimen showed both therapeutic efficacy and acceptable renal toxicity for these patients. | NO-RELATIONSHIP |
| Continuous infusion tobramycin combined with carbenicillin for DISEASE in cancer patients. The cure rate of DISEASE in cancer patients is adversely affected by neutropenia (less than 1,000/mm3). In particular, patients with severe neutropenia (less than 100/mm3) have shown a poor response to antibiotics. To overcome the adverse effects of neutropenia, tobramycin was given by continuous infusion and combined with intermittent carbenicillin. Tobramycin was given to a total daily dose of 300 mg/m2 and carbenicillin was given at a dose of 5 gm every four hours. There were 125 infectious episodes in 116 cancer patients receiving myelosuppressive chemotherapy. The overall cure rate was 70%. Pneumonia was the most common DISEASE and 61% of 59 episodes were cured. Gram-negative bacilli were the most common causative organisms and 69% of these DISEASE were cured. The most common pathogen was Klebsiella pneumoniae and this, together with Escherichia coli and Pseudomonas aeruginosa, accounted for 74% of all gram-negative bacillary infections. Response was not influenced by the initial neutrophil count, with a 62% cure rate for 39 episodes associated with severe neutropenia. However, failure of the neutrophil count to increase during therapy adversely affected response. Azotemia was the major side effect recognized, and it occurred in 11% of episodes. Major azotemia (serum CHEMICAL greater than 2.5 mg/dl or BUN greater than 50 mg/dl) occurred in only 2%. Azotemia was not related to duration of therapy or serum tobramycin concentration. This antibiotic regimen showed both therapeutic efficacy and acceptable renal toxicity for these patients. | NO-RELATIONSHIP |
| Recurrent DISEASE associated with aminocaproic acid therapy and acute renal artery thrombosis. Case report. CHEMICAL (CHEMICAL) has been used to prevent rebleeding in patients with DISEASE (DISEASE). Although this agent does decrease the frequency of rebleeding, several reports have described thrombotic complications of CHEMICAL therapy. These complications have included clinical deterioration and intracranial vascular thrombosis in patients with DISEASE, arteriolar and capillary fibrin thrombi in patients with fibrinolytic syndromes treated with CHEMICAL, or other thromboembolic phenomena. Since intravascular fibrin thrombi are often observed in patients with fibrinolytic disorders, CHEMICAL should not be implicated in the pathogenesis of fibrin thrombi in patients with disseminated intravascular coagulation or other "consumption coagulopathies." This report describes subtotal infarction of the kidney due to thrombosis of a normal renal artery. This occlusion occurred after CHEMICAL therapy in a patient with DISEASE and histopathological documentation of recurrent DISEASE. The corresponding clinical event was characterized by marked hypertension and abrupt neurological deterioration. | NO-RELATIONSHIP |
| Recurrent subarachnoid hemorrhage associated with aminocaproic acid therapy and DISEASE. Case report. CHEMICAL (CHEMICAL) has been used to prevent rebleeding in patients with subarachnoid hemorrhage (SAH). Although this agent does decrease the frequency of rebleeding, several reports have described thrombotic complications of CHEMICAL therapy. These complications have included clinical deterioration and intracranial vascular thrombosis in patients with SAH, arteriolar and capillary fibrin thrombi in patients with fibrinolytic syndromes treated with CHEMICAL, or other thromboembolic phenomena. Since intravascular fibrin thrombi are often observed in patients with fibrinolytic disorders, CHEMICAL should not be implicated in the pathogenesis of fibrin thrombi in patients with disseminated intravascular coagulation or other "consumption coagulopathies." This report describes subtotal infarction of the kidney due to DISEASE. This occlusion occurred after CHEMICAL therapy in a patient with SAH and histopathological documentation of recurrent SAH. The corresponding clinical event was characterized by marked hypertension and abrupt neurological deterioration. | CHEMICAL-INDUCED-DISEASE |
| Recurrent subarachnoid hemorrhage associated with aminocaproic acid therapy and acute renal artery thrombosis. Case report. CHEMICAL (CHEMICAL) has been used to prevent rebleeding in patients with subarachnoid hemorrhage (SAH). Although this agent does decrease the frequency of rebleeding, several reports have described DISEASE complications of CHEMICAL therapy. These complications have included clinical deterioration and intracranial vascular thrombosis in patients with SAH, arteriolar and capillary fibrin DISEASE in patients with fibrinolytic syndromes treated with CHEMICAL, or other thromboembolic phenomena. Since intravascular fibrin DISEASE are often observed in patients with fibrinolytic disorders, CHEMICAL should not be implicated in the pathogenesis of fibrin DISEASE in patients with disseminated intravascular coagulation or other "consumption coagulopathies." This report describes subtotal infarction of the kidney due to thrombosis of a normal renal artery. This occlusion occurred after CHEMICAL therapy in a patient with SAH and histopathological documentation of recurrent SAH. The corresponding clinical event was characterized by marked hypertension and abrupt neurological deterioration. | CHEMICAL-INDUCED-DISEASE |
| Recurrent subarachnoid hemorrhage associated with aminocaproic acid therapy and acute renal artery thrombosis. Case report. CHEMICAL (CHEMICAL) has been used to prevent rebleeding in patients with subarachnoid hemorrhage (SAH). Although this agent does decrease the frequency of rebleeding, several reports have described thrombotic complications of CHEMICAL therapy. These complications have included clinical deterioration and DISEASE in patients with SAH, arteriolar and capillary fibrin thrombi in patients with fibrinolytic syndromes treated with CHEMICAL, or other thromboembolic phenomena. Since intravascular fibrin thrombi are often observed in patients with fibrinolytic disorders, CHEMICAL should not be implicated in the pathogenesis of fibrin thrombi in patients with disseminated intravascular coagulation or other "consumption coagulopathies." This report describes subtotal infarction of the kidney due to thrombosis of a normal renal artery. This occlusion occurred after CHEMICAL therapy in a patient with SAH and histopathological documentation of recurrent SAH. The corresponding clinical event was characterized by marked hypertension and abrupt neurological deterioration. | CHEMICAL-INDUCED-DISEASE |
| Recurrent subarachnoid hemorrhage associated with aminocaproic acid therapy and acute renal artery thrombosis. Case report. CHEMICAL (CHEMICAL) has been used to prevent rebleeding in patients with subarachnoid hemorrhage (SAH). Although this agent does decrease the frequency of rebleeding, several reports have described thrombotic complications of CHEMICAL therapy. These complications have included clinical deterioration and intracranial vascular thrombosis in patients with SAH, arteriolar and capillary fibrin thrombi in patients with fibrinolytic syndromes treated with CHEMICAL, or other thromboembolic phenomena. Since intravascular fibrin thrombi are often observed in patients with fibrinolytic disorders, CHEMICAL should not be implicated in the pathogenesis of fibrin thrombi in patients with disseminated intravascular coagulation or other "consumption coagulopathies." This report describes subtotal infarction of the kidney due to thrombosis of a normal renal artery. This occlusion occurred after CHEMICAL therapy in a patient with SAH and histopathological documentation of recurrent SAH. The corresponding clinical event was characterized by marked DISEASE and abrupt neurological deterioration. | CHEMICAL-INDUCED-DISEASE |
| Recurrent subarachnoid hemorrhage associated with CHEMICAL therapy and acute renal artery thrombosis. Case report. Epsilon aminocaproic acid (EACA) has been used to prevent rebleeding in patients with subarachnoid hemorrhage (SAH). Although this agent does decrease the frequency of rebleeding, several reports have described thrombotic complications of EACA therapy. These complications have included clinical deterioration and intracranial vascular thrombosis in patients with SAH, arteriolar and capillary fibrin thrombi in patients with fibrinolytic syndromes treated with EACA, or other thromboembolic phenomena. Since intravascular fibrin thrombi are often observed in patients with fibrinolytic disorders, EACA should not be implicated in the pathogenesis of fibrin thrombi in patients with disseminated intravascular coagulation or other "consumption coagulopathies." This report describes subtotal DISEASE of the kidney due to thrombosis of a normal renal artery. This occlusion occurred after EACA therapy in a patient with SAH and histopathological documentation of recurrent SAH. The corresponding clinical event was characterized by marked hypertension and abrupt neurological deterioration. | NO-RELATIONSHIP |
| Recurrent subarachnoid hemorrhage associated with CHEMICAL therapy and acute renal artery thrombosis. Case report. Epsilon aminocaproic acid (EACA) has been used to prevent rebleeding in patients with subarachnoid hemorrhage (SAH). Although this agent does decrease the frequency of rebleeding, several reports have described thrombotic complications of EACA therapy. These complications have included clinical deterioration and intracranial vascular thrombosis in patients with SAH, arteriolar and capillary fibrin thrombi in patients with fibrinolytic syndromes treated with EACA, or other thromboembolic phenomena. Since intravascular fibrin thrombi are often observed in patients with fibrinolytic disorders, EACA should not be implicated in the pathogenesis of fibrin thrombi in patients with DISEASE or other "DISEASE." This report describes subtotal infarction of the kidney due to thrombosis of a normal renal artery. This occlusion occurred after EACA therapy in a patient with SAH and histopathological documentation of recurrent SAH. The corresponding clinical event was characterized by marked hypertension and abrupt neurological deterioration. | NO-RELATIONSHIP |
| Recurrent subarachnoid hemorrhage associated with CHEMICAL therapy and acute renal artery thrombosis. Case report. Epsilon aminocaproic acid (EACA) has been used to prevent rebleeding in patients with subarachnoid hemorrhage (SAH). Although this agent does decrease the frequency of rebleeding, several reports have described thrombotic complications of EACA therapy. These complications have included clinical deterioration and intracranial vascular thrombosis in patients with SAH, arteriolar and capillary fibrin thrombi in patients with fibrinolytic syndromes treated with EACA, or other DISEASE. Since intravascular fibrin thrombi are often observed in patients with fibrinolytic disorders, EACA should not be implicated in the pathogenesis of fibrin thrombi in patients with disseminated intravascular coagulation or other "consumption coagulopathies." This report describes subtotal infarction of the kidney due to thrombosis of a normal renal artery. This occlusion occurred after EACA therapy in a patient with SAH and histopathological documentation of recurrent SAH. The corresponding clinical event was characterized by marked hypertension and abrupt neurological deterioration. | NO-RELATIONSHIP |
| Long-term CHEMICAL therapy in pregnancy: maternal and fetal outcome. CHEMICAL, a beta-adrenergic blocking agent, has found an important position in the practice of medicine. Its use in pregnancy, however, is an open question as a number of detrimental side effects have been reported in the fetus and neonate. Ten patients and 12 pregnancies are reported where chronic CHEMICAL has been administered. Five patients with serial pregnancies with and without CHEMICAL therapy are also examined. Maternal, fetal, and neonatal complications are examined. An attempt is made to differentiate drug-related complications from maternal disease--related complications. We conclude that previously reported hypoglycemia, hyperbilirubinemia, polycythemia, neonatal apnea, and bradycardia are not invariable and cannot be statistically correlated with chronic CHEMICAL therapy. DISEASE, however, appears to be significant in both of our series. | CHEMICAL-INDUCED-DISEASE |
| Use of CHEMICAL in the treatment of idiopathic orthostatic hypotension. Five patients with idiopathic orthostatic hypotension who had physiologic and biochemical evidence of severe autonomic dysfunction were included in the study. They all exhibited markedly reduced plasma catecholamines and plasma renin activity in both recumbent and upright positions and had marked hypersensitivity to the pressor effects of infused norepinephrine. Treatment with CHEMICAL administered intravenously (1-5 mg) produced increases in supine and upright blood pressure in 4 of the 5 individuals with rises ranging from 11/6 to 22/11 mmHg. Chronic oral administration of CHEMICAL (40-160 mg/day) also elevated the blood pressures of these individuals with increases in the order of 20-35/15-25 mmg being observed. In 1 patient, marked DISEASE was induced by CHEMICAL and the drug had to be withdrawn. It otherwise was well tolerated and no important side effects were observed. Treatment has been continued in 3 individuals for 6-13 months with persistence of the pressor effect, although there appears to have been some decrease in the degree of response with time. Hemodynamic measurements in 1 of the patients demonstrated an increase in total peripheral resistance and essentially no change in cardiac output following CHEMICAL therapy. The studies suggest that CHEMICAL is a useful drug in selected patients with severe idiopathic orthostatic hypotension. | CHEMICAL-INDUCED-DISEASE |
| Use of propranolol in the treatment of idiopathic orthostatic hypotension. Five patients with idiopathic orthostatic hypotension who had physiologic and biochemical evidence of severe autonomic dysfunction were included in the study. They all exhibited markedly reduced plasma CHEMICAL and plasma renin activity in both recumbent and upright positions and had marked DISEASE to the pressor effects of infused norepinephrine. Treatment with propanolol administered intravenously (1-5 mg) produced increases in supine and upright blood pressure in 4 of the 5 individuals with rises ranging from 11/6 to 22/11 mmHg. Chronic oral administration of propranolol (40-160 mg/day) also elevated the blood pressures of these individuals with increases in the order of 20-35/15-25 mmg being observed. In 1 patient, marked hypertension was induced by propranolol and the drug had to be withdrawn. It otherwise was well tolerated and no important side effects were observed. Treatment has been continued in 3 individuals for 6-13 months with persistence of the pressor effect, although there appears to have been some decrease in the degree of response with time. Hemodynamic measurements in 1 of the patients demonstrated an increase in total peripheral resistance and essentially no change in cardiac output following propranolol therapy. The studies suggest that propranolol is a useful drug in selected patients with severe idiopathic orthostatic hypotension. | NO-RELATIONSHIP |
| Use of propranolol in the treatment of idiopathic orthostatic hypotension. Five patients with idiopathic orthostatic hypotension who had physiologic and biochemical evidence of severe autonomic dysfunction were included in the study. They all exhibited markedly reduced plasma catecholamines and plasma renin activity in both recumbent and upright positions and had marked DISEASE to the pressor effects of infused CHEMICAL. Treatment with propanolol administered intravenously (1-5 mg) produced increases in supine and upright blood pressure in 4 of the 5 individuals with rises ranging from 11/6 to 22/11 mmHg. Chronic oral administration of propranolol (40-160 mg/day) also elevated the blood pressures of these individuals with increases in the order of 20-35/15-25 mmg being observed. In 1 patient, marked hypertension was induced by propranolol and the drug had to be withdrawn. It otherwise was well tolerated and no important side effects were observed. Treatment has been continued in 3 individuals for 6-13 months with persistence of the pressor effect, although there appears to have been some decrease in the degree of response with time. Hemodynamic measurements in 1 of the patients demonstrated an increase in total peripheral resistance and essentially no change in cardiac output following propranolol therapy. The studies suggest that propranolol is a useful drug in selected patients with severe idiopathic orthostatic hypotension. | NO-RELATIONSHIP |
| Use of propranolol in the treatment of DISEASE. Five patients with DISEASE who had physiologic and biochemical evidence of severe autonomic dysfunction were included in the study. They all exhibited markedly reduced plasma CHEMICAL and plasma renin activity in both recumbent and upright positions and had marked hypersensitivity to the pressor effects of infused norepinephrine. Treatment with propanolol administered intravenously (1-5 mg) produced increases in supine and upright blood pressure in 4 of the 5 individuals with rises ranging from 11/6 to 22/11 mmHg. Chronic oral administration of propranolol (40-160 mg/day) also elevated the blood pressures of these individuals with increases in the order of 20-35/15-25 mmg being observed. In 1 patient, marked hypertension was induced by propranolol and the drug had to be withdrawn. It otherwise was well tolerated and no important side effects were observed. Treatment has been continued in 3 individuals for 6-13 months with persistence of the pressor effect, although there appears to have been some decrease in the degree of response with time. Hemodynamic measurements in 1 of the patients demonstrated an increase in total peripheral resistance and essentially no change in cardiac output following propranolol therapy. The studies suggest that propranolol is a useful drug in selected patients with severe DISEASE. | NO-RELATIONSHIP |
| Use of propranolol in the treatment of DISEASE. Five patients with DISEASE who had physiologic and biochemical evidence of severe autonomic dysfunction were included in the study. They all exhibited markedly reduced plasma catecholamines and plasma renin activity in both recumbent and upright positions and had marked hypersensitivity to the pressor effects of infused CHEMICAL. Treatment with propanolol administered intravenously (1-5 mg) produced increases in supine and upright blood pressure in 4 of the 5 individuals with rises ranging from 11/6 to 22/11 mmHg. Chronic oral administration of propranolol (40-160 mg/day) also elevated the blood pressures of these individuals with increases in the order of 20-35/15-25 mmg being observed. In 1 patient, marked hypertension was induced by propranolol and the drug had to be withdrawn. It otherwise was well tolerated and no important side effects were observed. Treatment has been continued in 3 individuals for 6-13 months with persistence of the pressor effect, although there appears to have been some decrease in the degree of response with time. Hemodynamic measurements in 1 of the patients demonstrated an increase in total peripheral resistance and essentially no change in cardiac output following propranolol therapy. The studies suggest that propranolol is a useful drug in selected patients with severe DISEASE. | NO-RELATIONSHIP |
| Total intravenous anesthesia with CHEMICAL. III. Some observations in adults. An investigation was undertaken to determine the dosage of CHEMICAL required to maintain sleep in adults undergoing surgery under regional local anesthesia. Premedication of diazepam 10 mg and atropine 0.5 mg was given, and sleep was induced and maintained by intermittent intravenous injections of CHEMICAL 0.1/mg/kg, given whenever the patient would open his eyes on request. A mean overall dose of CHEMICAL 17.4 microgram/kg/min. was required to maintain sleep, but great individual variation occurred, with older patients requiring less drug. The investigation was discontinued after 18 patients because of the frequency and intensity of side-effects, particularly pain and DISEASE, which caused the technique to be abandoned in two cases. It is considered unlikely that CHEMICAL will prove to be the hypnotic of choice for a totally intravenous anesthetic technique in adults because of the high incidence of DISEASE after prolonged administration. In several patients uncontrollable muscle movements persisted for many minutes after complete recovery of consciousness. | CHEMICAL-INDUCED-DISEASE |
| Total intravenous anesthesia with CHEMICAL. III. Some observations in adults. An investigation was undertaken to determine the dosage of CHEMICAL required to maintain sleep in adults undergoing surgery under regional local anesthesia. Premedication of diazepam 10 mg and atropine 0.5 mg was given, and sleep was induced and maintained by intermittent intravenous injections of CHEMICAL 0.1/mg/kg, given whenever the patient would open his eyes on request. A mean overall dose of CHEMICAL 17.4 microgram/kg/min. was required to maintain sleep, but great individual variation occurred, with older patients requiring less drug. The investigation was discontinued after 18 patients because of the frequency and intensity of side-effects, particularly DISEASE and myoclonia, which caused the technique to be abandoned in two cases. It is considered unlikely that CHEMICAL will prove to be the hypnotic of choice for a totally intravenous anesthetic technique in adults because of the high incidence of myoclonia after prolonged administration. In several patients uncontrollable muscle movements persisted for many minutes after complete recovery of consciousness. | CHEMICAL-INDUCED-DISEASE |
| A method for the measurement of DISEASE, and a comparison of the effects of tocolytic beta-mimetics. A method permitting measurement of finger DISEASE as a displacement-time curve is described, using a test system with simple amplitude calibration. The coordinates of the inversion points of the displacement-time curves were transferred through graphical input equipment to punched tape. By means of a computer program, periods and amplitudes of DISEASE oscillations were calculated and classified. The event frequency for each class of periods and amplitudes was determined. The actions of CHEMICAL, ritodrin-HCl and placebo given to 10 healthy subjects by intravenous infusion in a double-blind crossover study were tested by this method. At therapeutic doses both substances raised the mean DISEASE amplitude to about three times the control level. At the same time, the mean period within each class of amplitudes shortened by 10--20 ms, whereas the mean periods calculated from all oscillations together did not change significantly. After the end of CHEMICAL infusion, DISEASE amplitudes decreased significantly faster than those following ritodrin-HCl infusion. | CHEMICAL-INDUCED-DISEASE |
| A method for the measurement of DISEASE, and a comparison of the effects of tocolytic beta-mimetics. A method permitting measurement of finger DISEASE as a displacement-time curve is described, using a test system with simple amplitude calibration. The coordinates of the inversion points of the displacement-time curves were transferred through graphical input equipment to punched tape. By means of a computer program, periods and amplitudes of DISEASE oscillations were calculated and classified. The event frequency for each class of periods and amplitudes was determined. The actions of fenoterol-hydrobromide, CHEMICAL and placebo given to 10 healthy subjects by intravenous infusion in a double-blind crossover study were tested by this method. At therapeutic doses both substances raised the mean DISEASE amplitude to about three times the control level. At the same time, the mean period within each class of amplitudes shortened by 10--20 ms, whereas the mean periods calculated from all oscillations together did not change significantly. After the end of fenoterol-hydrobromide infusion, DISEASE amplitudes decreased significantly faster than those following CHEMICAL infusion. | CHEMICAL-INDUCED-DISEASE |
| Bilateral DISEASE following the injection of long-acting corticosteroid suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral DISEASE with blindness following head and neck soft-tissue injection with CHEMICAL in combination with lidocaine, epinephrine, or penicillin are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, pupillary abnormalities, and conjunctival hemorrhages with edema. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | CHEMICAL-INDUCED-DISEASE |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting corticosteroid suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with lidocaine, CHEMICAL, or penicillin are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze DISEASE, pupillary abnormalities, and conjunctival hemorrhages with edema. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting CHEMICAL suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with lidocaine, epinephrine, or penicillin are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, pupillary abnormalities, and conjunctival hemorrhages with DISEASE. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting corticosteroid suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with CHEMICAL, epinephrine, or penicillin are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, DISEASE, and conjunctival hemorrhages with edema. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting corticosteroid suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with lidocaine, epinephrine, or CHEMICAL are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, pupillary abnormalities, and conjunctival hemorrhages with DISEASE. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting corticosteroid suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with lidocaine, epinephrine, or CHEMICAL are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, pupillary abnormalities, and conjunctival DISEASE with edema. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting corticosteroid suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with CHEMICAL, epinephrine, or penicillin are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, pupillary abnormalities, and conjunctival hemorrhages with DISEASE. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting corticosteroid suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with lidocaine, epinephrine, or CHEMICAL are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, DISEASE, and conjunctival hemorrhages with edema. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting CHEMICAL suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with lidocaine, epinephrine, or penicillin are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, pupillary abnormalities, and conjunctival DISEASE with edema. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting corticosteroid suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with CHEMICAL, epinephrine, or penicillin are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, pupillary abnormalities, and conjunctival DISEASE with edema. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting corticosteroid suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with DISEASE following head and neck soft-tissue injection with methylprednisolone acetate in combination with CHEMICAL, epinephrine, or penicillin are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, pupillary abnormalities, and conjunctival hemorrhages with edema. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting corticosteroid suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with lidocaine, epinephrine, or CHEMICAL are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, pupillary abnormalities, and conjunctival hemorrhages with edema. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and DISEASE. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting corticosteroid suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with DISEASE following head and neck soft-tissue injection with methylprednisolone acetate in combination with lidocaine, epinephrine, or CHEMICAL are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, pupillary abnormalities, and conjunctival hemorrhages with edema. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting corticosteroid suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with lidocaine, CHEMICAL, or penicillin are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, pupillary abnormalities, and conjunctival DISEASE with edema. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting corticosteroid suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with lidocaine, CHEMICAL, or penicillin are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, DISEASE, and conjunctival hemorrhages with edema. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting corticosteroid suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with lidocaine, CHEMICAL, or penicillin are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, pupillary abnormalities, and conjunctival hemorrhages with DISEASE. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting CHEMICAL suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with lidocaine, epinephrine, or penicillin are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, pupillary abnormalities, and conjunctival hemorrhages with edema. Follow-up changes showed marked DISEASE, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting CHEMICAL suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with lidocaine, epinephrine, or penicillin are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, DISEASE, and conjunctival hemorrhages with edema. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting corticosteroid suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with lidocaine, CHEMICAL, or penicillin are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze palsy, pupillary abnormalities, and conjunctival hemorrhages with edema. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and DISEASE. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting CHEMICAL suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with lidocaine, epinephrine, or penicillin are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze DISEASE, pupillary abnormalities, and conjunctival hemorrhages with edema. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| Bilateral retinal artery and choriocapillaris occlusion following the injection of long-acting corticosteroid suspensions in combination with other drugs: I. Clinical studies. Two well-documented cases of bilateral retinal artery and choriocapillaris occlusions with blindness following head and neck soft-tissue injection with methylprednisolone acetate in combination with lidocaine, epinephrine, or CHEMICAL are reported. One case had only a unilateral injection. The acute observations included hazy sensorium, superior gaze DISEASE, pupillary abnormalities, and conjunctival hemorrhages with edema. Follow-up changes showed marked visual loss, constricted visual fields, optic nerve pallor, vascular attenuation, and chorioretinal atrophy. The literature is reviewed, and possible causes are discussed. | NO-RELATIONSHIP |
| CHEMICAL-induced immune DISEASE. A patient with renal disease developed Coombs-positive DISEASE while receiving CHEMICAL therapy. An anti-CHEMICAL IgG antibody was detected in the patient's serum and in the eluates from her erythrocytes. In addition, nonimmunologic binding of normal and patient's serum proteins to her own and CHEMICAL-coated normal red cells was demonstrated. Skin tests and in vitro lymphocyte stimulation revealed that the patient was sensitized to CHEMICAL and also to ampicillin. Careful investigation of drug-induced DISEASE reveals the complexity of the immune mechanisms involved. | CHEMICAL-INDUCED-DISEASE |
| Cephalothin-induced immune hemolytic anemia. A patient with DISEASE developed Coombs-positive hemolytic anemia while receiving cephalothin therapy. An anti-cephalothin IgG antibody was detected in the patient's serum and in the eluates from her erythrocytes. In addition, nonimmunologic binding of normal and patient's serum proteins to her own and cephalothin-coated normal red cells was demonstrated. Skin tests and in vitro lymphocyte stimulation revealed that the patient was sensitized to cephalothin and also to CHEMICAL. Careful investigation of drug-induced hemolytic anemias reveals the complexity of the immune mechanisms involved. | NO-RELATIONSHIP |
| Kaliuretic effect of CHEMICAL treatment in parkinsonian patients. DISEASE, sometimes severe, was observed in some CHEMICAL-treated parkinsonian patients. The influence of CHEMICAL on the renal excretion of potassium was studied in 3 patients with DISEASE and in 5 normokalemic patients by determination of renal plasma flow, glomerular filtration rate, plasma concentration of potassium and sodium as well as urinary excretion of potassium, sodium and aldosterone. CHEMICAL intake was found to cause an increased excretion of potassium, and sometimes also of sodium, in the hypokalemic but not in the normokalemic patients. This effect on the renal function could be prohibited by the administration of a peripheral dopa decarbodylase inhibitor. It is not known why this effect occurred in some individuals but not in others, but our results indicate a correlation between aldosterone production and this renal effect of CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Kaliuretic effect of L-dopa treatment in DISEASE patients. Hypokalemia, sometimes severe, was observed in some L-dopa-treated DISEASE patients. The influence of L-dopa on the renal excretion of potassium was studied in 3 patients with hypokalemia and in 5 normokalemic patients by determination of renal plasma flow, glomerular filtration rate, plasma concentration of potassium and CHEMICAL as well as urinary excretion of potassium, CHEMICAL and aldosterone. L-Dopa intake was found to cause an increased excretion of potassium, and sometimes also of CHEMICAL, in the hypokalemic but not in the normokalemic patients. This effect on the renal function could be prohibited by the administration of a peripheral dopa decarbodylase inhibitor. It is not known why this effect occurred in some individuals but not in others, but our results indicate a correlation between aldosterone production and this renal effect of L-dopa. | NO-RELATIONSHIP |
| Kaliuretic effect of L-dopa treatment in DISEASE patients. Hypokalemia, sometimes severe, was observed in some L-dopa-treated DISEASE patients. The influence of L-dopa on the renal excretion of potassium was studied in 3 patients with hypokalemia and in 5 normokalemic patients by determination of renal plasma flow, glomerular filtration rate, plasma concentration of potassium and sodium as well as urinary excretion of potassium, sodium and CHEMICAL. L-Dopa intake was found to cause an increased excretion of potassium, and sometimes also of sodium, in the hypokalemic but not in the normokalemic patients. This effect on the renal function could be prohibited by the administration of a peripheral dopa decarbodylase inhibitor. It is not known why this effect occurred in some individuals but not in others, but our results indicate a correlation between CHEMICAL production and this renal effect of L-dopa. | NO-RELATIONSHIP |
| Kaliuretic effect of L-dopa treatment in DISEASE patients. Hypokalemia, sometimes severe, was observed in some L-dopa-treated DISEASE patients. The influence of L-dopa on the renal excretion of CHEMICAL was studied in 3 patients with hypokalemia and in 5 normokalemic patients by determination of renal plasma flow, glomerular filtration rate, plasma concentration of CHEMICAL and sodium as well as urinary excretion of CHEMICAL, sodium and aldosterone. L-Dopa intake was found to cause an increased excretion of CHEMICAL, and sometimes also of sodium, in the hypokalemic but not in the normokalemic patients. This effect on the renal function could be prohibited by the administration of a peripheral dopa decarbodylase inhibitor. It is not known why this effect occurred in some individuals but not in others, but our results indicate a correlation between aldosterone production and this renal effect of L-dopa. | NO-RELATIONSHIP |
| CHEMICAL DISEASE as probable idiosyncratic reaction: case report. A case of CHEMICAL (CHEMICAL) DISEASE with increasing seizures and EEG and mental changes is described. Despite adequate oral dosage of CHEMICAL (5 mg/kg/daily) the plasma level was very low (2.8 microgramg/ml). The DISEASE was probably an idiosyncratic and not toxic or allergic reaction. In fact the concentration of free CHEMICAL was normal, the patient presented a retarded morbilliform rash during CHEMICAL treatment, the protidogram was normal, and an intradermic CHEMICAL injection had no local effect. The authors conclude that in a patient starting CHEMICAL treatment an unexpected increase in seizures, with EEG and mental changes occurring simultaneously, should alert the physician to the possible need for eliminating CHEMICAL from the therapeutic regimen, even if plasma concentrations are low. | CHEMICAL-INDUCED-DISEASE |
| Effects of exercise on the severity of CHEMICAL-induced DISEASE. The effect of exercise on the severity of CHEMICAL-induced DISEASE was studied in male rats. Ninety-three rats were randomly divided into three groups. The exercise-CHEMICAL (E-1) and exercise control (EC) groups exercised daily for thirty days on a treadmill at 1 mph, 2% grade while animals of the sedentary-CHEMICAL (S-I) group remained sedentary. Eight animals were assigned to the sedentary control (SC) group which remained sedentary throughout the experimental period. Forty-eight hours after the final exercise period, S-I and E-I animals received a single subcutaneous injection of CHEMICAL (250 mg/kg body weight). Animals of the S-I group exhibited significantly (Pp less than 0.05) greater mortality from the effects of CHEMICAL than animals of the E-I group. Serum CPK activity for E-I animals was significantly (p less than 0.05) greater than for animals in the S-I and EC groups twenty hours following CHEMICAL injection. No statistically significant differences were observed between the two CHEMICAL treated groups for severity of the induced lesions, changes in heart weight, or heart weight to body weight ratios. The results indicated that exercise reduced the mortality associated with the effects of large dosages of CHEMICAL but had little on the severity of the infarction. | CHEMICAL-INDUCED-DISEASE |
| Effect of D-Glucarates on basic antibiotic-induced renal damage in rats. Dehydrated rats regularly develop DISEASE following single injection of CHEMICAL antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against renal failure induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, hexauronic acids and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe TCA cycle and other acidic compounds. D-Glucarates were effective against renal damage induced by peptide antibiotics as well as various CHEMICAL antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against renal damages induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent renal damage but not to cure it. Rats excreted acidic urine when they were spared from renal lesions by monosaccharides. The reduction effect of D-glucarates against nephrotoxicity of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced renal damage in rats. Dehydrated rats regularly develop DISEASE following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against renal failure induced by CHEMICAL-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, hexauronic acids and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe TCA cycle and other acidic compounds. D-Glucarates were effective against renal damage induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against renal damages induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent renal damage but not to cure it. Rats excreted acidic urine when they were spared from renal lesions by monosaccharides. The reduction effect of D-glucarates against nephrotoxicity of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of CHEMICAL on basic antibiotic-induced DISEASE in rats. Dehydrated rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against renal failure induced by kanamycin-dextran. The protective effect was prevalent among CHEMICAL, and also to other CHEMICAL, hexauronic acids and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe TCA cycle and other acidic compounds. CHEMICAL were effective against DISEASE induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of CHEMICAL. With a CHEMICAL of a fixed size of dose, approximately the same degree of protection was obtained against DISEASE induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. CHEMICAL had the ability to prevent DISEASE but not to cure it. Rats excreted acidic urine when they were spared from DISEASE by monosaccharides. The reduction effect of CHEMICAL against DISEASE of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced renal damage in rats. DISEASE rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of CHEMICAL protected rats against renal failure induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, hexauronic acids and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe TCA cycle and other acidic compounds. D-Glucarates were effective against renal damage induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against renal damages induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent renal damage but not to cure it. Rats excreted acidic urine when they were spared from renal lesions by monosaccharides. The reduction effect of D-glucarates against nephrotoxicity of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced DISEASE in rats. Dehydrated rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against renal failure induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, hexauronic acids and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe CHEMICAL cycle and other acidic compounds. D-Glucarates were effective against DISEASE induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against DISEASE induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent DISEASE but not to cure it. Rats excreted acidic urine when they were spared from DISEASE by monosaccharides. The reduction effect of D-glucarates against DISEASE of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced renal damage in rats. Dehydrated rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against DISEASE induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, hexauronic acids and CHEMICAL, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe TCA cycle and other acidic compounds. D-Glucarates were effective against renal damage induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against renal damages induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent renal damage but not to cure it. Rats excreted acidic urine when they were spared from renal lesions by monosaccharides. The reduction effect of D-glucarates against nephrotoxicity of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced renal damage in rats. Dehydrated rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against DISEASE induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, CHEMICAL and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe TCA cycle and other acidic compounds. D-Glucarates were effective against renal damage induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against renal damages induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent renal damage but not to cure it. Rats excreted acidic urine when they were spared from renal lesions by monosaccharides. The reduction effect of D-glucarates against nephrotoxicity of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced DISEASE in rats. Dehydrated rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of CHEMICAL protected rats against renal failure induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, hexauronic acids and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe TCA cycle and other acidic compounds. D-Glucarates were effective against DISEASE induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against DISEASE induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent DISEASE but not to cure it. Rats excreted acidic urine when they were spared from DISEASE by monosaccharides. The reduction effect of D-glucarates against DISEASE of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced renal damage in rats. DISEASE rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against renal failure induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, CHEMICAL and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe TCA cycle and other acidic compounds. D-Glucarates were effective against renal damage induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against renal damages induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent renal damage but not to cure it. Rats excreted acidic urine when they were spared from renal lesions by monosaccharides. The reduction effect of D-glucarates against nephrotoxicity of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced renal damage in rats. DISEASE rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against renal failure induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, hexauronic acids and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe CHEMICAL cycle and other acidic compounds. D-Glucarates were effective against renal damage induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against renal damages induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent renal damage but not to cure it. Rats excreted acidic urine when they were spared from renal lesions by monosaccharides. The reduction effect of D-glucarates against nephrotoxicity of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of CHEMICAL on basic antibiotic-induced renal damage in rats. Dehydrated rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against DISEASE induced by kanamycin-dextran. The protective effect was prevalent among CHEMICAL, and also to other CHEMICAL, hexauronic acids and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe TCA cycle and other acidic compounds. CHEMICAL were effective against renal damage induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of CHEMICAL. With a CHEMICAL of a fixed size of dose, approximately the same degree of protection was obtained against renal damages induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. CHEMICAL had the ability to prevent renal damage but not to cure it. Rats excreted acidic urine when they were spared from renal lesions by monosaccharides. The reduction effect of CHEMICAL against nephrotoxicity of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced renal damage in rats. Dehydrated rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against DISEASE induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, hexauronic acids and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe TCA cycle and other acidic compounds. D-Glucarates were effective against renal damage induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against renal damages induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent renal damage but not to cure it. Rats excreted acidic urine when they were spared from renal lesions by CHEMICAL. The reduction effect of D-glucarates against nephrotoxicity of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced DISEASE in rats. Dehydrated rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against renal failure induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, hexauronic acids and CHEMICAL, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe TCA cycle and other acidic compounds. D-Glucarates were effective against DISEASE induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against DISEASE induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent DISEASE but not to cure it. Rats excreted acidic urine when they were spared from DISEASE by monosaccharides. The reduction effect of D-glucarates against DISEASE of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced DISEASE in rats. Dehydrated rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against renal failure induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, hexauronic acids and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, CHEMICAL, substances inthe TCA cycle and other acidic compounds. D-Glucarates were effective against DISEASE induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against DISEASE induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent DISEASE but not to cure it. Rats excreted acidic urine when they were spared from DISEASE by monosaccharides. The reduction effect of D-glucarates against DISEASE of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced renal damage in rats. DISEASE rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against renal failure induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, hexauronic acids and CHEMICAL, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe TCA cycle and other acidic compounds. D-Glucarates were effective against renal damage induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against renal damages induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent renal damage but not to cure it. Rats excreted acidic urine when they were spared from renal lesions by monosaccharides. The reduction effect of D-glucarates against nephrotoxicity of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of CHEMICAL on basic antibiotic-induced renal damage in rats. DISEASE rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against renal failure induced by kanamycin-dextran. The protective effect was prevalent among CHEMICAL, and also to other CHEMICAL, hexauronic acids and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe TCA cycle and other acidic compounds. CHEMICAL were effective against renal damage induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of CHEMICAL. With a CHEMICAL of a fixed size of dose, approximately the same degree of protection was obtained against renal damages induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. CHEMICAL had the ability to prevent renal damage but not to cure it. Rats excreted acidic urine when they were spared from renal lesions by monosaccharides. The reduction effect of CHEMICAL against nephrotoxicity of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced renal damage in rats. Dehydrated rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against DISEASE induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, hexauronic acids and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe CHEMICAL cycle and other acidic compounds. D-Glucarates were effective against renal damage induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against renal damages induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent renal damage but not to cure it. Rats excreted acidic urine when they were spared from renal lesions by monosaccharides. The reduction effect of D-glucarates against nephrotoxicity of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced renal damage in rats. Dehydrated rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against DISEASE induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, hexauronic acids and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, CHEMICAL, substances inthe TCA cycle and other acidic compounds. D-Glucarates were effective against renal damage induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against renal damages induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent renal damage but not to cure it. Rats excreted acidic urine when they were spared from renal lesions by monosaccharides. The reduction effect of D-glucarates against nephrotoxicity of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced renal damage in rats. DISEASE rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against renal failure induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, hexauronic acids and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe TCA cycle and other acidic compounds. D-Glucarates were effective against renal damage induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against renal damages induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent renal damage but not to cure it. Rats excreted acidic urine when they were spared from renal lesions by CHEMICAL. The reduction effect of D-glucarates against nephrotoxicity of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced DISEASE in rats. Dehydrated rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against renal failure induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, CHEMICAL and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe TCA cycle and other acidic compounds. D-Glucarates were effective against DISEASE induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against DISEASE induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent DISEASE but not to cure it. Rats excreted acidic urine when they were spared from DISEASE by monosaccharides. The reduction effect of D-glucarates against DISEASE of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced DISEASE in rats. Dehydrated rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against renal failure induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, hexauronic acids and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, sugar alcohols, substances inthe TCA cycle and other acidic compounds. D-Glucarates were effective against DISEASE induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against DISEASE induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent DISEASE but not to cure it. Rats excreted acidic urine when they were spared from DISEASE by CHEMICAL. The reduction effect of D-glucarates against DISEASE of basic antibiotics was discussed. | NO-RELATIONSHIP |
| Effect of D-Glucarates on basic antibiotic-induced renal damage in rats. DISEASE rats regularly develop acute renal failure following single injection of aminoglycoside antibiotics combined with dextran or of antibiotics only. Oral administration of 2,5-di-O-acetyl-D-glucaro-1,4-6,3-dilactone protected rats against renal failure induced by kanamycin-dextran. The protective effect was prevalent among D-glucarates, and also to other saccharic acid, hexauronic acids and hexaaldonic acids, although to a lesser degree, but not to a hexaaldose, CHEMICAL, substances inthe TCA cycle and other acidic compounds. D-Glucarates were effective against renal damage induced by peptide antibiotics as well as various aminoglycoside antibitocis. Dose-responses were observed in the protective effect of D-Glucarates. With a D-glucarate of a fixed size of dose, approximately the same degree of protection was obtained against renal damages induced by different basic antibiotics despite large disparities in administration doses of different antibiotics. D-Glucarates had the ability to prevent renal damage but not to cure it. Rats excreted acidic urine when they were spared from renal lesions by monosaccharides. The reduction effect of D-glucarates against nephrotoxicity of basic antibiotics was discussed. | NO-RELATIONSHIP |
| DISEASE following intrathecal CHEMICAL: report of a case and review of the literature. A patient who developed DISEASE following the intrathecal instillation of CHEMICAL is discribed. The ten previously reported cases of this unusual complication are reviewed. The following factors appear to predispose to the development of this complication: abnormal cerebrospinal dynamics related to the presence of central nervous system leukemia, and epidural cerebrospinal leakage; elevated cerebrospinal fluid CHEMICAL concentration related to abnormal cerebrospinal fluid dynamics and to inappropriately high CHEMICAL doses based on body surface area calculations in older children and adults; the presence of neurotoxic preservatives in commercially available CHEMICAL preparations and diluents; and the use of CHEMICAL diluents of unphysiologic pH, ionic content and osmolarity. The role of CHEMICAL contaminants, local folate deficiency, and cranial irradiation in the pathogenesis of intrathecal CHEMICAL toxicity is unclear. The incidence of neurotoxicity may be reduced by employing lower doses of CHEMICAL in the presence of central nervous system leukemia, in older children and adults, and in the presence of epidural leakage. Only preservative-free CHEMICAL in Elliott's B Solution at a concentration of not more than 1 mg/ml should be used for intrathecal administration. Periodic monitoring of cerebruspinal fluid CHEMICAL levels may be predictive of the development of serious neurotoxicity. | CHEMICAL-INDUCED-DISEASE |
| Centrally mediated cardiovascular effects of intracisternal application of CHEMICAL in anesthetized rats. The pressor response to the intracisternal (i.c.) injection of CHEMICAL (1 mug) in anesthetized rats was analyzed. This response was significantly reduced by the intravenous (i.v.) injection of guanethidine (5 mg), hexamethonium (10 mg) or phentolamine (5 mg), and conversely, potentiated by i.v. desmethylimipramine (0.3 mg), while propranolol (0.5 mg) i.v. selectively inhibited the enlargement of pulse pressure and the DISEASE following i.c. CHEMICAL (1 mug). On the other hand, the pressor response to i.c. CHEMICAL (1 mug) was almost completely blocked by i.c. atropine (3 mug) or hexamethonium (500 mug), and significantly reduced by i.c. chlorpromazine (50 mug) but significantly potentiated by i.c. desmethylimipramine (30 mug). The pressor response to i.c. CHEMICAL (1 mug) remained unchanged after sectioning of the bilateral cervical vagal nerves but disappeared after sectioning of the spinal cord (C7-C8). From the above result it is suggested that the pressor response to i.c. CHEMICAL ortral and peripheral adrenergic mechanisms, and that the sympathetic trunk is the main pathway. | CHEMICAL-INDUCED-DISEASE |
| Centrally mediated cardiovascular effects of intracisternal application of CHEMICAL in anesthetized rats. The pressor response to the intracisternal (i.c.) injection of CHEMICAL (1 mug) in anesthetized rats was analyzed. This response was significantly reduced by the intravenous (i.v.) injection of guanethidine (5 mg), hexamethonium (10 mg) or phentolamine (5 mg), and conversely, potentiated by i.v. desmethylimipramine (0.3 mg), while propranolol (0.5 mg) i.v. selectively inhibited the DISEASE and the tachycardia following i.c. CHEMICAL (1 mug). On the other hand, the pressor response to i.c. CHEMICAL (1 mug) was almost completely blocked by i.c. atropine (3 mug) or hexamethonium (500 mug), and significantly reduced by i.c. chlorpromazine (50 mug) but significantly potentiated by i.c. desmethylimipramine (30 mug). The pressor response to i.c. CHEMICAL (1 mug) remained unchanged after sectioning of the bilateral cervical vagal nerves but disappeared after sectioning of the spinal cord (C7-C8). From the above result it is suggested that the pressor response to i.c. CHEMICAL ortral and peripheral adrenergic mechanisms, and that the sympathetic trunk is the main pathway. | CHEMICAL-INDUCED-DISEASE |
| Centrally mediated cardiovascular effects of intracisternal application of carbachol in anesthetized rats. The pressor response to the intracisternal (i.c.) injection of carbachol (1 mug) in anesthetized rats was analyzed. This response was significantly reduced by the intravenous (i.v.) injection of guanethidine (5 mg), hexamethonium (10 mg) or phentolamine (5 mg), and conversely, potentiated by i.v. CHEMICAL (0.3 mg), while propranolol (0.5 mg) i.v. selectively inhibited the DISEASE and the tachycardia following i.c. carbachol (1 mug). On the other hand, the pressor response to i.c. carbachol (1 mug) was almost completely blocked by i.c. atropine (3 mug) or hexamethonium (500 mug), and significantly reduced by i.c. chlorpromazine (50 mug) but significantly potentiated by i.c. CHEMICAL (30 mug). The pressor response to i.c. carbachol (1 mug) remained unchanged after sectioning of the bilateral cervical vagal nerves but disappeared after sectioning of the spinal cord (C7-C8). From the above result it is suggested that the pressor response to i.c. carbachol ortral and peripheral adrenergic mechanisms, and that the sympathetic trunk is the main pathway. | NO-RELATIONSHIP |
| DISEASE effect of CHEMICAL compounds structurally related to caproate in rats. The chronic feeding of small amounts (0.3-3% of diet weight) of certain CHEMICAL derivatives of caproate resulted in DISEASE, an elevated glucose tolerance curve and, occasionally, glucosuria. Effective compounds included norleucine, norvaline, glutamate, epsilon-aminocaproate, methionine, and leucine. | CHEMICAL-INDUCED-DISEASE |
| Hyperglycemic effect of amino compounds structurally related to caproate in rats. The chronic feeding of small amounts (0.3-3% of diet weight) of certain amino derivatives of caproate resulted in hyperglycemia, an elevated glucose tolerance curve and, occasionally, DISEASE. Effective compounds included norleucine, norvaline, CHEMICAL, epsilon-aminocaproate, methionine, and leucine. | NO-RELATIONSHIP |
| Hyperglycemic effect of amino compounds structurally related to caproate in rats. The chronic feeding of small amounts (0.3-3% of diet weight) of certain amino derivatives of caproate resulted in hyperglycemia, an elevated CHEMICAL tolerance curve and, occasionally, DISEASE. Effective compounds included norleucine, norvaline, glutamate, epsilon-aminocaproate, methionine, and leucine. | NO-RELATIONSHIP |
| Hyperglycemic effect of amino compounds structurally related to caproate in rats. The chronic feeding of small amounts (0.3-3% of diet weight) of certain amino derivatives of caproate resulted in hyperglycemia, an elevated glucose tolerance curve and, occasionally, DISEASE. Effective compounds included CHEMICAL, CHEMICAL, glutamate, CHEMICAL, methionine, and CHEMICAL. | NO-RELATIONSHIP |
| Hyperglycemic effect of amino compounds structurally related to caproate in rats. The chronic feeding of small amounts (0.3-3% of diet weight) of certain amino derivatives of caproate resulted in hyperglycemia, an elevated glucose tolerance curve and, occasionally, DISEASE. Effective compounds included norleucine, norvaline, glutamate, epsilon-aminocaproate, CHEMICAL, and leucine. | NO-RELATIONSHIP |
| Hyperglycemic effect of amino compounds structurally related to CHEMICAL in rats. The chronic feeding of small amounts (0.3-3% of diet weight) of certain amino derivatives of CHEMICAL resulted in hyperglycemia, an elevated glucose tolerance curve and, occasionally, DISEASE. Effective compounds included norleucine, norvaline, glutamate, epsilon-aminocaproate, methionine, and leucine. | CHEMICAL-INDUCED-DISEASE |
| DISEASE induced by CHEMICAL in the rat. Dose-response relationships and effect of sex. Dose-response relationships, biochemical mechanisms, and sex differences in the experimental DISEASE induced by CHEMICAL were studied in the intact rat and with the isolated perfused rat liver in vitro. In the intact male and female rat, no direct relationship was observed between dose of CHEMICAL and hepatic accumulation of triglyceride. With provision of adequate oleic acid as a substrate for the isolated perfused liver, a direct relationship was observed between dose of CHEMICAL and both accumulation of triglyceride in the liver and depression of output of triglyceride by livers from male and female rats. Marked differences were observed between female and male rats with regard to base line (control) hepatic concentration of triglyceride and output of triglyceride. Accumulation of hepatic triglyceride, as a per cent of control values, in response to graded doses of CHEMICAL, did not differ significantly between male, female and pregnant rat livers. However, livers from female, and especially pregnant female rats, were strikingly resistant to the effects of CHEMICAL on depression of output of triglyceride under these experimental conditions. These differences between the sexes could not be related to altered disposition of CHEMICAL or altered uptake of oleic acid. Depressed hepatic secretion of triglyceride accounted only for 30 to 50% of accumulated hepatic triglyceride, indicating that additional mechanisms must be involved in the production of the triglyceride-rich DISEASE in response to CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Fatty liver induced by tetracycline in the rat. Dose-response relationships and effect of sex. Dose-response relationships, biochemical mechanisms, and sex differences in the experimental fatty liver induced by tetracycline were studied in the intact rat and with the isolated perfused rat liver in vitro. In the intact male and female rat, no direct relationship was observed between dose of tetracycline and hepatic accumulation of CHEMICAL. With provision of adequate oleic acid as a substrate for the isolated perfused liver, a direct relationship was observed between dose of tetracycline and both accumulation of CHEMICAL in the liver and DISEASE of output of CHEMICAL by livers from male and female rats. Marked differences were observed between female and male rats with regard to base line (control) hepatic concentration of CHEMICAL and output of CHEMICAL. Accumulation of hepatic CHEMICAL, as a per cent of control values, in response to graded doses of tetracycline, did not differ significantly between male, female and pregnant rat livers. However, livers from female, and especially pregnant female rats, were strikingly resistant to the effects of tetracycline on DISEASE of output of CHEMICAL under these experimental conditions. These differences between the sexes could not be related to altered disposition of tetracycline or altered uptake of oleic acid. Depressed hepatic secretion of CHEMICAL accounted only for 30 to 50% of accumulated hepatic CHEMICAL, indicating that additional mechanisms must be involved in the production of the CHEMICAL-rich fatty liver in response to tetracycline. | NO-RELATIONSHIP |
| Fatty liver induced by tetracycline in the rat. Dose-response relationships and effect of sex. Dose-response relationships, biochemical mechanisms, and sex differences in the experimental fatty liver induced by tetracycline were studied in the intact rat and with the isolated perfused rat liver in vitro. In the intact male and female rat, no direct relationship was observed between dose of tetracycline and hepatic accumulation of triglyceride. With provision of adequate CHEMICAL as a substrate for the isolated perfused liver, a direct relationship was observed between dose of tetracycline and both accumulation of triglyceride in the liver and DISEASE of output of triglyceride by livers from male and female rats. Marked differences were observed between female and male rats with regard to base line (control) hepatic concentration of triglyceride and output of triglyceride. Accumulation of hepatic triglyceride, as a per cent of control values, in response to graded doses of tetracycline, did not differ significantly between male, female and pregnant rat livers. However, livers from female, and especially pregnant female rats, were strikingly resistant to the effects of tetracycline on DISEASE of output of triglyceride under these experimental conditions. These differences between the sexes could not be related to altered disposition of tetracycline or altered uptake of CHEMICAL. Depressed hepatic secretion of triglyceride accounted only for 30 to 50% of accumulated hepatic triglyceride, indicating that additional mechanisms must be involved in the production of the triglyceride-rich fatty liver in response to tetracycline. | NO-RELATIONSHIP |
| Fatal myeloencephalopathy due to intrathecal CHEMICAL administration. CHEMICAL was accidentally given intrathecally to a child with leukaemia, producing DISEASE followed by encephalopathy and death. Separate times for administering CHEMICAL and intrathecal therapy is recommended. | CHEMICAL-INDUCED-DISEASE |
| Fatal DISEASE due to intrathecal CHEMICAL administration. CHEMICAL was accidentally given intrathecally to a child with leukaemia, producing sensory and motor dysfunction followed by DISEASE and death. Separate times for administering CHEMICAL and intrathecal therapy is recommended. | CHEMICAL-INDUCED-DISEASE |
| Progesterone potentiation of CHEMICAL arrhythmogenicity in pentobarbital-anesthetized rats and beating rat heart cell cultures. The effects of progesterone treatment on CHEMICAL arrhythmogenicity in beating rat heart myocyte cultures and on anesthetized rats were determined. After determining the CHEMICAL AD50 (the concentration of CHEMICAL that caused 50% of all beating rat heart myocyte cultures to become DISEASE), we determined the effect of 1-hour progesterone HCl exposure on myocyte contractile rhythm. Each concentration of progesterone (6.25, 12.5, 25, and 50 micrograms/ml) caused a significant and concentration-dependent reduction in the AD50 for CHEMICAL. Estradiol treatment also increased the arrhythmogenicity of CHEMICAL in myocyte cultures, but was only one fourth as potent as progesterone. Neither progesterone nor estradiol effects on CHEMICAL arrhythmogenicity were potentiated by epinephrine. Chronic progesterone pretreatment (5 mg/kg/day for 21 days) caused a significant increase in CHEMICAL arrhythmogenicity in intact pentobarbital-anesthetized rats. There was a significant decrease in the time to onset of DISEASE as compared with control nonprogesterone-treated rats (6.2 +/- 1.3 vs. 30.8 +/- 2.5 min, mean +/- SE). The results of this study indicate that progesterone can potentiate CHEMICAL arrhythmogenicity both in vivo and in vitro. Potentiation of CHEMICAL DISEASE in myocyte cultures suggests that this effect is at least partly mediated at the myocyte level. | CHEMICAL-INDUCED-DISEASE |
| Progesterone potentiation of bupivacaine arrhythmogenicity in pentobarbital-anesthetized rats and beating rat heart cell cultures. The effects of progesterone treatment on bupivacaine arrhythmogenicity in beating rat heart myocyte cultures and on anesthetized rats were determined. After determining the bupivacaine AD50 (the concentration of bupivacaine that caused 50% of all beating rat heart myocyte cultures to become DISEASE), we determined the effect of 1-hour progesterone HCl exposure on myocyte contractile rhythm. Each concentration of progesterone (6.25, 12.5, 25, and 50 micrograms/ml) caused a significant and concentration-dependent reduction in the AD50 for bupivacaine. CHEMICAL treatment also increased the arrhythmogenicity of bupivacaine in myocyte cultures, but was only one fourth as potent as progesterone. Neither progesterone nor CHEMICAL effects on bupivacaine arrhythmogenicity were potentiated by epinephrine. Chronic progesterone pretreatment (5 mg/kg/day for 21 days) caused a significant increase in bupivacaine arrhythmogenicity in intact pentobarbital-anesthetized rats. There was a significant decrease in the time to onset of DISEASE as compared with control nonprogesterone-treated rats (6.2 +/- 1.3 vs. 30.8 +/- 2.5 min, mean +/- SE). The results of this study indicate that progesterone can potentiate bupivacaine arrhythmogenicity both in vivo and in vitro. Potentiation of bupivacaine DISEASE in myocyte cultures suggests that this effect is at least partly mediated at the myocyte level. | NO-RELATIONSHIP |
| CHEMICAL potentiation of bupivacaine arrhythmogenicity in pentobarbital-anesthetized rats and beating rat heart cell cultures. The effects of CHEMICAL treatment on bupivacaine arrhythmogenicity in beating rat heart myocyte cultures and on anesthetized rats were determined. After determining the bupivacaine AD50 (the concentration of bupivacaine that caused 50% of all beating rat heart myocyte cultures to become DISEASE), we determined the effect of 1-hour CHEMICAL HCl exposure on myocyte contractile rhythm. Each concentration of CHEMICAL (6.25, 12.5, 25, and 50 micrograms/ml) caused a significant and concentration-dependent reduction in the AD50 for bupivacaine. Estradiol treatment also increased the arrhythmogenicity of bupivacaine in myocyte cultures, but was only one fourth as potent as CHEMICAL. Neither CHEMICAL nor estradiol effects on bupivacaine arrhythmogenicity were potentiated by epinephrine. Chronic CHEMICAL pretreatment (5 mg/kg/day for 21 days) caused a significant increase in bupivacaine arrhythmogenicity in intact pentobarbital-anesthetized rats. There was a significant decrease in the time to onset of DISEASE as compared with control nonprogesterone-treated rats (6.2 +/- 1.3 vs. 30.8 +/- 2.5 min, mean +/- SE). The results of this study indicate that CHEMICAL can potentiate bupivacaine arrhythmogenicity both in vivo and in vitro. Potentiation of bupivacaine DISEASE in myocyte cultures suggests that this effect is at least partly mediated at the myocyte level. | NO-RELATIONSHIP |
| Acute renal failure occurring during intravenous CHEMICAL therapy: recovery after haemodialysis. A patient with transfusion-dependent thalassemia was undergoing home intravenous CHEMICAL (CHEMICAL) treatment by means of a totally implanted system because of his poor compliance with the nightly subcutaneous therapy. Due to an accidental malfunctioning of the infusion pump, the patient was inadvertently administered a toxic dosage of the drug which caused DISEASE. Given the progressive deterioration of the symptoms and of the laboratory values, despite adequate medical treatment, a decision was made to introduce haemodialytical therapy in order to remove the drug and therapy reduce the nephrotoxicity. From the results obtained, haemodialysis can therefore be suggested as a useful therapy in rare cases of progressive acute renal failure caused by CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Neuroleptic-associated hyperprolactinemia. Can it be treated with CHEMICAL? Six stable psychiatric outpatients with hyperprolactinemia and amenorrhea/oligomenorrhea associated with their neuroleptic medications were treated with CHEMICAL. Daily dosages of 5-10 mg corrected the hyperprolactinemia and restored menstruation in four of the six patients. One woman, however, developed worsened DISEASE while taking CHEMICAL, and it was discontinued. Thus, three of six patients had their menstrual irregularity successfully corrected with CHEMICAL. This suggests that CHEMICAL should be further evaluated as potential therapy for neuroleptic-associated hyperprolactinemia and amenorrhea/galactorrhea. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-associated hyperprolactinemia. Can it be treated with bromocriptine? Six stable psychiatric outpatients with hyperprolactinemia and DISEASE/oligomenorrhea associated with their CHEMICAL were treated with bromocriptine. Daily dosages of 5-10 mg corrected the hyperprolactinemia and restored menstruation in four of the six patients. One woman, however, developed worsened psychiatric symptoms while taking bromocriptine, and it was discontinued. Thus, three of six patients had their menstrual irregularity successfully corrected with bromocriptine. This suggests that bromocriptine should be further evaluated as potential therapy for CHEMICAL-associated hyperprolactinemia and DISEASE/galactorrhea. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-associated hyperprolactinemia. Can it be treated with bromocriptine? Six stable psychiatric outpatients with hyperprolactinemia and amenorrhea/DISEASE associated with their CHEMICAL were treated with bromocriptine. Daily dosages of 5-10 mg corrected the hyperprolactinemia and restored menstruation in four of the six patients. One woman, however, developed worsened psychiatric symptoms while taking bromocriptine, and it was discontinued. Thus, three of six patients had their menstrual irregularity successfully corrected with bromocriptine. This suggests that bromocriptine should be further evaluated as potential therapy for CHEMICAL-associated hyperprolactinemia and amenorrhea/galactorrhea. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-associated DISEASE. Can it be treated with bromocriptine? Six stable psychiatric outpatients with DISEASE and amenorrhea/oligomenorrhea associated with their CHEMICAL were treated with bromocriptine. Daily dosages of 5-10 mg corrected the DISEASE and restored menstruation in four of the six patients. One woman, however, developed worsened psychiatric symptoms while taking bromocriptine, and it was discontinued. Thus, three of six patients had their menstrual irregularity successfully corrected with bromocriptine. This suggests that bromocriptine should be further evaluated as potential therapy for CHEMICAL-associated DISEASE and amenorrhea/galactorrhea. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced DISEASE and brain neurotransmitters in mice. Intracerebroventricular injection of CHEMICAL (50% DISEASE dose; 50 micrograms/mouse) accelerated the synthesis/turnover of 5-hydroxytryptamine (5-HT) but suppressed the synthesis of gamma-aminobutyric acid and acetylcholine in mouse brain. These effects were completely antagonized by pretreatment with a glutamate/N-methyl-D-aspartate antagonist, aminophosphonovaleric acid. In CHEMICAL-induced DISEASE, these neurotransmitter systems may be differentially modulated, probably through activation of glutaminergic neurons in the brain. | CHEMICAL-INDUCED-DISEASE |
| Pharmacology of gamma-aminobutyric acidA receptor complex after the in vivo administration of the anxioselective and anticonvulsant beta-carboline derivative abecarnil. In rodents, the effect of the beta-carboline derivative isopropyl-6- benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate (abecarrnil), a new ligand for benzodiazepine receptors possessing anxiolytic and anticonvulsant properties, was evaluated on the function of central gamma-aminobutyric acid (GABA)A receptor complex, both in vitro and in vivo. Added in vitro to rat cortical membrane preparation, abecarnil increased [3H]GABA binding, enhanced muscimol-stimulated 36Cl- uptake and reduced the binding of t-[35S]butylbicyclophosphorothionate ([35S]TBPS). These effects were similar to those induced by diazepam, whereas the partial agonist Ro 16-6028 (tert-butyl-(S)-8-bromo-11,12,13,13a-tetrahydro-9-oxo-9H- imidazo[1,5-a]-pyrrolo-[2,1-c][1,4]benzodiazepine-1-carboxylate) showed very weak efficacy in these biochemical tests. After i.p. injection to rats, abecarnil and diazepam decreased in a time-dependent and dose-related (0.25-20 mg/kg i.p.) manner [35S]TBPS binding measured ex vivo in the cerebral cortex. Moreover, both drugs at the dose of 0.5 mg/kg antagonized completely the convulsant activity and the increase of [35S]TBPS binding induced by CHEMICAL (350 mg/kg s.c.) as well as the increase of [35S]TBPS binding induced by foot-shock stress. To better correlate the biochemical and the pharmacological effects, we studied the action of abecarnil on [35S]TBPS binding, exploratory motility and on CHEMICAL-induced biochemical and pharmacological effects in mice. In these animals, abecarnil produced a paralleled dose-dependent (0.05-1 mg/kg i.p.) reduction of both motor behavior and cortical [35S]TBPS binding. Moreover, 0.05 mg/kg of this beta-carboline reduced markedly the increase of [35S]TBPS binding and the DISEASE induced by CHEMICAL (200 mg/kg s.c.).(ABSTRACT TRUNCATED AT 250 WORDS) | REGULATOR |
| Recurrent DISEASE in a postpartum patient receiving CHEMICAL. DISEASE in puerperium is infrequently reported. Spasm, coronary dissection, or atheromatous etiology has been described. CHEMICAL has been implicated in several previous case reports of DISEASE in the puerperium. Our case (including an inadvertent rechallenge) suggests such a relationship. Although generally regarded as "safe," possible serious cardiac effects of CHEMICAL should be acknowledged. | CHEMICAL-INDUCED-DISEASE |
| DISEASE induced by carbamazepine therapy. There are very few reports about DISEASE as a side effect of treatment with psychopharmacologic agents. In this report we present four patients treated with a combination of different psychotropic drugs, in whom DISEASE was triggered either by adding carbamazepine (CBZ) to a treatment regimen, or by increasing its dosage. Neither dosage nor serum levels of CBZ were in a higher range. We consider DISEASE to be an easily overlooked sign of neurotoxicity, which may occur even at low or moderate dosage levels, if certain drugs as CHEMICAL or clozapine are used in combination with CBZ. | CHEMICAL-INDUCED-DISEASE |
| DISEASE induced by carbamazepine therapy. There are very few reports about DISEASE as a side effect of treatment with psychopharmacologic agents. In this report we present four patients treated with a combination of different psychotropic drugs, in whom DISEASE was triggered either by adding carbamazepine (CBZ) to a treatment regimen, or by increasing its dosage. Neither dosage nor serum levels of CBZ were in a higher range. We consider DISEASE to be an easily overlooked sign of neurotoxicity, which may occur even at low or moderate dosage levels, if certain drugs as lithium or CHEMICAL are used in combination with CBZ. | CHEMICAL-INDUCED-DISEASE |
| Asterixis induced by CHEMICAL therapy. There are very few reports about asterixis as a side effect of treatment with psychopharmacologic agents. In this report we present four patients treated with a combination of different psychotropic drugs, in whom asterixis was triggered either by adding CHEMICAL (CHEMICAL) to a treatment regimen, or by increasing its dosage. Neither dosage nor serum levels of CHEMICAL were in a higher range. We consider asterixis to be an easily overlooked sign of DISEASE, which may occur even at low or moderate dosage levels, if certain drugs as lithium or clozapine are used in combination with CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Pharmacodynamics of the DISEASE effect of CHEMICAL in parkinsonian patients. Blood pressure effects of i.v. CHEMICAL were examined in parkinsonian patients with stable and fluctuating responses to CHEMICAL. The magnitude of the DISEASE effect of CHEMICAL was concentration dependent and was fit to an Emax model in fluctuating responders. Stable responders demonstrated a small DISEASE response. Baseline blood pressures were higher in fluctuating patients; a higher baseline blood pressure correlated with greater DISEASE effects. Antiparkinsonian effects of CHEMICAL temporally correlated with blood pressure changes. Phenylalanine, a large neutral amino acid (LNAA) competing with CHEMICAL for transport across the blood-brain barrier, reduced the DISEASE and antiparkinsonian effects of CHEMICAL. We conclude that CHEMICAL has a central DISEASE action that parallels the motor effects in fluctuating patients. The DISEASE effect appears to be related to the higher baseline blood pressure we observed in fluctuating patients relative to stable patients. | CHEMICAL-INDUCED-DISEASE |
| Pharmacodynamics of the hypotensive effect of levodopa in DISEASE patients. Blood pressure effects of i.v. levodopa were examined in DISEASE patients with stable and fluctuating responses to levodopa. The magnitude of the hypotensive effect of levodopa was concentration dependent and was fit to an Emax model in fluctuating responders. Stable responders demonstrated a small hypotensive response. Baseline blood pressures were higher in fluctuating patients; a higher baseline blood pressure correlated with greater hypotensive effects. Antiparkinsonian effects of levodopa temporally correlated with blood pressure changes. Phenylalanine, a large neutral CHEMICAL (LNAA) competing with levodopa for transport across the blood-brain barrier, reduced the hypotensive and antiparkinsonian effects of levodopa. We conclude that levodopa has a central hypotensive action that parallels the motor effects in fluctuating patients. The hypotensive effect appears to be related to the higher baseline blood pressure we observed in fluctuating patients relative to stable patients. | NO-RELATIONSHIP |
| Pharmacodynamics of the hypotensive effect of levodopa in DISEASE patients. Blood pressure effects of i.v. levodopa were examined in DISEASE patients with stable and fluctuating responses to levodopa. The magnitude of the hypotensive effect of levodopa was concentration dependent and was fit to an Emax model in fluctuating responders. Stable responders demonstrated a small hypotensive response. Baseline blood pressures were higher in fluctuating patients; a higher baseline blood pressure correlated with greater hypotensive effects. Antiparkinsonian effects of levodopa temporally correlated with blood pressure changes. CHEMICAL, a large neutral amino acid (LNAA) competing with levodopa for transport across the blood-brain barrier, reduced the hypotensive and antiparkinsonian effects of levodopa. We conclude that levodopa has a central hypotensive action that parallels the motor effects in fluctuating patients. The hypotensive effect appears to be related to the higher baseline blood pressure we observed in fluctuating patients relative to stable patients. | NO-RELATIONSHIP |
| DISEASE after infusional CHEMICAL. A 77-year-old woman with refractory multiple myeloma was treated with a 4-day continuous intravenous infusion of CHEMICAL and doxorubicin and 4 days of oral dexamethasone. Nine days after her second cycle she presented with lethargy and weakness associated with hyponatremia. Evaluation revealed the DISEASE, which was attributed to the CHEMICAL infusion. After normal serum sodium levels returned, further doxorubicin and dexamethasone chemotherapy without CHEMICAL did not produce this complication. | CHEMICAL-INDUCED-DISEASE |
| Syndrome of inappropriate secretion of antidiuretic hormone after infusional vincristine. A 77-year-old woman with refractory multiple myeloma was treated with a 4-day continuous intravenous infusion of vincristine and CHEMICAL and 4 days of oral dexamethasone. Nine days after her second cycle she presented with DISEASE and weakness associated with hyponatremia. Evaluation revealed the syndrome of inappropriate secretion of antidiuretic hormone, which was attributed to the vincristine infusion. After normal serum sodium levels returned, further CHEMICAL and dexamethasone chemotherapy without vincristine did not produce this complication. | NO-RELATIONSHIP |
| Syndrome of inappropriate secretion of antidiuretic hormone after infusional vincristine. A 77-year-old woman with refractory multiple myeloma was treated with a 4-day continuous intravenous infusion of vincristine and doxorubicin and 4 days of oral CHEMICAL. Nine days after her second cycle she presented with lethargy and DISEASE associated with hyponatremia. Evaluation revealed the syndrome of inappropriate secretion of antidiuretic hormone, which was attributed to the vincristine infusion. After normal serum sodium levels returned, further doxorubicin and CHEMICAL chemotherapy without vincristine did not produce this complication. | NO-RELATIONSHIP |
| Syndrome of inappropriate secretion of antidiuretic hormone after infusional vincristine. A 77-year-old woman with refractory DISEASE was treated with a 4-day continuous intravenous infusion of vincristine and CHEMICAL and 4 days of oral dexamethasone. Nine days after her second cycle she presented with lethargy and weakness associated with hyponatremia. Evaluation revealed the syndrome of inappropriate secretion of antidiuretic hormone, which was attributed to the vincristine infusion. After normal serum sodium levels returned, further CHEMICAL and dexamethasone chemotherapy without vincristine did not produce this complication. | NO-RELATIONSHIP |
| Syndrome of inappropriate secretion of antidiuretic hormone after infusional vincristine. A 77-year-old woman with refractory multiple myeloma was treated with a 4-day continuous intravenous infusion of vincristine and doxorubicin and 4 days of oral dexamethasone. Nine days after her second cycle she presented with lethargy and DISEASE associated with hyponatremia. Evaluation revealed the syndrome of inappropriate secretion of antidiuretic hormone, which was attributed to the vincristine infusion. After normal serum CHEMICAL levels returned, further doxorubicin and dexamethasone chemotherapy without vincristine did not produce this complication. | NO-RELATIONSHIP |
| Syndrome of inappropriate secretion of antidiuretic hormone after infusional vincristine. A 77-year-old woman with refractory DISEASE was treated with a 4-day continuous intravenous infusion of vincristine and doxorubicin and 4 days of oral CHEMICAL. Nine days after her second cycle she presented with lethargy and weakness associated with hyponatremia. Evaluation revealed the syndrome of inappropriate secretion of antidiuretic hormone, which was attributed to the vincristine infusion. After normal serum sodium levels returned, further doxorubicin and CHEMICAL chemotherapy without vincristine did not produce this complication. | NO-RELATIONSHIP |
| Syndrome of inappropriate secretion of antidiuretic hormone after infusional vincristine. A 77-year-old woman with refractory multiple myeloma was treated with a 4-day continuous intravenous infusion of vincristine and CHEMICAL and 4 days of oral dexamethasone. Nine days after her second cycle she presented with lethargy and DISEASE associated with hyponatremia. Evaluation revealed the syndrome of inappropriate secretion of antidiuretic hormone, which was attributed to the vincristine infusion. After normal serum sodium levels returned, further CHEMICAL and dexamethasone chemotherapy without vincristine did not produce this complication. | NO-RELATIONSHIP |
| Syndrome of inappropriate secretion of antidiuretic hormone after infusional vincristine. A 77-year-old woman with refractory multiple myeloma was treated with a 4-day continuous intravenous infusion of vincristine and CHEMICAL and 4 days of oral dexamethasone. Nine days after her second cycle she presented with lethargy and weakness associated with DISEASE. Evaluation revealed the syndrome of inappropriate secretion of antidiuretic hormone, which was attributed to the vincristine infusion. After normal serum sodium levels returned, further CHEMICAL and dexamethasone chemotherapy without vincristine did not produce this complication. | NO-RELATIONSHIP |
| Syndrome of inappropriate secretion of antidiuretic hormone after infusional vincristine. A 77-year-old woman with refractory multiple myeloma was treated with a 4-day continuous intravenous infusion of vincristine and doxorubicin and 4 days of oral dexamethasone. Nine days after her second cycle she presented with DISEASE and weakness associated with hyponatremia. Evaluation revealed the syndrome of inappropriate secretion of antidiuretic hormone, which was attributed to the vincristine infusion. After normal serum CHEMICAL levels returned, further doxorubicin and dexamethasone chemotherapy without vincristine did not produce this complication. | NO-RELATIONSHIP |
| Syndrome of inappropriate secretion of antidiuretic hormone after infusional vincristine. A 77-year-old woman with refractory multiple myeloma was treated with a 4-day continuous intravenous infusion of vincristine and doxorubicin and 4 days of oral CHEMICAL. Nine days after her second cycle she presented with DISEASE and weakness associated with hyponatremia. Evaluation revealed the syndrome of inappropriate secretion of antidiuretic hormone, which was attributed to the vincristine infusion. After normal serum sodium levels returned, further doxorubicin and CHEMICAL chemotherapy without vincristine did not produce this complication. | NO-RELATIONSHIP |
| Syndrome of inappropriate secretion of antidiuretic hormone after infusional vincristine. A 77-year-old woman with refractory DISEASE was treated with a 4-day continuous intravenous infusion of vincristine and doxorubicin and 4 days of oral dexamethasone. Nine days after her second cycle she presented with lethargy and weakness associated with hyponatremia. Evaluation revealed the syndrome of inappropriate secretion of antidiuretic hormone, which was attributed to the vincristine infusion. After normal serum CHEMICAL levels returned, further doxorubicin and dexamethasone chemotherapy without vincristine did not produce this complication. | NO-RELATIONSHIP |
| Syndrome of inappropriate secretion of antidiuretic hormone after infusional vincristine. A 77-year-old woman with refractory multiple myeloma was treated with a 4-day continuous intravenous infusion of vincristine and doxorubicin and 4 days of oral CHEMICAL. Nine days after her second cycle she presented with lethargy and weakness associated with DISEASE. Evaluation revealed the syndrome of inappropriate secretion of antidiuretic hormone, which was attributed to the vincristine infusion. After normal serum sodium levels returned, further doxorubicin and CHEMICAL chemotherapy without vincristine did not produce this complication. | NO-RELATIONSHIP |
| Syndrome of inappropriate secretion of antidiuretic hormone after infusional vincristine. A 77-year-old woman with refractory multiple myeloma was treated with a 4-day continuous intravenous infusion of vincristine and doxorubicin and 4 days of oral dexamethasone. Nine days after her second cycle she presented with lethargy and weakness associated with DISEASE. Evaluation revealed the syndrome of inappropriate secretion of antidiuretic hormone, which was attributed to the vincristine infusion. After normal serum CHEMICAL levels returned, further doxorubicin and dexamethasone chemotherapy without vincristine did not produce this complication. | NO-RELATIONSHIP |
| Heart failure: to digitalise or not? The view against. Despite extensive clinical experience the role of CHEMICAL is still not well defined. In patients with atrial fibrillation CHEMICAL is beneficial for ventricular rate control. For patients in sinus rhythm and heart failure the situation is less clear. CHEMICAL has a narrow therapeutic:toxic ratio and concentrations are affected by a number of drugs. Also, CHEMICAL has undesirable effects such as increasing peripheral resistance and myocardial demands, and causing DISEASE. There is a paucity of data from well-designed trials. The trials that are available are generally small with limitations in design and these show variation in patient benefit. More convincing evidence is required showing that CHEMICAL improves symptoms or exercise capacity. Furthermore, no trial has had sufficient power to evaluate mortality. Pooled analysis of the effects of other inotropic drugs shows an excess mortality and there is a possibility that CHEMICAL may increase mortality after myocardial infarction (MI). Angiotensin-converting enzyme (ACE) inhibitors should be used first as they are safer, do not require blood level monitoring, modify progression of disease, relieve symptoms, improve exercise tolerance and reduce mortality. Caution should be exercised in using CHEMICAL until large mortality trials are completed showing either benefit or harm. Until then CHEMICAL should be considered a third-line therapy. | CHEMICAL-INDUCED-DISEASE |
| Heart failure: to digitalise or not? The view against. Despite extensive clinical experience the role of digoxin is still not well defined. In patients with atrial fibrillation digoxin is beneficial for ventricular rate control. For patients in sinus rhythm and heart failure the situation is less clear. Digoxin has a narrow therapeutic:toxic ratio and concentrations are affected by a number of drugs. Also, digoxin has undesirable effects such as increasing peripheral resistance and myocardial demands, and causing arrhythmias. There is a paucity of data from well-designed trials. The trials that are available are generally small with limitations in design and these show variation in patient benefit. More convincing evidence is required showing that digoxin improves symptoms or exercise capacity. Furthermore, no trial has had sufficient power to evaluate mortality. Pooled analysis of the effects of other inotropic drugs shows an excess mortality and there is a possibility that digoxin may increase mortality after DISEASE (DISEASE). CHEMICAL-converting enzyme (ACE) inhibitors should be used first as they are safer, do not require blood level monitoring, modify progression of disease, relieve symptoms, improve exercise tolerance and reduce mortality. Caution should be exercised in using digoxin until large mortality trials are completed showing either benefit or harm. Until then digoxin should be considered a third-line therapy. | NO-RELATIONSHIP |
| DISEASE: to digitalise or not? The view against. Despite extensive clinical experience the role of digoxin is still not well defined. In patients with atrial fibrillation digoxin is beneficial for ventricular rate control. For patients in sinus rhythm and DISEASE the situation is less clear. Digoxin has a narrow therapeutic:toxic ratio and concentrations are affected by a number of drugs. Also, digoxin has undesirable effects such as increasing peripheral resistance and myocardial demands, and causing arrhythmias. There is a paucity of data from well-designed trials. The trials that are available are generally small with limitations in design and these show variation in patient benefit. More convincing evidence is required showing that digoxin improves symptoms or exercise capacity. Furthermore, no trial has had sufficient power to evaluate mortality. Pooled analysis of the effects of other inotropic drugs shows an excess mortality and there is a possibility that digoxin may increase mortality after myocardial infarction (MI). CHEMICAL-converting enzyme (ACE) inhibitors should be used first as they are safer, do not require blood level monitoring, modify progression of disease, relieve symptoms, improve exercise tolerance and reduce mortality. Caution should be exercised in using digoxin until large mortality trials are completed showing either benefit or harm. Until then digoxin should be considered a third-line therapy. | NO-RELATIONSHIP |
| Heart failure: to digitalise or not? The view against. Despite extensive clinical experience the role of digoxin is still not well defined. In patients with DISEASE digoxin is beneficial for ventricular rate control. For patients in sinus rhythm and heart failure the situation is less clear. Digoxin has a narrow therapeutic:toxic ratio and concentrations are affected by a number of drugs. Also, digoxin has undesirable effects such as increasing peripheral resistance and myocardial demands, and causing arrhythmias. There is a paucity of data from well-designed trials. The trials that are available are generally small with limitations in design and these show variation in patient benefit. More convincing evidence is required showing that digoxin improves symptoms or exercise capacity. Furthermore, no trial has had sufficient power to evaluate mortality. Pooled analysis of the effects of other inotropic drugs shows an excess mortality and there is a possibility that digoxin may increase mortality after myocardial infarction (MI). CHEMICAL-converting enzyme (ACE) inhibitors should be used first as they are safer, do not require blood level monitoring, modify progression of disease, relieve symptoms, improve exercise tolerance and reduce mortality. Caution should be exercised in using digoxin until large mortality trials are completed showing either benefit or harm. Until then digoxin should be considered a third-line therapy. | NO-RELATIONSHIP |
| Intravascular hemolysis and DISEASE following intermittent CHEMICAL therapy. Renal failure is a rare complication associated with the use of CHEMICAL. Intravascular hemolysis leading to DISEASE following CHEMICAL therapy is extremely rare. Two patients with leprosy who developed hemolysis and DISEASE following CHEMICAL are reported. | CHEMICAL-INDUCED-DISEASE |
| Intravascular DISEASE and acute renal failure following intermittent CHEMICAL therapy. Renal failure is a rare complication associated with the use of CHEMICAL. Intravascular DISEASE leading to acute renal failure following CHEMICAL therapy is extremely rare. Two patients with leprosy who developed DISEASE and acute renal failure following CHEMICAL are reported. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced DISEASE. A case of acute DISEASE induced by CHEMICAL in a 38-year-old patient with AIDS is presented. The mechanism whereby the DISEASE was induced is not known. However, the patient tolerated well an alternative reverse transcriptase inhibitor, 2'3' dideoxyinosine. Physicians caring for patients with AIDS should be aware of this hitherto rarely reported complication. | CHEMICAL-INDUCED-DISEASE |
| Zidovudine-induced hepatitis. A case of acute hepatitis induced by zidovudine in a 38-year-old patient with DISEASE is presented. The mechanism whereby the hepatitis was induced is not known. However, the patient tolerated well an alternative reverse transcriptase inhibitor, CHEMICAL. Physicians caring for patients with DISEASE should be aware of this hitherto rarely reported complication. | NO-RELATIONSHIP |
| DISEASE secondary to CHEMICAL anticoagulant therapy: a case report. A case of DISEASE secondary to anticoagulant therapy is presented. Clinical features, similar to 2 other previously reported cases, are discussed. A high index of suspicion may lead to a quick diagnostic procedure and successful decompressive surgery. | CHEMICAL-INDUCED-DISEASE |
| DISEASE associated with CHEMICAL treatment in adolescents. CHEMICAL, a selective serotonin reuptake inhibitor, is gaining increased acceptance in the treatment of adolescent depression. Generally safe and well tolerated by adults, CHEMICAL has been reported to induce DISEASE. The cases of five depressed adolescents, 14-16 years of age, who developed DISEASE during pharmacotherapy with CHEMICAL, are reported here. Apparent risk factors for the development of DISEASE or DISEASE during CHEMICAL pharmacotherapy in this population were the combination of attention-deficit hyperactivity disorder and affective instability; major depression with psychotic features; a family history of affective disorder, especially DISEASE; and a diagnosis of DISEASE. Further study is needed to determine the optimal dosage and to identify risk factors that increase individual vulnerability to CHEMICAL induced DISEASE in adolescents. | CHEMICAL-INDUCED-DISEASE |
| Mania associated with fluoxetine treatment in adolescents. Fluoxetine, a selective CHEMICAL reuptake inhibitor, is gaining increased acceptance in the treatment of adolescent DISEASE. Generally safe and well tolerated by adults, fluoxetine has been reported to induce mania. The cases of five DISEASE adolescents, 14-16 years of age, who developed mania during pharmacotherapy with fluoxetine, are reported here. Apparent risk factors for the development of mania or hypomania during fluoxetine pharmacotherapy in this population were the combination of attention-deficit hyperactivity disorder and affective instability; major DISEASE with psychotic features; a family history of affective disorder, especially bipolar disorder; and a diagnosis of bipolar disorder. Further study is needed to determine the optimal dosage and to identify risk factors that increase individual vulnerability to fluoxetine induced mania in adolescents. | NO-RELATIONSHIP |
| Mania associated with fluoxetine treatment in adolescents. Fluoxetine, a selective CHEMICAL reuptake inhibitor, is gaining increased acceptance in the treatment of adolescent depression. Generally safe and well tolerated by adults, fluoxetine has been reported to induce mania. The cases of five depressed adolescents, 14-16 years of age, who developed mania during pharmacotherapy with fluoxetine, are reported here. Apparent risk factors for the development of mania or hypomania during fluoxetine pharmacotherapy in this population were the combination of DISEASE and affective instability; major depression with psychotic features; a family history of affective disorder, especially bipolar disorder; and a diagnosis of bipolar disorder. Further study is needed to determine the optimal dosage and to identify risk factors that increase individual vulnerability to fluoxetine induced mania in adolescents. | NO-RELATIONSHIP |
| Mania associated with fluoxetine treatment in adolescents. Fluoxetine, a selective CHEMICAL reuptake inhibitor, is gaining increased acceptance in the treatment of adolescent depression. Generally safe and well tolerated by adults, fluoxetine has been reported to induce mania. The cases of five depressed adolescents, 14-16 years of age, who developed mania during pharmacotherapy with fluoxetine, are reported here. Apparent risk factors for the development of mania or hypomania during fluoxetine pharmacotherapy in this population were the combination of attention-deficit hyperactivity disorder and affective instability; major depression with DISEASE features; a family history of affective disorder, especially bipolar disorder; and a diagnosis of bipolar disorder. Further study is needed to determine the optimal dosage and to identify risk factors that increase individual vulnerability to fluoxetine induced mania in adolescents. | NO-RELATIONSHIP |
| Mania associated with fluoxetine treatment in adolescents. Fluoxetine, a selective CHEMICAL reuptake inhibitor, is gaining increased acceptance in the treatment of adolescent depression. Generally safe and well tolerated by adults, fluoxetine has been reported to induce mania. The cases of five depressed adolescents, 14-16 years of age, who developed mania during pharmacotherapy with fluoxetine, are reported here. Apparent risk factors for the development of mania or hypomania during fluoxetine pharmacotherapy in this population were the combination of attention-deficit hyperactivity disorder and affective instability; major depression with psychotic features; a family history of DISEASE, especially bipolar disorder; and a diagnosis of bipolar disorder. Further study is needed to determine the optimal dosage and to identify risk factors that increase individual vulnerability to fluoxetine induced mania in adolescents. | NO-RELATIONSHIP |
| CHEMICAL-lovastatin therapy for primary hyperlipoproteinemias. The specific aim of this retrospective, observational study was to assess safety and efficacy of long-term (21 months/patient), open-label, CHEMICAL-lovastatin treatment in 80 patients with primary mixed hyperlipidemia (68% of whom had atherosclerotic vascular disease). Because ideal lipid targets were not reached (low-density lipoprotein (LDL) cholesterol less than 130 mg/dl, high-density lipoprotein (HDL) cholesterol greater than 35 mg/dl, or total cholesterol/HDL cholesterol less than 4.5 mg/dl) with diet plus a single drug, CHEMICAL (1.2 g/day)-lovastatin (primarily 20 or 40 mg) treatment was given. Follow-up visits were scheduled with 2-drug therapy every 6 to 8 weeks, an average of 10.3 visits per patient, with 741 batteries of 6 liver function tests and 714 creatine phosphokinase levels measured. Only 1 of the 4,446 liver function tests (0.02%), a gamma glutamyl transferase, was greater than or equal to 3 times the upper normal limit. Of the 714 creatine phosphokinase levels, 9% were high; only 1 (0.1%) was greater than or equal to 3 times the upper normal limit. With 2-drug therapy, mean total cholesterol decreased 22% from 255 to 200 mg/dl, triglyceride levels decreased 35% from 236 to 154 mg/dl, LDL cholesterol decreased 26% from 176 to 131 mg/dl, and the total cholesterol/HDL cholesterol ratio decreased 24% from 7.1 to 5.4, all p less than or equal to 0.0001. DISEASE, attributable to the drug combination and symptomatic enough to discontinue it, occurred in 3% of patients, and in 1% with concurrent high creatine phosphokinase (769 U/liter); no patients had rhabdomyolysis or myoglobinuria.(ABSTRACT TRUNCATED AT 250 WORDS) | CHEMICAL-INDUCED-DISEASE |
| Gemfibrozil-CHEMICAL therapy for primary hyperlipoproteinemias. The specific aim of this retrospective, observational study was to assess safety and efficacy of long-term (21 months/patient), open-label, gemfibrozil-CHEMICAL treatment in 80 patients with primary mixed hyperlipidemia (68% of whom had atherosclerotic vascular disease). Because ideal lipid targets were not reached (low-density lipoprotein (LDL) cholesterol less than 130 mg/dl, high-density lipoprotein (HDL) cholesterol greater than 35 mg/dl, or total cholesterol/HDL cholesterol less than 4.5 mg/dl) with diet plus a single drug, gemfibrozil (1.2 g/day)-CHEMICAL (primarily 20 or 40 mg) treatment was given. Follow-up visits were scheduled with 2-drug therapy every 6 to 8 weeks, an average of 10.3 visits per patient, with 741 batteries of 6 liver function tests and 714 creatine phosphokinase levels measured. Only 1 of the 4,446 liver function tests (0.02%), a gamma glutamyl transferase, was greater than or equal to 3 times the upper normal limit. Of the 714 creatine phosphokinase levels, 9% were high; only 1 (0.1%) was greater than or equal to 3 times the upper normal limit. With 2-drug therapy, mean total cholesterol decreased 22% from 255 to 200 mg/dl, triglyceride levels decreased 35% from 236 to 154 mg/dl, LDL cholesterol decreased 26% from 176 to 131 mg/dl, and the total cholesterol/HDL cholesterol ratio decreased 24% from 7.1 to 5.4, all p less than or equal to 0.0001. DISEASE, attributable to the drug combination and symptomatic enough to discontinue it, occurred in 3% of patients, and in 1% with concurrent high creatine phosphokinase (769 U/liter); no patients had rhabdomyolysis or myoglobinuria.(ABSTRACT TRUNCATED AT 250 WORDS) | CHEMICAL-INDUCED-DISEASE |
| Gemfibrozil-lovastatin therapy for primary hyperlipoproteinemias. The specific aim of this retrospective, observational study was to assess safety and efficacy of long-term (21 months/patient), open-label, gemfibrozil-lovastatin treatment in 80 patients with primary mixed hyperlipidemia (68% of whom had DISEASE). Because ideal lipid targets were not reached (low-density lipoprotein (LDL) cholesterol less than 130 mg/dl, high-density lipoprotein (HDL) cholesterol greater than 35 mg/dl, or total cholesterol/HDL cholesterol less than 4.5 mg/dl) with diet plus a single drug, gemfibrozil (1.2 g/day)-lovastatin (primarily 20 or 40 mg) treatment was given. Follow-up visits were scheduled with 2-drug therapy every 6 to 8 weeks, an average of 10.3 visits per patient, with 741 batteries of 6 liver function tests and 714 CHEMICAL phosphokinase levels measured. Only 1 of the 4,446 liver function tests (0.02%), a gamma glutamyl transferase, was greater than or equal to 3 times the upper normal limit. Of the 714 CHEMICAL phosphokinase levels, 9% were high; only 1 (0.1%) was greater than or equal to 3 times the upper normal limit. With 2-drug therapy, mean total cholesterol decreased 22% from 255 to 200 mg/dl, triglyceride levels decreased 35% from 236 to 154 mg/dl, LDL cholesterol decreased 26% from 176 to 131 mg/dl, and the total cholesterol/HDL cholesterol ratio decreased 24% from 7.1 to 5.4, all p less than or equal to 0.0001. Myositis, attributable to the drug combination and symptomatic enough to discontinue it, occurred in 3% of patients, and in 1% with concurrent high CHEMICAL phosphokinase (769 U/liter); no patients had rhabdomyolysis or myoglobinuria.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Gemfibrozil-lovastatin therapy for primary hyperlipoproteinemias. The specific aim of this retrospective, observational study was to assess safety and efficacy of long-term (21 months/patient), open-label, gemfibrozil-lovastatin treatment in 80 patients with primary mixed hyperlipidemia (68% of whom had DISEASE). Because ideal lipid targets were not reached (low-density lipoprotein (LDL) CHEMICAL less than 130 mg/dl, high-density lipoprotein (HDL) CHEMICAL greater than 35 mg/dl, or total CHEMICAL/HDL CHEMICAL less than 4.5 mg/dl) with diet plus a single drug, gemfibrozil (1.2 g/day)-lovastatin (primarily 20 or 40 mg) treatment was given. Follow-up visits were scheduled with 2-drug therapy every 6 to 8 weeks, an average of 10.3 visits per patient, with 741 batteries of 6 liver function tests and 714 creatine phosphokinase levels measured. Only 1 of the 4,446 liver function tests (0.02%), a gamma glutamyl transferase, was greater than or equal to 3 times the upper normal limit. Of the 714 creatine phosphokinase levels, 9% were high; only 1 (0.1%) was greater than or equal to 3 times the upper normal limit. With 2-drug therapy, mean total CHEMICAL decreased 22% from 255 to 200 mg/dl, triglyceride levels decreased 35% from 236 to 154 mg/dl, LDL CHEMICAL decreased 26% from 176 to 131 mg/dl, and the total CHEMICAL/HDL CHEMICAL ratio decreased 24% from 7.1 to 5.4, all p less than or equal to 0.0001. Myositis, attributable to the drug combination and symptomatic enough to discontinue it, occurred in 3% of patients, and in 1% with concurrent high creatine phosphokinase (769 U/liter); no patients had rhabdomyolysis or myoglobinuria.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Gemfibrozil-lovastatin therapy for primary hyperlipoproteinemias. The specific aim of this retrospective, observational study was to assess safety and efficacy of long-term (21 months/patient), open-label, gemfibrozil-lovastatin treatment in 80 patients with primary mixed hyperlipidemia (68% of whom had atherosclerotic vascular disease). Because ideal lipid targets were not reached (low-density lipoprotein (LDL) cholesterol less than 130 mg/dl, high-density lipoprotein (HDL) cholesterol greater than 35 mg/dl, or total cholesterol/HDL cholesterol less than 4.5 mg/dl) with diet plus a single drug, gemfibrozil (1.2 g/day)-lovastatin (primarily 20 or 40 mg) treatment was given. Follow-up visits were scheduled with 2-drug therapy every 6 to 8 weeks, an average of 10.3 visits per patient, with 741 batteries of 6 liver function tests and 714 CHEMICAL phosphokinase levels measured. Only 1 of the 4,446 liver function tests (0.02%), a gamma glutamyl transferase, was greater than or equal to 3 times the upper normal limit. Of the 714 CHEMICAL phosphokinase levels, 9% were high; only 1 (0.1%) was greater than or equal to 3 times the upper normal limit. With 2-drug therapy, mean total cholesterol decreased 22% from 255 to 200 mg/dl, triglyceride levels decreased 35% from 236 to 154 mg/dl, LDL cholesterol decreased 26% from 176 to 131 mg/dl, and the total cholesterol/HDL cholesterol ratio decreased 24% from 7.1 to 5.4, all p less than or equal to 0.0001. Myositis, attributable to the drug combination and symptomatic enough to discontinue it, occurred in 3% of patients, and in 1% with concurrent high CHEMICAL phosphokinase (769 U/liter); no patients had rhabdomyolysis or DISEASE.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Gemfibrozil-lovastatin therapy for primary DISEASE. The specific aim of this retrospective, observational study was to assess safety and efficacy of long-term (21 months/patient), open-label, gemfibrozil-lovastatin treatment in 80 patients with primary mixed hyperlipidemia (68% of whom had atherosclerotic vascular disease). Because ideal lipid targets were not reached (low-density lipoprotein (LDL) cholesterol less than 130 mg/dl, high-density lipoprotein (HDL) cholesterol greater than 35 mg/dl, or total cholesterol/HDL cholesterol less than 4.5 mg/dl) with diet plus a single drug, gemfibrozil (1.2 g/day)-lovastatin (primarily 20 or 40 mg) treatment was given. Follow-up visits were scheduled with 2-drug therapy every 6 to 8 weeks, an average of 10.3 visits per patient, with 741 batteries of 6 liver function tests and 714 creatine phosphokinase levels measured. Only 1 of the 4,446 liver function tests (0.02%), a gamma glutamyl transferase, was greater than or equal to 3 times the upper normal limit. Of the 714 creatine phosphokinase levels, 9% were high; only 1 (0.1%) was greater than or equal to 3 times the upper normal limit. With 2-drug therapy, mean total cholesterol decreased 22% from 255 to 200 mg/dl, CHEMICAL levels decreased 35% from 236 to 154 mg/dl, LDL cholesterol decreased 26% from 176 to 131 mg/dl, and the total cholesterol/HDL cholesterol ratio decreased 24% from 7.1 to 5.4, all p less than or equal to 0.0001. Myositis, attributable to the drug combination and symptomatic enough to discontinue it, occurred in 3% of patients, and in 1% with concurrent high creatine phosphokinase (769 U/liter); no patients had rhabdomyolysis or myoglobinuria.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Gemfibrozil-lovastatin therapy for primary DISEASE. The specific aim of this retrospective, observational study was to assess safety and efficacy of long-term (21 months/patient), open-label, gemfibrozil-lovastatin treatment in 80 patients with primary mixed hyperlipidemia (68% of whom had atherosclerotic vascular disease). Because ideal lipid targets were not reached (low-density lipoprotein (LDL) cholesterol less than 130 mg/dl, high-density lipoprotein (HDL) cholesterol greater than 35 mg/dl, or total cholesterol/HDL cholesterol less than 4.5 mg/dl) with diet plus a single drug, gemfibrozil (1.2 g/day)-lovastatin (primarily 20 or 40 mg) treatment was given. Follow-up visits were scheduled with 2-drug therapy every 6 to 8 weeks, an average of 10.3 visits per patient, with 741 batteries of 6 liver function tests and 714 CHEMICAL phosphokinase levels measured. Only 1 of the 4,446 liver function tests (0.02%), a gamma glutamyl transferase, was greater than or equal to 3 times the upper normal limit. Of the 714 CHEMICAL phosphokinase levels, 9% were high; only 1 (0.1%) was greater than or equal to 3 times the upper normal limit. With 2-drug therapy, mean total cholesterol decreased 22% from 255 to 200 mg/dl, triglyceride levels decreased 35% from 236 to 154 mg/dl, LDL cholesterol decreased 26% from 176 to 131 mg/dl, and the total cholesterol/HDL cholesterol ratio decreased 24% from 7.1 to 5.4, all p less than or equal to 0.0001. Myositis, attributable to the drug combination and symptomatic enough to discontinue it, occurred in 3% of patients, and in 1% with concurrent high CHEMICAL phosphokinase (769 U/liter); no patients had rhabdomyolysis or myoglobinuria.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Gemfibrozil-lovastatin therapy for primary hyperlipoproteinemias. The specific aim of this retrospective, observational study was to assess safety and efficacy of long-term (21 months/patient), open-label, gemfibrozil-lovastatin treatment in 80 patients with primary mixed hyperlipidemia (68% of whom had atherosclerotic vascular disease). Because ideal lipid targets were not reached (low-density lipoprotein (LDL) CHEMICAL less than 130 mg/dl, high-density lipoprotein (HDL) CHEMICAL greater than 35 mg/dl, or total CHEMICAL/HDL CHEMICAL less than 4.5 mg/dl) with diet plus a single drug, gemfibrozil (1.2 g/day)-lovastatin (primarily 20 or 40 mg) treatment was given. Follow-up visits were scheduled with 2-drug therapy every 6 to 8 weeks, an average of 10.3 visits per patient, with 741 batteries of 6 liver function tests and 714 creatine phosphokinase levels measured. Only 1 of the 4,446 liver function tests (0.02%), a gamma glutamyl transferase, was greater than or equal to 3 times the upper normal limit. Of the 714 creatine phosphokinase levels, 9% were high; only 1 (0.1%) was greater than or equal to 3 times the upper normal limit. With 2-drug therapy, mean total CHEMICAL decreased 22% from 255 to 200 mg/dl, triglyceride levels decreased 35% from 236 to 154 mg/dl, LDL CHEMICAL decreased 26% from 176 to 131 mg/dl, and the total CHEMICAL/HDL CHEMICAL ratio decreased 24% from 7.1 to 5.4, all p less than or equal to 0.0001. Myositis, attributable to the drug combination and symptomatic enough to discontinue it, occurred in 3% of patients, and in 1% with concurrent high creatine phosphokinase (769 U/liter); no patients had rhabdomyolysis or DISEASE.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Gemfibrozil-lovastatin therapy for primary hyperlipoproteinemias. The specific aim of this retrospective, observational study was to assess safety and efficacy of long-term (21 months/patient), open-label, gemfibrozil-lovastatin treatment in 80 patients with primary mixed hyperlipidemia (68% of whom had atherosclerotic vascular disease). Because ideal lipid targets were not reached (low-density lipoprotein (LDL) cholesterol less than 130 mg/dl, high-density lipoprotein (HDL) cholesterol greater than 35 mg/dl, or total cholesterol/HDL cholesterol less than 4.5 mg/dl) with diet plus a single drug, gemfibrozil (1.2 g/day)-lovastatin (primarily 20 or 40 mg) treatment was given. Follow-up visits were scheduled with 2-drug therapy every 6 to 8 weeks, an average of 10.3 visits per patient, with 741 batteries of 6 liver function tests and 714 creatine phosphokinase levels measured. Only 1 of the 4,446 liver function tests (0.02%), a gamma glutamyl transferase, was greater than or equal to 3 times the upper normal limit. Of the 714 creatine phosphokinase levels, 9% were high; only 1 (0.1%) was greater than or equal to 3 times the upper normal limit. With 2-drug therapy, mean total cholesterol decreased 22% from 255 to 200 mg/dl, CHEMICAL levels decreased 35% from 236 to 154 mg/dl, LDL cholesterol decreased 26% from 176 to 131 mg/dl, and the total cholesterol/HDL cholesterol ratio decreased 24% from 7.1 to 5.4, all p less than or equal to 0.0001. Myositis, attributable to the drug combination and symptomatic enough to discontinue it, occurred in 3% of patients, and in 1% with concurrent high creatine phosphokinase (769 U/liter); no patients had rhabdomyolysis or DISEASE.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Gemfibrozil-lovastatin therapy for primary hyperlipoproteinemias. The specific aim of this retrospective, observational study was to assess safety and efficacy of long-term (21 months/patient), open-label, gemfibrozil-lovastatin treatment in 80 patients with primary mixed hyperlipidemia (68% of whom had atherosclerotic vascular disease). Because ideal lipid targets were not reached (low-density lipoprotein (LDL) cholesterol less than 130 mg/dl, high-density lipoprotein (HDL) cholesterol greater than 35 mg/dl, or total cholesterol/HDL cholesterol less than 4.5 mg/dl) with diet plus a single drug, gemfibrozil (1.2 g/day)-lovastatin (primarily 20 or 40 mg) treatment was given. Follow-up visits were scheduled with 2-drug therapy every 6 to 8 weeks, an average of 10.3 visits per patient, with 741 batteries of 6 liver function tests and 714 CHEMICAL phosphokinase levels measured. Only 1 of the 4,446 liver function tests (0.02%), a gamma glutamyl transferase, was greater than or equal to 3 times the upper normal limit. Of the 714 CHEMICAL phosphokinase levels, 9% were high; only 1 (0.1%) was greater than or equal to 3 times the upper normal limit. With 2-drug therapy, mean total cholesterol decreased 22% from 255 to 200 mg/dl, triglyceride levels decreased 35% from 236 to 154 mg/dl, LDL cholesterol decreased 26% from 176 to 131 mg/dl, and the total cholesterol/HDL cholesterol ratio decreased 24% from 7.1 to 5.4, all p less than or equal to 0.0001. Myositis, attributable to the drug combination and symptomatic enough to discontinue it, occurred in 3% of patients, and in 1% with concurrent high CHEMICAL phosphokinase (769 U/liter); no patients had DISEASE or myoglobinuria.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Gemfibrozil-lovastatin therapy for primary hyperlipoproteinemias. The specific aim of this retrospective, observational study was to assess safety and efficacy of long-term (21 months/patient), open-label, gemfibrozil-lovastatin treatment in 80 patients with primary mixed hyperlipidemia (68% of whom had atherosclerotic vascular disease). Because ideal lipid targets were not reached (low-density lipoprotein (LDL) cholesterol less than 130 mg/dl, high-density lipoprotein (HDL) cholesterol greater than 35 mg/dl, or total cholesterol/HDL cholesterol less than 4.5 mg/dl) with diet plus a single drug, gemfibrozil (1.2 g/day)-lovastatin (primarily 20 or 40 mg) treatment was given. Follow-up visits were scheduled with 2-drug therapy every 6 to 8 weeks, an average of 10.3 visits per patient, with 741 batteries of 6 liver function tests and 714 creatine phosphokinase levels measured. Only 1 of the 4,446 liver function tests (0.02%), a gamma glutamyl transferase, was greater than or equal to 3 times the upper normal limit. Of the 714 creatine phosphokinase levels, 9% were high; only 1 (0.1%) was greater than or equal to 3 times the upper normal limit. With 2-drug therapy, mean total cholesterol decreased 22% from 255 to 200 mg/dl, CHEMICAL levels decreased 35% from 236 to 154 mg/dl, LDL cholesterol decreased 26% from 176 to 131 mg/dl, and the total cholesterol/HDL cholesterol ratio decreased 24% from 7.1 to 5.4, all p less than or equal to 0.0001. Myositis, attributable to the drug combination and symptomatic enough to discontinue it, occurred in 3% of patients, and in 1% with concurrent high creatine phosphokinase (769 U/liter); no patients had DISEASE or myoglobinuria.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Gemfibrozil-lovastatin therapy for primary hyperlipoproteinemias. The specific aim of this retrospective, observational study was to assess safety and efficacy of long-term (21 months/patient), open-label, gemfibrozil-lovastatin treatment in 80 patients with primary mixed DISEASE (68% of whom had atherosclerotic vascular disease). Because ideal lipid targets were not reached (low-density lipoprotein (LDL) cholesterol less than 130 mg/dl, high-density lipoprotein (HDL) cholesterol greater than 35 mg/dl, or total cholesterol/HDL cholesterol less than 4.5 mg/dl) with diet plus a single drug, gemfibrozil (1.2 g/day)-lovastatin (primarily 20 or 40 mg) treatment was given. Follow-up visits were scheduled with 2-drug therapy every 6 to 8 weeks, an average of 10.3 visits per patient, with 741 batteries of 6 liver function tests and 714 creatine phosphokinase levels measured. Only 1 of the 4,446 liver function tests (0.02%), a gamma glutamyl transferase, was greater than or equal to 3 times the upper normal limit. Of the 714 creatine phosphokinase levels, 9% were high; only 1 (0.1%) was greater than or equal to 3 times the upper normal limit. With 2-drug therapy, mean total cholesterol decreased 22% from 255 to 200 mg/dl, CHEMICAL levels decreased 35% from 236 to 154 mg/dl, LDL cholesterol decreased 26% from 176 to 131 mg/dl, and the total cholesterol/HDL cholesterol ratio decreased 24% from 7.1 to 5.4, all p less than or equal to 0.0001. Myositis, attributable to the drug combination and symptomatic enough to discontinue it, occurred in 3% of patients, and in 1% with concurrent high creatine phosphokinase (769 U/liter); no patients had rhabdomyolysis or myoglobinuria.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Gemfibrozil-lovastatin therapy for primary hyperlipoproteinemias. The specific aim of this retrospective, observational study was to assess safety and efficacy of long-term (21 months/patient), open-label, gemfibrozil-lovastatin treatment in 80 patients with primary mixed DISEASE (68% of whom had atherosclerotic vascular disease). Because ideal lipid targets were not reached (low-density lipoprotein (LDL) CHEMICAL less than 130 mg/dl, high-density lipoprotein (HDL) CHEMICAL greater than 35 mg/dl, or total CHEMICAL/HDL CHEMICAL less than 4.5 mg/dl) with diet plus a single drug, gemfibrozil (1.2 g/day)-lovastatin (primarily 20 or 40 mg) treatment was given. Follow-up visits were scheduled with 2-drug therapy every 6 to 8 weeks, an average of 10.3 visits per patient, with 741 batteries of 6 liver function tests and 714 creatine phosphokinase levels measured. Only 1 of the 4,446 liver function tests (0.02%), a gamma glutamyl transferase, was greater than or equal to 3 times the upper normal limit. Of the 714 creatine phosphokinase levels, 9% were high; only 1 (0.1%) was greater than or equal to 3 times the upper normal limit. With 2-drug therapy, mean total CHEMICAL decreased 22% from 255 to 200 mg/dl, triglyceride levels decreased 35% from 236 to 154 mg/dl, LDL CHEMICAL decreased 26% from 176 to 131 mg/dl, and the total CHEMICAL/HDL CHEMICAL ratio decreased 24% from 7.1 to 5.4, all p less than or equal to 0.0001. Myositis, attributable to the drug combination and symptomatic enough to discontinue it, occurred in 3% of patients, and in 1% with concurrent high creatine phosphokinase (769 U/liter); no patients had rhabdomyolysis or myoglobinuria.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Gemfibrozil-lovastatin therapy for primary hyperlipoproteinemias. The specific aim of this retrospective, observational study was to assess safety and efficacy of long-term (21 months/patient), open-label, gemfibrozil-lovastatin treatment in 80 patients with primary mixed DISEASE (68% of whom had atherosclerotic vascular disease). Because ideal lipid targets were not reached (low-density lipoprotein (LDL) cholesterol less than 130 mg/dl, high-density lipoprotein (HDL) cholesterol greater than 35 mg/dl, or total cholesterol/HDL cholesterol less than 4.5 mg/dl) with diet plus a single drug, gemfibrozil (1.2 g/day)-lovastatin (primarily 20 or 40 mg) treatment was given. Follow-up visits were scheduled with 2-drug therapy every 6 to 8 weeks, an average of 10.3 visits per patient, with 741 batteries of 6 liver function tests and 714 CHEMICAL phosphokinase levels measured. Only 1 of the 4,446 liver function tests (0.02%), a gamma glutamyl transferase, was greater than or equal to 3 times the upper normal limit. Of the 714 CHEMICAL phosphokinase levels, 9% were high; only 1 (0.1%) was greater than or equal to 3 times the upper normal limit. With 2-drug therapy, mean total cholesterol decreased 22% from 255 to 200 mg/dl, triglyceride levels decreased 35% from 236 to 154 mg/dl, LDL cholesterol decreased 26% from 176 to 131 mg/dl, and the total cholesterol/HDL cholesterol ratio decreased 24% from 7.1 to 5.4, all p less than or equal to 0.0001. Myositis, attributable to the drug combination and symptomatic enough to discontinue it, occurred in 3% of patients, and in 1% with concurrent high CHEMICAL phosphokinase (769 U/liter); no patients had rhabdomyolysis or myoglobinuria.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Gemfibrozil-lovastatin therapy for primary hyperlipoproteinemias. The specific aim of this retrospective, observational study was to assess safety and efficacy of long-term (21 months/patient), open-label, gemfibrozil-lovastatin treatment in 80 patients with primary mixed hyperlipidemia (68% of whom had DISEASE). Because ideal lipid targets were not reached (low-density lipoprotein (LDL) cholesterol less than 130 mg/dl, high-density lipoprotein (HDL) cholesterol greater than 35 mg/dl, or total cholesterol/HDL cholesterol less than 4.5 mg/dl) with diet plus a single drug, gemfibrozil (1.2 g/day)-lovastatin (primarily 20 or 40 mg) treatment was given. Follow-up visits were scheduled with 2-drug therapy every 6 to 8 weeks, an average of 10.3 visits per patient, with 741 batteries of 6 liver function tests and 714 creatine phosphokinase levels measured. Only 1 of the 4,446 liver function tests (0.02%), a gamma glutamyl transferase, was greater than or equal to 3 times the upper normal limit. Of the 714 creatine phosphokinase levels, 9% were high; only 1 (0.1%) was greater than or equal to 3 times the upper normal limit. With 2-drug therapy, mean total cholesterol decreased 22% from 255 to 200 mg/dl, CHEMICAL levels decreased 35% from 236 to 154 mg/dl, LDL cholesterol decreased 26% from 176 to 131 mg/dl, and the total cholesterol/HDL cholesterol ratio decreased 24% from 7.1 to 5.4, all p less than or equal to 0.0001. Myositis, attributable to the drug combination and symptomatic enough to discontinue it, occurred in 3% of patients, and in 1% with concurrent high creatine phosphokinase (769 U/liter); no patients had rhabdomyolysis or myoglobinuria.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Gemfibrozil-lovastatin therapy for primary hyperlipoproteinemias. The specific aim of this retrospective, observational study was to assess safety and efficacy of long-term (21 months/patient), open-label, gemfibrozil-lovastatin treatment in 80 patients with primary mixed hyperlipidemia (68% of whom had atherosclerotic vascular disease). Because ideal lipid targets were not reached (low-density lipoprotein (LDL) CHEMICAL less than 130 mg/dl, high-density lipoprotein (HDL) CHEMICAL greater than 35 mg/dl, or total CHEMICAL/HDL CHEMICAL less than 4.5 mg/dl) with diet plus a single drug, gemfibrozil (1.2 g/day)-lovastatin (primarily 20 or 40 mg) treatment was given. Follow-up visits were scheduled with 2-drug therapy every 6 to 8 weeks, an average of 10.3 visits per patient, with 741 batteries of 6 liver function tests and 714 creatine phosphokinase levels measured. Only 1 of the 4,446 liver function tests (0.02%), a gamma glutamyl transferase, was greater than or equal to 3 times the upper normal limit. Of the 714 creatine phosphokinase levels, 9% were high; only 1 (0.1%) was greater than or equal to 3 times the upper normal limit. With 2-drug therapy, mean total CHEMICAL decreased 22% from 255 to 200 mg/dl, triglyceride levels decreased 35% from 236 to 154 mg/dl, LDL CHEMICAL decreased 26% from 176 to 131 mg/dl, and the total CHEMICAL/HDL CHEMICAL ratio decreased 24% from 7.1 to 5.4, all p less than or equal to 0.0001. Myositis, attributable to the drug combination and symptomatic enough to discontinue it, occurred in 3% of patients, and in 1% with concurrent high creatine phosphokinase (769 U/liter); no patients had DISEASE or myoglobinuria.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Gemfibrozil-lovastatin therapy for primary DISEASE. The specific aim of this retrospective, observational study was to assess safety and efficacy of long-term (21 months/patient), open-label, gemfibrozil-lovastatin treatment in 80 patients with primary mixed hyperlipidemia (68% of whom had atherosclerotic vascular disease). Because ideal lipid targets were not reached (low-density lipoprotein (LDL) CHEMICAL less than 130 mg/dl, high-density lipoprotein (HDL) CHEMICAL greater than 35 mg/dl, or total CHEMICAL/HDL CHEMICAL less than 4.5 mg/dl) with diet plus a single drug, gemfibrozil (1.2 g/day)-lovastatin (primarily 20 or 40 mg) treatment was given. Follow-up visits were scheduled with 2-drug therapy every 6 to 8 weeks, an average of 10.3 visits per patient, with 741 batteries of 6 liver function tests and 714 creatine phosphokinase levels measured. Only 1 of the 4,446 liver function tests (0.02%), a gamma glutamyl transferase, was greater than or equal to 3 times the upper normal limit. Of the 714 creatine phosphokinase levels, 9% were high; only 1 (0.1%) was greater than or equal to 3 times the upper normal limit. With 2-drug therapy, mean total CHEMICAL decreased 22% from 255 to 200 mg/dl, triglyceride levels decreased 35% from 236 to 154 mg/dl, LDL CHEMICAL decreased 26% from 176 to 131 mg/dl, and the total CHEMICAL/HDL CHEMICAL ratio decreased 24% from 7.1 to 5.4, all p less than or equal to 0.0001. Myositis, attributable to the drug combination and symptomatic enough to discontinue it, occurred in 3% of patients, and in 1% with concurrent high creatine phosphokinase (769 U/liter); no patients had rhabdomyolysis or myoglobinuria.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Hepatocellular carcinoma in Fanconi's anemia treated with androgen and CHEMICAL. The case of an 11-year-old boy is reported who was known to have Fanconi's anemia for 3 years and was treated with androgens, CHEMICAL and transfusions. Two weeks before his death he was readmitted because of aplastic crisis with septicemia and marked abnormalities in liver function and died of hemorrhagic bronchopneumonia. At autopsy DISEASE and multiple hepatic tumors were found which histologically proved to be well-differentiated hepatocellular carcinoma. This case contributes to the previous observations that non-metastasizing hepatic neoplasms and DISEASE can develop in patients with androgen- and CHEMICAL-treated Fanconi's anemia. | CHEMICAL-INDUCED-DISEASE |
| Hepatocellular carcinoma in Fanconi's anemia treated with CHEMICAL and corticosteroid. The case of an 11-year-old boy is reported who was known to have Fanconi's anemia for 3 years and was treated with CHEMICAL, corticosteroids and transfusions. Two weeks before his death he was readmitted because of aplastic crisis with septicemia and marked abnormalities in liver function and died of hemorrhagic bronchopneumonia. At autopsy DISEASE and multiple hepatic tumors were found which histologically proved to be well-differentiated hepatocellular carcinoma. This case contributes to the previous observations that non-metastasizing hepatic neoplasms and DISEASE can develop in patients with CHEMICAL- and corticosteroid-treated Fanconi's anemia. | CHEMICAL-INDUCED-DISEASE |
| DISEASE in Fanconi's anemia treated with androgen and CHEMICAL. The case of an 11-year-old boy is reported who was known to have Fanconi's anemia for 3 years and was treated with androgens, CHEMICAL and transfusions. Two weeks before his death he was readmitted because of aplastic crisis with septicemia and marked abnormalities in liver function and died of hemorrhagic bronchopneumonia. At autopsy peliosis and multiple hepatic tumors were found which histologically proved to be well-differentiated DISEASE. This case contributes to the previous observations that non-metastasizing hepatic neoplasms and peliosis can develop in patients with androgen- and CHEMICAL-treated Fanconi's anemia. | CHEMICAL-INDUCED-DISEASE |
| DISEASE in Fanconi's anemia treated with CHEMICAL and corticosteroid. The case of an 11-year-old boy is reported who was known to have Fanconi's anemia for 3 years and was treated with CHEMICAL, corticosteroids and transfusions. Two weeks before his death he was readmitted because of aplastic crisis with septicemia and marked abnormalities in liver function and died of hemorrhagic bronchopneumonia. At autopsy peliosis and multiple hepatic tumors were found which histologically proved to be well-differentiated DISEASE. This case contributes to the previous observations that non-metastasizing hepatic neoplasms and peliosis can develop in patients with CHEMICAL- and corticosteroid-treated Fanconi's anemia. | CHEMICAL-INDUCED-DISEASE |
| Chronic lesion of rostral ventrolateral medulla in spontaneously hypertensive rats. We studied the effects of chronic selective neuronal lesion of rostral ventrolateral medulla on mean arterial pressure, heart rate, and neurogenic tone in conscious, unrestrained spontaneously hypertensive rats. The lesions were placed via bilateral microinjections of 30 nmol/200 nl N-methyl-D-aspartic acid. The restimulation of this area with N-methyl-D-aspartic acid 15 days postlesion failed to produce a pressor response. One day postlesion, the resting mean arterial pressure was significantly decreased in lesioned rats when compared with sham rats (100 +/- 7 versus 173 +/- 4 mm Hg, p less than 0.05). Fifteen days later, the lesioned group still showed values significantly lower than the sham group (150 +/- 6 versus 167 +/- 5 mm Hg, p less than 0.05). No significant heart rate differences were observed between the sham and lesioned groups. The ganglionic blocker CHEMICAL (5 mg/kg i.v.) caused similar reductions in mean arterial pressure in both lesioned and sham groups. The CHEMICAL-induced DISEASE was accompanied by a significant bradycardia in lesioned rats (-32 +/- 13 beats per minute) but a tachycardia in sham rats (+33 +/- 12 beats per minute) 1 day postlesion. Therefore, rostral ventrolateral medulla neurons appear to play a significant role in maintaining hypertension in conscious spontaneously hypertensive rats. Spinal or suprabulbar structures could be responsible for the gradual recovery of the hypertension in the lesioned rats. | CHEMICAL-INDUCED-DISEASE |
| Chronic lesion of rostral ventrolateral medulla in spontaneously hypertensive rats. We studied the effects of chronic selective neuronal lesion of rostral ventrolateral medulla on mean arterial pressure, heart rate, and neurogenic tone in conscious, unrestrained spontaneously hypertensive rats. The lesions were placed via bilateral microinjections of 30 nmol/200 nl N-methyl-D-aspartic acid. The restimulation of this area with N-methyl-D-aspartic acid 15 days postlesion failed to produce a pressor response. One day postlesion, the resting mean arterial pressure was significantly decreased in lesioned rats when compared with sham rats (100 +/- 7 versus 173 +/- 4 mm Hg, p less than 0.05). Fifteen days later, the lesioned group still showed values significantly lower than the sham group (150 +/- 6 versus 167 +/- 5 mm Hg, p less than 0.05). No significant heart rate differences were observed between the sham and lesioned groups. The ganglionic blocker CHEMICAL (5 mg/kg i.v.) caused similar reductions in mean arterial pressure in both lesioned and sham groups. The CHEMICAL-induced hypotension was accompanied by a significant bradycardia in lesioned rats (-32 +/- 13 beats per minute) but a DISEASE in sham rats (+33 +/- 12 beats per minute) 1 day postlesion. Therefore, rostral ventrolateral medulla neurons appear to play a significant role in maintaining hypertension in conscious spontaneously hypertensive rats. Spinal or suprabulbar structures could be responsible for the gradual recovery of the hypertension in the lesioned rats. | CHEMICAL-INDUCED-DISEASE |
| Chronic lesion of rostral ventrolateral medulla in spontaneously DISEASE rats. We studied the effects of chronic selective neuronal lesion of rostral ventrolateral medulla on mean arterial pressure, heart rate, and neurogenic tone in conscious, unrestrained spontaneously DISEASE rats. The lesions were placed via bilateral microinjections of 30 nmol/200 nl CHEMICAL. The restimulation of this area with CHEMICAL 15 days postlesion failed to produce a pressor response. One day postlesion, the resting mean arterial pressure was significantly decreased in lesioned rats when compared with sham rats (100 +/- 7 versus 173 +/- 4 mm Hg, p less than 0.05). Fifteen days later, the lesioned group still showed values significantly lower than the sham group (150 +/- 6 versus 167 +/- 5 mm Hg, p less than 0.05). No significant heart rate differences were observed between the sham and lesioned groups. The ganglionic blocker trimethaphan (5 mg/kg i.v.) caused similar reductions in mean arterial pressure in both lesioned and sham groups. The trimethaphan-induced hypotension was accompanied by a significant bradycardia in lesioned rats (-32 +/- 13 beats per minute) but a tachycardia in sham rats (+33 +/- 12 beats per minute) 1 day postlesion. Therefore, rostral ventrolateral medulla neurons appear to play a significant role in maintaining DISEASE in conscious spontaneously DISEASE rats. Spinal or suprabulbar structures could be responsible for the gradual recovery of the DISEASE in the lesioned rats. | CHEMICAL-INDUCED-DISEASE |
| Chronic lesion of rostral ventrolateral medulla in spontaneously hypertensive rats. We studied the effects of chronic selective neuronal lesion of rostral ventrolateral medulla on mean arterial pressure, heart rate, and neurogenic tone in conscious, unrestrained spontaneously hypertensive rats. The lesions were placed via bilateral microinjections of 30 nmol/200 nl CHEMICAL. The restimulation of this area with CHEMICAL 15 days postlesion failed to produce a pressor response. One day postlesion, the resting mean arterial pressure was significantly decreased in lesioned rats when compared with sham rats (100 +/- 7 versus 173 +/- 4 mm Hg, p less than 0.05). Fifteen days later, the lesioned group still showed values significantly lower than the sham group (150 +/- 6 versus 167 +/- 5 mm Hg, p less than 0.05). No significant heart rate differences were observed between the sham and lesioned groups. The ganglionic blocker trimethaphan (5 mg/kg i.v.) caused similar reductions in mean arterial pressure in both lesioned and sham groups. The trimethaphan-induced hypotension was accompanied by a significant DISEASE in lesioned rats (-32 +/- 13 beats per minute) but a tachycardia in sham rats (+33 +/- 12 beats per minute) 1 day postlesion. Therefore, rostral ventrolateral medulla neurons appear to play a significant role in maintaining hypertension in conscious spontaneously hypertensive rats. Spinal or suprabulbar structures could be responsible for the gradual recovery of the hypertension in the lesioned rats. | NO-RELATIONSHIP |
| DISEASE during CHEMICAL-induced status epilepticus in the rat: immunohistochemical study of neurons, astrocytes and serum-protein extravasation. The substantia nigra has a gating function controlling the spread of epileptic seizure activity. Additionally, in models of prolonged status epilepticus the pars reticulata of substantia nigra (SNR) suffers from a massive lesion which may arise from a massive metabolic derangement and hyperexcitation developing in the activated SNR. In this study, status epilepticus was induced by systemic injection of CHEMICAL in rats. The neuropathology of SNR was investigated using immunohistochemical techniques with the major emphasis on the time-course of changes in neurons and astrocytes. Animals surviving 20, 30, 40, 60 min, 2, 3, 6 hours, 1, 2, and 3 days after induction of status epilepticus were perfusion-fixed, and brains processed for immunohistochemical staining of SNR. Nissl-staining and antibodies against the neuron-specific calcium-binding protein, parvalbumin, served to detect neuronal damage in SNR. Antibodies against the astroglia-specific cytoskeletal protein, glial fibrillary acidic protein (GFAP), and against the glial calcium-binding protein, S-100 protein, were used to assess the status of astrocytes. Immunohistochemical staining for serum-albumin and immunoglobulins in brain tissue was taken as indicator of blood-brain barrier disturbances and vasogenic edema formation. Immunohistochemical staining indicated loss of GFAP-staining already at 30 min after induction of seizures in an oval focus situated in the center of SNR while sparing medial and lateral aspects. At 1 h there was additional vacuolation in S-100 protein staining. By 2 hours, parvalbumin-staining changed in the central SNR indicating neuronal damage, and Nissl-staining visualized some neuronal distortion. Staining for serum-proteins occurred in a patchy manner throughout the forebrain during the first hours. By 6 h, vasogenic edema covered the DISEASE. By 24 h, glial and neuronal markers indicated a massive lesion in the center of SNR. By 48-72 h, astrocytes surrounding the lesion increased in size, and polymorphic phagocytotic cells invaded the damaged area. In a further group of animals surviving 1 to 5 days, conventional paraffin-sections confirmed the neuronal and glial DISEASE. Additional pathology of similar quality was found in the globus pallidus. Since astrocytes were always damaged in parallel with neurons in SNR it is proposed that the anatomical and functional interrelationship between neurons and astrocytes is particularly tight in SNR. Both cell elements may suffer in common from metabolic disturbance and neurotransmitter dysfunction as occur during massive status epilepticus. | CHEMICAL-INDUCED-DISEASE |
| Damage of substantia nigra pars reticulata during CHEMICAL-induced DISEASE in the rat: immunohistochemical study of neurons, astrocytes and serum-protein extravasation. The substantia nigra has a gating function controlling the spread of epileptic seizure activity. Additionally, in models of DISEASE the pars reticulata of substantia nigra (SNR) suffers from a massive lesion which may arise from a massive metabolic derangement and hyperexcitation developing in the activated SNR. In this study, DISEASE was induced by systemic injection of CHEMICAL in rats. The neuropathology of SNR was investigated using immunohistochemical techniques with the major emphasis on the time-course of changes in neurons and astrocytes. Animals surviving 20, 30, 40, 60 min, 2, 3, 6 hours, 1, 2, and 3 days after induction of DISEASE were perfusion-fixed, and brains processed for immunohistochemical staining of SNR. Nissl-staining and antibodies against the neuron-specific calcium-binding protein, parvalbumin, served to detect neuronal damage in SNR. Antibodies against the astroglia-specific cytoskeletal protein, glial fibrillary acidic protein (GFAP), and against the glial calcium-binding protein, S-100 protein, were used to assess the status of astrocytes. Immunohistochemical staining for serum-albumin and immunoglobulins in brain tissue was taken as indicator of blood-brain barrier disturbances and vasogenic edema formation. Immunohistochemical staining indicated loss of GFAP-staining already at 30 min after induction of seizures in an oval focus situated in the center of SNR while sparing medial and lateral aspects. At 1 h there was additional vacuolation in S-100 protein staining. By 2 hours, parvalbumin-staining changed in the central SNR indicating neuronal damage, and Nissl-staining visualized some neuronal distortion. Staining for serum-proteins occurred in a patchy manner throughout the forebrain during the first hours. By 6 h, vasogenic edema covered the lesioned SNR. By 24 h, glial and neuronal markers indicated a massive lesion in the center of SNR. By 48-72 h, astrocytes surrounding the lesion increased in size, and polymorphic phagocytotic cells invaded the damaged area. In a further group of animals surviving 1 to 5 days, conventional paraffin-sections confirmed the neuronal and glial damage of SNR. Additional pathology of similar quality was found in the globus pallidus. Since astrocytes were always damaged in parallel with neurons in SNR it is proposed that the anatomical and functional interrelationship between neurons and astrocytes is particularly tight in SNR. Both cell elements may suffer in common from metabolic disturbance and neurotransmitter dysfunction as occur during massive DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Damage of substantia nigra pars reticulata during CHEMICAL-induced status epilepticus in the rat: immunohistochemical study of neurons, astrocytes and serum-protein extravasation. The substantia nigra has a gating function controlling the spread of epileptic seizure activity. Additionally, in models of prolonged status epilepticus the pars reticulata of substantia nigra (SNR) suffers from a massive lesion which may arise from a massive metabolic derangement and hyperexcitation developing in the activated SNR. In this study, status epilepticus was induced by systemic injection of CHEMICAL in rats. The neuropathology of SNR was investigated using immunohistochemical techniques with the major emphasis on the time-course of changes in neurons and astrocytes. Animals surviving 20, 30, 40, 60 min, 2, 3, 6 hours, 1, 2, and 3 days after induction of status epilepticus were perfusion-fixed, and brains processed for immunohistochemical staining of SNR. Nissl-staining and antibodies against the neuron-specific calcium-binding protein, parvalbumin, served to detect neuronal damage in SNR. Antibodies against the astroglia-specific cytoskeletal protein, glial fibrillary acidic protein (GFAP), and against the glial calcium-binding protein, S-100 protein, were used to assess the status of astrocytes. Immunohistochemical staining for serum-albumin and immunoglobulins in brain tissue was taken as indicator of blood-brain barrier disturbances and vasogenic edema formation. Immunohistochemical staining indicated loss of GFAP-staining already at 30 min after induction of seizures in an oval focus situated in the center of SNR while sparing medial and lateral aspects. At 1 h there was additional vacuolation in S-100 protein staining. By 2 hours, parvalbumin-staining changed in the central SNR indicating neuronal damage, and Nissl-staining visualized some neuronal distortion. Staining for serum-proteins occurred in a patchy manner throughout the forebrain during the first hours. By 6 h, vasogenic edema covered the lesioned SNR. By 24 h, glial and neuronal markers indicated a massive lesion in the center of SNR. By 48-72 h, astrocytes surrounding the lesion increased in size, and polymorphic phagocytotic cells invaded the damaged area. In a further group of animals surviving 1 to 5 days, conventional paraffin-sections confirmed the neuronal and glial damage of SNR. Additional pathology of similar quality was found in the globus pallidus. Since astrocytes were always damaged in parallel with neurons in SNR it is proposed that the anatomical and functional interrelationship between neurons and astrocytes is particularly tight in SNR. Both cell elements may suffer in common from metabolic disturbance and DISEASE as occur during massive status epilepticus. | CHEMICAL-INDUCED-DISEASE |
| Damage of substantia nigra pars reticulata during pilocarpine-induced status epilepticus in the rat: immunohistochemical study of neurons, astrocytes and serum-protein extravasation. The substantia nigra has a gating function controlling the spread of epileptic seizure activity. Additionally, in models of prolonged status epilepticus the pars reticulata of substantia nigra (SNR) suffers from a massive lesion which may arise from a massive metabolic derangement and hyperexcitation developing in the activated SNR. In this study, status epilepticus was induced by systemic injection of pilocarpine in rats. The neuropathology of SNR was investigated using immunohistochemical techniques with the major emphasis on the time-course of changes in neurons and astrocytes. Animals surviving 20, 30, 40, 60 min, 2, 3, 6 hours, 1, 2, and 3 days after induction of status epilepticus were perfusion-fixed, and brains processed for immunohistochemical staining of SNR. Nissl-staining and antibodies against the neuron-specific CHEMICAL-binding protein, parvalbumin, served to detect neuronal damage in SNR. Antibodies against the astroglia-specific cytoskeletal protein, glial fibrillary acidic protein (GFAP), and against the glial CHEMICAL-binding protein, S-100 protein, were used to assess the status of astrocytes. Immunohistochemical staining for serum-albumin and immunoglobulins in brain tissue was taken as indicator of blood-brain barrier disturbances and DISEASE formation. Immunohistochemical staining indicated loss of GFAP-staining already at 30 min after induction of seizures in an oval focus situated in the center of SNR while sparing medial and lateral aspects. At 1 h there was additional vacuolation in S-100 protein staining. By 2 hours, parvalbumin-staining changed in the central SNR indicating neuronal damage, and Nissl-staining visualized some neuronal distortion. Staining for serum-proteins occurred in a patchy manner throughout the forebrain during the first hours. By 6 h, DISEASE covered the lesioned SNR. By 24 h, glial and neuronal markers indicated a massive lesion in the center of SNR. By 48-72 h, astrocytes surrounding the lesion increased in size, and polymorphic phagocytotic cells invaded the damaged area. In a further group of animals surviving 1 to 5 days, conventional paraffin-sections confirmed the neuronal and glial damage of SNR. Additional pathology of similar quality was found in the globus pallidus. Since astrocytes were always damaged in parallel with neurons in SNR it is proposed that the anatomical and functional interrelationship between neurons and astrocytes is particularly tight in SNR. Both cell elements may suffer in common from metabolic disturbance and neurotransmitter dysfunction as occur during massive status epilepticus. | NO-RELATIONSHIP |
| Damage of substantia nigra pars reticulata during pilocarpine-induced status epilepticus in the rat: immunohistochemical study of neurons, astrocytes and serum-protein extravasation. The substantia nigra has a gating function controlling the spread of epileptic seizure activity. Additionally, in models of prolonged status epilepticus the pars reticulata of substantia nigra (SNR) suffers from a massive lesion which may arise from a massive DISEASE and hyperexcitation developing in the activated SNR. In this study, status epilepticus was induced by systemic injection of pilocarpine in rats. The neuropathology of SNR was investigated using immunohistochemical techniques with the major emphasis on the time-course of changes in neurons and astrocytes. Animals surviving 20, 30, 40, 60 min, 2, 3, 6 hours, 1, 2, and 3 days after induction of status epilepticus were perfusion-fixed, and brains processed for immunohistochemical staining of SNR. Nissl-staining and antibodies against the neuron-specific CHEMICAL-binding protein, parvalbumin, served to detect neuronal damage in SNR. Antibodies against the astroglia-specific cytoskeletal protein, glial fibrillary acidic protein (GFAP), and against the glial CHEMICAL-binding protein, S-100 protein, were used to assess the status of astrocytes. Immunohistochemical staining for serum-albumin and immunoglobulins in brain tissue was taken as indicator of blood-brain barrier disturbances and vasogenic edema formation. Immunohistochemical staining indicated loss of GFAP-staining already at 30 min after induction of seizures in an oval focus situated in the center of SNR while sparing medial and lateral aspects. At 1 h there was additional vacuolation in S-100 protein staining. By 2 hours, parvalbumin-staining changed in the central SNR indicating neuronal damage, and Nissl-staining visualized some neuronal distortion. Staining for serum-proteins occurred in a patchy manner throughout the forebrain during the first hours. By 6 h, vasogenic edema covered the lesioned SNR. By 24 h, glial and neuronal markers indicated a massive lesion in the center of SNR. By 48-72 h, astrocytes surrounding the lesion increased in size, and polymorphic phagocytotic cells invaded the damaged area. In a further group of animals surviving 1 to 5 days, conventional paraffin-sections confirmed the neuronal and glial damage of SNR. Additional pathology of similar quality was found in the globus pallidus. Since astrocytes were always damaged in parallel with neurons in SNR it is proposed that the anatomical and functional interrelationship between neurons and astrocytes is particularly tight in SNR. Both cell elements may suffer in common from metabolic disturbance and neurotransmitter dysfunction as occur during massive status epilepticus. | NO-RELATIONSHIP |
| Damage of substantia nigra pars reticulata during pilocarpine-induced status epilepticus in the rat: immunohistochemical study of neurons, astrocytes and serum-protein extravasation. The substantia nigra has a gating function controlling the spread of epileptic seizure activity. Additionally, in models of prolonged status epilepticus the pars reticulata of substantia nigra (SNR) suffers from a massive lesion which may arise from a massive metabolic derangement and hyperexcitation developing in the activated SNR. In this study, status epilepticus was induced by systemic injection of pilocarpine in rats. The neuropathology of SNR was investigated using immunohistochemical techniques with the major emphasis on the time-course of changes in neurons and astrocytes. Animals surviving 20, 30, 40, 60 min, 2, 3, 6 hours, 1, 2, and 3 days after induction of status epilepticus were perfusion-fixed, and brains processed for immunohistochemical staining of SNR. Nissl-staining and antibodies against the neuron-specific CHEMICAL-binding protein, parvalbumin, served to detect DISEASE in SNR. Antibodies against the astroglia-specific cytoskeletal protein, glial fibrillary acidic protein (GFAP), and against the glial CHEMICAL-binding protein, S-100 protein, were used to assess the status of astrocytes. Immunohistochemical staining for serum-albumin and immunoglobulins in brain tissue was taken as indicator of blood-brain barrier disturbances and vasogenic edema formation. Immunohistochemical staining indicated loss of GFAP-staining already at 30 min after induction of seizures in an oval focus situated in the center of SNR while sparing medial and lateral aspects. At 1 h there was additional vacuolation in S-100 protein staining. By 2 hours, parvalbumin-staining changed in the central SNR indicating DISEASE, and Nissl-staining visualized some neuronal distortion. Staining for serum-proteins occurred in a patchy manner throughout the forebrain during the first hours. By 6 h, vasogenic edema covered the lesioned SNR. By 24 h, glial and neuronal markers indicated a massive lesion in the center of SNR. By 48-72 h, astrocytes surrounding the lesion increased in size, and polymorphic phagocytotic cells invaded the damaged area. In a further group of animals surviving 1 to 5 days, conventional paraffin-sections confirmed the neuronal and glial damage of SNR. Additional pathology of similar quality was found in the globus pallidus. Since astrocytes were always damaged in parallel with neurons in SNR it is proposed that the anatomical and functional interrelationship between neurons and astrocytes is particularly tight in SNR. Both cell elements may suffer in common from metabolic disturbance and neurotransmitter dysfunction as occur during massive status epilepticus. | NO-RELATIONSHIP |
| Damage of substantia nigra pars reticulata during pilocarpine-induced status epilepticus in the rat: immunohistochemical study of neurons, astrocytes and serum-protein extravasation. The substantia nigra has a gating function controlling the spread of DISEASE activity. Additionally, in models of prolonged status epilepticus the pars reticulata of substantia nigra (SNR) suffers from a massive lesion which may arise from a massive metabolic derangement and hyperexcitation developing in the activated SNR. In this study, status epilepticus was induced by systemic injection of pilocarpine in rats. The neuropathology of SNR was investigated using immunohistochemical techniques with the major emphasis on the time-course of changes in neurons and astrocytes. Animals surviving 20, 30, 40, 60 min, 2, 3, 6 hours, 1, 2, and 3 days after induction of status epilepticus were perfusion-fixed, and brains processed for immunohistochemical staining of SNR. Nissl-staining and antibodies against the neuron-specific CHEMICAL-binding protein, parvalbumin, served to detect neuronal damage in SNR. Antibodies against the astroglia-specific cytoskeletal protein, glial fibrillary acidic protein (GFAP), and against the glial CHEMICAL-binding protein, S-100 protein, were used to assess the status of astrocytes. Immunohistochemical staining for serum-albumin and immunoglobulins in brain tissue was taken as indicator of blood-brain barrier disturbances and vasogenic edema formation. Immunohistochemical staining indicated loss of GFAP-staining already at 30 min after induction of seizures in an oval focus situated in the center of SNR while sparing medial and lateral aspects. At 1 h there was additional vacuolation in S-100 protein staining. By 2 hours, parvalbumin-staining changed in the central SNR indicating neuronal damage, and Nissl-staining visualized some neuronal distortion. Staining for serum-proteins occurred in a patchy manner throughout the forebrain during the first hours. By 6 h, vasogenic edema covered the lesioned SNR. By 24 h, glial and neuronal markers indicated a massive lesion in the center of SNR. By 48-72 h, astrocytes surrounding the lesion increased in size, and polymorphic phagocytotic cells invaded the damaged area. In a further group of animals surviving 1 to 5 days, conventional paraffin-sections confirmed the neuronal and glial damage of SNR. Additional pathology of similar quality was found in the globus pallidus. Since astrocytes were always damaged in parallel with neurons in SNR it is proposed that the anatomical and functional interrelationship between neurons and astrocytes is particularly tight in SNR. Both cell elements may suffer in common from metabolic disturbance and neurotransmitter dysfunction as occur during massive status epilepticus. | NO-RELATIONSHIP |
| Damage of substantia nigra pars reticulata during pilocarpine-induced status epilepticus in the rat: immunohistochemical study of neurons, astrocytes and serum-protein extravasation. The substantia nigra has a gating function controlling the spread of epileptic seizure activity. Additionally, in models of prolonged status epilepticus the pars reticulata of substantia nigra (SNR) suffers from a massive lesion which may arise from a massive metabolic derangement and hyperexcitation developing in the activated SNR. In this study, status epilepticus was induced by systemic injection of pilocarpine in rats. The neuropathology of SNR was investigated using immunohistochemical techniques with the major emphasis on the time-course of changes in neurons and astrocytes. Animals surviving 20, 30, 40, 60 min, 2, 3, 6 hours, 1, 2, and 3 days after induction of status epilepticus were perfusion-fixed, and brains processed for immunohistochemical staining of SNR. Nissl-staining and antibodies against the neuron-specific CHEMICAL-binding protein, parvalbumin, served to detect neuronal damage in SNR. Antibodies against the astroglia-specific cytoskeletal protein, glial fibrillary acidic protein (GFAP), and against the glial CHEMICAL-binding protein, S-100 protein, were used to assess the status of astrocytes. Immunohistochemical staining for serum-albumin and immunoglobulins in brain tissue was taken as indicator of blood-brain barrier disturbances and vasogenic edema formation. Immunohistochemical staining indicated loss of GFAP-staining already at 30 min after induction of DISEASE in an oval focus situated in the center of SNR while sparing medial and lateral aspects. At 1 h there was additional vacuolation in S-100 protein staining. By 2 hours, parvalbumin-staining changed in the central SNR indicating neuronal damage, and Nissl-staining visualized some neuronal distortion. Staining for serum-proteins occurred in a patchy manner throughout the forebrain during the first hours. By 6 h, vasogenic edema covered the lesioned SNR. By 24 h, glial and neuronal markers indicated a massive lesion in the center of SNR. By 48-72 h, astrocytes surrounding the lesion increased in size, and polymorphic phagocytotic cells invaded the damaged area. In a further group of animals surviving 1 to 5 days, conventional paraffin-sections confirmed the neuronal and glial damage of SNR. Additional pathology of similar quality was found in the globus pallidus. Since astrocytes were always damaged in parallel with neurons in SNR it is proposed that the anatomical and functional interrelationship between neurons and astrocytes is particularly tight in SNR. Both cell elements may suffer in common from metabolic disturbance and neurotransmitter dysfunction as occur during massive status epilepticus. | NO-RELATIONSHIP |
| Reduced DISEASE of CHEMICAL given in the form of N-(2-hydroxypropyl)methacrylamide conjugates: and experimental study in the rat. A rat model was used to evaluate the general acute toxicity and the late DISEASE of 4 mg/kg CHEMICAL (CHEMICAL) given either as free drug or in the form of three N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates. In these HPMA copolymers, CHEMICAL was covalently bound via peptide linkages that were either non-biodegradable (Gly-Gly) or degradable by lysosomal proteinases (Gly-Phe-Leu-Gly). In addition, one biodegradable conjugate containing galactosamine was used; this residue was targeted to the liver. Over the first 3 weeks after the i.v. administration of free and polymer-bound CHEMICAL, all animals showed a transient reduction in body weight. However, the maximal reduction in body weight seen in animals that received polymer-bound CHEMICAL (4 mg/kg) was significantly lower than that observed in those that received free CHEMICAL (4 mg/kg) or a mixture of the unmodified parent HPMA copolymer and free CHEMICAL (4 mg/kg; P less than 0.01). Throughout the study (20 weeks), deaths related to DISEASE were observed only in animals that received either free CHEMICAL or the mixture of HPMA copolymer and free CHEMICAL; in these cases, histological investigations revealed marked changes in the heart that were consistent with CHEMICAL-induced DISEASE. Sequential measurements of cardiac output in surviving animals that received either free CHEMICAL or the mixture of HPMA copolymer and free CHEMICAL showed a reduction of approximately 30% in function beginning at the 4th week after drug administration. The heart rate in these animals was approximately 12% lower than that measured in age-matched control rats (P less than 0.05). Animals that were given the HPMA copolymer conjugates containing CHEMICAL exhibited no significant change in cardiac output throughout the study (P less than 0.05). In addition, no significant histological change was observed in the heart of animals that received CHEMICAL in the form of HPMA copolymer conjugates and were killed at the end of the study. However, these animals had shown a significant increase in heart rate beginning at 8 weeks after drug administration (P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS) | CHEMICAL-INDUCED-DISEASE |
| Reduced cardiotoxicity of doxorubicin given in the form of N-(2-hydroxypropyl)methacrylamide conjugates: and experimental study in the rat. A rat model was used to evaluate the general acute DISEASE and the late cardiotoxicity of 4 mg/kg doxorubicin (DOX) given either as free drug or in the form of three N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates. In these HPMA copolymers, DOX was covalently bound via peptide linkages that were either non-biodegradable (Gly-Gly) or degradable by lysosomal proteinases (Gly-Phe-Leu-Gly). In addition, one biodegradable conjugate containing CHEMICAL was used; this residue was targeted to the liver. Over the first 3 weeks after the i.v. administration of free and polymer-bound DOX, all animals showed a transient reduction in body weight. However, the maximal reduction in body weight seen in animals that received polymer-bound DOX (4 mg/kg) was significantly lower than that observed in those that received free DOX (4 mg/kg) or a mixture of the unmodified parent HPMA copolymer and free DOX (4 mg/kg; P less than 0.01). Throughout the study (20 weeks), deaths related to cardiotoxicity were observed only in animals that received either free DOX or the mixture of HPMA copolymer and free DOX; in these cases, histological investigations revealed marked changes in the heart that were consistent with DOX-induced cardiotoxicity. Sequential measurements of cardiac output in surviving animals that received either free DOX or the mixture of HPMA copolymer and free DOX showed a reduction of approximately 30% in function beginning at the 4th week after drug administration. The heart rate in these animals was approximately 12% lower than that measured in age-matched control rats (P less than 0.05). Animals that were given the HPMA copolymer conjugates containing DOX exhibited no significant change in cardiac output throughout the study (P less than 0.05). In addition, no significant histological change was observed in the heart of animals that received DOX in the form of HPMA copolymer conjugates and were killed at the end of the study. However, these animals had shown a significant increase in heart rate beginning at 8 weeks after drug administration (P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS) | NO-RELATIONSHIP |
| Reduced cardiotoxicity of doxorubicin given in the form of CHEMICAL conjugates: and experimental study in the rat. A rat model was used to evaluate the general acute DISEASE and the late cardiotoxicity of 4 mg/kg doxorubicin (DOX) given either as free drug or in the form of three CHEMICAL (CHEMICAL) copolymer conjugates. In these CHEMICAL copolymers, DOX was covalently bound via peptide linkages that were either non-biodegradable (Gly-Gly) or degradable by lysosomal proteinases (Gly-Phe-Leu-Gly). In addition, one biodegradable conjugate containing galactosamine was used; this residue was targeted to the liver. Over the first 3 weeks after the i.v. administration of free and polymer-bound DOX, all animals showed a transient reduction in body weight. However, the maximal reduction in body weight seen in animals that received polymer-bound DOX (4 mg/kg) was significantly lower than that observed in those that received free DOX (4 mg/kg) or a mixture of the unmodified parent CHEMICAL copolymer and free DOX (4 mg/kg; P less than 0.01). Throughout the study (20 weeks), deaths related to cardiotoxicity were observed only in animals that received either free DOX or the mixture of CHEMICAL copolymer and free DOX; in these cases, histological investigations revealed marked changes in the heart that were consistent with DOX-induced cardiotoxicity. Sequential measurements of cardiac output in surviving animals that received either free DOX or the mixture of CHEMICAL copolymer and free DOX showed a reduction of approximately 30% in function beginning at the 4th week after drug administration. The heart rate in these animals was approximately 12% lower than that measured in age-matched control rats (P less than 0.05). Animals that were given the CHEMICAL copolymer conjugates containing DOX exhibited no significant change in cardiac output throughout the study (P less than 0.05). In addition, no significant histological change was observed in the heart of animals that received DOX in the form of CHEMICAL copolymer conjugates and were killed at the end of the study. However, these animals had shown a significant increase in heart rate beginning at 8 weeks after drug administration (P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS) | NO-RELATIONSHIP |
| Reduced cardiotoxicity of doxorubicin given in the form of N-(2-hydroxypropyl)methacrylamide conjugates: and experimental study in the rat. A rat model was used to evaluate the general acute DISEASE and the late cardiotoxicity of 4 mg/kg doxorubicin (DOX) given either as free drug or in the form of three N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates. In these HPMA copolymers, DOX was covalently bound via peptide linkages that were either non-biodegradable (Gly-Gly) or degradable by lysosomal proteinases (CHEMICAL). In addition, one biodegradable conjugate containing galactosamine was used; this residue was targeted to the liver. Over the first 3 weeks after the i.v. administration of free and polymer-bound DOX, all animals showed a transient reduction in body weight. However, the maximal reduction in body weight seen in animals that received polymer-bound DOX (4 mg/kg) was significantly lower than that observed in those that received free DOX (4 mg/kg) or a mixture of the unmodified parent HPMA copolymer and free DOX (4 mg/kg; P less than 0.01). Throughout the study (20 weeks), deaths related to cardiotoxicity were observed only in animals that received either free DOX or the mixture of HPMA copolymer and free DOX; in these cases, histological investigations revealed marked changes in the heart that were consistent with DOX-induced cardiotoxicity. Sequential measurements of cardiac output in surviving animals that received either free DOX or the mixture of HPMA copolymer and free DOX showed a reduction of approximately 30% in function beginning at the 4th week after drug administration. The heart rate in these animals was approximately 12% lower than that measured in age-matched control rats (P less than 0.05). Animals that were given the HPMA copolymer conjugates containing DOX exhibited no significant change in cardiac output throughout the study (P less than 0.05). In addition, no significant histological change was observed in the heart of animals that received DOX in the form of HPMA copolymer conjugates and were killed at the end of the study. However, these animals had shown a significant increase in heart rate beginning at 8 weeks after drug administration (P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS) | NO-RELATIONSHIP |
| Topical 0.025% CHEMICAL in chronic post-herpetic neuralgia: efficacy, predictors of response and long-term course. In order to evaluate the efficacy, time-course of action and predictors of response to topical CHEMICAL, 39 patients with chronic post-herpetic neuralgia (PHN), median duration 24 months, were treated with 0.025% CHEMICAL cream for 8 weeks. During therapy the patients rated their DISEASE on a visual analogue scale (VAS) and a verbal outcome scale. A follow-up investigation was performed 10-12 months after study onset on the patients who had improved. Nineteen patients (48.7%) substantially improved after the 8-week trial; 5 (12.8%) discontinued therapy due to side-effects such as intolerable CHEMICAL-induced burning sensations (4) or mastitis (1); 15 (38.5%) reported no benefit. The decrease in VAS ratings was significant after 2 weeks of continuous application. Of the responders 72.2% were still improved at the follow-up; only one-third of them had continued application irregularly. Treatment effect was not dependent on patient's age, duration or localization of PHN (trigeminal involvement was excluded), sensory disturbance or DISEASE character. Treatment response was not correlated with the incidence, time-course or severity of CHEMICAL-induced burning. If confirmed in controlled trials, the long-term results of this open, non-randomized study might indicate that the analgesic effect of CHEMICAL in PHN is mediated by both interference with neuropeptide metabolism and morphological changes (perhaps degeneration) of nociceptive afferents. | CHEMICAL-INDUCED-DISEASE |
| Topical 0.025% CHEMICAL in chronic post-herpetic neuralgia: efficacy, predictors of response and long-term course. In order to evaluate the efficacy, time-course of action and predictors of response to topical CHEMICAL, 39 patients with chronic post-herpetic neuralgia (PHN), median duration 24 months, were treated with 0.025% CHEMICAL cream for 8 weeks. During therapy the patients rated their pain on a visual analogue scale (VAS) and a verbal outcome scale. A follow-up investigation was performed 10-12 months after study onset on the patients who had improved. Nineteen patients (48.7%) substantially improved after the 8-week trial; 5 (12.8%) discontinued therapy due to side-effects such as intolerable CHEMICAL-induced burning sensations (4) or DISEASE (1); 15 (38.5%) reported no benefit. The decrease in VAS ratings was significant after 2 weeks of continuous application. Of the responders 72.2% were still improved at the follow-up; only one-third of them had continued application irregularly. Treatment effect was not dependent on patient's age, duration or localization of PHN (trigeminal involvement was excluded), sensory disturbance or pain character. Treatment response was not correlated with the incidence, time-course or severity of CHEMICAL-induced burning. If confirmed in controlled trials, the long-term results of this open, non-randomized study might indicate that the analgesic effect of CHEMICAL in PHN is mediated by both interference with neuropeptide metabolism and morphological changes (perhaps degeneration) of nociceptive afferents. | CHEMICAL-INDUCED-DISEASE |
| Serotonin reuptake inhibitors, DISEASE, and the ventral basal ganglia. Antidepressants have previously been associated with DISEASE reactions in psychiatric patients. Five cases of DISEASE exacerbation with the serotonin reuptake inhibitors CHEMICAL and amitriptyline are reported here. Elements common to these cases included a history of DISEASE symptomatology and the concomitant occurrence of depressive and psychotic symptoms. Complicated depressive disorders (including atypicality of course and symptomatology, chronicity, psychosis, bipolarity, and secondary onset in the course of a primary psychosis) may present particular vulnerability to DISEASE exacerbations associated with serotonin reuptake inhibitors. Although the pharmacology and neurobiology of DISEASE remain cryptic, several mechanisms, including 5HT3 receptor-mediated dopamine release, beta-noradrenergic receptor downregulation, or GABAB receptor upregulation acting in the vicinity of the ventral basal ganglia (possibly in lateral orbitofrontal or anterior cingulate circuits), might apply to this phenomenon. These cases call attention to possible DISEASE exacerbations with serotonin reuptake blockers in select patients and raise neurobiological considerations regarding DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Serotonin reuptake inhibitors, DISEASE, and the ventral basal ganglia. Antidepressants have previously been associated with DISEASE reactions in psychiatric patients. Five cases of DISEASE exacerbation with the serotonin reuptake inhibitors fluoxetine and CHEMICAL are reported here. Elements common to these cases included a history of DISEASE symptomatology and the concomitant occurrence of depressive and psychotic symptoms. Complicated depressive disorders (including atypicality of course and symptomatology, chronicity, psychosis, bipolarity, and secondary onset in the course of a primary psychosis) may present particular vulnerability to DISEASE exacerbations associated with serotonin reuptake inhibitors. Although the pharmacology and neurobiology of DISEASE remain cryptic, several mechanisms, including 5HT3 receptor-mediated dopamine release, beta-noradrenergic receptor downregulation, or GABAB receptor upregulation acting in the vicinity of the ventral basal ganglia (possibly in lateral orbitofrontal or anterior cingulate circuits), might apply to this phenomenon. These cases call attention to possible DISEASE exacerbations with serotonin reuptake blockers in select patients and raise neurobiological considerations regarding DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Serotonin reuptake inhibitors, paranoia, and the ventral basal ganglia. Antidepressants have previously been associated with paranoid reactions in psychiatric patients. Five cases of paranoid exacerbation with the serotonin reuptake inhibitors fluoxetine and amitriptyline are reported here. Elements common to these cases included a history of paranoid symptomatology and the concomitant occurrence of depressive and psychotic symptoms. Complicated depressive disorders (including atypicality of course and symptomatology, chronicity, DISEASE, bipolarity, and secondary onset in the course of a primary DISEASE) may present particular vulnerability to paranoid exacerbations associated with serotonin reuptake inhibitors. Although the pharmacology and neurobiology of paranoia remain cryptic, several mechanisms, including 5HT3 receptor-mediated CHEMICAL release, beta-noradrenergic receptor downregulation, or GABAB receptor upregulation acting in the vicinity of the ventral basal ganglia (possibly in lateral orbitofrontal or anterior cingulate circuits), might apply to this phenomenon. These cases call attention to possible paranoid exacerbations with serotonin reuptake blockers in select patients and raise neurobiological considerations regarding paranoia. | NO-RELATIONSHIP |
| Serotonin reuptake inhibitors, paranoia, and the ventral basal ganglia. Antidepressants have previously been associated with paranoid reactions in psychiatric patients. Five cases of paranoid exacerbation with the serotonin reuptake inhibitors fluoxetine and amitriptyline are reported here. Elements common to these cases included a history of paranoid symptomatology and the concomitant occurrence of DISEASE. Complicated depressive disorders (including atypicality of course and symptomatology, chronicity, psychosis, bipolarity, and secondary onset in the course of a primary psychosis) may present particular vulnerability to paranoid exacerbations associated with serotonin reuptake inhibitors. Although the pharmacology and neurobiology of paranoia remain cryptic, several mechanisms, including 5HT3 receptor-mediated CHEMICAL release, beta-noradrenergic receptor downregulation, or GABAB receptor upregulation acting in the vicinity of the ventral basal ganglia (possibly in lateral orbitofrontal or anterior cingulate circuits), might apply to this phenomenon. These cases call attention to possible paranoid exacerbations with serotonin reuptake blockers in select patients and raise neurobiological considerations regarding paranoia. | NO-RELATIONSHIP |
| CHEMICAL reuptake inhibitors, paranoia, and the ventral basal ganglia. Antidepressants have previously been associated with paranoid reactions in psychiatric patients. Five cases of paranoid exacerbation with the CHEMICAL reuptake inhibitors fluoxetine and amitriptyline are reported here. Elements common to these cases included a history of paranoid symptomatology and the concomitant occurrence of depressive and psychotic symptoms. Complicated depressive disorders (including atypicality of course and symptomatology, chronicity, DISEASE, bipolarity, and secondary onset in the course of a primary DISEASE) may present particular vulnerability to paranoid exacerbations associated with CHEMICAL reuptake inhibitors. Although the pharmacology and neurobiology of paranoia remain cryptic, several mechanisms, including 5HT3 receptor-mediated dopamine release, beta-noradrenergic receptor downregulation, or GABAB receptor upregulation acting in the vicinity of the ventral basal ganglia (possibly in lateral orbitofrontal or anterior cingulate circuits), might apply to this phenomenon. These cases call attention to possible paranoid exacerbations with CHEMICAL reuptake blockers in select patients and raise neurobiological considerations regarding paranoia. | NO-RELATIONSHIP |
| CHEMICAL reuptake inhibitors, paranoia, and the ventral basal ganglia. Antidepressants have previously been associated with paranoid reactions in psychiatric patients. Five cases of paranoid exacerbation with the CHEMICAL reuptake inhibitors fluoxetine and amitriptyline are reported here. Elements common to these cases included a history of paranoid symptomatology and the concomitant occurrence of DISEASE. Complicated depressive disorders (including atypicality of course and symptomatology, chronicity, psychosis, bipolarity, and secondary onset in the course of a primary psychosis) may present particular vulnerability to paranoid exacerbations associated with CHEMICAL reuptake inhibitors. Although the pharmacology and neurobiology of paranoia remain cryptic, several mechanisms, including 5HT3 receptor-mediated dopamine release, beta-noradrenergic receptor downregulation, or GABAB receptor upregulation acting in the vicinity of the ventral basal ganglia (possibly in lateral orbitofrontal or anterior cingulate circuits), might apply to this phenomenon. These cases call attention to possible paranoid exacerbations with CHEMICAL reuptake blockers in select patients and raise neurobiological considerations regarding paranoia. | NO-RELATIONSHIP |
| Serotonin reuptake inhibitors, paranoia, and the ventral basal ganglia. Antidepressants have previously been associated with paranoid reactions in psychiatric patients. Five cases of paranoid exacerbation with the serotonin reuptake inhibitors fluoxetine and amitriptyline are reported here. Elements common to these cases included a history of paranoid symptomatology and the concomitant occurrence of depressive and psychotic symptoms. Complicated DISEASE (including atypicality of course and symptomatology, chronicity, psychosis, bipolarity, and secondary onset in the course of a primary psychosis) may present particular vulnerability to paranoid exacerbations associated with serotonin reuptake inhibitors. Although the pharmacology and neurobiology of paranoia remain cryptic, several mechanisms, including 5HT3 receptor-mediated CHEMICAL release, beta-noradrenergic receptor downregulation, or GABAB receptor upregulation acting in the vicinity of the ventral basal ganglia (possibly in lateral orbitofrontal or anterior cingulate circuits), might apply to this phenomenon. These cases call attention to possible paranoid exacerbations with serotonin reuptake blockers in select patients and raise neurobiological considerations regarding paranoia. | NO-RELATIONSHIP |
| CHEMICAL reuptake inhibitors, paranoia, and the ventral basal ganglia. Antidepressants have previously been associated with paranoid reactions in psychiatric patients. Five cases of paranoid exacerbation with the CHEMICAL reuptake inhibitors fluoxetine and amitriptyline are reported here. Elements common to these cases included a history of paranoid symptomatology and the concomitant occurrence of depressive and psychotic symptoms. Complicated DISEASE (including atypicality of course and symptomatology, chronicity, psychosis, bipolarity, and secondary onset in the course of a primary psychosis) may present particular vulnerability to paranoid exacerbations associated with CHEMICAL reuptake inhibitors. Although the pharmacology and neurobiology of paranoia remain cryptic, several mechanisms, including 5HT3 receptor-mediated dopamine release, beta-noradrenergic receptor downregulation, or GABAB receptor upregulation acting in the vicinity of the ventral basal ganglia (possibly in lateral orbitofrontal or anterior cingulate circuits), might apply to this phenomenon. These cases call attention to possible paranoid exacerbations with CHEMICAL reuptake blockers in select patients and raise neurobiological considerations regarding paranoia. | NO-RELATIONSHIP |
| Five cases of DISEASE during treatment of loiasis with CHEMICAL. Five cases of DISEASE following treatment with CHEMICAL (CHEMICAL) were observed in Congolese patients with Loa loa filariasis. Two cases had a fatal outcome and one resulted in severe sequelae. The notable fact was that this complication occurred in three patients hospitalized before treatment began, with whom particularly strict therapeutic precautions were taken, i.e., initial dose less than 10 mg of CHEMICAL, very gradual dose increases, and associated anti-allergic treatment. This type of drug-induced complication may not be that uncommon in highly endemic regions. It occurs primarily, but not exclusively, in subjects presenting with a high microfilarial load. The relationship between the occurrence of DISEASE and the decrease in microfilaremia is evident. The pathophysiological mechanisms are discussed in the light of these observations and the few other comments on this subject published in the literature. | CHEMICAL-INDUCED-DISEASE |
| DISEASE in an elderly woman possibly associated with administration of CHEMICAL. CHEMICAL has been associated with adverse reactions, including gastrointestinal symptoms, gynecologic problems, and headache. Changes in mental status, however, have not been reported. We present a case in which an 89-year-old woman in a long-term care facility became confused after the initiation of CHEMICAL therapy. The patient's change in mental status was first reported nine days after the initiation of therapy. Her DISEASE significantly improved after CHEMICAL was discontinued and her mental status returned to normal within a week. Because no other factors related to this patient changed significantly, the DISEASE experienced by this patient possibly resulted from CHEMICAL therapy. | CHEMICAL-INDUCED-DISEASE |
| Hepatocellular oxidant stress following intestinal ischemia-DISEASE. Reperfusion of ischemic intestine results in acute liver dysfunction characterized by hepatocellular enzyme release into plasma, reduction in bile flow rate, and neutrophil sequestration within the liver. The pathophysiology underlying this acute hepatic injury is unknown. This study was undertaken to determine whether oxidants are associated with the hepatic injury and to determine the relative value of several indirect methods of assessing oxidant exposure in vivo. Rats were subjected to a standardized intestinal ischemia-DISEASE. Hepatic tissue was assayed for lipid peroxidation products and oxidized and reduced glutathione. There was no change in hepatic tissue total glutathione following intestinal ischemia-DISEASE. CHEMICAL (CHEMICAL) increased significantly following 30 and 60 min of reperfusion. There was no increase in any of the products of lipid peroxidation associated with this injury. An increase in CHEMICAL within hepatic tissue during intestinal reperfusion suggests exposure of hepatocytes to an oxidant stress. The lack of a significant increase in products of lipid peroxidation suggests that the oxidant stress is of insufficient magnitude to result in irreversible injury to hepatocyte cell membranes. These data also suggest that the measurement of tissue CHEMICAL may be a more sensitive indicator of oxidant stress than measurement of products of lipid peroxidation. | CHEMICAL-INDUCED-DISEASE |
| Hepatocellular oxidant stress following intestinal DISEASE-reperfusion injury. Reperfusion of DISEASE intestine results in acute liver dysfunction characterized by hepatocellular enzyme release into plasma, reduction in bile flow rate, and neutrophil sequestration within the liver. The pathophysiology underlying this acute hepatic injury is unknown. This study was undertaken to determine whether oxidants are associated with the hepatic injury and to determine the relative value of several indirect methods of assessing oxidant exposure in vivo. Rats were subjected to a standardized intestinal DISEASE-reperfusion injury. Hepatic tissue was assayed for lipid peroxidation products and oxidized and reduced glutathione. There was no change in hepatic tissue total CHEMICAL following intestinal DISEASE-reperfusion injury. Oxidized glutathione (GSSG) increased significantly following 30 and 60 min of reperfusion. There was no increase in any of the products of lipid peroxidation associated with this injury. An increase in GSSG within hepatic tissue during intestinal reperfusion suggests exposure of hepatocytes to an oxidant stress. The lack of a significant increase in products of lipid peroxidation suggests that the oxidant stress is of insufficient magnitude to result in irreversible injury to hepatocyte cell membranes. These data also suggest that the measurement of tissue GSSG may be a more sensitive indicator of oxidant stress than measurement of products of lipid peroxidation. | CHEMICAL-INDUCED-DISEASE |
| Hepatocellular oxidant stress following intestinal DISEASE-reperfusion injury. Reperfusion of DISEASE intestine results in acute liver dysfunction characterized by hepatocellular enzyme release into plasma, reduction in bile flow rate, and neutrophil sequestration within the liver. The pathophysiology underlying this acute hepatic injury is unknown. This study was undertaken to determine whether oxidants are associated with the hepatic injury and to determine the relative value of several indirect methods of assessing oxidant exposure in vivo. Rats were subjected to a standardized intestinal DISEASE-reperfusion injury. Hepatic tissue was assayed for lipid peroxidation products and CHEMICAL. There was no change in hepatic tissue total glutathione following intestinal DISEASE-reperfusion injury. Oxidized glutathione (GSSG) increased significantly following 30 and 60 min of reperfusion. There was no increase in any of the products of lipid peroxidation associated with this injury. An increase in GSSG within hepatic tissue during intestinal reperfusion suggests exposure of hepatocytes to an oxidant stress. The lack of a significant increase in products of lipid peroxidation suggests that the oxidant stress is of insufficient magnitude to result in irreversible injury to hepatocyte cell membranes. These data also suggest that the measurement of tissue GSSG may be a more sensitive indicator of oxidant stress than measurement of products of lipid peroxidation. | NO-RELATIONSHIP |
| Hepatocellular oxidant stress following intestinal ischemia-reperfusion injury. Reperfusion of ischemic intestine results in acute liver dysfunction characterized by hepatocellular enzyme release into plasma, reduction in bile flow rate, and neutrophil sequestration within the liver. The pathophysiology underlying this acute DISEASE is unknown. This study was undertaken to determine whether oxidants are associated with the DISEASE and to determine the relative value of several indirect methods of assessing oxidant exposure in vivo. Rats were subjected to a standardized intestinal ischemia-reperfusion injury. Hepatic tissue was assayed for lipid peroxidation products and oxidized and reduced glutathione. There was no change in hepatic tissue total CHEMICAL following intestinal ischemia-reperfusion injury. Oxidized glutathione (GSSG) increased significantly following 30 and 60 min of reperfusion. There was no increase in any of the products of lipid peroxidation associated with this injury. An increase in GSSG within hepatic tissue during intestinal reperfusion suggests exposure of hepatocytes to an oxidant stress. The lack of a significant increase in products of lipid peroxidation suggests that the oxidant stress is of insufficient magnitude to result in irreversible injury to hepatocyte cell membranes. These data also suggest that the measurement of tissue GSSG may be a more sensitive indicator of oxidant stress than measurement of products of lipid peroxidation. | NO-RELATIONSHIP |
| Hepatocellular oxidant stress following intestinal ischemia-reperfusion injury. Reperfusion of ischemic intestine results in acute DISEASE characterized by hepatocellular enzyme release into plasma, reduction in bile flow rate, and neutrophil sequestration within the liver. The pathophysiology underlying this acute hepatic injury is unknown. This study was undertaken to determine whether oxidants are associated with the hepatic injury and to determine the relative value of several indirect methods of assessing oxidant exposure in vivo. Rats were subjected to a standardized intestinal ischemia-reperfusion injury. Hepatic tissue was assayed for lipid peroxidation products and CHEMICAL. There was no change in hepatic tissue total glutathione following intestinal ischemia-reperfusion injury. Oxidized glutathione (GSSG) increased significantly following 30 and 60 min of reperfusion. There was no increase in any of the products of lipid peroxidation associated with this injury. An increase in GSSG within hepatic tissue during intestinal reperfusion suggests exposure of hepatocytes to an oxidant stress. The lack of a significant increase in products of lipid peroxidation suggests that the oxidant stress is of insufficient magnitude to result in irreversible injury to hepatocyte cell membranes. These data also suggest that the measurement of tissue GSSG may be a more sensitive indicator of oxidant stress than measurement of products of lipid peroxidation. | NO-RELATIONSHIP |
| Hepatocellular oxidant stress following intestinal ischemia-reperfusion injury. Reperfusion of ischemic intestine results in acute DISEASE characterized by hepatocellular enzyme release into plasma, reduction in bile flow rate, and neutrophil sequestration within the liver. The pathophysiology underlying this acute hepatic injury is unknown. This study was undertaken to determine whether oxidants are associated with the hepatic injury and to determine the relative value of several indirect methods of assessing oxidant exposure in vivo. Rats were subjected to a standardized intestinal ischemia-reperfusion injury. Hepatic tissue was assayed for lipid peroxidation products and oxidized and reduced glutathione. There was no change in hepatic tissue total CHEMICAL following intestinal ischemia-reperfusion injury. Oxidized glutathione (GSSG) increased significantly following 30 and 60 min of reperfusion. There was no increase in any of the products of lipid peroxidation associated with this injury. An increase in GSSG within hepatic tissue during intestinal reperfusion suggests exposure of hepatocytes to an oxidant stress. The lack of a significant increase in products of lipid peroxidation suggests that the oxidant stress is of insufficient magnitude to result in irreversible injury to hepatocyte cell membranes. These data also suggest that the measurement of tissue GSSG may be a more sensitive indicator of oxidant stress than measurement of products of lipid peroxidation. | NO-RELATIONSHIP |
| Hepatocellular oxidant stress following intestinal ischemia-reperfusion injury. Reperfusion of ischemic intestine results in acute liver dysfunction characterized by hepatocellular enzyme release into plasma, reduction in bile flow rate, and neutrophil sequestration within the liver. The pathophysiology underlying this acute DISEASE is unknown. This study was undertaken to determine whether oxidants are associated with the DISEASE and to determine the relative value of several indirect methods of assessing oxidant exposure in vivo. Rats were subjected to a standardized intestinal ischemia-reperfusion injury. Hepatic tissue was assayed for lipid peroxidation products and CHEMICAL. There was no change in hepatic tissue total glutathione following intestinal ischemia-reperfusion injury. Oxidized glutathione (GSSG) increased significantly following 30 and 60 min of reperfusion. There was no increase in any of the products of lipid peroxidation associated with this injury. An increase in GSSG within hepatic tissue during intestinal reperfusion suggests exposure of hepatocytes to an oxidant stress. The lack of a significant increase in products of lipid peroxidation suggests that the oxidant stress is of insufficient magnitude to result in irreversible injury to hepatocyte cell membranes. These data also suggest that the measurement of tissue GSSG may be a more sensitive indicator of oxidant stress than measurement of products of lipid peroxidation. | NO-RELATIONSHIP |
| Diphenhydramine prevents the haemodynamic changes of CHEMICAL in ICU patients. CHEMICAL, a histamine 2 (H2) antagonist, produces a decrease in arterial pressure due to vasodilatation, especially in critically ill patients. This may be because CHEMICAL acts as a histamine agonist. We, therefore, investigated the effects of the histamine 1(H1) receptor antagonist, diphenhydramine, on the haemodynamic changes observed after CHEMICAL in ICU patients. Each patient was studied on two separate days. In a random fashion, they received CHEMICAL 200 mg iv on one day, and on the other, a pretreatment of diphenhydramine 40 mg iv with CHEMICAL 200 mg iv. In the non-pretreatment group, mean arterial pressure (MAP) decreased from 107.4 +/- 8.4 mmHg to 86.7 +/- 11.4 mmHg (P less than 0.01) two minutes after CHEMICAL. Also, systemic vascular resistance (SVR) decreased during the eight-minute observation period (P less than 0.01). In contrast, in the pretreatment group, little haemodynamic change was seen. We conclude that an H1 antagonist may be useful in preventing DISEASE caused by iv CHEMICAL, since the vasodilating activity of CHEMICAL is mediated, in part, through the H1 receptor. | CHEMICAL-INDUCED-DISEASE |
| DISEASE due to CHEMICAL. A 23-year-old male patient with bacteriologically proven pulmonary tuberculosis was treated with the various regimens of antituberculosis drugs for nearly 15 months. CHEMICAL was administered thrice as one of the 3-4 drug regimen and each time he developed untoward side effects like nausea, vomiting and fever with chills and rigors. The last such episode was of acute renal failure at which stage the patient was seen by the authors of this report. The patient, however, made a full recovery. | CHEMICAL-INDUCED-DISEASE |
| Severe DISEASE and motor loss after intrathecal thiotepa combination chemotherapy: description of two cases. Two cases of severe delayed neurologic toxicity related to the administration of intrathecal (IT) combination chemotherapy including thiotepa (TSPA) are presented. Both cases developed axonal neuropathy with motor predominance in the lower extremities 1 and 6 months after IT chemotherapy was administered. Neurologic toxicities have been described with IT-methotrexate, IT-CHEMICAL and IT-TSPA. To our knowledge, however, axonal neuropathy following administration of these three agents has not been previously described. In spite of the fact that TSPA is a useful IT agent, its combination with MTX, CHEMICAL and radiotherapy could cause severe neurotoxicity. This unexpected complication indicates the need for further toxicology research on IT-TSPA. | NO-RELATIONSHIP |
| Severe DISEASE and motor loss after intrathecal thiotepa combination chemotherapy: description of two cases. Two cases of severe delayed neurologic toxicity related to the administration of intrathecal (IT) combination chemotherapy including thiotepa (TSPA) are presented. Both cases developed axonal neuropathy with motor predominance in the lower extremities 1 and 6 months after IT chemotherapy was administered. Neurologic toxicities have been described with IT-CHEMICAL, IT-cytosine arabinoside and IT-TSPA. To our knowledge, however, axonal neuropathy following administration of these three agents has not been previously described. In spite of the fact that TSPA is a useful IT agent, its combination with CHEMICAL, ara-C and radiotherapy could cause severe neurotoxicity. This unexpected complication indicates the need for further toxicology research on IT-TSPA. | NO-RELATIONSHIP |
| Severe DISEASE and motor loss after intrathecal CHEMICAL combination chemotherapy: description of two cases. Two cases of severe delayed neurologic toxicity related to the administration of intrathecal (IT) combination chemotherapy including CHEMICAL (CHEMICAL) are presented. Both cases developed axonal neuropathy with motor predominance in the lower extremities 1 and 6 months after IT chemotherapy was administered. Neurologic toxicities have been described with IT-methotrexate, IT-cytosine arabinoside and IT-CHEMICAL. To our knowledge, however, axonal neuropathy following administration of these three agents has not been previously described. In spite of the fact that CHEMICAL is a useful IT agent, its combination with MTX, ara-C and radiotherapy could cause severe neurotoxicity. This unexpected complication indicates the need for further toxicology research on IT-CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Severe polyneuropathy and motor loss after intrathecal thiotepa combination chemotherapy: description of two cases. Two cases of severe delayed DISEASE related to the administration of intrathecal (IT) combination chemotherapy including thiotepa (TSPA) are presented. Both cases developed axonal neuropathy with motor predominance in the lower extremities 1 and 6 months after IT chemotherapy was administered. DISEASE have been described with IT-methotrexate, IT-CHEMICAL and IT-TSPA. To our knowledge, however, axonal neuropathy following administration of these three agents has not been previously described. In spite of the fact that TSPA is a useful IT agent, its combination with MTX, CHEMICAL and radiotherapy could cause severe DISEASE. This unexpected complication indicates the need for further toxicology research on IT-TSPA. | CHEMICAL-INDUCED-DISEASE |
| Severe polyneuropathy and motor loss after intrathecal thiotepa combination chemotherapy: description of two cases. Two cases of severe delayed DISEASE related to the administration of intrathecal (IT) combination chemotherapy including thiotepa (TSPA) are presented. Both cases developed axonal neuropathy with motor predominance in the lower extremities 1 and 6 months after IT chemotherapy was administered. DISEASE have been described with IT-CHEMICAL, IT-cytosine arabinoside and IT-TSPA. To our knowledge, however, axonal neuropathy following administration of these three agents has not been previously described. In spite of the fact that TSPA is a useful IT agent, its combination with CHEMICAL, ara-C and radiotherapy could cause severe DISEASE. This unexpected complication indicates the need for further toxicology research on IT-TSPA. | CHEMICAL-INDUCED-DISEASE |
| Severe polyneuropathy and motor loss after intrathecal CHEMICAL combination chemotherapy: description of two cases. Two cases of severe delayed DISEASE related to the administration of intrathecal (IT) combination chemotherapy including CHEMICAL (CHEMICAL) are presented. Both cases developed axonal neuropathy with motor predominance in the lower extremities 1 and 6 months after IT chemotherapy was administered. DISEASE have been described with IT-methotrexate, IT-cytosine arabinoside and IT-CHEMICAL. To our knowledge, however, axonal neuropathy following administration of these three agents has not been previously described. In spite of the fact that CHEMICAL is a useful IT agent, its combination with MTX, ara-C and radiotherapy could cause severe DISEASE. This unexpected complication indicates the need for further toxicology research on IT-CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Effects of CHEMICAL and pinacidil on large epicardial and small coronary arteries in conscious dogs. The effects of i.v. bolus administration of CHEMICAL (1-10 micrograms/kg) and pinacidil (3-100 micrograms/kg) on large (circumflex artery) and small coronary arteries and on systemic hemodynamics were investigated in chronically instrumented conscious dogs and compared to those of nitroglycerin (0.03-10 micrograms/kg). Nitroglycerin, up to 0.3 micrograms/kg, selectively increased circumflex artery diameter (CxAD) without simultaneously affecting any other cardiac or systemic hemodynamic parameter. In contrast, CHEMICAL and pinacidil at all doses and nitroglycerin at doses higher than 0.3 micrograms/kg simultaneously and dose-dependently increased CxAD, coronary blood flow and heart rate and decreased coronary vascular resistance and aortic pressure. CHEMICAL was approximately 8- to 9.5-fold more potent than pinacidil in increasing CxAD. Vasodilation of large and small coronary vessels and DISEASE induced by CHEMICAL and pinacidil were not affected by prior combined beta adrenergic and muscarinic receptors blockade but drug-induced tachycardia was abolished. When circumflex artery blood flow was maintained constant, the increases in CxAD induced by CHEMICAL (10 micrograms/kg), pinacidil (30 micrograms/kg) and nitroglycerin (10 micrograms/kg) were reduced by 68 +/- 7, 54 +/- 9 and 1 +/- 1%, respectively. Thus, whereas nitroglycerin preferentially and flow-independently dilates large coronary arteries, CHEMICAL and pinacidil dilate both large and small coronary arteries and this effect is not dependent upon the simultaneous beta adrenoceptors-mediated rise in myocardial metabolic demand. Finally, two mechanisms at least, direct vasodilation and flow dependency, are involved in the CHEMICAL- and pinacidil-induced increase in CxAD. | CHEMICAL-INDUCED-DISEASE |
| Effects of cromakalim and CHEMICAL on large epicardial and small coronary arteries in conscious dogs. The effects of i.v. bolus administration of cromakalim (1-10 micrograms/kg) and CHEMICAL (3-100 micrograms/kg) on large (circumflex artery) and small coronary arteries and on systemic hemodynamics were investigated in chronically instrumented conscious dogs and compared to those of nitroglycerin (0.03-10 micrograms/kg). Nitroglycerin, up to 0.3 micrograms/kg, selectively increased circumflex artery diameter (CxAD) without simultaneously affecting any other cardiac or systemic hemodynamic parameter. In contrast, cromakalim and CHEMICAL at all doses and nitroglycerin at doses higher than 0.3 micrograms/kg simultaneously and dose-dependently increased CxAD, coronary blood flow and heart rate and decreased coronary vascular resistance and aortic pressure. Cromakalim was approximately 8- to 9.5-fold more potent than CHEMICAL in increasing CxAD. Vasodilation of large and small coronary vessels and hypotension induced by cromakalim and CHEMICAL were not affected by prior combined beta adrenergic and muscarinic receptors blockade but drug-induced DISEASE was abolished. When circumflex artery blood flow was maintained constant, the increases in CxAD induced by cromakalim (10 micrograms/kg), CHEMICAL (30 micrograms/kg) and nitroglycerin (10 micrograms/kg) were reduced by 68 +/- 7, 54 +/- 9 and 1 +/- 1%, respectively. Thus, whereas nitroglycerin preferentially and flow-independently dilates large coronary arteries, cromakalim and CHEMICAL dilate both large and small coronary arteries and this effect is not dependent upon the simultaneous beta adrenoceptors-mediated rise in myocardial metabolic demand. Finally, two mechanisms at least, direct vasodilation and flow dependency, are involved in the cromakalim- and CHEMICAL-induced increase in CxAD. | CHEMICAL-INDUCED-DISEASE |
| Effects of CHEMICAL and pinacidil on large epicardial and small coronary arteries in conscious dogs. The effects of i.v. bolus administration of CHEMICAL (1-10 micrograms/kg) and pinacidil (3-100 micrograms/kg) on large (circumflex artery) and small coronary arteries and on systemic hemodynamics were investigated in chronically instrumented conscious dogs and compared to those of nitroglycerin (0.03-10 micrograms/kg). Nitroglycerin, up to 0.3 micrograms/kg, selectively increased circumflex artery diameter (CxAD) without simultaneously affecting any other cardiac or systemic hemodynamic parameter. In contrast, CHEMICAL and pinacidil at all doses and nitroglycerin at doses higher than 0.3 micrograms/kg simultaneously and dose-dependently increased CxAD, coronary blood flow and heart rate and decreased coronary vascular resistance and aortic pressure. CHEMICAL was approximately 8- to 9.5-fold more potent than pinacidil in increasing CxAD. Vasodilation of large and small coronary vessels and hypotension induced by CHEMICAL and pinacidil were not affected by prior combined beta adrenergic and muscarinic receptors blockade but drug-induced DISEASE was abolished. When circumflex artery blood flow was maintained constant, the increases in CxAD induced by CHEMICAL (10 micrograms/kg), pinacidil (30 micrograms/kg) and nitroglycerin (10 micrograms/kg) were reduced by 68 +/- 7, 54 +/- 9 and 1 +/- 1%, respectively. Thus, whereas nitroglycerin preferentially and flow-independently dilates large coronary arteries, CHEMICAL and pinacidil dilate both large and small coronary arteries and this effect is not dependent upon the simultaneous beta adrenoceptors-mediated rise in myocardial metabolic demand. Finally, two mechanisms at least, direct vasodilation and flow dependency, are involved in the CHEMICAL- and pinacidil-induced increase in CxAD. | CHEMICAL-INDUCED-DISEASE |
| Effects of cromakalim and CHEMICAL on large epicardial and small coronary arteries in conscious dogs. The effects of i.v. bolus administration of cromakalim (1-10 micrograms/kg) and CHEMICAL (3-100 micrograms/kg) on large (circumflex artery) and small coronary arteries and on systemic hemodynamics were investigated in chronically instrumented conscious dogs and compared to those of nitroglycerin (0.03-10 micrograms/kg). Nitroglycerin, up to 0.3 micrograms/kg, selectively increased circumflex artery diameter (CxAD) without simultaneously affecting any other cardiac or systemic hemodynamic parameter. In contrast, cromakalim and CHEMICAL at all doses and nitroglycerin at doses higher than 0.3 micrograms/kg simultaneously and dose-dependently increased CxAD, coronary blood flow and heart rate and decreased coronary vascular resistance and aortic pressure. Cromakalim was approximately 8- to 9.5-fold more potent than CHEMICAL in increasing CxAD. Vasodilation of large and small coronary vessels and DISEASE induced by cromakalim and CHEMICAL were not affected by prior combined beta adrenergic and muscarinic receptors blockade but drug-induced tachycardia was abolished. When circumflex artery blood flow was maintained constant, the increases in CxAD induced by cromakalim (10 micrograms/kg), CHEMICAL (30 micrograms/kg) and nitroglycerin (10 micrograms/kg) were reduced by 68 +/- 7, 54 +/- 9 and 1 +/- 1%, respectively. Thus, whereas nitroglycerin preferentially and flow-independently dilates large coronary arteries, cromakalim and CHEMICAL dilate both large and small coronary arteries and this effect is not dependent upon the simultaneous beta adrenoceptors-mediated rise in myocardial metabolic demand. Finally, two mechanisms at least, direct vasodilation and flow dependency, are involved in the cromakalim- and CHEMICAL-induced increase in CxAD. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced DISEASE and renal failure in elderly females with hypothyroidism. We report CHEMICAL-induced non-oliguric renal failure and severe DISEASE occurring simultaneously in two elderly females. The DISEASE was due to maturation arrest of the myeloid series in one patient. Both patients were also hypothyroid, but it is not clear whether this was a predisposing factor to the development of these adverse reactions. However, it would seem prudent not to use CHEMICAL in hypothyroid patients until the hypothyroidism has been corrected. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced neutropenia and DISEASE in elderly females with hypothyroidism. We report CHEMICAL-induced non-oliguric DISEASE and severe neutropenia occurring simultaneously in two elderly females. The neutropenia was due to maturation arrest of the myeloid series in one patient. Both patients were also hypothyroid, but it is not clear whether this was a predisposing factor to the development of these adverse reactions. However, it would seem prudent not to use CHEMICAL in hypothyroid patients until the hypothyroidism has been corrected. | CHEMICAL-INDUCED-DISEASE |
| Etiology of DISEASE in hemodialysis patients on CHEMICAL therapy. Fourteen of 39 dialysis patients (36%) became DISEASE after switching to CHEMICAL as their principal phosphate binder. In order to identify risk factors associated with the development of DISEASE, indirect parameters of intestinal calcium reabsorption and bone turnover rate in these 14 patients were compared with results in 14 eucalcemic patients matched for age, sex, length of time on dialysis, and etiology of renal disease. In addition to experiencing DISEASE episodes with peak calcium values of 2.7 to 3.8 mmol/L (10.7 to 15.0 mg/dL), patients in the DISEASE group exhibited a significant increase in the mean calcium concentration obtained during 6 months before the switch, compared with the mean value obtained during the 7 months of observation after the switch (2.4 +/- 0.03 to 2.5 +/- 0.03 mmol/L [9.7 +/- 0.2 to 10.2 +/- 0.1 mg/dL], P = 0.006). In contrast, eucalcemic patients exhibited no change in mean calcium values over the same time period (2.3 +/- 0.05 to 2.3 +/- 0.05 mmol/L [9.2 +/- 0.2 to 9.2 +/- 0.2 mg/dL]). CHEMICAL dosage, calculated dietary calcium intake, and circulating levels of vitamin D metabolites were similar in both groups. Physical activity index and predialysis serum bicarbonate levels also were similar in both groups. However, there was a significant difference in parameters reflecting bone turnover rates between groups.(ABSTRACT TRUNCATED AT 250 WORDS) | CHEMICAL-INDUCED-DISEASE |
| Etiology of hypercalcemia in hemodialysis patients on calcium carbonate therapy. Fourteen of 39 dialysis patients (36%) became hypercalcemic after switching to calcium carbonate as their principal phosphate binder. In order to identify risk factors associated with the development of hypercalcemia, indirect parameters of intestinal calcium reabsorption and bone turnover rate in these 14 patients were compared with results in 14 eucalcemic patients matched for age, sex, length of time on dialysis, and etiology of DISEASE. In addition to experiencing hypercalcemic episodes with peak calcium values of 2.7 to 3.8 mmol/L (10.7 to 15.0 mg/dL), patients in the hypercalcemic group exhibited a significant increase in the mean calcium concentration obtained during 6 months before the switch, compared with the mean value obtained during the 7 months of observation after the switch (2.4 +/- 0.03 to 2.5 +/- 0.03 mmol/L [9.7 +/- 0.2 to 10.2 +/- 0.1 mg/dL], P = 0.006). In contrast, eucalcemic patients exhibited no change in mean calcium values over the same time period (2.3 +/- 0.05 to 2.3 +/- 0.05 mmol/L [9.2 +/- 0.2 to 9.2 +/- 0.2 mg/dL]). CaCO3 dosage, calculated dietary calcium intake, and circulating levels of vitamin D metabolites were similar in both groups. Physical activity index and predialysis serum CHEMICAL levels also were similar in both groups. However, there was a significant difference in parameters reflecting bone turnover rates between groups.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Etiology of hypercalcemia in hemodialysis patients on calcium carbonate therapy. Fourteen of 39 dialysis patients (36%) became hypercalcemic after switching to calcium carbonate as their principal CHEMICAL binder. In order to identify risk factors associated with the development of hypercalcemia, indirect parameters of intestinal calcium reabsorption and bone turnover rate in these 14 patients were compared with results in 14 eucalcemic patients matched for age, sex, length of time on dialysis, and etiology of DISEASE. In addition to experiencing hypercalcemic episodes with peak calcium values of 2.7 to 3.8 mmol/L (10.7 to 15.0 mg/dL), patients in the hypercalcemic group exhibited a significant increase in the mean calcium concentration obtained during 6 months before the switch, compared with the mean value obtained during the 7 months of observation after the switch (2.4 +/- 0.03 to 2.5 +/- 0.03 mmol/L [9.7 +/- 0.2 to 10.2 +/- 0.1 mg/dL], P = 0.006). In contrast, eucalcemic patients exhibited no change in mean calcium values over the same time period (2.3 +/- 0.05 to 2.3 +/- 0.05 mmol/L [9.2 +/- 0.2 to 9.2 +/- 0.2 mg/dL]). CaCO3 dosage, calculated dietary calcium intake, and circulating levels of vitamin D metabolites were similar in both groups. Physical activity index and predialysis serum bicarbonate levels also were similar in both groups. However, there was a significant difference in parameters reflecting bone turnover rates between groups.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Etiology of hypercalcemia in hemodialysis patients on calcium carbonate therapy. Fourteen of 39 dialysis patients (36%) became hypercalcemic after switching to calcium carbonate as their principal phosphate binder. In order to identify risk factors associated with the development of hypercalcemia, indirect parameters of intestinal CHEMICAL reabsorption and bone turnover rate in these 14 patients were compared with results in 14 eucalcemic patients matched for age, sex, length of time on dialysis, and etiology of DISEASE. In addition to experiencing hypercalcemic episodes with peak CHEMICAL values of 2.7 to 3.8 mmol/L (10.7 to 15.0 mg/dL), patients in the hypercalcemic group exhibited a significant increase in the mean CHEMICAL concentration obtained during 6 months before the switch, compared with the mean value obtained during the 7 months of observation after the switch (2.4 +/- 0.03 to 2.5 +/- 0.03 mmol/L [9.7 +/- 0.2 to 10.2 +/- 0.1 mg/dL], P = 0.006). In contrast, eucalcemic patients exhibited no change in mean CHEMICAL values over the same time period (2.3 +/- 0.05 to 2.3 +/- 0.05 mmol/L [9.2 +/- 0.2 to 9.2 +/- 0.2 mg/dL]). CaCO3 dosage, calculated dietary CHEMICAL intake, and circulating levels of vitamin D metabolites were similar in both groups. Physical activity index and predialysis serum bicarbonate levels also were similar in both groups. However, there was a significant difference in parameters reflecting bone turnover rates between groups.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Etiology of hypercalcemia in hemodialysis patients on calcium carbonate therapy. Fourteen of 39 dialysis patients (36%) became hypercalcemic after switching to calcium carbonate as their principal phosphate binder. In order to identify risk factors associated with the development of hypercalcemia, indirect parameters of intestinal calcium reabsorption and bone turnover rate in these 14 patients were compared with results in 14 eucalcemic patients matched for age, sex, length of time on dialysis, and etiology of DISEASE. In addition to experiencing hypercalcemic episodes with peak calcium values of 2.7 to 3.8 mmol/L (10.7 to 15.0 mg/dL), patients in the hypercalcemic group exhibited a significant increase in the mean calcium concentration obtained during 6 months before the switch, compared with the mean value obtained during the 7 months of observation after the switch (2.4 +/- 0.03 to 2.5 +/- 0.03 mmol/L [9.7 +/- 0.2 to 10.2 +/- 0.1 mg/dL], P = 0.006). In contrast, eucalcemic patients exhibited no change in mean calcium values over the same time period (2.3 +/- 0.05 to 2.3 +/- 0.05 mmol/L [9.2 +/- 0.2 to 9.2 +/- 0.2 mg/dL]). CaCO3 dosage, calculated dietary calcium intake, and circulating levels of CHEMICAL metabolites were similar in both groups. Physical activity index and predialysis serum bicarbonate levels also were similar in both groups. However, there was a significant difference in parameters reflecting bone turnover rates between groups.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| CHEMICAL-induced DISEASE in a 15 year old presenting as near-syncope. CHEMICAL is an antihypertensive medication which is available generically and under the trade name CHEMICAL that is widely prescribed in the adult population and infrequently used in children. CHEMICAL causes an autoimmune hemolytic anemia in a small percentage of patients who take the drug. We report a case of CHEMICAL-induced DISEASE in a 15-year-old boy who presented to the emergency department with near-syncope. The boy had been treated with intravenous CHEMICAL during a trauma admission seven weeks prior to presentation. Evaluation revealed a hemoglobin of three grams, 3+ Coombs' test with polyspecific anti-human globulin and monospecific IgG reagents, and a warm reacting autoantibody. Transfusion and corticosteroid therapy resulted in a complete recovery of the patient. Emergency physicians treating children must be aware of this syndrome in order to diagnose and treat it correctly. A brief review of autoimmune and drug-induced DISEASE is provided. | CHEMICAL-INDUCED-DISEASE |
| Methyldopa-induced hemolytic anemia in a 15 year old presenting as near-syncope. Methyldopa is an antihypertensive medication which is available generically and under the trade name Aldomet that is widely prescribed in the adult population and infrequently used in children. Methyldopa causes an DISEASE in a small percentage of patients who take the drug. We report a case of methyldopa-induced hemolytic anemia in a 15-year-old boy who presented to the emergency department with near-syncope. The boy had been treated with intravenous methyldopa during a trauma admission seven weeks prior to presentation. Evaluation revealed a hemoglobin of three grams, 3+ Coombs' test with polyspecific anti-human globulin and monospecific IgG reagents, and a warm reacting autoantibody. Transfusion and CHEMICAL therapy resulted in a complete recovery of the patient. Emergency physicians treating children must be aware of this syndrome in order to diagnose and treat it correctly. A brief review of autoimmune and drug-induced hemolytic anemias is provided. | NO-RELATIONSHIP |
| Methyldopa-induced hemolytic anemia in a 15 year old presenting as near-DISEASE. Methyldopa is an antihypertensive medication which is available generically and under the trade name Aldomet that is widely prescribed in the adult population and infrequently used in children. Methyldopa causes an autoimmune hemolytic anemia in a small percentage of patients who take the drug. We report a case of methyldopa-induced hemolytic anemia in a 15-year-old boy who presented to the emergency department with near-DISEASE. The boy had been treated with intravenous methyldopa during a trauma admission seven weeks prior to presentation. Evaluation revealed a hemoglobin of three grams, 3+ Coombs' test with polyspecific anti-human globulin and monospecific IgG reagents, and a warm reacting autoantibody. Transfusion and CHEMICAL therapy resulted in a complete recovery of the patient. Emergency physicians treating children must be aware of this syndrome in order to diagnose and treat it correctly. A brief review of autoimmune and drug-induced hemolytic anemias is provided. | NO-RELATIONSHIP |
| Methyldopa-induced hemolytic anemia in a 15 year old presenting as near-syncope. Methyldopa is an antihypertensive medication which is available generically and under the trade name Aldomet that is widely prescribed in the adult population and infrequently used in children. Methyldopa causes an autoimmune hemolytic anemia in a small percentage of patients who take the drug. We report a case of methyldopa-induced hemolytic anemia in a 15-year-old boy who presented to the DISEASE with near-syncope. The boy had been treated with intravenous methyldopa during a trauma admission seven weeks prior to presentation. Evaluation revealed a hemoglobin of three grams, 3+ Coombs' test with polyspecific anti-human globulin and monospecific IgG reagents, and a warm reacting autoantibody. Transfusion and CHEMICAL therapy resulted in a complete recovery of the patient. Emergency physicians treating children must be aware of this syndrome in order to diagnose and treat it correctly. A brief review of autoimmune and drug-induced hemolytic anemias is provided. | NO-RELATIONSHIP |
| Methyldopa-induced hemolytic anemia in a 15 year old presenting as near-syncope. Methyldopa is an antihypertensive medication which is available generically and under the trade name Aldomet that is widely prescribed in the adult population and infrequently used in children. Methyldopa causes an autoimmune hemolytic anemia in a small percentage of patients who take the drug. We report a case of methyldopa-induced hemolytic anemia in a 15-year-old boy who presented to the emergency department with near-syncope. The boy had been treated with intravenous methyldopa during a DISEASE admission seven weeks prior to presentation. Evaluation revealed a hemoglobin of three grams, 3+ Coombs' test with polyspecific anti-human globulin and monospecific IgG reagents, and a warm reacting autoantibody. Transfusion and CHEMICAL therapy resulted in a complete recovery of the patient. Emergency physicians treating children must be aware of this syndrome in order to diagnose and treat it correctly. A brief review of autoimmune and drug-induced hemolytic anemias is provided. | NO-RELATIONSHIP |
| The long-term safety of CHEMICAL in women with hereditary angioedema. Although the short-term safety (less than or equal to 6 months) of CHEMICAL has been established in a variety of settings, no information exists as to its long-term safety. We therefore investigated the long-term safety of CHEMICAL by performing a retrospective chart review of 60 female patients with hereditary angioedema treated with CHEMICAL for a continuous period of 6 months or longer. The mean age of the patients was 35.2 years and the mean duration of therapy was 59.7 months. Virtually all patients experienced one or more adverse reactions. Menstrual abnormalities (79%), DISEASE (60%), muscle cramps/myalgias (40%), and transaminase elevations (40%) were the most common adverse reactions. The drug was discontinued due to adverse reactions in 8 patients. No patient has died or suffered any apparent long-term sequelae that were directly attributable to the drug. We conclude that, despite a relatively high incidence of adverse reactions, CHEMICAL has proven to be remarkably safe over the long-term in this group of patients. | CHEMICAL-INDUCED-DISEASE |
| The long-term safety of CHEMICAL in women with hereditary angioedema. Although the short-term safety (less than or equal to 6 months) of CHEMICAL has been established in a variety of settings, no information exists as to its long-term safety. We therefore investigated the long-term safety of CHEMICAL by performing a retrospective chart review of 60 female patients with hereditary angioedema treated with CHEMICAL for a continuous period of 6 months or longer. The mean age of the patients was 35.2 years and the mean duration of therapy was 59.7 months. Virtually all patients experienced one or more adverse reactions. Menstrual abnormalities (79%), weight gain (60%), DISEASE/myalgias (40%), and transaminase elevations (40%) were the most common adverse reactions. The drug was discontinued due to adverse reactions in 8 patients. No patient has died or suffered any apparent long-term sequelae that were directly attributable to the drug. We conclude that, despite a relatively high incidence of adverse reactions, CHEMICAL has proven to be remarkably safe over the long-term in this group of patients. | CHEMICAL-INDUCED-DISEASE |
| The long-term safety of CHEMICAL in women with hereditary angioedema. Although the short-term safety (less than or equal to 6 months) of CHEMICAL has been established in a variety of settings, no information exists as to its long-term safety. We therefore investigated the long-term safety of CHEMICAL by performing a retrospective chart review of 60 female patients with hereditary angioedema treated with CHEMICAL for a continuous period of 6 months or longer. The mean age of the patients was 35.2 years and the mean duration of therapy was 59.7 months. Virtually all patients experienced one or more adverse reactions. DISEASE (79%), weight gain (60%), muscle cramps/myalgias (40%), and transaminase elevations (40%) were the most common adverse reactions. The drug was discontinued due to adverse reactions in 8 patients. No patient has died or suffered any apparent long-term sequelae that were directly attributable to the drug. We conclude that, despite a relatively high incidence of adverse reactions, CHEMICAL has proven to be remarkably safe over the long-term in this group of patients. | CHEMICAL-INDUCED-DISEASE |
| Patient tolerance study of topical CHEMICAL: a new topical agent for burns. Effective topical antimicrobial agents decrease infection and mortality in burn patients. CHEMICAL (CHEMICAL), a new broad-spectrum antimicrobial agent, has been evaluated as a topical burn wound dressing in cream form, but preliminary clinical trials reported that it was painful upon application. This study compared various concentrations of CHEMICAL to determine if a tolerable concentration could be identified with retention of antimicrobial efficacy. Twenty-nine burn patients, each with two similar burns which could be separately treated, were given pairs of treatments at successive 12-h intervals over a 3-day period. One burn site was treated with each of four different CHEMICAL concentrations, from 0.25 per cent to 2 per cent, their vehicle, and 1 per cent silver sulphadiazine (AgSD) cream, an antimicrobial agent frequently used for topical treatment of burn wounds. The other site was always treated with AgSD cream. There was a direct relationship between CHEMICAL concentration and patients' ratings of DISEASE on an analogue scale. The 0.25 per cent CHEMICAL cream was closest to AgSD in DISEASE tolerance; however, none of the treatments differed statistically from AgSD or from each other. In addition, ease of application of CHEMICAL creams was less satisfactory than that of AgSD. It was concluded that formulations at or below 0.5 per cent CHEMICAL may prove acceptable for wound care, but the vehicle system needs pharmaceutical improvement to render it more tolerable and easier to use. | CHEMICAL-INDUCED-DISEASE |
| Patient tolerance study of topical chlorhexidine diphosphanilate: a new topical agent for burns. Effective topical antimicrobial agents decrease DISEASE and mortality in burn patients. Chlorhexidine phosphanilate (CHP), a new broad-spectrum antimicrobial agent, has been evaluated as a topical burn wound dressing in cream form, but preliminary clinical trials reported that it was painful upon application. This study compared various concentrations of CHP to determine if a tolerable concentration could be identified with retention of antimicrobial efficacy. Twenty-nine burn patients, each with two similar burns which could be separately treated, were given pairs of treatments at successive 12-h intervals over a 3-day period. One burn site was treated with each of four different CHP concentrations, from 0.25 per cent to 2 per cent, their vehicle, and 1 per cent CHEMICAL (CHEMICAL) cream, an antimicrobial agent frequently used for topical treatment of burn wounds. The other site was always treated with CHEMICAL cream. There was a direct relationship between CHP concentration and patients' ratings of pain on an analogue scale. The 0.25 per cent CHP cream was closest to CHEMICAL in pain tolerance; however, none of the treatments differed statistically from CHEMICAL or from each other. In addition, ease of application of CHP creams was less satisfactory than that of CHEMICAL. It was concluded that formulations at or below 0.5 per cent CHP may prove acceptable for wound care, but the vehicle system needs pharmaceutical improvement to render it more tolerable and easier to use. | NO-RELATIONSHIP |
| Patient tolerance study of topical chlorhexidine diphosphanilate: a new topical agent for DISEASE. Effective topical antimicrobial agents decrease infection and mortality in DISEASE patients. Chlorhexidine phosphanilate (CHP), a new broad-spectrum antimicrobial agent, has been evaluated as a topical DISEASE wound dressing in cream form, but preliminary clinical trials reported that it was painful upon application. This study compared various concentrations of CHP to determine if a tolerable concentration could be identified with retention of antimicrobial efficacy. Twenty-nine DISEASE patients, each with two similar DISEASE which could be separately treated, were given pairs of treatments at successive 12-h intervals over a 3-day period. One DISEASE site was treated with each of four different CHP concentrations, from 0.25 per cent to 2 per cent, their vehicle, and 1 per cent CHEMICAL (CHEMICAL) cream, an antimicrobial agent frequently used for topical treatment of DISEASE wounds. The other site was always treated with CHEMICAL cream. There was a direct relationship between CHP concentration and patients' ratings of pain on an analogue scale. The 0.25 per cent CHP cream was closest to CHEMICAL in pain tolerance; however, none of the treatments differed statistically from CHEMICAL or from each other. In addition, ease of application of CHP creams was less satisfactory than that of CHEMICAL. It was concluded that formulations at or below 0.5 per cent CHP may prove acceptable for wound care, but the vehicle system needs pharmaceutical improvement to render it more tolerable and easier to use. | NO-RELATIONSHIP |
| Dose-dependent neurotoxicity of high-dose CHEMICAL in children: a clinical and pharmacological study. CHEMICAL is known to be neurotoxic in animals and humans, but its acute neurotoxicity remains poorly characterized in children. We report here a retrospective study of 123 children (median age, 6.5 years) receiving high-dose CHEMICAL in combined chemotherapy before bone marrow transplantation for malignant solid tumors, brain tumors excluded. CHEMICAL was given p.o., every 6 hours for 16 doses over 4 days. Two total doses were consecutively used: 16 mg/kg, then 600 mg/m2. The dose calculation on the basis of body surface area results in higher doses in young children than in older patients (16 to 28 mg/kg). Ninety-six patients were not given anticonvulsive prophylaxis; 7 (7.5%) developed DISEASE during the 4 days of the CHEMICAL course or within 24 h after the last dosing. When the total CHEMICAL dose was taken into account, there was a significant difference in terms of neurotoxicity incidence among patients under 16 mg/kg (1 of 57, 1.7%) and patients under 600 mg/m2 (6 of 39, 15.4%) (P less than 0.02). Twenty-seven patients were given a 600-mg/m2 CHEMICAL total dose with continuous i.v. infusion of clonazepam; none had any neurological symptoms. CHEMICAL levels were measured by a gas chromatographic-mass spectrometry assay in the plasma and cerebrospinal fluid of 9 children without central nervous system disease under 600 mg/m2 CHEMICAL with clonazepam:CHEMICAL cerebrospinal fluid:plasma ratio was 1.39. This was significantly different (P less than 0.02) from the cerebrospinal fluid:plasma ratio previously defined in children receiving a 16-mg/kg total dose of CHEMICAL. This study shows that CHEMICAL neurotoxicity is dose-dependent in children and efficiently prevented by clonazepam. A CHEMICAL dose calculated on the basis of body surface area, resulting in higher doses in young children, was followed by increased neurotoxicity, close to neurotoxicity incidence observed in adults. Since plasma pharmacokinetic studies showed a faster CHEMICAL clearance in children than in adults, this new dose may approximate more closely the adult systemic exposure obtained after the usual 16-mg/kg total dose, with potential inferences in terms of anticancer or myeloablative effects. The CHEMICAL dose in children and infants undergoing bone marrow transplantation should be reconsidered on the basis of pharmacokinetic studies. | CHEMICAL-INDUCED-DISEASE |
| Dose-dependent neurotoxicity of high-dose busulfan in children: a clinical and pharmacological study. Busulfan is known to be neurotoxic in animals and humans, but its acute neurotoxicity remains poorly characterized in children. We report here a retrospective study of 123 children (median age, 6.5 years) receiving high-dose busulfan in combined chemotherapy before bone marrow transplantation for malignant solid tumors, DISEASE excluded. Busulfan was given p.o., every 6 hours for 16 doses over 4 days. Two total doses were consecutively used: 16 mg/kg, then 600 mg/m2. The dose calculation on the basis of body surface area results in higher doses in young children than in older patients (16 to 28 mg/kg). Ninety-six patients were not given anticonvulsive prophylaxis; 7 (7.5%) developed seizures during the 4 days of the busulfan course or within 24 h after the last dosing. When the total busulfan dose was taken into account, there was a significant difference in terms of neurotoxicity incidence among patients under 16 mg/kg (1 of 57, 1.7%) and patients under 600 mg/m2 (6 of 39, 15.4%) (P less than 0.02). Twenty-seven patients were given a 600-mg/m2 busulfan total dose with continuous i.v. infusion of CHEMICAL; none had any neurological symptoms. Busulfan levels were measured by a gas chromatographic-mass spectrometry assay in the plasma and cerebrospinal fluid of 9 children without central nervous system disease under 600 mg/m2 busulfan with CHEMICAL:busulfan cerebrospinal fluid:plasma ratio was 1.39. This was significantly different (P less than 0.02) from the cerebrospinal fluid:plasma ratio previously defined in children receiving a 16-mg/kg total dose of busulfan. This study shows that busulfan neurotoxicity is dose-dependent in children and efficiently prevented by CHEMICAL. A busulfan dose calculated on the basis of body surface area, resulting in higher doses in young children, was followed by increased neurotoxicity, close to neurotoxicity incidence observed in adults. Since plasma pharmacokinetic studies showed a faster busulfan clearance in children than in adults, this new dose may approximate more closely the adult systemic exposure obtained after the usual 16-mg/kg total dose, with potential inferences in terms of anticancer or myeloablative effects. The busulfan dose in children and infants undergoing bone marrow transplantation should be reconsidered on the basis of pharmacokinetic studies. | NO-RELATIONSHIP |
| Dose-dependent neurotoxicity of high-dose busulfan in children: a clinical and pharmacological study. Busulfan is known to be neurotoxic in animals and humans, but its acute neurotoxicity remains poorly characterized in children. We report here a retrospective study of 123 children (median age, 6.5 years) receiving high-dose busulfan in combined chemotherapy before bone marrow transplantation for malignant solid tumors, brain tumors excluded. Busulfan was given p.o., every 6 hours for 16 doses over 4 days. Two total doses were consecutively used: 16 mg/kg, then 600 mg/m2. The dose calculation on the basis of body surface area results in higher doses in young children than in older patients (16 to 28 mg/kg). Ninety-six patients were not given anticonvulsive prophylaxis; 7 (7.5%) developed seizures during the 4 days of the busulfan course or within 24 h after the last dosing. When the total busulfan dose was taken into account, there was a significant difference in terms of neurotoxicity incidence among patients under 16 mg/kg (1 of 57, 1.7%) and patients under 600 mg/m2 (6 of 39, 15.4%) (P less than 0.02). Twenty-seven patients were given a 600-mg/m2 busulfan total dose with continuous i.v. infusion of CHEMICAL; none had any DISEASE. Busulfan levels were measured by a gas chromatographic-mass spectrometry assay in the plasma and cerebrospinal fluid of 9 children without central nervous system disease under 600 mg/m2 busulfan with CHEMICAL:busulfan cerebrospinal fluid:plasma ratio was 1.39. This was significantly different (P less than 0.02) from the cerebrospinal fluid:plasma ratio previously defined in children receiving a 16-mg/kg total dose of busulfan. This study shows that busulfan neurotoxicity is dose-dependent in children and efficiently prevented by CHEMICAL. A busulfan dose calculated on the basis of body surface area, resulting in higher doses in young children, was followed by increased neurotoxicity, close to neurotoxicity incidence observed in adults. Since plasma pharmacokinetic studies showed a faster busulfan clearance in children than in adults, this new dose may approximate more closely the adult systemic exposure obtained after the usual 16-mg/kg total dose, with potential inferences in terms of anticancer or myeloablative effects. The busulfan dose in children and infants undergoing bone marrow transplantation should be reconsidered on the basis of pharmacokinetic studies. | NO-RELATIONSHIP |
| Dose-dependent neurotoxicity of high-dose busulfan in children: a clinical and pharmacological study. Busulfan is known to be neurotoxic in animals and humans, but its acute neurotoxicity remains poorly characterized in children. We report here a retrospective study of 123 children (median age, 6.5 years) receiving high-dose busulfan in combined chemotherapy before bone marrow transplantation for malignant solid tumors, brain tumors excluded. Busulfan was given p.o., every 6 hours for 16 doses over 4 days. Two total doses were consecutively used: 16 mg/kg, then 600 mg/m2. The dose calculation on the basis of body surface area results in higher doses in young children than in older patients (16 to 28 mg/kg). Ninety-six patients were not given anticonvulsive prophylaxis; 7 (7.5%) developed seizures during the 4 days of the busulfan course or within 24 h after the last dosing. When the total busulfan dose was taken into account, there was a significant difference in terms of neurotoxicity incidence among patients under 16 mg/kg (1 of 57, 1.7%) and patients under 600 mg/m2 (6 of 39, 15.4%) (P less than 0.02). Twenty-seven patients were given a 600-mg/m2 busulfan total dose with continuous i.v. infusion of CHEMICAL; none had any neurological symptoms. Busulfan levels were measured by a gas chromatographic-mass spectrometry assay in the plasma and cerebrospinal fluid of 9 children without DISEASE under 600 mg/m2 busulfan with CHEMICAL:busulfan cerebrospinal fluid:plasma ratio was 1.39. This was significantly different (P less than 0.02) from the cerebrospinal fluid:plasma ratio previously defined in children receiving a 16-mg/kg total dose of busulfan. This study shows that busulfan neurotoxicity is dose-dependent in children and efficiently prevented by CHEMICAL. A busulfan dose calculated on the basis of body surface area, resulting in higher doses in young children, was followed by increased neurotoxicity, close to neurotoxicity incidence observed in adults. Since plasma pharmacokinetic studies showed a faster busulfan clearance in children than in adults, this new dose may approximate more closely the adult systemic exposure obtained after the usual 16-mg/kg total dose, with potential inferences in terms of anticancer or myeloablative effects. The busulfan dose in children and infants undergoing bone marrow transplantation should be reconsidered on the basis of pharmacokinetic studies. | NO-RELATIONSHIP |
| Dose-dependent DISEASE of high-dose busulfan in children: a clinical and pharmacological study. Busulfan is known to be DISEASE in animals and humans, but its acute DISEASE remains poorly characterized in children. We report here a retrospective study of 123 children (median age, 6.5 years) receiving high-dose busulfan in combined chemotherapy before bone marrow transplantation for malignant solid tumors, brain tumors excluded. Busulfan was given p.o., every 6 hours for 16 doses over 4 days. Two total doses were consecutively used: 16 mg/kg, then 600 mg/m2. The dose calculation on the basis of body surface area results in higher doses in young children than in older patients (16 to 28 mg/kg). Ninety-six patients were not given anticonvulsive prophylaxis; 7 (7.5%) developed seizures during the 4 days of the busulfan course or within 24 h after the last dosing. When the total busulfan dose was taken into account, there was a significant difference in terms of DISEASE incidence among patients under 16 mg/kg (1 of 57, 1.7%) and patients under 600 mg/m2 (6 of 39, 15.4%) (P less than 0.02). Twenty-seven patients were given a 600-mg/m2 busulfan total dose with continuous i.v. infusion of CHEMICAL; none had any neurological symptoms. Busulfan levels were measured by a gas chromatographic-mass spectrometry assay in the plasma and cerebrospinal fluid of 9 children without central nervous system disease under 600 mg/m2 busulfan with CHEMICAL:busulfan cerebrospinal fluid:plasma ratio was 1.39. This was significantly different (P less than 0.02) from the cerebrospinal fluid:plasma ratio previously defined in children receiving a 16-mg/kg total dose of busulfan. This study shows that busulfan DISEASE is dose-dependent in children and efficiently prevented by CHEMICAL. A busulfan dose calculated on the basis of body surface area, resulting in higher doses in young children, was followed by increased DISEASE, close to DISEASE incidence observed in adults. Since plasma pharmacokinetic studies showed a faster busulfan clearance in children than in adults, this new dose may approximate more closely the adult systemic exposure obtained after the usual 16-mg/kg total dose, with potential inferences in terms of anticancer or myeloablative effects. The busulfan dose in children and infants undergoing bone marrow transplantation should be reconsidered on the basis of pharmacokinetic studies. | NO-RELATIONSHIP |
| Dose-dependent neurotoxicity of high-dose busulfan in children: a clinical and pharmacological study. Busulfan is known to be neurotoxic in animals and humans, but its acute neurotoxicity remains poorly characterized in children. We report here a retrospective study of 123 children (median age, 6.5 years) receiving high-dose busulfan in combined chemotherapy before bone marrow transplantation for malignant solid DISEASE, brain tumors excluded. Busulfan was given p.o., every 6 hours for 16 doses over 4 days. Two total doses were consecutively used: 16 mg/kg, then 600 mg/m2. The dose calculation on the basis of body surface area results in higher doses in young children than in older patients (16 to 28 mg/kg). Ninety-six patients were not given anticonvulsive prophylaxis; 7 (7.5%) developed seizures during the 4 days of the busulfan course or within 24 h after the last dosing. When the total busulfan dose was taken into account, there was a significant difference in terms of neurotoxicity incidence among patients under 16 mg/kg (1 of 57, 1.7%) and patients under 600 mg/m2 (6 of 39, 15.4%) (P less than 0.02). Twenty-seven patients were given a 600-mg/m2 busulfan total dose with continuous i.v. infusion of CHEMICAL; none had any neurological symptoms. Busulfan levels were measured by a gas chromatographic-mass spectrometry assay in the plasma and cerebrospinal fluid of 9 children without central nervous system disease under 600 mg/m2 busulfan with CHEMICAL:busulfan cerebrospinal fluid:plasma ratio was 1.39. This was significantly different (P less than 0.02) from the cerebrospinal fluid:plasma ratio previously defined in children receiving a 16-mg/kg total dose of busulfan. This study shows that busulfan neurotoxicity is dose-dependent in children and efficiently prevented by CHEMICAL. A busulfan dose calculated on the basis of body surface area, resulting in higher doses in young children, was followed by increased neurotoxicity, close to neurotoxicity incidence observed in adults. Since plasma pharmacokinetic studies showed a faster busulfan clearance in children than in adults, this new dose may approximate more closely the adult systemic exposure obtained after the usual 16-mg/kg total dose, with potential inferences in terms of anticancer or myeloablative effects. The busulfan dose in children and infants undergoing bone marrow transplantation should be reconsidered on the basis of pharmacokinetic studies. | NO-RELATIONSHIP |
| Histamine antagonists and CHEMICAL-induced DISEASE in cardiac surgical patients. Hemodynamic effects and histamine release by bolus injection of 0.35 mg/kg of CHEMICAL were studied in 24 patients. H1- and H2-histamine antagonists or placebo were given before dosing with CHEMICAL in a randomized double-blind fashion to four groups: group 1--placebo; group 2--cimetidine, 4 mg/kg, plus placebo; group 3--chlorpheniramine, 0.1 mg/kg, plus placebo; and group 4--cimetidine plus chlorpheniramine. Histamine release occurred in most patients, the highest level 2 minutes after CHEMICAL dosing. Group 1 had a moderate negative correlation between plasma histamine change and systemic vascular resistance (r = 0.58; P less than 0.05) not present in group 4. Prior dosing with antagonists partially prevented the fall in systemic vascular resistance. These data demonstrate that the hemodynamic changes associated with CHEMICAL dosing are only partially explained by histamine release. Thus prior dosing with H1- and H2-antagonists provides only partial protection. | CHEMICAL-INDUCED-DISEASE |
| Convulsant effect of CHEMICAL and regional brain concentration of GABA and dopamine. CHEMICAL (CHEMICAL) is an organochlorine insecticide with known neurotoxic effects. Its mechanism of action is not well understood although it has been proposed that CHEMICAL acts as a non-competitive antagonist at the gamma-aminobutyric acid (GABA)-A receptor. We studied the effect of CHEMICAL (150 mg/kg) on the GABAergic and dopaminergic systems by measuring the concentration of GABA, dopamine and its metabolites in 7 brain areas at the onset of DISEASE. All animals suffered tonic DISEASE at 18.3 +/- 1.4 min after CHEMICAL administration. The concentration of GABA was only slightly but significantly decreased in the colliculi without modifications in the other areas. The concentration of dopamine was increased in the mesencephalon and that of its metabolite DOPAC was also increased in the mesencephalon and the striatum. | CHEMICAL-INDUCED-DISEASE |
| Convulsant effect of lindane and regional brain concentration of CHEMICAL and dopamine. Lindane (gamma-hexachlorocyclohexane) is an organochlorine insecticide with known DISEASE effects. Its mechanism of action is not well understood although it has been proposed that lindane acts as a non-competitive antagonist at the CHEMICAL (CHEMICAL)-A receptor. We studied the effect of lindane (150 mg/kg) on the GABAergic and dopaminergic systems by measuring the concentration of CHEMICAL, dopamine and its metabolites in 7 brain areas at the onset of seizures. All animals suffered tonic convulsions at 18.3 +/- 1.4 min after lindane administration. The concentration of CHEMICAL was only slightly but significantly decreased in the colliculi without modifications in the other areas. The concentration of dopamine was increased in the mesencephalon and that of its metabolite DOPAC was also increased in the mesencephalon and the striatum. | NO-RELATIONSHIP |
| Convulsant effect of lindane and regional brain concentration of GABA and dopamine. Lindane (gamma-hexachlorocyclohexane) is an organochlorine insecticide with known DISEASE effects. Its mechanism of action is not well understood although it has been proposed that lindane acts as a non-competitive antagonist at the gamma-aminobutyric acid (GABA)-A receptor. We studied the effect of lindane (150 mg/kg) on the GABAergic and dopaminergic systems by measuring the concentration of GABA, dopamine and its metabolites in 7 brain areas at the onset of seizures. All animals suffered tonic convulsions at 18.3 +/- 1.4 min after lindane administration. The concentration of GABA was only slightly but significantly decreased in the colliculi without modifications in the other areas. The concentration of dopamine was increased in the mesencephalon and that of its metabolite CHEMICAL was also increased in the mesencephalon and the striatum. | NO-RELATIONSHIP |
| Convulsant effect of lindane and regional brain concentration of GABA and CHEMICAL. Lindane (gamma-hexachlorocyclohexane) is an organochlorine insecticide with known DISEASE effects. Its mechanism of action is not well understood although it has been proposed that lindane acts as a non-competitive antagonist at the gamma-aminobutyric acid (GABA)-A receptor. We studied the effect of lindane (150 mg/kg) on the GABAergic and dopaminergic systems by measuring the concentration of GABA, CHEMICAL and its metabolites in 7 brain areas at the onset of seizures. All animals suffered tonic convulsions at 18.3 +/- 1.4 min after lindane administration. The concentration of GABA was only slightly but significantly decreased in the colliculi without modifications in the other areas. The concentration of CHEMICAL was increased in the mesencephalon and that of its metabolite DOPAC was also increased in the mesencephalon and the striatum. | NO-RELATIONSHIP |
| Unusual complications of antithyroid drug therapy: four case reports and review of literature. Two cases of CHEMICAL-associated acute hepatitis, one case of fatal methimazole-associated hepatocellular necrosis and one case of CHEMICAL-associated DISEASE are described. The literature related to antithyroid drug side effects and the mechanisms for their occurrence are reviewed and the efficacy and complications of thyroidectomy and radioiodine compared to those of antithyroid drugs. It is concluded that in most circumstances 131I is the therapy of choice for hyperthyroidism. | CHEMICAL-INDUCED-DISEASE |
| Unusual complications of antithyroid drug therapy: four case reports and review of literature. Two cases of propylthiouracil-associated acute hepatitis, one case of fatal CHEMICAL-associated DISEASE and one case of propylthiouracil-associated lupus-like syndrome are described. The literature related to antithyroid drug side effects and the mechanisms for their occurrence are reviewed and the efficacy and complications of thyroidectomy and radioiodine compared to those of antithyroid drugs. It is concluded that in most circumstances 131I is the therapy of choice for hyperthyroidism. | CHEMICAL-INDUCED-DISEASE |
| Unusual complications of antithyroid drug therapy: four case reports and review of literature. Two cases of CHEMICAL-associated acute DISEASE, one case of fatal methimazole-associated hepatocellular necrosis and one case of CHEMICAL-associated lupus-like syndrome are described. The literature related to antithyroid drug side effects and the mechanisms for their occurrence are reviewed and the efficacy and complications of thyroidectomy and radioiodine compared to those of antithyroid drugs. It is concluded that in most circumstances 131I is the therapy of choice for hyperthyroidism. | CHEMICAL-INDUCED-DISEASE |
| Anticonvulsant actions of MK-801 on the lithium-CHEMICAL model of DISEASE in rats. MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, was tested for anticonvulsant effects in rats using two seizure models, coadministration of lithium and CHEMICAL and administration of a high dose of CHEMICAL alone. Three major results are reported. First, pretreatment with MK-801 produced an effective and dose-dependent anticonvulsant action with the lithium-CHEMICAL model but not with rats treated with CHEMICAL alone, suggesting that different biochemical mechanisms control seizures in these two models. Second, the anticonvulsant effect of MK-801 in the lithium-CHEMICAL model only occurred after initial periods of seizure activity. This observation is suggested to be an in vivo demonstration of the conclusion derived from in vitro experiments that MK-801 binding requires agonist-induced opening of the channel sites of the NMDA receptor. Third, although it is relatively easy to block seizures induced by lithium and CHEMICAL by administration of anticonvulsants prior to CHEMICAL, it is more difficult to terminate ongoing DISEASE and block the lethality of the seizures. Administration of MK-801 30 or 60 min after CHEMICAL, i.e., during DISEASE, gradually reduced electrical and behavioral seizure activity and greatly enhanced the survival rate. These results suggest that activation of NMDA receptors plays an important role in DISEASE and brain damage in the lithium-CHEMICAL model. This was further supported by results showing that nonconvulsive doses of NMDA and CHEMICAL were synergistic, resulting in DISEASE and subsequent mortality. | CHEMICAL-INDUCED-DISEASE |
| Anticonvulsant actions of MK-801 on the CHEMICAL-pilocarpine model of DISEASE in rats. MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, was tested for anticonvulsant effects in rats using two seizure models, coadministration of CHEMICAL and pilocarpine and administration of a high dose of pilocarpine alone. Three major results are reported. First, pretreatment with MK-801 produced an effective and dose-dependent anticonvulsant action with the CHEMICAL-pilocarpine model but not with rats treated with pilocarpine alone, suggesting that different biochemical mechanisms control seizures in these two models. Second, the anticonvulsant effect of MK-801 in the CHEMICAL-pilocarpine model only occurred after initial periods of seizure activity. This observation is suggested to be an in vivo demonstration of the conclusion derived from in vitro experiments that MK-801 binding requires agonist-induced opening of the channel sites of the NMDA receptor. Third, although it is relatively easy to block seizures induced by CHEMICAL and pilocarpine by administration of anticonvulsants prior to pilocarpine, it is more difficult to terminate ongoing DISEASE and block the lethality of the seizures. Administration of MK-801 30 or 60 min after pilocarpine, i.e., during DISEASE, gradually reduced electrical and behavioral seizure activity and greatly enhanced the survival rate. These results suggest that activation of NMDA receptors plays an important role in DISEASE and brain damage in the CHEMICAL-pilocarpine model. This was further supported by results showing that nonconvulsive doses of NMDA and pilocarpine were synergistic, resulting in DISEASE and subsequent mortality. | CHEMICAL-INDUCED-DISEASE |
| Anticonvulsant actions of CHEMICAL on the lithium-pilocarpine model of status epilepticus in rats. CHEMICAL, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, was tested for anticonvulsant effects in rats using two seizure models, coadministration of lithium and pilocarpine and administration of a high dose of pilocarpine alone. Three major results are reported. First, pretreatment with CHEMICAL produced an effective and dose-dependent anticonvulsant action with the lithium-pilocarpine model but not with rats treated with pilocarpine alone, suggesting that different biochemical mechanisms control seizures in these two models. Second, the anticonvulsant effect of CHEMICAL in the lithium-pilocarpine model only occurred after initial periods of seizure activity. This observation is suggested to be an in vivo demonstration of the conclusion derived from in vitro experiments that CHEMICAL binding requires agonist-induced opening of the channel sites of the NMDA receptor. Third, although it is relatively easy to block seizures induced by lithium and pilocarpine by administration of anticonvulsants prior to pilocarpine, it is more difficult to terminate ongoing status epilepticus and block the lethality of the seizures. Administration of CHEMICAL 30 or 60 min after pilocarpine, i.e., during status epilepticus, gradually reduced electrical and behavioral seizure activity and greatly enhanced the survival rate. These results suggest that activation of NMDA receptors plays an important role in status epilepticus and DISEASE in the lithium-pilocarpine model. This was further supported by results showing that nonconvulsive doses of NMDA and pilocarpine were synergistic, resulting in status epilepticus and subsequent mortality. | NO-RELATIONSHIP |
| Anticonvulsant actions of MK-801 on the lithium-pilocarpine model of status epilepticus in rats. MK-801, a noncompetitive CHEMICAL (CHEMICAL) receptor antagonist, was tested for anticonvulsant effects in rats using two DISEASE models, coadministration of lithium and pilocarpine and administration of a high dose of pilocarpine alone. Three major results are reported. First, pretreatment with MK-801 produced an effective and dose-dependent anticonvulsant action with the lithium-pilocarpine model but not with rats treated with pilocarpine alone, suggesting that different biochemical mechanisms control DISEASE in these two models. Second, the anticonvulsant effect of MK-801 in the lithium-pilocarpine model only occurred after initial periods of DISEASE activity. This observation is suggested to be an in vivo demonstration of the conclusion derived from in vitro experiments that MK-801 binding requires agonist-induced opening of the channel sites of the CHEMICAL receptor. Third, although it is relatively easy to block DISEASE induced by lithium and pilocarpine by administration of anticonvulsants prior to pilocarpine, it is more difficult to terminate ongoing status epilepticus and block the lethality of the DISEASE. Administration of MK-801 30 or 60 min after pilocarpine, i.e., during status epilepticus, gradually reduced electrical and behavioral DISEASE activity and greatly enhanced the survival rate. These results suggest that activation of CHEMICAL receptors plays an important role in status epilepticus and brain damage in the lithium-pilocarpine model. This was further supported by results showing that nonconvulsive doses of CHEMICAL and pilocarpine were synergistic, resulting in status epilepticus and subsequent mortality. | NO-RELATIONSHIP |
| Anticonvulsant actions of CHEMICAL on the lithium-pilocarpine model of status epilepticus in rats. CHEMICAL, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, was tested for anticonvulsant effects in rats using two DISEASE models, coadministration of lithium and pilocarpine and administration of a high dose of pilocarpine alone. Three major results are reported. First, pretreatment with CHEMICAL produced an effective and dose-dependent anticonvulsant action with the lithium-pilocarpine model but not with rats treated with pilocarpine alone, suggesting that different biochemical mechanisms control DISEASE in these two models. Second, the anticonvulsant effect of CHEMICAL in the lithium-pilocarpine model only occurred after initial periods of DISEASE activity. This observation is suggested to be an in vivo demonstration of the conclusion derived from in vitro experiments that CHEMICAL binding requires agonist-induced opening of the channel sites of the NMDA receptor. Third, although it is relatively easy to block DISEASE induced by lithium and pilocarpine by administration of anticonvulsants prior to pilocarpine, it is more difficult to terminate ongoing status epilepticus and block the lethality of the DISEASE. Administration of CHEMICAL 30 or 60 min after pilocarpine, i.e., during status epilepticus, gradually reduced electrical and behavioral DISEASE activity and greatly enhanced the survival rate. These results suggest that activation of NMDA receptors plays an important role in status epilepticus and brain damage in the lithium-pilocarpine model. This was further supported by results showing that nonconvulsive doses of NMDA and pilocarpine were synergistic, resulting in status epilepticus and subsequent mortality. | NO-RELATIONSHIP |
| Anticonvulsant actions of MK-801 on the lithium-pilocarpine model of status epilepticus in rats. MK-801, a noncompetitive CHEMICAL (CHEMICAL) receptor antagonist, was tested for anticonvulsant effects in rats using two seizure models, coadministration of lithium and pilocarpine and administration of a high dose of pilocarpine alone. Three major results are reported. First, pretreatment with MK-801 produced an effective and dose-dependent anticonvulsant action with the lithium-pilocarpine model but not with rats treated with pilocarpine alone, suggesting that different biochemical mechanisms control seizures in these two models. Second, the anticonvulsant effect of MK-801 in the lithium-pilocarpine model only occurred after initial periods of seizure activity. This observation is suggested to be an in vivo demonstration of the conclusion derived from in vitro experiments that MK-801 binding requires agonist-induced opening of the channel sites of the CHEMICAL receptor. Third, although it is relatively easy to block seizures induced by lithium and pilocarpine by administration of anticonvulsants prior to pilocarpine, it is more difficult to terminate ongoing status epilepticus and block the lethality of the seizures. Administration of MK-801 30 or 60 min after pilocarpine, i.e., during status epilepticus, gradually reduced electrical and behavioral seizure activity and greatly enhanced the survival rate. These results suggest that activation of CHEMICAL receptors plays an important role in status epilepticus and DISEASE in the lithium-pilocarpine model. This was further supported by results showing that nonconvulsive doses of CHEMICAL and pilocarpine were synergistic, resulting in status epilepticus and subsequent mortality. | NO-RELATIONSHIP |
| CHEMICAL induced bradycardia in a patient with autonomic neuropathy. An 80 year old diabetic male with evidence of peripheral and autonomic neuropathy was admitted with chest pain. He was found to have atrial flutter at a ventricular rate of 70/min which slowed down to 30-40/min when CHEMICAL (60 mg) in 3 divided doses, during which he was paced at a rate of 70/min. This is inconsistent with the well-established finding that CHEMICAL induces DISEASE in normally innervated hearts. However, in hearts deprived of compensatory sympathetic drive, it may lead to bradycardia. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL induced DISEASE in a patient with autonomic neuropathy. An 80 year old diabetic male with evidence of peripheral and autonomic neuropathy was admitted with chest pain. He was found to have atrial flutter at a ventricular rate of 70/min which slowed down to 30-40/min when CHEMICAL (60 mg) in 3 divided doses, during which he was paced at a rate of 70/min. This is inconsistent with the well-established finding that CHEMICAL induces tachycardia in normally innervated hearts. However, in hearts deprived of compensatory sympathetic drive, it may lead to DISEASE. | CHEMICAL-INDUCED-DISEASE |
| The effect of haloperidol in CHEMICAL and amphetamine intoxication. The effectiveness of haloperidol pretreatment in preventing the toxic effects of high doses of amphetamine and CHEMICAL was studied in rats. In this model, toxic effects were induced by intraperitoneal (i.p.) injection of amphetamine 75 mg/kg (100% death rate) or CHEMICAL 70 mg/kg (82% death rate). Haloperidol failed to prevent amphetamine-induced DISEASE, but did lower the mortality rate at most doses tested. Haloperidol decreased the incidence of CHEMICAL-induced DISEASE at the two highest doses, but the lowering of the mortality rate did not reach statistical significance at any dose. These data suggest a protective role for the central dopamine blocker haloperidol against death from high-dose amphetamine exposure without reducing the incidence of DISEASE. In contrast, haloperidol demonstrated an ability to reduce CHEMICAL-induced DISEASE without significantly reducing mortality. | CHEMICAL-INDUCED-DISEASE |
| The effect of haloperidol in cocaine and CHEMICAL intoxication. The effectiveness of haloperidol pretreatment in preventing the toxic effects of high doses of CHEMICAL and cocaine was studied in rats. In this model, toxic effects were induced by intraperitoneal (i.p.) injection of CHEMICAL 75 mg/kg (100% death rate) or cocaine 70 mg/kg (82% death rate). Haloperidol failed to prevent CHEMICAL-induced DISEASE, but did lower the mortality rate at most doses tested. Haloperidol decreased the incidence of cocaine-induced DISEASE at the two highest doses, but the lowering of the mortality rate did not reach statistical significance at any dose. These data suggest a protective role for the central dopamine blocker haloperidol against death from high-dose CHEMICAL exposure without reducing the incidence of DISEASE. In contrast, haloperidol demonstrated an ability to reduce cocaine-induced DISEASE without significantly reducing mortality. | CHEMICAL-INDUCED-DISEASE |
| Autoradiographic evidence of estrogen binding sites in nuclei of CHEMICAL induced hamster DISEASE. Estrogen binding sites were demonstrated by autoradiography in one transplantable and five primary CHEMICAL induced DISEASE in three hamsters. Radiolabelling, following the in vivo injection of 3H-17 beta estradiol, was increased only over the nuclei of tumor cells; stereologic analysis revealed a 4.5- to 6.7-times higher concentration of reduced silver grains over nuclei than cytoplasm of these cells. Despite rapid tubular excretion of estradiol which peaked in less than 1 h, the normal cells did not appear to bind the ligand. This is the first published report documenting the preferential in vivo binding of estrogen to nuclei of cells in estrogen induced hamster DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Autoradiographic evidence of CHEMICAL binding sites in nuclei of diethylstilbesterol induced hamster renal carcinomas. CHEMICAL binding sites were demonstrated by autoradiography in one transplantable and five primary diethylstilbesterol induced renal carcinomas in three hamsters. Radiolabelling, following the in vivo injection of 3H-17 beta estradiol, was increased only over the nuclei of DISEASE cells; stereologic analysis revealed a 4.5- to 6.7-times higher concentration of reduced silver grains over nuclei than cytoplasm of these cells. Despite rapid tubular excretion of estradiol which peaked in less than 1 h, the normal cells did not appear to bind the ligand. This is the first published report documenting the preferential in vivo binding of CHEMICAL to nuclei of cells in CHEMICAL induced hamster renal carcinomas. | NO-RELATIONSHIP |
| Autoradiographic evidence of estrogen binding sites in nuclei of diethylstilbesterol induced hamster renal carcinomas. Estrogen binding sites were demonstrated by autoradiography in one transplantable and five primary diethylstilbesterol induced renal carcinomas in three hamsters. Radiolabelling, following the in vivo injection of 3H-17 beta CHEMICAL, was increased only over the nuclei of DISEASE cells; stereologic analysis revealed a 4.5- to 6.7-times higher concentration of reduced silver grains over nuclei than cytoplasm of these cells. Despite rapid tubular excretion of CHEMICAL which peaked in less than 1 h, the normal cells did not appear to bind the ligand. This is the first published report documenting the preferential in vivo binding of estrogen to nuclei of cells in estrogen induced hamster renal carcinomas. | NO-RELATIONSHIP |
| Autoradiographic evidence of estrogen binding sites in nuclei of diethylstilbesterol induced hamster renal carcinomas. Estrogen binding sites were demonstrated by autoradiography in one transplantable and five primary diethylstilbesterol induced renal carcinomas in three hamsters. Radiolabelling, following the in vivo injection of 3H-17 beta estradiol, was increased only over the nuclei of DISEASE cells; stereologic analysis revealed a 4.5- to 6.7-times higher concentration of reduced CHEMICAL grains over nuclei than cytoplasm of these cells. Despite rapid tubular excretion of estradiol which peaked in less than 1 h, the normal cells did not appear to bind the ligand. This is the first published report documenting the preferential in vivo binding of estrogen to nuclei of cells in estrogen induced hamster renal carcinomas. | NO-RELATIONSHIP |
| DISEASE due to CHEMICAL. In a 38-year-old male patient suffering from a severe postzosteric trigeminal neuralgia, intravenous application of 10 mg biperiden lactate led to a long-lasting paradoxical reaction characterized by considerable DISEASE, dysarthria, and dysphagia. The heart rate was back to normal within 12 hours upon administration of orciprenaline under cardiac monitoring in an intensive care unit. DISEASE induced by CHEMICAL is attributed to the speed of injection and to a dose-related dual effect of atropine-like drugs on muscarine receptors. | CHEMICAL-INDUCED-DISEASE |
| Bradycardia due to CHEMICAL. In a 38-year-old male patient suffering from a severe postzosteric trigeminal neuralgia, intravenous application of 10 mg biperiden lactate led to a long-lasting paradoxical reaction characterized by considerable bradycardia, dysarthria, and DISEASE. The heart rate was back to normal within 12 hours upon administration of orciprenaline under cardiac monitoring in an intensive care unit. Bradycardia induced by CHEMICAL is attributed to the speed of injection and to a dose-related dual effect of atropine-like drugs on muscarine receptors. | CHEMICAL-INDUCED-DISEASE |
| Bradycardia due to CHEMICAL. In a 38-year-old male patient suffering from a severe postzosteric trigeminal neuralgia, intravenous application of 10 mg biperiden lactate led to a long-lasting paradoxical reaction characterized by considerable bradycardia, DISEASE, and dysphagia. The heart rate was back to normal within 12 hours upon administration of orciprenaline under cardiac monitoring in an intensive care unit. Bradycardia induced by CHEMICAL is attributed to the speed of injection and to a dose-related dual effect of atropine-like drugs on muscarine receptors. | CHEMICAL-INDUCED-DISEASE |
| Bradycardia due to biperiden. In a 38-year-old male patient suffering from a severe postzosteric DISEASE, intravenous application of 10 mg biperiden lactate led to a long-lasting paradoxical reaction characterized by considerable bradycardia, dysarthria, and dysphagia. The heart rate was back to normal within 12 hours upon administration of CHEMICAL under cardiac monitoring in an intensive care unit. Bradycardia induced by biperiden is attributed to the speed of injection and to a dose-related dual effect of atropine-like drugs on muscarine receptors. | NO-RELATIONSHIP |
| Bradycardia due to biperiden. In a 38-year-old male patient suffering from a severe DISEASE trigeminal neuralgia, intravenous application of 10 mg biperiden lactate led to a long-lasting paradoxical reaction characterized by considerable bradycardia, dysarthria, and dysphagia. The heart rate was back to normal within 12 hours upon administration of CHEMICAL under cardiac monitoring in an intensive care unit. Bradycardia induced by biperiden is attributed to the speed of injection and to a dose-related dual effect of atropine-like drugs on muscarine receptors. | NO-RELATIONSHIP |
| Bradycardia due to biperiden. In a 38-year-old male patient suffering from a severe postzosteric DISEASE, intravenous application of 10 mg CHEMICAL led to a long-lasting paradoxical reaction characterized by considerable bradycardia, dysarthria, and dysphagia. The heart rate was back to normal within 12 hours upon administration of orciprenaline under cardiac monitoring in an intensive care unit. Bradycardia induced by biperiden is attributed to the speed of injection and to a dose-related dual effect of atropine-like drugs on muscarine receptors. | NO-RELATIONSHIP |
| Bradycardia due to biperiden. In a 38-year-old male patient suffering from a severe DISEASE trigeminal neuralgia, intravenous application of 10 mg biperiden lactate led to a long-lasting paradoxical reaction characterized by considerable bradycardia, dysarthria, and dysphagia. The heart rate was back to normal within 12 hours upon administration of orciprenaline under cardiac monitoring in an intensive care unit. Bradycardia induced by biperiden is attributed to the speed of injection and to a dose-related dual effect of CHEMICAL-like drugs on muscarine receptors. | NO-RELATIONSHIP |
| Bradycardia due to biperiden. In a 38-year-old male patient suffering from a severe DISEASE trigeminal neuralgia, intravenous application of 10 mg CHEMICAL led to a long-lasting paradoxical reaction characterized by considerable bradycardia, dysarthria, and dysphagia. The heart rate was back to normal within 12 hours upon administration of orciprenaline under cardiac monitoring in an intensive care unit. Bradycardia induced by biperiden is attributed to the speed of injection and to a dose-related dual effect of atropine-like drugs on muscarine receptors. | NO-RELATIONSHIP |
| Bradycardia due to biperiden. In a 38-year-old male patient suffering from a severe DISEASE trigeminal neuralgia, intravenous application of 10 mg biperiden lactate led to a long-lasting paradoxical reaction characterized by considerable bradycardia, dysarthria, and dysphagia. The heart rate was back to normal within 12 hours upon administration of orciprenaline under cardiac monitoring in an intensive care unit. Bradycardia induced by biperiden is attributed to the speed of injection and to a dose-related dual effect of atropine-like drugs on CHEMICAL receptors. | NO-RELATIONSHIP |
| Bradycardia due to biperiden. In a 38-year-old male patient suffering from a severe postzosteric DISEASE, intravenous application of 10 mg biperiden lactate led to a long-lasting paradoxical reaction characterized by considerable bradycardia, dysarthria, and dysphagia. The heart rate was back to normal within 12 hours upon administration of orciprenaline under cardiac monitoring in an intensive care unit. Bradycardia induced by biperiden is attributed to the speed of injection and to a dose-related dual effect of CHEMICAL-like drugs on muscarine receptors. | NO-RELATIONSHIP |
| Bradycardia due to biperiden. In a 38-year-old male patient suffering from a severe postzosteric DISEASE, intravenous application of 10 mg biperiden lactate led to a long-lasting paradoxical reaction characterized by considerable bradycardia, dysarthria, and dysphagia. The heart rate was back to normal within 12 hours upon administration of orciprenaline under cardiac monitoring in an intensive care unit. Bradycardia induced by biperiden is attributed to the speed of injection and to a dose-related dual effect of atropine-like drugs on CHEMICAL receptors. | NO-RELATIONSHIP |
| Deliberate DISEASE induced by labetalol with halothane, CHEMICAL or isoflurane for middle-ear surgery. The feasibility of using labetalol, an alpha- and beta-adrenergic blocking agent, as a DISEASE agent in combination with inhalation anaesthetics (halothane, CHEMICAL or isoflurane) was studied in 23 adult patients undergoing middle-ear surgery. The mean arterial pressure was decreased from 86 +/- 5 (s.e. mean) mmHg to 52 +/- 1 mmHg (11.5 +/- 0.7 to 6.9 +/- 0.1 kPa) for 98 +/- 10 min in the halothane (H) group, from 79 +/- 5 to 53 +/- 1 mmHg (10.5 +/- 0.7 to 7.1 +/- 0.1 kPa) for 129 +/- 11 min in the enflurane (E) group, and from 80 +/- 4 to 49 +/- 1 mmHg (10.7 +/- 0.5 to 6.5 +/- 0.1 kPa) for 135 +/- 15 min in the isoflurane (I) group. The mean H concentration during hypotension in the inspiratory gas was 0.7 +/- 0.1 vol%, the mean E concentration 1.6 +/- 0.2 vol%, and the mean I concentration 1.0 +/- 0.1 vol%. In addition, the patients received fentanyl and d-tubocurarine. The initial dose of labetalol for lowering blood pressure was similar, 0.52-0.59 mg/kg, in all the groups. During hypotension, the heart rate was stable without tachy- or bradycardia. The operating conditions regarding bleeding were estimated in a double-blind manner, and did not differ significantly between the groups. During hypotension, the serum creatinine concentration rose significantly in all groups from the values before hypotension and returned postoperatively to the initial level in the other groups, except the isoflurane group. After hypotension there was no rebound phenomenon in either blood pressure or heart rate. These results indicate that labetalol induces easily adjustable hypotension without compensatory tachycardia and rebound hypertension. | CHEMICAL-INDUCED-DISEASE |
| Deliberate DISEASE induced by labetalol with halothane, enflurane or CHEMICAL for middle-ear surgery. The feasibility of using labetalol, an alpha- and beta-adrenergic blocking agent, as a DISEASE agent in combination with inhalation anaesthetics (halothane, enflurane or CHEMICAL) was studied in 23 adult patients undergoing middle-ear surgery. The mean arterial pressure was decreased from 86 +/- 5 (s.e. mean) mmHg to 52 +/- 1 mmHg (11.5 +/- 0.7 to 6.9 +/- 0.1 kPa) for 98 +/- 10 min in the halothane (H) group, from 79 +/- 5 to 53 +/- 1 mmHg (10.5 +/- 0.7 to 7.1 +/- 0.1 kPa) for 129 +/- 11 min in the enflurane (E) group, and from 80 +/- 4 to 49 +/- 1 mmHg (10.7 +/- 0.5 to 6.5 +/- 0.1 kPa) for 135 +/- 15 min in the isoflurane (I) group. The mean H concentration during hypotension in the inspiratory gas was 0.7 +/- 0.1 vol%, the mean E concentration 1.6 +/- 0.2 vol%, and the mean I concentration 1.0 +/- 0.1 vol%. In addition, the patients received fentanyl and d-tubocurarine. The initial dose of labetalol for lowering blood pressure was similar, 0.52-0.59 mg/kg, in all the groups. During hypotension, the heart rate was stable without tachy- or bradycardia. The operating conditions regarding bleeding were estimated in a double-blind manner, and did not differ significantly between the groups. During hypotension, the serum creatinine concentration rose significantly in all groups from the values before hypotension and returned postoperatively to the initial level in the other groups, except the isoflurane group. After hypotension there was no rebound phenomenon in either blood pressure or heart rate. These results indicate that labetalol induces easily adjustable hypotension without compensatory tachycardia and rebound hypertension. | CHEMICAL-INDUCED-DISEASE |
| Deliberate DISEASE induced by labetalol with CHEMICAL, enflurane or isoflurane for middle-ear surgery. The feasibility of using labetalol, an alpha- and beta-adrenergic blocking agent, as a DISEASE agent in combination with inhalation anaesthetics (CHEMICAL, enflurane or isoflurane) was studied in 23 adult patients undergoing middle-ear surgery. The mean arterial pressure was decreased from 86 +/- 5 (s.e. mean) mmHg to 52 +/- 1 mmHg (11.5 +/- 0.7 to 6.9 +/- 0.1 kPa) for 98 +/- 10 min in the CHEMICAL (CHEMICAL) group, from 79 +/- 5 to 53 +/- 1 mmHg (10.5 +/- 0.7 to 7.1 +/- 0.1 kPa) for 129 +/- 11 min in the enflurane (E) group, and from 80 +/- 4 to 49 +/- 1 mmHg (10.7 +/- 0.5 to 6.5 +/- 0.1 kPa) for 135 +/- 15 min in the isoflurane (I) group. The mean H concentration during hypotension in the inspiratory gas was 0.7 +/- 0.1 vol%, the mean E concentration 1.6 +/- 0.2 vol%, and the mean I concentration 1.0 +/- 0.1 vol%. In addition, the patients received fentanyl and d-tubocurarine. The initial dose of labetalol for lowering blood pressure was similar, 0.52-0.59 mg/kg, in all the groups. During hypotension, the heart rate was stable without tachy- or bradycardia. The operating conditions regarding bleeding were estimated in a double-blind manner, and did not differ significantly between the groups. During hypotension, the serum creatinine concentration rose significantly in all groups from the values before hypotension and returned postoperatively to the initial level in the other groups, except the isoflurane group. After hypotension there was no rebound phenomenon in either blood pressure or heart rate. These results indicate that labetalol induces easily adjustable hypotension without compensatory tachycardia and rebound hypertension. | CHEMICAL-INDUCED-DISEASE |
| Deliberate DISEASE induced by CHEMICAL with halothane, enflurane or isoflurane for middle-ear surgery. The feasibility of using CHEMICAL, an alpha- and beta-adrenergic blocking agent, as a DISEASE agent in combination with inhalation anaesthetics (halothane, enflurane or isoflurane) was studied in 23 adult patients undergoing middle-ear surgery. The mean arterial pressure was decreased from 86 +/- 5 (s.e. mean) mmHg to 52 +/- 1 mmHg (11.5 +/- 0.7 to 6.9 +/- 0.1 kPa) for 98 +/- 10 min in the halothane (H) group, from 79 +/- 5 to 53 +/- 1 mmHg (10.5 +/- 0.7 to 7.1 +/- 0.1 kPa) for 129 +/- 11 min in the enflurane (E) group, and from 80 +/- 4 to 49 +/- 1 mmHg (10.7 +/- 0.5 to 6.5 +/- 0.1 kPa) for 135 +/- 15 min in the isoflurane (I) group. The mean H concentration during hypotension in the inspiratory gas was 0.7 +/- 0.1 vol%, the mean E concentration 1.6 +/- 0.2 vol%, and the mean I concentration 1.0 +/- 0.1 vol%. In addition, the patients received fentanyl and d-tubocurarine. The initial dose of labetalol for lowering blood pressure was similar, 0.52-0.59 mg/kg, in all the groups. During hypotension, the heart rate was stable without tachy- or bradycardia. The operating conditions regarding bleeding were estimated in a double-blind manner, and did not differ significantly between the groups. During hypotension, the serum creatinine concentration rose significantly in all groups from the values before hypotension and returned postoperatively to the initial level in the other groups, except the isoflurane group. After hypotension there was no rebound phenomenon in either blood pressure or heart rate. These results indicate that labetalol induces easily adjustable hypotension without compensatory tachycardia and rebound hypertension. | CHEMICAL-INDUCED-DISEASE |
| Convulsion following intravenous CHEMICAL angiography. DISEASE followed intravenous CHEMICAL injection for fundus angiography in a 47-year-old male. Despite precautions this adverse reaction recurred on re-exposure to intravenous CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Pharmacology of ACC-9653 (phenytoin prodrug). ACC-9653, the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin, is a prodrug of phenytoin with advantageous physicochemical properties. ACC-9653 is rapidly converted enzymatically to phenytoin in vivo. ACC-9653 and phenytoin sodium have equivalent anticonvulsant activity against seizures induced by maximal electroshock (MES) in mice following i.p., oral, or i.v. administration. The ED50 doses were 16 mg/kg for i.v. ACC-9653 and 8 mg/kg for i.v. phenytoin sodium. ACC-9653 and phenytoin sodium have similar antiarrhythmic activity against CHEMICAL-induced DISEASE in anesthetized dogs. The total doses of ACC-9653 or phenytoin sodium necessary to convert the arrhythmia to a normal sinus rhythm were 24 +/- 6 and 14 +/- 3 mg/kg, respectively. Only phenytoin sodium displayed in vitro antiarrhythmic activity against strophanthidin-induced arrhythmias in guinea pig right atria. In anesthetized dogs, a high dose of ACC-9653 (31 mg/kg) was infused over 15, 20, and 30 min and the responses were compared to an equimolar dose of phenytoin sodium (21 mg/kg). The ACC-9653 and phenytoin sodium treatments produced similar marked reductions in diastolic blood pressure and contractile force (LVdP/dt). The maximum effects of each treatment occurred at the time of maximum phenytoin sodium levels. Acute toxicity studies of ACC-9653 and phenytoin sodium were carried out in mice, rats, rabbits, and dogs by i.v., i.m., and i.p. routes of administration. The systemic toxic signs of both agents were similar and occurred at approximately equivalent doses. Importantly, the local irritation of ACC-9653 was markedly less than phenytoin sodium following i.m. administration.(ABSTRACT TRUNCATED AT 250 WORDS) | CHEMICAL-INDUCED-DISEASE |
| Pharmacology of ACC-9653 (phenytoin prodrug). ACC-9653, the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin, is a prodrug of phenytoin with advantageous physicochemical properties. ACC-9653 is rapidly converted enzymatically to phenytoin in vivo. ACC-9653 and phenytoin sodium have equivalent anticonvulsant activity against seizures induced by maximal electroshock (MES) in mice following i.p., oral, or i.v. administration. The ED50 doses were 16 mg/kg for i.v. ACC-9653 and 8 mg/kg for i.v. phenytoin sodium. ACC-9653 and phenytoin sodium have similar antiarrhythmic activity against ouabain-induced ventricular tachycardia in anesthetized dogs. The total doses of ACC-9653 or phenytoin sodium necessary to convert the DISEASE to a normal sinus rhythm were 24 +/- 6 and 14 +/- 3 mg/kg, respectively. Only phenytoin sodium displayed in vitro antiarrhythmic activity against CHEMICAL-induced DISEASE in guinea pig right atria. In anesthetized dogs, a high dose of ACC-9653 (31 mg/kg) was infused over 15, 20, and 30 min and the responses were compared to an equimolar dose of phenytoin sodium (21 mg/kg). The ACC-9653 and phenytoin sodium treatments produced similar marked reductions in diastolic blood pressure and contractile force (LVdP/dt). The maximum effects of each treatment occurred at the time of maximum phenytoin sodium levels. Acute toxicity studies of ACC-9653 and phenytoin sodium were carried out in mice, rats, rabbits, and dogs by i.v., i.m., and i.p. routes of administration. The systemic toxic signs of both agents were similar and occurred at approximately equivalent doses. Importantly, the local irritation of ACC-9653 was markedly less than phenytoin sodium following i.m. administration.(ABSTRACT TRUNCATED AT 250 WORDS) | CHEMICAL-INDUCED-DISEASE |
| Pharmacology of ACC-9653 (phenytoin prodrug). ACC-9653, the CHEMICAL of 3-hydroxymethyl-5,5-diphenylhydantoin, is a prodrug of phenytoin with advantageous physicochemical properties. ACC-9653 is rapidly converted enzymatically to phenytoin in vivo. ACC-9653 and phenytoin sodium have equivalent anticonvulsant activity against DISEASE induced by maximal electroshock (MES) in mice following i.p., oral, or i.v. administration. The ED50 doses were 16 mg/kg for i.v. ACC-9653 and 8 mg/kg for i.v. phenytoin sodium. ACC-9653 and phenytoin sodium have similar antiarrhythmic activity against ouabain-induced ventricular tachycardia in anesthetized dogs. The total doses of ACC-9653 or phenytoin sodium necessary to convert the arrhythmia to a normal sinus rhythm were 24 +/- 6 and 14 +/- 3 mg/kg, respectively. Only phenytoin sodium displayed in vitro antiarrhythmic activity against strophanthidin-induced arrhythmias in guinea pig right atria. In anesthetized dogs, a high dose of ACC-9653 (31 mg/kg) was infused over 15, 20, and 30 min and the responses were compared to an equimolar dose of phenytoin sodium (21 mg/kg). The ACC-9653 and phenytoin sodium treatments produced similar marked reductions in diastolic blood pressure and contractile force (LVdP/dt). The maximum effects of each treatment occurred at the time of maximum phenytoin sodium levels. Acute toxicity studies of ACC-9653 and phenytoin sodium were carried out in mice, rats, rabbits, and dogs by i.v., i.m., and i.p. routes of administration. The systemic toxic signs of both agents were similar and occurred at approximately equivalent doses. Importantly, the local irritation of ACC-9653 was markedly less than phenytoin sodium following i.m. administration.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pharmacology of CHEMICAL (phenytoin prodrug). CHEMICAL, the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin, is a prodrug of phenytoin with advantageous physicochemical properties. CHEMICAL is rapidly converted enzymatically to phenytoin in vivo. CHEMICAL and CHEMICAL have equivalent anticonvulsant activity against seizures induced by maximal electroshock (MES) in mice following i.p., oral, or i.v. administration. The ED50 doses were 16 mg/kg for i.v. CHEMICAL and 8 mg/kg for i.v. CHEMICAL. CHEMICAL and CHEMICAL have similar antiarrhythmic activity against ouabain-induced ventricular tachycardia in anesthetized dogs. The total doses of CHEMICAL or CHEMICAL necessary to convert the arrhythmia to a normal sinus rhythm were 24 +/- 6 and 14 +/- 3 mg/kg, respectively. Only CHEMICAL displayed in vitro antiarrhythmic activity against strophanthidin-induced arrhythmias in guinea pig right atria. In anesthetized dogs, a high dose of CHEMICAL (31 mg/kg) was infused over 15, 20, and 30 min and the responses were compared to an equimolar dose of CHEMICAL (21 mg/kg). The CHEMICAL and CHEMICAL treatments produced similar marked reductions in diastolic blood pressure and contractile force (LVdP/dt). The maximum effects of each treatment occurred at the time of maximum CHEMICAL levels. Acute DISEASE studies of CHEMICAL and CHEMICAL were carried out in mice, rats, rabbits, and dogs by i.v., i.m., and i.p. routes of administration. The systemic toxic signs of both agents were similar and occurred at approximately equivalent doses. Importantly, the local irritation of CHEMICAL was markedly less than CHEMICAL following i.m. administration.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pharmacology of ACC-9653 (phenytoin prodrug). ACC-9653, the disodium phosphate ester of CHEMICAL, is a prodrug of phenytoin with advantageous physicochemical properties. ACC-9653 is rapidly converted enzymatically to phenytoin in vivo. ACC-9653 and phenytoin sodium have equivalent anticonvulsant activity against seizures induced by maximal electroshock (MES) in mice following i.p., oral, or i.v. administration. The ED50 doses were 16 mg/kg for i.v. ACC-9653 and 8 mg/kg for i.v. phenytoin sodium. ACC-9653 and phenytoin sodium have similar antiarrhythmic activity against ouabain-induced ventricular tachycardia in anesthetized dogs. The total doses of ACC-9653 or phenytoin sodium necessary to convert the arrhythmia to a normal sinus rhythm were 24 +/- 6 and 14 +/- 3 mg/kg, respectively. Only phenytoin sodium displayed in vitro antiarrhythmic activity against strophanthidin-induced arrhythmias in guinea pig right atria. In anesthetized dogs, a high dose of ACC-9653 (31 mg/kg) was infused over 15, 20, and 30 min and the responses were compared to an equimolar dose of phenytoin sodium (21 mg/kg). The ACC-9653 and phenytoin sodium treatments produced similar marked reductions in diastolic blood pressure and contractile force (LVdP/dt). The maximum effects of each treatment occurred at the time of maximum phenytoin sodium levels. Acute DISEASE studies of ACC-9653 and phenytoin sodium were carried out in mice, rats, rabbits, and dogs by i.v., i.m., and i.p. routes of administration. The systemic toxic signs of both agents were similar and occurred at approximately equivalent doses. Importantly, the local irritation of ACC-9653 was markedly less than phenytoin sodium following i.m. administration.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pharmacology of ACC-9653 (CHEMICAL prodrug). ACC-9653, the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin, is a prodrug of CHEMICAL with advantageous physicochemical properties. ACC-9653 is rapidly converted enzymatically to CHEMICAL in vivo. ACC-9653 and phenytoin sodium have equivalent anticonvulsant activity against seizures induced by maximal electroshock (MES) in mice following i.p., oral, or i.v. administration. The ED50 doses were 16 mg/kg for i.v. ACC-9653 and 8 mg/kg for i.v. phenytoin sodium. ACC-9653 and phenytoin sodium have similar antiarrhythmic activity against ouabain-induced ventricular tachycardia in anesthetized dogs. The total doses of ACC-9653 or phenytoin sodium necessary to convert the arrhythmia to a normal sinus rhythm were 24 +/- 6 and 14 +/- 3 mg/kg, respectively. Only phenytoin sodium displayed in vitro antiarrhythmic activity against strophanthidin-induced arrhythmias in guinea pig right atria. In anesthetized dogs, a high dose of ACC-9653 (31 mg/kg) was infused over 15, 20, and 30 min and the responses were compared to an equimolar dose of phenytoin sodium (21 mg/kg). The ACC-9653 and phenytoin sodium treatments produced similar marked reductions in diastolic blood pressure and contractile force (LVdP/dt). The maximum effects of each treatment occurred at the time of maximum phenytoin sodium levels. Acute DISEASE studies of ACC-9653 and phenytoin sodium were carried out in mice, rats, rabbits, and dogs by i.v., i.m., and i.p. routes of administration. The systemic toxic signs of both agents were similar and occurred at approximately equivalent doses. Importantly, the local irritation of ACC-9653 was markedly less than phenytoin sodium following i.m. administration.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pharmacology of ACC-9653 (phenytoin prodrug). ACC-9653, the disodium phosphate ester of CHEMICAL, is a prodrug of phenytoin with advantageous physicochemical properties. ACC-9653 is rapidly converted enzymatically to phenytoin in vivo. ACC-9653 and phenytoin sodium have equivalent anticonvulsant activity against DISEASE induced by maximal electroshock (MES) in mice following i.p., oral, or i.v. administration. The ED50 doses were 16 mg/kg for i.v. ACC-9653 and 8 mg/kg for i.v. phenytoin sodium. ACC-9653 and phenytoin sodium have similar antiarrhythmic activity against ouabain-induced ventricular tachycardia in anesthetized dogs. The total doses of ACC-9653 or phenytoin sodium necessary to convert the arrhythmia to a normal sinus rhythm were 24 +/- 6 and 14 +/- 3 mg/kg, respectively. Only phenytoin sodium displayed in vitro antiarrhythmic activity against strophanthidin-induced arrhythmias in guinea pig right atria. In anesthetized dogs, a high dose of ACC-9653 (31 mg/kg) was infused over 15, 20, and 30 min and the responses were compared to an equimolar dose of phenytoin sodium (21 mg/kg). The ACC-9653 and phenytoin sodium treatments produced similar marked reductions in diastolic blood pressure and contractile force (LVdP/dt). The maximum effects of each treatment occurred at the time of maximum phenytoin sodium levels. Acute toxicity studies of ACC-9653 and phenytoin sodium were carried out in mice, rats, rabbits, and dogs by i.v., i.m., and i.p. routes of administration. The systemic toxic signs of both agents were similar and occurred at approximately equivalent doses. Importantly, the local irritation of ACC-9653 was markedly less than phenytoin sodium following i.m. administration.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pharmacology of CHEMICAL (phenytoin prodrug). CHEMICAL, the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin, is a prodrug of phenytoin with advantageous physicochemical properties. CHEMICAL is rapidly converted enzymatically to phenytoin in vivo. CHEMICAL and CHEMICAL have equivalent anticonvulsant activity against DISEASE induced by maximal electroshock (MES) in mice following i.p., oral, or i.v. administration. The ED50 doses were 16 mg/kg for i.v. CHEMICAL and 8 mg/kg for i.v. CHEMICAL. CHEMICAL and CHEMICAL have similar antiarrhythmic activity against ouabain-induced ventricular tachycardia in anesthetized dogs. The total doses of CHEMICAL or CHEMICAL necessary to convert the arrhythmia to a normal sinus rhythm were 24 +/- 6 and 14 +/- 3 mg/kg, respectively. Only CHEMICAL displayed in vitro antiarrhythmic activity against strophanthidin-induced arrhythmias in guinea pig right atria. In anesthetized dogs, a high dose of CHEMICAL (31 mg/kg) was infused over 15, 20, and 30 min and the responses were compared to an equimolar dose of CHEMICAL (21 mg/kg). The CHEMICAL and CHEMICAL treatments produced similar marked reductions in diastolic blood pressure and contractile force (LVdP/dt). The maximum effects of each treatment occurred at the time of maximum CHEMICAL levels. Acute toxicity studies of CHEMICAL and CHEMICAL were carried out in mice, rats, rabbits, and dogs by i.v., i.m., and i.p. routes of administration. The systemic toxic signs of both agents were similar and occurred at approximately equivalent doses. Importantly, the local irritation of CHEMICAL was markedly less than CHEMICAL following i.m. administration.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pharmacology of ACC-9653 (CHEMICAL prodrug). ACC-9653, the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin, is a prodrug of CHEMICAL with advantageous physicochemical properties. ACC-9653 is rapidly converted enzymatically to CHEMICAL in vivo. ACC-9653 and phenytoin sodium have equivalent anticonvulsant activity against DISEASE induced by maximal electroshock (MES) in mice following i.p., oral, or i.v. administration. The ED50 doses were 16 mg/kg for i.v. ACC-9653 and 8 mg/kg for i.v. phenytoin sodium. ACC-9653 and phenytoin sodium have similar antiarrhythmic activity against ouabain-induced ventricular tachycardia in anesthetized dogs. The total doses of ACC-9653 or phenytoin sodium necessary to convert the arrhythmia to a normal sinus rhythm were 24 +/- 6 and 14 +/- 3 mg/kg, respectively. Only phenytoin sodium displayed in vitro antiarrhythmic activity against strophanthidin-induced arrhythmias in guinea pig right atria. In anesthetized dogs, a high dose of ACC-9653 (31 mg/kg) was infused over 15, 20, and 30 min and the responses were compared to an equimolar dose of phenytoin sodium (21 mg/kg). The ACC-9653 and phenytoin sodium treatments produced similar marked reductions in diastolic blood pressure and contractile force (LVdP/dt). The maximum effects of each treatment occurred at the time of maximum phenytoin sodium levels. Acute toxicity studies of ACC-9653 and phenytoin sodium were carried out in mice, rats, rabbits, and dogs by i.v., i.m., and i.p. routes of administration. The systemic toxic signs of both agents were similar and occurred at approximately equivalent doses. Importantly, the local irritation of ACC-9653 was markedly less than phenytoin sodium following i.m. administration.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pharmacology of ACC-9653 (phenytoin prodrug). ACC-9653, the CHEMICAL of 3-hydroxymethyl-5,5-diphenylhydantoin, is a prodrug of phenytoin with advantageous physicochemical properties. ACC-9653 is rapidly converted enzymatically to phenytoin in vivo. ACC-9653 and phenytoin sodium have equivalent anticonvulsant activity against seizures induced by maximal electroshock (MES) in mice following i.p., oral, or i.v. administration. The ED50 doses were 16 mg/kg for i.v. ACC-9653 and 8 mg/kg for i.v. phenytoin sodium. ACC-9653 and phenytoin sodium have similar antiarrhythmic activity against ouabain-induced ventricular tachycardia in anesthetized dogs. The total doses of ACC-9653 or phenytoin sodium necessary to convert the arrhythmia to a normal sinus rhythm were 24 +/- 6 and 14 +/- 3 mg/kg, respectively. Only phenytoin sodium displayed in vitro antiarrhythmic activity against strophanthidin-induced arrhythmias in guinea pig right atria. In anesthetized dogs, a high dose of ACC-9653 (31 mg/kg) was infused over 15, 20, and 30 min and the responses were compared to an equimolar dose of phenytoin sodium (21 mg/kg). The ACC-9653 and phenytoin sodium treatments produced similar marked reductions in diastolic blood pressure and contractile force (LVdP/dt). The maximum effects of each treatment occurred at the time of maximum phenytoin sodium levels. Acute DISEASE studies of ACC-9653 and phenytoin sodium were carried out in mice, rats, rabbits, and dogs by i.v., i.m., and i.p. routes of administration. The systemic toxic signs of both agents were similar and occurred at approximately equivalent doses. Importantly, the local irritation of ACC-9653 was markedly less than phenytoin sodium following i.m. administration.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| CHEMICAL induced fatal hepatic injury. A 61 year old female developed fatal DISEASE after CHEMICAL administration. A typical multisystem clinical pattern precedes the manifestations of hepatic injury. The hematologic, biochemical and pathologic features indicate a mixed hepatocellular damage due to drug hypersensitivity. In a patient receiving CHEMICAL who presents a viral-like illness, early recognition and discontinuation of the drug are mandatory. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL induced fatal hepatic injury. A 61 year old female developed fatal hepatic failure after CHEMICAL administration. A typical multisystem clinical pattern precedes the manifestations of hepatic injury. The hematologic, biochemical and pathologic features indicate a mixed hepatocellular damage due to DISEASE. In a patient receiving CHEMICAL who presents a viral-like illness, early recognition and discontinuation of the drug are mandatory. | CHEMICAL-INDUCED-DISEASE |
| Treatment of lethal CHEMICAL reaction with histamine H1 antagonists. We studied mortality after pertussis immunization in the mouse. Without treatment, 73 of 92 animals (80%) died after injection of bovine serum albumin (BSA) on day +7 of pertussis immunization. After pretreatment with 3 mg of cyproheptadine, 2 mg mianserin, or 2 mg chlorpheniramine, only 5 of 105 animals (5%) died after receiving BSA on day +7 (p less than 0.001). Blockade of histamine H1 receptors may reduce mortality in pertussis immunization-induced DISEASE in mice. | NO-RELATIONSHIP |
| Treatment of lethal pertussis vaccine reaction with histamine H1 antagonists. We studied mortality after DISEASE immunization in the mouse. Without treatment, 73 of 92 animals (80%) died after injection of bovine serum albumin (BSA) on day +7 of DISEASE immunization. After pretreatment with 3 mg of CHEMICAL, 2 mg mianserin, or 2 mg chlorpheniramine, only 5 of 105 animals (5%) died after receiving BSA on day +7 (p less than 0.001). Blockade of histamine H1 receptors may reduce mortality in DISEASE immunization-induced encephalopathy in mice. | NO-RELATIONSHIP |
| Treatment of lethal pertussis vaccine reaction with CHEMICAL H1 antagonists. We studied mortality after DISEASE immunization in the mouse. Without treatment, 73 of 92 animals (80%) died after injection of bovine serum albumin (BSA) on day +7 of DISEASE immunization. After pretreatment with 3 mg of cyproheptadine, 2 mg mianserin, or 2 mg chlorpheniramine, only 5 of 105 animals (5%) died after receiving BSA on day +7 (p less than 0.001). Blockade of CHEMICAL H1 receptors may reduce mortality in DISEASE immunization-induced encephalopathy in mice. | NO-RELATIONSHIP |
| Treatment of lethal pertussis vaccine reaction with histamine H1 antagonists. We studied mortality after DISEASE immunization in the mouse. Without treatment, 73 of 92 animals (80%) died after injection of bovine serum albumin (BSA) on day +7 of DISEASE immunization. After pretreatment with 3 mg of cyproheptadine, 2 mg CHEMICAL, or 2 mg chlorpheniramine, only 5 of 105 animals (5%) died after receiving BSA on day +7 (p less than 0.001). Blockade of histamine H1 receptors may reduce mortality in DISEASE immunization-induced encephalopathy in mice. | NO-RELATIONSHIP |
| Treatment of lethal pertussis vaccine reaction with histamine H1 antagonists. We studied mortality after DISEASE immunization in the mouse. Without treatment, 73 of 92 animals (80%) died after injection of bovine serum albumin (BSA) on day +7 of DISEASE immunization. After pretreatment with 3 mg of cyproheptadine, 2 mg mianserin, or 2 mg CHEMICAL, only 5 of 105 animals (5%) died after receiving BSA on day +7 (p less than 0.001). Blockade of histamine H1 receptors may reduce mortality in DISEASE immunization-induced encephalopathy in mice. | NO-RELATIONSHIP |
| Support for CHEMICAL-DISEASE hypothesis: 18 hour pressor effect after 6 hours CHEMICAL infusion. In a double blind, crossover study 6 h infusions of CHEMICAL (15 ng/kg/min; 1 ng = 5.458 pmol), noradrenaline (30 ng/kg/min; 1 ng = 5.911 pmol), and a 5% dextrose solution (5.4 ml/h), were given to ten healthy volunteers in random order 2 weeks apart. By means of intra-arterial ambulatory monitoring the haemodynamic effects were followed for 18 h after the infusions were stopped. CHEMICAL, but not noradrenaline, caused a delayed and protracted pressor effect. Over the total postinfusion period systolic and diastolic arterial pressure were 6 (SEM 2)% and 7 (2)%, respectively, higher than after dextrose infusion (ANOVA, p less than 0.001). Thus, "stress" levels of CHEMICAL (230 pg/ml) for 6 h cause a delayed and protracted pressor effect. These findings are strong support for the CHEMICAL-DISEASE hypothesis in man. | CHEMICAL-INDUCED-DISEASE |
| Effect of alkylxanthines on CHEMICAL-induced DISEASE in the rat. Adenosine antagonists have been previously shown to be of benefit in some ischaemic and nephrotoxic models of DISEASE (DISEASE). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing DISEASE after 4 daily injections of CHEMICAL (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in CHEMICAL-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. Adenosine antagonists have been previously shown to be of benefit in some DISEASE and nephrotoxic models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and CHEMICAL), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. Adenosine antagonists have been previously shown to be of benefit in some DISEASE and nephrotoxic models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists CHEMICAL, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. Adenosine antagonists have been previously shown to be of benefit in some ischaemic and nephrotoxic models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and CHEMICAL), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of DISEASE) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. Adenosine antagonists have been previously shown to be of benefit in some ischaemic and DISEASE models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists CHEMICAL, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. CHEMICAL antagonists have been previously shown to be of benefit in some ischaemic and nephrotoxic models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as CHEMICAL antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of DISEASE) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that CHEMICAL plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. Adenosine antagonists have been previously shown to be of benefit in some DISEASE and nephrotoxic models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists 8-phenyltheophylline, CHEMICAL and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. Adenosine antagonists have been previously shown to be of benefit in some ischaemic and nephrotoxic models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma CHEMICAL and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of DISEASE) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. CHEMICAL antagonists have been previously shown to be of benefit in some ischaemic and DISEASE models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as CHEMICAL antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that CHEMICAL plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. Adenosine antagonists have been previously shown to be of benefit in some ischaemic and DISEASE models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and CHEMICAL). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of CHEMICAL on gentamicin-induced acute renal failure in the rat. Adenosine antagonists have been previously shown to be of benefit in some DISEASE and nephrotoxic models of acute renal failure (ARF). In the present study, the effects of three CHEMICAL with different potencies as adenosine antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the CHEMICAL tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. Adenosine antagonists have been previously shown to be of benefit in some ischaemic and DISEASE models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and CHEMICAL), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. Adenosine antagonists have been previously shown to be of benefit in some DISEASE and nephrotoxic models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma CHEMICAL and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. Adenosine antagonists have been previously shown to be of benefit in some ischaemic and DISEASE models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists 8-phenyltheophylline, CHEMICAL and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. CHEMICAL antagonists have been previously shown to be of benefit in some DISEASE and nephrotoxic models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as CHEMICAL antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that CHEMICAL plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. Adenosine antagonists have been previously shown to be of benefit in some DISEASE and nephrotoxic models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (CHEMICAL and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. Adenosine antagonists have been previously shown to be of benefit in some ischaemic and nephrotoxic models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists 8-phenyltheophylline, theophylline and CHEMICAL, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of DISEASE) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. Adenosine antagonists have been previously shown to be of benefit in some DISEASE and nephrotoxic models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]CHEMICAL clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. Adenosine antagonists have been previously shown to be of benefit in some ischaemic and DISEASE models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma CHEMICAL and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of CHEMICAL on gentamicin-induced acute renal failure in the rat. Adenosine antagonists have been previously shown to be of benefit in some ischaemic and DISEASE models of acute renal failure (ARF). In the present study, the effects of three CHEMICAL with different potencies as adenosine antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of necrosis) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and NaOH). The lack of any consistent protective effect noted with the CHEMICAL tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Effect of alkylxanthines on gentamicin-induced acute renal failure in the rat. Adenosine antagonists have been previously shown to be of benefit in some ischaemic and nephrotoxic models of acute renal failure (ARF). In the present study, the effects of three alkylxanthines with different potencies as adenosine antagonists 8-phenyltheophylline, theophylline and enprofylline, were examined in rats developing acute renal failure after 4 daily injections of gentamicin (200 mg kg-1). Renal function was assessed by biochemical (plasma urea and creatinine), functional (urine analysis and [3H]inulin and [14C]p-aminohippuric acid clearances) and morphological (degree of DISEASE) indices. The various drug treatments produced improvements in some, but not all, measurements of renal function. However, any improvement produced by drug treatment was largely a result of a beneficial effect exerted by its vehicle (polyethylene glycol and CHEMICAL). The lack of any consistent protective effect noted with the alkylxanthines tested in the present study indicates that adenosine plays little, if any, pathophysiological role in gentamicin-induced ARF. | NO-RELATIONSHIP |
| Adverse ocular reactions possibly associated with CHEMICAL. A total of 261 adverse ocular reactions occurred in 237 patients who received CHEMICAL, a commonly used drug in the treatment of severe cystic acne. Blepharoconjunctivitis, subjective complaints of dry eyes, DISEASE, contact lens intolerance, and photodermatitis are reversible side effects. More serious ocular adverse reactions include papilledema, pseudotumor cerebri, and white or gray subepithelial corneal opacities; all of these are reversible if the drug is discontinued. Reported cases of decreased dark adaptation are under investigation. CHEMICAL is contraindicated in pregnancy because of the many reported congenital abnormalities after maternal use (including microphthalmos, orbital hypertelorism, and optic nerve hypoplasia). | CHEMICAL-INDUCED-DISEASE |
| Adverse ocular reactions possibly associated with CHEMICAL. A total of 261 adverse ocular reactions occurred in 237 patients who received CHEMICAL, a commonly used drug in the treatment of severe cystic acne. Blepharoconjunctivitis, subjective complaints of dry eyes, blurred vision, contact lens intolerance, and photodermatitis are reversible side effects. More serious ocular adverse reactions include papilledema, pseudotumor cerebri, and white or gray subepithelial DISEASE; all of these are reversible if the drug is discontinued. Reported cases of decreased dark adaptation are under investigation. CHEMICAL is contraindicated in pregnancy because of the many reported congenital abnormalities after maternal use (including microphthalmos, orbital hypertelorism, and optic nerve hypoplasia). | CHEMICAL-INDUCED-DISEASE |
| Adverse ocular reactions possibly associated with CHEMICAL. A total of 261 adverse ocular reactions occurred in 237 patients who received CHEMICAL, a commonly used drug in the treatment of severe cystic acne. Blepharoconjunctivitis, subjective complaints of dry eyes, blurred vision, contact lens intolerance, and photodermatitis are reversible side effects. More serious ocular adverse reactions include DISEASE, pseudotumor cerebri, and white or gray subepithelial corneal opacities; all of these are reversible if the drug is discontinued. Reported cases of decreased dark adaptation are under investigation. CHEMICAL is contraindicated in pregnancy because of the many reported congenital abnormalities after maternal use (including microphthalmos, orbital hypertelorism, and optic nerve hypoplasia). | CHEMICAL-INDUCED-DISEASE |
| Adverse ocular reactions possibly associated with CHEMICAL. A total of 261 adverse ocular reactions occurred in 237 patients who received CHEMICAL, a commonly used drug in the treatment of severe cystic acne. DISEASE, subjective complaints of dry eyes, blurred vision, contact lens intolerance, and photodermatitis are reversible side effects. More serious ocular adverse reactions include papilledema, pseudotumor cerebri, and white or gray subepithelial corneal opacities; all of these are reversible if the drug is discontinued. Reported cases of decreased dark adaptation are under investigation. CHEMICAL is contraindicated in pregnancy because of the many reported congenital abnormalities after maternal use (including microphthalmos, orbital hypertelorism, and optic nerve hypoplasia). | CHEMICAL-INDUCED-DISEASE |
| Adverse ocular reactions possibly associated with CHEMICAL. A total of 261 adverse ocular reactions occurred in 237 patients who received CHEMICAL, a commonly used drug in the treatment of severe cystic acne. Blepharoconjunctivitis, subjective complaints of dry eyes, blurred vision, contact lens intolerance, and photodermatitis are reversible side effects. More serious ocular adverse reactions include papilledema, DISEASE, and white or gray subepithelial corneal opacities; all of these are reversible if the drug is discontinued. Reported cases of decreased dark adaptation are under investigation. CHEMICAL is contraindicated in pregnancy because of the many reported congenital abnormalities after maternal use (including microphthalmos, orbital hypertelorism, and optic nerve hypoplasia). | CHEMICAL-INDUCED-DISEASE |
| Adverse ocular reactions possibly associated with CHEMICAL. A total of 261 adverse ocular reactions occurred in 237 patients who received CHEMICAL, a commonly used drug in the treatment of severe cystic acne. Blepharoconjunctivitis, subjective complaints of DISEASE, blurred vision, contact lens intolerance, and photodermatitis are reversible side effects. More serious ocular adverse reactions include papilledema, pseudotumor cerebri, and white or gray subepithelial corneal opacities; all of these are reversible if the drug is discontinued. Reported cases of decreased dark adaptation are under investigation. CHEMICAL is contraindicated in pregnancy because of the many reported congenital abnormalities after maternal use (including microphthalmos, orbital hypertelorism, and optic nerve hypoplasia). | CHEMICAL-INDUCED-DISEASE |
| Adverse ocular reactions possibly associated with CHEMICAL. A total of 261 adverse ocular reactions occurred in 237 patients who received CHEMICAL, a commonly used drug in the treatment of severe cystic acne. Blepharoconjunctivitis, subjective complaints of dry eyes, blurred vision, contact lens intolerance, and DISEASE are reversible side effects. More serious ocular adverse reactions include papilledema, pseudotumor cerebri, and white or gray subepithelial corneal opacities; all of these are reversible if the drug is discontinued. Reported cases of decreased dark adaptation are under investigation. CHEMICAL is contraindicated in pregnancy because of the many reported congenital abnormalities after maternal use (including microphthalmos, orbital hypertelorism, and optic nerve hypoplasia). | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL and terbutaline in bronchial asthma. A double-blind, placebo-controlled, cross-over study. CHEMICAL, a new beta-2 adrenoceptor stimulant, was studied in a double-blind, placebo-controlled, cross-over trial in patients with bronchial asthma. Oral CHEMICAL 50 micrograms b.d., CHEMICAL 100 micrograms b.d., and terbutaline 5 mg t.i.d., were compared when given randomly in 1-week treatment periods. The best clinical effect was found with terbutaline. Both anti-asthmatic and DISEASE effects of CHEMICAL were dose-related. CHEMICAL appeared effective in the doses tested, and a twice daily regimen would appear to be suitable with this drug. | CHEMICAL-INDUCED-DISEASE |
| Procaterol and CHEMICAL in DISEASE. A double-blind, placebo-controlled, cross-over study. Procaterol, a new beta-2 adrenoceptor stimulant, was studied in a double-blind, placebo-controlled, cross-over trial in patients with DISEASE. Oral procaterol 50 micrograms b.d., procaterol 100 micrograms b.d., and CHEMICAL 5 mg t.i.d., were compared when given randomly in 1-week treatment periods. The best clinical effect was found with CHEMICAL. Both anti-DISEASE and tremorgenic effects of procaterol were dose-related. Procaterol appeared effective in the doses tested, and a twice daily regimen would appear to be suitable with this drug. | CHEMICAL-INDUCED-DISEASE |
| Subacute effects of propranolol and B 24/76 on CHEMICAL-induced rat DISEASE in correlation with blood pressure. We compared the potential beta-receptor blocker, B 24/76 i.e. 1-(2,4-dichlorophenoxy)-3[2-3,4-dimethoxyphenyl)ethanolamino]-prop an-2-ol, which is characterized by beta 1-adrenoceptor blocking and beta 2-adrenoceptor stimulating properties with propranolol. The studies were performed using an experimental model of CHEMICAL-induced DISEASE in rats. A correlation of the blood pressure was neither found in the development nor in the attempt to suppress the development of DISEASE with the two beta-receptor blockers. Both beta-blockers influenced the development of hypertrophy to a different, but not reproducible extent. It was possible to suppress the increased ornithine decarboxylase activity with both beta-blockers in DISEASE, but there was no effect on the heart mass. Neither propranolol nor B 24/76 could stop the changes in the characteristic myosin isoenzyme pattern of the hypertrophied rat heart. Thus, the investigations did not provide any evidence that the beta-receptor blockers propranolol and B 24/76 have the potency to prevent CHEMICAL from producing DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Subacute effects of propranolol and B 24/76 on isoproterenol-induced rat heart hypertrophy in correlation with blood pressure. We compared the potential beta-receptor blocker, B 24/76 i.e. 1-(2,4-dichlorophenoxy)-3[2-3,4-dimethoxyphenyl)ethanolamino]-prop an-2-ol, which is characterized by beta 1-adrenoceptor blocking and beta 2-adrenoceptor stimulating properties with propranolol. The studies were performed using an experimental model of isoproterenol-induced heart hypertrophy in rats. A correlation of the blood pressure was neither found in the development nor in the attempt to suppress the development of heart hypertrophy with the two beta-receptor blockers. Both beta-blockers influenced the development of DISEASE to a different, but not reproducible extent. It was possible to suppress the increased CHEMICAL decarboxylase activity with both beta-blockers in hypertrophied hearts, but there was no effect on the heart mass. Neither propranolol nor B 24/76 could stop the changes in the characteristic myosin isoenzyme pattern of the DISEASE rat heart. Thus, the investigations did not provide any evidence that the beta-receptor blockers propranolol and B 24/76 have the potency to prevent isoproterenol from producing heart hypertrophy. | NO-RELATIONSHIP |
| Subacute effects of CHEMICAL and B 24/76 on isoproterenol-induced rat heart hypertrophy in correlation with blood pressure. We compared the potential beta-receptor blocker, B 24/76 i.e. 1-(2,4-dichlorophenoxy)-3[2-3,4-dimethoxyphenyl)ethanolamino]-prop an-2-ol, which is characterized by beta 1-adrenoceptor blocking and beta 2-adrenoceptor stimulating properties with CHEMICAL. The studies were performed using an experimental model of isoproterenol-induced heart hypertrophy in rats. A correlation of the blood pressure was neither found in the development nor in the attempt to suppress the development of heart hypertrophy with the two beta-receptor blockers. Both beta-blockers influenced the development of DISEASE to a different, but not reproducible extent. It was possible to suppress the increased ornithine decarboxylase activity with both beta-blockers in hypertrophied hearts, but there was no effect on the heart mass. Neither CHEMICAL nor B 24/76 could stop the changes in the characteristic myosin isoenzyme pattern of the DISEASE rat heart. Thus, the investigations did not provide any evidence that the beta-receptor blockers CHEMICAL and B 24/76 have the potency to prevent isoproterenol from producing heart hypertrophy. | NO-RELATIONSHIP |
| Comparison of the effect of oxitropium bromide and of slow-release CHEMICAL on nocturnal asthma. The effects of a new inhaled antimuscarinic drug, oxitropium bromide, and of a slow-release CHEMICAL preparation upon nocturnal asthma were compared in a placebo-controlled double-blind study. Two samples were studied: 12 patients received oxitropium at 600 micrograms (6 subjects) or at 400 micrograms t.i.d. (6 subjects) whereas 11 received CHEMICAL at 300 mg b.i.d. Morning dipping, assessed by the fall in peak flow overnight, was significantly reduced in the periods when either active drug was taken, whereas no difference was noticed during the placebo administration. No significant difference was noticed between results obtained with either active drug, as well as with either dosage of oxitropium. No subject reported side effects of oxitropium, as compared to three subjects reporting nausea, vomiting and DISEASE after CHEMICAL. Oxitropium proves to be a valuable alternative to CHEMICAL in nocturnal asthma, since it is equally potent, safer and does not require the titration of dosage. | CHEMICAL-INDUCED-DISEASE |
| Comparison of the effect of oxitropium bromide and of slow-release CHEMICAL on nocturnal asthma. The effects of a new inhaled antimuscarinic drug, oxitropium bromide, and of a slow-release CHEMICAL preparation upon nocturnal asthma were compared in a placebo-controlled double-blind study. Two samples were studied: 12 patients received oxitropium at 600 micrograms (6 subjects) or at 400 micrograms t.i.d. (6 subjects) whereas 11 received CHEMICAL at 300 mg b.i.d. Morning dipping, assessed by the fall in peak flow overnight, was significantly reduced in the periods when either active drug was taken, whereas no difference was noticed during the placebo administration. No significant difference was noticed between results obtained with either active drug, as well as with either dosage of oxitropium. No subject reported side effects of oxitropium, as compared to three subjects reporting DISEASE, vomiting and tremors after CHEMICAL. Oxitropium proves to be a valuable alternative to CHEMICAL in nocturnal asthma, since it is equally potent, safer and does not require the titration of dosage. | CHEMICAL-INDUCED-DISEASE |
| Comparison of the effect of oxitropium bromide and of slow-release CHEMICAL on nocturnal asthma. The effects of a new inhaled antimuscarinic drug, oxitropium bromide, and of a slow-release CHEMICAL preparation upon nocturnal asthma were compared in a placebo-controlled double-blind study. Two samples were studied: 12 patients received oxitropium at 600 micrograms (6 subjects) or at 400 micrograms t.i.d. (6 subjects) whereas 11 received CHEMICAL at 300 mg b.i.d. Morning dipping, assessed by the fall in peak flow overnight, was significantly reduced in the periods when either active drug was taken, whereas no difference was noticed during the placebo administration. No significant difference was noticed between results obtained with either active drug, as well as with either dosage of oxitropium. No subject reported side effects of oxitropium, as compared to three subjects reporting nausea, DISEASE and tremors after CHEMICAL. Oxitropium proves to be a valuable alternative to CHEMICAL in nocturnal asthma, since it is equally potent, safer and does not require the titration of dosage. | CHEMICAL-INDUCED-DISEASE |
| Comparison of the effect of CHEMICAL and of slow-release theophylline on nocturnal DISEASE. The effects of a new inhaled antimuscarinic drug, CHEMICAL, and of a slow-release theophylline preparation upon nocturnal DISEASE were compared in a placebo-controlled double-blind study. Two samples were studied: 12 patients received CHEMICAL at 600 micrograms (6 subjects) or at 400 micrograms t.i.d. (6 subjects) whereas 11 received theophylline at 300 mg b.i.d. Morning dipping, assessed by the fall in peak flow overnight, was significantly reduced in the periods when either active drug was taken, whereas no difference was noticed during the placebo administration. No significant difference was noticed between results obtained with either active drug, as well as with either dosage of CHEMICAL. No subject reported side effects of CHEMICAL, as compared to three subjects reporting nausea, vomiting and tremors after theophylline. CHEMICAL proves to be a valuable alternative to theophylline in nocturnal DISEASE, since it is equally potent, safer and does not require the titration of dosage. | NO-RELATIONSHIP |
| CHEMICAL DISEASE. A case of oral CHEMICAL DISEASE is described, and the terminology, occurrence, clinical manifestations, pathogenesis, prevention, and treatment of DISEASE are reviewed. Emergency physicians should be aware of oral CHEMICAL DISEASE in order to prevent its occurrence by prescribing the antibiotic judiciously and knowledgeably and to offer optimal medical therapy once this life-threatening reaction has begun. | CHEMICAL-INDUCED-DISEASE |
| Reversible CHEMICAL-induced DISEASE: a case report. Reversible CHEMICAL-induced DISEASE was documented in a 21-year-old man with epilepsy who had a 3-year history of insidious progressive decline in global cognitive abilities documented by serial neuropsychological studies. Repeat neuropsychological testing 7 weeks after discontinuation of the drug revealed dramatic improvement in IQ, memory, naming, and other tasks commensurate with clinical recovery in his intellectual capacity. Possible pathophysiological mechanisms which may have been operative in this case include: a direct central nervous system (CNS) toxic effect of CHEMICAL; a paradoxical epileptogenic effect secondary to the drug; and an indirect CNS toxic effect mediated through CHEMICAL-induced hyperammonemia. | CHEMICAL-INDUCED-DISEASE |
| Reversible CHEMICAL-induced dementia: a case report. Reversible CHEMICAL-induced dementia was documented in a 21-year-old man with epilepsy who had a 3-year history of insidious progressive decline in global cognitive abilities documented by serial neuropsychological studies. Repeat neuropsychological testing 7 weeks after discontinuation of the drug revealed dramatic improvement in IQ, memory, naming, and other tasks commensurate with clinical recovery in his intellectual capacity. Possible pathophysiological mechanisms which may have been operative in this case include: a direct central nervous system (CNS) toxic effect of CHEMICAL; a paradoxical epileptogenic effect secondary to the drug; and an indirect CNS toxic effect mediated through CHEMICAL-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Reversal of CHEMICAL-induced DISEASE of passive avoidance by pre- and post-training naloxone. In a series of five experiments, the modulating role of naloxone on a CHEMICAL-induced retention deficit in a passive avoidance paradigm was investigated in mice. CHEMICAL, but not methyl scopolamine (1 and 3 mg/kg), induced an DISEASE as measured by latency and duration parameters. Naloxone (0.3, 1, 3, and 10 mg/kg) injected prior to training attenuated the retention deficit with a peak of activity at 3 mg/kg. The effect of naloxone could be antagonized with morphine (1, 3, and 10 mg/kg), demonstrating the opioid specificity of the naloxone effect. Post-training administration of naloxone (3 mg/kg) as a single or as a split dose also attenuated the CHEMICAL-induced DISEASE. Control experiments indicated that neither an increase in pain sensitivity (pre-training naloxone) nor an induced aversive state (post-training naloxone) appear to be responsible for the influence of naloxone on the CHEMICAL-induced retention deficit. These results extend previous findings implicating a cholinergic-opioid interaction in memory processes. A possible mechanism for this interaction involving the septo-hippocampal cholinergic pathway is discussed. | CHEMICAL-INDUCED-DISEASE |
| Reversal of scopolamine-induced amnesia of passive avoidance by pre- and post-training naloxone. In a series of five experiments, the modulating role of naloxone on a scopolamine-induced retention deficit in a passive avoidance paradigm was investigated in mice. Scopolamine, but not CHEMICAL (1 and 3 mg/kg), induced an amnesia as measured by latency and duration parameters. Naloxone (0.3, 1, 3, and 10 mg/kg) injected prior to training attenuated the retention deficit with a peak of activity at 3 mg/kg. The effect of naloxone could be antagonized with morphine (1, 3, and 10 mg/kg), demonstrating the opioid specificity of the naloxone effect. Post-training administration of naloxone (3 mg/kg) as a single or as a split dose also attenuated the scopolamine-induced amnesia. Control experiments indicated that neither an increase in DISEASE sensitivity (pre-training naloxone) nor an induced aversive state (post-training naloxone) appear to be responsible for the influence of naloxone on the scopolamine-induced retention deficit. These results extend previous findings implicating a cholinergic-opioid interaction in memory processes. A possible mechanism for this interaction involving the septo-hippocampal cholinergic pathway is discussed. | NO-RELATIONSHIP |
| Reversal of scopolamine-induced amnesia of passive avoidance by pre- and post-training CHEMICAL. In a series of five experiments, the modulating role of CHEMICAL on a scopolamine-induced retention deficit in a passive avoidance paradigm was investigated in mice. Scopolamine, but not methyl scopolamine (1 and 3 mg/kg), induced an amnesia as measured by latency and duration parameters. CHEMICAL (0.3, 1, 3, and 10 mg/kg) injected prior to training attenuated the retention deficit with a peak of activity at 3 mg/kg. The effect of CHEMICAL could be antagonized with morphine (1, 3, and 10 mg/kg), demonstrating the opioid specificity of the CHEMICAL effect. Post-training administration of CHEMICAL (3 mg/kg) as a single or as a split dose also attenuated the scopolamine-induced amnesia. Control experiments indicated that neither an increase in DISEASE sensitivity (pre-training CHEMICAL) nor an induced aversive state (post-training CHEMICAL) appear to be responsible for the influence of CHEMICAL on the scopolamine-induced retention deficit. These results extend previous findings implicating a cholinergic-opioid interaction in memory processes. A possible mechanism for this interaction involving the septo-hippocampal cholinergic pathway is discussed. | NO-RELATIONSHIP |
| Reversal of scopolamine-induced amnesia of passive avoidance by pre- and post-training CHEMICAL. In a series of five experiments, the modulating role of CHEMICAL on a scopolamine-induced DISEASE in a passive avoidance paradigm was investigated in mice. Scopolamine, but not methyl scopolamine (1 and 3 mg/kg), induced an amnesia as measured by latency and duration parameters. CHEMICAL (0.3, 1, 3, and 10 mg/kg) injected prior to training attenuated the DISEASE with a peak of activity at 3 mg/kg. The effect of CHEMICAL could be antagonized with morphine (1, 3, and 10 mg/kg), demonstrating the opioid specificity of the CHEMICAL effect. Post-training administration of CHEMICAL (3 mg/kg) as a single or as a split dose also attenuated the scopolamine-induced amnesia. Control experiments indicated that neither an increase in pain sensitivity (pre-training CHEMICAL) nor an induced aversive state (post-training CHEMICAL) appear to be responsible for the influence of CHEMICAL on the scopolamine-induced DISEASE. These results extend previous findings implicating a cholinergic-opioid interaction in memory processes. A possible mechanism for this interaction involving the septo-hippocampal cholinergic pathway is discussed. | NO-RELATIONSHIP |
| Reversal of scopolamine-induced amnesia of passive avoidance by pre- and post-training naloxone. In a series of five experiments, the modulating role of naloxone on a scopolamine-induced DISEASE in a passive avoidance paradigm was investigated in mice. Scopolamine, but not methyl scopolamine (1 and 3 mg/kg), induced an amnesia as measured by latency and duration parameters. Naloxone (0.3, 1, 3, and 10 mg/kg) injected prior to training attenuated the DISEASE with a peak of activity at 3 mg/kg. The effect of naloxone could be antagonized with CHEMICAL (1, 3, and 10 mg/kg), demonstrating the opioid specificity of the naloxone effect. Post-training administration of naloxone (3 mg/kg) as a single or as a split dose also attenuated the scopolamine-induced amnesia. Control experiments indicated that neither an increase in pain sensitivity (pre-training naloxone) nor an induced aversive state (post-training naloxone) appear to be responsible for the influence of naloxone on the scopolamine-induced DISEASE. These results extend previous findings implicating a cholinergic-opioid interaction in memory processes. A possible mechanism for this interaction involving the septo-hippocampal cholinergic pathway is discussed. | CHEMICAL-INDUCED-DISEASE |
| Reversal of scopolamine-induced amnesia of passive avoidance by pre- and post-training naloxone. In a series of five experiments, the modulating role of naloxone on a scopolamine-induced DISEASE in a passive avoidance paradigm was investigated in mice. Scopolamine, but not CHEMICAL (1 and 3 mg/kg), induced an amnesia as measured by latency and duration parameters. Naloxone (0.3, 1, 3, and 10 mg/kg) injected prior to training attenuated the DISEASE with a peak of activity at 3 mg/kg. The effect of naloxone could be antagonized with morphine (1, 3, and 10 mg/kg), demonstrating the opioid specificity of the naloxone effect. Post-training administration of naloxone (3 mg/kg) as a single or as a split dose also attenuated the scopolamine-induced amnesia. Control experiments indicated that neither an increase in pain sensitivity (pre-training naloxone) nor an induced aversive state (post-training naloxone) appear to be responsible for the influence of naloxone on the scopolamine-induced DISEASE. These results extend previous findings implicating a cholinergic-opioid interaction in memory processes. A possible mechanism for this interaction involving the septo-hippocampal cholinergic pathway is discussed. | CHEMICAL-INDUCED-DISEASE |
| Reversal of scopolamine-induced amnesia of passive avoidance by pre- and post-training naloxone. In a series of five experiments, the modulating role of naloxone on a scopolamine-induced retention deficit in a passive avoidance paradigm was investigated in mice. Scopolamine, but not methyl scopolamine (1 and 3 mg/kg), induced an amnesia as measured by latency and duration parameters. Naloxone (0.3, 1, 3, and 10 mg/kg) injected prior to training attenuated the retention deficit with a peak of activity at 3 mg/kg. The effect of naloxone could be antagonized with CHEMICAL (1, 3, and 10 mg/kg), demonstrating the opioid specificity of the naloxone effect. Post-training administration of naloxone (3 mg/kg) as a single or as a split dose also attenuated the scopolamine-induced amnesia. Control experiments indicated that neither an increase in DISEASE sensitivity (pre-training naloxone) nor an induced aversive state (post-training naloxone) appear to be responsible for the influence of naloxone on the scopolamine-induced retention deficit. These results extend previous findings implicating a cholinergic-opioid interaction in memory processes. A possible mechanism for this interaction involving the septo-hippocampal cholinergic pathway is discussed. | NO-RELATIONSHIP |
| Electron microscopic investigations of the CHEMICAL-induced DISEASE of the rat and their prevention by mesna. Fully developed CHEMICAL-induced cystitis is characterized by nearly complete detachment of the urothelium, severe submucosal edema owing to damage to the microvascular bed and focal muscle necroses. The initial response to the primary attack by the CHEMICAL metabolites seems to be fragmentation of the luminal membrane. This damages the cellular barrier against the hypertonic urine. Subsequent breaks in the lateral cell membranes of the superficial cells and in all the plasma membranes of the intermediate and basal cells, intercellular and intracellular edema and disintegration of the desmosomes and hemidesmosomes lead to progressive degeneration and detachment of the epithelial cells with exposure and splitting of the basal membrane. The morphological changes of the endothelial cells, which become more pronounced in the later stages of the experiment, the involvement of blood vessels regardless of their diameter and the location-dependent extent of the damage indicate a direct type of damage which is preceded by a mediator-induced increase in permeability, the morphological correlate of which is the formation of gaps in the interendothelial cell connections on the venules. These changes can be effectively prevented by mesna. The only sign of a possible involvement is the increase in the number of specific granules with a presumed lysosomal function in the superficial cells. | CHEMICAL-INDUCED-DISEASE |
| Electron microscopic investigations of the cyclophosphamide-induced lesions of the urinary bladder of the rat and their prevention by CHEMICAL. Fully developed cyclophosphamide-induced cystitis is characterized by nearly complete detachment of the urothelium, severe submucosal DISEASE owing to damage to the microvascular bed and focal muscle necroses. The initial response to the primary attack by the cyclophosphamide metabolites seems to be fragmentation of the luminal membrane. This damages the cellular barrier against the hypertonic urine. Subsequent breaks in the lateral cell membranes of the superficial cells and in all the plasma membranes of the intermediate and basal cells, intercellular and intracellular DISEASE and disintegration of the desmosomes and hemidesmosomes lead to progressive degeneration and detachment of the epithelial cells with exposure and splitting of the basal membrane. The morphological changes of the endothelial cells, which become more pronounced in the later stages of the experiment, the involvement of blood vessels regardless of their diameter and the location-dependent extent of the damage indicate a direct type of damage which is preceded by a mediator-induced increase in permeability, the morphological correlate of which is the formation of gaps in the interendothelial cell connections on the venules. These changes can be effectively prevented by CHEMICAL. The only sign of a possible involvement is the increase in the number of specific granules with a presumed lysosomal function in the superficial cells. | NO-RELATIONSHIP |
| Electron microscopic investigations of the cyclophosphamide-induced lesions of the urinary bladder of the rat and their prevention by CHEMICAL. Fully developed cyclophosphamide-induced DISEASE is characterized by nearly complete detachment of the urothelium, severe submucosal edema owing to damage to the microvascular bed and focal muscle necroses. The initial response to the primary attack by the cyclophosphamide metabolites seems to be fragmentation of the luminal membrane. This damages the cellular barrier against the hypertonic urine. Subsequent breaks in the lateral cell membranes of the superficial cells and in all the plasma membranes of the intermediate and basal cells, intercellular and intracellular edema and disintegration of the desmosomes and hemidesmosomes lead to progressive degeneration and detachment of the epithelial cells with exposure and splitting of the basal membrane. The morphological changes of the endothelial cells, which become more pronounced in the later stages of the experiment, the involvement of blood vessels regardless of their diameter and the location-dependent extent of the damage indicate a direct type of damage which is preceded by a mediator-induced increase in permeability, the morphological correlate of which is the formation of gaps in the interendothelial cell connections on the venules. These changes can be effectively prevented by CHEMICAL. The only sign of a possible involvement is the increase in the number of specific granules with a presumed lysosomal function in the superficial cells. | NO-RELATIONSHIP |
| Electron microscopic investigations of the cyclophosphamide-induced lesions of the urinary bladder of the rat and their prevention by CHEMICAL. Fully developed cyclophosphamide-induced cystitis is characterized by nearly complete detachment of the urothelium, severe submucosal edema owing to damage to the microvascular bed and focal muscle DISEASE. The initial response to the primary attack by the cyclophosphamide metabolites seems to be fragmentation of the luminal membrane. This damages the cellular barrier against the hypertonic urine. Subsequent breaks in the lateral cell membranes of the superficial cells and in all the plasma membranes of the intermediate and basal cells, intercellular and intracellular edema and disintegration of the desmosomes and hemidesmosomes lead to progressive degeneration and detachment of the epithelial cells with exposure and splitting of the basal membrane. The morphological changes of the endothelial cells, which become more pronounced in the later stages of the experiment, the involvement of blood vessels regardless of their diameter and the location-dependent extent of the damage indicate a direct type of damage which is preceded by a mediator-induced increase in permeability, the morphological correlate of which is the formation of gaps in the interendothelial cell connections on the venules. These changes can be effectively prevented by CHEMICAL. The only sign of a possible involvement is the increase in the number of specific granules with a presumed lysosomal function in the superficial cells. | NO-RELATIONSHIP |
| Electron microscopic investigations of the cyclophosphamide-induced lesions of the urinary bladder of the rat and their prevention by mesna. Fully developed cyclophosphamide-induced cystitis is characterized by nearly complete detachment of the urothelium, severe submucosal edema owing to damage to the microvascular bed and focal muscle DISEASE. The initial response to the primary attack by the cyclophosphamide metabolites seems to be fragmentation of the CHEMICAL membrane. This damages the cellular barrier against the hypertonic urine. Subsequent breaks in the lateral cell membranes of the superficial cells and in all the plasma membranes of the intermediate and basal cells, intercellular and intracellular edema and disintegration of the desmosomes and hemidesmosomes lead to progressive degeneration and detachment of the epithelial cells with exposure and splitting of the basal membrane. The morphological changes of the endothelial cells, which become more pronounced in the later stages of the experiment, the involvement of blood vessels regardless of their diameter and the location-dependent extent of the damage indicate a direct type of damage which is preceded by a mediator-induced increase in permeability, the morphological correlate of which is the formation of gaps in the interendothelial cell connections on the venules. These changes can be effectively prevented by mesna. The only sign of a possible involvement is the increase in the number of specific granules with a presumed lysosomal function in the superficial cells. | NO-RELATIONSHIP |
| Electron microscopic investigations of the cyclophosphamide-induced lesions of the urinary bladder of the rat and their prevention by mesna. Fully developed cyclophosphamide-induced DISEASE is characterized by nearly complete detachment of the urothelium, severe submucosal edema owing to damage to the microvascular bed and focal muscle necroses. The initial response to the primary attack by the cyclophosphamide metabolites seems to be fragmentation of the CHEMICAL membrane. This damages the cellular barrier against the hypertonic urine. Subsequent breaks in the lateral cell membranes of the superficial cells and in all the plasma membranes of the intermediate and basal cells, intercellular and intracellular edema and disintegration of the desmosomes and hemidesmosomes lead to progressive degeneration and detachment of the epithelial cells with exposure and splitting of the basal membrane. The morphological changes of the endothelial cells, which become more pronounced in the later stages of the experiment, the involvement of blood vessels regardless of their diameter and the location-dependent extent of the damage indicate a direct type of damage which is preceded by a mediator-induced increase in permeability, the morphological correlate of which is the formation of gaps in the interendothelial cell connections on the venules. These changes can be effectively prevented by mesna. The only sign of a possible involvement is the increase in the number of specific granules with a presumed lysosomal function in the superficial cells. | NO-RELATIONSHIP |
| Electron microscopic investigations of the cyclophosphamide-induced lesions of the urinary bladder of the rat and their prevention by mesna. Fully developed cyclophosphamide-induced cystitis is characterized by nearly complete detachment of the urothelium, severe submucosal DISEASE owing to damage to the microvascular bed and focal muscle necroses. The initial response to the primary attack by the cyclophosphamide metabolites seems to be fragmentation of the CHEMICAL membrane. This damages the cellular barrier against the hypertonic urine. Subsequent breaks in the lateral cell membranes of the superficial cells and in all the plasma membranes of the intermediate and basal cells, intercellular and intracellular DISEASE and disintegration of the desmosomes and hemidesmosomes lead to progressive degeneration and detachment of the epithelial cells with exposure and splitting of the basal membrane. The morphological changes of the endothelial cells, which become more pronounced in the later stages of the experiment, the involvement of blood vessels regardless of their diameter and the location-dependent extent of the damage indicate a direct type of damage which is preceded by a mediator-induced increase in permeability, the morphological correlate of which is the formation of gaps in the interendothelial cell connections on the venules. These changes can be effectively prevented by mesna. The only sign of a possible involvement is the increase in the number of specific granules with a presumed lysosomal function in the superficial cells. | NO-RELATIONSHIP |
| Increase in intragastric pressure during CHEMICAL-induced DISEASE in children: inhibition by alfentanil. Changes in intragastric pressure after the administration of CHEMICAL 1.5 mg kg-1 i.v. were studied in 32 children (mean age 6.9 yr) pretreated with either physiological saline or alfentanil 50 micrograms kg-1. Anaesthesia was induced with thiopentone 5 mg kg-1. The incidence and intensity of DISEASE caused by CHEMICAL were significantly greater in the control than in the alfentanil group. The intragastric pressure during DISEASE was significantly higher in the control group (16 +/- 0.7 (SEM) cm H2O) than in the alfentanil group (7.7 +/- 1.5 (SEM) cm H2O). The increase in intragastric pressure was directly related to the intensity of DISEASE (regression line: y = 0.5 + 4.78x with r of 0.78). It is concluded that intragastric pressure increases significantly during DISEASE caused by CHEMICAL in healthy children. Alfentanil 50 micrograms kg-1 effectively inhibits the incidence and intensity of CHEMICAL-induced DISEASE; moreover, intragastric pressure remains at its control value. | CHEMICAL-INDUCED-DISEASE |
| Acute insulin treatment normalizes the resistance to the cardiotoxic effect of CHEMICAL in streptozotocin diabetic rats. A morphometric study of CHEMICAL induced myocardial DISEASE. The acute effect of insulin treatment on the earlier reported protective effect of streptozotocin diabetes against the cardiotoxic effect of high doses of CHEMICAL (CHEMICAL) was investigated in rats. Thirty to 135 min after the injection of crystalline insulin, CHEMICAL was given subcutaneously and when CHEMICAL induced DISEASE in the myocardium was morphometrically analyzed 7 days later, a highly significant correlation (r = 0.83, 2 p = 0.006) to the slope of the fall in blood glucose after insulin treatment appeared. The myocardial content of catecholamines was estimated in these 8 day diabetic rats. The norepinephrine content was significantly increased while epinephrine remained unchanged. An enhanced sympathetic nervous system activity with a consequent down regulation of the myocardial beta-adrenergic receptors could, therefore, explain this catecholamine resistance. The rapid reversion after insulin treatment excludes the possibility that streptozotocin in itself causes the CHEMICAL resistance and points towards a direct insulin effect on myocardial catecholamine sensitivity in diabetic rats. The phenomenon described might elucidate pathogenetic mechanisms behind toxic myocardial cell degeneration and may possibly have relevance for acute cardiovascular complications in diabetic patients. | CHEMICAL-INDUCED-DISEASE |
| Acute insulin treatment normalizes the resistance to the cardiotoxic effect of isoproterenol in CHEMICAL DISEASE rats. A morphometric study of isoproterenol induced myocardial fibrosis. The acute effect of insulin treatment on the earlier reported protective effect of CHEMICAL DISEASE against the cardiotoxic effect of high doses of isoproterenol (ISO) was investigated in rats. Thirty to 135 min after the injection of crystalline insulin, ISO was given subcutaneously and when ISO induced fibrosis in the myocardium was morphometrically analyzed 7 days later, a highly significant correlation (r = 0.83, 2 p = 0.006) to the slope of the fall in blood glucose after insulin treatment appeared. The myocardial content of catecholamines was estimated in these 8 day DISEASE rats. The norepinephrine content was significantly increased while epinephrine remained unchanged. An enhanced sympathetic nervous system activity with a consequent down regulation of the myocardial beta-adrenergic receptors could, therefore, explain this catecholamine resistance. The rapid reversion after insulin treatment excludes the possibility that CHEMICAL in itself causes the ISO resistance and points towards a direct insulin effect on myocardial catecholamine sensitivity in DISEASE rats. The phenomenon described might elucidate pathogenetic mechanisms behind toxic myocardial cell degeneration and may possibly have relevance for acute cardiovascular complications in DISEASE patients. | NO-RELATIONSHIP |
| Acute insulin treatment normalizes the resistance to the DISEASE effect of isoproterenol in streptozotocin diabetic rats. A morphometric study of isoproterenol induced myocardial fibrosis. The acute effect of insulin treatment on the earlier reported protective effect of streptozotocin diabetes against the DISEASE effect of high doses of isoproterenol (ISO) was investigated in rats. Thirty to 135 min after the injection of crystalline insulin, ISO was given subcutaneously and when ISO induced fibrosis in the myocardium was morphometrically analyzed 7 days later, a highly significant correlation (r = 0.83, 2 p = 0.006) to the slope of the fall in blood glucose after insulin treatment appeared. The myocardial content of catecholamines was estimated in these 8 day diabetic rats. The CHEMICAL content was significantly increased while epinephrine remained unchanged. An enhanced sympathetic nervous system activity with a consequent down regulation of the myocardial beta-adrenergic receptors could, therefore, explain this catecholamine resistance. The rapid reversion after insulin treatment excludes the possibility that streptozotocin in itself causes the ISO resistance and points towards a direct insulin effect on myocardial catecholamine sensitivity in diabetic rats. The phenomenon described might elucidate pathogenetic mechanisms behind toxic myocardial cell degeneration and may possibly have relevance for acute cardiovascular complications in diabetic patients. | NO-RELATIONSHIP |
| Acute insulin treatment normalizes the resistance to the DISEASE effect of isoproterenol in streptozotocin diabetic rats. A morphometric study of isoproterenol induced myocardial fibrosis. The acute effect of insulin treatment on the earlier reported protective effect of streptozotocin diabetes against the DISEASE effect of high doses of isoproterenol (ISO) was investigated in rats. Thirty to 135 min after the injection of crystalline insulin, ISO was given subcutaneously and when ISO induced fibrosis in the myocardium was morphometrically analyzed 7 days later, a highly significant correlation (r = 0.83, 2 p = 0.006) to the slope of the fall in blood glucose after insulin treatment appeared. The myocardial content of CHEMICAL was estimated in these 8 day diabetic rats. The norepinephrine content was significantly increased while epinephrine remained unchanged. An enhanced sympathetic nervous system activity with a consequent down regulation of the myocardial beta-adrenergic receptors could, therefore, explain this CHEMICAL resistance. The rapid reversion after insulin treatment excludes the possibility that streptozotocin in itself causes the ISO resistance and points towards a direct insulin effect on myocardial CHEMICAL sensitivity in diabetic rats. The phenomenon described might elucidate pathogenetic mechanisms behind toxic myocardial cell degeneration and may possibly have relevance for acute cardiovascular complications in diabetic patients. | NO-RELATIONSHIP |
| Acute insulin treatment normalizes the resistance to the DISEASE effect of isoproterenol in streptozotocin diabetic rats. A morphometric study of isoproterenol induced myocardial fibrosis. The acute effect of insulin treatment on the earlier reported protective effect of streptozotocin diabetes against the DISEASE effect of high doses of isoproterenol (ISO) was investigated in rats. Thirty to 135 min after the injection of crystalline insulin, ISO was given subcutaneously and when ISO induced fibrosis in the myocardium was morphometrically analyzed 7 days later, a highly significant correlation (r = 0.83, 2 p = 0.006) to the slope of the fall in blood glucose after insulin treatment appeared. The myocardial content of catecholamines was estimated in these 8 day diabetic rats. The norepinephrine content was significantly increased while CHEMICAL remained unchanged. An enhanced sympathetic nervous system activity with a consequent down regulation of the myocardial beta-adrenergic receptors could, therefore, explain this catecholamine resistance. The rapid reversion after insulin treatment excludes the possibility that streptozotocin in itself causes the ISO resistance and points towards a direct insulin effect on myocardial catecholamine sensitivity in diabetic rats. The phenomenon described might elucidate pathogenetic mechanisms behind toxic myocardial cell degeneration and may possibly have relevance for acute cardiovascular complications in diabetic patients. | NO-RELATIONSHIP |
| Acute insulin treatment normalizes the resistance to the DISEASE effect of isoproterenol in streptozotocin diabetic rats. A morphometric study of isoproterenol induced myocardial fibrosis. The acute effect of insulin treatment on the earlier reported protective effect of streptozotocin diabetes against the DISEASE effect of high doses of isoproterenol (ISO) was investigated in rats. Thirty to 135 min after the injection of crystalline insulin, ISO was given subcutaneously and when ISO induced fibrosis in the myocardium was morphometrically analyzed 7 days later, a highly significant correlation (r = 0.83, 2 p = 0.006) to the slope of the fall in blood CHEMICAL after insulin treatment appeared. The myocardial content of catecholamines was estimated in these 8 day diabetic rats. The norepinephrine content was significantly increased while epinephrine remained unchanged. An enhanced sympathetic nervous system activity with a consequent down regulation of the myocardial beta-adrenergic receptors could, therefore, explain this catecholamine resistance. The rapid reversion after insulin treatment excludes the possibility that streptozotocin in itself causes the ISO resistance and points towards a direct insulin effect on myocardial catecholamine sensitivity in diabetic rats. The phenomenon described might elucidate pathogenetic mechanisms behind toxic myocardial cell degeneration and may possibly have relevance for acute cardiovascular complications in diabetic patients. | NO-RELATIONSHIP |
| Differential effects of non-steroidal anti-inflammatory drugs on DISEASE produced by pilocarpine in rats. The muscarinic cholinergic agonist pilocarpine induces in rats DISEASE and status epilepticus followed by widespread damage to the forebrain. The present study was designed to investigate the effect of 5 non-steroidal anti-inflammatory drugs, sodium salicylate, CHEMICAL, indomethacin, ibuprofen and mefenamic acid, on DISEASE produced by pilocarpine. Pretreatment of rats with sodium salicylate, ED50 103 mg/kg (60-174), and CHEMICAL, 59 mg/kg (50-70) converted the non-convulsant dose of pilocarpine, 200 mg/kg, to a convulsant one. Indomethacin, 1-10 mg/kg, and ibuprofen, 10-100 mg/kg, failed to modulate DISEASE produced by pilocarpine. Mefenamic acid, 26 (22-30) mg/kg, prevented DISEASE and protected rats from DISEASE-related brain damage induced by pilocarpine, 380 mg/kg. These results indicate that non-steroidal anti-inflammatory drugs differentially modulate the threshold for pilocarpine-induced DISEASE. | NO-RELATIONSHIP |
| Differential effects of non-steroidal anti-inflammatory drugs on DISEASE produced by pilocarpine in rats. The muscarinic cholinergic agonist pilocarpine induces in rats DISEASE and status epilepticus followed by widespread damage to the forebrain. The present study was designed to investigate the effect of 5 non-steroidal anti-inflammatory drugs, CHEMICAL, phenylbutazone, indomethacin, ibuprofen and mefenamic acid, on DISEASE produced by pilocarpine. Pretreatment of rats with CHEMICAL, ED50 103 mg/kg (60-174), and phenylbutazone, 59 mg/kg (50-70) converted the non-convulsant dose of pilocarpine, 200 mg/kg, to a convulsant one. Indomethacin, 1-10 mg/kg, and ibuprofen, 10-100 mg/kg, failed to modulate DISEASE produced by pilocarpine. Mefenamic acid, 26 (22-30) mg/kg, prevented DISEASE and protected rats from DISEASE-related brain damage induced by pilocarpine, 380 mg/kg. These results indicate that non-steroidal anti-inflammatory drugs differentially modulate the threshold for pilocarpine-induced DISEASE. | NO-RELATIONSHIP |
| Differential effects of non-steroidal anti-inflammatory drugs on DISEASE produced by CHEMICAL in rats. The muscarinic cholinergic agonist CHEMICAL induces in rats DISEASE and status epilepticus followed by widespread damage to the forebrain. The present study was designed to investigate the effect of 5 non-steroidal anti-inflammatory drugs, sodium salicylate, phenylbutazone, indomethacin, ibuprofen and mefenamic acid, on DISEASE produced by CHEMICAL. Pretreatment of rats with sodium salicylate, ED50 103 mg/kg (60-174), and phenylbutazone, 59 mg/kg (50-70) converted the non-convulsant dose of CHEMICAL, 200 mg/kg, to a convulsant one. Indomethacin, 1-10 mg/kg, and ibuprofen, 10-100 mg/kg, failed to modulate DISEASE produced by CHEMICAL. Mefenamic acid, 26 (22-30) mg/kg, prevented DISEASE and protected rats from DISEASE-related brain damage induced by CHEMICAL, 380 mg/kg. These results indicate that non-steroidal anti-inflammatory drugs differentially modulate the threshold for CHEMICAL-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Differential effects of non-steroidal anti-inflammatory drugs on seizures produced by CHEMICAL in rats. The muscarinic cholinergic agonist CHEMICAL induces in rats seizures and DISEASE followed by widespread damage to the forebrain. The present study was designed to investigate the effect of 5 non-steroidal anti-inflammatory drugs, sodium salicylate, phenylbutazone, indomethacin, ibuprofen and mefenamic acid, on seizures produced by CHEMICAL. Pretreatment of rats with sodium salicylate, ED50 103 mg/kg (60-174), and phenylbutazone, 59 mg/kg (50-70) converted the non-convulsant dose of CHEMICAL, 200 mg/kg, to a convulsant one. Indomethacin, 1-10 mg/kg, and ibuprofen, 10-100 mg/kg, failed to modulate seizures produced by CHEMICAL. Mefenamic acid, 26 (22-30) mg/kg, prevented seizures and protected rats from seizure-related brain damage induced by CHEMICAL, 380 mg/kg. These results indicate that non-steroidal anti-inflammatory drugs differentially modulate the threshold for CHEMICAL-induced seizures. | CHEMICAL-INDUCED-DISEASE |
| Differential effects of non-steroidal anti-inflammatory drugs on seizures produced by pilocarpine in rats. The muscarinic cholinergic agonist pilocarpine induces in rats seizures and status epilepticus followed by widespread damage to the forebrain. The present study was designed to investigate the effect of 5 non-steroidal anti-inflammatory drugs, sodium salicylate, phenylbutazone, indomethacin, ibuprofen and CHEMICAL, on seizures produced by pilocarpine. Pretreatment of rats with sodium salicylate, ED50 103 mg/kg (60-174), and phenylbutazone, 59 mg/kg (50-70) converted the non-convulsant dose of pilocarpine, 200 mg/kg, to a convulsant one. Indomethacin, 1-10 mg/kg, and ibuprofen, 10-100 mg/kg, failed to modulate seizures produced by pilocarpine. CHEMICAL, 26 (22-30) mg/kg, prevented seizures and protected rats from seizure-related DISEASE induced by pilocarpine, 380 mg/kg. These results indicate that non-steroidal anti-inflammatory drugs differentially modulate the threshold for pilocarpine-induced seizures. | NO-RELATIONSHIP |
| Differential effects of non-steroidal anti-inflammatory drugs on seizures produced by pilocarpine in rats. The muscarinic cholinergic agonist pilocarpine induces in rats seizures and status epilepticus followed by widespread damage to the forebrain. The present study was designed to investigate the effect of 5 non-steroidal anti-inflammatory drugs, sodium salicylate, phenylbutazone, indomethacin, CHEMICAL and mefenamic acid, on seizures produced by pilocarpine. Pretreatment of rats with sodium salicylate, ED50 103 mg/kg (60-174), and phenylbutazone, 59 mg/kg (50-70) converted the non-convulsant dose of pilocarpine, 200 mg/kg, to a convulsant one. Indomethacin, 1-10 mg/kg, and CHEMICAL, 10-100 mg/kg, failed to modulate seizures produced by pilocarpine. Mefenamic acid, 26 (22-30) mg/kg, prevented seizures and protected rats from seizure-related DISEASE induced by pilocarpine, 380 mg/kg. These results indicate that non-steroidal anti-inflammatory drugs differentially modulate the threshold for pilocarpine-induced seizures. | NO-RELATIONSHIP |
| Differential effects of non-steroidal anti-inflammatory drugs on seizures produced by pilocarpine in rats. The muscarinic cholinergic agonist pilocarpine induces in rats seizures and status epilepticus followed by widespread damage to the forebrain. The present study was designed to investigate the effect of 5 non-steroidal anti-inflammatory drugs, sodium salicylate, phenylbutazone, CHEMICAL, ibuprofen and mefenamic acid, on seizures produced by pilocarpine. Pretreatment of rats with sodium salicylate, ED50 103 mg/kg (60-174), and phenylbutazone, 59 mg/kg (50-70) converted the non-convulsant dose of pilocarpine, 200 mg/kg, to a convulsant one. CHEMICAL, 1-10 mg/kg, and ibuprofen, 10-100 mg/kg, failed to modulate seizures produced by pilocarpine. Mefenamic acid, 26 (22-30) mg/kg, prevented seizures and protected rats from seizure-related DISEASE induced by pilocarpine, 380 mg/kg. These results indicate that non-steroidal anti-inflammatory drugs differentially modulate the threshold for pilocarpine-induced seizures. | NO-RELATIONSHIP |
| Acute neurologic dysfunction after high-dose CHEMICAL therapy for malignant glioma. CHEMICAL (CHEMICAL) has been used in the treatment of many solid tumors and hematologic malignancies. When used in high doses and in conjunction with autologous bone marrow transplantation, this agent has activity against several treatment-resistant cancers including malignant glioma. In six of eight patients (75%) who we treated for recurrent or resistant glioma, sudden severe neurologic deterioration occurred. This developed a median of 9 days after initiation of high-dose CHEMICAL therapy. Significant clinical manifestations have included DISEASE, papilledema, somnolence, exacerbation of motor deficits, and sharp increase in seizure activity. These abnormalities resolved rapidly after initiation of high-dose intravenous dexamethasone therapy. In all patients, computerized tomographic (CT) brain scans demonstrated stability in tumor size and peritumor edema when compared with pretransplant scans. This complication appears to represent a significant new toxicity of high-dose CHEMICAL therapy for malignant glioma. | CHEMICAL-INDUCED-DISEASE |
| Acute neurologic dysfunction after high-dose CHEMICAL therapy for malignant glioma. CHEMICAL (CHEMICAL) has been used in the treatment of many solid tumors and hematologic malignancies. When used in high doses and in conjunction with autologous bone marrow transplantation, this agent has activity against several treatment-resistant cancers including malignant glioma. In six of eight patients (75%) who we treated for recurrent or resistant glioma, sudden severe neurologic deterioration occurred. This developed a median of 9 days after initiation of high-dose CHEMICAL therapy. Significant clinical manifestations have included confusion, papilledema, somnolence, exacerbation of motor deficits, and sharp increase in DISEASE activity. These abnormalities resolved rapidly after initiation of high-dose intravenous dexamethasone therapy. In all patients, computerized tomographic (CT) brain scans demonstrated stability in tumor size and peritumor edema when compared with pretransplant scans. This complication appears to represent a significant new toxicity of high-dose CHEMICAL therapy for malignant glioma. | CHEMICAL-INDUCED-DISEASE |
| Acute neurologic dysfunction after high-dose CHEMICAL therapy for malignant glioma. CHEMICAL (CHEMICAL) has been used in the treatment of many solid tumors and hematologic malignancies. When used in high doses and in conjunction with autologous bone marrow transplantation, this agent has activity against several treatment-resistant cancers including malignant glioma. In six of eight patients (75%) who we treated for recurrent or resistant glioma, sudden severe neurologic deterioration occurred. This developed a median of 9 days after initiation of high-dose CHEMICAL therapy. Significant clinical manifestations have included confusion, DISEASE, somnolence, exacerbation of motor deficits, and sharp increase in seizure activity. These abnormalities resolved rapidly after initiation of high-dose intravenous dexamethasone therapy. In all patients, computerized tomographic (CT) brain scans demonstrated stability in tumor size and peritumor edema when compared with pretransplant scans. This complication appears to represent a significant new toxicity of high-dose CHEMICAL therapy for malignant glioma. | CHEMICAL-INDUCED-DISEASE |
| Acute neurologic dysfunction after high-dose etoposide therapy for DISEASE. Etoposide (VP-16-213) has been used in the treatment of many solid tumors and hematologic malignancies. When used in high doses and in conjunction with autologous bone marrow transplantation, this agent has activity against several treatment-resistant cancers including DISEASE. In six of eight patients (75%) who we treated for recurrent or resistant DISEASE, sudden severe neurologic deterioration occurred. This developed a median of 9 days after initiation of high-dose etoposide therapy. Significant clinical manifestations have included confusion, papilledema, somnolence, exacerbation of motor deficits, and sharp increase in seizure activity. These abnormalities resolved rapidly after initiation of high-dose intravenous CHEMICAL therapy. In all patients, computerized tomographic (CT) brain scans demonstrated stability in tumor size and peritumor edema when compared with pretransplant scans. This complication appears to represent a significant new toxicity of high-dose etoposide therapy for DISEASE. | NO-RELATIONSHIP |
| Acute neurologic dysfunction after high-dose etoposide therapy for malignant glioma. Etoposide (VP-16-213) has been used in the treatment of many solid DISEASE and hematologic malignancies. When used in high doses and in conjunction with autologous bone marrow transplantation, this agent has activity against several treatment-resistant DISEASE including malignant glioma. In six of eight patients (75%) who we treated for recurrent or resistant glioma, sudden severe neurologic deterioration occurred. This developed a median of 9 days after initiation of high-dose etoposide therapy. Significant clinical manifestations have included confusion, papilledema, somnolence, exacerbation of motor deficits, and sharp increase in seizure activity. These abnormalities resolved rapidly after initiation of high-dose intravenous CHEMICAL therapy. In all patients, computerized tomographic (CT) brain scans demonstrated stability in DISEASE size and peritumor edema when compared with pretransplant scans. This complication appears to represent a significant new toxicity of high-dose etoposide therapy for malignant glioma. | NO-RELATIONSHIP |
| Acute neurologic dysfunction after high-dose etoposide therapy for malignant glioma. Etoposide (VP-16-213) has been used in the treatment of many solid tumors and hematologic malignancies. When used in high doses and in conjunction with autologous bone marrow transplantation, this agent has activity against several treatment-resistant cancers including malignant glioma. In six of eight patients (75%) who we treated for recurrent or resistant glioma, sudden severe neurologic deterioration occurred. This developed a median of 9 days after initiation of high-dose etoposide therapy. Significant clinical manifestations have included confusion, papilledema, DISEASE, exacerbation of motor deficits, and sharp increase in seizure activity. These abnormalities resolved rapidly after initiation of high-dose intravenous CHEMICAL therapy. In all patients, computerized tomographic (CT) brain scans demonstrated stability in tumor size and peritumor edema when compared with pretransplant scans. This complication appears to represent a significant new toxicity of high-dose etoposide therapy for malignant glioma. | NO-RELATIONSHIP |
| DISEASE after high-dose etoposide therapy for malignant glioma. Etoposide (VP-16-213) has been used in the treatment of many solid tumors and hematologic malignancies. When used in high doses and in conjunction with autologous bone marrow transplantation, this agent has activity against several treatment-resistant cancers including malignant glioma. In six of eight patients (75%) who we treated for recurrent or resistant glioma, sudden severe DISEASE occurred. This developed a median of 9 days after initiation of high-dose etoposide therapy. Significant clinical manifestations have included confusion, papilledema, somnolence, exacerbation of motor deficits, and sharp increase in seizure activity. These abnormalities resolved rapidly after initiation of high-dose intravenous CHEMICAL therapy. In all patients, computerized tomographic (CT) brain scans demonstrated stability in tumor size and peritumor edema when compared with pretransplant scans. This complication appears to represent a significant new toxicity of high-dose etoposide therapy for malignant glioma. | NO-RELATIONSHIP |
| Acute neurologic dysfunction after high-dose etoposide therapy for malignant glioma. Etoposide (VP-16-213) has been used in the treatment of many solid tumors and hematologic malignancies. When used in high doses and in conjunction with autologous bone marrow transplantation, this agent has activity against several treatment-resistant cancers including malignant glioma. In six of eight patients (75%) who we treated for recurrent or resistant glioma, sudden severe neurologic deterioration occurred. This developed a median of 9 days after initiation of high-dose etoposide therapy. Significant clinical manifestations have included confusion, papilledema, somnolence, exacerbation of motor deficits, and sharp increase in seizure activity. These abnormalities resolved rapidly after initiation of high-dose intravenous CHEMICAL therapy. In all patients, computerized tomographic (CT) brain scans demonstrated stability in tumor size and peritumor DISEASE when compared with pretransplant scans. This complication appears to represent a significant new toxicity of high-dose etoposide therapy for malignant glioma. | NO-RELATIONSHIP |
| Acute neurologic dysfunction after high-dose etoposide therapy for malignant glioma. Etoposide (VP-16-213) has been used in the treatment of many solid tumors and hematologic malignancies. When used in high doses and in conjunction with autologous bone marrow transplantation, this agent has activity against several treatment-resistant cancers including malignant glioma. In six of eight patients (75%) who we treated for recurrent or resistant glioma, sudden severe neurologic deterioration occurred. This developed a median of 9 days after initiation of high-dose etoposide therapy. Significant clinical manifestations have included confusion, papilledema, somnolence, exacerbation of motor deficits, and sharp increase in seizure activity. These abnormalities resolved rapidly after initiation of high-dose intravenous CHEMICAL therapy. In all patients, computerized tomographic (CT) brain scans demonstrated stability in tumor size and peritumor edema when compared with pretransplant scans. This complication appears to represent a significant new DISEASE of high-dose etoposide therapy for malignant glioma. | NO-RELATIONSHIP |
| Acute neurologic dysfunction after high-dose etoposide therapy for malignant glioma. Etoposide (VP-16-213) has been used in the treatment of many solid tumors and hematologic malignancies. When used in high doses and in conjunction with autologous bone marrow transplantation, this agent has activity against several treatment-resistant cancers including malignant glioma. In six of eight patients (75%) who we treated for recurrent or resistant glioma, sudden severe neurologic deterioration occurred. This developed a median of 9 days after initiation of high-dose etoposide therapy. Significant clinical manifestations have included confusion, papilledema, somnolence, exacerbation of DISEASE, and sharp increase in seizure activity. These abnormalities resolved rapidly after initiation of high-dose intravenous CHEMICAL therapy. In all patients, computerized tomographic (CT) brain scans demonstrated stability in tumor size and peritumor edema when compared with pretransplant scans. This complication appears to represent a significant new toxicity of high-dose etoposide therapy for malignant glioma. | NO-RELATIONSHIP |
| Acute neurologic dysfunction after high-dose etoposide therapy for malignant glioma. Etoposide (VP-16-213) has been used in the treatment of many solid tumors and DISEASE. When used in high doses and in conjunction with autologous bone marrow transplantation, this agent has activity against several treatment-resistant cancers including malignant glioma. In six of eight patients (75%) who we treated for recurrent or resistant glioma, sudden severe neurologic deterioration occurred. This developed a median of 9 days after initiation of high-dose etoposide therapy. Significant clinical manifestations have included confusion, papilledema, somnolence, exacerbation of motor deficits, and sharp increase in seizure activity. These abnormalities resolved rapidly after initiation of high-dose intravenous CHEMICAL therapy. In all patients, computerized tomographic (CT) brain scans demonstrated stability in tumor size and peritumor edema when compared with pretransplant scans. This complication appears to represent a significant new toxicity of high-dose etoposide therapy for malignant glioma. | NO-RELATIONSHIP |
| Progressive bile duct injury after CHEMICAL administration. A 27-yr-old man developed jaundice 2 wk after exposure to CHEMICAL. Cholestasis persisted for 3 yr, at which time a liver transplant was performed. Two liver biopsy specimens and the hepatectomy specimen were remarkable for almost complete disappearance of interlobular bile ducts. Prominent fibrosis and hepatocellular regeneration were also present; however, the lobular architecture was preserved. This case represents an example of "idiosyncratic" DISEASE in which the primary target of injury is the bile duct. An autoimmune pathogenesis of the bile duct destruction is suggested. | CHEMICAL-INDUCED-DISEASE |
| Progressive bile duct injury after CHEMICAL administration. A 27-yr-old man developed jaundice 2 wk after exposure to CHEMICAL. DISEASE persisted for 3 yr, at which time a liver transplant was performed. Two liver biopsy specimens and the hepatectomy specimen were remarkable for almost complete disappearance of interlobular bile ducts. Prominent fibrosis and hepatocellular regeneration were also present; however, the lobular architecture was preserved. This case represents an example of "idiosyncratic" drug-induced liver damage in which the primary target of injury is the bile duct. An autoimmune pathogenesis of the bile duct destruction is suggested. | CHEMICAL-INDUCED-DISEASE |
| Differential effects of 1,4-dihydropyridine CHEMICAL: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of CHEMICAL for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of CHEMICAL parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine CHEMICAL are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of CHEMICAL have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine CHEMICAL are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, DISEASE, and dizziness being the more common adverse effects. | CHEMICAL-INDUCED-DISEASE |
| Differential effects of 1,4-dihydropyridine CHEMICAL: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of CHEMICAL for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of CHEMICAL parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine CHEMICAL are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of CHEMICAL have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine CHEMICAL are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and DISEASE being the more common adverse effects. | CHEMICAL-INDUCED-DISEASE |
| Differential effects of 1,4-dihydropyridine CHEMICAL: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of CHEMICAL for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of CHEMICAL parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine CHEMICAL are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of CHEMICAL have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine CHEMICAL are usually well tolerated, with headache, facial flushing, palpitations, DISEASE, nausea, anorexia, and dizziness being the more common adverse effects. | CHEMICAL-INDUCED-DISEASE |
| Differential effects of 1,4-dihydropyridine CHEMICAL: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of CHEMICAL for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of CHEMICAL parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine CHEMICAL are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of CHEMICAL have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine CHEMICAL are usually well tolerated, with DISEASE, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | CHEMICAL-INDUCED-DISEASE |
| Differential effects of 1,4-dihydropyridine CHEMICAL: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of CHEMICAL for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of CHEMICAL parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine CHEMICAL are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of CHEMICAL have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine CHEMICAL are usually well tolerated, with headache, facial flushing, palpitations, edema, DISEASE, anorexia, and dizziness being the more common adverse effects. | CHEMICAL-INDUCED-DISEASE |
| Differential effects of 1,4-dihydropyridine CHEMICAL: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of CHEMICAL for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of CHEMICAL parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine CHEMICAL are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of CHEMICAL have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine CHEMICAL are usually well tolerated, with headache, facial DISEASE, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | CHEMICAL-INDUCED-DISEASE |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes CHEMICAL potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, DISEASE, edema, nausea, anorexia, and dizziness being the more common adverse effects. | CHEMICAL-INDUCED-DISEASE |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of DISEASE has stimulated research into the use of calcium channel blocking agents for treatment of a variety of DISEASE. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and CHEMICAL, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of CHEMICAL in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls DISEASE and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in DISEASE. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, CHEMICAL controls DISEASE and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in DISEASE. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and CHEMICAL offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of CHEMICAL have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of DISEASE, migraine headache, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes CHEMICAL potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and DISEASE. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls DISEASE and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and CHEMICAL offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of CHEMICAL have led to the investigation of this agent for use in DISEASE. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls DISEASE and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with CHEMICAL and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in DISEASE. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and CHEMICAL, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls DISEASE and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in DISEASE. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, CHEMICAL controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, DISEASE, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| Differential effects of CHEMICAL calcium channel blockers: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the CHEMICAL calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first CHEMICAL available for use in the United States, nifedipine controls DISEASE and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in DISEASE. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the CHEMICAL calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of CHEMICAL in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of DISEASE, migraine headache, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of DISEASE has stimulated research into the use of calcium channel blocking agents for treatment of a variety of DISEASE. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to CHEMICAL and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes CHEMICAL potentially useful in the treatment of DISEASE, migraine headache, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with CHEMICAL and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, DISEASE, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with CHEMICAL and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, DISEASE, edema, nausea, anorexia, and dizziness being the more common adverse effects. | CHEMICAL-INDUCED-DISEASE |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and CHEMICAL, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, DISEASE, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of DISEASE has stimulated research into the use of calcium channel blocking agents for treatment of a variety of DISEASE. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with CHEMICAL and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of calcium in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to CHEMICAL and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and DISEASE with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of DISEASE. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and stroke. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| Differential effects of 1,4-dihydropyridine calcium channel blockers: therapeutic implications. Increasing recognition of the importance of CHEMICAL in the pathogenesis of cardiovascular disease has stimulated research into the use of calcium channel blocking agents for treatment of a variety of cardiovascular diseases. The favorable efficacy and tolerability profiles of these agents make them attractive therapeutic modalities. Clinical applications of calcium channel blockers parallel their tissue selectivity. In contrast to verapamil and diltiazem, which are roughly equipotent in their actions on the heart and vascular smooth muscle, the dihydropyridine calcium channel blockers are a group of potent peripheral vasodilator agents that exert minimal electrophysiologic effects on cardiac nodal or conduction tissue. As the first dihydropyridine available for use in the United States, nifedipine controls angina and hypertension with minimal depression of cardiac function. Additional members of this group of calcium channel blockers have been studied for a variety of indications for which they may offer advantages over current therapy. Once or twice daily dosage possible with nitrendipine and nisoldipine offers a convenient administration schedule, which encourages patient compliance in long-term therapy of hypertension. The coronary vasodilating properties of nisoldipine have led to the investigation of this agent for use in angina. Selectivity for the cerebrovascular bed makes nimodipine potentially useful in the treatment of subarachnoid hemorrhage, migraine headache, dementia, and DISEASE. In general, the dihydropyridine calcium channel blockers are usually well tolerated, with headache, facial flushing, palpitations, edema, nausea, anorexia, and dizziness being the more common adverse effects. | NO-RELATIONSHIP |
| The enhancement of CHEMICAL nephrosis by the co-administration of protamine. An experimental model of DISEASE (DISEASE) was developed in rats by the combined administration of CHEMICAL (CHEMICAL) and protamine sulfate (PS). Male Sprague-Dawley rats, uninephrectomized three weeks before, received daily injections of subcutaneous CHEMICAL (1 mg/100 g body wt) and intravenous PS (2 separated doses of 2.5 mg/100 g body wt) for four days. The series of injections were repeated another three times at 10 day intervals. The animals were sacrificed on days 24, 52, and 80. They developed nephrotic syndrome and finally renal failure. The time-course curve of creatinine clearance dropped and showed significant difference (P less than 0.01) from that of each control group, such as, CHEMICAL alone, PS alone or saline injected. Their glomeruli showed changes of progressive DISEASE. The ultrastructural studies in the initial stage revealed significant lack of particles of perfused ruthenium red on the lamina rara externa and marked changes in epithelial cell cytoplasm. Therefore, it is suggested that the administration of PS enhances the toxicity of CHEMICAL on the glomerulus and readily produces progressive DISEASE in rats resulting in the end-stage renal disease. | CHEMICAL-INDUCED-DISEASE |
| The enhancement of CHEMICAL nephrosis by the co-administration of protamine. An experimental model of focal segmental glomerular sclerosis (FSGS) was developed in rats by the combined administration of CHEMICAL (CHEMICAL) and protamine sulfate (PS). Male Sprague-Dawley rats, uninephrectomized three weeks before, received daily injections of subcutaneous CHEMICAL (1 mg/100 g body wt) and intravenous PS (2 separated doses of 2.5 mg/100 g body wt) for four days. The series of injections were repeated another three times at 10 day intervals. The animals were sacrificed on days 24, 52, and 80. They developed DISEASE and finally renal failure. The time-course curve of creatinine clearance dropped and showed significant difference (P less than 0.01) from that of each control group, such as, CHEMICAL alone, PS alone or saline injected. Their glomeruli showed changes of progressive FSGS. The ultrastructural studies in the initial stage revealed significant lack of particles of perfused ruthenium red on the lamina rara externa and marked changes in epithelial cell cytoplasm. Therefore, it is suggested that the administration of PS enhances the toxicity of CHEMICAL on the glomerulus and readily produces progressive FSGS in rats resulting in the end-stage renal disease. | CHEMICAL-INDUCED-DISEASE |
| The enhancement of CHEMICAL nephrosis by the co-administration of protamine. An experimental model of focal segmental glomerular sclerosis (FSGS) was developed in rats by the combined administration of CHEMICAL (CHEMICAL) and protamine sulfate (PS). Male Sprague-Dawley rats, uninephrectomized three weeks before, received daily injections of subcutaneous CHEMICAL (1 mg/100 g body wt) and intravenous PS (2 separated doses of 2.5 mg/100 g body wt) for four days. The series of injections were repeated another three times at 10 day intervals. The animals were sacrificed on days 24, 52, and 80. They developed nephrotic syndrome and finally renal failure. The time-course curve of creatinine clearance dropped and showed significant difference (P less than 0.01) from that of each control group, such as, CHEMICAL alone, PS alone or saline injected. Their glomeruli showed changes of progressive FSGS. The ultrastructural studies in the initial stage revealed significant lack of particles of perfused ruthenium red on the lamina rara externa and marked changes in epithelial cell cytoplasm. Therefore, it is suggested that the administration of PS enhances the toxicity of CHEMICAL on the glomerulus and readily produces progressive FSGS in rats resulting in the DISEASE. | CHEMICAL-INDUCED-DISEASE |
| The enhancement of aminonucleoside nephrosis by the co-administration of protamine. An experimental model of focal segmental glomerular sclerosis (FSGS) was developed in rats by the combined administration of puromycin-aminonucleoside (AMNS) and protamine sulfate (PS). Male Sprague-Dawley rats, uninephrectomized three weeks before, received daily injections of subcutaneous AMNS (1 mg/100 g body wt) and intravenous PS (2 separated doses of 2.5 mg/100 g body wt) for four days. The series of injections were repeated another three times at 10 day intervals. The animals were sacrificed on days 24, 52, and 80. They developed nephrotic syndrome and finally DISEASE. The time-course curve of CHEMICAL clearance dropped and showed significant difference (P less than 0.01) from that of each control group, such as, AMNS alone, PS alone or saline injected. Their glomeruli showed changes of progressive FSGS. The ultrastructural studies in the initial stage revealed significant lack of particles of perfused ruthenium red on the lamina rara externa and marked changes in epithelial cell cytoplasm. Therefore, it is suggested that the administration of PS enhances the toxicity of AMNS on the glomerulus and readily produces progressive FSGS in rats resulting in the end-stage renal disease. | NO-RELATIONSHIP |
| The enhancement of aminonucleoside nephrosis by the co-administration of protamine. An experimental model of focal segmental glomerular sclerosis (FSGS) was developed in rats by the combined administration of puromycin-aminonucleoside (AMNS) and protamine sulfate (PS). Male Sprague-Dawley rats, uninephrectomized three weeks before, received daily injections of subcutaneous AMNS (1 mg/100 g body wt) and intravenous PS (2 separated doses of 2.5 mg/100 g body wt) for four days. The series of injections were repeated another three times at 10 day intervals. The animals were sacrificed on days 24, 52, and 80. They developed nephrotic syndrome and finally renal failure. The time-course curve of CHEMICAL clearance dropped and showed significant difference (P less than 0.01) from that of each control group, such as, AMNS alone, PS alone or saline injected. Their glomeruli showed changes of progressive FSGS. The ultrastructural studies in the initial stage revealed significant lack of particles of perfused ruthenium red on the lamina rara externa and marked changes in epithelial cell cytoplasm. Therefore, it is suggested that the administration of PS enhances the DISEASE of AMNS on the glomerulus and readily produces progressive FSGS in rats resulting in the end-stage renal disease. | NO-RELATIONSHIP |
| The enhancement of aminonucleoside DISEASE by the co-administration of protamine. An experimental model of focal segmental glomerular sclerosis (FSGS) was developed in rats by the combined administration of puromycin-aminonucleoside (AMNS) and protamine sulfate (PS). Male Sprague-Dawley rats, uninephrectomized three weeks before, received daily injections of subcutaneous AMNS (1 mg/100 g body wt) and intravenous PS (2 separated doses of 2.5 mg/100 g body wt) for four days. The series of injections were repeated another three times at 10 day intervals. The animals were sacrificed on days 24, 52, and 80. They developed nephrotic syndrome and finally renal failure. The time-course curve of creatinine clearance dropped and showed significant difference (P less than 0.01) from that of each control group, such as, AMNS alone, PS alone or saline injected. Their glomeruli showed changes of progressive FSGS. The ultrastructural studies in the initial stage revealed significant lack of particles of perfused CHEMICAL red on the lamina rara externa and marked changes in epithelial cell cytoplasm. Therefore, it is suggested that the administration of PS enhances the toxicity of AMNS on the glomerulus and readily produces progressive FSGS in rats resulting in the end-stage renal disease. | NO-RELATIONSHIP |
| The enhancement of aminonucleoside DISEASE by the co-administration of protamine. An experimental model of focal segmental glomerular sclerosis (FSGS) was developed in rats by the combined administration of puromycin-aminonucleoside (AMNS) and protamine sulfate (PS). Male Sprague-Dawley rats, uninephrectomized three weeks before, received daily injections of subcutaneous AMNS (1 mg/100 g body wt) and intravenous PS (2 separated doses of 2.5 mg/100 g body wt) for four days. The series of injections were repeated another three times at 10 day intervals. The animals were sacrificed on days 24, 52, and 80. They developed nephrotic syndrome and finally renal failure. The time-course curve of CHEMICAL clearance dropped and showed significant difference (P less than 0.01) from that of each control group, such as, AMNS alone, PS alone or saline injected. Their glomeruli showed changes of progressive FSGS. The ultrastructural studies in the initial stage revealed significant lack of particles of perfused ruthenium red on the lamina rara externa and marked changes in epithelial cell cytoplasm. Therefore, it is suggested that the administration of PS enhances the toxicity of AMNS on the glomerulus and readily produces progressive FSGS in rats resulting in the end-stage renal disease. | NO-RELATIONSHIP |
| The enhancement of aminonucleoside nephrosis by the co-administration of protamine. An experimental model of focal segmental glomerular sclerosis (FSGS) was developed in rats by the combined administration of puromycin-aminonucleoside (AMNS) and protamine sulfate (PS). Male Sprague-Dawley rats, uninephrectomized three weeks before, received daily injections of subcutaneous AMNS (1 mg/100 g body wt) and intravenous PS (2 separated doses of 2.5 mg/100 g body wt) for four days. The series of injections were repeated another three times at 10 day intervals. The animals were sacrificed on days 24, 52, and 80. They developed nephrotic syndrome and finally renal failure. The time-course curve of creatinine clearance dropped and showed significant difference (P less than 0.01) from that of each control group, such as, AMNS alone, PS alone or saline injected. Their glomeruli showed changes of progressive FSGS. The ultrastructural studies in the initial stage revealed significant lack of particles of perfused CHEMICAL red on the lamina rara externa and marked changes in epithelial cell cytoplasm. Therefore, it is suggested that the administration of PS enhances the DISEASE of AMNS on the glomerulus and readily produces progressive FSGS in rats resulting in the end-stage renal disease. | NO-RELATIONSHIP |
| The enhancement of aminonucleoside DISEASE by the co-administration of protamine. An experimental model of focal segmental glomerular sclerosis (FSGS) was developed in rats by the combined administration of puromycin-aminonucleoside (AMNS) and CHEMICAL (CHEMICAL). Male Sprague-Dawley rats, uninephrectomized three weeks before, received daily injections of subcutaneous AMNS (1 mg/100 g body wt) and intravenous CHEMICAL (2 separated doses of 2.5 mg/100 g body wt) for four days. The series of injections were repeated another three times at 10 day intervals. The animals were sacrificed on days 24, 52, and 80. They developed nephrotic syndrome and finally renal failure. The time-course curve of creatinine clearance dropped and showed significant difference (P less than 0.01) from that of each control group, such as, AMNS alone, CHEMICAL alone or saline injected. Their glomeruli showed changes of progressive FSGS. The ultrastructural studies in the initial stage revealed significant lack of particles of perfused ruthenium red on the lamina rara externa and marked changes in epithelial cell cytoplasm. Therefore, it is suggested that the administration of CHEMICAL enhances the toxicity of AMNS on the glomerulus and readily produces progressive FSGS in rats resulting in the end-stage renal disease. | CHEMICAL-INDUCED-DISEASE |
| The enhancement of aminonucleoside nephrosis by the co-administration of protamine. An experimental model of focal segmental glomerular sclerosis (FSGS) was developed in rats by the combined administration of puromycin-aminonucleoside (AMNS) and CHEMICAL (CHEMICAL). Male Sprague-Dawley rats, uninephrectomized three weeks before, received daily injections of subcutaneous AMNS (1 mg/100 g body wt) and intravenous CHEMICAL (2 separated doses of 2.5 mg/100 g body wt) for four days. The series of injections were repeated another three times at 10 day intervals. The animals were sacrificed on days 24, 52, and 80. They developed nephrotic syndrome and finally renal failure. The time-course curve of creatinine clearance dropped and showed significant difference (P less than 0.01) from that of each control group, such as, AMNS alone, CHEMICAL alone or saline injected. Their glomeruli showed changes of progressive FSGS. The ultrastructural studies in the initial stage revealed significant lack of particles of perfused ruthenium red on the lamina rara externa and marked changes in epithelial cell cytoplasm. Therefore, it is suggested that the administration of CHEMICAL enhances the DISEASE of AMNS on the glomerulus and readily produces progressive FSGS in rats resulting in the end-stage renal disease. | CHEMICAL-INDUCED-DISEASE |
| The enhancement of aminonucleoside nephrosis by the co-administration of protamine. An experimental model of focal segmental glomerular sclerosis (FSGS) was developed in rats by the combined administration of puromycin-aminonucleoside (AMNS) and CHEMICAL (CHEMICAL). Male Sprague-Dawley rats, uninephrectomized three weeks before, received daily injections of subcutaneous AMNS (1 mg/100 g body wt) and intravenous CHEMICAL (2 separated doses of 2.5 mg/100 g body wt) for four days. The series of injections were repeated another three times at 10 day intervals. The animals were sacrificed on days 24, 52, and 80. They developed nephrotic syndrome and finally DISEASE. The time-course curve of creatinine clearance dropped and showed significant difference (P less than 0.01) from that of each control group, such as, AMNS alone, CHEMICAL alone or saline injected. Their glomeruli showed changes of progressive FSGS. The ultrastructural studies in the initial stage revealed significant lack of particles of perfused ruthenium red on the lamina rara externa and marked changes in epithelial cell cytoplasm. Therefore, it is suggested that the administration of CHEMICAL enhances the toxicity of AMNS on the glomerulus and readily produces progressive FSGS in rats resulting in the end-stage renal disease. | CHEMICAL-INDUCED-DISEASE |
| The enhancement of aminonucleoside nephrosis by the co-administration of protamine. An experimental model of focal segmental glomerular sclerosis (FSGS) was developed in rats by the combined administration of puromycin-aminonucleoside (AMNS) and protamine sulfate (PS). Male Sprague-Dawley rats, uninephrectomized three weeks before, received daily injections of subcutaneous AMNS (1 mg/100 g body wt) and intravenous PS (2 separated doses of 2.5 mg/100 g body wt) for four days. The series of injections were repeated another three times at 10 day intervals. The animals were sacrificed on days 24, 52, and 80. They developed nephrotic syndrome and finally DISEASE. The time-course curve of creatinine clearance dropped and showed significant difference (P less than 0.01) from that of each control group, such as, AMNS alone, PS alone or saline injected. Their glomeruli showed changes of progressive FSGS. The ultrastructural studies in the initial stage revealed significant lack of particles of perfused CHEMICAL red on the lamina rara externa and marked changes in epithelial cell cytoplasm. Therefore, it is suggested that the administration of PS enhances the toxicity of AMNS on the glomerulus and readily produces progressive FSGS in rats resulting in the end-stage renal disease. | NO-RELATIONSHIP |
| Theophylline neurotoxicity in pregnant rats. The purpose of this investigation was to determine whether the neurotoxicity of theophylline is altered in advanced pregnancy. Sprague-Dawley rats that were 20 days pregnant and nonpregnant rats of the same age and strain received infusions of CHEMICAL until onset of maximal DISEASE which occurred after 28 and 30 minutes respectively. Theophylline concentrations at this endpoint in serum (total) and CSF were similar but serum (free) and brain concentrations were slightly different in pregnant rats. Theophylline serum protein binding determined by equilibrium dialysis was lower in pregnant rats. Fetal serum concentrations at onset of DISEASE in the mother were similar to maternal brain and CSF concentrations and correlated significantly with the former. It is concluded that advanced pregnancy has a negligible effect on the neurotoxic response to theophylline in rats. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL DISEASE in pregnant rats. The purpose of this investigation was to determine whether the DISEASE of CHEMICAL is altered in advanced pregnancy. Sprague-Dawley rats that were 20 days pregnant and nonpregnant rats of the same age and strain received infusions of aminophylline until onset of maximal seizures which occurred after 28 and 30 minutes respectively. CHEMICAL concentrations at this endpoint in serum (total) and CSF were similar but serum (free) and brain concentrations were slightly different in pregnant rats. CHEMICAL serum protein binding determined by equilibrium dialysis was lower in pregnant rats. Fetal serum concentrations at onset of seizures in the mother were similar to maternal brain and CSF concentrations and correlated significantly with the former. It is concluded that advanced pregnancy has a negligible effect on the DISEASE response to CHEMICAL in rats. | CHEMICAL-INDUCED-DISEASE |
| Hyperkalemia induced by indomethacin and naproxen and reversed by fludrocortisone. We have described a patient with severe rheumatoid arthritis and a history of CHEMICAL DISEASE in whom hyperkalemia and inappropriate hypoaldosteronism were caused by both indomethacin and naproxen, without major decline in renal function. It is likely that preexisting DISEASE predisposed this patient to type IV renal tubular acidosis with prostaglandin synthetase inhibitors. Because he was unable to discontinue nonsteroidal anti-inflammatory drug therapy, fludrocortisone was added, correcting the hyperkalemia and allowing indomethacin therapy to be continued safely. | NO-RELATIONSHIP |
| DISEASE induced by CHEMICAL and naproxen and reversed by fludrocortisone. We have described a patient with severe rheumatoid arthritis and a history of mefenamic acid nephropathy in whom DISEASE and inappropriate hypoaldosteronism were caused by both CHEMICAL and naproxen, without major decline in renal function. It is likely that preexisting renal disease predisposed this patient to type IV renal tubular acidosis with prostaglandin synthetase inhibitors. Because he was unable to discontinue nonsteroidal anti-inflammatory drug therapy, fludrocortisone was added, correcting the DISEASE and allowing CHEMICAL therapy to be continued safely. | CHEMICAL-INDUCED-DISEASE |
| Hyperkalemia induced by indomethacin and CHEMICAL and reversed by fludrocortisone. We have described a patient with severe rheumatoid arthritis and a history of mefenamic acid nephropathy in whom hyperkalemia and inappropriate DISEASE were caused by both indomethacin and CHEMICAL, without major decline in renal function. It is likely that preexisting renal disease predisposed this patient to DISEASE with prostaglandin synthetase inhibitors. Because he was unable to discontinue nonsteroidal anti-inflammatory drug therapy, fludrocortisone was added, correcting the hyperkalemia and allowing indomethacin therapy to be continued safely. | CHEMICAL-INDUCED-DISEASE |
| DISEASE induced by indomethacin and CHEMICAL and reversed by fludrocortisone. We have described a patient with severe rheumatoid arthritis and a history of mefenamic acid nephropathy in whom DISEASE and inappropriate hypoaldosteronism were caused by both indomethacin and CHEMICAL, without major decline in renal function. It is likely that preexisting renal disease predisposed this patient to type IV renal tubular acidosis with prostaglandin synthetase inhibitors. Because he was unable to discontinue nonsteroidal anti-inflammatory drug therapy, fludrocortisone was added, correcting the DISEASE and allowing indomethacin therapy to be continued safely. | CHEMICAL-INDUCED-DISEASE |
| Hyperkalemia induced by CHEMICAL and naproxen and reversed by fludrocortisone. We have described a patient with severe rheumatoid arthritis and a history of mefenamic acid nephropathy in whom hyperkalemia and inappropriate DISEASE were caused by both CHEMICAL and naproxen, without major decline in renal function. It is likely that preexisting renal disease predisposed this patient to DISEASE with prostaglandin synthetase inhibitors. Because he was unable to discontinue nonsteroidal anti-inflammatory drug therapy, fludrocortisone was added, correcting the hyperkalemia and allowing CHEMICAL therapy to be continued safely. | CHEMICAL-INDUCED-DISEASE |
| Hyperkalemia induced by indomethacin and naproxen and reversed by fludrocortisone. We have described a patient with severe DISEASE and a history of mefenamic acid nephropathy in whom hyperkalemia and inappropriate hypoaldosteronism were caused by both indomethacin and naproxen, without major decline in renal function. It is likely that preexisting renal disease predisposed this patient to type IV renal tubular acidosis with CHEMICAL synthetase inhibitors. Because he was unable to discontinue nonsteroidal anti-inflammatory drug therapy, fludrocortisone was added, correcting the hyperkalemia and allowing indomethacin therapy to be continued safely. | NO-RELATIONSHIP |
| Hyperkalemia induced by indomethacin and naproxen and reversed by CHEMICAL. We have described a patient with severe DISEASE and a history of mefenamic acid nephropathy in whom hyperkalemia and inappropriate hypoaldosteronism were caused by both indomethacin and naproxen, without major decline in renal function. It is likely that preexisting renal disease predisposed this patient to type IV renal tubular acidosis with prostaglandin synthetase inhibitors. Because he was unable to discontinue nonsteroidal anti-inflammatory drug therapy, CHEMICAL was added, correcting the hyperkalemia and allowing indomethacin therapy to be continued safely. | NO-RELATIONSHIP |
| DISEASE as a manifestation of cardiotoxicity in three patients receiving cisplatin and CHEMICAL. Cardiac symptoms, including DISEASE, developed in three patients with advanced colorectal carcinoma while being treated with cisplatin (CDDP) and CHEMICAL (CHEMICAL). In two patients, DISEASE was associated with severe left ventricular dysfunction. All three patients required therapy discontinuation. Cardiac enzymes remained normal despite transient electrocardiographic (EKG) changes. The presentation and cardiac evaluation (hemodynamic, echocardiographic, and scintigraphic) of these patients suggest new manifestations of CHEMICAL cardiotoxicity that may be influenced by CDDP. The possible pathophysiologic mechanisms are discussed. | CHEMICAL-INDUCED-DISEASE |
| Hypotension as a manifestation of cardiotoxicity in three patients receiving cisplatin and CHEMICAL. Cardiac symptoms, including hypotension, developed in three patients with advanced colorectal carcinoma while being treated with cisplatin (CDDP) and CHEMICAL (CHEMICAL). In two patients, hypotension was associated with severe DISEASE. All three patients required therapy discontinuation. Cardiac enzymes remained normal despite transient electrocardiographic (EKG) changes. The presentation and cardiac evaluation (hemodynamic, echocardiographic, and scintigraphic) of these patients suggest new manifestations of CHEMICAL cardiotoxicity that may be influenced by CDDP. The possible pathophysiologic mechanisms are discussed. | CHEMICAL-INDUCED-DISEASE |
| DISEASE as a manifestation of cardiotoxicity in three patients receiving CHEMICAL and 5-fluorouracil. Cardiac symptoms, including DISEASE, developed in three patients with advanced colorectal carcinoma while being treated with CHEMICAL (CHEMICAL) and 5-fluorouracil (5-FU). In two patients, DISEASE was associated with severe left ventricular dysfunction. All three patients required therapy discontinuation. Cardiac enzymes remained normal despite transient electrocardiographic (EKG) changes. The presentation and cardiac evaluation (hemodynamic, echocardiographic, and scintigraphic) of these patients suggest new manifestations of 5-FU cardiotoxicity that may be influenced by CHEMICAL. The possible pathophysiologic mechanisms are discussed. | CHEMICAL-INDUCED-DISEASE |
| Hypotension as a manifestation of cardiotoxicity in three patients receiving CHEMICAL and 5-fluorouracil. Cardiac symptoms, including hypotension, developed in three patients with advanced colorectal carcinoma while being treated with CHEMICAL (CHEMICAL) and 5-fluorouracil (5-FU). In two patients, hypotension was associated with severe DISEASE. All three patients required therapy discontinuation. Cardiac enzymes remained normal despite transient electrocardiographic (EKG) changes. The presentation and cardiac evaluation (hemodynamic, echocardiographic, and scintigraphic) of these patients suggest new manifestations of 5-FU cardiotoxicity that may be influenced by CHEMICAL. The possible pathophysiologic mechanisms are discussed. | CHEMICAL-INDUCED-DISEASE |
| Fatal DISEASE in a patient treated with CHEMICAL. A case of fatal DISEASE due to CHEMICAL treatment in an epileptic woman is reported. Despite concerns of fatal bone marrow toxicity due to CHEMICAL, this is only the fourth documented and published report. CHEMICAL is a safe drug, but physicians and patients should be aware of the exceedingly rare but potentially fatal side effects, better prevented by clinical than by laboratory monitoring. | CHEMICAL-INDUCED-DISEASE |
| Participation of a bulbospinal serotonergic pathway in the rat brain in CHEMICAL-induced DISEASE and bradycardia. The effects of microinjection of CHEMICAL (1-10 micrograms in 1 microliter) into a region adjacent to the ventrolateral surface of the medulla oblongata on cardiovascular function were assessed in urethane-anesthetized rats. Intramedullary administration of CHEMICAL, but not saline vehicle, caused a dose-dependent decrease in both the mean arterial pressure and the heart rate. The CHEMICAL-induced DISEASE was antagonized by prior spinal transection, but not bilateral vagotomy. On the other hand, the CHEMICAL-induced bradycardia was antagonized by prior bilateral vagotomy, but not spinal transection. Furthermore, selective destruction of the spinal 5-HT nerves, produced by bilateral spinal injection of 5,7-dihydroxytryptamine, reduced the magnitude of the vasodepressor or the bradycardiac responses to CHEMICAL microinjected into the area near the ventrolateral surface of the medulla oblongata in rats. The data indicate that a bulbospinal serotonergic pathway is involved in development of CHEMICAL-induced DISEASE and bradycardia. The induced DISEASE is brought about by a decrease in sympathetic efferent activity, whereas the induced bradycardia was due to an increase in vagal efferent activity. | CHEMICAL-INDUCED-DISEASE |
| Participation of a bulbospinal serotonergic pathway in the rat brain in CHEMICAL-induced hypotension and DISEASE. The effects of microinjection of CHEMICAL (1-10 micrograms in 1 microliter) into a region adjacent to the ventrolateral surface of the medulla oblongata on cardiovascular function were assessed in urethane-anesthetized rats. Intramedullary administration of CHEMICAL, but not saline vehicle, caused a dose-dependent decrease in both the mean arterial pressure and the heart rate. The CHEMICAL-induced hypotension was antagonized by prior spinal transection, but not bilateral vagotomy. On the other hand, the CHEMICAL-induced DISEASE was antagonized by prior bilateral vagotomy, but not spinal transection. Furthermore, selective destruction of the spinal 5-HT nerves, produced by bilateral spinal injection of 5,7-dihydroxytryptamine, reduced the magnitude of the vasodepressor or the DISEASE responses to CHEMICAL microinjected into the area near the ventrolateral surface of the medulla oblongata in rats. The data indicate that a bulbospinal serotonergic pathway is involved in development of CHEMICAL-induced hypotension and DISEASE. The induced hypotension is brought about by a decrease in sympathetic efferent activity, whereas the induced DISEASE was due to an increase in vagal efferent activity. | CHEMICAL-INDUCED-DISEASE |
| DISEASE in neuroblastoma induced by CHEMICAL. DISEASE is a well-known finding in some patients with neuroblastoma. However, it has not previously been described in association with the use of CHEMICAL. We report the occurrence of severe DISEASE (blood pressure 190/160) in a 4-year-old girl with neuroblastoma who was given CHEMICAL to control a behavior disorder. It was determined later that this patient's tumor was recurring at the time of her DISEASE episode. Since she had no blood pressure elevation at initial diagnosis and none following discontinuation of the CHEMICAL (when she was in florid relapse), we believe that this drug rather than her underlying disease alone caused her DISEASE. The mechanism for this reaction is believed to be increased levels of vasoactive catecholamines due to interference of their physiologic inactivation by CHEMICAL. From this experience, we urge extreme caution in the use of tricyclic antidepressants in children with active neuroblastoma. | CHEMICAL-INDUCED-DISEASE |
| Hypertension in neuroblastoma induced by imipramine. Hypertension is a well-known finding in some patients with neuroblastoma. However, it has not previously been described in association with the use of Imipramine. We report the occurrence of severe hypertension (blood pressure 190/160) in a 4-year-old girl with neuroblastoma who was given Imipramine to control a DISEASE. It was determined later that this patient's tumor was recurring at the time of her hypertensive episode. Since she had no blood pressure elevation at initial diagnosis and none following discontinuation of the Imipramine (when she was in florid relapse), we believe that this drug rather than her underlying disease alone caused her hypertension. The mechanism for this reaction is believed to be increased levels of vasoactive CHEMICAL due to interference of their physiologic inactivation by Imipramine. From this experience, we urge extreme caution in the use of tricyclic antidepressants in children with active neuroblastoma. | NO-RELATIONSHIP |
| Hypertension in neuroblastoma induced by imipramine. Hypertension is a well-known finding in some patients with neuroblastoma. However, it has not previously been described in association with the use of Imipramine. We report the occurrence of severe hypertension (blood pressure 190/160) in a 4-year-old girl with neuroblastoma who was given Imipramine to control a behavior disorder. It was determined later that this patient's DISEASE was recurring at the time of her hypertensive episode. Since she had no blood pressure elevation at initial diagnosis and none following discontinuation of the Imipramine (when she was in florid relapse), we believe that this drug rather than her underlying disease alone caused her hypertension. The mechanism for this reaction is believed to be increased levels of vasoactive CHEMICAL due to interference of their physiologic inactivation by Imipramine. From this experience, we urge extreme caution in the use of tricyclic antidepressants in children with active neuroblastoma. | NO-RELATIONSHIP |
| Hypertension in DISEASE induced by imipramine. Hypertension is a well-known finding in some patients with DISEASE. However, it has not previously been described in association with the use of Imipramine. We report the occurrence of severe hypertension (blood pressure 190/160) in a 4-year-old girl with DISEASE who was given Imipramine to control a behavior disorder. It was determined later that this patient's tumor was recurring at the time of her hypertensive episode. Since she had no blood pressure elevation at initial diagnosis and none following discontinuation of the Imipramine (when she was in florid relapse), we believe that this drug rather than her underlying disease alone caused her hypertension. The mechanism for this reaction is believed to be increased levels of vasoactive CHEMICAL due to interference of their physiologic inactivation by Imipramine. From this experience, we urge extreme caution in the use of tricyclic antidepressants in children with active DISEASE. | NO-RELATIONSHIP |
| Rechallenge of patients who developed DISEASE or hoarseness with CHEMICAL. Of 158 asthmatic patients who were placed on inhaled CHEMICAL, 15 (9.5%) developed either hoarseness (8), oral DISEASE (6), or both (1). When their adverse reactions subsided, seven of these 15 patients were rechallenged with inhaled CHEMICAL. These included five cases who developed hoarseness and three who developed Candidiasis. One patient had both. Oral DISEASE did not recur, but 60% (3/5) of patients with hoarseness had recurrence. We conclude that patients may be restarted on inhaled CHEMICAL when clinically indicated; however, because of the high recurrence rate, patients who develop hoarseness should not be re-challenged. Concomitant use of oral prednisone and topical CHEMICAL may increase the risk of developing hoarseness or candidiasis. | CHEMICAL-INDUCED-DISEASE |
| Rechallenge of patients who developed oral candidiasis or DISEASE with CHEMICAL. Of 158 asthmatic patients who were placed on inhaled CHEMICAL, 15 (9.5%) developed either DISEASE (8), oral thrush (6), or both (1). When their adverse reactions subsided, seven of these 15 patients were rechallenged with inhaled CHEMICAL. These included five cases who developed DISEASE and three who developed Candidiasis. One patient had both. Oral thrush did not recur, but 60% (3/5) of patients with DISEASE had recurrence. We conclude that patients may be restarted on inhaled CHEMICAL when clinically indicated; however, because of the high recurrence rate, patients who develop DISEASE should not be re-challenged. Concomitant use of oral prednisone and topical CHEMICAL may increase the risk of developing DISEASE or candidiasis. | CHEMICAL-INDUCED-DISEASE |
| Rechallenge of patients who developed oral candidiasis or hoarseness with beclomethasone dipropionate. Of 158 DISEASE patients who were placed on inhaled beclomethasone, 15 (9.5%) developed either hoarseness (8), oral thrush (6), or both (1). When their adverse reactions subsided, seven of these 15 patients were rechallenged with inhaled beclomethasone. These included five cases who developed hoarseness and three who developed Candidiasis. One patient had both. Oral thrush did not recur, but 60% (3/5) of patients with hoarseness had recurrence. We conclude that patients may be restarted on inhaled beclomethasone when clinically indicated; however, because of the high recurrence rate, patients who develop hoarseness should not be re-challenged. Concomitant use of oral CHEMICAL and topical beclomethasone may increase the risk of developing hoarseness or candidiasis. | NO-RELATIONSHIP |
| Rechallenge of patients who developed oral candidiasis or hoarseness with beclomethasone dipropionate. Of 158 asthmatic patients who were placed on inhaled beclomethasone, 15 (9.5%) developed either hoarseness (8), oral thrush (6), or both (1). When their adverse reactions subsided, seven of these 15 patients were rechallenged with inhaled beclomethasone. These included five cases who developed hoarseness and three who developed DISEASE. One patient had both. Oral thrush did not recur, but 60% (3/5) of patients with hoarseness had recurrence. We conclude that patients may be restarted on inhaled beclomethasone when clinically indicated; however, because of the high recurrence rate, patients who develop hoarseness should not be re-challenged. Concomitant use of oral CHEMICAL and topical beclomethasone may increase the risk of developing hoarseness or DISEASE. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL cardiotoxicity: an analysis of dosing as a risk factor. Patients who undergo bone marrow transplantation are generally immunosuppressed with a dose of CHEMICAL (CHEMICAL) which is usually calculated based on the patient's weight. At these high doses of CHEMICAL, serious cardiotoxicity may occur, but definitive risk factors for the development of such cardiotoxicity have not been described. Since chemotherapeutic agent toxicity generally correlates with dose per body surface area, we retrospectively calculated the dose of CHEMICAL in patients transplanted at our institution to determine whether the incidence of CHEMICAL cardiotoxicity correlated with the dose per body surface area. Eighty patients who were to receive CHEMICAL 50 mg/kg/d for four days as preparation for marrow grafting underwent a total of 84 transplants for aplastic anemia, Wiskott-Aldrich syndrome, or severe combined immunodeficiency syndrome. Fourteen of 84 (17%) patients had symptoms and signs consistent with CHEMICAL cardiotoxicity within ten days of receiving 1 to 4 doses of CHEMICAL. Six of the 14 patients died with DISEASE. The dose of CHEMICAL per body surface area was calculated for all patients and the patients were divided into two groups based on daily CHEMICAL dose: Group 1, CHEMICAL less than or equal to 1.55 g/m2/d; Group 2, CHEMICAL greater than 1.55 g/m2/d. Cardiotoxicity that was thought to be related to CHEMICAL occurred in 1/32 (3%) of patients in Group 1 and in 13/52 (25%) patients in Group 2 (P less than 0.025). DISEASE caused or contributed to death in 0/32 patients in Group 1 v 6/52 (12%) of patients in Group 2 (P less than 0.25). There was no difference in the rate of engraftment of evaluable patients in the two groups (P greater than 0.5). We conclude that the CHEMICAL cardiotoxicity correlates with CHEMICAL dosage as calculated by body surface area, and that patients with aplastic anemia and immunodeficiencies can be effectively prepared for bone marrow grafting at a CHEMICAL dose of 1.55 g/m2/d for four days with a lower incidence of cardiotoxicity than patients whose CHEMICAL dosage is calculated based on weight. This study reaffirms the principle that drug toxicity correlates with dose per body surface area. | CHEMICAL-INDUCED-DISEASE |
| Studies of risk factors for CHEMICAL DISEASE. The epidemiology of CHEMICAL-induced DISEASE is not fully understood. Experimental studies in healthy human volunteers indicate CHEMICAL cause proximal tubular damage in most patients, but rarely, if ever, cause DISEASE. Clinical trials of CHEMICAL in seriously ill patients indicate that the relative risk for developing acute renal failure during therapy ranges from 8 to 10 and that the attributable risk is 70% to 80%. Further analysis of these data suggests that the duration of therapy, plasma CHEMICAL levels, liver disease, advanced age, high initial estimated creatinine clearance and, possibly, female gender all increase the risk for DISEASE. Other causes of acute renal failure, such as shock, appear to have an additive effect. Predictive models have been developed from these analyses that should be useful for identifying patients at high risk. These models may also be useful in developing insights into the pathophysiology of CHEMICAL-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Studies of risk factors for aminoglycoside nephrotoxicity. The epidemiology of aminoglycoside-induced nephrotoxicity is not fully understood. Experimental studies in healthy human volunteers indicate aminoglycosides cause proximal tubular damage in most patients, but rarely, if ever, cause glomerular or tubular dysfunction. Clinical trials of aminoglycosides in seriously ill patients indicate that the relative risk for developing DISEASE during therapy ranges from 8 to 10 and that the attributable risk is 70% to 80%. Further analysis of these data suggests that the duration of therapy, plasma aminoglycoside levels, liver disease, advanced age, high initial estimated CHEMICAL clearance and, possibly, female gender all increase the risk for nephrotoxicity. Other causes of DISEASE, such as shock, appear to have an additive effect. Predictive models have been developed from these analyses that should be useful for identifying patients at high risk. These models may also be useful in developing insights into the pathophysiology of aminoglycoside-induced nephrotoxicity. | NO-RELATIONSHIP |
| Studies of risk factors for aminoglycoside nephrotoxicity. The epidemiology of aminoglycoside-induced nephrotoxicity is not fully understood. Experimental studies in healthy human volunteers indicate aminoglycosides cause proximal tubular damage in most patients, but rarely, if ever, cause glomerular or tubular dysfunction. Clinical trials of aminoglycosides in seriously ill patients indicate that the relative risk for developing acute renal failure during therapy ranges from 8 to 10 and that the attributable risk is 70% to 80%. Further analysis of these data suggests that the duration of therapy, plasma aminoglycoside levels, liver disease, advanced age, high initial estimated CHEMICAL clearance and, possibly, female gender all increase the risk for nephrotoxicity. Other causes of acute renal failure, such as DISEASE, appear to have an additive effect. Predictive models have been developed from these analyses that should be useful for identifying patients at high risk. These models may also be useful in developing insights into the pathophysiology of aminoglycoside-induced nephrotoxicity. | NO-RELATIONSHIP |
| Studies of risk factors for aminoglycoside nephrotoxicity. The epidemiology of aminoglycoside-induced nephrotoxicity is not fully understood. Experimental studies in healthy human volunteers indicate aminoglycosides cause proximal tubular damage in most patients, but rarely, if ever, cause glomerular or tubular dysfunction. Clinical trials of aminoglycosides in seriously ill patients indicate that the relative risk for developing acute renal failure during therapy ranges from 8 to 10 and that the attributable risk is 70% to 80%. Further analysis of these data suggests that the duration of therapy, plasma aminoglycoside levels, DISEASE, advanced age, high initial estimated CHEMICAL clearance and, possibly, female gender all increase the risk for nephrotoxicity. Other causes of acute renal failure, such as shock, appear to have an additive effect. Predictive models have been developed from these analyses that should be useful for identifying patients at high risk. These models may also be useful in developing insights into the pathophysiology of aminoglycoside-induced nephrotoxicity. | NO-RELATIONSHIP |
| CHEMICAL seizure thresholds in mice treated neonatally with a single injection of monosodium glutamate (MSG): evaluation of experimental parameters in CHEMICAL seizure testing. Monosodium glutamate (MSG) administration to neonatal rodents produces convulsions and results in numerous biochemical and behavioral deficits. These studies were undertaken to determine if neonatal administration of MSG produced permanent alterations in seizure susceptibility, since previous investigations were inconclusive. A CHEMICAL ether seizure screening technique was used to evaluate seizure susceptibility in adult mice that received neonatal injections of MSG (4 mg/g and 1 mg/g). MSG treatment resulted in significant reductions in whole brain weight but did not alter seizure threshold. A naloxone (5 mg/kg) challenge was also ineffective in altering the seizure thresholds of either control of MSG-treated mice. CHEMICAL ether produced DISEASE which was correlated with the duration of CHEMICAL exposure; however, the relationship of DISEASE to seizure induction was unclear. CHEMICAL seizure testing proved to be a rapid and reliable technique with which to evaluate seizure susceptibility. | CHEMICAL-INDUCED-DISEASE |
| Flurothyl DISEASE thresholds in mice treated neonatally with a single injection of monosodium glutamate (MSG): evaluation of experimental parameters in flurothyl DISEASE testing. Monosodium glutamate (MSG) administration to neonatal rodents produces DISEASE and results in numerous biochemical and behavioral deficits. These studies were undertaken to determine if neonatal administration of MSG produced permanent alterations in DISEASE susceptibility, since previous investigations were inconclusive. A flurothyl ether DISEASE screening technique was used to evaluate DISEASE susceptibility in adult mice that received neonatal injections of MSG (4 mg/g and 1 mg/g). MSG treatment resulted in significant reductions in whole brain weight but did not alter DISEASE threshold. A CHEMICAL (5 mg/kg) challenge was also ineffective in altering the DISEASE thresholds of either control of MSG-treated mice. Flurothyl ether produced hypothermia which was correlated with the duration of flurothyl exposure; however, the relationship of hypothermia to DISEASE induction was unclear. Flurothyl DISEASE testing proved to be a rapid and reliable technique with which to evaluate DISEASE susceptibility. | NO-RELATIONSHIP |
| Flurothyl DISEASE thresholds in mice treated neonatally with a single injection of CHEMICAL (CHEMICAL): evaluation of experimental parameters in flurothyl DISEASE testing. CHEMICAL (CHEMICAL) administration to neonatal rodents produces DISEASE and results in numerous biochemical and behavioral deficits. These studies were undertaken to determine if neonatal administration of CHEMICAL produced permanent alterations in DISEASE susceptibility, since previous investigations were inconclusive. A flurothyl ether DISEASE screening technique was used to evaluate DISEASE susceptibility in adult mice that received neonatal injections of CHEMICAL (4 mg/g and 1 mg/g). CHEMICAL treatment resulted in significant reductions in whole brain weight but did not alter DISEASE threshold. A naloxone (5 mg/kg) challenge was also ineffective in altering the DISEASE thresholds of either control of CHEMICAL-treated mice. Flurothyl ether produced hypothermia which was correlated with the duration of flurothyl exposure; however, the relationship of hypothermia to DISEASE induction was unclear. Flurothyl DISEASE testing proved to be a rapid and reliable technique with which to evaluate DISEASE susceptibility. | CHEMICAL-INDUCED-DISEASE |
| Flurothyl DISEASE thresholds in mice treated neonatally with a single injection of monosodium glutamate (MSG): evaluation of experimental parameters in flurothyl DISEASE testing. Monosodium glutamate (MSG) administration to neonatal rodents produces DISEASE and results in numerous biochemical and behavioral deficits. These studies were undertaken to determine if neonatal administration of MSG produced permanent alterations in DISEASE susceptibility, since previous investigations were inconclusive. A flurothyl CHEMICAL DISEASE screening technique was used to evaluate DISEASE susceptibility in adult mice that received neonatal injections of MSG (4 mg/g and 1 mg/g). MSG treatment resulted in significant reductions in whole brain weight but did not alter DISEASE threshold. A naloxone (5 mg/kg) challenge was also ineffective in altering the DISEASE thresholds of either control of MSG-treated mice. Flurothyl CHEMICAL produced hypothermia which was correlated with the duration of flurothyl exposure; however, the relationship of hypothermia to DISEASE induction was unclear. Flurothyl DISEASE testing proved to be a rapid and reliable technique with which to evaluate DISEASE susceptibility. | NO-RELATIONSHIP |
| Susceptibility to DISEASE produced by CHEMICAL in rats after microinjection of isoniazid or gamma-vinyl-GABA into the substantia nigra. CHEMICAL, given intraperitoneally to rats, reproduces the neuropathological sequelae of temporal lobe epilepsy and provides a relevant animal model for studying mechanisms of buildup of DISEASE activity and pathways operative in the generalization and propagation of DISEASE within the forebrain. In the present study, the effects of manipulating the activity of the gamma-aminobutyric acid (GABA)-mediated synaptic inhibition within the substantia nigra on DISEASE produced by CHEMICAL in rats, were investigated. In animals pretreated with microinjections of isoniazid, 150 micrograms, an inhibitor of activity of the GABA-synthesizing enzyme, L-glutamic acid decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of CHEMICAL, 100 and 200 mg/kg, resulted in severe motor limbic DISEASE and status epilepticus. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for CHEMICAL-induced DISEASE. Morphological analysis of frontal forebrain sections with light microscopy revealed DISEASE-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with CHEMICAL in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of isoniazid did not augment DISEASE produced by CHEMICAL, 200 mg/kg. Application of an irreversible inhibitor of GABA transaminase, gamma-vinyl-GABA (D,L-4-amino-hex-5-enoic acid), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral DISEASE produced by CHEMICAL, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of brain damage. Microinjections of gamma-vinyl-GABA, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of DISEASE produced by CHEMICAL, 380 mg/kg. The results demonstrate that the threshold for CHEMICAL-induced DISEASE in rats is subjected to the regulation of the GABA-mediated synaptic inhibition within the substantia nigra. | CHEMICAL-INDUCED-DISEASE |
| Susceptibility to seizures produced by pilocarpine in rats after microinjection of isoniazid or CHEMICAL into the substantia nigra. Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of DISEASE and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the gamma-aminobutyric acid (GABA)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of isoniazid, 150 micrograms, an inhibitor of activity of the GABA-synthesizing enzyme, L-glutamic acid decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and status epilepticus. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of isoniazid did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of GABA transaminase, CHEMICAL (CHEMICAL), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of brain damage. Microinjections of CHEMICAL, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the GABA-mediated synaptic inhibition within the substantia nigra. | NO-RELATIONSHIP |
| Susceptibility to seizures produced by pilocarpine in rats after microinjection of CHEMICAL or gamma-vinyl-GABA into the substantia nigra. Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of DISEASE and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the gamma-aminobutyric acid (GABA)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of CHEMICAL, 150 micrograms, an inhibitor of activity of the GABA-synthesizing enzyme, L-glutamic acid decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and status epilepticus. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of CHEMICAL did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of GABA transaminase, gamma-vinyl-GABA (D,L-4-amino-hex-5-enoic acid), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of brain damage. Microinjections of gamma-vinyl-GABA, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the GABA-mediated synaptic inhibition within the substantia nigra. | NO-RELATIONSHIP |
| Susceptibility to seizures produced by pilocarpine in rats after microinjection of isoniazid or gamma-vinyl-GABA into the substantia nigra. Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of DISEASE and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the gamma-aminobutyric acid (GABA)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of isoniazid, 150 micrograms, an inhibitor of activity of the GABA-synthesizing enzyme, CHEMICAL decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and status epilepticus. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of isoniazid did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of GABA transaminase, gamma-vinyl-GABA (D,L-4-amino-hex-5-enoic acid), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of brain damage. Microinjections of gamma-vinyl-GABA, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the GABA-mediated synaptic inhibition within the substantia nigra. | NO-RELATIONSHIP |
| Susceptibility to seizures produced by pilocarpine in rats after microinjection of isoniazid or gamma-vinyl-GABA into the substantia nigra. Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of temporal lobe epilepsy and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the CHEMICAL (CHEMICAL)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of isoniazid, 150 micrograms, an inhibitor of activity of the CHEMICAL-synthesizing enzyme, L-glutamic acid decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and DISEASE. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of isoniazid did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of CHEMICAL transaminase, gamma-vinyl-GABA (D,L-4-amino-hex-5-enoic acid), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of brain damage. Microinjections of gamma-vinyl-GABA, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the CHEMICAL-mediated synaptic inhibition within the substantia nigra. | NO-RELATIONSHIP |
| Susceptibility to seizures produced by pilocarpine in rats after microinjection of isoniazid or gamma-vinyl-GABA into the substantia nigra. Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of temporal lobe epilepsy and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the gamma-aminobutyric acid (GABA)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of isoniazid, 150 micrograms, an inhibitor of activity of the GABA-synthesizing enzyme, CHEMICAL decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and DISEASE. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of isoniazid did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of GABA transaminase, gamma-vinyl-GABA (D,L-4-amino-hex-5-enoic acid), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of brain damage. Microinjections of gamma-vinyl-GABA, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the GABA-mediated synaptic inhibition within the substantia nigra. | NO-RELATIONSHIP |
| Susceptibility to seizures produced by pilocarpine in rats after microinjection of CHEMICAL or gamma-vinyl-GABA into the substantia nigra. Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of temporal lobe epilepsy and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the gamma-aminobutyric acid (GABA)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of CHEMICAL, 150 micrograms, an inhibitor of activity of the GABA-synthesizing enzyme, L-glutamic acid decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and status epilepticus. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of CHEMICAL did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of GABA transaminase, gamma-vinyl-GABA (D,L-4-amino-hex-5-enoic acid), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of DISEASE. Microinjections of gamma-vinyl-GABA, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the GABA-mediated synaptic inhibition within the substantia nigra. | NO-RELATIONSHIP |
| Susceptibility to seizures produced by pilocarpine in rats after microinjection of isoniazid or CHEMICAL into the substantia nigra. Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of temporal lobe epilepsy and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the gamma-aminobutyric acid (GABA)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of isoniazid, 150 micrograms, an inhibitor of activity of the GABA-synthesizing enzyme, L-glutamic acid decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and status epilepticus. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of isoniazid did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of GABA transaminase, CHEMICAL (CHEMICAL), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of DISEASE. Microinjections of CHEMICAL, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the GABA-mediated synaptic inhibition within the substantia nigra. | NO-RELATIONSHIP |
| Susceptibility to seizures produced by pilocarpine in rats after microinjection of isoniazid or CHEMICAL into the substantia nigra. Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of temporal lobe epilepsy and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the gamma-aminobutyric acid (GABA)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of isoniazid, 150 micrograms, an inhibitor of activity of the GABA-synthesizing enzyme, L-glutamic acid decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and DISEASE. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of isoniazid did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of GABA transaminase, CHEMICAL (CHEMICAL), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of brain damage. Microinjections of CHEMICAL, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the GABA-mediated synaptic inhibition within the substantia nigra. | NO-RELATIONSHIP |
| Susceptibility to seizures produced by pilocarpine in rats after microinjection of isoniazid or gamma-vinyl-GABA into the substantia nigra. Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of DISEASE and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the CHEMICAL (CHEMICAL)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of isoniazid, 150 micrograms, an inhibitor of activity of the CHEMICAL-synthesizing enzyme, L-glutamic acid decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and status epilepticus. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of isoniazid did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of CHEMICAL transaminase, gamma-vinyl-GABA (D,L-4-amino-hex-5-enoic acid), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of brain damage. Microinjections of gamma-vinyl-GABA, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the CHEMICAL-mediated synaptic inhibition within the substantia nigra. | NO-RELATIONSHIP |
| Susceptibility to seizures produced by pilocarpine in rats after microinjection of isoniazid or gamma-vinyl-GABA into the substantia nigra. Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of temporal lobe epilepsy and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the gamma-aminobutyric acid (GABA)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of isoniazid, 150 micrograms, an inhibitor of activity of the GABA-synthesizing enzyme, CHEMICAL decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and status epilepticus. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of isoniazid did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of GABA transaminase, gamma-vinyl-GABA (D,L-4-amino-hex-5-enoic acid), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of DISEASE. Microinjections of gamma-vinyl-GABA, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the GABA-mediated synaptic inhibition within the substantia nigra. | NO-RELATIONSHIP |
| Susceptibility to seizures produced by pilocarpine in rats after microinjection of CHEMICAL or gamma-vinyl-GABA into the substantia nigra. Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of temporal lobe epilepsy and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the gamma-aminobutyric acid (GABA)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of CHEMICAL, 150 micrograms, an inhibitor of activity of the GABA-synthesizing enzyme, L-glutamic acid decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and DISEASE. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of CHEMICAL did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of GABA transaminase, gamma-vinyl-GABA (D,L-4-amino-hex-5-enoic acid), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of brain damage. Microinjections of gamma-vinyl-GABA, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the GABA-mediated synaptic inhibition within the substantia nigra. | NO-RELATIONSHIP |
| Susceptibility to seizures produced by pilocarpine in rats after microinjection of isoniazid or gamma-vinyl-GABA into the substantia nigra. Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of temporal lobe epilepsy and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the CHEMICAL (CHEMICAL)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of isoniazid, 150 micrograms, an inhibitor of activity of the CHEMICAL-synthesizing enzyme, L-glutamic acid decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and status epilepticus. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of isoniazid did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of CHEMICAL transaminase, gamma-vinyl-GABA (D,L-4-amino-hex-5-enoic acid), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of DISEASE. Microinjections of gamma-vinyl-GABA, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the CHEMICAL-mediated synaptic inhibition within the substantia nigra. | NO-RELATIONSHIP |
| Non-invasive detection of coronary artery disease by body surface electrocardiographic mapping after CHEMICAL infusion. Electrocardiographic changes after CHEMICAL infusion (0.568 mg/kg/4 min) were studied in 41 patients with coronary artery disease and compared with those after submaximal treadmill exercise by use of the body surface mapping technique. Patients were divided into three groups; 19 patients without myocardial infarction (non-MI group), 14 with anterior infarction (ANT-MI) and eight with inferior infarction (INF-MI). Eighty-seven unipolar electrocardiograms (ECGs) distributed over the entire thoracic surface were simultaneously recorded. After CHEMICAL, ischemic ST-segment depression (0.05 mV or more) was observed in 84% of the non-MI group, 29% of the ANT-MI group, 63% of the INF-MI group and 61% of the total population. Exercise-induced ST depression was observed in 84% of the non-MI group, 43% of the ANT-MI group, 38% of the INF-MI group and 61% of the total. For individual patients, there were no obvious differences between the body surface distribution of ST depression in both tests. The increase in pressure rate product after CHEMICAL was significantly less than that during the treadmill exercise. The data suggest that the CHEMICAL-induced DISEASE is caused by the inhomogenous distribution of myocardial blood flow. We conclude that the CHEMICAL ECG test is as useful as the exercise ECG test for the assessment of coronary artery disease. | CHEMICAL-INDUCED-DISEASE |
| DISEASE after high-dose intravenous CHEMICAL therapy. In 5 consecutive patients with rheumatoid arthritis who received intravenous high-dose CHEMICAL (CHEMICAL) therapy (1 g daily for 2 or 3 consecutive days), a decline in pulse rate was observed, most pronounced on day 4. In one of the 5 patients the DISEASE was associated with complaints of substernal pressure. Reversal to normal heart rate was found on day 7. Electrocardiographic registrations showed sinus bradycardia in all cases. No significant changes in plasma concentrations of electrolytes were found. Careful observation of patients receiving high-dose CHEMICAL is recommended. High-dose CHEMICAL may be contraindicated in patients with known heart disease. | CHEMICAL-INDUCED-DISEASE |
| Two cases of downbeat nystagmus and DISEASE associated with CHEMICAL. Downbeat nystagmus is often associated with structural lesions at the craniocervical junction, but has occasionally been reported as a manifestation of metabolic imbalance or drug intoxication. We recorded the eye movements of two patients with reversible downbeat nystagmus related to CHEMICAL therapy. The nystagmus of both patients resolved after reduction of the serum CHEMICAL levels. Neuroradiologic investigations including magnetic resonance imaging scans in both patients showed no evidence of intracranial abnormality. In patients with downbeat nystagmus who are taking anticonvulsant medications, consideration should be given to reduction in dose before further investigation is undertaken. | CHEMICAL-INDUCED-DISEASE |
| Improvement by denopamine (TA-064) of CHEMICAL-induced DISEASE in the dog heart-lung preparation. The efficacy of denopamine, an orally active beta 1-adrenoceptor agonist, in improving DISEASE was assessed in dog heart-lung preparations. Cardiac functions depressed by CHEMICAL (118 +/- 28 mg; mean value +/- SD) such that cardiac output and maximum rate of rise of left ventricular pressure (LV dP/dt max) had been reduced by about 35% and 26% of the respective controls were improved by denopamine (10-300 micrograms) in a dose-dependent manner. With 100 micrograms denopamine, almost complete restoration of cardiac performance was attained, associated with a slight increase in heart rate. No arrhythmias were induced by these doses of denopamine. The results warrant clinical trials of denopamine in the treatment of DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Improvement by CHEMICAL (CHEMICAL) of pentobarbital-induced cardiac failure in the dog heart-lung preparation. The efficacy of CHEMICAL, an orally active beta 1-adrenoceptor agonist, in improving cardiac failure was assessed in dog heart-lung preparations. Cardiac functions depressed by pentobarbital (118 +/- 28 mg; mean value +/- SD) such that cardiac output and maximum rate of rise of left ventricular pressure (LV dP/dt max) had been reduced by about 35% and 26% of the respective controls were improved by CHEMICAL (10-300 micrograms) in a dose-dependent manner. With 100 micrograms CHEMICAL, almost complete restoration of cardiac performance was attained, associated with a slight increase in heart rate. No DISEASE were induced by these doses of CHEMICAL. The results warrant clinical trials of CHEMICAL in the treatment of cardiac failure. | NO-RELATIONSHIP |
| CHEMICAL monotherapy for epilepsy in childhood. Sixty patients (age-range one month to 14 years) with other types of epilepsy than infantile spasms were treated with CHEMICAL. Disappearance of seizures and normalization of abnormal EEG with disappearance of seizures were recognized in 77% and 50%, respectively. Seizures disappeared in 71% of the patients with generalized seizures and 89% of partial seizures. Improvement of abnormal EEG was noticed in 76% of diffuse paroxysms and in 67% of focal paroxysms. In excellent cases, mean effective dosages were 0.086 +/- 0.021 mg/kg/day in infants and 0.057 +/- 0.022 mg/kg/day in schoolchildren, this difference was statistically significant (p less than 0.005). The incidence of side effects such as DISEASE and ataxia was only 5%. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL monotherapy for epilepsy in childhood. Sixty patients (age-range one month to 14 years) with other types of epilepsy than infantile spasms were treated with CHEMICAL. Disappearance of seizures and normalization of abnormal EEG with disappearance of seizures were recognized in 77% and 50%, respectively. Seizures disappeared in 71% of the patients with generalized seizures and 89% of partial seizures. Improvement of abnormal EEG was noticed in 76% of diffuse paroxysms and in 67% of focal paroxysms. In excellent cases, mean effective dosages were 0.086 +/- 0.021 mg/kg/day in infants and 0.057 +/- 0.022 mg/kg/day in schoolchildren, this difference was statistically significant (p less than 0.005). The incidence of side effects such as drowsiness and DISEASE was only 5%. | CHEMICAL-INDUCED-DISEASE |
| Postmarketing study of CHEMICAL-hydrochlorothiazide antihypertensive therapy. A postmarketing surveillance study was conducted to determine the safety and efficacy of a fixed-ratio combination containing 10 mg of CHEMICAL and 25 mg of hydrochlorothiazide, administered twice daily for one month to hypertensive patients. Data on 9,037 patients were collected by 1,455 participating physicians. Mean systolic blood pressure decreased 25 mmHg and mean diastolic blood pressure declined 15 mmHg after one month of CHEMICAL-hydrochlorothiazide therapy (P less than 0.01, both comparisons). Age, race, and sex appeared to have no influence on the decrease in blood pressure. The antihypertensive effect of the drug was greater in patients with more severe hypertension. Overall, 1,453 patients experienced a total of 2,658 adverse events, the most common being DISEASE, dizziness, and weakness. Treatment in 590 patients was discontinued because of adverse events. | CHEMICAL-INDUCED-DISEASE |
| Postmarketing study of CHEMICAL-hydrochlorothiazide antihypertensive therapy. A postmarketing surveillance study was conducted to determine the safety and efficacy of a fixed-ratio combination containing 10 mg of CHEMICAL and 25 mg of hydrochlorothiazide, administered twice daily for one month to hypertensive patients. Data on 9,037 patients were collected by 1,455 participating physicians. Mean systolic blood pressure decreased 25 mmHg and mean diastolic blood pressure declined 15 mmHg after one month of CHEMICAL-hydrochlorothiazide therapy (P less than 0.01, both comparisons). Age, race, and sex appeared to have no influence on the decrease in blood pressure. The antihypertensive effect of the drug was greater in patients with more severe hypertension. Overall, 1,453 patients experienced a total of 2,658 adverse events, the most common being fatigue, DISEASE, and weakness. Treatment in 590 patients was discontinued because of adverse events. | CHEMICAL-INDUCED-DISEASE |
| Postmarketing study of timolol-CHEMICAL antihypertensive therapy. A postmarketing surveillance study was conducted to determine the safety and efficacy of a fixed-ratio combination containing 10 mg of timolol maleate and 25 mg of CHEMICAL, administered twice daily for one month to hypertensive patients. Data on 9,037 patients were collected by 1,455 participating physicians. Mean systolic blood pressure decreased 25 mmHg and mean diastolic blood pressure declined 15 mmHg after one month of timolol-CHEMICAL therapy (P less than 0.01, both comparisons). Age, race, and sex appeared to have no influence on the decrease in blood pressure. The antihypertensive effect of the drug was greater in patients with more severe hypertension. Overall, 1,453 patients experienced a total of 2,658 adverse events, the most common being DISEASE, dizziness, and weakness. Treatment in 590 patients was discontinued because of adverse events. | CHEMICAL-INDUCED-DISEASE |
| Postmarketing study of timolol-CHEMICAL antihypertensive therapy. A postmarketing surveillance study was conducted to determine the safety and efficacy of a fixed-ratio combination containing 10 mg of timolol maleate and 25 mg of CHEMICAL, administered twice daily for one month to hypertensive patients. Data on 9,037 patients were collected by 1,455 participating physicians. Mean systolic blood pressure decreased 25 mmHg and mean diastolic blood pressure declined 15 mmHg after one month of timolol-CHEMICAL therapy (P less than 0.01, both comparisons). Age, race, and sex appeared to have no influence on the decrease in blood pressure. The antihypertensive effect of the drug was greater in patients with more severe hypertension. Overall, 1,453 patients experienced a total of 2,658 adverse events, the most common being fatigue, DISEASE, and weakness. Treatment in 590 patients was discontinued because of adverse events. | CHEMICAL-INDUCED-DISEASE |
| Postmarketing study of timolol-CHEMICAL antihypertensive therapy. A postmarketing surveillance study was conducted to determine the safety and efficacy of a fixed-ratio combination containing 10 mg of timolol maleate and 25 mg of CHEMICAL, administered twice daily for one month to hypertensive patients. Data on 9,037 patients were collected by 1,455 participating physicians. Mean systolic blood pressure decreased 25 mmHg and mean diastolic blood pressure declined 15 mmHg after one month of timolol-CHEMICAL therapy (P less than 0.01, both comparisons). Age, race, and sex appeared to have no influence on the decrease in blood pressure. The antihypertensive effect of the drug was greater in patients with more severe hypertension. Overall, 1,453 patients experienced a total of 2,658 adverse events, the most common being fatigue, dizziness, and DISEASE. Treatment in 590 patients was discontinued because of adverse events. | CHEMICAL-INDUCED-DISEASE |
| Postmarketing study of CHEMICAL-hydrochlorothiazide antihypertensive therapy. A postmarketing surveillance study was conducted to determine the safety and efficacy of a fixed-ratio combination containing 10 mg of CHEMICAL and 25 mg of hydrochlorothiazide, administered twice daily for one month to hypertensive patients. Data on 9,037 patients were collected by 1,455 participating physicians. Mean systolic blood pressure decreased 25 mmHg and mean diastolic blood pressure declined 15 mmHg after one month of CHEMICAL-hydrochlorothiazide therapy (P less than 0.01, both comparisons). Age, race, and sex appeared to have no influence on the decrease in blood pressure. The antihypertensive effect of the drug was greater in patients with more severe hypertension. Overall, 1,453 patients experienced a total of 2,658 adverse events, the most common being fatigue, dizziness, and DISEASE. Treatment in 590 patients was discontinued because of adverse events. | CHEMICAL-INDUCED-DISEASE |
| Salicylate DISEASE in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic DISEASE in the Gunn strain of rat. The homozygous Gunn rats have unconjugated hyperbilirubinemia due to the absence of glucuronyl transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop papillary necrosis with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with CHEMICAL 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). CHEMICAL treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without CHEMICAL administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of DISEASE in CHEMICAL-treated jj but not jJ rats as evidenced by: increased incidence and severity of hematuria (p less than 0.01); increased serum creatinine (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or CHEMICAL-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to pathological renal medullary lesions and DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Salicylate nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated DISEASE due to the absence of glucuronyl transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop papillary necrosis with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). CHEMICAL was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of hematuria (p less than 0.01); increased serum creatinine (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to pathological renal medullary lesions and deterioration of renal function. | NO-RELATIONSHIP |
| CHEMICAL nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated hyperbilirubinemia due to the absence of glucuronyl transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop papillary necrosis with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of hematuria (p less than 0.01); increased serum creatinine (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to DISEASE and deterioration of renal function. | CHEMICAL-INDUCED-DISEASE |
| Salicylate nephropathy in the Gunn rat: potential role of CHEMICAL. We examined the potential role of CHEMICAL in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated hyperbilirubinemia due to the absence of glucuronyl transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop papillary necrosis with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and CHEMICAL synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of CHEMICAL synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal CHEMICAL synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of DISEASE (p less than 0.01); increased serum creatinine (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced CHEMICAL synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of CHEMICAL synthesis may lead to pathological renal medullary lesions and deterioration of renal function. | NO-RELATIONSHIP |
| Salicylate nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated DISEASE due to the absence of CHEMICAL transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop papillary necrosis with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of hematuria (p less than 0.01); increased serum creatinine (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to pathological renal medullary lesions and deterioration of renal function. | NO-RELATIONSHIP |
| Salicylate nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated hyperbilirubinemia due to the absence of glucuronyl transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop papillary necrosis with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). CHEMICAL was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of hematuria (p less than 0.01); increased serum creatinine (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to DISEASE and deterioration of renal function. | NO-RELATIONSHIP |
| Salicylate nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated hyperbilirubinemia due to the absence of glucuronyl transferase, leading to marked CHEMICAL deposition in renal medulla and papilla. These rats are also highly susceptible to develop papillary necrosis with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of hematuria (p less than 0.01); increased serum creatinine (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to DISEASE and deterioration of renal function. | NO-RELATIONSHIP |
| Salicylate nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated DISEASE due to the absence of glucuronyl transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop papillary necrosis with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of hematuria (p less than 0.01); increased serum CHEMICAL (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to pathological renal medullary lesions and deterioration of renal function. | NO-RELATIONSHIP |
| Salicylate nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated hyperbilirubinemia due to the absence of glucuronyl transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop DISEASE with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). CHEMICAL was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of hematuria (p less than 0.01); increased serum creatinine (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to pathological renal medullary lesions and deterioration of renal function. | NO-RELATIONSHIP |
| Salicylate nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated hyperbilirubinemia due to the absence of glucuronyl transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop DISEASE with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of hematuria (p less than 0.01); increased serum CHEMICAL (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to pathological renal medullary lesions and deterioration of renal function. | NO-RELATIONSHIP |
| Salicylate nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated DISEASE due to the absence of glucuronyl transferase, leading to marked CHEMICAL deposition in renal medulla and papilla. These rats are also highly susceptible to develop papillary necrosis with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of hematuria (p less than 0.01); increased serum creatinine (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to pathological renal medullary lesions and deterioration of renal function. | NO-RELATIONSHIP |
| Salicylate nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated hyperbilirubinemia due to the absence of CHEMICAL transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop papillary necrosis with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of hematuria (p less than 0.01); increased serum creatinine (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to DISEASE and deterioration of renal function. | NO-RELATIONSHIP |
| Salicylate nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated hyperbilirubinemia due to the absence of CHEMICAL transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop DISEASE with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of hematuria (p less than 0.01); increased serum creatinine (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to pathological renal medullary lesions and deterioration of renal function. | NO-RELATIONSHIP |
| Salicylate nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated hyperbilirubinemia due to the absence of glucuronyl transferase, leading to marked CHEMICAL deposition in renal medulla and papilla. These rats are also highly susceptible to develop papillary necrosis with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of DISEASE (p less than 0.01); increased serum creatinine (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to pathological renal medullary lesions and deterioration of renal function. | NO-RELATIONSHIP |
| Salicylate nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated hyperbilirubinemia due to the absence of glucuronyl transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop papillary necrosis with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of DISEASE (p less than 0.01); increased serum CHEMICAL (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to pathological renal medullary lesions and deterioration of renal function. | NO-RELATIONSHIP |
| Salicylate nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated hyperbilirubinemia due to the absence of glucuronyl transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop DISEASE with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. CHEMICAL synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced CHEMICAL synthesis in all regions, but outer medullary CHEMICAL remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of hematuria (p less than 0.01); increased serum creatinine (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to pathological renal medullary lesions and deterioration of renal function. | NO-RELATIONSHIP |
| Salicylate nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated hyperbilirubinemia due to the absence of CHEMICAL transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop papillary necrosis with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of DISEASE (p less than 0.01); increased serum creatinine (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to pathological renal medullary lesions and deterioration of renal function. | NO-RELATIONSHIP |
| CHEMICAL nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated hyperbilirubinemia due to the absence of glucuronyl transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop papillary necrosis with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of DISEASE (p less than 0.01); increased serum creatinine (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to pathological renal medullary lesions and deterioration of renal function. | CHEMICAL-INDUCED-DISEASE |
| Salicylate nephropathy in the Gunn rat: potential role of CHEMICAL. We examined the potential role of CHEMICAL in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated DISEASE due to the absence of glucuronyl transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop papillary necrosis with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and CHEMICAL synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of CHEMICAL synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal CHEMICAL synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of hematuria (p less than 0.01); increased serum creatinine (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced CHEMICAL synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of CHEMICAL synthesis may lead to pathological renal medullary lesions and deterioration of renal function. | NO-RELATIONSHIP |
| Salicylate nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated hyperbilirubinemia due to the absence of glucuronyl transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop papillary necrosis with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. PGE2 synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced PGE2 synthesis in all regions, but outer medullary PGE2 remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of hematuria (p less than 0.01); increased serum CHEMICAL (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to DISEASE and deterioration of renal function. | NO-RELATIONSHIP |
| Salicylate nephropathy in the Gunn rat: potential role of prostaglandins. We examined the potential role of prostaglandins in the development of analgesic nephropathy in the Gunn strain of rat. The homozygous Gunn rats have unconjugated hyperbilirubinemia due to the absence of glucuronyl transferase, leading to marked bilirubin deposition in renal medulla and papilla. These rats are also highly susceptible to develop papillary necrosis with analgesic administration. We used homozygous (jj) and phenotypically normal heterozygous (jJ) animals. Four groups of rats (n = 7) were studied: jj and jJ rats treated either with aspirin 300 mg/kg every other day or sham-treated. After one week, slices of cortex, outer and inner medulla from one kidney were incubated in buffer and prostaglandin synthesis was determined by radioimmunoassay. The other kidney was examined histologically. A marked corticomedullary gradient of prostaglandin synthesis was observed in all groups. CHEMICAL synthesis was significantly higher in outer medulla, but not cortex or inner medulla, of jj (38 +/- 6 ng/mg prot) than jJ rats (15 +/- 3) (p less than 0.01). Aspirin treatment reduced CHEMICAL synthesis in all regions, but outer medullary CHEMICAL remained higher in jj (18 +/- 3) than jJ rats (9 +/- 2) (p less than 0.05). PGF2 alpha was also significantly higher in the outer medulla of jj rats with and without aspirin administration (p less than 0.05). The changes in renal prostaglandin synthesis were accompanied by evidence of renal damage in aspirin-treated jj but not jJ rats as evidenced by: increased incidence and severity of hematuria (p less than 0.01); increased serum creatinine (p less than 0.05); and increase in outer medullary histopathologic lesions (p less than 0.005 compared to either sham-treated jj or aspirin-treated jJ). These results suggest that enhanced prostaglandin synthesis contributes to maintenance of renal function and morphological integrity, and that inhibition of prostaglandin synthesis may lead to DISEASE and deterioration of renal function. | NO-RELATIONSHIP |
| Prophylactic CHEMICAL in the early phase of suspected myocardial infarction. Four hundred two patients with suspected myocardial infarction seen within 6 hours of the onset of symptoms entered a double-blind randomized trial of CHEMICAL vs placebo. During the 1 hour after administration of the drug the incidence of ventricular fibrillation or sustained ventricular tachycardia among the 204 patients with acute myocardial infarction was low, 1.5%. CHEMICAL, given in a 300 mg dose intramuscularly followed by 100 mg intravenously, did not prevent sustained ventricular tachycardia, although there was a significant reduction in the number of patients with warning arrhythmias between 15 and 45 minutes after the administration of CHEMICAL (p less than 0.05). The average plasma CHEMICAL level 10 minutes after administration for patients without a myocardial infarction was significantly higher than that for patients with an acute infarction. The mean plasma CHEMICAL level of patients on beta-blocking agents was no different from that in patients not on beta blocking agents. During the 1-hour study period, the incidence of central nervous system side effects was significantly greater in the CHEMICAL group, DISEASE occurred in 11 patients, nine of whom had received CHEMICAL, and four patients died from asystole, three of whom had had CHEMICAL. We cannot advocate the administration of CHEMICAL prophylactically in the early hours of suspected myocardial infarction. | CHEMICAL-INDUCED-DISEASE |
| Evidence for a cholinergic role in haloperidol-induced DISEASE. Experiments in mice tested previous evidence that activation of cholinergic systems promotes DISEASE and that cholinergic mechanisms need to be intact for full expression of neuroleptic-induced DISEASE. Large doses of the cholinomimetic, CHEMICAL, could induce DISEASE when peripheral cholinergic receptors were blocked. Low doses of CHEMICAL caused a pronounced enhancement of the DISEASE that was induced by the dopaminergic blocker, haloperidol. A muscarinic receptor blocker, atropine, disrupted haloperidol-induced DISEASE. Intracranial injection of an acetylcholine-synthesis inhibitor, hemicholinium, prevented the DISEASE that is usually induced by haloperidol. These findings suggest the hypothesis that the DISEASE that is produced by neuroleptics such as haloperidol is actually mediated by intrinsic central cholinergic systems. Alternatively, activation of central cholinergic systems could promote DISEASE by suppression of dopaminergic systems. | CHEMICAL-INDUCED-DISEASE |
| Evidence for a cholinergic role in CHEMICAL-induced DISEASE. Experiments in mice tested previous evidence that activation of cholinergic systems promotes DISEASE and that cholinergic mechanisms need to be intact for full expression of neuroleptic-induced DISEASE. Large doses of the cholinomimetic, pilocarpine, could induce DISEASE when peripheral cholinergic receptors were blocked. Low doses of pilocarpine caused a pronounced enhancement of the DISEASE that was induced by the dopaminergic blocker, CHEMICAL. A muscarinic receptor blocker, atropine, disrupted CHEMICAL-induced DISEASE. Intracranial injection of an acetylcholine-synthesis inhibitor, hemicholinium, prevented the DISEASE that is usually induced by CHEMICAL. These findings suggest the hypothesis that the DISEASE that is produced by neuroleptics such as CHEMICAL is actually mediated by intrinsic central cholinergic systems. Alternatively, activation of central cholinergic systems could promote DISEASE by suppression of dopaminergic systems. | CHEMICAL-INDUCED-DISEASE |
| Cardiovascular dysfunction and hypersensitivity to sodium pentobarbital induced by chronic CHEMICAL ingestion. Barium-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of barium (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant barium-induced disturbances within the cardiovascular system. The most distinctive aspect of the barium effect was a demonstrated hypersensitivity of the cardiovascular system to sodium pentobarbital. Under barbiturate anesthesia, virtually all of the myocardial contractile indices were depressed significantly in barium-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to ketamine and xylazine anesthesia revealed that the cardiovascular actions of sodium pentobarbital in barium-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by barium were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the barium-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial metabolic disturbances, and the hypersensitivity of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed DISEASE induced by chronic barium exposure. These experimental findings represent the first indication that life-long barium ingestion may have significant adverse effects on the mammalian cardiovascular system. | CHEMICAL-INDUCED-DISEASE |
| Cardiovascular dysfunction and hypersensitivity to sodium pentobarbital induced by chronic CHEMICAL ingestion. Barium-supplemented Long-Evans hooded rats were characterized by a persistent DISEASE that was evident after 1 month of barium (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant barium-induced disturbances within the cardiovascular system. The most distinctive aspect of the barium effect was a demonstrated hypersensitivity of the cardiovascular system to sodium pentobarbital. Under barbiturate anesthesia, virtually all of the myocardial contractile indices were depressed significantly in barium-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to ketamine and xylazine anesthesia revealed that the cardiovascular actions of sodium pentobarbital in barium-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by barium were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the barium-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial metabolic disturbances, and the hypersensitivity of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic barium exposure. These experimental findings represent the first indication that life-long barium ingestion may have significant adverse effects on the mammalian cardiovascular system. | CHEMICAL-INDUCED-DISEASE |
| Cardiovascular dysfunction and DISEASE to sodium pentobarbital induced by chronic barium chloride ingestion. Barium-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of barium (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant barium-induced disturbances within the cardiovascular system. The most distinctive aspect of the barium effect was a demonstrated DISEASE of the cardiovascular system to sodium pentobarbital. Under barbiturate anesthesia, virtually all of the myocardial contractile indices were depressed significantly in barium-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to ketamine and CHEMICAL anesthesia revealed that the cardiovascular actions of sodium pentobarbital in barium-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by barium were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the barium-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial metabolic disturbances, and the DISEASE of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic barium exposure. These experimental findings represent the first indication that life-long barium ingestion may have significant adverse effects on the mammalian cardiovascular system. | NO-RELATIONSHIP |
| DISEASE and hypersensitivity to CHEMICAL induced by chronic barium chloride ingestion. Barium-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of barium (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant barium-induced DISEASE. The most distinctive aspect of the barium effect was a demonstrated hypersensitivity of the cardiovascular system to CHEMICAL. Under barbiturate anesthesia, virtually all of the myocardial contractile indices were depressed significantly in barium-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to ketamine and xylazine anesthesia revealed that the cardiovascular actions of CHEMICAL in barium-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by barium were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the barium-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial metabolic disturbances, and the hypersensitivity of the cardiovascular system to CHEMICAL suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic barium exposure. These experimental findings represent the first indication that life-long barium ingestion may have significant adverse effects on the mammalian cardiovascular system. | CHEMICAL-INDUCED-DISEASE |
| Cardiovascular dysfunction and hypersensitivity to sodium pentobarbital induced by chronic barium chloride ingestion. Barium-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of barium (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant barium-induced disturbances within the cardiovascular system. The most distinctive aspect of the barium effect was a demonstrated hypersensitivity of the cardiovascular system to sodium pentobarbital. Under barbiturate anesthesia, virtually all of the myocardial contractile indices were depressed significantly in barium-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to ketamine and CHEMICAL anesthesia revealed that the cardiovascular actions of sodium pentobarbital in barium-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by barium were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the barium-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial DISEASE, and the hypersensitivity of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic barium exposure. These experimental findings represent the first indication that life-long barium ingestion may have significant adverse effects on the mammalian cardiovascular system. | NO-RELATIONSHIP |
| Cardiovascular dysfunction and hypersensitivity to CHEMICAL induced by chronic barium chloride ingestion. Barium-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of barium (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant barium-induced disturbances within the cardiovascular system. The most distinctive aspect of the barium effect was a demonstrated hypersensitivity of the cardiovascular system to CHEMICAL. Under barbiturate anesthesia, virtually all of the myocardial contractile indices were depressed significantly in barium-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to ketamine and xylazine anesthesia revealed that the cardiovascular actions of CHEMICAL in barium-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by barium were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the barium-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial DISEASE, and the hypersensitivity of the cardiovascular system to CHEMICAL suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic barium exposure. These experimental findings represent the first indication that life-long barium ingestion may have significant adverse effects on the mammalian cardiovascular system. | NO-RELATIONSHIP |
| Cardiovascular dysfunction and DISEASE to CHEMICAL induced by chronic barium chloride ingestion. Barium-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of barium (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant barium-induced disturbances within the cardiovascular system. The most distinctive aspect of the barium effect was a demonstrated DISEASE of the cardiovascular system to CHEMICAL. Under barbiturate anesthesia, virtually all of the myocardial contractile indices were depressed significantly in barium-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to ketamine and xylazine anesthesia revealed that the cardiovascular actions of CHEMICAL in barium-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by barium were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the barium-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial metabolic disturbances, and the DISEASE of the cardiovascular system to CHEMICAL suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic barium exposure. These experimental findings represent the first indication that life-long barium ingestion may have significant adverse effects on the mammalian cardiovascular system. | CHEMICAL-INDUCED-DISEASE |
| DISEASE and hypersensitivity to sodium pentobarbital induced by chronic barium chloride ingestion. Barium-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of barium (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant barium-induced DISEASE. The most distinctive aspect of the barium effect was a demonstrated hypersensitivity of the cardiovascular system to sodium pentobarbital. Under barbiturate anesthesia, virtually all of the myocardial contractile indices were depressed significantly in barium-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to CHEMICAL and xylazine anesthesia revealed that the cardiovascular actions of sodium pentobarbital in barium-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by barium were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the barium-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial metabolic disturbances, and the hypersensitivity of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic barium exposure. These experimental findings represent the first indication that life-long barium ingestion may have significant adverse effects on the mammalian cardiovascular system. | NO-RELATIONSHIP |
| DISEASE and hypersensitivity to sodium pentobarbital induced by chronic barium chloride ingestion. CHEMICAL-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of CHEMICAL (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant CHEMICAL-induced DISEASE. The most distinctive aspect of the CHEMICAL effect was a demonstrated hypersensitivity of the cardiovascular system to sodium pentobarbital. Under barbiturate anesthesia, virtually all of the myocardial contractile indices were depressed significantly in CHEMICAL-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to ketamine and xylazine anesthesia revealed that the cardiovascular actions of sodium pentobarbital in CHEMICAL-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by CHEMICAL were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of CHEMICAL-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the CHEMICAL-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from CHEMICAL-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial metabolic disturbances, and the hypersensitivity of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic CHEMICAL exposure. These experimental findings represent the first indication that life-long CHEMICAL ingestion may have significant adverse effects on the mammalian cardiovascular system. | CHEMICAL-INDUCED-DISEASE |
| DISEASE and hypersensitivity to sodium pentobarbital induced by chronic barium chloride ingestion. Barium-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of barium (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant barium-induced DISEASE. The most distinctive aspect of the barium effect was a demonstrated hypersensitivity of the cardiovascular system to sodium pentobarbital. Under barbiturate anesthesia, virtually all of the myocardial contractile indices were depressed significantly in barium-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to ketamine and CHEMICAL anesthesia revealed that the cardiovascular actions of sodium pentobarbital in barium-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by barium were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the barium-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial metabolic disturbances, and the hypersensitivity of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic barium exposure. These experimental findings represent the first indication that life-long barium ingestion may have significant adverse effects on the mammalian cardiovascular system. | NO-RELATIONSHIP |
| DISEASE and hypersensitivity to sodium pentobarbital induced by chronic barium chloride ingestion. Barium-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of barium (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant barium-induced DISEASE. The most distinctive aspect of the barium effect was a demonstrated hypersensitivity of the cardiovascular system to sodium pentobarbital. Under CHEMICAL anesthesia, virtually all of the myocardial contractile indices were depressed significantly in barium-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to ketamine and xylazine anesthesia revealed that the cardiovascular actions of sodium pentobarbital in barium-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by barium were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the barium-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial metabolic disturbances, and the hypersensitivity of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic barium exposure. These experimental findings represent the first indication that life-long barium ingestion may have significant adverse effects on the mammalian cardiovascular system. | NO-RELATIONSHIP |
| Cardiovascular dysfunction and hypersensitivity to sodium pentobarbital induced by chronic barium chloride ingestion. Barium-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of barium (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant barium-induced disturbances within the cardiovascular system. The most distinctive aspect of the barium effect was a demonstrated hypersensitivity of the cardiovascular system to sodium pentobarbital. Under barbiturate anesthesia, virtually all of the myocardial contractile indices were depressed significantly in barium-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to CHEMICAL and xylazine anesthesia revealed that the cardiovascular actions of sodium pentobarbital in barium-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by barium were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the barium-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial DISEASE, and the hypersensitivity of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic barium exposure. These experimental findings represent the first indication that life-long barium ingestion may have significant adverse effects on the mammalian cardiovascular system. | NO-RELATIONSHIP |
| Cardiovascular dysfunction and hypersensitivity to sodium pentobarbital induced by chronic barium chloride ingestion. Barium-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of barium (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant barium-induced disturbances within the cardiovascular system. The most distinctive aspect of the barium effect was a demonstrated hypersensitivity of the cardiovascular system to sodium pentobarbital. Under CHEMICAL anesthesia, virtually all of the myocardial contractile indices were depressed significantly in barium-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to ketamine and xylazine anesthesia revealed that the cardiovascular actions of sodium pentobarbital in barium-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by barium were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the barium-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial DISEASE, and the hypersensitivity of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic barium exposure. These experimental findings represent the first indication that life-long barium ingestion may have significant adverse effects on the mammalian cardiovascular system. | NO-RELATIONSHIP |
| Cardiovascular dysfunction and DISEASE to sodium pentobarbital induced by chronic barium chloride ingestion. Barium-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of barium (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant barium-induced disturbances within the cardiovascular system. The most distinctive aspect of the barium effect was a demonstrated DISEASE of the cardiovascular system to sodium pentobarbital. Under CHEMICAL anesthesia, virtually all of the myocardial contractile indices were depressed significantly in barium-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to ketamine and xylazine anesthesia revealed that the cardiovascular actions of sodium pentobarbital in barium-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by barium were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the barium-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial metabolic disturbances, and the DISEASE of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic barium exposure. These experimental findings represent the first indication that life-long barium ingestion may have significant adverse effects on the mammalian cardiovascular system. | NO-RELATIONSHIP |
| Cardiovascular dysfunction and hypersensitivity to sodium pentobarbital induced by chronic barium chloride ingestion. CHEMICAL-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of CHEMICAL (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant CHEMICAL-induced disturbances within the cardiovascular system. The most distinctive aspect of the CHEMICAL effect was a demonstrated hypersensitivity of the cardiovascular system to sodium pentobarbital. Under barbiturate anesthesia, virtually all of the myocardial contractile indices were depressed significantly in CHEMICAL-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to ketamine and xylazine anesthesia revealed that the cardiovascular actions of sodium pentobarbital in CHEMICAL-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by CHEMICAL were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of CHEMICAL-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the CHEMICAL-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from CHEMICAL-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial DISEASE, and the hypersensitivity of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic CHEMICAL exposure. These experimental findings represent the first indication that life-long CHEMICAL ingestion may have significant adverse effects on the mammalian cardiovascular system. | CHEMICAL-INDUCED-DISEASE |
| Cardiovascular dysfunction and DISEASE to sodium pentobarbital induced by chronic barium chloride ingestion. CHEMICAL-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of CHEMICAL (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant CHEMICAL-induced disturbances within the cardiovascular system. The most distinctive aspect of the CHEMICAL effect was a demonstrated DISEASE of the cardiovascular system to sodium pentobarbital. Under barbiturate anesthesia, virtually all of the myocardial contractile indices were depressed significantly in CHEMICAL-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to ketamine and xylazine anesthesia revealed that the cardiovascular actions of sodium pentobarbital in CHEMICAL-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by CHEMICAL were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of CHEMICAL-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the CHEMICAL-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from CHEMICAL-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial metabolic disturbances, and the DISEASE of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic CHEMICAL exposure. These experimental findings represent the first indication that life-long CHEMICAL ingestion may have significant adverse effects on the mammalian cardiovascular system. | CHEMICAL-INDUCED-DISEASE |
| Cardiovascular dysfunction and DISEASE to sodium pentobarbital induced by chronic barium chloride ingestion. Barium-supplemented Long-Evans hooded rats were characterized by a persistent hypertension that was evident after 1 month of barium (100 micrograms/ml mineral fortified water) treatment. Analysis of in vivo myocardial excitability, contractility, and metabolic characteristics at 16 months revealed other significant barium-induced disturbances within the cardiovascular system. The most distinctive aspect of the barium effect was a demonstrated DISEASE of the cardiovascular system to sodium pentobarbital. Under barbiturate anesthesia, virtually all of the myocardial contractile indices were depressed significantly in barium-exposed rats relative to the corresponding control-fed rats. The lack of a similar response to CHEMICAL and xylazine anesthesia revealed that the cardiovascular actions of sodium pentobarbital in barium-treated rats were linked specifically to this anesthetic, and were not representative of a generalized anesthetic response. Other myocardial pathophysiologic and metabolic changes induced by barium were manifest, irrespective of the anesthetic employed. The contractile element shortening velocity of the cardiac muscle fibers was significantly slower in both groups of barium-treated rats relative to the control groups, irrespective of the anesthetic regimen. Similarly, significant disturbances in myocardial energy metabolism were detected in the barium-exposed rats which were consistent with the reduced contractile element shortening velocity. In addition, the excitability of the cardiac conduction system was depressed preferentially in the atrioventricular nodal region of hearts from barium-exposed rats. Overall, the altered cardiac contractility and excitability characteristics, the myocardial metabolic disturbances, and the DISEASE of the cardiovascular system to sodium pentobarbital suggest the existence of a heretofore undescribed cardiomyopathic disorder induced by chronic barium exposure. These experimental findings represent the first indication that life-long barium ingestion may have significant adverse effects on the mammalian cardiovascular system. | NO-RELATIONSHIP |
| Propranolol antagonism of CHEMICAL-induced DISEASE. CHEMICAL (CHEMICAL) overdose can cause severe DISEASE, intracerebral hemorrhage, and death. We studied the efficacy and safety of propranolol in the treatment of CHEMICAL-induced DISEASE. Subjects received propranolol either by mouth for 48 hours before CHEMICAL or as a rapid intravenous infusion after CHEMICAL. CHEMICAL, 75 mg alone, increased blood pressure (31 +/- 14 mm Hg systolic, 20 +/- 5 mm Hg diastolic), and propranolol pretreatment antagonized this increase (12 +/- 10 mm Hg systolic, 10 +/- 7 mm Hg diastolic). Intravenous propranolol after CHEMICAL also decreased blood pressure. Left ventricular function (assessed by echocardiography) showed that CHEMICAL increased the stroke volume 30% (from 62.5 +/- 20.9 to 80.8 +/- 22.4 ml), the ejection fraction 9% (from 64% +/- 10% to 70% +/- 7%), and cardiac output 14% (from 3.6 +/- 0.6 to 4.1 +/- 1.0 L/min). Intravenous propranolol reversed these effects. Systemic vascular resistance was increased by CHEMICAL 28% (from 1710 +/- 200 to 2190 +/- 700 dyne X sec/cm5) and was further increased by propranolol 22% (to 2660 +/- 1200 dyne X sec/cm5). We conclude that CHEMICAL increases blood pressure by increasing systemic vascular resistance and cardiac output, and that propranolol antagonizes this increase by reversing the effect of CHEMICAL on cardiac output. That propranolol antagonizes the pressor effect of CHEMICAL is in contrast to the interaction in which propranolol enhances the pressor effect of norepinephrine. This is probably because CHEMICAL has less beta 2 activity than does norepinephrine. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL antagonism of phenylpropanolamine-induced hypertension. Phenylpropanolamine (PPA) DISEASE can cause severe hypertension, intracerebral hemorrhage, and death. We studied the efficacy and safety of CHEMICAL in the treatment of PPA-induced hypertension. Subjects received CHEMICAL either by mouth for 48 hours before PPA or as a rapid intravenous infusion after PPA. PPA, 75 mg alone, increased blood pressure (31 +/- 14 mm Hg systolic, 20 +/- 5 mm Hg diastolic), and CHEMICAL pretreatment antagonized this increase (12 +/- 10 mm Hg systolic, 10 +/- 7 mm Hg diastolic). Intravenous CHEMICAL after PPA also decreased blood pressure. Left ventricular function (assessed by echocardiography) showed that PPA increased the stroke volume 30% (from 62.5 +/- 20.9 to 80.8 +/- 22.4 ml), the ejection fraction 9% (from 64% +/- 10% to 70% +/- 7%), and cardiac output 14% (from 3.6 +/- 0.6 to 4.1 +/- 1.0 L/min). Intravenous CHEMICAL reversed these effects. Systemic vascular resistance was increased by PPA 28% (from 1710 +/- 200 to 2190 +/- 700 dyne X sec/cm5) and was further increased by CHEMICAL 22% (to 2660 +/- 1200 dyne X sec/cm5). We conclude that PPA increases blood pressure by increasing systemic vascular resistance and cardiac output, and that CHEMICAL antagonizes this increase by reversing the effect of PPA on cardiac output. That CHEMICAL antagonizes the pressor effect of PPA is in contrast to the interaction in which CHEMICAL enhances the pressor effect of norepinephrine. This is probably because PPA has less beta 2 activity than does norepinephrine. | NO-RELATIONSHIP |
| CHEMICAL antagonism of phenylpropanolamine-induced hypertension. Phenylpropanolamine (PPA) overdose can cause severe hypertension, DISEASE, and death. We studied the efficacy and safety of CHEMICAL in the treatment of PPA-induced hypertension. Subjects received CHEMICAL either by mouth for 48 hours before PPA or as a rapid intravenous infusion after PPA. PPA, 75 mg alone, increased blood pressure (31 +/- 14 mm Hg systolic, 20 +/- 5 mm Hg diastolic), and CHEMICAL pretreatment antagonized this increase (12 +/- 10 mm Hg systolic, 10 +/- 7 mm Hg diastolic). Intravenous CHEMICAL after PPA also decreased blood pressure. Left ventricular function (assessed by echocardiography) showed that PPA increased the stroke volume 30% (from 62.5 +/- 20.9 to 80.8 +/- 22.4 ml), the ejection fraction 9% (from 64% +/- 10% to 70% +/- 7%), and cardiac output 14% (from 3.6 +/- 0.6 to 4.1 +/- 1.0 L/min). Intravenous CHEMICAL reversed these effects. Systemic vascular resistance was increased by PPA 28% (from 1710 +/- 200 to 2190 +/- 700 dyne X sec/cm5) and was further increased by CHEMICAL 22% (to 2660 +/- 1200 dyne X sec/cm5). We conclude that PPA increases blood pressure by increasing systemic vascular resistance and cardiac output, and that CHEMICAL antagonizes this increase by reversing the effect of PPA on cardiac output. That CHEMICAL antagonizes the pressor effect of PPA is in contrast to the interaction in which CHEMICAL enhances the pressor effect of norepinephrine. This is probably because PPA has less beta 2 activity than does norepinephrine. | NO-RELATIONSHIP |
| Propranolol antagonism of phenylpropanolamine-induced hypertension. Phenylpropanolamine (PPA) DISEASE can cause severe hypertension, intracerebral hemorrhage, and death. We studied the efficacy and safety of propranolol in the treatment of PPA-induced hypertension. Subjects received propranolol either by mouth for 48 hours before PPA or as a rapid intravenous infusion after PPA. PPA, 75 mg alone, increased blood pressure (31 +/- 14 mm Hg systolic, 20 +/- 5 mm Hg diastolic), and propranolol pretreatment antagonized this increase (12 +/- 10 mm Hg systolic, 10 +/- 7 mm Hg diastolic). Intravenous propranolol after PPA also decreased blood pressure. Left ventricular function (assessed by echocardiography) showed that PPA increased the stroke volume 30% (from 62.5 +/- 20.9 to 80.8 +/- 22.4 ml), the ejection fraction 9% (from 64% +/- 10% to 70% +/- 7%), and cardiac output 14% (from 3.6 +/- 0.6 to 4.1 +/- 1.0 L/min). Intravenous propranolol reversed these effects. Systemic vascular resistance was increased by PPA 28% (from 1710 +/- 200 to 2190 +/- 700 dyne X sec/cm5) and was further increased by propranolol 22% (to 2660 +/- 1200 dyne X sec/cm5). We conclude that PPA increases blood pressure by increasing systemic vascular resistance and cardiac output, and that propranolol antagonizes this increase by reversing the effect of PPA on cardiac output. That propranolol antagonizes the pressor effect of PPA is in contrast to the interaction in which propranolol enhances the pressor effect of CHEMICAL. This is probably because PPA has less beta 2 activity than does CHEMICAL. | NO-RELATIONSHIP |
| Propranolol antagonism of phenylpropanolamine-induced hypertension. Phenylpropanolamine (PPA) overdose can cause severe hypertension, DISEASE, and death. We studied the efficacy and safety of propranolol in the treatment of PPA-induced hypertension. Subjects received propranolol either by mouth for 48 hours before PPA or as a rapid intravenous infusion after PPA. PPA, 75 mg alone, increased blood pressure (31 +/- 14 mm Hg systolic, 20 +/- 5 mm Hg diastolic), and propranolol pretreatment antagonized this increase (12 +/- 10 mm Hg systolic, 10 +/- 7 mm Hg diastolic). Intravenous propranolol after PPA also decreased blood pressure. Left ventricular function (assessed by echocardiography) showed that PPA increased the stroke volume 30% (from 62.5 +/- 20.9 to 80.8 +/- 22.4 ml), the ejection fraction 9% (from 64% +/- 10% to 70% +/- 7%), and cardiac output 14% (from 3.6 +/- 0.6 to 4.1 +/- 1.0 L/min). Intravenous propranolol reversed these effects. Systemic vascular resistance was increased by PPA 28% (from 1710 +/- 200 to 2190 +/- 700 dyne X sec/cm5) and was further increased by propranolol 22% (to 2660 +/- 1200 dyne X sec/cm5). We conclude that PPA increases blood pressure by increasing systemic vascular resistance and cardiac output, and that propranolol antagonizes this increase by reversing the effect of PPA on cardiac output. That propranolol antagonizes the pressor effect of PPA is in contrast to the interaction in which propranolol enhances the pressor effect of CHEMICAL. This is probably because PPA has less beta 2 activity than does CHEMICAL. | NO-RELATIONSHIP |
| Propranolol antagonism of phenylpropanolamine-induced hypertension. Phenylpropanolamine (PPA) overdose can cause severe hypertension, intracerebral hemorrhage, and death. We studied the efficacy and safety of propranolol in the treatment of PPA-induced hypertension. Subjects received propranolol either by mouth for 48 hours before PPA or as a rapid intravenous infusion after PPA. PPA, 75 mg alone, increased blood pressure (31 +/- 14 mm Hg systolic, 20 +/- 5 mm Hg diastolic), and propranolol pretreatment antagonized this increase (12 +/- 10 mm Hg systolic, 10 +/- 7 mm Hg diastolic). Intravenous propranolol after PPA also decreased blood pressure. Left ventricular function (assessed by echocardiography) showed that PPA increased the DISEASE volume 30% (from 62.5 +/- 20.9 to 80.8 +/- 22.4 ml), the ejection fraction 9% (from 64% +/- 10% to 70% +/- 7%), and cardiac output 14% (from 3.6 +/- 0.6 to 4.1 +/- 1.0 L/min). Intravenous propranolol reversed these effects. Systemic vascular resistance was increased by PPA 28% (from 1710 +/- 200 to 2190 +/- 700 dyne X sec/cm5) and was further increased by propranolol 22% (to 2660 +/- 1200 dyne X sec/cm5). We conclude that PPA increases blood pressure by increasing systemic vascular resistance and cardiac output, and that propranolol antagonizes this increase by reversing the effect of PPA on cardiac output. That propranolol antagonizes the pressor effect of PPA is in contrast to the interaction in which propranolol enhances the pressor effect of CHEMICAL. This is probably because PPA has less beta 2 activity than does CHEMICAL. | NO-RELATIONSHIP |
| CHEMICAL antagonism of phenylpropanolamine-induced hypertension. Phenylpropanolamine (PPA) overdose can cause severe hypertension, intracerebral hemorrhage, and death. We studied the efficacy and safety of CHEMICAL in the treatment of PPA-induced hypertension. Subjects received CHEMICAL either by mouth for 48 hours before PPA or as a rapid intravenous infusion after PPA. PPA, 75 mg alone, increased blood pressure (31 +/- 14 mm Hg systolic, 20 +/- 5 mm Hg diastolic), and CHEMICAL pretreatment antagonized this increase (12 +/- 10 mm Hg systolic, 10 +/- 7 mm Hg diastolic). Intravenous CHEMICAL after PPA also decreased blood pressure. Left ventricular function (assessed by echocardiography) showed that PPA increased the DISEASE volume 30% (from 62.5 +/- 20.9 to 80.8 +/- 22.4 ml), the ejection fraction 9% (from 64% +/- 10% to 70% +/- 7%), and cardiac output 14% (from 3.6 +/- 0.6 to 4.1 +/- 1.0 L/min). Intravenous CHEMICAL reversed these effects. Systemic vascular resistance was increased by PPA 28% (from 1710 +/- 200 to 2190 +/- 700 dyne X sec/cm5) and was further increased by CHEMICAL 22% (to 2660 +/- 1200 dyne X sec/cm5). We conclude that PPA increases blood pressure by increasing systemic vascular resistance and cardiac output, and that CHEMICAL antagonizes this increase by reversing the effect of PPA on cardiac output. That CHEMICAL antagonizes the pressor effect of PPA is in contrast to the interaction in which CHEMICAL enhances the pressor effect of norepinephrine. This is probably because PPA has less beta 2 activity than does norepinephrine. | NO-RELATIONSHIP |
| Mesangial function and glomerular sclerosis in rats with CHEMICAL nephrosis. The possible relationship between mesangial dysfunction and development of glomerular sclerosis was studied in the CHEMICAL (CHEMICAL) model. Five male Wistar rats received repeated subcutaneous CHEMICAL injections; five controls received saline only. After 4 weeks the CHEMICAL rats were severely DISEASE (190 +/- 80 mg/24 hr), and all rats were given colloidal carbon (CC) intravenously. At 5 months glomerular sclerosis was found in 7.6 +/- 3.4% of the glomeruli of CHEMICAL rats; glomeruli of the controls were normal. Glomeruli of CHEMICAL rats contained significantly more CC than glomeruli of controls. Glomeruli with sclerosis contained significantly more CC than non-sclerotic glomeruli in the same kidneys. CC was preferentially localized within the sclerotic areas of the affected glomeruli. Since mesangial CC clearance from the mesangium did not change during chronic CHEMICAL treatment, we conclude that this preferential CC localization within the lesions is caused by an increased CC uptake shortly after injection in apparent vulnerable areas where sclerosis will develop subsequently. Cluster analysis showed a random distribution of lesions in the CHEMICAL glomeruli in concordance with the random localization of mesangial areas with dysfunction in this model. Similar to the remnant kidney model in CHEMICAL nephrosis the development of glomerular sclerosis may be related to "mesangial overloading." | CHEMICAL-INDUCED-DISEASE |
| Mesangial function and glomerular sclerosis in rats with aminonucleoside nephrosis. The possible relationship between mesangial dysfunction and development of glomerular sclerosis was studied in the puromycin aminonucleoside (PAN) model. Five male Wistar rats received repeated subcutaneous PAN injections; five controls received saline only. After 4 weeks the PAN rats were severely proteinuric (190 +/- 80 mg/24 hr), and all rats were given colloidal CHEMICAL (CC) intravenously. At 5 months glomerular sclerosis was found in 7.6 +/- 3.4% of the glomeruli of PAN rats; glomeruli of the controls were normal. Glomeruli of PAN rats contained significantly more CC than glomeruli of controls. Glomeruli with DISEASE contained significantly more CC than non-sclerotic glomeruli in the same kidneys. CC was preferentially localized within the sclerotic areas of the affected glomeruli. Since mesangial CC clearance from the mesangium did not change during chronic PAN treatment, we conclude that this preferential CC localization within the lesions is caused by an increased CC uptake shortly after injection in apparent vulnerable areas where DISEASE will develop subsequently. Cluster analysis showed a random distribution of lesions in the PAN glomeruli in concordance with the random localization of mesangial areas with dysfunction in this model. Similar to the remnant kidney model in PAN nephrosis the development of glomerular sclerosis may be related to "mesangial overloading." | NO-RELATIONSHIP |
| Mesangial function and DISEASE in rats with aminonucleoside nephrosis. The possible relationship between DISEASE and development of DISEASE was studied in the puromycin aminonucleoside (PAN) model. Five male Wistar rats received repeated subcutaneous PAN injections; five controls received saline only. After 4 weeks the PAN rats were severely proteinuric (190 +/- 80 mg/24 hr), and all rats were given colloidal CHEMICAL (CC) intravenously. At 5 months DISEASE was found in 7.6 +/- 3.4% of the glomeruli of PAN rats; glomeruli of the controls were normal. Glomeruli of PAN rats contained significantly more CC than glomeruli of controls. Glomeruli with sclerosis contained significantly more CC than non-sclerotic glomeruli in the same kidneys. CC was preferentially localized within the sclerotic areas of the affected glomeruli. Since mesangial CC clearance from the mesangium did not change during chronic PAN treatment, we conclude that this preferential CC localization within the lesions is caused by an increased CC uptake shortly after injection in apparent vulnerable areas where sclerosis will develop subsequently. Cluster analysis showed a random distribution of lesions in the PAN glomeruli in concordance with the random localization of mesangial areas with dysfunction in this model. Similar to the remnant kidney model in PAN nephrosis the development of DISEASE may be related to "mesangial overloading." | CHEMICAL-INDUCED-DISEASE |
| Mesangial function and glomerular sclerosis in rats with aminonucleoside DISEASE. The possible relationship between mesangial dysfunction and development of glomerular sclerosis was studied in the puromycin aminonucleoside (PAN) model. Five male Wistar rats received repeated subcutaneous PAN injections; five controls received saline only. After 4 weeks the PAN rats were severely proteinuric (190 +/- 80 mg/24 hr), and all rats were given colloidal CHEMICAL (CC) intravenously. At 5 months glomerular sclerosis was found in 7.6 +/- 3.4% of the glomeruli of PAN rats; glomeruli of the controls were normal. Glomeruli of PAN rats contained significantly more CC than glomeruli of controls. Glomeruli with sclerosis contained significantly more CC than non-sclerotic glomeruli in the same kidneys. CC was preferentially localized within the sclerotic areas of the affected glomeruli. Since mesangial CC clearance from the mesangium did not change during chronic PAN treatment, we conclude that this preferential CC localization within the lesions is caused by an increased CC uptake shortly after injection in apparent vulnerable areas where sclerosis will develop subsequently. Cluster analysis showed a random distribution of lesions in the PAN glomeruli in concordance with the random localization of mesangial areas with dysfunction in this model. Similar to the remnant kidney model in PAN DISEASE the development of glomerular sclerosis may be related to "mesangial overloading." | NO-RELATIONSHIP |
| Relationship between CHEMICAL-induced DISEASE and hippocampal nicotinic receptors. A controversy has existed for several years concerning the physiological relevance of the nicotinic receptor measured by alpha-bungarotoxin binding. Using mice derived from a classical F2 and backcross genetic design, a relationship between CHEMICAL-induced DISEASE and alpha-bungarotoxin nicotinic receptor concentration was found. Mice sensitive to the convulsant effects of CHEMICAL had greater alpha-bungarotoxin binding in the hippocampus than DISEASE insensitive mice. The binding sites from DISEASE sensitive and resistant mice were equally affected by treatment with dithiothreitol, trypsin or heat. Thus it appears that the difference between DISEASE sensitive and insensitive animals may be due to a difference in hippocampal nicotinic receptor concentration as measured with alpha-bungarotoxin binding. | CHEMICAL-INDUCED-DISEASE |
| The role of CHEMICAL in acetaminophen-induced nephrotoxicity: effect of bis(p-nitrophenyl) phosphate on acetaminophen and CHEMICAL nephrotoxicity and metabolism in Fischer 344 rats. Acetaminophen (APAP) produces proximal DISEASE in Fischer 344 (F344) rats. Recently, CHEMICAL (CHEMICAL), a known potent nephrotoxicant, was identified as a metabolite of APAP in F344 rats. The purpose of this study was to determine if CHEMICAL formation is a requisite step in APAP-induced nephrotoxicity. Therefore, the effect of bis(p-nitrophenyl) phosphate (BNPP), an acylamidase inhibitor, on APAP and CHEMICAL nephrotoxicity and metabolism was determined. BNPP (1 to 8 mM) reduced APAP deacetylation and covalent binding in F344 renal cortical homogenates in a concentration-dependent manner. Pretreatment of animals with BNPP prior to APAP or CHEMICAL administration resulted in marked reduction of APAP (900 mg/kg) nephrotoxicity but not CHEMICAL nephrotoxicity. This result was not due to altered disposition of either APAP or acetylated metabolites in plasma or renal cortical and hepatic tissue. Rather, BNPP pretreatment reduced the fraction of APAP excreted as CHEMICAL by 64 and 75% after APAP doses of 750 and 900 mg/kg. BNPP did not alter the excretion of APAP or any of its non-deacetylated metabolites nor did BNPP alter excretion of CHEMICAL or its metabolites after CHEMICAL doses of 150 and 300 mg/kg. Therefore, the BNPP-induced reduction in APAP-induced nephrotoxicity appears to be due to inhibition of APAP deacetylation. It is concluded that CHEMICAL formation, in vivo, accounts, at least in part, for APAP-induced DISEASE. | NO-RELATIONSHIP |
| The role of p-aminophenol in CHEMICAL-induced nephrotoxicity: effect of bis(p-nitrophenyl) phosphate on CHEMICAL and p-aminophenol nephrotoxicity and metabolism in Fischer 344 rats. CHEMICAL (CHEMICAL) produces proximal DISEASE in Fischer 344 (F344) rats. Recently, p-aminophenol (PAP), a known potent nephrotoxicant, was identified as a metabolite of CHEMICAL in F344 rats. The purpose of this study was to determine if PAP formation is a requisite step in CHEMICAL-induced nephrotoxicity. Therefore, the effect of bis(p-nitrophenyl) phosphate (BNPP), an acylamidase inhibitor, on CHEMICAL and PAP nephrotoxicity and metabolism was determined. BNPP (1 to 8 mM) reduced CHEMICAL deacetylation and covalent binding in F344 renal cortical homogenates in a concentration-dependent manner. Pretreatment of animals with BNPP prior to CHEMICAL or PAP administration resulted in marked reduction of CHEMICAL (900 mg/kg) nephrotoxicity but not PAP nephrotoxicity. This result was not due to altered disposition of either CHEMICAL or acetylated metabolites in plasma or renal cortical and hepatic tissue. Rather, BNPP pretreatment reduced the fraction of CHEMICAL excreted as PAP by 64 and 75% after CHEMICAL doses of 750 and 900 mg/kg. BNPP did not alter the excretion of CHEMICAL or any of its non-deacetylated metabolites nor did BNPP alter excretion of PAP or its metabolites after PAP doses of 150 and 300 mg/kg. Therefore, the BNPP-induced reduction in CHEMICAL-induced nephrotoxicity appears to be due to inhibition of CHEMICAL deacetylation. It is concluded that PAP formation, in vivo, accounts, at least in part, for CHEMICAL-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| The role of p-aminophenol in acetaminophen-induced DISEASE: effect of CHEMICAL on acetaminophen and p-aminophenol DISEASE and metabolism in Fischer 344 rats. Acetaminophen (APAP) produces proximal tubular necrosis in Fischer 344 (F344) rats. Recently, p-aminophenol (PAP), a known potent nephrotoxicant, was identified as a metabolite of APAP in F344 rats. The purpose of this study was to determine if PAP formation is a requisite step in APAP-induced DISEASE. Therefore, the effect of CHEMICAL (CHEMICAL), an acylamidase inhibitor, on APAP and PAP DISEASE and metabolism was determined. CHEMICAL (1 to 8 mM) reduced APAP deacetylation and covalent binding in F344 renal cortical homogenates in a concentration-dependent manner. Pretreatment of animals with CHEMICAL prior to APAP or PAP administration resulted in marked reduction of APAP (900 mg/kg) DISEASE but not PAP DISEASE. This result was not due to altered disposition of either APAP or acetylated metabolites in plasma or renal cortical and hepatic tissue. Rather, CHEMICAL pretreatment reduced the fraction of APAP excreted as PAP by 64 and 75% after APAP doses of 750 and 900 mg/kg. CHEMICAL did not alter the excretion of APAP or any of its non-deacetylated metabolites nor did CHEMICAL alter excretion of PAP or its metabolites after PAP doses of 150 and 300 mg/kg. Therefore, the CHEMICAL-induced reduction in APAP-induced DISEASE appears to be due to inhibition of APAP deacetylation. It is concluded that PAP formation, in vivo, accounts, at least in part, for APAP-induced renal tubular necrosis. | NO-RELATIONSHIP |
| CHEMICAL-induced DISEASE in newborn infants. Two neonates suffered from generalized DISEASE during the course of intravenous CHEMICAL for post-operative analgesia. They received CHEMICAL in doses of 32 micrograms/kg/hr and 40 micrograms/kg/hr larger than a group of 10 neonates who received 6-24 micrograms/kg/hr and had no DISEASE. Plasma concentrations of CHEMICAL in these neonates was excessive (60 and 90 mg/ml). Other known reasons for DISEASE were ruled out and the DISEASE stopped a few hours after cessation of CHEMICAL and did not reoccur in the subsequent 8 months. It is suggested that post-operative intravenous CHEMICAL should not exceed 20 micrograms/kg/ml in neonates. | CHEMICAL-INDUCED-DISEASE |
| Effect of CHEMICAL on Pseudomonas infections in monkeys. In rhesus monkeys, intravenous challenge with 0.6 x 10(10) to 2.2 x 10(10)Pseudomonas aeruginosa organisms caused acute illness of 4 to 5 days' duration with spontaneous recovery in 13 of 15 monkeys; blood cultures became negative 3 to 17 days after challenge. Leukocytosis was observed in all monkeys. Intravenous or intratracheal inoculation of 2.0 to 2.5 mg of CHEMICAL was followed by leukopenia in 4 to 5 days. Intravenous inoculation of 4.2 x 10(10) to 7.8 x 10(10) pyocin type 6 Pseudomonas organisms in monkeys given CHEMICAL 4 days previously resulted in fatal infection in 11 of 14 monkeys, whereas none of four receiving Pseudomonas alone died. These studies suggest that an antimetabolite-induced leukopenia predisposes to severe Pseudomonas DISEASE and that such monkeys may serve as a biological model for study of comparative efficacy of antimicrobial agents. | CHEMICAL-INDUCED-DISEASE |
| Effect of CHEMICAL on Pseudomonas infections in monkeys. In rhesus monkeys, intravenous challenge with 0.6 x 10(10) to 2.2 x 10(10)Pseudomonas aeruginosa organisms caused acute illness of 4 to 5 days' duration with spontaneous recovery in 13 of 15 monkeys; blood cultures became negative 3 to 17 days after challenge. Leukocytosis was observed in all monkeys. Intravenous or intratracheal inoculation of 2.0 to 2.5 mg of CHEMICAL was followed by DISEASE in 4 to 5 days. Intravenous inoculation of 4.2 x 10(10) to 7.8 x 10(10) pyocin type 6 Pseudomonas organisms in monkeys given CHEMICAL 4 days previously resulted in fatal infection in 11 of 14 monkeys, whereas none of four receiving Pseudomonas alone died. These studies suggest that an antimetabolite-induced DISEASE predisposes to severe Pseudomonas sepsis and that such monkeys may serve as a biological model for study of comparative efficacy of antimicrobial agents. | CHEMICAL-INDUCED-DISEASE |
| Effect of CHEMICAL on DISEASE in monkeys. In rhesus monkeys, intravenous challenge with 0.6 x 10(10) to 2.2 x 10(10)Pseudomonas aeruginosa organisms caused acute illness of 4 to 5 days' duration with spontaneous recovery in 13 of 15 monkeys; blood cultures became negative 3 to 17 days after challenge. Leukocytosis was observed in all monkeys. Intravenous or intratracheal inoculation of 2.0 to 2.5 mg of CHEMICAL was followed by leukopenia in 4 to 5 days. Intravenous inoculation of 4.2 x 10(10) to 7.8 x 10(10) pyocin type 6 Pseudomonas organisms in monkeys given CHEMICAL 4 days previously resulted in fatal infection in 11 of 14 monkeys, whereas none of four receiving Pseudomonas alone died. These studies suggest that an antimetabolite-induced leukopenia predisposes to severe Pseudomonas sepsis and that such monkeys may serve as a biological model for study of comparative efficacy of antimicrobial agents. | CHEMICAL-INDUCED-DISEASE |
| Central excitatory actions of CHEMICAL. Toxic actions of CHEMICAL (CHEMICAL) were studied in cats, mice and rats. High doses caused an apparent central excitation, most clearly seen as clonic DISEASE, superimposed on general depression. Following a lethal dose, death was always associated with DISEASE. Comparing the relative sensitivity to central depression and excitation revealed that rats were least likely to have DISEASE at doses that did not first cause loss of consciousness, while cats most clearly showed marked central excitatory actions. Signs of CHEMICAL toxocity in cats included excessive salivation, extreme apprehensive behavior, retching, muscle tremors and DISEASE. An interaction between CHEMICAL and pentylenetetrazol (PTZ) was shown by pretreating mice with CHEMICAL before PTZ challenge. As a function of dose, CHEMICAL first protected against DISEASE and death. At higher doses, however, DISEASE again emerged. These doses of CHEMICAL were lower than those that would alone cause DISEASE. These results may be relevant to the use of CHEMICAL in clinical situations in which there is increased neural excitability, such as epilepsy or sedative-hypnotic drug withdrawal. | CHEMICAL-INDUCED-DISEASE |
| Central excitatory actions of flurazepam. Toxic actions of flurazepam (FZP) were studied in cats, mice and rats. High doses caused an apparent central excitation, most clearly seen as clonic DISEASE, superimposed on general depression. Following a lethal dose, death was always associated with DISEASE. Comparing the relative sensitivity to central depression and excitation revealed that rats were least likely to have DISEASE at doses that did not first cause loss of consciousness, while cats most clearly showed marked central excitatory actions. Signs of FZP toxocity in cats included excessive salivation, extreme apprehensive behavior, retching, muscle tremors and DISEASE. An interaction between FZP and CHEMICAL (CHEMICAL) was shown by pretreating mice with FZP before CHEMICAL challenge. As a function of dose, FZP first protected against DISEASE and death. At higher doses, however, DISEASE again emerged. These doses of FZP were lower than those that would alone cause DISEASE. These results may be relevant to the use of FZP in clinical situations in which there is increased neural excitability, such as epilepsy or sedative-hypnotic drug withdrawal. | CHEMICAL-INDUCED-DISEASE |
| Evidence for cardiac beta 2-adrenoceptors in man. We compared the effects of single doses of 50 mg atenolol (cardioselective), 40 mg propranolol (nonselective), and placebo on both exercise- and CHEMICAL-induced DISEASE in two experiments involving nine normal subjects. Maximal exercise heart rate was reduced from 187 +/- 4(SEM) after placebo to 146 +/- 7 bpm after atenolol and 138 +/- 6 bpm after propranolol, but there were no differences between the drugs. The effects on CHEMICAL DISEASE were determined before and after atropine (0.04 mg/kg IV). CHEMICAL sensitivity was determined as the intravenous dose that increased heart rate by 25 bpm (CD25) and this was increased from 1.8 +/- 0.3 micrograms after placebo to 38.9 +/- 8.3 micrograms after propranolol and 8.3 +/- 1.7 micrograms after atenolol. The difference in the effects of the two was significant. After atropine the CD25 was unchanged after placebo (2.3 +/- 0.3 micrograms) and atenolol (7.7 +/- 1.3 micrograms); it was reduced after propranolol (24.8 +/- 5.0 micrograms), but remained different from atenolol. This change with propranolol sensitivity was calculated as the apparent Ka, this was unchanged by atropine (11.7 +/- 2.1 and 10.1 +/- 2.5 ml/ng). These data are consistent with the hypothesis that exercise-induced DISEASE results largely from beta 1-receptor activation that is blocked by both cardioselective and nonselective drugs, whereas CHEMICAL activates both beta 1- and beta 2-receptors so that after cardioselective blockade there remains a beta 2-component that can be blocked with a nonselective drug. While there appear to be beta 2-receptors in the human heart, their physiologic or pathologic roles remain to be defined. | CHEMICAL-INDUCED-DISEASE |
| Hormones and risk of breast cancer. This paper reports the results of a study of 50 menopausal women receiving hormonal replacement therapy. The majority (29) had surgical menopause; their mean age was 45.7 years. It was hypothesized that progestins could equilibrate the effects of the estrogenic stimulation on the mammary and endometrial target tissues of women on hormonal replacement therapy. The treatment schedule consisted of CHEMICAL (CHEMICAL) 1.25 mg/day for 21 days and Medroxyprogesterone acetate 10 mg/day for 10 days in each month. The mean treatment period was 18 months. During the follow-up period, attention was paid to breast modifications as evidenced by symptomatology, physical examination, and plate thermography. DISEASE was reported by 21 patients, and physical examination revealed a light increase in breast firmness in 12 women and a moderate increase in breast nodularity in 2 women. Themography confirmed the existence of an excessive breast stimulation in 1 women who complained of moderate DISEASE and in 5 of the 7 women who complained of severe DISEASE. Normalization was obtained by halving the estrogen dose. These results suggest that hormonal replacement therapy can be safely prescribed if the following criteria are satisfied: 1) preliminary evaluation of patients from a clinical, metabolic, cytologic, and mammographic perspective; 2) cyclic treatment schedule, with a progestative phase of 10 days; and 3) periodic complete follow-up, with accurate thermographic evaluation of the breast target tissues. | CHEMICAL-INDUCED-DISEASE |
| Hormones and risk of breast cancer. This paper reports the results of a study of 50 menopausal women receiving hormonal replacement therapy. The majority (29) had surgical menopause; their mean age was 45.7 years. It was hypothesized that progestins could equilibrate the effects of the estrogenic stimulation on the mammary and endometrial target tissues of women on hormonal replacement therapy. The treatment schedule consisted of conjugated estrogens (Premarin) 1.25 mg/day for 21 days and CHEMICAL 10 mg/day for 10 days in each month. The mean treatment period was 18 months. During the follow-up period, attention was paid to breast modifications as evidenced by symptomatology, physical examination, and plate thermography. DISEASE was reported by 21 patients, and physical examination revealed a light increase in breast firmness in 12 women and a moderate increase in breast nodularity in 2 women. Themography confirmed the existence of an excessive breast stimulation in 1 women who complained of moderate DISEASE and in 5 of the 7 women who complained of severe DISEASE. Normalization was obtained by halving the estrogen dose. These results suggest that hormonal replacement therapy can be safely prescribed if the following criteria are satisfied: 1) preliminary evaluation of patients from a clinical, metabolic, cytologic, and mammographic perspective; 2) cyclic treatment schedule, with a progestative phase of 10 days; and 3) periodic complete follow-up, with accurate thermographic evaluation of the breast target tissues. | CHEMICAL-INDUCED-DISEASE |
| Hormones and risk of DISEASE. This paper reports the results of a study of 50 menopausal women receiving hormonal replacement therapy. The majority (29) had surgical menopause; their mean age was 45.7 years. It was hypothesized that progestins could equilibrate the effects of the estrogenic stimulation on the mammary and endometrial target tissues of women on hormonal replacement therapy. The treatment schedule consisted of conjugated estrogens (Premarin) 1.25 mg/day for 21 days and Medroxyprogesterone acetate 10 mg/day for 10 days in each month. The mean treatment period was 18 months. During the follow-up period, attention was paid to breast modifications as evidenced by symptomatology, physical examination, and plate thermography. Mastodynia was reported by 21 patients, and physical examination revealed a light increase in breast firmness in 12 women and a moderate increase in breast nodularity in 2 women. Themography confirmed the existence of an excessive breast stimulation in 1 women who complained of moderate mastodynia and in 5 of the 7 women who complained of severe mastodynia. Normalization was obtained by halving the CHEMICAL dose. These results suggest that hormonal replacement therapy can be safely prescribed if the following criteria are satisfied: 1) preliminary evaluation of patients from a clinical, metabolic, cytologic, and mammographic perspective; 2) cyclic treatment schedule, with a progestative phase of 10 days; and 3) periodic complete follow-up, with accurate thermographic evaluation of the breast target tissues. | NO-RELATIONSHIP |
| Hormones and risk of DISEASE. This paper reports the results of a study of 50 menopausal women receiving hormonal replacement therapy. The majority (29) had surgical menopause; their mean age was 45.7 years. It was hypothesized that CHEMICAL could equilibrate the effects of the estrogenic stimulation on the mammary and endometrial target tissues of women on hormonal replacement therapy. The treatment schedule consisted of conjugated estrogens (Premarin) 1.25 mg/day for 21 days and Medroxyprogesterone acetate 10 mg/day for 10 days in each month. The mean treatment period was 18 months. During the follow-up period, attention was paid to breast modifications as evidenced by symptomatology, physical examination, and plate thermography. Mastodynia was reported by 21 patients, and physical examination revealed a light increase in breast firmness in 12 women and a moderate increase in breast nodularity in 2 women. Themography confirmed the existence of an excessive breast stimulation in 1 women who complained of moderate mastodynia and in 5 of the 7 women who complained of severe mastodynia. Normalization was obtained by halving the estrogen dose. These results suggest that hormonal replacement therapy can be safely prescribed if the following criteria are satisfied: 1) preliminary evaluation of patients from a clinical, metabolic, cytologic, and mammographic perspective; 2) cyclic treatment schedule, with a progestative phase of 10 days; and 3) periodic complete follow-up, with accurate thermographic evaluation of the breast target tissues. | NO-RELATIONSHIP |
| Early DISEASE in kidney, heart, and liver transplant recipients on CHEMICAL. Eighty-one renal, seventeen heart, and twenty-four liver transplant patients were followed for DISEASE. Seventeen renal patients received azathioprine (Aza) and prednisone as part of a randomized trial of immunosuppression with 21 CHEMICAL-and-prednisone-treated renal transplant patients. All others received CHEMICAL and prednisone. The randomized Aza patients had more overall DISEASE (P less than 0.05) and more nonviral DISEASE (P less than 0.02) than the randomized CHEMICAL patients. Heart and liver patients had more DISEASE than CHEMICAL renal patients but fewer DISEASE than the Aza renal patients. There were no infectious deaths in renal transplant patients on CHEMICAL or Aza, but DISEASE played a major role in 3 out of 6 cardiac transplant deaths and in 8 out of 9 liver transplant deaths. Renal patients on CHEMICAL had the fewest bacteremias. Analysis of site of DISEASE showed a preponderance of abdominal infections in liver patients, intrathoracic DISEASE in heart patients, and urinary tract infections in renal patients. Pulmonary DISEASE were less common in CHEMICAL-treated renal patients than in Aza-treated patients (P less than 0.05). Aza patients had significantly more staphylococcal infections than all other transplant groups (P less than 0.005), and systemic fungal infections occurred only in the liver transplant group. Cytomegalovirus (CMV) shedding or serological rises in antibody titer, or both occurred in 78% of CHEMICAL patients and 76% of Aza patients. Of the CHEMICAL patients, 15% had symptoms related to CMV infection. Serological evidence for Epstein Barr Virus infection was found in 20% of 65 CHEMICAL patients studied. Three had associated symptoms, and one developed a lymphoma. | CHEMICAL-INDUCED-DISEASE |
| Early DISEASE in kidney, heart, and liver transplant recipients on cyclosporine. Eighty-one renal, seventeen heart, and twenty-four liver transplant patients were followed for DISEASE. Seventeen renal patients received CHEMICAL (CHEMICAL) and prednisone as part of a randomized trial of immunosuppression with 21 cyclosporine-and-prednisone-treated renal transplant patients. All others received cyclosporine and prednisone. The randomized CHEMICAL patients had more overall DISEASE (P less than 0.05) and more nonviral DISEASE (P less than 0.02) than the randomized cyclosporine patients. Heart and liver patients had more DISEASE than cyclosporine renal patients but fewer DISEASE than the CHEMICAL renal patients. There were no infectious deaths in renal transplant patients on cyclosporine or CHEMICAL, but DISEASE played a major role in 3 out of 6 cardiac transplant deaths and in 8 out of 9 liver transplant deaths. Renal patients on cyclosporine had the fewest bacteremias. Analysis of site of DISEASE showed a preponderance of abdominal infections in liver patients, intrathoracic DISEASE in heart patients, and urinary tract infections in renal patients. Pulmonary DISEASE were less common in cyclosporine-treated renal patients than in CHEMICAL-treated patients (P less than 0.05). CHEMICAL patients had significantly more staphylococcal infections than all other transplant groups (P less than 0.005), and systemic fungal infections occurred only in the liver transplant group. Cytomegalovirus (CMV) shedding or serological rises in antibody titer, or both occurred in 78% of cyclosporine patients and 76% of CHEMICAL patients. Of the cyclosporine patients, 15% had symptoms related to CMV infection. Serological evidence for Epstein Barr Virus infection was found in 20% of 65 cyclosporine patients studied. Three had associated symptoms, and one developed a lymphoma. | CHEMICAL-INDUCED-DISEASE |
| Early infections in kidney, heart, and liver transplant recipients on cyclosporine. Eighty-one renal, seventeen heart, and twenty-four liver transplant patients were followed for infection. Seventeen renal patients received azathioprine (Aza) and CHEMICAL as part of a randomized trial of immunosuppression with 21 cyclosporine-and-CHEMICAL-treated renal transplant patients. All others received cyclosporine and CHEMICAL. The randomized Aza patients had more overall infections (P less than 0.05) and more nonviral infections (P less than 0.02) than the randomized cyclosporine patients. Heart and liver patients had more infections than cyclosporine renal patients but fewer infections than the Aza renal patients. There were no infectious deaths in renal transplant patients on cyclosporine or Aza, but infection played a major role in 3 out of 6 cardiac transplant deaths and in 8 out of 9 liver transplant deaths. Renal patients on cyclosporine had the fewest bacteremias. Analysis of site of infection showed a preponderance of abdominal infections in liver patients, intrathoracic infections in heart patients, and urinary tract infections in renal patients. Pulmonary infections were less common in cyclosporine-treated renal patients than in Aza-treated patients (P less than 0.05). Aza patients had significantly more DISEASE than all other transplant groups (P less than 0.005), and systemic fungal infections occurred only in the liver transplant group. Cytomegalovirus (CMV) shedding or serological rises in antibody titer, or both occurred in 78% of cyclosporine patients and 76% of Aza patients. Of the cyclosporine patients, 15% had symptoms related to CMV infection. Serological evidence for Epstein Barr Virus infection was found in 20% of 65 cyclosporine patients studied. Three had associated symptoms, and one developed a lymphoma. | CHEMICAL-INDUCED-DISEASE |
| Early infections in kidney, heart, and liver transplant recipients on cyclosporine. Eighty-one renal, seventeen heart, and twenty-four liver transplant patients were followed for infection. Seventeen renal patients received azathioprine (Aza) and CHEMICAL as part of a randomized trial of immunosuppression with 21 cyclosporine-and-CHEMICAL-treated renal transplant patients. All others received cyclosporine and CHEMICAL. The randomized Aza patients had more overall infections (P less than 0.05) and more nonviral infections (P less than 0.02) than the randomized cyclosporine patients. Heart and liver patients had more infections than cyclosporine renal patients but fewer infections than the Aza renal patients. There were no infectious deaths in renal transplant patients on cyclosporine or Aza, but infection played a major role in 3 out of 6 cardiac transplant deaths and in 8 out of 9 liver transplant deaths. Renal patients on cyclosporine had the fewest bacteremias. Analysis of site of infection showed a preponderance of abdominal infections in liver patients, intrathoracic infections in heart patients, and urinary tract infections in renal patients. Pulmonary infections were less common in cyclosporine-treated renal patients than in Aza-treated patients (P less than 0.05). Aza patients had significantly more staphylococcal infections than all other transplant groups (P less than 0.005), and systemic fungal infections occurred only in the liver transplant group. Cytomegalovirus (CMV) shedding or serological rises in antibody titer, or both occurred in 78% of cyclosporine patients and 76% of Aza patients. Of the cyclosporine patients, 15% had symptoms related to DISEASE. Serological evidence for Epstein Barr Virus infection was found in 20% of 65 cyclosporine patients studied. Three had associated symptoms, and one developed a lymphoma. | NO-RELATIONSHIP |
| Early infections in kidney, heart, and liver transplant recipients on cyclosporine. Eighty-one renal, seventeen heart, and twenty-four liver transplant patients were followed for infection. Seventeen renal patients received azathioprine (Aza) and CHEMICAL as part of a randomized trial of immunosuppression with 21 cyclosporine-and-CHEMICAL-treated renal transplant patients. All others received cyclosporine and CHEMICAL. The randomized Aza patients had more overall infections (P less than 0.05) and more nonviral infections (P less than 0.02) than the randomized cyclosporine patients. Heart and liver patients had more infections than cyclosporine renal patients but fewer infections than the Aza renal patients. There were no infectious deaths in renal transplant patients on cyclosporine or Aza, but infection played a major role in 3 out of 6 cardiac transplant deaths and in 8 out of 9 liver transplant deaths. Renal patients on cyclosporine had the fewest bacteremias. Analysis of site of infection showed a preponderance of abdominal infections in liver patients, intrathoracic infections in heart patients, and urinary tract infections in renal patients. Pulmonary infections were less common in cyclosporine-treated renal patients than in Aza-treated patients (P less than 0.05). Aza patients had significantly more staphylococcal infections than all other transplant groups (P less than 0.005), and systemic fungal infections occurred only in the liver transplant group. Cytomegalovirus (CMV) shedding or serological rises in antibody titer, or both occurred in 78% of cyclosporine patients and 76% of Aza patients. Of the cyclosporine patients, 15% had symptoms related to CMV infection. Serological evidence for DISEASE was found in 20% of 65 cyclosporine patients studied. Three had associated symptoms, and one developed a lymphoma. | NO-RELATIONSHIP |
| Early infections in kidney, heart, and liver transplant recipients on cyclosporine. Eighty-one renal, seventeen heart, and twenty-four liver transplant patients were followed for infection. Seventeen renal patients received azathioprine (Aza) and CHEMICAL as part of a randomized trial of immunosuppression with 21 cyclosporine-and-CHEMICAL-treated renal transplant patients. All others received cyclosporine and CHEMICAL. The randomized Aza patients had more overall infections (P less than 0.05) and more nonviral infections (P less than 0.02) than the randomized cyclosporine patients. Heart and liver patients had more infections than cyclosporine renal patients but fewer infections than the Aza renal patients. There were no infectious deaths in renal transplant patients on cyclosporine or Aza, but infection played a major role in 3 out of 6 cardiac transplant deaths and in 8 out of 9 liver transplant deaths. Renal patients on cyclosporine had the fewest DISEASE. Analysis of site of infection showed a preponderance of abdominal infections in liver patients, intrathoracic infections in heart patients, and urinary tract infections in renal patients. Pulmonary infections were less common in cyclosporine-treated renal patients than in Aza-treated patients (P less than 0.05). Aza patients had significantly more staphylococcal infections than all other transplant groups (P less than 0.005), and systemic fungal infections occurred only in the liver transplant group. Cytomegalovirus (CMV) shedding or serological rises in antibody titer, or both occurred in 78% of cyclosporine patients and 76% of Aza patients. Of the cyclosporine patients, 15% had symptoms related to CMV infection. Serological evidence for Epstein Barr Virus infection was found in 20% of 65 cyclosporine patients studied. Three had associated symptoms, and one developed a lymphoma. | NO-RELATIONSHIP |
| Early infections in kidney, heart, and liver transplant recipients on cyclosporine. Eighty-one renal, seventeen heart, and twenty-four liver transplant patients were followed for infection. Seventeen renal patients received azathioprine (Aza) and CHEMICAL as part of a randomized trial of immunosuppression with 21 cyclosporine-and-CHEMICAL-treated renal transplant patients. All others received cyclosporine and CHEMICAL. The randomized Aza patients had more overall infections (P less than 0.05) and more nonviral infections (P less than 0.02) than the randomized cyclosporine patients. Heart and liver patients had more infections than cyclosporine renal patients but fewer infections than the Aza renal patients. There were no infectious deaths in renal transplant patients on cyclosporine or Aza, but infection played a major role in 3 out of 6 cardiac transplant deaths and in 8 out of 9 liver transplant deaths. Renal patients on cyclosporine had the fewest bacteremias. Analysis of site of infection showed a preponderance of abdominal infections in liver patients, intrathoracic infections in heart patients, and urinary tract infections in renal patients. Pulmonary infections were less common in cyclosporine-treated renal patients than in Aza-treated patients (P less than 0.05). Aza patients had significantly more staphylococcal infections than all other transplant groups (P less than 0.005), and systemic DISEASE occurred only in the liver transplant group. Cytomegalovirus (CMV) shedding or serological rises in antibody titer, or both occurred in 78% of cyclosporine patients and 76% of Aza patients. Of the cyclosporine patients, 15% had symptoms related to CMV infection. Serological evidence for Epstein Barr Virus infection was found in 20% of 65 cyclosporine patients studied. Three had associated symptoms, and one developed a lymphoma. | CHEMICAL-INDUCED-DISEASE |
| Early infections in kidney, heart, and liver transplant recipients on cyclosporine. Eighty-one renal, seventeen heart, and twenty-four liver transplant patients were followed for infection. Seventeen renal patients received azathioprine (Aza) and CHEMICAL as part of a randomized trial of immunosuppression with 21 cyclosporine-and-CHEMICAL-treated renal transplant patients. All others received cyclosporine and CHEMICAL. The randomized Aza patients had more overall infections (P less than 0.05) and more nonviral infections (P less than 0.02) than the randomized cyclosporine patients. Heart and liver patients had more infections than cyclosporine renal patients but fewer infections than the Aza renal patients. There were no infectious deaths in renal transplant patients on cyclosporine or Aza, but infection played a major role in 3 out of 6 cardiac transplant deaths and in 8 out of 9 liver transplant deaths. Renal patients on cyclosporine had the fewest bacteremias. Analysis of site of infection showed a preponderance of abdominal infections in liver patients, intrathoracic infections in heart patients, and urinary tract infections in renal patients. Pulmonary infections were less common in cyclosporine-treated renal patients than in Aza-treated patients (P less than 0.05). Aza patients had significantly more staphylococcal infections than all other transplant groups (P less than 0.005), and systemic fungal infections occurred only in the liver transplant group. Cytomegalovirus (CMV) shedding or serological rises in antibody titer, or both occurred in 78% of cyclosporine patients and 76% of Aza patients. Of the cyclosporine patients, 15% had symptoms related to CMV infection. Serological evidence for Epstein Barr Virus infection was found in 20% of 65 cyclosporine patients studied. Three had associated symptoms, and one developed a DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Early infections in kidney, heart, and liver transplant recipients on cyclosporine. Eighty-one renal, seventeen heart, and twenty-four liver transplant patients were followed for infection. Seventeen renal patients received azathioprine (Aza) and CHEMICAL as part of a randomized trial of immunosuppression with 21 cyclosporine-and-CHEMICAL-treated renal transplant patients. All others received cyclosporine and CHEMICAL. The randomized Aza patients had more overall infections (P less than 0.05) and more nonviral infections (P less than 0.02) than the randomized cyclosporine patients. Heart and liver patients had more infections than cyclosporine renal patients but fewer infections than the Aza renal patients. There were no infectious deaths in renal transplant patients on cyclosporine or Aza, but infection played a major role in 3 out of 6 cardiac transplant deaths and in 8 out of 9 liver transplant deaths. Renal patients on cyclosporine had the fewest bacteremias. Analysis of site of infection showed a preponderance of DISEASE in liver patients, intrathoracic infections in heart patients, and urinary tract infections in renal patients. Pulmonary infections were less common in cyclosporine-treated renal patients than in Aza-treated patients (P less than 0.05). Aza patients had significantly more staphylococcal infections than all other transplant groups (P less than 0.005), and systemic fungal infections occurred only in the liver transplant group. Cytomegalovirus (CMV) shedding or serological rises in antibody titer, or both occurred in 78% of cyclosporine patients and 76% of Aza patients. Of the cyclosporine patients, 15% had symptoms related to CMV infection. Serological evidence for Epstein Barr Virus infection was found in 20% of 65 cyclosporine patients studied. Three had associated symptoms, and one developed a lymphoma. | CHEMICAL-INDUCED-DISEASE |
| Early infections in kidney, heart, and liver transplant recipients on cyclosporine. Eighty-one renal, seventeen heart, and twenty-four liver transplant patients were followed for infection. Seventeen renal patients received azathioprine (Aza) and CHEMICAL as part of a randomized trial of immunosuppression with 21 cyclosporine-and-CHEMICAL-treated renal transplant patients. All others received cyclosporine and CHEMICAL. The randomized Aza patients had more overall infections (P less than 0.05) and more nonviral infections (P less than 0.02) than the randomized cyclosporine patients. Heart and liver patients had more infections than cyclosporine renal patients but fewer infections than the Aza renal patients. There were no infectious deaths in renal transplant patients on cyclosporine or Aza, but infection played a major role in 3 out of 6 cardiac transplant deaths and in 8 out of 9 liver transplant deaths. Renal patients on cyclosporine had the fewest bacteremias. Analysis of site of infection showed a preponderance of abdominal infections in liver patients, intrathoracic infections in heart patients, and DISEASE in renal patients. Pulmonary infections were less common in cyclosporine-treated renal patients than in Aza-treated patients (P less than 0.05). Aza patients had significantly more staphylococcal infections than all other transplant groups (P less than 0.005), and systemic fungal infections occurred only in the liver transplant group. Cytomegalovirus (CMV) shedding or serological rises in antibody titer, or both occurred in 78% of cyclosporine patients and 76% of Aza patients. Of the cyclosporine patients, 15% had symptoms related to CMV infection. Serological evidence for Epstein Barr Virus infection was found in 20% of 65 cyclosporine patients studied. Three had associated symptoms, and one developed a lymphoma. | CHEMICAL-INDUCED-DISEASE |
| Structure-activity and dose-effect relationships of the antagonism of CHEMICAL-induced DISEASE by cholecystokinin, fragments and analogues of cholecystokinin in mice. Intraperitoneal administration of cholecystokinin octapeptide sulphate ester (CCK-8-SE) and nonsulphated cholecystokinin octapeptide (CCK-8-NS) enhanced the latency of DISEASE induced by CHEMICAL in mice. Experiments with N- and C-terminal fragments revealed that the C-terminal tetrapeptide (CCK-5-8) was the active centre of the CCK octapeptide molecule. The analogues CCK-8-SE and CCK-8-NS (dose range 0.2-6.4 mumol/kg) and caerulein dose range 0.1-0.8 mumol/kg) showed bell-shaped dose-effect curves, with the greatest maximum inhibition for CCK-8-NS. The peptide CCK-5-8 had weak anticonvulsant activity in comparison to the octapeptides, 3.2 mumol/kg and larger doses of the reference drug, diazepam, totally prevented CHEMICAL-induced DISEASE and mortality. The maximum effect of the peptides tested was less than that of diazepam. Experiments with analogues and derivatives of CCK-5-8 demonstrated that the effectiveness of the beta-alanyl derivatives of CCK-5-8 were enhanced and that they were equipotent with CCK-8-SE. Of the CCK-2-8 analogues, Ser(SO3H)7-Ac-CCK-2-8-SE and Thr(SO3H)7-Ac-CCK-2-8-SE and Hyp(SO3H)-Ac-CCK-2-8-SE were slightly more active than CCK-8-SE. | CHEMICAL-INDUCED-DISEASE |
| Vasopressin as a possible contributor to DISEASE. The role of vasopressin as a pressor agent to the DISEASE process was examined. Vasopressin plays a major role in the pathogenesis of CHEMICAL-salt DISEASE, since the elevation of blood pressure was not substantial in the rats with lithium-treated diabetes insipidus after CHEMICAL-salt treatment. Administration of DDAVP which has antidiuretic action but minimal vasopressor effect failed to increase blood pressure to the levels observed after administration of AVP. Furthermore, the pressor action of vasopressin appears to be important in the development of this model of DISEASE, since the enhanced pressor responsiveness to the hormone was observed in the initial stage of DISEASE. Increased secretion of vasopressin from neurohypophysis also promotes the function of the hormone as a pathogenetic factor in DISEASE. An unproportional release of vasopressin compared to plasma osmolality may be induced by the absence of an adjusting control of angiotensin II forming and receptor binding capacity for sodium balance in the brain. However, the role of vasopressin remains to be determined in human essential DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Vasopressin as a possible contributor to hypertension. The role of vasopressin as a pressor agent to the hypertensive process was examined. Vasopressin plays a major role in the pathogenesis of DOCA-salt hypertension, since the elevation of blood pressure was not substantial in the rats with CHEMICAL-treated DISEASE after DOCA-salt treatment. Administration of DDAVP which has antidiuretic action but minimal vasopressor effect failed to increase blood pressure to the levels observed after administration of AVP. Furthermore, the pressor action of vasopressin appears to be important in the development of this model of hypertension, since the enhanced pressor responsiveness to the hormone was observed in the initial stage of hypertension. Increased secretion of vasopressin from neurohypophysis also promotes the function of the hormone as a pathogenetic factor in hypertension. An unproportional release of vasopressin compared to plasma osmolality may be induced by the absence of an adjusting control of angiotensin II forming and receptor binding capacity for sodium balance in the brain. However, the role of vasopressin remains to be determined in human essential hypertension. | CHEMICAL-INDUCED-DISEASE |
| DISEASE induced by CHEMICAL in a non-alcoholic. A reversible DISEASE was observed in a non-alcoholic woman treated with CHEMICAL. The causative relationship was proven by challenge. | CHEMICAL-INDUCED-DISEASE |
| Atrial thrombosis involving the heart of F-344 rats ingesting CHEMICAL. CHEMICAL is toxic for the heart of F-344 rats. Rats treated with 500 ppm CHEMICAL in the diet all developed a high incidence of left atrial thrombosis. The lesion was associated with DISEASE and dilatation and focal myocardial degeneration. Rats died from DISEASE with severe acute and chronic congestion of the lungs, liver, and other organs. Seventy percent of rats given 250 ppm CHEMICAL and 1,000 ppm sodium nitrite simultaneously in the diet had thrombosis of the atria of the heart, while untreated control rats in this laboratory did not have atrial thrombosis. Sodium nitrite in combination with CHEMICAL appeared to have no additional effect. | CHEMICAL-INDUCED-DISEASE |
| DISEASE involving the heart of F-344 rats ingesting CHEMICAL. CHEMICAL is toxic for the heart of F-344 rats. Rats treated with 500 ppm CHEMICAL in the diet all developed a high incidence of left DISEASE. The lesion was associated with cardiac hypertrophy and dilatation and focal myocardial degeneration. Rats died from cardiac hypertrophy with severe acute and chronic congestion of the lungs, liver, and other organs. Seventy percent of rats given 250 ppm CHEMICAL and 1,000 ppm sodium nitrite simultaneously in the diet had thrombosis of the atria of the heart, while untreated control rats in this laboratory did not have DISEASE. Sodium nitrite in combination with CHEMICAL appeared to have no additional effect. | CHEMICAL-INDUCED-DISEASE |
| Atrial thrombosis involving the heart of F-344 rats ingesting quinacrine hydrochloride. Quinacrine hydrochloride is toxic for the heart of F-344 rats. Rats treated with 500 ppm quinacrine hydrochloride in the diet all developed a high incidence of left atrial thrombosis. The lesion was associated with cardiac hypertrophy and dilatation and focal DISEASE. Rats died from cardiac hypertrophy with severe acute and chronic congestion of the lungs, liver, and other organs. Seventy percent of rats given 250 ppm quinacrine hydrochloride and 1,000 ppm CHEMICAL simultaneously in the diet had thrombosis of the atria of the heart, while untreated control rats in this laboratory did not have atrial thrombosis. CHEMICAL in combination with quinacrine hydrochloride appeared to have no additional effect. | NO-RELATIONSHIP |
| Atrial thrombosis involving the heart of F-344 rats ingesting quinacrine hydrochloride. Quinacrine hydrochloride is toxic for the heart of F-344 rats. Rats treated with 500 ppm quinacrine hydrochloride in the diet all developed a high incidence of left atrial thrombosis. The lesion was associated with cardiac hypertrophy and dilatation and focal myocardial degeneration. Rats died from cardiac hypertrophy with severe acute and chronic congestion of the lungs, liver, and other organs. Seventy percent of rats given 250 ppm quinacrine hydrochloride and 1,000 ppm CHEMICAL simultaneously in the diet had DISEASE of the atria of the heart, while untreated control rats in this laboratory did not have atrial thrombosis. CHEMICAL in combination with quinacrine hydrochloride appeared to have no additional effect. | NO-RELATIONSHIP |
| Alternating sinus rhythm and intermittent DISEASE induced by CHEMICAL. Alternating sinus rhythm and intermittent DISEASE was observed in a 57-year-old woman, under treatment for angina with 80 mg CHEMICAL daily. The electrocardiogram showed alternation of long and short P-P intervals and occasional pauses. These pauses were always preceded by the short P-P intervals and were usually followed by one or two P-P intervals of 0.92-0.95 s representing the basic sinus cycle. Following these basic sinus cycles, alternating rhythm started with the longer P-P interval. The long P-P intervals ranged between 1.04-1.12 s and the short P-P intervals between 0.80-0.84 s, respectively. The duration of the pauses were equal or almost equal to one short plus one long P-P interval or to twice the basic sinus cycle. In one recording a short period of regular sinus rhythm with intermittent 2/1 DISEASE was observed. This short period of sinus rhythm was interrupted by sudden prolongation of the P-P interval starting the alternative rhythm. There were small changes in the shape of the P waves and P-R intervals. S-A conduction through two pathways, the first with 2/1 block the second having 0.12-0.14 s longer conduction time and with occasional 2/1 block was proposed for the explanation of the alternating P-P interval and other electrocardiographic features seen. Atropine 1 mg given intravenously resulted in shortening of all P-P intervals without changing the rhythm. The abnormal rhythm disappeared with the withdrawal of CHEMICAL and when the drug was restarted a 2/1 DISEASE was seen. This was accepted as evidence for CHEMICAL being the cause of this conduction disorder. | CHEMICAL-INDUCED-DISEASE |
| DISEASE and intermittent sinoatrial block induced by CHEMICAL. DISEASE and intermittent sinoatrial (S-A) block was observed in a 57-year-old woman, under treatment for angina with 80 mg CHEMICAL daily. The electrocardiogram showed alternation of long and short P-P intervals and occasional pauses. These pauses were always preceded by the short P-P intervals and were usually followed by one or two P-P intervals of 0.92-0.95 s representing the basic sinus cycle. Following these basic sinus cycles, DISEASE started with the longer P-P interval. The long P-P intervals ranged between 1.04-1.12 s and the short P-P intervals between 0.80-0.84 s, respectively. The duration of the pauses were equal or almost equal to one short plus one long P-P interval or to twice the basic sinus cycle. In one recording a short period of regular sinus rhythm with intermittent 2/1 S-A block was observed. This short period of sinus rhythm was interrupted by sudden prolongation of the P-P interval starting the alternative rhythm. There were small changes in the shape of the P waves and P-R intervals. S-A conduction through two pathways, the first with 2/1 block the second having 0.12-0.14 s longer conduction time and with occasional 2/1 block was proposed for the explanation of the alternating P-P interval and other electrocardiographic features seen. Atropine 1 mg given intravenously resulted in shortening of all P-P intervals without changing the rhythm. The abnormal rhythm disappeared with the withdrawal of CHEMICAL and when the drug was restarted a 2/1 S-A block was seen. This was accepted as evidence for CHEMICAL being the cause of this conduction disorder. | CHEMICAL-INDUCED-DISEASE |
| Alternating sinus rhythm and intermittent sinoatrial block induced by propranolol. Alternating sinus rhythm and intermittent sinoatrial (S-A) block was observed in a 57-year-old woman, under treatment for DISEASE with 80 mg propranolol daily. The electrocardiogram showed alternation of long and short P-P intervals and occasional pauses. These pauses were always preceded by the short P-P intervals and were usually followed by one or two P-P intervals of 0.92-0.95 s representing the basic sinus cycle. Following these basic sinus cycles, alternating rhythm started with the longer P-P interval. The long P-P intervals ranged between 1.04-1.12 s and the short P-P intervals between 0.80-0.84 s, respectively. The duration of the pauses were equal or almost equal to one short plus one long P-P interval or to twice the basic sinus cycle. In one recording a short period of regular sinus rhythm with intermittent 2/1 S-A block was observed. This short period of sinus rhythm was interrupted by sudden prolongation of the P-P interval starting the alternative rhythm. There were small changes in the shape of the P waves and P-R intervals. S-A conduction through two pathways, the first with 2/1 block the second having 0.12-0.14 s longer conduction time and with occasional 2/1 block was proposed for the explanation of the alternating P-P interval and other electrocardiographic features seen. CHEMICAL 1 mg given intravenously resulted in shortening of all P-P intervals without changing the rhythm. The abnormal rhythm disappeared with the withdrawal of propranolol and when the drug was restarted a 2/1 S-A block was seen. This was accepted as evidence for propranolol being the cause of this conduction disorder. | NO-RELATIONSHIP |
| Alternating sinus rhythm and intermittent sinoatrial block induced by propranolol. Alternating sinus rhythm and intermittent sinoatrial (S-A) block was observed in a 57-year-old woman, under treatment for angina with 80 mg propranolol daily. The electrocardiogram showed alternation of long and short P-P intervals and occasional pauses. These pauses were always preceded by the short P-P intervals and were usually followed by one or two P-P intervals of 0.92-0.95 s representing the basic sinus cycle. Following these basic sinus cycles, alternating rhythm started with the longer P-P interval. The long P-P intervals ranged between 1.04-1.12 s and the short P-P intervals between 0.80-0.84 s, respectively. The duration of the pauses were equal or almost equal to one short plus one long P-P interval or to twice the basic sinus cycle. In one recording a short period of regular sinus rhythm with intermittent 2/1 S-A block was observed. This short period of sinus rhythm was interrupted by sudden prolongation of the P-P interval starting the alternative rhythm. There were small changes in the shape of the P waves and P-R intervals. S-A conduction through two pathways, the first with 2/1 block the second having 0.12-0.14 s longer conduction time and with occasional 2/1 block was proposed for the explanation of the alternating P-P interval and other electrocardiographic features seen. CHEMICAL 1 mg given intravenously resulted in shortening of all P-P intervals without changing the rhythm. The abnormal rhythm disappeared with the withdrawal of propranolol and when the drug was restarted a 2/1 S-A block was seen. This was accepted as evidence for propranolol being the cause of this DISEASE. | NO-RELATIONSHIP |
| Antitumor effect, cardiotoxicity, and nephrotoxicity of CHEMICAL in the IgM solid immunocytoma-bearing LOU/M/WSL rat. Antitumor activity, cardiotoxicity, and nephrotoxicity induced by CHEMICAL were studied in LOU/M/WSL inbred rats each bearing a transplantable solid IgM immunocytoma. Animals with a tumor (diameter, 15.8 +/- 3.3 mm) were treated with iv injections of CHEMICAL on 5 consecutive days, followed by 1 weekly injection for 7 weeks (dose range, 0.015-4.0 mg/kg body wt). Tumor regression was observed with 0.5 mg CHEMICAL/kg. Complete disappearance of the tumor was induced with 1.0 mg CHEMICAL/kg. Histologic evidence of cardiotoxicity scored as grade III was only observed at a dose of 1.0 mg CHEMICAL/kg. Light microscopic evidence of renal damage was seen above a dose of 0.5 mg CHEMICAL/kg, which resulted in albuminuria and very low serum albumin levels. In the group that received 1.0 mg CHEMICAL/kg, the serum albumin level decreased from 33.6 +/- 4.1 to 1.5 +/- 0.5 g/liter. Ascites and DISEASE were observed simultaneously. The same experiments were performed with non-tumor-bearing rats, in which no major differences were observed. In conclusion, antitumor activity, cardiotoxicity, and nephrotoxicity were studied simultaneously in the same LOU/M/WSL rat. Albuminuria due to renal damage led to extremely low serum albumin levels, so ascites and DISEASE were not necessarily a consequence of the observed cardiomyopathy. | CHEMICAL-INDUCED-DISEASE |
| Antitumor effect, cardiotoxicity, and nephrotoxicity of CHEMICAL in the IgM solid immunocytoma-bearing LOU/M/WSL rat. Antitumor activity, cardiotoxicity, and nephrotoxicity induced by CHEMICAL were studied in LOU/M/WSL inbred rats each bearing a transplantable solid IgM immunocytoma. Animals with a tumor (diameter, 15.8 +/- 3.3 mm) were treated with iv injections of CHEMICAL on 5 consecutive days, followed by 1 weekly injection for 7 weeks (dose range, 0.015-4.0 mg/kg body wt). Tumor regression was observed with 0.5 mg CHEMICAL/kg. Complete disappearance of the tumor was induced with 1.0 mg CHEMICAL/kg. Histologic evidence of cardiotoxicity scored as grade III was only observed at a dose of 1.0 mg CHEMICAL/kg. Light microscopic evidence of renal damage was seen above a dose of 0.5 mg CHEMICAL/kg, which resulted in albuminuria and very low serum albumin levels. In the group that received 1.0 mg CHEMICAL/kg, the serum albumin level decreased from 33.6 +/- 4.1 to 1.5 +/- 0.5 g/liter. DISEASE and hydrothorax were observed simultaneously. The same experiments were performed with non-tumor-bearing rats, in which no major differences were observed. In conclusion, antitumor activity, cardiotoxicity, and nephrotoxicity were studied simultaneously in the same LOU/M/WSL rat. Albuminuria due to renal damage led to extremely low serum albumin levels, so DISEASE and hydrothorax were not necessarily a consequence of the observed cardiomyopathy. | CHEMICAL-INDUCED-DISEASE |
| Antitumor effect, cardiotoxicity, and nephrotoxicity of CHEMICAL in the IgM solid immunocytoma-bearing LOU/M/WSL rat. Antitumor activity, cardiotoxicity, and nephrotoxicity induced by CHEMICAL were studied in LOU/M/WSL inbred rats each bearing a transplantable solid IgM immunocytoma. Animals with a tumor (diameter, 15.8 +/- 3.3 mm) were treated with iv injections of CHEMICAL on 5 consecutive days, followed by 1 weekly injection for 7 weeks (dose range, 0.015-4.0 mg/kg body wt). Tumor regression was observed with 0.5 mg CHEMICAL/kg. Complete disappearance of the tumor was induced with 1.0 mg CHEMICAL/kg. Histologic evidence of cardiotoxicity scored as grade III was only observed at a dose of 1.0 mg CHEMICAL/kg. Light microscopic evidence of renal damage was seen above a dose of 0.5 mg CHEMICAL/kg, which resulted in DISEASE and very low serum albumin levels. In the group that received 1.0 mg CHEMICAL/kg, the serum albumin level decreased from 33.6 +/- 4.1 to 1.5 +/- 0.5 g/liter. Ascites and hydrothorax were observed simultaneously. The same experiments were performed with non-tumor-bearing rats, in which no major differences were observed. In conclusion, antitumor activity, cardiotoxicity, and nephrotoxicity were studied simultaneously in the same LOU/M/WSL rat. DISEASE due to renal damage led to extremely low serum albumin levels, so ascites and hydrothorax were not necessarily a consequence of the observed cardiomyopathy. | CHEMICAL-INDUCED-DISEASE |
| Intraoperative bradycardia and DISEASE associated with CHEMICAL and pilocarpine eye drops. A 69-yr-old man, who was concurrently being treated with pilocarpine nitrate and CHEMICAL eye drops, developed a bradycardia and became DISEASE during halothane anaesthesia. Both CHEMICAL and pilocarpine were subsequently identified in a 24-h collection of urine. CHEMICAL (but not pilocarpine) was detected in a sample of plasma removed during surgery; the plasma concentration of CHEMICAL (2.6 ng ml-1) was consistent with partial beta-adrenoceptor blockade. It is postulated that this action may have been enhanced during halothane anaesthesia with resultant bradycardia and DISEASE. Pilocarpine may have had a contributory effect. | CHEMICAL-INDUCED-DISEASE |
| Intraoperative DISEASE and hypotension associated with timolol and CHEMICAL eye drops. A 69-yr-old man, who was concurrently being treated with CHEMICAL and timolol maleate eye drops, developed a DISEASE and became hypotensive during halothane anaesthesia. Both timolol and CHEMICAL were subsequently identified in a 24-h collection of urine. Timolol (but not CHEMICAL) was detected in a sample of plasma removed during surgery; the plasma concentration of timolol (2.6 ng ml-1) was consistent with partial beta-adrenoceptor blockade. It is postulated that this action may have been enhanced during halothane anaesthesia with resultant DISEASE and hypotension. CHEMICAL may have had a contributory effect. | CHEMICAL-INDUCED-DISEASE |
| Intraoperative bradycardia and DISEASE associated with timolol and CHEMICAL eye drops. A 69-yr-old man, who was concurrently being treated with CHEMICAL and timolol maleate eye drops, developed a bradycardia and became DISEASE during halothane anaesthesia. Both timolol and CHEMICAL were subsequently identified in a 24-h collection of urine. Timolol (but not CHEMICAL) was detected in a sample of plasma removed during surgery; the plasma concentration of timolol (2.6 ng ml-1) was consistent with partial beta-adrenoceptor blockade. It is postulated that this action may have been enhanced during halothane anaesthesia with resultant bradycardia and DISEASE. CHEMICAL may have had a contributory effect. | CHEMICAL-INDUCED-DISEASE |
| Intraoperative DISEASE and hypotension associated with CHEMICAL and pilocarpine eye drops. A 69-yr-old man, who was concurrently being treated with pilocarpine nitrate and CHEMICAL eye drops, developed a DISEASE and became hypotensive during halothane anaesthesia. Both CHEMICAL and pilocarpine were subsequently identified in a 24-h collection of urine. CHEMICAL (but not pilocarpine) was detected in a sample of plasma removed during surgery; the plasma concentration of CHEMICAL (2.6 ng ml-1) was consistent with partial beta-adrenoceptor blockade. It is postulated that this action may have been enhanced during halothane anaesthesia with resultant DISEASE and hypotension. Pilocarpine may have had a contributory effect. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL DISEASE: attempted reversal with anticholinesterases. Anticholinesterases were administered in an attempt to antagonize prolonged neuromuscular blockade following the administration of CHEMICAL in a patient later found to be homozygous for atypical plasma cholinesterase. Edrophonium 10 mg, given 74 min after CHEMICAL, when train-of-four stimulation was characteristic of phase II block, produced partial antagonism which was not sustained. Repeated doses of edrophonium to 70 mg and neostigmine to 2.5 mg did not antagonize or augment the block. Spontaneous respiration recommenced 200 min after CHEMICAL administration. It is concluded that anticholinesterases are only partially effective in restoring neuromuscular function in CHEMICAL DISEASE despite muscle twitch activity typical of phase II block. | CHEMICAL-INDUCED-DISEASE |
| Succinylcholine apnoea: attempted reversal with anticholinesterases. Anticholinesterases were administered in an attempt to antagonize prolonged DISEASE following the administration of succinylcholine in a patient later found to be homozygous for atypical plasma cholinesterase. Edrophonium 10 mg, given 74 min after succinylcholine, when train-of-four stimulation was characteristic of phase II block, produced partial antagonism which was not sustained. Repeated doses of edrophonium to 70 mg and CHEMICAL to 2.5 mg did not antagonize or augment the block. Spontaneous respiration recommenced 200 min after succinylcholine administration. It is concluded that anticholinesterases are only partially effective in restoring neuromuscular function in succinylcholine apnoea despite muscle twitch activity typical of phase II block. | NO-RELATIONSHIP |
| Succinylcholine apnoea: attempted reversal with anticholinesterases. Anticholinesterases were administered in an attempt to antagonize prolonged DISEASE following the administration of succinylcholine in a patient later found to be homozygous for atypical plasma cholinesterase. CHEMICAL 10 mg, given 74 min after succinylcholine, when train-of-four stimulation was characteristic of phase II block, produced partial antagonism which was not sustained. Repeated doses of CHEMICAL to 70 mg and neostigmine to 2.5 mg did not antagonize or augment the block. Spontaneous respiration recommenced 200 min after succinylcholine administration. It is concluded that anticholinesterases are only partially effective in restoring neuromuscular function in succinylcholine apnoea despite muscle twitch activity typical of phase II block. | NO-RELATIONSHIP |
| Effect of CHEMICAL on [omega-I-131]heptadecanoic acid myocardial scintigraphy and echocardiography in dogs. The effects of serial treatment with CHEMICAL on dynamic myocardial scintigraphy with [omega-I-131]heptadecanoic acid (I-131 HA), and on global left-ventricular function determined echocardiographically, were studied in a group of nine mongrel dogs. Total extractable myocardial lipid was compared postmortem between a group of control dogs and CHEMICAL-treated dogs. A significant and then progressive fall in global LV function was observed at a cumulative CHEMICAL dose of 4 mg/kg. A significant increase in the myocardial t1/2 of the I-131 HA was observed only at a higher cumulative dose, 10 mg/kg. No significant alteration in total extractable myocardial lipids was observed between control dogs and those treated with CHEMICAL. Our findings suggest that the changes leading to an alteration of myocardial dynamic imaging with I-131 HA are not the initiating factor in CHEMICAL DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Hemodynamics and myocardial metabolism under deliberate DISEASE. An experimental study in dogs. Coronary blood flow, cardiac work and metabolism were studied in dogs under sodium nitroprusside (SNP) and CHEMICAL (CHEMICAL) deliberate DISEASE (20% and 40% mean pressure decrease from baseline). Regarding the effects of drug-induced DISEASE on coronary blood flow, aortic and coronary sinus metabolic data (pH, pO2, pCO2) we could confirm that nitroprusside DISEASE could be safely used to 30% mean blood pressure decrease from control, CHEMICAL DISEASE to 20% mean blood pressure decrease. Cardiac work was significantly reduced during SNP DISEASE. Myocardial O2 consumption and O2 availability were directly dependent on the coronary perfusion. Careful invasive monitoring of the blood pressure, blood gases and of the ECG ST-T segment is mandatory. | CHEMICAL-INDUCED-DISEASE |
| Hemodynamics and myocardial metabolism under deliberate DISEASE. An experimental study in dogs. Coronary blood flow, cardiac work and metabolism were studied in dogs under CHEMICAL (CHEMICAL) and trimetaphan (TMP) deliberate DISEASE (20% and 40% mean pressure decrease from baseline). Regarding the effects of drug-induced DISEASE on coronary blood flow, aortic and coronary sinus metabolic data (pH, pO2, pCO2) we could confirm that CHEMICAL DISEASE could be safely used to 30% mean blood pressure decrease from control, trimetaphan DISEASE to 20% mean blood pressure decrease. Cardiac work was significantly reduced during CHEMICAL DISEASE. Myocardial O2 consumption and O2 availability were directly dependent on the coronary perfusion. Careful invasive monitoring of the blood pressure, blood gases and of the ECG ST-T segment is mandatory. | CHEMICAL-INDUCED-DISEASE |
| Evidence for a selective brain noradrenergic involvement in the locomotor stimulant effects of amphetamine in the rat. Male rats received the noradrenaline neurotoxin DSP4 (50 mg/kg) 7 days prior to injection of CHEMICAL (10 or 40 mumol/kg i.p.). The DISEASE induced by CHEMICAL (10 mumol/kg) was significantly reduced by DSP4 pretreatment. However, the increased rearings and the amphetamine-induced stereotypies were not blocked by pretreatment with DSP4. The reduction of amphetamine DISEASE induced by DSP4 was blocked by pretreatment with the noradrenaline-uptake blocking agent, desipramine, which prevents the neurotoxic action of DSP4. The present results suggest a selective involvement of central noradrenergic neurones in the locomotor stimulant effect of amphetamine in the rat. | CHEMICAL-INDUCED-DISEASE |
| Evidence for a selective brain noradrenergic involvement in the locomotor stimulant effects of amphetamine in the rat. Male rats received the noradrenaline neurotoxin DSP4 (50 mg/kg) 7 days prior to injection of D-amphetamine (10 or 40 mumol/kg i.p.). The hyperactivity induced by D-amphetamine (10 mumol/kg) was significantly reduced by DSP4 pretreatment. However, the increased rearings and the amphetamine-induced stereotypies were not blocked by pretreatment with DSP4. The reduction of amphetamine hyperactivity induced by DSP4 was blocked by pretreatment with the noradrenaline-uptake blocking agent, CHEMICAL, which prevents the DISEASE action of DSP4. The present results suggest a selective involvement of central noradrenergic neurones in the locomotor stimulant effect of amphetamine in the rat. | NO-RELATIONSHIP |
| Evidence for a selective brain noradrenergic involvement in the locomotor stimulant effects of amphetamine in the rat. Male rats received the CHEMICAL neurotoxin DSP4 (50 mg/kg) 7 days prior to injection of D-amphetamine (10 or 40 mumol/kg i.p.). The hyperactivity induced by D-amphetamine (10 mumol/kg) was significantly reduced by DSP4 pretreatment. However, the increased rearings and the amphetamine-induced DISEASE were not blocked by pretreatment with DSP4. The reduction of amphetamine hyperactivity induced by DSP4 was blocked by pretreatment with the CHEMICAL-uptake blocking agent, desipramine, which prevents the neurotoxic action of DSP4. The present results suggest a selective involvement of central noradrenergic neurones in the locomotor stimulant effect of amphetamine in the rat. | NO-RELATIONSHIP |
| Evidence for a selective brain noradrenergic involvement in the locomotor stimulant effects of amphetamine in the rat. Male rats received the noradrenaline neurotoxin CHEMICAL (50 mg/kg) 7 days prior to injection of D-amphetamine (10 or 40 mumol/kg i.p.). The hyperactivity induced by D-amphetamine (10 mumol/kg) was significantly reduced by CHEMICAL pretreatment. However, the increased rearings and the amphetamine-induced stereotypies were not blocked by pretreatment with CHEMICAL. The reduction of amphetamine hyperactivity induced by CHEMICAL was blocked by pretreatment with the noradrenaline-uptake blocking agent, desipramine, which prevents the DISEASE action of CHEMICAL. The present results suggest a selective involvement of central noradrenergic neurones in the locomotor stimulant effect of amphetamine in the rat. | NO-RELATIONSHIP |
| Evidence for a selective brain noradrenergic involvement in the locomotor stimulant effects of amphetamine in the rat. Male rats received the CHEMICAL neurotoxin DSP4 (50 mg/kg) 7 days prior to injection of D-amphetamine (10 or 40 mumol/kg i.p.). The hyperactivity induced by D-amphetamine (10 mumol/kg) was significantly reduced by DSP4 pretreatment. However, the increased rearings and the amphetamine-induced stereotypies were not blocked by pretreatment with DSP4. The reduction of amphetamine hyperactivity induced by DSP4 was blocked by pretreatment with the CHEMICAL-uptake blocking agent, desipramine, which prevents the DISEASE action of DSP4. The present results suggest a selective involvement of central noradrenergic neurones in the locomotor stimulant effect of amphetamine in the rat. | NO-RELATIONSHIP |
| Evidence for a selective brain noradrenergic involvement in the locomotor stimulant effects of CHEMICAL in the rat. Male rats received the noradrenaline neurotoxin DSP4 (50 mg/kg) 7 days prior to injection of D-amphetamine (10 or 40 mumol/kg i.p.). The hyperactivity induced by D-amphetamine (10 mumol/kg) was significantly reduced by DSP4 pretreatment. However, the increased rearings and the CHEMICAL-induced stereotypies were not blocked by pretreatment with DSP4. The reduction of CHEMICAL hyperactivity induced by DSP4 was blocked by pretreatment with the noradrenaline-uptake blocking agent, desipramine, which prevents the DISEASE action of DSP4. The present results suggest a selective involvement of central noradrenergic neurones in the locomotor stimulant effect of CHEMICAL in the rat. | NO-RELATIONSHIP |
| Evidence for a selective brain noradrenergic involvement in the locomotor stimulant effects of amphetamine in the rat. Male rats received the noradrenaline neurotoxin DSP4 (50 mg/kg) 7 days prior to injection of D-amphetamine (10 or 40 mumol/kg i.p.). The hyperactivity induced by D-amphetamine (10 mumol/kg) was significantly reduced by DSP4 pretreatment. However, the increased rearings and the amphetamine-induced DISEASE were not blocked by pretreatment with DSP4. The reduction of amphetamine hyperactivity induced by DSP4 was blocked by pretreatment with the noradrenaline-uptake blocking agent, CHEMICAL, which prevents the neurotoxic action of DSP4. The present results suggest a selective involvement of central noradrenergic neurones in the locomotor stimulant effect of amphetamine in the rat. | NO-RELATIONSHIP |
| Evidence for a selective brain noradrenergic involvement in the locomotor stimulant effects of amphetamine in the rat. Male rats received the noradrenaline neurotoxin CHEMICAL (50 mg/kg) 7 days prior to injection of D-amphetamine (10 or 40 mumol/kg i.p.). The hyperactivity induced by D-amphetamine (10 mumol/kg) was significantly reduced by CHEMICAL pretreatment. However, the increased rearings and the amphetamine-induced DISEASE were not blocked by pretreatment with CHEMICAL. The reduction of amphetamine hyperactivity induced by CHEMICAL was blocked by pretreatment with the noradrenaline-uptake blocking agent, desipramine, which prevents the neurotoxic action of CHEMICAL. The present results suggest a selective involvement of central noradrenergic neurones in the locomotor stimulant effect of amphetamine in the rat. | NO-RELATIONSHIP |
| Evidence for a selective brain noradrenergic involvement in the locomotor stimulant effects of CHEMICAL in the rat. Male rats received the noradrenaline neurotoxin DSP4 (50 mg/kg) 7 days prior to injection of D-amphetamine (10 or 40 mumol/kg i.p.). The hyperactivity induced by D-amphetamine (10 mumol/kg) was significantly reduced by DSP4 pretreatment. However, the increased rearings and the CHEMICAL-induced DISEASE were not blocked by pretreatment with DSP4. The reduction of CHEMICAL hyperactivity induced by DSP4 was blocked by pretreatment with the noradrenaline-uptake blocking agent, desipramine, which prevents the neurotoxic action of DSP4. The present results suggest a selective involvement of central noradrenergic neurones in the locomotor stimulant effect of CHEMICAL in the rat. | CHEMICAL-INDUCED-DISEASE |
| DISEASE during oral CHEMICAL therapy. This study examined the frequency of atrioventricular (AV) dissociation and DISEASE in 59 patients receiving oral CHEMICAL. DISEASE and AV dissociation were frequent in patients with supraventricular tachyarrhythmias, particularly AV nodal reentry. CHEMICAL administration to these patients led to an asymptomatic increase in activity of these junctional pacemakers. In patients with various chest pain syndromes, CHEMICAL neither increased the frequency of junctional rhythms nor suppressed their role as escape rhythms under physiologically appropriate circumstances. | CHEMICAL-INDUCED-DISEASE |
| Treatment of ovarian cancer with a combination of cis-platinum, adriamycin, cyclophosphamide and hexamethylmelamine. During the last 2 1/2 years, 38 patients with ovarian cancer were treated with a combination of cisplatinum (CHEMICAL), 50 mg/m2, adriamycin, 30 mg/m2, cyclophosphamide, 300 mg/m2, on day 1; and hexamethylmelamine (HMM), 6 mg/kg daily, for 14 days. Each course was repeated monthly. 2 patients had stage II, 14 stage III and 22 stage IV disease. 14 of the 38 patients were previously treated with chemotherapy, 1 with radiation, 6 with both chemotherapy and radiation, and 17 did not have any treatment before CHEMICAL combination. 31 of the 38 cases (81.5%) demonstrated objective responses lasting for 2 months or more. These responses were partial in 19 and complete in 12 cases. Hematologic toxicity was moderate and with reversible DISEASE developing in 71% of patients. Gastrointestinal side effects from CHEMICAL were universal. HMM gastrointestinal toxicity necessitated discontinuation of the drug in 5 patients. Severe nephrotoxicity was observed in 2 patients but was reversible. There were no drug-related deaths. | CHEMICAL-INDUCED-DISEASE |
| Treatment of ovarian cancer with a combination of cis-platinum, adriamycin, cyclophosphamide and hexamethylmelamine. During the last 2 1/2 years, 38 patients with ovarian cancer were treated with a combination of cisplatinum (CHEMICAL), 50 mg/m2, adriamycin, 30 mg/m2, cyclophosphamide, 300 mg/m2, on day 1; and hexamethylmelamine (HMM), 6 mg/kg daily, for 14 days. Each course was repeated monthly. 2 patients had stage II, 14 stage III and 22 stage IV disease. 14 of the 38 patients were previously treated with chemotherapy, 1 with radiation, 6 with both chemotherapy and radiation, and 17 did not have any treatment before CHEMICAL combination. 31 of the 38 cases (81.5%) demonstrated objective responses lasting for 2 months or more. These responses were partial in 19 and complete in 12 cases. Hematologic toxicity was moderate and with reversible anemia developing in 71% of patients. Gastrointestinal side effects from CHEMICAL were universal. HMM gastrointestinal toxicity necessitated discontinuation of the drug in 5 patients. Severe DISEASE was observed in 2 patients but was reversible. There were no drug-related deaths. | CHEMICAL-INDUCED-DISEASE |
| Treatment of ovarian cancer with a combination of cis-platinum, adriamycin, cyclophosphamide and hexamethylmelamine. During the last 2 1/2 years, 38 patients with ovarian cancer were treated with a combination of cisplatinum (CHEMICAL), 50 mg/m2, adriamycin, 30 mg/m2, cyclophosphamide, 300 mg/m2, on day 1; and hexamethylmelamine (HMM), 6 mg/kg daily, for 14 days. Each course was repeated monthly. 2 patients had stage II, 14 stage III and 22 stage IV disease. 14 of the 38 patients were previously treated with chemotherapy, 1 with radiation, 6 with both chemotherapy and radiation, and 17 did not have any treatment before CHEMICAL combination. 31 of the 38 cases (81.5%) demonstrated objective responses lasting for 2 months or more. These responses were partial in 19 and complete in 12 cases. Hematologic toxicity was moderate and with reversible anemia developing in 71% of patients. Gastrointestinal side effects from CHEMICAL were universal. HMM DISEASE necessitated discontinuation of the drug in 5 patients. Severe nephrotoxicity was observed in 2 patients but was reversible. There were no drug-related deaths. | CHEMICAL-INDUCED-DISEASE |
| Treatment of DISEASE with a combination of cis-platinum, adriamycin, cyclophosphamide and CHEMICAL. During the last 2 1/2 years, 38 patients with DISEASE were treated with a combination of cisplatinum (CPDD), 50 mg/m2, adriamycin, 30 mg/m2, cyclophosphamide, 300 mg/m2, on day 1; and CHEMICAL (CHEMICAL), 6 mg/kg daily, for 14 days. Each course was repeated monthly. 2 patients had stage II, 14 stage III and 22 stage IV disease. 14 of the 38 patients were previously treated with chemotherapy, 1 with radiation, 6 with both chemotherapy and radiation, and 17 did not have any treatment before CPDD combination. 31 of the 38 cases (81.5%) demonstrated objective responses lasting for 2 months or more. These responses were partial in 19 and complete in 12 cases. Hematologic toxicity was moderate and with reversible anemia developing in 71% of patients. Gastrointestinal side effects from CPDD were universal. CHEMICAL gastrointestinal toxicity necessitated discontinuation of the drug in 5 patients. Severe nephrotoxicity was observed in 2 patients but was reversible. There were no drug-related deaths. | NO-RELATIONSHIP |
| Treatment of DISEASE with a combination of cis-platinum, CHEMICAL, cyclophosphamide and hexamethylmelamine. During the last 2 1/2 years, 38 patients with DISEASE were treated with a combination of cisplatinum (CPDD), 50 mg/m2, CHEMICAL, 30 mg/m2, cyclophosphamide, 300 mg/m2, on day 1; and hexamethylmelamine (HMM), 6 mg/kg daily, for 14 days. Each course was repeated monthly. 2 patients had stage II, 14 stage III and 22 stage IV disease. 14 of the 38 patients were previously treated with chemotherapy, 1 with radiation, 6 with both chemotherapy and radiation, and 17 did not have any treatment before CPDD combination. 31 of the 38 cases (81.5%) demonstrated objective responses lasting for 2 months or more. These responses were partial in 19 and complete in 12 cases. Hematologic toxicity was moderate and with reversible anemia developing in 71% of patients. Gastrointestinal side effects from CPDD were universal. HMM gastrointestinal toxicity necessitated discontinuation of the drug in 5 patients. Severe nephrotoxicity was observed in 2 patients but was reversible. There were no drug-related deaths. | NO-RELATIONSHIP |
| Treatment of ovarian cancer with a combination of cis-platinum, adriamycin, CHEMICAL and hexamethylmelamine. During the last 2 1/2 years, 38 patients with ovarian cancer were treated with a combination of cisplatinum (CPDD), 50 mg/m2, adriamycin, 30 mg/m2, CHEMICAL, 300 mg/m2, on day 1; and hexamethylmelamine (HMM), 6 mg/kg daily, for 14 days. Each course was repeated monthly. 2 patients had stage II, 14 stage III and 22 stage IV disease. 14 of the 38 patients were previously treated with chemotherapy, 1 with radiation, 6 with both chemotherapy and radiation, and 17 did not have any treatment before CPDD combination. 31 of the 38 cases (81.5%) demonstrated objective responses lasting for 2 months or more. These responses were partial in 19 and complete in 12 cases. DISEASE was moderate and with reversible anemia developing in 71% of patients. Gastrointestinal side effects from CPDD were universal. HMM gastrointestinal toxicity necessitated discontinuation of the drug in 5 patients. Severe nephrotoxicity was observed in 2 patients but was reversible. There were no drug-related deaths. | CHEMICAL-INDUCED-DISEASE |
| Treatment of DISEASE with a combination of CHEMICAL, adriamycin, cyclophosphamide and hexamethylmelamine. During the last 2 1/2 years, 38 patients with DISEASE were treated with a combination of CHEMICAL (CPDD), 50 mg/m2, adriamycin, 30 mg/m2, cyclophosphamide, 300 mg/m2, on day 1; and hexamethylmelamine (HMM), 6 mg/kg daily, for 14 days. Each course was repeated monthly. 2 patients had stage II, 14 stage III and 22 stage IV disease. 14 of the 38 patients were previously treated with chemotherapy, 1 with radiation, 6 with both chemotherapy and radiation, and 17 did not have any treatment before CPDD combination. 31 of the 38 cases (81.5%) demonstrated objective responses lasting for 2 months or more. These responses were partial in 19 and complete in 12 cases. Hematologic toxicity was moderate and with reversible anemia developing in 71% of patients. Gastrointestinal side effects from CPDD were universal. HMM gastrointestinal toxicity necessitated discontinuation of the drug in 5 patients. Severe nephrotoxicity was observed in 2 patients but was reversible. There were no drug-related deaths. | CHEMICAL-INDUCED-DISEASE |
| Treatment of ovarian cancer with a combination of cis-platinum, CHEMICAL, cyclophosphamide and hexamethylmelamine. During the last 2 1/2 years, 38 patients with ovarian cancer were treated with a combination of cisplatinum (CPDD), 50 mg/m2, CHEMICAL, 30 mg/m2, cyclophosphamide, 300 mg/m2, on day 1; and hexamethylmelamine (HMM), 6 mg/kg daily, for 14 days. Each course was repeated monthly. 2 patients had stage II, 14 stage III and 22 stage IV disease. 14 of the 38 patients were previously treated with chemotherapy, 1 with radiation, 6 with both chemotherapy and radiation, and 17 did not have any treatment before CPDD combination. 31 of the 38 cases (81.5%) demonstrated objective responses lasting for 2 months or more. These responses were partial in 19 and complete in 12 cases. DISEASE was moderate and with reversible anemia developing in 71% of patients. Gastrointestinal side effects from CPDD were universal. HMM gastrointestinal toxicity necessitated discontinuation of the drug in 5 patients. Severe nephrotoxicity was observed in 2 patients but was reversible. There were no drug-related deaths. | CHEMICAL-INDUCED-DISEASE |
| Treatment of ovarian cancer with a combination of CHEMICAL, adriamycin, cyclophosphamide and hexamethylmelamine. During the last 2 1/2 years, 38 patients with ovarian cancer were treated with a combination of CHEMICAL (CPDD), 50 mg/m2, adriamycin, 30 mg/m2, cyclophosphamide, 300 mg/m2, on day 1; and hexamethylmelamine (HMM), 6 mg/kg daily, for 14 days. Each course was repeated monthly. 2 patients had stage II, 14 stage III and 22 stage IV disease. 14 of the 38 patients were previously treated with chemotherapy, 1 with radiation, 6 with both chemotherapy and radiation, and 17 did not have any treatment before CPDD combination. 31 of the 38 cases (81.5%) demonstrated objective responses lasting for 2 months or more. These responses were partial in 19 and complete in 12 cases. DISEASE was moderate and with reversible anemia developing in 71% of patients. Gastrointestinal side effects from CPDD were universal. HMM gastrointestinal toxicity necessitated discontinuation of the drug in 5 patients. Severe nephrotoxicity was observed in 2 patients but was reversible. There were no drug-related deaths. | CHEMICAL-INDUCED-DISEASE |
| Treatment of DISEASE with a combination of cis-platinum, adriamycin, CHEMICAL and hexamethylmelamine. During the last 2 1/2 years, 38 patients with DISEASE were treated with a combination of cisplatinum (CPDD), 50 mg/m2, adriamycin, 30 mg/m2, CHEMICAL, 300 mg/m2, on day 1; and hexamethylmelamine (HMM), 6 mg/kg daily, for 14 days. Each course was repeated monthly. 2 patients had stage II, 14 stage III and 22 stage IV disease. 14 of the 38 patients were previously treated with chemotherapy, 1 with radiation, 6 with both chemotherapy and radiation, and 17 did not have any treatment before CPDD combination. 31 of the 38 cases (81.5%) demonstrated objective responses lasting for 2 months or more. These responses were partial in 19 and complete in 12 cases. Hematologic toxicity was moderate and with reversible anemia developing in 71% of patients. Gastrointestinal side effects from CPDD were universal. HMM gastrointestinal toxicity necessitated discontinuation of the drug in 5 patients. Severe nephrotoxicity was observed in 2 patients but was reversible. There were no drug-related deaths. | NO-RELATIONSHIP |
| Treatment of ovarian cancer with a combination of cis-platinum, adriamycin, cyclophosphamide and CHEMICAL. During the last 2 1/2 years, 38 patients with ovarian cancer were treated with a combination of cisplatinum (CPDD), 50 mg/m2, adriamycin, 30 mg/m2, cyclophosphamide, 300 mg/m2, on day 1; and CHEMICAL (CHEMICAL), 6 mg/kg daily, for 14 days. Each course was repeated monthly. 2 patients had stage II, 14 stage III and 22 stage IV disease. 14 of the 38 patients were previously treated with chemotherapy, 1 with radiation, 6 with both chemotherapy and radiation, and 17 did not have any treatment before CPDD combination. 31 of the 38 cases (81.5%) demonstrated objective responses lasting for 2 months or more. These responses were partial in 19 and complete in 12 cases. DISEASE was moderate and with reversible anemia developing in 71% of patients. Gastrointestinal side effects from CPDD were universal. CHEMICAL gastrointestinal toxicity necessitated discontinuation of the drug in 5 patients. Severe nephrotoxicity was observed in 2 patients but was reversible. There were no drug-related deaths. | CHEMICAL-INDUCED-DISEASE |
| Nontraumatic DISEASE of the basilar artery. A case of nontraumatic DISEASE of the basilar artery in association with hypertension, smoke, and CHEMICAL is reported in a young female patient with a locked-in syndrome. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced hepatic damage. Two cases of CHEMICAL-induced liver damage have been observed. The first case is of an acute type of damage, proven by rechallenge; the second presents a clinical and histologic picture resembling DISEASE, with spontaneous remission. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced DISEASE. Two cases of CHEMICAL-induced DISEASE have been observed. The first case is of an acute type of damage, proven by rechallenge; the second presents a clinical and histologic picture resembling chronic active hepatitis, with spontaneous remission. | CHEMICAL-INDUCED-DISEASE |
| Studies on the DISEASE induced by CHEMICAL. CHEMICAL, a novel active compound for prophylactic treatment of anginal attacks, induced persistent DISEASE and a non-specific anti-tachycardial effect, the mechanisms of which were investigated in vitro and in vivo. In vitro perfusion of CHEMICAL in the life-support medium for isolated sino-atrial tissue from rabbit heart, caused a reduction in action potential (AP) spike frequency (recorded by KCl microelectrodes) starting at doses of 5 X 10(-6) M. This effect was dose-dependent up to concentrations of 5 X 10(-5) M, whereupon blockade of sinus activity set in. CHEMICAL at a dose of 5 X 10(-6) M, induced a concomitant reduction in AP amplitude (falling from 71 +/- 8 mV to 47 +/- 6 mV), maximum systolic depolarization velocity (phase 0) which fell from 1.85 +/- 0.35 V/s to 0.84 +/- 0.28 V/s, together with maximum diastolic depolarization velocity (phase 4) which fell from 38 +/- 3 mV/s to 24 +/- 5 mV/s. In vivo injection of CHEMICAL at a dose of 5 mg/kg (i.v.) into 6 anaesthetized dogs which had undergone ablation of all the extrinsic cardiac afferent nerve supply, together with a bilateral medullo-adrenalectomy, caused a marked reduction in heart rate which fell from 98.7 +/- 4.2 beats/min to 76 +/- 5.3 beats/min sustained for more than 45 min. It is concluded that CHEMICAL reduces heart rate by acting directly on the sinus node. This effect, which results in a flattening of the phase 0 and phase 4 slope, together with a longer AP duration, may be due to an increase in the time constants of slow inward ionic currents (already demonstrated elsewhere), but also to an increased time constant for deactivation of the outward potassium current (Ip). | CHEMICAL-INDUCED-DISEASE |
| Studies on the bradycardia induced by bepridil. Bepridil, a novel active compound for prophylactic treatment of anginal attacks, induced persistent bradycardia and a non-specific anti-DISEASE effect, the mechanisms of which were investigated in vitro and in vivo. In vitro perfusion of bepridil in the life-support medium for isolated sino-atrial tissue from rabbit heart, caused a reduction in action potential (AP) spike frequency (recorded by CHEMICAL microelectrodes) starting at doses of 5 X 10(-6) M. This effect was dose-dependent up to concentrations of 5 X 10(-5) M, whereupon blockade of sinus activity set in. Bepridil at a dose of 5 X 10(-6) M, induced a concomitant reduction in AP amplitude (falling from 71 +/- 8 mV to 47 +/- 6 mV), maximum systolic depolarization velocity (phase 0) which fell from 1.85 +/- 0.35 V/s to 0.84 +/- 0.28 V/s, together with maximum diastolic depolarization velocity (phase 4) which fell from 38 +/- 3 mV/s to 24 +/- 5 mV/s. In vivo injection of bepridil at a dose of 5 mg/kg (i.v.) into 6 anaesthetized dogs which had undergone ablation of all the extrinsic cardiac afferent nerve supply, together with a bilateral medullo-adrenalectomy, caused a marked reduction in heart rate which fell from 98.7 +/- 4.2 beats/min to 76 +/- 5.3 beats/min sustained for more than 45 min. It is concluded that bepridil reduces heart rate by acting directly on the sinus node. This effect, which results in a flattening of the phase 0 and phase 4 slope, together with a longer AP duration, may be due to an increase in the time constants of slow inward ionic currents (already demonstrated elsewhere), but also to an increased time constant for deactivation of the outward potassium current (Ip). | NO-RELATIONSHIP |
| Studies on the bradycardia induced by bepridil. Bepridil, a novel active compound for prophylactic treatment of DISEASE, induced persistent bradycardia and a non-specific anti-tachycardial effect, the mechanisms of which were investigated in vitro and in vivo. In vitro perfusion of bepridil in the life-support medium for isolated sino-atrial tissue from rabbit heart, caused a reduction in action potential (AP) spike frequency (recorded by CHEMICAL microelectrodes) starting at doses of 5 X 10(-6) M. This effect was dose-dependent up to concentrations of 5 X 10(-5) M, whereupon blockade of sinus activity set in. Bepridil at a dose of 5 X 10(-6) M, induced a concomitant reduction in AP amplitude (falling from 71 +/- 8 mV to 47 +/- 6 mV), maximum systolic depolarization velocity (phase 0) which fell from 1.85 +/- 0.35 V/s to 0.84 +/- 0.28 V/s, together with maximum diastolic depolarization velocity (phase 4) which fell from 38 +/- 3 mV/s to 24 +/- 5 mV/s. In vivo injection of bepridil at a dose of 5 mg/kg (i.v.) into 6 anaesthetized dogs which had undergone ablation of all the extrinsic cardiac afferent nerve supply, together with a bilateral medullo-adrenalectomy, caused a marked reduction in heart rate which fell from 98.7 +/- 4.2 beats/min to 76 +/- 5.3 beats/min sustained for more than 45 min. It is concluded that bepridil reduces heart rate by acting directly on the sinus node. This effect, which results in a flattening of the phase 0 and phase 4 slope, together with a longer AP duration, may be due to an increase in the time constants of slow inward ionic currents (already demonstrated elsewhere), but also to an increased time constant for deactivation of the outward potassium current (Ip). | NO-RELATIONSHIP |
| Studies on the bradycardia induced by bepridil. Bepridil, a novel active compound for prophylactic treatment of DISEASE, induced persistent bradycardia and a non-specific anti-tachycardial effect, the mechanisms of which were investigated in vitro and in vivo. In vitro perfusion of bepridil in the life-support medium for isolated sino-atrial tissue from rabbit heart, caused a reduction in action potential (AP) spike frequency (recorded by KCl microelectrodes) starting at doses of 5 X 10(-6) M. This effect was dose-dependent up to concentrations of 5 X 10(-5) M, whereupon blockade of sinus activity set in. Bepridil at a dose of 5 X 10(-6) M, induced a concomitant reduction in AP amplitude (falling from 71 +/- 8 mV to 47 +/- 6 mV), maximum systolic depolarization velocity (phase 0) which fell from 1.85 +/- 0.35 V/s to 0.84 +/- 0.28 V/s, together with maximum diastolic depolarization velocity (phase 4) which fell from 38 +/- 3 mV/s to 24 +/- 5 mV/s. In vivo injection of bepridil at a dose of 5 mg/kg (i.v.) into 6 anaesthetized dogs which had undergone ablation of all the extrinsic cardiac afferent nerve supply, together with a bilateral medullo-adrenalectomy, caused a marked reduction in heart rate which fell from 98.7 +/- 4.2 beats/min to 76 +/- 5.3 beats/min sustained for more than 45 min. It is concluded that bepridil reduces heart rate by acting directly on the sinus node. This effect, which results in a flattening of the phase 0 and phase 4 slope, together with a longer AP duration, may be due to an increase in the time constants of slow inward ionic currents (already demonstrated elsewhere), but also to an increased time constant for deactivation of the outward CHEMICAL current (Ip). | NO-RELATIONSHIP |
| Studies on the bradycardia induced by bepridil. Bepridil, a novel active compound for prophylactic treatment of anginal attacks, induced persistent bradycardia and a non-specific anti-DISEASE effect, the mechanisms of which were investigated in vitro and in vivo. In vitro perfusion of bepridil in the life-support medium for isolated sino-atrial tissue from rabbit heart, caused a reduction in action potential (AP) spike frequency (recorded by KCl microelectrodes) starting at doses of 5 X 10(-6) M. This effect was dose-dependent up to concentrations of 5 X 10(-5) M, whereupon blockade of sinus activity set in. Bepridil at a dose of 5 X 10(-6) M, induced a concomitant reduction in AP amplitude (falling from 71 +/- 8 mV to 47 +/- 6 mV), maximum systolic depolarization velocity (phase 0) which fell from 1.85 +/- 0.35 V/s to 0.84 +/- 0.28 V/s, together with maximum diastolic depolarization velocity (phase 4) which fell from 38 +/- 3 mV/s to 24 +/- 5 mV/s. In vivo injection of bepridil at a dose of 5 mg/kg (i.v.) into 6 anaesthetized dogs which had undergone ablation of all the extrinsic cardiac afferent nerve supply, together with a bilateral medullo-adrenalectomy, caused a marked reduction in heart rate which fell from 98.7 +/- 4.2 beats/min to 76 +/- 5.3 beats/min sustained for more than 45 min. It is concluded that bepridil reduces heart rate by acting directly on the sinus node. This effect, which results in a flattening of the phase 0 and phase 4 slope, together with a longer AP duration, may be due to an increase in the time constants of slow inward ionic currents (already demonstrated elsewhere), but also to an increased time constant for deactivation of the outward CHEMICAL current (Ip). | NO-RELATIONSHIP |
| Hepatitis and DISEASE after anesthesia with CHEMICAL. A 69-year-old man operated for acute cholecystitis under CHEMICAL anesthesia developed postoperatively a hepatic insufficiency syndrome and DISEASE. Massive bleeding appeared during surgery which lasted for six hours. Postoperative evolution under supportive therapy was favourable. Complete recovery was confirmed by repeated controls performed over a period of one year after surgery. | NO-RELATIONSHIP |
| DISEASE and renal tubular acidosis after anesthesia with CHEMICAL. A 69-year-old man operated for acute cholecystitis under CHEMICAL anesthesia developed postoperatively a hepatic insufficiency syndrome and renal tubular acidosis. Massive bleeding appeared during surgery which lasted for six hours. Postoperative evolution under supportive therapy was favourable. Complete recovery was confirmed by repeated controls performed over a period of one year after surgery. | CHEMICAL-INDUCED-DISEASE |
| Pituitary response to luteinizing hormone-releasing hormone during CHEMICAL-induced DISEASE. The effects of a 6-hour infusion with CHEMICAL on serum prolactin and luteinizing hormone (LH) levels was studied in a group of male subjects. Five hours after starting the infusions, a study of the pituitary responses to LH-releasing hormone (LH-RH) was carried out. Control patients received infusions of 0.9% NaCl solution. During the course of CHEMICAL infusions, significant DISEASE was found, together with an abolished pituitary response to LH-RH, as compared with responses of control subjects. | CHEMICAL-INDUCED-DISEASE |
| Antirifampicin antibodies in acute CHEMICAL-associated renal failure. 5 patients with acute renal failure (3 with thrombopenia and DISEASE) induced by the reintroduction of CHEMICAL are described. No correlation was found between the severity of clinical manifestations and the total dose taken by the patients. In all but 1 patient, antirifampicin antibodies were detected. Antibodies suggested to be of the IgM class were detected in all 3 patients with hematological disorders. The pattern of non-specific acute tubular necrosis found in the 2 biopsied patients, indistinguishable from that of ischemic origin, raised the possibility of a vascular-mediated damage. In 3 patients, the possibility of a triggering immunoallergic mechanism is discussed. | CHEMICAL-INDUCED-DISEASE |
| Antirifampicin antibodies in acute CHEMICAL-associated renal failure. 5 patients with acute renal failure (3 with DISEASE and hemolysis) induced by the reintroduction of CHEMICAL are described. No correlation was found between the severity of clinical manifestations and the total dose taken by the patients. In all but 1 patient, antirifampicin antibodies were detected. Antibodies suggested to be of the IgM class were detected in all 3 patients with hematological disorders. The pattern of non-specific acute tubular necrosis found in the 2 biopsied patients, indistinguishable from that of ischemic origin, raised the possibility of a vascular-mediated damage. In 3 patients, the possibility of a triggering immunoallergic mechanism is discussed. | CHEMICAL-INDUCED-DISEASE |
| Antirifampicin antibodies in acute CHEMICAL-associated renal failure. 5 patients with acute renal failure (3 with thrombopenia and hemolysis) induced by the reintroduction of CHEMICAL are described. No correlation was found between the severity of clinical manifestations and the total dose taken by the patients. In all but 1 patient, antirifampicin antibodies were detected. Antibodies suggested to be of the IgM class were detected in all 3 patients with hematological disorders. The pattern of non-specific DISEASE found in the 2 biopsied patients, indistinguishable from that of ischemic origin, raised the possibility of a vascular-mediated damage. In 3 patients, the possibility of a triggering immunoallergic mechanism is discussed. | CHEMICAL-INDUCED-DISEASE |
| Cardiovascular effects of DISEASE induced by adenosine triphosphate and CHEMICAL on dogs with denervated hearts. Adenosine triphosphate (ATP) and CHEMICAL (CHEMICAL) are administered to patients to induce and control DISEASE during anesthesia. CHEMICAL is authorized for clinical use in USA and UK, and ATP is clinically used in other countries such as Japan. We investigated how these two drugs act on the cardiovascular systems of 20 dogs whose hearts had been denervated by a procedure we had devised. ATP (10 dogs) or CHEMICAL (10 dogs) was administered to reduce mean arterial pressure by 30% to 70% of control. Before, during and after induced DISEASE, we measured major cardiovascular parameters. DISEASE induced by ATP was accompanied by significant decreases in mean pulmonary arterial pressure (p less than 0.001), central venous pressure (p less than 0.001), left ventricular end-diastolic pressure (p less than 0.001), total peripheral resistance (p less than 0.001), rate pressure product (p less than 0.001), total body oxygen consumption (p less than 0.05), and heart rate (p less than 0.001); all these variables returned normal within 30 min after ATP was stopped. Cardiac output did not change. During DISEASE produced by CHEMICAL similar decreases were observed in mean pulmonary arterial pressure (p less than 0.01), central venous pressure (p less than 0.001), left ventricular end-diastolic pressure (p less than 0.01), total peripheral resistance (p less than 0.001), rate pressure product (p less than 0.001), and oxygen content difference between arterial and mixed venous blood (p less than 0.05), while heart rate (p less than 0.001) and cardiac output (p less than 0.05) were increased. Recoveries of heart rate and left ventricular end-diastolic pressure were not shown within 60 min after CHEMICAL had been stopped. Both ATP and CHEMICAL should act on the pacemaker tissue of the heart. | CHEMICAL-INDUCED-DISEASE |
| Cardiovascular effects of DISEASE induced by CHEMICAL and sodium nitroprusside on dogs with denervated hearts. CHEMICAL (CHEMICAL) and sodium nitroprusside (SNP) are administered to patients to induce and control DISEASE during anesthesia. SNP is authorized for clinical use in USA and UK, and CHEMICAL is clinically used in other countries such as Japan. We investigated how these two drugs act on the cardiovascular systems of 20 dogs whose hearts had been denervated by a procedure we had devised. CHEMICAL (10 dogs) or SNP (10 dogs) was administered to reduce mean arterial pressure by 30% to 70% of control. Before, during and after induced DISEASE, we measured major cardiovascular parameters. DISEASE induced by CHEMICAL was accompanied by significant decreases in mean pulmonary arterial pressure (p less than 0.001), central venous pressure (p less than 0.001), left ventricular end-diastolic pressure (p less than 0.001), total peripheral resistance (p less than 0.001), rate pressure product (p less than 0.001), total body oxygen consumption (p less than 0.05), and heart rate (p less than 0.001); all these variables returned normal within 30 min after CHEMICAL was stopped. Cardiac output did not change. During DISEASE produced by SNP similar decreases were observed in mean pulmonary arterial pressure (p less than 0.01), central venous pressure (p less than 0.001), left ventricular end-diastolic pressure (p less than 0.01), total peripheral resistance (p less than 0.001), rate pressure product (p less than 0.001), and oxygen content difference between arterial and mixed venous blood (p less than 0.05), while heart rate (p less than 0.001) and cardiac output (p less than 0.05) were increased. Recoveries of heart rate and left ventricular end-diastolic pressure were not shown within 60 min after SNP had been stopped. Both CHEMICAL and SNP should act on the pacemaker tissue of the heart. | CHEMICAL-INDUCED-DISEASE |
| Comparative study: CHEMICAL (diatrizoate), Vasurix polyvidone (acetrizoate), Dimer-X (iocarmate) and Hexabrix (ioxaglate) in hysterosalpingography. Side effects of hysterosalpingography with Dimer-X, Hexabrix, Vasurix polyvidone and CHEMICAL in 142 consecutive patients, receiving one of the four tested media were evaluated from replies to postal questionnaires. The Dimer-X group had a higher incidence of nausea and dizziness. The CHEMICAL group had a higher incidence of DISEASE. These differences occur especially in the age groups under 30 years. Hexabrix and Vasurix polyvidone are considered the best contrast media for hysterosalpingography and perhaps because of its low toxicity Hexabrix should be preferred. | CHEMICAL-INDUCED-DISEASE |
| Comparative study: Endografine (diatrizoate), Vasurix polyvidone (acetrizoate), CHEMICAL (CHEMICAL) and Hexabrix (ioxaglate) in hysterosalpingography. Side effects of hysterosalpingography with CHEMICAL, Hexabrix, Vasurix polyvidone and Endografine in 142 consecutive patients, receiving one of the four tested media were evaluated from replies to postal questionnaires. The CHEMICAL group had a higher incidence of nausea and DISEASE. The Endografine group had a higher incidence of abdominal pain. These differences occur especially in the age groups under 30 years. Hexabrix and Vasurix polyvidone are considered the best contrast media for hysterosalpingography and perhaps because of its low toxicity Hexabrix should be preferred. | CHEMICAL-INDUCED-DISEASE |
| Comparative study: Endografine (diatrizoate), Vasurix polyvidone (acetrizoate), CHEMICAL (CHEMICAL) and Hexabrix (ioxaglate) in hysterosalpingography. Side effects of hysterosalpingography with CHEMICAL, Hexabrix, Vasurix polyvidone and Endografine in 142 consecutive patients, receiving one of the four tested media were evaluated from replies to postal questionnaires. The CHEMICAL group had a higher incidence of DISEASE and dizziness. The Endografine group had a higher incidence of abdominal pain. These differences occur especially in the age groups under 30 years. Hexabrix and Vasurix polyvidone are considered the best contrast media for hysterosalpingography and perhaps because of its low toxicity Hexabrix should be preferred. | CHEMICAL-INDUCED-DISEASE |
| Comparative study: Endografine (diatrizoate), Vasurix polyvidone (acetrizoate), Dimer-X (iocarmate) and CHEMICAL (CHEMICAL) in hysterosalpingography. Side effects of hysterosalpingography with Dimer-X, CHEMICAL, Vasurix polyvidone and Endografine in 142 consecutive patients, receiving one of the four tested media were evaluated from replies to postal questionnaires. The Dimer-X group had a higher incidence of nausea and dizziness. The Endografine group had a higher incidence of abdominal pain. These differences occur especially in the age groups under 30 years. CHEMICAL and Vasurix polyvidone are considered the best contrast media for hysterosalpingography and perhaps because of its low DISEASE CHEMICAL should be preferred. | CHEMICAL-INDUCED-DISEASE |
| Comparative study: Endografine (CHEMICAL), Vasurix polyvidone (acetrizoate), Dimer-X (iocarmate) and Hexabrix (ioxaglate) in hysterosalpingography. Side effects of hysterosalpingography with Dimer-X, Hexabrix, Vasurix polyvidone and Endografine in 142 consecutive patients, receiving one of the four tested media were evaluated from replies to postal questionnaires. The Dimer-X group had a higher incidence of nausea and dizziness. The Endografine group had a higher incidence of abdominal pain. These differences occur especially in the age groups under 30 years. Hexabrix and Vasurix polyvidone are considered the best contrast media for hysterosalpingography and perhaps because of its low DISEASE Hexabrix should be preferred. | CHEMICAL-INDUCED-DISEASE |
| Comparative study: Endografine (diatrizoate), CHEMICAL (CHEMICAL), Dimer-X (iocarmate) and Hexabrix (ioxaglate) in hysterosalpingography. Side effects of hysterosalpingography with Dimer-X, Hexabrix, CHEMICAL and Endografine in 142 consecutive patients, receiving one of the four tested media were evaluated from replies to postal questionnaires. The Dimer-X group had a higher incidence of nausea and dizziness. The Endografine group had a higher incidence of abdominal pain. These differences occur especially in the age groups under 30 years. Hexabrix and CHEMICAL are considered the best contrast media for hysterosalpingography and perhaps because of its low DISEASE Hexabrix should be preferred. | CHEMICAL-INDUCED-DISEASE |
| Comparative study: Endografine (diatrizoate), Vasurix polyvidone (acetrizoate), Dimer-X (iocarmate) and Hexabrix (ioxaglate) in hysterosalpingography. Side effects of hysterosalpingography with Dimer-X, Hexabrix, Vasurix polyvidone and Endografine in 142 consecutive patients, receiving one of the four tested media were evaluated from replies to postal questionnaires. The Dimer-X group had a higher incidence of nausea and dizziness. The Endografine group had a higher incidence of abdominal pain. These differences occur especially in the age groups under 30 years. Hexabrix and Vasurix polyvidone are considered the best CHEMICAL for hysterosalpingography and perhaps because of its low DISEASE Hexabrix should be preferred. | NO-RELATIONSHIP |
| Post-CHEMICAL pains in Nigerian surgical patients. Contrary to an earlier report by Coxon, CHEMICAL pain occurs in African negroes. Its incidence was determined in a prospective study involving a total of 100 Nigerian patients (50 out-patients and 50 in-patients). About 62% of the out-patients developed CHEMICAL pain as compared with about 26% among the in-patients. The abolition of muscle DISEASE (by 0.075mg/kg dose of Fazadinium) did not influence the occurrence of CHEMICAL pain. Neither the type of induction agent (Althesin or Thiopentone) nor the salt preparation of CHEMICAL used (chloride or bromide), affected the incidence of CHEMICAL pain. | CHEMICAL-INDUCED-DISEASE |
| Post-CHEMICAL DISEASE in Nigerian surgical patients. Contrary to an earlier report by Coxon, CHEMICAL DISEASE occurs in African negroes. Its incidence was determined in a prospective study involving a total of 100 Nigerian patients (50 out-patients and 50 in-patients). About 62% of the out-patients developed CHEMICAL DISEASE as compared with about 26% among the in-patients. The abolition of muscle fasciculations (by 0.075mg/kg dose of Fazadinium) did not influence the occurrence of CHEMICAL DISEASE. Neither the type of induction agent (Althesin or Thiopentone) nor the salt preparation of CHEMICAL used (chloride or bromide), affected the incidence of CHEMICAL DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Medial changes in arterial DISEASE induced by CHEMICAL. In normal rats, the media of small arteries (0.4--0.2 mm in diameter) previously was shown to contain intracellular vacuoles, identified ultrastructurally as herniations of one smooth muscle cell into another. The hypothesis that intense vasoconstriction would increase the number of such vacuoles has been tested. In the media of the saphenous artery and its distal branch, vasoconstriction induced by CHEMICAL produced many cell-to-cell hernias within 15 minutes. At 1 day their number was reduced to about 1/10 of the original number. By 7 days the vessel was almost restored to normal. Triple stimulation over 1 day induced more severe changes in the media. These findings suggest that smooth muscle cells are susceptible to damage in the course of their specific function. The experimental data are discussed in relation to medial changes observed in other instances of arterial DISEASE. Endothelial changes that developed in the same experimental model were described in a previous paper. | CHEMICAL-INDUCED-DISEASE |
| Abnormalities of the pupil and visual-evoked potential in CHEMICAL amblyopia. Total blindness with a transient DISEASE response, denervation supersensitivity, and abnormal visual-evoked potentials developed in a 54-year-old man after the use of CHEMICAL for leg cramps. He later recovered normal visual acuity. A transient DISEASE response, denervation supersensitivity, and abnormal visual-evoked potentials in CHEMICAL toxicity, to our knowledge, have not been previously reported. | CHEMICAL-INDUCED-DISEASE |
| Abnormalities of the pupil and visual-evoked potential in CHEMICAL DISEASE. Total blindness with a transient tonic pupillary response, denervation supersensitivity, and abnormal visual-evoked potentials developed in a 54-year-old man after the use of CHEMICAL for leg cramps. He later recovered normal visual acuity. A transient tonic pupillary response, denervation supersensitivity, and abnormal visual-evoked potentials in CHEMICAL toxicity, to our knowledge, have not been previously reported. | CHEMICAL-INDUCED-DISEASE |
| Abnormalities of the pupil and visual-evoked potential in CHEMICAL amblyopia. Total DISEASE with a transient tonic pupillary response, denervation supersensitivity, and abnormal visual-evoked potentials developed in a 54-year-old man after the use of CHEMICAL for leg cramps. He later recovered normal visual acuity. A transient tonic pupillary response, denervation supersensitivity, and abnormal visual-evoked potentials in CHEMICAL toxicity, to our knowledge, have not been previously reported. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced DISEASE and myalgia associated with atypical cholinesterase: case report. An 11-year-old boy was given halothane, nitrous oxide and oxygen, pancuronium 0.4 mg and CHEMICAL 100 mg for induction of anaesthesia. In response to this a marked DISEASE occurred which lasted for two minutes and the anaesthesia were terminated. Four hours of apnoea ensued and he suffered generalized severe myalgia lasting for one week. He was found to have atypical plasma cholinesterase with a dibucaine number of 12, indicating homozygocity. This was verified by study of the family. The case shows that DISEASE and myalgia may occur after CHEMICAL in patients with atypical cholinesterase despite pretreatment with pancuronium. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced jaw stiffness and myalgia associated with atypical cholinesterase: case report. An 11-year-old boy was given halothane, nitrous oxide and oxygen, pancuronium 0.4 mg and CHEMICAL 100 mg for induction of anaesthesia. In response to this a marked jaw stiffness occurred which lasted for two minutes and the anaesthesia were terminated. Four hours of DISEASE ensued and he suffered generalized severe myalgia lasting for one week. He was found to have atypical plasma cholinesterase with a dibucaine number of 12, indicating homozygocity. This was verified by study of the family. The case shows that prolonged jaw rigidity and myalgia may occur after CHEMICAL in patients with atypical cholinesterase despite pretreatment with pancuronium. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced jaw stiffness and DISEASE associated with atypical cholinesterase: case report. An 11-year-old boy was given halothane, nitrous oxide and oxygen, pancuronium 0.4 mg and CHEMICAL 100 mg for induction of anaesthesia. In response to this a marked jaw stiffness occurred which lasted for two minutes and the anaesthesia were terminated. Four hours of apnoea ensued and he suffered generalized severe DISEASE lasting for one week. He was found to have atypical plasma cholinesterase with a dibucaine number of 12, indicating homozygocity. This was verified by study of the family. The case shows that prolonged jaw rigidity and DISEASE may occur after CHEMICAL in patients with atypical cholinesterase despite pretreatment with pancuronium. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced DISEASE in three patients with gouty arthritis. We describe three patients in whom severe, life-threatening DISEASE and renal insufficiency developed after treatment of acute gouty arthritis with CHEMICAL. This complication may result from an inhibition of prostaglandin synthesis and consequent hyporeninemic hypoaidosteronism. Careful attention to renal function and potassium balance in patients receiving CHEMICAL or other nonsteroidal anti-inflammatory agents, particularly in those patients with diabetes mellitus or preexisting renal disease, will help prevent this potentially serious complication. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced hyperkalemia in three patients with gouty arthritis. We describe three patients in whom severe, life-threatening hyperkalemia and DISEASE developed after treatment of acute gouty arthritis with CHEMICAL. This complication may result from an inhibition of prostaglandin synthesis and consequent hyporeninemic hypoaidosteronism. Careful attention to renal function and potassium balance in patients receiving CHEMICAL or other nonsteroidal anti-inflammatory agents, particularly in those patients with diabetes mellitus or preexisting renal disease, will help prevent this potentially serious complication. | CHEMICAL-INDUCED-DISEASE |
| Indomethacin-induced hyperkalemia in three patients with gouty arthritis. We describe three patients in whom severe, life-threatening hyperkalemia and renal insufficiency developed after treatment of acute gouty arthritis with indomethacin. This complication may result from an inhibition of CHEMICAL synthesis and consequent hyporeninemic hypoaidosteronism. Careful attention to renal function and potassium balance in patients receiving indomethacin or other nonsteroidal anti-inflammatory agents, particularly in those patients with diabetes mellitus or preexisting DISEASE, will help prevent this potentially serious complication. | NO-RELATIONSHIP |
| Indomethacin-induced hyperkalemia in three patients with gouty arthritis. We describe three patients in whom severe, life-threatening hyperkalemia and renal insufficiency developed after treatment of acute gouty arthritis with indomethacin. This complication may result from an inhibition of prostaglandin synthesis and consequent hyporeninemic hypoaidosteronism. Careful attention to renal function and CHEMICAL balance in patients receiving indomethacin or other nonsteroidal anti-inflammatory agents, particularly in those patients with diabetes mellitus or preexisting DISEASE, will help prevent this potentially serious complication. | NO-RELATIONSHIP |
| Indomethacin-induced hyperkalemia in three patients with gouty arthritis. We describe three patients in whom severe, life-threatening hyperkalemia and renal insufficiency developed after treatment of acute gouty arthritis with indomethacin. This complication may result from an inhibition of CHEMICAL synthesis and consequent DISEASE. Careful attention to renal function and potassium balance in patients receiving indomethacin or other nonsteroidal anti-inflammatory agents, particularly in those patients with diabetes mellitus or preexisting renal disease, will help prevent this potentially serious complication. | NO-RELATIONSHIP |
| Indomethacin-induced hyperkalemia in three patients with gouty arthritis. We describe three patients in whom severe, life-threatening hyperkalemia and renal insufficiency developed after treatment of acute gouty arthritis with indomethacin. This complication may result from an inhibition of prostaglandin synthesis and consequent hyporeninemic hypoaidosteronism. Careful attention to renal function and CHEMICAL balance in patients receiving indomethacin or other nonsteroidal anti-inflammatory agents, particularly in those patients with DISEASE or preexisting renal disease, will help prevent this potentially serious complication. | NO-RELATIONSHIP |
| Indomethacin-induced hyperkalemia in three patients with DISEASE. We describe three patients in whom severe, life-threatening hyperkalemia and renal insufficiency developed after treatment of acute DISEASE with indomethacin. This complication may result from an inhibition of prostaglandin synthesis and consequent hyporeninemic hypoaidosteronism. Careful attention to renal function and CHEMICAL balance in patients receiving indomethacin or other nonsteroidal anti-inflammatory agents, particularly in those patients with diabetes mellitus or preexisting renal disease, will help prevent this potentially serious complication. | NO-RELATIONSHIP |
| Indomethacin-induced hyperkalemia in three patients with DISEASE. We describe three patients in whom severe, life-threatening hyperkalemia and renal insufficiency developed after treatment of acute DISEASE with indomethacin. This complication may result from an inhibition of CHEMICAL synthesis and consequent hyporeninemic hypoaidosteronism. Careful attention to renal function and potassium balance in patients receiving indomethacin or other nonsteroidal anti-inflammatory agents, particularly in those patients with diabetes mellitus or preexisting renal disease, will help prevent this potentially serious complication. | NO-RELATIONSHIP |
| Indomethacin-induced hyperkalemia in three patients with gouty arthritis. We describe three patients in whom severe, life-threatening hyperkalemia and renal insufficiency developed after treatment of acute gouty arthritis with indomethacin. This complication may result from an inhibition of CHEMICAL synthesis and consequent hyporeninemic hypoaidosteronism. Careful attention to renal function and potassium balance in patients receiving indomethacin or other nonsteroidal anti-inflammatory agents, particularly in those patients with DISEASE or preexisting renal disease, will help prevent this potentially serious complication. | NO-RELATIONSHIP |
| Indomethacin-induced hyperkalemia in three patients with gouty arthritis. We describe three patients in whom severe, life-threatening hyperkalemia and renal insufficiency developed after treatment of acute gouty arthritis with indomethacin. This complication may result from an inhibition of prostaglandin synthesis and consequent DISEASE. Careful attention to renal function and CHEMICAL balance in patients receiving indomethacin or other nonsteroidal anti-inflammatory agents, particularly in those patients with diabetes mellitus or preexisting renal disease, will help prevent this potentially serious complication. | NO-RELATIONSHIP |
| CHEMICAL: a foreshortened clinical trial. A clinical evaluation of CHEMICAL for outpatient cystoscopy was embarked upon. Unpremedicated patients were given fentanyl 1 microgram/kg followed by CHEMICAL 0.3 mg/kg. Anaesthesia was maintained with intermittent CHEMICAL in 2-4 mg doses. Patients were interviewed personally later the same day, and by questionnaire three to four weeks later. The trial was discontinued after 20 cases because of an unacceptable incidence of side effects. Venous pain occurred in 68% of patients and 50% had redness, pain or swelling related to the injection site, in some cases lasting up to three weeks after anaesthesia. Skeletal movements occurred in 50% of patients; 30% experienced respiratory upset, one sufficiently severe to necessitate abandoning the technique. DISEASE and vomiting occurred in 40% and 25% had disturbing emergence psychoses. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL: a foreshortened clinical trial. A clinical evaluation of CHEMICAL for outpatient cystoscopy was embarked upon. Unpremedicated patients were given fentanyl 1 microgram/kg followed by CHEMICAL 0.3 mg/kg. Anaesthesia was maintained with intermittent CHEMICAL in 2-4 mg doses. Patients were interviewed personally later the same day, and by questionnaire three to four weeks later. The trial was discontinued after 20 cases because of an unacceptable incidence of side effects. Venous pain occurred in 68% of patients and 50% had redness, pain or swelling related to the injection site, in some cases lasting up to three weeks after anaesthesia. Skeletal movements occurred in 50% of patients; 30% experienced respiratory upset, one sufficiently severe to necessitate abandoning the technique. Nausea and DISEASE occurred in 40% and 25% had disturbing emergence psychoses. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL: a foreshortened clinical trial. A clinical evaluation of CHEMICAL for outpatient cystoscopy was embarked upon. Unpremedicated patients were given fentanyl 1 microgram/kg followed by CHEMICAL 0.3 mg/kg. Anaesthesia was maintained with intermittent CHEMICAL in 2-4 mg doses. Patients were interviewed personally later the same day, and by questionnaire three to four weeks later. The trial was discontinued after 20 cases because of an unacceptable incidence of side effects. Venous DISEASE occurred in 68% of patients and 50% had redness, DISEASE or swelling related to the injection site, in some cases lasting up to three weeks after anaesthesia. Skeletal movements occurred in 50% of patients; 30% experienced respiratory upset, one sufficiently severe to necessitate abandoning the technique. Nausea and vomiting occurred in 40% and 25% had disturbing emergence psychoses. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL: a foreshortened clinical trial. A clinical evaluation of CHEMICAL for outpatient cystoscopy was embarked upon. Unpremedicated patients were given fentanyl 1 microgram/kg followed by CHEMICAL 0.3 mg/kg. Anaesthesia was maintained with intermittent CHEMICAL in 2-4 mg doses. Patients were interviewed personally later the same day, and by questionnaire three to four weeks later. The trial was discontinued after 20 cases because of an unacceptable incidence of side effects. Venous pain occurred in 68% of patients and 50% had redness, pain or swelling related to the injection site, in some cases lasting up to three weeks after anaesthesia. Skeletal movements occurred in 50% of patients; 30% experienced DISEASE, one sufficiently severe to necessitate abandoning the technique. Nausea and vomiting occurred in 40% and 25% had disturbing emergence psychoses. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL: a foreshortened clinical trial. A clinical evaluation of CHEMICAL for outpatient cystoscopy was embarked upon. Unpremedicated patients were given fentanyl 1 microgram/kg followed by CHEMICAL 0.3 mg/kg. Anaesthesia was maintained with intermittent CHEMICAL in 2-4 mg doses. Patients were interviewed personally later the same day, and by questionnaire three to four weeks later. The trial was discontinued after 20 cases because of an unacceptable incidence of side effects. Venous pain occurred in 68% of patients and 50% had redness, pain or swelling related to the injection site, in some cases lasting up to three weeks after anaesthesia. Skeletal movements occurred in 50% of patients; 30% experienced respiratory upset, one sufficiently severe to necessitate abandoning the technique. Nausea and vomiting occurred in 40% and 25% had disturbing emergence DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Etomidate: a foreshortened clinical trial. A clinical evaluation of etomidate for outpatient cystoscopy was embarked upon. Unpremedicated patients were given CHEMICAL 1 microgram/kg followed by etomidate 0.3 mg/kg. Anaesthesia was maintained with intermittent etomidate in 2-4 mg doses. Patients were interviewed personally later the same day, and by questionnaire three to four weeks later. The trial was discontinued after 20 cases because of an unacceptable incidence of side effects. Venous pain occurred in 68% of patients and 50% had redness, pain or DISEASE related to the injection site, in some cases lasting up to three weeks after anaesthesia. Skeletal movements occurred in 50% of patients; 30% experienced respiratory upset, one sufficiently severe to necessitate abandoning the technique. Nausea and vomiting occurred in 40% and 25% had disturbing emergence psychoses. | NO-RELATIONSHIP |
| Levodopa-induced DISEASE are improved by fluoxetine. We evaluated the severity of motor disability and DISEASE in seven levodopa-responsive patients with Parkinson's disease after an acute challenge with the mixed dopamine agonist, CHEMICAL, before and after the administration of fluoxetine (20 mg twice per day) for 11 +/- 1 days. After fluoxetine treatment, there was a significant 47% improvement (p < 0.05) of CHEMICAL-induced DISEASE without modification of parkinsonian motor disability. The DISEASE were reduced predominantly in the lower limbs during the onset and disappearance of dystonic dyskinesias (onset- and end-of-dose DISEASE) and in the upper limbs during choreic mid-dose dyskinesias. The results suggest that increased brain serotoninergic transmission with fluoxetine may reduce levodopa- or dopamine agonist-induced DISEASE without aggravating parkinsonian motor disability. | CHEMICAL-INDUCED-DISEASE |
| Levodopa-induced DISEASE are improved by CHEMICAL. We evaluated the severity of motor disability and DISEASE in seven levodopa-responsive patients with Parkinson's disease after an acute challenge with the mixed dopamine agonist, apomorphine, before and after the administration of CHEMICAL (20 mg twice per day) for 11 +/- 1 days. After CHEMICAL treatment, there was a significant 47% improvement (p < 0.05) of apomorphine-induced DISEASE without modification of parkinsonian motor disability. The DISEASE were reduced predominantly in the lower limbs during the onset and disappearance of dystonic dyskinesias (onset- and end-of-dose DISEASE) and in the upper limbs during choreic mid-dose dyskinesias. The results suggest that increased brain serotoninergic transmission with CHEMICAL may reduce levodopa- or dopamine agonist-induced DISEASE without aggravating parkinsonian motor disability. | CHEMICAL-INDUCED-DISEASE |
| Levodopa-induced dyskinesias are improved by fluoxetine. We evaluated the severity of DISEASE and dyskinesias in seven levodopa-responsive patients with Parkinson's disease after an acute challenge with the mixed CHEMICAL agonist, apomorphine, before and after the administration of fluoxetine (20 mg twice per day) for 11 +/- 1 days. After fluoxetine treatment, there was a significant 47% improvement (p < 0.05) of apomorphine-induced dyskinesias without modification of parkinsonian DISEASE. The dyskinesias were reduced predominantly in the lower limbs during the onset and disappearance of dystonic dyskinesias (onset- and end-of-dose dyskinesias) and in the upper limbs during choreic mid-dose dyskinesias. The results suggest that increased brain serotoninergic transmission with fluoxetine may reduce levodopa- or CHEMICAL agonist-induced dyskinesias without aggravating parkinsonian DISEASE. | NO-RELATIONSHIP |
| CHEMICAL-induced dyskinesias are improved by fluoxetine. We evaluated the severity of DISEASE and dyskinesias in seven CHEMICAL-responsive patients with Parkinson's disease after an acute challenge with the mixed dopamine agonist, apomorphine, before and after the administration of fluoxetine (20 mg twice per day) for 11 +/- 1 days. After fluoxetine treatment, there was a significant 47% improvement (p < 0.05) of apomorphine-induced dyskinesias without modification of parkinsonian DISEASE. The dyskinesias were reduced predominantly in the lower limbs during the onset and disappearance of dystonic dyskinesias (onset- and end-of-dose dyskinesias) and in the upper limbs during choreic mid-dose dyskinesias. The results suggest that increased brain serotoninergic transmission with fluoxetine may reduce CHEMICAL- or dopamine agonist-induced dyskinesias without aggravating parkinsonian DISEASE. | NO-RELATIONSHIP |
| CHEMICAL-induced dyskinesias are improved by fluoxetine. We evaluated the severity of motor disability and dyskinesias in seven CHEMICAL-responsive patients with Parkinson's disease after an acute challenge with the mixed dopamine agonist, apomorphine, before and after the administration of fluoxetine (20 mg twice per day) for 11 +/- 1 days. After fluoxetine treatment, there was a significant 47% improvement (p < 0.05) of apomorphine-induced dyskinesias without modification of parkinsonian motor disability. The dyskinesias were reduced predominantly in the lower limbs during the onset and disappearance of DISEASE (onset- and end-of-dose dyskinesias) and in the upper limbs during choreic mid-dose dyskinesias. The results suggest that increased brain serotoninergic transmission with fluoxetine may reduce CHEMICAL- or dopamine agonist-induced dyskinesias without aggravating parkinsonian motor disability. | NO-RELATIONSHIP |
| CHEMICAL-induced dyskinesias are improved by fluoxetine. We evaluated the severity of motor disability and dyskinesias in seven CHEMICAL-responsive patients with DISEASE after an acute challenge with the mixed dopamine agonist, apomorphine, before and after the administration of fluoxetine (20 mg twice per day) for 11 +/- 1 days. After fluoxetine treatment, there was a significant 47% improvement (p < 0.05) of apomorphine-induced dyskinesias without modification of DISEASE motor disability. The dyskinesias were reduced predominantly in the lower limbs during the onset and disappearance of dystonic dyskinesias (onset- and end-of-dose dyskinesias) and in the upper limbs during choreic mid-dose dyskinesias. The results suggest that increased brain serotoninergic transmission with fluoxetine may reduce CHEMICAL- or dopamine agonist-induced dyskinesias without aggravating DISEASE motor disability. | NO-RELATIONSHIP |
| CHEMICAL-induced dyskinesias are improved by fluoxetine. We evaluated the severity of motor disability and dyskinesias in seven CHEMICAL-responsive patients with Parkinson's disease after an acute challenge with the mixed dopamine agonist, apomorphine, before and after the administration of fluoxetine (20 mg twice per day) for 11 +/- 1 days. After fluoxetine treatment, there was a significant 47% improvement (p < 0.05) of apomorphine-induced dyskinesias without modification of parkinsonian motor disability. The dyskinesias were reduced predominantly in the lower limbs during the onset and disappearance of dystonic dyskinesias (onset- and end-of-dose dyskinesias) and in the upper limbs during DISEASE. The results suggest that increased brain serotoninergic transmission with fluoxetine may reduce CHEMICAL- or dopamine agonist-induced dyskinesias without aggravating parkinsonian motor disability. | NO-RELATIONSHIP |
| Levodopa-induced dyskinesias are improved by fluoxetine. We evaluated the severity of motor disability and dyskinesias in seven levodopa-responsive patients with Parkinson's disease after an acute challenge with the mixed CHEMICAL agonist, apomorphine, before and after the administration of fluoxetine (20 mg twice per day) for 11 +/- 1 days. After fluoxetine treatment, there was a significant 47% improvement (p < 0.05) of apomorphine-induced dyskinesias without modification of parkinsonian motor disability. The dyskinesias were reduced predominantly in the lower limbs during the onset and disappearance of DISEASE (onset- and end-of-dose dyskinesias) and in the upper limbs during choreic mid-dose dyskinesias. The results suggest that increased brain serotoninergic transmission with fluoxetine may reduce levodopa- or CHEMICAL agonist-induced dyskinesias without aggravating parkinsonian motor disability. | NO-RELATIONSHIP |
| Levodopa-induced dyskinesias are improved by fluoxetine. We evaluated the severity of motor disability and dyskinesias in seven levodopa-responsive patients with DISEASE after an acute challenge with the mixed CHEMICAL agonist, apomorphine, before and after the administration of fluoxetine (20 mg twice per day) for 11 +/- 1 days. After fluoxetine treatment, there was a significant 47% improvement (p < 0.05) of apomorphine-induced dyskinesias without modification of DISEASE motor disability. The dyskinesias were reduced predominantly in the lower limbs during the onset and disappearance of dystonic dyskinesias (onset- and end-of-dose dyskinesias) and in the upper limbs during choreic mid-dose dyskinesias. The results suggest that increased brain serotoninergic transmission with fluoxetine may reduce levodopa- or CHEMICAL agonist-induced dyskinesias without aggravating DISEASE motor disability. | NO-RELATIONSHIP |
| Levodopa-induced dyskinesias are improved by fluoxetine. We evaluated the severity of motor disability and dyskinesias in seven levodopa-responsive patients with Parkinson's disease after an acute challenge with the mixed CHEMICAL agonist, apomorphine, before and after the administration of fluoxetine (20 mg twice per day) for 11 +/- 1 days. After fluoxetine treatment, there was a significant 47% improvement (p < 0.05) of apomorphine-induced dyskinesias without modification of parkinsonian motor disability. The dyskinesias were reduced predominantly in the lower limbs during the onset and disappearance of dystonic dyskinesias (onset- and end-of-dose dyskinesias) and in the upper limbs during DISEASE. The results suggest that increased brain serotoninergic transmission with fluoxetine may reduce levodopa- or CHEMICAL agonist-induced dyskinesias without aggravating parkinsonian motor disability. | NO-RELATIONSHIP |
| A large population-based follow-up study of trimethoprim-sulfamethoxazole, CHEMICAL, and cephalexin for uncommon serious drug toxicity. We conducted a population-based 45-day follow-up study of 232,390 people who were prescribed trimethoprim-sulfamethoxazole (TMP-SMZ), 266,951 prescribed CHEMICAL alone, and 196,397 prescribed cephalexin, to estimate the risk of serious liver, blood, skin, and renal disorders resulting in referral or hospitalization associated with these drugs. The results were based on information recorded on office computers by selected general practitioners in the United Kingdom, together with a review of clinical records. The risk of clinically important idiopathic DISEASE was similar for persons prescribed TMP-SMZ (5.2/100,000) and those prescribed CHEMICAL alone (3.8/100,000). The risk for those prescribed cephalexin was somewhat lower (2.0/100,000). Only five patients experienced blood disorders, one of whom was exposed to TMP-SMZ; of seven with erythema multiforme and Stevens-Johnson syndrome, four were exposed to TMP-SMZ. The one case of toxic epidermal necrolysis occurred in a patient who took cephalexin. Finally, only five cases of acute parenchymal renal disease occurred, none likely to be caused by a study drug. We conclude that the risk of the serious diseases studied is small for the three agents, and compares reasonably with the risk for many other antibiotics. | CHEMICAL-INDUCED-DISEASE |
| A large population-based follow-up study of CHEMICAL, trimethoprim, and cephalexin for uncommon serious drug toxicity. We conducted a population-based 45-day follow-up study of 232,390 people who were prescribed CHEMICAL (CHEMICAL), 266,951 prescribed trimethoprim alone, and 196,397 prescribed cephalexin, to estimate the risk of serious liver, blood, skin, and renal disorders resulting in referral or hospitalization associated with these drugs. The results were based on information recorded on office computers by selected general practitioners in the United Kingdom, together with a review of clinical records. The risk of clinically important idiopathic DISEASE was similar for persons prescribed CHEMICAL (5.2/100,000) and those prescribed trimethoprim alone (3.8/100,000). The risk for those prescribed cephalexin was somewhat lower (2.0/100,000). Only five patients experienced blood disorders, one of whom was exposed to CHEMICAL; of seven with erythema multiforme and Stevens-Johnson syndrome, four were exposed to CHEMICAL. The one case of toxic epidermal necrolysis occurred in a patient who took cephalexin. Finally, only five cases of acute parenchymal renal disease occurred, none likely to be caused by a study drug. We conclude that the risk of the serious diseases studied is small for the three agents, and compares reasonably with the risk for many other antibiotics. | CHEMICAL-INDUCED-DISEASE |
| A large population-based follow-up study of trimethoprim-sulfamethoxazole, trimethoprim, and CHEMICAL for uncommon serious drug toxicity. We conducted a population-based 45-day follow-up study of 232,390 people who were prescribed trimethoprim-sulfamethoxazole (TMP-SMZ), 266,951 prescribed trimethoprim alone, and 196,397 prescribed CHEMICAL, to estimate the risk of serious liver, blood, skin, and renal disorders resulting in referral or hospitalization associated with these drugs. The results were based on information recorded on office computers by selected general practitioners in the United Kingdom, together with a review of clinical records. The risk of clinically important idiopathic DISEASE was similar for persons prescribed TMP-SMZ (5.2/100,000) and those prescribed trimethoprim alone (3.8/100,000). The risk for those prescribed CHEMICAL was somewhat lower (2.0/100,000). Only five patients experienced blood disorders, one of whom was exposed to TMP-SMZ; of seven with erythema multiforme and Stevens-Johnson syndrome, four were exposed to TMP-SMZ. The one case of toxic epidermal necrolysis occurred in a patient who took CHEMICAL. Finally, only five cases of acute parenchymal renal disease occurred, none likely to be caused by a study drug. We conclude that the risk of the serious diseases studied is small for the three agents, and compares reasonably with the risk for many other antibiotics. | CHEMICAL-INDUCED-DISEASE |
| A large population-based follow-up study of trimethoprim-sulfamethoxazole, trimethoprim, and CHEMICAL for uncommon serious drug toxicity. We conducted a population-based 45-day follow-up study of 232,390 people who were prescribed trimethoprim-sulfamethoxazole (TMP-SMZ), 266,951 prescribed trimethoprim alone, and 196,397 prescribed CHEMICAL, to estimate the risk of serious liver, blood, skin, and renal disorders resulting in referral or hospitalization associated with these drugs. The results were based on information recorded on office computers by selected general practitioners in the United Kingdom, together with a review of clinical records. The risk of clinically important idiopathic liver disease was similar for persons prescribed TMP-SMZ (5.2/100,000) and those prescribed trimethoprim alone (3.8/100,000). The risk for those prescribed CHEMICAL was somewhat lower (2.0/100,000). Only five patients experienced blood disorders, one of whom was exposed to TMP-SMZ; of seven with erythema multiforme and DISEASE, four were exposed to TMP-SMZ. The one case of DISEASE occurred in a patient who took CHEMICAL. Finally, only five cases of acute parenchymal renal disease occurred, none likely to be caused by a study drug. We conclude that the risk of the serious diseases studied is small for the three agents, and compares reasonably with the risk for many other antibiotics. | CHEMICAL-INDUCED-DISEASE |
| A large population-based follow-up study of CHEMICAL, trimethoprim, and cephalexin for uncommon serious drug toxicity. We conducted a population-based 45-day follow-up study of 232,390 people who were prescribed CHEMICAL (CHEMICAL), 266,951 prescribed trimethoprim alone, and 196,397 prescribed cephalexin, to estimate the risk of serious liver, blood, skin, and renal disorders resulting in referral or hospitalization associated with these drugs. The results were based on information recorded on office computers by selected general practitioners in the United Kingdom, together with a review of clinical records. The risk of clinically important idiopathic liver disease was similar for persons prescribed CHEMICAL (5.2/100,000) and those prescribed trimethoprim alone (3.8/100,000). The risk for those prescribed cephalexin was somewhat lower (2.0/100,000). Only five patients experienced blood disorders, one of whom was exposed to CHEMICAL; of seven with erythema multiforme and DISEASE, four were exposed to CHEMICAL. The one case of DISEASE occurred in a patient who took cephalexin. Finally, only five cases of acute parenchymal renal disease occurred, none likely to be caused by a study drug. We conclude that the risk of the serious diseases studied is small for the three agents, and compares reasonably with the risk for many other antibiotics. | CHEMICAL-INDUCED-DISEASE |
| Clinical safety of lidocaine in patients with CHEMICAL-associated DISEASE. STUDY OBJECTIVE: To evaluate the safety of lidocaine in the setting of CHEMICAL-induced DISEASE (DISEASE). DESIGN: A retrospective, multicenter study. SETTING: Twenty-nine university, university-affiliated, or community hospitals during a 6-year period (total of 117 cumulative hospital-years). PARTICIPANTS: Patients with CHEMICAL-associated DISEASE who received lidocaine in the emergency department. RESULTS: Of 29 patients who received lidocaine in the setting of CHEMICAL-associated DISEASE, no patient died; exhibited bradydysrhythmias, ventricular tachycardia, or ventricular fibrillation; or experienced seizures after administration of lidocaine (95% confidence interval, 0% to 11%). CONCLUSION: Despite theoretical concerns that lidocaine may enhance CHEMICAL toxicity, the use of lidocaine in patients with CHEMICAL-associated DISEASE was not associated with significant cardiovascular or central nervous system toxicity. | CHEMICAL-INDUCED-DISEASE |
| Clinical safety of CHEMICAL in patients with cocaine-associated myocardial infarction. STUDY OBJECTIVE: To evaluate the safety of CHEMICAL in the setting of cocaine-induced myocardial infarction (MI). DESIGN: A retrospective, multicenter study. SETTING: Twenty-nine university, university-affiliated, or community hospitals during a 6-year period (total of 117 cumulative hospital-years). PARTICIPANTS: Patients with cocaine-associated MI who received CHEMICAL in the emergency department. RESULTS: Of 29 patients who received CHEMICAL in the setting of cocaine-associated MI, no patient died; exhibited bradydysrhythmias, ventricular tachycardia, or ventricular fibrillation; or experienced DISEASE after administration of CHEMICAL (95% confidence interval, 0% to 11%). CONCLUSION: Despite theoretical concerns that CHEMICAL may enhance cocaine toxicity, the use of CHEMICAL in patients with cocaine-associated MI was not associated with significant cardiovascular or central nervous system toxicity. | CHEMICAL-INDUCED-DISEASE |
| Clinical safety of CHEMICAL in patients with cocaine-associated myocardial infarction. STUDY OBJECTIVE: To evaluate the safety of CHEMICAL in the setting of cocaine-induced myocardial infarction (MI). DESIGN: A retrospective, multicenter study. SETTING: Twenty-nine university, university-affiliated, or community hospitals during a 6-year period (total of 117 cumulative hospital-years). PARTICIPANTS: Patients with cocaine-associated MI who received CHEMICAL in the emergency department. RESULTS: Of 29 patients who received CHEMICAL in the setting of cocaine-associated MI, no patient died; exhibited bradydysrhythmias, ventricular tachycardia, or ventricular fibrillation; or experienced seizures after administration of CHEMICAL (95% confidence interval, 0% to 11%). CONCLUSION: Despite theoretical concerns that CHEMICAL may enhance cocaine toxicity, the use of CHEMICAL in patients with cocaine-associated MI was not associated with significant DISEASE. | NO-RELATIONSHIP |
| Clinical safety of CHEMICAL in patients with cocaine-associated myocardial infarction. STUDY OBJECTIVE: To evaluate the safety of CHEMICAL in the setting of cocaine-induced myocardial infarction (MI). DESIGN: A retrospective, multicenter study. SETTING: Twenty-nine university, university-affiliated, or community hospitals during a 6-year period (total of 117 cumulative hospital-years). PARTICIPANTS: Patients with cocaine-associated MI who received CHEMICAL in the emergency department. RESULTS: Of 29 patients who received CHEMICAL in the setting of cocaine-associated MI, no patient died; exhibited bradydysrhythmias, ventricular tachycardia, or DISEASE; or experienced seizures after administration of CHEMICAL (95% confidence interval, 0% to 11%). CONCLUSION: Despite theoretical concerns that CHEMICAL may enhance cocaine toxicity, the use of CHEMICAL in patients with cocaine-associated MI was not associated with significant cardiovascular or central nervous system toxicity. | CHEMICAL-INDUCED-DISEASE |
| Clinical safety of CHEMICAL in patients with cocaine-associated myocardial infarction. STUDY OBJECTIVE: To evaluate the safety of CHEMICAL in the setting of cocaine-induced myocardial infarction (MI). DESIGN: A retrospective, multicenter study. SETTING: Twenty-nine university, university-affiliated, or community hospitals during a 6-year period (total of 117 cumulative hospital-years). PARTICIPANTS: Patients with cocaine-associated MI who received CHEMICAL in the emergency department. RESULTS: Of 29 patients who received CHEMICAL in the setting of cocaine-associated MI, no patient died; exhibited bradydysrhythmias, ventricular tachycardia, or ventricular fibrillation; or experienced seizures after administration of CHEMICAL (95% confidence interval, 0% to 11%). CONCLUSION: Despite theoretical concerns that CHEMICAL may enhance cocaine DISEASE, the use of CHEMICAL in patients with cocaine-associated MI was not associated with significant cardiovascular or central nervous system toxicity. | NO-RELATIONSHIP |
| Clinical safety of CHEMICAL in patients with cocaine-associated myocardial infarction. STUDY OBJECTIVE: To evaluate the safety of CHEMICAL in the setting of cocaine-induced myocardial infarction (MI). DESIGN: A retrospective, multicenter study. SETTING: Twenty-nine university, university-affiliated, or community hospitals during a 6-year period (total of 117 cumulative hospital-years). PARTICIPANTS: Patients with cocaine-associated MI who received CHEMICAL in the emergency department. RESULTS: Of 29 patients who received CHEMICAL in the setting of cocaine-associated MI, no patient died; exhibited bradydysrhythmias, DISEASE, or ventricular fibrillation; or experienced seizures after administration of CHEMICAL (95% confidence interval, 0% to 11%). CONCLUSION: Despite theoretical concerns that CHEMICAL may enhance cocaine toxicity, the use of CHEMICAL in patients with cocaine-associated MI was not associated with significant cardiovascular or central nervous system toxicity. | CHEMICAL-INDUCED-DISEASE |
| Clinical safety of CHEMICAL in patients with cocaine-associated myocardial infarction. STUDY OBJECTIVE: To evaluate the safety of CHEMICAL in the setting of cocaine-induced myocardial infarction (MI). DESIGN: A retrospective, multicenter study. SETTING: Twenty-nine university, university-affiliated, or community hospitals during a 6-year period (total of 117 cumulative hospital-years). PARTICIPANTS: Patients with cocaine-associated MI who received CHEMICAL in the emergency department. RESULTS: Of 29 patients who received CHEMICAL in the setting of cocaine-associated MI, no patient died; exhibited DISEASE, ventricular tachycardia, or ventricular fibrillation; or experienced seizures after administration of CHEMICAL (95% confidence interval, 0% to 11%). CONCLUSION: Despite theoretical concerns that CHEMICAL may enhance cocaine toxicity, the use of CHEMICAL in patients with cocaine-associated MI was not associated with significant cardiovascular or central nervous system toxicity. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL 3-hour infusion given alone and combined with carboplatin: preliminary results of dose-escalation trials. CHEMICAL (CHEMICAL; Bristol-Myers Squibb Company, Princeton, NJ) by 3-hour infusion was combined with carboplatin in a phase I/II study directed to patients with non-small cell lung cancer. Carboplatin was given at a fixed target area under the concentration-time curve of 6.0 by the Calvert formula, whereas CHEMICAL was escalated in patient cohorts from 150 mg/m2 (dose level I) to 175, 200, 225, and 250 mg/m2. The 225 mg/m2 level was expanded for the phase II study since the highest level achieved (250 mg/m2) required modification because of nonhematologic toxicities (arthralgia and DISEASE). Therapeutic effects were noted at all dose levels, with objective responses in 17 (two complete and 15 partial regressions) of 41 previously untreated patients. Toxicities were compared with a cohort of patients in a phase I trial of CHEMICAL alone at identical dose levels. Carboplatin did not appear to add to the hematologic toxicities observed, and the CHEMICAL/carboplatin combination could be dosed every 3 weeks. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL 3-hour infusion given alone and combined with carboplatin: preliminary results of dose-escalation trials. CHEMICAL (CHEMICAL; Bristol-Myers Squibb Company, Princeton, NJ) by 3-hour infusion was combined with carboplatin in a phase I/II study directed to patients with non-small cell lung cancer. Carboplatin was given at a fixed target area under the concentration-time curve of 6.0 by the Calvert formula, whereas CHEMICAL was escalated in patient cohorts from 150 mg/m2 (dose level I) to 175, 200, 225, and 250 mg/m2. The 225 mg/m2 level was expanded for the phase II study since the highest level achieved (250 mg/m2) required modification because of nonhematologic toxicities (arthralgia and sensory neuropathy). Therapeutic effects were noted at all dose levels, with objective responses in 17 (two complete and 15 partial regressions) of 41 previously untreated patients. Toxicities were compared with a cohort of patients in a phase I trial of CHEMICAL alone at identical dose levels. Carboplatin did not appear to add to the DISEASE observed, and the CHEMICAL/carboplatin combination could be dosed every 3 weeks. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL 3-hour infusion given alone and combined with carboplatin: preliminary results of dose-escalation trials. CHEMICAL (CHEMICAL; Bristol-Myers Squibb Company, Princeton, NJ) by 3-hour infusion was combined with carboplatin in a phase I/II study directed to patients with non-small cell lung cancer. Carboplatin was given at a fixed target area under the concentration-time curve of 6.0 by the Calvert formula, whereas CHEMICAL was escalated in patient cohorts from 150 mg/m2 (dose level I) to 175, 200, 225, and 250 mg/m2. The 225 mg/m2 level was expanded for the phase II study since the highest level achieved (250 mg/m2) required modification because of nonhematologic toxicities (DISEASE and sensory neuropathy). Therapeutic effects were noted at all dose levels, with objective responses in 17 (two complete and 15 partial regressions) of 41 previously untreated patients. Toxicities were compared with a cohort of patients in a phase I trial of CHEMICAL alone at identical dose levels. Carboplatin did not appear to add to the hematologic toxicities observed, and the CHEMICAL/carboplatin combination could be dosed every 3 weeks. | CHEMICAL-INDUCED-DISEASE |
| Paclitaxel 3-hour infusion given alone and combined with CHEMICAL: preliminary results of dose-escalation trials. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) by 3-hour infusion was combined with CHEMICAL in a phase I/II study directed to patients with non-small cell lung cancer. CHEMICAL was given at a fixed target area under the concentration-time curve of 6.0 by the Calvert formula, whereas paclitaxel was escalated in patient cohorts from 150 mg/m2 (dose level I) to 175, 200, 225, and 250 mg/m2. The 225 mg/m2 level was expanded for the phase II study since the highest level achieved (250 mg/m2) required modification because of nonhematologic DISEASE (arthralgia and sensory neuropathy). Therapeutic effects were noted at all dose levels, with objective responses in 17 (two complete and 15 partial regressions) of 41 previously untreated patients. DISEASE were compared with a cohort of patients in a phase I trial of paclitaxel alone at identical dose levels. CHEMICAL did not appear to add to the hematologic toxicities observed, and the paclitaxel/CHEMICAL combination could be dosed every 3 weeks. | CHEMICAL-INDUCED-DISEASE |
| Paclitaxel 3-hour infusion given alone and combined with CHEMICAL: preliminary results of dose-escalation trials. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) by 3-hour infusion was combined with CHEMICAL in a phase I/II study directed to patients with DISEASE. CHEMICAL was given at a fixed target area under the concentration-time curve of 6.0 by the Calvert formula, whereas paclitaxel was escalated in patient cohorts from 150 mg/m2 (dose level I) to 175, 200, 225, and 250 mg/m2. The 225 mg/m2 level was expanded for the phase II study since the highest level achieved (250 mg/m2) required modification because of nonhematologic toxicities (arthralgia and sensory neuropathy). Therapeutic effects were noted at all dose levels, with objective responses in 17 (two complete and 15 partial regressions) of 41 previously untreated patients. Toxicities were compared with a cohort of patients in a phase I trial of paclitaxel alone at identical dose levels. CHEMICAL did not appear to add to the hematologic toxicities observed, and the paclitaxel/CHEMICAL combination could be dosed every 3 weeks. | NO-RELATIONSHIP |
| The dose-dependent effect of misoprostol on CHEMICAL-induced DISEASE in well compensated cirrhosis. Misoprostol (200 micrograms) has been shown to acutely counteract the CHEMICAL-induced DISEASE in well compensated cirrhotic patients. The aim of this study was to determine if the prophylactic value of misoprostol was dose-dependent. Parameters of renal hemodynamics and tubular sodium and water handling were assessed by clearance techniques in 26 well compensated cirrhotic patients before and after an oral combination of 50 mg of CHEMICAL and various doses of misoprostol. The 200-micrograms dose was able to totally abolish the deleterious renal effects of CHEMICAL, whereas the 800-micrograms dose resulted in significant worsening of renal hemodynamics and sodium retention. These changes were maximal in the hour immediately after medications and slowly returned toward base-line levels thereafter. These results suggest that the renal protective effects of misoprostol is dose-dependent. However, until this apparent ability of 200 micrograms of misoprostol to prevent the adverse effects of CHEMICAL on renal function is confirmed with chronic frequent dosing, it would be prudent to avoid nonsteroidal anti-inflammatory therapy in patients with cirrhosis. | CHEMICAL-INDUCED-DISEASE |
| The dose-dependent effect of misoprostol on indomethacin-induced renal dysfunction in well compensated DISEASE. Misoprostol (200 micrograms) has been shown to acutely counteract the indomethacin-induced renal dysfunction in well compensated DISEASE patients. The aim of this study was to determine if the prophylactic value of misoprostol was dose-dependent. Parameters of renal hemodynamics and tubular CHEMICAL and water handling were assessed by clearance techniques in 26 well compensated DISEASE patients before and after an oral combination of 50 mg of indomethacin and various doses of misoprostol. The 200-micrograms dose was able to totally abolish the deleterious renal effects of indomethacin, whereas the 800-micrograms dose resulted in significant worsening of renal hemodynamics and CHEMICAL retention. These changes were maximal in the hour immediately after medications and slowly returned toward base-line levels thereafter. These results suggest that the renal protective effects of misoprostol is dose-dependent. However, until this apparent ability of 200 micrograms of misoprostol to prevent the adverse effects of indomethacin on renal function is confirmed with chronic frequent dosing, it would be prudent to avoid nonsteroidal anti-inflammatory therapy in patients with DISEASE. | NO-RELATIONSHIP |
| The dose-dependent effect of CHEMICAL on indomethacin-induced renal dysfunction in well compensated DISEASE. CHEMICAL (200 micrograms) has been shown to acutely counteract the indomethacin-induced renal dysfunction in well compensated DISEASE patients. The aim of this study was to determine if the prophylactic value of CHEMICAL was dose-dependent. Parameters of renal hemodynamics and tubular sodium and water handling were assessed by clearance techniques in 26 well compensated DISEASE patients before and after an oral combination of 50 mg of indomethacin and various doses of CHEMICAL. The 200-micrograms dose was able to totally abolish the deleterious renal effects of indomethacin, whereas the 800-micrograms dose resulted in significant worsening of renal hemodynamics and sodium retention. These changes were maximal in the hour immediately after medications and slowly returned toward base-line levels thereafter. These results suggest that the renal protective effects of CHEMICAL is dose-dependent. However, until this apparent ability of 200 micrograms of CHEMICAL to prevent the adverse effects of indomethacin on renal function is confirmed with chronic frequent dosing, it would be prudent to avoid nonsteroidal anti-inflammatory therapy in patients with DISEASE. | NO-RELATIONSHIP |
| Increased frequency and severity of DISEASE related to long-term therapy with CHEMICAL in two patients. Adverse reactions to drugs are well recognized as a cause of acute or chronic urticaria, and DISEASE. CHEMICAL, used to treat hypertension and congestive heart failure, were introduced in Europe in the middle of the eighties, and the use of these drugs has increased progressively. Soon after the introduction of CHEMICAL, acute bouts of DISEASE were reported in association with the use of these drugs. We wish to draw attention to the possibility of adverse reactions to CHEMICAL after long-term use and in patients with pre-existing DISEASE. | CHEMICAL-INDUCED-DISEASE |
| DISEASE associated with CHEMICAL therapy in very-low-birth-weight infants. CHEMICAL is being used with increasing frequency as a sedative in the newborn and the young infant. Concern has been raised with regard to the safety of CHEMICAL in this age group, especially in very-low-birth-weight (VLBW; < 1,500 g) infants. Three young infants, all of birth weight < 1,500 g, experienced DISEASE following the intravenous administration of CHEMICAL. The potential neurotoxic effects of the drug (and its vehicle) in this population are discussed. Injectable CHEMICAL should be used with caution in VLBW infants. | CHEMICAL-INDUCED-DISEASE |
| Transvenous right ventricular pacing during cardiopulmonary resuscitation of pediatric patients with acute cardiomyopathy. We describe the cardiopulmonary resuscitation efforts on five patients who presented in acute circulatory failure from myocardial dysfunction. Three patients had acute viral DISEASE, one had a CHEMICAL-induced acute eosinophilic myocarditis, and one had cardiac hemosiderosis resulting in acute cardiogenic shock. All patients were continuously monitored with central venous and arterial catheters in addition to routine noninvasive monitoring. An introducer sheath, a pacemaker, and sterile pacing wires were made readily available for the patients, should the need arise to terminate resistant cardiac dysrhythmias. All patients developed cardiocirculatory arrest associated with extreme hypotension and dysrhythmias within the first 48 hours of their admission to the pediatric intensive care unit (PICU). Right ventricular pacemaker wires were inserted in all of them during cardiopulmonary resuscitation (CPR). In four patients, cardiac pacing was used, resulting in a temporary captured rhythm and restoration of their cardiac output. These patients had a second event of cardiac arrest, resulting in death, within 10 to 60 minutes. In one patient, cardiac pacing was not used, because he converted to normal sinus rhythm by electrical defibrillation within three minutes of initiating CPR. We conclude that cardiac pacing during resuscitative efforts in pediatric patients suffering from acute myocardial dysfunction may not have long-term value in and of itself; however, if temporary hemodynamic stability is achieved by this procedure, it may provide additional time needed to institute other therapeutic modalities. | CHEMICAL-INDUCED-DISEASE |
| Efficacy and safety of granisetron, a selective 5-hydroxytryptamine-3 receptor antagonist, in the prevention of nausea and DISEASE induced by high-dose CHEMICAL. PURPOSE: To assess the antiemetic effects and safety profile of four different doses of granisetron (Kytril; SmithKline Beecham Pharmaceuticals, Philadelphia, PA) when administered as a single intravenous (IV) dose for prophylaxis of CHEMICAL-induced nausea and DISEASE. PATIENTS AND METHODS: One hundred eighty-four chemotherapy-naive patients receiving high-dose CHEMICAL (81 to 120 mg/m2) were randomized to receive one of four granisetron doses (5, 10, 20, or 40 micrograms/kg) administered before chemotherapy. Patients were observed on an inpatient basis for 18 to 24 hours, and vital signs, nausea, DISEASE, retching, and appetite were assessed. Safety analyses included incidence of adverse experiences and laboratory parameter changes. RESULTS: After granisetron doses of 5, 10, 20, and 40 micrograms/kg, a major response (< or = two DISEASE or retching episodes, and no antiemetic rescue) was recorded in 23%, 57%, 58%, and 60% of patients, respectively, and a complete response (no DISEASE or retching, and no antiemetic rescue) in 18%, 41%, 40%, and 47% of patients, respectively. There was a statistically longer time to first episode of nausea (P = .0015) and DISEASE (P = .0001), and fewer patients were administered additional antiemetic medication in the 10-micrograms/kg dosing groups than in the 5-micrograms/kg dosing group. As granisetron dose increased, appetite return increased (P = .040). Headache was the most frequently reported adverse event (20%). CONCLUSION: A single 10-, 20-, or 40-micrograms/kg dose of granisetron was effective in controlling DISEASE in 57% to 60% of patients who received CHEMICAL at doses greater than 81 mg/m2 and totally prevented DISEASE in 40% to 47% of patients. There were no statistically significant differences in efficacy between the 10-micrograms/kg dose and the 20- and 40-micrograms/kg doses. Granisetron was well tolerated at all doses. | CHEMICAL-INDUCED-DISEASE |
| Efficacy and safety of CHEMICAL, a selective 5-hydroxytryptamine-3 receptor antagonist, in the prevention of nausea and vomiting induced by high-dose cisplatin. PURPOSE: To assess the antiemetic effects and safety profile of four different doses of CHEMICAL (CHEMICAL; SmithKline Beecham Pharmaceuticals, Philadelphia, PA) when administered as a single intravenous (IV) dose for prophylaxis of cisplatin-induced nausea and vomiting. PATIENTS AND METHODS: One hundred eighty-four chemotherapy-naive patients receiving high-dose cisplatin (81 to 120 mg/m2) were randomized to receive one of four CHEMICAL doses (5, 10, 20, or 40 micrograms/kg) administered before chemotherapy. Patients were observed on an inpatient basis for 18 to 24 hours, and vital signs, nausea, vomiting, retching, and appetite were assessed. Safety analyses included incidence of adverse experiences and laboratory parameter changes. RESULTS: After CHEMICAL doses of 5, 10, 20, and 40 micrograms/kg, a major response (< or = two vomiting or retching episodes, and no antiemetic rescue) was recorded in 23%, 57%, 58%, and 60% of patients, respectively, and a complete response (no vomiting or retching, and no antiemetic rescue) in 18%, 41%, 40%, and 47% of patients, respectively. There was a statistically longer time to first episode of nausea (P = .0015) and vomiting (P = .0001), and fewer patients were administered additional antiemetic medication in the 10-micrograms/kg dosing groups than in the 5-micrograms/kg dosing group. As CHEMICAL dose increased, appetite return increased (P = .040). DISEASE was the most frequently reported adverse event (20%). CONCLUSION: A single 10-, 20-, or 40-micrograms/kg dose of CHEMICAL was effective in controlling vomiting in 57% to 60% of patients who received cisplatin at doses greater than 81 mg/m2 and totally prevented vomiting in 40% to 47% of patients. There were no statistically significant differences in efficacy between the 10-micrograms/kg dose and the 20- and 40-micrograms/kg doses. CHEMICAL was well tolerated at all doses. | CHEMICAL-INDUCED-DISEASE |
| Efficacy and safety of granisetron, a selective 5-hydroxytryptamine-3 receptor antagonist, in the prevention of DISEASE and vomiting induced by high-dose CHEMICAL. PURPOSE: To assess the antiemetic effects and safety profile of four different doses of granisetron (Kytril; SmithKline Beecham Pharmaceuticals, Philadelphia, PA) when administered as a single intravenous (IV) dose for prophylaxis of CHEMICAL-induced DISEASE and vomiting. PATIENTS AND METHODS: One hundred eighty-four chemotherapy-naive patients receiving high-dose CHEMICAL (81 to 120 mg/m2) were randomized to receive one of four granisetron doses (5, 10, 20, or 40 micrograms/kg) administered before chemotherapy. Patients were observed on an inpatient basis for 18 to 24 hours, and vital signs, DISEASE, vomiting, retching, and appetite were assessed. Safety analyses included incidence of adverse experiences and laboratory parameter changes. RESULTS: After granisetron doses of 5, 10, 20, and 40 micrograms/kg, a major response (< or = two vomiting or retching episodes, and no antiemetic rescue) was recorded in 23%, 57%, 58%, and 60% of patients, respectively, and a complete response (no vomiting or retching, and no antiemetic rescue) in 18%, 41%, 40%, and 47% of patients, respectively. There was a statistically longer time to first episode of DISEASE (P = .0015) and vomiting (P = .0001), and fewer patients were administered additional antiemetic medication in the 10-micrograms/kg dosing groups than in the 5-micrograms/kg dosing group. As granisetron dose increased, appetite return increased (P = .040). Headache was the most frequently reported adverse event (20%). CONCLUSION: A single 10-, 20-, or 40-micrograms/kg dose of granisetron was effective in controlling vomiting in 57% to 60% of patients who received CHEMICAL at doses greater than 81 mg/m2 and totally prevented vomiting in 40% to 47% of patients. There were no statistically significant differences in efficacy between the 10-micrograms/kg dose and the 20- and 40-micrograms/kg doses. Granisetron was well tolerated at all doses. | CHEMICAL-INDUCED-DISEASE |
| Adverse interaction between clonidine and CHEMICAL. OBJECTIVE: To report two cases of a possible adverse interaction between clonidine and CHEMICAL resulting in atrioventricular (AV) block in both patients and severe DISEASE in one patient. CASE SUMMARIES: A 54-year-old woman with hyperaldosteronism was treated with CHEMICAL 480 mg/d and spironolactone 100 mg/d. After the addition of a minimal dose of clonidine (0.15 mg bid), she developed complete AV block and severe DISEASE, which resolved upon cessation of all medications. A 65-year-old woman was treated with extended-release CHEMICAL 240 mg/d. After the addition of clonidine 0.15 mg bid she developed complete AV block, which resolved after all therapy was stopped. DISCUSSION: An adverse interaction between clonidine and CHEMICAL has not been reported previously. We describe two such cases and discuss the various mechanisms that might cause such an interaction. Clinicians should be acquainted with this possibly fatal interaction between two commonly used antihypertensive drugs. CONCLUSIONS: Caution is recommended in combining clonidine and CHEMICAL therapy, even in patients who do not have sinus or AV node dysfunction. The two drugs may act synergistically on both the AV node and the peripheral circulation. | CHEMICAL-INDUCED-DISEASE |
| Adverse interaction between clonidine and CHEMICAL. OBJECTIVE: To report two cases of a possible adverse interaction between clonidine and CHEMICAL resulting in DISEASE in both patients and severe hypotension in one patient. CASE SUMMARIES: A 54-year-old woman with hyperaldosteronism was treated with CHEMICAL 480 mg/d and spironolactone 100 mg/d. After the addition of a minimal dose of clonidine (0.15 mg bid), she developed complete DISEASE and severe hypotension, which resolved upon cessation of all medications. A 65-year-old woman was treated with extended-release CHEMICAL 240 mg/d. After the addition of clonidine 0.15 mg bid she developed complete DISEASE, which resolved after all therapy was stopped. DISCUSSION: An adverse interaction between clonidine and CHEMICAL has not been reported previously. We describe two such cases and discuss the various mechanisms that might cause such an interaction. Clinicians should be acquainted with this possibly fatal interaction between two commonly used antihypertensive drugs. CONCLUSIONS: Caution is recommended in combining clonidine and CHEMICAL therapy, even in patients who do not have sinus or AV node dysfunction. The two drugs may act synergistically on both the AV node and the peripheral circulation. | CHEMICAL-INDUCED-DISEASE |
| Adverse interaction between CHEMICAL and verapamil. OBJECTIVE: To report two cases of a possible adverse interaction between CHEMICAL and verapamil resulting in DISEASE in both patients and severe hypotension in one patient. CASE SUMMARIES: A 54-year-old woman with hyperaldosteronism was treated with verapamil 480 mg/d and spironolactone 100 mg/d. After the addition of a minimal dose of CHEMICAL (0.15 mg bid), she developed complete DISEASE and severe hypotension, which resolved upon cessation of all medications. A 65-year-old woman was treated with extended-release verapamil 240 mg/d. After the addition of CHEMICAL 0.15 mg bid she developed complete DISEASE, which resolved after all therapy was stopped. DISCUSSION: An adverse interaction between CHEMICAL and verapamil has not been reported previously. We describe two such cases and discuss the various mechanisms that might cause such an interaction. Clinicians should be acquainted with this possibly fatal interaction between two commonly used antihypertensive drugs. CONCLUSIONS: Caution is recommended in combining CHEMICAL and verapamil therapy, even in patients who do not have sinus or AV node dysfunction. The two drugs may act synergistically on both the AV node and the peripheral circulation. | CHEMICAL-INDUCED-DISEASE |
| Adverse interaction between CHEMICAL and verapamil. OBJECTIVE: To report two cases of a possible adverse interaction between CHEMICAL and verapamil resulting in atrioventricular (AV) block in both patients and severe DISEASE in one patient. CASE SUMMARIES: A 54-year-old woman with hyperaldosteronism was treated with verapamil 480 mg/d and spironolactone 100 mg/d. After the addition of a minimal dose of CHEMICAL (0.15 mg bid), she developed complete AV block and severe DISEASE, which resolved upon cessation of all medications. A 65-year-old woman was treated with extended-release verapamil 240 mg/d. After the addition of CHEMICAL 0.15 mg bid she developed complete AV block, which resolved after all therapy was stopped. DISCUSSION: An adverse interaction between CHEMICAL and verapamil has not been reported previously. We describe two such cases and discuss the various mechanisms that might cause such an interaction. Clinicians should be acquainted with this possibly fatal interaction between two commonly used antihypertensive drugs. CONCLUSIONS: Caution is recommended in combining CHEMICAL and verapamil therapy, even in patients who do not have sinus or AV node dysfunction. The two drugs may act synergistically on both the AV node and the peripheral circulation. | CHEMICAL-INDUCED-DISEASE |
| Adverse interaction between clonidine and verapamil. OBJECTIVE: To report two cases of a possible adverse interaction between clonidine and verapamil resulting in atrioventricular (AV) block in both patients and severe hypotension in one patient. CASE SUMMARIES: A 54-year-old woman with DISEASE was treated with verapamil 480 mg/d and CHEMICAL 100 mg/d. After the addition of a minimal dose of clonidine (0.15 mg bid), she developed complete AV block and severe hypotension, which resolved upon cessation of all medications. A 65-year-old woman was treated with extended-release verapamil 240 mg/d. After the addition of clonidine 0.15 mg bid she developed complete AV block, which resolved after all therapy was stopped. DISCUSSION: An adverse interaction between clonidine and verapamil has not been reported previously. We describe two such cases and discuss the various mechanisms that might cause such an interaction. Clinicians should be acquainted with this possibly fatal interaction between two commonly used antihypertensive drugs. CONCLUSIONS: Caution is recommended in combining clonidine and verapamil therapy, even in patients who do not have sinus or AV node dysfunction. The two drugs may act synergistically on both the AV node and the peripheral circulation. | NO-RELATIONSHIP |
| Pharmacological studies on a new dihydrothienopyridine calcium antagonist, S-312-d. 5th communication: anticonvulsant effects in mice. S-312, S-312-d, but not S-312-l, L-type calcium channel antagonists, showed anticonvulsant effects on the audiogenic tonic convulsions in DBA/2 mice; and their ED50 values were 18.4 (12.8-27.1) mg/kg, p.o. and 15.0 (10.2-23.7) mg/kg, p.o., respectively, while that of flunarizine was 34.0 (26.0-44.8) mg/kg, p.o. Although moderate anticonvulsant effects of S-312-d in higher doses were observed against the clonic DISEASE induced by pentylenetetrazole (85 mg/kg, s.c.) or bemegride (40 mg/kg, s.c.), no effects were observed in DISEASE induced by N-methyl-D-aspartate, CHEMICAL, or electroshock in Slc:ddY mice. S-312-d may be useful in the therapy of certain types of human epilepsy. | CHEMICAL-INDUCED-DISEASE |
| Pharmacological studies on a new dihydrothienopyridine calcium antagonist, S-312-d. 5th communication: anticonvulsant effects in mice. S-312, S-312-d, but not S-312-l, L-type calcium channel antagonists, showed anticonvulsant effects on the audiogenic tonic convulsions in DBA/2 mice; and their ED50 values were 18.4 (12.8-27.1) mg/kg, p.o. and 15.0 (10.2-23.7) mg/kg, p.o., respectively, while that of flunarizine was 34.0 (26.0-44.8) mg/kg, p.o. Although moderate anticonvulsant effects of S-312-d in higher doses were observed against the clonic DISEASE induced by CHEMICAL (85 mg/kg, s.c.) or bemegride (40 mg/kg, s.c.), no effects were observed in DISEASE induced by N-methyl-D-aspartate, picrotoxin, or electroshock in Slc:ddY mice. S-312-d may be useful in the therapy of certain types of human epilepsy. | CHEMICAL-INDUCED-DISEASE |
| Pharmacological studies on a new dihydrothienopyridine calcium antagonist, S-312-d. 5th communication: anticonvulsant effects in mice. S-312, S-312-d, but not S-312-l, L-type calcium channel antagonists, showed anticonvulsant effects on the audiogenic tonic convulsions in DBA/2 mice; and their ED50 values were 18.4 (12.8-27.1) mg/kg, p.o. and 15.0 (10.2-23.7) mg/kg, p.o., respectively, while that of flunarizine was 34.0 (26.0-44.8) mg/kg, p.o. Although moderate anticonvulsant effects of S-312-d in higher doses were observed against the clonic DISEASE induced by pentylenetetrazole (85 mg/kg, s.c.) or CHEMICAL (40 mg/kg, s.c.), no effects were observed in DISEASE induced by N-methyl-D-aspartate, picrotoxin, or electroshock in Slc:ddY mice. S-312-d may be useful in the therapy of certain types of human epilepsy. | CHEMICAL-INDUCED-DISEASE |
| Pharmacological studies on a new dihydrothienopyridine calcium antagonist, S-312-d. 5th communication: anticonvulsant effects in mice. S-312, S-312-d, but not S-312-l, L-type calcium channel antagonists, showed anticonvulsant effects on the DISEASE in DBA/2 mice; and their ED50 values were 18.4 (12.8-27.1) mg/kg, p.o. and 15.0 (10.2-23.7) mg/kg, p.o., respectively, while that of CHEMICAL was 34.0 (26.0-44.8) mg/kg, p.o. Although moderate anticonvulsant effects of S-312-d in higher doses were observed against the clonic convulsions induced by pentylenetetrazole (85 mg/kg, s.c.) or bemegride (40 mg/kg, s.c.), no effects were observed in convulsions induced by N-methyl-D-aspartate, picrotoxin, or electroshock in Slc:ddY mice. S-312-d may be useful in the therapy of certain types of human epilepsy. | NO-RELATIONSHIP |
| Pharmacological studies on a new CHEMICAL antagonist, S-312-d. 5th communication: anticonvulsant effects in mice. S-312, S-312-d, but not CHEMICAL, L-type calcium channel antagonists, showed anticonvulsant effects on the audiogenic tonic convulsions in DBA/2 mice; and their ED50 values were 18.4 (12.8-27.1) mg/kg, p.o. and 15.0 (10.2-23.7) mg/kg, p.o., respectively, while that of flunarizine was 34.0 (26.0-44.8) mg/kg, p.o. Although moderate anticonvulsant effects of S-312-d in higher doses were observed against the clonic convulsions induced by pentylenetetrazole (85 mg/kg, s.c.) or bemegride (40 mg/kg, s.c.), no effects were observed in convulsions induced by N-methyl-D-aspartate, picrotoxin, or electroshock in Slc:ddY mice. S-312-d may be useful in the therapy of certain types of human DISEASE. | NO-RELATIONSHIP |
| Pharmacological studies on a new dihydrothienopyridine calcium antagonist, S-312-d. 5th communication: anticonvulsant effects in mice. S-312, S-312-d, but not S-312-l, L-type CHEMICAL channel antagonists, showed anticonvulsant effects on the DISEASE in DBA/2 mice; and their ED50 values were 18.4 (12.8-27.1) mg/kg, p.o. and 15.0 (10.2-23.7) mg/kg, p.o., respectively, while that of flunarizine was 34.0 (26.0-44.8) mg/kg, p.o. Although moderate anticonvulsant effects of S-312-d in higher doses were observed against the clonic convulsions induced by pentylenetetrazole (85 mg/kg, s.c.) or bemegride (40 mg/kg, s.c.), no effects were observed in convulsions induced by N-methyl-D-aspartate, picrotoxin, or electroshock in Slc:ddY mice. S-312-d may be useful in the therapy of certain types of human epilepsy. | NO-RELATIONSHIP |
| Pharmacological studies on a new CHEMICAL antagonist, S-312-d. 5th communication: anticonvulsant effects in mice. S-312, S-312-d, but not CHEMICAL, L-type calcium channel antagonists, showed anticonvulsant effects on the DISEASE in DBA/2 mice; and their ED50 values were 18.4 (12.8-27.1) mg/kg, p.o. and 15.0 (10.2-23.7) mg/kg, p.o., respectively, while that of flunarizine was 34.0 (26.0-44.8) mg/kg, p.o. Although moderate anticonvulsant effects of S-312-d in higher doses were observed against the clonic convulsions induced by pentylenetetrazole (85 mg/kg, s.c.) or bemegride (40 mg/kg, s.c.), no effects were observed in convulsions induced by N-methyl-D-aspartate, picrotoxin, or electroshock in Slc:ddY mice. S-312-d may be useful in the therapy of certain types of human epilepsy. | NO-RELATIONSHIP |
| Pharmacological studies on a new dihydrothienopyridine calcium antagonist, S-312-d. 5th communication: anticonvulsant effects in mice. S-312, S-312-d, but not S-312-l, L-type calcium channel antagonists, showed anticonvulsant effects on the audiogenic tonic convulsions in DBA/2 mice; and their ED50 values were 18.4 (12.8-27.1) mg/kg, p.o. and 15.0 (10.2-23.7) mg/kg, p.o., respectively, while that of flunarizine was 34.0 (26.0-44.8) mg/kg, p.o. Although moderate anticonvulsant effects of S-312-d in higher doses were observed against the clonic convulsions induced by pentylenetetrazole (85 mg/kg, s.c.) or bemegride (40 mg/kg, s.c.), no effects were observed in convulsions induced by CHEMICAL, picrotoxin, or electroshock in Slc:ddY mice. S-312-d may be useful in the therapy of certain types of human DISEASE. | NO-RELATIONSHIP |
| Pharmacological studies on a new dihydrothienopyridine calcium antagonist, S-312-d. 5th communication: anticonvulsant effects in mice. S-312, S-312-d, but not S-312-l, L-type calcium channel antagonists, showed anticonvulsant effects on the DISEASE in DBA/2 mice; and their ED50 values were 18.4 (12.8-27.1) mg/kg, p.o. and 15.0 (10.2-23.7) mg/kg, p.o., respectively, while that of flunarizine was 34.0 (26.0-44.8) mg/kg, p.o. Although moderate anticonvulsant effects of S-312-d in higher doses were observed against the clonic convulsions induced by pentylenetetrazole (85 mg/kg, s.c.) or bemegride (40 mg/kg, s.c.), no effects were observed in convulsions induced by CHEMICAL, picrotoxin, or electroshock in Slc:ddY mice. S-312-d may be useful in the therapy of certain types of human epilepsy. | NO-RELATIONSHIP |
| Pharmacological studies on a new dihydrothienopyridine calcium antagonist, CHEMICAL. 5th communication: anticonvulsant effects in mice. CHEMICAL, CHEMICAL, but not S-312-l, L-type calcium channel antagonists, showed anticonvulsant effects on the DISEASE in DBA/2 mice; and their ED50 values were 18.4 (12.8-27.1) mg/kg, p.o. and 15.0 (10.2-23.7) mg/kg, p.o., respectively, while that of flunarizine was 34.0 (26.0-44.8) mg/kg, p.o. Although moderate anticonvulsant effects of CHEMICAL in higher doses were observed against the clonic convulsions induced by pentylenetetrazole (85 mg/kg, s.c.) or bemegride (40 mg/kg, s.c.), no effects were observed in convulsions induced by N-methyl-D-aspartate, picrotoxin, or electroshock in Slc:ddY mice. CHEMICAL may be useful in the therapy of certain types of human epilepsy. | NO-RELATIONSHIP |
| Pharmacological studies on a new dihydrothienopyridine calcium antagonist, S-312-d. 5th communication: anticonvulsant effects in mice. S-312, S-312-d, but not S-312-l, L-type calcium channel antagonists, showed anticonvulsant effects on the audiogenic tonic convulsions in DBA/2 mice; and their ED50 values were 18.4 (12.8-27.1) mg/kg, p.o. and 15.0 (10.2-23.7) mg/kg, p.o., respectively, while that of CHEMICAL was 34.0 (26.0-44.8) mg/kg, p.o. Although moderate anticonvulsant effects of S-312-d in higher doses were observed against the clonic convulsions induced by pentylenetetrazole (85 mg/kg, s.c.) or bemegride (40 mg/kg, s.c.), no effects were observed in convulsions induced by N-methyl-D-aspartate, picrotoxin, or electroshock in Slc:ddY mice. S-312-d may be useful in the therapy of certain types of human DISEASE. | NO-RELATIONSHIP |
| Pharmacological studies on a new dihydrothienopyridine calcium antagonist, S-312-d. 5th communication: anticonvulsant effects in mice. S-312, S-312-d, but not S-312-l, L-type CHEMICAL channel antagonists, showed anticonvulsant effects on the audiogenic tonic convulsions in DBA/2 mice; and their ED50 values were 18.4 (12.8-27.1) mg/kg, p.o. and 15.0 (10.2-23.7) mg/kg, p.o., respectively, while that of flunarizine was 34.0 (26.0-44.8) mg/kg, p.o. Although moderate anticonvulsant effects of S-312-d in higher doses were observed against the clonic convulsions induced by pentylenetetrazole (85 mg/kg, s.c.) or bemegride (40 mg/kg, s.c.), no effects were observed in convulsions induced by N-methyl-D-aspartate, picrotoxin, or electroshock in Slc:ddY mice. S-312-d may be useful in the therapy of certain types of human DISEASE. | NO-RELATIONSHIP |
| Pharmacological studies on a new dihydrothienopyridine calcium antagonist, CHEMICAL. 5th communication: anticonvulsant effects in mice. CHEMICAL, CHEMICAL, but not S-312-l, L-type calcium channel antagonists, showed anticonvulsant effects on the audiogenic tonic convulsions in DBA/2 mice; and their ED50 values were 18.4 (12.8-27.1) mg/kg, p.o. and 15.0 (10.2-23.7) mg/kg, p.o., respectively, while that of flunarizine was 34.0 (26.0-44.8) mg/kg, p.o. Although moderate anticonvulsant effects of CHEMICAL in higher doses were observed against the clonic convulsions induced by pentylenetetrazole (85 mg/kg, s.c.) or bemegride (40 mg/kg, s.c.), no effects were observed in convulsions induced by N-methyl-D-aspartate, picrotoxin, or electroshock in Slc:ddY mice. CHEMICAL may be useful in the therapy of certain types of human DISEASE. | NO-RELATIONSHIP |
| Transmural DISEASE with CHEMICAL. For CHEMICAL, tightness in the chest caused by an unknown mechanism has been reported in 3-5% of users. We describe a 47-year-old woman with an acute DISEASE after administration of CHEMICAL 6 mg subcutaneously for cluster headache. The patient had no history of underlying ischaemic heart disease or Prinzmetal's angina. She recovered without complications. | CHEMICAL-INDUCED-DISEASE |
| Flumazenil induces DISEASE and death in mixed cocaine-CHEMICAL intoxications. STUDY HYPOTHESIS: Administration of the benzodiazepine antagonist flumazenil may unmask DISEASE in mixed cocaine-benzodiazepine intoxication. DESIGN: Male Sprague-Dawley rats received 100 mg/kg cocaine IP alone, 5 mg/kg CHEMICAL alone, or a combination of CHEMICAL and cocaine. Three minutes later, groups were challenged with vehicle or flumazenil 5 or 10 mg/kg IP. Animal behavior, DISEASE (time to and incidence), death (time to and incidence), and cortical EEG tracings were recorded. INTERVENTIONS: Administration of flumazenil to animals after they had received a combination dose of cocaine and CHEMICAL. RESULTS: In group 1, animals received cocaine followed by vehicle. This resulted in 100% developing DISEASE and death. Group 2 received CHEMICAL alone followed by vehicle. Animals became somnolent and none died. Group 3 received CHEMICAL followed by 5 mg/kg flumazenil. Animals became somnolent after CHEMICAL and then active after flumazenil administration. In group 4, a combination of cocaine and CHEMICAL was administered simultaneously. This resulted in no overt or EEG-detectable DISEASE and a 50% incidence of death. Group 5 received a similar combination of cocaine and CHEMICAL, followed later by 5 mg/kg flumazenil. This resulted in an increased incidence of DISEASE, 90% (P < .01), and death, 100% (P < or = .01), compared with group 4. Group 6 received cocaine and CHEMICAL followed by 10 mg/kg flumazenil. This also resulted in an increased incidence of DISEASE, 90% (P < or = .01), and death, 90% (P < or = .05), compared with group 4. CONCLUSION: Flumazenil can unmask DISEASE and increase the incidence of death in a model of combined cocaine-CHEMICAL intoxications. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL induces DISEASE and death in mixed cocaine-diazepam intoxications. STUDY HYPOTHESIS: Administration of the benzodiazepine antagonist CHEMICAL may unmask DISEASE in mixed cocaine-benzodiazepine intoxication. DESIGN: Male Sprague-Dawley rats received 100 mg/kg cocaine IP alone, 5 mg/kg diazepam alone, or a combination of diazepam and cocaine. Three minutes later, groups were challenged with vehicle or CHEMICAL 5 or 10 mg/kg IP. Animal behavior, DISEASE (time to and incidence), death (time to and incidence), and cortical EEG tracings were recorded. INTERVENTIONS: Administration of CHEMICAL to animals after they had received a combination dose of cocaine and diazepam. RESULTS: In group 1, animals received cocaine followed by vehicle. This resulted in 100% developing DISEASE and death. Group 2 received diazepam alone followed by vehicle. Animals became somnolent and none died. Group 3 received diazepam followed by 5 mg/kg CHEMICAL. Animals became somnolent after diazepam and then active after CHEMICAL administration. In group 4, a combination of cocaine and diazepam was administered simultaneously. This resulted in no overt or EEG-detectable DISEASE and a 50% incidence of death. Group 5 received a similar combination of cocaine and diazepam, followed later by 5 mg/kg CHEMICAL. This resulted in an increased incidence of DISEASE, 90% (P < .01), and death, 100% (P < or = .01), compared with group 4. Group 6 received cocaine and diazepam followed by 10 mg/kg CHEMICAL. This also resulted in an increased incidence of DISEASE, 90% (P < or = .01), and death, 90% (P < or = .05), compared with group 4. CONCLUSION: CHEMICAL can unmask DISEASE and increase the incidence of death in a model of combined cocaine-diazepam intoxications. | CHEMICAL-INDUCED-DISEASE |
| Flumazenil induces DISEASE and death in mixed CHEMICAL-diazepam intoxications. STUDY HYPOTHESIS: Administration of the benzodiazepine antagonist flumazenil may unmask DISEASE in mixed CHEMICAL-benzodiazepine intoxication. DESIGN: Male Sprague-Dawley rats received 100 mg/kg CHEMICAL IP alone, 5 mg/kg diazepam alone, or a combination of diazepam and CHEMICAL. Three minutes later, groups were challenged with vehicle or flumazenil 5 or 10 mg/kg IP. Animal behavior, DISEASE (time to and incidence), death (time to and incidence), and cortical EEG tracings were recorded. INTERVENTIONS: Administration of flumazenil to animals after they had received a combination dose of CHEMICAL and diazepam. RESULTS: In group 1, animals received CHEMICAL followed by vehicle. This resulted in 100% developing DISEASE and death. Group 2 received diazepam alone followed by vehicle. Animals became somnolent and none died. Group 3 received diazepam followed by 5 mg/kg flumazenil. Animals became somnolent after diazepam and then active after flumazenil administration. In group 4, a combination of CHEMICAL and diazepam was administered simultaneously. This resulted in no overt or EEG-detectable DISEASE and a 50% incidence of death. Group 5 received a similar combination of CHEMICAL and diazepam, followed later by 5 mg/kg flumazenil. This resulted in an increased incidence of DISEASE, 90% (P < .01), and death, 100% (P < or = .01), compared with group 4. Group 6 received CHEMICAL and diazepam followed by 10 mg/kg flumazenil. This also resulted in an increased incidence of DISEASE, 90% (P < or = .01), and death, 90% (P < or = .05), compared with group 4. CONCLUSION: Flumazenil can unmask DISEASE and increase the incidence of death in a model of combined CHEMICAL-diazepam intoxications. | CHEMICAL-INDUCED-DISEASE |
| Mechanisms for protective effects of free radical scavengers on CHEMICAL-mediated DISEASE in rats. Studies were performed to examine the mechanisms for the protective effects of free radical scavengers on CHEMICAL (CHEMICAL)-mediated DISEASE. Administration of CHEMICAL at 40 mg/kg sc for 13 days to rats induced a significant reduction in renal blood flow (RBF) and inulin clearance (CIn) as well as marked DISEASE. A significant reduction in urinary guanosine 3',5'-cyclic monophosphate (cGMP) excretion and a significant increase in renal cortical renin and endothelin-1 contents were also observed in CHEMICAL-mediated DISEASE. Superoxide dismutase (SOD) or dimethylthiourea (DMTU) significantly lessened the CHEMICAL-induced decrement in CIn. The SOD-induced increase in glomerular filtration rate was associated with a marked improvement in RBF, an increase in urinary cGMP excretion, and a decrease in renal renin and endothelin-1 content. SOD did not attenuate the DISEASE. In contrast, DMTU significantly reduced the DISEASE and lipid peroxidation, but it did not affect renal hemodynamics and vasoactive substances. Neither SOD nor DMTU affected the renal cortical CHEMICAL content in CHEMICAL-treated rats. These results suggest that 1) both SOD and DMTU have protective effects on CHEMICAL-mediated DISEASE, 2) the mechanisms for the protective effects differ for SOD and DMTU, and 3) superoxide anions play a critical role in CHEMICAL-induced renal vasoconstriction. | CHEMICAL-INDUCED-DISEASE |
| Assessment of cardiomyocyte DNA synthesis during hypertrophy in adult mice. The ability of cardiomyocytes to synthesize DNA in response to experimentally induced DISEASE was assessed in adult mice. CHEMICAL delivered by osmotic minipump implantation in adult C3Heb/FeJ mice resulted in a 46% increase in heart weight and a 19.3% increase in cardiomyocyte area. No DNA synthesis, as assessed by autoradiographic analysis of isolated cardiomyocytes, was observed in control or DISEASE. A survey of 15 independent inbred strains of mice revealed that ventricular cardiomyocyte nuclear number ranged from 3 to 13% mononucleate, suggesting that cardiomyocyte terminal differentiation is influenced directly or indirectly by genetic background. To determine whether the capacity for reactive DNA synthesis was also subject to genetic regulation, DISEASE was induced in the strains of mice comprising the extremes of the nuclear number survey. These data indicate that adult mouse atrial and ventricular cardiomyocytes do not synthesize DNA in response to CHEMICAL-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Central cardiovascular effects of AVP and ANP in normotensive and spontaneously DISEASE rats. The purpose of the present study was to compare influence of central arginine vasopressin (AVP) and of atrial natriuretic peptide (ANP) on control of arterial blood pressure (MAP) and heart rate (HR) in normotensive (WKY) and spontaneously DISEASE (SHR) rats. Three series of experiments were performed on 30 WKY and 30 SHR, chronically instrumented with guide tubes in the lateral ventricle (LV) and arterial and venous catheters. MAP and HR were monitored before and after i.v. injections of either vehicle or 1, 10 and 50 ng of AVP and 25, 125 and 500 ng of ANP. Sensitivity of cardiac component of baroreflex (CCB), expressed as a slope of the regression line was determined from relationships between systolic arterial pressure (SAP) and HR period (HRp) during CHEMICAL (CHEMICAL)-induced DISEASE and sodium nitroprusside (SN)-induced hypotension. CCB was measured before and after administration of either vehicle, AVP, ANP, or both peptides together. Increases of MAP occurred after LV administration of 1, 10 and 50 ng of AVP in WKY and of 10 and 50 ng in SHR. ANP did not cause significant changes in MAP in both strains as compared to vehicle, but it abolished AVP-induced MAP increase in WKY and SHR. CCB was reduced in WKY and SHR after LV administration of AVP during SN-induced hypotension. In SHR but not in WKY administration of ANP, AVP and ANP + AVP decreased CCB during CHEMICAL-induced MAP elevation. The results indicate that centrally applied AVP and ANP exert differential effects on blood pressure and baroreflex control of heart rate in WKY and SHR and suggest interaction of these two peptides in blood pressure regulation at the level of central nervous system. | CHEMICAL-INDUCED-DISEASE |
| Central cardiovascular effects of AVP and ANP in normotensive and spontaneously hypertensive rats. The purpose of the present study was to compare influence of central arginine vasopressin (AVP) and of atrial natriuretic peptide (ANP) on control of arterial blood pressure (MAP) and heart rate (HR) in normotensive (WKY) and spontaneously hypertensive (SHR) rats. Three series of experiments were performed on 30 WKY and 30 SHR, chronically instrumented with guide tubes in the lateral ventricle (LV) and arterial and venous catheters. MAP and HR were monitored before and after i.v. injections of either vehicle or 1, 10 and 50 ng of AVP and 25, 125 and 500 ng of ANP. Sensitivity of cardiac component of baroreflex (CCB), expressed as a slope of the regression line was determined from relationships between systolic arterial pressure (SAP) and HR period (HRp) during phenylephrine (Phe)-induced hypertension and CHEMICAL (CHEMICAL)-induced DISEASE. CCB was measured before and after administration of either vehicle, AVP, ANP, or both peptides together. Increases of MAP occurred after LV administration of 1, 10 and 50 ng of AVP in WKY and of 10 and 50 ng in SHR. ANP did not cause significant changes in MAP in both strains as compared to vehicle, but it abolished AVP-induced MAP increase in WKY and SHR. CCB was reduced in WKY and SHR after LV administration of AVP during CHEMICAL-induced DISEASE. In SHR but not in WKY administration of ANP, AVP and ANP + AVP decreased CCB during Phe-induced MAP elevation. The results indicate that centrally applied AVP and ANP exert differential effects on blood pressure and baroreflex control of heart rate in WKY and SHR and suggest interaction of these two peptides in blood pressure regulation at the level of central nervous system. | CHEMICAL-INDUCED-DISEASE |
| Central cardiovascular effects of CHEMICAL and ANP in normotensive and spontaneously DISEASE rats. The purpose of the present study was to compare influence of central CHEMICAL (CHEMICAL) and of atrial natriuretic peptide (ANP) on control of arterial blood pressure (MAP) and heart rate (HR) in normotensive (WKY) and spontaneously DISEASE (SHR) rats. Three series of experiments were performed on 30 WKY and 30 SHR, chronically instrumented with guide tubes in the lateral ventricle (LV) and arterial and venous catheters. MAP and HR were monitored before and after i.v. injections of either vehicle or 1, 10 and 50 ng of CHEMICAL and 25, 125 and 500 ng of ANP. Sensitivity of cardiac component of baroreflex (CCB), expressed as a slope of the regression line was determined from relationships between systolic arterial pressure (SAP) and HR period (HRp) during phenylephrine (Phe)-induced DISEASE and sodium nitroprusside (SN)-induced hypotension. CCB was measured before and after administration of either vehicle, CHEMICAL, ANP, or both peptides together. Increases of MAP occurred after LV administration of 1, 10 and 50 ng of CHEMICAL in WKY and of 10 and 50 ng in SHR. ANP did not cause significant changes in MAP in both strains as compared to vehicle, but it abolished CHEMICAL-induced MAP increase in WKY and SHR. CCB was reduced in WKY and SHR after LV administration of CHEMICAL during SN-induced hypotension. In SHR but not in WKY administration of ANP, CHEMICAL and ANP + CHEMICAL decreased CCB during Phe-induced MAP elevation. The results indicate that centrally applied CHEMICAL and ANP exert differential effects on blood pressure and baroreflex control of heart rate in WKY and SHR and suggest interaction of these two peptides in blood pressure regulation at the level of central nervous system. | NO-RELATIONSHIP |
| Cutaneous exposure to CHEMICAL-like anticoagulant causing an DISEASE: a case report. A case of intercerebral hematoma due to CHEMICAL-induced coagulopathy is presented. The 39-year-old woman had spread a CHEMICAL-type rat poison around her house weekly using her bare hands, with no washing post application. Percutaneous absorption of CHEMICAL causing coagulopathy, reported three times in the past, is a significant risk if protective measures, such as gloves, are not used. An adverse drug interaction with piroxicam, which she took occasionally, may have exacerbated the coagulopathy. | CHEMICAL-INDUCED-DISEASE |
| Cutaneous exposure to warfarin-like anticoagulant causing an intracerebral hemorrhage: a case report. A case of intercerebral DISEASE due to warfarin-induced coagulopathy is presented. The 39-year-old woman had spread a warfarin-type rat poison around her house weekly using her bare hands, with no washing post application. Percutaneous absorption of warfarin causing coagulopathy, reported three times in the past, is a significant risk if protective measures, such as gloves, are not used. An adverse drug interaction with CHEMICAL, which she took occasionally, may have exacerbated the coagulopathy. | NO-RELATIONSHIP |
| Cutaneous exposure to warfarin-like anticoagulant causing an intracerebral hemorrhage: a case report. A case of intercerebral hematoma due to warfarin-induced DISEASE is presented. The 39-year-old woman had spread a warfarin-type rat poison around her house weekly using her bare hands, with no washing post application. Percutaneous absorption of warfarin causing DISEASE, reported three times in the past, is a significant risk if protective measures, such as gloves, are not used. An adverse drug interaction with CHEMICAL, which she took occasionally, may have exacerbated the DISEASE. | NO-RELATIONSHIP |
| Pediatric heart transplantation without chronic maintenance steroids. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and CHEMICAL DISEASE (5%). Patients were managed with cyclosporine and azathioprine. No prophylaxis with antilymphocyte globulin was used. Steroids were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance steroids. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pediatric heart transplantation without chronic maintenance steroids. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with cyclosporine and azathioprine. No prophylaxis with antilymphocyte globulin was used. Steroids were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance steroids. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with CHEMICAL in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. Seizures occurred in five patients (14%) and DISEASE was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pediatric heart transplantation without chronic maintenance steroids. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), DISEASE (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with CHEMICAL and azathioprine. No prophylaxis with antilymphocyte globulin was used. Steroids were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance steroids. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pediatric heart transplantation without chronic maintenance steroids. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with CHEMICAL and azathioprine. No prophylaxis with antilymphocyte globulin was used. Steroids were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance steroids. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft DISEASE has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pediatric heart transplantation without chronic maintenance steroids. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), DISEASE (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with cyclosporine and azathioprine. No prophylaxis with antilymphocyte globulin was used. Steroids were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance steroids. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with CHEMICAL in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pediatric heart transplantation without chronic maintenance CHEMICAL. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), DISEASE (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with cyclosporine and azathioprine. No prophylaxis with antilymphocyte globulin was used. CHEMICAL were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance CHEMICAL. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | CHEMICAL-INDUCED-DISEASE |
| Pediatric heart transplantation without chronic maintenance steroids. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), DISEASE (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with CHEMICAL and azathioprine. No prophylaxis with antilymphocyte globulin was used. Steroids were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance steroids. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pediatric heart transplantation without chronic maintenance CHEMICAL. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), DISEASE (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with cyclosporine and azathioprine. No prophylaxis with antilymphocyte globulin was used. CHEMICAL were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance CHEMICAL. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pediatric heart transplantation without chronic maintenance steroids. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were DISEASE (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with cyclosporine and azathioprine. No prophylaxis with antilymphocyte globulin was used. Steroids were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance steroids. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with CHEMICAL in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pediatric heart transplantation without chronic maintenance steroids. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with cyclosporine and CHEMICAL. No prophylaxis with antilymphocyte globulin was used. Steroids were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance steroids. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft DISEASE has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pediatric heart transplantation without chronic maintenance steroids. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with CHEMICAL and azathioprine. No prophylaxis with antilymphocyte globulin was used. Steroids were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance steroids. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. DISEASE occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pediatric heart transplantation without chronic maintenance CHEMICAL. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with cyclosporine and azathioprine. No prophylaxis with antilymphocyte globulin was used. CHEMICAL were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance CHEMICAL. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. Seizures occurred in five patients (14%) and DISEASE was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | CHEMICAL-INDUCED-DISEASE |
| Pediatric heart transplantation without chronic maintenance steroids. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with CHEMICAL and azathioprine. No prophylaxis with antilymphocyte globulin was used. Steroids were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance steroids. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no DISEASE was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pediatric heart transplantation without chronic maintenance steroids. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with CHEMICAL and azathioprine. No prophylaxis with antilymphocyte globulin was used. Steroids were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance steroids. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or DISEASE. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious DISEASE was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pediatric heart transplantation without chronic maintenance CHEMICAL. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with cyclosporine and azathioprine. No prophylaxis with antilymphocyte globulin was used. CHEMICAL were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance CHEMICAL. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft DISEASE has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | CHEMICAL-INDUCED-DISEASE |
| Pediatric heart transplantation without chronic maintenance steroids. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with cyclosporine and CHEMICAL. No prophylaxis with antilymphocyte globulin was used. Steroids were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance steroids. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. Seizures occurred in five patients (14%) and DISEASE was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pediatric heart transplantation without chronic maintenance CHEMICAL. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with cyclosporine and azathioprine. No prophylaxis with antilymphocyte globulin was used. CHEMICAL were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance CHEMICAL. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or DISEASE. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious DISEASE was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | CHEMICAL-INDUCED-DISEASE |
| Pediatric heart transplantation without chronic maintenance CHEMICAL. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with cyclosporine and azathioprine. No prophylaxis with antilymphocyte globulin was used. CHEMICAL were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance CHEMICAL. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. DISEASE occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | CHEMICAL-INDUCED-DISEASE |
| Pediatric heart transplantation without chronic maintenance steroids. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with cyclosporine and azathioprine. No prophylaxis with antilymphocyte globulin was used. Steroids were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance steroids. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. DISEASE were treated successfully with CHEMICAL in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pediatric heart transplantation without chronic maintenance steroids. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), DISEASE (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with CHEMICAL and azathioprine. No prophylaxis with antilymphocyte globulin was used. Steroids were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance steroids. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with ganciclovir in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft atherosclerosis has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Pediatric heart transplantation without chronic maintenance steroids. From 1986 to February 1993, 40 children aged 2 months to 18 years (average age 10.4 +/- 5.8 years) underwent heart transplantation. Indications for transplantation were idiopathic cardiomyopathy (52%), congenital heart disease (35%) with and without prior repair (71% and 29%, respectively), hypertrophic cardiomyopathy (5%), valvular heart disease (3%), and doxorubicin cardiomyopathy (5%). Patients were managed with cyclosporine and azathioprine. No prophylaxis with antilymphocyte globulin was used. Steroids were given to 39% of patients for refractory rejection, but weaning was always attempted and generally successful (64%). Five patients (14%) received maintenance steroids. Four patients died in the perioperative period and one died 4 months later. There have been no deaths related to rejection or infection. Average follow-up was 36 +/- 19 months (range 1 to 65 months). Cumulative survival is 88% at 5 years. In patients less than 7 years of age, rejection was monitored noninvasively. In the first postoperative month, 89% of patients were treated for rejection. Freedom from serious infections was 83% at 1 month and 65% at 1 year. Cytomegalovirus infections were treated successfully with CHEMICAL in 11 patients. No impairment of growth was observed in children who underwent transplantation compared with a control population. Twenty-one patients (60%) have undergone annual catheterizations and no sign of graft DISEASE has been observed. Seizures occurred in five patients (14%) and hypertension was treated in 10 patients (28%). No patient was disabled and no lymphoproliferative disorder was observed.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Delirium during CHEMICAL treatment. A case report. The correlation between high serum tricyclic antidepressant concentrations and central nervous system side effects has been well established. Only a few reports exist, however, on the relationship between the serum concentrations of selective serotonin reuptake inhibitors (SSRIs) and their toxic effects. In some cases, a high serum concentration of citalopram (> 600 nmol/L) in elderly patients has been associated with increased somnolence and movement difficulties. Widespread cognitive disorders, such as delirium, have not been previously linked with high blood levels of SSRIs. In this report, we describe a patient with acute DISEASE delirium connected with a high serum total CHEMICAL (CHEMICAL plus desmethylfluoxetine) concentration. | CHEMICAL-INDUCED-DISEASE |
| DISEASE during CHEMICAL treatment. A case report. The correlation between high serum tricyclic antidepressant concentrations and central nervous system side effects has been well established. Only a few reports exist, however, on the relationship between the serum concentrations of selective serotonin reuptake inhibitors (SSRIs) and their toxic effects. In some cases, a high serum concentration of citalopram (> 600 nmol/L) in elderly patients has been associated with increased somnolence and movement difficulties. Widespread cognitive disorders, such as DISEASE, have not been previously linked with high blood levels of SSRIs. In this report, we describe a patient with acute hyperkinetic DISEASE connected with a high serum total CHEMICAL (CHEMICAL plus desmethylfluoxetine) concentration. | CHEMICAL-INDUCED-DISEASE |
| Delirium during fluoxetine treatment. A case report. The correlation between high serum tricyclic antidepressant concentrations and central nervous system side effects has been well established. Only a few reports exist, however, on the relationship between the serum concentrations of selective serotonin reuptake inhibitors (SSRIs) and their toxic effects. In some cases, a high serum concentration of citalopram (> 600 nmol/L) in elderly patients has been associated with increased somnolence and DISEASE. Widespread cognitive disorders, such as delirium, have not been previously linked with high blood levels of SSRIs. In this report, we describe a patient with acute hyperkinetic delirium connected with a high serum total fluoxetine (fluoxetine plus CHEMICAL) concentration. | NO-RELATIONSHIP |
| Delirium during fluoxetine treatment. A case report. The correlation between high serum tricyclic antidepressant concentrations and central nervous system side effects has been well established. Only a few reports exist, however, on the relationship between the serum concentrations of selective CHEMICAL reuptake inhibitors (SSRIs) and their toxic effects. In some cases, a high serum concentration of citalopram (> 600 nmol/L) in elderly patients has been associated with increased somnolence and DISEASE. Widespread cognitive disorders, such as delirium, have not been previously linked with high blood levels of SSRIs. In this report, we describe a patient with acute hyperkinetic delirium connected with a high serum total fluoxetine (fluoxetine plus desmethylfluoxetine) concentration. | NO-RELATIONSHIP |
| Delirium during fluoxetine treatment. A case report. The correlation between high serum tricyclic antidepressant concentrations and central nervous system side effects has been well established. Only a few reports exist, however, on the relationship between the serum concentrations of selective serotonin reuptake inhibitors (SSRIs) and their toxic effects. In some cases, a high serum concentration of citalopram (> 600 nmol/L) in elderly patients has been associated with increased DISEASE and movement difficulties. Widespread cognitive disorders, such as delirium, have not been previously linked with high blood levels of SSRIs. In this report, we describe a patient with acute hyperkinetic delirium connected with a high serum total fluoxetine (fluoxetine plus CHEMICAL) concentration. | NO-RELATIONSHIP |
| Delirium during fluoxetine treatment. A case report. The correlation between high serum tricyclic antidepressant concentrations and central nervous system side effects has been well established. Only a few reports exist, however, on the relationship between the serum concentrations of selective serotonin reuptake inhibitors (SSRIs) and their toxic effects. In some cases, a high serum concentration of CHEMICAL (> 600 nmol/L) in elderly patients has been associated with increased somnolence and movement difficulties. Widespread DISEASE, such as delirium, have not been previously linked with high blood levels of SSRIs. In this report, we describe a patient with acute hyperkinetic delirium connected with a high serum total fluoxetine (fluoxetine plus desmethylfluoxetine) concentration. | NO-RELATIONSHIP |
| Delirium during fluoxetine treatment. A case report. The correlation between high serum tricyclic antidepressant concentrations and central nervous system side effects has been well established. Only a few reports exist, however, on the relationship between the serum concentrations of selective serotonin reuptake inhibitors (SSRIs) and their toxic effects. In some cases, a high serum concentration of citalopram (> 600 nmol/L) in elderly patients has been associated with increased somnolence and movement difficulties. Widespread DISEASE, such as delirium, have not been previously linked with high blood levels of SSRIs. In this report, we describe a patient with acute hyperkinetic delirium connected with a high serum total fluoxetine (fluoxetine plus CHEMICAL) concentration. | NO-RELATIONSHIP |
| Delirium during fluoxetine treatment. A case report. The correlation between high serum tricyclic antidepressant concentrations and central nervous system side effects has been well established. Only a few reports exist, however, on the relationship between the serum concentrations of selective CHEMICAL reuptake inhibitors (SSRIs) and their toxic effects. In some cases, a high serum concentration of citalopram (> 600 nmol/L) in elderly patients has been associated with increased DISEASE and movement difficulties. Widespread cognitive disorders, such as delirium, have not been previously linked with high blood levels of SSRIs. In this report, we describe a patient with acute hyperkinetic delirium connected with a high serum total fluoxetine (fluoxetine plus desmethylfluoxetine) concentration. | NO-RELATIONSHIP |
| Delirium during fluoxetine treatment. A case report. The correlation between high serum tricyclic antidepressant concentrations and central nervous system side effects has been well established. Only a few reports exist, however, on the relationship between the serum concentrations of selective serotonin reuptake inhibitors (SSRIs) and their toxic effects. In some cases, a high serum concentration of CHEMICAL (> 600 nmol/L) in elderly patients has been associated with increased DISEASE and movement difficulties. Widespread cognitive disorders, such as delirium, have not been previously linked with high blood levels of SSRIs. In this report, we describe a patient with acute hyperkinetic delirium connected with a high serum total fluoxetine (fluoxetine plus desmethylfluoxetine) concentration. | NO-RELATIONSHIP |
| Delirium during fluoxetine treatment. A case report. The correlation between high serum tricyclic antidepressant concentrations and central nervous system side effects has been well established. Only a few reports exist, however, on the relationship between the serum concentrations of selective CHEMICAL reuptake inhibitors (SSRIs) and their toxic effects. In some cases, a high serum concentration of citalopram (> 600 nmol/L) in elderly patients has been associated with increased somnolence and movement difficulties. Widespread DISEASE, such as delirium, have not been previously linked with high blood levels of SSRIs. In this report, we describe a patient with acute hyperkinetic delirium connected with a high serum total fluoxetine (fluoxetine plus desmethylfluoxetine) concentration. | NO-RELATIONSHIP |
| Delirium during fluoxetine treatment. A case report. The correlation between high serum tricyclic antidepressant concentrations and central nervous system side effects has been well established. Only a few reports exist, however, on the relationship between the serum concentrations of selective serotonin reuptake inhibitors (SSRIs) and their toxic effects. In some cases, a high serum concentration of CHEMICAL (> 600 nmol/L) in elderly patients has been associated with increased somnolence and DISEASE. Widespread cognitive disorders, such as delirium, have not been previously linked with high blood levels of SSRIs. In this report, we describe a patient with acute hyperkinetic delirium connected with a high serum total fluoxetine (fluoxetine plus desmethylfluoxetine) concentration. | CHEMICAL-INDUCED-DISEASE |
| Pulmonary edema and shock after high-dose CHEMICAL for lymphoma; possible role of TNF-alpha and PAF. Four out of 23 consecutive patients treated with high-dose CHEMICAL for lymphomas in our institution developed a strikingly similar syndrome during the perfusion. It was characterized by the onset of fever, DISEASE, shock, pulmonary edema, acute renal failure, metabolic acidosis, weight gain and leukocytosis. Thorough bacteriological screening failed to provide evidence of infection. Sequential biological assays of IL-1, IL-2, TNF and PAF were performed during CHEMICAL infusion to ten patients, including the four who developed the syndrome. TNF and PAF activity was found in the serum of respectively two and four of the cases, but not in the six controls. As TNF and PAF are thought to be involved in the development of septic shock and adult respiratory distress syndrome, we hypothesize that high-dose CHEMICAL may be associated with cytokine release. | CHEMICAL-INDUCED-DISEASE |
| Pulmonary edema and shock after high-dose CHEMICAL for lymphoma; possible role of TNF-alpha and PAF. Four out of 23 consecutive patients treated with high-dose CHEMICAL for lymphomas in our institution developed a strikingly similar syndrome during the perfusion. It was characterized by the onset of DISEASE, diarrhea, shock, pulmonary edema, acute renal failure, metabolic acidosis, weight gain and leukocytosis. Thorough bacteriological screening failed to provide evidence of infection. Sequential biological assays of IL-1, IL-2, TNF and PAF were performed during CHEMICAL infusion to ten patients, including the four who developed the syndrome. TNF and PAF activity was found in the serum of respectively two and four of the cases, but not in the six controls. As TNF and PAF are thought to be involved in the development of septic shock and adult respiratory distress syndrome, we hypothesize that high-dose CHEMICAL may be associated with cytokine release. | CHEMICAL-INDUCED-DISEASE |
| DISEASE and shock after high-dose CHEMICAL for lymphoma; possible role of TNF-alpha and PAF. Four out of 23 consecutive patients treated with high-dose CHEMICAL for lymphomas in our institution developed a strikingly similar syndrome during the perfusion. It was characterized by the onset of fever, diarrhea, shock, DISEASE, acute renal failure, metabolic acidosis, weight gain and leukocytosis. Thorough bacteriological screening failed to provide evidence of infection. Sequential biological assays of IL-1, IL-2, TNF and PAF were performed during CHEMICAL infusion to ten patients, including the four who developed the syndrome. TNF and PAF activity was found in the serum of respectively two and four of the cases, but not in the six controls. As TNF and PAF are thought to be involved in the development of septic shock and adult respiratory distress syndrome, we hypothesize that high-dose CHEMICAL may be associated with cytokine release. | CHEMICAL-INDUCED-DISEASE |
| Pulmonary edema and shock after high-dose CHEMICAL for lymphoma; possible role of TNF-alpha and PAF. Four out of 23 consecutive patients treated with high-dose CHEMICAL for lymphomas in our institution developed a strikingly similar syndrome during the perfusion. It was characterized by the onset of fever, diarrhea, shock, pulmonary edema, DISEASE, metabolic acidosis, weight gain and leukocytosis. Thorough bacteriological screening failed to provide evidence of infection. Sequential biological assays of IL-1, IL-2, TNF and PAF were performed during CHEMICAL infusion to ten patients, including the four who developed the syndrome. TNF and PAF activity was found in the serum of respectively two and four of the cases, but not in the six controls. As TNF and PAF are thought to be involved in the development of septic shock and adult respiratory distress syndrome, we hypothesize that high-dose CHEMICAL may be associated with cytokine release. | CHEMICAL-INDUCED-DISEASE |
| Pulmonary edema and shock after high-dose CHEMICAL for lymphoma; possible role of TNF-alpha and PAF. Four out of 23 consecutive patients treated with high-dose CHEMICAL for lymphomas in our institution developed a strikingly similar syndrome during the perfusion. It was characterized by the onset of fever, diarrhea, shock, pulmonary edema, acute renal failure, metabolic acidosis, DISEASE and leukocytosis. Thorough bacteriological screening failed to provide evidence of infection. Sequential biological assays of IL-1, IL-2, TNF and PAF were performed during CHEMICAL infusion to ten patients, including the four who developed the syndrome. TNF and PAF activity was found in the serum of respectively two and four of the cases, but not in the six controls. As TNF and PAF are thought to be involved in the development of septic shock and adult respiratory distress syndrome, we hypothesize that high-dose CHEMICAL may be associated with cytokine release. | CHEMICAL-INDUCED-DISEASE |
| Pulmonary edema and DISEASE after high-dose CHEMICAL for lymphoma; possible role of TNF-alpha and PAF. Four out of 23 consecutive patients treated with high-dose CHEMICAL for lymphomas in our institution developed a strikingly similar syndrome during the perfusion. It was characterized by the onset of fever, diarrhea, DISEASE, pulmonary edema, acute renal failure, metabolic acidosis, weight gain and leukocytosis. Thorough bacteriological screening failed to provide evidence of infection. Sequential biological assays of IL-1, IL-2, TNF and PAF were performed during CHEMICAL infusion to ten patients, including the four who developed the syndrome. TNF and PAF activity was found in the serum of respectively two and four of the cases, but not in the six controls. As TNF and PAF are thought to be involved in the development of septic DISEASE and adult respiratory distress syndrome, we hypothesize that high-dose CHEMICAL may be associated with cytokine release. | CHEMICAL-INDUCED-DISEASE |
| Pulmonary edema and shock after high-dose CHEMICAL for lymphoma; possible role of TNF-alpha and PAF. Four out of 23 consecutive patients treated with high-dose CHEMICAL for lymphomas in our institution developed a strikingly similar syndrome during the perfusion. It was characterized by the onset of fever, diarrhea, shock, pulmonary edema, acute renal failure, metabolic acidosis, weight gain and DISEASE. Thorough bacteriological screening failed to provide evidence of infection. Sequential biological assays of IL-1, IL-2, TNF and PAF were performed during CHEMICAL infusion to ten patients, including the four who developed the syndrome. TNF and PAF activity was found in the serum of respectively two and four of the cases, but not in the six controls. As TNF and PAF are thought to be involved in the development of septic shock and adult respiratory distress syndrome, we hypothesize that high-dose CHEMICAL may be associated with cytokine release. | CHEMICAL-INDUCED-DISEASE |
| Pulmonary edema and shock after high-dose CHEMICAL for lymphoma; possible role of TNF-alpha and PAF. Four out of 23 consecutive patients treated with high-dose CHEMICAL for lymphomas in our institution developed a strikingly similar syndrome during the perfusion. It was characterized by the onset of fever, diarrhea, shock, pulmonary edema, acute renal failure, DISEASE, weight gain and leukocytosis. Thorough bacteriological screening failed to provide evidence of infection. Sequential biological assays of IL-1, IL-2, TNF and PAF were performed during CHEMICAL infusion to ten patients, including the four who developed the syndrome. TNF and PAF activity was found in the serum of respectively two and four of the cases, but not in the six controls. As TNF and PAF are thought to be involved in the development of septic shock and adult respiratory distress syndrome, we hypothesize that high-dose CHEMICAL may be associated with cytokine release. | CHEMICAL-INDUCED-DISEASE |
| Protective effect of clentiazem against CHEMICAL-induced cardiac injury in rats. We investigated the effects of clentiazem, a 1,5-benzothiazepine calcium antagonist, on CHEMICAL-induced DISEASE in rats. With 2-week chronic CHEMICAL infusion, 16 of 30 rats died within 4 days, and severe ischemic lesions and fibrosis of the left ventricles were observed. In CHEMICAL-treated rats, left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced, but responses to calcium were normal or enhanced compared to controls. Left ventricular alpha and beta adrenoceptor densities were also reduced compared to controls. Treatment with clentiazem prevented CHEMICAL-induced death (P < .05), and attenuated the ventricular ischemic lesions and fibrosis, in a dose-dependent manner. Left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced compared to controls in groups treated with clentiazem alone, but combined with CHEMICAL, clentiazem restored left atrial responses and enhanced left ventricular papillary responses to isoproterenol. On the other hand clentiazem did not prevent CHEMICAL-induced down-regulation of alpha and beta adrenoceptors. Interestingly, clentiazem, infused alone, resulted in decreased adrenergic receptor densities in the left ventricle. Clentiazem also did not prevent the enhanced responses to calcium seen in the CHEMICAL-treated animals, although the high dose of clentiazem partially attenuated the maximal response to calcium compared to CHEMICAL-treated animals. In conclusion, clentiazem attenuated CHEMICAL-induced cardiac injury, possibly through its effect on the adrenergic pathway. | CHEMICAL-INDUCED-DISEASE |
| Protective effect of clentiazem against epinephrine-induced cardiac injury in rats. We investigated the effects of clentiazem, a 1,5-benzothiazepine CHEMICAL antagonist, on epinephrine-induced cardiomyopathy in rats. With 2-week chronic epinephrine infusion, 16 of 30 rats died within 4 days, and severe ischemic lesions and DISEASE of the left ventricles were observed. In epinephrine-treated rats, left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced, but responses to CHEMICAL were normal or enhanced compared to controls. Left ventricular alpha and beta adrenoceptor densities were also reduced compared to controls. Treatment with clentiazem prevented epinephrine-induced death (P < .05), and attenuated the ventricular ischemic lesions and DISEASE, in a dose-dependent manner. Left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced compared to controls in groups treated with clentiazem alone, but combined with epinephrine, clentiazem restored left atrial responses and enhanced left ventricular papillary responses to isoproterenol. On the other hand clentiazem did not prevent epinephrine-induced down-regulation of alpha and beta adrenoceptors. Interestingly, clentiazem, infused alone, resulted in decreased adrenergic receptor densities in the left ventricle. Clentiazem also did not prevent the enhanced responses to CHEMICAL seen in the epinephrine-treated animals, although the high dose of clentiazem partially attenuated the maximal response to CHEMICAL compared to epinephrine-treated animals. In conclusion, clentiazem attenuated epinephrine-induced cardiac injury, possibly through its effect on the adrenergic pathway. | NO-RELATIONSHIP |
| Protective effect of clentiazem against epinephrine-induced cardiac injury in rats. We investigated the effects of clentiazem, a CHEMICAL calcium antagonist, on epinephrine-induced cardiomyopathy in rats. With 2-week chronic epinephrine infusion, 16 of 30 rats died within 4 days, and severe ischemic lesions and DISEASE of the left ventricles were observed. In epinephrine-treated rats, left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced, but responses to calcium were normal or enhanced compared to controls. Left ventricular alpha and beta adrenoceptor densities were also reduced compared to controls. Treatment with clentiazem prevented epinephrine-induced death (P < .05), and attenuated the ventricular ischemic lesions and DISEASE, in a dose-dependent manner. Left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced compared to controls in groups treated with clentiazem alone, but combined with epinephrine, clentiazem restored left atrial responses and enhanced left ventricular papillary responses to isoproterenol. On the other hand clentiazem did not prevent epinephrine-induced down-regulation of alpha and beta adrenoceptors. Interestingly, clentiazem, infused alone, resulted in decreased adrenergic receptor densities in the left ventricle. Clentiazem also did not prevent the enhanced responses to calcium seen in the epinephrine-treated animals, although the high dose of clentiazem partially attenuated the maximal response to calcium compared to epinephrine-treated animals. In conclusion, clentiazem attenuated epinephrine-induced cardiac injury, possibly through its effect on the adrenergic pathway. | NO-RELATIONSHIP |
| Protective effect of clentiazem against epinephrine-induced DISEASE in rats. We investigated the effects of clentiazem, a 1,5-benzothiazepine CHEMICAL antagonist, on epinephrine-induced cardiomyopathy in rats. With 2-week chronic epinephrine infusion, 16 of 30 rats died within 4 days, and severe ischemic lesions and fibrosis of the left ventricles were observed. In epinephrine-treated rats, left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced, but responses to CHEMICAL were normal or enhanced compared to controls. Left ventricular alpha and beta adrenoceptor densities were also reduced compared to controls. Treatment with clentiazem prevented epinephrine-induced death (P < .05), and attenuated the ventricular ischemic lesions and fibrosis, in a dose-dependent manner. Left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced compared to controls in groups treated with clentiazem alone, but combined with epinephrine, clentiazem restored left atrial responses and enhanced left ventricular papillary responses to isoproterenol. On the other hand clentiazem did not prevent epinephrine-induced down-regulation of alpha and beta adrenoceptors. Interestingly, clentiazem, infused alone, resulted in decreased adrenergic receptor densities in the left ventricle. Clentiazem also did not prevent the enhanced responses to CHEMICAL seen in the epinephrine-treated animals, although the high dose of clentiazem partially attenuated the maximal response to CHEMICAL compared to epinephrine-treated animals. In conclusion, clentiazem attenuated epinephrine-induced DISEASE, possibly through its effect on the adrenergic pathway. | NO-RELATIONSHIP |
| Protective effect of clentiazem against epinephrine-induced cardiac injury in rats. We investigated the effects of clentiazem, a 1,5-benzothiazepine calcium antagonist, on epinephrine-induced cardiomyopathy in rats. With 2-week chronic epinephrine infusion, 16 of 30 rats died within 4 days, and severe ischemic lesions and DISEASE of the left ventricles were observed. In epinephrine-treated rats, left atrial and left ventricular papillary muscle contractile responses to CHEMICAL were reduced, but responses to calcium were normal or enhanced compared to controls. Left ventricular alpha and beta adrenoceptor densities were also reduced compared to controls. Treatment with clentiazem prevented epinephrine-induced death (P < .05), and attenuated the ventricular ischemic lesions and DISEASE, in a dose-dependent manner. Left atrial and left ventricular papillary muscle contractile responses to CHEMICAL were reduced compared to controls in groups treated with clentiazem alone, but combined with epinephrine, clentiazem restored left atrial responses and enhanced left ventricular papillary responses to CHEMICAL. On the other hand clentiazem did not prevent epinephrine-induced down-regulation of alpha and beta adrenoceptors. Interestingly, clentiazem, infused alone, resulted in decreased adrenergic receptor densities in the left ventricle. Clentiazem also did not prevent the enhanced responses to calcium seen in the epinephrine-treated animals, although the high dose of clentiazem partially attenuated the maximal response to calcium compared to epinephrine-treated animals. In conclusion, clentiazem attenuated epinephrine-induced cardiac injury, possibly through its effect on the adrenergic pathway. | NO-RELATIONSHIP |
| Protective effect of clentiazem against epinephrine-induced DISEASE in rats. We investigated the effects of clentiazem, a 1,5-benzothiazepine calcium antagonist, on epinephrine-induced cardiomyopathy in rats. With 2-week chronic epinephrine infusion, 16 of 30 rats died within 4 days, and severe ischemic lesions and fibrosis of the left ventricles were observed. In epinephrine-treated rats, left atrial and left ventricular papillary muscle contractile responses to CHEMICAL were reduced, but responses to calcium were normal or enhanced compared to controls. Left ventricular alpha and beta adrenoceptor densities were also reduced compared to controls. Treatment with clentiazem prevented epinephrine-induced death (P < .05), and attenuated the ventricular ischemic lesions and fibrosis, in a dose-dependent manner. Left atrial and left ventricular papillary muscle contractile responses to CHEMICAL were reduced compared to controls in groups treated with clentiazem alone, but combined with epinephrine, clentiazem restored left atrial responses and enhanced left ventricular papillary responses to CHEMICAL. On the other hand clentiazem did not prevent epinephrine-induced down-regulation of alpha and beta adrenoceptors. Interestingly, clentiazem, infused alone, resulted in decreased adrenergic receptor densities in the left ventricle. Clentiazem also did not prevent the enhanced responses to calcium seen in the epinephrine-treated animals, although the high dose of clentiazem partially attenuated the maximal response to calcium compared to epinephrine-treated animals. In conclusion, clentiazem attenuated epinephrine-induced DISEASE, possibly through its effect on the adrenergic pathway. | NO-RELATIONSHIP |
| Protective effect of CHEMICAL against epinephrine-induced DISEASE in rats. We investigated the effects of CHEMICAL, a 1,5-benzothiazepine calcium antagonist, on epinephrine-induced cardiomyopathy in rats. With 2-week chronic epinephrine infusion, 16 of 30 rats died within 4 days, and severe ischemic lesions and fibrosis of the left ventricles were observed. In epinephrine-treated rats, left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced, but responses to calcium were normal or enhanced compared to controls. Left ventricular alpha and beta adrenoceptor densities were also reduced compared to controls. Treatment with CHEMICAL prevented epinephrine-induced death (P < .05), and attenuated the ventricular ischemic lesions and fibrosis, in a dose-dependent manner. Left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced compared to controls in groups treated with CHEMICAL alone, but combined with epinephrine, CHEMICAL restored left atrial responses and enhanced left ventricular papillary responses to isoproterenol. On the other hand CHEMICAL did not prevent epinephrine-induced down-regulation of alpha and beta adrenoceptors. Interestingly, CHEMICAL, infused alone, resulted in decreased adrenergic receptor densities in the left ventricle. CHEMICAL also did not prevent the enhanced responses to calcium seen in the epinephrine-treated animals, although the high dose of CHEMICAL partially attenuated the maximal response to calcium compared to epinephrine-treated animals. In conclusion, CHEMICAL attenuated epinephrine-induced DISEASE, possibly through its effect on the adrenergic pathway. | NO-RELATIONSHIP |
| Protective effect of clentiazem against epinephrine-induced cardiac injury in rats. We investigated the effects of clentiazem, a CHEMICAL calcium antagonist, on epinephrine-induced cardiomyopathy in rats. With 2-week chronic epinephrine infusion, 16 of 30 rats died within 4 days, and severe DISEASE and fibrosis of the left ventricles were observed. In epinephrine-treated rats, left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced, but responses to calcium were normal or enhanced compared to controls. Left ventricular alpha and beta adrenoceptor densities were also reduced compared to controls. Treatment with clentiazem prevented epinephrine-induced death (P < .05), and attenuated the ventricular DISEASE and fibrosis, in a dose-dependent manner. Left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced compared to controls in groups treated with clentiazem alone, but combined with epinephrine, clentiazem restored left atrial responses and enhanced left ventricular papillary responses to isoproterenol. On the other hand clentiazem did not prevent epinephrine-induced down-regulation of alpha and beta adrenoceptors. Interestingly, clentiazem, infused alone, resulted in decreased adrenergic receptor densities in the left ventricle. Clentiazem also did not prevent the enhanced responses to calcium seen in the epinephrine-treated animals, although the high dose of clentiazem partially attenuated the maximal response to calcium compared to epinephrine-treated animals. In conclusion, clentiazem attenuated epinephrine-induced cardiac injury, possibly through its effect on the adrenergic pathway. | NO-RELATIONSHIP |
| Protective effect of clentiazem against epinephrine-induced cardiac injury in rats. We investigated the effects of clentiazem, a 1,5-benzothiazepine CHEMICAL antagonist, on epinephrine-induced cardiomyopathy in rats. With 2-week chronic epinephrine infusion, 16 of 30 rats died within 4 days, and severe DISEASE and fibrosis of the left ventricles were observed. In epinephrine-treated rats, left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced, but responses to CHEMICAL were normal or enhanced compared to controls. Left ventricular alpha and beta adrenoceptor densities were also reduced compared to controls. Treatment with clentiazem prevented epinephrine-induced death (P < .05), and attenuated the ventricular DISEASE and fibrosis, in a dose-dependent manner. Left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced compared to controls in groups treated with clentiazem alone, but combined with epinephrine, clentiazem restored left atrial responses and enhanced left ventricular papillary responses to isoproterenol. On the other hand clentiazem did not prevent epinephrine-induced down-regulation of alpha and beta adrenoceptors. Interestingly, clentiazem, infused alone, resulted in decreased adrenergic receptor densities in the left ventricle. Clentiazem also did not prevent the enhanced responses to CHEMICAL seen in the epinephrine-treated animals, although the high dose of clentiazem partially attenuated the maximal response to CHEMICAL compared to epinephrine-treated animals. In conclusion, clentiazem attenuated epinephrine-induced cardiac injury, possibly through its effect on the adrenergic pathway. | NO-RELATIONSHIP |
| Protective effect of clentiazem against epinephrine-induced DISEASE in rats. We investigated the effects of clentiazem, a CHEMICAL calcium antagonist, on epinephrine-induced cardiomyopathy in rats. With 2-week chronic epinephrine infusion, 16 of 30 rats died within 4 days, and severe ischemic lesions and fibrosis of the left ventricles were observed. In epinephrine-treated rats, left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced, but responses to calcium were normal or enhanced compared to controls. Left ventricular alpha and beta adrenoceptor densities were also reduced compared to controls. Treatment with clentiazem prevented epinephrine-induced death (P < .05), and attenuated the ventricular ischemic lesions and fibrosis, in a dose-dependent manner. Left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced compared to controls in groups treated with clentiazem alone, but combined with epinephrine, clentiazem restored left atrial responses and enhanced left ventricular papillary responses to isoproterenol. On the other hand clentiazem did not prevent epinephrine-induced down-regulation of alpha and beta adrenoceptors. Interestingly, clentiazem, infused alone, resulted in decreased adrenergic receptor densities in the left ventricle. Clentiazem also did not prevent the enhanced responses to calcium seen in the epinephrine-treated animals, although the high dose of clentiazem partially attenuated the maximal response to calcium compared to epinephrine-treated animals. In conclusion, clentiazem attenuated epinephrine-induced DISEASE, possibly through its effect on the adrenergic pathway. | NO-RELATIONSHIP |
| Protective effect of CHEMICAL against epinephrine-induced cardiac injury in rats. We investigated the effects of CHEMICAL, a 1,5-benzothiazepine calcium antagonist, on epinephrine-induced cardiomyopathy in rats. With 2-week chronic epinephrine infusion, 16 of 30 rats died within 4 days, and severe DISEASE and fibrosis of the left ventricles were observed. In epinephrine-treated rats, left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced, but responses to calcium were normal or enhanced compared to controls. Left ventricular alpha and beta adrenoceptor densities were also reduced compared to controls. Treatment with CHEMICAL prevented epinephrine-induced death (P < .05), and attenuated the ventricular DISEASE and fibrosis, in a dose-dependent manner. Left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced compared to controls in groups treated with CHEMICAL alone, but combined with epinephrine, CHEMICAL restored left atrial responses and enhanced left ventricular papillary responses to isoproterenol. On the other hand CHEMICAL did not prevent epinephrine-induced down-regulation of alpha and beta adrenoceptors. Interestingly, CHEMICAL, infused alone, resulted in decreased adrenergic receptor densities in the left ventricle. CHEMICAL also did not prevent the enhanced responses to calcium seen in the epinephrine-treated animals, although the high dose of CHEMICAL partially attenuated the maximal response to calcium compared to epinephrine-treated animals. In conclusion, CHEMICAL attenuated epinephrine-induced cardiac injury, possibly through its effect on the adrenergic pathway. | NO-RELATIONSHIP |
| Protective effect of clentiazem against epinephrine-induced cardiac injury in rats. We investigated the effects of clentiazem, a 1,5-benzothiazepine calcium antagonist, on epinephrine-induced cardiomyopathy in rats. With 2-week chronic epinephrine infusion, 16 of 30 rats died within 4 days, and severe DISEASE and fibrosis of the left ventricles were observed. In epinephrine-treated rats, left atrial and left ventricular papillary muscle contractile responses to CHEMICAL were reduced, but responses to calcium were normal or enhanced compared to controls. Left ventricular alpha and beta adrenoceptor densities were also reduced compared to controls. Treatment with clentiazem prevented epinephrine-induced death (P < .05), and attenuated the ventricular DISEASE and fibrosis, in a dose-dependent manner. Left atrial and left ventricular papillary muscle contractile responses to CHEMICAL were reduced compared to controls in groups treated with clentiazem alone, but combined with epinephrine, clentiazem restored left atrial responses and enhanced left ventricular papillary responses to CHEMICAL. On the other hand clentiazem did not prevent epinephrine-induced down-regulation of alpha and beta adrenoceptors. Interestingly, clentiazem, infused alone, resulted in decreased adrenergic receptor densities in the left ventricle. Clentiazem also did not prevent the enhanced responses to calcium seen in the epinephrine-treated animals, although the high dose of clentiazem partially attenuated the maximal response to calcium compared to epinephrine-treated animals. In conclusion, clentiazem attenuated epinephrine-induced cardiac injury, possibly through its effect on the adrenergic pathway. | NO-RELATIONSHIP |
| Protective effect of CHEMICAL against epinephrine-induced cardiac injury in rats. We investigated the effects of CHEMICAL, a 1,5-benzothiazepine calcium antagonist, on epinephrine-induced cardiomyopathy in rats. With 2-week chronic epinephrine infusion, 16 of 30 rats died within 4 days, and severe ischemic lesions and DISEASE of the left ventricles were observed. In epinephrine-treated rats, left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced, but responses to calcium were normal or enhanced compared to controls. Left ventricular alpha and beta adrenoceptor densities were also reduced compared to controls. Treatment with CHEMICAL prevented epinephrine-induced death (P < .05), and attenuated the ventricular ischemic lesions and DISEASE, in a dose-dependent manner. Left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced compared to controls in groups treated with CHEMICAL alone, but combined with epinephrine, CHEMICAL restored left atrial responses and enhanced left ventricular papillary responses to isoproterenol. On the other hand CHEMICAL did not prevent epinephrine-induced down-regulation of alpha and beta adrenoceptors. Interestingly, CHEMICAL, infused alone, resulted in decreased adrenergic receptor densities in the left ventricle. CHEMICAL also did not prevent the enhanced responses to calcium seen in the epinephrine-treated animals, although the high dose of CHEMICAL partially attenuated the maximal response to calcium compared to epinephrine-treated animals. In conclusion, CHEMICAL attenuated epinephrine-induced cardiac injury, possibly through its effect on the adrenergic pathway. | NO-RELATIONSHIP |
| CHEMICAL induced DISEASE. We report a case of DISEASE induced by CHEMICAL. The ischemia probably induced by coronary artery spasm was reversed by nitroglycerin and calcium blocking agents. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL induced myocardial ischemia. We report a case of myocardial ischemia induced by CHEMICAL. The ischemia probably induced by DISEASE was reversed by nitroglycerin and calcium blocking agents. | CHEMICAL-INDUCED-DISEASE |
| Cocaine induced myocardial ischemia. We report a case of myocardial ischemia induced by cocaine. The DISEASE probably induced by coronary artery spasm was reversed by CHEMICAL and calcium blocking agents. | NO-RELATIONSHIP |
| Cocaine induced myocardial ischemia. We report a case of myocardial ischemia induced by cocaine. The DISEASE probably induced by coronary artery spasm was reversed by nitroglycerin and CHEMICAL blocking agents. | NO-RELATIONSHIP |
| CHEMICAL-induced DISEASE monitored by ECG in freely moving mice. A new model to test potential protectors. In laboratory animals, histology is most commonly used to study CHEMICAL-induced DISEASE. However, for monitoring during treatment, large numbers of animals are needed. Recently we developed a new method to measure ECG values in freely moving mice by telemetry. With this model we investigated the effect of chronic CHEMICAL administration on the ECG of freely moving BALB/c mice and the efficacy of ICRF-187 as a protective agent. The ST interval significantly widened from 15.0 +/- 1.5 to 56.8 +/- 11.8 ms in week 10 (7 weekly doses of 4 mg/kg CHEMICAL given i.v. plus 3 weeks of observation). The ECG of the control animals did not change during the entire study. After sacrifice the hearts of CHEMICAL-treated animals were enlarged and the atria were hypertrophic. As this schedule exerted more toxicity than needed to investigate protective agents, the protection of ICRF-187 was determined using a dose schedule with lower general toxicity (6 weekly doses of 4 mg/kg CHEMICAL given i.v. plus 2 weeks of observation). On this schedule, the animals' hearts appeared normal after sacrifice and ICRF-187 (50 mg/kg given i.p. 1 h before CHEMICAL) provided almost full protection. These data were confirmed by histology. The results indicate that this new model is very sensitive and enables monitoring of the development of DISEASE with time. These findings result in a model that allows the testing of protectors against CHEMICAL-induced DISEASE as demonstrated by the protection provided by ICRF-187. | CHEMICAL-INDUCED-DISEASE |
| Doxorubicin-induced cardiotoxicity monitored by ECG in freely moving mice. A new model to test potential protectors. In laboratory animals, histology is most commonly used to study doxorubicin-induced cardiotoxicity. However, for monitoring during treatment, large numbers of animals are needed. Recently we developed a new method to measure ECG values in freely moving mice by telemetry. With this model we investigated the effect of chronic doxorubicin administration on the ECG of freely moving BALB/c mice and the efficacy of CHEMICAL as a protective agent. The ST interval significantly widened from 15.0 +/- 1.5 to 56.8 +/- 11.8 ms in week 10 (7 weekly doses of 4 mg/kg doxorubicin given i.v. plus 3 weeks of observation). The ECG of the control animals did not change during the entire study. After sacrifice the hearts of doxorubicin-treated animals were enlarged and the atria were DISEASE. As this schedule exerted more toxicity than needed to investigate protective agents, the protection of CHEMICAL was determined using a dose schedule with lower general toxicity (6 weekly doses of 4 mg/kg doxorubicin given i.v. plus 2 weeks of observation). On this schedule, the animals' hearts appeared normal after sacrifice and CHEMICAL (50 mg/kg given i.p. 1 h before doxorubicin) provided almost full protection. These data were confirmed by histology. The results indicate that this new model is very sensitive and enables monitoring of the development of cardiotoxicity with time. These findings result in a model that allows the testing of protectors against doxorubicin-induced cardiotoxicity as demonstrated by the protection provided by CHEMICAL. | NO-RELATIONSHIP |
| Doxorubicin-induced cardiotoxicity monitored by ECG in freely moving mice. A new model to test potential protectors. In laboratory animals, histology is most commonly used to study doxorubicin-induced cardiotoxicity. However, for monitoring during treatment, large numbers of animals are needed. Recently we developed a new method to measure ECG values in freely moving mice by telemetry. With this model we investigated the effect of chronic doxorubicin administration on the ECG of freely moving BALB/c mice and the efficacy of CHEMICAL as a protective agent. The ST interval significantly widened from 15.0 +/- 1.5 to 56.8 +/- 11.8 ms in week 10 (7 weekly doses of 4 mg/kg doxorubicin given i.v. plus 3 weeks of observation). The ECG of the control animals did not change during the entire study. After sacrifice the hearts of doxorubicin-treated animals were enlarged and the atria were hypertrophic. As this schedule exerted more DISEASE than needed to investigate protective agents, the protection of CHEMICAL was determined using a dose schedule with lower general DISEASE (6 weekly doses of 4 mg/kg doxorubicin given i.v. plus 2 weeks of observation). On this schedule, the animals' hearts appeared normal after sacrifice and CHEMICAL (50 mg/kg given i.p. 1 h before doxorubicin) provided almost full protection. These data were confirmed by histology. The results indicate that this new model is very sensitive and enables monitoring of the development of cardiotoxicity with time. These findings result in a model that allows the testing of protectors against doxorubicin-induced cardiotoxicity as demonstrated by the protection provided by CHEMICAL. | NO-RELATIONSHIP |
| CHEMICAL dysrhythmogenicity is not enhanced by subtoxic bupivacaine in dogs. Since bupivacaine and CHEMICAL may both precipitate dysrhythmias, circulating bupivacaine during regional anesthesia could potentiate dysrhythmogenic effects of CHEMICAL. We therefore examined whether bupivacaine alters the dysrhythmogenicity of subsequent administration of CHEMICAL in conscious, healthy dogs and in anesthetized dogs with myocardial infarction. Forty-one conscious dogs received 10 micrograms.kg-1.min-1 CHEMICAL. Seventeen animals responded with DISEASE (DISEASE) within 3 min. After 3 h, these responders randomly received 1 or 2 mg/kg bupivacaine or saline over 5 min, followed by 10 micrograms.kg-1.min-1 CHEMICAL. In the bupivacaine groups, CHEMICAL caused fewer prodysrhythmic effects than without bupivacaine. DISEASE appeared in fewer dogs and at a later time, and there were more sinoatrial beats and less ectopies. CHEMICAL shortened QT less after bupivacaine than in control animals. One day after experimental myocardial infarction, six additional halothane-anesthetized dogs received 4 micrograms.kg-1.min-1 CHEMICAL until DISEASE appeared. After 45 min, 1 mg/kg bupivacaine was injected over 5 min, again followed by 4 micrograms.kg-1.min-1 CHEMICAL. In these dogs, the prodysrhythmic response to CHEMICAL was also mitigated by preceding bupivacaine. Bupivacaine antagonizes CHEMICAL dysrhythmogenicity in conscious dogs susceptible to DISEASE and in anesthetized dogs with spontaneous postinfarct dysrhythmias. There is no evidence that systemic subtoxic bupivacaine administration enhances the dysrhythmogenicity of subsequent CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Epinephrine dysrhythmogenicity is not enhanced by subtoxic CHEMICAL in dogs. Since CHEMICAL and epinephrine may both precipitate dysrhythmias, circulating CHEMICAL during regional anesthesia could potentiate dysrhythmogenic effects of epinephrine. We therefore examined whether CHEMICAL alters the dysrhythmogenicity of subsequent administration of epinephrine in conscious, healthy dogs and in anesthetized dogs with DISEASE. Forty-one conscious dogs received 10 micrograms.kg-1.min-1 epinephrine. Seventeen animals responded with ventricular tachycardia (VT) within 3 min. After 3 h, these responders randomly received 1 or 2 mg/kg CHEMICAL or saline over 5 min, followed by 10 micrograms.kg-1.min-1 epinephrine. In the CHEMICAL groups, epinephrine caused fewer prodysrhythmic effects than without CHEMICAL. VT appeared in fewer dogs and at a later time, and there were more sinoatrial beats and less ectopies. Epinephrine shortened QT less after CHEMICAL than in control animals. One day after experimental DISEASE, six additional halothane-anesthetized dogs received 4 micrograms.kg-1.min-1 epinephrine until VT appeared. After 45 min, 1 mg/kg CHEMICAL was injected over 5 min, again followed by 4 micrograms.kg-1.min-1 epinephrine. In these dogs, the prodysrhythmic response to epinephrine was also mitigated by preceding CHEMICAL. CHEMICAL antagonizes epinephrine dysrhythmogenicity in conscious dogs susceptible to VT and in anesthetized dogs with spontaneous postinfarct dysrhythmias. There is no evidence that systemic subtoxic CHEMICAL administration enhances the dysrhythmogenicity of subsequent epinephrine. | NO-RELATIONSHIP |
| Epinephrine dysrhythmogenicity is not enhanced by subtoxic bupivacaine in dogs. Since bupivacaine and epinephrine may both precipitate dysrhythmias, circulating bupivacaine during regional anesthesia could potentiate dysrhythmogenic effects of epinephrine. We therefore examined whether bupivacaine alters the dysrhythmogenicity of subsequent administration of epinephrine in conscious, healthy dogs and in anesthetized dogs with DISEASE. Forty-one conscious dogs received 10 micrograms.kg-1.min-1 epinephrine. Seventeen animals responded with ventricular tachycardia (VT) within 3 min. After 3 h, these responders randomly received 1 or 2 mg/kg bupivacaine or saline over 5 min, followed by 10 micrograms.kg-1.min-1 epinephrine. In the bupivacaine groups, epinephrine caused fewer prodysrhythmic effects than without bupivacaine. VT appeared in fewer dogs and at a later time, and there were more sinoatrial beats and less ectopies. Epinephrine shortened QT less after bupivacaine than in control animals. One day after experimental DISEASE, six additional CHEMICAL-anesthetized dogs received 4 micrograms.kg-1.min-1 epinephrine until VT appeared. After 45 min, 1 mg/kg bupivacaine was injected over 5 min, again followed by 4 micrograms.kg-1.min-1 epinephrine. In these dogs, the prodysrhythmic response to epinephrine was also mitigated by preceding bupivacaine. Bupivacaine antagonizes epinephrine dysrhythmogenicity in conscious dogs susceptible to VT and in anesthetized dogs with spontaneous postinfarct dysrhythmias. There is no evidence that systemic subtoxic bupivacaine administration enhances the dysrhythmogenicity of subsequent epinephrine. | NO-RELATIONSHIP |
| Epinephrine dysrhythmogenicity is not enhanced by subtoxic CHEMICAL in dogs. Since CHEMICAL and epinephrine may both precipitate DISEASE, circulating CHEMICAL during regional anesthesia could potentiate dysrhythmogenic effects of epinephrine. We therefore examined whether CHEMICAL alters the dysrhythmogenicity of subsequent administration of epinephrine in conscious, healthy dogs and in anesthetized dogs with myocardial infarction. Forty-one conscious dogs received 10 micrograms.kg-1.min-1 epinephrine. Seventeen animals responded with ventricular tachycardia (VT) within 3 min. After 3 h, these responders randomly received 1 or 2 mg/kg CHEMICAL or saline over 5 min, followed by 10 micrograms.kg-1.min-1 epinephrine. In the CHEMICAL groups, epinephrine caused fewer prodysrhythmic effects than without CHEMICAL. VT appeared in fewer dogs and at a later time, and there were more sinoatrial beats and less ectopies. Epinephrine shortened QT less after CHEMICAL than in control animals. One day after experimental myocardial infarction, six additional halothane-anesthetized dogs received 4 micrograms.kg-1.min-1 epinephrine until VT appeared. After 45 min, 1 mg/kg CHEMICAL was injected over 5 min, again followed by 4 micrograms.kg-1.min-1 epinephrine. In these dogs, the prodysrhythmic response to epinephrine was also mitigated by preceding CHEMICAL. CHEMICAL antagonizes epinephrine dysrhythmogenicity in conscious dogs susceptible to VT and in anesthetized dogs with spontaneous postinfarct DISEASE. There is no evidence that systemic subtoxic CHEMICAL administration enhances the dysrhythmogenicity of subsequent epinephrine. | NO-RELATIONSHIP |
| Epinephrine dysrhythmogenicity is not enhanced by subtoxic bupivacaine in dogs. Since bupivacaine and epinephrine may both precipitate DISEASE, circulating bupivacaine during regional anesthesia could potentiate dysrhythmogenic effects of epinephrine. We therefore examined whether bupivacaine alters the dysrhythmogenicity of subsequent administration of epinephrine in conscious, healthy dogs and in anesthetized dogs with myocardial infarction. Forty-one conscious dogs received 10 micrograms.kg-1.min-1 epinephrine. Seventeen animals responded with ventricular tachycardia (VT) within 3 min. After 3 h, these responders randomly received 1 or 2 mg/kg bupivacaine or saline over 5 min, followed by 10 micrograms.kg-1.min-1 epinephrine. In the bupivacaine groups, epinephrine caused fewer prodysrhythmic effects than without bupivacaine. VT appeared in fewer dogs and at a later time, and there were more sinoatrial beats and less ectopies. Epinephrine shortened QT less after bupivacaine than in control animals. One day after experimental myocardial infarction, six additional CHEMICAL-anesthetized dogs received 4 micrograms.kg-1.min-1 epinephrine until VT appeared. After 45 min, 1 mg/kg bupivacaine was injected over 5 min, again followed by 4 micrograms.kg-1.min-1 epinephrine. In these dogs, the prodysrhythmic response to epinephrine was also mitigated by preceding bupivacaine. Bupivacaine antagonizes epinephrine dysrhythmogenicity in conscious dogs susceptible to VT and in anesthetized dogs with spontaneous postinfarct DISEASE. There is no evidence that systemic subtoxic bupivacaine administration enhances the dysrhythmogenicity of subsequent epinephrine. | NO-RELATIONSHIP |
| Milk-alkali syndrome induced by CHEMICAL in a patient with hypoparathyroidism. Milk-alkali syndrome was first described 70 years ago in the context of the treatment of peptic ulcer disease with large amounts of calcium and alkali. Although with current ulcer therapy (H-2 blockers, omeprazole, and sucralfate), the frequency of milk-alkali syndrome has decreased significantly, the classic triad of hypercalcemia, alkalosis, and DISEASE remains the hallmark of the syndrome. Milk-alkali syndrome can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with hypoparathyroidism who was treated with calcium carbonate and CHEMICAL resulting in two admissions to the hospital for milk-alkali syndrome. The patient was successfully treated with intravenous pamidronate on his first admission and with hydrocortisone on the second. This illustrates intravenous pamidronate as a valuable therapeutic tool when milk-alkali syndrome presents as hypercalcemic emergency. | CHEMICAL-INDUCED-DISEASE |
| Milk-alkali syndrome induced by 1,25(OH)2D in a patient with hypoparathyroidism. Milk-alkali syndrome was first described 70 years ago in the context of the treatment of DISEASE with large amounts of calcium and alkali. Although with current ulcer therapy (H-2 blockers, omeprazole, and CHEMICAL), the frequency of milk-alkali syndrome has decreased significantly, the classic triad of hypercalcemia, alkalosis, and renal impairment remains the hallmark of the syndrome. Milk-alkali syndrome can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with hypoparathyroidism who was treated with calcium carbonate and calcitriol resulting in two admissions to the hospital for milk-alkali syndrome. The patient was successfully treated with intravenous pamidronate on his first admission and with hydrocortisone on the second. This illustrates intravenous pamidronate as a valuable therapeutic tool when milk-alkali syndrome presents as hypercalcemic emergency. | NO-RELATIONSHIP |
| Milk-alkali syndrome induced by 1,25(OH)2D in a patient with hypoparathyroidism. Milk-alkali syndrome was first described 70 years ago in the context of the treatment of peptic ulcer disease with large amounts of CHEMICAL and alkali. Although with current ulcer therapy (H-2 blockers, omeprazole, and sucralfate), the frequency of milk-alkali syndrome has decreased significantly, the classic triad of hypercalcemia, DISEASE, and renal impairment remains the hallmark of the syndrome. Milk-alkali syndrome can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with hypoparathyroidism who was treated with calcium carbonate and calcitriol resulting in two admissions to the hospital for milk-alkali syndrome. The patient was successfully treated with intravenous pamidronate on his first admission and with hydrocortisone on the second. This illustrates intravenous pamidronate as a valuable therapeutic tool when milk-alkali syndrome presents as hypercalcemic emergency. | NO-RELATIONSHIP |
| Milk-alkali syndrome induced by 1,25(OH)2D in a patient with hypoparathyroidism. Milk-alkali syndrome was first described 70 years ago in the context of the treatment of peptic ulcer disease with large amounts of calcium and CHEMICAL. Although with current ulcer therapy (H-2 blockers, omeprazole, and sucralfate), the frequency of milk-alkali syndrome has decreased significantly, the classic triad of hypercalcemia, alkalosis, and DISEASE remains the hallmark of the syndrome. Milk-alkali syndrome can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with hypoparathyroidism who was treated with calcium carbonate and calcitriol resulting in two admissions to the hospital for milk-alkali syndrome. The patient was successfully treated with intravenous pamidronate on his first admission and with hydrocortisone on the second. This illustrates intravenous pamidronate as a valuable therapeutic tool when milk-alkali syndrome presents as hypercalcemic emergency. | NO-RELATIONSHIP |
| Milk-alkali syndrome induced by 1,25(OH)2D in a patient with hypoparathyroidism. Milk-alkali syndrome was first described 70 years ago in the context of the treatment of peptic ulcer disease with large amounts of calcium and CHEMICAL. Although with current ulcer therapy (H-2 blockers, omeprazole, and sucralfate), the frequency of milk-alkali syndrome has decreased significantly, the classic triad of hypercalcemia, DISEASE, and renal impairment remains the hallmark of the syndrome. Milk-alkali syndrome can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with hypoparathyroidism who was treated with calcium carbonate and calcitriol resulting in two admissions to the hospital for milk-alkali syndrome. The patient was successfully treated with intravenous pamidronate on his first admission and with hydrocortisone on the second. This illustrates intravenous pamidronate as a valuable therapeutic tool when milk-alkali syndrome presents as hypercalcemic emergency. | NO-RELATIONSHIP |
| Milk-alkali syndrome induced by 1,25(OH)2D in a patient with hypoparathyroidism. Milk-alkali syndrome was first described 70 years ago in the context of the treatment of peptic ulcer disease with large amounts of calcium and alkali. Although with current ulcer therapy (H-2 blockers, omeprazole, and sucralfate), the frequency of milk-alkali syndrome has decreased significantly, the classic triad of hypercalcemia, DISEASE, and renal impairment remains the hallmark of the syndrome. Milk-alkali syndrome can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with hypoparathyroidism who was treated with CHEMICAL and calcitriol resulting in two admissions to the hospital for milk-alkali syndrome. The patient was successfully treated with intravenous pamidronate on his first admission and with hydrocortisone on the second. This illustrates intravenous pamidronate as a valuable therapeutic tool when milk-alkali syndrome presents as hypercalcemic emergency. | NO-RELATIONSHIP |
| Milk-alkali syndrome induced by 1,25(OH)2D in a patient with hypoparathyroidism. Milk-alkali syndrome was first described 70 years ago in the context of the treatment of DISEASE with large amounts of calcium and alkali. Although with current ulcer therapy (H-2 blockers, CHEMICAL, and sucralfate), the frequency of milk-alkali syndrome has decreased significantly, the classic triad of hypercalcemia, alkalosis, and renal impairment remains the hallmark of the syndrome. Milk-alkali syndrome can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with hypoparathyroidism who was treated with calcium carbonate and calcitriol resulting in two admissions to the hospital for milk-alkali syndrome. The patient was successfully treated with intravenous pamidronate on his first admission and with hydrocortisone on the second. This illustrates intravenous pamidronate as a valuable therapeutic tool when milk-alkali syndrome presents as hypercalcemic emergency. | NO-RELATIONSHIP |
| DISEASE induced by CHEMICAL in a patient with hypoparathyroidism. DISEASE was first described 70 years ago in the context of the treatment of peptic ulcer disease with large amounts of calcium and alkali. Although with current ulcer therapy (H-2 blockers, omeprazole, and sucralfate), the frequency of DISEASE has decreased significantly, the classic triad of DISEASE, alkalosis, and renal impairment remains the hallmark of the syndrome. DISEASE can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with hypoparathyroidism who was treated with calcium carbonate and CHEMICAL resulting in two admissions to the hospital for DISEASE. The patient was successfully treated with intravenous pamidronate on his first admission and with hydrocortisone on the second. This illustrates intravenous pamidronate as a valuable therapeutic tool when DISEASE presents as DISEASE. | CHEMICAL-INDUCED-DISEASE |
| DISEASE induced by 1,25(OH)2D in a patient with hypoparathyroidism. DISEASE was first described 70 years ago in the context of the treatment of peptic ulcer disease with large amounts of calcium and CHEMICAL. Although with current ulcer therapy (H-2 blockers, omeprazole, and sucralfate), the frequency of DISEASE has decreased significantly, the classic triad of DISEASE, alkalosis, and renal impairment remains the hallmark of the syndrome. DISEASE can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with hypoparathyroidism who was treated with calcium carbonate and calcitriol resulting in two admissions to the hospital for DISEASE. The patient was successfully treated with intravenous pamidronate on his first admission and with hydrocortisone on the second. This illustrates intravenous pamidronate as a valuable therapeutic tool when DISEASE presents as DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Milk-alkali syndrome induced by CHEMICAL in a patient with hypoparathyroidism. Milk-alkali syndrome was first described 70 years ago in the context of the treatment of peptic ulcer disease with large amounts of calcium and alkali. Although with current ulcer therapy (H-2 blockers, omeprazole, and sucralfate), the frequency of milk-alkali syndrome has decreased significantly, the classic triad of hypercalcemia, DISEASE, and renal impairment remains the hallmark of the syndrome. Milk-alkali syndrome can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with hypoparathyroidism who was treated with calcium carbonate and CHEMICAL resulting in two admissions to the hospital for milk-alkali syndrome. The patient was successfully treated with intravenous pamidronate on his first admission and with hydrocortisone on the second. This illustrates intravenous pamidronate as a valuable therapeutic tool when milk-alkali syndrome presents as hypercalcemic emergency. | CHEMICAL-INDUCED-DISEASE |
| DISEASE induced by 1,25(OH)2D in a patient with hypoparathyroidism. DISEASE was first described 70 years ago in the context of the treatment of peptic ulcer disease with large amounts of CHEMICAL and alkali. Although with current ulcer therapy (H-2 blockers, omeprazole, and sucralfate), the frequency of DISEASE has decreased significantly, the classic triad of DISEASE, alkalosis, and renal impairment remains the hallmark of the syndrome. DISEASE can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with hypoparathyroidism who was treated with calcium carbonate and calcitriol resulting in two admissions to the hospital for DISEASE. The patient was successfully treated with intravenous pamidronate on his first admission and with hydrocortisone on the second. This illustrates intravenous pamidronate as a valuable therapeutic tool when DISEASE presents as DISEASE. | CHEMICAL-INDUCED-DISEASE |
| DISEASE induced by 1,25(OH)2D in a patient with hypoparathyroidism. DISEASE was first described 70 years ago in the context of the treatment of peptic ulcer disease with large amounts of calcium and alkali. Although with current ulcer therapy (H-2 blockers, omeprazole, and sucralfate), the frequency of DISEASE has decreased significantly, the classic triad of DISEASE, alkalosis, and renal impairment remains the hallmark of the syndrome. DISEASE can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with hypoparathyroidism who was treated with CHEMICAL and calcitriol resulting in two admissions to the hospital for DISEASE. The patient was successfully treated with intravenous pamidronate on his first admission and with hydrocortisone on the second. This illustrates intravenous pamidronate as a valuable therapeutic tool when DISEASE presents as DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Milk-alkali syndrome induced by 1,25(OH)2D in a patient with hypoparathyroidism. Milk-alkali syndrome was first described 70 years ago in the context of the treatment of peptic ulcer disease with large amounts of calcium and alkali. Although with current ulcer therapy (H-2 blockers, omeprazole, and sucralfate), the frequency of milk-alkali syndrome has decreased significantly, the classic triad of hypercalcemia, alkalosis, and DISEASE remains the hallmark of the syndrome. Milk-alkali syndrome can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with hypoparathyroidism who was treated with CHEMICAL and calcitriol resulting in two admissions to the hospital for milk-alkali syndrome. The patient was successfully treated with intravenous pamidronate on his first admission and with hydrocortisone on the second. This illustrates intravenous pamidronate as a valuable therapeutic tool when milk-alkali syndrome presents as hypercalcemic emergency. | NO-RELATIONSHIP |
| Milk-alkali syndrome induced by 1,25(OH)2D in a patient with hypoparathyroidism. Milk-alkali syndrome was first described 70 years ago in the context of the treatment of peptic ulcer disease with large amounts of CHEMICAL and alkali. Although with current ulcer therapy (H-2 blockers, omeprazole, and sucralfate), the frequency of milk-alkali syndrome has decreased significantly, the classic triad of hypercalcemia, alkalosis, and DISEASE remains the hallmark of the syndrome. Milk-alkali syndrome can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with hypoparathyroidism who was treated with calcium carbonate and calcitriol resulting in two admissions to the hospital for milk-alkali syndrome. The patient was successfully treated with intravenous pamidronate on his first admission and with hydrocortisone on the second. This illustrates intravenous pamidronate as a valuable therapeutic tool when milk-alkali syndrome presents as hypercalcemic emergency. | NO-RELATIONSHIP |
| Milk-alkali syndrome induced by 1,25(OH)2D in a patient with DISEASE. Milk-alkali syndrome was first described 70 years ago in the context of the treatment of peptic ulcer disease with large amounts of calcium and alkali. Although with current ulcer therapy (H-2 blockers, omeprazole, and sucralfate), the frequency of milk-alkali syndrome has decreased significantly, the classic triad of hypercalcemia, alkalosis, and renal impairment remains the hallmark of the syndrome. Milk-alkali syndrome can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with DISEASE who was treated with calcium carbonate and calcitriol resulting in two admissions to the hospital for milk-alkali syndrome. The patient was successfully treated with intravenous pamidronate on his first admission and with CHEMICAL on the second. This illustrates intravenous pamidronate as a valuable therapeutic tool when milk-alkali syndrome presents as hypercalcemic emergency. | NO-RELATIONSHIP |
| Milk-alkali syndrome induced by 1,25(OH)2D in a patient with hypoparathyroidism. Milk-alkali syndrome was first described 70 years ago in the context of the treatment of peptic ulcer disease with large amounts of calcium and alkali. Although with current DISEASE therapy (H-2 blockers, omeprazole, and sucralfate), the frequency of milk-alkali syndrome has decreased significantly, the classic triad of hypercalcemia, alkalosis, and renal impairment remains the hallmark of the syndrome. Milk-alkali syndrome can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with hypoparathyroidism who was treated with calcium carbonate and calcitriol resulting in two admissions to the hospital for milk-alkali syndrome. The patient was successfully treated with intravenous CHEMICAL on his first admission and with hydrocortisone on the second. This illustrates intravenous CHEMICAL as a valuable therapeutic tool when milk-alkali syndrome presents as hypercalcemic emergency. | NO-RELATIONSHIP |
| Milk-alkali syndrome induced by 1,25(OH)2D in a patient with DISEASE. Milk-alkali syndrome was first described 70 years ago in the context of the treatment of peptic ulcer disease with large amounts of calcium and alkali. Although with current ulcer therapy (H-2 blockers, omeprazole, and sucralfate), the frequency of milk-alkali syndrome has decreased significantly, the classic triad of hypercalcemia, alkalosis, and renal impairment remains the hallmark of the syndrome. Milk-alkali syndrome can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with DISEASE who was treated with calcium carbonate and calcitriol resulting in two admissions to the hospital for milk-alkali syndrome. The patient was successfully treated with intravenous CHEMICAL on his first admission and with hydrocortisone on the second. This illustrates intravenous CHEMICAL as a valuable therapeutic tool when milk-alkali syndrome presents as hypercalcemic emergency. | NO-RELATIONSHIP |
| Milk-alkali syndrome induced by 1,25(OH)2D in a patient with hypoparathyroidism. Milk-alkali syndrome was first described 70 years ago in the context of the treatment of peptic ulcer disease with large amounts of calcium and alkali. Although with current DISEASE therapy (H-2 blockers, omeprazole, and sucralfate), the frequency of milk-alkali syndrome has decreased significantly, the classic triad of hypercalcemia, alkalosis, and renal impairment remains the hallmark of the syndrome. Milk-alkali syndrome can present serious and occasionally life-threatening illness unless diagnosed and treated appropriately. This article presents a patient with hypoparathyroidism who was treated with calcium carbonate and calcitriol resulting in two admissions to the hospital for milk-alkali syndrome. The patient was successfully treated with intravenous pamidronate on his first admission and with CHEMICAL on the second. This illustrates intravenous pamidronate as a valuable therapeutic tool when milk-alkali syndrome presents as hypercalcemic emergency. | NO-RELATIONSHIP |
| DISEASE during CHEMICAL therapy: are neuroleptic malignant syndrome and serotonin syndrome spectrum disorders? This report describes a case of DISEASE developed in the course of CHEMICAL therapy, during a remission of unipolar depression. This patient could have been diagnosed as having either neuroleptic malignant syndrome (NMS) or serotonin syndrome (SS). The major determinant of the symptoms may have been dopamine/serotonin imbalance in the central nervous system. The NMS-like DISEASE that develops in association with the use of antidepressants indicates that NMS and SS are spectrum disorders induced by drugs with both antidopaminergic and serotonergic effects. | CHEMICAL-INDUCED-DISEASE |
| Encephalopathy during amitriptyline therapy: are DISEASE and serotonin syndrome spectrum disorders? This report describes a case of encephalopathy developed in the course of amitriptyline therapy, during a remission of unipolar depression. This patient could have been diagnosed as having either DISEASE (DISEASE) or serotonin syndrome (SS). The major determinant of the symptoms may have been dopamine/CHEMICAL imbalance in the central nervous system. The DISEASE-like encephalopathy that develops in association with the use of antidepressants indicates that DISEASE and SS are spectrum disorders induced by drugs with both antidopaminergic and serotonergic effects. | NO-RELATIONSHIP |
| Encephalopathy during amitriptyline therapy: are neuroleptic malignant syndrome and serotonin syndrome spectrum disorders? This report describes a case of encephalopathy developed in the course of amitriptyline therapy, during a remission of DISEASE. This patient could have been diagnosed as having either neuroleptic malignant syndrome (NMS) or serotonin syndrome (SS). The major determinant of the symptoms may have been CHEMICAL/serotonin imbalance in the central nervous system. The NMS-like encephalopathy that develops in association with the use of antidepressants indicates that NMS and SS are spectrum disorders induced by drugs with both antidopaminergic and serotonergic effects. | NO-RELATIONSHIP |
| Encephalopathy during amitriptyline therapy: are neuroleptic malignant syndrome and DISEASE spectrum disorders? This report describes a case of encephalopathy developed in the course of amitriptyline therapy, during a remission of unipolar depression. This patient could have been diagnosed as having either neuroleptic malignant syndrome (NMS) or DISEASE (DISEASE). The major determinant of the symptoms may have been dopamine/CHEMICAL imbalance in the central nervous system. The NMS-like encephalopathy that develops in association with the use of antidepressants indicates that NMS and DISEASE are spectrum disorders induced by drugs with both antidopaminergic and serotonergic effects. | NO-RELATIONSHIP |
| Encephalopathy during amitriptyline therapy: are neuroleptic malignant syndrome and DISEASE spectrum disorders? This report describes a case of encephalopathy developed in the course of amitriptyline therapy, during a remission of unipolar depression. This patient could have been diagnosed as having either neuroleptic malignant syndrome (NMS) or DISEASE (DISEASE). The major determinant of the symptoms may have been CHEMICAL/serotonin imbalance in the central nervous system. The NMS-like encephalopathy that develops in association with the use of antidepressants indicates that NMS and DISEASE are spectrum disorders induced by drugs with both antidopaminergic and serotonergic effects. | NO-RELATIONSHIP |
| Encephalopathy during amitriptyline therapy: are DISEASE and serotonin syndrome spectrum disorders? This report describes a case of encephalopathy developed in the course of amitriptyline therapy, during a remission of unipolar depression. This patient could have been diagnosed as having either DISEASE (DISEASE) or serotonin syndrome (SS). The major determinant of the symptoms may have been CHEMICAL/serotonin imbalance in the central nervous system. The DISEASE-like encephalopathy that develops in association with the use of antidepressants indicates that DISEASE and SS are spectrum disorders induced by drugs with both antidopaminergic and serotonergic effects. | NO-RELATIONSHIP |
| Encephalopathy during amitriptyline therapy: are neuroleptic malignant syndrome and serotonin syndrome spectrum disorders? This report describes a case of encephalopathy developed in the course of amitriptyline therapy, during a remission of DISEASE. This patient could have been diagnosed as having either neuroleptic malignant syndrome (NMS) or serotonin syndrome (SS). The major determinant of the symptoms may have been dopamine/CHEMICAL imbalance in the central nervous system. The NMS-like encephalopathy that develops in association with the use of antidepressants indicates that NMS and SS are spectrum disorders induced by drugs with both antidopaminergic and serotonergic effects. | NO-RELATIONSHIP |
| Genetic separation of tumor growth and hemorrhagic phenotypes in an estrogen-induced tumor. Chronic administration of estrogen to the Fischer 344 (F344) rat induces growth of large, hemorrhagic DISEASE. Ten weeks of CHEMICAL (CHEMICAL) treatment caused female F344 rat pituitaries to grow to an average of 109.2 +/- 6.3 mg (mean +/- SE) versus 11.3 +/- 1.4 mg for untreated rats, and to become highly hemorrhagic. The same CHEMICAL treatment produced no significant growth (8.9 +/- 0.5 mg for treated females versus 8.7 +/- 1.1 for untreated females) or morphological changes in Brown Norway (BN) rat pituitaries. An F1 hybrid of F344 and BN exhibited significant pituitary growth after 10 weeks of CHEMICAL treatment with an average mass of 26.3 +/- 0.7 mg compared with 8.6 +/- 0.9 mg for untreated rats. Surprisingly, the F1 hybrid tumors were not hemorrhagic and had hemoglobin content and outward appearance identical to that of BN. Expression of both growth and morphological changes is due to multiple genes. However, while CHEMICAL-induced pituitary growth exhibited quantitative, additive inheritance, the hemorrhagic phenotype exhibited recessive, epistatic inheritance. Only 5 of the 160 F2 pituitaries exhibited the hemorrhagic phenotype; 36 of the 160 F2 pituitaries were in the F344 range of mass, but 31 of these were not hemorrhagic, indicating that the hemorrhagic phenotype is not merely a consequence of extensive growth. The hemorrhagic F2 pituitaries were all among the most massive, indicating that some of the genes regulate both phenotypes. | CHEMICAL-INDUCED-DISEASE |
| Genetic separation of tumor growth and DISEASE phenotypes in an CHEMICAL-induced tumor. Chronic administration of CHEMICAL to the Fischer 344 (F344) rat induces growth of large, DISEASE pituitary tumors. Ten weeks of diethylstilbestrol (DES) treatment caused female F344 rat pituitaries to grow to an average of 109.2 +/- 6.3 mg (mean +/- SE) versus 11.3 +/- 1.4 mg for untreated rats, and to become highly DISEASE. The same DES treatment produced no significant growth (8.9 +/- 0.5 mg for treated females versus 8.7 +/- 1.1 for untreated females) or morphological changes in Brown Norway (BN) rat pituitaries. An F1 hybrid of F344 and BN exhibited significant pituitary growth after 10 weeks of DES treatment with an average mass of 26.3 +/- 0.7 mg compared with 8.6 +/- 0.9 mg for untreated rats. Surprisingly, the F1 hybrid tumors were not DISEASE and had hemoglobin content and outward appearance identical to that of BN. Expression of both growth and morphological changes is due to multiple genes. However, while DES-induced pituitary growth exhibited quantitative, additive inheritance, the DISEASE phenotype exhibited recessive, epistatic inheritance. Only 5 of the 160 F2 pituitaries exhibited the DISEASE phenotype; 36 of the 160 F2 pituitaries were in the F344 range of mass, but 31 of these were not DISEASE, indicating that the DISEASE phenotype is not merely a consequence of extensive growth. The DISEASE F2 pituitaries were all among the most massive, indicating that some of the genes regulate both phenotypes. | CHEMICAL-INDUCED-DISEASE |
| Genetic separation of DISEASE growth and hemorrhagic phenotypes in an CHEMICAL-induced DISEASE. Chronic administration of CHEMICAL to the Fischer 344 (F344) rat induces growth of large, hemorrhagic pituitary tumors. Ten weeks of diethylstilbestrol (DES) treatment caused female F344 rat pituitaries to grow to an average of 109.2 +/- 6.3 mg (mean +/- SE) versus 11.3 +/- 1.4 mg for untreated rats, and to become highly hemorrhagic. The same DES treatment produced no significant growth (8.9 +/- 0.5 mg for treated females versus 8.7 +/- 1.1 for untreated females) or morphological changes in Brown Norway (BN) rat pituitaries. An F1 hybrid of F344 and BN exhibited significant pituitary growth after 10 weeks of DES treatment with an average mass of 26.3 +/- 0.7 mg compared with 8.6 +/- 0.9 mg for untreated rats. Surprisingly, the F1 hybrid DISEASE were not hemorrhagic and had hemoglobin content and outward appearance identical to that of BN. Expression of both growth and morphological changes is due to multiple genes. However, while DES-induced pituitary growth exhibited quantitative, additive inheritance, the hemorrhagic phenotype exhibited recessive, epistatic inheritance. Only 5 of the 160 F2 pituitaries exhibited the hemorrhagic phenotype; 36 of the 160 F2 pituitaries were in the F344 range of mass, but 31 of these were not hemorrhagic, indicating that the hemorrhagic phenotype is not merely a consequence of extensive growth. The hemorrhagic F2 pituitaries were all among the most massive, indicating that some of the genes regulate both phenotypes. | CHEMICAL-INDUCED-DISEASE |
| Increased expression of neuronal nitric oxide synthase in bladder afferent pathways following chronic bladder irritation. Immunocytochemical techniques were used to examine alterations in the expression of neuronal nitric oxide synthase (NOS) in bladder pathways following acute and chronic irritation of the urinary tract of the rat. Chemical DISEASE was induced by CHEMICAL (CHEMICAL) which is metabolized to acrolein, an irritant eliminated in the urine. Injection of CHEMICAL (n = 10, 75 mg/kg, i.p.) 2 hours prior to perfusion (acute treatment) of the animals increased Fos-immunoreactivity (IR) in neurons in the dorsal commissure, dorsal horn, and autonomic regions of spinal segments (L1-L2 and L6-S1) which receive afferent inputs from the bladder, urethra, and ureter. Fos-IR in the spinal cord was not changed in rats receiving chronic CHEMICAL treatment (n = 15, 75 mg/kg, i.p., every 3rd day for 2 weeks). In control animals and in animals treated acutely with CHEMICAL, only small numbers of NOS-IR cells (0.5-0.7 cell profiles/sections) were detected in the L6-S1 dorsal root ganglia (DRG). Chronic CHEMICAL administration significantly (P < or = .002) increased bladder weight by 60% and increased (7- to 11-fold) the numbers of NOS-immunoreactive (IR) afferent neurons in the L6-S1 DRG. A small increase (1.5-fold) also occurred in the L1 DRG, but no change was detected in the L2 and L5 DRG. Bladder afferent cells in the L6-S1 DRG labeled by Fluorogold (40 microliters) injected into the bladder wall did not exhibit NOS-IR in control animals; however, following chronic CHEMICAL administration, a significant percentage of bladder afferent neurons were NOS-IR: L6 (19.8 +/- 4.6%) and S1 (25.3 +/- 2.9%). These results indicate that neuronal gene expression in visceral sensory pathways can be upregulated by chemical irritation of afferent receptors in the urinary tract and/or that pathological changes in the urinary tract can initiate chemical signals that alter the chemical properties of visceral afferent neurons. | CHEMICAL-INDUCED-DISEASE |
| Increased expression of neuronal nitric oxide synthase in bladder afferent pathways following chronic DISEASE. Immunocytochemical techniques were used to examine alterations in the expression of neuronal nitric oxide synthase (NOS) in bladder pathways following acute and chronic irritation of the urinary tract of the rat. Chemical cystitis was induced by cyclophosphamide (CYP) which is metabolized to CHEMICAL, an irritant eliminated in the urine. Injection of CYP (n = 10, 75 mg/kg, i.p.) 2 hours prior to perfusion (acute treatment) of the animals increased Fos-immunoreactivity (IR) in neurons in the dorsal commissure, dorsal horn, and autonomic regions of spinal segments (L1-L2 and L6-S1) which receive afferent inputs from the bladder, urethra, and ureter. Fos-IR in the spinal cord was not changed in rats receiving chronic CYP treatment (n = 15, 75 mg/kg, i.p., every 3rd day for 2 weeks). In control animals and in animals treated acutely with CYP, only small numbers of NOS-IR cells (0.5-0.7 cell profiles/sections) were detected in the L6-S1 dorsal root ganglia (DRG). Chronic CYP administration significantly (P < or = .002) increased bladder weight by 60% and increased (7- to 11-fold) the numbers of NOS-immunoreactive (IR) afferent neurons in the L6-S1 DRG. A small increase (1.5-fold) also occurred in the L1 DRG, but no change was detected in the L2 and L5 DRG. Bladder afferent cells in the L6-S1 DRG labeled by Fluorogold (40 microliters) injected into the bladder wall did not exhibit NOS-IR in control animals; however, following chronic CYP administration, a significant percentage of bladder afferent neurons were NOS-IR: L6 (19.8 +/- 4.6%) and S1 (25.3 +/- 2.9%). These results indicate that neuronal gene expression in visceral sensory pathways can be upregulated by chemical irritation of afferent receptors in the urinary tract and/or that pathological changes in the urinary tract can initiate chemical signals that alter the chemical properties of visceral afferent neurons. | NO-RELATIONSHIP |
| Increased expression of neuronal CHEMICAL synthase in bladder afferent pathways following chronic bladder irritation. Immunocytochemical techniques were used to examine alterations in the expression of neuronal CHEMICAL synthase (NOS) in bladder pathways following acute and chronic DISEASE of the rat. Chemical cystitis was induced by cyclophosphamide (CYP) which is metabolized to acrolein, an irritant eliminated in the urine. Injection of CYP (n = 10, 75 mg/kg, i.p.) 2 hours prior to perfusion (acute treatment) of the animals increased Fos-immunoreactivity (IR) in neurons in the dorsal commissure, dorsal horn, and autonomic regions of spinal segments (L1-L2 and L6-S1) which receive afferent inputs from the bladder, urethra, and ureter. Fos-IR in the spinal cord was not changed in rats receiving chronic CYP treatment (n = 15, 75 mg/kg, i.p., every 3rd day for 2 weeks). In control animals and in animals treated acutely with CYP, only small numbers of NOS-IR cells (0.5-0.7 cell profiles/sections) were detected in the L6-S1 dorsal root ganglia (DRG). Chronic CYP administration significantly (P < or = .002) increased bladder weight by 60% and increased (7- to 11-fold) the numbers of NOS-immunoreactive (IR) afferent neurons in the L6-S1 DRG. A small increase (1.5-fold) also occurred in the L1 DRG, but no change was detected in the L2 and L5 DRG. Bladder afferent cells in the L6-S1 DRG labeled by Fluorogold (40 microliters) injected into the bladder wall did not exhibit NOS-IR in control animals; however, following chronic CYP administration, a significant percentage of bladder afferent neurons were NOS-IR: L6 (19.8 +/- 4.6%) and S1 (25.3 +/- 2.9%). These results indicate that neuronal gene expression in visceral sensory pathways can be upregulated by chemical irritation of afferent receptors in the urinary tract and/or that pathological changes in the urinary tract can initiate chemical signals that alter the chemical properties of visceral afferent neurons. | NO-RELATIONSHIP |
| Increased expression of neuronal nitric oxide synthase in bladder afferent pathways following chronic bladder irritation. Immunocytochemical techniques were used to examine alterations in the expression of neuronal nitric oxide synthase (NOS) in bladder pathways following acute and chronic DISEASE of the rat. Chemical cystitis was induced by cyclophosphamide (CYP) which is metabolized to CHEMICAL, an irritant eliminated in the urine. Injection of CYP (n = 10, 75 mg/kg, i.p.) 2 hours prior to perfusion (acute treatment) of the animals increased Fos-immunoreactivity (IR) in neurons in the dorsal commissure, dorsal horn, and autonomic regions of spinal segments (L1-L2 and L6-S1) which receive afferent inputs from the bladder, urethra, and ureter. Fos-IR in the spinal cord was not changed in rats receiving chronic CYP treatment (n = 15, 75 mg/kg, i.p., every 3rd day for 2 weeks). In control animals and in animals treated acutely with CYP, only small numbers of NOS-IR cells (0.5-0.7 cell profiles/sections) were detected in the L6-S1 dorsal root ganglia (DRG). Chronic CYP administration significantly (P < or = .002) increased bladder weight by 60% and increased (7- to 11-fold) the numbers of NOS-immunoreactive (IR) afferent neurons in the L6-S1 DRG. A small increase (1.5-fold) also occurred in the L1 DRG, but no change was detected in the L2 and L5 DRG. Bladder afferent cells in the L6-S1 DRG labeled by Fluorogold (40 microliters) injected into the bladder wall did not exhibit NOS-IR in control animals; however, following chronic CYP administration, a significant percentage of bladder afferent neurons were NOS-IR: L6 (19.8 +/- 4.6%) and S1 (25.3 +/- 2.9%). These results indicate that neuronal gene expression in visceral sensory pathways can be upregulated by chemical irritation of afferent receptors in the urinary tract and/or that pathological changes in the urinary tract can initiate chemical signals that alter the chemical properties of visceral afferent neurons. | NO-RELATIONSHIP |
| Increased expression of neuronal CHEMICAL synthase in bladder afferent pathways following chronic DISEASE. Immunocytochemical techniques were used to examine alterations in the expression of neuronal CHEMICAL synthase (NOS) in bladder pathways following acute and chronic irritation of the urinary tract of the rat. Chemical cystitis was induced by cyclophosphamide (CYP) which is metabolized to acrolein, an irritant eliminated in the urine. Injection of CYP (n = 10, 75 mg/kg, i.p.) 2 hours prior to perfusion (acute treatment) of the animals increased Fos-immunoreactivity (IR) in neurons in the dorsal commissure, dorsal horn, and autonomic regions of spinal segments (L1-L2 and L6-S1) which receive afferent inputs from the bladder, urethra, and ureter. Fos-IR in the spinal cord was not changed in rats receiving chronic CYP treatment (n = 15, 75 mg/kg, i.p., every 3rd day for 2 weeks). In control animals and in animals treated acutely with CYP, only small numbers of NOS-IR cells (0.5-0.7 cell profiles/sections) were detected in the L6-S1 dorsal root ganglia (DRG). Chronic CYP administration significantly (P < or = .002) increased bladder weight by 60% and increased (7- to 11-fold) the numbers of NOS-immunoreactive (IR) afferent neurons in the L6-S1 DRG. A small increase (1.5-fold) also occurred in the L1 DRG, but no change was detected in the L2 and L5 DRG. Bladder afferent cells in the L6-S1 DRG labeled by Fluorogold (40 microliters) injected into the bladder wall did not exhibit NOS-IR in control animals; however, following chronic CYP administration, a significant percentage of bladder afferent neurons were NOS-IR: L6 (19.8 +/- 4.6%) and S1 (25.3 +/- 2.9%). These results indicate that neuronal gene expression in visceral sensory pathways can be upregulated by chemical irritation of afferent receptors in the urinary tract and/or that pathological changes in the urinary tract can initiate chemical signals that alter the chemical properties of visceral afferent neurons. | NO-RELATIONSHIP |
| Effects of a new calcium antagonist, CD-832, on CHEMICAL-induced DISEASE in dogs with partial coronary stenosis. Effects of CD-832 on CHEMICAL (CHEMICAL)-induced DISEASE were studied in dogs with partial coronary stenosis of the left circumflex coronary artery and findings were compared with those for nifedipine or diltiazem. In the presence of coronary artery stenosis, 3-min periods of intracoronary CHEMICAL infusion (10 ng/kg/min) increased heart rate and maximal rate of left ventricular pressure rise, which resulted in a decrease in percentage segmental shortening and ST-segment elevation of the epicardial electrocardiogram. After the control CHEMICAL infusion with stenosis was performed, equihypotensive doses of CD-832 (3 and 10 micrograms/kg/min, n = 7), nifedipine (1 and 3 micrograms/kg/min, n = 9) or diltiazem (10 and 30 micrograms/kg/min, n = 7) were infused 5 min before and during the second and third CHEMICAL infusion. Both CD-832 and diltiazem, but not nifedipine, significantly reduced the increase in heart rate induced by CHEMICAL infusion. In contrast to nifedipine, CD-832 (10 micrograms/kg/min) prevented the decrease in percentage segmental shortening from 32 +/- 12% to 115 +/- 26% of the control value (P < .01) and ST-segment elevation from 5.6 +/- 1.0 mV to 1.6 +/- 1.3 mV (P < .01) at 3 min after CHEMICAL infusion with stenosis. Diltiazem (30 micrograms/kg/min) also prevented the decrease in percentage segmental shortening from 34 +/- 14% to 63 +/- 18% of the control value (P < .05) and ST-segment elevation from 4.7 +/- 0.7 mV to 2.1 +/- 0.7 mV (P < .01) at 3 min after CHEMICAL infusion with stenosis. These data show that CD-832 improves DISEASE during CHEMICAL infusion with stenosis and suggest that the negative chronotropic property of CD-832 plays a major role in the beneficial effects of CD-832. | CHEMICAL-INDUCED-DISEASE |
| Effects of a new calcium antagonist, CHEMICAL, on isoproterenol-induced myocardial ischemia in dogs with partial coronary stenosis. Effects of CHEMICAL on isoproterenol (ISO)-induced myocardial ischemia were studied in dogs with partial coronary stenosis of the left circumflex coronary artery and findings were compared with those for nifedipine or diltiazem. In the presence of coronary artery stenosis, 3-min periods of intracoronary ISO infusion (10 ng/kg/min) increased heart rate and maximal rate of left ventricular pressure rise, which resulted in a decrease in percentage segmental shortening and ST-segment elevation of the epicardial electrocardiogram. After the control ISO infusion with DISEASE was performed, equihypotensive doses of CHEMICAL (3 and 10 micrograms/kg/min, n = 7), nifedipine (1 and 3 micrograms/kg/min, n = 9) or diltiazem (10 and 30 micrograms/kg/min, n = 7) were infused 5 min before and during the second and third ISO infusion. Both CHEMICAL and diltiazem, but not nifedipine, significantly reduced the increase in heart rate induced by ISO infusion. In contrast to nifedipine, CHEMICAL (10 micrograms/kg/min) prevented the decrease in percentage segmental shortening from 32 +/- 12% to 115 +/- 26% of the control value (P < .01) and ST-segment elevation from 5.6 +/- 1.0 mV to 1.6 +/- 1.3 mV (P < .01) at 3 min after ISO infusion with DISEASE. Diltiazem (30 micrograms/kg/min) also prevented the decrease in percentage segmental shortening from 34 +/- 14% to 63 +/- 18% of the control value (P < .05) and ST-segment elevation from 4.7 +/- 0.7 mV to 2.1 +/- 0.7 mV (P < .01) at 3 min after ISO infusion with DISEASE. These data show that CHEMICAL improves myocardial ischemia during ISO infusion with DISEASE and suggest that the negative chronotropic property of CHEMICAL plays a major role in the beneficial effects of CHEMICAL. | NO-RELATIONSHIP |
| Effects of a new CHEMICAL antagonist, CD-832, on isoproterenol-induced myocardial ischemia in dogs with partial DISEASE. Effects of CD-832 on isoproterenol (ISO)-induced myocardial ischemia were studied in dogs with partial DISEASE of the left circumflex coronary artery and findings were compared with those for nifedipine or diltiazem. In the presence of DISEASE, 3-min periods of intracoronary ISO infusion (10 ng/kg/min) increased heart rate and maximal rate of left ventricular pressure rise, which resulted in a decrease in percentage segmental shortening and ST-segment elevation of the epicardial electrocardiogram. After the control ISO infusion with stenosis was performed, equihypotensive doses of CD-832 (3 and 10 micrograms/kg/min, n = 7), nifedipine (1 and 3 micrograms/kg/min, n = 9) or diltiazem (10 and 30 micrograms/kg/min, n = 7) were infused 5 min before and during the second and third ISO infusion. Both CD-832 and diltiazem, but not nifedipine, significantly reduced the increase in heart rate induced by ISO infusion. In contrast to nifedipine, CD-832 (10 micrograms/kg/min) prevented the decrease in percentage segmental shortening from 32 +/- 12% to 115 +/- 26% of the control value (P < .01) and ST-segment elevation from 5.6 +/- 1.0 mV to 1.6 +/- 1.3 mV (P < .01) at 3 min after ISO infusion with stenosis. Diltiazem (30 micrograms/kg/min) also prevented the decrease in percentage segmental shortening from 34 +/- 14% to 63 +/- 18% of the control value (P < .05) and ST-segment elevation from 4.7 +/- 0.7 mV to 2.1 +/- 0.7 mV (P < .01) at 3 min after ISO infusion with stenosis. These data show that CD-832 improves myocardial ischemia during ISO infusion with stenosis and suggest that the negative chronotropic property of CD-832 plays a major role in the beneficial effects of CD-832. | NO-RELATIONSHIP |
| Effects of a new calcium antagonist, CD-832, on isoproterenol-induced myocardial ischemia in dogs with partial coronary stenosis. Effects of CD-832 on isoproterenol (ISO)-induced myocardial ischemia were studied in dogs with partial coronary stenosis of the left circumflex coronary artery and findings were compared with those for nifedipine or CHEMICAL. In the presence of coronary artery stenosis, 3-min periods of intracoronary ISO infusion (10 ng/kg/min) increased heart rate and maximal rate of left ventricular pressure rise, which resulted in a decrease in percentage segmental shortening and ST-segment elevation of the epicardial electrocardiogram. After the control ISO infusion with DISEASE was performed, equihypotensive doses of CD-832 (3 and 10 micrograms/kg/min, n = 7), nifedipine (1 and 3 micrograms/kg/min, n = 9) or CHEMICAL (10 and 30 micrograms/kg/min, n = 7) were infused 5 min before and during the second and third ISO infusion. Both CD-832 and CHEMICAL, but not nifedipine, significantly reduced the increase in heart rate induced by ISO infusion. In contrast to nifedipine, CD-832 (10 micrograms/kg/min) prevented the decrease in percentage segmental shortening from 32 +/- 12% to 115 +/- 26% of the control value (P < .01) and ST-segment elevation from 5.6 +/- 1.0 mV to 1.6 +/- 1.3 mV (P < .01) at 3 min after ISO infusion with DISEASE. CHEMICAL (30 micrograms/kg/min) also prevented the decrease in percentage segmental shortening from 34 +/- 14% to 63 +/- 18% of the control value (P < .05) and ST-segment elevation from 4.7 +/- 0.7 mV to 2.1 +/- 0.7 mV (P < .01) at 3 min after ISO infusion with DISEASE. These data show that CD-832 improves myocardial ischemia during ISO infusion with DISEASE and suggest that the negative chronotropic property of CD-832 plays a major role in the beneficial effects of CD-832. | NO-RELATIONSHIP |
| Effects of a new calcium antagonist, CD-832, on isoproterenol-induced myocardial ischemia in dogs with partial DISEASE. Effects of CD-832 on isoproterenol (ISO)-induced myocardial ischemia were studied in dogs with partial DISEASE of the left circumflex coronary artery and findings were compared with those for nifedipine or CHEMICAL. In the presence of DISEASE, 3-min periods of intracoronary ISO infusion (10 ng/kg/min) increased heart rate and maximal rate of left ventricular pressure rise, which resulted in a decrease in percentage segmental shortening and ST-segment elevation of the epicardial electrocardiogram. After the control ISO infusion with stenosis was performed, equihypotensive doses of CD-832 (3 and 10 micrograms/kg/min, n = 7), nifedipine (1 and 3 micrograms/kg/min, n = 9) or CHEMICAL (10 and 30 micrograms/kg/min, n = 7) were infused 5 min before and during the second and third ISO infusion. Both CD-832 and CHEMICAL, but not nifedipine, significantly reduced the increase in heart rate induced by ISO infusion. In contrast to nifedipine, CD-832 (10 micrograms/kg/min) prevented the decrease in percentage segmental shortening from 32 +/- 12% to 115 +/- 26% of the control value (P < .01) and ST-segment elevation from 5.6 +/- 1.0 mV to 1.6 +/- 1.3 mV (P < .01) at 3 min after ISO infusion with stenosis. CHEMICAL (30 micrograms/kg/min) also prevented the decrease in percentage segmental shortening from 34 +/- 14% to 63 +/- 18% of the control value (P < .05) and ST-segment elevation from 4.7 +/- 0.7 mV to 2.1 +/- 0.7 mV (P < .01) at 3 min after ISO infusion with stenosis. These data show that CD-832 improves myocardial ischemia during ISO infusion with stenosis and suggest that the negative chronotropic property of CD-832 plays a major role in the beneficial effects of CD-832. | NO-RELATIONSHIP |
| Effects of a new calcium antagonist, CHEMICAL, on isoproterenol-induced myocardial ischemia in dogs with partial DISEASE. Effects of CHEMICAL on isoproterenol (ISO)-induced myocardial ischemia were studied in dogs with partial DISEASE of the left circumflex coronary artery and findings were compared with those for nifedipine or diltiazem. In the presence of DISEASE, 3-min periods of intracoronary ISO infusion (10 ng/kg/min) increased heart rate and maximal rate of left ventricular pressure rise, which resulted in a decrease in percentage segmental shortening and ST-segment elevation of the epicardial electrocardiogram. After the control ISO infusion with stenosis was performed, equihypotensive doses of CHEMICAL (3 and 10 micrograms/kg/min, n = 7), nifedipine (1 and 3 micrograms/kg/min, n = 9) or diltiazem (10 and 30 micrograms/kg/min, n = 7) were infused 5 min before and during the second and third ISO infusion. Both CHEMICAL and diltiazem, but not nifedipine, significantly reduced the increase in heart rate induced by ISO infusion. In contrast to nifedipine, CHEMICAL (10 micrograms/kg/min) prevented the decrease in percentage segmental shortening from 32 +/- 12% to 115 +/- 26% of the control value (P < .01) and ST-segment elevation from 5.6 +/- 1.0 mV to 1.6 +/- 1.3 mV (P < .01) at 3 min after ISO infusion with stenosis. Diltiazem (30 micrograms/kg/min) also prevented the decrease in percentage segmental shortening from 34 +/- 14% to 63 +/- 18% of the control value (P < .05) and ST-segment elevation from 4.7 +/- 0.7 mV to 2.1 +/- 0.7 mV (P < .01) at 3 min after ISO infusion with stenosis. These data show that CHEMICAL improves myocardial ischemia during ISO infusion with stenosis and suggest that the negative chronotropic property of CHEMICAL plays a major role in the beneficial effects of CHEMICAL. | NO-RELATIONSHIP |
| Effects of a new calcium antagonist, CD-832, on isoproterenol-induced myocardial ischemia in dogs with partial coronary stenosis. Effects of CD-832 on isoproterenol (ISO)-induced myocardial ischemia were studied in dogs with partial coronary stenosis of the left circumflex coronary artery and findings were compared with those for CHEMICAL or diltiazem. In the presence of coronary artery stenosis, 3-min periods of intracoronary ISO infusion (10 ng/kg/min) increased heart rate and maximal rate of left ventricular pressure rise, which resulted in a decrease in percentage segmental shortening and ST-segment elevation of the epicardial electrocardiogram. After the control ISO infusion with DISEASE was performed, equihypotensive doses of CD-832 (3 and 10 micrograms/kg/min, n = 7), CHEMICAL (1 and 3 micrograms/kg/min, n = 9) or diltiazem (10 and 30 micrograms/kg/min, n = 7) were infused 5 min before and during the second and third ISO infusion. Both CD-832 and diltiazem, but not CHEMICAL, significantly reduced the increase in heart rate induced by ISO infusion. In contrast to CHEMICAL, CD-832 (10 micrograms/kg/min) prevented the decrease in percentage segmental shortening from 32 +/- 12% to 115 +/- 26% of the control value (P < .01) and ST-segment elevation from 5.6 +/- 1.0 mV to 1.6 +/- 1.3 mV (P < .01) at 3 min after ISO infusion with DISEASE. Diltiazem (30 micrograms/kg/min) also prevented the decrease in percentage segmental shortening from 34 +/- 14% to 63 +/- 18% of the control value (P < .05) and ST-segment elevation from 4.7 +/- 0.7 mV to 2.1 +/- 0.7 mV (P < .01) at 3 min after ISO infusion with DISEASE. These data show that CD-832 improves myocardial ischemia during ISO infusion with DISEASE and suggest that the negative chronotropic property of CD-832 plays a major role in the beneficial effects of CD-832. | NO-RELATIONSHIP |
| Effects of a new CHEMICAL antagonist, CD-832, on isoproterenol-induced myocardial ischemia in dogs with partial coronary stenosis. Effects of CD-832 on isoproterenol (ISO)-induced myocardial ischemia were studied in dogs with partial coronary stenosis of the left circumflex coronary artery and findings were compared with those for nifedipine or diltiazem. In the presence of coronary artery stenosis, 3-min periods of intracoronary ISO infusion (10 ng/kg/min) increased heart rate and maximal rate of left ventricular pressure rise, which resulted in a decrease in percentage segmental shortening and ST-segment elevation of the epicardial electrocardiogram. After the control ISO infusion with DISEASE was performed, equihypotensive doses of CD-832 (3 and 10 micrograms/kg/min, n = 7), nifedipine (1 and 3 micrograms/kg/min, n = 9) or diltiazem (10 and 30 micrograms/kg/min, n = 7) were infused 5 min before and during the second and third ISO infusion. Both CD-832 and diltiazem, but not nifedipine, significantly reduced the increase in heart rate induced by ISO infusion. In contrast to nifedipine, CD-832 (10 micrograms/kg/min) prevented the decrease in percentage segmental shortening from 32 +/- 12% to 115 +/- 26% of the control value (P < .01) and ST-segment elevation from 5.6 +/- 1.0 mV to 1.6 +/- 1.3 mV (P < .01) at 3 min after ISO infusion with DISEASE. Diltiazem (30 micrograms/kg/min) also prevented the decrease in percentage segmental shortening from 34 +/- 14% to 63 +/- 18% of the control value (P < .05) and ST-segment elevation from 4.7 +/- 0.7 mV to 2.1 +/- 0.7 mV (P < .01) at 3 min after ISO infusion with DISEASE. These data show that CD-832 improves myocardial ischemia during ISO infusion with DISEASE and suggest that the negative chronotropic property of CD-832 plays a major role in the beneficial effects of CD-832. | NO-RELATIONSHIP |
| Effects of a new calcium antagonist, CD-832, on isoproterenol-induced myocardial ischemia in dogs with partial DISEASE. Effects of CD-832 on isoproterenol (ISO)-induced myocardial ischemia were studied in dogs with partial DISEASE of the left circumflex coronary artery and findings were compared with those for CHEMICAL or diltiazem. In the presence of DISEASE, 3-min periods of intracoronary ISO infusion (10 ng/kg/min) increased heart rate and maximal rate of left ventricular pressure rise, which resulted in a decrease in percentage segmental shortening and ST-segment elevation of the epicardial electrocardiogram. After the control ISO infusion with stenosis was performed, equihypotensive doses of CD-832 (3 and 10 micrograms/kg/min, n = 7), CHEMICAL (1 and 3 micrograms/kg/min, n = 9) or diltiazem (10 and 30 micrograms/kg/min, n = 7) were infused 5 min before and during the second and third ISO infusion. Both CD-832 and diltiazem, but not CHEMICAL, significantly reduced the increase in heart rate induced by ISO infusion. In contrast to CHEMICAL, CD-832 (10 micrograms/kg/min) prevented the decrease in percentage segmental shortening from 32 +/- 12% to 115 +/- 26% of the control value (P < .01) and ST-segment elevation from 5.6 +/- 1.0 mV to 1.6 +/- 1.3 mV (P < .01) at 3 min after ISO infusion with stenosis. Diltiazem (30 micrograms/kg/min) also prevented the decrease in percentage segmental shortening from 34 +/- 14% to 63 +/- 18% of the control value (P < .05) and ST-segment elevation from 4.7 +/- 0.7 mV to 2.1 +/- 0.7 mV (P < .01) at 3 min after ISO infusion with stenosis. These data show that CD-832 improves myocardial ischemia during ISO infusion with stenosis and suggest that the negative chronotropic property of CD-832 plays a major role in the beneficial effects of CD-832. | NO-RELATIONSHIP |
| The effect of recombinant human insulin-like growth factor-I on chronic CHEMICAL DISEASE in rats. We recently demonstrated that recombinant hGH exacerbates renal functional and structural injury in chronic CHEMICAL (CHEMICAL) DISEASE, an experimental model of DISEASE. Therefore, we examined whether recombinant human (rh) IGF-I is a safer alternative for the treatment of growth failure in rats with chronic CHEMICAL DISEASE. The DISEASE was induced by seven serial injections of CHEMICAL over 12 wk. Experimental animals (n = 6) received rhIGF-I, 400 micrograms/d, whereas control rats (n = 6) received the vehicle. rhIGF-I improved weight gain by 14% (p < 0.05), without altering hematocrit or blood pressure in rats with DISEASE. Urinary protein excretion was unaltered by rhIGF-I treatment in rats with chronic CHEMICAL DISEASE. After 12 wk, the inulin clearance was higher in rhIGF-I-treated rats, 0.48 +/- 0.08 versus 0.24 +/- 0.06 mL/min/100 g of body weight in untreated CHEMICAL DISEASE animals, p < 0.05. The improvement in GFR was not associated with enhanced DISEASE or increased segmental glomerulosclerosis, tubulointerstitial injury, or renal cortical malondialdehyde content. In rats with CHEMICAL DISEASE, administration of rhIGF-I increased IGF-I and GH receptor gene expression, without altering the steady state level of IGF-I receptor mRNA. In normal rats with intact kidneys, rhIGF-I administration (n = 4) did not alter weight gain, blood pressure, proteinuria, GFR, glomerular planar area, renal cortical malondialdehyde content, or glomerular or DISEASE, compared with untreated animals (n = 4). rhIGF-I treatment reduced the steady state renal IGF-I mRNA level but did not modify gene expression of the IGF-I or GH receptors. We conclude that: 1) administration of rhIGF-I improves growth and GFR in rats with chronic CHEMICAL DISEASE and 2) unlike rhGH, long-term use of rhIGF-I does not worsen renal functional and structural injury in this disease model. | CHEMICAL-INDUCED-DISEASE |
| The effect of recombinant human insulin-like growth factor-I on chronic puromycin aminonucleoside nephropathy in rats. We recently demonstrated that recombinant hGH exacerbates renal functional and structural injury in chronic puromycin aminonucleoside (PAN) nephropathy, an experimental model of glomerular disease. Therefore, we examined whether recombinant human (rh) IGF-I is a safer alternative for the treatment of growth failure in rats with chronic PAN nephropathy. The glomerulopathy was induced by seven serial injections of PAN over 12 wk. Experimental animals (n = 6) received rhIGF-I, 400 micrograms/d, whereas control rats (n = 6) received the vehicle. rhIGF-I improved weight gain by 14% (p < 0.05), without altering hematocrit or blood pressure in rats with renal disease. Urinary protein excretion was unaltered by rhIGF-I treatment in rats with chronic PAN nephropathy. After 12 wk, the inulin clearance was higher in rhIGF-I-treated rats, 0.48 +/- 0.08 versus 0.24 +/- 0.06 mL/min/100 g of body weight in untreated PAN nephropathy animals, p < 0.05. The improvement in GFR was not associated with enhanced glomerular hypertrophy or increased segmental glomerulosclerosis, DISEASE, or renal cortical CHEMICAL content. In rats with PAN nephropathy, administration of rhIGF-I increased IGF-I and GH receptor gene expression, without altering the steady state level of IGF-I receptor mRNA. In normal rats with intact kidneys, rhIGF-I administration (n = 4) did not alter weight gain, blood pressure, proteinuria, GFR, glomerular planar area, renal cortical CHEMICAL content, or glomerular or tubulointerstitial damage, compared with untreated animals (n = 4). rhIGF-I treatment reduced the steady state renal IGF-I mRNA level but did not modify gene expression of the IGF-I or GH receptors. We conclude that: 1) administration of rhIGF-I improves growth and GFR in rats with chronic PAN nephropathy and 2) unlike rhGH, long-term use of rhIGF-I does not worsen renal functional and structural injury in this disease model. | NO-RELATIONSHIP |
| The effect of recombinant human insulin-like growth factor-I on chronic puromycin aminonucleoside nephropathy in rats. We recently demonstrated that recombinant hGH exacerbates renal functional and structural injury in chronic puromycin aminonucleoside (PAN) nephropathy, an experimental model of glomerular disease. Therefore, we examined whether recombinant human (rh) IGF-I is a safer alternative for the treatment of DISEASE in rats with chronic PAN nephropathy. The glomerulopathy was induced by seven serial injections of PAN over 12 wk. Experimental animals (n = 6) received rhIGF-I, 400 micrograms/d, whereas control rats (n = 6) received the vehicle. rhIGF-I improved weight gain by 14% (p < 0.05), without altering hematocrit or blood pressure in rats with renal disease. Urinary protein excretion was unaltered by rhIGF-I treatment in rats with chronic PAN nephropathy. After 12 wk, the inulin clearance was higher in rhIGF-I-treated rats, 0.48 +/- 0.08 versus 0.24 +/- 0.06 mL/min/100 g of body weight in untreated PAN nephropathy animals, p < 0.05. The improvement in GFR was not associated with enhanced glomerular hypertrophy or increased segmental glomerulosclerosis, tubulointerstitial injury, or renal cortical CHEMICAL content. In rats with PAN nephropathy, administration of rhIGF-I increased IGF-I and GH receptor gene expression, without altering the steady state level of IGF-I receptor mRNA. In normal rats with intact kidneys, rhIGF-I administration (n = 4) did not alter weight gain, blood pressure, proteinuria, GFR, glomerular planar area, renal cortical CHEMICAL content, or glomerular or tubulointerstitial damage, compared with untreated animals (n = 4). rhIGF-I treatment reduced the steady state renal IGF-I mRNA level but did not modify gene expression of the IGF-I or GH receptors. We conclude that: 1) administration of rhIGF-I improves growth and GFR in rats with chronic PAN nephropathy and 2) unlike rhGH, long-term use of rhIGF-I does not worsen renal functional and structural injury in this disease model. | NO-RELATIONSHIP |
| The effect of recombinant human insulin-like growth factor-I on chronic puromycin aminonucleoside nephropathy in rats. We recently demonstrated that recombinant hGH exacerbates renal functional and structural injury in chronic puromycin aminonucleoside (PAN) nephropathy, an experimental model of glomerular disease. Therefore, we examined whether recombinant human (rh) IGF-I is a safer alternative for the treatment of growth failure in rats with chronic PAN nephropathy. The glomerulopathy was induced by seven serial injections of PAN over 12 wk. Experimental animals (n = 6) received rhIGF-I, 400 micrograms/d, whereas control rats (n = 6) received the vehicle. rhIGF-I improved weight gain by 14% (p < 0.05), without altering hematocrit or blood pressure in rats with renal disease. Urinary protein excretion was unaltered by rhIGF-I treatment in rats with chronic PAN nephropathy. After 12 wk, the inulin clearance was higher in rhIGF-I-treated rats, 0.48 +/- 0.08 versus 0.24 +/- 0.06 mL/min/100 g of body weight in untreated PAN nephropathy animals, p < 0.05. The improvement in GFR was not associated with enhanced glomerular hypertrophy or increased segmental glomerulosclerosis, tubulointerstitial injury, or renal cortical CHEMICAL content. In rats with PAN nephropathy, administration of rhIGF-I increased IGF-I and GH receptor gene expression, without altering the steady state level of IGF-I receptor mRNA. In normal rats with intact kidneys, rhIGF-I administration (n = 4) did not alter weight gain, blood pressure, DISEASE, GFR, glomerular planar area, renal cortical CHEMICAL content, or glomerular or tubulointerstitial damage, compared with untreated animals (n = 4). rhIGF-I treatment reduced the steady state renal IGF-I mRNA level but did not modify gene expression of the IGF-I or GH receptors. We conclude that: 1) administration of rhIGF-I improves growth and GFR in rats with chronic PAN nephropathy and 2) unlike rhGH, long-term use of rhIGF-I does not worsen renal functional and structural injury in this disease model. | NO-RELATIONSHIP |
| The effect of recombinant human insulin-like growth factor-I on chronic puromycin aminonucleoside nephropathy in rats. We recently demonstrated that recombinant hGH exacerbates renal functional and structural injury in chronic puromycin aminonucleoside (PAN) nephropathy, an experimental model of glomerular disease. Therefore, we examined whether recombinant human (rh) IGF-I is a safer alternative for the treatment of growth failure in rats with chronic PAN nephropathy. The glomerulopathy was induced by seven serial injections of PAN over 12 wk. Experimental animals (n = 6) received rhIGF-I, 400 micrograms/d, whereas control rats (n = 6) received the vehicle. rhIGF-I improved weight gain by 14% (p < 0.05), without altering hematocrit or blood pressure in rats with renal disease. Urinary protein excretion was unaltered by rhIGF-I treatment in rats with chronic PAN nephropathy. After 12 wk, the inulin clearance was higher in rhIGF-I-treated rats, 0.48 +/- 0.08 versus 0.24 +/- 0.06 mL/min/100 g of body weight in untreated PAN nephropathy animals, p < 0.05. The improvement in GFR was not associated with enhanced glomerular hypertrophy or increased segmental DISEASE, tubulointerstitial injury, or renal cortical CHEMICAL content. In rats with PAN nephropathy, administration of rhIGF-I increased IGF-I and GH receptor gene expression, without altering the steady state level of IGF-I receptor mRNA. In normal rats with intact kidneys, rhIGF-I administration (n = 4) did not alter weight gain, blood pressure, proteinuria, GFR, glomerular planar area, renal cortical CHEMICAL content, or glomerular or tubulointerstitial damage, compared with untreated animals (n = 4). rhIGF-I treatment reduced the steady state renal IGF-I mRNA level but did not modify gene expression of the IGF-I or GH receptors. We conclude that: 1) administration of rhIGF-I improves growth and GFR in rats with chronic PAN nephropathy and 2) unlike rhGH, long-term use of rhIGF-I does not worsen renal functional and structural injury in this disease model. | NO-RELATIONSHIP |
| Nefiracetam (DM-9384) reverses apomorphine-induced amnesia of a passive avoidance response: delayed emergence of the memory retention effects. Nefiracetam is a novel pyrrolidone derivative which attenuates CHEMICAL-induced DISEASE. Given that apomorphine inhibits passive avoidance retention when given during training or in a defined 10-12h post-training period, we evaluated the ability of nefiracetam to attenuate amnesia induced by dopaminergic agonism. A step-down passive avoidance paradigm was employed and nefiracetam (3 mg/kg) and apomorphine (0.5 mg/kg) were given alone or in combination during training and at the 10-12h post-training period of consolidation. Co-administration of nefiracetam and apomorphine during training or 10h thereafter produced no significant anti-amnesic effect. However, administration of nefiracetam during training completely reversed the amnesia induced by apomorphine at the 10h post-training time and the converse was also true. These effects were not mediated by a dopaminergic mechanism as nefiracetam, at millimolar concentrations, failed to displace either [3H]SCH 23390 or [3H]spiperone binding from D1 or D2 dopamine receptor subtypes, respectively. It is suggested that nefiracetam augments molecular processes in the early stages of events which ultimately lead to consolidation of memory. | CHEMICAL-INDUCED-DISEASE |
| Nefiracetam (DM-9384) reverses CHEMICAL-induced DISEASE of a passive avoidance response: delayed emergence of the memory retention effects. Nefiracetam is a novel pyrrolidone derivative which attenuates scopolamine-induced learning and post-training consolidation deficits. Given that CHEMICAL inhibits passive avoidance retention when given during training or in a defined 10-12h post-training period, we evaluated the ability of nefiracetam to attenuate DISEASE induced by dopaminergic agonism. A step-down passive avoidance paradigm was employed and nefiracetam (3 mg/kg) and CHEMICAL (0.5 mg/kg) were given alone or in combination during training and at the 10-12h post-training period of consolidation. Co-administration of nefiracetam and CHEMICAL during training or 10h thereafter produced no significant anti-amnesic effect. However, administration of nefiracetam during training completely reversed the DISEASE induced by CHEMICAL at the 10h post-training time and the converse was also true. These effects were not mediated by a dopaminergic mechanism as nefiracetam, at millimolar concentrations, failed to displace either [3H]SCH 23390 or [3H]spiperone binding from D1 or D2 dopamine receptor subtypes, respectively. It is suggested that nefiracetam augments molecular processes in the early stages of events which ultimately lead to consolidation of memory. | CHEMICAL-INDUCED-DISEASE |
| Human corticotropin-releasing hormone and thyrotropin-releasing hormone modulate the DISEASE ventilatory response in humans. Human corticotropin-releasing hormone (hCRH) and thyrotropin-releasing hormone (TRH) are known to stimulate ventilation after i.v. administration in humans. In a placebo-controlled, single-blind study we aimed to clarify if both peptides act by altering central chemosensitivity. Two subsequent CHEMICAL-rebreathing tests were performed in healthy young volunteers. During the first test 0.9% NaCl was given i.v.; during the second test 200 micrograms of hCRH (n = 12) or 400 micrograms of TRH (n = 6) was administered i.v. Nine subjects received 0.9% NaCl i.v. during both rebreathing manoeuvres. The CHEMICAL-response curves for the two tests were compared within the same subject. In the hCRH group a marked parallel shift of the CHEMICAL-response curve to the left was observed after hCRH (P < 0.01). The same effect occurred following TRH but was less striking (P = 0.05). hCRH and TRH caused a reduction in the CHEMICAL threshold. The CHEMICAL-response curves in the control group were nearly identical. The results indicate an additive effect of both releasing hormones on the DISEASE ventilatory response in humans, presumably independent of central chemosensitivity. | NO-RELATIONSHIP |
| Lamivudine is effective in suppressing DISEASE virus DNA in Chinese CHEMICAL carriers: a placebo-controlled trial. Lamivudine is a novel 2',3'-dideoxy cytosine analogue that has potent inhibitory effects on DISEASE virus replication in vitro and in vivo. We performed a single-blind, placebo-controlled study to assess its effectiveness and safety in Chinese CHEMICAL (CHEMICAL) carriers. Forty-two Chinese CHEMICAL carriers were randomized to receive placebo (6 patients) or lamivudine orally in dosages of 25 mg, 100 mg, or 300 mg daily (12 patients for each dosage). The drug was given for 4 weeks. The patients were closely monitored clinically, biochemically, and serologically up to 4 weeks after drug treatment. All 36 patients receiving lamivudine had a decrease in DISEASE virus (HBV) DNA values of >90% (P < .001 compared with placebo). Although 25 mg of lamivudine was slightly less effective than 100 mg (P = .011) and 300 mg (P = .005), it still induced 94% suppression of HBV DNA after the fourth week of therapy. HBV DNA values returned to pretreatment levels within 4 weeks of cessation of therapy. There was no change in the DISEASE e antigen status or in aminotransferase levels. No serious adverse events were observed. In conclusion, a 4-week course of lamivudine was safe and effective in suppression of HBV DNA in Chinese CHEMICAL carriers. The suppression was >90% but reversible. Studies with long-term lamivudine administration should be performed to determine if prolonged suppression of HBV DNA can be achieved. | CHEMICAL-INDUCED-DISEASE |
| Population-based study of risk of DISEASE associated with various CHEMICAL. BACKGROUND: Four studies published since December, 1995, reported that the incidence of DISEASE (DISEASE) was higher in women who used CHEMICAL (CHEMICAL) containing the third-generation progestagens gestodene or desogestrel than in users of CHEMICAL containing second-generation progestagens. However, confounding and bias in the design of these studies may have affected the findings. The aim of our study was to re-examine the association between risk of DISEASE and CHEMICAL use with a different study design and analysis to avoid some of the bias and confounding of the earlier studies. METHODS: We used computer records of patients from 143 general practices in the UK. The study was based on the medical records of about 540,000 women born between 1941 and 1981. All women who had a recorded diagnosis of deep-vein thrombosis, venous thrombosis not otherwise specified, or pulmonary embolus during the study period, and who had been treated with an anticoagulant were identified as potential cases of DISEASE. We did a cohort analysis to estimate and compare incidence of DISEASE in users of the main CHEMICAL preparations, and a nested case-control study to calculate the odds ratios of DISEASE associated with use of different types of CHEMICAL, after adjustment for potential confounding factors. In the case-control study, we matched cases to controls by exact year of birth, practice, and current use of CHEMICAL. We used a multiple logistic regression model that included body-mass index, number of cycles, change in type of CHEMICAL prescribed within 3 months of the event, previous pregnancy, and concurrent disease. FINDINGS: 85 women met the inclusion criteria for DISEASE, two of whom were users of progestagen-only CHEMICAL. Of the 83 cases of DISEASE associated with use of combined CHEMICAL, 43 were recorded as deep-vein thrombosis, 35 as pulmonary thrombosis, and five as venous thrombosis not otherwise specified. The crude rate of DISEASE per 10,000 woman-years was 4.10 in current users of any CHEMICAL, 3.10 in users of second-generation CHEMICAL, and 4.96 in users of third-generation preparations. After adjustment for age, the rate ratio of DISEASE in users of third-generation relative to second-generation CHEMICAL was 1.68 (95% CI 1.04-2.75). Logistic regression showed no significant difference in the risk of DISEASE between users of third-generation and second-generation CHEMICAL. Among users of third-generation progestagens, the risk of DISEASE was higher in users of desogestrel with 20 g ethinyloestradiol than in users of gestodene or desogestrel with 30 g ethinyloestradiol. With all second-generation CHEMICAL as the reference, the odds ratios for DISEASE were 3.49 (1.21-10.12) for desogestrel plus 20 g ethinyloestradiol and 1.18 (0.66-2.17) for the other third-generation progestagens. INTERPRETATION: The previously reported increase in odds ratio associated with third-generation CHEMICAL when compared with second-generation products is likely to have been the result of residual confounding by age. The increased odds ratio associated with products containing 20 micrograms ethinyloestradiol and desogestrel compared with the 30 micrograms product is biologically implausible, and is likely to be the result of preferential prescribing and, thus, confounding. | CHEMICAL-INDUCED-DISEASE |
| Population-based study of risk of venous thromboembolism associated with various oral contraceptives. BACKGROUND: Four studies published since December, 1995, reported that the incidence of venous thromboembolism (VTE) was higher in women who used oral contraceptives (OCs) containing the third-generation progestagens CHEMICAL or desogestrel than in users of OCs containing second-generation progestagens. However, confounding and bias in the design of these studies may have affected the findings. The aim of our study was to re-examine the association between risk of VTE and OC use with a different study design and analysis to avoid some of the bias and confounding of the earlier studies. METHODS: We used computer records of patients from 143 general practices in the UK. The study was based on the medical records of about 540,000 women born between 1941 and 1981. All women who had a recorded diagnosis of DISEASE, DISEASE not otherwise specified, or pulmonary embolus during the study period, and who had been treated with an anticoagulant were identified as potential cases of VTE. We did a cohort analysis to estimate and compare incidence of VTE in users of the main OC preparations, and a nested case-control study to calculate the odds ratios of VTE associated with use of different types of OC, after adjustment for potential confounding factors. In the case-control study, we matched cases to controls by exact year of birth, practice, and current use of OCs. We used a multiple logistic regression model that included body-mass index, number of cycles, change in type of OC prescribed within 3 months of the event, previous pregnancy, and concurrent disease. FINDINGS: 85 women met the inclusion criteria for VTE, two of whom were users of progestagen-only OCs. Of the 83 cases of VTE associated with use of combined OCs, 43 were recorded as DISEASE, 35 as pulmonary thrombosis, and five as DISEASE not otherwise specified. The crude rate of VTE per 10,000 woman-years was 4.10 in current users of any OC, 3.10 in users of second-generation OCs, and 4.96 in users of third-generation preparations. After adjustment for age, the rate ratio of VTE in users of third-generation relative to second-generation OCs was 1.68 (95% CI 1.04-2.75). Logistic regression showed no significant difference in the risk of VTE between users of third-generation and second-generation OCs. Among users of third-generation progestagens, the risk of VTE was higher in users of desogestrel with 20 g ethinyloestradiol than in users of CHEMICAL or desogestrel with 30 g ethinyloestradiol. With all second-generation OCs as the reference, the odds ratios for VTE were 3.49 (1.21-10.12) for desogestrel plus 20 g ethinyloestradiol and 1.18 (0.66-2.17) for the other third-generation progestagens. INTERPRETATION: The previously reported increase in odds ratio associated with third-generation OCs when compared with second-generation products is likely to have been the result of residual confounding by age. The increased odds ratio associated with products containing 20 micrograms ethinyloestradiol and desogestrel compared with the 30 micrograms product is biologically implausible, and is likely to be the result of preferential prescribing and, thus, confounding. | CHEMICAL-INDUCED-DISEASE |
| Population-based study of risk of venous thromboembolism associated with various oral contraceptives. BACKGROUND: Four studies published since December, 1995, reported that the incidence of venous thromboembolism (VTE) was higher in women who used oral contraceptives (OCs) containing the third-generation progestagens CHEMICAL or desogestrel than in users of OCs containing second-generation progestagens. However, confounding and bias in the design of these studies may have affected the findings. The aim of our study was to re-examine the association between risk of VTE and OC use with a different study design and analysis to avoid some of the bias and confounding of the earlier studies. METHODS: We used computer records of patients from 143 general practices in the UK. The study was based on the medical records of about 540,000 women born between 1941 and 1981. All women who had a recorded diagnosis of deep-vein thrombosis, venous thrombosis not otherwise specified, or pulmonary embolus during the study period, and who had been treated with an anticoagulant were identified as potential cases of VTE. We did a cohort analysis to estimate and compare incidence of VTE in users of the main OC preparations, and a nested case-control study to calculate the odds ratios of VTE associated with use of different types of OC, after adjustment for potential confounding factors. In the case-control study, we matched cases to controls by exact year of birth, practice, and current use of OCs. We used a multiple logistic regression model that included body-mass index, number of cycles, change in type of OC prescribed within 3 months of the event, previous pregnancy, and concurrent disease. FINDINGS: 85 women met the inclusion criteria for VTE, two of whom were users of progestagen-only OCs. Of the 83 cases of VTE associated with use of combined OCs, 43 were recorded as deep-vein thrombosis, 35 as pulmonary DISEASE, and five as venous thrombosis not otherwise specified. The crude rate of VTE per 10,000 woman-years was 4.10 in current users of any OC, 3.10 in users of second-generation OCs, and 4.96 in users of third-generation preparations. After adjustment for age, the rate ratio of VTE in users of third-generation relative to second-generation OCs was 1.68 (95% CI 1.04-2.75). Logistic regression showed no significant difference in the risk of VTE between users of third-generation and second-generation OCs. Among users of third-generation progestagens, the risk of VTE was higher in users of desogestrel with 20 g ethinyloestradiol than in users of CHEMICAL or desogestrel with 30 g ethinyloestradiol. With all second-generation OCs as the reference, the odds ratios for VTE were 3.49 (1.21-10.12) for desogestrel plus 20 g ethinyloestradiol and 1.18 (0.66-2.17) for the other third-generation progestagens. INTERPRETATION: The previously reported increase in odds ratio associated with third-generation OCs when compared with second-generation products is likely to have been the result of residual confounding by age. The increased odds ratio associated with products containing 20 micrograms ethinyloestradiol and desogestrel compared with the 30 micrograms product is biologically implausible, and is likely to be the result of preferential prescribing and, thus, confounding. | NO-RELATIONSHIP |
| Population-based study of risk of venous thromboembolism associated with various oral contraceptives. BACKGROUND: Four studies published since December, 1995, reported that the incidence of venous thromboembolism (VTE) was higher in women who used oral contraceptives (OCs) containing the third-generation progestagens gestodene or desogestrel than in users of OCs containing second-generation progestagens. However, confounding and bias in the design of these studies may have affected the findings. The aim of our study was to re-examine the association between risk of VTE and OC use with a different study design and analysis to avoid some of the bias and confounding of the earlier studies. METHODS: We used computer records of patients from 143 general practices in the UK. The study was based on the medical records of about 540,000 women born between 1941 and 1981. All women who had a recorded diagnosis of deep-vein thrombosis, venous thrombosis not otherwise specified, or pulmonary embolus during the study period, and who had been treated with an anticoagulant were identified as potential cases of VTE. We did a cohort analysis to estimate and compare incidence of VTE in users of the main OC preparations, and a nested case-control study to calculate the odds ratios of VTE associated with use of different types of OC, after adjustment for potential confounding factors. In the case-control study, we matched cases to controls by exact year of birth, practice, and current use of OCs. We used a multiple logistic regression model that included body-mass index, number of cycles, change in type of OC prescribed within 3 months of the event, previous pregnancy, and concurrent disease. FINDINGS: 85 women met the inclusion criteria for VTE, two of whom were users of progestagen-only OCs. Of the 83 cases of VTE associated with use of combined OCs, 43 were recorded as deep-vein thrombosis, 35 as pulmonary DISEASE, and five as venous thrombosis not otherwise specified. The crude rate of VTE per 10,000 woman-years was 4.10 in current users of any OC, 3.10 in users of second-generation OCs, and 4.96 in users of third-generation preparations. After adjustment for age, the rate ratio of VTE in users of third-generation relative to second-generation OCs was 1.68 (95% CI 1.04-2.75). Logistic regression showed no significant difference in the risk of VTE between users of third-generation and second-generation OCs. Among users of third-generation progestagens, the risk of VTE was higher in users of desogestrel with 20 g CHEMICAL than in users of gestodene or desogestrel with 30 g CHEMICAL. With all second-generation OCs as the reference, the odds ratios for VTE were 3.49 (1.21-10.12) for desogestrel plus 20 g CHEMICAL and 1.18 (0.66-2.17) for the other third-generation progestagens. INTERPRETATION: The previously reported increase in odds ratio associated with third-generation OCs when compared with second-generation products is likely to have been the result of residual confounding by age. The increased odds ratio associated with products containing 20 micrograms CHEMICAL and desogestrel compared with the 30 micrograms product is biologically implausible, and is likely to be the result of preferential prescribing and, thus, confounding. | NO-RELATIONSHIP |
| Population-based study of risk of venous thromboembolism associated with various oral contraceptives. BACKGROUND: Four studies published since December, 1995, reported that the incidence of venous thromboembolism (VTE) was higher in women who used oral contraceptives (OCs) containing the third-generation progestagens gestodene or desogestrel than in users of OCs containing second-generation progestagens. However, confounding and bias in the design of these studies may have affected the findings. The aim of our study was to re-examine the association between risk of VTE and OC use with a different study design and analysis to avoid some of the bias and confounding of the earlier studies. METHODS: We used computer records of patients from 143 general practices in the UK. The study was based on the medical records of about 540,000 women born between 1941 and 1981. All women who had a recorded diagnosis of DISEASE, DISEASE not otherwise specified, or pulmonary embolus during the study period, and who had been treated with an anticoagulant were identified as potential cases of VTE. We did a cohort analysis to estimate and compare incidence of VTE in users of the main OC preparations, and a nested case-control study to calculate the odds ratios of VTE associated with use of different types of OC, after adjustment for potential confounding factors. In the case-control study, we matched cases to controls by exact year of birth, practice, and current use of OCs. We used a multiple logistic regression model that included body-mass index, number of cycles, change in type of OC prescribed within 3 months of the event, previous pregnancy, and concurrent disease. FINDINGS: 85 women met the inclusion criteria for VTE, two of whom were users of progestagen-only OCs. Of the 83 cases of VTE associated with use of combined OCs, 43 were recorded as DISEASE, 35 as pulmonary thrombosis, and five as DISEASE not otherwise specified. The crude rate of VTE per 10,000 woman-years was 4.10 in current users of any OC, 3.10 in users of second-generation OCs, and 4.96 in users of third-generation preparations. After adjustment for age, the rate ratio of VTE in users of third-generation relative to second-generation OCs was 1.68 (95% CI 1.04-2.75). Logistic regression showed no significant difference in the risk of VTE between users of third-generation and second-generation OCs. Among users of third-generation progestagens, the risk of VTE was higher in users of desogestrel with 20 g CHEMICAL than in users of gestodene or desogestrel with 30 g CHEMICAL. With all second-generation OCs as the reference, the odds ratios for VTE were 3.49 (1.21-10.12) for desogestrel plus 20 g CHEMICAL and 1.18 (0.66-2.17) for the other third-generation progestagens. INTERPRETATION: The previously reported increase in odds ratio associated with third-generation OCs when compared with second-generation products is likely to have been the result of residual confounding by age. The increased odds ratio associated with products containing 20 micrograms CHEMICAL and desogestrel compared with the 30 micrograms product is biologically implausible, and is likely to be the result of preferential prescribing and, thus, confounding. | NO-RELATIONSHIP |
| Population-based study of risk of venous thromboembolism associated with various oral contraceptives. BACKGROUND: Four studies published since December, 1995, reported that the incidence of venous thromboembolism (VTE) was higher in women who used oral contraceptives (OCs) containing the third-generation progestagens gestodene or CHEMICAL than in users of OCs containing second-generation progestagens. However, confounding and bias in the design of these studies may have affected the findings. The aim of our study was to re-examine the association between risk of VTE and OC use with a different study design and analysis to avoid some of the bias and confounding of the earlier studies. METHODS: We used computer records of patients from 143 general practices in the UK. The study was based on the medical records of about 540,000 women born between 1941 and 1981. All women who had a recorded diagnosis of deep-vein thrombosis, venous thrombosis not otherwise specified, or pulmonary embolus during the study period, and who had been treated with an anticoagulant were identified as potential cases of VTE. We did a cohort analysis to estimate and compare incidence of VTE in users of the main OC preparations, and a nested case-control study to calculate the odds ratios of VTE associated with use of different types of OC, after adjustment for potential confounding factors. In the case-control study, we matched cases to controls by exact year of birth, practice, and current use of OCs. We used a multiple logistic regression model that included body-mass index, number of cycles, change in type of OC prescribed within 3 months of the event, previous pregnancy, and concurrent disease. FINDINGS: 85 women met the inclusion criteria for VTE, two of whom were users of progestagen-only OCs. Of the 83 cases of VTE associated with use of combined OCs, 43 were recorded as deep-vein thrombosis, 35 as pulmonary DISEASE, and five as venous thrombosis not otherwise specified. The crude rate of VTE per 10,000 woman-years was 4.10 in current users of any OC, 3.10 in users of second-generation OCs, and 4.96 in users of third-generation preparations. After adjustment for age, the rate ratio of VTE in users of third-generation relative to second-generation OCs was 1.68 (95% CI 1.04-2.75). Logistic regression showed no significant difference in the risk of VTE between users of third-generation and second-generation OCs. Among users of third-generation progestagens, the risk of VTE was higher in users of CHEMICAL with 20 g ethinyloestradiol than in users of gestodene or CHEMICAL with 30 g ethinyloestradiol. With all second-generation OCs as the reference, the odds ratios for VTE were 3.49 (1.21-10.12) for CHEMICAL plus 20 g ethinyloestradiol and 1.18 (0.66-2.17) for the other third-generation progestagens. INTERPRETATION: The previously reported increase in odds ratio associated with third-generation OCs when compared with second-generation products is likely to have been the result of residual confounding by age. The increased odds ratio associated with products containing 20 micrograms ethinyloestradiol and CHEMICAL compared with the 30 micrograms product is biologically implausible, and is likely to be the result of preferential prescribing and, thus, confounding. | NO-RELATIONSHIP |
| Population-based study of risk of venous thromboembolism associated with various oral contraceptives. BACKGROUND: Four studies published since December, 1995, reported that the incidence of venous thromboembolism (VTE) was higher in women who used oral contraceptives (OCs) containing the third-generation progestagens gestodene or desogestrel than in users of OCs containing second-generation progestagens. However, confounding and bias in the design of these studies may have affected the findings. The aim of our study was to re-examine the association between risk of VTE and OC use with a different study design and analysis to avoid some of the bias and confounding of the earlier studies. METHODS: We used computer records of patients from 143 general practices in the UK. The study was based on the medical records of about 540,000 women born between 1941 and 1981. All women who had a recorded diagnosis of DISEASE, DISEASE not otherwise specified, or pulmonary embolus during the study period, and who had been treated with an anticoagulant were identified as potential cases of VTE. We did a cohort analysis to estimate and compare incidence of VTE in users of the main OC preparations, and a nested case-control study to calculate the odds ratios of VTE associated with use of different types of OC, after adjustment for potential confounding factors. In the case-control study, we matched cases to controls by exact year of birth, practice, and current use of OCs. We used a multiple logistic regression model that included body-mass index, number of cycles, change in type of OC prescribed within 3 months of the event, previous pregnancy, and concurrent disease. FINDINGS: 85 women met the inclusion criteria for VTE, two of whom were users of CHEMICAL-only OCs. Of the 83 cases of VTE associated with use of combined OCs, 43 were recorded as DISEASE, 35 as pulmonary thrombosis, and five as DISEASE not otherwise specified. The crude rate of VTE per 10,000 woman-years was 4.10 in current users of any OC, 3.10 in users of second-generation OCs, and 4.96 in users of third-generation preparations. After adjustment for age, the rate ratio of VTE in users of third-generation relative to second-generation OCs was 1.68 (95% CI 1.04-2.75). Logistic regression showed no significant difference in the risk of VTE between users of third-generation and second-generation OCs. Among users of third-generation progestagens, the risk of VTE was higher in users of desogestrel with 20 g ethinyloestradiol than in users of gestodene or desogestrel with 30 g ethinyloestradiol. With all second-generation OCs as the reference, the odds ratios for VTE were 3.49 (1.21-10.12) for desogestrel plus 20 g ethinyloestradiol and 1.18 (0.66-2.17) for the other third-generation progestagens. INTERPRETATION: The previously reported increase in odds ratio associated with third-generation OCs when compared with second-generation products is likely to have been the result of residual confounding by age. The increased odds ratio associated with products containing 20 micrograms ethinyloestradiol and desogestrel compared with the 30 micrograms product is biologically implausible, and is likely to be the result of preferential prescribing and, thus, confounding. | CHEMICAL-INDUCED-DISEASE |
| Population-based study of risk of venous thromboembolism associated with various oral contraceptives. BACKGROUND: Four studies published since December, 1995, reported that the incidence of venous thromboembolism (VTE) was higher in women who used oral contraceptives (OCs) containing the third-generation CHEMICAL gestodene or desogestrel than in users of OCs containing second-generation CHEMICAL. However, confounding and bias in the design of these studies may have affected the findings. The aim of our study was to re-examine the association between risk of VTE and OC use with a different study design and analysis to avoid some of the bias and confounding of the earlier studies. METHODS: We used computer records of patients from 143 general practices in the UK. The study was based on the medical records of about 540,000 women born between 1941 and 1981. All women who had a recorded diagnosis of deep-vein thrombosis, venous thrombosis not otherwise specified, or pulmonary embolus during the study period, and who had been treated with an anticoagulant were identified as potential cases of VTE. We did a cohort analysis to estimate and compare incidence of VTE in users of the main OC preparations, and a nested case-control study to calculate the odds ratios of VTE associated with use of different types of OC, after adjustment for potential confounding factors. In the case-control study, we matched cases to controls by exact year of birth, practice, and current use of OCs. We used a multiple logistic regression model that included body-mass index, number of cycles, change in type of OC prescribed within 3 months of the event, previous pregnancy, and concurrent disease. FINDINGS: 85 women met the inclusion criteria for VTE, two of whom were users of progestagen-only OCs. Of the 83 cases of VTE associated with use of combined OCs, 43 were recorded as deep-vein thrombosis, 35 as pulmonary DISEASE, and five as venous thrombosis not otherwise specified. The crude rate of VTE per 10,000 woman-years was 4.10 in current users of any OC, 3.10 in users of second-generation OCs, and 4.96 in users of third-generation preparations. After adjustment for age, the rate ratio of VTE in users of third-generation relative to second-generation OCs was 1.68 (95% CI 1.04-2.75). Logistic regression showed no significant difference in the risk of VTE between users of third-generation and second-generation OCs. Among users of third-generation CHEMICAL, the risk of VTE was higher in users of desogestrel with 20 g ethinyloestradiol than in users of gestodene or desogestrel with 30 g ethinyloestradiol. With all second-generation OCs as the reference, the odds ratios for VTE were 3.49 (1.21-10.12) for desogestrel plus 20 g ethinyloestradiol and 1.18 (0.66-2.17) for the other third-generation CHEMICAL. INTERPRETATION: The previously reported increase in odds ratio associated with third-generation OCs when compared with second-generation products is likely to have been the result of residual confounding by age. The increased odds ratio associated with products containing 20 micrograms ethinyloestradiol and desogestrel compared with the 30 micrograms product is biologically implausible, and is likely to be the result of preferential prescribing and, thus, confounding. | CHEMICAL-INDUCED-DISEASE |
| Population-based study of risk of venous thromboembolism associated with various oral contraceptives. BACKGROUND: Four studies published since December, 1995, reported that the incidence of venous thromboembolism (VTE) was higher in women who used oral contraceptives (OCs) containing the third-generation progestagens gestodene or desogestrel than in users of OCs containing second-generation progestagens. However, confounding and bias in the design of these studies may have affected the findings. The aim of our study was to re-examine the association between risk of VTE and OC use with a different study design and analysis to avoid some of the bias and confounding of the earlier studies. METHODS: We used computer records of patients from 143 general practices in the UK. The study was based on the medical records of about 540,000 women born between 1941 and 1981. All women who had a recorded diagnosis of deep-vein thrombosis, venous thrombosis not otherwise specified, or pulmonary embolus during the study period, and who had been treated with an anticoagulant were identified as potential cases of VTE. We did a cohort analysis to estimate and compare incidence of VTE in users of the main OC preparations, and a nested case-control study to calculate the odds ratios of VTE associated with use of different types of OC, after adjustment for potential confounding factors. In the case-control study, we matched cases to controls by exact year of birth, practice, and current use of OCs. We used a multiple logistic regression model that included body-mass index, number of cycles, change in type of OC prescribed within 3 months of the event, previous pregnancy, and concurrent disease. FINDINGS: 85 women met the inclusion criteria for VTE, two of whom were users of CHEMICAL-only OCs. Of the 83 cases of VTE associated with use of combined OCs, 43 were recorded as deep-vein thrombosis, 35 as pulmonary DISEASE, and five as venous thrombosis not otherwise specified. The crude rate of VTE per 10,000 woman-years was 4.10 in current users of any OC, 3.10 in users of second-generation OCs, and 4.96 in users of third-generation preparations. After adjustment for age, the rate ratio of VTE in users of third-generation relative to second-generation OCs was 1.68 (95% CI 1.04-2.75). Logistic regression showed no significant difference in the risk of VTE between users of third-generation and second-generation OCs. Among users of third-generation progestagens, the risk of VTE was higher in users of desogestrel with 20 g ethinyloestradiol than in users of gestodene or desogestrel with 30 g ethinyloestradiol. With all second-generation OCs as the reference, the odds ratios for VTE were 3.49 (1.21-10.12) for desogestrel plus 20 g ethinyloestradiol and 1.18 (0.66-2.17) for the other third-generation progestagens. INTERPRETATION: The previously reported increase in odds ratio associated with third-generation OCs when compared with second-generation products is likely to have been the result of residual confounding by age. The increased odds ratio associated with products containing 20 micrograms ethinyloestradiol and desogestrel compared with the 30 micrograms product is biologically implausible, and is likely to be the result of preferential prescribing and, thus, confounding. | CHEMICAL-INDUCED-DISEASE |
| Population-based study of risk of venous thromboembolism associated with various oral contraceptives. BACKGROUND: Four studies published since December, 1995, reported that the incidence of venous thromboembolism (VTE) was higher in women who used oral contraceptives (OCs) containing the third-generation progestagens gestodene or CHEMICAL than in users of OCs containing second-generation progestagens. However, confounding and bias in the design of these studies may have affected the findings. The aim of our study was to re-examine the association between risk of VTE and OC use with a different study design and analysis to avoid some of the bias and confounding of the earlier studies. METHODS: We used computer records of patients from 143 general practices in the UK. The study was based on the medical records of about 540,000 women born between 1941 and 1981. All women who had a recorded diagnosis of DISEASE, DISEASE not otherwise specified, or pulmonary embolus during the study period, and who had been treated with an anticoagulant were identified as potential cases of VTE. We did a cohort analysis to estimate and compare incidence of VTE in users of the main OC preparations, and a nested case-control study to calculate the odds ratios of VTE associated with use of different types of OC, after adjustment for potential confounding factors. In the case-control study, we matched cases to controls by exact year of birth, practice, and current use of OCs. We used a multiple logistic regression model that included body-mass index, number of cycles, change in type of OC prescribed within 3 months of the event, previous pregnancy, and concurrent disease. FINDINGS: 85 women met the inclusion criteria for VTE, two of whom were users of progestagen-only OCs. Of the 83 cases of VTE associated with use of combined OCs, 43 were recorded as DISEASE, 35 as pulmonary thrombosis, and five as DISEASE not otherwise specified. The crude rate of VTE per 10,000 woman-years was 4.10 in current users of any OC, 3.10 in users of second-generation OCs, and 4.96 in users of third-generation preparations. After adjustment for age, the rate ratio of VTE in users of third-generation relative to second-generation OCs was 1.68 (95% CI 1.04-2.75). Logistic regression showed no significant difference in the risk of VTE between users of third-generation and second-generation OCs. Among users of third-generation progestagens, the risk of VTE was higher in users of CHEMICAL with 20 g ethinyloestradiol than in users of gestodene or CHEMICAL with 30 g ethinyloestradiol. With all second-generation OCs as the reference, the odds ratios for VTE were 3.49 (1.21-10.12) for CHEMICAL plus 20 g ethinyloestradiol and 1.18 (0.66-2.17) for the other third-generation progestagens. INTERPRETATION: The previously reported increase in odds ratio associated with third-generation OCs when compared with second-generation products is likely to have been the result of residual confounding by age. The increased odds ratio associated with products containing 20 micrograms ethinyloestradiol and CHEMICAL compared with the 30 micrograms product is biologically implausible, and is likely to be the result of preferential prescribing and, thus, confounding. | CHEMICAL-INDUCED-DISEASE |
| Population-based study of risk of venous thromboembolism associated with various oral contraceptives. BACKGROUND: Four studies published since December, 1995, reported that the incidence of venous thromboembolism (VTE) was higher in women who used oral contraceptives (OCs) containing the third-generation CHEMICAL gestodene or desogestrel than in users of OCs containing second-generation CHEMICAL. However, confounding and bias in the design of these studies may have affected the findings. The aim of our study was to re-examine the association between risk of VTE and OC use with a different study design and analysis to avoid some of the bias and confounding of the earlier studies. METHODS: We used computer records of patients from 143 general practices in the UK. The study was based on the medical records of about 540,000 women born between 1941 and 1981. All women who had a recorded diagnosis of DISEASE, DISEASE not otherwise specified, or pulmonary embolus during the study period, and who had been treated with an anticoagulant were identified as potential cases of VTE. We did a cohort analysis to estimate and compare incidence of VTE in users of the main OC preparations, and a nested case-control study to calculate the odds ratios of VTE associated with use of different types of OC, after adjustment for potential confounding factors. In the case-control study, we matched cases to controls by exact year of birth, practice, and current use of OCs. We used a multiple logistic regression model that included body-mass index, number of cycles, change in type of OC prescribed within 3 months of the event, previous pregnancy, and concurrent disease. FINDINGS: 85 women met the inclusion criteria for VTE, two of whom were users of progestagen-only OCs. Of the 83 cases of VTE associated with use of combined OCs, 43 were recorded as DISEASE, 35 as pulmonary thrombosis, and five as DISEASE not otherwise specified. The crude rate of VTE per 10,000 woman-years was 4.10 in current users of any OC, 3.10 in users of second-generation OCs, and 4.96 in users of third-generation preparations. After adjustment for age, the rate ratio of VTE in users of third-generation relative to second-generation OCs was 1.68 (95% CI 1.04-2.75). Logistic regression showed no significant difference in the risk of VTE between users of third-generation and second-generation OCs. Among users of third-generation CHEMICAL, the risk of VTE was higher in users of desogestrel with 20 g ethinyloestradiol than in users of gestodene or desogestrel with 30 g ethinyloestradiol. With all second-generation OCs as the reference, the odds ratios for VTE were 3.49 (1.21-10.12) for desogestrel plus 20 g ethinyloestradiol and 1.18 (0.66-2.17) for the other third-generation CHEMICAL. INTERPRETATION: The previously reported increase in odds ratio associated with third-generation OCs when compared with second-generation products is likely to have been the result of residual confounding by age. The increased odds ratio associated with products containing 20 micrograms ethinyloestradiol and desogestrel compared with the 30 micrograms product is biologically implausible, and is likely to be the result of preferential prescribing and, thus, confounding. | CHEMICAL-INDUCED-DISEASE |
| MK-801 augments CHEMICAL-induced electrographic seizure but protects against brain damage in rats. 1. The authors examined the anticonvulsant effects of MK-801 on the CHEMICAL-induced seizure model. Intraperitoneal injection of CHEMICAL (400 mg/kg) induced tonic and clonic seizure. Scopolamine (10 mg/kg) and pentobarbital (5 mg/kg) prevented development of CHEMICAL-induced behavioral seizure but MK-801 (0.5 mg/kg) did not. 2. An electrical seizure measured with hippocampal EEG appeared in the CHEMICAL-treated group. Scopolamine and pentobarbital blocked the CHEMICAL-induced electrographic seizure, MK-801 treatment augmented the electrographic seizure induced by CHEMICAL. 3. Brain damage was assessed by examining the hippocampus microscopically. CHEMICAL produced DISEASE in the hippocampus, which showed pyknotic changes. Pentobarbital, scopolamine and MK-801 protected the brain damage by CHEMICAL, though in the MK-801-treated group, the pyramidal cells of hippocampus appeared darker than normal. In all treatments, granule cells of the dentate gyrus were not affected. 4. These results indicate that status epilepticus induced by CHEMICAL is initiated by cholinergic overstimulation and propagated by glutamatergic transmission, the elevation of which may cause brain damage through an excitatory NMDA receptor-mediated mechanism. | CHEMICAL-INDUCED-DISEASE |
| MK-801 augments CHEMICAL-induced electrographic seizure but protects against brain damage in rats. 1. The authors examined the anticonvulsant effects of MK-801 on the CHEMICAL-induced seizure model. Intraperitoneal injection of CHEMICAL (400 mg/kg) induced tonic and clonic seizure. Scopolamine (10 mg/kg) and pentobarbital (5 mg/kg) prevented development of CHEMICAL-induced behavioral seizure but MK-801 (0.5 mg/kg) did not. 2. An electrical seizure measured with hippocampal EEG appeared in the CHEMICAL-treated group. Scopolamine and pentobarbital blocked the CHEMICAL-induced electrographic seizure, MK-801 treatment augmented the electrographic seizure induced by CHEMICAL. 3. Brain damage was assessed by examining the hippocampus microscopically. CHEMICAL produced neuronal death in the hippocampus, which showed pyknotic changes. Pentobarbital, scopolamine and MK-801 protected the brain damage by CHEMICAL, though in the MK-801-treated group, the pyramidal cells of hippocampus appeared darker than normal. In all treatments, granule cells of the dentate gyrus were not affected. 4. These results indicate that DISEASE induced by CHEMICAL is initiated by cholinergic overstimulation and propagated by glutamatergic transmission, the elevation of which may cause brain damage through an excitatory NMDA receptor-mediated mechanism. | CHEMICAL-INDUCED-DISEASE |
| MK-801 augments CHEMICAL-induced electrographic DISEASE but protects against brain damage in rats. 1. The authors examined the anticonvulsant effects of MK-801 on the CHEMICAL-induced DISEASE model. Intraperitoneal injection of CHEMICAL (400 mg/kg) induced DISEASE. Scopolamine (10 mg/kg) and pentobarbital (5 mg/kg) prevented development of CHEMICAL-induced behavioral DISEASE but MK-801 (0.5 mg/kg) did not. 2. An electrical DISEASE measured with hippocampal EEG appeared in the CHEMICAL-treated group. Scopolamine and pentobarbital blocked the CHEMICAL-induced electrographic DISEASE, MK-801 treatment augmented the electrographic DISEASE induced by CHEMICAL. 3. Brain damage was assessed by examining the hippocampus microscopically. CHEMICAL produced neuronal death in the hippocampus, which showed pyknotic changes. Pentobarbital, scopolamine and MK-801 protected the brain damage by CHEMICAL, though in the MK-801-treated group, the pyramidal cells of hippocampus appeared darker than normal. In all treatments, granule cells of the dentate gyrus were not affected. 4. These results indicate that status epilepticus induced by CHEMICAL is initiated by cholinergic overstimulation and propagated by glutamatergic transmission, the elevation of which may cause brain damage through an excitatory NMDA receptor-mediated mechanism. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL augments pilocarpine-induced electrographic DISEASE but protects against brain damage in rats. 1. The authors examined the anticonvulsant effects of CHEMICAL on the pilocarpine-induced DISEASE model. Intraperitoneal injection of pilocarpine (400 mg/kg) induced DISEASE. Scopolamine (10 mg/kg) and pentobarbital (5 mg/kg) prevented development of pilocarpine-induced behavioral DISEASE but CHEMICAL (0.5 mg/kg) did not. 2. An electrical DISEASE measured with hippocampal EEG appeared in the pilocarpine-treated group. Scopolamine and pentobarbital blocked the pilocarpine-induced electrographic DISEASE, CHEMICAL treatment augmented the electrographic DISEASE induced by pilocarpine. 3. Brain damage was assessed by examining the hippocampus microscopically. Pilocarpine produced neuronal death in the hippocampus, which showed pyknotic changes. Pentobarbital, scopolamine and CHEMICAL protected the brain damage by pilocarpine, though in the CHEMICAL-treated group, the pyramidal cells of hippocampus appeared darker than normal. In all treatments, granule cells of the dentate gyrus were not affected. 4. These results indicate that status epilepticus induced by pilocarpine is initiated by cholinergic overstimulation and propagated by glutamatergic transmission, the elevation of which may cause brain damage through an excitatory NMDA receptor-mediated mechanism. | NO-RELATIONSHIP |
| MK-801 augments pilocarpine-induced electrographic seizure but protects against DISEASE in rats. 1. The authors examined the anticonvulsant effects of MK-801 on the pilocarpine-induced seizure model. Intraperitoneal injection of pilocarpine (400 mg/kg) induced tonic and clonic seizure. CHEMICAL (10 mg/kg) and pentobarbital (5 mg/kg) prevented development of pilocarpine-induced behavioral seizure but MK-801 (0.5 mg/kg) did not. 2. An electrical seizure measured with hippocampal EEG appeared in the pilocarpine-treated group. CHEMICAL and pentobarbital blocked the pilocarpine-induced electrographic seizure, MK-801 treatment augmented the electrographic seizure induced by pilocarpine. 3. DISEASE was assessed by examining the hippocampus microscopically. Pilocarpine produced neuronal death in the hippocampus, which showed pyknotic changes. Pentobarbital, CHEMICAL and MK-801 protected the DISEASE by pilocarpine, though in the MK-801-treated group, the pyramidal cells of hippocampus appeared darker than normal. In all treatments, granule cells of the dentate gyrus were not affected. 4. These results indicate that status epilepticus induced by pilocarpine is initiated by cholinergic overstimulation and propagated by glutamatergic transmission, the elevation of which may cause DISEASE through an excitatory NMDA receptor-mediated mechanism. | NO-RELATIONSHIP |
| MK-801 augments pilocarpine-induced electrographic seizure but protects against DISEASE in rats. 1. The authors examined the anticonvulsant effects of MK-801 on the pilocarpine-induced seizure model. Intraperitoneal injection of pilocarpine (400 mg/kg) induced tonic and clonic seizure. Scopolamine (10 mg/kg) and CHEMICAL (5 mg/kg) prevented development of pilocarpine-induced behavioral seizure but MK-801 (0.5 mg/kg) did not. 2. An electrical seizure measured with hippocampal EEG appeared in the pilocarpine-treated group. Scopolamine and CHEMICAL blocked the pilocarpine-induced electrographic seizure, MK-801 treatment augmented the electrographic seizure induced by pilocarpine. 3. DISEASE was assessed by examining the hippocampus microscopically. Pilocarpine produced neuronal death in the hippocampus, which showed pyknotic changes. CHEMICAL, scopolamine and MK-801 protected the DISEASE by pilocarpine, though in the MK-801-treated group, the pyramidal cells of hippocampus appeared darker than normal. In all treatments, granule cells of the dentate gyrus were not affected. 4. These results indicate that status epilepticus induced by pilocarpine is initiated by cholinergic overstimulation and propagated by glutamatergic transmission, the elevation of which may cause DISEASE through an excitatory NMDA receptor-mediated mechanism. | NO-RELATIONSHIP |
| MK-801 augments pilocarpine-induced electrographic seizure but protects against DISEASE in rats. 1. The authors examined the anticonvulsant effects of MK-801 on the pilocarpine-induced seizure model. Intraperitoneal injection of pilocarpine (400 mg/kg) induced tonic and clonic seizure. Scopolamine (10 mg/kg) and pentobarbital (5 mg/kg) prevented development of pilocarpine-induced behavioral seizure but MK-801 (0.5 mg/kg) did not. 2. An electrical seizure measured with hippocampal EEG appeared in the pilocarpine-treated group. Scopolamine and pentobarbital blocked the pilocarpine-induced electrographic seizure, MK-801 treatment augmented the electrographic seizure induced by pilocarpine. 3. DISEASE was assessed by examining the hippocampus microscopically. Pilocarpine produced neuronal death in the hippocampus, which showed pyknotic changes. Pentobarbital, scopolamine and MK-801 protected the DISEASE by pilocarpine, though in the MK-801-treated group, the pyramidal cells of hippocampus appeared darker than normal. In all treatments, granule cells of the dentate gyrus were not affected. 4. These results indicate that status epilepticus induced by pilocarpine is initiated by cholinergic overstimulation and propagated by glutamatergic transmission, the elevation of which may cause DISEASE through an excitatory CHEMICAL receptor-mediated mechanism. | NO-RELATIONSHIP |
| Paclitaxel, 5-fluorouracil, and CHEMICAL in metastatic breast cancer: BRE-26, a phase II trial. 5-Fluorouracil plus CHEMICAL and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) are effective salvage therapies for metastatic breast cancer patients. Paclitaxel and 5-fluorouracil have additive cytotoxicity in MCF-7 cell lines. We performed a phase II trial of paclitaxel 175 mg/m2 over 3 hours on day I followed by CHEMICAL 300 mg over 1 hour before 5-fluorouracil 350 mg/m2 on days 1 to 3 every 28 days (TFL) in women with metastatic breast cancer. Analysis is reported on 37 patients with a minimum of 6 months follow-up who received a total of 192 cycles of TFL: nine cycles (5%) were associated with grade 3/4 DISEASE requiring hospitalization; seven (4%) cycles in two patients required granulocyte colony-stimulating factor due to DISEASE; no patient required platelet transfusions. Grade 3/4 nonhematologic toxicities were uncommon. Among the 34 patients evaluable for response, there were three complete responses (9%) and 18 partial responses (53%) for an overall response rate of 62%. Of the 19 evaluable patients with prior doxorubicin exposure, 11 (58%) responded compared with nine of 15 (60%) without prior doxorubicin. Plasma paclitaxel concentrations were measured at the completion of paclitaxel infusion and at 24 hours in 19 patients. TFL is an active, well-tolerated regimen in metastatic breast cancer. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL, 5-fluorouracil, and folinic acid in metastatic breast cancer: BRE-26, a phase II trial. 5-Fluorouracil plus folinic acid and CHEMICAL (CHEMICAL; Bristol-Myers Squibb Company, Princeton, NJ) are effective salvage therapies for metastatic breast cancer patients. CHEMICAL and 5-fluorouracil have additive cytotoxicity in MCF-7 cell lines. We performed a phase II trial of CHEMICAL 175 mg/m2 over 3 hours on day I followed by folinic acid 300 mg over 1 hour before 5-fluorouracil 350 mg/m2 on days 1 to 3 every 28 days (TFL) in women with metastatic breast cancer. Analysis is reported on 37 patients with a minimum of 6 months follow-up who received a total of 192 cycles of TFL: nine cycles (5%) were associated with grade 3/4 DISEASE requiring hospitalization; seven (4%) cycles in two patients required granulocyte colony-stimulating factor due to DISEASE; no patient required platelet transfusions. Grade 3/4 nonhematologic toxicities were uncommon. Among the 34 patients evaluable for response, there were three complete responses (9%) and 18 partial responses (53%) for an overall response rate of 62%. Of the 19 evaluable patients with prior doxorubicin exposure, 11 (58%) responded compared with nine of 15 (60%) without prior doxorubicin. Plasma CHEMICAL concentrations were measured at the completion of CHEMICAL infusion and at 24 hours in 19 patients. TFL is an active, well-tolerated regimen in metastatic breast cancer. | CHEMICAL-INDUCED-DISEASE |
| Paclitaxel, CHEMICAL, and folinic acid in metastatic breast cancer: BRE-26, a phase II trial. CHEMICAL plus folinic acid and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) are effective salvage therapies for metastatic breast cancer patients. Paclitaxel and CHEMICAL have additive cytotoxicity in MCF-7 cell lines. We performed a phase II trial of paclitaxel 175 mg/m2 over 3 hours on day I followed by folinic acid 300 mg over 1 hour before CHEMICAL 350 mg/m2 on days 1 to 3 every 28 days (TFL) in women with metastatic breast cancer. Analysis is reported on 37 patients with a minimum of 6 months follow-up who received a total of 192 cycles of TFL: nine cycles (5%) were associated with grade 3/4 DISEASE requiring hospitalization; seven (4%) cycles in two patients required granulocyte colony-stimulating factor due to DISEASE; no patient required platelet transfusions. Grade 3/4 nonhematologic toxicities were uncommon. Among the 34 patients evaluable for response, there were three complete responses (9%) and 18 partial responses (53%) for an overall response rate of 62%. Of the 19 evaluable patients with prior doxorubicin exposure, 11 (58%) responded compared with nine of 15 (60%) without prior doxorubicin. Plasma paclitaxel concentrations were measured at the completion of paclitaxel infusion and at 24 hours in 19 patients. TFL is an active, well-tolerated regimen in metastatic breast cancer. | CHEMICAL-INDUCED-DISEASE |
| Paclitaxel, 5-fluorouracil, and folinic acid in metastatic DISEASE: BRE-26, a phase II trial. 5-Fluorouracil plus folinic acid and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) are effective salvage therapies for metastatic DISEASE patients. Paclitaxel and 5-fluorouracil have additive cytotoxicity in MCF-7 cell lines. We performed a phase II trial of paclitaxel 175 mg/m2 over 3 hours on day I followed by folinic acid 300 mg over 1 hour before 5-fluorouracil 350 mg/m2 on days 1 to 3 every 28 days (TFL) in women with metastatic DISEASE. Analysis is reported on 37 patients with a minimum of 6 months follow-up who received a total of 192 cycles of TFL: nine cycles (5%) were associated with grade 3/4 neutropenia requiring hospitalization; seven (4%) cycles in two patients required granulocyte colony-stimulating factor due to neutropenia; no patient required platelet transfusions. Grade 3/4 nonhematologic toxicities were uncommon. Among the 34 patients evaluable for response, there were three complete responses (9%) and 18 partial responses (53%) for an overall response rate of 62%. Of the 19 evaluable patients with prior CHEMICAL exposure, 11 (58%) responded compared with nine of 15 (60%) without prior CHEMICAL. Plasma paclitaxel concentrations were measured at the completion of paclitaxel infusion and at 24 hours in 19 patients. TFL is an active, well-tolerated regimen in metastatic DISEASE. | NO-RELATIONSHIP |
| Paclitaxel, 5-fluorouracil, and folinic acid in metastatic breast cancer: BRE-26, a phase II trial. 5-Fluorouracil plus folinic acid and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) are effective salvage therapies for metastatic breast cancer patients. Paclitaxel and 5-fluorouracil have additive DISEASE in MCF-7 cell lines. We performed a phase II trial of paclitaxel 175 mg/m2 over 3 hours on day I followed by folinic acid 300 mg over 1 hour before 5-fluorouracil 350 mg/m2 on days 1 to 3 every 28 days (TFL) in women with metastatic breast cancer. Analysis is reported on 37 patients with a minimum of 6 months follow-up who received a total of 192 cycles of TFL: nine cycles (5%) were associated with grade 3/4 neutropenia requiring hospitalization; seven (4%) cycles in two patients required CHEMICAL due to neutropenia; no patient required platelet transfusions. Grade 3/4 nonhematologic DISEASE were uncommon. Among the 34 patients evaluable for response, there were three complete responses (9%) and 18 partial responses (53%) for an overall response rate of 62%. Of the 19 evaluable patients with prior doxorubicin exposure, 11 (58%) responded compared with nine of 15 (60%) without prior doxorubicin. Plasma paclitaxel concentrations were measured at the completion of paclitaxel infusion and at 24 hours in 19 patients. TFL is an active, well-tolerated regimen in metastatic breast cancer. | NO-RELATIONSHIP |
| Paclitaxel, 5-fluorouracil, and folinic acid in metastatic breast cancer: BRE-26, a phase II trial. 5-Fluorouracil plus folinic acid and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) are effective salvage therapies for metastatic breast cancer patients. Paclitaxel and 5-fluorouracil have additive DISEASE in MCF-7 cell lines. We performed a phase II trial of paclitaxel 175 mg/m2 over 3 hours on day I followed by folinic acid 300 mg over 1 hour before 5-fluorouracil 350 mg/m2 on days 1 to 3 every 28 days (TFL) in women with metastatic breast cancer. Analysis is reported on 37 patients with a minimum of 6 months follow-up who received a total of 192 cycles of TFL: nine cycles (5%) were associated with grade 3/4 neutropenia requiring hospitalization; seven (4%) cycles in two patients required granulocyte colony-stimulating factor due to neutropenia; no patient required platelet transfusions. Grade 3/4 nonhematologic DISEASE were uncommon. Among the 34 patients evaluable for response, there were three complete responses (9%) and 18 partial responses (53%) for an overall response rate of 62%. Of the 19 evaluable patients with prior CHEMICAL exposure, 11 (58%) responded compared with nine of 15 (60%) without prior CHEMICAL. Plasma paclitaxel concentrations were measured at the completion of paclitaxel infusion and at 24 hours in 19 patients. TFL is an active, well-tolerated regimen in metastatic breast cancer. | NO-RELATIONSHIP |
| Paclitaxel, 5-fluorouracil, and folinic acid in metastatic DISEASE: BRE-26, a phase II trial. 5-Fluorouracil plus folinic acid and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) are effective salvage therapies for metastatic DISEASE patients. Paclitaxel and 5-fluorouracil have additive cytotoxicity in MCF-7 cell lines. We performed a phase II trial of paclitaxel 175 mg/m2 over 3 hours on day I followed by folinic acid 300 mg over 1 hour before 5-fluorouracil 350 mg/m2 on days 1 to 3 every 28 days (TFL) in women with metastatic DISEASE. Analysis is reported on 37 patients with a minimum of 6 months follow-up who received a total of 192 cycles of TFL: nine cycles (5%) were associated with grade 3/4 neutropenia requiring hospitalization; seven (4%) cycles in two patients required CHEMICAL due to neutropenia; no patient required platelet transfusions. Grade 3/4 nonhematologic toxicities were uncommon. Among the 34 patients evaluable for response, there were three complete responses (9%) and 18 partial responses (53%) for an overall response rate of 62%. Of the 19 evaluable patients with prior doxorubicin exposure, 11 (58%) responded compared with nine of 15 (60%) without prior doxorubicin. Plasma paclitaxel concentrations were measured at the completion of paclitaxel infusion and at 24 hours in 19 patients. TFL is an active, well-tolerated regimen in metastatic DISEASE. | NO-RELATIONSHIP |
| Efficacy and proarrhythmia with the use of CHEMICAL for sustained ventricular tachyarrhythmias. This study prospectively evaluated the clinical efficacy, the incidence of DISEASE, and the presumable risk factors for DISEASE in patients treated with CHEMICAL for sustained ventricular tachyarrhythmias. Eighty-one consecutive patients (54 with coronary artery disease, and 20 with dilated cardiomyopathy) with inducible sustained ventricular tachycardia or ventricular fibrillation received oral CHEMICAL to prevent induction of the ventricular tachyarrhythmia. During oral loading with CHEMICAL, continuous electrocardiographic (ECG) monitoring was performed. Those patients in whom CHEMICAL prevented induction of ventricular tachycardia or ventricular fibrillation were discharged with the drug and followed up on an outpatient basis for 21 +/- 18 months. Induction of the ventricular tachyarrhythmia was prevented by oral CHEMICAL in 35 (43%) patients; the ventricular tachyarrhythmia remained inducible in 40 (49%) patients; and two (2.5%) patients did not tolerate even 40 mg of CHEMICAL once daily. Four (5%) patients had from DISEASE during the initial oral treatment with CHEMICAL. Neither ECG [sinus-cycle length (SCL), QT or QTc interval, or U wave] nor clinical parameters identified patients at risk for DISEASE. However, the oral dose of CHEMICAL was significantly lower in patients with DISEASE (200 +/- 46 vs. 328 +/- 53 mg/day; p = 0.0017). Risk factors associated with the development of DISEASE were the appearance of an U wave (p = 0.049), female gender (p = 0.015), and significant dose-corrected changes of SCL, QT interval, and QTc interval (p < 0.05). During follow-up, seven (20%) patients had a nonfatal ventricular tachycardia recurrence, and two (6%) patients died suddenly. One female patient with stable cardiac disease had recurrent DISEASE after 2 years of successful treatment with CHEMICAL. DISEASE occurred early during treatment even with low doses of oral CHEMICAL. Pronounced changes in the surface ECG (cycle length, QT, and QTc) in relation to the dose of oral CHEMICAL might identify a subgroup of patients with an increased risk for DISEASE. Other ECG parameters before the application of CHEMICAL did not identify patients at increased risk for DISEASE. Recurrence rates of ventricular tachyarrhythmias are high despite complete suppression of the arrhythmia during programmed stimulation. Therefore programmed electrical stimulation in the case of CHEMICAL seems to be of limited prognostic value. | CHEMICAL-INDUCED-DISEASE |
| Chronic DISEASE and changes in dopamine neurons. The tuberoinfundibular dopaminergic (TIDA) system is known to inhibit prolactin (PRL) secretion. In young animals this system responds to acute elevations in serum PRL by increasing its activity. However, this responsiveness is lost in aging rats with chronically high serum PRL levels. The purpose of this study was to induce DISEASE in rats for extended periods of time and examine its effects on dopaminergic systems in the brain. DISEASE was induced by treatment with CHEMICAL, a dopamine receptor antagonist, and Palkovits' microdissection technique in combination with high-performance liquid chromatography was used to measure neurotransmitter concentrations in several areas of the brain. After 6 months of DISEASE, dopamine (DA) concentrations in the median eminence (ME) increased by 84% over the control group. Nine months of DISEASE produced a 50% increase in DA concentrations in the ME over the control group. However, DA response was lost if a 9-month long CHEMICAL-induced DISEASE was followed by a 1 1/2 month-long extremely high increase in serum PRL levels produced by implantation of MMQ cells under the kidney capsule. There was no change in the levels of DA, norepinephrine (NE), serotonin (5-HT), or their metabolites in the arcuate nucleus (AN), medial preoptic area (MPA), caudate putamen (CP), substantia nigra (SN), and zona incerta (ZI), except for a decrease in 5-hydroxyindoleacetic acid (5-HIAA) in the AN after 6-months of DISEASE and an increase in DA concentrations in the AN after 9-months of DISEASE. These results demonstrate that DISEASE specifically affects TIDA neurons and these effects vary, depending on the duration and intensity of DISEASE. The age-related decrease in hypothalamic dopamine function may be associated with increases in PRL secretion. | CHEMICAL-INDUCED-DISEASE |
| Treatment-related disseminated necrotizing leukoencephalopathy with characteristic contrast enhancement of the white matter. This report describes unique contrast enhancement of the white matter on T1-weighted magnetic resonance images of two patients with disseminated necrotizing leukoencephalopathy, which developed from acute lymphoblastic leukemia treated with high-dose CHEMICAL. In both patients, the enhancement was more pronounced near the base of the brain than at the vertex. Necropsy of the first case revealed DISEASE and necrosis of the white matter. Possible mechanisms causing such a leukoencephalopathy are discussed. | CHEMICAL-INDUCED-DISEASE |
| Treatment-related disseminated necrotizing DISEASE with characteristic contrast enhancement of the white matter. This report describes unique contrast enhancement of the white matter on T1-weighted magnetic resonance images of two patients with disseminated necrotizing DISEASE, which developed from acute lymphoblastic leukemia treated with high-dose CHEMICAL. In both patients, the enhancement was more pronounced near the base of the brain than at the vertex. Necropsy of the first case revealed loss of myelination and necrosis of the white matter. Possible mechanisms causing such a DISEASE are discussed. | CHEMICAL-INDUCED-DISEASE |
| Treatment-related disseminated necrotizing leukoencephalopathy with characteristic contrast enhancement of the white matter. This report describes unique contrast enhancement of the white matter on T1-weighted magnetic resonance images of two patients with disseminated necrotizing leukoencephalopathy, which developed from acute lymphoblastic leukemia treated with high-dose CHEMICAL. In both patients, the enhancement was more pronounced near the base of the brain than at the vertex. Necropsy of the first case revealed loss of myelination and DISEASE of the white matter. Possible mechanisms causing such a leukoencephalopathy are discussed. | CHEMICAL-INDUCED-DISEASE |
| DISEASE complications in acute promyelocytic leukemia during CHEMICAL therapy. A case of acute renal failure, due to occlusion of renal vessels in a patient with acute promyelocytic leukemia (APL) treated with CHEMICAL (CHEMICAL) and tranexamic acid has been described recently. We report a case of acute renal failure in an APL patient treated with CHEMICAL alone. This case further supports the concern about thromboembolic complications associated with CHEMICAL therapy in APL patients. The patients, a 43-year-old man, presented all the signs and symptoms of APL and was included in a treatment protocol with CHEMICAL. After 10 days of treatment, he developed acute renal failure that was completely reversible after complete remission of APL was achieved and therapy discontinued. We conclude that CHEMICAL is a valid therapeutic choice for patients with APL, although the procoagulant tendency is not completely corrected. DISEASE events, however, could be avoided by using low-dose heparin. | CHEMICAL-INDUCED-DISEASE |
| Thrombotic complications in acute promyelocytic leukemia during CHEMICAL therapy. A case of DISEASE, due to occlusion of renal vessels in a patient with acute promyelocytic leukemia (APL) treated with CHEMICAL (CHEMICAL) and tranexamic acid has been described recently. We report a case of DISEASE in an APL patient treated with CHEMICAL alone. This case further supports the concern about thromboembolic complications associated with CHEMICAL therapy in APL patients. The patients, a 43-year-old man, presented all the signs and symptoms of APL and was included in a treatment protocol with CHEMICAL. After 10 days of treatment, he developed DISEASE that was completely reversible after complete remission of APL was achieved and therapy discontinued. We conclude that CHEMICAL is a valid therapeutic choice for patients with APL, although the procoagulant tendency is not completely corrected. Thrombotic events, however, could be avoided by using low-dose heparin. | CHEMICAL-INDUCED-DISEASE |
| Thrombotic complications in DISEASE during all-trans-retinoic acid therapy. A case of acute renal failure, due to occlusion of renal vessels in a patient with DISEASE (DISEASE) treated with all-trans-retinoic acid (ATRA) and CHEMICAL has been described recently. We report a case of acute renal failure in an DISEASE patient treated with ATRA alone. This case further supports the concern about thromboembolic complications associated with ATRA therapy in DISEASE patients. The patients, a 43-year-old man, presented all the signs and symptoms of DISEASE and was included in a treatment protocol with ATRA. After 10 days of treatment, he developed acute renal failure that was completely reversible after complete remission of DISEASE was achieved and therapy discontinued. We conclude that ATRA is a valid therapeutic choice for patients with DISEASE, although the procoagulant tendency is not completely corrected. Thrombotic events, however, could be avoided by using low-dose heparin. | NO-RELATIONSHIP |
| Thrombotic complications in DISEASE during all-trans-retinoic acid therapy. A case of acute renal failure, due to occlusion of renal vessels in a patient with DISEASE (DISEASE) treated with all-trans-retinoic acid (ATRA) and tranexamic acid has been described recently. We report a case of acute renal failure in an DISEASE patient treated with ATRA alone. This case further supports the concern about thromboembolic complications associated with ATRA therapy in DISEASE patients. The patients, a 43-year-old man, presented all the signs and symptoms of DISEASE and was included in a treatment protocol with ATRA. After 10 days of treatment, he developed acute renal failure that was completely reversible after complete remission of DISEASE was achieved and therapy discontinued. We conclude that ATRA is a valid therapeutic choice for patients with DISEASE, although the procoagulant tendency is not completely corrected. Thrombotic events, however, could be avoided by using low-dose CHEMICAL. | NO-RELATIONSHIP |
| Thrombotic complications in acute promyelocytic leukemia during all-trans-retinoic acid therapy. A case of acute renal failure, due to occlusion of renal vessels in a patient with acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and tranexamic acid has been described recently. We report a case of acute renal failure in an APL patient treated with ATRA alone. This case further supports the concern about DISEASE complications associated with ATRA therapy in APL patients. The patients, a 43-year-old man, presented all the signs and symptoms of APL and was included in a treatment protocol with ATRA. After 10 days of treatment, he developed acute renal failure that was completely reversible after complete remission of APL was achieved and therapy discontinued. We conclude that ATRA is a valid therapeutic choice for patients with APL, although the procoagulant tendency is not completely corrected. Thrombotic events, however, could be avoided by using low-dose CHEMICAL. | NO-RELATIONSHIP |
| Thrombotic complications in acute promyelocytic leukemia during all-trans-retinoic acid therapy. A case of acute renal failure, due to DISEASE in a patient with acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and tranexamic acid has been described recently. We report a case of acute renal failure in an APL patient treated with ATRA alone. This case further supports the concern about thromboembolic complications associated with ATRA therapy in APL patients. The patients, a 43-year-old man, presented all the signs and symptoms of APL and was included in a treatment protocol with ATRA. After 10 days of treatment, he developed acute renal failure that was completely reversible after complete remission of APL was achieved and therapy discontinued. We conclude that ATRA is a valid therapeutic choice for patients with APL, although the procoagulant tendency is not completely corrected. Thrombotic events, however, could be avoided by using low-dose CHEMICAL. | NO-RELATIONSHIP |
| Thrombotic complications in acute promyelocytic leukemia during all-trans-retinoic acid therapy. A case of acute renal failure, due to DISEASE in a patient with acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and CHEMICAL has been described recently. We report a case of acute renal failure in an APL patient treated with ATRA alone. This case further supports the concern about thromboembolic complications associated with ATRA therapy in APL patients. The patients, a 43-year-old man, presented all the signs and symptoms of APL and was included in a treatment protocol with ATRA. After 10 days of treatment, he developed acute renal failure that was completely reversible after complete remission of APL was achieved and therapy discontinued. We conclude that ATRA is a valid therapeutic choice for patients with APL, although the procoagulant tendency is not completely corrected. Thrombotic events, however, could be avoided by using low-dose heparin. | NO-RELATIONSHIP |
| Thrombotic complications in acute promyelocytic leukemia during all-trans-retinoic acid therapy. A case of acute renal failure, due to occlusion of renal vessels in a patient with acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and CHEMICAL has been described recently. We report a case of acute renal failure in an APL patient treated with ATRA alone. This case further supports the concern about DISEASE complications associated with ATRA therapy in APL patients. The patients, a 43-year-old man, presented all the signs and symptoms of APL and was included in a treatment protocol with ATRA. After 10 days of treatment, he developed acute renal failure that was completely reversible after complete remission of APL was achieved and therapy discontinued. We conclude that ATRA is a valid therapeutic choice for patients with APL, although the procoagulant tendency is not completely corrected. Thrombotic events, however, could be avoided by using low-dose heparin. | NO-RELATIONSHIP |
| Pupillary changes associated with the development of stimulant-induced DISEASE: a case report. A 30-year-old cocaine-dependent man who was a subject in a study evaluating the anticraving efficacy of the stimulant medication CHEMICAL (CHEMICAL) became DISEASE during his second week on the study drug. Pupillometric changes while on CHEMICAL, especially changes in the total power of pupillary oscillation, were dramatically different than those observed in the eight other study subjects who did not become DISEASE. The large changes in total power of pupillary oscillation occurred a few days before the patient became fully DISEASE. Such medication-associated changes in the total power of pupillary oscillation might be of utility in identifying persons at risk for DISEASE-like adverse effects during the medical use of psychomotor stimulants or sympathomimetic agents. | CHEMICAL-INDUCED-DISEASE |
| Pupillary changes associated with the development of stimulant-induced mania: a case report. A 30-year-old CHEMICAL-dependent man who was a subject in a study evaluating the anticraving efficacy of the stimulant medication diethylpropion (DEP) became manic during his second week on the study drug. Pupillometric changes while on DEP, especially changes in the total power of DISEASE, were dramatically different than those observed in the eight other study subjects who did not become manic. The large changes in total power of DISEASE occurred a few days before the patient became fully manic. Such medication-associated changes in the total power of DISEASE might be of utility in identifying persons at risk for manic-like adverse effects during the medical use of psychomotor stimulants or sympathomimetic agents. | NO-RELATIONSHIP |
| The negative mucosal potential: separating central and peripheral effects of NSAIDs in man. OBJECTIVE: We wanted to test whether assessment of both a central DISEASE-related signal (chemo-somatosensory evoked potential, CSSEP) and a concomitantly recorded peripheral signal (negative mucosal potential, NMP) allows for separation of central and peripheral effects of NSAIDs. For this purpose, experimental conditions were created in which NSAIDs had previously been observed to produce effects on phasic and tonic DISEASE by either central or peripheral mechanisms. METHODS: According to a double-blind, randomised, controlled, threefold cross-over design, 18 healthy subjects (11 males, 7 females; mean age 26 years) received either placebo, 400 mg CHEMICAL, or 800 mg CHEMICAL. Phasic DISEASE was applied by means of short pulses of CO2 to the nasal mucosa (stimulus duration 500 ms, interval approximately 60 s), and tonic DISEASE was induced in the nasal cavity by means of dry air of controlled temperature, humidity and flow rate (22 degrees C, 0% relative humidity, 145 ml.s-1). Both CSSEPs as central and NMPs as peripheral correlates of DISEASE were obtained in response to the CO2 stimuli. Additionally, the subjects rated the intensity of both phasic and tonic DISEASE by means of visual analogue scales. RESULTS: As described earlier, administration of CHEMICAL was followed by a decrease in tonic DISEASE but-relative to placebo-an increase in correlates of phasic DISEASE, indicating a specific effect of CHEMICAL on the interaction between the DISEASE stimuli under these special experimental conditions. Based on the similar behaviour of CSSEP and NMP, it was concluded that the pharmacological process underlying this phenomenon was localised in the periphery. By means of the simultaneous recording of interrelated peripheral and central electrophysiologic correlates of nociception, it was possible to separate central and peripheral effects of an NSAID. The major advantage of this DISEASE model is the possibility of obtaining peripheral DISEASE-related activity directly using a non-invasive technique in humans. | CHEMICAL-INDUCED-DISEASE |
| Acute severe depression following peri-operative CHEMICAL. A 41-year-old woman with a strong history of postoperative nausea and vomiting presented for abdominal hysterectomy 3 months after a previous anaesthetic where CHEMICAL prophylaxis had been used. She had developed a severe acute DISEASE almost immediately thereafter, possibly related to the use of a serotonin antagonist. Nine years before she had experienced a self-limited puerperal depressive episode. Anaesthesia with a propofol infusion and avoidance of serotonin antagonists provided a nausea-free postoperative course without exacerbation of the depression disorder. | CHEMICAL-INDUCED-DISEASE |
| Acute severe depression following peri-operative ondansetron. A 41-year-old woman with a strong history of DISEASE presented for abdominal hysterectomy 3 months after a previous anaesthetic where ondansetron prophylaxis had been used. She had developed a severe acute major depression disorder almost immediately thereafter, possibly related to the use of a CHEMICAL antagonist. Nine years before she had experienced a self-limited puerperal depressive episode. Anaesthesia with a propofol infusion and avoidance of CHEMICAL antagonists provided a nausea-free postoperative course without exacerbation of the depression disorder. | NO-RELATIONSHIP |
| Acute severe depression following peri-operative ondansetron. A 41-year-old woman with a strong history of DISEASE presented for abdominal hysterectomy 3 months after a previous anaesthetic where ondansetron prophylaxis had been used. She had developed a severe acute major depression disorder almost immediately thereafter, possibly related to the use of a serotonin antagonist. Nine years before she had experienced a self-limited puerperal depressive episode. Anaesthesia with a CHEMICAL infusion and avoidance of serotonin antagonists provided a nausea-free postoperative course without exacerbation of the depression disorder. | NO-RELATIONSHIP |
| Acute severe depression following peri-operative ondansetron. A 41-year-old woman with a strong history of postoperative nausea and vomiting presented for abdominal hysterectomy 3 months after a previous anaesthetic where ondansetron prophylaxis had been used. She had developed a severe acute major depression disorder almost immediately thereafter, possibly related to the use of a serotonin antagonist. Nine years before she had experienced a self-limited puerperal depressive episode. Anaesthesia with a CHEMICAL infusion and avoidance of serotonin antagonists provided a DISEASE-free postoperative course without exacerbation of the depression disorder. | NO-RELATIONSHIP |
| Acute severe DISEASE following peri-operative ondansetron. A 41-year-old woman with a strong history of postoperative nausea and vomiting presented for abdominal hysterectomy 3 months after a previous anaesthetic where ondansetron prophylaxis had been used. She had developed a severe acute major depression disorder almost immediately thereafter, possibly related to the use of a CHEMICAL antagonist. Nine years before she had experienced a self-limited puerperal DISEASE. Anaesthesia with a propofol infusion and avoidance of CHEMICAL antagonists provided a nausea-free postoperative course without exacerbation of the DISEASE. | NO-RELATIONSHIP |
| Acute severe DISEASE following peri-operative ondansetron. A 41-year-old woman with a strong history of postoperative nausea and vomiting presented for abdominal hysterectomy 3 months after a previous anaesthetic where ondansetron prophylaxis had been used. She had developed a severe acute major depression disorder almost immediately thereafter, possibly related to the use of a serotonin antagonist. Nine years before she had experienced a self-limited puerperal DISEASE. Anaesthesia with a CHEMICAL infusion and avoidance of serotonin antagonists provided a nausea-free postoperative course without exacerbation of the DISEASE. | NO-RELATIONSHIP |
| Acute severe depression following peri-operative ondansetron. A 41-year-old woman with a strong history of postoperative nausea and vomiting presented for abdominal hysterectomy 3 months after a previous anaesthetic where ondansetron prophylaxis had been used. She had developed a severe acute major depression disorder almost immediately thereafter, possibly related to the use of a CHEMICAL antagonist. Nine years before she had experienced a self-limited puerperal depressive episode. Anaesthesia with a propofol infusion and avoidance of CHEMICAL antagonists provided a DISEASE-free postoperative course without exacerbation of the depression disorder. | NO-RELATIONSHIP |
| DISEASE response during CHEMICAL stress echocardiography. Among 3,129 CHEMICAL stress echocardiographic studies, a DISEASE response, defined as systolic blood pressure (BP) > or = 220 mm Hg and/or diastolic BP > or = 110 mm Hg, occurred in 30 patients (1%). Patients with this response more often had a history of DISEASE and had higher resting systolic and diastolic BP before CHEMICAL infusion. | CHEMICAL-INDUCED-DISEASE |
| Continuously nebulized CHEMICAL in severe exacerbations of asthma in adults: a case-controlled study. A retrospective, case-controlled analysis comparing patients admitted to a medical intensive care unit with severe exacerbations of asthma who received continuously nebulized CHEMICAL (CNA) versus intermittent CHEMICAL (INA) treatments is reported. Forty matched pairs of patients with asthma are compared. CNA was administered for a mean of 11 +/- 10 hr. The incidence of DISEASE was similar between groups. Symptomatic hypokalemia did not occur. CNA patients had higher heart rates during treatment, which may reflect severity of illness. The incidence of intubation was similar. We conclude that CNA and INA demonstrated similar profiles with regard to safety, morbidity, and mortality. | CHEMICAL-INDUCED-DISEASE |
| Hyperosmolar nonketotic coma precipitated by CHEMICAL-induced nephrogenic diabetes insipidus. A 45-year-old man, with a 10-year history of manic depression treated with CHEMICAL, was admitted with hyperosmolar, nonketotic coma. He gave a five-year history of DISEASE and polydipsia, during which time urinalysis had been negative for glucose. After recovery from hyperglycaemia, he remained DISEASE despite normal blood glucose concentrations; water deprivation testing indicated nephrogenic diabetes insipidus, likely to be CHEMICAL-induced. We hypothesize that when this man developed type 2 diabetes, chronic DISEASE due to nephrogenic diabetes insipidus was sufficient to precipitate hyperosmolar dehydration. | CHEMICAL-INDUCED-DISEASE |
| Hyperosmolar nonketotic coma precipitated by CHEMICAL-induced DISEASE. A 45-year-old man, with a 10-year history of manic depression treated with CHEMICAL, was admitted with hyperosmolar, nonketotic coma. He gave a five-year history of polyuria and polydipsia, during which time urinalysis had been negative for glucose. After recovery from hyperglycaemia, he remained polyuric despite normal blood glucose concentrations; water deprivation testing indicated DISEASE, likely to be CHEMICAL-induced. We hypothesize that when this man developed type 2 diabetes, chronic polyuria due to DISEASE was sufficient to precipitate hyperosmolar dehydration. | CHEMICAL-INDUCED-DISEASE |
| DISEASE precipitated by CHEMICAL-induced nephrogenic diabetes insipidus. A 45-year-old man, with a 10-year history of manic depression treated with CHEMICAL, was admitted with DISEASE. He gave a five-year history of polyuria and polydipsia, during which time urinalysis had been negative for glucose. After recovery from hyperglycaemia, he remained polyuric despite normal blood glucose concentrations; water deprivation testing indicated nephrogenic diabetes insipidus, likely to be CHEMICAL-induced. We hypothesize that when this man developed type 2 diabetes, chronic polyuria due to nephrogenic diabetes insipidus was sufficient to precipitate hyperosmolar dehydration. | CHEMICAL-INDUCED-DISEASE |
| Hyperosmolar nonketotic coma precipitated by lithium-induced nephrogenic diabetes insipidus. A 45-year-old man, with a 10-year history of manic depression treated with lithium, was admitted with hyperosmolar, nonketotic coma. He gave a five-year history of polyuria and DISEASE, during which time urinalysis had been negative for CHEMICAL. After recovery from hyperglycaemia, he remained polyuric despite normal blood CHEMICAL concentrations; water deprivation testing indicated nephrogenic diabetes insipidus, likely to be lithium-induced. We hypothesize that when this man developed type 2 diabetes, chronic polyuria due to nephrogenic diabetes insipidus was sufficient to precipitate hyperosmolar dehydration. | NO-RELATIONSHIP |
| Hyperosmolar nonketotic coma precipitated by lithium-induced nephrogenic diabetes insipidus. A 45-year-old man, with a 10-year history of manic depression treated with lithium, was admitted with hyperosmolar, nonketotic coma. He gave a five-year history of polyuria and polydipsia, during which time urinalysis had been negative for CHEMICAL. After recovery from DISEASE, he remained polyuric despite normal blood CHEMICAL concentrations; water deprivation testing indicated nephrogenic diabetes insipidus, likely to be lithium-induced. We hypothesize that when this man developed type 2 diabetes, chronic polyuria due to nephrogenic diabetes insipidus was sufficient to precipitate hyperosmolar dehydration. | NO-RELATIONSHIP |
| Hyperosmolar nonketotic coma precipitated by lithium-induced nephrogenic diabetes insipidus. A 45-year-old man, with a 10-year history of manic depression treated with lithium, was admitted with hyperosmolar, nonketotic coma. He gave a five-year history of polyuria and polydipsia, during which time urinalysis had been negative for CHEMICAL. After recovery from hyperglycaemia, he remained polyuric despite normal blood CHEMICAL concentrations; water deprivation testing indicated nephrogenic diabetes insipidus, likely to be lithium-induced. We hypothesize that when this man developed type 2 diabetes, chronic polyuria due to nephrogenic diabetes insipidus was sufficient to precipitate hyperosmolar DISEASE. | NO-RELATIONSHIP |
| Hyperosmolar nonketotic coma precipitated by lithium-induced nephrogenic diabetes insipidus. A 45-year-old man, with a 10-year history of DISEASE treated with lithium, was admitted with hyperosmolar, nonketotic coma. He gave a five-year history of polyuria and polydipsia, during which time urinalysis had been negative for CHEMICAL. After recovery from hyperglycaemia, he remained polyuric despite normal blood CHEMICAL concentrations; water deprivation testing indicated nephrogenic diabetes insipidus, likely to be lithium-induced. We hypothesize that when this man developed type 2 diabetes, chronic polyuria due to nephrogenic diabetes insipidus was sufficient to precipitate hyperosmolar dehydration. | NO-RELATIONSHIP |
| Hyperosmolar nonketotic coma precipitated by lithium-induced nephrogenic diabetes insipidus. A 45-year-old man, with a 10-year history of manic depression treated with lithium, was admitted with hyperosmolar, nonketotic coma. He gave a five-year history of polyuria and polydipsia, during which time urinalysis had been negative for CHEMICAL. After recovery from hyperglycaemia, he remained polyuric despite normal blood CHEMICAL concentrations; water deprivation testing indicated nephrogenic diabetes insipidus, likely to be lithium-induced. We hypothesize that when this man developed DISEASE, chronic polyuria due to nephrogenic diabetes insipidus was sufficient to precipitate hyperosmolar dehydration. | NO-RELATIONSHIP |
| Effects of the intracoronary infusion of CHEMICAL on left ventricular systolic and diastolic function in humans. BACKGROUND: In dogs, a large amount of intravenous CHEMICAL causes a profound DISEASE and an increase in LV end-diastolic pressure. This study was done to assess the influence of a high intracoronary CHEMICAL concentration on LV systolic and diastolic function in humans. METHODS AND RESULTS: In 20 patients (14 men and 6 women aged 39 to 72 years) referred for cardiac catheterization for the evaluation of chest pain, we measured heart rate, systemic arterial pressure, LV pressure and its first derivative (dP/dt), and LV volumes and ejection fraction before and during the final 2 to 3 minutes of a 15-minute intracoronary infusion of saline (n=10, control subjects) or CHEMICAL 1 mg/min (n=10). No variable changed with saline. With CHEMICAL, the drug concentration in blood obtained from the coronary sinus was 3.0+/-0.4 (mean+/-SD) mg/L, similar in magnitude to the blood CHEMICAL concentration reported in abusers dying of CHEMICAL intoxication. CHEMICAL induced no significant change in heart rate, LV dP/dt (positive or negative), or LV end-diastolic volume, but it caused an increase in systolic and mean arterial pressures, LV end-diastolic pressure, and LV end-systolic volume, as well as a decrease in LV ejection fraction. CONCLUSIONS: In humans, the intracoronary infusion of CHEMICAL sufficient in amount to achieve a high drug concentration in coronary sinus blood causes a DISEASE. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced thrombocytopenia, paradoxical thromboembolism, and other side effects of CHEMICAL therapy. Although several new anticoagulant drugs are in development, CHEMICAL remains the drug of choice for most anticoagulation needs. The clinical effects of CHEMICAL are meritorious, but side effects do exist. Important untoward effects of CHEMICAL therapy including CHEMICAL-induced thrombocytopenia, CHEMICAL-associated osteoporosis, eosinophilia, skin reactions, allergic reactions other than thrombocytopenia and DISEASE will be discussed in this article. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced thrombocytopenia, paradoxical thromboembolism, and other side effects of CHEMICAL therapy. Although several new anticoagulant drugs are in development, CHEMICAL remains the drug of choice for most anticoagulation needs. The clinical effects of CHEMICAL are meritorious, but side effects do exist. Important untoward effects of CHEMICAL therapy including CHEMICAL-induced thrombocytopenia, CHEMICAL-associated DISEASE, eosinophilia, skin reactions, allergic reactions other than thrombocytopenia and alopecia will be discussed in this article. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced thrombocytopenia, paradoxical DISEASE, and other side effects of CHEMICAL therapy. Although several new anticoagulant drugs are in development, CHEMICAL remains the drug of choice for most anticoagulation needs. The clinical effects of CHEMICAL are meritorious, but side effects do exist. Important untoward effects of CHEMICAL therapy including CHEMICAL-induced thrombocytopenia, CHEMICAL-associated osteoporosis, eosinophilia, skin reactions, allergic reactions other than thrombocytopenia and alopecia will be discussed in this article. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced DISEASE, paradoxical thromboembolism, and other side effects of CHEMICAL therapy. Although several new anticoagulant drugs are in development, CHEMICAL remains the drug of choice for most anticoagulation needs. The clinical effects of CHEMICAL are meritorious, but side effects do exist. Important untoward effects of CHEMICAL therapy including CHEMICAL-induced DISEASE, CHEMICAL-associated osteoporosis, eosinophilia, skin reactions, allergic reactions other than DISEASE and alopecia will be discussed in this article. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced thrombocytopenia, paradoxical thromboembolism, and other side effects of CHEMICAL therapy. Although several new anticoagulant drugs are in development, CHEMICAL remains the drug of choice for most anticoagulation needs. The clinical effects of CHEMICAL are meritorious, but side effects do exist. Important untoward effects of CHEMICAL therapy including CHEMICAL-induced thrombocytopenia, CHEMICAL-associated osteoporosis, eosinophilia, skin reactions, DISEASE other than thrombocytopenia and alopecia will be discussed in this article. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced thrombocytopenia, paradoxical thromboembolism, and other side effects of CHEMICAL therapy. Although several new anticoagulant drugs are in development, CHEMICAL remains the drug of choice for most anticoagulation needs. The clinical effects of CHEMICAL are meritorious, but side effects do exist. Important untoward effects of CHEMICAL therapy including CHEMICAL-induced thrombocytopenia, CHEMICAL-associated osteoporosis, DISEASE, skin reactions, allergic reactions other than thrombocytopenia and alopecia will be discussed in this article. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced thrombocytopenia, paradoxical thromboembolism, and other side effects of CHEMICAL therapy. Although several new anticoagulant drugs are in development, CHEMICAL remains the drug of choice for most anticoagulation needs. The clinical effects of CHEMICAL are meritorious, but side effects do exist. Important untoward effects of CHEMICAL therapy including CHEMICAL-induced thrombocytopenia, CHEMICAL-associated osteoporosis, eosinophilia, DISEASE, allergic reactions other than thrombocytopenia and alopecia will be discussed in this article. | CHEMICAL-INDUCED-DISEASE |
| Nonopaque crystal deposition causing ureteric obstruction in patients with HIV undergoing CHEMICAL therapy. OBJECTIVE: We describe the unique CT features of DISEASE in six HIV-infected patients receiving CHEMICAL, the most commonly used HIV protease inhibitor, which is associated with an increased incidence of urolithiasis. CONCLUSION: Ureteric obstruction caused by precipitated CHEMICAL crystals may be difficult to diagnose with unenhanced CT. The calculi are not opaque, and secondary signs of obstruction may be absent or minimal and should be sought carefully. Images may need to be obtained using i.v. contrast material to enable diagnosis of ureteric stones or obstruction in patients with HIV infection who receive CHEMICAL therapy. | CHEMICAL-INDUCED-DISEASE |
| DISEASE and CHEMICAL use. CHEMICAL, a serotonin-1 (5-hydroxytryptamine-1) receptor agonist, is an antimigraine drug that is reported to act by selectively constricting intracranial arteries. Recently, vasopressor responses that are distinct from the cranial circulation have been demonstrated to occur in the systemic, pulmonary, and coronary circulations. Cases have been published of coronary vasospasm, myocardial ischemia, and myocardial infarction occurring after CHEMICAL use. We report on the development of 8 serious cases of DISEASE in patients with migraine treated with CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Ischemic colitis and sumatriptan use. Sumatriptan succinate, a CHEMICAL-1 (CHEMICAL-1) receptor agonist, is an antimigraine drug that is reported to act by selectively constricting intracranial arteries. Recently, vasopressor responses that are distinct from the cranial circulation have been demonstrated to occur in the systemic, pulmonary, and coronary circulations. Cases have been published of coronary vasospasm, myocardial ischemia, and DISEASE occurring after sumatriptan use. We report on the development of 8 serious cases of ischemic colitis in patients with migraine treated with sumatriptan. | NO-RELATIONSHIP |
| Ischemic colitis and sumatriptan use. Sumatriptan succinate, a CHEMICAL-1 (CHEMICAL-1) receptor agonist, is an antimigraine drug that is reported to act by selectively constricting intracranial arteries. Recently, vasopressor responses that are distinct from the cranial circulation have been demonstrated to occur in the systemic, pulmonary, and coronary circulations. Cases have been published of DISEASE, myocardial ischemia, and myocardial infarction occurring after sumatriptan use. We report on the development of 8 serious cases of ischemic colitis in patients with migraine treated with sumatriptan. | NO-RELATIONSHIP |
| Ischemic colitis and sumatriptan use. Sumatriptan succinate, a CHEMICAL-1 (CHEMICAL-1) receptor agonist, is an antimigraine drug that is reported to act by selectively constricting intracranial arteries. Recently, vasopressor responses that are distinct from the cranial circulation have been demonstrated to occur in the systemic, pulmonary, and coronary circulations. Cases have been published of coronary vasospasm, myocardial ischemia, and myocardial infarction occurring after sumatriptan use. We report on the development of 8 serious cases of ischemic colitis in patients with DISEASE treated with sumatriptan. | NO-RELATIONSHIP |
| Ischemic colitis and sumatriptan use. Sumatriptan succinate, a CHEMICAL-1 (CHEMICAL-1) receptor agonist, is an antimigraine drug that is reported to act by selectively constricting intracranial arteries. Recently, vasopressor responses that are distinct from the cranial circulation have been demonstrated to occur in the systemic, pulmonary, and coronary circulations. Cases have been published of coronary vasospasm, DISEASE, and myocardial infarction occurring after sumatriptan use. We report on the development of 8 serious cases of ischemic colitis in patients with migraine treated with sumatriptan. | NO-RELATIONSHIP |
| Pallidotomy with the gamma knife: a positive experience. 51 patients with medically refractory Parkinson's disease underwent stereotactic posteromedial pallidotomy between August 1993 and February 1997 for treatment of bradykinesia, rigidity, and CHEMICAL-induced DISEASE. In 29 patients, the pallidotomies were performed with the Leksell Gamma Knife and in 22 they were performed with the standard radiofrequency (RF) method. Clinical assessment as well as blinded ratings of Unified Parkinson's Disease Rating Scale (UPDRS) scores were carried out pre- and postoperatively. Mean follow-up time is 20.6 months (range 6-48) and all except 4 patients have been followed more than one year. 85 percent of patients with DISEASE were relieved of symptoms, regardless of whether the pallidotomies were performed with the Gamma Knife or radiofrequency methods. About 2/3 of the patients in both Gamma Knife and radiofrequency groups showed improvements in bradykinesia and rigidity, although when considered as a group neither the Gamma Knife nor the radiofrequency group showed statistically significant improvements in UPDRS scores. One patient in the Gamma Knife group (3.4%) developed a homonymous hemianopsia 9 months following treatment and 5 patients (27.7%) in the radiofrequency group became transiently confused postoperatively. No other complications were seen. Gamma Knife pallidotomy is as effective as radiofrequency pallidotomy in controlling certain of the symptoms of Parkinson's disease. It may be the only practical technique available in certain patients, such as those who take anticoagulants, have bleeding diatheses or serious systemic medical illnesses. It is a viable option for other patients as well. | CHEMICAL-INDUCED-DISEASE |
| DISEASE and CHEMICAL. A 1-year-old female presented with DISEASE probably caused by CHEMICAL. She had defects in the supratentorial brain including the basal ganglia and the striatum (multicystic encephalomalacia) due to severe perinatal hypoxic-ischemic encephalopathy, which was considered to be a possible predisposing factor causing DISEASE. A dopaminergic blockade mechanism generally is accepted as the pathogenesis of this syndrome. However, CHEMICAL is a dopamine agonist via the inhibition of uptake of dopamine, and therefore dopaminergic systems in the brainstem (mainly the midbrain) and the spinal cord were unlikely to participate in the onset of this syndrome. A relative gamma-aminobutyric acid-ergic deficiency might occur because diazepam, a gamma-aminobutyric acid-mimetic agent, was strikingly effective. This is the first reported patient with DISEASE probably caused by CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Neuroleptic malignant syndrome and methylphenidate. A 1-year-old female presented with neuroleptic malignant syndrome probably caused by methylphenidate. She had defects in the supratentorial brain including the basal ganglia and the striatum (DISEASE) due to severe perinatal hypoxic-ischemic encephalopathy, which was considered to be a possible predisposing factor causing neuroleptic malignant syndrome. A dopaminergic blockade mechanism generally is accepted as the pathogenesis of this syndrome. However, methylphenidate is a dopamine agonist via the inhibition of uptake of dopamine, and therefore dopaminergic systems in the brainstem (mainly the midbrain) and the spinal cord were unlikely to participate in the onset of this syndrome. A relative CHEMICAL-ergic deficiency might occur because diazepam, a CHEMICAL-mimetic agent, was strikingly effective. This is the first reported patient with neuroleptic malignant syndrome probably caused by methylphenidate. | NO-RELATIONSHIP |
| Neuroleptic malignant syndrome and methylphenidate. A 1-year-old female presented with neuroleptic malignant syndrome probably caused by methylphenidate. She had defects in the supratentorial brain including the basal ganglia and the striatum (DISEASE) due to severe perinatal hypoxic-ischemic encephalopathy, which was considered to be a possible predisposing factor causing neuroleptic malignant syndrome. A dopaminergic blockade mechanism generally is accepted as the pathogenesis of this syndrome. However, methylphenidate is a CHEMICAL agonist via the inhibition of uptake of CHEMICAL, and therefore dopaminergic systems in the brainstem (mainly the midbrain) and the spinal cord were unlikely to participate in the onset of this syndrome. A relative gamma-aminobutyric acid-ergic deficiency might occur because diazepam, a gamma-aminobutyric acid-mimetic agent, was strikingly effective. This is the first reported patient with neuroleptic malignant syndrome probably caused by methylphenidate. | NO-RELATIONSHIP |
| Neuroleptic malignant syndrome and methylphenidate. A 1-year-old female presented with neuroleptic malignant syndrome probably caused by methylphenidate. She had defects in the supratentorial brain including the basal ganglia and the striatum (multicystic encephalomalacia) due to severe perinatal DISEASE, which was considered to be a possible predisposing factor causing neuroleptic malignant syndrome. A dopaminergic blockade mechanism generally is accepted as the pathogenesis of this syndrome. However, methylphenidate is a dopamine agonist via the inhibition of uptake of dopamine, and therefore dopaminergic systems in the brainstem (mainly the midbrain) and the spinal cord were unlikely to participate in the onset of this syndrome. A relative gamma-aminobutyric acid-ergic deficiency might occur because CHEMICAL, a gamma-aminobutyric acid-mimetic agent, was strikingly effective. This is the first reported patient with neuroleptic malignant syndrome probably caused by methylphenidate. | NO-RELATIONSHIP |
| Neuroleptic malignant syndrome and methylphenidate. A 1-year-old female presented with neuroleptic malignant syndrome probably caused by methylphenidate. She had defects in the supratentorial brain including the basal ganglia and the striatum (DISEASE) due to severe perinatal hypoxic-ischemic encephalopathy, which was considered to be a possible predisposing factor causing neuroleptic malignant syndrome. A dopaminergic blockade mechanism generally is accepted as the pathogenesis of this syndrome. However, methylphenidate is a dopamine agonist via the inhibition of uptake of dopamine, and therefore dopaminergic systems in the brainstem (mainly the midbrain) and the spinal cord were unlikely to participate in the onset of this syndrome. A relative gamma-aminobutyric acid-ergic deficiency might occur because CHEMICAL, a gamma-aminobutyric acid-mimetic agent, was strikingly effective. This is the first reported patient with neuroleptic malignant syndrome probably caused by methylphenidate. | NO-RELATIONSHIP |
| Neuroleptic malignant syndrome and methylphenidate. A 1-year-old female presented with neuroleptic malignant syndrome probably caused by methylphenidate. She had defects in the supratentorial brain including the basal ganglia and the striatum (multicystic encephalomalacia) due to severe perinatal DISEASE, which was considered to be a possible predisposing factor causing neuroleptic malignant syndrome. A dopaminergic blockade mechanism generally is accepted as the pathogenesis of this syndrome. However, methylphenidate is a dopamine agonist via the inhibition of uptake of dopamine, and therefore dopaminergic systems in the brainstem (mainly the midbrain) and the spinal cord were unlikely to participate in the onset of this syndrome. A relative CHEMICAL-ergic deficiency might occur because diazepam, a CHEMICAL-mimetic agent, was strikingly effective. This is the first reported patient with neuroleptic malignant syndrome probably caused by methylphenidate. | NO-RELATIONSHIP |
| Neuroleptic malignant syndrome and methylphenidate. A 1-year-old female presented with neuroleptic malignant syndrome probably caused by methylphenidate. She had defects in the supratentorial brain including the basal ganglia and the striatum (multicystic encephalomalacia) due to severe perinatal DISEASE, which was considered to be a possible predisposing factor causing neuroleptic malignant syndrome. A dopaminergic blockade mechanism generally is accepted as the pathogenesis of this syndrome. However, methylphenidate is a CHEMICAL agonist via the inhibition of uptake of CHEMICAL, and therefore dopaminergic systems in the brainstem (mainly the midbrain) and the spinal cord were unlikely to participate in the onset of this syndrome. A relative gamma-aminobutyric acid-ergic deficiency might occur because diazepam, a gamma-aminobutyric acid-mimetic agent, was strikingly effective. This is the first reported patient with neuroleptic malignant syndrome probably caused by methylphenidate. | NO-RELATIONSHIP |
| Differential effects of CHEMICAL on the neutral and acidic pathways of bile salt synthesis in the rat. Effects of CHEMICAL (CHEMICAL) on the neutral and acidic biosynthetic pathways of bile salt (BS) synthesis were evaluated in rats with an intact enterohepatic circulation and in rats with long-term bile diversion to induce BS synthesis. For this purpose, bile salt pool composition, synthesis of individual BS in vivo, hepatic activities, and expression levels of cholesterol 7alpha-hydroxylase (CYP7A), and sterol 27-hydroxylase (CYP27), as well as of other enzymes involved in BS synthesis, were analyzed in rats treated with CHEMICAL (5 mg/kg, 3 days) or its vehicle. BS pool size was decreased by 27% but total BS synthesis was not affected by CHEMICAL in intact rats. Synthesis of cholate was reduced by 68% in CHEMICAL-treated rats, while that of chenodeoxycholate was increased by 60%. The recently identified Delta22-isomer of beta-muricholate contributed for 5.4% and 18.3 % (P < 0.01) to the pool in control and CHEMICAL-treated rats, respectively, but could not be detected in bile after exhaustion of the pool. A clear reduction of BS synthesis was found in bile-diverted rats treated with CHEMICAL, yet biliary BS composition was only minimally affected. Activity of CYP7A was decreased by CHEMICAL in both intact and bile-diverted rats, whereas the activity of the CYP27 was not affected. Hepatic mRNA levels of CYP7A were significantly reduced by CHEMICAL in bile-diverted rats only; CYP27 mRNA levels were not affected by CHEMICAL. In addition, mRNA levels of sterol 12alpha-hydroxylase and lithocholate 6beta-hydroxylase were increased by bile diversion and suppressed by CHEMICAL. This study shows that CHEMICAL (CHEMICAL)-induced DISEASE in rats is associated with selective inhibition of the neutral pathway of bile salt (BS) synthesis. Simultaneous impairment of other enzymes in the BS biosynthetic pathways may contribute to overall effects of CHEMICAL on BS synthesis. | CHEMICAL-INDUCED-DISEASE |
| Glibenclamide-sensitive DISEASE produced by CHEMICAL assessed in the rat. The effects of CHEMICAL, a basic 35-amino acid peptide isolated from the venom of a lizard salivary gland, on arterial blood pressure and heart rate were examined in the rat, focusing on the possibility that activation of ATP sensitive K+ (K(ATP)) channels is involved in the responses. The results were also compared with those of vasoactive intestinal polypeptide (VIP). Helodermin produced hypotension in a dose-dependent manner with approximately similar potency and duration to VIP. Hypotension induced by both peptides was significantly attenuated by glibenclamide, which abolished a levcromakalim-produced decrease in arterial blood pressure. Oxyhemoglobin did not affect helodermin-induced hypotension, whereas it shortened the duration of acetylcholine (ACh)-produced hypotension. These findings suggest that helodermin-produced hypotension is partly attributable to the activation of glibenclamide-sensitive K+ channels (K(ATP) channels), which presumably exist on arterial smooth muscle cells. EDRF (endothelium-derived relaxing factor)/nitric oxide does not seem to play an important role in the peptide-produced hypotension. | CHEMICAL-INDUCED-DISEASE |
| Long-term efficacy and adverse event of nifedipine sustained-release tablets for CHEMICAL-induced hypertension in patients with psoriasis. Thirteen psoriatic patients with hypertension during the course of CHEMICAL therapy were treated for 25 months with a calcium channel blocker, sustained-release nifedipine, to study the clinical antihypertensive effects and adverse events during treatment with both drugs. Seven of the 13 patients had exhibited a subclinical hypertensive state before CHEMICAL therapy. Both systolic and diastolic blood pressures of these 13 patients were decreased significantly after 4 weeks of nifedipine therapy, and blood pressure was maintained within the normal range thereafter for 25 months. The adverse events during combined therapy with CHEMICAL and nifedipine included an increase in blood urea nitrogen levels in 9 of the 13 patients and development of DISEASE in 2 of the 13 patients. Our findings indicate that sustained-release nifedipine is useful for hypertensive psoriatic patients under long-term treatment with CHEMICAL, but that these patients should be monitored for DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Long-term efficacy and adverse event of nifedipine sustained-release tablets for CHEMICAL-induced DISEASE in patients with psoriasis. Thirteen psoriatic patients with DISEASE during the course of CHEMICAL therapy were treated for 25 months with a calcium channel blocker, sustained-release nifedipine, to study the clinical antihypertensive effects and adverse events during treatment with both drugs. Seven of the 13 patients had exhibited a subclinical DISEASE state before CHEMICAL therapy. Both systolic and diastolic blood pressures of these 13 patients were decreased significantly after 4 weeks of nifedipine therapy, and blood pressure was maintained within the normal range thereafter for 25 months. The adverse events during combined therapy with CHEMICAL and nifedipine included an increase in blood urea nitrogen levels in 9 of the 13 patients and development of gingival hyperplasia in 2 of the 13 patients. Our findings indicate that sustained-release nifedipine is useful for DISEASE psoriatic patients under long-term treatment with CHEMICAL, but that these patients should be monitored for gingival hyperplasia. | CHEMICAL-INDUCED-DISEASE |
| Long-term efficacy and adverse event of CHEMICAL sustained-release tablets for cyclosporin A-induced hypertension in patients with psoriasis. Thirteen psoriatic patients with hypertension during the course of cyclosporin A therapy were treated for 25 months with a calcium channel blocker, sustained-release CHEMICAL, to study the clinical antihypertensive effects and adverse events during treatment with both drugs. Seven of the 13 patients had exhibited a subclinical hypertensive state before cyclosporin A therapy. Both systolic and diastolic blood pressures of these 13 patients were decreased significantly after 4 weeks of CHEMICAL therapy, and blood pressure was maintained within the normal range thereafter for 25 months. The adverse events during combined therapy with cyclosporin A and CHEMICAL included an increase in blood urea nitrogen levels in 9 of the 13 patients and development of DISEASE in 2 of the 13 patients. Our findings indicate that sustained-release CHEMICAL is useful for hypertensive psoriatic patients under long-term treatment with cyclosporin A, but that these patients should be monitored for DISEASE. | NO-RELATIONSHIP |
| Long-term efficacy and adverse event of nifedipine sustained-release tablets for cyclosporin A-induced hypertension in patients with DISEASE. Thirteen DISEASE patients with hypertension during the course of cyclosporin A therapy were treated for 25 months with a CHEMICAL channel blocker, sustained-release nifedipine, to study the clinical antihypertensive effects and adverse events during treatment with both drugs. Seven of the 13 patients had exhibited a subclinical hypertensive state before cyclosporin A therapy. Both systolic and diastolic blood pressures of these 13 patients were decreased significantly after 4 weeks of nifedipine therapy, and blood pressure was maintained within the normal range thereafter for 25 months. The adverse events during combined therapy with cyclosporin A and nifedipine included an increase in blood urea nitrogen levels in 9 of the 13 patients and development of gingival hyperplasia in 2 of the 13 patients. Our findings indicate that sustained-release nifedipine is useful for hypertensive DISEASE patients under long-term treatment with cyclosporin A, but that these patients should be monitored for gingival hyperplasia. | NO-RELATIONSHIP |
| Long-term efficacy and adverse event of nifedipine sustained-release tablets for cyclosporin A-induced hypertension in patients with DISEASE. Thirteen DISEASE patients with hypertension during the course of cyclosporin A therapy were treated for 25 months with a calcium channel blocker, sustained-release nifedipine, to study the clinical antihypertensive effects and adverse events during treatment with both drugs. Seven of the 13 patients had exhibited a subclinical hypertensive state before cyclosporin A therapy. Both systolic and diastolic blood pressures of these 13 patients were decreased significantly after 4 weeks of nifedipine therapy, and blood pressure was maintained within the normal range thereafter for 25 months. The adverse events during combined therapy with cyclosporin A and nifedipine included an increase in CHEMICAL levels in 9 of the 13 patients and development of gingival hyperplasia in 2 of the 13 patients. Our findings indicate that sustained-release nifedipine is useful for hypertensive DISEASE patients under long-term treatment with cyclosporin A, but that these patients should be monitored for gingival hyperplasia. | NO-RELATIONSHIP |
| DISEASE ventricular tachycardia during low dose intermittent CHEMICAL treatment in a patient with dilated cardiomyopathy and congestive heart failure. The authors describe the case of a 56-year-old woman with chronic, severe heart failure secondary to dilated cardiomyopathy and absence of significant ventricular arrhythmias who developed QT prolongation and DISEASE ventricular tachycardia during one cycle of intermittent low dose (2.5 mcg/kg per min) CHEMICAL. This report of DISEASE ventricular tachycardia during intermittent CHEMICAL supports the hypothesis that unpredictable fatal arrhythmias may occur even with low doses and in patients with no history of significant rhythm disturbances. The mechanisms of proarrhythmic effects of CHEMICAL are discussed. | CHEMICAL-INDUCED-DISEASE |
| Positive skin tests in late reactions to radiographic CHEMICAL. In the last few years delayed reactions several hours after the injection of radiographic and CHEMICAL (CHEMICAL) have been described with increasing frequency. The authors report two observations on patients with delayed reactions in whom intradermoreactions (IDR) and patch tests to a series of ionic and non ionic CHEMICAL were studied. After angiography by the venous route in patient n degree 1 a biphasic reaction with an immediate reaction (dyspnea, loss of consciousness) and delayed macro-papular rash appeared, whilst patient n degree 2 developed a generalised sensation of heat, persistent DISEASE at the site of injection immediately and a generalised macro-papular reaction after 24 hours. The skin tests revealed positive delayed reactions of 24 hours and 48 hours by IDR and patch tests to only some CHEMICAL with common chains in their structures. The positive skin tests are in favour of immunological reactions and may help in diagnosis of allergy in the patients. | CHEMICAL-INDUCED-DISEASE |
| Positive skin tests in late reactions to radiographic CHEMICAL. In the last few years delayed reactions several hours after the injection of radiographic and CHEMICAL (CHEMICAL) have been described with increasing frequency. The authors report two observations on patients with delayed reactions in whom intradermoreactions (IDR) and patch tests to a series of ionic and non ionic CHEMICAL were studied. After angiography by the venous route in patient n degree 1 a biphasic reaction with an immediate reaction (dyspnea, loss of consciousness) and delayed DISEASE appeared, whilst patient n degree 2 developed a generalised sensation of heat, persistent pain at the site of injection immediately and a generalised macro-papular reaction after 24 hours. The skin tests revealed positive delayed reactions of 24 hours and 48 hours by IDR and patch tests to only some CHEMICAL with common chains in their structures. The positive skin tests are in favour of immunological reactions and may help in diagnosis of allergy in the patients. | CHEMICAL-INDUCED-DISEASE |
| Positive skin tests in late reactions to radiographic CHEMICAL. In the last few years delayed reactions several hours after the injection of radiographic and CHEMICAL (CHEMICAL) have been described with increasing frequency. The authors report two observations on patients with delayed reactions in whom intradermoreactions (IDR) and patch tests to a series of ionic and non ionic CHEMICAL were studied. After angiography by the venous route in patient n degree 1 a biphasic reaction with an immediate reaction (DISEASE, loss of consciousness) and delayed macro-papular rash appeared, whilst patient n degree 2 developed a generalised sensation of heat, persistent pain at the site of injection immediately and a generalised macro-papular reaction after 24 hours. The skin tests revealed positive delayed reactions of 24 hours and 48 hours by IDR and patch tests to only some CHEMICAL with common chains in their structures. The positive skin tests are in favour of immunological reactions and may help in diagnosis of allergy in the patients. | CHEMICAL-INDUCED-DISEASE |
| Positive skin tests in late reactions to radiographic CHEMICAL. In the last few years delayed reactions several hours after the injection of radiographic and CHEMICAL (CHEMICAL) have been described with increasing frequency. The authors report two observations on patients with delayed reactions in whom intradermoreactions (IDR) and patch tests to a series of ionic and non ionic CHEMICAL were studied. After angiography by the venous route in patient n degree 1 a biphasic reaction with an immediate reaction (dyspnea, DISEASE) and delayed macro-papular rash appeared, whilst patient n degree 2 developed a generalised sensation of heat, persistent pain at the site of injection immediately and a generalised macro-papular reaction after 24 hours. The skin tests revealed positive delayed reactions of 24 hours and 48 hours by IDR and patch tests to only some CHEMICAL with common chains in their structures. The positive skin tests are in favour of immunological reactions and may help in diagnosis of allergy in the patients. | CHEMICAL-INDUCED-DISEASE |
| Risk of transient hyperammonemic encephalopathy in cancer patients who received continuous infusion of CHEMICAL with the complication of dehydration and infection. From 1986 to 1998, 29 cancer patients who had 32 episodes of transient hyperammonemic encephalopathy related to continuous infusion of CHEMICAL (CHEMICAL) were identified. None of the patients had decompensated liver disease. Onset of hyperammonemic encephalopathy varied from 0.5 to 5 days (mean: 2.6 +/- 1.3 days) after the initiation of chemotherapy. Plasma ammonium level ranged from 248 to 2387 microg% (mean: 626 +/- 431 microg%). Among the 32 episodes, 26 (81%) had various degrees of azotemia, 18 (56%) occurred during bacterial infections and 14 (44%) without infection occurred during periods of dehydration. Higher plasma ammonium levels and more rapid onset of DISEASE were seen in 18 patients with bacterial infections (p=0.003 and 0.0006, respectively) and in nine patients receiving high daily doses (2600 or 1800 mg/m2) of CHEMICAL (p=0.0001 and < 0.0001, respectively). In 25 out of 32 episodes (78%), plasma ammonium levels and mental status returned to normal within 2 days after adequate management. In conclusion, hyperammonemic encephalopathy can occur in patients receiving continuous infusion of CHEMICAL. Azotemia, body fluid insufficiency and bacterial infections were frequently found in these patients. It is therefore important to recognize this condition in patients receiving continuous infusion of CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Risk of transient DISEASE in cancer patients who received continuous infusion of 5-fluorouracil with the complication of dehydration and infection. From 1986 to 1998, 29 cancer patients who had 32 episodes of transient DISEASE related to continuous infusion of 5-fluorouracil (5-FU) were identified. None of the patients had decompensated liver disease. Onset of DISEASE varied from 0.5 to 5 days (mean: 2.6 +/- 1.3 days) after the initiation of chemotherapy. Plasma CHEMICAL level ranged from 248 to 2387 microg% (mean: 626 +/- 431 microg%). Among the 32 episodes, 26 (81%) had various degrees of azotemia, 18 (56%) occurred during bacterial infections and 14 (44%) without infection occurred during periods of dehydration. Higher plasma CHEMICAL levels and more rapid onset of hyperammonemia were seen in 18 patients with bacterial infections (p=0.003 and 0.0006, respectively) and in nine patients receiving high daily doses (2600 or 1800 mg/m2) of 5-FU (p=0.0001 and < 0.0001, respectively). In 25 out of 32 episodes (78%), plasma CHEMICAL levels and mental status returned to normal within 2 days after adequate management. In conclusion, DISEASE can occur in patients receiving continuous infusion of 5-FU. Azotemia, body fluid insufficiency and bacterial infections were frequently found in these patients. It is therefore important to recognize this condition in patients receiving continuous infusion of 5-FU. | NO-RELATIONSHIP |
| Risk of transient hyperammonemic encephalopathy in cancer patients who received continuous infusion of 5-fluorouracil with the complication of dehydration and infection. From 1986 to 1998, 29 cancer patients who had 32 episodes of transient hyperammonemic encephalopathy related to continuous infusion of 5-fluorouracil (5-FU) were identified. None of the patients had decompensated liver disease. Onset of hyperammonemic encephalopathy varied from 0.5 to 5 days (mean: 2.6 +/- 1.3 days) after the initiation of chemotherapy. Plasma CHEMICAL level ranged from 248 to 2387 microg% (mean: 626 +/- 431 microg%). Among the 32 episodes, 26 (81%) had various degrees of azotemia, 18 (56%) occurred during DISEASE and 14 (44%) without infection occurred during periods of dehydration. Higher plasma CHEMICAL levels and more rapid onset of hyperammonemia were seen in 18 patients with DISEASE (p=0.003 and 0.0006, respectively) and in nine patients receiving high daily doses (2600 or 1800 mg/m2) of 5-FU (p=0.0001 and < 0.0001, respectively). In 25 out of 32 episodes (78%), plasma CHEMICAL levels and mental status returned to normal within 2 days after adequate management. In conclusion, hyperammonemic encephalopathy can occur in patients receiving continuous infusion of 5-FU. Azotemia, body fluid insufficiency and DISEASE were frequently found in these patients. It is therefore important to recognize this condition in patients receiving continuous infusion of 5-FU. | NO-RELATIONSHIP |
| Risk of transient hyperammonemic encephalopathy in cancer patients who received continuous infusion of 5-fluorouracil with the complication of dehydration and infection. From 1986 to 1998, 29 cancer patients who had 32 episodes of transient hyperammonemic encephalopathy related to continuous infusion of 5-fluorouracil (5-FU) were identified. None of the patients had decompensated liver disease. Onset of hyperammonemic encephalopathy varied from 0.5 to 5 days (mean: 2.6 +/- 1.3 days) after the initiation of chemotherapy. Plasma CHEMICAL level ranged from 248 to 2387 microg% (mean: 626 +/- 431 microg%). Among the 32 episodes, 26 (81%) had various degrees of DISEASE, 18 (56%) occurred during bacterial infections and 14 (44%) without infection occurred during periods of dehydration. Higher plasma CHEMICAL levels and more rapid onset of hyperammonemia were seen in 18 patients with bacterial infections (p=0.003 and 0.0006, respectively) and in nine patients receiving high daily doses (2600 or 1800 mg/m2) of 5-FU (p=0.0001 and < 0.0001, respectively). In 25 out of 32 episodes (78%), plasma CHEMICAL levels and mental status returned to normal within 2 days after adequate management. In conclusion, hyperammonemic encephalopathy can occur in patients receiving continuous infusion of 5-FU. DISEASE, body fluid insufficiency and bacterial infections were frequently found in these patients. It is therefore important to recognize this condition in patients receiving continuous infusion of 5-FU. | NO-RELATIONSHIP |
| Risk of transient hyperammonemic encephalopathy in DISEASE patients who received continuous infusion of 5-fluorouracil with the complication of dehydration and infection. From 1986 to 1998, 29 DISEASE patients who had 32 episodes of transient hyperammonemic encephalopathy related to continuous infusion of 5-fluorouracil (5-FU) were identified. None of the patients had decompensated liver disease. Onset of hyperammonemic encephalopathy varied from 0.5 to 5 days (mean: 2.6 +/- 1.3 days) after the initiation of chemotherapy. Plasma CHEMICAL level ranged from 248 to 2387 microg% (mean: 626 +/- 431 microg%). Among the 32 episodes, 26 (81%) had various degrees of azotemia, 18 (56%) occurred during bacterial infections and 14 (44%) without infection occurred during periods of dehydration. Higher plasma CHEMICAL levels and more rapid onset of hyperammonemia were seen in 18 patients with bacterial infections (p=0.003 and 0.0006, respectively) and in nine patients receiving high daily doses (2600 or 1800 mg/m2) of 5-FU (p=0.0001 and < 0.0001, respectively). In 25 out of 32 episodes (78%), plasma CHEMICAL levels and mental status returned to normal within 2 days after adequate management. In conclusion, hyperammonemic encephalopathy can occur in patients receiving continuous infusion of 5-FU. Azotemia, body fluid insufficiency and bacterial infections were frequently found in these patients. It is therefore important to recognize this condition in patients receiving continuous infusion of 5-FU. | NO-RELATIONSHIP |
| Risk of transient hyperammonemic encephalopathy in cancer patients who received continuous infusion of 5-fluorouracil with the complication of dehydration and DISEASE. From 1986 to 1998, 29 cancer patients who had 32 episodes of transient hyperammonemic encephalopathy related to continuous infusion of 5-fluorouracil (5-FU) were identified. None of the patients had decompensated liver disease. Onset of hyperammonemic encephalopathy varied from 0.5 to 5 days (mean: 2.6 +/- 1.3 days) after the initiation of chemotherapy. Plasma CHEMICAL level ranged from 248 to 2387 microg% (mean: 626 +/- 431 microg%). Among the 32 episodes, 26 (81%) had various degrees of azotemia, 18 (56%) occurred during bacterial infections and 14 (44%) without DISEASE occurred during periods of dehydration. Higher plasma CHEMICAL levels and more rapid onset of hyperammonemia were seen in 18 patients with bacterial infections (p=0.003 and 0.0006, respectively) and in nine patients receiving high daily doses (2600 or 1800 mg/m2) of 5-FU (p=0.0001 and < 0.0001, respectively). In 25 out of 32 episodes (78%), plasma CHEMICAL levels and mental status returned to normal within 2 days after adequate management. In conclusion, hyperammonemic encephalopathy can occur in patients receiving continuous infusion of 5-FU. Azotemia, body fluid insufficiency and bacterial infections were frequently found in these patients. It is therefore important to recognize this condition in patients receiving continuous infusion of 5-FU. | NO-RELATIONSHIP |
| Risk of transient hyperammonemic encephalopathy in cancer patients who received continuous infusion of 5-fluorouracil with the complication of dehydration and infection. From 1986 to 1998, 29 cancer patients who had 32 episodes of transient hyperammonemic encephalopathy related to continuous infusion of 5-fluorouracil (5-FU) were identified. None of the patients had decompensated DISEASE. Onset of hyperammonemic encephalopathy varied from 0.5 to 5 days (mean: 2.6 +/- 1.3 days) after the initiation of chemotherapy. Plasma CHEMICAL level ranged from 248 to 2387 microg% (mean: 626 +/- 431 microg%). Among the 32 episodes, 26 (81%) had various degrees of azotemia, 18 (56%) occurred during bacterial infections and 14 (44%) without infection occurred during periods of dehydration. Higher plasma CHEMICAL levels and more rapid onset of hyperammonemia were seen in 18 patients with bacterial infections (p=0.003 and 0.0006, respectively) and in nine patients receiving high daily doses (2600 or 1800 mg/m2) of 5-FU (p=0.0001 and < 0.0001, respectively). In 25 out of 32 episodes (78%), plasma CHEMICAL levels and mental status returned to normal within 2 days after adequate management. In conclusion, hyperammonemic encephalopathy can occur in patients receiving continuous infusion of 5-FU. Azotemia, body fluid insufficiency and bacterial infections were frequently found in these patients. It is therefore important to recognize this condition in patients receiving continuous infusion of 5-FU. | NO-RELATIONSHIP |
| Risk of transient hyperammonemic encephalopathy in cancer patients who received continuous infusion of 5-fluorouracil with the complication of DISEASE and infection. From 1986 to 1998, 29 cancer patients who had 32 episodes of transient hyperammonemic encephalopathy related to continuous infusion of 5-fluorouracil (5-FU) were identified. None of the patients had decompensated liver disease. Onset of hyperammonemic encephalopathy varied from 0.5 to 5 days (mean: 2.6 +/- 1.3 days) after the initiation of chemotherapy. Plasma CHEMICAL level ranged from 248 to 2387 microg% (mean: 626 +/- 431 microg%). Among the 32 episodes, 26 (81%) had various degrees of azotemia, 18 (56%) occurred during bacterial infections and 14 (44%) without infection occurred during periods of DISEASE. Higher plasma CHEMICAL levels and more rapid onset of hyperammonemia were seen in 18 patients with bacterial infections (p=0.003 and 0.0006, respectively) and in nine patients receiving high daily doses (2600 or 1800 mg/m2) of 5-FU (p=0.0001 and < 0.0001, respectively). In 25 out of 32 episodes (78%), plasma CHEMICAL levels and mental status returned to normal within 2 days after adequate management. In conclusion, hyperammonemic encephalopathy can occur in patients receiving continuous infusion of 5-FU. Azotemia, body fluid insufficiency and bacterial infections were frequently found in these patients. It is therefore important to recognize this condition in patients receiving continuous infusion of 5-FU. | NO-RELATIONSHIP |
| Nociceptin/orphanin FQ and CHEMICAL on learning and memory impairment induced by scopolamine in mice. 1. Nociceptin, also known as orphanin FQ, is an endogenous ligand for the orphan opioid receptor-like receptor 1 (ORL1) and involves in various functions in the central nervous system (CNS). On the other hand, CHEMICAL is recently isolated from the same precursor as nociceptin and blocks nociceptin-induced DISEASE and DISEASE. 2. Although ORL1 receptors which display a high degree of sequence homology with classical opioid receptors are abundant in the hippocampus, little is known regarding their role in learning and memory. 3. The present study was designed to investigate whether nociceptin/orphanin FQ and CHEMICAL could modulate impairment of learning and memory induced by scopolamine, a muscarinic cholinergic receptor antagonist, using spontaneous alternation of Y-maze and step-down type passive avoidance tasks in mice. 4. While CHEMICAL (0.5-5.0 nmol mouse-1, i.c.v.) administered 30 min before spontaneous alternation performance or the training session of the passive avoidance task, had no effect on spontaneous alternation or passive avoidance behaviours, a lower per cent alternation and shorter median step-down latency in the retention test were obtained in nociceptin (1.5 and/or 5.0 nmol mouse-1, i.c.v.)-treated normal mice. 5. Administration of CHEMICAL (1.5 and/or 5.0 nmol mouse-1, i.c.v.) 30 min before spontaneous alternation performance or the training session of the passive avoidance task, attenuated the scopolamine-induced impairment of spontaneous alternation and passive avoidance behaviours. 6. These results indicated that CHEMICAL, a new biologically active peptide, ameliorates impairments of spontaneous alternation and passive avoidance induced by scopolamine, and suggested that these peptides play opposite roles in learning and memory. | NO-RELATIONSHIP |
| Nociceptin/orphanin FQ and CHEMICAL on DISEASE induced by scopolamine in mice. 1. Nociceptin, also known as orphanin FQ, is an endogenous ligand for the orphan opioid receptor-like receptor 1 (ORL1) and involves in various functions in the central nervous system (CNS). On the other hand, CHEMICAL is recently isolated from the same precursor as nociceptin and blocks nociceptin-induced allodynia and hyperalgesia. 2. Although ORL1 receptors which display a high degree of sequence homology with classical opioid receptors are abundant in the hippocampus, little is known regarding their role in learning and memory. 3. The present study was designed to investigate whether nociceptin/orphanin FQ and CHEMICAL could modulate DISEASE induced by scopolamine, a muscarinic cholinergic receptor antagonist, using spontaneous alternation of Y-maze and step-down type passive avoidance tasks in mice. 4. While CHEMICAL (0.5-5.0 nmol mouse-1, i.c.v.) administered 30 min before spontaneous alternation performance or the training session of the passive avoidance task, had no effect on spontaneous alternation or passive avoidance behaviours, a lower per cent alternation and shorter median step-down latency in the retention test were obtained in nociceptin (1.5 and/or 5.0 nmol mouse-1, i.c.v.)-treated normal mice. 5. Administration of CHEMICAL (1.5 and/or 5.0 nmol mouse-1, i.c.v.) 30 min before spontaneous alternation performance or the training session of the passive avoidance task, attenuated the scopolamine-induced impairment of spontaneous alternation and passive avoidance behaviours. 6. These results indicated that CHEMICAL, a new biologically active peptide, ameliorates impairments of spontaneous alternation and passive avoidance induced by scopolamine, and suggested that these peptides play opposite roles in learning and memory. | NO-RELATIONSHIP |
| CHEMICAL/CHEMICAL and nocistatin on learning and memory impairment induced by scopolamine in mice. 1. CHEMICAL, also known as CHEMICAL, is an endogenous ligand for the orphan opioid receptor-like receptor 1 (ORL1) and involves in various functions in the central nervous system (CNS). On the other hand, nocistatin is recently isolated from the same precursor as CHEMICAL and blocks CHEMICAL-induced DISEASE and DISEASE. 2. Although ORL1 receptors which display a high degree of sequence homology with classical opioid receptors are abundant in the hippocampus, little is known regarding their role in learning and memory. 3. The present study was designed to investigate whether CHEMICAL/CHEMICAL and nocistatin could modulate impairment of learning and memory induced by scopolamine, a muscarinic cholinergic receptor antagonist, using spontaneous alternation of Y-maze and step-down type passive avoidance tasks in mice. 4. While nocistatin (0.5-5.0 nmol mouse-1, i.c.v.) administered 30 min before spontaneous alternation performance or the training session of the passive avoidance task, had no effect on spontaneous alternation or passive avoidance behaviours, a lower per cent alternation and shorter median step-down latency in the retention test were obtained in CHEMICAL (1.5 and/or 5.0 nmol mouse-1, i.c.v.)-treated normal mice. 5. Administration of nocistatin (1.5 and/or 5.0 nmol mouse-1, i.c.v.) 30 min before spontaneous alternation performance or the training session of the passive avoidance task, attenuated the scopolamine-induced impairment of spontaneous alternation and passive avoidance behaviours. 6. These results indicated that nocistatin, a new biologically active peptide, ameliorates impairments of spontaneous alternation and passive avoidance induced by scopolamine, and suggested that these peptides play opposite roles in learning and memory. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL/CHEMICAL and nocistatin on DISEASE induced by scopolamine in mice. 1. CHEMICAL, also known as CHEMICAL, is an endogenous ligand for the orphan opioid receptor-like receptor 1 (ORL1) and involves in various functions in the central nervous system (CNS). On the other hand, nocistatin is recently isolated from the same precursor as CHEMICAL and blocks CHEMICAL-induced allodynia and hyperalgesia. 2. Although ORL1 receptors which display a high degree of sequence homology with classical opioid receptors are abundant in the hippocampus, little is known regarding their role in learning and memory. 3. The present study was designed to investigate whether CHEMICAL/CHEMICAL and nocistatin could modulate DISEASE induced by scopolamine, a muscarinic cholinergic receptor antagonist, using spontaneous alternation of Y-maze and step-down type passive avoidance tasks in mice. 4. While nocistatin (0.5-5.0 nmol mouse-1, i.c.v.) administered 30 min before spontaneous alternation performance or the training session of the passive avoidance task, had no effect on spontaneous alternation or passive avoidance behaviours, a lower per cent alternation and shorter median step-down latency in the retention test were obtained in CHEMICAL (1.5 and/or 5.0 nmol mouse-1, i.c.v.)-treated normal mice. 5. Administration of nocistatin (1.5 and/or 5.0 nmol mouse-1, i.c.v.) 30 min before spontaneous alternation performance or the training session of the passive avoidance task, attenuated the scopolamine-induced impairment of spontaneous alternation and passive avoidance behaviours. 6. These results indicated that nocistatin, a new biologically active peptide, ameliorates impairments of spontaneous alternation and passive avoidance induced by scopolamine, and suggested that these peptides play opposite roles in learning and memory. | NO-RELATIONSHIP |
| CHEMICAL-induced liver toxicity. We report the case of a female patient with rheumatoid arthritis who developed acute cytolytic hepatitis due to CHEMICAL. Recently introduced in Belgium, CHEMICAL is the first nonsteroidal antiinflammatory drug with selective action on the inducible form of cyclooxygenase 2. The acute cytolytic hepatitis occurred rapidly after CHEMICAL administration and was associated with the development of antinuclear antibodies suggesting a DISEASE mechanism. This first case of CHEMICAL related liver toxicity demonstrates the potential of this drug to induce hepatic damage. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced DISEASE. We report the case of a female patient with rheumatoid arthritis who developed acute cytolytic DISEASE due to CHEMICAL. Recently introduced in Belgium, CHEMICAL is the first nonsteroidal antiinflammatory drug with selective action on the inducible form of cyclooxygenase 2. The acute cytolytic DISEASE occurred rapidly after CHEMICAL administration and was associated with the development of antinuclear antibodies suggesting a hypersensitivity mechanism. This first case of CHEMICAL related DISEASE demonstrates the potential of this drug to induce DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Induction of apoptosis by CHEMICAL metabolites in HL60 and CD34+/CD19- human bone marrow progenitor cells: potential relevance to CHEMICAL-induced DISEASE. The antipsychotic agent, CHEMICAL [CHEMICAL] has been associated with acquired DISEASE. We have examined the ability of CHEMICAL, three pyrrolidine ring metabolites and five aromatic ring metabolites of the parent compound to induce apoptosis in HL60 cells and human bone marrow progenitor (HBMP) cells. Cells were treated for 0-24 h with each compound (0-200 microM). Apoptosis was assessed by fluorescence microscopy in Hoechst 33342- and propidium iodide stained cell samples. Results were confirmed by determination of internucleosomal DNA fragmentation using gel electrophoresis for HL60 cell samples and terminal deoxynucleotidyl transferase assay in HBMP cells. The catechol and hydroquinone metabolites, NCQ436 and NCQ344, induced apoptosis in HL60 and HBMP cells in a time- and concentration dependent manner, while the phenols, NCR181, FLA873, and FLA797, and the derivatives formed by oxidation of the pyrrolidine ring, FLA838, NCM001, and NCL118, had no effect. No necrosis was observed in cells treated with NCQ436 but NCQ344 had a biphasic effect in both cell types, inducing apoptosis at lower concentrations and necrosis at higher concentrations. These data show that the catechol and hydroquinone metabolites of CHEMICAL have direct toxic effects in HL60 and HBMP cells, leading to apoptosis, while the phenol metabolites were inactive. Similarly, benzene-derived catechol and hydroquinone, but not phenol, induce apoptosis in HBMP cells [Moran et al., Mol. Pharmacol., 50 (1996) 610-615]. We propose that CHEMICAL and benzene may induce DISEASE via production of similar reactive metabolites and that the ability of NCQ436 and NCQ344 to induce apoptosis in HBMP cells may contribute to the mechanism underlying acquired DISEASE that has been associated with CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Induction of apoptosis by remoxipride metabolites in HL60 and CD34+/CD19- human bone marrow progenitor cells: potential relevance to remoxipride-induced DISEASE. The antipsychotic agent, remoxipride [(S)-(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenz amide] has been associated with acquired DISEASE. We have examined the ability of remoxipride, three pyrrolidine ring metabolites and five aromatic ring metabolites of the parent compound to induce apoptosis in HL60 cells and human bone marrow progenitor (HBMP) cells. Cells were treated for 0-24 h with each compound (0-200 microM). Apoptosis was assessed by fluorescence microscopy in Hoechst 33342- and propidium iodide stained cell samples. Results were confirmed by determination of internucleosomal DNA fragmentation using gel electrophoresis for HL60 cell samples and terminal deoxynucleotidyl transferase assay in HBMP cells. The catechol and hydroquinone metabolites, NCQ436 and NCQ344, induced apoptosis in HL60 and HBMP cells in a time- and concentration dependent manner, while the phenols, NCR181, FLA873, and FLA797, and the derivatives formed by oxidation of the pyrrolidine ring, FLA838, NCM001, and NCL118, had no effect. No necrosis was observed in cells treated with NCQ436 but NCQ344 had a biphasic effect in both cell types, inducing apoptosis at lower concentrations and necrosis at higher concentrations. These data show that the catechol and hydroquinone metabolites of remoxipride have direct toxic effects in HL60 and HBMP cells, leading to apoptosis, while the phenol metabolites were inactive. Similarly, CHEMICAL-derived catechol and hydroquinone, but not phenol, induce apoptosis in HBMP cells [Moran et al., Mol. Pharmacol., 50 (1996) 610-615]. We propose that remoxipride and CHEMICAL may induce DISEASE via production of similar reactive metabolites and that the ability of NCQ436 and NCQ344 to induce apoptosis in HBMP cells may contribute to the mechanism underlying acquired DISEASE that has been associated with remoxipride. | CHEMICAL-INDUCED-DISEASE |
| Induction of apoptosis by remoxipride metabolites in HL60 and CD34+/CD19- human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia. The antipsychotic agent, remoxipride [(S)-(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenz amide] has been associated with acquired aplastic anemia. We have examined the ability of remoxipride, three pyrrolidine ring metabolites and five aromatic ring metabolites of the parent compound to induce apoptosis in HL60 cells and human bone marrow progenitor (HBMP) cells. Cells were treated for 0-24 h with each compound (0-200 microM). Apoptosis was assessed by fluorescence microscopy in Hoechst 33342- and propidium iodide stained cell samples. Results were confirmed by determination of internucleosomal DNA fragmentation using gel electrophoresis for HL60 cell samples and terminal deoxynucleotidyl transferase assay in HBMP cells. The CHEMICAL and hydroquinone metabolites, NCQ436 and NCQ344, induced apoptosis in HL60 and HBMP cells in a time- and concentration dependent manner, while the phenols, NCR181, FLA873, and FLA797, and the derivatives formed by oxidation of the pyrrolidine ring, FLA838, NCM001, and NCL118, had no effect. No DISEASE was observed in cells treated with NCQ436 but NCQ344 had a biphasic effect in both cell types, inducing apoptosis at lower concentrations and DISEASE at higher concentrations. These data show that the CHEMICAL and hydroquinone metabolites of remoxipride have direct toxic effects in HL60 and HBMP cells, leading to apoptosis, while the phenol metabolites were inactive. Similarly, benzene-derived CHEMICAL and hydroquinone, but not phenol, induce apoptosis in HBMP cells [Moran et al., Mol. Pharmacol., 50 (1996) 610-615]. We propose that remoxipride and benzene may induce aplastic anemia via production of similar reactive metabolites and that the ability of NCQ436 and NCQ344 to induce apoptosis in HBMP cells may contribute to the mechanism underlying acquired aplastic anemia that has been associated with remoxipride. | NO-RELATIONSHIP |
| Induction of apoptosis by remoxipride metabolites in HL60 and CD34+/CD19- human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia. The antipsychotic agent, remoxipride [(S)-(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenz amide] has been associated with acquired aplastic anemia. We have examined the ability of remoxipride, three pyrrolidine ring metabolites and five aromatic ring metabolites of the parent compound to induce apoptosis in HL60 cells and human bone marrow progenitor (HBMP) cells. Cells were treated for 0-24 h with each compound (0-200 microM). Apoptosis was assessed by fluorescence microscopy in Hoechst 33342- and propidium iodide stained cell samples. Results were confirmed by determination of internucleosomal DNA fragmentation using gel electrophoresis for HL60 cell samples and terminal deoxynucleotidyl transferase assay in HBMP cells. The catechol and CHEMICAL metabolites, NCQ436 and NCQ344, induced apoptosis in HL60 and HBMP cells in a time- and concentration dependent manner, while the phenols, NCR181, FLA873, and FLA797, and the derivatives formed by oxidation of the pyrrolidine ring, FLA838, NCM001, and NCL118, had no effect. No DISEASE was observed in cells treated with NCQ436 but NCQ344 had a biphasic effect in both cell types, inducing apoptosis at lower concentrations and DISEASE at higher concentrations. These data show that the catechol and CHEMICAL metabolites of remoxipride have direct toxic effects in HL60 and HBMP cells, leading to apoptosis, while the phenol metabolites were inactive. Similarly, benzene-derived catechol and CHEMICAL, but not phenol, induce apoptosis in HBMP cells [Moran et al., Mol. Pharmacol., 50 (1996) 610-615]. We propose that remoxipride and benzene may induce aplastic anemia via production of similar reactive metabolites and that the ability of NCQ436 and NCQ344 to induce apoptosis in HBMP cells may contribute to the mechanism underlying acquired aplastic anemia that has been associated with remoxipride. | NO-RELATIONSHIP |
| Induction of apoptosis by remoxipride metabolites in HL60 and CD34+/CD19- human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia. The antipsychotic agent, remoxipride [(S)-(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenz amide] has been associated with acquired aplastic anemia. We have examined the ability of remoxipride, three pyrrolidine ring metabolites and five aromatic ring metabolites of the parent compound to induce apoptosis in HL60 cells and human bone marrow progenitor (HBMP) cells. Cells were treated for 0-24 h with each compound (0-200 microM). Apoptosis was assessed by fluorescence microscopy in CHEMICAL- and propidium iodide stained cell samples. Results were confirmed by determination of internucleosomal DNA fragmentation using gel electrophoresis for HL60 cell samples and terminal deoxynucleotidyl transferase assay in HBMP cells. The catechol and hydroquinone metabolites, NCQ436 and NCQ344, induced apoptosis in HL60 and HBMP cells in a time- and concentration dependent manner, while the phenols, NCR181, FLA873, and FLA797, and the derivatives formed by oxidation of the pyrrolidine ring, FLA838, NCM001, and NCL118, had no effect. No DISEASE was observed in cells treated with NCQ436 but NCQ344 had a biphasic effect in both cell types, inducing apoptosis at lower concentrations and DISEASE at higher concentrations. These data show that the catechol and hydroquinone metabolites of remoxipride have direct toxic effects in HL60 and HBMP cells, leading to apoptosis, while the phenol metabolites were inactive. Similarly, benzene-derived catechol and hydroquinone, but not phenol, induce apoptosis in HBMP cells [Moran et al., Mol. Pharmacol., 50 (1996) 610-615]. We propose that remoxipride and benzene may induce aplastic anemia via production of similar reactive metabolites and that the ability of NCQ436 and NCQ344 to induce apoptosis in HBMP cells may contribute to the mechanism underlying acquired aplastic anemia that has been associated with remoxipride. | NO-RELATIONSHIP |
| Induction of apoptosis by remoxipride metabolites in HL60 and CD34+/CD19- human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia. The antipsychotic agent, remoxipride [(S)-(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenz amide] has been associated with acquired aplastic anemia. We have examined the ability of remoxipride, three CHEMICAL ring metabolites and five aromatic ring metabolites of the parent compound to induce apoptosis in HL60 cells and human bone marrow progenitor (HBMP) cells. Cells were treated for 0-24 h with each compound (0-200 microM). Apoptosis was assessed by fluorescence microscopy in Hoechst 33342- and propidium iodide stained cell samples. Results were confirmed by determination of internucleosomal DNA fragmentation using gel electrophoresis for HL60 cell samples and terminal deoxynucleotidyl transferase assay in HBMP cells. The catechol and hydroquinone metabolites, NCQ436 and NCQ344, induced apoptosis in HL60 and HBMP cells in a time- and concentration dependent manner, while the phenols, NCR181, FLA873, and FLA797, and the derivatives formed by oxidation of the CHEMICAL ring, FLA838, NCM001, and NCL118, had no effect. No DISEASE was observed in cells treated with NCQ436 but NCQ344 had a biphasic effect in both cell types, inducing apoptosis at lower concentrations and DISEASE at higher concentrations. These data show that the catechol and hydroquinone metabolites of remoxipride have direct toxic effects in HL60 and HBMP cells, leading to apoptosis, while the phenol metabolites were inactive. Similarly, benzene-derived catechol and hydroquinone, but not phenol, induce apoptosis in HBMP cells [Moran et al., Mol. Pharmacol., 50 (1996) 610-615]. We propose that remoxipride and benzene may induce aplastic anemia via production of similar reactive metabolites and that the ability of NCQ436 and NCQ344 to induce apoptosis in HBMP cells may contribute to the mechanism underlying acquired aplastic anemia that has been associated with remoxipride. | NO-RELATIONSHIP |
| Induction of apoptosis by remoxipride metabolites in HL60 and CD34+/CD19- human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia. The antipsychotic agent, remoxipride [(S)-(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenz amide] has been associated with acquired aplastic anemia. We have examined the ability of remoxipride, three pyrrolidine ring metabolites and five aromatic ring metabolites of the parent compound to induce apoptosis in HL60 cells and human bone marrow progenitor (HBMP) cells. Cells were treated for 0-24 h with each compound (0-200 microM). Apoptosis was assessed by fluorescence microscopy in Hoechst 33342- and propidium iodide stained cell samples. Results were confirmed by determination of internucleosomal DNA fragmentation using gel electrophoresis for HL60 cell samples and terminal deoxynucleotidyl transferase assay in HBMP cells. The catechol and hydroquinone metabolites, NCQ436 and CHEMICAL, induced apoptosis in HL60 and HBMP cells in a time- and concentration dependent manner, while the phenols, NCR181, FLA873, and FLA797, and the derivatives formed by oxidation of the pyrrolidine ring, FLA838, NCM001, and NCL118, had no effect. No DISEASE was observed in cells treated with NCQ436 but CHEMICAL had a biphasic effect in both cell types, inducing apoptosis at lower concentrations and DISEASE at higher concentrations. These data show that the catechol and hydroquinone metabolites of remoxipride have direct toxic effects in HL60 and HBMP cells, leading to apoptosis, while the phenol metabolites were inactive. Similarly, benzene-derived catechol and hydroquinone, but not phenol, induce apoptosis in HBMP cells [Moran et al., Mol. Pharmacol., 50 (1996) 610-615]. We propose that remoxipride and benzene may induce aplastic anemia via production of similar reactive metabolites and that the ability of NCQ436 and CHEMICAL to induce apoptosis in HBMP cells may contribute to the mechanism underlying acquired aplastic anemia that has been associated with remoxipride. | NO-RELATIONSHIP |
| Induction of apoptosis by remoxipride metabolites in HL60 and CD34+/CD19- human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia. The antipsychotic agent, remoxipride [(S)-(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenz amide] has been associated with acquired aplastic anemia. We have examined the ability of remoxipride, three pyrrolidine ring metabolites and five aromatic ring metabolites of the parent compound to induce apoptosis in HL60 cells and human bone marrow progenitor (HBMP) cells. Cells were treated for 0-24 h with each compound (0-200 microM). Apoptosis was assessed by fluorescence microscopy in Hoechst 33342- and propidium iodide stained cell samples. Results were confirmed by determination of internucleosomal DNA fragmentation using gel electrophoresis for HL60 cell samples and terminal deoxynucleotidyl transferase assay in HBMP cells. The catechol and hydroquinone metabolites, CHEMICAL and NCQ344, induced apoptosis in HL60 and HBMP cells in a time- and concentration dependent manner, while the phenols, NCR181, FLA873, and FLA797, and the derivatives formed by oxidation of the pyrrolidine ring, FLA838, NCM001, and NCL118, had no effect. No DISEASE was observed in cells treated with CHEMICAL but NCQ344 had a biphasic effect in both cell types, inducing apoptosis at lower concentrations and DISEASE at higher concentrations. These data show that the catechol and hydroquinone metabolites of remoxipride have direct toxic effects in HL60 and HBMP cells, leading to apoptosis, while the phenol metabolites were inactive. Similarly, benzene-derived catechol and hydroquinone, but not phenol, induce apoptosis in HBMP cells [Moran et al., Mol. Pharmacol., 50 (1996) 610-615]. We propose that remoxipride and benzene may induce aplastic anemia via production of similar reactive metabolites and that the ability of CHEMICAL and NCQ344 to induce apoptosis in HBMP cells may contribute to the mechanism underlying acquired aplastic anemia that has been associated with remoxipride. | NO-RELATIONSHIP |
| Induction of apoptosis by remoxipride metabolites in HL60 and CD34+/CD19- human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia. The antipsychotic agent, remoxipride [(S)-(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenz amide] has been associated with acquired aplastic anemia. We have examined the ability of remoxipride, three pyrrolidine ring metabolites and five aromatic ring metabolites of the parent compound to induce apoptosis in HL60 cells and human bone marrow progenitor (HBMP) cells. Cells were treated for 0-24 h with each compound (0-200 microM). Apoptosis was assessed by fluorescence microscopy in Hoechst 33342- and CHEMICAL stained cell samples. Results were confirmed by determination of internucleosomal DNA fragmentation using gel electrophoresis for HL60 cell samples and terminal deoxynucleotidyl transferase assay in HBMP cells. The catechol and hydroquinone metabolites, NCQ436 and NCQ344, induced apoptosis in HL60 and HBMP cells in a time- and concentration dependent manner, while the phenols, NCR181, FLA873, and FLA797, and the derivatives formed by oxidation of the pyrrolidine ring, FLA838, NCM001, and NCL118, had no effect. No DISEASE was observed in cells treated with NCQ436 but NCQ344 had a biphasic effect in both cell types, inducing apoptosis at lower concentrations and DISEASE at higher concentrations. These data show that the catechol and hydroquinone metabolites of remoxipride have direct toxic effects in HL60 and HBMP cells, leading to apoptosis, while the phenol metabolites were inactive. Similarly, benzene-derived catechol and hydroquinone, but not phenol, induce apoptosis in HBMP cells [Moran et al., Mol. Pharmacol., 50 (1996) 610-615]. We propose that remoxipride and benzene may induce aplastic anemia via production of similar reactive metabolites and that the ability of NCQ436 and NCQ344 to induce apoptosis in HBMP cells may contribute to the mechanism underlying acquired aplastic anemia that has been associated with remoxipride. | NO-RELATIONSHIP |
| Induction of apoptosis by remoxipride metabolites in HL60 and CD34+/CD19- human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia. The antipsychotic agent, remoxipride [(S)-(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenz amide] has been associated with acquired aplastic anemia. We have examined the ability of remoxipride, three pyrrolidine ring metabolites and five aromatic ring metabolites of the parent compound to induce apoptosis in HL60 cells and human bone marrow progenitor (HBMP) cells. Cells were treated for 0-24 h with each compound (0-200 microM). Apoptosis was assessed by fluorescence microscopy in Hoechst 33342- and propidium iodide stained cell samples. Results were confirmed by determination of internucleosomal DNA fragmentation using gel electrophoresis for HL60 cell samples and terminal deoxynucleotidyl transferase assay in HBMP cells. The catechol and hydroquinone metabolites, NCQ436 and NCQ344, induced apoptosis in HL60 and HBMP cells in a time- and concentration dependent manner, while the CHEMICAL, NCR181, FLA873, and FLA797, and the derivatives formed by oxidation of the pyrrolidine ring, FLA838, NCM001, and NCL118, had no effect. No DISEASE was observed in cells treated with NCQ436 but NCQ344 had a biphasic effect in both cell types, inducing apoptosis at lower concentrations and DISEASE at higher concentrations. These data show that the catechol and hydroquinone metabolites of remoxipride have direct toxic effects in HL60 and HBMP cells, leading to apoptosis, while the phenol metabolites were inactive. Similarly, benzene-derived catechol and hydroquinone, but not phenol, induce apoptosis in HBMP cells [Moran et al., Mol. Pharmacol., 50 (1996) 610-615]. We propose that remoxipride and benzene may induce aplastic anemia via production of similar reactive metabolites and that the ability of NCQ436 and NCQ344 to induce apoptosis in HBMP cells may contribute to the mechanism underlying acquired aplastic anemia that has been associated with remoxipride. | NO-RELATIONSHIP |
| Induction of apoptosis by remoxipride metabolites in HL60 and CD34+/CD19- human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia. The antipsychotic agent, remoxipride [(S)-(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenz amide] has been associated with acquired aplastic anemia. We have examined the ability of remoxipride, three pyrrolidine ring metabolites and five aromatic ring metabolites of the parent compound to induce apoptosis in HL60 cells and human bone marrow progenitor (HBMP) cells. Cells were treated for 0-24 h with each compound (0-200 microM). Apoptosis was assessed by fluorescence microscopy in Hoechst 33342- and propidium iodide stained cell samples. Results were confirmed by determination of internucleosomal DNA fragmentation using gel electrophoresis for HL60 cell samples and terminal deoxynucleotidyl transferase assay in HBMP cells. The catechol and hydroquinone metabolites, NCQ436 and NCQ344, induced apoptosis in HL60 and HBMP cells in a time- and concentration dependent manner, while the phenols, NCR181, FLA873, and CHEMICAL, and the derivatives formed by oxidation of the pyrrolidine ring, FLA838, NCM001, and NCL118, had no effect. No DISEASE was observed in cells treated with NCQ436 but NCQ344 had a biphasic effect in both cell types, inducing apoptosis at lower concentrations and DISEASE at higher concentrations. These data show that the catechol and hydroquinone metabolites of remoxipride have direct toxic effects in HL60 and HBMP cells, leading to apoptosis, while the phenol metabolites were inactive. Similarly, benzene-derived catechol and hydroquinone, but not phenol, induce apoptosis in HBMP cells [Moran et al., Mol. Pharmacol., 50 (1996) 610-615]. We propose that remoxipride and benzene may induce aplastic anemia via production of similar reactive metabolites and that the ability of NCQ436 and NCQ344 to induce apoptosis in HBMP cells may contribute to the mechanism underlying acquired aplastic anemia that has been associated with remoxipride. | NO-RELATIONSHIP |
| Induction of apoptosis by remoxipride metabolites in HL60 and CD34+/CD19- human bone marrow progenitor cells: potential relevance to remoxipride-induced aplastic anemia. The antipsychotic agent, remoxipride [(S)-(-)-3-bromo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenz amide] has been associated with acquired aplastic anemia. We have examined the ability of remoxipride, three pyrrolidine ring metabolites and five aromatic ring metabolites of the parent compound to induce apoptosis in HL60 cells and human bone marrow progenitor (HBMP) cells. Cells were treated for 0-24 h with each compound (0-200 microM). Apoptosis was assessed by fluorescence microscopy in Hoechst 33342- and propidium iodide stained cell samples. Results were confirmed by determination of internucleosomal DNA fragmentation using gel electrophoresis for HL60 cell samples and terminal deoxynucleotidyl transferase assay in HBMP cells. The catechol and hydroquinone metabolites, NCQ436 and NCQ344, induced apoptosis in HL60 and HBMP cells in a time- and concentration dependent manner, while the phenols, NCR181, FLA873, and FLA797, and the derivatives formed by oxidation of the pyrrolidine ring, FLA838, NCM001, and NCL118, had no effect. No DISEASE was observed in cells treated with NCQ436 but NCQ344 had a biphasic effect in both cell types, inducing apoptosis at lower concentrations and DISEASE at higher concentrations. These data show that the catechol and hydroquinone metabolites of remoxipride have direct toxic effects in HL60 and HBMP cells, leading to apoptosis, while the CHEMICAL metabolites were inactive. Similarly, benzene-derived catechol and hydroquinone, but not CHEMICAL, induce apoptosis in HBMP cells [Moran et al., Mol. Pharmacol., 50 (1996) 610-615]. We propose that remoxipride and benzene may induce aplastic anemia via production of similar reactive metabolites and that the ability of NCQ436 and NCQ344 to induce apoptosis in HBMP cells may contribute to the mechanism underlying acquired aplastic anemia that has been associated with remoxipride. | NO-RELATIONSHIP |
| Synthesis and preliminary pharmacological investigations of 1-(1,2-dihydro-2-acenaphthylenyl)piperazine derivatives as potential atypical antipsychotic agents in mice. In research towards the development of new atypical antipsychotic agents, one strategy is that the dopaminergic system can be modulated through manipulation of the serotonergic system. The synthesis and preliminary pharmacological evaluation of a series of potential atypical antipsychotic agents based on the structure of 1-(1,2-dihydro-2-acenaphthylenyl)piperazine (7) is described. Compound 7e, 5-{2-[4-(1,2-dihydro-2-acenaphthylenyl)piperazinyl]ethyl}-2,3-dihy dro-1H- indol-2-one, from this series showed significant affinities at the 5-HT1A and 5-HT2A receptors and moderate affinity at the D2 receptor. 7e exhibits a high reversal of DISEASE induced by CHEMICAL indicating its atypical antipsychotic nature. | CHEMICAL-INDUCED-DISEASE |
| Sub-chronic inhibition of nitric-oxide synthesis modifies CHEMICAL-induced DISEASE and the number of NADPH-diaphorase neurons in mice. RATIONALE: NG-nitro-L-arginine (L-NOARG), an inhibitor of nitric-oxide synthase (NOS), induces DISEASE in mice. This effect undergoes rapid tolerance, showing a significant decrease after 2 days of sub-chronic L-NOARG treatment. Nitric oxide (NO) has been shown to influence dopaminergic neurotransmission in the striatum. Neuroleptic drugs such as CHEMICAL, which block dopamine receptors, also cause DISEASE in rodents. OBJECTIVES: To investigate the effects of subchronic L-NOARG treatment in CHEMICAL-induced DISEASE and the number of NOS neurons in areas related to motor control. METHODS: Male albino Swiss mice were treated sub-chronically (twice a day for 4 days) with L-NOARG (40 mg/kg i.p.) or CHEMICAL (1 mg/kg i.p.). DISEASE was evaluated at the beginning and the end of the treatments. Reduced nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry was also employed to visualize NOS as an index of enzyme expression in mice brain regions related to motor control. RESULTS: L-NOARG sub-chronic administration produced tolerance of L-NOARG and of CHEMICAL-induced DISEASE. It also induced an increase in the number of NADPH-d-positive cells in the dorsal part of the caudate and accumbens nuclei compared with CHEMICAL and in the pedunculopontine tegmental nucleus compared with saline. In contrast, there was a decrease in NADPH-d neuron number in the substantia nigra, pars compacta in both CHEMICAL-treated and L-NOARG-treated animals. CONCLUSIONS: The results give further support to the hypothesis that NO plays a role in motor behavior control and suggest that it may take part in the synaptic changes produced by antipsychotic treatment. | CHEMICAL-INDUCED-DISEASE |
| Prolonged DISEASE occurs in patients with coronary artery disease after both CHEMICAL and exercise induced myocardial ischaemia. OBJECTIVE: To determine whether pharmacological stress leads to prolonged but reversible DISEASE in patients with coronary artery disease, similar to that seen after exercise. DESIGN: A randomised crossover study of recovery time of systolic and diastolic left ventricular function after exercise and CHEMICAL induced ischaemia. SUBJECTS: 10 patients with stable angina, angiographically proven coronary artery disease, and normal left ventricular function. INTERVENTIONS: Treadmill exercise and CHEMICAL stress were performed on different days. Quantitative assessment of systolic and diastolic left ventricular function was performed using transthoracic echocardiography at baseline and at regular intervals after each test. RESULTS: Both forms of stress led to prolonged but reversible systolic and diastolic dysfunction. There was no difference in the maximum double product (p = 0.53) or ST depression (p = 0.63) with either form of stress. After exercise, ejection fraction was reduced at 15 and 30 minutes compared with baseline (mean (SEM), -5.6 (1.5)%, p < 0.05; and -6.1 (2.2)%, p < 0. 01), and at 30 and 45 minutes after CHEMICAL (-10.8 (1.8)% and -5. 5 (1.8)%, both p < 0.01). Regional analysis showed a reduction in the worst affected segment 15 and 30 minutes after exercise (-27.9 (7.2)% and -28.6 (5.7)%, both p < 0.01), and at 30 minutes after CHEMICAL (-32 (5.3)%, p < 0.01). The isovolumic relaxation period was prolonged 45 minutes after each form of stress (p < 0.05). CONCLUSIONS: In patients with coronary artery disease, CHEMICAL induced ischaemia results in prolonged reversible DISEASE, presumed to be myocardial stunning, similar to that seen after exercise. CHEMICAL induced ischaemia could therefore be used to study the pathophysiology of this phenomenon further in patients with coronary artery disease. | CHEMICAL-INDUCED-DISEASE |
| Prolonged left ventricular dysfunction occurs in patients with coronary artery disease after both CHEMICAL and exercise induced myocardial ischaemia. OBJECTIVE: To determine whether pharmacological stress leads to prolonged but reversible left ventricular dysfunction in patients with coronary artery disease, similar to that seen after exercise. DESIGN: A randomised crossover study of recovery time of systolic and diastolic left ventricular function after exercise and CHEMICAL induced ischaemia. SUBJECTS: 10 patients with stable angina, angiographically proven coronary artery disease, and normal left ventricular function. INTERVENTIONS: Treadmill exercise and CHEMICAL stress were performed on different days. Quantitative assessment of systolic and diastolic left ventricular function was performed using transthoracic echocardiography at baseline and at regular intervals after each test. RESULTS: Both forms of stress led to prolonged but reversible systolic and diastolic dysfunction. There was no difference in the maximum double product (p = 0.53) or ST depression (p = 0.63) with either form of stress. After exercise, ejection fraction was reduced at 15 and 30 minutes compared with baseline (mean (SEM), -5.6 (1.5)%, p < 0.05; and -6.1 (2.2)%, p < 0. 01), and at 30 and 45 minutes after CHEMICAL (-10.8 (1.8)% and -5. 5 (1.8)%, both p < 0.01). Regional analysis showed a reduction in the worst affected segment 15 and 30 minutes after exercise (-27.9 (7.2)% and -28.6 (5.7)%, both p < 0.01), and at 30 minutes after CHEMICAL (-32 (5.3)%, p < 0.01). The isovolumic relaxation period was prolonged 45 minutes after each form of stress (p < 0.05). CONCLUSIONS: In patients with coronary artery disease, CHEMICAL induced ischaemia results in prolonged reversible left ventricular dysfunction, presumed to be DISEASE, similar to that seen after exercise. CHEMICAL induced ischaemia could therefore be used to study the pathophysiology of this phenomenon further in patients with coronary artery disease. | CHEMICAL-INDUCED-DISEASE |
| Anorexigens and DISEASE in the United States: results from the surveillance of North American DISEASE. BACKGROUND: The use of appetite suppressants in Europe has been associated with the development of DISEASE (DISEASE). Recently, CHEMICAL appetite suppressants became widely used in the United States but were withdrawn in September 1997 because of concerns over adverse effects. MATERIALS AND METHODS: We conducted a prospective surveillance study on patients diagnosed with DISEASE at 12 large referral centers in North America. Data collected on patients seen from September 1, 1996, to December 31, 1997, included the cause of the DISEASE and its severity. Patients with no identifiable cause of DISEASE were classed as DISEASE. A history of drug exposure also was taken with special attention on the use of antidepressants, anorexigens, and amphetamines. RESULTS: Five hundred seventy-nine patients were studied, 205 with DISEASE and 374 with DISEASE from other causes (secondary DISEASE [SPH]). The use of anorexigens was common in both groups. However, of the medications surveyed, only the CHEMICAL had a significant preferential association with DISEASE as compared with SPH (adjusted odds ratio for use > 6 months, 7.5; 95% confidence interval, 1.7 to 32.4). The association was stronger with longer duration of use when compared to shorter duration of use and was more pronounced in recent users than in remote users. An unexpectedly high (11.4%) number of patients with SPH had used anorexigens. CONCLUSION: The magnitude of the association with DISEASE, the increase of association with increasing duration of use, and the specificity for CHEMICAL are consistent with previous studies indicating that CHEMICAL are causally related to DISEASE. The high prevalence of anorexigen use in patients with SPH also raises the possibility that these drugs precipitate DISEASE in patients with underlying conditions associated with SPH. | CHEMICAL-INDUCED-DISEASE |
| Clinical aspects of CHEMICAL-induced thrombocytopenia and thrombosis and other side effects of CHEMICAL therapy. CHEMICAL, first used to prevent the clotting of blood in vitro, has been clinically used to treat thrombosis for more than 50 years. Although several new anticoagulant drugs are in development, CHEMICAL remains the anticoagulant of choice to treat acute thrombotic episodes. The clinical effects of CHEMICAL are meritorious, but side effects do exist. Bleeding is the primary untoward effect of CHEMICAL. Major bleeding is of primary concern in patients receiving CHEMICAL therapy. However, additional important untoward effects of CHEMICAL therapy include CHEMICAL-induced thrombocytopenia, CHEMICAL-associated osteoporosis, eosinophilia, DISEASE, allergic reactions other than thrombocytopenia, alopecia, transaminasemia, hyperkalemia, hypoaldosteronism, and priapism. These side effects are relatively rare in a given individual, but given the extremely widespread use of CHEMICAL, some are quite common, particularly HITT and osteoporosis. Although reasonable incidences of many of these side effects can be "softly" deduced from current reports dealing with unfractionated CHEMICAL, at present the incidences of these side effects with newer low molecular weight CHEMICAL appear to be much less common. However, only longer experience will more clearly define the incidence of each side effect with low molecular weight preparations. | CHEMICAL-INDUCED-DISEASE |
| Clinical aspects of CHEMICAL-induced thrombocytopenia and thrombosis and other side effects of CHEMICAL therapy. CHEMICAL, first used to prevent the clotting of blood in vitro, has been clinically used to treat thrombosis for more than 50 years. Although several new anticoagulant drugs are in development, CHEMICAL remains the anticoagulant of choice to treat acute thrombotic episodes. The clinical effects of CHEMICAL are meritorious, but side effects do exist. Bleeding is the primary untoward effect of CHEMICAL. Major bleeding is of primary concern in patients receiving CHEMICAL therapy. However, additional important untoward effects of CHEMICAL therapy include CHEMICAL-induced thrombocytopenia, CHEMICAL-associated osteoporosis, eosinophilia, skin reactions, DISEASE other than thrombocytopenia, alopecia, transaminasemia, hyperkalemia, hypoaldosteronism, and priapism. These side effects are relatively rare in a given individual, but given the extremely widespread use of CHEMICAL, some are quite common, particularly HITT and osteoporosis. Although reasonable incidences of many of these side effects can be "softly" deduced from current reports dealing with unfractionated CHEMICAL, at present the incidences of these side effects with newer low molecular weight CHEMICAL appear to be much less common. However, only longer experience will more clearly define the incidence of each side effect with low molecular weight preparations. | CHEMICAL-INDUCED-DISEASE |
| Clinical aspects of CHEMICAL-induced DISEASE and thrombosis and other side effects of CHEMICAL therapy. CHEMICAL, first used to prevent the clotting of blood in vitro, has been clinically used to treat thrombosis for more than 50 years. Although several new anticoagulant drugs are in development, CHEMICAL remains the anticoagulant of choice to treat acute thrombotic episodes. The clinical effects of CHEMICAL are meritorious, but side effects do exist. Bleeding is the primary untoward effect of CHEMICAL. Major bleeding is of primary concern in patients receiving CHEMICAL therapy. However, additional important untoward effects of CHEMICAL therapy include CHEMICAL-induced DISEASE, CHEMICAL-associated osteoporosis, eosinophilia, skin reactions, allergic reactions other than DISEASE, alopecia, transaminasemia, hyperkalemia, hypoaldosteronism, and priapism. These side effects are relatively rare in a given individual, but given the extremely widespread use of CHEMICAL, some are quite common, particularly HITT and osteoporosis. Although reasonable incidences of many of these side effects can be "softly" deduced from current reports dealing with unfractionated CHEMICAL, at present the incidences of these side effects with newer low molecular weight CHEMICAL appear to be much less common. However, only longer experience will more clearly define the incidence of each side effect with low molecular weight preparations. | CHEMICAL-INDUCED-DISEASE |
| Clinical aspects of CHEMICAL-induced thrombocytopenia and thrombosis and other side effects of CHEMICAL therapy. CHEMICAL, first used to prevent the clotting of blood in vitro, has been clinically used to treat thrombosis for more than 50 years. Although several new anticoagulant drugs are in development, CHEMICAL remains the anticoagulant of choice to treat acute thrombotic episodes. The clinical effects of CHEMICAL are meritorious, but side effects do exist. Bleeding is the primary untoward effect of CHEMICAL. Major bleeding is of primary concern in patients receiving CHEMICAL therapy. However, additional important untoward effects of CHEMICAL therapy include CHEMICAL-induced thrombocytopenia, CHEMICAL-associated osteoporosis, eosinophilia, skin reactions, allergic reactions other than thrombocytopenia, alopecia, transaminasemia, DISEASE, hypoaldosteronism, and priapism. These side effects are relatively rare in a given individual, but given the extremely widespread use of CHEMICAL, some are quite common, particularly HITT and osteoporosis. Although reasonable incidences of many of these side effects can be "softly" deduced from current reports dealing with unfractionated CHEMICAL, at present the incidences of these side effects with newer low molecular weight CHEMICAL appear to be much less common. However, only longer experience will more clearly define the incidence of each side effect with low molecular weight preparations. | CHEMICAL-INDUCED-DISEASE |
| Clinical aspects of CHEMICAL-induced thrombocytopenia and thrombosis and other side effects of CHEMICAL therapy. CHEMICAL, first used to prevent the clotting of blood in vitro, has been clinically used to treat thrombosis for more than 50 years. Although several new anticoagulant drugs are in development, CHEMICAL remains the anticoagulant of choice to treat acute thrombotic episodes. The clinical effects of CHEMICAL are meritorious, but side effects do exist. Bleeding is the primary untoward effect of CHEMICAL. Major bleeding is of primary concern in patients receiving CHEMICAL therapy. However, additional important untoward effects of CHEMICAL therapy include CHEMICAL-induced thrombocytopenia, CHEMICAL-associated DISEASE, eosinophilia, skin reactions, allergic reactions other than thrombocytopenia, alopecia, transaminasemia, hyperkalemia, hypoaldosteronism, and priapism. These side effects are relatively rare in a given individual, but given the extremely widespread use of CHEMICAL, some are quite common, particularly HITT and DISEASE. Although reasonable incidences of many of these side effects can be "softly" deduced from current reports dealing with unfractionated CHEMICAL, at present the incidences of these side effects with newer low molecular weight CHEMICAL appear to be much less common. However, only longer experience will more clearly define the incidence of each side effect with low molecular weight preparations. | CHEMICAL-INDUCED-DISEASE |
| Clinical aspects of CHEMICAL-induced thrombocytopenia and thrombosis and other side effects of CHEMICAL therapy. CHEMICAL, first used to prevent the clotting of blood in vitro, has been clinically used to treat thrombosis for more than 50 years. Although several new anticoagulant drugs are in development, CHEMICAL remains the anticoagulant of choice to treat acute thrombotic episodes. The clinical effects of CHEMICAL are meritorious, but side effects do exist. Bleeding is the primary untoward effect of CHEMICAL. Major bleeding is of primary concern in patients receiving CHEMICAL therapy. However, additional important untoward effects of CHEMICAL therapy include CHEMICAL-induced thrombocytopenia, CHEMICAL-associated osteoporosis, eosinophilia, skin reactions, allergic reactions other than thrombocytopenia, alopecia, transaminasemia, hyperkalemia, hypoaldosteronism, and DISEASE. These side effects are relatively rare in a given individual, but given the extremely widespread use of CHEMICAL, some are quite common, particularly HITT and osteoporosis. Although reasonable incidences of many of these side effects can be "softly" deduced from current reports dealing with unfractionated CHEMICAL, at present the incidences of these side effects with newer low molecular weight CHEMICAL appear to be much less common. However, only longer experience will more clearly define the incidence of each side effect with low molecular weight preparations. | CHEMICAL-INDUCED-DISEASE |
| Clinical aspects of CHEMICAL-induced thrombocytopenia and thrombosis and other side effects of CHEMICAL therapy. CHEMICAL, first used to prevent the clotting of blood in vitro, has been clinically used to treat thrombosis for more than 50 years. Although several new anticoagulant drugs are in development, CHEMICAL remains the anticoagulant of choice to treat acute thrombotic episodes. The clinical effects of CHEMICAL are meritorious, but side effects do exist. Bleeding is the primary untoward effect of CHEMICAL. Major bleeding is of primary concern in patients receiving CHEMICAL therapy. However, additional important untoward effects of CHEMICAL therapy include CHEMICAL-induced thrombocytopenia, CHEMICAL-associated osteoporosis, eosinophilia, skin reactions, allergic reactions other than thrombocytopenia, alopecia, transaminasemia, hyperkalemia, DISEASE, and priapism. These side effects are relatively rare in a given individual, but given the extremely widespread use of CHEMICAL, some are quite common, particularly HITT and osteoporosis. Although reasonable incidences of many of these side effects can be "softly" deduced from current reports dealing with unfractionated CHEMICAL, at present the incidences of these side effects with newer low molecular weight CHEMICAL appear to be much less common. However, only longer experience will more clearly define the incidence of each side effect with low molecular weight preparations. | CHEMICAL-INDUCED-DISEASE |
| Clinical aspects of CHEMICAL-induced thrombocytopenia and thrombosis and other side effects of CHEMICAL therapy. CHEMICAL, first used to prevent the clotting of blood in vitro, has been clinically used to treat thrombosis for more than 50 years. Although several new anticoagulant drugs are in development, CHEMICAL remains the anticoagulant of choice to treat acute thrombotic episodes. The clinical effects of CHEMICAL are meritorious, but side effects do exist. Bleeding is the primary untoward effect of CHEMICAL. Major bleeding is of primary concern in patients receiving CHEMICAL therapy. However, additional important untoward effects of CHEMICAL therapy include CHEMICAL-induced thrombocytopenia, CHEMICAL-associated osteoporosis, DISEASE, skin reactions, allergic reactions other than thrombocytopenia, alopecia, transaminasemia, hyperkalemia, hypoaldosteronism, and priapism. These side effects are relatively rare in a given individual, but given the extremely widespread use of CHEMICAL, some are quite common, particularly HITT and osteoporosis. Although reasonable incidences of many of these side effects can be "softly" deduced from current reports dealing with unfractionated CHEMICAL, at present the incidences of these side effects with newer low molecular weight CHEMICAL appear to be much less common. However, only longer experience will more clearly define the incidence of each side effect with low molecular weight preparations. | CHEMICAL-INDUCED-DISEASE |
| Clinical aspects of CHEMICAL-induced thrombocytopenia and thrombosis and other side effects of CHEMICAL therapy. CHEMICAL, first used to prevent the clotting of blood in vitro, has been clinically used to treat thrombosis for more than 50 years. Although several new anticoagulant drugs are in development, CHEMICAL remains the anticoagulant of choice to treat acute thrombotic episodes. The clinical effects of CHEMICAL are meritorious, but side effects do exist. Bleeding is the primary untoward effect of CHEMICAL. Major bleeding is of primary concern in patients receiving CHEMICAL therapy. However, additional important untoward effects of CHEMICAL therapy include CHEMICAL-induced thrombocytopenia, CHEMICAL-associated osteoporosis, eosinophilia, skin reactions, allergic reactions other than thrombocytopenia, DISEASE, transaminasemia, hyperkalemia, hypoaldosteronism, and priapism. These side effects are relatively rare in a given individual, but given the extremely widespread use of CHEMICAL, some are quite common, particularly HITT and osteoporosis. Although reasonable incidences of many of these side effects can be "softly" deduced from current reports dealing with unfractionated CHEMICAL, at present the incidences of these side effects with newer low molecular weight CHEMICAL appear to be much less common. However, only longer experience will more clearly define the incidence of each side effect with low molecular weight preparations. | CHEMICAL-INDUCED-DISEASE |
| A case of bilateral DISEASE in a patient on CHEMICAL (CHEMICAL) therapy after liver transplantation. PURPOSE: To report a case of bilateral DISEASE in a patient receiving CHEMICAL (CHEMICAL, Prograf; Fujisawa USA, Inc, Deerfield, Illinois) for immunosuppression after orthotropic liver transplantation. METHOD: Case report. In a 58-year-old man receiving CHEMICAL after orthotropic liver transplantation, serial neuro-ophthalmologic examinations and laboratory studies were performed. RESULTS: The patient had episodic deterioration of vision in both eyes, with clinical features resembling ischemic optic neuropathies. Deterioration of vision occurred despite discontinuation of the CHEMICAL. CONCLUSION: CHEMICAL and other immunosuppressive agents may be associated with DISEASE. | CHEMICAL-INDUCED-DISEASE |
| DISEASE, arrhythmia, and mood stabilizers. Recent findings in a bipolar patient receiving maintenance CHEMICAL therapy who developed DISEASE and severe bradyarrhythmia prompted the authors to conduct a retrospective study of bipolar patients with CHEMICAL-associated DISEASE. A printout of all cases of DISEASE that presented during a 1-year period was generated. After eliminating spurious DISEASE or those associated with intravenous fluids, the authors identified 18 non-CHEMICAL-treated patients with DISEASE related to malignancies and other medical conditions (group A) and 12 patients with CHEMICAL-associated DISEASE (group B). Patients in group B were not comparable to those in group A, as the latter were medically compromised and were receiving multiple pharmacotherapies. Thus, two control groups were generated: group C1, which included age- and sex-comparable CHEMICAL-treated bipolar normocalcemic patients, and group C2, which included bipolar normocalcemic patients treated with anticonvulsant mood stabilizers. The electrocardiographic (ECG) findings for patients in group B were compared with those of patients in groups C1 and C2. It was found that these groups did not differ in their overall frequency of ECG abnormalities; however, there were significant differences in the frequency of conduction defects. Patients with DISEASE resulting from medical diseases and bipolar patients with CHEMICAL-associated DISEASE had significantly higher frequencies of conduction defects. Patients in group A had significant mortality at 2-year follow-up (28%), in contrast to zero mortality in the other three groups. The clinical implications of these findings are discussed. | CHEMICAL-INDUCED-DISEASE |
| Attenuation of nephrotoxicity by a novel lipid nanosphere (NS-718) incorporating amphotericin B. NS-718, a lipid nanosphere incorporating amphotericin B, is effective against pathogenic fungi and has low toxicity. We compared the toxicity of NS-718 with that of Fungizone (CHEMICAL; CHEMICAL) in vitro using renal cell cultures and in vivo by biochemical analysis, histopathological study of the kidney and pharmacokinetic study of amphotericin B following intravenous infusion of the formulation in rats. Incubation with NS-718 resulted in significantly less damage of cultured human renal proximal tubular epithelial cells compared with CHEMICAL. Serum blood urea and creatinine concentrations increased significantly in rats given an iv infusion of CHEMICAL 3 mg/kg but not in those given the same dose of NS-718. Histopathological examination of the kidney showed DISEASE in CHEMICAL-treated rats but no change in NS-718-treated rats. Amphotericin B concentrations in the kidney in NS-718-treated rats were higher than those in CHEMICAL-treated rats. Our in vitro and in vivo results suggest that incorporation of amphotericin B into lipid nanospheres of NS-718 attenuates the nephrotoxicity of amphotericin B. | CHEMICAL-INDUCED-DISEASE |
| Attenuation of DISEASE by a novel lipid nanosphere (NS-718) incorporating amphotericin B. NS-718, a lipid nanosphere incorporating amphotericin B, is effective against pathogenic fungi and has low toxicity. We compared the toxicity of NS-718 with that of Fungizone (amphotericin B-sodium deoxycholate; D-AmB) in vitro using renal cell cultures and in vivo by biochemical analysis, histopathological study of the kidney and pharmacokinetic study of amphotericin B following intravenous infusion of the formulation in rats. Incubation with NS-718 resulted in significantly less damage of cultured human renal proximal tubular epithelial cells compared with D-AmB. Serum blood CHEMICAL and creatinine concentrations increased significantly in rats given an iv infusion of D-AmB 3 mg/kg but not in those given the same dose of NS-718. Histopathological examination of the kidney showed tubular necrosis in D-AmB-treated rats but no change in NS-718-treated rats. Amphotericin B concentrations in the kidney in NS-718-treated rats were higher than those in D-AmB-treated rats. Our in vitro and in vivo results suggest that incorporation of amphotericin B into lipid nanospheres of NS-718 attenuates the DISEASE of amphotericin B. | NO-RELATIONSHIP |
| Attenuation of nephrotoxicity by a novel lipid nanosphere (NS-718) incorporating amphotericin B. NS-718, a lipid nanosphere incorporating amphotericin B, is effective against pathogenic fungi and has low DISEASE. We compared the DISEASE of NS-718 with that of Fungizone (amphotericin B-sodium deoxycholate; D-AmB) in vitro using renal cell cultures and in vivo by biochemical analysis, histopathological study of the kidney and pharmacokinetic study of amphotericin B following intravenous infusion of the formulation in rats. Incubation with NS-718 resulted in significantly less damage of cultured human renal proximal tubular epithelial cells compared with D-AmB. Serum blood urea and CHEMICAL concentrations increased significantly in rats given an iv infusion of D-AmB 3 mg/kg but not in those given the same dose of NS-718. Histopathological examination of the kidney showed tubular necrosis in D-AmB-treated rats but no change in NS-718-treated rats. Amphotericin B concentrations in the kidney in NS-718-treated rats were higher than those in D-AmB-treated rats. Our in vitro and in vivo results suggest that incorporation of amphotericin B into lipid nanospheres of NS-718 attenuates the nephrotoxicity of amphotericin B. | NO-RELATIONSHIP |
| Attenuation of nephrotoxicity by a novel lipid nanosphere (NS-718) incorporating CHEMICAL. NS-718, a lipid nanosphere incorporating CHEMICAL, is effective against pathogenic fungi and has low DISEASE. We compared the DISEASE of NS-718 with that of CHEMICAL (amphotericin B-sodium deoxycholate; D-AmB) in vitro using renal cell cultures and in vivo by biochemical analysis, histopathological study of the kidney and pharmacokinetic study of CHEMICAL following intravenous infusion of the formulation in rats. Incubation with NS-718 resulted in significantly less damage of cultured human renal proximal tubular epithelial cells compared with D-AmB. Serum blood urea and creatinine concentrations increased significantly in rats given an iv infusion of D-AmB 3 mg/kg but not in those given the same dose of NS-718. Histopathological examination of the kidney showed tubular necrosis in D-AmB-treated rats but no change in NS-718-treated rats. CHEMICAL concentrations in the kidney in NS-718-treated rats were higher than those in D-AmB-treated rats. Our in vitro and in vivo results suggest that incorporation of CHEMICAL into lipid nanospheres of NS-718 attenuates the nephrotoxicity of CHEMICAL. | NO-RELATIONSHIP |
| Attenuation of nephrotoxicity by a novel lipid nanosphere (NS-718) incorporating amphotericin B. NS-718, a lipid nanosphere incorporating amphotericin B, is effective against pathogenic fungi and has low DISEASE. We compared the DISEASE of NS-718 with that of Fungizone (amphotericin B-sodium deoxycholate; D-AmB) in vitro using renal cell cultures and in vivo by biochemical analysis, histopathological study of the kidney and pharmacokinetic study of amphotericin B following intravenous infusion of the formulation in rats. Incubation with NS-718 resulted in significantly less damage of cultured human renal proximal tubular epithelial cells compared with D-AmB. Serum blood CHEMICAL and creatinine concentrations increased significantly in rats given an iv infusion of D-AmB 3 mg/kg but not in those given the same dose of NS-718. Histopathological examination of the kidney showed tubular necrosis in D-AmB-treated rats but no change in NS-718-treated rats. Amphotericin B concentrations in the kidney in NS-718-treated rats were higher than those in D-AmB-treated rats. Our in vitro and in vivo results suggest that incorporation of amphotericin B into lipid nanospheres of NS-718 attenuates the nephrotoxicity of amphotericin B. | NO-RELATIONSHIP |
| Attenuation of DISEASE by a novel lipid nanosphere (NS-718) incorporating CHEMICAL. NS-718, a lipid nanosphere incorporating CHEMICAL, is effective against pathogenic fungi and has low toxicity. We compared the toxicity of NS-718 with that of CHEMICAL (amphotericin B-sodium deoxycholate; D-AmB) in vitro using renal cell cultures and in vivo by biochemical analysis, histopathological study of the kidney and pharmacokinetic study of CHEMICAL following intravenous infusion of the formulation in rats. Incubation with NS-718 resulted in significantly less damage of cultured human renal proximal tubular epithelial cells compared with D-AmB. Serum blood urea and creatinine concentrations increased significantly in rats given an iv infusion of D-AmB 3 mg/kg but not in those given the same dose of NS-718. Histopathological examination of the kidney showed tubular necrosis in D-AmB-treated rats but no change in NS-718-treated rats. CHEMICAL concentrations in the kidney in NS-718-treated rats were higher than those in D-AmB-treated rats. Our in vitro and in vivo results suggest that incorporation of CHEMICAL into lipid nanospheres of NS-718 attenuates the DISEASE of CHEMICAL. | NO-RELATIONSHIP |
| Attenuation of DISEASE by a novel lipid nanosphere (NS-718) incorporating amphotericin B. NS-718, a lipid nanosphere incorporating amphotericin B, is effective against pathogenic fungi and has low toxicity. We compared the toxicity of NS-718 with that of Fungizone (amphotericin B-sodium deoxycholate; D-AmB) in vitro using renal cell cultures and in vivo by biochemical analysis, histopathological study of the kidney and pharmacokinetic study of amphotericin B following intravenous infusion of the formulation in rats. Incubation with NS-718 resulted in significantly less damage of cultured human renal proximal tubular epithelial cells compared with D-AmB. Serum blood urea and CHEMICAL concentrations increased significantly in rats given an iv infusion of D-AmB 3 mg/kg but not in those given the same dose of NS-718. Histopathological examination of the kidney showed tubular necrosis in D-AmB-treated rats but no change in NS-718-treated rats. Amphotericin B concentrations in the kidney in NS-718-treated rats were higher than those in D-AmB-treated rats. Our in vitro and in vivo results suggest that incorporation of amphotericin B into lipid nanospheres of NS-718 attenuates the DISEASE of amphotericin B. | NO-RELATIONSHIP |
| Patterns of CHEMICAL acute nephrotoxicity. CHEMICAL acute nephrotoxicity is reviving specially because of its use in toxoplasmosis in HIV-positive patients. We report 4 cases, one of them in a previously healthy person. Under treatment with CHEMICAL they developed oliguria, abdominal pain, renal failure and showed multiple radiolucent DISEASE in echography. All patients recovered their previous normal renal function after adequate hydration and alcalinization. A nephrostomy tube had to be placed in one of the patients for ureteral lithiasis in a single functional kidney. None of them needed dialysis or a renal biopsy because of a typical benign course. Treatment with CHEMICAL requires exquisite control of renal function, an increase in water ingestion and possibly the alcalinization of the urine. We communicate a case in a previously healthy person, a fact not found in the recent literature. Probably many more cases are not detected. We think that a prospective study would be useful. | CHEMICAL-INDUCED-DISEASE |
| Patterns of CHEMICAL DISEASE. CHEMICAL DISEASE is reviving specially because of its use in toxoplasmosis in HIV-positive patients. We report 4 cases, one of them in a previously healthy person. Under treatment with CHEMICAL they developed oliguria, abdominal pain, renal failure and showed multiple radiolucent renal calculi in echography. All patients recovered their previous normal renal function after adequate hydration and alcalinization. A nephrostomy tube had to be placed in one of the patients for ureteral lithiasis in a single functional kidney. None of them needed dialysis or a renal biopsy because of a typical benign course. Treatment with CHEMICAL requires exquisite control of renal function, an increase in water ingestion and possibly the alcalinization of the urine. We communicate a case in a previously healthy person, a fact not found in the recent literature. Probably many more cases are not detected. We think that a prospective study would be useful. | CHEMICAL-INDUCED-DISEASE |
| Downbeat nystagmus associated with intravenous patient-controlled administration of CHEMICAL. IMPLICATIONS: This case documents a patient who developed DISEASE with downbeating nystagmus while receiving a relatively large dose of IV patient-controlled analgesia CHEMICAL. Although there have been case reports of epidural CHEMICAL with these symptoms and signs, this has not been previously documented with IV or patient-controlled analgesia CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| DISEASE associated with intravenous patient-controlled administration of CHEMICAL. IMPLICATIONS: This case documents a patient who developed dizziness with DISEASE while receiving a relatively large dose of IV patient-controlled analgesia CHEMICAL. Although there have been case reports of epidural CHEMICAL with these symptoms and signs, this has not been previously documented with IV or patient-controlled analgesia CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Hemodynamic and antiadrenergic effects of dronedarone and amiodarone in animals with a healed myocardial infarction. The hemodynamic and antiadrenergic effects of dronedarone, a noniodinated compound structurally related to amiodarone, were compared with those of amiodarone after prolonged oral administration, both at rest and during sympathetic stimulation in conscious dogs with a healed myocardial infarction. All dogs (n = 6) randomly received orally dronedarone (10 and 30 mg/kg), amiodarone (10 and 30 mg/kg), and placebo twice daily for 7 days, with a 3-week washout between consecutive treatments. Heart rate (HR), mean arterial pressure (MBP), positive rate of increase of left ventricular pressure (+LVdP/dt), echocardiographically assessed left ventricular ejection fraction (LVEF), and fractional shortening (FS), as well as chronotropic response to CHEMICAL and exercise-induced sympathetic stimulation were evaluated under baseline and posttreatment conditions. Resting values of LVEF, FS, +LVdP/dt, and MBP remained unchanged whatever the drug and the dosing regimen, whereas resting HR was significantly and dose-dependently lowered after dronedarone and to a lesser extent after amiodarone. Both dronedarone and amiodarone significantly reduced the exercise-induced DISEASE and, at the highest dose, decreased the CHEMICAL-induced DISEASE. Thus, dronedarone and amiodarone displayed a similar level of antiadrenergic effect and did not impair the resting left ventricular function. Consequently, dronedarone might be particularly suitable for the treatment and prevention of various clinical arrhythmias, without compromising the left ventricular function. | CHEMICAL-INDUCED-DISEASE |
| Hemodynamic and antiadrenergic effects of CHEMICAL and amiodarone in animals with a healed DISEASE. The hemodynamic and antiadrenergic effects of CHEMICAL, a noniodinated compound structurally related to amiodarone, were compared with those of amiodarone after prolonged oral administration, both at rest and during sympathetic stimulation in conscious dogs with a healed DISEASE. All dogs (n = 6) randomly received orally CHEMICAL (10 and 30 mg/kg), amiodarone (10 and 30 mg/kg), and placebo twice daily for 7 days, with a 3-week washout between consecutive treatments. Heart rate (HR), mean arterial pressure (MBP), positive rate of increase of left ventricular pressure (+LVdP/dt), echocardiographically assessed left ventricular ejection fraction (LVEF), and fractional shortening (FS), as well as chronotropic response to isoproterenol and exercise-induced sympathetic stimulation were evaluated under baseline and posttreatment conditions. Resting values of LVEF, FS, +LVdP/dt, and MBP remained unchanged whatever the drug and the dosing regimen, whereas resting HR was significantly and dose-dependently lowered after CHEMICAL and to a lesser extent after amiodarone. Both CHEMICAL and amiodarone significantly reduced the exercise-induced tachycardia and, at the highest dose, decreased the isoproterenol-induced tachycardia. Thus, CHEMICAL and amiodarone displayed a similar level of antiadrenergic effect and did not impair the resting left ventricular function. Consequently, CHEMICAL might be particularly suitable for the treatment and prevention of various clinical arrhythmias, without compromising the left ventricular function. | NO-RELATIONSHIP |
| Hemodynamic and antiadrenergic effects of dronedarone and CHEMICAL in animals with a healed myocardial infarction. The hemodynamic and antiadrenergic effects of dronedarone, a noniodinated compound structurally related to CHEMICAL, were compared with those of CHEMICAL after prolonged oral administration, both at rest and during sympathetic stimulation in conscious dogs with a healed myocardial infarction. All dogs (n = 6) randomly received orally dronedarone (10 and 30 mg/kg), CHEMICAL (10 and 30 mg/kg), and placebo twice daily for 7 days, with a 3-week washout between consecutive treatments. Heart rate (HR), mean arterial pressure (MBP), positive rate of increase of left ventricular pressure (+LVdP/dt), echocardiographically assessed left ventricular ejection fraction (LVEF), and fractional shortening (FS), as well as chronotropic response to isoproterenol and exercise-induced sympathetic stimulation were evaluated under baseline and posttreatment conditions. Resting values of LVEF, FS, +LVdP/dt, and MBP remained unchanged whatever the drug and the dosing regimen, whereas resting HR was significantly and dose-dependently lowered after dronedarone and to a lesser extent after CHEMICAL. Both dronedarone and CHEMICAL significantly reduced the exercise-induced tachycardia and, at the highest dose, decreased the isoproterenol-induced tachycardia. Thus, dronedarone and CHEMICAL displayed a similar level of antiadrenergic effect and did not impair the resting left ventricular function. Consequently, dronedarone might be particularly suitable for the treatment and prevention of various clinical DISEASE, without compromising the left ventricular function. | NO-RELATIONSHIP |
| Hemodynamic and antiadrenergic effects of CHEMICAL and amiodarone in animals with a healed myocardial infarction. The hemodynamic and antiadrenergic effects of CHEMICAL, a noniodinated compound structurally related to amiodarone, were compared with those of amiodarone after prolonged oral administration, both at rest and during sympathetic stimulation in conscious dogs with a healed myocardial infarction. All dogs (n = 6) randomly received orally CHEMICAL (10 and 30 mg/kg), amiodarone (10 and 30 mg/kg), and placebo twice daily for 7 days, with a 3-week washout between consecutive treatments. Heart rate (HR), mean arterial pressure (MBP), positive rate of increase of left ventricular pressure (+LVdP/dt), echocardiographically assessed left ventricular ejection fraction (LVEF), and fractional shortening (FS), as well as chronotropic response to isoproterenol and exercise-induced sympathetic stimulation were evaluated under baseline and posttreatment conditions. Resting values of LVEF, FS, +LVdP/dt, and MBP remained unchanged whatever the drug and the dosing regimen, whereas resting HR was significantly and dose-dependently lowered after CHEMICAL and to a lesser extent after amiodarone. Both CHEMICAL and amiodarone significantly reduced the exercise-induced tachycardia and, at the highest dose, decreased the isoproterenol-induced tachycardia. Thus, CHEMICAL and amiodarone displayed a similar level of antiadrenergic effect and did not impair the resting left ventricular function. Consequently, CHEMICAL might be particularly suitable for the treatment and prevention of various clinical DISEASE, without compromising the left ventricular function. | NO-RELATIONSHIP |
| Hemodynamic and antiadrenergic effects of dronedarone and CHEMICAL in animals with a healed DISEASE. The hemodynamic and antiadrenergic effects of dronedarone, a noniodinated compound structurally related to CHEMICAL, were compared with those of CHEMICAL after prolonged oral administration, both at rest and during sympathetic stimulation in conscious dogs with a healed DISEASE. All dogs (n = 6) randomly received orally dronedarone (10 and 30 mg/kg), CHEMICAL (10 and 30 mg/kg), and placebo twice daily for 7 days, with a 3-week washout between consecutive treatments. Heart rate (HR), mean arterial pressure (MBP), positive rate of increase of left ventricular pressure (+LVdP/dt), echocardiographically assessed left ventricular ejection fraction (LVEF), and fractional shortening (FS), as well as chronotropic response to isoproterenol and exercise-induced sympathetic stimulation were evaluated under baseline and posttreatment conditions. Resting values of LVEF, FS, +LVdP/dt, and MBP remained unchanged whatever the drug and the dosing regimen, whereas resting HR was significantly and dose-dependently lowered after dronedarone and to a lesser extent after CHEMICAL. Both dronedarone and CHEMICAL significantly reduced the exercise-induced tachycardia and, at the highest dose, decreased the isoproterenol-induced tachycardia. Thus, dronedarone and CHEMICAL displayed a similar level of antiadrenergic effect and did not impair the resting left ventricular function. Consequently, dronedarone might be particularly suitable for the treatment and prevention of various clinical arrhythmias, without compromising the left ventricular function. | NO-RELATIONSHIP |
| Phase 2 trial of liposomal CHEMICAL (40 mg/m(2)) in platinum/paclitaxel-refractory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum. BACKGROUND: Several studies have demonstrated liposomal CHEMICAL (CHEMICAL) to be an active antineoplastic agent in platinum-resistant ovarian cancer, with dose limiting toxicity of the standard dosing regimen (50 mg/m(2) q 4 weeks) being severe erythrodysesthesia ("hand-foot syndrome") and DISEASE. We wished to develop a more tolerable liposomal CHEMICAL treatment regimen and document its level of activity in a well-defined patient population with platinum/paclitaxel-refractory disease. METHODS AND MATERIALS: Patients with ovarian or fallopian tube cancers or primary peritoneal carcinoma with platinum/paclitaxel-refractory disease (stable or progressive disease following treatment with these agents or previous objective response <3 months in duration) were treated with liposomal CHEMICAL at a dose of 40 mg/m(2) q 4 weeks. RESULTS: A total of 49 patients (median age: 60; range 41-81) entered this phase 2 trial. The median number of prior regimens was 2 (range: 1-6). Six (12%) and 4 (8%) patients experienced grade 2 hand-foot syndrome and DISEASE, respectively (no episodes of grade 3). One patient developed grade 3 diarrhea requiring hospitalization for hydration. Six (12%) individuals required dose reductions. The median number of courses of liposomal CHEMICAL administered on this protocol was 2 (range: 1-12). Four of 44 patients (9%) evaluable for response exhibited objective and subjective evidence of an antineoplastic effect of therapy. CONCLUSION: This modified liposomal CHEMICAL regimen results in less toxicity (DISEASE, hand-foot syndrome) than the standard FDA-approved dose schedule. Definite, although limited, antineoplastic activity is observed in patients with well-defined platinum- and paclitaxel-refractory ovarian cancer. | CHEMICAL-INDUCED-DISEASE |
| Phase 2 trial of liposomal CHEMICAL (40 mg/m(2)) in platinum/paclitaxel-refractory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum. BACKGROUND: Several studies have demonstrated liposomal CHEMICAL (CHEMICAL) to be an active antineoplastic agent in platinum-resistant ovarian cancer, with dose limiting toxicity of the standard dosing regimen (50 mg/m(2) q 4 weeks) being severe erythrodysesthesia ("hand-foot syndrome") and stomatitis. We wished to develop a more tolerable liposomal CHEMICAL treatment regimen and document its level of activity in a well-defined patient population with platinum/paclitaxel-refractory disease. METHODS AND MATERIALS: Patients with ovarian or fallopian tube cancers or primary peritoneal carcinoma with platinum/paclitaxel-refractory disease (stable or progressive disease following treatment with these agents or previous objective response <3 months in duration) were treated with liposomal CHEMICAL at a dose of 40 mg/m(2) q 4 weeks. RESULTS: A total of 49 patients (median age: 60; range 41-81) entered this phase 2 trial. The median number of prior regimens was 2 (range: 1-6). Six (12%) and 4 (8%) patients experienced grade 2 hand-foot syndrome and stomatitis, respectively (no episodes of grade 3). One patient developed grade 3 DISEASE requiring hospitalization for hydration. Six (12%) individuals required dose reductions. The median number of courses of liposomal CHEMICAL administered on this protocol was 2 (range: 1-12). Four of 44 patients (9%) evaluable for response exhibited objective and subjective evidence of an antineoplastic effect of therapy. CONCLUSION: This modified liposomal CHEMICAL regimen results in less toxicity (stomatitis, hand-foot syndrome) than the standard FDA-approved dose schedule. Definite, although limited, antineoplastic activity is observed in patients with well-defined platinum- and paclitaxel-refractory ovarian cancer. | CHEMICAL-INDUCED-DISEASE |
| Phase 2 trial of liposomal CHEMICAL (40 mg/m(2)) in platinum/paclitaxel-refractory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum. BACKGROUND: Several studies have demonstrated liposomal CHEMICAL (CHEMICAL) to be an active antineoplastic agent in platinum-resistant ovarian cancer, with dose limiting toxicity of the standard dosing regimen (50 mg/m(2) q 4 weeks) being severe DISEASE ("DISEASE") and stomatitis. We wished to develop a more tolerable liposomal CHEMICAL treatment regimen and document its level of activity in a well-defined patient population with platinum/paclitaxel-refractory disease. METHODS AND MATERIALS: Patients with ovarian or fallopian tube cancers or primary peritoneal carcinoma with platinum/paclitaxel-refractory disease (stable or progressive disease following treatment with these agents or previous objective response <3 months in duration) were treated with liposomal CHEMICAL at a dose of 40 mg/m(2) q 4 weeks. RESULTS: A total of 49 patients (median age: 60; range 41-81) entered this phase 2 trial. The median number of prior regimens was 2 (range: 1-6). Six (12%) and 4 (8%) patients experienced grade 2 DISEASE and stomatitis, respectively (no episodes of grade 3). One patient developed grade 3 diarrhea requiring hospitalization for hydration. Six (12%) individuals required dose reductions. The median number of courses of liposomal CHEMICAL administered on this protocol was 2 (range: 1-12). Four of 44 patients (9%) evaluable for response exhibited objective and subjective evidence of an antineoplastic effect of therapy. CONCLUSION: This modified liposomal CHEMICAL regimen results in less toxicity (stomatitis, DISEASE) than the standard FDA-approved dose schedule. Definite, although limited, antineoplastic activity is observed in patients with well-defined platinum- and paclitaxel-refractory ovarian cancer. | CHEMICAL-INDUCED-DISEASE |
| Phase 2 trial of liposomal doxorubicin (40 mg/m(2)) in CHEMICAL/paclitaxel-refractory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum. BACKGROUND: Several studies have demonstrated liposomal doxorubicin (Doxil) to be an active antineoplastic agent in CHEMICAL-resistant ovarian cancer, with dose limiting DISEASE of the standard dosing regimen (50 mg/m(2) q 4 weeks) being severe erythrodysesthesia ("hand-foot syndrome") and stomatitis. We wished to develop a more tolerable liposomal doxorubicin treatment regimen and document its level of activity in a well-defined patient population with CHEMICAL/paclitaxel-refractory disease. METHODS AND MATERIALS: Patients with ovarian or fallopian tube cancers or primary peritoneal carcinoma with CHEMICAL/paclitaxel-refractory disease (stable or progressive disease following treatment with these agents or previous objective response <3 months in duration) were treated with liposomal doxorubicin at a dose of 40 mg/m(2) q 4 weeks. RESULTS: A total of 49 patients (median age: 60; range 41-81) entered this phase 2 trial. The median number of prior regimens was 2 (range: 1-6). Six (12%) and 4 (8%) patients experienced grade 2 hand-foot syndrome and stomatitis, respectively (no episodes of grade 3). One patient developed grade 3 diarrhea requiring hospitalization for hydration. Six (12%) individuals required dose reductions. The median number of courses of liposomal doxorubicin administered on this protocol was 2 (range: 1-12). Four of 44 patients (9%) evaluable for response exhibited objective and subjective evidence of an antineoplastic effect of therapy. CONCLUSION: This modified liposomal doxorubicin regimen results in less DISEASE (stomatitis, hand-foot syndrome) than the standard FDA-approved dose schedule. Definite, although limited, antineoplastic activity is observed in patients with well-defined CHEMICAL- and paclitaxel-refractory ovarian cancer. | CHEMICAL-INDUCED-DISEASE |
| Phase 2 trial of liposomal doxorubicin (40 mg/m(2)) in platinum/CHEMICAL-refractory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum. BACKGROUND: Several studies have demonstrated liposomal doxorubicin (Doxil) to be an active antineoplastic agent in platinum-resistant ovarian cancer, with dose limiting DISEASE of the standard dosing regimen (50 mg/m(2) q 4 weeks) being severe erythrodysesthesia ("hand-foot syndrome") and stomatitis. We wished to develop a more tolerable liposomal doxorubicin treatment regimen and document its level of activity in a well-defined patient population with platinum/CHEMICAL-refractory disease. METHODS AND MATERIALS: Patients with ovarian or fallopian tube cancers or primary peritoneal carcinoma with platinum/CHEMICAL-refractory disease (stable or progressive disease following treatment with these agents or previous objective response <3 months in duration) were treated with liposomal doxorubicin at a dose of 40 mg/m(2) q 4 weeks. RESULTS: A total of 49 patients (median age: 60; range 41-81) entered this phase 2 trial. The median number of prior regimens was 2 (range: 1-6). Six (12%) and 4 (8%) patients experienced grade 2 hand-foot syndrome and stomatitis, respectively (no episodes of grade 3). One patient developed grade 3 diarrhea requiring hospitalization for hydration. Six (12%) individuals required dose reductions. The median number of courses of liposomal doxorubicin administered on this protocol was 2 (range: 1-12). Four of 44 patients (9%) evaluable for response exhibited objective and subjective evidence of an antineoplastic effect of therapy. CONCLUSION: This modified liposomal doxorubicin regimen results in less DISEASE (stomatitis, hand-foot syndrome) than the standard FDA-approved dose schedule. Definite, although limited, antineoplastic activity is observed in patients with well-defined platinum- and CHEMICAL-refractory ovarian cancer. | NO-RELATIONSHIP |
| Phase 2 trial of liposomal doxorubicin (40 mg/m(2)) in CHEMICAL/paclitaxel-refractory DISEASE and primary carcinoma of the peritoneum. BACKGROUND: Several studies have demonstrated liposomal doxorubicin (Doxil) to be an active antineoplastic agent in CHEMICAL-resistant ovarian cancer, with dose limiting toxicity of the standard dosing regimen (50 mg/m(2) q 4 weeks) being severe erythrodysesthesia ("hand-foot syndrome") and stomatitis. We wished to develop a more tolerable liposomal doxorubicin treatment regimen and document its level of activity in a well-defined patient population with CHEMICAL/paclitaxel-refractory disease. METHODS AND MATERIALS: Patients with DISEASE or primary peritoneal carcinoma with CHEMICAL/paclitaxel-refractory disease (stable or progressive disease following treatment with these agents or previous objective response <3 months in duration) were treated with liposomal doxorubicin at a dose of 40 mg/m(2) q 4 weeks. RESULTS: A total of 49 patients (median age: 60; range 41-81) entered this phase 2 trial. The median number of prior regimens was 2 (range: 1-6). Six (12%) and 4 (8%) patients experienced grade 2 hand-foot syndrome and stomatitis, respectively (no episodes of grade 3). One patient developed grade 3 diarrhea requiring hospitalization for hydration. Six (12%) individuals required dose reductions. The median number of courses of liposomal doxorubicin administered on this protocol was 2 (range: 1-12). Four of 44 patients (9%) evaluable for response exhibited objective and subjective evidence of an antineoplastic effect of therapy. CONCLUSION: This modified liposomal doxorubicin regimen results in less toxicity (stomatitis, hand-foot syndrome) than the standard FDA-approved dose schedule. Definite, although limited, antineoplastic activity is observed in patients with well-defined CHEMICAL- and paclitaxel-refractory ovarian cancer. | NO-RELATIONSHIP |
| Phase 2 trial of liposomal doxorubicin (40 mg/m(2)) in CHEMICAL/paclitaxel-refractory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum. BACKGROUND: Several studies have demonstrated liposomal doxorubicin (Doxil) to be an active antineoplastic agent in CHEMICAL-resistant DISEASE, with dose limiting toxicity of the standard dosing regimen (50 mg/m(2) q 4 weeks) being severe erythrodysesthesia ("hand-foot syndrome") and stomatitis. We wished to develop a more tolerable liposomal doxorubicin treatment regimen and document its level of activity in a well-defined patient population with CHEMICAL/paclitaxel-refractory disease. METHODS AND MATERIALS: Patients with ovarian or fallopian tube cancers or primary peritoneal carcinoma with CHEMICAL/paclitaxel-refractory disease (stable or progressive disease following treatment with these agents or previous objective response <3 months in duration) were treated with liposomal doxorubicin at a dose of 40 mg/m(2) q 4 weeks. RESULTS: A total of 49 patients (median age: 60; range 41-81) entered this phase 2 trial. The median number of prior regimens was 2 (range: 1-6). Six (12%) and 4 (8%) patients experienced grade 2 hand-foot syndrome and stomatitis, respectively (no episodes of grade 3). One patient developed grade 3 diarrhea requiring hospitalization for hydration. Six (12%) individuals required dose reductions. The median number of courses of liposomal doxorubicin administered on this protocol was 2 (range: 1-12). Four of 44 patients (9%) evaluable for response exhibited objective and subjective evidence of an antineoplastic effect of therapy. CONCLUSION: This modified liposomal doxorubicin regimen results in less toxicity (stomatitis, hand-foot syndrome) than the standard FDA-approved dose schedule. Definite, although limited, antineoplastic activity is observed in patients with well-defined CHEMICAL- and paclitaxel-refractory DISEASE. | NO-RELATIONSHIP |
| Phase 2 trial of liposomal doxorubicin (40 mg/m(2)) in platinum/CHEMICAL-refractory ovarian and fallopian tube cancers and primary DISEASE. BACKGROUND: Several studies have demonstrated liposomal doxorubicin (Doxil) to be an active antineoplastic agent in platinum-resistant ovarian cancer, with dose limiting toxicity of the standard dosing regimen (50 mg/m(2) q 4 weeks) being severe erythrodysesthesia ("hand-foot syndrome") and stomatitis. We wished to develop a more tolerable liposomal doxorubicin treatment regimen and document its level of activity in a well-defined patient population with platinum/CHEMICAL-refractory disease. METHODS AND MATERIALS: Patients with ovarian or fallopian tube cancers or primary DISEASE with platinum/CHEMICAL-refractory disease (stable or progressive disease following treatment with these agents or previous objective response <3 months in duration) were treated with liposomal doxorubicin at a dose of 40 mg/m(2) q 4 weeks. RESULTS: A total of 49 patients (median age: 60; range 41-81) entered this phase 2 trial. The median number of prior regimens was 2 (range: 1-6). Six (12%) and 4 (8%) patients experienced grade 2 hand-foot syndrome and stomatitis, respectively (no episodes of grade 3). One patient developed grade 3 diarrhea requiring hospitalization for hydration. Six (12%) individuals required dose reductions. The median number of courses of liposomal doxorubicin administered on this protocol was 2 (range: 1-12). Four of 44 patients (9%) evaluable for response exhibited objective and subjective evidence of an antineoplastic effect of therapy. CONCLUSION: This modified liposomal doxorubicin regimen results in less toxicity (stomatitis, hand-foot syndrome) than the standard FDA-approved dose schedule. Definite, although limited, antineoplastic activity is observed in patients with well-defined platinum- and CHEMICAL-refractory ovarian cancer. | NO-RELATIONSHIP |
| Phase 2 trial of liposomal doxorubicin (40 mg/m(2)) in CHEMICAL/paclitaxel-refractory ovarian and fallopian tube cancers and primary DISEASE. BACKGROUND: Several studies have demonstrated liposomal doxorubicin (Doxil) to be an active antineoplastic agent in CHEMICAL-resistant ovarian cancer, with dose limiting toxicity of the standard dosing regimen (50 mg/m(2) q 4 weeks) being severe erythrodysesthesia ("hand-foot syndrome") and stomatitis. We wished to develop a more tolerable liposomal doxorubicin treatment regimen and document its level of activity in a well-defined patient population with CHEMICAL/paclitaxel-refractory disease. METHODS AND MATERIALS: Patients with ovarian or fallopian tube cancers or primary DISEASE with CHEMICAL/paclitaxel-refractory disease (stable or progressive disease following treatment with these agents or previous objective response <3 months in duration) were treated with liposomal doxorubicin at a dose of 40 mg/m(2) q 4 weeks. RESULTS: A total of 49 patients (median age: 60; range 41-81) entered this phase 2 trial. The median number of prior regimens was 2 (range: 1-6). Six (12%) and 4 (8%) patients experienced grade 2 hand-foot syndrome and stomatitis, respectively (no episodes of grade 3). One patient developed grade 3 diarrhea requiring hospitalization for hydration. Six (12%) individuals required dose reductions. The median number of courses of liposomal doxorubicin administered on this protocol was 2 (range: 1-12). Four of 44 patients (9%) evaluable for response exhibited objective and subjective evidence of an antineoplastic effect of therapy. CONCLUSION: This modified liposomal doxorubicin regimen results in less toxicity (stomatitis, hand-foot syndrome) than the standard FDA-approved dose schedule. Definite, although limited, antineoplastic activity is observed in patients with well-defined CHEMICAL- and paclitaxel-refractory ovarian cancer. | NO-RELATIONSHIP |
| Phase 2 trial of liposomal doxorubicin (40 mg/m(2)) in platinum/CHEMICAL-refractory DISEASE and primary carcinoma of the peritoneum. BACKGROUND: Several studies have demonstrated liposomal doxorubicin (Doxil) to be an active antineoplastic agent in platinum-resistant ovarian cancer, with dose limiting toxicity of the standard dosing regimen (50 mg/m(2) q 4 weeks) being severe erythrodysesthesia ("hand-foot syndrome") and stomatitis. We wished to develop a more tolerable liposomal doxorubicin treatment regimen and document its level of activity in a well-defined patient population with platinum/CHEMICAL-refractory disease. METHODS AND MATERIALS: Patients with DISEASE or primary peritoneal carcinoma with platinum/CHEMICAL-refractory disease (stable or progressive disease following treatment with these agents or previous objective response <3 months in duration) were treated with liposomal doxorubicin at a dose of 40 mg/m(2) q 4 weeks. RESULTS: A total of 49 patients (median age: 60; range 41-81) entered this phase 2 trial. The median number of prior regimens was 2 (range: 1-6). Six (12%) and 4 (8%) patients experienced grade 2 hand-foot syndrome and stomatitis, respectively (no episodes of grade 3). One patient developed grade 3 diarrhea requiring hospitalization for hydration. Six (12%) individuals required dose reductions. The median number of courses of liposomal doxorubicin administered on this protocol was 2 (range: 1-12). Four of 44 patients (9%) evaluable for response exhibited objective and subjective evidence of an antineoplastic effect of therapy. CONCLUSION: This modified liposomal doxorubicin regimen results in less toxicity (stomatitis, hand-foot syndrome) than the standard FDA-approved dose schedule. Definite, although limited, antineoplastic activity is observed in patients with well-defined platinum- and CHEMICAL-refractory ovarian cancer. | NO-RELATIONSHIP |
| Phase 2 trial of liposomal doxorubicin (40 mg/m(2)) in platinum/CHEMICAL-refractory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum. BACKGROUND: Several studies have demonstrated liposomal doxorubicin (Doxil) to be an active antineoplastic agent in platinum-resistant DISEASE, with dose limiting toxicity of the standard dosing regimen (50 mg/m(2) q 4 weeks) being severe erythrodysesthesia ("hand-foot syndrome") and stomatitis. We wished to develop a more tolerable liposomal doxorubicin treatment regimen and document its level of activity in a well-defined patient population with platinum/CHEMICAL-refractory disease. METHODS AND MATERIALS: Patients with ovarian or fallopian tube cancers or primary peritoneal carcinoma with platinum/CHEMICAL-refractory disease (stable or progressive disease following treatment with these agents or previous objective response <3 months in duration) were treated with liposomal doxorubicin at a dose of 40 mg/m(2) q 4 weeks. RESULTS: A total of 49 patients (median age: 60; range 41-81) entered this phase 2 trial. The median number of prior regimens was 2 (range: 1-6). Six (12%) and 4 (8%) patients experienced grade 2 hand-foot syndrome and stomatitis, respectively (no episodes of grade 3). One patient developed grade 3 diarrhea requiring hospitalization for hydration. Six (12%) individuals required dose reductions. The median number of courses of liposomal doxorubicin administered on this protocol was 2 (range: 1-12). Four of 44 patients (9%) evaluable for response exhibited objective and subjective evidence of an antineoplastic effect of therapy. CONCLUSION: This modified liposomal doxorubicin regimen results in less toxicity (stomatitis, hand-foot syndrome) than the standard FDA-approved dose schedule. Definite, although limited, antineoplastic activity is observed in patients with well-defined platinum- and CHEMICAL-refractory DISEASE. | NO-RELATIONSHIP |
| Efficacy of CHEMICAL in acute bipolar mania: a double-blind, placebo-controlled study. The CHEMICAL HGGW Study Group. BACKGROUND: We compared the efficacy and safety of CHEMICAL vs placebo for the treatment of acute bipolar mania. METHODS: Four-week, randomized, double-blind, parallel study. A total of 115 patients with a DSM-IV diagnosis of bipolar disorder, manic or mixed, were randomized to CHEMICAL, 5 to 20 mg/d (n = 55), or placebo (n = 60). The primary efficacy measure was the Young-Mania Rating Scale (Y-MRS) total score. Response and euthymia were defined, a priori, as at least a 50% improvement from baseline to end point and as a score of no less than 12 at end point in the Y-MRS total score, respectively. Safety was assessed using adverse events, Extrapyramidal Symptom (EPS) rating scales, laboratory values, electrocardiograms, vital signs, and weight change. RESULTS: CHEMICAL-treated patients demonstrated a statistically significant greater mean (+/- SD) improvement in Y-MRS total score than placebo-treated patients (-14.8 +/- 12.5 and -8.1 +/- 12.7, respectively; P<.001), which was evident at the first postbaseline observation 1 week after randomization and was maintained throughout the study (last observation carried forward). CHEMICAL-treated patients demonstrated a higher rate of response (65% vs 43%, respectively; P =.02) and euthymia (61% vs 36%, respectively; P =. 01) than placebo-treated patients. There were no statistically significant differences in EPSs between groups. However, CHEMICAL-treated patients had a statistically significant greater mean (+/- SD) weight gain than placebo-treated patients (2.1 +/- 2.8 vs 0.45 +/- 2.3 kg, respectively) and also experienced more treatment-emergent DISEASE (21 patients [38.2%] vs 5 [8.3% ], respectively). CONCLUSION: CHEMICAL demonstrated greater efficacy than placebo in the treatment of acute bipolar mania and was generally well tolerated. | CHEMICAL-INDUCED-DISEASE |
| Efficacy of CHEMICAL in acute bipolar mania: a double-blind, placebo-controlled study. The CHEMICAL HGGW Study Group. BACKGROUND: We compared the efficacy and safety of CHEMICAL vs placebo for the treatment of acute bipolar mania. METHODS: Four-week, randomized, double-blind, parallel study. A total of 115 patients with a DSM-IV diagnosis of bipolar disorder, manic or mixed, were randomized to CHEMICAL, 5 to 20 mg/d (n = 55), or placebo (n = 60). The primary efficacy measure was the Young-Mania Rating Scale (Y-MRS) total score. Response and euthymia were defined, a priori, as at least a 50% improvement from baseline to end point and as a score of no less than 12 at end point in the Y-MRS total score, respectively. Safety was assessed using adverse events, Extrapyramidal Symptom (EPS) rating scales, laboratory values, electrocardiograms, vital signs, and weight change. RESULTS: CHEMICAL-treated patients demonstrated a statistically significant greater mean (+/- SD) improvement in Y-MRS total score than placebo-treated patients (-14.8 +/- 12.5 and -8.1 +/- 12.7, respectively; P<.001), which was evident at the first postbaseline observation 1 week after randomization and was maintained throughout the study (last observation carried forward). CHEMICAL-treated patients demonstrated a higher rate of response (65% vs 43%, respectively; P =.02) and euthymia (61% vs 36%, respectively; P =. 01) than placebo-treated patients. There were no statistically significant differences in EPSs between groups. However, CHEMICAL-treated patients had a statistically significant greater mean (+/- SD) DISEASE than placebo-treated patients (2.1 +/- 2.8 vs 0.45 +/- 2.3 kg, respectively) and also experienced more treatment-emergent somnolence (21 patients [38.2%] vs 5 [8.3% ], respectively). CONCLUSION: CHEMICAL demonstrated greater efficacy than placebo in the treatment of acute bipolar mania and was generally well tolerated. | CHEMICAL-INDUCED-DISEASE |
| The effect of DISEASE with CHEMICAL on vision and driving simulator performance. PURPOSE: To assess the effect of DISEASE on vision and driving ability. METHODS: A series of tests on various parameters of visual function and driving simulator performance were performed on 12 healthy drivers, before and after DISEASE using guttae CHEMICAL 1%. A driving simulator (Transport Research Laboratory) was used to measure reaction time (RT), speed maintenance and steering accuracy. Tests of basic visual function included high- and low-contrast visual acuity (HCVA and LCVA), Pelli-Robson contrast threshold (CT) and Goldmann perimetry (FIELDS). Useful Field of View (UFOV--a test of visual attention) was also undertaken. The mean differences in the pre- and post-dilatation measurements were tested for statistical significance at the 95% level using one-tail paired t-tests. RESULTS: DISEASE resulted in a statistically significant deterioration in CT and HCVA only. Five of 12 drivers also exhibited deterioration in LCVA, CT and RT. Little evidence emerged for deterioration in FIELDS and UFOV. Also, 7 of 12 drivers appeared to adjust their driving behaviour by reducing their speed on the driving simulator, leading to improved steering accuracy. CONCLUSIONS: DISEASE may lead to a decrease in vision and daylight driving performance in young people. A larger study, including a broader spectrum of subjects, is warranted before guidelines can be recommended. | CHEMICAL-INDUCED-DISEASE |
| A case of isotretinoin embryopathy with bilateral anotia and DISEASE. We report a newborn infant with multiple congenital anomalies (anotia and DISEASE) due to exposure to CHEMICAL within the first trimester. In this paper we aim to draw to the fact that caution is needed when prescribing vitamin A-containing drugs to women of childbearing years. | CHEMICAL-INDUCED-DISEASE |
| A case of isotretinoin embryopathy with bilateral DISEASE and Taussig-Bing malformation. We report a newborn infant with multiple congenital anomalies (DISEASE and Taussig-Bing malformation) due to exposure to CHEMICAL within the first trimester. In this paper we aim to draw to the fact that caution is needed when prescribing vitamin A-containing drugs to women of childbearing years. | CHEMICAL-INDUCED-DISEASE |
| A case of DISEASE with bilateral anotia and Taussig-Bing malformation. We report a newborn infant with multiple congenital anomalies (anotia and Taussig-Bing malformation) due to exposure to CHEMICAL within the first trimester. In this paper we aim to draw to the fact that caution is needed when prescribing vitamin A-containing drugs to women of childbearing years. | CHEMICAL-INDUCED-DISEASE |
| Effect of CHEMICAL on maximum urethral pressure in women with genuine stress incontinence: a placebo-controlled, double-blind crossover study. The aim of the study was to evaluate the potential role for a selective alpha1-adrenoceptor agonist in the treatment of urinary stress incontinence. A randomised, double-blind, placebo-controlled, crossover study design was employed. Half log incremental doses of intravenous CHEMICAL or placebo (saline) were administered to a group of women with genuine stress incontinence while measuring maximum urethral pressure (MUP), blood pressure, heart rate, and symptomatic side effects. CHEMICAL evoked non-significant increases in MUP and diastolic blood pressure but caused DISEASE and significant fall in heart rate at maximum dosage. Systemic side effects including piloerection, headache, and cold extremities were experienced in all subjects. The results indicate that the clinical usefulness of direct, peripherally acting sub-type-selective alpha1-adrenoceptor agonists in the medical treatment of stress incontinence may be limited by associated piloerection and cardiovascular side effects. | CHEMICAL-INDUCED-DISEASE |
| Effect of CHEMICAL on maximum urethral pressure in women with genuine stress incontinence: a placebo-controlled, double-blind crossover study. The aim of the study was to evaluate the potential role for a selective alpha1-adrenoceptor agonist in the treatment of urinary stress incontinence. A randomised, double-blind, placebo-controlled, crossover study design was employed. Half log incremental doses of intravenous CHEMICAL or placebo (saline) were administered to a group of women with genuine stress incontinence while measuring maximum urethral pressure (MUP), blood pressure, heart rate, and symptomatic side effects. CHEMICAL evoked non-significant increases in MUP and diastolic blood pressure but caused a significant rise in systolic blood pressure and significant fall in heart rate at maximum dosage. Systemic side effects including piloerection, DISEASE, and cold extremities were experienced in all subjects. The results indicate that the clinical usefulness of direct, peripherally acting sub-type-selective alpha1-adrenoceptor agonists in the medical treatment of stress incontinence may be limited by associated piloerection and cardiovascular side effects. | CHEMICAL-INDUCED-DISEASE |
| Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure: results from the ATLAS trial. The Assessment of Treatment with CHEMICAL and Survival. BACKGROUND: Treatment with angiotensin-converting enzyme (ACE) inhibitors reduces mortality and morbidity in patients with chronic heart failure (CHF), but most affected patients are not receiving these agents or are being treated with doses lower than those found to be efficacious in trials, primarily because of concerns about the safety and tolerability of these agents, especially at the recommended doses. The present study examines the safety and tolerability of high- compared with low-dose CHEMICAL in CHF. METHODS: The Assessment of CHEMICAL and Survival study was a multicenter, randomized, double-blind trial in which patients with or without previous ACE inhibitor treatment were stabilized receiving medium-dose CHEMICAL (12.5 or 15.0 mg once daily [OD]) for 2 to 4 weeks and then randomized to high- (35.0 or 32.5 mg OD) or low-dose (5.0 or 2.5 mg OD) groups. Patients with New York Heart Association classes II to IV CHF and left ventricular ejection fractions of no greater than 0.30 (n = 3164) were randomized and followed up for a median of 46 months. We examined the occurrence of adverse events and the need for discontinuation and dose reduction during treatment, with a focus on hypotension and DISEASE. RESULTS: Of 405 patients not previously receiving an ACE inhibitor, doses in only 4.2% could not be titrated to the medium doses required for randomization because of symptoms possibly related to hypotension (2.0%) or because of DISEASE or hyperkalemia (2.3%). Doses in more than 90% of randomized patients in the high- and low-dose groups were titrated to their assigned target, and the mean doses of blinded medication in both groups remained similar throughout the study. Withdrawals occurred in 27.1% of the high- and 30.7% of the low-dose groups. Subgroups presumed to be at higher risk for ACE inhibitor intolerance (blood pressure, <120 mm Hg; creatinine, > or =132.6 micromol/L [> or =1.5 mg/dL]; age, > or =70 years; and patients with diabetes) generally tolerated the high-dose strategy. CONCLUSIONS: These findings demonstrate that ACE inhibitor therapy in most patients with CHF can be successfully titrated to and maintained at high doses, and that more aggressive use of these agents is warranted. | CHEMICAL-INDUCED-DISEASE |
| Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure: results from the ATLAS trial. The Assessment of Treatment with CHEMICAL and Survival. BACKGROUND: Treatment with angiotensin-converting enzyme (ACE) inhibitors reduces mortality and morbidity in patients with chronic heart failure (CHF), but most affected patients are not receiving these agents or are being treated with doses lower than those found to be efficacious in trials, primarily because of concerns about the safety and tolerability of these agents, especially at the recommended doses. The present study examines the safety and tolerability of high- compared with low-dose CHEMICAL in CHF. METHODS: The Assessment of CHEMICAL and Survival study was a multicenter, randomized, double-blind trial in which patients with or without previous ACE inhibitor treatment were stabilized receiving medium-dose CHEMICAL (12.5 or 15.0 mg once daily [OD]) for 2 to 4 weeks and then randomized to high- (35.0 or 32.5 mg OD) or low-dose (5.0 or 2.5 mg OD) groups. Patients with New York Heart Association classes II to IV CHF and left ventricular ejection fractions of no greater than 0.30 (n = 3164) were randomized and followed up for a median of 46 months. We examined the occurrence of adverse events and the need for discontinuation and dose reduction during treatment, with a focus on hypotension and renal dysfunction. RESULTS: Of 405 patients not previously receiving an ACE inhibitor, doses in only 4.2% could not be titrated to the medium doses required for randomization because of symptoms possibly related to hypotension (2.0%) or because of renal dysfunction or DISEASE (2.3%). Doses in more than 90% of randomized patients in the high- and low-dose groups were titrated to their assigned target, and the mean doses of blinded medication in both groups remained similar throughout the study. Withdrawals occurred in 27.1% of the high- and 30.7% of the low-dose groups. Subgroups presumed to be at higher risk for ACE inhibitor intolerance (blood pressure, <120 mm Hg; creatinine, > or =132.6 micromol/L [> or =1.5 mg/dL]; age, > or =70 years; and patients with diabetes) generally tolerated the high-dose strategy. CONCLUSIONS: These findings demonstrate that ACE inhibitor therapy in most patients with CHF can be successfully titrated to and maintained at high doses, and that more aggressive use of these agents is warranted. | CHEMICAL-INDUCED-DISEASE |
| Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure: results from the ATLAS trial. The Assessment of Treatment with CHEMICAL and Survival. BACKGROUND: Treatment with angiotensin-converting enzyme (ACE) inhibitors reduces mortality and morbidity in patients with chronic heart failure (CHF), but most affected patients are not receiving these agents or are being treated with doses lower than those found to be efficacious in trials, primarily because of concerns about the safety and tolerability of these agents, especially at the recommended doses. The present study examines the safety and tolerability of high- compared with low-dose CHEMICAL in CHF. METHODS: The Assessment of CHEMICAL and Survival study was a multicenter, randomized, double-blind trial in which patients with or without previous ACE inhibitor treatment were stabilized receiving medium-dose CHEMICAL (12.5 or 15.0 mg once daily [OD]) for 2 to 4 weeks and then randomized to high- (35.0 or 32.5 mg OD) or low-dose (5.0 or 2.5 mg OD) groups. Patients with New York Heart Association classes II to IV CHF and left ventricular ejection fractions of no greater than 0.30 (n = 3164) were randomized and followed up for a median of 46 months. We examined the occurrence of adverse events and the need for discontinuation and dose reduction during treatment, with a focus on DISEASE and renal dysfunction. RESULTS: Of 405 patients not previously receiving an ACE inhibitor, doses in only 4.2% could not be titrated to the medium doses required for randomization because of symptoms possibly related to DISEASE (2.0%) or because of renal dysfunction or hyperkalemia (2.3%). Doses in more than 90% of randomized patients in the high- and low-dose groups were titrated to their assigned target, and the mean doses of blinded medication in both groups remained similar throughout the study. Withdrawals occurred in 27.1% of the high- and 30.7% of the low-dose groups. Subgroups presumed to be at higher risk for ACE inhibitor intolerance (blood pressure, <120 mm Hg; creatinine, > or =132.6 micromol/L [> or =1.5 mg/dL]; age, > or =70 years; and patients with diabetes) generally tolerated the high-dose strategy. CONCLUSIONS: These findings demonstrate that ACE inhibitor therapy in most patients with CHF can be successfully titrated to and maintained at high doses, and that more aggressive use of these agents is warranted. | CHEMICAL-INDUCED-DISEASE |
| Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure: results from the ATLAS trial. The Assessment of Treatment with Lisinopril and Survival. BACKGROUND: Treatment with angiotensin-converting enzyme (ACE) inhibitors reduces mortality and morbidity in patients with chronic heart failure (CHF), but most affected patients are not receiving these agents or are being treated with doses lower than those found to be efficacious in trials, primarily because of concerns about the safety and tolerability of these agents, especially at the recommended doses. The present study examines the safety and tolerability of high- compared with low-dose lisinopril in CHF. METHODS: The Assessment of Lisinopril and Survival study was a multicenter, randomized, double-blind trial in which patients with or without previous ACE inhibitor treatment were stabilized receiving medium-dose lisinopril (12.5 or 15.0 mg once daily [OD]) for 2 to 4 weeks and then randomized to high- (35.0 or 32.5 mg OD) or low-dose (5.0 or 2.5 mg OD) groups. Patients with New York Heart Association classes II to IV CHF and left ventricular ejection fractions of no greater than 0.30 (n = 3164) were randomized and followed up for a median of 46 months. We examined the occurrence of adverse events and the need for discontinuation and dose reduction during treatment, with a focus on hypotension and renal dysfunction. RESULTS: Of 405 patients not previously receiving an ACE inhibitor, doses in only 4.2% could not be titrated to the medium doses required for randomization because of symptoms possibly related to hypotension (2.0%) or because of renal dysfunction or hyperkalemia (2.3%). Doses in more than 90% of randomized patients in the high- and low-dose groups were titrated to their assigned target, and the mean doses of blinded medication in both groups remained similar throughout the study. Withdrawals occurred in 27.1% of the high- and 30.7% of the low-dose groups. Subgroups presumed to be at higher risk for ACE inhibitor intolerance (blood pressure, <120 mm Hg; CHEMICAL, > or =132.6 micromol/L [> or =1.5 mg/dL]; age, > or =70 years; and patients with DISEASE) generally tolerated the high-dose strategy. CONCLUSIONS: These findings demonstrate that ACE inhibitor therapy in most patients with CHF can be successfully titrated to and maintained at high doses, and that more aggressive use of these agents is warranted. | NO-RELATIONSHIP |
| Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic DISEASE: results from the ATLAS trial. The Assessment of Treatment with Lisinopril and Survival. BACKGROUND: Treatment with angiotensin-converting enzyme (ACE) inhibitors reduces mortality and morbidity in patients with chronic DISEASE (DISEASE), but most affected patients are not receiving these agents or are being treated with doses lower than those found to be efficacious in trials, primarily because of concerns about the safety and tolerability of these agents, especially at the recommended doses. The present study examines the safety and tolerability of high- compared with low-dose lisinopril in DISEASE. METHODS: The Assessment of Lisinopril and Survival study was a multicenter, randomized, double-blind trial in which patients with or without previous ACE inhibitor treatment were stabilized receiving medium-dose lisinopril (12.5 or 15.0 mg once daily [OD]) for 2 to 4 weeks and then randomized to high- (35.0 or 32.5 mg OD) or low-dose (5.0 or 2.5 mg OD) groups. Patients with New York Heart Association classes II to IV DISEASE and left ventricular ejection fractions of no greater than 0.30 (n = 3164) were randomized and followed up for a median of 46 months. We examined the occurrence of adverse events and the need for discontinuation and dose reduction during treatment, with a focus on hypotension and renal dysfunction. RESULTS: Of 405 patients not previously receiving an ACE inhibitor, doses in only 4.2% could not be titrated to the medium doses required for randomization because of symptoms possibly related to hypotension (2.0%) or because of renal dysfunction or hyperkalemia (2.3%). Doses in more than 90% of randomized patients in the high- and low-dose groups were titrated to their assigned target, and the mean doses of blinded medication in both groups remained similar throughout the study. Withdrawals occurred in 27.1% of the high- and 30.7% of the low-dose groups. Subgroups presumed to be at higher risk for ACE inhibitor intolerance (blood pressure, <120 mm Hg; CHEMICAL, > or =132.6 micromol/L [> or =1.5 mg/dL]; age, > or =70 years; and patients with diabetes) generally tolerated the high-dose strategy. CONCLUSIONS: These findings demonstrate that ACE inhibitor therapy in most patients with DISEASE can be successfully titrated to and maintained at high doses, and that more aggressive use of these agents is warranted. | NO-RELATIONSHIP |
| Toleration of high doses of CHEMICAL in patients with chronic heart failure: results from the ATLAS trial. The Assessment of Treatment with Lisinopril and Survival. BACKGROUND: Treatment with CHEMICAL reduces mortality and morbidity in patients with chronic heart failure (CHF), but most affected patients are not receiving these agents or are being treated with doses lower than those found to be efficacious in trials, primarily because of concerns about the safety and tolerability of these agents, especially at the recommended doses. The present study examines the safety and tolerability of high- compared with low-dose lisinopril in CHF. METHODS: The Assessment of Lisinopril and Survival study was a multicenter, randomized, double-blind trial in which patients with or without previous CHEMICAL treatment were stabilized receiving medium-dose lisinopril (12.5 or 15.0 mg once daily [OD]) for 2 to 4 weeks and then randomized to high- (35.0 or 32.5 mg OD) or low-dose (5.0 or 2.5 mg OD) groups. Patients with New York Heart Association classes II to IV CHF and left ventricular ejection fractions of no greater than 0.30 (n = 3164) were randomized and followed up for a median of 46 months. We examined the occurrence of adverse events and the need for discontinuation and dose reduction during treatment, with a focus on hypotension and renal dysfunction. RESULTS: Of 405 patients not previously receiving an CHEMICAL, doses in only 4.2% could not be titrated to the medium doses required for randomization because of symptoms possibly related to hypotension (2.0%) or because of renal dysfunction or hyperkalemia (2.3%). Doses in more than 90% of randomized patients in the high- and low-dose groups were titrated to their assigned target, and the mean doses of blinded medication in both groups remained similar throughout the study. Withdrawals occurred in 27.1% of the high- and 30.7% of the low-dose groups. Subgroups presumed to be at higher risk for CHEMICAL intolerance (blood pressure, <120 mm Hg; creatinine, > or =132.6 micromol/L [> or =1.5 mg/dL]; age, > or =70 years; and patients with DISEASE) generally tolerated the high-dose strategy. CONCLUSIONS: These findings demonstrate that CHEMICAL therapy in most patients with CHF can be successfully titrated to and maintained at high doses, and that more aggressive use of these agents is warranted. | CHEMICAL-INDUCED-DISEASE |
| Toleration of high doses of CHEMICAL in patients with chronic DISEASE: results from the ATLAS trial. The Assessment of Treatment with Lisinopril and Survival. BACKGROUND: Treatment with CHEMICAL reduces mortality and morbidity in patients with chronic DISEASE (DISEASE), but most affected patients are not receiving these agents or are being treated with doses lower than those found to be efficacious in trials, primarily because of concerns about the safety and tolerability of these agents, especially at the recommended doses. The present study examines the safety and tolerability of high- compared with low-dose lisinopril in DISEASE. METHODS: The Assessment of Lisinopril and Survival study was a multicenter, randomized, double-blind trial in which patients with or without previous CHEMICAL treatment were stabilized receiving medium-dose lisinopril (12.5 or 15.0 mg once daily [OD]) for 2 to 4 weeks and then randomized to high- (35.0 or 32.5 mg OD) or low-dose (5.0 or 2.5 mg OD) groups. Patients with New York Heart Association classes II to IV DISEASE and left ventricular ejection fractions of no greater than 0.30 (n = 3164) were randomized and followed up for a median of 46 months. We examined the occurrence of adverse events and the need for discontinuation and dose reduction during treatment, with a focus on hypotension and renal dysfunction. RESULTS: Of 405 patients not previously receiving an CHEMICAL, doses in only 4.2% could not be titrated to the medium doses required for randomization because of symptoms possibly related to hypotension (2.0%) or because of renal dysfunction or hyperkalemia (2.3%). Doses in more than 90% of randomized patients in the high- and low-dose groups were titrated to their assigned target, and the mean doses of blinded medication in both groups remained similar throughout the study. Withdrawals occurred in 27.1% of the high- and 30.7% of the low-dose groups. Subgroups presumed to be at higher risk for CHEMICAL intolerance (blood pressure, <120 mm Hg; creatinine, > or =132.6 micromol/L [> or =1.5 mg/dL]; age, > or =70 years; and patients with diabetes) generally tolerated the high-dose strategy. CONCLUSIONS: These findings demonstrate that CHEMICAL therapy in most patients with DISEASE can be successfully titrated to and maintained at high doses, and that more aggressive use of these agents is warranted. | NO-RELATIONSHIP |
| Cocaine, CHEMICAL, and cocaethylene cardiotoxity in an animal model of cocaine and ethanol abuse. OBJECTIVES: Simultaneous abuse of cocaine and ethanol affects 12 million Americans annually. In combination, these substances are substantially more toxic than either drug alone. Their combined cardiac toxicity may be due to independent effects of each drug; however, they may also be due to cocaethylene (CE), a cocaine metabolite formed only in the presence of CHEMICAL. The purpose of this study was to delineate the role of CE in the combined cardiotoxicity of cocaine and CHEMICAL in a model simulating their abuse. METHODS: Twenty-three dogs were randomized to receive either 1) three intravenous (IV) boluses of cocaine 7.5 mg/kg with CHEMICAL (1 g/kg) as an IV infusion (C+E, n = 8), 2) three cocaine boluses only (C, n = 6), 3) CHEMICAL infusion only (E, n = 5), or 4) placebo boluses and infusion (n = 4). Hemodynamic measurements, electrocardiograms, and serum drug concentrations were obtained at baseline, and then at fixed time intervals after each drug was administered. RESULTS: Two of eight dogs in the C+E group experienced cardiovascular collapse. The most dramatic hemodynamic changes occurred after each cocaine bolus in the C+E and C only groups; however, persistent hemodynamic changes occurred in the C+E group. Peak CE levels were associated with a 45% (SD +/- 22%, 95% CI = 22% to 69%) decrease in cardiac output (p < 0.05), a 56% (SD +/- 23%, 95% CI = 32% to 80%) decrease in dP/dt(max) (p <.006), and a 23% (SD +/- 15%, 95% CI = 7% to 49%) decrease in SVO(2) (p < 0.025). Ventricular arrhythmias were primarily observed in the C+E group, in which four of eight dogs experienced DISEASE. CONCLUSIONS: Cocaine and CHEMICAL in combination were more toxic than either substance alone. Co-administration resulted in prolonged cardiac toxicity and was dysrhythmogenic. Peak serum cocaethylene concentrations were associated with prolonged myocardial depression. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL, ethanol, and cocaethylene cardiotoxity in an animal model of cocaine and ethanol abuse. OBJECTIVES: Simultaneous abuse of cocaine and ethanol affects 12 million Americans annually. In combination, these substances are substantially more toxic than either drug alone. Their combined cardiac toxicity may be due to independent effects of each drug; however, they may also be due to cocaethylene (CE), a CHEMICAL metabolite formed only in the presence of ethanol. The purpose of this study was to delineate the role of CE in the combined cardiotoxicity of CHEMICAL and ethanol in a model simulating their abuse. METHODS: Twenty-three dogs were randomized to receive either 1) three intravenous (IV) boluses of CHEMICAL 7.5 mg/kg with ethanol (1 g/kg) as an IV infusion (C+E, n = 8), 2) three CHEMICAL boluses only (C, n = 6), 3) ethanol infusion only (E, n = 5), or 4) placebo boluses and infusion (n = 4). Hemodynamic measurements, electrocardiograms, and serum drug concentrations were obtained at baseline, and then at fixed time intervals after each drug was administered. RESULTS: Two of eight dogs in the C+E group experienced cardiovascular collapse. The most dramatic hemodynamic changes occurred after each CHEMICAL bolus in the C+E and C only groups; however, persistent hemodynamic changes occurred in the C+E group. Peak CE levels were associated with a 45% (SD +/- 22%, 95% CI = 22% to 69%) decrease in cardiac output (p < 0.05), a 56% (SD +/- 23%, 95% CI = 32% to 80%) decrease in dP/dt(max) (p <.006), and a 23% (SD +/- 15%, 95% CI = 7% to 49%) decrease in SVO(2) (p < 0.025). Ventricular arrhythmias were primarily observed in the C+E group, in which four of eight dogs experienced DISEASE. CONCLUSIONS: CHEMICAL and ethanol in combination were more toxic than either substance alone. Co-administration resulted in prolonged cardiac toxicity and was dysrhythmogenic. Peak serum cocaethylene concentrations were associated with prolonged myocardial depression. | CHEMICAL-INDUCED-DISEASE |
| Cocaine, ethanol, and CHEMICAL cardiotoxity in an animal model of cocaine and ethanol abuse. OBJECTIVES: Simultaneous abuse of cocaine and ethanol affects 12 million Americans annually. In combination, these substances are substantially more toxic than either drug alone. Their combined cardiac toxicity may be due to independent effects of each drug; however, they may also be due to CHEMICAL (CHEMICAL), a cocaine metabolite formed only in the presence of ethanol. The purpose of this study was to delineate the role of CHEMICAL in the combined cardiotoxicity of cocaine and ethanol in a model simulating their abuse. METHODS: Twenty-three dogs were randomized to receive either 1) three intravenous (IV) boluses of cocaine 7.5 mg/kg with ethanol (1 g/kg) as an IV infusion (C+E, n = 8), 2) three cocaine boluses only (C, n = 6), 3) ethanol infusion only (E, n = 5), or 4) placebo boluses and infusion (n = 4). Hemodynamic measurements, electrocardiograms, and serum drug concentrations were obtained at baseline, and then at fixed time intervals after each drug was administered. RESULTS: Two of eight dogs in the C+E group experienced cardiovascular collapse. The most dramatic hemodynamic changes occurred after each cocaine bolus in the C+E and C only groups; however, persistent hemodynamic changes occurred in the C+E group. Peak CHEMICAL levels were associated with a 45% (SD +/- 22%, 95% CI = 22% to 69%) DISEASE (p < 0.05), a 56% (SD +/- 23%, 95% CI = 32% to 80%) decrease in dP/dt(max) (p <.006), and a 23% (SD +/- 15%, 95% CI = 7% to 49%) decrease in SVO(2) (p < 0.025). Ventricular arrhythmias were primarily observed in the C+E group, in which four of eight dogs experienced ventricular tachycardia. CONCLUSIONS: Cocaine and ethanol in combination were more toxic than either substance alone. Co-administration resulted in prolonged cardiac toxicity and was dysrhythmogenic. Peak serum CHEMICAL concentrations were associated with prolonged myocardial depression. | CHEMICAL-INDUCED-DISEASE |
| Worsening of DISEASE after the use of CHEMICAL for treatment of menopause: case report. We describe a female patient with stable DISEASE who has shown a marked worsening of her motor functions following therapy of menopause related symptoms with CHEMICAL, as well as the improvement of her symptoms back to baseline after discontinuation of the drug. We emphasize the anti-dopaminergic effect of CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL and irregular heartbeat warning. A group of doctors in Boston warn that the protease inhibitor CHEMICAL may cause an irregular heart beat, known as DISEASE, in people with HIV. DISEASE occurred in a 45-year-old male patient who was CHEMICAL in combination with other anti-HIV drugs. The symptoms ceased after switching to another drug combination. | CHEMICAL-INDUCED-DISEASE |
| Frequency of appearance of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) in Graves' disease patients treated with CHEMICAL and the relationship between MPO-ANCA and clinical manifestations. OBJECTIVE: Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-positive vasculitis has been reported in patients with Graves' disease who were treated with CHEMICAL (CHEMICAL). The appearance of MPO-ANCA in these cases was suspected of being related to CHEMICAL because the titres of MPO-ANCA decreased when CHEMICAL was stopped. Nevertheless, there have been no studies on the temporal relationship between the appearance of MPO-ANCA and vasculitis during CHEMICAL therapy, or on the incidence of MPO-ANCA in untreated Graves' disease patients. Therefore, we sought to address these parameters in patients with Graves' disease. PATIENTS: We investigated 102 untreated patients with hyperthyroidism due to Graves' disease for the presence of MPO-ANCA, and for the development vasculitis after starting CHEMICAL therapy. Twenty-nine of them were later excluded because of adverse effects of CHEMICAL or because the observation period was less than 3 months. The remaining 73 patients (55 women and 18 men), all of whom were examined for more than 3 months, were adopted as the subjects of the investigation. The median observation period was 23.6 months (range: 3-37 months). MEASUREMENTS: MPO-ANCA was measured at intervals of 2-6 months. RESULTS: Before treatment, the MPO-ANCA titres of all 102 untreated Graves' disease patients were within the reference range (below 10 U/ml). Three (4.1%) of the 73 patients were positive for MPO-ANCA at 13, 16 and 17 months, respectively, after the start of CHEMICAL therapy. In two of them, the MPO-ANCA titres transiently increased to 12.8 and 15.0 U/ml, respectively, despite continued CHEMICAL therapy, but no vasculitic disorders developed. In the third patient, the MPO-ANCA titre increased to 204 U/ml and she developed a higher DISEASE, oral ulcers and polyarthralgia, but the symptoms resolved 2 weeks after stopping CHEMICAL therapy, and the MPO-ANCA titre decreased to 20.7 U/ml by 4 months after discontinuing CHEMICAL. CONCLUSIONS: CHEMICAL therapy may be related to the appearance of MPO-ANCA, but MPO-ANCA does not appear to be closely related to vasculitis. | CHEMICAL-INDUCED-DISEASE |
| Frequency of appearance of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) in Graves' disease patients treated with CHEMICAL and the relationship between MPO-ANCA and clinical manifestations. OBJECTIVE: Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-positive vasculitis has been reported in patients with Graves' disease who were treated with CHEMICAL (CHEMICAL). The appearance of MPO-ANCA in these cases was suspected of being related to CHEMICAL because the titres of MPO-ANCA decreased when CHEMICAL was stopped. Nevertheless, there have been no studies on the temporal relationship between the appearance of MPO-ANCA and vasculitis during CHEMICAL therapy, or on the incidence of MPO-ANCA in untreated Graves' disease patients. Therefore, we sought to address these parameters in patients with Graves' disease. PATIENTS: We investigated 102 untreated patients with hyperthyroidism due to Graves' disease for the presence of MPO-ANCA, and for the development vasculitis after starting CHEMICAL therapy. Twenty-nine of them were later excluded because of adverse effects of CHEMICAL or because the observation period was less than 3 months. The remaining 73 patients (55 women and 18 men), all of whom were examined for more than 3 months, were adopted as the subjects of the investigation. The median observation period was 23.6 months (range: 3-37 months). MEASUREMENTS: MPO-ANCA was measured at intervals of 2-6 months. RESULTS: Before treatment, the MPO-ANCA titres of all 102 untreated Graves' disease patients were within the reference range (below 10 U/ml). Three (4.1%) of the 73 patients were positive for MPO-ANCA at 13, 16 and 17 months, respectively, after the start of CHEMICAL therapy. In two of them, the MPO-ANCA titres transiently increased to 12.8 and 15.0 U/ml, respectively, despite continued CHEMICAL therapy, but no vasculitic disorders developed. In the third patient, the MPO-ANCA titre increased to 204 U/ml and she developed a higher fever, oral ulcers and DISEASE, but the symptoms resolved 2 weeks after stopping CHEMICAL therapy, and the MPO-ANCA titre decreased to 20.7 U/ml by 4 months after discontinuing CHEMICAL. CONCLUSIONS: CHEMICAL therapy may be related to the appearance of MPO-ANCA, but MPO-ANCA does not appear to be closely related to vasculitis. | CHEMICAL-INDUCED-DISEASE |
| Frequency of appearance of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) in Graves' disease patients treated with CHEMICAL and the relationship between MPO-ANCA and clinical manifestations. OBJECTIVE: Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-positive vasculitis has been reported in patients with Graves' disease who were treated with CHEMICAL (CHEMICAL). The appearance of MPO-ANCA in these cases was suspected of being related to CHEMICAL because the titres of MPO-ANCA decreased when CHEMICAL was stopped. Nevertheless, there have been no studies on the temporal relationship between the appearance of MPO-ANCA and vasculitis during CHEMICAL therapy, or on the incidence of MPO-ANCA in untreated Graves' disease patients. Therefore, we sought to address these parameters in patients with Graves' disease. PATIENTS: We investigated 102 untreated patients with hyperthyroidism due to Graves' disease for the presence of MPO-ANCA, and for the development vasculitis after starting CHEMICAL therapy. Twenty-nine of them were later excluded because of adverse effects of CHEMICAL or because the observation period was less than 3 months. The remaining 73 patients (55 women and 18 men), all of whom were examined for more than 3 months, were adopted as the subjects of the investigation. The median observation period was 23.6 months (range: 3-37 months). MEASUREMENTS: MPO-ANCA was measured at intervals of 2-6 months. RESULTS: Before treatment, the MPO-ANCA titres of all 102 untreated Graves' disease patients were within the reference range (below 10 U/ml). Three (4.1%) of the 73 patients were positive for MPO-ANCA at 13, 16 and 17 months, respectively, after the start of CHEMICAL therapy. In two of them, the MPO-ANCA titres transiently increased to 12.8 and 15.0 U/ml, respectively, despite continued CHEMICAL therapy, but no vasculitic disorders developed. In the third patient, the MPO-ANCA titre increased to 204 U/ml and she developed a higher fever, DISEASE and polyarthralgia, but the symptoms resolved 2 weeks after stopping CHEMICAL therapy, and the MPO-ANCA titre decreased to 20.7 U/ml by 4 months after discontinuing CHEMICAL. CONCLUSIONS: CHEMICAL therapy may be related to the appearance of MPO-ANCA, but MPO-ANCA does not appear to be closely related to vasculitis. | CHEMICAL-INDUCED-DISEASE |
| Prevalence of heart disease in asymptomatic chronic CHEMICAL users. To determine the prevalence of heart disease in outpatient young asymptomatic chronic CHEMICAL users, 35 CHEMICAL users and 32 age-matched controls underwent resting and exercise electrocardiography (ECG) and Doppler echocardiography. Findings consistent with DISEASE were detected in 12 (34%) patients and 3 (9%) controls (p = 0.01). Decreased left ventricular systolic function was demonstrated in 5 (14%) patients, but in none of the controls (p = 0.055). Finally, resting and peak exercise abnormal left ventricular filling was detected in 38 and 35% of patients as compared to 19 and 9% of controls, respectively (p = 0.11 and 0.02, respectively). We conclude that coronary artery or myocardial disease is common (38%) in young asymptomatic chronic CHEMICAL users. Therefore, screening ECG and echocardiography may be warranted in these patients. | CHEMICAL-INDUCED-DISEASE |
| Cardioprotective effects of Picrorrhiza kurroa against CHEMICAL-induced myocardial stress in rats. The cardioprotective effect of the ethanol extract of Picrorrhiza kurroa rhizomes and roots (PK) on CHEMICAL-induced DISEASE in rats with respect to lipid metabolism in serum and heart tissue has been investigated. Oral pre-treatment with PK (80 mg kg(-1) day(-1) for 15 days) significantly prevented the CHEMICAL-induced DISEASE and maintained the rats at near normal status. | CHEMICAL-INDUCED-DISEASE |
| Phase 2 early afterdepolarization as a trigger of polymorphic ventricular tachycardia in acquired DISEASE : direct evidence from intracellular recordings in the intact left ventricular wall. BACKGROUND: This study examined the role of phase 2 early afterdepolarization (EAD) in producing a trigger to initiate torsade de pointes (TdP) with DISEASE induced by dl-CHEMICAL and azimilide. The contribution of transmural dispersion of repolarization (TDR) to transmural propagation of EAD and the maintenance of TdP was also evaluated. METHODS AND RESULTS: Transmembrane action potentials from epicardium, midmyocardium, and endocardium were recorded simultaneously, together with a transmural ECG, in arterially perfused canine and rabbit left ventricular preparations. dl-CHEMICAL preferentially prolonged action potential duration (APD) in M cells dose-dependently (1 to 100 micromol/L), leading to DISEASE and an increase in TDR. Azimilide, however, significantly prolonged APD and QT interval at concentrations from 0.1 to 10 micromol/L but shortened them at 30 micromol/L. Unlike dl-CHEMICAL, azimilide (>3 micromol/L) increased epicardial APD markedly, causing a diminished TDR. Although both dl-CHEMICAL and azimilide rarely induced EADs in canine left ventricles, they produced frequent EADs in rabbits, in which more pronounced DISEASE was seen. An increase in TDR by dl-CHEMICAL facilitated transmural propagation of EADs that initiated multiple episodes of spontaneous TdP in 3 of 6 rabbit left ventricles. Of note, although azimilide (3 to 10 micromol/L) increased APD more than dl-CHEMICAL, its EADs often failed to propagate transmurally, probably because of a diminished TDR. CONCLUSIONS: This study provides the first direct evidence from intracellular action potential recordings that phase 2 EAD can be generated from intact ventricular wall and produce a trigger to initiate the onset of TdP under DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Phase 2 early afterdepolarization as a trigger of polymorphic ventricular tachycardia in acquired long-QT syndrome : direct evidence from intracellular recordings in the intact left ventricular wall. BACKGROUND: This study examined the role of phase 2 early afterdepolarization (EAD) in producing a trigger to initiate DISEASE (DISEASE) with QT prolongation induced by dl-CHEMICAL and azimilide. The contribution of transmural dispersion of repolarization (TDR) to transmural propagation of EAD and the maintenance of DISEASE was also evaluated. METHODS AND RESULTS: Transmembrane action potentials from epicardium, midmyocardium, and endocardium were recorded simultaneously, together with a transmural ECG, in arterially perfused canine and rabbit left ventricular preparations. dl-CHEMICAL preferentially prolonged action potential duration (APD) in M cells dose-dependently (1 to 100 micromol/L), leading to QT prolongation and an increase in TDR. Azimilide, however, significantly prolonged APD and QT interval at concentrations from 0.1 to 10 micromol/L but shortened them at 30 micromol/L. Unlike dl-CHEMICAL, azimilide (>3 micromol/L) increased epicardial APD markedly, causing a diminished TDR. Although both dl-CHEMICAL and azimilide rarely induced EADs in canine left ventricles, they produced frequent EADs in rabbits, in which more pronounced QT prolongation was seen. An increase in TDR by dl-CHEMICAL facilitated transmural propagation of EADs that initiated multiple episodes of spontaneous DISEASE in 3 of 6 rabbit left ventricles. Of note, although azimilide (3 to 10 micromol/L) increased APD more than dl-CHEMICAL, its EADs often failed to propagate transmurally, probably because of a diminished TDR. CONCLUSIONS: This study provides the first direct evidence from intracellular action potential recordings that phase 2 EAD can be generated from intact ventricular wall and produce a trigger to initiate the onset of DISEASE under QT prolongation. | CHEMICAL-INDUCED-DISEASE |
| Phase 2 early afterdepolarization as a trigger of polymorphic DISEASE in acquired long-QT syndrome : direct evidence from intracellular recordings in the intact left ventricular wall. BACKGROUND: This study examined the role of phase 2 early afterdepolarization (EAD) in producing a trigger to initiate torsade de pointes (TdP) with QT prolongation induced by dl-sotalol and CHEMICAL. The contribution of transmural dispersion of repolarization (TDR) to transmural propagation of EAD and the maintenance of TdP was also evaluated. METHODS AND RESULTS: Transmembrane action potentials from epicardium, midmyocardium, and endocardium were recorded simultaneously, together with a transmural ECG, in arterially perfused canine and rabbit left ventricular preparations. dl-Sotalol preferentially prolonged action potential duration (APD) in M cells dose-dependently (1 to 100 micromol/L), leading to QT prolongation and an increase in TDR. CHEMICAL, however, significantly prolonged APD and QT interval at concentrations from 0.1 to 10 micromol/L but shortened them at 30 micromol/L. Unlike dl-sotalol, CHEMICAL (>3 micromol/L) increased epicardial APD markedly, causing a diminished TDR. Although both dl-sotalol and CHEMICAL rarely induced EADs in canine left ventricles, they produced frequent EADs in rabbits, in which more pronounced QT prolongation was seen. An increase in TDR by dl-sotalol facilitated transmural propagation of EADs that initiated multiple episodes of spontaneous TdP in 3 of 6 rabbit left ventricles. Of note, although CHEMICAL (3 to 10 micromol/L) increased APD more than dl-sotalol, its EADs often failed to propagate transmurally, probably because of a diminished TDR. CONCLUSIONS: This study provides the first direct evidence from intracellular action potential recordings that phase 2 EAD can be generated from intact ventricular wall and produce a trigger to initiate the onset of TdP under QT prolongation. | CHEMICAL-INDUCED-DISEASE |
| Prenatal CHEMICAL exposure and cranial sonographic findings in preterm infants. PURPOSE: Prenatal CHEMICAL exposure has been linked with subependymal hemorrhage and the formation of DISEASE that are detectable on cranial sonography in neonates born at term. We sought to determine if prenatal CHEMICAL exposure increases the incidence of subependymal cysts in preterm infants. METHODS: We retrospectively reviewed the medical records and cranial sonograms obtained during a 1-year period on 122 premature (< 36 weeks of gestation) infants. Infants were categorized into 1 of 2 groups: those exposed to CHEMICAL and those not exposed to CHEMICAL. Infants were assigned to the CHEMICAL-exposed group if there was a maternal history of cocaine abuse during pregnancy or if maternal or neonatal urine toxicology results were positive at the time of delivery. RESULTS: Five of the 122 infants were excluded from the study because of insufficient medical and drug histories. The incidence of subependymal cysts in the 117 remaining infants was 14% (16 of 117). The incidence of subependymal cysts in infants exposed to CHEMICAL prenatally was 44% (8 of 18) compared with 8% (8 of 99) in the unexposed group (p < 0.01). CONCLUSIONS: We found an increased incidence of subependymal cyst formation in preterm infants who were exposed to CHEMICAL prenatally. This result is consistent with results of similar studies in term infants. | CHEMICAL-INDUCED-DISEASE |
| Prenatal CHEMICAL exposure and cranial sonographic findings in DISEASE. PURPOSE: Prenatal CHEMICAL exposure has been linked with subependymal hemorrhage and the formation of cysts that are detectable on cranial sonography in neonates born at term. We sought to determine if prenatal CHEMICAL exposure increases the incidence of subependymal cysts in DISEASE. METHODS: We retrospectively reviewed the medical records and cranial sonograms obtained during a 1-year period on 122 DISEASE. Infants were categorized into 1 of 2 groups: those exposed to CHEMICAL and those not exposed to CHEMICAL. Infants were assigned to the CHEMICAL-exposed group if there was a maternal history of cocaine abuse during pregnancy or if maternal or neonatal urine toxicology results were positive at the time of delivery. RESULTS: Five of the 122 infants were excluded from the study because of insufficient medical and drug histories. The incidence of subependymal cysts in the 117 remaining infants was 14% (16 of 117). The incidence of subependymal cysts in infants exposed to CHEMICAL prenatally was 44% (8 of 18) compared with 8% (8 of 99) in the unexposed group (p < 0.01). CONCLUSIONS: We found an increased incidence of subependymal cyst formation in DISEASE who were exposed to CHEMICAL prenatally. This result is consistent with results of similar studies in term infants. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL neuropathy in patients treated for metastatic prostate cancer. We prospectively evaluated CHEMICAL-induced neuropathy using electrodiagnostic studies. Sixty-seven men with metastatic androgen-independent prostate cancer in an open-label trial of oral CHEMICAL underwent neurologic examinations and nerve conduction studies (NCS) prior to and at 3-month intervals during treatment. NCS included recording of sensory nerve action potentials (SNAPs) from median, radial, ulnar, and sural nerves. SNAP amplitudes for each nerve were expressed as the percentage of its baseline, and the mean of the four was termed the SNAP index. A 40% decline in the SNAP index was considered clinically significant. CHEMICAL was discontinued in 55 patients for lack of therapeutic response. Of 67 patients initially enrolled, 24 remained on CHEMICAL for 3 months, 8 remained at 6 months, and 3 remained at 9 months. Six patients developed neuropathy. Clinical symptoms and a decline in the SNAP index occurred concurrently. Older age and cumulative dose were possible contributing factors. Neuropathy may thus be a common complication of CHEMICAL in older patients. The SNAP index can be used to monitor DISEASE, but not for early detection. | CHEMICAL-INDUCED-DISEASE |
| Thalidomide neuropathy in patients treated for metastatic DISEASE. We prospectively evaluated thalidomide-induced neuropathy using electrodiagnostic studies. Sixty-seven men with metastatic CHEMICAL-independent DISEASE in an open-label trial of oral thalidomide underwent neurologic examinations and nerve conduction studies (NCS) prior to and at 3-month intervals during treatment. NCS included recording of sensory nerve action potentials (SNAPs) from median, radial, ulnar, and sural nerves. SNAP amplitudes for each nerve were expressed as the percentage of its baseline, and the mean of the four was termed the SNAP index. A 40% decline in the SNAP index was considered clinically significant. Thalidomide was discontinued in 55 patients for lack of therapeutic response. Of 67 patients initially enrolled, 24 remained on thalidomide for 3 months, 8 remained at 6 months, and 3 remained at 9 months. Six patients developed neuropathy. Clinical symptoms and a decline in the SNAP index occurred concurrently. Older age and cumulative dose were possible contributing factors. Neuropathy may thus be a common complication of thalidomide in older patients. The SNAP index can be used to monitor peripheral neuropathy, but not for early detection. | NO-RELATIONSHIP |
| Thalidomide DISEASE in patients treated for metastatic prostate cancer. We prospectively evaluated thalidomide-induced DISEASE using electrodiagnostic studies. Sixty-seven men with metastatic CHEMICAL-independent prostate cancer in an open-label trial of oral thalidomide underwent neurologic examinations and nerve conduction studies (NCS) prior to and at 3-month intervals during treatment. NCS included recording of sensory nerve action potentials (SNAPs) from median, radial, ulnar, and sural nerves. SNAP amplitudes for each nerve were expressed as the percentage of its baseline, and the mean of the four was termed the SNAP index. A 40% decline in the SNAP index was considered clinically significant. Thalidomide was discontinued in 55 patients for lack of therapeutic response. Of 67 patients initially enrolled, 24 remained on thalidomide for 3 months, 8 remained at 6 months, and 3 remained at 9 months. Six patients developed DISEASE. Clinical symptoms and a decline in the SNAP index occurred concurrently. Older age and cumulative dose were possible contributing factors. DISEASE may thus be a common complication of thalidomide in older patients. The SNAP index can be used to monitor peripheral neuropathy, but not for early detection. | NO-RELATIONSHIP |
| Overexpression of copper/zinc-superoxide dismutase protects from CHEMICAL-induced DISEASE. The participation of reactive oxygen species in aminoglycoside-induced ototoxicity has been deduced from observations that aminoglycoside-iron complexes catalyze the formation of superoxide radicals in vitro and that antioxidants attenuate ototoxicity in vivo. We therefore hypothesized that overexpression of Cu/Zn-superoxide dismutase (h-SOD1) should protect transgenic mice from ototoxicity. Immunocytochemistry confirmed expression of h-SOD1 in inner ear tissues of transgenic C57BL/6-TgN[SOD1]3Cje mice. Transgenic and nontransgenic littermates received CHEMICAL (400 mg/kg body weight/day) for 10 days beginning on day 10 after birth. Auditory thresholds were tested by evoked auditory brain stem responses at 1 month after birth. In nontransgenic animals, the threshold in the CHEMICAL-treated group was 45-50 dB higher than in saline-injected controls. In the transgenic group, CHEMICAL increased the threshold by only 15 dB over the respective controls. The effects were similar at 12 and 24 kHz. The protection by overexpression of superoxide dismutase supports the hypothesis that oxidant stress plays a significant role in aminoglycoside-induced ototoxicity. The results also suggest transgenic animals as suitable models to investigate the underlying mechanisms and possible strategies for prevention. | CHEMICAL-INDUCED-DISEASE |
| Overexpression of copper/CHEMICAL-superoxide dismutase protects from kanamycin-induced hearing loss. The participation of reactive oxygen species in aminoglycoside-induced DISEASE has been deduced from observations that aminoglycoside-iron complexes catalyze the formation of superoxide radicals in vitro and that antioxidants attenuate DISEASE in vivo. We therefore hypothesized that overexpression of Cu/CHEMICAL-superoxide dismutase (h-SOD1) should protect transgenic mice from DISEASE. Immunocytochemistry confirmed expression of h-SOD1 in inner ear tissues of transgenic C57BL/6-TgN[SOD1]3Cje mice. Transgenic and nontransgenic littermates received kanamycin (400 mg/kg body weight/day) for 10 days beginning on day 10 after birth. Auditory thresholds were tested by evoked auditory brain stem responses at 1 month after birth. In nontransgenic animals, the threshold in the kanamycin-treated group was 45-50 dB higher than in saline-injected controls. In the transgenic group, kanamycin increased the threshold by only 15 dB over the respective controls. The effects were similar at 12 and 24 kHz. The protection by overexpression of superoxide dismutase supports the hypothesis that oxidant stress plays a significant role in aminoglycoside-induced DISEASE. The results also suggest transgenic animals as suitable models to investigate the underlying mechanisms and possible strategies for prevention. | NO-RELATIONSHIP |
| Overexpression of CHEMICAL/zinc-superoxide dismutase protects from kanamycin-induced hearing loss. The participation of reactive oxygen species in aminoglycoside-induced DISEASE has been deduced from observations that aminoglycoside-iron complexes catalyze the formation of superoxide radicals in vitro and that antioxidants attenuate DISEASE in vivo. We therefore hypothesized that overexpression of CHEMICAL/Zn-superoxide dismutase (h-SOD1) should protect transgenic mice from DISEASE. Immunocytochemistry confirmed expression of h-SOD1 in inner ear tissues of transgenic C57BL/6-TgN[SOD1]3Cje mice. Transgenic and nontransgenic littermates received kanamycin (400 mg/kg body weight/day) for 10 days beginning on day 10 after birth. Auditory thresholds were tested by evoked auditory brain stem responses at 1 month after birth. In nontransgenic animals, the threshold in the kanamycin-treated group was 45-50 dB higher than in saline-injected controls. In the transgenic group, kanamycin increased the threshold by only 15 dB over the respective controls. The effects were similar at 12 and 24 kHz. The protection by overexpression of superoxide dismutase supports the hypothesis that oxidant stress plays a significant role in aminoglycoside-induced DISEASE. The results also suggest transgenic animals as suitable models to investigate the underlying mechanisms and possible strategies for prevention. | NO-RELATIONSHIP |
| Overexpression of copper/zinc-CHEMICAL dismutase protects from kanamycin-induced hearing loss. The participation of reactive oxygen species in aminoglycoside-induced DISEASE has been deduced from observations that aminoglycoside-iron complexes catalyze the formation of CHEMICAL radicals in vitro and that antioxidants attenuate DISEASE in vivo. We therefore hypothesized that overexpression of Cu/Zn-CHEMICAL dismutase (h-SOD1) should protect transgenic mice from DISEASE. Immunocytochemistry confirmed expression of h-SOD1 in inner ear tissues of transgenic C57BL/6-TgN[SOD1]3Cje mice. Transgenic and nontransgenic littermates received kanamycin (400 mg/kg body weight/day) for 10 days beginning on day 10 after birth. Auditory thresholds were tested by evoked auditory brain stem responses at 1 month after birth. In nontransgenic animals, the threshold in the kanamycin-treated group was 45-50 dB higher than in saline-injected controls. In the transgenic group, kanamycin increased the threshold by only 15 dB over the respective controls. The effects were similar at 12 and 24 kHz. The protection by overexpression of CHEMICAL dismutase supports the hypothesis that oxidant stress plays a significant role in aminoglycoside-induced DISEASE. The results also suggest transgenic animals as suitable models to investigate the underlying mechanisms and possible strategies for prevention. | NO-RELATIONSHIP |
| Overexpression of copper/zinc-superoxide dismutase protects from kanamycin-induced hearing loss. The participation of reactive oxygen species in aminoglycoside-induced DISEASE has been deduced from observations that aminoglycoside-CHEMICAL complexes catalyze the formation of superoxide radicals in vitro and that antioxidants attenuate DISEASE in vivo. We therefore hypothesized that overexpression of Cu/Zn-superoxide dismutase (h-SOD1) should protect transgenic mice from DISEASE. Immunocytochemistry confirmed expression of h-SOD1 in inner ear tissues of transgenic C57BL/6-TgN[SOD1]3Cje mice. Transgenic and nontransgenic littermates received kanamycin (400 mg/kg body weight/day) for 10 days beginning on day 10 after birth. Auditory thresholds were tested by evoked auditory brain stem responses at 1 month after birth. In nontransgenic animals, the threshold in the kanamycin-treated group was 45-50 dB higher than in saline-injected controls. In the transgenic group, kanamycin increased the threshold by only 15 dB over the respective controls. The effects were similar at 12 and 24 kHz. The protection by overexpression of superoxide dismutase supports the hypothesis that oxidant stress plays a significant role in aminoglycoside-induced DISEASE. The results also suggest transgenic animals as suitable models to investigate the underlying mechanisms and possible strategies for prevention. | NO-RELATIONSHIP |
| Overexpression of copper/zinc-superoxide dismutase protects from kanamycin-induced hearing loss. The participation of reactive oxygen species in CHEMICAL-induced DISEASE has been deduced from observations that CHEMICAL-iron complexes catalyze the formation of superoxide radicals in vitro and that antioxidants attenuate DISEASE in vivo. We therefore hypothesized that overexpression of Cu/Zn-superoxide dismutase (h-SOD1) should protect transgenic mice from DISEASE. Immunocytochemistry confirmed expression of h-SOD1 in inner ear tissues of transgenic C57BL/6-TgN[SOD1]3Cje mice. Transgenic and nontransgenic littermates received kanamycin (400 mg/kg body weight/day) for 10 days beginning on day 10 after birth. Auditory thresholds were tested by evoked auditory brain stem responses at 1 month after birth. In nontransgenic animals, the threshold in the kanamycin-treated group was 45-50 dB higher than in saline-injected controls. In the transgenic group, kanamycin increased the threshold by only 15 dB over the respective controls. The effects were similar at 12 and 24 kHz. The protection by overexpression of superoxide dismutase supports the hypothesis that oxidant stress plays a significant role in CHEMICAL-induced DISEASE. The results also suggest transgenic animals as suitable models to investigate the underlying mechanisms and possible strategies for prevention. | NO-RELATIONSHIP |
| Overexpression of copper/zinc-superoxide dismutase protects from kanamycin-induced hearing loss. The participation of reactive CHEMICAL species in aminoglycoside-induced DISEASE has been deduced from observations that aminoglycoside-iron complexes catalyze the formation of superoxide radicals in vitro and that antioxidants attenuate DISEASE in vivo. We therefore hypothesized that overexpression of Cu/Zn-superoxide dismutase (h-SOD1) should protect transgenic mice from DISEASE. Immunocytochemistry confirmed expression of h-SOD1 in inner ear tissues of transgenic C57BL/6-TgN[SOD1]3Cje mice. Transgenic and nontransgenic littermates received kanamycin (400 mg/kg body weight/day) for 10 days beginning on day 10 after birth. Auditory thresholds were tested by evoked auditory brain stem responses at 1 month after birth. In nontransgenic animals, the threshold in the kanamycin-treated group was 45-50 dB higher than in saline-injected controls. In the transgenic group, kanamycin increased the threshold by only 15 dB over the respective controls. The effects were similar at 12 and 24 kHz. The protection by overexpression of superoxide dismutase supports the hypothesis that oxidant stress plays a significant role in aminoglycoside-induced DISEASE. The results also suggest transgenic animals as suitable models to investigate the underlying mechanisms and possible strategies for prevention. | NO-RELATIONSHIP |
| CHEMICAL induces DISEASE and glial cerebral changes in rats. OBJECTIVE: To assess whether CHEMICAL (CHEMICAL) produces DISEASE and/or cerebral glial changes in rats. METHODS: Male Wistar rats were studied and 3 groups were formed (8 rats per group). The moderate-dose group received 5 mg/kg/day CHEMICAL released from a subcutaneous implant. In the high-dose group, implants containing CHEMICAL equivalent to 60 mg/kg/day were applied. In the control group implants contained no CHEMICAL. DISEASE was assessed using an open field and elevated plus-maze devices. The number of cells and cytoplasmic transformation of astrocytes and microglia cells were assessed by immunohistochemical analyses. RESULTS: DISEASE was documented in both groups of CHEMICAL treated rats compared with controls. The magnitude of transformation of the microglia assessed by the number of intersections was significantly higher in the CHEMICAL groups than in controls in the prefrontal cortex (moderate-dose, 24.1; high-dose, 23.6; controls 18.7; p < 0.01) and striatum (moderate-dose 25.6; high-dose 26.3; controls 18.9; p < 0.01), but not in hippocampus. The number of stained microglia cells was significantly higher in the CHEMICAL treated groups in the prefrontal cortex than in controls (moderate-dose, 29.1; high-dose, 28.4; control, 17.7 cells per field; p < 0.01). Stained microglia cells were significantly more numerous striatum and hippocampus in the high-dose group compared to controls. CONCLUSION: Subacute exposure to CHEMICAL induced DISEASE and reactivity of microglia. The relevance of these features for patients using CHEMICAL remains to be elucidated. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of carboplatin and liposomal CHEMICAL in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of carboplatin and liposomal CHEMICAL was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of carboplatin (area under the concentration curve [AUC], 5) and liposomal CHEMICAL (CHEMICAL; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 DISEASE in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal CHEMICAL, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of carboplatin and liposomal CHEMICAL has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of carboplatin and liposomal CHEMICAL in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of carboplatin and liposomal CHEMICAL was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of carboplatin (area under the concentration curve [AUC], 5) and liposomal CHEMICAL (CHEMICAL; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal CHEMICAL, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, DISEASE in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of carboplatin and liposomal CHEMICAL has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of CHEMICAL and liposomal doxorubicin in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of CHEMICAL and liposomal doxorubicin was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of CHEMICAL (area under the concentration curve [AUC], 5) and liposomal doxorubicin (Doxil; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 DISEASE in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal doxorubicin, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of CHEMICAL and liposomal doxorubicin has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of CHEMICAL and liposomal doxorubicin in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of CHEMICAL and liposomal doxorubicin was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of CHEMICAL (area under the concentration curve [AUC], 5) and liposomal doxorubicin (Doxil; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, DISEASE in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal doxorubicin, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of CHEMICAL and liposomal doxorubicin has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of carboplatin and liposomal CHEMICAL in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of carboplatin and liposomal CHEMICAL was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of carboplatin (area under the concentration curve [AUC], 5) and liposomal CHEMICAL (CHEMICAL; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal CHEMICAL, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, fatigue in 9 patients, DISEASE and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of carboplatin and liposomal CHEMICAL has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of CHEMICAL and liposomal doxorubicin in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of CHEMICAL and liposomal doxorubicin was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of CHEMICAL (area under the concentration curve [AUC], 5) and liposomal doxorubicin (Doxil; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal doxorubicin, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, DISEASE in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of CHEMICAL and liposomal doxorubicin has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of carboplatin and liposomal CHEMICAL in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of carboplatin and liposomal CHEMICAL was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of carboplatin (area under the concentration curve [AUC], 5) and liposomal CHEMICAL (CHEMICAL; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal CHEMICAL, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, DISEASE in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of carboplatin and liposomal CHEMICAL has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of CHEMICAL and liposomal doxorubicin in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of CHEMICAL and liposomal doxorubicin was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of CHEMICAL (area under the concentration curve [AUC], 5) and liposomal doxorubicin (Doxil; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal doxorubicin, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, DISEASE in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of CHEMICAL and liposomal doxorubicin has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of carboplatin and liposomal CHEMICAL in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of carboplatin and liposomal CHEMICAL was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of carboplatin (area under the concentration curve [AUC], 5) and liposomal CHEMICAL (CHEMICAL; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal CHEMICAL, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and DISEASE in 3 patients. CONCLUSIONS: The combination of carboplatin and liposomal CHEMICAL has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of carboplatin and liposomal CHEMICAL in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of carboplatin and liposomal CHEMICAL was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of carboplatin (area under the concentration curve [AUC], 5) and liposomal CHEMICAL (CHEMICAL; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, DISEASE in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal CHEMICAL, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of carboplatin and liposomal CHEMICAL has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of carboplatin and liposomal CHEMICAL in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of carboplatin and liposomal CHEMICAL was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of carboplatin (area under the concentration curve [AUC], 5) and liposomal CHEMICAL (CHEMICAL; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal CHEMICAL, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included DISEASE in 17 patients, emesis in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of carboplatin and liposomal CHEMICAL has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of CHEMICAL and liposomal doxorubicin in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of CHEMICAL and liposomal doxorubicin was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of CHEMICAL (area under the concentration curve [AUC], 5) and liposomal doxorubicin (Doxil; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal doxorubicin, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and DISEASE in 3 patients. CONCLUSIONS: The combination of CHEMICAL and liposomal doxorubicin has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of CHEMICAL and liposomal doxorubicin in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of CHEMICAL and liposomal doxorubicin was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of CHEMICAL (area under the concentration curve [AUC], 5) and liposomal doxorubicin (Doxil; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal doxorubicin, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, DISEASE in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of CHEMICAL and liposomal doxorubicin has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of carboplatin and liposomal CHEMICAL in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of carboplatin and liposomal CHEMICAL was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of carboplatin (area under the concentration curve [AUC], 5) and liposomal CHEMICAL (CHEMICAL; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal CHEMICAL, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, DISEASE in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of carboplatin and liposomal CHEMICAL has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of CHEMICAL and liposomal doxorubicin in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of CHEMICAL and liposomal doxorubicin was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of CHEMICAL (area under the concentration curve [AUC], 5) and liposomal doxorubicin (Doxil; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal doxorubicin, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included DISEASE in 17 patients, emesis in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of CHEMICAL and liposomal doxorubicin has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of carboplatin and liposomal CHEMICAL in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of carboplatin and liposomal CHEMICAL was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of carboplatin (area under the concentration curve [AUC], 5) and liposomal CHEMICAL (CHEMICAL; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal CHEMICAL, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, DISEASE in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of carboplatin and liposomal CHEMICAL has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of CHEMICAL and liposomal doxorubicin in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of CHEMICAL and liposomal doxorubicin was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of CHEMICAL (area under the concentration curve [AUC], 5) and liposomal doxorubicin (Doxil; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal doxorubicin, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, fatigue in 9 patients, DISEASE and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of CHEMICAL and liposomal doxorubicin has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of CHEMICAL and liposomal doxorubicin in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of CHEMICAL and liposomal doxorubicin was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of CHEMICAL (area under the concentration curve [AUC], 5) and liposomal doxorubicin (Doxil; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal doxorubicin, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, DISEASE in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of CHEMICAL and liposomal doxorubicin has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of carboplatin and liposomal CHEMICAL in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of carboplatin and liposomal CHEMICAL was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of carboplatin (area under the concentration curve [AUC], 5) and liposomal CHEMICAL (CHEMICAL; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, anemia in 12 patients, DISEASE in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal CHEMICAL, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of carboplatin and liposomal CHEMICAL has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Phase II study of CHEMICAL and liposomal doxorubicin in patients with recurrent squamous cell carcinoma of the cervix. BACKGROUND: The activity of the combination of CHEMICAL and liposomal doxorubicin was tested in a Phase II study of patients with recurrent cervical carcinoma. METHODS: The combination of CHEMICAL (area under the concentration curve [AUC], 5) and liposomal doxorubicin (Doxil; starting dose, 40 mg/m(2)) was administered intravenously every 28 days to 37 patients with recurrent squamous cell cervical carcinoma to determine antitumor activity and toxicity profile. RESULTS: Twenty-nine patients were assessable for response, and 35 patients were assessable for toxicity. The overall response rate was 38%, the median time to response was 10 weeks, the median duration of response was 26 weeks, and the median survival was 37 weeks. The main toxic effect was myelosuppression, with Grade 3 and 4 neutropenia in 16 patients, DISEASE in 12 patients, thrombocytopenia in 11 patients, and neutropenic fever in 3 patients. Four patients had five infusion-related reactions during the infusion of liposomal doxorubicin, leading to treatment discontinuation in three patients. Grade > or = 2 nonhematologic toxicity included nausea in 17 patients, emesis in 14 patients, fatigue in 9 patients, mucositis and/or stomatitis in 8 patients, constipation in 6 patients, weight loss in 5 patients, hand-foot syndrome in 2 patients, and skin reactions in 3 patients. CONCLUSIONS: The combination of CHEMICAL and liposomal doxorubicin has modest activity in patients with recurrent cervical carcinoma. | CHEMICAL-INDUCED-DISEASE |
| Antimicrobial-induced DISEASE (DISEASE): a review of spontaneous reports. The authors reviewed reported cases of antibiotic-induced DISEASE episodes by means of a MEDLINE and PsychLit search for reports of antibiotic-induced DISEASE. Unpublished reports were requested from the World Health Organization (WHO) and the Food and Drug Administration (FDA). Twenty-one reports of antimicrobial-induced DISEASE were found in the literature. There were 6 cases implicating clarithromycin, 13 implicating isoniazid, and 1 case each implicating erythromycin and amoxicillin. The WHO reported 82 cases. Of these, clarithromycin was implicated in 23 (27.6%) cases, CHEMICAL in 12 (14.4%) cases, and ofloxacin in 10 (12%) cases. Cotrimoxazole, metronidazole, and erythromycin were involved in 15 reported DISEASE episodes. Cases reported by the FDA showed clarithromycin and CHEMICAL to be the most frequently associated with the development of DISEASE. Statistical analysis of the data would not have demonstrated a significant statistical correlative risk and was therefore not undertaken. Patients have an increased risk of developing DISEASE while being treated with antimicrobials. Although this is not a statistically significant risk, physicians must be aware of the effect and reversibility. Further research clearly is required to determine the incidence of antimicrobial-induced DISEASE, the relative risk factors of developing an antimicrobial-induced DISEASE episode among various demographic populations, and the incidence of patients who continue to have persistent affective disorders once the initial episode, which occurs while the patient is taking antibiotics, subsides. The authors elected to name this syndrome "DISEASE." | CHEMICAL-INDUCED-DISEASE |
| Antimicrobial-induced DISEASE (DISEASE): a review of spontaneous reports. The authors reviewed reported cases of antibiotic-induced DISEASE episodes by means of a MEDLINE and PsychLit search for reports of antibiotic-induced DISEASE. Unpublished reports were requested from the World Health Organization (WHO) and the Food and Drug Administration (FDA). Twenty-one reports of antimicrobial-induced DISEASE were found in the literature. There were 6 cases implicating clarithromycin, 13 implicating isoniazid, and 1 case each implicating erythromycin and amoxicillin. The WHO reported 82 cases. Of these, clarithromycin was implicated in 23 (27.6%) cases, ciprofloxacin in 12 (14.4%) cases, and ofloxacin in 10 (12%) cases. CHEMICAL, metronidazole, and erythromycin were involved in 15 reported DISEASE episodes. Cases reported by the FDA showed clarithromycin and ciprofloxacin to be the most frequently associated with the development of DISEASE. Statistical analysis of the data would not have demonstrated a significant statistical correlative risk and was therefore not undertaken. Patients have an increased risk of developing DISEASE while being treated with antimicrobials. Although this is not a statistically significant risk, physicians must be aware of the effect and reversibility. Further research clearly is required to determine the incidence of antimicrobial-induced DISEASE, the relative risk factors of developing an antimicrobial-induced DISEASE episode among various demographic populations, and the incidence of patients who continue to have persistent affective disorders once the initial episode, which occurs while the patient is taking antibiotics, subsides. The authors elected to name this syndrome "DISEASE." | CHEMICAL-INDUCED-DISEASE |
| Antimicrobial-induced DISEASE (DISEASE): a review of spontaneous reports. The authors reviewed reported cases of antibiotic-induced DISEASE episodes by means of a MEDLINE and PsychLit search for reports of antibiotic-induced DISEASE. Unpublished reports were requested from the World Health Organization (WHO) and the Food and Drug Administration (FDA). Twenty-one reports of antimicrobial-induced DISEASE were found in the literature. There were 6 cases implicating clarithromycin, 13 implicating isoniazid, and 1 case each implicating erythromycin and amoxicillin. The WHO reported 82 cases. Of these, clarithromycin was implicated in 23 (27.6%) cases, ciprofloxacin in 12 (14.4%) cases, and ofloxacin in 10 (12%) cases. Cotrimoxazole, CHEMICAL, and erythromycin were involved in 15 reported DISEASE episodes. Cases reported by the FDA showed clarithromycin and ciprofloxacin to be the most frequently associated with the development of DISEASE. Statistical analysis of the data would not have demonstrated a significant statistical correlative risk and was therefore not undertaken. Patients have an increased risk of developing DISEASE while being treated with antimicrobials. Although this is not a statistically significant risk, physicians must be aware of the effect and reversibility. Further research clearly is required to determine the incidence of antimicrobial-induced DISEASE, the relative risk factors of developing an antimicrobial-induced DISEASE episode among various demographic populations, and the incidence of patients who continue to have persistent affective disorders once the initial episode, which occurs while the patient is taking antibiotics, subsides. The authors elected to name this syndrome "DISEASE." | CHEMICAL-INDUCED-DISEASE |
| Antimicrobial-induced DISEASE (DISEASE): a review of spontaneous reports. The authors reviewed reported cases of antibiotic-induced DISEASE episodes by means of a MEDLINE and PsychLit search for reports of antibiotic-induced DISEASE. Unpublished reports were requested from the World Health Organization (WHO) and the Food and Drug Administration (FDA). Twenty-one reports of antimicrobial-induced DISEASE were found in the literature. There were 6 cases implicating clarithromycin, 13 implicating CHEMICAL, and 1 case each implicating erythromycin and amoxicillin. The WHO reported 82 cases. Of these, clarithromycin was implicated in 23 (27.6%) cases, ciprofloxacin in 12 (14.4%) cases, and ofloxacin in 10 (12%) cases. Cotrimoxazole, metronidazole, and erythromycin were involved in 15 reported DISEASE episodes. Cases reported by the FDA showed clarithromycin and ciprofloxacin to be the most frequently associated with the development of DISEASE. Statistical analysis of the data would not have demonstrated a significant statistical correlative risk and was therefore not undertaken. Patients have an increased risk of developing DISEASE while being treated with antimicrobials. Although this is not a statistically significant risk, physicians must be aware of the effect and reversibility. Further research clearly is required to determine the incidence of antimicrobial-induced DISEASE, the relative risk factors of developing an antimicrobial-induced DISEASE episode among various demographic populations, and the incidence of patients who continue to have persistent affective disorders once the initial episode, which occurs while the patient is taking antibiotics, subsides. The authors elected to name this syndrome "DISEASE." | CHEMICAL-INDUCED-DISEASE |
| Antimicrobial-induced DISEASE (DISEASE): a review of spontaneous reports. The authors reviewed reported cases of antibiotic-induced DISEASE episodes by means of a MEDLINE and PsychLit search for reports of antibiotic-induced DISEASE. Unpublished reports were requested from the World Health Organization (WHO) and the Food and Drug Administration (FDA). Twenty-one reports of antimicrobial-induced DISEASE were found in the literature. There were 6 cases implicating clarithromycin, 13 implicating isoniazid, and 1 case each implicating erythromycin and amoxicillin. The WHO reported 82 cases. Of these, clarithromycin was implicated in 23 (27.6%) cases, ciprofloxacin in 12 (14.4%) cases, and CHEMICAL in 10 (12%) cases. Cotrimoxazole, metronidazole, and erythromycin were involved in 15 reported DISEASE episodes. Cases reported by the FDA showed clarithromycin and ciprofloxacin to be the most frequently associated with the development of DISEASE. Statistical analysis of the data would not have demonstrated a significant statistical correlative risk and was therefore not undertaken. Patients have an increased risk of developing DISEASE while being treated with antimicrobials. Although this is not a statistically significant risk, physicians must be aware of the effect and reversibility. Further research clearly is required to determine the incidence of antimicrobial-induced DISEASE, the relative risk factors of developing an antimicrobial-induced DISEASE episode among various demographic populations, and the incidence of patients who continue to have persistent affective disorders once the initial episode, which occurs while the patient is taking antibiotics, subsides. The authors elected to name this syndrome "DISEASE." | CHEMICAL-INDUCED-DISEASE |
| Antimicrobial-induced DISEASE (DISEASE): a review of spontaneous reports. The authors reviewed reported cases of antibiotic-induced DISEASE episodes by means of a MEDLINE and PsychLit search for reports of antibiotic-induced DISEASE. Unpublished reports were requested from the World Health Organization (WHO) and the Food and Drug Administration (FDA). Twenty-one reports of antimicrobial-induced DISEASE were found in the literature. There were 6 cases implicating clarithromycin, 13 implicating isoniazid, and 1 case each implicating erythromycin and CHEMICAL. The WHO reported 82 cases. Of these, clarithromycin was implicated in 23 (27.6%) cases, ciprofloxacin in 12 (14.4%) cases, and ofloxacin in 10 (12%) cases. Cotrimoxazole, metronidazole, and erythromycin were involved in 15 reported DISEASE episodes. Cases reported by the FDA showed clarithromycin and ciprofloxacin to be the most frequently associated with the development of DISEASE. Statistical analysis of the data would not have demonstrated a significant statistical correlative risk and was therefore not undertaken. Patients have an increased risk of developing DISEASE while being treated with antimicrobials. Although this is not a statistically significant risk, physicians must be aware of the effect and reversibility. Further research clearly is required to determine the incidence of antimicrobial-induced DISEASE, the relative risk factors of developing an antimicrobial-induced DISEASE episode among various demographic populations, and the incidence of patients who continue to have persistent affective disorders once the initial episode, which occurs while the patient is taking antibiotics, subsides. The authors elected to name this syndrome "DISEASE." | CHEMICAL-INDUCED-DISEASE |
| Antimicrobial-induced DISEASE (DISEASE): a review of spontaneous reports. The authors reviewed reported cases of antibiotic-induced DISEASE episodes by means of a MEDLINE and PsychLit search for reports of antibiotic-induced DISEASE. Unpublished reports were requested from the World Health Organization (WHO) and the Food and Drug Administration (FDA). Twenty-one reports of antimicrobial-induced DISEASE were found in the literature. There were 6 cases implicating CHEMICAL, 13 implicating isoniazid, and 1 case each implicating erythromycin and amoxicillin. The WHO reported 82 cases. Of these, CHEMICAL was implicated in 23 (27.6%) cases, ciprofloxacin in 12 (14.4%) cases, and ofloxacin in 10 (12%) cases. Cotrimoxazole, metronidazole, and erythromycin were involved in 15 reported DISEASE episodes. Cases reported by the FDA showed CHEMICAL and ciprofloxacin to be the most frequently associated with the development of DISEASE. Statistical analysis of the data would not have demonstrated a significant statistical correlative risk and was therefore not undertaken. Patients have an increased risk of developing DISEASE while being treated with antimicrobials. Although this is not a statistically significant risk, physicians must be aware of the effect and reversibility. Further research clearly is required to determine the incidence of antimicrobial-induced DISEASE, the relative risk factors of developing an antimicrobial-induced DISEASE episode among various demographic populations, and the incidence of patients who continue to have persistent affective disorders once the initial episode, which occurs while the patient is taking antibiotics, subsides. The authors elected to name this syndrome "DISEASE." | CHEMICAL-INDUCED-DISEASE |
| Antimicrobial-induced DISEASE (DISEASE): a review of spontaneous reports. The authors reviewed reported cases of antibiotic-induced DISEASE episodes by means of a MEDLINE and PsychLit search for reports of antibiotic-induced DISEASE. Unpublished reports were requested from the World Health Organization (WHO) and the Food and Drug Administration (FDA). Twenty-one reports of antimicrobial-induced DISEASE were found in the literature. There were 6 cases implicating clarithromycin, 13 implicating isoniazid, and 1 case each implicating CHEMICAL and amoxicillin. The WHO reported 82 cases. Of these, clarithromycin was implicated in 23 (27.6%) cases, ciprofloxacin in 12 (14.4%) cases, and ofloxacin in 10 (12%) cases. Cotrimoxazole, metronidazole, and CHEMICAL were involved in 15 reported DISEASE episodes. Cases reported by the FDA showed clarithromycin and ciprofloxacin to be the most frequently associated with the development of DISEASE. Statistical analysis of the data would not have demonstrated a significant statistical correlative risk and was therefore not undertaken. Patients have an increased risk of developing DISEASE while being treated with antimicrobials. Although this is not a statistically significant risk, physicians must be aware of the effect and reversibility. Further research clearly is required to determine the incidence of antimicrobial-induced DISEASE, the relative risk factors of developing an antimicrobial-induced DISEASE episode among various demographic populations, and the incidence of patients who continue to have persistent affective disorders once the initial episode, which occurs while the patient is taking antibiotics, subsides. The authors elected to name this syndrome "DISEASE." | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced DISEASE in Parkinson's disease. CHEMICAL-induced DISEASE are very uncommon. Usually they occur simultaneously with limb peak-dose choreatic dyskinesias. We report on a patient with leftward and upward deviations of gaze during the peak effect of CHEMICAL, and hypothesize that a severe dopaminergic denervation in the caudate nucleus is needed for the appearance of these CHEMICAL-induce DISEASE. | CHEMICAL-INDUCED-DISEASE |
| A comparison of CHEMICAL with diclofenac for the treatment of primary dysmenorrhea: an open, randomized, cross-over trial. Primary dysmenorrhea is a syndrome characterized by painful uterine contractility caused by a hypersecretion of endometrial prostaglandins; non-steroidal anti-inflammatory drugs are the first choice for its treatment. However, in vivo and in vitro studies have demonstrated that myometrial cells are also targets of the relaxant effects of nitric oxide (NO). The aim of the present study was to determine the efficacy of CHEMICAL (CHEMICAL), an NO donor, in the resolution of primary dysmenorrhea in comparison with diclofenac (DCF). A total of 24 patients with the diagnosis of severe primary dysmenorrhea were studied during two consecutive menstrual cycles. In an open, cross-over, controlled design, patients were randomized to receive either DCF per os or CHEMICAL patches the first days of menses, when menstrual cramps became unendurable. In the subsequent cycle the other treatment was used. Patients received up to 3 doses/day of 50 mg DCF or 2.5 mg/24 h transdermal CHEMICAL for the first 3 days of the cycle, according to their needs. The participants recorded menstrual symptoms and possible side-effects at different times (0, 30, 60, 120 minutes) after the first dose of medication on the first day of the cycle, with both drugs. The difference in pain intensity score (DPI) was the main outcome variable. Both treatments significantly reduced DPI by the 30th minute (CHEMICAL, -12.8 +/- 17.9; DCF, -18.9 +/- 16.6). However, DCF continued to be effective in reducing pelvic pain for two hours, whereas CHEMICAL scores remained more or less stable after 30 min and significantly higher than those for DFC (after one hour: CHEMICAL, -12.8 +/- 17.9; DFC, -18.9 +/- 16.6 and after two hours: CHEMICAL, -23.7 +/- 20.5; DFC, -59.7 +/- 17.9, p = 0.0001). Low back pain was also relieved by both drugs. DISEASE was significantly increased by CHEMICAL but not by DCF. Eight patients stopped using CHEMICAL because DISEASE--attributed to its use--became intolerable. These findings indicate that CHEMICAL has a reduced efficacy and tolerability by comparison with DCF in the treatment of primary dysmenorrhea. | CHEMICAL-INDUCED-DISEASE |
| A comparison of glyceryl trinitrate with diclofenac for the treatment of primary dysmenorrhea: an open, randomized, cross-over trial. Primary dysmenorrhea is a syndrome characterized by painful uterine contractility caused by a hypersecretion of endometrial prostaglandins; non-steroidal anti-inflammatory drugs are the first choice for its treatment. However, in vivo and in vitro studies have demonstrated that myometrial cells are also targets of the relaxant effects of CHEMICAL (CHEMICAL). The aim of the present study was to determine the efficacy of glyceryl trinitrate (GTN), an CHEMICAL donor, in the resolution of primary dysmenorrhea in comparison with diclofenac (DCF). A total of 24 patients with the diagnosis of severe primary dysmenorrhea were studied during two consecutive menstrual cycles. In an open, cross-over, controlled design, patients were randomized to receive either DCF per os or GTN patches the first days of menses, when menstrual cramps became unendurable. In the subsequent cycle the other treatment was used. Patients received up to 3 doses/day of 50 mg DCF or 2.5 mg/24 h transdermal GTN for the first 3 days of the cycle, according to their needs. The participants recorded menstrual symptoms and possible side-effects at different times (0, 30, 60, 120 minutes) after the first dose of medication on the first day of the cycle, with both drugs. The difference in pain intensity score (DPI) was the main outcome variable. Both treatments significantly reduced DPI by the 30th minute (GTN, -12.8 +/- 17.9; DCF, -18.9 +/- 16.6). However, DCF continued to be effective in reducing DISEASE for two hours, whereas GTN scores remained more or less stable after 30 min and significantly higher than those for DFC (after one hour: GTN, -12.8 +/- 17.9; DFC, -18.9 +/- 16.6 and after two hours: GTN, -23.7 +/- 20.5; DFC, -59.7 +/- 17.9, p = 0.0001). Low back pain was also relieved by both drugs. Headache was significantly increased by GTN but not by DCF. Eight patients stopped using GTN because headache--attributed to its use--became intolerable. These findings indicate that GTN has a reduced efficacy and tolerability by comparison with DCF in the treatment of primary dysmenorrhea. | NO-RELATIONSHIP |
| A comparison of glyceryl trinitrate with CHEMICAL for the treatment of primary dysmenorrhea: an open, randomized, cross-over trial. Primary dysmenorrhea is a syndrome characterized by painful uterine contractility caused by a hypersecretion of endometrial prostaglandins; non-steroidal anti-inflammatory drugs are the first choice for its treatment. However, in vivo and in vitro studies have demonstrated that myometrial cells are also targets of the relaxant effects of nitric oxide (NO). The aim of the present study was to determine the efficacy of glyceryl trinitrate (GTN), an NO donor, in the resolution of primary dysmenorrhea in comparison with CHEMICAL (CHEMICAL). A total of 24 patients with the diagnosis of severe primary dysmenorrhea were studied during two consecutive menstrual cycles. In an open, cross-over, controlled design, patients were randomized to receive either CHEMICAL per os or GTN patches the first days of menses, when menstrual cramps became unendurable. In the subsequent cycle the other treatment was used. Patients received up to 3 doses/day of 50 mg CHEMICAL or 2.5 mg/24 h transdermal GTN for the first 3 days of the cycle, according to their needs. The participants recorded menstrual symptoms and possible side-effects at different times (0, 30, 60, 120 minutes) after the first dose of medication on the first day of the cycle, with both drugs. The difference in pain intensity score (DPI) was the main outcome variable. Both treatments significantly reduced DPI by the 30th minute (GTN, -12.8 +/- 17.9; CHEMICAL, -18.9 +/- 16.6). However, CHEMICAL continued to be effective in reducing pelvic pain for two hours, whereas GTN scores remained more or less stable after 30 min and significantly higher than those for DFC (after one hour: GTN, -12.8 +/- 17.9; DFC, -18.9 +/- 16.6 and after two hours: GTN, -23.7 +/- 20.5; DFC, -59.7 +/- 17.9, p = 0.0001). DISEASE was also relieved by both drugs. Headache was significantly increased by GTN but not by CHEMICAL. Eight patients stopped using GTN because headache--attributed to its use--became intolerable. These findings indicate that GTN has a reduced efficacy and tolerability by comparison with CHEMICAL in the treatment of primary dysmenorrhea. | NO-RELATIONSHIP |
| A comparison of glyceryl trinitrate with diclofenac for the treatment of primary dysmenorrhea: an open, randomized, cross-over trial. Primary dysmenorrhea is a syndrome characterized by painful uterine contractility caused by a hypersecretion of endometrial prostaglandins; non-steroidal anti-inflammatory drugs are the first choice for its treatment. However, in vivo and in vitro studies have demonstrated that myometrial cells are also targets of the relaxant effects of CHEMICAL (CHEMICAL). The aim of the present study was to determine the efficacy of glyceryl trinitrate (GTN), an CHEMICAL donor, in the resolution of primary dysmenorrhea in comparison with diclofenac (DCF). A total of 24 patients with the diagnosis of severe primary dysmenorrhea were studied during two consecutive menstrual cycles. In an open, cross-over, controlled design, patients were randomized to receive either DCF per os or GTN patches the first days of menses, when menstrual cramps became unendurable. In the subsequent cycle the other treatment was used. Patients received up to 3 doses/day of 50 mg DCF or 2.5 mg/24 h transdermal GTN for the first 3 days of the cycle, according to their needs. The participants recorded menstrual symptoms and possible side-effects at different times (0, 30, 60, 120 minutes) after the first dose of medication on the first day of the cycle, with both drugs. The difference in pain intensity score (DPI) was the main outcome variable. Both treatments significantly reduced DPI by the 30th minute (GTN, -12.8 +/- 17.9; DCF, -18.9 +/- 16.6). However, DCF continued to be effective in reducing pelvic pain for two hours, whereas GTN scores remained more or less stable after 30 min and significantly higher than those for DFC (after one hour: GTN, -12.8 +/- 17.9; DFC, -18.9 +/- 16.6 and after two hours: GTN, -23.7 +/- 20.5; DFC, -59.7 +/- 17.9, p = 0.0001). DISEASE was also relieved by both drugs. Headache was significantly increased by GTN but not by DCF. Eight patients stopped using GTN because headache--attributed to its use--became intolerable. These findings indicate that GTN has a reduced efficacy and tolerability by comparison with DCF in the treatment of primary dysmenorrhea. | NO-RELATIONSHIP |
| A comparison of glyceryl trinitrate with diclofenac for the treatment of primary dysmenorrhea: an open, randomized, cross-over trial. Primary dysmenorrhea is a syndrome characterized by painful uterine contractility caused by a hypersecretion of endometrial prostaglandins; non-steroidal anti-inflammatory drugs are the first choice for its treatment. However, in vivo and in vitro studies have demonstrated that myometrial cells are also targets of the relaxant effects of CHEMICAL (CHEMICAL). The aim of the present study was to determine the efficacy of glyceryl trinitrate (GTN), an CHEMICAL donor, in the resolution of primary dysmenorrhea in comparison with diclofenac (DCF). A total of 24 patients with the diagnosis of severe primary dysmenorrhea were studied during two consecutive menstrual cycles. In an open, cross-over, controlled design, patients were randomized to receive either DCF per os or GTN patches the first days of menses, when menstrual cramps became unendurable. In the subsequent cycle the other treatment was used. Patients received up to 3 doses/day of 50 mg DCF or 2.5 mg/24 h transdermal GTN for the first 3 days of the cycle, according to their needs. The participants recorded menstrual symptoms and possible side-effects at different times (0, 30, 60, 120 minutes) after the first dose of medication on the first day of the cycle, with both drugs. The difference in DISEASE intensity score (DPI) was the main outcome variable. Both treatments significantly reduced DPI by the 30th minute (GTN, -12.8 +/- 17.9; DCF, -18.9 +/- 16.6). However, DCF continued to be effective in reducing pelvic pain for two hours, whereas GTN scores remained more or less stable after 30 min and significantly higher than those for DFC (after one hour: GTN, -12.8 +/- 17.9; DFC, -18.9 +/- 16.6 and after two hours: GTN, -23.7 +/- 20.5; DFC, -59.7 +/- 17.9, p = 0.0001). Low back pain was also relieved by both drugs. Headache was significantly increased by GTN but not by DCF. Eight patients stopped using GTN because headache--attributed to its use--became intolerable. These findings indicate that GTN has a reduced efficacy and tolerability by comparison with DCF in the treatment of primary dysmenorrhea. | NO-RELATIONSHIP |
| A comparison of glyceryl trinitrate with diclofenac for the treatment of primary dysmenorrhea: an open, randomized, cross-over trial. Primary dysmenorrhea is a syndrome characterized by painful uterine contractility caused by a hypersecretion of endometrial CHEMICAL; non-steroidal anti-inflammatory drugs are the first choice for its treatment. However, in vivo and in vitro studies have demonstrated that myometrial cells are also targets of the relaxant effects of nitric oxide (NO). The aim of the present study was to determine the efficacy of glyceryl trinitrate (GTN), an NO donor, in the resolution of primary dysmenorrhea in comparison with diclofenac (DCF). A total of 24 patients with the diagnosis of severe primary dysmenorrhea were studied during two consecutive menstrual cycles. In an open, cross-over, controlled design, patients were randomized to receive either DCF per os or GTN patches the first days of menses, when menstrual cramps became unendurable. In the subsequent cycle the other treatment was used. Patients received up to 3 doses/day of 50 mg DCF or 2.5 mg/24 h transdermal GTN for the first 3 days of the cycle, according to their needs. The participants recorded menstrual symptoms and possible side-effects at different times (0, 30, 60, 120 minutes) after the first dose of medication on the first day of the cycle, with both drugs. The difference in pain intensity score (DPI) was the main outcome variable. Both treatments significantly reduced DPI by the 30th minute (GTN, -12.8 +/- 17.9; DCF, -18.9 +/- 16.6). However, DCF continued to be effective in reducing pelvic pain for two hours, whereas GTN scores remained more or less stable after 30 min and significantly higher than those for DFC (after one hour: GTN, -12.8 +/- 17.9; DFC, -18.9 +/- 16.6 and after two hours: GTN, -23.7 +/- 20.5; DFC, -59.7 +/- 17.9, p = 0.0001). DISEASE was also relieved by both drugs. Headache was significantly increased by GTN but not by DCF. Eight patients stopped using GTN because headache--attributed to its use--became intolerable. These findings indicate that GTN has a reduced efficacy and tolerability by comparison with DCF in the treatment of primary dysmenorrhea. | NO-RELATIONSHIP |
| A comparison of glyceryl trinitrate with diclofenac for the treatment of primary DISEASE: an open, randomized, cross-over trial. Primary DISEASE is a syndrome characterized by painful uterine contractility caused by a hypersecretion of endometrial CHEMICAL; non-steroidal anti-inflammatory drugs are the first choice for its treatment. However, in vivo and in vitro studies have demonstrated that myometrial cells are also targets of the relaxant effects of nitric oxide (NO). The aim of the present study was to determine the efficacy of glyceryl trinitrate (GTN), an NO donor, in the resolution of primary DISEASE in comparison with diclofenac (DCF). A total of 24 patients with the diagnosis of severe primary DISEASE were studied during two consecutive menstrual cycles. In an open, cross-over, controlled design, patients were randomized to receive either DCF per os or GTN patches the first days of menses, when menstrual cramps became unendurable. In the subsequent cycle the other treatment was used. Patients received up to 3 doses/day of 50 mg DCF or 2.5 mg/24 h transdermal GTN for the first 3 days of the cycle, according to their needs. The participants recorded menstrual symptoms and possible side-effects at different times (0, 30, 60, 120 minutes) after the first dose of medication on the first day of the cycle, with both drugs. The difference in pain intensity score (DPI) was the main outcome variable. Both treatments significantly reduced DPI by the 30th minute (GTN, -12.8 +/- 17.9; DCF, -18.9 +/- 16.6). However, DCF continued to be effective in reducing pelvic pain for two hours, whereas GTN scores remained more or less stable after 30 min and significantly higher than those for DFC (after one hour: GTN, -12.8 +/- 17.9; DFC, -18.9 +/- 16.6 and after two hours: GTN, -23.7 +/- 20.5; DFC, -59.7 +/- 17.9, p = 0.0001). Low back pain was also relieved by both drugs. Headache was significantly increased by GTN but not by DCF. Eight patients stopped using GTN because headache--attributed to its use--became intolerable. These findings indicate that GTN has a reduced efficacy and tolerability by comparison with DCF in the treatment of primary DISEASE. | NO-RELATIONSHIP |
| A comparison of glyceryl trinitrate with CHEMICAL for the treatment of primary dysmenorrhea: an open, randomized, cross-over trial. Primary dysmenorrhea is a syndrome characterized by painful uterine contractility caused by a hypersecretion of endometrial prostaglandins; non-steroidal anti-inflammatory drugs are the first choice for its treatment. However, in vivo and in vitro studies have demonstrated that myometrial cells are also targets of the relaxant effects of nitric oxide (NO). The aim of the present study was to determine the efficacy of glyceryl trinitrate (GTN), an NO donor, in the resolution of primary dysmenorrhea in comparison with CHEMICAL (CHEMICAL). A total of 24 patients with the diagnosis of severe primary dysmenorrhea were studied during two consecutive menstrual cycles. In an open, cross-over, controlled design, patients were randomized to receive either CHEMICAL per os or GTN patches the first days of menses, when menstrual cramps became unendurable. In the subsequent cycle the other treatment was used. Patients received up to 3 doses/day of 50 mg CHEMICAL or 2.5 mg/24 h transdermal GTN for the first 3 days of the cycle, according to their needs. The participants recorded menstrual symptoms and possible side-effects at different times (0, 30, 60, 120 minutes) after the first dose of medication on the first day of the cycle, with both drugs. The difference in pain intensity score (DPI) was the main outcome variable. Both treatments significantly reduced DPI by the 30th minute (GTN, -12.8 +/- 17.9; CHEMICAL, -18.9 +/- 16.6). However, CHEMICAL continued to be effective in reducing DISEASE for two hours, whereas GTN scores remained more or less stable after 30 min and significantly higher than those for DFC (after one hour: GTN, -12.8 +/- 17.9; DFC, -18.9 +/- 16.6 and after two hours: GTN, -23.7 +/- 20.5; DFC, -59.7 +/- 17.9, p = 0.0001). Low back pain was also relieved by both drugs. Headache was significantly increased by GTN but not by CHEMICAL. Eight patients stopped using GTN because headache--attributed to its use--became intolerable. These findings indicate that GTN has a reduced efficacy and tolerability by comparison with CHEMICAL in the treatment of primary dysmenorrhea. | NO-RELATIONSHIP |
| A comparison of glyceryl trinitrate with CHEMICAL for the treatment of primary dysmenorrhea: an open, randomized, cross-over trial. Primary dysmenorrhea is a syndrome characterized by painful uterine contractility caused by a hypersecretion of endometrial prostaglandins; non-steroidal anti-inflammatory drugs are the first choice for its treatment. However, in vivo and in vitro studies have demonstrated that myometrial cells are also targets of the relaxant effects of nitric oxide (NO). The aim of the present study was to determine the efficacy of glyceryl trinitrate (GTN), an NO donor, in the resolution of primary dysmenorrhea in comparison with CHEMICAL (CHEMICAL). A total of 24 patients with the diagnosis of severe primary dysmenorrhea were studied during two consecutive menstrual cycles. In an open, cross-over, controlled design, patients were randomized to receive either CHEMICAL per os or GTN patches the first days of menses, when menstrual cramps became unendurable. In the subsequent cycle the other treatment was used. Patients received up to 3 doses/day of 50 mg CHEMICAL or 2.5 mg/24 h transdermal GTN for the first 3 days of the cycle, according to their needs. The participants recorded menstrual symptoms and possible side-effects at different times (0, 30, 60, 120 minutes) after the first dose of medication on the first day of the cycle, with both drugs. The difference in DISEASE intensity score (DPI) was the main outcome variable. Both treatments significantly reduced DPI by the 30th minute (GTN, -12.8 +/- 17.9; CHEMICAL, -18.9 +/- 16.6). However, CHEMICAL continued to be effective in reducing pelvic pain for two hours, whereas GTN scores remained more or less stable after 30 min and significantly higher than those for DFC (after one hour: GTN, -12.8 +/- 17.9; DFC, -18.9 +/- 16.6 and after two hours: GTN, -23.7 +/- 20.5; DFC, -59.7 +/- 17.9, p = 0.0001). Low back pain was also relieved by both drugs. Headache was significantly increased by GTN but not by CHEMICAL. Eight patients stopped using GTN because headache--attributed to its use--became intolerable. These findings indicate that GTN has a reduced efficacy and tolerability by comparison with CHEMICAL in the treatment of primary dysmenorrhea. | NO-RELATIONSHIP |
| A comparison of glyceryl trinitrate with CHEMICAL for the treatment of primary DISEASE: an open, randomized, cross-over trial. Primary DISEASE is a syndrome characterized by painful uterine contractility caused by a hypersecretion of endometrial prostaglandins; non-steroidal anti-inflammatory drugs are the first choice for its treatment. However, in vivo and in vitro studies have demonstrated that myometrial cells are also targets of the relaxant effects of nitric oxide (NO). The aim of the present study was to determine the efficacy of glyceryl trinitrate (GTN), an NO donor, in the resolution of primary DISEASE in comparison with CHEMICAL (CHEMICAL). A total of 24 patients with the diagnosis of severe primary DISEASE were studied during two consecutive menstrual cycles. In an open, cross-over, controlled design, patients were randomized to receive either CHEMICAL per os or GTN patches the first days of menses, when menstrual cramps became unendurable. In the subsequent cycle the other treatment was used. Patients received up to 3 doses/day of 50 mg CHEMICAL or 2.5 mg/24 h transdermal GTN for the first 3 days of the cycle, according to their needs. The participants recorded menstrual symptoms and possible side-effects at different times (0, 30, 60, 120 minutes) after the first dose of medication on the first day of the cycle, with both drugs. The difference in pain intensity score (DPI) was the main outcome variable. Both treatments significantly reduced DPI by the 30th minute (GTN, -12.8 +/- 17.9; CHEMICAL, -18.9 +/- 16.6). However, CHEMICAL continued to be effective in reducing pelvic pain for two hours, whereas GTN scores remained more or less stable after 30 min and significantly higher than those for DFC (after one hour: GTN, -12.8 +/- 17.9; DFC, -18.9 +/- 16.6 and after two hours: GTN, -23.7 +/- 20.5; DFC, -59.7 +/- 17.9, p = 0.0001). Low back pain was also relieved by both drugs. Headache was significantly increased by GTN but not by CHEMICAL. Eight patients stopped using GTN because headache--attributed to its use--became intolerable. These findings indicate that GTN has a reduced efficacy and tolerability by comparison with CHEMICAL in the treatment of primary DISEASE. | NO-RELATIONSHIP |
| A comparison of glyceryl trinitrate with diclofenac for the treatment of primary DISEASE: an open, randomized, cross-over trial. Primary DISEASE is a syndrome characterized by painful uterine contractility caused by a hypersecretion of endometrial prostaglandins; non-steroidal anti-inflammatory drugs are the first choice for its treatment. However, in vivo and in vitro studies have demonstrated that myometrial cells are also targets of the relaxant effects of CHEMICAL (CHEMICAL). The aim of the present study was to determine the efficacy of glyceryl trinitrate (GTN), an CHEMICAL donor, in the resolution of primary DISEASE in comparison with diclofenac (DCF). A total of 24 patients with the diagnosis of severe primary DISEASE were studied during two consecutive menstrual cycles. In an open, cross-over, controlled design, patients were randomized to receive either DCF per os or GTN patches the first days of menses, when menstrual cramps became unendurable. In the subsequent cycle the other treatment was used. Patients received up to 3 doses/day of 50 mg DCF or 2.5 mg/24 h transdermal GTN for the first 3 days of the cycle, according to their needs. The participants recorded menstrual symptoms and possible side-effects at different times (0, 30, 60, 120 minutes) after the first dose of medication on the first day of the cycle, with both drugs. The difference in pain intensity score (DPI) was the main outcome variable. Both treatments significantly reduced DPI by the 30th minute (GTN, -12.8 +/- 17.9; DCF, -18.9 +/- 16.6). However, DCF continued to be effective in reducing pelvic pain for two hours, whereas GTN scores remained more or less stable after 30 min and significantly higher than those for DFC (after one hour: GTN, -12.8 +/- 17.9; DFC, -18.9 +/- 16.6 and after two hours: GTN, -23.7 +/- 20.5; DFC, -59.7 +/- 17.9, p = 0.0001). Low back pain was also relieved by both drugs. Headache was significantly increased by GTN but not by DCF. Eight patients stopped using GTN because headache--attributed to its use--became intolerable. These findings indicate that GTN has a reduced efficacy and tolerability by comparison with DCF in the treatment of primary DISEASE. | NO-RELATIONSHIP |
| A comparison of glyceryl trinitrate with diclofenac for the treatment of primary dysmenorrhea: an open, randomized, cross-over trial. Primary dysmenorrhea is a syndrome characterized by painful uterine contractility caused by a hypersecretion of endometrial CHEMICAL; non-steroidal anti-inflammatory drugs are the first choice for its treatment. However, in vivo and in vitro studies have demonstrated that myometrial cells are also targets of the relaxant effects of nitric oxide (NO). The aim of the present study was to determine the efficacy of glyceryl trinitrate (GTN), an NO donor, in the resolution of primary dysmenorrhea in comparison with diclofenac (DCF). A total of 24 patients with the diagnosis of severe primary dysmenorrhea were studied during two consecutive menstrual cycles. In an open, cross-over, controlled design, patients were randomized to receive either DCF per os or GTN patches the first days of menses, when menstrual cramps became unendurable. In the subsequent cycle the other treatment was used. Patients received up to 3 doses/day of 50 mg DCF or 2.5 mg/24 h transdermal GTN for the first 3 days of the cycle, according to their needs. The participants recorded menstrual symptoms and possible side-effects at different times (0, 30, 60, 120 minutes) after the first dose of medication on the first day of the cycle, with both drugs. The difference in DISEASE intensity score (DPI) was the main outcome variable. Both treatments significantly reduced DPI by the 30th minute (GTN, -12.8 +/- 17.9; DCF, -18.9 +/- 16.6). However, DCF continued to be effective in reducing pelvic pain for two hours, whereas GTN scores remained more or less stable after 30 min and significantly higher than those for DFC (after one hour: GTN, -12.8 +/- 17.9; DFC, -18.9 +/- 16.6 and after two hours: GTN, -23.7 +/- 20.5; DFC, -59.7 +/- 17.9, p = 0.0001). Low back pain was also relieved by both drugs. Headache was significantly increased by GTN but not by DCF. Eight patients stopped using GTN because headache--attributed to its use--became intolerable. These findings indicate that GTN has a reduced efficacy and tolerability by comparison with DCF in the treatment of primary dysmenorrhea. | NO-RELATIONSHIP |
| A comparison of glyceryl trinitrate with diclofenac for the treatment of primary dysmenorrhea: an open, randomized, cross-over trial. Primary dysmenorrhea is a syndrome characterized by painful uterine contractility caused by a hypersecretion of endometrial CHEMICAL; non-steroidal anti-inflammatory drugs are the first choice for its treatment. However, in vivo and in vitro studies have demonstrated that myometrial cells are also targets of the relaxant effects of nitric oxide (NO). The aim of the present study was to determine the efficacy of glyceryl trinitrate (GTN), an NO donor, in the resolution of primary dysmenorrhea in comparison with diclofenac (DCF). A total of 24 patients with the diagnosis of severe primary dysmenorrhea were studied during two consecutive menstrual cycles. In an open, cross-over, controlled design, patients were randomized to receive either DCF per os or GTN patches the first days of menses, when menstrual cramps became unendurable. In the subsequent cycle the other treatment was used. Patients received up to 3 doses/day of 50 mg DCF or 2.5 mg/24 h transdermal GTN for the first 3 days of the cycle, according to their needs. The participants recorded menstrual symptoms and possible side-effects at different times (0, 30, 60, 120 minutes) after the first dose of medication on the first day of the cycle, with both drugs. The difference in pain intensity score (DPI) was the main outcome variable. Both treatments significantly reduced DPI by the 30th minute (GTN, -12.8 +/- 17.9; DCF, -18.9 +/- 16.6). However, DCF continued to be effective in reducing DISEASE for two hours, whereas GTN scores remained more or less stable after 30 min and significantly higher than those for DFC (after one hour: GTN, -12.8 +/- 17.9; DFC, -18.9 +/- 16.6 and after two hours: GTN, -23.7 +/- 20.5; DFC, -59.7 +/- 17.9, p = 0.0001). Low back pain was also relieved by both drugs. Headache was significantly increased by GTN but not by DCF. Eight patients stopped using GTN because headache--attributed to its use--became intolerable. These findings indicate that GTN has a reduced efficacy and tolerability by comparison with DCF in the treatment of primary dysmenorrhea. | NO-RELATIONSHIP |
| Temocapril, a long-acting non-SH group angiotensin converting enzyme inhibitor, modulates glomerular injury in chronic CHEMICAL nephrosis. The purpose of the present study was to determine whether chronic administration of temocapril, a long-acting non-SH group angiotensin converting enzyme (ACE) inhibitor, reduced DISEASE, inhibited glomerular hypertrophy and prevented glomerulosclerosis in chronic CHEMICAL (CHEMICAL) - induced nephrotic rats. Nephrosis was induced by injection of CHEMICAL (15mg/100g body weight) in male Sprague-Dawley (SD) rats. Four groups were used, i) the CHEMICAL group (14), ii) CHEMICAL/temocapril (13), iii) temocapril (14) and iv) untreated controls (15). Temocapril (8 mg/kg/day) was administered to the rats which were killed at weeks 4, 14 or 20. At each time point, systolic blood pressure (BP), urinary protein excretion and renal histopathological findings were evaluated, and morphometric image analysis was done. Systolic BP in the CHEMICAL group was significantly high at 4, 14 and 20 weeks, but was normal in the CHEMICAL/temocapril group. Urinary protein excretion in the CHEMICAL group increased significantly, peaking at 8 days, then decreased at 4 weeks, but rose again significantly at 14 and 20 weeks. Temocapril did not attenuate DISEASE at 8 days, but it did markedly lower it from weeks 4 to 20. The glomerulosclerosis index (GSI) was 6.21 % at 4 weeks and respectively 25.35 % and 30.49 % at 14 and 20 weeks in the CHEMICAL group. There was a significant correlation between urinary protein excretion and GSI (r = 0.808, p < 0.0001). The ratio of glomerular tuft area to the area of Bowman's capsules (GT/BC) in the CHEMICAL group was significantly increased, but it was significantly lower in the CHEMICAL/temocapril group. It appears that temocapril was effective in retarding renal progression and protected renal function in CHEMICAL neprotic rats. | CHEMICAL-INDUCED-DISEASE |
| Temocapril, a long-acting non-SH group angiotensin converting enzyme inhibitor, modulates glomerular injury in chronic CHEMICAL DISEASE. The purpose of the present study was to determine whether chronic administration of temocapril, a long-acting non-SH group angiotensin converting enzyme (ACE) inhibitor, reduced proteinuria, inhibited glomerular hypertrophy and prevented glomerulosclerosis in chronic CHEMICAL (CHEMICAL) - induced nephrotic rats. DISEASE was induced by injection of CHEMICAL (15mg/100g body weight) in male Sprague-Dawley (SD) rats. Four groups were used, i) the CHEMICAL group (14), ii) CHEMICAL/temocapril (13), iii) temocapril (14) and iv) untreated controls (15). Temocapril (8 mg/kg/day) was administered to the rats which were killed at weeks 4, 14 or 20. At each time point, systolic blood pressure (BP), urinary protein excretion and renal histopathological findings were evaluated, and morphometric image analysis was done. Systolic BP in the CHEMICAL group was significantly high at 4, 14 and 20 weeks, but was normal in the CHEMICAL/temocapril group. Urinary protein excretion in the CHEMICAL group increased significantly, peaking at 8 days, then decreased at 4 weeks, but rose again significantly at 14 and 20 weeks. Temocapril did not attenuate proteinuria at 8 days, but it did markedly lower it from weeks 4 to 20. The glomerulosclerosis index (GSI) was 6.21 % at 4 weeks and respectively 25.35 % and 30.49 % at 14 and 20 weeks in the CHEMICAL group. There was a significant correlation between urinary protein excretion and GSI (r = 0.808, p < 0.0001). The ratio of glomerular tuft area to the area of Bowman's capsules (GT/BC) in the CHEMICAL group was significantly increased, but it was significantly lower in the CHEMICAL/temocapril group. It appears that temocapril was effective in retarding renal progression and protected renal function in CHEMICAL DISEASE rats. | CHEMICAL-INDUCED-DISEASE |
| Temocapril, a long-acting non-SH group CHEMICAL converting enzyme inhibitor, modulates glomerular injury in chronic puromycin aminonucleoside nephrosis. The purpose of the present study was to determine whether chronic administration of temocapril, a long-acting non-SH group CHEMICAL converting enzyme (ACE) inhibitor, reduced proteinuria, inhibited glomerular hypertrophy and prevented glomerulosclerosis in chronic puromycin aminonucleoside (PAN) - induced DISEASE rats. Nephrosis was induced by injection of PAN (15mg/100g body weight) in male Sprague-Dawley (SD) rats. Four groups were used, i) the PAN group (14), ii) PAN/temocapril (13), iii) temocapril (14) and iv) untreated controls (15). Temocapril (8 mg/kg/day) was administered to the rats which were killed at weeks 4, 14 or 20. At each time point, systolic blood pressure (BP), urinary protein excretion and renal histopathological findings were evaluated, and morphometric image analysis was done. Systolic BP in the PAN group was significantly high at 4, 14 and 20 weeks, but was normal in the PAN/temocapril group. Urinary protein excretion in the PAN group increased significantly, peaking at 8 days, then decreased at 4 weeks, but rose again significantly at 14 and 20 weeks. Temocapril did not attenuate proteinuria at 8 days, but it did markedly lower it from weeks 4 to 20. The glomerulosclerosis index (GSI) was 6.21 % at 4 weeks and respectively 25.35 % and 30.49 % at 14 and 20 weeks in the PAN group. There was a significant correlation between urinary protein excretion and GSI (r = 0.808, p < 0.0001). The ratio of glomerular tuft area to the area of Bowman's capsules (GT/BC) in the PAN group was significantly increased, but it was significantly lower in the PAN/temocapril group. It appears that temocapril was effective in retarding renal progression and protected renal function in PAN neprotic rats. | NO-RELATIONSHIP |
| CHEMICAL, a long-acting non-SH group angiotensin converting enzyme inhibitor, modulates glomerular injury in chronic puromycin aminonucleoside nephrosis. The purpose of the present study was to determine whether chronic administration of CHEMICAL, a long-acting non-SH group angiotensin converting enzyme (ACE) inhibitor, reduced proteinuria, inhibited glomerular hypertrophy and prevented DISEASE in chronic puromycin aminonucleoside (PAN) - induced nephrotic rats. Nephrosis was induced by injection of PAN (15mg/100g body weight) in male Sprague-Dawley (SD) rats. Four groups were used, i) the PAN group (14), ii) PAN/CHEMICAL (13), iii) CHEMICAL (14) and iv) untreated controls (15). CHEMICAL (8 mg/kg/day) was administered to the rats which were killed at weeks 4, 14 or 20. At each time point, systolic blood pressure (BP), urinary protein excretion and renal histopathological findings were evaluated, and morphometric image analysis was done. Systolic BP in the PAN group was significantly high at 4, 14 and 20 weeks, but was normal in the PAN/CHEMICAL group. Urinary protein excretion in the PAN group increased significantly, peaking at 8 days, then decreased at 4 weeks, but rose again significantly at 14 and 20 weeks. CHEMICAL did not attenuate proteinuria at 8 days, but it did markedly lower it from weeks 4 to 20. The DISEASE index (GSI) was 6.21 % at 4 weeks and respectively 25.35 % and 30.49 % at 14 and 20 weeks in the PAN group. There was a significant correlation between urinary protein excretion and GSI (r = 0.808, p < 0.0001). The ratio of glomerular tuft area to the area of Bowman's capsules (GT/BC) in the PAN group was significantly increased, but it was significantly lower in the PAN/CHEMICAL group. It appears that CHEMICAL was effective in retarding renal progression and protected renal function in PAN neprotic rats. | NO-RELATIONSHIP |
| CHEMICAL, a long-acting non-SH group angiotensin converting enzyme inhibitor, modulates glomerular injury in chronic puromycin aminonucleoside nephrosis. The purpose of the present study was to determine whether chronic administration of CHEMICAL, a long-acting non-SH group angiotensin converting enzyme (ACE) inhibitor, reduced proteinuria, inhibited glomerular hypertrophy and prevented glomerulosclerosis in chronic puromycin aminonucleoside (PAN) - induced DISEASE rats. Nephrosis was induced by injection of PAN (15mg/100g body weight) in male Sprague-Dawley (SD) rats. Four groups were used, i) the PAN group (14), ii) PAN/CHEMICAL (13), iii) CHEMICAL (14) and iv) untreated controls (15). CHEMICAL (8 mg/kg/day) was administered to the rats which were killed at weeks 4, 14 or 20. At each time point, systolic blood pressure (BP), urinary protein excretion and renal histopathological findings were evaluated, and morphometric image analysis was done. Systolic BP in the PAN group was significantly high at 4, 14 and 20 weeks, but was normal in the PAN/CHEMICAL group. Urinary protein excretion in the PAN group increased significantly, peaking at 8 days, then decreased at 4 weeks, but rose again significantly at 14 and 20 weeks. CHEMICAL did not attenuate proteinuria at 8 days, but it did markedly lower it from weeks 4 to 20. The glomerulosclerosis index (GSI) was 6.21 % at 4 weeks and respectively 25.35 % and 30.49 % at 14 and 20 weeks in the PAN group. There was a significant correlation between urinary protein excretion and GSI (r = 0.808, p < 0.0001). The ratio of glomerular tuft area to the area of Bowman's capsules (GT/BC) in the PAN group was significantly increased, but it was significantly lower in the PAN/CHEMICAL group. It appears that CHEMICAL was effective in retarding renal progression and protected renal function in PAN neprotic rats. | NO-RELATIONSHIP |
| CHEMICAL, a long-acting non-SH group angiotensin converting enzyme inhibitor, modulates glomerular injury in chronic puromycin aminonucleoside nephrosis. The purpose of the present study was to determine whether chronic administration of CHEMICAL, a long-acting non-SH group angiotensin converting enzyme (ACE) inhibitor, reduced proteinuria, inhibited glomerular DISEASE and prevented glomerulosclerosis in chronic puromycin aminonucleoside (PAN) - induced nephrotic rats. Nephrosis was induced by injection of PAN (15mg/100g body weight) in male Sprague-Dawley (SD) rats. Four groups were used, i) the PAN group (14), ii) PAN/CHEMICAL (13), iii) CHEMICAL (14) and iv) untreated controls (15). CHEMICAL (8 mg/kg/day) was administered to the rats which were killed at weeks 4, 14 or 20. At each time point, systolic blood pressure (BP), urinary protein excretion and renal histopathological findings were evaluated, and morphometric image analysis was done. Systolic BP in the PAN group was significantly high at 4, 14 and 20 weeks, but was normal in the PAN/CHEMICAL group. Urinary protein excretion in the PAN group increased significantly, peaking at 8 days, then decreased at 4 weeks, but rose again significantly at 14 and 20 weeks. CHEMICAL did not attenuate proteinuria at 8 days, but it did markedly lower it from weeks 4 to 20. The glomerulosclerosis index (GSI) was 6.21 % at 4 weeks and respectively 25.35 % and 30.49 % at 14 and 20 weeks in the PAN group. There was a significant correlation between urinary protein excretion and GSI (r = 0.808, p < 0.0001). The ratio of glomerular tuft area to the area of Bowman's capsules (GT/BC) in the PAN group was significantly increased, but it was significantly lower in the PAN/CHEMICAL group. It appears that CHEMICAL was effective in retarding renal progression and protected renal function in PAN neprotic rats. | NO-RELATIONSHIP |
| Temocapril, a long-acting non-SH group CHEMICAL converting enzyme inhibitor, modulates glomerular injury in chronic puromycin aminonucleoside nephrosis. The purpose of the present study was to determine whether chronic administration of temocapril, a long-acting non-SH group CHEMICAL converting enzyme (ACE) inhibitor, reduced proteinuria, inhibited glomerular hypertrophy and prevented DISEASE in chronic puromycin aminonucleoside (PAN) - induced nephrotic rats. Nephrosis was induced by injection of PAN (15mg/100g body weight) in male Sprague-Dawley (SD) rats. Four groups were used, i) the PAN group (14), ii) PAN/temocapril (13), iii) temocapril (14) and iv) untreated controls (15). Temocapril (8 mg/kg/day) was administered to the rats which were killed at weeks 4, 14 or 20. At each time point, systolic blood pressure (BP), urinary protein excretion and renal histopathological findings were evaluated, and morphometric image analysis was done. Systolic BP in the PAN group was significantly high at 4, 14 and 20 weeks, but was normal in the PAN/temocapril group. Urinary protein excretion in the PAN group increased significantly, peaking at 8 days, then decreased at 4 weeks, but rose again significantly at 14 and 20 weeks. Temocapril did not attenuate proteinuria at 8 days, but it did markedly lower it from weeks 4 to 20. The DISEASE index (GSI) was 6.21 % at 4 weeks and respectively 25.35 % and 30.49 % at 14 and 20 weeks in the PAN group. There was a significant correlation between urinary protein excretion and GSI (r = 0.808, p < 0.0001). The ratio of glomerular tuft area to the area of Bowman's capsules (GT/BC) in the PAN group was significantly increased, but it was significantly lower in the PAN/temocapril group. It appears that temocapril was effective in retarding renal progression and protected renal function in PAN neprotic rats. | NO-RELATIONSHIP |
| Temocapril, a long-acting non-SH group CHEMICAL converting enzyme inhibitor, modulates glomerular injury in chronic puromycin aminonucleoside nephrosis. The purpose of the present study was to determine whether chronic administration of temocapril, a long-acting non-SH group CHEMICAL converting enzyme (ACE) inhibitor, reduced proteinuria, inhibited glomerular DISEASE and prevented glomerulosclerosis in chronic puromycin aminonucleoside (PAN) - induced nephrotic rats. Nephrosis was induced by injection of PAN (15mg/100g body weight) in male Sprague-Dawley (SD) rats. Four groups were used, i) the PAN group (14), ii) PAN/temocapril (13), iii) temocapril (14) and iv) untreated controls (15). Temocapril (8 mg/kg/day) was administered to the rats which were killed at weeks 4, 14 or 20. At each time point, systolic blood pressure (BP), urinary protein excretion and renal histopathological findings were evaluated, and morphometric image analysis was done. Systolic BP in the PAN group was significantly high at 4, 14 and 20 weeks, but was normal in the PAN/temocapril group. Urinary protein excretion in the PAN group increased significantly, peaking at 8 days, then decreased at 4 weeks, but rose again significantly at 14 and 20 weeks. Temocapril did not attenuate proteinuria at 8 days, but it did markedly lower it from weeks 4 to 20. The glomerulosclerosis index (GSI) was 6.21 % at 4 weeks and respectively 25.35 % and 30.49 % at 14 and 20 weeks in the PAN group. There was a significant correlation between urinary protein excretion and GSI (r = 0.808, p < 0.0001). The ratio of glomerular tuft area to the area of Bowman's capsules (GT/BC) in the PAN group was significantly increased, but it was significantly lower in the PAN/temocapril group. It appears that temocapril was effective in retarding renal progression and protected renal function in PAN neprotic rats. | NO-RELATIONSHIP |
| Temocapril, a long-acting non-SH group CHEMICAL converting enzyme inhibitor, modulates DISEASE in chronic puromycin aminonucleoside nephrosis. The purpose of the present study was to determine whether chronic administration of temocapril, a long-acting non-SH group CHEMICAL converting enzyme (ACE) inhibitor, reduced proteinuria, inhibited glomerular hypertrophy and prevented glomerulosclerosis in chronic puromycin aminonucleoside (PAN) - induced nephrotic rats. Nephrosis was induced by injection of PAN (15mg/100g body weight) in male Sprague-Dawley (SD) rats. Four groups were used, i) the PAN group (14), ii) PAN/temocapril (13), iii) temocapril (14) and iv) untreated controls (15). Temocapril (8 mg/kg/day) was administered to the rats which were killed at weeks 4, 14 or 20. At each time point, systolic blood pressure (BP), urinary protein excretion and renal histopathological findings were evaluated, and morphometric image analysis was done. Systolic BP in the PAN group was significantly high at 4, 14 and 20 weeks, but was normal in the PAN/temocapril group. Urinary protein excretion in the PAN group increased significantly, peaking at 8 days, then decreased at 4 weeks, but rose again significantly at 14 and 20 weeks. Temocapril did not attenuate proteinuria at 8 days, but it did markedly lower it from weeks 4 to 20. The glomerulosclerosis index (GSI) was 6.21 % at 4 weeks and respectively 25.35 % and 30.49 % at 14 and 20 weeks in the PAN group. There was a significant correlation between urinary protein excretion and GSI (r = 0.808, p < 0.0001). The ratio of glomerular tuft area to the area of Bowman's capsules (GT/BC) in the PAN group was significantly increased, but it was significantly lower in the PAN/temocapril group. It appears that temocapril was effective in retarding renal progression and protected renal function in PAN neprotic rats. | NO-RELATIONSHIP |
| CHEMICAL, a long-acting non-SH group angiotensin converting enzyme inhibitor, modulates DISEASE in chronic puromycin aminonucleoside nephrosis. The purpose of the present study was to determine whether chronic administration of CHEMICAL, a long-acting non-SH group angiotensin converting enzyme (ACE) inhibitor, reduced proteinuria, inhibited glomerular hypertrophy and prevented glomerulosclerosis in chronic puromycin aminonucleoside (PAN) - induced nephrotic rats. Nephrosis was induced by injection of PAN (15mg/100g body weight) in male Sprague-Dawley (SD) rats. Four groups were used, i) the PAN group (14), ii) PAN/CHEMICAL (13), iii) CHEMICAL (14) and iv) untreated controls (15). CHEMICAL (8 mg/kg/day) was administered to the rats which were killed at weeks 4, 14 or 20. At each time point, systolic blood pressure (BP), urinary protein excretion and renal histopathological findings were evaluated, and morphometric image analysis was done. Systolic BP in the PAN group was significantly high at 4, 14 and 20 weeks, but was normal in the PAN/CHEMICAL group. Urinary protein excretion in the PAN group increased significantly, peaking at 8 days, then decreased at 4 weeks, but rose again significantly at 14 and 20 weeks. CHEMICAL did not attenuate proteinuria at 8 days, but it did markedly lower it from weeks 4 to 20. The glomerulosclerosis index (GSI) was 6.21 % at 4 weeks and respectively 25.35 % and 30.49 % at 14 and 20 weeks in the PAN group. There was a significant correlation between urinary protein excretion and GSI (r = 0.808, p < 0.0001). The ratio of glomerular tuft area to the area of Bowman's capsules (GT/BC) in the PAN group was significantly increased, but it was significantly lower in the PAN/CHEMICAL group. It appears that CHEMICAL was effective in retarding renal progression and protected renal function in PAN neprotic rats. | NO-RELATIONSHIP |
| DISEASE after CHEMICAL prophylaxis in very preterm infants. We report three cases of severe hypoxaemia after CHEMICAL administration during a randomised controlled trial of prophylactic treatment of patent ductus arteriosus with CHEMICAL in premature infants born at less than 28 weeks of gestation. Echocardiography showed severely decreased pulmonary blood flow. Hypoxaemia resolved quickly on inhaled nitric oxide therapy. We suggest that investigators involved in similar trials pay close attention to pulmonary pressure if hypoxaemia occurs after prophylactic administration of CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Pulmonary hypertension after CHEMICAL prophylaxis in very preterm infants. We report three cases of severe DISEASE after CHEMICAL administration during a randomised controlled trial of prophylactic treatment of patent ductus arteriosus with CHEMICAL in premature infants born at less than 28 weeks of gestation. Echocardiography showed severely decreased pulmonary blood flow. DISEASE resolved quickly on inhaled nitric oxide therapy. We suggest that investigators involved in similar trials pay close attention to pulmonary pressure if DISEASE occurs after prophylactic administration of CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants. We report three cases of severe hypoxaemia after ibuprofen administration during a randomised controlled trial of prophylactic treatment of DISEASE with ibuprofen in premature infants born at less than 28 weeks of gestation. Echocardiography showed severely decreased pulmonary blood flow. Hypoxaemia resolved quickly on inhaled CHEMICAL therapy. We suggest that investigators involved in similar trials pay close attention to pulmonary pressure if hypoxaemia occurs after prophylactic administration of ibuprofen. | NO-RELATIONSHIP |
| Hyponatremia and DISEASE reported with the use of CHEMICAL: an over-representation of Asians? PURPOSE: This retrospective study used a pharmaceutical company's global safety database to determine the reporting rate of hyponatremia and/or DISEASE (DISEASE) among CHEMICAL-treated patients and to explore the possibility of at-risk population subgroups. METHOD: We searched the Eli Lilly and Company's computerized adverse event database for all reported cases of hyponatremia and/or DISEASE as of 1 November 1999 that had been reported during the use of CHEMICAL. RESULTS: A total of 76 cases of hyponatremia and/or DISEASE associated with CHEMICAL use were identified. The overall reporting rate was estimated to be 1.3/100,000 treated patients. The average age of patients was 35.6 +/- 28.3 years, and 62% were males. Approximately 75% of the patients were receiving treatment for leukemia or lymphoma. Among the 39 reports that included information on race, the racial distribution was: 1 Black, 3 Caucasian, and 35 Asian. CONCLUSION: Our data suggest that Asian patients may be at increased risk of hyponatremia and/or DISEASE associated with CHEMICAL use. Although the overall reported rate of DISEASE associated with CHEMICAL is very low, physicians caring for Asian oncology patients should be aware of this potential serious but reversible adverse event. | CHEMICAL-INDUCED-DISEASE |
| DISEASE and syndrome of inappropriate anti-diuretic hormone reported with the use of CHEMICAL: an over-representation of Asians? PURPOSE: This retrospective study used a pharmaceutical company's global safety database to determine the reporting rate of DISEASE and/or syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) among CHEMICAL-treated patients and to explore the possibility of at-risk population subgroups. METHOD: We searched the Eli Lilly and Company's computerized adverse event database for all reported cases of DISEASE and/or SIADH as of 1 November 1999 that had been reported during the use of CHEMICAL. RESULTS: A total of 76 cases of DISEASE and/or SIADH associated with CHEMICAL use were identified. The overall reporting rate was estimated to be 1.3/100,000 treated patients. The average age of patients was 35.6 +/- 28.3 years, and 62% were males. Approximately 75% of the patients were receiving treatment for leukemia or lymphoma. Among the 39 reports that included information on race, the racial distribution was: 1 Black, 3 Caucasian, and 35 Asian. CONCLUSION: Our data suggest that Asian patients may be at increased risk of DISEASE and/or SIADH associated with CHEMICAL use. Although the overall reported rate of SIADH associated with CHEMICAL is very low, physicians caring for Asian oncology patients should be aware of this potential serious but reversible adverse event. | CHEMICAL-INDUCED-DISEASE |
| Delayed toxicity of CHEMICAL on the bladder of DBA/2 and C57BL/6 female mouse. The present study describes the delayed development of a severe bladder pathology in a susceptible strain of mice (DBA/2) but not in a resistant strain (C57BL/6) when both were treated with a single 300 mg/kg dose of CHEMICAL (CHEMICAL). Inbred DBA/2 and C57BL/6 female mice were injected with CHEMICAL, and the effect of the drug on the bladder was assessed during 100 days by light microscopy using different staining procedures, and after 30 days by conventional electron microscopy. Early CHEMICAL toxicity caused a typical DISEASE cystitis in both strains that was completely repaired in about 7-10 days. After 30 days of CHEMICAL injection ulcerous and non-ulcerous forms of chronic cystitis appeared in 86% of DBA/2 mice but only in 4% of C57BL/6 mice. Delayed cystitis was characterized by infiltration and transepithelial passage into the lumen of inflammatory cells and by frequent exfoliation of the urothelium. Mast cells appeared in the connective and muscular layers of the bladder at a much higher number in DBA/2 mice than in C57BL/6 mice or untreated controls. Electron microscopy disclosed the absence of the typical discoidal vesicles normally present in the cytoplasm of surface cells. Instead, numerous abnormal vesicles containing one or several dark granules were observed in the cytoplasm of cells from all the epithelial layers. Delayed cystitis still persisted in DBA/2 mice 100 days after treatment. These results indicate that delayed toxicity of CHEMICAL in female DBA/2 mice causes a bladder pathology that is not observed in C57BL/6 mice. This pathology resembles interstitial cystitis in humans and could perhaps be used as an animal model for studies on the disease. | CHEMICAL-INDUCED-DISEASE |
| Delayed toxicity of CHEMICAL on the bladder of DBA/2 and C57BL/6 female mouse. The present study describes the delayed development of a severe bladder pathology in a susceptible strain of mice (DBA/2) but not in a resistant strain (C57BL/6) when both were treated with a single 300 mg/kg dose of CHEMICAL (CHEMICAL). Inbred DBA/2 and C57BL/6 female mice were injected with CHEMICAL, and the effect of the drug on the bladder was assessed during 100 days by light microscopy using different staining procedures, and after 30 days by conventional electron microscopy. Early CHEMICAL toxicity caused a typical haemorrhagic DISEASE in both strains that was completely repaired in about 7-10 days. After 30 days of CHEMICAL injection ulcerous and non-ulcerous forms of chronic DISEASE appeared in 86% of DBA/2 mice but only in 4% of C57BL/6 mice. Delayed DISEASE was characterized by infiltration and transepithelial passage into the lumen of inflammatory cells and by frequent exfoliation of the urothelium. Mast cells appeared in the connective and muscular layers of the bladder at a much higher number in DBA/2 mice than in C57BL/6 mice or untreated controls. Electron microscopy disclosed the absence of the typical discoidal vesicles normally present in the cytoplasm of surface cells. Instead, numerous abnormal vesicles containing one or several dark granules were observed in the cytoplasm of cells from all the epithelial layers. Delayed DISEASE still persisted in DBA/2 mice 100 days after treatment. These results indicate that delayed toxicity of CHEMICAL in female DBA/2 mice causes a bladder pathology that is not observed in C57BL/6 mice. This pathology resembles interstitial cystitis in humans and could perhaps be used as an animal model for studies on the disease. | CHEMICAL-INDUCED-DISEASE |
| High-dose 5-fluorouracil / CHEMICAL in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and CHEMICAL (CHEMICAL) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, CHEMICAL and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose 5-FU/CHEMICAL and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour CHEMICAL 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, DISEASE 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/CHEMICAL/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose 5-fluorouracil / CHEMICAL in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and CHEMICAL (CHEMICAL) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, CHEMICAL and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose 5-FU/CHEMICAL and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour CHEMICAL 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, DISEASE 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/CHEMICAL/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose 5-fluorouracil / folinic acid in combination with three-weekly CHEMICAL in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, FA and CHEMICAL (CHEMICAL) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this CHEMICAL-dependent schedule we initiated a phase II study with high-dose 5-FU/FA and 3-weekly bolus CHEMICAL. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus CHEMICAL 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, DISEASE 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/FA/CHEMICAL is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose 5-fluorouracil / CHEMICAL in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and CHEMICAL (CHEMICAL) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, CHEMICAL and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose 5-FU/CHEMICAL and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour CHEMICAL 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, DISEASE 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/CHEMICAL/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose 5-fluorouracil / folinic acid in combination with three-weekly CHEMICAL in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, FA and CHEMICAL (CHEMICAL) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this CHEMICAL-dependent schedule we initiated a phase II study with high-dose 5-FU/FA and 3-weekly bolus CHEMICAL. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus CHEMICAL 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, DISEASE 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/FA/CHEMICAL is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose CHEMICAL / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of CHEMICAL (CHEMICAL) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus CHEMICAL, FA and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose CHEMICAL/FA and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour CHEMICAL 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, DISEASE 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose CHEMICAL/FA/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose 5-fluorouracil / folinic acid in combination with three-weekly CHEMICAL in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, FA and CHEMICAL (CHEMICAL) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this CHEMICAL-dependent schedule we initiated a phase II study with high-dose 5-FU/FA and 3-weekly bolus CHEMICAL. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus CHEMICAL 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): DISEASE 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/FA/CHEMICAL is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose 5-fluorouracil / folinic acid in combination with three-weekly CHEMICAL in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, FA and CHEMICAL (CHEMICAL) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this CHEMICAL-dependent schedule we initiated a phase II study with high-dose 5-FU/FA and 3-weekly bolus CHEMICAL. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus CHEMICAL 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed DISEASE (DISEASE). CONCLUSIONS: High-dose 5-FU/FA/CHEMICAL is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly DISEASE may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose CHEMICAL / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of CHEMICAL (CHEMICAL) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus CHEMICAL, FA and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose CHEMICAL/FA and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour CHEMICAL 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, DISEASE 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose CHEMICAL/FA/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose 5-fluorouracil / CHEMICAL in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and CHEMICAL (CHEMICAL) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, CHEMICAL and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose 5-FU/CHEMICAL and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour CHEMICAL 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, DISEASE 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/CHEMICAL/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose CHEMICAL / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of CHEMICAL (CHEMICAL) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus CHEMICAL, FA and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose CHEMICAL/FA and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour CHEMICAL 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed DISEASE (DISEASE). CONCLUSIONS: High-dose CHEMICAL/FA/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly DISEASE may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose CHEMICAL / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of CHEMICAL (CHEMICAL) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus CHEMICAL, FA and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose CHEMICAL/FA and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour CHEMICAL 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, DISEASE 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose CHEMICAL/FA/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose CHEMICAL / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of CHEMICAL (CHEMICAL) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus CHEMICAL, FA and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose CHEMICAL/FA and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour CHEMICAL 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): DISEASE 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose CHEMICAL/FA/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose CHEMICAL / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of CHEMICAL (CHEMICAL) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus CHEMICAL, FA and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose CHEMICAL/FA and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour CHEMICAL 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, DISEASE 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose CHEMICAL/FA/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose 5-fluorouracil / CHEMICAL in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and CHEMICAL (CHEMICAL) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, CHEMICAL and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose 5-FU/CHEMICAL and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour CHEMICAL 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): DISEASE 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/CHEMICAL/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose 5-fluorouracil / folinic acid in combination with three-weekly CHEMICAL in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, FA and CHEMICAL (CHEMICAL) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this CHEMICAL-dependent schedule we initiated a phase II study with high-dose 5-FU/FA and 3-weekly bolus CHEMICAL. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus CHEMICAL 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, DISEASE 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/FA/CHEMICAL is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose 5-fluorouracil / folinic acid in combination with three-weekly CHEMICAL in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, FA and CHEMICAL (CHEMICAL) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this CHEMICAL-dependent schedule we initiated a phase II study with high-dose 5-FU/FA and 3-weekly bolus CHEMICAL. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus CHEMICAL 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, DISEASE 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/FA/CHEMICAL is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose 5-fluorouracil / CHEMICAL in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and CHEMICAL (CHEMICAL) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, CHEMICAL and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose 5-FU/CHEMICAL and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour CHEMICAL 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed DISEASE (DISEASE). CONCLUSIONS: High-dose 5-FU/CHEMICAL/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly DISEASE may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose CHEMICAL / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of CHEMICAL (CHEMICAL) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus CHEMICAL, FA and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose CHEMICAL/FA and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour CHEMICAL 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, DISEASE 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose CHEMICAL/FA/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose 5-fluorouracil / CHEMICAL in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and CHEMICAL (CHEMICAL) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, CHEMICAL and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose 5-FU/CHEMICAL and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour CHEMICAL 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, DISEASE 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/CHEMICAL/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose 5-fluorouracil / folinic acid in combination with three-weekly CHEMICAL in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, FA and CHEMICAL (CHEMICAL) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this CHEMICAL-dependent schedule we initiated a phase II study with high-dose 5-FU/FA and 3-weekly bolus CHEMICAL. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus CHEMICAL 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, DISEASE 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/FA/CHEMICAL is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur. | CHEMICAL-INDUCED-DISEASE |
| High-dose 5-fluorouracil / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study. BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low DISEASE. In a previous phase II study with 3-weekly bolus 5-FU, FA and mitomycin C (MMC) we found a low DISEASE rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose 5-FU/FA and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst DISEASE (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/FA/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to CHEMICAL-containing regimens; however, it has to be considered that possibly HUS may occur. | NO-RELATIONSHIP |
| High-dose 5-fluorouracil / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced DISEASE. A phase II study. BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced DISEASE (DISEASE) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, FA and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose 5-FU/FA and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with DISEASE to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary DISEASE, and 15 showed a relapsed DISEASE. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/FA/MMC is an effective and well-tolerated outpatient regimen for DISEASE (objective response rate 54.6%). It may serve as an alternative to CHEMICAL-containing regimens; however, it has to be considered that possibly HUS may occur. | NO-RELATIONSHIP |
| Persistent sterile leukocyturia is associated with DISEASE in human immunodeficiency virus type 1-infected children treated with CHEMICAL. BACKGROUND: Prolonged administration of CHEMICAL is associated with the occurrence of a variety of renal complications in adults. These well-documented side effects have restricted the use of this potent protease inhibitor in children. DESIGN: A prospective study to monitor CHEMICAL-related DISEASE in a cohort of 30 human immunodeficiency virus type 1-infected children treated with CHEMICAL. METHODS: Urinary pH, albumin, creatinine, the presence of erythrocytes, leukocytes, bacteria and crystals, and culture were analyzed every 3 months for 96 weeks. Serum creatinine levels were routinely determined at the same time points. Steady-state pharmacokinetics of CHEMICAL were done at week 4 after the initiation of CHEMICAL. RESULTS: The cumulative incidence of persistent sterile leukocyturia (> or =75 cells/ micro L in at least 2 consecutive visits) after 96 weeks was 53%. Persistent sterile leukocyturia was frequently associated with a mild increase in the urine albumin/creatinine ratio and by microscopic hematuria. The cumulative incidence of serum creatinine levels >50% above normal was 33% after 96 weeks. Children with persistent sterile leukocyturia more frequently had serum creatinine levels of 50% above normal than those children without persistent sterile leukocyturia. In children younger than 5.6 years, persistent sterile leukocyturia was significantly more frequent than in older children. A higher cumulative incidence of persistent leukocyturia was found in children with an area under the curve >19 mg/L x h or a peak serum level of CHEMICAL >12 mg/L. In 4 children, CHEMICAL was discontinued because of DISEASE. Subsequently, the serum creatinine levels decreased, the urine albumin/creatinine ratios returned to zero, and the leukocyturia disappeared within 3 months. CONCLUSIONS: Children treated with CHEMICAL have a high cumulative incidence of persistent sterile leukocyturia. Children with persistent sterile leukocyturia more frequently had an increase in serum creatinine levels of >50% above normal. Younger children have an additional risk for renal complications. The DISEASE in these children occurred in the absence of clinical symptoms of nephrolithiasis. CHEMICAL-associated DISEASE must be monitored closely, especially in children with risk factors such as persistent sterile leukocyturia, age <5.6 years, an area under the curve of CHEMICAL >19 mg/L x h, and a C(max) >12 mg/L. | CHEMICAL-INDUCED-DISEASE |
| Persistent sterile leukocyturia is associated with impaired renal function in human immunodeficiency virus type 1-infected children treated with CHEMICAL. BACKGROUND: Prolonged administration of CHEMICAL is associated with the occurrence of a variety of renal complications in adults. These well-documented side effects have restricted the use of this potent protease inhibitor in children. DESIGN: A prospective study to monitor CHEMICAL-related nephrotoxicity in a cohort of 30 human immunodeficiency virus type 1-infected children treated with CHEMICAL. METHODS: Urinary pH, albumin, creatinine, the presence of erythrocytes, leukocytes, bacteria and crystals, and culture were analyzed every 3 months for 96 weeks. Serum creatinine levels were routinely determined at the same time points. Steady-state pharmacokinetics of CHEMICAL were done at week 4 after the initiation of CHEMICAL. RESULTS: The cumulative incidence of persistent sterile leukocyturia (> or =75 cells/ micro L in at least 2 consecutive visits) after 96 weeks was 53%. Persistent sterile leukocyturia was frequently associated with a mild increase in the urine albumin/creatinine ratio and by microscopic DISEASE. The cumulative incidence of serum creatinine levels >50% above normal was 33% after 96 weeks. Children with persistent sterile leukocyturia more frequently had serum creatinine levels of 50% above normal than those children without persistent sterile leukocyturia. In children younger than 5.6 years, persistent sterile leukocyturia was significantly more frequent than in older children. A higher cumulative incidence of persistent leukocyturia was found in children with an area under the curve >19 mg/L x h or a peak serum level of CHEMICAL >12 mg/L. In 4 children, CHEMICAL was discontinued because of nephrotoxicity. Subsequently, the serum creatinine levels decreased, the urine albumin/creatinine ratios returned to zero, and the leukocyturia disappeared within 3 months. CONCLUSIONS: Children treated with CHEMICAL have a high cumulative incidence of persistent sterile leukocyturia. Children with persistent sterile leukocyturia more frequently had an increase in serum creatinine levels of >50% above normal. Younger children have an additional risk for renal complications. The impairment of the renal function in these children occurred in the absence of clinical symptoms of nephrolithiasis. CHEMICAL-associated nephrotoxicity must be monitored closely, especially in children with risk factors such as persistent sterile leukocyturia, age <5.6 years, an area under the curve of CHEMICAL >19 mg/L x h, and a C(max) >12 mg/L. | CHEMICAL-INDUCED-DISEASE |
| Persistent sterile leukocyturia is associated with impaired renal function in human immunodeficiency virus type 1-infected children treated with indinavir. BACKGROUND: Prolonged administration of indinavir is associated with the occurrence of a variety of renal complications in adults. These well-documented side effects have restricted the use of this potent protease inhibitor in children. DESIGN: A prospective study to monitor indinavir-related nephrotoxicity in a cohort of 30 human immunodeficiency virus type 1-infected children treated with indinavir. METHODS: Urinary pH, albumin, CHEMICAL, the presence of erythrocytes, leukocytes, bacteria and crystals, and culture were analyzed every 3 months for 96 weeks. Serum CHEMICAL levels were routinely determined at the same time points. Steady-state pharmacokinetics of indinavir were done at week 4 after the initiation of indinavir. RESULTS: The cumulative incidence of persistent sterile leukocyturia (> or =75 cells/ micro L in at least 2 consecutive visits) after 96 weeks was 53%. Persistent sterile leukocyturia was frequently associated with a mild increase in the urine albumin/CHEMICAL ratio and by microscopic hematuria. The cumulative incidence of serum CHEMICAL levels >50% above normal was 33% after 96 weeks. Children with persistent sterile leukocyturia more frequently had serum CHEMICAL levels of 50% above normal than those children without persistent sterile leukocyturia. In children younger than 5.6 years, persistent sterile leukocyturia was significantly more frequent than in older children. A higher cumulative incidence of persistent leukocyturia was found in children with an area under the curve >19 mg/L x h or a peak serum level of indinavir >12 mg/L. In 4 children, indinavir was discontinued because of nephrotoxicity. Subsequently, the serum CHEMICAL levels decreased, the urine albumin/CHEMICAL ratios returned to zero, and the leukocyturia disappeared within 3 months. CONCLUSIONS: Children treated with indinavir have a high cumulative incidence of persistent sterile leukocyturia. Children with persistent sterile leukocyturia more frequently had an increase in serum CHEMICAL levels of >50% above normal. Younger children have an additional risk for renal complications. The impairment of the renal function in these children occurred in the absence of clinical symptoms of DISEASE. Indinavir-associated nephrotoxicity must be monitored closely, especially in children with risk factors such as persistent sterile leukocyturia, age <5.6 years, an area under the curve of indinavir >19 mg/L x h, and a C(max) >12 mg/L. | NO-RELATIONSHIP |
| Persistent sterile leukocyturia is associated with impaired renal function in DISEASE children treated with indinavir. BACKGROUND: Prolonged administration of indinavir is associated with the occurrence of a variety of renal complications in adults. These well-documented side effects have restricted the use of this potent protease inhibitor in children. DESIGN: A prospective study to monitor indinavir-related nephrotoxicity in a cohort of 30 DISEASE children treated with indinavir. METHODS: Urinary pH, albumin, CHEMICAL, the presence of erythrocytes, leukocytes, bacteria and crystals, and culture were analyzed every 3 months for 96 weeks. Serum CHEMICAL levels were routinely determined at the same time points. Steady-state pharmacokinetics of indinavir were done at week 4 after the initiation of indinavir. RESULTS: The cumulative incidence of persistent sterile leukocyturia (> or =75 cells/ micro L in at least 2 consecutive visits) after 96 weeks was 53%. Persistent sterile leukocyturia was frequently associated with a mild increase in the urine albumin/CHEMICAL ratio and by microscopic hematuria. The cumulative incidence of serum CHEMICAL levels >50% above normal was 33% after 96 weeks. Children with persistent sterile leukocyturia more frequently had serum CHEMICAL levels of 50% above normal than those children without persistent sterile leukocyturia. In children younger than 5.6 years, persistent sterile leukocyturia was significantly more frequent than in older children. A higher cumulative incidence of persistent leukocyturia was found in children with an area under the curve >19 mg/L x h or a peak serum level of indinavir >12 mg/L. In 4 children, indinavir was discontinued because of nephrotoxicity. Subsequently, the serum CHEMICAL levels decreased, the urine albumin/CHEMICAL ratios returned to zero, and the leukocyturia disappeared within 3 months. CONCLUSIONS: Children treated with indinavir have a high cumulative incidence of persistent sterile leukocyturia. Children with persistent sterile leukocyturia more frequently had an increase in serum CHEMICAL levels of >50% above normal. Younger children have an additional risk for renal complications. The impairment of the renal function in these children occurred in the absence of clinical symptoms of nephrolithiasis. Indinavir-associated nephrotoxicity must be monitored closely, especially in children with risk factors such as persistent sterile leukocyturia, age <5.6 years, an area under the curve of indinavir >19 mg/L x h, and a C(max) >12 mg/L. | NO-RELATIONSHIP |
| Persistent sterile DISEASE is associated with impaired renal function in human immunodeficiency virus type 1-infected children treated with indinavir. BACKGROUND: Prolonged administration of indinavir is associated with the occurrence of a variety of renal complications in adults. These well-documented side effects have restricted the use of this potent protease inhibitor in children. DESIGN: A prospective study to monitor indinavir-related nephrotoxicity in a cohort of 30 human immunodeficiency virus type 1-infected children treated with indinavir. METHODS: Urinary pH, albumin, CHEMICAL, the presence of erythrocytes, leukocytes, bacteria and crystals, and culture were analyzed every 3 months for 96 weeks. Serum CHEMICAL levels were routinely determined at the same time points. Steady-state pharmacokinetics of indinavir were done at week 4 after the initiation of indinavir. RESULTS: The cumulative incidence of persistent sterile DISEASE (> or =75 cells/ micro L in at least 2 consecutive visits) after 96 weeks was 53%. Persistent sterile DISEASE was frequently associated with a mild increase in the urine albumin/CHEMICAL ratio and by microscopic hematuria. The cumulative incidence of serum CHEMICAL levels >50% above normal was 33% after 96 weeks. Children with persistent sterile DISEASE more frequently had serum CHEMICAL levels of 50% above normal than those children without persistent sterile DISEASE. In children younger than 5.6 years, persistent sterile DISEASE was significantly more frequent than in older children. A higher cumulative incidence of persistent DISEASE was found in children with an area under the curve >19 mg/L x h or a peak serum level of indinavir >12 mg/L. In 4 children, indinavir was discontinued because of nephrotoxicity. Subsequently, the serum CHEMICAL levels decreased, the urine albumin/CHEMICAL ratios returned to zero, and the DISEASE disappeared within 3 months. CONCLUSIONS: Children treated with indinavir have a high cumulative incidence of persistent sterile DISEASE. Children with persistent sterile DISEASE more frequently had an increase in serum CHEMICAL levels of >50% above normal. Younger children have an additional risk for renal complications. The impairment of the renal function in these children occurred in the absence of clinical symptoms of nephrolithiasis. Indinavir-associated nephrotoxicity must be monitored closely, especially in children with risk factors such as persistent sterile DISEASE, age <5.6 years, an area under the curve of indinavir >19 mg/L x h, and a C(max) >12 mg/L. | NO-RELATIONSHIP |
| Utility of troponin I in patients with CHEMICAL-associated chest pain. Baseline electrocardiogram abnormalities and market elevations not associated with myocardial necrosis make accurate diagnosis of DISEASE (DISEASE) difficult in patients with CHEMICAL-associated chest pain. Troponin sampling may offer greater diagnostic utility in these patients. OBJECTIVE: To assess outcomes based on troponin positivity in patients with CHEMICAL chest pain admitted for exclusion of DISEASE. METHODS: Outcomes were examined in patients admitted for possible DISEASE after CHEMICAL use. All patients underwent a rapid rule-in protocol that included serial sampling of creatine kinase (CK), CK-MB, and cardiac troponin I (cTnI) over eight hours. Outcomes included CK-MB DISEASE (CK-MB >or= 8 ng/mL with a relative index [(CK-MB x 100)/total CK] >or= 4, cardiac death, and significant coronary disease (>or=50%). RESULTS: Of the 246 admitted patients, 34 (14%) met CK-MB criteria for DISEASE and 38 (16%) had cTnI elevations. Angiography was performed in 29 of 38 patients who were cTnI-positive, with significant disease present in 25 (86%). Three of the four patients without significant disease who had cTnI elevations met CK-MB criteria for DISEASE, and the other had a peak CK-MB level of 13 ng/mL. Sensitivities, specificities, and positive and negative likelihood ratios for predicting cardiac death or significant disease were high for both CK-MB DISEASE and cTnI and were not significantly different. CONCLUSIONS: Most patients with cTnI elevations meet CK-MB criteria for DISEASE, as well as have a high incidence of underlying significant disease. Troponin appears to have an equivalent diagnostic accuracy compared with CK-MB for diagnosing necrosis in patients with CHEMICAL-associated chest pain and suspected DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Utility of troponin I in patients with cocaine-associated chest pain. Baseline electrocardiogram abnormalities and market elevations not associated with myocardial necrosis make accurate diagnosis of myocardial infarction (MI) difficult in patients with cocaine-associated chest pain. Troponin sampling may offer greater diagnostic utility in these patients. OBJECTIVE: To assess outcomes based on troponin positivity in patients with cocaine chest pain admitted for exclusion of MI. METHODS: Outcomes were examined in patients admitted for possible MI after cocaine use. All patients underwent a rapid rule-in protocol that included serial sampling of CHEMICAL kinase (CK), CK-MB, and cardiac troponin I (cTnI) over eight hours. Outcomes included CK-MB MI (CK-MB >or= 8 ng/mL with a relative index [(CK-MB x 100)/total CK] >or= 4, cardiac death, and significant coronary disease (>or=50%). RESULTS: Of the 246 admitted patients, 34 (14%) met CK-MB criteria for MI and 38 (16%) had cTnI elevations. Angiography was performed in 29 of 38 patients who were cTnI-positive, with significant disease present in 25 (86%). Three of the four patients without significant disease who had cTnI elevations met CK-MB criteria for MI, and the other had a peak CK-MB level of 13 ng/mL. Sensitivities, specificities, and positive and negative likelihood ratios for predicting cardiac death or significant disease were high for both CK-MB MI and cTnI and were not significantly different. CONCLUSIONS: Most patients with cTnI elevations meet CK-MB criteria for MI, as well as have a high incidence of underlying significant disease. Troponin appears to have an equivalent diagnostic accuracy compared with CK-MB for diagnosing DISEASE in patients with cocaine-associated chest pain and suspected MI. | NO-RELATIONSHIP |
| Utility of troponin I in patients with cocaine-associated DISEASE. Baseline electrocardiogram abnormalities and market elevations not associated with myocardial necrosis make accurate diagnosis of myocardial infarction (MI) difficult in patients with cocaine-associated DISEASE. Troponin sampling may offer greater diagnostic utility in these patients. OBJECTIVE: To assess outcomes based on troponin positivity in patients with cocaine DISEASE admitted for exclusion of MI. METHODS: Outcomes were examined in patients admitted for possible MI after cocaine use. All patients underwent a rapid rule-in protocol that included serial sampling of CHEMICAL kinase (CK), CK-MB, and cardiac troponin I (cTnI) over eight hours. Outcomes included CK-MB MI (CK-MB >or= 8 ng/mL with a relative index [(CK-MB x 100)/total CK] >or= 4, cardiac death, and significant coronary disease (>or=50%). RESULTS: Of the 246 admitted patients, 34 (14%) met CK-MB criteria for MI and 38 (16%) had cTnI elevations. Angiography was performed in 29 of 38 patients who were cTnI-positive, with significant disease present in 25 (86%). Three of the four patients without significant disease who had cTnI elevations met CK-MB criteria for MI, and the other had a peak CK-MB level of 13 ng/mL. Sensitivities, specificities, and positive and negative likelihood ratios for predicting cardiac death or significant disease were high for both CK-MB MI and cTnI and were not significantly different. CONCLUSIONS: Most patients with cTnI elevations meet CK-MB criteria for MI, as well as have a high incidence of underlying significant disease. Troponin appears to have an equivalent diagnostic accuracy compared with CK-MB for diagnosing necrosis in patients with cocaine-associated DISEASE and suspected MI. | NO-RELATIONSHIP |
| Utility of troponin I in patients with cocaine-associated chest pain. Baseline electrocardiogram abnormalities and market elevations not associated with DISEASE make accurate diagnosis of myocardial infarction (MI) difficult in patients with cocaine-associated chest pain. Troponin sampling may offer greater diagnostic utility in these patients. OBJECTIVE: To assess outcomes based on troponin positivity in patients with cocaine chest pain admitted for exclusion of MI. METHODS: Outcomes were examined in patients admitted for possible MI after cocaine use. All patients underwent a rapid rule-in protocol that included serial sampling of CHEMICAL kinase (CK), CK-MB, and cardiac troponin I (cTnI) over eight hours. Outcomes included CK-MB MI (CK-MB >or= 8 ng/mL with a relative index [(CK-MB x 100)/total CK] >or= 4, cardiac death, and significant coronary disease (>or=50%). RESULTS: Of the 246 admitted patients, 34 (14%) met CK-MB criteria for MI and 38 (16%) had cTnI elevations. Angiography was performed in 29 of 38 patients who were cTnI-positive, with significant disease present in 25 (86%). Three of the four patients without significant disease who had cTnI elevations met CK-MB criteria for MI, and the other had a peak CK-MB level of 13 ng/mL. Sensitivities, specificities, and positive and negative likelihood ratios for predicting cardiac death or significant disease were high for both CK-MB MI and cTnI and were not significantly different. CONCLUSIONS: Most patients with cTnI elevations meet CK-MB criteria for MI, as well as have a high incidence of underlying significant disease. Troponin appears to have an equivalent diagnostic accuracy compared with CK-MB for diagnosing necrosis in patients with cocaine-associated chest pain and suspected MI. | NO-RELATIONSHIP |
| Utility of troponin I in patients with cocaine-associated chest pain. Baseline electrocardiogram abnormalities and market elevations not associated with myocardial necrosis make accurate diagnosis of myocardial infarction (MI) difficult in patients with cocaine-associated chest pain. Troponin sampling may offer greater diagnostic utility in these patients. OBJECTIVE: To assess outcomes based on troponin positivity in patients with cocaine chest pain admitted for exclusion of MI. METHODS: Outcomes were examined in patients admitted for possible MI after cocaine use. All patients underwent a rapid rule-in protocol that included serial sampling of CHEMICAL kinase (CK), CK-MB, and cardiac troponin I (cTnI) over eight hours. Outcomes included CK-MB MI (CK-MB >or= 8 ng/mL with a relative index [(CK-MB x 100)/total CK] >or= 4, cardiac death, and significant DISEASE (>or=50%). RESULTS: Of the 246 admitted patients, 34 (14%) met CK-MB criteria for MI and 38 (16%) had cTnI elevations. Angiography was performed in 29 of 38 patients who were cTnI-positive, with significant disease present in 25 (86%). Three of the four patients without significant disease who had cTnI elevations met CK-MB criteria for MI, and the other had a peak CK-MB level of 13 ng/mL. Sensitivities, specificities, and positive and negative likelihood ratios for predicting cardiac death or significant disease were high for both CK-MB MI and cTnI and were not significantly different. CONCLUSIONS: Most patients with cTnI elevations meet CK-MB criteria for MI, as well as have a high incidence of underlying significant disease. Troponin appears to have an equivalent diagnostic accuracy compared with CK-MB for diagnosing necrosis in patients with cocaine-associated chest pain and suspected MI. | NO-RELATIONSHIP |
| Utility of troponin I in patients with cocaine-associated chest pain. Baseline electrocardiogram abnormalities and market elevations not associated with myocardial necrosis make accurate diagnosis of myocardial infarction (MI) difficult in patients with cocaine-associated chest pain. Troponin sampling may offer greater diagnostic utility in these patients. OBJECTIVE: To assess outcomes based on troponin positivity in patients with cocaine chest pain admitted for exclusion of MI. METHODS: Outcomes were examined in patients admitted for possible MI after cocaine use. All patients underwent a rapid rule-in protocol that included serial sampling of CHEMICAL kinase (CK), CK-MB, and cardiac troponin I (cTnI) over eight hours. Outcomes included CK-MB MI (CK-MB >or= 8 ng/mL with a relative index [(CK-MB x 100)/total CK] >or= 4, DISEASE, and significant coronary disease (>or=50%). RESULTS: Of the 246 admitted patients, 34 (14%) met CK-MB criteria for MI and 38 (16%) had cTnI elevations. Angiography was performed in 29 of 38 patients who were cTnI-positive, with significant disease present in 25 (86%). Three of the four patients without significant disease who had cTnI elevations met CK-MB criteria for MI, and the other had a peak CK-MB level of 13 ng/mL. Sensitivities, specificities, and positive and negative likelihood ratios for predicting DISEASE or significant disease were high for both CK-MB MI and cTnI and were not significantly different. CONCLUSIONS: Most patients with cTnI elevations meet CK-MB criteria for MI, as well as have a high incidence of underlying significant disease. Troponin appears to have an equivalent diagnostic accuracy compared with CK-MB for diagnosing necrosis in patients with cocaine-associated chest pain and suspected MI. | NO-RELATIONSHIP |
| Acute interstitial nephritis due to CHEMICAL (CHEMICAL). We report a case of acute interstitial nephritis (AIN) due to CHEMICAL (CHEMICAL). A 50-year-old patient admitted to our hospital for fever and acute renal failure. Before admission, he had been taking CHEMICAL and bendazac lysine due to retinal vein occlusion at ophthalmologic department. Thereafter, he experienced intermittent fever and skin rash. On admission, clinical symptoms (i.e. arthralgia and fever) and laboratory findings (i.e. DISEASE and renal failure) suggested AIN, and which was confirmed by pathologic findings on renal biopsy. A lymphocyte transformation test demonstrated a positive result against CHEMICAL. Treatment was consisted of withdrawal of CHEMICAL and intravenous methylprednisolone, and his renal function was completely recovered. To our knowledge, this is the first report of CHEMICAL-associated AIN. | CHEMICAL-INDUCED-DISEASE |
| Acute interstitial nephritis due to CHEMICAL (CHEMICAL). We report a case of acute interstitial nephritis (AIN) due to CHEMICAL (CHEMICAL). A 50-year-old patient admitted to our hospital for fever and acute renal failure. Before admission, he had been taking CHEMICAL and bendazac lysine due to retinal vein occlusion at ophthalmologic department. Thereafter, he experienced intermittent fever and skin rash. On admission, clinical symptoms (i.e. arthralgia and fever) and laboratory findings (i.e. eosinophilia and DISEASE) suggested AIN, and which was confirmed by pathologic findings on renal biopsy. A lymphocyte transformation test demonstrated a positive result against CHEMICAL. Treatment was consisted of withdrawal of CHEMICAL and intravenous methylprednisolone, and his renal function was completely recovered. To our knowledge, this is the first report of CHEMICAL-associated AIN. | CHEMICAL-INDUCED-DISEASE |
| Acute DISEASE due to CHEMICAL (CHEMICAL). We report a case of acute DISEASE (DISEASE) due to CHEMICAL (CHEMICAL). A 50-year-old patient admitted to our hospital for fever and acute renal failure. Before admission, he had been taking CHEMICAL and bendazac lysine due to retinal vein occlusion at ophthalmologic department. Thereafter, he experienced intermittent fever and skin rash. On admission, clinical symptoms (i.e. arthralgia and fever) and laboratory findings (i.e. eosinophilia and renal failure) suggested DISEASE, and which was confirmed by pathologic findings on renal biopsy. A lymphocyte transformation test demonstrated a positive result against CHEMICAL. Treatment was consisted of withdrawal of CHEMICAL and intravenous methylprednisolone, and his renal function was completely recovered. To our knowledge, this is the first report of CHEMICAL-associated DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Acute interstitial nephritis due to CHEMICAL (CHEMICAL). We report a case of acute interstitial nephritis (AIN) due to CHEMICAL (CHEMICAL). A 50-year-old patient admitted to our hospital for DISEASE and acute renal failure. Before admission, he had been taking CHEMICAL and bendazac lysine due to retinal vein occlusion at ophthalmologic department. Thereafter, he experienced intermittent DISEASE and skin rash. On admission, clinical symptoms (i.e. arthralgia and DISEASE) and laboratory findings (i.e. eosinophilia and renal failure) suggested AIN, and which was confirmed by pathologic findings on renal biopsy. A lymphocyte transformation test demonstrated a positive result against CHEMICAL. Treatment was consisted of withdrawal of CHEMICAL and intravenous methylprednisolone, and his renal function was completely recovered. To our knowledge, this is the first report of CHEMICAL-associated AIN. | CHEMICAL-INDUCED-DISEASE |
| Acute interstitial nephritis due to CHEMICAL (CHEMICAL). We report a case of acute interstitial nephritis (AIN) due to CHEMICAL (CHEMICAL). A 50-year-old patient admitted to our hospital for fever and acute renal failure. Before admission, he had been taking CHEMICAL and bendazac lysine due to retinal vein occlusion at ophthalmologic department. Thereafter, he experienced intermittent fever and skin rash. On admission, clinical symptoms (i.e. DISEASE and fever) and laboratory findings (i.e. eosinophilia and renal failure) suggested AIN, and which was confirmed by pathologic findings on renal biopsy. A lymphocyte transformation test demonstrated a positive result against CHEMICAL. Treatment was consisted of withdrawal of CHEMICAL and intravenous methylprednisolone, and his renal function was completely recovered. To our knowledge, this is the first report of CHEMICAL-associated AIN. | CHEMICAL-INDUCED-DISEASE |
| Acute interstitial nephritis due to nicergoline (Sermion). We report a case of acute interstitial nephritis (AIN) due to nicergoline (Sermion). A 50-year-old patient admitted to our hospital for fever and acute renal failure. Before admission, he had been taking nicergoline and bendazac lysine due to retinal vein occlusion at ophthalmologic department. Thereafter, he experienced intermittent fever and DISEASE. On admission, clinical symptoms (i.e. arthralgia and fever) and laboratory findings (i.e. eosinophilia and renal failure) suggested AIN, and which was confirmed by pathologic findings on renal biopsy. A lymphocyte transformation test demonstrated a positive result against nicergoline. Treatment was consisted of withdrawal of nicergoline and intravenous CHEMICAL, and his renal function was completely recovered. To our knowledge, this is the first report of nicergoline-associated AIN. | NO-RELATIONSHIP |
| Acute interstitial nephritis due to nicergoline (Sermion). We report a case of acute interstitial nephritis (AIN) due to nicergoline (Sermion). A 50-year-old patient admitted to our hospital for fever and acute renal failure. Before admission, he had been taking nicergoline and CHEMICAL due to retinal vein occlusion at ophthalmologic department. Thereafter, he experienced intermittent fever and DISEASE. On admission, clinical symptoms (i.e. arthralgia and fever) and laboratory findings (i.e. eosinophilia and renal failure) suggested AIN, and which was confirmed by pathologic findings on renal biopsy. A lymphocyte transformation test demonstrated a positive result against nicergoline. Treatment was consisted of withdrawal of nicergoline and intravenous methylprednisolone, and his renal function was completely recovered. To our knowledge, this is the first report of nicergoline-associated AIN. | NO-RELATIONSHIP |
| Acute interstitial nephritis due to nicergoline (Sermion). We report a case of acute interstitial nephritis (AIN) due to nicergoline (Sermion). A 50-year-old patient admitted to our hospital for fever and DISEASE. Before admission, he had been taking nicergoline and CHEMICAL due to retinal vein occlusion at ophthalmologic department. Thereafter, he experienced intermittent fever and skin rash. On admission, clinical symptoms (i.e. arthralgia and fever) and laboratory findings (i.e. eosinophilia and renal failure) suggested AIN, and which was confirmed by pathologic findings on renal biopsy. A lymphocyte transformation test demonstrated a positive result against nicergoline. Treatment was consisted of withdrawal of nicergoline and intravenous methylprednisolone, and his renal function was completely recovered. To our knowledge, this is the first report of nicergoline-associated AIN. | NO-RELATIONSHIP |
| Acute interstitial nephritis due to nicergoline (Sermion). We report a case of acute interstitial nephritis (AIN) due to nicergoline (Sermion). A 50-year-old patient admitted to our hospital for fever and acute renal failure. Before admission, he had been taking nicergoline and bendazac lysine due to DISEASE at ophthalmologic department. Thereafter, he experienced intermittent fever and skin rash. On admission, clinical symptoms (i.e. arthralgia and fever) and laboratory findings (i.e. eosinophilia and renal failure) suggested AIN, and which was confirmed by pathologic findings on renal biopsy. A lymphocyte transformation test demonstrated a positive result against nicergoline. Treatment was consisted of withdrawal of nicergoline and intravenous CHEMICAL, and his renal function was completely recovered. To our knowledge, this is the first report of nicergoline-associated AIN. | NO-RELATIONSHIP |
| Acute interstitial nephritis due to nicergoline (Sermion). We report a case of acute interstitial nephritis (AIN) due to nicergoline (Sermion). A 50-year-old patient admitted to our hospital for fever and DISEASE. Before admission, he had been taking nicergoline and bendazac lysine due to retinal vein occlusion at ophthalmologic department. Thereafter, he experienced intermittent fever and skin rash. On admission, clinical symptoms (i.e. arthralgia and fever) and laboratory findings (i.e. eosinophilia and renal failure) suggested AIN, and which was confirmed by pathologic findings on renal biopsy. A lymphocyte transformation test demonstrated a positive result against nicergoline. Treatment was consisted of withdrawal of nicergoline and intravenous CHEMICAL, and his renal function was completely recovered. To our knowledge, this is the first report of nicergoline-associated AIN. | NO-RELATIONSHIP |
| Acute interstitial nephritis due to nicergoline (Sermion). We report a case of acute interstitial nephritis (AIN) due to nicergoline (Sermion). A 50-year-old patient admitted to our hospital for fever and acute renal failure. Before admission, he had been taking nicergoline and CHEMICAL due to DISEASE at ophthalmologic department. Thereafter, he experienced intermittent fever and skin rash. On admission, clinical symptoms (i.e. arthralgia and fever) and laboratory findings (i.e. eosinophilia and renal failure) suggested AIN, and which was confirmed by pathologic findings on renal biopsy. A lymphocyte transformation test demonstrated a positive result against nicergoline. Treatment was consisted of withdrawal of nicergoline and intravenous methylprednisolone, and his renal function was completely recovered. To our knowledge, this is the first report of nicergoline-associated AIN. | NO-RELATIONSHIP |
| DISEASE complicated by massive intestinal bleeding in a patient with chronic renal failure. A patient with chronic renal failure (CRF) developed DISEASE (DISEASE) after administration of CHEMICAL and levomepromazine. In addition to the typical symptoms of DISEASE, massive intestinal bleeding was observed during the episode. This report suggests that DISEASE in a patient with CRF may be complicated by intestinal bleeding and needs special caution for this complication. | CHEMICAL-INDUCED-DISEASE |
| DISEASE complicated by massive intestinal bleeding in a patient with chronic renal failure. A patient with chronic renal failure (CRF) developed DISEASE (DISEASE) after administration of risperidone and CHEMICAL. In addition to the typical symptoms of DISEASE, massive intestinal bleeding was observed during the episode. This report suggests that DISEASE in a patient with CRF may be complicated by intestinal bleeding and needs special caution for this complication. | CHEMICAL-INDUCED-DISEASE |
| Blood brain barrier in right- and left-pawed female rats assessed by a new staining method. The asymmetrical breakdown of the blood-brain barrier (BBB) was studied in female rats. Paw preference was assessed by a food reaching test. CHEMICAL-induced DISEASE was used to destroy the BBB, which was evaluated using triphenyltetrazolium (TTC) staining of the brain slices just after giving CHEMICAL for 30 s. In normal rats, the whole brain sections exhibited complete staining with TTC. After CHEMICAL infusion for 30 s, there were large unstained areas in the left brain in right-pawed animals, and vice versa in left-pawed animals. Similar results were obtained in seizure-induced breakdown of BBB. These results were explained by an asymmetric cerebral blood flow depending upon the paw preference in rats. It was suggested that this new method and the results are consistent with contralateral motor control that may be important in determining the dominant cerebral hemisphere in animals. | CHEMICAL-INDUCED-DISEASE |
| Blood brain barrier in right- and left-pawed female rats assessed by a new staining method. The asymmetrical breakdown of the blood-brain barrier (BBB) was studied in female rats. Paw preference was assessed by a food reaching test. Adrenaline-induced hypertension was used to destroy the BBB, which was evaluated using CHEMICAL (CHEMICAL) staining of the brain slices just after giving adrenaline for 30 s. In normal rats, the whole brain sections exhibited complete staining with CHEMICAL. After adrenaline infusion for 30 s, there were large unstained areas in the left brain in right-pawed animals, and vice versa in left-pawed animals. Similar results were obtained in DISEASE-induced breakdown of BBB. These results were explained by an asymmetric cerebral blood flow depending upon the paw preference in rats. It was suggested that this new method and the results are consistent with contralateral motor control that may be important in determining the dominant cerebral hemisphere in animals. | NO-RELATIONSHIP |
| Carvedilol protects against CHEMICAL-induced mitochondrial DISEASE. Several cytopathic mechanisms have been suggested to mediate the dose-limiting cumulative and irreversible DISEASE caused by CHEMICAL. Recent evidence indicates that oxidative stress and mitochondrial dysfunction are key factors in the pathogenic process. The objective of this investigation was to test the hypothesis that carvedilol, a nonselective beta-adrenergic receptor antagonist with potent antioxidant properties, protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic CHEMICAL toxicity. Heart and liver mitochondria were isolated from rats treated for 7 weeks with CHEMICAL (2 mg/kg sc/week), carvedilol (1 mg/kg ip/week), or the combination of the two drugs. Heart mitochondria isolated from CHEMICAL-treated rats exhibited depressed rates for state 3 respiration (336 +/- 26 versus 425 +/- 53 natom O/min/mg protein) and a lower respiratory control ratio (RCR) (4.3 +/- 0.6 versus 5.8 +/- 0.4) compared with cardiac mitochondria isolated from saline-treated rats. Mitochondrial calcium-loading capacity and the activity of NADH-dehydrogenase were also suppressed in cardiac mitochondria from CHEMICAL-treated rats. CHEMICAL treatment also caused a decrease in RCR for liver mitochondria (3.9 +/- 0.9 versus 5.6 +/- 0.7 for control rats) and inhibition of hepatic cytochrome oxidase activity. Coadministration of carvedilol decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of CHEMICAL on mitochondrial respiration in both heart and liver. Carvedilol also prevented the decrease in mitochondrial Ca(2+) loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by CHEMICAL. Carvedilol by itself did not affect any of the parameters measured for heart or liver mitochondria. It is concluded that this protection by carvedilol against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose-limiting mitochondrial dysfunction and DISEASE that accompanies long-term CHEMICAL therapy in cancer patients. | CHEMICAL-INDUCED-DISEASE |
| Carvedilol protects against doxorubicin-induced mitochondrial cardiomyopathy. Several cytopathic mechanisms have been suggested to mediate the dose-limiting cumulative and irreversible cardiomyopathy caused by doxorubicin. Recent evidence indicates that oxidative stress and mitochondrial dysfunction are key factors in the pathogenic process. The objective of this investigation was to test the hypothesis that carvedilol, a nonselective beta-adrenergic receptor antagonist with potent antioxidant properties, protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic doxorubicin DISEASE. Heart and liver mitochondria were isolated from rats treated for 7 weeks with doxorubicin (2 mg/kg sc/week), carvedilol (1 mg/kg ip/week), or the combination of the two drugs. Heart mitochondria isolated from doxorubicin-treated rats exhibited depressed rates for state 3 respiration (336 +/- 26 versus 425 +/- 53 natom O/min/mg protein) and a lower respiratory control ratio (RCR) (4.3 +/- 0.6 versus 5.8 +/- 0.4) compared with cardiac mitochondria isolated from saline-treated rats. Mitochondrial CHEMICAL-loading capacity and the activity of NADH-dehydrogenase were also suppressed in cardiac mitochondria from doxorubicin-treated rats. Doxorubicin treatment also caused a decrease in RCR for liver mitochondria (3.9 +/- 0.9 versus 5.6 +/- 0.7 for control rats) and inhibition of hepatic cytochrome oxidase activity. Coadministration of carvedilol decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of doxorubicin on mitochondrial respiration in both heart and liver. Carvedilol also prevented the decrease in mitochondrial CHEMICAL(2+) loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by doxorubicin. Carvedilol by itself did not affect any of the parameters measured for heart or liver mitochondria. It is concluded that this protection by carvedilol against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose-limiting mitochondrial dysfunction and cardiomyopathy that accompanies long-term doxorubicin therapy in cancer patients. | NO-RELATIONSHIP |
| CHEMICAL protects against doxorubicin-induced mitochondrial cardiomyopathy. Several cytopathic mechanisms have been suggested to mediate the dose-limiting cumulative and irreversible cardiomyopathy caused by doxorubicin. Recent evidence indicates that oxidative stress and mitochondrial dysfunction are key factors in the pathogenic process. The objective of this investigation was to test the hypothesis that CHEMICAL, a nonselective beta-adrenergic receptor antagonist with potent antioxidant properties, protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic doxorubicin toxicity. Heart and liver mitochondria were isolated from rats treated for 7 weeks with doxorubicin (2 mg/kg sc/week), CHEMICAL (1 mg/kg ip/week), or the combination of the two drugs. Heart mitochondria isolated from doxorubicin-treated rats exhibited depressed rates for state 3 respiration (336 +/- 26 versus 425 +/- 53 natom O/min/mg protein) and a lower respiratory control ratio (RCR) (4.3 +/- 0.6 versus 5.8 +/- 0.4) compared with cardiac mitochondria isolated from saline-treated rats. Mitochondrial calcium-loading capacity and the activity of NADH-dehydrogenase were also suppressed in cardiac mitochondria from doxorubicin-treated rats. Doxorubicin treatment also caused a decrease in RCR for liver mitochondria (3.9 +/- 0.9 versus 5.6 +/- 0.7 for control rats) and inhibition of hepatic cytochrome oxidase activity. Coadministration of CHEMICAL decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of doxorubicin on mitochondrial respiration in both heart and liver. CHEMICAL also prevented the decrease in mitochondrial Ca(2+) loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by doxorubicin. CHEMICAL by itself did not affect any of the parameters measured for heart or liver mitochondria. It is concluded that this protection by CHEMICAL against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose-limiting mitochondrial dysfunction and cardiomyopathy that accompanies long-term doxorubicin therapy in DISEASE patients. | NO-RELATIONSHIP |
| Carvedilol protects against doxorubicin-induced mitochondrial cardiomyopathy. Several cytopathic mechanisms have been suggested to mediate the dose-limiting cumulative and irreversible cardiomyopathy caused by doxorubicin. Recent evidence indicates that oxidative stress and DISEASE are key factors in the pathogenic process. The objective of this investigation was to test the hypothesis that carvedilol, a nonselective beta-adrenergic receptor antagonist with potent antioxidant properties, protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic doxorubicin toxicity. Heart and liver mitochondria were isolated from rats treated for 7 weeks with doxorubicin (2 mg/kg sc/week), carvedilol (1 mg/kg ip/week), or the combination of the two drugs. Heart mitochondria isolated from doxorubicin-treated rats exhibited depressed rates for state 3 respiration (336 +/- 26 versus 425 +/- 53 natom O/min/mg protein) and a lower respiratory control ratio (RCR) (4.3 +/- 0.6 versus 5.8 +/- 0.4) compared with cardiac mitochondria isolated from saline-treated rats. Mitochondrial CHEMICAL-loading capacity and the activity of NADH-dehydrogenase were also suppressed in cardiac mitochondria from doxorubicin-treated rats. Doxorubicin treatment also caused a decrease in RCR for liver mitochondria (3.9 +/- 0.9 versus 5.6 +/- 0.7 for control rats) and inhibition of hepatic cytochrome oxidase activity. Coadministration of carvedilol decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of doxorubicin on mitochondrial respiration in both heart and liver. Carvedilol also prevented the decrease in mitochondrial CHEMICAL(2+) loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by doxorubicin. Carvedilol by itself did not affect any of the parameters measured for heart or liver mitochondria. It is concluded that this protection by carvedilol against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose-limiting DISEASE and cardiomyopathy that accompanies long-term doxorubicin therapy in cancer patients. | NO-RELATIONSHIP |
| Carvedilol protects against doxorubicin-induced mitochondrial cardiomyopathy. Several cytopathic mechanisms have been suggested to mediate the dose-limiting cumulative and irreversible cardiomyopathy caused by doxorubicin. Recent evidence indicates that oxidative stress and mitochondrial dysfunction are key factors in the pathogenic process. The objective of this investigation was to test the hypothesis that carvedilol, a nonselective beta-adrenergic receptor antagonist with potent antioxidant properties, protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic doxorubicin toxicity. Heart and liver mitochondria were isolated from rats treated for 7 weeks with doxorubicin (2 mg/kg sc/week), carvedilol (1 mg/kg ip/week), or the combination of the two drugs. Heart mitochondria isolated from doxorubicin-treated rats exhibited depressed rates for state 3 respiration (336 +/- 26 versus 425 +/- 53 natom O/min/mg protein) and a lower respiratory control ratio (RCR) (4.3 +/- 0.6 versus 5.8 +/- 0.4) compared with cardiac mitochondria isolated from saline-treated rats. Mitochondrial CHEMICAL-loading capacity and the activity of NADH-dehydrogenase were also suppressed in cardiac mitochondria from doxorubicin-treated rats. Doxorubicin treatment also caused a decrease in RCR for liver mitochondria (3.9 +/- 0.9 versus 5.6 +/- 0.7 for control rats) and inhibition of hepatic cytochrome oxidase activity. Coadministration of carvedilol decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of doxorubicin on mitochondrial respiration in both heart and liver. Carvedilol also prevented the decrease in mitochondrial CHEMICAL(2+) loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by doxorubicin. Carvedilol by itself did not affect any of the parameters measured for heart or liver mitochondria. It is concluded that this protection by carvedilol against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose-limiting mitochondrial dysfunction and cardiomyopathy that accompanies long-term doxorubicin therapy in DISEASE patients. | NO-RELATIONSHIP |
| CHEMICAL protects against doxorubicin-induced mitochondrial cardiomyopathy. Several cytopathic mechanisms have been suggested to mediate the dose-limiting cumulative and irreversible cardiomyopathy caused by doxorubicin. Recent evidence indicates that oxidative stress and DISEASE are key factors in the pathogenic process. The objective of this investigation was to test the hypothesis that CHEMICAL, a nonselective beta-adrenergic receptor antagonist with potent antioxidant properties, protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic doxorubicin toxicity. Heart and liver mitochondria were isolated from rats treated for 7 weeks with doxorubicin (2 mg/kg sc/week), CHEMICAL (1 mg/kg ip/week), or the combination of the two drugs. Heart mitochondria isolated from doxorubicin-treated rats exhibited depressed rates for state 3 respiration (336 +/- 26 versus 425 +/- 53 natom O/min/mg protein) and a lower respiratory control ratio (RCR) (4.3 +/- 0.6 versus 5.8 +/- 0.4) compared with cardiac mitochondria isolated from saline-treated rats. Mitochondrial calcium-loading capacity and the activity of NADH-dehydrogenase were also suppressed in cardiac mitochondria from doxorubicin-treated rats. Doxorubicin treatment also caused a decrease in RCR for liver mitochondria (3.9 +/- 0.9 versus 5.6 +/- 0.7 for control rats) and inhibition of hepatic cytochrome oxidase activity. Coadministration of CHEMICAL decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of doxorubicin on mitochondrial respiration in both heart and liver. CHEMICAL also prevented the decrease in mitochondrial Ca(2+) loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by doxorubicin. CHEMICAL by itself did not affect any of the parameters measured for heart or liver mitochondria. It is concluded that this protection by CHEMICAL against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose-limiting DISEASE and cardiomyopathy that accompanies long-term doxorubicin therapy in cancer patients. | NO-RELATIONSHIP |
| CHEMICAL protects against doxorubicin-induced mitochondrial cardiomyopathy. Several cytopathic mechanisms have been suggested to mediate the dose-limiting cumulative and irreversible cardiomyopathy caused by doxorubicin. Recent evidence indicates that oxidative stress and mitochondrial dysfunction are key factors in the pathogenic process. The objective of this investigation was to test the hypothesis that CHEMICAL, a nonselective beta-adrenergic receptor antagonist with potent antioxidant properties, protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic doxorubicin DISEASE. Heart and liver mitochondria were isolated from rats treated for 7 weeks with doxorubicin (2 mg/kg sc/week), CHEMICAL (1 mg/kg ip/week), or the combination of the two drugs. Heart mitochondria isolated from doxorubicin-treated rats exhibited depressed rates for state 3 respiration (336 +/- 26 versus 425 +/- 53 natom O/min/mg protein) and a lower respiratory control ratio (RCR) (4.3 +/- 0.6 versus 5.8 +/- 0.4) compared with cardiac mitochondria isolated from saline-treated rats. Mitochondrial calcium-loading capacity and the activity of NADH-dehydrogenase were also suppressed in cardiac mitochondria from doxorubicin-treated rats. Doxorubicin treatment also caused a decrease in RCR for liver mitochondria (3.9 +/- 0.9 versus 5.6 +/- 0.7 for control rats) and inhibition of hepatic cytochrome oxidase activity. Coadministration of CHEMICAL decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of doxorubicin on mitochondrial respiration in both heart and liver. CHEMICAL also prevented the decrease in mitochondrial Ca(2+) loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by doxorubicin. CHEMICAL by itself did not affect any of the parameters measured for heart or liver mitochondria. It is concluded that this protection by CHEMICAL against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose-limiting mitochondrial dysfunction and cardiomyopathy that accompanies long-term doxorubicin therapy in cancer patients. | NO-RELATIONSHIP |
| Cocaine-induced hyperactivity is more influenced by adenosine receptor agonists than CHEMICAL-induced hyperactivity. The influence of adenosine receptor agonists and antagonists on cocaine-and CHEMICAL-induced hyperactivity was examined in mice. All adenosine receptor agonists significantly DISEASE in mice, and the effects were dose-dependent. It seems that adenosine A1 and A2 receptors might be involved in this reaction. Moreover, all adenosine receptor agonists: 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680), A2A receptor agonist, N6-cyclopentyladenosine (CPA), A1 receptor agonist, and 5'-N-ethylcarboxamidoadenosine (NECA), A2/A1 receptor agonist significantly and dose-dependently decreased cocaine-induced locomotor activity. CPA reduced cocaine action at the doses which, given alone, did not influence motility, while CGS 21680 and NECA decreased the action of cocaine at the doses which, given alone, decreased locomotor activity in animals. These results suggest the involvement of both adenosine receptors in the action of cocaine although agonists of A1 receptors seem to have stronger influence on it. The selective blockade of A2 adenosine receptor by DMPX (3,7-dimethyl-1-propargylxanthine) significantly enhanced cocaine-induced locomotor activity of animals. Caffeine had similar action but the effect was not significant. CPT (8-cyclopentyltheophylline)--A1 receptor antagonist, did not show any influence in this test. Similarly, all adenosine receptor agonists decreased CHEMICAL-induced hyperactivity, but at the higher doses than those which were active in cocaine-induced hyperactivity. The selective blockade of A2 adenosine receptors (DMPX) and non-selective blockade of adenosine receptors (caffeine) significantly increased the action of CHEMICAL in the locomotor activity test. Our results have shown that all adenosine receptor agonists (A1 and A2) reduce cocaine- and CHEMICAL-induced locomotor activity and indicate that cocaine-induced hyperactivity is more influenced by adenosine receptor agonists (particularly A1 receptors) than CHEMICAL-induced hyperactivity. | NO-RELATIONSHIP |
| CHEMICAL-induced hyperactivity is more influenced by adenosine receptor agonists than amphetamine-induced hyperactivity. The influence of adenosine receptor agonists and antagonists on CHEMICAL-and amphetamine-induced hyperactivity was examined in mice. All adenosine receptor agonists significantly DISEASE in mice, and the effects were dose-dependent. It seems that adenosine A1 and A2 receptors might be involved in this reaction. Moreover, all adenosine receptor agonists: 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680), A2A receptor agonist, N6-cyclopentyladenosine (CPA), A1 receptor agonist, and 5'-N-ethylcarboxamidoadenosine (NECA), A2/A1 receptor agonist significantly and dose-dependently decreased CHEMICAL-induced locomotor activity. CPA reduced CHEMICAL action at the doses which, given alone, did not influence motility, while CGS 21680 and NECA decreased the action of CHEMICAL at the doses which, given alone, decreased locomotor activity in animals. These results suggest the involvement of both adenosine receptors in the action of CHEMICAL although agonists of A1 receptors seem to have stronger influence on it. The selective blockade of A2 adenosine receptor by DMPX (3,7-dimethyl-1-propargylxanthine) significantly enhanced CHEMICAL-induced locomotor activity of animals. Caffeine had similar action but the effect was not significant. CPT (8-cyclopentyltheophylline)--A1 receptor antagonist, did not show any influence in this test. Similarly, all adenosine receptor agonists decreased amphetamine-induced hyperactivity, but at the higher doses than those which were active in CHEMICAL-induced hyperactivity. The selective blockade of A2 adenosine receptors (DMPX) and non-selective blockade of adenosine receptors (caffeine) significantly increased the action of amphetamine in the locomotor activity test. Our results have shown that all adenosine receptor agonists (A1 and A2) reduce CHEMICAL- and amphetamine-induced locomotor activity and indicate that CHEMICAL-induced hyperactivity is more influenced by adenosine receptor agonists (particularly A1 receptors) than amphetamine-induced hyperactivity. | NO-RELATIONSHIP |
| Cocaine-induced hyperactivity is more influenced by adenosine receptor agonists than amphetamine-induced hyperactivity. The influence of adenosine receptor agonists and antagonists on cocaine-and amphetamine-induced hyperactivity was examined in mice. All adenosine receptor agonists significantly DISEASE in mice, and the effects were dose-dependent. It seems that adenosine A1 and A2 receptors might be involved in this reaction. Moreover, all adenosine receptor agonists: 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680), A2A receptor agonist, N6-cyclopentyladenosine (CPA), A1 receptor agonist, and 5'-N-ethylcarboxamidoadenosine (NECA), A2/A1 receptor agonist significantly and dose-dependently decreased cocaine-induced locomotor activity. CPA reduced cocaine action at the doses which, given alone, did not influence motility, while CGS 21680 and NECA decreased the action of cocaine at the doses which, given alone, decreased locomotor activity in animals. These results suggest the involvement of both adenosine receptors in the action of cocaine although agonists of A1 receptors seem to have stronger influence on it. The selective blockade of A2 adenosine receptor by CHEMICAL (CHEMICAL) significantly enhanced cocaine-induced locomotor activity of animals. Caffeine had similar action but the effect was not significant. CPT (8-cyclopentyltheophylline)--A1 receptor antagonist, did not show any influence in this test. Similarly, all adenosine receptor agonists decreased amphetamine-induced hyperactivity, but at the higher doses than those which were active in cocaine-induced hyperactivity. The selective blockade of A2 adenosine receptors (CHEMICAL) and non-selective blockade of adenosine receptors (caffeine) significantly increased the action of amphetamine in the locomotor activity test. Our results have shown that all adenosine receptor agonists (A1 and A2) reduce cocaine- and amphetamine-induced locomotor activity and indicate that cocaine-induced hyperactivity is more influenced by adenosine receptor agonists (particularly A1 receptors) than amphetamine-induced hyperactivity. | NO-RELATIONSHIP |
| Cocaine-induced DISEASE is more influenced by CHEMICAL receptor agonists than amphetamine-induced DISEASE. The influence of CHEMICAL receptor agonists and antagonists on cocaine-and amphetamine-induced DISEASE was examined in mice. All CHEMICAL receptor agonists significantly decreased the locomotor activity in mice, and the effects were dose-dependent. It seems that CHEMICAL A1 and A2 receptors might be involved in this reaction. Moreover, all CHEMICAL receptor agonists: 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680), A2A receptor agonist, N6-cyclopentyladenosine (CPA), A1 receptor agonist, and 5'-N-ethylcarboxamidoadenosine (NECA), A2/A1 receptor agonist significantly and dose-dependently decreased cocaine-induced locomotor activity. CPA reduced cocaine action at the doses which, given alone, did not influence motility, while CGS 21680 and NECA decreased the action of cocaine at the doses which, given alone, decreased locomotor activity in animals. These results suggest the involvement of both CHEMICAL receptors in the action of cocaine although agonists of A1 receptors seem to have stronger influence on it. The selective blockade of A2 CHEMICAL receptor by DMPX (3,7-dimethyl-1-propargylxanthine) significantly enhanced cocaine-induced locomotor activity of animals. Caffeine had similar action but the effect was not significant. CPT (8-cyclopentyltheophylline)--A1 receptor antagonist, did not show any influence in this test. Similarly, all CHEMICAL receptor agonists decreased amphetamine-induced DISEASE, but at the higher doses than those which were active in cocaine-induced DISEASE. The selective blockade of A2 CHEMICAL receptors (DMPX) and non-selective blockade of CHEMICAL receptors (caffeine) significantly increased the action of amphetamine in the locomotor activity test. Our results have shown that all CHEMICAL receptor agonists (A1 and A2) reduce cocaine- and amphetamine-induced locomotor activity and indicate that cocaine-induced DISEASE is more influenced by CHEMICAL receptor agonists (particularly A1 receptors) than amphetamine-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Cocaine-induced DISEASE is more influenced by adenosine receptor agonists than amphetamine-induced DISEASE. The influence of adenosine receptor agonists and antagonists on cocaine-and amphetamine-induced DISEASE was examined in mice. All adenosine receptor agonists significantly decreased the locomotor activity in mice, and the effects were dose-dependent. It seems that adenosine A1 and A2 receptors might be involved in this reaction. Moreover, all adenosine receptor agonists: CHEMICAL (CHEMICAL), A2A receptor agonist, N6-cyclopentyladenosine (CPA), A1 receptor agonist, and 5'-N-ethylcarboxamidoadenosine (NECA), A2/A1 receptor agonist significantly and dose-dependently decreased cocaine-induced locomotor activity. CPA reduced cocaine action at the doses which, given alone, did not influence motility, while CHEMICAL and NECA decreased the action of cocaine at the doses which, given alone, decreased locomotor activity in animals. These results suggest the involvement of both adenosine receptors in the action of cocaine although agonists of A1 receptors seem to have stronger influence on it. The selective blockade of A2 adenosine receptor by DMPX (3,7-dimethyl-1-propargylxanthine) significantly enhanced cocaine-induced locomotor activity of animals. Caffeine had similar action but the effect was not significant. CPT (8-cyclopentyltheophylline)--A1 receptor antagonist, did not show any influence in this test. Similarly, all adenosine receptor agonists decreased amphetamine-induced DISEASE, but at the higher doses than those which were active in cocaine-induced DISEASE. The selective blockade of A2 adenosine receptors (DMPX) and non-selective blockade of adenosine receptors (caffeine) significantly increased the action of amphetamine in the locomotor activity test. Our results have shown that all adenosine receptor agonists (A1 and A2) reduce cocaine- and amphetamine-induced locomotor activity and indicate that cocaine-induced DISEASE is more influenced by adenosine receptor agonists (particularly A1 receptors) than amphetamine-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Cocaine-induced DISEASE is more influenced by adenosine receptor agonists than amphetamine-induced DISEASE. The influence of adenosine receptor agonists and antagonists on cocaine-and amphetamine-induced DISEASE was examined in mice. All adenosine receptor agonists significantly decreased the locomotor activity in mice, and the effects were dose-dependent. It seems that adenosine A1 and A2 receptors might be involved in this reaction. Moreover, all adenosine receptor agonists: 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680), A2A receptor agonist, N6-cyclopentyladenosine (CPA), A1 receptor agonist, and CHEMICAL (CHEMICAL), A2/A1 receptor agonist significantly and dose-dependently decreased cocaine-induced locomotor activity. CPA reduced cocaine action at the doses which, given alone, did not influence motility, while CGS 21680 and CHEMICAL decreased the action of cocaine at the doses which, given alone, decreased locomotor activity in animals. These results suggest the involvement of both adenosine receptors in the action of cocaine although agonists of A1 receptors seem to have stronger influence on it. The selective blockade of A2 adenosine receptor by DMPX (3,7-dimethyl-1-propargylxanthine) significantly enhanced cocaine-induced locomotor activity of animals. Caffeine had similar action but the effect was not significant. CPT (8-cyclopentyltheophylline)--A1 receptor antagonist, did not show any influence in this test. Similarly, all adenosine receptor agonists decreased amphetamine-induced DISEASE, but at the higher doses than those which were active in cocaine-induced DISEASE. The selective blockade of A2 adenosine receptors (DMPX) and non-selective blockade of adenosine receptors (caffeine) significantly increased the action of amphetamine in the locomotor activity test. Our results have shown that all adenosine receptor agonists (A1 and A2) reduce cocaine- and amphetamine-induced locomotor activity and indicate that cocaine-induced DISEASE is more influenced by adenosine receptor agonists (particularly A1 receptors) than amphetamine-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Cocaine-induced DISEASE is more influenced by adenosine receptor agonists than amphetamine-induced DISEASE. The influence of adenosine receptor agonists and antagonists on cocaine-and amphetamine-induced DISEASE was examined in mice. All adenosine receptor agonists significantly decreased the locomotor activity in mice, and the effects were dose-dependent. It seems that adenosine A1 and A2 receptors might be involved in this reaction. Moreover, all adenosine receptor agonists: 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680), A2A receptor agonist, N6-cyclopentyladenosine (CPA), A1 receptor agonist, and 5'-N-ethylcarboxamidoadenosine (NECA), A2/A1 receptor agonist significantly and dose-dependently decreased cocaine-induced locomotor activity. CPA reduced cocaine action at the doses which, given alone, did not influence motility, while CGS 21680 and NECA decreased the action of cocaine at the doses which, given alone, decreased locomotor activity in animals. These results suggest the involvement of both adenosine receptors in the action of cocaine although agonists of A1 receptors seem to have stronger influence on it. The selective blockade of A2 adenosine receptor by DMPX (3,7-dimethyl-1-propargylxanthine) significantly enhanced cocaine-induced locomotor activity of animals. CHEMICAL had similar action but the effect was not significant. CPT (8-cyclopentyltheophylline)--A1 receptor antagonist, did not show any influence in this test. Similarly, all adenosine receptor agonists decreased amphetamine-induced DISEASE, but at the higher doses than those which were active in cocaine-induced DISEASE. The selective blockade of A2 adenosine receptors (DMPX) and non-selective blockade of adenosine receptors (CHEMICAL) significantly increased the action of amphetamine in the locomotor activity test. Our results have shown that all adenosine receptor agonists (A1 and A2) reduce cocaine- and amphetamine-induced locomotor activity and indicate that cocaine-induced DISEASE is more influenced by adenosine receptor agonists (particularly A1 receptors) than amphetamine-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Cocaine-induced DISEASE is more influenced by adenosine receptor agonists than amphetamine-induced DISEASE. The influence of adenosine receptor agonists and antagonists on cocaine-and amphetamine-induced DISEASE was examined in mice. All adenosine receptor agonists significantly decreased the locomotor activity in mice, and the effects were dose-dependent. It seems that adenosine A1 and A2 receptors might be involved in this reaction. Moreover, all adenosine receptor agonists: 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680), A2A receptor agonist, CHEMICAL (CHEMICAL), A1 receptor agonist, and 5'-N-ethylcarboxamidoadenosine (NECA), A2/A1 receptor agonist significantly and dose-dependently decreased cocaine-induced locomotor activity. CHEMICAL reduced cocaine action at the doses which, given alone, did not influence motility, while CGS 21680 and NECA decreased the action of cocaine at the doses which, given alone, decreased locomotor activity in animals. These results suggest the involvement of both adenosine receptors in the action of cocaine although agonists of A1 receptors seem to have stronger influence on it. The selective blockade of A2 adenosine receptor by DMPX (3,7-dimethyl-1-propargylxanthine) significantly enhanced cocaine-induced locomotor activity of animals. Caffeine had similar action but the effect was not significant. CPT (8-cyclopentyltheophylline)--A1 receptor antagonist, did not show any influence in this test. Similarly, all adenosine receptor agonists decreased amphetamine-induced DISEASE, but at the higher doses than those which were active in cocaine-induced DISEASE. The selective blockade of A2 adenosine receptors (DMPX) and non-selective blockade of adenosine receptors (caffeine) significantly increased the action of amphetamine in the locomotor activity test. Our results have shown that all adenosine receptor agonists (A1 and A2) reduce cocaine- and amphetamine-induced locomotor activity and indicate that cocaine-induced DISEASE is more influenced by adenosine receptor agonists (particularly A1 receptors) than amphetamine-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Cocaine-induced DISEASE is more influenced by adenosine receptor agonists than amphetamine-induced DISEASE. The influence of adenosine receptor agonists and antagonists on cocaine-and amphetamine-induced DISEASE was examined in mice. All adenosine receptor agonists significantly decreased the locomotor activity in mice, and the effects were dose-dependent. It seems that adenosine A1 and A2 receptors might be involved in this reaction. Moreover, all adenosine receptor agonists: 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680), A2A receptor agonist, N6-cyclopentyladenosine (CPA), A1 receptor agonist, and 5'-N-ethylcarboxamidoadenosine (NECA), A2/A1 receptor agonist significantly and dose-dependently decreased cocaine-induced locomotor activity. CPA reduced cocaine action at the doses which, given alone, did not influence motility, while CGS 21680 and NECA decreased the action of cocaine at the doses which, given alone, decreased locomotor activity in animals. These results suggest the involvement of both adenosine receptors in the action of cocaine although agonists of A1 receptors seem to have stronger influence on it. The selective blockade of A2 adenosine receptor by DMPX (3,7-dimethyl-1-propargylxanthine) significantly enhanced cocaine-induced locomotor activity of animals. Caffeine had similar action but the effect was not significant. CHEMICAL (CHEMICAL)--A1 receptor antagonist, did not show any influence in this test. Similarly, all adenosine receptor agonists decreased amphetamine-induced DISEASE, but at the higher doses than those which were active in cocaine-induced DISEASE. The selective blockade of A2 adenosine receptors (DMPX) and non-selective blockade of adenosine receptors (caffeine) significantly increased the action of amphetamine in the locomotor activity test. Our results have shown that all adenosine receptor agonists (A1 and A2) reduce cocaine- and amphetamine-induced locomotor activity and indicate that cocaine-induced DISEASE is more influenced by adenosine receptor agonists (particularly A1 receptors) than amphetamine-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL and the risk of DISEASE requiring permanent pacemaker in elderly patients with atrial fibrillation and prior myocardial infarction. OBJECTIVES: The aim of this study was to determine whether the use of CHEMICAL in patients with atrial fibrillation (AF) increases the risk of DISEASE requiring a permanent pacemaker. BACKGROUND: Reports of severe DISEASE during CHEMICAL therapy are infrequent and limited to studies assessing the therapy's use in the management of patients with ventricular arrhythmias. METHODS: A study cohort of 8,770 patients age > or =65 years with a new diagnosis of AF was identified from a provincewide database of Quebec residents with a myocardial infarction (MI) between 1991 and 1999. Using a nested case-control design, 477 cases of DISEASE requiring a permanent pacemaker were matched (1:4) to 1,908 controls. Multivariable logistic regression was used to estimate the odds ratio (OR) of pacemaker insertion associated with CHEMICAL use, controlling for baseline risk factors and exposure to sotalol, Class I antiarrhythmic agents, beta-blockers, calcium channel blockers, and digoxin. RESULTS: CHEMICAL use was associated with an increased risk of pacemaker insertion (OR: 2.14, 95% confidence interval [CI]: 1.30 to 3.54). This effect was modified by gender, with a greater risk in women versus men (OR: 3.86, 95% CI: 1.70 to 8.75 vs. OR: 1.52, 95% CI: 0.80 to 2.89). Digoxin was the only other medication associated with an increased risk of pacemaker insertion (OR: 1.78, 95% CI: 1.37 to 2.31). CONCLUSIONS: This study suggests that the use of CHEMICAL in elderly patients with AF and a previous MI increases the risk of DISEASE requiring a permanent pacemaker. The finding of an augmented risk of pacemaker insertion in elderly women receiving CHEMICAL requires further investigation. | CHEMICAL-INDUCED-DISEASE |
| Amiodarone and the risk of bradyarrhythmia requiring permanent pacemaker in elderly patients with DISEASE and prior myocardial infarction. OBJECTIVES: The aim of this study was to determine whether the use of amiodarone in patients with DISEASE (DISEASE) increases the risk of bradyarrhythmia requiring a permanent pacemaker. BACKGROUND: Reports of severe bradyarrhythmia during amiodarone therapy are infrequent and limited to studies assessing the therapy's use in the management of patients with ventricular arrhythmias. METHODS: A study cohort of 8,770 patients age > or =65 years with a new diagnosis of DISEASE was identified from a provincewide database of Quebec residents with a myocardial infarction (MI) between 1991 and 1999. Using a nested case-control design, 477 cases of bradyarrhythmia requiring a permanent pacemaker were matched (1:4) to 1,908 controls. Multivariable logistic regression was used to estimate the odds ratio (OR) of pacemaker insertion associated with amiodarone use, controlling for baseline risk factors and exposure to sotalol, Class I antiarrhythmic agents, beta-blockers, CHEMICAL channel blockers, and digoxin. RESULTS: amiodarone use was associated with an increased risk of pacemaker insertion (OR: 2.14, 95% confidence interval [CI]: 1.30 to 3.54). This effect was modified by gender, with a greater risk in women versus men (OR: 3.86, 95% CI: 1.70 to 8.75 vs. OR: 1.52, 95% CI: 0.80 to 2.89). Digoxin was the only other medication associated with an increased risk of pacemaker insertion (OR: 1.78, 95% CI: 1.37 to 2.31). CONCLUSIONS: This study suggests that the use of amiodarone in elderly patients with DISEASE and a previous MI increases the risk of bradyarrhythmia requiring a permanent pacemaker. The finding of an augmented risk of pacemaker insertion in elderly women receiving amiodarone requires further investigation. | NO-RELATIONSHIP |
| Amiodarone and the risk of bradyarrhythmia requiring permanent pacemaker in elderly patients with atrial fibrillation and prior myocardial infarction. OBJECTIVES: The aim of this study was to determine whether the use of amiodarone in patients with atrial fibrillation (AF) increases the risk of bradyarrhythmia requiring a permanent pacemaker. BACKGROUND: Reports of severe bradyarrhythmia during amiodarone therapy are infrequent and limited to studies assessing the therapy's use in the management of patients with DISEASE. METHODS: A study cohort of 8,770 patients age > or =65 years with a new diagnosis of AF was identified from a provincewide database of Quebec residents with a myocardial infarction (MI) between 1991 and 1999. Using a nested case-control design, 477 cases of bradyarrhythmia requiring a permanent pacemaker were matched (1:4) to 1,908 controls. Multivariable logistic regression was used to estimate the odds ratio (OR) of pacemaker insertion associated with amiodarone use, controlling for baseline risk factors and exposure to sotalol, Class I antiarrhythmic agents, beta-blockers, calcium channel blockers, and CHEMICAL. RESULTS: amiodarone use was associated with an increased risk of pacemaker insertion (OR: 2.14, 95% confidence interval [CI]: 1.30 to 3.54). This effect was modified by gender, with a greater risk in women versus men (OR: 3.86, 95% CI: 1.70 to 8.75 vs. OR: 1.52, 95% CI: 0.80 to 2.89). CHEMICAL was the only other medication associated with an increased risk of pacemaker insertion (OR: 1.78, 95% CI: 1.37 to 2.31). CONCLUSIONS: This study suggests that the use of amiodarone in elderly patients with AF and a previous MI increases the risk of bradyarrhythmia requiring a permanent pacemaker. The finding of an augmented risk of pacemaker insertion in elderly women receiving amiodarone requires further investigation. | NO-RELATIONSHIP |
| Amiodarone and the risk of bradyarrhythmia requiring permanent pacemaker in elderly patients with DISEASE and prior myocardial infarction. OBJECTIVES: The aim of this study was to determine whether the use of amiodarone in patients with DISEASE (DISEASE) increases the risk of bradyarrhythmia requiring a permanent pacemaker. BACKGROUND: Reports of severe bradyarrhythmia during amiodarone therapy are infrequent and limited to studies assessing the therapy's use in the management of patients with ventricular arrhythmias. METHODS: A study cohort of 8,770 patients age > or =65 years with a new diagnosis of DISEASE was identified from a provincewide database of Quebec residents with a myocardial infarction (MI) between 1991 and 1999. Using a nested case-control design, 477 cases of bradyarrhythmia requiring a permanent pacemaker were matched (1:4) to 1,908 controls. Multivariable logistic regression was used to estimate the odds ratio (OR) of pacemaker insertion associated with amiodarone use, controlling for baseline risk factors and exposure to CHEMICAL, Class I antiarrhythmic agents, beta-blockers, calcium channel blockers, and digoxin. RESULTS: amiodarone use was associated with an increased risk of pacemaker insertion (OR: 2.14, 95% confidence interval [CI]: 1.30 to 3.54). This effect was modified by gender, with a greater risk in women versus men (OR: 3.86, 95% CI: 1.70 to 8.75 vs. OR: 1.52, 95% CI: 0.80 to 2.89). Digoxin was the only other medication associated with an increased risk of pacemaker insertion (OR: 1.78, 95% CI: 1.37 to 2.31). CONCLUSIONS: This study suggests that the use of amiodarone in elderly patients with DISEASE and a previous MI increases the risk of bradyarrhythmia requiring a permanent pacemaker. The finding of an augmented risk of pacemaker insertion in elderly women receiving amiodarone requires further investigation. | NO-RELATIONSHIP |
| Amiodarone and the risk of bradyarrhythmia requiring permanent pacemaker in elderly patients with atrial fibrillation and prior myocardial infarction. OBJECTIVES: The aim of this study was to determine whether the use of amiodarone in patients with atrial fibrillation (AF) increases the risk of bradyarrhythmia requiring a permanent pacemaker. BACKGROUND: Reports of severe bradyarrhythmia during amiodarone therapy are infrequent and limited to studies assessing the therapy's use in the management of patients with DISEASE. METHODS: A study cohort of 8,770 patients age > or =65 years with a new diagnosis of AF was identified from a provincewide database of Quebec residents with a myocardial infarction (MI) between 1991 and 1999. Using a nested case-control design, 477 cases of bradyarrhythmia requiring a permanent pacemaker were matched (1:4) to 1,908 controls. Multivariable logistic regression was used to estimate the odds ratio (OR) of pacemaker insertion associated with amiodarone use, controlling for baseline risk factors and exposure to sotalol, Class I antiarrhythmic agents, beta-blockers, CHEMICAL channel blockers, and digoxin. RESULTS: amiodarone use was associated with an increased risk of pacemaker insertion (OR: 2.14, 95% confidence interval [CI]: 1.30 to 3.54). This effect was modified by gender, with a greater risk in women versus men (OR: 3.86, 95% CI: 1.70 to 8.75 vs. OR: 1.52, 95% CI: 0.80 to 2.89). Digoxin was the only other medication associated with an increased risk of pacemaker insertion (OR: 1.78, 95% CI: 1.37 to 2.31). CONCLUSIONS: This study suggests that the use of amiodarone in elderly patients with AF and a previous MI increases the risk of bradyarrhythmia requiring a permanent pacemaker. The finding of an augmented risk of pacemaker insertion in elderly women receiving amiodarone requires further investigation. | NO-RELATIONSHIP |
| Amiodarone and the risk of bradyarrhythmia requiring permanent pacemaker in elderly patients with DISEASE and prior myocardial infarction. OBJECTIVES: The aim of this study was to determine whether the use of amiodarone in patients with DISEASE (DISEASE) increases the risk of bradyarrhythmia requiring a permanent pacemaker. BACKGROUND: Reports of severe bradyarrhythmia during amiodarone therapy are infrequent and limited to studies assessing the therapy's use in the management of patients with ventricular arrhythmias. METHODS: A study cohort of 8,770 patients age > or =65 years with a new diagnosis of DISEASE was identified from a provincewide database of Quebec residents with a myocardial infarction (MI) between 1991 and 1999. Using a nested case-control design, 477 cases of bradyarrhythmia requiring a permanent pacemaker were matched (1:4) to 1,908 controls. Multivariable logistic regression was used to estimate the odds ratio (OR) of pacemaker insertion associated with amiodarone use, controlling for baseline risk factors and exposure to sotalol, Class I antiarrhythmic agents, beta-blockers, calcium channel blockers, and CHEMICAL. RESULTS: amiodarone use was associated with an increased risk of pacemaker insertion (OR: 2.14, 95% confidence interval [CI]: 1.30 to 3.54). This effect was modified by gender, with a greater risk in women versus men (OR: 3.86, 95% CI: 1.70 to 8.75 vs. OR: 1.52, 95% CI: 0.80 to 2.89). CHEMICAL was the only other medication associated with an increased risk of pacemaker insertion (OR: 1.78, 95% CI: 1.37 to 2.31). CONCLUSIONS: This study suggests that the use of amiodarone in elderly patients with DISEASE and a previous MI increases the risk of bradyarrhythmia requiring a permanent pacemaker. The finding of an augmented risk of pacemaker insertion in elderly women receiving amiodarone requires further investigation. | NO-RELATIONSHIP |
| Amiodarone and the risk of bradyarrhythmia requiring permanent pacemaker in elderly patients with atrial fibrillation and prior DISEASE. OBJECTIVES: The aim of this study was to determine whether the use of amiodarone in patients with atrial fibrillation (AF) increases the risk of bradyarrhythmia requiring a permanent pacemaker. BACKGROUND: Reports of severe bradyarrhythmia during amiodarone therapy are infrequent and limited to studies assessing the therapy's use in the management of patients with ventricular arrhythmias. METHODS: A study cohort of 8,770 patients age > or =65 years with a new diagnosis of AF was identified from a provincewide database of Quebec residents with a DISEASE (DISEASE) between 1991 and 1999. Using a nested case-control design, 477 cases of bradyarrhythmia requiring a permanent pacemaker were matched (1:4) to 1,908 controls. Multivariable logistic regression was used to estimate the odds ratio (OR) of pacemaker insertion associated with amiodarone use, controlling for baseline risk factors and exposure to sotalol, Class I antiarrhythmic agents, beta-blockers, CHEMICAL channel blockers, and digoxin. RESULTS: amiodarone use was associated with an increased risk of pacemaker insertion (OR: 2.14, 95% confidence interval [CI]: 1.30 to 3.54). This effect was modified by gender, with a greater risk in women versus men (OR: 3.86, 95% CI: 1.70 to 8.75 vs. OR: 1.52, 95% CI: 0.80 to 2.89). Digoxin was the only other medication associated with an increased risk of pacemaker insertion (OR: 1.78, 95% CI: 1.37 to 2.31). CONCLUSIONS: This study suggests that the use of amiodarone in elderly patients with AF and a previous DISEASE increases the risk of bradyarrhythmia requiring a permanent pacemaker. The finding of an augmented risk of pacemaker insertion in elderly women receiving amiodarone requires further investigation. | NO-RELATIONSHIP |
| Amiodarone and the risk of bradyarrhythmia requiring permanent pacemaker in elderly patients with atrial fibrillation and prior DISEASE. OBJECTIVES: The aim of this study was to determine whether the use of amiodarone in patients with atrial fibrillation (AF) increases the risk of bradyarrhythmia requiring a permanent pacemaker. BACKGROUND: Reports of severe bradyarrhythmia during amiodarone therapy are infrequent and limited to studies assessing the therapy's use in the management of patients with ventricular arrhythmias. METHODS: A study cohort of 8,770 patients age > or =65 years with a new diagnosis of AF was identified from a provincewide database of Quebec residents with a DISEASE (DISEASE) between 1991 and 1999. Using a nested case-control design, 477 cases of bradyarrhythmia requiring a permanent pacemaker were matched (1:4) to 1,908 controls. Multivariable logistic regression was used to estimate the odds ratio (OR) of pacemaker insertion associated with amiodarone use, controlling for baseline risk factors and exposure to sotalol, Class I antiarrhythmic agents, beta-blockers, calcium channel blockers, and CHEMICAL. RESULTS: amiodarone use was associated with an increased risk of pacemaker insertion (OR: 2.14, 95% confidence interval [CI]: 1.30 to 3.54). This effect was modified by gender, with a greater risk in women versus men (OR: 3.86, 95% CI: 1.70 to 8.75 vs. OR: 1.52, 95% CI: 0.80 to 2.89). CHEMICAL was the only other medication associated with an increased risk of pacemaker insertion (OR: 1.78, 95% CI: 1.37 to 2.31). CONCLUSIONS: This study suggests that the use of amiodarone in elderly patients with AF and a previous DISEASE increases the risk of bradyarrhythmia requiring a permanent pacemaker. The finding of an augmented risk of pacemaker insertion in elderly women receiving amiodarone requires further investigation. | NO-RELATIONSHIP |
| Amiodarone and the risk of bradyarrhythmia requiring permanent pacemaker in elderly patients with atrial fibrillation and prior DISEASE. OBJECTIVES: The aim of this study was to determine whether the use of amiodarone in patients with atrial fibrillation (AF) increases the risk of bradyarrhythmia requiring a permanent pacemaker. BACKGROUND: Reports of severe bradyarrhythmia during amiodarone therapy are infrequent and limited to studies assessing the therapy's use in the management of patients with ventricular arrhythmias. METHODS: A study cohort of 8,770 patients age > or =65 years with a new diagnosis of AF was identified from a provincewide database of Quebec residents with a DISEASE (DISEASE) between 1991 and 1999. Using a nested case-control design, 477 cases of bradyarrhythmia requiring a permanent pacemaker were matched (1:4) to 1,908 controls. Multivariable logistic regression was used to estimate the odds ratio (OR) of pacemaker insertion associated with amiodarone use, controlling for baseline risk factors and exposure to CHEMICAL, Class I antiarrhythmic agents, beta-blockers, calcium channel blockers, and digoxin. RESULTS: amiodarone use was associated with an increased risk of pacemaker insertion (OR: 2.14, 95% confidence interval [CI]: 1.30 to 3.54). This effect was modified by gender, with a greater risk in women versus men (OR: 3.86, 95% CI: 1.70 to 8.75 vs. OR: 1.52, 95% CI: 0.80 to 2.89). Digoxin was the only other medication associated with an increased risk of pacemaker insertion (OR: 1.78, 95% CI: 1.37 to 2.31). CONCLUSIONS: This study suggests that the use of amiodarone in elderly patients with AF and a previous DISEASE increases the risk of bradyarrhythmia requiring a permanent pacemaker. The finding of an augmented risk of pacemaker insertion in elderly women receiving amiodarone requires further investigation. | NO-RELATIONSHIP |
| Amiodarone and the risk of bradyarrhythmia requiring permanent pacemaker in elderly patients with atrial fibrillation and prior myocardial infarction. OBJECTIVES: The aim of this study was to determine whether the use of amiodarone in patients with atrial fibrillation (AF) increases the risk of bradyarrhythmia requiring a permanent pacemaker. BACKGROUND: Reports of severe bradyarrhythmia during amiodarone therapy are infrequent and limited to studies assessing the therapy's use in the management of patients with DISEASE. METHODS: A study cohort of 8,770 patients age > or =65 years with a new diagnosis of AF was identified from a provincewide database of Quebec residents with a myocardial infarction (MI) between 1991 and 1999. Using a nested case-control design, 477 cases of bradyarrhythmia requiring a permanent pacemaker were matched (1:4) to 1,908 controls. Multivariable logistic regression was used to estimate the odds ratio (OR) of pacemaker insertion associated with amiodarone use, controlling for baseline risk factors and exposure to CHEMICAL, Class I antiarrhythmic agents, beta-blockers, calcium channel blockers, and digoxin. RESULTS: amiodarone use was associated with an increased risk of pacemaker insertion (OR: 2.14, 95% confidence interval [CI]: 1.30 to 3.54). This effect was modified by gender, with a greater risk in women versus men (OR: 3.86, 95% CI: 1.70 to 8.75 vs. OR: 1.52, 95% CI: 0.80 to 2.89). Digoxin was the only other medication associated with an increased risk of pacemaker insertion (OR: 1.78, 95% CI: 1.37 to 2.31). CONCLUSIONS: This study suggests that the use of amiodarone in elderly patients with AF and a previous MI increases the risk of bradyarrhythmia requiring a permanent pacemaker. The finding of an augmented risk of pacemaker insertion in elderly women receiving amiodarone requires further investigation. | NO-RELATIONSHIP |
| CHEMICAL-induced morphologic changes in the rat urinary bladder epithelium. OBJECTIVES: To evaluate the morphologic changes in rat urothelium induced by CHEMICAL. Nonsteroidal anti-inflammatory drug-induced cystitis is a poorly recognized and under-reported condition. In addition to tiaprofenic acid, CHEMICAL has been reported to be associated with this condition. METHODS: Three groups were established: a control group (n = 10), a high-dose group (n = 10), treated with one intraperitoneal injection of CHEMICAL 20 mg/kg, and a therapeutic dose group (n = 10) in which oral CHEMICAL was administered 3.25 mg/kg body weight daily for 3 weeks. The animals were then killed and the bladders removed for light and electron microscopic studies. RESULTS: The light microscopic findings showed some focal epithelial degeneration that was more prominent in the high-dose group. When compared with the control group, both CHEMICAL groups revealed statistically increased numbers of mast cells in the mucosa (P <0.0001) and penetration of lanthanum nitrate through intercellular areas of the epithelium. Furthermore, the difference in mast cell counts between the high and therapeutic dose groups was also statistically significant (P <0.0001). CONCLUSIONS: CHEMICAL resulted in histopathologic findings typical of interstitial cystitis, such as leaky bladder epithelium and mucosal DISEASE. The true incidence of nonsteroidal anti-inflammatory drug-induced cystitis in humans must be clarified by prospective clinical trials. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced morphologic changes in the rat urinary bladder epithelium. OBJECTIVES: To evaluate the morphologic changes in rat urothelium induced by CHEMICAL. Nonsteroidal anti-inflammatory drug-induced cystitis is a poorly recognized and under-reported condition. In addition to tiaprofenic acid, CHEMICAL has been reported to be associated with this condition. METHODS: Three groups were established: a control group (n = 10), a high-dose group (n = 10), treated with one intraperitoneal injection of CHEMICAL 20 mg/kg, and a therapeutic dose group (n = 10) in which oral CHEMICAL was administered 3.25 mg/kg body weight daily for 3 weeks. The animals were then killed and the bladders removed for light and electron microscopic studies. RESULTS: The light microscopic findings showed some focal epithelial degeneration that was more prominent in the high-dose group. When compared with the control group, both CHEMICAL groups revealed statistically increased numbers of mast cells in the mucosa (P <0.0001) and penetration of lanthanum nitrate through intercellular areas of the epithelium. Furthermore, the difference in mast cell counts between the high and therapeutic dose groups was also statistically significant (P <0.0001). CONCLUSIONS: CHEMICAL resulted in histopathologic findings typical of DISEASE, such as leaky bladder epithelium and mucosal mastocytosis. The true incidence of nonsteroidal anti-inflammatory drug-induced cystitis in humans must be clarified by prospective clinical trials. | CHEMICAL-INDUCED-DISEASE |
| Indomethacin-induced morphologic changes in the rat urinary bladder epithelium. OBJECTIVES: To evaluate the morphologic changes in rat urothelium induced by indomethacin. Nonsteroidal anti-inflammatory drug-induced DISEASE is a poorly recognized and under-reported condition. In addition to tiaprofenic acid, indomethacin has been reported to be associated with this condition. METHODS: Three groups were established: a control group (n = 10), a high-dose group (n = 10), treated with one intraperitoneal injection of indomethacin 20 mg/kg, and a therapeutic dose group (n = 10) in which oral indomethacin was administered 3.25 mg/kg body weight daily for 3 weeks. The animals were then killed and the bladders removed for light and electron microscopic studies. RESULTS: The light microscopic findings showed some focal epithelial degeneration that was more prominent in the high-dose group. When compared with the control group, both indomethacin groups revealed statistically increased numbers of mast cells in the mucosa (P <0.0001) and penetration of CHEMICAL through intercellular areas of the epithelium. Furthermore, the difference in mast cell counts between the high and therapeutic dose groups was also statistically significant (P <0.0001). CONCLUSIONS: Indomethacin resulted in histopathologic findings typical of interstitial cystitis, such as leaky bladder epithelium and mucosal mastocytosis. The true incidence of nonsteroidal anti-inflammatory drug-induced DISEASE in humans must be clarified by prospective clinical trials. | NO-RELATIONSHIP |
| Indomethacin-induced morphologic changes in the rat urinary bladder epithelium. OBJECTIVES: To evaluate the morphologic changes in rat urothelium induced by indomethacin. Nonsteroidal anti-inflammatory drug-induced DISEASE is a poorly recognized and under-reported condition. In addition to CHEMICAL, indomethacin has been reported to be associated with this condition. METHODS: Three groups were established: a control group (n = 10), a high-dose group (n = 10), treated with one intraperitoneal injection of indomethacin 20 mg/kg, and a therapeutic dose group (n = 10) in which oral indomethacin was administered 3.25 mg/kg body weight daily for 3 weeks. The animals were then killed and the bladders removed for light and electron microscopic studies. RESULTS: The light microscopic findings showed some focal epithelial degeneration that was more prominent in the high-dose group. When compared with the control group, both indomethacin groups revealed statistically increased numbers of mast cells in the mucosa (P <0.0001) and penetration of lanthanum nitrate through intercellular areas of the epithelium. Furthermore, the difference in mast cell counts between the high and therapeutic dose groups was also statistically significant (P <0.0001). CONCLUSIONS: Indomethacin resulted in histopathologic findings typical of interstitial cystitis, such as leaky bladder epithelium and mucosal mastocytosis. The true incidence of nonsteroidal anti-inflammatory drug-induced DISEASE in humans must be clarified by prospective clinical trials. | NO-RELATIONSHIP |
| An open-label phase II study of low-dose CHEMICAL in androgen-independent prostate cancer. The antiangiogenic effects of CHEMICAL have been assessed in clinical trials in patients with various solid and haematological malignancies. CHEMICAL blocks the activity of angiogenic agents including bFGF, VEGF and IL-6. We undertook an open-label study using CHEMICAL 100 mg once daily for up to 6 months in 20 men with androgen-independent prostate cancer. The mean time of study was 109 days (median 107, range 4-184 days). Patients underwent regular measurement of prostate-specific antigen (PSA), urea and electrolytes, serum bFGF and VEGF. Three men (15%) showed a decline in serum PSA of at least 50%, sustained throughout treatment. Of 16 men treated for at least 2 months, six (37.5%) showed a fall in absolute PSA by a median of 48%. Increasing levels of serum bFGF and VEGF were associated with progressive disease; five of six men who demonstrated a fall in PSA also showed a decline in bFGF and VEGF levels, and three of four men with a rising PSA showed an increase in both growth factors. Adverse effects included constipation, morning drowsiness, DISEASE and rash, and resulted in withdrawal from the study by three men. Evidence of peripheral sensory neuropathy was found in nine of 13 men before treatment. In the seven men who completed six months on CHEMICAL, subclinical evidence of peripheral neuropathy was found in four before treatment, but in all seven at repeat testing. The findings indicate that CHEMICAL may be an option for patients who have failed other forms of therapy, provided close follow-up is maintained for development of peripheral neuropathy. | CHEMICAL-INDUCED-DISEASE |
| An open-label phase II study of low-dose CHEMICAL in androgen-independent prostate cancer. The antiangiogenic effects of CHEMICAL have been assessed in clinical trials in patients with various solid and haematological malignancies. CHEMICAL blocks the activity of angiogenic agents including bFGF, VEGF and IL-6. We undertook an open-label study using CHEMICAL 100 mg once daily for up to 6 months in 20 men with androgen-independent prostate cancer. The mean time of study was 109 days (median 107, range 4-184 days). Patients underwent regular measurement of prostate-specific antigen (PSA), urea and electrolytes, serum bFGF and VEGF. Three men (15%) showed a decline in serum PSA of at least 50%, sustained throughout treatment. Of 16 men treated for at least 2 months, six (37.5%) showed a fall in absolute PSA by a median of 48%. Increasing levels of serum bFGF and VEGF were associated with progressive disease; five of six men who demonstrated a fall in PSA also showed a decline in bFGF and VEGF levels, and three of four men with a rising PSA showed an increase in both growth factors. Adverse effects included DISEASE, morning drowsiness, dizziness and rash, and resulted in withdrawal from the study by three men. Evidence of peripheral sensory neuropathy was found in nine of 13 men before treatment. In the seven men who completed six months on CHEMICAL, subclinical evidence of peripheral neuropathy was found in four before treatment, but in all seven at repeat testing. The findings indicate that CHEMICAL may be an option for patients who have failed other forms of therapy, provided close follow-up is maintained for development of peripheral neuropathy. | CHEMICAL-INDUCED-DISEASE |
| An open-label phase II study of low-dose CHEMICAL in androgen-independent prostate cancer. The antiangiogenic effects of CHEMICAL have been assessed in clinical trials in patients with various solid and haematological malignancies. CHEMICAL blocks the activity of angiogenic agents including bFGF, VEGF and IL-6. We undertook an open-label study using CHEMICAL 100 mg once daily for up to 6 months in 20 men with androgen-independent prostate cancer. The mean time of study was 109 days (median 107, range 4-184 days). Patients underwent regular measurement of prostate-specific antigen (PSA), urea and electrolytes, serum bFGF and VEGF. Three men (15%) showed a decline in serum PSA of at least 50%, sustained throughout treatment. Of 16 men treated for at least 2 months, six (37.5%) showed a fall in absolute PSA by a median of 48%. Increasing levels of serum bFGF and VEGF were associated with progressive disease; five of six men who demonstrated a fall in PSA also showed a decline in bFGF and VEGF levels, and three of four men with a rising PSA showed an increase in both growth factors. Adverse effects included constipation, morning drowsiness, dizziness and DISEASE, and resulted in withdrawal from the study by three men. Evidence of peripheral sensory neuropathy was found in nine of 13 men before treatment. In the seven men who completed six months on CHEMICAL, subclinical evidence of peripheral neuropathy was found in four before treatment, but in all seven at repeat testing. The findings indicate that CHEMICAL may be an option for patients who have failed other forms of therapy, provided close follow-up is maintained for development of peripheral neuropathy. | CHEMICAL-INDUCED-DISEASE |
| An open-label phase II study of low-dose CHEMICAL in androgen-independent prostate cancer. The antiangiogenic effects of CHEMICAL have been assessed in clinical trials in patients with various solid and haematological malignancies. CHEMICAL blocks the activity of angiogenic agents including bFGF, VEGF and IL-6. We undertook an open-label study using CHEMICAL 100 mg once daily for up to 6 months in 20 men with androgen-independent prostate cancer. The mean time of study was 109 days (median 107, range 4-184 days). Patients underwent regular measurement of prostate-specific antigen (PSA), urea and electrolytes, serum bFGF and VEGF. Three men (15%) showed a decline in serum PSA of at least 50%, sustained throughout treatment. Of 16 men treated for at least 2 months, six (37.5%) showed a fall in absolute PSA by a median of 48%. Increasing levels of serum bFGF and VEGF were associated with progressive disease; five of six men who demonstrated a fall in PSA also showed a decline in bFGF and VEGF levels, and three of four men with a rising PSA showed an increase in both growth factors. Adverse effects included constipation, morning DISEASE, dizziness and rash, and resulted in withdrawal from the study by three men. Evidence of peripheral sensory neuropathy was found in nine of 13 men before treatment. In the seven men who completed six months on CHEMICAL, subclinical evidence of peripheral neuropathy was found in four before treatment, but in all seven at repeat testing. The findings indicate that CHEMICAL may be an option for patients who have failed other forms of therapy, provided close follow-up is maintained for development of peripheral neuropathy. | CHEMICAL-INDUCED-DISEASE |
| An open-label phase II study of low-dose CHEMICAL in androgen-independent prostate cancer. The antiangiogenic effects of CHEMICAL have been assessed in clinical trials in patients with various solid and haematological malignancies. CHEMICAL blocks the activity of angiogenic agents including bFGF, VEGF and IL-6. We undertook an open-label study using CHEMICAL 100 mg once daily for up to 6 months in 20 men with androgen-independent prostate cancer. The mean time of study was 109 days (median 107, range 4-184 days). Patients underwent regular measurement of prostate-specific antigen (PSA), urea and electrolytes, serum bFGF and VEGF. Three men (15%) showed a decline in serum PSA of at least 50%, sustained throughout treatment. Of 16 men treated for at least 2 months, six (37.5%) showed a fall in absolute PSA by a median of 48%. Increasing levels of serum bFGF and VEGF were associated with progressive disease; five of six men who demonstrated a fall in PSA also showed a decline in bFGF and VEGF levels, and three of four men with a rising PSA showed an increase in both growth factors. Adverse effects included constipation, morning drowsiness, dizziness and rash, and resulted in withdrawal from the study by three men. Evidence of DISEASE was found in nine of 13 men before treatment. In the seven men who completed six months on CHEMICAL, subclinical evidence of DISEASE was found in four before treatment, but in all seven at repeat testing. The findings indicate that CHEMICAL may be an option for patients who have failed other forms of therapy, provided close follow-up is maintained for development of DISEASE. | CHEMICAL-INDUCED-DISEASE |
| An open-label phase II study of low-dose thalidomide in CHEMICAL-independent prostate cancer. The antiangiogenic effects of thalidomide have been assessed in clinical trials in patients with various solid and DISEASE. Thalidomide blocks the activity of angiogenic agents including bFGF, VEGF and IL-6. We undertook an open-label study using thalidomide 100 mg once daily for up to 6 months in 20 men with CHEMICAL-independent prostate cancer. The mean time of study was 109 days (median 107, range 4-184 days). Patients underwent regular measurement of prostate-specific antigen (PSA), urea and electrolytes, serum bFGF and VEGF. Three men (15%) showed a decline in serum PSA of at least 50%, sustained throughout treatment. Of 16 men treated for at least 2 months, six (37.5%) showed a fall in absolute PSA by a median of 48%. Increasing levels of serum bFGF and VEGF were associated with progressive disease; five of six men who demonstrated a fall in PSA also showed a decline in bFGF and VEGF levels, and three of four men with a rising PSA showed an increase in both growth factors. Adverse effects included constipation, morning drowsiness, dizziness and rash, and resulted in withdrawal from the study by three men. Evidence of peripheral sensory neuropathy was found in nine of 13 men before treatment. In the seven men who completed six months on thalidomide, subclinical evidence of peripheral neuropathy was found in four before treatment, but in all seven at repeat testing. The findings indicate that thalidomide may be an option for patients who have failed other forms of therapy, provided close follow-up is maintained for development of peripheral neuropathy. | NO-RELATIONSHIP |
| An open-label phase II study of low-dose thalidomide in CHEMICAL-independent DISEASE. The antiangiogenic effects of thalidomide have been assessed in clinical trials in patients with various solid and haematological malignancies. Thalidomide blocks the activity of angiogenic agents including bFGF, VEGF and IL-6. We undertook an open-label study using thalidomide 100 mg once daily for up to 6 months in 20 men with CHEMICAL-independent DISEASE. The mean time of study was 109 days (median 107, range 4-184 days). Patients underwent regular measurement of prostate-specific antigen (PSA), urea and electrolytes, serum bFGF and VEGF. Three men (15%) showed a decline in serum PSA of at least 50%, sustained throughout treatment. Of 16 men treated for at least 2 months, six (37.5%) showed a fall in absolute PSA by a median of 48%. Increasing levels of serum bFGF and VEGF were associated with progressive disease; five of six men who demonstrated a fall in PSA also showed a decline in bFGF and VEGF levels, and three of four men with a rising PSA showed an increase in both growth factors. Adverse effects included constipation, morning drowsiness, dizziness and rash, and resulted in withdrawal from the study by three men. Evidence of peripheral sensory neuropathy was found in nine of 13 men before treatment. In the seven men who completed six months on thalidomide, subclinical evidence of peripheral neuropathy was found in four before treatment, but in all seven at repeat testing. The findings indicate that thalidomide may be an option for patients who have failed other forms of therapy, provided close follow-up is maintained for development of peripheral neuropathy. | NO-RELATIONSHIP |
| An open-label phase II study of low-dose thalidomide in androgen-independent DISEASE. The antiangiogenic effects of thalidomide have been assessed in clinical trials in patients with various solid and haematological malignancies. Thalidomide blocks the activity of angiogenic agents including bFGF, VEGF and IL-6. We undertook an open-label study using thalidomide 100 mg once daily for up to 6 months in 20 men with androgen-independent DISEASE. The mean time of study was 109 days (median 107, range 4-184 days). Patients underwent regular measurement of prostate-specific antigen (PSA), CHEMICAL and electrolytes, serum bFGF and VEGF. Three men (15%) showed a decline in serum PSA of at least 50%, sustained throughout treatment. Of 16 men treated for at least 2 months, six (37.5%) showed a fall in absolute PSA by a median of 48%. Increasing levels of serum bFGF and VEGF were associated with progressive disease; five of six men who demonstrated a fall in PSA also showed a decline in bFGF and VEGF levels, and three of four men with a rising PSA showed an increase in both growth factors. Adverse effects included constipation, morning drowsiness, dizziness and rash, and resulted in withdrawal from the study by three men. Evidence of peripheral sensory neuropathy was found in nine of 13 men before treatment. In the seven men who completed six months on thalidomide, subclinical evidence of peripheral neuropathy was found in four before treatment, but in all seven at repeat testing. The findings indicate that thalidomide may be an option for patients who have failed other forms of therapy, provided close follow-up is maintained for development of peripheral neuropathy. | NO-RELATIONSHIP |
| An open-label phase II study of low-dose thalidomide in androgen-independent prostate cancer. The antiangiogenic effects of thalidomide have been assessed in clinical trials in patients with various solid and DISEASE. Thalidomide blocks the activity of angiogenic agents including bFGF, VEGF and IL-6. We undertook an open-label study using thalidomide 100 mg once daily for up to 6 months in 20 men with androgen-independent prostate cancer. The mean time of study was 109 days (median 107, range 4-184 days). Patients underwent regular measurement of prostate-specific antigen (PSA), CHEMICAL and electrolytes, serum bFGF and VEGF. Three men (15%) showed a decline in serum PSA of at least 50%, sustained throughout treatment. Of 16 men treated for at least 2 months, six (37.5%) showed a fall in absolute PSA by a median of 48%. Increasing levels of serum bFGF and VEGF were associated with progressive disease; five of six men who demonstrated a fall in PSA also showed a decline in bFGF and VEGF levels, and three of four men with a rising PSA showed an increase in both growth factors. Adverse effects included constipation, morning drowsiness, dizziness and rash, and resulted in withdrawal from the study by three men. Evidence of peripheral sensory neuropathy was found in nine of 13 men before treatment. In the seven men who completed six months on thalidomide, subclinical evidence of peripheral neuropathy was found in four before treatment, but in all seven at repeat testing. The findings indicate that thalidomide may be an option for patients who have failed other forms of therapy, provided close follow-up is maintained for development of peripheral neuropathy. | NO-RELATIONSHIP |
| Central nervous system toxicity following the administration of CHEMICAL for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. CHEMICAL, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of DISEASE following accidental intravascular injection of CHEMICAL. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of CHEMICAL 0.5% with epinephrine 2.5 microgram/mL, the patients developed DISEASE, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The seizures were successfully treated with sodium thiopental in addition to succinylcholine in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of CHEMICAL with epinephrine. CONCLUSIONS: Although CHEMICAL may have a safer cardiac toxicity profile than racemic bupivacaine, if adequate amounts of CHEMICAL reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of cardiac toxicity in these 2 patients. | CHEMICAL-INDUCED-DISEASE |
| DISEASE following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of CHEMICAL, was developed to improve the cardiac safety profile of CHEMICAL. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with epinephrine 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The seizures were successfully treated with sodium thiopental in addition to succinylcholine in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine. CONCLUSIONS: Although levobupivacaine may have a safer cardiac toxicity profile than racemic CHEMICAL, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in DISEASE did not produce manifestations of cardiac toxicity in these 2 patients. | NO-RELATIONSHIP |
| Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with epinephrine 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The DISEASE were successfully treated with CHEMICAL in addition to succinylcholine in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine. CONCLUSIONS: Although levobupivacaine may have a safer cardiac toxicity profile than racemic bupivacaine, if adequate amounts of levobupivacaine reach the circulation, it will result in DISEASE. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of cardiac toxicity in these 2 patients. | NO-RELATIONSHIP |
| DISEASE following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with CHEMICAL 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous CHEMICAL administration. The seizures were successfully treated with sodium thiopental in addition to succinylcholine in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with CHEMICAL. CONCLUSIONS: Although levobupivacaine may have a safer cardiac toxicity profile than racemic bupivacaine, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in DISEASE did not produce manifestations of cardiac toxicity in these 2 patients. | NO-RELATIONSHIP |
| Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with epinephrine 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The seizures were successfully treated with sodium thiopental in addition to CHEMICAL in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine. CONCLUSIONS: Although levobupivacaine may have a safer DISEASE profile than racemic bupivacaine, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of DISEASE in these 2 patients. | NO-RELATIONSHIP |
| Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with CHEMICAL 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous CHEMICAL administration. The DISEASE were successfully treated with sodium thiopental in addition to succinylcholine in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with CHEMICAL. CONCLUSIONS: Although levobupivacaine may have a safer cardiac toxicity profile than racemic bupivacaine, if adequate amounts of levobupivacaine reach the circulation, it will result in DISEASE. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of cardiac toxicity in these 2 patients. | NO-RELATIONSHIP |
| DISEASE following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with epinephrine 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The seizures were successfully treated with CHEMICAL in addition to succinylcholine in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine. CONCLUSIONS: Although levobupivacaine may have a safer cardiac toxicity profile than racemic bupivacaine, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in DISEASE did not produce manifestations of cardiac toxicity in these 2 patients. | NO-RELATIONSHIP |
| Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with epinephrine 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The seizures were successfully treated with sodium thiopental in addition to CHEMICAL in 1 patient. Neither patient developed signs of DISEASE. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine. CONCLUSIONS: Although levobupivacaine may have a safer cardiac toxicity profile than racemic bupivacaine, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of cardiac toxicity in these 2 patients. | NO-RELATIONSHIP |
| Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: DISEASE following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with epinephrine 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The seizures were successfully treated with CHEMICAL in addition to succinylcholine in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine. CONCLUSIONS: Although levobupivacaine may have a safer cardiac toxicity profile than racemic bupivacaine, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of cardiac toxicity in these 2 patients. | NO-RELATIONSHIP |
| Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with CHEMICAL 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous CHEMICAL administration. The seizures were successfully treated with sodium thiopental in addition to succinylcholine in 1 patient. Neither patient developed signs of DISEASE. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with CHEMICAL. CONCLUSIONS: Although levobupivacaine may have a safer cardiac toxicity profile than racemic bupivacaine, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of cardiac toxicity in these 2 patients. | NO-RELATIONSHIP |
| Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with CHEMICAL 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous CHEMICAL administration. The seizures were successfully treated with sodium thiopental in addition to succinylcholine in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with CHEMICAL. CONCLUSIONS: Although levobupivacaine may have a safer DISEASE profile than racemic bupivacaine, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of DISEASE in these 2 patients. | NO-RELATIONSHIP |
| Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: DISEASE following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of CHEMICAL, was developed to improve the cardiac safety profile of CHEMICAL. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with epinephrine 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The seizures were successfully treated with sodium thiopental in addition to succinylcholine in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine. CONCLUSIONS: Although levobupivacaine may have a safer cardiac toxicity profile than racemic CHEMICAL, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of cardiac toxicity in these 2 patients. | NO-RELATIONSHIP |
| Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of CHEMICAL, was developed to improve the cardiac safety profile of CHEMICAL. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with epinephrine 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The DISEASE were successfully treated with sodium thiopental in addition to succinylcholine in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine. CONCLUSIONS: Although levobupivacaine may have a safer cardiac toxicity profile than racemic CHEMICAL, if adequate amounts of levobupivacaine reach the circulation, it will result in DISEASE. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of cardiac toxicity in these 2 patients. | NO-RELATIONSHIP |
| Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of CHEMICAL, was developed to improve the cardiac safety profile of CHEMICAL. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with epinephrine 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The seizures were successfully treated with sodium thiopental in addition to succinylcholine in 1 patient. Neither patient developed signs of DISEASE. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine. CONCLUSIONS: Although levobupivacaine may have a safer cardiac toxicity profile than racemic CHEMICAL, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of cardiac toxicity in these 2 patients. | NO-RELATIONSHIP |
| Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: DISEASE following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with CHEMICAL 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous CHEMICAL administration. The seizures were successfully treated with sodium thiopental in addition to succinylcholine in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with CHEMICAL. CONCLUSIONS: Although levobupivacaine may have a safer cardiac toxicity profile than racemic bupivacaine, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of cardiac toxicity in these 2 patients. | NO-RELATIONSHIP |
| Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with epinephrine 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The seizures were successfully treated with CHEMICAL in addition to succinylcholine in 1 patient. Neither patient developed signs of DISEASE. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine. CONCLUSIONS: Although levobupivacaine may have a safer cardiac toxicity profile than racemic bupivacaine, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of cardiac toxicity in these 2 patients. | NO-RELATIONSHIP |
| Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: DISEASE following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with epinephrine 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The seizures were successfully treated with sodium thiopental in addition to CHEMICAL in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine. CONCLUSIONS: Although levobupivacaine may have a safer cardiac toxicity profile than racemic bupivacaine, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of cardiac toxicity in these 2 patients. | NO-RELATIONSHIP |
| DISEASE following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with epinephrine 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The seizures were successfully treated with sodium thiopental in addition to CHEMICAL in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine. CONCLUSIONS: Although levobupivacaine may have a safer cardiac toxicity profile than racemic bupivacaine, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in DISEASE did not produce manifestations of cardiac toxicity in these 2 patients. | NO-RELATIONSHIP |
| Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with epinephrine 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The DISEASE were successfully treated with sodium thiopental in addition to CHEMICAL in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine. CONCLUSIONS: Although levobupivacaine may have a safer cardiac toxicity profile than racemic bupivacaine, if adequate amounts of levobupivacaine reach the circulation, it will result in DISEASE. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of cardiac toxicity in these 2 patients. | NO-RELATIONSHIP |
| Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of bupivacaine, was developed to improve the cardiac safety profile of bupivacaine. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with epinephrine 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The seizures were successfully treated with CHEMICAL in addition to succinylcholine in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine. CONCLUSIONS: Although levobupivacaine may have a safer DISEASE profile than racemic bupivacaine, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of DISEASE in these 2 patients. | NO-RELATIONSHIP |
| Central nervous system toxicity following the administration of levobupivacaine for lumbar plexus block: A report of two cases. BACKGROUND AND OBJECTIVES: Central nervous system and cardiac toxicity following the administration of local anesthetics is a recognized complication of regional anesthesia. Levobupivacaine, the pure S(-) enantiomer of CHEMICAL, was developed to improve the cardiac safety profile of CHEMICAL. We describe 2 cases of grand mal seizures following accidental intravascular injection of levobupivacaine. CASE REPORT: Two patients presenting for elective orthopedic surgery of the lower limb underwent blockade of the lumbar plexus via the posterior approach. Immediately after the administration of levobupivacaine 0.5% with epinephrine 2.5 microgram/mL, the patients developed grand mal seizures, despite negative aspiration for blood and no clinical signs of intravenous epinephrine administration. The seizures were successfully treated with sodium thiopental in addition to succinylcholine in 1 patient. Neither patient developed signs of cardiovascular toxicity. Both patients were treated preoperatively with beta-adrenergic antagonist medications, which may have masked the cardiovascular signs of the unintentional intravascular administration of levobupivacaine with epinephrine. CONCLUSIONS: Although levobupivacaine may have a safer DISEASE profile than racemic CHEMICAL, if adequate amounts of levobupivacaine reach the circulation, it will result in convulsions. Plasma concentrations sufficient to result in central nervous system toxicity did not produce manifestations of DISEASE in these 2 patients. | NO-RELATIONSHIP |
| Anaesthetic complications associated with myotonia congenita: case study and comparison with other myotonic disorders. Myotonia congenita (MC) is caused by a defect in the skeletal muscle chloride channel function, which may cause sustained membrane depolarisation. We describe a previously healthy 32-year-old woman who developed a life-threatening DISEASE and secondary ventilation difficulties following a preoperative injection of CHEMICAL. The DISEASE disappeared spontaneously and the surgery proceeded without further problems. When subsequently questioned, she reported minor symptoms suggesting a myotonic condition. Myotonia was found on clinical examination and EMG. The diagnosis MC was confirmed genetically. Neither the patient nor the anaesthetist were aware of the diagnosis before this potentially lethal complication occurred. We give a brief overview of ion channel disorders including malignant hyperthermia and their anaesthetic considerations. | CHEMICAL-INDUCED-DISEASE |
| Anaesthetic complications associated with myotonia congenita: case study and comparison with other DISEASE. Myotonia congenita (MC) is caused by a defect in the skeletal muscle CHEMICAL channel function, which may cause sustained membrane depolarisation. We describe a previously healthy 32-year-old woman who developed a life-threatening muscle spasm and secondary ventilation difficulties following a preoperative injection of suxamethonium. The muscle spasms disappeared spontaneously and the surgery proceeded without further problems. When subsequently questioned, she reported minor symptoms suggesting a DISEASE. Myotonia was found on clinical examination and EMG. The diagnosis MC was confirmed genetically. Neither the patient nor the anaesthetist were aware of the diagnosis before this potentially lethal complication occurred. We give a brief overview of ion channel disorders including malignant hyperthermia and their anaesthetic considerations. | NO-RELATIONSHIP |
| Anaesthetic complications associated with myotonia congenita: case study and comparison with other myotonic disorders. Myotonia congenita (MC) is caused by a defect in the skeletal muscle CHEMICAL channel function, which may cause DISEASE. We describe a previously healthy 32-year-old woman who developed a life-threatening muscle spasm and secondary ventilation difficulties following a preoperative injection of suxamethonium. The muscle spasms disappeared spontaneously and the surgery proceeded without further problems. When subsequently questioned, she reported minor symptoms suggesting a myotonic condition. Myotonia was found on clinical examination and EMG. The diagnosis MC was confirmed genetically. Neither the patient nor the anaesthetist were aware of the diagnosis before this potentially lethal complication occurred. We give a brief overview of DISEASE including malignant hyperthermia and their anaesthetic considerations. | NO-RELATIONSHIP |
| Anaesthetic complications associated with myotonia congenita: case study and comparison with other myotonic disorders. Myotonia congenita (MC) is caused by a defect in the skeletal muscle CHEMICAL channel function, which may cause sustained membrane depolarisation. We describe a previously healthy 32-year-old woman who developed a life-threatening muscle spasm and secondary ventilation difficulties following a preoperative injection of suxamethonium. The muscle spasms disappeared spontaneously and the surgery proceeded without further problems. When subsequently questioned, she reported minor symptoms suggesting a myotonic condition. Myotonia was found on clinical examination and EMG. The diagnosis MC was confirmed genetically. Neither the patient nor the anaesthetist were aware of the diagnosis before this potentially lethal complication occurred. We give a brief overview of ion channel disorders including DISEASE and their anaesthetic considerations. | NO-RELATIONSHIP |
| Anaesthetic complications associated with myotonia congenita: case study and comparison with other myotonic disorders. Myotonia congenita (MC) is caused by a defect in the skeletal muscle CHEMICAL channel function, which may cause sustained membrane depolarisation. We describe a previously healthy 32-year-old woman who developed a life-threatening muscle spasm and secondary ventilation difficulties following a preoperative injection of suxamethonium. The muscle spasms disappeared spontaneously and the surgery proceeded without further problems. When subsequently questioned, she reported minor symptoms suggesting a myotonic condition. DISEASE was found on clinical examination and EMG. The diagnosis MC was confirmed genetically. Neither the patient nor the anaesthetist were aware of the diagnosis before this potentially lethal complication occurred. We give a brief overview of ion channel disorders including malignant hyperthermia and their anaesthetic considerations. | NO-RELATIONSHIP |
| Anaesthetic complications associated with DISEASE: case study and comparison with other myotonic disorders. DISEASE (DISEASE) is caused by a defect in the skeletal muscle CHEMICAL channel function, which may cause sustained membrane depolarisation. We describe a previously healthy 32-year-old woman who developed a life-threatening muscle spasm and secondary ventilation difficulties following a preoperative injection of suxamethonium. The muscle spasms disappeared spontaneously and the surgery proceeded without further problems. When subsequently questioned, she reported minor symptoms suggesting a myotonic condition. Myotonia was found on clinical examination and EMG. The diagnosis DISEASE was confirmed genetically. Neither the patient nor the anaesthetist were aware of the diagnosis before this potentially lethal complication occurred. We give a brief overview of ion channel disorders including malignant hyperthermia and their anaesthetic considerations. | NO-RELATIONSHIP |
| Respiratory pattern in a rat model of DISEASE. PURPOSE: Apnea is known to occur during seizures, but systematic studies of ictal respiratory changes in adults are few. Data regarding respiratory pattern defects during interictal periods also are scarce. Here we sought to generate information with regard to the interictal period in animals with CHEMICAL-induced DISEASE. METHODS: Twelve rats (six chronically DISEASE animals and six controls) were anesthetized, given tracheotomies, and subjected to hyperventilation or hypoventilation conditions. Breathing movements caused changes in thoracic volume and forced air to flow tidally through a pneumotachograph. This flow was measured by using a differential pressure transducer, passed through a polygraph, and from this to a computer with custom software that derived ventilation (VE), tidal volume (VT), inspiratory time (TI), expiratory time (TE), breathing frequency (f), and mean inspiratory flow (VT/TI) on a breath-by-breath basis. RESULTS: The hyperventilation maneuver caused a decrease in spontaneous ventilation in CHEMICAL-treated and control rats. Although VE had a similar decrease in both groups, in the DISEASE group, the decrease in VE was due to a significant (p < 0.05) increase in TE peak in relation to that of the control animals. The hypoventilation maneuver led to an increase in the arterial Paco2, followed by an increase in VE. In the DISEASE group, the increase in VE was mediated by a significant (p < 0.05) decrease in TE peak compared with the control group. Systemic application of KCN, to evaluate the effects of peripheral chemoreception activation on ventilation, led to a similar increase in VE for both groups. CONCLUSIONS: The data indicate that CHEMICAL-treated animals have an altered ability to react to (or compensate for) blood gas changes with changes in ventilation and suggest that it is centrally determined. We speculate on the possible relation of the current findings on treating different DISEASE-associated conditions. | CHEMICAL-INDUCED-DISEASE |
| Increased serum soluble Fas in patients with DISEASE due to CHEMICAL overdose. BACKGROUND/AIMS: Experimental studies have suggested that apoptosis via the Fas/Fas Ligand signaling system may play an important role in the development of DISEASE. The aim of the study was to investigate the soluble form of Fas in patients with DISEASE. METHODOLOGY: Serum levels of sFas (soluble Fas) were measured by ELISA in 24 patients with DISEASE and 10 normal control subjects. Serum levels of tumor necrosis factor-alpha and interferon-gamma were also determined by ELISA. RESULTS: Serum sFas was significantly increased in patients with DISEASE (median, 26.8 U/mL; range, 6.9-52.7 U/mL) compared to the normal controls (median, 8.6 U/mL; range, 6.5-12.0 U/mL, P < 0.0001). Levels were significantly greater in patients with DISEASE due to CHEMICAL overdose (median, 28.7 U/mL; range, 12.8-52.7 U/mL, n = 17) than those due to non-A to E hepatitis (median, 12.5 U/mL; range, 6.9-46.0 U/mL, n = 7, P < 0.01). There was no relationship of sFas to eventual outcome in the patients. A significant correlation was observed between serum sFas levels and aspartate aminotransferase (r = 0.613, P < 0.01). CONCLUSIONS: The increased concentration of sFas in serum of patients with DISEASE may reflect activation of Fas-mediated apoptosis in the liver and this together with increased tumor necrosis factor-alpha may be an important factor in liver cell loss. | CHEMICAL-INDUCED-DISEASE |
| Increased serum soluble Fas in patients with acute liver failure due to paracetamol overdose. BACKGROUND/AIMS: Experimental studies have suggested that apoptosis via the Fas/Fas Ligand signaling system may play an important role in the development of acute liver failure. The aim of the study was to investigate the soluble form of Fas in patients with acute liver failure. METHODOLOGY: Serum levels of sFas (soluble Fas) were measured by ELISA in 24 patients with acute liver failure and 10 normal control subjects. Serum levels of tumor necrosis factor-alpha and interferon-gamma were also determined by ELISA. RESULTS: Serum sFas was significantly increased in patients with acute liver failure (median, 26.8 U/mL; range, 6.9-52.7 U/mL) compared to the normal controls (median, 8.6 U/mL; range, 6.5-12.0 U/mL, P < 0.0001). Levels were significantly greater in patients with acute liver failure due to paracetamol overdose (median, 28.7 U/mL; range, 12.8-52.7 U/mL, n = 17) than those due to non-A to E DISEASE (median, 12.5 U/mL; range, 6.9-46.0 U/mL, n = 7, P < 0.01). There was no relationship of sFas to eventual outcome in the patients. A significant correlation was observed between serum sFas levels and CHEMICAL aminotransferase (r = 0.613, P < 0.01). CONCLUSIONS: The increased concentration of sFas in serum of patients with acute liver failure may reflect activation of Fas-mediated apoptosis in the liver and this together with increased tumor necrosis factor-alpha may be an important factor in liver cell loss. | NO-RELATIONSHIP |
| Increased serum soluble Fas in patients with acute liver failure due to paracetamol overdose. BACKGROUND/AIMS: Experimental studies have suggested that apoptosis via the Fas/Fas Ligand signaling system may play an important role in the development of acute liver failure. The aim of the study was to investigate the soluble form of Fas in patients with acute liver failure. METHODOLOGY: Serum levels of sFas (soluble Fas) were measured by ELISA in 24 patients with acute liver failure and 10 normal control subjects. Serum levels of tumor DISEASE factor-alpha and interferon-gamma were also determined by ELISA. RESULTS: Serum sFas was significantly increased in patients with acute liver failure (median, 26.8 U/mL; range, 6.9-52.7 U/mL) compared to the normal controls (median, 8.6 U/mL; range, 6.5-12.0 U/mL, P < 0.0001). Levels were significantly greater in patients with acute liver failure due to paracetamol overdose (median, 28.7 U/mL; range, 12.8-52.7 U/mL, n = 17) than those due to non-A to E hepatitis (median, 12.5 U/mL; range, 6.9-46.0 U/mL, n = 7, P < 0.01). There was no relationship of sFas to eventual outcome in the patients. A significant correlation was observed between serum sFas levels and CHEMICAL aminotransferase (r = 0.613, P < 0.01). CONCLUSIONS: The increased concentration of sFas in serum of patients with acute liver failure may reflect activation of Fas-mediated apoptosis in the liver and this together with increased tumor DISEASE factor-alpha may be an important factor in liver cell loss. | NO-RELATIONSHIP |
| Increased serum soluble Fas in patients with acute liver failure due to paracetamol DISEASE. BACKGROUND/AIMS: Experimental studies have suggested that apoptosis via the Fas/Fas Ligand signaling system may play an important role in the development of acute liver failure. The aim of the study was to investigate the soluble form of Fas in patients with acute liver failure. METHODOLOGY: Serum levels of sFas (soluble Fas) were measured by ELISA in 24 patients with acute liver failure and 10 normal control subjects. Serum levels of tumor necrosis factor-alpha and interferon-gamma were also determined by ELISA. RESULTS: Serum sFas was significantly increased in patients with acute liver failure (median, 26.8 U/mL; range, 6.9-52.7 U/mL) compared to the normal controls (median, 8.6 U/mL; range, 6.5-12.0 U/mL, P < 0.0001). Levels were significantly greater in patients with acute liver failure due to paracetamol DISEASE (median, 28.7 U/mL; range, 12.8-52.7 U/mL, n = 17) than those due to non-A to E hepatitis (median, 12.5 U/mL; range, 6.9-46.0 U/mL, n = 7, P < 0.01). There was no relationship of sFas to eventual outcome in the patients. A significant correlation was observed between serum sFas levels and CHEMICAL aminotransferase (r = 0.613, P < 0.01). CONCLUSIONS: The increased concentration of sFas in serum of patients with acute liver failure may reflect activation of Fas-mediated apoptosis in the liver and this together with increased tumor necrosis factor-alpha may be an important factor in liver cell loss. | NO-RELATIONSHIP |
| Increased serum soluble Fas in patients with acute liver failure due to paracetamol overdose. BACKGROUND/AIMS: Experimental studies have suggested that apoptosis via the Fas/Fas Ligand signaling system may play an important role in the development of acute liver failure. The aim of the study was to investigate the soluble form of Fas in patients with acute liver failure. METHODOLOGY: Serum levels of sFas (soluble Fas) were measured by ELISA in 24 patients with acute liver failure and 10 normal control subjects. Serum levels of DISEASE necrosis factor-alpha and interferon-gamma were also determined by ELISA. RESULTS: Serum sFas was significantly increased in patients with acute liver failure (median, 26.8 U/mL; range, 6.9-52.7 U/mL) compared to the normal controls (median, 8.6 U/mL; range, 6.5-12.0 U/mL, P < 0.0001). Levels were significantly greater in patients with acute liver failure due to paracetamol overdose (median, 28.7 U/mL; range, 12.8-52.7 U/mL, n = 17) than those due to non-A to E hepatitis (median, 12.5 U/mL; range, 6.9-46.0 U/mL, n = 7, P < 0.01). There was no relationship of sFas to eventual outcome in the patients. A significant correlation was observed between serum sFas levels and CHEMICAL aminotransferase (r = 0.613, P < 0.01). CONCLUSIONS: The increased concentration of sFas in serum of patients with acute liver failure may reflect activation of Fas-mediated apoptosis in the liver and this together with increased DISEASE necrosis factor-alpha may be an important factor in liver cell loss. | NO-RELATIONSHIP |
| Bilateral subthalamic nucleus stimulation for Parkinson's disease. High frequency stimulation of the subthalamic nucleus (STN) is known to ameliorate the signs and symptoms of advanced Parkinson's disease. AIM: We studied the effect of high frequency STN stimulation in 23 patients. METHOD: Twenty-three patients suffering from severe Parkinson's disease (Stages III-V on Hoehn and Yahr scale) and, particularly bradykinesia, rigidity, and CHEMICAL-induced DISEASE underwent bilateral implantation of electrodes in the STN. Preoperative and postoperative assessments of these patients at 1, 3, 6 and 12 months follow-up, in "on" and "off" drug conditions, was carried out using Unified Parkinson's Disease Rating Scale, Hoehn and Yahr staging, England activities of daily living score and video recordings. RESULTS: After one year of electrical stimulation of the STN, the patients' scores for activities of daily living and motor examination scores (Unified Parkinson's Disease Rating Scale parts II and III) off medication improved by 62% and 61% respectively (p<0.0005). The subscores for the DISEASE, rigidity, tremor and gait also improved. (p<0.0005). The average CHEMICAL dose decreased from 813 mg to 359 mg. The cognitive functions remained unchanged. Two patients developed device-related complications and two patients experienced abnormal weight gain. CONCLUSION: Bilateral subthalamic nucleus stimulation is an effective treatment for advanced Parkinson's disease. It reduces the severity of "off" phase symptoms, improves the axial symptoms and reduces CHEMICAL requirements. The reduction in the CHEMICAL dose is useful in controlling DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Ocular motility changes after subtenon CHEMICAL chemotherapy for retinoblastoma. BACKGROUND: Focal subtenon CHEMICAL injections have recently been used as a presumably toxicity-free adjunct to systemic chemotherapy for intraocular retinoblastoma. OBJECTIVE: To report our clinical experience with DISEASE in patients treated with subtenon CHEMICAL chemotherapy. METHODS: We noted DISEASE in 10 consecutive patients with retinoblastoma who had received subtenon CHEMICAL. During ocular manipulation under general anesthesia, we assessed their eyes by forced duction testing, comparing ocular motility after tumor control with ocular motility at diagnosis. Eyes subsequently enucleated because of treatment failure (n = 4) were examined histologically. RESULTS: Limitation of ocular motility was detected in all 12 eyes of 10 patients treated for intraocular retinoblastoma with 1 to 6 injections of subtenon CHEMICAL as part of multimodality therapy. Histopathological examination revealed many lipophages in the periorbital fat surrounding the optic nerve in 1 eye, indicative of phagocytosis of previously existing fat cells and suggesting prior fat necrosis. The enucleations were technically difficult and hazardous for globe rupture because of extensive orbital soft tissue adhesions. CONCLUSIONS: Subtenon CHEMICAL chemotherapy is associated with significant fibrosis of orbital soft tissues, leading to mechanical restriction of eye movements and making subsequent enucleation difficult. Subtenon CHEMICAL is not free of toxicity, and its use is best restricted to specific indications. | CHEMICAL-INDUCED-DISEASE |
| Ocular motility changes after subtenon CHEMICAL chemotherapy for retinoblastoma. BACKGROUND: Focal subtenon CHEMICAL injections have recently been used as a presumably toxicity-free adjunct to systemic chemotherapy for intraocular retinoblastoma. OBJECTIVE: To report our clinical experience with abnormal ocular motility in patients treated with subtenon CHEMICAL chemotherapy. METHODS: We noted abnormal ocular motility in 10 consecutive patients with retinoblastoma who had received subtenon CHEMICAL. During ocular manipulation under general anesthesia, we assessed their eyes by forced duction testing, comparing ocular motility after tumor control with ocular motility at diagnosis. Eyes subsequently enucleated because of treatment failure (n = 4) were examined histologically. RESULTS: Limitation of ocular motility was detected in all 12 eyes of 10 patients treated for intraocular retinoblastoma with 1 to 6 injections of subtenon CHEMICAL as part of multimodality therapy. Histopathological examination revealed many lipophages in the periorbital fat surrounding the optic nerve in 1 eye, indicative of phagocytosis of previously existing fat cells and suggesting prior fat necrosis. The enucleations were technically difficult and hazardous for globe rupture because of extensive orbital soft tissue adhesions. CONCLUSIONS: Subtenon CHEMICAL chemotherapy is associated with significant DISEASE of orbital soft tissues, leading to mechanical restriction of eye movements and making subsequent enucleation difficult. Subtenon CHEMICAL is not free of toxicity, and its use is best restricted to specific indications. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL and DISEASE. PURPOSE: To demonstrate the association between CHEMICAL and DISEASE. METHOD: Thirteen patients who developed DISEASE after being treated with CHEMICAL for tuberculosis of the lung or lymph node at Siriraj Hospital between 1997 and 2001 were retrospectively reviewed. The clinical characteristics and initial and final visual acuity were analyzed to determine visual outcome. RESULTS: All patients had DISEASE between 1 to 6 months (mean = 2.9 months) after starting CHEMICAL therapy at a dosage ranging from 13 to 20 mg/kg/day (mean = 17 mg/kg/day). Seven (54%) of the 13 patients experienced visual recovery after stopping the drug. Of 6 patients with irreversible visual impairment, 4 patients had diabetes mellitus, glaucoma and a history of heavy smoking. CONCLUSION: Early recognition of DISEASE should be considered in patients with CHEMICAL therapy. A low dose and prompt discontinuation of the drug is recommended particularly in individuals with diabetes mellitus, glaucoma or who are heavy smokers. | CHEMICAL-INDUCED-DISEASE |
| Treatment of compensatory gustatory hyperhidrosis with topical CHEMICAL. Gustatory hyperhidrosis is facial sweating usually associated with the eating of hot spicy food or even smelling this food. Current options of treatment include oral anticholinergic drugs, the topical application of anticholinergics or aluminum chloride, and the injection of botulinum toxin. Thirteen patients have been treated to date with 1.5% or 2% topical CHEMICAL. All patients had gustatory hyperhidrosis, which interfered with their social activities, after transthroacic endoscopic sympathectomy, and which was associated with compensatory focal hyperhidrosis. After applying topical CHEMICAL, the subjective effect was excellent (no sweating after eating hot spicy food) in 10 patients (77%), and fair (clearly reduced sweating) in 3 patients (23%). All had reported incidents of being very embarrassed whilst eating hot spicy foods. Adverse effects included a mildly dry mouth and a sore throat in 2 patients (2% CHEMICAL), a light DISEASE in 1 patient (1.5% CHEMICAL). The topical application of a CHEMICAL pad appeared to be safe, efficacious, well tolerated, and a convenient method of treatment for moderate to severe symptoms of gustatory hyperhidrosis in post transthoracic endoscopic sympathectomy or sympathicotomy patients, with few side effects. | CHEMICAL-INDUCED-DISEASE |
| Treatment of compensatory gustatory hyperhidrosis with topical CHEMICAL. Gustatory hyperhidrosis is facial sweating usually associated with the eating of hot spicy food or even smelling this food. Current options of treatment include oral anticholinergic drugs, the topical application of anticholinergics or aluminum chloride, and the injection of botulinum toxin. Thirteen patients have been treated to date with 1.5% or 2% topical CHEMICAL. All patients had gustatory hyperhidrosis, which interfered with their social activities, after transthroacic endoscopic sympathectomy, and which was associated with compensatory focal hyperhidrosis. After applying topical CHEMICAL, the subjective effect was excellent (no sweating after eating hot spicy food) in 10 patients (77%), and fair (clearly reduced sweating) in 3 patients (23%). All had reported incidents of being very embarrassed whilst eating hot spicy foods. Adverse effects included a mildly dry mouth and a DISEASE in 2 patients (2% CHEMICAL), a light headache in 1 patient (1.5% CHEMICAL). The topical application of a CHEMICAL pad appeared to be safe, efficacious, well tolerated, and a convenient method of treatment for moderate to severe symptoms of gustatory hyperhidrosis in post transthoracic endoscopic sympathectomy or sympathicotomy patients, with few side effects. | CHEMICAL-INDUCED-DISEASE |
| Treatment of compensatory gustatory hyperhidrosis with topical glycopyrrolate. Gustatory hyperhidrosis is facial sweating usually associated with the eating of hot spicy food or even smelling this food. Current options of treatment include oral anticholinergic drugs, the topical application of anticholinergics or CHEMICAL, and the injection of botulinum toxin. Thirteen patients have been treated to date with 1.5% or 2% topical glycopyrrolate. All patients had gustatory hyperhidrosis, which interfered with their social activities, after transthroacic endoscopic sympathectomy, and which was associated with compensatory focal DISEASE. After applying topical glycopyrrolate, the subjective effect was excellent (no sweating after eating hot spicy food) in 10 patients (77%), and fair (clearly reduced sweating) in 3 patients (23%). All had reported incidents of being very embarrassed whilst eating hot spicy foods. Adverse effects included a mildly dry mouth and a sore throat in 2 patients (2% glycopyrrolate), a light headache in 1 patient (1.5% glycopyrrolate). The topical application of a glycopyrrolate pad appeared to be safe, efficacious, well tolerated, and a convenient method of treatment for moderate to severe symptoms of gustatory hyperhidrosis in post transthoracic endoscopic sympathectomy or sympathicotomy patients, with few side effects. | NO-RELATIONSHIP |
| Treatment of compensatory gustatory hyperhidrosis with topical glycopyrrolate. Gustatory hyperhidrosis is facial sweating usually associated with the eating of hot spicy food or even smelling this food. Current options of treatment include oral anticholinergic drugs, the topical application of anticholinergics or CHEMICAL, and the injection of botulinum toxin. Thirteen patients have been treated to date with 1.5% or 2% topical glycopyrrolate. All patients had gustatory hyperhidrosis, which interfered with their social activities, after transthroacic endoscopic sympathectomy, and which was associated with compensatory focal hyperhidrosis. After applying topical glycopyrrolate, the subjective effect was excellent (no sweating after eating hot spicy food) in 10 patients (77%), and fair (clearly reduced sweating) in 3 patients (23%). All had reported incidents of being very embarrassed whilst eating hot spicy foods. Adverse effects included a mildly DISEASE and a sore throat in 2 patients (2% glycopyrrolate), a light headache in 1 patient (1.5% glycopyrrolate). The topical application of a glycopyrrolate pad appeared to be safe, efficacious, well tolerated, and a convenient method of treatment for moderate to severe symptoms of gustatory hyperhidrosis in post transthoracic endoscopic sympathectomy or sympathicotomy patients, with few side effects. | NO-RELATIONSHIP |
| Treatment of compensatory DISEASE with topical glycopyrrolate. DISEASE is facial DISEASE usually associated with the eating of hot spicy food or even smelling this food. Current options of treatment include oral anticholinergic drugs, the topical application of anticholinergics or CHEMICAL, and the injection of botulinum toxin. Thirteen patients have been treated to date with 1.5% or 2% topical glycopyrrolate. All patients had DISEASE, which interfered with their social activities, after transthroacic endoscopic sympathectomy, and which was associated with compensatory focal hyperhidrosis. After applying topical glycopyrrolate, the subjective effect was excellent (no DISEASE after eating hot spicy food) in 10 patients (77%), and fair (clearly reduced DISEASE) in 3 patients (23%). All had reported incidents of being very embarrassed whilst eating hot spicy foods. Adverse effects included a mildly dry mouth and a sore throat in 2 patients (2% glycopyrrolate), a light headache in 1 patient (1.5% glycopyrrolate). The topical application of a glycopyrrolate pad appeared to be safe, efficacious, well tolerated, and a convenient method of treatment for moderate to severe symptoms of DISEASE in post transthoracic endoscopic sympathectomy or sympathicotomy patients, with few side effects. | CHEMICAL-INDUCED-DISEASE |
| Pharmacological characteristics and side effects of a new galenic formulation of CHEMICAL without soyabean oil. We compared the pharmacokinetics, pharmacodynamics and safety profile of a new galenic formulation of CHEMICAL (AM149 1%), which does not contain soyabean oil, with a standard formulation of CHEMICAL (CHEMICAL 1%). In a randomised, double-blind, cross-over study, 30 healthy volunteers received a single intravenous bolus injection of 2.5 mg.kg-1 CHEMICAL. Plasma CHEMICAL levels were measured for 48 h following drug administration and evaluated according to a three-compartment model. The pharmacodynamic parameters assessed included induction and emergence times, respiratory and cardiovascular effects, and pain on injection. Patients were monitored for side effects over 48 h. Owing to a high incidence of DISEASE, the study was terminated prematurely and only the data of the two parallel treatment groups (15 patients in each group) were analysed. Plasma concentrations did not differ significantly between the two formulations. Anaesthesia induction and emergence times, respiratory and cardiovascular variables showed no significant differences between the two treatment groups. Pain on injection (80 vs. 20%, p < 0.01) and DISEASE (93.3 vs. 6.6%, p < 0.001) occurred more frequently with AM149 than with CHEMICAL. Although both formulations had similar pharmacokinetic and pharmacodynamic profiles the new formulation is not suitable for clinical use due to the high incidence of DISEASE produced. | CHEMICAL-INDUCED-DISEASE |
| Pharmacological characteristics and side effects of a new galenic formulation of CHEMICAL without soyabean oil. We compared the pharmacokinetics, pharmacodynamics and safety profile of a new galenic formulation of CHEMICAL (AM149 1%), which does not contain soyabean oil, with a standard formulation of CHEMICAL (CHEMICAL 1%). In a randomised, double-blind, cross-over study, 30 healthy volunteers received a single intravenous bolus injection of 2.5 mg.kg-1 CHEMICAL. Plasma CHEMICAL levels were measured for 48 h following drug administration and evaluated according to a three-compartment model. The pharmacodynamic parameters assessed included induction and emergence times, respiratory and cardiovascular effects, and DISEASE on injection. Patients were monitored for side effects over 48 h. Owing to a high incidence of thrombophlebitis, the study was terminated prematurely and only the data of the two parallel treatment groups (15 patients in each group) were analysed. Plasma concentrations did not differ significantly between the two formulations. Anaesthesia induction and emergence times, respiratory and cardiovascular variables showed no significant differences between the two treatment groups. DISEASE on injection (80 vs. 20%, p < 0.01) and thrombophlebitis (93.3 vs. 6.6%, p < 0.001) occurred more frequently with AM149 than with CHEMICAL. Although both formulations had similar pharmacokinetic and pharmacodynamic profiles the new formulation is not suitable for clinical use due to the high incidence of thrombophlebitis produced. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-related cardiac events: a meta-analysis of randomized clinical trials. Several cases of cardiac adverse reactions related to CHEMICAL (CHEMICAL) have been reported in the literature. In order to quantify the incidence of these cardiac events, we performed a meta-analysis of clinical trials comparing CHEMICAL with other chemotherapeutic agents in the treatment of various malignancies. Randomized clinical trials comparing CHEMICAL with other drugs in the treatment of cancer were searched in Medline, Embase, Evidence-based Medicine Reviews databases and the Cochrane library from 1987 to 2002. Outcomes of interest were severe cardiac events, toxic deaths and cardiac event-related deaths reported in each publication. We found 19 trials, involving 2441 patients treated by CHEMICAL and 2050 control patients. The incidence of cardiac events with CHEMICAL was 1.19% [95% confidence interval (CI) (0.75; 1.67)]. There was no difference in the risk of cardiac events between CHEMICAL and other drugs [odds ratio: 0.92, 95% CI (0.54; 1.55)]. The risk of CHEMICAL cardiac events was similar to vindesine (VDS) and other DISEASE drugs [fluorouracil, anthracyclines, gemcitabine (GEM) em leader ]. Even if it did not reach statistical significance because of a few number of cases, the risk was lower in trials excluding patients with cardiac history, and seemed to be higher in trials including patients with pre-existing cardiac diseases. CHEMICAL-related cardiac events concern about 1% of treated patients in clinical trials. However, the risk associated with CHEMICAL seems to be similar to that of other chemotherapeutic agents in the same indications. | CHEMICAL-INDUCED-DISEASE |
| Vinorelbine-related cardiac events: a meta-analysis of randomized clinical trials. Several cases of cardiac adverse reactions related to vinorelbine (VNR) have been reported in the literature. In order to quantify the incidence of these cardiac events, we performed a meta-analysis of clinical trials comparing VNR with other chemotherapeutic agents in the treatment of various malignancies. Randomized clinical trials comparing VNR with other drugs in the treatment of cancer were searched in Medline, Embase, Evidence-based Medicine Reviews databases and the Cochrane library from 1987 to 2002. Outcomes of interest were severe cardiac events, toxic deaths and cardiac event-related deaths reported in each publication. We found 19 trials, involving 2441 patients treated by VNR and 2050 control patients. The incidence of cardiac events with VNR was 1.19% [95% confidence interval (CI) (0.75; 1.67)]. There was no difference in the risk of cardiac events between VNR and other drugs [odds ratio: 0.92, 95% CI (0.54; 1.55)]. The risk of VNR cardiac events was similar to vindesine (VDS) and other cardiotoxic drugs [fluorouracil, CHEMICAL, gemcitabine (GEM) em leader ]. Even if it did not reach statistical significance because of a few number of cases, the risk was lower in trials excluding patients with cardiac history, and seemed to be higher in trials including patients with pre-existing DISEASE. Vinorelbine-related cardiac events concern about 1% of treated patients in clinical trials. However, the risk associated with VNR seems to be similar to that of other chemotherapeutic agents in the same indications. | NO-RELATIONSHIP |
| Vinorelbine-related cardiac events: a meta-analysis of randomized clinical trials. Several cases of cardiac adverse reactions related to vinorelbine (VNR) have been reported in the literature. In order to quantify the incidence of these cardiac events, we performed a meta-analysis of clinical trials comparing VNR with other chemotherapeutic agents in the treatment of various DISEASE. Randomized clinical trials comparing VNR with other drugs in the treatment of DISEASE were searched in Medline, Embase, Evidence-based Medicine Reviews databases and the Cochrane library from 1987 to 2002. Outcomes of interest were severe cardiac events, toxic deaths and cardiac event-related deaths reported in each publication. We found 19 trials, involving 2441 patients treated by VNR and 2050 control patients. The incidence of cardiac events with VNR was 1.19% [95% confidence interval (CI) (0.75; 1.67)]. There was no difference in the risk of cardiac events between VNR and other drugs [odds ratio: 0.92, 95% CI (0.54; 1.55)]. The risk of VNR cardiac events was similar to vindesine (VDS) and other cardiotoxic drugs [CHEMICAL, anthracyclines, gemcitabine (GEM) em leader ]. Even if it did not reach statistical significance because of a few number of cases, the risk was lower in trials excluding patients with cardiac history, and seemed to be higher in trials including patients with pre-existing cardiac diseases. Vinorelbine-related cardiac events concern about 1% of treated patients in clinical trials. However, the risk associated with VNR seems to be similar to that of other chemotherapeutic agents in the same indications. | NO-RELATIONSHIP |
| Vinorelbine-related cardiac events: a meta-analysis of randomized clinical trials. Several cases of cardiac adverse reactions related to vinorelbine (VNR) have been reported in the literature. In order to quantify the incidence of these cardiac events, we performed a meta-analysis of clinical trials comparing VNR with other chemotherapeutic agents in the treatment of various DISEASE. Randomized clinical trials comparing VNR with other drugs in the treatment of DISEASE were searched in Medline, Embase, Evidence-based Medicine Reviews databases and the Cochrane library from 1987 to 2002. Outcomes of interest were severe cardiac events, toxic deaths and cardiac event-related deaths reported in each publication. We found 19 trials, involving 2441 patients treated by VNR and 2050 control patients. The incidence of cardiac events with VNR was 1.19% [95% confidence interval (CI) (0.75; 1.67)]. There was no difference in the risk of cardiac events between VNR and other drugs [odds ratio: 0.92, 95% CI (0.54; 1.55)]. The risk of VNR cardiac events was similar to CHEMICAL (CHEMICAL) and other cardiotoxic drugs [fluorouracil, anthracyclines, gemcitabine (GEM) em leader ]. Even if it did not reach statistical significance because of a few number of cases, the risk was lower in trials excluding patients with cardiac history, and seemed to be higher in trials including patients with pre-existing cardiac diseases. Vinorelbine-related cardiac events concern about 1% of treated patients in clinical trials. However, the risk associated with VNR seems to be similar to that of other chemotherapeutic agents in the same indications. | NO-RELATIONSHIP |
| Vinorelbine-related cardiac events: a meta-analysis of randomized clinical trials. Several cases of cardiac adverse reactions related to vinorelbine (VNR) have been reported in the literature. In order to quantify the incidence of these cardiac events, we performed a meta-analysis of clinical trials comparing VNR with other chemotherapeutic agents in the treatment of various malignancies. Randomized clinical trials comparing VNR with other drugs in the treatment of cancer were searched in Medline, Embase, Evidence-based Medicine Reviews databases and the Cochrane library from 1987 to 2002. Outcomes of interest were severe cardiac events, toxic deaths and cardiac event-related deaths reported in each publication. We found 19 trials, involving 2441 patients treated by VNR and 2050 control patients. The incidence of cardiac events with VNR was 1.19% [95% confidence interval (CI) (0.75; 1.67)]. There was no difference in the risk of cardiac events between VNR and other drugs [odds ratio: 0.92, 95% CI (0.54; 1.55)]. The risk of VNR cardiac events was similar to CHEMICAL (CHEMICAL) and other cardiotoxic drugs [fluorouracil, anthracyclines, gemcitabine (GEM) em leader ]. Even if it did not reach statistical significance because of a few number of cases, the risk was lower in trials excluding patients with cardiac history, and seemed to be higher in trials including patients with pre-existing DISEASE. Vinorelbine-related cardiac events concern about 1% of treated patients in clinical trials. However, the risk associated with VNR seems to be similar to that of other chemotherapeutic agents in the same indications. | NO-RELATIONSHIP |
| Vinorelbine-related cardiac events: a meta-analysis of randomized clinical trials. Several cases of cardiac adverse reactions related to vinorelbine (VNR) have been reported in the literature. In order to quantify the incidence of these cardiac events, we performed a meta-analysis of clinical trials comparing VNR with other chemotherapeutic agents in the treatment of various malignancies. Randomized clinical trials comparing VNR with other drugs in the treatment of cancer were searched in Medline, Embase, Evidence-based Medicine Reviews databases and the Cochrane library from 1987 to 2002. Outcomes of interest were severe cardiac events, toxic deaths and cardiac event-related deaths reported in each publication. We found 19 trials, involving 2441 patients treated by VNR and 2050 control patients. The incidence of cardiac events with VNR was 1.19% [95% confidence interval (CI) (0.75; 1.67)]. There was no difference in the risk of cardiac events between VNR and other drugs [odds ratio: 0.92, 95% CI (0.54; 1.55)]. The risk of VNR cardiac events was similar to vindesine (VDS) and other cardiotoxic drugs [CHEMICAL, anthracyclines, gemcitabine (GEM) em leader ]. Even if it did not reach statistical significance because of a few number of cases, the risk was lower in trials excluding patients with cardiac history, and seemed to be higher in trials including patients with pre-existing DISEASE. Vinorelbine-related cardiac events concern about 1% of treated patients in clinical trials. However, the risk associated with VNR seems to be similar to that of other chemotherapeutic agents in the same indications. | NO-RELATIONSHIP |
| Vinorelbine-related cardiac events: a meta-analysis of randomized clinical trials. Several cases of cardiac adverse reactions related to vinorelbine (VNR) have been reported in the literature. In order to quantify the incidence of these cardiac events, we performed a meta-analysis of clinical trials comparing VNR with other chemotherapeutic agents in the treatment of various malignancies. Randomized clinical trials comparing VNR with other drugs in the treatment of cancer were searched in Medline, Embase, Evidence-based Medicine Reviews databases and the Cochrane library from 1987 to 2002. Outcomes of interest were severe cardiac events, toxic deaths and cardiac event-related deaths reported in each publication. We found 19 trials, involving 2441 patients treated by VNR and 2050 control patients. The incidence of cardiac events with VNR was 1.19% [95% confidence interval (CI) (0.75; 1.67)]. There was no difference in the risk of cardiac events between VNR and other drugs [odds ratio: 0.92, 95% CI (0.54; 1.55)]. The risk of VNR cardiac events was similar to vindesine (VDS) and other cardiotoxic drugs [fluorouracil, anthracyclines, CHEMICAL (CHEMICAL) em leader ]. Even if it did not reach statistical significance because of a few number of cases, the risk was lower in trials excluding patients with cardiac history, and seemed to be higher in trials including patients with pre-existing DISEASE. Vinorelbine-related cardiac events concern about 1% of treated patients in clinical trials. However, the risk associated with VNR seems to be similar to that of other chemotherapeutic agents in the same indications. | NO-RELATIONSHIP |
| Vinorelbine-related cardiac events: a meta-analysis of randomized clinical trials. Several cases of cardiac adverse reactions related to vinorelbine (VNR) have been reported in the literature. In order to quantify the incidence of these cardiac events, we performed a meta-analysis of clinical trials comparing VNR with other chemotherapeutic agents in the treatment of various DISEASE. Randomized clinical trials comparing VNR with other drugs in the treatment of DISEASE were searched in Medline, Embase, Evidence-based Medicine Reviews databases and the Cochrane library from 1987 to 2002. Outcomes of interest were severe cardiac events, toxic deaths and cardiac event-related deaths reported in each publication. We found 19 trials, involving 2441 patients treated by VNR and 2050 control patients. The incidence of cardiac events with VNR was 1.19% [95% confidence interval (CI) (0.75; 1.67)]. There was no difference in the risk of cardiac events between VNR and other drugs [odds ratio: 0.92, 95% CI (0.54; 1.55)]. The risk of VNR cardiac events was similar to vindesine (VDS) and other cardiotoxic drugs [fluorouracil, CHEMICAL, gemcitabine (GEM) em leader ]. Even if it did not reach statistical significance because of a few number of cases, the risk was lower in trials excluding patients with cardiac history, and seemed to be higher in trials including patients with pre-existing cardiac diseases. Vinorelbine-related cardiac events concern about 1% of treated patients in clinical trials. However, the risk associated with VNR seems to be similar to that of other chemotherapeutic agents in the same indications. | NO-RELATIONSHIP |
| Vinorelbine-related cardiac events: a meta-analysis of randomized clinical trials. Several cases of cardiac adverse reactions related to vinorelbine (VNR) have been reported in the literature. In order to quantify the incidence of these cardiac events, we performed a meta-analysis of clinical trials comparing VNR with other chemotherapeutic agents in the treatment of various DISEASE. Randomized clinical trials comparing VNR with other drugs in the treatment of DISEASE were searched in Medline, Embase, Evidence-based Medicine Reviews databases and the Cochrane library from 1987 to 2002. Outcomes of interest were severe cardiac events, toxic deaths and cardiac event-related deaths reported in each publication. We found 19 trials, involving 2441 patients treated by VNR and 2050 control patients. The incidence of cardiac events with VNR was 1.19% [95% confidence interval (CI) (0.75; 1.67)]. There was no difference in the risk of cardiac events between VNR and other drugs [odds ratio: 0.92, 95% CI (0.54; 1.55)]. The risk of VNR cardiac events was similar to vindesine (VDS) and other cardiotoxic drugs [fluorouracil, anthracyclines, CHEMICAL (CHEMICAL) em leader ]. Even if it did not reach statistical significance because of a few number of cases, the risk was lower in trials excluding patients with cardiac history, and seemed to be higher in trials including patients with pre-existing cardiac diseases. Vinorelbine-related cardiac events concern about 1% of treated patients in clinical trials. However, the risk associated with VNR seems to be similar to that of other chemotherapeutic agents in the same indications. | NO-RELATIONSHIP |
| MRI findings of hypoxic cortical laminar necrosis in a child with DISEASE crisis. We present magnetic resonance imaging findings of a 5-year-old girl who had a rapidly installing DISEASE crisis induced by CHEMICAL, resulting in cerebral anoxia leading to permanent damage. Magnetic Resonance imaging revealed cortical laminar necrosis in arterial border zones in both cerebral hemispheres, ischemic changes in subcortical white matter of left cerebral hemisphere, and in the left putamen. Although cortical laminar necrosis is a classic entity in adulthood related to conditions of energy depletions, there are few reports available in children. A wide review of the literature is also presented. | CHEMICAL-INDUCED-DISEASE |
| The natural history of CHEMICAL associated DISEASE in patients electing to continue their medication. PURPOSE: To determine the natural history of DISEASE in a group of patients known to have CHEMICAL-associated changes who elected to continue the medication because of good seizure control. METHODS: All patients taking CHEMICAL alone or in combination with other antiepileptic drugs for at least 5 years (range 5-12 years) were entered into a visual surveillance programme. Patients were followed up at 6-monthly intervals for not less than 18 months (range 18-43 months). In all, 16 patients with unequivocal defects continued the medication. Following already published methodology (Eye 2002; 16;567-571) monocular mean radial degrees (MRDs) to the I/4e isopter on Goldmann perimetry was calculated for the right eye at the time of discovery of a DISEASE and again after not less than 18 months follow-up. RESULTS: Mean right eye MRD at presentation was 36.98 degrees (range 22.25-51.0), compared to 38.40 degrees (range 22.5-49.75) after follow-up; P=0.338 unpaired t-test. Only one patient demonstrated a DISEASE during the study period and discontinued treatment. CONCLUSION: Established DISEASE presumed to be due to CHEMICAL therapy did not usually progress in spite of continuing use of the medication. These data give support to the hypothesis that the pathogenesis of CHEMICAL-associated DISEASE may be an idiosyncratic adverse drug reaction rather than dose-dependent toxicity. | CHEMICAL-INDUCED-DISEASE |
| Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with CHEMICAL ointment. BACKGROUND: CHEMICAL ointment is increasingly used for anti-inflammatory treatment of sensitive areas such as the face, and recent observations indicate that the treatment is effective in steroid-aggravated DISEASE and perioral dermatitis. We report on rosaceiform dermatitis as a complication of treatment with CHEMICAL ointment. OBSERVATIONS: Six adult patients with inflammatory facial dermatoses were treated with CHEMICAL ointment because of the ineffectiveness of standard treatments. Within 2 to 3 weeks of initially effective and well-tolerated treatment, 3 patients with a history of DISEASE and 1 with a history of acne experienced sudden worsening with pustular rosaceiform lesions. Biopsy revealed an abundance of Demodex mites in 2 of these patients. In 1 patient with eyelid eczema, rosaceiform periocular dermatitis gradually appeared after 3 weeks of treatment. In 1 patient with atopic dermatitis, telangiectatic and DISEASE insidiously appeared after 5 months of treatment. CONCLUSIONS: Our observations suggest that the spectrum of rosaceiform dermatitis as a complication of treatment with CHEMICAL ointment is heterogeneous. A variety of factors, such as vasoactive properties of CHEMICAL, proliferation of Demodex due to local immunosuppression, and the occlusive properties of the ointment, may be involved in the observed phenomena. Future studies are needed to identify individual risk factors. | CHEMICAL-INDUCED-DISEASE |
| Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with tacrolimus ointment. BACKGROUND: Tacrolimus ointment is increasingly used for anti-inflammatory treatment of sensitive areas such as the face, and recent observations indicate that the treatment is effective in CHEMICAL-aggravated rosacea and perioral dermatitis. We report on rosaceiform dermatitis as a complication of treatment with tacrolimus ointment. OBSERVATIONS: Six adult patients with inflammatory facial dermatoses were treated with tacrolimus ointment because of the ineffectiveness of standard treatments. Within 2 to 3 weeks of initially effective and well-tolerated treatment, 3 patients with a history of rosacea and 1 with a history of acne experienced sudden worsening with pustular rosaceiform lesions. Biopsy revealed an abundance of Demodex mites in 2 of these patients. In 1 patient with eyelid DISEASE, rosaceiform periocular dermatitis gradually appeared after 3 weeks of treatment. In 1 patient with atopic dermatitis, telangiectatic and papular rosacea insidiously appeared after 5 months of treatment. CONCLUSIONS: Our observations suggest that the spectrum of rosaceiform dermatitis as a complication of treatment with tacrolimus ointment is heterogeneous. A variety of factors, such as vasoactive properties of tacrolimus, proliferation of Demodex due to local immunosuppression, and the occlusive properties of the ointment, may be involved in the observed phenomena. Future studies are needed to identify individual risk factors. | NO-RELATIONSHIP |
| Induction of rosaceiform DISEASE during treatment of facial inflammatory dermatoses with tacrolimus ointment. BACKGROUND: Tacrolimus ointment is increasingly used for anti-inflammatory treatment of sensitive areas such as the face, and recent observations indicate that the treatment is effective in CHEMICAL-aggravated rosacea and perioral dermatitis. We report on rosaceiform DISEASE as a complication of treatment with tacrolimus ointment. OBSERVATIONS: Six adult patients with inflammatory facial dermatoses were treated with tacrolimus ointment because of the ineffectiveness of standard treatments. Within 2 to 3 weeks of initially effective and well-tolerated treatment, 3 patients with a history of rosacea and 1 with a history of acne experienced sudden worsening with pustular rosaceiform lesions. Biopsy revealed an abundance of Demodex mites in 2 of these patients. In 1 patient with eyelid eczema, rosaceiform periocular dermatitis gradually appeared after 3 weeks of treatment. In 1 patient with atopic dermatitis, telangiectatic and papular rosacea insidiously appeared after 5 months of treatment. CONCLUSIONS: Our observations suggest that the spectrum of rosaceiform DISEASE as a complication of treatment with tacrolimus ointment is heterogeneous. A variety of factors, such as vasoactive properties of tacrolimus, proliferation of Demodex due to local immunosuppression, and the occlusive properties of the ointment, may be involved in the observed phenomena. Future studies are needed to identify individual risk factors. | CHEMICAL-INDUCED-DISEASE |
| Induction of rosaceiform dermatitis during treatment of DISEASE with tacrolimus ointment. BACKGROUND: Tacrolimus ointment is increasingly used for anti-inflammatory treatment of sensitive areas such as the face, and recent observations indicate that the treatment is effective in CHEMICAL-aggravated rosacea and perioral dermatitis. We report on rosaceiform dermatitis as a complication of treatment with tacrolimus ointment. OBSERVATIONS: Six adult patients with DISEASE were treated with tacrolimus ointment because of the ineffectiveness of standard treatments. Within 2 to 3 weeks of initially effective and well-tolerated treatment, 3 patients with a history of rosacea and 1 with a history of acne experienced sudden worsening with pustular rosaceiform lesions. Biopsy revealed an abundance of Demodex mites in 2 of these patients. In 1 patient with eyelid eczema, rosaceiform periocular dermatitis gradually appeared after 3 weeks of treatment. In 1 patient with atopic dermatitis, telangiectatic and papular rosacea insidiously appeared after 5 months of treatment. CONCLUSIONS: Our observations suggest that the spectrum of rosaceiform dermatitis as a complication of treatment with tacrolimus ointment is heterogeneous. A variety of factors, such as vasoactive properties of tacrolimus, proliferation of Demodex due to local immunosuppression, and the occlusive properties of the ointment, may be involved in the observed phenomena. Future studies are needed to identify individual risk factors. | NO-RELATIONSHIP |
| Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with tacrolimus ointment. BACKGROUND: Tacrolimus ointment is increasingly used for anti-inflammatory treatment of sensitive areas such as the face, and recent observations indicate that the treatment is effective in CHEMICAL-aggravated rosacea and DISEASE. We report on rosaceiform dermatitis as a complication of treatment with tacrolimus ointment. OBSERVATIONS: Six adult patients with inflammatory facial dermatoses were treated with tacrolimus ointment because of the ineffectiveness of standard treatments. Within 2 to 3 weeks of initially effective and well-tolerated treatment, 3 patients with a history of rosacea and 1 with a history of acne experienced sudden worsening with pustular rosaceiform lesions. Biopsy revealed an abundance of Demodex mites in 2 of these patients. In 1 patient with eyelid eczema, rosaceiform DISEASE gradually appeared after 3 weeks of treatment. In 1 patient with atopic dermatitis, telangiectatic and papular rosacea insidiously appeared after 5 months of treatment. CONCLUSIONS: Our observations suggest that the spectrum of rosaceiform dermatitis as a complication of treatment with tacrolimus ointment is heterogeneous. A variety of factors, such as vasoactive properties of tacrolimus, proliferation of Demodex due to local immunosuppression, and the occlusive properties of the ointment, may be involved in the observed phenomena. Future studies are needed to identify individual risk factors. | CHEMICAL-INDUCED-DISEASE |
| Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with tacrolimus ointment. BACKGROUND: Tacrolimus ointment is increasingly used for anti-inflammatory treatment of sensitive areas such as the face, and recent observations indicate that the treatment is effective in CHEMICAL-aggravated rosacea and perioral dermatitis. We report on rosaceiform dermatitis as a complication of treatment with tacrolimus ointment. OBSERVATIONS: Six adult patients with inflammatory facial dermatoses were treated with tacrolimus ointment because of the ineffectiveness of standard treatments. Within 2 to 3 weeks of initially effective and well-tolerated treatment, 3 patients with a history of rosacea and 1 with a history of DISEASE experienced sudden worsening with pustular rosaceiform lesions. Biopsy revealed an abundance of Demodex mites in 2 of these patients. In 1 patient with eyelid eczema, rosaceiform periocular dermatitis gradually appeared after 3 weeks of treatment. In 1 patient with atopic dermatitis, telangiectatic and papular rosacea insidiously appeared after 5 months of treatment. CONCLUSIONS: Our observations suggest that the spectrum of rosaceiform dermatitis as a complication of treatment with tacrolimus ointment is heterogeneous. A variety of factors, such as vasoactive properties of tacrolimus, proliferation of Demodex due to local immunosuppression, and the occlusive properties of the ointment, may be involved in the observed phenomena. Future studies are needed to identify individual risk factors. | NO-RELATIONSHIP |
| Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with tacrolimus ointment. BACKGROUND: Tacrolimus ointment is increasingly used for anti-inflammatory treatment of sensitive areas such as the face, and recent observations indicate that the treatment is effective in CHEMICAL-aggravated rosacea and perioral dermatitis. We report on rosaceiform dermatitis as a complication of treatment with tacrolimus ointment. OBSERVATIONS: Six adult patients with inflammatory facial dermatoses were treated with tacrolimus ointment because of the ineffectiveness of standard treatments. Within 2 to 3 weeks of initially effective and well-tolerated treatment, 3 patients with a history of rosacea and 1 with a history of acne experienced sudden worsening with pustular rosaceiform lesions. Biopsy revealed an abundance of Demodex mites in 2 of these patients. In 1 patient with eyelid eczema, rosaceiform periocular dermatitis gradually appeared after 3 weeks of treatment. In 1 patient with DISEASE, telangiectatic and papular rosacea insidiously appeared after 5 months of treatment. CONCLUSIONS: Our observations suggest that the spectrum of rosaceiform dermatitis as a complication of treatment with tacrolimus ointment is heterogeneous. A variety of factors, such as vasoactive properties of tacrolimus, proliferation of Demodex due to local immunosuppression, and the occlusive properties of the ointment, may be involved in the observed phenomena. Future studies are needed to identify individual risk factors. | NO-RELATIONSHIP |
| Structural abnormalities in the brains of human subjects who use CHEMICAL. We visualize, for the first time, the profile of structural deficits in the human brain associated with chronic CHEMICAL (CHEMICAL) abuse. Studies of human subjects who have used CHEMICAL chronically have revealed deficits in dopaminergic and serotonergic systems and cerebral metabolic abnormalities. Using magnetic resonance imaging (MRI) and new computational brain-mapping techniques, we determined the pattern of structural brain alterations associated with chronic CHEMICAL abuse in human subjects and related these deficits to cognitive impairment. We used high-resolution MRI and surface-based computational image analyses to map regional abnormalities in the cortex, hippocampus, white matter, and ventricles in 22 human subjects who used CHEMICAL and 21 age-matched, healthy controls. Cortical maps revealed severe gray-matter deficits in the cingulate, limbic, and paralimbic cortices of CHEMICAL abusers (averaging 11.3% below control; p < 0.05). On average, CHEMICAL abusers had 7.8% smaller hippocampal volumes than control subjects (p < 0.01; left, p = 0.01; right, p < 0.05) and significant white-matter hypertrophy (7.0%; p < 0.01). Hippocampal deficits were mapped and correlated with memory performance on a word-recall test (p < 0.05). MRI-based maps suggest that chronic CHEMICAL abuse causes a selective pattern of cerebral deterioration that contributes to DISEASE. CHEMICAL may selectively damage the medial temporal lobe and, consistent with metabolic studies, the cingulate-limbic cortex, inducing neuroadaptation, neuropil reduction, or cell death. Prominent white-matter hypertrophy may result from altered myelination and adaptive glial changes, including gliosis secondary to neuronal damage. These brain substrates may help account for the symptoms of CHEMICAL abuse, providing therapeutic targets for drug-induced brain injury. | CHEMICAL-INDUCED-DISEASE |
| Structural abnormalities in the brains of human subjects who use CHEMICAL. We visualize, for the first time, the profile of DISEASE associated with chronic CHEMICAL (CHEMICAL) abuse. Studies of human subjects who have used CHEMICAL chronically have revealed deficits in dopaminergic and serotonergic systems and cerebral metabolic abnormalities. Using magnetic resonance imaging (MRI) and new computational brain-mapping techniques, we determined the pattern of structural brain alterations associated with chronic CHEMICAL abuse in human subjects and related these deficits to cognitive impairment. We used high-resolution MRI and surface-based computational image analyses to map regional DISEASE in 22 human subjects who used CHEMICAL and 21 age-matched, healthy controls. Cortical maps revealed severe gray-matter deficits in the cingulate, limbic, and paralimbic cortices of CHEMICAL abusers (averaging 11.3% below control; p < 0.05). On average, CHEMICAL abusers had 7.8% smaller hippocampal volumes than control subjects (p < 0.01; left, p = 0.01; right, p < 0.05) and significant white-matter hypertrophy (7.0%; p < 0.01). Hippocampal deficits were mapped and correlated with memory performance on a word-recall test (p < 0.05). MRI-based maps suggest that chronic CHEMICAL abuse causes a selective pattern of cerebral deterioration that contributes to impaired memory performance. CHEMICAL may selectively damage the medial temporal lobe and, consistent with metabolic studies, the cingulate-limbic cortex, inducing neuroadaptation, neuropil reduction, or cell death. Prominent white-matter hypertrophy may result from altered myelination and adaptive glial changes, including gliosis secondary to neuronal damage. These brain substrates may help account for the symptoms of CHEMICAL abuse, providing therapeutic targets for drug-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Disruption of hepatic lipid homeostasis in mice after CHEMICAL treatment is associated with peroxisome proliferator-activated receptor-alpha target gene activation. CHEMICAL, an efficacious and widely used antiarrhythmic agent, has been reported to cause hepatotoxicity in some patients. To gain insight into the mechanism of this unwanted effect, mice were administered various doses of CHEMICAL and examined for changes in hepatic histology and gene regulation. CHEMICAL induced DISEASE, hepatocyte microvesicular lipid accumulation, and a significant decrease in serum triglycerides and glucose. Northern blot analysis of hepatic RNA revealed a dose-dependent increase in the expression of a number of genes critical for fatty acid oxidation, lipoprotein assembly, and lipid transport. Many of these genes are regulated by the peroxisome proliferator-activated receptor-alpha (PPARalpha), a ligand-activated nuclear hormone receptor transcription factor. The absence of induction of these genes as well as DISEASE in PPARalpha knockout [PPARalpha-/-] mice indicated that the effects of CHEMICAL were dependent upon the presence of a functional PPARalpha gene. Compared to wild-type mice, treatment of PPARalpha-/- mice with CHEMICAL resulted in an increased rate and extent of total body weight loss. The inability of CHEMICAL to directly activate either human or mouse PPARalpha transiently expressed in human HepG2 hepatoma cells indicates that the effects of CHEMICAL on the function of this receptor were indirect. Based upon these results, we conclude that CHEMICAL disrupts hepatic lipid homeostasis and that the increased expression of PPARalpha target genes is secondary to this toxic effect. These results provide important new mechanistic information regarding the hepatotoxic effects of CHEMICAL and indicate that PPARalpha protects against CHEMICAL-induced hepatotoxicity. | CHEMICAL-INDUCED-DISEASE |
| Disruption of hepatic lipid homeostasis in mice after CHEMICAL treatment is associated with peroxisome proliferator-activated receptor-alpha target gene activation. CHEMICAL, an efficacious and widely used antiarrhythmic agent, has been reported to cause DISEASE in some patients. To gain insight into the mechanism of this unwanted effect, mice were administered various doses of CHEMICAL and examined for changes in hepatic histology and gene regulation. CHEMICAL induced hepatomegaly, hepatocyte microvesicular lipid accumulation, and a significant decrease in serum triglycerides and glucose. Northern blot analysis of hepatic RNA revealed a dose-dependent increase in the expression of a number of genes critical for fatty acid oxidation, lipoprotein assembly, and lipid transport. Many of these genes are regulated by the peroxisome proliferator-activated receptor-alpha (PPARalpha), a ligand-activated nuclear hormone receptor transcription factor. The absence of induction of these genes as well as hepatomegaly in PPARalpha knockout [PPARalpha-/-] mice indicated that the effects of CHEMICAL were dependent upon the presence of a functional PPARalpha gene. Compared to wild-type mice, treatment of PPARalpha-/- mice with CHEMICAL resulted in an increased rate and extent of total body weight loss. The inability of CHEMICAL to directly activate either human or mouse PPARalpha transiently expressed in human HepG2 hepatoma cells indicates that the effects of CHEMICAL on the function of this receptor were indirect. Based upon these results, we conclude that CHEMICAL disrupts hepatic lipid homeostasis and that the increased expression of PPARalpha target genes is secondary to this toxic effect. These results provide important new mechanistic information regarding the DISEASE effects of CHEMICAL and indicate that PPARalpha protects against CHEMICAL-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Disruption of hepatic lipid homeostasis in mice after amiodarone treatment is associated with peroxisome proliferator-activated receptor-alpha target gene activation. Amiodarone, an efficacious and widely used antiarrhythmic agent, has been reported to cause hepatotoxicity in some patients. To gain insight into the mechanism of this unwanted effect, mice were administered various doses of amiodarone and examined for changes in hepatic histology and gene regulation. Amiodarone induced hepatomegaly, hepatocyte microvesicular lipid accumulation, and a significant decrease in serum triglycerides and CHEMICAL. Northern blot analysis of hepatic RNA revealed a dose-dependent increase in the expression of a number of genes critical for fatty acid oxidation, lipoprotein assembly, and lipid transport. Many of these genes are regulated by the peroxisome proliferator-activated receptor-alpha (PPARalpha), a ligand-activated nuclear hormone receptor transcription factor. The absence of induction of these genes as well as hepatomegaly in PPARalpha knockout [PPARalpha-/-] mice indicated that the effects of amiodarone were dependent upon the presence of a functional PPARalpha gene. Compared to wild-type mice, treatment of PPARalpha-/- mice with amiodarone resulted in an increased rate and extent of total body DISEASE. The inability of amiodarone to directly activate either human or mouse PPARalpha transiently expressed in human HepG2 hepatoma cells indicates that the effects of amiodarone on the function of this receptor were indirect. Based upon these results, we conclude that amiodarone disrupts hepatic lipid homeostasis and that the increased expression of PPARalpha target genes is secondary to this toxic effect. These results provide important new mechanistic information regarding the hepatotoxic effects of amiodarone and indicate that PPARalpha protects against amiodarone-induced hepatotoxicity. | NO-RELATIONSHIP |
| Disruption of hepatic lipid homeostasis in mice after amiodarone treatment is associated with peroxisome proliferator-activated receptor-alpha target gene activation. Amiodarone, an efficacious and widely used antiarrhythmic agent, has been reported to cause hepatotoxicity in some patients. To gain insight into the mechanism of this unwanted effect, mice were administered various doses of amiodarone and examined for changes in hepatic histology and gene regulation. Amiodarone induced hepatomegaly, hepatocyte microvesicular lipid accumulation, and a significant decrease in serum triglycerides and glucose. Northern blot analysis of hepatic RNA revealed a dose-dependent increase in the expression of a number of genes critical for CHEMICAL oxidation, lipoprotein assembly, and lipid transport. Many of these genes are regulated by the peroxisome proliferator-activated receptor-alpha (PPARalpha), a ligand-activated nuclear hormone receptor transcription factor. The absence of induction of these genes as well as hepatomegaly in PPARalpha knockout [PPARalpha-/-] mice indicated that the effects of amiodarone were dependent upon the presence of a functional PPARalpha gene. Compared to wild-type mice, treatment of PPARalpha-/- mice with amiodarone resulted in an increased rate and extent of total body weight loss. The inability of amiodarone to directly activate either human or mouse PPARalpha transiently expressed in human HepG2 DISEASE cells indicates that the effects of amiodarone on the function of this receptor were indirect. Based upon these results, we conclude that amiodarone disrupts hepatic lipid homeostasis and that the increased expression of PPARalpha target genes is secondary to this toxic effect. These results provide important new mechanistic information regarding the hepatotoxic effects of amiodarone and indicate that PPARalpha protects against amiodarone-induced hepatotoxicity. | NO-RELATIONSHIP |
| Disruption of hepatic lipid homeostasis in mice after amiodarone treatment is associated with peroxisome proliferator-activated receptor-alpha target gene activation. Amiodarone, an efficacious and widely used antiarrhythmic agent, has been reported to cause hepatotoxicity in some patients. To gain insight into the mechanism of this unwanted effect, mice were administered various doses of amiodarone and examined for changes in hepatic histology and gene regulation. Amiodarone induced hepatomegaly, hepatocyte microvesicular lipid accumulation, and a significant decrease in serum CHEMICAL and glucose. Northern blot analysis of hepatic RNA revealed a dose-dependent increase in the expression of a number of genes critical for fatty acid oxidation, lipoprotein assembly, and lipid transport. Many of these genes are regulated by the peroxisome proliferator-activated receptor-alpha (PPARalpha), a ligand-activated nuclear hormone receptor transcription factor. The absence of induction of these genes as well as hepatomegaly in PPARalpha knockout [PPARalpha-/-] mice indicated that the effects of amiodarone were dependent upon the presence of a functional PPARalpha gene. Compared to wild-type mice, treatment of PPARalpha-/- mice with amiodarone resulted in an increased rate and extent of total body weight loss. The inability of amiodarone to directly activate either human or mouse PPARalpha transiently expressed in human HepG2 DISEASE cells indicates that the effects of amiodarone on the function of this receptor were indirect. Based upon these results, we conclude that amiodarone disrupts hepatic lipid homeostasis and that the increased expression of PPARalpha target genes is secondary to this toxic effect. These results provide important new mechanistic information regarding the hepatotoxic effects of amiodarone and indicate that PPARalpha protects against amiodarone-induced hepatotoxicity. | NO-RELATIONSHIP |
| Disruption of hepatic lipid homeostasis in mice after amiodarone treatment is associated with peroxisome proliferator-activated receptor-alpha target gene activation. Amiodarone, an efficacious and widely used antiarrhythmic agent, has been reported to cause hepatotoxicity in some patients. To gain insight into the mechanism of this unwanted effect, mice were administered various doses of amiodarone and examined for changes in hepatic histology and gene regulation. Amiodarone induced hepatomegaly, hepatocyte microvesicular lipid accumulation, and a significant decrease in serum triglycerides and CHEMICAL. Northern blot analysis of hepatic RNA revealed a dose-dependent increase in the expression of a number of genes critical for fatty acid oxidation, lipoprotein assembly, and lipid transport. Many of these genes are regulated by the peroxisome proliferator-activated receptor-alpha (PPARalpha), a ligand-activated nuclear hormone receptor transcription factor. The absence of induction of these genes as well as hepatomegaly in PPARalpha knockout [PPARalpha-/-] mice indicated that the effects of amiodarone were dependent upon the presence of a functional PPARalpha gene. Compared to wild-type mice, treatment of PPARalpha-/- mice with amiodarone resulted in an increased rate and extent of total body weight loss. The inability of amiodarone to directly activate either human or mouse PPARalpha transiently expressed in human HepG2 DISEASE cells indicates that the effects of amiodarone on the function of this receptor were indirect. Based upon these results, we conclude that amiodarone disrupts hepatic lipid homeostasis and that the increased expression of PPARalpha target genes is secondary to this toxic effect. These results provide important new mechanistic information regarding the hepatotoxic effects of amiodarone and indicate that PPARalpha protects against amiodarone-induced hepatotoxicity. | NO-RELATIONSHIP |
| Disruption of hepatic lipid homeostasis in mice after amiodarone treatment is associated with peroxisome proliferator-activated receptor-alpha target gene activation. Amiodarone, an efficacious and widely used antiarrhythmic agent, has been reported to cause hepatotoxicity in some patients. To gain insight into the mechanism of this unwanted effect, mice were administered various doses of amiodarone and examined for changes in hepatic histology and gene regulation. Amiodarone induced hepatomegaly, hepatocyte microvesicular lipid accumulation, and a significant decrease in serum triglycerides and glucose. Northern blot analysis of hepatic RNA revealed a dose-dependent increase in the expression of a number of genes critical for CHEMICAL oxidation, lipoprotein assembly, and lipid transport. Many of these genes are regulated by the peroxisome proliferator-activated receptor-alpha (PPARalpha), a ligand-activated nuclear hormone receptor transcription factor. The absence of induction of these genes as well as hepatomegaly in PPARalpha knockout [PPARalpha-/-] mice indicated that the effects of amiodarone were dependent upon the presence of a functional PPARalpha gene. Compared to wild-type mice, treatment of PPARalpha-/- mice with amiodarone resulted in an increased rate and extent of total body DISEASE. The inability of amiodarone to directly activate either human or mouse PPARalpha transiently expressed in human HepG2 hepatoma cells indicates that the effects of amiodarone on the function of this receptor were indirect. Based upon these results, we conclude that amiodarone disrupts hepatic lipid homeostasis and that the increased expression of PPARalpha target genes is secondary to this toxic effect. These results provide important new mechanistic information regarding the hepatotoxic effects of amiodarone and indicate that PPARalpha protects against amiodarone-induced hepatotoxicity. | NO-RELATIONSHIP |
| Disruption of hepatic lipid homeostasis in mice after amiodarone treatment is associated with peroxisome proliferator-activated receptor-alpha target gene activation. Amiodarone, an efficacious and widely used antiarrhythmic agent, has been reported to cause hepatotoxicity in some patients. To gain insight into the mechanism of this unwanted effect, mice were administered various doses of amiodarone and examined for changes in hepatic histology and gene regulation. Amiodarone induced hepatomegaly, hepatocyte microvesicular lipid accumulation, and a significant decrease in serum CHEMICAL and glucose. Northern blot analysis of hepatic RNA revealed a dose-dependent increase in the expression of a number of genes critical for fatty acid oxidation, lipoprotein assembly, and lipid transport. Many of these genes are regulated by the peroxisome proliferator-activated receptor-alpha (PPARalpha), a ligand-activated nuclear hormone receptor transcription factor. The absence of induction of these genes as well as hepatomegaly in PPARalpha knockout [PPARalpha-/-] mice indicated that the effects of amiodarone were dependent upon the presence of a functional PPARalpha gene. Compared to wild-type mice, treatment of PPARalpha-/- mice with amiodarone resulted in an increased rate and extent of total body DISEASE. The inability of amiodarone to directly activate either human or mouse PPARalpha transiently expressed in human HepG2 hepatoma cells indicates that the effects of amiodarone on the function of this receptor were indirect. Based upon these results, we conclude that amiodarone disrupts hepatic lipid homeostasis and that the increased expression of PPARalpha target genes is secondary to this toxic effect. These results provide important new mechanistic information regarding the hepatotoxic effects of amiodarone and indicate that PPARalpha protects against amiodarone-induced hepatotoxicity. | NO-RELATIONSHIP |
| Safety and compliance with once-daily CHEMICAL as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study. CHEMICAL is a new combination product approved for treatment of primary hypercholesterolemia and mixed dyslipidemia. This open-labeled, multicenter study evaluated the safety of bedtime CHEMICAL when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with dyslipidemia requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of niacin extended-release/20 mg of lovastatin) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about dyslipidemia and CHEMICAL. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical myopathy. Final study status was available for 4,217 patients (94%). Compliance to CHEMICAL was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. DISEASE was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased aspartate aminotransferase and/or alanine aminotransferase >3 times the upper limit of normal was <0.3%. An increase of creatine phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced myopathy were observed. CHEMICAL 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes. | CHEMICAL-INDUCED-DISEASE |
| Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study. Niacin extended-release/lovastatin is a new combination product approved for treatment of primary hypercholesterolemia and mixed dyslipidemia. This open-labeled, multicenter study evaluated the safety of bedtime niacin extended-release/lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with dyslipidemia requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of niacin extended-release/20 mg of lovastatin) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about dyslipidemia and niacin extended-release/lovastatin. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical DISEASE. Final study status was available for 4,217 patients (94%). Compliance to niacin extended-release/lovastatin was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. Flushing was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased aspartate aminotransferase and/or alanine aminotransferase >3 times the upper limit of normal was <0.3%. An increase of CHEMICAL phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced DISEASE were observed. Niacin extended-release/lovastatin 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes. | NO-RELATIONSHIP |
| Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study. Niacin extended-release/lovastatin is a new combination product approved for treatment of primary hypercholesterolemia and mixed DISEASE. This open-labeled, multicenter study evaluated the safety of bedtime niacin extended-release/lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with DISEASE requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of niacin extended-release/20 mg of lovastatin) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about DISEASE and niacin extended-release/lovastatin. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical myopathy. Final study status was available for 4,217 patients (94%). Compliance to niacin extended-release/lovastatin was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. Flushing was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased CHEMICAL aminotransferase and/or alanine aminotransferase >3 times the upper limit of normal was <0.3%. An increase of creatine phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced myopathy were observed. Niacin extended-release/lovastatin 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes. | NO-RELATIONSHIP |
| Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study. Niacin extended-release/lovastatin is a new combination product approved for treatment of primary hypercholesterolemia and mixed dyslipidemia. This open-labeled, multicenter study evaluated the safety of bedtime niacin extended-release/lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with dyslipidemia requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of niacin extended-release/20 mg of lovastatin) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about dyslipidemia and niacin extended-release/lovastatin. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical DISEASE. Final study status was available for 4,217 patients (94%). Compliance to niacin extended-release/lovastatin was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. Flushing was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased CHEMICAL aminotransferase and/or alanine aminotransferase >3 times the upper limit of normal was <0.3%. An increase of creatine phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced DISEASE were observed. Niacin extended-release/lovastatin 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes. | NO-RELATIONSHIP |
| Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study. Niacin extended-release/lovastatin is a new combination product approved for treatment of primary hypercholesterolemia and mixed dyslipidemia. This open-labeled, multicenter study evaluated the safety of bedtime niacin extended-release/lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with dyslipidemia requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of niacin extended-release/20 mg of CHEMICAL) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about dyslipidemia and niacin extended-release/lovastatin. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical DISEASE. Final study status was available for 4,217 patients (94%). Compliance to niacin extended-release/lovastatin was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. Flushing was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased aspartate aminotransferase and/or alanine aminotransferase >3 times the upper limit of normal was <0.3%. An increase of creatine phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced DISEASE were observed. Niacin extended-release/lovastatin 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes. | NO-RELATIONSHIP |
| Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study. Niacin extended-release/lovastatin is a new combination product approved for treatment of primary DISEASE and mixed dyslipidemia. This open-labeled, multicenter study evaluated the safety of bedtime niacin extended-release/lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with dyslipidemia requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of CHEMICAL extended-release/20 mg of lovastatin) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about dyslipidemia and niacin extended-release/lovastatin. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical myopathy. Final study status was available for 4,217 patients (94%). Compliance to niacin extended-release/lovastatin was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. Flushing was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased aspartate aminotransferase and/or alanine aminotransferase >3 times the upper limit of normal was <0.3%. An increase of creatine phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced myopathy were observed. Niacin extended-release/lovastatin 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes. | NO-RELATIONSHIP |
| Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study. Niacin extended-release/lovastatin is a new combination product approved for treatment of primary hypercholesterolemia and mixed DISEASE. This open-labeled, multicenter study evaluated the safety of bedtime niacin extended-release/lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with DISEASE requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of niacin extended-release/20 mg of lovastatin) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about DISEASE and niacin extended-release/lovastatin. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical myopathy. Final study status was available for 4,217 patients (94%). Compliance to niacin extended-release/lovastatin was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. Flushing was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased aspartate aminotransferase and/or CHEMICAL aminotransferase >3 times the upper limit of normal was <0.3%. An increase of creatine phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced myopathy were observed. Niacin extended-release/lovastatin 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes. | NO-RELATIONSHIP |
| Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study. Niacin extended-release/lovastatin is a new combination product approved for treatment of primary hypercholesterolemia and mixed DISEASE. This open-labeled, multicenter study evaluated the safety of bedtime niacin extended-release/lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with DISEASE requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of CHEMICAL extended-release/20 mg of lovastatin) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about DISEASE and niacin extended-release/lovastatin. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical myopathy. Final study status was available for 4,217 patients (94%). Compliance to niacin extended-release/lovastatin was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. Flushing was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased aspartate aminotransferase and/or alanine aminotransferase >3 times the upper limit of normal was <0.3%. An increase of creatine phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced myopathy were observed. Niacin extended-release/lovastatin 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes. | NO-RELATIONSHIP |
| Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study. Niacin extended-release/lovastatin is a new combination product approved for treatment of primary DISEASE and mixed dyslipidemia. This open-labeled, multicenter study evaluated the safety of bedtime niacin extended-release/lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with dyslipidemia requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of niacin extended-release/20 mg of CHEMICAL) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about dyslipidemia and niacin extended-release/lovastatin. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical myopathy. Final study status was available for 4,217 patients (94%). Compliance to niacin extended-release/lovastatin was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. Flushing was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased aspartate aminotransferase and/or alanine aminotransferase >3 times the upper limit of normal was <0.3%. An increase of creatine phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced myopathy were observed. Niacin extended-release/lovastatin 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes. | NO-RELATIONSHIP |
| Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study. Niacin extended-release/lovastatin is a new combination product approved for treatment of primary DISEASE and mixed dyslipidemia. This open-labeled, multicenter study evaluated the safety of bedtime niacin extended-release/lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with dyslipidemia requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of niacin extended-release/20 mg of lovastatin) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about dyslipidemia and niacin extended-release/lovastatin. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical myopathy. Final study status was available for 4,217 patients (94%). Compliance to niacin extended-release/lovastatin was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. Flushing was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased CHEMICAL aminotransferase and/or alanine aminotransferase >3 times the upper limit of normal was <0.3%. An increase of creatine phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced myopathy were observed. Niacin extended-release/lovastatin 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes. | NO-RELATIONSHIP |
| Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study. Niacin extended-release/lovastatin is a new combination product approved for treatment of primary hypercholesterolemia and mixed DISEASE. This open-labeled, multicenter study evaluated the safety of bedtime niacin extended-release/lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with DISEASE requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of niacin extended-release/20 mg of CHEMICAL) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about DISEASE and niacin extended-release/lovastatin. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical myopathy. Final study status was available for 4,217 patients (94%). Compliance to niacin extended-release/lovastatin was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. Flushing was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased aspartate aminotransferase and/or alanine aminotransferase >3 times the upper limit of normal was <0.3%. An increase of creatine phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced myopathy were observed. Niacin extended-release/lovastatin 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes. | NO-RELATIONSHIP |
| Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study. Niacin extended-release/lovastatin is a new combination product approved for treatment of primary hypercholesterolemia and mixed dyslipidemia. This open-labeled, multicenter study evaluated the safety of bedtime niacin extended-release/lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with dyslipidemia requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of niacin extended-release/20 mg of lovastatin) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about dyslipidemia and niacin extended-release/lovastatin. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical DISEASE. Final study status was available for 4,217 patients (94%). Compliance to niacin extended-release/lovastatin was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. Flushing was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased aspartate aminotransferase and/or CHEMICAL aminotransferase >3 times the upper limit of normal was <0.3%. An increase of creatine phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced DISEASE were observed. Niacin extended-release/lovastatin 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes. | NO-RELATIONSHIP |
| Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study. Niacin extended-release/lovastatin is a new combination product approved for treatment of primary hypercholesterolemia and mixed dyslipidemia. This open-labeled, multicenter study evaluated the safety of bedtime niacin extended-release/lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with dyslipidemia requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of CHEMICAL extended-release/20 mg of lovastatin) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about dyslipidemia and niacin extended-release/lovastatin. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical DISEASE. Final study status was available for 4,217 patients (94%). Compliance to niacin extended-release/lovastatin was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. Flushing was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased aspartate aminotransferase and/or alanine aminotransferase >3 times the upper limit of normal was <0.3%. An increase of creatine phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced DISEASE were observed. Niacin extended-release/lovastatin 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes. | NO-RELATIONSHIP |
| Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study. Niacin extended-release/lovastatin is a new combination product approved for treatment of primary DISEASE and mixed dyslipidemia. This open-labeled, multicenter study evaluated the safety of bedtime niacin extended-release/lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with dyslipidemia requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of niacin extended-release/20 mg of lovastatin) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about dyslipidemia and niacin extended-release/lovastatin. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical myopathy. Final study status was available for 4,217 patients (94%). Compliance to niacin extended-release/lovastatin was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. Flushing was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased aspartate aminotransferase and/or CHEMICAL aminotransferase >3 times the upper limit of normal was <0.3%. An increase of creatine phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced myopathy were observed. Niacin extended-release/lovastatin 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes. | NO-RELATIONSHIP |
| Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study. Niacin extended-release/lovastatin is a new combination product approved for treatment of primary hypercholesterolemia and mixed DISEASE. This open-labeled, multicenter study evaluated the safety of bedtime niacin extended-release/lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with DISEASE requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of niacin extended-release/20 mg of lovastatin) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about DISEASE and niacin extended-release/lovastatin. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical myopathy. Final study status was available for 4,217 patients (94%). Compliance to niacin extended-release/lovastatin was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. Flushing was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased aspartate aminotransferase and/or alanine aminotransferase >3 times the upper limit of normal was <0.3%. An increase of CHEMICAL phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced myopathy were observed. Niacin extended-release/lovastatin 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes. | NO-RELATIONSHIP |
| Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study. Niacin extended-release/lovastatin is a new combination product approved for treatment of primary DISEASE and mixed dyslipidemia. This open-labeled, multicenter study evaluated the safety of bedtime niacin extended-release/lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with dyslipidemia requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of niacin extended-release/20 mg of lovastatin) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about dyslipidemia and niacin extended-release/lovastatin. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical myopathy. Final study status was available for 4,217 patients (94%). Compliance to niacin extended-release/lovastatin was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. Flushing was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased aspartate aminotransferase and/or alanine aminotransferase >3 times the upper limit of normal was <0.3%. An increase of CHEMICAL phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced myopathy were observed. Niacin extended-release/lovastatin 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes. | NO-RELATIONSHIP |
| Protective effect of Terminalia chebula against experimental myocardial injury induced by CHEMICAL. Cardioprotective effect of ethanolic extract of Terminalia chebula fruits (500 mg/kg body wt) was examined in CHEMICAL (200 mg/kg body wt) induced myocardial damage in rats. In CHEMICAL administered rats, the level of lipid peroxides increased significantly in the serum and heart. A significant decrease was observed in the activity of the myocardial marker enzymes with a concomitant increase in their activity in serum. Histopathological examination was carried out to confirm the myocardial DISEASE. T. chebula extract pretreatment was found to ameliorate the effect of CHEMICAL on lipid peroxide formation and retained the activities of the diagnostic marker enzymes. | CHEMICAL-INDUCED-DISEASE |
| Protective effect of Terminalia chebula against experimental DISEASE induced by CHEMICAL. Cardioprotective effect of ethanolic extract of Terminalia chebula fruits (500 mg/kg body wt) was examined in CHEMICAL (200 mg/kg body wt) induced DISEASE in rats. In CHEMICAL administered rats, the level of lipid peroxides increased significantly in the serum and heart. A significant decrease was observed in the activity of the myocardial marker enzymes with a concomitant increase in their activity in serum. Histopathological examination was carried out to confirm the myocardial necrosis. T. chebula extract pretreatment was found to ameliorate the effect of CHEMICAL on lipid peroxide formation and retained the activities of the diagnostic marker enzymes. | CHEMICAL-INDUCED-DISEASE |
| A case of postoperative DISEASE due to low dose CHEMICAL used with patient-controlled analgesia. A multiparous woman in good psychological health underwent urgent caesarean section in labour. Postoperatively, she was given a patient-controlled analgesia device delivering boluses of diamorphine 0.5 mg and CHEMICAL 0.025 mg. Whilst using the device she gradually became anxious, the feeling worsening after each bolus. The diagnosis of CHEMICAL-induced DISEASE was not made straight away although on subsequent close questioning the patient gave a very clear history. After she had received a total of only 0.9 mg CHEMICAL, a syringe containing diamorphine only was substituted and her unease resolved completely. We feel that, although the dramatic extrapyramidal side effects of dopaminergic antiemetics are well known, more subtle manifestations may easily be overlooked. | CHEMICAL-INDUCED-DISEASE |
| Accurate patient history contributes to differentiating diabetes insipidus: a case study. This case study highlights the important contribution of nursing in obtaining an accurate health history. The case discussed herein initially appeared to be DISEASE (DI) secondary to a traumatic brain injury. The nursing staff, by reviewing the patient's health history with his family, discovered a history of polydipsia and long-standing CHEMICAL use. CHEMICAL is implicated in drug-induced DISEASE, and because the patient had not received CHEMICAL since being admitted to the hospital, his treatment changed to focus on DISEASE. By combining information from the patient history, the physical examination, and radiologic and laboratory studies, the critical care team demonstrated that the patient had been self-treating his CHEMICAL-induced DISEASE and developed DISEASE secondary to brain trauma. Thus successful treatment required that nephrogenic and DISEASE be treated concomitantly. | CHEMICAL-INDUCED-DISEASE |
| Factors contributing to CHEMICAL-induced anemia. BACKGROUND AND AIM: Interferon and CHEMICAL combination therapy for chronic hepatitis C produces DISEASE. This study was conducted to identify the factors contributing to CHEMICAL-induced anemia. METHODS: Eighty-eight patients with chronic hepatitis C who received interferon-alpha-2b at a dose of 6 MU administered intramuscularly for 24 weeks in combination with CHEMICAL administered orally at a dose of 600 mg or 800 mg participated in the study. A hemoglobin concentration of <10 g/dL was defined as CHEMICAL-induced anemia. RESULTS: CHEMICAL-induced anemia occurred in 18 (20.5%) patients during treatment. A 2 g/dL decrease in hemoglobin concentrations in patients with anemia was observed at week 2 after the start of treatment. The hemoglobin concentration in patients with > or =2 g/dL decrease at week 2 was observed to be significantly lower even after week 2 than in patients with <2 g/dL decrease (P < 0.01). A significant relationship was observed between the rate of reduction of hemoglobin concentrations at week 2 and the severity of anemia (P < 0.01). Such factors as sex (female), age (> or =60 years old), and the CHEMICAL dose by body weight (12 mg/kg or more) were significant by univariate analysis. CONCLUSIONS: Careful administration is necessary in patients > or =60 years old, in female patients, and in patients receiving a CHEMICAL dose of 12 mg/kg or more. Patients who experience a fall in hemoglobin concentrations of 2 g/dL or more at week 2 after the start of treatment should be monitored with particular care. | CHEMICAL-INDUCED-DISEASE |
| Factors contributing to ribavirin-induced anemia. BACKGROUND AND AIM: CHEMICAL and ribavirin combination therapy for chronic hepatitis C produces DISEASE. This study was conducted to identify the factors contributing to ribavirin-induced anemia. METHODS: Eighty-eight patients with chronic hepatitis C who received CHEMICAL at a dose of 6 MU administered intramuscularly for 24 weeks in combination with ribavirin administered orally at a dose of 600 mg or 800 mg participated in the study. A hemoglobin concentration of <10 g/dL was defined as ribavirin-induced anemia. RESULTS: Ribavirin-induced anemia occurred in 18 (20.5%) patients during treatment. A 2 g/dL decrease in hemoglobin concentrations in patients with anemia was observed at week 2 after the start of treatment. The hemoglobin concentration in patients with > or =2 g/dL decrease at week 2 was observed to be significantly lower even after week 2 than in patients with <2 g/dL decrease (P < 0.01). A significant relationship was observed between the rate of reduction of hemoglobin concentrations at week 2 and the severity of anemia (P < 0.01). Such factors as sex (female), age (> or =60 years old), and the ribavirin dose by body weight (12 mg/kg or more) were significant by univariate analysis. CONCLUSIONS: Careful administration is necessary in patients > or =60 years old, in female patients, and in patients receiving a ribavirin dose of 12 mg/kg or more. Patients who experience a fall in hemoglobin concentrations of 2 g/dL or more at week 2 after the start of treatment should be monitored with particular care. | CHEMICAL-INDUCED-DISEASE |
| Oxidative damage precedes nitrative damage in CHEMICAL-induced cardiac DISEASE. The purpose of the present study was to determine if elevated reactive oxygen (ROS)/nitrogen species (RNS) reported to be present in CHEMICAL (CHEMICAL)-induced cardiotoxicity actually resulted in cardiomyocyte oxidative/nitrative damage, and to quantitatively determine the time course and subcellular localization of these postulated damage products using an in vivo approach. B6C3 mice were treated with a single dose of 20 mg/kg CHEMICAL. Ultrastructural damage and levels of 4-hydroxy-2-nonenal (4HNE)-protein adducts and 3-nitrotyrosine (3NT) were analyzed. Quantitative ultrastructural damage using computerized image techniques showed cardiomyocyte injury as early as 3 hours, with mitochondria being the most extensively and progressively injured subcellular organelle. Analysis of 4HNE protein adducts by immunogold electron microscopy showed appearance of 4HNE protein adducts in mitochondria as early as 3 hours, with a peak at 6 hours and subsequent decline at 24 hours. 3NT levels were significantly increased in all subcellular compartments at 6 hours and subsequently declined at 24 hours. Our data showed CHEMICAL induced 4HNE-protein adducts in mitochondria at the same time point as when DISEASE initially appeared. These results document for the first time in vivo that DISEASE precedes nitrative damage. The progressive nature of DISEASE suggests that mitochondria, not other subcellular organelles, are the major site of intracellular injury. | CHEMICAL-INDUCED-DISEASE |
| Oxidative damage precedes nitrative damage in adriamycin-induced cardiac mitochondrial injury. The purpose of the present study was to determine if elevated reactive CHEMICAL (ROS)/nitrogen species (RNS) reported to be present in adriamycin (ADR)-induced DISEASE actually resulted in cardiomyocyte oxidative/nitrative damage, and to quantitatively determine the time course and subcellular localization of these postulated damage products using an in vivo approach. B6C3 mice were treated with a single dose of 20 mg/kg ADR. Ultrastructural damage and levels of 4-hydroxy-2-nonenal (4HNE)-protein adducts and 3-nitrotyrosine (3NT) were analyzed. Quantitative ultrastructural damage using computerized image techniques showed cardiomyocyte injury as early as 3 hours, with mitochondria being the most extensively and progressively injured subcellular organelle. Analysis of 4HNE protein adducts by immunogold electron microscopy showed appearance of 4HNE protein adducts in mitochondria as early as 3 hours, with a peak at 6 hours and subsequent decline at 24 hours. 3NT levels were significantly increased in all subcellular compartments at 6 hours and subsequently declined at 24 hours. Our data showed ADR induced 4HNE-protein adducts in mitochondria at the same time point as when mitochondrial injury initially appeared. These results document for the first time in vivo that mitochondrial oxidative damage precedes nitrative damage. The progressive nature of mitochondrial injury suggests that mitochondria, not other subcellular organelles, are the major site of intracellular injury. | NO-RELATIONSHIP |
| Oxidative damage precedes nitrative damage in adriamycin-induced cardiac mitochondrial injury. The purpose of the present study was to determine if elevated reactive oxygen (ROS)/nitrogen species (RNS) reported to be present in adriamycin (ADR)-induced DISEASE actually resulted in cardiomyocyte oxidative/nitrative damage, and to quantitatively determine the time course and subcellular localization of these postulated damage products using an in vivo approach. B6C3 mice were treated with a single dose of 20 mg/kg ADR. Ultrastructural damage and levels of CHEMICAL (CHEMICAL)-protein adducts and 3-nitrotyrosine (3NT) were analyzed. Quantitative ultrastructural damage using computerized image techniques showed cardiomyocyte injury as early as 3 hours, with mitochondria being the most extensively and progressively injured subcellular organelle. Analysis of CHEMICAL protein adducts by immunogold electron microscopy showed appearance of CHEMICAL protein adducts in mitochondria as early as 3 hours, with a peak at 6 hours and subsequent decline at 24 hours. 3NT levels were significantly increased in all subcellular compartments at 6 hours and subsequently declined at 24 hours. Our data showed ADR induced CHEMICAL-protein adducts in mitochondria at the same time point as when mitochondrial injury initially appeared. These results document for the first time in vivo that mitochondrial oxidative damage precedes nitrative damage. The progressive nature of mitochondrial injury suggests that mitochondria, not other subcellular organelles, are the major site of intracellular injury. | NO-RELATIONSHIP |
| Oxidative damage precedes nitrative damage in adriamycin-induced cardiac mitochondrial injury. The purpose of the present study was to determine if elevated reactive oxygen (ROS)/nitrogen species (RNS) reported to be present in adriamycin (ADR)-induced DISEASE actually resulted in cardiomyocyte oxidative/nitrative damage, and to quantitatively determine the time course and subcellular localization of these postulated damage products using an in vivo approach. B6C3 mice were treated with a single dose of 20 mg/kg ADR. Ultrastructural damage and levels of 4-hydroxy-2-nonenal (4HNE)-protein adducts and CHEMICAL (CHEMICAL) were analyzed. Quantitative ultrastructural damage using computerized image techniques showed cardiomyocyte injury as early as 3 hours, with mitochondria being the most extensively and progressively injured subcellular organelle. Analysis of 4HNE protein adducts by immunogold electron microscopy showed appearance of 4HNE protein adducts in mitochondria as early as 3 hours, with a peak at 6 hours and subsequent decline at 24 hours. CHEMICAL levels were significantly increased in all subcellular compartments at 6 hours and subsequently declined at 24 hours. Our data showed ADR induced 4HNE-protein adducts in mitochondria at the same time point as when mitochondrial injury initially appeared. These results document for the first time in vivo that mitochondrial oxidative damage precedes nitrative damage. The progressive nature of mitochondrial injury suggests that mitochondria, not other subcellular organelles, are the major site of intracellular injury. | NO-RELATIONSHIP |
| Oxidative damage precedes nitrative damage in adriamycin-induced cardiac mitochondrial injury. The purpose of the present study was to determine if elevated reactive oxygen (ROS)/CHEMICAL species (RNS) reported to be present in adriamycin (ADR)-induced DISEASE actually resulted in cardiomyocyte oxidative/nitrative damage, and to quantitatively determine the time course and subcellular localization of these postulated damage products using an in vivo approach. B6C3 mice were treated with a single dose of 20 mg/kg ADR. Ultrastructural damage and levels of 4-hydroxy-2-nonenal (4HNE)-protein adducts and 3-nitrotyrosine (3NT) were analyzed. Quantitative ultrastructural damage using computerized image techniques showed cardiomyocyte injury as early as 3 hours, with mitochondria being the most extensively and progressively injured subcellular organelle. Analysis of 4HNE protein adducts by immunogold electron microscopy showed appearance of 4HNE protein adducts in mitochondria as early as 3 hours, with a peak at 6 hours and subsequent decline at 24 hours. 3NT levels were significantly increased in all subcellular compartments at 6 hours and subsequently declined at 24 hours. Our data showed ADR induced 4HNE-protein adducts in mitochondria at the same time point as when mitochondrial injury initially appeared. These results document for the first time in vivo that mitochondrial oxidative damage precedes nitrative damage. The progressive nature of mitochondrial injury suggests that mitochondria, not other subcellular organelles, are the major site of intracellular injury. | NO-RELATIONSHIP |
| CHEMICAL-induced DISEASE in a patient with dilated cardiomyopathy associated with sustained ventricular tachycardia. A 54-year-old man with severe left ventricular dysfunction due to dilated cardiomyopathy was referred to our hospital for symptomatic incessant sustained ventricular tachycardia (VT). After the administration of nifekalant hydrochloride, sustained VT was terminated. An alternate class III agent, CHEMICAL, was also effective for the prevention of VT. However, one month after switching over nifekalant to CHEMICAL, a short duration of ST elevation was documented in ECG monitoring at almost the same time for three consecutive days. ST elevation with chest discomfort disappeared since he began taking long-acting diltiazem. DISEASE may be induced by the non-selective beta-blocking properties of CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Sotalol-induced coronary spasm in a patient with dilated cardiomyopathy associated with sustained DISEASE. A 54-year-old man with severe left ventricular dysfunction due to dilated cardiomyopathy was referred to our hospital for symptomatic incessant sustained DISEASE (DISEASE). After the administration of CHEMICAL, sustained DISEASE was terminated. An alternate class III agent, sotalol, was also effective for the prevention of DISEASE. However, one month after switching over CHEMICAL to sotalol, a short duration of ST elevation was documented in ECG monitoring at almost the same time for three consecutive days. ST elevation with chest discomfort disappeared since he began taking long-acting diltiazem. Coronary vasospasm may be induced by the non-selective beta-blocking properties of sotalol. | CHEMICAL-INDUCED-DISEASE |
| Sotalol-induced coronary spasm in a patient with DISEASE associated with sustained ventricular tachycardia. A 54-year-old man with severe left ventricular dysfunction due to DISEASE was referred to our hospital for symptomatic incessant sustained ventricular tachycardia (VT). After the administration of nifekalant hydrochloride, sustained VT was terminated. An alternate class III agent, sotalol, was also effective for the prevention of VT. However, one month after switching over nifekalant to sotalol, a short duration of ST elevation was documented in ECG monitoring at almost the same time for three consecutive days. ST elevation with chest discomfort disappeared since he began taking long-acting CHEMICAL. Coronary vasospasm may be induced by the non-selective beta-blocking properties of sotalol. | NO-RELATIONSHIP |
| Sotalol-induced coronary spasm in a patient with dilated cardiomyopathy associated with sustained ventricular tachycardia. A 54-year-old man with severe left DISEASE due to dilated cardiomyopathy was referred to our hospital for symptomatic incessant sustained ventricular tachycardia (VT). After the administration of nifekalant hydrochloride, sustained VT was terminated. An alternate class III agent, sotalol, was also effective for the prevention of VT. However, one month after switching over nifekalant to sotalol, a short duration of ST elevation was documented in ECG monitoring at almost the same time for three consecutive days. ST elevation with chest discomfort disappeared since he began taking long-acting CHEMICAL. Coronary vasospasm may be induced by the non-selective beta-blocking properties of sotalol. | NO-RELATIONSHIP |
| Sotalol-induced coronary spasm in a patient with DISEASE associated with sustained ventricular tachycardia. A 54-year-old man with severe left ventricular dysfunction due to DISEASE was referred to our hospital for symptomatic incessant sustained ventricular tachycardia (VT). After the administration of CHEMICAL, sustained VT was terminated. An alternate class III agent, sotalol, was also effective for the prevention of VT. However, one month after switching over CHEMICAL to sotalol, a short duration of ST elevation was documented in ECG monitoring at almost the same time for three consecutive days. ST elevation with chest discomfort disappeared since he began taking long-acting diltiazem. Coronary vasospasm may be induced by the non-selective beta-blocking properties of sotalol. | NO-RELATIONSHIP |
| Sotalol-induced coronary spasm in a patient with dilated cardiomyopathy associated with sustained ventricular tachycardia. A 54-year-old man with severe left DISEASE due to dilated cardiomyopathy was referred to our hospital for symptomatic incessant sustained ventricular tachycardia (VT). After the administration of CHEMICAL, sustained VT was terminated. An alternate class III agent, sotalol, was also effective for the prevention of VT. However, one month after switching over CHEMICAL to sotalol, a short duration of ST elevation was documented in ECG monitoring at almost the same time for three consecutive days. ST elevation with chest discomfort disappeared since he began taking long-acting diltiazem. Coronary vasospasm may be induced by the non-selective beta-blocking properties of sotalol. | NO-RELATIONSHIP |
| Sotalol-induced coronary spasm in a patient with dilated cardiomyopathy associated with sustained DISEASE. A 54-year-old man with severe left ventricular dysfunction due to dilated cardiomyopathy was referred to our hospital for symptomatic incessant sustained DISEASE (DISEASE). After the administration of nifekalant hydrochloride, sustained DISEASE was terminated. An alternate class III agent, sotalol, was also effective for the prevention of DISEASE. However, one month after switching over nifekalant to sotalol, a short duration of ST elevation was documented in ECG monitoring at almost the same time for three consecutive days. ST elevation with chest discomfort disappeared since he began taking long-acting CHEMICAL. Coronary vasospasm may be induced by the non-selective beta-blocking properties of sotalol. | NO-RELATIONSHIP |
| Effects of the antidepressant trazodone, a 5-HT 2A/2C receptor antagonist, on dopamine-dependent behaviors in rats. RATIONALE: 5-Hydroxytryptamine, via stimulation of 5-HT 2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT 2A receptors enhances stimulated DAergic neurotransmission. The antidepressant trazodone is a 5-HT 2A/2C receptor antagonist. OBJECTIVES: To evaluate the effect of trazodone treatment on behaviors dependent on the functional status of the nigrostriatal DAergic system. METHODS: The effect of pretreatment with trazodone on dexamphetamine- and CHEMICAL-induced oral stereotypies, on DISEASE induced by haloperidol and CHEMICAL (0.05 mg/kg, i.p.), on ergometrine-induced wet dog shake (WDS) behavior and fluoxetine-induced penile erections was studied in rats. We also investigated whether trazodone induces DISEASE in rats. RESULTS: Trazodone at 2.5-20 mg/kg i.p. did not induce DISEASE, and did not antagonize CHEMICAL (1.5 and 3 mg/kg) stereotypy and CHEMICAL (0.05 mg/kg)-induced DISEASE. However, pretreatment with 5, 10 and 20 mg/kg i.p. trazodone enhanced dexamphetamine stereotypy, and antagonized haloperidol DISEASE, ergometrine-induced WDS behavior and fluoxetine-induced penile erections. Trazodone at 30, 40 and 50 mg/kg i.p. induced DISEASE and antagonized CHEMICAL and dexamphetamine stereotypies. CONCLUSIONS: Our results indicate that trazodone at 2.5-20 mg/kg does not block pre- and postsynaptic striatal D2 DA receptors, while at 30, 40 and 50 mg/kg it blocks postsynaptic striatal D2 DA receptors. Furthermore, at 5, 10 and 20 mg/kg, trazodone blocks 5-HT 2A and 5-HT 2C receptors. We suggest that trazodone (5, 10 and 20 mg/kg), by blocking the 5-HT 2C receptors, releases the nigrostriatal DAergic neurons from tonic inhibition caused by 5-HT, and thereby potentiates dexamphetamine stereotypy and antagonizes haloperidol DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Effects of the antidepressant trazodone, a 5-HT 2A/2C receptor antagonist, on dopamine-dependent behaviors in rats. RATIONALE: 5-Hydroxytryptamine, via stimulation of 5-HT 2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT 2A receptors enhances stimulated DAergic neurotransmission. The antidepressant trazodone is a 5-HT 2A/2C receptor antagonist. OBJECTIVES: To evaluate the effect of trazodone treatment on behaviors dependent on the functional status of the nigrostriatal DAergic system. METHODS: The effect of pretreatment with trazodone on dexamphetamine- and apomorphine-induced oral stereotypies, on DISEASE induced by CHEMICAL and apomorphine (0.05 mg/kg, i.p.), on ergometrine-induced wet dog shake (WDS) behavior and fluoxetine-induced penile erections was studied in rats. We also investigated whether trazodone induces DISEASE in rats. RESULTS: Trazodone at 2.5-20 mg/kg i.p. did not induce DISEASE, and did not antagonize apomorphine (1.5 and 3 mg/kg) stereotypy and apomorphine (0.05 mg/kg)-induced DISEASE. However, pretreatment with 5, 10 and 20 mg/kg i.p. trazodone enhanced dexamphetamine stereotypy, and antagonized CHEMICAL DISEASE, ergometrine-induced WDS behavior and fluoxetine-induced penile erections. Trazodone at 30, 40 and 50 mg/kg i.p. induced DISEASE and antagonized apomorphine and dexamphetamine stereotypies. CONCLUSIONS: Our results indicate that trazodone at 2.5-20 mg/kg does not block pre- and postsynaptic striatal D2 DA receptors, while at 30, 40 and 50 mg/kg it blocks postsynaptic striatal D2 DA receptors. Furthermore, at 5, 10 and 20 mg/kg, trazodone blocks 5-HT 2A and 5-HT 2C receptors. We suggest that trazodone (5, 10 and 20 mg/kg), by blocking the 5-HT 2C receptors, releases the nigrostriatal DAergic neurons from tonic inhibition caused by 5-HT, and thereby potentiates dexamphetamine stereotypy and antagonizes CHEMICAL DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Effects of the antidepressant trazodone, a 5-HT 2A/2C receptor antagonist, on dopamine-dependent behaviors in rats. RATIONALE: 5-Hydroxytryptamine, via stimulation of 5-HT 2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT 2A receptors enhances stimulated DAergic neurotransmission. The antidepressant trazodone is a 5-HT 2A/2C receptor antagonist. OBJECTIVES: To evaluate the effect of trazodone treatment on behaviors dependent on the functional status of the nigrostriatal DAergic system. METHODS: The effect of pretreatment with trazodone on CHEMICAL- and apomorphine-induced DISEASE, on catalepsy induced by haloperidol and apomorphine (0.05 mg/kg, i.p.), on ergometrine-induced wet dog shake (WDS) behavior and fluoxetine-induced penile erections was studied in rats. We also investigated whether trazodone induces catalepsy in rats. RESULTS: Trazodone at 2.5-20 mg/kg i.p. did not induce catalepsy, and did not antagonize apomorphine (1.5 and 3 mg/kg) stereotypy and apomorphine (0.05 mg/kg)-induced catalepsy. However, pretreatment with 5, 10 and 20 mg/kg i.p. trazodone enhanced CHEMICAL stereotypy, and antagonized haloperidol catalepsy, ergometrine-induced WDS behavior and fluoxetine-induced penile erections. Trazodone at 30, 40 and 50 mg/kg i.p. induced catalepsy and antagonized apomorphine and CHEMICAL stereotypies. CONCLUSIONS: Our results indicate that trazodone at 2.5-20 mg/kg does not block pre- and postsynaptic striatal D2 DA receptors, while at 30, 40 and 50 mg/kg it blocks postsynaptic striatal D2 DA receptors. Furthermore, at 5, 10 and 20 mg/kg, trazodone blocks 5-HT 2A and 5-HT 2C receptors. We suggest that trazodone (5, 10 and 20 mg/kg), by blocking the 5-HT 2C receptors, releases the nigrostriatal DAergic neurons from tonic inhibition caused by 5-HT, and thereby potentiates CHEMICAL stereotypy and antagonizes haloperidol catalepsy. | CHEMICAL-INDUCED-DISEASE |
| Effects of the antidepressant trazodone, a 5-HT 2A/2C receptor antagonist, on CHEMICAL-dependent behaviors in rats. RATIONALE: 5-Hydroxytryptamine, via stimulation of 5-HT 2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT 2A receptors enhances stimulated DAergic neurotransmission. The antidepressant trazodone is a 5-HT 2A/2C receptor antagonist. OBJECTIVES: To evaluate the effect of trazodone treatment on behaviors dependent on the functional status of the nigrostriatal DAergic system. METHODS: The effect of pretreatment with trazodone on dexamphetamine- and apomorphine-induced DISEASE, on catalepsy induced by haloperidol and apomorphine (0.05 mg/kg, i.p.), on ergometrine-induced wet dog shake (WDS) behavior and fluoxetine-induced penile erections was studied in rats. We also investigated whether trazodone induces catalepsy in rats. RESULTS: Trazodone at 2.5-20 mg/kg i.p. did not induce catalepsy, and did not antagonize apomorphine (1.5 and 3 mg/kg) stereotypy and apomorphine (0.05 mg/kg)-induced catalepsy. However, pretreatment with 5, 10 and 20 mg/kg i.p. trazodone enhanced dexamphetamine stereotypy, and antagonized haloperidol catalepsy, ergometrine-induced WDS behavior and fluoxetine-induced penile erections. Trazodone at 30, 40 and 50 mg/kg i.p. induced catalepsy and antagonized apomorphine and dexamphetamine stereotypies. CONCLUSIONS: Our results indicate that trazodone at 2.5-20 mg/kg does not block pre- and postsynaptic striatal D2 DA receptors, while at 30, 40 and 50 mg/kg it blocks postsynaptic striatal D2 DA receptors. Furthermore, at 5, 10 and 20 mg/kg, trazodone blocks 5-HT 2A and 5-HT 2C receptors. We suggest that trazodone (5, 10 and 20 mg/kg), by blocking the 5-HT 2C receptors, releases the nigrostriatal DAergic neurons from tonic inhibition caused by 5-HT, and thereby potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy. | NO-RELATIONSHIP |
| Effects of the antidepressant trazodone, a CHEMICAL 2A/2C receptor antagonist, on dopamine-dependent behaviors in rats. RATIONALE: CHEMICAL, via stimulation of CHEMICAL 2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of CHEMICAL 2A receptors enhances stimulated DAergic neurotransmission. The antidepressant trazodone is a CHEMICAL 2A/2C receptor antagonist. OBJECTIVES: To evaluate the effect of trazodone treatment on behaviors dependent on the functional status of the nigrostriatal DAergic system. METHODS: The effect of pretreatment with trazodone on dexamphetamine- and apomorphine-induced DISEASE, on catalepsy induced by haloperidol and apomorphine (0.05 mg/kg, i.p.), on ergometrine-induced wet dog shake (WDS) behavior and fluoxetine-induced penile erections was studied in rats. We also investigated whether trazodone induces catalepsy in rats. RESULTS: Trazodone at 2.5-20 mg/kg i.p. did not induce catalepsy, and did not antagonize apomorphine (1.5 and 3 mg/kg) stereotypy and apomorphine (0.05 mg/kg)-induced catalepsy. However, pretreatment with 5, 10 and 20 mg/kg i.p. trazodone enhanced dexamphetamine stereotypy, and antagonized haloperidol catalepsy, ergometrine-induced WDS behavior and fluoxetine-induced penile erections. Trazodone at 30, 40 and 50 mg/kg i.p. induced catalepsy and antagonized apomorphine and dexamphetamine stereotypies. CONCLUSIONS: Our results indicate that trazodone at 2.5-20 mg/kg does not block pre- and postsynaptic striatal D2 DA receptors, while at 30, 40 and 50 mg/kg it blocks postsynaptic striatal D2 DA receptors. Furthermore, at 5, 10 and 20 mg/kg, trazodone blocks CHEMICAL 2A and CHEMICAL 2C receptors. We suggest that trazodone (5, 10 and 20 mg/kg), by blocking the CHEMICAL 2C receptors, releases the nigrostriatal DAergic neurons from tonic inhibition caused by CHEMICAL, and thereby potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy. | NO-RELATIONSHIP |
| Effects of the antidepressant trazodone, a 5-HT 2A/2C receptor antagonist, on dopamine-dependent behaviors in rats. RATIONALE: 5-Hydroxytryptamine, via stimulation of 5-HT 2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT 2A receptors enhances stimulated DAergic neurotransmission. The antidepressant trazodone is a 5-HT 2A/2C receptor antagonist. OBJECTIVES: To evaluate the effect of trazodone treatment on behaviors dependent on the functional status of the nigrostriatal DAergic system. METHODS: The effect of pretreatment with trazodone on dexamphetamine- and apomorphine-induced DISEASE, on catalepsy induced by haloperidol and apomorphine (0.05 mg/kg, i.p.), on ergometrine-induced wet dog shake (WDS) behavior and CHEMICAL-induced penile erections was studied in rats. We also investigated whether trazodone induces catalepsy in rats. RESULTS: Trazodone at 2.5-20 mg/kg i.p. did not induce catalepsy, and did not antagonize apomorphine (1.5 and 3 mg/kg) stereotypy and apomorphine (0.05 mg/kg)-induced catalepsy. However, pretreatment with 5, 10 and 20 mg/kg i.p. trazodone enhanced dexamphetamine stereotypy, and antagonized haloperidol catalepsy, ergometrine-induced WDS behavior and CHEMICAL-induced penile erections. Trazodone at 30, 40 and 50 mg/kg i.p. induced catalepsy and antagonized apomorphine and dexamphetamine stereotypies. CONCLUSIONS: Our results indicate that trazodone at 2.5-20 mg/kg does not block pre- and postsynaptic striatal D2 DA receptors, while at 30, 40 and 50 mg/kg it blocks postsynaptic striatal D2 DA receptors. Furthermore, at 5, 10 and 20 mg/kg, trazodone blocks 5-HT 2A and 5-HT 2C receptors. We suggest that trazodone (5, 10 and 20 mg/kg), by blocking the 5-HT 2C receptors, releases the nigrostriatal DAergic neurons from tonic inhibition caused by 5-HT, and thereby potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy. | CHEMICAL-INDUCED-DISEASE |
| Effects of the antidepressant CHEMICAL, a 5-HT 2A/2C receptor antagonist, on dopamine-dependent behaviors in rats. RATIONALE: 5-Hydroxytryptamine, via stimulation of 5-HT 2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT 2A receptors enhances stimulated DAergic neurotransmission. The antidepressant CHEMICAL is a 5-HT 2A/2C receptor antagonist. OBJECTIVES: To evaluate the effect of CHEMICAL treatment on behaviors dependent on the functional status of the nigrostriatal DAergic system. METHODS: The effect of pretreatment with CHEMICAL on dexamphetamine- and apomorphine-induced DISEASE, on catalepsy induced by haloperidol and apomorphine (0.05 mg/kg, i.p.), on ergometrine-induced wet dog shake (WDS) behavior and fluoxetine-induced penile erections was studied in rats. We also investigated whether CHEMICAL induces catalepsy in rats. RESULTS: CHEMICAL at 2.5-20 mg/kg i.p. did not induce catalepsy, and did not antagonize apomorphine (1.5 and 3 mg/kg) stereotypy and apomorphine (0.05 mg/kg)-induced catalepsy. However, pretreatment with 5, 10 and 20 mg/kg i.p. CHEMICAL enhanced dexamphetamine stereotypy, and antagonized haloperidol catalepsy, ergometrine-induced WDS behavior and fluoxetine-induced penile erections. CHEMICAL at 30, 40 and 50 mg/kg i.p. induced catalepsy and antagonized apomorphine and dexamphetamine stereotypies. CONCLUSIONS: Our results indicate that CHEMICAL at 2.5-20 mg/kg does not block pre- and postsynaptic striatal D2 DA receptors, while at 30, 40 and 50 mg/kg it blocks postsynaptic striatal D2 DA receptors. Furthermore, at 5, 10 and 20 mg/kg, CHEMICAL blocks 5-HT 2A and 5-HT 2C receptors. We suggest that CHEMICAL (5, 10 and 20 mg/kg), by blocking the 5-HT 2C receptors, releases the nigrostriatal DAergic neurons from tonic inhibition caused by 5-HT, and thereby potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy. | NO-RELATIONSHIP |
| Effects of the antidepressant trazodone, a 5-HT 2A/2C receptor antagonist, on dopamine-dependent behaviors in rats. RATIONALE: 5-Hydroxytryptamine, via stimulation of 5-HT 2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT 2A receptors enhances stimulated DAergic neurotransmission. The antidepressant trazodone is a 5-HT 2A/2C receptor antagonist. OBJECTIVES: To evaluate the effect of trazodone treatment on behaviors dependent on the functional status of the nigrostriatal DAergic system. METHODS: The effect of pretreatment with trazodone on dexamphetamine- and apomorphine-induced DISEASE, on catalepsy induced by haloperidol and apomorphine (0.05 mg/kg, i.p.), on CHEMICAL-induced wet dog shake (WDS) behavior and fluoxetine-induced penile erections was studied in rats. We also investigated whether trazodone induces catalepsy in rats. RESULTS: Trazodone at 2.5-20 mg/kg i.p. did not induce catalepsy, and did not antagonize apomorphine (1.5 and 3 mg/kg) stereotypy and apomorphine (0.05 mg/kg)-induced catalepsy. However, pretreatment with 5, 10 and 20 mg/kg i.p. trazodone enhanced dexamphetamine stereotypy, and antagonized haloperidol catalepsy, CHEMICAL-induced WDS behavior and fluoxetine-induced penile erections. Trazodone at 30, 40 and 50 mg/kg i.p. induced catalepsy and antagonized apomorphine and dexamphetamine stereotypies. CONCLUSIONS: Our results indicate that trazodone at 2.5-20 mg/kg does not block pre- and postsynaptic striatal D2 DA receptors, while at 30, 40 and 50 mg/kg it blocks postsynaptic striatal D2 DA receptors. Furthermore, at 5, 10 and 20 mg/kg, trazodone blocks 5-HT 2A and 5-HT 2C receptors. We suggest that trazodone (5, 10 and 20 mg/kg), by blocking the 5-HT 2C receptors, releases the nigrostriatal DAergic neurons from tonic inhibition caused by 5-HT, and thereby potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy. | CHEMICAL-INDUCED-DISEASE |
| Swallowing abnormalities and DISEASE in Parkinson's disease. Gastrointestinal abnormalities in Parkinson's disease (PD) have been known for almost two centuries, but many aspects concerning their pathophysiology have not been completely clarified. The aim of this study was to characterize the oropharyngeal dynamics in PD patients with and without CHEMICAL-induced DISEASE. Fifteen DISEASE, 12 nondyskinetic patients, and a control group were included. Patients were asked about dysphagia and evaluated with the Unified Parkinson's Disease Rating Scale Parts II and III and the Hoehn and Yahr scale. Deglutition was assessed using modified barium swallow with videofluoroscopy. Nondyskinetic patients, but not the DISEASE ones, showed less oropharyngeal swallowing efficiency (OPSE) for liquid food than controls (Dunnett, P = 0.02). DISEASE patients tended to have a greater OPSE than nondyskinetic (Dunnett, P = 0.06). Patients who were using a higher dose of CHEMICAL had a greater OPSE and a trend toward a smaller oral transit time (Pearson's correlation, P = 0.01 and 0.08, respectively). Neither the report of dysphagia nor any of the PD severity parameters correlated to the videofluoroscopic variables. In the current study, DISEASE patients performed better in swallowing function, which could be explained on the basis of a greater CHEMICAL dose. Our results suggest a role for CHEMICAL in the oral phase of deglutition and confirm that dysphagia is not a good predictor of deglutition alterations in PD. | CHEMICAL-INDUCED-DISEASE |
| Swallowing abnormalities and dyskinesia in Parkinson's disease. Gastrointestinal abnormalities in Parkinson's disease (PD) have been known for almost two centuries, but many aspects concerning their pathophysiology have not been completely clarified. The aim of this study was to characterize the oropharyngeal dynamics in PD patients with and without levodopa-induced dyskinesia. Fifteen dyskinetic, 12 nondyskinetic patients, and a control group were included. Patients were asked about DISEASE and evaluated with the Unified Parkinson's Disease Rating Scale Parts II and III and the Hoehn and Yahr scale. Deglutition was assessed using modified CHEMICAL swallow with videofluoroscopy. Nondyskinetic patients, but not the dyskinetic ones, showed less oropharyngeal swallowing efficiency (OPSE) for liquid food than controls (Dunnett, P = 0.02). Dyskinetic patients tended to have a greater OPSE than nondyskinetic (Dunnett, P = 0.06). Patients who were using a higher dose of levodopa had a greater OPSE and a trend toward a smaller oral transit time (Pearson's correlation, P = 0.01 and 0.08, respectively). Neither the report of DISEASE nor any of the PD severity parameters correlated to the videofluoroscopic variables. In the current study, dyskinetic patients performed better in swallowing function, which could be explained on the basis of a greater levodopa dose. Our results suggest a role for levodopa in the oral phase of deglutition and confirm that DISEASE is not a good predictor of deglutition alterations in PD. | NO-RELATIONSHIP |
| Swallowing abnormalities and dyskinesia in DISEASE. Gastrointestinal abnormalities in DISEASE (DISEASE) have been known for almost two centuries, but many aspects concerning their pathophysiology have not been completely clarified. The aim of this study was to characterize the oropharyngeal dynamics in DISEASE patients with and without levodopa-induced dyskinesia. Fifteen dyskinetic, 12 nondyskinetic patients, and a control group were included. Patients were asked about dysphagia and evaluated with the Unified DISEASE Rating Scale Parts II and III and the Hoehn and Yahr scale. Deglutition was assessed using modified CHEMICAL swallow with videofluoroscopy. Nondyskinetic patients, but not the dyskinetic ones, showed less oropharyngeal swallowing efficiency (OPSE) for liquid food than controls (Dunnett, P = 0.02). Dyskinetic patients tended to have a greater OPSE than nondyskinetic (Dunnett, P = 0.06). Patients who were using a higher dose of levodopa had a greater OPSE and a trend toward a smaller oral transit time (Pearson's correlation, P = 0.01 and 0.08, respectively). Neither the report of dysphagia nor any of the DISEASE severity parameters correlated to the videofluoroscopic variables. In the current study, dyskinetic patients performed better in swallowing function, which could be explained on the basis of a greater levodopa dose. Our results suggest a role for levodopa in the oral phase of deglutition and confirm that dysphagia is not a good predictor of deglutition alterations in DISEASE. | NO-RELATIONSHIP |
| Swallowing abnormalities and dyskinesia in Parkinson's disease. DISEASE in Parkinson's disease (PD) have been known for almost two centuries, but many aspects concerning their pathophysiology have not been completely clarified. The aim of this study was to characterize the oropharyngeal dynamics in PD patients with and without levodopa-induced dyskinesia. Fifteen dyskinetic, 12 nondyskinetic patients, and a control group were included. Patients were asked about dysphagia and evaluated with the Unified Parkinson's Disease Rating Scale Parts II and III and the Hoehn and Yahr scale. Deglutition was assessed using modified CHEMICAL swallow with videofluoroscopy. Nondyskinetic patients, but not the dyskinetic ones, showed less oropharyngeal swallowing efficiency (OPSE) for liquid food than controls (Dunnett, P = 0.02). Dyskinetic patients tended to have a greater OPSE than nondyskinetic (Dunnett, P = 0.06). Patients who were using a higher dose of levodopa had a greater OPSE and a trend toward a smaller oral transit time (Pearson's correlation, P = 0.01 and 0.08, respectively). Neither the report of dysphagia nor any of the PD severity parameters correlated to the videofluoroscopic variables. In the current study, dyskinetic patients performed better in swallowing function, which could be explained on the basis of a greater levodopa dose. Our results suggest a role for levodopa in the oral phase of deglutition and confirm that dysphagia is not a good predictor of deglutition alterations in PD. | NO-RELATIONSHIP |
| DISEASE and dyskinesia in Parkinson's disease. Gastrointestinal abnormalities in Parkinson's disease (PD) have been known for almost two centuries, but many aspects concerning their pathophysiology have not been completely clarified. The aim of this study was to characterize the oropharyngeal dynamics in PD patients with and without levodopa-induced dyskinesia. Fifteen dyskinetic, 12 nondyskinetic patients, and a control group were included. Patients were asked about dysphagia and evaluated with the Unified Parkinson's Disease Rating Scale Parts II and III and the Hoehn and Yahr scale. Deglutition was assessed using modified CHEMICAL swallow with videofluoroscopy. Nondyskinetic patients, but not the dyskinetic ones, showed less oropharyngeal swallowing efficiency (OPSE) for liquid food than controls (Dunnett, P = 0.02). Dyskinetic patients tended to have a greater OPSE than nondyskinetic (Dunnett, P = 0.06). Patients who were using a higher dose of levodopa had a greater OPSE and a trend toward a smaller oral transit time (Pearson's correlation, P = 0.01 and 0.08, respectively). Neither the report of dysphagia nor any of the PD severity parameters correlated to the videofluoroscopic variables. In the current study, dyskinetic patients performed better in swallowing function, which could be explained on the basis of a greater levodopa dose. Our results suggest a role for levodopa in the oral phase of deglutition and confirm that dysphagia is not a good predictor of deglutition alterations in PD. | NO-RELATIONSHIP |
| Inhibition of nuclear factor-kappaB activation attenuates DISEASE induced by CHEMICAL. BACKGROUND: Animals treated with CHEMICAL can show residual areas of interstitial fibrosis in the renal cortex. This study investigated the expression of nuclear factor-kappaB (NF-kappaB), mitogen-activated protein (MAP) kinases and macrophages in the renal cortex and structural and functional renal changes of rats treated with CHEMICAL or CHEMICAL + pyrrolidine dithiocarbamate (PDTC), an NF-kappaB inhibitor. METHODS: 38 female Wistar rats were injected with CHEMICAL, 40 mg/kg, twice a day for 9 days, 38 with CHEMICAL + PDTC, and 28 with 0.15 M NaCl solution. The animals were killed 5 and 30 days after these injections and the kidneys were removed for histological and immunohistochemical studies. The results of the immunohistochemical studies were scored according to the extent of staining. The fractional interstitial area was determined by morphometry. RESULTS: CHEMICAL-treated rats presented a transitory increase in plasma creatinine levels. Increased ED-1, MAP kinases and NF-kappaB staining were also observed in the renal cortex from all CHEMICAL-treated rats compared to control (p < 0.05). The animals killed on day 30 also presented fibrosis in the renal cortex despite the recovery of renal function. Treatment with PDTC reduced the functional and structural changes induced by CHEMICAL. CONCLUSIONS: These data show that inhibition of NF-kappaB activation attenuates DISEASE induced by CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Inhibition of nuclear factor-kappaB activation attenuates tubulointerstitial nephritis induced by gentamicin. BACKGROUND: Animals treated with gentamicin can show residual areas of interstitial DISEASE in the renal cortex. This study investigated the expression of nuclear factor-kappaB (NF-kappaB), mitogen-activated protein (MAP) kinases and macrophages in the renal cortex and structural and functional renal changes of rats treated with gentamicin or gentamicin + pyrrolidine dithiocarbamate (PDTC), an NF-kappaB inhibitor. METHODS: 38 female Wistar rats were injected with gentamicin, 40 mg/kg, twice a day for 9 days, 38 with gentamicin + PDTC, and 28 with 0.15 M NaCl solution. The animals were killed 5 and 30 days after these injections and the kidneys were removed for histological and immunohistochemical studies. The results of the immunohistochemical studies were scored according to the extent of staining. The fractional interstitial area was determined by morphometry. RESULTS: Gentamicin-treated rats presented a transitory increase in plasma CHEMICAL levels. Increased ED-1, MAP kinases and NF-kappaB staining were also observed in the renal cortex from all gentamicin-treated rats compared to control (p < 0.05). The animals killed on day 30 also presented DISEASE in the renal cortex despite the recovery of renal function. Treatment with PDTC reduced the functional and structural changes induced by gentamicin. CONCLUSIONS: These data show that inhibition of NF-kappaB activation attenuates tubulointerstitial nephritis induced by gentamicin. | NO-RELATIONSHIP |
| Inhibition of nuclear factor-kappaB activation attenuates tubulointerstitial nephritis induced by gentamicin. BACKGROUND: Animals treated with gentamicin can show residual areas of interstitial DISEASE in the renal cortex. This study investigated the expression of nuclear factor-kappaB (NF-kappaB), mitogen-activated protein (MAP) kinases and macrophages in the renal cortex and structural and functional renal changes of rats treated with gentamicin or gentamicin + pyrrolidine dithiocarbamate (PDTC), an NF-kappaB inhibitor. METHODS: 38 female Wistar rats were injected with gentamicin, 40 mg/kg, twice a day for 9 days, 38 with gentamicin + PDTC, and 28 with 0.15 M CHEMICAL solution. The animals were killed 5 and 30 days after these injections and the kidneys were removed for histological and immunohistochemical studies. The results of the immunohistochemical studies were scored according to the extent of staining. The fractional interstitial area was determined by morphometry. RESULTS: Gentamicin-treated rats presented a transitory increase in plasma creatinine levels. Increased ED-1, MAP kinases and NF-kappaB staining were also observed in the renal cortex from all gentamicin-treated rats compared to control (p < 0.05). The animals killed on day 30 also presented DISEASE in the renal cortex despite the recovery of renal function. Treatment with PDTC reduced the functional and structural changes induced by gentamicin. CONCLUSIONS: These data show that inhibition of NF-kappaB activation attenuates tubulointerstitial nephritis induced by gentamicin. | NO-RELATIONSHIP |
| Inhibition of nuclear factor-kappaB activation attenuates tubulointerstitial nephritis induced by gentamicin. BACKGROUND: Animals treated with gentamicin can show residual areas of interstitial DISEASE in the renal cortex. This study investigated the expression of nuclear factor-kappaB (NF-kappaB), mitogen-activated protein (MAP) kinases and macrophages in the renal cortex and structural and functional renal changes of rats treated with gentamicin or gentamicin + CHEMICAL (CHEMICAL), an NF-kappaB inhibitor. METHODS: 38 female Wistar rats were injected with gentamicin, 40 mg/kg, twice a day for 9 days, 38 with gentamicin + CHEMICAL, and 28 with 0.15 M NaCl solution. The animals were killed 5 and 30 days after these injections and the kidneys were removed for histological and immunohistochemical studies. The results of the immunohistochemical studies were scored according to the extent of staining. The fractional interstitial area was determined by morphometry. RESULTS: Gentamicin-treated rats presented a transitory increase in plasma creatinine levels. Increased ED-1, MAP kinases and NF-kappaB staining were also observed in the renal cortex from all gentamicin-treated rats compared to control (p < 0.05). The animals killed on day 30 also presented DISEASE in the renal cortex despite the recovery of renal function. Treatment with CHEMICAL reduced the functional and structural changes induced by gentamicin. CONCLUSIONS: These data show that inhibition of NF-kappaB activation attenuates tubulointerstitial nephritis induced by gentamicin. | NO-RELATIONSHIP |
| Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis. BACKGROUND: While the incidence of new-onset diabetes mellitus may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for diabetes. OBJECTIVE: To study the 2 drugs most clearly implicated (clozapine and CHEMICAL) and risperidone using a frequently sampled intravenous glucose tolerance test. DESIGN: A cross-sectional design in stable, treated patients with schizophrenia evaluated using a frequently sampled intravenous glucose tolerance test and the Bergman minimal model analysis. SETTING: Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center. Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous glucose tolerance test. Thirty-six nonobese subjects with schizophrenia or schizoaffective disorder, matched by body mass index and treated with either clozapine, CHEMICAL, or risperidone, were included in the analysis. MAIN OUTCOME MEASURES: Fasting plasma glucose and fasting serum insulin levels, DISEASE index, homeostasis model assessment of DISEASE, and glucose effectiveness. RESULTS: The mean +/- SD duration of treatment with the identified atypical antipsychotic agent was 68.3 +/- 28.9 months (clozapine), 29.5 +/- 17.5 months (CHEMICAL), and 40.9 +/- 33.7 (risperidone). Fasting serum insulin concentrations differed among groups (F(33) = 3.35; P = .047) (clozapine>CHEMICAL>risperidone) with significant differences between clozapine and risperidone (t(33) = 2.32; P = .03) and CHEMICAL and risperidone (t(33) = 2.15; P = .04). There was a significant difference in DISEASE index among groups (F(33) = 10.66; P<.001) (clozapine<CHEMICAL | CHEMICAL-INDUCED-DISEASE |
| Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis. BACKGROUND: While the incidence of new-onset diabetes mellitus may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for diabetes. OBJECTIVE: To study the 2 drugs most clearly implicated (CHEMICAL and olanzapine) and risperidone using a frequently sampled intravenous glucose tolerance test. DESIGN: A cross-sectional design in stable, treated patients with schizophrenia evaluated using a frequently sampled intravenous glucose tolerance test and the Bergman minimal model analysis. SETTING: Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center. Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous glucose tolerance test. Thirty-six nonobese subjects with schizophrenia or schizoaffective disorder, matched by body mass index and treated with either CHEMICAL, olanzapine, or risperidone, were included in the analysis. MAIN OUTCOME MEASURES: Fasting plasma glucose and fasting serum insulin levels, DISEASE index, homeostasis model assessment of DISEASE, and glucose effectiveness. RESULTS: The mean +/- SD duration of treatment with the identified atypical antipsychotic agent was 68.3 +/- 28.9 months (CHEMICAL), 29.5 +/- 17.5 months (olanzapine), and 40.9 +/- 33.7 (risperidone). Fasting serum insulin concentrations differed among groups (F(33) = 3.35; P = .047) (CHEMICAL>olanzapine>risperidone) with significant differences between CHEMICAL and risperidone (t(33) = 2.32; P = .03) and olanzapine and risperidone (t(33) = 2.15; P = .04). There was a significant difference in DISEASE index among groups (F(33) = 10.66; P<.001) (CHEMICAL | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous CHEMICAL tolerance test and minimal model analysis. BACKGROUND: While the incidence of new-onset diabetes mellitus may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting CHEMICAL metabolism or simply increasing known risk factors for diabetes. OBJECTIVE: To study the 2 drugs most clearly implicated (clozapine and olanzapine) and risperidone using a frequently sampled intravenous CHEMICAL tolerance test. DESIGN: A cross-sectional design in stable, treated patients with schizophrenia evaluated using a frequently sampled intravenous CHEMICAL tolerance test and the Bergman minimal model analysis. SETTING: Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center. Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous CHEMICAL tolerance test. Thirty-six nonobese subjects with schizophrenia or DISEASE, matched by body mass index and treated with either clozapine, olanzapine, or risperidone, were included in the analysis. MAIN OUTCOME MEASURES: Fasting plasma CHEMICAL and fasting serum insulin levels, insulin sensitivity index, homeostasis model assessment of insulin resistance, and CHEMICAL effectiveness. RESULTS: The mean +/- SD duration of treatment with the identified atypical antipsychotic agent was 68.3 +/- 28.9 months (clozapine), 29.5 +/- 17.5 months (olanzapine), and 40.9 +/- 33.7 (risperidone). Fasting serum insulin concentrations differed among groups (F(33) = 3.35; P = .047) (clozapine>olanzapine>risperidone) with significant differences between clozapine and risperidone (t(33) = 2.32; P = .03) and olanzapine and risperidone (t(33) = 2.15; P = .04). There was a significant difference in insulin sensitivity index among groups (F(33) = 10.66; P<.001) (clozapine | NO-RELATIONSHIP |
| Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis. BACKGROUND: While the incidence of new-onset DISEASE may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for DISEASE. OBJECTIVE: To study the 2 drugs most clearly implicated (clozapine and olanzapine) and CHEMICAL using a frequently sampled intravenous glucose tolerance test. DESIGN: A cross-sectional design in stable, treated patients with schizophrenia evaluated using a frequently sampled intravenous glucose tolerance test and the Bergman minimal model analysis. SETTING: Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center. Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous glucose tolerance test. Thirty-six nonobese subjects with schizophrenia or schizoaffective disorder, matched by body mass index and treated with either clozapine, olanzapine, or CHEMICAL, were included in the analysis. MAIN OUTCOME MEASURES: Fasting plasma glucose and fasting serum insulin levels, insulin sensitivity index, homeostasis model assessment of insulin resistance, and glucose effectiveness. RESULTS: The mean +/- SD duration of treatment with the identified atypical antipsychotic agent was 68.3 +/- 28.9 months (clozapine), 29.5 +/- 17.5 months (olanzapine), and 40.9 +/- 33.7 (CHEMICAL). Fasting serum insulin concentrations differed among groups (F(33) = 3.35; P = .047) (clozapine>olanzapine>CHEMICAL) with significant differences between clozapine and CHEMICAL (t(33) = 2.32; P = .03) and olanzapine and CHEMICAL (t(33) = 2.15; P = .04). There was a significant difference in insulin sensitivity index among groups (F(33) = 10.66; P<.001) (clozapine | CHEMICAL-INDUCED-DISEASE |
| Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis. BACKGROUND: While the incidence of new-onset diabetes mellitus may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for diabetes. OBJECTIVE: To study the 2 drugs most clearly implicated (clozapine and olanzapine) and CHEMICAL using a frequently sampled intravenous glucose tolerance test. DESIGN: A cross-sectional design in stable, treated patients with schizophrenia evaluated using a frequently sampled intravenous glucose tolerance test and the Bergman minimal model analysis. SETTING: Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center. Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous glucose tolerance test. Thirty-six nonobese subjects with schizophrenia or DISEASE, matched by body mass index and treated with either clozapine, olanzapine, or CHEMICAL, were included in the analysis. MAIN OUTCOME MEASURES: Fasting plasma glucose and fasting serum insulin levels, insulin sensitivity index, homeostasis model assessment of insulin resistance, and glucose effectiveness. RESULTS: The mean +/- SD duration of treatment with the identified atypical antipsychotic agent was 68.3 +/- 28.9 months (clozapine), 29.5 +/- 17.5 months (olanzapine), and 40.9 +/- 33.7 (CHEMICAL). Fasting serum insulin concentrations differed among groups (F(33) = 3.35; P = .047) (clozapine>olanzapine>CHEMICAL) with significant differences between clozapine and CHEMICAL (t(33) = 2.32; P = .03) and olanzapine and CHEMICAL (t(33) = 2.15; P = .04). There was a significant difference in insulin sensitivity index among groups (F(33) = 10.66; P<.001) (clozapine | NO-RELATIONSHIP |
| CHEMICAL metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous CHEMICAL tolerance test and minimal model analysis. BACKGROUND: While the incidence of new-onset DISEASE may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting CHEMICAL metabolism or simply increasing known risk factors for DISEASE. OBJECTIVE: To study the 2 drugs most clearly implicated (clozapine and olanzapine) and risperidone using a frequently sampled intravenous CHEMICAL tolerance test. DESIGN: A cross-sectional design in stable, treated patients with schizophrenia evaluated using a frequently sampled intravenous CHEMICAL tolerance test and the Bergman minimal model analysis. SETTING: Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center. Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous CHEMICAL tolerance test. Thirty-six nonobese subjects with schizophrenia or schizoaffective disorder, matched by body mass index and treated with either clozapine, olanzapine, or risperidone, were included in the analysis. MAIN OUTCOME MEASURES: Fasting plasma CHEMICAL and fasting serum insulin levels, insulin sensitivity index, homeostasis model assessment of insulin resistance, and CHEMICAL effectiveness. RESULTS: The mean +/- SD duration of treatment with the identified atypical antipsychotic agent was 68.3 +/- 28.9 months (clozapine), 29.5 +/- 17.5 months (olanzapine), and 40.9 +/- 33.7 (risperidone). Fasting serum insulin concentrations differed among groups (F(33) = 3.35; P = .047) (clozapine>olanzapine>risperidone) with significant differences between clozapine and risperidone (t(33) = 2.32; P = .03) and olanzapine and risperidone (t(33) = 2.15; P = .04). There was a significant difference in insulin sensitivity index among groups (F(33) = 10.66; P<.001) (clozapine | NO-RELATIONSHIP |
| Glucose metabolism in patients with DISEASE treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis. BACKGROUND: While the incidence of new-onset diabetes mellitus may be increasing in patients with DISEASE treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for diabetes. OBJECTIVE: To study the 2 drugs most clearly implicated (clozapine and olanzapine) and CHEMICAL using a frequently sampled intravenous glucose tolerance test. DESIGN: A cross-sectional design in stable, treated patients with DISEASE evaluated using a frequently sampled intravenous glucose tolerance test and the Bergman minimal model analysis. SETTING: Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center. Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous glucose tolerance test. Thirty-six nonobese subjects with DISEASE or schizoaffective disorder, matched by body mass index and treated with either clozapine, olanzapine, or CHEMICAL, were included in the analysis. MAIN OUTCOME MEASURES: Fasting plasma glucose and fasting serum insulin levels, insulin sensitivity index, homeostasis model assessment of insulin resistance, and glucose effectiveness. RESULTS: The mean +/- SD duration of treatment with the identified atypical antipsychotic agent was 68.3 +/- 28.9 months (clozapine), 29.5 +/- 17.5 months (olanzapine), and 40.9 +/- 33.7 (CHEMICAL). Fasting serum insulin concentrations differed among groups (F(33) = 3.35; P = .047) (clozapine>olanzapine>CHEMICAL) with significant differences between clozapine and CHEMICAL (t(33) = 2.32; P = .03) and olanzapine and CHEMICAL (t(33) = 2.15; P = .04). There was a significant difference in insulin sensitivity index among groups (F(33) = 10.66; P<.001) (clozapine | NO-RELATIONSHIP |
| CHEMICAL metabolism in patients with DISEASE treated with atypical antipsychotic agents: a frequently sampled intravenous CHEMICAL tolerance test and minimal model analysis. BACKGROUND: While the incidence of new-onset diabetes mellitus may be increasing in patients with DISEASE treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting CHEMICAL metabolism or simply increasing known risk factors for diabetes. OBJECTIVE: To study the 2 drugs most clearly implicated (clozapine and olanzapine) and risperidone using a frequently sampled intravenous CHEMICAL tolerance test. DESIGN: A cross-sectional design in stable, treated patients with DISEASE evaluated using a frequently sampled intravenous CHEMICAL tolerance test and the Bergman minimal model analysis. SETTING: Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center. Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous CHEMICAL tolerance test. Thirty-six nonobese subjects with DISEASE or schizoaffective disorder, matched by body mass index and treated with either clozapine, olanzapine, or risperidone, were included in the analysis. MAIN OUTCOME MEASURES: Fasting plasma CHEMICAL and fasting serum insulin levels, insulin sensitivity index, homeostasis model assessment of insulin resistance, and CHEMICAL effectiveness. RESULTS: The mean +/- SD duration of treatment with the identified atypical antipsychotic agent was 68.3 +/- 28.9 months (clozapine), 29.5 +/- 17.5 months (olanzapine), and 40.9 +/- 33.7 (risperidone). Fasting serum insulin concentrations differed among groups (F(33) = 3.35; P = .047) (clozapine>olanzapine>risperidone) with significant differences between clozapine and risperidone (t(33) = 2.32; P = .03) and olanzapine and risperidone (t(33) = 2.15; P = .04). There was a significant difference in insulin sensitivity index among groups (F(33) = 10.66; P<.001) (clozapine | NO-RELATIONSHIP |
| Focal cerebral ischemia in rats: effect of CHEMICAL-induced DISEASE during reperfusion. After 180 min of temporary middle cerebral artery occlusion in spontaneously DISEASE rats, the effect of CHEMICAL-induced DISEASE on ischemic brain injury and blood-brain barrier permeability was determined. Blood pressure was manipulated by one of the following schedules during 120 min of reperfusion: Control, normotensive reperfusion; 90/DISEASE (90/DISEASE), blood pressure was increased by 35 mm Hg during the initial 90 min of reperfusion only; 15/DISEASE (15/DISEASE), normotensive reperfusion for 30 min followed by 15 min of DISEASE and 75 min of normotension. Part A, for eight rats in each group brain injury was evaluated by staining tissue using 2,3,5-triphenyltetrazolium chloride and edema was evaluated by microgravimetry. Part B, for eight different rats in each group blood-brain barrier permeability was evaluated by measuring the amount and extent of extravasation of Evans Blue dye. Brain injury (percentage of the ischemic hemisphere) was less in the 15/DISEASE group (16 +/- 6, mean +/- SD) versus the 90/DISEASE group (30 +/- 6), which was in turn less than the control group (42 +/- 5). Specific gravity was greater in the 15/DISEASE group (1.043 +/- 0.002) versus the 90/DISEASE (1.036 +/- 0.003) and control (1.037 +/- 0.003) groups. Evans Blue (mug g-1 of brain tissue) was greater in the 90/DISEASE group (24.4 +/- 6.0) versus the control group (12.3 +/- 4.1), which was in turn greater than the 15/DISEASE group (7.3 +/- 3.2). This study supports a hypothesis that during reperfusion, a short interval of DISEASE decreases brain injury and edema; and that sustained DISEASE increases the risk of vasogenic edema. | CHEMICAL-INDUCED-DISEASE |
| Focal cerebral ischemia in rats: effect of phenylephrine-induced hypertension during reperfusion. After 180 min of temporary middle cerebral artery occlusion in spontaneously hypertensive rats, the effect of phenylephrine-induced hypertension on DISEASE and blood-brain barrier permeability was determined. Blood pressure was manipulated by one of the following schedules during 120 min of reperfusion: Control, normotensive reperfusion; 90/hypertension (90/HTN), blood pressure was increased by 35 mm Hg during the initial 90 min of reperfusion only; 15/hypertension (15/HTN), normotensive reperfusion for 30 min followed by 15 min of hypertension and 75 min of normotension. Part A, for eight rats in each group DISEASE was evaluated by staining tissue using CHEMICAL and edema was evaluated by microgravimetry. Part B, for eight different rats in each group blood-brain barrier permeability was evaluated by measuring the amount and extent of extravasation of Evans Blue dye. DISEASE (percentage of the ischemic hemisphere) was less in the 15/HTN group (16 +/- 6, mean +/- SD) versus the 90/HTN group (30 +/- 6), which was in turn less than the control group (42 +/- 5). Specific gravity was greater in the 15/HTN group (1.043 +/- 0.002) versus the 90/HTN (1.036 +/- 0.003) and control (1.037 +/- 0.003) groups. Evans Blue (mug g-1 of brain tissue) was greater in the 90/HTN group (24.4 +/- 6.0) versus the control group (12.3 +/- 4.1), which was in turn greater than the 15/HTN group (7.3 +/- 3.2). This study supports a hypothesis that during reperfusion, a short interval of hypertension decreases DISEASE and edema; and that sustained hypertension increases the risk of vasogenic edema. | NO-RELATIONSHIP |
| Focal cerebral ischemia in rats: effect of phenylephrine-induced hypertension during reperfusion. After 180 min of temporary DISEASE in spontaneously hypertensive rats, the effect of phenylephrine-induced hypertension on ischemic brain injury and blood-brain barrier permeability was determined. Blood pressure was manipulated by one of the following schedules during 120 min of reperfusion: Control, normotensive reperfusion; 90/hypertension (90/HTN), blood pressure was increased by 35 mm Hg during the initial 90 min of reperfusion only; 15/hypertension (15/HTN), normotensive reperfusion for 30 min followed by 15 min of hypertension and 75 min of normotension. Part A, for eight rats in each group brain injury was evaluated by staining tissue using 2,3,5-triphenyltetrazolium chloride and edema was evaluated by microgravimetry. Part B, for eight different rats in each group blood-brain barrier permeability was evaluated by measuring the amount and extent of extravasation of Evans Blue dye. Brain injury (percentage of the ischemic hemisphere) was less in the 15/HTN group (16 +/- 6, mean +/- SD) versus the 90/HTN group (30 +/- 6), which was in turn less than the control group (42 +/- 5). Specific gravity was greater in the 15/HTN group (1.043 +/- 0.002) versus the 90/HTN (1.036 +/- 0.003) and control (1.037 +/- 0.003) groups. CHEMICAL (mug g-1 of brain tissue) was greater in the 90/HTN group (24.4 +/- 6.0) versus the control group (12.3 +/- 4.1), which was in turn greater than the 15/HTN group (7.3 +/- 3.2). This study supports a hypothesis that during reperfusion, a short interval of hypertension decreases brain injury and edema; and that sustained hypertension increases the risk of vasogenic edema. | NO-RELATIONSHIP |
| Focal cerebral ischemia in rats: effect of phenylephrine-induced hypertension during reperfusion. After 180 min of temporary DISEASE in spontaneously hypertensive rats, the effect of phenylephrine-induced hypertension on ischemic brain injury and blood-brain barrier permeability was determined. Blood pressure was manipulated by one of the following schedules during 120 min of reperfusion: Control, normotensive reperfusion; 90/hypertension (90/HTN), blood pressure was increased by 35 mm Hg during the initial 90 min of reperfusion only; 15/hypertension (15/HTN), normotensive reperfusion for 30 min followed by 15 min of hypertension and 75 min of normotension. Part A, for eight rats in each group brain injury was evaluated by staining tissue using CHEMICAL and edema was evaluated by microgravimetry. Part B, for eight different rats in each group blood-brain barrier permeability was evaluated by measuring the amount and extent of extravasation of Evans Blue dye. Brain injury (percentage of the ischemic hemisphere) was less in the 15/HTN group (16 +/- 6, mean +/- SD) versus the 90/HTN group (30 +/- 6), which was in turn less than the control group (42 +/- 5). Specific gravity was greater in the 15/HTN group (1.043 +/- 0.002) versus the 90/HTN (1.036 +/- 0.003) and control (1.037 +/- 0.003) groups. Evans Blue (mug g-1 of brain tissue) was greater in the 90/HTN group (24.4 +/- 6.0) versus the control group (12.3 +/- 4.1), which was in turn greater than the 15/HTN group (7.3 +/- 3.2). This study supports a hypothesis that during reperfusion, a short interval of hypertension decreases brain injury and edema; and that sustained hypertension increases the risk of vasogenic edema. | NO-RELATIONSHIP |
| Focal cerebral ischemia in rats: effect of phenylephrine-induced hypertension during reperfusion. After 180 min of temporary middle cerebral artery occlusion in spontaneously hypertensive rats, the effect of phenylephrine-induced hypertension on ischemic brain injury and blood-brain barrier permeability was determined. Blood pressure was manipulated by one of the following schedules during 120 min of reperfusion: Control, normotensive reperfusion; 90/hypertension (90/HTN), blood pressure was increased by 35 mm Hg during the initial 90 min of reperfusion only; 15/hypertension (15/HTN), normotensive reperfusion for 30 min followed by 15 min of hypertension and 75 min of normotension. Part A, for eight rats in each group brain injury was evaluated by staining tissue using 2,3,5-triphenyltetrazolium chloride and DISEASE was evaluated by microgravimetry. Part B, for eight different rats in each group blood-brain barrier permeability was evaluated by measuring the amount and extent of extravasation of Evans Blue dye. Brain injury (percentage of the ischemic hemisphere) was less in the 15/HTN group (16 +/- 6, mean +/- SD) versus the 90/HTN group (30 +/- 6), which was in turn less than the control group (42 +/- 5). Specific gravity was greater in the 15/HTN group (1.043 +/- 0.002) versus the 90/HTN (1.036 +/- 0.003) and control (1.037 +/- 0.003) groups. CHEMICAL (mug g-1 of brain tissue) was greater in the 90/HTN group (24.4 +/- 6.0) versus the control group (12.3 +/- 4.1), which was in turn greater than the 15/HTN group (7.3 +/- 3.2). This study supports a hypothesis that during reperfusion, a short interval of hypertension decreases brain injury and DISEASE; and that sustained hypertension increases the risk of vasogenic edema. | NO-RELATIONSHIP |
| Focal cerebral ischemia in rats: effect of phenylephrine-induced hypertension during reperfusion. After 180 min of temporary middle cerebral artery occlusion in spontaneously hypertensive rats, the effect of phenylephrine-induced hypertension on DISEASE and blood-brain barrier permeability was determined. Blood pressure was manipulated by one of the following schedules during 120 min of reperfusion: Control, normotensive reperfusion; 90/hypertension (90/HTN), blood pressure was increased by 35 mm Hg during the initial 90 min of reperfusion only; 15/hypertension (15/HTN), normotensive reperfusion for 30 min followed by 15 min of hypertension and 75 min of normotension. Part A, for eight rats in each group DISEASE was evaluated by staining tissue using 2,3,5-triphenyltetrazolium chloride and edema was evaluated by microgravimetry. Part B, for eight different rats in each group blood-brain barrier permeability was evaluated by measuring the amount and extent of extravasation of Evans Blue dye. DISEASE (percentage of the ischemic hemisphere) was less in the 15/HTN group (16 +/- 6, mean +/- SD) versus the 90/HTN group (30 +/- 6), which was in turn less than the control group (42 +/- 5). Specific gravity was greater in the 15/HTN group (1.043 +/- 0.002) versus the 90/HTN (1.036 +/- 0.003) and control (1.037 +/- 0.003) groups. CHEMICAL (mug g-1 of brain tissue) was greater in the 90/HTN group (24.4 +/- 6.0) versus the control group (12.3 +/- 4.1), which was in turn greater than the 15/HTN group (7.3 +/- 3.2). This study supports a hypothesis that during reperfusion, a short interval of hypertension decreases DISEASE and edema; and that sustained hypertension increases the risk of vasogenic edema. | NO-RELATIONSHIP |
| Focal cerebral ischemia in rats: effect of phenylephrine-induced hypertension during reperfusion. After 180 min of temporary middle cerebral artery occlusion in spontaneously hypertensive rats, the effect of phenylephrine-induced hypertension on ischemic brain injury and blood-brain barrier permeability was determined. Blood pressure was manipulated by one of the following schedules during 120 min of reperfusion: Control, normotensive reperfusion; 90/hypertension (90/HTN), blood pressure was increased by 35 mm Hg during the initial 90 min of reperfusion only; 15/hypertension (15/HTN), normotensive reperfusion for 30 min followed by 15 min of hypertension and 75 min of normotension. Part A, for eight rats in each group brain injury was evaluated by staining tissue using CHEMICAL and edema was evaluated by microgravimetry. Part B, for eight different rats in each group blood-brain barrier permeability was evaluated by measuring the amount and extent of extravasation of Evans Blue dye. Brain injury (percentage of the ischemic hemisphere) was less in the 15/HTN group (16 +/- 6, mean +/- SD) versus the 90/HTN group (30 +/- 6), which was in turn less than the control group (42 +/- 5). Specific gravity was greater in the 15/HTN group (1.043 +/- 0.002) versus the 90/HTN (1.036 +/- 0.003) and control (1.037 +/- 0.003) groups. Evans Blue (mug g-1 of brain tissue) was greater in the 90/HTN group (24.4 +/- 6.0) versus the control group (12.3 +/- 4.1), which was in turn greater than the 15/HTN group (7.3 +/- 3.2). This study supports a hypothesis that during reperfusion, a short interval of hypertension decreases brain injury and edema; and that sustained hypertension increases the risk of DISEASE. | NO-RELATIONSHIP |
| Focal DISEASE in rats: effect of phenylephrine-induced hypertension during reperfusion. After 180 min of temporary middle cerebral artery occlusion in spontaneously hypertensive rats, the effect of phenylephrine-induced hypertension on ischemic brain injury and blood-brain barrier permeability was determined. Blood pressure was manipulated by one of the following schedules during 120 min of reperfusion: Control, normotensive reperfusion; 90/hypertension (90/HTN), blood pressure was increased by 35 mm Hg during the initial 90 min of reperfusion only; 15/hypertension (15/HTN), normotensive reperfusion for 30 min followed by 15 min of hypertension and 75 min of normotension. Part A, for eight rats in each group brain injury was evaluated by staining tissue using CHEMICAL and edema was evaluated by microgravimetry. Part B, for eight different rats in each group blood-brain barrier permeability was evaluated by measuring the amount and extent of extravasation of Evans Blue dye. Brain injury (percentage of the DISEASE) was less in the 15/HTN group (16 +/- 6, mean +/- SD) versus the 90/HTN group (30 +/- 6), which was in turn less than the control group (42 +/- 5). Specific gravity was greater in the 15/HTN group (1.043 +/- 0.002) versus the 90/HTN (1.036 +/- 0.003) and control (1.037 +/- 0.003) groups. Evans Blue (mug g-1 of brain tissue) was greater in the 90/HTN group (24.4 +/- 6.0) versus the control group (12.3 +/- 4.1), which was in turn greater than the 15/HTN group (7.3 +/- 3.2). This study supports a hypothesis that during reperfusion, a short interval of hypertension decreases brain injury and edema; and that sustained hypertension increases the risk of vasogenic edema. | NO-RELATIONSHIP |
| Focal cerebral ischemia in rats: effect of phenylephrine-induced hypertension during reperfusion. After 180 min of temporary middle cerebral artery occlusion in spontaneously hypertensive rats, the effect of phenylephrine-induced hypertension on ischemic brain injury and blood-brain barrier permeability was determined. Blood pressure was manipulated by one of the following schedules during 120 min of reperfusion: Control, normotensive reperfusion; 90/hypertension (90/HTN), blood pressure was increased by 35 mm Hg during the initial 90 min of reperfusion only; 15/hypertension (15/HTN), normotensive reperfusion for 30 min followed by 15 min of hypertension and 75 min of normotension. Part A, for eight rats in each group brain injury was evaluated by staining tissue using 2,3,5-triphenyltetrazolium chloride and edema was evaluated by microgravimetry. Part B, for eight different rats in each group blood-brain barrier permeability was evaluated by measuring the amount and extent of extravasation of Evans Blue dye. Brain injury (percentage of the ischemic hemisphere) was less in the 15/HTN group (16 +/- 6, mean +/- SD) versus the 90/HTN group (30 +/- 6), which was in turn less than the control group (42 +/- 5). Specific gravity was greater in the 15/HTN group (1.043 +/- 0.002) versus the 90/HTN (1.036 +/- 0.003) and control (1.037 +/- 0.003) groups. CHEMICAL (mug g-1 of brain tissue) was greater in the 90/HTN group (24.4 +/- 6.0) versus the control group (12.3 +/- 4.1), which was in turn greater than the 15/HTN group (7.3 +/- 3.2). This study supports a hypothesis that during reperfusion, a short interval of hypertension decreases brain injury and edema; and that sustained hypertension increases the risk of DISEASE. | NO-RELATIONSHIP |
| Focal cerebral ischemia in rats: effect of phenylephrine-induced hypertension during reperfusion. After 180 min of temporary middle cerebral artery occlusion in spontaneously hypertensive rats, the effect of phenylephrine-induced hypertension on ischemic brain injury and blood-brain barrier permeability was determined. Blood pressure was manipulated by one of the following schedules during 120 min of reperfusion: Control, normotensive reperfusion; 90/hypertension (90/HTN), blood pressure was increased by 35 mm Hg during the initial 90 min of reperfusion only; 15/hypertension (15/HTN), normotensive reperfusion for 30 min followed by 15 min of hypertension and 75 min of normotension. Part A, for eight rats in each group brain injury was evaluated by staining tissue using CHEMICAL and DISEASE was evaluated by microgravimetry. Part B, for eight different rats in each group blood-brain barrier permeability was evaluated by measuring the amount and extent of extravasation of Evans Blue dye. Brain injury (percentage of the ischemic hemisphere) was less in the 15/HTN group (16 +/- 6, mean +/- SD) versus the 90/HTN group (30 +/- 6), which was in turn less than the control group (42 +/- 5). Specific gravity was greater in the 15/HTN group (1.043 +/- 0.002) versus the 90/HTN (1.036 +/- 0.003) and control (1.037 +/- 0.003) groups. Evans Blue (mug g-1 of brain tissue) was greater in the 90/HTN group (24.4 +/- 6.0) versus the control group (12.3 +/- 4.1), which was in turn greater than the 15/HTN group (7.3 +/- 3.2). This study supports a hypothesis that during reperfusion, a short interval of hypertension decreases brain injury and DISEASE; and that sustained hypertension increases the risk of vasogenic edema. | NO-RELATIONSHIP |
| Focal DISEASE in rats: effect of phenylephrine-induced hypertension during reperfusion. After 180 min of temporary middle cerebral artery occlusion in spontaneously hypertensive rats, the effect of phenylephrine-induced hypertension on ischemic brain injury and blood-brain barrier permeability was determined. Blood pressure was manipulated by one of the following schedules during 120 min of reperfusion: Control, normotensive reperfusion; 90/hypertension (90/HTN), blood pressure was increased by 35 mm Hg during the initial 90 min of reperfusion only; 15/hypertension (15/HTN), normotensive reperfusion for 30 min followed by 15 min of hypertension and 75 min of normotension. Part A, for eight rats in each group brain injury was evaluated by staining tissue using 2,3,5-triphenyltetrazolium chloride and edema was evaluated by microgravimetry. Part B, for eight different rats in each group blood-brain barrier permeability was evaluated by measuring the amount and extent of extravasation of Evans Blue dye. Brain injury (percentage of the DISEASE) was less in the 15/HTN group (16 +/- 6, mean +/- SD) versus the 90/HTN group (30 +/- 6), which was in turn less than the control group (42 +/- 5). Specific gravity was greater in the 15/HTN group (1.043 +/- 0.002) versus the 90/HTN (1.036 +/- 0.003) and control (1.037 +/- 0.003) groups. CHEMICAL (mug g-1 of brain tissue) was greater in the 90/HTN group (24.4 +/- 6.0) versus the control group (12.3 +/- 4.1), which was in turn greater than the 15/HTN group (7.3 +/- 3.2). This study supports a hypothesis that during reperfusion, a short interval of hypertension decreases brain injury and edema; and that sustained hypertension increases the risk of vasogenic edema. | NO-RELATIONSHIP |
| People aged over 75 in atrial fibrillation on CHEMICAL: the rate of major DISEASE and stroke in more than 500 patient-years of follow-up. OBJECTIVES: To determine the incidence of major DISEASE and stroke in people aged 76 and older with atrial fibrillation on adjusted-dose CHEMICAL who had been recently been admitted to hospital. DESIGN: A retrospective observational cohort study. SETTING: A major healthcare network involving four tertiary hospitals. PARTICIPANTS: Two hundred thirty-five patients aged 76 and older admitted to a major healthcare network between July 1, 2001, and June 30, 2002, with atrial fibrillation on CHEMICAL were enrolled. MEASUREMENTS: Information regarding major DISEASE episodes, strokes, and CHEMICAL use was obtained from patients, relatives, primary physicians, and medical records. RESULTS: Two hundred twenty-eight patients (42% men) with a mean age of 81.1 (range 76-94) were included in the analysis. Total follow-up on CHEMICAL was 530 years (mean 28 months). There were 53 major DISEASE, for an annual rate of 10.0%, including 24 (45.3%) life-threatening and five (9.4%) fatal bleeds. The annual stroke rate after initiation of CHEMICAL was 2.6%. CONCLUSION: The rate of major DISEASE was high in this old, frail group, but excluding fatalities, resulted in no long-term sequelae, and the stroke rate on CHEMICAL was low, demonstrating how effective CHEMICAL treatment is. | CHEMICAL-INDUCED-DISEASE |
| Safety of celecoxib in patients with adverse DISEASE to CHEMICAL (CHEMICAL) and nimesulide associated or not with common non-steroidal anti-inflammatory drugs. BACKGROUND: CHEMICAL (CHEMICAL--CHEMICAL) and Nimesulide (N) are widely used analgesic-antipyretic/anti-inflammatory drugs. The rate of adverse hypersensitivity reactions to these agents is generally low. On the contrary non-steroidal anti-inflammatory drugs (NSAIDs) are commonly involved in such reactions. Celecoxib (CE) is a novel drug, with high selectivity and affinity for COX-2 enzyme. OBJECTIVE: We evaluated the tolerability of CE in a group of patients with documented history of adverse cutaneous reactions to P and N associated or not to classic NSAIDs. METHODS: We studied 9 patients with hypersensitivity to P and N with or without associated reactions to classic NSAIDs. The diagnosis of P and N-induced skin reactions was based in vivo challenge. The placebo was blindly administered at the beginning of each challenge. After three days, a cumulative dosage of 200 mg of CE in refracted doses were given. After 2-3 days, a single dose of 200 mg was administered. All patients were observed for 6 hours after each challenge, and controlled again after 24 hours to exclude delayed reactions. The challenge was considered positive if one or more of the following appeared: erythema, rush or urticaria-angioedema. RESULTS: No reaction was observed with placebo and eight patients (88.8%) tolerated CE. Only one patient developed a moderate angioedema of the lips. CONCLUSION: Only one hypersensitivity reaction to CE was documented among 9 P and N-highly NSAIDs intolerant patients. Thus, we conclude that CE is a reasonably safe alternative to be used in subjects who do not tolerate P and N. | NO-RELATIONSHIP |
| Safety of celecoxib in patients with adverse DISEASE to acetaminophen (paracetamol) and CHEMICAL associated or not with common non-steroidal anti-inflammatory drugs. BACKGROUND: Acetaminophen (paracetamol--P) and Nimesulide (N) are widely used analgesic-antipyretic/anti-inflammatory drugs. The rate of adverse hypersensitivity reactions to these agents is generally low. On the contrary non-steroidal anti-inflammatory drugs (NSAIDs) are commonly involved in such reactions. Celecoxib (CE) is a novel drug, with high selectivity and affinity for COX-2 enzyme. OBJECTIVE: We evaluated the tolerability of CE in a group of patients with documented history of adverse cutaneous reactions to P and N associated or not to classic NSAIDs. METHODS: We studied 9 patients with hypersensitivity to P and N with or without associated reactions to classic NSAIDs. The diagnosis of P and N-induced skin reactions was based in vivo challenge. The placebo was blindly administered at the beginning of each challenge. After three days, a cumulative dosage of 200 mg of CE in refracted doses were given. After 2-3 days, a single dose of 200 mg was administered. All patients were observed for 6 hours after each challenge, and controlled again after 24 hours to exclude delayed reactions. The challenge was considered positive if one or more of the following appeared: erythema, rush or urticaria-angioedema. RESULTS: No reaction was observed with placebo and eight patients (88.8%) tolerated CE. Only one patient developed a moderate angioedema of the lips. CONCLUSION: Only one hypersensitivity reaction to CE was documented among 9 P and N-highly NSAIDs intolerant patients. Thus, we conclude that CE is a reasonably safe alternative to be used in subjects who do not tolerate P and N. | NO-RELATIONSHIP |
| Case-control study of regular analgesic and nonsteroidal anti-inflammatory use and DISEASE. BACKGROUND: Studies on the association between the long-term use of CHEMICAL and other analgesic and nonsteroidal anti-inflammatory drugs (NSAIDs) and DISEASE (DISEASE) have given conflicting results. In order to examine this association, a case-control study with incident cases of DISEASE was carried out. METHODS: The cases were all patients entering the local dialysis program because of DISEASE in the study area between June 1, 1995 and November 30, 1997. They were classified according to the underlying disease, which had presumably led them to DISEASE. Controls were patients admitted to the same hospitals from where the cases arose, also matched by age and sex. Odds ratios were calculated using a conditional logistic model, including potential confounding factors, both for the whole study population and for the various underlying diseases. RESULTS: Five hundred and eighty-three cases and 1190 controls were included in the analysis. Long-term use of any analgesic was associated with an overall odds ratio of 1.22 (95% CI, 0.89-1.66). For specific groups of drugs, the risks were 1.56 (1.05-2.30) for CHEMICAL, 1.03 (0.60-1.76) for pyrazolones, 0.80 (0.39-1.63) for paracetamol, and 0.94 (0.57-1.56) for nonaspirin NSAIDs. The risk of DISEASE associated with CHEMICAL was related to the cumulated dose and duration of use, and it was particularly high among the subset of patients with vascular nephropathy as underlying disease [2.35 (1.17-4.72)]. CONCLUSION: Our data indicate that long-term use of nonaspirin analgesic drugs and NSAIDs is not associated with an increased risk of DISEASE. However, the chronic use of CHEMICAL may increase the risk of DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Case-control study of regular analgesic and nonsteroidal anti-inflammatory use and end-stage renal disease. BACKGROUND: Studies on the association between the long-term use of aspirin and other analgesic and nonsteroidal anti-inflammatory drugs (NSAIDs) and end-stage renal disease (ESRD) have given conflicting results. In order to examine this association, a case-control study with incident cases of ESRD was carried out. METHODS: The cases were all patients entering the local dialysis program because of ESRD in the study area between June 1, 1995 and November 30, 1997. They were classified according to the underlying disease, which had presumably led them to ESRD. Controls were patients admitted to the same hospitals from where the cases arose, also matched by age and sex. Odds ratios were calculated using a conditional logistic model, including potential confounding factors, both for the whole study population and for the various underlying diseases. RESULTS: Five hundred and eighty-three cases and 1190 controls were included in the analysis. Long-term use of any analgesic was associated with an overall odds ratio of 1.22 (95% CI, 0.89-1.66). For specific groups of drugs, the risks were 1.56 (1.05-2.30) for aspirin, 1.03 (0.60-1.76) for CHEMICAL, 0.80 (0.39-1.63) for paracetamol, and 0.94 (0.57-1.56) for nonaspirin NSAIDs. The risk of ESRD associated with aspirin was related to the cumulated dose and duration of use, and it was particularly high among the subset of patients with vascular DISEASE as underlying disease [2.35 (1.17-4.72)]. CONCLUSION: Our data indicate that long-term use of nonaspirin analgesic drugs and NSAIDs is not associated with an increased risk of ESRD. However, the chronic use of aspirin may increase the risk of ESRD. | NO-RELATIONSHIP |
| Case-control study of regular analgesic and nonsteroidal anti-inflammatory use and end-stage renal disease. BACKGROUND: Studies on the association between the long-term use of aspirin and other analgesic and nonsteroidal anti-inflammatory drugs (NSAIDs) and end-stage renal disease (ESRD) have given conflicting results. In order to examine this association, a case-control study with incident cases of ESRD was carried out. METHODS: The cases were all patients entering the local dialysis program because of ESRD in the study area between June 1, 1995 and November 30, 1997. They were classified according to the underlying disease, which had presumably led them to ESRD. Controls were patients admitted to the same hospitals from where the cases arose, also matched by age and sex. Odds ratios were calculated using a conditional logistic model, including potential confounding factors, both for the whole study population and for the various underlying diseases. RESULTS: Five hundred and eighty-three cases and 1190 controls were included in the analysis. Long-term use of any analgesic was associated with an overall odds ratio of 1.22 (95% CI, 0.89-1.66). For specific groups of drugs, the risks were 1.56 (1.05-2.30) for aspirin, 1.03 (0.60-1.76) for pyrazolones, 0.80 (0.39-1.63) for CHEMICAL, and 0.94 (0.57-1.56) for nonaspirin NSAIDs. The risk of ESRD associated with aspirin was related to the cumulated dose and duration of use, and it was particularly high among the subset of patients with vascular DISEASE as underlying disease [2.35 (1.17-4.72)]. CONCLUSION: Our data indicate that long-term use of nonaspirin analgesic drugs and NSAIDs is not associated with an increased risk of ESRD. However, the chronic use of aspirin may increase the risk of ESRD. | NO-RELATIONSHIP |
| Two cases of CHEMICAL overdose: a cause for DISEASE. Two cases of deliberate self-poisoning with 5 g and 3.6 g of CHEMICAL, respectively, are reported. In both cases, DISEASE and hypocalcaemia were noted. The DISEASE appeared to respond to administration of i.v. calcium gluconate. | CHEMICAL-INDUCED-DISEASE |
| Two cases of CHEMICAL overdose: a cause for prolonged QT syndrome. Two cases of deliberate self-poisoning with 5 g and 3.6 g of CHEMICAL, respectively, are reported. In both cases, QT prolongation and DISEASE were noted. The QT prolongation appeared to respond to administration of i.v. calcium gluconate. | CHEMICAL-INDUCED-DISEASE |
| Two cases of amisulpride DISEASE: a cause for prolonged QT syndrome. Two cases of deliberate self-poisoning with 5 g and 3.6 g of amisulpride, respectively, are reported. In both cases, QT prolongation and hypocalcaemia were noted. The QT prolongation appeared to respond to administration of i.v. CHEMICAL. | NO-RELATIONSHIP |
| Two cases of amisulpride overdose: a cause for prolonged QT syndrome. Two cases of deliberate self-DISEASE with 5 g and 3.6 g of amisulpride, respectively, are reported. In both cases, QT prolongation and hypocalcaemia were noted. The QT prolongation appeared to respond to administration of i.v. CHEMICAL. | NO-RELATIONSHIP |
| Growth-associated protein 43 expression in hippocampal molecular layer of chronic epileptic rats treated with cycloheximide. PURPOSE: GAP43 has been thought to be linked with mossy fiber sprouting (MFS) in various experimental models of epilepsy. To investigate how GAP43 expression (GAP43-ir) correlates with MFS, we assessed the intensity (densitometry) and extension (width) of GAP43-ir in the inner molecular layer of the dentate gyrus (IML) of rats subject to DISEASE induced by CHEMICAL (CHEMICAL), previously injected or not with cycloheximide (CHX), which has been shown to inhibit MFS. METHODS: CHX was injected before the CHEMICAL injection in adult Wistar rats. The CHEMICAL group was injected with the same drugs, except for CHX. Animals were killed between 30 and 60 days later, and brain sections were processed for GAP43 immunohistochemistry. RESULTS: Densitometry showed no significant difference regarding GAP43-ir in the IML between CHEMICAL, CHX+CHEMICAL, and control groups. However, the results of the width of the GAP43-ir band in the IML showed that CHX+CHEMICAL and control animals had a significantly larger band (p = 0.03) as compared with that in the CHEMICAL group. CONCLUSIONS: Our current finding that animals in the CHX+CHEMICAL group have a GAP43-ir band in the IML, similar to that of controls, reinforces prior data on the blockade of MFS in these animals. The change in GAP43-ir present in CHEMICAL-treated animals was a thinning of the band to a very narrow layer just above the granule cell layer that is likely to be associated with the loss of hilar cell projections that express GAP-43. | CHEMICAL-INDUCED-DISEASE |
| Growth-associated protein 43 expression in hippocampal molecular layer of chronic DISEASE rats treated with CHEMICAL. PURPOSE: GAP43 has been thought to be linked with mossy fiber sprouting (MFS) in various experimental models of DISEASE. To investigate how GAP43 expression (GAP43-ir) correlates with MFS, we assessed the intensity (densitometry) and extension (width) of GAP43-ir in the inner molecular layer of the dentate gyrus (IML) of rats subject to status epilepticus induced by pilocarpine (Pilo), previously injected or not with CHEMICAL (CHEMICAL), which has been shown to inhibit MFS. METHODS: CHEMICAL was injected before the Pilo injection in adult Wistar rats. The Pilo group was injected with the same drugs, except for CHEMICAL. Animals were killed between 30 and 60 days later, and brain sections were processed for GAP43 immunohistochemistry. RESULTS: Densitometry showed no significant difference regarding GAP43-ir in the IML between Pilo, CHEMICAL+Pilo, and control groups. However, the results of the width of the GAP43-ir band in the IML showed that CHEMICAL+Pilo and control animals had a significantly larger band (p = 0.03) as compared with that in the Pilo group. CONCLUSIONS: Our current finding that animals in the CHEMICAL+Pilo group have a GAP43-ir band in the IML, similar to that of controls, reinforces prior data on the blockade of MFS in these animals. The change in GAP43-ir present in Pilo-treated animals was a thinning of the band to a very narrow layer just above the granule cell layer that is likely to be associated with the loss of hilar cell projections that express GAP-43. | NO-RELATIONSHIP |
| Nicotine antagonizes caffeine- but not CHEMICAL-induced anxiogenic effect in mice. RATIONALE: Nicotine and caffeine are widely consumed licit psychoactive drugs worldwide. Epidemiological studies showed that they were generally used concurrently. Although some studies in experimental animals indicate clear pharmacological interactions between them, no studies have shown a specific interaction on DISEASE responses. OBJECTIVES: The present study investigates the effects of nicotine on DISEASE induced by caffeine and another anxiogenic drug, CHEMICAL, in mice. The elevated plus-maze (EPM) test was used to evaluate the effects of drugs on DISEASE. METHODS: Adult male Swiss Webster mice (25-32 g) were given nicotine (0.05-0.25 mg/kg s.c.) or saline 10 min before caffeine (70 mg/kg i.p.) or CHEMICAL (15 and 30 mg/kg i.p.) injections. After 15 min, mice were evaluated for their open- and closed-arm time and entries on the EPM for a 10-min session. Locomotor activity was recorded for individual groups by using the same treatment protocol with the EPM test. RESULTS: Nicotine (0.05-0.25 mg/kg) itself did not produce any significant effect in the EPM test, whereas caffeine (70 mg/kg) and CHEMICAL (30 mg/kg) produced an anxiogenic effect, apparent with decreases in open-arm time and entry. Nicotine (0.25 mg/kg) pretreatment blocked the caffeine- but not CHEMICAL-induced DISEASE. Administration of each drug and their combinations did not produce any effect on locomotor activity. CONCLUSIONS: Our results suggest that the antagonistic effect of nicotine on caffeine-induced DISEASE is specific to caffeine, instead of a non-specific anxiolytic effect. Thus, it may extend the current findings on the interaction between nicotine and caffeine. | CHEMICAL-INDUCED-DISEASE |
| Nicotine antagonizes CHEMICAL- but not pentylenetetrazole-induced anxiogenic effect in mice. RATIONALE: Nicotine and CHEMICAL are widely consumed licit psychoactive drugs worldwide. Epidemiological studies showed that they were generally used concurrently. Although some studies in experimental animals indicate clear pharmacological interactions between them, no studies have shown a specific interaction on DISEASE responses. OBJECTIVES: The present study investigates the effects of nicotine on DISEASE induced by CHEMICAL and another anxiogenic drug, pentylenetetrazole, in mice. The elevated plus-maze (EPM) test was used to evaluate the effects of drugs on DISEASE. METHODS: Adult male Swiss Webster mice (25-32 g) were given nicotine (0.05-0.25 mg/kg s.c.) or saline 10 min before CHEMICAL (70 mg/kg i.p.) or pentylenetetrazole (15 and 30 mg/kg i.p.) injections. After 15 min, mice were evaluated for their open- and closed-arm time and entries on the EPM for a 10-min session. Locomotor activity was recorded for individual groups by using the same treatment protocol with the EPM test. RESULTS: Nicotine (0.05-0.25 mg/kg) itself did not produce any significant effect in the EPM test, whereas CHEMICAL (70 mg/kg) and pentylenetetrazole (30 mg/kg) produced an anxiogenic effect, apparent with decreases in open-arm time and entry. Nicotine (0.25 mg/kg) pretreatment blocked the CHEMICAL- but not pentylenetetrazole-induced DISEASE. Administration of each drug and their combinations did not produce any effect on locomotor activity. CONCLUSIONS: Our results suggest that the antagonistic effect of nicotine on CHEMICAL-induced DISEASE is specific to CHEMICAL, instead of a non-specific anxiolytic effect. Thus, it may extend the current findings on the interaction between nicotine and CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Long term hormone therapy for perimenopausal and postmenopausal women. BACKGROUND: Hormone therapy (HT) is widely used for controlling menopausal symptoms. It has also been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women but the evidence supporting its use for these indications is largely observational. OBJECTIVES: To assess the effect of long-term HT on mortality, heart disease, venous thromboembolism, stroke, transient ischaemic attacks, breast cancer, colorectal cancer, ovarian cancer, endometrial cancer, DISEASE, cognitive function, dementia, fractures and quality of life. SEARCH STRATEGY: We searched the following databases up to November 2004: the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Biological Abstracts. Relevant non-indexed journals and conference abstracts were also searched. SELECTION CRITERIA: Randomised double-blind trials of HT (oestrogens with or without CHEMICAL) versus placebo, taken for at least one year by perimenopausal or postmenopausal women. DATA COLLECTION AND ANALYSIS: Fifteen RCTs were included. Trials were assessed for quality and two review authors extracted data independently. They calculated risk ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Clinical heterogeneity precluded meta-analysis for most outcomes. MAIN RESULTS: All the statistically significant results were derived from the two biggest trials. In relatively healthy women, combined continuous HT significantly increased the risk of venous thromboembolism or coronary event (after one year's use), stroke (after 3 years), breast cancer (after 5 years) and DISEASE. Long-term oestrogen-only HT also significantly increased the risk of stroke and DISEASE. Overall, the only statistically significant benefits of HT were a decreased incidence of fractures and colon cancer with long-term use. Among relatively healthy women over 65 years taking continuous combined HT, there was a statistically significant increase in the incidence of dementia. Among women with cardiovascular disease, long-term use of combined continuous HT significantly increased the risk of venous thromboembolism. No trials focussed specifically on younger women. However, one trial analysed subgroups of 2839 relatively healthy 50 to 59 year-old women taking combined continuous HT and 1637 taking oestrogen-only HT, versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT; their absolute risk remained very low. AUTHORS' CONCLUSIONS: HT is not indicated for the routine management of chronic disease. We need more evidence on the safety of HT for menopausal symptom control, though short-term use appears to be relatively safe for healthy younger women. | CHEMICAL-INDUCED-DISEASE |
| Long term hormone therapy for perimenopausal and postmenopausal women. BACKGROUND: Hormone therapy (HT) is widely used for controlling menopausal symptoms. It has also been used for the management and prevention of cardiovascular disease, osteoporosis and DISEASE in older women but the evidence supporting its use for these indications is largely observational. OBJECTIVES: To assess the effect of long-term HT on mortality, heart disease, venous thromboembolism, stroke, transient ischaemic attacks, breast cancer, colorectal cancer, ovarian cancer, endometrial cancer, gallbladder disease, cognitive function, DISEASE, fractures and quality of life. SEARCH STRATEGY: We searched the following databases up to November 2004: the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Biological Abstracts. Relevant non-indexed journals and conference abstracts were also searched. SELECTION CRITERIA: Randomised double-blind trials of HT (CHEMICAL with or without progestogens) versus placebo, taken for at least one year by perimenopausal or postmenopausal women. DATA COLLECTION AND ANALYSIS: Fifteen RCTs were included. Trials were assessed for quality and two review authors extracted data independently. They calculated risk ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Clinical heterogeneity precluded meta-analysis for most outcomes. MAIN RESULTS: All the statistically significant results were derived from the two biggest trials. In relatively healthy women, combined continuous HT significantly increased the risk of venous thromboembolism or coronary event (after one year's use), stroke (after 3 years), breast cancer (after 5 years) and gallbladder disease. Long-term CHEMICAL-only HT also significantly increased the risk of stroke and gallbladder disease. Overall, the only statistically significant benefits of HT were a decreased incidence of fractures and colon cancer with long-term use. Among relatively healthy women over 65 years taking continuous combined HT, there was a statistically significant increase in the incidence of DISEASE. Among women with cardiovascular disease, long-term use of combined continuous HT significantly increased the risk of venous thromboembolism. No trials focussed specifically on younger women. However, one trial analysed subgroups of 2839 relatively healthy 50 to 59 year-old women taking combined continuous HT and 1637 taking CHEMICAL-only HT, versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT; their absolute risk remained very low. AUTHORS' CONCLUSIONS: HT is not indicated for the routine management of chronic disease. We need more evidence on the safety of HT for menopausal symptom control, though short-term use appears to be relatively safe for healthy younger women. | CHEMICAL-INDUCED-DISEASE |
| Long term hormone therapy for perimenopausal and postmenopausal women. BACKGROUND: Hormone therapy (HT) is widely used for controlling menopausal symptoms. It has also been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women but the evidence supporting its use for these indications is largely observational. OBJECTIVES: To assess the effect of long-term HT on mortality, heart disease, DISEASE, stroke, transient ischaemic attacks, breast cancer, colorectal cancer, ovarian cancer, endometrial cancer, gallbladder disease, cognitive function, dementia, fractures and quality of life. SEARCH STRATEGY: We searched the following databases up to November 2004: the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Biological Abstracts. Relevant non-indexed journals and conference abstracts were also searched. SELECTION CRITERIA: Randomised double-blind trials of HT (CHEMICAL with or without progestogens) versus placebo, taken for at least one year by perimenopausal or postmenopausal women. DATA COLLECTION AND ANALYSIS: Fifteen RCTs were included. Trials were assessed for quality and two review authors extracted data independently. They calculated risk ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Clinical heterogeneity precluded meta-analysis for most outcomes. MAIN RESULTS: All the statistically significant results were derived from the two biggest trials. In relatively healthy women, combined continuous HT significantly increased the risk of DISEASE or coronary event (after one year's use), stroke (after 3 years), breast cancer (after 5 years) and gallbladder disease. Long-term CHEMICAL-only HT also significantly increased the risk of stroke and gallbladder disease. Overall, the only statistically significant benefits of HT were a decreased incidence of fractures and colon cancer with long-term use. Among relatively healthy women over 65 years taking continuous combined HT, there was a statistically significant increase in the incidence of dementia. Among women with cardiovascular disease, long-term use of combined continuous HT significantly increased the risk of DISEASE. No trials focussed specifically on younger women. However, one trial analysed subgroups of 2839 relatively healthy 50 to 59 year-old women taking combined continuous HT and 1637 taking CHEMICAL-only HT, versus similar-sized placebo groups. The only significantly increased risk reported was for DISEASE in women taking combined continuous HT; their absolute risk remained very low. AUTHORS' CONCLUSIONS: HT is not indicated for the routine management of chronic disease. We need more evidence on the safety of HT for menopausal symptom control, though short-term use appears to be relatively safe for healthy younger women. | CHEMICAL-INDUCED-DISEASE |
| Long term hormone therapy for perimenopausal and postmenopausal women. BACKGROUND: Hormone therapy (HT) is widely used for controlling menopausal symptoms. It has also been used for the management and prevention of DISEASE, osteoporosis and dementia in older women but the evidence supporting its use for these indications is largely observational. OBJECTIVES: To assess the effect of long-term HT on mortality, heart disease, venous thromboembolism, stroke, transient ischaemic attacks, breast cancer, colorectal cancer, ovarian cancer, endometrial cancer, gallbladder disease, cognitive function, dementia, fractures and quality of life. SEARCH STRATEGY: We searched the following databases up to November 2004: the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Biological Abstracts. Relevant non-indexed journals and conference abstracts were also searched. SELECTION CRITERIA: Randomised double-blind trials of HT (CHEMICAL with or without progestogens) versus placebo, taken for at least one year by perimenopausal or postmenopausal women. DATA COLLECTION AND ANALYSIS: Fifteen RCTs were included. Trials were assessed for quality and two review authors extracted data independently. They calculated risk ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Clinical heterogeneity precluded meta-analysis for most outcomes. MAIN RESULTS: All the statistically significant results were derived from the two biggest trials. In relatively healthy women, combined continuous HT significantly increased the risk of venous thromboembolism or coronary event (after one year's use), stroke (after 3 years), breast cancer (after 5 years) and gallbladder disease. Long-term CHEMICAL-only HT also significantly increased the risk of stroke and gallbladder disease. Overall, the only statistically significant benefits of HT were a decreased incidence of fractures and colon cancer with long-term use. Among relatively healthy women over 65 years taking continuous combined HT, there was a statistically significant increase in the incidence of dementia. Among women with DISEASE, long-term use of combined continuous HT significantly increased the risk of venous thromboembolism. No trials focussed specifically on younger women. However, one trial analysed subgroups of 2839 relatively healthy 50 to 59 year-old women taking combined continuous HT and 1637 taking CHEMICAL-only HT, versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT; their absolute risk remained very low. AUTHORS' CONCLUSIONS: HT is not indicated for the routine management of chronic disease. We need more evidence on the safety of HT for menopausal symptom control, though short-term use appears to be relatively safe for healthy younger women. | CHEMICAL-INDUCED-DISEASE |
| Long term hormone therapy for perimenopausal and postmenopausal women. BACKGROUND: Hormone therapy (HT) is widely used for controlling menopausal symptoms. It has also been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women but the evidence supporting its use for these indications is largely observational. OBJECTIVES: To assess the effect of long-term HT on mortality, heart disease, venous thromboembolism, stroke, transient ischaemic attacks, breast cancer, colorectal cancer, ovarian cancer, endometrial cancer, DISEASE, cognitive function, dementia, fractures and quality of life. SEARCH STRATEGY: We searched the following databases up to November 2004: the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Biological Abstracts. Relevant non-indexed journals and conference abstracts were also searched. SELECTION CRITERIA: Randomised double-blind trials of HT (CHEMICAL with or without progestogens) versus placebo, taken for at least one year by perimenopausal or postmenopausal women. DATA COLLECTION AND ANALYSIS: Fifteen RCTs were included. Trials were assessed for quality and two review authors extracted data independently. They calculated risk ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Clinical heterogeneity precluded meta-analysis for most outcomes. MAIN RESULTS: All the statistically significant results were derived from the two biggest trials. In relatively healthy women, combined continuous HT significantly increased the risk of venous thromboembolism or coronary event (after one year's use), stroke (after 3 years), breast cancer (after 5 years) and DISEASE. Long-term CHEMICAL-only HT also significantly increased the risk of stroke and DISEASE. Overall, the only statistically significant benefits of HT were a decreased incidence of fractures and colon cancer with long-term use. Among relatively healthy women over 65 years taking continuous combined HT, there was a statistically significant increase in the incidence of dementia. Among women with cardiovascular disease, long-term use of combined continuous HT significantly increased the risk of venous thromboembolism. No trials focussed specifically on younger women. However, one trial analysed subgroups of 2839 relatively healthy 50 to 59 year-old women taking combined continuous HT and 1637 taking CHEMICAL-only HT, versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT; their absolute risk remained very low. AUTHORS' CONCLUSIONS: HT is not indicated for the routine management of chronic disease. We need more evidence on the safety of HT for menopausal symptom control, though short-term use appears to be relatively safe for healthy younger women. | CHEMICAL-INDUCED-DISEASE |
| Long term hormone therapy for perimenopausal and postmenopausal women. BACKGROUND: Hormone therapy (HT) is widely used for controlling menopausal symptoms. It has also been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women but the evidence supporting its use for these indications is largely observational. OBJECTIVES: To assess the effect of long-term HT on mortality, heart disease, DISEASE, stroke, transient ischaemic attacks, breast cancer, colorectal cancer, ovarian cancer, endometrial cancer, gallbladder disease, cognitive function, dementia, fractures and quality of life. SEARCH STRATEGY: We searched the following databases up to November 2004: the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Biological Abstracts. Relevant non-indexed journals and conference abstracts were also searched. SELECTION CRITERIA: Randomised double-blind trials of HT (oestrogens with or without CHEMICAL) versus placebo, taken for at least one year by perimenopausal or postmenopausal women. DATA COLLECTION AND ANALYSIS: Fifteen RCTs were included. Trials were assessed for quality and two review authors extracted data independently. They calculated risk ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Clinical heterogeneity precluded meta-analysis for most outcomes. MAIN RESULTS: All the statistically significant results were derived from the two biggest trials. In relatively healthy women, combined continuous HT significantly increased the risk of DISEASE or coronary event (after one year's use), stroke (after 3 years), breast cancer (after 5 years) and gallbladder disease. Long-term oestrogen-only HT also significantly increased the risk of stroke and gallbladder disease. Overall, the only statistically significant benefits of HT were a decreased incidence of fractures and colon cancer with long-term use. Among relatively healthy women over 65 years taking continuous combined HT, there was a statistically significant increase in the incidence of dementia. Among women with cardiovascular disease, long-term use of combined continuous HT significantly increased the risk of DISEASE. No trials focussed specifically on younger women. However, one trial analysed subgroups of 2839 relatively healthy 50 to 59 year-old women taking combined continuous HT and 1637 taking oestrogen-only HT, versus similar-sized placebo groups. The only significantly increased risk reported was for DISEASE in women taking combined continuous HT; their absolute risk remained very low. AUTHORS' CONCLUSIONS: HT is not indicated for the routine management of chronic disease. We need more evidence on the safety of HT for menopausal symptom control, though short-term use appears to be relatively safe for healthy younger women. | CHEMICAL-INDUCED-DISEASE |
| Long term hormone therapy for perimenopausal and postmenopausal women. BACKGROUND: Hormone therapy (HT) is widely used for controlling menopausal symptoms. It has also been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women but the evidence supporting its use for these indications is largely observational. OBJECTIVES: To assess the effect of long-term HT on mortality, heart disease, venous thromboembolism, DISEASE, transient ischaemic attacks, breast cancer, colorectal cancer, ovarian cancer, endometrial cancer, gallbladder disease, cognitive function, dementia, fractures and quality of life. SEARCH STRATEGY: We searched the following databases up to November 2004: the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Biological Abstracts. Relevant non-indexed journals and conference abstracts were also searched. SELECTION CRITERIA: Randomised double-blind trials of HT (CHEMICAL with or without progestogens) versus placebo, taken for at least one year by perimenopausal or postmenopausal women. DATA COLLECTION AND ANALYSIS: Fifteen RCTs were included. Trials were assessed for quality and two review authors extracted data independently. They calculated risk ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Clinical heterogeneity precluded meta-analysis for most outcomes. MAIN RESULTS: All the statistically significant results were derived from the two biggest trials. In relatively healthy women, combined continuous HT significantly increased the risk of venous thromboembolism or coronary event (after one year's use), DISEASE (after 3 years), breast cancer (after 5 years) and gallbladder disease. Long-term CHEMICAL-only HT also significantly increased the risk of DISEASE and gallbladder disease. Overall, the only statistically significant benefits of HT were a decreased incidence of fractures and colon cancer with long-term use. Among relatively healthy women over 65 years taking continuous combined HT, there was a statistically significant increase in the incidence of dementia. Among women with cardiovascular disease, long-term use of combined continuous HT significantly increased the risk of venous thromboembolism. No trials focussed specifically on younger women. However, one trial analysed subgroups of 2839 relatively healthy 50 to 59 year-old women taking combined continuous HT and 1637 taking CHEMICAL-only HT, versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT; their absolute risk remained very low. AUTHORS' CONCLUSIONS: HT is not indicated for the routine management of chronic disease. We need more evidence on the safety of HT for menopausal symptom control, though short-term use appears to be relatively safe for healthy younger women. | CHEMICAL-INDUCED-DISEASE |
| Long term hormone therapy for perimenopausal and postmenopausal women. BACKGROUND: Hormone therapy (HT) is widely used for controlling menopausal symptoms. It has also been used for the management and prevention of DISEASE, osteoporosis and dementia in older women but the evidence supporting its use for these indications is largely observational. OBJECTIVES: To assess the effect of long-term HT on mortality, heart disease, venous thromboembolism, stroke, transient ischaemic attacks, breast cancer, colorectal cancer, ovarian cancer, endometrial cancer, gallbladder disease, cognitive function, dementia, fractures and quality of life. SEARCH STRATEGY: We searched the following databases up to November 2004: the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Biological Abstracts. Relevant non-indexed journals and conference abstracts were also searched. SELECTION CRITERIA: Randomised double-blind trials of HT (oestrogens with or without CHEMICAL) versus placebo, taken for at least one year by perimenopausal or postmenopausal women. DATA COLLECTION AND ANALYSIS: Fifteen RCTs were included. Trials were assessed for quality and two review authors extracted data independently. They calculated risk ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Clinical heterogeneity precluded meta-analysis for most outcomes. MAIN RESULTS: All the statistically significant results were derived from the two biggest trials. In relatively healthy women, combined continuous HT significantly increased the risk of venous thromboembolism or coronary event (after one year's use), stroke (after 3 years), breast cancer (after 5 years) and gallbladder disease. Long-term oestrogen-only HT also significantly increased the risk of stroke and gallbladder disease. Overall, the only statistically significant benefits of HT were a decreased incidence of fractures and colon cancer with long-term use. Among relatively healthy women over 65 years taking continuous combined HT, there was a statistically significant increase in the incidence of dementia. Among women with DISEASE, long-term use of combined continuous HT significantly increased the risk of venous thromboembolism. No trials focussed specifically on younger women. However, one trial analysed subgroups of 2839 relatively healthy 50 to 59 year-old women taking combined continuous HT and 1637 taking oestrogen-only HT, versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT; their absolute risk remained very low. AUTHORS' CONCLUSIONS: HT is not indicated for the routine management of chronic disease. We need more evidence on the safety of HT for menopausal symptom control, though short-term use appears to be relatively safe for healthy younger women. | NO-RELATIONSHIP |
| Long term hormone therapy for perimenopausal and postmenopausal women. BACKGROUND: Hormone therapy (HT) is widely used for controlling menopausal symptoms. It has also been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women but the evidence supporting its use for these indications is largely observational. OBJECTIVES: To assess the effect of long-term HT on mortality, heart disease, venous thromboembolism, stroke, transient ischaemic attacks, DISEASE, colorectal cancer, ovarian cancer, endometrial cancer, gallbladder disease, cognitive function, dementia, fractures and quality of life. SEARCH STRATEGY: We searched the following databases up to November 2004: the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Biological Abstracts. Relevant non-indexed journals and conference abstracts were also searched. SELECTION CRITERIA: Randomised double-blind trials of HT (oestrogens with or without CHEMICAL) versus placebo, taken for at least one year by perimenopausal or postmenopausal women. DATA COLLECTION AND ANALYSIS: Fifteen RCTs were included. Trials were assessed for quality and two review authors extracted data independently. They calculated risk ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Clinical heterogeneity precluded meta-analysis for most outcomes. MAIN RESULTS: All the statistically significant results were derived from the two biggest trials. In relatively healthy women, combined continuous HT significantly increased the risk of venous thromboembolism or coronary event (after one year's use), stroke (after 3 years), DISEASE (after 5 years) and gallbladder disease. Long-term oestrogen-only HT also significantly increased the risk of stroke and gallbladder disease. Overall, the only statistically significant benefits of HT were a decreased incidence of fractures and colon cancer with long-term use. Among relatively healthy women over 65 years taking continuous combined HT, there was a statistically significant increase in the incidence of dementia. Among women with cardiovascular disease, long-term use of combined continuous HT significantly increased the risk of venous thromboembolism. No trials focussed specifically on younger women. However, one trial analysed subgroups of 2839 relatively healthy 50 to 59 year-old women taking combined continuous HT and 1637 taking oestrogen-only HT, versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT; their absolute risk remained very low. AUTHORS' CONCLUSIONS: HT is not indicated for the routine management of chronic disease. We need more evidence on the safety of HT for menopausal symptom control, though short-term use appears to be relatively safe for healthy younger women. | CHEMICAL-INDUCED-DISEASE |
| Long term hormone therapy for perimenopausal and postmenopausal women. BACKGROUND: Hormone therapy (HT) is widely used for controlling menopausal symptoms. It has also been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women but the evidence supporting its use for these indications is largely observational. OBJECTIVES: To assess the effect of long-term HT on mortality, heart disease, venous thromboembolism, DISEASE, transient ischaemic attacks, breast cancer, colorectal cancer, ovarian cancer, endometrial cancer, gallbladder disease, cognitive function, dementia, fractures and quality of life. SEARCH STRATEGY: We searched the following databases up to November 2004: the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Biological Abstracts. Relevant non-indexed journals and conference abstracts were also searched. SELECTION CRITERIA: Randomised double-blind trials of HT (oestrogens with or without CHEMICAL) versus placebo, taken for at least one year by perimenopausal or postmenopausal women. DATA COLLECTION AND ANALYSIS: Fifteen RCTs were included. Trials were assessed for quality and two review authors extracted data independently. They calculated risk ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Clinical heterogeneity precluded meta-analysis for most outcomes. MAIN RESULTS: All the statistically significant results were derived from the two biggest trials. In relatively healthy women, combined continuous HT significantly increased the risk of venous thromboembolism or coronary event (after one year's use), DISEASE (after 3 years), breast cancer (after 5 years) and gallbladder disease. Long-term oestrogen-only HT also significantly increased the risk of DISEASE and gallbladder disease. Overall, the only statistically significant benefits of HT were a decreased incidence of fractures and colon cancer with long-term use. Among relatively healthy women over 65 years taking continuous combined HT, there was a statistically significant increase in the incidence of dementia. Among women with cardiovascular disease, long-term use of combined continuous HT significantly increased the risk of venous thromboembolism. No trials focussed specifically on younger women. However, one trial analysed subgroups of 2839 relatively healthy 50 to 59 year-old women taking combined continuous HT and 1637 taking oestrogen-only HT, versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT; their absolute risk remained very low. AUTHORS' CONCLUSIONS: HT is not indicated for the routine management of chronic disease. We need more evidence on the safety of HT for menopausal symptom control, though short-term use appears to be relatively safe for healthy younger women. | CHEMICAL-INDUCED-DISEASE |
| Long term hormone therapy for perimenopausal and postmenopausal women. BACKGROUND: Hormone therapy (HT) is widely used for controlling menopausal symptoms. It has also been used for the management and prevention of cardiovascular disease, osteoporosis and DISEASE in older women but the evidence supporting its use for these indications is largely observational. OBJECTIVES: To assess the effect of long-term HT on mortality, heart disease, venous thromboembolism, stroke, transient ischaemic attacks, breast cancer, colorectal cancer, ovarian cancer, endometrial cancer, gallbladder disease, cognitive function, DISEASE, fractures and quality of life. SEARCH STRATEGY: We searched the following databases up to November 2004: the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Biological Abstracts. Relevant non-indexed journals and conference abstracts were also searched. SELECTION CRITERIA: Randomised double-blind trials of HT (oestrogens with or without CHEMICAL) versus placebo, taken for at least one year by perimenopausal or postmenopausal women. DATA COLLECTION AND ANALYSIS: Fifteen RCTs were included. Trials were assessed for quality and two review authors extracted data independently. They calculated risk ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Clinical heterogeneity precluded meta-analysis for most outcomes. MAIN RESULTS: All the statistically significant results were derived from the two biggest trials. In relatively healthy women, combined continuous HT significantly increased the risk of venous thromboembolism or coronary event (after one year's use), stroke (after 3 years), breast cancer (after 5 years) and gallbladder disease. Long-term oestrogen-only HT also significantly increased the risk of stroke and gallbladder disease. Overall, the only statistically significant benefits of HT were a decreased incidence of fractures and colon cancer with long-term use. Among relatively healthy women over 65 years taking continuous combined HT, there was a statistically significant increase in the incidence of DISEASE. Among women with cardiovascular disease, long-term use of combined continuous HT significantly increased the risk of venous thromboembolism. No trials focussed specifically on younger women. However, one trial analysed subgroups of 2839 relatively healthy 50 to 59 year-old women taking combined continuous HT and 1637 taking oestrogen-only HT, versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT; their absolute risk remained very low. AUTHORS' CONCLUSIONS: HT is not indicated for the routine management of chronic disease. We need more evidence on the safety of HT for menopausal symptom control, though short-term use appears to be relatively safe for healthy younger women. | CHEMICAL-INDUCED-DISEASE |
| Long term hormone therapy for perimenopausal and postmenopausal women. BACKGROUND: Hormone therapy (HT) is widely used for controlling menopausal symptoms. It has also been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women but the evidence supporting its use for these indications is largely observational. OBJECTIVES: To assess the effect of long-term HT on mortality, heart disease, venous thromboembolism, stroke, transient ischaemic attacks, DISEASE, colorectal cancer, ovarian cancer, endometrial cancer, gallbladder disease, cognitive function, dementia, fractures and quality of life. SEARCH STRATEGY: We searched the following databases up to November 2004: the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Biological Abstracts. Relevant non-indexed journals and conference abstracts were also searched. SELECTION CRITERIA: Randomised double-blind trials of HT (CHEMICAL with or without progestogens) versus placebo, taken for at least one year by perimenopausal or postmenopausal women. DATA COLLECTION AND ANALYSIS: Fifteen RCTs were included. Trials were assessed for quality and two review authors extracted data independently. They calculated risk ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Clinical heterogeneity precluded meta-analysis for most outcomes. MAIN RESULTS: All the statistically significant results were derived from the two biggest trials. In relatively healthy women, combined continuous HT significantly increased the risk of venous thromboembolism or coronary event (after one year's use), stroke (after 3 years), DISEASE (after 5 years) and gallbladder disease. Long-term CHEMICAL-only HT also significantly increased the risk of stroke and gallbladder disease. Overall, the only statistically significant benefits of HT were a decreased incidence of fractures and colon cancer with long-term use. Among relatively healthy women over 65 years taking continuous combined HT, there was a statistically significant increase in the incidence of dementia. Among women with cardiovascular disease, long-term use of combined continuous HT significantly increased the risk of venous thromboembolism. No trials focussed specifically on younger women. However, one trial analysed subgroups of 2839 relatively healthy 50 to 59 year-old women taking combined continuous HT and 1637 taking CHEMICAL-only HT, versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT; their absolute risk remained very low. AUTHORS' CONCLUSIONS: HT is not indicated for the routine management of chronic disease. We need more evidence on the safety of HT for menopausal symptom control, though short-term use appears to be relatively safe for healthy younger women. | CHEMICAL-INDUCED-DISEASE |
| DISEASE: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. BACKGROUND & AIMS: Progress in the understanding of susceptibility factors to DISEASE (DISEASE) and outcome predictability are hampered by the lack of systematic programs to detect bona fide cases. METHODS: A cooperative network was created in 1994 in Spain to identify all suspicions of DISEASE following a prospective structured report form. The DISEASE was characterized according to hepatocellular, cholestatic, and mixed laboratory criteria and to histologic criteria when available. Further evaluation of causality assessment was centrally performed. RESULTS: Since April 1994 to August 2004, 461 out of 570 submitted cases, involving 505 drugs, were deemed to be related to DISEASE. The antiinfective group of drugs was the more frequently incriminated, CHEMICAL accounting for the 12.8% of the whole series. The hepatocellular pattern of damage was the most common (58%), was inversely correlated with age (P < .0001), and had the worst outcome (Cox regression, P < .034). Indeed, the incidence of liver transplantation and death in this group was 11.7% if patients had jaundice at presentation, whereas the corresponding figure was 3.8% in nonjaundiced patients (P < .04). Factors associated with the development of fulminant hepatic failure were female sex (OR = 25; 95% CI: 4.1-151; P < .0001), hepatocellular damage (OR = 7.9; 95% CI: 1.6-37; P < .009), and higher baseline plasma bilirubin value (OR = 1.15; 95% CI: 1.09-1.22; P < .0001). CONCLUSIONS: Patients with drug-induced hepatocellular jaundice have 11.7% chance of progressing to death or transplantation. CHEMICAL stands out as the most common drug related to DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. BACKGROUND & AIMS: Progress in the understanding of susceptibility factors to drug-induced liver injury (DILI) and outcome predictability are hampered by the lack of systematic programs to detect bona fide cases. METHODS: A cooperative network was created in 1994 in Spain to identify all suspicions of DILI following a prospective structured report form. The liver damage was characterized according to hepatocellular, cholestatic, and mixed laboratory criteria and to histologic criteria when available. Further evaluation of causality assessment was centrally performed. RESULTS: Since April 1994 to August 2004, 461 out of 570 submitted cases, involving 505 drugs, were deemed to be related to DILI. The antiinfective group of drugs was the more frequently incriminated, CHEMICAL accounting for the 12.8% of the whole series. The hepatocellular pattern of damage was the most common (58%), was inversely correlated with age (P < .0001), and had the worst outcome (Cox regression, P < .034). Indeed, the incidence of liver transplantation and death in this group was 11.7% if patients had DISEASE at presentation, whereas the corresponding figure was 3.8% in nonjaundiced patients (P < .04). Factors associated with the development of fulminant hepatic failure were female sex (OR = 25; 95% CI: 4.1-151; P < .0001), hepatocellular damage (OR = 7.9; 95% CI: 1.6-37; P < .009), and higher baseline plasma bilirubin value (OR = 1.15; 95% CI: 1.09-1.22; P < .0001). CONCLUSIONS: Patients with drug-induced hepatocellular DISEASE have 11.7% chance of progressing to death or transplantation. CHEMICAL stands out as the most common drug related to DILI. | CHEMICAL-INDUCED-DISEASE |
| Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. BACKGROUND & AIMS: Progress in the understanding of susceptibility factors to drug-induced liver injury (DILI) and outcome predictability are hampered by the lack of systematic programs to detect bona fide cases. METHODS: A cooperative network was created in 1994 in Spain to identify all suspicions of DILI following a prospective structured report form. The liver damage was characterized according to hepatocellular, DISEASE, and mixed laboratory criteria and to histologic criteria when available. Further evaluation of causality assessment was centrally performed. RESULTS: Since April 1994 to August 2004, 461 out of 570 submitted cases, involving 505 drugs, were deemed to be related to DILI. The antiinfective group of drugs was the more frequently incriminated, amoxicillin-clavulanate accounting for the 12.8% of the whole series. The hepatocellular pattern of damage was the most common (58%), was inversely correlated with age (P < .0001), and had the worst outcome (Cox regression, P < .034). Indeed, the incidence of liver transplantation and death in this group was 11.7% if patients had jaundice at presentation, whereas the corresponding figure was 3.8% in nonjaundiced patients (P < .04). Factors associated with the development of fulminant hepatic failure were female sex (OR = 25; 95% CI: 4.1-151; P < .0001), hepatocellular damage (OR = 7.9; 95% CI: 1.6-37; P < .009), and higher baseline plasma CHEMICAL value (OR = 1.15; 95% CI: 1.09-1.22; P < .0001). CONCLUSIONS: Patients with drug-induced hepatocellular jaundice have 11.7% chance of progressing to death or transplantation. Amoxicillin-clavulanate stands out as the most common drug related to DILI. | NO-RELATIONSHIP |
| Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. BACKGROUND & AIMS: Progress in the understanding of susceptibility factors to drug-induced liver injury (DILI) and outcome predictability are hampered by the lack of systematic programs to detect bona fide cases. METHODS: A cooperative network was created in 1994 in Spain to identify all suspicions of DILI following a prospective structured report form. The liver damage was characterized according to hepatocellular, cholestatic, and mixed laboratory criteria and to histologic criteria when available. Further evaluation of causality assessment was centrally performed. RESULTS: Since April 1994 to August 2004, 461 out of 570 submitted cases, involving 505 drugs, were deemed to be related to DILI. The antiinfective group of drugs was the more frequently incriminated, amoxicillin-clavulanate accounting for the 12.8% of the whole series. The hepatocellular pattern of damage was the most common (58%), was inversely correlated with age (P < .0001), and had the worst outcome (Cox regression, P < .034). Indeed, the incidence of liver transplantation and death in this group was 11.7% if patients had jaundice at presentation, whereas the corresponding figure was 3.8% in nonjaundiced patients (P < .04). Factors associated with the development of DISEASE were female sex (OR = 25; 95% CI: 4.1-151; P < .0001), hepatocellular damage (OR = 7.9; 95% CI: 1.6-37; P < .009), and higher baseline plasma CHEMICAL value (OR = 1.15; 95% CI: 1.09-1.22; P < .0001). CONCLUSIONS: Patients with drug-induced hepatocellular jaundice have 11.7% chance of progressing to death or transplantation. Amoxicillin-clavulanate stands out as the most common drug related to DILI. | NO-RELATIONSHIP |
| Morphological evaluation of the effect of d-ribose on CHEMICAL-evoked cardiotoxicity in rats. The influence of d-ribose on CHEMICAL-induced DISEASE in rats was studied. CHEMICAL in the cumulative dose of 25 mg/kg evoked fully developed cardiac toxicity. D-ribose in the multiple doses of 200 mg/kg did not influence CHEMICAL cardiotoxicity. | CHEMICAL-INDUCED-DISEASE |
| Morphological evaluation of the effect of CHEMICAL on adriamycin-evoked DISEASE in rats. The influence of CHEMICAL on adriamycin-induced myocardiopathy in rats was studied. Adriamycin in the cumulative dose of 25 mg/kg evoked fully developed DISEASE. CHEMICAL in the multiple doses of 200 mg/kg did not influence ADR DISEASE. | NO-RELATIONSHIP |
| In vivo evidences suggesting the role of oxidative stress in pathogenesis of CHEMICAL-induced DISEASE: protection by erdosteine. The aims of this study were to examine CHEMICAL (CHEMICAL)-induced oxidative stress that promotes production of reactive oxygen species (ROS) and to investigate the role of erdosteine, an expectorant agent, which has also antioxidant properties, on kidney tissue against the possible CHEMICAL-induced DISEASE in rats. Rats were divided into three groups: sham, CHEMICAL and CHEMICAL plus erdosteine. CHEMICAL was administrated intraperitoneally (i.p.) with 200mgkg(-1) twice daily for 7 days. Erdosteine was administered orally. CHEMICAL administration to control rats significantly increased renal malondialdehyde (MDA) and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of DISEASE) excretion but decreased superoxide dismutase (SOD) and catalase (CAT) activities. Erdosteine administration with CHEMICAL injections caused significantly decreased renal MDA and urinary NAG excretion, and increased SOD activity, but not CAT activity in renal tissue when compared with CHEMICAL alone. Erdosteine showed histopathological protection against CHEMICAL-induced DISEASE. There were a significant dilatation of tubular lumens, extensive epithelial cell vacuolization, atrophy, desquamation, and necrosis in CHEMICAL-treated rats more than those of the control and the erdosteine groups. Erdosteine caused a marked reduction in the extent of tubular damage. It is concluded that oxidative tubular damage plays an important role in the CHEMICAL-induced DISEASE and the modulation of oxidative stress with erdosteine reduces the CHEMICAL-induced DISEASE both at the biochemical and histological levels. | CHEMICAL-INDUCED-DISEASE |
| In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: protection by erdosteine. The aims of this study were to examine vancomycin (VCM)-induced oxidative stress that promotes production of reactive CHEMICAL species (ROS) and to investigate the role of erdosteine, an expectorant agent, which has also antioxidant properties, on kidney tissue against the possible VCM-induced renal impairment in rats. Rats were divided into three groups: sham, VCM and VCM plus erdosteine. VCM was administrated intraperitoneally (i.p.) with 200mgkg(-1) twice daily for 7 days. Erdosteine was administered orally. VCM administration to control rats significantly increased renal malondialdehyde (MDA) and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of renal tubular injury) excretion but decreased superoxide dismutase (SOD) and catalase (CAT) activities. Erdosteine administration with VCM injections caused significantly decreased renal MDA and urinary NAG excretion, and increased SOD activity, but not CAT activity in renal tissue when compared with VCM alone. Erdosteine showed histopathological protection against VCM-induced nephrotoxicity. There were a significant dilatation of tubular lumens, extensive epithelial cell vacuolization, DISEASE, desquamation, and necrosis in VCM-treated rats more than those of the control and the erdosteine groups. Erdosteine caused a marked reduction in the extent of tubular damage. It is concluded that oxidative tubular damage plays an important role in the VCM-induced nephrotoxicity and the modulation of oxidative stress with erdosteine reduces the VCM-induced kidney damage both at the biochemical and histological levels. | NO-RELATIONSHIP |
| In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: protection by CHEMICAL. The aims of this study were to examine vancomycin (VCM)-induced oxidative stress that promotes production of reactive oxygen species (ROS) and to investigate the role of CHEMICAL, an expectorant agent, which has also antioxidant properties, on kidney tissue against the possible VCM-induced renal impairment in rats. Rats were divided into three groups: sham, VCM and VCM plus CHEMICAL. VCM was administrated intraperitoneally (i.p.) with 200mgkg(-1) twice daily for 7 days. CHEMICAL was administered orally. VCM administration to control rats significantly increased renal malondialdehyde (MDA) and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of renal tubular injury) excretion but decreased superoxide dismutase (SOD) and catalase (CAT) activities. CHEMICAL administration with VCM injections caused significantly decreased renal MDA and urinary NAG excretion, and increased SOD activity, but not CAT activity in renal tissue when compared with VCM alone. CHEMICAL showed histopathological protection against VCM-induced nephrotoxicity. There were a significant dilatation of tubular lumens, extensive epithelial cell vacuolization, atrophy, DISEASE, and necrosis in VCM-treated rats more than those of the control and the CHEMICAL groups. CHEMICAL caused a marked reduction in the extent of tubular damage. It is concluded that oxidative tubular damage plays an important role in the VCM-induced nephrotoxicity and the modulation of oxidative stress with CHEMICAL reduces the VCM-induced kidney damage both at the biochemical and histological levels. | NO-RELATIONSHIP |
| In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: protection by erdosteine. The aims of this study were to examine vancomycin (VCM)-induced oxidative stress that promotes production of reactive oxygen species (ROS) and to investigate the role of erdosteine, an expectorant agent, which has also antioxidant properties, on kidney tissue against the possible VCM-induced renal impairment in rats. Rats were divided into three groups: sham, VCM and VCM plus erdosteine. VCM was administrated intraperitoneally (i.p.) with 200mgkg(-1) twice daily for 7 days. Erdosteine was administered orally. VCM administration to control rats significantly increased renal malondialdehyde (MDA) and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of renal tubular injury) excretion but decreased CHEMICAL dismutase (SOD) and catalase (CAT) activities. Erdosteine administration with VCM injections caused significantly decreased renal MDA and urinary NAG excretion, and increased SOD activity, but not CAT activity in renal tissue when compared with VCM alone. Erdosteine showed histopathological protection against VCM-induced nephrotoxicity. There were a significant dilatation of tubular lumens, extensive epithelial cell vacuolization, atrophy, desquamation, and DISEASE in VCM-treated rats more than those of the control and the erdosteine groups. Erdosteine caused a marked reduction in the extent of tubular damage. It is concluded that oxidative tubular damage plays an important role in the VCM-induced nephrotoxicity and the modulation of oxidative stress with erdosteine reduces the VCM-induced kidney damage both at the biochemical and histological levels. | NO-RELATIONSHIP |
| In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: protection by erdosteine. The aims of this study were to examine vancomycin (VCM)-induced oxidative stress that promotes production of reactive oxygen species (ROS) and to investigate the role of erdosteine, an expectorant agent, which has also antioxidant properties, on kidney tissue against the possible VCM-induced renal impairment in rats. Rats were divided into three groups: sham, VCM and VCM plus erdosteine. VCM was administrated intraperitoneally (i.p.) with 200mgkg(-1) twice daily for 7 days. Erdosteine was administered orally. VCM administration to control rats significantly increased renal CHEMICAL (CHEMICAL) and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of renal tubular injury) excretion but decreased superoxide dismutase (SOD) and catalase (CAT) activities. Erdosteine administration with VCM injections caused significantly decreased renal CHEMICAL and urinary NAG excretion, and increased SOD activity, but not CAT activity in renal tissue when compared with VCM alone. Erdosteine showed histopathological protection against VCM-induced nephrotoxicity. There were a significant dilatation of tubular lumens, extensive epithelial cell vacuolization, atrophy, DISEASE, and necrosis in VCM-treated rats more than those of the control and the erdosteine groups. Erdosteine caused a marked reduction in the extent of tubular damage. It is concluded that oxidative tubular damage plays an important role in the VCM-induced nephrotoxicity and the modulation of oxidative stress with erdosteine reduces the VCM-induced kidney damage both at the biochemical and histological levels. | NO-RELATIONSHIP |
| In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: protection by erdosteine. The aims of this study were to examine vancomycin (VCM)-induced oxidative stress that promotes production of reactive CHEMICAL species (ROS) and to investigate the role of erdosteine, an expectorant agent, which has also antioxidant properties, on kidney tissue against the possible VCM-induced renal impairment in rats. Rats were divided into three groups: sham, VCM and VCM plus erdosteine. VCM was administrated intraperitoneally (i.p.) with 200mgkg(-1) twice daily for 7 days. Erdosteine was administered orally. VCM administration to control rats significantly increased renal malondialdehyde (MDA) and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of renal tubular injury) excretion but decreased superoxide dismutase (SOD) and catalase (CAT) activities. Erdosteine administration with VCM injections caused significantly decreased renal MDA and urinary NAG excretion, and increased SOD activity, but not CAT activity in renal tissue when compared with VCM alone. Erdosteine showed histopathological protection against VCM-induced nephrotoxicity. There were a significant dilatation of tubular lumens, extensive epithelial cell vacuolization, atrophy, desquamation, and DISEASE in VCM-treated rats more than those of the control and the erdosteine groups. Erdosteine caused a marked reduction in the extent of tubular damage. It is concluded that oxidative tubular damage plays an important role in the VCM-induced nephrotoxicity and the modulation of oxidative stress with erdosteine reduces the VCM-induced kidney damage both at the biochemical and histological levels. | NO-RELATIONSHIP |
| In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: protection by CHEMICAL. The aims of this study were to examine vancomycin (VCM)-induced oxidative stress that promotes production of reactive oxygen species (ROS) and to investigate the role of CHEMICAL, an expectorant agent, which has also antioxidant properties, on kidney tissue against the possible VCM-induced renal impairment in rats. Rats were divided into three groups: sham, VCM and VCM plus CHEMICAL. VCM was administrated intraperitoneally (i.p.) with 200mgkg(-1) twice daily for 7 days. CHEMICAL was administered orally. VCM administration to control rats significantly increased renal malondialdehyde (MDA) and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of renal tubular injury) excretion but decreased superoxide dismutase (SOD) and catalase (CAT) activities. CHEMICAL administration with VCM injections caused significantly decreased renal MDA and urinary NAG excretion, and increased SOD activity, but not CAT activity in renal tissue when compared with VCM alone. CHEMICAL showed histopathological protection against VCM-induced nephrotoxicity. There were a significant dilatation of tubular lumens, extensive epithelial cell vacuolization, atrophy, desquamation, and DISEASE in VCM-treated rats more than those of the control and the CHEMICAL groups. CHEMICAL caused a marked reduction in the extent of tubular damage. It is concluded that oxidative tubular damage plays an important role in the VCM-induced nephrotoxicity and the modulation of oxidative stress with CHEMICAL reduces the VCM-induced kidney damage both at the biochemical and histological levels. | NO-RELATIONSHIP |
| In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: protection by erdosteine. The aims of this study were to examine vancomycin (VCM)-induced oxidative stress that promotes production of reactive oxygen species (ROS) and to investigate the role of erdosteine, an expectorant agent, which has also antioxidant properties, on kidney tissue against the possible VCM-induced renal impairment in rats. Rats were divided into three groups: sham, VCM and VCM plus erdosteine. VCM was administrated intraperitoneally (i.p.) with 200mgkg(-1) twice daily for 7 days. Erdosteine was administered orally. VCM administration to control rats significantly increased renal malondialdehyde (MDA) and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of renal tubular injury) excretion but decreased CHEMICAL dismutase (SOD) and catalase (CAT) activities. Erdosteine administration with VCM injections caused significantly decreased renal MDA and urinary NAG excretion, and increased SOD activity, but not CAT activity in renal tissue when compared with VCM alone. Erdosteine showed histopathological protection against VCM-induced nephrotoxicity. There were a significant dilatation of tubular lumens, extensive epithelial cell vacuolization, DISEASE, desquamation, and necrosis in VCM-treated rats more than those of the control and the erdosteine groups. Erdosteine caused a marked reduction in the extent of tubular damage. It is concluded that oxidative tubular damage plays an important role in the VCM-induced nephrotoxicity and the modulation of oxidative stress with erdosteine reduces the VCM-induced kidney damage both at the biochemical and histological levels. | NO-RELATIONSHIP |
| In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: protection by CHEMICAL. The aims of this study were to examine vancomycin (VCM)-induced oxidative stress that promotes production of reactive oxygen species (ROS) and to investigate the role of CHEMICAL, an expectorant agent, which has also antioxidant properties, on kidney tissue against the possible VCM-induced renal impairment in rats. Rats were divided into three groups: sham, VCM and VCM plus CHEMICAL. VCM was administrated intraperitoneally (i.p.) with 200mgkg(-1) twice daily for 7 days. CHEMICAL was administered orally. VCM administration to control rats significantly increased renal malondialdehyde (MDA) and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of renal tubular injury) excretion but decreased superoxide dismutase (SOD) and catalase (CAT) activities. CHEMICAL administration with VCM injections caused significantly decreased renal MDA and urinary NAG excretion, and increased SOD activity, but not CAT activity in renal tissue when compared with VCM alone. CHEMICAL showed histopathological protection against VCM-induced nephrotoxicity. There were a significant dilatation of tubular lumens, extensive epithelial cell vacuolization, DISEASE, desquamation, and necrosis in VCM-treated rats more than those of the control and the CHEMICAL groups. CHEMICAL caused a marked reduction in the extent of tubular damage. It is concluded that oxidative tubular damage plays an important role in the VCM-induced nephrotoxicity and the modulation of oxidative stress with CHEMICAL reduces the VCM-induced kidney damage both at the biochemical and histological levels. | NO-RELATIONSHIP |
| In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: protection by erdosteine. The aims of this study were to examine vancomycin (VCM)-induced oxidative stress that promotes production of reactive oxygen species (ROS) and to investigate the role of erdosteine, an expectorant agent, which has also antioxidant properties, on kidney tissue against the possible VCM-induced renal impairment in rats. Rats were divided into three groups: sham, VCM and VCM plus erdosteine. VCM was administrated intraperitoneally (i.p.) with 200mgkg(-1) twice daily for 7 days. Erdosteine was administered orally. VCM administration to control rats significantly increased renal malondialdehyde (MDA) and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of renal tubular injury) excretion but decreased CHEMICAL dismutase (SOD) and catalase (CAT) activities. Erdosteine administration with VCM injections caused significantly decreased renal MDA and urinary NAG excretion, and increased SOD activity, but not CAT activity in renal tissue when compared with VCM alone. Erdosteine showed histopathological protection against VCM-induced nephrotoxicity. There were a significant dilatation of tubular lumens, extensive epithelial cell vacuolization, atrophy, DISEASE, and necrosis in VCM-treated rats more than those of the control and the erdosteine groups. Erdosteine caused a marked reduction in the extent of tubular damage. It is concluded that oxidative tubular damage plays an important role in the VCM-induced nephrotoxicity and the modulation of oxidative stress with erdosteine reduces the VCM-induced kidney damage both at the biochemical and histological levels. | NO-RELATIONSHIP |
| In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: protection by erdosteine. The aims of this study were to examine vancomycin (VCM)-induced oxidative stress that promotes production of reactive oxygen species (ROS) and to investigate the role of erdosteine, an expectorant agent, which has also antioxidant properties, on kidney tissue against the possible VCM-induced renal impairment in rats. Rats were divided into three groups: sham, VCM and VCM plus erdosteine. VCM was administrated intraperitoneally (i.p.) with 200mgkg(-1) twice daily for 7 days. Erdosteine was administered orally. VCM administration to control rats significantly increased renal CHEMICAL (CHEMICAL) and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of renal tubular injury) excretion but decreased superoxide dismutase (SOD) and catalase (CAT) activities. Erdosteine administration with VCM injections caused significantly decreased renal CHEMICAL and urinary NAG excretion, and increased SOD activity, but not CAT activity in renal tissue when compared with VCM alone. Erdosteine showed histopathological protection against VCM-induced nephrotoxicity. There were a significant dilatation of tubular lumens, extensive epithelial cell vacuolization, atrophy, desquamation, and DISEASE in VCM-treated rats more than those of the control and the erdosteine groups. Erdosteine caused a marked reduction in the extent of tubular damage. It is concluded that oxidative tubular damage plays an important role in the VCM-induced nephrotoxicity and the modulation of oxidative stress with erdosteine reduces the VCM-induced kidney damage both at the biochemical and histological levels. | NO-RELATIONSHIP |
| In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: protection by erdosteine. The aims of this study were to examine vancomycin (VCM)-induced oxidative stress that promotes production of reactive oxygen species (ROS) and to investigate the role of erdosteine, an expectorant agent, which has also antioxidant properties, on kidney tissue against the possible VCM-induced renal impairment in rats. Rats were divided into three groups: sham, VCM and VCM plus erdosteine. VCM was administrated intraperitoneally (i.p.) with 200mgkg(-1) twice daily for 7 days. Erdosteine was administered orally. VCM administration to control rats significantly increased renal CHEMICAL (CHEMICAL) and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of renal tubular injury) excretion but decreased superoxide dismutase (SOD) and catalase (CAT) activities. Erdosteine administration with VCM injections caused significantly decreased renal CHEMICAL and urinary NAG excretion, and increased SOD activity, but not CAT activity in renal tissue when compared with VCM alone. Erdosteine showed histopathological protection against VCM-induced nephrotoxicity. There were a significant dilatation of tubular lumens, extensive epithelial cell vacuolization, DISEASE, desquamation, and necrosis in VCM-treated rats more than those of the control and the erdosteine groups. Erdosteine caused a marked reduction in the extent of tubular damage. It is concluded that oxidative tubular damage plays an important role in the VCM-induced nephrotoxicity and the modulation of oxidative stress with erdosteine reduces the VCM-induced kidney damage both at the biochemical and histological levels. | NO-RELATIONSHIP |
| In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: protection by erdosteine. The aims of this study were to examine vancomycin (VCM)-induced oxidative stress that promotes production of reactive CHEMICAL species (ROS) and to investigate the role of erdosteine, an expectorant agent, which has also antioxidant properties, on kidney tissue against the possible VCM-induced renal impairment in rats. Rats were divided into three groups: sham, VCM and VCM plus erdosteine. VCM was administrated intraperitoneally (i.p.) with 200mgkg(-1) twice daily for 7 days. Erdosteine was administered orally. VCM administration to control rats significantly increased renal malondialdehyde (MDA) and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of renal tubular injury) excretion but decreased superoxide dismutase (SOD) and catalase (CAT) activities. Erdosteine administration with VCM injections caused significantly decreased renal MDA and urinary NAG excretion, and increased SOD activity, but not CAT activity in renal tissue when compared with VCM alone. Erdosteine showed histopathological protection against VCM-induced nephrotoxicity. There were a significant dilatation of tubular lumens, extensive epithelial cell vacuolization, atrophy, DISEASE, and necrosis in VCM-treated rats more than those of the control and the erdosteine groups. Erdosteine caused a marked reduction in the extent of tubular damage. It is concluded that oxidative tubular damage plays an important role in the VCM-induced nephrotoxicity and the modulation of oxidative stress with erdosteine reduces the VCM-induced kidney damage both at the biochemical and histological levels. | NO-RELATIONSHIP |
| Does domperidone potentiate CHEMICAL-associated DISEASE? There is now evidence to suggest a central role for the dopaminergic system in DISEASE (DISEASE). For example, the symptoms of DISEASE can be dramatically improved by levodopa and dopamine agonists, whereas central dopamine D2 receptor antagonists can induce or aggravate DISEASE symptoms. To our knowledge, there is no previous report regarding whether domperidone, a peripheral dopamine D2 receptor antagonist, can also induce or aggravate symptoms of DISEASE. CHEMICAL, the first noradrenergic and specific serotonergic antidepressant (NaSSA), has been associated with DISEASE in several recent publications. The authors report here a depressed patient comorbid with postprandial dyspepsia who developed DISEASE after CHEMICAL had been added to his domperidone therapy. Our patient started to have symptoms of DISEASE only after he had been treated with CHEMICAL, and his DISEASE symptoms resolved completely upon discontinuation of his CHEMICAL. Such a temporal relationship between the use of CHEMICAL and the symptoms of DISEASE in our patient did not support a potentiating effect of domperione on CHEMICAL-associated DISEASE. However, physicians should be aware of the possibility that CHEMICAL can be associated with DISEASE in some individuals, especially those receiving concomitant dopamine D2 receptor antagonists. | CHEMICAL-INDUCED-DISEASE |
| Does domperidone potentiate mirtazapine-associated restless legs syndrome? There is now evidence to suggest a central role for the dopaminergic system in restless legs syndrome (RLS). For example, the symptoms of RLS can be dramatically improved by CHEMICAL and dopamine agonists, whereas central dopamine D2 receptor antagonists can induce or aggravate RLS symptoms. To our knowledge, there is no previous report regarding whether domperidone, a peripheral dopamine D2 receptor antagonist, can also induce or aggravate symptoms of RLS. Mirtazapine, the first noradrenergic and specific serotonergic antidepressant (NaSSA), has been associated with RLS in several recent publications. The authors report here a depressed patient comorbid with DISEASE who developed RLS after mirtazapine had been added to his domperidone therapy. Our patient started to have symptoms of RLS only after he had been treated with mirtazapine, and his RLS symptoms resolved completely upon discontinuation of his mirtazapine. Such a temporal relationship between the use of mirtazapine and the symptoms of RLS in our patient did not support a potentiating effect of domperione on mirtazapine-associated RLS. However, physicians should be aware of the possibility that mirtazapine can be associated with RLS in some individuals, especially those receiving concomitant dopamine D2 receptor antagonists. | NO-RELATIONSHIP |
| Does CHEMICAL potentiate mirtazapine-associated restless legs syndrome? There is now evidence to suggest a central role for the dopaminergic system in restless legs syndrome (RLS). For example, the symptoms of RLS can be dramatically improved by levodopa and dopamine agonists, whereas central dopamine D2 receptor antagonists can induce or aggravate RLS symptoms. To our knowledge, there is no previous report regarding whether CHEMICAL, a peripheral dopamine D2 receptor antagonist, can also induce or aggravate symptoms of RLS. Mirtazapine, the first noradrenergic and specific serotonergic antidepressant (NaSSA), has been associated with RLS in several recent publications. The authors report here a depressed patient comorbid with DISEASE who developed RLS after mirtazapine had been added to his CHEMICAL therapy. Our patient started to have symptoms of RLS only after he had been treated with mirtazapine, and his RLS symptoms resolved completely upon discontinuation of his mirtazapine. Such a temporal relationship between the use of mirtazapine and the symptoms of RLS in our patient did not support a potentiating effect of CHEMICAL on mirtazapine-associated RLS. However, physicians should be aware of the possibility that mirtazapine can be associated with RLS in some individuals, especially those receiving concomitant dopamine D2 receptor antagonists. | NO-RELATIONSHIP |
| Does domperidone potentiate mirtazapine-associated restless legs syndrome? There is now evidence to suggest a central role for the dopaminergic system in restless legs syndrome (RLS). For example, the symptoms of RLS can be dramatically improved by levodopa and CHEMICAL agonists, whereas central CHEMICAL D2 receptor antagonists can induce or aggravate RLS symptoms. To our knowledge, there is no previous report regarding whether domperidone, a peripheral CHEMICAL D2 receptor antagonist, can also induce or aggravate symptoms of RLS. Mirtazapine, the first noradrenergic and specific serotonergic antidepressant (NaSSA), has been associated with RLS in several recent publications. The authors report here a depressed patient comorbid with DISEASE who developed RLS after mirtazapine had been added to his domperidone therapy. Our patient started to have symptoms of RLS only after he had been treated with mirtazapine, and his RLS symptoms resolved completely upon discontinuation of his mirtazapine. Such a temporal relationship between the use of mirtazapine and the symptoms of RLS in our patient did not support a potentiating effect of domperione on mirtazapine-associated RLS. However, physicians should be aware of the possibility that mirtazapine can be associated with RLS in some individuals, especially those receiving concomitant CHEMICAL D2 receptor antagonists. | NO-RELATIONSHIP |
| Antiandrogenic therapy can cause coronary arterial disease. AIM: To study the change of lipid metabolism by antiandrogen therapy in patients with DISEASE. MATERIALS AND METHODS: We studied with a 2.5 years follow-up the changes in plasma CHEMICAL (CHEMICAL), triglycerides (TG), lipoproteins (LP), and apolipoproteins (Apo) B-100, A-I, and A-II pro fi les in 24 patients of mean age 60 years with low risk prostate cancer (stage: T1cN0M0, Gleason score: 2-5) during treatment with cyproterone acetate (CPA) without surgical management or radiation therapy. RESULTS: Significant decreases of HDL-C, Apo A-I and Apo A-II and an increase of triglyceride levels in VLDL were induced by CPA. After a period of 2.5 years on CPA treatment, four patients out of twenty-four were found to be affected by coronary heart disease. CONCLUSIONS: Ischaemic coronary arteriosclerosis with an incidence rate of 16.6% as caused by prolonged CPA therapy is mediated through changes in HDL cholesterol, Apo A-I and Apo A-II pro fi les, other than the well-known hyperglyceridemic effect caused by estrogen. | NO-RELATIONSHIP |
| CHEMICAL cardiotoxicity induced by alpha-fluoro-beta-alanine. Cardiotoxicity is a rare complication occurring during CHEMICAL (CHEMICAL) treatment for malignancies. We herein report the case of a 70-year-old man with CHEMICAL-induced cardiotoxicity, in whom a high serum level of alpha-fluoro-beta-alanine (FBAL) was observed. The patient, who had unresectable colon cancer metastases to the liver and lung, was referred to us for chemotherapy from an affiliated hospital; he had no cardiac history. After admission, the patient received a continuous intravenous infusion of CHEMICAL (1000 mg/day), during which DISEASE with right bundle branch block occurred concomitantly with a high serum FBAL concentration of 1955 ng/ml. Both the DISEASE and the electrocardiographic changes disappeared spontaneously after the discontinuation of CHEMICAL. As the DISEASE in this patient was considered to have been due to CHEMICAL-induced cardiotoxicity, the administration of CHEMICAL was abandoned. Instead, oral administration of S-1 (a derivative of CHEMICAL), at 200 mg/day twice a week, was instituted, because S-1 has a strong inhibitory effect on dihydropyrimidine dehydrogenase, which catalyzes the degradative of CHEMICAL into FBAL. The serum FBAL concentration subsequently decreased to 352 ng/ml, the same as the value measured on the first day of S-1 administration. Thereafter, no cardiac symptoms were observed. The patient achieved a partial response 6 months after the initiation of the S-1 treatment. The experience of this case, together with a review of the literature, suggests that FBAL is related to CHEMICAL-induced cardiotoxicity. S-1 may be administered safely to patients with CHEMICAL-induced cardiotoxicity. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL cardiotoxicity induced by alpha-fluoro-beta-alanine. Cardiotoxicity is a rare complication occurring during CHEMICAL (CHEMICAL) treatment for malignancies. We herein report the case of a 70-year-old man with CHEMICAL-induced cardiotoxicity, in whom a high serum level of alpha-fluoro-beta-alanine (FBAL) was observed. The patient, who had unresectable colon cancer metastases to the liver and lung, was referred to us for chemotherapy from an affiliated hospital; he had no cardiac history. After admission, the patient received a continuous intravenous infusion of CHEMICAL (1000 mg/day), during which precordial pain with DISEASE occurred concomitantly with a high serum FBAL concentration of 1955 ng/ml. Both the precordial pain and the electrocardiographic changes disappeared spontaneously after the discontinuation of CHEMICAL. As the precordial pain in this patient was considered to have been due to CHEMICAL-induced cardiotoxicity, the administration of CHEMICAL was abandoned. Instead, oral administration of S-1 (a derivative of CHEMICAL), at 200 mg/day twice a week, was instituted, because S-1 has a strong inhibitory effect on dihydropyrimidine dehydrogenase, which catalyzes the degradative of CHEMICAL into FBAL. The serum FBAL concentration subsequently decreased to 352 ng/ml, the same as the value measured on the first day of S-1 administration. Thereafter, no cardiac symptoms were observed. The patient achieved a partial response 6 months after the initiation of the S-1 treatment. The experience of this case, together with a review of the literature, suggests that FBAL is related to CHEMICAL-induced cardiotoxicity. S-1 may be administered safely to patients with CHEMICAL-induced cardiotoxicity. | CHEMICAL-INDUCED-DISEASE |
| 5-Fluorouracil cardiotoxicity induced by alpha-fluoro-beta-alanine. Cardiotoxicity is a rare complication occurring during 5-fluorouracil (5-FU) treatment for malignancies. We herein report the case of a 70-year-old man with 5-FU-induced cardiotoxicity, in whom a high serum level of alpha-fluoro-beta-alanine (FBAL) was observed. The patient, who had unresectable DISEASE metastases to the liver and lung, was referred to us for chemotherapy from an affiliated hospital; he had no cardiac history. After admission, the patient received a continuous intravenous infusion of 5-FU (1000 mg/day), during which precordial pain with right bundle branch block occurred concomitantly with a high serum FBAL concentration of 1955 ng/ml. Both the precordial pain and the electrocardiographic changes disappeared spontaneously after the discontinuation of 5-FU. As the precordial pain in this patient was considered to have been due to 5-FU-induced cardiotoxicity, the administration of 5-FU was abandoned. Instead, oral administration of S-1 (a derivative of 5-FU), at 200 mg/day twice a week, was instituted, because S-1 has a strong inhibitory effect on CHEMICAL dehydrogenase, which catalyzes the degradative of 5-FU into FBAL. The serum FBAL concentration subsequently decreased to 352 ng/ml, the same as the value measured on the first day of S-1 administration. Thereafter, no cardiac symptoms were observed. The patient achieved a partial response 6 months after the initiation of the S-1 treatment. The experience of this case, together with a review of the literature, suggests that FBAL is related to 5-FU-induced cardiotoxicity. S-1 may be administered safely to patients with 5-FU-induced cardiotoxicity. | NO-RELATIONSHIP |
| 5-Fluorouracil DISEASE induced by alpha-fluoro-beta-alanine. DISEASE is a rare complication occurring during 5-fluorouracil (5-FU) treatment for malignancies. We herein report the case of a 70-year-old man with 5-FU-induced DISEASE, in whom a high serum level of alpha-fluoro-beta-alanine (FBAL) was observed. The patient, who had unresectable colon cancer metastases to the liver and lung, was referred to us for chemotherapy from an affiliated hospital; he had no cardiac history. After admission, the patient received a continuous intravenous infusion of 5-FU (1000 mg/day), during which precordial pain with right bundle branch block occurred concomitantly with a high serum FBAL concentration of 1955 ng/ml. Both the precordial pain and the electrocardiographic changes disappeared spontaneously after the discontinuation of 5-FU. As the precordial pain in this patient was considered to have been due to 5-FU-induced DISEASE, the administration of 5-FU was abandoned. Instead, oral administration of S-1 (a derivative of 5-FU), at 200 mg/day twice a week, was instituted, because S-1 has a strong inhibitory effect on CHEMICAL dehydrogenase, which catalyzes the degradative of 5-FU into FBAL. The serum FBAL concentration subsequently decreased to 352 ng/ml, the same as the value measured on the first day of S-1 administration. Thereafter, no cardiac symptoms were observed. The patient achieved a partial response 6 months after the initiation of the S-1 treatment. The experience of this case, together with a review of the literature, suggests that FBAL is related to 5-FU-induced DISEASE. S-1 may be administered safely to patients with 5-FU-induced DISEASE. | NO-RELATIONSHIP |
| 5-Fluorouracil cardiotoxicity induced by alpha-fluoro-beta-alanine. Cardiotoxicity is a rare complication occurring during 5-fluorouracil (5-FU) treatment for DISEASE. We herein report the case of a 70-year-old man with 5-FU-induced cardiotoxicity, in whom a high serum level of alpha-fluoro-beta-alanine (FBAL) was observed. The patient, who had unresectable colon cancer metastases to the liver and lung, was referred to us for chemotherapy from an affiliated hospital; he had no cardiac history. After admission, the patient received a continuous intravenous infusion of 5-FU (1000 mg/day), during which precordial pain with right bundle branch block occurred concomitantly with a high serum FBAL concentration of 1955 ng/ml. Both the precordial pain and the electrocardiographic changes disappeared spontaneously after the discontinuation of 5-FU. As the precordial pain in this patient was considered to have been due to 5-FU-induced cardiotoxicity, the administration of 5-FU was abandoned. Instead, oral administration of S-1 (a derivative of 5-FU), at 200 mg/day twice a week, was instituted, because S-1 has a strong inhibitory effect on CHEMICAL dehydrogenase, which catalyzes the degradative of 5-FU into FBAL. The serum FBAL concentration subsequently decreased to 352 ng/ml, the same as the value measured on the first day of S-1 administration. Thereafter, no cardiac symptoms were observed. The patient achieved a partial response 6 months after the initiation of the S-1 treatment. The experience of this case, together with a review of the literature, suggests that FBAL is related to 5-FU-induced cardiotoxicity. S-1 may be administered safely to patients with 5-FU-induced cardiotoxicity. | NO-RELATIONSHIP |
| 5-Fluorouracil cardiotoxicity induced by CHEMICAL. Cardiotoxicity is a rare complication occurring during 5-fluorouracil (5-FU) treatment for DISEASE. We herein report the case of a 70-year-old man with 5-FU-induced cardiotoxicity, in whom a high serum level of CHEMICAL (CHEMICAL) was observed. The patient, who had unresectable colon cancer metastases to the liver and lung, was referred to us for chemotherapy from an affiliated hospital; he had no cardiac history. After admission, the patient received a continuous intravenous infusion of 5-FU (1000 mg/day), during which precordial pain with right bundle branch block occurred concomitantly with a high serum CHEMICAL concentration of 1955 ng/ml. Both the precordial pain and the electrocardiographic changes disappeared spontaneously after the discontinuation of 5-FU. As the precordial pain in this patient was considered to have been due to 5-FU-induced cardiotoxicity, the administration of 5-FU was abandoned. Instead, oral administration of S-1 (a derivative of 5-FU), at 200 mg/day twice a week, was instituted, because S-1 has a strong inhibitory effect on dihydropyrimidine dehydrogenase, which catalyzes the degradative of 5-FU into CHEMICAL. The serum CHEMICAL concentration subsequently decreased to 352 ng/ml, the same as the value measured on the first day of S-1 administration. Thereafter, no cardiac symptoms were observed. The patient achieved a partial response 6 months after the initiation of the S-1 treatment. The experience of this case, together with a review of the literature, suggests that CHEMICAL is related to 5-FU-induced cardiotoxicity. S-1 may be administered safely to patients with 5-FU-induced cardiotoxicity. | NO-RELATIONSHIP |
| 5-Fluorouracil cardiotoxicity induced by alpha-fluoro-beta-alanine. Cardiotoxicity is a rare complication occurring during 5-fluorouracil (5-FU) treatment for malignancies. We herein report the case of a 70-year-old man with 5-FU-induced cardiotoxicity, in whom a high serum level of alpha-fluoro-beta-alanine (FBAL) was observed. The patient, who had unresectable colon cancer metastases to the liver and lung, was referred to us for chemotherapy from an affiliated hospital; he had no cardiac history. After admission, the patient received a continuous intravenous infusion of 5-FU (1000 mg/day), during which precordial pain with right bundle branch block occurred concomitantly with a high serum FBAL concentration of 1955 ng/ml. Both the precordial pain and the electrocardiographic changes disappeared spontaneously after the discontinuation of 5-FU. As the precordial pain in this patient was considered to have been due to 5-FU-induced cardiotoxicity, the administration of 5-FU was abandoned. Instead, oral administration of S-1 (a derivative of 5-FU), at 200 mg/day twice a week, was instituted, because S-1 has a strong inhibitory effect on CHEMICAL dehydrogenase, which catalyzes the degradative of 5-FU into FBAL. The serum FBAL concentration subsequently decreased to 352 ng/ml, the same as the value measured on the first day of S-1 administration. Thereafter, no DISEASE were observed. The patient achieved a partial response 6 months after the initiation of the S-1 treatment. The experience of this case, together with a review of the literature, suggests that FBAL is related to 5-FU-induced cardiotoxicity. S-1 may be administered safely to patients with 5-FU-induced cardiotoxicity. | NO-RELATIONSHIP |
| 5-Fluorouracil cardiotoxicity induced by CHEMICAL. Cardiotoxicity is a rare complication occurring during 5-fluorouracil (5-FU) treatment for malignancies. We herein report the case of a 70-year-old man with 5-FU-induced cardiotoxicity, in whom a high serum level of CHEMICAL (CHEMICAL) was observed. The patient, who had unresectable DISEASE metastases to the liver and lung, was referred to us for chemotherapy from an affiliated hospital; he had no cardiac history. After admission, the patient received a continuous intravenous infusion of 5-FU (1000 mg/day), during which precordial pain with right bundle branch block occurred concomitantly with a high serum CHEMICAL concentration of 1955 ng/ml. Both the precordial pain and the electrocardiographic changes disappeared spontaneously after the discontinuation of 5-FU. As the precordial pain in this patient was considered to have been due to 5-FU-induced cardiotoxicity, the administration of 5-FU was abandoned. Instead, oral administration of S-1 (a derivative of 5-FU), at 200 mg/day twice a week, was instituted, because S-1 has a strong inhibitory effect on dihydropyrimidine dehydrogenase, which catalyzes the degradative of 5-FU into CHEMICAL. The serum CHEMICAL concentration subsequently decreased to 352 ng/ml, the same as the value measured on the first day of S-1 administration. Thereafter, no cardiac symptoms were observed. The patient achieved a partial response 6 months after the initiation of the S-1 treatment. The experience of this case, together with a review of the literature, suggests that CHEMICAL is related to 5-FU-induced cardiotoxicity. S-1 may be administered safely to patients with 5-FU-induced cardiotoxicity. | NO-RELATIONSHIP |
| 5-Fluorouracil cardiotoxicity induced by CHEMICAL. Cardiotoxicity is a rare complication occurring during 5-fluorouracil (5-FU) treatment for malignancies. We herein report the case of a 70-year-old man with 5-FU-induced cardiotoxicity, in whom a high serum level of CHEMICAL (CHEMICAL) was observed. The patient, who had unresectable colon cancer metastases to the liver and lung, was referred to us for chemotherapy from an affiliated hospital; he had no cardiac history. After admission, the patient received a continuous intravenous infusion of 5-FU (1000 mg/day), during which precordial pain with right bundle branch block occurred concomitantly with a high serum CHEMICAL concentration of 1955 ng/ml. Both the precordial pain and the electrocardiographic changes disappeared spontaneously after the discontinuation of 5-FU. As the precordial pain in this patient was considered to have been due to 5-FU-induced cardiotoxicity, the administration of 5-FU was abandoned. Instead, oral administration of S-1 (a derivative of 5-FU), at 200 mg/day twice a week, was instituted, because S-1 has a strong inhibitory effect on dihydropyrimidine dehydrogenase, which catalyzes the degradative of 5-FU into CHEMICAL. The serum CHEMICAL concentration subsequently decreased to 352 ng/ml, the same as the value measured on the first day of S-1 administration. Thereafter, no DISEASE were observed. The patient achieved a partial response 6 months after the initiation of the S-1 treatment. The experience of this case, together with a review of the literature, suggests that CHEMICAL is related to 5-FU-induced cardiotoxicity. S-1 may be administered safely to patients with 5-FU-induced cardiotoxicity. | NO-RELATIONSHIP |
| 5-Fluorouracil DISEASE induced by CHEMICAL. DISEASE is a rare complication occurring during 5-fluorouracil (5-FU) treatment for malignancies. We herein report the case of a 70-year-old man with 5-FU-induced DISEASE, in whom a high serum level of CHEMICAL (CHEMICAL) was observed. The patient, who had unresectable colon cancer metastases to the liver and lung, was referred to us for chemotherapy from an affiliated hospital; he had no cardiac history. After admission, the patient received a continuous intravenous infusion of 5-FU (1000 mg/day), during which precordial pain with right bundle branch block occurred concomitantly with a high serum CHEMICAL concentration of 1955 ng/ml. Both the precordial pain and the electrocardiographic changes disappeared spontaneously after the discontinuation of 5-FU. As the precordial pain in this patient was considered to have been due to 5-FU-induced DISEASE, the administration of 5-FU was abandoned. Instead, oral administration of S-1 (a derivative of 5-FU), at 200 mg/day twice a week, was instituted, because S-1 has a strong inhibitory effect on dihydropyrimidine dehydrogenase, which catalyzes the degradative of 5-FU into CHEMICAL. The serum CHEMICAL concentration subsequently decreased to 352 ng/ml, the same as the value measured on the first day of S-1 administration. Thereafter, no cardiac symptoms were observed. The patient achieved a partial response 6 months after the initiation of the S-1 treatment. The experience of this case, together with a review of the literature, suggests that CHEMICAL is related to 5-FU-induced DISEASE. S-1 may be administered safely to patients with 5-FU-induced DISEASE. | NO-RELATIONSHIP |
| The influence of the time interval between monoHER and CHEMICAL administration on the protection against CHEMICAL-induced cardiotoxicity in mice. PURPOSE: Despite its well-known cardiotoxicity, the anthracyclin CHEMICAL (CHEMICAL) continues to be an effective and widely used chemotherapeutic agent. CHEMICAL-induced cardiac damage presumably results from the formation of free radicals by CHEMICAL. Reactive oxygen species particularly affect the cardiac myocytes because these cells seem to have a relatively poor antioxidant defense system. The semisynthetic flavonoid monohydroxyethylrutoside (monoHER) showed cardioprotection against CHEMICAL-induced cardiotoxicity through its radical scavenging and iron chelating properties. Because of the relatively short final half-life of monoHER (about 30 min), it is expected that the time interval between monoHER and CHEMICAL might be of influence on the cardioprotective effect of monoHER. Therefore, the aim of the present study was to investigate this possible effect. METHODS: Six groups of 6 BALB/c mice were treated with saline, CHEMICAL alone or CHEMICAL (4 mg/kg i.v.) preceded by monoHER (500 mg/kg i.p.) with an interval of 10, 30, 60 or 120 min. After a 6-week treatment period and additional observation for 2 weeks, the mice were sacrificed. Their cardiac tissues were processed for light microscopy, after which DISEASE was evaluated according to Billingham (in Cancer Treat Rep 62(6):865-872, 1978). Microscopic evaluation revealed that treatment with CHEMICAL alone induced significant cardiac damage in comparison to the saline control group (P<0.001). RESULTS: The number of damaged cardiomyocytes was 9.6-fold (95% CI 4.4-21.0) higher in mice treated with CHEMICAL alone than that in animals of the control group. The ratio of aberrant cardiomyocytes in mice treated with CHEMICAL preceded by monoHER and those in mice treated with saline ranged from 1.6 to 2.8 (mean 2.2, 95% CI 1.2-4.1, P=0.019). The mean protective effect by adding monoHER before CHEMICAL led to a significant 4.4-fold reduction (P<0.001, 95% CI 2.3-8.2) of abnormal cardiomyocytes. This protective effect did not depend on the time interval between monoHER and CHEMICAL administration (P=0.345). CONCLUSION: The results indicate that in an outpatient clinical setting monoHER may be administered shortly before CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| The influence of the time interval between CHEMICAL and doxorubicin administration on the protection against doxorubicin-induced DISEASE in mice. PURPOSE: Despite its well-known DISEASE, the anthracyclin doxorubicin (DOX) continues to be an effective and widely used chemotherapeutic agent. DOX-induced cardiac damage presumably results from the formation of free radicals by DOX. Reactive oxygen species particularly affect the cardiac myocytes because these cells seem to have a relatively poor antioxidant defense system. The semisynthetic flavonoid CHEMICAL (CHEMICAL) showed cardioprotection against DOX-induced DISEASE through its radical scavenging and iron chelating properties. Because of the relatively short final half-life of CHEMICAL (about 30 min), it is expected that the time interval between CHEMICAL and DOX might be of influence on the cardioprotective effect of CHEMICAL. Therefore, the aim of the present study was to investigate this possible effect. METHODS: Six groups of 6 BALB/c mice were treated with saline, DOX alone or DOX (4 mg/kg i.v.) preceded by CHEMICAL (500 mg/kg i.p.) with an interval of 10, 30, 60 or 120 min. After a 6-week treatment period and additional observation for 2 weeks, the mice were sacrificed. Their cardiac tissues were processed for light microscopy, after which cardiomyocyte damage was evaluated according to Billingham (in Cancer Treat Rep 62(6):865-872, 1978). Microscopic evaluation revealed that treatment with DOX alone induced significant cardiac damage in comparison to the saline control group (P<0.001). RESULTS: The number of damaged cardiomyocytes was 9.6-fold (95% CI 4.4-21.0) higher in mice treated with DOX alone than that in animals of the control group. The ratio of aberrant cardiomyocytes in mice treated with DOX preceded by CHEMICAL and those in mice treated with saline ranged from 1.6 to 2.8 (mean 2.2, 95% CI 1.2-4.1, P=0.019). The mean protective effect by adding CHEMICAL before DOX led to a significant 4.4-fold reduction (P<0.001, 95% CI 2.3-8.2) of abnormal cardiomyocytes. This protective effect did not depend on the time interval between CHEMICAL and DOX administration (P=0.345). CONCLUSION: The results indicate that in an outpatient clinical setting CHEMICAL may be administered shortly before DOX. | NO-RELATIONSHIP |
| The influence of the time interval between monoHER and doxorubicin administration on the protection against doxorubicin-induced cardiotoxicity in mice. PURPOSE: Despite its well-known cardiotoxicity, the anthracyclin doxorubicin (DOX) continues to be an effective and widely used chemotherapeutic agent. DOX-induced cardiac damage presumably results from the formation of free radicals by DOX. Reactive CHEMICAL species particularly affect the cardiac myocytes because these cells seem to have a relatively poor antioxidant defense system. The semisynthetic flavonoid monohydroxyethylrutoside (monoHER) showed cardioprotection against DOX-induced cardiotoxicity through its radical scavenging and iron chelating properties. Because of the relatively short final half-life of monoHER (about 30 min), it is expected that the time interval between monoHER and DOX might be of influence on the cardioprotective effect of monoHER. Therefore, the aim of the present study was to investigate this possible effect. METHODS: Six groups of 6 BALB/c mice were treated with saline, DOX alone or DOX (4 mg/kg i.v.) preceded by monoHER (500 mg/kg i.p.) with an interval of 10, 30, 60 or 120 min. After a 6-week treatment period and additional observation for 2 weeks, the mice were sacrificed. Their cardiac tissues were processed for light microscopy, after which cardiomyocyte damage was evaluated according to Billingham (in DISEASE Treat Rep 62(6):865-872, 1978). Microscopic evaluation revealed that treatment with DOX alone induced significant cardiac damage in comparison to the saline control group (P<0.001). RESULTS: The number of damaged cardiomyocytes was 9.6-fold (95% CI 4.4-21.0) higher in mice treated with DOX alone than that in animals of the control group. The ratio of aberrant cardiomyocytes in mice treated with DOX preceded by monoHER and those in mice treated with saline ranged from 1.6 to 2.8 (mean 2.2, 95% CI 1.2-4.1, P=0.019). The mean protective effect by adding monoHER before DOX led to a significant 4.4-fold reduction (P<0.001, 95% CI 2.3-8.2) of abnormal cardiomyocytes. This protective effect did not depend on the time interval between monoHER and DOX administration (P=0.345). CONCLUSION: The results indicate that in an outpatient clinical setting monoHER may be administered shortly before DOX. | NO-RELATIONSHIP |
| The influence of the time interval between monoHER and doxorubicin administration on the protection against doxorubicin-induced cardiotoxicity in mice. PURPOSE: Despite its well-known cardiotoxicity, the anthracyclin doxorubicin (DOX) continues to be an effective and widely used chemotherapeutic agent. DOX-induced DISEASE presumably results from the formation of free radicals by DOX. Reactive CHEMICAL species particularly affect the cardiac myocytes because these cells seem to have a relatively poor antioxidant defense system. The semisynthetic flavonoid monohydroxyethylrutoside (monoHER) showed cardioprotection against DOX-induced cardiotoxicity through its radical scavenging and iron chelating properties. Because of the relatively short final half-life of monoHER (about 30 min), it is expected that the time interval between monoHER and DOX might be of influence on the cardioprotective effect of monoHER. Therefore, the aim of the present study was to investigate this possible effect. METHODS: Six groups of 6 BALB/c mice were treated with saline, DOX alone or DOX (4 mg/kg i.v.) preceded by monoHER (500 mg/kg i.p.) with an interval of 10, 30, 60 or 120 min. After a 6-week treatment period and additional observation for 2 weeks, the mice were sacrificed. Their cardiac tissues were processed for light microscopy, after which cardiomyocyte damage was evaluated according to Billingham (in Cancer Treat Rep 62(6):865-872, 1978). Microscopic evaluation revealed that treatment with DOX alone induced significant DISEASE in comparison to the saline control group (P<0.001). RESULTS: The number of damaged cardiomyocytes was 9.6-fold (95% CI 4.4-21.0) higher in mice treated with DOX alone than that in animals of the control group. The ratio of aberrant cardiomyocytes in mice treated with DOX preceded by monoHER and those in mice treated with saline ranged from 1.6 to 2.8 (mean 2.2, 95% CI 1.2-4.1, P=0.019). The mean protective effect by adding monoHER before DOX led to a significant 4.4-fold reduction (P<0.001, 95% CI 2.3-8.2) of abnormal cardiomyocytes. This protective effect did not depend on the time interval between monoHER and DOX administration (P=0.345). CONCLUSION: The results indicate that in an outpatient clinical setting monoHER may be administered shortly before DOX. | NO-RELATIONSHIP |
| The influence of the time interval between monoHER and doxorubicin administration on the protection against doxorubicin-induced cardiotoxicity in mice. PURPOSE: Despite its well-known cardiotoxicity, the anthracyclin doxorubicin (DOX) continues to be an effective and widely used chemotherapeutic agent. DOX-induced DISEASE presumably results from the formation of free radicals by DOX. Reactive oxygen species particularly affect the cardiac myocytes because these cells seem to have a relatively poor antioxidant defense system. The semisynthetic flavonoid monohydroxyethylrutoside (monoHER) showed cardioprotection against DOX-induced cardiotoxicity through its radical scavenging and CHEMICAL chelating properties. Because of the relatively short final half-life of monoHER (about 30 min), it is expected that the time interval between monoHER and DOX might be of influence on the cardioprotective effect of monoHER. Therefore, the aim of the present study was to investigate this possible effect. METHODS: Six groups of 6 BALB/c mice were treated with saline, DOX alone or DOX (4 mg/kg i.v.) preceded by monoHER (500 mg/kg i.p.) with an interval of 10, 30, 60 or 120 min. After a 6-week treatment period and additional observation for 2 weeks, the mice were sacrificed. Their cardiac tissues were processed for light microscopy, after which cardiomyocyte damage was evaluated according to Billingham (in Cancer Treat Rep 62(6):865-872, 1978). Microscopic evaluation revealed that treatment with DOX alone induced significant DISEASE in comparison to the saline control group (P<0.001). RESULTS: The number of damaged cardiomyocytes was 9.6-fold (95% CI 4.4-21.0) higher in mice treated with DOX alone than that in animals of the control group. The ratio of aberrant cardiomyocytes in mice treated with DOX preceded by monoHER and those in mice treated with saline ranged from 1.6 to 2.8 (mean 2.2, 95% CI 1.2-4.1, P=0.019). The mean protective effect by adding monoHER before DOX led to a significant 4.4-fold reduction (P<0.001, 95% CI 2.3-8.2) of abnormal cardiomyocytes. This protective effect did not depend on the time interval between monoHER and DOX administration (P=0.345). CONCLUSION: The results indicate that in an outpatient clinical setting monoHER may be administered shortly before DOX. | NO-RELATIONSHIP |
| The influence of the time interval between CHEMICAL and doxorubicin administration on the protection against doxorubicin-induced cardiotoxicity in mice. PURPOSE: Despite its well-known cardiotoxicity, the anthracyclin doxorubicin (DOX) continues to be an effective and widely used chemotherapeutic agent. DOX-induced DISEASE presumably results from the formation of free radicals by DOX. Reactive oxygen species particularly affect the cardiac myocytes because these cells seem to have a relatively poor antioxidant defense system. The semisynthetic flavonoid CHEMICAL (CHEMICAL) showed cardioprotection against DOX-induced cardiotoxicity through its radical scavenging and iron chelating properties. Because of the relatively short final half-life of CHEMICAL (about 30 min), it is expected that the time interval between CHEMICAL and DOX might be of influence on the cardioprotective effect of CHEMICAL. Therefore, the aim of the present study was to investigate this possible effect. METHODS: Six groups of 6 BALB/c mice were treated with saline, DOX alone or DOX (4 mg/kg i.v.) preceded by CHEMICAL (500 mg/kg i.p.) with an interval of 10, 30, 60 or 120 min. After a 6-week treatment period and additional observation for 2 weeks, the mice were sacrificed. Their cardiac tissues were processed for light microscopy, after which cardiomyocyte damage was evaluated according to Billingham (in Cancer Treat Rep 62(6):865-872, 1978). Microscopic evaluation revealed that treatment with DOX alone induced significant DISEASE in comparison to the saline control group (P<0.001). RESULTS: The number of damaged cardiomyocytes was 9.6-fold (95% CI 4.4-21.0) higher in mice treated with DOX alone than that in animals of the control group. The ratio of aberrant cardiomyocytes in mice treated with DOX preceded by CHEMICAL and those in mice treated with saline ranged from 1.6 to 2.8 (mean 2.2, 95% CI 1.2-4.1, P=0.019). The mean protective effect by adding CHEMICAL before DOX led to a significant 4.4-fold reduction (P<0.001, 95% CI 2.3-8.2) of abnormal cardiomyocytes. This protective effect did not depend on the time interval between CHEMICAL and DOX administration (P=0.345). CONCLUSION: The results indicate that in an outpatient clinical setting CHEMICAL may be administered shortly before DOX. | NO-RELATIONSHIP |
| The influence of the time interval between monoHER and doxorubicin administration on the protection against doxorubicin-induced cardiotoxicity in mice. PURPOSE: Despite its well-known cardiotoxicity, the anthracyclin doxorubicin (DOX) continues to be an effective and widely used chemotherapeutic agent. DOX-induced DISEASE presumably results from the formation of free radicals by DOX. Reactive oxygen species particularly affect the cardiac myocytes because these cells seem to have a relatively poor antioxidant defense system. The semisynthetic CHEMICAL monohydroxyethylrutoside (monoHER) showed cardioprotection against DOX-induced cardiotoxicity through its radical scavenging and iron chelating properties. Because of the relatively short final half-life of monoHER (about 30 min), it is expected that the time interval between monoHER and DOX might be of influence on the cardioprotective effect of monoHER. Therefore, the aim of the present study was to investigate this possible effect. METHODS: Six groups of 6 BALB/c mice were treated with saline, DOX alone or DOX (4 mg/kg i.v.) preceded by monoHER (500 mg/kg i.p.) with an interval of 10, 30, 60 or 120 min. After a 6-week treatment period and additional observation for 2 weeks, the mice were sacrificed. Their cardiac tissues were processed for light microscopy, after which cardiomyocyte damage was evaluated according to Billingham (in Cancer Treat Rep 62(6):865-872, 1978). Microscopic evaluation revealed that treatment with DOX alone induced significant DISEASE in comparison to the saline control group (P<0.001). RESULTS: The number of damaged cardiomyocytes was 9.6-fold (95% CI 4.4-21.0) higher in mice treated with DOX alone than that in animals of the control group. The ratio of aberrant cardiomyocytes in mice treated with DOX preceded by monoHER and those in mice treated with saline ranged from 1.6 to 2.8 (mean 2.2, 95% CI 1.2-4.1, P=0.019). The mean protective effect by adding monoHER before DOX led to a significant 4.4-fold reduction (P<0.001, 95% CI 2.3-8.2) of abnormal cardiomyocytes. This protective effect did not depend on the time interval between monoHER and DOX administration (P=0.345). CONCLUSION: The results indicate that in an outpatient clinical setting monoHER may be administered shortly before DOX. | NO-RELATIONSHIP |
| The influence of the time interval between monoHER and doxorubicin administration on the protection against doxorubicin-induced DISEASE in mice. PURPOSE: Despite its well-known DISEASE, the anthracyclin doxorubicin (DOX) continues to be an effective and widely used chemotherapeutic agent. DOX-induced cardiac damage presumably results from the formation of free radicals by DOX. Reactive CHEMICAL species particularly affect the cardiac myocytes because these cells seem to have a relatively poor antioxidant defense system. The semisynthetic flavonoid monohydroxyethylrutoside (monoHER) showed cardioprotection against DOX-induced DISEASE through its radical scavenging and iron chelating properties. Because of the relatively short final half-life of monoHER (about 30 min), it is expected that the time interval between monoHER and DOX might be of influence on the cardioprotective effect of monoHER. Therefore, the aim of the present study was to investigate this possible effect. METHODS: Six groups of 6 BALB/c mice were treated with saline, DOX alone or DOX (4 mg/kg i.v.) preceded by monoHER (500 mg/kg i.p.) with an interval of 10, 30, 60 or 120 min. After a 6-week treatment period and additional observation for 2 weeks, the mice were sacrificed. Their cardiac tissues were processed for light microscopy, after which cardiomyocyte damage was evaluated according to Billingham (in Cancer Treat Rep 62(6):865-872, 1978). Microscopic evaluation revealed that treatment with DOX alone induced significant cardiac damage in comparison to the saline control group (P<0.001). RESULTS: The number of damaged cardiomyocytes was 9.6-fold (95% CI 4.4-21.0) higher in mice treated with DOX alone than that in animals of the control group. The ratio of aberrant cardiomyocytes in mice treated with DOX preceded by monoHER and those in mice treated with saline ranged from 1.6 to 2.8 (mean 2.2, 95% CI 1.2-4.1, P=0.019). The mean protective effect by adding monoHER before DOX led to a significant 4.4-fold reduction (P<0.001, 95% CI 2.3-8.2) of abnormal cardiomyocytes. This protective effect did not depend on the time interval between monoHER and DOX administration (P=0.345). CONCLUSION: The results indicate that in an outpatient clinical setting monoHER may be administered shortly before DOX. | NO-RELATIONSHIP |
| The influence of the time interval between CHEMICAL and doxorubicin administration on the protection against doxorubicin-induced cardiotoxicity in mice. PURPOSE: Despite its well-known cardiotoxicity, the anthracyclin doxorubicin (DOX) continues to be an effective and widely used chemotherapeutic agent. DOX-induced cardiac damage presumably results from the formation of free radicals by DOX. Reactive oxygen species particularly affect the cardiac myocytes because these cells seem to have a relatively poor antioxidant defense system. The semisynthetic flavonoid CHEMICAL (CHEMICAL) showed cardioprotection against DOX-induced cardiotoxicity through its radical scavenging and iron chelating properties. Because of the relatively short final half-life of CHEMICAL (about 30 min), it is expected that the time interval between CHEMICAL and DOX might be of influence on the cardioprotective effect of CHEMICAL. Therefore, the aim of the present study was to investigate this possible effect. METHODS: Six groups of 6 BALB/c mice were treated with saline, DOX alone or DOX (4 mg/kg i.v.) preceded by CHEMICAL (500 mg/kg i.p.) with an interval of 10, 30, 60 or 120 min. After a 6-week treatment period and additional observation for 2 weeks, the mice were sacrificed. Their cardiac tissues were processed for light microscopy, after which cardiomyocyte damage was evaluated according to Billingham (in DISEASE Treat Rep 62(6):865-872, 1978). Microscopic evaluation revealed that treatment with DOX alone induced significant cardiac damage in comparison to the saline control group (P<0.001). RESULTS: The number of damaged cardiomyocytes was 9.6-fold (95% CI 4.4-21.0) higher in mice treated with DOX alone than that in animals of the control group. The ratio of aberrant cardiomyocytes in mice treated with DOX preceded by CHEMICAL and those in mice treated with saline ranged from 1.6 to 2.8 (mean 2.2, 95% CI 1.2-4.1, P=0.019). The mean protective effect by adding CHEMICAL before DOX led to a significant 4.4-fold reduction (P<0.001, 95% CI 2.3-8.2) of abnormal cardiomyocytes. This protective effect did not depend on the time interval between CHEMICAL and DOX administration (P=0.345). CONCLUSION: The results indicate that in an outpatient clinical setting CHEMICAL may be administered shortly before DOX. | NO-RELATIONSHIP |
| The influence of the time interval between monoHER and doxorubicin administration on the protection against doxorubicin-induced DISEASE in mice. PURPOSE: Despite its well-known DISEASE, the anthracyclin doxorubicin (DOX) continues to be an effective and widely used chemotherapeutic agent. DOX-induced cardiac damage presumably results from the formation of free radicals by DOX. Reactive oxygen species particularly affect the cardiac myocytes because these cells seem to have a relatively poor antioxidant defense system. The semisynthetic CHEMICAL monohydroxyethylrutoside (monoHER) showed cardioprotection against DOX-induced DISEASE through its radical scavenging and iron chelating properties. Because of the relatively short final half-life of monoHER (about 30 min), it is expected that the time interval between monoHER and DOX might be of influence on the cardioprotective effect of monoHER. Therefore, the aim of the present study was to investigate this possible effect. METHODS: Six groups of 6 BALB/c mice were treated with saline, DOX alone or DOX (4 mg/kg i.v.) preceded by monoHER (500 mg/kg i.p.) with an interval of 10, 30, 60 or 120 min. After a 6-week treatment period and additional observation for 2 weeks, the mice were sacrificed. Their cardiac tissues were processed for light microscopy, after which cardiomyocyte damage was evaluated according to Billingham (in Cancer Treat Rep 62(6):865-872, 1978). Microscopic evaluation revealed that treatment with DOX alone induced significant cardiac damage in comparison to the saline control group (P<0.001). RESULTS: The number of damaged cardiomyocytes was 9.6-fold (95% CI 4.4-21.0) higher in mice treated with DOX alone than that in animals of the control group. The ratio of aberrant cardiomyocytes in mice treated with DOX preceded by monoHER and those in mice treated with saline ranged from 1.6 to 2.8 (mean 2.2, 95% CI 1.2-4.1, P=0.019). The mean protective effect by adding monoHER before DOX led to a significant 4.4-fold reduction (P<0.001, 95% CI 2.3-8.2) of abnormal cardiomyocytes. This protective effect did not depend on the time interval between monoHER and DOX administration (P=0.345). CONCLUSION: The results indicate that in an outpatient clinical setting monoHER may be administered shortly before DOX. | NO-RELATIONSHIP |
| The influence of the time interval between monoHER and doxorubicin administration on the protection against doxorubicin-induced cardiotoxicity in mice. PURPOSE: Despite its well-known cardiotoxicity, the anthracyclin doxorubicin (DOX) continues to be an effective and widely used chemotherapeutic agent. DOX-induced cardiac damage presumably results from the formation of free radicals by DOX. Reactive oxygen species particularly affect the cardiac myocytes because these cells seem to have a relatively poor antioxidant defense system. The semisynthetic flavonoid monohydroxyethylrutoside (monoHER) showed cardioprotection against DOX-induced cardiotoxicity through its radical scavenging and CHEMICAL chelating properties. Because of the relatively short final half-life of monoHER (about 30 min), it is expected that the time interval between monoHER and DOX might be of influence on the cardioprotective effect of monoHER. Therefore, the aim of the present study was to investigate this possible effect. METHODS: Six groups of 6 BALB/c mice were treated with saline, DOX alone or DOX (4 mg/kg i.v.) preceded by monoHER (500 mg/kg i.p.) with an interval of 10, 30, 60 or 120 min. After a 6-week treatment period and additional observation for 2 weeks, the mice were sacrificed. Their cardiac tissues were processed for light microscopy, after which cardiomyocyte damage was evaluated according to Billingham (in DISEASE Treat Rep 62(6):865-872, 1978). Microscopic evaluation revealed that treatment with DOX alone induced significant cardiac damage in comparison to the saline control group (P<0.001). RESULTS: The number of damaged cardiomyocytes was 9.6-fold (95% CI 4.4-21.0) higher in mice treated with DOX alone than that in animals of the control group. The ratio of aberrant cardiomyocytes in mice treated with DOX preceded by monoHER and those in mice treated with saline ranged from 1.6 to 2.8 (mean 2.2, 95% CI 1.2-4.1, P=0.019). The mean protective effect by adding monoHER before DOX led to a significant 4.4-fold reduction (P<0.001, 95% CI 2.3-8.2) of abnormal cardiomyocytes. This protective effect did not depend on the time interval between monoHER and DOX administration (P=0.345). CONCLUSION: The results indicate that in an outpatient clinical setting monoHER may be administered shortly before DOX. | NO-RELATIONSHIP |
| The influence of the time interval between monoHER and doxorubicin administration on the protection against doxorubicin-induced cardiotoxicity in mice. PURPOSE: Despite its well-known cardiotoxicity, the anthracyclin doxorubicin (DOX) continues to be an effective and widely used chemotherapeutic agent. DOX-induced cardiac damage presumably results from the formation of free radicals by DOX. Reactive oxygen species particularly affect the cardiac myocytes because these cells seem to have a relatively poor antioxidant defense system. The semisynthetic CHEMICAL monohydroxyethylrutoside (monoHER) showed cardioprotection against DOX-induced cardiotoxicity through its radical scavenging and iron chelating properties. Because of the relatively short final half-life of monoHER (about 30 min), it is expected that the time interval between monoHER and DOX might be of influence on the cardioprotective effect of monoHER. Therefore, the aim of the present study was to investigate this possible effect. METHODS: Six groups of 6 BALB/c mice were treated with saline, DOX alone or DOX (4 mg/kg i.v.) preceded by monoHER (500 mg/kg i.p.) with an interval of 10, 30, 60 or 120 min. After a 6-week treatment period and additional observation for 2 weeks, the mice were sacrificed. Their cardiac tissues were processed for light microscopy, after which cardiomyocyte damage was evaluated according to Billingham (in DISEASE Treat Rep 62(6):865-872, 1978). Microscopic evaluation revealed that treatment with DOX alone induced significant cardiac damage in comparison to the saline control group (P<0.001). RESULTS: The number of damaged cardiomyocytes was 9.6-fold (95% CI 4.4-21.0) higher in mice treated with DOX alone than that in animals of the control group. The ratio of aberrant cardiomyocytes in mice treated with DOX preceded by monoHER and those in mice treated with saline ranged from 1.6 to 2.8 (mean 2.2, 95% CI 1.2-4.1, P=0.019). The mean protective effect by adding monoHER before DOX led to a significant 4.4-fold reduction (P<0.001, 95% CI 2.3-8.2) of abnormal cardiomyocytes. This protective effect did not depend on the time interval between monoHER and DOX administration (P=0.345). CONCLUSION: The results indicate that in an outpatient clinical setting monoHER may be administered shortly before DOX. | NO-RELATIONSHIP |
| The influence of the time interval between monoHER and doxorubicin administration on the protection against doxorubicin-induced DISEASE in mice. PURPOSE: Despite its well-known DISEASE, the anthracyclin doxorubicin (DOX) continues to be an effective and widely used chemotherapeutic agent. DOX-induced cardiac damage presumably results from the formation of free radicals by DOX. Reactive oxygen species particularly affect the cardiac myocytes because these cells seem to have a relatively poor antioxidant defense system. The semisynthetic flavonoid monohydroxyethylrutoside (monoHER) showed cardioprotection against DOX-induced DISEASE through its radical scavenging and CHEMICAL chelating properties. Because of the relatively short final half-life of monoHER (about 30 min), it is expected that the time interval between monoHER and DOX might be of influence on the cardioprotective effect of monoHER. Therefore, the aim of the present study was to investigate this possible effect. METHODS: Six groups of 6 BALB/c mice were treated with saline, DOX alone or DOX (4 mg/kg i.v.) preceded by monoHER (500 mg/kg i.p.) with an interval of 10, 30, 60 or 120 min. After a 6-week treatment period and additional observation for 2 weeks, the mice were sacrificed. Their cardiac tissues were processed for light microscopy, after which cardiomyocyte damage was evaluated according to Billingham (in Cancer Treat Rep 62(6):865-872, 1978). Microscopic evaluation revealed that treatment with DOX alone induced significant cardiac damage in comparison to the saline control group (P<0.001). RESULTS: The number of damaged cardiomyocytes was 9.6-fold (95% CI 4.4-21.0) higher in mice treated with DOX alone than that in animals of the control group. The ratio of aberrant cardiomyocytes in mice treated with DOX preceded by monoHER and those in mice treated with saline ranged from 1.6 to 2.8 (mean 2.2, 95% CI 1.2-4.1, P=0.019). The mean protective effect by adding monoHER before DOX led to a significant 4.4-fold reduction (P<0.001, 95% CI 2.3-8.2) of abnormal cardiomyocytes. This protective effect did not depend on the time interval between monoHER and DOX administration (P=0.345). CONCLUSION: The results indicate that in an outpatient clinical setting monoHER may be administered shortly before DOX. | NO-RELATIONSHIP |
| Clinical evaluation of adverse effects during CHEMICAL administration for atrial fibrillation and flutter. BACKGROUND: CHEMICAL (CHEMICAL) has attracted attention as an effective drug for atrial fibrillation (AF) and atrial flutter (AFL). However, serious adverse effects, including torsade de pointes (Tdp), have been reported. METHODS AND RESULTS: Adverse effects of CHEMICAL requiring discontinuation of treatment were evaluated. CHEMICAL was administered to 459 patients (361 males, 63+/-12 years old) comprising 378 AF and 81 AFL cases. Mean left ventricular ejection fraction and atrial dimension (LAD) were 66+/-11% and 40+/-6 mm, respectively. Adverse effects were observed in 19 patients (4%) during an average follow-up of 20 months. There was marked DISEASE greater than 0.55 s in 13 patients, bradycardia less than 40 beats/min in 6 patients, dizziness and general fatigue in 1 patient each. In 4 of 13 patients with DISEASE, Tdp occurred. The major triggering factors of Tdp were hypokalemia and sudden decrease in heart rate. There were no differences in the clinical backgrounds of the patients with and without Tdp other than LAD and age, which were larger and older in the patients with Tdp. CONCLUSION: Careful observation of serum potassium concentration and the ECG should always be done during CHEMICAL administration, particularly in elderly patients. | CHEMICAL-INDUCED-DISEASE |
| Clinical evaluation of adverse effects during CHEMICAL administration for atrial fibrillation and flutter. BACKGROUND: CHEMICAL (CHEMICAL) has attracted attention as an effective drug for atrial fibrillation (AF) and atrial flutter (AFL). However, serious adverse effects, including DISEASE (DISEASE), have been reported. METHODS AND RESULTS: Adverse effects of CHEMICAL requiring discontinuation of treatment were evaluated. CHEMICAL was administered to 459 patients (361 males, 63+/-12 years old) comprising 378 AF and 81 AFL cases. Mean left ventricular ejection fraction and atrial dimension (LAD) were 66+/-11% and 40+/-6 mm, respectively. Adverse effects were observed in 19 patients (4%) during an average follow-up of 20 months. There was marked QT prolongation greater than 0.55 s in 13 patients, bradycardia less than 40 beats/min in 6 patients, dizziness and general fatigue in 1 patient each. In 4 of 13 patients with QT prolongation, DISEASE occurred. The major triggering factors of DISEASE were hypokalemia and sudden decrease in heart rate. There were no differences in the clinical backgrounds of the patients with and without DISEASE other than LAD and age, which were larger and older in the patients with DISEASE. CONCLUSION: Careful observation of serum potassium concentration and the ECG should always be done during CHEMICAL administration, particularly in elderly patients. | CHEMICAL-INDUCED-DISEASE |
| Clinical evaluation of adverse effects during CHEMICAL administration for atrial fibrillation and flutter. BACKGROUND: CHEMICAL (CHEMICAL) has attracted attention as an effective drug for atrial fibrillation (AF) and atrial flutter (AFL). However, serious adverse effects, including torsade de pointes (Tdp), have been reported. METHODS AND RESULTS: Adverse effects of CHEMICAL requiring discontinuation of treatment were evaluated. CHEMICAL was administered to 459 patients (361 males, 63+/-12 years old) comprising 378 AF and 81 AFL cases. Mean left ventricular ejection fraction and atrial dimension (LAD) were 66+/-11% and 40+/-6 mm, respectively. Adverse effects were observed in 19 patients (4%) during an average follow-up of 20 months. There was marked QT prolongation greater than 0.55 s in 13 patients, DISEASE less than 40 beats/min in 6 patients, dizziness and general fatigue in 1 patient each. In 4 of 13 patients with QT prolongation, Tdp occurred. The major triggering factors of Tdp were hypokalemia and sudden decrease in heart rate. There were no differences in the clinical backgrounds of the patients with and without Tdp other than LAD and age, which were larger and older in the patients with Tdp. CONCLUSION: Careful observation of serum potassium concentration and the ECG should always be done during CHEMICAL administration, particularly in elderly patients. | CHEMICAL-INDUCED-DISEASE |
| Clinical evaluation of adverse effects during CHEMICAL administration for atrial fibrillation and flutter. BACKGROUND: CHEMICAL (CHEMICAL) has attracted attention as an effective drug for atrial fibrillation (AF) and atrial flutter (AFL). However, serious adverse effects, including torsade de pointes (Tdp), have been reported. METHODS AND RESULTS: Adverse effects of CHEMICAL requiring discontinuation of treatment were evaluated. CHEMICAL was administered to 459 patients (361 males, 63+/-12 years old) comprising 378 AF and 81 AFL cases. Mean left ventricular ejection fraction and atrial dimension (LAD) were 66+/-11% and 40+/-6 mm, respectively. Adverse effects were observed in 19 patients (4%) during an average follow-up of 20 months. There was marked QT prolongation greater than 0.55 s in 13 patients, bradycardia less than 40 beats/min in 6 patients, DISEASE and general fatigue in 1 patient each. In 4 of 13 patients with QT prolongation, Tdp occurred. The major triggering factors of Tdp were hypokalemia and sudden decrease in heart rate. There were no differences in the clinical backgrounds of the patients with and without Tdp other than LAD and age, which were larger and older in the patients with Tdp. CONCLUSION: Careful observation of serum potassium concentration and the ECG should always be done during CHEMICAL administration, particularly in elderly patients. | CHEMICAL-INDUCED-DISEASE |
| Clinical evaluation of adverse effects during CHEMICAL administration for atrial fibrillation and flutter. BACKGROUND: CHEMICAL (CHEMICAL) has attracted attention as an effective drug for atrial fibrillation (AF) and atrial flutter (AFL). However, serious adverse effects, including torsade de pointes (Tdp), have been reported. METHODS AND RESULTS: Adverse effects of CHEMICAL requiring discontinuation of treatment were evaluated. CHEMICAL was administered to 459 patients (361 males, 63+/-12 years old) comprising 378 AF and 81 AFL cases. Mean left ventricular ejection fraction and atrial dimension (LAD) were 66+/-11% and 40+/-6 mm, respectively. Adverse effects were observed in 19 patients (4%) during an average follow-up of 20 months. There was marked QT prolongation greater than 0.55 s in 13 patients, bradycardia less than 40 beats/min in 6 patients, dizziness and general DISEASE in 1 patient each. In 4 of 13 patients with QT prolongation, Tdp occurred. The major triggering factors of Tdp were hypokalemia and sudden decrease in heart rate. There were no differences in the clinical backgrounds of the patients with and without Tdp other than LAD and age, which were larger and older in the patients with Tdp. CONCLUSION: Careful observation of serum potassium concentration and the ECG should always be done during CHEMICAL administration, particularly in elderly patients. | CHEMICAL-INDUCED-DISEASE |
| Clinical evaluation of adverse effects during bepridil administration for atrial fibrillation and flutter. BACKGROUND: Bepridil hydrochloride (Bpd) has attracted attention as an effective drug for atrial fibrillation (AF) and atrial flutter (AFL). However, serious adverse effects, including DISEASE (DISEASE), have been reported. METHODS AND RESULTS: Adverse effects of Bpd requiring discontinuation of treatment were evaluated. Bpd was administered to 459 patients (361 males, 63+/-12 years old) comprising 378 AF and 81 AFL cases. Mean left ventricular ejection fraction and atrial dimension (LAD) were 66+/-11% and 40+/-6 mm, respectively. Adverse effects were observed in 19 patients (4%) during an average follow-up of 20 months. There was marked QT prolongation greater than 0.55 s in 13 patients, bradycardia less than 40 beats/min in 6 patients, dizziness and general fatigue in 1 patient each. In 4 of 13 patients with QT prolongation, DISEASE occurred. The major triggering factors of DISEASE were hypokalemia and sudden decrease in heart rate. There were no differences in the clinical backgrounds of the patients with and without DISEASE other than LAD and age, which were larger and older in the patients with DISEASE. CONCLUSION: Careful observation of serum CHEMICAL concentration and the ECG should always be done during Bpd administration, particularly in elderly patients. | NO-RELATIONSHIP |
| Enhanced CHEMICAL-induced DISEASE in transgenic rats with low brain angiotensinogen. We have previously shown that a permanent deficiency in the brain renin-angiotensin system (RAS) may increase the sensitivity of the baroreflex control of heart rate. In this study we aimed at studying the involvement of the brain RAS in the cardiac reactivity to the beta-adrenoceptor (beta-AR) agonist CHEMICAL (CHEMICAL). Transgenic rats with low brain angiotensinogen (TGR) were used. In isolated hearts, CHEMICAL induced a significantly greater increase in left ventricular (LV) pressure and maximal contraction (+dP/dt(max)) in the TGR than in the Sprague-Dawley (SD) rats. DISEASE induced by CHEMICAL treatment was significantly higher in TGR than in SD rats (in g LV wt/100 g body wt, 0.28 +/- 0.004 vs. 0.24 +/- 0.004, respectively). The greater DISEASE in TGR rats was associated with more pronounced downregulation of beta-AR and upregulation of LV beta-AR kinase-1 mRNA levels compared with those in SD rats. The decrease in the heart rate (HR) induced by the beta-AR antagonist metoprolol in conscious rats was significantly attenuated in TGR compared with SD rats (-9.9 +/- 1.7% vs. -18.1 +/- 1.5%), whereas the effect of parasympathetic blockade by atropine on HR was similar in both strains. These results indicate that TGR are more sensitive to beta-AR agonist-induced cardiac inotropic response and hypertrophy, possibly due to chronically low sympathetic outflow directed to the heart. | CHEMICAL-INDUCED-DISEASE |
| Enhanced isoproterenol-induced cardiac hypertrophy in transgenic rats with low brain angiotensinogen. We have previously shown that a permanent deficiency in the brain renin-angiotensin system (RAS) may increase the sensitivity of the baroreflex control of heart rate. In this study we aimed at studying the involvement of the brain RAS in the cardiac reactivity to the beta-adrenoceptor (beta-AR) agonist isoproterenol (Iso). Transgenic rats with low brain angiotensinogen (TGR) were used. In isolated hearts, Iso induced a significantly greater increase in left ventricular (LV) pressure and maximal contraction (+dP/dt(max)) in the TGR than in the Sprague-Dawley (SD) rats. LV hypertrophy induced by Iso treatment was significantly higher in TGR than in SD rats (in g LV wt/100 g body wt, 0.28 +/- 0.004 vs. 0.24 +/- 0.004, respectively). The greater LV hypertrophy in TGR rats was associated with more pronounced downregulation of beta-AR and upregulation of LV beta-AR kinase-1 mRNA levels compared with those in SD rats. The decrease in the heart rate (HR) induced by the beta-AR antagonist CHEMICAL in conscious rats was significantly attenuated in TGR compared with SD rats (-9.9 +/- 1.7% vs. -18.1 +/- 1.5%), whereas the effect of parasympathetic blockade by atropine on HR was similar in both strains. These results indicate that TGR are more sensitive to beta-AR agonist-induced cardiac inotropic response and DISEASE, possibly due to chronically low sympathetic outflow directed to the heart. | NO-RELATIONSHIP |
| Enhanced isoproterenol-induced cardiac hypertrophy in transgenic rats with low brain angiotensinogen. We have previously shown that a permanent deficiency in the brain renin-angiotensin system (RAS) may increase the sensitivity of the baroreflex control of heart rate. In this study we aimed at studying the involvement of the brain RAS in the cardiac reactivity to the beta-adrenoceptor (beta-AR) agonist isoproterenol (Iso). Transgenic rats with low brain angiotensinogen (TGR) were used. In isolated hearts, Iso induced a significantly greater increase in left ventricular (LV) pressure and maximal contraction (+dP/dt(max)) in the TGR than in the Sprague-Dawley (SD) rats. LV hypertrophy induced by Iso treatment was significantly higher in TGR than in SD rats (in g LV wt/100 g body wt, 0.28 +/- 0.004 vs. 0.24 +/- 0.004, respectively). The greater LV hypertrophy in TGR rats was associated with more pronounced downregulation of beta-AR and upregulation of LV beta-AR kinase-1 mRNA levels compared with those in SD rats. The decrease in the heart rate (HR) induced by the beta-AR antagonist metoprolol in conscious rats was significantly attenuated in TGR compared with SD rats (-9.9 +/- 1.7% vs. -18.1 +/- 1.5%), whereas the effect of parasympathetic blockade by CHEMICAL on HR was similar in both strains. These results indicate that TGR are more sensitive to beta-AR agonist-induced cardiac inotropic response and DISEASE, possibly due to chronically low sympathetic outflow directed to the heart. | NO-RELATIONSHIP |
| Enhanced isoproterenol-induced cardiac hypertrophy in transgenic rats with low brain angiotensinogen. We have previously shown that a permanent deficiency in the brain renin-angiotensin system (RAS) may increase the sensitivity of the baroreflex control of heart rate. In this study we aimed at studying the involvement of the brain RAS in the cardiac reactivity to the beta-adrenoceptor (beta-AR) agonist isoproterenol (Iso). Transgenic rats with low brain angiotensinogen (TGR) were used. In isolated hearts, Iso induced a significantly greater increase in left ventricular (LV) pressure and maximal contraction (+dP/dt(max)) in the TGR than in the Sprague-Dawley (SD) rats. LV hypertrophy induced by Iso treatment was significantly higher in TGR than in SD rats (in g LV wt/100 g body wt, 0.28 +/- 0.004 vs. 0.24 +/- 0.004, respectively). The greater LV hypertrophy in TGR rats was associated with more pronounced downregulation of beta-AR and upregulation of LV beta-AR kinase-1 mRNA levels compared with those in SD rats. The decrease in the heart rate (HR) induced by the beta-AR antagonist metoprolol in conscious rats was significantly attenuated in TGR compared with SD rats (-9.9 +/- 1.7% vs. -18.1 +/- 1.5%), whereas the effect of parasympathetic blockade by CHEMICAL on HR was similar in both strains. These results indicate that TGR are more sensitive to beta-AR agonist-induced DISEASE response and hypertrophy, possibly due to chronically low sympathetic outflow directed to the heart. | NO-RELATIONSHIP |
| Enhanced isoproterenol-induced cardiac hypertrophy in transgenic rats with low brain angiotensinogen. We have previously shown that a permanent deficiency in the brain renin-CHEMICAL system (RAS) may increase the sensitivity of the baroreflex control of heart rate. In this study we aimed at studying the involvement of the brain RAS in the cardiac reactivity to the beta-adrenoceptor (beta-AR) agonist isoproterenol (Iso). Transgenic rats with low brain angiotensinogen (TGR) were used. In isolated hearts, Iso induced a significantly greater increase in left ventricular (LV) pressure and maximal contraction (+dP/dt(max)) in the TGR than in the Sprague-Dawley (SD) rats. LV hypertrophy induced by Iso treatment was significantly higher in TGR than in SD rats (in g LV wt/100 g body wt, 0.28 +/- 0.004 vs. 0.24 +/- 0.004, respectively). The greater LV hypertrophy in TGR rats was associated with more pronounced downregulation of beta-AR and upregulation of LV beta-AR kinase-1 mRNA levels compared with those in SD rats. The decrease in the heart rate (HR) induced by the beta-AR antagonist metoprolol in conscious rats was significantly attenuated in TGR compared with SD rats (-9.9 +/- 1.7% vs. -18.1 +/- 1.5%), whereas the effect of parasympathetic blockade by atropine on HR was similar in both strains. These results indicate that TGR are more sensitive to beta-AR agonist-induced cardiac inotropic response and DISEASE, possibly due to chronically low sympathetic outflow directed to the heart. | NO-RELATIONSHIP |
| Enhanced isoproterenol-induced cardiac hypertrophy in transgenic rats with low brain angiotensinogen. We have previously shown that a permanent deficiency in the brain renin-angiotensin system (RAS) may increase the sensitivity of the baroreflex control of heart rate. In this study we aimed at studying the involvement of the brain RAS in the cardiac reactivity to the beta-adrenoceptor (beta-AR) agonist isoproterenol (Iso). Transgenic rats with low brain angiotensinogen (TGR) were used. In isolated hearts, Iso induced a significantly greater increase in left ventricular (LV) pressure and maximal contraction (+dP/dt(max)) in the TGR than in the Sprague-Dawley (SD) rats. LV hypertrophy induced by Iso treatment was significantly higher in TGR than in SD rats (in g LV wt/100 g body wt, 0.28 +/- 0.004 vs. 0.24 +/- 0.004, respectively). The greater LV hypertrophy in TGR rats was associated with more pronounced downregulation of beta-AR and upregulation of LV beta-AR kinase-1 mRNA levels compared with those in SD rats. The decrease in the heart rate (HR) induced by the beta-AR antagonist CHEMICAL in conscious rats was significantly attenuated in TGR compared with SD rats (-9.9 +/- 1.7% vs. -18.1 +/- 1.5%), whereas the effect of parasympathetic blockade by atropine on HR was similar in both strains. These results indicate that TGR are more sensitive to beta-AR agonist-induced DISEASE response and hypertrophy, possibly due to chronically low sympathetic outflow directed to the heart. | NO-RELATIONSHIP |
| Enhanced isoproterenol-induced cardiac hypertrophy in transgenic rats with low brain angiotensinogen. We have previously shown that a permanent deficiency in the brain renin-CHEMICAL system (RAS) may increase the sensitivity of the baroreflex control of heart rate. In this study we aimed at studying the involvement of the brain RAS in the cardiac reactivity to the beta-adrenoceptor (beta-AR) agonist isoproterenol (Iso). Transgenic rats with low brain angiotensinogen (TGR) were used. In isolated hearts, Iso induced a significantly greater increase in left ventricular (LV) pressure and maximal contraction (+dP/dt(max)) in the TGR than in the Sprague-Dawley (SD) rats. LV hypertrophy induced by Iso treatment was significantly higher in TGR than in SD rats (in g LV wt/100 g body wt, 0.28 +/- 0.004 vs. 0.24 +/- 0.004, respectively). The greater LV hypertrophy in TGR rats was associated with more pronounced downregulation of beta-AR and upregulation of LV beta-AR kinase-1 mRNA levels compared with those in SD rats. The decrease in the heart rate (HR) induced by the beta-AR antagonist metoprolol in conscious rats was significantly attenuated in TGR compared with SD rats (-9.9 +/- 1.7% vs. -18.1 +/- 1.5%), whereas the effect of parasympathetic blockade by atropine on HR was similar in both strains. These results indicate that TGR are more sensitive to beta-AR agonist-induced DISEASE response and hypertrophy, possibly due to chronically low sympathetic outflow directed to the heart. | NO-RELATIONSHIP |
| Drug-induced DISEASE in injection drug users receiving CHEMICAL: high frequency in hospitalized patients and risk factors. BACKGROUND: Drug-induced DISEASE is a serious adverse drug reaction. CHEMICAL prolongs the QT interval in vitro in a dose-dependent manner. In the inpatient setting, the frequency of DISEASE with CHEMICAL treatment, its dose dependence, and the importance of cofactors such as drug-drug interactions remain unknown. METHODS: We performed a systematic, retrospective study comparing active or former intravenous drug users receiving CHEMICAL and those not receiving CHEMICAL among all patients hospitalized over a 5-year period in a tertiary care hospital. A total of 167 patients receiving CHEMICAL fulfilled the inclusion criteria and were compared with a control group of 80 injection drug users not receiving CHEMICAL. In addition to CHEMICAL dose, 15 demographic, biological, and pharmacological variables were considered as potential risk factors for DISEASE. RESULTS: Among 167 CHEMICAL maintenance patients, the prevalence of QTc prolongation to 0.50 second((1/2)) or longer was 16.2% compared with 0% in 80 control subjects. Six patients (3.6%) in the CHEMICAL group presented torsades de pointes. QTc length was weakly but significantly associated with CHEMICAL daily dose (Spearman rank correlation coefficient, 0.20; P<.01). Multivariate regression analysis allowed attribution of 31.8% of QTc variability to CHEMICAL dose, cytochrome P-450 3A4 drug-drug interactions, hypokalemia, and altered liver function. CONCLUSIONS: DISEASE in CHEMICAL maintenance patients hospitalized in a tertiary care center is a frequent finding. CHEMICAL dose, presence of cytochrome P-450 3A4 inhibitors, potassium level, and liver function contribute to DISEASE. DISEASE can occur with low doses of CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors. BACKGROUND: Drug-induced long QT syndrome is a serious adverse drug reaction. Methadone prolongs the QT interval in vitro in a dose-dependent manner. In the inpatient setting, the frequency of QT interval prolongation with methadone treatment, its dose dependence, and the importance of cofactors such as drug-drug interactions remain unknown. METHODS: We performed a systematic, retrospective study comparing active or former intravenous drug users receiving methadone and those not receiving methadone among all patients hospitalized over a 5-year period in a tertiary care hospital. A total of 167 patients receiving methadone fulfilled the inclusion criteria and were compared with a control group of 80 injection drug users not receiving methadone. In addition to methadone dose, 15 demographic, biological, and pharmacological variables were considered as potential risk factors for QT prolongation. RESULTS: Among 167 methadone maintenance patients, the prevalence of QTc prolongation to 0.50 second((1/2)) or longer was 16.2% compared with 0% in 80 control subjects. Six patients (3.6%) in the methadone group presented torsades de pointes. QTc length was weakly but significantly associated with methadone daily dose (Spearman rank correlation coefficient, 0.20; P<.01). Multivariate regression analysis allowed attribution of 31.8% of QTc variability to methadone dose, cytochrome P-450 3A4 drug-drug interactions, DISEASE, and altered liver function. CONCLUSIONS: QT interval prolongation in methadone maintenance patients hospitalized in a tertiary care center is a frequent finding. Methadone dose, presence of cytochrome P-450 3A4 inhibitors, CHEMICAL level, and liver function contribute to QT prolongation. Long QT syndrome can occur with low doses of methadone. | NO-RELATIONSHIP |
| Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors. BACKGROUND: Drug-induced long QT syndrome is a serious adverse drug reaction. Methadone prolongs the QT interval in vitro in a dose-dependent manner. In the inpatient setting, the frequency of QT interval prolongation with methadone treatment, its dose dependence, and the importance of cofactors such as drug-drug interactions remain unknown. METHODS: We performed a systematic, retrospective study comparing active or former intravenous drug users receiving methadone and those not receiving methadone among all patients hospitalized over a 5-year period in a tertiary care hospital. A total of 167 patients receiving methadone fulfilled the inclusion criteria and were compared with a control group of 80 injection drug users not receiving methadone. In addition to methadone dose, 15 demographic, biological, and pharmacological variables were considered as potential risk factors for QT prolongation. RESULTS: Among 167 methadone maintenance patients, the prevalence of QTc prolongation to 0.50 second((1/2)) or longer was 16.2% compared with 0% in 80 control subjects. Six patients (3.6%) in the methadone group presented DISEASE. QTc length was weakly but significantly associated with methadone daily dose (Spearman rank correlation coefficient, 0.20; P<.01). Multivariate regression analysis allowed attribution of 31.8% of QTc variability to methadone dose, cytochrome P-450 3A4 drug-drug interactions, hypokalemia, and altered liver function. CONCLUSIONS: QT interval prolongation in methadone maintenance patients hospitalized in a tertiary care center is a frequent finding. Methadone dose, presence of cytochrome P-450 3A4 inhibitors, CHEMICAL level, and liver function contribute to QT prolongation. Long QT syndrome can occur with low doses of methadone. | NO-RELATIONSHIP |
| Mechanisms of DISEASE induced by CHEMICAL (CHEMICAL) deficiency: focus on venous function. Loss of endothelial cell-derived CHEMICAL (CHEMICAL) in DISEASE is a hallmark of arterial dysfunction. Experimental DISEASE created by the removal of CHEMICAL, however, involves mechanisms in addition to decreased arterial vasodilator activity. These include augmented endothelin-1 (ET-1) release, increased sympathetic nervous system activity, and elevated tissue oxidative stress. We hypothesized that increased venous smooth muscle (venomotor) tone plays a role in Nomega-nitro-L-arginine (LNNA) DISEASE through these mechanisms. Rats were treated with the CHEMICAL synthase inhibitor LNNA (0.5 g/L in drinking water) for 2 weeks. Mean arterial pressure of conscious rats was 119 +/- 2 mm Hg in control and 194 +/- 5 mm Hg in LNNA rats (P<0.05). Carotid arteries and vena cava were removed for measurement of isometric contraction. Maximal contraction to norepinephrine was modestly reduced in arteries from LNNA compared with control rats whereas the maximum contraction to ET-1 was significantly reduced (54% control). Maximum contraction of vena cava to norepinephrine (37% control) also was reduced but no change in response to ET-1 was observed. Mean circulatory filling pressure, an in vivo measure of venomotor tone, was not elevated in LNNA DISEASE at 1 or 2 weeks after LNNA. The superoxide scavenger tempol (30, 100, and 300 micromol kg(-1), IV) did not change arterial pressure in control rats but caused a dose-dependent decrease in LNNA rats (-18 +/- 8, -26 +/- 15, and -54 +/- 11 mm Hg). Similarly, ganglionic blockade with hexamethonium caused a significantly greater fall in LNNA DISEASE rats (76 +/- 9 mm Hg) compared with control rats (35 +/- 10 mm Hg). Carotid arteries, vena cava, and sympathetic ganglia from LNNA rats had higher basal levels of superoxide compared with those from control rats. These data suggest that while CHEMICAL deficiency increases oxidative stress and sympathetic activity in both arterial and venous vessels, the impact on veins does not make a major contribution to this form of DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Mechanisms of hypertension induced by nitric oxide (NO) deficiency: focus on venous function. Loss of endothelial cell-derived nitric oxide (NO) in hypertension is a hallmark of DISEASE. Experimental hypertension created by the removal of NO, however, involves mechanisms in addition to decreased arterial vasodilator activity. These include augmented endothelin-1 (ET-1) release, increased sympathetic nervous system activity, and elevated tissue oxidative stress. We hypothesized that increased venous smooth muscle (venomotor) tone plays a role in CHEMICAL (CHEMICAL) hypertension through these mechanisms. Rats were treated with the NO synthase inhibitor CHEMICAL (0.5 g/L in drinking water) for 2 weeks. Mean arterial pressure of conscious rats was 119 +/- 2 mm Hg in control and 194 +/- 5 mm Hg in CHEMICAL rats (P<0.05). Carotid arteries and vena cava were removed for measurement of isometric contraction. Maximal contraction to norepinephrine was modestly reduced in arteries from CHEMICAL compared with control rats whereas the maximum contraction to ET-1 was significantly reduced (54% control). Maximum contraction of vena cava to norepinephrine (37% control) also was reduced but no change in response to ET-1 was observed. Mean circulatory filling pressure, an in vivo measure of venomotor tone, was not elevated in CHEMICAL hypertension at 1 or 2 weeks after CHEMICAL. The superoxide scavenger tempol (30, 100, and 300 micromol kg(-1), IV) did not change arterial pressure in control rats but caused a dose-dependent decrease in CHEMICAL rats (-18 +/- 8, -26 +/- 15, and -54 +/- 11 mm Hg). Similarly, ganglionic blockade with hexamethonium caused a significantly greater fall in CHEMICAL hypertensive rats (76 +/- 9 mm Hg) compared with control rats (35 +/- 10 mm Hg). Carotid arteries, vena cava, and sympathetic ganglia from CHEMICAL rats had higher basal levels of superoxide compared with those from control rats. These data suggest that while NO deficiency increases oxidative stress and sympathetic activity in both arterial and venous vessels, the impact on veins does not make a major contribution to this form of hypertension. | NO-RELATIONSHIP |
| Mechanisms of hypertension induced by nitric oxide (NO) deficiency: focus on venous function. Loss of endothelial cell-derived nitric oxide (NO) in hypertension is a hallmark of DISEASE. Experimental hypertension created by the removal of NO, however, involves mechanisms in addition to decreased arterial vasodilator activity. These include augmented endothelin-1 (ET-1) release, increased sympathetic nervous system activity, and elevated tissue oxidative stress. We hypothesized that increased venous smooth muscle (venomotor) tone plays a role in Nomega-nitro-L-arginine (LNNA) hypertension through these mechanisms. Rats were treated with the NO synthase inhibitor LNNA (0.5 g/L in drinking water) for 2 weeks. Mean arterial pressure of conscious rats was 119 +/- 2 mm Hg in control and 194 +/- 5 mm Hg in LNNA rats (P<0.05). Carotid arteries and vena cava were removed for measurement of isometric contraction. Maximal contraction to norepinephrine was modestly reduced in arteries from LNNA compared with control rats whereas the maximum contraction to ET-1 was significantly reduced (54% control). Maximum contraction of vena cava to norepinephrine (37% control) also was reduced but no change in response to ET-1 was observed. Mean circulatory filling pressure, an in vivo measure of venomotor tone, was not elevated in LNNA hypertension at 1 or 2 weeks after LNNA. The superoxide scavenger CHEMICAL (30, 100, and 300 micromol kg(-1), IV) did not change arterial pressure in control rats but caused a dose-dependent decrease in LNNA rats (-18 +/- 8, -26 +/- 15, and -54 +/- 11 mm Hg). Similarly, ganglionic blockade with hexamethonium caused a significantly greater fall in LNNA hypertensive rats (76 +/- 9 mm Hg) compared with control rats (35 +/- 10 mm Hg). Carotid arteries, vena cava, and sympathetic ganglia from LNNA rats had higher basal levels of superoxide compared with those from control rats. These data suggest that while NO deficiency increases oxidative stress and sympathetic activity in both arterial and venous vessels, the impact on veins does not make a major contribution to this form of hypertension. | NO-RELATIONSHIP |
| Mechanisms of hypertension induced by nitric oxide (NO) deficiency: focus on venous function. Loss of endothelial cell-derived nitric oxide (NO) in hypertension is a hallmark of DISEASE. Experimental hypertension created by the removal of NO, however, involves mechanisms in addition to decreased arterial vasodilator activity. These include augmented endothelin-1 (ET-1) release, increased sympathetic nervous system activity, and elevated tissue oxidative stress. We hypothesized that increased venous smooth muscle (venomotor) tone plays a role in Nomega-nitro-L-arginine (LNNA) hypertension through these mechanisms. Rats were treated with the NO synthase inhibitor LNNA (0.5 g/L in drinking water) for 2 weeks. Mean arterial pressure of conscious rats was 119 +/- 2 mm Hg in control and 194 +/- 5 mm Hg in LNNA rats (P<0.05). Carotid arteries and vena cava were removed for measurement of isometric contraction. Maximal contraction to norepinephrine was modestly reduced in arteries from LNNA compared with control rats whereas the maximum contraction to ET-1 was significantly reduced (54% control). Maximum contraction of vena cava to norepinephrine (37% control) also was reduced but no change in response to ET-1 was observed. Mean circulatory filling pressure, an in vivo measure of venomotor tone, was not elevated in LNNA hypertension at 1 or 2 weeks after LNNA. The superoxide scavenger tempol (30, 100, and 300 micromol kg(-1), IV) did not change arterial pressure in control rats but caused a dose-dependent decrease in LNNA rats (-18 +/- 8, -26 +/- 15, and -54 +/- 11 mm Hg). Similarly, ganglionic blockade with CHEMICAL caused a significantly greater fall in LNNA hypertensive rats (76 +/- 9 mm Hg) compared with control rats (35 +/- 10 mm Hg). Carotid arteries, vena cava, and sympathetic ganglia from LNNA rats had higher basal levels of superoxide compared with those from control rats. These data suggest that while NO deficiency increases oxidative stress and sympathetic activity in both arterial and venous vessels, the impact on veins does not make a major contribution to this form of hypertension. | NO-RELATIONSHIP |
| Mechanisms of hypertension induced by nitric oxide (NO) deficiency: focus on venous function. Loss of endothelial cell-derived nitric oxide (NO) in hypertension is a hallmark of DISEASE. Experimental hypertension created by the removal of NO, however, involves mechanisms in addition to decreased arterial vasodilator activity. These include augmented endothelin-1 (ET-1) release, increased sympathetic nervous system activity, and elevated tissue oxidative stress. We hypothesized that increased venous smooth muscle (venomotor) tone plays a role in Nomega-nitro-L-arginine (LNNA) hypertension through these mechanisms. Rats were treated with the NO synthase inhibitor LNNA (0.5 g/L in drinking water) for 2 weeks. Mean arterial pressure of conscious rats was 119 +/- 2 mm Hg in control and 194 +/- 5 mm Hg in LNNA rats (P<0.05). Carotid arteries and vena cava were removed for measurement of isometric contraction. Maximal contraction to norepinephrine was modestly reduced in arteries from LNNA compared with control rats whereas the maximum contraction to ET-1 was significantly reduced (54% control). Maximum contraction of vena cava to norepinephrine (37% control) also was reduced but no change in response to ET-1 was observed. Mean circulatory filling pressure, an in vivo measure of venomotor tone, was not elevated in LNNA hypertension at 1 or 2 weeks after LNNA. The CHEMICAL scavenger tempol (30, 100, and 300 micromol kg(-1), IV) did not change arterial pressure in control rats but caused a dose-dependent decrease in LNNA rats (-18 +/- 8, -26 +/- 15, and -54 +/- 11 mm Hg). Similarly, ganglionic blockade with hexamethonium caused a significantly greater fall in LNNA hypertensive rats (76 +/- 9 mm Hg) compared with control rats (35 +/- 10 mm Hg). Carotid arteries, vena cava, and sympathetic ganglia from LNNA rats had higher basal levels of CHEMICAL compared with those from control rats. These data suggest that while NO deficiency increases oxidative stress and sympathetic activity in both arterial and venous vessels, the impact on veins does not make a major contribution to this form of hypertension. | NO-RELATIONSHIP |
| Mechanisms of hypertension induced by nitric oxide (NO) deficiency: focus on venous function. Loss of endothelial cell-derived nitric oxide (NO) in hypertension is a hallmark of DISEASE. Experimental hypertension created by the removal of NO, however, involves mechanisms in addition to decreased arterial vasodilator activity. These include augmented endothelin-1 (ET-1) release, increased sympathetic nervous system activity, and elevated tissue oxidative stress. We hypothesized that increased venous smooth muscle (venomotor) tone plays a role in Nomega-nitro-L-arginine (LNNA) hypertension through these mechanisms. Rats were treated with the NO synthase inhibitor LNNA (0.5 g/L in drinking water) for 2 weeks. Mean arterial pressure of conscious rats was 119 +/- 2 mm Hg in control and 194 +/- 5 mm Hg in LNNA rats (P<0.05). Carotid arteries and vena cava were removed for measurement of isometric contraction. Maximal contraction to CHEMICAL was modestly reduced in arteries from LNNA compared with control rats whereas the maximum contraction to ET-1 was significantly reduced (54% control). Maximum contraction of vena cava to CHEMICAL (37% control) also was reduced but no change in response to ET-1 was observed. Mean circulatory filling pressure, an in vivo measure of venomotor tone, was not elevated in LNNA hypertension at 1 or 2 weeks after LNNA. The superoxide scavenger tempol (30, 100, and 300 micromol kg(-1), IV) did not change arterial pressure in control rats but caused a dose-dependent decrease in LNNA rats (-18 +/- 8, -26 +/- 15, and -54 +/- 11 mm Hg). Similarly, ganglionic blockade with hexamethonium caused a significantly greater fall in LNNA hypertensive rats (76 +/- 9 mm Hg) compared with control rats (35 +/- 10 mm Hg). Carotid arteries, vena cava, and sympathetic ganglia from LNNA rats had higher basal levels of superoxide compared with those from control rats. These data suggest that while NO deficiency increases oxidative stress and sympathetic activity in both arterial and venous vessels, the impact on veins does not make a major contribution to this form of hypertension. | NO-RELATIONSHIP |
| Association of DRD2 polymorphisms and CHEMICAL-induced DISEASE in Chinese schizophrenic patients. AIM: DISEASE (DISEASE) is most commonly affected by typical antipsychotic drugs that have a high affinity with the D2 receptor. Recently, many research groups have reported on the positive relationship between the genetic variations in the DRD2 gene and the therapeutic response in schizophrenia patients as a result of the role of variations in the receptor in modulating receptor expression. In this study, we evaluate the role DRD2 plays in CHEMICAL-induced DISEASE in schizophrenic patients. METHODS: We identified seven SNP(single nucleotide polymorphism) (-141Cins>del, TaqIB, TaqID, Ser311Cys, rs6275, rs6277 and TaqIA) in the DRD2 gene in 146 schizophrenic inpatients (59 with DISEASE and 87 without DISEASE according to the Simpson-Angus Scale) treated with CHEMICAL after 8 weeks. The alleles of all loci were determined by PCR (polymerase chain reaction). RESULTS: Polymorphisms TaqID, Ser311Cys and rs6277 were not polymorphic in the population recruited in the present study. No statistical significance was found in the allele distribution of -141Cins>del, TaqIB, rs6275 and TaqIA or in the estimated haplotypes (constituted by TaqIB, rs6275 and TaqIA) in linkage disequilibrium between the two groups. CONCLUSION: Our results did not lend strong support to the view that the genetic variation of the DRD2 gene plays a major role in the individually variable adverse effect induced by CHEMICAL, at least in Chinese patients with schizophrenia. Our results confirmed a previous study on the relationship between DRD2 and DISEASE in Caucasians. | CHEMICAL-INDUCED-DISEASE |
| Physical training decreases susceptibility to subsequent CHEMICAL-induced DISEASE in the rat. Regular motor activity has many benefits for mental and physical condition but its implications for epilepsy are still controversial. In order to elucidate this problem, we have studied the effect of long-term physical activity on susceptibility to subsequent DISEASE. Male Wistar rats were subjected to repeated training sessions in a treadmill and swimming pool. Thereafter, DISEASE were induced by CHEMICAL injections in trained and non-trained control groups. During the acute period of status epilepticus, we measured: (1) the latency of the first motor sign, (2) the intensity of DISEASE, (3) the time when it occurred within the 6-h observation period, and (4) the time when the acute period ended. All these behavioral parameters showed statistically significant changes suggesting that regular physical exercises decrease susceptibility to subsequently induced DISEASE and ameliorate the course of experimentally induced status epilepticus. | CHEMICAL-INDUCED-DISEASE |
| Physical training decreases susceptibility to subsequent CHEMICAL-induced seizures in the rat. Regular motor activity has many benefits for mental and physical condition but its implications for epilepsy are still controversial. In order to elucidate this problem, we have studied the effect of long-term physical activity on susceptibility to subsequent seizures. Male Wistar rats were subjected to repeated training sessions in a treadmill and swimming pool. Thereafter, seizures were induced by CHEMICAL injections in trained and non-trained control groups. During the acute period of DISEASE, we measured: (1) the latency of the first motor sign, (2) the intensity of seizures, (3) the time when it occurred within the 6-h observation period, and (4) the time when the acute period ended. All these behavioral parameters showed statistically significant changes suggesting that regular physical exercises decrease susceptibility to subsequently induced seizures and ameliorate the course of experimentally induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Tonic dopaminergic stimulation DISEASE in healthy subjects. Endogenous dopamine plays a central role in salience coding during associative learning. Administration of the dopamine precursor levodopa enhances learning in healthy subjects and stroke patients. Because levodopa increases both phasic and tonic dopaminergic neurotransmission, the critical mechanism mediating the enhancement of learning is unresolved. We here probed how selective tonic dopaminergic stimulation affects associative learning. Forty healthy subjects were trained in a novel vocabulary of 45 concrete nouns over the course of 5 consecutive training days in a prospective, randomized, double-blind, placebo-controlled design. Subjects received the tonically stimulating dopamine-receptor agonist CHEMICAL (0.1 mg) vs placebo 120 min before training on each training day. The dopamine agonist significantly DISEASE compared to placebo. This learning decrement persisted up to the last follow-up 4 weeks post-training. Subjects treated with CHEMICAL also showed restricted emotional responses compared to the PLACEBO group. The extent of 'flattened' affect with CHEMICAL was related to the degree of learning inhibition. These findings suggest that tonic occupation of dopamine receptors impairs learning by competition with phasic dopamine signals. Thus, phasic signaling seems to be the critical mechanism by which dopamine enhances associative learning in healthy subjects and stroke patients. | CHEMICAL-INDUCED-DISEASE |
| Tonic dopaminergic stimulation impairs associative learning in healthy subjects. Endogenous dopamine plays a central role in salience coding during associative learning. Administration of the dopamine precursor CHEMICAL enhances learning in healthy subjects and DISEASE patients. Because CHEMICAL increases both phasic and tonic dopaminergic neurotransmission, the critical mechanism mediating the enhancement of learning is unresolved. We here probed how selective tonic dopaminergic stimulation affects associative learning. Forty healthy subjects were trained in a novel vocabulary of 45 concrete nouns over the course of 5 consecutive training days in a prospective, randomized, double-blind, placebo-controlled design. Subjects received the tonically stimulating dopamine-receptor agonist pergolide (0.1 mg) vs placebo 120 min before training on each training day. The dopamine agonist significantly impaired novel word learning compared to placebo. This learning decrement persisted up to the last follow-up 4 weeks post-training. Subjects treated with pergolide also showed restricted emotional responses compared to the PLACEBO group. The extent of 'flattened' affect with pergolide was related to the degree of learning inhibition. These findings suggest that tonic occupation of dopamine receptors impairs learning by competition with phasic dopamine signals. Thus, phasic signaling seems to be the critical mechanism by which dopamine enhances associative learning in healthy subjects and DISEASE patients. | NO-RELATIONSHIP |
| Tonic dopaminergic stimulation impairs associative learning in healthy subjects. Endogenous CHEMICAL plays a central role in salience coding during associative learning. Administration of the CHEMICAL precursor levodopa enhances learning in healthy subjects and DISEASE patients. Because levodopa increases both phasic and tonic dopaminergic neurotransmission, the critical mechanism mediating the enhancement of learning is unresolved. We here probed how selective tonic dopaminergic stimulation affects associative learning. Forty healthy subjects were trained in a novel vocabulary of 45 concrete nouns over the course of 5 consecutive training days in a prospective, randomized, double-blind, placebo-controlled design. Subjects received the tonically stimulating CHEMICAL-receptor agonist pergolide (0.1 mg) vs placebo 120 min before training on each training day. The CHEMICAL agonist significantly impaired novel word learning compared to placebo. This learning decrement persisted up to the last follow-up 4 weeks post-training. Subjects treated with pergolide also showed restricted emotional responses compared to the PLACEBO group. The extent of 'flattened' affect with pergolide was related to the degree of learning inhibition. These findings suggest that tonic occupation of CHEMICAL receptors impairs learning by competition with phasic CHEMICAL signals. Thus, phasic signaling seems to be the critical mechanism by which CHEMICAL enhances associative learning in healthy subjects and DISEASE patients. | NO-RELATIONSHIP |
| CHEMICAL-induced vasculitis fulfilling the criteria of DISEASE. A 47-year-old man who had been taking CHEMICAL for palmoplantar pustulosis developed fever, myalgias, polyneuropathy, and testicular pain, with elevated C-reactive protein (CRP). Neither myeloperoxidase- nor proteinase-3-antineutrophil cytoplasmic antibody was positive. These manifestations met the American College of Rheumatology 1990 criteria for the classification of DISEASE. Stopping CHEMICAL led to amelioration of symptoms and normalization of CRP level. To our knowledge, this is the second case of CHEMICAL-induced vasculitis satisfying the criteria. Differential diagnosis for drug-induced disease is invaluable even for patients with classical DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Intramuscular DISEASE immune globulin combined with lamivudine in prevention of DISEASE recurrence after liver transplantation. BACKGROUND: Combined DISEASE immune globulin (HBIg) and lamivudine in prophylaxis of the recurrence of DISEASE after liver transplantation has significantly improved the survival of HBsAg positive patients. This study was undertaken to evaluate the outcomes of liver transplantation for patients with DISEASE virus (HBV). METHODS: A retrospective chart analysis and a review of the organ transplant database identified 51 patients (43 men and 8 women) transplanted for benign HBV-related cirrhotic diseases between June 2002 and December 2004 who had survived more than 3 months. HBIg was administered intravenously during the first week and intramuscularly thereafter. RESULTS: At a median follow-up of 14.1 months, the overall recurrence rate in the 51 patients was 3.9% (2/51). The overall patient survival was 88.3%, and 82.4% after 1 and 2 years, respectively. A daily oral dose of 100 mg lamivudine for 2 weeks before transplantation for 10 patients enabled 57.1% (4/7) and 62.5% (5/8) of HBV-DNA and CHEMICAL positive patients respectively to convert to be negative. Intramuscular HBIg was well tolerated in all patients. CONCLUSION: Lamivudine combined with intramuscular HBIg can effectively prevent allograft from the recurrence of HBV after liver transplantation. | NO-RELATIONSHIP |
| Intramuscular hepatitis B immune globulin combined with lamivudine in prevention of hepatitis B recurrence after liver transplantation. BACKGROUND: Combined hepatitis B immune globulin (HBIg) and lamivudine in prophylaxis of the recurrence of hepatitis B after liver transplantation has significantly improved the survival of CHEMICAL positive patients. This study was undertaken to evaluate the outcomes of liver transplantation for patients with hepatitis B virus (HBV). METHODS: A retrospective chart analysis and a review of the organ transplant database identified 51 patients (43 men and 8 women) transplanted for benign HBV-related DISEASE between June 2002 and December 2004 who had survived more than 3 months. HBIg was administered intravenously during the first week and intramuscularly thereafter. RESULTS: At a median follow-up of 14.1 months, the overall recurrence rate in the 51 patients was 3.9% (2/51). The overall patient survival was 88.3%, and 82.4% after 1 and 2 years, respectively. A daily oral dose of 100 mg lamivudine for 2 weeks before transplantation for 10 patients enabled 57.1% (4/7) and 62.5% (5/8) of HBV-DNA and HBeAg positive patients respectively to convert to be negative. Intramuscular HBIg was well tolerated in all patients. CONCLUSION: Lamivudine combined with intramuscular HBIg can effectively prevent allograft from the recurrence of HBV after liver transplantation. | NO-RELATIONSHIP |
| Intramuscular hepatitis B immune globulin combined with CHEMICAL in prevention of hepatitis B recurrence after liver transplantation. BACKGROUND: Combined hepatitis B immune globulin (HBIg) and CHEMICAL in prophylaxis of the recurrence of hepatitis B after liver transplantation has significantly improved the survival of HBsAg positive patients. This study was undertaken to evaluate the outcomes of liver transplantation for patients with hepatitis B virus (HBV). METHODS: A retrospective chart analysis and a review of the organ transplant database identified 51 patients (43 men and 8 women) transplanted for benign HBV-related DISEASE between June 2002 and December 2004 who had survived more than 3 months. HBIg was administered intravenously during the first week and intramuscularly thereafter. RESULTS: At a median follow-up of 14.1 months, the overall recurrence rate in the 51 patients was 3.9% (2/51). The overall patient survival was 88.3%, and 82.4% after 1 and 2 years, respectively. A daily oral dose of 100 mg CHEMICAL for 2 weeks before transplantation for 10 patients enabled 57.1% (4/7) and 62.5% (5/8) of HBV-DNA and HBeAg positive patients respectively to convert to be negative. Intramuscular HBIg was well tolerated in all patients. CONCLUSION: CHEMICAL combined with intramuscular HBIg can effectively prevent allograft from the recurrence of HBV after liver transplantation. | NO-RELATIONSHIP |
| Anticonvulsant effect of eslicarbazepine acetate (BIA 2-093) on DISEASE induced by microperfusion of CHEMICAL in the hippocampus of freely moving rats. Eslicarbazepine acetate (BIA 2-093, S-(-)-10-acetoxy-10,11-dihydro-5H-dibenzo/b,f/azepine-5-carboxamide) is a novel antiepileptic drug, now in Phase III clinical trials, designed with the aim of improving efficacy and safety in comparison with the structurally related drugs carbamazepine (CBZ) and oxcarbazepine (OXC). We have studied the effects of oral treatment with eslicarbazepine acetate on a whole-animal model in which partial DISEASE can be elicited repeatedly on different days without changes in threshold or DISEASE patterns. In the animals treated with threshold doses of CHEMICAL, the average number of DISEASE was 2.3+/-1.2, and average DISEASE duration was 39.5+/-8.4s. Pre-treatment with a dose of 30 mg/kg 2h before CHEMICAL microperfusion prevented DISEASE in the 75% of the rats. Lower doses (3 and 10mg/kg) did not suppress DISEASE, however, after administration of 10mg/kg, significant reductions in DISEASE duration (24.3+/-6.8s) and DISEASE number (1.6+/-0.34) were found. No adverse effects of eslicarbazepine acetate were observed in the behavioral/EEG patterns studied, including sleep/wakefulness cycle, at the doses studied. | CHEMICAL-INDUCED-DISEASE |
| DISEASE associated with prolonged intake of slimming pills containing anthraquinones. Chinese herbal medicine preparations are widely available and often regarded by the public as natural and safe remedies for a variety of medical conditions. Nephropathy caused by Chinese herbs has previously been reported, usually involving the use of aristolochic acids. We report a 23-year-old woman who developed DISEASE following prolonged use of a proprietary Chinese herbal slimming pill that contained anthraquinone derivatives, extracted from Rhizoma Rhei (rhubarb). The DISEASE was probably aggravated by the concomitant intake of a non-steroidal anti-inflammatory drug, CHEMICAL. Renal pathology was that of hypocellular interstitial fibrosis. Spontaneous renal recovery occurred upon cessation of the slimming pills, but mild interstitial fibrosis and tubular atrophy was still evident histologically 4 months later. Although a causal relationship between the use of an anthraquinone-containing herbal agent and DISEASE remains to be proven, phytotherapy-associated interstitial nephropathy should be considered in patients who present with unexplained renal failure. | CHEMICAL-INDUCED-DISEASE |
| DISEASE associated with prolonged intake of slimming pills containing anthraquinones. CHEMICAL medicine preparations are widely available and often regarded by the public as natural and safe remedies for a variety of medical conditions. Nephropathy caused by CHEMICAL has previously been reported, usually involving the use of aristolochic acids. We report a 23-year-old woman who developed DISEASE following prolonged use of a proprietary CHEMICAL slimming pill that contained anthraquinone derivatives, extracted from Rhizoma Rhei (rhubarb). The DISEASE was probably aggravated by the concomitant intake of a non-steroidal anti-inflammatory drug, diclofenac. Renal pathology was that of hypocellular interstitial fibrosis. Spontaneous renal recovery occurred upon cessation of the slimming pills, but mild interstitial fibrosis and tubular atrophy was still evident histologically 4 months later. Although a causal relationship between the use of an anthraquinone-containing herbal agent and DISEASE remains to be proven, phytotherapy-associated interstitial nephropathy should be considered in patients who present with unexplained renal failure. | CHEMICAL-INDUCED-DISEASE |
| Acute renal failure associated with prolonged intake of slimming pills containing anthraquinones. Chinese herbal medicine preparations are widely available and often regarded by the public as natural and safe remedies for a variety of medical conditions. Nephropathy caused by Chinese herbs has previously been reported, usually involving the use of CHEMICAL. We report a 23-year-old woman who developed acute renal failure following prolonged use of a proprietary Chinese herbal slimming pill that contained anthraquinone derivatives, extracted from Rhizoma Rhei (rhubarb). The renal injury was probably aggravated by the concomitant intake of a non-steroidal anti-inflammatory drug, diclofenac. Renal pathology was that of hypocellular interstitial fibrosis. Spontaneous renal recovery occurred upon cessation of the slimming pills, but mild interstitial fibrosis and tubular DISEASE was still evident histologically 4 months later. Although a causal relationship between the use of an anthraquinone-containing herbal agent and renal injury remains to be proven, phytotherapy-associated interstitial nephropathy should be considered in patients who present with unexplained renal failure. | NO-RELATIONSHIP |
| Acute renal failure associated with prolonged intake of slimming pills containing CHEMICAL. Chinese herbal medicine preparations are widely available and often regarded by the public as natural and safe remedies for a variety of medical conditions. Nephropathy caused by Chinese herbs has previously been reported, usually involving the use of aristolochic acids. We report a 23-year-old woman who developed acute renal failure following prolonged use of a proprietary Chinese herbal slimming pill that contained CHEMICAL derivatives, extracted from Rhizoma Rhei (rhubarb). The renal injury was probably aggravated by the concomitant intake of a non-steroidal anti-inflammatory drug, diclofenac. Renal pathology was that of hypocellular interstitial fibrosis. Spontaneous renal recovery occurred upon cessation of the slimming pills, but mild interstitial fibrosis and tubular DISEASE was still evident histologically 4 months later. Although a causal relationship between the use of an CHEMICAL-containing herbal agent and renal injury remains to be proven, phytotherapy-associated interstitial nephropathy should be considered in patients who present with unexplained renal failure. | CHEMICAL-INDUCED-DISEASE |
| Acute renal failure associated with prolonged intake of slimming pills containing CHEMICAL. Chinese herbal medicine preparations are widely available and often regarded by the public as natural and safe remedies for a variety of medical conditions. Nephropathy caused by Chinese herbs has previously been reported, usually involving the use of aristolochic acids. We report a 23-year-old woman who developed acute renal failure following prolonged use of a proprietary Chinese herbal slimming pill that contained CHEMICAL derivatives, extracted from Rhizoma Rhei (rhubarb). The renal injury was probably aggravated by the concomitant intake of a non-steroidal anti-inflammatory drug, diclofenac. Renal pathology was that of hypocellular interstitial fibrosis. Spontaneous renal recovery occurred upon cessation of the slimming pills, but mild interstitial fibrosis and tubular atrophy was still evident histologically 4 months later. Although a causal relationship between the use of an CHEMICAL-containing herbal agent and renal injury remains to be proven, phytotherapy-associated interstitial nephropathy should be considered in patients who present with unexplained DISEASE. | NO-RELATIONSHIP |
| Acute renal failure associated with prolonged intake of slimming pills containing CHEMICAL. Chinese herbal medicine preparations are widely available and often regarded by the public as natural and safe remedies for a variety of medical conditions. DISEASE caused by Chinese herbs has previously been reported, usually involving the use of aristolochic acids. We report a 23-year-old woman who developed acute renal failure following prolonged use of a proprietary Chinese herbal slimming pill that contained CHEMICAL derivatives, extracted from Rhizoma Rhei (rhubarb). The renal injury was probably aggravated by the concomitant intake of a non-steroidal anti-inflammatory drug, diclofenac. Renal pathology was that of hypocellular interstitial fibrosis. Spontaneous renal recovery occurred upon cessation of the slimming pills, but mild interstitial fibrosis and tubular atrophy was still evident histologically 4 months later. Although a causal relationship between the use of an CHEMICAL-containing herbal agent and renal injury remains to be proven, phytotherapy-associated interstitial DISEASE should be considered in patients who present with unexplained renal failure. | CHEMICAL-INDUCED-DISEASE |
| Acute renal failure associated with prolonged intake of slimming pills containing anthraquinones. Chinese herbal medicine preparations are widely available and often regarded by the public as natural and safe remedies for a variety of medical conditions. Nephropathy caused by Chinese herbs has previously been reported, usually involving the use of CHEMICAL. We report a 23-year-old woman who developed acute renal failure following prolonged use of a proprietary Chinese herbal slimming pill that contained anthraquinone derivatives, extracted from Rhizoma Rhei (rhubarb). The renal injury was probably aggravated by the concomitant intake of a non-steroidal anti-inflammatory drug, diclofenac. Renal pathology was that of hypocellular interstitial DISEASE. Spontaneous renal recovery occurred upon cessation of the slimming pills, but mild interstitial DISEASE and tubular atrophy was still evident histologically 4 months later. Although a causal relationship between the use of an anthraquinone-containing herbal agent and renal injury remains to be proven, phytotherapy-associated interstitial nephropathy should be considered in patients who present with unexplained renal failure. | NO-RELATIONSHIP |
| Acute renal failure associated with prolonged intake of slimming pills containing CHEMICAL. Chinese herbal medicine preparations are widely available and often regarded by the public as natural and safe remedies for a variety of medical conditions. Nephropathy caused by Chinese herbs has previously been reported, usually involving the use of aristolochic acids. We report a 23-year-old woman who developed acute renal failure following prolonged use of a proprietary Chinese herbal slimming pill that contained CHEMICAL derivatives, extracted from Rhizoma Rhei (rhubarb). The renal injury was probably aggravated by the concomitant intake of a non-steroidal anti-inflammatory drug, diclofenac. Renal pathology was that of hypocellular interstitial DISEASE. Spontaneous renal recovery occurred upon cessation of the slimming pills, but mild interstitial DISEASE and tubular atrophy was still evident histologically 4 months later. Although a causal relationship between the use of an CHEMICAL-containing herbal agent and renal injury remains to be proven, phytotherapy-associated interstitial nephropathy should be considered in patients who present with unexplained renal failure. | CHEMICAL-INDUCED-DISEASE |
| Acute renal failure associated with prolonged intake of slimming pills containing anthraquinones. Chinese herbal medicine preparations are widely available and often regarded by the public as natural and safe remedies for a variety of medical conditions. DISEASE caused by Chinese herbs has previously been reported, usually involving the use of CHEMICAL. We report a 23-year-old woman who developed acute renal failure following prolonged use of a proprietary Chinese herbal slimming pill that contained anthraquinone derivatives, extracted from Rhizoma Rhei (rhubarb). The renal injury was probably aggravated by the concomitant intake of a non-steroidal anti-inflammatory drug, diclofenac. Renal pathology was that of hypocellular interstitial fibrosis. Spontaneous renal recovery occurred upon cessation of the slimming pills, but mild interstitial fibrosis and tubular atrophy was still evident histologically 4 months later. Although a causal relationship between the use of an anthraquinone-containing herbal agent and renal injury remains to be proven, phytotherapy-associated interstitial DISEASE should be considered in patients who present with unexplained renal failure. | CHEMICAL-INDUCED-DISEASE |
| Acute renal failure associated with prolonged intake of slimming pills containing anthraquinones. Chinese herbal medicine preparations are widely available and often regarded by the public as natural and safe remedies for a variety of medical conditions. Nephropathy caused by Chinese herbs has previously been reported, usually involving the use of CHEMICAL. We report a 23-year-old woman who developed acute renal failure following prolonged use of a proprietary Chinese herbal slimming pill that contained anthraquinone derivatives, extracted from Rhizoma Rhei (rhubarb). The renal injury was probably aggravated by the concomitant intake of a non-steroidal anti-inflammatory drug, diclofenac. Renal pathology was that of hypocellular interstitial fibrosis. Spontaneous renal recovery occurred upon cessation of the slimming pills, but mild interstitial fibrosis and tubular atrophy was still evident histologically 4 months later. Although a causal relationship between the use of an anthraquinone-containing herbal agent and renal injury remains to be proven, phytotherapy-associated interstitial nephropathy should be considered in patients who present with unexplained DISEASE. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a sulfhydryl reagent: the role of critical thiol groups in CHEMICAL DISEASE. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent CHEMICAL (CHEMICAL) and putatively responsible for DISEASE following anti-tumor therapy with CHEMICAL. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. Toxicity of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in necrosis markers. CAA but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on necrosis markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its toxicity on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent CHEMICAL DISEASE in patients. | CHEMICAL-INDUCED-DISEASE |
| Chloroacetaldehyde as a CHEMICAL reagent: the role of critical thiol groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-DISEASE therapy with IFO. Depletion of CHEMICAL (CHEMICAL) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. Toxicity of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in necrosis markers. CAA but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on necrosis markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its toxicity on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a sulfhydryl reagent: the role of critical thiol groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-DISEASE therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. Toxicity of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in necrosis markers. CAA but not acrolein inhibited the CHEMICAL proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on CHEMICAL protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on necrosis markers, thiol depletion and CHEMICAL protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its toxicity on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a sulfhydryl reagent: the role of critical thiol groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-tumor therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. Toxicity of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in DISEASE markers. CAA but not CHEMICAL inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on DISEASE markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its toxicity on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| CHEMICAL as a sulfhydryl reagent: the role of critical thiol groups in ifosfamide nephropathy. CHEMICAL (CHEMICAL) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-tumor therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CHEMICAL on human proximal tubule cells in primary culture (hRPTEC) was investigated. DISEASE of CHEMICAL was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CHEMICAL reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in necrosis markers. CHEMICAL but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CHEMICAL. In cells stained with fluorescent dyes targeting lysosomes, CHEMICAL induced an increase in lysosomal size and lysosomal leakage. The effects of CHEMICAL on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CHEMICAL with thiol donors, could also attenuate effects of CHEMICAL on necrosis markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CHEMICAL directly reacts with cellular protein and non-protein thiols, mediating its DISEASE on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a sulfhydryl reagent: the role of critical CHEMICAL groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-DISEASE therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. Toxicity of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free CHEMICAL were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular CHEMICAL and an increase in necrosis markers. CAA but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and CHEMICAL could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with CHEMICAL donors, could also attenuate effects of CAA on necrosis markers, CHEMICAL depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein CHEMICAL, mediating its toxicity on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a sulfhydryl reagent: the role of critical thiol groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-tumor therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. DISEASE of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in necrosis markers. CAA but not acrolein inhibited the CHEMICAL proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on CHEMICAL protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on necrosis markers, thiol depletion and CHEMICAL protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its DISEASE on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a sulfhydryl reagent: the role of critical CHEMICAL groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-tumor therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. DISEASE of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free CHEMICAL were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular CHEMICAL and an increase in necrosis markers. CAA but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and CHEMICAL could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with CHEMICAL donors, could also attenuate effects of CAA on necrosis markers, CHEMICAL depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein CHEMICAL, mediating its DISEASE on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| CHEMICAL as a sulfhydryl reagent: the role of critical thiol groups in ifosfamide nephropathy. CHEMICAL (CHEMICAL) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-DISEASE therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CHEMICAL on human proximal tubule cells in primary culture (hRPTEC) was investigated. Toxicity of CHEMICAL was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CHEMICAL reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in necrosis markers. CHEMICAL but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CHEMICAL. In cells stained with fluorescent dyes targeting lysosomes, CHEMICAL induced an increase in lysosomal size and lysosomal leakage. The effects of CHEMICAL on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CHEMICAL with thiol donors, could also attenuate effects of CHEMICAL on necrosis markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CHEMICAL directly reacts with cellular protein and non-protein thiols, mediating its toxicity on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a CHEMICAL reagent: the role of critical thiol groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-tumor therapy with IFO. Depletion of CHEMICAL (CHEMICAL) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. DISEASE of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in necrosis markers. CAA but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on necrosis markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its DISEASE on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a sulfhydryl reagent: the role of critical thiol groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-DISEASE therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. Toxicity of CAA was determined by protein content, cell number, LDH release, CHEMICAL exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in necrosis markers. CAA but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on necrosis markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its toxicity on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a sulfhydryl reagent: the role of critical thiol groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-tumor therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. Toxicity of CAA was determined by protein content, cell number, LDH release, CHEMICAL exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in DISEASE markers. CAA but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on DISEASE markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its toxicity on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a CHEMICAL reagent: the role of critical thiol groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-tumor therapy with IFO. Depletion of CHEMICAL (CHEMICAL) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. Toxicity of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in DISEASE markers. CAA but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on DISEASE markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its toxicity on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a sulfhydryl reagent: the role of critical thiol groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-tumor therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. DISEASE of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in necrosis markers. CAA but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by CHEMICAL was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on necrosis markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its DISEASE on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a sulfhydryl reagent: the role of critical thiol groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-DISEASE therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. Toxicity of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in necrosis markers. CAA but not CHEMICAL inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on necrosis markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its toxicity on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a sulfhydryl reagent: the role of critical thiol groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-tumor therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. Toxicity of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in DISEASE markers. CAA but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by CHEMICAL was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on DISEASE markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its toxicity on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a sulfhydryl reagent: the role of critical thiol groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-DISEASE therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. Toxicity of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in necrosis markers. CAA but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by CHEMICAL was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on necrosis markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its toxicity on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a sulfhydryl reagent: the role of critical thiol groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-tumor therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. DISEASE of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in necrosis markers. CAA but not CHEMICAL inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on necrosis markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its DISEASE on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a sulfhydryl reagent: the role of critical CHEMICAL groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-tumor therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. Toxicity of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free CHEMICAL were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular CHEMICAL and an increase in DISEASE markers. CAA but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and CHEMICAL could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with CHEMICAL donors, could also attenuate effects of CAA on DISEASE markers, CHEMICAL depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein CHEMICAL, mediating its toxicity on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a sulfhydryl reagent: the role of critical thiol groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-tumor therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. DISEASE of CAA was determined by protein content, cell number, LDH release, CHEMICAL exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in necrosis markers. CAA but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on necrosis markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its DISEASE on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Chloroacetaldehyde as a sulfhydryl reagent: the role of critical thiol groups in ifosfamide nephropathy. Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-tumor therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. Toxicity of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in DISEASE markers. CAA but not acrolein inhibited the CHEMICAL proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on CHEMICAL protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on DISEASE markers, thiol depletion and CHEMICAL protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its toxicity on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients. | NO-RELATIONSHIP |
| Stereological methods reveal the robust size and stability of ectopic hilar granule cells after CHEMICAL-induced status epilepticus in the adult rat. Following status epilepticus in the rat, dentate granule cell neurogenesis increases greatly, and many of the new neurons appear to develop ectopically, in the hilar region of the hippocampal formation. It has been suggested that the ectopic hilar granule cells could contribute to the spontaneous seizures that ultimately develop after status epilepticus. However, the population has never been quantified, so it is unclear whether it is substantial enough to have a strong influence on epileptogenesis. To quantify this population, the total number of ectopic hilar granule cells was estimated using unbiased stereology at different times after CHEMICAL-induced status epilepticus. The number of hilar neurons immunoreactive for Prox-1, a granule-cell-specific marker, was estimated using the optical fractionator method. The results indicate that the size of the hilar ectopic granule cell population after status epilepticus is substantial, and stable over time. Interestingly, the size of the population appears to be correlated with the frequency of behavioral seizures, because animals with more ectopic granule cells in the hilus have more frequent behavioral seizures. The hilar ectopic granule cell population does not appear to vary systematically across the septotemporal axis, although it is associated with an increase in volume of the hilus. The results provide new insight into the potential role of ectopic hilar granule cells in the CHEMICAL model of DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Stereological methods reveal the robust size and stability of ectopic hilar granule cells after CHEMICAL-induced DISEASE in the adult rat. Following DISEASE in the rat, dentate granule cell neurogenesis increases greatly, and many of the new neurons appear to develop ectopically, in the hilar region of the hippocampal formation. It has been suggested that the ectopic hilar granule cells could contribute to the spontaneous seizures that ultimately develop after DISEASE. However, the population has never been quantified, so it is unclear whether it is substantial enough to have a strong influence on epileptogenesis. To quantify this population, the total number of ectopic hilar granule cells was estimated using unbiased stereology at different times after CHEMICAL-induced DISEASE. The number of hilar neurons immunoreactive for Prox-1, a granule-cell-specific marker, was estimated using the optical fractionator method. The results indicate that the size of the hilar ectopic granule cell population after DISEASE is substantial, and stable over time. Interestingly, the size of the population appears to be correlated with the frequency of behavioral seizures, because animals with more ectopic granule cells in the hilus have more frequent behavioral seizures. The hilar ectopic granule cell population does not appear to vary systematically across the septotemporal axis, although it is associated with an increase in volume of the hilus. The results provide new insight into the potential role of ectopic hilar granule cells in the CHEMICAL model of temporal lobe epilepsy. | CHEMICAL-INDUCED-DISEASE |
| A prospective, open-label trial of CHEMICAL in autistic disorder. OBJECTIVE: Post-mortem studies have reported abnormalities of the cholinergic system in autism. The purpose of this study was to assess the use of CHEMICAL, an acetylcholinesterase inhibitor and nicotinic receptor modulator, in the treatment of interfering behaviors in children with autism. METHODS: Thirteen medication-free children with autism (mean age, 8.8 +/- 3.5 years) participated in a 12-week, open-label trial of CHEMICAL. Patients were rated monthly by parents on the Aberrant Behavior Checklist (ABC) and the Conners' Parent Rating Scale-Revised, and by a physician using the Children's Psychiatric Rating Scale and the Clinical Global Impressions scale. RESULTS: Patients showed a significant reduction in parent-rated irritability and social withdrawal on the ABC as well as significant improvements in emotional lability and inattention on the Conners' Parent Rating Scale--Revised. Similarly, clinician ratings showed reductions in the anger subscale of the Children's Psychiatric Rating Scale. Eight of 13 participants were rated as responders on the basis of their improvement scores on the Clinical Global Impressions scale. Overall, CHEMICAL was well-tolerated, with no significant adverse effects apart from DISEASE in one patient. CONCLUSION: In this open trial, CHEMICAL was well-tolerated and appeared to be beneficial for the treatment of interfering behaviors in children with autism, particularly aggression, behavioral dyscontrol, and inattention. Further controlled trials are warranted. | CHEMICAL-INDUCED-DISEASE |
| Randomized comparison of olanzapine versus CHEMICAL for the treatment of first-episode schizophrenia: 4-month outcomes. OBJECTIVE: The authors compared 4-month treatment outcomes for olanzapine versus CHEMICAL in patients with first-episode schizophrenia spectrum disorders. METHOD: One hundred twelve subjects (70% male; mean age=23.3 years [SD = 5.1]) with first-episode schizophrenia (75%), schizophreniform disorder (17%), or schizoaffective disorder (8%) were randomly assigned to treatment with olanzapine (2.5-20 mg/day) or CHEMICAL (1-6 mg/day). RESULTS: Response rates did not significantly differ between olanzapine (43.7%, 95% CI=28.8%-58.6%) and CHEMICAL (54.3%, 95% CI=39.9%-68.7%). Among those responding to treatment, more subjects in the olanzapine group (40.9%, 95% CI=16.8%-65.0%) than in the CHEMICAL group (18.9%, 95% CI=0%-39.2%) had subsequent ratings not meeting response criteria. Negative symptom outcomes and measures of parkinsonism and akathisia did not differ between medications. DISEASE severity scores were 1.4 (95% CI=1.2-1.6) with CHEMICAL and 1.2 (95% CI=1.0-1.4) with olanzapine. Significantly more weight gain occurred with olanzapine than with CHEMICAL: the increase in weight at 4 months relative to baseline weight was 17.3% (95% CI=14.2%-20.5%) with olanzapine and 11.3% (95% CI=8.4%-14.3%) with CHEMICAL. Body mass index at baseline and at 4 months was 24.3 (95% CI=22.8-25.7) versus 28.2 (95% CI=26.7-29.7) with olanzapine and 23.9 (95% CI=22.5-25.3) versus 26.7 (95% CI=25.2-28.2) with CHEMICAL. CONCLUSIONS: Clinical outcomes with CHEMICAL were equal to those with olanzapine, and response may be more stable. Olanzapine may have an advantage for motor side effects. Both medications caused substantial rapid weight gain, but weight gain was greater with olanzapine. | CHEMICAL-INDUCED-DISEASE |
| Randomized comparison of CHEMICAL versus risperidone for the treatment of first-episode schizophrenia: 4-month outcomes. OBJECTIVE: The authors compared 4-month treatment outcomes for CHEMICAL versus risperidone in patients with first-episode schizophrenia spectrum disorders. METHOD: One hundred twelve subjects (70% male; mean age=23.3 years [SD = 5.1]) with first-episode schizophrenia (75%), schizophreniform disorder (17%), or schizoaffective disorder (8%) were randomly assigned to treatment with CHEMICAL (2.5-20 mg/day) or risperidone (1-6 mg/day). RESULTS: Response rates did not significantly differ between CHEMICAL (43.7%, 95% CI=28.8%-58.6%) and risperidone (54.3%, 95% CI=39.9%-68.7%). Among those responding to treatment, more subjects in the CHEMICAL group (40.9%, 95% CI=16.8%-65.0%) than in the risperidone group (18.9%, 95% CI=0%-39.2%) had subsequent ratings not meeting response criteria. Negative symptom outcomes and measures of parkinsonism and akathisia did not differ between medications. Extrapyramidal symptom severity scores were 1.4 (95% CI=1.2-1.6) with risperidone and 1.2 (95% CI=1.0-1.4) with CHEMICAL. Significantly more DISEASE occurred with CHEMICAL than with risperidone: the increase in weight at 4 months relative to baseline weight was 17.3% (95% CI=14.2%-20.5%) with CHEMICAL and 11.3% (95% CI=8.4%-14.3%) with risperidone. Body mass index at baseline and at 4 months was 24.3 (95% CI=22.8-25.7) versus 28.2 (95% CI=26.7-29.7) with CHEMICAL and 23.9 (95% CI=22.5-25.3) versus 26.7 (95% CI=25.2-28.2) with risperidone. CONCLUSIONS: Clinical outcomes with risperidone were equal to those with CHEMICAL, and response may be more stable. CHEMICAL may have an advantage for motor side effects. Both medications caused substantial rapid DISEASE, but DISEASE was greater with CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Randomized comparison of CHEMICAL versus risperidone for the treatment of first-episode schizophrenia: 4-month outcomes. OBJECTIVE: The authors compared 4-month treatment outcomes for CHEMICAL versus risperidone in patients with first-episode schizophrenia spectrum disorders. METHOD: One hundred twelve subjects (70% male; mean age=23.3 years [SD = 5.1]) with first-episode schizophrenia (75%), schizophreniform disorder (17%), or schizoaffective disorder (8%) were randomly assigned to treatment with CHEMICAL (2.5-20 mg/day) or risperidone (1-6 mg/day). RESULTS: Response rates did not significantly differ between CHEMICAL (43.7%, 95% CI=28.8%-58.6%) and risperidone (54.3%, 95% CI=39.9%-68.7%). Among those responding to treatment, more subjects in the CHEMICAL group (40.9%, 95% CI=16.8%-65.0%) than in the risperidone group (18.9%, 95% CI=0%-39.2%) had subsequent ratings not meeting response criteria. Negative symptom outcomes and measures of parkinsonism and akathisia did not differ between medications. DISEASE severity scores were 1.4 (95% CI=1.2-1.6) with risperidone and 1.2 (95% CI=1.0-1.4) with CHEMICAL. Significantly more weight gain occurred with CHEMICAL than with risperidone: the increase in weight at 4 months relative to baseline weight was 17.3% (95% CI=14.2%-20.5%) with CHEMICAL and 11.3% (95% CI=8.4%-14.3%) with risperidone. Body mass index at baseline and at 4 months was 24.3 (95% CI=22.8-25.7) versus 28.2 (95% CI=26.7-29.7) with CHEMICAL and 23.9 (95% CI=22.5-25.3) versus 26.7 (95% CI=25.2-28.2) with risperidone. CONCLUSIONS: Clinical outcomes with risperidone were equal to those with CHEMICAL, and response may be more stable. CHEMICAL may have an advantage for motor side effects. Both medications caused substantial rapid weight gain, but weight gain was greater with CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Randomized comparison of olanzapine versus CHEMICAL for the treatment of first-episode schizophrenia: 4-month outcomes. OBJECTIVE: The authors compared 4-month treatment outcomes for olanzapine versus CHEMICAL in patients with first-episode schizophrenia spectrum disorders. METHOD: One hundred twelve subjects (70% male; mean age=23.3 years [SD = 5.1]) with first-episode schizophrenia (75%), schizophreniform disorder (17%), or schizoaffective disorder (8%) were randomly assigned to treatment with olanzapine (2.5-20 mg/day) or CHEMICAL (1-6 mg/day). RESULTS: Response rates did not significantly differ between olanzapine (43.7%, 95% CI=28.8%-58.6%) and CHEMICAL (54.3%, 95% CI=39.9%-68.7%). Among those responding to treatment, more subjects in the olanzapine group (40.9%, 95% CI=16.8%-65.0%) than in the CHEMICAL group (18.9%, 95% CI=0%-39.2%) had subsequent ratings not meeting response criteria. Negative symptom outcomes and measures of parkinsonism and akathisia did not differ between medications. Extrapyramidal symptom severity scores were 1.4 (95% CI=1.2-1.6) with CHEMICAL and 1.2 (95% CI=1.0-1.4) with olanzapine. Significantly more DISEASE occurred with olanzapine than with CHEMICAL: the increase in weight at 4 months relative to baseline weight was 17.3% (95% CI=14.2%-20.5%) with olanzapine and 11.3% (95% CI=8.4%-14.3%) with CHEMICAL. Body mass index at baseline and at 4 months was 24.3 (95% CI=22.8-25.7) versus 28.2 (95% CI=26.7-29.7) with olanzapine and 23.9 (95% CI=22.5-25.3) versus 26.7 (95% CI=25.2-28.2) with CHEMICAL. CONCLUSIONS: Clinical outcomes with CHEMICAL were equal to those with olanzapine, and response may be more stable. Olanzapine may have an advantage for motor side effects. Both medications caused substantial rapid DISEASE, but DISEASE was greater with olanzapine. | CHEMICAL-INDUCED-DISEASE |
| Early paracentral DISEASE in patients taking CHEMICAL. OBJECTIVE: To review the natural history and ocular and systemic adverse effects of patients taking CHEMICAL who attended an ophthalmic screening program. DESIGN: Retrospective study. RESULTS: Records of 262 patients who were taking CHEMICAL and screened in the Department of Ophthalmology were reviewed. Of the 262 patients, 14 (18%) of 76 who had stopped treatment at the time of the study experienced documented adverse effects. Systemic adverse effects occurred in 8 patients (10.5%) and ocular adverse effects, in 5 (6.5%). Thirty-five patients (13.4%) had DISEASE, which were attributed to CHEMICAL treatment in 4 patients (1.5%). Three of the 4 patients were taking less than 6.5 mg/kg per day and all patients had normal renal and liver function test results. CONCLUSIONS: The current study used a protocol of visual acuity and color vision assessment, funduscopy, and Humphrey 10-2 visual field testing and shows that DISEASE appeared before any corresponding changes in any other tested clinical parameters; the defects were reproducible and the test parameters were reliable. Patients taking CHEMICAL can demonstrate a toxic reaction in the retina despite the absence of known risk factors. Screening, including Humphrey 10-2 visual field assessment, is recommended 2 years after the initial baseline and yearly thereafter. | CHEMICAL-INDUCED-DISEASE |
| Peri-operative DISEASE as a result of chemotherapy with epirubicin and paclitaxel. A 47-year-old woman presented for mastectomy and immediate latissimus dorsi flap reconstruction having been diagnosed with carcinoma of the breast 6 months previously. In the preceding months she had received neo-adjuvant chemotherapy with epirubicin, paclitaxel (Taxol) and CHEMICAL. This had been apparently uncomplicated and she had maintained a remarkably high level of physical activity. She was found to be bradycardic at pre-operative assessment but had no cardiac symptoms. Second degree Mobitz type II DISEASE was diagnosed on electrocardiogram, and temporary transvenous ventricular pacing instituted in the peri-operative period. We discuss how evidence-based guidelines would not have been helpful in this case, and how chemotherapy can exhibit substantial cardiotoxicity that may develop over many years. We suggest that patients who have received chemotherapy at any time should have a pre-operative electrocardiogram even if they are asymptomatic. | CHEMICAL-INDUCED-DISEASE |
| Peri-operative DISEASE as a result of chemotherapy with epirubicin and CHEMICAL. A 47-year-old woman presented for mastectomy and immediate latissimus dorsi flap reconstruction having been diagnosed with carcinoma of the breast 6 months previously. In the preceding months she had received neo-adjuvant chemotherapy with epirubicin, CHEMICAL (CHEMICAL) and cyclophosphamide. This had been apparently uncomplicated and she had maintained a remarkably high level of physical activity. She was found to be bradycardic at pre-operative assessment but had no cardiac symptoms. Second degree Mobitz type II DISEASE was diagnosed on electrocardiogram, and temporary transvenous ventricular pacing instituted in the peri-operative period. We discuss how evidence-based guidelines would not have been helpful in this case, and how chemotherapy can exhibit substantial cardiotoxicity that may develop over many years. We suggest that patients who have received chemotherapy at any time should have a pre-operative electrocardiogram even if they are asymptomatic. | CHEMICAL-INDUCED-DISEASE |
| Peri-operative DISEASE as a result of chemotherapy with CHEMICAL and paclitaxel. A 47-year-old woman presented for mastectomy and immediate latissimus dorsi flap reconstruction having been diagnosed with carcinoma of the breast 6 months previously. In the preceding months she had received neo-adjuvant chemotherapy with CHEMICAL, paclitaxel (Taxol) and cyclophosphamide. This had been apparently uncomplicated and she had maintained a remarkably high level of physical activity. She was found to be bradycardic at pre-operative assessment but had no cardiac symptoms. Second degree Mobitz type II DISEASE was diagnosed on electrocardiogram, and temporary transvenous ventricular pacing instituted in the peri-operative period. We discuss how evidence-based guidelines would not have been helpful in this case, and how chemotherapy can exhibit substantial cardiotoxicity that may develop over many years. We suggest that patients who have received chemotherapy at any time should have a pre-operative electrocardiogram even if they are asymptomatic. | CHEMICAL-INDUCED-DISEASE |
| Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study. OBJECTIVES: The risk of DISEASE (DISEASE) with COX-2 inhibitors may offset their gastrointestinal (GI) benefit compared with non-selective (NS) non-steroidal anti-inflammatory drugs (NSAIDs). We aimed to compare the risks of hospitalization for DISEASE and GI bleeding among elderly patients using COX-2 inhibitors, NS-NSAIDs and acetaminophen. METHODS: We conducted a retrospective cohort study using administrative data of patients > or =65 years of age who filled a prescription for NSAID or acetaminophen during 1999-2002. Outcomes were compared using Cox regression models with time-dependent exposures. RESULTS: Person-years of exposure among non-users of aspirin were: 75,761 to acetaminophen, 42,671 to rofecoxib 65,860 to celecoxib, and 37,495 to NS-NSAIDs. Among users of aspirin, they were: 14,671 to rofecoxib, 22,875 to celecoxib, 9,832 to NS-NSAIDs and 38,048 to acetaminophen. Among non-users of aspirin, the adjusted hazard ratios (95% confidence interval) of hospitalization for DISEASE/GI vs the acetaminophen (with no aspirin) group were: rofecoxib 1.27 (1.13, 1.42), celecoxib 0.93 (0.83, 1.03), CHEMICAL 1.59 (1.31, 1.93), diclofenac 1.17 (0.99, 1.38) and ibuprofen 1.05 (0.74, 1.51). Among users of aspirin, they were: rofecoxib 1.73 (1.52, 1.98), celecoxib 1.34 (1.19, 1.52), ibuprofen 1.51 (0.95, 2.41), diclofenac 1.69 (1.35, 2.10), CHEMICAL 1.35 (0.97, 1.88) and acetaminophen 1.29 (1.17, 1.42). CONCLUSION: Among non-users of aspirin, CHEMICAL seemed to carry the highest risk for DISEASE/GI bleeding. The DISEASE/GI toxicity of celecoxib was similar to that of acetaminophen and seemed to be better than those of rofecoxib and NS-NSAIDs. Among users of aspirin, both celecoxib and CHEMICAL seemed to be the least toxic. | CHEMICAL-INDUCED-DISEASE |
| Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study. OBJECTIVES: The risk of acute myocardial infarction (AMI) with COX-2 inhibitors may offset their gastrointestinal (GI) benefit compared with non-selective (NS) CHEMICAL (NSAIDs). We aimed to compare the risks of hospitalization for AMI and DISEASE among elderly patients using COX-2 inhibitors, NS-NSAIDs and acetaminophen. METHODS: We conducted a retrospective cohort study using administrative data of patients > or =65 years of age who filled a prescription for NSAID or acetaminophen during 1999-2002. Outcomes were compared using Cox regression models with time-dependent exposures. RESULTS: Person-years of exposure among non-users of aspirin were: 75,761 to acetaminophen, 42,671 to rofecoxib 65,860 to celecoxib, and 37,495 to NS-NSAIDs. Among users of aspirin, they were: 14,671 to rofecoxib, 22,875 to celecoxib, 9,832 to NS-NSAIDs and 38,048 to acetaminophen. Among non-users of aspirin, the adjusted hazard ratios (95% confidence interval) of hospitalization for AMI/GI vs the acetaminophen (with no aspirin) group were: rofecoxib 1.27 (1.13, 1.42), celecoxib 0.93 (0.83, 1.03), naproxen 1.59 (1.31, 1.93), diclofenac 1.17 (0.99, 1.38) and ibuprofen 1.05 (0.74, 1.51). Among users of aspirin, they were: rofecoxib 1.73 (1.52, 1.98), celecoxib 1.34 (1.19, 1.52), ibuprofen 1.51 (0.95, 2.41), diclofenac 1.69 (1.35, 2.10), naproxen 1.35 (0.97, 1.88) and acetaminophen 1.29 (1.17, 1.42). CONCLUSION: Among non-users of aspirin, naproxen seemed to carry the highest risk for AMI/DISEASE. The AMI/GI toxicity of celecoxib was similar to that of acetaminophen and seemed to be better than those of rofecoxib and NS-NSAIDs. Among users of aspirin, both celecoxib and naproxen seemed to be the least toxic. | NO-RELATIONSHIP |
| Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study. OBJECTIVES: The risk of acute myocardial infarction (AMI) with COX-2 inhibitors may offset their gastrointestinal (GI) benefit compared with non-selective (NS) non-steroidal anti-inflammatory drugs (NSAIDs). We aimed to compare the risks of hospitalization for AMI and DISEASE among elderly patients using COX-2 inhibitors, NS-NSAIDs and acetaminophen. METHODS: We conducted a retrospective cohort study using administrative data of patients > or =65 years of age who filled a prescription for NSAID or acetaminophen during 1999-2002. Outcomes were compared using Cox regression models with time-dependent exposures. RESULTS: Person-years of exposure among non-users of aspirin were: 75,761 to acetaminophen, 42,671 to CHEMICAL 65,860 to celecoxib, and 37,495 to NS-NSAIDs. Among users of aspirin, they were: 14,671 to CHEMICAL, 22,875 to celecoxib, 9,832 to NS-NSAIDs and 38,048 to acetaminophen. Among non-users of aspirin, the adjusted hazard ratios (95% confidence interval) of hospitalization for AMI/GI vs the acetaminophen (with no aspirin) group were: CHEMICAL 1.27 (1.13, 1.42), celecoxib 0.93 (0.83, 1.03), naproxen 1.59 (1.31, 1.93), diclofenac 1.17 (0.99, 1.38) and ibuprofen 1.05 (0.74, 1.51). Among users of aspirin, they were: CHEMICAL 1.73 (1.52, 1.98), celecoxib 1.34 (1.19, 1.52), ibuprofen 1.51 (0.95, 2.41), diclofenac 1.69 (1.35, 2.10), naproxen 1.35 (0.97, 1.88) and acetaminophen 1.29 (1.17, 1.42). CONCLUSION: Among non-users of aspirin, naproxen seemed to carry the highest risk for AMI/DISEASE. The AMI/GI toxicity of celecoxib was similar to that of acetaminophen and seemed to be better than those of CHEMICAL and NS-NSAIDs. Among users of aspirin, both celecoxib and naproxen seemed to be the least toxic. | NO-RELATIONSHIP |
| Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study. OBJECTIVES: The risk of acute myocardial infarction (AMI) with COX-2 inhibitors may offset their gastrointestinal (GI) benefit compared with non-selective (NS) non-steroidal anti-inflammatory drugs (NSAIDs). We aimed to compare the risks of hospitalization for AMI and DISEASE among elderly patients using COX-2 inhibitors, NS-NSAIDs and acetaminophen. METHODS: We conducted a retrospective cohort study using administrative data of patients > or =65 years of age who filled a prescription for NSAID or acetaminophen during 1999-2002. Outcomes were compared using Cox regression models with time-dependent exposures. RESULTS: Person-years of exposure among non-users of aspirin were: 75,761 to acetaminophen, 42,671 to rofecoxib 65,860 to celecoxib, and 37,495 to NS-NSAIDs. Among users of aspirin, they were: 14,671 to rofecoxib, 22,875 to celecoxib, 9,832 to NS-NSAIDs and 38,048 to acetaminophen. Among non-users of aspirin, the adjusted hazard ratios (95% confidence interval) of hospitalization for AMI/GI vs the acetaminophen (with no aspirin) group were: rofecoxib 1.27 (1.13, 1.42), celecoxib 0.93 (0.83, 1.03), CHEMICAL 1.59 (1.31, 1.93), diclofenac 1.17 (0.99, 1.38) and ibuprofen 1.05 (0.74, 1.51). Among users of aspirin, they were: rofecoxib 1.73 (1.52, 1.98), celecoxib 1.34 (1.19, 1.52), ibuprofen 1.51 (0.95, 2.41), diclofenac 1.69 (1.35, 2.10), CHEMICAL 1.35 (0.97, 1.88) and acetaminophen 1.29 (1.17, 1.42). CONCLUSION: Among non-users of aspirin, CHEMICAL seemed to carry the highest risk for AMI/DISEASE. The AMI/GI toxicity of celecoxib was similar to that of acetaminophen and seemed to be better than those of rofecoxib and NS-NSAIDs. Among users of aspirin, both celecoxib and CHEMICAL seemed to be the least toxic. | CHEMICAL-INDUCED-DISEASE |
| Risks and benefits of CHEMICAL vs non-selective NSAIDs: does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study. OBJECTIVES: The risk of DISEASE (DISEASE) with CHEMICAL may offset their gastrointestinal (GI) benefit compared with non-selective (NS) non-steroidal anti-inflammatory drugs (NSAIDs). We aimed to compare the risks of hospitalization for DISEASE and GI bleeding among elderly patients using CHEMICAL, NS-NSAIDs and acetaminophen. METHODS: We conducted a retrospective cohort study using administrative data of patients > or =65 years of age who filled a prescription for NSAID or acetaminophen during 1999-2002. Outcomes were compared using Cox regression models with time-dependent exposures. RESULTS: Person-years of exposure among non-users of aspirin were: 75,761 to acetaminophen, 42,671 to rofecoxib 65,860 to celecoxib, and 37,495 to NS-NSAIDs. Among users of aspirin, they were: 14,671 to rofecoxib, 22,875 to celecoxib, 9,832 to NS-NSAIDs and 38,048 to acetaminophen. Among non-users of aspirin, the adjusted hazard ratios (95% confidence interval) of hospitalization for DISEASE/GI vs the acetaminophen (with no aspirin) group were: rofecoxib 1.27 (1.13, 1.42), celecoxib 0.93 (0.83, 1.03), naproxen 1.59 (1.31, 1.93), diclofenac 1.17 (0.99, 1.38) and ibuprofen 1.05 (0.74, 1.51). Among users of aspirin, they were: rofecoxib 1.73 (1.52, 1.98), celecoxib 1.34 (1.19, 1.52), ibuprofen 1.51 (0.95, 2.41), diclofenac 1.69 (1.35, 2.10), naproxen 1.35 (0.97, 1.88) and acetaminophen 1.29 (1.17, 1.42). CONCLUSION: Among non-users of aspirin, naproxen seemed to carry the highest risk for DISEASE/GI bleeding. The DISEASE/GI toxicity of celecoxib was similar to that of acetaminophen and seemed to be better than those of rofecoxib and NS-NSAIDs. Among users of aspirin, both celecoxib and naproxen seemed to be the least toxic. | CHEMICAL-INDUCED-DISEASE |
| Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study. OBJECTIVES: The risk of DISEASE (DISEASE) with COX-2 inhibitors may offset their gastrointestinal (GI) benefit compared with non-selective (NS) non-steroidal anti-inflammatory drugs (NSAIDs). We aimed to compare the risks of hospitalization for DISEASE and GI bleeding among elderly patients using COX-2 inhibitors, NS-NSAIDs and acetaminophen. METHODS: We conducted a retrospective cohort study using administrative data of patients > or =65 years of age who filled a prescription for NSAID or acetaminophen during 1999-2002. Outcomes were compared using Cox regression models with time-dependent exposures. RESULTS: Person-years of exposure among non-users of aspirin were: 75,761 to acetaminophen, 42,671 to CHEMICAL 65,860 to celecoxib, and 37,495 to NS-NSAIDs. Among users of aspirin, they were: 14,671 to CHEMICAL, 22,875 to celecoxib, 9,832 to NS-NSAIDs and 38,048 to acetaminophen. Among non-users of aspirin, the adjusted hazard ratios (95% confidence interval) of hospitalization for DISEASE/GI vs the acetaminophen (with no aspirin) group were: CHEMICAL 1.27 (1.13, 1.42), celecoxib 0.93 (0.83, 1.03), naproxen 1.59 (1.31, 1.93), diclofenac 1.17 (0.99, 1.38) and ibuprofen 1.05 (0.74, 1.51). Among users of aspirin, they were: CHEMICAL 1.73 (1.52, 1.98), celecoxib 1.34 (1.19, 1.52), ibuprofen 1.51 (0.95, 2.41), diclofenac 1.69 (1.35, 2.10), naproxen 1.35 (0.97, 1.88) and acetaminophen 1.29 (1.17, 1.42). CONCLUSION: Among non-users of aspirin, naproxen seemed to carry the highest risk for DISEASE/GI bleeding. The DISEASE/GI toxicity of celecoxib was similar to that of acetaminophen and seemed to be better than those of CHEMICAL and NS-NSAIDs. Among users of aspirin, both celecoxib and naproxen seemed to be the least toxic. | NO-RELATIONSHIP |
| Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study. OBJECTIVES: The risk of DISEASE (DISEASE) with COX-2 inhibitors may offset their gastrointestinal (GI) benefit compared with non-selective (NS) CHEMICAL (NSAIDs). We aimed to compare the risks of hospitalization for DISEASE and GI bleeding among elderly patients using COX-2 inhibitors, NS-NSAIDs and acetaminophen. METHODS: We conducted a retrospective cohort study using administrative data of patients > or =65 years of age who filled a prescription for NSAID or acetaminophen during 1999-2002. Outcomes were compared using Cox regression models with time-dependent exposures. RESULTS: Person-years of exposure among non-users of aspirin were: 75,761 to acetaminophen, 42,671 to rofecoxib 65,860 to celecoxib, and 37,495 to NS-NSAIDs. Among users of aspirin, they were: 14,671 to rofecoxib, 22,875 to celecoxib, 9,832 to NS-NSAIDs and 38,048 to acetaminophen. Among non-users of aspirin, the adjusted hazard ratios (95% confidence interval) of hospitalization for DISEASE/GI vs the acetaminophen (with no aspirin) group were: rofecoxib 1.27 (1.13, 1.42), celecoxib 0.93 (0.83, 1.03), naproxen 1.59 (1.31, 1.93), diclofenac 1.17 (0.99, 1.38) and ibuprofen 1.05 (0.74, 1.51). Among users of aspirin, they were: rofecoxib 1.73 (1.52, 1.98), celecoxib 1.34 (1.19, 1.52), ibuprofen 1.51 (0.95, 2.41), diclofenac 1.69 (1.35, 2.10), naproxen 1.35 (0.97, 1.88) and acetaminophen 1.29 (1.17, 1.42). CONCLUSION: Among non-users of aspirin, naproxen seemed to carry the highest risk for DISEASE/GI bleeding. The DISEASE/GI toxicity of celecoxib was similar to that of acetaminophen and seemed to be better than those of rofecoxib and NS-NSAIDs. Among users of aspirin, both celecoxib and naproxen seemed to be the least toxic. | CHEMICAL-INDUCED-DISEASE |
| Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study. OBJECTIVES: The risk of acute myocardial infarction (AMI) with COX-2 inhibitors may offset their gastrointestinal (GI) benefit compared with non-selective (NS) non-steroidal anti-inflammatory drugs (NSAIDs). We aimed to compare the risks of hospitalization for AMI and GI bleeding among elderly patients using COX-2 inhibitors, NS-NSAIDs and acetaminophen. METHODS: We conducted a retrospective cohort study using administrative data of patients > or =65 years of age who filled a prescription for NSAID or acetaminophen during 1999-2002. Outcomes were compared using Cox regression models with time-dependent exposures. RESULTS: Person-years of exposure among non-users of aspirin were: 75,761 to acetaminophen, 42,671 to rofecoxib 65,860 to celecoxib, and 37,495 to NS-NSAIDs. Among users of aspirin, they were: 14,671 to rofecoxib, 22,875 to celecoxib, 9,832 to NS-NSAIDs and 38,048 to acetaminophen. Among non-users of aspirin, the adjusted hazard ratios (95% confidence interval) of hospitalization for AMI/GI vs the acetaminophen (with no aspirin) group were: rofecoxib 1.27 (1.13, 1.42), celecoxib 0.93 (0.83, 1.03), naproxen 1.59 (1.31, 1.93), CHEMICAL 1.17 (0.99, 1.38) and ibuprofen 1.05 (0.74, 1.51). Among users of aspirin, they were: rofecoxib 1.73 (1.52, 1.98), celecoxib 1.34 (1.19, 1.52), ibuprofen 1.51 (0.95, 2.41), CHEMICAL 1.69 (1.35, 2.10), naproxen 1.35 (0.97, 1.88) and acetaminophen 1.29 (1.17, 1.42). CONCLUSION: Among non-users of aspirin, naproxen seemed to carry the highest risk for AMI/GI bleeding. The AMI/GI DISEASE of celecoxib was similar to that of acetaminophen and seemed to be better than those of rofecoxib and NS-NSAIDs. Among users of aspirin, both celecoxib and naproxen seemed to be the least toxic. | NO-RELATIONSHIP |
| Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study. OBJECTIVES: The risk of acute myocardial infarction (AMI) with COX-2 inhibitors may offset their gastrointestinal (GI) benefit compared with non-selective (NS) non-steroidal anti-inflammatory drugs (NSAIDs). We aimed to compare the risks of hospitalization for AMI and GI bleeding among elderly patients using COX-2 inhibitors, NS-NSAIDs and CHEMICAL. METHODS: We conducted a retrospective cohort study using administrative data of patients > or =65 years of age who filled a prescription for NSAID or CHEMICAL during 1999-2002. Outcomes were compared using Cox regression models with time-dependent exposures. RESULTS: Person-years of exposure among non-users of aspirin were: 75,761 to CHEMICAL, 42,671 to rofecoxib 65,860 to celecoxib, and 37,495 to NS-NSAIDs. Among users of aspirin, they were: 14,671 to rofecoxib, 22,875 to celecoxib, 9,832 to NS-NSAIDs and 38,048 to CHEMICAL. Among non-users of aspirin, the adjusted hazard ratios (95% confidence interval) of hospitalization for AMI/GI vs the CHEMICAL (with no aspirin) group were: rofecoxib 1.27 (1.13, 1.42), celecoxib 0.93 (0.83, 1.03), naproxen 1.59 (1.31, 1.93), diclofenac 1.17 (0.99, 1.38) and ibuprofen 1.05 (0.74, 1.51). Among users of aspirin, they were: rofecoxib 1.73 (1.52, 1.98), celecoxib 1.34 (1.19, 1.52), ibuprofen 1.51 (0.95, 2.41), diclofenac 1.69 (1.35, 2.10), naproxen 1.35 (0.97, 1.88) and CHEMICAL 1.29 (1.17, 1.42). CONCLUSION: Among non-users of aspirin, naproxen seemed to carry the highest risk for AMI/GI bleeding. The AMI/GI DISEASE of celecoxib was similar to that of CHEMICAL and seemed to be better than those of rofecoxib and NS-NSAIDs. Among users of aspirin, both celecoxib and naproxen seemed to be the least toxic. | CHEMICAL-INDUCED-DISEASE |
| Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study. OBJECTIVES: The risk of acute myocardial infarction (AMI) with COX-2 inhibitors may offset their gastrointestinal (GI) benefit compared with non-selective (NS) non-steroidal anti-inflammatory drugs (NSAIDs). We aimed to compare the risks of hospitalization for AMI and GI bleeding among elderly patients using COX-2 inhibitors, NS-NSAIDs and acetaminophen. METHODS: We conducted a retrospective cohort study using administrative data of patients > or =65 years of age who filled a prescription for NSAID or acetaminophen during 1999-2002. Outcomes were compared using Cox regression models with time-dependent exposures. RESULTS: Person-years of exposure among non-users of CHEMICAL were: 75,761 to acetaminophen, 42,671 to rofecoxib 65,860 to celecoxib, and 37,495 to NS-NSAIDs. Among users of CHEMICAL, they were: 14,671 to rofecoxib, 22,875 to celecoxib, 9,832 to NS-NSAIDs and 38,048 to acetaminophen. Among non-users of CHEMICAL, the adjusted hazard ratios (95% confidence interval) of hospitalization for AMI/GI vs the acetaminophen (with no CHEMICAL) group were: rofecoxib 1.27 (1.13, 1.42), celecoxib 0.93 (0.83, 1.03), naproxen 1.59 (1.31, 1.93), diclofenac 1.17 (0.99, 1.38) and ibuprofen 1.05 (0.74, 1.51). Among users of CHEMICAL, they were: rofecoxib 1.73 (1.52, 1.98), celecoxib 1.34 (1.19, 1.52), ibuprofen 1.51 (0.95, 2.41), diclofenac 1.69 (1.35, 2.10), naproxen 1.35 (0.97, 1.88) and acetaminophen 1.29 (1.17, 1.42). CONCLUSION: Among non-users of CHEMICAL, naproxen seemed to carry the highest risk for AMI/GI bleeding. The AMI/GI DISEASE of celecoxib was similar to that of acetaminophen and seemed to be better than those of rofecoxib and NS-NSAIDs. Among users of CHEMICAL, both celecoxib and naproxen seemed to be the least toxic. | NO-RELATIONSHIP |
| Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study. OBJECTIVES: The risk of acute myocardial infarction (AMI) with COX-2 inhibitors may offset their gastrointestinal (GI) benefit compared with non-selective (NS) non-steroidal anti-inflammatory drugs (NSAIDs). We aimed to compare the risks of hospitalization for AMI and GI bleeding among elderly patients using COX-2 inhibitors, NS-NSAIDs and acetaminophen. METHODS: We conducted a retrospective cohort study using administrative data of patients > or =65 years of age who filled a prescription for NSAID or acetaminophen during 1999-2002. Outcomes were compared using Cox regression models with time-dependent exposures. RESULTS: Person-years of exposure among non-users of aspirin were: 75,761 to acetaminophen, 42,671 to rofecoxib 65,860 to celecoxib, and 37,495 to NS-NSAIDs. Among users of aspirin, they were: 14,671 to rofecoxib, 22,875 to celecoxib, 9,832 to NS-NSAIDs and 38,048 to acetaminophen. Among non-users of aspirin, the adjusted hazard ratios (95% confidence interval) of hospitalization for AMI/GI vs the acetaminophen (with no aspirin) group were: rofecoxib 1.27 (1.13, 1.42), celecoxib 0.93 (0.83, 1.03), naproxen 1.59 (1.31, 1.93), diclofenac 1.17 (0.99, 1.38) and CHEMICAL 1.05 (0.74, 1.51). Among users of aspirin, they were: rofecoxib 1.73 (1.52, 1.98), celecoxib 1.34 (1.19, 1.52), CHEMICAL 1.51 (0.95, 2.41), diclofenac 1.69 (1.35, 2.10), naproxen 1.35 (0.97, 1.88) and acetaminophen 1.29 (1.17, 1.42). CONCLUSION: Among non-users of aspirin, naproxen seemed to carry the highest risk for AMI/GI bleeding. The AMI/GI DISEASE of celecoxib was similar to that of acetaminophen and seemed to be better than those of rofecoxib and NS-NSAIDs. Among users of aspirin, both celecoxib and naproxen seemed to be the least toxic. | NO-RELATIONSHIP |
| Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study. OBJECTIVES: The risk of acute myocardial infarction (AMI) with COX-2 inhibitors may offset their gastrointestinal (GI) benefit compared with non-selective (NS) non-steroidal anti-inflammatory drugs (NSAIDs). We aimed to compare the risks of hospitalization for AMI and GI bleeding among elderly patients using COX-2 inhibitors, NS-NSAIDs and acetaminophen. METHODS: We conducted a retrospective cohort study using administrative data of patients > or =65 years of age who filled a prescription for NSAID or acetaminophen during 1999-2002. Outcomes were compared using Cox regression models with time-dependent exposures. RESULTS: Person-years of exposure among non-users of aspirin were: 75,761 to acetaminophen, 42,671 to rofecoxib 65,860 to CHEMICAL, and 37,495 to NS-NSAIDs. Among users of aspirin, they were: 14,671 to rofecoxib, 22,875 to CHEMICAL, 9,832 to NS-NSAIDs and 38,048 to acetaminophen. Among non-users of aspirin, the adjusted hazard ratios (95% confidence interval) of hospitalization for AMI/GI vs the acetaminophen (with no aspirin) group were: rofecoxib 1.27 (1.13, 1.42), CHEMICAL 0.93 (0.83, 1.03), naproxen 1.59 (1.31, 1.93), diclofenac 1.17 (0.99, 1.38) and ibuprofen 1.05 (0.74, 1.51). Among users of aspirin, they were: rofecoxib 1.73 (1.52, 1.98), CHEMICAL 1.34 (1.19, 1.52), ibuprofen 1.51 (0.95, 2.41), diclofenac 1.69 (1.35, 2.10), naproxen 1.35 (0.97, 1.88) and acetaminophen 1.29 (1.17, 1.42). CONCLUSION: Among non-users of aspirin, naproxen seemed to carry the highest risk for AMI/GI bleeding. The AMI/GI DISEASE of CHEMICAL was similar to that of acetaminophen and seemed to be better than those of rofecoxib and NS-NSAIDs. Among users of aspirin, both CHEMICAL and naproxen seemed to be the least toxic. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (DISEASE) while getting CHEMICAL infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got CHEMICAL infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of CHEMICAL infusion the patient felt palpitation and electrocardiography (ECG) recording showed DISEASE (DISEASE) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and potassium aspartate tablet. CHEMICAL infusion was discontinued and changed with sulfate CHEMICAL tablets. Three hours later the patient felt better, the frequency of DISEASE reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. CHEMICAL, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple DISEASE. Administration of parenteral CHEMICAL must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases. | CHEMICAL-INDUCED-DISEASE |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in CHEMICAL 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, DISEASE. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in CHEMICAL 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, CHEMICAL 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--DISEASE, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, CHEMICAL level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with DISEASE who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, DISEASE. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with DISEASE and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like CHEMICAL, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with DISEASE who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, DISEASE. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with DISEASE and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and CHEMICAL tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, DISEASE, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in CHEMICAL 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in CHEMICAL 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt DISEASE and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and CHEMICAL tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total CHEMICAL 8.25 mg/dL, conjugated CHEMICAL 4.36 mg/dL, unconjugated CHEMICAL 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have DISEASE or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and CHEMICAL tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have DISEASE or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--DISEASE, positive U wave. He was treated with CHEMICAL 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, CHEMICAL 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, DISEASE, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, CHEMICAL level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and CHEMICAL tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (DISEASE) which frequently occurs due to vomiting and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total CHEMICAL 8.25 mg/dL, conjugated CHEMICAL 4.36 mg/dL, unconjugated CHEMICAL 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in DISEASE cases. | NO-RELATIONSHIP |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in CHEMICAL 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, DISEASE, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in CHEMICAL 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with CHEMICAL 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (DISEASE) which frequently occurs due to vomiting and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| Quinine-induced DISEASE in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with DISEASE (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in CHEMICAL 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in CHEMICAL 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-DISEASE property, although it also pro-DISEASE that can cause various DISEASE, including severe DISEASE such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-DISEASE effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with CHEMICAL 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in DISEASE cases. | NO-RELATIONSHIP |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high DISEASE, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, CHEMICAL 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, CHEMICAL level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, DISEASE, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total CHEMICAL 8.25 mg/dL, conjugated CHEMICAL 4.36 mg/dL, unconjugated CHEMICAL 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had DISEASE, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to DISEASE and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| Quinine-induced DISEASE in a patient with severe malaria. It was reported that there was a case of severe malaria patient with jaundice who presented with DISEASE (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, CHEMICAL 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, CHEMICAL level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-DISEASE property, although it also pro-DISEASE that can cause various DISEASE, including severe DISEASE such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-DISEASE effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| Quinine-induced arrhythmia in a patient with severe malaria. It was reported that there was a case of severe malaria patient with DISEASE who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, DISEASE. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with DISEASE and got quinine infusion in CHEMICAL 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in CHEMICAL 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases. | NO-RELATIONSHIP |
| CHEMICAL-related DISEASE and utility of zinc acetate in a Wilson disease patient with hepatic presentation, anxiety and SPECT abnormalities. Wilson's disease is an autosomal recessive disorder of hepatic copper metabolism with consequent copper accumulation and toxicity in many tissues and consequent hepatic, neurologic and psychiatric disorders. We report a case of Wilson's disease with chronic liver disease; moreover, in our patient, presenting also with high levels of state anxiety without depression, 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, CHEMICAL was interrupted after the appearance of a DISEASE, and zinc acetate permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with zinc acetate represented an effective treatment for a Wilson's disease patient in which CHEMICAL-related side effects appeared. The safety of the zinc acetate allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of Wilson's disease. Since most of Wilson's disease CHEMICAL-treated patients do not seem to develop this skin lesion, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of Wilson's disease therapy, and in particular to differentiate specific therapies for different Wilson's disease phenotypes. | CHEMICAL-INDUCED-DISEASE |
| Penicillamine-related lichenoid dermatitis and utility of CHEMICAL in a Wilson disease patient with hepatic presentation, DISEASE and SPECT abnormalities. Wilson's disease is an autosomal recessive disorder of hepatic copper metabolism with consequent copper accumulation and toxicity in many tissues and consequent hepatic, neurologic and psychiatric disorders. We report a case of Wilson's disease with chronic liver disease; moreover, in our patient, presenting also with high levels of state DISEASE without depression, 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, penicillamine was interrupted after the appearance of a lichenoid dermatitis, and CHEMICAL permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with CHEMICAL represented an effective treatment for a Wilson's disease patient in which penicillamine-related side effects appeared. The safety of the CHEMICAL allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of Wilson's disease. Since most of Wilson's disease penicillamine-treated patients do not seem to develop this skin lesion, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of Wilson's disease therapy, and in particular to differentiate specific therapies for different Wilson's disease phenotypes. | NO-RELATIONSHIP |
| Penicillamine-related lichenoid dermatitis and utility of zinc acetate in a Wilson disease patient with hepatic presentation, anxiety and SPECT abnormalities. Wilson's disease is an autosomal recessive disorder of hepatic CHEMICAL metabolism with consequent CHEMICAL accumulation and toxicity in many tissues and consequent DISEASE. We report a case of Wilson's disease with chronic liver disease; moreover, in our patient, presenting also with high levels of state anxiety without depression, 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, penicillamine was interrupted after the appearance of a lichenoid dermatitis, and zinc acetate permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with zinc acetate represented an effective treatment for a Wilson's disease patient in which penicillamine-related side effects appeared. The safety of the zinc acetate allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of Wilson's disease. Since most of Wilson's disease penicillamine-treated patients do not seem to develop this skin lesion, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of Wilson's disease therapy, and in particular to differentiate specific therapies for different Wilson's disease phenotypes. | NO-RELATIONSHIP |
| Penicillamine-related lichenoid dermatitis and utility of CHEMICAL in a Wilson disease patient with hepatic presentation, anxiety and SPECT abnormalities. Wilson's disease is an autosomal recessive disorder of hepatic copper metabolism with consequent copper accumulation and DISEASE in many tissues and consequent hepatic, neurologic and psychiatric disorders. We report a case of Wilson's disease with chronic liver disease; moreover, in our patient, presenting also with high levels of state anxiety without depression, 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, penicillamine was interrupted after the appearance of a lichenoid dermatitis, and CHEMICAL permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with CHEMICAL represented an effective treatment for a Wilson's disease patient in which penicillamine-related side effects appeared. The safety of the CHEMICAL allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of Wilson's disease. Since most of Wilson's disease penicillamine-treated patients do not seem to develop this skin lesion, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of Wilson's disease therapy, and in particular to differentiate specific therapies for different Wilson's disease phenotypes. | NO-RELATIONSHIP |
| Penicillamine-related lichenoid dermatitis and utility of zinc acetate in a DISEASE patient with hepatic presentation, anxiety and SPECT abnormalities. DISEASE is an autosomal recessive disorder of hepatic CHEMICAL metabolism with consequent CHEMICAL accumulation and toxicity in many tissues and consequent hepatic, neurologic and psychiatric disorders. We report a case of DISEASE with chronic liver disease; moreover, in our patient, presenting also with high levels of state anxiety without depression, 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, penicillamine was interrupted after the appearance of a lichenoid dermatitis, and zinc acetate permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with zinc acetate represented an effective treatment for a DISEASE patient in which penicillamine-related side effects appeared. The safety of the zinc acetate allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of DISEASE. Since most of DISEASE penicillamine-treated patients do not seem to develop this skin lesion, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of DISEASE therapy, and in particular to differentiate specific therapies for different DISEASE phenotypes. | NO-RELATIONSHIP |
| Penicillamine-related lichenoid dermatitis and utility of zinc acetate in a Wilson disease patient with hepatic presentation, anxiety and SPECT abnormalities. Wilson's disease is an autosomal recessive disorder of hepatic CHEMICAL metabolism with consequent CHEMICAL accumulation and toxicity in many tissues and consequent hepatic, neurologic and psychiatric disorders. We report a case of Wilson's disease with DISEASE; moreover, in our patient, presenting also with high levels of state anxiety without depression, 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, penicillamine was interrupted after the appearance of a lichenoid dermatitis, and zinc acetate permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with zinc acetate represented an effective treatment for a Wilson's disease patient in which penicillamine-related side effects appeared. The safety of the zinc acetate allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of Wilson's disease. Since most of Wilson's disease penicillamine-treated patients do not seem to develop this skin lesion, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of Wilson's disease therapy, and in particular to differentiate specific therapies for different Wilson's disease phenotypes. | NO-RELATIONSHIP |
| Penicillamine-related lichenoid dermatitis and utility of CHEMICAL in a DISEASE patient with hepatic presentation, anxiety and SPECT abnormalities. DISEASE is an autosomal recessive disorder of hepatic copper metabolism with consequent copper accumulation and toxicity in many tissues and consequent hepatic, neurologic and psychiatric disorders. We report a case of DISEASE with chronic liver disease; moreover, in our patient, presenting also with high levels of state anxiety without depression, 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, penicillamine was interrupted after the appearance of a lichenoid dermatitis, and CHEMICAL permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with CHEMICAL represented an effective treatment for a DISEASE patient in which penicillamine-related side effects appeared. The safety of the CHEMICAL allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of DISEASE. Since most of DISEASE penicillamine-treated patients do not seem to develop this skin lesion, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of DISEASE therapy, and in particular to differentiate specific therapies for different DISEASE phenotypes. | NO-RELATIONSHIP |
| Penicillamine-related lichenoid dermatitis and utility of zinc acetate in a Wilson disease patient with hepatic presentation, anxiety and SPECT abnormalities. Wilson's disease is an autosomal recessive disorder of hepatic CHEMICAL metabolism with consequent CHEMICAL accumulation and toxicity in many tissues and consequent hepatic, neurologic and psychiatric disorders. We report a case of Wilson's disease with chronic liver disease; moreover, in our patient, presenting also with high levels of state anxiety without DISEASE, 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, penicillamine was interrupted after the appearance of a lichenoid dermatitis, and zinc acetate permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with zinc acetate represented an effective treatment for a Wilson's disease patient in which penicillamine-related side effects appeared. The safety of the zinc acetate allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of Wilson's disease. Since most of Wilson's disease penicillamine-treated patients do not seem to develop this skin lesion, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of Wilson's disease therapy, and in particular to differentiate specific therapies for different Wilson's disease phenotypes. | NO-RELATIONSHIP |
| Penicillamine-related lichenoid dermatitis and utility of zinc acetate in a Wilson disease patient with hepatic presentation, anxiety and SPECT abnormalities. Wilson's disease is an autosomal recessive disorder of hepatic CHEMICAL metabolism with consequent CHEMICAL accumulation and toxicity in many tissues and consequent hepatic, neurologic and psychiatric disorders. We report a case of Wilson's disease with chronic liver disease; moreover, in our patient, presenting also with high levels of state anxiety without depression, 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, penicillamine was interrupted after the appearance of a lichenoid dermatitis, and zinc acetate permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with zinc acetate represented an effective treatment for a Wilson's disease patient in which penicillamine-related side effects appeared. The safety of the zinc acetate allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of Wilson's disease. Since most of Wilson's disease penicillamine-treated patients do not seem to develop this DISEASE, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of Wilson's disease therapy, and in particular to differentiate specific therapies for different Wilson's disease phenotypes. | NO-RELATIONSHIP |
| Penicillamine-related lichenoid dermatitis and utility of CHEMICAL in a Wilson disease patient with hepatic presentation, anxiety and SPECT abnormalities. Wilson's disease is an autosomal recessive disorder of hepatic copper metabolism with consequent copper accumulation and toxicity in many tissues and consequent DISEASE. We report a case of Wilson's disease with chronic liver disease; moreover, in our patient, presenting also with high levels of state anxiety without depression, 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, penicillamine was interrupted after the appearance of a lichenoid dermatitis, and CHEMICAL permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with CHEMICAL represented an effective treatment for a Wilson's disease patient in which penicillamine-related side effects appeared. The safety of the CHEMICAL allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of Wilson's disease. Since most of Wilson's disease penicillamine-treated patients do not seem to develop this skin lesion, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of Wilson's disease therapy, and in particular to differentiate specific therapies for different Wilson's disease phenotypes. | NO-RELATIONSHIP |
| Penicillamine-related lichenoid dermatitis and utility of zinc acetate in a Wilson disease patient with hepatic presentation, anxiety and SPECT abnormalities. Wilson's disease is an autosomal recessive disorder of hepatic CHEMICAL metabolism with consequent CHEMICAL accumulation and DISEASE in many tissues and consequent hepatic, neurologic and psychiatric disorders. We report a case of Wilson's disease with chronic liver disease; moreover, in our patient, presenting also with high levels of state anxiety without depression, 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, penicillamine was interrupted after the appearance of a lichenoid dermatitis, and zinc acetate permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with zinc acetate represented an effective treatment for a Wilson's disease patient in which penicillamine-related side effects appeared. The safety of the zinc acetate allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of Wilson's disease. Since most of Wilson's disease penicillamine-treated patients do not seem to develop this skin lesion, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of Wilson's disease therapy, and in particular to differentiate specific therapies for different Wilson's disease phenotypes. | NO-RELATIONSHIP |
| Penicillamine-related lichenoid dermatitis and utility of CHEMICAL in a Wilson disease patient with hepatic presentation, anxiety and SPECT abnormalities. Wilson's disease is an autosomal recessive disorder of hepatic copper metabolism with consequent copper accumulation and toxicity in many tissues and consequent hepatic, neurologic and psychiatric disorders. We report a case of Wilson's disease with chronic liver disease; moreover, in our patient, presenting also with high levels of state anxiety without DISEASE, 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, penicillamine was interrupted after the appearance of a lichenoid dermatitis, and CHEMICAL permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with CHEMICAL represented an effective treatment for a Wilson's disease patient in which penicillamine-related side effects appeared. The safety of the CHEMICAL allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of Wilson's disease. Since most of Wilson's disease penicillamine-treated patients do not seem to develop this skin lesion, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of Wilson's disease therapy, and in particular to differentiate specific therapies for different Wilson's disease phenotypes. | NO-RELATIONSHIP |
| Penicillamine-related lichenoid dermatitis and utility of CHEMICAL in a Wilson disease patient with hepatic presentation, anxiety and SPECT abnormalities. Wilson's disease is an autosomal recessive disorder of hepatic copper metabolism with consequent copper accumulation and toxicity in many tissues and consequent hepatic, neurologic and psychiatric disorders. We report a case of Wilson's disease with DISEASE; moreover, in our patient, presenting also with high levels of state anxiety without depression, 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, penicillamine was interrupted after the appearance of a lichenoid dermatitis, and CHEMICAL permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with CHEMICAL represented an effective treatment for a Wilson's disease patient in which penicillamine-related side effects appeared. The safety of the CHEMICAL allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of Wilson's disease. Since most of Wilson's disease penicillamine-treated patients do not seem to develop this skin lesion, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of Wilson's disease therapy, and in particular to differentiate specific therapies for different Wilson's disease phenotypes. | NO-RELATIONSHIP |
| Penicillamine-related lichenoid dermatitis and utility of zinc acetate in a Wilson disease patient with hepatic presentation, DISEASE and SPECT abnormalities. Wilson's disease is an autosomal recessive disorder of hepatic CHEMICAL metabolism with consequent CHEMICAL accumulation and toxicity in many tissues and consequent hepatic, neurologic and psychiatric disorders. We report a case of Wilson's disease with chronic liver disease; moreover, in our patient, presenting also with high levels of state DISEASE without depression, 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, penicillamine was interrupted after the appearance of a lichenoid dermatitis, and zinc acetate permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with zinc acetate represented an effective treatment for a Wilson's disease patient in which penicillamine-related side effects appeared. The safety of the zinc acetate allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of Wilson's disease. Since most of Wilson's disease penicillamine-treated patients do not seem to develop this skin lesion, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of Wilson's disease therapy, and in particular to differentiate specific therapies for different Wilson's disease phenotypes. | NO-RELATIONSHIP |
| Penicillamine-related lichenoid dermatitis and utility of CHEMICAL in a Wilson disease patient with hepatic presentation, anxiety and SPECT abnormalities. Wilson's disease is an autosomal recessive disorder of hepatic copper metabolism with consequent copper accumulation and toxicity in many tissues and consequent hepatic, neurologic and psychiatric disorders. We report a case of Wilson's disease with chronic liver disease; moreover, in our patient, presenting also with high levels of state anxiety without depression, 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, penicillamine was interrupted after the appearance of a lichenoid dermatitis, and CHEMICAL permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with CHEMICAL represented an effective treatment for a Wilson's disease patient in which penicillamine-related side effects appeared. The safety of the CHEMICAL allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of Wilson's disease. Since most of Wilson's disease penicillamine-treated patients do not seem to develop this DISEASE, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of Wilson's disease therapy, and in particular to differentiate specific therapies for different Wilson's disease phenotypes. | NO-RELATIONSHIP |
| A dramatic DISEASE following prehospital GTN administration. A male in his sixties with no history of cardiac chest pain awoke with chest pain following an afternoon sleep. The patient did not self medicate. The patient's observations were within normal limits, he was administered CHEMICAL via a face mask and glyceryl trinitrate (GTN). Several minutes after the GTN the patient experienced a sudden DISEASE and heart rate, this was rectified by atropine sulphate and a fluid challenge. There was no further deterioration in the patient's condition during transport to hospital. There are very few documented case like this in the prehospital scientific literature. The cause appears to be the Bezold-Jarish reflex, stimulation of the ventricular walls which in turn decreases sympathetic outflow from the vasomotor centre. Prehospital care providers who are managing any patient with a syncopal episode that fails to recover within a reasonable time frame should consider the Bezold-Jarisch reflex as the cause and manage the patient accordingly. | CHEMICAL-INDUCED-DISEASE |
| A dramatic DISEASE following prehospital CHEMICAL administration. A male in his sixties with no history of cardiac chest pain awoke with chest pain following an afternoon sleep. The patient did not self medicate. The patient's observations were within normal limits, he was administered oxygen via a face mask and CHEMICAL (CHEMICAL). Several minutes after the CHEMICAL the patient experienced a sudden DISEASE and heart rate, this was rectified by atropine sulphate and a fluid challenge. There was no further deterioration in the patient's condition during transport to hospital. There are very few documented case like this in the prehospital scientific literature. The cause appears to be the Bezold-Jarish reflex, stimulation of the ventricular walls which in turn decreases sympathetic outflow from the vasomotor centre. Prehospital care providers who are managing any patient with a syncopal episode that fails to recover within a reasonable time frame should consider the Bezold-Jarisch reflex as the cause and manage the patient accordingly. | CHEMICAL-INDUCED-DISEASE |
| A dramatic drop in blood pressure following prehospital GTN administration. A male in his sixties with no history of cardiac chest pain awoke with chest pain following an afternoon sleep. The patient did not self medicate. The patient's observations were within normal limits, he was administered oxygen via a face mask and glyceryl trinitrate (GTN). Several minutes after the GTN the patient experienced a sudden drop in blood pressure and heart rate, this was rectified by CHEMICAL and a fluid challenge. There was no further deterioration in the patient's condition during transport to hospital. There are very few documented case like this in the prehospital scientific literature. The cause appears to be the Bezold-Jarish reflex, stimulation of the ventricular walls which in turn decreases sympathetic outflow from the vasomotor centre. Prehospital care providers who are managing any patient with a DISEASE that fails to recover within a reasonable time frame should consider the Bezold-Jarisch reflex as the cause and manage the patient accordingly. | NO-RELATIONSHIP |
| A dramatic drop in blood pressure following prehospital GTN administration. A male in his sixties with no history of cardiac DISEASE awoke with DISEASE following an afternoon sleep. The patient did not self medicate. The patient's observations were within normal limits, he was administered oxygen via a face mask and glyceryl trinitrate (GTN). Several minutes after the GTN the patient experienced a sudden drop in blood pressure and heart rate, this was rectified by CHEMICAL and a fluid challenge. There was no further deterioration in the patient's condition during transport to hospital. There are very few documented case like this in the prehospital scientific literature. The cause appears to be the Bezold-Jarish reflex, stimulation of the ventricular walls which in turn decreases sympathetic outflow from the vasomotor centre. Prehospital care providers who are managing any patient with a syncopal episode that fails to recover within a reasonable time frame should consider the Bezold-Jarisch reflex as the cause and manage the patient accordingly. | NO-RELATIONSHIP |
| Acute encephalopathy and DISEASE after multiagent chemotherapy including PEG-asparaginase and intrathecal CHEMICAL for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, incontinence, visual hallucinations, and right-sided weakness with diffuse DISEASE on magnetic resonance angiography after the administration of intrathecal CHEMICAL. Vincristine, dexamethasone, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and DISEASE after multiagent chemotherapy including PEG-asparaginase and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, incontinence, visual hallucinations, and right-sided weakness with diffuse DISEASE on magnetic resonance angiography after the administration of intrathecal cytarabine. CHEMICAL, dexamethasone, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including PEG-asparaginase and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, incontinence, visual hallucinations, and right-sided DISEASE with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal cytarabine. CHEMICAL, dexamethasone, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including PEG-asparaginase and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, incontinence, visual hallucinations, and right-sided DISEASE with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal cytarabine. Vincristine, CHEMICAL, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including PEG-asparaginase and intrathecal CHEMICAL for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, DISEASE, incontinence, visual hallucinations, and right-sided weakness with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal CHEMICAL. Vincristine, dexamethasone, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including CHEMICAL and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, incontinence, DISEASE, and right-sided weakness with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal cytarabine. Vincristine, dexamethasone, and CHEMICAL were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including PEG-asparaginase and intrathecal CHEMICAL for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, incontinence, DISEASE, and right-sided weakness with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal CHEMICAL. Vincristine, dexamethasone, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including PEG-asparaginase and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, DISEASE, incontinence, visual hallucinations, and right-sided weakness with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal cytarabine. Vincristine, CHEMICAL, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including PEG-asparaginase and intrathecal CHEMICAL for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, DISEASE, visual hallucinations, and right-sided weakness with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal CHEMICAL. Vincristine, dexamethasone, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including CHEMICAL and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, incontinence, visual hallucinations, and right-sided DISEASE with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal cytarabine. Vincristine, dexamethasone, and CHEMICAL were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including CHEMICAL and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, DISEASE, visual hallucinations, and right-sided weakness with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal cytarabine. Vincristine, dexamethasone, and CHEMICAL were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including PEG-asparaginase and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, DISEASE, visual hallucinations, and right-sided weakness with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal cytarabine. Vincristine, CHEMICAL, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including PEG-asparaginase and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, DISEASE, incontinence, visual hallucinations, and right-sided weakness with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal cytarabine. CHEMICAL, dexamethasone, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including PEG-asparaginase and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, incontinence, DISEASE, and right-sided weakness with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal cytarabine. CHEMICAL, dexamethasone, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including PEG-asparaginase and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, incontinence, DISEASE, and right-sided weakness with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal cytarabine. Vincristine, CHEMICAL, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including PEG-asparaginase and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, DISEASE, visual hallucinations, and right-sided weakness with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal cytarabine. CHEMICAL, dexamethasone, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including PEG-asparaginase and intrathecal CHEMICAL for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, incontinence, visual hallucinations, and right-sided DISEASE with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal CHEMICAL. Vincristine, dexamethasone, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including CHEMICAL and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, DISEASE, incontinence, visual hallucinations, and right-sided weakness with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal cytarabine. Vincristine, dexamethasone, and CHEMICAL were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and DISEASE after multiagent chemotherapy including CHEMICAL and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, incontinence, visual hallucinations, and right-sided weakness with diffuse DISEASE on magnetic resonance angiography after the administration of intrathecal cytarabine. Vincristine, dexamethasone, and CHEMICAL were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Acute encephalopathy and DISEASE after multiagent chemotherapy including PEG-asparaginase and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia. A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, incontinence, visual hallucinations, and right-sided weakness with diffuse DISEASE on magnetic resonance angiography after the administration of intrathecal cytarabine. Vincristine, CHEMICAL, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later. | CHEMICAL-INDUCED-DISEASE |
| Comparison of valsartan/CHEMICAL combination therapy at doses up to 320/25 mg versus monotherapy: a double-blind, placebo-controlled study followed by long-term combination therapy in hypertensive adults. BACKGROUND: One third of patients treated for hypertension attain adequate blood pressure (BP) control, and multidrug regimens are often required. Given the lifelong nature of hypertension, there is a need to evaluate the long-term efficacy and tolerability of higher doses of combination anti-hypertensive therapies. OBJECTIVE: This study investigated the efficacy and tolerability of valsartan (VAL) or CHEMICAL (CHEMICAL)-monotherapy and higher-dose combinations in patients with essential hypertension. METHODS: The first part of this study was an 8-week, multicenter, randomized, double-blind, placebo controlled, parallel-group trial. Patients with essential hypertension (mean sitting diastolic BP [MSDBP], > or =95 mm Hg and <110 mm Hg) were randomized to 1 of 8 treatment groups: VAL 160 or 320 mg; CHEMICAL 12.5 or 25 mg; VAL/CHEMICAL 160/12.5, 320/12.5, or 320/25 mg; or placebo. Mean changes in MSDBP and mean sitting systolic BP (MSSBP) were analyzed at the 8-week core study end point. VAL/CHEMICAL 320/12.5 and 320/25 mg were further investigated in a 54-week, open-label extension. Response was defined as MSDBP <90 mm Hg or a > or =10 mm Hg decrease compared to baseline. Control was defined as MSDBP <90 mm Hg compared with baseline. Tolerability was assessed by monitoring adverse events at randomization and all subsequent study visits and regular evaluation of hematology and blood chemistry. RESULTS: A total of 1346 patients were randomized into the 8-week core study (734 men, 612 women; 924 white, 291 black, 23 Asian, 108 other; mean age, 52.7 years; mean weight, 92.6 kg). All active treatments were associated with significantly reduced MSSBP and MSDBP during the core 8-week study, with each monotherapy significantly contributing to the overall effect of combination therapy (VAL and CHEMICAL, P < 0.001). Each combination was associated with significantly greater reductions in MSSBP and MSDBP compared with the monotherapies and placebo (all, P < 0.001). The mean reduction in MSSBP/MSDBP with VAL/CHEMICAL 320/25 mg was 24.7/16.6 mm Hg, compared with 5.9/7.0 mm Hg with placebo. The reduction in MSSBP was significantly greater with VAL/CHEMICAL 320/25 mg compared with VAL/CHEMICAL 160/12.5 mg (P < 0.002). Rates of response and BP control were significantly higher in the groups that received combination treatment compared with those that received monotherapy. The incidence of DISEASE was lower with VAL/CHEMICAL combinations (1.8%-6.1%) than with CHEMICAL monotherapies (7.1%-13.3%). The majority of adverse events in the core study were of mild to moderate severity. The efficacy and tolerability of VAL/CHEMICAL combinations were maintained during the extension (797 patients). CONCLUSIONS: In this study population, combination therapies with VAL/CHEMICAL were associated with significantly greater BP reductions compared with either monotherapy, were well tolerated, and were associated with less DISEASE than CHEMICAL alone. | CHEMICAL-INDUCED-DISEASE |
| Comparison of CHEMICAL/hydrochlorothiazide combination therapy at doses up to 320/25 mg versus monotherapy: a double-blind, placebo-controlled study followed by long-term combination therapy in hypertensive adults. BACKGROUND: One third of patients treated for hypertension attain adequate blood pressure (BP) control, and multidrug regimens are often required. Given the lifelong nature of hypertension, there is a need to evaluate the long-term efficacy and tolerability of higher doses of combination anti-hypertensive therapies. OBJECTIVE: This study investigated the efficacy and tolerability of CHEMICAL (CHEMICAL) or hydrochlorothiazide (HCTZ)-monotherapy and higher-dose combinations in patients with DISEASE. METHODS: The first part of this study was an 8-week, multicenter, randomized, double-blind, placebo controlled, parallel-group trial. Patients with DISEASE (mean sitting diastolic BP [MSDBP], > or =95 mm Hg and <110 mm Hg) were randomized to 1 of 8 treatment groups: CHEMICAL 160 or 320 mg; HCTZ 12.5 or 25 mg; CHEMICAL/HCTZ 160/12.5, 320/12.5, or 320/25 mg; or placebo. Mean changes in MSDBP and mean sitting systolic BP (MSSBP) were analyzed at the 8-week core study end point. CHEMICAL/HCTZ 320/12.5 and 320/25 mg were further investigated in a 54-week, open-label extension. Response was defined as MSDBP <90 mm Hg or a > or =10 mm Hg decrease compared to baseline. Control was defined as MSDBP <90 mm Hg compared with baseline. Tolerability was assessed by monitoring adverse events at randomization and all subsequent study visits and regular evaluation of hematology and blood chemistry. RESULTS: A total of 1346 patients were randomized into the 8-week core study (734 men, 612 women; 924 white, 291 black, 23 Asian, 108 other; mean age, 52.7 years; mean weight, 92.6 kg). All active treatments were associated with significantly reduced MSSBP and MSDBP during the core 8-week study, with each monotherapy significantly contributing to the overall effect of combination therapy (CHEMICAL and HCTZ, P < 0.001). Each combination was associated with significantly greater reductions in MSSBP and MSDBP compared with the monotherapies and placebo (all, P < 0.001). The mean reduction in MSSBP/MSDBP with CHEMICAL/HCTZ 320/25 mg was 24.7/16.6 mm Hg, compared with 5.9/7.0 mm Hg with placebo. The reduction in MSSBP was significantly greater with CHEMICAL/HCTZ 320/25 mg compared with CHEMICAL/HCTZ 160/12.5 mg (P < 0.002). Rates of response and BP control were significantly higher in the groups that received combination treatment compared with those that received monotherapy. The incidence of hypokalemia was lower with CHEMICAL/HCTZ combinations (1.8%-6.1%) than with HCTZ monotherapies (7.1%-13.3%). The majority of adverse events in the core study were of mild to moderate severity. The efficacy and tolerability of CHEMICAL/HCTZ combinations were maintained during the extension (797 patients). CONCLUSIONS: In this study population, combination therapies with CHEMICAL/HCTZ were associated with significantly greater BP reductions compared with either monotherapy, were well tolerated, and were associated with less hypokalemia than HCTZ alone. | CHEMICAL-INDUCED-DISEASE |
| Comparison of CHEMICAL/hydrochlorothiazide combination therapy at doses up to 320/25 mg versus monotherapy: a double-blind, placebo-controlled study followed by long-term combination therapy in DISEASE adults. BACKGROUND: One third of patients treated for DISEASE attain adequate blood pressure (BP) control, and multidrug regimens are often required. Given the lifelong nature of DISEASE, there is a need to evaluate the long-term efficacy and tolerability of higher doses of combination anti-DISEASE therapies. OBJECTIVE: This study investigated the efficacy and tolerability of CHEMICAL (CHEMICAL) or hydrochlorothiazide (HCTZ)-monotherapy and higher-dose combinations in patients with essential hypertension. METHODS: The first part of this study was an 8-week, multicenter, randomized, double-blind, placebo controlled, parallel-group trial. Patients with essential hypertension (mean sitting diastolic BP [MSDBP], > or =95 mm Hg and <110 mm Hg) were randomized to 1 of 8 treatment groups: CHEMICAL 160 or 320 mg; HCTZ 12.5 or 25 mg; CHEMICAL/HCTZ 160/12.5, 320/12.5, or 320/25 mg; or placebo. Mean changes in MSDBP and mean sitting systolic BP (MSSBP) were analyzed at the 8-week core study end point. CHEMICAL/HCTZ 320/12.5 and 320/25 mg were further investigated in a 54-week, open-label extension. Response was defined as MSDBP <90 mm Hg or a > or =10 mm Hg decrease compared to baseline. Control was defined as MSDBP <90 mm Hg compared with baseline. Tolerability was assessed by monitoring adverse events at randomization and all subsequent study visits and regular evaluation of hematology and blood chemistry. RESULTS: A total of 1346 patients were randomized into the 8-week core study (734 men, 612 women; 924 white, 291 black, 23 Asian, 108 other; mean age, 52.7 years; mean weight, 92.6 kg). All active treatments were associated with significantly reduced MSSBP and MSDBP during the core 8-week study, with each monotherapy significantly contributing to the overall effect of combination therapy (CHEMICAL and HCTZ, P < 0.001). Each combination was associated with significantly greater reductions in MSSBP and MSDBP compared with the monotherapies and placebo (all, P < 0.001). The mean reduction in MSSBP/MSDBP with CHEMICAL/HCTZ 320/25 mg was 24.7/16.6 mm Hg, compared with 5.9/7.0 mm Hg with placebo. The reduction in MSSBP was significantly greater with CHEMICAL/HCTZ 320/25 mg compared with CHEMICAL/HCTZ 160/12.5 mg (P < 0.002). Rates of response and BP control were significantly higher in the groups that received combination treatment compared with those that received monotherapy. The incidence of hypokalemia was lower with CHEMICAL/HCTZ combinations (1.8%-6.1%) than with HCTZ monotherapies (7.1%-13.3%). The majority of adverse events in the core study were of mild to moderate severity. The efficacy and tolerability of CHEMICAL/HCTZ combinations were maintained during the extension (797 patients). CONCLUSIONS: In this study population, combination therapies with CHEMICAL/HCTZ were associated with significantly greater BP reductions compared with either monotherapy, were well tolerated, and were associated with less hypokalemia than HCTZ alone. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL chelation improves learning, attention, and arousal regulation in lead-exposed rats but produces lasting DISEASE in the absence of lead exposure. BACKGROUND: There is growing pressure for clinicians to prescribe chelation therapy at only slightly elevated blood lead levels. However, very few studies have evaluated whether chelation improves cognitive outcomes in Pb-exposed children, or whether these agents have adverse effects that may affect brain development in the absence of Pb exposure. OBJECTIVES: The present study was designed to answer these questions, using a rodent model of early childhood Pb exposure and treatment with CHEMICAL, a widely used chelating agent for the treatment of Pb poisoning. RESULTS: Pb exposure produced lasting impairments in learning, attention, inhibitory control, and arousal regulation, paralleling the areas of dysfunction seen in Pb-exposed children. CHEMICAL treatment of the Pb-exposed rats significantly improved learning, attention, and arousal regulation, although the efficacy of the treatment varied as a function of the Pb exposure level and the specific functional deficit. In contrast, CHEMICAL treatment of rats not previously exposed to Pb produced lasting and pervasive cognitive and affective dysfunction comparable in magnitude to that produced by the higher Pb exposure regimen. CONCLUSIONS: These are the first data, to our knowledge, to show that treatment with any chelating agent can alleviate DISEASE due to Pb exposure. These findings suggest that it may be possible to identify a CHEMICAL treatment protocol that improves cognitive outcomes in Pb-exposed children. However, they also suggest that CHEMICAL treatment should be strongly discouraged for children who do not have elevated tissue levels of Pb or other heavy metals. | NO-RELATIONSHIP |
| CHEMICAL challenge test in DISEASE and depression with DISEASE. Our aim was to observe if patients with DISEASE (DISEASE) and patients with major depression with DISEASE (MDP) (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) respond in a similar way to the induction of DISEASE by an oral CHEMICAL challenge test. We randomly selected 29 patients with DISEASE, 27 with MDP, 25 with major depression without DISEASE (MD), and 28 healthy volunteers. The patients had no psychotropic drug for at least a 4-week period. In a randomized double-blind experiment performed in 2 occasions 7 days apart, 480 mg CHEMICAL and a CHEMICAL-free (placebo) solution were administered in a coffee form and anxiety scales were applied before and after each test. A total of 58.6% (n = 17) of patients with DISEASE, 44.4% (n = 12) of patients with MDP, 12.0% (n = 3) of patients with MD, and 7.1% (n= 2) of control subjects had a DISEASE after the 480-mg CHEMICAL challenge test (chi(2)(3) = 16.22, P = .001). The patients with DISEASE and MDP were more sensitive to CHEMICAL than were patients with MD and healthy volunteers. No DISEASE was observed after the CHEMICAL-free solution intake. The patients with MD had a lower heart rate response to the test than all the other groups (2-way analysis of variance, group by time interaction with Greenhouse-Geisser correction: F(3,762) = 2.85, P = .026). Our data suggest that there is an association between DISEASE, no matter if associated with DISEASE or MDP, and hyperreactivity to an oral CHEMICAL challenge test. | CHEMICAL-INDUCED-DISEASE |
| Mitral annuloplasty as a ventricular restoration method for the DISEASE: a pilot study. BACKGROUND AND AIM OF THE STUDY: Undersized mitral annuloplasty (MAP) is effective in patients with dilated cardiomyopathy and functional mitral regurgitation (MR) since, as well as addressing the MR, the MAP may also reshape the dilated left ventricular (LV) base. However, the direct benefits of this possible reshaping on LV function in the absence of underlying MR remain incompletely understood. The study aim was to identify these benefits in a canine model of acute DISEASE. METHODS: Six dogs underwent MAP with a prosthetic band on the posterior mitral annulus, using four mattress sutures. The sutures were passed individually through four tourniquets and exteriorized untied via the left atriotomy. Sonomicrometry crystals were implanted around the mitral annulus and left ventricle to measure geometry and regional function. Acute DISEASE was induced by CHEMICAL and volume loading after weaning from cardiopulmonary bypass; an absence of MR was confirmed by echocardiography. MAP was accomplished by cinching the tourniquets. Data were acquired at baseline, after induction of acute DISEASE, and after MAP. RESULTS: MAP decreased mitral annular dimensions in both commissure-commissure and septal-lateral directions. Concomitantly, the diastolic diameter of the LV base and LV sphericity decreased (i.e., improved) from 37.4 +/- 9.3 to 35.9 +/- 10 mm (p = 0.063), and from 67.9 +/- 18.6% to 65.3 +/- 18.9% (p = 0.016), respectively. Decreases were evident in both LV end-diastolic pressure (from 17 +/- 7 to 15 +/- 6 mmHg, p = 0.0480 and Tau (from 48 +/- 8 to 45 +/- 8 ms, p <0.01), while fractional shortening at the LV base increased from 7.7 +/- 4.5% to 9.4 +/- 4.5% (p = 0.045). After MAP, increases were identified in both cardiac output (from 1.54 +/- 0.57 to 1.65 +/- 0.57 1/min) and Emax (from 1.86 +/- 0.9 to 2.41 +/- 1.31 mmHg/ml). CONCLUSION: The data acquired suggest that isolated MAP may have certain benefits on LV dimension/function in acute DISEASE, even in the absence of MR. However, further investigations are warranted in a model of chronic DISEASE. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of piperacillin, the dire neurotoxicity associated with piperacillin still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental DISEASE, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of CHEMICAL (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and ammonia levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of CHEMICAL. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. Piperacillin-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing piperacillin, whereas hemodialysis can rapidly terminate the piperacillin-induced encephalopathy. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of piperacillin, the dire neurotoxicity associated with piperacillin still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized DISEASE (DISEASE) after 5 doses of CHEMICAL (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and ammonia levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another DISEASE episode recurred after the sixth dose of CHEMICAL. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. Piperacillin-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing piperacillin, whereas hemodialysis can rapidly terminate the piperacillin-induced encephalopathy. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of piperacillin, the dire neurotoxicity associated with piperacillin still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, DISEASE, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of CHEMICAL (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and ammonia levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of CHEMICAL. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. Piperacillin-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing piperacillin, whereas hemodialysis can rapidly terminate the piperacillin-induced encephalopathy. | CHEMICAL-INDUCED-DISEASE |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of CHEMICAL, the dire neurotoxicity associated with CHEMICAL still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for DISEASE with secondary infection. The laboratory data revealed normal plasma electrolyte and ammonia levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. CHEMICAL-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing CHEMICAL, whereas hemodialysis can rapidly terminate the CHEMICAL-induced encephalopathy. | NO-RELATIONSHIP |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of CHEMICAL, the dire neurotoxicity associated with CHEMICAL still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and ammonia levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. CHEMICAL-induced DISEASE should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing CHEMICAL, whereas hemodialysis can rapidly terminate the CHEMICAL-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of CHEMICAL, the dire neurotoxicity associated with CHEMICAL still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and ammonia levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute DISEASE and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. CHEMICAL-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing CHEMICAL, whereas hemodialysis can rapidly terminate the CHEMICAL-induced encephalopathy. | CHEMICAL-INDUCED-DISEASE |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of piperacillin, the dire neurotoxicity associated with piperacillin still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and CHEMICAL levels but DISEASE. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. Piperacillin-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing piperacillin, whereas hemodialysis can rapidly terminate the piperacillin-induced encephalopathy. | NO-RELATIONSHIP |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of piperacillin, the dire neurotoxicity associated with piperacillin still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and CHEMICAL levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. Piperacillin-induced DISEASE should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing piperacillin, whereas hemodialysis can rapidly terminate the piperacillin-induced DISEASE. | NO-RELATIONSHIP |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of CHEMICAL, the dire neurotoxicity associated with CHEMICAL still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and ammonia levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and DISEASE. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. CHEMICAL-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing CHEMICAL, whereas hemodialysis can rapidly terminate the CHEMICAL-induced encephalopathy. | CHEMICAL-INDUCED-DISEASE |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of piperacillin, the dire neurotoxicity associated with piperacillin still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and CHEMICAL levels but leukocytosis. Neurologic examinations showed DISEASE and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. Piperacillin-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing piperacillin, whereas hemodialysis can rapidly terminate the piperacillin-induced encephalopathy. | NO-RELATIONSHIP |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of CHEMICAL, the dire DISEASE associated with CHEMICAL still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and ammonia levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. CHEMICAL-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing CHEMICAL, whereas hemodialysis can rapidly terminate the CHEMICAL-induced encephalopathy. | CHEMICAL-INDUCED-DISEASE |
| Piperacillin/tazobactam-induced DISEASE rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of CHEMICAL, the dire neurotoxicity associated with CHEMICAL still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and ammonia levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. CHEMICAL-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing CHEMICAL, whereas hemodialysis can rapidly terminate the CHEMICAL-induced encephalopathy. | CHEMICAL-INDUCED-DISEASE |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of piperacillin, the dire neurotoxicity associated with piperacillin still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with DISEASE receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and CHEMICAL levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. Piperacillin-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing piperacillin, whereas hemodialysis can rapidly terminate the piperacillin-induced encephalopathy. | NO-RELATIONSHIP |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of piperacillin, the dire neurotoxicity associated with piperacillin still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and CHEMICAL levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute DISEASE and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. Piperacillin-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing piperacillin, whereas hemodialysis can rapidly terminate the piperacillin-induced encephalopathy. | NO-RELATIONSHIP |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of piperacillin, the dire DISEASE associated with piperacillin still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and CHEMICAL levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. Piperacillin-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing piperacillin, whereas hemodialysis can rapidly terminate the piperacillin-induced encephalopathy. | NO-RELATIONSHIP |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of piperacillin, the dire neurotoxicity associated with piperacillin still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and CHEMICAL levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and DISEASE. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. Piperacillin-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing piperacillin, whereas hemodialysis can rapidly terminate the piperacillin-induced encephalopathy. | NO-RELATIONSHIP |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of piperacillin, the dire neurotoxicity associated with piperacillin still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and CHEMICAL levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. Piperacillin-induced encephalopathy should be considered in any DISEASE patients with unexplained neurological manifestations. CAPD is inefficient in removing piperacillin, whereas hemodialysis can rapidly terminate the piperacillin-induced encephalopathy. | NO-RELATIONSHIP |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of CHEMICAL, the dire neurotoxicity associated with CHEMICAL still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and ammonia levels but leukocytosis. Neurologic examinations showed DISEASE and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. CHEMICAL-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing CHEMICAL, whereas hemodialysis can rapidly terminate the CHEMICAL-induced encephalopathy. | CHEMICAL-INDUCED-DISEASE |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of CHEMICAL, the dire neurotoxicity associated with CHEMICAL still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with DISEASE receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and ammonia levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. CHEMICAL-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing CHEMICAL, whereas hemodialysis can rapidly terminate the CHEMICAL-induced encephalopathy. | NO-RELATIONSHIP |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of piperacillin, the dire neurotoxicity associated with piperacillin still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with DISEASE. The laboratory data revealed normal plasma electrolyte and CHEMICAL levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. Piperacillin-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing piperacillin, whereas hemodialysis can rapidly terminate the piperacillin-induced encephalopathy. | NO-RELATIONSHIP |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of CHEMICAL, the dire neurotoxicity associated with CHEMICAL still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and ammonia levels but DISEASE. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. CHEMICAL-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing CHEMICAL, whereas hemodialysis can rapidly terminate the CHEMICAL-induced encephalopathy. | CHEMICAL-INDUCED-DISEASE |
| Piperacillin/tazobactam-induced seizure rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of CHEMICAL, the dire neurotoxicity associated with CHEMICAL still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and ammonia levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. CHEMICAL-induced encephalopathy should be considered in any DISEASE patients with unexplained neurological manifestations. CAPD is inefficient in removing CHEMICAL, whereas hemodialysis can rapidly terminate the CHEMICAL-induced encephalopathy. | NO-RELATIONSHIP |
| Piperacillin/tazobactam-induced DISEASE rapidly reversed by high flux hemodialysis in a patient on peritoneal dialysis. Despite popular use of piperacillin, the dire neurotoxicity associated with piperacillin still goes unrecognized, leading to a delay in appropriate management. We report a 57-year-old woman with end-stage renal disease receiving continuous ambulatory peritoneal dialysis (CAPD), who developed slurred speech, tremor, bizarre behavior, progressive mental confusion, and 2 episodes of generalized tonic-clonic seizure (GTCS) after 5 doses of piperacillin/tazobactam (2 g/250 mg) were given for bronchiectasis with secondary infection. The laboratory data revealed normal plasma electrolyte and CHEMICAL levels but leukocytosis. Neurologic examinations showed dysarthria and bilateral Babinski sign. Computed tomography of brain and electroencephalogram were unremarkable. Despite the use of antiepileptic agents, another GTCS episode recurred after the sixth dose of piperacillin/tazobactam. Brain magnetic resonance imaging did not demonstrate acute infarction and organic brain lesions. Initiation of high-flux hemodialysis rapidly reversed the neurologic symptoms within 4 hours. Piperacillin-induced encephalopathy should be considered in any uremic patients with unexplained neurological manifestations. CAPD is inefficient in removing piperacillin, whereas hemodialysis can rapidly terminate the piperacillin-induced encephalopathy. | NO-RELATIONSHIP |
| Frequency of transient ipsilateral DISEASE in patients undergoing carotid endarterectomy under local anesthesia. BACKGROUND: Especially because of improvements in clinical neurologic monitoring, carotid endarterectomy done under local anesthesia has become the technique of choice in several centers. Temporary ipsilateral DISEASE due to local anesthetics have been described, however. Such complications are most important in situations where there is a pre-existing contralateral paralysis. We therefore examined the effect of local anesthesia on vocal cord function to better understand its possible consequences. METHODS: This prospective study included 28 patients undergoing carotid endarterectomy under local anesthesia. Vocal cord function was evaluated before, during, and after surgery (postoperative day 1) using flexible laryngoscopy. Anesthesia was performed by injecting 20 to 40 mL of a mixture of long-acting (ropivacaine) and short-acting (CHEMICAL) anesthetic. RESULTS: All patients had normal vocal cord function preoperatively. Twelve patients (43%) were found to have intraoperative ipsilateral DISEASE. It resolved in all cases < or =24 hours. There were no significant differences in operating time or volume or frequency of anesthetic administration in patients with temporary DISEASE compared with those without. CONCLUSION: Local anesthesia led to temporary ipsilateral DISEASE in almost half of these patients. Because pre-existing paralysis is of a relevant frequency (up to 3%), a preoperative evaluation of vocal cord function before carotid endarterectomy under local anesthesia is recommended to avoid intraoperative bilateral paralysis. In patients with preoperative contralateral DISEASE, surgery under general anesthesia should be considered. | CHEMICAL-INDUCED-DISEASE |
| Frequency of transient ipsilateral vocal cord paralysis in patients undergoing carotid endarterectomy under local anesthesia. BACKGROUND: Especially because of improvements in clinical neurologic monitoring, carotid endarterectomy done under local anesthesia has become the technique of choice in several centers. Temporary ipsilateral vocal nerve palsies due to local anesthetics have been described, however. Such complications are most important in situations where there is a pre-existing contralateral DISEASE. We therefore examined the effect of local anesthesia on vocal cord function to better understand its possible consequences. METHODS: This prospective study included 28 patients undergoing carotid endarterectomy under local anesthesia. Vocal cord function was evaluated before, during, and after surgery (postoperative day 1) using flexible laryngoscopy. Anesthesia was performed by injecting 20 to 40 mL of a mixture of long-acting (CHEMICAL) and short-acting (prilocaine) anesthetic. RESULTS: All patients had normal vocal cord function preoperatively. Twelve patients (43%) were found to have intraoperative ipsilateral vocal cord paralysis. It resolved in all cases < or =24 hours. There were no significant differences in operating time or volume or frequency of anesthetic administration in patients with temporary vocal cord paralysis compared with those without. CONCLUSION: Local anesthesia led to temporary ipsilateral vocal cord paralysis in almost half of these patients. Because pre-existing DISEASE is of a relevant frequency (up to 3%), a preoperative evaluation of vocal cord function before carotid endarterectomy under local anesthesia is recommended to avoid intraoperative bilateral DISEASE. In patients with preoperative contralateral vocal cord paralysis, surgery under general anesthesia should be considered. | NO-RELATIONSHIP |
| Neuroprotective effects of melatonin upon the offspring cerebellar cortex in the rat model of CHEMICAL-induced DISEASE. DISEASE is a malformation characterized by defects in proliferation, migration and maturation. This study was designed to evaluate the alterations in offspring rat cerebellum induced by maternal exposure to CHEMICAL-[CHEMICAL] (CHEMICAL) and to investigate the effects of exogenous melatonin upon cerebellar CHEMICAL-induced DISEASE, using histological and biochemical analyses. Pregnant Wistar rats were assigned to five groups: intact-control, saline-control, melatonin-treated, CHEMICAL-exposed and CHEMICAL-exposed plus melatonin. Rats were exposed to CHEMICAL on embryonic day 15 and melatonin was given until delivery. Immuno/histochemistry and electron microscopy were carried out on the offspring cerebellum, and levels of malondialdehyde and superoxide dismutase were determined. Histopathologically, typical findings were observed in the cerebella from the control groups, but the findings consistent with early embryonic development were noted in CHEMICAL-exposed DISEASE group. There was a marked increase in the number of TUNEL positive cells and nestin positive cells in CHEMICAL-exposed group, but a decreased immunoreactivity to glial fibrillary acidic protein, synaptophysin and transforming growth factor beta1 was observed, indicating a delayed maturation, and melatonin significantly reversed these changes. Malondialdehyde level in CHEMICAL-exposed group was higher than those in control groups and melatonin decreased malondialdehyde levels in CHEMICAL group (P<0.01), while there were no significant differences in the superoxide dismutase levels between these groups. These data suggest that exposure of animals to CHEMICAL during pregnancy leads to delayed maturation of offspring cerebellum and melatonin protects the cerebellum against the effects of CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Myo-inositol-1-phosphate (MIP) synthase inhibition: in-vivo study in rats. Lithium and valproate are the prototypic mood stabilizers and have diverse structures and targets. Both drugs influence inositol metabolism. Lithium inhibits IMPase and valproate inhibits MIP synthase. This study shows that MIP synthase inhibition does not replicate or augment the effects of lithium in the inositol sensitive CHEMICAL-induced DISEASE model. This lack of effects may stem from the low contribution of de-novo synthesis to cellular inositol supply or to the inhibition of the de-novo synthesis by lithium itself. | CHEMICAL-INDUCED-DISEASE |
| Non-steroidal anti-inflammatory drugs-associated acute interstitial nephritis with granular tubular basement membrane deposits. Acute tubulo-interstitial nephritis (ATIN) is an important cause of DISEASE resulting from a variety of insults, including immune complex-mediated tubulo-interstitial injury, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, ATIN remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed DISEASE 2 weeks after aortic valve surgery. He was put on aspirin following surgery and took CHEMICAL for fever for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a blood urea nitrogen (BUN) concentration of of 147 mg/dl, creatinine of 15.3 mg/dl and serum potassium of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with ATIN. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with steroids for 6 months. His renal recovery and disappearance of proteinuria took a year. In conclusion, this is a first report of NSAIDs-associated ATIN, showing deposits of granular immune complex present only in the TBM and not in the glomeruli. | NO-RELATIONSHIP |
| Non-steroidal anti-inflammatory drugs-associated acute DISEASE with granular tubular basement membrane deposits. Acute tubulo-interstitial nephritis (ATIN) is an important cause of acute renal failure resulting from a variety of insults, including immune complex-mediated DISEASE, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, ATIN remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed acute renal failure 2 weeks after aortic valve surgery. He was put on aspirin following surgery and took CHEMICAL for fever for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a blood urea nitrogen (BUN) concentration of of 147 mg/dl, creatinine of 15.3 mg/dl and serum potassium of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with ATIN. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with steroids for 6 months. His renal recovery and disappearance of proteinuria took a year. In conclusion, this is a first report of NSAIDs-associated ATIN, showing deposits of granular immune complex present only in the TBM and not in the glomeruli. | NO-RELATIONSHIP |
| Non-steroidal anti-inflammatory drugs-associated acute interstitial nephritis with granular tubular basement membrane deposits. Acute tubulo-interstitial nephritis (ATIN) is an important cause of acute renal failure resulting from a variety of insults, including immune complex-mediated tubulo-interstitial injury, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, ATIN remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed acute renal failure 2 weeks after aortic valve surgery. He was put on aspirin following surgery and took ibuprofen for DISEASE for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a CHEMICAL (CHEMICAL) concentration of of 147 mg/dl, creatinine of 15.3 mg/dl and serum potassium of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with ATIN. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with steroids for 6 months. His renal recovery and disappearance of proteinuria took a year. In conclusion, this is a first report of NSAIDs-associated ATIN, showing deposits of granular immune complex present only in the TBM and not in the glomeruli. | NO-RELATIONSHIP |
| Non-steroidal anti-inflammatory drugs-associated acute interstitial nephritis with granular tubular basement membrane deposits. DISEASE (DISEASE) is an important cause of acute renal failure resulting from a variety of insults, including immune complex-mediated tubulo-interstitial injury, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, DISEASE remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed acute renal failure 2 weeks after aortic valve surgery. He was put on aspirin following surgery and took ibuprofen for fever for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a blood urea nitrogen (BUN) concentration of of 147 mg/dl, CHEMICAL of 15.3 mg/dl and serum potassium of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with DISEASE. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with steroids for 6 months. His renal recovery and disappearance of proteinuria took a year. In conclusion, this is a first report of NSAIDs-associated DISEASE, showing deposits of granular immune complex present only in the TBM and not in the glomeruli. | NO-RELATIONSHIP |
| Non-steroidal anti-inflammatory drugs-associated acute interstitial nephritis with granular tubular basement membrane deposits. DISEASE (DISEASE) is an important cause of acute renal failure resulting from a variety of insults, including immune complex-mediated tubulo-interstitial injury, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, DISEASE remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed acute renal failure 2 weeks after aortic valve surgery. He was put on aspirin following surgery and took ibuprofen for fever for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a blood urea nitrogen (BUN) concentration of of 147 mg/dl, creatinine of 15.3 mg/dl and serum potassium of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with DISEASE. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with CHEMICAL for 6 months. His renal recovery and disappearance of proteinuria took a year. In conclusion, this is a first report of NSAIDs-associated DISEASE, showing deposits of granular immune complex present only in the TBM and not in the glomeruli. | NO-RELATIONSHIP |
| Non-steroidal anti-inflammatory drugs-associated acute interstitial nephritis with granular tubular basement membrane deposits. DISEASE (DISEASE) is an important cause of acute renal failure resulting from a variety of insults, including immune complex-mediated tubulo-interstitial injury, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, DISEASE remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed acute renal failure 2 weeks after aortic valve surgery. He was put on aspirin following surgery and took ibuprofen for fever for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a CHEMICAL (CHEMICAL) concentration of of 147 mg/dl, creatinine of 15.3 mg/dl and serum potassium of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with DISEASE. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with steroids for 6 months. His renal recovery and disappearance of proteinuria took a year. In conclusion, this is a first report of NSAIDs-associated DISEASE, showing deposits of granular immune complex present only in the TBM and not in the glomeruli. | NO-RELATIONSHIP |
| Non-steroidal anti-inflammatory drugs-associated acute interstitial nephritis with granular tubular basement membrane deposits. Acute tubulo-interstitial nephritis (ATIN) is an important cause of acute renal failure resulting from a variety of insults, including immune complex-mediated tubulo-interstitial injury, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, ATIN remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed acute renal failure 2 weeks after aortic valve surgery. He was put on CHEMICAL following surgery and took ibuprofen for DISEASE for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a blood urea nitrogen (BUN) concentration of of 147 mg/dl, creatinine of 15.3 mg/dl and serum potassium of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with ATIN. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with steroids for 6 months. His renal recovery and disappearance of proteinuria took a year. In conclusion, this is a first report of NSAIDs-associated ATIN, showing deposits of granular immune complex present only in the TBM and not in the glomeruli. | NO-RELATIONSHIP |
| Non-steroidal anti-inflammatory drugs-associated acute interstitial nephritis with granular tubular basement membrane deposits. Acute tubulo-interstitial nephritis (ATIN) is an important cause of acute renal failure resulting from a variety of insults, including immune complex-mediated tubulo-interstitial injury, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, ATIN remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed acute renal failure 2 weeks after aortic valve surgery. He was put on aspirin following surgery and took ibuprofen for DISEASE for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a blood urea nitrogen (BUN) concentration of of 147 mg/dl, CHEMICAL of 15.3 mg/dl and serum potassium of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with ATIN. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with steroids for 6 months. His renal recovery and disappearance of proteinuria took a year. In conclusion, this is a first report of NSAIDs-associated ATIN, showing deposits of granular immune complex present only in the TBM and not in the glomeruli. | NO-RELATIONSHIP |
| Non-steroidal anti-inflammatory drugs-associated acute interstitial nephritis with granular tubular basement membrane deposits. Acute tubulo-interstitial nephritis (ATIN) is an important cause of acute renal failure resulting from a variety of insults, including immune complex-mediated tubulo-interstitial injury, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, ATIN remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed acute renal failure 2 weeks after aortic valve surgery. He was put on aspirin following surgery and took ibuprofen for fever for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a CHEMICAL (CHEMICAL) concentration of of 147 mg/dl, creatinine of 15.3 mg/dl and serum potassium of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with ATIN. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with steroids for 6 months. His renal recovery and disappearance of DISEASE took a year. In conclusion, this is a first report of NSAIDs-associated ATIN, showing deposits of granular immune complex present only in the TBM and not in the glomeruli. | NO-RELATIONSHIP |
| Non-steroidal anti-inflammatory drugs-associated acute interstitial nephritis with granular tubular basement membrane deposits. Acute tubulo-interstitial nephritis (ATIN) is an important cause of acute renal failure resulting from a variety of insults, including immune complex-mediated tubulo-interstitial injury, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, ATIN remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed acute renal failure 2 weeks after aortic valve surgery. He was put on aspirin following surgery and took ibuprofen for fever for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a blood urea nitrogen (BUN) concentration of of 147 mg/dl, creatinine of 15.3 mg/dl and serum CHEMICAL of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with ATIN. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with steroids for 6 months. His renal recovery and disappearance of DISEASE took a year. In conclusion, this is a first report of NSAIDs-associated ATIN, showing deposits of granular immune complex present only in the TBM and not in the glomeruli. | NO-RELATIONSHIP |
| Non-steroidal anti-inflammatory drugs-associated acute interstitial nephritis with granular tubular basement membrane deposits. Acute tubulo-interstitial nephritis (ATIN) is an important cause of acute renal failure resulting from a variety of insults, including immune complex-mediated tubulo-interstitial injury, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, ATIN remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed acute renal failure 2 weeks after aortic valve surgery. He was put on CHEMICAL following surgery and took ibuprofen for fever for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a blood urea nitrogen (BUN) concentration of of 147 mg/dl, creatinine of 15.3 mg/dl and serum potassium of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with ATIN. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with steroids for 6 months. His renal recovery and disappearance of DISEASE took a year. In conclusion, this is a first report of NSAIDs-associated ATIN, showing deposits of granular immune complex present only in the TBM and not in the glomeruli. | NO-RELATIONSHIP |
| Non-steroidal anti-inflammatory drugs-associated acute interstitial nephritis with granular tubular basement membrane deposits. Acute tubulo-interstitial nephritis (ATIN) is an important cause of acute renal failure resulting from a variety of insults, including immune complex-mediated tubulo-interstitial injury, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, ATIN remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed acute renal failure 2 weeks after aortic valve surgery. He was put on aspirin following surgery and took ibuprofen for fever for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a blood urea nitrogen (BUN) concentration of of 147 mg/dl, CHEMICAL of 15.3 mg/dl and serum potassium of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with ATIN. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with steroids for 6 months. His renal recovery and disappearance of DISEASE took a year. In conclusion, this is a first report of NSAIDs-associated ATIN, showing deposits of granular immune complex present only in the TBM and not in the glomeruli. | NO-RELATIONSHIP |
| Non-steroidal anti-inflammatory drugs-associated acute interstitial nephritis with granular tubular basement membrane deposits. DISEASE (DISEASE) is an important cause of acute renal failure resulting from a variety of insults, including immune complex-mediated tubulo-interstitial injury, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, DISEASE remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed acute renal failure 2 weeks after aortic valve surgery. He was put on aspirin following surgery and took ibuprofen for fever for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a blood urea nitrogen (BUN) concentration of of 147 mg/dl, creatinine of 15.3 mg/dl and serum CHEMICAL of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with DISEASE. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with steroids for 6 months. His renal recovery and disappearance of proteinuria took a year. In conclusion, this is a first report of NSAIDs-associated DISEASE, showing deposits of granular immune complex present only in the TBM and not in the glomeruli. | NO-RELATIONSHIP |
| Non-steroidal anti-inflammatory drugs-associated acute interstitial nephritis with granular tubular basement membrane deposits. Acute tubulo-interstitial nephritis (ATIN) is an important cause of acute renal failure resulting from a variety of insults, including immune complex-mediated tubulo-interstitial injury, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, ATIN remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed acute renal failure 2 weeks after aortic valve surgery. He was put on aspirin following surgery and took ibuprofen for fever for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a blood urea nitrogen (BUN) concentration of of 147 mg/dl, creatinine of 15.3 mg/dl and serum potassium of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with ATIN. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with CHEMICAL for 6 months. His renal recovery and disappearance of DISEASE took a year. In conclusion, this is a first report of NSAIDs-associated ATIN, showing deposits of granular immune complex present only in the TBM and not in the glomeruli. | NO-RELATIONSHIP |
| Non-steroidal anti-inflammatory drugs-associated acute interstitial nephritis with granular tubular basement membrane deposits. DISEASE (DISEASE) is an important cause of acute renal failure resulting from a variety of insults, including immune complex-mediated tubulo-interstitial injury, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, DISEASE remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed acute renal failure 2 weeks after aortic valve surgery. He was put on CHEMICAL following surgery and took ibuprofen for fever for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a blood urea nitrogen (BUN) concentration of of 147 mg/dl, creatinine of 15.3 mg/dl and serum potassium of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with DISEASE. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with steroids for 6 months. His renal recovery and disappearance of proteinuria took a year. In conclusion, this is a first report of NSAIDs-associated DISEASE, showing deposits of granular immune complex present only in the TBM and not in the glomeruli. | NO-RELATIONSHIP |
| Non-steroidal anti-inflammatory drugs-associated acute interstitial nephritis with granular tubular basement membrane deposits. Acute tubulo-interstitial nephritis (ATIN) is an important cause of acute renal failure resulting from a variety of insults, including immune complex-mediated tubulo-interstitial injury, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, ATIN remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed acute renal failure 2 weeks after aortic valve surgery. He was put on aspirin following surgery and took ibuprofen for DISEASE for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a blood urea nitrogen (BUN) concentration of of 147 mg/dl, creatinine of 15.3 mg/dl and serum potassium of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with ATIN. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with CHEMICAL for 6 months. His renal recovery and disappearance of proteinuria took a year. In conclusion, this is a first report of NSAIDs-associated ATIN, showing deposits of granular immune complex present only in the TBM and not in the glomeruli. | NO-RELATIONSHIP |
| Non-steroidal anti-inflammatory drugs-associated acute interstitial nephritis with granular tubular basement membrane deposits. Acute tubulo-interstitial nephritis (ATIN) is an important cause of acute renal failure resulting from a variety of insults, including immune complex-mediated tubulo-interstitial injury, but drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) are a far more frequent cause. Overall, as an entity, ATIN remains under-diagnosed, as symptoms resolve spontaneously if the medication is stopped. We report on a 14-year-old boy who developed acute renal failure 2 weeks after aortic valve surgery. He was put on aspirin following surgery and took ibuprofen for DISEASE for nearly a week prior to presentation. He then presented to the emergency department feeling quite ill and was found to have a blood urea nitrogen (BUN) concentration of of 147 mg/dl, creatinine of 15.3 mg/dl and serum CHEMICAL of 8.7 mEq/l. Dialysis was immediately initiated. A kidney biopsy showed inflammatory infiltrate consistent with ATIN. However, in the tubular basement membrane (TBM), very intense granular deposits of polyclonal IgG and C3 were noted. He needed dialysis for 2 weeks and was treated successfully with steroids for 6 months. His renal recovery and disappearance of proteinuria took a year. In conclusion, this is a first report of NSAIDs-associated ATIN, showing deposits of granular immune complex present only in the TBM and not in the glomeruli. | NO-RELATIONSHIP |
| CHEMICAL-associated segmental necrotizing glomerulonephritis in staphylococcal endocarditis. Segmental necrotising glomerulonephritis has been reported as complication of CHEMICAL therapy in patients receiving treatment for tuberculosis. Changing epidemiology of infections such as infective endocarditis (IE) has led to an increase in the use of CHEMICAL for Staphylococcal infections. We describe a case of a patient with Staphylococcal IE who developed DISEASE secondary to a segmental necrotising glomerulonephritis while being treated with CHEMICAL, and review the literature regarding this complication of CHEMICAL therapy. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-associated segmental necrotizing DISEASE in staphylococcal endocarditis. Segmental necrotising DISEASE has been reported as complication of CHEMICAL therapy in patients receiving treatment for tuberculosis. Changing epidemiology of infections such as infective endocarditis (IE) has led to an increase in the use of CHEMICAL for Staphylococcal infections. We describe a case of a patient with Staphylococcal IE who developed acute renal failure secondary to a segmental necrotising DISEASE while being treated with CHEMICAL, and review the literature regarding this complication of CHEMICAL therapy. | CHEMICAL-INDUCED-DISEASE |
| Rate of YMDD motif mutants in lamivudine-untreated Iranian patients with DISEASE. BACKGROUND: Lamivudine is used for the treatment of DISEASE patients. Recent studies show that the YMDD motif mutants (resistant hepatitis B virus) occur as natural genome variability in lamivudine-untreated DISEASE patients. In this study we aimed to determine the rate of YMDD motif mutants in lamivudine-untreated DISEASE patients in Iran. PATIENTS AND METHODS: A total of 77 DISEASE patients who had not been treated with lamivudine were included in the study. Serum samples from patients were tested by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for detection of YMDD motif mutants. All patients were also tested for liver enzymes, anti-HCV, CHEMICAL, and anti-HBe. RESULTS: Of the 77 patients enrolled in the study, 73% were male and 27% were female. Mean ALT and AST levels were 124.4+/-73.4 and 103.1+/-81 IU/l, respectively. CHEMICAL was positive in 40% and anti-HBe in 60% of the patients. Anti-HCV was negative in all of them. YMDD motif mutants were not detected in any of the patients despite the liver enzyme levels and the presence of CHEMICAL or anti-HBe. CONCLUSION: Although the natural occurrence of YMDD motif mutants in lamivudine-untreated patients with DISEASE has been reported, these mutants were not detected in Iranian lamivudine-untreated DISEASE patients. | CHEMICAL-INDUCED-DISEASE |
| Rate of YMDD motif mutants in CHEMICAL-untreated Iranian patients with chronic hepatitis B virus infection. BACKGROUND: CHEMICAL is used for the treatment of chronic hepatitis B patients. Recent studies show that the YMDD motif mutants (resistant DISEASE virus) occur as natural genome variability in CHEMICAL-untreated chronic hepatitis B patients. In this study we aimed to determine the rate of YMDD motif mutants in CHEMICAL-untreated chronic hepatitis B patients in Iran. PATIENTS AND METHODS: A total of 77 chronic hepatitis B patients who had not been treated with CHEMICAL were included in the study. Serum samples from patients were tested by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for detection of YMDD motif mutants. All patients were also tested for liver enzymes, anti-HCV, HBeAg, and anti-HBe. RESULTS: Of the 77 patients enrolled in the study, 73% were male and 27% were female. Mean ALT and AST levels were 124.4+/-73.4 and 103.1+/-81 IU/l, respectively. HBeAg was positive in 40% and anti-HBe in 60% of the patients. Anti-HCV was negative in all of them. YMDD motif mutants were not detected in any of the patients despite the liver enzyme levels and the presence of HBeAg or anti-HBe. CONCLUSION: Although the natural occurrence of YMDD motif mutants in CHEMICAL-untreated patients with chronic hepatitis B has been reported, these mutants were not detected in Iranian CHEMICAL-untreated chronic hepatitis B patients. | NO-RELATIONSHIP |
| Branch DISEASE and CHEMICAL. A case of branch DISEASE associated with CHEMICAL-induced secondary hypertension is described. Although an infrequent complication of selective serotonin reuptake inhibitor therapy, it is important that ophthalmologists are aware that these agents can cause hypertension because this class of drugs is widely prescribed. | CHEMICAL-INDUCED-DISEASE |
| Branch retinal vein occlusion and CHEMICAL. A case of branch retinal vein occlusion associated with CHEMICAL-induced secondary DISEASE is described. Although an infrequent complication of selective serotonin reuptake inhibitor therapy, it is important that ophthalmologists are aware that these agents can cause DISEASE because this class of drugs is widely prescribed. | CHEMICAL-INDUCED-DISEASE |
| The differential effects of CHEMICAL and lidocaine on prostaglandin E2 release, cyclooxygenase gene expression and pain in a clinical pain model. BACKGROUND: In addition to blocking nociceptive input from surgical sites, long-acting local anesthetics might directly modulate DISEASE. In the present study, we describe the proinflammatory effects of CHEMICAL on local prostaglandin E2 (PGE2) production and cyclooxygenase (COX) gene expression that increases postoperative pain in human subjects. METHODS: Subjects (n = 114) undergoing extraction of impacted third molars received either 2% lidocaine or 0.5% CHEMICAL before surgery and either rofecoxib 50 mg or placebo orally 90 min before surgery and for the following 48 h. Oral mucosal biopsies were taken before surgery and 48 h after surgery. After extraction, a microdialysis probe was placed at the surgical site for PGE2 and thromboxane B2 (TXB2) measurements. RESULTS: The CHEMICAL/rofecoxib group reported significantly less pain, as assessed by a visual analog scale, compared with the other three treatment groups over the first 4 h. However, the CHEMICAL/placebo group reported significantly more pain at 24 h and PGE2 levels during the first 4 h were significantly higher than the other three treatment groups. Moreover, CHEMICAL significantly increased COX-2 gene expression at 48 h as compared with the lidocaine/placebo group. Thromboxane levels were not significantly affected by any of the treatments, indicating that the effects seen were attributable to inhibition of COX-2, but not COX-1. CONCLUSIONS: These results suggest that CHEMICAL stimulates COX-2 gene expression after tissue injury, which is associated with higher PGE2 production and pain after the local anesthetic effect dissipates. | GENE-CHEMICAL |
| The differential effects of CHEMICAL and lidocaine on prostaglandin E2 release, cyclooxygenase gene expression and pain in a clinical pain model. BACKGROUND: In addition to blocking nociceptive input from surgical sites, long-acting local anesthetics might directly modulate inflammation. In the present study, we describe the proinflammatory effects of CHEMICAL on local prostaglandin E2 (PGE2) production and cyclooxygenase (COX) gene expression that increases DISEASE in human subjects. METHODS: Subjects (n = 114) undergoing extraction of impacted third molars received either 2% lidocaine or 0.5% CHEMICAL before surgery and either rofecoxib 50 mg or placebo orally 90 min before surgery and for the following 48 h. Oral mucosal biopsies were taken before surgery and 48 h after surgery. After extraction, a microdialysis probe was placed at the surgical site for PGE2 and thromboxane B2 (TXB2) measurements. RESULTS: The CHEMICAL/rofecoxib group reported significantly less pain, as assessed by a visual analog scale, compared with the other three treatment groups over the first 4 h. However, the CHEMICAL/placebo group reported significantly more pain at 24 h and PGE2 levels during the first 4 h were significantly higher than the other three treatment groups. Moreover, CHEMICAL significantly increased COX-2 gene expression at 48 h as compared with the lidocaine/placebo group. Thromboxane levels were not significantly affected by any of the treatments, indicating that the effects seen were attributable to inhibition of COX-2, but not COX-1. CONCLUSIONS: These results suggest that CHEMICAL stimulates COX-2 gene expression after tissue injury, which is associated with higher PGE2 production and pain after the local anesthetic effect dissipates. | INDIRECT-UPREGULATOR |
| The differential effects of bupivacaine and lidocaine on prostaglandin E2 release, cyclooxygenase gene expression and DISEASE in a clinical DISEASE model. BACKGROUND: In addition to blocking nociceptive input from surgical sites, long-acting local anesthetics might directly modulate inflammation. In the present study, we describe the proinflammatory effects of bupivacaine on local prostaglandin E2 (PGE2) production and cyclooxygenase (COX) gene expression that increases postoperative pain in human subjects. METHODS: Subjects (n = 114) undergoing extraction of impacted third molars received either 2% lidocaine or 0.5% bupivacaine before surgery and either rofecoxib 50 mg or placebo orally 90 min before surgery and for the following 48 h. Oral mucosal biopsies were taken before surgery and 48 h after surgery. After extraction, a microdialysis probe was placed at the surgical site for PGE2 and CHEMICAL (CHEMICAL) measurements. RESULTS: The bupivacaine/rofecoxib group reported significantly less DISEASE, as assessed by a visual analog scale, compared with the other three treatment groups over the first 4 h. However, the bupivacaine/placebo group reported significantly more DISEASE at 24 h and PGE2 levels during the first 4 h were significantly higher than the other three treatment groups. Moreover, bupivacaine significantly increased COX-2 gene expression at 48 h as compared with the lidocaine/placebo group. Thromboxane levels were not significantly affected by any of the treatments, indicating that the effects seen were attributable to inhibition of COX-2, but not COX-1. CONCLUSIONS: These results suggest that bupivacaine stimulates COX-2 gene expression after tissue injury, which is associated with higher PGE2 production and DISEASE after the local anesthetic effect dissipates. | NO-RELATIONSHIP |
| The differential effects of bupivacaine and CHEMICAL on prostaglandin E2 release, cyclooxygenase gene expression and pain in a clinical pain model. BACKGROUND: In addition to blocking nociceptive input from surgical sites, long-acting local anesthetics might directly modulate inflammation. In the present study, we describe the proinflammatory effects of bupivacaine on local prostaglandin E2 (PGE2) production and cyclooxygenase (COX) gene expression that increases postoperative pain in human subjects. METHODS: Subjects (n = 114) undergoing extraction of impacted third molars received either 2% CHEMICAL or 0.5% bupivacaine before surgery and either rofecoxib 50 mg or placebo orally 90 min before surgery and for the following 48 h. Oral mucosal biopsies were taken before surgery and 48 h after surgery. After extraction, a microdialysis probe was placed at the surgical site for PGE2 and thromboxane B2 (TXB2) measurements. RESULTS: The bupivacaine/rofecoxib group reported significantly less pain, as assessed by a visual analog scale, compared with the other three treatment groups over the first 4 h. However, the bupivacaine/placebo group reported significantly more pain at 24 h and PGE2 levels during the first 4 h were significantly higher than the other three treatment groups. Moreover, bupivacaine significantly increased COX-2 gene expression at 48 h as compared with the CHEMICAL/placebo group. Thromboxane levels were not significantly affected by any of the treatments, indicating that the effects seen were attributable to inhibition of COX-2, but not COX-1. CONCLUSIONS: These results suggest that bupivacaine stimulates COX-2 gene expression after DISEASE, which is associated with higher PGE2 production and pain after the local anesthetic effect dissipates. | NO-RELATIONSHIP |
| The differential effects of bupivacaine and CHEMICAL on prostaglandin E2 release, cyclooxygenase gene expression and DISEASE in a clinical DISEASE model. BACKGROUND: In addition to blocking nociceptive input from surgical sites, long-acting local anesthetics might directly modulate inflammation. In the present study, we describe the proinflammatory effects of bupivacaine on local prostaglandin E2 (PGE2) production and cyclooxygenase (COX) gene expression that increases postoperative pain in human subjects. METHODS: Subjects (n = 114) undergoing extraction of impacted third molars received either 2% CHEMICAL or 0.5% bupivacaine before surgery and either rofecoxib 50 mg or placebo orally 90 min before surgery and for the following 48 h. Oral mucosal biopsies were taken before surgery and 48 h after surgery. After extraction, a microdialysis probe was placed at the surgical site for PGE2 and thromboxane B2 (TXB2) measurements. RESULTS: The bupivacaine/rofecoxib group reported significantly less DISEASE, as assessed by a visual analog scale, compared with the other three treatment groups over the first 4 h. However, the bupivacaine/placebo group reported significantly more DISEASE at 24 h and PGE2 levels during the first 4 h were significantly higher than the other three treatment groups. Moreover, bupivacaine significantly increased COX-2 gene expression at 48 h as compared with the CHEMICAL/placebo group. Thromboxane levels were not significantly affected by any of the treatments, indicating that the effects seen were attributable to inhibition of COX-2, but not COX-1. CONCLUSIONS: These results suggest that bupivacaine stimulates COX-2 gene expression after tissue injury, which is associated with higher PGE2 production and DISEASE after the local anesthetic effect dissipates. | CHEMICAL-INDUCED-DISEASE |
| The differential effects of bupivacaine and lidocaine on prostaglandin E2 release, cyclooxygenase gene expression and pain in a clinical pain model. BACKGROUND: In addition to blocking nociceptive input from surgical sites, long-acting local anesthetics might directly modulate inflammation. In the present study, we describe the proinflammatory effects of bupivacaine on local prostaglandin E2 (PGE2) production and cyclooxygenase (COX) gene expression that increases postoperative pain in human subjects. METHODS: Subjects (n = 114) undergoing extraction of impacted third molars received either 2% lidocaine or 0.5% bupivacaine before surgery and either rofecoxib 50 mg or placebo orally 90 min before surgery and for the following 48 h. Oral mucosal biopsies were taken before surgery and 48 h after surgery. After extraction, a microdialysis probe was placed at the surgical site for PGE2 and thromboxane B2 (TXB2) measurements. RESULTS: The bupivacaine/rofecoxib group reported significantly less pain, as assessed by a visual analog scale, compared with the other three treatment groups over the first 4 h. However, the bupivacaine/placebo group reported significantly more pain at 24 h and PGE2 levels during the first 4 h were significantly higher than the other three treatment groups. Moreover, bupivacaine significantly increased COX-2 gene expression at 48 h as compared with the lidocaine/placebo group. CHEMICAL levels were not significantly affected by any of the treatments, indicating that the effects seen were attributable to inhibition of COX-2, but not COX-1. CONCLUSIONS: These results suggest that bupivacaine stimulates COX-2 gene expression after DISEASE, which is associated with higher PGE2 production and pain after the local anesthetic effect dissipates. | NO-RELATIONSHIP |
| The differential effects of bupivacaine and lidocaine on prostaglandin E2 release, cyclooxygenase gene expression and DISEASE in a clinical DISEASE model. BACKGROUND: In addition to blocking nociceptive input from surgical sites, long-acting local anesthetics might directly modulate inflammation. In the present study, we describe the proinflammatory effects of bupivacaine on local prostaglandin E2 (PGE2) production and cyclooxygenase (COX) gene expression that increases postoperative pain in human subjects. METHODS: Subjects (n = 114) undergoing extraction of impacted third molars received either 2% lidocaine or 0.5% bupivacaine before surgery and either rofecoxib 50 mg or placebo orally 90 min before surgery and for the following 48 h. Oral mucosal biopsies were taken before surgery and 48 h after surgery. After extraction, a microdialysis probe was placed at the surgical site for PGE2 and thromboxane B2 (TXB2) measurements. RESULTS: The bupivacaine/rofecoxib group reported significantly less DISEASE, as assessed by a visual analog scale, compared with the other three treatment groups over the first 4 h. However, the bupivacaine/placebo group reported significantly more DISEASE at 24 h and PGE2 levels during the first 4 h were significantly higher than the other three treatment groups. Moreover, bupivacaine significantly increased COX-2 gene expression at 48 h as compared with the lidocaine/placebo group. CHEMICAL levels were not significantly affected by any of the treatments, indicating that the effects seen were attributable to inhibition of COX-2, but not COX-1. CONCLUSIONS: These results suggest that bupivacaine stimulates COX-2 gene expression after tissue injury, which is associated with higher PGE2 production and DISEASE after the local anesthetic effect dissipates. | NO-RELATIONSHIP |
| The differential effects of bupivacaine and lidocaine on CHEMICAL release, cyclooxygenase gene expression and pain in a clinical pain model. BACKGROUND: In addition to blocking nociceptive input from surgical sites, long-acting local anesthetics might directly modulate inflammation. In the present study, we describe the proinflammatory effects of bupivacaine on local CHEMICAL (CHEMICAL) production and cyclooxygenase (COX) gene expression that increases postoperative pain in human subjects. METHODS: Subjects (n = 114) undergoing extraction of impacted third molars received either 2% lidocaine or 0.5% bupivacaine before surgery and either rofecoxib 50 mg or placebo orally 90 min before surgery and for the following 48 h. Oral mucosal biopsies were taken before surgery and 48 h after surgery. After extraction, a microdialysis probe was placed at the surgical site for CHEMICAL and thromboxane B2 (TXB2) measurements. RESULTS: The bupivacaine/rofecoxib group reported significantly less pain, as assessed by a visual analog scale, compared with the other three treatment groups over the first 4 h. However, the bupivacaine/placebo group reported significantly more pain at 24 h and CHEMICAL levels during the first 4 h were significantly higher than the other three treatment groups. Moreover, bupivacaine significantly increased COX-2 gene expression at 48 h as compared with the lidocaine/placebo group. Thromboxane levels were not significantly affected by any of the treatments, indicating that the effects seen were attributable to inhibition of COX-2, but not COX-1. CONCLUSIONS: These results suggest that bupivacaine stimulates COX-2 gene expression after DISEASE, which is associated with higher CHEMICAL production and pain after the local anesthetic effect dissipates. | NO-RELATIONSHIP |
| The differential effects of bupivacaine and lidocaine on prostaglandin E2 release, cyclooxygenase gene expression and pain in a clinical pain model. BACKGROUND: In addition to blocking nociceptive input from surgical sites, long-acting local anesthetics might directly modulate inflammation. In the present study, we describe the proinflammatory effects of bupivacaine on local prostaglandin E2 (PGE2) production and cyclooxygenase (COX) gene expression that increases postoperative pain in human subjects. METHODS: Subjects (n = 114) undergoing extraction of impacted third molars received either 2% lidocaine or 0.5% bupivacaine before surgery and either CHEMICAL 50 mg or placebo orally 90 min before surgery and for the following 48 h. Oral mucosal biopsies were taken before surgery and 48 h after surgery. After extraction, a microdialysis probe was placed at the surgical site for PGE2 and thromboxane B2 (TXB2) measurements. RESULTS: The bupivacaine/CHEMICAL group reported significantly less pain, as assessed by a visual analog scale, compared with the other three treatment groups over the first 4 h. However, the bupivacaine/placebo group reported significantly more pain at 24 h and PGE2 levels during the first 4 h were significantly higher than the other three treatment groups. Moreover, bupivacaine significantly increased COX-2 gene expression at 48 h as compared with the lidocaine/placebo group. Thromboxane levels were not significantly affected by any of the treatments, indicating that the effects seen were attributable to inhibition of COX-2, but not COX-1. CONCLUSIONS: These results suggest that bupivacaine stimulates COX-2 gene expression after DISEASE, which is associated with higher PGE2 production and pain after the local anesthetic effect dissipates. | NO-RELATIONSHIP |
| The differential effects of bupivacaine and lidocaine on CHEMICAL release, cyclooxygenase gene expression and DISEASE in a clinical DISEASE model. BACKGROUND: In addition to blocking nociceptive input from surgical sites, long-acting local anesthetics might directly modulate inflammation. In the present study, we describe the proinflammatory effects of bupivacaine on local CHEMICAL (CHEMICAL) production and cyclooxygenase (COX) gene expression that increases postoperative pain in human subjects. METHODS: Subjects (n = 114) undergoing extraction of impacted third molars received either 2% lidocaine or 0.5% bupivacaine before surgery and either rofecoxib 50 mg or placebo orally 90 min before surgery and for the following 48 h. Oral mucosal biopsies were taken before surgery and 48 h after surgery. After extraction, a microdialysis probe was placed at the surgical site for CHEMICAL and thromboxane B2 (TXB2) measurements. RESULTS: The bupivacaine/rofecoxib group reported significantly less DISEASE, as assessed by a visual analog scale, compared with the other three treatment groups over the first 4 h. However, the bupivacaine/placebo group reported significantly more DISEASE at 24 h and CHEMICAL levels during the first 4 h were significantly higher than the other three treatment groups. Moreover, bupivacaine significantly increased COX-2 gene expression at 48 h as compared with the lidocaine/placebo group. Thromboxane levels were not significantly affected by any of the treatments, indicating that the effects seen were attributable to inhibition of COX-2, but not COX-1. CONCLUSIONS: These results suggest that bupivacaine stimulates COX-2 gene expression after tissue injury, which is associated with higher CHEMICAL production and DISEASE after the local anesthetic effect dissipates. | PRODUCT-OF |
| The differential effects of bupivacaine and lidocaine on prostaglandin E2 release, cyclooxygenase gene expression and pain in a clinical pain model. BACKGROUND: In addition to blocking nociceptive input from surgical sites, long-acting local anesthetics might directly modulate inflammation. In the present study, we describe the proinflammatory effects of bupivacaine on local prostaglandin E2 (PGE2) production and cyclooxygenase (COX) gene expression that increases postoperative pain in human subjects. METHODS: Subjects (n = 114) undergoing extraction of impacted third molars received either 2% lidocaine or 0.5% bupivacaine before surgery and either rofecoxib 50 mg or placebo orally 90 min before surgery and for the following 48 h. Oral mucosal biopsies were taken before surgery and 48 h after surgery. After extraction, a microdialysis probe was placed at the surgical site for PGE2 and CHEMICAL (CHEMICAL) measurements. RESULTS: The bupivacaine/rofecoxib group reported significantly less pain, as assessed by a visual analog scale, compared with the other three treatment groups over the first 4 h. However, the bupivacaine/placebo group reported significantly more pain at 24 h and PGE2 levels during the first 4 h were significantly higher than the other three treatment groups. Moreover, bupivacaine significantly increased COX-2 gene expression at 48 h as compared with the lidocaine/placebo group. Thromboxane levels were not significantly affected by any of the treatments, indicating that the effects seen were attributable to inhibition of COX-2, but not COX-1. CONCLUSIONS: These results suggest that bupivacaine stimulates COX-2 gene expression after DISEASE, which is associated with higher PGE2 production and pain after the local anesthetic effect dissipates. | PRODUCT-OF |
| The differential effects of bupivacaine and lidocaine on prostaglandin E2 release, cyclooxygenase gene expression and DISEASE in a clinical DISEASE model. BACKGROUND: In addition to blocking nociceptive input from surgical sites, long-acting local anesthetics might directly modulate inflammation. In the present study, we describe the proinflammatory effects of bupivacaine on local prostaglandin E2 (PGE2) production and cyclooxygenase (COX) gene expression that increases postoperative pain in human subjects. METHODS: Subjects (n = 114) undergoing extraction of impacted third molars received either 2% lidocaine or 0.5% bupivacaine before surgery and either CHEMICAL 50 mg or placebo orally 90 min before surgery and for the following 48 h. Oral mucosal biopsies were taken before surgery and 48 h after surgery. After extraction, a microdialysis probe was placed at the surgical site for PGE2 and thromboxane B2 (TXB2) measurements. RESULTS: The bupivacaine/CHEMICAL group reported significantly less DISEASE, as assessed by a visual analog scale, compared with the other three treatment groups over the first 4 h. However, the bupivacaine/placebo group reported significantly more DISEASE at 24 h and PGE2 levels during the first 4 h were significantly higher than the other three treatment groups. Moreover, bupivacaine significantly increased COX-2 gene expression at 48 h as compared with the lidocaine/placebo group. Thromboxane levels were not significantly affected by any of the treatments, indicating that the effects seen were attributable to inhibition of COX-2, but not COX-1. CONCLUSIONS: These results suggest that bupivacaine stimulates COX-2 gene expression after tissue injury, which is associated with higher PGE2 production and DISEASE after the local anesthetic effect dissipates. | NO-RELATIONSHIP |
| p75NTR expression in rat urinary bladder sensory neurons and spinal cord with CHEMICAL-induced DISEASE. A role for nerve growth factor (NGF) in contributing to increased voiding frequency and altered sensation from the urinary bladder has been suggested. Previous studies have examined the expression and regulation of tyrosine kinase receptors (Trks) in micturition reflexes with DISEASE. The present studies examine the expression and regulation of another receptor known to bind NGF, p75(NTR), after various durations of DISEASE induced by CHEMICAL (CHEMICAL). CHEMICAL-induced DISEASE increased (P < or = 0.001) p75(NTR) expression in the superficial lateral and medial dorsal horn in L1-L2 and L6-S1 spinal segments. The number of p75(NTR)-immunoreactive (-IR) cells in the lumbosacral dorsal root ganglia (DRG) also increased (P < or = 0.05) with CHEMICAL-induced DISEASE (acute, intermediate, and chronic). Quantitative, real-time polymerase chain reaction also demonstrated significant increases (P < or = 0.01) in p75(NTR) mRNA in DRG with intermediate and chronic CHEMICAL-induced DISEASE. Retrograde dye-tracing techniques with Fastblue were used to identify presumptive bladder afferent cells in the lumbosacral DRG. In bladder afferent cells in DRG, p75(NTR)-IR was also increased (P < or = 0.01) with DISEASE. In addition to increases in p75(NTR)-IR in DRG cell bodies, increases (P < or = 0.001) in pericellular (encircling DRG cells) p75(NTR)-IR in DRG also increased. Confocal analyses demonstrated that pericellular p75(NTR)-IR was not colocalized with the glial marker, glial fibrillary acidic protein (GFAP). These studies demonstrate that p75(NTR) expression in micturition reflexes is present constitutively and modified by DISEASE. The functional significance of p75(NTR) expression in micturition reflexes remains to be determined. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced suicidal erythrocyte death. BACKGROUND: CHEMICAL is widely used as an immunosuppressive drug. The side effects of CHEMICAL include DISEASE, which has been attributed to bone marrow suppression. Alternatively, DISEASE could result from accelerated suicidal erythrocyte death or eryptosis, which is characterized by exposure of phosphatidylserine (PS) at the erythrocyte surface and by cell shrinkage. METHODS: The present experiments explored whether CHEMICAL influences eryptosis. According to annexin V binding, erythrocytes from patients indeed showed a significant increase of PS exposure within 1 week of treatment with CHEMICAL. In a second series, cytosolic Ca2+ activity (Fluo3 fluorescence), cell volume (forward scatter), and PS-exposure (annexin V binding) were determined by FACS analysis in erythrocytes from healthy volunteers. RESULTS: Exposure to CHEMICAL (> or =2 microg/mL) for 48 hours increased cytosolic Ca2+ activity and annexin V binding and decreased forward scatter. The effect of CHEMICAL on both annexin V binding and forward scatter was significantly blunted in the nominal absence of extracellular Ca2+. CONCLUSIONS: CHEMICAL triggers suicidal erythrocyte death, an effect presumably contributing to CHEMICAL-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Clinical comparison of cardiorespiratory effects during unilateral and conventional spinal anaesthesia. BACKGROUND: Spinal anaesthesia is widely employed in clinical practice but has the main drawback of post-spinal block DISEASE. Efforts must therefore continue to be made to obviate this setback OBJECTIVE: To evaluate the cardiovascular and respiratory changes during unilateral and conventional spinal anaesthesia. METHODS: With ethical approval, we studied 74 American Society of Anesthesiologists (ASA), physical status class 1 and 2 patients scheduled for elective unilateral lower limb surgery. Patients were randomly allocated into one of two groups: lateral and conventional spinal anaesthesia groups. In the lateral position with operative side down, patients recived 10 mg (2mls) of 0.5% hyperbaric CHEMICAL through a 25-gauge spinal needle. Patients in the unilateral group were maintained in the lateral position for 15 minutes following spinal injection while those in the conventional group were turned supine immediately after injection. Blood pressure, heart rate, respiratory rate and oxygen saturation were monitored over 1 hour. RESULTS: Three patients (8.1%) in the unilateral group and 5 (13.5%) in the conventional group developed DISEASE, P= 0.71. Four (10.8%) patients in the conventional group and 1 (2.7%) in the unilateral group, P= 0.17 required epinephrine infusion to treat DISEASE. Patients in the conventional group had statistically significant greater fall in the systolic blood pressures at 15, 30 and 45 minutes when compared to the baseline (P= 0.003, 0.001 and 0.004). The mean respiratory rate and oxygen saturations in the two groups were similar. CONCLUSION: Compared to conventional spinal anaesthesia, unilateral spinal anaesthesia was associated with fewer cardiovascular perturbations. Also, the type of spinal block instituted affected neither the respiratory rate nor the arterial oxygen saturation. | CHEMICAL-INDUCED-DISEASE |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were 3TC + CHEMICAL + nevirapine (NVP) (54.8%), zidovudine (AZT) + 3TC + NVP (14.5%), 3TC + CHEMICAL + efavirenz (EFV) (20.1%), and AZT + 3TC + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and DISEASE (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and CHEMICAL therapy with developing DISEASE (p < 0.05). Anemia and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were 3TC + d4T + CHEMICAL (CHEMICAL) (54.8%), zidovudine (AZT) + 3TC + CHEMICAL (14.5%), 3TC + d4T + efavirenz (EFV) (20.1%), and AZT + 3TC + EFV (5.4%). The most common adverse events and median CD4 at time of event were DISEASE (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, CHEMICAL therapy was significantly associated with developing DISEASE and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | CHEMICAL-INDUCED-DISEASE |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were CHEMICAL + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + CHEMICAL + NVP (14.5%), CHEMICAL + d4T + efavirenz (EFV) (20.1%), and AZT + CHEMICAL + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical DISEASE with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were 3TC + d4T + nevirapine (NVP) (54.8%), CHEMICAL (CHEMICAL) + 3TC + NVP (14.5%), 3TC + d4T + efavirenz (EFV) (20.1%), and CHEMICAL + 3TC + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience DISEASE (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were 3TC + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + 3TC + NVP (14.5%), 3TC + d4T + efavirenz (EFV) (20.1%), and AZT + 3TC + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with CHEMICAL aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these DISEASE is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were 3TC + d4T + nevirapine (NVP) (54.8%), CHEMICAL (CHEMICAL) + 3TC + NVP (14.5%), 3TC + d4T + efavirenz (EFV) (20.1%), and CHEMICAL + 3TC + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical DISEASE with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were CHEMICAL + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + CHEMICAL + NVP (14.5%), CHEMICAL + d4T + efavirenz (EFV) (20.1%), and AZT + CHEMICAL + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these DISEASE is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were 3TC + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + 3TC + NVP (14.5%), 3TC + d4T + efavirenz (EFV) (20.1%), and AZT + 3TC + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with CHEMICAL aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience DISEASE, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were CHEMICAL + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + CHEMICAL + NVP (14.5%), CHEMICAL + d4T + efavirenz (EFV) (20.1%), and AZT + CHEMICAL + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and DISEASE (clinical jaundice with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and DISEASE often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian DISEASE patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among DISEASE individuals in South India, we examined the experiences of 3154 DISEASE individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were 3TC + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + 3TC + NVP (14.5%), 3TC + d4T + CHEMICAL (CHEMICAL) (20.1%), and AZT + 3TC + CHEMICAL (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were 3TC + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + 3TC + NVP (14.5%), 3TC + d4T + efavirenz (EFV) (20.1%), and AZT + 3TC + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant DISEASE (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with CHEMICAL aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). DISEASE and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were 3TC + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + 3TC + NVP (14.5%), 3TC + d4T + efavirenz (EFV) (20.1%), and AZT + 3TC + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and DISEASE (clinical jaundice with CHEMICAL aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and DISEASE often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were 3TC + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + 3TC + NVP (14.5%), 3TC + d4T + CHEMICAL (CHEMICAL) (20.1%), and AZT + 3TC + CHEMICAL (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience DISEASE (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were CHEMICAL + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + CHEMICAL + NVP (14.5%), CHEMICAL + d4T + efavirenz (EFV) (20.1%), and AZT + CHEMICAL + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience DISEASE, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian DISEASE patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among DISEASE individuals in South India, we examined the experiences of 3154 DISEASE individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were CHEMICAL + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + CHEMICAL + NVP (14.5%), CHEMICAL + d4T + efavirenz (EFV) (20.1%), and AZT + CHEMICAL + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were 3TC + d4T + nevirapine (NVP) (54.8%), CHEMICAL (CHEMICAL) + 3TC + NVP (14.5%), 3TC + d4T + efavirenz (EFV) (20.1%), and CHEMICAL + 3TC + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant DISEASE (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). DISEASE and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were 3TC + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + 3TC + NVP (14.5%), 3TC + d4T + CHEMICAL (CHEMICAL) (20.1%), and AZT + 3TC + CHEMICAL (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience DISEASE, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were 3TC + d4T + nevirapine (NVP) (54.8%), CHEMICAL (CHEMICAL) + 3TC + NVP (14.5%), 3TC + d4T + efavirenz (EFV) (20.1%), and CHEMICAL + 3TC + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and DISEASE (clinical jaundice with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and DISEASE often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were CHEMICAL + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + CHEMICAL + NVP (14.5%), CHEMICAL + d4T + efavirenz (EFV) (20.1%), and AZT + CHEMICAL + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant DISEASE (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). DISEASE and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were 3TC + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + 3TC + NVP (14.5%), 3TC + d4T + efavirenz (EFV) (20.1%), and AZT + 3TC + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical DISEASE with CHEMICAL aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were CHEMICAL + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + CHEMICAL + NVP (14.5%), CHEMICAL + d4T + efavirenz (EFV) (20.1%), and AZT + CHEMICAL + EFV (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant anemia (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience DISEASE (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). Anemia and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| Spectrum of adverse events after generic HAART in southern Indian HIV-infected patients. To determine the incidence of clinically significant adverse events after long-term, fixed-dose, generic highly active antiretroviral therapy (HAART) use among HIV-infected individuals in South India, we examined the experiences of 3154 HIV-infected individuals who received a minimum of 3 months of generic HAART between February 1996 and December 2006 at a tertiary HIV care referral center in South India. The most common regimens were 3TC + d4T + nevirapine (NVP) (54.8%), zidovudine (AZT) + 3TC + NVP (14.5%), 3TC + d4T + CHEMICAL (CHEMICAL) (20.1%), and AZT + 3TC + CHEMICAL (5.4%). The most common adverse events and median CD4 at time of event were rash (15.2%; CD4, 285 cells/microL) and peripheral neuropathy (9.0% and 348 cells/microL). Clinically significant DISEASE (hemoglobin <7 g/dL) was observed in 5.4% of patients (CD4, 165 cells/microL) and hepatitis (clinical jaundice with alanine aminotransferase > 5 times upper limits of normal) in 3.5% of patients (CD4, 260 cells/microL). Women were significantly more likely to experience lactic acidosis, while men were significantly more likely to experience immune reconstitution syndrome (p < 0.05). Among the patients with 1 year of follow-up, NVP therapy was significantly associated with developing rash and d4T therapy with developing peripheral neuropathy (p < 0.05). DISEASE and hepatitis often occur within 12 weeks of initiating generic HAART. Frequent and early monitoring for these toxicities is warranted in developing countries where generic HAART is increasingly available. | NO-RELATIONSHIP |
| CHEMICAL and sensory neurotoxicity: a neurophysiological study. BACKGROUND: Recent studies confirmed a high incidence of sensory axonal neuropathy in patients treated with different doses of CHEMICAL. The study's aims were to measure variations in sural nerve sensory action potential (SAP) amplitude in patients with refractory cutaneous lupus erythematosus (CLE) treated with CHEMICAL and use these findings to identify the neurotoxic potential of CHEMICAL and the recovery capacity of sensory fibres after discontinuation of treatment. PATIENTS AND METHODS: Clinical and electrophysiological data in 12 female patients with CLE during treatment with CHEMICAL and up to 47 months after discontinuation of treatment were analysed. Sural nerve SAP amplitude reduction > or =40% was the criteria for discontinuing therapy. RESULTS: During treatment, 11 patients showed a reduction in sural nerve SAP amplitude compared to baseline values (9 with a reduction > or =50% and 2 <50%). One patient showed no changes in SAP amplitude. Five patients complained of paresthesias and leg DISEASE. After CHEMICAL treatment, sural SAP amplitude recovered in 3 patients. At detection of reduction in sural nerve SAP amplitude, the median CHEMICAL cumulative dose was 21.4 g. The threshold neurotoxic dosage is lower than previously reported. CONCLUSIONS: Sural nerve SAP amplitude reduction is a reliable and sensitive marker of degeneration and recovery of sensory fibres. This electrophysiological parameter provides information about subclinical neurotoxic potential of CHEMICAL but is not helpful in predicting the appearance of sensory symptoms. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL and DISEASE: a neurophysiological study. BACKGROUND: Recent studies confirmed a high incidence of DISEASE in patients treated with different doses of CHEMICAL. The study's aims were to measure variations in sural nerve sensory action potential (SAP) amplitude in patients with refractory cutaneous lupus erythematosus (CLE) treated with CHEMICAL and use these findings to identify the neurotoxic potential of CHEMICAL and the recovery capacity of sensory fibres after discontinuation of treatment. PATIENTS AND METHODS: Clinical and electrophysiological data in 12 female patients with CLE during treatment with CHEMICAL and up to 47 months after discontinuation of treatment were analysed. Sural nerve SAP amplitude reduction > or =40% was the criteria for discontinuing therapy. RESULTS: During treatment, 11 patients showed a reduction in sural nerve SAP amplitude compared to baseline values (9 with a reduction > or =50% and 2 <50%). One patient showed no changes in SAP amplitude. Five patients complained of paresthesias and leg cramps. After CHEMICAL treatment, sural SAP amplitude recovered in 3 patients. At detection of reduction in sural nerve SAP amplitude, the median CHEMICAL cumulative dose was 21.4 g. The threshold neurotoxic dosage is lower than previously reported. CONCLUSIONS: Sural nerve SAP amplitude reduction is a reliable and sensitive marker of degeneration and recovery of sensory fibres. This electrophysiological parameter provides information about subclinical neurotoxic potential of CHEMICAL but is not helpful in predicting the appearance of sensory symptoms. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL and sensory neurotoxicity: a neurophysiological study. BACKGROUND: Recent studies confirmed a high incidence of sensory axonal neuropathy in patients treated with different doses of CHEMICAL. The study's aims were to measure variations in sural nerve sensory action potential (SAP) amplitude in patients with refractory cutaneous lupus erythematosus (CLE) treated with CHEMICAL and use these findings to identify the neurotoxic potential of CHEMICAL and the recovery capacity of sensory fibres after discontinuation of treatment. PATIENTS AND METHODS: Clinical and electrophysiological data in 12 female patients with CLE during treatment with CHEMICAL and up to 47 months after discontinuation of treatment were analysed. Sural nerve SAP amplitude reduction > or =40% was the criteria for discontinuing therapy. RESULTS: During treatment, 11 patients showed a reduction in sural nerve SAP amplitude compared to baseline values (9 with a reduction > or =50% and 2 <50%). One patient showed no changes in SAP amplitude. Five patients complained of DISEASE and leg cramps. After CHEMICAL treatment, sural SAP amplitude recovered in 3 patients. At detection of reduction in sural nerve SAP amplitude, the median CHEMICAL cumulative dose was 21.4 g. The threshold neurotoxic dosage is lower than previously reported. CONCLUSIONS: Sural nerve SAP amplitude reduction is a reliable and sensitive marker of degeneration and recovery of sensory fibres. This electrophysiological parameter provides information about subclinical neurotoxic potential of CHEMICAL but is not helpful in predicting the appearance of sensory symptoms. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-related DISEASE and unique membranous glomerulonephritis in a patient with valvular heart disease: Diagnostic pitfall and new findings. CHEMICAL is an anti-arrhythmic drug for life-threatening tachycardia, but various adverse effects have been reported. Reported herein is an autopsy case of valvular heart disease, in a patient who developed a DISEASE (1.5 cm in diameter) and proteinuria (2.76 g/day) after treatment with CHEMICAL for a long time. The DISEASE was highly suspected to be lung cancer on CT and positron emission tomography, but histologically the lesion was composed of lymphoplasmacytic infiltrates in alveolar walls and intra-alveolar accumulation of foamy macrophages containing characteristic myelinoid bodies, indicating that it was an CHEMICAL-related lesion. In addition, the lung tissue had unevenly distributed hemosiderin deposition, and abnormally tortuous capillaries were seen in the mass and in heavily hemosiderotic lung portions outside the mass. In the kidneys, glomeruli had membrane spikes, prominent swelling of podocytes and subepithelial deposits, which were sometimes large and hump-like. Autoimmune diseases, viral hepatitis, malignant neoplasms or other diseases with a known relationship to membranous glomerulonephritis were not found. The present case highlights the possibility that differential diagnosis between an CHEMICAL-related DISEASE and a neoplasm can be very difficult radiologically, and suggests that membranous glomerulonephritis might be another possible complication of CHEMICAL treatment. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-related pulmonary mass and unique DISEASE in a patient with valvular heart disease: Diagnostic pitfall and new findings. CHEMICAL is an anti-arrhythmic drug for life-threatening tachycardia, but various adverse effects have been reported. Reported herein is an autopsy case of valvular heart disease, in a patient who developed a lung mass (1.5 cm in diameter) and proteinuria (2.76 g/day) after treatment with CHEMICAL for a long time. The lung mass was highly suspected to be lung cancer on CT and positron emission tomography, but histologically the lesion was composed of lymphoplasmacytic infiltrates in alveolar walls and intra-alveolar accumulation of foamy macrophages containing characteristic myelinoid bodies, indicating that it was an CHEMICAL-related lesion. In addition, the lung tissue had unevenly distributed hemosiderin deposition, and abnormally tortuous capillaries were seen in the mass and in heavily hemosiderotic lung portions outside the mass. In the kidneys, glomeruli had membrane spikes, prominent swelling of podocytes and subepithelial deposits, which were sometimes large and hump-like. Autoimmune diseases, viral hepatitis, malignant neoplasms or other diseases with a known relationship to DISEASE were not found. The present case highlights the possibility that differential diagnosis between an CHEMICAL-related pulmonary lesion and a neoplasm can be very difficult radiologically, and suggests that DISEASE might be another possible complication of CHEMICAL treatment. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-related pulmonary mass and unique membranous glomerulonephritis in a patient with valvular heart disease: Diagnostic pitfall and new findings. CHEMICAL is an anti-arrhythmic drug for life-threatening tachycardia, but various adverse effects have been reported. Reported herein is an autopsy case of valvular heart disease, in a patient who developed a lung mass (1.5 cm in diameter) and proteinuria (2.76 g/day) after treatment with CHEMICAL for a long time. The lung mass was highly suspected to be lung cancer on CT and positron emission tomography, but histologically the lesion was composed of lymphoplasmacytic infiltrates in alveolar walls and intra-alveolar accumulation of foamy macrophages containing characteristic myelinoid bodies, indicating that it was an CHEMICAL-related lesion. In addition, the lung tissue had unevenly distributed DISEASE deposition, and abnormally tortuous capillaries were seen in the mass and in heavily DISEASE lung portions outside the mass. In the kidneys, glomeruli had membrane spikes, prominent swelling of podocytes and subepithelial deposits, which were sometimes large and hump-like. Autoimmune diseases, viral hepatitis, malignant neoplasms or other diseases with a known relationship to membranous glomerulonephritis were not found. The present case highlights the possibility that differential diagnosis between an CHEMICAL-related pulmonary lesion and a neoplasm can be very difficult radiologically, and suggests that membranous glomerulonephritis might be another possible complication of CHEMICAL treatment. | CHEMICAL-INDUCED-DISEASE |
| Risk of DISEASE associated with initial sulphonylurea treatment of patients with type 2 diabetes: a matched case-control study. AIMS: This study sought to assess the risk of developing DISEASE (DISEASE) associated with initial treatment of type 2 diabetes with different sulphonylureas. METHODS: In type 2 diabetic patients, cases who developed DISEASE were compared retrospectively with controls that did not. The 20-year risk of DISEASE at diagnosis of diabetes, using the UKPDS risk engine, was used to match cases with controls. RESULTS: The 76 cases of DISEASE were compared with 152 controls. The hazard of developing DISEASE (95% CI) associated with initial treatment increased by 2.4-fold (1.3-4.3, P=0.004) with CHEMICAL; 2-fold (0.9-4.6, P=0.099) with glipizide; 2.9-fold (1.6-5.1, P=0.000) with either, and was unchanged with metformin. The hazard decreased 0.3-fold (0.7-1.7, P=0.385) with glimepiride, 0.4-fold (0.7-1.3, P=0.192) with gliclazide, and 0.4-fold (0.7-1.1, P=0.09) with either. CONCLUSIONS: Initiating treatment of type 2 diabetes with CHEMICAL or glipizide is associated with increased risk of DISEASE in comparison to gliclazide or glimepiride. If confirmed, this may be important because most Indian patients receive the cheaper older sulphonylureas, and present guidelines do not distinguish between individual agents. | CHEMICAL-INDUCED-DISEASE |
| Risk of coronary artery disease associated with initial sulphonylurea treatment of patients with type 2 diabetes: a matched case-control study. AIMS: This study sought to assess the risk of developing coronary artery disease (CAD) associated with initial treatment of type 2 diabetes with different sulphonylureas. METHODS: In type 2 diabetic patients, cases who developed CAD were compared retrospectively with controls that did not. The 20-year risk of CAD at diagnosis of DISEASE, using the UKPDS risk engine, was used to match cases with controls. RESULTS: The 76 cases of CAD were compared with 152 controls. The hazard of developing CAD (95% CI) associated with initial treatment increased by 2.4-fold (1.3-4.3, P=0.004) with glibenclamide; 2-fold (0.9-4.6, P=0.099) with glipizide; 2.9-fold (1.6-5.1, P=0.000) with either, and was unchanged with metformin. The hazard decreased 0.3-fold (0.7-1.7, P=0.385) with glimepiride, 0.4-fold (0.7-1.3, P=0.192) with CHEMICAL, and 0.4-fold (0.7-1.1, P=0.09) with either. CONCLUSIONS: Initiating treatment of type 2 diabetes with glibenclamide or glipizide is associated with increased risk of CAD in comparison to CHEMICAL or glimepiride. If confirmed, this may be important because most Indian patients receive the cheaper older sulphonylureas, and present guidelines do not distinguish between individual agents. | NO-RELATIONSHIP |
| Risk of coronary artery disease associated with initial sulphonylurea treatment of patients with type 2 diabetes: a matched case-control study. AIMS: This study sought to assess the risk of developing coronary artery disease (CAD) associated with initial treatment of type 2 diabetes with different sulphonylureas. METHODS: In type 2 diabetic patients, cases who developed CAD were compared retrospectively with controls that did not. The 20-year risk of CAD at diagnosis of DISEASE, using the UKPDS risk engine, was used to match cases with controls. RESULTS: The 76 cases of CAD were compared with 152 controls. The hazard of developing CAD (95% CI) associated with initial treatment increased by 2.4-fold (1.3-4.3, P=0.004) with glibenclamide; 2-fold (0.9-4.6, P=0.099) with CHEMICAL; 2.9-fold (1.6-5.1, P=0.000) with either, and was unchanged with metformin. The hazard decreased 0.3-fold (0.7-1.7, P=0.385) with glimepiride, 0.4-fold (0.7-1.3, P=0.192) with gliclazide, and 0.4-fold (0.7-1.1, P=0.09) with either. CONCLUSIONS: Initiating treatment of type 2 diabetes with glibenclamide or CHEMICAL is associated with increased risk of CAD in comparison to gliclazide or glimepiride. If confirmed, this may be important because most Indian patients receive the cheaper older sulphonylureas, and present guidelines do not distinguish between individual agents. | CHEMICAL-INDUCED-DISEASE |
| Risk of coronary artery disease associated with initial sulphonylurea treatment of patients with DISEASE: a matched case-control study. AIMS: This study sought to assess the risk of developing coronary artery disease (CAD) associated with initial treatment of DISEASE with different sulphonylureas. METHODS: In DISEASE patients, cases who developed CAD were compared retrospectively with controls that did not. The 20-year risk of CAD at diagnosis of diabetes, using the UKPDS risk engine, was used to match cases with controls. RESULTS: The 76 cases of CAD were compared with 152 controls. The hazard of developing CAD (95% CI) associated with initial treatment increased by 2.4-fold (1.3-4.3, P=0.004) with glibenclamide; 2-fold (0.9-4.6, P=0.099) with glipizide; 2.9-fold (1.6-5.1, P=0.000) with either, and was unchanged with CHEMICAL. The hazard decreased 0.3-fold (0.7-1.7, P=0.385) with glimepiride, 0.4-fold (0.7-1.3, P=0.192) with gliclazide, and 0.4-fold (0.7-1.1, P=0.09) with either. CONCLUSIONS: Initiating treatment of DISEASE with glibenclamide or glipizide is associated with increased risk of CAD in comparison to gliclazide or glimepiride. If confirmed, this may be important because most Indian patients receive the cheaper older sulphonylureas, and present guidelines do not distinguish between individual agents. | NO-RELATIONSHIP |
| Risk of coronary artery disease associated with initial sulphonylurea treatment of patients with DISEASE: a matched case-control study. AIMS: This study sought to assess the risk of developing coronary artery disease (CAD) associated with initial treatment of DISEASE with different sulphonylureas. METHODS: In DISEASE patients, cases who developed CAD were compared retrospectively with controls that did not. The 20-year risk of CAD at diagnosis of diabetes, using the UKPDS risk engine, was used to match cases with controls. RESULTS: The 76 cases of CAD were compared with 152 controls. The hazard of developing CAD (95% CI) associated with initial treatment increased by 2.4-fold (1.3-4.3, P=0.004) with glibenclamide; 2-fold (0.9-4.6, P=0.099) with CHEMICAL; 2.9-fold (1.6-5.1, P=0.000) with either, and was unchanged with metformin. The hazard decreased 0.3-fold (0.7-1.7, P=0.385) with glimepiride, 0.4-fold (0.7-1.3, P=0.192) with gliclazide, and 0.4-fold (0.7-1.1, P=0.09) with either. CONCLUSIONS: Initiating treatment of DISEASE with glibenclamide or CHEMICAL is associated with increased risk of CAD in comparison to gliclazide or glimepiride. If confirmed, this may be important because most Indian patients receive the cheaper older sulphonylureas, and present guidelines do not distinguish between individual agents. | CHEMICAL-INDUCED-DISEASE |
| Risk of coronary artery disease associated with initial sulphonylurea treatment of patients with DISEASE: a matched case-control study. AIMS: This study sought to assess the risk of developing coronary artery disease (CAD) associated with initial treatment of DISEASE with different sulphonylureas. METHODS: In DISEASE patients, cases who developed CAD were compared retrospectively with controls that did not. The 20-year risk of CAD at diagnosis of diabetes, using the UKPDS risk engine, was used to match cases with controls. RESULTS: The 76 cases of CAD were compared with 152 controls. The hazard of developing CAD (95% CI) associated with initial treatment increased by 2.4-fold (1.3-4.3, P=0.004) with glibenclamide; 2-fold (0.9-4.6, P=0.099) with glipizide; 2.9-fold (1.6-5.1, P=0.000) with either, and was unchanged with metformin. The hazard decreased 0.3-fold (0.7-1.7, P=0.385) with glimepiride, 0.4-fold (0.7-1.3, P=0.192) with CHEMICAL, and 0.4-fold (0.7-1.1, P=0.09) with either. CONCLUSIONS: Initiating treatment of DISEASE with glibenclamide or glipizide is associated with increased risk of CAD in comparison to CHEMICAL or glimepiride. If confirmed, this may be important because most Indian patients receive the cheaper older sulphonylureas, and present guidelines do not distinguish between individual agents. | NO-RELATIONSHIP |
| Risk of coronary artery disease associated with initial sulphonylurea treatment of patients with DISEASE: a matched case-control study. AIMS: This study sought to assess the risk of developing coronary artery disease (CAD) associated with initial treatment of DISEASE with different sulphonylureas. METHODS: In DISEASE patients, cases who developed CAD were compared retrospectively with controls that did not. The 20-year risk of CAD at diagnosis of diabetes, using the UKPDS risk engine, was used to match cases with controls. RESULTS: The 76 cases of CAD were compared with 152 controls. The hazard of developing CAD (95% CI) associated with initial treatment increased by 2.4-fold (1.3-4.3, P=0.004) with glibenclamide; 2-fold (0.9-4.6, P=0.099) with glipizide; 2.9-fold (1.6-5.1, P=0.000) with either, and was unchanged with metformin. The hazard decreased 0.3-fold (0.7-1.7, P=0.385) with CHEMICAL, 0.4-fold (0.7-1.3, P=0.192) with gliclazide, and 0.4-fold (0.7-1.1, P=0.09) with either. CONCLUSIONS: Initiating treatment of DISEASE with glibenclamide or glipizide is associated with increased risk of CAD in comparison to gliclazide or CHEMICAL. If confirmed, this may be important because most Indian patients receive the cheaper older sulphonylureas, and present guidelines do not distinguish between individual agents. | NO-RELATIONSHIP |
| Risk of coronary artery disease associated with initial sulphonylurea treatment of patients with type 2 diabetes: a matched case-control study. AIMS: This study sought to assess the risk of developing coronary artery disease (CAD) associated with initial treatment of type 2 diabetes with different sulphonylureas. METHODS: In type 2 diabetic patients, cases who developed CAD were compared retrospectively with controls that did not. The 20-year risk of CAD at diagnosis of DISEASE, using the UKPDS risk engine, was used to match cases with controls. RESULTS: The 76 cases of CAD were compared with 152 controls. The hazard of developing CAD (95% CI) associated with initial treatment increased by 2.4-fold (1.3-4.3, P=0.004) with glibenclamide; 2-fold (0.9-4.6, P=0.099) with glipizide; 2.9-fold (1.6-5.1, P=0.000) with either, and was unchanged with CHEMICAL. The hazard decreased 0.3-fold (0.7-1.7, P=0.385) with glimepiride, 0.4-fold (0.7-1.3, P=0.192) with gliclazide, and 0.4-fold (0.7-1.1, P=0.09) with either. CONCLUSIONS: Initiating treatment of type 2 diabetes with glibenclamide or glipizide is associated with increased risk of CAD in comparison to gliclazide or glimepiride. If confirmed, this may be important because most Indian patients receive the cheaper older sulphonylureas, and present guidelines do not distinguish between individual agents. | NO-RELATIONSHIP |
| Risk of coronary artery disease associated with initial sulphonylurea treatment of patients with type 2 diabetes: a matched case-control study. AIMS: This study sought to assess the risk of developing coronary artery disease (CAD) associated with initial treatment of type 2 diabetes with different sulphonylureas. METHODS: In type 2 diabetic patients, cases who developed CAD were compared retrospectively with controls that did not. The 20-year risk of CAD at diagnosis of DISEASE, using the UKPDS risk engine, was used to match cases with controls. RESULTS: The 76 cases of CAD were compared with 152 controls. The hazard of developing CAD (95% CI) associated with initial treatment increased by 2.4-fold (1.3-4.3, P=0.004) with glibenclamide; 2-fold (0.9-4.6, P=0.099) with glipizide; 2.9-fold (1.6-5.1, P=0.000) with either, and was unchanged with metformin. The hazard decreased 0.3-fold (0.7-1.7, P=0.385) with CHEMICAL, 0.4-fold (0.7-1.3, P=0.192) with gliclazide, and 0.4-fold (0.7-1.1, P=0.09) with either. CONCLUSIONS: Initiating treatment of type 2 diabetes with glibenclamide or glipizide is associated with increased risk of CAD in comparison to gliclazide or CHEMICAL. If confirmed, this may be important because most Indian patients receive the cheaper older sulphonylureas, and present guidelines do not distinguish between individual agents. | NO-RELATIONSHIP |
| Risk of coronary artery disease associated with initial CHEMICAL treatment of patients with DISEASE: a matched case-control study. AIMS: This study sought to assess the risk of developing coronary artery disease (CAD) associated with initial treatment of DISEASE with different CHEMICAL. METHODS: In DISEASE patients, cases who developed CAD were compared retrospectively with controls that did not. The 20-year risk of CAD at diagnosis of diabetes, using the UKPDS risk engine, was used to match cases with controls. RESULTS: The 76 cases of CAD were compared with 152 controls. The hazard of developing CAD (95% CI) associated with initial treatment increased by 2.4-fold (1.3-4.3, P=0.004) with glibenclamide; 2-fold (0.9-4.6, P=0.099) with glipizide; 2.9-fold (1.6-5.1, P=0.000) with either, and was unchanged with metformin. The hazard decreased 0.3-fold (0.7-1.7, P=0.385) with glimepiride, 0.4-fold (0.7-1.3, P=0.192) with gliclazide, and 0.4-fold (0.7-1.1, P=0.09) with either. CONCLUSIONS: Initiating treatment of DISEASE with glibenclamide or glipizide is associated with increased risk of CAD in comparison to gliclazide or glimepiride. If confirmed, this may be important because most Indian patients receive the cheaper older CHEMICAL, and present guidelines do not distinguish between individual agents. | NO-RELATIONSHIP |
| Risk of coronary artery disease associated with initial CHEMICAL treatment of patients with type 2 diabetes: a matched case-control study. AIMS: This study sought to assess the risk of developing coronary artery disease (CAD) associated with initial treatment of type 2 diabetes with different CHEMICAL. METHODS: In type 2 diabetic patients, cases who developed CAD were compared retrospectively with controls that did not. The 20-year risk of CAD at diagnosis of DISEASE, using the UKPDS risk engine, was used to match cases with controls. RESULTS: The 76 cases of CAD were compared with 152 controls. The hazard of developing CAD (95% CI) associated with initial treatment increased by 2.4-fold (1.3-4.3, P=0.004) with glibenclamide; 2-fold (0.9-4.6, P=0.099) with glipizide; 2.9-fold (1.6-5.1, P=0.000) with either, and was unchanged with metformin. The hazard decreased 0.3-fold (0.7-1.7, P=0.385) with glimepiride, 0.4-fold (0.7-1.3, P=0.192) with gliclazide, and 0.4-fold (0.7-1.1, P=0.09) with either. CONCLUSIONS: Initiating treatment of type 2 diabetes with glibenclamide or glipizide is associated with increased risk of CAD in comparison to gliclazide or glimepiride. If confirmed, this may be important because most Indian patients receive the cheaper older CHEMICAL, and present guidelines do not distinguish between individual agents. | NO-RELATIONSHIP |
| Reduced progression of CHEMICAL nephropathy in spontaneously hypertensive rats treated by losartan. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of angiotensin II type-1 receptor blocker, losartan, and its potential in slowing down renal disease progression in spontaneously hypertensive rats (SHR) with CHEMICAL (CHEMICAL) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups CHEMICAL(6), CHEMICAL+LOS(6) and CHEMICAL(12), and CHEMICAL+LOS(12) received CHEMICAL (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group CHEMICAL+LOS(6) received losartan (10 mg/kg/b.w./day by gavages) for 6 weeks and group CHEMICAL+LOS(12) for 12 weeks after second injection of CHEMICAL. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term losartan treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with losartan showed further reduction of glomerulosclerosis associated with reduced progression of tubular atrophy and interstitial fibrosis, thus preventing heavy proteinuria and chronic renal failure. Losartan reduced DISEASE and increased urea clearance in advanced CHEMICAL nephropathy in SHR. Histological examination showed that losartan could prevent tubular atrophy, interstitial infiltration and fibrosis in CHEMICAL nephropathy. CONCLUSION: Losartan reduces the rate of progression of CHEMICAL-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR. | CHEMICAL-INDUCED-DISEASE |
| Reduced progression of CHEMICAL nephropathy in spontaneously hypertensive rats treated by losartan. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of angiotensin II type-1 receptor blocker, losartan, and its potential in slowing down renal disease progression in spontaneously hypertensive rats (SHR) with CHEMICAL (CHEMICAL) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups CHEMICAL(6), CHEMICAL+LOS(6) and CHEMICAL(12), and CHEMICAL+LOS(12) received CHEMICAL (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group CHEMICAL+LOS(6) received losartan (10 mg/kg/b.w./day by gavages) for 6 weeks and group CHEMICAL+LOS(12) for 12 weeks after second injection of CHEMICAL. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term losartan treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with losartan showed further reduction of glomerulosclerosis associated with reduced progression of tubular atrophy and interstitial fibrosis, thus preventing heavy proteinuria and chronic renal failure. Losartan reduced uraemia and increased urea clearance in advanced CHEMICAL nephropathy in SHR. Histological examination showed that losartan could prevent tubular atrophy, interstitial infiltration and fibrosis in CHEMICAL nephropathy. CONCLUSION: Losartan reduces the rate of progression of CHEMICAL-induced DISEASE to end-stage renal disease in SHR. | CHEMICAL-INDUCED-DISEASE |
| Reduced progression of CHEMICAL nephropathy in spontaneously hypertensive rats treated by losartan. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of angiotensin II type-1 receptor blocker, losartan, and its potential in slowing down renal disease progression in spontaneously hypertensive rats (SHR) with CHEMICAL (CHEMICAL) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups CHEMICAL(6), CHEMICAL+LOS(6) and CHEMICAL(12), and CHEMICAL+LOS(12) received CHEMICAL (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group CHEMICAL+LOS(6) received losartan (10 mg/kg/b.w./day by gavages) for 6 weeks and group CHEMICAL+LOS(12) for 12 weeks after second injection of CHEMICAL. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term losartan treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased DISEASE. Prolonged treatment with losartan showed further reduction of glomerulosclerosis associated with reduced progression of tubular atrophy and interstitial fibrosis, thus preventing heavy DISEASE and chronic renal failure. Losartan reduced uraemia and increased urea clearance in advanced CHEMICAL nephropathy in SHR. Histological examination showed that losartan could prevent tubular atrophy, interstitial infiltration and fibrosis in CHEMICAL nephropathy. CONCLUSION: Losartan reduces the rate of progression of CHEMICAL-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR. | CHEMICAL-INDUCED-DISEASE |
| Reduced progression of adriamycin nephropathy in spontaneously DISEASE rats treated by losartan. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of angiotensin II type-1 receptor blocker, losartan, and its potential in slowing down renal disease progression in spontaneously DISEASE rats (SHR) with adriamycin (ADR) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+LOS(6) and ADR(12), and ADR+LOS(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+LOS(6) received losartan (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+LOS(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term losartan treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with losartan showed further reduction of glomerulosclerosis associated with reduced progression of tubular atrophy and interstitial fibrosis, thus preventing heavy proteinuria and chronic renal failure. Losartan reduced uraemia and increased CHEMICAL clearance in advanced ADR nephropathy in SHR. Histological examination showed that losartan could prevent tubular atrophy, interstitial infiltration and fibrosis in ADR nephropathy. CONCLUSION: Losartan reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR. | NO-RELATIONSHIP |
| Reduced progression of adriamycin nephropathy in spontaneously hypertensive rats treated by CHEMICAL. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of angiotensin II type-1 receptor blocker, CHEMICAL, and its potential in slowing down renal disease progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+CHEMICAL(6) and ADR(12), and ADR+CHEMICAL(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+CHEMICAL(6) received CHEMICAL (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+CHEMICAL(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term CHEMICAL treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated DISEASE resulting in decreased proteinuria. Prolonged treatment with CHEMICAL showed further reduction of DISEASE associated with reduced progression of tubular atrophy and interstitial fibrosis, thus preventing heavy proteinuria and chronic renal failure. CHEMICAL reduced uraemia and increased urea clearance in advanced ADR nephropathy in SHR. Histological examination showed that CHEMICAL could prevent tubular atrophy, interstitial infiltration and fibrosis in ADR nephropathy. CONCLUSION: CHEMICAL reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR. | NO-RELATIONSHIP |
| Reduced progression of adriamycin nephropathy in spontaneously hypertensive rats treated by losartan. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of angiotensin II type-1 receptor blocker, losartan, and its potential in slowing down renal disease progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+LOS(6) and ADR(12), and ADR+LOS(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+LOS(6) received losartan (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+LOS(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term losartan treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with losartan showed further reduction of glomerulosclerosis associated with reduced progression of tubular DISEASE and interstitial fibrosis, thus preventing heavy proteinuria and chronic renal failure. Losartan reduced uraemia and increased CHEMICAL clearance in advanced ADR nephropathy in SHR. Histological examination showed that losartan could prevent tubular DISEASE, interstitial infiltration and fibrosis in ADR nephropathy. CONCLUSION: Losartan reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR. | NO-RELATIONSHIP |
| Reduced progression of adriamycin DISEASE in spontaneously hypertensive rats treated by losartan. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of CHEMICAL type-1 receptor blocker, losartan, and its potential in slowing down DISEASE progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) DISEASE. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+LOS(6) and ADR(12), and ADR+LOS(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+LOS(6) received losartan (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+LOS(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term losartan treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with losartan showed further reduction of glomerulosclerosis associated with reduced progression of tubular atrophy and interstitial fibrosis, thus preventing heavy proteinuria and chronic renal failure. Losartan reduced uraemia and increased urea clearance in advanced ADR DISEASE in SHR. Histological examination showed that losartan could prevent tubular atrophy, interstitial infiltration and fibrosis in ADR DISEASE. CONCLUSION: Losartan reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR. | NO-RELATIONSHIP |
| Reduced progression of adriamycin nephropathy in spontaneously hypertensive rats treated by losartan. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of angiotensin II type-1 receptor blocker, losartan, and its potential in slowing down renal disease progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+LOS(6) and ADR(12), and ADR+LOS(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+LOS(6) received losartan (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+LOS(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term losartan treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with losartan showed further reduction of glomerulosclerosis associated with reduced progression of tubular atrophy and DISEASE, thus preventing heavy proteinuria and chronic renal failure. Losartan reduced uraemia and increased CHEMICAL clearance in advanced ADR nephropathy in SHR. Histological examination showed that losartan could prevent tubular atrophy, interstitial infiltration and DISEASE in ADR nephropathy. CONCLUSION: Losartan reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR. | NO-RELATIONSHIP |
| Reduced progression of adriamycin nephropathy in spontaneously DISEASE rats treated by losartan. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of CHEMICAL type-1 receptor blocker, losartan, and its potential in slowing down renal disease progression in spontaneously DISEASE rats (SHR) with adriamycin (ADR) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+LOS(6) and ADR(12), and ADR+LOS(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+LOS(6) received losartan (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+LOS(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term losartan treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with losartan showed further reduction of glomerulosclerosis associated with reduced progression of tubular atrophy and interstitial fibrosis, thus preventing heavy proteinuria and chronic renal failure. Losartan reduced uraemia and increased urea clearance in advanced ADR nephropathy in SHR. Histological examination showed that losartan could prevent tubular atrophy, interstitial infiltration and fibrosis in ADR nephropathy. CONCLUSION: Losartan reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR. | NO-RELATIONSHIP |
| Reduced progression of adriamycin DISEASE in spontaneously hypertensive rats treated by losartan. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of angiotensin II type-1 receptor blocker, losartan, and its potential in slowing down DISEASE progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) DISEASE. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+LOS(6) and ADR(12), and ADR+LOS(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+LOS(6) received losartan (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+LOS(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term losartan treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with losartan showed further reduction of glomerulosclerosis associated with reduced progression of tubular atrophy and interstitial fibrosis, thus preventing heavy proteinuria and chronic renal failure. Losartan reduced uraemia and increased CHEMICAL clearance in advanced ADR DISEASE in SHR. Histological examination showed that losartan could prevent tubular atrophy, interstitial infiltration and fibrosis in ADR DISEASE. CONCLUSION: Losartan reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR. | NO-RELATIONSHIP |
| Reduced progression of adriamycin nephropathy in spontaneously hypertensive rats treated by losartan. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of angiotensin II type-1 receptor blocker, losartan, and its potential in slowing down renal disease progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+LOS(6) and ADR(12), and ADR+LOS(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+LOS(6) received losartan (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+LOS(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term losartan treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with losartan showed further reduction of glomerulosclerosis associated with reduced progression of tubular atrophy and interstitial fibrosis, thus preventing heavy proteinuria and DISEASE. Losartan reduced uraemia and increased CHEMICAL clearance in advanced ADR nephropathy in SHR. Histological examination showed that losartan could prevent tubular atrophy, interstitial infiltration and fibrosis in ADR nephropathy. CONCLUSION: Losartan reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to DISEASE in SHR. | NO-RELATIONSHIP |
| Reduced progression of adriamycin nephropathy in spontaneously hypertensive rats treated by losartan. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of CHEMICAL type-1 receptor blocker, losartan, and its potential in slowing down renal disease progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+LOS(6) and ADR(12), and ADR+LOS(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+LOS(6) received losartan (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+LOS(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term losartan treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with losartan showed further reduction of glomerulosclerosis associated with reduced progression of tubular DISEASE and interstitial fibrosis, thus preventing heavy proteinuria and chronic renal failure. Losartan reduced uraemia and increased urea clearance in advanced ADR nephropathy in SHR. Histological examination showed that losartan could prevent tubular DISEASE, interstitial infiltration and fibrosis in ADR nephropathy. CONCLUSION: Losartan reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR. | NO-RELATIONSHIP |
| Reduced progression of adriamycin nephropathy in spontaneously hypertensive rats treated by losartan. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of angiotensin II type-1 receptor blocker, losartan, and its potential in slowing down renal disease progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+LOS(6) and ADR(12), and ADR+LOS(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+LOS(6) received losartan (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+LOS(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term losartan treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated DISEASE resulting in decreased proteinuria. Prolonged treatment with losartan showed further reduction of DISEASE associated with reduced progression of tubular atrophy and interstitial fibrosis, thus preventing heavy proteinuria and chronic renal failure. Losartan reduced uraemia and increased CHEMICAL clearance in advanced ADR nephropathy in SHR. Histological examination showed that losartan could prevent tubular atrophy, interstitial infiltration and fibrosis in ADR nephropathy. CONCLUSION: Losartan reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR. | NO-RELATIONSHIP |
| Reduced progression of adriamycin nephropathy in spontaneously hypertensive rats treated by CHEMICAL. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of angiotensin II type-1 receptor blocker, CHEMICAL, and its potential in slowing down renal disease progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+CHEMICAL(6) and ADR(12), and ADR+CHEMICAL(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+CHEMICAL(6) received CHEMICAL (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+CHEMICAL(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term CHEMICAL treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with CHEMICAL showed further reduction of glomerulosclerosis associated with reduced progression of tubular DISEASE and interstitial fibrosis, thus preventing heavy proteinuria and chronic renal failure. CHEMICAL reduced uraemia and increased urea clearance in advanced ADR nephropathy in SHR. Histological examination showed that CHEMICAL could prevent tubular DISEASE, interstitial infiltration and fibrosis in ADR nephropathy. CONCLUSION: CHEMICAL reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR. | NO-RELATIONSHIP |
| Reduced progression of adriamycin nephropathy in spontaneously hypertensive rats treated by losartan. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of CHEMICAL type-1 receptor blocker, losartan, and its potential in slowing down renal disease progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+LOS(6) and ADR(12), and ADR+LOS(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+LOS(6) received losartan (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+LOS(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term losartan treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated DISEASE resulting in decreased proteinuria. Prolonged treatment with losartan showed further reduction of DISEASE associated with reduced progression of tubular atrophy and interstitial fibrosis, thus preventing heavy proteinuria and chronic renal failure. Losartan reduced uraemia and increased urea clearance in advanced ADR nephropathy in SHR. Histological examination showed that losartan could prevent tubular atrophy, interstitial infiltration and fibrosis in ADR nephropathy. CONCLUSION: Losartan reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR. | NO-RELATIONSHIP |
| Reduced progression of adriamycin nephropathy in spontaneously hypertensive rats treated by losartan. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of CHEMICAL type-1 receptor blocker, losartan, and its potential in slowing down renal disease progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+LOS(6) and ADR(12), and ADR+LOS(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+LOS(6) received losartan (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+LOS(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term losartan treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with losartan showed further reduction of glomerulosclerosis associated with reduced progression of tubular atrophy and interstitial fibrosis, thus preventing heavy proteinuria and DISEASE. Losartan reduced uraemia and increased urea clearance in advanced ADR nephropathy in SHR. Histological examination showed that losartan could prevent tubular atrophy, interstitial infiltration and fibrosis in ADR nephropathy. CONCLUSION: Losartan reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to DISEASE in SHR. | NO-RELATIONSHIP |
| Reduced progression of adriamycin nephropathy in spontaneously hypertensive rats treated by losartan. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of CHEMICAL type-1 receptor blocker, losartan, and its potential in slowing down renal disease progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+LOS(6) and ADR(12), and ADR+LOS(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+LOS(6) received losartan (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+LOS(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term losartan treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with losartan showed further reduction of glomerulosclerosis associated with reduced progression of tubular atrophy and DISEASE, thus preventing heavy proteinuria and chronic renal failure. Losartan reduced uraemia and increased urea clearance in advanced ADR nephropathy in SHR. Histological examination showed that losartan could prevent tubular atrophy, interstitial infiltration and DISEASE in ADR nephropathy. CONCLUSION: Losartan reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR. | NO-RELATIONSHIP |
| Reduced progression of adriamycin DISEASE in spontaneously hypertensive rats treated by CHEMICAL. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of angiotensin II type-1 receptor blocker, CHEMICAL, and its potential in slowing down DISEASE progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) DISEASE. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+CHEMICAL(6) and ADR(12), and ADR+CHEMICAL(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+CHEMICAL(6) received CHEMICAL (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+CHEMICAL(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term CHEMICAL treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with CHEMICAL showed further reduction of glomerulosclerosis associated with reduced progression of tubular atrophy and interstitial fibrosis, thus preventing heavy proteinuria and chronic renal failure. CHEMICAL reduced uraemia and increased urea clearance in advanced ADR DISEASE in SHR. Histological examination showed that CHEMICAL could prevent tubular atrophy, interstitial infiltration and fibrosis in ADR DISEASE. CONCLUSION: CHEMICAL reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR. | NO-RELATIONSHIP |
| Reduced progression of adriamycin nephropathy in spontaneously hypertensive rats treated by CHEMICAL. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of angiotensin II type-1 receptor blocker, CHEMICAL, and its potential in slowing down renal disease progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+CHEMICAL(6) and ADR(12), and ADR+CHEMICAL(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+CHEMICAL(6) received CHEMICAL (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+CHEMICAL(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term CHEMICAL treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with CHEMICAL showed further reduction of glomerulosclerosis associated with reduced progression of tubular atrophy and interstitial fibrosis, thus preventing heavy proteinuria and DISEASE. CHEMICAL reduced uraemia and increased urea clearance in advanced ADR nephropathy in SHR. Histological examination showed that CHEMICAL could prevent tubular atrophy, interstitial infiltration and fibrosis in ADR nephropathy. CONCLUSION: CHEMICAL reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to DISEASE in SHR. | NO-RELATIONSHIP |
| Reduced progression of adriamycin nephropathy in spontaneously hypertensive rats treated by CHEMICAL. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of angiotensin II type-1 receptor blocker, CHEMICAL, and its potential in slowing down renal disease progression in spontaneously hypertensive rats (SHR) with adriamycin (ADR) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+CHEMICAL(6) and ADR(12), and ADR+CHEMICAL(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+CHEMICAL(6) received CHEMICAL (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+CHEMICAL(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term CHEMICAL treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with CHEMICAL showed further reduction of glomerulosclerosis associated with reduced progression of tubular atrophy and DISEASE, thus preventing heavy proteinuria and chronic renal failure. CHEMICAL reduced uraemia and increased urea clearance in advanced ADR nephropathy in SHR. Histological examination showed that CHEMICAL could prevent tubular atrophy, interstitial infiltration and DISEASE in ADR nephropathy. CONCLUSION: CHEMICAL reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR. | NO-RELATIONSHIP |
| Reduced progression of adriamycin nephropathy in spontaneously DISEASE rats treated by CHEMICAL. BACKGROUND: The aim of the study was to investigate the antihypertensive effects of angiotensin II type-1 receptor blocker, CHEMICAL, and its potential in slowing down renal disease progression in spontaneously DISEASE rats (SHR) with adriamycin (ADR) nephropathy. METHODS: Six-month-old female SHR were randomly selected in six groups. Two control groups (SH(6), SH(12)) received vehicle. Groups ADR(6), ADR+CHEMICAL(6) and ADR(12), and ADR+CHEMICAL(12) received ADR (2 mg/kg/b.w. i.v.) twice in a 3-week interval. Group ADR+CHEMICAL(6) received CHEMICAL (10 mg/kg/b.w./day by gavages) for 6 weeks and group ADR+CHEMICAL(12) for 12 weeks after second injection of ADR. Animals were killed after 6 or 12 weeks, respectively. Haemodynamic measurements were performed on anaesthetized animals, blood and urine samples were taken for biochemical analysis and the left kidney was processed for morphological studies. RESULTS: Short-term CHEMICAL treatment, besides antihypertensive effect, improved glomerular filtration rate and ameliorated glomerulosclerosis resulting in decreased proteinuria. Prolonged treatment with CHEMICAL showed further reduction of glomerulosclerosis associated with reduced progression of tubular atrophy and interstitial fibrosis, thus preventing heavy proteinuria and chronic renal failure. CHEMICAL reduced uraemia and increased urea clearance in advanced ADR nephropathy in SHR. Histological examination showed that CHEMICAL could prevent tubular atrophy, interstitial infiltration and fibrosis in ADR nephropathy. CONCLUSION: CHEMICAL reduces the rate of progression of ADR-induced focal segmental glomerulosclerosis to end-stage renal disease in SHR. | NO-RELATIONSHIP |
| The risks of aprotinin and CHEMICAL in cardiac surgery: a one-year follow-up of 1188 consecutive patients. BACKGROUND: Our aim was to investigate postoperative complications and mortality after administration of aprotinin compared to CHEMICAL in an unselected, consecutive cohort. METHODS: Perioperative data from consecutive cardiac surgery patients were prospectively collected between September 2005 and June 2006 in a university-affiliated clinic (n = 1188). During the first 5 mo, 596 patients received aprotinin (Group A); in the next 5 mo, 592 patients were treated with CHEMICAL (Group T). Except for antifibrinolytic therapy, the anesthetic and surgical protocols remained unchanged. RESULTS: The pre- and intraoperative variables were comparable between the treatment groups. Postoperatively, a significantly higher incidence of seizures was found in Group T (4.6% vs 1.2%, P < 0.001). This difference was also significant in the primary valve surgery and the high risk surgery subgroups (7.9% vs 1.2%, P = 0.003; 7.3% vs 2.4%, P = 0.035, respectively). Persistent atrial fibrillation (7.9% vs 2.3%, P = 0.020) and DISEASE (9.7% vs 1.7%, P = 0.002) were also more common in Group T, in the primary valve surgery subgroup. On the contrary, among primary coronary artery bypass surgery patients, there were more acute myocardial infarctions and renal dysfunction in Group A (5.8% vs 2.0%, P = 0.027; 22.5% vs 15.2%, P = 0.036, respectively). The 1-yr mortality was significantly higher after aprotinin treatment in the high risk surgery group (17.7% vs 9.8%, P = 0.034). CONCLUSION: Both antifibrinolytic drugs bear the risk of adverse outcome depending on the type of cardiac surgery. Administration of aprotinin should be avoided in coronary artery bypass graft and high risk patients, whereas administration of CHEMICAL is not recommended in valve surgery. | CHEMICAL-INDUCED-DISEASE |
| The risks of aprotinin and CHEMICAL in cardiac surgery: a one-year follow-up of 1188 consecutive patients. BACKGROUND: Our aim was to investigate postoperative complications and mortality after administration of aprotinin compared to CHEMICAL in an unselected, consecutive cohort. METHODS: Perioperative data from consecutive cardiac surgery patients were prospectively collected between September 2005 and June 2006 in a university-affiliated clinic (n = 1188). During the first 5 mo, 596 patients received aprotinin (Group A); in the next 5 mo, 592 patients were treated with CHEMICAL (Group T). Except for antifibrinolytic therapy, the anesthetic and surgical protocols remained unchanged. RESULTS: The pre- and intraoperative variables were comparable between the treatment groups. Postoperatively, a significantly higher incidence of DISEASE was found in Group T (4.6% vs 1.2%, P < 0.001). This difference was also significant in the primary valve surgery and the high risk surgery subgroups (7.9% vs 1.2%, P = 0.003; 7.3% vs 2.4%, P = 0.035, respectively). Persistent atrial fibrillation (7.9% vs 2.3%, P = 0.020) and renal failure (9.7% vs 1.7%, P = 0.002) were also more common in Group T, in the primary valve surgery subgroup. On the contrary, among primary coronary artery bypass surgery patients, there were more acute myocardial infarctions and renal dysfunction in Group A (5.8% vs 2.0%, P = 0.027; 22.5% vs 15.2%, P = 0.036, respectively). The 1-yr mortality was significantly higher after aprotinin treatment in the high risk surgery group (17.7% vs 9.8%, P = 0.034). CONCLUSION: Both antifibrinolytic drugs bear the risk of adverse outcome depending on the type of cardiac surgery. Administration of aprotinin should be avoided in coronary artery bypass graft and high risk patients, whereas administration of CHEMICAL is not recommended in valve surgery. | CHEMICAL-INDUCED-DISEASE |
| The biological properties of the optical isomers of propranolol and their effects on DISEASE. 1. The optical isomers of propranolol have been compared for their beta-blocking and antiarrhythmic activities.2. In blocking the positive inotropic and chronotropic responses to isoprenaline, (+)-propranolol had less than one hundredth the potency of (-)-propranolol. At dose levels of (+)-propranolol which attenuated the responses to isoprenaline, there was a significant prolongation of the PR interval of the electrocardiogram.3. The metabolic responses to isoprenaline in dogs (an increase in circulating glucose, lactate and free fatty acids) were all blocked by (-)-propranolol. (+)-Propranolol had no effect on fatty acid mobilization but significantly reduced the increments in both lactate and glucose.4. Both isomers of propranolol possessed similar depressant potency on isolated atrial muscle taken from guinea-pigs.5. The isomers of propranolol exhibited similar local anaesthetic potencies on an isolated frog nerve preparation at a level approximately three times that of procaine. The racemic compound was significantly less potent than either isomer.6. Both isomers of propranolol were capable of preventing adrenaline-induced DISEASE in cats anaesthetized with CHEMICAL, but the mean dose of (-)-propranolol was 0.09+/-0.02 mg/kg whereas that of (+)-propranolol was 4.2+/-1.2 mg/kg. At the effective dose level of (+)-propranolol there was a significant prolongation of the PR interval of the electrocardiogram. Blockade of DISEASE with both isomers was surmountable by increasing the dose of adrenaline.7. Both isomers of propranolol were also capable of reversing ventricular tachycardia caused by ouabain in anaesthetized cats and dogs. The dose of (-)-propranolol was significantly smaller than that of (+)-propranolol in both species but much higher than that required to produce evidence of beta-blockade.8. The implications of these results are discussed. | NO-RELATIONSHIP |
| The biological properties of the optical isomers of propranolol and their effects on cardiac arrhythmias. 1. The optical isomers of propranolol have been compared for their beta-blocking and antiarrhythmic activities.2. In blocking the positive inotropic and chronotropic responses to isoprenaline, (+)-propranolol had less than one hundredth the potency of (-)-propranolol. At dose levels of (+)-propranolol which attenuated the responses to isoprenaline, there was a significant prolongation of the PR interval of the electrocardiogram.3. The metabolic responses to isoprenaline in dogs (an increase in circulating glucose, lactate and free fatty acids) were all blocked by (-)-propranolol. (+)-Propranolol had no effect on fatty acid mobilization but significantly reduced the increments in both lactate and glucose.4. Both isomers of propranolol possessed similar depressant potency on isolated atrial muscle taken from guinea-pigs.5. The isomers of propranolol exhibited similar local anaesthetic potencies on an isolated frog nerve preparation at a level approximately three times that of procaine. The racemic compound was significantly less potent than either isomer.6. Both isomers of propranolol were capable of preventing adrenaline-induced cardiac arrhythmias in cats anaesthetized with halothane, but the mean dose of (-)-propranolol was 0.09+/-0.02 mg/kg whereas that of (+)-propranolol was 4.2+/-1.2 mg/kg. At the effective dose level of (+)-propranolol there was a significant prolongation of the PR interval of the electrocardiogram. Blockade of arrhythmias with both isomers was surmountable by increasing the dose of adrenaline.7. Both isomers of propranolol were also capable of reversing DISEASE caused by CHEMICAL in anaesthetized cats and dogs. The dose of (-)-propranolol was significantly smaller than that of (+)-propranolol in both species but much higher than that required to produce evidence of beta-blockade.8. The implications of these results are discussed. | CHEMICAL-INDUCED-DISEASE |
| The biological properties of the optical isomers of propranolol and their effects on DISEASE. 1. The optical isomers of propranolol have been compared for their beta-blocking and antiarrhythmic activities.2. In blocking the positive inotropic and chronotropic responses to isoprenaline, (+)-propranolol had less than one hundredth the potency of (-)-propranolol. At dose levels of (+)-propranolol which attenuated the responses to isoprenaline, there was a significant prolongation of the PR interval of the electrocardiogram.3. The metabolic responses to isoprenaline in dogs (an increase in circulating glucose, lactate and free fatty acids) were all blocked by (-)-propranolol. (+)-Propranolol had no effect on fatty acid mobilization but significantly reduced the increments in both lactate and glucose.4. Both isomers of propranolol possessed similar depressant potency on isolated atrial muscle taken from guinea-pigs.5. The isomers of propranolol exhibited similar local anaesthetic potencies on an isolated frog nerve preparation at a level approximately three times that of procaine. The racemic compound was significantly less potent than either isomer.6. Both isomers of propranolol were capable of preventing CHEMICAL-induced DISEASE in cats anaesthetized with halothane, but the mean dose of (-)-propranolol was 0.09+/-0.02 mg/kg whereas that of (+)-propranolol was 4.2+/-1.2 mg/kg. At the effective dose level of (+)-propranolol there was a significant prolongation of the PR interval of the electrocardiogram. Blockade of DISEASE with both isomers was surmountable by increasing the dose of CHEMICAL.7. Both isomers of propranolol were also capable of reversing ventricular tachycardia caused by ouabain in anaesthetized cats and dogs. The dose of (-)-propranolol was significantly smaller than that of (+)-propranolol in both species but much higher than that required to produce evidence of beta-blockade.8. The implications of these results are discussed. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL in combination with radiotherapy in unresectable glioblastoma: a phase 2 study. Improving glioblastoma multiforme (GBM) treatment with radio-chemotherapy remains a challenge. CHEMICAL is an attractive option as it exhibits growth inhibition of human glioma as well as brain penetration. The present study assessed the combination of radiotherapy (60 Gy/30 fractions/40 days) and CHEMICAL (0.9 mg/m(2)/day on days 1-5 on weeks 1, 3 and 5) in 50 adults with histologically proven and untreated GBM. The incidence of non-hematological toxicities was low and grade 3-4 hematological toxicities were reported in 20 patients (mainly lymphopenia and DISEASE). Partial response and stabilization rates were 2% and 32%, respectively, with an overall time to progression of 12 weeks. One-year overall survival (OS) rate was 42%, with a median OS of 40 weeks. CHEMICAL in combination with radiotherapy was well tolerated. However, while response and stabilization concerned one-third of the patients, the study did not show increased benefits in terms of survival in patients with unresectable GBM. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL in combination with radiotherapy in unresectable glioblastoma: a phase 2 study. Improving glioblastoma multiforme (GBM) treatment with radio-chemotherapy remains a challenge. CHEMICAL is an attractive option as it exhibits growth inhibition of human glioma as well as brain penetration. The present study assessed the combination of radiotherapy (60 Gy/30 fractions/40 days) and CHEMICAL (0.9 mg/m(2)/day on days 1-5 on weeks 1, 3 and 5) in 50 adults with histologically proven and untreated GBM. The incidence of non-hematological toxicities was low and grade 3-4 hematological toxicities were reported in 20 patients (mainly DISEASE and neutropenia). Partial response and stabilization rates were 2% and 32%, respectively, with an overall time to progression of 12 weeks. One-year overall survival (OS) rate was 42%, with a median OS of 40 weeks. CHEMICAL in combination with radiotherapy was well tolerated. However, while response and stabilization concerned one-third of the patients, the study did not show increased benefits in terms of survival in patients with unresectable GBM. | CHEMICAL-INDUCED-DISEASE |
| Long-term CHEMICAL therapy leading to DISEASE: a case report. PURPOSE: This paper reviews the effect of chronic CHEMICAL therapy on serum calcium level and parathyroid glands, its pathogenesis, and treatment options. We examined the case of a CHEMICAL-treated patient who had recurrent hypercalcemia to better understand the disease process. CONCLUSION: Primary hyperparathyroidism is a rare but potentially life-threatening side effect of long-term CHEMICAL therapy. Careful patient selection and long-term follow-up can reduce morbidity. PRACTICAL IMPLICATIONS: As much as 15% of CHEMICAL-treated patients become hypercalcemic. By routinely monitoring serum calcium levels, healthcare providers can improve the quality of life of this patient group. | CHEMICAL-INDUCED-DISEASE |
| Long-term CHEMICAL therapy leading to hyperparathyroidism: a case report. PURPOSE: This paper reviews the effect of chronic CHEMICAL therapy on serum calcium level and parathyroid glands, its pathogenesis, and treatment options. We examined the case of a CHEMICAL-treated patient who had recurrent DISEASE to better understand the disease process. CONCLUSION: Primary hyperparathyroidism is a rare but potentially life-threatening side effect of long-term CHEMICAL therapy. Careful patient selection and long-term follow-up can reduce morbidity. PRACTICAL IMPLICATIONS: As much as 15% of CHEMICAL-treated patients become DISEASE. By routinely monitoring serum calcium levels, healthcare providers can improve the quality of life of this patient group. | CHEMICAL-INDUCED-DISEASE |
| Long-term lithium therapy leading to hyperparathyroidism: a case report. PURPOSE: This paper reviews the effect of chronic lithium therapy on serum CHEMICAL level and parathyroid glands, its pathogenesis, and treatment options. We examined the case of a lithium-treated patient who had recurrent hypercalcemia to better understand the disease process. CONCLUSION: DISEASE is a rare but potentially life-threatening side effect of long-term lithium therapy. Careful patient selection and long-term follow-up can reduce morbidity. PRACTICAL IMPLICATIONS: As much as 15% of lithium-treated patients become hypercalcemic. By routinely monitoring serum CHEMICAL levels, healthcare providers can improve the quality of life of this patient group. | NO-RELATIONSHIP |
| Comparison of laryngeal mask with endotracheal tube for anesthesia in endoscopic sinus surgery. BACKGROUND: The purpose of this study was to compare surgical conditions, including the amount of intraoperative bleeding as well as intraoperative blood pressure, during functional endoscopic sinus surgery (FESS) using flexible reinforced laryngeal mask airway (FRLMA) versus endotracheal tube (ETT) in maintaining controlled DISEASE anesthesia induced by CHEMICAL-remifentanil total i.v. anesthesia (TIVA). METHODS: Sixty normotensive American Society of Anesthesiologists I-II adult patients undergoing FESS under controlled DISEASE anesthesia caused by CHEMICAL-remifentanil-TIVA were randomly assigned into two groups: group I, FRLMA; group II, ETT. Hemorrhage was measured and the visibility of the operative field was evaluated according to a six-point scale. RESULTS: Controlled DISEASE was achieved within a shorter period using laryngeal mask using lower rates of remifentanil infusion and lower total dose of remifentanil. CONCLUSION: In summary, our results indicate that airway management using FRLMA during controlled DISEASE anesthesia provided better surgical conditions in terms of quality of operative field and blood loss and allowed for convenient induced DISEASE with low doses of remifentanil during TIVA in patients undergoing FESS. | CHEMICAL-INDUCED-DISEASE |
| Comparison of laryngeal mask with endotracheal tube for anesthesia in endoscopic sinus surgery. BACKGROUND: The purpose of this study was to compare surgical conditions, including the amount of intraoperative bleeding as well as intraoperative blood pressure, during functional endoscopic sinus surgery (FESS) using flexible reinforced laryngeal mask airway (FRLMA) versus endotracheal tube (ETT) in maintaining controlled DISEASE anesthesia induced by propofol-CHEMICAL total i.v. anesthesia (TIVA). METHODS: Sixty normotensive American Society of Anesthesiologists I-II adult patients undergoing FESS under controlled DISEASE anesthesia caused by propofol-CHEMICAL-TIVA were randomly assigned into two groups: group I, FRLMA; group II, ETT. Hemorrhage was measured and the visibility of the operative field was evaluated according to a six-point scale. RESULTS: Controlled DISEASE was achieved within a shorter period using laryngeal mask using lower rates of CHEMICAL infusion and lower total dose of CHEMICAL. CONCLUSION: In summary, our results indicate that airway management using FRLMA during controlled DISEASE anesthesia provided better surgical conditions in terms of quality of operative field and blood loss and allowed for convenient induced DISEASE with low doses of CHEMICAL during TIVA in patients undergoing FESS. | CHEMICAL-INDUCED-DISEASE |
| Nonalcoholic fatty liver disease during CHEMICAL therapy. CHEMICAL (CHEMICAL) is effective for the treatment of many types of epilepsy, but its use can be associated with an increase in body weight. We report a case of nonalcoholic fatty liver disease (NAFLD) arising in a child who developed DISEASE during CHEMICAL treatment. Laboratory data revealed hyperinsulinemia with insulin resistance. After the withdrawal of CHEMICAL therapy, our patient showed a significant weight loss, a decrease of body mass index, and normalization of metabolic and endocrine parameters; moreover, ultrasound measurements showed a complete normalization. The present case suggests that DISEASE, hyperinsulinemia, insulin resistance, and long-term treatment with CHEMICAL may be all associated with the development of NAFLD; this side effect is reversible after CHEMICAL withdrawal. | CHEMICAL-INDUCED-DISEASE |
| Nonalcoholic fatty liver disease during CHEMICAL therapy. CHEMICAL (CHEMICAL) is effective for the treatment of many types of epilepsy, but its use can be associated with an increase in body weight. We report a case of nonalcoholic fatty liver disease (NAFLD) arising in a child who developed obesity during CHEMICAL treatment. Laboratory data revealed DISEASE with insulin resistance. After the withdrawal of CHEMICAL therapy, our patient showed a significant weight loss, a decrease of body mass index, and normalization of metabolic and endocrine parameters; moreover, ultrasound measurements showed a complete normalization. The present case suggests that obesity, DISEASE, insulin resistance, and long-term treatment with CHEMICAL may be all associated with the development of NAFLD; this side effect is reversible after CHEMICAL withdrawal. | CHEMICAL-INDUCED-DISEASE |
| DISEASE during CHEMICAL therapy. CHEMICAL (CHEMICAL) is effective for the treatment of many types of epilepsy, but its use can be associated with an increase in body weight. We report a case of DISEASE (DISEASE) arising in a child who developed obesity during CHEMICAL treatment. Laboratory data revealed hyperinsulinemia with insulin resistance. After the withdrawal of CHEMICAL therapy, our patient showed a significant weight loss, a decrease of body mass index, and normalization of metabolic and endocrine parameters; moreover, ultrasound measurements showed a complete normalization. The present case suggests that obesity, hyperinsulinemia, insulin resistance, and long-term treatment with CHEMICAL may be all associated with the development of DISEASE; this side effect is reversible after CHEMICAL withdrawal. | CHEMICAL-INDUCED-DISEASE |
| Nonalcoholic fatty liver disease during CHEMICAL therapy. CHEMICAL (CHEMICAL) is effective for the treatment of many types of epilepsy, but its use can be associated with an increase in body weight. We report a case of nonalcoholic fatty liver disease (NAFLD) arising in a child who developed obesity during CHEMICAL treatment. Laboratory data revealed hyperinsulinemia with DISEASE. After the withdrawal of CHEMICAL therapy, our patient showed a significant weight loss, a decrease of body mass index, and normalization of metabolic and endocrine parameters; moreover, ultrasound measurements showed a complete normalization. The present case suggests that obesity, hyperinsulinemia, DISEASE, and long-term treatment with CHEMICAL may be all associated with the development of NAFLD; this side effect is reversible after CHEMICAL withdrawal. | CHEMICAL-INDUCED-DISEASE |
| Carbimazole induced ANCA positive vasculitis. CHEMICAL, like carbimazole and propylthiouracil (PTU) are commonly prescribed for the treatment of hyperthyroidism. One should be aware of the side effects of CHEMICAL. Antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis is a potentially life-threatening adverse effect of CHEMICAL. We report a patient with Graves' disease who developed ANCA positive carbimazole induced vasculitis. The episode was characterized by a vasculitic skin rash associated with large joint arthritis, pyrexia and DISEASE but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have myositis. Carbimazole and methimazole have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive carbimazole induced vasculitis case reported from India. | NO-RELATIONSHIP |
| Carbimazole induced DISEASE. CHEMICAL, like carbimazole and propylthiouracil (PTU) are commonly prescribed for the treatment of hyperthyroidism. One should be aware of the side effects of CHEMICAL. DISEASE is a potentially life-threatening adverse effect of CHEMICAL. We report a patient with Graves' disease who developed ANCA positive carbimazole induced vasculitis. The episode was characterized by a vasculitic skin rash associated with large joint arthritis, pyrexia and parotiditis but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have myositis. Carbimazole and methimazole have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive carbimazole induced vasculitis case reported from India. | CHEMICAL-INDUCED-DISEASE |
| Carbimazole induced ANCA positive vasculitis. CHEMICAL, like carbimazole and propylthiouracil (PTU) are commonly prescribed for the treatment of hyperthyroidism. One should be aware of the side effects of CHEMICAL. Antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis is a potentially life-threatening adverse effect of CHEMICAL. We report a patient with Graves' disease who developed ANCA positive carbimazole induced vasculitis. The episode was characterized by a vasculitic skin rash associated with large joint DISEASE, pyrexia and parotiditis but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have myositis. Carbimazole and methimazole have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive carbimazole induced vasculitis case reported from India. | NO-RELATIONSHIP |
| CHEMICAL induced ANCA positive vasculitis. Anti-thyroid drugs, like CHEMICAL and propylthiouracil (PTU) are commonly prescribed for the treatment of hyperthyroidism. One should be aware of the side effects of antithyroid medications. Antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis is a potentially life-threatening adverse effect of antithyroidmedications. We report a patient with Graves' disease who developed ANCA positive CHEMICAL induced vasculitis. The episode was characterized by a vasculitic skin rash associated with large joint arthritis, pyrexia and DISEASE but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have myositis. CHEMICAL and methimazole have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive CHEMICAL induced vasculitis case reported from India. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL induced ANCA positive vasculitis. Anti-thyroid drugs, like CHEMICAL and propylthiouracil (PTU) are commonly prescribed for the treatment of hyperthyroidism. One should be aware of the side effects of antithyroid medications. Antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis is a potentially life-threatening adverse effect of antithyroidmedications. We report a patient with Graves' disease who developed ANCA positive CHEMICAL induced vasculitis. The episode was characterized by a vasculitic skin rash associated with large joint arthritis, DISEASE and parotiditis but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have myositis. CHEMICAL and methimazole have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive CHEMICAL induced vasculitis case reported from India. | CHEMICAL-INDUCED-DISEASE |
| Carbimazole induced ANCA positive vasculitis. CHEMICAL, like carbimazole and propylthiouracil (PTU) are commonly prescribed for the treatment of hyperthyroidism. One should be aware of the side effects of CHEMICAL. Antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis is a potentially life-threatening adverse effect of CHEMICAL. We report a patient with Graves' disease who developed ANCA positive carbimazole induced vasculitis. The episode was characterized by a vasculitic skin rash associated with large joint arthritis, DISEASE and parotiditis but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have myositis. Carbimazole and methimazole have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive carbimazole induced vasculitis case reported from India. | NO-RELATIONSHIP |
| CHEMICAL induced ANCA positive vasculitis. Anti-thyroid drugs, like CHEMICAL and propylthiouracil (PTU) are commonly prescribed for the treatment of hyperthyroidism. One should be aware of the side effects of antithyroid medications. Antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis is a potentially life-threatening adverse effect of antithyroidmedications. We report a patient with Graves' disease who developed ANCA positive CHEMICAL induced vasculitis. The episode was characterized by a vasculitic skin rash associated with large joint DISEASE, pyrexia and parotiditis but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have myositis. CHEMICAL and methimazole have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive CHEMICAL induced vasculitis case reported from India. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL induced DISEASE. Anti-thyroid drugs, like CHEMICAL and propylthiouracil (PTU) are commonly prescribed for the treatment of hyperthyroidism. One should be aware of the side effects of antithyroid medications. DISEASE is a potentially life-threatening adverse effect of antithyroidmedications. We report a patient with Graves' disease who developed ANCA positive CHEMICAL induced vasculitis. The episode was characterized by a vasculitic skin rash associated with large joint arthritis, pyrexia and parotiditis but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have myositis. CHEMICAL and methimazole have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive CHEMICAL induced vasculitis case reported from India. | CHEMICAL-INDUCED-DISEASE |
| Carbimazole induced ANCA positive vasculitis. Anti-thyroid drugs, like carbimazole and propylthiouracil (PTU) are commonly prescribed for the treatment of hyperthyroidism. One should be aware of the side effects of antithyroid medications. Antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis is a potentially life-threatening adverse effect of antithyroidmedications. We report a patient with Graves' disease who developed ANCA positive carbimazole induced vasculitis. The episode was characterized by a vasculitic skin rash associated with large joint arthritis, pyrexia and parotiditis but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have DISEASE. Carbimazole and CHEMICAL have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive carbimazole induced vasculitis case reported from India. | NO-RELATIONSHIP |
| Carbimazole induced ANCA positive vasculitis. Anti-thyroid drugs, like carbimazole and CHEMICAL (CHEMICAL) are commonly prescribed for the treatment of hyperthyroidism. One should be aware of the side effects of antithyroid medications. Antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis is a potentially life-threatening adverse effect of antithyroidmedications. We report a patient with Graves' disease who developed ANCA positive carbimazole induced vasculitis. The episode was characterized by a vasculitic skin rash associated with large joint arthritis, pyrexia and parotiditis but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have DISEASE. Carbimazole and methimazole have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive carbimazole induced vasculitis case reported from India. | NO-RELATIONSHIP |
| Carbimazole induced ANCA positive vasculitis. Anti-thyroid drugs, like carbimazole and CHEMICAL (CHEMICAL) are commonly prescribed for the treatment of hyperthyroidism. One should be aware of the side effects of antithyroid medications. Antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis is a potentially life-threatening adverse effect of antithyroidmedications. We report a patient with DISEASE who developed ANCA positive carbimazole induced vasculitis. The episode was characterized by a vasculitic skin rash associated with large joint arthritis, pyrexia and parotiditis but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have myositis. Carbimazole and methimazole have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive carbimazole induced vasculitis case reported from India. | NO-RELATIONSHIP |
| Carbimazole induced ANCA positive vasculitis. Anti-thyroid drugs, like carbimazole and CHEMICAL (CHEMICAL) are commonly prescribed for the treatment of hyperthyroidism. One should be aware of the side effects of antithyroid medications. Antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis is a potentially life-threatening adverse effect of antithyroidmedications. We report a patient with Graves' disease who developed ANCA positive carbimazole induced DISEASE. The episode was characterized by a DISEASE skin rash associated with large joint arthritis, pyrexia and parotiditis but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have myositis. Carbimazole and methimazole have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive carbimazole induced DISEASE case reported from India. | NO-RELATIONSHIP |
| Carbimazole induced ANCA positive vasculitis. Anti-thyroid drugs, like carbimazole and propylthiouracil (PTU) are commonly prescribed for the treatment of hyperthyroidism. One should be aware of the side effects of antithyroid medications. Antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis is a potentially life-threatening adverse effect of antithyroidmedications. We report a patient with Graves' disease who developed ANCA positive carbimazole induced vasculitis. The episode was characterized by a vasculitic DISEASE associated with large joint arthritis, pyrexia and parotiditis but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have myositis. Carbimazole and CHEMICAL have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive carbimazole induced vasculitis case reported from India. | NO-RELATIONSHIP |
| Carbimazole induced ANCA positive vasculitis. Anti-thyroid drugs, like carbimazole and CHEMICAL (CHEMICAL) are commonly prescribed for the treatment of DISEASE. One should be aware of the side effects of antithyroid medications. Antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis is a potentially life-threatening adverse effect of antithyroidmedications. We report a patient with Graves' disease who developed ANCA positive carbimazole induced vasculitis. The episode was characterized by a vasculitic skin rash associated with large joint arthritis, pyrexia and parotiditis but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have myositis. Carbimazole and methimazole have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive carbimazole induced vasculitis case reported from India. | NO-RELATIONSHIP |
| Carbimazole induced ANCA positive vasculitis. Anti-thyroid drugs, like carbimazole and CHEMICAL (CHEMICAL) are commonly prescribed for the treatment of hyperthyroidism. One should be aware of the side effects of antithyroid medications. Antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis is a potentially life-threatening adverse effect of antithyroidmedications. We report a patient with Graves' disease who developed ANCA positive carbimazole induced vasculitis. The episode was characterized by a vasculitic DISEASE associated with large joint arthritis, pyrexia and parotiditis but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have myositis. Carbimazole and methimazole have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive carbimazole induced vasculitis case reported from India. | NO-RELATIONSHIP |
| Carbimazole induced ANCA positive vasculitis. Anti-thyroid drugs, like carbimazole and propylthiouracil (PTU) are commonly prescribed for the treatment of hyperthyroidism. One should be aware of the side effects of antithyroid medications. Antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis is a potentially life-threatening adverse effect of antithyroidmedications. We report a patient with Graves' disease who developed ANCA positive carbimazole induced DISEASE. The episode was characterized by a DISEASE skin rash associated with large joint arthritis, pyrexia and parotiditis but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have myositis. Carbimazole and CHEMICAL have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive carbimazole induced DISEASE case reported from India. | NO-RELATIONSHIP |
| Carbimazole induced ANCA positive vasculitis. Anti-thyroid drugs, like carbimazole and propylthiouracil (PTU) are commonly prescribed for the treatment of DISEASE. One should be aware of the side effects of antithyroid medications. Antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis is a potentially life-threatening adverse effect of antithyroidmedications. We report a patient with Graves' disease who developed ANCA positive carbimazole induced vasculitis. The episode was characterized by a vasculitic skin rash associated with large joint arthritis, pyrexia and parotiditis but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have myositis. Carbimazole and CHEMICAL have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive carbimazole induced vasculitis case reported from India. | NO-RELATIONSHIP |
| Carbimazole induced ANCA positive vasculitis. Anti-thyroid drugs, like carbimazole and propylthiouracil (PTU) are commonly prescribed for the treatment of hyperthyroidism. One should be aware of the side effects of antithyroid medications. Antineutrophil cytoplasmic antibody (ANCA)--associated vasculitis is a potentially life-threatening adverse effect of antithyroidmedications. We report a patient with DISEASE who developed ANCA positive carbimazole induced vasculitis. The episode was characterized by a vasculitic skin rash associated with large joint arthritis, pyrexia and parotiditis but no renal or pulmonary involvement. He was referred to us for neurological evaluation because he had difficulty in getting up from squatting position and was suspected to have myositis. Carbimazole and CHEMICAL have a lower incidence of reported ANCA positive side effects than PUT. To the best of our knowledge this is the first ANCA positive carbimazole induced vasculitis case reported from India. | NO-RELATIONSHIP |
| CHEMICAL for the primary prevention of cardiovascular events: an update of the evidence for the U.S. Preventive Services Task Force. BACKGROUND: Coronary heart disease and cerebrovascular disease are leading causes of death in the United States. In 2002, the U.S. Preventive Services Task Force (USPSTF) strongly recommended that clinicians discuss CHEMICAL with adults who are at increased risk for coronary heart disease. PURPOSE: To determine the benefits and harms of taking CHEMICAL for the primary prevention of myocardial infarctions, DISEASE, and death. DATA SOURCES: MEDLINE and Cochrane Library (search dates, 1 January 2001 to 28 August 2008), recent systematic reviews, reference lists of retrieved articles, and suggestions from experts. STUDY SELECTION: English-language randomized, controlled trials (RCTs); case-control studies; meta-analyses; and systematic reviews of CHEMICAL versus control for the primary prevention of cardiovascular disease (CVD) were selected to answer the following questions: Does CHEMICAL decrease coronary heart events, DISEASE, death from coronary heart events or DISEASE, or all-cause mortality in adults without known CVD? Does CHEMICAL increase gastrointestinal bleeding or hemorrhagic strokes? DATA EXTRACTION: All studies were reviewed, abstracted, and rated for quality by using predefined USPSTF criteria. DATA SYNTHESIS: New evidence from 1 good-quality RCT, 1 good-quality meta-analysis, and 2 fair-quality subanalyses of RCTs demonstrates that CHEMICAL use reduces the number of CVD events in patients without known CVD. Men in these studies experienced fewer myocardial infarctions and women experienced fewer ischemic DISEASE. CHEMICAL does not seem to affect CVD mortality or all-cause mortality in either men or women. The use of CHEMICAL for primary prevention increases the risk for major bleeding events, primarily gastrointestinal bleeding events, in both men and women. Men have an increased risk for hemorrhagic strokes with CHEMICAL use. A new RCT and meta-analysis suggest that the risk for hemorrhagic strokes in women is not statistically significantly increased. LIMITATIONS: New evidence on CHEMICAL for the primary prevention of CVD is limited. The dose of CHEMICAL used in the RCTs varied, which prevented the estimation of the most appropriate dose for primary prevention. Several of the RCTs were conducted within populations of health professionals, which potentially limits generalizability. CONCLUSION: CHEMICAL reduces the risk for myocardial infarction in men and DISEASE in women. CHEMICAL use increases the risk for serious bleeding events. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL for the primary prevention of cardiovascular events: an update of the evidence for the U.S. Preventive Services Task Force. BACKGROUND: Coronary heart disease and cerebrovascular disease are leading causes of death in the United States. In 2002, the U.S. Preventive Services Task Force (USPSTF) strongly recommended that clinicians discuss CHEMICAL with adults who are at increased risk for coronary heart disease. PURPOSE: To determine the benefits and harms of taking CHEMICAL for the primary prevention of myocardial infarctions, strokes, and death. DATA SOURCES: MEDLINE and Cochrane Library (search dates, 1 January 2001 to 28 August 2008), recent systematic reviews, reference lists of retrieved articles, and suggestions from experts. STUDY SELECTION: English-language randomized, controlled trials (RCTs); case-control studies; meta-analyses; and systematic reviews of CHEMICAL versus control for the primary prevention of cardiovascular disease (CVD) were selected to answer the following questions: Does CHEMICAL decrease coronary heart events, strokes, death from coronary heart events or stroke, or all-cause mortality in adults without known CVD? Does CHEMICAL increase DISEASE or hemorrhagic strokes? DATA EXTRACTION: All studies were reviewed, abstracted, and rated for quality by using predefined USPSTF criteria. DATA SYNTHESIS: New evidence from 1 good-quality RCT, 1 good-quality meta-analysis, and 2 fair-quality subanalyses of RCTs demonstrates that CHEMICAL use reduces the number of CVD events in patients without known CVD. Men in these studies experienced fewer myocardial infarctions and women experienced fewer ischemic strokes. CHEMICAL does not seem to affect CVD mortality or all-cause mortality in either men or women. The use of CHEMICAL for primary prevention increases the risk for major bleeding events, primarily DISEASE events, in both men and women. Men have an increased risk for hemorrhagic strokes with CHEMICAL use. A new RCT and meta-analysis suggest that the risk for hemorrhagic strokes in women is not statistically significantly increased. LIMITATIONS: New evidence on CHEMICAL for the primary prevention of CVD is limited. The dose of CHEMICAL used in the RCTs varied, which prevented the estimation of the most appropriate dose for primary prevention. Several of the RCTs were conducted within populations of health professionals, which potentially limits generalizability. CONCLUSION: CHEMICAL reduces the risk for myocardial infarction in men and strokes in women. CHEMICAL use increases the risk for serious bleeding events. | CHEMICAL-INDUCED-DISEASE |
| Reducing harm associated with anticoagulation: practical considerations of CHEMICAL therapy in heparin-induced thrombocytopenia. CHEMICAL is a hepatically metabolized, direct thrombin inhibitor used for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT) and for patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI). The objective of this review is to summarize practical considerations of CHEMICAL therapy in HIT. The US FDA-recommended CHEMICAL dose in HIT is 2 microg/kg/min (reduced in patients with hepatic impairment and in paediatric patients), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline (not >100 seconds). Contemporary experiences indicate that reduced doses are also needed in patients with conditions associated with hepatic hypoperfusion, e.g. heart failure, yet are unnecessary for renal dysfunction, adult age, sex, race/ethnicity or obesity. CHEMICAL 0.5-1.2 microg/kg/min typically supports therapeutic aPTTs. The FDA-recommended dose during PCI is 25 microg/kg/min (350 microg/kg initial bolus), adjusted to achieve activated clotting times (ACTs) of 300-450 sec. For PCI, CHEMICAL has not been investigated in hepatically impaired patients; dose adjustment is unnecessary for adult age, sex, race/ethnicity or obesity, and lesser doses may be adequate with concurrent glycoprotein IIb/IIIa inhibition. CHEMICAL prolongs the International Normalized Ratio, and published approaches for monitoring the CHEMICAL-to-warfarin transition should be followed. Major DISEASE with CHEMICAL is 0-10% in the non-interventional setting and 0-5.8% periprocedurally. CHEMICAL has no specific antidote, and if excessive anticoagulation occurs, CHEMICAL infusion should be stopped or reduced. Improved familiarity of healthcare professionals with CHEMICAL therapy in HIT, including in special populations and during PCI, may facilitate reduction of harm associated with HIT (e.g. fewer thromboses) or its treatment (e.g. fewer CHEMICAL medication errors). | CHEMICAL-INDUCED-DISEASE |
| Reducing harm associated with anticoagulation: practical considerations of argatroban therapy in heparin-induced thrombocytopenia. Argatroban is a hepatically metabolized, direct thrombin inhibitor used for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT) and for patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI). The objective of this review is to summarize practical considerations of argatroban therapy in HIT. The US FDA-recommended argatroban dose in HIT is 2 microg/kg/min (reduced in patients with hepatic impairment and in paediatric patients), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline (not >100 seconds). Contemporary experiences indicate that reduced doses are also needed in patients with conditions associated with hepatic hypoperfusion, e.g. heart failure, yet are unnecessary for DISEASE, adult age, sex, race/ethnicity or obesity. Argatroban 0.5-1.2 microg/kg/min typically supports therapeutic aPTTs. The FDA-recommended dose during PCI is 25 microg/kg/min (350 microg/kg initial bolus), adjusted to achieve activated clotting times (ACTs) of 300-450 sec. For PCI, argatroban has not been investigated in hepatically impaired patients; dose adjustment is unnecessary for adult age, sex, race/ethnicity or obesity, and lesser doses may be adequate with concurrent glycoprotein IIb/IIIa inhibition. Argatroban prolongs the International Normalized Ratio, and published approaches for monitoring the argatroban-to-CHEMICAL transition should be followed. Major bleeding with argatroban is 0-10% in the non-interventional setting and 0-5.8% periprocedurally. Argatroban has no specific antidote, and if excessive anticoagulation occurs, argatroban infusion should be stopped or reduced. Improved familiarity of healthcare professionals with argatroban therapy in HIT, including in special populations and during PCI, may facilitate reduction of harm associated with HIT (e.g. fewer thromboses) or its treatment (e.g. fewer argatroban medication errors). | NO-RELATIONSHIP |
| Reducing harm associated with anticoagulation: practical considerations of argatroban therapy in heparin-induced thrombocytopenia. Argatroban is a hepatically metabolized, direct thrombin inhibitor used for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT) and for patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI). The objective of this review is to summarize practical considerations of argatroban therapy in HIT. The US FDA-recommended argatroban dose in HIT is 2 microg/kg/min (reduced in patients with hepatic impairment and in paediatric patients), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline (not >100 seconds). Contemporary experiences indicate that reduced doses are also needed in patients with conditions associated with hepatic hypoperfusion, e.g. DISEASE, yet are unnecessary for renal dysfunction, adult age, sex, race/ethnicity or obesity. Argatroban 0.5-1.2 microg/kg/min typically supports therapeutic aPTTs. The FDA-recommended dose during PCI is 25 microg/kg/min (350 microg/kg initial bolus), adjusted to achieve activated clotting times (ACTs) of 300-450 sec. For PCI, argatroban has not been investigated in hepatically impaired patients; dose adjustment is unnecessary for adult age, sex, race/ethnicity or obesity, and lesser doses may be adequate with concurrent glycoprotein IIb/IIIa inhibition. Argatroban prolongs the International Normalized Ratio, and published approaches for monitoring the argatroban-to-CHEMICAL transition should be followed. Major bleeding with argatroban is 0-10% in the non-interventional setting and 0-5.8% periprocedurally. Argatroban has no specific antidote, and if excessive anticoagulation occurs, argatroban infusion should be stopped or reduced. Improved familiarity of healthcare professionals with argatroban therapy in HIT, including in special populations and during PCI, may facilitate reduction of harm associated with HIT (e.g. fewer thromboses) or its treatment (e.g. fewer argatroban medication errors). | NO-RELATIONSHIP |
| Reducing harm associated with anticoagulation: practical considerations of argatroban therapy in CHEMICAL-induced thrombocytopenia. Argatroban is a hepatically metabolized, direct thrombin inhibitor used for prophylaxis or treatment of thrombosis in CHEMICAL-induced thrombocytopenia (HIT) and for patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI). The objective of this review is to summarize practical considerations of argatroban therapy in HIT. The US FDA-recommended argatroban dose in HIT is 2 microg/kg/min (reduced in patients with DISEASE and in paediatric patients), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline (not >100 seconds). Contemporary experiences indicate that reduced doses are also needed in patients with conditions associated with hepatic hypoperfusion, e.g. heart failure, yet are unnecessary for renal dysfunction, adult age, sex, race/ethnicity or obesity. Argatroban 0.5-1.2 microg/kg/min typically supports therapeutic aPTTs. The FDA-recommended dose during PCI is 25 microg/kg/min (350 microg/kg initial bolus), adjusted to achieve activated clotting times (ACTs) of 300-450 sec. For PCI, argatroban has not been investigated in hepatically impaired patients; dose adjustment is unnecessary for adult age, sex, race/ethnicity or obesity, and lesser doses may be adequate with concurrent glycoprotein IIb/IIIa inhibition. Argatroban prolongs the International Normalized Ratio, and published approaches for monitoring the argatroban-to-warfarin transition should be followed. Major bleeding with argatroban is 0-10% in the non-interventional setting and 0-5.8% periprocedurally. Argatroban has no specific antidote, and if excessive anticoagulation occurs, argatroban infusion should be stopped or reduced. Improved familiarity of healthcare professionals with argatroban therapy in HIT, including in special populations and during PCI, may facilitate reduction of harm associated with HIT (e.g. fewer thromboses) or its treatment (e.g. fewer argatroban medication errors). | NO-RELATIONSHIP |
| Reducing harm associated with anticoagulation: practical considerations of argatroban therapy in heparin-induced thrombocytopenia. Argatroban is a hepatically metabolized, direct thrombin inhibitor used for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT) and for patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI). The objective of this review is to summarize practical considerations of argatroban therapy in HIT. The US FDA-recommended argatroban dose in HIT is 2 microg/kg/min (reduced in patients with DISEASE and in paediatric patients), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline (not >100 seconds). Contemporary experiences indicate that reduced doses are also needed in patients with conditions associated with hepatic hypoperfusion, e.g. heart failure, yet are unnecessary for renal dysfunction, adult age, sex, race/ethnicity or obesity. Argatroban 0.5-1.2 microg/kg/min typically supports therapeutic aPTTs. The FDA-recommended dose during PCI is 25 microg/kg/min (350 microg/kg initial bolus), adjusted to achieve activated clotting times (ACTs) of 300-450 sec. For PCI, argatroban has not been investigated in hepatically impaired patients; dose adjustment is unnecessary for adult age, sex, race/ethnicity or obesity, and lesser doses may be adequate with concurrent glycoprotein IIb/IIIa inhibition. Argatroban prolongs the International Normalized Ratio, and published approaches for monitoring the argatroban-to-CHEMICAL transition should be followed. Major bleeding with argatroban is 0-10% in the non-interventional setting and 0-5.8% periprocedurally. Argatroban has no specific antidote, and if excessive anticoagulation occurs, argatroban infusion should be stopped or reduced. Improved familiarity of healthcare professionals with argatroban therapy in HIT, including in special populations and during PCI, may facilitate reduction of harm associated with HIT (e.g. fewer thromboses) or its treatment (e.g. fewer argatroban medication errors). | NO-RELATIONSHIP |
| Reducing harm associated with anticoagulation: practical considerations of argatroban therapy in CHEMICAL-induced thrombocytopenia. Argatroban is a hepatically metabolized, direct thrombin inhibitor used for prophylaxis or treatment of thrombosis in CHEMICAL-induced thrombocytopenia (HIT) and for patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI). The objective of this review is to summarize practical considerations of argatroban therapy in HIT. The US FDA-recommended argatroban dose in HIT is 2 microg/kg/min (reduced in patients with hepatic impairment and in paediatric patients), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline (not >100 seconds). Contemporary experiences indicate that reduced doses are also needed in patients with conditions associated with hepatic hypoperfusion, e.g. heart failure, yet are unnecessary for DISEASE, adult age, sex, race/ethnicity or obesity. Argatroban 0.5-1.2 microg/kg/min typically supports therapeutic aPTTs. The FDA-recommended dose during PCI is 25 microg/kg/min (350 microg/kg initial bolus), adjusted to achieve activated clotting times (ACTs) of 300-450 sec. For PCI, argatroban has not been investigated in hepatically impaired patients; dose adjustment is unnecessary for adult age, sex, race/ethnicity or obesity, and lesser doses may be adequate with concurrent glycoprotein IIb/IIIa inhibition. Argatroban prolongs the International Normalized Ratio, and published approaches for monitoring the argatroban-to-warfarin transition should be followed. Major bleeding with argatroban is 0-10% in the non-interventional setting and 0-5.8% periprocedurally. Argatroban has no specific antidote, and if excessive anticoagulation occurs, argatroban infusion should be stopped or reduced. Improved familiarity of healthcare professionals with argatroban therapy in HIT, including in special populations and during PCI, may facilitate reduction of harm associated with HIT (e.g. fewer thromboses) or its treatment (e.g. fewer argatroban medication errors). | NO-RELATIONSHIP |
| Reducing harm associated with anticoagulation: practical considerations of argatroban therapy in heparin-induced DISEASE. Argatroban is a hepatically metabolized, direct thrombin inhibitor used for prophylaxis or treatment of thrombosis in heparin-induced DISEASE (DISEASE) and for patients with or at risk of DISEASE undergoing percutaneous coronary intervention (PCI). The objective of this review is to summarize practical considerations of argatroban therapy in DISEASE. The US FDA-recommended argatroban dose in DISEASE is 2 microg/kg/min (reduced in patients with hepatic impairment and in paediatric patients), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline (not >100 seconds). Contemporary experiences indicate that reduced doses are also needed in patients with conditions associated with hepatic hypoperfusion, e.g. heart failure, yet are unnecessary for renal dysfunction, adult age, sex, race/ethnicity or obesity. Argatroban 0.5-1.2 microg/kg/min typically supports therapeutic aPTTs. The FDA-recommended dose during PCI is 25 microg/kg/min (350 microg/kg initial bolus), adjusted to achieve activated clotting times (ACTs) of 300-450 sec. For PCI, argatroban has not been investigated in hepatically impaired patients; dose adjustment is unnecessary for adult age, sex, race/ethnicity or obesity, and lesser doses may be adequate with concurrent glycoprotein IIb/IIIa inhibition. Argatroban prolongs the International Normalized Ratio, and published approaches for monitoring the argatroban-to-CHEMICAL transition should be followed. Major bleeding with argatroban is 0-10% in the non-interventional setting and 0-5.8% periprocedurally. Argatroban has no specific antidote, and if excessive anticoagulation occurs, argatroban infusion should be stopped or reduced. Improved familiarity of healthcare professionals with argatroban therapy in DISEASE, including in special populations and during PCI, may facilitate reduction of harm associated with DISEASE (e.g. fewer thromboses) or its treatment (e.g. fewer argatroban medication errors). | NO-RELATIONSHIP |
| Reducing harm associated with anticoagulation: practical considerations of argatroban therapy in CHEMICAL-induced thrombocytopenia. Argatroban is a hepatically metabolized, direct thrombin inhibitor used for prophylaxis or treatment of DISEASE in CHEMICAL-induced thrombocytopenia (HIT) and for patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI). The objective of this review is to summarize practical considerations of argatroban therapy in HIT. The US FDA-recommended argatroban dose in HIT is 2 microg/kg/min (reduced in patients with hepatic impairment and in paediatric patients), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline (not >100 seconds). Contemporary experiences indicate that reduced doses are also needed in patients with conditions associated with hepatic hypoperfusion, e.g. heart failure, yet are unnecessary for renal dysfunction, adult age, sex, race/ethnicity or obesity. Argatroban 0.5-1.2 microg/kg/min typically supports therapeutic aPTTs. The FDA-recommended dose during PCI is 25 microg/kg/min (350 microg/kg initial bolus), adjusted to achieve activated clotting times (ACTs) of 300-450 sec. For PCI, argatroban has not been investigated in hepatically impaired patients; dose adjustment is unnecessary for adult age, sex, race/ethnicity or obesity, and lesser doses may be adequate with concurrent glycoprotein IIb/IIIa inhibition. Argatroban prolongs the International Normalized Ratio, and published approaches for monitoring the argatroban-to-warfarin transition should be followed. Major bleeding with argatroban is 0-10% in the non-interventional setting and 0-5.8% periprocedurally. Argatroban has no specific antidote, and if excessive anticoagulation occurs, argatroban infusion should be stopped or reduced. Improved familiarity of healthcare professionals with argatroban therapy in HIT, including in special populations and during PCI, may facilitate reduction of harm associated with HIT (e.g. fewer thromboses) or its treatment (e.g. fewer argatroban medication errors). | NO-RELATIONSHIP |
| Reducing harm associated with anticoagulation: practical considerations of argatroban therapy in heparin-induced thrombocytopenia. Argatroban is a hepatically metabolized, direct thrombin inhibitor used for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT) and for patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI). The objective of this review is to summarize practical considerations of argatroban therapy in HIT. The US FDA-recommended argatroban dose in HIT is 2 microg/kg/min (reduced in patients with hepatic impairment and in paediatric patients), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline (not >100 seconds). Contemporary experiences indicate that reduced doses are also needed in patients with conditions associated with hepatic hypoperfusion, e.g. heart failure, yet are unnecessary for renal dysfunction, adult age, sex, race/ethnicity or DISEASE. Argatroban 0.5-1.2 microg/kg/min typically supports therapeutic aPTTs. The FDA-recommended dose during PCI is 25 microg/kg/min (350 microg/kg initial bolus), adjusted to achieve activated clotting times (ACTs) of 300-450 sec. For PCI, argatroban has not been investigated in hepatically impaired patients; dose adjustment is unnecessary for adult age, sex, race/ethnicity or DISEASE, and lesser doses may be adequate with concurrent glycoprotein IIb/IIIa inhibition. Argatroban prolongs the International Normalized Ratio, and published approaches for monitoring the argatroban-to-CHEMICAL transition should be followed. Major bleeding with argatroban is 0-10% in the non-interventional setting and 0-5.8% periprocedurally. Argatroban has no specific antidote, and if excessive anticoagulation occurs, argatroban infusion should be stopped or reduced. Improved familiarity of healthcare professionals with argatroban therapy in HIT, including in special populations and during PCI, may facilitate reduction of harm associated with HIT (e.g. fewer thromboses) or its treatment (e.g. fewer argatroban medication errors). | NO-RELATIONSHIP |
| Reducing harm associated with anticoagulation: practical considerations of argatroban therapy in CHEMICAL-induced thrombocytopenia. Argatroban is a hepatically metabolized, direct thrombin inhibitor used for prophylaxis or treatment of thrombosis in CHEMICAL-induced thrombocytopenia (HIT) and for patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI). The objective of this review is to summarize practical considerations of argatroban therapy in HIT. The US FDA-recommended argatroban dose in HIT is 2 microg/kg/min (reduced in patients with hepatic impairment and in paediatric patients), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline (not >100 seconds). Contemporary experiences indicate that reduced doses are also needed in patients with conditions associated with hepatic hypoperfusion, e.g. heart failure, yet are unnecessary for renal dysfunction, adult age, sex, race/ethnicity or DISEASE. Argatroban 0.5-1.2 microg/kg/min typically supports therapeutic aPTTs. The FDA-recommended dose during PCI is 25 microg/kg/min (350 microg/kg initial bolus), adjusted to achieve activated clotting times (ACTs) of 300-450 sec. For PCI, argatroban has not been investigated in hepatically impaired patients; dose adjustment is unnecessary for adult age, sex, race/ethnicity or DISEASE, and lesser doses may be adequate with concurrent glycoprotein IIb/IIIa inhibition. Argatroban prolongs the International Normalized Ratio, and published approaches for monitoring the argatroban-to-warfarin transition should be followed. Major bleeding with argatroban is 0-10% in the non-interventional setting and 0-5.8% periprocedurally. Argatroban has no specific antidote, and if excessive anticoagulation occurs, argatroban infusion should be stopped or reduced. Improved familiarity of healthcare professionals with argatroban therapy in HIT, including in special populations and during PCI, may facilitate reduction of harm associated with HIT (e.g. fewer thromboses) or its treatment (e.g. fewer argatroban medication errors). | NO-RELATIONSHIP |
| Reducing harm associated with anticoagulation: practical considerations of argatroban therapy in CHEMICAL-induced DISEASE. Argatroban is a hepatically metabolized, direct thrombin inhibitor used for prophylaxis or treatment of thrombosis in CHEMICAL-induced DISEASE (DISEASE) and for patients with or at risk of DISEASE undergoing percutaneous coronary intervention (PCI). The objective of this review is to summarize practical considerations of argatroban therapy in DISEASE. The US FDA-recommended argatroban dose in DISEASE is 2 microg/kg/min (reduced in patients with hepatic impairment and in paediatric patients), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline (not >100 seconds). Contemporary experiences indicate that reduced doses are also needed in patients with conditions associated with hepatic hypoperfusion, e.g. heart failure, yet are unnecessary for renal dysfunction, adult age, sex, race/ethnicity or obesity. Argatroban 0.5-1.2 microg/kg/min typically supports therapeutic aPTTs. The FDA-recommended dose during PCI is 25 microg/kg/min (350 microg/kg initial bolus), adjusted to achieve activated clotting times (ACTs) of 300-450 sec. For PCI, argatroban has not been investigated in hepatically impaired patients; dose adjustment is unnecessary for adult age, sex, race/ethnicity or obesity, and lesser doses may be adequate with concurrent glycoprotein IIb/IIIa inhibition. Argatroban prolongs the International Normalized Ratio, and published approaches for monitoring the argatroban-to-warfarin transition should be followed. Major bleeding with argatroban is 0-10% in the non-interventional setting and 0-5.8% periprocedurally. Argatroban has no specific antidote, and if excessive anticoagulation occurs, argatroban infusion should be stopped or reduced. Improved familiarity of healthcare professionals with argatroban therapy in DISEASE, including in special populations and during PCI, may facilitate reduction of harm associated with DISEASE (e.g. fewer thromboses) or its treatment (e.g. fewer argatroban medication errors). | CHEMICAL-INDUCED-DISEASE |
| Reducing harm associated with anticoagulation: practical considerations of argatroban therapy in CHEMICAL-induced thrombocytopenia. Argatroban is a hepatically metabolized, direct thrombin inhibitor used for prophylaxis or treatment of thrombosis in CHEMICAL-induced thrombocytopenia (HIT) and for patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI). The objective of this review is to summarize practical considerations of argatroban therapy in HIT. The US FDA-recommended argatroban dose in HIT is 2 microg/kg/min (reduced in patients with hepatic impairment and in paediatric patients), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline (not >100 seconds). Contemporary experiences indicate that reduced doses are also needed in patients with conditions associated with hepatic hypoperfusion, e.g. DISEASE, yet are unnecessary for renal dysfunction, adult age, sex, race/ethnicity or obesity. Argatroban 0.5-1.2 microg/kg/min typically supports therapeutic aPTTs. The FDA-recommended dose during PCI is 25 microg/kg/min (350 microg/kg initial bolus), adjusted to achieve activated clotting times (ACTs) of 300-450 sec. For PCI, argatroban has not been investigated in hepatically impaired patients; dose adjustment is unnecessary for adult age, sex, race/ethnicity or obesity, and lesser doses may be adequate with concurrent glycoprotein IIb/IIIa inhibition. Argatroban prolongs the International Normalized Ratio, and published approaches for monitoring the argatroban-to-warfarin transition should be followed. Major bleeding with argatroban is 0-10% in the non-interventional setting and 0-5.8% periprocedurally. Argatroban has no specific antidote, and if excessive anticoagulation occurs, argatroban infusion should be stopped or reduced. Improved familiarity of healthcare professionals with argatroban therapy in HIT, including in special populations and during PCI, may facilitate reduction of harm associated with HIT (e.g. fewer thromboses) or its treatment (e.g. fewer argatroban medication errors). | NO-RELATIONSHIP |
| Reducing harm associated with anticoagulation: practical considerations of argatroban therapy in heparin-induced thrombocytopenia. Argatroban is a hepatically metabolized, direct thrombin inhibitor used for prophylaxis or treatment of DISEASE in heparin-induced thrombocytopenia (HIT) and for patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI). The objective of this review is to summarize practical considerations of argatroban therapy in HIT. The US FDA-recommended argatroban dose in HIT is 2 microg/kg/min (reduced in patients with hepatic impairment and in paediatric patients), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline (not >100 seconds). Contemporary experiences indicate that reduced doses are also needed in patients with conditions associated with hepatic hypoperfusion, e.g. heart failure, yet are unnecessary for renal dysfunction, adult age, sex, race/ethnicity or obesity. Argatroban 0.5-1.2 microg/kg/min typically supports therapeutic aPTTs. The FDA-recommended dose during PCI is 25 microg/kg/min (350 microg/kg initial bolus), adjusted to achieve activated clotting times (ACTs) of 300-450 sec. For PCI, argatroban has not been investigated in hepatically impaired patients; dose adjustment is unnecessary for adult age, sex, race/ethnicity or obesity, and lesser doses may be adequate with concurrent glycoprotein IIb/IIIa inhibition. Argatroban prolongs the International Normalized Ratio, and published approaches for monitoring the argatroban-to-CHEMICAL transition should be followed. Major bleeding with argatroban is 0-10% in the non-interventional setting and 0-5.8% periprocedurally. Argatroban has no specific antidote, and if excessive anticoagulation occurs, argatroban infusion should be stopped or reduced. Improved familiarity of healthcare professionals with argatroban therapy in HIT, including in special populations and during PCI, may facilitate reduction of harm associated with HIT (e.g. fewer thromboses) or its treatment (e.g. fewer argatroban medication errors). | NO-RELATIONSHIP |
| DISEASE and brain ischemic stroke in a CHEMICAL-dependent male under methadone maintenance therapy. OBJECTIVE: There are several complications associated with heroin abuse, some of which are life-threatening. Methadone may aggravate this problem. METHOD: A clinical case description. RESULTS: A 33-year-old man presented with DISEASE and cerebral ischemic stroke after intravenous CHEMICAL. He had used CHEMICAL since age 20, and had used 150 mg methadone daily for 6 months. He was found unconsciousness at home and was sent to our hospital. In the ER, his opiate level was 4497 ng/ml. In the ICU, we found DISEASE, acute renal failure and acute respiratory failure. After transfer to an internal ward, we noted aphasia and weakness of his left limbs. After MRI, we found cerebral ischemic infarction. CONCLUSION: Those using methadone and CHEMICAL simultaneously may increase risk of DISEASE and ischemic stroke. Patients under methadone maintenance therapy should be warned regarding these serious adverse events. Hypotheses of CHEMICAL-related DISEASE and stroke in CHEMICAL abusers are discussed. | CHEMICAL-INDUCED-DISEASE |
| DISEASE and brain ischemic stroke in a heroin-dependent male under CHEMICAL maintenance therapy. OBJECTIVE: There are several complications associated with heroin abuse, some of which are life-threatening. CHEMICAL may aggravate this problem. METHOD: A clinical case description. RESULTS: A 33-year-old man presented with DISEASE and cerebral ischemic stroke after intravenous heroin. He had used heroin since age 20, and had used 150 mg CHEMICAL daily for 6 months. He was found unconsciousness at home and was sent to our hospital. In the ER, his opiate level was 4497 ng/ml. In the ICU, we found DISEASE, acute renal failure and acute respiratory failure. After transfer to an internal ward, we noted aphasia and weakness of his left limbs. After MRI, we found cerebral ischemic infarction. CONCLUSION: Those using CHEMICAL and heroin simultaneously may increase risk of DISEASE and ischemic stroke. Patients under CHEMICAL maintenance therapy should be warned regarding these serious adverse events. Hypotheses of heroin-related DISEASE and stroke in heroin abusers are discussed. | CHEMICAL-INDUCED-DISEASE |
| Rhabdomyolysis and brain ischemic stroke in a CHEMICAL-dependent male under methadone maintenance therapy. OBJECTIVE: There are several complications associated with heroin abuse, some of which are life-threatening. Methadone may aggravate this problem. METHOD: A clinical case description. RESULTS: A 33-year-old man presented with rhabdomyolysis and cerebral ischemic stroke after intravenous CHEMICAL. He had used CHEMICAL since age 20, and had used 150 mg methadone daily for 6 months. He was found unconsciousness at home and was sent to our hospital. In the ER, his opiate level was 4497 ng/ml. In the ICU, we found rhabdomyolysis, acute renal failure and acute respiratory failure. After transfer to an internal ward, we noted aphasia and weakness of his left limbs. After MRI, we found cerebral ischemic infarction. CONCLUSION: Those using methadone and CHEMICAL simultaneously may increase risk of rhabdomyolysis and ischemic stroke. Patients under methadone maintenance therapy should be warned regarding these serious adverse events. Hypotheses of CHEMICAL-related rhabdomyolysis and DISEASE in CHEMICAL abusers are discussed. | CHEMICAL-INDUCED-DISEASE |
| Rhabdomyolysis and brain ischemic stroke in a heroin-dependent male under CHEMICAL maintenance therapy. OBJECTIVE: There are several complications associated with heroin abuse, some of which are life-threatening. CHEMICAL may aggravate this problem. METHOD: A clinical case description. RESULTS: A 33-year-old man presented with rhabdomyolysis and cerebral ischemic stroke after intravenous heroin. He had used heroin since age 20, and had used 150 mg CHEMICAL daily for 6 months. He was found unconsciousness at home and was sent to our hospital. In the ER, his opiate level was 4497 ng/ml. In the ICU, we found rhabdomyolysis, acute renal failure and acute respiratory failure. After transfer to an internal ward, we noted aphasia and weakness of his left limbs. After MRI, we found cerebral ischemic infarction. CONCLUSION: Those using CHEMICAL and heroin simultaneously may increase risk of rhabdomyolysis and ischemic stroke. Patients under CHEMICAL maintenance therapy should be warned regarding these serious adverse events. Hypotheses of heroin-related rhabdomyolysis and DISEASE in heroin abusers are discussed. | CHEMICAL-INDUCED-DISEASE |
| Increased vulnerability to 6-hydroxydopamine lesion and reduced development of DISEASE in mice lacking CB1 cannabinoid receptors. Motor impairment, dopamine (DA) neuronal activity and proenkephalin (PENK) gene expression in the caudate-putamen (CPu) were measured in 6-OHDA-lesioned and treated (L-DOPA+benserazide) CB1 KO and WT mice. A lesion induced by 6-OHDA produced more severe motor deterioration in CB1 KO mice accompanied by more loss of DA neurons and increased PENK gene expression in the CPu. Oxidative/nitrosative and neuroinflammatory parameters were estimated in the CPu and cingulate cortex (Cg). CB1 KO mice exhibited higher MDA levels and iNOS protein expression in the CPu and Cg compared to WT mice. Treatment with L-DOPA+benserazide (12 weeks) resulted in less severe DISEASE in CB1 KO than in WT mice. The results revealed that the lack of cannabinoid CB1 receptors increased the severity of motor impairment and DA lesion, and reduced CHEMICAL-induced DISEASE. These results suggest that activation of CB1 receptors offers neuroprotection against dopaminergic lesion and the development of CHEMICAL-induced DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Animal model of DISEASE induced by CHEMICAL: Evidence of oxidative stress in submitochondrial particles of the rat brain. The intracerebroventricular (ICV) administration of CHEMICAL (a Na(+)/K(+)-ATPase inhibitor) in rats has been suggested to mimic some symptoms of human bipolar mania. Clinical studies have shown that bipolar disorder may be related to mitochondrial dysfunction. Herein, we investigated the behavioral and biochemical effects induced by the ICV administration of ouabain in rats. To achieve this aim, the effects of ouabain injection immediately after and 7 days following a single ICV administration (at concentrations of 10(-2) and 10(-3)M) on locomotion was measured using the open-field test. Additionally, thiobarbituric acid reactive substances (TBARSs) and superoxide production were measured in submitochondrial particles of the prefrontal cortex, hippocampus, striatum and amygdala. Our findings demonstrated that ouabain at 10(-2) and 10(-3)M induced hyperlocomotion in rats, and this response remained up to 7 days following a single ICV injection. In addition, we observed that the persistent increase in the rat spontaneous locomotion is associated with increased TBARS levels and superoxide generation in submitochondrial particles in the prefrontal cortex, striatum and amygdala. In conclusion, ouabain-induced mania-like behavior may provide a useful animal model to test the hypothesis of the involvement of oxidative stress in bipolar disorder. | CHEMICAL-INDUCED-DISEASE |
| Intraoperative dialysis during liver transplantation with citrate dialysate. Liver transplantation for acutely ill patients with DISEASE carries high intraoperative and immediate postoperative risks. These are increased with the presence of concomitant acute kidney injury (AKI) and intraoperative dialysis is sometimes required to allow the transplant to proceed. The derangements in the procoagulant and anticoagulant pathways during DISEASE can lead to difficulties with anticoagulation during dialysis, especially when continued in the operating room. Systemic anticoagulation is unsafe and regional citrate anticoagulation in the absence of a functional liver carries the risk of citrate toxicity. Citrate dialysate, a new dialysate with citric acid can be used for anticoagulation in patients who cannot tolerate heparin or regional citrate. We report a case of a 40-year-old female with CHEMICAL-induced DISEASE with associated AKI who underwent intraoperative dialytic support during liver transplantation anticoagulated with citrate dialysate during the entire procedure. The patient tolerated the procedure well without any signs of citrate toxicity and maintained adequate anticoagulation for patency of the dialysis circuit. Citrate dialysate is a safe alternative for intradialytic support of liver transplantation in DISEASE. | CHEMICAL-INDUCED-DISEASE |
| Intraoperative dialysis during liver transplantation with citrate dialysate. Liver transplantation for acutely ill patients with fulminant liver failure carries high intraoperative and immediate postoperative risks. These are increased with the presence of concomitant DISEASE (DISEASE) and intraoperative dialysis is sometimes required to allow the transplant to proceed. The derangements in the procoagulant and anticoagulant pathways during fulminant liver failure can lead to difficulties with anticoagulation during dialysis, especially when continued in the operating room. Systemic anticoagulation is unsafe and regional citrate anticoagulation in the absence of a functional liver carries the risk of citrate toxicity. Citrate dialysate, a new dialysate with citric acid can be used for anticoagulation in patients who cannot tolerate heparin or regional citrate. We report a case of a 40-year-old female with CHEMICAL-induced fulminant liver failure with associated DISEASE who underwent intraoperative dialytic support during liver transplantation anticoagulated with citrate dialysate during the entire procedure. The patient tolerated the procedure well without any signs of citrate toxicity and maintained adequate anticoagulation for patency of the dialysis circuit. Citrate dialysate is a safe alternative for intradialytic support of liver transplantation in fulminant liver failure. | CHEMICAL-INDUCED-DISEASE |
| Intraoperative dialysis during liver transplantation with citrate dialysate. Liver transplantation for acutely ill patients with fulminant liver failure carries high intraoperative and immediate postoperative risks. These are increased with the presence of concomitant acute kidney injury (AKI) and intraoperative dialysis is sometimes required to allow the transplant to proceed. The derangements in the procoagulant and anticoagulant pathways during fulminant liver failure can lead to difficulties with anticoagulation during dialysis, especially when continued in the operating room. Systemic anticoagulation is unsafe and regional citrate anticoagulation in the absence of a functional liver carries the risk of citrate DISEASE. Citrate dialysate, a new dialysate with citric acid can be used for anticoagulation in patients who cannot tolerate CHEMICAL or regional citrate. We report a case of a 40-year-old female with acetaminophen-induced fulminant liver failure with associated AKI who underwent intraoperative dialytic support during liver transplantation anticoagulated with citrate dialysate during the entire procedure. The patient tolerated the procedure well without any signs of citrate DISEASE and maintained adequate anticoagulation for patency of the dialysis circuit. Citrate dialysate is a safe alternative for intradialytic support of liver transplantation in fulminant liver failure. | NO-RELATIONSHIP |
| Intraoperative dialysis during liver transplantation with CHEMICAL dialysate. Liver transplantation for acutely ill patients with fulminant liver failure carries high intraoperative and immediate postoperative risks. These are increased with the presence of concomitant acute kidney injury (AKI) and intraoperative dialysis is sometimes required to allow the transplant to proceed. The derangements in the procoagulant and anticoagulant pathways during fulminant liver failure can lead to difficulties with anticoagulation during dialysis, especially when continued in the operating room. Systemic anticoagulation is unsafe and regional CHEMICAL anticoagulation in the absence of a functional liver carries the risk of CHEMICAL DISEASE. CHEMICAL dialysate, a new dialysate with CHEMICAL can be used for anticoagulation in patients who cannot tolerate heparin or regional CHEMICAL. We report a case of a 40-year-old female with acetaminophen-induced fulminant liver failure with associated AKI who underwent intraoperative dialytic support during liver transplantation anticoagulated with CHEMICAL dialysate during the entire procedure. The patient tolerated the procedure well without any signs of CHEMICAL DISEASE and maintained adequate anticoagulation for patency of the dialysis circuit. CHEMICAL dialysate is a safe alternative for intradialytic support of liver transplantation in fulminant liver failure. | NO-RELATIONSHIP |
| DISEASE in a patient with toxic CHEMICAL plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of CHEMICAL-induced DISEASE associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and paranoia over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, warfarin 2 mg/day, folic acid 1 mg/day, levothyroxine 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and CHEMICAL 100 mg twice daily. CHEMICAL had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a CHEMICAL plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between CHEMICAL and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of CHEMICAL was reduced to 50 mg twice daily. Her DISEASE resolved 3 days later. DISCUSSION: CHEMICAL and pharmacologically similar agents that interact with sodium channels may cause DISEASE in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between CHEMICAL, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of CHEMICAL-induced DISEASE. According to the Naranjo probability scale, CHEMICAL was the probable cause of the patient's DISEASE; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between CHEMICAL and paroxetine. CONCLUSIONS: Supratherapeutic CHEMICAL plasma concentrations may cause DISEASE. Because toxicity may occur when CHEMICAL is prescribed with paroxetine and other potent CYP2D6 inhibitors, CHEMICAL plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | CHEMICAL-INDUCED-DISEASE |
| DISEASE in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with CHEMICAL. OBJECTIVE: To describe a case of flecainide-induced DISEASE associated with a pharmacokinetic drug interaction with CHEMICAL. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and paranoia over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, warfarin 2 mg/day, folic acid 1 mg/day, levothyroxine 100 microg/day, pantoprazole 40 mg/day, CHEMICAL 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and CHEMICAL, which the patient had been taking for more than 5 years, was considered. CHEMICAL was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her DISEASE resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause DISEASE in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and CHEMICAL, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced DISEASE. According to the Naranjo probability scale, flecainide was the probable cause of the patient's DISEASE; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and CHEMICAL. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause DISEASE. Because toxicity may occur when flecainide is prescribed with CHEMICAL and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | CHEMICAL-INDUCED-DISEASE |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and paranoia over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, warfarin 2 mg/day, folic acid 1 mg/day, levothyroxine 100 microg/day, CHEMICAL 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because DISEASE may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and paranoia over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, CHEMICAL 2 mg/day, folic acid 1 mg/day, levothyroxine 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because DISEASE may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and paranoia over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, warfarin 2 mg/day, CHEMICAL 1 mg/day, levothyroxine 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because DISEASE may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and DISEASE over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, warfarin 2 mg/day, folic acid 1 mg/day, CHEMICAL 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of DISEASE and paranoia over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, warfarin 2 mg/day, folic acid 1 mg/day, levothyroxine 100 microg/day, CHEMICAL 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of DISEASE and paranoia over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, warfarin 2 mg/day, folic acid 1 mg/day, CHEMICAL 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and paranoia over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, warfarin 2 mg/day, folic acid 1 mg/day, levothyroxine 100 microg/day, CHEMICAL 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for DISEASE. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and DISEASE over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, CHEMICAL 2 mg/day, folic acid 1 mg/day, levothyroxine 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of DISEASE and paranoia over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, warfarin 2 mg/day, folic acid 1 mg/day, levothyroxine 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with CHEMICAL channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and DISEASE over the past several days. On admission the patient was taking CHEMICAL 12 mg twice daily, warfarin 2 mg/day, folic acid 1 mg/day, levothyroxine 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of DISEASE and paranoia over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, CHEMICAL 2 mg/day, folic acid 1 mg/day, levothyroxine 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and paranoia over the past several days. On admission the patient was taking CHEMICAL 12 mg twice daily, warfarin 2 mg/day, folic acid 1 mg/day, levothyroxine 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because DISEASE may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and DISEASE over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, warfarin 2 mg/day, folic acid 1 mg/day, levothyroxine 100 microg/day, CHEMICAL 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and paranoia over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, CHEMICAL 2 mg/day, folic acid 1 mg/day, levothyroxine 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for DISEASE. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and paranoia over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, warfarin 2 mg/day, CHEMICAL 1 mg/day, levothyroxine 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for DISEASE. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and DISEASE over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, warfarin 2 mg/day, CHEMICAL 1 mg/day, levothyroxine 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and paranoia over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, warfarin 2 mg/day, folic acid 1 mg/day, CHEMICAL 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for DISEASE. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and paranoia over the past several days. On admission the patient was taking carvedilol 12 mg twice daily, warfarin 2 mg/day, folic acid 1 mg/day, CHEMICAL 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because DISEASE may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of DISEASE and paranoia over the past several days. On admission the patient was taking CHEMICAL 12 mg twice daily, warfarin 2 mg/day, folic acid 1 mg/day, levothyroxine 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for atrial fibrillation. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Delirium in a patient with toxic flecainide plasma concentrations: the role of a pharmacokinetic drug interaction with paroxetine. OBJECTIVE: To describe a case of flecainide-induced delirium associated with a pharmacokinetic drug interaction with paroxetine. CASE SUMMARY: A 69-year-old white female presented to the emergency department with a history of confusion and paranoia over the past several days. On admission the patient was taking CHEMICAL 12 mg twice daily, warfarin 2 mg/day, folic acid 1 mg/day, levothyroxine 100 microg/day, pantoprazole 40 mg/day, paroxetine 40 mg/day, and flecainide 100 mg twice daily. Flecainide had been started 2 weeks prior for DISEASE. Laboratory test findings on admission were notable only for a flecainide plasma concentration of 1360 microg/L (reference range 200-1000). A metabolic drug interaction between flecainide and paroxetine, which the patient had been taking for more than 5 years, was considered. Paroxetine was discontinued and the dose of flecainide was reduced to 50 mg twice daily. Her delirium resolved 3 days later. DISCUSSION: Flecainide and pharmacologically similar agents that interact with sodium channels may cause delirium in susceptible patients. A MEDLINE search (1966-January 2009) revealed one in vivo pharmacokinetic study on the interaction between flecainide, a CYP2D6 substrate, and paroxetine, a CYP2D6 inhibitor, as well as 3 case reports of flecainide-induced delirium. According to the Naranjo probability scale, flecainide was the probable cause of the patient's delirium; the Horn Drug Interaction Probability Scale indicates a possible pharmacokinetic drug interaction between flecainide and paroxetine. CONCLUSIONS: Supratherapeutic flecainide plasma concentrations may cause delirium. Because toxicity may occur when flecainide is prescribed with paroxetine and other potent CYP2D6 inhibitors, flecainide plasma concentrations should be monitored closely with commencement of CYP2D6 inhibitors. | NO-RELATIONSHIP |
| Efficacy of CHEMICAL (CHEMICAL) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. CHEMICAL, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received CHEMICAL 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and DISEASE. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: CHEMICAL 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of CHEMICAL plus standard therapy for metastatic NSCLC continues. | CHEMICAL-INDUCED-DISEASE |
| Efficacy of CHEMICAL (CHEMICAL) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. CHEMICAL, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received CHEMICAL 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, DISEASE, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: CHEMICAL 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of CHEMICAL plus standard therapy for metastatic NSCLC continues. | CHEMICAL-INDUCED-DISEASE |
| Efficacy of CHEMICAL (CHEMICAL) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. CHEMICAL, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received CHEMICAL 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, DISEASE, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: CHEMICAL 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of CHEMICAL plus standard therapy for metastatic NSCLC continues. | CHEMICAL-INDUCED-DISEASE |
| Efficacy of CHEMICAL (CHEMICAL) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. CHEMICAL, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received CHEMICAL 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were DISEASE, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: CHEMICAL 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of CHEMICAL plus standard therapy for metastatic NSCLC continues. | CHEMICAL-INDUCED-DISEASE |
| Efficacy of CHEMICAL (CHEMICAL) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. CHEMICAL, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received CHEMICAL 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, DISEASE, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: CHEMICAL 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of CHEMICAL plus standard therapy for metastatic NSCLC continues. | CHEMICAL-INDUCED-DISEASE |
| Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of CHEMICAL (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable DISEASE. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues. | NO-RELATIONSHIP |
| Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of CHEMICAL (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. DISEASE, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues. | NO-RELATIONSHIP |
| Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of CHEMICAL (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival DISEASE from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues. | NO-RELATIONSHIP |
| Efficacy of everolimus (RAD001) in patients with advanced DISEASE previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced DISEASE (DISEASE) patients. RAD001, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in DISEASE. METHODS: Stage IIIb or IV DISEASE patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor CHEMICAL kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated DISEASE. Evaluation of RAD001 plus standard therapy for metastatic DISEASE continues. | NO-RELATIONSHIP |
| Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor CHEMICAL kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival DISEASE from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues. | NO-RELATIONSHIP |
| Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one CHEMICAL based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival DISEASE from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues. | NO-RELATIONSHIP |
| Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one CHEMICAL based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. DISEASE, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues. | NO-RELATIONSHIP |
| Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor CHEMICAL kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable DISEASE. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues. | NO-RELATIONSHIP |
| Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one CHEMICAL based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable DISEASE. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues. | NO-RELATIONSHIP |
| Efficacy of everolimus (RAD001) in patients with advanced DISEASE previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced DISEASE (DISEASE) patients. RAD001, an oral inhibitor of the mammalian target of CHEMICAL (mTOR), has shown phase I efficacy in DISEASE. METHODS: Stage IIIb or IV DISEASE patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated DISEASE. Evaluation of RAD001 plus standard therapy for metastatic DISEASE continues. | NO-RELATIONSHIP |
| Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor CHEMICAL kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. DISEASE, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues. | NO-RELATIONSHIP |
| Efficacy of everolimus (RAD001) in patients with advanced DISEASE previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. BACKGROUND: Treatment options are scarce in pretreated advanced DISEASE (DISEASE) patients. RAD001, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in DISEASE. METHODS: Stage IIIb or IV DISEASE patients, with two or fewer prior chemotherapy regimens, one CHEMICAL based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated DISEASE. Evaluation of RAD001 plus standard therapy for metastatic DISEASE continues. | NO-RELATIONSHIP |
| Posttransplant DISEASE: the role of CHEMICAL. Posttransplant DISEASE is a common problem that may hinder patients' quality of life. It occurs in 12 to 76% of patients, and is most common in the immediate posttransplant period. A variety of factors have been identified that increase the risk of posttransplant DISEASE, of which the level of renal function is most important. CHEMICAL, a mammalian target of CHEMICAL inhibitor, has been implicated as playing a special role in posttransplant DISEASE. This review considers DISEASE associated with CHEMICAL, including its presentation, mechanisms, and management. | CHEMICAL-INDUCED-DISEASE |
| Coronary computerized tomography angiography for rapid discharge of low-risk patients with CHEMICAL-associated DISEASE. BACKGROUND: Most patients presenting to emergency departments (EDs) with CHEMICAL-associated DISEASE are admitted for at least 12 hours and receive a "rule out acute coronary syndrome" protocol, often with noninvasive testing prior to discharge. In patients without CHEMICAL use, coronary computerized tomography angiography (CTA) has been shown to be useful for identifying a group of patients at low risk for cardiac events who can be safely discharged. It is unclear whether a coronary CTA strategy would be efficacious in CHEMICAL-associated DISEASE, as coronary vasospasm may account for some of the ischemia. We studied whether a negative coronary CTA in patients with CHEMICAL-associated DISEASE could identify a subset safe for discharge. METHODS: We prospectively evaluated the safety of coronary CTA for low-risk patients who presented to the ED with cocaineassociated DISEASE (self-reported or positive urine test). Consecutive patients received either immediate coronary CTA in the ED (without serial markers) or underwent coronary CTA after a brief observation period with serial cardiac marker measurements. Patients with negative coronary CTA (maximal stenosis less than 50%) were discharged. The main outcome was 30-day cardiovascular death or myocardial infarction. RESULTS: A total of 59 patients with CHEMICAL-associated DISEASE were evaluated. Patients had a mean age of 45.6 +/- 6.6 yrs and were 86% black, 66% male. Seventy-nine percent had a normal or nonspecific ECG and 85% had a TIMI score <2. Twenty patients received coronary CTA immediately in the ED, 18 of whom were discharged following CTA (90%). Thirty-nine received coronary CTA after a brief observation period, with 37 discharged home following CTA (95%). Six patients had coronary stenosis >or=50%. During the 30-day follow-up period, no patients died of a cardiovascular event (0%; 95% CI, 0-6.1%) and no patient sustained a nonfatal myocardial infarction (0%; 95% CI, 0-6.1%). CONCLUSIONS: Although CHEMICAL-associated myocardial ischemia can result from coronary vasoconstriction, patients with CHEMICAL associated DISEASE, a non-ischemic ECG, and a TIMI risk score <2 may be safely discharged from the ED after a negative coronary CTA with a low risk of 30-day adverse events. | CHEMICAL-INDUCED-DISEASE |
| Coronary computerized tomography angiography for rapid discharge of low-risk patients with CHEMICAL-associated chest pain. BACKGROUND: Most patients presenting to emergency departments (EDs) with CHEMICAL-associated chest pain are admitted for at least 12 hours and receive a "rule out acute coronary syndrome" protocol, often with noninvasive testing prior to discharge. In patients without CHEMICAL use, coronary computerized tomography angiography (CTA) has been shown to be useful for identifying a group of patients at low risk for cardiac events who can be safely discharged. It is unclear whether a coronary CTA strategy would be efficacious in CHEMICAL-associated chest pain, as coronary vasospasm may account for some of the ischemia. We studied whether a negative coronary CTA in patients with CHEMICAL-associated chest pain could identify a subset safe for discharge. METHODS: We prospectively evaluated the safety of coronary CTA for low-risk patients who presented to the ED with cocaineassociated chest pain (self-reported or positive urine test). Consecutive patients received either immediate coronary CTA in the ED (without serial markers) or underwent coronary CTA after a brief observation period with serial cardiac marker measurements. Patients with negative coronary CTA (maximal stenosis less than 50%) were discharged. The main outcome was 30-day cardiovascular death or myocardial infarction. RESULTS: A total of 59 patients with CHEMICAL-associated chest pain were evaluated. Patients had a mean age of 45.6 +/- 6.6 yrs and were 86% black, 66% male. Seventy-nine percent had a normal or nonspecific ECG and 85% had a TIMI score <2. Twenty patients received coronary CTA immediately in the ED, 18 of whom were discharged following CTA (90%). Thirty-nine received coronary CTA after a brief observation period, with 37 discharged home following CTA (95%). Six patients had coronary stenosis >or=50%. During the 30-day follow-up period, no patients died of a cardiovascular event (0%; 95% CI, 0-6.1%) and no patient sustained a nonfatal myocardial infarction (0%; 95% CI, 0-6.1%). CONCLUSIONS: Although CHEMICAL-associated DISEASE can result from coronary vasoconstriction, patients with CHEMICAL associated chest pain, a non-ischemic ECG, and a TIMI risk score <2 may be safely discharged from the ED after a negative coronary CTA with a low risk of 30-day adverse events. | CHEMICAL-INDUCED-DISEASE |
| Late fulminant DISEASE after liver transplant. OBJECTIVES: DISEASE due to calcineurin-inhibitor-related neurotoxicity is a rare but severe complication that results from treatment with immunosuppressive agents (primarily those administered after a liver or kidney transplant). The pathophysiologic mechanisms of that disorder remain unknown. CASE: We report the case of a 46-year-old woman who received a liver transplant in our center as treatment for alcoholic cirrhosis and in whom either a fulminant course of DISEASE or DISEASE developed 110 days after transplant. After an initially uneventful course after the transplant, the patient rapidly fell into deep coma. RESULTS: Cerebral MRI scan showed typical signs of enhancement in the pontine and posterior regions. Switching the immunosuppressive regimen from CHEMICAL to cyclosporine did not improve the clinical situation. The termination of treatment with any calcineurin inhibitor resulted in a complete resolution of that complication. CONCLUSIONS: DISEASE after liver transplant is rare. We recommend a complete cessation of any calcineurin inhibitor rather than a dose reduction. | NO-RELATIONSHIP |
| Late fulminant posterior reversible encephalopathy syndrome after liver transplant. OBJECTIVES: Posterior leukoencephalopathy due to calcineurin-inhibitor-related neurotoxicity is a rare but severe complication that results from treatment with immunosuppressive agents (primarily those administered after a liver or kidney transplant). The pathophysiologic mechanisms of that disorder remain unknown. CASE: We report the case of a 46-year-old woman who received a liver transplant in our center as treatment for DISEASE and in whom either a fulminant course of posterior leukoencephalopathy or posterior reversible encephalopathy syndrome developed 110 days after transplant. After an initially uneventful course after the transplant, the patient rapidly fell into deep coma. RESULTS: Cerebral MRI scan showed typical signs of enhancement in the pontine and posterior regions. Switching the immunosuppressive regimen from tacrolimus to CHEMICAL did not improve the clinical situation. The termination of treatment with any calcineurin inhibitor resulted in a complete resolution of that complication. CONCLUSIONS: Posterior reversible encephalopathy syndrome after liver transplant is rare. We recommend a complete cessation of any calcineurin inhibitor rather than a dose reduction. | NO-RELATIONSHIP |
| Late fulminant posterior reversible encephalopathy syndrome after liver transplant. OBJECTIVES: Posterior leukoencephalopathy due to calcineurin-inhibitor-related DISEASE is a rare but severe complication that results from treatment with immunosuppressive agents (primarily those administered after a liver or kidney transplant). The pathophysiologic mechanisms of that disorder remain unknown. CASE: We report the case of a 46-year-old woman who received a liver transplant in our center as treatment for alcoholic cirrhosis and in whom either a fulminant course of posterior leukoencephalopathy or posterior reversible encephalopathy syndrome developed 110 days after transplant. After an initially uneventful course after the transplant, the patient rapidly fell into deep coma. RESULTS: Cerebral MRI scan showed typical signs of enhancement in the pontine and posterior regions. Switching the immunosuppressive regimen from tacrolimus to CHEMICAL did not improve the clinical situation. The termination of treatment with any calcineurin inhibitor resulted in a complete resolution of that complication. CONCLUSIONS: Posterior reversible encephalopathy syndrome after liver transplant is rare. We recommend a complete cessation of any calcineurin inhibitor rather than a dose reduction. | NO-RELATIONSHIP |
| Prolonged hypothermia as a bridge to recovery for cerebral edema and intracranial hypertension associated with DISEASE. BACKGROUND: To review evidence-based treatment options in patients with cerebral edema complicating DISEASE (DISEASE) and discuss the potential applications of hypothermia. METHOD: Case-based observations from a medical intensive care unit (MICU) in a tertiary care facility in a 27-year-old female with DISEASE from CHEMICAL and resultant cerebral edema. RESULTS: Our patient was admitted to the MICU after being found unresponsive with presumed toxicity from CHEMICAL which was ingested over a 2-day period. The patient had depressed of mental status lasting at least 24 h prior to admission. Initial evaluation confirmed DISEASE from CHEMICAL and cerebral edema. The patient was treated with hyperosmolar therapy, hyperventilation, sedation, and chemical paralysis. Her intracranial pressure remained elevated despite maximal medical therapy. We then initiated therapeutic hypothermia which was continued for 5 days. At re-warming, patient had resolution of her cerebral edema and intracranial hypertension. At discharge, she had complete recovery of neurological and hepatic functions. CONCLUSION: In patients with DISEASE and cerebral edema from CHEMICAL overdose, prolonged therapeutic hypothermia could potentially be used as a life saving therapy and a bridge to hepatic and neurological recovery. A clinical trial of hypothermia in patients with this condition is warranted. | CHEMICAL-INDUCED-DISEASE |
| Prolonged hypothermia as a bridge to recovery for cerebral edema and DISEASE associated with fulminant hepatic failure. BACKGROUND: To review evidence-based treatment options in patients with cerebral edema complicating fulminant hepatic failure (FHF) and discuss the potential applications of hypothermia. METHOD: Case-based observations from a medical intensive care unit (MICU) in a tertiary care facility in a 27-year-old female with FHF from CHEMICAL and resultant cerebral edema. RESULTS: Our patient was admitted to the MICU after being found unresponsive with presumed toxicity from CHEMICAL which was ingested over a 2-day period. The patient had depressed of mental status lasting at least 24 h prior to admission. Initial evaluation confirmed FHF from CHEMICAL and cerebral edema. The patient was treated with hyperosmolar therapy, hyperventilation, sedation, and chemical paralysis. Her intracranial pressure remained elevated despite maximal medical therapy. We then initiated therapeutic hypothermia which was continued for 5 days. At re-warming, patient had resolution of her cerebral edema and DISEASE. At discharge, she had complete recovery of neurological and hepatic functions. CONCLUSION: In patients with FHF and cerebral edema from CHEMICAL overdose, prolonged therapeutic hypothermia could potentially be used as a life saving therapy and a bridge to hepatic and neurological recovery. A clinical trial of hypothermia in patients with this condition is warranted. | CHEMICAL-INDUCED-DISEASE |
| Prolonged hypothermia as a bridge to recovery for DISEASE and intracranial hypertension associated with fulminant hepatic failure. BACKGROUND: To review evidence-based treatment options in patients with DISEASE complicating fulminant hepatic failure (FHF) and discuss the potential applications of hypothermia. METHOD: Case-based observations from a medical intensive care unit (MICU) in a tertiary care facility in a 27-year-old female with FHF from CHEMICAL and resultant DISEASE. RESULTS: Our patient was admitted to the MICU after being found unresponsive with presumed toxicity from CHEMICAL which was ingested over a 2-day period. The patient had depressed of mental status lasting at least 24 h prior to admission. Initial evaluation confirmed FHF from CHEMICAL and DISEASE. The patient was treated with hyperosmolar therapy, hyperventilation, sedation, and chemical paralysis. Her intracranial pressure remained elevated despite maximal medical therapy. We then initiated therapeutic hypothermia which was continued for 5 days. At re-warming, patient had resolution of her DISEASE and intracranial hypertension. At discharge, she had complete recovery of neurological and hepatic functions. CONCLUSION: In patients with FHF and DISEASE from CHEMICAL overdose, prolonged therapeutic hypothermia could potentially be used as a life saving therapy and a bridge to hepatic and neurological recovery. A clinical trial of hypothermia in patients with this condition is warranted. | CHEMICAL-INDUCED-DISEASE |
| DISEASE are not specific to CHEMICAL. This study investigated the DISEASE associated with the antiepileptic drug CHEMICAL (CHEMICAL). Two hundred four people with epilepsy were grouped on the basis of antiepileptic drug therapy (current, previous, or no exposure to CHEMICAL). Groups were matched with respect to age, gender, and seizure frequency. All patients underwent objective assessment of electrophysiological function (wide-field multifocal electroretinography) and conventional visual field testing (static perimetry). Bilateral visual field constriction was observed in 59% of patients currently taking CHEMICAL, 43% of patients who previously took CHEMICAL, and 24% of patients with no exposure to CHEMICAL. Assessment of retinal function revealed abnormal responses in 48% of current CHEMICAL users and 22% of prior CHEMICAL users, but in none of the patients without previous exposure to CHEMICAL. DISEASE are common in the treated epilepsy population, irrespective of drug history. Assessment by conventional static perimetry may neither be sufficiently sensitive nor specific to reliably identify retinal toxicity associated with CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Binasal visual field defects are not specific to CHEMICAL. This study investigated the visual defects associated with the antiepileptic drug CHEMICAL (CHEMICAL). Two hundred four people with epilepsy were grouped on the basis of antiepileptic drug therapy (current, previous, or no exposure to CHEMICAL). Groups were matched with respect to age, gender, and seizure frequency. All patients underwent objective assessment of electrophysiological function (wide-field multifocal electroretinography) and conventional visual field testing (static perimetry). Bilateral visual field constriction was observed in 59% of patients currently taking CHEMICAL, 43% of patients who previously took CHEMICAL, and 24% of patients with no exposure to CHEMICAL. Assessment of retinal function revealed abnormal responses in 48% of current CHEMICAL users and 22% of prior CHEMICAL users, but in none of the patients without previous exposure to CHEMICAL. Bilateral visual field abnormalities are common in the treated epilepsy population, irrespective of drug history. Assessment by conventional static perimetry may neither be sufficiently sensitive nor specific to reliably identify DISEASE associated with CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Smoking of CHEMICAL as a risk factor for HIV infection among people who use injection drugs. BACKGROUND: Little is known about the possible role that smoking CHEMICAL has on the incidence of HIV infection. Given the increasing use of CHEMICAL, we sought to examine whether use of this illicit drug has become a risk factor for HIV infection. METHODS: We included data from people participating in the Vancouver Injection Drug Users Study who reported injecting illicit drugs at least once in the month before enrolment, lived in the greater Vancouver area, were HIV-negative at enrolment and completed at least 1 follow-up study visit. To determine whether the risk of DISEASE among daily smokers of CHEMICAL changed over time, we used Cox proportional hazards regression and divided the study into 3 periods: May 1, 1996-Nov. 30, 1999 (period 1), Dec. 1, 1999-Nov. 30, 2002 (period 2), and Dec. 1, 2002-Dec. 30, 2005 (period 3). RESULTS: Overall, 1048 eligible injection drug users were included in our study. Of these, 137 acquired HIV infection during follow-up. The mean proportion of participants who reported daily smoking of CHEMICAL increased from 11.6% in period 1 to 39.7% in period 3. After adjusting for potential confounders, we found that the risk of DISEASE among participants who were daily smokers of CHEMICAL increased over time (period 1: hazard ratio [HR] 1.03, 95% confidence interval [CI] 0.57-1.85; period 2: HR 1.68, 95% CI 1.01-2.80; and period 3: HR 2.74, 95% CI 1.06-7.11). INTERPRETATION: Smoking of CHEMICAL was found to be an independent risk factor for DISEASE among people who were injection drug users. This finding points to the urgent need for evidence-based public health initiatives targeted at people who smoke CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Fluoxetine improves the DISEASE caused by the chemotherapy agent CHEMICAL. Cancer patients who have been treated with systemic adjuvant chemotherapy have described experiencing deteriorations in cognition. A widely used chemotherapeutic agent, CHEMICAL (CHEMICAL), readily crosses the blood-brain barrier and so could have a direct effect on brain function. In particular this anti mitotic drug could reduce cell proliferation in the neurogenic regions of the adult brain. In contrast reports indicate that hippocampal dependent neurogenesis and cognition are enhanced by the SSRI antidepressant Fluoxetine. In this investigation the behavioural effects of chronic (two week) treatment with CHEMICAL and (three weeks) with Fluoxetine either separately or in combination with CHEMICAL were tested on adult Lister hooded rats. Behavioural effects were tested using a context dependent conditioned emotional response test (CER) which showed that animals treated with CHEMICAL had a significant reduction in freezing time compared to controls. A separate group of animals was tested using a hippocampal dependent spatial working memory test, the object location recognition test (OLR). Animals treated only with CHEMICAL showed significant deficits in their ability to carry out the OLR task but co administration of Fluoxetine improved their performance. CHEMICAL chemotherapy caused a significant reduction in the number of proliferating cells in the sub granular zone of the dentate gyrus compared to controls. This reduction was eliminated when Fluoxetine was co administered with CHEMICAL. Fluoxetine on its own had no effect on proliferating cell number or behaviour. These findings suggest that CHEMICAL can negatively affect both cell proliferation and hippocampal dependent working memory and that these deficits can be reversed by the simultaneous administration of the antidepressant Fluoxetine. | CHEMICAL-INDUCED-DISEASE |
| Fluoxetine improves the memory deficits caused by the chemotherapy agent 5-fluorouracil. DISEASE patients who have been treated with systemic adjuvant chemotherapy have described experiencing deteriorations in cognition. A widely used chemotherapeutic agent, 5-fluorouracil (5-FU), readily crosses the blood-brain barrier and so could have a direct effect on brain function. In particular this anti mitotic drug could reduce cell proliferation in the neurogenic regions of the adult brain. In contrast reports indicate that hippocampal dependent neurogenesis and cognition are enhanced by the CHEMICAL antidepressant Fluoxetine. In this investigation the behavioural effects of chronic (two week) treatment with 5-FU and (three weeks) with Fluoxetine either separately or in combination with 5-FU were tested on adult Lister hooded rats. Behavioural effects were tested using a context dependent conditioned emotional response test (CER) which showed that animals treated with 5-FU had a significant reduction in freezing time compared to controls. A separate group of animals was tested using a hippocampal dependent spatial working memory test, the object location recognition test (OLR). Animals treated only with 5-FU showed significant deficits in their ability to carry out the OLR task but co administration of Fluoxetine improved their performance. 5-FU chemotherapy caused a significant reduction in the number of proliferating cells in the sub granular zone of the dentate gyrus compared to controls. This reduction was eliminated when Fluoxetine was co administered with 5-FU. Fluoxetine on its own had no effect on proliferating cell number or behaviour. These findings suggest that 5-FU can negatively affect both cell proliferation and hippocampal dependent working memory and that these deficits can be reversed by the simultaneous administration of the antidepressant Fluoxetine. | NO-RELATIONSHIP |
| CHEMICAL improves the memory deficits caused by the chemotherapy agent 5-fluorouracil. DISEASE patients who have been treated with systemic adjuvant chemotherapy have described experiencing deteriorations in cognition. A widely used chemotherapeutic agent, 5-fluorouracil (5-FU), readily crosses the blood-brain barrier and so could have a direct effect on brain function. In particular this anti mitotic drug could reduce cell proliferation in the neurogenic regions of the adult brain. In contrast reports indicate that hippocampal dependent neurogenesis and cognition are enhanced by the SSRI antidepressant CHEMICAL. In this investigation the behavioural effects of chronic (two week) treatment with 5-FU and (three weeks) with CHEMICAL either separately or in combination with 5-FU were tested on adult Lister hooded rats. Behavioural effects were tested using a context dependent conditioned emotional response test (CER) which showed that animals treated with 5-FU had a significant reduction in freezing time compared to controls. A separate group of animals was tested using a hippocampal dependent spatial working memory test, the object location recognition test (OLR). Animals treated only with 5-FU showed significant deficits in their ability to carry out the OLR task but co administration of CHEMICAL improved their performance. 5-FU chemotherapy caused a significant reduction in the number of proliferating cells in the sub granular zone of the dentate gyrus compared to controls. This reduction was eliminated when CHEMICAL was co administered with 5-FU. CHEMICAL on its own had no effect on proliferating cell number or behaviour. These findings suggest that 5-FU can negatively affect both cell proliferation and hippocampal dependent working memory and that these deficits can be reversed by the simultaneous administration of the antidepressant CHEMICAL. | NO-RELATIONSHIP |
| Liver-specific ablation of integrin-linked kinase in mice results in enhanced and prolonged cell proliferation and DISEASE after CHEMICAL administration. We have recently demonstrated that disruption of extracellular matrix (ECM)/integrin signaling via elimination of integrin-linked kinase (ILK) in hepatocytes interferes with signals leading to termination of liver regeneration. This study investigates the role of ILK in liver enlargement induced by CHEMICAL (CHEMICAL). Wild-type (WT) and ILK:liver-/- mice were given CHEMICAL (0.1% in drinking water) for 10 days. Livers were harvested on 2, 5, and 10 days during CHEMICAL administration. In the hepatocyte-specific ILK/liver-/- mice, the liver:body weight ratio was more than double as compared to 0 h at day 2 (2.5 times), while at days 5 and 10, it was enlarged three times. In the WT mice, the increase was as expected from previous literature (1.8 times) and seems to have leveled off after day 2. There were slightly increased proliferating cell nuclear antigen-positive cells in the ILK/liver-/- animals at day 2 as compared to WT after CHEMICAL administration. In the WT animals, the proliferative response had come back to normal by days 5 and 10. Hepatocytes of the ILK/liver-/- mice continued to proliferate up until day 10. ILK/liver-/- mice also showed increased expression of key genes involved in hepatocyte proliferation at different time points during CHEMICAL administration. In summary, ECM proteins communicate with the signaling machinery of dividing cells via ILK to regulate hepatocyte proliferation and termination of the proliferative response. Lack of ILK in the hepatocytes imparts prolonged proliferative response not only to stimuli related to liver regeneration but also to xenobiotic chemical mitogens, such as CHEMICAL. | CHEMICAL-INDUCED-DISEASE |
| Longitudinal association of CHEMICAL use with HIV disease progression and psychological health of women with HIV. We evaluated the association of CHEMICAL consumption and DISEASE, and their effects on HIV disease progression among women with HIV. The study included 871 women with HIV who were recruited from 1993-1995 in four US cities. The participants had physical examination, medical record extraction, and venipuncture, CD4+T-cell counts determination, measurement of DISEASE symptoms (using the self-report Center for Epidemiological Studies-DISEASE Scale), and CHEMICAL use assessment at enrollment, and semiannually until March 2000. Multilevel random coefficient ordinal models as well as multilevel models with joint responses were used in the analysis. There was no significant association between level of CHEMICAL use and CD4+ T-cell counts. When participants were stratified by antiretroviral therapy (ART) use, the association between CHEMICAL and CD4+ T-cell did not reach statistical significance. The association between CHEMICAL consumption and DISEASE was significant (p<0.001). DISEASE had a significant negative effect on CD4+ T-cell counts over time regardless of ART use. Our findings suggest that CHEMICAL consumption has a direct association with DISEASE. Moreover, DISEASE is associated with HIV disease progression. Our findings have implications for the provision of CHEMICAL use interventions and psychological resources to improve the health of women with HIV. | CHEMICAL-INDUCED-DISEASE |
| Chemokine CCL2 and its receptor CCR2 are increased in the hippocampus following CHEMICAL-induced DISEASE. BACKGROUND: Neuroinflammation occurs after seizures and is implicated in epileptogenesis. CCR2 is a chemokine receptor for CCL2 and their interaction mediates monocyte infiltration in the neuroinflammatory cascade triggered in different brain pathologies. In this work CCR2 and CCL2 expression were examined following DISEASE (DISEASE) induced by CHEMICAL injection. METHODS: DISEASE was induced by CHEMICAL injection. Control rats were injected with saline instead of CHEMICAL. Five days after DISEASE, CCR2 staining in neurons and glial cells was examined using imunohistochemical analyses. The number of CCR2 positive cells was determined using stereology probes in the hippocampus. CCL2 expression in the hippocampus was examined by molecular assay. RESULTS: Increased CCR2 was observed in the hippocampus after DISEASE. Seizures also resulted in alterations to the cell types expressing CCR2. Increased numbers of neurons that expressed CCR2 was observed following DISEASE. Microglial cells were more closely apposed to the CCR2-labeled cells in DISEASE rats. In addition, rats that experienced DISEASE exhibited CCR2-labeling in populations of hypertrophied astrocytes, especially in CA1 and dentate gyrus. These CCR2+ astroctytes were not observed in control rats. Examination of CCL2 expression showed that it was elevated in the hippocampus following DISEASE. CONCLUSION: The data show that CCR2 and CCL2 are up-regulated in the hippocampus after CHEMICAL-induced DISEASE. Seizures also result in changes to CCR2 receptor expression in neurons and astrocytes. These changes might be involved in detrimental neuroplasticity and neuroinflammatory changes that occur following seizures. | CHEMICAL-INDUCED-DISEASE |
| Metallothionein induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in CHEMICAL-treated rats. Hippocampal integrity is essential for cognitive functions. On the other hand, induction of metallothionein (MT) by ZnSO(4) and its role in neuroprotection has been documented. The present study aimed to explore the effect of MT induction on CHEMICAL (CHEMICAL)-induced hippocampal DISEASE in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by CHEMICAL solvent (i.v). The second group administered ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v, once) then CHEMICAL solvent (i.v) after 24 h. Third group received CHEMICAL (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v) then CHEMICAL (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that CHEMICAL administration resulted in deterioration of learning and short-term memory (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal glutathione reductase (GR) activity and reduced glutathione (GSH) content. Also, CHEMICAL administration increased serum tumor necrosis factor-alpha (TNFalpha), hippocampal MT and malondialdehyde (MDA) contents as well as caspase-3 activity in addition to histological alterations. ZnSO(4) pretreatment counteracted CHEMICAL-induced inhibition of GR and depletion of GSH and resulted in significant reduction in the levels of MDA and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with ZnSO(4) + CHEMICAL compared to only CHEMICAL-treated animals. In conclusion, MT induction halts CHEMICAL-induced hippocampal toxicity as it prevented GR inhibition and GSH depletion and counteracted the increased levels of TNFalpha, MDA and caspase-3 activity with subsequent preservation of cognition. | CHEMICAL-INDUCED-DISEASE |
| Metallothionein induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats. Hippocampal integrity is essential for cognitive functions. On the other hand, induction of metallothionein (MT) by ZnSO(4) and its role in neuroprotection has been documented. The present study aimed to explore the effect of MT induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in deterioration of learning and short-term memory (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal CHEMICAL reductase (GR) activity and reduced CHEMICAL (CHEMICAL) content. Also, BCNU administration increased serum tumor DISEASE factor-alpha (TNFalpha), hippocampal MT and malondialdehyde (MDA) contents as well as caspase-3 activity in addition to histological alterations. ZnSO(4) pretreatment counteracted BCNU-induced inhibition of GR and depletion of CHEMICAL and resulted in significant reduction in the levels of MDA and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with ZnSO(4) + BCNU compared to only BCNU-treated animals. In conclusion, MT induction halts BCNU-induced hippocampal toxicity as it prevented GR inhibition and CHEMICAL depletion and counteracted the increased levels of TNFalpha, MDA and caspase-3 activity with subsequent preservation of cognition. | NO-RELATIONSHIP |
| Metallothionein induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats. Hippocampal integrity is essential for cognitive functions. On the other hand, induction of metallothionein (MT) by ZnSO(4) and its role in neuroprotection has been documented. The present study aimed to explore the effect of MT induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in deterioration of learning and short-term memory (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal glutathione reductase (GR) activity and reduced glutathione (GSH) content. Also, BCNU administration increased serum tumor necrosis factor-alpha (TNFalpha), hippocampal MT and CHEMICAL (CHEMICAL) contents as well as caspase-3 activity in addition to histological alterations. ZnSO(4) pretreatment counteracted BCNU-induced inhibition of GR and depletion of GSH and resulted in significant reduction in the levels of CHEMICAL and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with ZnSO(4) + BCNU compared to only BCNU-treated animals. In conclusion, MT induction halts BCNU-induced hippocampal DISEASE as it prevented GR inhibition and GSH depletion and counteracted the increased levels of TNFalpha, CHEMICAL and caspase-3 activity with subsequent preservation of cognition. | NO-RELATIONSHIP |
| Metallothionein induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats. Hippocampal integrity is essential for cognitive functions. On the other hand, induction of metallothionein (MT) by CHEMICAL and its role in neuroprotection has been documented. The present study aimed to explore the effect of MT induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered CHEMICAL (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of CHEMICAL (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in deterioration of learning and short-term memory (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal glutathione reductase (GR) activity and reduced glutathione (GSH) content. Also, BCNU administration increased serum tumor DISEASE factor-alpha (TNFalpha), hippocampal MT and malondialdehyde (MDA) contents as well as caspase-3 activity in addition to histological alterations. CHEMICAL pretreatment counteracted BCNU-induced inhibition of GR and depletion of GSH and resulted in significant reduction in the levels of MDA and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with CHEMICAL + BCNU compared to only BCNU-treated animals. In conclusion, MT induction halts BCNU-induced hippocampal toxicity as it prevented GR inhibition and GSH depletion and counteracted the increased levels of TNFalpha, MDA and caspase-3 activity with subsequent preservation of cognition. | NO-RELATIONSHIP |
| Metallothionein induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats. Hippocampal integrity is essential for cognitive functions. On the other hand, induction of metallothionein (MT) by CHEMICAL and its role in neuroprotection has been documented. The present study aimed to explore the effect of MT induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered CHEMICAL (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of CHEMICAL (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in DISEASE (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal glutathione reductase (GR) activity and reduced glutathione (GSH) content. Also, BCNU administration increased serum tumor necrosis factor-alpha (TNFalpha), hippocampal MT and malondialdehyde (MDA) contents as well as caspase-3 activity in addition to histological alterations. CHEMICAL pretreatment counteracted BCNU-induced inhibition of GR and depletion of GSH and resulted in significant reduction in the levels of MDA and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with CHEMICAL + BCNU compared to only BCNU-treated animals. In conclusion, MT induction halts BCNU-induced hippocampal toxicity as it prevented GR inhibition and GSH depletion and counteracted the increased levels of TNFalpha, MDA and caspase-3 activity with subsequent preservation of cognition. | NO-RELATIONSHIP |
| Metallothionein induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats. Hippocampal integrity is essential for cognitive functions. On the other hand, induction of metallothionein (MT) by ZnSO(4) and its role in neuroprotection has been documented. The present study aimed to explore the effect of MT induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in deterioration of learning and short-term memory (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal CHEMICAL reductase (GR) activity and reduced CHEMICAL (CHEMICAL) content. Also, BCNU administration increased serum DISEASE necrosis factor-alpha (TNFalpha), hippocampal MT and malondialdehyde (MDA) contents as well as caspase-3 activity in addition to histological alterations. ZnSO(4) pretreatment counteracted BCNU-induced inhibition of GR and depletion of CHEMICAL and resulted in significant reduction in the levels of MDA and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with ZnSO(4) + BCNU compared to only BCNU-treated animals. In conclusion, MT induction halts BCNU-induced hippocampal toxicity as it prevented GR inhibition and CHEMICAL depletion and counteracted the increased levels of TNFalpha, MDA and caspase-3 activity with subsequent preservation of cognition. | NO-RELATIONSHIP |
| CHEMICAL induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats. Hippocampal integrity is essential for cognitive functions. On the other hand, induction of CHEMICAL (CHEMICAL) by ZnSO(4) and its role in neuroprotection has been documented. The present study aimed to explore the effect of CHEMICAL induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in deterioration of learning and short-term memory (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal glutathione reductase (GR) activity and reduced glutathione (GSH) content. Also, BCNU administration increased serum tumor DISEASE factor-alpha (TNFalpha), hippocampal CHEMICAL and malondialdehyde (MDA) contents as well as caspase-3 activity in addition to histological alterations. ZnSO(4) pretreatment counteracted BCNU-induced inhibition of GR and depletion of GSH and resulted in significant reduction in the levels of MDA and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with ZnSO(4) + BCNU compared to only BCNU-treated animals. In conclusion, CHEMICAL induction halts BCNU-induced hippocampal toxicity as it prevented GR inhibition and GSH depletion and counteracted the increased levels of TNFalpha, MDA and caspase-3 activity with subsequent preservation of cognition. | NO-RELATIONSHIP |
| CHEMICAL induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats. Hippocampal integrity is essential for cognitive functions. On the other hand, induction of CHEMICAL (CHEMICAL) by ZnSO(4) and its role in neuroprotection has been documented. The present study aimed to explore the effect of CHEMICAL induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in deterioration of learning and short-term memory (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal glutathione reductase (GR) activity and reduced glutathione (GSH) content. Also, BCNU administration increased serum DISEASE necrosis factor-alpha (TNFalpha), hippocampal CHEMICAL and malondialdehyde (MDA) contents as well as caspase-3 activity in addition to histological alterations. ZnSO(4) pretreatment counteracted BCNU-induced inhibition of GR and depletion of GSH and resulted in significant reduction in the levels of MDA and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with ZnSO(4) + BCNU compared to only BCNU-treated animals. In conclusion, CHEMICAL induction halts BCNU-induced hippocampal toxicity as it prevented GR inhibition and GSH depletion and counteracted the increased levels of TNFalpha, MDA and caspase-3 activity with subsequent preservation of cognition. | NO-RELATIONSHIP |
| Metallothionein induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats. Hippocampal integrity is essential for cognitive functions. On the other hand, induction of metallothionein (MT) by ZnSO(4) and its role in neuroprotection has been documented. The present study aimed to explore the effect of MT induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in deterioration of learning and short-term memory (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal glutathione reductase (GR) activity and reduced glutathione (GSH) content. Also, BCNU administration increased serum tumor DISEASE factor-alpha (TNFalpha), hippocampal MT and CHEMICAL (CHEMICAL) contents as well as caspase-3 activity in addition to histological alterations. ZnSO(4) pretreatment counteracted BCNU-induced inhibition of GR and depletion of GSH and resulted in significant reduction in the levels of CHEMICAL and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with ZnSO(4) + BCNU compared to only BCNU-treated animals. In conclusion, MT induction halts BCNU-induced hippocampal toxicity as it prevented GR inhibition and GSH depletion and counteracted the increased levels of TNFalpha, CHEMICAL and caspase-3 activity with subsequent preservation of cognition. | NO-RELATIONSHIP |
| Metallothionein induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats. Hippocampal integrity is essential for cognitive functions. On the other hand, induction of metallothionein (MT) by CHEMICAL and its role in neuroprotection has been documented. The present study aimed to explore the effect of MT induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered CHEMICAL (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of CHEMICAL (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in deterioration of learning and short-term memory (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal glutathione reductase (GR) activity and reduced glutathione (GSH) content. Also, BCNU administration increased serum tumor necrosis factor-alpha (TNFalpha), hippocampal MT and malondialdehyde (MDA) contents as well as caspase-3 activity in addition to histological alterations. CHEMICAL pretreatment counteracted BCNU-induced inhibition of GR and depletion of GSH and resulted in significant reduction in the levels of MDA and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with CHEMICAL + BCNU compared to only BCNU-treated animals. In conclusion, MT induction halts BCNU-induced hippocampal DISEASE as it prevented GR inhibition and GSH depletion and counteracted the increased levels of TNFalpha, MDA and caspase-3 activity with subsequent preservation of cognition. | NO-RELATIONSHIP |
| Metallothionein induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats. Hippocampal integrity is essential for cognitive functions. On the other hand, induction of metallothionein (MT) by ZnSO(4) and its role in neuroprotection has been documented. The present study aimed to explore the effect of MT induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in DISEASE (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal CHEMICAL reductase (GR) activity and reduced CHEMICAL (CHEMICAL) content. Also, BCNU administration increased serum tumor necrosis factor-alpha (TNFalpha), hippocampal MT and malondialdehyde (MDA) contents as well as caspase-3 activity in addition to histological alterations. ZnSO(4) pretreatment counteracted BCNU-induced inhibition of GR and depletion of CHEMICAL and resulted in significant reduction in the levels of MDA and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with ZnSO(4) + BCNU compared to only BCNU-treated animals. In conclusion, MT induction halts BCNU-induced hippocampal toxicity as it prevented GR inhibition and CHEMICAL depletion and counteracted the increased levels of TNFalpha, MDA and caspase-3 activity with subsequent preservation of cognition. | NO-RELATIONSHIP |
| CHEMICAL induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats. Hippocampal integrity is essential for cognitive functions. On the other hand, induction of CHEMICAL (CHEMICAL) by ZnSO(4) and its role in neuroprotection has been documented. The present study aimed to explore the effect of CHEMICAL induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in deterioration of learning and short-term memory (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal glutathione reductase (GR) activity and reduced glutathione (GSH) content. Also, BCNU administration increased serum tumor necrosis factor-alpha (TNFalpha), hippocampal CHEMICAL and malondialdehyde (MDA) contents as well as caspase-3 activity in addition to histological alterations. ZnSO(4) pretreatment counteracted BCNU-induced inhibition of GR and depletion of GSH and resulted in significant reduction in the levels of MDA and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with ZnSO(4) + BCNU compared to only BCNU-treated animals. In conclusion, CHEMICAL induction halts BCNU-induced hippocampal DISEASE as it prevented GR inhibition and GSH depletion and counteracted the increased levels of TNFalpha, MDA and caspase-3 activity with subsequent preservation of cognition. | NO-RELATIONSHIP |
| CHEMICAL induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats. Hippocampal integrity is essential for cognitive functions. On the other hand, induction of CHEMICAL (CHEMICAL) by ZnSO(4) and its role in neuroprotection has been documented. The present study aimed to explore the effect of CHEMICAL induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in DISEASE (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal glutathione reductase (GR) activity and reduced glutathione (GSH) content. Also, BCNU administration increased serum tumor necrosis factor-alpha (TNFalpha), hippocampal CHEMICAL and malondialdehyde (MDA) contents as well as caspase-3 activity in addition to histological alterations. ZnSO(4) pretreatment counteracted BCNU-induced inhibition of GR and depletion of GSH and resulted in significant reduction in the levels of MDA and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with ZnSO(4) + BCNU compared to only BCNU-treated animals. In conclusion, CHEMICAL induction halts BCNU-induced hippocampal toxicity as it prevented GR inhibition and GSH depletion and counteracted the increased levels of TNFalpha, MDA and caspase-3 activity with subsequent preservation of cognition. | NO-RELATIONSHIP |
| Metallothionein induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats. Hippocampal integrity is essential for cognitive functions. On the other hand, induction of metallothionein (MT) by ZnSO(4) and its role in neuroprotection has been documented. The present study aimed to explore the effect of MT induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in deterioration of learning and short-term memory (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal glutathione reductase (GR) activity and reduced glutathione (GSH) content. Also, BCNU administration increased serum DISEASE necrosis factor-alpha (TNFalpha), hippocampal MT and CHEMICAL (CHEMICAL) contents as well as caspase-3 activity in addition to histological alterations. ZnSO(4) pretreatment counteracted BCNU-induced inhibition of GR and depletion of GSH and resulted in significant reduction in the levels of CHEMICAL and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with ZnSO(4) + BCNU compared to only BCNU-treated animals. In conclusion, MT induction halts BCNU-induced hippocampal toxicity as it prevented GR inhibition and GSH depletion and counteracted the increased levels of TNFalpha, CHEMICAL and caspase-3 activity with subsequent preservation of cognition. | NO-RELATIONSHIP |
| Metallothionein induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats. Hippocampal integrity is essential for cognitive functions. On the other hand, induction of metallothionein (MT) by ZnSO(4) and its role in neuroprotection has been documented. The present study aimed to explore the effect of MT induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in deterioration of learning and short-term memory (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal CHEMICAL reductase (GR) activity and reduced CHEMICAL (CHEMICAL) content. Also, BCNU administration increased serum tumor necrosis factor-alpha (TNFalpha), hippocampal MT and malondialdehyde (MDA) contents as well as caspase-3 activity in addition to histological alterations. ZnSO(4) pretreatment counteracted BCNU-induced inhibition of GR and depletion of CHEMICAL and resulted in significant reduction in the levels of MDA and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with ZnSO(4) + BCNU compared to only BCNU-treated animals. In conclusion, MT induction halts BCNU-induced hippocampal DISEASE as it prevented GR inhibition and CHEMICAL depletion and counteracted the increased levels of TNFalpha, MDA and caspase-3 activity with subsequent preservation of cognition. | NO-RELATIONSHIP |
| Metallothionein induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats. Hippocampal integrity is essential for cognitive functions. On the other hand, induction of metallothionein (MT) by ZnSO(4) and its role in neuroprotection has been documented. The present study aimed to explore the effect of MT induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of ZnSO(4) (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in DISEASE (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal glutathione reductase (GR) activity and reduced glutathione (GSH) content. Also, BCNU administration increased serum tumor necrosis factor-alpha (TNFalpha), hippocampal MT and CHEMICAL (CHEMICAL) contents as well as caspase-3 activity in addition to histological alterations. ZnSO(4) pretreatment counteracted BCNU-induced inhibition of GR and depletion of GSH and resulted in significant reduction in the levels of CHEMICAL and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with ZnSO(4) + BCNU compared to only BCNU-treated animals. In conclusion, MT induction halts BCNU-induced hippocampal toxicity as it prevented GR inhibition and GSH depletion and counteracted the increased levels of TNFalpha, CHEMICAL and caspase-3 activity with subsequent preservation of cognition. | NO-RELATIONSHIP |
| Metallothionein induction reduces caspase-3 activity and TNFalpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats. Hippocampal integrity is essential for cognitive functions. On the other hand, induction of metallothionein (MT) by CHEMICAL and its role in neuroprotection has been documented. The present study aimed to explore the effect of MT induction on carmustine (BCNU)-induced hippocampal cognitive dysfunction in rats. A total of 60 male Wistar albino rats were randomly divided into four groups (15/group): The control group injected with single doses of normal saline (i.c.v) followed 24 h later by BCNU solvent (i.v). The second group administered CHEMICAL (0.1 micromol/10 microl normal saline, i.c.v, once) then BCNU solvent (i.v) after 24 h. Third group received BCNU (20 mg/kg, i.v, once) 24 h after injection with normal saline (i.c.v). Fourth group received a single dose of CHEMICAL (0.1 micromol/10 microl normal saline, i.c.v) then BCNU (20 mg/kg, i.v, once) after 24 h. The obtained data revealed that BCNU administration resulted in deterioration of learning and short-term memory (STM), as measured by using radial arm water maze, accompanied with decreased hippocampal glutathione reductase (GR) activity and reduced glutathione (GSH) content. Also, BCNU administration increased serum DISEASE necrosis factor-alpha (TNFalpha), hippocampal MT and malondialdehyde (MDA) contents as well as caspase-3 activity in addition to histological alterations. CHEMICAL pretreatment counteracted BCNU-induced inhibition of GR and depletion of GSH and resulted in significant reduction in the levels of MDA and TNFalpha as well as the activity of caspase-3. The histological features were improved in hippocampus of rats treated with CHEMICAL + BCNU compared to only BCNU-treated animals. In conclusion, MT induction halts BCNU-induced hippocampal toxicity as it prevented GR inhibition and GSH depletion and counteracted the increased levels of TNFalpha, MDA and caspase-3 activity with subsequent preservation of cognition. | GENE-CHEMICAL |
| Fatal CHEMICAL induced fulminant eosinophilic (hypersensitivity) myocarditis: emphasis on anatomical and histological characteristics, mechanisms and genetics of drug hypersensitivity and differential diagnosis. The most severe adverse reactions to CHEMICAL have been observed in the haemopoietic system, the liver and the cardiovascular system. A frequently fatal, although exceptionally rare side effect of CHEMICAL is necrotizing eosinophilic (hypersensitivity) myocarditis. We report a case of hypersensitivity myocarditis secondary to administration of CHEMICAL. Acute hypersensitivity myocarditis was not suspected clinically, and the diagnosis was made post-mortem. Histology revealed diffuse infiltration of the myocardium by eosinophils and lymphocytes with myocyte damage. Clinically, death was due to DISEASE. To best of our knowledge this is the second case of fatal CHEMICAL induced myocarditis reported in English literature. | CHEMICAL-INDUCED-DISEASE |
| Fatal CHEMICAL induced fulminant eosinophilic (hypersensitivity) DISEASE: emphasis on anatomical and histological characteristics, mechanisms and genetics of drug hypersensitivity and differential diagnosis. The most severe adverse reactions to CHEMICAL have been observed in the haemopoietic system, the liver and the cardiovascular system. A frequently fatal, although exceptionally rare side effect of CHEMICAL is necrotizing eosinophilic (hypersensitivity) DISEASE. We report a case of hypersensitivity DISEASE secondary to administration of CHEMICAL. Acute hypersensitivity DISEASE was not suspected clinically, and the diagnosis was made post-mortem. Histology revealed diffuse infiltration of the myocardium by eosinophils and lymphocytes with myocyte damage. Clinically, death was due to cardiogenic shock. To best of our knowledge this is the second case of fatal CHEMICAL induced DISEASE reported in English literature. | CHEMICAL-INDUCED-DISEASE |
| Fatal CHEMICAL induced DISEASE (hypersensitivity) myocarditis: emphasis on anatomical and histological characteristics, mechanisms and genetics of drug hypersensitivity and differential diagnosis. The most severe adverse reactions to CHEMICAL have been observed in the haemopoietic system, the liver and the cardiovascular system. A frequently fatal, although exceptionally rare side effect of CHEMICAL is necrotizing eosinophilic (hypersensitivity) myocarditis. We report a case of hypersensitivity myocarditis secondary to administration of CHEMICAL. Acute hypersensitivity myocarditis was not suspected clinically, and the diagnosis was made post-mortem. Histology revealed diffuse infiltration of the myocardium by eosinophils and lymphocytes with myocyte damage. Clinically, death was due to cardiogenic shock. To best of our knowledge this is the second case of fatal CHEMICAL induced myocarditis reported in English literature. | CHEMICAL-INDUCED-DISEASE |
| Fatal CHEMICAL induced fulminant eosinophilic (DISEASE) myocarditis: emphasis on anatomical and histological characteristics, mechanisms and genetics of DISEASE and differential diagnosis. The most severe adverse reactions to CHEMICAL have been observed in the haemopoietic system, the liver and the cardiovascular system. A frequently fatal, although exceptionally rare side effect of CHEMICAL is necrotizing eosinophilic (DISEASE) myocarditis. We report a case of DISEASE myocarditis secondary to administration of CHEMICAL. Acute DISEASE myocarditis was not suspected clinically, and the diagnosis was made post-mortem. Histology revealed diffuse infiltration of the myocardium by eosinophils and lymphocytes with myocyte damage. Clinically, death was due to cardiogenic shock. To best of our knowledge this is the second case of fatal CHEMICAL induced myocarditis reported in English literature. | CHEMICAL-INDUCED-DISEASE |
| Neuropsychiatric behaviors in the MPTP marmoset model of Parkinson's disease. OBJECTIVES: Neuropsychiatric symptoms are increasingly recognised as a significant problem in patients with Parkinson's disease (PD). These symptoms may be due to 'sensitisation' following repeated CHEMICAL treatment or a direct effect of dopamine on the disease state. The CHEMICAL-treated MPTP-lesioned marmoset was used as a model of neuropsychiatric symptoms in PD patients. Here we compare the time course of CHEMICAL-induced motor fluctuations and neuropsychiatric-like behaviors to determine the relationship between duration of treatment and onset of symptoms. METHODS: Marmosets were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (2.0 mg/kg s.c.) for five days, resulting in stable parkinsonism. CHEMICAL (15 mg/kg and benserazide, 3.75 mg/kg) p.o. b.i.d, was administered for 30 days. Animals were evaluated for parkinsonian disability, DISEASE and on-time (motor fluctuations) and neuropsychiatric-like behaviors on Day 0 (prior to CHEMICAL) and on Days 1, 7, 13, 27 and 30 of treatment using post hoc DVD analysis by a trained rater, blind to the treatment day. RESULTS: The neuropsychiatric-like behavior rating scale demonstrated high interrater reliability between three trained raters of differing professional backgrounds. As anticipated, animals exhibited a progressive increase in CHEMICAL-induced motor fluctuations, DISEASE and wearing-off, that correlated with the duration of CHEMICAL therapy. In contrast, CHEMICAL-induced neuropsychiatric-like behaviors were present on Day 1 of CHEMICAL treatment and their severity did not correlate with duration of treatment. CONCLUSIONS: The data suggest that neuropsychiatric disorders in PD are more likely an interaction between CHEMICAL and the disease state than a consequence of sensitisation to repeated dopaminergic therapy. | CHEMICAL-INDUCED-DISEASE |
| Neuropsychiatric behaviors in the CHEMICAL marmoset model of Parkinson's disease. OBJECTIVES: Neuropsychiatric symptoms are increasingly recognised as a significant problem in patients with Parkinson's disease (PD). These symptoms may be due to 'sensitisation' following repeated levodopa treatment or a direct effect of dopamine on the disease state. The levodopa-treated CHEMICAL-lesioned marmoset was used as a model of neuropsychiatric symptoms in PD patients. Here we compare the time course of levodopa-induced motor fluctuations and neuropsychiatric-like behaviors to determine the relationship between duration of treatment and onset of symptoms. METHODS: Marmosets were administered CHEMICAL (2.0 mg/kg s.c.) for five days, resulting in stable parkinsonism. Levodopa (15 mg/kg and benserazide, 3.75 mg/kg) p.o. b.i.d, was administered for 30 days. Animals were evaluated for DISEASE, dyskinesia and on-time (motor fluctuations) and neuropsychiatric-like behaviors on Day 0 (prior to levodopa) and on Days 1, 7, 13, 27 and 30 of treatment using post hoc DVD analysis by a trained rater, blind to the treatment day. RESULTS: The neuropsychiatric-like behavior rating scale demonstrated high interrater reliability between three trained raters of differing professional backgrounds. As anticipated, animals exhibited a progressive increase in levodopa-induced motor fluctuations, dyskinesia and wearing-off, that correlated with the duration of levodopa therapy. In contrast, levodopa-induced neuropsychiatric-like behaviors were present on Day 1 of levodopa treatment and their severity did not correlate with duration of treatment. CONCLUSIONS: The data suggest that neuropsychiatric disorders in PD are more likely an interaction between levodopa and the disease state than a consequence of sensitisation to repeated dopaminergic therapy. | CHEMICAL-INDUCED-DISEASE |
| Neuropsychiatric behaviors in the MPTP marmoset model of Parkinson's disease. OBJECTIVES: Neuropsychiatric symptoms are increasingly recognised as a significant problem in patients with Parkinson's disease (PD). These symptoms may be due to 'sensitisation' following repeated levodopa treatment or a direct effect of dopamine on the disease state. The levodopa-treated MPTP-lesioned marmoset was used as a model of DISEASE in PD patients. Here we compare the time course of levodopa-induced motor fluctuations and DISEASE to determine the relationship between duration of treatment and onset of symptoms. METHODS: Marmosets were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (2.0 mg/kg s.c.) for five days, resulting in stable parkinsonism. Levodopa (15 mg/kg and CHEMICAL, 3.75 mg/kg) p.o. b.i.d, was administered for 30 days. Animals were evaluated for parkinsonian disability, dyskinesia and on-time (motor fluctuations) and DISEASE on Day 0 (prior to levodopa) and on Days 1, 7, 13, 27 and 30 of treatment using post hoc DVD analysis by a trained rater, blind to the treatment day. RESULTS: The DISEASE rating scale demonstrated high interrater reliability between three trained raters of differing professional backgrounds. As anticipated, animals exhibited a progressive increase in levodopa-induced motor fluctuations, dyskinesia and wearing-off, that correlated with the duration of levodopa therapy. In contrast, levodopa-induced DISEASE were present on Day 1 of levodopa treatment and their severity did not correlate with duration of treatment. CONCLUSIONS: The data suggest that DISEASE in PD are more likely an interaction between levodopa and the disease state than a consequence of sensitisation to repeated dopaminergic therapy. | CHEMICAL-INDUCED-DISEASE |
| Neuropsychiatric behaviors in the MPTP marmoset model of DISEASE. OBJECTIVES: Neuropsychiatric symptoms are increasingly recognised as a significant problem in patients with DISEASE (DISEASE). These symptoms may be due to 'sensitisation' following repeated levodopa treatment or a direct effect of CHEMICAL on the disease state. The levodopa-treated MPTP-lesioned marmoset was used as a model of neuropsychiatric symptoms in DISEASE patients. Here we compare the time course of levodopa-induced motor fluctuations and neuropsychiatric-like behaviors to determine the relationship between duration of treatment and onset of symptoms. METHODS: Marmosets were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (2.0 mg/kg s.c.) for five days, resulting in stable DISEASE. Levodopa (15 mg/kg and benserazide, 3.75 mg/kg) p.o. b.i.d, was administered for 30 days. Animals were evaluated for parkinsonian disability, dyskinesia and on-time (motor fluctuations) and neuropsychiatric-like behaviors on Day 0 (prior to levodopa) and on Days 1, 7, 13, 27 and 30 of treatment using post hoc DVD analysis by a trained rater, blind to the treatment day. RESULTS: The neuropsychiatric-like behavior rating scale demonstrated high interrater reliability between three trained raters of differing professional backgrounds. As anticipated, animals exhibited a progressive increase in levodopa-induced motor fluctuations, dyskinesia and wearing-off, that correlated with the duration of levodopa therapy. In contrast, levodopa-induced neuropsychiatric-like behaviors were present on Day 1 of levodopa treatment and their severity did not correlate with duration of treatment. CONCLUSIONS: The data suggest that neuropsychiatric disorders in DISEASE are more likely an interaction between levodopa and the disease state than a consequence of sensitisation to repeated dopaminergic therapy. | NO-RELATIONSHIP |
| Neuropsychiatric behaviors in the MPTP marmoset model of DISEASE. OBJECTIVES: Neuropsychiatric symptoms are increasingly recognised as a significant problem in patients with DISEASE (DISEASE). These symptoms may be due to 'sensitisation' following repeated levodopa treatment or a direct effect of dopamine on the disease state. The levodopa-treated MPTP-lesioned marmoset was used as a model of neuropsychiatric symptoms in DISEASE patients. Here we compare the time course of levodopa-induced motor fluctuations and neuropsychiatric-like behaviors to determine the relationship between duration of treatment and onset of symptoms. METHODS: Marmosets were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (2.0 mg/kg s.c.) for five days, resulting in stable DISEASE. Levodopa (15 mg/kg and CHEMICAL, 3.75 mg/kg) p.o. b.i.d, was administered for 30 days. Animals were evaluated for parkinsonian disability, dyskinesia and on-time (motor fluctuations) and neuropsychiatric-like behaviors on Day 0 (prior to levodopa) and on Days 1, 7, 13, 27 and 30 of treatment using post hoc DVD analysis by a trained rater, blind to the treatment day. RESULTS: The neuropsychiatric-like behavior rating scale demonstrated high interrater reliability between three trained raters of differing professional backgrounds. As anticipated, animals exhibited a progressive increase in levodopa-induced motor fluctuations, dyskinesia and wearing-off, that correlated with the duration of levodopa therapy. In contrast, levodopa-induced neuropsychiatric-like behaviors were present on Day 1 of levodopa treatment and their severity did not correlate with duration of treatment. CONCLUSIONS: The data suggest that neuropsychiatric disorders in DISEASE are more likely an interaction between levodopa and the disease state than a consequence of sensitisation to repeated dopaminergic therapy. | NO-RELATIONSHIP |
| Neuropsychiatric behaviors in the MPTP marmoset model of Parkinson's disease. OBJECTIVES: Neuropsychiatric symptoms are increasingly recognised as a significant problem in patients with Parkinson's disease (PD). These symptoms may be due to 'sensitisation' following repeated levodopa treatment or a direct effect of CHEMICAL on the disease state. The levodopa-treated MPTP-lesioned marmoset was used as a model of DISEASE in PD patients. Here we compare the time course of levodopa-induced motor fluctuations and DISEASE to determine the relationship between duration of treatment and onset of symptoms. METHODS: Marmosets were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (2.0 mg/kg s.c.) for five days, resulting in stable parkinsonism. Levodopa (15 mg/kg and benserazide, 3.75 mg/kg) p.o. b.i.d, was administered for 30 days. Animals were evaluated for parkinsonian disability, dyskinesia and on-time (motor fluctuations) and DISEASE on Day 0 (prior to levodopa) and on Days 1, 7, 13, 27 and 30 of treatment using post hoc DVD analysis by a trained rater, blind to the treatment day. RESULTS: The DISEASE rating scale demonstrated high interrater reliability between three trained raters of differing professional backgrounds. As anticipated, animals exhibited a progressive increase in levodopa-induced motor fluctuations, dyskinesia and wearing-off, that correlated with the duration of levodopa therapy. In contrast, levodopa-induced DISEASE were present on Day 1 of levodopa treatment and their severity did not correlate with duration of treatment. CONCLUSIONS: The data suggest that DISEASE in PD are more likely an interaction between levodopa and the disease state than a consequence of sensitisation to repeated dopaminergic therapy. | NO-RELATIONSHIP |
| CHEMICAL DISEASE after renal artery and coronary angioplasty. BACKGROUND: DISEASE induced by iodinated CHEMICAL (CHEMICAL) administration can minimize the benefit of the interventional procedure in patients undergoing renal angioplasty (PTRA). PURPOSE: To compare the susceptibility to DISEASE effect of CHEMICAL in patients undergoing PTRA with that of patients submitted to percutaneous coronary intervention (PCI). MATERIAL AND METHODS: A total of 33 patients successfully treated with PTRA (PTRA group, mean age 70+/-12 years, 23 female, basal creatinine 1.46+/-0.79, range 0.7-4.9 mg/dl) were compared with 33 patients undergoing successful PCI (PCI group), matched for basal creatinine (1.44+/-0.6, range 0.7-3.4 mg/dl), gender, and age. In both groups postprocedural (48 h) serum creatinine was measured. RESULTS: Postprocedural creatinine level decreased nonsignificantly in the PTRA group (1.46+/-0.8 vs. 1.34+/-0.5 mg/dl, P=NS) and increased significantly in the PCI group (1.44+/-0.6 vs. 1.57+/-0.7 mg/dl, P<0.02). Changes in serum creatinine after intervention (after-before) were significantly different between the PTRA and PCI groups (-0.12+/-0.5 vs. 0.13+/-0.3, P=0.014). This difference was not related to either a different clinical risk profile or to the volume of CHEMICAL administered. CONCLUSION: In this preliminary study patients submitted to PTRA showed a lower susceptibility to DISEASE induced by CHEMICAL administration than PCI patients. The effectiveness of PTRA on renal function seems to be barely influenced by CHEMICAL toxicity. | CHEMICAL-INDUCED-DISEASE |
| Contrast medium nephrotoxicity after renal artery and coronary angioplasty. BACKGROUND: Renal dysfunction induced by iodinated contrast medium (CM) administration can minimize the benefit of the interventional procedure in patients undergoing renal angioplasty (PTRA). PURPOSE: To compare the susceptibility to nephrotoxic effect of CM in patients undergoing PTRA with that of patients submitted to percutaneous coronary intervention (PCI). MATERIAL AND METHODS: A total of 33 patients successfully treated with PTRA (PTRA group, mean age 70+/-12 years, 23 female, basal CHEMICAL 1.46+/-0.79, range 0.7-4.9 mg/dl) were compared with 33 patients undergoing successful PCI (PCI group), matched for basal CHEMICAL (1.44+/-0.6, range 0.7-3.4 mg/dl), gender, and age. In both groups postprocedural (48 h) serum CHEMICAL was measured. RESULTS: Postprocedural CHEMICAL level decreased nonsignificantly in the PTRA group (1.46+/-0.8 vs. 1.34+/-0.5 mg/dl, P=NS) and increased significantly in the PCI group (1.44+/-0.6 vs. 1.57+/-0.7 mg/dl, P<0.02). Changes in serum CHEMICAL after intervention (after-before) were significantly different between the PTRA and PCI groups (-0.12+/-0.5 vs. 0.13+/-0.3, P=0.014). This difference was not related to either a different clinical risk profile or to the volume of CM administered. CONCLUSION: In this preliminary study patients submitted to PTRA showed a lower susceptibility to renal damage induced by CM administration than PCI patients. The effectiveness of PTRA on renal function seems to be barely influenced by CM DISEASE. | NO-RELATIONSHIP |
| Medical and psychiatric outcomes for patients transplanted for CHEMICAL-induced acute liver failure: a case-control study. BACKGROUND: CHEMICAL-induced DISEASE is the most common cause of acute liver failure (ALF) in the UK. Patients often consume the drug with suicidal intent or with a background of substance dependence. AIMS AND METHODS: We compared the severity of pretransplant illness, psychiatric co-morbidity, medical and psychosocial outcomes of all patients who had undergone liver transplantation (LT) emergently between 1999-2004 for CHEMICAL-induced ALF (n=36) with age- and sex-matched patients undergoing emergent LT for non-CHEMICAL-induced ALF (n=35) and elective LT for chronic liver disease (CLD, n=34). RESULTS: CHEMICAL-induced ALF patients undergoing LT had a greater severity of pre-LT illness reflected by higher Acute Physiology and Chronic Health Evaluation II scores and requirement for organ support compared with the other two groups. Twenty (56%) CHEMICAL-induced ALF patients had a formal psychiatric diagnosis before LT (non-CHEMICAL-induced ALF=0/35, CLD=2/34; P<0.01 for all) and nine (25%) had a previous suicide attempt. During follow-up (median 5 years), there were no significant differences in rejection (acute and chronic), graft failure or survival between the groups (CHEMICAL-induced ALF 1 year 87%, 5 years 75%; non-CHEMICAL-induced ALF 88%, 78%; CLD 93%, 82%: P>0.6 log rank). Two CHEMICAL-induced ALF patients reattempted suicide post-LT (one died 8 years post-LT). CONCLUSIONS: Despite a high prevalence of psychiatric disturbance, outcomes for patients transplanted emergently for CHEMICAL-induced ALF were comparable to those transplanted for non-CHEMICAL-induced ALF and electively for CLD. Multidisciplinary approaches with long-term psychiatric follow-up may contribute to low post-transplant suicide rates seen and low rates of graft loss because of non-compliance. | CHEMICAL-INDUCED-DISEASE |
| Medical and psychiatric outcomes for patients transplanted for CHEMICAL-induced DISEASE: a case-control study. BACKGROUND: CHEMICAL-induced hepatotoxicity is the most common cause of DISEASE (DISEASE) in the UK. Patients often consume the drug with suicidal intent or with a background of substance dependence. AIMS AND METHODS: We compared the severity of pretransplant illness, psychiatric co-morbidity, medical and psychosocial outcomes of all patients who had undergone liver transplantation (LT) emergently between 1999-2004 for CHEMICAL-induced DISEASE (n=36) with age- and sex-matched patients undergoing emergent LT for non-CHEMICAL-induced DISEASE (n=35) and elective LT for chronic liver disease (CLD, n=34). RESULTS: CHEMICAL-induced DISEASE patients undergoing LT had a greater severity of pre-LT illness reflected by higher Acute Physiology and Chronic Health Evaluation II scores and requirement for organ support compared with the other two groups. Twenty (56%) CHEMICAL-induced DISEASE patients had a formal psychiatric diagnosis before LT (non-CHEMICAL-induced DISEASE=0/35, CLD=2/34; P<0.01 for all) and nine (25%) had a previous suicide attempt. During follow-up (median 5 years), there were no significant differences in rejection (acute and chronic), graft failure or survival between the groups (CHEMICAL-induced DISEASE 1 year 87%, 5 years 75%; non-CHEMICAL-induced DISEASE 88%, 78%; CLD 93%, 82%: P>0.6 log rank). Two CHEMICAL-induced DISEASE patients reattempted suicide post-LT (one died 8 years post-LT). CONCLUSIONS: Despite a high prevalence of psychiatric disturbance, outcomes for patients transplanted emergently for CHEMICAL-induced DISEASE were comparable to those transplanted for non-CHEMICAL-induced DISEASE and electively for CLD. Multidisciplinary approaches with long-term psychiatric follow-up may contribute to low post-transplant suicide rates seen and low rates of graft loss because of non-compliance. | CHEMICAL-INDUCED-DISEASE |
| Studies of synergy between morphine and a novel sodium channel blocker, CNSB002, in rat models of inflammatory and neuropathic pain. OBJECTIVE: This study determined the antihyperalgesic effect of CNSB002, a sodium channel blocker with antioxidant properties given alone and in combinations with morphine in rat models of inflammatory and neuropathic pain. DESIGN: Dose response curves for nonsedating doses of morphine and CNSB002 given intraperitoneally alone and together in combinations were constructed for antihyperalgesic effect using paw withdrawal from noxious heat in two rat pain models: carrageenan-induced paw inflammation and CHEMICAL (CHEMICAL)-induced DISEASE. RESULTS: The maximum nonsedating doses were: morphine, 3.2 mg/kg; CNSB002 10.0 mg/kg; 5.0 mg/kg CNSB002 with morphine 3.2 mg/kg in combination. The doses calculated to cause 50% reversal of hyperalgesia (ED50) were 7.54 (1.81) and 4.83 (1.54) in the carrageenan model and 44.18 (1.37) and 9.14 (1.24) in the CHEMICAL-induced neuropathy model for CNSB002 and morphine, respectively (mg/kg; mean, SEM). These values were greater than the maximum nonsedating doses. The ED50 values for morphine when given in combination with CNSB002 (5 mg/kg) were less than the maximum nonsedating dose: 0.56 (1.55) in the carrageenan model and 1.37 (1.23) in the neuropathy model (mg/kg; mean, SEM). The antinociception after morphine (3.2 mg/kg) was increased by co-administration with CNSB002 from 28.0 and 31.7% to 114.6 and 56.9% reversal of hyperalgesia in the inflammatory and neuropathic models, respectively (P < 0.01; one-way analysis of variance-significantly greater than either drug given alone). CONCLUSIONS: The maximum antihyperalgesic effect achievable with nonsedating doses of morphine may be increased significantly when the drug is used in combination with CNSB002. | CHEMICAL-INDUCED-DISEASE |
| Studies of synergy between morphine and a novel sodium channel blocker, CNSB002, in rat models of inflammatory and neuropathic pain. OBJECTIVE: This study determined the antihyperalgesic effect of CNSB002, a sodium channel blocker with antioxidant properties given alone and in combinations with morphine in rat models of inflammatory and neuropathic pain. DESIGN: Dose response curves for nonsedating doses of morphine and CNSB002 given intraperitoneally alone and together in combinations were constructed for antihyperalgesic effect using paw withdrawal from noxious heat in two rat pain models: carrageenan-induced paw inflammation and CHEMICAL (CHEMICAL)-induced diabetic neuropathy. RESULTS: The maximum nonsedating doses were: morphine, 3.2 mg/kg; CNSB002 10.0 mg/kg; 5.0 mg/kg CNSB002 with morphine 3.2 mg/kg in combination. The doses calculated to cause 50% reversal of DISEASE (ED50) were 7.54 (1.81) and 4.83 (1.54) in the carrageenan model and 44.18 (1.37) and 9.14 (1.24) in the CHEMICAL-induced neuropathy model for CNSB002 and morphine, respectively (mg/kg; mean, SEM). These values were greater than the maximum nonsedating doses. The ED50 values for morphine when given in combination with CNSB002 (5 mg/kg) were less than the maximum nonsedating dose: 0.56 (1.55) in the carrageenan model and 1.37 (1.23) in the neuropathy model (mg/kg; mean, SEM). The antinociception after morphine (3.2 mg/kg) was increased by co-administration with CNSB002 from 28.0 and 31.7% to 114.6 and 56.9% reversal of DISEASE in the inflammatory and neuropathic models, respectively (P < 0.01; one-way analysis of variance-significantly greater than either drug given alone). CONCLUSIONS: The maximum antihyperalgesic effect achievable with nonsedating doses of morphine may be increased significantly when the drug is used in combination with CNSB002. | CHEMICAL-INDUCED-DISEASE |
| Studies of synergy between morphine and a novel sodium channel blocker, CNSB002, in rat models of inflammatory and neuropathic pain. OBJECTIVE: This study determined the antihyperalgesic effect of CNSB002, a sodium channel blocker with antioxidant properties given alone and in combinations with morphine in rat models of inflammatory and neuropathic pain. DESIGN: Dose response curves for nonsedating doses of morphine and CNSB002 given intraperitoneally alone and together in combinations were constructed for antihyperalgesic effect using paw withdrawal from noxious heat in two rat pain models: CHEMICAL-induced paw DISEASE and streptozotocin (STZ)-induced diabetic neuropathy. RESULTS: The maximum nonsedating doses were: morphine, 3.2 mg/kg; CNSB002 10.0 mg/kg; 5.0 mg/kg CNSB002 with morphine 3.2 mg/kg in combination. The doses calculated to cause 50% reversal of hyperalgesia (ED50) were 7.54 (1.81) and 4.83 (1.54) in the CHEMICAL model and 44.18 (1.37) and 9.14 (1.24) in the STZ-induced neuropathy model for CNSB002 and morphine, respectively (mg/kg; mean, SEM). These values were greater than the maximum nonsedating doses. The ED50 values for morphine when given in combination with CNSB002 (5 mg/kg) were less than the maximum nonsedating dose: 0.56 (1.55) in the CHEMICAL model and 1.37 (1.23) in the neuropathy model (mg/kg; mean, SEM). The antinociception after morphine (3.2 mg/kg) was increased by co-administration with CNSB002 from 28.0 and 31.7% to 114.6 and 56.9% reversal of hyperalgesia in the inflammatory and neuropathic models, respectively (P < 0.01; one-way analysis of variance-significantly greater than either drug given alone). CONCLUSIONS: The maximum antihyperalgesic effect achievable with nonsedating doses of morphine may be increased significantly when the drug is used in combination with CNSB002. | CHEMICAL-INDUCED-DISEASE |
| Studies of synergy between morphine and a novel sodium channel blocker, CNSB002, in rat models of inflammatory and neuropathic pain. OBJECTIVE: This study determined the antihyperalgesic effect of CNSB002, a sodium channel blocker with antioxidant properties given alone and in combinations with morphine in rat models of inflammatory and neuropathic pain. DESIGN: Dose response curves for nonsedating doses of morphine and CNSB002 given intraperitoneally alone and together in combinations were constructed for antihyperalgesic effect using paw withdrawal from noxious heat in two rat pain models: CHEMICAL-induced paw inflammation and streptozotocin (STZ)-induced diabetic neuropathy. RESULTS: The maximum nonsedating doses were: morphine, 3.2 mg/kg; CNSB002 10.0 mg/kg; 5.0 mg/kg CNSB002 with morphine 3.2 mg/kg in combination. The doses calculated to cause 50% reversal of DISEASE (ED50) were 7.54 (1.81) and 4.83 (1.54) in the CHEMICAL model and 44.18 (1.37) and 9.14 (1.24) in the STZ-induced neuropathy model for CNSB002 and morphine, respectively (mg/kg; mean, SEM). These values were greater than the maximum nonsedating doses. The ED50 values for morphine when given in combination with CNSB002 (5 mg/kg) were less than the maximum nonsedating dose: 0.56 (1.55) in the CHEMICAL model and 1.37 (1.23) in the neuropathy model (mg/kg; mean, SEM). The antinociception after morphine (3.2 mg/kg) was increased by co-administration with CNSB002 from 28.0 and 31.7% to 114.6 and 56.9% reversal of DISEASE in the inflammatory and neuropathic models, respectively (P < 0.01; one-way analysis of variance-significantly greater than either drug given alone). CONCLUSIONS: The maximum antihyperalgesic effect achievable with nonsedating doses of morphine may be increased significantly when the drug is used in combination with CNSB002. | CHEMICAL-INDUCED-DISEASE |
| Studies of synergy between morphine and a novel CHEMICAL channel blocker, CNSB002, in rat models of inflammatory and DISEASE. OBJECTIVE: This study determined the antihyperalgesic effect of CNSB002, a CHEMICAL channel blocker with antioxidant properties given alone and in combinations with morphine in rat models of inflammatory and DISEASE. DESIGN: Dose response curves for nonsedating doses of morphine and CNSB002 given intraperitoneally alone and together in combinations were constructed for antihyperalgesic effect using paw withdrawal from noxious heat in two rat pain models: carrageenan-induced paw inflammation and streptozotocin (STZ)-induced diabetic neuropathy. RESULTS: The maximum nonsedating doses were: morphine, 3.2 mg/kg; CNSB002 10.0 mg/kg; 5.0 mg/kg CNSB002 with morphine 3.2 mg/kg in combination. The doses calculated to cause 50% reversal of hyperalgesia (ED50) were 7.54 (1.81) and 4.83 (1.54) in the carrageenan model and 44.18 (1.37) and 9.14 (1.24) in the STZ-induced neuropathy model for CNSB002 and morphine, respectively (mg/kg; mean, SEM). These values were greater than the maximum nonsedating doses. The ED50 values for morphine when given in combination with CNSB002 (5 mg/kg) were less than the maximum nonsedating dose: 0.56 (1.55) in the carrageenan model and 1.37 (1.23) in the neuropathy model (mg/kg; mean, SEM). The antinociception after morphine (3.2 mg/kg) was increased by co-administration with CNSB002 from 28.0 and 31.7% to 114.6 and 56.9% reversal of hyperalgesia in the inflammatory and neuropathic models, respectively (P < 0.01; one-way analysis of variance-significantly greater than either drug given alone). CONCLUSIONS: The maximum antihyperalgesic effect achievable with nonsedating doses of morphine may be increased significantly when the drug is used in combination with CNSB002. | NO-RELATIONSHIP |
| Studies of synergy between morphine and a novel CHEMICAL channel blocker, CNSB002, in rat models of inflammatory and neuropathic pain. OBJECTIVE: This study determined the antihyperalgesic effect of CNSB002, a CHEMICAL channel blocker with antioxidant properties given alone and in combinations with morphine in rat models of inflammatory and neuropathic pain. DESIGN: Dose response curves for nonsedating doses of morphine and CNSB002 given intraperitoneally alone and together in combinations were constructed for antihyperalgesic effect using paw withdrawal from noxious heat in two rat DISEASE models: carrageenan-induced paw inflammation and streptozotocin (STZ)-induced diabetic neuropathy. RESULTS: The maximum nonsedating doses were: morphine, 3.2 mg/kg; CNSB002 10.0 mg/kg; 5.0 mg/kg CNSB002 with morphine 3.2 mg/kg in combination. The doses calculated to cause 50% reversal of hyperalgesia (ED50) were 7.54 (1.81) and 4.83 (1.54) in the carrageenan model and 44.18 (1.37) and 9.14 (1.24) in the STZ-induced neuropathy model for CNSB002 and morphine, respectively (mg/kg; mean, SEM). These values were greater than the maximum nonsedating doses. The ED50 values for morphine when given in combination with CNSB002 (5 mg/kg) were less than the maximum nonsedating dose: 0.56 (1.55) in the carrageenan model and 1.37 (1.23) in the neuropathy model (mg/kg; mean, SEM). The antinociception after morphine (3.2 mg/kg) was increased by co-administration with CNSB002 from 28.0 and 31.7% to 114.6 and 56.9% reversal of hyperalgesia in the inflammatory and neuropathic models, respectively (P < 0.01; one-way analysis of variance-significantly greater than either drug given alone). CONCLUSIONS: The maximum antihyperalgesic effect achievable with nonsedating doses of morphine may be increased significantly when the drug is used in combination with CNSB002. | NO-RELATIONSHIP |
| Studies of synergy between morphine and a novel sodium channel blocker, CHEMICAL, in rat models of inflammatory and DISEASE. OBJECTIVE: This study determined the antihyperalgesic effect of CHEMICAL, a sodium channel blocker with antioxidant properties given alone and in combinations with morphine in rat models of inflammatory and DISEASE. DESIGN: Dose response curves for nonsedating doses of morphine and CHEMICAL given intraperitoneally alone and together in combinations were constructed for antihyperalgesic effect using paw withdrawal from noxious heat in two rat pain models: carrageenan-induced paw inflammation and streptozotocin (STZ)-induced diabetic neuropathy. RESULTS: The maximum nonsedating doses were: morphine, 3.2 mg/kg; CHEMICAL 10.0 mg/kg; 5.0 mg/kg CHEMICAL with morphine 3.2 mg/kg in combination. The doses calculated to cause 50% reversal of hyperalgesia (ED50) were 7.54 (1.81) and 4.83 (1.54) in the carrageenan model and 44.18 (1.37) and 9.14 (1.24) in the STZ-induced neuropathy model for CHEMICAL and morphine, respectively (mg/kg; mean, SEM). These values were greater than the maximum nonsedating doses. The ED50 values for morphine when given in combination with CHEMICAL (5 mg/kg) were less than the maximum nonsedating dose: 0.56 (1.55) in the carrageenan model and 1.37 (1.23) in the neuropathy model (mg/kg; mean, SEM). The antinociception after morphine (3.2 mg/kg) was increased by co-administration with CHEMICAL from 28.0 and 31.7% to 114.6 and 56.9% reversal of hyperalgesia in the inflammatory and neuropathic models, respectively (P < 0.01; one-way analysis of variance-significantly greater than either drug given alone). CONCLUSIONS: The maximum antihyperalgesic effect achievable with nonsedating doses of morphine may be increased significantly when the drug is used in combination with CHEMICAL. | NO-RELATIONSHIP |
| Studies of synergy between CHEMICAL and a novel sodium channel blocker, CNSB002, in rat models of inflammatory and neuropathic pain. OBJECTIVE: This study determined the antihyperalgesic effect of CNSB002, a sodium channel blocker with antioxidant properties given alone and in combinations with CHEMICAL in rat models of inflammatory and neuropathic pain. DESIGN: Dose response curves for nonsedating doses of CHEMICAL and CNSB002 given intraperitoneally alone and together in combinations were constructed for antihyperalgesic effect using paw withdrawal from noxious heat in two rat DISEASE models: carrageenan-induced paw inflammation and streptozotocin (STZ)-induced diabetic neuropathy. RESULTS: The maximum nonsedating doses were: CHEMICAL, 3.2 mg/kg; CNSB002 10.0 mg/kg; 5.0 mg/kg CNSB002 with CHEMICAL 3.2 mg/kg in combination. The doses calculated to cause 50% reversal of hyperalgesia (ED50) were 7.54 (1.81) and 4.83 (1.54) in the carrageenan model and 44.18 (1.37) and 9.14 (1.24) in the STZ-induced neuropathy model for CNSB002 and CHEMICAL, respectively (mg/kg; mean, SEM). These values were greater than the maximum nonsedating doses. The ED50 values for CHEMICAL when given in combination with CNSB002 (5 mg/kg) were less than the maximum nonsedating dose: 0.56 (1.55) in the carrageenan model and 1.37 (1.23) in the neuropathy model (mg/kg; mean, SEM). The antinociception after CHEMICAL (3.2 mg/kg) was increased by co-administration with CNSB002 from 28.0 and 31.7% to 114.6 and 56.9% reversal of hyperalgesia in the inflammatory and neuropathic models, respectively (P < 0.01; one-way analysis of variance-significantly greater than either drug given alone). CONCLUSIONS: The maximum antihyperalgesic effect achievable with nonsedating doses of CHEMICAL may be increased significantly when the drug is used in combination with CNSB002. | NO-RELATIONSHIP |
| Studies of synergy between morphine and a novel CHEMICAL channel blocker, CNSB002, in rat models of inflammatory and neuropathic pain. OBJECTIVE: This study determined the antihyperalgesic effect of CNSB002, a CHEMICAL channel blocker with antioxidant properties given alone and in combinations with morphine in rat models of inflammatory and neuropathic pain. DESIGN: Dose response curves for nonsedating doses of morphine and CNSB002 given intraperitoneally alone and together in combinations were constructed for antihyperalgesic effect using paw withdrawal from noxious heat in two rat pain models: carrageenan-induced paw inflammation and streptozotocin (STZ)-induced diabetic neuropathy. RESULTS: The maximum nonsedating doses were: morphine, 3.2 mg/kg; CNSB002 10.0 mg/kg; 5.0 mg/kg CNSB002 with morphine 3.2 mg/kg in combination. The doses calculated to cause 50% reversal of hyperalgesia (ED50) were 7.54 (1.81) and 4.83 (1.54) in the carrageenan model and 44.18 (1.37) and 9.14 (1.24) in the STZ-induced DISEASE model for CNSB002 and morphine, respectively (mg/kg; mean, SEM). These values were greater than the maximum nonsedating doses. The ED50 values for morphine when given in combination with CNSB002 (5 mg/kg) were less than the maximum nonsedating dose: 0.56 (1.55) in the carrageenan model and 1.37 (1.23) in the DISEASE model (mg/kg; mean, SEM). The antinociception after morphine (3.2 mg/kg) was increased by co-administration with CNSB002 from 28.0 and 31.7% to 114.6 and 56.9% reversal of hyperalgesia in the inflammatory and DISEASE models, respectively (P < 0.01; one-way analysis of variance-significantly greater than either drug given alone). CONCLUSIONS: The maximum antihyperalgesic effect achievable with nonsedating doses of morphine may be increased significantly when the drug is used in combination with CNSB002. | NO-RELATIONSHIP |
| Studies of synergy between morphine and a novel sodium channel blocker, CHEMICAL, in rat models of inflammatory and neuropathic pain. OBJECTIVE: This study determined the antihyperalgesic effect of CHEMICAL, a sodium channel blocker with antioxidant properties given alone and in combinations with morphine in rat models of inflammatory and neuropathic pain. DESIGN: Dose response curves for nonsedating doses of morphine and CHEMICAL given intraperitoneally alone and together in combinations were constructed for antihyperalgesic effect using paw withdrawal from noxious heat in two rat pain models: carrageenan-induced paw inflammation and streptozotocin (STZ)-induced diabetic neuropathy. RESULTS: The maximum nonsedating doses were: morphine, 3.2 mg/kg; CHEMICAL 10.0 mg/kg; 5.0 mg/kg CHEMICAL with morphine 3.2 mg/kg in combination. The doses calculated to cause 50% reversal of hyperalgesia (ED50) were 7.54 (1.81) and 4.83 (1.54) in the carrageenan model and 44.18 (1.37) and 9.14 (1.24) in the STZ-induced DISEASE model for CHEMICAL and morphine, respectively (mg/kg; mean, SEM). These values were greater than the maximum nonsedating doses. The ED50 values for morphine when given in combination with CHEMICAL (5 mg/kg) were less than the maximum nonsedating dose: 0.56 (1.55) in the carrageenan model and 1.37 (1.23) in the DISEASE model (mg/kg; mean, SEM). The antinociception after morphine (3.2 mg/kg) was increased by co-administration with CHEMICAL from 28.0 and 31.7% to 114.6 and 56.9% reversal of hyperalgesia in the inflammatory and DISEASE models, respectively (P < 0.01; one-way analysis of variance-significantly greater than either drug given alone). CONCLUSIONS: The maximum antihyperalgesic effect achievable with nonsedating doses of morphine may be increased significantly when the drug is used in combination with CHEMICAL. | NO-RELATIONSHIP |
| Studies of synergy between CHEMICAL and a novel sodium channel blocker, CNSB002, in rat models of inflammatory and neuropathic pain. OBJECTIVE: This study determined the antihyperalgesic effect of CNSB002, a sodium channel blocker with antioxidant properties given alone and in combinations with CHEMICAL in rat models of inflammatory and neuropathic pain. DESIGN: Dose response curves for nonsedating doses of CHEMICAL and CNSB002 given intraperitoneally alone and together in combinations were constructed for antihyperalgesic effect using paw withdrawal from noxious heat in two rat pain models: carrageenan-induced paw inflammation and streptozotocin (STZ)-induced diabetic neuropathy. RESULTS: The maximum nonsedating doses were: CHEMICAL, 3.2 mg/kg; CNSB002 10.0 mg/kg; 5.0 mg/kg CNSB002 with CHEMICAL 3.2 mg/kg in combination. The doses calculated to cause 50% reversal of hyperalgesia (ED50) were 7.54 (1.81) and 4.83 (1.54) in the carrageenan model and 44.18 (1.37) and 9.14 (1.24) in the STZ-induced DISEASE model for CNSB002 and CHEMICAL, respectively (mg/kg; mean, SEM). These values were greater than the maximum nonsedating doses. The ED50 values for CHEMICAL when given in combination with CNSB002 (5 mg/kg) were less than the maximum nonsedating dose: 0.56 (1.55) in the carrageenan model and 1.37 (1.23) in the DISEASE model (mg/kg; mean, SEM). The antinociception after CHEMICAL (3.2 mg/kg) was increased by co-administration with CNSB002 from 28.0 and 31.7% to 114.6 and 56.9% reversal of hyperalgesia in the inflammatory and DISEASE models, respectively (P < 0.01; one-way analysis of variance-significantly greater than either drug given alone). CONCLUSIONS: The maximum antihyperalgesic effect achievable with nonsedating doses of CHEMICAL may be increased significantly when the drug is used in combination with CNSB002. | NO-RELATIONSHIP |
| Studies of synergy between CHEMICAL and a novel sodium channel blocker, CNSB002, in rat models of inflammatory and DISEASE. OBJECTIVE: This study determined the antihyperalgesic effect of CNSB002, a sodium channel blocker with antioxidant properties given alone and in combinations with CHEMICAL in rat models of inflammatory and DISEASE. DESIGN: Dose response curves for nonsedating doses of CHEMICAL and CNSB002 given intraperitoneally alone and together in combinations were constructed for antihyperalgesic effect using paw withdrawal from noxious heat in two rat pain models: carrageenan-induced paw inflammation and streptozotocin (STZ)-induced diabetic neuropathy. RESULTS: The maximum nonsedating doses were: CHEMICAL, 3.2 mg/kg; CNSB002 10.0 mg/kg; 5.0 mg/kg CNSB002 with CHEMICAL 3.2 mg/kg in combination. The doses calculated to cause 50% reversal of hyperalgesia (ED50) were 7.54 (1.81) and 4.83 (1.54) in the carrageenan model and 44.18 (1.37) and 9.14 (1.24) in the STZ-induced neuropathy model for CNSB002 and CHEMICAL, respectively (mg/kg; mean, SEM). These values were greater than the maximum nonsedating doses. The ED50 values for CHEMICAL when given in combination with CNSB002 (5 mg/kg) were less than the maximum nonsedating dose: 0.56 (1.55) in the carrageenan model and 1.37 (1.23) in the neuropathy model (mg/kg; mean, SEM). The antinociception after CHEMICAL (3.2 mg/kg) was increased by co-administration with CNSB002 from 28.0 and 31.7% to 114.6 and 56.9% reversal of hyperalgesia in the inflammatory and neuropathic models, respectively (P < 0.01; one-way analysis of variance-significantly greater than either drug given alone). CONCLUSIONS: The maximum antihyperalgesic effect achievable with nonsedating doses of CHEMICAL may be increased significantly when the drug is used in combination with CNSB002. | NO-RELATIONSHIP |
| Studies of synergy between morphine and a novel sodium channel blocker, CHEMICAL, in rat models of inflammatory and neuropathic pain. OBJECTIVE: This study determined the antihyperalgesic effect of CHEMICAL, a sodium channel blocker with antioxidant properties given alone and in combinations with morphine in rat models of inflammatory and neuropathic pain. DESIGN: Dose response curves for nonsedating doses of morphine and CHEMICAL given intraperitoneally alone and together in combinations were constructed for antihyperalgesic effect using paw withdrawal from noxious heat in two rat DISEASE models: carrageenan-induced paw inflammation and streptozotocin (STZ)-induced diabetic neuropathy. RESULTS: The maximum nonsedating doses were: morphine, 3.2 mg/kg; CHEMICAL 10.0 mg/kg; 5.0 mg/kg CHEMICAL with morphine 3.2 mg/kg in combination. The doses calculated to cause 50% reversal of hyperalgesia (ED50) were 7.54 (1.81) and 4.83 (1.54) in the carrageenan model and 44.18 (1.37) and 9.14 (1.24) in the STZ-induced neuropathy model for CHEMICAL and morphine, respectively (mg/kg; mean, SEM). These values were greater than the maximum nonsedating doses. The ED50 values for morphine when given in combination with CHEMICAL (5 mg/kg) were less than the maximum nonsedating dose: 0.56 (1.55) in the carrageenan model and 1.37 (1.23) in the neuropathy model (mg/kg; mean, SEM). The antinociception after morphine (3.2 mg/kg) was increased by co-administration with CHEMICAL from 28.0 and 31.7% to 114.6 and 56.9% reversal of hyperalgesia in the inflammatory and neuropathic models, respectively (P < 0.01; one-way analysis of variance-significantly greater than either drug given alone). CONCLUSIONS: The maximum antihyperalgesic effect achievable with nonsedating doses of morphine may be increased significantly when the drug is used in combination with CHEMICAL. | NO-RELATIONSHIP |
| CHEMICAL-induced DISEASE: a practical review. CHEMICAL-induced DISEASE (DISEASE) remains under-recognized despite its potentially devastating outcomes. It begins when CHEMICAL exposure stimulates the formation of CHEMICAL-platelet factor 4 antibodies, which in turn triggers the release of procoagulant platelet particles. Thrombosis and DISEASE that follow comprise the 2 hallmark traits of DISEASE, with the former largely responsible for significant vascular complications. The prevalence of DISEASE varies among several subgroups, with greater incidence in surgical as compared with medical populations. DISEASE must be acknowledged for its intense predilection for thrombosis and suspected whenever thrombosis occurs after CHEMICAL exposure. Early recognition that incorporates the clinical and serologic clues is paramount to timely institution of treatment, as its delay may result in catastrophic outcomes. The treatment of DISEASE mandates an immediate cessation of all CHEMICAL exposure and the institution of an antithrombotic therapy, most commonly using a direct thrombin inhibitor. Current "diagnostic" tests, which primarily include functional and antigenic assays, have more of a confirmatory than diagnostic role in the management of DISEASE. Special attention must be paid to cardiac patients who are often exposed to CHEMICAL multiple times during their course of treatment. Direct thrombin inhibitors are appropriate, evidence-based alternatives to CHEMICAL in patients with a history of DISEASE, who need to undergo percutaneous coronary intervention. As CHEMICAL remains one of the most frequently used medications today with potential for DISEASE with every CHEMICAL exposure, a close vigilance of platelet counts must be practiced whenever CHEMICAL is initiated. | CHEMICAL-INDUCED-DISEASE |
| CHEMICAL-induced thrombocytopenia: a practical review. CHEMICAL-induced thrombocytopenia (HIT) remains under-recognized despite its potentially devastating outcomes. It begins when CHEMICAL exposure stimulates the formation of CHEMICAL-platelet factor 4 antibodies, which in turn triggers the release of procoagulant platelet particles. DISEASE and thrombocytopenia that follow comprise the 2 hallmark traits of HIT, with the former largely responsible for significant vascular complications. The prevalence of HIT varies among several subgroups, with greater incidence in surgical as compared with medical populations. HIT must be acknowledged for its intense predilection for DISEASE and suspected whenever DISEASE occurs after CHEMICAL exposure. Early recognition that incorporates the clinical and serologic clues is paramount to timely institution of treatment, as its delay may result in catastrophic outcomes. The treatment of HIT mandates an immediate cessation of all CHEMICAL exposure and the institution of an antithrombotic therapy, most commonly using a direct thrombin inhibitor. Current "diagnostic" tests, which primarily include functional and antigenic assays, have more of a confirmatory than diagnostic role in the management of HIT. Special attention must be paid to cardiac patients who are often exposed to CHEMICAL multiple times during their course of treatment. Direct thrombin inhibitors are appropriate, evidence-based alternatives to CHEMICAL in patients with a history of HIT, who need to undergo percutaneous coronary intervention. As CHEMICAL remains one of the most frequently used medications today with potential for HIT with every CHEMICAL exposure, a close vigilance of platelet counts must be practiced whenever CHEMICAL is initiated. | CHEMICAL-INDUCED-DISEASE |
| Abductor paralysis after CHEMICAL injection for DISEASE. OBJECTIVES/HYPOTHESIS: Botulinum toxin (CHEMICAL) injections into the thyroarytenoid muscles are the current standard of care for DISEASE (DISEASE). Reported adverse effects include a period of breathiness, throat pain, and difficulty with swallowing liquids. Here we report multiple cases of bilateral abductor paralysis following CHEMICAL injections for DISEASE, a complication previously unreported. STUDY DESIGN: Retrospective case series. METHODS: Patients that received CHEMICAL injections for spasmodic dysphonia between January 2000 and October 2009 were evaluated. Patients with DISEASE were identified. The number of treatments received and adverse effects were noted. For patients with bilateral abductor paralysis, age, sex, paralytic CHEMICAL dose, prior CHEMICAL dose, and course following paralysis were noted. RESULTS: From a database of 452 patients receiving CHEMICAL, 352 patients had been diagnosed with DISEASE. Of these 352 patients, eight patients suffered bilateral abductor paralysis, and two suffered this complication twice. All affected patients were females over the age of 50 years. Most patients had received treatments prior to abductor paralysis and continued receiving after paralysis. Seven patients recovered after a brief period of activity restrictions, and one underwent a tracheotomy. The incidence of abductor paralysis after CHEMICAL injection for DISEASE was 0.34%. CONCLUSIONS: Bilateral abductor paralysis is a rare complication of CHEMICAL injections for DISEASE, causing difficulty with breathing upon exertion. The likely mechanism of paralysis is diffusion of CHEMICAL around the muscular process of the arytenoid to the posterior cricoarytenoid muscles. The paralysis is temporary, and watchful waiting with restriction of activity is the recommended management. | CHEMICAL-INDUCED-DISEASE |
| Mitochondrial impairment contributes to CHEMICAL-induced DISEASE: Prevention by the targeted antioxidant MitoQ. The goal of this study was to assess mitochondrial function and ROS production in an experimental model of CHEMICAL-induced DISEASE. We hypothesized that cocaine abuse may lead to altered mitochondrial function that in turn may cause left ventricular dysfunction. Seven days of CHEMICAL administration to rats led to an increased oxygen consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in ATP synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to CHEMICAL, suggesting that these mitochondrial abnormalities were a late rather than a primary event in the pathological response to CHEMICAL. MitoQ, a mitochondrial-targeted antioxidant, was shown to completely prevent these mitochondrial abnormalities as well as DISEASE characterized here by a diastolic dysfunction studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that CHEMICAL-induced DISEASE may be due to a mitochondrial defect. | CHEMICAL-INDUCED-DISEASE |
| Mitochondrial impairment contributes to cocaine-induced cardiac dysfunction: Prevention by the targeted antioxidant CHEMICAL. The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine-induced cardiac dysfunction. We hypothesized that cocaine abuse may lead to altered mitochondrial function that in turn may cause left ventricular dysfunction. Seven days of cocaine administration to rats led to an increased oxygen consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in ATP synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to cocaine, suggesting that these mitochondrial abnormalities were a late rather than a primary event in the pathological response to cocaine. CHEMICAL, a mitochondrial-targeted antioxidant, was shown to completely prevent these mitochondrial abnormalities as well as cardiac dysfunction characterized here by a DISEASE studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that cocaine-induced cardiac dysfunction may be due to a mitochondrial defect. | NO-RELATIONSHIP |
| Mitochondrial impairment contributes to cocaine-induced cardiac dysfunction: Prevention by the targeted antioxidant MitoQ. The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine-induced cardiac dysfunction. We hypothesized that cocaine abuse may lead to altered mitochondrial function that in turn may cause DISEASE. Seven days of cocaine administration to rats led to an increased CHEMICAL consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in ATP synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to cocaine, suggesting that these mitochondrial abnormalities were a late rather than a primary event in the pathological response to cocaine. MitoQ, a mitochondrial-targeted antioxidant, was shown to completely prevent these mitochondrial abnormalities as well as cardiac dysfunction characterized here by a diastolic dysfunction studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that cocaine-induced cardiac dysfunction may be due to a mitochondrial defect. | NO-RELATIONSHIP |
| Mitochondrial impairment contributes to cocaine-induced cardiac dysfunction: Prevention by the targeted antioxidant MitoQ. The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine-induced cardiac dysfunction. We hypothesized that cocaine abuse may lead to altered mitochondrial function that in turn may cause DISEASE. Seven days of cocaine administration to rats led to an increased oxygen consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in CHEMICAL synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to cocaine, suggesting that these mitochondrial abnormalities were a late rather than a primary event in the pathological response to cocaine. MitoQ, a mitochondrial-targeted antioxidant, was shown to completely prevent these mitochondrial abnormalities as well as cardiac dysfunction characterized here by a diastolic dysfunction studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that cocaine-induced cardiac dysfunction may be due to a mitochondrial defect. | NO-RELATIONSHIP |
| Mitochondrial impairment contributes to cocaine-induced cardiac dysfunction: Prevention by the targeted antioxidant CHEMICAL. The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine-induced cardiac dysfunction. We hypothesized that cocaine abuse may lead to altered mitochondrial function that in turn may cause DISEASE. Seven days of cocaine administration to rats led to an increased oxygen consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in ATP synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to cocaine, suggesting that these mitochondrial abnormalities were a late rather than a primary event in the pathological response to cocaine. CHEMICAL, a mitochondrial-targeted antioxidant, was shown to completely prevent these mitochondrial abnormalities as well as cardiac dysfunction characterized here by a diastolic dysfunction studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that cocaine-induced cardiac dysfunction may be due to a mitochondrial defect. | NO-RELATIONSHIP |
| Mitochondrial impairment contributes to cocaine-induced cardiac dysfunction: Prevention by the targeted antioxidant MitoQ. The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine-induced cardiac dysfunction. We hypothesized that DISEASE may lead to altered mitochondrial function that in turn may cause left ventricular dysfunction. Seven days of cocaine administration to rats led to an increased CHEMICAL consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in ATP synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to cocaine, suggesting that these mitochondrial abnormalities were a late rather than a primary event in the pathological response to cocaine. MitoQ, a mitochondrial-targeted antioxidant, was shown to completely prevent these mitochondrial abnormalities as well as cardiac dysfunction characterized here by a diastolic dysfunction studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that cocaine-induced cardiac dysfunction may be due to a mitochondrial defect. | NO-RELATIONSHIP |
| Mitochondrial impairment contributes to cocaine-induced cardiac dysfunction: Prevention by the targeted antioxidant MitoQ. The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine-induced cardiac dysfunction. We hypothesized that cocaine abuse may lead to altered mitochondrial function that in turn may cause left ventricular dysfunction. Seven days of cocaine administration to rats led to an increased oxygen consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in CHEMICAL synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to cocaine, suggesting that these mitochondrial abnormalities were a late rather than a primary event in the pathological response to cocaine. MitoQ, a mitochondrial-targeted antioxidant, was shown to completely prevent these mitochondrial abnormalities as well as cardiac dysfunction characterized here by a DISEASE studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that cocaine-induced cardiac dysfunction may be due to a mitochondrial defect. | NO-RELATIONSHIP |
| Mitochondrial impairment contributes to cocaine-induced cardiac dysfunction: Prevention by the targeted antioxidant CHEMICAL. The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine-induced cardiac dysfunction. We hypothesized that DISEASE may lead to altered mitochondrial function that in turn may cause left ventricular dysfunction. Seven days of cocaine administration to rats led to an increased oxygen consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in ATP synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to cocaine, suggesting that these mitochondrial abnormalities were a late rather than a primary event in the pathological response to cocaine. CHEMICAL, a mitochondrial-targeted antioxidant, was shown to completely prevent these mitochondrial abnormalities as well as cardiac dysfunction characterized here by a diastolic dysfunction studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that cocaine-induced cardiac dysfunction may be due to a mitochondrial defect. | NO-RELATIONSHIP |
| DISEASE contributes to cocaine-induced cardiac dysfunction: Prevention by the targeted antioxidant MitoQ. The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine-induced cardiac dysfunction. We hypothesized that cocaine abuse may lead to altered mitochondrial function that in turn may cause left ventricular dysfunction. Seven days of cocaine administration to rats led to an increased CHEMICAL consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in ATP synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to cocaine, suggesting that these DISEASE were a late rather than a primary event in the pathological response to cocaine. MitoQ, a mitochondrial-targeted antioxidant, was shown to completely prevent these DISEASE as well as cardiac dysfunction characterized here by a diastolic dysfunction studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that cocaine-induced cardiac dysfunction may be due to a DISEASE. | NO-RELATIONSHIP |
| DISEASE contributes to cocaine-induced cardiac dysfunction: Prevention by the targeted antioxidant MitoQ. The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine-induced cardiac dysfunction. We hypothesized that cocaine abuse may lead to altered mitochondrial function that in turn may cause left ventricular dysfunction. Seven days of cocaine administration to rats led to an increased oxygen consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in CHEMICAL synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to cocaine, suggesting that these DISEASE were a late rather than a primary event in the pathological response to cocaine. MitoQ, a mitochondrial-targeted antioxidant, was shown to completely prevent these DISEASE as well as cardiac dysfunction characterized here by a diastolic dysfunction studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that cocaine-induced cardiac dysfunction may be due to a DISEASE. | NO-RELATIONSHIP |
| Mitochondrial impairment contributes to cocaine-induced cardiac dysfunction: Prevention by the targeted antioxidant MitoQ. The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine-induced cardiac dysfunction. We hypothesized that cocaine abuse may lead to altered mitochondrial function that in turn may cause left ventricular dysfunction. Seven days of cocaine administration to rats led to an increased CHEMICAL consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in ATP synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to cocaine, suggesting that these mitochondrial abnormalities were a late rather than a primary event in the pathological response to cocaine. MitoQ, a mitochondrial-targeted antioxidant, was shown to completely prevent these mitochondrial abnormalities as well as cardiac dysfunction characterized here by a DISEASE studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that cocaine-induced cardiac dysfunction may be due to a mitochondrial defect. | NO-RELATIONSHIP |
| DISEASE contributes to cocaine-induced cardiac dysfunction: Prevention by the targeted antioxidant CHEMICAL. The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine-induced cardiac dysfunction. We hypothesized that cocaine abuse may lead to altered mitochondrial function that in turn may cause left ventricular dysfunction. Seven days of cocaine administration to rats led to an increased oxygen consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in ATP synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to cocaine, suggesting that these DISEASE were a late rather than a primary event in the pathological response to cocaine. CHEMICAL, a mitochondrial-targeted antioxidant, was shown to completely prevent these DISEASE as well as cardiac dysfunction characterized here by a diastolic dysfunction studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that cocaine-induced cardiac dysfunction may be due to a DISEASE. | NO-RELATIONSHIP |
| Mitochondrial impairment contributes to cocaine-induced cardiac dysfunction: Prevention by the targeted antioxidant MitoQ. The goal of this study was to assess mitochondrial function and ROS production in an experimental model of cocaine-induced cardiac dysfunction. We hypothesized that DISEASE may lead to altered mitochondrial function that in turn may cause left ventricular dysfunction. Seven days of cocaine administration to rats led to an increased oxygen consumption detected in cardiac fibers, specifically through complex I and complex III. ROS levels were increased, specifically in interfibrillar mitochondria. In parallel there was a decrease in CHEMICAL synthesis, whereas no difference was observed in subsarcolemmal mitochondria. This uncoupling effect on oxidative phosphorylation was not detectable after short-term exposure to cocaine, suggesting that these mitochondrial abnormalities were a late rather than a primary event in the pathological response to cocaine. MitoQ, a mitochondrial-targeted antioxidant, was shown to completely prevent these mitochondrial abnormalities as well as cardiac dysfunction characterized here by a diastolic dysfunction studied with a conductance catheter to obtain pressure-volume data. Taken together, these results extend previous studies and demonstrate that cocaine-induced cardiac dysfunction may be due to a mitochondrial defect. | NO-RELATIONSHIP |
| CHEMICAL-induced immune DISEASE in a pediatric oncology patient presenting as an acute hemolytic transfusion reaction. A 10-year-old male with acute leukemia presented with post-chemotherapy anemia. During red cell transfusion, he developed hemoglobinuria. Transfusion reaction workup was negative. Drug-induced immune DISEASE was suspected because of positive direct antiglobulin test, negative eluate, and microspherocytes on smear pre- and post-transfusion. Drug studies using the indirect antiglobulin test were strongly positive with CHEMICAL and trimethoprim-sulfamethoxazole but negative with sulfamethoxazole. The patient recovered after discontinuing the drug, with no recurrence in 2 years. Other causes of anemia should be considered in patients with worse-than-expected anemia after chemotherapy. Furthermore, hemolysis during transfusion is not always a transfusion reaction. | CHEMICAL-INDUCED-DISEASE |
| Trimethoprim-induced immune hemolytic anemia in a pediatric oncology patient presenting as an acute hemolytic transfusion reaction. A 10-year-old male with DISEASE presented with post-chemotherapy anemia. During red cell transfusion, he developed hemoglobinuria. Transfusion reaction workup was negative. Drug-induced immune hemolytic anemia was suspected because of positive direct antiglobulin test, negative eluate, and microspherocytes on smear pre- and post-transfusion. Drug studies using the indirect antiglobulin test were strongly positive with trimethoprim and CHEMICAL but negative with sulfamethoxazole. The patient recovered after discontinuing the drug, with no recurrence in 2 years. Other causes of anemia should be considered in patients with worse-than-expected anemia after chemotherapy. Furthermore, hemolysis during transfusion is not always a transfusion reaction. | NO-RELATIONSHIP |
| Trimethoprim-induced immune hemolytic anemia in a pediatric oncology patient presenting as an acute hemolytic transfusion reaction. A 10-year-old male with acute leukemia presented with post-chemotherapy anemia. During red cell transfusion, he developed DISEASE. Transfusion reaction workup was negative. Drug-induced immune hemolytic anemia was suspected because of positive direct antiglobulin test, negative eluate, and microspherocytes on smear pre- and post-transfusion. Drug studies using the indirect antiglobulin test were strongly positive with trimethoprim and trimethoprim-sulfamethoxazole but negative with CHEMICAL. The patient recovered after discontinuing the drug, with no recurrence in 2 years. Other causes of anemia should be considered in patients with worse-than-expected anemia after chemotherapy. Furthermore, hemolysis during transfusion is not always a transfusion reaction. | NO-RELATIONSHIP |
| Trimethoprim-induced immune hemolytic anemia in a pediatric oncology patient presenting as an acute hemolytic transfusion reaction. A 10-year-old male with acute leukemia presented with post-chemotherapy anemia. During red cell transfusion, he developed hemoglobinuria. Transfusion reaction workup was negative. Drug-induced immune hemolytic anemia was suspected because of positive direct antiglobulin test, negative eluate, and microspherocytes on smear pre- and post-transfusion. Drug studies using the indirect antiglobulin test were strongly positive with trimethoprim and trimethoprim-sulfamethoxazole but negative with CHEMICAL. The patient recovered after discontinuing the drug, with no recurrence in 2 years. Other causes of anemia should be considered in patients with worse-than-expected anemia after chemotherapy. Furthermore, DISEASE during transfusion is not always a transfusion reaction. | NO-RELATIONSHIP |
| Trimethoprim-induced immune hemolytic anemia in a pediatric oncology patient presenting as an acute hemolytic transfusion reaction. A 10-year-old male with acute leukemia presented with post-chemotherapy DISEASE. During red cell transfusion, he developed hemoglobinuria. Transfusion reaction workup was negative. Drug-induced immune hemolytic anemia was suspected because of positive direct antiglobulin test, negative eluate, and microspherocytes on smear pre- and post-transfusion. Drug studies using the indirect antiglobulin test were strongly positive with trimethoprim and CHEMICAL but negative with sulfamethoxazole. The patient recovered after discontinuing the drug, with no recurrence in 2 years. Other causes of DISEASE should be considered in patients with worse-than-expected DISEASE after chemotherapy. Furthermore, hemolysis during transfusion is not always a transfusion reaction. | NO-RELATIONSHIP |
| Trimethoprim-induced immune hemolytic anemia in a pediatric oncology patient presenting as an acute hemolytic transfusion reaction. A 10-year-old male with acute leukemia presented with post-chemotherapy DISEASE. During red cell transfusion, he developed hemoglobinuria. Transfusion reaction workup was negative. Drug-induced immune hemolytic anemia was suspected because of positive direct antiglobulin test, negative eluate, and microspherocytes on smear pre- and post-transfusion. Drug studies using the indirect antiglobulin test were strongly positive with trimethoprim and trimethoprim-sulfamethoxazole but negative with CHEMICAL. The patient recovered after discontinuing the drug, with no recurrence in 2 years. Other causes of DISEASE should be considered in patients with worse-than-expected DISEASE after chemotherapy. Furthermore, hemolysis during transfusion is not always a transfusion reaction. | NO-RELATIONSHIP |
| Trimethoprim-induced immune hemolytic anemia in a pediatric oncology patient presenting as an acute hemolytic transfusion reaction. A 10-year-old male with acute leukemia presented with post-chemotherapy anemia. During red cell transfusion, he developed hemoglobinuria. Transfusion reaction workup was negative. Drug-induced immune hemolytic anemia was suspected because of positive direct antiglobulin test, negative eluate, and microspherocytes on smear pre- and post-transfusion. Drug studies using the indirect antiglobulin test were strongly positive with trimethoprim and CHEMICAL but negative with sulfamethoxazole. The patient recovered after discontinuing the drug, with no recurrence in 2 years. Other causes of anemia should be considered in patients with worse-than-expected anemia after chemotherapy. Furthermore, DISEASE during transfusion is not always a transfusion reaction. | NO-RELATIONSHIP |
| Trimethoprim-induced immune hemolytic anemia in a pediatric oncology patient presenting as an acute hemolytic transfusion reaction. A 10-year-old male with acute leukemia presented with post-chemotherapy anemia. During red cell transfusion, he developed DISEASE. Transfusion reaction workup was negative. Drug-induced immune hemolytic anemia was suspected because of positive direct antiglobulin test, negative eluate, and microspherocytes on smear pre- and post-transfusion. Drug studies using the indirect antiglobulin test were strongly positive with trimethoprim and CHEMICAL but negative with sulfamethoxazole. The patient recovered after discontinuing the drug, with no recurrence in 2 years. Other causes of anemia should be considered in patients with worse-than-expected anemia after chemotherapy. Furthermore, hemolysis during transfusion is not always a transfusion reaction. | NO-RELATIONSHIP |
| Trimethoprim-induced immune hemolytic anemia in a pediatric oncology patient presenting as an acute hemolytic transfusion reaction. A 10-year-old male with DISEASE presented with post-chemotherapy anemia. During red cell transfusion, he developed hemoglobinuria. Transfusion reaction workup was negative. Drug-induced immune hemolytic anemia was suspected because of positive direct antiglobulin test, negative eluate, and microspherocytes on smear pre- and post-transfusion. Drug studies using the indirect antiglobulin test were strongly positive with trimethoprim and trimethoprim-sulfamethoxazole but negative with CHEMICAL. The patient recovered after discontinuing the drug, with no recurrence in 2 years. Other causes of anemia should be considered in patients with worse-than-expected anemia after chemotherapy. Furthermore, hemolysis during transfusion is not always a transfusion reaction. | NO-RELATIONSHIP |
| Blockade of endothelial-mesenchymal transition by a Smad3 inhibitor delays the early development of CHEMICAL-induced DISEASE. OBJECTIVE: A multicenter, controlled trial showed that early blockade of the renin-angiotensin system in patients with type 1 diabetes and normoalbuminuria did not retard the progression of nephropathy, suggesting that other mechanism(s) are involved in the pathogenesis of early DISEASE (DISEASE). We have previously demonstrated that endothelial-mesenchymal-transition (EndoMT) contributes to the early development of renal interstitial fibrosis independently of microalbuminuria in mice with CHEMICAL (CHEMICAL)-induced diabetes. In the present study, we hypothesized that blocking EndoMT reduces the early development of DISEASE. RESEARCH DESIGN AND METHODS: EndoMT was induced in a mouse pancreatic microvascular endothelial cell line (MMEC) in the presence of advanced glycation end products (AGEs) and in the endothelial lineage-traceble mouse line Tie2-Cre;Loxp-EGFP by administration of AGEs, with nonglycated mouse albumin serving as a control. Phosphorylated Smad3 was detected by immunoprecipitation/Western blotting and confocal microscopy. Blocking studies using receptor for AGE siRNA and a specific inhibitor of Smad3 (SIS3) were performed in MMECs and in CHEMICAL-induced DISEASE in Tie2-Cre;Loxp-EGFP mice. RESULTS: Confocal microscopy and real-time PCR demonstrated that AGEs induced EndoMT in MMECs and in Tie2-Cre;Loxp-EGFP mice. Immunoprecipitation/Western blotting showed that Smad3 was activated by AGEs but was inhibited by SIS3 in MMECs and in CHEMICAL-induced DISEASE. Confocal microscopy and real-time PCR further demonstrated that SIS3 abrogated EndoMT, reduced renal fibrosis, and retarded progression of nephropathy. CONCLUSIONS: EndoMT is a novel pathway leading to early development of DISEASE. Blockade of EndoMT by SIS3 may provide a new strategy to retard the progression of DISEASE and other diabetes complications. | CHEMICAL-INDUCED-DISEASE |
| Blockade of endothelial-mesenchymal transition by a Smad3 inhibitor delays the early development of streptozotocin-induced diabetic nephropathy. OBJECTIVE: A multicenter, controlled trial showed that early blockade of the renin-CHEMICAL system in patients with DISEASE and normoalbuminuria did not retard the progression of nephropathy, suggesting that other mechanism(s) are involved in the pathogenesis of early diabetic nephropathy (diabetic nephropathy). We have previously demonstrated that endothelial-mesenchymal-transition (EndoMT) contributes to the early development of renal interstitial fibrosis independently of microalbuminuria in mice with streptozotocin (STZ)-induced diabetes. In the present study, we hypothesized that blocking EndoMT reduces the early development of diabetic nephropathy. RESEARCH DESIGN AND METHODS: EndoMT was induced in a mouse pancreatic microvascular endothelial cell line (MMEC) in the presence of advanced glycation end products (AGEs) and in the endothelial lineage-traceble mouse line Tie2-Cre;Loxp-EGFP by administration of AGEs, with nonglycated mouse albumin serving as a control. Phosphorylated Smad3 was detected by immunoprecipitation/Western blotting and confocal microscopy. Blocking studies using receptor for AGE siRNA and a specific inhibitor of Smad3 (SIS3) were performed in MMECs and in STZ-induced diabetic nephropathy in Tie2-Cre;Loxp-EGFP mice. RESULTS: Confocal microscopy and real-time PCR demonstrated that AGEs induced EndoMT in MMECs and in Tie2-Cre;Loxp-EGFP mice. Immunoprecipitation/Western blotting showed that Smad3 was activated by AGEs but was inhibited by SIS3 in MMECs and in STZ-induced diabetic nephropathy. Confocal microscopy and real-time PCR further demonstrated that SIS3 abrogated EndoMT, reduced renal fibrosis, and retarded progression of nephropathy. CONCLUSIONS: EndoMT is a novel pathway leading to early development of diabetic nephropathy. Blockade of EndoMT by SIS3 may provide a new strategy to retard the progression of diabetic nephropathy and other diabetes complications. | NO-RELATIONSHIP |
| Blockade of endothelial-mesenchymal transition by a Smad3 inhibitor delays the early development of streptozotocin-induced diabetic nephropathy. OBJECTIVE: A multicenter, controlled trial showed that early blockade of the renin-CHEMICAL system in patients with type 1 diabetes and normoalbuminuria did not retard the progression of nephropathy, suggesting that other mechanism(s) are involved in the pathogenesis of early diabetic nephropathy (diabetic nephropathy). We have previously demonstrated that endothelial-mesenchymal-transition (EndoMT) contributes to the early development of renal interstitial fibrosis independently of microalbuminuria in mice with streptozotocin (STZ)-induced DISEASE. In the present study, we hypothesized that blocking EndoMT reduces the early development of diabetic nephropathy. RESEARCH DESIGN AND METHODS: EndoMT was induced in a mouse pancreatic microvascular endothelial cell line (MMEC) in the presence of advanced glycation end products (AGEs) and in the endothelial lineage-traceble mouse line Tie2-Cre;Loxp-EGFP by administration of AGEs, with nonglycated mouse albumin serving as a control. Phosphorylated Smad3 was detected by immunoprecipitation/Western blotting and confocal microscopy. Blocking studies using receptor for AGE siRNA and a specific inhibitor of Smad3 (SIS3) were performed in MMECs and in STZ-induced diabetic nephropathy in Tie2-Cre;Loxp-EGFP mice. RESULTS: Confocal microscopy and real-time PCR demonstrated that AGEs induced EndoMT in MMECs and in Tie2-Cre;Loxp-EGFP mice. Immunoprecipitation/Western blotting showed that Smad3 was activated by AGEs but was inhibited by SIS3 in MMECs and in STZ-induced diabetic nephropathy. Confocal microscopy and real-time PCR further demonstrated that SIS3 abrogated EndoMT, reduced renal fibrosis, and retarded progression of nephropathy. CONCLUSIONS: EndoMT is a novel pathway leading to early development of diabetic nephropathy. Blockade of EndoMT by SIS3 may provide a new strategy to retard the progression of diabetic nephropathy and other diabetes complications. | NO-RELATIONSHIP |
| Blockade of endothelial-mesenchymal transition by a Smad3 inhibitor delays the early development of streptozotocin-induced diabetic nephropathy. OBJECTIVE: A multicenter, controlled trial showed that early blockade of the renin-CHEMICAL system in patients with type 1 diabetes and normoalbuminuria did not retard the progression of nephropathy, suggesting that other mechanism(s) are involved in the pathogenesis of early diabetic nephropathy (diabetic nephropathy). We have previously demonstrated that endothelial-mesenchymal-transition (EndoMT) contributes to the early development of renal interstitial fibrosis independently of microalbuminuria in mice with streptozotocin (STZ)-induced diabetes. In the present study, we hypothesized that blocking EndoMT reduces the early development of diabetic nephropathy. RESEARCH DESIGN AND METHODS: EndoMT was induced in a mouse pancreatic microvascular endothelial cell line (MMEC) in the presence of advanced glycation end products (AGEs) and in the endothelial lineage-traceble mouse line Tie2-Cre;Loxp-EGFP by administration of AGEs, with nonglycated mouse albumin serving as a control. Phosphorylated Smad3 was detected by immunoprecipitation/Western blotting and confocal microscopy. Blocking studies using receptor for AGE siRNA and a specific inhibitor of Smad3 (SIS3) were performed in MMECs and in STZ-induced diabetic nephropathy in Tie2-Cre;Loxp-EGFP mice. RESULTS: Confocal microscopy and real-time PCR demonstrated that AGEs induced EndoMT in MMECs and in Tie2-Cre;Loxp-EGFP mice. Immunoprecipitation/Western blotting showed that Smad3 was activated by AGEs but was inhibited by SIS3 in MMECs and in STZ-induced diabetic nephropathy. Confocal microscopy and real-time PCR further demonstrated that SIS3 abrogated EndoMT, reduced renal fibrosis, and retarded progression of nephropathy. CONCLUSIONS: EndoMT is a novel pathway leading to early development of diabetic nephropathy. Blockade of EndoMT by SIS3 may provide a new strategy to retard the progression of diabetic nephropathy and other DISEASE. | NO-RELATIONSHIP |
| Blockade of endothelial-mesenchymal transition by a Smad3 inhibitor delays the early development of streptozotocin-induced diabetic nephropathy. OBJECTIVE: A multicenter, controlled trial showed that early blockade of the renin-CHEMICAL system in patients with type 1 diabetes and normoalbuminuria did not retard the progression of DISEASE, suggesting that other mechanism(s) are involved in the pathogenesis of early diabetic nephropathy (diabetic nephropathy). We have previously demonstrated that endothelial-mesenchymal-transition (EndoMT) contributes to the early development of renal interstitial fibrosis independently of microalbuminuria in mice with streptozotocin (STZ)-induced diabetes. In the present study, we hypothesized that blocking EndoMT reduces the early development of diabetic nephropathy. RESEARCH DESIGN AND METHODS: EndoMT was induced in a mouse pancreatic microvascular endothelial cell line (MMEC) in the presence of advanced glycation end products (AGEs) and in the endothelial lineage-traceble mouse line Tie2-Cre;Loxp-EGFP by administration of AGEs, with nonglycated mouse albumin serving as a control. Phosphorylated Smad3 was detected by immunoprecipitation/Western blotting and confocal microscopy. Blocking studies using receptor for AGE siRNA and a specific inhibitor of Smad3 (SIS3) were performed in MMECs and in STZ-induced diabetic nephropathy in Tie2-Cre;Loxp-EGFP mice. RESULTS: Confocal microscopy and real-time PCR demonstrated that AGEs induced EndoMT in MMECs and in Tie2-Cre;Loxp-EGFP mice. Immunoprecipitation/Western blotting showed that Smad3 was activated by AGEs but was inhibited by SIS3 in MMECs and in STZ-induced diabetic nephropathy. Confocal microscopy and real-time PCR further demonstrated that SIS3 abrogated EndoMT, reduced renal fibrosis, and retarded progression of DISEASE. CONCLUSIONS: EndoMT is a novel pathway leading to early development of diabetic nephropathy. Blockade of EndoMT by SIS3 may provide a new strategy to retard the progression of diabetic nephropathy and other diabetes complications. | NO-RELATIONSHIP |
| Blockade of endothelial-mesenchymal transition by a Smad3 inhibitor delays the early development of streptozotocin-induced diabetic nephropathy. OBJECTIVE: A multicenter, controlled trial showed that early blockade of the renin-CHEMICAL system in patients with type 1 diabetes and normoalbuminuria did not retard the progression of nephropathy, suggesting that other mechanism(s) are involved in the pathogenesis of early diabetic nephropathy (diabetic nephropathy). We have previously demonstrated that endothelial-mesenchymal-transition (EndoMT) contributes to the early development of renal interstitial DISEASE independently of microalbuminuria in mice with streptozotocin (STZ)-induced diabetes. In the present study, we hypothesized that blocking EndoMT reduces the early development of diabetic nephropathy. RESEARCH DESIGN AND METHODS: EndoMT was induced in a mouse pancreatic microvascular endothelial cell line (MMEC) in the presence of advanced glycation end products (AGEs) and in the endothelial lineage-traceble mouse line Tie2-Cre;Loxp-EGFP by administration of AGEs, with nonglycated mouse albumin serving as a control. Phosphorylated Smad3 was detected by immunoprecipitation/Western blotting and confocal microscopy. Blocking studies using receptor for AGE siRNA and a specific inhibitor of Smad3 (SIS3) were performed in MMECs and in STZ-induced diabetic nephropathy in Tie2-Cre;Loxp-EGFP mice. RESULTS: Confocal microscopy and real-time PCR demonstrated that AGEs induced EndoMT in MMECs and in Tie2-Cre;Loxp-EGFP mice. Immunoprecipitation/Western blotting showed that Smad3 was activated by AGEs but was inhibited by SIS3 in MMECs and in STZ-induced diabetic nephropathy. Confocal microscopy and real-time PCR further demonstrated that SIS3 abrogated EndoMT, reduced renal DISEASE, and retarded progression of nephropathy. CONCLUSIONS: EndoMT is a novel pathway leading to early development of diabetic nephropathy. Blockade of EndoMT by SIS3 may provide a new strategy to retard the progression of diabetic nephropathy and other diabetes complications. | NO-RELATIONSHIP |
| Cytostatic and anti-angiogenic effects of CHEMICAL in refractory mantle cell lymphoma. Mantle cell lymphoma (MCL) is a rare and aggressive type of B-cell non-Hodgkin's lymphoma. Patients become progressively refractory to conventional chemotherapy, and their prognosis is poor. However, a 38% remission rate has been recently reported in refractory MCL treated with CHEMICAL, a mTOR inhibitor.Here we had the opportunity to study a case of refractory MCL who had tumor regression two months after CHEMICAL treatment, and a progression-free survival of 10 months. In this case, lymph node biopsies were performed before and six months after CHEMICAL therapy. Comparison of the two biopsies showed that CHEMICAL inhibited tumor cell proliferation through cell cycle arrest, but did not induce any change in the number of apoptotic tumor cells. Apart from this cytostatic effect, CHEMICAL had an antiangiogenic effect with decrease of tumor microvessel density and of VEGF expression. Moreover, numerous patchy, well-limited fibrotic areas, compatible with post-DISEASE tissue repair, were found after 6-month CHEMICAL therapy. Thus, CHEMICAL reduced tumor burden through associated cytostatic and anti-angiogenic effects.This dual effect of CHEMICAL on tumor tissue could contribute to its recently reported efficiency in refractory MCL resistant to conventional chemotherapy. | CHEMICAL-INDUCED-DISEASE |
| Syncope caused by hyperkalemia during use of a combined therapy with the angiotensin-converting enzyme inhibitor and spironolactone. A 76 year-old woman with a history of coronary artery bypass grafting and prior myocardial infarction was transferred to the emergency room with loss of consciousness due to marked DISEASE caused by hyperkalemia. The concentration of serum CHEMICAL was high, and normal sinus rhythm was restored after correction of the serum CHEMICAL level. The cause of hyperkalemia was considered to be several doses of spiranolactone, an aldosterone antagonist, in addition to the long-term intake of ramipril, an ACE inhibitor. This case is a good example of electrolyte imbalance causing acute life-threatening cardiac events. Clinicians should be alert to the possibility of hyperkalemia, especially in elderly patients using ACE/ARB in combination with CHEMICAL sparing agents and who have mild renal disturbance. | NO-RELATIONSHIP |
| Syncope caused by DISEASE during use of a combined therapy with the angiotensin-converting enzyme inhibitor and CHEMICAL. A 76 year-old woman with a history of coronary artery bypass grafting and prior myocardial infarction was transferred to the emergency room with loss of consciousness due to marked bradycardia caused by DISEASE. The concentration of serum potassium was high, and normal sinus rhythm was restored after correction of the serum potassium level. The cause of DISEASE was considered to be several doses of CHEMICAL, an aldosterone antagonist, in addition to the long-term intake of ramipril, an ACE inhibitor. This case is a good example of electrolyte imbalance causing acute life-threatening cardiac events. Clinicians should be alert to the possibility of DISEASE, especially in elderly patients using ACE/ARB in combination with potassium sparing agents and who have mild renal disturbance. | CHEMICAL-INDUCED-DISEASE |
| Syncope caused by DISEASE during use of a combined therapy with the angiotensin-converting enzyme inhibitor and spironolactone. A 76 year-old woman with a history of coronary artery bypass grafting and prior myocardial infarction was transferred to the emergency room with loss of consciousness due to marked bradycardia caused by DISEASE. The concentration of serum potassium was high, and normal sinus rhythm was restored after correction of the serum potassium level. The cause of DISEASE was considered to be several doses of spiranolactone, an aldosterone antagonist, in addition to the long-term intake of CHEMICAL, an ACE inhibitor. This case is a good example of electrolyte imbalance causing acute life-threatening cardiac events. Clinicians should be alert to the possibility of DISEASE, especially in elderly patients using ACE/ARB in combination with potassium sparing agents and who have mild renal disturbance. | CHEMICAL-INDUCED-DISEASE |
| Syncope caused by hyperkalemia during use of a combined therapy with the CHEMICAL-converting enzyme inhibitor and spironolactone. A 76 year-old woman with a history of coronary artery bypass grafting and prior myocardial infarction was transferred to the emergency room with DISEASE due to marked bradycardia caused by hyperkalemia. The concentration of serum potassium was high, and normal sinus rhythm was restored after correction of the serum potassium level. The cause of hyperkalemia was considered to be several doses of spiranolactone, an aldosterone antagonist, in addition to the long-term intake of ramipril, an ACE inhibitor. This case is a good example of electrolyte imbalance causing acute life-threatening cardiac events. Clinicians should be alert to the possibility of hyperkalemia, especially in elderly patients using ACE/ARB in combination with potassium sparing agents and who have mild renal disturbance. | NO-RELATIONSHIP |
| DISEASE caused by hyperkalemia during use of a combined therapy with the CHEMICAL-converting enzyme inhibitor and spironolactone. A 76 year-old woman with a history of coronary artery bypass grafting and prior myocardial infarction was transferred to the emergency room with loss of consciousness due to marked bradycardia caused by hyperkalemia. The concentration of serum potassium was high, and normal sinus rhythm was restored after correction of the serum potassium level. The cause of hyperkalemia was considered to be several doses of spiranolactone, an aldosterone antagonist, in addition to the long-term intake of ramipril, an ACE inhibitor. This case is a good example of electrolyte imbalance causing acute life-threatening cardiac events. Clinicians should be alert to the possibility of hyperkalemia, especially in elderly patients using ACE/ARB in combination with potassium sparing agents and who have mild renal disturbance. | NO-RELATIONSHIP |
| Syncope caused by hyperkalemia during use of a combined therapy with the angiotensin-converting enzyme inhibitor and spironolactone. A 76 year-old woman with a history of coronary artery bypass grafting and prior DISEASE was transferred to the emergency room with loss of consciousness due to marked bradycardia caused by hyperkalemia. The concentration of serum potassium was high, and normal sinus rhythm was restored after correction of the serum potassium level. The cause of hyperkalemia was considered to be several doses of spiranolactone, an CHEMICAL antagonist, in addition to the long-term intake of ramipril, an ACE inhibitor. This case is a good example of electrolyte imbalance causing acute life-threatening cardiac events. Clinicians should be alert to the possibility of hyperkalemia, especially in elderly patients using ACE/ARB in combination with potassium sparing agents and who have mild renal disturbance. | NO-RELATIONSHIP |
| DISEASE caused by hyperkalemia during use of a combined therapy with the angiotensin-converting enzyme inhibitor and spironolactone. A 76 year-old woman with a history of coronary artery bypass grafting and prior myocardial infarction was transferred to the emergency room with loss of consciousness due to marked bradycardia caused by hyperkalemia. The concentration of serum potassium was high, and normal sinus rhythm was restored after correction of the serum potassium level. The cause of hyperkalemia was considered to be several doses of spiranolactone, an CHEMICAL antagonist, in addition to the long-term intake of ramipril, an ACE inhibitor. This case is a good example of electrolyte imbalance causing acute life-threatening cardiac events. Clinicians should be alert to the possibility of hyperkalemia, especially in elderly patients using ACE/ARB in combination with potassium sparing agents and who have mild renal disturbance. | NO-RELATIONSHIP |
| Syncope caused by hyperkalemia during use of a combined therapy with the angiotensin-converting enzyme inhibitor and spironolactone. A 76 year-old woman with a history of coronary artery bypass grafting and prior myocardial infarction was transferred to the emergency room with DISEASE due to marked bradycardia caused by hyperkalemia. The concentration of serum potassium was high, and normal sinus rhythm was restored after correction of the serum potassium level. The cause of hyperkalemia was considered to be several doses of spiranolactone, an CHEMICAL antagonist, in addition to the long-term intake of ramipril, an ACE inhibitor. This case is a good example of electrolyte imbalance causing acute life-threatening cardiac events. Clinicians should be alert to the possibility of hyperkalemia, especially in elderly patients using ACE/ARB in combination with potassium sparing agents and who have mild renal disturbance. | NO-RELATIONSHIP |
| Syncope caused by hyperkalemia during use of a combined therapy with the CHEMICAL-converting enzyme inhibitor and spironolactone. A 76 year-old woman with a history of coronary artery bypass grafting and prior myocardial infarction was transferred to the emergency room with loss of consciousness due to marked bradycardia caused by hyperkalemia. The concentration of serum potassium was high, and normal sinus rhythm was restored after correction of the serum potassium level. The cause of hyperkalemia was considered to be several doses of spiranolactone, an aldosterone antagonist, in addition to the long-term intake of ramipril, an ACE inhibitor. This case is a good example of electrolyte imbalance causing acute life-threatening cardiac events. Clinicians should be alert to the possibility of hyperkalemia, especially in elderly patients using ACE/ARB in combination with potassium sparing agents and who have mild DISEASE. | NO-RELATIONSHIP |
| Syncope caused by hyperkalemia during use of a combined therapy with the CHEMICAL-converting enzyme inhibitor and spironolactone. A 76 year-old woman with a history of coronary artery bypass grafting and prior DISEASE was transferred to the emergency room with loss of consciousness due to marked bradycardia caused by hyperkalemia. The concentration of serum potassium was high, and normal sinus rhythm was restored after correction of the serum potassium level. The cause of hyperkalemia was considered to be several doses of spiranolactone, an aldosterone antagonist, in addition to the long-term intake of ramipril, an ACE inhibitor. This case is a good example of electrolyte imbalance causing acute life-threatening cardiac events. Clinicians should be alert to the possibility of hyperkalemia, especially in elderly patients using ACE/ARB in combination with potassium sparing agents and who have mild renal disturbance. | NO-RELATIONSHIP |
| Syncope caused by hyperkalemia during use of a combined therapy with the angiotensin-converting enzyme inhibitor and spironolactone. A 76 year-old woman with a history of coronary artery bypass grafting and prior myocardial infarction was transferred to the emergency room with loss of consciousness due to marked bradycardia caused by hyperkalemia. The concentration of serum potassium was high, and normal sinus rhythm was restored after correction of the serum potassium level. The cause of hyperkalemia was considered to be several doses of spiranolactone, an CHEMICAL antagonist, in addition to the long-term intake of ramipril, an ACE inhibitor. This case is a good example of electrolyte imbalance causing acute life-threatening cardiac events. Clinicians should be alert to the possibility of hyperkalemia, especially in elderly patients using ACE/ARB in combination with potassium sparing agents and who have mild DISEASE. | NO-RELATIONSHIP |
| Diffuse skeletal DISEASE after administration of CHEMICAL. BACKGROUND: Osteoporosis is caused by bone resorption in excess of bone formation, and bisphosphonates, are used to inhibit bone resorption. CHEMICAL, a biphosphonate, is effective for both the treatment and prevention of osteoporosis in postmenopausal women. Side effects are relatively few and prominently gastrointestinal. Musculoskeletal pain may be an important side effect in these patients. We presented a patient admitted to our out-patient clinic with diffuse skeletal DISEASE after three consecutive administration of CHEMICAL. CONCLUSION: We conclude that patients with osteoporosis can report DISEASE, and bisphosphonate-related DISEASE should also be considered before ascribing this complaint to osteoporosis. | CHEMICAL-INDUCED-DISEASE |
| Diffuse skeletal pain after administration of alendronate. BACKGROUND: Osteoporosis is caused by bone resorption in excess of bone formation, and CHEMICAL, are used to inhibit bone resorption. Alendronate, a biphosphonate, is effective for both the treatment and prevention of osteoporosis in postmenopausal women. Side effects are relatively few and prominently gastrointestinal. DISEASE may be an important side effect in these patients. We presented a patient admitted to our out-patient clinic with diffuse skeletal pain after three consecutive administration of alendronate. CONCLUSION: We conclude that patients with osteoporosis can report pain, and CHEMICAL-related pain should also be considered before ascribing this complaint to osteoporosis. | NO-RELATIONSHIP |
| Diffuse skeletal pain after administration of alendronate. BACKGROUND: Osteoporosis is caused by bone resorption in excess of bone formation, and bisphosphonates, are used to inhibit bone resorption. Alendronate, a CHEMICAL, is effective for both the treatment and prevention of osteoporosis in postmenopausal women. Side effects are relatively few and prominently gastrointestinal. DISEASE may be an important side effect in these patients. We presented a patient admitted to our out-patient clinic with diffuse skeletal pain after three consecutive administration of alendronate. CONCLUSION: We conclude that patients with osteoporosis can report pain, and bisphosphonate-related pain should also be considered before ascribing this complaint to osteoporosis. | NO-RELATIONSHIP |
| Diffuse skeletal pain after administration of alendronate. BACKGROUND: DISEASE is caused by bone resorption in excess of bone formation, and bisphosphonates, are used to inhibit bone resorption. Alendronate, a CHEMICAL, is effective for both the treatment and prevention of DISEASE in postmenopausal women. Side effects are relatively few and prominently gastrointestinal. Musculoskeletal pain may be an important side effect in these patients. We presented a patient admitted to our out-patient clinic with diffuse skeletal pain after three consecutive administration of alendronate. CONCLUSION: We conclude that patients with DISEASE can report pain, and bisphosphonate-related pain should also be considered before ascribing this complaint to DISEASE. | NO-RELATIONSHIP |
| Diffuse skeletal pain after administration of alendronate. BACKGROUND: DISEASE is caused by bone resorption in excess of bone formation, and CHEMICAL, are used to inhibit bone resorption. Alendronate, a biphosphonate, is effective for both the treatment and prevention of DISEASE in postmenopausal women. Side effects are relatively few and prominently gastrointestinal. Musculoskeletal pain may be an important side effect in these patients. We presented a patient admitted to our out-patient clinic with diffuse skeletal pain after three consecutive administration of alendronate. CONCLUSION: We conclude that patients with DISEASE can report pain, and CHEMICAL-related pain should also be considered before ascribing this complaint to DISEASE. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to CHEMICAL on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. CHEMICAL was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible CHEMICAL-induced acute DISEASE and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | CHEMICAL-INDUCED-DISEASE |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized DISEASE and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, CHEMICAL, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose CHEMICAL in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose CHEMICAL assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated DISEASE shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and CHEMICAL 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. CHEMICAL serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to CHEMICAL therapy and were not reassessed. DISCUSSION: CHEMICAL was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose CHEMICAL may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | CHEMICAL-INDUCED-DISEASE |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to CHEMICAL. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of DISEASE on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of CHEMICAL-sensitive Staphylococcus aureus (MSSA) DISEASE with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA DISEASE on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing DISEASE. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA DISEASE with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated DISEASE shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/CHEMICAL. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus DISEASE. OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA DISEASE treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected DISEASE and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. CHEMICAL kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed DISEASE is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum CHEMICAL 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) DISEASE. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/CHEMICAL. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) DISEASE. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) DISEASE with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, CHEMICAL, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA DISEASE on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing DISEASE. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA DISEASE with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of CHEMICAL-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of DISEASE on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/CHEMICAL. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed DISEASE (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated DISEASE shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to CHEMICAL. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated DISEASE shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and CHEMICAL/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus DISEASE. OBJECTIVE: To report a case of CHEMICAL-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA DISEASE treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected DISEASE and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed DISEASE is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with CHEMICAL, levofloxacin, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of DISEASE on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of CHEMICAL-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed DISEASE (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized DISEASE and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and CHEMICAL/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of CHEMICAL-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated DISEASE shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose CHEMICAL in suspected Staphylococcus aureus DISEASE. OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA DISEASE treated with high-dose CHEMICAL assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized weakness and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/tazobactam. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and CHEMICAL 9 mg/kg daily was initiated for suspected DISEASE and was continued until the patient's death on day 16. CHEMICAL serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to CHEMICAL therapy and were not reassessed. DISCUSSION: CHEMICAL was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose CHEMICAL may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed DISEASE is warranted. | NO-RELATIONSHIP |
| Cerebrospinal fluid penetration of high-dose daptomycin in suspected Staphylococcus aureus meningitis. OBJECTIVE: To report a case of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia with suspected MSSA meningitis treated with high-dose daptomycin assessed with concurrent serum and cerebrospinal fluid (CSF) concentrations. CASE SUMMARY: A 54-year-old male presented to the emergency department with generalized DISEASE and presumed health-care-associated pneumonia shown on chest radiograph. Treatment was empirically initiated with vancomycin, levofloxacin, and piperacillin/CHEMICAL. Blood cultures revealed S. aureus susceptible to oxacillin. Empiric antibiotic treatment was narrowed to nafcillin on day 4. On day 8, the patient developed acute renal failure (serum creatinine 1.9 mg/dL, increased from 1.2 mg/dL the previous day and 0.8 mg/dL on admission). The patient's Glasgow Coma Score was 3, with normal findings shown on computed tomography scan of the head 72 hours following an episode of cardiac arrest on day 10. The patient experienced relapsing MSSA bacteremia on day 9, increasing the suspicion for a central nervous system (CNS) infection. Nafcillin was discontinued and daptomycin 9 mg/kg daily was initiated for suspected meningitis and was continued until the patient's death on day 16. Daptomycin serum and CSF trough concentrations were 11.21 ug/mL and 0.52 ug/mL, respectively, prior to the third dose. Lumbar puncture results were inconclusive and no further blood cultures were positive for MSSA. Creatine kinase levels were normal prior to daptomycin therapy and were not reassessed. DISCUSSION: Daptomycin was initiated in our patient secondary to possible nafcillin-induced acute interstitial nephritis and relapsing bacteremia. At a dose of 9 mg/kg, resultant penetration of 5% was higher than in previous reports, more consistent with inflamed meninges. CONCLUSIONS: High-dose daptomycin may be an alternative option for MSSA bacteremia with or without a CNS source in patients who have failed or cannot tolerate standard therapy. Further clinical evaluation in patients with confirmed meningitis is warranted. | NO-RELATIONSHIP |
| The role of nitric oxide in DISEASE induced by CHEMICAL in rats. CHEMICAL is an organochloride pesticide and scabicide. It evokes DISEASE mainly trough the blockage of GABA(A) receptors. Nitric oxide (NO), gaseous neurotransmitter, has contradictor role in epileptogenesis due to opposite effects of L-arginine, precursor of NO syntheses (NOS), and L-NAME (NOS inhibitor) observed in different epilepsy models. The aim of the current study was to determine the effects of NO on the behavioral and EEG characteristics of CHEMICAL-induced epilepsy in male Wistar albino rats. The administration of L-arginine (600, 800 and 1000 mg/kg, i.p.) in dose-dependent manner significantly increased DISEASE incidence and severity and shortened latency time to first DISEASE elicited by lower CHEMICAL dose (4 mg/kg, i.p.). On the contrary, pretreatment with L-NAME (500, 700 and 900 mg/kg, i.p.) decreased DISEASE incidence and severity and prolonged latency time to DISEASE following injection with a DISEASE dose of CHEMICAL (8 mg/kg, i.p.). EEG analyses showed increase of number and duration of ictal periods in EEG of rats receiving l-arginine prior to CHEMICAL and decrease of this number in rats pretreated with L-NAME. These results support the conclusion that NO plays a role of endogenous convulsant in rat model of CHEMICAL DISEASE. | CHEMICAL-INDUCED-DISEASE |
| The role of nitric oxide in convulsions induced by lindane in rats. Lindane is an organochloride pesticide and scabicide. It evokes convulsions mainly trough the blockage of GABA(A) receptors. Nitric oxide (NO), gaseous neurotransmitter, has contradictor role in epileptogenesis due to opposite effects of CHEMICAL, precursor of NO syntheses (NOS), and L-NAME (NOS inhibitor) observed in different DISEASE models. The aim of the current study was to determine the effects of NO on the behavioral and EEG characteristics of lindane-induced DISEASE in male Wistar albino rats. The administration of CHEMICAL (600, 800 and 1000 mg/kg, i.p.) in dose-dependent manner significantly increased convulsion incidence and severity and shortened latency time to first convulsion elicited by lower lindane dose (4 mg/kg, i.p.). On the contrary, pretreatment with L-NAME (500, 700 and 900 mg/kg, i.p.) decreased convulsion incidence and severity and prolonged latency time to convulsion following injection with a convulsive dose of lindane (8 mg/kg, i.p.). EEG analyses showed increase of number and duration of ictal periods in EEG of rats receiving CHEMICAL prior to lindane and decrease of this number in rats pretreated with L-NAME. These results support the conclusion that NO plays a role of endogenous convulsant in rat model of lindane seizures. | NO-RELATIONSHIP |
| The role of CHEMICAL in convulsions induced by lindane in rats. Lindane is an organochloride pesticide and scabicide. It evokes convulsions mainly trough the blockage of GABA(A) receptors. CHEMICAL (CHEMICAL), gaseous neurotransmitter, has contradictor role in epileptogenesis due to opposite effects of L-arginine, precursor of CHEMICAL syntheses (NOS), and L-NAME (NOS inhibitor) observed in different DISEASE models. The aim of the current study was to determine the effects of CHEMICAL on the behavioral and EEG characteristics of lindane-induced DISEASE in male Wistar albino rats. The administration of L-arginine (600, 800 and 1000 mg/kg, i.p.) in dose-dependent manner significantly increased convulsion incidence and severity and shortened latency time to first convulsion elicited by lower lindane dose (4 mg/kg, i.p.). On the contrary, pretreatment with L-NAME (500, 700 and 900 mg/kg, i.p.) decreased convulsion incidence and severity and prolonged latency time to convulsion following injection with a convulsive dose of lindane (8 mg/kg, i.p.). EEG analyses showed increase of number and duration of ictal periods in EEG of rats receiving l-arginine prior to lindane and decrease of this number in rats pretreated with L-NAME. These results support the conclusion that CHEMICAL plays a role of endogenous convulsant in rat model of lindane seizures. | NO-RELATIONSHIP |
| The role of nitric oxide in convulsions induced by lindane in rats. Lindane is an organochloride pesticide and scabicide. It evokes convulsions mainly trough the blockage of GABA(A) receptors. Nitric oxide (NO), gaseous neurotransmitter, has contradictor role in epileptogenesis due to opposite effects of L-arginine, precursor of NO syntheses (NOS), and CHEMICAL (NOS inhibitor) observed in different DISEASE models. The aim of the current study was to determine the effects of NO on the behavioral and EEG characteristics of lindane-induced DISEASE in male Wistar albino rats. The administration of L-arginine (600, 800 and 1000 mg/kg, i.p.) in dose-dependent manner significantly increased convulsion incidence and severity and shortened latency time to first convulsion elicited by lower lindane dose (4 mg/kg, i.p.). On the contrary, pretreatment with CHEMICAL (500, 700 and 900 mg/kg, i.p.) decreased convulsion incidence and severity and prolonged latency time to convulsion following injection with a convulsive dose of lindane (8 mg/kg, i.p.). EEG analyses showed increase of number and duration of ictal periods in EEG of rats receiving l-arginine prior to lindane and decrease of this number in rats pretreated with CHEMICAL. These results support the conclusion that NO plays a role of endogenous convulsant in rat model of lindane seizures. | NO-RELATIONSHIP |
| The role of nitric oxide in convulsions induced by lindane in rats. Lindane is an organochloride pesticide and scabicide. It evokes convulsions mainly trough the blockage of CHEMICAL(A) receptors. Nitric oxide (NO), gaseous neurotransmitter, has contradictor role in epileptogenesis due to opposite effects of L-arginine, precursor of NO syntheses (NOS), and L-NAME (NOS inhibitor) observed in different DISEASE models. The aim of the current study was to determine the effects of NO on the behavioral and EEG characteristics of lindane-induced DISEASE in male Wistar albino rats. The administration of L-arginine (600, 800 and 1000 mg/kg, i.p.) in dose-dependent manner significantly increased convulsion incidence and severity and shortened latency time to first convulsion elicited by lower lindane dose (4 mg/kg, i.p.). On the contrary, pretreatment with L-NAME (500, 700 and 900 mg/kg, i.p.) decreased convulsion incidence and severity and prolonged latency time to convulsion following injection with a convulsive dose of lindane (8 mg/kg, i.p.). EEG analyses showed increase of number and duration of ictal periods in EEG of rats receiving l-arginine prior to lindane and decrease of this number in rats pretreated with L-NAME. These results support the conclusion that NO plays a role of endogenous convulsant in rat model of lindane seizures. | NO-RELATIONSHIP |
| Long-term oral galactose treatment prevents cognitive deficits in male Wistar rats treated intracerebroventricularly with streptozotocin. Basic and clinical research has demonstrated that dementia of sporadic DISEASE (sAD) type is associated with dysfunction of the insulin-receptor (IR) system followed by decreased CHEMICAL transport via CHEMICAL transporter GLUT4 and decreased CHEMICAL metabolism in brain cells. An alternative source of energy is d-galactose (the C-4-epimer of CHEMICAL) which is transported into the brain by insulin-independent GLUT3 transporter where it might be metabolized to CHEMICAL via the Leloir pathway. Exclusively parenteral daily injections of galactose induce memory deterioration in rodents and are used to generate animal aging model, but the effects of oral galactose treatment on cognitive functions have never been tested. We have investigated the effects of continuous daily oral galactose (200 mg/kg/day) treatment on cognitive deficits in streptozotocin-induced (STZ-icv) rat model of sAD, tested by Morris Water Maze and Passive Avoidance test, respectively. One month of oral galactose treatment initiated immediately after the STZ-icv administration, successfully prevented development of the STZ-icv-induced cognitive deficits. Beneficial effect of oral galactose was independent of the rat age and of the galactose dose ranging from 100 to 300 mg/kg/day. Additionally, oral galactose administration led to the appearance of galactose in the blood. The increase of galactose concentration in the cerebrospinal fluid was several times lower after oral than after parenteral administration of the same galactose dose. Oral galactose exposure might have beneficial effects on learning and memory ability and could be worth investigating for improvement of cognitive deficits associated with glucose hypometabolism in DISEASE. | NO-RELATIONSHIP |
| Long-term oral galactose treatment prevents cognitive deficits in male Wistar rats treated intracerebroventricularly with CHEMICAL. Basic and clinical research has demonstrated that dementia of sporadic DISEASE (sAD) type is associated with dysfunction of the insulin-receptor (IR) system followed by decreased glucose transport via glucose transporter GLUT4 and decreased glucose metabolism in brain cells. An alternative source of energy is d-galactose (the C-4-epimer of d-glucose) which is transported into the brain by insulin-independent GLUT3 transporter where it might be metabolized to glucose via the Leloir pathway. Exclusively parenteral daily injections of galactose induce memory deterioration in rodents and are used to generate animal aging model, but the effects of oral galactose treatment on cognitive functions have never been tested. We have investigated the effects of continuous daily oral galactose (200 mg/kg/day) treatment on cognitive deficits in CHEMICAL-induced (CHEMICAL-icv) rat model of sAD, tested by Morris Water Maze and Passive Avoidance test, respectively. One month of oral galactose treatment initiated immediately after the CHEMICAL-icv administration, successfully prevented development of the CHEMICAL-icv-induced cognitive deficits. Beneficial effect of oral galactose was independent of the rat age and of the galactose dose ranging from 100 to 300 mg/kg/day. Additionally, oral galactose administration led to the appearance of galactose in the blood. The increase of galactose concentration in the cerebrospinal fluid was several times lower after oral than after parenteral administration of the same galactose dose. Oral galactose exposure might have beneficial effects on learning and memory ability and could be worth investigating for improvement of cognitive deficits associated with glucose hypometabolism in DISEASE. | NO-RELATIONSHIP |
| Long-term oral galactose treatment prevents DISEASE in male Wistar rats treated intracerebroventricularly with CHEMICAL. Basic and clinical research has demonstrated that dementia of sporadic Alzheimer's disease (sAD) type is associated with dysfunction of the insulin-receptor (IR) system followed by decreased glucose transport via glucose transporter GLUT4 and decreased glucose metabolism in brain cells. An alternative source of energy is d-galactose (the C-4-epimer of d-glucose) which is transported into the brain by insulin-independent GLUT3 transporter where it might be metabolized to glucose via the Leloir pathway. Exclusively parenteral daily injections of galactose induce memory deterioration in rodents and are used to generate animal aging model, but the effects of oral galactose treatment on cognitive functions have never been tested. We have investigated the effects of continuous daily oral galactose (200 mg/kg/day) treatment on DISEASE in CHEMICAL-induced (CHEMICAL-icv) rat model of sAD, tested by Morris Water Maze and Passive Avoidance test, respectively. One month of oral galactose treatment initiated immediately after the CHEMICAL-icv administration, successfully prevented development of the CHEMICAL-icv-induced DISEASE. Beneficial effect of oral galactose was independent of the rat age and of the galactose dose ranging from 100 to 300 mg/kg/day. Additionally, oral galactose administration led to the appearance of galactose in the blood. The increase of galactose concentration in the cerebrospinal fluid was several times lower after oral than after parenteral administration of the same galactose dose. Oral galactose exposure might have beneficial effects on learning and memory ability and could be worth investigating for improvement of DISEASE associated with glucose hypometabolism in AD. | CHEMICAL-INDUCED-DISEASE |
| Long-term oral CHEMICAL treatment prevents DISEASE in male Wistar rats treated intracerebroventricularly with streptozotocin. Basic and clinical research has demonstrated that dementia of sporadic Alzheimer's disease (sAD) type is associated with dysfunction of the insulin-receptor (IR) system followed by decreased glucose transport via glucose transporter GLUT4 and decreased glucose metabolism in brain cells. An alternative source of energy is CHEMICAL (the C-4-epimer of d-glucose) which is transported into the brain by insulin-independent GLUT3 transporter where it might be metabolized to glucose via the Leloir pathway. Exclusively parenteral daily injections of CHEMICAL induce memory deterioration in rodents and are used to generate animal aging model, but the effects of oral CHEMICAL treatment on cognitive functions have never been tested. We have investigated the effects of continuous daily oral CHEMICAL (200 mg/kg/day) treatment on DISEASE in streptozotocin-induced (STZ-icv) rat model of sAD, tested by Morris Water Maze and Passive Avoidance test, respectively. One month of oral CHEMICAL treatment initiated immediately after the STZ-icv administration, successfully prevented development of the STZ-icv-induced DISEASE. Beneficial effect of oral CHEMICAL was independent of the rat age and of the CHEMICAL dose ranging from 100 to 300 mg/kg/day. Additionally, oral CHEMICAL administration led to the appearance of CHEMICAL in the blood. The increase of CHEMICAL concentration in the cerebrospinal fluid was several times lower after oral than after parenteral administration of the same CHEMICAL dose. Oral CHEMICAL exposure might have beneficial effects on learning and memory ability and could be worth investigating for improvement of DISEASE associated with glucose hypometabolism in AD. | NO-RELATIONSHIP |
| Androgen antagonistic effect of estramustine phosphate (EMP) metabolites on wild-type and mutated androgen receptor. Estramustine phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. Estramustine phosphate is metabolically activated in vivo, and its metabolites, estramustine, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of estramustine phosphate and its metabolites, estramustine, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, bicalutamide, and CHEMICAL, to the mutated androgen receptor (m-AR) in LNCaP cells and to the wild-type androgen receptor in wild-type GENE cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, bicalutamide and CHEMICAL, binding of estramustine phosphate metabolites to the androgen receptor was observed. The EC50 values (in microM) were: estramustine phosphate, > 10; estramustine, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; bicalutamide, 4.920 +/- 0.361; and CHEMICAL, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to bicalutamide, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (PSA) expression, an AR-target gene, by estramustine and bicalutamide was accompanied by the blockade of the mutated androgen receptor. Exposure of LNCaP cells to estramustine for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner. The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of estramustine, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of CHEMICAL to m-GENE in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that CHEMICAL acted as an agonist of the m-AR. Our data indicate that estramustine phosphate metabolites perform as androgen antagonists of GENE, an additional mechanism involved in the therapeutic effect of estramustine phosphate in patients with prostate cancer. | INHIBITOR |
| Androgen antagonistic effect of estramustine phosphate (EMP) metabolites on wild-type and mutated GENE. Estramustine phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. Estramustine phosphate is metabolically activated in vivo, and its metabolites, estramustine, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of estramustine phosphate and its metabolites, estramustine, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, CHEMICAL, and hydroxyflutamide, to the mutated GENE (m-AR) in LNCaP cells and to the wild-type GENE in wild-type AR cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, CHEMICAL and hydroxyflutamide, binding of estramustine phosphate metabolites to the GENE was observed. The EC50 values (in microM) were: estramustine phosphate, > 10; estramustine, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; CHEMICAL, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to CHEMICAL, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (PSA) expression, an AR-target gene, by estramustine and CHEMICAL was accompanied by the blockade of the mutated GENE. Exposure of LNCaP cells to estramustine for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner. The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of estramustine, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR. Our data indicate that estramustine phosphate metabolites perform as androgen antagonists of AR, an additional mechanism involved in the therapeutic effect of estramustine phosphate in patients with prostate cancer. | DIRECT-REGULATOR |
| Androgen antagonistic effect of estramustine phosphate (EMP) metabolites on wild-type and mutated GENE. Estramustine phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. Estramustine phosphate is metabolically activated in vivo, and its metabolites, estramustine, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of estramustine phosphate and its metabolites, estramustine, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, bicalutamide, and CHEMICAL, to the mutated GENE (m-AR) in LNCaP cells and to the wild-type GENE in wild-type AR cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, bicalutamide and CHEMICAL, binding of estramustine phosphate metabolites to the GENE was observed. The EC50 values (in microM) were: estramustine phosphate, > 10; estramustine, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; bicalutamide, 4.920 +/- 0.361; and CHEMICAL, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to bicalutamide, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (PSA) expression, an AR-target gene, by estramustine and bicalutamide was accompanied by the blockade of the mutated GENE. Exposure of LNCaP cells to estramustine for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner. The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of estramustine, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of CHEMICAL to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that CHEMICAL acted as an agonist of the m-AR. Our data indicate that estramustine phosphate metabolites perform as androgen antagonists of AR, an additional mechanism involved in the therapeutic effect of estramustine phosphate in patients with prostate cancer. | DIRECT-REGULATOR |
| Androgen antagonistic effect of CHEMICAL (EMP) metabolites on wild-type and mutated GENE. CHEMICAL is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. CHEMICAL is metabolically activated in vivo, and its metabolites, estramustine, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of CHEMICAL and its metabolites, estramustine, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, bicalutamide, and hydroxyflutamide, to the mutated GENE (m-AR) in LNCaP cells and to the wild-type GENE in wild-type AR cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, bicalutamide and hydroxyflutamide, binding of CHEMICAL metabolites to the GENE was observed. The EC50 values (in microM) were: CHEMICAL, > 10; estramustine, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; bicalutamide, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to bicalutamide, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (PSA) expression, an AR-target gene, by estramustine and bicalutamide was accompanied by the blockade of the mutated GENE. Exposure of LNCaP cells to estramustine for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner. The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of estramustine, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR. Our data indicate that CHEMICAL metabolites perform as androgen antagonists of AR, an additional mechanism involved in the therapeutic effect of CHEMICAL in patients with prostate cancer. | DIRECT-REGULATOR |
| Androgen antagonistic effect of estramustine phosphate (EMP) metabolites on wild-type and mutated androgen receptor. Estramustine phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. Estramustine phosphate is metabolically activated in vivo, and its metabolites, estramustine, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of estramustine phosphate and its metabolites, estramustine, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, bicalutamide, and CHEMICAL, to the mutated androgen receptor (m-AR) in LNCaP cells and to the wild-type androgen receptor in wild-type AR cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, bicalutamide and CHEMICAL, binding of estramustine phosphate metabolites to the androgen receptor was observed. The EC50 values (in microM) were: estramustine phosphate, > 10; estramustine, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; bicalutamide, 4.920 +/- 0.361; and CHEMICAL, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to bicalutamide, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (PSA) expression, an AR-target gene, by estramustine and bicalutamide was accompanied by the blockade of the mutated androgen receptor. Exposure of LNCaP cells to estramustine for 24 hr caused transcriptional inhibition of GENE in a concentration-dependent manner. The levels of GENE mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of estramustine, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of CHEMICAL to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of GENE expression, suggesting that CHEMICAL acted as an agonist of the m-AR. Our data indicate that estramustine phosphate metabolites perform as androgen antagonists of AR, an additional mechanism involved in the therapeutic effect of estramustine phosphate in patients with prostate cancer. | INHIBITOR |
| Androgen antagonistic effect of CHEMICAL phosphate (EMP) metabolites on wild-type and mutated androgen receptor. CHEMICAL phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. CHEMICAL phosphate is metabolically activated in vivo, and its metabolites, CHEMICAL, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of CHEMICAL phosphate and its metabolites, CHEMICAL, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, bicalutamide, and hydroxyflutamide, to the mutated androgen receptor (m-AR) in LNCaP cells and to the wild-type androgen receptor in wild-type AR cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, bicalutamide and hydroxyflutamide, binding of CHEMICAL phosphate metabolites to the androgen receptor was observed. The EC50 values (in microM) were: CHEMICAL phosphate, > 10; CHEMICAL, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; bicalutamide, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to bicalutamide, CHEMICAL could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of GENE (PSA) expression, an AR-target gene, by CHEMICAL and bicalutamide was accompanied by the blockade of the mutated androgen receptor. Exposure of LNCaP cells to CHEMICAL for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner. The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of CHEMICAL, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR. Our data indicate that CHEMICAL phosphate metabolites perform as androgen antagonists of AR, an additional mechanism involved in the therapeutic effect of CHEMICAL phosphate in patients with prostate cancer. | INDIRECT-DOWNREGULATOR |
| Androgen antagonistic effect of CHEMICAL phosphate (EMP) metabolites on wild-type and mutated androgen receptor. CHEMICAL phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. CHEMICAL phosphate is metabolically activated in vivo, and its metabolites, CHEMICAL, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of CHEMICAL phosphate and its metabolites, CHEMICAL, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, bicalutamide, and hydroxyflutamide, to the mutated androgen receptor (m-AR) in LNCaP cells and to the wild-type androgen receptor in wild-type AR cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, bicalutamide and hydroxyflutamide, binding of CHEMICAL phosphate metabolites to the androgen receptor was observed. The EC50 values (in microM) were: CHEMICAL phosphate, > 10; CHEMICAL, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; bicalutamide, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to bicalutamide, CHEMICAL could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (GENE) expression, an AR-target gene, by CHEMICAL and bicalutamide was accompanied by the blockade of the mutated androgen receptor. Exposure of LNCaP cells to CHEMICAL for 24 hr caused transcriptional inhibition of GENE in a concentration-dependent manner. The levels of GENE mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of CHEMICAL, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of GENE expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR. Our data indicate that CHEMICAL phosphate metabolites perform as androgen antagonists of AR, an additional mechanism involved in the therapeutic effect of CHEMICAL phosphate in patients with prostate cancer. | INDIRECT-DOWNREGULATOR |
| Androgen antagonistic effect of CHEMICAL phosphate (EMP) metabolites on wild-type and mutated androgen receptor. CHEMICAL phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. CHEMICAL phosphate is metabolically activated in vivo, and its metabolites, CHEMICAL, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of CHEMICAL phosphate and its metabolites, CHEMICAL, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, bicalutamide, and hydroxyflutamide, to the mutated androgen receptor (m-AR) in LNCaP cells and to the wild-type androgen receptor in wild-type GENE cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, bicalutamide and hydroxyflutamide, binding of CHEMICAL phosphate metabolites to the androgen receptor was observed. The EC50 values (in microM) were: CHEMICAL phosphate, > 10; CHEMICAL, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; bicalutamide, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to bicalutamide, CHEMICAL could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (PSA) expression, an GENE-target gene, by CHEMICAL and bicalutamide was accompanied by the blockade of the mutated androgen receptor. Exposure of LNCaP cells to CHEMICAL for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner. The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of CHEMICAL, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR. Our data indicate that CHEMICAL phosphate metabolites perform as androgen antagonists of GENE, an additional mechanism involved in the therapeutic effect of CHEMICAL phosphate in patients with prostate cancer. | REGULATOR |
| Androgen antagonistic effect of estramustine phosphate (EMP) metabolites on wild-type and mutated androgen receptor. Estramustine phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. Estramustine phosphate is metabolically activated in vivo, and its metabolites, estramustine, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of estramustine phosphate and its metabolites, estramustine, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, CHEMICAL, and hydroxyflutamide, to the mutated androgen receptor (m-AR) in LNCaP cells and to the wild-type androgen receptor in wild-type AR cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, CHEMICAL and hydroxyflutamide, binding of estramustine phosphate metabolites to the androgen receptor was observed. The EC50 values (in microM) were: estramustine phosphate, > 10; estramustine, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; CHEMICAL, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to CHEMICAL, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of GENE (PSA) expression, an AR-target gene, by estramustine and CHEMICAL was accompanied by the blockade of the mutated androgen receptor. Exposure of LNCaP cells to estramustine for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner. The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of estramustine, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR. Our data indicate that estramustine phosphate metabolites perform as androgen antagonists of AR, an additional mechanism involved in the therapeutic effect of estramustine phosphate in patients with prostate cancer. | GENE-CHEMICAL |
| Androgen antagonistic effect of estramustine phosphate (EMP) metabolites on wild-type and mutated androgen receptor. Estramustine phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. Estramustine phosphate is metabolically activated in vivo, and its metabolites, estramustine, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of estramustine phosphate and its metabolites, estramustine, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, CHEMICAL, and hydroxyflutamide, to the mutated androgen receptor (m-AR) in LNCaP cells and to the wild-type androgen receptor in wild-type AR cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, CHEMICAL and hydroxyflutamide, binding of estramustine phosphate metabolites to the androgen receptor was observed. The EC50 values (in microM) were: estramustine phosphate, > 10; estramustine, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; CHEMICAL, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to CHEMICAL, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (GENE) expression, an AR-target gene, by estramustine and CHEMICAL was accompanied by the blockade of the mutated androgen receptor. Exposure of LNCaP cells to estramustine for 24 hr caused transcriptional inhibition of GENE in a concentration-dependent manner. The levels of GENE mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of estramustine, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of GENE expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR. Our data indicate that estramustine phosphate metabolites perform as androgen antagonists of AR, an additional mechanism involved in the therapeutic effect of estramustine phosphate in patients with prostate cancer. | GENE-CHEMICAL |
| Androgen antagonistic effect of estramustine phosphate (EMP) metabolites on wild-type and mutated androgen receptor. Estramustine phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. Estramustine phosphate is metabolically activated in vivo, and its metabolites, estramustine, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of estramustine phosphate and its metabolites, estramustine, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, CHEMICAL, and hydroxyflutamide, to the mutated androgen receptor (m-AR) in LNCaP cells and to the wild-type androgen receptor in wild-type GENE cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, CHEMICAL and hydroxyflutamide, binding of estramustine phosphate metabolites to the androgen receptor was observed. The EC50 values (in microM) were: estramustine phosphate, > 10; estramustine, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; CHEMICAL, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to CHEMICAL, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (PSA) expression, an GENE-target gene, by estramustine and CHEMICAL was accompanied by the blockade of the mutated androgen receptor. Exposure of LNCaP cells to estramustine for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner. The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of estramustine, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR. Our data indicate that estramustine phosphate metabolites perform as androgen antagonists of GENE, an additional mechanism involved in the therapeutic effect of estramustine phosphate in patients with prostate cancer. | REGULATOR |
| Androgen antagonistic effect of CHEMICAL phosphate (EMP) metabolites on wild-type and mutated GENE. CHEMICAL phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. CHEMICAL phosphate is metabolically activated in vivo, and its metabolites, CHEMICAL, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of CHEMICAL phosphate and its metabolites, CHEMICAL, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, bicalutamide, and hydroxyflutamide, to the mutated GENE (m-AR) in LNCaP cells and to the wild-type GENE in wild-type AR cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, bicalutamide and hydroxyflutamide, binding of CHEMICAL phosphate metabolites to the GENE was observed. The EC50 values (in microM) were: CHEMICAL phosphate, > 10; CHEMICAL, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; bicalutamide, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to bicalutamide, CHEMICAL could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (PSA) expression, an AR-target gene, by CHEMICAL and bicalutamide was accompanied by the blockade of the mutated GENE. Exposure of LNCaP cells to CHEMICAL for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner. The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of CHEMICAL, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR. Our data indicate that CHEMICAL phosphate metabolites perform as androgen antagonists of AR, an additional mechanism involved in the therapeutic effect of CHEMICAL phosphate in patients with prostate cancer. | DIRECT-REGULATOR |
| Androgen antagonistic effect of CHEMICAL (EMP) metabolites on wild-type and mutated androgen receptor. CHEMICAL is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. CHEMICAL is metabolically activated in vivo, and its metabolites, estramustine, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of CHEMICAL and its metabolites, estramustine, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, bicalutamide, and hydroxyflutamide, to the mutated androgen receptor (m-AR) in LNCaP cells and to the wild-type androgen receptor in wild-type GENE cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, bicalutamide and hydroxyflutamide, binding of CHEMICAL metabolites to the androgen receptor was observed. The EC50 values (in microM) were: CHEMICAL, > 10; estramustine, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; bicalutamide, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to bicalutamide, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (PSA) expression, an AR-target gene, by estramustine and bicalutamide was accompanied by the blockade of the mutated androgen receptor. Exposure of LNCaP cells to estramustine for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner. The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of estramustine, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR. Our data indicate that CHEMICAL metabolites perform as androgen antagonists of GENE, an additional mechanism involved in the therapeutic effect of CHEMICAL in patients with prostate cancer. | DIRECT-REGULATOR |
| CHEMICAL antagonistic effect of estramustine phosphate (EMP) metabolites on wild-type and mutated CHEMICAL receptor. Estramustine phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. Estramustine phosphate is metabolically activated in vivo, and its metabolites, estramustine, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of estramustine phosphate and its metabolites, estramustine, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, bicalutamide, and hydroxyflutamide, to the mutated CHEMICAL receptor (m-AR) in LNCaP cells and to the wild-type CHEMICAL receptor in wild-type GENE cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, bicalutamide and hydroxyflutamide, binding of estramustine phosphate metabolites to the CHEMICAL receptor was observed. The EC50 values (in microM) were: estramustine phosphate, > 10; estramustine, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; bicalutamide, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to bicalutamide, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (PSA) expression, an AR-target gene, by estramustine and bicalutamide was accompanied by the blockade of the mutated CHEMICAL receptor. Exposure of LNCaP cells to estramustine for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner. The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of estramustine, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR. Our data indicate that estramustine phosphate metabolites perform as CHEMICAL antagonists of GENE, an additional mechanism involved in the therapeutic effect of estramustine phosphate in patients with prostate cancer. | DIRECT-REGULATOR |
| CHEMICAL antagonistic effect of estramustine phosphate (EMP) metabolites on wild-type and mutated GENE. Estramustine phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. Estramustine phosphate is metabolically activated in vivo, and its metabolites, estramustine, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of estramustine phosphate and its metabolites, estramustine, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, bicalutamide, and hydroxyflutamide, to the mutated GENE (m-AR) in LNCaP cells and to the wild-type GENE in wild-type AR cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, bicalutamide and hydroxyflutamide, binding of estramustine phosphate metabolites to the GENE was observed. The EC50 values (in microM) were: estramustine phosphate, > 10; estramustine, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; bicalutamide, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to bicalutamide, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (PSA) expression, an AR-target gene, by estramustine and bicalutamide was accompanied by the blockade of the mutated GENE. Exposure of LNCaP cells to estramustine for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner. The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of estramustine, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR. Our data indicate that estramustine phosphate metabolites perform as androgen antagonists of AR, an additional mechanism involved in the therapeutic effect of estramustine phosphate in patients with prostate cancer. | PART-OF |
| Androgen antagonistic effect of estramustine phosphate (CHEMICAL) metabolites on wild-type and mutated GENE. Estramustine phosphate is used frequently, alone or in combination with other antitumor agents, for the treatment of hormone-refractory prostate cancer. Estramustine phosphate is metabolically activated in vivo, and its metabolites, estramustine, estromustine, estrone, and beta-estradiol inhibit the assembly of microtubules [for review see: Kreis W, In: Concepts, Mechanisms, and New Targets for Chemotherapy (Ed. Muggia FM), pp. 163-184. Kluwer Academic Publishers, Boston, 1995]. We investigated, by displacement of [3H]methyltrienolone in the presence of 2.5 mM of triamcinolone acetonide, the binding of estramustine phosphate and its metabolites, estramustine, estromustine, estrone, and beta-estradiol, as well as other antiandrogen agents including alpha-estradiol, bicalutamide, and hydroxyflutamide, to the mutated GENE (m-AR) in LNCaP cells and to the wild-type GENE in wild-type AR cDNA expression plasmid (w-pAR0) cDNA-transfected HeLa cells. Analogous to the antiandrogens, bicalutamide and hydroxyflutamide, binding of estramustine phosphate metabolites to the GENE was observed. The EC50 values (in microM) were: estramustine phosphate, > 10; estramustine, 3.129 +/- 0.312; estromustine; 2.612 +/- 0.584; estrone, 0.800 +/- 0.090; alpha-estradiol, 1.051 +/- 0.096; beta-estradiol, 0.523 +/- 0.028; bicalutamide, 4.920 +/- 0.361; and hydroxyflutamide, 0.254 +/- 0.012. The transactivation assay demonstrated that, analogous to bicalutamide, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells. In contrast, a strong induction of the reporter activity by dihydrotestosterone was observed. Down-regulation of prostate-specific antigen (PSA) expression, an AR-target gene, by estramustine and bicalutamide was accompanied by the blockade of the mutated GENE. Exposure of LNCaP cells to estramustine for 24 hr caused transcriptional inhibition of PSA in a concentration-dependent manner. The levels of PSA mRNA decreased 56 and 90% when LNCaP cells were treated with 5 and 10 microM of estramustine, respectively (IC50 = 10.97 +/- 1.68 microM). Binding of hydroxyflutamide to m-AR in LNCaP cells resulted in a concentration-dependent stimulation of PSA expression, suggesting that hydroxyflutamide acted as an agonist of the m-AR. Our data indicate that estramustine phosphate metabolites perform as androgen antagonists of AR, an additional mechanism involved in the therapeutic effect of estramustine phosphate in patients with prostate cancer. | REGULATOR |
| Static Laue diffraction studies on acetylcholinesterase. Acetylcholinesterase (AChE) is one of nature's fastest enzymes, despite the fact that its three-dimensional structure reveals its active site to be deeply sequestered within the molecule. This raises questions with respect to traffic of substrate to, and products from, the active site, which may be investigated by time-resolved crystallography. In order to address one aspect of the feasibility of performing time-resolved studies on AChE, a data set has been collected using the Laue technique on a trigonal crystal of GENE soaked with the reversible inhibitor CHEMICAL, using a total X-ray exposure time of 24 ms. Electron-density maps obtained from the Laue data, which are of surprisingly good quality compared with similar maps from monochromatic data, show essentially the same features. They clearly reveal the bound ligand, as well as a structural change in the conformation of the active-site Ser200 induced upon binding. | INHIBITOR |
| Selective inhibition of cyclooxygenase 2 spares renal function and prostaglandin synthesis in cirrhotic rats with ascites. BACKGROUND & AIMS: The critical role of cyclooxygenase (COX) products in maintenance of renal function in cirrhosis with ascites discourages the use of nonsteroidal anti-inflammatory drugs in this disease. The recent development of selective GENE inhibitors opens new avenues for the use of these compounds in decompensated cirrhosis. The current study evaluates the effects of a selective GENE inhibitor (CHEMICAL) on renal function in cirrhotic rats with ascites. METHODS: In protocol 1, urine volume, urinary excretion of sodium and prostaglandins, glomerular filtration rate, and renal plasma flow were measured before and after administration of CHEMICAL (n = 12) or ketorolac (n = 10) to rats with cirrhosis. Protocol 2 was aimed at assessing the effects of COX inhibitors on renal water metabolism in 28 cirrhotic rats. RESULTS: Administration of CHEMICAL to cirrhotic animals did not produce significant renal effects, whereas administration of the nonselective COX-1/COX-2 inhibitor, ketorolac, resulted in a marked reduction in urine volume, urinary excretion of prostaglandins, and glomerular filtration rate and in a significant impairment in renal water metabolism. CONCLUSIONS: These findings indicate that CHEMICAL does not significantly impair renal function in rats with cirrhosis. | INHIBITOR |
| Selective inhibition of cyclooxygenase 2 spares renal function and prostaglandin synthesis in cirrhotic rats with ascites. BACKGROUND & AIMS: The critical role of cyclooxygenase (COX) products in maintenance of renal function in cirrhosis with ascites discourages the use of nonsteroidal anti-inflammatory drugs in this disease. The recent development of selective COX-2 inhibitors opens new avenues for the use of these compounds in decompensated cirrhosis. The current study evaluates the effects of a selective COX-2 inhibitor (SC-236) on renal function in cirrhotic rats with ascites. METHODS: In protocol 1, urine volume, urinary excretion of sodium and prostaglandins, glomerular filtration rate, and renal plasma flow were measured before and after administration of SC-236 (n = 12) or CHEMICAL (n = 10) to rats with cirrhosis. Protocol 2 was aimed at assessing the effects of COX inhibitors on renal water metabolism in 28 cirrhotic rats. RESULTS: Administration of SC-236 to cirrhotic animals did not produce significant renal effects, whereas administration of the nonselective GENE/COX-2 inhibitor, CHEMICAL, resulted in a marked reduction in urine volume, urinary excretion of prostaglandins, and glomerular filtration rate and in a significant impairment in renal water metabolism. CONCLUSIONS: These findings indicate that SC-236 does not significantly impair renal function in rats with cirrhosis. | INHIBITOR |
| Selective inhibition of cyclooxygenase 2 spares renal function and prostaglandin synthesis in cirrhotic rats with ascites. BACKGROUND & AIMS: The critical role of cyclooxygenase (COX) products in maintenance of renal function in cirrhosis with ascites discourages the use of nonsteroidal anti-inflammatory drugs in this disease. The recent development of selective GENE inhibitors opens new avenues for the use of these compounds in decompensated cirrhosis. The current study evaluates the effects of a selective GENE inhibitor (SC-236) on renal function in cirrhotic rats with ascites. METHODS: In protocol 1, urine volume, urinary excretion of sodium and prostaglandins, glomerular filtration rate, and renal plasma flow were measured before and after administration of SC-236 (n = 12) or CHEMICAL (n = 10) to rats with cirrhosis. Protocol 2 was aimed at assessing the effects of COX inhibitors on renal water metabolism in 28 cirrhotic rats. RESULTS: Administration of SC-236 to cirrhotic animals did not produce significant renal effects, whereas administration of the nonselective COX-1/GENE inhibitor, CHEMICAL, resulted in a marked reduction in urine volume, urinary excretion of prostaglandins, and glomerular filtration rate and in a significant impairment in renal water metabolism. CONCLUSIONS: These findings indicate that SC-236 does not significantly impair renal function in rats with cirrhosis. | INHIBITOR |
| Selective inhibition of GENE spares renal function and CHEMICAL synthesis in cirrhotic rats with ascites. BACKGROUND & AIMS: The critical role of cyclooxygenase (COX) products in maintenance of renal function in cirrhosis with ascites discourages the use of nonsteroidal anti-inflammatory drugs in this disease. The recent development of selective COX-2 inhibitors opens new avenues for the use of these compounds in decompensated cirrhosis. The current study evaluates the effects of a selective COX-2 inhibitor (SC-236) on renal function in cirrhotic rats with ascites. METHODS: In protocol 1, urine volume, urinary excretion of sodium and prostaglandins, glomerular filtration rate, and renal plasma flow were measured before and after administration of SC-236 (n = 12) or ketorolac (n = 10) to rats with cirrhosis. Protocol 2 was aimed at assessing the effects of COX inhibitors on renal water metabolism in 28 cirrhotic rats. RESULTS: Administration of SC-236 to cirrhotic animals did not produce significant renal effects, whereas administration of the nonselective COX-1/COX-2 inhibitor, ketorolac, resulted in a marked reduction in urine volume, urinary excretion of prostaglandins, and glomerular filtration rate and in a significant impairment in renal water metabolism. CONCLUSIONS: These findings indicate that SC-236 does not significantly impair renal function in rats with cirrhosis. | PRODUCT-OF |
| Selective inhibition of cyclooxygenase 2 spares renal function and prostaglandin synthesis in cirrhotic rats with ascites. BACKGROUND & AIMS: The critical role of cyclooxygenase (COX) products in maintenance of renal function in cirrhosis with ascites discourages the use of nonsteroidal anti-inflammatory drugs in this disease. The recent development of selective COX-2 inhibitors opens new avenues for the use of these compounds in decompensated cirrhosis. The current study evaluates the effects of a selective COX-2 inhibitor (SC-236) on renal function in cirrhotic rats with ascites. METHODS: In protocol 1, urine volume, urinary excretion of sodium and CHEMICAL, glomerular filtration rate, and renal plasma flow were measured before and after administration of SC-236 (n = 12) or ketorolac (n = 10) to rats with cirrhosis. Protocol 2 was aimed at assessing the effects of COX inhibitors on renal water metabolism in 28 cirrhotic rats. RESULTS: Administration of SC-236 to cirrhotic animals did not produce significant renal effects, whereas administration of the nonselective GENE/COX-2 inhibitor, ketorolac, resulted in a marked reduction in urine volume, urinary excretion of CHEMICAL, and glomerular filtration rate and in a significant impairment in renal water metabolism. CONCLUSIONS: These findings indicate that SC-236 does not significantly impair renal function in rats with cirrhosis. | PRODUCT-OF |
| Selective inhibition of cyclooxygenase 2 spares renal function and prostaglandin synthesis in cirrhotic rats with ascites. BACKGROUND & AIMS: The critical role of cyclooxygenase (COX) products in maintenance of renal function in cirrhosis with ascites discourages the use of nonsteroidal anti-inflammatory drugs in this disease. The recent development of selective GENE inhibitors opens new avenues for the use of these compounds in decompensated cirrhosis. The current study evaluates the effects of a selective GENE inhibitor (SC-236) on renal function in cirrhotic rats with ascites. METHODS: In protocol 1, urine volume, urinary excretion of sodium and CHEMICAL, glomerular filtration rate, and renal plasma flow were measured before and after administration of SC-236 (n = 12) or ketorolac (n = 10) to rats with cirrhosis. Protocol 2 was aimed at assessing the effects of COX inhibitors on renal water metabolism in 28 cirrhotic rats. RESULTS: Administration of SC-236 to cirrhotic animals did not produce significant renal effects, whereas administration of the nonselective COX-1/GENE inhibitor, ketorolac, resulted in a marked reduction in urine volume, urinary excretion of CHEMICAL, and glomerular filtration rate and in a significant impairment in renal water metabolism. CONCLUSIONS: These findings indicate that SC-236 does not significantly impair renal function in rats with cirrhosis. | PRODUCT-OF |
| Inhibition of cPLA2 translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M CHEMICAL in the presence of 10 pg/ml human recombinant interleukin-5 (rhIL-5) and activated with formyl-met-leu-phe (FMLP) + cytochalasin B (CB). At 24 h, stimulated LTC4 secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC4 secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M CHEMICAL (p < 0.003). FMLP/CB-stimulated translocation of cPLA2 to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by CHEMICAL. By contrast, membrane expression of GENE, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M CHEMICAL, and inhibition of LTC4 synthesis was reversed by exogenous arachidonic acid (AA). We find that CHEMICAL causes a decrease in stimulated eosinophil secretion of LTC4 that is regulated by phospholipase A2 (PLA2). Inhibition of LTC4 synthesis precedes the global cytotoxic effects of CHEMICAL as indicated by the simultaneous upregulation of GENE expression. Inhibited stimulated secretion corresponds to inhibited translocation of cPLA2 to the nuclear envelope during cellular activation. | INDIRECT-UPREGULATOR |
| Inhibition of GENE translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M FP in the presence of 10 pg/ml human recombinant interleukin-5 (rhIL-5) and activated with formyl-met-leu-phe (FMLP) + cytochalasin B (CB). At 24 h, stimulated LTC4 secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC4 secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M FP (p < 0.003). CHEMICAL/CB-stimulated translocation of GENE to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by FP. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M FP, and inhibition of LTC4 synthesis was reversed by exogenous arachidonic acid (AA). We find that FP causes a decrease in stimulated eosinophil secretion of LTC4 that is regulated by phospholipase A2 (PLA2). Inhibition of LTC4 synthesis precedes the global cytotoxic effects of FP as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of GENE to the nuclear envelope during cellular activation. | GENE-CHEMICAL |
| Inhibition of GENE translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M FP in the presence of 10 pg/ml human recombinant interleukin-5 (rhIL-5) and activated with formyl-met-leu-phe (FMLP) + cytochalasin B (CB). At 24 h, stimulated LTC4 secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC4 secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M FP (p < 0.003). FMLP/CHEMICAL-stimulated translocation of GENE to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by FP. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M FP, and inhibition of LTC4 synthesis was reversed by exogenous arachidonic acid (AA). We find that FP causes a decrease in stimulated eosinophil secretion of LTC4 that is regulated by phospholipase A2 (PLA2). Inhibition of LTC4 synthesis precedes the global cytotoxic effects of FP as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of GENE to the nuclear envelope during cellular activation. | GENE-CHEMICAL |
| Inhibition of cPLA2 translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M CHEMICAL in the presence of 10 pg/ml GENE (rhIL-5) and activated with formyl-met-leu-phe (FMLP) + cytochalasin B (CB). At 24 h, stimulated LTC4 secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC4 secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M CHEMICAL (p < 0.003). FMLP/CB-stimulated translocation of cPLA2 to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by CHEMICAL. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M CHEMICAL, and inhibition of LTC4 synthesis was reversed by exogenous arachidonic acid (AA). We find that CHEMICAL causes a decrease in stimulated eosinophil secretion of LTC4 that is regulated by phospholipase A2 (PLA2). Inhibition of LTC4 synthesis precedes the global cytotoxic effects of CHEMICAL as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of cPLA2 to the nuclear envelope during cellular activation. | GENE-CHEMICAL |
| Inhibition of cPLA2 translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M CHEMICAL in the presence of 10 pg/ml human recombinant interleukin-5 (GENE) and activated with formyl-met-leu-phe (FMLP) + cytochalasin B (CB). At 24 h, stimulated LTC4 secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC4 secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M CHEMICAL (p < 0.003). FMLP/CB-stimulated translocation of cPLA2 to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by CHEMICAL. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M CHEMICAL, and inhibition of LTC4 synthesis was reversed by exogenous arachidonic acid (AA). We find that CHEMICAL causes a decrease in stimulated eosinophil secretion of LTC4 that is regulated by phospholipase A2 (PLA2). Inhibition of LTC4 synthesis precedes the global cytotoxic effects of CHEMICAL as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of cPLA2 to the nuclear envelope during cellular activation. | GENE-CHEMICAL |
| Inhibition of cPLA2 translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M FP in the presence of 10 pg/ml GENE (rhIL-5) and activated with CHEMICAL (FMLP) + cytochalasin B (CB). At 24 h, stimulated LTC4 secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC4 secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M FP (p < 0.003). FMLP/CB-stimulated translocation of cPLA2 to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by FP. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M FP, and inhibition of LTC4 synthesis was reversed by exogenous arachidonic acid (AA). We find that FP causes a decrease in stimulated eosinophil secretion of LTC4 that is regulated by phospholipase A2 (PLA2). Inhibition of LTC4 synthesis precedes the global cytotoxic effects of FP as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of cPLA2 to the nuclear envelope during cellular activation. | ACTIVATOR |
| Inhibition of cPLA2 translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M FP in the presence of 10 pg/ml human recombinant interleukin-5 (GENE) and activated with CHEMICAL (FMLP) + cytochalasin B (CB). At 24 h, stimulated LTC4 secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC4 secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M FP (p < 0.003). FMLP/CB-stimulated translocation of cPLA2 to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by FP. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M FP, and inhibition of LTC4 synthesis was reversed by exogenous arachidonic acid (AA). We find that FP causes a decrease in stimulated eosinophil secretion of LTC4 that is regulated by phospholipase A2 (PLA2). Inhibition of LTC4 synthesis precedes the global cytotoxic effects of FP as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of cPLA2 to the nuclear envelope during cellular activation. | ACTIVATOR |
| Inhibition of cPLA2 translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M FP in the presence of 10 pg/ml GENE (rhIL-5) and activated with formyl-met-leu-phe (CHEMICAL) + cytochalasin B (CB). At 24 h, stimulated LTC4 secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC4 secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M FP (p < 0.003). FMLP/CB-stimulated translocation of cPLA2 to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by FP. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M FP, and inhibition of LTC4 synthesis was reversed by exogenous arachidonic acid (AA). We find that FP causes a decrease in stimulated eosinophil secretion of LTC4 that is regulated by phospholipase A2 (PLA2). Inhibition of LTC4 synthesis precedes the global cytotoxic effects of FP as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of cPLA2 to the nuclear envelope during cellular activation. | ACTIVATOR |
| Inhibition of cPLA2 translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M FP in the presence of 10 pg/ml human recombinant interleukin-5 (GENE) and activated with formyl-met-leu-phe (CHEMICAL) + cytochalasin B (CB). At 24 h, stimulated LTC4 secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC4 secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M FP (p < 0.003). FMLP/CB-stimulated translocation of cPLA2 to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by FP. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M FP, and inhibition of LTC4 synthesis was reversed by exogenous arachidonic acid (AA). We find that FP causes a decrease in stimulated eosinophil secretion of LTC4 that is regulated by phospholipase A2 (PLA2). Inhibition of LTC4 synthesis precedes the global cytotoxic effects of FP as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of cPLA2 to the nuclear envelope during cellular activation. | ACTIVATOR |
| Inhibition of cPLA2 translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M FP in the presence of 10 pg/ml GENE (rhIL-5) and activated with formyl-met-leu-phe (FMLP) + CHEMICAL (CB). At 24 h, stimulated LTC4 secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC4 secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M FP (p < 0.003). FMLP/CB-stimulated translocation of cPLA2 to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by FP. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M FP, and inhibition of LTC4 synthesis was reversed by exogenous arachidonic acid (AA). We find that FP causes a decrease in stimulated eosinophil secretion of LTC4 that is regulated by phospholipase A2 (PLA2). Inhibition of LTC4 synthesis precedes the global cytotoxic effects of FP as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of cPLA2 to the nuclear envelope during cellular activation. | ACTIVATOR |
| Inhibition of cPLA2 translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M FP in the presence of 10 pg/ml human recombinant interleukin-5 (GENE) and activated with formyl-met-leu-phe (FMLP) + CHEMICAL (CB). At 24 h, stimulated LTC4 secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC4 secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M FP (p < 0.003). FMLP/CB-stimulated translocation of cPLA2 to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by FP. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M FP, and inhibition of LTC4 synthesis was reversed by exogenous arachidonic acid (AA). We find that FP causes a decrease in stimulated eosinophil secretion of LTC4 that is regulated by phospholipase A2 (PLA2). Inhibition of LTC4 synthesis precedes the global cytotoxic effects of FP as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of cPLA2 to the nuclear envelope during cellular activation. | ACTIVATOR |
| Inhibition of cPLA2 translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M FP in the presence of 10 pg/ml GENE (rhIL-5) and activated with formyl-met-leu-phe (FMLP) + cytochalasin B (CHEMICAL). At 24 h, stimulated LTC4 secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC4 secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M FP (p < 0.003). FMLP/CB-stimulated translocation of cPLA2 to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by FP. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M FP, and inhibition of LTC4 synthesis was reversed by exogenous arachidonic acid (AA). We find that FP causes a decrease in stimulated eosinophil secretion of LTC4 that is regulated by phospholipase A2 (PLA2). Inhibition of LTC4 synthesis precedes the global cytotoxic effects of FP as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of cPLA2 to the nuclear envelope during cellular activation. | ACTIVATOR |
| Inhibition of cPLA2 translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M FP in the presence of 10 pg/ml human recombinant interleukin-5 (GENE) and activated with formyl-met-leu-phe (FMLP) + cytochalasin B (CHEMICAL). At 24 h, stimulated LTC4 secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC4 secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M FP (p < 0.003). FMLP/CB-stimulated translocation of cPLA2 to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by FP. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M FP, and inhibition of LTC4 synthesis was reversed by exogenous arachidonic acid (AA). We find that FP causes a decrease in stimulated eosinophil secretion of LTC4 that is regulated by phospholipase A2 (PLA2). Inhibition of LTC4 synthesis precedes the global cytotoxic effects of FP as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of cPLA2 to the nuclear envelope during cellular activation. | ACTIVATOR |
| Inhibition of GENE translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M CHEMICAL in the presence of 10 pg/ml human recombinant interleukin-5 (rhIL-5) and activated with formyl-met-leu-phe (FMLP) + cytochalasin B (CB). At 24 h, stimulated LTC4 secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC4 secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M CHEMICAL (p < 0.003). FMLP/CB-stimulated translocation of GENE to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by CHEMICAL. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M CHEMICAL, and inhibition of LTC4 synthesis was reversed by exogenous arachidonic acid (AA). We find that CHEMICAL causes a decrease in stimulated eosinophil secretion of LTC4 that is regulated by phospholipase A2 (PLA2). Inhibition of LTC4 synthesis precedes the global cytotoxic effects of CHEMICAL as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of GENE to the nuclear envelope during cellular activation. | INDIRECT-DOWNREGULATOR |
| Inhibition of GENE translocation and leukotriene C4 secretion by CHEMICAL in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, CHEMICAL (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M FP in the presence of 10 pg/ml human recombinant interleukin-5 (rhIL-5) and activated with formyl-met-leu-phe (FMLP) + cytochalasin B (CB). At 24 h, stimulated LTC4 secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC4 secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M FP (p < 0.003). FMLP/CB-stimulated translocation of GENE to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by FP. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M FP, and inhibition of LTC4 synthesis was reversed by exogenous arachidonic acid (AA). We find that FP causes a decrease in stimulated eosinophil secretion of LTC4 that is regulated by phospholipase A2 (PLA2). Inhibition of LTC4 synthesis precedes the global cytotoxic effects of FP as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of GENE to the nuclear envelope during cellular activation. | INHIBITOR |
| Inhibition of cPLA2 translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic GENE (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M CHEMICAL in the presence of 10 pg/ml human recombinant interleukin-5 (rhIL-5) and activated with formyl-met-leu-phe (FMLP) + cytochalasin B (CB). At 24 h, stimulated LTC4 secretion from eosinophils was unchanged; however, when corrected for cell viability, LTC4 secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M CHEMICAL (p < 0.003). FMLP/CB-stimulated translocation of cPLA2 to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by CHEMICAL. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M CHEMICAL, and inhibition of LTC4 synthesis was reversed by exogenous arachidonic acid (AA). We find that CHEMICAL causes a decrease in stimulated eosinophil secretion of LTC4 that is regulated by GENE (PLA2). Inhibition of LTC4 synthesis precedes the global cytotoxic effects of CHEMICAL as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of cPLA2 to the nuclear envelope during cellular activation. | REGULATOR |
| Inhibition of cPLA2 translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic GENE (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M FP in the presence of 10 pg/ml human recombinant interleukin-5 (rhIL-5) and activated with formyl-met-leu-phe (FMLP) + cytochalasin B (CB). At 24 h, stimulated CHEMICAL secretion from eosinophils was unchanged; however, when corrected for cell viability, CHEMICAL secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M FP (p < 0.003). FMLP/CB-stimulated translocation of cPLA2 to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by FP. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M FP, and inhibition of CHEMICAL synthesis was reversed by exogenous arachidonic acid (AA). We find that FP causes a decrease in stimulated eosinophil secretion of CHEMICAL that is regulated by GENE (PLA2). Inhibition of CHEMICAL synthesis precedes the global cytotoxic effects of FP as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of cPLA2 to the nuclear envelope during cellular activation. | PRODUCT-OF |
| Inhibition of cPLA2 translocation and leukotriene C4 secretion by fluticasone propionate in exogenously activated human eosinophils. We examined the effect of the highly lipophilic corticosteroid, fluticasone propionate (FP), in causing (1) inhibition of nuclear translocation of cytosolic phospholipase A2 (cPLA2), and (2) blockade of leukotriene C4 (LTC4) synthesis in isolated human eosinophils in vitro. Eosinophils were isolated from peripheral blood, treated with either buffer or 10(-)10 M to 10(-)6 M FP in the presence of 10 pg/ml human recombinant interleukin-5 (rhIL-5) and activated with formyl-met-leu-phe (FMLP) + cytochalasin B (CB). At 24 h, stimulated CHEMICAL secretion from eosinophils was unchanged; however, when corrected for cell viability, CHEMICAL secretion decreased from 1,429 +/- 327 pg/10(6) cells to 762 +/- 113 pg/10(6) cells for eosinophils treated for 48 h with >/= 10(-)8 M FP (p < 0.003). FMLP/CB-stimulated translocation of cPLA2 to the nuclear envelope assessed by specific immunohistochemical staining also was blocked by FP. By contrast, membrane expression of annexin-1, which was not minimal at 30 min, was substantial at 48 h for eosinophils treated with > 10(-)10 M FP, and inhibition of CHEMICAL synthesis was reversed by exogenous arachidonic acid (AA). We find that FP causes a decrease in stimulated eosinophil secretion of CHEMICAL that is regulated by phospholipase A2 (GENE). Inhibition of CHEMICAL synthesis precedes the global cytotoxic effects of FP as indicated by the simultaneous upregulation of annexin-1 expression. Inhibited stimulated secretion corresponds to inhibited translocation of cPLA2 to the nuclear envelope during cellular activation. | PRODUCT-OF |
| Desipramine treatment decreases CHEMICAL binding and GENE mRNA in SK-N-SHSY5Y cells. The antidepressant desipramine has been shown to decrease synaptic membrane concentrations of the norepinephrine re-uptake transporter (NET) in vivo and in vitro, on both an acute and a chronic basis. The possible contribution of decreased NET synthesis to the chronic downregulation of the NETs has not been definitively established. In this study, we treated SK-N-SHSY5Y cells with 100 nM desipramine for 24 or 72 h, and measured CHEMICAL binding (as an estimate of NETs) and NET mRNA by quantitative reverse transcription polymerase chain reaction. Similar to what has been reported previously, membrane CHEMICAL binding was significantly decreased at both 24 and 72 h (approximately 50% at both time points). However, a significant decrease (64 +/- 8% of paired control) of NET mRNA was observed only at the 72-h time point. We conclude that decreased NET synthesis may contribute to the chronic, but not acute, effect of desipramine to downregulate the NET. | DIRECT-REGULATOR |
| CHEMICAL treatment decreases 3H-nisoxetine binding and norepinephrine transporter mRNA in SK-N-SHSY5Y cells. The antidepressant CHEMICAL has been shown to decrease synaptic membrane concentrations of the norepinephrine re-uptake transporter (NET) in vivo and in vitro, on both an acute and a chronic basis. The possible contribution of decreased GENE synthesis to the chronic downregulation of the NETs has not been definitively established. In this study, we treated SK-N-SHSY5Y cells with 100 nM CHEMICAL for 24 or 72 h, and measured 3H-nisoxetine binding (as an estimate of NETs) and GENE mRNA by quantitative reverse transcription polymerase chain reaction. Similar to what has been reported previously, membrane 3H-nisoxetine binding was significantly decreased at both 24 and 72 h (approximately 50% at both time points). However, a significant decrease (64 +/- 8% of paired control) of GENE mRNA was observed only at the 72-h time point. We conclude that decreased GENE synthesis may contribute to the chronic, but not acute, effect of CHEMICAL to downregulate the GENE. | INDIRECT-DOWNREGULATOR |
| CHEMICAL treatment decreases 3H-nisoxetine binding and norepinephrine transporter mRNA in SK-N-SHSY5Y cells. The antidepressant CHEMICAL has been shown to decrease synaptic membrane concentrations of the GENE (NET) in vivo and in vitro, on both an acute and a chronic basis. The possible contribution of decreased NET synthesis to the chronic downregulation of the NETs has not been definitively established. In this study, we treated SK-N-SHSY5Y cells with 100 nM CHEMICAL for 24 or 72 h, and measured 3H-nisoxetine binding (as an estimate of NETs) and NET mRNA by quantitative reverse transcription polymerase chain reaction. Similar to what has been reported previously, membrane 3H-nisoxetine binding was significantly decreased at both 24 and 72 h (approximately 50% at both time points). However, a significant decrease (64 +/- 8% of paired control) of NET mRNA was observed only at the 72-h time point. We conclude that decreased NET synthesis may contribute to the chronic, but not acute, effect of CHEMICAL to downregulate the NET. | INDIRECT-DOWNREGULATOR |
| CHEMICAL treatment decreases 3H-nisoxetine binding and GENE mRNA in SK-N-SHSY5Y cells. The antidepressant desipramine has been shown to decrease synaptic membrane concentrations of the norepinephrine re-uptake transporter (NET) in vivo and in vitro, on both an acute and a chronic basis. The possible contribution of decreased NET synthesis to the chronic downregulation of the NETs has not been definitively established. In this study, we treated SK-N-SHSY5Y cells with 100 nM desipramine for 24 or 72 h, and measured 3H-nisoxetine binding (as an estimate of NETs) and NET mRNA by quantitative reverse transcription polymerase chain reaction. Similar to what has been reported previously, membrane 3H-nisoxetine binding was significantly decreased at both 24 and 72 h (approximately 50% at both time points). However, a significant decrease (64 +/- 8% of paired control) of NET mRNA was observed only at the 72-h time point. We conclude that decreased NET synthesis may contribute to the chronic, but not acute, effect of desipramine to downregulate the NET. | INDIRECT-DOWNREGULATOR |
| Inhibition of the human ether-a-go-go-related gene (HERG) CHEMICAL channel by cisapride: affinity for open and inactivated states. 1 Cisapride is a prokinetic agent which has been associated with QT prolongation, torsades de pointes and cardiac arrest. The cellular mechanism for these observations is high affinity blockade of IKr (encoded by HERG). 2 In a chronic transfection model using CHO-K1 cells, cisapride inhibited GENE tail currents after a step to +25 mV with similar potency at room and physiological temperatures (IC50 16. 4 nM at 20-22 degrees C and 23.6 nM at 37 degrees C). 3 Channel inhibition exhibited time-, voltage- and frequency-dependence. In an envelope of tails test, channel blockade increased from 27+/-8% after a 120 ms depolarizing step to 50+/-4% after a 1.0 s step. These findings suggested affinity for open and/or inactivated channel states. 4 Inactivation was significantly accelerated by cisapride in a concentration-dependent manner and there was a small (-7 mV) shift in the voltage dependence of steady state inactivation. 5 Channel blockade by cisapride was modulated by [K+]o, with a 26% reduction in the potency of channel blockade when [K+]o was increased from 1 to 10 mM. 6 In conclusion, GENE channel inhibition by cisapride exhibits features consistent with open and inactivated state binding and is sensitive to external CHEMICAL concentration. These features may have significant clinical implications with regard to the mechanism and treatment of cisapride-induced proarrhythmia. | REGULATOR |
| Inhibition of the GENE by CHEMICAL: affinity for open and inactivated states. 1 CHEMICAL is a prokinetic agent which has been associated with QT prolongation, torsades de pointes and cardiac arrest. The cellular mechanism for these observations is high affinity blockade of IKr (encoded by HERG). 2 In a chronic transfection model using CHO-K1 cells, CHEMICAL inhibited HERG tail currents after a step to +25 mV with similar potency at room and physiological temperatures (IC50 16. 4 nM at 20-22 degrees C and 23.6 nM at 37 degrees C). 3 Channel inhibition exhibited time-, voltage- and frequency-dependence. In an envelope of tails test, channel blockade increased from 27+/-8% after a 120 ms depolarizing step to 50+/-4% after a 1.0 s step. These findings suggested affinity for open and/or inactivated channel states. 4 Inactivation was significantly accelerated by CHEMICAL in a concentration-dependent manner and there was a small (-7 mV) shift in the voltage dependence of steady state inactivation. 5 Channel blockade by CHEMICAL was modulated by [K+]o, with a 26% reduction in the potency of channel blockade when [K+]o was increased from 1 to 10 mM. 6 In conclusion, HERG channel inhibition by CHEMICAL exhibits features consistent with open and inactivated state binding and is sensitive to external potassium concentration. These features may have significant clinical implications with regard to the mechanism and treatment of cisapride-induced proarrhythmia. | INHIBITOR |
| Inhibition of the human ether-a-go-go-related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states. 1 CHEMICAL is a prokinetic agent which has been associated with QT prolongation, torsades de pointes and cardiac arrest. The cellular mechanism for these observations is high affinity blockade of IKr (encoded by HERG). 2 In a chronic transfection model using CHO-K1 cells, CHEMICAL inhibited GENE tail currents after a step to +25 mV with similar potency at room and physiological temperatures (IC50 16. 4 nM at 20-22 degrees C and 23.6 nM at 37 degrees C). 3 Channel inhibition exhibited time-, voltage- and frequency-dependence. In an envelope of tails test, channel blockade increased from 27+/-8% after a 120 ms depolarizing step to 50+/-4% after a 1.0 s step. These findings suggested affinity for open and/or inactivated channel states. 4 Inactivation was significantly accelerated by CHEMICAL in a concentration-dependent manner and there was a small (-7 mV) shift in the voltage dependence of steady state inactivation. 5 Channel blockade by CHEMICAL was modulated by [K+]o, with a 26% reduction in the potency of channel blockade when [K+]o was increased from 1 to 10 mM. 6 In conclusion, GENE channel inhibition by CHEMICAL exhibits features consistent with open and inactivated state binding and is sensitive to external potassium concentration. These features may have significant clinical implications with regard to the mechanism and treatment of cisapride-induced proarrhythmia. | INHIBITOR |
| Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine: inhibition of dorsal raphe cell firing and the role of 5-HT1A receptor activation. CHEMICAL is a novel antipsychotic agent which binds with high affinity to 5-HT1A receptors (Ki = 3.4 nM), in addition to GENE, 5-HT2, and D2 sites. While it is an antagonist at these latter receptors, ziprasidone behaves as a 5-HT1A agonist in vitro in adenylate cyclase measurements. The goal of the present study was to examine the 5-HT1A properties of ziprasidone in vivo using as a marker of central 5-HT1A activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus. In anesthetized rats, ziprasidone dose-dependently slowed raphe unit activity (ED50 = 300 micrograms/kg i.v.) as did the atypical antipsychotics clozapine (ED50 = 250 micrograms/kg i.v.) and olanzapine (ED50 = 1000 micrograms/kg i.v.). Pretreatment with the 5-HT1A antagonist WAY-100,635 (10 micrograms/kg i.v.) prevented the ziprasidone-induced inhibition; the same dose of WAY-100,635 had little effect on the inhibition produced by clozapine and olanzapine. Because all three agents also bind to alpha 1 receptors, antagonists of which inhibit serotonin neuronal firing, this aspect of their pharmacology was assessed with desipramine (DMI), a NE re-uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity. DMI (5 mg/kg i.v.) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine. These profiles suggest a mechanism of action for each agent, 5-HT1A agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine. The 5-HT1A agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions. | DIRECT-REGULATOR |
| Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine: inhibition of dorsal raphe cell firing and the role of 5-HT1A receptor activation. CHEMICAL is a novel antipsychotic agent which binds with high affinity to 5-HT1A receptors (Ki = 3.4 nM), in addition to 5-HT1D, GENE, and D2 sites. While it is an antagonist at these latter receptors, ziprasidone behaves as a 5-HT1A agonist in vitro in adenylate cyclase measurements. The goal of the present study was to examine the 5-HT1A properties of ziprasidone in vivo using as a marker of central 5-HT1A activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus. In anesthetized rats, ziprasidone dose-dependently slowed raphe unit activity (ED50 = 300 micrograms/kg i.v.) as did the atypical antipsychotics clozapine (ED50 = 250 micrograms/kg i.v.) and olanzapine (ED50 = 1000 micrograms/kg i.v.). Pretreatment with the 5-HT1A antagonist WAY-100,635 (10 micrograms/kg i.v.) prevented the ziprasidone-induced inhibition; the same dose of WAY-100,635 had little effect on the inhibition produced by clozapine and olanzapine. Because all three agents also bind to alpha 1 receptors, antagonists of which inhibit serotonin neuronal firing, this aspect of their pharmacology was assessed with desipramine (DMI), a NE re-uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity. DMI (5 mg/kg i.v.) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine. These profiles suggest a mechanism of action for each agent, 5-HT1A agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine. The 5-HT1A agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions. | DIRECT-REGULATOR |
| Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine: inhibition of dorsal raphe cell firing and the role of 5-HT1A receptor activation. CHEMICAL is a novel antipsychotic agent which binds with high affinity to 5-HT1A receptors (Ki = 3.4 nM), in addition to 5-HT1D, 5-HT2, and GENE sites. While it is an antagonist at these latter receptors, ziprasidone behaves as a 5-HT1A agonist in vitro in adenylate cyclase measurements. The goal of the present study was to examine the 5-HT1A properties of ziprasidone in vivo using as a marker of central 5-HT1A activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus. In anesthetized rats, ziprasidone dose-dependently slowed raphe unit activity (ED50 = 300 micrograms/kg i.v.) as did the atypical antipsychotics clozapine (ED50 = 250 micrograms/kg i.v.) and olanzapine (ED50 = 1000 micrograms/kg i.v.). Pretreatment with the 5-HT1A antagonist WAY-100,635 (10 micrograms/kg i.v.) prevented the ziprasidone-induced inhibition; the same dose of WAY-100,635 had little effect on the inhibition produced by clozapine and olanzapine. Because all three agents also bind to alpha 1 receptors, antagonists of which inhibit serotonin neuronal firing, this aspect of their pharmacology was assessed with desipramine (DMI), a NE re-uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity. DMI (5 mg/kg i.v.) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine. These profiles suggest a mechanism of action for each agent, 5-HT1A agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine. The 5-HT1A agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions. | DIRECT-REGULATOR |
| Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine: inhibition of dorsal raphe cell firing and the role of 5-HT1A receptor activation. CHEMICAL is a novel antipsychotic agent which binds with high affinity to GENE (Ki = 3.4 nM), in addition to 5-HT1D, 5-HT2, and D2 sites. While it is an antagonist at these latter receptors, ziprasidone behaves as a 5-HT1A agonist in vitro in adenylate cyclase measurements. The goal of the present study was to examine the 5-HT1A properties of ziprasidone in vivo using as a marker of central 5-HT1A activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus. In anesthetized rats, ziprasidone dose-dependently slowed raphe unit activity (ED50 = 300 micrograms/kg i.v.) as did the atypical antipsychotics clozapine (ED50 = 250 micrograms/kg i.v.) and olanzapine (ED50 = 1000 micrograms/kg i.v.). Pretreatment with the 5-HT1A antagonist WAY-100,635 (10 micrograms/kg i.v.) prevented the ziprasidone-induced inhibition; the same dose of WAY-100,635 had little effect on the inhibition produced by clozapine and olanzapine. Because all three agents also bind to alpha 1 receptors, antagonists of which inhibit serotonin neuronal firing, this aspect of their pharmacology was assessed with desipramine (DMI), a NE re-uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity. DMI (5 mg/kg i.v.) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine. These profiles suggest a mechanism of action for each agent, 5-HT1A agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine. The 5-HT1A agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions. | DIRECT-REGULATOR |
| Comparison of the novel antipsychotic CHEMICAL with clozapine and olanzapine: inhibition of dorsal raphe cell firing and the role of GENE receptor activation. CHEMICAL is a novel antipsychotic agent which binds with high affinity to GENE receptors (Ki = 3.4 nM), in addition to 5-HT1D, 5-HT2, and D2 sites. While it is an antagonist at these latter receptors, CHEMICAL behaves as a GENE agonist in vitro in adenylate cyclase measurements. The goal of the present study was to examine the GENE properties of CHEMICAL in vivo using as a marker of central GENE activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus. In anesthetized rats, CHEMICAL dose-dependently slowed raphe unit activity (ED50 = 300 micrograms/kg i.v.) as did the atypical antipsychotics clozapine (ED50 = 250 micrograms/kg i.v.) and olanzapine (ED50 = 1000 micrograms/kg i.v.). Pretreatment with the GENE antagonist WAY-100,635 (10 micrograms/kg i.v.) prevented the ziprasidone-induced inhibition; the same dose of WAY-100,635 had little effect on the inhibition produced by clozapine and olanzapine. Because all three agents also bind to alpha 1 receptors, antagonists of which inhibit serotonin neuronal firing, this aspect of their pharmacology was assessed with desipramine (DMI), a NE re-uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity. DMI (5 mg/kg i.v.) failed to reverse the inhibitory effect of CHEMICAL but produced nearly complete reversal of that of clozapine and olanzapine. These profiles suggest a mechanism of action for each agent, GENE agonism for CHEMICAL and alpha 1 antagonism for clozapine and olanzapine. The GENE agonist activity reported here clearly distinguishes CHEMICAL from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions. | REGULATOR |
| Comparison of the novel antipsychotic ziprasidone with CHEMICAL and olanzapine: inhibition of dorsal raphe cell firing and the role of GENE receptor activation. Ziprasidone is a novel antipsychotic agent which binds with high affinity to GENE receptors (Ki = 3.4 nM), in addition to 5-HT1D, 5-HT2, and D2 sites. While it is an antagonist at these latter receptors, ziprasidone behaves as a GENE agonist in vitro in adenylate cyclase measurements. The goal of the present study was to examine the GENE properties of ziprasidone in vivo using as a marker of central GENE activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus. In anesthetized rats, ziprasidone dose-dependently slowed raphe unit activity (ED50 = 300 micrograms/kg i.v.) as did the atypical antipsychotics CHEMICAL (ED50 = 250 micrograms/kg i.v.) and olanzapine (ED50 = 1000 micrograms/kg i.v.). Pretreatment with the GENE antagonist WAY-100,635 (10 micrograms/kg i.v.) prevented the ziprasidone-induced inhibition; the same dose of WAY-100,635 had little effect on the inhibition produced by CHEMICAL and olanzapine. Because all three agents also bind to alpha 1 receptors, antagonists of which inhibit serotonin neuronal firing, this aspect of their pharmacology was assessed with desipramine (DMI), a NE re-uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity. DMI (5 mg/kg i.v.) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of CHEMICAL and olanzapine. These profiles suggest a mechanism of action for each agent, GENE agonism for ziprasidone and alpha 1 antagonism for CHEMICAL and olanzapine. The GENE agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions. | REGULATOR |
| Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine: inhibition of dorsal raphe cell firing and the role of GENE receptor activation. Ziprasidone is a novel antipsychotic agent which binds with high affinity to GENE receptors (Ki = 3.4 nM), in addition to 5-HT1D, 5-HT2, and D2 sites. While it is an antagonist at these latter receptors, ziprasidone behaves as a GENE agonist in vitro in adenylate cyclase measurements. The goal of the present study was to examine the GENE properties of ziprasidone in vivo using as a marker of central GENE activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus. In anesthetized rats, ziprasidone dose-dependently slowed raphe unit activity (ED50 = 300 micrograms/kg i.v.) as did the atypical antipsychotics clozapine (ED50 = 250 micrograms/kg i.v.) and CHEMICAL (ED50 = 1000 micrograms/kg i.v.). Pretreatment with the GENE antagonist WAY-100,635 (10 micrograms/kg i.v.) prevented the ziprasidone-induced inhibition; the same dose of WAY-100,635 had little effect on the inhibition produced by clozapine and CHEMICAL. Because all three agents also bind to alpha 1 receptors, antagonists of which inhibit serotonin neuronal firing, this aspect of their pharmacology was assessed with desipramine (DMI), a NE re-uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity. DMI (5 mg/kg i.v.) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and CHEMICAL. These profiles suggest a mechanism of action for each agent, GENE agonism for ziprasidone and alpha 1 antagonism for clozapine and CHEMICAL. The GENE agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions. | ACTIVATOR |
| Comparison of the novel antipsychotic CHEMICAL with clozapine and olanzapine: inhibition of dorsal raphe cell firing and the role of GENE activation. CHEMICAL is a novel antipsychotic agent which binds with high affinity to 5-HT1A receptors (Ki = 3.4 nM), in addition to 5-HT1D, 5-HT2, and D2 sites. While it is an antagonist at these latter receptors, CHEMICAL behaves as a 5-HT1A agonist in vitro in adenylate cyclase measurements. The goal of the present study was to examine the 5-HT1A properties of CHEMICAL in vivo using as a marker of central 5-HT1A activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus. In anesthetized rats, CHEMICAL dose-dependently slowed raphe unit activity (ED50 = 300 micrograms/kg i.v.) as did the atypical antipsychotics clozapine (ED50 = 250 micrograms/kg i.v.) and olanzapine (ED50 = 1000 micrograms/kg i.v.). Pretreatment with the 5-HT1A antagonist WAY-100,635 (10 micrograms/kg i.v.) prevented the ziprasidone-induced inhibition; the same dose of WAY-100,635 had little effect on the inhibition produced by clozapine and olanzapine. Because all three agents also bind to alpha 1 receptors, antagonists of which inhibit serotonin neuronal firing, this aspect of their pharmacology was assessed with desipramine (DMI), a NE re-uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity. DMI (5 mg/kg i.v.) failed to reverse the inhibitory effect of CHEMICAL but produced nearly complete reversal of that of clozapine and olanzapine. These profiles suggest a mechanism of action for each agent, 5-HT1A agonism for CHEMICAL and alpha 1 antagonism for clozapine and olanzapine. The 5-HT1A agonist activity reported here clearly distinguishes CHEMICAL from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions. | ACTIVATOR |
| Comparison of the novel antipsychotic ziprasidone with CHEMICAL and olanzapine: inhibition of dorsal raphe cell firing and the role of GENE activation. Ziprasidone is a novel antipsychotic agent which binds with high affinity to 5-HT1A receptors (Ki = 3.4 nM), in addition to 5-HT1D, 5-HT2, and D2 sites. While it is an antagonist at these latter receptors, ziprasidone behaves as a 5-HT1A agonist in vitro in adenylate cyclase measurements. The goal of the present study was to examine the 5-HT1A properties of ziprasidone in vivo using as a marker of central 5-HT1A activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus. In anesthetized rats, ziprasidone dose-dependently slowed raphe unit activity (ED50 = 300 micrograms/kg i.v.) as did the atypical antipsychotics CHEMICAL (ED50 = 250 micrograms/kg i.v.) and olanzapine (ED50 = 1000 micrograms/kg i.v.). Pretreatment with the 5-HT1A antagonist WAY-100,635 (10 micrograms/kg i.v.) prevented the ziprasidone-induced inhibition; the same dose of WAY-100,635 had little effect on the inhibition produced by CHEMICAL and olanzapine. Because all three agents also bind to alpha 1 receptors, antagonists of which inhibit serotonin neuronal firing, this aspect of their pharmacology was assessed with desipramine (DMI), a NE re-uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity. DMI (5 mg/kg i.v.) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of CHEMICAL and olanzapine. These profiles suggest a mechanism of action for each agent, 5-HT1A agonism for ziprasidone and alpha 1 antagonism for CHEMICAL and olanzapine. The 5-HT1A agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions. | ACTIVATOR |
| Comparison of the novel antipsychotic ziprasidone with clozapine and CHEMICAL: inhibition of dorsal raphe cell firing and the role of GENE activation. Ziprasidone is a novel antipsychotic agent which binds with high affinity to 5-HT1A receptors (Ki = 3.4 nM), in addition to 5-HT1D, 5-HT2, and D2 sites. While it is an antagonist at these latter receptors, ziprasidone behaves as a 5-HT1A agonist in vitro in adenylate cyclase measurements. The goal of the present study was to examine the 5-HT1A properties of ziprasidone in vivo using as a marker of central 5-HT1A activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus. In anesthetized rats, ziprasidone dose-dependently slowed raphe unit activity (ED50 = 300 micrograms/kg i.v.) as did the atypical antipsychotics clozapine (ED50 = 250 micrograms/kg i.v.) and CHEMICAL (ED50 = 1000 micrograms/kg i.v.). Pretreatment with the 5-HT1A antagonist WAY-100,635 (10 micrograms/kg i.v.) prevented the ziprasidone-induced inhibition; the same dose of WAY-100,635 had little effect on the inhibition produced by clozapine and CHEMICAL. Because all three agents also bind to alpha 1 receptors, antagonists of which inhibit serotonin neuronal firing, this aspect of their pharmacology was assessed with desipramine (DMI), a NE re-uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity. DMI (5 mg/kg i.v.) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and CHEMICAL. These profiles suggest a mechanism of action for each agent, 5-HT1A agonism for ziprasidone and alpha 1 antagonism for clozapine and CHEMICAL. The 5-HT1A agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions. | ACTIVATOR |
| Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine: inhibition of dorsal raphe cell firing and the role of GENE receptor activation. Ziprasidone is a novel antipsychotic agent which binds with high affinity to GENE receptors (Ki = 3.4 nM), in addition to 5-HT1D, 5-HT2, and D2 sites. While it is an antagonist at these latter receptors, ziprasidone behaves as a GENE agonist in vitro in adenylate cyclase measurements. The goal of the present study was to examine the GENE properties of ziprasidone in vivo using as a marker of central GENE activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus. In anesthetized rats, ziprasidone dose-dependently slowed raphe unit activity (ED50 = 300 micrograms/kg i.v.) as did the atypical antipsychotics clozapine (ED50 = 250 micrograms/kg i.v.) and olanzapine (ED50 = 1000 micrograms/kg i.v.). Pretreatment with the GENE antagonist CHEMICAL (10 micrograms/kg i.v.) prevented the ziprasidone-induced inhibition; the same dose of CHEMICAL had little effect on the inhibition produced by clozapine and olanzapine. Because all three agents also bind to alpha 1 receptors, antagonists of which inhibit serotonin neuronal firing, this aspect of their pharmacology was assessed with desipramine (DMI), a NE re-uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity. DMI (5 mg/kg i.v.) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine. These profiles suggest a mechanism of action for each agent, GENE agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine. The GENE agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions. | INHIBITOR |
| Reduction of oral ethanol self-administration in rats by monoamine oxidase inhibitors. Evidence for a role of dopamine and serotonin in the control of ethanol intake in animals suggests that monoamine oxidase (MAO) inhibitors, which increase the synaptic availability of serotonin and dopamine by blocking their metabolism, might have efficacy in the treatment of alcohol dependence. The aim of the present study was, therefore, to evaluate several GENE inhibitors for their capacity to affect ethanol self-administration in rats trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task. The nonselective and irreversible GENE inhibitors, CHEMICAL (3-10 mg/kg), tranylcypromine (1-3 mg/kg), and nialamide (30 mg/kg), decreased rates of responding maintained by ethanol reinforcement. The reversible MAO-A inhibitor, befloxatone (0.3-3 mg/kg), and the irreversible MAO-A inhibitor, clorgyline (10-30 mg/kg), also reduced ethanol self-administration. However, befloxatone-induced effects leveled off at a 50% decrease. The irreversible MAO-B inhibitors, pargyline (30 mg/kg) and l-deprenyl (3-10 mg/kg) also decreased responding maintained by ethanol reinforcement; these results are consistent with previous findings that both drugs decreased ethanol intake in mice. In conclusion, the present results showing that several GENE inhibitors decreased ethanol self-administration in rats are consistent with previous findings that synaptic levels of serotonin and dopamine play a critical role in the control of ethanol self-administration. | INHIBITOR |
| Reduction of oral ethanol self-administration in rats by monoamine oxidase inhibitors. Evidence for a role of dopamine and serotonin in the control of ethanol intake in animals suggests that monoamine oxidase (MAO) inhibitors, which increase the synaptic availability of serotonin and dopamine by blocking their metabolism, might have efficacy in the treatment of alcohol dependence. The aim of the present study was, therefore, to evaluate several GENE inhibitors for their capacity to affect ethanol self-administration in rats trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task. The nonselective and irreversible GENE inhibitors, phenelzine (3-10 mg/kg), CHEMICAL (1-3 mg/kg), and nialamide (30 mg/kg), decreased rates of responding maintained by ethanol reinforcement. The reversible MAO-A inhibitor, befloxatone (0.3-3 mg/kg), and the irreversible MAO-A inhibitor, clorgyline (10-30 mg/kg), also reduced ethanol self-administration. However, befloxatone-induced effects leveled off at a 50% decrease. The irreversible MAO-B inhibitors, pargyline (30 mg/kg) and l-deprenyl (3-10 mg/kg) also decreased responding maintained by ethanol reinforcement; these results are consistent with previous findings that both drugs decreased ethanol intake in mice. In conclusion, the present results showing that several GENE inhibitors decreased ethanol self-administration in rats are consistent with previous findings that synaptic levels of serotonin and dopamine play a critical role in the control of ethanol self-administration. | INHIBITOR |
| Reduction of oral ethanol self-administration in rats by monoamine oxidase inhibitors. Evidence for a role of dopamine and serotonin in the control of ethanol intake in animals suggests that monoamine oxidase (MAO) inhibitors, which increase the synaptic availability of serotonin and dopamine by blocking their metabolism, might have efficacy in the treatment of alcohol dependence. The aim of the present study was, therefore, to evaluate several GENE inhibitors for their capacity to affect ethanol self-administration in rats trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task. The nonselective and irreversible GENE inhibitors, phenelzine (3-10 mg/kg), tranylcypromine (1-3 mg/kg), and CHEMICAL (30 mg/kg), decreased rates of responding maintained by ethanol reinforcement. The reversible MAO-A inhibitor, befloxatone (0.3-3 mg/kg), and the irreversible MAO-A inhibitor, clorgyline (10-30 mg/kg), also reduced ethanol self-administration. However, befloxatone-induced effects leveled off at a 50% decrease. The irreversible MAO-B inhibitors, pargyline (30 mg/kg) and l-deprenyl (3-10 mg/kg) also decreased responding maintained by ethanol reinforcement; these results are consistent with previous findings that both drugs decreased ethanol intake in mice. In conclusion, the present results showing that several GENE inhibitors decreased ethanol self-administration in rats are consistent with previous findings that synaptic levels of serotonin and dopamine play a critical role in the control of ethanol self-administration. | INHIBITOR |
| Reduction of oral ethanol self-administration in rats by monoamine oxidase inhibitors. Evidence for a role of dopamine and serotonin in the control of ethanol intake in animals suggests that monoamine oxidase (MAO) inhibitors, which increase the synaptic availability of serotonin and dopamine by blocking their metabolism, might have efficacy in the treatment of alcohol dependence. The aim of the present study was, therefore, to evaluate several MAO inhibitors for their capacity to affect ethanol self-administration in rats trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task. The nonselective and irreversible MAO inhibitors, phenelzine (3-10 mg/kg), tranylcypromine (1-3 mg/kg), and nialamide (30 mg/kg), decreased rates of responding maintained by ethanol reinforcement. The reversible MAO-A inhibitor, befloxatone (0.3-3 mg/kg), and the irreversible MAO-A inhibitor, clorgyline (10-30 mg/kg), also reduced ethanol self-administration. However, befloxatone-induced effects leveled off at a 50% decrease. The irreversible GENE inhibitors, CHEMICAL (30 mg/kg) and l-deprenyl (3-10 mg/kg) also decreased responding maintained by ethanol reinforcement; these results are consistent with previous findings that both drugs decreased ethanol intake in mice. In conclusion, the present results showing that several MAO inhibitors decreased ethanol self-administration in rats are consistent with previous findings that synaptic levels of serotonin and dopamine play a critical role in the control of ethanol self-administration. | INHIBITOR |
| Reduction of oral ethanol self-administration in rats by monoamine oxidase inhibitors. Evidence for a role of dopamine and serotonin in the control of ethanol intake in animals suggests that monoamine oxidase (MAO) inhibitors, which increase the synaptic availability of serotonin and dopamine by blocking their metabolism, might have efficacy in the treatment of alcohol dependence. The aim of the present study was, therefore, to evaluate several MAO inhibitors for their capacity to affect ethanol self-administration in rats trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task. The nonselective and irreversible MAO inhibitors, phenelzine (3-10 mg/kg), tranylcypromine (1-3 mg/kg), and nialamide (30 mg/kg), decreased rates of responding maintained by ethanol reinforcement. The reversible GENE inhibitor, CHEMICAL (0.3-3 mg/kg), and the irreversible GENE inhibitor, clorgyline (10-30 mg/kg), also reduced ethanol self-administration. However, befloxatone-induced effects leveled off at a 50% decrease. The irreversible MAO-B inhibitors, pargyline (30 mg/kg) and l-deprenyl (3-10 mg/kg) also decreased responding maintained by ethanol reinforcement; these results are consistent with previous findings that both drugs decreased ethanol intake in mice. In conclusion, the present results showing that several MAO inhibitors decreased ethanol self-administration in rats are consistent with previous findings that synaptic levels of serotonin and dopamine play a critical role in the control of ethanol self-administration. | INHIBITOR |
| Reduction of oral ethanol self-administration in rats by monoamine oxidase inhibitors. Evidence for a role of dopamine and serotonin in the control of ethanol intake in animals suggests that monoamine oxidase (MAO) inhibitors, which increase the synaptic availability of serotonin and dopamine by blocking their metabolism, might have efficacy in the treatment of alcohol dependence. The aim of the present study was, therefore, to evaluate several MAO inhibitors for their capacity to affect ethanol self-administration in rats trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task. The nonselective and irreversible MAO inhibitors, phenelzine (3-10 mg/kg), tranylcypromine (1-3 mg/kg), and nialamide (30 mg/kg), decreased rates of responding maintained by ethanol reinforcement. The reversible GENE inhibitor, befloxatone (0.3-3 mg/kg), and the irreversible GENE inhibitor, CHEMICAL (10-30 mg/kg), also reduced ethanol self-administration. However, befloxatone-induced effects leveled off at a 50% decrease. The irreversible MAO-B inhibitors, pargyline (30 mg/kg) and l-deprenyl (3-10 mg/kg) also decreased responding maintained by ethanol reinforcement; these results are consistent with previous findings that both drugs decreased ethanol intake in mice. In conclusion, the present results showing that several MAO inhibitors decreased ethanol self-administration in rats are consistent with previous findings that synaptic levels of serotonin and dopamine play a critical role in the control of ethanol self-administration. | INHIBITOR |
| Reduction of oral ethanol self-administration in rats by monoamine oxidase inhibitors. Evidence for a role of dopamine and serotonin in the control of ethanol intake in animals suggests that monoamine oxidase (MAO) inhibitors, which increase the synaptic availability of serotonin and dopamine by blocking their metabolism, might have efficacy in the treatment of alcohol dependence. The aim of the present study was, therefore, to evaluate several MAO inhibitors for their capacity to affect ethanol self-administration in rats trained to self-administer ethanol (10% v/v) orally in a free-choice two-lever operant task. The nonselective and irreversible MAO inhibitors, phenelzine (3-10 mg/kg), tranylcypromine (1-3 mg/kg), and nialamide (30 mg/kg), decreased rates of responding maintained by ethanol reinforcement. The reversible MAO-A inhibitor, befloxatone (0.3-3 mg/kg), and the irreversible MAO-A inhibitor, clorgyline (10-30 mg/kg), also reduced ethanol self-administration. However, befloxatone-induced effects leveled off at a 50% decrease. The irreversible GENE inhibitors, pargyline (30 mg/kg) and CHEMICAL (3-10 mg/kg) also decreased responding maintained by ethanol reinforcement; these results are consistent with previous findings that both drugs decreased ethanol intake in mice. In conclusion, the present results showing that several MAO inhibitors decreased ethanol self-administration in rats are consistent with previous findings that synaptic levels of serotonin and dopamine play a critical role in the control of ethanol self-administration. | INHIBITOR |
| Decreased intracellular proteolysis correlates with the maintenance of a specific isoenzyme of cytochrome P-450. The rates of intracellular protein degradation, of identically labelled populations of proteins, were compared in hepatocytes cultured at 37 degrees (on an adsorbed collagen layer) and in cells preserved on gelatin gels at 10 degrees C. The half-lives of the long-lived proteins were 35.4+/-8.6 h (N=4) and 692.9+/-216.9 h (N=4) respectively. Proteolysis was substantially decreased at 10 degrees C but the rate of decrease remained constant. Hepatocytes rapidly removed resorufin from the culture medium. The resorufin was not being conjugated or accumulated within the cells. CHEMICAL, a potent inhibitor of GENE, at high concentration (500 microm ) caused only a 72% decrease in the utilization of resorufin. The microsomal detoxifying enzyme, cytochrome P-450 1A1 remained at a constant level in the preserved hepatocyte monolayers. The results of this study strongly favour storing hepatocytes at 10 degrees C rather than at 4 degrees or 37 degrees C. | INHIBITOR |
| A novel mutation of the erythroid-specific gamma-Aminolevulinate synthase gene in a patient with non-inherited pyridoxine-responsive sideroblastic anemia. A novel missense mutation, GENE, in exon 5 of the erythroid-specific delta-aminolevulinate synthase gene (ALAS2) was identified in a Japanese male with CHEMICAL-responsive sideroblastic anemia. Activity of the mutant delta-aminolevulinate synthase protein expressed in vitro was 15.1% compared with the normal control, but was increased up to 34.5% by the addition of pyridoxal 5'-phosphate, consistent with the clinical response of the patient to CHEMICAL treatment. The same mutation was also detected in genomic DNa from the oral mucosal membrane of the patiet; however, it was not detected in other family member. These findings suggest that this GENE mutation is responsible for sideroblastic anemia in the proband, and may be an index mutation in this pedigree. | REGULATOR |
| A novel mutation of the erythroid-specific gamma-Aminolevulinate synthase gene in a patient with non-inherited pyridoxine-responsive sideroblastic anemia. A novel missense mutation, G663A, in exon 5 of the GENE gene (ALAS2) was identified in a Japanese male with CHEMICAL-responsive sideroblastic anemia. Activity of the mutant delta-aminolevulinate synthase protein expressed in vitro was 15.1% compared with the normal control, but was increased up to 34.5% by the addition of pyridoxal 5'-phosphate, consistent with the clinical response of the patient to CHEMICAL treatment. The same mutation was also detected in genomic DNa from the oral mucosal membrane of the patiet; however, it was not detected in other family member. These findings suggest that this G663A mutation is responsible for sideroblastic anemia in the proband, and may be an index mutation in this pedigree. | REGULATOR |
| A novel mutation of the erythroid-specific gamma-Aminolevulinate synthase gene in a patient with non-inherited pyridoxine-responsive sideroblastic anemia. A novel missense mutation, G663A, in exon 5 of the erythroid-specific delta-aminolevulinate synthase gene (GENE) was identified in a Japanese male with CHEMICAL-responsive sideroblastic anemia. Activity of the mutant delta-aminolevulinate synthase protein expressed in vitro was 15.1% compared with the normal control, but was increased up to 34.5% by the addition of pyridoxal 5'-phosphate, consistent with the clinical response of the patient to CHEMICAL treatment. The same mutation was also detected in genomic DNa from the oral mucosal membrane of the patiet; however, it was not detected in other family member. These findings suggest that this G663A mutation is responsible for sideroblastic anemia in the proband, and may be an index mutation in this pedigree. | REGULATOR |
| A novel mutation of the erythroid-specific gamma-Aminolevulinate synthase gene in a patient with non-inherited pyridoxine-responsive sideroblastic anemia. A novel missense mutation, G663A, in exon 5 of the erythroid-specific GENE gene (ALAS2) was identified in a Japanese male with pyridoxine-responsive sideroblastic anemia. Activity of the mutant GENE protein expressed in vitro was 15.1% compared with the normal control, but was increased up to 34.5% by the addition of pyridoxal 5'-phosphate, consistent with the clinical response of the patient to CHEMICAL treatment. The same mutation was also detected in genomic DNa from the oral mucosal membrane of the patiet; however, it was not detected in other family member. These findings suggest that this G663A mutation is responsible for sideroblastic anemia in the proband, and may be an index mutation in this pedigree. | REGULATOR |
| A novel mutation of the GENE gene in a patient with non-inherited CHEMICAL-responsive sideroblastic anemia. A novel missense mutation, G663A, in exon 5 of the erythroid-specific delta-aminolevulinate synthase gene (ALAS2) was identified in a Japanese male with pyridoxine-responsive sideroblastic anemia. Activity of the mutant delta-aminolevulinate synthase protein expressed in vitro was 15.1% compared with the normal control, but was increased up to 34.5% by the addition of pyridoxal 5'-phosphate, consistent with the clinical response of the patient to CHEMICAL treatment. The same mutation was also detected in genomic DNa from the oral mucosal membrane of the patiet; however, it was not detected in other family member. These findings suggest that this G663A mutation is responsible for sideroblastic anemia in the proband, and may be an index mutation in this pedigree. | NO-RELATIONSHIP |
| A novel mutation of the erythroid-specific gamma-Aminolevulinate synthase gene in a patient with non-inherited pyridoxine-responsive sideroblastic anemia. A novel missense mutation, G663A, in exon 5 of the erythroid-specific GENE gene (ALAS2) was identified in a Japanese male with pyridoxine-responsive sideroblastic anemia. Activity of the mutant GENE protein expressed in vitro was 15.1% compared with the normal control, but was increased up to 34.5% by the addition of CHEMICAL, consistent with the clinical response of the patient to pyridoxine treatment. The same mutation was also detected in genomic DNa from the oral mucosal membrane of the patiet; however, it was not detected in other family member. These findings suggest that this G663A mutation is responsible for sideroblastic anemia in the proband, and may be an index mutation in this pedigree. | ACTIVATOR |
| Preferential cerebrospinal fluid GENE inhibition by CHEMICAL in humans. This study sought to examine the feasibility of prolonged assessment of GENE (AChE) activity in the cerebrospinal fluid (CSF) of volunteers and to test the hypothesis that CHEMICAL (ENA-713; Exelon, Novartis Pharma AG, Basel, Switzerland) selectively inhibits AChE in CSF in humans at a dose producing minimal inhibition of the peripheral enzyme. Lumbar CSF samples were collected continuously (0.1 mL x min(-1)) for 49 hours from eight healthy volunteers who took either placebo or a single oral dose of CHEMICAL (3 mg). CSF specimens and samples of blood cells and blood plasma were analyzed at intervals for CHEMICAL and its metabolite NAP 226-90 ([-] [3-([1-dimethylaminolethyl)-phenol]), erythrocyte AChE activity, CSF AChE activity, and plasma and CSF butyrylcholinesterase (BuChE) activity. Safety evaluations were performed 23 hours after drug dosing and at the end of the study. Evaluable data were obtained from six subjects. The mean time to maximal CHEMICAL plasma concentration (tmax) was 0.83 +/- 0.26 hours, the mean maximal plasma concentration (Cmax) was 4.88 +/- 3.82 ng x mL(-1), the mean plasma area under the concentration versus time curve (AUC0-infinity) was 7.43 +/- 4.74 ng x hr x mL(-1), and the mean plasma t1/2 was 0.85 +/- 0.115 hours. The concentration of CHEMICAL in CSF was lower than the quantification limit for assay (0.65 ng x mL(-1)), but NAP 226-90 reached a mean Cmax of 3.14 +/- 0.57 ng x mL(-1). Only minimal inhibition of erythrocyte AChE activity (approximately 3%) was observed. Inhibition of AChE in the CSF after CHEMICAL administration was significantly greater than after placebo for up to 8.4 hours after the dose and was maximal (40%) at 2.4 hours. Plasma BuChE activity was significantly lower after CHEMICAL than after placebo, but this was not clinically relevant. BuChE activity in CSF was significantly lower after CHEMICAL than after placebo for up to 3.6 hours after dosing, but this difference was not sustained. This study confirms the feasibility of using continuous measurement of AChE activity in CSF over prolonged periods, that CHEMICAL markedly inhibits CSF AChE after a single oral dose of 3 mg, and that the inhibition of central AChE is substantially greater than that of peripheral AChE or BuChE. | INHIBITOR |
| Preferential cerebrospinal fluid acetylcholinesterase inhibition by CHEMICAL in humans. This study sought to examine the feasibility of prolonged assessment of acetylcholinesterase (AChE) activity in the cerebrospinal fluid (CSF) of volunteers and to test the hypothesis that CHEMICAL (ENA-713; Exelon, Novartis Pharma AG, Basel, Switzerland) selectively inhibits GENE in CSF in humans at a dose producing minimal inhibition of the peripheral enzyme. Lumbar CSF samples were collected continuously (0.1 mL x min(-1)) for 49 hours from eight healthy volunteers who took either placebo or a single oral dose of CHEMICAL (3 mg). CSF specimens and samples of blood cells and blood plasma were analyzed at intervals for CHEMICAL and its metabolite NAP 226-90 ([-] [3-([1-dimethylaminolethyl)-phenol]), erythrocyte GENE activity, CSF GENE activity, and plasma and CSF butyrylcholinesterase (BuChE) activity. Safety evaluations were performed 23 hours after drug dosing and at the end of the study. Evaluable data were obtained from six subjects. The mean time to maximal CHEMICAL plasma concentration (tmax) was 0.83 +/- 0.26 hours, the mean maximal plasma concentration (Cmax) was 4.88 +/- 3.82 ng x mL(-1), the mean plasma area under the concentration versus time curve (AUC0-infinity) was 7.43 +/- 4.74 ng x hr x mL(-1), and the mean plasma t1/2 was 0.85 +/- 0.115 hours. The concentration of CHEMICAL in CSF was lower than the quantification limit for assay (0.65 ng x mL(-1)), but NAP 226-90 reached a mean Cmax of 3.14 +/- 0.57 ng x mL(-1). Only minimal inhibition of erythrocyte GENE activity (approximately 3%) was observed. Inhibition of GENE in the CSF after CHEMICAL administration was significantly greater than after placebo for up to 8.4 hours after the dose and was maximal (40%) at 2.4 hours. Plasma BuChE activity was significantly lower after CHEMICAL than after placebo, but this was not clinically relevant. BuChE activity in CSF was significantly lower after CHEMICAL than after placebo for up to 3.6 hours after dosing, but this difference was not sustained. This study confirms the feasibility of using continuous measurement of GENE activity in CSF over prolonged periods, that CHEMICAL markedly inhibits CSF GENE after a single oral dose of 3 mg, and that the inhibition of central GENE is substantially greater than that of peripheral GENE or BuChE. | INHIBITOR |
| Preferential cerebrospinal fluid acetylcholinesterase inhibition by CHEMICAL in humans. This study sought to examine the feasibility of prolonged assessment of acetylcholinesterase (AChE) activity in the cerebrospinal fluid (CSF) of volunteers and to test the hypothesis that CHEMICAL (ENA-713; Exelon, Novartis Pharma AG, Basel, Switzerland) selectively inhibits AChE in CSF in humans at a dose producing minimal inhibition of the peripheral enzyme. Lumbar CSF samples were collected continuously (0.1 mL x min(-1)) for 49 hours from eight healthy volunteers who took either placebo or a single oral dose of CHEMICAL (3 mg). CSF specimens and samples of blood cells and blood plasma were analyzed at intervals for CHEMICAL and its metabolite NAP 226-90 ([-] [3-([1-dimethylaminolethyl)-phenol]), erythrocyte AChE activity, CSF AChE activity, and plasma and CSF butyrylcholinesterase (BuChE) activity. Safety evaluations were performed 23 hours after drug dosing and at the end of the study. Evaluable data were obtained from six subjects. The mean time to maximal CHEMICAL plasma concentration (tmax) was 0.83 +/- 0.26 hours, the mean maximal plasma concentration (Cmax) was 4.88 +/- 3.82 ng x mL(-1), the mean plasma area under the concentration versus time curve (AUC0-infinity) was 7.43 +/- 4.74 ng x hr x mL(-1), and the mean plasma t1/2 was 0.85 +/- 0.115 hours. The concentration of CHEMICAL in CSF was lower than the quantification limit for assay (0.65 ng x mL(-1)), but NAP 226-90 reached a mean Cmax of 3.14 +/- 0.57 ng x mL(-1). Only minimal inhibition of erythrocyte AChE activity (approximately 3%) was observed. Inhibition of AChE in the CSF after CHEMICAL administration was significantly greater than after placebo for up to 8.4 hours after the dose and was maximal (40%) at 2.4 hours. Plasma GENE activity was significantly lower after CHEMICAL than after placebo, but this was not clinically relevant. GENE activity in CSF was significantly lower after CHEMICAL than after placebo for up to 3.6 hours after dosing, but this difference was not sustained. This study confirms the feasibility of using continuous measurement of AChE activity in CSF over prolonged periods, that CHEMICAL markedly inhibits CSF AChE after a single oral dose of 3 mg, and that the inhibition of central AChE is substantially greater than that of peripheral AChE or GENE. | INHIBITOR |
| Identification of amino acids in the factor XI apple 3 domain required for activation of GENE. Activated coagulation factor XI (factor XIa) proteolytically cleaves its substrate, GENE, in an interaction requiring the factor XI A3 domain (Sun, Y., and Gailani, D. (1996) J. Biol. Chem. 271, 29023-29028). To identify key amino acids involved in GENE activation, recombinant factor XIa proteins containing alanine substitutions for wild-type sequence were expressed in 293 fibroblasts and tested in a plasma clotting assay. Substitutions for Ile(183)-Val(191) and Ser(195)-Ile(197) at the N terminus and for Ser(258)-Ser(264) at the C terminus of the A3 domain markedly decreased factor XI coagulant activity. The plasma protease prekallikrein is structurally homologous to factor XI, but activated GENE poorly. A chimeric factor XIa molecule with the A3 domain replaced with A3 from prekallikrein (FXI/PKA3) activated GENE with a K(m) 35-fold greater than that of wild-type factor XI. FXI/PKA3 was used as a template for a series of proteins in which prekallikrein A3 sequence was replaced with factor XI sequence to restore GENE activation. Clotting and kinetics studies using these chimeras confirmed the results obtained with alanine mutants. CHEMICAL between Ile(183) and Val(191) are necessary for proper GENE activation, but additional sequence between Ser(195) and Ile(197) or between Phe(260) and Ser(265) is required for complete restoration of activation. | PART-OF |
| Identification of amino acids in the factor XI apple 3 domain required for activation of factor IX. Activated coagulation factor XI (factor XIa) proteolytically cleaves its substrate, factor IX, in an interaction requiring the factor XI A3 domain (Sun, Y., and Gailani, D. (1996) J. Biol. Chem. 271, 29023-29028). To identify key amino acids involved in factor IX activation, recombinant GENE proteins containing CHEMICAL substitutions for wild-type sequence were expressed in 293 fibroblasts and tested in a plasma clotting assay. Substitutions for Ile(183)-Val(191) and Ser(195)-Ile(197) at the N terminus and for Ser(258)-Ser(264) at the C terminus of the A3 domain markedly decreased factor XI coagulant activity. The plasma protease prekallikrein is structurally homologous to factor XI, but activated factor IX poorly. A chimeric GENE molecule with the A3 domain replaced with A3 from prekallikrein (FXI/PKA3) activated factor IX with a K(m) 35-fold greater than that of wild-type factor XI. FXI/PKA3 was used as a template for a series of proteins in which prekallikrein A3 sequence was replaced with factor XI sequence to restore factor IX activation. Clotting and kinetics studies using these chimeras confirmed the results obtained with CHEMICAL mutants. Amino acids between Ile(183) and Val(191) are necessary for proper factor IX activation, but additional sequence between Ser(195) and Ile(197) or between Phe(260) and Ser(265) is required for complete restoration of activation. | PART-OF |
| Identification of amino acids in the factor XI apple 3 domain required for activation of factor IX. Activated coagulation factor XI (factor XIa) proteolytically cleaves its substrate, factor IX, in an interaction requiring the factor XI GENE (Sun, Y., and Gailani, D. (1996) J. Biol. Chem. 271, 29023-29028). To identify key amino acids involved in factor IX activation, recombinant factor XIa proteins containing alanine substitutions for wild-type sequence were expressed in 293 fibroblasts and tested in a plasma clotting assay. Substitutions for Ile(183)-Val(191) and Ser(195)-Ile(197) at the CHEMICAL terminus and for Ser(258)-Ser(264) at the C terminus of the GENE markedly decreased factor XI coagulant activity. The plasma protease prekallikrein is structurally homologous to factor XI, but activated factor IX poorly. A chimeric factor XIa molecule with the GENE replaced with A3 from prekallikrein (FXI/PKA3) activated factor IX with a K(m) 35-fold greater than that of wild-type factor XI. FXI/PKA3 was used as a template for a series of proteins in which prekallikrein A3 sequence was replaced with factor XI sequence to restore factor IX activation. Clotting and kinetics studies using these chimeras confirmed the results obtained with alanine mutants. Amino acids between Ile(183) and Val(191) are necessary for proper factor IX activation, but additional sequence between Ser(195) and Ile(197) or between Phe(260) and Ser(265) is required for complete restoration of activation. | PART-OF |
| Identification of amino acids in the factor XI apple 3 domain required for activation of factor IX. Activated coagulation factor XI (factor XIa) proteolytically cleaves its substrate, factor IX, in an interaction requiring the factor XI GENE (Sun, Y., and Gailani, D. (1996) J. Biol. Chem. 271, 29023-29028). To identify key amino acids involved in factor IX activation, recombinant factor XIa proteins containing alanine substitutions for wild-type sequence were expressed in 293 fibroblasts and tested in a plasma clotting assay. Substitutions for Ile(183)-Val(191) and Ser(195)-Ile(197) at the N terminus and for Ser(258)-Ser(264) at the CHEMICAL terminus of the GENE markedly decreased factor XI coagulant activity. The plasma protease prekallikrein is structurally homologous to factor XI, but activated factor IX poorly. A chimeric factor XIa molecule with the GENE replaced with A3 from prekallikrein (FXI/PKA3) activated factor IX with a K(m) 35-fold greater than that of wild-type factor XI. FXI/PKA3 was used as a template for a series of proteins in which prekallikrein A3 sequence was replaced with factor XI sequence to restore factor IX activation. Clotting and kinetics studies using these chimeras confirmed the results obtained with alanine mutants. Amino acids between Ile(183) and Val(191) are necessary for proper factor IX activation, but additional sequence between Ser(195) and Ile(197) or between Phe(260) and Ser(265) is required for complete restoration of activation. | PART-OF |
| Identification of CHEMICAL in the GENE required for activation of factor IX. Activated coagulation factor XI (factor XIa) proteolytically cleaves its substrate, factor IX, in an interaction requiring the factor XI A3 domain (Sun, Y., and Gailani, D. (1996) J. Biol. Chem. 271, 29023-29028). To identify key CHEMICAL involved in factor IX activation, recombinant factor XIa proteins containing alanine substitutions for wild-type sequence were expressed in 293 fibroblasts and tested in a plasma clotting assay. Substitutions for Ile(183)-Val(191) and Ser(195)-Ile(197) at the N terminus and for Ser(258)-Ser(264) at the C terminus of the A3 domain markedly decreased factor XI coagulant activity. The plasma protease prekallikrein is structurally homologous to factor XI, but activated factor IX poorly. A chimeric factor XIa molecule with the A3 domain replaced with A3 from prekallikrein (FXI/PKA3) activated factor IX with a K(m) 35-fold greater than that of wild-type factor XI. FXI/PKA3 was used as a template for a series of proteins in which prekallikrein A3 sequence was replaced with factor XI sequence to restore factor IX activation. Clotting and kinetics studies using these chimeras confirmed the results obtained with alanine mutants. CHEMICAL between Ile(183) and Val(191) are necessary for proper factor IX activation, but additional sequence between Ser(195) and Ile(197) or between Phe(260) and Ser(265) is required for complete restoration of activation. | PART-OF |
| Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for GENE, h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at GENE sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at GENE sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | DIRECT-REGULATOR |
| Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), GENE, h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, GENE, h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | DIRECT-REGULATOR |
| Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), GENE, and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), GENE, and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | DIRECT-REGULATOR |
| Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and GENE and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | DIRECT-REGULATOR |
| Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for GENE. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | DIRECT-REGULATOR |
| Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [CHEMICAL]GTPgammaS binding protocols, yohimbine exerts antagonist actions at GENE, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | INHIBITOR |
| Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), GENE, h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [CHEMICAL]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, GENE, h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | DIRECT-REGULATOR |
| Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), GENE, and hD(2) receptors and weak affinity for hD(3) receptors. In [CHEMICAL]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), GENE, and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | DIRECT-REGULATOR |
| Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and GENE receptors and weak affinity for hD(3) receptors. In [CHEMICAL]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and GENE sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | DIRECT-REGULATOR |
| Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for GENE, h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [CHEMICAL]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at GENE sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at GENE sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | DIRECT-REGULATOR |
| Agonist and antagonist actions of CHEMICAL as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, CHEMICAL, as compared to fluparoxan, at multiple GENE and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, CHEMICAL exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of CHEMICAL at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of CHEMICAL at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to CHEMICAL, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, CHEMICAL also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, CHEMICAL decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, CHEMICAL enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of CHEMICAL increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of CHEMICAL suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | REGULATOR |
| Agonist and antagonist actions of yohimbine as compared to CHEMICAL at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to CHEMICAL, at multiple GENE and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, CHEMICAL shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While CHEMICAL selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. CHEMICAL increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by CHEMICAL. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, CHEMICAL, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | REGULATOR |
| Agonist and antagonist actions of CHEMICAL as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, CHEMICAL, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, CHEMICAL exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of CHEMICAL at GENE sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of CHEMICAL at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to CHEMICAL, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, CHEMICAL also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, CHEMICAL decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, CHEMICAL enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of CHEMICAL increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the GENE agonist actions of CHEMICAL suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | ACTIVATOR |
| Agonist and antagonist actions of CHEMICAL as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, CHEMICAL, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for GENE, h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, CHEMICAL exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at GENE sites. In vivo, agonist actions of CHEMICAL at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of CHEMICAL at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to CHEMICAL, fluparoxan shows only modest partial agonist actions at GENE sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, CHEMICAL also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, CHEMICAL decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, CHEMICAL enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of CHEMICAL increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of CHEMICAL suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | DIRECT-REGULATOR |
| Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), GENE, 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at GENE receptors are revealed by blockade of hypothermia evoked by the GENE agonist, CHEMICAL. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | ACTIVATOR |
| Agonist and antagonist actions of yohimbine as compared to CHEMICAL at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to CHEMICAL, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for GENE, h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at GENE sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, CHEMICAL shows only modest partial agonist actions at GENE sites versus marked antagonist actions at halpha(2)-ARs. While CHEMICAL selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. CHEMICAL increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by CHEMICAL. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, CHEMICAL, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | ACTIVATOR |
| Agonist and antagonist actions of CHEMICAL as compared to fluparoxan at alpha(2)-adrenergic receptors GENE, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, CHEMICAL, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, CHEMICAL exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of CHEMICAL at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of CHEMICAL at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to CHEMICAL, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, CHEMICAL also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, CHEMICAL decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, CHEMICAL enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of CHEMICAL increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of CHEMICAL suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | REGULATOR |
| Agonist and antagonist actions of CHEMICAL as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin GENE, 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, CHEMICAL, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, CHEMICAL exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of CHEMICAL at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of CHEMICAL at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to CHEMICAL, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, CHEMICAL also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, CHEMICAL decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, CHEMICAL enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of CHEMICAL increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of CHEMICAL suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | REGULATOR |
| Agonist and antagonist actions of CHEMICAL as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), GENE, 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, CHEMICAL, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, CHEMICAL exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of CHEMICAL at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of CHEMICAL at GENE receptors are revealed by blockade of hypothermia evoked by the GENE agonist, GR46,611. In distinction to CHEMICAL, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, CHEMICAL also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, CHEMICAL decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, CHEMICAL enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of CHEMICAL increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of CHEMICAL suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | INHIBITOR |
| Agonist and antagonist actions of CHEMICAL as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), GENE and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, CHEMICAL, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, CHEMICAL exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of CHEMICAL at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of CHEMICAL at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to CHEMICAL, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, CHEMICAL also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, CHEMICAL decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, CHEMICAL enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of CHEMICAL increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of CHEMICAL suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | INHIBITOR |
| Agonist and antagonist actions of CHEMICAL as compared to fluparoxan at GENE (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, CHEMICAL, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, CHEMICAL exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of CHEMICAL at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of CHEMICAL at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to CHEMICAL, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, CHEMICAL also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, CHEMICAL decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, CHEMICAL enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of CHEMICAL increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of CHEMICAL suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | REGULATOR |
| Agonist and antagonist actions of yohimbine as compared to CHEMICAL at alpha(2)-adrenergic receptors GENE, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to CHEMICAL, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, CHEMICAL shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While CHEMICAL selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. CHEMICAL increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by CHEMICAL. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, CHEMICAL, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | REGULATOR |
| Agonist and antagonist actions of yohimbine as compared to CHEMICAL at GENE (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to CHEMICAL, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, CHEMICAL shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While CHEMICAL selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. CHEMICAL increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by CHEMICAL. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, CHEMICAL, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | REGULATOR |
| Agonist and antagonist actions of CHEMICAL as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the GENE antagonist, CHEMICAL, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, CHEMICAL exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of CHEMICAL at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of CHEMICAL at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to CHEMICAL, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, CHEMICAL also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, CHEMICAL decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, CHEMICAL enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the GENE antagonist properties of CHEMICAL increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective GENE antagonist, fluparoxan, the 5-HT(1A) agonist actions of CHEMICAL suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | INHIBITOR |
| Agonist and antagonist actions of yohimbine as compared to CHEMICAL at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the GENE antagonist, yohimbine, as compared to CHEMICAL, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, CHEMICAL shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While CHEMICAL selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. CHEMICAL increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by CHEMICAL. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the GENE antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective GENE antagonist, CHEMICAL, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | INHIBITOR |
| Agonist and antagonist actions of CHEMICAL as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, CHEMICAL, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, CHEMICAL exerts antagonist actions at GENE, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of CHEMICAL at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of CHEMICAL at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to CHEMICAL, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, CHEMICAL also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, CHEMICAL decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, CHEMICAL enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of CHEMICAL increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of CHEMICAL suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | INHIBITOR |
| Agonist and antagonist actions of CHEMICAL as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, CHEMICAL, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), GENE, h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, CHEMICAL exerts antagonist actions at halpha(2A)-AR, GENE, h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of CHEMICAL at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of CHEMICAL at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to CHEMICAL, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, CHEMICAL also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, CHEMICAL decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, CHEMICAL enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of CHEMICAL increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of CHEMICAL suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | DIRECT-REGULATOR |
| Agonist and antagonist actions of CHEMICAL as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, CHEMICAL, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), GENE, and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, CHEMICAL exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), GENE, and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of CHEMICAL at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of CHEMICAL at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to CHEMICAL, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, CHEMICAL also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, CHEMICAL decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, CHEMICAL enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of CHEMICAL increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of CHEMICAL suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | DIRECT-REGULATOR |
| Agonist and antagonist actions of CHEMICAL as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, CHEMICAL, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and GENE receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, CHEMICAL exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and GENE sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of CHEMICAL at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of CHEMICAL at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to CHEMICAL, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, CHEMICAL also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, CHEMICAL decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, CHEMICAL enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of CHEMICAL increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of CHEMICAL suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | INHIBITOR |
| Agonist and antagonist actions of CHEMICAL as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the GENE, CHEMICAL, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, CHEMICAL exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of CHEMICAL at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of CHEMICAL at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to CHEMICAL, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, CHEMICAL also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, CHEMICAL decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, CHEMICAL enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the GENE properties of CHEMICAL increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective GENE, fluparoxan, the 5-HT(1A) agonist actions of CHEMICAL suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | REGULATOR |
| Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at GENE sites are revealed by CHEMICAL-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by CHEMICAL. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by CHEMICAL. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the GENE agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | INHIBITOR |
| Agonist and antagonist actions of yohimbine as compared to CHEMICAL at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the GENE, yohimbine, as compared to CHEMICAL, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, CHEMICAL shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at halpha(2)-ARs. While CHEMICAL selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. CHEMICAL increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by CHEMICAL. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the GENE properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective GENE, CHEMICAL, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | REGULATOR |
| Agonist and antagonist actions of CHEMICAL as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, CHEMICAL, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. CHEMICAL displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, CHEMICAL exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of CHEMICAL at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of CHEMICAL at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to CHEMICAL, fluparoxan shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at GENE. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, CHEMICAL also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, CHEMICAL decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, CHEMICAL enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by fluparoxan. CHEMICAL likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of CHEMICAL increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, fluparoxan, the 5-HT(1A) agonist actions of CHEMICAL suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | INHIBITOR |
| Agonist and antagonist actions of yohimbine as compared to CHEMICAL at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Herein, we evaluate the interaction of the alpha(2)-AR antagonist, yohimbine, as compared to CHEMICAL, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely-moving rats. Yohimbine displays marked affinity at human (h)alpha(2A)-, halpha(2B)- and halpha(2C)-ARs, significant affinity for h5-HT(1A), h5-HT(1B), h5-HT(1D), and hD(2) receptors and weak affinity for hD(3) receptors. In [(35)S]GTPgammaS binding protocols, yohimbine exerts antagonist actions at halpha(2A)-AR, h5-HT(1B), h5-HT(1D), and hD(2) sites, yet partial agonist actions at h5-HT(1A) sites. In vivo, agonist actions of yohimbine at 5-HT(1A) sites are revealed by WAY100,635-reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5-HT(1B) receptors are revealed by blockade of hypothermia evoked by the 5-HT(1B) agonist, GR46,611. In distinction to yohimbine, CHEMICAL shows only modest partial agonist actions at h5-HT(1A) sites versus marked antagonist actions at GENE. While CHEMICAL selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5-HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. CHEMICAL increases extracellular levels of DA and NAD, but not 5-HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5-HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5-HT, DA, and NAD is potentiated by CHEMICAL. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5-HT. In conclusion, the alpha(2)-AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective alpha(2)-AR antagonist, CHEMICAL, the 5-HT(1A) agonist actions of yohimbine suppress 5-HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5-HT levels. | INHIBITOR |
| The antitussive activity of delta-opioid receptor stimulation in guinea pigs. In this study, the activity of the delta-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and GENE (CHEMICAL) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor. | ACTIVATOR |
| The antitussive activity of delta-opioid receptor stimulation in guinea pigs. In this study, the activity of the delta-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective GENE antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of CHEMICAL or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor. | INHIBITOR |
| The antitussive activity of delta-opioid receptor stimulation in guinea pigs. In this study, the activity of the delta-opioid receptor subtype-selective agonist, CHEMICAL, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective GENE antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or CHEMICAL, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of CHEMICAL (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of CHEMICAL (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of CHEMICAL. These studies provide compelling evidence that the antitussive effects of CHEMICAL in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor. | INHIBITOR |
| The antitussive activity of delta-opioid receptor stimulation in guinea pigs. In this study, the activity of the delta-opioid receptor subtype-selective agonist, CHEMICAL, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or CHEMICAL, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The GENE antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of CHEMICAL (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of CHEMICAL (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of CHEMICAL. These studies provide compelling evidence that the antitussive effects of CHEMICAL in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor. | INHIBITOR |
| The antitussive activity of GENE stimulation in guinea pigs. In this study, the activity of the GENE subtype-selective agonist, CHEMICAL, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the GENE (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or CHEMICAL, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of CHEMICAL (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of CHEMICAL (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of CHEMICAL. These studies provide compelling evidence that the antitussive effects of CHEMICAL in this guinea pig cough model are mediated by agonist activity at the GENE. | ACTIVATOR |
| The antitussive activity of delta-opioid receptor stimulation in guinea pigs. In this study, the activity of the delta-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The GENE antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of CHEMICAL (30 mg/kg, i.p.), a GENE agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor. | ACTIVATOR |
| The antitussive activity of delta-opioid receptor stimulation in guinea pigs. In this study, the activity of the delta-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), GENE (CHEMICAL and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of CHEMICAL or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor. | ACTIVATOR |
| The antitussive activity of delta-opioid receptor stimulation in guinea pigs. In this study, the activity of the delta-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), GENE (codeine and CHEMICAL), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor. | ACTIVATOR |
| The antitussive activity of delta-opioid receptor stimulation in guinea pigs. In this study, the activity of the delta-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective GENE antagonist, CHEMICAL (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor. | INHIBITOR |
| The antitussive activity of delta-opioid receptor stimulation in guinea pigs. In this study, the activity of the delta-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The GENE antagonist, CHEMICAL (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor. | INHIBITOR |
| The antitussive activity of delta-opioid receptor stimulation in guinea pigs. In this study, the activity of the delta-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with CHEMICAL (GENE antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor. | INHIBITOR |
| The antitussive activity of delta-opioid receptor stimulation in guinea pigs. In this study, the activity of the delta-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and CHEMICAL (GENE antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and GENE agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The sigma-receptor antagonist rimcazole (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a sigma-receptor agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor. | INHIBITOR |
| The antitussive activity of delta-opioid receptor stimulation in guinea pigs. In this study, the activity of the delta-opioid receptor subtype-selective agonist, SB 227122, was investigated in a guinea pig model of citric acid-induced cough. Parenteral administration of selective agonists of the delta-opioid receptor (SB 227122), mu-opioid receptor (codeine and hydrocodone), and kappa-opioid receptor (BRL 52974) produced dose-related inhibition of citric acid-induced cough with ED(50) values of 7.3, 5.2, 5.1, and 5.3 mg/kg, respectively. The nonselective opioid receptor antagonist, naloxone (3 mg/kg, i.m.), attenuated the antitussive effects of codeine or SB 227122, indicating that the antitussive activity of both compounds is opioid receptor-mediated. The delta-receptor antagonist, SB 244525 (10 mg/kg, i.p.), inhibited the antitussive effect of SB 227122 (20 mg/kg, i.p.). In contrast, combined pretreatment with beta-funaltrexamine (mu-receptor antagonist; 20 mg/kg, s.c.) and norbinaltorphimine (kappa-receptor antagonist; 20 mg/kg, s.c.), at doses that inhibited the antitussive activity of mu- and kappa-receptor agonists, respectively, was without effect on the antitussive response of SB 227122 (20 mg/kg, i.p.). The GENE antagonist CHEMICAL (3 mg/kg, i.p.) inhibited the antitussive effect of dextromethorphan (30 mg/kg, i.p.), a GENE agonist, but not that of SB 227122. These studies provide compelling evidence that the antitussive effects of SB 227122 in this guinea pig cough model are mediated by agonist activity at the delta-opioid receptor. | INHIBITOR |
| COX-2-specific inhibition: implications for clinical practice. Although conventional nonsteroidal anti-inflammatory drugs (NSAIDs) have long been a major therapeutic choice for the management of arthritic conditions, the potential adverse effects of these agents sometimes compromise their clinical utility. New modes of therapy have recently been introduced, and data on the GENE (COX-2)-specific inhibitors CHEMICAL and rofecoxib suggest that these agents will meet the need for safe and effective therapeutic alternatives to conventional NSAIDs. | INHIBITOR |
| COX-2-specific inhibition: implications for clinical practice. Although conventional nonsteroidal anti-inflammatory drugs (NSAIDs) have long been a major therapeutic choice for the management of arthritic conditions, the potential adverse effects of these agents sometimes compromise their clinical utility. New modes of therapy have recently been introduced, and data on the cyclooxygenase-2 (GENE)-specific inhibitors CHEMICAL and rofecoxib suggest that these agents will meet the need for safe and effective therapeutic alternatives to conventional NSAIDs. | INHIBITOR |
| COX-2-specific inhibition: implications for clinical practice. Although conventional nonsteroidal anti-inflammatory drugs (NSAIDs) have long been a major therapeutic choice for the management of arthritic conditions, the potential adverse effects of these agents sometimes compromise their clinical utility. New modes of therapy have recently been introduced, and data on the GENE (COX-2)-specific inhibitors celecoxib and CHEMICAL suggest that these agents will meet the need for safe and effective therapeutic alternatives to conventional NSAIDs. | INHIBITOR |
| COX-2-specific inhibition: implications for clinical practice. Although conventional nonsteroidal anti-inflammatory drugs (NSAIDs) have long been a major therapeutic choice for the management of arthritic conditions, the potential adverse effects of these agents sometimes compromise their clinical utility. New modes of therapy have recently been introduced, and data on the cyclooxygenase-2 (GENE)-specific inhibitors celecoxib and CHEMICAL suggest that these agents will meet the need for safe and effective therapeutic alternatives to conventional NSAIDs. | INHIBITOR |
| Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid. Mitochondrially-bound dihydroorotate dehydrogenase (EC 1.3.99.11) catalyzes the fourth sequential step in the de novo synthesis of uridine monophosphate. The enzyme has been identified as or surmised to be the pharmacological target for isoxazol, triazine, cinchoninic acid and (naphtho)quinone derivatives, which exerted antiproliferative, immunosuppressive, and antiparasitic effects. Despite this broad spectrum of biological and clinical relevance, there have been no comparative studies on drug-dihydroorotate dehydrogenase interactions. Here, we describe a study of the inhibition of the purified recombinant human and rat dihydroorotate dehydrogenase by ten compounds. 1,4-Naphthoquinone, 5,8-hydroxy-naphthoquinone and the natural compounds juglon, plumbagin and polyporic acid (quinone derivative) were found to function as alternative electron acceptors with 10-30% of control enzyme activity. The human and rat enzyme activity was decreased by 50% by the natural compound lawsone ( > 500 and 49 microM, respectively) and by the derivatives dichloroally-lawsone (67 and 10 nM), lapachol (618 and 61 nM) and atovaquone (15 microM and 698 nM). With respect to the quinone co-substrate of the dihydroorotate dehydrogenase, atovaquone (Kic = 2.7 microM) and dichloroally-lawsone (Kic = 9.8 nM) were shown to be competitive inhibitors of human dihydroorotate dehydrogenase. Atovaquone (Kic = 60 nM) was also acompetitive inhibitor of the rat enzyme. CHEMICAL was found to be a time-dependent inhibitor of the rat enzyme, with the lowest inhibition constant (Ki* = 0.77 nM) determined so far for GENE. Another inhibitor, brequinar was previously reported to be a slow-binding inhibitor of the human dihydroorotate dehydrogenase [W. Knecht, M. Loffler, Species-related inhibition of human and rat dihyroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives, Biochem. Pharmacol. 56 (1998) 1259-1264]. The slow binding features of this potent inhibitor (Ki* = 1.8 nM) with the human enzyme, were verified and seen to be one of the reasons for the narrow therapeutic window (efficacy versus toxicity) reported from clinical trials on its antiproliferative and immunosuppressive action. With respect to the substrate dihydroorotate, atovaquone was an uncompetitive inhibitor of human dihydroorotate dehydrogenase (Kiu = 11.6 microM) and a non-competitive inhibitor of the rat enzyme (Kiu = 905/ Kic = 1,012 nM). 1.5 mM polyporic acid, a natural quinone from fungi, influenced the activity of the human enzyme only slightly; the activity of the rat enzyme was decreased by 30%. | INHIBITOR |
| Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, CHEMICAL sodium and polyporic acid. Mitochondrially-bound dihydroorotate dehydrogenase (EC 1.3.99.11) catalyzes the fourth sequential step in the de novo synthesis of uridine monophosphate. The enzyme has been identified as or surmised to be the pharmacological target for isoxazol, triazine, cinchoninic acid and (naphtho)quinone derivatives, which exerted antiproliferative, immunosuppressive, and antiparasitic effects. Despite this broad spectrum of biological and clinical relevance, there have been no comparative studies on drug-dihydroorotate dehydrogenase interactions. Here, we describe a study of the inhibition of the purified recombinant human and rat dihydroorotate dehydrogenase by ten compounds. 1,4-Naphthoquinone, 5,8-hydroxy-naphthoquinone and the natural compounds juglon, plumbagin and polyporic acid (quinone derivative) were found to function as alternative electron acceptors with 10-30% of control enzyme activity. The human and rat enzyme activity was decreased by 50% by the natural compound lawsone ( > 500 and 49 microM, respectively) and by the derivatives dichloroally-lawsone (67 and 10 nM), lapachol (618 and 61 nM) and atovaquone (15 microM and 698 nM). With respect to the quinone co-substrate of the dihydroorotate dehydrogenase, atovaquone (Kic = 2.7 microM) and dichloroally-lawsone (Kic = 9.8 nM) were shown to be competitive inhibitors of GENE. Atovaquone (Kic = 60 nM) was also acompetitive inhibitor of the rat enzyme. Dichloroally]-lawsone was found to be a time-dependent inhibitor of the rat enzyme, with the lowest inhibition constant (Ki* = 0.77 nM) determined so far for mammalian dihydroorotate dehydrogenases. Another inhibitor, CHEMICAL was previously reported to be a slow-binding inhibitor of the GENE [W. Knecht, M. Loffler, Species-related inhibition of human and rat dihyroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives, Biochem. Pharmacol. 56 (1998) 1259-1264]. The slow binding features of this potent inhibitor (Ki* = 1.8 nM) with the human enzyme, were verified and seen to be one of the reasons for the narrow therapeutic window (efficacy versus toxicity) reported from clinical trials on its antiproliferative and immunosuppressive action. With respect to the substrate dihydroorotate, atovaquone was an uncompetitive inhibitor of GENE (Kiu = 11.6 microM) and a non-competitive inhibitor of the rat enzyme (Kiu = 905/ Kic = 1,012 nM). 1.5 mM polyporic acid, a natural quinone from fungi, influenced the activity of the human enzyme only slightly; the activity of the rat enzyme was decreased by 30%. | INHIBITOR |
| Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid. Mitochondrially-bound dihydroorotate dehydrogenase (EC 1.3.99.11) catalyzes the fourth sequential step in the de novo synthesis of uridine monophosphate. The enzyme has been identified as or surmised to be the pharmacological target for CHEMICAL, triazine, cinchoninic acid and (naphtho)quinone derivatives, which exerted antiproliferative, immunosuppressive, and antiparasitic effects. Despite this broad spectrum of biological and clinical relevance, there have been no comparative studies on drug-dihydroorotate dehydrogenase interactions. Here, we describe a study of the inhibition of the purified recombinant human and rat dihydroorotate dehydrogenase by ten compounds. 1,4-Naphthoquinone, 5,8-hydroxy-naphthoquinone and the natural compounds juglon, plumbagin and polyporic acid (quinone derivative) were found to function as alternative electron acceptors with 10-30% of control enzyme activity. The human and rat enzyme activity was decreased by 50% by the natural compound lawsone ( > 500 and 49 microM, respectively) and by the derivatives dichloroally-lawsone (67 and 10 nM), lapachol (618 and 61 nM) and atovaquone (15 microM and 698 nM). With respect to the quinone co-substrate of the dihydroorotate dehydrogenase, atovaquone (Kic = 2.7 microM) and dichloroally-lawsone (Kic = 9.8 nM) were shown to be competitive inhibitors of human dihydroorotate dehydrogenase. Atovaquone (Kic = 60 nM) was also acompetitive inhibitor of the rat enzyme. Dichloroally]-lawsone was found to be a time-dependent inhibitor of the rat enzyme, with the lowest inhibition constant (Ki* = 0.77 nM) determined so far for mammalian dihydroorotate dehydrogenases. Another inhibitor, brequinar was previously reported to be a slow-binding inhibitor of the human dihydroorotate dehydrogenase [W. Knecht, M. Loffler, Species-related inhibition of GENE by immunosuppressive CHEMICAL and cinchoninic acid derivatives, Biochem. Pharmacol. 56 (1998) 1259-1264]. The slow binding features of this potent inhibitor (Ki* = 1.8 nM) with the human enzyme, were verified and seen to be one of the reasons for the narrow therapeutic window (efficacy versus toxicity) reported from clinical trials on its antiproliferative and immunosuppressive action. With respect to the substrate dihydroorotate, atovaquone was an uncompetitive inhibitor of human dihydroorotate dehydrogenase (Kiu = 11.6 microM) and a non-competitive inhibitor of the rat enzyme (Kiu = 905/ Kic = 1,012 nM). 1.5 mM polyporic acid, a natural quinone from fungi, influenced the activity of the human enzyme only slightly; the activity of the rat enzyme was decreased by 30%. | INHIBITOR |
| Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid. Mitochondrially-bound dihydroorotate dehydrogenase (EC 1.3.99.11) catalyzes the fourth sequential step in the de novo synthesis of uridine monophosphate. The enzyme has been identified as or surmised to be the pharmacological target for isoxazol, triazine, CHEMICAL and (naphtho)quinone derivatives, which exerted antiproliferative, immunosuppressive, and antiparasitic effects. Despite this broad spectrum of biological and clinical relevance, there have been no comparative studies on drug-dihydroorotate dehydrogenase interactions. Here, we describe a study of the inhibition of the purified recombinant human and rat dihydroorotate dehydrogenase by ten compounds. 1,4-Naphthoquinone, 5,8-hydroxy-naphthoquinone and the natural compounds juglon, plumbagin and polyporic acid (quinone derivative) were found to function as alternative electron acceptors with 10-30% of control enzyme activity. The human and rat enzyme activity was decreased by 50% by the natural compound lawsone ( > 500 and 49 microM, respectively) and by the derivatives dichloroally-lawsone (67 and 10 nM), lapachol (618 and 61 nM) and atovaquone (15 microM and 698 nM). With respect to the quinone co-substrate of the dihydroorotate dehydrogenase, atovaquone (Kic = 2.7 microM) and dichloroally-lawsone (Kic = 9.8 nM) were shown to be competitive inhibitors of human dihydroorotate dehydrogenase. Atovaquone (Kic = 60 nM) was also acompetitive inhibitor of the rat enzyme. Dichloroally]-lawsone was found to be a time-dependent inhibitor of the rat enzyme, with the lowest inhibition constant (Ki* = 0.77 nM) determined so far for mammalian dihydroorotate dehydrogenases. Another inhibitor, brequinar was previously reported to be a slow-binding inhibitor of the human dihydroorotate dehydrogenase [W. Knecht, M. Loffler, Species-related inhibition of GENE by immunosuppressive isoxazol and CHEMICAL derivatives, Biochem. Pharmacol. 56 (1998) 1259-1264]. The slow binding features of this potent inhibitor (Ki* = 1.8 nM) with the human enzyme, were verified and seen to be one of the reasons for the narrow therapeutic window (efficacy versus toxicity) reported from clinical trials on its antiproliferative and immunosuppressive action. With respect to the substrate dihydroorotate, atovaquone was an uncompetitive inhibitor of human dihydroorotate dehydrogenase (Kiu = 11.6 microM) and a non-competitive inhibitor of the rat enzyme (Kiu = 905/ Kic = 1,012 nM). 1.5 mM polyporic acid, a natural quinone from fungi, influenced the activity of the human enzyme only slightly; the activity of the rat enzyme was decreased by 30%. | INHIBITOR |
| Kinetics of inhibition of human and rat CHEMICAL dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid. Mitochondrially-bound CHEMICAL dehydrogenase (EC 1.3.99.11) catalyzes the fourth sequential step in the de novo synthesis of uridine monophosphate. The enzyme has been identified as or surmised to be the pharmacological target for isoxazol, triazine, cinchoninic acid and (naphtho)quinone derivatives, which exerted antiproliferative, immunosuppressive, and antiparasitic effects. Despite this broad spectrum of biological and clinical relevance, there have been no comparative studies on drug-dihydroorotate dehydrogenase interactions. Here, we describe a study of the inhibition of the purified recombinant human and rat CHEMICAL dehydrogenase by ten compounds. 1,4-Naphthoquinone, 5,8-hydroxy-naphthoquinone and the natural compounds juglon, plumbagin and polyporic acid (quinone derivative) were found to function as alternative electron acceptors with 10-30% of control enzyme activity. The human and rat enzyme activity was decreased by 50% by the natural compound lawsone ( > 500 and 49 microM, respectively) and by the derivatives dichloroally-lawsone (67 and 10 nM), lapachol (618 and 61 nM) and atovaquone (15 microM and 698 nM). With respect to the quinone co-substrate of the CHEMICAL dehydrogenase, atovaquone (Kic = 2.7 microM) and dichloroally-lawsone (Kic = 9.8 nM) were shown to be competitive inhibitors of human CHEMICAL dehydrogenase. Atovaquone (Kic = 60 nM) was also acompetitive inhibitor of the rat enzyme. Dichloroally]-lawsone was found to be a time-dependent inhibitor of the rat enzyme, with the lowest inhibition constant (Ki* = 0.77 nM) determined so far for mammalian CHEMICAL dehydrogenases. Another inhibitor, brequinar was previously reported to be a slow-binding inhibitor of the human CHEMICAL dehydrogenase [W. Knecht, M. Loffler, Species-related inhibition of human and rat dihyroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives, Biochem. Pharmacol. 56 (1998) 1259-1264]. The slow binding features of this potent inhibitor (Ki* = 1.8 nM) with the human enzyme, were verified and seen to be one of the reasons for the narrow therapeutic window (efficacy versus toxicity) reported from clinical trials on its antiproliferative and immunosuppressive action. With respect to the substrate CHEMICAL, atovaquone was an uncompetitive inhibitor of GENE (Kiu = 11.6 microM) and a non-competitive inhibitor of the rat enzyme (Kiu = 905/ Kic = 1,012 nM). 1.5 mM polyporic acid, a natural quinone from fungi, influenced the activity of the human enzyme only slightly; the activity of the rat enzyme was decreased by 30%. | INHIBITOR |
| Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by CHEMICAL, lawsone derivatives, brequinar sodium and polyporic acid. Mitochondrially-bound dihydroorotate dehydrogenase (EC 1.3.99.11) catalyzes the fourth sequential step in the de novo synthesis of uridine monophosphate. The enzyme has been identified as or surmised to be the pharmacological target for isoxazol, triazine, cinchoninic acid and (naphtho)quinone derivatives, which exerted antiproliferative, immunosuppressive, and antiparasitic effects. Despite this broad spectrum of biological and clinical relevance, there have been no comparative studies on drug-dihydroorotate dehydrogenase interactions. Here, we describe a study of the inhibition of the purified recombinant human and rat dihydroorotate dehydrogenase by ten compounds. 1,4-Naphthoquinone, 5,8-hydroxy-naphthoquinone and the natural compounds juglon, plumbagin and polyporic acid (quinone derivative) were found to function as alternative electron acceptors with 10-30% of control enzyme activity. The human and rat enzyme activity was decreased by 50% by the natural compound lawsone ( > 500 and 49 microM, respectively) and by the derivatives dichloroally-lawsone (67 and 10 nM), lapachol (618 and 61 nM) and CHEMICAL (15 microM and 698 nM). With respect to the quinone co-substrate of the dihydroorotate dehydrogenase, CHEMICAL (Kic = 2.7 microM) and dichloroally-lawsone (Kic = 9.8 nM) were shown to be competitive inhibitors of GENE. CHEMICAL (Kic = 60 nM) was also acompetitive inhibitor of the rat enzyme. Dichloroally]-lawsone was found to be a time-dependent inhibitor of the rat enzyme, with the lowest inhibition constant (Ki* = 0.77 nM) determined so far for mammalian dihydroorotate dehydrogenases. Another inhibitor, brequinar was previously reported to be a slow-binding inhibitor of the GENE [W. Knecht, M. Loffler, Species-related inhibition of human and rat dihyroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives, Biochem. Pharmacol. 56 (1998) 1259-1264]. The slow binding features of this potent inhibitor (Ki* = 1.8 nM) with the human enzyme, were verified and seen to be one of the reasons for the narrow therapeutic window (efficacy versus toxicity) reported from clinical trials on its antiproliferative and immunosuppressive action. With respect to the substrate dihydroorotate, CHEMICAL was an uncompetitive inhibitor of GENE (Kiu = 11.6 microM) and a non-competitive inhibitor of the rat enzyme (Kiu = 905/ Kic = 1,012 nM). 1.5 mM polyporic acid, a natural quinone from fungi, influenced the activity of the human enzyme only slightly; the activity of the rat enzyme was decreased by 30%. | INHIBITOR |
| Kinetics of inhibition of GENE by atovaquone, lawsone derivatives, CHEMICAL and polyporic acid. Mitochondrially-bound dihydroorotate dehydrogenase (EC 1.3.99.11) catalyzes the fourth sequential step in the de novo synthesis of uridine monophosphate. The enzyme has been identified as or surmised to be the pharmacological target for isoxazol, triazine, cinchoninic acid and (naphtho)quinone derivatives, which exerted antiproliferative, immunosuppressive, and antiparasitic effects. Despite this broad spectrum of biological and clinical relevance, there have been no comparative studies on drug-dihydroorotate dehydrogenase interactions. Here, we describe a study of the inhibition of the purified recombinant GENE by ten compounds. 1,4-Naphthoquinone, 5,8-hydroxy-naphthoquinone and the natural compounds juglon, plumbagin and polyporic acid (quinone derivative) were found to function as alternative electron acceptors with 10-30% of control enzyme activity. The human and rat enzyme activity was decreased by 50% by the natural compound lawsone ( > 500 and 49 microM, respectively) and by the derivatives dichloroally-lawsone (67 and 10 nM), lapachol (618 and 61 nM) and atovaquone (15 microM and 698 nM). With respect to the quinone co-substrate of the dihydroorotate dehydrogenase, atovaquone (Kic = 2.7 microM) and dichloroally-lawsone (Kic = 9.8 nM) were shown to be competitive inhibitors of human dihydroorotate dehydrogenase. Atovaquone (Kic = 60 nM) was also acompetitive inhibitor of the rat enzyme. Dichloroally]-lawsone was found to be a time-dependent inhibitor of the rat enzyme, with the lowest inhibition constant (Ki* = 0.77 nM) determined so far for mammalian dihydroorotate dehydrogenases. Another inhibitor, brequinar was previously reported to be a slow-binding inhibitor of the human dihydroorotate dehydrogenase [W. Knecht, M. Loffler, Species-related inhibition of human and rat dihyroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives, Biochem. Pharmacol. 56 (1998) 1259-1264]. The slow binding features of this potent inhibitor (Ki* = 1.8 nM) with the human enzyme, were verified and seen to be one of the reasons for the narrow therapeutic window (efficacy versus toxicity) reported from clinical trials on its antiproliferative and immunosuppressive action. With respect to the substrate dihydroorotate, atovaquone was an uncompetitive inhibitor of human dihydroorotate dehydrogenase (Kiu = 11.6 microM) and a non-competitive inhibitor of the rat enzyme (Kiu = 905/ Kic = 1,012 nM). 1.5 mM polyporic acid, a natural quinone from fungi, influenced the activity of the human enzyme only slightly; the activity of the rat enzyme was decreased by 30%. | INHIBITOR |
| Kinetics of inhibition of GENE by atovaquone, lawsone derivatives, brequinar sodium and CHEMICAL. Mitochondrially-bound dihydroorotate dehydrogenase (EC 1.3.99.11) catalyzes the fourth sequential step in the de novo synthesis of uridine monophosphate. The enzyme has been identified as or surmised to be the pharmacological target for isoxazol, triazine, cinchoninic acid and (naphtho)quinone derivatives, which exerted antiproliferative, immunosuppressive, and antiparasitic effects. Despite this broad spectrum of biological and clinical relevance, there have been no comparative studies on drug-dihydroorotate dehydrogenase interactions. Here, we describe a study of the inhibition of the purified recombinant GENE by ten compounds. 1,4-Naphthoquinone, 5,8-hydroxy-naphthoquinone and the natural compounds juglon, plumbagin and CHEMICAL (quinone derivative) were found to function as alternative electron acceptors with 10-30% of control enzyme activity. The human and rat enzyme activity was decreased by 50% by the natural compound lawsone ( > 500 and 49 microM, respectively) and by the derivatives dichloroally-lawsone (67 and 10 nM), lapachol (618 and 61 nM) and atovaquone (15 microM and 698 nM). With respect to the quinone co-substrate of the dihydroorotate dehydrogenase, atovaquone (Kic = 2.7 microM) and dichloroally-lawsone (Kic = 9.8 nM) were shown to be competitive inhibitors of human dihydroorotate dehydrogenase. Atovaquone (Kic = 60 nM) was also acompetitive inhibitor of the rat enzyme. Dichloroally]-lawsone was found to be a time-dependent inhibitor of the rat enzyme, with the lowest inhibition constant (Ki* = 0.77 nM) determined so far for mammalian dihydroorotate dehydrogenases. Another inhibitor, brequinar was previously reported to be a slow-binding inhibitor of the human dihydroorotate dehydrogenase [W. Knecht, M. Loffler, Species-related inhibition of human and rat dihyroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives, Biochem. Pharmacol. 56 (1998) 1259-1264]. The slow binding features of this potent inhibitor (Ki* = 1.8 nM) with the human enzyme, were verified and seen to be one of the reasons for the narrow therapeutic window (efficacy versus toxicity) reported from clinical trials on its antiproliferative and immunosuppressive action. With respect to the substrate dihydroorotate, atovaquone was an uncompetitive inhibitor of human dihydroorotate dehydrogenase (Kiu = 11.6 microM) and a non-competitive inhibitor of the rat enzyme (Kiu = 905/ Kic = 1,012 nM). 1.5 mM CHEMICAL, a natural quinone from fungi, influenced the activity of the human enzyme only slightly; the activity of the rat enzyme was decreased by 30%. | INHIBITOR |
| Kinetics of inhibition of GENE by CHEMICAL, lawsone derivatives, brequinar sodium and polyporic acid. Mitochondrially-bound dihydroorotate dehydrogenase (EC 1.3.99.11) catalyzes the fourth sequential step in the de novo synthesis of uridine monophosphate. The enzyme has been identified as or surmised to be the pharmacological target for isoxazol, triazine, cinchoninic acid and (naphtho)quinone derivatives, which exerted antiproliferative, immunosuppressive, and antiparasitic effects. Despite this broad spectrum of biological and clinical relevance, there have been no comparative studies on drug-dihydroorotate dehydrogenase interactions. Here, we describe a study of the inhibition of the purified recombinant GENE by ten compounds. 1,4-Naphthoquinone, 5,8-hydroxy-naphthoquinone and the natural compounds juglon, plumbagin and polyporic acid (quinone derivative) were found to function as alternative electron acceptors with 10-30% of control enzyme activity. The human and rat enzyme activity was decreased by 50% by the natural compound lawsone ( > 500 and 49 microM, respectively) and by the derivatives dichloroally-lawsone (67 and 10 nM), lapachol (618 and 61 nM) and CHEMICAL (15 microM and 698 nM). With respect to the quinone co-substrate of the dihydroorotate dehydrogenase, CHEMICAL (Kic = 2.7 microM) and dichloroally-lawsone (Kic = 9.8 nM) were shown to be competitive inhibitors of human dihydroorotate dehydrogenase. CHEMICAL (Kic = 60 nM) was also acompetitive inhibitor of the rat enzyme. Dichloroally]-lawsone was found to be a time-dependent inhibitor of the rat enzyme, with the lowest inhibition constant (Ki* = 0.77 nM) determined so far for mammalian dihydroorotate dehydrogenases. Another inhibitor, brequinar was previously reported to be a slow-binding inhibitor of the human dihydroorotate dehydrogenase [W. Knecht, M. Loffler, Species-related inhibition of human and rat dihyroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives, Biochem. Pharmacol. 56 (1998) 1259-1264]. The slow binding features of this potent inhibitor (Ki* = 1.8 nM) with the human enzyme, were verified and seen to be one of the reasons for the narrow therapeutic window (efficacy versus toxicity) reported from clinical trials on its antiproliferative and immunosuppressive action. With respect to the substrate dihydroorotate, CHEMICAL was an uncompetitive inhibitor of human dihydroorotate dehydrogenase (Kiu = 11.6 microM) and a non-competitive inhibitor of the rat enzyme (Kiu = 905/ Kic = 1,012 nM). 1.5 mM polyporic acid, a natural quinone from fungi, influenced the activity of the human enzyme only slightly; the activity of the rat enzyme was decreased by 30%. | INHIBITOR |
| Kinetics of inhibition of GENE by atovaquone, CHEMICAL derivatives, brequinar sodium and polyporic acid. Mitochondrially-bound dihydroorotate dehydrogenase (EC 1.3.99.11) catalyzes the fourth sequential step in the de novo synthesis of uridine monophosphate. The enzyme has been identified as or surmised to be the pharmacological target for isoxazol, triazine, cinchoninic acid and (naphtho)quinone derivatives, which exerted antiproliferative, immunosuppressive, and antiparasitic effects. Despite this broad spectrum of biological and clinical relevance, there have been no comparative studies on drug-dihydroorotate dehydrogenase interactions. Here, we describe a study of the inhibition of the purified recombinant GENE by ten compounds. 1,4-Naphthoquinone, 5,8-hydroxy-naphthoquinone and the natural compounds juglon, plumbagin and polyporic acid (quinone derivative) were found to function as alternative electron acceptors with 10-30% of control enzyme activity. The human and rat enzyme activity was decreased by 50% by the natural compound CHEMICAL ( > 500 and 49 microM, respectively) and by the derivatives dichloroally-lawsone (67 and 10 nM), lapachol (618 and 61 nM) and atovaquone (15 microM and 698 nM). With respect to the quinone co-substrate of the dihydroorotate dehydrogenase, atovaquone (Kic = 2.7 microM) and dichloroally-lawsone (Kic = 9.8 nM) were shown to be competitive inhibitors of human dihydroorotate dehydrogenase. Atovaquone (Kic = 60 nM) was also acompetitive inhibitor of the rat enzyme. Dichloroally]-lawsone was found to be a time-dependent inhibitor of the rat enzyme, with the lowest inhibition constant (Ki* = 0.77 nM) determined so far for mammalian dihydroorotate dehydrogenases. Another inhibitor, brequinar was previously reported to be a slow-binding inhibitor of the human dihydroorotate dehydrogenase [W. Knecht, M. Loffler, Species-related inhibition of human and rat dihyroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives, Biochem. Pharmacol. 56 (1998) 1259-1264]. The slow binding features of this potent inhibitor (Ki* = 1.8 nM) with the human enzyme, were verified and seen to be one of the reasons for the narrow therapeutic window (efficacy versus toxicity) reported from clinical trials on its antiproliferative and immunosuppressive action. With respect to the substrate dihydroorotate, atovaquone was an uncompetitive inhibitor of human dihydroorotate dehydrogenase (Kiu = 11.6 microM) and a non-competitive inhibitor of the rat enzyme (Kiu = 905/ Kic = 1,012 nM). 1.5 mM polyporic acid, a natural quinone from fungi, influenced the activity of the human enzyme only slightly; the activity of the rat enzyme was decreased by 30%. | INHIBITOR |
| Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid. Mitochondrially-bound dihydroorotate dehydrogenase (EC 1.3.99.11) catalyzes the fourth sequential step in the de novo synthesis of uridine monophosphate. The enzyme has been identified as or surmised to be the pharmacological target for isoxazol, triazine, cinchoninic acid and (naphtho)quinone derivatives, which exerted antiproliferative, immunosuppressive, and antiparasitic effects. Despite this broad spectrum of biological and clinical relevance, there have been no comparative studies on drug-dihydroorotate dehydrogenase interactions. Here, we describe a study of the inhibition of the purified recombinant human and rat dihydroorotate dehydrogenase by ten compounds. 1,4-Naphthoquinone, 5,8-hydroxy-naphthoquinone and the natural compounds juglon, plumbagin and polyporic acid (quinone derivative) were found to function as alternative electron acceptors with 10-30% of control enzyme activity. The human and rat enzyme activity was decreased by 50% by the natural compound lawsone ( > 500 and 49 microM, respectively) and by the derivatives CHEMICAL (67 and 10 nM), lapachol (618 and 61 nM) and atovaquone (15 microM and 698 nM). With respect to the quinone co-substrate of the dihydroorotate dehydrogenase, atovaquone (Kic = 2.7 microM) and CHEMICAL (Kic = 9.8 nM) were shown to be competitive inhibitors of GENE. Atovaquone (Kic = 60 nM) was also acompetitive inhibitor of the rat enzyme. Dichloroally]-lawsone was found to be a time-dependent inhibitor of the rat enzyme, with the lowest inhibition constant (Ki* = 0.77 nM) determined so far for mammalian dihydroorotate dehydrogenases. Another inhibitor, brequinar was previously reported to be a slow-binding inhibitor of the GENE [W. Knecht, M. Loffler, Species-related inhibition of human and rat dihyroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives, Biochem. Pharmacol. 56 (1998) 1259-1264]. The slow binding features of this potent inhibitor (Ki* = 1.8 nM) with the human enzyme, were verified and seen to be one of the reasons for the narrow therapeutic window (efficacy versus toxicity) reported from clinical trials on its antiproliferative and immunosuppressive action. With respect to the substrate dihydroorotate, atovaquone was an uncompetitive inhibitor of GENE (Kiu = 11.6 microM) and a non-competitive inhibitor of the rat enzyme (Kiu = 905/ Kic = 1,012 nM). 1.5 mM polyporic acid, a natural quinone from fungi, influenced the activity of the human enzyme only slightly; the activity of the rat enzyme was decreased by 30%. | INHIBITOR |
| Kinetics of inhibition of human and rat GENE by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid. Mitochondrially-bound GENE (EC 1.3.99.11) catalyzes the fourth sequential step in the de novo synthesis of CHEMICAL. The enzyme has been identified as or surmised to be the pharmacological target for isoxazol, triazine, cinchoninic acid and (naphtho)quinone derivatives, which exerted antiproliferative, immunosuppressive, and antiparasitic effects. Despite this broad spectrum of biological and clinical relevance, there have been no comparative studies on drug-dihydroorotate dehydrogenase interactions. Here, we describe a study of the inhibition of the purified recombinant human and rat GENE by ten compounds. 1,4-Naphthoquinone, 5,8-hydroxy-naphthoquinone and the natural compounds juglon, plumbagin and polyporic acid (quinone derivative) were found to function as alternative electron acceptors with 10-30% of control enzyme activity. The human and rat enzyme activity was decreased by 50% by the natural compound lawsone ( > 500 and 49 microM, respectively) and by the derivatives dichloroally-lawsone (67 and 10 nM), lapachol (618 and 61 nM) and atovaquone (15 microM and 698 nM). With respect to the quinone co-substrate of the GENE, atovaquone (Kic = 2.7 microM) and dichloroally-lawsone (Kic = 9.8 nM) were shown to be competitive inhibitors of human GENE. Atovaquone (Kic = 60 nM) was also acompetitive inhibitor of the rat enzyme. Dichloroally]-lawsone was found to be a time-dependent inhibitor of the rat enzyme, with the lowest inhibition constant (Ki* = 0.77 nM) determined so far for mammalian dihydroorotate dehydrogenases. Another inhibitor, brequinar was previously reported to be a slow-binding inhibitor of the human GENE [W. Knecht, M. Loffler, Species-related inhibition of human and rat dihyroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives, Biochem. Pharmacol. 56 (1998) 1259-1264]. The slow binding features of this potent inhibitor (Ki* = 1.8 nM) with the human enzyme, were verified and seen to be one of the reasons for the narrow therapeutic window (efficacy versus toxicity) reported from clinical trials on its antiproliferative and immunosuppressive action. With respect to the substrate dihydroorotate, atovaquone was an uncompetitive inhibitor of human GENE (Kiu = 11.6 microM) and a non-competitive inhibitor of the rat enzyme (Kiu = 905/ Kic = 1,012 nM). 1.5 mM polyporic acid, a natural quinone from fungi, influenced the activity of the human enzyme only slightly; the activity of the rat enzyme was decreased by 30%. | PRODUCT-OF |
| Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid. Mitochondrially-bound dihydroorotate dehydrogenase (GENE) catalyzes the fourth sequential step in the de novo synthesis of CHEMICAL. The enzyme has been identified as or surmised to be the pharmacological target for isoxazol, triazine, cinchoninic acid and (naphtho)quinone derivatives, which exerted antiproliferative, immunosuppressive, and antiparasitic effects. Despite this broad spectrum of biological and clinical relevance, there have been no comparative studies on drug-dihydroorotate dehydrogenase interactions. Here, we describe a study of the inhibition of the purified recombinant human and rat dihydroorotate dehydrogenase by ten compounds. 1,4-Naphthoquinone, 5,8-hydroxy-naphthoquinone and the natural compounds juglon, plumbagin and polyporic acid (quinone derivative) were found to function as alternative electron acceptors with 10-30% of control enzyme activity. The human and rat enzyme activity was decreased by 50% by the natural compound lawsone ( > 500 and 49 microM, respectively) and by the derivatives dichloroally-lawsone (67 and 10 nM), lapachol (618 and 61 nM) and atovaquone (15 microM and 698 nM). With respect to the quinone co-substrate of the dihydroorotate dehydrogenase, atovaquone (Kic = 2.7 microM) and dichloroally-lawsone (Kic = 9.8 nM) were shown to be competitive inhibitors of human dihydroorotate dehydrogenase. Atovaquone (Kic = 60 nM) was also acompetitive inhibitor of the rat enzyme. Dichloroally]-lawsone was found to be a time-dependent inhibitor of the rat enzyme, with the lowest inhibition constant (Ki* = 0.77 nM) determined so far for mammalian dihydroorotate dehydrogenases. Another inhibitor, brequinar was previously reported to be a slow-binding inhibitor of the human dihydroorotate dehydrogenase [W. Knecht, M. Loffler, Species-related inhibition of human and rat dihyroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives, Biochem. Pharmacol. 56 (1998) 1259-1264]. The slow binding features of this potent inhibitor (Ki* = 1.8 nM) with the human enzyme, were verified and seen to be one of the reasons for the narrow therapeutic window (efficacy versus toxicity) reported from clinical trials on its antiproliferative and immunosuppressive action. With respect to the substrate dihydroorotate, atovaquone was an uncompetitive inhibitor of human dihydroorotate dehydrogenase (Kiu = 11.6 microM) and a non-competitive inhibitor of the rat enzyme (Kiu = 905/ Kic = 1,012 nM). 1.5 mM polyporic acid, a natural quinone from fungi, influenced the activity of the human enzyme only slightly; the activity of the rat enzyme was decreased by 30%. | PRODUCT-OF |
| Kinetics of inhibition of human and rat GENE by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid. Mitochondrially-bound GENE (EC 1.3.99.11) catalyzes the fourth sequential step in the de novo synthesis of uridine monophosphate. The enzyme has been identified as or surmised to be the pharmacological target for isoxazol, triazine, cinchoninic acid and (naphtho)quinone derivatives, which exerted antiproliferative, immunosuppressive, and antiparasitic effects. Despite this broad spectrum of biological and clinical relevance, there have been no comparative studies on drug-dihydroorotate dehydrogenase interactions. Here, we describe a study of the inhibition of the purified recombinant human and rat GENE by ten compounds. 1,4-Naphthoquinone, 5,8-hydroxy-naphthoquinone and the natural compounds juglon, plumbagin and polyporic acid (quinone derivative) were found to function as alternative electron acceptors with 10-30% of control enzyme activity. The human and rat enzyme activity was decreased by 50% by the natural compound lawsone ( > 500 and 49 microM, respectively) and by the derivatives dichloroally-lawsone (67 and 10 nM), lapachol (618 and 61 nM) and atovaquone (15 microM and 698 nM). With respect to the CHEMICAL co-substrate of the GENE, atovaquone (Kic = 2.7 microM) and dichloroally-lawsone (Kic = 9.8 nM) were shown to be competitive inhibitors of human GENE. Atovaquone (Kic = 60 nM) was also acompetitive inhibitor of the rat enzyme. Dichloroally]-lawsone was found to be a time-dependent inhibitor of the rat enzyme, with the lowest inhibition constant (Ki* = 0.77 nM) determined so far for mammalian dihydroorotate dehydrogenases. Another inhibitor, brequinar was previously reported to be a slow-binding inhibitor of the human GENE [W. Knecht, M. Loffler, Species-related inhibition of human and rat dihyroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives, Biochem. Pharmacol. 56 (1998) 1259-1264]. The slow binding features of this potent inhibitor (Ki* = 1.8 nM) with the human enzyme, were verified and seen to be one of the reasons for the narrow therapeutic window (efficacy versus toxicity) reported from clinical trials on its antiproliferative and immunosuppressive action. With respect to the substrate dihydroorotate, atovaquone was an uncompetitive inhibitor of human GENE (Kiu = 11.6 microM) and a non-competitive inhibitor of the rat enzyme (Kiu = 905/ Kic = 1,012 nM). 1.5 mM polyporic acid, a natural CHEMICAL from fungi, influenced the activity of the human enzyme only slightly; the activity of the rat enzyme was decreased by 30%. | SUBSTRATE |
| Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. BACKGROUND: A mutation in the cardiac sodium channel gene (SCN5A) has been described in patients with the syndrome of right bundle branch block, ST-segment elevation in leads V1 to V3, and sudden death (Brugada syndrome). These electrocardiographic manifestations are transient in many patients with the syndrome. The present study examined arrhythmic risk in patients with overt and concealed forms of the disease and the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk. METHODS AND RESULTS: The effect of intravenous CHEMICAL (1 mg/kg), procainamide (10 mg/kg), or flecainide (2 mg/kg) on the ECG was studied in 34 patients with the syndrome and transient normalization of the ECG (group A), 11 members of 3 families in whom a GENE mutation was associated with the syndrome and 8 members in whom it was not (group B), and 53 control subjects (group C). CHEMICAL, procainamide, or flecainide administration resulted in ST-segment elevation and right bundle branch block in all patients in group A and in all 11 patients with the mutation in group B. A similar pattern could not be elicited in the 8 patients in group B who lacked the mutation or in any person in group C. The follow-up period (37+/-33 months) revealed no differences in the incidence of arrhythmia between the 34 patients in whom the phenotypic manifestation of the syndrome was transient and the 24 patients in whom it was persistent (log-rank, 0.639). CONCLUSIONS: The data demonstrated a similar incidence of potentially lethal arrhythmias in patients displaying transient versus persistent ST-segment elevation and right bundle branch block, as well as the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk. | NO-RELATIONSHIP |
| Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. BACKGROUND: A mutation in the cardiac sodium channel gene (SCN5A) has been described in patients with the syndrome of right bundle branch block, ST-segment elevation in leads V1 to V3, and sudden death (Brugada syndrome). These electrocardiographic manifestations are transient in many patients with the syndrome. The present study examined arrhythmic risk in patients with overt and concealed forms of the disease and the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk. METHODS AND RESULTS: The effect of intravenous ajmaline (1 mg/kg), CHEMICAL (10 mg/kg), or flecainide (2 mg/kg) on the ECG was studied in 34 patients with the syndrome and transient normalization of the ECG (group A), 11 members of 3 families in whom a GENE mutation was associated with the syndrome and 8 members in whom it was not (group B), and 53 control subjects (group C). Ajmaline, CHEMICAL, or flecainide administration resulted in ST-segment elevation and right bundle branch block in all patients in group A and in all 11 patients with the mutation in group B. A similar pattern could not be elicited in the 8 patients in group B who lacked the mutation or in any person in group C. The follow-up period (37+/-33 months) revealed no differences in the incidence of arrhythmia between the 34 patients in whom the phenotypic manifestation of the syndrome was transient and the 24 patients in whom it was persistent (log-rank, 0.639). CONCLUSIONS: The data demonstrated a similar incidence of potentially lethal arrhythmias in patients displaying transient versus persistent ST-segment elevation and right bundle branch block, as well as the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk. | NO-RELATIONSHIP |
| Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. BACKGROUND: A mutation in the cardiac sodium channel gene (SCN5A) has been described in patients with the syndrome of right bundle branch block, ST-segment elevation in leads V1 to V3, and sudden death (Brugada syndrome). These electrocardiographic manifestations are transient in many patients with the syndrome. The present study examined arrhythmic risk in patients with overt and concealed forms of the disease and the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk. METHODS AND RESULTS: The effect of intravenous ajmaline (1 mg/kg), procainamide (10 mg/kg), or CHEMICAL (2 mg/kg) on the ECG was studied in 34 patients with the syndrome and transient normalization of the ECG (group A), 11 members of 3 families in whom a GENE mutation was associated with the syndrome and 8 members in whom it was not (group B), and 53 control subjects (group C). Ajmaline, procainamide, or CHEMICAL administration resulted in ST-segment elevation and right bundle branch block in all patients in group A and in all 11 patients with the mutation in group B. A similar pattern could not be elicited in the 8 patients in group B who lacked the mutation or in any person in group C. The follow-up period (37+/-33 months) revealed no differences in the incidence of arrhythmia between the 34 patients in whom the phenotypic manifestation of the syndrome was transient and the 24 patients in whom it was persistent (log-rank, 0.639). CONCLUSIONS: The data demonstrated a similar incidence of potentially lethal arrhythmias in patients displaying transient versus persistent ST-segment elevation and right bundle branch block, as well as the effectiveness of sodium channel blockers to unmask the syndrome and, thus, identify patients at risk. | NO-RELATIONSHIP |
| Determinants of voltage-dependent inactivation affect CHEMICAL block of calcium channels. The voltage gated calcium channel family is a major target for a range of therapeutic drugs. CHEMICAL (Ro 40-5967) belongs to a new chemical class of these molecules which differs from other Ca2+ antagonists by its ability to potently block T-type Ca2+ channels. However, this molecule has also been shown to inhibit other GENE subtypes. To further analyze the mechanism governing the GENE-CHEMICAL interaction, we examined the effect of CHEMICAL on various recombinant Ca2+ channels expressed in mammalian cells from their cloned cDNAs, using Ca2+ as the permeant ion at physiological concentration. Expression of alpha1A, alpha1C, and alpha1E in tsA 201 cells resulted in Ca2+ currents with functional characteristics closely related to those of their native counterparts. CHEMICAL blocked alpha1A and alpha1E with a Kd comparable to that reported for T-type channels, but had a lower affinity (approximately 30-fold) for alpha1C. For each channel, inhibition by CHEMICAL was consistent with high-affinity binding to the inactivated state. Modulation of the voltage-dependent inactivation properties by the nature of the coexpressed beta subunit or the alpha1 splice variant altered block at the CHEMICAL receptor site. Therefore, we conclude that the tissue and sub-cellular localization of calcium channel subunits as well as their specific associations are essential parameters to understand the in vivo effects of CHEMICAL. | DIRECT-REGULATOR |
| Determinants of voltage-dependent inactivation affect CHEMICAL block of calcium channels. The voltage gated GENE family is a major target for a range of therapeutic drugs. CHEMICAL (Ro 40-5967) belongs to a new chemical class of these molecules which differs from other Ca2+ antagonists by its ability to potently block T-type Ca2+ channels. However, this molecule has also been shown to inhibit other Ca2+ channel subtypes. To further analyze the mechanism governing the Ca2+ channel-Mibefradil interaction, we examined the effect of CHEMICAL on various recombinant Ca2+ channels expressed in mammalian cells from their cloned cDNAs, using Ca2+ as the permeant ion at physiological concentration. Expression of alpha1A, alpha1C, and alpha1E in tsA 201 cells resulted in Ca2+ currents with functional characteristics closely related to those of their native counterparts. CHEMICAL blocked alpha1A and alpha1E with a Kd comparable to that reported for T-type channels, but had a lower affinity (approximately 30-fold) for alpha1C. For each channel, inhibition by CHEMICAL was consistent with high-affinity binding to the inactivated state. Modulation of the voltage-dependent inactivation properties by the nature of the coexpressed beta subunit or the alpha1 splice variant altered block at the CHEMICAL receptor site. Therefore, we conclude that the tissue and sub-cellular localization of GENE subunits as well as their specific associations are essential parameters to understand the in vivo effects of CHEMICAL. | REGULATOR |
| Determinants of voltage-dependent inactivation affect CHEMICAL block of calcium channels. The voltage gated calcium channel family is a major target for a range of therapeutic drugs. CHEMICAL (Ro 40-5967) belongs to a new chemical class of these molecules which differs from other Ca2+ antagonists by its ability to potently block T-type Ca2+ channels. However, this molecule has also been shown to inhibit other Ca2+ channel subtypes. To further analyze the mechanism governing the Ca2+ channel-Mibefradil interaction, we examined the effect of CHEMICAL on various recombinant Ca2+ channels expressed in mammalian cells from their cloned cDNAs, using Ca2+ as the permeant ion at physiological concentration. Expression of alpha1A, alpha1C, and alpha1E in tsA 201 cells resulted in Ca2+ currents with functional characteristics closely related to those of their native counterparts. CHEMICAL blocked alpha1A and alpha1E with a Kd comparable to that reported for GENE, but had a lower affinity (approximately 30-fold) for alpha1C. For each channel, inhibition by CHEMICAL was consistent with high-affinity binding to the inactivated state. Modulation of the voltage-dependent inactivation properties by the nature of the coexpressed beta subunit or the alpha1 splice variant altered block at the CHEMICAL receptor site. Therefore, we conclude that the tissue and sub-cellular localization of calcium channel subunits as well as their specific associations are essential parameters to understand the in vivo effects of CHEMICAL. | DIRECT-REGULATOR |
| Determinants of voltage-dependent inactivation affect CHEMICAL block of calcium channels. The voltage gated calcium channel family is a major target for a range of therapeutic drugs. CHEMICAL (Ro 40-5967) belongs to a new chemical class of these molecules which differs from other Ca2+ antagonists by its ability to potently block GENE. However, this molecule has also been shown to inhibit other Ca2+ channel subtypes. To further analyze the mechanism governing the Ca2+ channel-Mibefradil interaction, we examined the effect of CHEMICAL on various recombinant Ca2+ channels expressed in mammalian cells from their cloned cDNAs, using Ca2+ as the permeant ion at physiological concentration. Expression of alpha1A, alpha1C, and alpha1E in tsA 201 cells resulted in Ca2+ currents with functional characteristics closely related to those of their native counterparts. CHEMICAL blocked alpha1A and alpha1E with a Kd comparable to that reported for T-type channels, but had a lower affinity (approximately 30-fold) for alpha1C. For each channel, inhibition by CHEMICAL was consistent with high-affinity binding to the inactivated state. Modulation of the voltage-dependent inactivation properties by the nature of the coexpressed beta subunit or the alpha1 splice variant altered block at the CHEMICAL receptor site. Therefore, we conclude that the tissue and sub-cellular localization of calcium channel subunits as well as their specific associations are essential parameters to understand the in vivo effects of CHEMICAL. | INHIBITOR |
| Determinants of voltage-dependent inactivation affect CHEMICAL block of GENE. The voltage gated calcium channel family is a major target for a range of therapeutic drugs. CHEMICAL (Ro 40-5967) belongs to a new chemical class of these molecules which differs from other Ca2+ antagonists by its ability to potently block T-type Ca2+ channels. However, this molecule has also been shown to inhibit other Ca2+ channel subtypes. To further analyze the mechanism governing the Ca2+ channel-Mibefradil interaction, we examined the effect of CHEMICAL on various recombinant Ca2+ channels expressed in mammalian cells from their cloned cDNAs, using Ca2+ as the permeant ion at physiological concentration. Expression of alpha1A, alpha1C, and alpha1E in tsA 201 cells resulted in Ca2+ currents with functional characteristics closely related to those of their native counterparts. CHEMICAL blocked alpha1A and alpha1E with a Kd comparable to that reported for T-type channels, but had a lower affinity (approximately 30-fold) for alpha1C. For each channel, inhibition by CHEMICAL was consistent with high-affinity binding to the inactivated state. Modulation of the voltage-dependent inactivation properties by the nature of the coexpressed beta subunit or the alpha1 splice variant altered block at the CHEMICAL receptor site. Therefore, we conclude that the tissue and sub-cellular localization of calcium channel subunits as well as their specific associations are essential parameters to understand the in vivo effects of CHEMICAL. | INHIBITOR |
| Determinants of voltage-dependent inactivation affect Mibefradil block of calcium channels. The voltage gated calcium channel family is a major target for a range of therapeutic drugs. Mibefradil (CHEMICAL) belongs to a new chemical class of these molecules which differs from other Ca2+ antagonists by its ability to potently block GENE. However, this molecule has also been shown to inhibit other Ca2+ channel subtypes. To further analyze the mechanism governing the Ca2+ channel-Mibefradil interaction, we examined the effect of Mibefradil on various recombinant Ca2+ channels expressed in mammalian cells from their cloned cDNAs, using Ca2+ as the permeant ion at physiological concentration. Expression of alpha1A, alpha1C, and alpha1E in tsA 201 cells resulted in Ca2+ currents with functional characteristics closely related to those of their native counterparts. Mibefradil blocked alpha1A and alpha1E with a Kd comparable to that reported for T-type channels, but had a lower affinity (approximately 30-fold) for alpha1C. For each channel, inhibition by Mibefradil was consistent with high-affinity binding to the inactivated state. Modulation of the voltage-dependent inactivation properties by the nature of the coexpressed beta subunit or the alpha1 splice variant altered block at the Mibefradil receptor site. Therefore, we conclude that the tissue and sub-cellular localization of calcium channel subunits as well as their specific associations are essential parameters to understand the in vivo effects of Mibefradil. | INHIBITOR |
| Use of CHEMICAL for an effective blood conservation strategy after total knee arthroplasty. We have investigated the effect of treatment with CHEMICAL, an inhibitor of fibrinolysis, on blood loss, blood transfusion requirements and blood coagulation in a randomized, double-blind, placebo-controlled study of 42 patients after total knee arthroplasty. CHEMICAL 15 mg kg-1 (n = 21) or an equivalent volume of normal saline (n = 21) was given 30 min before surgery and subsequently every 8 h for 3 days. Coagulation and fibrinolysis values, blood loss and blood units administered were measured before administration of CHEMICAL, 8 h after the end of surgery and at 24 and 72 h after operation. Coagulation profile was examined (bleeding time, platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), GENE, beta-thromboglobulin and fibrinogen). Fibrinolysis was evaluated by measurement of concentrations of D-dimer and fibrinogen degradation products (FDP). Total blood loss in the CHEMICAL group was 678 (SD 352) ml compared with 1419 (607) ml in the control group (P < 0.001), and occurred primarily during the first 24 h after surgery. Thirteen patients received 1-5 u. of packed red blood cells in the control group compared with two patients in the CHEMICAL group, who received 3 u. (P < 0.001). Postoperative packed cell volume values were higher in the CHEMICAL group despite fewer blood transfusions. Postoperative concentrations of GENE were decreased significantly in the CHEMICAL group (P < 0.001). Platelet count, PT, aPTT, bleeding time, beta-thromboglobulin, fibrinogen and FDP concentrations did not differ between groups, but D-dimer concentrations were increased in the control group. Thromboembolic complications occurred in two patients in the control group compared with none in the CHEMICAL group. | INDIRECT-DOWNREGULATOR |
| Correlations between serotonin level and single-cell firing in the rat's nucleus raphe magnus. The relation between serotonin release and electrical activity was examined in the nucleus raphe magnus of rats anesthetized with pentobarbital. Serotonin levels were monitored through a carbon-fiber microelectrode by fast cyclic voltammetry (usually at 1 Hz). Single-cell firing was recorded through the same microelectrode, except during the voltammetry waveform and associated electrical artifact (totaling about 30 ms). Multi-barrel micropipettes incorporating the voltammetry electrode were used for iontophoresis of drugs. Cells were inhibited, excited or unaffected by noxious mechanical skin stimulation. These were respectively designated as off(M) cells, on(M) cells and neutral(M) cells, M denoting mechanical. During 3 min of pinching, serotonin slowly rose near seven of 14 on(M) cells and 26 of 46 off(M) cells; it fell near two off(M) cells; it was unchanged near all other cells, including six neutral(M) cells. On a finer spatiotemporal scale, near four of seven on(M) cells, 10 of 14 off(M) cells and 0 of four neutral(M) cells, average serotonin levels fell significantly within +/- 100 ms of spontaneous spikes. Lower serotonin may have caused the higher spike probability; the converse is theoretically unlikely, since delays between release and detection are estimated to exceed 100 ms. Increased serotonin and decreased firing were always seen following iontophoresis or intravenous injection (1 mg/kg) of the serotonin re-uptake inhibitor clomipramine (n = 7). Iontophoresis of CHEMICAL, whose serotonergic actions include antagonism and partial agonism at GENE receptors, also increased serotonin and decreased firing (n=4). Methiothepin (intravenous, 1 mg/kg), whose serotonergic actions include GENE and 5-HT2 antagonism, typically raised serotonin levels (four of five cells) and always blocked inhibition by clomipramine (n = 3). Iontophoresis of glutamate always lowered serotonin and increased firing (n = 4). Since serotonin levels and firing were usually inversely correlated, except near on(M) cells during pinch, we propose that serotonin is released from terminals of incoming nociceptive afferents. Prior neuroanatomical knowledge favors a midbrain origin for these afferents, while some of the drug findings suggest that their terminals possess inhibitory serotonergic autoreceptors, possibly of 5-HT1b subtype. The released serotonin could contribute to the inhibition of off(M) cells and excitation of on(M) cells by noxious stimulation, since inhibitory 5-HT1a receptors and excitatory 5-HT2 receptors, respectively, have previously been shown to dominate their serotonergic responses. | ACTIVATOR |
| Correlations between serotonin level and single-cell firing in the rat's nucleus raphe magnus. The relation between serotonin release and electrical activity was examined in the nucleus raphe magnus of rats anesthetized with pentobarbital. Serotonin levels were monitored through a carbon-fiber microelectrode by fast cyclic voltammetry (usually at 1 Hz). Single-cell firing was recorded through the same microelectrode, except during the voltammetry waveform and associated electrical artifact (totaling about 30 ms). Multi-barrel micropipettes incorporating the voltammetry electrode were used for iontophoresis of drugs. Cells were inhibited, excited or unaffected by noxious mechanical skin stimulation. These were respectively designated as off(M) cells, on(M) cells and neutral(M) cells, M denoting mechanical. During 3 min of pinching, serotonin slowly rose near seven of 14 on(M) cells and 26 of 46 off(M) cells; it fell near two off(M) cells; it was unchanged near all other cells, including six neutral(M) cells. On a finer spatiotemporal scale, near four of seven on(M) cells, 10 of 14 off(M) cells and 0 of four neutral(M) cells, average serotonin levels fell significantly within +/- 100 ms of spontaneous spikes. Lower serotonin may have caused the higher spike probability; the converse is theoretically unlikely, since delays between release and detection are estimated to exceed 100 ms. Increased serotonin and decreased firing were always seen following iontophoresis or intravenous injection (1 mg/kg) of the serotonin re-uptake inhibitor clomipramine (n = 7). Iontophoresis of +/- propranolol, whose serotonergic actions include antagonism and partial agonism at GENE receptors, also increased serotonin and decreased firing (n=4). CHEMICAL (intravenous, 1 mg/kg), whose serotonergic actions include GENE and 5-HT2 antagonism, typically raised serotonin levels (four of five cells) and always blocked inhibition by clomipramine (n = 3). Iontophoresis of glutamate always lowered serotonin and increased firing (n = 4). Since serotonin levels and firing were usually inversely correlated, except near on(M) cells during pinch, we propose that serotonin is released from terminals of incoming nociceptive afferents. Prior neuroanatomical knowledge favors a midbrain origin for these afferents, while some of the drug findings suggest that their terminals possess inhibitory serotonergic autoreceptors, possibly of 5-HT1b subtype. The released serotonin could contribute to the inhibition of off(M) cells and excitation of on(M) cells by noxious stimulation, since inhibitory 5-HT1a receptors and excitatory 5-HT2 receptors, respectively, have previously been shown to dominate their serotonergic responses. | REGULATOR |
| Correlations between serotonin level and single-cell firing in the rat's nucleus raphe magnus. The relation between serotonin release and electrical activity was examined in the nucleus raphe magnus of rats anesthetized with pentobarbital. Serotonin levels were monitored through a carbon-fiber microelectrode by fast cyclic voltammetry (usually at 1 Hz). Single-cell firing was recorded through the same microelectrode, except during the voltammetry waveform and associated electrical artifact (totaling about 30 ms). Multi-barrel micropipettes incorporating the voltammetry electrode were used for iontophoresis of drugs. Cells were inhibited, excited or unaffected by noxious mechanical skin stimulation. These were respectively designated as off(M) cells, on(M) cells and neutral(M) cells, M denoting mechanical. During 3 min of pinching, serotonin slowly rose near seven of 14 on(M) cells and 26 of 46 off(M) cells; it fell near two off(M) cells; it was unchanged near all other cells, including six neutral(M) cells. On a finer spatiotemporal scale, near four of seven on(M) cells, 10 of 14 off(M) cells and 0 of four neutral(M) cells, average serotonin levels fell significantly within +/- 100 ms of spontaneous spikes. Lower serotonin may have caused the higher spike probability; the converse is theoretically unlikely, since delays between release and detection are estimated to exceed 100 ms. Increased serotonin and decreased firing were always seen following iontophoresis or intravenous injection (1 mg/kg) of the serotonin re-uptake inhibitor clomipramine (n = 7). Iontophoresis of +/- propranolol, whose serotonergic actions include antagonism and partial agonism at 5-HT1 receptors, also increased serotonin and decreased firing (n=4). CHEMICAL (intravenous, 1 mg/kg), whose serotonergic actions include 5-HT1 and GENE antagonism, typically raised serotonin levels (four of five cells) and always blocked inhibition by clomipramine (n = 3). Iontophoresis of glutamate always lowered serotonin and increased firing (n = 4). Since serotonin levels and firing were usually inversely correlated, except near on(M) cells during pinch, we propose that serotonin is released from terminals of incoming nociceptive afferents. Prior neuroanatomical knowledge favors a midbrain origin for these afferents, while some of the drug findings suggest that their terminals possess inhibitory serotonergic autoreceptors, possibly of 5-HT1b subtype. The released serotonin could contribute to the inhibition of off(M) cells and excitation of on(M) cells by noxious stimulation, since inhibitory 5-HT1a receptors and excitatory GENE receptors, respectively, have previously been shown to dominate their serotonergic responses. | INHIBITOR |
| The Hsp90-specific inhibitor CHEMICAL selectively disrupts kinase-mediated signaling events of T-lymphocyte activation. The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone of eukaryotic cells. Its chaperone function in folding nascent proteins seems to be restricted to a subset of proteins including major components of signal transduction pathways (eg, nuclear hormone receptors, transcription factors, and protein kinases). Improper function of these proteins can be induced by selective disruption of their complexes with Hsp90 using the benzoquinonoid ansamycin CHEMICAL. In this study, we demonstrate that CHEMICAL treatment blocks interleukin (IL)-2 secretion, IL-2 receptor expression, and proliferation of stimulated T-lymphocytes. Moreover, CHEMICAL decreases the amount and phosphorylation of Lck and Raf-1 kinases and prevents activation of the extracellular signal regulated kinase (ERK)-2 kinase. CHEMICAL also disrupts the T-cell receptor-mediated activation of nuclear factor of activated T-cells (NF-AT). Treatment with CHEMICAL, however, does not affect the activation of GENE, which is a plasma membrane enzyme coupled to the T-cell receptor after T-cell stimulation. Through demonstrating the selective inhibition of kinase-related T-lymphocyte responses by CHEMICAL, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation. | NO-RELATIONSHIP |
| The Hsp90-specific inhibitor CHEMICAL selectively disrupts kinase-mediated signaling events of T-lymphocyte activation. The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone of eukaryotic cells. Its chaperone function in folding nascent proteins seems to be restricted to a subset of proteins including major components of signal transduction pathways (eg, nuclear hormone receptors, transcription factors, and protein kinases). Improper function of these proteins can be induced by selective disruption of their complexes with Hsp90 using the benzoquinonoid ansamycin CHEMICAL. In this study, we demonstrate that CHEMICAL treatment blocks GENE secretion, IL-2 receptor expression, and proliferation of stimulated T-lymphocytes. Moreover, CHEMICAL decreases the amount and phosphorylation of Lck and Raf-1 kinases and prevents activation of the extracellular signal regulated kinase (ERK)-2 kinase. CHEMICAL also disrupts the T-cell receptor-mediated activation of nuclear factor of activated T-cells (NF-AT). Treatment with CHEMICAL, however, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the T-cell receptor after T-cell stimulation. Through demonstrating the selective inhibition of kinase-related T-lymphocyte responses by CHEMICAL, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation. | INDIRECT-DOWNREGULATOR |
| The Hsp90-specific inhibitor CHEMICAL selectively disrupts kinase-mediated signaling events of T-lymphocyte activation. The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone of eukaryotic cells. Its chaperone function in folding nascent proteins seems to be restricted to a subset of proteins including major components of signal transduction pathways (eg, nuclear hormone receptors, transcription factors, and protein kinases). Improper function of these proteins can be induced by selective disruption of their complexes with Hsp90 using the benzoquinonoid ansamycin CHEMICAL. In this study, we demonstrate that CHEMICAL treatment blocks interleukin (IL)-2 secretion, GENE expression, and proliferation of stimulated T-lymphocytes. Moreover, CHEMICAL decreases the amount and phosphorylation of Lck and Raf-1 kinases and prevents activation of the extracellular signal regulated kinase (ERK)-2 kinase. CHEMICAL also disrupts the T-cell receptor-mediated activation of nuclear factor of activated T-cells (NF-AT). Treatment with CHEMICAL, however, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the T-cell receptor after T-cell stimulation. Through demonstrating the selective inhibition of kinase-related T-lymphocyte responses by CHEMICAL, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation. | INDIRECT-DOWNREGULATOR |
| The Hsp90-specific inhibitor CHEMICAL selectively disrupts kinase-mediated signaling events of T-lymphocyte activation. The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone of eukaryotic cells. Its chaperone function in folding nascent proteins seems to be restricted to a subset of proteins including major components of signal transduction pathways (eg, nuclear hormone receptors, transcription factors, and protein kinases). Improper function of these proteins can be induced by selective disruption of their complexes with Hsp90 using the benzoquinonoid ansamycin CHEMICAL. In this study, we demonstrate that CHEMICAL treatment blocks interleukin (IL)-2 secretion, IL-2 receptor expression, and proliferation of stimulated T-lymphocytes. Moreover, CHEMICAL decreases the amount and phosphorylation of GENE and Raf-1 kinases and prevents activation of the extracellular signal regulated kinase (ERK)-2 kinase. CHEMICAL also disrupts the T-cell receptor-mediated activation of nuclear factor of activated T-cells (NF-AT). Treatment with CHEMICAL, however, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the T-cell receptor after T-cell stimulation. Through demonstrating the selective inhibition of kinase-related T-lymphocyte responses by CHEMICAL, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation. | INHIBITOR |
| The Hsp90-specific inhibitor CHEMICAL selectively disrupts kinase-mediated signaling events of T-lymphocyte activation. The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone of eukaryotic cells. Its chaperone function in folding nascent proteins seems to be restricted to a subset of proteins including major components of signal transduction pathways (eg, nuclear hormone receptors, transcription factors, and protein kinases). Improper function of these proteins can be induced by selective disruption of their complexes with Hsp90 using the benzoquinonoid ansamycin CHEMICAL. In this study, we demonstrate that CHEMICAL treatment blocks interleukin (IL)-2 secretion, IL-2 receptor expression, and proliferation of stimulated T-lymphocytes. Moreover, CHEMICAL decreases the amount and phosphorylation of Lck and GENE kinases and prevents activation of the extracellular signal regulated kinase (ERK)-2 kinase. CHEMICAL also disrupts the T-cell receptor-mediated activation of nuclear factor of activated T-cells (NF-AT). Treatment with CHEMICAL, however, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the T-cell receptor after T-cell stimulation. Through demonstrating the selective inhibition of kinase-related T-lymphocyte responses by CHEMICAL, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation. | INHIBITOR |
| The Hsp90-specific inhibitor CHEMICAL selectively disrupts kinase-mediated signaling events of T-lymphocyte activation. The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone of eukaryotic cells. Its chaperone function in folding nascent proteins seems to be restricted to a subset of proteins including major components of signal transduction pathways (eg, nuclear hormone receptors, transcription factors, and protein kinases). Improper function of these proteins can be induced by selective disruption of their complexes with Hsp90 using the benzoquinonoid ansamycin CHEMICAL. In this study, we demonstrate that CHEMICAL treatment blocks interleukin (IL)-2 secretion, IL-2 receptor expression, and proliferation of stimulated T-lymphocytes. Moreover, CHEMICAL decreases the amount and phosphorylation of Lck and Raf-1 GENE and prevents activation of the extracellular signal regulated kinase (ERK)-2 kinase. CHEMICAL also disrupts the T-cell receptor-mediated activation of nuclear factor of activated T-cells (NF-AT). Treatment with CHEMICAL, however, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the T-cell receptor after T-cell stimulation. Through demonstrating the selective inhibition of kinase-related T-lymphocyte responses by CHEMICAL, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation. | INHIBITOR |
| The Hsp90-specific inhibitor CHEMICAL selectively disrupts kinase-mediated signaling events of T-lymphocyte activation. The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone of eukaryotic cells. Its chaperone function in folding nascent proteins seems to be restricted to a subset of proteins including major components of signal transduction pathways (eg, nuclear hormone receptors, transcription factors, and protein kinases). Improper function of these proteins can be induced by selective disruption of their complexes with Hsp90 using the benzoquinonoid ansamycin CHEMICAL. In this study, we demonstrate that CHEMICAL treatment blocks interleukin (IL)-2 secretion, IL-2 receptor expression, and proliferation of stimulated T-lymphocytes. Moreover, CHEMICAL decreases the amount and phosphorylation of Lck and Raf-1 kinases and prevents activation of the extracellular signal regulated GENE (ERK)-2 GENE. CHEMICAL also disrupts the T-cell receptor-mediated activation of nuclear factor of activated T-cells (NF-AT). Treatment with CHEMICAL, however, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the T-cell receptor after T-cell stimulation. Through demonstrating the selective inhibition of GENE-related T-lymphocyte responses by CHEMICAL, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation. | INHIBITOR |
| The Hsp90-specific inhibitor geldanamycin selectively disrupts kinase-mediated signaling events of T-lymphocyte activation. The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone of eukaryotic cells. Its chaperone function in folding nascent proteins seems to be restricted to a subset of proteins including major components of signal transduction pathways (eg, nuclear hormone receptors, transcription factors, and protein kinases). Improper function of these proteins can be induced by selective disruption of their complexes with GENE using the CHEMICAL geldanamycin. In this study, we demonstrate that geldanamycin treatment blocks interleukin (IL)-2 secretion, IL-2 receptor expression, and proliferation of stimulated T-lymphocytes. Moreover, geldanamycin decreases the amount and phosphorylation of Lck and Raf-1 kinases and prevents activation of the extracellular signal regulated kinase (ERK)-2 kinase. Geldanamycin also disrupts the T-cell receptor-mediated activation of nuclear factor of activated T-cells (NF-AT). Treatment with geldanamycin, however, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the T-cell receptor after T-cell stimulation. Through demonstrating the selective inhibition of kinase-related T-lymphocyte responses by geldanamycin, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation. | REGULATOR |
| The Hsp90-specific inhibitor CHEMICAL selectively disrupts kinase-mediated signaling events of T-lymphocyte activation. The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone of eukaryotic cells. Its chaperone function in folding nascent proteins seems to be restricted to a subset of proteins including major components of signal transduction pathways (eg, nuclear hormone receptors, transcription factors, and protein kinases). Improper function of these proteins can be induced by selective disruption of their complexes with GENE using the benzoquinonoid ansamycin CHEMICAL. In this study, we demonstrate that CHEMICAL treatment blocks interleukin (IL)-2 secretion, IL-2 receptor expression, and proliferation of stimulated T-lymphocytes. Moreover, CHEMICAL decreases the amount and phosphorylation of Lck and Raf-1 kinases and prevents activation of the extracellular signal regulated kinase (ERK)-2 kinase. CHEMICAL also disrupts the T-cell receptor-mediated activation of nuclear factor of activated T-cells (NF-AT). Treatment with CHEMICAL, however, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the T-cell receptor after T-cell stimulation. Through demonstrating the selective inhibition of kinase-related T-lymphocyte responses by CHEMICAL, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation. | INHIBITOR |
| The Hsp90-specific inhibitor CHEMICAL selectively disrupts kinase-mediated signaling events of T-lymphocyte activation. The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone of eukaryotic cells. Its chaperone function in folding nascent proteins seems to be restricted to a subset of proteins including major components of signal transduction pathways (eg, nuclear hormone receptors, transcription factors, and protein kinases). Improper function of these proteins can be induced by selective disruption of their complexes with Hsp90 using the benzoquinonoid ansamycin CHEMICAL. In this study, we demonstrate that CHEMICAL treatment blocks interleukin (IL)-2 secretion, IL-2 receptor expression, and proliferation of stimulated T-lymphocytes. Moreover, CHEMICAL decreases the amount and phosphorylation of Lck and Raf-1 kinases and prevents activation of the GENE kinase. CHEMICAL also disrupts the T-cell receptor-mediated activation of nuclear factor of activated T-cells (NF-AT). Treatment with CHEMICAL, however, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the T-cell receptor after T-cell stimulation. Through demonstrating the selective inhibition of kinase-related T-lymphocyte responses by CHEMICAL, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation. | INHIBITOR |
| The Hsp90-specific inhibitor geldanamycin selectively disrupts kinase-mediated signaling events of T-lymphocyte activation. The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone of eukaryotic cells. Its chaperone function in folding nascent proteins seems to be restricted to a subset of proteins including major components of signal transduction pathways (eg, nuclear hormone receptors, transcription factors, and protein kinases). Improper function of these proteins can be induced by selective disruption of their complexes with Hsp90 using the benzoquinonoid ansamycin geldanamycin. In this study, we demonstrate that geldanamycin treatment blocks interleukin (IL)-2 secretion, IL-2 receptor expression, and proliferation of stimulated T-lymphocytes. Moreover, geldanamycin decreases the amount and phosphorylation of Lck and Raf-1 kinases and prevents activation of the extracellular signal regulated kinase (ERK)-2 kinase. CHEMICAL also disrupts the GENE-mediated activation of nuclear factor of activated T-cells (NF-AT). Treatment with geldanamycin, however, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the GENE after T-cell stimulation. Through demonstrating the selective inhibition of kinase-related T-lymphocyte responses by geldanamycin, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation. | INHIBITOR |
| The Hsp90-specific inhibitor geldanamycin selectively disrupts kinase-mediated signaling events of T-lymphocyte activation. The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone of eukaryotic cells. Its chaperone function in folding nascent proteins seems to be restricted to a subset of proteins including major components of signal transduction pathways (eg, nuclear hormone receptors, transcription factors, and protein kinases). Improper function of these proteins can be induced by selective disruption of their complexes with Hsp90 using the benzoquinonoid ansamycin geldanamycin. In this study, we demonstrate that geldanamycin treatment blocks interleukin (IL)-2 secretion, IL-2 receptor expression, and proliferation of stimulated T-lymphocytes. Moreover, geldanamycin decreases the amount and phosphorylation of Lck and Raf-1 kinases and prevents activation of the extracellular signal regulated kinase (ERK)-2 kinase. CHEMICAL also disrupts the T-cell receptor-mediated activation of GENE (NF-AT). Treatment with geldanamycin, however, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the T-cell receptor after T-cell stimulation. Through demonstrating the selective inhibition of kinase-related T-lymphocyte responses by geldanamycin, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation. | INHIBITOR |
| The Hsp90-specific inhibitor geldanamycin selectively disrupts kinase-mediated signaling events of T-lymphocyte activation. The 90-kDa heat shock protein (Hsp90) is the most abundant molecular chaperone of eukaryotic cells. Its chaperone function in folding nascent proteins seems to be restricted to a subset of proteins including major components of signal transduction pathways (eg, nuclear hormone receptors, transcription factors, and protein kinases). Improper function of these proteins can be induced by selective disruption of their complexes with Hsp90 using the benzoquinonoid ansamycin geldanamycin. In this study, we demonstrate that geldanamycin treatment blocks interleukin (IL)-2 secretion, IL-2 receptor expression, and proliferation of stimulated T-lymphocytes. Moreover, geldanamycin decreases the amount and phosphorylation of Lck and Raf-1 kinases and prevents activation of the extracellular signal regulated kinase (ERK)-2 kinase. CHEMICAL also disrupts the T-cell receptor-mediated activation of nuclear factor of activated T-cells (GENE). Treatment with geldanamycin, however, does not affect the activation of lysophosphatide acyltransferase, which is a plasma membrane enzyme coupled to the T-cell receptor after T-cell stimulation. Through demonstrating the selective inhibition of kinase-related T-lymphocyte responses by geldanamycin, our results emphasize the substantial role of Hsp90-kinase complexes in T-cell activation. | INHIBITOR |
| Carnitine biosynthesis. Purification of gamma-butyrobetaine hydroxylase from rat liver. GENE catalyse the last step in carnitine biosynthesis, the formation of L-carnitine from gamma-butyrobetaine, a reaction dependent on CHEMICAL, alpha-ketoglutarate, ascorbate and oxygen. Initial attempts to purify the protein from rat liver showed that gamma-butyrobetaine hydroxylase is unstable. We, therefore, determined the influence of various compounds on the stability of gamma-butyrobetaine hydroxylase at different storage temperatures. The enzyme activity was best conserved by storing the protein at 4 degrees C in the presence of 200 g/l glycerol and 10 mM DTT. We subsequently purified the enzyme from rat liver to apparent homogeneity by liquid chromatography. | GENE-CHEMICAL |
| Carnitine biosynthesis. Purification of gamma-butyrobetaine hydroxylase from rat liver. GENE catalyse the last step in carnitine biosynthesis, the formation of L-carnitine from gamma-butyrobetaine, a reaction dependent on Fe2+, CHEMICAL, ascorbate and oxygen. Initial attempts to purify the protein from rat liver showed that gamma-butyrobetaine hydroxylase is unstable. We, therefore, determined the influence of various compounds on the stability of gamma-butyrobetaine hydroxylase at different storage temperatures. The enzyme activity was best conserved by storing the protein at 4 degrees C in the presence of 200 g/l glycerol and 10 mM DTT. We subsequently purified the enzyme from rat liver to apparent homogeneity by liquid chromatography. | GENE-CHEMICAL |
| Carnitine biosynthesis. Purification of gamma-butyrobetaine hydroxylase from rat liver. GENE catalyse the last step in carnitine biosynthesis, the formation of L-carnitine from gamma-butyrobetaine, a reaction dependent on Fe2+, alpha-ketoglutarate, CHEMICAL and oxygen. Initial attempts to purify the protein from rat liver showed that gamma-butyrobetaine hydroxylase is unstable. We, therefore, determined the influence of various compounds on the stability of gamma-butyrobetaine hydroxylase at different storage temperatures. The enzyme activity was best conserved by storing the protein at 4 degrees C in the presence of 200 g/l glycerol and 10 mM DTT. We subsequently purified the enzyme from rat liver to apparent homogeneity by liquid chromatography. | GENE-CHEMICAL |
| Carnitine biosynthesis. Purification of gamma-butyrobetaine hydroxylase from rat liver. GENE catalyse the last step in carnitine biosynthesis, the formation of L-carnitine from gamma-butyrobetaine, a reaction dependent on Fe2+, alpha-ketoglutarate, ascorbate and CHEMICAL. Initial attempts to purify the protein from rat liver showed that gamma-butyrobetaine hydroxylase is unstable. We, therefore, determined the influence of various compounds on the stability of gamma-butyrobetaine hydroxylase at different storage temperatures. The enzyme activity was best conserved by storing the protein at 4 degrees C in the presence of 200 g/l glycerol and 10 mM DTT. We subsequently purified the enzyme from rat liver to apparent homogeneity by liquid chromatography. | GENE-CHEMICAL |
| CHEMICAL biosynthesis. Purification of gamma-butyrobetaine hydroxylase from rat liver. GENE catalyse the last step in CHEMICAL biosynthesis, the formation of L-carnitine from gamma-butyrobetaine, a reaction dependent on Fe2+, alpha-ketoglutarate, ascorbate and oxygen. Initial attempts to purify the protein from rat liver showed that gamma-butyrobetaine hydroxylase is unstable. We, therefore, determined the influence of various compounds on the stability of gamma-butyrobetaine hydroxylase at different storage temperatures. The enzyme activity was best conserved by storing the protein at 4 degrees C in the presence of 200 g/l glycerol and 10 mM DTT. We subsequently purified the enzyme from rat liver to apparent homogeneity by liquid chromatography. | PRODUCT-OF |
| Carnitine biosynthesis. Purification of gamma-butyrobetaine hydroxylase from rat liver. GENE catalyse the last step in carnitine biosynthesis, the formation of CHEMICAL from gamma-butyrobetaine, a reaction dependent on Fe2+, alpha-ketoglutarate, ascorbate and oxygen. Initial attempts to purify the protein from rat liver showed that gamma-butyrobetaine hydroxylase is unstable. We, therefore, determined the influence of various compounds on the stability of gamma-butyrobetaine hydroxylase at different storage temperatures. The enzyme activity was best conserved by storing the protein at 4 degrees C in the presence of 200 g/l glycerol and 10 mM DTT. We subsequently purified the enzyme from rat liver to apparent homogeneity by liquid chromatography. | PRODUCT-OF |
| Carnitine biosynthesis. Purification of CHEMICAL hydroxylase from rat liver. GENE catalyse the last step in carnitine biosynthesis, the formation of L-carnitine from CHEMICAL, a reaction dependent on Fe2+, alpha-ketoglutarate, ascorbate and oxygen. Initial attempts to purify the protein from rat liver showed that CHEMICAL hydroxylase is unstable. We, therefore, determined the influence of various compounds on the stability of CHEMICAL hydroxylase at different storage temperatures. The enzyme activity was best conserved by storing the protein at 4 degrees C in the presence of 200 g/l glycerol and 10 mM DTT. We subsequently purified the enzyme from rat liver to apparent homogeneity by liquid chromatography. | SUBSTRATE |
| Aspirin and sodium salicylate inhibit endothelin ETA receptors by an allosteric type of mechanism. Aspirin is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions. This study shows that aspirin and sodium salicylate, its major blood metabolite, reverse contractile actions of endothelin-1 (ET-1) in isolated rat aorta and human mammary arteries. They also prevent the intracellular Ca(2+) mobilizing action of GENE in cultured endothelial cells but not those of neuromedin B or UTP. Inhibition of the actions of GENE by salicylates is apparently competitive. CHEMICAL inhibit (125)I-ET-1 binding to recombinant rat ETA receptors. Salicylic acid promotes dissociation of (125)I-ET-1 ETA receptor complexes both in the absence and the presence of unlabeled GENE. It has no influence on the rate of association of (125)I-ET-1 to ETA receptors. CHEMICAL do not promote dissociation of (125)I-GENE ETB receptor complexes. CHEMICAL potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that salicylates are allosteric inhibitors of ETA receptors. The results also suggest that: 1) irreversible GENE binding probably limits actions of receptor antagonists in vivo, and 2) an association of salicylates and ETA receptor antagonists should be used to evaluate the physiopathological role of GENE and may be of therapeutic interest in the treatment of ischemic heart disease. | NO-RELATIONSHIP |
| Aspirin and sodium salicylate inhibit endothelin ETA receptors by an allosteric type of mechanism. Aspirin is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions. This study shows that aspirin and sodium salicylate, its major blood metabolite, reverse contractile actions of endothelin-1 (ET-1) in isolated rat aorta and human mammary arteries. They also prevent the intracellular Ca(2+) mobilizing action of ET-1 in cultured endothelial cells but not those of neuromedin B or UTP. Inhibition of the actions of ET-1 by salicylates is apparently competitive. CHEMICAL inhibit (125)I-ET-1 binding to recombinant rat ETA receptors. Salicylic acid promotes dissociation of (125)I-ET-1 ETA receptor complexes both in the absence and the presence of unlabeled ET-1. It has no influence on the rate of association of (125)I-ET-1 to ETA receptors. CHEMICAL do not promote dissociation of (125)I-ET-1 GENE complexes. CHEMICAL potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that salicylates are allosteric inhibitors of ETA receptors. The results also suggest that: 1) irreversible ET-1 binding probably limits actions of receptor antagonists in vivo, and 2) an association of salicylates and ETA receptor antagonists should be used to evaluate the physiopathological role of ET-1 and may be of therapeutic interest in the treatment of ischemic heart disease. | NO-RELATIONSHIP |
| Aspirin and sodium salicylate inhibit endothelin ETA receptors by an allosteric type of mechanism. Aspirin is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions. This study shows that aspirin and sodium salicylate, its major blood metabolite, reverse contractile actions of endothelin-1 (ET-1) in isolated rat aorta and human mammary arteries. They also prevent the intracellular Ca(2+) mobilizing action of GENE in cultured endothelial cells but not those of neuromedin B or UTP. Inhibition of the actions of GENE by salicylates is apparently competitive. Salicylates inhibit (125)I-ET-1 binding to recombinant rat ETA receptors. CHEMICAL promotes dissociation of (125)I-GENE ETA receptor complexes both in the absence and the presence of unlabeled GENE. It has no influence on the rate of association of (125)I-ET-1 to ETA receptors. Salicylates do not promote dissociation of (125)I-ET-1 ETB receptor complexes. Salicylates potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that salicylates are allosteric inhibitors of ETA receptors. The results also suggest that: 1) irreversible GENE binding probably limits actions of receptor antagonists in vivo, and 2) an association of salicylates and ETA receptor antagonists should be used to evaluate the physiopathological role of GENE and may be of therapeutic interest in the treatment of ischemic heart disease. | DIRECT-REGULATOR |
| Aspirin and sodium salicylate inhibit endothelin ETA receptors by an allosteric type of mechanism. Aspirin is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions. This study shows that aspirin and sodium salicylate, its major blood metabolite, reverse contractile actions of endothelin-1 (ET-1) in isolated rat aorta and human mammary arteries. They also prevent the intracellular Ca(2+) mobilizing action of ET-1 in cultured endothelial cells but not those of neuromedin B or UTP. Inhibition of the actions of ET-1 by salicylates is apparently competitive. Salicylates inhibit (125)I-ET-1 binding to recombinant rat ETA receptors. CHEMICAL promotes dissociation of (125)I-ET-1 GENE complexes both in the absence and the presence of unlabeled ET-1. It has no influence on the rate of association of (125)I-ET-1 to ETA receptors. Salicylates do not promote dissociation of (125)I-ET-1 ETB receptor complexes. Salicylates potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that salicylates are allosteric inhibitors of ETA receptors. The results also suggest that: 1) irreversible ET-1 binding probably limits actions of receptor antagonists in vivo, and 2) an association of salicylates and GENE antagonists should be used to evaluate the physiopathological role of ET-1 and may be of therapeutic interest in the treatment of ischemic heart disease. | DIRECT-REGULATOR |
| Aspirin and sodium salicylate inhibit endothelin ETA receptors by an allosteric type of mechanism. Aspirin is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions. This study shows that aspirin and sodium salicylate, its major blood metabolite, reverse contractile actions of endothelin-1 (ET-1) in isolated rat aorta and human mammary arteries. They also prevent the intracellular Ca(2+) mobilizing action of GENE in cultured endothelial cells but not those of neuromedin B or UTP. Inhibition of the actions of GENE by salicylates is apparently competitive. Salicylates inhibit (125)I-ET-1 binding to recombinant rat ETA receptors. Salicylic acid promotes dissociation of CHEMICAL-GENE ETA receptor complexes both in the absence and the presence of unlabeled GENE. It has no influence on the rate of association of (125)I-ET-1 to ETA receptors. Salicylates do not promote dissociation of (125)I-ET-1 ETB receptor complexes. Salicylates potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that salicylates are allosteric inhibitors of ETA receptors. The results also suggest that: 1) irreversible GENE binding probably limits actions of receptor antagonists in vivo, and 2) an association of salicylates and ETA receptor antagonists should be used to evaluate the physiopathological role of GENE and may be of therapeutic interest in the treatment of ischemic heart disease. | DIRECT-REGULATOR |
| Aspirin and sodium salicylate inhibit endothelin ETA receptors by an allosteric type of mechanism. Aspirin is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions. This study shows that aspirin and sodium salicylate, its major blood metabolite, reverse contractile actions of endothelin-1 (ET-1) in isolated rat aorta and human mammary arteries. They also prevent the intracellular Ca(2+) mobilizing action of ET-1 in cultured endothelial cells but not those of neuromedin B or UTP. Inhibition of the actions of ET-1 by salicylates is apparently competitive. Salicylates inhibit (125)I-ET-1 binding to recombinant rat ETA receptors. Salicylic acid promotes dissociation of CHEMICAL-ET-1 GENE complexes both in the absence and the presence of unlabeled ET-1. It has no influence on the rate of association of (125)I-ET-1 to ETA receptors. Salicylates do not promote dissociation of (125)I-ET-1 ETB receptor complexes. Salicylates potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that salicylates are allosteric inhibitors of ETA receptors. The results also suggest that: 1) irreversible ET-1 binding probably limits actions of receptor antagonists in vivo, and 2) an association of salicylates and GENE antagonists should be used to evaluate the physiopathological role of ET-1 and may be of therapeutic interest in the treatment of ischemic heart disease. | DIRECT-REGULATOR |
| Aspirin and sodium salicylate inhibit endothelin GENE by an allosteric type of mechanism. Aspirin is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions. This study shows that aspirin and sodium salicylate, its major blood metabolite, reverse contractile actions of endothelin-1 (ET-1) in isolated rat aorta and human mammary arteries. They also prevent the intracellular Ca(2+) mobilizing action of ET-1 in cultured endothelial cells but not those of neuromedin B or UTP. Inhibition of the actions of ET-1 by salicylates is apparently competitive. Salicylates inhibit (125)I-ET-1 binding to recombinant rat GENE. Salicylic acid promotes dissociation of (125)I-ET-1 ETA receptor complexes both in the absence and the presence of unlabeled ET-1. It has no influence on the rate of association of CHEMICAL-ET-1 to GENE. Salicylates do not promote dissociation of (125)I-ET-1 ETB receptor complexes. Salicylates potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that salicylates are allosteric inhibitors of GENE. The results also suggest that: 1) irreversible ET-1 binding probably limits actions of receptor antagonists in vivo, and 2) an association of salicylates and ETA receptor antagonists should be used to evaluate the physiopathological role of ET-1 and may be of therapeutic interest in the treatment of ischemic heart disease. | DIRECT-REGULATOR |
| Aspirin and sodium salicylate inhibit endothelin ETA receptors by an allosteric type of mechanism. Aspirin is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions. This study shows that aspirin and sodium salicylate, its major blood metabolite, reverse contractile actions of endothelin-1 (ET-1) in isolated rat aorta and human mammary arteries. They also prevent the intracellular Ca(2+) mobilizing action of ET-1 in cultured endothelial cells but not those of neuromedin B or UTP. Inhibition of the actions of ET-1 by salicylates is apparently competitive. Salicylates inhibit (125)I-ET-1 binding to recombinant rat ETA receptors. Salicylic acid promotes dissociation of (125)I-ET-1 ETA receptor complexes both in the absence and the presence of unlabeled ET-1. It has no influence on the rate of association of (125)I-ET-1 to ETA receptors. Salicylates do not promote dissociation of CHEMICAL-ET-1 GENE complexes. Salicylates potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that salicylates are allosteric inhibitors of ETA receptors. The results also suggest that: 1) irreversible ET-1 binding probably limits actions of receptor antagonists in vivo, and 2) an association of salicylates and ETA receptor antagonists should be used to evaluate the physiopathological role of ET-1 and may be of therapeutic interest in the treatment of ischemic heart disease. | DIRECT-REGULATOR |
| Aspirin and sodium salicylate inhibit endothelin ETA receptors by an allosteric type of mechanism. Aspirin is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions. This study shows that aspirin and sodium salicylate, its major blood metabolite, reverse contractile actions of endothelin-1 (ET-1) in isolated rat aorta and human mammary arteries. They also prevent the intracellular Ca(2+) mobilizing action of ET-1 in cultured endothelial cells but not those of neuromedin B or UTP. Inhibition of the actions of ET-1 by salicylates is apparently competitive. CHEMICAL inhibit (125)I-ET-1 binding to recombinant GENE. Salicylic acid promotes dissociation of (125)I-ET-1 ETA receptor complexes both in the absence and the presence of unlabeled ET-1. It has no influence on the rate of association of (125)I-ET-1 to ETA receptors. CHEMICAL do not promote dissociation of (125)I-ET-1 ETB receptor complexes. CHEMICAL potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that salicylates are allosteric inhibitors of ETA receptors. The results also suggest that: 1) irreversible ET-1 binding probably limits actions of receptor antagonists in vivo, and 2) an association of salicylates and ETA receptor antagonists should be used to evaluate the physiopathological role of ET-1 and may be of therapeutic interest in the treatment of ischemic heart disease. | DIRECT-REGULATOR |
| CHEMICAL and sodium salicylate inhibit endothelin ETA receptors by an allosteric type of mechanism. CHEMICAL is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions. This study shows that CHEMICAL and sodium salicylate, its major blood metabolite, reverse contractile actions of GENE (ET-1) in isolated rat aorta and human mammary arteries. They also prevent the intracellular Ca(2+) mobilizing action of ET-1 in cultured endothelial cells but not those of neuromedin B or UTP. Inhibition of the actions of ET-1 by salicylates is apparently competitive. Salicylates inhibit (125)I-ET-1 binding to recombinant rat ETA receptors. Salicylic acid promotes dissociation of (125)I-ET-1 ETA receptor complexes both in the absence and the presence of unlabeled ET-1. It has no influence on the rate of association of (125)I-ET-1 to ETA receptors. Salicylates do not promote dissociation of (125)I-ET-1 ETB receptor complexes. Salicylates potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that salicylates are allosteric inhibitors of ETA receptors. The results also suggest that: 1) irreversible ET-1 binding probably limits actions of receptor antagonists in vivo, and 2) an association of salicylates and ETA receptor antagonists should be used to evaluate the physiopathological role of ET-1 and may be of therapeutic interest in the treatment of ischemic heart disease. | INHIBITOR |
| CHEMICAL and sodium salicylate inhibit endothelin ETA receptors by an allosteric type of mechanism. CHEMICAL is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions. This study shows that CHEMICAL and sodium salicylate, its major blood metabolite, reverse contractile actions of endothelin-1 (GENE) in isolated rat aorta and human mammary arteries. They also prevent the intracellular Ca(2+) mobilizing action of GENE in cultured endothelial cells but not those of neuromedin B or UTP. Inhibition of the actions of GENE by salicylates is apparently competitive. Salicylates inhibit (125)I-ET-1 binding to recombinant rat ETA receptors. Salicylic acid promotes dissociation of (125)I-ET-1 ETA receptor complexes both in the absence and the presence of unlabeled GENE. It has no influence on the rate of association of (125)I-ET-1 to ETA receptors. Salicylates do not promote dissociation of (125)I-ET-1 ETB receptor complexes. Salicylates potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that salicylates are allosteric inhibitors of ETA receptors. The results also suggest that: 1) irreversible GENE binding probably limits actions of receptor antagonists in vivo, and 2) an association of salicylates and ETA receptor antagonists should be used to evaluate the physiopathological role of GENE and may be of therapeutic interest in the treatment of ischemic heart disease. | INHIBITOR |
| Aspirin and CHEMICAL inhibit endothelin ETA receptors by an allosteric type of mechanism. Aspirin is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions. This study shows that aspirin and CHEMICAL, its major blood metabolite, reverse contractile actions of GENE (ET-1) in isolated rat aorta and human mammary arteries. They also prevent the intracellular Ca(2+) mobilizing action of ET-1 in cultured endothelial cells but not those of neuromedin B or UTP. Inhibition of the actions of ET-1 by salicylates is apparently competitive. Salicylates inhibit (125)I-ET-1 binding to recombinant rat ETA receptors. Salicylic acid promotes dissociation of (125)I-ET-1 ETA receptor complexes both in the absence and the presence of unlabeled ET-1. It has no influence on the rate of association of (125)I-ET-1 to ETA receptors. Salicylates do not promote dissociation of (125)I-ET-1 ETB receptor complexes. Salicylates potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that salicylates are allosteric inhibitors of ETA receptors. The results also suggest that: 1) irreversible ET-1 binding probably limits actions of receptor antagonists in vivo, and 2) an association of salicylates and ETA receptor antagonists should be used to evaluate the physiopathological role of ET-1 and may be of therapeutic interest in the treatment of ischemic heart disease. | INHIBITOR |
| Aspirin and CHEMICAL inhibit endothelin ETA receptors by an allosteric type of mechanism. Aspirin is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions. This study shows that aspirin and CHEMICAL, its major blood metabolite, reverse contractile actions of endothelin-1 (GENE) in isolated rat aorta and human mammary arteries. They also prevent the intracellular Ca(2+) mobilizing action of GENE in cultured endothelial cells but not those of neuromedin B or UTP. Inhibition of the actions of GENE by salicylates is apparently competitive. Salicylates inhibit (125)I-ET-1 binding to recombinant rat ETA receptors. Salicylic acid promotes dissociation of (125)I-ET-1 ETA receptor complexes both in the absence and the presence of unlabeled GENE. It has no influence on the rate of association of (125)I-ET-1 to ETA receptors. Salicylates do not promote dissociation of (125)I-ET-1 ETB receptor complexes. Salicylates potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that salicylates are allosteric inhibitors of ETA receptors. The results also suggest that: 1) irreversible GENE binding probably limits actions of receptor antagonists in vivo, and 2) an association of salicylates and ETA receptor antagonists should be used to evaluate the physiopathological role of GENE and may be of therapeutic interest in the treatment of ischemic heart disease. | INHIBITOR |
| CHEMICAL and sodium salicylate inhibit endothelin GENE by an allosteric type of mechanism. CHEMICAL is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions. This study shows that aspirin and sodium salicylate, its major blood metabolite, reverse contractile actions of endothelin-1 (ET-1) in isolated rat aorta and human mammary arteries. They also prevent the intracellular Ca(2+) mobilizing action of ET-1 in cultured endothelial cells but not those of neuromedin B or UTP. Inhibition of the actions of ET-1 by salicylates is apparently competitive. Salicylates inhibit (125)I-ET-1 binding to recombinant rat GENE. Salicylic acid promotes dissociation of (125)I-ET-1 ETA receptor complexes both in the absence and the presence of unlabeled ET-1. It has no influence on the rate of association of (125)I-ET-1 to GENE. Salicylates do not promote dissociation of (125)I-ET-1 ETB receptor complexes. Salicylates potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that salicylates are allosteric inhibitors of GENE. The results also suggest that: 1) irreversible ET-1 binding probably limits actions of receptor antagonists in vivo, and 2) an association of salicylates and ETA receptor antagonists should be used to evaluate the physiopathological role of ET-1 and may be of therapeutic interest in the treatment of ischemic heart disease. | INHIBITOR |
| Aspirin and CHEMICAL inhibit endothelin GENE by an allosteric type of mechanism. Aspirin is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions. This study shows that aspirin and CHEMICAL, its major blood metabolite, reverse contractile actions of endothelin-1 (ET-1) in isolated rat aorta and human mammary arteries. They also prevent the intracellular Ca(2+) mobilizing action of ET-1 in cultured endothelial cells but not those of neuromedin B or UTP. Inhibition of the actions of ET-1 by salicylates is apparently competitive. Salicylates inhibit (125)I-ET-1 binding to recombinant rat GENE. Salicylic acid promotes dissociation of (125)I-ET-1 ETA receptor complexes both in the absence and the presence of unlabeled ET-1. It has no influence on the rate of association of (125)I-ET-1 to GENE. Salicylates do not promote dissociation of (125)I-ET-1 ETB receptor complexes. Salicylates potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that salicylates are allosteric inhibitors of GENE. The results also suggest that: 1) irreversible ET-1 binding probably limits actions of receptor antagonists in vivo, and 2) an association of salicylates and ETA receptor antagonists should be used to evaluate the physiopathological role of ET-1 and may be of therapeutic interest in the treatment of ischemic heart disease. | INHIBITOR |
| Aspirin and sodium salicylate inhibit endothelin GENE by an allosteric type of mechanism. Aspirin is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions. This study shows that aspirin and sodium salicylate, its major blood metabolite, reverse contractile actions of endothelin-1 (ET-1) in isolated rat aorta and human mammary arteries. They also prevent the intracellular Ca(2+) mobilizing action of ET-1 in cultured endothelial cells but not those of neuromedin B or UTP. Inhibition of the actions of ET-1 by CHEMICAL is apparently competitive. CHEMICAL inhibit (125)I-ET-1 binding to recombinant rat GENE. Salicylic acid promotes dissociation of (125)I-ET-1 ETA receptor complexes both in the absence and the presence of unlabeled ET-1. It has no influence on the rate of association of (125)I-ET-1 to GENE. CHEMICAL do not promote dissociation of (125)I-ET-1 ETB receptor complexes. CHEMICAL potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that CHEMICAL are allosteric inhibitors of GENE. The results also suggest that: 1) irreversible ET-1 binding probably limits actions of receptor antagonists in vivo, and 2) an association of CHEMICAL and ETA receptor antagonists should be used to evaluate the physiopathological role of ET-1 and may be of therapeutic interest in the treatment of ischemic heart disease. | INHIBITOR |
| A unique cytosolic activity related but distinct from GENE catalyses metabolic activation of mitomycin C. Mitomycin C (MMC) is a prototype bioreductive drug employed to treat a variety of cancers including head and neck cancer. Among the various enzymes, dicoumarol inhibitable cytosolic NAD(P)H:quinone oxidoreductase1 (NQO1) was shown to catalyse bioreductive activation of CHEMICAL leading to cross-linking of the DNA and cytotoxicity. However, the role of GENE in metabolic activation of CHEMICAL has been disputed. In this report, we present cellular and animal models to demonstrate that GENE may play only a minor role in metabolic activation of CHEMICAL. We further demonstrate that bioreductive activation of CHEMICAL is catalysed by a unique cytosolic activity which is related but distinct from GENE. Chinese hamster ovary (CHO) cells were developed that permanently express higher levels of cDNA-derived GENE. These cells showed significantly increased protection against menadione toxicity. However, they failed to demonstrate higher cytotoxicity due to exposure to CHEMICAL under oxygen (normal air) or hypoxia, as compared to the wild-type control CHO cells. Disruption of the GENE gene by homologous recombination generated NQO1-/- mice that do not express the GENE gene resulting in the loss of GENE protein and activity. The cytosolic fractions from liver and colon tissues of NQO1-/- mice showed similar amounts of DNA cross-linking upon exposure to CHEMICAL, as observed in GENE+/+ mice. The unique cytosolic activity that activated CHEMICAL in cytosolic fractions of liver and colon tissues of NQO1-/- mice was designated as cytosolic CHEMICAL reductase. This activity, like GENE, was inhibited by dicoumarol and immunologically related to GENE. | SUBSTRATE |
| A unique cytosolic activity related but distinct from NQO1 catalyses metabolic activation of mitomycin C. Mitomycin C (MMC) is a prototype bioreductive drug employed to treat a variety of cancers including head and neck cancer. Among the various enzymes, CHEMICAL inhibitable cytosolic GENE (NQO1) was shown to catalyse bioreductive activation of MMC leading to cross-linking of the DNA and cytotoxicity. However, the role of NQO1 in metabolic activation of MMC has been disputed. In this report, we present cellular and animal models to demonstrate that NQO1 may play only a minor role in metabolic activation of MMC. We further demonstrate that bioreductive activation of MMC is catalysed by a unique cytosolic activity which is related but distinct from NQO1. Chinese hamster ovary (CHO) cells were developed that permanently express higher levels of cDNA-derived NQO1. These cells showed significantly increased protection against menadione toxicity. However, they failed to demonstrate higher cytotoxicity due to exposure to MMC under oxygen (normal air) or hypoxia, as compared to the wild-type control CHO cells. Disruption of the NQO1 gene by homologous recombination generated NQO1-/- mice that do not express the NQO1 gene resulting in the loss of NQO1 protein and activity. The cytosolic fractions from liver and colon tissues of NQO1-/- mice showed similar amounts of DNA cross-linking upon exposure to MMC, as observed in NQO1+/+ mice. The unique cytosolic activity that activated MMC in cytosolic fractions of liver and colon tissues of NQO1-/- mice was designated as cytosolic MMC reductase. This activity, like NQO1, was inhibited by CHEMICAL and immunologically related to NQO1. | INHIBITOR |
| A unique cytosolic activity related but distinct from GENE catalyses metabolic activation of mitomycin C. Mitomycin C (MMC) is a prototype bioreductive drug employed to treat a variety of cancers including head and neck cancer. Among the various enzymes, CHEMICAL inhibitable cytosolic NAD(P)H:quinone oxidoreductase1 (GENE) was shown to catalyse bioreductive activation of MMC leading to cross-linking of the DNA and cytotoxicity. However, the role of GENE in metabolic activation of MMC has been disputed. In this report, we present cellular and animal models to demonstrate that GENE may play only a minor role in metabolic activation of MMC. We further demonstrate that bioreductive activation of MMC is catalysed by a unique cytosolic activity which is related but distinct from GENE. Chinese hamster ovary (CHO) cells were developed that permanently express higher levels of cDNA-derived GENE. These cells showed significantly increased protection against menadione toxicity. However, they failed to demonstrate higher cytotoxicity due to exposure to MMC under oxygen (normal air) or hypoxia, as compared to the wild-type control CHO cells. Disruption of the GENE gene by homologous recombination generated NQO1-/- mice that do not express the GENE gene resulting in the loss of GENE protein and activity. The cytosolic fractions from liver and colon tissues of NQO1-/- mice showed similar amounts of DNA cross-linking upon exposure to MMC, as observed in NQO1+/+ mice. The unique cytosolic activity that activated MMC in cytosolic fractions of liver and colon tissues of NQO1-/- mice was designated as cytosolic MMC reductase. This activity, like GENE, was inhibited by CHEMICAL and immunologically related to GENE. | INHIBITOR |
| A unique cytosolic activity related but distinct from NQO1 catalyses metabolic activation of mitomycin C. Mitomycin C (MMC) is a prototype bioreductive drug employed to treat a variety of cancers including head and neck cancer. Among the various enzymes, dicoumarol inhibitable cytosolic GENE (NQO1) was shown to catalyse bioreductive activation of CHEMICAL leading to cross-linking of the DNA and cytotoxicity. However, the role of NQO1 in metabolic activation of CHEMICAL has been disputed. In this report, we present cellular and animal models to demonstrate that NQO1 may play only a minor role in metabolic activation of CHEMICAL. We further demonstrate that bioreductive activation of CHEMICAL is catalysed by a unique cytosolic activity which is related but distinct from NQO1. Chinese hamster ovary (CHO) cells were developed that permanently express higher levels of cDNA-derived NQO1. These cells showed significantly increased protection against menadione toxicity. However, they failed to demonstrate higher cytotoxicity due to exposure to CHEMICAL under oxygen (normal air) or hypoxia, as compared to the wild-type control CHO cells. Disruption of the NQO1 gene by homologous recombination generated NQO1-/- mice that do not express the NQO1 gene resulting in the loss of NQO1 protein and activity. The cytosolic fractions from liver and colon tissues of NQO1-/- mice showed similar amounts of DNA cross-linking upon exposure to CHEMICAL, as observed in NQO1+/+ mice. The unique cytosolic activity that activated CHEMICAL in cytosolic fractions of liver and colon tissues of NQO1-/- mice was designated as cytosolic CHEMICAL reductase. This activity, like NQO1, was inhibited by dicoumarol and immunologically related to NQO1. | SUBSTRATE |
| A unique cytosolic activity related but distinct from GENE catalyses metabolic activation of CHEMICAL. Mitomycin C (MMC) is a prototype bioreductive drug employed to treat a variety of cancers including head and neck cancer. Among the various enzymes, dicoumarol inhibitable cytosolic NAD(P)H:quinone oxidoreductase1 (NQO1) was shown to catalyse bioreductive activation of MMC leading to cross-linking of the DNA and cytotoxicity. However, the role of GENE in metabolic activation of MMC has been disputed. In this report, we present cellular and animal models to demonstrate that GENE may play only a minor role in metabolic activation of MMC. We further demonstrate that bioreductive activation of MMC is catalysed by a unique cytosolic activity which is related but distinct from GENE. Chinese hamster ovary (CHO) cells were developed that permanently express higher levels of cDNA-derived GENE. These cells showed significantly increased protection against menadione toxicity. However, they failed to demonstrate higher cytotoxicity due to exposure to MMC under oxygen (normal air) or hypoxia, as compared to the wild-type control CHO cells. Disruption of the GENE gene by homologous recombination generated NQO1-/- mice that do not express the GENE gene resulting in the loss of GENE protein and activity. The cytosolic fractions from liver and colon tissues of NQO1-/- mice showed similar amounts of DNA cross-linking upon exposure to MMC, as observed in NQO1+/+ mice. The unique cytosolic activity that activated MMC in cytosolic fractions of liver and colon tissues of NQO1-/- mice was designated as cytosolic MMC reductase. This activity, like GENE, was inhibited by dicoumarol and immunologically related to GENE. | SUBSTRATE |
| CHEMICAL reduces plasminogen activator inhibitor-1 expression and secretion in cultured human adipocytes. AIMS/HYPOTHESIS: Increased plasma plasminogen activator inhibitor-1 (PAI-1) concentrations are characteristic for subjects with insulin resistance and could contribute to the increased cardiovascular risk in this state. In this study, we investigated the effect of CHEMICAL, a ligand of the GENE peroxisome proliferator activated receptor-gamma, on PAI-1 expression and secretion in human adipocytes. METHODS: We used two models: in vitro differentiated subcutaneous and omental adipocytes cultured under serum-free conditions and isolated subcutaneous and omental fat cells kept in suspension culture. Plasminogen activator inhibitor-1 protein was measured by ELISA, PAI-1 mRNA by a semiquantitative RT-PCR technique. RESULTS: Exposure of in vitro differentiated subcutaneous adipocytes from young normal-weight females to 1 microgram/ml CHEMICAL for 72 h caused a reduction of both PAI-1 secretion (by 29 +/- 5%; p < 0.01) and PAI-1 mRNA expression (by 26 +/- 3%; p < 0.05). In cultures from severely obese subjects, CHEMICAL induced a decrease of PAI-1 antigen secretion from newly differentiated omental adipocytes by 49 +/- 8% (p < 0.01) and from subcutaneous adipocytes by 30 +/- 7% (p < 0.05). Exposure of freshly isolated subcutaneous and omental adipocytes in suspension culture to CHEMICAL induced a similar reduction of PAI-1 concentration in the culture medium (by 35 +/- 11%, p < 0.05, and 33 +/- 8%, p < 0.05 compared with control, respectively). CONCLUSION/INTERPRETATION: This study provides evidence that CHEMICAL reduces PAI-1 production in human adipocytes, probably at the transcriptional level. This observation could point to a new beneficial effect of CHEMICAL, particularly in obese subjects, which could be associated with a reduced cardiovascular risk. | DIRECT-REGULATOR |
| CHEMICAL reduces plasminogen activator inhibitor-1 expression and secretion in cultured human adipocytes. AIMS/HYPOTHESIS: Increased plasma plasminogen activator inhibitor-1 (PAI-1) concentrations are characteristic for subjects with insulin resistance and could contribute to the increased cardiovascular risk in this state. In this study, we investigated the effect of CHEMICAL, a ligand of the nuclear receptor GENE, on PAI-1 expression and secretion in human adipocytes. METHODS: We used two models: in vitro differentiated subcutaneous and omental adipocytes cultured under serum-free conditions and isolated subcutaneous and omental fat cells kept in suspension culture. Plasminogen activator inhibitor-1 protein was measured by ELISA, PAI-1 mRNA by a semiquantitative RT-PCR technique. RESULTS: Exposure of in vitro differentiated subcutaneous adipocytes from young normal-weight females to 1 microgram/ml CHEMICAL for 72 h caused a reduction of both PAI-1 secretion (by 29 +/- 5%; p < 0.01) and PAI-1 mRNA expression (by 26 +/- 3%; p < 0.05). In cultures from severely obese subjects, CHEMICAL induced a decrease of PAI-1 antigen secretion from newly differentiated omental adipocytes by 49 +/- 8% (p < 0.01) and from subcutaneous adipocytes by 30 +/- 7% (p < 0.05). Exposure of freshly isolated subcutaneous and omental adipocytes in suspension culture to CHEMICAL induced a similar reduction of PAI-1 concentration in the culture medium (by 35 +/- 11%, p < 0.05, and 33 +/- 8%, p < 0.05 compared with control, respectively). CONCLUSION/INTERPRETATION: This study provides evidence that CHEMICAL reduces PAI-1 production in human adipocytes, probably at the transcriptional level. This observation could point to a new beneficial effect of CHEMICAL, particularly in obese subjects, which could be associated with a reduced cardiovascular risk. | DIRECT-REGULATOR |
| CHEMICAL reduces plasminogen activator inhibitor-1 expression and secretion in cultured human adipocytes. AIMS/HYPOTHESIS: Increased plasma plasminogen activator inhibitor-1 (PAI-1) concentrations are characteristic for subjects with insulin resistance and could contribute to the increased cardiovascular risk in this state. In this study, we investigated the effect of CHEMICAL, a ligand of the nuclear receptor peroxisome proliferator activated receptor-gamma, on GENE expression and secretion in human adipocytes. METHODS: We used two models: in vitro differentiated subcutaneous and omental adipocytes cultured under serum-free conditions and isolated subcutaneous and omental fat cells kept in suspension culture. Plasminogen activator inhibitor-1 protein was measured by ELISA, GENE mRNA by a semiquantitative RT-PCR technique. RESULTS: Exposure of in vitro differentiated subcutaneous adipocytes from young normal-weight females to 1 microgram/ml CHEMICAL for 72 h caused a reduction of both GENE secretion (by 29 +/- 5%; p < 0.01) and GENE mRNA expression (by 26 +/- 3%; p < 0.05). In cultures from severely obese subjects, CHEMICAL induced a decrease of GENE antigen secretion from newly differentiated omental adipocytes by 49 +/- 8% (p < 0.01) and from subcutaneous adipocytes by 30 +/- 7% (p < 0.05). Exposure of freshly isolated subcutaneous and omental adipocytes in suspension culture to CHEMICAL induced a similar reduction of GENE concentration in the culture medium (by 35 +/- 11%, p < 0.05, and 33 +/- 8%, p < 0.05 compared with control, respectively). CONCLUSION/INTERPRETATION: This study provides evidence that CHEMICAL reduces GENE production in human adipocytes, probably at the transcriptional level. This observation could point to a new beneficial effect of CHEMICAL, particularly in obese subjects, which could be associated with a reduced cardiovascular risk. | INDIRECT-DOWNREGULATOR |
| CHEMICAL reduces GENE expression and secretion in cultured human adipocytes. AIMS/HYPOTHESIS: Increased plasma GENE (PAI-1) concentrations are characteristic for subjects with insulin resistance and could contribute to the increased cardiovascular risk in this state. In this study, we investigated the effect of troglitazone, a ligand of the nuclear receptor peroxisome proliferator activated receptor-gamma, on PAI-1 expression and secretion in human adipocytes. METHODS: We used two models: in vitro differentiated subcutaneous and omental adipocytes cultured under serum-free conditions and isolated subcutaneous and omental fat cells kept in suspension culture. GENE protein was measured by ELISA, PAI-1 mRNA by a semiquantitative RT-PCR technique. RESULTS: Exposure of in vitro differentiated subcutaneous adipocytes from young normal-weight females to 1 microgram/ml troglitazone for 72 h caused a reduction of both PAI-1 secretion (by 29 +/- 5%; p < 0.01) and PAI-1 mRNA expression (by 26 +/- 3%; p < 0.05). In cultures from severely obese subjects, troglitazone induced a decrease of PAI-1 antigen secretion from newly differentiated omental adipocytes by 49 +/- 8% (p < 0.01) and from subcutaneous adipocytes by 30 +/- 7% (p < 0.05). Exposure of freshly isolated subcutaneous and omental adipocytes in suspension culture to troglitazone induced a similar reduction of PAI-1 concentration in the culture medium (by 35 +/- 11%, p < 0.05, and 33 +/- 8%, p < 0.05 compared with control, respectively). CONCLUSION/INTERPRETATION: This study provides evidence that troglitazone reduces PAI-1 production in human adipocytes, probably at the transcriptional level. This observation could point to a new beneficial effect of troglitazone, particularly in obese subjects, which could be associated with a reduced cardiovascular risk. | INDIRECT-DOWNREGULATOR |
| Effect of CHEMICAL, a novel GENE antagonist, on prostate function in dogs. We examined the effect of CHEMICAL (3- inverted question markN-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminom ethyl inverted question mark-4-methoxy-2,5,6-trimethylphenol hemifumarate), a new alpha(1L)-adrenoceptor antagonist, on prostatic function in isolated canine prostate and in anesthetized dogs. In the contraction study, phenylephrine and noradrenaline produced concentration-dependent contractions in canine prostate and carotid artery, respectively. In these tissues, CHEMICAL, prazosin (a non-selective GENE antagonist), and tamsulosin (an alpha(1A)-adrenoceptor antagonist) competitively antagonized contraction in a concentration-dependent manner. The pA(2) (pK(B)) values with prostate were 8.49+/-0.07 for CHEMICAL, 7.94+/-0.04 for prazosin and 9.42+/-0.22 for tamsulosin. The ratio of pA(2) (carotid artery/prostate), i.e. prostatic selectivity, was 10.471 for CHEMICAL, 0.008 for prazosin and 0.371 for tamsulosin, respectively. In anesthetized dogs, CHEMICAL (1 mg/kg, i.d.) significantly decreased urethral pressure by 15% without affecting blood pressure or heart rate. Tamsulosin (0.1 mg/kg, i.d.) decreased urethral pressure to the same extent as did CHEMICAL, but with a significant effect on blood pressure and heart rate. CHEMICAL showed higher selectivity for canine prostate both in vitro and in vivo. In prostate, an important role of the alpha(1L)-adrenoceptor is suggested in the smooth muscle contraction mediated by alpha(1)-adrenoceptors. CHEMICAL is expected to be an effective GENE antagonist for the treatment of urinary outlet obstruction by benign prostatic hypertrophy with a minimum effect on the cardiovascular system. | INHIBITOR |
| Effect of JTH-601, a novel GENE antagonist, on prostate function in dogs. We examined the effect of JTH-601 (3- inverted question markN-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminom ethyl inverted question mark-4-methoxy-2,5,6-trimethylphenol hemifumarate), a new alpha(1L)-adrenoceptor antagonist, on prostatic function in isolated canine prostate and in anesthetized dogs. In the contraction study, phenylephrine and noradrenaline produced concentration-dependent contractions in canine prostate and carotid artery, respectively. In these tissues, JTH-601, CHEMICAL (a non-selective GENE antagonist), and tamsulosin (an alpha(1A)-adrenoceptor antagonist) competitively antagonized contraction in a concentration-dependent manner. The pA(2) (pK(B)) values with prostate were 8.49+/-0.07 for JTH-601, 7.94+/-0.04 for CHEMICAL and 9.42+/-0.22 for tamsulosin. The ratio of pA(2) (carotid artery/prostate), i.e. prostatic selectivity, was 10.471 for JTH-601, 0.008 for CHEMICAL and 0.371 for tamsulosin, respectively. In anesthetized dogs, JTH-601 (1 mg/kg, i.d.) significantly decreased urethral pressure by 15% without affecting blood pressure or heart rate. Tamsulosin (0.1 mg/kg, i.d.) decreased urethral pressure to the same extent as did JTH-601, but with a significant effect on blood pressure and heart rate. JTH-601 showed higher selectivity for canine prostate both in vitro and in vivo. In prostate, an important role of the alpha(1L)-adrenoceptor is suggested in the smooth muscle contraction mediated by alpha(1)-adrenoceptors. JTH-601 is expected to be an effective GENE antagonist for the treatment of urinary outlet obstruction by benign prostatic hypertrophy with a minimum effect on the cardiovascular system. | INHIBITOR |
| Effect of JTH-601, a novel alpha(1)-adrenoceptor antagonist, on prostate function in dogs. We examined the effect of JTH-601 (3- inverted question markN-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminom ethyl inverted question mark-4-methoxy-2,5,6-trimethylphenol hemifumarate), a new alpha(1L)-adrenoceptor antagonist, on prostatic function in isolated canine prostate and in anesthetized dogs. In the contraction study, phenylephrine and noradrenaline produced concentration-dependent contractions in canine prostate and carotid artery, respectively. In these tissues, JTH-601, prazosin (a non-selective alpha(1)-adrenoceptor antagonist), and CHEMICAL (an GENE antagonist) competitively antagonized contraction in a concentration-dependent manner. The pA(2) (pK(B)) values with prostate were 8.49+/-0.07 for JTH-601, 7.94+/-0.04 for prazosin and 9.42+/-0.22 for CHEMICAL. The ratio of pA(2) (carotid artery/prostate), i.e. prostatic selectivity, was 10.471 for JTH-601, 0.008 for prazosin and 0.371 for CHEMICAL, respectively. In anesthetized dogs, JTH-601 (1 mg/kg, i.d.) significantly decreased urethral pressure by 15% without affecting blood pressure or heart rate. CHEMICAL (0.1 mg/kg, i.d.) decreased urethral pressure to the same extent as did JTH-601, but with a significant effect on blood pressure and heart rate. JTH-601 showed higher selectivity for canine prostate both in vitro and in vivo. In prostate, an important role of the alpha(1L)-adrenoceptor is suggested in the smooth muscle contraction mediated by alpha(1)-adrenoceptors. JTH-601 is expected to be an effective alpha(1)-adrenoceptor antagonist for the treatment of urinary outlet obstruction by benign prostatic hypertrophy with a minimum effect on the cardiovascular system. | INHIBITOR |
| Effect of JTH-601, a novel alpha(1)-adrenoceptor antagonist, on prostate function in dogs. We examined the effect of JTH-601 (3- inverted question markCHEMICAL ethyl inverted question mark-4-methoxy-2,5,6-trimethylphenol hemifumarate), a new GENE antagonist, on prostatic function in isolated canine prostate and in anesthetized dogs. In the contraction study, phenylephrine and noradrenaline produced concentration-dependent contractions in canine prostate and carotid artery, respectively. In these tissues, JTH-601, prazosin (a non-selective alpha(1)-adrenoceptor antagonist), and tamsulosin (an alpha(1A)-adrenoceptor antagonist) competitively antagonized contraction in a concentration-dependent manner. The pA(2) (pK(B)) values with prostate were 8.49+/-0.07 for JTH-601, 7.94+/-0.04 for prazosin and 9.42+/-0.22 for tamsulosin. The ratio of pA(2) (carotid artery/prostate), i.e. prostatic selectivity, was 10.471 for JTH-601, 0.008 for prazosin and 0.371 for tamsulosin, respectively. In anesthetized dogs, JTH-601 (1 mg/kg, i.d.) significantly decreased urethral pressure by 15% without affecting blood pressure or heart rate. Tamsulosin (0.1 mg/kg, i.d.) decreased urethral pressure to the same extent as did JTH-601, but with a significant effect on blood pressure and heart rate. JTH-601 showed higher selectivity for canine prostate both in vitro and in vivo. In prostate, an important role of the GENE is suggested in the smooth muscle contraction mediated by alpha(1)-adrenoceptors. JTH-601 is expected to be an effective alpha(1)-adrenoceptor antagonist for the treatment of urinary outlet obstruction by benign prostatic hypertrophy with a minimum effect on the cardiovascular system. | INHIBITOR |
| Effect of JTH-601, a novel alpha(1)-adrenoceptor antagonist, on prostate function in dogs. We examined the effect of JTH-601 (3- inverted question markN-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminom CHEMICAL inverted question mark-4-methoxy-2,5,6-trimethylphenol hemifumarate), a new GENE antagonist, on prostatic function in isolated canine prostate and in anesthetized dogs. In the contraction study, phenylephrine and noradrenaline produced concentration-dependent contractions in canine prostate and carotid artery, respectively. In these tissues, JTH-601, prazosin (a non-selective alpha(1)-adrenoceptor antagonist), and tamsulosin (an alpha(1A)-adrenoceptor antagonist) competitively antagonized contraction in a concentration-dependent manner. The pA(2) (pK(B)) values with prostate were 8.49+/-0.07 for JTH-601, 7.94+/-0.04 for prazosin and 9.42+/-0.22 for tamsulosin. The ratio of pA(2) (carotid artery/prostate), i.e. prostatic selectivity, was 10.471 for JTH-601, 0.008 for prazosin and 0.371 for tamsulosin, respectively. In anesthetized dogs, JTH-601 (1 mg/kg, i.d.) significantly decreased urethral pressure by 15% without affecting blood pressure or heart rate. Tamsulosin (0.1 mg/kg, i.d.) decreased urethral pressure to the same extent as did JTH-601, but with a significant effect on blood pressure and heart rate. JTH-601 showed higher selectivity for canine prostate both in vitro and in vivo. In prostate, an important role of the GENE is suggested in the smooth muscle contraction mediated by alpha(1)-adrenoceptors. JTH-601 is expected to be an effective alpha(1)-adrenoceptor antagonist for the treatment of urinary outlet obstruction by benign prostatic hypertrophy with a minimum effect on the cardiovascular system. | INHIBITOR |
| Effect of JTH-601, a novel alpha(1)-adrenoceptor antagonist, on prostate function in dogs. We examined the effect of JTH-601 (3- inverted question markN-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminom ethyl inverted question mark-CHEMICAL), a new GENE antagonist, on prostatic function in isolated canine prostate and in anesthetized dogs. In the contraction study, phenylephrine and noradrenaline produced concentration-dependent contractions in canine prostate and carotid artery, respectively. In these tissues, JTH-601, prazosin (a non-selective alpha(1)-adrenoceptor antagonist), and tamsulosin (an alpha(1A)-adrenoceptor antagonist) competitively antagonized contraction in a concentration-dependent manner. The pA(2) (pK(B)) values with prostate were 8.49+/-0.07 for JTH-601, 7.94+/-0.04 for prazosin and 9.42+/-0.22 for tamsulosin. The ratio of pA(2) (carotid artery/prostate), i.e. prostatic selectivity, was 10.471 for JTH-601, 0.008 for prazosin and 0.371 for tamsulosin, respectively. In anesthetized dogs, JTH-601 (1 mg/kg, i.d.) significantly decreased urethral pressure by 15% without affecting blood pressure or heart rate. Tamsulosin (0.1 mg/kg, i.d.) decreased urethral pressure to the same extent as did JTH-601, but with a significant effect on blood pressure and heart rate. JTH-601 showed higher selectivity for canine prostate both in vitro and in vivo. In prostate, an important role of the GENE is suggested in the smooth muscle contraction mediated by alpha(1)-adrenoceptors. JTH-601 is expected to be an effective alpha(1)-adrenoceptor antagonist for the treatment of urinary outlet obstruction by benign prostatic hypertrophy with a minimum effect on the cardiovascular system. | INHIBITOR |
| Effect of CHEMICAL, a novel alpha(1)-adrenoceptor antagonist, on prostate function in dogs. We examined the effect of CHEMICAL (3- inverted question markN-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminom ethyl inverted question mark-4-methoxy-2,5,6-trimethylphenol hemifumarate), a new GENE antagonist, on prostatic function in isolated canine prostate and in anesthetized dogs. In the contraction study, phenylephrine and noradrenaline produced concentration-dependent contractions in canine prostate and carotid artery, respectively. In these tissues, CHEMICAL, prazosin (a non-selective alpha(1)-adrenoceptor antagonist), and tamsulosin (an alpha(1A)-adrenoceptor antagonist) competitively antagonized contraction in a concentration-dependent manner. The pA(2) (pK(B)) values with prostate were 8.49+/-0.07 for CHEMICAL, 7.94+/-0.04 for prazosin and 9.42+/-0.22 for tamsulosin. The ratio of pA(2) (carotid artery/prostate), i.e. prostatic selectivity, was 10.471 for CHEMICAL, 0.008 for prazosin and 0.371 for tamsulosin, respectively. In anesthetized dogs, CHEMICAL (1 mg/kg, i.d.) significantly decreased urethral pressure by 15% without affecting blood pressure or heart rate. Tamsulosin (0.1 mg/kg, i.d.) decreased urethral pressure to the same extent as did CHEMICAL, but with a significant effect on blood pressure and heart rate. CHEMICAL showed higher selectivity for canine prostate both in vitro and in vivo. In prostate, an important role of the GENE is suggested in the smooth muscle contraction mediated by alpha(1)-adrenoceptors. CHEMICAL is expected to be an effective alpha(1)-adrenoceptor antagonist for the treatment of urinary outlet obstruction by benign prostatic hypertrophy with a minimum effect on the cardiovascular system. | INHIBITOR |
| Severe impairment of salivation in Na+/K+/2Cl- cotransporter (NKCC1)-deficient mice. The salivary fluid secretory mechanism is thought to require Na(+)/K(+)/2Cl(-) cotransporter-mediated CHEMICAL uptake. To directly test this possibility we studied the in vivo and in vitro functioning of acinar cells from the parotid glands of mice with targeted disruption of Na(+)/K(+)/2Cl(-) cotransporter isoform 1 (Nkcc1), the gene encoding the salivary Na(+)/K(+)/2Cl(-) cotransporter. In wild-type mice GENE was localized to the basolateral membranes of parotid acinar cells, whereas expression was not detected in duct cells. The lack of functional GENE resulted in a dramatic reduction (>60%) in the volume of saliva secreted in response to a muscarinic agonist, the primary in situ salivation signal. Consistent with defective CHEMICAL uptake, a loss of bumetanide-sensitive CHEMICAL influx was observed in parotid acinar cells from mice lacking GENE. Cl(-)/ HCO(3)(-) exchanger activity was increased in parotid acinar cells isolated from knockout mice suggesting that the residual saliva secreted by mice lacking GENE is associated with anion exchanger-dependent CHEMICAL uptake. Indeed, expression of the Cl(-)/ HCO(3)(-) exchanger AE2 was enhanced suggesting that this transporter compensates for the loss of functional Na(+)/K(+)/2Cl(-) cotransporter. Furthermore, the ability of the parotid gland to conserve NaCl was abolished in NKCC1-deficient mice. This deficit was not associated with changes in the morphology of the ducts, but transcript levels for the alpha-, beta-, and gamma-subunits of the epithelial Na(+) channel were reduced. These data directly demonstrate that GENE is the major CHEMICAL uptake mechanism across the basolateral membrane of acinar cells and is critical for driving saliva secretion in vivo. | SUBSTRATE |
| Severe impairment of salivation in Na+/K+/2Cl- cotransporter (NKCC1)-deficient mice. The salivary fluid secretory mechanism is thought to require GENE-mediated CHEMICAL uptake. To directly test this possibility we studied the in vivo and in vitro functioning of acinar cells from the parotid glands of mice with targeted disruption of GENE isoform 1 (Nkcc1), the gene encoding the salivary GENE. In wild-type mice NKCC1 was localized to the basolateral membranes of parotid acinar cells, whereas expression was not detected in duct cells. The lack of functional NKCC1 resulted in a dramatic reduction (>60%) in the volume of saliva secreted in response to a muscarinic agonist, the primary in situ salivation signal. Consistent with defective CHEMICAL uptake, a loss of bumetanide-sensitive CHEMICAL influx was observed in parotid acinar cells from mice lacking NKCC1. Cl(-)/ HCO(3)(-) exchanger activity was increased in parotid acinar cells isolated from knockout mice suggesting that the residual saliva secreted by mice lacking NKCC1 is associated with anion exchanger-dependent CHEMICAL uptake. Indeed, expression of the Cl(-)/ HCO(3)(-) exchanger AE2 was enhanced suggesting that this transporter compensates for the loss of functional GENE. Furthermore, the ability of the parotid gland to conserve NaCl was abolished in NKCC1-deficient mice. This deficit was not associated with changes in the morphology of the ducts, but transcript levels for the alpha-, beta-, and gamma-subunits of the epithelial Na(+) channel were reduced. These data directly demonstrate that NKCC1 is the major CHEMICAL uptake mechanism across the basolateral membrane of acinar cells and is critical for driving saliva secretion in vivo. | SUBSTRATE |
| Evaluation of in vivo binding properties of CHEMICAL and 3H-QNB in mouse brain. UNLABELLED: Apparent GENE occupancy in mouse cerebral cortex, hippocampus, and striatum by scopolamine, an antagonist, and biperiden, a relatively selective M1 antagonist, was estimated with competitive binding studies using two different radioligands: 3H-N-methyl piperidyl benzilate (CHEMICAL) and 3H-quinuclidinyl benzilate (3H-QNB). Both radioligands labeled mAch receptors in these brain regions, and the relative regional distributions of the specific binding of CHEMICAL in vivo paralleled the distribution of mAch receptors. CHEMICAL binding in vivo was much more sensitive to direct competitive inhibition by scopolamine than was 3H-QNB. A similar discrepancy in sensitivity to competitors between CHEMICAL and 3H-QNB was also observed when biperiden was used as a competitor, indicating that binding to different subtypes of the mAch receptor could not account for the observed differences in sensitivity to competition. An in vivo saturation study suggested that the apparent association rate constant (k on) of 3H-QNB binding might be changed by ligand concentration. The heterogeneity of the free ligand concentration in intact brain was assessed in relation to the ligand concentration dependency of the apparent association rate constant (k on) of 3H-QNB binding. This finding, together with the more favorable accumulation of CHEMICAL in cerebral cortex, hippocampus, and striatum, leads us to conclude that CHEMICAL, or its positron emitting counterpart, should be the more favorable radiotracer for the estimation of mAch receptor occupancy by cholinergic drugs in the brain. KEYWORDS: mAch receptor, QNB, NMPB, in vivo, mouse. | DIRECT-REGULATOR |
| Evaluation of in vivo binding properties of 3H-NMPB and 3H-QNB in mouse brain. UNLABELLED: Apparent GENE occupancy in mouse cerebral cortex, hippocampus, and striatum by scopolamine, an antagonist, and biperiden, a relatively selective M1 antagonist, was estimated with competitive binding studies using two different radioligands: 3H-N-methyl piperidyl benzilate (3H-NMPB) and CHEMICAL (3H-QNB). Both radioligands labeled mAch receptors in these brain regions, and the relative regional distributions of the specific binding of 3H-NMPB in vivo paralleled the distribution of mAch receptors. 3H-NMPB binding in vivo was much more sensitive to direct competitive inhibition by scopolamine than was 3H-QNB. A similar discrepancy in sensitivity to competitors between 3H-NMPB and 3H-QNB was also observed when biperiden was used as a competitor, indicating that binding to different subtypes of the mAch receptor could not account for the observed differences in sensitivity to competition. An in vivo saturation study suggested that the apparent association rate constant (k on) of 3H-QNB binding might be changed by ligand concentration. The heterogeneity of the free ligand concentration in intact brain was assessed in relation to the ligand concentration dependency of the apparent association rate constant (k on) of 3H-QNB binding. This finding, together with the more favorable accumulation of 3H-NMPB in cerebral cortex, hippocampus, and striatum, leads us to conclude that 3H-NMPB, or its positron emitting counterpart, should be the more favorable radiotracer for the estimation of mAch receptor occupancy by cholinergic drugs in the brain. KEYWORDS: mAch receptor, QNB, NMPB, in vivo, mouse. | DIRECT-REGULATOR |
| Evaluation of in vivo binding properties of 3H-NMPB and CHEMICAL in mouse brain. UNLABELLED: Apparent GENE occupancy in mouse cerebral cortex, hippocampus, and striatum by scopolamine, an antagonist, and biperiden, a relatively selective M1 antagonist, was estimated with competitive binding studies using two different radioligands: 3H-N-methyl piperidyl benzilate (3H-NMPB) and 3H-quinuclidinyl benzilate (CHEMICAL). Both radioligands labeled mAch receptors in these brain regions, and the relative regional distributions of the specific binding of 3H-NMPB in vivo paralleled the distribution of mAch receptors. 3H-NMPB binding in vivo was much more sensitive to direct competitive inhibition by scopolamine than was CHEMICAL. A similar discrepancy in sensitivity to competitors between 3H-NMPB and CHEMICAL was also observed when biperiden was used as a competitor, indicating that binding to different subtypes of the mAch receptor could not account for the observed differences in sensitivity to competition. An in vivo saturation study suggested that the apparent association rate constant (k on) of CHEMICAL binding might be changed by ligand concentration. The heterogeneity of the free ligand concentration in intact brain was assessed in relation to the ligand concentration dependency of the apparent association rate constant (k on) of CHEMICAL binding. This finding, together with the more favorable accumulation of 3H-NMPB in cerebral cortex, hippocampus, and striatum, leads us to conclude that 3H-NMPB, or its positron emitting counterpart, should be the more favorable radiotracer for the estimation of mAch receptor occupancy by cholinergic drugs in the brain. KEYWORDS: mAch receptor, QNB, NMPB, in vivo, mouse. | DIRECT-REGULATOR |
| Evaluation of in vivo binding properties of CHEMICAL and 3H-QNB in mouse brain. UNLABELLED: Apparent muscarinic acetylcholine (mAch) receptor occupancy in mouse cerebral cortex, hippocampus, and striatum by scopolamine, an antagonist, and biperiden, a relatively selective M1 antagonist, was estimated with competitive binding studies using two different radioligands: 3H-N-methyl piperidyl benzilate (3H-NMPB) and 3H-quinuclidinyl benzilate (3H-QNB). Both radioligands labeled GENE in these brain regions, and the relative regional distributions of the specific binding of CHEMICAL in vivo paralleled the distribution of GENE. CHEMICAL binding in vivo was much more sensitive to direct competitive inhibition by scopolamine than was 3H-QNB. A similar discrepancy in sensitivity to competitors between CHEMICAL and 3H-QNB was also observed when biperiden was used as a competitor, indicating that binding to different subtypes of the mAch receptor could not account for the observed differences in sensitivity to competition. An in vivo saturation study suggested that the apparent association rate constant (k on) of 3H-QNB binding might be changed by ligand concentration. The heterogeneity of the free ligand concentration in intact brain was assessed in relation to the ligand concentration dependency of the apparent association rate constant (k on) of 3H-QNB binding. This finding, together with the more favorable accumulation of CHEMICAL in cerebral cortex, hippocampus, and striatum, leads us to conclude that CHEMICAL, or its positron emitting counterpart, should be the more favorable radiotracer for the estimation of mAch receptor occupancy by cholinergic drugs in the brain. KEYWORDS: mAch receptor, QNB, NMPB, in vivo, mouse. | DIRECT-REGULATOR |
| Evaluation of in vivo binding properties of CHEMICAL and 3H-QNB in mouse brain. UNLABELLED: Apparent muscarinic acetylcholine (mAch) receptor occupancy in mouse cerebral cortex, hippocampus, and striatum by scopolamine, an antagonist, and biperiden, a relatively selective M1 antagonist, was estimated with competitive binding studies using two different radioligands: 3H-N-methyl piperidyl benzilate (3H-NMPB) and 3H-quinuclidinyl benzilate (3H-QNB). Both radioligands labeled mAch receptors in these brain regions, and the relative regional distributions of the specific binding of CHEMICAL in vivo paralleled the distribution of mAch receptors. CHEMICAL binding in vivo was much more sensitive to direct competitive inhibition by scopolamine than was 3H-QNB. A similar discrepancy in sensitivity to competitors between CHEMICAL and 3H-QNB was also observed when biperiden was used as a competitor, indicating that binding to different subtypes of the GENE could not account for the observed differences in sensitivity to competition. An in vivo saturation study suggested that the apparent association rate constant (k on) of 3H-QNB binding might be changed by ligand concentration. The heterogeneity of the free ligand concentration in intact brain was assessed in relation to the ligand concentration dependency of the apparent association rate constant (k on) of 3H-QNB binding. This finding, together with the more favorable accumulation of CHEMICAL in cerebral cortex, hippocampus, and striatum, leads us to conclude that CHEMICAL, or its positron emitting counterpart, should be the more favorable radiotracer for the estimation of GENE occupancy by cholinergic drugs in the brain. KEYWORDS: GENE, QNB, NMPB, in vivo, mouse. | DIRECT-REGULATOR |
| Evaluation of in vivo binding properties of 3H-NMPB and CHEMICAL in mouse brain. UNLABELLED: Apparent muscarinic acetylcholine (mAch) receptor occupancy in mouse cerebral cortex, hippocampus, and striatum by scopolamine, an antagonist, and biperiden, a relatively selective M1 antagonist, was estimated with competitive binding studies using two different radioligands: 3H-N-methyl piperidyl benzilate (3H-NMPB) and 3H-quinuclidinyl benzilate (3H-QNB). Both radioligands labeled mAch receptors in these brain regions, and the relative regional distributions of the specific binding of 3H-NMPB in vivo paralleled the distribution of mAch receptors. 3H-NMPB binding in vivo was much more sensitive to direct competitive inhibition by scopolamine than was CHEMICAL. A similar discrepancy in sensitivity to competitors between 3H-NMPB and CHEMICAL was also observed when biperiden was used as a competitor, indicating that binding to different subtypes of the GENE could not account for the observed differences in sensitivity to competition. An in vivo saturation study suggested that the apparent association rate constant (k on) of CHEMICAL binding might be changed by ligand concentration. The heterogeneity of the free ligand concentration in intact brain was assessed in relation to the ligand concentration dependency of the apparent association rate constant (k on) of CHEMICAL binding. This finding, together with the more favorable accumulation of 3H-NMPB in cerebral cortex, hippocampus, and striatum, leads us to conclude that 3H-NMPB, or its positron emitting counterpart, should be the more favorable radiotracer for the estimation of GENE occupancy by cholinergic drugs in the brain. KEYWORDS: GENE, QNB, NMPB, in vivo, mouse. | DIRECT-REGULATOR |
| Evaluation of in vivo binding properties of 3H-NMPB and 3H-QNB in mouse brain. UNLABELLED: Apparent muscarinic acetylcholine (mAch) receptor occupancy in mouse cerebral cortex, hippocampus, and striatum by scopolamine, an antagonist, and CHEMICAL, a relatively selective M1 antagonist, was estimated with competitive binding studies using two different radioligands: 3H-N-methyl piperidyl benzilate (3H-NMPB) and 3H-quinuclidinyl benzilate (3H-QNB). Both radioligands labeled mAch receptors in these brain regions, and the relative regional distributions of the specific binding of 3H-NMPB in vivo paralleled the distribution of mAch receptors. 3H-NMPB binding in vivo was much more sensitive to direct competitive inhibition by scopolamine than was 3H-QNB. A similar discrepancy in sensitivity to competitors between 3H-NMPB and 3H-QNB was also observed when CHEMICAL was used as a competitor, indicating that binding to different subtypes of the GENE could not account for the observed differences in sensitivity to competition. An in vivo saturation study suggested that the apparent association rate constant (k on) of 3H-QNB binding might be changed by ligand concentration. The heterogeneity of the free ligand concentration in intact brain was assessed in relation to the ligand concentration dependency of the apparent association rate constant (k on) of 3H-QNB binding. This finding, together with the more favorable accumulation of 3H-NMPB in cerebral cortex, hippocampus, and striatum, leads us to conclude that 3H-NMPB, or its positron emitting counterpart, should be the more favorable radiotracer for the estimation of GENE occupancy by cholinergic drugs in the brain. KEYWORDS: GENE, QNB, NMPB, in vivo, mouse. | DIRECT-REGULATOR |
| Evaluation of in vivo binding properties of 3H-NMPB and 3H-QNB in mouse brain. UNLABELLED: Apparent GENE occupancy in mouse cerebral cortex, hippocampus, and striatum by scopolamine, an antagonist, and biperiden, a relatively selective M1 antagonist, was estimated with competitive binding studies using two different radioligands: CHEMICAL (3H-NMPB) and 3H-quinuclidinyl benzilate (3H-QNB). Both radioligands labeled mAch receptors in these brain regions, and the relative regional distributions of the specific binding of 3H-NMPB in vivo paralleled the distribution of mAch receptors. 3H-NMPB binding in vivo was much more sensitive to direct competitive inhibition by scopolamine than was 3H-QNB. A similar discrepancy in sensitivity to competitors between 3H-NMPB and 3H-QNB was also observed when biperiden was used as a competitor, indicating that binding to different subtypes of the mAch receptor could not account for the observed differences in sensitivity to competition. An in vivo saturation study suggested that the apparent association rate constant (k on) of 3H-QNB binding might be changed by ligand concentration. The heterogeneity of the free ligand concentration in intact brain was assessed in relation to the ligand concentration dependency of the apparent association rate constant (k on) of 3H-QNB binding. This finding, together with the more favorable accumulation of 3H-NMPB in cerebral cortex, hippocampus, and striatum, leads us to conclude that 3H-NMPB, or its positron emitting counterpart, should be the more favorable radiotracer for the estimation of mAch receptor occupancy by cholinergic drugs in the brain. KEYWORDS: mAch receptor, QNB, NMPB, in vivo, mouse. | DIRECT-REGULATOR |
| Evaluation of in vivo binding properties of 3H-NMPB and 3H-QNB in mouse brain. UNLABELLED: Apparent GENE occupancy in mouse cerebral cortex, hippocampus, and striatum by CHEMICAL, an antagonist, and biperiden, a relatively selective M1 antagonist, was estimated with competitive binding studies using two different radioligands: 3H-N-methyl piperidyl benzilate (3H-NMPB) and 3H-quinuclidinyl benzilate (3H-QNB). Both radioligands labeled mAch receptors in these brain regions, and the relative regional distributions of the specific binding of 3H-NMPB in vivo paralleled the distribution of mAch receptors. 3H-NMPB binding in vivo was much more sensitive to direct competitive inhibition by CHEMICAL than was 3H-QNB. A similar discrepancy in sensitivity to competitors between 3H-NMPB and 3H-QNB was also observed when biperiden was used as a competitor, indicating that binding to different subtypes of the mAch receptor could not account for the observed differences in sensitivity to competition. An in vivo saturation study suggested that the apparent association rate constant (k on) of 3H-QNB binding might be changed by ligand concentration. The heterogeneity of the free ligand concentration in intact brain was assessed in relation to the ligand concentration dependency of the apparent association rate constant (k on) of 3H-QNB binding. This finding, together with the more favorable accumulation of 3H-NMPB in cerebral cortex, hippocampus, and striatum, leads us to conclude that 3H-NMPB, or its positron emitting counterpart, should be the more favorable radiotracer for the estimation of mAch receptor occupancy by cholinergic drugs in the brain. KEYWORDS: mAch receptor, QNB, NMPB, in vivo, mouse. | DIRECT-REGULATOR |
| Evaluation of in vivo binding properties of 3H-NMPB and 3H-QNB in mouse brain. UNLABELLED: Apparent muscarinic acetylcholine (mAch) receptor occupancy in mouse cerebral cortex, hippocampus, and striatum by scopolamine, an antagonist, and CHEMICAL, a relatively selective GENE antagonist, was estimated with competitive binding studies using two different radioligands: 3H-N-methyl piperidyl benzilate (3H-NMPB) and 3H-quinuclidinyl benzilate (3H-QNB). Both radioligands labeled mAch receptors in these brain regions, and the relative regional distributions of the specific binding of 3H-NMPB in vivo paralleled the distribution of mAch receptors. 3H-NMPB binding in vivo was much more sensitive to direct competitive inhibition by scopolamine than was 3H-QNB. A similar discrepancy in sensitivity to competitors between 3H-NMPB and 3H-QNB was also observed when CHEMICAL was used as a competitor, indicating that binding to different subtypes of the mAch receptor could not account for the observed differences in sensitivity to competition. An in vivo saturation study suggested that the apparent association rate constant (k on) of 3H-QNB binding might be changed by ligand concentration. The heterogeneity of the free ligand concentration in intact brain was assessed in relation to the ligand concentration dependency of the apparent association rate constant (k on) of 3H-QNB binding. This finding, together with the more favorable accumulation of 3H-NMPB in cerebral cortex, hippocampus, and striatum, leads us to conclude that 3H-NMPB, or its positron emitting counterpart, should be the more favorable radiotracer for the estimation of mAch receptor occupancy by cholinergic drugs in the brain. KEYWORDS: mAch receptor, QNB, NMPB, in vivo, mouse. | INHIBITOR |
| Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation: fibrates and troglitazone reverse lactation-induced downregulation of the uncoupling protein-3 gene. The expression of uncoupling protein (UCP)-3 mRNA in skeletal muscle is dramatically reduced during lactation in mice. The reduction in GENE mRNA levels lowers the amount of the GENE protein in skeletal muscle mitochondria during lactation. Spontaneous or abrupt weaning reverses the downregulation of the GENE mRNA but not the reduction in GENE protein levels. In lactating and virgin mice, however, fasting increases GENE mRNA levels. Changes in GENE mRNA occur in parallel with modifications in the levels of free fatty acids, which are reduced in lactation and are upregulated due to weaning or fasting. Modifications in the energy nutritional stress of lactating dams achieved by manipulating litter sizes do not influence GENE mRNA levels in skeletal muscle. Conversely, when mice are fed a high-fat diet after parturition, the downregulation of GENE mRNA and GENE protein levels due to lactation is partially reversed, as is the reduction in serum free fatty acid levels. Treatment of lactating mice with a single injection of CHEMICAL, an activator of the peroxisome proliferator-activated receptor (PPAR), raises GENE mRNA in skeletal muscle to levels similar to those in virgin mice. 4-chloro-6-[(2,3-xylidine)-pirimidinylthio] acetic acid (WY-14,643), a specific ligand of the PPAR-alpha subtype, causes the most dramatic increase in GENE mRNA, whereas troglitazone, a specific activator of PPAR-gamma, also significantly increases GENE mRNA abundance in skeletal muscle of lactating mice. However, in virgin mice, CHEMICAL and WY-14,643 do not significantly affect GENE mRNA expression, whereas troglitazone is at least as effective as it is in lactating dams. It is proposed that the GENE gene is regulated in skeletal muscle during lactation in response to changes in circulating free fatty acids by mechanisms involving activation of PPARs. The impaired expression of the GENE gene is consistent with the involvement of GENE gene regulation in the reduction of the use of fatty acids as fuel by the skeletal muscle and in impaired adaptative thermogenesis, both of which are major metabolic adaptations that occur during lactation. | NO-RELATIONSHIP |
| Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation: fibrates and troglitazone reverse lactation-induced downregulation of the uncoupling protein-3 gene. The expression of uncoupling protein (UCP)-3 mRNA in skeletal muscle is dramatically reduced during lactation in mice. The reduction in GENE mRNA levels lowers the amount of the GENE protein in skeletal muscle mitochondria during lactation. Spontaneous or abrupt weaning reverses the downregulation of the GENE mRNA but not the reduction in GENE protein levels. In lactating and virgin mice, however, fasting increases GENE mRNA levels. Changes in GENE mRNA occur in parallel with modifications in the levels of free fatty acids, which are reduced in lactation and are upregulated due to weaning or fasting. Modifications in the energy nutritional stress of lactating dams achieved by manipulating litter sizes do not influence GENE mRNA levels in skeletal muscle. Conversely, when mice are fed a high-fat diet after parturition, the downregulation of GENE mRNA and GENE protein levels due to lactation is partially reversed, as is the reduction in serum free fatty acid levels. Treatment of lactating mice with a single injection of bezafibrate, an activator of the peroxisome proliferator-activated receptor (PPAR), raises GENE mRNA in skeletal muscle to levels similar to those in virgin mice. 4-chloro-6-[(2,3-xylidine)-pirimidinylthio] acetic acid (WY-14,643), a specific ligand of the PPAR-alpha subtype, causes the most dramatic increase in GENE mRNA, whereas troglitazone, a specific activator of PPAR-gamma, also significantly increases GENE mRNA abundance in skeletal muscle of lactating mice. However, in virgin mice, bezafibrate and CHEMICAL do not significantly affect GENE mRNA expression, whereas troglitazone is at least as effective as it is in lactating dams. It is proposed that the GENE gene is regulated in skeletal muscle during lactation in response to changes in circulating free fatty acids by mechanisms involving activation of PPARs. The impaired expression of the GENE gene is consistent with the involvement of GENE gene regulation in the reduction of the use of fatty acids as fuel by the skeletal muscle and in impaired adaptative thermogenesis, both of which are major metabolic adaptations that occur during lactation. | NO-RELATIONSHIP |
| Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation: fibrates and troglitazone reverse lactation-induced downregulation of the uncoupling protein-3 gene. The expression of uncoupling protein (UCP)-3 mRNA in skeletal muscle is dramatically reduced during lactation in mice. The reduction in UCP-3 mRNA levels lowers the amount of the UCP-3 protein in skeletal muscle mitochondria during lactation. Spontaneous or abrupt weaning reverses the downregulation of the UCP-3 mRNA but not the reduction in UCP-3 protein levels. In lactating and virgin mice, however, fasting increases UCP-3 mRNA levels. Changes in UCP-3 mRNA occur in parallel with modifications in the levels of free fatty acids, which are reduced in lactation and are upregulated due to weaning or fasting. Modifications in the energy nutritional stress of lactating dams achieved by manipulating litter sizes do not influence UCP-3 mRNA levels in skeletal muscle. Conversely, when mice are fed a high-fat diet after parturition, the downregulation of UCP-3 mRNA and UCP-3 protein levels due to lactation is partially reversed, as is the reduction in serum free fatty acid levels. Treatment of lactating mice with a single injection of bezafibrate, an activator of the peroxisome proliferator-activated receptor (PPAR), raises UCP-3 mRNA in skeletal muscle to levels similar to those in virgin mice. CHEMICAL (WY-14,643), a specific ligand of the GENE subtype, causes the most dramatic increase in UCP-3 mRNA, whereas troglitazone, a specific activator of PPAR-gamma, also significantly increases UCP-3 mRNA abundance in skeletal muscle of lactating mice. However, in virgin mice, bezafibrate and WY-14,643 do not significantly affect UCP-3 mRNA expression, whereas troglitazone is at least as effective as it is in lactating dams. It is proposed that the UCP-3 gene is regulated in skeletal muscle during lactation in response to changes in circulating free fatty acids by mechanisms involving activation of PPARs. The impaired expression of the UCP-3 gene is consistent with the involvement of UCP-3 gene regulation in the reduction of the use of fatty acids as fuel by the skeletal muscle and in impaired adaptative thermogenesis, both of which are major metabolic adaptations that occur during lactation. | DIRECT-REGULATOR |
| Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation: fibrates and troglitazone reverse lactation-induced downregulation of the uncoupling protein-3 gene. The expression of uncoupling protein (UCP)-3 mRNA in skeletal muscle is dramatically reduced during lactation in mice. The reduction in UCP-3 mRNA levels lowers the amount of the UCP-3 protein in skeletal muscle mitochondria during lactation. Spontaneous or abrupt weaning reverses the downregulation of the UCP-3 mRNA but not the reduction in UCP-3 protein levels. In lactating and virgin mice, however, fasting increases UCP-3 mRNA levels. Changes in UCP-3 mRNA occur in parallel with modifications in the levels of free fatty acids, which are reduced in lactation and are upregulated due to weaning or fasting. Modifications in the energy nutritional stress of lactating dams achieved by manipulating litter sizes do not influence UCP-3 mRNA levels in skeletal muscle. Conversely, when mice are fed a high-fat diet after parturition, the downregulation of UCP-3 mRNA and UCP-3 protein levels due to lactation is partially reversed, as is the reduction in serum free fatty acid levels. Treatment of lactating mice with a single injection of bezafibrate, an activator of the peroxisome proliferator-activated receptor (PPAR), raises UCP-3 mRNA in skeletal muscle to levels similar to those in virgin mice. 4-chloro-6-[(2,3-xylidine)-pirimidinylthio] acetic acid (CHEMICAL), a specific ligand of the GENE subtype, causes the most dramatic increase in UCP-3 mRNA, whereas troglitazone, a specific activator of PPAR-gamma, also significantly increases UCP-3 mRNA abundance in skeletal muscle of lactating mice. However, in virgin mice, bezafibrate and CHEMICAL do not significantly affect UCP-3 mRNA expression, whereas troglitazone is at least as effective as it is in lactating dams. It is proposed that the UCP-3 gene is regulated in skeletal muscle during lactation in response to changes in circulating free fatty acids by mechanisms involving activation of PPARs. The impaired expression of the UCP-3 gene is consistent with the involvement of UCP-3 gene regulation in the reduction of the use of fatty acids as fuel by the skeletal muscle and in impaired adaptative thermogenesis, both of which are major metabolic adaptations that occur during lactation. | DIRECT-REGULATOR |
| Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation: fibrates and troglitazone reverse lactation-induced downregulation of the uncoupling protein-3 gene. The expression of uncoupling protein (UCP)-3 mRNA in skeletal muscle is dramatically reduced during lactation in mice. The reduction in GENE mRNA levels lowers the amount of the GENE protein in skeletal muscle mitochondria during lactation. Spontaneous or abrupt weaning reverses the downregulation of the GENE mRNA but not the reduction in GENE protein levels. In lactating and virgin mice, however, fasting increases GENE mRNA levels. Changes in GENE mRNA occur in parallel with modifications in the levels of free CHEMICAL, which are reduced in lactation and are upregulated due to weaning or fasting. Modifications in the energy nutritional stress of lactating dams achieved by manipulating litter sizes do not influence GENE mRNA levels in skeletal muscle. Conversely, when mice are fed a high-fat diet after parturition, the downregulation of GENE mRNA and GENE protein levels due to lactation is partially reversed, as is the reduction in serum free fatty acid levels. Treatment of lactating mice with a single injection of bezafibrate, an activator of the peroxisome proliferator-activated receptor (PPAR), raises GENE mRNA in skeletal muscle to levels similar to those in virgin mice. 4-chloro-6-[(2,3-xylidine)-pirimidinylthio] acetic acid (WY-14,643), a specific ligand of the PPAR-alpha subtype, causes the most dramatic increase in GENE mRNA, whereas troglitazone, a specific activator of PPAR-gamma, also significantly increases GENE mRNA abundance in skeletal muscle of lactating mice. However, in virgin mice, bezafibrate and WY-14,643 do not significantly affect GENE mRNA expression, whereas troglitazone is at least as effective as it is in lactating dams. It is proposed that the GENE gene is regulated in skeletal muscle during lactation in response to changes in circulating free CHEMICAL by mechanisms involving activation of PPARs. The impaired expression of the GENE gene is consistent with the involvement of GENE gene regulation in the reduction of the use of CHEMICAL as fuel by the skeletal muscle and in impaired adaptative thermogenesis, both of which are major metabolic adaptations that occur during lactation. | GENE-CHEMICAL |
| Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation: fibrates and troglitazone reverse lactation-induced downregulation of the uncoupling protein-3 gene. The expression of uncoupling protein (UCP)-3 mRNA in skeletal muscle is dramatically reduced during lactation in mice. The reduction in GENE mRNA levels lowers the amount of the GENE protein in skeletal muscle mitochondria during lactation. Spontaneous or abrupt weaning reverses the downregulation of the GENE mRNA but not the reduction in GENE protein levels. In lactating and virgin mice, however, fasting increases GENE mRNA levels. Changes in GENE mRNA occur in parallel with modifications in the levels of free fatty acids, which are reduced in lactation and are upregulated due to weaning or fasting. Modifications in the energy nutritional stress of lactating dams achieved by manipulating litter sizes do not influence GENE mRNA levels in skeletal muscle. Conversely, when mice are fed a high-fat diet after parturition, the downregulation of GENE mRNA and GENE protein levels due to lactation is partially reversed, as is the reduction in serum free CHEMICAL levels. Treatment of lactating mice with a single injection of bezafibrate, an activator of the peroxisome proliferator-activated receptor (PPAR), raises GENE mRNA in skeletal muscle to levels similar to those in virgin mice. 4-chloro-6-[(2,3-xylidine)-pirimidinylthio] acetic acid (WY-14,643), a specific ligand of the PPAR-alpha subtype, causes the most dramatic increase in GENE mRNA, whereas troglitazone, a specific activator of PPAR-gamma, also significantly increases GENE mRNA abundance in skeletal muscle of lactating mice. However, in virgin mice, bezafibrate and WY-14,643 do not significantly affect GENE mRNA expression, whereas troglitazone is at least as effective as it is in lactating dams. It is proposed that the GENE gene is regulated in skeletal muscle during lactation in response to changes in circulating free fatty acids by mechanisms involving activation of PPARs. The impaired expression of the GENE gene is consistent with the involvement of GENE gene regulation in the reduction of the use of fatty acids as fuel by the skeletal muscle and in impaired adaptative thermogenesis, both of which are major metabolic adaptations that occur during lactation. | GENE-CHEMICAL |
| Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation: fibrates and CHEMICAL reverse lactation-induced downregulation of the uncoupling protein-3 gene. The expression of uncoupling protein (UCP)-3 mRNA in skeletal muscle is dramatically reduced during lactation in mice. The reduction in GENE mRNA levels lowers the amount of the GENE protein in skeletal muscle mitochondria during lactation. Spontaneous or abrupt weaning reverses the downregulation of the GENE mRNA but not the reduction in GENE protein levels. In lactating and virgin mice, however, fasting increases GENE mRNA levels. Changes in GENE mRNA occur in parallel with modifications in the levels of free fatty acids, which are reduced in lactation and are upregulated due to weaning or fasting. Modifications in the energy nutritional stress of lactating dams achieved by manipulating litter sizes do not influence GENE mRNA levels in skeletal muscle. Conversely, when mice are fed a high-fat diet after parturition, the downregulation of GENE mRNA and GENE protein levels due to lactation is partially reversed, as is the reduction in serum free fatty acid levels. Treatment of lactating mice with a single injection of bezafibrate, an activator of the peroxisome proliferator-activated receptor (PPAR), raises GENE mRNA in skeletal muscle to levels similar to those in virgin mice. 4-chloro-6-[(2,3-xylidine)-pirimidinylthio] acetic acid (WY-14,643), a specific ligand of the PPAR-alpha subtype, causes the most dramatic increase in GENE mRNA, whereas CHEMICAL, a specific activator of PPAR-gamma, also significantly increases GENE mRNA abundance in skeletal muscle of lactating mice. However, in virgin mice, bezafibrate and WY-14,643 do not significantly affect GENE mRNA expression, whereas CHEMICAL is at least as effective as it is in lactating dams. It is proposed that the GENE gene is regulated in skeletal muscle during lactation in response to changes in circulating free fatty acids by mechanisms involving activation of PPARs. The impaired expression of the GENE gene is consistent with the involvement of GENE gene regulation in the reduction of the use of fatty acids as fuel by the skeletal muscle and in impaired adaptative thermogenesis, both of which are major metabolic adaptations that occur during lactation. | INDIRECT-UPREGULATOR |
| Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation: fibrates and troglitazone reverse lactation-induced downregulation of the uncoupling protein-3 gene. The expression of uncoupling protein (UCP)-3 mRNA in skeletal muscle is dramatically reduced during lactation in mice. The reduction in UCP-3 mRNA levels lowers the amount of the UCP-3 protein in skeletal muscle mitochondria during lactation. Spontaneous or abrupt weaning reverses the downregulation of the UCP-3 mRNA but not the reduction in UCP-3 protein levels. In lactating and virgin mice, however, fasting increases UCP-3 mRNA levels. Changes in UCP-3 mRNA occur in parallel with modifications in the levels of free fatty acids, which are reduced in lactation and are upregulated due to weaning or fasting. Modifications in the energy nutritional stress of lactating dams achieved by manipulating litter sizes do not influence UCP-3 mRNA levels in skeletal muscle. Conversely, when mice are fed a high-fat diet after parturition, the downregulation of UCP-3 mRNA and UCP-3 protein levels due to lactation is partially reversed, as is the reduction in serum free fatty acid levels. Treatment of lactating mice with a single injection of CHEMICAL, an activator of the GENE (PPAR), raises UCP-3 mRNA in skeletal muscle to levels similar to those in virgin mice. 4-chloro-6-[(2,3-xylidine)-pirimidinylthio] acetic acid (WY-14,643), a specific ligand of the PPAR-alpha subtype, causes the most dramatic increase in UCP-3 mRNA, whereas troglitazone, a specific activator of PPAR-gamma, also significantly increases UCP-3 mRNA abundance in skeletal muscle of lactating mice. However, in virgin mice, CHEMICAL and WY-14,643 do not significantly affect UCP-3 mRNA expression, whereas troglitazone is at least as effective as it is in lactating dams. It is proposed that the UCP-3 gene is regulated in skeletal muscle during lactation in response to changes in circulating free fatty acids by mechanisms involving activation of PPARs. The impaired expression of the UCP-3 gene is consistent with the involvement of UCP-3 gene regulation in the reduction of the use of fatty acids as fuel by the skeletal muscle and in impaired adaptative thermogenesis, both of which are major metabolic adaptations that occur during lactation. | ACTIVATOR |
| Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation: fibrates and troglitazone reverse lactation-induced downregulation of the uncoupling protein-3 gene. The expression of uncoupling protein (UCP)-3 mRNA in skeletal muscle is dramatically reduced during lactation in mice. The reduction in UCP-3 mRNA levels lowers the amount of the UCP-3 protein in skeletal muscle mitochondria during lactation. Spontaneous or abrupt weaning reverses the downregulation of the UCP-3 mRNA but not the reduction in UCP-3 protein levels. In lactating and virgin mice, however, fasting increases UCP-3 mRNA levels. Changes in UCP-3 mRNA occur in parallel with modifications in the levels of free fatty acids, which are reduced in lactation and are upregulated due to weaning or fasting. Modifications in the energy nutritional stress of lactating dams achieved by manipulating litter sizes do not influence UCP-3 mRNA levels in skeletal muscle. Conversely, when mice are fed a high-fat diet after parturition, the downregulation of UCP-3 mRNA and UCP-3 protein levels due to lactation is partially reversed, as is the reduction in serum free fatty acid levels. Treatment of lactating mice with a single injection of CHEMICAL, an activator of the peroxisome proliferator-activated receptor (GENE), raises UCP-3 mRNA in skeletal muscle to levels similar to those in virgin mice. 4-chloro-6-[(2,3-xylidine)-pirimidinylthio] acetic acid (WY-14,643), a specific ligand of the PPAR-alpha subtype, causes the most dramatic increase in UCP-3 mRNA, whereas troglitazone, a specific activator of PPAR-gamma, also significantly increases UCP-3 mRNA abundance in skeletal muscle of lactating mice. However, in virgin mice, CHEMICAL and WY-14,643 do not significantly affect UCP-3 mRNA expression, whereas troglitazone is at least as effective as it is in lactating dams. It is proposed that the UCP-3 gene is regulated in skeletal muscle during lactation in response to changes in circulating free fatty acids by mechanisms involving activation of PPARs. The impaired expression of the UCP-3 gene is consistent with the involvement of UCP-3 gene regulation in the reduction of the use of fatty acids as fuel by the skeletal muscle and in impaired adaptative thermogenesis, both of which are major metabolic adaptations that occur during lactation. | ACTIVATOR |
| Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation: fibrates and CHEMICAL reverse lactation-induced downregulation of the uncoupling protein-3 gene. The expression of uncoupling protein (UCP)-3 mRNA in skeletal muscle is dramatically reduced during lactation in mice. The reduction in UCP-3 mRNA levels lowers the amount of the UCP-3 protein in skeletal muscle mitochondria during lactation. Spontaneous or abrupt weaning reverses the downregulation of the UCP-3 mRNA but not the reduction in UCP-3 protein levels. In lactating and virgin mice, however, fasting increases UCP-3 mRNA levels. Changes in UCP-3 mRNA occur in parallel with modifications in the levels of free fatty acids, which are reduced in lactation and are upregulated due to weaning or fasting. Modifications in the energy nutritional stress of lactating dams achieved by manipulating litter sizes do not influence UCP-3 mRNA levels in skeletal muscle. Conversely, when mice are fed a high-fat diet after parturition, the downregulation of UCP-3 mRNA and UCP-3 protein levels due to lactation is partially reversed, as is the reduction in serum free fatty acid levels. Treatment of lactating mice with a single injection of bezafibrate, an activator of the peroxisome proliferator-activated receptor (PPAR), raises UCP-3 mRNA in skeletal muscle to levels similar to those in virgin mice. 4-chloro-6-[(2,3-xylidine)-pirimidinylthio] acetic acid (WY-14,643), a specific ligand of the PPAR-alpha subtype, causes the most dramatic increase in UCP-3 mRNA, whereas CHEMICAL, a specific activator of GENE, also significantly increases UCP-3 mRNA abundance in skeletal muscle of lactating mice. However, in virgin mice, bezafibrate and WY-14,643 do not significantly affect UCP-3 mRNA expression, whereas CHEMICAL is at least as effective as it is in lactating dams. It is proposed that the UCP-3 gene is regulated in skeletal muscle during lactation in response to changes in circulating free fatty acids by mechanisms involving activation of PPARs. The impaired expression of the UCP-3 gene is consistent with the involvement of UCP-3 gene regulation in the reduction of the use of fatty acids as fuel by the skeletal muscle and in impaired adaptative thermogenesis, both of which are major metabolic adaptations that occur during lactation. | ACTIVATOR |
| Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation: fibrates and troglitazone reverse lactation-induced downregulation of the uncoupling protein-3 gene. The expression of uncoupling protein (UCP)-3 mRNA in skeletal muscle is dramatically reduced during lactation in mice. The reduction in UCP-3 mRNA levels lowers the amount of the UCP-3 protein in skeletal muscle mitochondria during lactation. Spontaneous or abrupt weaning reverses the downregulation of the UCP-3 mRNA but not the reduction in UCP-3 protein levels. In lactating and virgin mice, however, fasting increases UCP-3 mRNA levels. Changes in UCP-3 mRNA occur in parallel with modifications in the levels of free CHEMICAL, which are reduced in lactation and are upregulated due to weaning or fasting. Modifications in the energy nutritional stress of lactating dams achieved by manipulating litter sizes do not influence UCP-3 mRNA levels in skeletal muscle. Conversely, when mice are fed a high-fat diet after parturition, the downregulation of UCP-3 mRNA and UCP-3 protein levels due to lactation is partially reversed, as is the reduction in serum free fatty acid levels. Treatment of lactating mice with a single injection of bezafibrate, an activator of the peroxisome proliferator-activated receptor (PPAR), raises UCP-3 mRNA in skeletal muscle to levels similar to those in virgin mice. 4-chloro-6-[(2,3-xylidine)-pirimidinylthio] acetic acid (WY-14,643), a specific ligand of the PPAR-alpha subtype, causes the most dramatic increase in UCP-3 mRNA, whereas troglitazone, a specific activator of PPAR-gamma, also significantly increases UCP-3 mRNA abundance in skeletal muscle of lactating mice. However, in virgin mice, bezafibrate and WY-14,643 do not significantly affect UCP-3 mRNA expression, whereas troglitazone is at least as effective as it is in lactating dams. It is proposed that the UCP-3 gene is regulated in skeletal muscle during lactation in response to changes in circulating free CHEMICAL by mechanisms involving activation of GENE. The impaired expression of the UCP-3 gene is consistent with the involvement of UCP-3 gene regulation in the reduction of the use of CHEMICAL as fuel by the skeletal muscle and in impaired adaptative thermogenesis, both of which are major metabolic adaptations that occur during lactation. | ACTIVATOR |
| Impaired expression of the GENE gene in skeletal muscle during lactation: fibrates and CHEMICAL reverse lactation-induced downregulation of the GENE gene. The expression of uncoupling protein (UCP)-3 mRNA in skeletal muscle is dramatically reduced during lactation in mice. The reduction in UCP-3 mRNA levels lowers the amount of the UCP-3 protein in skeletal muscle mitochondria during lactation. Spontaneous or abrupt weaning reverses the downregulation of the UCP-3 mRNA but not the reduction in UCP-3 protein levels. In lactating and virgin mice, however, fasting increases UCP-3 mRNA levels. Changes in UCP-3 mRNA occur in parallel with modifications in the levels of free fatty acids, which are reduced in lactation and are upregulated due to weaning or fasting. Modifications in the energy nutritional stress of lactating dams achieved by manipulating litter sizes do not influence UCP-3 mRNA levels in skeletal muscle. Conversely, when mice are fed a high-fat diet after parturition, the downregulation of UCP-3 mRNA and UCP-3 protein levels due to lactation is partially reversed, as is the reduction in serum free fatty acid levels. Treatment of lactating mice with a single injection of bezafibrate, an activator of the peroxisome proliferator-activated receptor (PPAR), raises UCP-3 mRNA in skeletal muscle to levels similar to those in virgin mice. 4-chloro-6-[(2,3-xylidine)-pirimidinylthio] acetic acid (WY-14,643), a specific ligand of the PPAR-alpha subtype, causes the most dramatic increase in UCP-3 mRNA, whereas CHEMICAL, a specific activator of PPAR-gamma, also significantly increases UCP-3 mRNA abundance in skeletal muscle of lactating mice. However, in virgin mice, bezafibrate and WY-14,643 do not significantly affect UCP-3 mRNA expression, whereas CHEMICAL is at least as effective as it is in lactating dams. It is proposed that the UCP-3 gene is regulated in skeletal muscle during lactation in response to changes in circulating free fatty acids by mechanisms involving activation of PPARs. The impaired expression of the UCP-3 gene is consistent with the involvement of UCP-3 gene regulation in the reduction of the use of fatty acids as fuel by the skeletal muscle and in impaired adaptative thermogenesis, both of which are major metabolic adaptations that occur during lactation. | INDIRECT-UPREGULATOR |
| Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation: fibrates and troglitazone reverse lactation-induced downregulation of the uncoupling protein-3 gene. The expression of uncoupling protein (UCP)-3 mRNA in skeletal muscle is dramatically reduced during lactation in mice. The reduction in GENE mRNA levels lowers the amount of the GENE protein in skeletal muscle mitochondria during lactation. Spontaneous or abrupt weaning reverses the downregulation of the GENE mRNA but not the reduction in GENE protein levels. In lactating and virgin mice, however, fasting increases GENE mRNA levels. Changes in GENE mRNA occur in parallel with modifications in the levels of free fatty acids, which are reduced in lactation and are upregulated due to weaning or fasting. Modifications in the energy nutritional stress of lactating dams achieved by manipulating litter sizes do not influence GENE mRNA levels in skeletal muscle. Conversely, when mice are fed a high-fat diet after parturition, the downregulation of GENE mRNA and GENE protein levels due to lactation is partially reversed, as is the reduction in serum free fatty acid levels. Treatment of lactating mice with a single injection of bezafibrate, an activator of the peroxisome proliferator-activated receptor (PPAR), raises GENE mRNA in skeletal muscle to levels similar to those in virgin mice. CHEMICAL (WY-14,643), a specific ligand of the PPAR-alpha subtype, causes the most dramatic increase in GENE mRNA, whereas troglitazone, a specific activator of PPAR-gamma, also significantly increases GENE mRNA abundance in skeletal muscle of lactating mice. However, in virgin mice, bezafibrate and WY-14,643 do not significantly affect GENE mRNA expression, whereas troglitazone is at least as effective as it is in lactating dams. It is proposed that the GENE gene is regulated in skeletal muscle during lactation in response to changes in circulating free fatty acids by mechanisms involving activation of PPARs. The impaired expression of the GENE gene is consistent with the involvement of GENE gene regulation in the reduction of the use of fatty acids as fuel by the skeletal muscle and in impaired adaptative thermogenesis, both of which are major metabolic adaptations that occur during lactation. | INDIRECT-UPREGULATOR |
| CHEMICAL, a novel anti-convulsant, enhances activation of KCNQ2/Q3 GENE. CHEMICAL [N-(2-amino-4-[fluorobenzylamino]-phenyl) carbamic acid; D-23129] is a novel anticonvulsant, unrelated to currently available antiepileptic agents, with activity in a broad range of seizure models. In the present study, we sought to determine whether retigabine could enhance current through M-like currents in PC12 cells and KCNQ2/Q3 K(+) channels expressed in Chinese hamster ovary cells (CHO-KCNQ2/Q3). In differentiated PC12 cells, retigabine enhanced a linopirdine-sensitive current. The effect of retigabine was associated with a slowing of M-like tail current deactivation in these cells. CHEMICAL (0.1 to 10 microM) induced a potassium current and hyperpolarized CHO cells expressing KCNQ2/Q3 cells but not in wild-type cells. Retigabine-induced currents in CHO-KCNQ2/Q3 cells were inhibited by 60.6 +/- 11% (n = 4) by the KCNQ2/Q3 blocker, linopirdine (10 microM), and 82.7 +/- 5.4% (n = 4) by BaCl(2) (10 mM). The mechanism by which retigabine enhanced KCNQ2/Q3 currents involved large, drug-induced, leftward shifts in the voltage dependence of channel activation (-33.1 +/- 2.6 mV, n = 4, by 10 microM retigabine). CHEMICAL shifted the voltage dependence of channel activation with an EC(50) value of 1.6 +/- 0.3 microM (slope factor was 1.2 +/- 0.1, n = 4 to 5 cells per concentration). CHEMICAL (0.1 to 10 microM) also slowed the rate of channel deactivation, predominantly by increasing the contribution of a slowly deactivating tail current component. Our findings identify KCNQ2/Q3 channels as a molecular target for retigabine and suggest that activation of KCNQ2/Q3 channels may be responsible for at least some of the anticonvulsant activity of this agent. | ACTIVATOR |
| Serotonin transporter gene regulatory region polymorphism (5-HTTLPR), CHEMICAL binding in healthy control subjects and alcohol-dependent patients and their relationships to impulsivity. The aim of this study was to investigate CHEMICAL binding and impulsivity in alcohol-dependent and age-matched control subjects in relation to a 5'-promoter region serotonin transporter (5-HTT) polymorphism (5-HTTLPR). Alcohol-dependent subjects were hypothesized to show a decreased number of bindings sites and a lower dissociation constant. GENE S-genotype carriers in both alcohol-dependent and control subjects were expected to show significantly fewer binding sites and a lower dissociation constant. Influences of impulsive traits, chronic daily alcohol intake, duration of alcohol dependence, age of onset and age on CHEMICAL binding were also investigated. Inpatients meeting DSM IV alcohol dependence criteria and of German descent were recruited to avoid ethnic stratification effects. One hundred and seventeen control subjects of similar social status were recruited from a town community. Blood samples were taken from both alcohol-dependent and control subjects to determine GENE genotypes using PCR of lymphocyte DNA, and to perform platelet CHEMICAL binding (binding capacity: B(max); and dissociation constant: K(D)). Impulsivity was assessed using the Barratt impulsiveness scale version 5 (BIS-5) in alcohol-dependent subjects only. Alcohol-dependent subjects were subdivided into low or high impulsivity groups using a median-split of the BIS-5 scale. The control group was slightly older than the alcohol-dependent group (not statistically significant). CHEMICAL binding was investigated in 72 control subjects and 72 patients, of which five patients met type 2 alcohol dependence criteria. Genotyping was carried out in all patients and control subjects. A significant influence of duration of alcohol dependence was found on the CHEMICAL binding K(D) but not B(max.) Neither alcohol-dependent nor control subjects showed any differences in B(max) or K(D). S-allele carriers did not show a decreased binding or lower dissociation constant. Furthermore, no significant interaction between B(max) and K(D) with either GENE genotype or impulsivity was revealed. This was the first study to investigate platelet CHEMICAL binding in alcohol-dependent and age-matched control subjects in relation to the GENE genotype. No differences concerning 5-HTTLPR-alleles were found in these groups Furthermore, no significant interaction between these parameters and impulsivity was shown in alcohol-dependent subjects. These results do not support previous results of altered CHEMICAL binding sites in alcohol-dependent subjects or GENE S-allele carriers. K(D) might be influenced by duration of alcohol dependence, but not sufficiently to yield differences between alcohol-dependent and control subjects. | DIRECT-REGULATOR |
| GENE gene regulatory region polymorphism (5-HTTLPR), CHEMICAL binding in healthy control subjects and alcohol-dependent patients and their relationships to impulsivity. The aim of this study was to investigate CHEMICAL binding and impulsivity in alcohol-dependent and age-matched control subjects in relation to a 5'-promoter region serotonin transporter (5-HTT) polymorphism (5-HTTLPR). Alcohol-dependent subjects were hypothesized to show a decreased number of bindings sites and a lower dissociation constant. 5-HTTLPR S-genotype carriers in both alcohol-dependent and control subjects were expected to show significantly fewer binding sites and a lower dissociation constant. Influences of impulsive traits, chronic daily alcohol intake, duration of alcohol dependence, age of onset and age on CHEMICAL binding were also investigated. Inpatients meeting DSM IV alcohol dependence criteria and of German descent were recruited to avoid ethnic stratification effects. One hundred and seventeen control subjects of similar social status were recruited from a town community. Blood samples were taken from both alcohol-dependent and control subjects to determine 5-HTTLPR genotypes using PCR of lymphocyte DNA, and to perform platelet CHEMICAL binding (binding capacity: B(max); and dissociation constant: K(D)). Impulsivity was assessed using the Barratt impulsiveness scale version 5 (BIS-5) in alcohol-dependent subjects only. Alcohol-dependent subjects were subdivided into low or high impulsivity groups using a median-split of the BIS-5 scale. The control group was slightly older than the alcohol-dependent group (not statistically significant). CHEMICAL binding was investigated in 72 control subjects and 72 patients, of which five patients met type 2 alcohol dependence criteria. Genotyping was carried out in all patients and control subjects. A significant influence of duration of alcohol dependence was found on the CHEMICAL binding K(D) but not B(max.) Neither alcohol-dependent nor control subjects showed any differences in B(max) or K(D). S-allele carriers did not show a decreased binding or lower dissociation constant. Furthermore, no significant interaction between B(max) and K(D) with either 5-HTTLPR genotype or impulsivity was revealed. This was the first study to investigate platelet CHEMICAL binding in alcohol-dependent and age-matched control subjects in relation to the 5-HTTLPR genotype. No differences concerning 5-HTTLPR-alleles were found in these groups Furthermore, no significant interaction between these parameters and impulsivity was shown in alcohol-dependent subjects. These results do not support previous results of altered CHEMICAL binding sites in alcohol-dependent subjects or 5-HTTLPR S-allele carriers. K(D) might be influenced by duration of alcohol dependence, but not sufficiently to yield differences between alcohol-dependent and control subjects. | DIRECT-REGULATOR |
| CHEMICAL and nonsteroidal anti-inflammatory drugs induce conformational changes in the human prostaglandin endoperoxide H2 synthase-2 (cyclooxygenase-2). By using the technique of site-directed spin labeling combined with EPR spectroscopy, we have observed that binding of CHEMICAL and nonsteroidal anti-inflammatory drugs induces conformational changes in the GENE (PGHS-2). Line shape broadening resulting from spin-spin coupling of nitroxide pairs introduced into the membrane-binding helices of PGHS-2 was used to calculate the inter-helical distances and changes in these distances that occur in response to binding various ligands. The inter-residue distances determined for the PGHS-2 holoenzyme using EPR were 1-7.9 A shorter than those of the crystal structure of the PGHS-2 holoenzyme. However, inter-helical distances calculated and determined by EPR for PGHS-2 complexed with CHEMICAL, flurbiprofen, and SC-58125 were in close agreement with those obtained from the cognate crystal structures. These results indicate that the structure of the solubilized PGHS-2 holoenzyme measured in solution differs from the crystal structure of PGHS-2 holoenzyme obtained by x-ray analysis. Furthermore, binding of ligands induces a conformational change in the holo-PGHS-2, converting it to a structure similar to those obtained by x-ray analysis. Proteolysis protection assays had previously provided circumstantial evidence that binding of heme and non-steroidal anti-inflammatory drugs alters the conformation of PGHS, but the present experiments are the first to directly measure such changes. The finding that arachidonate can also induce a conformational change in PGHS-2 was unexpected, and the magnitude of changes suggests this structural flexibility may be integral to the cyclooxygenase catalytic mechanism. | REGULATOR |
| CHEMICAL and nonsteroidal anti-inflammatory drugs induce conformational changes in the human prostaglandin endoperoxide H2 synthase-2 (cyclooxygenase-2). By using the technique of site-directed spin labeling combined with EPR spectroscopy, we have observed that binding of CHEMICAL and nonsteroidal anti-inflammatory drugs induces conformational changes in the human prostaglandin endoperoxide H(2) synthase enzyme (GENE). Line shape broadening resulting from spin-spin coupling of nitroxide pairs introduced into the membrane-binding helices of GENE was used to calculate the inter-helical distances and changes in these distances that occur in response to binding various ligands. The inter-residue distances determined for the GENE holoenzyme using EPR were 1-7.9 A shorter than those of the crystal structure of the GENE holoenzyme. However, inter-helical distances calculated and determined by EPR for GENE complexed with CHEMICAL, flurbiprofen, and SC-58125 were in close agreement with those obtained from the cognate crystal structures. These results indicate that the structure of the solubilized GENE holoenzyme measured in solution differs from the crystal structure of GENE holoenzyme obtained by x-ray analysis. Furthermore, binding of ligands induces a conformational change in the holo-PGHS-2, converting it to a structure similar to those obtained by x-ray analysis. Proteolysis protection assays had previously provided circumstantial evidence that binding of heme and non-steroidal anti-inflammatory drugs alters the conformation of PGHS, but the present experiments are the first to directly measure such changes. The finding that arachidonate can also induce a conformational change in GENE was unexpected, and the magnitude of changes suggests this structural flexibility may be integral to the cyclooxygenase catalytic mechanism. | DIRECT-REGULATOR |
| Arachidonic acid and nonsteroidal anti-inflammatory drugs induce conformational changes in the human prostaglandin endoperoxide H2 synthase-2 (cyclooxygenase-2). By using the technique of site-directed spin labeling combined with EPR spectroscopy, we have observed that binding of arachidonic acid and nonsteroidal anti-inflammatory drugs induces conformational changes in the human prostaglandin endoperoxide H(2) synthase enzyme (PGHS-2). Line shape broadening resulting from spin-spin coupling of nitroxide pairs introduced into the membrane-binding helices of PGHS-2 was used to calculate the inter-helical distances and changes in these distances that occur in response to binding various ligands. The inter-residue distances determined for the PGHS-2 holoenzyme using EPR were 1-7.9 A shorter than those of the crystal structure of the PGHS-2 holoenzyme. However, inter-helical distances calculated and determined by EPR for PGHS-2 complexed with arachidonic acid, flurbiprofen, and SC-58125 were in close agreement with those obtained from the cognate crystal structures. These results indicate that the structure of the solubilized PGHS-2 holoenzyme measured in solution differs from the crystal structure of PGHS-2 holoenzyme obtained by x-ray analysis. Furthermore, binding of ligands induces a conformational change in the holo-PGHS-2, converting it to a structure similar to those obtained by x-ray analysis. Proteolysis protection assays had previously provided circumstantial evidence that binding of heme and non-CHEMICAL anti-inflammatory drugs alters the conformation of GENE, but the present experiments are the first to directly measure such changes. The finding that arachidonate can also induce a conformational change in PGHS-2 was unexpected, and the magnitude of changes suggests this structural flexibility may be integral to the cyclooxygenase catalytic mechanism. | REGULATOR |
| Arachidonic acid and nonsteroidal anti-inflammatory drugs induce conformational changes in the human prostaglandin endoperoxide H2 synthase-2 (cyclooxygenase-2). By using the technique of site-directed spin labeling combined with EPR spectroscopy, we have observed that binding of arachidonic acid and nonsteroidal anti-inflammatory drugs induces conformational changes in the human prostaglandin endoperoxide H(2) synthase enzyme (PGHS-2). Line shape broadening resulting from spin-spin coupling of nitroxide pairs introduced into the membrane-binding helices of GENE was used to calculate the inter-helical distances and changes in these distances that occur in response to binding various ligands. The inter-residue distances determined for the GENE holoenzyme using EPR were 1-7.9 A shorter than those of the crystal structure of the GENE holoenzyme. However, inter-helical distances calculated and determined by EPR for GENE complexed with arachidonic acid, flurbiprofen, and SC-58125 were in close agreement with those obtained from the cognate crystal structures. These results indicate that the structure of the solubilized GENE holoenzyme measured in solution differs from the crystal structure of GENE holoenzyme obtained by x-ray analysis. Furthermore, binding of ligands induces a conformational change in the holo-PGHS-2, converting it to a structure similar to those obtained by x-ray analysis. Proteolysis protection assays had previously provided circumstantial evidence that binding of heme and non-steroidal anti-inflammatory drugs alters the conformation of PGHS, but the present experiments are the first to directly measure such changes. The finding that CHEMICAL can also induce a conformational change in GENE was unexpected, and the magnitude of changes suggests this structural flexibility may be integral to the cyclooxygenase catalytic mechanism. | REGULATOR |
| Arachidonic acid and nonsteroidal anti-inflammatory drugs induce conformational changes in the human prostaglandin endoperoxide H2 synthase-2 (cyclooxygenase-2). By using the technique of site-directed spin labeling combined with EPR spectroscopy, we have observed that binding of arachidonic acid and nonsteroidal anti-inflammatory drugs induces conformational changes in the human prostaglandin endoperoxide H(2) synthase enzyme (PGHS-2). Line shape broadening resulting from spin-spin coupling of nitroxide pairs introduced into the membrane-binding helices of PGHS-2 was used to calculate the inter-helical distances and changes in these distances that occur in response to binding various ligands. The inter-residue distances determined for the PGHS-2 holoenzyme using EPR were 1-7.9 A shorter than those of the crystal structure of the PGHS-2 holoenzyme. However, inter-helical distances calculated and determined by EPR for PGHS-2 complexed with arachidonic acid, flurbiprofen, and SC-58125 were in close agreement with those obtained from the cognate crystal structures. These results indicate that the structure of the solubilized PGHS-2 holoenzyme measured in solution differs from the crystal structure of PGHS-2 holoenzyme obtained by x-ray analysis. Furthermore, binding of ligands induces a conformational change in the holo-PGHS-2, converting it to a structure similar to those obtained by x-ray analysis. Proteolysis protection assays had previously provided circumstantial evidence that binding of heme and non-steroidal anti-inflammatory drugs alters the conformation of PGHS, but the present experiments are the first to directly measure such changes. The finding that CHEMICAL can also induce a conformational change in PGHS-2 was unexpected, and the magnitude of changes suggests this structural flexibility may be integral to the GENE catalytic mechanism. | REGULATOR |
| Arachidonic acid and nonsteroidal anti-inflammatory drugs induce conformational changes in the human prostaglandin endoperoxide H2 synthase-2 (cyclooxygenase-2). By using the technique of site-directed spin labeling combined with EPR spectroscopy, we have observed that binding of arachidonic acid and nonsteroidal anti-inflammatory drugs induces conformational changes in the human prostaglandin endoperoxide H(2) synthase enzyme (PGHS-2). Line shape broadening resulting from spin-spin coupling of CHEMICAL pairs introduced into the membrane-binding helices of GENE was used to calculate the inter-helical distances and changes in these distances that occur in response to binding various ligands. The inter-residue distances determined for the GENE holoenzyme using EPR were 1-7.9 A shorter than those of the crystal structure of the GENE holoenzyme. However, inter-helical distances calculated and determined by EPR for GENE complexed with arachidonic acid, flurbiprofen, and SC-58125 were in close agreement with those obtained from the cognate crystal structures. These results indicate that the structure of the solubilized GENE holoenzyme measured in solution differs from the crystal structure of GENE holoenzyme obtained by x-ray analysis. Furthermore, binding of ligands induces a conformational change in the holo-PGHS-2, converting it to a structure similar to those obtained by x-ray analysis. Proteolysis protection assays had previously provided circumstantial evidence that binding of heme and non-steroidal anti-inflammatory drugs alters the conformation of PGHS, but the present experiments are the first to directly measure such changes. The finding that arachidonate can also induce a conformational change in GENE was unexpected, and the magnitude of changes suggests this structural flexibility may be integral to the cyclooxygenase catalytic mechanism. | PART-OF |
| Arachidonic acid and nonsteroidal anti-inflammatory drugs induce conformational changes in the human prostaglandin endoperoxide H2 synthase-2 (cyclooxygenase-2). By using the technique of site-directed spin labeling combined with EPR spectroscopy, we have observed that binding of arachidonic acid and nonsteroidal anti-inflammatory drugs induces conformational changes in the human prostaglandin endoperoxide H(2) synthase enzyme (PGHS-2). Line shape broadening resulting from spin-spin coupling of nitroxide pairs introduced into the membrane-binding helices of GENE was used to calculate the inter-helical distances and changes in these distances that occur in response to binding various ligands. The inter-residue distances determined for the GENE holoenzyme using EPR were 1-7.9 A shorter than those of the crystal structure of the GENE holoenzyme. However, inter-helical distances calculated and determined by EPR for GENE complexed with arachidonic acid, CHEMICAL, and SC-58125 were in close agreement with those obtained from the cognate crystal structures. These results indicate that the structure of the solubilized GENE holoenzyme measured in solution differs from the crystal structure of GENE holoenzyme obtained by x-ray analysis. Furthermore, binding of ligands induces a conformational change in the holo-PGHS-2, converting it to a structure similar to those obtained by x-ray analysis. Proteolysis protection assays had previously provided circumstantial evidence that binding of heme and non-steroidal anti-inflammatory drugs alters the conformation of PGHS, but the present experiments are the first to directly measure such changes. The finding that arachidonate can also induce a conformational change in GENE was unexpected, and the magnitude of changes suggests this structural flexibility may be integral to the cyclooxygenase catalytic mechanism. | DIRECT-REGULATOR |
| Arachidonic acid and nonsteroidal anti-inflammatory drugs induce conformational changes in the human prostaglandin endoperoxide H2 synthase-2 (cyclooxygenase-2). By using the technique of site-directed spin labeling combined with EPR spectroscopy, we have observed that binding of arachidonic acid and nonsteroidal anti-inflammatory drugs induces conformational changes in the human prostaglandin endoperoxide H(2) synthase enzyme (PGHS-2). Line shape broadening resulting from spin-spin coupling of nitroxide pairs introduced into the membrane-binding helices of GENE was used to calculate the inter-helical distances and changes in these distances that occur in response to binding various ligands. The inter-residue distances determined for the GENE holoenzyme using EPR were 1-7.9 A shorter than those of the crystal structure of the GENE holoenzyme. However, inter-helical distances calculated and determined by EPR for GENE complexed with arachidonic acid, flurbiprofen, and CHEMICAL were in close agreement with those obtained from the cognate crystal structures. These results indicate that the structure of the solubilized GENE holoenzyme measured in solution differs from the crystal structure of GENE holoenzyme obtained by x-ray analysis. Furthermore, binding of ligands induces a conformational change in the holo-PGHS-2, converting it to a structure similar to those obtained by x-ray analysis. Proteolysis protection assays had previously provided circumstantial evidence that binding of heme and non-steroidal anti-inflammatory drugs alters the conformation of PGHS, but the present experiments are the first to directly measure such changes. The finding that arachidonate can also induce a conformational change in GENE was unexpected, and the magnitude of changes suggests this structural flexibility may be integral to the cyclooxygenase catalytic mechanism. | DIRECT-REGULATOR |
| CHEMICAL and nonsteroidal anti-inflammatory drugs induce conformational changes in the human prostaglandin endoperoxide H2 synthase-2 (GENE). By using the technique of site-directed spin labeling combined with EPR spectroscopy, we have observed that binding of arachidonic acid and nonsteroidal anti-inflammatory drugs induces conformational changes in the human prostaglandin endoperoxide H(2) synthase enzyme (PGHS-2). Line shape broadening resulting from spin-spin coupling of nitroxide pairs introduced into the membrane-binding helices of PGHS-2 was used to calculate the inter-helical distances and changes in these distances that occur in response to binding various ligands. The inter-residue distances determined for the PGHS-2 holoenzyme using EPR were 1-7.9 A shorter than those of the crystal structure of the PGHS-2 holoenzyme. However, inter-helical distances calculated and determined by EPR for PGHS-2 complexed with arachidonic acid, flurbiprofen, and SC-58125 were in close agreement with those obtained from the cognate crystal structures. These results indicate that the structure of the solubilized PGHS-2 holoenzyme measured in solution differs from the crystal structure of PGHS-2 holoenzyme obtained by x-ray analysis. Furthermore, binding of ligands induces a conformational change in the holo-PGHS-2, converting it to a structure similar to those obtained by x-ray analysis. Proteolysis protection assays had previously provided circumstantial evidence that binding of heme and non-steroidal anti-inflammatory drugs alters the conformation of PGHS, but the present experiments are the first to directly measure such changes. The finding that arachidonate can also induce a conformational change in PGHS-2 was unexpected, and the magnitude of changes suggests this structural flexibility may be integral to the cyclooxygenase catalytic mechanism. | REGULATOR |
| CHEMICAL and nonsteroidal anti-inflammatory drugs induce conformational changes in the GENE (cyclooxygenase-2). By using the technique of site-directed spin labeling combined with EPR spectroscopy, we have observed that binding of arachidonic acid and nonsteroidal anti-inflammatory drugs induces conformational changes in the human prostaglandin endoperoxide H(2) synthase enzyme (PGHS-2). Line shape broadening resulting from spin-spin coupling of nitroxide pairs introduced into the membrane-binding helices of PGHS-2 was used to calculate the inter-helical distances and changes in these distances that occur in response to binding various ligands. The inter-residue distances determined for the PGHS-2 holoenzyme using EPR were 1-7.9 A shorter than those of the crystal structure of the PGHS-2 holoenzyme. However, inter-helical distances calculated and determined by EPR for PGHS-2 complexed with arachidonic acid, flurbiprofen, and SC-58125 were in close agreement with those obtained from the cognate crystal structures. These results indicate that the structure of the solubilized PGHS-2 holoenzyme measured in solution differs from the crystal structure of PGHS-2 holoenzyme obtained by x-ray analysis. Furthermore, binding of ligands induces a conformational change in the holo-PGHS-2, converting it to a structure similar to those obtained by x-ray analysis. Proteolysis protection assays had previously provided circumstantial evidence that binding of heme and non-steroidal anti-inflammatory drugs alters the conformation of PGHS, but the present experiments are the first to directly measure such changes. The finding that arachidonate can also induce a conformational change in PGHS-2 was unexpected, and the magnitude of changes suggests this structural flexibility may be integral to the cyclooxygenase catalytic mechanism. | REGULATOR |
| Suppression of NF-kappaB activity by CHEMICAL is mediated by direct inhibition of IkappaB kinases alpha and beta. BACKGROUND & AIMS: Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Various drugs used in the treatment of IBD, such as glucocorticoids, 5-aminosalicylic acid, and CHEMICAL, interfere with NF-kappaB/Rel signaling. The aim of this study was to define the molecular mechanism by which CHEMICAL inhibits NF-kappaB activation. METHODS: The effects of CHEMICAL and its moieties on NF-kappaB signaling were evaluated using electromobility shift, transfection, and immune complex kinase assays. The direct effect of CHEMICAL on IkappaB kinase (IKK) activity was investigated using purified recombinant IKK-alpha and -beta proteins. RESULTS: NF-kappaB/Rel activity induced by tumor necrosis factor alpha, 12-O-tetradecanoylphorbol-13-acetate, or overexpression of NF-kappaB-inducing kinase, IKK-alpha, IKK-beta, or constitutively active IKK-alpha and IKK-beta mutants was inhibited dose dependently by CHEMICAL. CHEMICAL inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells, as well as the catalytic activity of purified IKK-alpha and IKK-beta in vitro. In contrast, the moieties of CHEMICAL, 5-aminosalicylic acid, and sulfapyridine or 4-aminosalicylic acid had no effect. Activation of extracellular signal-related kinase (ERK) 1 and 2, GENE, and p38 was unaffected by CHEMICAL. The decrease in substrate phosphorylation by IKK-alpha and -beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate. CONCLUSIONS: These data identify CHEMICAL as a direct inhibitor of IKK-alpha and -beta by antagonizing adenosine triphosphate binding. The suppression of NF-kappaB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of CHEMICAL. | NO-RELATIONSHIP |
| Suppression of NF-kappaB activity by CHEMICAL is mediated by direct inhibition of IkappaB kinases alpha and beta. BACKGROUND & AIMS: Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Various drugs used in the treatment of IBD, such as glucocorticoids, 5-aminosalicylic acid, and CHEMICAL, interfere with NF-kappaB/Rel signaling. The aim of this study was to define the molecular mechanism by which CHEMICAL inhibits NF-kappaB activation. METHODS: The effects of CHEMICAL and its moieties on NF-kappaB signaling were evaluated using electromobility shift, transfection, and immune complex kinase assays. The direct effect of CHEMICAL on IkappaB kinase (IKK) activity was investigated using purified recombinant IKK-alpha and -beta proteins. RESULTS: NF-kappaB/Rel activity induced by tumor necrosis factor alpha, 12-O-tetradecanoylphorbol-13-acetate, or overexpression of NF-kappaB-inducing kinase, IKK-alpha, IKK-beta, or constitutively active IKK-alpha and IKK-beta mutants was inhibited dose dependently by CHEMICAL. CHEMICAL inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells, as well as the catalytic activity of purified IKK-alpha and IKK-beta in vitro. In contrast, the moieties of CHEMICAL, 5-aminosalicylic acid, and sulfapyridine or 4-aminosalicylic acid had no effect. Activation of extracellular signal-related kinase (ERK) 1 and 2, c-Jun-N-terminal kinase (JNK) 1, and GENE was unaffected by CHEMICAL. The decrease in substrate phosphorylation by IKK-alpha and -beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate. CONCLUSIONS: These data identify CHEMICAL as a direct inhibitor of IKK-alpha and -beta by antagonizing adenosine triphosphate binding. The suppression of NF-kappaB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of CHEMICAL. | NO-RELATIONSHIP |
| Suppression of GENE activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. BACKGROUND & AIMS: Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Various drugs used in the treatment of IBD, such as glucocorticoids, CHEMICAL, and sulfasalazine, interfere with GENE/Rel signaling. The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits GENE activation. METHODS: The effects of sulfasalazine and its moieties on GENE signaling were evaluated using electromobility shift, transfection, and immune complex kinase assays. The direct effect of sulfasalazine on IkappaB kinase (IKK) activity was investigated using purified recombinant IKK-alpha and -beta proteins. RESULTS: NF-kappaB/Rel activity induced by tumor necrosis factor alpha, 12-O-tetradecanoylphorbol-13-acetate, or overexpression of NF-kappaB-inducing kinase, IKK-alpha, IKK-beta, or constitutively active IKK-alpha and IKK-beta mutants was inhibited dose dependently by sulfasalazine. Sulfasalazine inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells, as well as the catalytic activity of purified IKK-alpha and IKK-beta in vitro. In contrast, the moieties of sulfasalazine, CHEMICAL, and sulfapyridine or 4-aminosalicylic acid had no effect. Activation of extracellular signal-related kinase (ERK) 1 and 2, c-Jun-N-terminal kinase (JNK) 1, and p38 was unaffected by sulfasalazine. The decrease in substrate phosphorylation by IKK-alpha and -beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate. CONCLUSIONS: These data identify sulfasalazine as a direct inhibitor of IKK-alpha and -beta by antagonizing adenosine triphosphate binding. The suppression of GENE activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of sulfasalazine. | REGULATOR |
| Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. BACKGROUND & AIMS: Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Various drugs used in the treatment of IBD, such as glucocorticoids, CHEMICAL, and sulfasalazine, interfere with NF-kappaB/GENE signaling. The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF-kappaB activation. METHODS: The effects of sulfasalazine and its moieties on NF-kappaB signaling were evaluated using electromobility shift, transfection, and immune complex kinase assays. The direct effect of sulfasalazine on IkappaB kinase (IKK) activity was investigated using purified recombinant IKK-alpha and -beta proteins. RESULTS: NF-kappaB/Rel activity induced by tumor necrosis factor alpha, 12-O-tetradecanoylphorbol-13-acetate, or overexpression of NF-kappaB-inducing kinase, IKK-alpha, IKK-beta, or constitutively active IKK-alpha and IKK-beta mutants was inhibited dose dependently by sulfasalazine. Sulfasalazine inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells, as well as the catalytic activity of purified IKK-alpha and IKK-beta in vitro. In contrast, the moieties of sulfasalazine, CHEMICAL, and sulfapyridine or 4-aminosalicylic acid had no effect. Activation of extracellular signal-related kinase (ERK) 1 and 2, c-Jun-N-terminal kinase (JNK) 1, and p38 was unaffected by sulfasalazine. The decrease in substrate phosphorylation by IKK-alpha and -beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate. CONCLUSIONS: These data identify sulfasalazine as a direct inhibitor of IKK-alpha and -beta by antagonizing adenosine triphosphate binding. The suppression of NF-kappaB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of sulfasalazine. | REGULATOR |
| Suppression of GENE activity by CHEMICAL is mediated by direct inhibition of IkappaB kinases alpha and beta. BACKGROUND & AIMS: Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Various drugs used in the treatment of IBD, such as glucocorticoids, 5-aminosalicylic acid, and CHEMICAL, interfere with GENE/Rel signaling. The aim of this study was to define the molecular mechanism by which CHEMICAL inhibits GENE activation. METHODS: The effects of CHEMICAL and its moieties on GENE signaling were evaluated using electromobility shift, transfection, and immune complex kinase assays. The direct effect of CHEMICAL on IkappaB kinase (IKK) activity was investigated using purified recombinant IKK-alpha and -beta proteins. RESULTS: NF-kappaB/Rel activity induced by tumor necrosis factor alpha, 12-O-tetradecanoylphorbol-13-acetate, or overexpression of NF-kappaB-inducing kinase, IKK-alpha, IKK-beta, or constitutively active IKK-alpha and IKK-beta mutants was inhibited dose dependently by CHEMICAL. CHEMICAL inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells, as well as the catalytic activity of purified IKK-alpha and IKK-beta in vitro. In contrast, the moieties of CHEMICAL, 5-aminosalicylic acid, and sulfapyridine or 4-aminosalicylic acid had no effect. Activation of extracellular signal-related kinase (ERK) 1 and 2, c-Jun-N-terminal kinase (JNK) 1, and p38 was unaffected by CHEMICAL. The decrease in substrate phosphorylation by IKK-alpha and -beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate. CONCLUSIONS: These data identify CHEMICAL as a direct inhibitor of IKK-alpha and -beta by antagonizing adenosine triphosphate binding. The suppression of GENE activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of CHEMICAL. | GENE-CHEMICAL |
| Suppression of NF-kappaB activity by CHEMICAL is mediated by direct inhibition of IkappaB kinases alpha and beta. BACKGROUND & AIMS: Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Various drugs used in the treatment of IBD, such as glucocorticoids, 5-aminosalicylic acid, and CHEMICAL, interfere with NF-kappaB/GENE signaling. The aim of this study was to define the molecular mechanism by which CHEMICAL inhibits NF-kappaB activation. METHODS: The effects of CHEMICAL and its moieties on NF-kappaB signaling were evaluated using electromobility shift, transfection, and immune complex kinase assays. The direct effect of CHEMICAL on IkappaB kinase (IKK) activity was investigated using purified recombinant IKK-alpha and -beta proteins. RESULTS: NF-kappaB/Rel activity induced by tumor necrosis factor alpha, 12-O-tetradecanoylphorbol-13-acetate, or overexpression of NF-kappaB-inducing kinase, IKK-alpha, IKK-beta, or constitutively active IKK-alpha and IKK-beta mutants was inhibited dose dependently by CHEMICAL. CHEMICAL inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells, as well as the catalytic activity of purified IKK-alpha and IKK-beta in vitro. In contrast, the moieties of CHEMICAL, 5-aminosalicylic acid, and sulfapyridine or 4-aminosalicylic acid had no effect. Activation of extracellular signal-related kinase (ERK) 1 and 2, c-Jun-N-terminal kinase (JNK) 1, and p38 was unaffected by CHEMICAL. The decrease in substrate phosphorylation by IKK-alpha and -beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate. CONCLUSIONS: These data identify CHEMICAL as a direct inhibitor of IKK-alpha and -beta by antagonizing adenosine triphosphate binding. The suppression of NF-kappaB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of CHEMICAL. | REGULATOR |
| Suppression of GENE activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. BACKGROUND & AIMS: Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Various drugs used in the treatment of IBD, such as glucocorticoids, 5-aminosalicylic acid, and sulfasalazine, interfere with NF-kappaB/Rel signaling. The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits GENE activation. METHODS: The effects of sulfasalazine and its moieties on GENE signaling were evaluated using electromobility shift, transfection, and immune complex kinase assays. The direct effect of sulfasalazine on IkappaB kinase (IKK) activity was investigated using purified recombinant IKK-alpha and -beta proteins. RESULTS: GENE/Rel activity induced by tumor necrosis factor alpha, CHEMICAL, or overexpression of NF-kappaB-inducing kinase, IKK-alpha, IKK-beta, or constitutively active IKK-alpha and IKK-beta mutants was inhibited dose dependently by sulfasalazine. Sulfasalazine inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells, as well as the catalytic activity of purified IKK-alpha and IKK-beta in vitro. In contrast, the moieties of sulfasalazine, 5-aminosalicylic acid, and sulfapyridine or 4-aminosalicylic acid had no effect. Activation of extracellular signal-related kinase (ERK) 1 and 2, c-Jun-N-terminal kinase (JNK) 1, and p38 was unaffected by sulfasalazine. The decrease in substrate phosphorylation by IKK-alpha and -beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate. CONCLUSIONS: These data identify sulfasalazine as a direct inhibitor of IKK-alpha and -beta by antagonizing adenosine triphosphate binding. The suppression of GENE activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of sulfasalazine. | ACTIVATOR |
| Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. BACKGROUND & AIMS: Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Various drugs used in the treatment of IBD, such as glucocorticoids, 5-aminosalicylic acid, and sulfasalazine, interfere with NF-kappaB/Rel signaling. The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF-kappaB activation. METHODS: The effects of sulfasalazine and its moieties on NF-kappaB signaling were evaluated using electromobility shift, transfection, and immune complex kinase assays. The direct effect of sulfasalazine on IkappaB kinase (IKK) activity was investigated using purified recombinant IKK-alpha and -beta proteins. RESULTS: NF-kappaB/GENE activity induced by tumor necrosis factor alpha, CHEMICAL, or overexpression of NF-kappaB-inducing kinase, IKK-alpha, IKK-beta, or constitutively active IKK-alpha and IKK-beta mutants was inhibited dose dependently by sulfasalazine. Sulfasalazine inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells, as well as the catalytic activity of purified IKK-alpha and IKK-beta in vitro. In contrast, the moieties of sulfasalazine, 5-aminosalicylic acid, and sulfapyridine or 4-aminosalicylic acid had no effect. Activation of extracellular signal-related kinase (ERK) 1 and 2, c-Jun-N-terminal kinase (JNK) 1, and p38 was unaffected by sulfasalazine. The decrease in substrate phosphorylation by IKK-alpha and -beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate. CONCLUSIONS: These data identify sulfasalazine as a direct inhibitor of IKK-alpha and -beta by antagonizing adenosine triphosphate binding. The suppression of NF-kappaB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of sulfasalazine. | ACTIVATOR |
| Suppression of NF-kappaB activity by CHEMICAL is mediated by direct inhibition of IkappaB kinases alpha and beta. BACKGROUND & AIMS: Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Various drugs used in the treatment of IBD, such as glucocorticoids, 5-aminosalicylic acid, and CHEMICAL, interfere with NF-kappaB/Rel signaling. The aim of this study was to define the molecular mechanism by which CHEMICAL inhibits NF-kappaB activation. METHODS: The effects of CHEMICAL and its moieties on NF-kappaB signaling were evaluated using electromobility shift, transfection, and immune complex kinase assays. The direct effect of CHEMICAL on IkappaB kinase (IKK) activity was investigated using purified recombinant IKK-alpha and -beta proteins. RESULTS: NF-kappaB/Rel activity induced by tumor necrosis factor alpha, 12-O-tetradecanoylphorbol-13-acetate, or overexpression of NF-kappaB-inducing kinase, IKK-alpha, IKK-beta, or constitutively active IKK-alpha and IKK-beta mutants was inhibited dose dependently by CHEMICAL. CHEMICAL inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells, as well as the catalytic activity of purified IKK-alpha and IKK-beta in vitro. In contrast, the moieties of CHEMICAL, 5-aminosalicylic acid, and sulfapyridine or 4-aminosalicylic acid had no effect. Activation of extracellular signal-related kinase (ERK) 1 and 2, c-Jun-N-terminal kinase (JNK) 1, and p38 was unaffected by CHEMICAL. The decrease in substrate phosphorylation by IKK-alpha and -beta is associated with a decrease in autophosphorylation of GENE and can be antagonized by excess adenosine triphosphate. CONCLUSIONS: These data identify CHEMICAL as a direct inhibitor of IKK-alpha and -beta by antagonizing adenosine triphosphate binding. The suppression of NF-kappaB activation by inhibition of the GENE contributes to the well-known anti-inflammatory and immunosuppressive effects of CHEMICAL. | INHIBITOR |
| Suppression of NF-kappaB activity by CHEMICAL is mediated by direct inhibition of IkappaB kinases alpha and beta. BACKGROUND & AIMS: Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Various drugs used in the treatment of IBD, such as glucocorticoids, 5-aminosalicylic acid, and CHEMICAL, interfere with NF-kappaB/Rel signaling. The aim of this study was to define the molecular mechanism by which CHEMICAL inhibits NF-kappaB activation. METHODS: The effects of CHEMICAL and its moieties on NF-kappaB signaling were evaluated using electromobility shift, transfection, and immune complex kinase assays. The direct effect of CHEMICAL on IkappaB kinase (IKK) activity was investigated using purified recombinant IKK-alpha and -beta proteins. RESULTS: NF-kappaB/Rel activity induced by tumor necrosis factor alpha, 12-O-tetradecanoylphorbol-13-acetate, or overexpression of GENE, IKK-alpha, IKK-beta, or constitutively active IKK-alpha and IKK-beta mutants was inhibited dose dependently by CHEMICAL. CHEMICAL inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells, as well as the catalytic activity of purified IKK-alpha and IKK-beta in vitro. In contrast, the moieties of CHEMICAL, 5-aminosalicylic acid, and sulfapyridine or 4-aminosalicylic acid had no effect. Activation of extracellular signal-related kinase (ERK) 1 and 2, c-Jun-N-terminal kinase (JNK) 1, and p38 was unaffected by CHEMICAL. The decrease in substrate phosphorylation by IKK-alpha and -beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate. CONCLUSIONS: These data identify CHEMICAL as a direct inhibitor of IKK-alpha and -beta by antagonizing adenosine triphosphate binding. The suppression of NF-kappaB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of CHEMICAL. | INDIRECT-DOWNREGULATOR |
| Suppression of NF-kappaB activity by CHEMICAL is mediated by direct inhibition of IkappaB kinases alpha and beta. BACKGROUND & AIMS: Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Various drugs used in the treatment of IBD, such as glucocorticoids, 5-aminosalicylic acid, and CHEMICAL, interfere with NF-kappaB/Rel signaling. The aim of this study was to define the molecular mechanism by which CHEMICAL inhibits NF-kappaB activation. METHODS: The effects of CHEMICAL and its moieties on NF-kappaB signaling were evaluated using electromobility shift, transfection, and immune complex kinase assays. The direct effect of CHEMICAL on IkappaB kinase (IKK) activity was investigated using purified recombinant GENE and -beta proteins. RESULTS: NF-kappaB/Rel activity induced by tumor necrosis factor alpha, 12-O-tetradecanoylphorbol-13-acetate, or overexpression of NF-kappaB-inducing kinase, GENE, IKK-beta, or constitutively active GENE and IKK-beta mutants was inhibited dose dependently by CHEMICAL. CHEMICAL inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells, as well as the catalytic activity of purified GENE and IKK-beta in vitro. In contrast, the moieties of CHEMICAL, 5-aminosalicylic acid, and sulfapyridine or 4-aminosalicylic acid had no effect. Activation of extracellular signal-related kinase (ERK) 1 and 2, c-Jun-N-terminal kinase (JNK) 1, and p38 was unaffected by CHEMICAL. The decrease in substrate phosphorylation by GENE and -beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate. CONCLUSIONS: These data identify CHEMICAL as a direct inhibitor of GENE and -beta by antagonizing adenosine triphosphate binding. The suppression of NF-kappaB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of CHEMICAL. | INHIBITOR |
| Suppression of NF-kappaB activity by CHEMICAL is mediated by direct inhibition of IkappaB kinases alpha and beta. BACKGROUND & AIMS: Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Various drugs used in the treatment of IBD, such as glucocorticoids, 5-aminosalicylic acid, and CHEMICAL, interfere with NF-kappaB/Rel signaling. The aim of this study was to define the molecular mechanism by which CHEMICAL inhibits NF-kappaB activation. METHODS: The effects of CHEMICAL and its moieties on NF-kappaB signaling were evaluated using electromobility shift, transfection, and immune complex kinase assays. The direct effect of CHEMICAL on IkappaB kinase (IKK) activity was investigated using purified recombinant IKK-alpha and -beta proteins. RESULTS: NF-kappaB/Rel activity induced by tumor necrosis factor alpha, 12-O-tetradecanoylphorbol-13-acetate, or overexpression of NF-kappaB-inducing kinase, IKK-alpha, GENE, or constitutively active IKK-alpha and GENE mutants was inhibited dose dependently by CHEMICAL. CHEMICAL inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells, as well as the catalytic activity of purified IKK-alpha and GENE in vitro. In contrast, the moieties of CHEMICAL, 5-aminosalicylic acid, and sulfapyridine or 4-aminosalicylic acid had no effect. Activation of extracellular signal-related kinase (ERK) 1 and 2, c-Jun-N-terminal kinase (JNK) 1, and p38 was unaffected by CHEMICAL. The decrease in substrate phosphorylation by IKK-alpha and -beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate. CONCLUSIONS: These data identify CHEMICAL as a direct inhibitor of IKK-alpha and -beta by antagonizing adenosine triphosphate binding. The suppression of NF-kappaB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of CHEMICAL. | INHIBITOR |
| Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. BACKGROUND & AIMS: Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Various drugs used in the treatment of IBD, such as glucocorticoids, 5-aminosalicylic acid, and sulfasalazine, interfere with NF-kappaB/Rel signaling. The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF-kappaB activation. METHODS: The effects of sulfasalazine and its moieties on NF-kappaB signaling were evaluated using electromobility shift, transfection, and immune complex kinase assays. The direct effect of sulfasalazine on IkappaB kinase (IKK) activity was investigated using purified recombinant IKK-alpha and -beta proteins. RESULTS: NF-kappaB/Rel activity induced by GENE, 12-O-tetradecanoylphorbol-13-acetate, or overexpression of NF-kappaB-inducing kinase, IKK-alpha, IKK-beta, or constitutively active IKK-alpha and IKK-beta mutants was inhibited dose dependently by sulfasalazine. CHEMICAL inhibited GENE-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells, as well as the catalytic activity of purified IKK-alpha and IKK-beta in vitro. In contrast, the moieties of sulfasalazine, 5-aminosalicylic acid, and sulfapyridine or 4-aminosalicylic acid had no effect. Activation of extracellular signal-related kinase (ERK) 1 and 2, c-Jun-N-terminal kinase (JNK) 1, and p38 was unaffected by sulfasalazine. The decrease in substrate phosphorylation by IKK-alpha and -beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate. CONCLUSIONS: These data identify sulfasalazine as a direct inhibitor of IKK-alpha and -beta by antagonizing adenosine triphosphate binding. The suppression of NF-kappaB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of sulfasalazine. | INHIBITOR |
| Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. BACKGROUND & AIMS: Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Various drugs used in the treatment of IBD, such as glucocorticoids, 5-aminosalicylic acid, and sulfasalazine, interfere with NF-kappaB/Rel signaling. The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF-kappaB activation. METHODS: The effects of sulfasalazine and its moieties on NF-kappaB signaling were evaluated using electromobility shift, transfection, and immune complex kinase assays. The direct effect of sulfasalazine on IkappaB kinase (IKK) activity was investigated using purified recombinant IKK-alpha and -beta proteins. RESULTS: NF-kappaB/Rel activity induced by tumor necrosis factor alpha, 12-O-tetradecanoylphorbol-13-acetate, or overexpression of NF-kappaB-inducing kinase, IKK-alpha, IKK-beta, or constitutively active IKK-alpha and IKK-beta mutants was inhibited dose dependently by sulfasalazine. CHEMICAL inhibited tumor necrosis factor alpha-induced activation of endogenous GENE in Jurkat T cells and SW620 colon cells, as well as the catalytic activity of purified IKK-alpha and IKK-beta in vitro. In contrast, the moieties of sulfasalazine, 5-aminosalicylic acid, and sulfapyridine or 4-aminosalicylic acid had no effect. Activation of extracellular signal-related kinase (ERK) 1 and 2, c-Jun-N-terminal kinase (JNK) 1, and p38 was unaffected by sulfasalazine. The decrease in substrate phosphorylation by IKK-alpha and -beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate. CONCLUSIONS: These data identify sulfasalazine as a direct inhibitor of IKK-alpha and -beta by antagonizing adenosine triphosphate binding. The suppression of NF-kappaB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of sulfasalazine. | INHIBITOR |
| Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. BACKGROUND & AIMS: Activation of NF-kappaB/Rel has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Various drugs used in the treatment of IBD, such as glucocorticoids, 5-aminosalicylic acid, and sulfasalazine, interfere with NF-kappaB/Rel signaling. The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF-kappaB activation. METHODS: The effects of sulfasalazine and its moieties on NF-kappaB signaling were evaluated using electromobility shift, transfection, and immune complex kinase assays. The direct effect of sulfasalazine on IkappaB kinase (IKK) activity was investigated using purified recombinant IKK-alpha and -beta proteins. RESULTS: NF-kappaB/Rel activity induced by tumor necrosis factor alpha, 12-O-tetradecanoylphorbol-13-acetate, or overexpression of NF-kappaB-inducing kinase, IKK-alpha, IKK-beta, or constitutively active IKK-alpha and IKK-beta mutants was inhibited dose dependently by sulfasalazine. Sulfasalazine inhibited tumor necrosis factor alpha-induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells, as well as the catalytic activity of purified IKK-alpha and IKK-beta in vitro. In contrast, the moieties of sulfasalazine, 5-aminosalicylic acid, and sulfapyridine or 4-aminosalicylic acid had no effect. Activation of extracellular signal-related kinase (ERK) 1 and 2, c-Jun-N-terminal kinase (JNK) 1, and p38 was unaffected by sulfasalazine. The decrease in substrate phosphorylation by IKK-alpha and -beta is associated with a decrease in autophosphorylation of GENE and can be antagonized by excess CHEMICAL. CONCLUSIONS: These data identify sulfasalazine as a direct inhibitor of IKK-alpha and -beta by antagonizing CHEMICAL binding. The suppression of NF-kappaB activation by inhibition of the GENE contributes to the well-known anti-inflammatory and immunosuppressive effects of sulfasalazine. | INHIBITOR |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not GENE, and gene knockout transfection experiments demonstrate a central role of COX-2 in experimental tumorigenesis. COX-2 produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective COX-2 inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory COX-2 but the constitutively expressed, cytoprotective GENE as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of COX-2 to treat neoplastic proliferation is preferable to nonselective inhibition. Selective COX-2 inhibitors, such as CHEMICAL, celecoxib (SC-58635), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit COX-2 but not GENE. For instance, CHEMICAL inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express COX-2 but has no effect on HCT-116 tumor cells that do not express COX-2. NS-398 induces apoptosis in COX-2 expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express COX-2. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. COX-2 mRNA and COX-2 protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, COX-2 is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective COX-2 inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | NO-RELATIONSHIP |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not GENE, and gene knockout transfection experiments demonstrate a central role of COX-2 in experimental tumorigenesis. COX-2 produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective COX-2 inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory COX-2 but the constitutively expressed, cytoprotective GENE as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of COX-2 to treat neoplastic proliferation is preferable to nonselective inhibition. Selective COX-2 inhibitors, such as meloxicam, CHEMICAL (SC-58635), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit COX-2 but not GENE. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express COX-2 but has no effect on HCT-116 tumor cells that do not express COX-2. NS-398 induces apoptosis in COX-2 expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express COX-2. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. COX-2 mRNA and COX-2 protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, COX-2 is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective COX-2 inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | NO-RELATIONSHIP |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not GENE, and gene knockout transfection experiments demonstrate a central role of COX-2 in experimental tumorigenesis. COX-2 produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective COX-2 inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory COX-2 but the constitutively expressed, cytoprotective GENE as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of COX-2 to treat neoplastic proliferation is preferable to nonselective inhibition. Selective COX-2 inhibitors, such as meloxicam, celecoxib (CHEMICAL), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit COX-2 but not GENE. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express COX-2 but has no effect on HCT-116 tumor cells that do not express COX-2. NS-398 induces apoptosis in COX-2 expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express COX-2. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. COX-2 mRNA and COX-2 protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, COX-2 is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective COX-2 inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | NO-RELATIONSHIP |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not GENE, and gene knockout transfection experiments demonstrate a central role of COX-2 in experimental tumorigenesis. COX-2 produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective COX-2 inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory COX-2 but the constitutively expressed, cytoprotective GENE as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of COX-2 to treat neoplastic proliferation is preferable to nonselective inhibition. Selective COX-2 inhibitors, such as meloxicam, celecoxib (SC-58635), and CHEMICAL (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit COX-2 but not GENE. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express COX-2 but has no effect on HCT-116 tumor cells that do not express COX-2. NS-398 induces apoptosis in COX-2 expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express COX-2. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. COX-2 mRNA and COX-2 protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, COX-2 is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective COX-2 inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | NO-RELATIONSHIP |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not GENE, and gene knockout transfection experiments demonstrate a central role of COX-2 in experimental tumorigenesis. COX-2 produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective COX-2 inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory COX-2 but the constitutively expressed, cytoprotective GENE as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of COX-2 to treat neoplastic proliferation is preferable to nonselective inhibition. Selective COX-2 inhibitors, such as meloxicam, celecoxib (SC-58635), and rofecoxib (CHEMICAL), are NSAIDs that have been modified chemically to preferentially inhibit COX-2 but not GENE. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express COX-2 but has no effect on HCT-116 tumor cells that do not express COX-2. NS-398 induces apoptosis in COX-2 expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express COX-2. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. COX-2 mRNA and COX-2 protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, COX-2 is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective COX-2 inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | NO-RELATIONSHIP |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of GENE in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not COX-1, and gene knockout transfection experiments demonstrate a central role of GENE in experimental tumorigenesis. GENE produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective GENE inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory GENE but the constitutively expressed, cytoprotective COX-1 as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of GENE to treat neoplastic proliferation is preferable to nonselective inhibition. Selective GENE inhibitors, such as CHEMICAL, celecoxib (SC-58635), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit GENE but not COX-1. For instance, CHEMICAL inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express GENE but has no effect on HCT-116 tumor cells that do not express GENE. NS-398 induces apoptosis in GENE expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express GENE. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. GENE mRNA and GENE protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, GENE is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective GENE inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | NO-RELATIONSHIP |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not COX-1, and gene knockout transfection experiments demonstrate a central role of COX-2 in experimental tumorigenesis. COX-2 produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective COX-2 inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory COX-2 but the constitutively expressed, cytoprotective COX-1 as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of COX-2 to treat neoplastic proliferation is preferable to nonselective inhibition. Selective COX-2 inhibitors, such as meloxicam, celecoxib (SC-58635), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit COX-2 but not COX-1. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express COX-2 but has no effect on HCT-116 tumor cells that do not express COX-2. NS-398 induces apoptosis in COX-2 expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express COX-2. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of GENE, as has been demonstrated for some nonselective NSAIDs, for instance, CHEMICAL. COX-2 mRNA and COX-2 protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, COX-2 is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective COX-2 inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | GENE-CHEMICAL |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of GENE in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not COX-1, and gene knockout transfection experiments demonstrate a central role of GENE in experimental tumorigenesis. GENE produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective GENE inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and CHEMICAL inhibit not only the enzymatic action of the highly inducible, proinflammatory GENE but the constitutively expressed, cytoprotective COX-1 as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of GENE to treat neoplastic proliferation is preferable to nonselective inhibition. Selective GENE inhibitors, such as meloxicam, celecoxib (SC-58635), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit GENE but not COX-1. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express GENE but has no effect on HCT-116 tumor cells that do not express GENE. NS-398 induces apoptosis in GENE expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express GENE. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. GENE mRNA and GENE protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, GENE is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective GENE inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | INHIBITOR |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not GENE, and gene knockout transfection experiments demonstrate a central role of COX-2 in experimental tumorigenesis. COX-2 produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective COX-2 inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and CHEMICAL inhibit not only the enzymatic action of the highly inducible, proinflammatory COX-2 but the constitutively expressed, cytoprotective GENE as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of COX-2 to treat neoplastic proliferation is preferable to nonselective inhibition. Selective COX-2 inhibitors, such as meloxicam, celecoxib (SC-58635), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit COX-2 but not GENE. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express COX-2 but has no effect on HCT-116 tumor cells that do not express COX-2. NS-398 induces apoptosis in COX-2 expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express COX-2. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. COX-2 mRNA and COX-2 protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, COX-2 is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective COX-2 inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | INHIBITOR |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of GENE in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not COX-1, and gene knockout transfection experiments demonstrate a central role of GENE in experimental tumorigenesis. GENE produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective GENE inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory GENE but the constitutively expressed, cytoprotective COX-1 as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of GENE to treat neoplastic proliferation is preferable to nonselective inhibition. Selective GENE inhibitors, such as meloxicam, CHEMICAL (SC-58635), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit GENE but not COX-1. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express GENE but has no effect on HCT-116 tumor cells that do not express GENE. NS-398 induces apoptosis in GENE expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express GENE. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. GENE mRNA and GENE protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, GENE is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective GENE inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | INHIBITOR |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of GENE in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not COX-1, and gene knockout transfection experiments demonstrate a central role of GENE in experimental tumorigenesis. GENE produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective GENE inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory GENE but the constitutively expressed, cytoprotective COX-1 as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of GENE to treat neoplastic proliferation is preferable to nonselective inhibition. Selective GENE inhibitors, such as meloxicam, celecoxib (CHEMICAL), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit GENE but not COX-1. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express GENE but has no effect on HCT-116 tumor cells that do not express GENE. NS-398 induces apoptosis in GENE expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express GENE. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. GENE mRNA and GENE protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, GENE is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective GENE inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | INHIBITOR |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of GENE in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not COX-1, and gene knockout transfection experiments demonstrate a central role of GENE in experimental tumorigenesis. GENE produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective GENE inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory GENE but the constitutively expressed, cytoprotective COX-1 as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of GENE to treat neoplastic proliferation is preferable to nonselective inhibition. Selective GENE inhibitors, such as meloxicam, celecoxib (SC-58635), and CHEMICAL (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit GENE but not COX-1. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express GENE but has no effect on HCT-116 tumor cells that do not express GENE. NS-398 induces apoptosis in GENE expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express GENE. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. GENE mRNA and GENE protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, GENE is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective GENE inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | INHIBITOR |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of GENE in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not COX-1, and gene knockout transfection experiments demonstrate a central role of GENE in experimental tumorigenesis. GENE produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective GENE inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory GENE but the constitutively expressed, cytoprotective COX-1 as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of GENE to treat neoplastic proliferation is preferable to nonselective inhibition. Selective GENE inhibitors, such as meloxicam, celecoxib (SC-58635), and rofecoxib (CHEMICAL), are NSAIDs that have been modified chemically to preferentially inhibit GENE but not COX-1. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express GENE but has no effect on HCT-116 tumor cells that do not express GENE. NS-398 induces apoptosis in GENE expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express GENE. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. GENE mRNA and GENE protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, GENE is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective GENE inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | INHIBITOR |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of GENE in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not COX-1, and gene knockout transfection experiments demonstrate a central role of GENE in experimental tumorigenesis. GENE produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective GENE inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, CHEMICAL-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory GENE but the constitutively expressed, cytoprotective COX-1 as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of GENE to treat neoplastic proliferation is preferable to nonselective inhibition. Selective GENE inhibitors, such as meloxicam, celecoxib (SC-58635), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit GENE but not COX-1. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express GENE but has no effect on HCT-116 tumor cells that do not express GENE. NS-398 induces apoptosis in GENE expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express GENE. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. GENE mRNA and GENE protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, GENE is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective GENE inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | INHIBITOR |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not GENE, and gene knockout transfection experiments demonstrate a central role of COX-2 in experimental tumorigenesis. COX-2 produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective COX-2 inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, CHEMICAL-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory COX-2 but the constitutively expressed, cytoprotective GENE as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of COX-2 to treat neoplastic proliferation is preferable to nonselective inhibition. Selective COX-2 inhibitors, such as meloxicam, celecoxib (SC-58635), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit COX-2 but not GENE. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express COX-2 but has no effect on HCT-116 tumor cells that do not express COX-2. NS-398 induces apoptosis in COX-2 expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express COX-2. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. COX-2 mRNA and COX-2 protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, COX-2 is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective COX-2 inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | NO-RELATIONSHIP |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of GENE in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not COX-1, and gene knockout transfection experiments demonstrate a central role of GENE in experimental tumorigenesis. GENE produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective GENE inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as CHEMICAL and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory GENE but the constitutively expressed, cytoprotective COX-1 as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of GENE to treat neoplastic proliferation is preferable to nonselective inhibition. Selective GENE inhibitors, such as meloxicam, celecoxib (SC-58635), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit GENE but not COX-1. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express GENE but has no effect on HCT-116 tumor cells that do not express GENE. NS-398 induces apoptosis in GENE expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express GENE. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. GENE mRNA and GENE protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, GENE is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective GENE inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | INHIBITOR |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not GENE, and gene knockout transfection experiments demonstrate a central role of COX-2 in experimental tumorigenesis. COX-2 produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective COX-2 inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as CHEMICAL and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory COX-2 but the constitutively expressed, cytoprotective GENE as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of COX-2 to treat neoplastic proliferation is preferable to nonselective inhibition. Selective COX-2 inhibitors, such as meloxicam, celecoxib (SC-58635), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit COX-2 but not GENE. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express COX-2 but has no effect on HCT-116 tumor cells that do not express COX-2. NS-398 induces apoptosis in COX-2 expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express COX-2. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. COX-2 mRNA and COX-2 protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, COX-2 is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective COX-2 inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | INHIBITOR |
| Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of GENE in neoplasia. Several types of human tumors overexpress cyclooxygenase (COX) -2 but not COX-1, and gene knockout transfection experiments demonstrate a central role of GENE in experimental tumorigenesis. GENE produces CHEMICAL that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective GENE inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory GENE but the constitutively expressed, cytoprotective COX-1 as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of GENE to treat neoplastic proliferation is preferable to nonselective inhibition. Selective GENE inhibitors, such as meloxicam, celecoxib (SC-58635), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit GENE but not COX-1. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express GENE but has no effect on HCT-116 tumor cells that do not express GENE. NS-398 induces apoptosis in GENE expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express GENE. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. GENE mRNA and GENE protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, GENE is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective GENE inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers. | PRODUCT-OF |
| The aromatic-L-amino acid decarboxylase inhibitor CHEMICAL is selectively cytotoxic to human pulmonary carcinoid and small cell lung carcinoma cells. The carcinoid tumor is an uncommon neuroendocrine neoplasm the hallmark of which is excessive serotonin production. In studying kinetics of tryptophan hydroxylase and aromatic-L-amino acid decarboxylase (AAAD) in human carcinoid hepatic metastases and adjacent normal liver (J. A. Gilbert et al, Biochem. Pharmacol., 50: 845-850, 1995), we identified one significant difference: the Vmax of carcinoid GENE was 50-fold higher than that in normal liver. Here, we report Western and Northern analyses detecting large quantities of GENE polypeptide and mRNA in human carcinoid primary as well as metastatic tumors compared with normal surrounding tissues. To assess the feasibility of targeting these high GENE levels for chemotherapy, GENE inhibitors CHEMICAL (alpha-methyl-dopahydrazine), alpha-monofluoromethyldopa (MFMD), and 3-hydroxybenzylhydrazine (NSD-1015) were incubated (72 h) with NCI-H727 human lung carcinoid cells. CHEMICAL and MFMD were lethal (IC50 = 29 +/- 2 microM and 56 +/- 6 microM, respectively); NSD-1015 had no effect on proliferation. On exposure to other human tumor lines, CHEMICAL was lethal only to NCI-H146 and NCI-H209 small cell lung carcinoma (SCLC) lines (IC50 = 12 +/- 1 microM and 22 +/- 5 microM, respectively). CHEMICAL (100 microM) decreased growth of (but did not kill) SK-N-SH neuroblastoma and A204 rhabdomyosarcoma cells and did not affect proliferation of DU 145 prostate, MCF7 breast, or NCI-H460 large cell lung carcinoma lines. The rank order of lines by GENE activity was NCI-H146 > NCI-H209 > SK-N-SH > NCI-H727, whereas A204, DU 145, MCF7, and NCI-H460 had no measurable activity. For lung tumor lines (carcinoid, two SCLC, and one large cell lung carcinoma), GENE activity was correlated with the potency of CHEMICAL-induced cytotoxicity. However, carcinoid cell death was not solely attributable to complete inhibition of either GENE activity or the serotonin synthetic pathway. In further evaluating potential applications of these findings with CHEMICAL, we determined that sublethal doses of CHEMICAL produced additive cytotoxic effects in carcinoid cells in combination with etoposide and cytotoxic synergy in SCLC cells when coincubated with topotecan. | INHIBITOR |
| The aromatic-L-amino acid decarboxylase inhibitor carbidopa is selectively cytotoxic to human pulmonary carcinoid and small cell lung carcinoma cells. The carcinoid tumor is an uncommon neuroendocrine neoplasm the hallmark of which is excessive serotonin production. In studying kinetics of tryptophan hydroxylase and aromatic-L-amino acid decarboxylase (AAAD) in human carcinoid hepatic metastases and adjacent normal liver (J. A. Gilbert et al, Biochem. Pharmacol., 50: 845-850, 1995), we identified one significant difference: the Vmax of carcinoid GENE was 50-fold higher than that in normal liver. Here, we report Western and Northern analyses detecting large quantities of GENE polypeptide and mRNA in human carcinoid primary as well as metastatic tumors compared with normal surrounding tissues. To assess the feasibility of targeting these high GENE levels for chemotherapy, GENE inhibitors carbidopa (CHEMICAL), alpha-monofluoromethyldopa (MFMD), and 3-hydroxybenzylhydrazine (NSD-1015) were incubated (72 h) with NCI-H727 human lung carcinoid cells. Carbidopa and MFMD were lethal (IC50 = 29 +/- 2 microM and 56 +/- 6 microM, respectively); NSD-1015 had no effect on proliferation. On exposure to other human tumor lines, carbidopa was lethal only to NCI-H146 and NCI-H209 small cell lung carcinoma (SCLC) lines (IC50 = 12 +/- 1 microM and 22 +/- 5 microM, respectively). Carbidopa (100 microM) decreased growth of (but did not kill) SK-N-SH neuroblastoma and A204 rhabdomyosarcoma cells and did not affect proliferation of DU 145 prostate, MCF7 breast, or NCI-H460 large cell lung carcinoma lines. The rank order of lines by GENE activity was NCI-H146 > NCI-H209 > SK-N-SH > NCI-H727, whereas A204, DU 145, MCF7, and NCI-H460 had no measurable activity. For lung tumor lines (carcinoid, two SCLC, and one large cell lung carcinoma), GENE activity was correlated with the potency of carbidopa-induced cytotoxicity. However, carcinoid cell death was not solely attributable to complete inhibition of either GENE activity or the serotonin synthetic pathway. In further evaluating potential applications of these findings with carbidopa, we determined that sublethal doses of carbidopa produced additive cytotoxic effects in carcinoid cells in combination with etoposide and cytotoxic synergy in SCLC cells when coincubated with topotecan. | INHIBITOR |
| The aromatic-L-amino acid decarboxylase inhibitor carbidopa is selectively cytotoxic to human pulmonary carcinoid and small cell lung carcinoma cells. The carcinoid tumor is an uncommon neuroendocrine neoplasm the hallmark of which is excessive serotonin production. In studying kinetics of tryptophan hydroxylase and aromatic-L-amino acid decarboxylase (AAAD) in human carcinoid hepatic metastases and adjacent normal liver (J. A. Gilbert et al, Biochem. Pharmacol., 50: 845-850, 1995), we identified one significant difference: the Vmax of carcinoid GENE was 50-fold higher than that in normal liver. Here, we report Western and Northern analyses detecting large quantities of GENE polypeptide and mRNA in human carcinoid primary as well as metastatic tumors compared with normal surrounding tissues. To assess the feasibility of targeting these high GENE levels for chemotherapy, GENE inhibitors carbidopa (alpha-methyl-dopahydrazine), CHEMICAL (MFMD), and 3-hydroxybenzylhydrazine (NSD-1015) were incubated (72 h) with NCI-H727 human lung carcinoid cells. Carbidopa and MFMD were lethal (IC50 = 29 +/- 2 microM and 56 +/- 6 microM, respectively); NSD-1015 had no effect on proliferation. On exposure to other human tumor lines, carbidopa was lethal only to NCI-H146 and NCI-H209 small cell lung carcinoma (SCLC) lines (IC50 = 12 +/- 1 microM and 22 +/- 5 microM, respectively). Carbidopa (100 microM) decreased growth of (but did not kill) SK-N-SH neuroblastoma and A204 rhabdomyosarcoma cells and did not affect proliferation of DU 145 prostate, MCF7 breast, or NCI-H460 large cell lung carcinoma lines. The rank order of lines by GENE activity was NCI-H146 > NCI-H209 > SK-N-SH > NCI-H727, whereas A204, DU 145, MCF7, and NCI-H460 had no measurable activity. For lung tumor lines (carcinoid, two SCLC, and one large cell lung carcinoma), GENE activity was correlated with the potency of carbidopa-induced cytotoxicity. However, carcinoid cell death was not solely attributable to complete inhibition of either GENE activity or the serotonin synthetic pathway. In further evaluating potential applications of these findings with carbidopa, we determined that sublethal doses of carbidopa produced additive cytotoxic effects in carcinoid cells in combination with etoposide and cytotoxic synergy in SCLC cells when coincubated with topotecan. | INHIBITOR |
| The aromatic-L-amino acid decarboxylase inhibitor carbidopa is selectively cytotoxic to human pulmonary carcinoid and small cell lung carcinoma cells. The carcinoid tumor is an uncommon neuroendocrine neoplasm the hallmark of which is excessive serotonin production. In studying kinetics of tryptophan hydroxylase and aromatic-L-amino acid decarboxylase (AAAD) in human carcinoid hepatic metastases and adjacent normal liver (J. A. Gilbert et al, Biochem. Pharmacol., 50: 845-850, 1995), we identified one significant difference: the Vmax of carcinoid GENE was 50-fold higher than that in normal liver. Here, we report Western and Northern analyses detecting large quantities of GENE polypeptide and mRNA in human carcinoid primary as well as metastatic tumors compared with normal surrounding tissues. To assess the feasibility of targeting these high GENE levels for chemotherapy, GENE inhibitors carbidopa (alpha-methyl-dopahydrazine), alpha-monofluoromethyldopa (CHEMICAL), and 3-hydroxybenzylhydrazine (NSD-1015) were incubated (72 h) with NCI-H727 human lung carcinoid cells. Carbidopa and CHEMICAL were lethal (IC50 = 29 +/- 2 microM and 56 +/- 6 microM, respectively); NSD-1015 had no effect on proliferation. On exposure to other human tumor lines, carbidopa was lethal only to NCI-H146 and NCI-H209 small cell lung carcinoma (SCLC) lines (IC50 = 12 +/- 1 microM and 22 +/- 5 microM, respectively). Carbidopa (100 microM) decreased growth of (but did not kill) SK-N-SH neuroblastoma and A204 rhabdomyosarcoma cells and did not affect proliferation of DU 145 prostate, MCF7 breast, or NCI-H460 large cell lung carcinoma lines. The rank order of lines by GENE activity was NCI-H146 > NCI-H209 > SK-N-SH > NCI-H727, whereas A204, DU 145, MCF7, and NCI-H460 had no measurable activity. For lung tumor lines (carcinoid, two SCLC, and one large cell lung carcinoma), GENE activity was correlated with the potency of carbidopa-induced cytotoxicity. However, carcinoid cell death was not solely attributable to complete inhibition of either GENE activity or the serotonin synthetic pathway. In further evaluating potential applications of these findings with carbidopa, we determined that sublethal doses of carbidopa produced additive cytotoxic effects in carcinoid cells in combination with etoposide and cytotoxic synergy in SCLC cells when coincubated with topotecan. | INHIBITOR |
| The aromatic-L-amino acid decarboxylase inhibitor carbidopa is selectively cytotoxic to human pulmonary carcinoid and small cell lung carcinoma cells. The carcinoid tumor is an uncommon neuroendocrine neoplasm the hallmark of which is excessive serotonin production. In studying kinetics of tryptophan hydroxylase and aromatic-L-amino acid decarboxylase (AAAD) in human carcinoid hepatic metastases and adjacent normal liver (J. A. Gilbert et al, Biochem. Pharmacol., 50: 845-850, 1995), we identified one significant difference: the Vmax of carcinoid GENE was 50-fold higher than that in normal liver. Here, we report Western and Northern analyses detecting large quantities of GENE polypeptide and mRNA in human carcinoid primary as well as metastatic tumors compared with normal surrounding tissues. To assess the feasibility of targeting these high GENE levels for chemotherapy, GENE inhibitors carbidopa (alpha-methyl-dopahydrazine), alpha-monofluoromethyldopa (MFMD), and CHEMICAL (NSD-1015) were incubated (72 h) with NCI-H727 human lung carcinoid cells. Carbidopa and MFMD were lethal (IC50 = 29 +/- 2 microM and 56 +/- 6 microM, respectively); NSD-1015 had no effect on proliferation. On exposure to other human tumor lines, carbidopa was lethal only to NCI-H146 and NCI-H209 small cell lung carcinoma (SCLC) lines (IC50 = 12 +/- 1 microM and 22 +/- 5 microM, respectively). Carbidopa (100 microM) decreased growth of (but did not kill) SK-N-SH neuroblastoma and A204 rhabdomyosarcoma cells and did not affect proliferation of DU 145 prostate, MCF7 breast, or NCI-H460 large cell lung carcinoma lines. The rank order of lines by GENE activity was NCI-H146 > NCI-H209 > SK-N-SH > NCI-H727, whereas A204, DU 145, MCF7, and NCI-H460 had no measurable activity. For lung tumor lines (carcinoid, two SCLC, and one large cell lung carcinoma), GENE activity was correlated with the potency of carbidopa-induced cytotoxicity. However, carcinoid cell death was not solely attributable to complete inhibition of either GENE activity or the serotonin synthetic pathway. In further evaluating potential applications of these findings with carbidopa, we determined that sublethal doses of carbidopa produced additive cytotoxic effects in carcinoid cells in combination with etoposide and cytotoxic synergy in SCLC cells when coincubated with topotecan. | INHIBITOR |
| The aromatic-L-amino acid decarboxylase inhibitor carbidopa is selectively cytotoxic to human pulmonary carcinoid and small cell lung carcinoma cells. The carcinoid tumor is an uncommon neuroendocrine neoplasm the hallmark of which is excessive serotonin production. In studying kinetics of tryptophan hydroxylase and aromatic-L-amino acid decarboxylase (AAAD) in human carcinoid hepatic metastases and adjacent normal liver (J. A. Gilbert et al, Biochem. Pharmacol., 50: 845-850, 1995), we identified one significant difference: the Vmax of carcinoid GENE was 50-fold higher than that in normal liver. Here, we report Western and Northern analyses detecting large quantities of GENE polypeptide and mRNA in human carcinoid primary as well as metastatic tumors compared with normal surrounding tissues. To assess the feasibility of targeting these high GENE levels for chemotherapy, GENE inhibitors carbidopa (alpha-methyl-dopahydrazine), alpha-monofluoromethyldopa (MFMD), and 3-hydroxybenzylhydrazine (CHEMICAL) were incubated (72 h) with NCI-H727 human lung carcinoid cells. Carbidopa and MFMD were lethal (IC50 = 29 +/- 2 microM and 56 +/- 6 microM, respectively); CHEMICAL had no effect on proliferation. On exposure to other human tumor lines, carbidopa was lethal only to NCI-H146 and NCI-H209 small cell lung carcinoma (SCLC) lines (IC50 = 12 +/- 1 microM and 22 +/- 5 microM, respectively). Carbidopa (100 microM) decreased growth of (but did not kill) SK-N-SH neuroblastoma and A204 rhabdomyosarcoma cells and did not affect proliferation of DU 145 prostate, MCF7 breast, or NCI-H460 large cell lung carcinoma lines. The rank order of lines by GENE activity was NCI-H146 > NCI-H209 > SK-N-SH > NCI-H727, whereas A204, DU 145, MCF7, and NCI-H460 had no measurable activity. For lung tumor lines (carcinoid, two SCLC, and one large cell lung carcinoma), GENE activity was correlated with the potency of carbidopa-induced cytotoxicity. However, carcinoid cell death was not solely attributable to complete inhibition of either GENE activity or the serotonin synthetic pathway. In further evaluating potential applications of these findings with carbidopa, we determined that sublethal doses of carbidopa produced additive cytotoxic effects in carcinoid cells in combination with etoposide and cytotoxic synergy in SCLC cells when coincubated with topotecan. | INHIBITOR |
| Hexahydrochromeno[4,3-b]pyrrole derivatives as acetylcholinesterase inhibitors. In a search for less flexible analogues of caproctamine (1), a diamine CHEMICAL endowed with an interesting GENE affinity profile, we discovered compound 2, in which the terminal 2-methoxybenzyl groups of 1 have been incorporated into a tricyclic system. Since this compound retains good GENE inhibitory activity and its hexahydrochromeno[4,3-b]pyrrole moiety is reminiscent of the hexahydropyrrolo[2,3-b]indole of physostigmine (3), we have designed and synthesized carbamates 4-6, and their biological evaluation has been assessed in vitro against human GENE and BChE. The 6-carbamate 4 was almost as potent as physostigmine and was 60- and 550-fold more potent than the 7-carbamate 5 and the 8-carbamate 6, respectively. The two enantiomers of 4, (-)-4 and (+)-4, did not show a marked enantioselectivity. Finally, a similar time-dependent pattern of inhibition of GENE was observed for 3 and 4. | DIRECT-REGULATOR |
| Hexahydrochromeno[4,3-b]pyrrole derivatives as acetylcholinesterase inhibitors. In a search for less flexible analogues of CHEMICAL (1), a diamine diamide endowed with an interesting GENE affinity profile, we discovered compound 2, in which the terminal 2-methoxybenzyl groups of 1 have been incorporated into a tricyclic system. Since this compound retains good GENE inhibitory activity and its hexahydrochromeno[4,3-b]pyrrole moiety is reminiscent of the hexahydropyrrolo[2,3-b]indole of physostigmine (3), we have designed and synthesized carbamates 4-6, and their biological evaluation has been assessed in vitro against human GENE and BChE. The 6-carbamate 4 was almost as potent as physostigmine and was 60- and 550-fold more potent than the 7-carbamate 5 and the 8-carbamate 6, respectively. The two enantiomers of 4, (-)-4 and (+)-4, did not show a marked enantioselectivity. Finally, a similar time-dependent pattern of inhibition of GENE was observed for 3 and 4. | DIRECT-REGULATOR |
| Hexahydrochromeno[4,3-b]pyrrole derivatives as acetylcholinesterase inhibitors. In a search for less flexible analogues of caproctamine (1), a CHEMICAL diamide endowed with an interesting GENE affinity profile, we discovered compound 2, in which the terminal 2-methoxybenzyl groups of 1 have been incorporated into a tricyclic system. Since this compound retains good GENE inhibitory activity and its hexahydrochromeno[4,3-b]pyrrole moiety is reminiscent of the hexahydropyrrolo[2,3-b]indole of physostigmine (3), we have designed and synthesized carbamates 4-6, and their biological evaluation has been assessed in vitro against human GENE and BChE. The 6-carbamate 4 was almost as potent as physostigmine and was 60- and 550-fold more potent than the 7-carbamate 5 and the 8-carbamate 6, respectively. The two enantiomers of 4, (-)-4 and (+)-4, did not show a marked enantioselectivity. Finally, a similar time-dependent pattern of inhibition of GENE was observed for 3 and 4. | DIRECT-REGULATOR |
| CHEMICAL derivatives as GENE inhibitors. In a search for less flexible analogues of caproctamine (1), a diamine diamide endowed with an interesting AChE affinity profile, we discovered compound 2, in which the terminal 2-methoxybenzyl groups of 1 have been incorporated into a tricyclic system. Since this compound retains good AChE inhibitory activity and its hexahydrochromeno[4,3-b]pyrrole moiety is reminiscent of the hexahydropyrrolo[2,3-b]indole of physostigmine (3), we have designed and synthesized carbamates 4-6, and their biological evaluation has been assessed in vitro against human AChE and BChE. The 6-carbamate 4 was almost as potent as physostigmine and was 60- and 550-fold more potent than the 7-carbamate 5 and the 8-carbamate 6, respectively. The two enantiomers of 4, (-)-4 and (+)-4, did not show a marked enantioselectivity. Finally, a similar time-dependent pattern of inhibition of AChE was observed for 3 and 4. | INHIBITOR |
| CHEMICAL derivatives as acetylcholinesterase inhibitors. In a search for less flexible analogues of caproctamine (1), a diamine diamide endowed with an interesting GENE affinity profile, we discovered compound 2, in which the terminal 2-methoxybenzyl groups of 1 have been incorporated into a tricyclic system. Since this compound retains good GENE inhibitory activity and its CHEMICAL moiety is reminiscent of the hexahydropyrrolo[2,3-b]indole of physostigmine (3), we have designed and synthesized carbamates 4-6, and their biological evaluation has been assessed in vitro against human GENE and BChE. The 6-carbamate 4 was almost as potent as physostigmine and was 60- and 550-fold more potent than the 7-carbamate 5 and the 8-carbamate 6, respectively. The two enantiomers of 4, (-)-4 and (+)-4, did not show a marked enantioselectivity. Finally, a similar time-dependent pattern of inhibition of GENE was observed for 3 and 4. | DIRECT-REGULATOR |
| Hexahydrochromeno[4,3-b]pyrrole derivatives as acetylcholinesterase inhibitors. In a search for less flexible analogues of caproctamine (1), a diamine diamide endowed with an interesting GENE affinity profile, we discovered compound 2, in which the terminal 2-methoxybenzyl groups of 1 have been incorporated into a tricyclic system. Since this compound retains good GENE inhibitory activity and its hexahydrochromeno[4,3-b]pyrrole moiety is reminiscent of the CHEMICAL (3), we have designed and synthesized carbamates 4-6, and their biological evaluation has been assessed in vitro against human GENE and BChE. The 6-carbamate 4 was almost as potent as physostigmine and was 60- and 550-fold more potent than the 7-carbamate 5 and the 8-carbamate 6, respectively. The two enantiomers of 4, (-)-4 and (+)-4, did not show a marked enantioselectivity. Finally, a similar time-dependent pattern of inhibition of GENE was observed for 3 and 4. | INHIBITOR |
| Breakdown of Th cell immune responses and steroidogenic GENE expression in CD4+ T cells in a murine model implanted with B16 melanoma. The association between the balance of Th1/Th2 cell responses and GENE expression in CD4+ T cells was investigated in a murine model implanted with highly metastatic B16F10 melanoma cells (B16F10 mice). When 2 x 10(5) cells/mouse of B16F10 cells were inoculated into C57BL/6 mice, Th2 cell responses and pulmonary metastasis were increased. In addition, CHEMICAL levels in splenic tissue or serum and GENE mRNA expression (mRNA encoding cholesterol side-chain cleavage p450 enzyme) in CD4+ T cells were increased in these mice. When the anti-corticosterone drug aminoglutethimide (CYP11A1 inhibitor) was administered to B16F10 mice, CHEMICAL levels in splenic tissue or serum and GENE mRNA expression were decreased at 14 days after tumor inoculation. In addition, Th1 cell responses were restored and pulmonary metastasis was reduced by aminoglutethimide. These results indicated that the breakdown of Th cell responses and increase of pulmonary metastasis were due to an increase in steroidogenic GENE mRNA expression in CD4+ T cells. Moreover, it was suggested that promotion of GENE mRNA expression in Th2 cells was partially involved due to an increase in level of CHEMICAL in splenic tissue and the breakdown of Th cell responses locally in the splenic tissue, which then affected the maintenance of Th2 cell functions in the microenvironment of tumor-bearing mice. | GENE-CHEMICAL |
| Breakdown of Th cell immune responses and steroidogenic GENE expression in CD4+ T cells in a murine model implanted with B16 melanoma. The association between the balance of Th1/Th2 cell responses and GENE expression in CD4+ T cells was investigated in a murine model implanted with highly metastatic B16F10 melanoma cells (B16F10 mice). When 2 x 10(5) cells/mouse of B16F10 cells were inoculated into C57BL/6 mice, Th2 cell responses and pulmonary metastasis were increased. In addition, corticosterone levels in splenic tissue or serum and GENE mRNA expression (mRNA encoding cholesterol side-chain cleavage p450 enzyme) in CD4+ T cells were increased in these mice. When the anti-corticosterone drug CHEMICAL (CYP11A1 inhibitor) was administered to B16F10 mice, corticosterone levels in splenic tissue or serum and GENE mRNA expression were decreased at 14 days after tumor inoculation. In addition, Th1 cell responses were restored and pulmonary metastasis was reduced by CHEMICAL. These results indicated that the breakdown of Th cell responses and increase of pulmonary metastasis were due to an increase in steroidogenic GENE mRNA expression in CD4+ T cells. Moreover, it was suggested that promotion of GENE mRNA expression in Th2 cells was partially involved due to an increase in level of corticosterone in splenic tissue and the breakdown of Th cell responses locally in the splenic tissue, which then affected the maintenance of Th2 cell functions in the microenvironment of tumor-bearing mice. | INDIRECT-DOWNREGULATOR |
| A nonsense mutation in the NDUFS4 gene encoding the 18 kDa (AQDQ) subunit of complex I abolishes assembly and activity of the complex in a patient with Leigh-like syndrome. Sequence analysis of mitochondrial and nuclear candidate genes of complex I in children with deficiency of this complex and exhibiting Leigh-like syndrome has revealed, in one of them, a novel mutation in the NDUFS4 gene encoding the 18 kDa subunit. Phosphorylation of this subunit by cAMP-dependent protein kinase has previously been found to activate the complex. The present mutation consists of a homozygous G-->A transition at nucleotide position +44 of the coding sequence of the gene, resulting in the change of a tryptophan codon to a stop codon. Such mutation causes premature termination of the protein after only 14 amino acids of the putative mitochondrial targeting peptide. Fibroblast cultures from the patient exhibited severe reduction of the rotenone-sensitive GENE activity of complex I, which was insensitive to CHEMICAL stimulation. Two-dimensional electrophoresis showed the absence of detectable normally assembled complex I in the inner mitochondrial membrane. These findings show that the expression of the NDUFS4 gene is essential for the assembly of a functional complex I. | NO-RELATIONSHIP |
| A nonsense mutation in the NDUFS4 gene encoding the 18 kDa (AQDQ) subunit of GENE abolishes assembly and activity of the complex in a patient with Leigh-like syndrome. Sequence analysis of mitochondrial and nuclear candidate genes of GENE in children with deficiency of this complex and exhibiting Leigh-like syndrome has revealed, in one of them, a novel mutation in the NDUFS4 gene encoding the 18 kDa subunit. Phosphorylation of this subunit by cAMP-dependent protein kinase has previously been found to activate the complex. The present mutation consists of a homozygous G-->A transition at nucleotide position +44 of the coding sequence of the gene, resulting in the change of a tryptophan codon to a stop codon. Such mutation causes premature termination of the protein after only 14 amino acids of the putative mitochondrial targeting peptide. Fibroblast cultures from the patient exhibited severe reduction of the rotenone-sensitive NADH-->UQ oxidoreductase activity of GENE, which was insensitive to CHEMICAL stimulation. Two-dimensional electrophoresis showed the absence of detectable normally assembled GENE in the inner mitochondrial membrane. These findings show that the expression of the NDUFS4 gene is essential for the assembly of a functional GENE. | NO-RELATIONSHIP |
| Glucagon-like peptide (GLP)-2 reduces chemotherapy-associated mortality and enhances cell survival in cells expressing a transfected GENE. Chemotherapeutic agents produce cytotoxicity via induction of apoptosis and cell cycle arrest. Rapidly proliferating cells in the bone marrow and intestinal crypts are highly susceptible to chemotherapy, and damage to these cellular compartments may preclude maximally effective chemotherapy administration. Glucagon-like peptide (GLP)-2 is an enteroendocrine-derived regulatory peptide that inhibits crypt cell apoptosis after administration of agents that damage the intestinal epithelium. We report here that a human degradation-resistant GLP-2 analogue, h[Gly2]-GLP-2 significantly improves survival, reduces bacteremia, attenuates epithelial injury, and inhibits crypt apoptosis in the murine gastrointestinal tract after administration of topoisomerase I inhibitor irinotecan hydrochloride or the antimetabolite 5-fluorouracil. h[Gly2]-GLP-2 significantly improved survival and reduced weight loss but did not impair chemotherapy effectiveness in tumor-bearing mice treated with cyclical irinotecan. Furthermore, h[CHEMICAL]-GLP-2 reduced chemotherapy-induced apoptosis, decreased activation of caspase-8 and -3, and inhibited poly(ADP-ribose) polymerase cleavage in heterologous cells transfected with the GENE. These observations demonstrate that the antiapoptotic effects of GLP-2 on intestinal crypt cells may be useful for the attenuation of chemotherapy-induced intestinal mucositis. | INHIBITOR |
| Glucagon-like peptide (GLP)-2 reduces chemotherapy-associated mortality and enhances cell survival in cells expressing a transfected GENE receptor. Chemotherapeutic agents produce cytotoxicity via induction of apoptosis and cell cycle arrest. Rapidly proliferating cells in the bone marrow and intestinal crypts are highly susceptible to chemotherapy, and damage to these cellular compartments may preclude maximally effective chemotherapy administration. Glucagon-like peptide (GLP)-2 is an enteroendocrine-derived regulatory peptide that inhibits crypt cell apoptosis after administration of agents that damage the intestinal epithelium. We report here that a human degradation-resistant GENE analogue, h[CHEMICAL]-GLP-2 significantly improves survival, reduces bacteremia, attenuates epithelial injury, and inhibits crypt apoptosis in the murine gastrointestinal tract after administration of topoisomerase I inhibitor irinotecan hydrochloride or the antimetabolite 5-fluorouracil. h[Gly2]-GLP-2 significantly improved survival and reduced weight loss but did not impair chemotherapy effectiveness in tumor-bearing mice treated with cyclical irinotecan. Furthermore, h[Gly2]-GLP-2 reduced chemotherapy-induced apoptosis, decreased activation of caspase-8 and -3, and inhibited poly(ADP-ribose) polymerase cleavage in heterologous cells transfected with the GENE receptor. These observations demonstrate that the antiapoptotic effects of GENE on intestinal crypt cells may be useful for the attenuation of chemotherapy-induced intestinal mucositis. | INHIBITOR |
| Glucagon-like peptide (GLP)-2 reduces chemotherapy-associated mortality and enhances cell survival in cells expressing a transfected GLP-2 receptor. Chemotherapeutic agents produce cytotoxicity via induction of apoptosis and cell cycle arrest. Rapidly proliferating cells in the bone marrow and intestinal crypts are highly susceptible to chemotherapy, and damage to these cellular compartments may preclude maximally effective chemotherapy administration. Glucagon-like peptide (GLP)-2 is an enteroendocrine-derived regulatory peptide that inhibits crypt cell apoptosis after administration of agents that damage the intestinal epithelium. We report here that a human degradation-resistant GLP-2 analogue, h[Gly2]-GLP-2 significantly improves survival, reduces bacteremia, attenuates epithelial injury, and inhibits crypt apoptosis in the murine gastrointestinal tract after administration of topoisomerase I inhibitor irinotecan hydrochloride or the antimetabolite 5-fluorouracil. h[Gly2]-GLP-2 significantly improved survival and reduced weight loss but did not impair chemotherapy effectiveness in tumor-bearing mice treated with cyclical irinotecan. Furthermore, h[CHEMICAL]-GLP-2 reduced chemotherapy-induced apoptosis, decreased activation of caspase-8 and -3, and inhibited GENE cleavage in heterologous cells transfected with the GLP-2 receptor. These observations demonstrate that the antiapoptotic effects of GLP-2 on intestinal crypt cells may be useful for the attenuation of chemotherapy-induced intestinal mucositis. | INHIBITOR |
| Glucagon-like peptide (GLP)-2 reduces chemotherapy-associated mortality and enhances cell survival in cells expressing a transfected GLP-2 receptor. Chemotherapeutic agents produce cytotoxicity via induction of apoptosis and cell cycle arrest. Rapidly proliferating cells in the bone marrow and intestinal crypts are highly susceptible to chemotherapy, and damage to these cellular compartments may preclude maximally effective chemotherapy administration. Glucagon-like peptide (GLP)-2 is an enteroendocrine-derived regulatory peptide that inhibits crypt cell apoptosis after administration of agents that damage the intestinal epithelium. We report here that a human degradation-resistant GLP-2 analogue, h[Gly2]-GLP-2 significantly improves survival, reduces bacteremia, attenuates epithelial injury, and inhibits crypt apoptosis in the murine gastrointestinal tract after administration of GENE inhibitor CHEMICAL or the antimetabolite 5-fluorouracil. h[Gly2]-GLP-2 significantly improved survival and reduced weight loss but did not impair chemotherapy effectiveness in tumor-bearing mice treated with cyclical irinotecan. Furthermore, h[Gly2]-GLP-2 reduced chemotherapy-induced apoptosis, decreased activation of caspase-8 and -3, and inhibited poly(ADP-ribose) polymerase cleavage in heterologous cells transfected with the GLP-2 receptor. These observations demonstrate that the antiapoptotic effects of GLP-2 on intestinal crypt cells may be useful for the attenuation of chemotherapy-induced intestinal mucositis. | INHIBITOR |
| On the relationship between the GENE and the reinforcing effects of local anesthetics in rhesus monkeys: practical and theoretical concerns. RATIONALE: Drugs that are self-administered appear to vary in their potency and effectiveness as positive reinforcers. Understanding mechanisms that determine relative effectiveness of drugs as reinforcers will enhance our understanding of drug abuse. OBJECTIVES: The hypothesis of the present study was that differences among GENE (DAT) ligands in potency and effectiveness as a positive reinforcers were related to potency and effectiveness as CHEMICAL uptake inhibitors. Accordingly, self-administration of a group of local anesthetics that are DAT ligands was compared to their effects as CHEMICAL uptake blockers in vitro in brain tissue. METHODS: Rhesus monkeys were allowed to self-administer cocaine and other local anesthetics i.v. under a progressive-ratio schedule. The same compounds were compared in standard in vitro CHEMICAL uptake assays using monkey caudate tissue. RESULTS: The rank order of both potency and effectiveness as reinforcers was cocaine > dimethocaine > procaine > chloroprocaine. Tetracaine did not maintain self-administration. For inhibiting CHEMICAL uptake, the potency order was cocaine > dimethocaine > tetracaine > procaine > chloro-procaine. At maximum, these compounds were equally effective in blocking CHEMICAL uptake. Lidocaine did not inhibit CHEMICAL uptake. CONCLUSIONS: The potency of local anesthetics as positive reinforcers is likely related to their potency as CHEMICAL uptake inhibitors. Variation in their effectiveness as positive reinforcers was not a function of differences in effectiveness as CHEMICAL uptake blockers, but may be related to relative potency over the concentrations that are achieved in vivo. Effects at sodium channels may limit the reinforcing effects of local anesthetics. | SUBSTRATE |
| On the relationship between the dopamine transporter and the reinforcing effects of local anesthetics in rhesus monkeys: practical and theoretical concerns. RATIONALE: Drugs that are self-administered appear to vary in their potency and effectiveness as positive reinforcers. Understanding mechanisms that determine relative effectiveness of drugs as reinforcers will enhance our understanding of drug abuse. OBJECTIVES: The hypothesis of the present study was that differences among dopamine transporter (GENE) ligands in potency and effectiveness as a positive reinforcers were related to potency and effectiveness as CHEMICAL uptake inhibitors. Accordingly, self-administration of a group of local anesthetics that are GENE ligands was compared to their effects as CHEMICAL uptake blockers in vitro in brain tissue. METHODS: Rhesus monkeys were allowed to self-administer cocaine and other local anesthetics i.v. under a progressive-ratio schedule. The same compounds were compared in standard in vitro CHEMICAL uptake assays using monkey caudate tissue. RESULTS: The rank order of both potency and effectiveness as reinforcers was cocaine > dimethocaine > procaine > chloroprocaine. Tetracaine did not maintain self-administration. For inhibiting CHEMICAL uptake, the potency order was cocaine > dimethocaine > tetracaine > procaine > chloro-procaine. At maximum, these compounds were equally effective in blocking CHEMICAL uptake. Lidocaine did not inhibit CHEMICAL uptake. CONCLUSIONS: The potency of local anesthetics as positive reinforcers is likely related to their potency as CHEMICAL uptake inhibitors. Variation in their effectiveness as positive reinforcers was not a function of differences in effectiveness as CHEMICAL uptake blockers, but may be related to relative potency over the concentrations that are achieved in vivo. Effects at sodium channels may limit the reinforcing effects of local anesthetics. | SUBSTRATE |
| Contribution of the Na+-K+-2Cl- cotransporter GENE to Cl- secretion in rat OMCD. In rat kidney the "secretory" isoform of the Na+-K+-2Cl- cotransporter (NKCC1) localizes to the basolateral membrane of the alpha-intercalated cell. The purpose of this study was to determine whether rat outer medullary collecting duct (OMCD) secretes Cl- and whether transepithelial Cl- transport occurs, in part, through Cl- uptake across the basolateral membrane mediated by GENE in series with Cl- efflux across the apical membrane. OMCD tubules from rats treated with CHEMICAL were perfused in vitro in symmetrical HCO/CO2-buffered solutions. Cl- secretion was observed in this segment, accompanied by a lumen positive transepithelial potential. Bumetanide (100 microM), when added to the bath, reduced Cl- secretion by 78%, although the lumen positive transepithelial potential and fluid flux were unchanged. Bumetanide-sensitive Cl- secretion was dependent on extracellular Na+ and either K+ or NH, consistent with the ion dependency of NKCC1-mediated Cl- transport. In conclusion, OMCD tubules from CHEMICAL-treated rats secrete Cl- into the luminal fluid through GENE-mediated Cl- uptake across the basolateral membrane in series with Cl- efflux across the apical membrane. The physiological role of NKCC1-mediated Cl- uptake remains to be determined. However, the role of GENE in the process of fluid secretion could not be demonstrated. | NO-RELATIONSHIP |
| Contribution of the Na+-K+-2Cl- cotransporter GENE to CHEMICAL secretion in rat OMCD. In rat kidney the "secretory" isoform of the Na+-K+-2Cl- cotransporter (NKCC1) localizes to the basolateral membrane of the alpha-intercalated cell. The purpose of this study was to determine whether rat outer medullary collecting duct (OMCD) secretes CHEMICAL and whether transepithelial CHEMICAL transport occurs, in part, through CHEMICAL uptake across the basolateral membrane mediated by GENE in series with CHEMICAL efflux across the apical membrane. OMCD tubules from rats treated with deoxycorticosterone pivalate were perfused in vitro in symmetrical HCO/CO2-buffered solutions. CHEMICAL secretion was observed in this segment, accompanied by a lumen positive transepithelial potential. Bumetanide (100 microM), when added to the bath, reduced CHEMICAL secretion by 78%, although the lumen positive transepithelial potential and fluid flux were unchanged. Bumetanide-sensitive CHEMICAL secretion was dependent on extracellular Na+ and either K+ or NH, consistent with the ion dependency of GENE-mediated CHEMICAL transport. In conclusion, OMCD tubules from deoxycorticosterone pivalate-treated rats secrete CHEMICAL into the luminal fluid through NKCC1-mediated CHEMICAL uptake across the basolateral membrane in series with CHEMICAL efflux across the apical membrane. The physiological role of NKCC1-mediated CHEMICAL uptake remains to be determined. However, the role of GENE in the process of fluid secretion could not be demonstrated. | SUBSTRATE |
| Contribution of the GENE NKCC1 to CHEMICAL secretion in rat OMCD. In rat kidney the "secretory" isoform of the GENE (NKCC1) localizes to the basolateral membrane of the alpha-intercalated cell. The purpose of this study was to determine whether rat outer medullary collecting duct (OMCD) secretes CHEMICAL and whether transepithelial CHEMICAL transport occurs, in part, through CHEMICAL uptake across the basolateral membrane mediated by NKCC1 in series with CHEMICAL efflux across the apical membrane. OMCD tubules from rats treated with deoxycorticosterone pivalate were perfused in vitro in symmetrical HCO/CO2-buffered solutions. CHEMICAL secretion was observed in this segment, accompanied by a lumen positive transepithelial potential. Bumetanide (100 microM), when added to the bath, reduced CHEMICAL secretion by 78%, although the lumen positive transepithelial potential and fluid flux were unchanged. Bumetanide-sensitive CHEMICAL secretion was dependent on extracellular Na+ and either K+ or NH, consistent with the ion dependency of NKCC1-mediated CHEMICAL transport. In conclusion, OMCD tubules from deoxycorticosterone pivalate-treated rats secrete CHEMICAL into the luminal fluid through NKCC1-mediated CHEMICAL uptake across the basolateral membrane in series with CHEMICAL efflux across the apical membrane. The physiological role of NKCC1-mediated CHEMICAL uptake remains to be determined. However, the role of NKCC1 in the process of fluid secretion could not be demonstrated. | PRODUCT-OF |
| Evidence for genetic heterogeneity of pseudohypoaldosteronism type 1: identification of a novel mutation in the human mineralocorticoid receptor in one sporadic case and no mutations in two autosomal dominant kindreds. Pseudohypoaldosteronism type 1 (PHA1) is characterized by neonatal salt wasting resistant to mineralocorticoids. There are 2 forms of PHA1: the autosomal recessive form with symptoms persisting into adulthood, caused by mutations in the amiloride-sensitive luminal sodium channel, and the autosomal dominant or sporadic form, which shows milder symptoms that remit with age. Mutations in the gene encoding the human mineralocorticoid receptor (hMR) are, at least in some patients, responsible for the latter form of PHA1. We here report the results of a genetic study in a sporadic case and in 5 affected patients from 2 families with autosomal dominant PHA1. In the sporadic case we identified a new frameshift mutation, Ins2871C, in exon 9 of the hMR gene. Family members were asymptomatic and had no mutation. This mutation is the first described in exon 9 and impairs the last 27 CHEMICAL of the GENE. In 2 kindreds with autosomal dominant PHA1 we found no mutation of the hMR gene. Our results confirm the hypothesis that autosomal dominant or sporadic PHA1 is a genetically heterogeneous disease involving other, as yet unidentified, genes. | PART-OF |
| The broad-spectrum anti-emetic activity of CHEMICAL, a novel dopamine D2, D3 and 5-HT3 receptors antagonist. The anti-emetic and pharmacological profile of CHEMICAL ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and GENE ligand, was investigated in the present study. In guinea-pig isolated colon, CHEMICAL produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a 5-HT3 receptor agonist (pA2 value of 7.04). Other 5-HT3 receptor antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>metoclopramide. In mice, CHEMICAL (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the dopamine D3 receptor agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol, which have affinity for dopamine D3 receptor, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, CHEMICAL dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of CHEMICAL significantly inhibited emesis induced by these emetogens. CHEMICAL (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, CHEMICAL is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation. | DIRECT-REGULATOR |
| The broad-spectrum anti-emetic activity of AS-8112, a novel dopamine D2, D3 and 5-HT3 receptors antagonist. The anti-emetic and pharmacological profile of AS-8112 (CHEMICAL), a novel and potent dopamine D2, D3 and GENE ligand, was investigated in the present study. In guinea-pig isolated colon, AS-8112 produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a 5-HT3 receptor agonist (pA2 value of 7.04). Other 5-HT3 receptor antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>metoclopramide. In mice, AS-8112 (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the dopamine D3 receptor agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol, which have affinity for dopamine D3 receptor, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, AS-8112 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of AS-8112 significantly inhibited emesis induced by these emetogens. AS-8112 (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, AS-8112 is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation. | DIRECT-REGULATOR |
| The broad-spectrum anti-emetic activity of AS-8112, a novel dopamine D2, D3 and 5-HT3 receptors antagonist. The anti-emetic and pharmacological profile of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study. In guinea-pig isolated colon, AS-8112 produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a 5-HT3 receptor agonist (pA2 value of 7.04). Other 5-HT3 receptor antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>metoclopramide. In mice, AS-8112 (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the GENE agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). CHEMICAL and haloperidol, which have affinity for GENE, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, AS-8112 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of AS-8112 significantly inhibited emesis induced by these emetogens. AS-8112 (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, AS-8112 is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation. | DIRECT-REGULATOR |
| The broad-spectrum anti-emetic activity of AS-8112, a novel dopamine D2, D3 and 5-HT3 receptors antagonist. The anti-emetic and pharmacological profile of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study. In guinea-pig isolated colon, AS-8112 produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a 5-HT3 receptor agonist (pA2 value of 7.04). Other 5-HT3 receptor antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>metoclopramide. In mice, AS-8112 (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the GENE agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). Domperidone and CHEMICAL, which have affinity for GENE, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, AS-8112 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of AS-8112 significantly inhibited emesis induced by these emetogens. AS-8112 (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, AS-8112 is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation. | DIRECT-REGULATOR |
| The broad-spectrum anti-emetic activity of AS-8112, a novel dopamine D2, D3 and 5-HT3 receptors antagonist. The anti-emetic and pharmacological profile of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study. In guinea-pig isolated colon, AS-8112 produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a 5-HT3 receptor agonist (pA2 value of 7.04). Other 5-HT3 receptor antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>metoclopramide. In mice, AS-8112 (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the GENE agonist; CHEMICAL (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol, which have affinity for GENE, also inhibited CHEMICAL-induced hypothermia. In ferrets or dogs, AS-8112 dose-dependently inhibited emesis induced by CHEMICAL, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of AS-8112 significantly inhibited emesis induced by these emetogens. AS-8112 (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, AS-8112 is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation. | ACTIVATOR |
| The broad-spectrum anti-emetic activity of CHEMICAL, a novel dopamine D2, D3 and 5-HT3 receptors antagonist. The anti-emetic and pharmacological profile of CHEMICAL ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study. In guinea-pig isolated colon, CHEMICAL produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a 5-HT3 receptor agonist (pA2 value of 7.04). Other 5-HT3 receptor antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>metoclopramide. In mice, CHEMICAL (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the GENE agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol, which have affinity for GENE, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, CHEMICAL dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of CHEMICAL significantly inhibited emesis induced by these emetogens. CHEMICAL (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, CHEMICAL is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation. | INHIBITOR |
| The broad-spectrum anti-emetic activity of AS-8112, a novel dopamine D2, D3 and 5-HT3 receptors antagonist. The anti-emetic and pharmacological profile of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study. In guinea-pig isolated colon, AS-8112 produced a rightward shift of the concentration-response curves of CHEMICAL, a GENE agonist (pA2 value of 7.04). Other GENE antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>metoclopramide. In mice, AS-8112 (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the dopamine D3 receptor agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol, which have affinity for dopamine D3 receptor, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, AS-8112 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of AS-8112 significantly inhibited emesis induced by these emetogens. AS-8112 (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, AS-8112 is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation. | ACTIVATOR |
| The broad-spectrum anti-emetic activity of AS-8112, a novel dopamine D2, D3 and 5-HT3 receptors antagonist. The anti-emetic and pharmacological profile of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study. In guinea-pig isolated colon, AS-8112 produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a 5-HT3 receptor agonist (pA2 value of 7.04). Other 5-HT3 receptor antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>metoclopramide. In mice, AS-8112 (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the GENE agonist; R(+)-7-OH-DPAT (CHEMICAL) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol, which have affinity for GENE, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, AS-8112 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of AS-8112 significantly inhibited emesis induced by these emetogens. AS-8112 (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, AS-8112 is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation. | ACTIVATOR |
| The broad-spectrum anti-emetic activity of CHEMICAL, a novel dopamine D2, D3 and 5-HT3 receptors antagonist. The anti-emetic and pharmacological profile of CHEMICAL ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study. In guinea-pig isolated colon, CHEMICAL produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a GENE agonist (pA2 value of 7.04). Other GENE antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>metoclopramide. In mice, CHEMICAL (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the dopamine D3 receptor agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol, which have affinity for dopamine D3 receptor, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, CHEMICAL dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of CHEMICAL significantly inhibited emesis induced by these emetogens. CHEMICAL (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, CHEMICAL is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation. | ACTIVATOR |
| The broad-spectrum anti-emetic activity of AS-8112, a novel dopamine D2, D3 and 5-HT3 receptors antagonist. The anti-emetic and pharmacological profile of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study. In guinea-pig isolated colon, AS-8112 produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a GENE agonist (pA2 value of 7.04). Other GENE antagonists also produced such a shift in the following antagonistic-potency order: CHEMICAL> ondansetron=AS-8112>>metoclopramide. In mice, AS-8112 (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the dopamine D3 receptor agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol, which have affinity for dopamine D3 receptor, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, AS-8112 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of AS-8112 significantly inhibited emesis induced by these emetogens. AS-8112 (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, AS-8112 is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation. | INHIBITOR |
| The broad-spectrum anti-emetic activity of AS-8112, a novel dopamine D2, D3 and 5-HT3 receptors antagonist. The anti-emetic and pharmacological profile of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study. In guinea-pig isolated colon, AS-8112 produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a GENE agonist (pA2 value of 7.04). Other GENE antagonists also produced such a shift in the following antagonistic-potency order: granisetron> CHEMICAL=AS-8112>>metoclopramide. In mice, AS-8112 (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the dopamine D3 receptor agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol, which have affinity for dopamine D3 receptor, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, AS-8112 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of AS-8112 significantly inhibited emesis induced by these emetogens. AS-8112 (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, AS-8112 is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation. | INHIBITOR |
| The broad-spectrum anti-emetic activity of AS-8112, a novel dopamine D2, D3 and 5-HT3 receptors antagonist. The anti-emetic and pharmacological profile of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study. In guinea-pig isolated colon, AS-8112 produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a GENE agonist (pA2 value of 7.04). Other GENE antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>CHEMICAL. In mice, AS-8112 (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the dopamine D3 receptor agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol, which have affinity for dopamine D3 receptor, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, AS-8112 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of AS-8112 significantly inhibited emesis induced by these emetogens. AS-8112 (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, AS-8112 is a potent dopamine D2, D3 and 5-HT3 receptors antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation. | INHIBITOR |
| The broad-spectrum anti-emetic activity of CHEMICAL, a novel dopamine D2, D3 and GENE antagonist. The anti-emetic and pharmacological profile of CHEMICAL ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methy lamino-3-pyridinecarboxamide.2 fumarate), a novel and potent dopamine D2, D3 and 5-hydroxytryptamine-3 (5-HT3) receptors ligand, was investigated in the present study. In guinea-pig isolated colon, CHEMICAL produced a rightward shift of the concentration-response curves of 2-methyl-5HT, a 5-HT3 receptor agonist (pA2 value of 7.04). Other 5-HT3 receptor antagonists also produced such a shift in the following antagonistic-potency order: granisetron> ondansetron=AS-8112>>metoclopramide. In mice, CHEMICAL (1.0 - 3.0 mg kg(-1) s.c.) potently inhibited hypothermia induced by the dopamine D3 receptor agonist; R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline) (0.3 mg kg(-1) s.c.). Domperidone and haloperidol, which have affinity for dopamine D3 receptor, also inhibited R(+)-7-OH-DPAT-induced hypothermia. In ferrets or dogs, CHEMICAL dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 microg kg(-1) s.c., 10.5 microg kg(-1) s.c., 14.2 microg kg(-1) i.v. and 17.6 microg kg(-1) i.v., respectively. Moreover, oral administration of CHEMICAL significantly inhibited emesis induced by these emetogens. CHEMICAL (0.3 mg kg(-1) i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin. In conclusion, CHEMICAL is a potent dopamine D2, D3 and GENE antagonist, and a novel anti-emetic agent with a broad-spectrum of anti-emetic activity. These results suggest that this compound is worthy of clinical investigation. | INHIBITOR |
| Heparin-binding exosite of factor Xa. Recent studies have indicated that the basic residues Arg(93), Lys(96), CHEMICAL(125), Arg(165), Lys(169), Lys(236), and Arg(240) (GENE numbering) constitute an exosite in the catalytic domain of factor Xa that can effectively bind heparin only if the acidic N-terminal Gla domain of the proteinase was neutralized by physiological levels of calcium. Binding of a full-length heparin chain to this site of factor Xa in the presence of calcium makes a significant contribution to acceleration of the proteinase inhibition by antithrombin through a ternary complex bridging or template mechanism. Moreover, certain basic residues of this site, particularly Arg(165) and Lys(169), play a key role in factor Va and/or prothrombin recognition by factor Xa in the prothrombinase complex. This article reviews recent structural, mutagenesis and kinetic data that lead to identification of this exosite and discusses how the binding of protein or polysaccharide cofactors to this site of factor Xa can modulate the specificity and physiological function of this key coagulant enzyme in plasma. | PART-OF |
| Heparin-binding exosite of GENE. Recent studies have indicated that the basic residues Arg(93), Lys(96), CHEMICAL(125), Arg(165), Lys(169), Lys(236), and Arg(240) (chymotrypsin numbering) constitute an exosite in the catalytic domain of GENE that can effectively bind heparin only if the acidic N-terminal Gla domain of the proteinase was neutralized by physiological levels of calcium. Binding of a full-length heparin chain to this site of GENE in the presence of calcium makes a significant contribution to acceleration of the proteinase inhibition by antithrombin through a ternary complex bridging or template mechanism. Moreover, certain basic residues of this site, particularly Arg(165) and Lys(169), play a key role in factor Va and/or prothrombin recognition by GENE in the prothrombinase complex. This article reviews recent structural, mutagenesis and kinetic data that lead to identification of this exosite and discusses how the binding of protein or polysaccharide cofactors to this site of GENE can modulate the specificity and physiological function of this key coagulant enzyme in plasma. | PART-OF |
| Heparin-binding exosite of factor Xa. Recent studies have indicated that the basic residues Arg(93), Lys(96), Arg(125), Arg(165), CHEMICAL(169), Lys(236), and Arg(240) (GENE numbering) constitute an exosite in the catalytic domain of factor Xa that can effectively bind heparin only if the acidic N-terminal Gla domain of the proteinase was neutralized by physiological levels of calcium. Binding of a full-length heparin chain to this site of factor Xa in the presence of calcium makes a significant contribution to acceleration of the proteinase inhibition by antithrombin through a ternary complex bridging or template mechanism. Moreover, certain basic residues of this site, particularly Arg(165) and Lys(169), play a key role in factor Va and/or prothrombin recognition by factor Xa in the prothrombinase complex. This article reviews recent structural, mutagenesis and kinetic data that lead to identification of this exosite and discusses how the binding of protein or polysaccharide cofactors to this site of factor Xa can modulate the specificity and physiological function of this key coagulant enzyme in plasma. | PART-OF |
| Heparin-binding exosite of GENE. Recent studies have indicated that the basic residues Arg(93), Lys(96), Arg(125), Arg(165), CHEMICAL(169), Lys(236), and Arg(240) (chymotrypsin numbering) constitute an exosite in the catalytic domain of GENE that can effectively bind heparin only if the acidic N-terminal Gla domain of the proteinase was neutralized by physiological levels of calcium. Binding of a full-length heparin chain to this site of GENE in the presence of calcium makes a significant contribution to acceleration of the proteinase inhibition by antithrombin through a ternary complex bridging or template mechanism. Moreover, certain basic residues of this site, particularly Arg(165) and Lys(169), play a key role in factor Va and/or prothrombin recognition by GENE in the prothrombinase complex. This article reviews recent structural, mutagenesis and kinetic data that lead to identification of this exosite and discusses how the binding of protein or polysaccharide cofactors to this site of GENE can modulate the specificity and physiological function of this key coagulant enzyme in plasma. | PART-OF |
| Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis. CHEMICAL is a selective cyclo-oxygenase (COX)-2 inhibitor which has little or no effect on the GENE isoenzyme at doses up to 1000 mg/day. CHEMICAL has greater selectivity for COX-2 than celecoxib, meloxicam, diclofenac and indomethacin. In well-controlled clinical trials, rofecoxib 12.5 to 500 mg/day has been evaluated for its efficacy in the treatment of osteoarthritis, acute pain and rheumatoid arthritis [lower dosages (5 to 125 mg/day) were generally used in the chronic pain indications]. In the treatment of patients with osteoarthritis, rofecoxib was more effective in providing symptomatic relief than placebo, paracetamol (acetaminophen) and celecoxib and was similar in efficacy to ibuprofen, diclofenac, naproxen and nabumetone. Overall, both the physician's assessment of disease status and the patient's assessment of response to therapy tended to favour rofecoxib. In patients with postsurgical dental pain, pain after spinal fusion or orthopaedic surgery, or primary dysmenorrhoea, rofecoxib provided more rapid and more sustained pain relief and reduced requirements for supplemental morphine use after surgery than placebo. CHEMICAL was more efficacious than celecoxib in patients with acute dental pain and pain after spinal fusion surgery, although celecoxib may have been used at a subtherapeutic dose. In comparison with traditional nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, diclofenac and naproxen sodium, rofecoxib was similar in efficacy in the treatment of acute pain. Although naproxen sodium provided more rapid pain relief than rofecoxib in patients with primary dysmenorrhoea, the reverse was true after orthopaedic surgery: rofecoxib provided more rapid pain relief and less supplemental morphine was needed. CHEMICAL was as effective as naproxen in providing symptomatic relief for over 8700 patients with rheumatoid arthritis. Compared with traditional NSAID therapy, rofecoxib had a significantly lower incidence of endoscopically confirmed gastroduodenal ulceration and, in approximately 13,000 patients with osteoarthritis and rheumatoid arthritis, a lower incidence of gastrointestinal (GI) adverse events. CHEMICAL was generally well tolerated in all indications with an overall tolerability profile similar to traditional NSAIDs. The most common adverse events in rofecoxib recipients were nausea, dizziness and headache. In conclusion, rofecoxib is at least as effective as traditional NSAID therapy in providing pain relief for both chronic and acute pain conditions. CHEMICAL provides an alternative treatment option to traditional NSAID therapy in the management of symptomatic pain relief in patients with osteoarthritis. Initial data from patients with primary dysmenorrhoea and postoperative pain are promising and further trials may confirm its place in the treatment of these indications. CHEMICAL has also shown promising results in patients with rheumatoid arthritis and is likely to become a valuable addition to current drug therapy for this patient population. Importantly, rofecoxib is associated with a lower incidence of GI adverse events than traditional NSAIDs making it a primary treatment option in patients at risk of developing GI complications or patients with chronic conditions requiring long term treatment. | NO-RELATIONSHIP |
| Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis. Rofecoxib is a selective cyclo-oxygenase (COX)-2 inhibitor which has little or no effect on the COX-1 isoenzyme at doses up to 1000 mg/day. Rofecoxib has greater selectivity for GENE than CHEMICAL, meloxicam, diclofenac and indomethacin. In well-controlled clinical trials, rofecoxib 12.5 to 500 mg/day has been evaluated for its efficacy in the treatment of osteoarthritis, acute pain and rheumatoid arthritis [lower dosages (5 to 125 mg/day) were generally used in the chronic pain indications]. In the treatment of patients with osteoarthritis, rofecoxib was more effective in providing symptomatic relief than placebo, paracetamol (acetaminophen) and CHEMICAL and was similar in efficacy to ibuprofen, diclofenac, naproxen and nabumetone. Overall, both the physician's assessment of disease status and the patient's assessment of response to therapy tended to favour rofecoxib. In patients with postsurgical dental pain, pain after spinal fusion or orthopaedic surgery, or primary dysmenorrhoea, rofecoxib provided more rapid and more sustained pain relief and reduced requirements for supplemental morphine use after surgery than placebo. Rofecoxib was more efficacious than CHEMICAL in patients with acute dental pain and pain after spinal fusion surgery, although CHEMICAL may have been used at a subtherapeutic dose. In comparison with traditional nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, diclofenac and naproxen sodium, rofecoxib was similar in efficacy in the treatment of acute pain. Although naproxen sodium provided more rapid pain relief than rofecoxib in patients with primary dysmenorrhoea, the reverse was true after orthopaedic surgery: rofecoxib provided more rapid pain relief and less supplemental morphine was needed. Rofecoxib was as effective as naproxen in providing symptomatic relief for over 8700 patients with rheumatoid arthritis. Compared with traditional NSAID therapy, rofecoxib had a significantly lower incidence of endoscopically confirmed gastroduodenal ulceration and, in approximately 13,000 patients with osteoarthritis and rheumatoid arthritis, a lower incidence of gastrointestinal (GI) adverse events. Rofecoxib was generally well tolerated in all indications with an overall tolerability profile similar to traditional NSAIDs. The most common adverse events in rofecoxib recipients were nausea, dizziness and headache. In conclusion, rofecoxib is at least as effective as traditional NSAID therapy in providing pain relief for both chronic and acute pain conditions. Rofecoxib provides an alternative treatment option to traditional NSAID therapy in the management of symptomatic pain relief in patients with osteoarthritis. Initial data from patients with primary dysmenorrhoea and postoperative pain are promising and further trials may confirm its place in the treatment of these indications. Rofecoxib has also shown promising results in patients with rheumatoid arthritis and is likely to become a valuable addition to current drug therapy for this patient population. Importantly, rofecoxib is associated with a lower incidence of GI adverse events than traditional NSAIDs making it a primary treatment option in patients at risk of developing GI complications or patients with chronic conditions requiring long term treatment. | REGULATOR |
| Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis. Rofecoxib is a selective cyclo-oxygenase (COX)-2 inhibitor which has little or no effect on the COX-1 isoenzyme at doses up to 1000 mg/day. Rofecoxib has greater selectivity for GENE than celecoxib, CHEMICAL, diclofenac and indomethacin. In well-controlled clinical trials, rofecoxib 12.5 to 500 mg/day has been evaluated for its efficacy in the treatment of osteoarthritis, acute pain and rheumatoid arthritis [lower dosages (5 to 125 mg/day) were generally used in the chronic pain indications]. In the treatment of patients with osteoarthritis, rofecoxib was more effective in providing symptomatic relief than placebo, paracetamol (acetaminophen) and celecoxib and was similar in efficacy to ibuprofen, diclofenac, naproxen and nabumetone. Overall, both the physician's assessment of disease status and the patient's assessment of response to therapy tended to favour rofecoxib. In patients with postsurgical dental pain, pain after spinal fusion or orthopaedic surgery, or primary dysmenorrhoea, rofecoxib provided more rapid and more sustained pain relief and reduced requirements for supplemental morphine use after surgery than placebo. Rofecoxib was more efficacious than celecoxib in patients with acute dental pain and pain after spinal fusion surgery, although celecoxib may have been used at a subtherapeutic dose. In comparison with traditional nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, diclofenac and naproxen sodium, rofecoxib was similar in efficacy in the treatment of acute pain. Although naproxen sodium provided more rapid pain relief than rofecoxib in patients with primary dysmenorrhoea, the reverse was true after orthopaedic surgery: rofecoxib provided more rapid pain relief and less supplemental morphine was needed. Rofecoxib was as effective as naproxen in providing symptomatic relief for over 8700 patients with rheumatoid arthritis. Compared with traditional NSAID therapy, rofecoxib had a significantly lower incidence of endoscopically confirmed gastroduodenal ulceration and, in approximately 13,000 patients with osteoarthritis and rheumatoid arthritis, a lower incidence of gastrointestinal (GI) adverse events. Rofecoxib was generally well tolerated in all indications with an overall tolerability profile similar to traditional NSAIDs. The most common adverse events in rofecoxib recipients were nausea, dizziness and headache. In conclusion, rofecoxib is at least as effective as traditional NSAID therapy in providing pain relief for both chronic and acute pain conditions. Rofecoxib provides an alternative treatment option to traditional NSAID therapy in the management of symptomatic pain relief in patients with osteoarthritis. Initial data from patients with primary dysmenorrhoea and postoperative pain are promising and further trials may confirm its place in the treatment of these indications. Rofecoxib has also shown promising results in patients with rheumatoid arthritis and is likely to become a valuable addition to current drug therapy for this patient population. Importantly, rofecoxib is associated with a lower incidence of GI adverse events than traditional NSAIDs making it a primary treatment option in patients at risk of developing GI complications or patients with chronic conditions requiring long term treatment. | REGULATOR |
| Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis. Rofecoxib is a selective cyclo-oxygenase (COX)-2 inhibitor which has little or no effect on the COX-1 isoenzyme at doses up to 1000 mg/day. Rofecoxib has greater selectivity for GENE than celecoxib, meloxicam, CHEMICAL and indomethacin. In well-controlled clinical trials, rofecoxib 12.5 to 500 mg/day has been evaluated for its efficacy in the treatment of osteoarthritis, acute pain and rheumatoid arthritis [lower dosages (5 to 125 mg/day) were generally used in the chronic pain indications]. In the treatment of patients with osteoarthritis, rofecoxib was more effective in providing symptomatic relief than placebo, paracetamol (acetaminophen) and celecoxib and was similar in efficacy to ibuprofen, CHEMICAL, naproxen and nabumetone. Overall, both the physician's assessment of disease status and the patient's assessment of response to therapy tended to favour rofecoxib. In patients with postsurgical dental pain, pain after spinal fusion or orthopaedic surgery, or primary dysmenorrhoea, rofecoxib provided more rapid and more sustained pain relief and reduced requirements for supplemental morphine use after surgery than placebo. Rofecoxib was more efficacious than celecoxib in patients with acute dental pain and pain after spinal fusion surgery, although celecoxib may have been used at a subtherapeutic dose. In comparison with traditional nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, CHEMICAL and naproxen sodium, rofecoxib was similar in efficacy in the treatment of acute pain. Although naproxen sodium provided more rapid pain relief than rofecoxib in patients with primary dysmenorrhoea, the reverse was true after orthopaedic surgery: rofecoxib provided more rapid pain relief and less supplemental morphine was needed. Rofecoxib was as effective as naproxen in providing symptomatic relief for over 8700 patients with rheumatoid arthritis. Compared with traditional NSAID therapy, rofecoxib had a significantly lower incidence of endoscopically confirmed gastroduodenal ulceration and, in approximately 13,000 patients with osteoarthritis and rheumatoid arthritis, a lower incidence of gastrointestinal (GI) adverse events. Rofecoxib was generally well tolerated in all indications with an overall tolerability profile similar to traditional NSAIDs. The most common adverse events in rofecoxib recipients were nausea, dizziness and headache. In conclusion, rofecoxib is at least as effective as traditional NSAID therapy in providing pain relief for both chronic and acute pain conditions. Rofecoxib provides an alternative treatment option to traditional NSAID therapy in the management of symptomatic pain relief in patients with osteoarthritis. Initial data from patients with primary dysmenorrhoea and postoperative pain are promising and further trials may confirm its place in the treatment of these indications. Rofecoxib has also shown promising results in patients with rheumatoid arthritis and is likely to become a valuable addition to current drug therapy for this patient population. Importantly, rofecoxib is associated with a lower incidence of GI adverse events than traditional NSAIDs making it a primary treatment option in patients at risk of developing GI complications or patients with chronic conditions requiring long term treatment. | REGULATOR |
| Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis. Rofecoxib is a selective cyclo-oxygenase (COX)-2 inhibitor which has little or no effect on the COX-1 isoenzyme at doses up to 1000 mg/day. Rofecoxib has greater selectivity for GENE than celecoxib, meloxicam, diclofenac and CHEMICAL. In well-controlled clinical trials, rofecoxib 12.5 to 500 mg/day has been evaluated for its efficacy in the treatment of osteoarthritis, acute pain and rheumatoid arthritis [lower dosages (5 to 125 mg/day) were generally used in the chronic pain indications]. In the treatment of patients with osteoarthritis, rofecoxib was more effective in providing symptomatic relief than placebo, paracetamol (acetaminophen) and celecoxib and was similar in efficacy to ibuprofen, diclofenac, naproxen and nabumetone. Overall, both the physician's assessment of disease status and the patient's assessment of response to therapy tended to favour rofecoxib. In patients with postsurgical dental pain, pain after spinal fusion or orthopaedic surgery, or primary dysmenorrhoea, rofecoxib provided more rapid and more sustained pain relief and reduced requirements for supplemental morphine use after surgery than placebo. Rofecoxib was more efficacious than celecoxib in patients with acute dental pain and pain after spinal fusion surgery, although celecoxib may have been used at a subtherapeutic dose. In comparison with traditional nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, diclofenac and naproxen sodium, rofecoxib was similar in efficacy in the treatment of acute pain. Although naproxen sodium provided more rapid pain relief than rofecoxib in patients with primary dysmenorrhoea, the reverse was true after orthopaedic surgery: rofecoxib provided more rapid pain relief and less supplemental morphine was needed. Rofecoxib was as effective as naproxen in providing symptomatic relief for over 8700 patients with rheumatoid arthritis. Compared with traditional NSAID therapy, rofecoxib had a significantly lower incidence of endoscopically confirmed gastroduodenal ulceration and, in approximately 13,000 patients with osteoarthritis and rheumatoid arthritis, a lower incidence of gastrointestinal (GI) adverse events. Rofecoxib was generally well tolerated in all indications with an overall tolerability profile similar to traditional NSAIDs. The most common adverse events in rofecoxib recipients were nausea, dizziness and headache. In conclusion, rofecoxib is at least as effective as traditional NSAID therapy in providing pain relief for both chronic and acute pain conditions. Rofecoxib provides an alternative treatment option to traditional NSAID therapy in the management of symptomatic pain relief in patients with osteoarthritis. Initial data from patients with primary dysmenorrhoea and postoperative pain are promising and further trials may confirm its place in the treatment of these indications. Rofecoxib has also shown promising results in patients with rheumatoid arthritis and is likely to become a valuable addition to current drug therapy for this patient population. Importantly, rofecoxib is associated with a lower incidence of GI adverse events than traditional NSAIDs making it a primary treatment option in patients at risk of developing GI complications or patients with chronic conditions requiring long term treatment. | REGULATOR |
| Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis. CHEMICAL is a selective GENE inhibitor which has little or no effect on the COX-1 isoenzyme at doses up to 1000 mg/day. CHEMICAL has greater selectivity for COX-2 than celecoxib, meloxicam, diclofenac and indomethacin. In well-controlled clinical trials, rofecoxib 12.5 to 500 mg/day has been evaluated for its efficacy in the treatment of osteoarthritis, acute pain and rheumatoid arthritis [lower dosages (5 to 125 mg/day) were generally used in the chronic pain indications]. In the treatment of patients with osteoarthritis, rofecoxib was more effective in providing symptomatic relief than placebo, paracetamol (acetaminophen) and celecoxib and was similar in efficacy to ibuprofen, diclofenac, naproxen and nabumetone. Overall, both the physician's assessment of disease status and the patient's assessment of response to therapy tended to favour rofecoxib. In patients with postsurgical dental pain, pain after spinal fusion or orthopaedic surgery, or primary dysmenorrhoea, rofecoxib provided more rapid and more sustained pain relief and reduced requirements for supplemental morphine use after surgery than placebo. CHEMICAL was more efficacious than celecoxib in patients with acute dental pain and pain after spinal fusion surgery, although celecoxib may have been used at a subtherapeutic dose. In comparison with traditional nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, diclofenac and naproxen sodium, rofecoxib was similar in efficacy in the treatment of acute pain. Although naproxen sodium provided more rapid pain relief than rofecoxib in patients with primary dysmenorrhoea, the reverse was true after orthopaedic surgery: rofecoxib provided more rapid pain relief and less supplemental morphine was needed. CHEMICAL was as effective as naproxen in providing symptomatic relief for over 8700 patients with rheumatoid arthritis. Compared with traditional NSAID therapy, rofecoxib had a significantly lower incidence of endoscopically confirmed gastroduodenal ulceration and, in approximately 13,000 patients with osteoarthritis and rheumatoid arthritis, a lower incidence of gastrointestinal (GI) adverse events. CHEMICAL was generally well tolerated in all indications with an overall tolerability profile similar to traditional NSAIDs. The most common adverse events in rofecoxib recipients were nausea, dizziness and headache. In conclusion, rofecoxib is at least as effective as traditional NSAID therapy in providing pain relief for both chronic and acute pain conditions. CHEMICAL provides an alternative treatment option to traditional NSAID therapy in the management of symptomatic pain relief in patients with osteoarthritis. Initial data from patients with primary dysmenorrhoea and postoperative pain are promising and further trials may confirm its place in the treatment of these indications. CHEMICAL has also shown promising results in patients with rheumatoid arthritis and is likely to become a valuable addition to current drug therapy for this patient population. Importantly, rofecoxib is associated with a lower incidence of GI adverse events than traditional NSAIDs making it a primary treatment option in patients at risk of developing GI complications or patients with chronic conditions requiring long term treatment. | INHIBITOR |
| Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis. CHEMICAL is a selective cyclo-oxygenase (COX)-2 inhibitor which has little or no effect on the COX-1 isoenzyme at doses up to 1000 mg/day. CHEMICAL has greater selectivity for GENE than celecoxib, meloxicam, diclofenac and indomethacin. In well-controlled clinical trials, rofecoxib 12.5 to 500 mg/day has been evaluated for its efficacy in the treatment of osteoarthritis, acute pain and rheumatoid arthritis [lower dosages (5 to 125 mg/day) were generally used in the chronic pain indications]. In the treatment of patients with osteoarthritis, rofecoxib was more effective in providing symptomatic relief than placebo, paracetamol (acetaminophen) and celecoxib and was similar in efficacy to ibuprofen, diclofenac, naproxen and nabumetone. Overall, both the physician's assessment of disease status and the patient's assessment of response to therapy tended to favour rofecoxib. In patients with postsurgical dental pain, pain after spinal fusion or orthopaedic surgery, or primary dysmenorrhoea, rofecoxib provided more rapid and more sustained pain relief and reduced requirements for supplemental morphine use after surgery than placebo. CHEMICAL was more efficacious than celecoxib in patients with acute dental pain and pain after spinal fusion surgery, although celecoxib may have been used at a subtherapeutic dose. In comparison with traditional nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, diclofenac and naproxen sodium, rofecoxib was similar in efficacy in the treatment of acute pain. Although naproxen sodium provided more rapid pain relief than rofecoxib in patients with primary dysmenorrhoea, the reverse was true after orthopaedic surgery: rofecoxib provided more rapid pain relief and less supplemental morphine was needed. CHEMICAL was as effective as naproxen in providing symptomatic relief for over 8700 patients with rheumatoid arthritis. Compared with traditional NSAID therapy, rofecoxib had a significantly lower incidence of endoscopically confirmed gastroduodenal ulceration and, in approximately 13,000 patients with osteoarthritis and rheumatoid arthritis, a lower incidence of gastrointestinal (GI) adverse events. CHEMICAL was generally well tolerated in all indications with an overall tolerability profile similar to traditional NSAIDs. The most common adverse events in rofecoxib recipients were nausea, dizziness and headache. In conclusion, rofecoxib is at least as effective as traditional NSAID therapy in providing pain relief for both chronic and acute pain conditions. CHEMICAL provides an alternative treatment option to traditional NSAID therapy in the management of symptomatic pain relief in patients with osteoarthritis. Initial data from patients with primary dysmenorrhoea and postoperative pain are promising and further trials may confirm its place in the treatment of these indications. CHEMICAL has also shown promising results in patients with rheumatoid arthritis and is likely to become a valuable addition to current drug therapy for this patient population. Importantly, rofecoxib is associated with a lower incidence of GI adverse events than traditional NSAIDs making it a primary treatment option in patients at risk of developing GI complications or patients with chronic conditions requiring long term treatment. | REGULATOR |
| Clinical, biochemical and molecular genetic data in five children with Gitelman's syndrome. Gitelman's variant of Bartter's syndrome, inherited hypokalemic alkalosis, is caused by mutation in the thiazide-sensitive NaCl co-transporter (NCCT). The main clinical symptoms are: muscular weakness, carpopedal spasm, constipation and short stature. The diagnosis was suspected in five children according to clinical criteria. All patients exhibited carpopedal spasm during febrile illness, three patients had short stature. Biochemical features were: metabolic alkalosis, hypokalemia, hypomagnesemia, low GENE levels, hyperkaliuria, hypernatriuria, hypocalciuria and normoprostaglandinuria. Three patients had elevated plasma renin activity and hyperaldosteronism. Mutational analysis of the NCCT gene confirmed the diagnosis in all five patients. Different forms of therapy, CHEMICAL and magnesium substitution, spironolactone and indomethacin failed to fully correct hypokalemia and hypomagnesemia, but markedly improved growth velocity and normalized GENE levels in the three patients with short stature. During therapy, clinical symptoms disappeared. We conclude that Gitelman's syndrome is a disorder with a variable symptom profile, but can be suspected on clinical signs already in early childhood. The early diagnosis is essential in preventing complications. | GENE-CHEMICAL |
| Clinical, biochemical and molecular genetic data in five children with Gitelman's syndrome. Gitelman's variant of Bartter's syndrome, inherited hypokalemic alkalosis, is caused by mutation in the thiazide-sensitive NaCl co-transporter (NCCT). The main clinical symptoms are: muscular weakness, carpopedal spasm, constipation and short stature. The diagnosis was suspected in five children according to clinical criteria. All patients exhibited carpopedal spasm during febrile illness, three patients had short stature. Biochemical features were: metabolic alkalosis, hypokalemia, hypomagnesemia, low GENE levels, hyperkaliuria, hypernatriuria, hypocalciuria and normoprostaglandinuria. Three patients had elevated plasma renin activity and hyperaldosteronism. Mutational analysis of the NCCT gene confirmed the diagnosis in all five patients. Different forms of therapy, potassium and CHEMICAL substitution, spironolactone and indomethacin failed to fully correct hypokalemia and hypomagnesemia, but markedly improved growth velocity and normalized GENE levels in the three patients with short stature. During therapy, clinical symptoms disappeared. We conclude that Gitelman's syndrome is a disorder with a variable symptom profile, but can be suspected on clinical signs already in early childhood. The early diagnosis is essential in preventing complications. | GENE-CHEMICAL |
| Clinical, biochemical and molecular genetic data in five children with Gitelman's syndrome. Gitelman's variant of Bartter's syndrome, inherited hypokalemic alkalosis, is caused by mutation in the thiazide-sensitive NaCl co-transporter (NCCT). The main clinical symptoms are: muscular weakness, carpopedal spasm, constipation and short stature. The diagnosis was suspected in five children according to clinical criteria. All patients exhibited carpopedal spasm during febrile illness, three patients had short stature. Biochemical features were: metabolic alkalosis, hypokalemia, hypomagnesemia, low GENE levels, hyperkaliuria, hypernatriuria, hypocalciuria and normoprostaglandinuria. Three patients had elevated plasma renin activity and hyperaldosteronism. Mutational analysis of the NCCT gene confirmed the diagnosis in all five patients. Different forms of therapy, potassium and magnesium substitution, CHEMICAL and indomethacin failed to fully correct hypokalemia and hypomagnesemia, but markedly improved growth velocity and normalized GENE levels in the three patients with short stature. During therapy, clinical symptoms disappeared. We conclude that Gitelman's syndrome is a disorder with a variable symptom profile, but can be suspected on clinical signs already in early childhood. The early diagnosis is essential in preventing complications. | INDIRECT-DOWNREGULATOR |
| Clinical, biochemical and molecular genetic data in five children with Gitelman's syndrome. Gitelman's variant of Bartter's syndrome, inherited hypokalemic alkalosis, is caused by mutation in the thiazide-sensitive NaCl co-transporter (NCCT). The main clinical symptoms are: muscular weakness, carpopedal spasm, constipation and short stature. The diagnosis was suspected in five children according to clinical criteria. All patients exhibited carpopedal spasm during febrile illness, three patients had short stature. Biochemical features were: metabolic alkalosis, hypokalemia, hypomagnesemia, low GENE levels, hyperkaliuria, hypernatriuria, hypocalciuria and normoprostaglandinuria. Three patients had elevated plasma renin activity and hyperaldosteronism. Mutational analysis of the NCCT gene confirmed the diagnosis in all five patients. Different forms of therapy, potassium and magnesium substitution, spironolactone and CHEMICAL failed to fully correct hypokalemia and hypomagnesemia, but markedly improved growth velocity and normalized GENE levels in the three patients with short stature. During therapy, clinical symptoms disappeared. We conclude that Gitelman's syndrome is a disorder with a variable symptom profile, but can be suspected on clinical signs already in early childhood. The early diagnosis is essential in preventing complications. | INDIRECT-DOWNREGULATOR |
| Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat. Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of GENE. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a GENE-specific ligand, CHEMICAL, and a PPAR-alpha/-gamma coagonist, GW2331, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. Fenofibrate and GW2331 induced expression of acyl-coenzyme A (CoA) oxidase and enoyl-CoA hydratase and reduced apolipoprotein C-III and phosphoenolpyruvate carboxykinase mRNAs. CHEMICAL modestly increased apolipoprotein C-III mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and phosphoenolpyruvate carboxykinase in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as GENE in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues. | DIRECT-REGULATOR |
| Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat. CHEMICAL and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. CHEMICAL bind to the GENE, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, GW2331, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. Fenofibrate and GW2331 induced expression of acyl-coenzyme A (CoA) oxidase and enoyl-CoA hydratase and reduced apolipoprotein C-III and phosphoenolpyruvate carboxykinase mRNAs. Rosiglitazone modestly increased apolipoprotein C-III mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and phosphoenolpyruvate carboxykinase in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues. | DIRECT-REGULATOR |
| Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat. Fibrates and CHEMICAL are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and CHEMICAL are ligands of GENE. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, GW2331, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. Fenofibrate and GW2331 induced expression of acyl-coenzyme A (CoA) oxidase and enoyl-CoA hydratase and reduced apolipoprotein C-III and phosphoenolpyruvate carboxykinase mRNAs. Rosiglitazone modestly increased apolipoprotein C-III mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and phosphoenolpyruvate carboxykinase in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as GENE in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues. | DIRECT-REGULATOR |
| Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat. Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a GENE-specific compound, CHEMICAL, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, GW2331, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. CHEMICAL and GW2331 induced expression of acyl-coenzyme A (CoA) oxidase and enoyl-CoA hydratase and reduced apolipoprotein C-III and phosphoenolpyruvate carboxykinase mRNAs. Rosiglitazone modestly increased apolipoprotein C-III mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and phosphoenolpyruvate carboxykinase in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by GENE agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of GENE as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues. | DIRECT-REGULATOR |
| Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat. Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, GW2331, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. CHEMICAL and GW2331 induced expression of GENE and enoyl-CoA hydratase and reduced apolipoprotein C-III and phosphoenolpyruvate carboxykinase mRNAs. Rosiglitazone modestly increased apolipoprotein C-III mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and phosphoenolpyruvate carboxykinase in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues. | INDIRECT-UPREGULATOR |
| Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat. Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, GW2331, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. CHEMICAL and GW2331 induced expression of acyl-coenzyme A (CoA) oxidase and GENE and reduced apolipoprotein C-III and phosphoenolpyruvate carboxykinase mRNAs. Rosiglitazone modestly increased apolipoprotein C-III mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and phosphoenolpyruvate carboxykinase in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues. | INDIRECT-UPREGULATOR |
| Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat. Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, CHEMICAL, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. Fenofibrate and CHEMICAL induced expression of GENE and enoyl-CoA hydratase and reduced apolipoprotein C-III and phosphoenolpyruvate carboxykinase mRNAs. Rosiglitazone modestly increased apolipoprotein C-III mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and phosphoenolpyruvate carboxykinase in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues. | INDIRECT-UPREGULATOR |
| Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat. Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, CHEMICAL, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. Fenofibrate and CHEMICAL induced expression of acyl-coenzyme A (CoA) oxidase and GENE and reduced apolipoprotein C-III and phosphoenolpyruvate carboxykinase mRNAs. Rosiglitazone modestly increased apolipoprotein C-III mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and phosphoenolpyruvate carboxykinase in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues. | INDIRECT-UPREGULATOR |
| Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat. Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, GW2331, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. Fenofibrate and GW2331 induced expression of acyl-coenzyme A (CoA) oxidase and enoyl-CoA hydratase and reduced apolipoprotein C-III and phosphoenolpyruvate carboxykinase mRNAs. CHEMICAL modestly increased apolipoprotein C-III mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of GENE and phosphoenolpyruvate carboxykinase in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues. | INDIRECT-UPREGULATOR |
| Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat. Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, GW2331, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. Fenofibrate and GW2331 induced expression of acyl-coenzyme A (CoA) oxidase and enoyl-CoA hydratase and reduced apolipoprotein C-III and GENE mRNAs. CHEMICAL modestly increased apolipoprotein C-III mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and GENE in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues. | INDIRECT-UPREGULATOR |
| Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat. Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, GW2331, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. Fenofibrate and GW2331 induced expression of acyl-coenzyme A (CoA) oxidase and enoyl-CoA hydratase and reduced GENE and phosphoenolpyruvate carboxykinase mRNAs. CHEMICAL modestly increased GENE mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and phosphoenolpyruvate carboxykinase in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues. | INDIRECT-UPREGULATOR |
| Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat. Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, GW2331, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. CHEMICAL and GW2331 induced expression of acyl-coenzyme A (CoA) oxidase and enoyl-CoA hydratase and reduced GENE and phosphoenolpyruvate carboxykinase mRNAs. Rosiglitazone modestly increased GENE mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and phosphoenolpyruvate carboxykinase in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues. | INDIRECT-DOWNREGULATOR |
| Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat. Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, GW2331, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. CHEMICAL and GW2331 induced expression of acyl-coenzyme A (CoA) oxidase and enoyl-CoA hydratase and reduced apolipoprotein C-III and GENE mRNAs. Rosiglitazone modestly increased apolipoprotein C-III mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and GENE in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues. | INDIRECT-DOWNREGULATOR |
| Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat. Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, CHEMICAL, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. Fenofibrate and CHEMICAL induced expression of acyl-coenzyme A (CoA) oxidase and enoyl-CoA hydratase and reduced GENE and phosphoenolpyruvate carboxykinase mRNAs. Rosiglitazone modestly increased GENE mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and phosphoenolpyruvate carboxykinase in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues. | INDIRECT-DOWNREGULATOR |
| Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat. Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription. To elucidate the target genes regulated by these compounds, we treated Zucker diabetic fatty rats (ZDF) for 15 days with a PPAR-alpha-specific compound, fenofibrate, a PPAR-gamma-specific ligand, rosiglitazone, and a PPAR-alpha/-gamma coagonist, CHEMICAL, and measured the levels of several messenger RNAs (mRNAs) in liver by real-time polymerase chain reaction. All 3 compounds decreased serum glucose and triglyceride levels. Fenofibrate and CHEMICAL induced expression of acyl-coenzyme A (CoA) oxidase and enoyl-CoA hydratase and reduced apolipoprotein C-III and GENE mRNAs. Rosiglitazone modestly increased apolipoprotein C-III mRNA and had no effect on expression of the other 2 genes in the liver but increased the expression of glucose transporter 4 and GENE in adipose tissue. We identified a novel target in liver, mitogen-activated phosphokinase phosphatase 1, whose down-regulation by PPAR-alpha agonists may improve insulin sensitivity in that tissue by prolonging insulin responses. The results of these studies suggest that activation of PPAR-alpha as well as PPAR-gamma in therapy for type 2 diabetes will enhance glucose and triglyceride control by combining actions in hepatic and peripheral tissues. | INDIRECT-DOWNREGULATOR |
| Urokinase plasminogen activator and plasmin efficiently convert GENE into its active. We have previously isolated from human hemofiltrate an CHEMICAL-terminally truncated form of the GENE (HCC-1), and characterized HCC-1[9-74] as a strong agonist of CCR1, CCR5, and to a lower extent CCR3. In this study, we show that conditioned media from human tumor cell lines PC-3 and 143B contain proteolytic activities that convert HCC-1 into the [9-74] form. This activity was fully inhibited by inhibitors of urokinase-type plasminogen activator (uPA), including PA inhibitor-1, an anti-uPA mAb, and amiloride. Pure preparations of uPA processed HCC-1 with high efficiency, without further degrading HCC-1[9-74]. Plasmin could also generate HCC-1[9-74], but degraded the active product as well. The kinetics of HCC-1 cleavage by uPA and plasmin (Michaelis constant, K(m), of 0.76 +/- 0.4 microM for uPA, and 0.096 +/- 0.05 microM for plasmin; catalytic rate constant, k(cat): 3.36 +/- 0.96 s(-1) for uPA and 6 +/- 3.6 s(-1) for plasmin) are fully compatible with a role in vivo. The activation of an abundant inactive precursor into a broad-spectrum chemokine by uPA and plasmin directly links the production of uPA by numerous tumors and their ability to recruit mononuclear leukocytes, without the need for the transcriptional activation of chemokine genes. | PART-OF |
| Urokinase plasminogen activator and plasmin efficiently convert hemofiltrate CC chemokine 1 into its active. We have previously isolated from human hemofiltrate an CHEMICAL-terminally truncated form of the hemofiltrate CC chemokine 1 (GENE), and characterized HCC-1[9-74] as a strong agonist of CCR1, CCR5, and to a lower extent CCR3. In this study, we show that conditioned media from human tumor cell lines PC-3 and 143B contain proteolytic activities that convert GENE into the [9-74] form. This activity was fully inhibited by inhibitors of urokinase-type plasminogen activator (uPA), including PA inhibitor-1, an anti-uPA mAb, and amiloride. Pure preparations of uPA processed GENE with high efficiency, without further degrading HCC-1[9-74]. Plasmin could also generate HCC-1[9-74], but degraded the active product as well. The kinetics of GENE cleavage by uPA and plasmin (Michaelis constant, K(m), of 0.76 +/- 0.4 microM for uPA, and 0.096 +/- 0.05 microM for plasmin; catalytic rate constant, k(cat): 3.36 +/- 0.96 s(-1) for uPA and 6 +/- 3.6 s(-1) for plasmin) are fully compatible with a role in vivo. The activation of an abundant inactive precursor into a broad-spectrum chemokine by uPA and plasmin directly links the production of uPA by numerous tumors and their ability to recruit mononuclear leukocytes, without the need for the transcriptional activation of chemokine genes. | PART-OF |
| Cembranoid and long-chain alkanol sites on the nicotinic acetylcholine receptor and their allosteric interaction. CHEMICAL are general anesthetics which can also act as uncharged noncompetitive inhibitors of the peripheral nicotinic acetylcholine receptor (AChR) by binding to one or more specific sites on the GENE. Cembranoids are naturally occurring, uncharged noncompetitive inhibitors of peripheral and neuronal AChRs, which have no demonstrable general anesthetic activity in vivo. In this study, [3H]tenocyclidine ([3H]TCP), an analogue of the cationic noncompetitive inhibitor phencyclidine (PCP), was used to characterize the cembranoid and long-chain alkanol sites on the desensitized Torpedo californica GENE and to investigate if these sites interact. These studies confirm that there is a single cembranoid site which sterically overlaps the [3H]TCP channel site. This cembranoid site probably also overlaps the sites for the cationic noncompetitive inhibitors, procaine and quinacrine. Evidence is also presented for one or more allosteric cembranoid sites which negatively modulate cembranoid affinity for the inhibitory site. In contrast, long-chain alkanols inhibit [3H]TCP binding through an allosteric mechanism involving two or more alkanol sites which display positive cooperativity toward each other. Double inhibitor studies show that the cembranoid inhibitory site and the alkanol sites are not independent of each other but interfere allosterically with each other's inhibition of [3H]TCP binding. The simplest models consistent with the observed data are presented and discussed. | DIRECT-REGULATOR |
| CHEMICAL and long-chain alkanol sites on the GENE and their allosteric interaction. Long-chain alkanols are general anesthetics which can also act as uncharged noncompetitive inhibitors of the peripheral GENE (AChR) by binding to one or more specific sites on the AChR. Cembranoids are naturally occurring, uncharged noncompetitive inhibitors of peripheral and neuronal AChRs, which have no demonstrable general anesthetic activity in vivo. In this study, [3H]tenocyclidine ([3H]TCP), an analogue of the cationic noncompetitive inhibitor phencyclidine (PCP), was used to characterize the cembranoid and long-chain alkanol sites on the desensitized Torpedo californica AChR and to investigate if these sites interact. These studies confirm that there is a single cembranoid site which sterically overlaps the [3H]TCP channel site. This cembranoid site probably also overlaps the sites for the cationic noncompetitive inhibitors, procaine and quinacrine. Evidence is also presented for one or more allosteric cembranoid sites which negatively modulate cembranoid affinity for the inhibitory site. In contrast, long-chain alkanols inhibit [3H]TCP binding through an allosteric mechanism involving two or more alkanol sites which display positive cooperativity toward each other. Double inhibitor studies show that the cembranoid inhibitory site and the alkanol sites are not independent of each other but interfere allosterically with each other's inhibition of [3H]TCP binding. The simplest models consistent with the observed data are presented and discussed. | DIRECT-REGULATOR |
| Cembranoid and CHEMICAL sites on the GENE and their allosteric interaction. Long-chain alkanols are general anesthetics which can also act as uncharged noncompetitive inhibitors of the peripheral GENE (AChR) by binding to one or more specific sites on the AChR. Cembranoids are naturally occurring, uncharged noncompetitive inhibitors of peripheral and neuronal AChRs, which have no demonstrable general anesthetic activity in vivo. In this study, [3H]tenocyclidine ([3H]TCP), an analogue of the cationic noncompetitive inhibitor phencyclidine (PCP), was used to characterize the cembranoid and CHEMICAL sites on the desensitized Torpedo californica AChR and to investigate if these sites interact. These studies confirm that there is a single cembranoid site which sterically overlaps the [3H]TCP channel site. This cembranoid site probably also overlaps the sites for the cationic noncompetitive inhibitors, procaine and quinacrine. Evidence is also presented for one or more allosteric cembranoid sites which negatively modulate cembranoid affinity for the inhibitory site. In contrast, long-chain alkanols inhibit [3H]TCP binding through an allosteric mechanism involving two or more alkanol sites which display positive cooperativity toward each other. Double inhibitor studies show that the cembranoid inhibitory site and the alkanol sites are not independent of each other but interfere allosterically with each other's inhibition of [3H]TCP binding. The simplest models consistent with the observed data are presented and discussed. | DIRECT-REGULATOR |
| Cembranoid and long-chain alkanol sites on the GENE and their allosteric interaction. CHEMICAL are general anesthetics which can also act as uncharged noncompetitive inhibitors of the peripheral GENE (AChR) by binding to one or more specific sites on the AChR. Cembranoids are naturally occurring, uncharged noncompetitive inhibitors of peripheral and neuronal AChRs, which have no demonstrable general anesthetic activity in vivo. In this study, [3H]tenocyclidine ([3H]TCP), an analogue of the cationic noncompetitive inhibitor phencyclidine (PCP), was used to characterize the cembranoid and long-chain alkanol sites on the desensitized Torpedo californica AChR and to investigate if these sites interact. These studies confirm that there is a single cembranoid site which sterically overlaps the [3H]TCP channel site. This cembranoid site probably also overlaps the sites for the cationic noncompetitive inhibitors, procaine and quinacrine. Evidence is also presented for one or more allosteric cembranoid sites which negatively modulate cembranoid affinity for the inhibitory site. In contrast, long-chain alkanols inhibit [3H]TCP binding through an allosteric mechanism involving two or more alkanol sites which display positive cooperativity toward each other. Double inhibitor studies show that the cembranoid inhibitory site and the alkanol sites are not independent of each other but interfere allosterically with each other's inhibition of [3H]TCP binding. The simplest models consistent with the observed data are presented and discussed. | INHIBITOR |
| Cembranoid and long-chain alkanol sites on the nicotinic acetylcholine receptor and their allosteric interaction. Long-chain alkanols are general anesthetics which can also act as uncharged noncompetitive inhibitors of the peripheral nicotinic acetylcholine receptor (AChR) by binding to one or more specific sites on the AChR. CHEMICAL are naturally occurring, uncharged noncompetitive inhibitors of peripheral and neuronal GENE, which have no demonstrable general anesthetic activity in vivo. In this study, [3H]tenocyclidine ([3H]TCP), an analogue of the cationic noncompetitive inhibitor phencyclidine (PCP), was used to characterize the cembranoid and long-chain alkanol sites on the desensitized Torpedo californica AChR and to investigate if these sites interact. These studies confirm that there is a single cembranoid site which sterically overlaps the [3H]TCP channel site. This cembranoid site probably also overlaps the sites for the cationic noncompetitive inhibitors, procaine and quinacrine. Evidence is also presented for one or more allosteric cembranoid sites which negatively modulate cembranoid affinity for the inhibitory site. In contrast, long-chain alkanols inhibit [3H]TCP binding through an allosteric mechanism involving two or more alkanol sites which display positive cooperativity toward each other. Double inhibitor studies show that the cembranoid inhibitory site and the alkanol sites are not independent of each other but interfere allosterically with each other's inhibition of [3H]TCP binding. The simplest models consistent with the observed data are presented and discussed. | INHIBITOR |
| CHEMICAL, a potent suppressor of lymphoma growth by inhibition of the x(c)- cystine transporter: a new action for an old drug. Although cyst(e)ine is nutritionally a non-essential amino acid, lymphoid cells cannot synthesize it, rendering their growth dependent on uptake of cyst(e)ine from their microenvironment. Accordingly, we previously suggested that the x(c)- plasma membrane cystine transporter provided a target for lymphoid cancer therapy. Its inhibition could lead to cyst(e)ine deficiency in lymphoma cells via reduction of both their cystine uptake and cysteine supply by somatic cells. In this study, using rat Nb2 lymphoma cultures, drugs were screened for growth arrest based on x(c)- inhibition. CHEMICAL was fortuitously found to be a novel, potent inhibitor of the x(c)- transporter. It showed high rat lymphoma growth-inhibitory and lytic activity in vitro (IC50 = 0.16 mM), based specifically on inhibition of x(c)--mediated cystine uptake, in contrast to its colonic metabolites, sulfapyridine and 5-aminosalicylic acid. CHEMICAL was even more effective against human non-Hodgkin's lymphoma (DoHH2) cultures. In rats (n = 13), CHEMICAL (i.p.) markedly inhibited growth of well-developed, rapidly growing rat Nb2 lymphoma transplants without apparent side-effects. Reduced, macrophage-mediated supply of cysteine was probably involved. In five rats, 90-100% tumor growth suppression, relative to controls, was obtained. The GENE represents a novel target for CHEMICAL-like drugs with high potential for application in therapy of lymphoblastic and other malignancies dependent on extracellular cyst(e)ine. | REGULATOR |
| CHEMICAL, a potent suppressor of lymphoma growth by inhibition of the x(c)- cystine transporter: a new action for an old drug. Although cyst(e)ine is nutritionally a non-essential amino acid, lymphoid cells cannot synthesize it, rendering their growth dependent on uptake of cyst(e)ine from their microenvironment. Accordingly, we previously suggested that the x(c)- plasma membrane cystine transporter provided a target for lymphoid cancer therapy. Its inhibition could lead to cyst(e)ine deficiency in lymphoma cells via reduction of both their cystine uptake and cysteine supply by somatic cells. In this study, using rat Nb2 lymphoma cultures, drugs were screened for growth arrest based on x(c)- inhibition. CHEMICAL was fortuitously found to be a novel, potent inhibitor of the GENE. It showed high rat lymphoma growth-inhibitory and lytic activity in vitro (IC50 = 0.16 mM), based specifically on inhibition of x(c)--mediated cystine uptake, in contrast to its colonic metabolites, sulfapyridine and 5-aminosalicylic acid. CHEMICAL was even more effective against human non-Hodgkin's lymphoma (DoHH2) cultures. In rats (n = 13), sulfasalazine (i.p.) markedly inhibited growth of well-developed, rapidly growing rat Nb2 lymphoma transplants without apparent side-effects. Reduced, macrophage-mediated supply of cysteine was probably involved. In five rats, 90-100% tumor growth suppression, relative to controls, was obtained. The x(c)- cystine transporter represents a novel target for sulfasalazine-like drugs with high potential for application in therapy of lymphoblastic and other malignancies dependent on extracellular cyst(e)ine. | INHIBITOR |
| Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x(c)- cystine transporter: a new action for an old drug. Although cyst(e)ine is nutritionally a non-essential amino acid, lymphoid cells cannot synthesize it, rendering their growth dependent on uptake of cyst(e)ine from their microenvironment. Accordingly, we previously suggested that the x(c)- plasma membrane cystine transporter provided a target for lymphoid cancer therapy. Its inhibition could lead to cyst(e)ine deficiency in lymphoma cells via reduction of both their cystine uptake and cysteine supply by somatic cells. In this study, using rat Nb2 lymphoma cultures, drugs were screened for growth arrest based on x(c)- inhibition. Sulfasalazine was fortuitously found to be a novel, potent inhibitor of the x(c)- transporter. It showed high rat lymphoma growth-inhibitory and lytic activity in vitro (IC50 = 0.16 mM), based specifically on inhibition of GENE--mediated cystine uptake, in contrast to its colonic metabolites, CHEMICAL and 5-aminosalicylic acid. Sulfasalazine was even more effective against human non-Hodgkin's lymphoma (DoHH2) cultures. In rats (n = 13), sulfasalazine (i.p.) markedly inhibited growth of well-developed, rapidly growing rat Nb2 lymphoma transplants without apparent side-effects. Reduced, macrophage-mediated supply of cysteine was probably involved. In five rats, 90-100% tumor growth suppression, relative to controls, was obtained. The x(c)- cystine transporter represents a novel target for sulfasalazine-like drugs with high potential for application in therapy of lymphoblastic and other malignancies dependent on extracellular cyst(e)ine. | INHIBITOR |
| Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x(c)- cystine transporter: a new action for an old drug. Although cyst(e)ine is nutritionally a non-essential amino acid, lymphoid cells cannot synthesize it, rendering their growth dependent on uptake of cyst(e)ine from their microenvironment. Accordingly, we previously suggested that the x(c)- plasma membrane cystine transporter provided a target for lymphoid cancer therapy. Its inhibition could lead to cyst(e)ine deficiency in lymphoma cells via reduction of both their cystine uptake and cysteine supply by somatic cells. In this study, using rat Nb2 lymphoma cultures, drugs were screened for growth arrest based on x(c)- inhibition. Sulfasalazine was fortuitously found to be a novel, potent inhibitor of the x(c)- transporter. It showed high rat lymphoma growth-inhibitory and lytic activity in vitro (IC50 = 0.16 mM), based specifically on inhibition of GENE--mediated cystine uptake, in contrast to its colonic metabolites, sulfapyridine and CHEMICAL. Sulfasalazine was even more effective against human non-Hodgkin's lymphoma (DoHH2) cultures. In rats (n = 13), sulfasalazine (i.p.) markedly inhibited growth of well-developed, rapidly growing rat Nb2 lymphoma transplants without apparent side-effects. Reduced, macrophage-mediated supply of cysteine was probably involved. In five rats, 90-100% tumor growth suppression, relative to controls, was obtained. The x(c)- cystine transporter represents a novel target for sulfasalazine-like drugs with high potential for application in therapy of lymphoblastic and other malignancies dependent on extracellular cyst(e)ine. | INHIBITOR |
| Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x(c)- CHEMICAL transporter: a new action for an old drug. Although cyst(e)ine is nutritionally a non-essential amino acid, lymphoid cells cannot synthesize it, rendering their growth dependent on uptake of cyst(e)ine from their microenvironment. Accordingly, we previously suggested that the x(c)- plasma membrane CHEMICAL transporter provided a target for lymphoid cancer therapy. Its inhibition could lead to cyst(e)ine deficiency in lymphoma cells via reduction of both their CHEMICAL uptake and cysteine supply by somatic cells. In this study, using rat Nb2 lymphoma cultures, drugs were screened for growth arrest based on x(c)- inhibition. Sulfasalazine was fortuitously found to be a novel, potent inhibitor of the x(c)- transporter. It showed high rat lymphoma growth-inhibitory and lytic activity in vitro (IC50 = 0.16 mM), based specifically on inhibition of GENE--mediated CHEMICAL uptake, in contrast to its colonic metabolites, sulfapyridine and 5-aminosalicylic acid. Sulfasalazine was even more effective against human non-Hodgkin's lymphoma (DoHH2) cultures. In rats (n = 13), sulfasalazine (i.p.) markedly inhibited growth of well-developed, rapidly growing rat Nb2 lymphoma transplants without apparent side-effects. Reduced, macrophage-mediated supply of cysteine was probably involved. In five rats, 90-100% tumor growth suppression, relative to controls, was obtained. The x(c)- CHEMICAL transporter represents a novel target for sulfasalazine-like drugs with high potential for application in therapy of lymphoblastic and other malignancies dependent on extracellular cyst(e)ine. | SUBSTRATE |
| Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x(c)- cystine transporter: a new action for an old drug. Although CHEMICAL is nutritionally a non-essential amino acid, lymphoid cells cannot synthesize it, rendering their growth dependent on uptake of CHEMICAL from their microenvironment. Accordingly, we previously suggested that the x(c)- plasma membrane cystine transporter provided a target for lymphoid cancer therapy. Its inhibition could lead to CHEMICAL deficiency in lymphoma cells via reduction of both their cystine uptake and cysteine supply by somatic cells. In this study, using rat Nb2 lymphoma cultures, drugs were screened for growth arrest based on x(c)- inhibition. Sulfasalazine was fortuitously found to be a novel, potent inhibitor of the x(c)- transporter. It showed high rat lymphoma growth-inhibitory and lytic activity in vitro (IC50 = 0.16 mM), based specifically on inhibition of x(c)--mediated cystine uptake, in contrast to its colonic metabolites, sulfapyridine and 5-aminosalicylic acid. Sulfasalazine was even more effective against human non-Hodgkin's lymphoma (DoHH2) cultures. In rats (n = 13), sulfasalazine (i.p.) markedly inhibited growth of well-developed, rapidly growing rat Nb2 lymphoma transplants without apparent side-effects. Reduced, macrophage-mediated supply of cysteine was probably involved. In five rats, 90-100% tumor growth suppression, relative to controls, was obtained. The GENE represents a novel target for sulfasalazine-like drugs with high potential for application in therapy of lymphoblastic and other malignancies dependent on extracellular CHEMICAL. | SUBSTRATE |
| Advances in antihypertensive combination therapy: benefits of low-dose thiazide diuretics in conjunction with CHEMICAL, a vasopeptidase inhibitor. The preferred initial agents for the treatment of high blood pressure are low-dose thiazide diuretics, beta blockers, calcium antagonists, and angiotensin-converting enzyme (ACE) inhibitors. In high-risk patients, including those with diabetes, renal insufficiency, left ventricular dysfunction, and atherosclerosis, ACE inhibitors may have specific benefit in reducing cardiovascular morbidity and mortality. CHEMICAL, the prototypical vasopeptidase inhibitor, inhibits not only ACE but also neutral endopeptidase. Like conventional ACE inhibitors, CHEMICAL causes extracellular volume reduction and vasodilatation; moreover, it increases levels of GENE and bradykinin. Effective blood pressure control, especially in the high-risk patient, usually necessitates combination therapy. A recent study randomized 274 subjects with mild to severe hypertension (stages 1-3 diastolic blood pressure elevation) and confirmed the benefits of CHEMICAL combined with hydrochlorothiazide in patients not controlled on hydrochlorothiazide alone. The frequencies of adverse events, serious adverse events, and discontinuation attributed to adverse events were similar for CHEMICAL and placebo. Furthermore, there were no clinically significant changes in serum creatinine, potassium, or other laboratory parameters. Adding CHEMICAL to the background of hydrochlorothiazide treatment produced statistically significant additional reductions in trough diastolic and systolic blood pressures at weeks 4 and 8. | INDIRECT-UPREGULATOR |
| Advances in antihypertensive combination therapy: benefits of low-dose thiazide diuretics in conjunction with CHEMICAL, a vasopeptidase inhibitor. The preferred initial agents for the treatment of high blood pressure are low-dose thiazide diuretics, beta blockers, calcium antagonists, and angiotensin-converting enzyme (ACE) inhibitors. In high-risk patients, including those with diabetes, renal insufficiency, left ventricular dysfunction, and atherosclerosis, ACE inhibitors may have specific benefit in reducing cardiovascular morbidity and mortality. CHEMICAL, the prototypical vasopeptidase inhibitor, inhibits not only ACE but also neutral endopeptidase. Like conventional ACE inhibitors, CHEMICAL causes extracellular volume reduction and vasodilatation; moreover, it increases levels of atrial and brain natriuretic peptides and GENE. Effective blood pressure control, especially in the high-risk patient, usually necessitates combination therapy. A recent study randomized 274 subjects with mild to severe hypertension (stages 1-3 diastolic blood pressure elevation) and confirmed the benefits of CHEMICAL combined with hydrochlorothiazide in patients not controlled on hydrochlorothiazide alone. The frequencies of adverse events, serious adverse events, and discontinuation attributed to adverse events were similar for CHEMICAL and placebo. Furthermore, there were no clinically significant changes in serum creatinine, potassium, or other laboratory parameters. Adding CHEMICAL to the background of hydrochlorothiazide treatment produced statistically significant additional reductions in trough diastolic and systolic blood pressures at weeks 4 and 8. | INDIRECT-UPREGULATOR |
| Advances in antihypertensive combination therapy: benefits of low-dose thiazide diuretics in conjunction with CHEMICAL, a vasopeptidase inhibitor. The preferred initial agents for the treatment of high blood pressure are low-dose thiazide diuretics, beta blockers, calcium antagonists, and angiotensin-converting enzyme (ACE) inhibitors. In high-risk patients, including those with diabetes, renal insufficiency, left ventricular dysfunction, and atherosclerosis, GENE inhibitors may have specific benefit in reducing cardiovascular morbidity and mortality. CHEMICAL, the prototypical vasopeptidase inhibitor, inhibits not only GENE but also neutral endopeptidase. Like conventional GENE inhibitors, CHEMICAL causes extracellular volume reduction and vasodilatation; moreover, it increases levels of atrial and brain natriuretic peptides and bradykinin. Effective blood pressure control, especially in the high-risk patient, usually necessitates combination therapy. A recent study randomized 274 subjects with mild to severe hypertension (stages 1-3 diastolic blood pressure elevation) and confirmed the benefits of CHEMICAL combined with hydrochlorothiazide in patients not controlled on hydrochlorothiazide alone. The frequencies of adverse events, serious adverse events, and discontinuation attributed to adverse events were similar for CHEMICAL and placebo. Furthermore, there were no clinically significant changes in serum creatinine, potassium, or other laboratory parameters. Adding CHEMICAL to the background of hydrochlorothiazide treatment produced statistically significant additional reductions in trough diastolic and systolic blood pressures at weeks 4 and 8. | INHIBITOR |
| Advances in antihypertensive combination therapy: benefits of low-dose thiazide diuretics in conjunction with CHEMICAL, a GENE inhibitor. The preferred initial agents for the treatment of high blood pressure are low-dose thiazide diuretics, beta blockers, calcium antagonists, and angiotensin-converting enzyme (ACE) inhibitors. In high-risk patients, including those with diabetes, renal insufficiency, left ventricular dysfunction, and atherosclerosis, ACE inhibitors may have specific benefit in reducing cardiovascular morbidity and mortality. CHEMICAL, the prototypical GENE inhibitor, inhibits not only ACE but also neutral endopeptidase. Like conventional ACE inhibitors, CHEMICAL causes extracellular volume reduction and vasodilatation; moreover, it increases levels of atrial and brain natriuretic peptides and bradykinin. Effective blood pressure control, especially in the high-risk patient, usually necessitates combination therapy. A recent study randomized 274 subjects with mild to severe hypertension (stages 1-3 diastolic blood pressure elevation) and confirmed the benefits of CHEMICAL combined with hydrochlorothiazide in patients not controlled on hydrochlorothiazide alone. The frequencies of adverse events, serious adverse events, and discontinuation attributed to adverse events were similar for CHEMICAL and placebo. Furthermore, there were no clinically significant changes in serum creatinine, potassium, or other laboratory parameters. Adding CHEMICAL to the background of hydrochlorothiazide treatment produced statistically significant additional reductions in trough diastolic and systolic blood pressures at weeks 4 and 8. | INHIBITOR |
| Advances in antihypertensive combination therapy: benefits of low-dose thiazide diuretics in conjunction with omapatrilat, a vasopeptidase inhibitor. The preferred initial agents for the treatment of high blood pressure are low-dose thiazide diuretics, beta blockers, calcium antagonists, and angiotensin-converting enzyme (ACE) inhibitors. In high-risk patients, including those with diabetes, renal insufficiency, left ventricular dysfunction, and atherosclerosis, ACE inhibitors may have specific benefit in reducing cardiovascular morbidity and mortality. CHEMICAL, the prototypical vasopeptidase inhibitor, inhibits not only ACE but also GENE. Like conventional ACE inhibitors, omapatrilat causes extracellular volume reduction and vasodilatation; moreover, it increases levels of atrial and brain natriuretic peptides and bradykinin. Effective blood pressure control, especially in the high-risk patient, usually necessitates combination therapy. A recent study randomized 274 subjects with mild to severe hypertension (stages 1-3 diastolic blood pressure elevation) and confirmed the benefits of omapatrilat combined with hydrochlorothiazide in patients not controlled on hydrochlorothiazide alone. The frequencies of adverse events, serious adverse events, and discontinuation attributed to adverse events were similar for omapatrilat and placebo. Furthermore, there were no clinically significant changes in serum creatinine, potassium, or other laboratory parameters. Adding omapatrilat to the background of hydrochlorothiazide treatment produced statistically significant additional reductions in trough diastolic and systolic blood pressures at weeks 4 and 8. | INHIBITOR |
| Neonatal red blood cells: amiloride-insensitive Na+-H+ transport isoform would express Na+-Li+ exchange. Neonatal red cells (umbilical cord blood) were in vitro incubated in isotonic media (thiocyanate as predominant anion). This experimental condition was selected as it was known that this chaotropic anion induced activation of Na+-H+ exchange. The transport amiloride-sensitive mechanism, that decreased the acidic intracellular pH change occurring in this medium, would correspond to CHEMICAL-H+ exchange (GENE isoform). However, the Na+-Li+ exchange, also determined in the cells in the above-mentioned medium was not affected by amiloride. The present data suggest that an amiloride insensitive Na+-H+ exchange isoform would express Na+-Li+ countertransport in these cells. | SUBSTRATE |
| Neonatal red blood cells: amiloride-insensitive Na+-H+ transport isoform would express Na+-Li+ exchange. Neonatal red cells (umbilical cord blood) were in vitro incubated in isotonic media (thiocyanate as predominant anion). This experimental condition was selected as it was known that this chaotropic anion induced activation of Na+-H+ exchange. The transport amiloride-sensitive mechanism, that decreased the acidic intracellular pH change occurring in this medium, would correspond to Na+-CHEMICAL exchange (GENE isoform). However, the Na+-Li+ exchange, also determined in the cells in the above-mentioned medium was not affected by amiloride. The present data suggest that an amiloride insensitive Na+-H+ exchange isoform would express Na+-Li+ countertransport in these cells. | SUBSTRATE |
| Aspirin and salicylate bind to immunoglobulin heavy chain binding protein (BiP) and inhibit its ATPase activity in human fibroblasts. Salicylic acid (SA), an endogenous signaling molecule of plants, possesses anti-inflammatory and anti-neoplastic actions in human. Its derivative, aspirin, is the most commonly used anti-inflammatory and analgesic drug. Aspirin and sodium salicylate (salicylates) have been reported to have multiple pharmacological actions. However, it is unclear whether they bind to a cellular protein. Here, we report for the first time the purification from human fibroblasts of a approximately 78 kDa salicylate binding protein with sequence identity to immunoglobulin heavy chain binding protein (BiP). The Kd values of SA binding to crude extract and to recombinant GENE were 45.2 and 54.6 microM, respectively. GENE is a chaperone protein containing a polypeptide binding site recognizing specific heptapeptide sequence and an ATP binding site. A heptapeptide with the specific sequence displaced SA binding in a concentration-dependent manner whereas a control heptapeptide did not. CHEMICAL inhibited ATPase activity stimulated by this specific heptapeptide but did not block ATP binding or induce GENE expression. These results indicate that salicylates bind specifically to the polypeptide binding site of GENE in human cells that may interfere with folding and transport of proteins important in inflammation. | NO-RELATIONSHIP |
| CHEMICAL and salicylate bind to GENE (BiP) and inhibit its ATPase activity in human fibroblasts. Salicylic acid (SA), an endogenous signaling molecule of plants, possesses anti-inflammatory and anti-neoplastic actions in human. Its derivative, aspirin, is the most commonly used anti-inflammatory and analgesic drug. CHEMICAL and sodium salicylate (salicylates) have been reported to have multiple pharmacological actions. However, it is unclear whether they bind to a cellular protein. Here, we report for the first time the purification from human fibroblasts of a approximately 78 kDa salicylate binding protein with sequence identity to GENE (BiP). The Kd values of SA binding to crude extract and to recombinant BiP were 45.2 and 54.6 microM, respectively. BiP is a chaperone protein containing a polypeptide binding site recognizing specific heptapeptide sequence and an ATP binding site. A heptapeptide with the specific sequence displaced SA binding in a concentration-dependent manner whereas a control heptapeptide did not. Salicylates inhibited ATPase activity stimulated by this specific heptapeptide but did not block ATP binding or induce BiP expression. These results indicate that salicylates bind specifically to the polypeptide binding site of BiP in human cells that may interfere with folding and transport of proteins important in inflammation. | DIRECT-REGULATOR |
| Aspirin and CHEMICAL bind to GENE (BiP) and inhibit its ATPase activity in human fibroblasts. Salicylic acid (SA), an endogenous signaling molecule of plants, possesses anti-inflammatory and anti-neoplastic actions in human. Its derivative, aspirin, is the most commonly used anti-inflammatory and analgesic drug. Aspirin and sodium CHEMICAL (salicylates) have been reported to have multiple pharmacological actions. However, it is unclear whether they bind to a cellular protein. Here, we report for the first time the purification from human fibroblasts of a approximately 78 kDa CHEMICAL binding protein with sequence identity to GENE (BiP). The Kd values of SA binding to crude extract and to recombinant BiP were 45.2 and 54.6 microM, respectively. BiP is a chaperone protein containing a polypeptide binding site recognizing specific heptapeptide sequence and an ATP binding site. A heptapeptide with the specific sequence displaced SA binding in a concentration-dependent manner whereas a control heptapeptide did not. Salicylates inhibited ATPase activity stimulated by this specific heptapeptide but did not block ATP binding or induce BiP expression. These results indicate that salicylates bind specifically to the polypeptide binding site of BiP in human cells that may interfere with folding and transport of proteins important in inflammation. | DIRECT-REGULATOR |
| Aspirin and salicylate bind to immunoglobulin heavy chain binding protein (BiP) and inhibit its GENE activity in human fibroblasts. Salicylic acid (SA), an endogenous signaling molecule of plants, possesses anti-inflammatory and anti-neoplastic actions in human. Its derivative, aspirin, is the most commonly used anti-inflammatory and analgesic drug. Aspirin and sodium salicylate (salicylates) have been reported to have multiple pharmacological actions. However, it is unclear whether they bind to a cellular protein. Here, we report for the first time the purification from human fibroblasts of a approximately 78 kDa salicylate binding protein with sequence identity to immunoglobulin heavy chain binding protein (BiP). The Kd values of SA binding to crude extract and to recombinant BiP were 45.2 and 54.6 microM, respectively. BiP is a chaperone protein containing a polypeptide binding site recognizing specific heptapeptide sequence and an CHEMICAL binding site. A heptapeptide with the specific sequence displaced SA binding in a concentration-dependent manner whereas a control heptapeptide did not. Salicylates inhibited GENE activity stimulated by this specific heptapeptide but did not block CHEMICAL binding or induce BiP expression. These results indicate that salicylates bind specifically to the polypeptide binding site of BiP in human cells that may interfere with folding and transport of proteins important in inflammation. | DIRECT-REGULATOR |
| Aspirin and salicylate bind to immunoglobulin heavy chain binding protein (BiP) and inhibit its ATPase activity in human fibroblasts. Salicylic acid (SA), an endogenous signaling molecule of plants, possesses anti-inflammatory and anti-neoplastic actions in human. Its derivative, aspirin, is the most commonly used anti-inflammatory and analgesic drug. Aspirin and sodium salicylate (salicylates) have been reported to have multiple pharmacological actions. However, it is unclear whether they bind to a cellular protein. Here, we report for the first time the purification from human fibroblasts of a approximately 78 kDa salicylate binding protein with sequence identity to immunoglobulin heavy chain binding protein (BiP). The Kd values of CHEMICAL binding to crude extract and to recombinant GENE were 45.2 and 54.6 microM, respectively. GENE is a chaperone protein containing a polypeptide binding site recognizing specific heptapeptide sequence and an ATP binding site. A heptapeptide with the specific sequence displaced CHEMICAL binding in a concentration-dependent manner whereas a control heptapeptide did not. Salicylates inhibited ATPase activity stimulated by this specific heptapeptide but did not block ATP binding or induce GENE expression. These results indicate that salicylates bind specifically to the polypeptide binding site of GENE in human cells that may interfere with folding and transport of proteins important in inflammation. | DIRECT-REGULATOR |
| Aspirin and salicylate bind to immunoglobulin heavy chain binding protein (BiP) and inhibit its GENE activity in human fibroblasts. Salicylic acid (SA), an endogenous signaling molecule of plants, possesses anti-inflammatory and anti-neoplastic actions in human. Its derivative, aspirin, is the most commonly used anti-inflammatory and analgesic drug. Aspirin and sodium salicylate (salicylates) have been reported to have multiple pharmacological actions. However, it is unclear whether they bind to a cellular protein. Here, we report for the first time the purification from human fibroblasts of a approximately 78 kDa salicylate binding protein with sequence identity to immunoglobulin heavy chain binding protein (BiP). The Kd values of SA binding to crude extract and to recombinant BiP were 45.2 and 54.6 microM, respectively. BiP is a chaperone protein containing a polypeptide binding site recognizing specific heptapeptide sequence and an ATP binding site. A heptapeptide with the specific sequence displaced SA binding in a concentration-dependent manner whereas a control heptapeptide did not. CHEMICAL inhibited GENE activity stimulated by this specific heptapeptide but did not block ATP binding or induce BiP expression. These results indicate that salicylates bind specifically to the polypeptide binding site of BiP in human cells that may interfere with folding and transport of proteins important in inflammation. | INHIBITOR |
| CHEMICAL and salicylate bind to immunoglobulin heavy chain binding protein (BiP) and inhibit its GENE activity in human fibroblasts. Salicylic acid (SA), an endogenous signaling molecule of plants, possesses anti-inflammatory and anti-neoplastic actions in human. Its derivative, aspirin, is the most commonly used anti-inflammatory and analgesic drug. CHEMICAL and sodium salicylate (salicylates) have been reported to have multiple pharmacological actions. However, it is unclear whether they bind to a cellular protein. Here, we report for the first time the purification from human fibroblasts of a approximately 78 kDa salicylate binding protein with sequence identity to immunoglobulin heavy chain binding protein (BiP). The Kd values of SA binding to crude extract and to recombinant BiP were 45.2 and 54.6 microM, respectively. BiP is a chaperone protein containing a polypeptide binding site recognizing specific heptapeptide sequence and an ATP binding site. A heptapeptide with the specific sequence displaced SA binding in a concentration-dependent manner whereas a control heptapeptide did not. Salicylates inhibited GENE activity stimulated by this specific heptapeptide but did not block ATP binding or induce BiP expression. These results indicate that salicylates bind specifically to the polypeptide binding site of BiP in human cells that may interfere with folding and transport of proteins important in inflammation. | INHIBITOR |
| Aspirin and CHEMICAL bind to immunoglobulin heavy chain binding protein (BiP) and inhibit its GENE activity in human fibroblasts. Salicylic acid (SA), an endogenous signaling molecule of plants, possesses anti-inflammatory and anti-neoplastic actions in human. Its derivative, aspirin, is the most commonly used anti-inflammatory and analgesic drug. Aspirin and sodium CHEMICAL (salicylates) have been reported to have multiple pharmacological actions. However, it is unclear whether they bind to a cellular protein. Here, we report for the first time the purification from human fibroblasts of a approximately 78 kDa CHEMICAL binding protein with sequence identity to immunoglobulin heavy chain binding protein (BiP). The Kd values of SA binding to crude extract and to recombinant BiP were 45.2 and 54.6 microM, respectively. BiP is a chaperone protein containing a polypeptide binding site recognizing specific heptapeptide sequence and an ATP binding site. A heptapeptide with the specific sequence displaced SA binding in a concentration-dependent manner whereas a control heptapeptide did not. Salicylates inhibited GENE activity stimulated by this specific heptapeptide but did not block ATP binding or induce BiP expression. These results indicate that salicylates bind specifically to the polypeptide binding site of BiP in human cells that may interfere with folding and transport of proteins important in inflammation. | INHIBITOR |
| Compensatory changes in enzymes of arginine metabolism during renal hypertrophy in mice. The present study investigates enzyme activities of the urea cycle, transamidinase and ornithine-proline inter-conversion in the hypertrophied kidney after unilateral nephrectomy in mice. Surgical removal of the left kidney in mice led to compensatory enlargement of the right kidney after 1 and 14 days. This renal growth was associated with an increase in glomerular volume (but not number) and enlargement of the proximal convoluted tubules. The total renal protein content increased in proportion to the increase in kidney weight, but the protein per gram weight of kidney did not change. The specific activity of only GENE (OAT), the rate-limiting enzyme in the conversion of ornithine to CHEMICAL, increased in 2 weeks of hypertrophy. The specific activity of all other enzymes was unchanged. However, the total enzyme activity per kidney of all the enzymes, without exception, was elevated in the hypertrophied kidney. While the increase in total OAT activity was much more than the increase in kidney weight, all other enzymes increased more or less in proportion to the increase in renal mass. The results suggest that compensation in OAT activity to chronic reduction in renal mass was complete, but only partial in the case of other enzymes. | PRODUCT-OF |
| Compensatory changes in enzymes of arginine metabolism during renal hypertrophy in mice. The present study investigates enzyme activities of the urea cycle, transamidinase and ornithine-proline inter-conversion in the hypertrophied kidney after unilateral nephrectomy in mice. Surgical removal of the left kidney in mice led to compensatory enlargement of the right kidney after 1 and 14 days. This renal growth was associated with an increase in glomerular volume (but not number) and enlargement of the proximal convoluted tubules. The total renal protein content increased in proportion to the increase in kidney weight, but the protein per gram weight of kidney did not change. The specific activity of only ornithine aminotransferase (GENE), the rate-limiting enzyme in the conversion of ornithine to CHEMICAL, increased in 2 weeks of hypertrophy. The specific activity of all other enzymes was unchanged. However, the total enzyme activity per kidney of all the enzymes, without exception, was elevated in the hypertrophied kidney. While the increase in total GENE activity was much more than the increase in kidney weight, all other enzymes increased more or less in proportion to the increase in renal mass. The results suggest that compensation in GENE activity to chronic reduction in renal mass was complete, but only partial in the case of other enzymes. | PRODUCT-OF |
| Compensatory changes in enzymes of arginine metabolism during renal hypertrophy in mice. The present study investigates enzyme activities of the urea cycle, transamidinase and ornithine-proline inter-conversion in the hypertrophied kidney after unilateral nephrectomy in mice. Surgical removal of the left kidney in mice led to compensatory enlargement of the right kidney after 1 and 14 days. This renal growth was associated with an increase in glomerular volume (but not number) and enlargement of the proximal convoluted tubules. The total renal protein content increased in proportion to the increase in kidney weight, but the protein per gram weight of kidney did not change. The specific activity of only GENE (OAT), the rate-limiting enzyme in the conversion of CHEMICAL to proline, increased in 2 weeks of hypertrophy. The specific activity of all other enzymes was unchanged. However, the total enzyme activity per kidney of all the enzymes, without exception, was elevated in the hypertrophied kidney. While the increase in total OAT activity was much more than the increase in kidney weight, all other enzymes increased more or less in proportion to the increase in renal mass. The results suggest that compensation in OAT activity to chronic reduction in renal mass was complete, but only partial in the case of other enzymes. | SUBSTRATE |
| Compensatory changes in enzymes of arginine metabolism during renal hypertrophy in mice. The present study investigates enzyme activities of the urea cycle, transamidinase and ornithine-proline inter-conversion in the hypertrophied kidney after unilateral nephrectomy in mice. Surgical removal of the left kidney in mice led to compensatory enlargement of the right kidney after 1 and 14 days. This renal growth was associated with an increase in glomerular volume (but not number) and enlargement of the proximal convoluted tubules. The total renal protein content increased in proportion to the increase in kidney weight, but the protein per gram weight of kidney did not change. The specific activity of only CHEMICAL aminotransferase (GENE), the rate-limiting enzyme in the conversion of CHEMICAL to proline, increased in 2 weeks of hypertrophy. The specific activity of all other enzymes was unchanged. However, the total enzyme activity per kidney of all the enzymes, without exception, was elevated in the hypertrophied kidney. While the increase in total GENE activity was much more than the increase in kidney weight, all other enzymes increased more or less in proportion to the increase in renal mass. The results suggest that compensation in GENE activity to chronic reduction in renal mass was complete, but only partial in the case of other enzymes. | SUBSTRATE |
| Analgesia and COX-2 inhibition. While non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for the management of acute pain and rheumatoid arthritis, toxicity associated with chronic administration limits their benefit-to-risk relationship in many patients. A series of studies is reviewed that assesses the relationship between cytokines released at the site of tissue injury and NSAID analgesia, and the in vivo selectivity of a selective cyclooxygenase (COX)-2 inhibitor (celecoxib) in comparison to a dual COX-1/COX-2 inhibitor (ketorolac). Three replicate studies in the oral surgery model of acute pain used submucosal microdialysis sample collection for the measurement of prostaglandin E2 (PGE2; a product of both GENE and COX-2) and CHEMICAL (as a biomarker for GENE activity) with parallel assessments of pain. The time course of PGE2 production was consistent with early release due to GENE activity followed by increased production 2-3 hours after surgery, consistent with COX-2 expression. Ketorolac 30 mg at pain onset suppressed both pain and peripheral PGE2 levels. Ketorolac 1 mg either at the site of injury or intramuscularly also produced analgesia but without any effect on peripheral PGE2 levels. Celecoxib selectively suppressed PGE2 but not TxB2 at time points consistent with COX-2 activity, while producing analgesia. These studies demonstrate the ability to assess the time course and selective effects of COX-2 inhibitors in vivo and suggest that suppression of COX-2 mediated PGE2 is temporally related to NSAID analgesia. | PRODUCT-OF |
| Analgesia and GENE inhibition. While non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for the management of acute pain and rheumatoid arthritis, toxicity associated with chronic administration limits their benefit-to-risk relationship in many patients. A series of studies is reviewed that assesses the relationship between cytokines released at the site of tissue injury and NSAID analgesia, and the in vivo selectivity of a selective cyclooxygenase (COX)-2 inhibitor (celecoxib) in comparison to a dual COX-1/COX-2 inhibitor (ketorolac). Three replicate studies in the oral surgery model of acute pain used submucosal microdialysis sample collection for the measurement of prostaglandin E2 (PGE2; a product of both COX-1 and COX-2) and thromboxane B2 (as a biomarker for COX-1 activity) with parallel assessments of pain. The time course of PGE2 production was consistent with early release due to COX-1 activity followed by increased production 2-3 hours after surgery, consistent with GENE expression. Ketorolac 30 mg at pain onset suppressed both pain and peripheral PGE2 levels. Ketorolac 1 mg either at the site of injury or intramuscularly also produced analgesia but without any effect on peripheral PGE2 levels. Celecoxib selectively suppressed PGE2 but not CHEMICAL at time points consistent with GENE activity, while producing analgesia. These studies demonstrate the ability to assess the time course and selective effects of GENE inhibitors in vivo and suggest that suppression of GENE mediated PGE2 is temporally related to NSAID analgesia. | ACTIVATOR |
| Analgesia and COX-2 inhibition. While non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for the management of acute pain and rheumatoid arthritis, toxicity associated with chronic administration limits their benefit-to-risk relationship in many patients. A series of studies is reviewed that assesses the relationship between cytokines released at the site of tissue injury and NSAID analgesia, and the in vivo selectivity of a selective GENE inhibitor (CHEMICAL) in comparison to a dual COX-1/COX-2 inhibitor (ketorolac). Three replicate studies in the oral surgery model of acute pain used submucosal microdialysis sample collection for the measurement of prostaglandin E2 (PGE2; a product of both COX-1 and COX-2) and thromboxane B2 (as a biomarker for COX-1 activity) with parallel assessments of pain. The time course of PGE2 production was consistent with early release due to COX-1 activity followed by increased production 2-3 hours after surgery, consistent with COX-2 expression. Ketorolac 30 mg at pain onset suppressed both pain and peripheral PGE2 levels. Ketorolac 1 mg either at the site of injury or intramuscularly also produced analgesia but without any effect on peripheral PGE2 levels. CHEMICAL selectively suppressed PGE2 but not TxB2 at time points consistent with COX-2 activity, while producing analgesia. These studies demonstrate the ability to assess the time course and selective effects of COX-2 inhibitors in vivo and suggest that suppression of COX-2 mediated PGE2 is temporally related to NSAID analgesia. | INHIBITOR |
| Analgesia and COX-2 inhibition. While non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for the management of acute pain and rheumatoid arthritis, toxicity associated with chronic administration limits their benefit-to-risk relationship in many patients. A series of studies is reviewed that assesses the relationship between cytokines released at the site of tissue injury and NSAID analgesia, and the in vivo selectivity of a selective cyclooxygenase (COX)-2 inhibitor (celecoxib) in comparison to a dual GENE/COX-2 inhibitor (CHEMICAL). Three replicate studies in the oral surgery model of acute pain used submucosal microdialysis sample collection for the measurement of prostaglandin E2 (PGE2; a product of both GENE and COX-2) and thromboxane B2 (as a biomarker for GENE activity) with parallel assessments of pain. The time course of PGE2 production was consistent with early release due to GENE activity followed by increased production 2-3 hours after surgery, consistent with COX-2 expression. CHEMICAL 30 mg at pain onset suppressed both pain and peripheral PGE2 levels. CHEMICAL 1 mg either at the site of injury or intramuscularly also produced analgesia but without any effect on peripheral PGE2 levels. Celecoxib selectively suppressed PGE2 but not TxB2 at time points consistent with COX-2 activity, while producing analgesia. These studies demonstrate the ability to assess the time course and selective effects of COX-2 inhibitors in vivo and suggest that suppression of COX-2 mediated PGE2 is temporally related to NSAID analgesia. | INHIBITOR |
| Analgesia and GENE inhibition. While non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for the management of acute pain and rheumatoid arthritis, toxicity associated with chronic administration limits their benefit-to-risk relationship in many patients. A series of studies is reviewed that assesses the relationship between cytokines released at the site of tissue injury and NSAID analgesia, and the in vivo selectivity of a selective cyclooxygenase (COX)-2 inhibitor (celecoxib) in comparison to a dual COX-1/GENE inhibitor (CHEMICAL). Three replicate studies in the oral surgery model of acute pain used submucosal microdialysis sample collection for the measurement of prostaglandin E2 (PGE2; a product of both COX-1 and COX-2) and thromboxane B2 (as a biomarker for COX-1 activity) with parallel assessments of pain. The time course of PGE2 production was consistent with early release due to COX-1 activity followed by increased production 2-3 hours after surgery, consistent with GENE expression. CHEMICAL 30 mg at pain onset suppressed both pain and peripheral PGE2 levels. CHEMICAL 1 mg either at the site of injury or intramuscularly also produced analgesia but without any effect on peripheral PGE2 levels. Celecoxib selectively suppressed PGE2 but not TxB2 at time points consistent with GENE activity, while producing analgesia. These studies demonstrate the ability to assess the time course and selective effects of GENE inhibitors in vivo and suggest that suppression of GENE mediated PGE2 is temporally related to NSAID analgesia. | INHIBITOR |
| Analgesia and GENE inhibition. While non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for the management of acute pain and rheumatoid arthritis, toxicity associated with chronic administration limits their benefit-to-risk relationship in many patients. A series of studies is reviewed that assesses the relationship between cytokines released at the site of tissue injury and NSAID analgesia, and the in vivo selectivity of a selective cyclooxygenase (COX)-2 inhibitor (celecoxib) in comparison to a dual COX-1/COX-2 inhibitor (ketorolac). Three replicate studies in the oral surgery model of acute pain used submucosal microdialysis sample collection for the measurement of prostaglandin E2 (PGE2; a product of both COX-1 and COX-2) and thromboxane B2 (as a biomarker for COX-1 activity) with parallel assessments of pain. The time course of PGE2 production was consistent with early release due to COX-1 activity followed by increased production 2-3 hours after surgery, consistent with GENE expression. Ketorolac 30 mg at pain onset suppressed both pain and peripheral PGE2 levels. Ketorolac 1 mg either at the site of injury or intramuscularly also produced analgesia but without any effect on peripheral PGE2 levels. CHEMICAL selectively suppressed PGE2 but not TxB2 at time points consistent with GENE activity, while producing analgesia. These studies demonstrate the ability to assess the time course and selective effects of GENE inhibitors in vivo and suggest that suppression of GENE mediated PGE2 is temporally related to NSAID analgesia. | INHIBITOR |
| Analgesia and COX-2 inhibition. While non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for the management of acute pain and rheumatoid arthritis, toxicity associated with chronic administration limits their benefit-to-risk relationship in many patients. A series of studies is reviewed that assesses the relationship between cytokines released at the site of tissue injury and NSAID analgesia, and the in vivo selectivity of a selective cyclooxygenase (COX)-2 inhibitor (celecoxib) in comparison to a dual COX-1/COX-2 inhibitor (ketorolac). Three replicate studies in the oral surgery model of acute pain used submucosal microdialysis sample collection for the measurement of CHEMICAL (PGE2; a product of both GENE and COX-2) and thromboxane B2 (as a biomarker for GENE activity) with parallel assessments of pain. The time course of PGE2 production was consistent with early release due to GENE activity followed by increased production 2-3 hours after surgery, consistent with COX-2 expression. Ketorolac 30 mg at pain onset suppressed both pain and peripheral PGE2 levels. Ketorolac 1 mg either at the site of injury or intramuscularly also produced analgesia but without any effect on peripheral PGE2 levels. Celecoxib selectively suppressed PGE2 but not TxB2 at time points consistent with COX-2 activity, while producing analgesia. These studies demonstrate the ability to assess the time course and selective effects of COX-2 inhibitors in vivo and suggest that suppression of COX-2 mediated PGE2 is temporally related to NSAID analgesia. | PRODUCT-OF |
| Analgesia and GENE inhibition. While non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for the management of acute pain and rheumatoid arthritis, toxicity associated with chronic administration limits their benefit-to-risk relationship in many patients. A series of studies is reviewed that assesses the relationship between cytokines released at the site of tissue injury and NSAID analgesia, and the in vivo selectivity of a selective cyclooxygenase (COX)-2 inhibitor (celecoxib) in comparison to a dual COX-1/COX-2 inhibitor (ketorolac). Three replicate studies in the oral surgery model of acute pain used submucosal microdialysis sample collection for the measurement of CHEMICAL (PGE2; a product of both COX-1 and GENE) and thromboxane B2 (as a biomarker for COX-1 activity) with parallel assessments of pain. The time course of PGE2 production was consistent with early release due to COX-1 activity followed by increased production 2-3 hours after surgery, consistent with GENE expression. Ketorolac 30 mg at pain onset suppressed both pain and peripheral PGE2 levels. Ketorolac 1 mg either at the site of injury or intramuscularly also produced analgesia but without any effect on peripheral PGE2 levels. Celecoxib selectively suppressed PGE2 but not TxB2 at time points consistent with GENE activity, while producing analgesia. These studies demonstrate the ability to assess the time course and selective effects of GENE inhibitors in vivo and suggest that suppression of GENE mediated PGE2 is temporally related to NSAID analgesia. | PRODUCT-OF |
| Analgesia and COX-2 inhibition. While non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for the management of acute pain and rheumatoid arthritis, toxicity associated with chronic administration limits their benefit-to-risk relationship in many patients. A series of studies is reviewed that assesses the relationship between cytokines released at the site of tissue injury and NSAID analgesia, and the in vivo selectivity of a selective cyclooxygenase (COX)-2 inhibitor (celecoxib) in comparison to a dual COX-1/COX-2 inhibitor (ketorolac). Three replicate studies in the oral surgery model of acute pain used submucosal microdialysis sample collection for the measurement of prostaglandin E2 (CHEMICAL; a product of both GENE and COX-2) and thromboxane B2 (as a biomarker for GENE activity) with parallel assessments of pain. The time course of CHEMICAL production was consistent with early release due to GENE activity followed by increased production 2-3 hours after surgery, consistent with COX-2 expression. Ketorolac 30 mg at pain onset suppressed both pain and peripheral CHEMICAL levels. Ketorolac 1 mg either at the site of injury or intramuscularly also produced analgesia but without any effect on peripheral CHEMICAL levels. Celecoxib selectively suppressed CHEMICAL but not TxB2 at time points consistent with COX-2 activity, while producing analgesia. These studies demonstrate the ability to assess the time course and selective effects of COX-2 inhibitors in vivo and suggest that suppression of COX-2 mediated CHEMICAL is temporally related to NSAID analgesia. | PRODUCT-OF |
| Analgesia and GENE inhibition. While non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for the management of acute pain and rheumatoid arthritis, toxicity associated with chronic administration limits their benefit-to-risk relationship in many patients. A series of studies is reviewed that assesses the relationship between cytokines released at the site of tissue injury and NSAID analgesia, and the in vivo selectivity of a selective cyclooxygenase (COX)-2 inhibitor (celecoxib) in comparison to a dual COX-1/COX-2 inhibitor (ketorolac). Three replicate studies in the oral surgery model of acute pain used submucosal microdialysis sample collection for the measurement of prostaglandin E2 (CHEMICAL; a product of both COX-1 and GENE) and thromboxane B2 (as a biomarker for COX-1 activity) with parallel assessments of pain. The time course of CHEMICAL production was consistent with early release due to COX-1 activity followed by increased production 2-3 hours after surgery, consistent with GENE expression. Ketorolac 30 mg at pain onset suppressed both pain and peripheral CHEMICAL levels. Ketorolac 1 mg either at the site of injury or intramuscularly also produced analgesia but without any effect on peripheral CHEMICAL levels. Celecoxib selectively suppressed CHEMICAL but not TxB2 at time points consistent with GENE activity, while producing analgesia. These studies demonstrate the ability to assess the time course and selective effects of GENE inhibitors in vivo and suggest that suppression of GENE mediated CHEMICAL is temporally related to NSAID analgesia. | PRODUCT-OF |
| CHEMICAL binding to GENE transfected membranes: a potential high throughput preclinical screen. The pharmacological characteristics of CHEMICAL binding were examined in membranes prepared from human embryonic kidney (HEK293) cells stably expressing human ether-a-go-go related gene (HERG) K+ channels. The classIII antiarrhythmic compounds dofetilide, clofilium, 4'-[[1-[2-(6-methyl-2-pyridyl)ethyl]-4-piperidyl]carbonyl]methanesulfonanilide (E-4031), N-methyl-N-[2-[methyl-(1-methyl-1H-benzimidazol-2-yl)amino]ethyl]-4-[(methylsulfo nyl)amino]benzene-sulfonamide (WAY-123,398) and d-sotalol all inhibited CHEMICAL binding. In addition, the structurally unrelated compounds pimozide, terfenadine and haloperidol, all of which prolong the QT interval in man, also inhibited binding. These data indicate that a CHEMICAL binding assay using GENE membranes may help identify compounds that prolong the QT interval. | DIRECT-REGULATOR |
| Effects of the antidepressant/antipanic drug phenelzine on alanine and alanine transaminase in rat brain. 1. Phenelzine (PLZ) is an antidepressant with anxiolytic properties. Acute and chronic CHEMICAL administration increase brain GABA levels, an effect due, at least in part, to an inhibition of the activity of the GABA metabolizing enzyme, GENE (GABA-T). 2. Previous preliminary reports have indicated that acute CHEMICAL treatment also elevates brain alanine levels. As with GABA, the metabolism of alanine involves a pyridoxal phosphate-dependent transaminase. 3. In the study reported here, the effects of acute CHEMICAL treatment on the levels of various amino acids, some of which are also metabolized by pyridoxal phosphate-dependent transaminases were compared in rat whole brain. Of the 6 amino acids investigated, only GABA and alanine levels were elevated (in a time- and dose-dependent manner). 4. The elevation in brain alanine levels could be explained, at least in part, by a time- and dose-dependent inhibitory effect of CHEMICAL on alanine transaminase (ALA-T), although as with GABA the increases are higher than expected from the degree of enzyme inhibition produced. In addition, we also showed that the elevation in alanine levels and the inhibition of alanine transaminase in the brain are retained after 14 days of CHEMICAL treatment, and that CHEMICAL produces a marked increase in extracellular levels of alanine. 5. These results are discussed in terms of their relevance to synaptic function and to the pharmacological profile of CHEMICAL. | INHIBITOR |
| Effects of the antidepressant/antipanic drug phenelzine on alanine and alanine transaminase in rat brain. 1. Phenelzine (PLZ) is an antidepressant with anxiolytic properties. Acute and chronic CHEMICAL administration increase brain GABA levels, an effect due, at least in part, to an inhibition of the activity of the GABA metabolizing enzyme, GABA transaminase (GENE). 2. Previous preliminary reports have indicated that acute CHEMICAL treatment also elevates brain alanine levels. As with GABA, the metabolism of alanine involves a pyridoxal phosphate-dependent transaminase. 3. In the study reported here, the effects of acute CHEMICAL treatment on the levels of various amino acids, some of which are also metabolized by pyridoxal phosphate-dependent transaminases were compared in rat whole brain. Of the 6 amino acids investigated, only GABA and alanine levels were elevated (in a time- and dose-dependent manner). 4. The elevation in brain alanine levels could be explained, at least in part, by a time- and dose-dependent inhibitory effect of CHEMICAL on alanine transaminase (ALA-T), although as with GABA the increases are higher than expected from the degree of enzyme inhibition produced. In addition, we also showed that the elevation in alanine levels and the inhibition of alanine transaminase in the brain are retained after 14 days of CHEMICAL treatment, and that CHEMICAL produces a marked increase in extracellular levels of alanine. 5. These results are discussed in terms of their relevance to synaptic function and to the pharmacological profile of CHEMICAL. | INHIBITOR |
| Effects of the antidepressant/antipanic drug phenelzine on alanine and GENE in rat brain. 1. Phenelzine (PLZ) is an antidepressant with anxiolytic properties. Acute and chronic CHEMICAL administration increase brain GABA levels, an effect due, at least in part, to an inhibition of the activity of the GABA metabolizing enzyme, GABA transaminase (GABA-T). 2. Previous preliminary reports have indicated that acute CHEMICAL treatment also elevates brain alanine levels. As with GABA, the metabolism of alanine involves a pyridoxal phosphate-dependent transaminase. 3. In the study reported here, the effects of acute CHEMICAL treatment on the levels of various amino acids, some of which are also metabolized by pyridoxal phosphate-dependent transaminases were compared in rat whole brain. Of the 6 amino acids investigated, only GABA and alanine levels were elevated (in a time- and dose-dependent manner). 4. The elevation in brain alanine levels could be explained, at least in part, by a time- and dose-dependent inhibitory effect of CHEMICAL on GENE (ALA-T), although as with GABA the increases are higher than expected from the degree of enzyme inhibition produced. In addition, we also showed that the elevation in alanine levels and the inhibition of GENE in the brain are retained after 14 days of CHEMICAL treatment, and that CHEMICAL produces a marked increase in extracellular levels of alanine. 5. These results are discussed in terms of their relevance to synaptic function and to the pharmacological profile of CHEMICAL. | INHIBITOR |
| Effects of the antidepressant/antipanic drug phenelzine on alanine and alanine transaminase in rat brain. 1. Phenelzine (PLZ) is an antidepressant with anxiolytic properties. Acute and chronic CHEMICAL administration increase brain GABA levels, an effect due, at least in part, to an inhibition of the activity of the GABA metabolizing enzyme, GABA transaminase (GABA-T). 2. Previous preliminary reports have indicated that acute CHEMICAL treatment also elevates brain alanine levels. As with GABA, the metabolism of alanine involves a pyridoxal phosphate-dependent transaminase. 3. In the study reported here, the effects of acute CHEMICAL treatment on the levels of various amino acids, some of which are also metabolized by pyridoxal phosphate-dependent transaminases were compared in rat whole brain. Of the 6 amino acids investigated, only GABA and alanine levels were elevated (in a time- and dose-dependent manner). 4. The elevation in brain alanine levels could be explained, at least in part, by a time- and dose-dependent inhibitory effect of CHEMICAL on alanine transaminase (GENE), although as with GABA the increases are higher than expected from the degree of enzyme inhibition produced. In addition, we also showed that the elevation in alanine levels and the inhibition of alanine transaminase in the brain are retained after 14 days of CHEMICAL treatment, and that CHEMICAL produces a marked increase in extracellular levels of alanine. 5. These results are discussed in terms of their relevance to synaptic function and to the pharmacological profile of CHEMICAL. | INHIBITOR |
| Effects of the antidepressant/antipanic drug phenelzine on CHEMICAL and CHEMICAL transaminase in rat brain. 1. Phenelzine (PLZ) is an antidepressant with anxiolytic properties. Acute and chronic PLZ administration increase brain GABA levels, an effect due, at least in part, to an inhibition of the activity of the GABA metabolizing enzyme, GABA transaminase (GABA-T). 2. Previous preliminary reports have indicated that acute PLZ treatment also elevates brain CHEMICAL levels. As with GABA, the metabolism of CHEMICAL involves a GENE. 3. In the study reported here, the effects of acute PLZ treatment on the levels of various amino acids, some of which are also metabolized by pyridoxal phosphate-dependent transaminases were compared in rat whole brain. Of the 6 amino acids investigated, only GABA and CHEMICAL levels were elevated (in a time- and dose-dependent manner). 4. The elevation in brain CHEMICAL levels could be explained, at least in part, by a time- and dose-dependent inhibitory effect of PLZ on CHEMICAL transaminase (ALA-T), although as with GABA the increases are higher than expected from the degree of enzyme inhibition produced. In addition, we also showed that the elevation in CHEMICAL levels and the inhibition of CHEMICAL transaminase in the brain are retained after 14 days of PLZ treatment, and that PLZ produces a marked increase in extracellular levels of CHEMICAL. 5. These results are discussed in terms of their relevance to synaptic function and to the pharmacological profile of PLZ. | SUBSTRATE |
| Effects of the antidepressant/antipanic drug phenelzine on alanine and alanine transaminase in rat brain. 1. Phenelzine (PLZ) is an antidepressant with anxiolytic properties. Acute and chronic PLZ administration increase brain GABA levels, an effect due, at least in part, to an inhibition of the activity of the GABA metabolizing enzyme, GABA transaminase (GABA-T). 2. Previous preliminary reports have indicated that acute PLZ treatment also elevates brain alanine levels. As with GABA, the metabolism of alanine involves a pyridoxal phosphate-dependent transaminase. 3. In the study reported here, the effects of acute PLZ treatment on the levels of various CHEMICAL, some of which are also metabolized by GENE were compared in rat whole brain. Of the 6 CHEMICAL investigated, only GABA and alanine levels were elevated (in a time- and dose-dependent manner). 4. The elevation in brain alanine levels could be explained, at least in part, by a time- and dose-dependent inhibitory effect of PLZ on alanine transaminase (ALA-T), although as with GABA the increases are higher than expected from the degree of enzyme inhibition produced. In addition, we also showed that the elevation in alanine levels and the inhibition of alanine transaminase in the brain are retained after 14 days of PLZ treatment, and that PLZ produces a marked increase in extracellular levels of alanine. 5. These results are discussed in terms of their relevance to synaptic function and to the pharmacological profile of PLZ. | SUBSTRATE |
| Effects of the antidepressant/antipanic drug phenelzine on CHEMICAL and CHEMICAL transaminase in rat brain. 1. Phenelzine (PLZ) is an antidepressant with anxiolytic properties. Acute and chronic PLZ administration increase brain GABA levels, an effect due, at least in part, to an inhibition of the activity of the GABA metabolizing enzyme, GABA transaminase (GABA-T). 2. Previous preliminary reports have indicated that acute PLZ treatment also elevates brain CHEMICAL levels. As with GABA, the metabolism of CHEMICAL involves a pyridoxal phosphate-dependent transaminase. 3. In the study reported here, the effects of acute PLZ treatment on the levels of various amino acids, some of which are also metabolized by pyridoxal phosphate-dependent transaminases were compared in rat whole brain. Of the 6 amino acids investigated, only GABA and CHEMICAL levels were elevated (in a time- and dose-dependent manner). 4. The elevation in brain CHEMICAL levels could be explained, at least in part, by a time- and dose-dependent inhibitory effect of PLZ on CHEMICAL transaminase (ALA-T), although as with GABA the increases are higher than expected from the degree of enzyme inhibition produced. In addition, we also showed that the elevation in CHEMICAL levels and the inhibition of GENE in the brain are retained after 14 days of PLZ treatment, and that PLZ produces a marked increase in extracellular levels of CHEMICAL. 5. These results are discussed in terms of their relevance to synaptic function and to the pharmacological profile of PLZ. | SUBSTRATE |
| Effects of the antidepressant/antipanic drug phenelzine on CHEMICAL and CHEMICAL transaminase in rat brain. 1. Phenelzine (PLZ) is an antidepressant with anxiolytic properties. Acute and chronic PLZ administration increase brain GABA levels, an effect due, at least in part, to an inhibition of the activity of the GABA metabolizing enzyme, GABA transaminase (GABA-T). 2. Previous preliminary reports have indicated that acute PLZ treatment also elevates brain CHEMICAL levels. As with GABA, the metabolism of CHEMICAL involves a pyridoxal phosphate-dependent transaminase. 3. In the study reported here, the effects of acute PLZ treatment on the levels of various amino acids, some of which are also metabolized by pyridoxal phosphate-dependent transaminases were compared in rat whole brain. Of the 6 amino acids investigated, only GABA and CHEMICAL levels were elevated (in a time- and dose-dependent manner). 4. The elevation in brain CHEMICAL levels could be explained, at least in part, by a time- and dose-dependent inhibitory effect of PLZ on CHEMICAL transaminase (GENE), although as with GABA the increases are higher than expected from the degree of enzyme inhibition produced. In addition, we also showed that the elevation in CHEMICAL levels and the inhibition of CHEMICAL transaminase in the brain are retained after 14 days of PLZ treatment, and that PLZ produces a marked increase in extracellular levels of CHEMICAL. 5. These results are discussed in terms of their relevance to synaptic function and to the pharmacological profile of PLZ. | SUBSTRATE |
| Effects of the antidepressant/antipanic drug phenelzine on alanine and alanine transaminase in rat brain. 1. Phenelzine (PLZ) is an antidepressant with anxiolytic properties. Acute and chronic PLZ administration increase brain CHEMICAL levels, an effect due, at least in part, to an inhibition of the activity of the CHEMICAL metabolizing enzyme, GENE (GABA-T). 2. Previous preliminary reports have indicated that acute PLZ treatment also elevates brain alanine levels. As with CHEMICAL, the metabolism of alanine involves a pyridoxal phosphate-dependent transaminase. 3. In the study reported here, the effects of acute PLZ treatment on the levels of various amino acids, some of which are also metabolized by pyridoxal phosphate-dependent transaminases were compared in rat whole brain. Of the 6 amino acids investigated, only CHEMICAL and alanine levels were elevated (in a time- and dose-dependent manner). 4. The elevation in brain alanine levels could be explained, at least in part, by a time- and dose-dependent inhibitory effect of PLZ on alanine transaminase (ALA-T), although as with CHEMICAL the increases are higher than expected from the degree of enzyme inhibition produced. In addition, we also showed that the elevation in alanine levels and the inhibition of alanine transaminase in the brain are retained after 14 days of PLZ treatment, and that PLZ produces a marked increase in extracellular levels of alanine. 5. These results are discussed in terms of their relevance to synaptic function and to the pharmacological profile of PLZ. | SUBSTRATE |
| Effects of the antidepressant/antipanic drug phenelzine on alanine and alanine transaminase in rat brain. 1. Phenelzine (PLZ) is an antidepressant with anxiolytic properties. Acute and chronic PLZ administration increase brain CHEMICAL levels, an effect due, at least in part, to an inhibition of the activity of the CHEMICAL metabolizing enzyme, CHEMICAL transaminase (GENE). 2. Previous preliminary reports have indicated that acute PLZ treatment also elevates brain alanine levels. As with CHEMICAL, the metabolism of alanine involves a pyridoxal phosphate-dependent transaminase. 3. In the study reported here, the effects of acute PLZ treatment on the levels of various amino acids, some of which are also metabolized by pyridoxal phosphate-dependent transaminases were compared in rat whole brain. Of the 6 amino acids investigated, only CHEMICAL and alanine levels were elevated (in a time- and dose-dependent manner). 4. The elevation in brain alanine levels could be explained, at least in part, by a time- and dose-dependent inhibitory effect of PLZ on alanine transaminase (ALA-T), although as with CHEMICAL the increases are higher than expected from the degree of enzyme inhibition produced. In addition, we also showed that the elevation in alanine levels and the inhibition of alanine transaminase in the brain are retained after 14 days of PLZ treatment, and that PLZ produces a marked increase in extracellular levels of alanine. 5. These results are discussed in terms of their relevance to synaptic function and to the pharmacological profile of PLZ. | SUBSTRATE |
| Nicotine-induced contraction in the rat coronary artery: possible involvement of the endothelium, reactive oxygen species and COX-1 metabolites. Nicotine caused a contraction of the rat coronary artery in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME) and arachidonic acid, and did not in the absence of these agents. The present experiments were undertaken to pharmacologically characterize the nicotine-induced contraction in ring preparations of the rat coronary artery. The contraction was abolished by chemical removal of endothelium saponin. Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. GENE (COX-1) inhibitors (CHEMICAL, ketoprofen and ketrolack) attenuated the nicotine-induced contraction in a concentration-dependent manner, and cyclooxygenase-2 (COX-2) inhibitors at high concentrations (nimesulide and NS-389) slightly attenuated the contraction. A TXA2 synthetase inhibitor (OKY-046) attenuated the contraction to a small extent only at high concentrations. A TXA2 receptor antagonist (S-1452) attenuated the contraction in a concentration-dependent manner. A nicotinic receptor antagonist (hexamethonium) attenuated the contraction in part and an alpha-adrenoceptor antagonist (prazosin) nearly abolished the contraction. From these results, it was suggested that the contraction induced by nicotine in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium dependent, and involves reactive oxygen species and endothelial COX-1 metabolites of arachidonic acid. Part of the contraction is probably due to release of norepinephrine. | INHIBITOR |
| Nicotine-induced contraction in the rat coronary artery: possible involvement of the endothelium, reactive oxygen species and GENE metabolites. Nicotine caused a contraction of the rat coronary artery in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME) and arachidonic acid, and did not in the absence of these agents. The present experiments were undertaken to pharmacologically characterize the nicotine-induced contraction in ring preparations of the rat coronary artery. The contraction was abolished by chemical removal of endothelium saponin. Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. Cyclooxygenase-1 (GENE) inhibitors (CHEMICAL, ketoprofen and ketrolack) attenuated the nicotine-induced contraction in a concentration-dependent manner, and cyclooxygenase-2 (COX-2) inhibitors at high concentrations (nimesulide and NS-389) slightly attenuated the contraction. A TXA2 synthetase inhibitor (OKY-046) attenuated the contraction to a small extent only at high concentrations. A TXA2 receptor antagonist (S-1452) attenuated the contraction in a concentration-dependent manner. A nicotinic receptor antagonist (hexamethonium) attenuated the contraction in part and an alpha-adrenoceptor antagonist (prazosin) nearly abolished the contraction. From these results, it was suggested that the contraction induced by nicotine in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium dependent, and involves reactive oxygen species and endothelial GENE metabolites of arachidonic acid. Part of the contraction is probably due to release of norepinephrine. | INHIBITOR |
| Nicotine-induced contraction in the rat coronary artery: possible involvement of the endothelium, reactive oxygen species and COX-1 metabolites. Nicotine caused a contraction of the rat coronary artery in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME) and arachidonic acid, and did not in the absence of these agents. The present experiments were undertaken to pharmacologically characterize the nicotine-induced contraction in ring preparations of the rat coronary artery. The contraction was abolished by chemical removal of endothelium saponin. Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. GENE (COX-1) inhibitors (flurbiprofen, CHEMICAL and ketrolack) attenuated the nicotine-induced contraction in a concentration-dependent manner, and cyclooxygenase-2 (COX-2) inhibitors at high concentrations (nimesulide and NS-389) slightly attenuated the contraction. A TXA2 synthetase inhibitor (OKY-046) attenuated the contraction to a small extent only at high concentrations. A TXA2 receptor antagonist (S-1452) attenuated the contraction in a concentration-dependent manner. A nicotinic receptor antagonist (hexamethonium) attenuated the contraction in part and an alpha-adrenoceptor antagonist (prazosin) nearly abolished the contraction. From these results, it was suggested that the contraction induced by nicotine in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium dependent, and involves reactive oxygen species and endothelial COX-1 metabolites of arachidonic acid. Part of the contraction is probably due to release of norepinephrine. | INHIBITOR |
| Nicotine-induced contraction in the rat coronary artery: possible involvement of the endothelium, reactive oxygen species and GENE metabolites. Nicotine caused a contraction of the rat coronary artery in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME) and arachidonic acid, and did not in the absence of these agents. The present experiments were undertaken to pharmacologically characterize the nicotine-induced contraction in ring preparations of the rat coronary artery. The contraction was abolished by chemical removal of endothelium saponin. Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. Cyclooxygenase-1 (GENE) inhibitors (flurbiprofen, CHEMICAL and ketrolack) attenuated the nicotine-induced contraction in a concentration-dependent manner, and cyclooxygenase-2 (COX-2) inhibitors at high concentrations (nimesulide and NS-389) slightly attenuated the contraction. A TXA2 synthetase inhibitor (OKY-046) attenuated the contraction to a small extent only at high concentrations. A TXA2 receptor antagonist (S-1452) attenuated the contraction in a concentration-dependent manner. A nicotinic receptor antagonist (hexamethonium) attenuated the contraction in part and an alpha-adrenoceptor antagonist (prazosin) nearly abolished the contraction. From these results, it was suggested that the contraction induced by nicotine in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium dependent, and involves reactive oxygen species and endothelial GENE metabolites of arachidonic acid. Part of the contraction is probably due to release of norepinephrine. | INHIBITOR |
| Nicotine-induced contraction in the rat coronary artery: possible involvement of the endothelium, reactive oxygen species and COX-1 metabolites. Nicotine caused a contraction of the rat coronary artery in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME) and arachidonic acid, and did not in the absence of these agents. The present experiments were undertaken to pharmacologically characterize the nicotine-induced contraction in ring preparations of the rat coronary artery. The contraction was abolished by chemical removal of endothelium saponin. Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. GENE (COX-1) inhibitors (flurbiprofen, ketoprofen and CHEMICAL) attenuated the nicotine-induced contraction in a concentration-dependent manner, and cyclooxygenase-2 (COX-2) inhibitors at high concentrations (nimesulide and NS-389) slightly attenuated the contraction. A TXA2 synthetase inhibitor (OKY-046) attenuated the contraction to a small extent only at high concentrations. A TXA2 receptor antagonist (S-1452) attenuated the contraction in a concentration-dependent manner. A nicotinic receptor antagonist (hexamethonium) attenuated the contraction in part and an alpha-adrenoceptor antagonist (prazosin) nearly abolished the contraction. From these results, it was suggested that the contraction induced by nicotine in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium dependent, and involves reactive oxygen species and endothelial COX-1 metabolites of arachidonic acid. Part of the contraction is probably due to release of norepinephrine. | INHIBITOR |
| Nicotine-induced contraction in the rat coronary artery: possible involvement of the endothelium, reactive oxygen species and GENE metabolites. Nicotine caused a contraction of the rat coronary artery in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME) and arachidonic acid, and did not in the absence of these agents. The present experiments were undertaken to pharmacologically characterize the nicotine-induced contraction in ring preparations of the rat coronary artery. The contraction was abolished by chemical removal of endothelium saponin. Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. Cyclooxygenase-1 (GENE) inhibitors (flurbiprofen, ketoprofen and CHEMICAL) attenuated the nicotine-induced contraction in a concentration-dependent manner, and cyclooxygenase-2 (COX-2) inhibitors at high concentrations (nimesulide and NS-389) slightly attenuated the contraction. A TXA2 synthetase inhibitor (OKY-046) attenuated the contraction to a small extent only at high concentrations. A TXA2 receptor antagonist (S-1452) attenuated the contraction in a concentration-dependent manner. A nicotinic receptor antagonist (hexamethonium) attenuated the contraction in part and an alpha-adrenoceptor antagonist (prazosin) nearly abolished the contraction. From these results, it was suggested that the contraction induced by nicotine in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium dependent, and involves reactive oxygen species and endothelial GENE metabolites of arachidonic acid. Part of the contraction is probably due to release of norepinephrine. | INHIBITOR |
| Nicotine-induced contraction in the rat coronary artery: possible involvement of the endothelium, reactive oxygen species and COX-1 metabolites. Nicotine caused a contraction of the rat coronary artery in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME) and arachidonic acid, and did not in the absence of these agents. The present experiments were undertaken to pharmacologically characterize the nicotine-induced contraction in ring preparations of the rat coronary artery. The contraction was abolished by chemical removal of endothelium saponin. Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. Cyclooxygenase-1 (COX-1) inhibitors (flurbiprofen, ketoprofen and ketrolack) attenuated the nicotine-induced contraction in a concentration-dependent manner, and GENE (COX-2) inhibitors at high concentrations (CHEMICAL and NS-389) slightly attenuated the contraction. A TXA2 synthetase inhibitor (OKY-046) attenuated the contraction to a small extent only at high concentrations. A TXA2 receptor antagonist (S-1452) attenuated the contraction in a concentration-dependent manner. A nicotinic receptor antagonist (hexamethonium) attenuated the contraction in part and an alpha-adrenoceptor antagonist (prazosin) nearly abolished the contraction. From these results, it was suggested that the contraction induced by nicotine in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium dependent, and involves reactive oxygen species and endothelial COX-1 metabolites of arachidonic acid. Part of the contraction is probably due to release of norepinephrine. | INHIBITOR |
| Nicotine-induced contraction in the rat coronary artery: possible involvement of the endothelium, reactive oxygen species and COX-1 metabolites. Nicotine caused a contraction of the rat coronary artery in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME) and arachidonic acid, and did not in the absence of these agents. The present experiments were undertaken to pharmacologically characterize the nicotine-induced contraction in ring preparations of the rat coronary artery. The contraction was abolished by chemical removal of endothelium saponin. Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. Cyclooxygenase-1 (COX-1) inhibitors (flurbiprofen, ketoprofen and ketrolack) attenuated the nicotine-induced contraction in a concentration-dependent manner, and cyclooxygenase-2 (GENE) inhibitors at high concentrations (CHEMICAL and NS-389) slightly attenuated the contraction. A TXA2 synthetase inhibitor (OKY-046) attenuated the contraction to a small extent only at high concentrations. A TXA2 receptor antagonist (S-1452) attenuated the contraction in a concentration-dependent manner. A nicotinic receptor antagonist (hexamethonium) attenuated the contraction in part and an alpha-adrenoceptor antagonist (prazosin) nearly abolished the contraction. From these results, it was suggested that the contraction induced by nicotine in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium dependent, and involves reactive oxygen species and endothelial COX-1 metabolites of arachidonic acid. Part of the contraction is probably due to release of norepinephrine. | INHIBITOR |
| Nicotine-induced contraction in the rat coronary artery: possible involvement of the endothelium, reactive oxygen species and COX-1 metabolites. Nicotine caused a contraction of the rat coronary artery in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME) and arachidonic acid, and did not in the absence of these agents. The present experiments were undertaken to pharmacologically characterize the nicotine-induced contraction in ring preparations of the rat coronary artery. The contraction was abolished by chemical removal of endothelium saponin. Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. Cyclooxygenase-1 (COX-1) inhibitors (flurbiprofen, ketoprofen and ketrolack) attenuated the nicotine-induced contraction in a concentration-dependent manner, and GENE (COX-2) inhibitors at high concentrations (nimesulide and CHEMICAL) slightly attenuated the contraction. A TXA2 synthetase inhibitor (OKY-046) attenuated the contraction to a small extent only at high concentrations. A TXA2 receptor antagonist (S-1452) attenuated the contraction in a concentration-dependent manner. A nicotinic receptor antagonist (hexamethonium) attenuated the contraction in part and an alpha-adrenoceptor antagonist (prazosin) nearly abolished the contraction. From these results, it was suggested that the contraction induced by nicotine in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium dependent, and involves reactive oxygen species and endothelial COX-1 metabolites of arachidonic acid. Part of the contraction is probably due to release of norepinephrine. | INHIBITOR |
| Nicotine-induced contraction in the rat coronary artery: possible involvement of the endothelium, reactive oxygen species and COX-1 metabolites. Nicotine caused a contraction of the rat coronary artery in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME) and arachidonic acid, and did not in the absence of these agents. The present experiments were undertaken to pharmacologically characterize the nicotine-induced contraction in ring preparations of the rat coronary artery. The contraction was abolished by chemical removal of endothelium saponin. Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. Cyclooxygenase-1 (COX-1) inhibitors (flurbiprofen, ketoprofen and ketrolack) attenuated the nicotine-induced contraction in a concentration-dependent manner, and cyclooxygenase-2 (GENE) inhibitors at high concentrations (nimesulide and CHEMICAL) slightly attenuated the contraction. A TXA2 synthetase inhibitor (OKY-046) attenuated the contraction to a small extent only at high concentrations. A TXA2 receptor antagonist (S-1452) attenuated the contraction in a concentration-dependent manner. A nicotinic receptor antagonist (hexamethonium) attenuated the contraction in part and an alpha-adrenoceptor antagonist (prazosin) nearly abolished the contraction. From these results, it was suggested that the contraction induced by nicotine in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium dependent, and involves reactive oxygen species and endothelial COX-1 metabolites of arachidonic acid. Part of the contraction is probably due to release of norepinephrine. | INHIBITOR |
| Nicotine-induced contraction in the rat coronary artery: possible involvement of the endothelium, reactive oxygen species and COX-1 metabolites. Nicotine caused a contraction of the rat coronary artery in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME) and arachidonic acid, and did not in the absence of these agents. The present experiments were undertaken to pharmacologically characterize the nicotine-induced contraction in ring preparations of the rat coronary artery. The contraction was abolished by chemical removal of endothelium saponin. Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. Cyclooxygenase-1 (COX-1) inhibitors (flurbiprofen, ketoprofen and ketrolack) attenuated the nicotine-induced contraction in a concentration-dependent manner, and cyclooxygenase-2 (COX-2) inhibitors at high concentrations (nimesulide and NS-389) slightly attenuated the contraction. A GENE inhibitor (CHEMICAL) attenuated the contraction to a small extent only at high concentrations. A TXA2 receptor antagonist (S-1452) attenuated the contraction in a concentration-dependent manner. A nicotinic receptor antagonist (hexamethonium) attenuated the contraction in part and an alpha-adrenoceptor antagonist (prazosin) nearly abolished the contraction. From these results, it was suggested that the contraction induced by nicotine in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium dependent, and involves reactive oxygen species and endothelial COX-1 metabolites of arachidonic acid. Part of the contraction is probably due to release of norepinephrine. | INHIBITOR |
| Nicotine-induced contraction in the rat coronary artery: possible involvement of the endothelium, reactive oxygen species and COX-1 metabolites. Nicotine caused a contraction of the rat coronary artery in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME) and arachidonic acid, and did not in the absence of these agents. The present experiments were undertaken to pharmacologically characterize the nicotine-induced contraction in ring preparations of the rat coronary artery. The contraction was abolished by chemical removal of endothelium saponin. Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. Cyclooxygenase-1 (COX-1) inhibitors (flurbiprofen, ketoprofen and ketrolack) attenuated the nicotine-induced contraction in a concentration-dependent manner, and cyclooxygenase-2 (COX-2) inhibitors at high concentrations (nimesulide and NS-389) slightly attenuated the contraction. A TXA2 synthetase inhibitor (OKY-046) attenuated the contraction to a small extent only at high concentrations. A GENE antagonist (CHEMICAL) attenuated the contraction in a concentration-dependent manner. A nicotinic receptor antagonist (hexamethonium) attenuated the contraction in part and an alpha-adrenoceptor antagonist (prazosin) nearly abolished the contraction. From these results, it was suggested that the contraction induced by nicotine in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium dependent, and involves reactive oxygen species and endothelial COX-1 metabolites of arachidonic acid. Part of the contraction is probably due to release of norepinephrine. | INHIBITOR |
| Nicotine-induced contraction in the rat coronary artery: possible involvement of the endothelium, reactive oxygen species and COX-1 metabolites. Nicotine caused a contraction of the rat coronary artery in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME) and arachidonic acid, and did not in the absence of these agents. The present experiments were undertaken to pharmacologically characterize the nicotine-induced contraction in ring preparations of the rat coronary artery. The contraction was abolished by chemical removal of endothelium saponin. Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. Cyclooxygenase-1 (COX-1) inhibitors (flurbiprofen, ketoprofen and ketrolack) attenuated the nicotine-induced contraction in a concentration-dependent manner, and cyclooxygenase-2 (COX-2) inhibitors at high concentrations (nimesulide and NS-389) slightly attenuated the contraction. A TXA2 synthetase inhibitor (OKY-046) attenuated the contraction to a small extent only at high concentrations. A TXA2 receptor antagonist (S-1452) attenuated the contraction in a concentration-dependent manner. A GENE antagonist (CHEMICAL) attenuated the contraction in part and an alpha-adrenoceptor antagonist (prazosin) nearly abolished the contraction. From these results, it was suggested that the contraction induced by nicotine in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium dependent, and involves reactive oxygen species and endothelial COX-1 metabolites of arachidonic acid. Part of the contraction is probably due to release of norepinephrine. | INHIBITOR |
| Nicotine-induced contraction in the rat coronary artery: possible involvement of the endothelium, reactive oxygen species and COX-1 metabolites. Nicotine caused a contraction of the rat coronary artery in the presence of Nomega-nitro-L-arginine methyl ester (L-NAME) and arachidonic acid, and did not in the absence of these agents. The present experiments were undertaken to pharmacologically characterize the nicotine-induced contraction in ring preparations of the rat coronary artery. The contraction was abolished by chemical removal of endothelium saponin. Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. Cyclooxygenase-1 (COX-1) inhibitors (flurbiprofen, ketoprofen and ketrolack) attenuated the nicotine-induced contraction in a concentration-dependent manner, and cyclooxygenase-2 (COX-2) inhibitors at high concentrations (nimesulide and NS-389) slightly attenuated the contraction. A TXA2 synthetase inhibitor (OKY-046) attenuated the contraction to a small extent only at high concentrations. A TXA2 receptor antagonist (S-1452) attenuated the contraction in a concentration-dependent manner. A nicotinic receptor antagonist (hexamethonium) attenuated the contraction in part and an GENE antagonist (CHEMICAL) nearly abolished the contraction. From these results, it was suggested that the contraction induced by nicotine in the rat coronary artery in the presence of L-NAME and arachidonic acid is endothelium dependent, and involves reactive oxygen species and endothelial COX-1 metabolites of arachidonic acid. Part of the contraction is probably due to release of norepinephrine. | INHIBITOR |
| Differential binding mode of diverse cyclooxygenase inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of cyclooxygenase (COX), the enzyme that mediates biosynthesis of prostaglandins and thromboxanes from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective GENE inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of GENE available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different GENE inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, suprofen, carprofen, CHEMICAL, indomethacin, diclofenac and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of GENE inhibitors, and are expected to contribute to the design of new selective compounds. | DIRECT-REGULATOR |
| Differential binding mode of diverse cyclooxygenase inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of cyclooxygenase (COX), the enzyme that mediates biosynthesis of prostaglandins and thromboxanes from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective GENE inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of GENE available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different GENE inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, suprofen, carprofen, zomepirac, CHEMICAL, diclofenac and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of GENE inhibitors, and are expected to contribute to the design of new selective compounds. | DIRECT-REGULATOR |
| Differential binding mode of diverse cyclooxygenase inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of cyclooxygenase (COX), the enzyme that mediates biosynthesis of prostaglandins and thromboxanes from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective GENE inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of GENE available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different GENE inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, suprofen, carprofen, zomepirac, indomethacin, CHEMICAL and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of GENE inhibitors, and are expected to contribute to the design of new selective compounds. | DIRECT-REGULATOR |
| Differential binding mode of diverse cyclooxygenase inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of cyclooxygenase (COX), the enzyme that mediates biosynthesis of prostaglandins and thromboxanes from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective GENE inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of GENE available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different GENE inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, suprofen, carprofen, zomepirac, indomethacin, diclofenac and CHEMICAL were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of GENE inhibitors, and are expected to contribute to the design of new selective compounds. | DIRECT-REGULATOR |
| Differential binding mode of diverse cyclooxygenase inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of cyclooxygenase (COX), the enzyme that mediates biosynthesis of prostaglandins and thromboxanes from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective GENE inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of GENE available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different GENE inhibitors, including selective and non-selective ligands: CHEMICAL, ketoprofen, suprofen, carprofen, zomepirac, indomethacin, diclofenac and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of GENE inhibitors, and are expected to contribute to the design of new selective compounds. | DIRECT-REGULATOR |
| Differential binding mode of diverse cyclooxygenase inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of cyclooxygenase (COX), the enzyme that mediates biosynthesis of prostaglandins and thromboxanes from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective GENE inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of GENE available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different GENE inhibitors, including selective and non-selective ligands: rofecoxib, CHEMICAL, suprofen, carprofen, zomepirac, indomethacin, diclofenac and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of GENE inhibitors, and are expected to contribute to the design of new selective compounds. | DIRECT-REGULATOR |
| Differential binding mode of diverse cyclooxygenase inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of cyclooxygenase (COX), the enzyme that mediates biosynthesis of prostaglandins and thromboxanes from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective GENE inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of GENE available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different GENE inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, CHEMICAL, carprofen, zomepirac, indomethacin, diclofenac and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of GENE inhibitors, and are expected to contribute to the design of new selective compounds. | DIRECT-REGULATOR |
| Differential binding mode of diverse cyclooxygenase inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of cyclooxygenase (COX), the enzyme that mediates biosynthesis of prostaglandins and thromboxanes from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective GENE inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of GENE available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different GENE inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, suprofen, CHEMICAL, zomepirac, indomethacin, diclofenac and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of GENE inhibitors, and are expected to contribute to the design of new selective compounds. | DIRECT-REGULATOR |
| Differential binding mode of diverse GENE inhibitors. Non-CHEMICAL anti-inflammatory drugs (NSAIDs) are competitive inhibitors of GENE (COX), the enzyme that mediates biosynthesis of prostaglandins and thromboxanes from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective COX inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of COX available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different COX inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, suprofen, carprofen, zomepirac, indomethacin, diclofenac and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of COX inhibitors, and are expected to contribute to the design of new selective compounds. | INHIBITOR |
| Differential binding mode of diverse cyclooxygenase inhibitors. Non-CHEMICAL anti-inflammatory drugs (NSAIDs) are competitive inhibitors of cyclooxygenase (GENE), the enzyme that mediates biosynthesis of prostaglandins and thromboxanes from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective GENE inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of GENE available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different GENE inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, suprofen, carprofen, zomepirac, indomethacin, diclofenac and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of GENE inhibitors, and are expected to contribute to the design of new selective compounds. | INHIBITOR |
| Differential binding mode of diverse GENE inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of GENE (COX), the enzyme that mediates biosynthesis of CHEMICAL and thromboxanes from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective COX inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of COX available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different COX inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, suprofen, carprofen, zomepirac, indomethacin, diclofenac and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of COX inhibitors, and are expected to contribute to the design of new selective compounds. | PRODUCT-OF |
| Differential binding mode of diverse cyclooxygenase inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of cyclooxygenase (GENE), the enzyme that mediates biosynthesis of CHEMICAL and thromboxanes from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective GENE inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of GENE available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different GENE inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, suprofen, carprofen, zomepirac, indomethacin, diclofenac and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of GENE inhibitors, and are expected to contribute to the design of new selective compounds. | PRODUCT-OF |
| Differential binding mode of diverse GENE inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of GENE (COX), the enzyme that mediates biosynthesis of prostaglandins and CHEMICAL from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective COX inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of COX available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different COX inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, suprofen, carprofen, zomepirac, indomethacin, diclofenac and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of COX inhibitors, and are expected to contribute to the design of new selective compounds. | PRODUCT-OF |
| Differential binding mode of diverse cyclooxygenase inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of cyclooxygenase (GENE), the enzyme that mediates biosynthesis of prostaglandins and CHEMICAL from arachidonic acid. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective GENE inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of GENE available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different GENE inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, suprofen, carprofen, zomepirac, indomethacin, diclofenac and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of GENE inhibitors, and are expected to contribute to the design of new selective compounds. | PRODUCT-OF |
| Differential binding mode of diverse GENE inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of GENE (COX), the enzyme that mediates biosynthesis of prostaglandins and thromboxanes from CHEMICAL. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective COX inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of COX available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different COX inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, suprofen, carprofen, zomepirac, indomethacin, diclofenac and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of COX inhibitors, and are expected to contribute to the design of new selective compounds. | SUBSTRATE |
| Differential binding mode of diverse cyclooxygenase inhibitors. Non-steroidal anti-inflammatory drugs (NSAIDs) are competitive inhibitors of cyclooxygenase (GENE), the enzyme that mediates biosynthesis of prostaglandins and thromboxanes from CHEMICAL. There are at least two different isoforms of the enzyme known as COX-1 and -2. Site directed mutagenesis studies suggest that non-selective GENE inhibitors of diverse chemical families exhibit differential binding modes to the two isozymes. These results cannot clearly be explained from the sole analysis of the crystal structures of GENE available from X-ray diffraction studies. With the aim to elucidate the structural features governing the differential inhibitory binding behavior of these inhibitors, molecular modeling studies were undertaken to generate atomic models compatible with the experimental data available. Accordingly, docking of different GENE inhibitors, including selective and non-selective ligands: rofecoxib, ketoprofen, suprofen, carprofen, zomepirac, indomethacin, diclofenac and meclofenamic acid were undertaken using the AMBER program. The results of the present study provide new insights into a better understanding of the differential binding mode of diverse families of GENE inhibitors, and are expected to contribute to the design of new selective compounds. | SUBSTRATE |
| Pure antiestrogens and breast cancer. Tamoxifen, which is the most commonly used drug for treatment of breast cancer, has both estrogen agonist and antagonist actions. Pure antiestrogens are devoid of any estrogen agonist effects. ICI 182,780 (fulvestrant) (Faslodex) and CHEMICAL are competitive inhibitors of estrogen by binding to the GENE (ER). Preclinical and clinical studies show that fulvestrant and CHEMICAL are more potent than tamoxifen in inhibiting the growth of breast cancer cells. They are devoid of any estrogen-agonist action on the uterus and vagina but lack the beneficial effects of tamoxifen on the bone and serum lipid profile. Fulvestrant is the first pure antiestrogen to complete phase III clinical trials. Such studies have shown that fulvestrant is at least as good as anastrozole in the treatment of post-menopausal women with advanced breast cancer who had relapsed or progressed on prior endocrine therapy. The drug was well tolerated and only minor side-effects were reported. Its potential role in the adjuvant setting will be determined by its adverse effects on bone mass and serum lipids. EM-800 and EM-652 are the most potent pure antiestrogens and EM-652 has the highest affinity of all antiestrogens to ER. They have no stimulatory effects on the uterus or vagina. It seems reasonable to expect that pure antiestrogens will be good alternatives to tamoxifen and aromatase inhibitors in the treatment of breast cancer. | DIRECT-REGULATOR |
| Pure antiestrogens and breast cancer. Tamoxifen, which is the most commonly used drug for treatment of breast cancer, has both estrogen agonist and antagonist actions. Pure antiestrogens are devoid of any estrogen agonist effects. ICI 182,780 (fulvestrant) (Faslodex) and CHEMICAL are competitive inhibitors of estrogen by binding to the estrogen receptor (GENE). Preclinical and clinical studies show that fulvestrant and CHEMICAL are more potent than tamoxifen in inhibiting the growth of breast cancer cells. They are devoid of any estrogen-agonist action on the uterus and vagina but lack the beneficial effects of tamoxifen on the bone and serum lipid profile. Fulvestrant is the first pure antiestrogen to complete phase III clinical trials. Such studies have shown that fulvestrant is at least as good as anastrozole in the treatment of post-menopausal women with advanced breast cancer who had relapsed or progressed on prior endocrine therapy. The drug was well tolerated and only minor side-effects were reported. Its potential role in the adjuvant setting will be determined by its adverse effects on bone mass and serum lipids. EM-800 and EM-652 are the most potent pure antiestrogens and EM-652 has the highest affinity of all antiestrogens to GENE. They have no stimulatory effects on the uterus or vagina. It seems reasonable to expect that pure antiestrogens will be good alternatives to tamoxifen and aromatase inhibitors in the treatment of breast cancer. | DIRECT-REGULATOR |
| Pure antiestrogens and breast cancer. Tamoxifen, which is the most commonly used drug for treatment of breast cancer, has both CHEMICAL agonist and antagonist actions. Pure antiestrogens are devoid of any CHEMICAL agonist effects. ICI 182,780 (fulvestrant) (Faslodex) and ICI 164,384 are competitive inhibitors of CHEMICAL by binding to the GENE (ER). Preclinical and clinical studies show that fulvestrant and ICI 164,384 are more potent than tamoxifen in inhibiting the growth of breast cancer cells. They are devoid of any estrogen-agonist action on the uterus and vagina but lack the beneficial effects of tamoxifen on the bone and serum lipid profile. Fulvestrant is the first pure antiestrogen to complete phase III clinical trials. Such studies have shown that fulvestrant is at least as good as anastrozole in the treatment of post-menopausal women with advanced breast cancer who had relapsed or progressed on prior endocrine therapy. The drug was well tolerated and only minor side-effects were reported. Its potential role in the adjuvant setting will be determined by its adverse effects on bone mass and serum lipids. EM-800 and EM-652 are the most potent pure antiestrogens and EM-652 has the highest affinity of all antiestrogens to ER. They have no stimulatory effects on the uterus or vagina. It seems reasonable to expect that pure antiestrogens will be good alternatives to tamoxifen and aromatase inhibitors in the treatment of breast cancer. | DIRECT-REGULATOR |
| Pure antiestrogens and breast cancer. Tamoxifen, which is the most commonly used drug for treatment of breast cancer, has both CHEMICAL agonist and antagonist actions. Pure antiestrogens are devoid of any CHEMICAL agonist effects. ICI 182,780 (fulvestrant) (Faslodex) and ICI 164,384 are competitive inhibitors of CHEMICAL by binding to the CHEMICAL receptor (GENE). Preclinical and clinical studies show that fulvestrant and ICI 164,384 are more potent than tamoxifen in inhibiting the growth of breast cancer cells. They are devoid of any estrogen-agonist action on the uterus and vagina but lack the beneficial effects of tamoxifen on the bone and serum lipid profile. Fulvestrant is the first pure antiestrogen to complete phase III clinical trials. Such studies have shown that fulvestrant is at least as good as anastrozole in the treatment of post-menopausal women with advanced breast cancer who had relapsed or progressed on prior endocrine therapy. The drug was well tolerated and only minor side-effects were reported. Its potential role in the adjuvant setting will be determined by its adverse effects on bone mass and serum lipids. EM-800 and EM-652 are the most potent pure antiestrogens and EM-652 has the highest affinity of all antiestrogens to GENE. They have no stimulatory effects on the uterus or vagina. It seems reasonable to expect that pure antiestrogens will be good alternatives to tamoxifen and aromatase inhibitors in the treatment of breast cancer. | DIRECT-REGULATOR |
| Pure antiestrogens and breast cancer. Tamoxifen, which is the most commonly used drug for treatment of breast cancer, has both estrogen agonist and antagonist actions. Pure antiestrogens are devoid of any estrogen agonist effects. ICI 182,780 (fulvestrant) (Faslodex) and ICI 164,384 are competitive inhibitors of estrogen by binding to the estrogen receptor (ER). Preclinical and clinical studies show that fulvestrant and ICI 164,384 are more potent than tamoxifen in inhibiting the growth of breast cancer cells. They are devoid of any estrogen-agonist action on the uterus and vagina but lack the beneficial effects of tamoxifen on the bone and serum lipid profile. Fulvestrant is the first pure antiestrogen to complete phase III clinical trials. Such studies have shown that fulvestrant is at least as good as anastrozole in the treatment of post-menopausal women with advanced breast cancer who had relapsed or progressed on prior endocrine therapy. The drug was well tolerated and only minor side-effects were reported. Its potential role in the adjuvant setting will be determined by its adverse effects on bone mass and serum lipids. CHEMICAL and EM-652 are the most potent pure antiestrogens and EM-652 has the highest affinity of all antiestrogens to GENE. They have no stimulatory effects on the uterus or vagina. It seems reasonable to expect that pure antiestrogens will be good alternatives to tamoxifen and aromatase inhibitors in the treatment of breast cancer. | DIRECT-REGULATOR |
| Pure antiestrogens and breast cancer. Tamoxifen, which is the most commonly used drug for treatment of breast cancer, has both estrogen agonist and antagonist actions. Pure antiestrogens are devoid of any estrogen agonist effects. ICI 182,780 (fulvestrant) (Faslodex) and ICI 164,384 are competitive inhibitors of estrogen by binding to the estrogen receptor (ER). Preclinical and clinical studies show that fulvestrant and ICI 164,384 are more potent than tamoxifen in inhibiting the growth of breast cancer cells. They are devoid of any estrogen-agonist action on the uterus and vagina but lack the beneficial effects of tamoxifen on the bone and serum lipid profile. Fulvestrant is the first pure antiestrogen to complete phase III clinical trials. Such studies have shown that fulvestrant is at least as good as anastrozole in the treatment of post-menopausal women with advanced breast cancer who had relapsed or progressed on prior endocrine therapy. The drug was well tolerated and only minor side-effects were reported. Its potential role in the adjuvant setting will be determined by its adverse effects on bone mass and serum lipids. EM-800 and CHEMICAL are the most potent pure antiestrogens and CHEMICAL has the highest affinity of all antiestrogens to GENE. They have no stimulatory effects on the uterus or vagina. It seems reasonable to expect that pure antiestrogens will be good alternatives to tamoxifen and aromatase inhibitors in the treatment of breast cancer. | DIRECT-REGULATOR |
| Pure antiestrogens and breast cancer. Tamoxifen, which is the most commonly used drug for treatment of breast cancer, has both estrogen agonist and antagonist actions. Pure antiestrogens are devoid of any estrogen agonist effects. CHEMICAL (fulvestrant) (Faslodex) and ICI 164,384 are competitive inhibitors of estrogen by binding to the GENE (ER). Preclinical and clinical studies show that fulvestrant and ICI 164,384 are more potent than tamoxifen in inhibiting the growth of breast cancer cells. They are devoid of any estrogen-agonist action on the uterus and vagina but lack the beneficial effects of tamoxifen on the bone and serum lipid profile. Fulvestrant is the first pure antiestrogen to complete phase III clinical trials. Such studies have shown that fulvestrant is at least as good as anastrozole in the treatment of post-menopausal women with advanced breast cancer who had relapsed or progressed on prior endocrine therapy. The drug was well tolerated and only minor side-effects were reported. Its potential role in the adjuvant setting will be determined by its adverse effects on bone mass and serum lipids. EM-800 and EM-652 are the most potent pure antiestrogens and EM-652 has the highest affinity of all antiestrogens to ER. They have no stimulatory effects on the uterus or vagina. It seems reasonable to expect that pure antiestrogens will be good alternatives to tamoxifen and aromatase inhibitors in the treatment of breast cancer. | DIRECT-REGULATOR |
| Pure antiestrogens and breast cancer. Tamoxifen, which is the most commonly used drug for treatment of breast cancer, has both estrogen agonist and antagonist actions. Pure antiestrogens are devoid of any estrogen agonist effects. CHEMICAL (fulvestrant) (Faslodex) and ICI 164,384 are competitive inhibitors of estrogen by binding to the estrogen receptor (GENE). Preclinical and clinical studies show that fulvestrant and ICI 164,384 are more potent than tamoxifen in inhibiting the growth of breast cancer cells. They are devoid of any estrogen-agonist action on the uterus and vagina but lack the beneficial effects of tamoxifen on the bone and serum lipid profile. Fulvestrant is the first pure antiestrogen to complete phase III clinical trials. Such studies have shown that fulvestrant is at least as good as anastrozole in the treatment of post-menopausal women with advanced breast cancer who had relapsed or progressed on prior endocrine therapy. The drug was well tolerated and only minor side-effects were reported. Its potential role in the adjuvant setting will be determined by its adverse effects on bone mass and serum lipids. EM-800 and EM-652 are the most potent pure antiestrogens and EM-652 has the highest affinity of all antiestrogens to GENE. They have no stimulatory effects on the uterus or vagina. It seems reasonable to expect that pure antiestrogens will be good alternatives to tamoxifen and aromatase inhibitors in the treatment of breast cancer. | DIRECT-REGULATOR |
| Pure antiestrogens and breast cancer. Tamoxifen, which is the most commonly used drug for treatment of breast cancer, has both estrogen agonist and antagonist actions. Pure antiestrogens are devoid of any estrogen agonist effects. ICI 182,780 (CHEMICAL) (Faslodex) and ICI 164,384 are competitive inhibitors of estrogen by binding to the GENE (ER). Preclinical and clinical studies show that CHEMICAL and ICI 164,384 are more potent than tamoxifen in inhibiting the growth of breast cancer cells. They are devoid of any estrogen-agonist action on the uterus and vagina but lack the beneficial effects of tamoxifen on the bone and serum lipid profile. CHEMICAL is the first pure antiestrogen to complete phase III clinical trials. Such studies have shown that CHEMICAL is at least as good as anastrozole in the treatment of post-menopausal women with advanced breast cancer who had relapsed or progressed on prior endocrine therapy. The drug was well tolerated and only minor side-effects were reported. Its potential role in the adjuvant setting will be determined by its adverse effects on bone mass and serum lipids. EM-800 and EM-652 are the most potent pure antiestrogens and EM-652 has the highest affinity of all antiestrogens to ER. They have no stimulatory effects on the uterus or vagina. It seems reasonable to expect that pure antiestrogens will be good alternatives to tamoxifen and aromatase inhibitors in the treatment of breast cancer. | DIRECT-REGULATOR |
| Pure antiestrogens and breast cancer. Tamoxifen, which is the most commonly used drug for treatment of breast cancer, has both estrogen agonist and antagonist actions. Pure antiestrogens are devoid of any estrogen agonist effects. ICI 182,780 (CHEMICAL) (Faslodex) and ICI 164,384 are competitive inhibitors of estrogen by binding to the estrogen receptor (GENE). Preclinical and clinical studies show that CHEMICAL and ICI 164,384 are more potent than tamoxifen in inhibiting the growth of breast cancer cells. They are devoid of any estrogen-agonist action on the uterus and vagina but lack the beneficial effects of tamoxifen on the bone and serum lipid profile. CHEMICAL is the first pure antiestrogen to complete phase III clinical trials. Such studies have shown that CHEMICAL is at least as good as anastrozole in the treatment of post-menopausal women with advanced breast cancer who had relapsed or progressed on prior endocrine therapy. The drug was well tolerated and only minor side-effects were reported. Its potential role in the adjuvant setting will be determined by its adverse effects on bone mass and serum lipids. EM-800 and EM-652 are the most potent pure antiestrogens and EM-652 has the highest affinity of all antiestrogens to GENE. They have no stimulatory effects on the uterus or vagina. It seems reasonable to expect that pure antiestrogens will be good alternatives to tamoxifen and aromatase inhibitors in the treatment of breast cancer. | DIRECT-REGULATOR |
| Pure antiestrogens and breast cancer. Tamoxifen, which is the most commonly used drug for treatment of breast cancer, has both estrogen agonist and antagonist actions. Pure antiestrogens are devoid of any estrogen agonist effects. ICI 182,780 (fulvestrant) (CHEMICAL) and ICI 164,384 are competitive inhibitors of estrogen by binding to the GENE (ER). Preclinical and clinical studies show that fulvestrant and ICI 164,384 are more potent than tamoxifen in inhibiting the growth of breast cancer cells. They are devoid of any estrogen-agonist action on the uterus and vagina but lack the beneficial effects of tamoxifen on the bone and serum lipid profile. Fulvestrant is the first pure antiestrogen to complete phase III clinical trials. Such studies have shown that fulvestrant is at least as good as anastrozole in the treatment of post-menopausal women with advanced breast cancer who had relapsed or progressed on prior endocrine therapy. The drug was well tolerated and only minor side-effects were reported. Its potential role in the adjuvant setting will be determined by its adverse effects on bone mass and serum lipids. EM-800 and EM-652 are the most potent pure antiestrogens and EM-652 has the highest affinity of all antiestrogens to ER. They have no stimulatory effects on the uterus or vagina. It seems reasonable to expect that pure antiestrogens will be good alternatives to tamoxifen and aromatase inhibitors in the treatment of breast cancer. | DIRECT-REGULATOR |
| Pure antiestrogens and breast cancer. Tamoxifen, which is the most commonly used drug for treatment of breast cancer, has both estrogen agonist and antagonist actions. Pure antiestrogens are devoid of any estrogen agonist effects. ICI 182,780 (fulvestrant) (CHEMICAL) and ICI 164,384 are competitive inhibitors of estrogen by binding to the estrogen receptor (GENE). Preclinical and clinical studies show that fulvestrant and ICI 164,384 are more potent than tamoxifen in inhibiting the growth of breast cancer cells. They are devoid of any estrogen-agonist action on the uterus and vagina but lack the beneficial effects of tamoxifen on the bone and serum lipid profile. Fulvestrant is the first pure antiestrogen to complete phase III clinical trials. Such studies have shown that fulvestrant is at least as good as anastrozole in the treatment of post-menopausal women with advanced breast cancer who had relapsed or progressed on prior endocrine therapy. The drug was well tolerated and only minor side-effects were reported. Its potential role in the adjuvant setting will be determined by its adverse effects on bone mass and serum lipids. EM-800 and EM-652 are the most potent pure antiestrogens and EM-652 has the highest affinity of all antiestrogens to GENE. They have no stimulatory effects on the uterus or vagina. It seems reasonable to expect that pure antiestrogens will be good alternatives to tamoxifen and aromatase inhibitors in the treatment of breast cancer. | DIRECT-REGULATOR |
| Pharmacological, pharmacokinetic and clinical properties of olopatadine hydrochloride, a new antiallergic drug. CHEMICAL hydrochloride (olopatadine, 11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid monohydrochloride) is a novel antiallergic/histamine H1-receptor antagonistic drug that was synthesized and evaluated in our laboratories. Oral administration of olopatadine at doses of 0.03 mg/kg or higher inhibited the symptoms of experimental allergic skin responses, rhinoconjunctivitis and bronchial asthma in sensitized guinea pigs and rats. CHEMICAL is a selective histamine H1-receptor antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils. CHEMICAL also inhibited the tachykininergic contraction in the guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves. CHEMICAL exerted no significant effects on action potential duration in isolated guinea pig ventricular myocytes, myocardium and GENE. CHEMICAL was highly and rapidly absorbed in healthy human volunteers. The urinary excretion of olopatadine accounted for not less than 58% and the contribution of metabolism was considerably low in the clearance of olopatadine in humans. CHEMICAL is one of the few renal clearance drugs in antiallergic drugs. CHEMICAL was shown to be useful for the treatment of allergic rhinitis and chronic urticaria in double-blind clinical trials. CHEMICAL was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, pruritus cutaneous, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000. Ophthalmic solution of olopatadine was also approved in the United States for the treatment of seasonal allergic conjunctivitis in December, 1996 (Appendix: also in the European Union, it was approved in February 2002). | NO-RELATIONSHIP |
| Pharmacological, pharmacokinetic and clinical properties of CHEMICAL hydrochloride, a new antiallergic drug. CHEMICAL hydrochloride (CHEMICAL, 11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid monohydrochloride) is a novel antiallergic/GENE antagonistic drug that was synthesized and evaluated in our laboratories. Oral administration of CHEMICAL at doses of 0.03 mg/kg or higher inhibited the symptoms of experimental allergic skin responses, rhinoconjunctivitis and bronchial asthma in sensitized guinea pigs and rats. CHEMICAL is a selective GENE antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils. CHEMICAL also inhibited the tachykininergic contraction in the guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves. CHEMICAL exerted no significant effects on action potential duration in isolated guinea pig ventricular myocytes, myocardium and human ether-a-go-go-related gene channel. CHEMICAL was highly and rapidly absorbed in healthy human volunteers. The urinary excretion of CHEMICAL accounted for not less than 58% and the contribution of metabolism was considerably low in the clearance of CHEMICAL in humans. CHEMICAL is one of the few renal clearance drugs in antiallergic drugs. CHEMICAL was shown to be useful for the treatment of allergic rhinitis and chronic urticaria in double-blind clinical trials. CHEMICAL was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, pruritus cutaneous, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000. Ophthalmic solution of CHEMICAL was also approved in the United States for the treatment of seasonal allergic conjunctivitis in December, 1996 (Appendix: also in the European Union, it was approved in February 2002). | INHIBITOR |
| Pharmacological, pharmacokinetic and clinical properties of olopatadine hydrochloride, a new antiallergic drug. Olopatadine hydrochloride (olopatadine, CHEMICAL) is a novel antiallergic/GENE antagonistic drug that was synthesized and evaluated in our laboratories. Oral administration of olopatadine at doses of 0.03 mg/kg or higher inhibited the symptoms of experimental allergic skin responses, rhinoconjunctivitis and bronchial asthma in sensitized guinea pigs and rats. Olopatadine is a selective GENE antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils. Olopatadine also inhibited the tachykininergic contraction in the guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves. Olopatadine exerted no significant effects on action potential duration in isolated guinea pig ventricular myocytes, myocardium and human ether-a-go-go-related gene channel. Olopatadine was highly and rapidly absorbed in healthy human volunteers. The urinary excretion of olopatadine accounted for not less than 58% and the contribution of metabolism was considerably low in the clearance of olopatadine in humans. Olopatadine is one of the few renal clearance drugs in antiallergic drugs. Olopatadine was shown to be useful for the treatment of allergic rhinitis and chronic urticaria in double-blind clinical trials. Olopatadine was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, pruritus cutaneous, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000. Ophthalmic solution of olopatadine was also approved in the United States for the treatment of seasonal allergic conjunctivitis in December, 1996 (Appendix: also in the European Union, it was approved in February 2002). | INHIBITOR |
| Pharmacological, pharmacokinetic and clinical properties of olopatadine hydrochloride, a new antiallergic drug. CHEMICAL hydrochloride (olopatadine, 11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid monohydrochloride) is a novel antiallergic/histamine H1-receptor antagonistic drug that was synthesized and evaluated in our laboratories. Oral administration of olopatadine at doses of 0.03 mg/kg or higher inhibited the symptoms of experimental allergic skin responses, rhinoconjunctivitis and bronchial asthma in sensitized guinea pigs and rats. CHEMICAL is a selective GENE antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils. CHEMICAL also inhibited the tachykininergic contraction in the guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves. CHEMICAL exerted no significant effects on action potential duration in isolated guinea pig ventricular myocytes, myocardium and human ether-a-go-go-related gene channel. CHEMICAL was highly and rapidly absorbed in healthy human volunteers. The urinary excretion of olopatadine accounted for not less than 58% and the contribution of metabolism was considerably low in the clearance of olopatadine in humans. CHEMICAL is one of the few renal clearance drugs in antiallergic drugs. CHEMICAL was shown to be useful for the treatment of allergic rhinitis and chronic urticaria in double-blind clinical trials. CHEMICAL was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, pruritus cutaneous, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000. Ophthalmic solution of olopatadine was also approved in the United States for the treatment of seasonal allergic conjunctivitis in December, 1996 (Appendix: also in the European Union, it was approved in February 2002). | INHIBITOR |
| Pharmacological, pharmacokinetic and clinical properties of olopatadine hydrochloride, a new antiallergic drug. CHEMICAL (olopatadine, 11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid monohydrochloride) is a novel antiallergic/GENE antagonistic drug that was synthesized and evaluated in our laboratories. Oral administration of olopatadine at doses of 0.03 mg/kg or higher inhibited the symptoms of experimental allergic skin responses, rhinoconjunctivitis and bronchial asthma in sensitized guinea pigs and rats. Olopatadine is a selective GENE antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils. Olopatadine also inhibited the tachykininergic contraction in the guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves. Olopatadine exerted no significant effects on action potential duration in isolated guinea pig ventricular myocytes, myocardium and human ether-a-go-go-related gene channel. Olopatadine was highly and rapidly absorbed in healthy human volunteers. The urinary excretion of olopatadine accounted for not less than 58% and the contribution of metabolism was considerably low in the clearance of olopatadine in humans. Olopatadine is one of the few renal clearance drugs in antiallergic drugs. Olopatadine was shown to be useful for the treatment of allergic rhinitis and chronic urticaria in double-blind clinical trials. Olopatadine was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, pruritus cutaneous, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000. Ophthalmic solution of olopatadine was also approved in the United States for the treatment of seasonal allergic conjunctivitis in December, 1996 (Appendix: also in the European Union, it was approved in February 2002). | INHIBITOR |
| Serotonin transporter polymorphisms and measures of impulsivity, aggression, and sensation seeking among African-American cocaine-dependent individuals. Considerable evidence indicates that serotonergic mechanisms, particularly the serotonin transporter (GENE), may mediate central effects of CHEMICAL and may also be involved in impulsive and aggressive behavior. We investigated whether polymorphisms in the GENE gene were related to traits of impulsivity, sensation seeking, and aggression among CHEMICAL abusers. Standardized measures of these personality traits were obtained in a sample of 105 severely affected cocaine-dependent African-American subjects and 44 African-American controls. Two polymorphisms of the GENE gene were examined involving the 5' promoter (5HTTLPR) region and a 17 base pair variable-number-tandem-repeat (VNTR) marker among CHEMICAL patients. No significant relationships were observed between polymorphic variants of the 5HTTLPR and VNTR regions and scores on any of the trait measures. Similarly, demographic variables and measures of severity of substance use and depression were unrelated to allele frequencies or genotype distributions of the variants among CHEMICAL patients. As expected, CHEMICAL patients scored significantly higher on total scores of impulsivity, aggression, and sensation seeking compared to controls. The findings do not seem to support an association between these polymorphisms in the GENE gene and impulsive-aggressive traits among cocaine-dependent African-American individuals. | REGULATOR |
| GENE polymorphisms and measures of impulsivity, aggression, and sensation seeking among African-American cocaine-dependent individuals. Considerable evidence indicates that serotonergic mechanisms, particularly the GENE (5HTT), may mediate central effects of CHEMICAL and may also be involved in impulsive and aggressive behavior. We investigated whether polymorphisms in the 5HTT gene were related to traits of impulsivity, sensation seeking, and aggression among CHEMICAL abusers. Standardized measures of these personality traits were obtained in a sample of 105 severely affected cocaine-dependent African-American subjects and 44 African-American controls. Two polymorphisms of the 5HTT gene were examined involving the 5' promoter (5HTTLPR) region and a 17 base pair variable-number-tandem-repeat (VNTR) marker among CHEMICAL patients. No significant relationships were observed between polymorphic variants of the 5HTTLPR and VNTR regions and scores on any of the trait measures. Similarly, demographic variables and measures of severity of substance use and depression were unrelated to allele frequencies or genotype distributions of the variants among CHEMICAL patients. As expected, CHEMICAL patients scored significantly higher on total scores of impulsivity, aggression, and sensation seeking compared to controls. The findings do not seem to support an association between these polymorphisms in the 5HTT gene and impulsive-aggressive traits among cocaine-dependent African-American individuals. | REGULATOR |
| A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to CHEMICAL in controlling asthma. CHEMICAL act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show both in vitro and in vivo that low-dose theophylline enhances GENE activity in epithelial cells and macrophages. This increased GENE activity is then available for corticosteroid recruitment and predicts a cooperative interaction between CHEMICAL and theophylline. This mechanism occurs at therapeutic concentrations of theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose theophylline exerts an anti-asthma effect through increasing activation of GENE which is subsequently recruited by CHEMICAL to suppress inflammatory genes. | PRODUCT-OF |
| A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to corticosteroids in controlling asthma. CHEMICAL act, at least in part, by recruitment of GENE (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show both in vitro and in vivo that low-dose theophylline enhances HDAC activity in epithelial cells and macrophages. This increased HDAC activity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and theophylline. This mechanism occurs at therapeutic concentrations of theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose theophylline exerts an anti-asthma effect through increasing activation of HDAC which is subsequently recruited by corticosteroids to suppress inflammatory genes. | GENE-CHEMICAL |
| A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to corticosteroids in controlling asthma. CHEMICAL act, at least in part, by recruitment of histone deacetylases (GENE) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show both in vitro and in vivo that low-dose theophylline enhances HDAC activity in epithelial cells and macrophages. This increased HDAC activity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and theophylline. This mechanism occurs at therapeutic concentrations of theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose theophylline exerts an anti-asthma effect through increasing activation of HDAC which is subsequently recruited by corticosteroids to suppress inflammatory genes. | REGULATOR |
| A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to corticosteroids in controlling asthma. Corticosteroids act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show both in vitro and in vivo that low-dose theophylline enhances GENE activity in epithelial cells and macrophages. This increased GENE activity is then available for CHEMICAL recruitment and predicts a cooperative interaction between corticosteroids and theophylline. This mechanism occurs at therapeutic concentrations of theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose theophylline exerts an anti-asthma effect through increasing activation of GENE which is subsequently recruited by corticosteroids to suppress inflammatory genes. | PRODUCT-OF |
| A molecular mechanism of action of CHEMICAL: Induction of GENE activity to decrease inflammatory gene expression. The molecular mechanism for the anti-inflammatory action of CHEMICAL is currently unknown, but low-dose CHEMICAL is an effective add-on therapy to corticosteroids in controlling asthma. Corticosteroids act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show both in vitro and in vivo that low-dose CHEMICAL enhances HDAC activity in epithelial cells and macrophages. This increased HDAC activity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and CHEMICAL. This mechanism occurs at therapeutic concentrations of CHEMICAL and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose CHEMICAL exerts an anti-asthma effect through increasing activation of HDAC which is subsequently recruited by corticosteroids to suppress inflammatory genes. | ACTIVATOR |
| A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. The molecular mechanism for the anti-inflammatory action of CHEMICAL is currently unknown, but low-dose CHEMICAL is an effective add-on therapy to corticosteroids in controlling asthma. Corticosteroids act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show both in vitro and in vivo that low-dose CHEMICAL enhances GENE activity in epithelial cells and macrophages. This increased GENE activity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and CHEMICAL. This mechanism occurs at therapeutic concentrations of CHEMICAL and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose CHEMICAL exerts an anti-asthma effect through increasing activation of GENE which is subsequently recruited by corticosteroids to suppress inflammatory genes. | ACTIVATOR |
| Interactions of CHEMICAL and rifampicin with organic anion uptake systems of human liver. The antibiotics CHEMICAL and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, CHEMICAL and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of CHEMICAL and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, CHEMICAL (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L CHEMICAL, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that CHEMICAL and rifampicin interact with GENE-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of CHEMICAL and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of rifamycin SV and CHEMICAL with organic anion uptake systems of human liver. The antibiotics rifamycin SV and CHEMICAL substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, rifamycin SV and CHEMICAL were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of rifamycin SV and CHEMICAL on the OATPs of human liver and determined whether CHEMICAL is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L rifamycin SV, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. CHEMICAL (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L CHEMICAL inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of CHEMICAL could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that rifamycin SV and CHEMICAL interact with GENE-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of rifamycin SV and CHEMICAL on hepatic organic anion elimination. | SUBSTRATE |
| Interactions of CHEMICAL and rifampicin with organic anion uptake systems of human liver. The antibiotics CHEMICAL and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, CHEMICAL and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of CHEMICAL and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, CHEMICAL (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L CHEMICAL, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that CHEMICAL and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of GENE can explain the previously observed effects of CHEMICAL and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of rifamycin SV and CHEMICAL with organic anion uptake systems of human liver. The antibiotics rifamycin SV and CHEMICAL substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, rifamycin SV and CHEMICAL were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of rifamycin SV and CHEMICAL on the OATPs of human liver and determined whether CHEMICAL is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L rifamycin SV, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. CHEMICAL (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L CHEMICAL inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of CHEMICAL could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that rifamycin SV and CHEMICAL interact with OATP-mediated substrate transport to different extents. Inhibition of GENE can explain the previously observed effects of rifamycin SV and CHEMICAL on hepatic organic anion elimination. | SUBSTRATE |
| Interactions of CHEMICAL and rifampicin with organic anion uptake systems of human liver. The antibiotics CHEMICAL and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, CHEMICAL and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of CHEMICAL and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, CHEMICAL (10 micromol/L) cis-inhibited GENE (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L CHEMICAL, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that CHEMICAL and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of CHEMICAL and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of CHEMICAL and rifampicin with organic anion uptake systems of human liver. The antibiotics CHEMICAL and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, CHEMICAL and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of CHEMICAL and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, CHEMICAL (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (GENE) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L CHEMICAL, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that CHEMICAL and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of CHEMICAL and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of CHEMICAL and rifampicin with organic anion uptake systems of human liver. The antibiotics CHEMICAL and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, CHEMICAL and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of CHEMICAL and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, CHEMICAL (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (GENE), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L CHEMICAL, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for GENE, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for GENE, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for GENE (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that CHEMICAL and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of CHEMICAL and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of CHEMICAL and rifampicin with organic anion uptake systems of human liver. The antibiotics CHEMICAL and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, CHEMICAL and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of CHEMICAL and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, CHEMICAL (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), GENE (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L CHEMICAL, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that CHEMICAL and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of CHEMICAL and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of CHEMICAL and rifampicin with organic anion uptake systems of human liver. The antibiotics CHEMICAL and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, CHEMICAL and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of CHEMICAL and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, CHEMICAL (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (GENE) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L CHEMICAL, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that CHEMICAL and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of CHEMICAL and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of CHEMICAL and rifampicin with organic anion uptake systems of human liver. The antibiotics CHEMICAL and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, CHEMICAL and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of CHEMICAL and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, CHEMICAL (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (GENE), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L CHEMICAL, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for GENE, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for GENE, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and GENE (2.3 micromol/L). In conclusion, these results show that CHEMICAL and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of CHEMICAL and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of CHEMICAL and rifampicin with organic anion uptake systems of human liver. The antibiotics CHEMICAL and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, CHEMICAL and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of CHEMICAL and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, CHEMICAL (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), GENE (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L CHEMICAL, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that CHEMICAL and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of CHEMICAL and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of CHEMICAL and rifampicin with organic anion uptake systems of human liver. The antibiotics CHEMICAL and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, CHEMICAL and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of CHEMICAL and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, CHEMICAL (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (GENE) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L CHEMICAL, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that CHEMICAL and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of CHEMICAL and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of CHEMICAL and rifampicin with organic anion uptake systems of human liver. The antibiotics CHEMICAL and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, CHEMICAL and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of CHEMICAL and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, CHEMICAL (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (GENE), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L CHEMICAL, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for GENE and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that CHEMICAL and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of CHEMICAL and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of CHEMICAL and rifampicin with organic anion uptake systems of human liver. The antibiotics CHEMICAL and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, CHEMICAL and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of CHEMICAL and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, CHEMICAL (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and GENE (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L CHEMICAL, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that CHEMICAL and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of CHEMICAL and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of CHEMICAL and rifampicin with organic anion uptake systems of human liver. The antibiotics CHEMICAL and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, CHEMICAL and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of CHEMICAL and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, CHEMICAL (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (GENE) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L CHEMICAL, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that CHEMICAL and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of CHEMICAL and rifampicin on hepatic organic anion elimination. | SUBSTRATE |
| Interactions of CHEMICAL and rifampicin with organic anion uptake systems of human liver. The antibiotics CHEMICAL and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, CHEMICAL and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of CHEMICAL and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, CHEMICAL (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (GENE) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L CHEMICAL, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for GENE. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for GENE. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that CHEMICAL and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of CHEMICAL and rifampicin on hepatic organic anion elimination. | SUBSTRATE |
| Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. The antibiotics rifamycin SV and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, rifamycin SV and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of rifamycin SV and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L rifamycin SV, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for GENE, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. CHEMICAL (10 micromol/L) inhibited GENE-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for GENE, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and GENE (2.3 micromol/L). In conclusion, these results show that rifamycin SV and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of rifamycin SV and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. The antibiotics rifamycin SV and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, rifamycin SV and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of rifamycin SV and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L rifamycin SV, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for GENE, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. CHEMICAL (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of GENE-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for GENE, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for GENE (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that rifamycin SV and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of rifamycin SV and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. The antibiotics rifamycin SV and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, rifamycin SV and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of rifamycin SV and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L rifamycin SV, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for GENE and 11 micromol/L for OATP-A. CHEMICAL (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, GENE-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that rifamycin SV and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of rifamycin SV and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. The antibiotics rifamycin SV and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, rifamycin SV and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of rifamycin SV and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L rifamycin SV, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for GENE. CHEMICAL (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and GENE-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for GENE. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that rifamycin SV and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of rifamycin SV and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of CHEMICAL and rifampicin with organic anion uptake systems of human liver. The antibiotics CHEMICAL and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, CHEMICAL and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the GENE Oatp1 and Oatp2. Therefore, we investigated the effects of CHEMICAL and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, CHEMICAL (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L CHEMICAL, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that CHEMICAL and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of CHEMICAL and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of CHEMICAL and rifampicin with organic anion uptake systems of human liver. The antibiotics CHEMICAL and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, CHEMICAL and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides GENE and Oatp2. Therefore, we investigated the effects of CHEMICAL and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, CHEMICAL (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L CHEMICAL, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that CHEMICAL and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of CHEMICAL and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of CHEMICAL and rifampicin with organic anion uptake systems of human liver. The antibiotics CHEMICAL and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, CHEMICAL and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and GENE. Therefore, we investigated the effects of CHEMICAL and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, CHEMICAL (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L CHEMICAL, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that CHEMICAL and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of CHEMICAL and rifampicin on hepatic organic anion elimination. | INHIBITOR |
| Interactions of rifamycin SV and CHEMICAL with organic anion uptake systems of human liver. The antibiotics rifamycin SV and CHEMICAL substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, rifamycin SV and CHEMICAL were shown to interfere with hepatic organic anion uptake by inhibition of the GENE Oatp1 and Oatp2. Therefore, we investigated the effects of rifamycin SV and CHEMICAL on the OATPs of human liver and determined whether CHEMICAL is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L rifamycin SV, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. CHEMICAL (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L CHEMICAL inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of CHEMICAL could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that rifamycin SV and CHEMICAL interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of rifamycin SV and CHEMICAL on hepatic organic anion elimination. | INHIBITOR |
| Interactions of rifamycin SV and CHEMICAL with organic anion uptake systems of human liver. The antibiotics rifamycin SV and CHEMICAL substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, rifamycin SV and CHEMICAL were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides GENE and Oatp2. Therefore, we investigated the effects of rifamycin SV and CHEMICAL on the OATPs of human liver and determined whether CHEMICAL is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L rifamycin SV, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. CHEMICAL (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L CHEMICAL inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of CHEMICAL could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that rifamycin SV and CHEMICAL interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of rifamycin SV and CHEMICAL on hepatic organic anion elimination. | INHIBITOR |
| Interactions of rifamycin SV and CHEMICAL with organic anion uptake systems of human liver. The antibiotics rifamycin SV and CHEMICAL substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, rifamycin SV and CHEMICAL were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and GENE. Therefore, we investigated the effects of rifamycin SV and CHEMICAL on the OATPs of human liver and determined whether CHEMICAL is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L rifamycin SV, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. CHEMICAL (10 micromol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated BSP transport was below 15%. 100 micromol/L CHEMICAL inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of CHEMICAL could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that rifamycin SV and CHEMICAL interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of rifamycin SV and CHEMICAL on hepatic organic anion elimination. | INHIBITOR |
| Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. The antibiotics rifamycin SV and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, rifamycin SV and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of rifamycin SV and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated CHEMICAL uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L rifamycin SV, CHEMICAL uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for GENE, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited GENE-mediated CHEMICAL uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and OATP-A-mediated CHEMICAL transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated CHEMICAL uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for GENE, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and GENE (2.3 micromol/L). In conclusion, these results show that rifamycin SV and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of rifamycin SV and rifampicin on hepatic organic anion elimination. | SUBSTRATE |
| Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. The antibiotics rifamycin SV and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, rifamycin SV and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of rifamycin SV and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated CHEMICAL uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L rifamycin SV, CHEMICAL uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for GENE, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated CHEMICAL uptake by 50%, whereas inhibition of GENE-, OATP-B-, and OATP-A-mediated CHEMICAL transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated CHEMICAL uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for GENE, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for GENE (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that rifamycin SV and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of rifamycin SV and rifampicin on hepatic organic anion elimination. | SUBSTRATE |
| Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. The antibiotics rifamycin SV and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, rifamycin SV and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of rifamycin SV and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated CHEMICAL uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L rifamycin SV, CHEMICAL uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for GENE and 11 micromol/L for OATP-A. Rifampicin (10 micromol/L) inhibited OATP8-mediated CHEMICAL uptake by 50%, whereas inhibition of OATP-C-, GENE-, and OATP-A-mediated CHEMICAL transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated CHEMICAL uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that rifamycin SV and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of rifamycin SV and rifampicin on hepatic organic anion elimination. | SUBSTRATE |
| Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. The antibiotics rifamycin SV and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, rifamycin SV and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of rifamycin SV and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 micromol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated CHEMICAL uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 micromol/L rifamycin SV, CHEMICAL uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for GENE. Rifampicin (10 micromol/L) inhibited OATP8-mediated CHEMICAL uptake by 50%, whereas inhibition of OATP-C-, OATP-B-, and GENE-mediated CHEMICAL transport was below 15%. 100 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated CHEMICAL uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for GENE. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/L). In conclusion, these results show that rifamycin SV and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of rifamycin SV and rifampicin on hepatic organic anion elimination. | SUBSTRATE |
| Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased GENE activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in GENE activity was likely due to a change in muscle energy status because CHEMICAL and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of GENE. | GENE-CHEMICAL |
| Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Metformin is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased GENE activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in GENE activity was likely due to a change in muscle energy status because ATP and CHEMICAL concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of GENE. | PRODUCT-OF |
| CHEMICAL increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. CHEMICAL is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of CHEMICAL action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that GENE is activated by CHEMICAL in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of CHEMICAL increase GENE activity in vivo in subjects with type 2 diabetes. CHEMICAL treatment for 10 weeks significantly increased GENE alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of GENE on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in GENE alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after CHEMICAL treatment. Metformin-induced increases in GENE activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of CHEMICAL in subjects with type 2 diabetes may be mediated by the activation of GENE alpha2. | ACTIVATOR |
| CHEMICAL increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. CHEMICAL is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. CHEMICAL treatment for 10 weeks significantly increased GENE activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in GENE activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of GENE. | ACTIVATOR |
| CHEMICAL increases GENE activity in skeletal muscle of subjects with type 2 diabetes. CHEMICAL is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. GENE (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. CHEMICAL treatment for 10 weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK alpha2. | ACTIVATOR |
| CHEMICAL increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. CHEMICAL is an effective hypoglycemic drug that lowers blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of glucose uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic glucose production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. CHEMICAL treatment for 10 weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased GENE activity. The increase in AMPK alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of glucose disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK alpha2. | INHIBITOR |
| Metformin increases GENE activity in skeletal muscle of subjects with type 2 diabetes. Metformin is an effective hypoglycemic drug that lowers blood CHEMICAL concentrations by decreasing hepatic CHEMICAL production and increasing CHEMICAL disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. GENE (AMPK) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of CHEMICAL uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that AMPK is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic CHEMICAL production. In the present study, we evaluated whether therapeutic doses of metformin increase AMPK activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased AMPK alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of AMPK on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in AMPK alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in AMPK activity were associated with higher rates of CHEMICAL disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of AMPK alpha2. | SUBSTRATE |
| Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Metformin is an effective hypoglycemic drug that lowers blood CHEMICAL concentrations by decreasing hepatic CHEMICAL production and increasing CHEMICAL disposal in skeletal muscle; however, the molecular site of metformin action is not well understood. AMP-activated protein kinase (GENE) activity increases in response to depletion of cellular energy stores, and this enzyme has been implicated in the stimulation of CHEMICAL uptake into skeletal muscle and the inhibition of liver gluconeogenesis. We recently reported that GENE is activated by metformin in cultured rat hepatocytes, mediating the inhibitory effects of the drug on hepatic CHEMICAL production. In the present study, we evaluated whether therapeutic doses of metformin increase GENE activity in vivo in subjects with type 2 diabetes. Metformin treatment for 10 weeks significantly increased GENE alpha2 activity in the skeletal muscle, and this was associated with increased phosphorylation of GENE on Thr172 and decreased acetyl-CoA carboxylase-2 activity. The increase in GENE alpha2 activity was likely due to a change in muscle energy status because ATP and phosphocreatine concentrations were lower after metformin treatment. Metformin-induced increases in GENE activity were associated with higher rates of CHEMICAL disposal and muscle glycogen concentrations. These findings suggest that the metabolic effects of metformin in subjects with type 2 diabetes may be mediated by the activation of GENE alpha2. | SUBSTRATE |
| Thalidomide prevents CHEMICAL liver injury in rats through suppression of Kupffer cell sensitization and TNF-alpha production. BACKGROUND & AIMS: Sensitization of Kupffer cells (KCs) to lipopolysaccharide (LPS) and overproduction of GENE are critical for progression of CHEMICAL liver injury. Thalidomide has been shown to suppress TNF-alpha production from macrophages. Accordingly, the purpose of this study was to determine whether thalidomide could prevent alcohol-induced liver injury. METHODS: Rats were given ethanol (5 g/kg body wt) and thalidomide (5 mg/kg) once every 24 hours intragastrically. To assess the sensitization of Kupffer cells, LPS (5 mg/kg intravenously) was administered and liver histology was evaluated 24 hours later. KCs were isolated after 4 weeks of ethanol treatment and intracellular Ca2+ ([Ca2+]i) was measured using fura-2, whereas TNF-alpha was evaluated by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. CD14 was determined by Western and fluorescence staining. RESULTS: Treatment with ethanol for 8 weeks caused marked steatosis, necrosis, and inflammation in the liver. These pathologic parameters were diminished markedly by treatment with thalidomide. In the 4-week ethanol group, the LPS-induced liver damage was aggravated and KCs were sensitized to LPS. Coadministration of thalidomide with ethanol prevented the KC sensitization completely. Furthermore, thalidomide abolished the LPS-induced increase in CD14 expression and [Ca2+]i elevation in KCs. Gut permeability was increased about 10-fold after 4 weeks of ethanol exposure, which was not affected by thalidomide. Moreover, thalidomide reduced the LPS-induced TNF-alpha production by KCs by decreasing TNF-alpha messenger RNA. CONCLUSIONS: These results collectively indicate that thalidomide prevents CHEMICAL liver injury through suppression of TNF-alpha production and abolishment of KC sensitization. | GENE-CHEMICAL |
| CHEMICAL prevents alcoholic liver injury in rats through suppression of Kupffer cell sensitization and GENE production. BACKGROUND & AIMS: Sensitization of Kupffer cells (KCs) to lipopolysaccharide (LPS) and overproduction of tumor necrosis factor (TNF) alpha are critical for progression of alcoholic liver injury. CHEMICAL has been shown to suppress GENE production from macrophages. Accordingly, the purpose of this study was to determine whether CHEMICAL could prevent alcohol-induced liver injury. METHODS: Rats were given ethanol (5 g/kg body wt) and CHEMICAL (5 mg/kg) once every 24 hours intragastrically. To assess the sensitization of Kupffer cells, LPS (5 mg/kg intravenously) was administered and liver histology was evaluated 24 hours later. KCs were isolated after 4 weeks of ethanol treatment and intracellular Ca2+ ([Ca2+]i) was measured using fura-2, whereas GENE was evaluated by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. CD14 was determined by Western and fluorescence staining. RESULTS: Treatment with ethanol for 8 weeks caused marked steatosis, necrosis, and inflammation in the liver. These pathologic parameters were diminished markedly by treatment with CHEMICAL. In the 4-week ethanol group, the LPS-induced liver damage was aggravated and KCs were sensitized to LPS. Coadministration of CHEMICAL with ethanol prevented the KC sensitization completely. Furthermore, CHEMICAL abolished the LPS-induced increase in CD14 expression and [Ca2+]i elevation in KCs. Gut permeability was increased about 10-fold after 4 weeks of ethanol exposure, which was not affected by CHEMICAL. Moreover, CHEMICAL reduced the LPS-induced GENE production by KCs by decreasing GENE messenger RNA. CONCLUSIONS: These results collectively indicate that CHEMICAL prevents alcoholic liver injury through suppression of GENE production and abolishment of KC sensitization. | INDIRECT-DOWNREGULATOR |
| CHEMICAL prevents alcoholic liver injury in rats through suppression of Kupffer cell sensitization and TNF-alpha production. BACKGROUND & AIMS: Sensitization of Kupffer cells (KCs) to lipopolysaccharide (LPS) and overproduction of tumor necrosis factor (TNF) alpha are critical for progression of alcoholic liver injury. CHEMICAL has been shown to suppress TNF-alpha production from macrophages. Accordingly, the purpose of this study was to determine whether CHEMICAL could prevent alcohol-induced liver injury. METHODS: Rats were given ethanol (5 g/kg body wt) and CHEMICAL (5 mg/kg) once every 24 hours intragastrically. To assess the sensitization of Kupffer cells, LPS (5 mg/kg intravenously) was administered and liver histology was evaluated 24 hours later. KCs were isolated after 4 weeks of ethanol treatment and intracellular Ca2+ ([Ca2+]i) was measured using fura-2, whereas TNF-alpha was evaluated by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. GENE was determined by Western and fluorescence staining. RESULTS: Treatment with ethanol for 8 weeks caused marked steatosis, necrosis, and inflammation in the liver. These pathologic parameters were diminished markedly by treatment with CHEMICAL. In the 4-week ethanol group, the LPS-induced liver damage was aggravated and KCs were sensitized to LPS. Coadministration of CHEMICAL with ethanol prevented the KC sensitization completely. Furthermore, CHEMICAL abolished the LPS-induced increase in GENE expression and [Ca2+]i elevation in KCs. Gut permeability was increased about 10-fold after 4 weeks of ethanol exposure, which was not affected by CHEMICAL. Moreover, CHEMICAL reduced the LPS-induced TNF-alpha production by KCs by decreasing TNF-alpha messenger RNA. CONCLUSIONS: These results collectively indicate that CHEMICAL prevents alcoholic liver injury through suppression of TNF-alpha production and abolishment of KC sensitization. | INDIRECT-DOWNREGULATOR |
| Identification and characterization of a novel flavin-containing spermine GENE of mammalian cell origin. During polyamine catabolism, spermine and spermidine are first acetylated by spermidine/spermine N(1)-acetyltransferase (SSAT) and subsequently oxidized by polyamine GENE (PAO) to produce spermidine and putrescine, respectively. In attempting to clone the PAO involved in this back-conversion pathway, we encountered an GENE that preferentially cleaves spermine in the absence of prior acetylation by SSAT. A BLAST search using maize PAO sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular spermine pools decreased by 75% while spermidine and CHEMICAL pools increased, suggesting that spermine was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified GENE strongly favoured spermine over N (1)-acetylspermine and that it failed to act on CHEMICAL, spermidine or the preferred PAO substrate, N (1), N (12)-diacetylspermine. The PAO inhibitor, MDL-72,527, only partially blocked oxidation of spermine while a previously reported PAO substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian GENE which, on the basis of substrate specificity, we have designated spermine GENE in order to distinguish it from the PAO involved in polyamine back-conversion. The identification of an enzyme capable of directly oxidizing spermine to spermidine has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors. | NO-RELATIONSHIP |
| Identification and characterization of a novel flavin-containing spermine GENE of mammalian cell origin. During polyamine catabolism, spermine and CHEMICAL are first acetylated by spermidine/spermine N(1)-acetyltransferase (SSAT) and subsequently oxidized by polyamine GENE (PAO) to produce CHEMICAL and putrescine, respectively. In attempting to clone the PAO involved in this back-conversion pathway, we encountered an GENE that preferentially cleaves spermine in the absence of prior acetylation by SSAT. A BLAST search using maize PAO sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular spermine pools decreased by 75% while CHEMICAL and N (1)-acetylspermidine pools increased, suggesting that spermine was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified GENE strongly favoured spermine over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, CHEMICAL or the preferred PAO substrate, N (1), N (12)-diacetylspermine. The PAO inhibitor, MDL-72,527, only partially blocked oxidation of spermine while a previously reported PAO substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian GENE which, on the basis of substrate specificity, we have designated spermine GENE in order to distinguish it from the PAO involved in polyamine back-conversion. The identification of an enzyme capable of directly oxidizing spermine to CHEMICAL has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors. | NO-RELATIONSHIP |
| Identification and characterization of a novel flavin-containing spermine oxidase of mammalian cell origin. During polyamine catabolism, spermine and spermidine are first acetylated by spermidine/spermine N(1)-acetyltransferase (SSAT) and subsequently oxidized by polyamine oxidase (PAO) to produce spermidine and putrescine, respectively. In attempting to clone the PAO involved in this back-conversion pathway, we encountered an oxidase that preferentially cleaves spermine in the absence of prior acetylation by SSAT. A BLAST search using GENE sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 CHEMICAL. When either cDNA was transiently transfected into HEK-293 cells, intracellular spermine pools decreased by 75% while spermidine and N (1)-acetylspermidine pools increased, suggesting that spermine was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified oxidase strongly favoured spermine over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, spermidine or the preferred PAO substrate, N (1), N (12)-diacetylspermine. The PAO inhibitor, MDL-72,527, only partially blocked oxidation of spermine while a previously reported PAO substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian oxidase which, on the basis of substrate specificity, we have designated spermine oxidase in order to distinguish it from the PAO involved in polyamine back-conversion. The identification of an enzyme capable of directly oxidizing spermine to spermidine has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors. | PART-OF |
| Identification and characterization of a novel CHEMICAL-containing GENE of mammalian cell origin. During polyamine catabolism, spermine and spermidine are first acetylated by spermidine/spermine N(1)-acetyltransferase (SSAT) and subsequently oxidized by polyamine oxidase (PAO) to produce spermidine and putrescine, respectively. In attempting to clone the PAO involved in this back-conversion pathway, we encountered an oxidase that preferentially cleaves spermine in the absence of prior acetylation by SSAT. A BLAST search using maize PAO sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular spermine pools decreased by 75% while spermidine and N (1)-acetylspermidine pools increased, suggesting that spermine was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified oxidase strongly favoured spermine over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, spermidine or the preferred PAO substrate, N (1), N (12)-diacetylspermine. The PAO inhibitor, MDL-72,527, only partially blocked oxidation of spermine while a previously reported PAO substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian oxidase which, on the basis of substrate specificity, we have designated GENE in order to distinguish it from the PAO involved in polyamine back-conversion. The identification of an enzyme capable of directly oxidizing spermine to spermidine has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors. | PART-OF |
| Identification and characterization of a novel flavin-containing spermine oxidase of mammalian cell origin. During polyamine catabolism, spermine and spermidine are first acetylated by spermidine/spermine N(1)-acetyltransferase (SSAT) and subsequently oxidized by polyamine oxidase (PAO) to produce spermidine and putrescine, respectively. In attempting to clone the GENE involved in this back-conversion pathway, we encountered an oxidase that preferentially cleaves spermine in the absence of prior acetylation by SSAT. A BLAST search using maize GENE sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular spermine pools decreased by 75% while spermidine and N (1)-acetylspermidine pools increased, suggesting that spermine was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified oxidase strongly favoured spermine over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, spermidine or the preferred GENE substrate, N (1), N (12)-diacetylspermine. The GENE inhibitor, CHEMICAL, only partially blocked oxidation of spermine while a previously reported GENE substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian oxidase which, on the basis of substrate specificity, we have designated spermine oxidase in order to distinguish it from the GENE involved in polyamine back-conversion. The identification of an enzyme capable of directly oxidizing spermine to spermidine has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors. | INHIBITOR |
| Identification and characterization of a novel flavin-containing spermine oxidase of mammalian cell origin. During polyamine catabolism, spermine and CHEMICAL are first acetylated by spermidine/spermine N(1)-acetyltransferase (SSAT) and subsequently oxidized by GENE (PAO) to produce CHEMICAL and putrescine, respectively. In attempting to clone the PAO involved in this back-conversion pathway, we encountered an oxidase that preferentially cleaves spermine in the absence of prior acetylation by SSAT. A BLAST search using maize PAO sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular spermine pools decreased by 75% while CHEMICAL and N (1)-acetylspermidine pools increased, suggesting that spermine was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified oxidase strongly favoured spermine over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, CHEMICAL or the preferred PAO substrate, N (1), N (12)-diacetylspermine. The PAO inhibitor, MDL-72,527, only partially blocked oxidation of spermine while a previously reported PAO substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian oxidase which, on the basis of substrate specificity, we have designated spermine oxidase in order to distinguish it from the PAO involved in polyamine back-conversion. The identification of an enzyme capable of directly oxidizing spermine to CHEMICAL has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors. | PRODUCT-OF |
| Identification and characterization of a novel flavin-containing spermine oxidase of mammalian cell origin. During polyamine catabolism, spermine and CHEMICAL are first acetylated by spermidine/spermine N(1)-acetyltransferase (SSAT) and subsequently oxidized by polyamine oxidase (GENE) to produce CHEMICAL and putrescine, respectively. In attempting to clone the GENE involved in this back-conversion pathway, we encountered an oxidase that preferentially cleaves spermine in the absence of prior acetylation by SSAT. A BLAST search using maize GENE sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular spermine pools decreased by 75% while CHEMICAL and N (1)-acetylspermidine pools increased, suggesting that spermine was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified oxidase strongly favoured spermine over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, CHEMICAL or the preferred GENE substrate, N (1), N (12)-diacetylspermine. The GENE inhibitor, MDL-72,527, only partially blocked oxidation of spermine while a previously reported GENE substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian oxidase which, on the basis of substrate specificity, we have designated spermine oxidase in order to distinguish it from the GENE involved in polyamine back-conversion. The identification of an enzyme capable of directly oxidizing spermine to CHEMICAL has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors. | PRODUCT-OF |
| Identification and characterization of a novel flavin-containing spermine oxidase of mammalian cell origin. During polyamine catabolism, spermine and spermidine are first acetylated by spermidine/spermine N(1)-acetyltransferase (SSAT) and subsequently oxidized by GENE (PAO) to produce spermidine and CHEMICAL, respectively. In attempting to clone the PAO involved in this back-conversion pathway, we encountered an oxidase that preferentially cleaves spermine in the absence of prior acetylation by SSAT. A BLAST search using maize PAO sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular spermine pools decreased by 75% while spermidine and N (1)-acetylspermidine pools increased, suggesting that spermine was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified oxidase strongly favoured spermine over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, spermidine or the preferred PAO substrate, N (1), N (12)-diacetylspermine. The PAO inhibitor, MDL-72,527, only partially blocked oxidation of spermine while a previously reported PAO substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian oxidase which, on the basis of substrate specificity, we have designated spermine oxidase in order to distinguish it from the PAO involved in polyamine back-conversion. The identification of an enzyme capable of directly oxidizing spermine to spermidine has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors. | PRODUCT-OF |
| Identification and characterization of a novel flavin-containing spermine oxidase of mammalian cell origin. During polyamine catabolism, spermine and spermidine are first acetylated by spermidine/spermine N(1)-acetyltransferase (SSAT) and subsequently oxidized by polyamine oxidase (GENE) to produce spermidine and CHEMICAL, respectively. In attempting to clone the GENE involved in this back-conversion pathway, we encountered an oxidase that preferentially cleaves spermine in the absence of prior acetylation by SSAT. A BLAST search using maize GENE sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular spermine pools decreased by 75% while spermidine and N (1)-acetylspermidine pools increased, suggesting that spermine was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified oxidase strongly favoured spermine over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, spermidine or the preferred GENE substrate, N (1), N (12)-diacetylspermine. The GENE inhibitor, MDL-72,527, only partially blocked oxidation of spermine while a previously reported GENE substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian oxidase which, on the basis of substrate specificity, we have designated spermine oxidase in order to distinguish it from the GENE involved in polyamine back-conversion. The identification of an enzyme capable of directly oxidizing spermine to spermidine has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors. | PRODUCT-OF |
| Identification and characterization of a novel flavin-containing CHEMICAL oxidase of mammalian cell origin. During polyamine catabolism, CHEMICAL and spermidine are first acetylated by spermidine/spermine N(1)-acetyltransferase (GENE) and subsequently oxidized by polyamine oxidase (PAO) to produce spermidine and putrescine, respectively. In attempting to clone the PAO involved in this back-conversion pathway, we encountered an oxidase that preferentially cleaves CHEMICAL in the absence of prior acetylation by GENE. A BLAST search using maize PAO sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular CHEMICAL pools decreased by 75% while spermidine and N (1)-acetylspermidine pools increased, suggesting that CHEMICAL was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified oxidase strongly favoured CHEMICAL over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, spermidine or the preferred PAO substrate, N (1), N (12)-diacetylspermine. The PAO inhibitor, MDL-72,527, only partially blocked oxidation of CHEMICAL while a previously reported PAO substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian oxidase which, on the basis of substrate specificity, we have designated CHEMICAL oxidase in order to distinguish it from the PAO involved in polyamine back-conversion. The identification of an enzyme capable of directly oxidizing CHEMICAL to spermidine has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors. | SUBSTRATE |
| Identification and characterization of a novel flavin-containing CHEMICAL oxidase of mammalian cell origin. During polyamine catabolism, CHEMICAL and spermidine are first acetylated by GENE (SSAT) and subsequently oxidized by polyamine oxidase (PAO) to produce spermidine and putrescine, respectively. In attempting to clone the PAO involved in this back-conversion pathway, we encountered an oxidase that preferentially cleaves CHEMICAL in the absence of prior acetylation by SSAT. A BLAST search using maize PAO sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular CHEMICAL pools decreased by 75% while spermidine and N (1)-acetylspermidine pools increased, suggesting that CHEMICAL was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified oxidase strongly favoured CHEMICAL over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, spermidine or the preferred PAO substrate, N (1), N (12)-diacetylspermine. The PAO inhibitor, MDL-72,527, only partially blocked oxidation of CHEMICAL while a previously reported PAO substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian oxidase which, on the basis of substrate specificity, we have designated CHEMICAL oxidase in order to distinguish it from the PAO involved in polyamine back-conversion. The identification of an enzyme capable of directly oxidizing CHEMICAL to spermidine has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors. | SUBSTRATE |
| Identification and characterization of a novel flavin-containing spermine oxidase of mammalian cell origin. During polyamine catabolism, spermine and CHEMICAL are first acetylated by spermidine/spermine N(1)-acetyltransferase (GENE) and subsequently oxidized by polyamine oxidase (PAO) to produce CHEMICAL and putrescine, respectively. In attempting to clone the PAO involved in this back-conversion pathway, we encountered an oxidase that preferentially cleaves spermine in the absence of prior acetylation by GENE. A BLAST search using maize PAO sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular spermine pools decreased by 75% while CHEMICAL and N (1)-acetylspermidine pools increased, suggesting that spermine was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified oxidase strongly favoured spermine over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, CHEMICAL or the preferred PAO substrate, N (1), N (12)-diacetylspermine. The PAO inhibitor, MDL-72,527, only partially blocked oxidation of spermine while a previously reported PAO substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian oxidase which, on the basis of substrate specificity, we have designated spermine oxidase in order to distinguish it from the PAO involved in polyamine back-conversion. The identification of an enzyme capable of directly oxidizing spermine to CHEMICAL has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors. | SUBSTRATE |
| Identification and characterization of a novel flavin-containing spermine oxidase of mammalian cell origin. During polyamine catabolism, spermine and CHEMICAL are first acetylated by GENE (SSAT) and subsequently oxidized by polyamine oxidase (PAO) to produce CHEMICAL and putrescine, respectively. In attempting to clone the PAO involved in this back-conversion pathway, we encountered an oxidase that preferentially cleaves spermine in the absence of prior acetylation by SSAT. A BLAST search using maize PAO sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular spermine pools decreased by 75% while CHEMICAL and N (1)-acetylspermidine pools increased, suggesting that spermine was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified oxidase strongly favoured spermine over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, CHEMICAL or the preferred PAO substrate, N (1), N (12)-diacetylspermine. The PAO inhibitor, MDL-72,527, only partially blocked oxidation of spermine while a previously reported PAO substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian oxidase which, on the basis of substrate specificity, we have designated spermine oxidase in order to distinguish it from the PAO involved in polyamine back-conversion. The identification of an enzyme capable of directly oxidizing spermine to CHEMICAL has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors. | SUBSTRATE |
| Identification and characterization of a novel flavin-containing spermine oxidase of mammalian cell origin. During CHEMICAL catabolism, spermine and spermidine are first acetylated by spermidine/spermine N(1)-acetyltransferase (GENE) and subsequently oxidized by CHEMICAL oxidase (PAO) to produce spermidine and putrescine, respectively. In attempting to clone the PAO involved in this back-conversion pathway, we encountered an oxidase that preferentially cleaves spermine in the absence of prior acetylation by GENE. A BLAST search using maize PAO sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular spermine pools decreased by 75% while spermidine and N (1)-acetylspermidine pools increased, suggesting that spermine was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified oxidase strongly favoured spermine over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, spermidine or the preferred PAO substrate, N (1), N (12)-diacetylspermine. The PAO inhibitor, MDL-72,527, only partially blocked oxidation of spermine while a previously reported PAO substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian oxidase which, on the basis of substrate specificity, we have designated spermine oxidase in order to distinguish it from the PAO involved in CHEMICAL back-conversion. The identification of an enzyme capable of directly oxidizing spermine to spermidine has important implications for understanding CHEMICAL homoeostasis and for interpreting metabolic and cellular responses to clinically relevant CHEMICAL analogues and inhibitors. | SUBSTRATE |
| Identification and characterization of a novel flavin-containing spermine oxidase of mammalian cell origin. During CHEMICAL catabolism, spermine and spermidine are first acetylated by GENE (SSAT) and subsequently oxidized by CHEMICAL oxidase (PAO) to produce spermidine and putrescine, respectively. In attempting to clone the PAO involved in this back-conversion pathway, we encountered an oxidase that preferentially cleaves spermine in the absence of prior acetylation by SSAT. A BLAST search using maize PAO sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular spermine pools decreased by 75% while spermidine and N (1)-acetylspermidine pools increased, suggesting that spermine was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified oxidase strongly favoured spermine over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, spermidine or the preferred PAO substrate, N (1), N (12)-diacetylspermine. The PAO inhibitor, MDL-72,527, only partially blocked oxidation of spermine while a previously reported PAO substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian oxidase which, on the basis of substrate specificity, we have designated spermine oxidase in order to distinguish it from the PAO involved in CHEMICAL back-conversion. The identification of an enzyme capable of directly oxidizing spermine to spermidine has important implications for understanding CHEMICAL homoeostasis and for interpreting metabolic and cellular responses to clinically relevant CHEMICAL analogues and inhibitors. | SUBSTRATE |
| Identification and characterization of a novel flavin-containing CHEMICAL GENE of mammalian cell origin. During polyamine catabolism, CHEMICAL and spermidine are first acetylated by spermidine/spermine N(1)-acetyltransferase (SSAT) and subsequently oxidized by polyamine GENE (PAO) to produce spermidine and putrescine, respectively. In attempting to clone the PAO involved in this back-conversion pathway, we encountered an GENE that preferentially cleaves CHEMICAL in the absence of prior acetylation by SSAT. A BLAST search using maize PAO sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular CHEMICAL pools decreased by 75% while spermidine and N (1)-acetylspermidine pools increased, suggesting that CHEMICAL was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified GENE strongly favoured CHEMICAL over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, spermidine or the preferred PAO substrate, N (1), N (12)-diacetylspermine. The PAO inhibitor, MDL-72,527, only partially blocked oxidation of CHEMICAL while a previously reported PAO substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian GENE which, on the basis of substrate specificity, we have designated CHEMICAL GENE in order to distinguish it from the PAO involved in polyamine back-conversion. The identification of an enzyme capable of directly oxidizing CHEMICAL to spermidine has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors. | SUBSTRATE |
| Identification and characterization of a novel flavin-containing spermine GENE of mammalian cell origin. During polyamine catabolism, spermine and spermidine are first acetylated by spermidine/spermine N(1)-acetyltransferase (SSAT) and subsequently oxidized by polyamine GENE (PAO) to produce spermidine and putrescine, respectively. In attempting to clone the PAO involved in this back-conversion pathway, we encountered an GENE that preferentially cleaves spermine in the absence of prior acetylation by SSAT. A BLAST search using maize PAO sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular spermine pools decreased by 75% while spermidine and N (1)-acetylspermidine pools increased, suggesting that spermine was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified GENE strongly favoured spermine over CHEMICAL and that it failed to act on N (1)-acetylspermidine, spermidine or the preferred PAO substrate, N (1), N (12)-diacetylspermine. The PAO inhibitor, MDL-72,527, only partially blocked oxidation of spermine while a previously reported PAO substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian GENE which, on the basis of substrate specificity, we have designated spermine GENE in order to distinguish it from the PAO involved in polyamine back-conversion. The identification of an enzyme capable of directly oxidizing spermine to spermidine has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors. | SUBSTRATE |
| Identification and characterization of a novel flavin-containing spermine oxidase of mammalian cell origin. During polyamine catabolism, spermine and spermidine are first acetylated by spermidine/spermine N(1)-acetyltransferase (SSAT) and subsequently oxidized by polyamine oxidase (PAO) to produce spermidine and putrescine, respectively. In attempting to clone the GENE involved in this back-conversion pathway, we encountered an oxidase that preferentially cleaves spermine in the absence of prior acetylation by SSAT. A BLAST search using maize GENE sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular spermine pools decreased by 75% while spermidine and N (1)-acetylspermidine pools increased, suggesting that spermine was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified oxidase strongly favoured spermine over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, spermidine or the preferred GENE substrate, CHEMICAL. The GENE inhibitor, MDL-72,527, only partially blocked oxidation of spermine while a previously reported GENE substrate, N (1)-( n -octanesulphonyl)spermine, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian oxidase which, on the basis of substrate specificity, we have designated spermine oxidase in order to distinguish it from the GENE involved in polyamine back-conversion. The identification of an enzyme capable of directly oxidizing spermine to spermidine has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors. | SUBSTRATE |
| Identification and characterization of a novel flavin-containing spermine oxidase of mammalian cell origin. During polyamine catabolism, spermine and spermidine are first acetylated by spermidine/spermine N(1)-acetyltransferase (SSAT) and subsequently oxidized by polyamine oxidase (PAO) to produce spermidine and putrescine, respectively. In attempting to clone the GENE involved in this back-conversion pathway, we encountered an oxidase that preferentially cleaves spermine in the absence of prior acetylation by SSAT. A BLAST search using maize GENE sequences identified homologous mammalian cDNAs derived from human hepatoma and mouse mammary carcinoma: the encoded proteins differed by 20 amino acids. When either cDNA was transiently transfected into HEK-293 cells, intracellular spermine pools decreased by 75% while spermidine and N (1)-acetylspermidine pools increased, suggesting that spermine was selectively and directly oxidized by the enzyme. Substrate specificity using lysates of oxidase-transfected HEK-293 cells revealed that the newly identified oxidase strongly favoured spermine over N (1)-acetylspermine and that it failed to act on N (1)-acetylspermidine, spermidine or the preferred GENE substrate, N (1), N (12)-diacetylspermine. The GENE inhibitor, MDL-72,527, only partially blocked oxidation of spermine while a previously reported GENE substrate, CHEMICAL, potently inhibited the reaction. Overall, the data indicate that the enzyme represents a novel mammalian oxidase which, on the basis of substrate specificity, we have designated spermine oxidase in order to distinguish it from the GENE involved in polyamine back-conversion. The identification of an enzyme capable of directly oxidizing spermine to spermidine has important implications for understanding polyamine homoeostasis and for interpreting metabolic and cellular responses to clinically relevant polyamine analogues and inhibitors. | SUBSTRATE |
| Low incidence of paradoxical platelet activation by glycoprotein IIb/IIIa inhibitors. The human platelet antigen-1 (HPA-1, Pl(A)) polymorphism has been proposed to influence the inhibitory actions of abciximab. Thus, we hypothesized that this polymorphism might also be the cause for paradoxical activation of platelets by GPIIb/IIIa inhibitors. The effects of abciximab (1-10 microg/ml), CHEMICAL (3-30 nM), or eptifibatide (0.3-3 microg/ml) on basal and ADP (3 microM)-induced GENE externalization were measured in n=62 healthy blood donors and n=177 patients with stable coronary artery disease. All subjects were genotyped for the human platelet antigen-1 (HPA-1, Pl(A)) polymorphism by GALIOS(R) and fluorescence correlation spectroscopy. Although a significant platelet hyperreactivity was observed in the patients, the HPA-1 genotype did not influence basal or ADP-induced GENE expression. A moderate (twofold) stimulation of GENE expression by abciximab but not by CHEMICAL or eptifibatide was observed in one patient. Interestingly, this patient carried the HPA-1 b/b genotype. In no other subject any activation of platelets by GP IIb/IIIa inhibitors was observed and there were no statistically significant differences between HPA-1 genotypes with respect to the effects of GP IIb/IIIa inhibitors on basal or ADP-stimulated GENE expression. It is concluded that paradoxical platelet activation by abciximab is a rare (<2%) phenomenon. HPA-1 b/b genotype might be a contributing factor but clearly does not predict platelet activation by GP IIb/IIIa inhibitors. | NO-RELATIONSHIP |
| Low incidence of paradoxical platelet activation by glycoprotein IIb/IIIa inhibitors. The human platelet antigen-1 (HPA-1, Pl(A)) polymorphism has been proposed to influence the inhibitory actions of abciximab. Thus, we hypothesized that this polymorphism might also be the cause for paradoxical activation of platelets by GPIIb/IIIa inhibitors. The effects of abciximab (1-10 microg/ml), tirofiban (3-30 nM), or CHEMICAL (0.3-3 microg/ml) on basal and ADP (3 microM)-induced GENE externalization were measured in n=62 healthy blood donors and n=177 patients with stable coronary artery disease. All subjects were genotyped for the human platelet antigen-1 (HPA-1, Pl(A)) polymorphism by GALIOS(R) and fluorescence correlation spectroscopy. Although a significant platelet hyperreactivity was observed in the patients, the HPA-1 genotype did not influence basal or ADP-induced GENE expression. A moderate (twofold) stimulation of GENE expression by abciximab but not by tirofiban or CHEMICAL was observed in one patient. Interestingly, this patient carried the HPA-1 b/b genotype. In no other subject any activation of platelets by GP IIb/IIIa inhibitors was observed and there were no statistically significant differences between HPA-1 genotypes with respect to the effects of GP IIb/IIIa inhibitors on basal or ADP-stimulated GENE expression. It is concluded that paradoxical platelet activation by abciximab is a rare (<2%) phenomenon. HPA-1 b/b genotype might be a contributing factor but clearly does not predict platelet activation by GP IIb/IIIa inhibitors. | NO-RELATIONSHIP |
| Low incidence of paradoxical platelet activation by glycoprotein IIb/IIIa inhibitors. The human platelet antigen-1 (HPA-1, Pl(A)) polymorphism has been proposed to influence the inhibitory actions of abciximab. Thus, we hypothesized that this polymorphism might also be the cause for paradoxical activation of platelets by GPIIb/IIIa inhibitors. The effects of abciximab (1-10 microg/ml), tirofiban (3-30 nM), or eptifibatide (0.3-3 microg/ml) on basal and CHEMICAL (3 microM)-induced GENE externalization were measured in n=62 healthy blood donors and n=177 patients with stable coronary artery disease. All subjects were genotyped for the human platelet antigen-1 (HPA-1, Pl(A)) polymorphism by GALIOS(R) and fluorescence correlation spectroscopy. Although a significant platelet hyperreactivity was observed in the patients, the HPA-1 genotype did not influence basal or ADP-induced GENE expression. A moderate (twofold) stimulation of GENE expression by abciximab but not by tirofiban or eptifibatide was observed in one patient. Interestingly, this patient carried the HPA-1 b/b genotype. In no other subject any activation of platelets by GP IIb/IIIa inhibitors was observed and there were no statistically significant differences between HPA-1 genotypes with respect to the effects of GP IIb/IIIa inhibitors on basal or CHEMICAL-stimulated GENE expression. It is concluded that paradoxical platelet activation by abciximab is a rare (<2%) phenomenon. HPA-1 b/b genotype might be a contributing factor but clearly does not predict platelet activation by GP IIb/IIIa inhibitors. | REGULATOR |
| Toxic, halogenated cysteine S-conjugates and targeting of mitochondrial enzymes of energy metabolism. Several haloalkenes are metabolized in part to nephrotoxic cysteine S-conjugates; for example, trichloroethylene and tetrafluoroethylene are converted to S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), respectively. Although DCVC-induced toxicity has been investigated since the 1950s, the toxicity of TFEC and other haloalkene-derived cysteine S-conjugates has been studied more recently. Some segments of the US population are exposed to haloalkenes either through drinking water or in the workplace. Therefore, it is important to define the toxicological consequences of such exposures. Most halogenated cysteine S-conjugates are metabolized by cysteine S-conjugate GENE to pyruvate, ammonia, and an alpha-chloroenethiolate (with DCVC) or an alpha-difluoroalkylthiolate (with TFEC) that may eliminate halide to give a thioacyl halide, which reacts with CHEMICAL groups of lysine residues in proteins. Nine mammalian pyridoxal 5'-phosphate (PLP)-containing enzymes catalyze cysteine S-conjugate beta-lyase reactions, including mitochondrial aspartate aminotransferase (mitAspAT), and mitochondrial branched-chain amino acid aminotransferase (BCAT(m)). Most of the cysteine S-conjugate GENE are syncatalytically inactivated. TFEC-induced toxicity is associated with covalent modification of several mitochondrial enzymes of energy metabolism. Interestingly, the alpha-ketoglutarate- and branched-chain alpha-keto acid dehydrogenase complexes (KGDHC and BCDHC), but not the pyruvate dehydrogenase complex (PDHC), are susceptible to inactivation. mitAspAT and BCAT(m) may form metabolons with KGDHC and BCDHC, respectively, but no PLP enzyme is known to associate with PDHC. Consequently, we hypothesize that not only do these metabolons facilitate substrate channeling, but they also facilitate toxicant channeling, thereby promoting the inactivation of proximate mitochondrial enzymes and the induction of mitochondrial dysfunction. | PART-OF |
| Toxic, halogenated cysteine S-conjugates and targeting of mitochondrial enzymes of energy metabolism. Several haloalkenes are metabolized in part to nephrotoxic cysteine S-conjugates; for example, trichloroethylene and tetrafluoroethylene are converted to S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), respectively. Although DCVC-induced toxicity has been investigated since the 1950s, the toxicity of TFEC and other haloalkene-derived cysteine S-conjugates has been studied more recently. Some segments of the US population are exposed to haloalkenes either through drinking water or in the workplace. Therefore, it is important to define the toxicological consequences of such exposures. Most halogenated cysteine S-conjugates are metabolized by cysteine S-conjugate GENE to pyruvate, ammonia, and an alpha-chloroenethiolate (with DCVC) or an alpha-difluoroalkylthiolate (with TFEC) that may eliminate halide to give a thioacyl halide, which reacts with epsilon-amino groups of CHEMICAL residues in proteins. Nine mammalian pyridoxal 5'-phosphate (PLP)-containing enzymes catalyze cysteine S-conjugate beta-lyase reactions, including mitochondrial aspartate aminotransferase (mitAspAT), and mitochondrial branched-chain amino acid aminotransferase (BCAT(m)). Most of the cysteine S-conjugate GENE are syncatalytically inactivated. TFEC-induced toxicity is associated with covalent modification of several mitochondrial enzymes of energy metabolism. Interestingly, the alpha-ketoglutarate- and branched-chain alpha-keto acid dehydrogenase complexes (KGDHC and BCDHC), but not the pyruvate dehydrogenase complex (PDHC), are susceptible to inactivation. mitAspAT and BCAT(m) may form metabolons with KGDHC and BCDHC, respectively, but no PLP enzyme is known to associate with PDHC. Consequently, we hypothesize that not only do these metabolons facilitate substrate channeling, but they also facilitate toxicant channeling, thereby promoting the inactivation of proximate mitochondrial enzymes and the induction of mitochondrial dysfunction. | PART-OF |
| Toxic, halogenated cysteine S-conjugates and targeting of mitochondrial enzymes of energy metabolism. Several haloalkenes are metabolized in part to nephrotoxic cysteine S-conjugates; for example, trichloroethylene and tetrafluoroethylene are converted to S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), respectively. Although DCVC-induced toxicity has been investigated since the 1950s, the toxicity of TFEC and other haloalkene-derived cysteine S-conjugates has been studied more recently. Some segments of the US population are exposed to haloalkenes either through drinking water or in the workplace. Therefore, it is important to define the toxicological consequences of such exposures. Most halogenated cysteine S-conjugates are metabolized by cysteine S-conjugate GENE to CHEMICAL, ammonia, and an alpha-chloroenethiolate (with DCVC) or an alpha-difluoroalkylthiolate (with TFEC) that may eliminate halide to give a thioacyl halide, which reacts with epsilon-amino groups of lysine residues in proteins. Nine mammalian pyridoxal 5'-phosphate (PLP)-containing enzymes catalyze cysteine S-conjugate beta-lyase reactions, including mitochondrial aspartate aminotransferase (mitAspAT), and mitochondrial branched-chain amino acid aminotransferase (BCAT(m)). Most of the cysteine S-conjugate GENE are syncatalytically inactivated. TFEC-induced toxicity is associated with covalent modification of several mitochondrial enzymes of energy metabolism. Interestingly, the alpha-ketoglutarate- and branched-chain alpha-keto acid dehydrogenase complexes (KGDHC and BCDHC), but not the CHEMICAL dehydrogenase complex (PDHC), are susceptible to inactivation. mitAspAT and BCAT(m) may form metabolons with KGDHC and BCDHC, respectively, but no PLP enzyme is known to associate with PDHC. Consequently, we hypothesize that not only do these metabolons facilitate substrate channeling, but they also facilitate toxicant channeling, thereby promoting the inactivation of proximate mitochondrial enzymes and the induction of mitochondrial dysfunction. | PRODUCT-OF |
| Toxic, halogenated cysteine S-conjugates and targeting of mitochondrial enzymes of energy metabolism. Several haloalkenes are metabolized in part to nephrotoxic cysteine S-conjugates; for example, trichloroethylene and tetrafluoroethylene are converted to S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), respectively. Although DCVC-induced toxicity has been investigated since the 1950s, the toxicity of TFEC and other haloalkene-derived cysteine S-conjugates has been studied more recently. Some segments of the US population are exposed to haloalkenes either through drinking water or in the workplace. Therefore, it is important to define the toxicological consequences of such exposures. Most halogenated cysteine S-conjugates are metabolized by cysteine S-conjugate GENE to pyruvate, CHEMICAL, and an alpha-chloroenethiolate (with DCVC) or an alpha-difluoroalkylthiolate (with TFEC) that may eliminate halide to give a thioacyl halide, which reacts with epsilon-amino groups of lysine residues in proteins. Nine mammalian pyridoxal 5'-phosphate (PLP)-containing enzymes catalyze cysteine S-conjugate beta-lyase reactions, including mitochondrial aspartate aminotransferase (mitAspAT), and mitochondrial branched-chain amino acid aminotransferase (BCAT(m)). Most of the cysteine S-conjugate GENE are syncatalytically inactivated. TFEC-induced toxicity is associated with covalent modification of several mitochondrial enzymes of energy metabolism. Interestingly, the alpha-ketoglutarate- and branched-chain alpha-keto acid dehydrogenase complexes (KGDHC and BCDHC), but not the pyruvate dehydrogenase complex (PDHC), are susceptible to inactivation. mitAspAT and BCAT(m) may form metabolons with KGDHC and BCDHC, respectively, but no PLP enzyme is known to associate with PDHC. Consequently, we hypothesize that not only do these metabolons facilitate substrate channeling, but they also facilitate toxicant channeling, thereby promoting the inactivation of proximate mitochondrial enzymes and the induction of mitochondrial dysfunction. | PRODUCT-OF |
| Toxic, halogenated cysteine S-conjugates and targeting of mitochondrial enzymes of energy metabolism. Several haloalkenes are metabolized in part to nephrotoxic cysteine S-conjugates; for example, trichloroethylene and tetrafluoroethylene are converted to S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), respectively. Although DCVC-induced toxicity has been investigated since the 1950s, the toxicity of TFEC and other haloalkene-derived cysteine S-conjugates has been studied more recently. Some segments of the US population are exposed to haloalkenes either through drinking water or in the workplace. Therefore, it is important to define the toxicological consequences of such exposures. Most halogenated cysteine S-conjugates are metabolized by cysteine S-conjugate GENE to pyruvate, ammonia, and an CHEMICAL (with DCVC) or an alpha-difluoroalkylthiolate (with TFEC) that may eliminate halide to give a thioacyl halide, which reacts with epsilon-amino groups of lysine residues in proteins. Nine mammalian pyridoxal 5'-phosphate (PLP)-containing enzymes catalyze cysteine S-conjugate beta-lyase reactions, including mitochondrial aspartate aminotransferase (mitAspAT), and mitochondrial branched-chain amino acid aminotransferase (BCAT(m)). Most of the cysteine S-conjugate GENE are syncatalytically inactivated. TFEC-induced toxicity is associated with covalent modification of several mitochondrial enzymes of energy metabolism. Interestingly, the alpha-ketoglutarate- and branched-chain alpha-keto acid dehydrogenase complexes (KGDHC and BCDHC), but not the pyruvate dehydrogenase complex (PDHC), are susceptible to inactivation. mitAspAT and BCAT(m) may form metabolons with KGDHC and BCDHC, respectively, but no PLP enzyme is known to associate with PDHC. Consequently, we hypothesize that not only do these metabolons facilitate substrate channeling, but they also facilitate toxicant channeling, thereby promoting the inactivation of proximate mitochondrial enzymes and the induction of mitochondrial dysfunction. | PRODUCT-OF |
| Toxic, halogenated cysteine S-conjugates and targeting of mitochondrial enzymes of energy metabolism. Several haloalkenes are metabolized in part to nephrotoxic cysteine S-conjugates; for example, trichloroethylene and tetrafluoroethylene are converted to S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), respectively. Although DCVC-induced toxicity has been investigated since the 1950s, the toxicity of TFEC and other haloalkene-derived cysteine S-conjugates has been studied more recently. Some segments of the US population are exposed to haloalkenes either through drinking water or in the workplace. Therefore, it is important to define the toxicological consequences of such exposures. Most halogenated cysteine S-conjugates are metabolized by cysteine S-conjugate GENE to pyruvate, ammonia, and an alpha-chloroenethiolate (with CHEMICAL) or an alpha-difluoroalkylthiolate (with TFEC) that may eliminate halide to give a thioacyl halide, which reacts with epsilon-amino groups of lysine residues in proteins. Nine mammalian pyridoxal 5'-phosphate (PLP)-containing enzymes catalyze cysteine S-conjugate beta-lyase reactions, including mitochondrial aspartate aminotransferase (mitAspAT), and mitochondrial branched-chain amino acid aminotransferase (BCAT(m)). Most of the cysteine S-conjugate GENE are syncatalytically inactivated. TFEC-induced toxicity is associated with covalent modification of several mitochondrial enzymes of energy metabolism. Interestingly, the alpha-ketoglutarate- and branched-chain alpha-keto acid dehydrogenase complexes (KGDHC and BCDHC), but not the pyruvate dehydrogenase complex (PDHC), are susceptible to inactivation. mitAspAT and BCAT(m) may form metabolons with KGDHC and BCDHC, respectively, but no PLP enzyme is known to associate with PDHC. Consequently, we hypothesize that not only do these metabolons facilitate substrate channeling, but they also facilitate toxicant channeling, thereby promoting the inactivation of proximate mitochondrial enzymes and the induction of mitochondrial dysfunction. | SUBSTRATE |
| Toxic, halogenated cysteine S-conjugates and targeting of mitochondrial enzymes of energy metabolism. Several haloalkenes are metabolized in part to nephrotoxic cysteine S-conjugates; for example, trichloroethylene and tetrafluoroethylene are converted to S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), respectively. Although DCVC-induced toxicity has been investigated since the 1950s, the toxicity of TFEC and other haloalkene-derived cysteine S-conjugates has been studied more recently. Some segments of the US population are exposed to haloalkenes either through drinking water or in the workplace. Therefore, it is important to define the toxicological consequences of such exposures. Most halogenated cysteine S-conjugates are metabolized by cysteine S-conjugate GENE to pyruvate, ammonia, and an alpha-chloroenethiolate (with DCVC) or an CHEMICAL (with TFEC) that may eliminate halide to give a thioacyl halide, which reacts with epsilon-amino groups of lysine residues in proteins. Nine mammalian pyridoxal 5'-phosphate (PLP)-containing enzymes catalyze cysteine S-conjugate beta-lyase reactions, including mitochondrial aspartate aminotransferase (mitAspAT), and mitochondrial branched-chain amino acid aminotransferase (BCAT(m)). Most of the cysteine S-conjugate GENE are syncatalytically inactivated. TFEC-induced toxicity is associated with covalent modification of several mitochondrial enzymes of energy metabolism. Interestingly, the alpha-ketoglutarate- and branched-chain alpha-keto acid dehydrogenase complexes (KGDHC and BCDHC), but not the pyruvate dehydrogenase complex (PDHC), are susceptible to inactivation. mitAspAT and BCAT(m) may form metabolons with KGDHC and BCDHC, respectively, but no PLP enzyme is known to associate with PDHC. Consequently, we hypothesize that not only do these metabolons facilitate substrate channeling, but they also facilitate toxicant channeling, thereby promoting the inactivation of proximate mitochondrial enzymes and the induction of mitochondrial dysfunction. | PRODUCT-OF |
| Toxic, halogenated cysteine S-conjugates and targeting of mitochondrial enzymes of energy metabolism. Several haloalkenes are metabolized in part to nephrotoxic cysteine S-conjugates; for example, trichloroethylene and tetrafluoroethylene are converted to S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), respectively. Although DCVC-induced toxicity has been investigated since the 1950s, the toxicity of CHEMICAL and other haloalkene-derived cysteine S-conjugates has been studied more recently. Some segments of the US population are exposed to haloalkenes either through drinking water or in the workplace. Therefore, it is important to define the toxicological consequences of such exposures. Most halogenated cysteine S-conjugates are metabolized by cysteine S-conjugate GENE to pyruvate, ammonia, and an alpha-chloroenethiolate (with DCVC) or an alpha-difluoroalkylthiolate (with CHEMICAL) that may eliminate halide to give a thioacyl halide, which reacts with epsilon-amino groups of lysine residues in proteins. Nine mammalian pyridoxal 5'-phosphate (PLP)-containing enzymes catalyze cysteine S-conjugate beta-lyase reactions, including mitochondrial aspartate aminotransferase (mitAspAT), and mitochondrial branched-chain amino acid aminotransferase (BCAT(m)). Most of the cysteine S-conjugate GENE are syncatalytically inactivated. TFEC-induced toxicity is associated with covalent modification of several mitochondrial enzymes of energy metabolism. Interestingly, the alpha-ketoglutarate- and branched-chain alpha-keto acid dehydrogenase complexes (KGDHC and BCDHC), but not the pyruvate dehydrogenase complex (PDHC), are susceptible to inactivation. mitAspAT and BCAT(m) may form metabolons with KGDHC and BCDHC, respectively, but no PLP enzyme is known to associate with PDHC. Consequently, we hypothesize that not only do these metabolons facilitate substrate channeling, but they also facilitate toxicant channeling, thereby promoting the inactivation of proximate mitochondrial enzymes and the induction of mitochondrial dysfunction. | INHIBITOR |
| Toxic, halogenated CHEMICAL and targeting of mitochondrial enzymes of energy metabolism. Several haloalkenes are metabolized in part to nephrotoxic cysteine S-conjugates; for example, trichloroethylene and tetrafluoroethylene are converted to S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), respectively. Although DCVC-induced toxicity has been investigated since the 1950s, the toxicity of TFEC and other haloalkene-derived CHEMICAL has been studied more recently. Some segments of the US population are exposed to haloalkenes either through drinking water or in the workplace. Therefore, it is important to define the toxicological consequences of such exposures. Most halogenated CHEMICAL are metabolized by cysteine S-conjugate GENE to pyruvate, ammonia, and an alpha-chloroenethiolate (with DCVC) or an alpha-difluoroalkylthiolate (with TFEC) that may eliminate halide to give a thioacyl halide, which reacts with epsilon-amino groups of lysine residues in proteins. Nine mammalian pyridoxal 5'-phosphate (PLP)-containing enzymes catalyze cysteine S-conjugate beta-lyase reactions, including mitochondrial aspartate aminotransferase (mitAspAT), and mitochondrial branched-chain amino acid aminotransferase (BCAT(m)). Most of the cysteine S-conjugate GENE are syncatalytically inactivated. TFEC-induced toxicity is associated with covalent modification of several mitochondrial enzymes of energy metabolism. Interestingly, the alpha-ketoglutarate- and branched-chain alpha-keto acid dehydrogenase complexes (KGDHC and BCDHC), but not the pyruvate dehydrogenase complex (PDHC), are susceptible to inactivation. mitAspAT and BCAT(m) may form metabolons with KGDHC and BCDHC, respectively, but no PLP enzyme is known to associate with PDHC. Consequently, we hypothesize that not only do these metabolons facilitate substrate channeling, but they also facilitate toxicant channeling, thereby promoting the inactivation of proximate mitochondrial enzymes and the induction of mitochondrial dysfunction. | SUBSTRATE |
| A heterozygote phenotype is present in the jvs +/- mutant mouse livers. The juvenile visceral steatosis (jvs) mouse, having a mutation in the CHEMICAL transporter gene GENE, is a model of primary systemic CHEMICAL deficiency in humans (SCD, OMIM 212140). Like humans with SCD, homozygous jvs -/- mice have hepatic and cardiac steatoses, reduced plasma and tissue carnitines, and increased urinary CHEMICAL clearance. Because symptomatic heterozygotes have been reported for some fatty acid oxidation disorders, including SCD, we compared the jvs heterozygotes to normal control mice. We measured the free and esterified CHEMICAL, total cholesterol, and triglycerides in adult liver samples, myocardium, and skeletal muscle. Our results indicate significant differences between the livers of nonfasting adult normal (n = 8) vs jvs heterozygotes (n = 8) (means +/- SEM, p < 0.01) for the following parameters: free CHEMICAL, 2.28 +/- 0.36 nmol/mg protein vs 0.41 +/- 0.13; total CHEMICAL, 3.48 +/- 0.36 vs 1.27 +/- 0.25; triglycerides, 0.14 +/- 0.04 vs 0.39 +/- 0.02; and total cholesterol, 0.21 +/- 0.02 vs 0.39 +/- 0.04, but not for esterified CHEMICAL, 1.18 +/- 0.17 vs 0.90 +/- 0.17 (p > 0.05). There is also a negative correlation between hepatic free CHEMICAL and triglycerides from jvs heterozygotes (p < 0.05). Similar results were obtained with myocardium and skeletal muscle. We conclude that free and total CHEMICAL levels are significantly lower in the heterozygote mouse liver and heart while triglyceride and total cholesterol levels are significantly higher. We speculate that in situations of lipolytic stress, some SCD heterozygotes might develop clinical symptoms of CHEMICAL deficiency. | SUBSTRATE |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of [3H]-MPP+ was significantly enhanced by CHEMICAL, guanidine, choline and amantadine as potential substrates for OCT-related transmembrane transporters. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of CHEMICAL, indicating the NAT and not an GENE as their primary site of action. The MPP+-induced release of [3H]-MPP+ was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of [3H]-MPP+ outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of [3H]-MPP+. Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of [3H]-MPP+ release. | REGULATOR |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of CHEMICAL was significantly enhanced by MPP+, guanidine, choline and amantadine as potential substrates for OCT-related transmembrane transporters. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the NAT and not an OCT as their primary site of action. The MPP+-induced release of CHEMICAL was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of CHEMICAL outflow was observed by the GENE and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of CHEMICAL. Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of CHEMICAL release. | NO-RELATIONSHIP |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of CHEMICAL was significantly enhanced by MPP+, guanidine, choline and amantadine as potential substrates for OCT-related transmembrane transporters. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the NAT and not an OCT as their primary site of action. The MPP+-induced release of CHEMICAL was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of CHEMICAL outflow was observed by the OCTN1 and GENE substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of CHEMICAL. Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of CHEMICAL release. | NO-RELATIONSHIP |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the GENE inhibitors cyanine 863, CHEMICAL and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of [3H]-MPP+ was significantly enhanced by MPP+, guanidine, choline and amantadine as potential substrates for OCT-related transmembrane transporters. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the NAT and not an OCT as their primary site of action. The MPP+-induced release of [3H]-MPP+ was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of [3H]-MPP+ outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of [3H]-MPP+. Amongst the three OCTs expressed in the SCG, GENE best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of [3H]-MPP+ release. | INHIBITOR |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the GENE inhibitors cyanine 863, oestradiol and CHEMICAL. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of [3H]-MPP+ was significantly enhanced by MPP+, guanidine, choline and amantadine as potential substrates for OCT-related transmembrane transporters. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the NAT and not an OCT as their primary site of action. The MPP+-induced release of [3H]-MPP+ was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of [3H]-MPP+ outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of [3H]-MPP+. Amongst the three OCTs expressed in the SCG, GENE best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of [3H]-MPP+ release. | INHIBITOR |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the GENE as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of [3H]-MPP+ was significantly enhanced by CHEMICAL, guanidine, choline and amantadine as potential substrates for OCT-related transmembrane transporters. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of CHEMICAL, indicating the GENE and not an OCT as their primary site of action. The MPP+-induced release of [3H]-MPP+ was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of [3H]-MPP+ outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of [3H]-MPP+. Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of [3H]-MPP+ release. | REGULATOR |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of CHEMICAL was significantly enhanced by MPP+, guanidine, choline and amantadine as potential substrates for OCT-related transmembrane transporters. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the NAT and not an GENE as their primary site of action. The MPP+-induced release of CHEMICAL was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of CHEMICAL outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an GENE-mediated transmembrane transport of CHEMICAL. Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of CHEMICAL release. | SUBSTRATE |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of CHEMICAL was significantly enhanced by MPP+, guanidine, choline and amantadine as potential substrates for OCT-related transmembrane transporters. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the NAT and not an OCT as their primary site of action. The MPP+-induced release of CHEMICAL was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of CHEMICAL outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of CHEMICAL. Amongst the three GENE expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of CHEMICAL release. | PRODUCT-OF |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the GENE inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of CHEMICAL was significantly enhanced by MPP+, guanidine, choline and amantadine as potential substrates for OCT-related transmembrane transporters. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the NAT and not an OCT as their primary site of action. The MPP+-induced release of CHEMICAL was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of CHEMICAL outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of CHEMICAL. Amongst the three OCTs expressed in the SCG, GENE best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of CHEMICAL release. | PRODUCT-OF |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular CHEMICAL (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the GENE (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of [3H]-MPP+ was significantly enhanced by MPP+, guanidine, choline and amantadine as potential substrates for OCT-related transmembrane transporters. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the NAT and not an OCT as their primary site of action. The MPP+-induced release of [3H]-MPP+ was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of [3H]-MPP+ outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of [3H]-MPP+. Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of [3H]-MPP+ release. | SUBSTRATE |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular CHEMICAL (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the CHEMICAL transporter (GENE, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the GENE as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of [3H]-MPP+ was significantly enhanced by MPP+, guanidine, choline and amantadine as potential substrates for OCT-related transmembrane transporters. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the GENE and not an OCT as their primary site of action. The MPP+-induced release of [3H]-MPP+ was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of [3H]-MPP+ outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of [3H]-MPP+. Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of [3H]-MPP+ release. | SUBSTRATE |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (CHEMICAL) into superior cervical ganglion (SCG) neurones is mediated by means of the GENE (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of [3H]-MPP+ was significantly enhanced by MPP+, guanidine, choline and amantadine as potential substrates for OCT-related transmembrane transporters. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the NAT and not an OCT as their primary site of action. The MPP+-induced release of [3H]-MPP+ was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of [3H]-MPP+ outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of [3H]-MPP+. Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of [3H]-MPP+ release. | SUBSTRATE |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (CHEMICAL) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (GENE, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the GENE as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of [3H]-MPP+ was significantly enhanced by MPP+, guanidine, choline and amantadine as potential substrates for OCT-related transmembrane transporters. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the GENE and not an OCT as their primary site of action. The MPP+-induced release of [3H]-MPP+ was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of [3H]-MPP+ outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of [3H]-MPP+. Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of [3H]-MPP+ release. | SUBSTRATE |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of CHEMICAL was significantly enhanced by MPP+, guanidine, choline and amantadine as potential substrates for OCT-related GENE. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the NAT and not an OCT as their primary site of action. The MPP+-induced release of CHEMICAL was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of CHEMICAL outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of CHEMICAL. Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of CHEMICAL release. | PRODUCT-OF |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of [3H]-MPP+ was significantly enhanced by CHEMICAL, guanidine, choline and amantadine as potential substrates for OCT-related GENE. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of CHEMICAL, indicating the NAT and not an OCT as their primary site of action. The MPP+-induced release of [3H]-MPP+ was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of [3H]-MPP+ outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of [3H]-MPP+. Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of [3H]-MPP+ release. | SUBSTRATE |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of [3H]-MPP+ was significantly enhanced by MPP+, CHEMICAL, choline and amantadine as potential substrates for GENE-related transmembrane transporters. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the NAT and not an GENE as their primary site of action. The MPP+-induced release of [3H]-MPP+ was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of [3H]-MPP+ outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of [3H]-MPP+. Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of [3H]-MPP+ release. | SUBSTRATE |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of [3H]-MPP+ was significantly enhanced by MPP+, CHEMICAL, choline and amantadine as potential substrates for OCT-related GENE. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the NAT and not an OCT as their primary site of action. The MPP+-induced release of [3H]-MPP+ was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of [3H]-MPP+ outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of [3H]-MPP+. Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of [3H]-MPP+ release. | SUBSTRATE |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of [3H]-MPP+ was significantly enhanced by MPP+, guanidine, CHEMICAL and amantadine as potential substrates for GENE-related transmembrane transporters. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the NAT and not an GENE as their primary site of action. The MPP+-induced release of [3H]-MPP+ was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of [3H]-MPP+ outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of [3H]-MPP+. Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of [3H]-MPP+ release. | SUBSTRATE |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of [3H]-MPP+ was significantly enhanced by MPP+, guanidine, CHEMICAL and amantadine as potential substrates for OCT-related GENE. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the NAT and not an OCT as their primary site of action. The MPP+-induced release of [3H]-MPP+ was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of [3H]-MPP+ outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of [3H]-MPP+. Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of [3H]-MPP+ release. | SUBSTRATE |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of [3H]-MPP+ was significantly enhanced by MPP+, guanidine, choline and CHEMICAL as potential substrates for GENE-related transmembrane transporters. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the NAT and not an GENE as their primary site of action. The MPP+-induced release of [3H]-MPP+ was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of [3H]-MPP+ outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of [3H]-MPP+. Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of [3H]-MPP+ release. | SUBSTRATE |
| Organic cation transporter mRNA and function in the rat superior cervical ganglion. Reuptake of extracellular noradrenaline (NA) into superior cervical ganglion (SCG) neurones is mediated by means of the noradrenaline transporter (NAT, uptake 1). We now demonstrate by single-cell RT-PCR that mRNA of the organic cation transporter 3 (OCT3, uptake 2) occurs in rat SCG neurones as well. Furthermore, our RT-PCR analyses reveal the presence of mRNA for novel organic cation transporters 1 and 2 (OCTN1 and OCTN2), but not for OCT1 or OCT2 in the ganglion. Making use of the NAT as a powerful, neurone-specific transporter system, we loaded[3H]-N-methyl-4-phenylpyridinium ([3H]-MPP+) into cultured rat SCG neurones. The ensuing radioactive outflow from these cultures was enhanced by desipramine and reserpine, but reduced (in the presence of desipramine) by the OCT3 inhibitors cyanine 863, oestradiol and corticosterone. In contrast, cyanine 863 enhanced the radioactive outflow from cultures preloaded with [3H]-NA. Two observations suggest that a depletion of storage vesicles by cyanine 863 accounts for the latter phenomenon: first, the primary radioactive product isolated from supernatants of cultures loaded with [3H]-NA was the metabolite [3H]-DHPG; and second, inhibition of MAO significantly reduced the radioactive outflow in response to cyanine 863. The outflow of [3H]-MPP+ was significantly enhanced by MPP+, guanidine, choline and CHEMICAL as potential substrates for OCT-related GENE. However, desipramine at a low concentration essentially blocked the radioactive outflow induced by all of these substances with the exception of MPP+, indicating the NAT and not an OCT as their primary site of action. The MPP+-induced release of [3H]-MPP+ was fully prevented by a combined application of desipramine and cyanine 863. No trans-stimulation of [3H]-MPP+ outflow was observed by the OCTN1 and OCTN2 substrate carnitine at 100 microM. Our observations indicate an OCT-mediated transmembrane transport of [3H]-MPP+. Amongst the three OCTs expressed in the SCG, OCT3 best fits the profile of substrates and antagonists that cause trans-stimulation and trans-inhibition, respectively, of [3H]-MPP+ release. | SUBSTRATE |
| Neuroprotection by CHEMICAL in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of type B monoamine oxidase (MAO-B), (-)deprenyl (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that selegiline protects neurons from cell death. Among selegiline-related CHEMICAL, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. Rasagiline prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). Long-term administration of CHEMICAL to rats increased the activities of antioxidative enzymes GENE (SOD) and catalase in the brain regions containing dopamine neurons. Rasagiline and related CHEMICAL may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT. | ACTIVATOR |
| Neuroprotection by CHEMICAL in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of type B monoamine oxidase (MAO-B), (-)deprenyl (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that selegiline protects neurons from cell death. Among selegiline-related CHEMICAL, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. Rasagiline prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). Long-term administration of CHEMICAL to rats increased the activities of antioxidative enzymes superoxide dismutase (GENE) and catalase in the brain regions containing dopamine neurons. Rasagiline and related CHEMICAL may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT. | ACTIVATOR |
| Neuroprotection by CHEMICAL in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of type B monoamine oxidase (MAO-B), (-)deprenyl (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that selegiline protects neurons from cell death. Among selegiline-related CHEMICAL, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. Rasagiline prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). Long-term administration of CHEMICAL to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and GENE in the brain regions containing dopamine neurons. Rasagiline and related CHEMICAL may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT. | ACTIVATOR |
| Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of type B monoamine oxidase (MAO-B), (-)deprenyl (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that selegiline protects neurons from cell death. Among selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. CHEMICAL prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic GENE and a neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). Long-term administration of propargylamines to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and catalase in the brain regions containing dopamine neurons. CHEMICAL and related propargylamines may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT. | ACTIVATOR |
| Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of type B monoamine oxidase (MAO-B), (-)deprenyl (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that selegiline protects neurons from cell death. Among selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. CHEMICAL prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a GENE, glial cell line-derived GENE (GDNF). Long-term administration of propargylamines to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and catalase in the brain regions containing dopamine neurons. CHEMICAL and related propargylamines may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT. | ACTIVATOR |
| Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of type B monoamine oxidase (MAO-B), (-)deprenyl (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that selegiline protects neurons from cell death. Among selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. CHEMICAL prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, GENE (GDNF). Long-term administration of propargylamines to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and catalase in the brain regions containing dopamine neurons. CHEMICAL and related propargylamines may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT. | ACTIVATOR |
| Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of type B monoamine oxidase (MAO-B), (-)deprenyl (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that selegiline protects neurons from cell death. Among selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. CHEMICAL prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, glial cell line-derived neurotrophic factor (GENE). Long-term administration of propargylamines to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and catalase in the brain regions containing dopamine neurons. CHEMICAL and related propargylamines may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT. | ACTIVATOR |
| Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of GENE (MAO-B), CHEMICAL (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that selegiline protects neurons from cell death. Among selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. Rasagiline prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). Long-term administration of propargylamines to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and catalase in the brain regions containing dopamine neurons. Rasagiline and related propargylamines may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT. | INHIBITOR |
| Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of type B monoamine oxidase (GENE), CHEMICAL (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that selegiline protects neurons from cell death. Among selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. Rasagiline prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). Long-term administration of propargylamines to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and catalase in the brain regions containing dopamine neurons. Rasagiline and related propargylamines may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT. | INHIBITOR |
| Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of GENE (MAO-B), (-)deprenyl (CHEMICAL), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that CHEMICAL protects neurons from cell death. Among selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. Rasagiline prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). Long-term administration of propargylamines to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and catalase in the brain regions containing dopamine neurons. Rasagiline and related propargylamines may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT. | INHIBITOR |
| Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of type B monoamine oxidase (GENE), (-)deprenyl (CHEMICAL), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that CHEMICAL protects neurons from cell death. Among selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. Rasagiline prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). Long-term administration of propargylamines to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and catalase in the brain regions containing dopamine neurons. Rasagiline and related propargylamines may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT. | INHIBITOR |
| Pharmacodynamics and pharmacokinetics of phenylbutazone in calves. Phenylbutazone (PBZ) was administered to six calves intravenously (i.v.) and orally at a dose rate of 4.4 mg/kg in a three-period cross-over study incorporating a placebo treatment to establish its pharmacokinetic and pharmacodynamic properties. Extravascular distribution was determined by measuring penetration into tissue chamber fluid in the absence of stimulation (transudate) and after stimulation of chamber tissue with the mild irritant carrageenan (exudate). CHEMICAL pharmacokinetics after i.v. dosage was characterized by slow clearance (1.29 mL/kg/h), long-terminal half-life (53.4 h), low distribution volume (0.09 L/kg) and low concentrations in plasma of the metabolite oxyphenbutazone (OPBZ), confirming previously published data for adult cattle. After oral dosage bioavailability (F) was 66%. Passage into exudate was slow and limited, and penetration into transudate was even slower and more limited; area under curve values for plasma, exudate and transudate after i.v. dosage were 3604, 1117 and 766 microg h/mL and corresponding values after oral dosage were 2435, 647 and 486 microg h/mL. These concentrations were approximately 15-20 (plasma) and nine (exudate) times greater than those previously reported in horses (receiving the same dose rate of PBZ). In the horse, the lower concentrations had produced marked inhibition of eicosanoid synthesis and suppressed the inflammatory response. The higher concentrations in calves were insufficient to inhibit significantly exudate prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and beta-glucuronidase concentrations and exudate leucocyte numbers, serum thromboxane B2 (TxB2), and bradykinin-induced skin swelling. These differences from the horse might be the result of: (a) the presence in equine biological fluids of higher concentrations than in calves of the active CHEMICAL metabolite, OPBZ; (b) a greater degree of binding of CHEMICAL to plasma protein in calves; (c) species differences in the sensitivity to CHEMICAL of the GENE (COX) isoenzymes, COX-1 and COX-2 or; (d) a combination of these factors. To achieve clinical efficacy with single doses of CHEMICAL in calves, higher dosages than 4.4 mg/kg will be probably required. | REGULATOR |
| Pharmacodynamics and pharmacokinetics of phenylbutazone in calves. Phenylbutazone (PBZ) was administered to six calves intravenously (i.v.) and orally at a dose rate of 4.4 mg/kg in a three-period cross-over study incorporating a placebo treatment to establish its pharmacokinetic and pharmacodynamic properties. Extravascular distribution was determined by measuring penetration into tissue chamber fluid in the absence of stimulation (transudate) and after stimulation of chamber tissue with the mild irritant carrageenan (exudate). CHEMICAL pharmacokinetics after i.v. dosage was characterized by slow clearance (1.29 mL/kg/h), long-terminal half-life (53.4 h), low distribution volume (0.09 L/kg) and low concentrations in plasma of the metabolite oxyphenbutazone (OPBZ), confirming previously published data for adult cattle. After oral dosage bioavailability (F) was 66%. Passage into exudate was slow and limited, and penetration into transudate was even slower and more limited; area under curve values for plasma, exudate and transudate after i.v. dosage were 3604, 1117 and 766 microg h/mL and corresponding values after oral dosage were 2435, 647 and 486 microg h/mL. These concentrations were approximately 15-20 (plasma) and nine (exudate) times greater than those previously reported in horses (receiving the same dose rate of PBZ). In the horse, the lower concentrations had produced marked inhibition of eicosanoid synthesis and suppressed the inflammatory response. The higher concentrations in calves were insufficient to inhibit significantly exudate prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and beta-glucuronidase concentrations and exudate leucocyte numbers, serum thromboxane B2 (TxB2), and bradykinin-induced skin swelling. These differences from the horse might be the result of: (a) the presence in equine biological fluids of higher concentrations than in calves of the active CHEMICAL metabolite, OPBZ; (b) a greater degree of binding of CHEMICAL to plasma protein in calves; (c) species differences in the sensitivity to CHEMICAL of the cyclo-oxygenase (GENE) isoenzymes, COX-1 and COX-2 or; (d) a combination of these factors. To achieve clinical efficacy with single doses of CHEMICAL in calves, higher dosages than 4.4 mg/kg will be probably required. | REGULATOR |
| Pharmacodynamics and pharmacokinetics of phenylbutazone in calves. Phenylbutazone (PBZ) was administered to six calves intravenously (i.v.) and orally at a dose rate of 4.4 mg/kg in a three-period cross-over study incorporating a placebo treatment to establish its pharmacokinetic and pharmacodynamic properties. Extravascular distribution was determined by measuring penetration into tissue chamber fluid in the absence of stimulation (transudate) and after stimulation of chamber tissue with the mild irritant carrageenan (exudate). CHEMICAL pharmacokinetics after i.v. dosage was characterized by slow clearance (1.29 mL/kg/h), long-terminal half-life (53.4 h), low distribution volume (0.09 L/kg) and low concentrations in plasma of the metabolite oxyphenbutazone (OPBZ), confirming previously published data for adult cattle. After oral dosage bioavailability (F) was 66%. Passage into exudate was slow and limited, and penetration into transudate was even slower and more limited; area under curve values for plasma, exudate and transudate after i.v. dosage were 3604, 1117 and 766 microg h/mL and corresponding values after oral dosage were 2435, 647 and 486 microg h/mL. These concentrations were approximately 15-20 (plasma) and nine (exudate) times greater than those previously reported in horses (receiving the same dose rate of PBZ). In the horse, the lower concentrations had produced marked inhibition of eicosanoid synthesis and suppressed the inflammatory response. The higher concentrations in calves were insufficient to inhibit significantly exudate prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and beta-glucuronidase concentrations and exudate leucocyte numbers, serum thromboxane B2 (TxB2), and bradykinin-induced skin swelling. These differences from the horse might be the result of: (a) the presence in equine biological fluids of higher concentrations than in calves of the active CHEMICAL metabolite, OPBZ; (b) a greater degree of binding of CHEMICAL to plasma protein in calves; (c) species differences in the sensitivity to CHEMICAL of the cyclo-oxygenase (COX) isoenzymes, GENE and COX-2 or; (d) a combination of these factors. To achieve clinical efficacy with single doses of CHEMICAL in calves, higher dosages than 4.4 mg/kg will be probably required. | REGULATOR |
| Pharmacodynamics and pharmacokinetics of phenylbutazone in calves. Phenylbutazone (PBZ) was administered to six calves intravenously (i.v.) and orally at a dose rate of 4.4 mg/kg in a three-period cross-over study incorporating a placebo treatment to establish its pharmacokinetic and pharmacodynamic properties. Extravascular distribution was determined by measuring penetration into tissue chamber fluid in the absence of stimulation (transudate) and after stimulation of chamber tissue with the mild irritant carrageenan (exudate). CHEMICAL pharmacokinetics after i.v. dosage was characterized by slow clearance (1.29 mL/kg/h), long-terminal half-life (53.4 h), low distribution volume (0.09 L/kg) and low concentrations in plasma of the metabolite oxyphenbutazone (OPBZ), confirming previously published data for adult cattle. After oral dosage bioavailability (F) was 66%. Passage into exudate was slow and limited, and penetration into transudate was even slower and more limited; area under curve values for plasma, exudate and transudate after i.v. dosage were 3604, 1117 and 766 microg h/mL and corresponding values after oral dosage were 2435, 647 and 486 microg h/mL. These concentrations were approximately 15-20 (plasma) and nine (exudate) times greater than those previously reported in horses (receiving the same dose rate of PBZ). In the horse, the lower concentrations had produced marked inhibition of eicosanoid synthesis and suppressed the inflammatory response. The higher concentrations in calves were insufficient to inhibit significantly exudate prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and beta-glucuronidase concentrations and exudate leucocyte numbers, serum thromboxane B2 (TxB2), and bradykinin-induced skin swelling. These differences from the horse might be the result of: (a) the presence in equine biological fluids of higher concentrations than in calves of the active CHEMICAL metabolite, OPBZ; (b) a greater degree of binding of CHEMICAL to plasma protein in calves; (c) species differences in the sensitivity to CHEMICAL of the cyclo-oxygenase (COX) isoenzymes, COX-1 and GENE or; (d) a combination of these factors. To achieve clinical efficacy with single doses of CHEMICAL in calves, higher dosages than 4.4 mg/kg will be probably required. | REGULATOR |
| Practical asymmetric synthesis of CHEMICAL, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction. A streamlined and high-yielding synthesis of CHEMICAL (1), a potent GENE antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81%) and with only two isolations. | INHIBITOR |
| Practical asymmetric synthesis of CHEMICAL, a potent human GENE antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction. A streamlined and high-yielding synthesis of CHEMICAL (1), a potent substance P (SP) receptor antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81%) and with only two isolations. | INHIBITOR |
| Effects of pentosan polysulfate CHEMICAL on the estrogen-induced pituitary prolactinoma in Fischer 344 rats. The development of estrogen-induced pituitary prolactinoma in Fischer 344 (F344) rats is associated with enhanced neovascularization. This type of tumor is a rich source of basic fibroblast growth factor (bFGF), which possesses strong mitogenic and angiogenic properties. Pentosan polysulfate CHEMICAL (PPS) has been shown to exert antitumor activity by antagonizing the binding of GENE to cell surface receptors. We have examined the effects of pentosan on tumor growth, hyperprolactinemia and angiogenesis in diethylstilbestrol-induced anterior pituitary adenoma in F344 rats. Chronic treatment with PPS did not cause any changes in the pituitary weight and serum prolactin concentration in comparison with untreated animals. The density of microvessels identified by CD-31 was also not affected by the tested drug. On the other hand, pentosan has been found to decrease cell proliferation evaluated by a number of PCNA-positive stained cell nuclei. Moreover, the TUNEL method has revealed an increased number of apoptotic bodies within the anterior pituitary after treatment with PPS. Despite the antiproliferative and proapoptotic activity of pentosan, the drug failed to inhibit tumor growth. This fact might be due to the lack of antiangiogenic activity of PPS in this experimental design. | INHIBITOR |
| Localization of the ammonium transporter proteins GENE and RhCG in mouse kidney. Ammonia is both produced and transported by renal epithelial cells, and it regulates renal ion transport. Recent studies have identified a family of putative ammonium transporters; mRNA for two members of this family, Rh B-glycoprotein (RhBG) and Rh C-glycoprotein (RhCG), is expressed in the kidney. The purpose of this study was to determine the cellular location of GENE and RhCG protein in the mouse kidney. We generated RhBG- and RhCG-specific anti-peptide antibodies. Immunoblot analysis confirmed that both proteins were expressed in the mouse kidney. GENE localization with immunohistochemistry revealed discrete basolateral labeling in the connecting segment (CNT) and in the majority of initial collecting tubule (ICT) and cortical collecting duct (CCD) cells. In the outer medullary collecting duct (OMCD) and inner medullary collecting duct (IMCD) only a subpopulation of cells exhibited basolateral immunoreactivity. Colocalization of GENE with carbonic anhydrase II, the CHEMICAL-sensitive transporter, and the anion exchangers AE1 and pendrin demonstrated GENE immunoreactivity in all CNT cells and all CCD and ICT principal cells. In the ICT and CCD, basolateral GENE immunoreactivity is also present in A-type intercalated cells but not in pendrin-positive CCD intercalated cells. In the OMCD and IMCD, only intercalated cells exhibit GENE immunoreactivity. Immunoreactivity for a second putative ammonium transporter, RhCG, was present in the apical region of cells with almost the same distribution as GENE. However, RhCG immunoreactivity was present in all CCD cells, and it was present in outer stripe OMCD principal cells, in addition to OMCD and IMCD intercalated cells. Thus the majority of GENE and RhCG protein expression is present in the same epithelial cell types in the CNT and collecting duct but with opposite polarity. These findings suggest that GENE and RhCG may play important and cell-specific roles in ammonium transport and signaling in these regions of the kidney. | SUBSTRATE |
| Localization of the CHEMICAL transporter proteins GENE and RhCG in mouse kidney. Ammonia is both produced and transported by renal epithelial cells, and it regulates renal ion transport. Recent studies have identified a family of putative CHEMICAL transporters; mRNA for two members of this family, Rh B-glycoprotein (RhBG) and Rh C-glycoprotein (RhCG), is expressed in the kidney. The purpose of this study was to determine the cellular location of GENE and RhCG protein in the mouse kidney. We generated RhBG- and RhCG-specific anti-peptide antibodies. Immunoblot analysis confirmed that both proteins were expressed in the mouse kidney. GENE localization with immunohistochemistry revealed discrete basolateral labeling in the connecting segment (CNT) and in the majority of initial collecting tubule (ICT) and cortical collecting duct (CCD) cells. In the outer medullary collecting duct (OMCD) and inner medullary collecting duct (IMCD) only a subpopulation of cells exhibited basolateral immunoreactivity. Colocalization of GENE with carbonic anhydrase II, the thiazide-sensitive transporter, and the anion exchangers AE1 and pendrin demonstrated GENE immunoreactivity in all CNT cells and all CCD and ICT principal cells. In the ICT and CCD, basolateral GENE immunoreactivity is also present in A-type intercalated cells but not in pendrin-positive CCD intercalated cells. In the OMCD and IMCD, only intercalated cells exhibit GENE immunoreactivity. Immunoreactivity for a second putative CHEMICAL transporter, RhCG, was present in the apical region of cells with almost the same distribution as GENE. However, RhCG immunoreactivity was present in all CCD cells, and it was present in outer stripe OMCD principal cells, in addition to OMCD and IMCD intercalated cells. Thus the majority of GENE and RhCG protein expression is present in the same epithelial cell types in the CNT and collecting duct but with opposite polarity. These findings suggest that GENE and RhCG may play important and cell-specific roles in CHEMICAL transport and signaling in these regions of the kidney. | SUBSTRATE |
| Localization of the CHEMICAL transporter proteins RhBG and GENE in mouse kidney. Ammonia is both produced and transported by renal epithelial cells, and it regulates renal ion transport. Recent studies have identified a family of putative CHEMICAL transporters; mRNA for two members of this family, Rh B-glycoprotein (RhBG) and Rh C-glycoprotein (RhCG), is expressed in the kidney. The purpose of this study was to determine the cellular location of RhBG and GENE protein in the mouse kidney. We generated RhBG- and RhCG-specific anti-peptide antibodies. Immunoblot analysis confirmed that both proteins were expressed in the mouse kidney. RhBG localization with immunohistochemistry revealed discrete basolateral labeling in the connecting segment (CNT) and in the majority of initial collecting tubule (ICT) and cortical collecting duct (CCD) cells. In the outer medullary collecting duct (OMCD) and inner medullary collecting duct (IMCD) only a subpopulation of cells exhibited basolateral immunoreactivity. Colocalization of RhBG with carbonic anhydrase II, the thiazide-sensitive transporter, and the anion exchangers AE1 and pendrin demonstrated RhBG immunoreactivity in all CNT cells and all CCD and ICT principal cells. In the ICT and CCD, basolateral RhBG immunoreactivity is also present in A-type intercalated cells but not in pendrin-positive CCD intercalated cells. In the OMCD and IMCD, only intercalated cells exhibit RhBG immunoreactivity. Immunoreactivity for a second putative CHEMICAL transporter, GENE, was present in the apical region of cells with almost the same distribution as RhBG. However, GENE immunoreactivity was present in all CCD cells, and it was present in outer stripe OMCD principal cells, in addition to OMCD and IMCD intercalated cells. Thus the majority of RhBG and GENE protein expression is present in the same epithelial cell types in the CNT and collecting duct but with opposite polarity. These findings suggest that RhBG and GENE may play important and cell-specific roles in CHEMICAL transport and signaling in these regions of the kidney. | SUBSTRATE |
| Phosphodiesterase type 5 as a pharmacologic target in erectile dysfunction. The scientific rationale of pharmacologically inhibiting phosphodiesterase type 5 (PDE5) in the treatment of erectile dysfunction (ED) is reviewed. Published literature on the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway for penile erection and on GENE inhibition using CHEMICAL as the model for pharmacologic GENE inhibition are assessed. The key second messenger in the mediation of penile erection is cGMP. GENE is the predominant PDE in the corpus cavernosum, and cGMP is its primary substrate. Therefore, in men with ED, elevation of cGMP in corpus cavernosal tissue via selective inhibition of cGMP-specific GENE is a means of improving erectile function at minimal risk of adverse events. This approach is validated by the clinical efficacy and safety of CHEMICAL, the pioneering drug for selective GENE inhibitor therapy for ED. CHEMICAL exhibits inhibitory potency against GENE and a 10-fold lower dose-related inhibitory potency against rod outer segment PDE6, the predominant PDE in the phototransduction cascade in rods. Thus, its pharmacologic profile is predictable, with close correlation between pharmacodynamic and pharmacokinetic properties. Clinically, CHEMICAL improves erectile function in a large percentage of men with ED. The most common adverse events are due to GENE inhibition in vascular and visceral smooth muscle; similar adverse events are expected during therapeutic use of all GENE inhibitors. As free CHEMICAL plasma concentrations approach concentrations sufficient to inhibit retinal PDE6, usually at higher therapeutic doses, transient, reversible visual adverse events can occur, albeit infrequently. Selective inhibition of GENE is a rational therapeutic approach in ED, as proved by the clinical success of CHEMICAL. | INHIBITOR |
| Phosphodiesterase type 5 as a pharmacologic target in erectile dysfunction. The scientific rationale of pharmacologically inhibiting phosphodiesterase type 5 (PDE5) in the treatment of erectile dysfunction (ED) is reviewed. Published literature on the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway for penile erection and on PDE5 inhibition using sildenafil as the model for pharmacologic PDE5 inhibition are assessed. The key second messenger in the mediation of penile erection is cGMP. PDE5 is the predominant GENE in the corpus cavernosum, and cGMP is its primary substrate. Therefore, in men with ED, elevation of cGMP in corpus cavernosal tissue via selective inhibition of cGMP-specific PDE5 is a means of improving erectile function at minimal risk of adverse events. This approach is validated by the clinical efficacy and safety of sildenafil, the pioneering drug for selective PDE5 inhibitor therapy for ED. CHEMICAL exhibits inhibitory potency against PDE5 and a 10-fold lower dose-related inhibitory potency against rod outer segment PDE6, the predominant GENE in the phototransduction cascade in rods. Thus, its pharmacologic profile is predictable, with close correlation between pharmacodynamic and pharmacokinetic properties. Clinically, sildenafil improves erectile function in a large percentage of men with ED. The most common adverse events are due to PDE5 inhibition in vascular and visceral smooth muscle; similar adverse events are expected during therapeutic use of all PDE5 inhibitors. As free sildenafil plasma concentrations approach concentrations sufficient to inhibit retinal PDE6, usually at higher therapeutic doses, transient, reversible visual adverse events can occur, albeit infrequently. Selective inhibition of PDE5 is a rational therapeutic approach in ED, as proved by the clinical success of sildenafil. | INHIBITOR |
| Phosphodiesterase type 5 as a pharmacologic target in erectile dysfunction. The scientific rationale of pharmacologically inhibiting phosphodiesterase type 5 (PDE5) in the treatment of erectile dysfunction (ED) is reviewed. Published literature on the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway for penile erection and on PDE5 inhibition using sildenafil as the model for pharmacologic PDE5 inhibition are assessed. The key second messenger in the mediation of penile erection is cGMP. PDE5 is the predominant PDE in the corpus cavernosum, and cGMP is its primary substrate. Therefore, in men with ED, elevation of cGMP in corpus cavernosal tissue via selective inhibition of cGMP-specific PDE5 is a means of improving erectile function at minimal risk of adverse events. This approach is validated by the clinical efficacy and safety of sildenafil, the pioneering drug for selective PDE5 inhibitor therapy for ED. CHEMICAL exhibits inhibitory potency against PDE5 and a 10-fold lower dose-related inhibitory potency against rod outer segment GENE, the predominant PDE in the phototransduction cascade in rods. Thus, its pharmacologic profile is predictable, with close correlation between pharmacodynamic and pharmacokinetic properties. Clinically, sildenafil improves erectile function in a large percentage of men with ED. The most common adverse events are due to PDE5 inhibition in vascular and visceral smooth muscle; similar adverse events are expected during therapeutic use of all PDE5 inhibitors. As free sildenafil plasma concentrations approach concentrations sufficient to inhibit retinal GENE, usually at higher therapeutic doses, transient, reversible visual adverse events can occur, albeit infrequently. Selective inhibition of PDE5 is a rational therapeutic approach in ED, as proved by the clinical success of sildenafil. | INHIBITOR |
| Phosphodiesterase type 5 as a pharmacologic target in erectile dysfunction. The scientific rationale of pharmacologically inhibiting phosphodiesterase type 5 (PDE5) in the treatment of erectile dysfunction (ED) is reviewed. Published literature on the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway for penile erection and on GENE inhibition using sildenafil as the model for pharmacologic GENE inhibition are assessed. The key second messenger in the mediation of penile erection is CHEMICAL. GENE is the predominant PDE in the corpus cavernosum, and CHEMICAL is its primary substrate. Therefore, in men with ED, elevation of CHEMICAL in corpus cavernosal tissue via selective inhibition of CHEMICAL-specific GENE is a means of improving erectile function at minimal risk of adverse events. This approach is validated by the clinical efficacy and safety of sildenafil, the pioneering drug for selective GENE inhibitor therapy for ED. Sildenafil exhibits inhibitory potency against GENE and a 10-fold lower dose-related inhibitory potency against rod outer segment PDE6, the predominant PDE in the phototransduction cascade in rods. Thus, its pharmacologic profile is predictable, with close correlation between pharmacodynamic and pharmacokinetic properties. Clinically, sildenafil improves erectile function in a large percentage of men with ED. The most common adverse events are due to GENE inhibition in vascular and visceral smooth muscle; similar adverse events are expected during therapeutic use of all GENE inhibitors. As free sildenafil plasma concentrations approach concentrations sufficient to inhibit retinal PDE6, usually at higher therapeutic doses, transient, reversible visual adverse events can occur, albeit infrequently. Selective inhibition of GENE is a rational therapeutic approach in ED, as proved by the clinical success of sildenafil. | SUBSTRATE |
| Phosphodiesterase type 5 as a pharmacologic target in erectile dysfunction. The scientific rationale of pharmacologically inhibiting phosphodiesterase type 5 (PDE5) in the treatment of erectile dysfunction (ED) is reviewed. Published literature on the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway for penile erection and on PDE5 inhibition using sildenafil as the model for pharmacologic PDE5 inhibition are assessed. The key second messenger in the mediation of penile erection is CHEMICAL. PDE5 is the predominant GENE in the corpus cavernosum, and CHEMICAL is its primary substrate. Therefore, in men with ED, elevation of CHEMICAL in corpus cavernosal tissue via selective inhibition of cGMP-specific PDE5 is a means of improving erectile function at minimal risk of adverse events. This approach is validated by the clinical efficacy and safety of sildenafil, the pioneering drug for selective PDE5 inhibitor therapy for ED. Sildenafil exhibits inhibitory potency against PDE5 and a 10-fold lower dose-related inhibitory potency against rod outer segment PDE6, the predominant GENE in the phototransduction cascade in rods. Thus, its pharmacologic profile is predictable, with close correlation between pharmacodynamic and pharmacokinetic properties. Clinically, sildenafil improves erectile function in a large percentage of men with ED. The most common adverse events are due to PDE5 inhibition in vascular and visceral smooth muscle; similar adverse events are expected during therapeutic use of all PDE5 inhibitors. As free sildenafil plasma concentrations approach concentrations sufficient to inhibit retinal PDE6, usually at higher therapeutic doses, transient, reversible visual adverse events can occur, albeit infrequently. Selective inhibition of PDE5 is a rational therapeutic approach in ED, as proved by the clinical success of sildenafil. | SUBSTRATE |
| Study of the nematode putative GABA type-A receptor subunits: evidence for modulation by CHEMICAL. Two alleles of the HG1 gene, which encodes a putative GABA receptor alpha/gamma subunit, were isolated from Haemonchus contortus. These two alleles were shown previously to be associated with CHEMICAL susceptibility (HG1A) and resistance (GENE), respectively. Sequence analysis indicates that they differ in four amino acids. To explore the functional properties of the two alleles, a full-length cDNA encoding the beta subunit, a key functional component of the GABA receptor, was isolated from Caenorhabditis elegans (gab-1, corresponding to the GenBank locus ZC482.1) and coexpressed in Xenopus oocytes with the HG1 alleles. When gab-1 was coexpressed with either the HG1A allele or the GENE allele in Xenopus oocytes, gamma-aminobutyric acid (GABA)-responsive channels with different sensitivity to the agonist were formed. The effects of CHEMICAL on the hetero-oligomeric receptors were determined. Application of CHEMICAL alone had no effect on the receptors. However, when coapplied with 10 micro m GABA, CHEMICAL potentiated the GABA-evoked current of the GAB-1/HG1A receptor, but attenuated the GABA response of the GAB-1/HG1E receptor. We demonstrated that the coexpressed HG1 and GAB-1 receptors are GABA-responsive, and provide evidence for the possible involvement of GABA receptors in the mechanism of CHEMICAL resistance. | NO-RELATIONSHIP |
| Study of the nematode putative GABA type-A receptor subunits: evidence for modulation by CHEMICAL. Two alleles of the HG1 gene, which encodes a putative GABA receptor alpha/gamma subunit, were isolated from Haemonchus contortus. These two alleles were shown previously to be associated with CHEMICAL susceptibility (GENE) and resistance (HG1E), respectively. Sequence analysis indicates that they differ in four amino acids. To explore the functional properties of the two alleles, a full-length cDNA encoding the beta subunit, a key functional component of the GABA receptor, was isolated from Caenorhabditis elegans (gab-1, corresponding to the GenBank locus ZC482.1) and coexpressed in Xenopus oocytes with the HG1 alleles. When gab-1 was coexpressed with either the GENE allele or the HG1E allele in Xenopus oocytes, gamma-aminobutyric acid (GABA)-responsive channels with different sensitivity to the agonist were formed. The effects of CHEMICAL on the hetero-oligomeric receptors were determined. Application of CHEMICAL alone had no effect on the receptors. However, when coapplied with 10 micro m GABA, CHEMICAL potentiated the GABA-evoked current of the GAB-1/HG1A receptor, but attenuated the GABA response of the GAB-1/HG1E receptor. We demonstrated that the coexpressed HG1 and GAB-1 receptors are GABA-responsive, and provide evidence for the possible involvement of GABA receptors in the mechanism of CHEMICAL resistance. | REGULATOR |
| Study of the nematode putative GENE subunits: evidence for modulation by CHEMICAL. Two alleles of the HG1 gene, which encodes a putative GABA receptor alpha/gamma subunit, were isolated from Haemonchus contortus. These two alleles were shown previously to be associated with CHEMICAL susceptibility (HG1A) and resistance (HG1E), respectively. Sequence analysis indicates that they differ in four amino acids. To explore the functional properties of the two alleles, a full-length cDNA encoding the beta subunit, a key functional component of the GABA receptor, was isolated from Caenorhabditis elegans (gab-1, corresponding to the GenBank locus ZC482.1) and coexpressed in Xenopus oocytes with the HG1 alleles. When gab-1 was coexpressed with either the HG1A allele or the HG1E allele in Xenopus oocytes, gamma-aminobutyric acid (GABA)-responsive channels with different sensitivity to the agonist were formed. The effects of CHEMICAL on the hetero-oligomeric receptors were determined. Application of CHEMICAL alone had no effect on the receptors. However, when coapplied with 10 micro m GABA, CHEMICAL potentiated the GABA-evoked current of the GAB-1/HG1A receptor, but attenuated the GABA response of the GAB-1/HG1E receptor. We demonstrated that the coexpressed HG1 and GAB-1 receptors are GABA-responsive, and provide evidence for the possible involvement of GABA receptors in the mechanism of CHEMICAL resistance. | REGULATOR |
| Study of the nematode putative CHEMICAL type-A receptor subunits: evidence for modulation by ivermectin. Two alleles of the HG1 gene, which encodes a putative CHEMICAL receptor alpha/gamma subunit, were isolated from Haemonchus contortus. These two alleles were shown previously to be associated with ivermectin susceptibility (HG1A) and resistance (HG1E), respectively. Sequence analysis indicates that they differ in four amino acids. To explore the functional properties of the two alleles, a full-length cDNA encoding the beta subunit, a key functional component of the CHEMICAL receptor, was isolated from Caenorhabditis elegans (gab-1, corresponding to the GenBank locus ZC482.1) and coexpressed in Xenopus oocytes with the HG1 alleles. When gab-1 was coexpressed with either the HG1A allele or the HG1E allele in Xenopus oocytes, gamma-aminobutyric acid (GABA)-responsive channels with different sensitivity to the agonist were formed. The effects of ivermectin on the hetero-oligomeric receptors were determined. Application of ivermectin alone had no effect on the receptors. However, when coapplied with 10 micro m CHEMICAL, ivermectin potentiated the CHEMICAL-evoked current of the GENE/HG1A receptor, but attenuated the CHEMICAL response of the GAB-1/HG1E receptor. We demonstrated that the coexpressed HG1 and GENE receptors are GABA-responsive, and provide evidence for the possible involvement of CHEMICAL receptors in the mechanism of ivermectin resistance. | ACTIVATOR |
| Study of the nematode putative CHEMICAL type-A receptor subunits: evidence for modulation by ivermectin. Two alleles of the HG1 gene, which encodes a putative CHEMICAL receptor alpha/gamma subunit, were isolated from Haemonchus contortus. These two alleles were shown previously to be associated with ivermectin susceptibility (HG1A) and resistance (HG1E), respectively. Sequence analysis indicates that they differ in four amino acids. To explore the functional properties of the two alleles, a full-length cDNA encoding the beta subunit, a key functional component of the CHEMICAL receptor, was isolated from Caenorhabditis elegans (gab-1, corresponding to the GenBank locus ZC482.1) and coexpressed in Xenopus oocytes with the HG1 alleles. When gab-1 was coexpressed with either the GENE allele or the HG1E allele in Xenopus oocytes, gamma-aminobutyric acid (GABA)-responsive channels with different sensitivity to the agonist were formed. The effects of ivermectin on the hetero-oligomeric receptors were determined. Application of ivermectin alone had no effect on the receptors. However, when coapplied with 10 micro m CHEMICAL, ivermectin potentiated the CHEMICAL-evoked current of the GAB-1/GENE receptor, but attenuated the CHEMICAL response of the GAB-1/HG1E receptor. We demonstrated that the coexpressed HG1 and GAB-1 receptors are GABA-responsive, and provide evidence for the possible involvement of CHEMICAL receptors in the mechanism of ivermectin resistance. | ACTIVATOR |
| Study of the nematode putative CHEMICAL type-A receptor subunits: evidence for modulation by ivermectin. Two alleles of the HG1 gene, which encodes a putative CHEMICAL receptor alpha/gamma subunit, were isolated from Haemonchus contortus. These two alleles were shown previously to be associated with ivermectin susceptibility (HG1A) and resistance (HG1E), respectively. Sequence analysis indicates that they differ in four amino acids. To explore the functional properties of the two alleles, a full-length cDNA encoding the beta subunit, a key functional component of the CHEMICAL receptor, was isolated from Caenorhabditis elegans (gab-1, corresponding to the GenBank locus ZC482.1) and coexpressed in Xenopus oocytes with the HG1 alleles. When gab-1 was coexpressed with either the HG1A allele or the GENE allele in Xenopus oocytes, gamma-aminobutyric acid (GABA)-responsive channels with different sensitivity to the agonist were formed. The effects of ivermectin on the hetero-oligomeric receptors were determined. Application of ivermectin alone had no effect on the receptors. However, when coapplied with 10 micro m CHEMICAL, ivermectin potentiated the GABA-evoked current of the GAB-1/HG1A receptor, but attenuated the CHEMICAL response of the GAB-1/GENE receptor. We demonstrated that the coexpressed HG1 and GAB-1 receptors are GABA-responsive, and provide evidence for the possible involvement of CHEMICAL receptors in the mechanism of ivermectin resistance. | ACTIVATOR |
| Study of the nematode putative CHEMICAL type-A receptor subunits: evidence for modulation by ivermectin. Two alleles of the GENE gene, which encodes a putative CHEMICAL receptor alpha/gamma subunit, were isolated from Haemonchus contortus. These two alleles were shown previously to be associated with ivermectin susceptibility (HG1A) and resistance (HG1E), respectively. Sequence analysis indicates that they differ in four amino acids. To explore the functional properties of the two alleles, a full-length cDNA encoding the beta subunit, a key functional component of the CHEMICAL receptor, was isolated from Caenorhabditis elegans (gab-1, corresponding to the GenBank locus ZC482.1) and coexpressed in Xenopus oocytes with the GENE alleles. When gab-1 was coexpressed with either the HG1A allele or the HG1E allele in Xenopus oocytes, gamma-aminobutyric acid (GABA)-responsive channels with different sensitivity to the agonist were formed. The effects of ivermectin on the hetero-oligomeric receptors were determined. Application of ivermectin alone had no effect on the receptors. However, when coapplied with 10 micro m CHEMICAL, ivermectin potentiated the GABA-evoked current of the GAB-1/HG1A receptor, but attenuated the CHEMICAL response of the GAB-1/HG1E receptor. We demonstrated that the coexpressed GENE and GAB-1 receptors are CHEMICAL-responsive, and provide evidence for the possible involvement of CHEMICAL receptors in the mechanism of ivermectin resistance. | REGULATOR |
| Study of the nematode putative GABA type-A receptor subunits: evidence for modulation by CHEMICAL. Two alleles of the HG1 gene, which encodes a putative GABA receptor alpha/gamma subunit, were isolated from Haemonchus contortus. These two alleles were shown previously to be associated with CHEMICAL susceptibility (HG1A) and resistance (HG1E), respectively. Sequence analysis indicates that they differ in four amino acids. To explore the functional properties of the two alleles, a full-length cDNA encoding the beta subunit, a key functional component of the GABA receptor, was isolated from Caenorhabditis elegans (gab-1, corresponding to the GenBank locus ZC482.1) and coexpressed in Xenopus oocytes with the HG1 alleles. When gab-1 was coexpressed with either the HG1A allele or the HG1E allele in Xenopus oocytes, gamma-aminobutyric acid (GABA)-responsive channels with different sensitivity to the agonist were formed. The effects of CHEMICAL on the hetero-oligomeric receptors were determined. Application of CHEMICAL alone had no effect on the receptors. However, when coapplied with 10 micro m GABA, CHEMICAL potentiated the GABA-evoked current of the GAB-1/HG1A receptor, but attenuated the GABA response of the GAB-1/HG1E receptor. We demonstrated that the coexpressed HG1 and GAB-1 receptors are GABA-responsive, and provide evidence for the possible involvement of GENE in the mechanism of CHEMICAL resistance. | REGULATOR |
| Study of the nematode putative GABA type-A receptor subunits: evidence for modulation by CHEMICAL. Two alleles of the HG1 gene, which encodes a putative GABA receptor alpha/gamma subunit, were isolated from Haemonchus contortus. These two alleles were shown previously to be associated with CHEMICAL susceptibility (HG1A) and resistance (HG1E), respectively. Sequence analysis indicates that they differ in four amino acids. To explore the functional properties of the two alleles, a full-length cDNA encoding the beta subunit, a key functional component of the GABA receptor, was isolated from Caenorhabditis elegans (gab-1, corresponding to the GenBank locus ZC482.1) and coexpressed in Xenopus oocytes with the HG1 alleles. When gab-1 was coexpressed with either the HG1A allele or the HG1E allele in Xenopus oocytes, gamma-aminobutyric acid (GABA)-responsive channels with different sensitivity to the agonist were formed. The effects of CHEMICAL on the hetero-oligomeric receptors were determined. Application of CHEMICAL alone had no effect on the receptors. However, when coapplied with 10 micro m GABA, CHEMICAL potentiated the GABA-evoked current of the GENE/HG1A receptor, but attenuated the GABA response of the GAB-1/HG1E receptor. We demonstrated that the coexpressed HG1 and GENE receptors are GABA-responsive, and provide evidence for the possible involvement of GABA receptors in the mechanism of CHEMICAL resistance. | NO-RELATIONSHIP |
| CHEMICAL dimers exhibiting selectivity for the human alpha 2C-adrenoceptor subtype. CHEMICAL is a potent and selective alpha2- versus alpha1-adrenoceptor antagonist. To date, drugs with high specificity for the alpha2-adrenoceptor show marginal selectivity among the three alpha2-adrenoceptor subtypes. Initial studies showed that CHEMICAL was about 4- and 15-fold more selective for the human GENE in comparison with the alpha2A- and alpha2B-adrenoceptors, respectively. To improve on this alpha2-adrenoceptor subtype selectivity, a series of CHEMICAL dimers (varying from n = 2 to 24 spacer atoms) were prepared and evaluated for receptor binding on human alpha2-adrenoceptor subtypes expressed in Chinese hamster ovary cells. Each dimeric analog showed higher affinities for alpha2A- and GENE versus the alpha2B-adrenoceptor; and CHEMICAL dimers with spacers of n = 2, 3, 4, 18, and 24 exhibited selectivity for the GENE. The CHEMICAL dimers n = 3 and n = 24 showed the highest potency and selectivity (32- and 82-fold. respectively) for the GENE in receptor binding and in functional studies (42- and 29-fold, respectively) measuring cAMP changes using a cell-based luciferase reporter gene assay. The dimers (n = 3 and n = 24) had high selectivity (>1000-fold) for the GENE compared with the three alpha1-adrenoceptor subtypes. These findings demonstrate that the addition of spacer linkages to bivalent CHEMICAL molecules provides a successful approach to the development of ligands that are potent and highly selective for the GENE. | DIRECT-REGULATOR |
| CHEMICAL dimers exhibiting selectivity for the human alpha 2C-adrenoceptor subtype. CHEMICAL is a potent and selective alpha2- versus alpha1-adrenoceptor antagonist. To date, drugs with high specificity for the alpha2-adrenoceptor show marginal selectivity among the three alpha2-adrenoceptor subtypes. Initial studies showed that CHEMICAL was about 4- and 15-fold more selective for the GENE in comparison with the alpha2A- and alpha2B-adrenoceptors, respectively. To improve on this alpha2-adrenoceptor subtype selectivity, a series of CHEMICAL dimers (varying from n = 2 to 24 spacer atoms) were prepared and evaluated for receptor binding on human alpha2-adrenoceptor subtypes expressed in Chinese hamster ovary cells. Each dimeric analog showed higher affinities for alpha2A- and alpha2C-adrenoceptor versus the alpha2B-adrenoceptor; and CHEMICAL dimers with spacers of n = 2, 3, 4, 18, and 24 exhibited selectivity for the alpha2C-adrenoceptor. The CHEMICAL dimers n = 3 and n = 24 showed the highest potency and selectivity (32- and 82-fold. respectively) for the alpha2C-adrenoceptor in receptor binding and in functional studies (42- and 29-fold, respectively) measuring cAMP changes using a cell-based luciferase reporter gene assay. The dimers (n = 3 and n = 24) had high selectivity (>1000-fold) for the alpha2C-adrenoceptor compared with the three alpha1-adrenoceptor subtypes. These findings demonstrate that the addition of spacer linkages to bivalent CHEMICAL molecules provides a successful approach to the development of ligands that are potent and highly selective for the alpha2C-adrenoceptor. | REGULATOR |
| CHEMICAL dimers exhibiting selectivity for the GENE subtype. CHEMICAL is a potent and selective alpha2- versus alpha1-adrenoceptor antagonist. To date, drugs with high specificity for the alpha2-adrenoceptor show marginal selectivity among the three alpha2-adrenoceptor subtypes. Initial studies showed that yohimbine was about 4- and 15-fold more selective for the human alpha2C-adrenoceptor in comparison with the alpha2A- and alpha2B-adrenoceptors, respectively. To improve on this alpha2-adrenoceptor subtype selectivity, a series of yohimbine dimers (varying from n = 2 to 24 spacer atoms) were prepared and evaluated for receptor binding on human alpha2-adrenoceptor subtypes expressed in Chinese hamster ovary cells. Each dimeric analog showed higher affinities for alpha2A- and alpha2C-adrenoceptor versus the alpha2B-adrenoceptor; and yohimbine dimers with spacers of n = 2, 3, 4, 18, and 24 exhibited selectivity for the alpha2C-adrenoceptor. The yohimbine dimers n = 3 and n = 24 showed the highest potency and selectivity (32- and 82-fold. respectively) for the alpha2C-adrenoceptor in receptor binding and in functional studies (42- and 29-fold, respectively) measuring cAMP changes using a cell-based luciferase reporter gene assay. The dimers (n = 3 and n = 24) had high selectivity (>1000-fold) for the alpha2C-adrenoceptor compared with the three alpha1-adrenoceptor subtypes. These findings demonstrate that the addition of spacer linkages to bivalent yohimbine molecules provides a successful approach to the development of ligands that are potent and highly selective for the alpha2C-adrenoceptor. | REGULATOR |
| CHEMICAL dimers exhibiting selectivity for the human alpha 2C-adrenoceptor subtype. CHEMICAL is a potent and selective GENE antagonist. To date, drugs with high specificity for the alpha2-adrenoceptor show marginal selectivity among the three alpha2-adrenoceptor subtypes. Initial studies showed that yohimbine was about 4- and 15-fold more selective for the human alpha2C-adrenoceptor in comparison with the alpha2A- and alpha2B-adrenoceptors, respectively. To improve on this alpha2-adrenoceptor subtype selectivity, a series of yohimbine dimers (varying from n = 2 to 24 spacer atoms) were prepared and evaluated for receptor binding on human alpha2-adrenoceptor subtypes expressed in Chinese hamster ovary cells. Each dimeric analog showed higher affinities for alpha2A- and alpha2C-adrenoceptor versus the alpha2B-adrenoceptor; and yohimbine dimers with spacers of n = 2, 3, 4, 18, and 24 exhibited selectivity for the alpha2C-adrenoceptor. The yohimbine dimers n = 3 and n = 24 showed the highest potency and selectivity (32- and 82-fold. respectively) for the alpha2C-adrenoceptor in receptor binding and in functional studies (42- and 29-fold, respectively) measuring cAMP changes using a cell-based luciferase reporter gene assay. The dimers (n = 3 and n = 24) had high selectivity (>1000-fold) for the alpha2C-adrenoceptor compared with the three alpha1-adrenoceptor subtypes. These findings demonstrate that the addition of spacer linkages to bivalent yohimbine molecules provides a successful approach to the development of ligands that are potent and highly selective for the alpha2C-adrenoceptor. | INHIBITOR |
| Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod. The immune response modifiers, imiquimod and resiquimod, are TLR7 agonists that induce type I interferon in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the TLR7 agonists imiquimod and resiquimod. Results indicate that imiquimod and resiquimod induce IFN-alpha and IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the blood. Resiquimod-stimulated pDC also produce a number of other cytokines including TNF-alpha and IP-10. Resiquimod enhances co-stimulatory marker expression, GENE expression, and pDC viability. Resiquimod was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; resiquimod more effectively matures pDC than either IL-3 or IFN-alpha alone. These results demonstrate that CHEMICAL molecules directly induce pDC maturation as determined by cytokine induction, GENE and co-stimulatory marker expression and prolonging viability. | GENE-CHEMICAL |
| Plasmacytoid dendritic cells produce GENE and mature in response to the TLR7 agonists, imiquimod and CHEMICAL. The immune response modifiers, imiquimod and CHEMICAL, are TLR7 agonists that induce type I interferon in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the TLR7 agonists imiquimod and CHEMICAL. Results indicate that imiquimod and CHEMICAL induce IFN-alpha and IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the blood. Resiquimod-stimulated pDC also produce a number of other GENE including TNF-alpha and IP-10. CHEMICAL enhances co-stimulatory marker expression, CCR7 expression, and pDC viability. CHEMICAL was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; CHEMICAL more effectively matures pDC than either IL-3 or IFN-alpha alone. These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, CCR7 and co-stimulatory marker expression and prolonging viability. | GENE-CHEMICAL |
| Plasmacytoid dendritic cells produce GENE and mature in response to the TLR7 agonists, CHEMICAL and resiquimod. The immune response modifiers, CHEMICAL and resiquimod, are TLR7 agonists that induce type I interferon in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the TLR7 agonists CHEMICAL and resiquimod. Results indicate that CHEMICAL and resiquimod induce IFN-alpha and IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the blood. Resiquimod-stimulated pDC also produce a number of other GENE including TNF-alpha and IP-10. Resiquimod enhances co-stimulatory marker expression, CCR7 expression, and pDC viability. Resiquimod was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; resiquimod more effectively matures pDC than either IL-3 or IFN-alpha alone. These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, CCR7 and co-stimulatory marker expression and prolonging viability. | GENE-CHEMICAL |
| Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, CHEMICAL and resiquimod. The immune response modifiers, CHEMICAL and resiquimod, are TLR7 agonists that induce type I interferon in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the TLR7 agonists CHEMICAL and resiquimod. Results indicate that CHEMICAL and resiquimod induce IFN-alpha and IFN-omega from purified pDC, and pDC are the principle GENE-producing cells in the blood. Resiquimod-stimulated pDC also produce a number of other cytokines including TNF-alpha and IP-10. Resiquimod enhances co-stimulatory marker expression, CCR7 expression, and pDC viability. Resiquimod was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; resiquimod more effectively matures pDC than either IL-3 or IFN-alpha alone. These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, CCR7 and co-stimulatory marker expression and prolonging viability. | REGULATOR |
| Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and CHEMICAL. The immune response modifiers, imiquimod and CHEMICAL, are TLR7 agonists that induce type I interferon in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the TLR7 agonists imiquimod and CHEMICAL. Results indicate that imiquimod and CHEMICAL induce GENE and IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the blood. Resiquimod-stimulated pDC also produce a number of other cytokines including TNF-alpha and IP-10. CHEMICAL enhances co-stimulatory marker expression, CCR7 expression, and pDC viability. CHEMICAL was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; CHEMICAL more effectively matures pDC than either IL-3 or GENE alone. These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, CCR7 and co-stimulatory marker expression and prolonging viability. | ACTIVATOR |
| Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and CHEMICAL. The immune response modifiers, imiquimod and CHEMICAL, are TLR7 agonists that induce type I interferon in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the TLR7 agonists imiquimod and CHEMICAL. Results indicate that imiquimod and CHEMICAL induce IFN-alpha and IFN-omega from purified pDC, and pDC are the principle GENE-producing cells in the blood. Resiquimod-stimulated pDC also produce a number of other cytokines including TNF-alpha and IP-10. CHEMICAL enhances co-stimulatory marker expression, CCR7 expression, and pDC viability. CHEMICAL was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; CHEMICAL more effectively matures pDC than either IL-3 or IFN-alpha alone. These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, CCR7 and co-stimulatory marker expression and prolonging viability. | REGULATOR |
| Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod. The immune response modifiers, imiquimod and resiquimod, are TLR7 agonists that induce type I interferon in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the TLR7 agonists imiquimod and resiquimod. Results indicate that imiquimod and resiquimod induce IFN-alpha and IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the blood. Resiquimod-stimulated pDC also produce a number of other cytokines including TNF-alpha and IP-10. Resiquimod enhances co-stimulatory marker expression, CCR7 expression, and pDC viability. Resiquimod was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; resiquimod more effectively matures pDC than either IL-3 or IFN-alpha alone. These results demonstrate that CHEMICAL molecules directly induce pDC maturation as determined by GENE induction, CCR7 and co-stimulatory marker expression and prolonging viability. | ACTIVATOR |
| Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, CHEMICAL and resiquimod. The immune response modifiers, CHEMICAL and resiquimod, are TLR7 agonists that induce GENE in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the TLR7 agonists CHEMICAL and resiquimod. Results indicate that CHEMICAL and resiquimod induce IFN-alpha and IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the blood. Resiquimod-stimulated pDC also produce a number of other cytokines including TNF-alpha and IP-10. Resiquimod enhances co-stimulatory marker expression, CCR7 expression, and pDC viability. Resiquimod was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; resiquimod more effectively matures pDC than either IL-3 or IFN-alpha alone. These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, CCR7 and co-stimulatory marker expression and prolonging viability. | ACTIVATOR |
| Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, CHEMICAL and resiquimod. The immune response modifiers, CHEMICAL and resiquimod, are TLR7 agonists that induce type I interferon in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the TLR7 agonists CHEMICAL and resiquimod. Results indicate that CHEMICAL and resiquimod induce GENE and IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the blood. Resiquimod-stimulated pDC also produce a number of other cytokines including TNF-alpha and IP-10. Resiquimod enhances co-stimulatory marker expression, CCR7 expression, and pDC viability. Resiquimod was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; resiquimod more effectively matures pDC than either IL-3 or GENE alone. These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, CCR7 and co-stimulatory marker expression and prolonging viability. | INDIRECT-UPREGULATOR |
| Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, CHEMICAL and resiquimod. The immune response modifiers, CHEMICAL and resiquimod, are TLR7 agonists that induce type I interferon in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the TLR7 agonists CHEMICAL and resiquimod. Results indicate that CHEMICAL and resiquimod induce IFN-alpha and GENE from purified pDC, and pDC are the principle IFN-producing cells in the blood. Resiquimod-stimulated pDC also produce a number of other cytokines including TNF-alpha and IP-10. Resiquimod enhances co-stimulatory marker expression, CCR7 expression, and pDC viability. Resiquimod was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; resiquimod more effectively matures pDC than either IL-3 or IFN-alpha alone. These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, CCR7 and co-stimulatory marker expression and prolonging viability. | INDIRECT-UPREGULATOR |
| Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and CHEMICAL. The immune response modifiers, imiquimod and CHEMICAL, are TLR7 agonists that induce GENE in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the TLR7 agonists imiquimod and CHEMICAL. Results indicate that imiquimod and CHEMICAL induce IFN-alpha and IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the blood. Resiquimod-stimulated pDC also produce a number of other cytokines including TNF-alpha and IP-10. CHEMICAL enhances co-stimulatory marker expression, CCR7 expression, and pDC viability. CHEMICAL was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; CHEMICAL more effectively matures pDC than either IL-3 or IFN-alpha alone. These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, CCR7 and co-stimulatory marker expression and prolonging viability. | ACTIVATOR |
| Plasmacytoid dendritic cells produce GENE and mature in response to the TLR7 agonists, imiquimod and resiquimod. The immune response modifiers, imiquimod and resiquimod, are TLR7 agonists that induce type I interferon in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the TLR7 agonists imiquimod and resiquimod. Results indicate that imiquimod and resiquimod induce IFN-alpha and IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the blood. CHEMICAL-stimulated pDC also produce a number of other GENE including TNF-alpha and IP-10. CHEMICAL enhances co-stimulatory marker expression, CCR7 expression, and pDC viability. CHEMICAL was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; resiquimod more effectively matures pDC than either IL-3 or IFN-alpha alone. These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, CCR7 and co-stimulatory marker expression and prolonging viability. | GENE-CHEMICAL |
| Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod. The immune response modifiers, imiquimod and resiquimod, are TLR7 agonists that induce type I interferon in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the TLR7 agonists imiquimod and resiquimod. Results indicate that imiquimod and resiquimod induce IFN-alpha and IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the blood. CHEMICAL-stimulated pDC also produce a number of other cytokines including GENE and IP-10. CHEMICAL enhances co-stimulatory marker expression, CCR7 expression, and pDC viability. CHEMICAL was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; resiquimod more effectively matures pDC than either IL-3 or IFN-alpha alone. These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, CCR7 and co-stimulatory marker expression and prolonging viability. | INDIRECT-UPREGULATOR |
| Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod. The immune response modifiers, imiquimod and resiquimod, are TLR7 agonists that induce type I interferon in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the TLR7 agonists imiquimod and resiquimod. Results indicate that imiquimod and resiquimod induce IFN-alpha and IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the blood. CHEMICAL-stimulated pDC also produce a number of other cytokines including TNF-alpha and GENE. CHEMICAL enhances co-stimulatory marker expression, CCR7 expression, and pDC viability. CHEMICAL was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; resiquimod more effectively matures pDC than either IL-3 or IFN-alpha alone. These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, CCR7 and co-stimulatory marker expression and prolonging viability. | INDIRECT-UPREGULATOR |
| Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod. The immune response modifiers, imiquimod and resiquimod, are TLR7 agonists that induce type I interferon in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the TLR7 agonists imiquimod and resiquimod. Results indicate that imiquimod and resiquimod induce IFN-alpha and IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the blood. Resiquimod-stimulated pDC also produce a number of other cytokines including TNF-alpha and IP-10. CHEMICAL enhances co-stimulatory marker expression, GENE expression, and pDC viability. CHEMICAL was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; resiquimod more effectively matures pDC than either IL-3 or IFN-alpha alone. These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, GENE and co-stimulatory marker expression and prolonging viability. | INDIRECT-UPREGULATOR |
| Plasmacytoid dendritic cells produce cytokines and mature in response to the GENE agonists, imiquimod and CHEMICAL. The immune response modifiers, imiquimod and CHEMICAL, are GENE agonists that induce type I interferon in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the GENE agonists imiquimod and CHEMICAL. Results indicate that imiquimod and CHEMICAL induce IFN-alpha and IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the blood. Resiquimod-stimulated pDC also produce a number of other cytokines including TNF-alpha and IP-10. CHEMICAL enhances co-stimulatory marker expression, CCR7 expression, and pDC viability. CHEMICAL was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; CHEMICAL more effectively matures pDC than either IL-3 or IFN-alpha alone. These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, CCR7 and co-stimulatory marker expression and prolonging viability. | ACTIVATOR |
| Plasmacytoid dendritic cells produce cytokines and mature in response to the GENE agonists, CHEMICAL and resiquimod. The immune response modifiers, CHEMICAL and resiquimod, are GENE agonists that induce type I interferon in numerous species, including humans. Recently, it was shown that plasmacytoid dendritic cells (pDC) are the primary interferon-producing cells in the blood in response to viral infections. Here, we characterize the activation of human pDC with the GENE agonists CHEMICAL and resiquimod. Results indicate that CHEMICAL and resiquimod induce IFN-alpha and IFN-omega from purified pDC, and pDC are the principle IFN-producing cells in the blood. Resiquimod-stimulated pDC also produce a number of other cytokines including TNF-alpha and IP-10. Resiquimod enhances co-stimulatory marker expression, CCR7 expression, and pDC viability. Resiquimod was compared throughout the study to the pDC survival factors, IL-3 and IFN-alpha; resiquimod more effectively matures pDC than either IL-3 or IFN-alpha alone. These results demonstrate that imidazoquinoline molecules directly induce pDC maturation as determined by cytokine induction, CCR7 and co-stimulatory marker expression and prolonging viability. | ACTIVATOR |
| Induction of heat shock proteins (HSPs) by sodium arsenite in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. Induction of heat shock proteins (HSPs) protects cells from oxidative injury. Here Hsp72, Hsp27 and heme oxygenase-1 (HO-1) were induced in cultured rat astrocytes, and protection against oxidative stress was investigated. Astrocytes were treated with sodium arsenite (20-50 micro m) for 1 h, which was non-toxic to cells, 24 h later they were exposed to 400 micro m CHEMICAL for 1 h, and cell death was evaluated at different time points. Arsenite triggered strong induction of HSPs, which was prevented by 1 micro g/mL cycloheximide (CXH). CHEMICAL caused cell loss and increased cell death with features of apoptosis, i.e. TdT-mediated dUTP nick-end labelling (TUNEL) reaction and caspase-3 activation. These features were abrogated by pre-treatment with arsenite, which prevented cell loss and significantly reduced the number of dead cells. The protective effect of arsenite was not detected in the presence of CHX. Pre-treatment with arsenite increased protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation after CHEMICAL. However, while GENE phosphorylation was prevented by CHX, Erk1/2 phosphorylation was further enhanced by CHX. The results show that transient arsenite pre-treatment induces Hsp72, HO-1 and, to a lesser extent, Hsp27; it reduces H2O2-induced astrocyte death; and it causes selective activation of GENE following CHEMICAL. It is suggested that HSP expression at the time of CHEMICAL exposure protects astrocytes from oxidative injury and apoptotic cell death by means of pro-survival GENE. | ACTIVATOR |
| Induction of heat shock proteins (HSPs) by sodium arsenite in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. Induction of heat shock proteins (HSPs) protects cells from oxidative injury. Here Hsp72, Hsp27 and heme oxygenase-1 (HO-1) were induced in cultured rat astrocytes, and protection against oxidative stress was investigated. Astrocytes were treated with sodium arsenite (20-50 micro m) for 1 h, which was non-toxic to cells, 24 h later they were exposed to 400 micro m CHEMICAL for 1 h, and cell death was evaluated at different time points. Arsenite triggered strong induction of HSPs, which was prevented by 1 micro g/mL cycloheximide (CXH). CHEMICAL caused cell loss and increased cell death with features of apoptosis, i.e. TdT-mediated dUTP nick-end labelling (TUNEL) reaction and GENE activation. These features were abrogated by pre-treatment with arsenite, which prevented cell loss and significantly reduced the number of dead cells. The protective effect of arsenite was not detected in the presence of CHX. Pre-treatment with arsenite increased protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation after CHEMICAL. However, while Akt phosphorylation was prevented by CHX, Erk1/2 phosphorylation was further enhanced by CHX. The results show that transient arsenite pre-treatment induces Hsp72, HO-1 and, to a lesser extent, Hsp27; it reduces H2O2-induced astrocyte death; and it causes selective activation of Akt following CHEMICAL. It is suggested that HSP expression at the time of CHEMICAL exposure protects astrocytes from oxidative injury and apoptotic cell death by means of pro-survival Akt. | ACTIVATOR |
| Induction of heat shock proteins (HSPs) by sodium arsenite in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. Induction of heat shock proteins (HSPs) protects cells from oxidative injury. Here Hsp72, Hsp27 and heme oxygenase-1 (HO-1) were induced in cultured rat astrocytes, and protection against oxidative stress was investigated. Astrocytes were treated with sodium arsenite (20-50 micro m) for 1 h, which was non-toxic to cells, 24 h later they were exposed to 400 micro m CHEMICAL for 1 h, and cell death was evaluated at different time points. Arsenite triggered strong induction of HSPs, which was prevented by 1 micro g/mL cycloheximide (CXH). CHEMICAL caused cell loss and increased cell death with features of apoptosis, i.e. TdT-mediated dUTP nick-end labelling (TUNEL) reaction and caspase-3 activation. These features were abrogated by pre-treatment with arsenite, which prevented cell loss and significantly reduced the number of dead cells. The protective effect of arsenite was not detected in the presence of CHX. Pre-treatment with arsenite increased GENE (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation after CHEMICAL. However, while Akt phosphorylation was prevented by CHX, Erk1/2 phosphorylation was further enhanced by CHX. The results show that transient arsenite pre-treatment induces Hsp72, HO-1 and, to a lesser extent, Hsp27; it reduces H2O2-induced astrocyte death; and it causes selective activation of Akt following CHEMICAL. It is suggested that HSP expression at the time of CHEMICAL exposure protects astrocytes from oxidative injury and apoptotic cell death by means of pro-survival Akt. | ACTIVATOR |
| Induction of heat shock proteins (HSPs) by sodium CHEMICAL in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. Induction of heat shock proteins (HSPs) protects cells from oxidative injury. Here Hsp72, Hsp27 and heme oxygenase-1 (HO-1) were induced in cultured rat astrocytes, and protection against oxidative stress was investigated. Astrocytes were treated with sodium CHEMICAL (20-50 micro m) for 1 h, which was non-toxic to cells, 24 h later they were exposed to 400 micro m H2O2 for 1 h, and cell death was evaluated at different time points. CHEMICAL triggered strong induction of HSPs, which was prevented by 1 micro g/mL cycloheximide (CXH). H2O2 caused cell loss and increased cell death with features of apoptosis, i.e. TdT-mediated dUTP nick-end labelling (TUNEL) reaction and caspase-3 activation. These features were abrogated by pre-treatment with CHEMICAL, which prevented cell loss and significantly reduced the number of dead cells. The protective effect of CHEMICAL was not detected in the presence of CHX. Pre-treatment with CHEMICAL increased protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation after H2O2. However, while GENE phosphorylation was prevented by CHX, Erk1/2 phosphorylation was further enhanced by CHX. The results show that transient CHEMICAL pre-treatment induces Hsp72, HO-1 and, to a lesser extent, Hsp27; it reduces H2O2-induced astrocyte death; and it causes selective activation of GENE following H2O2. It is suggested that HSP expression at the time of H2O2 exposure protects astrocytes from oxidative injury and apoptotic cell death by means of pro-survival GENE. | ACTIVATOR |
| Induction of GENE (HSPs) by CHEMICAL in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. Induction of GENE (HSPs) protects cells from oxidative injury. Here Hsp72, Hsp27 and heme oxygenase-1 (HO-1) were induced in cultured rat astrocytes, and protection against oxidative stress was investigated. Astrocytes were treated with CHEMICAL (20-50 micro m) for 1 h, which was non-toxic to cells, 24 h later they were exposed to 400 micro m H2O2 for 1 h, and cell death was evaluated at different time points. Arsenite triggered strong induction of HSPs, which was prevented by 1 micro g/mL cycloheximide (CXH). H2O2 caused cell loss and increased cell death with features of apoptosis, i.e. TdT-mediated dUTP nick-end labelling (TUNEL) reaction and caspase-3 activation. These features were abrogated by pre-treatment with arsenite, which prevented cell loss and significantly reduced the number of dead cells. The protective effect of arsenite was not detected in the presence of CHX. Pre-treatment with arsenite increased protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation after H2O2. However, while Akt phosphorylation was prevented by CHX, Erk1/2 phosphorylation was further enhanced by CHX. The results show that transient arsenite pre-treatment induces Hsp72, HO-1 and, to a lesser extent, Hsp27; it reduces H2O2-induced astrocyte death; and it causes selective activation of Akt following H2O2. It is suggested that HSP expression at the time of H2O2 exposure protects astrocytes from oxidative injury and apoptotic cell death by means of pro-survival Akt. | ACTIVATOR |
| Induction of heat shock proteins (GENE) by CHEMICAL in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. Induction of heat shock proteins (HSPs) protects cells from oxidative injury. Here Hsp72, Hsp27 and heme oxygenase-1 (HO-1) were induced in cultured rat astrocytes, and protection against oxidative stress was investigated. Astrocytes were treated with CHEMICAL (20-50 micro m) for 1 h, which was non-toxic to cells, 24 h later they were exposed to 400 micro m H2O2 for 1 h, and cell death was evaluated at different time points. Arsenite triggered strong induction of GENE, which was prevented by 1 micro g/mL cycloheximide (CXH). H2O2 caused cell loss and increased cell death with features of apoptosis, i.e. TdT-mediated dUTP nick-end labelling (TUNEL) reaction and caspase-3 activation. These features were abrogated by pre-treatment with arsenite, which prevented cell loss and significantly reduced the number of dead cells. The protective effect of arsenite was not detected in the presence of CHX. Pre-treatment with arsenite increased protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation after H2O2. However, while Akt phosphorylation was prevented by CHX, Erk1/2 phosphorylation was further enhanced by CHX. The results show that transient arsenite pre-treatment induces Hsp72, HO-1 and, to a lesser extent, Hsp27; it reduces H2O2-induced astrocyte death; and it causes selective activation of Akt following H2O2. It is suggested that HSP expression at the time of H2O2 exposure protects astrocytes from oxidative injury and apoptotic cell death by means of pro-survival Akt. | ACTIVATOR |
| Induction of heat shock proteins (HSPs) by sodium CHEMICAL in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. Induction of heat shock proteins (HSPs) protects cells from oxidative injury. Here GENE, Hsp27 and heme oxygenase-1 (HO-1) were induced in cultured rat astrocytes, and protection against oxidative stress was investigated. Astrocytes were treated with sodium CHEMICAL (20-50 micro m) for 1 h, which was non-toxic to cells, 24 h later they were exposed to 400 micro m H2O2 for 1 h, and cell death was evaluated at different time points. CHEMICAL triggered strong induction of HSPs, which was prevented by 1 micro g/mL cycloheximide (CXH). H2O2 caused cell loss and increased cell death with features of apoptosis, i.e. TdT-mediated dUTP nick-end labelling (TUNEL) reaction and caspase-3 activation. These features were abrogated by pre-treatment with CHEMICAL, which prevented cell loss and significantly reduced the number of dead cells. The protective effect of CHEMICAL was not detected in the presence of CHX. Pre-treatment with CHEMICAL increased protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation after H2O2. However, while Akt phosphorylation was prevented by CHX, Erk1/2 phosphorylation was further enhanced by CHX. The results show that transient CHEMICAL pre-treatment induces GENE, HO-1 and, to a lesser extent, Hsp27; it reduces H2O2-induced astrocyte death; and it causes selective activation of Akt following H2O2. It is suggested that HSP expression at the time of H2O2 exposure protects astrocytes from oxidative injury and apoptotic cell death by means of pro-survival Akt. | ACTIVATOR |
| Induction of heat shock proteins (HSPs) by sodium CHEMICAL in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. Induction of heat shock proteins (HSPs) protects cells from oxidative injury. Here Hsp72, Hsp27 and heme oxygenase-1 (HO-1) were induced in cultured rat astrocytes, and protection against oxidative stress was investigated. Astrocytes were treated with sodium CHEMICAL (20-50 micro m) for 1 h, which was non-toxic to cells, 24 h later they were exposed to 400 micro m H2O2 for 1 h, and cell death was evaluated at different time points. CHEMICAL triggered strong induction of HSPs, which was prevented by 1 micro g/mL cycloheximide (CXH). H2O2 caused cell loss and increased cell death with features of apoptosis, i.e. TdT-mediated dUTP nick-end labelling (TUNEL) reaction and caspase-3 activation. These features were abrogated by pre-treatment with CHEMICAL, which prevented cell loss and significantly reduced the number of dead cells. The protective effect of CHEMICAL was not detected in the presence of CHX. Pre-treatment with CHEMICAL increased protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation after H2O2. However, while Akt phosphorylation was prevented by CHX, Erk1/2 phosphorylation was further enhanced by CHX. The results show that transient CHEMICAL pre-treatment induces Hsp72, GENE and, to a lesser extent, Hsp27; it reduces H2O2-induced astrocyte death; and it causes selective activation of Akt following H2O2. It is suggested that HSP expression at the time of H2O2 exposure protects astrocytes from oxidative injury and apoptotic cell death by means of pro-survival Akt. | INDIRECT-UPREGULATOR |
| Induction of heat shock proteins (HSPs) by sodium CHEMICAL in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. Induction of heat shock proteins (HSPs) protects cells from oxidative injury. Here Hsp72, GENE and heme oxygenase-1 (HO-1) were induced in cultured rat astrocytes, and protection against oxidative stress was investigated. Astrocytes were treated with sodium CHEMICAL (20-50 micro m) for 1 h, which was non-toxic to cells, 24 h later they were exposed to 400 micro m H2O2 for 1 h, and cell death was evaluated at different time points. CHEMICAL triggered strong induction of HSPs, which was prevented by 1 micro g/mL cycloheximide (CXH). H2O2 caused cell loss and increased cell death with features of apoptosis, i.e. TdT-mediated dUTP nick-end labelling (TUNEL) reaction and caspase-3 activation. These features were abrogated by pre-treatment with CHEMICAL, which prevented cell loss and significantly reduced the number of dead cells. The protective effect of CHEMICAL was not detected in the presence of CHX. Pre-treatment with CHEMICAL increased protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation after H2O2. However, while Akt phosphorylation was prevented by CHX, Erk1/2 phosphorylation was further enhanced by CHX. The results show that transient CHEMICAL pre-treatment induces Hsp72, HO-1 and, to a lesser extent, GENE; it reduces H2O2-induced astrocyte death; and it causes selective activation of Akt following H2O2. It is suggested that HSP expression at the time of H2O2 exposure protects astrocytes from oxidative injury and apoptotic cell death by means of pro-survival Akt. | ACTIVATOR |
| Induction of heat shock proteins (HSPs) by sodium arsenite in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. Induction of heat shock proteins (HSPs) protects cells from oxidative injury. Here Hsp72, Hsp27 and heme oxygenase-1 (HO-1) were induced in cultured rat astrocytes, and protection against oxidative stress was investigated. Astrocytes were treated with sodium arsenite (20-50 micro m) for 1 h, which was non-toxic to cells, 24 h later they were exposed to 400 micro m H2O2 for 1 h, and cell death was evaluated at different time points. CHEMICAL triggered strong induction of GENE, which was prevented by 1 micro g/mL cycloheximide (CXH). H2O2 caused cell loss and increased cell death with features of apoptosis, i.e. TdT-mediated dUTP nick-end labelling (TUNEL) reaction and caspase-3 activation. These features were abrogated by pre-treatment with arsenite, which prevented cell loss and significantly reduced the number of dead cells. The protective effect of arsenite was not detected in the presence of CHX. Pre-treatment with arsenite increased protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation after H2O2. However, while Akt phosphorylation was prevented by CHX, Erk1/2 phosphorylation was further enhanced by CHX. The results show that transient arsenite pre-treatment induces Hsp72, HO-1 and, to a lesser extent, Hsp27; it reduces H2O2-induced astrocyte death; and it causes selective activation of Akt following H2O2. It is suggested that HSP expression at the time of H2O2 exposure protects astrocytes from oxidative injury and apoptotic cell death by means of pro-survival Akt. | ACTIVATOR |
| Induction of heat shock proteins (HSPs) by sodium arsenite in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. Induction of heat shock proteins (HSPs) protects cells from oxidative injury. Here Hsp72, Hsp27 and heme oxygenase-1 (HO-1) were induced in cultured rat astrocytes, and protection against oxidative stress was investigated. Astrocytes were treated with sodium arsenite (20-50 micro m) for 1 h, which was non-toxic to cells, 24 h later they were exposed to 400 micro m H2O2 for 1 h, and cell death was evaluated at different time points. Arsenite triggered strong induction of GENE, which was prevented by 1 micro g/mL CHEMICAL (CXH). H2O2 caused cell loss and increased cell death with features of apoptosis, i.e. TdT-mediated dUTP nick-end labelling (TUNEL) reaction and caspase-3 activation. These features were abrogated by pre-treatment with arsenite, which prevented cell loss and significantly reduced the number of dead cells. The protective effect of arsenite was not detected in the presence of CHX. Pre-treatment with arsenite increased protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation after H2O2. However, while Akt phosphorylation was prevented by CHX, Erk1/2 phosphorylation was further enhanced by CHX. The results show that transient arsenite pre-treatment induces Hsp72, HO-1 and, to a lesser extent, Hsp27; it reduces H2O2-induced astrocyte death; and it causes selective activation of Akt following H2O2. It is suggested that HSP expression at the time of H2O2 exposure protects astrocytes from oxidative injury and apoptotic cell death by means of pro-survival Akt. | GENE-CHEMICAL |
| Induction of heat shock proteins (HSPs) by sodium arsenite in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. Induction of heat shock proteins (HSPs) protects cells from oxidative injury. Here Hsp72, Hsp27 and heme oxygenase-1 (HO-1) were induced in cultured rat astrocytes, and protection against oxidative stress was investigated. Astrocytes were treated with sodium arsenite (20-50 micro m) for 1 h, which was non-toxic to cells, 24 h later they were exposed to 400 micro m H2O2 for 1 h, and cell death was evaluated at different time points. Arsenite triggered strong induction of GENE, which was prevented by 1 micro g/mL cycloheximide (CHEMICAL). H2O2 caused cell loss and increased cell death with features of apoptosis, i.e. TdT-mediated dUTP nick-end labelling (TUNEL) reaction and caspase-3 activation. These features were abrogated by pre-treatment with arsenite, which prevented cell loss and significantly reduced the number of dead cells. The protective effect of arsenite was not detected in the presence of CHX. Pre-treatment with arsenite increased protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation after H2O2. However, while Akt phosphorylation was prevented by CHX, Erk1/2 phosphorylation was further enhanced by CHX. The results show that transient arsenite pre-treatment induces Hsp72, HO-1 and, to a lesser extent, Hsp27; it reduces H2O2-induced astrocyte death; and it causes selective activation of Akt following H2O2. It is suggested that HSP expression at the time of H2O2 exposure protects astrocytes from oxidative injury and apoptotic cell death by means of pro-survival Akt. | INHIBITOR |
| Induction of heat shock proteins (HSPs) by sodium arsenite in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. Induction of heat shock proteins (HSPs) protects cells from oxidative injury. Here Hsp72, Hsp27 and heme oxygenase-1 (HO-1) were induced in cultured rat astrocytes, and protection against oxidative stress was investigated. Astrocytes were treated with sodium arsenite (20-50 micro m) for 1 h, which was non-toxic to cells, 24 h later they were exposed to 400 micro m H2O2 for 1 h, and cell death was evaluated at different time points. Arsenite triggered strong induction of HSPs, which was prevented by 1 micro g/mL cycloheximide (CXH). H2O2 caused cell loss and increased cell death with features of apoptosis, i.e. TdT-mediated dUTP nick-end labelling (TUNEL) reaction and caspase-3 activation. These features were abrogated by pre-treatment with arsenite, which prevented cell loss and significantly reduced the number of dead cells. The protective effect of arsenite was not detected in the presence of CHEMICAL. Pre-treatment with arsenite increased protein kinase B (Akt) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation after H2O2. However, while GENE phosphorylation was prevented by CHEMICAL, Erk1/2 phosphorylation was further enhanced by CHEMICAL. The results show that transient arsenite pre-treatment induces Hsp72, HO-1 and, to a lesser extent, Hsp27; it reduces H2O2-induced astrocyte death; and it causes selective activation of GENE following H2O2. It is suggested that HSP expression at the time of H2O2 exposure protects astrocytes from oxidative injury and apoptotic cell death by means of pro-survival GENE. | INHIBITOR |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors CHEMICAL and omapatrilat. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (3.8 microM) or omapatrilat (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike CHEMICAL, omapatrilat abolished the production of BrBK1-5 and BrBK1-7, suggesting a better ACE inhibition effect over CHEMICAL as no NEP activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with omapatrilat. The production of Br-Phe5 was reduced with CHEMICAL while no significant change was observed with omapatrilat after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (530 nM) or omapatrilat (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe5 plus BrBK2-9, GENE and BrBK2-8 metabolites not found in human plasma. CHEMICAL and omapatrilat reduced the production of BrBK1-5 and BrBK1-7 with more effect being observed with omapatrilat. CHEMICAL and omapatrilat increased the production of both BrBK1-8 and Br-Phe5 but not that of GENE and BrBK2-8. This study shows that the potency of CHEMICAL in comparison with omapatrilat is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | NO-RELATIONSHIP |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors CHEMICAL and omapatrilat. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (3.8 microM) or omapatrilat (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike CHEMICAL, omapatrilat abolished the production of BrBK1-5 and BrBK1-7, suggesting a better ACE inhibition effect over CHEMICAL as no NEP activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with omapatrilat. The production of Br-Phe5 was reduced with CHEMICAL while no significant change was observed with omapatrilat after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (530 nM) or omapatrilat (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe5 plus BrBK2-9, BrBK4-8 and GENE metabolites not found in human plasma. CHEMICAL and omapatrilat reduced the production of BrBK1-5 and BrBK1-7 with more effect being observed with omapatrilat. CHEMICAL and omapatrilat increased the production of both BrBK1-8 and Br-Phe5 but not that of BrBK4-8 and GENE. This study shows that the potency of CHEMICAL in comparison with omapatrilat is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | NO-RELATIONSHIP |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors GW660511X and CHEMICAL. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of GW660511X (3.8 microM) or CHEMICAL (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike GW660511X, CHEMICAL abolished the production of BrBK1-5 and BrBK1-7, suggesting a better ACE inhibition effect over GW660511X as no NEP activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with CHEMICAL. The production of Br-Phe5 was reduced with GW660511X while no significant change was observed with CHEMICAL after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of GW660511X (530 nM) or CHEMICAL (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe5 plus BrBK2-9, GENE and BrBK2-8 metabolites not found in human plasma. GW660511X and CHEMICAL reduced the production of BrBK1-5 and BrBK1-7 with more effect being observed with CHEMICAL. GW660511X and CHEMICAL increased the production of both BrBK1-8 and Br-Phe5 but not that of GENE and BrBK2-8. This study shows that the potency of GW660511X in comparison with CHEMICAL is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | NO-RELATIONSHIP |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors GW660511X and CHEMICAL. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of GW660511X (3.8 microM) or CHEMICAL (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike GW660511X, CHEMICAL abolished the production of BrBK1-5 and BrBK1-7, suggesting a better ACE inhibition effect over GW660511X as no NEP activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with CHEMICAL. The production of Br-Phe5 was reduced with GW660511X while no significant change was observed with CHEMICAL after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of GW660511X (530 nM) or CHEMICAL (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe5 plus BrBK2-9, BrBK4-8 and GENE metabolites not found in human plasma. GW660511X and CHEMICAL reduced the production of BrBK1-5 and BrBK1-7 with more effect being observed with CHEMICAL. GW660511X and CHEMICAL increased the production of both BrBK1-8 and Br-Phe5 but not that of BrBK4-8 and GENE. This study shows that the potency of GW660511X in comparison with CHEMICAL is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | NO-RELATIONSHIP |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors CHEMICAL and omapatrilat. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (3.8 microM) or omapatrilat (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, GENE and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike CHEMICAL, omapatrilat abolished the production of GENE and BrBK1-7, suggesting a better ACE inhibition effect over CHEMICAL as no NEP activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with omapatrilat. The production of Br-Phe5 was reduced with CHEMICAL while no significant change was observed with omapatrilat after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (530 nM) or omapatrilat (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, GENE and Br-Phe5 plus BrBK2-9, BrBK4-8 and BrBK2-8 metabolites not found in human plasma. CHEMICAL and omapatrilat reduced the production of GENE and BrBK1-7 with more effect being observed with omapatrilat. CHEMICAL and omapatrilat increased the production of both BrBK1-8 and Br-Phe5 but not that of BrBK4-8 and BrBK2-8. This study shows that the potency of CHEMICAL in comparison with omapatrilat is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | INDIRECT-DOWNREGULATOR |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors CHEMICAL and omapatrilat. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (3.8 microM) or omapatrilat (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into BrBK1-8, GENE, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike CHEMICAL, omapatrilat abolished the production of BrBK1-5 and GENE, suggesting a better ACE inhibition effect over CHEMICAL as no NEP activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with omapatrilat. The production of Br-Phe5 was reduced with CHEMICAL while no significant change was observed with omapatrilat after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (530 nM) or omapatrilat (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into BrBK1-8, GENE, BrBK1-5 and Br-Phe5 plus BrBK2-9, BrBK4-8 and BrBK2-8 metabolites not found in human plasma. CHEMICAL and omapatrilat reduced the production of BrBK1-5 and GENE with more effect being observed with omapatrilat. CHEMICAL and omapatrilat increased the production of both BrBK1-8 and Br-Phe5 but not that of BrBK4-8 and BrBK2-8. This study shows that the potency of CHEMICAL in comparison with omapatrilat is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | INDIRECT-DOWNREGULATOR |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors CHEMICAL and omapatrilat. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (3.8 microM) or omapatrilat (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike CHEMICAL, omapatrilat abolished the production of BrBK1-5 and BrBK1-7, suggesting a better ACE inhibition effect over CHEMICAL as no GENE activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with omapatrilat. The production of Br-Phe5 was reduced with CHEMICAL while no significant change was observed with omapatrilat after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (530 nM) or omapatrilat (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe5 plus BrBK2-9, BrBK4-8 and BrBK2-8 metabolites not found in human plasma. CHEMICAL and omapatrilat reduced the production of BrBK1-5 and BrBK1-7 with more effect being observed with omapatrilat. CHEMICAL and omapatrilat increased the production of both BrBK1-8 and Br-Phe5 but not that of BrBK4-8 and BrBK2-8. This study shows that the potency of CHEMICAL in comparison with omapatrilat is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | NO-RELATIONSHIP |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors GW660511X and CHEMICAL. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of GW660511X (3.8 microM) or CHEMICAL (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike GW660511X, CHEMICAL abolished the production of BrBK1-5 and BrBK1-7, suggesting a better ACE inhibition effect over GW660511X as no NEP activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with CHEMICAL. The production of GENE was reduced with GW660511X while no significant change was observed with CHEMICAL after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of GW660511X (530 nM) or CHEMICAL (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and GENE plus BrBK2-9, BrBK4-8 and BrBK2-8 metabolites not found in human plasma. GW660511X and CHEMICAL reduced the production of BrBK1-5 and BrBK1-7 with more effect being observed with CHEMICAL. GW660511X and CHEMICAL increased the production of both BrBK1-8 and GENE but not that of BrBK4-8 and BrBK2-8. This study shows that the potency of GW660511X in comparison with CHEMICAL is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | NO-RELATIONSHIP |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors CHEMICAL and omapatrilat. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) GENE in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the GENE half-life values in the absence or in the presence of CHEMICAL (3.8 microM) or omapatrilat (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and GENE was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike CHEMICAL, omapatrilat abolished the production of BrBK1-5 and BrBK1-7, suggesting a better ACE inhibition effect over CHEMICAL as no NEP activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with omapatrilat. The production of Br-Phe5 was reduced with CHEMICAL while no significant change was observed with omapatrilat after 4 h of incubation. In rat plasma the GENE half-life values in the absence or in the presence of CHEMICAL (530 nM) or omapatrilat (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and GENE was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe5 plus BrBK2-9, BrBK4-8 and BrBK2-8 metabolites not found in human plasma. CHEMICAL and omapatrilat reduced the production of BrBK1-5 and BrBK1-7 with more effect being observed with omapatrilat. CHEMICAL and omapatrilat increased the production of both BrBK1-8 and Br-Phe5 but not that of BrBK4-8 and BrBK2-8. This study shows that the potency of CHEMICAL in comparison with omapatrilat is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | SUBSTRATE |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors GW660511X and CHEMICAL. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) GENE in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the GENE half-life values in the absence or in the presence of GW660511X (3.8 microM) or CHEMICAL (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and GENE was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike GW660511X, CHEMICAL abolished the production of BrBK1-5 and BrBK1-7, suggesting a better ACE inhibition effect over GW660511X as no NEP activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with CHEMICAL. The production of Br-Phe5 was reduced with GW660511X while no significant change was observed with CHEMICAL after 4 h of incubation. In rat plasma the GENE half-life values in the absence or in the presence of GW660511X (530 nM) or CHEMICAL (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and GENE was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe5 plus BrBK2-9, BrBK4-8 and BrBK2-8 metabolites not found in human plasma. GW660511X and CHEMICAL reduced the production of BrBK1-5 and BrBK1-7 with more effect being observed with CHEMICAL. GW660511X and CHEMICAL increased the production of both BrBK1-8 and Br-Phe5 but not that of BrBK4-8 and BrBK2-8. This study shows that the potency of GW660511X in comparison with CHEMICAL is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | SUBSTRATE |
| Investigation of GENE metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors CHEMICAL and omapatrilat. Several studies have suggested that the accumulation of GENE, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (3.8 microM) or omapatrilat (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike CHEMICAL, omapatrilat abolished the production of BrBK1-5 and BrBK1-7, suggesting a better ACE inhibition effect over CHEMICAL as no NEP activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with omapatrilat. The production of Br-Phe5 was reduced with CHEMICAL while no significant change was observed with omapatrilat after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (530 nM) or omapatrilat (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe5 plus BrBK2-9, BrBK4-8 and BrBK2-8 metabolites not found in human plasma. CHEMICAL and omapatrilat reduced the production of BrBK1-5 and BrBK1-7 with more effect being observed with omapatrilat. CHEMICAL and omapatrilat increased the production of both BrBK1-8 and Br-Phe5 but not that of BrBK4-8 and BrBK2-8. This study shows that the potency of CHEMICAL in comparison with omapatrilat is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | GENE-CHEMICAL |
| Investigation of GENE metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors GW660511X and CHEMICAL. Several studies have suggested that the accumulation of GENE, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of GW660511X (3.8 microM) or CHEMICAL (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike GW660511X, CHEMICAL abolished the production of BrBK1-5 and BrBK1-7, suggesting a better ACE inhibition effect over GW660511X as no NEP activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with CHEMICAL. The production of Br-Phe5 was reduced with GW660511X while no significant change was observed with CHEMICAL after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of GW660511X (530 nM) or CHEMICAL (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe5 plus BrBK2-9, BrBK4-8 and BrBK2-8 metabolites not found in human plasma. GW660511X and CHEMICAL reduced the production of BrBK1-5 and BrBK1-7 with more effect being observed with CHEMICAL. GW660511X and CHEMICAL increased the production of both BrBK1-8 and Br-Phe5 but not that of BrBK4-8 and BrBK2-8. This study shows that the potency of GW660511X in comparison with CHEMICAL is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | GENE-CHEMICAL |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors CHEMICAL and omapatrilat. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (3.8 microM) or omapatrilat (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into GENE, BrBK1-7, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike CHEMICAL, omapatrilat abolished the production of BrBK1-5 and BrBK1-7, suggesting a better ACE inhibition effect over CHEMICAL as no NEP activity was found. In addition the production of GENE was enhanced in the presence of these inhibitors with a greater accumulation being observed with omapatrilat. The production of Br-Phe5 was reduced with CHEMICAL while no significant change was observed with omapatrilat after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (530 nM) or omapatrilat (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into GENE, BrBK1-7, BrBK1-5 and Br-Phe5 plus BrBK2-9, BrBK4-8 and BrBK2-8 metabolites not found in human plasma. CHEMICAL and omapatrilat reduced the production of BrBK1-5 and BrBK1-7 with more effect being observed with omapatrilat. CHEMICAL and omapatrilat increased the production of both GENE and Br-Phe5 but not that of BrBK4-8 and BrBK2-8. This study shows that the potency of CHEMICAL in comparison with omapatrilat is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | GENE-CHEMICAL |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors CHEMICAL and omapatrilat. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (3.8 microM) or omapatrilat (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike CHEMICAL, omapatrilat abolished the production of BrBK1-5 and BrBK1-7, suggesting a better ACE inhibition effect over CHEMICAL as no NEP activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with omapatrilat. The production of GENE was reduced with CHEMICAL while no significant change was observed with omapatrilat after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (530 nM) or omapatrilat (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and GENE plus BrBK2-9, BrBK4-8 and BrBK2-8 metabolites not found in human plasma. CHEMICAL and omapatrilat reduced the production of BrBK1-5 and BrBK1-7 with more effect being observed with omapatrilat. CHEMICAL and omapatrilat increased the production of both BrBK1-8 and GENE but not that of BrBK4-8 and BrBK2-8. This study shows that the potency of CHEMICAL in comparison with omapatrilat is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | INDIRECT-DOWNREGULATOR |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors GW660511X and CHEMICAL. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of GW660511X (3.8 microM) or CHEMICAL (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into GENE, BrBK1-7, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike GW660511X, CHEMICAL abolished the production of BrBK1-5 and BrBK1-7, suggesting a better ACE inhibition effect over GW660511X as no NEP activity was found. In addition the production of GENE was enhanced in the presence of these inhibitors with a greater accumulation being observed with CHEMICAL. The production of Br-Phe5 was reduced with GW660511X while no significant change was observed with CHEMICAL after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of GW660511X (530 nM) or CHEMICAL (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into GENE, BrBK1-7, BrBK1-5 and Br-Phe5 plus BrBK2-9, BrBK4-8 and BrBK2-8 metabolites not found in human plasma. GW660511X and CHEMICAL reduced the production of BrBK1-5 and BrBK1-7 with more effect being observed with CHEMICAL. GW660511X and CHEMICAL increased the production of both GENE and Br-Phe5 but not that of BrBK4-8 and BrBK2-8. This study shows that the potency of GW660511X in comparison with CHEMICAL is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | NO-RELATIONSHIP |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors GW660511X and CHEMICAL. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of GW660511X (3.8 microM) or CHEMICAL (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, GENE and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike GW660511X, CHEMICAL abolished the production of GENE and BrBK1-7, suggesting a better ACE inhibition effect over GW660511X as no NEP activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with CHEMICAL. The production of Br-Phe5 was reduced with GW660511X while no significant change was observed with CHEMICAL after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of GW660511X (530 nM) or CHEMICAL (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, GENE and Br-Phe5 plus BrBK2-9, BrBK4-8 and BrBK2-8 metabolites not found in human plasma. GW660511X and CHEMICAL reduced the production of GENE and BrBK1-7 with more effect being observed with CHEMICAL. GW660511X and CHEMICAL increased the production of both BrBK1-8 and Br-Phe5 but not that of BrBK4-8 and BrBK2-8. This study shows that the potency of GW660511X in comparison with CHEMICAL is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | NO-RELATIONSHIP |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors GW660511X and CHEMICAL. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of GW660511X (3.8 microM) or CHEMICAL (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into BrBK1-8, GENE, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike GW660511X, CHEMICAL abolished the production of BrBK1-5 and GENE, suggesting a better ACE inhibition effect over GW660511X as no NEP activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with CHEMICAL. The production of Br-Phe5 was reduced with GW660511X while no significant change was observed with CHEMICAL after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of GW660511X (530 nM) or CHEMICAL (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into BrBK1-8, GENE, BrBK1-5 and Br-Phe5 plus BrBK2-9, BrBK4-8 and BrBK2-8 metabolites not found in human plasma. GW660511X and CHEMICAL reduced the production of BrBK1-5 and GENE with more effect being observed with CHEMICAL. GW660511X and CHEMICAL increased the production of both BrBK1-8 and Br-Phe5 but not that of BrBK4-8 and BrBK2-8. This study shows that the potency of GW660511X in comparison with CHEMICAL is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | GENE-CHEMICAL |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors CHEMICAL and omapatrilat. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (3.8 microM) or omapatrilat (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike CHEMICAL, omapatrilat abolished the production of BrBK1-5 and BrBK1-7, suggesting a better GENE inhibition effect over CHEMICAL as no NEP activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with omapatrilat. The production of Br-Phe5 was reduced with CHEMICAL while no significant change was observed with omapatrilat after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of CHEMICAL (530 nM) or omapatrilat (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe5 plus BrBK2-9, BrBK4-8 and BrBK2-8 metabolites not found in human plasma. CHEMICAL and omapatrilat reduced the production of BrBK1-5 and BrBK1-7 with more effect being observed with omapatrilat. CHEMICAL and omapatrilat increased the production of both BrBK1-8 and Br-Phe5 but not that of BrBK4-8 and BrBK2-8. This study shows that the potency of CHEMICAL in comparison with omapatrilat is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of GENE/NEP inhibition in relation to effects in humans. | INHIBITOR |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors GW660511X and CHEMICAL. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual ACE/NEP inhibitors (GW660511X and omapatrilat) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of GW660511X (3.8 microM) or CHEMICAL (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike GW660511X, CHEMICAL abolished the production of BrBK1-5 and BrBK1-7, suggesting a better ACE inhibition effect over GW660511X as no GENE activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with CHEMICAL. The production of Br-Phe5 was reduced with GW660511X while no significant change was observed with CHEMICAL after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of GW660511X (530 nM) or CHEMICAL (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe5 plus BrBK2-9, BrBK4-8 and BrBK2-8 metabolites not found in human plasma. GW660511X and CHEMICAL reduced the production of BrBK1-5 and BrBK1-7 with more effect being observed with CHEMICAL. GW660511X and CHEMICAL increased the production of both BrBK1-8 and Br-Phe5 but not that of BrBK4-8 and BrBK2-8. This study shows that the potency of GW660511X in comparison with CHEMICAL is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/GENE inhibition in relation to effects in humans. | NO-RELATIONSHIP |
| Investigation of bradykinin metabolism in human and rat plasma in the presence of the dual ACE/NEP inhibitors GW660511X and CHEMICAL. Several studies have suggested that the accumulation of bradykinin, or that of one its metabolites BK1-8, is involved in the occurrence of side effects such as AE associated with the use of various ACEi. In this work a novel approach combining HPLC-UV on-line with oaTOF-MS and ICPMS was applied to investigate in human and rat plasma the metabolism of labelled BK (79/81 Br-Phe5) BrBK in the presence of two new dual GENE/NEP inhibitors (GW660511X and CHEMICAL) currently under clinical trial. In human plasma the BrBK half-life values in the absence or in the presence of GW660511X (3.8 microM) or CHEMICAL (32 nM) were 38.7 +/- 2.4, 51.2 +/- 4.7 and 114.7 +/- 9.3 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe. In the presence of inhibitors, however, the levels of these resultant metabolites were different. Unlike GW660511X, CHEMICAL abolished the production of BrBK1-5 and BrBK1-7, suggesting a better GENE inhibition effect over GW660511X as no NEP activity was found. In addition the production of BrBK1-8 was enhanced in the presence of these inhibitors with a greater accumulation being observed with CHEMICAL. The production of Br-Phe5 was reduced with GW660511X while no significant change was observed with CHEMICAL after 4 h of incubation. In rat plasma the BrBK half-life values in the absence or in the presence of GW660511X (530 nM) or CHEMICAL (50 nM) were 9.31 +/- 1.7, 22.06 +/- 3.1 and 25.3 +/- 1.7 min, respectively and BrBK was degraded into BrBK1-8, BrBK1-7, BrBK1-5 and Br-Phe5 plus BrBK2-9, BrBK4-8 and BrBK2-8 metabolites not found in human plasma. GW660511X and CHEMICAL reduced the production of BrBK1-5 and BrBK1-7 with more effect being observed with CHEMICAL. GW660511X and CHEMICAL increased the production of both BrBK1-8 and Br-Phe5 but not that of BrBK4-8 and BrBK2-8. This study shows that the potency of GW660511X in comparison with CHEMICAL is more than 100-fold lower in human, but less than 10-fold lower in rat plasma, suggesting that rat may not be a suitable in vivo model for the evaluation of ACE/NEP inhibition in relation to effects in humans. | INHIBITOR |
| Butyrylcholinesterase: an important new target in Alzheimer's disease therapy. Acetylcholinesterase (AChE) predominates in the healthy brain, with butyrylcholinesterase (BuChE) considered to play a minor role in regulating brain acetylcholine (ACh) levels. However, GENE activity progressively increases in patients with Alzheimer's disease (AD), while AChE activity remains unchanged or declines. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioral and global functioning characteristic of AD. The two enzymes differ in substrate specificity, kinetics and activity in different brain regions. Experimental evidence from the use of agents with enhanced selectivity for GENE (CHEMICAL analogues, MF-8622) and the dual inhibitor of both AChE and GENE, rivastigmine, indicates potential therapeutic benefits of inhibiting both AChE and GENE in AD and related dementias. Recent evidence suggests that both AChE and GENE may have roles in the aetiology and progression of AD beyond regulation of synaptic ACh levels. The development of specific GENE inhibitors and further experience with the dual enzyme inhibitor rivastigmine will improve understanding of the aetiology of AD and should lead to a wider variety of potent treatment options. | INHIBITOR |
| Butyrylcholinesterase: an important new target in Alzheimer's disease therapy. Acetylcholinesterase (AChE) predominates in the healthy brain, with butyrylcholinesterase (BuChE) considered to play a minor role in regulating brain acetylcholine (ACh) levels. However, GENE activity progressively increases in patients with Alzheimer's disease (AD), while AChE activity remains unchanged or declines. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioral and global functioning characteristic of AD. The two enzymes differ in substrate specificity, kinetics and activity in different brain regions. Experimental evidence from the use of agents with enhanced selectivity for GENE (cymserine analogues, CHEMICAL) and the dual inhibitor of both AChE and GENE, rivastigmine, indicates potential therapeutic benefits of inhibiting both AChE and GENE in AD and related dementias. Recent evidence suggests that both AChE and GENE may have roles in the aetiology and progression of AD beyond regulation of synaptic ACh levels. The development of specific GENE inhibitors and further experience with the dual enzyme inhibitor rivastigmine will improve understanding of the aetiology of AD and should lead to a wider variety of potent treatment options. | INHIBITOR |
| Butyrylcholinesterase: an important new target in Alzheimer's disease therapy. Acetylcholinesterase (AChE) predominates in the healthy brain, with butyrylcholinesterase (BuChE) considered to play a minor role in regulating brain acetylcholine (ACh) levels. However, GENE activity progressively increases in patients with Alzheimer's disease (AD), while AChE activity remains unchanged or declines. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioral and global functioning characteristic of AD. The two enzymes differ in substrate specificity, kinetics and activity in different brain regions. Experimental evidence from the use of agents with enhanced selectivity for GENE (cymserine analogues, MF-8622) and the dual inhibitor of both AChE and GENE, CHEMICAL, indicates potential therapeutic benefits of inhibiting both AChE and GENE in AD and related dementias. Recent evidence suggests that both AChE and GENE may have roles in the aetiology and progression of AD beyond regulation of synaptic ACh levels. The development of specific GENE inhibitors and further experience with the dual enzyme inhibitor CHEMICAL will improve understanding of the aetiology of AD and should lead to a wider variety of potent treatment options. | INHIBITOR |
| Butyrylcholinesterase: an important new target in Alzheimer's disease therapy. Acetylcholinesterase (AChE) predominates in the healthy brain, with butyrylcholinesterase (BuChE) considered to play a minor role in regulating brain acetylcholine (ACh) levels. However, BuChE activity progressively increases in patients with Alzheimer's disease (AD), while GENE activity remains unchanged or declines. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioral and global functioning characteristic of AD. The two enzymes differ in substrate specificity, kinetics and activity in different brain regions. Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine analogues, MF-8622) and the dual inhibitor of both GENE and BuChE, CHEMICAL, indicates potential therapeutic benefits of inhibiting both GENE and BuChE in AD and related dementias. Recent evidence suggests that both GENE and BuChE may have roles in the aetiology and progression of AD beyond regulation of synaptic ACh levels. The development of specific BuChE inhibitors and further experience with the dual enzyme inhibitor CHEMICAL will improve understanding of the aetiology of AD and should lead to a wider variety of potent treatment options. | INHIBITOR |
| Butyrylcholinesterase: an important new target in Alzheimer's disease therapy. Acetylcholinesterase (GENE) predominates in the healthy brain, with butyrylcholinesterase (BuChE) considered to play a minor role in regulating brain CHEMICAL (ACh) levels. However, BuChE activity progressively increases in patients with Alzheimer's disease (AD), while GENE activity remains unchanged or declines. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioral and global functioning characteristic of AD. The two enzymes differ in substrate specificity, kinetics and activity in different brain regions. Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine analogues, MF-8622) and the dual inhibitor of both GENE and BuChE, rivastigmine, indicates potential therapeutic benefits of inhibiting both GENE and BuChE in AD and related dementias. Recent evidence suggests that both GENE and BuChE may have roles in the aetiology and progression of AD beyond regulation of synaptic ACh levels. The development of specific BuChE inhibitors and further experience with the dual enzyme inhibitor rivastigmine will improve understanding of the aetiology of AD and should lead to a wider variety of potent treatment options. | SUBSTRATE |
| Butyrylcholinesterase: an important new target in Alzheimer's disease therapy. Acetylcholinesterase (AChE) predominates in the healthy brain, with GENE (BuChE) considered to play a minor role in regulating brain CHEMICAL (ACh) levels. However, BuChE activity progressively increases in patients with Alzheimer's disease (AD), while AChE activity remains unchanged or declines. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioral and global functioning characteristic of AD. The two enzymes differ in substrate specificity, kinetics and activity in different brain regions. Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine analogues, MF-8622) and the dual inhibitor of both AChE and BuChE, rivastigmine, indicates potential therapeutic benefits of inhibiting both AChE and BuChE in AD and related dementias. Recent evidence suggests that both AChE and BuChE may have roles in the aetiology and progression of AD beyond regulation of synaptic ACh levels. The development of specific BuChE inhibitors and further experience with the dual enzyme inhibitor rivastigmine will improve understanding of the aetiology of AD and should lead to a wider variety of potent treatment options. | PRODUCT-OF |
| Butyrylcholinesterase: an important new target in Alzheimer's disease therapy. Acetylcholinesterase (AChE) predominates in the healthy brain, with butyrylcholinesterase (GENE) considered to play a minor role in regulating brain CHEMICAL (ACh) levels. However, GENE activity progressively increases in patients with Alzheimer's disease (AD), while AChE activity remains unchanged or declines. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioral and global functioning characteristic of AD. The two enzymes differ in substrate specificity, kinetics and activity in different brain regions. Experimental evidence from the use of agents with enhanced selectivity for GENE (cymserine analogues, MF-8622) and the dual inhibitor of both AChE and GENE, rivastigmine, indicates potential therapeutic benefits of inhibiting both AChE and GENE in AD and related dementias. Recent evidence suggests that both AChE and GENE may have roles in the aetiology and progression of AD beyond regulation of synaptic ACh levels. The development of specific GENE inhibitors and further experience with the dual enzyme inhibitor rivastigmine will improve understanding of the aetiology of AD and should lead to a wider variety of potent treatment options. | SUBSTRATE |
| Butyrylcholinesterase: an important new target in Alzheimer's disease therapy. GENE (AChE) predominates in the healthy brain, with butyrylcholinesterase (BuChE) considered to play a minor role in regulating brain CHEMICAL (ACh) levels. However, BuChE activity progressively increases in patients with Alzheimer's disease (AD), while AChE activity remains unchanged or declines. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioral and global functioning characteristic of AD. The two enzymes differ in substrate specificity, kinetics and activity in different brain regions. Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine analogues, MF-8622) and the dual inhibitor of both AChE and BuChE, rivastigmine, indicates potential therapeutic benefits of inhibiting both AChE and BuChE in AD and related dementias. Recent evidence suggests that both AChE and BuChE may have roles in the aetiology and progression of AD beyond regulation of synaptic ACh levels. The development of specific BuChE inhibitors and further experience with the dual enzyme inhibitor rivastigmine will improve understanding of the aetiology of AD and should lead to a wider variety of potent treatment options. | PRODUCT-OF |
| Butyrylcholinesterase: an important new target in Alzheimer's disease therapy. Acetylcholinesterase (GENE) predominates in the healthy brain, with butyrylcholinesterase (BuChE) considered to play a minor role in regulating brain acetylcholine (CHEMICAL) levels. However, BuChE activity progressively increases in patients with Alzheimer's disease (AD), while GENE activity remains unchanged or declines. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioral and global functioning characteristic of AD. The two enzymes differ in substrate specificity, kinetics and activity in different brain regions. Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine analogues, MF-8622) and the dual inhibitor of both GENE and BuChE, rivastigmine, indicates potential therapeutic benefits of inhibiting both GENE and BuChE in AD and related dementias. Recent evidence suggests that both GENE and BuChE may have roles in the aetiology and progression of AD beyond regulation of synaptic CHEMICAL levels. The development of specific BuChE inhibitors and further experience with the dual enzyme inhibitor rivastigmine will improve understanding of the aetiology of AD and should lead to a wider variety of potent treatment options. | SUBSTRATE |
| Butyrylcholinesterase: an important new target in Alzheimer's disease therapy. Acetylcholinesterase (AChE) predominates in the healthy brain, with GENE (BuChE) considered to play a minor role in regulating brain acetylcholine (CHEMICAL) levels. However, BuChE activity progressively increases in patients with Alzheimer's disease (AD), while AChE activity remains unchanged or declines. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioral and global functioning characteristic of AD. The two enzymes differ in substrate specificity, kinetics and activity in different brain regions. Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine analogues, MF-8622) and the dual inhibitor of both AChE and BuChE, rivastigmine, indicates potential therapeutic benefits of inhibiting both AChE and BuChE in AD and related dementias. Recent evidence suggests that both AChE and BuChE may have roles in the aetiology and progression of AD beyond regulation of synaptic CHEMICAL levels. The development of specific BuChE inhibitors and further experience with the dual enzyme inhibitor rivastigmine will improve understanding of the aetiology of AD and should lead to a wider variety of potent treatment options. | PRODUCT-OF |
| Butyrylcholinesterase: an important new target in Alzheimer's disease therapy. Acetylcholinesterase (AChE) predominates in the healthy brain, with butyrylcholinesterase (GENE) considered to play a minor role in regulating brain acetylcholine (CHEMICAL) levels. However, GENE activity progressively increases in patients with Alzheimer's disease (AD), while AChE activity remains unchanged or declines. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioral and global functioning characteristic of AD. The two enzymes differ in substrate specificity, kinetics and activity in different brain regions. Experimental evidence from the use of agents with enhanced selectivity for GENE (cymserine analogues, MF-8622) and the dual inhibitor of both AChE and GENE, rivastigmine, indicates potential therapeutic benefits of inhibiting both AChE and GENE in AD and related dementias. Recent evidence suggests that both AChE and GENE may have roles in the aetiology and progression of AD beyond regulation of synaptic CHEMICAL levels. The development of specific GENE inhibitors and further experience with the dual enzyme inhibitor rivastigmine will improve understanding of the aetiology of AD and should lead to a wider variety of potent treatment options. | SUBSTRATE |
| Butyrylcholinesterase: an important new target in Alzheimer's disease therapy. GENE (AChE) predominates in the healthy brain, with butyrylcholinesterase (BuChE) considered to play a minor role in regulating brain acetylcholine (CHEMICAL) levels. However, BuChE activity progressively increases in patients with Alzheimer's disease (AD), while AChE activity remains unchanged or declines. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioral and global functioning characteristic of AD. The two enzymes differ in substrate specificity, kinetics and activity in different brain regions. Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine analogues, MF-8622) and the dual inhibitor of both AChE and BuChE, rivastigmine, indicates potential therapeutic benefits of inhibiting both AChE and BuChE in AD and related dementias. Recent evidence suggests that both AChE and BuChE may have roles in the aetiology and progression of AD beyond regulation of synaptic CHEMICAL levels. The development of specific BuChE inhibitors and further experience with the dual enzyme inhibitor rivastigmine will improve understanding of the aetiology of AD and should lead to a wider variety of potent treatment options. | PRODUCT-OF |
| A low toxicity maintenance regime, using CHEMICAL and readily available drugs, for mantle cell lymphoma and other malignancies with excess GENE levels. Mantle cell lymphoma is a difficult to treat non-Hodgkin's lymphoma (NHL) whose biochemistry is unusually well characterised. Almost all and perhaps all patients overexpress the GENE protein which is crucial in driving cells from the G1 to the S phase. This overexpression may be responsible for the refractoriness. Despite this understanding, treatments for mantle cell lymphoma are based on standard NHL regimes of cyclophosphamide, doxorubicin, vincristine and prednisone, perhaps supplemented with the monoclonal antibody rituximab. There has never been any attempt to direct treatment to the GENE mechanism or to angiogenesis which is now known to be important in all lymphomas. Both these targets lend themselves to long-term maintenance regimes of relatively low toxicity which can be used as adjuvants to standard therapy. Agents which have recently been shown to block GENE translation by regulating calcium levels are the unsaturated essential fatty acid, CHEMICAL (EPA), the antidiabetic thiazolidinediones, and the antifungal agent, clotrimazole. Two types of agent which have been shown to inhibit angiogenesis are the teratogen, thalidomide, and the selective inhibitors of cyclo-oxygenase 2 (COX-2). Retinoids exert synergistic effects with EPA and have been shown to inhibit both tumour growth and angiogenesis. The mechanisms of action of these various agents are discussed, and specific suggestions are made for low toxicity maintenance therapy of mantle cell lymphoma and of other tumours which overexpress GENE. | GENE-CHEMICAL |
| A low toxicity maintenance regime, using eicosapentaenoic acid and readily available drugs, for mantle cell lymphoma and other malignancies with excess GENE levels. Mantle cell lymphoma is a difficult to treat non-Hodgkin's lymphoma (NHL) whose biochemistry is unusually well characterised. Almost all and perhaps all patients overexpress the GENE protein which is crucial in driving cells from the G1 to the S phase. This overexpression may be responsible for the refractoriness. Despite this understanding, treatments for mantle cell lymphoma are based on standard NHL regimes of cyclophosphamide, doxorubicin, vincristine and prednisone, perhaps supplemented with the monoclonal antibody rituximab. There has never been any attempt to direct treatment to the GENE mechanism or to angiogenesis which is now known to be important in all lymphomas. Both these targets lend themselves to long-term maintenance regimes of relatively low toxicity which can be used as adjuvants to standard therapy. Agents which have recently been shown to block GENE translation by regulating calcium levels are the CHEMICAL, eicosapentaenoic acid (EPA), the antidiabetic thiazolidinediones, and the antifungal agent, clotrimazole. Two types of agent which have been shown to inhibit angiogenesis are the teratogen, thalidomide, and the selective inhibitors of cyclo-oxygenase 2 (COX-2). Retinoids exert synergistic effects with EPA and have been shown to inhibit both tumour growth and angiogenesis. The mechanisms of action of these various agents are discussed, and specific suggestions are made for low toxicity maintenance therapy of mantle cell lymphoma and of other tumours which overexpress GENE. | REGULATOR |
| A low toxicity maintenance regime, using eicosapentaenoic acid and readily available drugs, for mantle cell lymphoma and other malignancies with excess GENE levels. Mantle cell lymphoma is a difficult to treat non-Hodgkin's lymphoma (NHL) whose biochemistry is unusually well characterised. Almost all and perhaps all patients overexpress the GENE protein which is crucial in driving cells from the G1 to the S phase. This overexpression may be responsible for the refractoriness. Despite this understanding, treatments for mantle cell lymphoma are based on standard NHL regimes of cyclophosphamide, doxorubicin, vincristine and prednisone, perhaps supplemented with the monoclonal antibody rituximab. There has never been any attempt to direct treatment to the GENE mechanism or to angiogenesis which is now known to be important in all lymphomas. Both these targets lend themselves to long-term maintenance regimes of relatively low toxicity which can be used as adjuvants to standard therapy. Agents which have recently been shown to block GENE translation by regulating calcium levels are the unsaturated essential fatty acid, eicosapentaenoic acid (CHEMICAL), the antidiabetic thiazolidinediones, and the antifungal agent, clotrimazole. Two types of agent which have been shown to inhibit angiogenesis are the teratogen, thalidomide, and the selective inhibitors of cyclo-oxygenase 2 (COX-2). Retinoids exert synergistic effects with CHEMICAL and have been shown to inhibit both tumour growth and angiogenesis. The mechanisms of action of these various agents are discussed, and specific suggestions are made for low toxicity maintenance therapy of mantle cell lymphoma and of other tumours which overexpress GENE. | REGULATOR |
| A low toxicity maintenance regime, using eicosapentaenoic acid and readily available drugs, for mantle cell lymphoma and other malignancies with excess GENE levels. Mantle cell lymphoma is a difficult to treat non-Hodgkin's lymphoma (NHL) whose biochemistry is unusually well characterised. Almost all and perhaps all patients overexpress the GENE protein which is crucial in driving cells from the G1 to the S phase. This overexpression may be responsible for the refractoriness. Despite this understanding, treatments for mantle cell lymphoma are based on standard NHL regimes of cyclophosphamide, doxorubicin, vincristine and prednisone, perhaps supplemented with the monoclonal antibody rituximab. There has never been any attempt to direct treatment to the GENE mechanism or to angiogenesis which is now known to be important in all lymphomas. Both these targets lend themselves to long-term maintenance regimes of relatively low toxicity which can be used as adjuvants to standard therapy. Agents which have recently been shown to block GENE translation by regulating calcium levels are the unsaturated essential fatty acid, eicosapentaenoic acid (EPA), the antidiabetic CHEMICAL, and the antifungal agent, clotrimazole. Two types of agent which have been shown to inhibit angiogenesis are the teratogen, thalidomide, and the selective inhibitors of cyclo-oxygenase 2 (COX-2). Retinoids exert synergistic effects with EPA and have been shown to inhibit both tumour growth and angiogenesis. The mechanisms of action of these various agents are discussed, and specific suggestions are made for low toxicity maintenance therapy of mantle cell lymphoma and of other tumours which overexpress GENE. | GENE-CHEMICAL |
| A low toxicity maintenance regime, using eicosapentaenoic acid and readily available drugs, for mantle cell lymphoma and other malignancies with excess GENE levels. Mantle cell lymphoma is a difficult to treat non-Hodgkin's lymphoma (NHL) whose biochemistry is unusually well characterised. Almost all and perhaps all patients overexpress the GENE protein which is crucial in driving cells from the G1 to the S phase. This overexpression may be responsible for the refractoriness. Despite this understanding, treatments for mantle cell lymphoma are based on standard NHL regimes of cyclophosphamide, doxorubicin, vincristine and prednisone, perhaps supplemented with the monoclonal antibody rituximab. There has never been any attempt to direct treatment to the GENE mechanism or to angiogenesis which is now known to be important in all lymphomas. Both these targets lend themselves to long-term maintenance regimes of relatively low toxicity which can be used as adjuvants to standard therapy. Agents which have recently been shown to block GENE translation by regulating calcium levels are the unsaturated essential fatty acid, eicosapentaenoic acid (EPA), the antidiabetic thiazolidinediones, and the antifungal agent, CHEMICAL. Two types of agent which have been shown to inhibit angiogenesis are the teratogen, thalidomide, and the selective inhibitors of cyclo-oxygenase 2 (COX-2). Retinoids exert synergistic effects with EPA and have been shown to inhibit both tumour growth and angiogenesis. The mechanisms of action of these various agents are discussed, and specific suggestions are made for low toxicity maintenance therapy of mantle cell lymphoma and of other tumours which overexpress GENE. | REGULATOR |
| Angiotensin AT1 receptor antagonist losartan and the defence reaction in the anaesthetised rat. Effect on the carotid chemoreflex. Modulation at the level of the nucleus tractus solitarii (NTS) appears to be an effective way of controlling cardiovascular reflexes. CHEMICAL acting on GENE at the central nervous system appears to have an important role in these modulatory processes. The hypothalamic defence area (HDA) is a potential source of descending fibres containing angiotensin II that innervate the NTS. We investigated the effect of AT1 receptor blockade in the NTS on the response to stimulation of HDA in anaesthetised rats treated with the neuromuscular blocking agent pancuronium bromide. The characteristic increase in heart rate, blood pressure and phrenic nerve activity evoked by electrical stimulation of HDA is decreased by the microinjection of the AT1 receptor antagonist losartan into the NTS and the cardiovascular response to carotid body chemical stimulation is also reduced. These results support the hypothesis that AT1 receptors in the NTS play a role in the modulation of cardiovascular reflexes, and modify the influence exerted on the processing of these reflexes by other areas of the central nervous system. | REGULATOR |
| Angiotensin GENE antagonist losartan and the defence reaction in the anaesthetised rat. Effect on the carotid chemoreflex. Modulation at the level of the nucleus tractus solitarii (NTS) appears to be an effective way of controlling cardiovascular reflexes. Angiotensin II acting on angiotensin AT1 receptors at the central nervous system appears to have an important role in these modulatory processes. The hypothalamic defence area (HDA) is a potential source of descending fibres containing angiotensin II that innervate the NTS. We investigated the effect of GENE blockade in the NTS on the response to stimulation of HDA in anaesthetised rats treated with the neuromuscular blocking agent CHEMICAL. The characteristic increase in heart rate, blood pressure and phrenic nerve activity evoked by electrical stimulation of HDA is decreased by the microinjection of the GENE antagonist losartan into the NTS and the cardiovascular response to carotid body chemical stimulation is also reduced. These results support the hypothesis that AT1 receptors in the NTS play a role in the modulation of cardiovascular reflexes, and modify the influence exerted on the processing of these reflexes by other areas of the central nervous system. | INHIBITOR |
| GENE antagonist CHEMICAL and the defence reaction in the anaesthetised rat. Effect on the carotid chemoreflex. Modulation at the level of the nucleus tractus solitarii (NTS) appears to be an effective way of controlling cardiovascular reflexes. Angiotensin II acting on angiotensin AT1 receptors at the central nervous system appears to have an important role in these modulatory processes. The hypothalamic defence area (HDA) is a potential source of descending fibres containing angiotensin II that innervate the NTS. We investigated the effect of AT1 receptor blockade in the NTS on the response to stimulation of HDA in anaesthetised rats treated with the neuromuscular blocking agent pancuronium bromide. The characteristic increase in heart rate, blood pressure and phrenic nerve activity evoked by electrical stimulation of HDA is decreased by the microinjection of the AT1 receptor antagonist CHEMICAL into the NTS and the cardiovascular response to carotid body chemical stimulation is also reduced. These results support the hypothesis that AT1 receptors in the NTS play a role in the modulation of cardiovascular reflexes, and modify the influence exerted on the processing of these reflexes by other areas of the central nervous system. | INHIBITOR |
| Defective processing of the GENE in CHEMICAL-induced mouse colon tumors. High levels of the cell growth inhibitor GENE (TGF-beta1) are often found in a variety of human cancers. However, the physiological significance of this overexpression depends on the availability of the biologically active form of TGF-beta1 within the extracellular matrix of the tumor microenvironment. To determine the expression and activation status of TGF-beta1 in chemically induced tumors, 6-wk-old A/J mice were injected intraperitoneally with either CHEMICAL (AOM) (10 mg/kg body weight, once a week for 6 wk) or normal saline solution, and colon tumors were isolated 24 wk following the last injection. An enzyme-linked immunosorbent assay for TGF-beta1 revealed a significant increase (1.7-fold, P < 0.05) in total TGF-beta1 protein in tumors. Interestingly, while 80% of the total TGF-beta1 in the control colon tissues was in the active form, only 50% was found to be active in tumors. Together with our earlier observations that TGF-beta1 mRNA levels are unchanged in A/J tumors, these data further support a mechanism whereby elevated TGF-beta1 levels result from a defective activation and turnover of this protein. Because plasmin is known to be a major activator of TGF-beta1 in vivo, we hypothesized that reduced plasmin activity may be responsible for the observed dysregulation of TGF-beta1 processing in these behaviorally benign tumors. With a fluorogenic peptide substrate for serine proteases, a deficiency in plasmin activity was found in the tumors. Furthermore, semiquantitative reverse transcription (RT)-polymerase chain reaction (PCR) analysis of a panel of genes involved in the plasminogen activation system, including plasminogen activator inhibitor-1 (PAI-1), urokinase-plasminogen activator (u-PA), and urokinase-receptor (u-PAR-1), demonstrated a significant upregulation (approximately fourfold to sixfold, P < 0.05) in the expression of each of these genes in the tumor tissue. In addition, no significant changes were observed in the expression levels of thrombospondin-1 (TSP-1) and insulin-like growth factor type II receptor (IGF-IIR), which also mediate the activation of latent TGF-beta1. To gain further insight into the functionality of the TGF-beta1 pathway, cDNA microarrays were performed and the expression levels of a panel of 21 TGF-beta1-specific target genes were determined in AOM-induced tumors that overexpress the ligand. A significant dysregulation in the expression of each of these targets was observed, providing evidence of aberrant TGF-beta1 signaling in tumors. Overall, the present study demonstrates a very low plasmin activity in A/J colon tumors, possibly as a result of the potent inhibitory effect of PAI-1 on the plasminogen activation cascade. The observed deficiency in plasmin activity may not be sufficiently compensated for by other mechanisms of latent TGF-beta1 activation, including TSP-1 and IGF-IIR, thereby resulting in a decreased fraction of the biologically active form of TGF-beta1 and subsequent aberration in TGF-beta1-specific gene regulation in A/J tumors. | GENE-CHEMICAL |
| Binding and GTPgammaS autoradiographic analysis of preproorphanin precursor peptide products at the ORL1 and opioid receptors. Utilizing agonist-stimulated GTPgammaS autoradiography, we analyzed the ability of preproorphanin FQ (ppOFQ) peptides to stimulate CHEMICAL binding in adult rat brain. Orphanin FQ (OFQ) stimulated CHEMICAL binding in a pattern similar to that described for [125I]-OFQ at the endogenous opioid receptor-like (ORL1) receptor. The ppOFQ peptides nocistatin and orphanin FQ2 (OFQ II(1-17)) had no effect, suggesting that they do not mediate their reported analgesic effects via a G(i/o)-coupled receptor (i.e. opioid or ORL1). Unlike OFQ II(1-17), high concentrations of its C-terminal extension, GENE, stimulated CHEMICAL binding in a mu (mu) opioid receptor-like distribution and the effect was blocked by naloxone. To explore these observations, we evaluated the receptor binding profile of GENE at the cloned ORL1 and mu opioid receptors. GENE had no specific binding at either ORL1 or mu opioid receptors at concentrations up to 50 microM. This lack of affinity was not consistent with a mu-mediated effect, as suggested by preliminary observation using functional autoradiography in rat brain sections. Although behavioral studies suggest that GENE possesses analgesic activity, this effect does not appear to be mediated via direct binding at the mu opioid receptor. Taken together, these findings support the view that (1) OFQ is the only ppOFQ peptide that binds to and activates the ORL1 receptor and (2) GENE does not bind or stimulate CHEMICAL binding in cells expressing the mu opioid receptor. | NO-RELATIONSHIP |
| Binding and GTPgammaS autoradiographic analysis of preproorphanin precursor peptide products at the ORL1 and opioid receptors. Utilizing agonist-stimulated GTPgammaS autoradiography, we analyzed the ability of preproorphanin FQ (ppOFQ) peptides to stimulate CHEMICAL binding in adult rat brain. Orphanin FQ (OFQ) stimulated CHEMICAL binding in a pattern similar to that described for [125I]-OFQ at the endogenous opioid receptor-like (ORL1) receptor. The ppOFQ peptides nocistatin and orphanin FQ2 (OFQ II(1-17)) had no effect, suggesting that they do not mediate their reported analgesic effects via a G(i/o)-coupled receptor (i.e. opioid or ORL1). Unlike OFQ II(1-17), high concentrations of its C-terminal extension, OFQ II(1-28), stimulated CHEMICAL binding in a mu (mu) opioid receptor-like distribution and the effect was blocked by naloxone. To explore these observations, we evaluated the receptor binding profile of OFQ II(1-28) at the cloned ORL1 and mu opioid receptors. OFQ II(1-28) had no specific binding at either ORL1 or mu opioid receptors at concentrations up to 50 microM. This lack of affinity was not consistent with a mu-mediated effect, as suggested by preliminary observation using functional autoradiography in rat brain sections. Although behavioral studies suggest that OFQ II(1-28) possesses analgesic activity, this effect does not appear to be mediated via direct binding at the GENE. Taken together, these findings support the view that (1) OFQ is the only ppOFQ peptide that binds to and activates the ORL1 receptor and (2) OFQ II(1-28) does not bind or stimulate CHEMICAL binding in cells expressing the GENE. | DIRECT-REGULATOR |
| Binding and GTPgammaS autoradiographic analysis of preproorphanin precursor peptide products at the ORL1 and opioid receptors. Utilizing agonist-stimulated GTPgammaS autoradiography, we analyzed the ability of preproorphanin FQ (ppOFQ) peptides to stimulate [35S]-GTPgammaS binding in adult rat brain. Orphanin FQ (OFQ) stimulated [35S]-GTPgammaS binding in a pattern similar to that described for [125I]-OFQ at the endogenous opioid receptor-like (ORL1) receptor. The ppOFQ peptides nocistatin and orphanin FQ2 (OFQ II(1-17)) had no effect, suggesting that they do not mediate their reported analgesic effects via a G(i/o)-coupled receptor (i.e. opioid or ORL1). Unlike OFQ II(1-17), high concentrations of its CHEMICAL-terminal extension, GENE, stimulated [35S]-GTPgammaS binding in a mu (mu) opioid receptor-like distribution and the effect was blocked by naloxone. To explore these observations, we evaluated the receptor binding profile of GENE at the cloned ORL1 and mu opioid receptors. GENE had no specific binding at either ORL1 or mu opioid receptors at concentrations up to 50 microM. This lack of affinity was not consistent with a mu-mediated effect, as suggested by preliminary observation using functional autoradiography in rat brain sections. Although behavioral studies suggest that GENE possesses analgesic activity, this effect does not appear to be mediated via direct binding at the mu opioid receptor. Taken together, these findings support the view that (1) OFQ is the only ppOFQ peptide that binds to and activates the ORL1 receptor and (2) GENE does not bind or stimulate [35S]-GTPgammaS binding in cells expressing the mu opioid receptor. | PART-OF |
| Binding and GTPgammaS autoradiographic analysis of preproorphanin precursor peptide products at the ORL1 and opioid receptors. Utilizing agonist-stimulated GTPgammaS autoradiography, we analyzed the ability of preproorphanin FQ (ppOFQ) peptides to stimulate CHEMICAL binding in adult rat brain. Orphanin FQ (OFQ) stimulated CHEMICAL binding in a pattern similar to that described for [125I]-OFQ at the endogenous opioid receptor-like (ORL1) receptor. The ppOFQ peptides nocistatin and orphanin FQ2 (OFQ II(1-17)) had no effect, suggesting that they do not mediate their reported analgesic effects via a G(i/o)-coupled receptor (i.e. opioid or ORL1). Unlike GENE II(1-17), high concentrations of its C-terminal extension, GENE II(1-28), stimulated CHEMICAL binding in a mu (mu) opioid receptor-like distribution and the effect was blocked by naloxone. To explore these observations, we evaluated the receptor binding profile of GENE II(1-28) at the cloned ORL1 and mu opioid receptors. GENE II(1-28) had no specific binding at either ORL1 or mu opioid receptors at concentrations up to 50 microM. This lack of affinity was not consistent with a mu-mediated effect, as suggested by preliminary observation using functional autoradiography in rat brain sections. Although behavioral studies suggest that GENE II(1-28) possesses analgesic activity, this effect does not appear to be mediated via direct binding at the mu opioid receptor. Taken together, these findings support the view that (1) GENE is the only ppOFQ peptide that binds to and activates the ORL1 receptor and (2) GENE II(1-28) does not bind or stimulate CHEMICAL binding in cells expressing the mu opioid receptor. | NO-RELATIONSHIP |
| Binding and GTPgammaS autoradiographic analysis of preproorphanin precursor peptide products at the ORL1 and opioid receptors. Utilizing agonist-stimulated GTPgammaS autoradiography, we analyzed the ability of preproorphanin FQ (ppOFQ) peptides to stimulate CHEMICAL binding in adult rat brain. Orphanin FQ (OFQ) stimulated CHEMICAL binding in a pattern similar to that described for [125I]-OFQ at the endogenous opioid receptor-like (ORL1) receptor. The GENE peptides nocistatin and orphanin FQ2 (OFQ II(1-17)) had no effect, suggesting that they do not mediate their reported analgesic effects via a G(i/o)-coupled receptor (i.e. opioid or ORL1). Unlike OFQ II(1-17), high concentrations of its C-terminal extension, OFQ II(1-28), stimulated CHEMICAL binding in a mu (mu) opioid receptor-like distribution and the effect was blocked by naloxone. To explore these observations, we evaluated the receptor binding profile of OFQ II(1-28) at the cloned ORL1 and mu opioid receptors. OFQ II(1-28) had no specific binding at either ORL1 or mu opioid receptors at concentrations up to 50 microM. This lack of affinity was not consistent with a mu-mediated effect, as suggested by preliminary observation using functional autoradiography in rat brain sections. Although behavioral studies suggest that OFQ II(1-28) possesses analgesic activity, this effect does not appear to be mediated via direct binding at the mu opioid receptor. Taken together, these findings support the view that (1) OFQ is the only GENE peptide that binds to and activates the ORL1 receptor and (2) OFQ II(1-28) does not bind or stimulate CHEMICAL binding in cells expressing the mu opioid receptor. | DIRECT-REGULATOR |
| Binding and GTPgammaS autoradiographic analysis of preproorphanin precursor peptide products at the GENE and opioid receptors. Utilizing agonist-stimulated GTPgammaS autoradiography, we analyzed the ability of preproorphanin FQ (ppOFQ) peptides to stimulate CHEMICAL binding in adult rat brain. Orphanin FQ (OFQ) stimulated CHEMICAL binding in a pattern similar to that described for [125I]-OFQ at the endogenous opioid receptor-like (ORL1) receptor. The ppOFQ peptides nocistatin and orphanin FQ2 (OFQ II(1-17)) had no effect, suggesting that they do not mediate their reported analgesic effects via a G(i/o)-coupled receptor (i.e. opioid or ORL1). Unlike OFQ II(1-17), high concentrations of its C-terminal extension, OFQ II(1-28), stimulated CHEMICAL binding in a mu (mu) opioid receptor-like distribution and the effect was blocked by naloxone. To explore these observations, we evaluated the receptor binding profile of OFQ II(1-28) at the cloned GENE and mu opioid receptors. OFQ II(1-28) had no specific binding at either GENE or mu opioid receptors at concentrations up to 50 microM. This lack of affinity was not consistent with a mu-mediated effect, as suggested by preliminary observation using functional autoradiography in rat brain sections. Although behavioral studies suggest that OFQ II(1-28) possesses analgesic activity, this effect does not appear to be mediated via direct binding at the mu opioid receptor. Taken together, these findings support the view that (1) OFQ is the only ppOFQ peptide that binds to and activates the GENE receptor and (2) OFQ II(1-28) does not bind or stimulate CHEMICAL binding in cells expressing the mu opioid receptor. | DIRECT-REGULATOR |
| Binding and GTPgammaS autoradiographic analysis of preproorphanin precursor peptide products at the ORL1 and opioid receptors. Utilizing agonist-stimulated GTPgammaS autoradiography, we analyzed the ability of preproorphanin FQ (ppOFQ) peptides to stimulate CHEMICAL binding in adult rat brain. GENE (OFQ) stimulated CHEMICAL binding in a pattern similar to that described for [125I]-OFQ at the endogenous opioid receptor-like (ORL1) receptor. The ppOFQ peptides nocistatin and orphanin FQ2 (OFQ II(1-17)) had no effect, suggesting that they do not mediate their reported analgesic effects via a G(i/o)-coupled receptor (i.e. opioid or ORL1). Unlike OFQ II(1-17), high concentrations of its C-terminal extension, OFQ II(1-28), stimulated CHEMICAL binding in a mu (mu) opioid receptor-like distribution and the effect was blocked by naloxone. To explore these observations, we evaluated the receptor binding profile of OFQ II(1-28) at the cloned ORL1 and mu opioid receptors. OFQ II(1-28) had no specific binding at either ORL1 or mu opioid receptors at concentrations up to 50 microM. This lack of affinity was not consistent with a mu-mediated effect, as suggested by preliminary observation using functional autoradiography in rat brain sections. Although behavioral studies suggest that OFQ II(1-28) possesses analgesic activity, this effect does not appear to be mediated via direct binding at the mu opioid receptor. Taken together, these findings support the view that (1) OFQ is the only ppOFQ peptide that binds to and activates the ORL1 receptor and (2) OFQ II(1-28) does not bind or stimulate CHEMICAL binding in cells expressing the mu opioid receptor. | DIRECT-REGULATOR |
| Binding and GTPgammaS autoradiographic analysis of preproorphanin precursor peptide products at the ORL1 and opioid receptors. Utilizing agonist-stimulated GTPgammaS autoradiography, we analyzed the ability of preproorphanin FQ (ppOFQ) peptides to stimulate [35S]-GTPgammaS binding in adult rat brain. Orphanin FQ (OFQ) stimulated [35S]-GTPgammaS binding in a pattern similar to that described for [CHEMICAL]-GENE at the endogenous opioid receptor-like (ORL1) receptor. The ppOFQ peptides nocistatin and orphanin FQ2 (OFQ II(1-17)) had no effect, suggesting that they do not mediate their reported analgesic effects via a G(i/o)-coupled receptor (i.e. opioid or ORL1). Unlike GENE II(1-17), high concentrations of its C-terminal extension, GENE II(1-28), stimulated [35S]-GTPgammaS binding in a mu (mu) opioid receptor-like distribution and the effect was blocked by naloxone. To explore these observations, we evaluated the receptor binding profile of GENE II(1-28) at the cloned ORL1 and mu opioid receptors. GENE II(1-28) had no specific binding at either ORL1 or mu opioid receptors at concentrations up to 50 microM. This lack of affinity was not consistent with a mu-mediated effect, as suggested by preliminary observation using functional autoradiography in rat brain sections. Although behavioral studies suggest that GENE II(1-28) possesses analgesic activity, this effect does not appear to be mediated via direct binding at the mu opioid receptor. Taken together, these findings support the view that (1) GENE is the only ppOFQ peptide that binds to and activates the ORL1 receptor and (2) GENE II(1-28) does not bind or stimulate [35S]-GTPgammaS binding in cells expressing the mu opioid receptor. | REGULATOR |
| Binding and GTPgammaS autoradiographic analysis of preproorphanin precursor peptide products at the ORL1 and opioid receptors. Utilizing agonist-stimulated GTPgammaS autoradiography, we analyzed the ability of preproorphanin FQ (ppOFQ) peptides to stimulate CHEMICAL binding in adult rat brain. Orphanin FQ (OFQ) stimulated CHEMICAL binding in a pattern similar to that described for [125I]-OFQ at the endogenous opioid receptor-like (ORL1) receptor. The ppOFQ peptides nocistatin and orphanin FQ2 (OFQ II(1-17)) had no effect, suggesting that they do not mediate their reported analgesic effects via a G(i/o)-coupled receptor (i.e. opioid or ORL1). Unlike GENE, high concentrations of its C-terminal extension, OFQ II(1-28), stimulated CHEMICAL binding in a mu (mu) opioid receptor-like distribution and the effect was blocked by naloxone. To explore these observations, we evaluated the receptor binding profile of OFQ II(1-28) at the cloned ORL1 and mu opioid receptors. OFQ II(1-28) had no specific binding at either ORL1 or mu opioid receptors at concentrations up to 50 microM. This lack of affinity was not consistent with a mu-mediated effect, as suggested by preliminary observation using functional autoradiography in rat brain sections. Although behavioral studies suggest that OFQ II(1-28) possesses analgesic activity, this effect does not appear to be mediated via direct binding at the mu opioid receptor. Taken together, these findings support the view that (1) OFQ is the only ppOFQ peptide that binds to and activates the ORL1 receptor and (2) OFQ II(1-28) does not bind or stimulate CHEMICAL binding in cells expressing the mu opioid receptor. | DIRECT-REGULATOR |
| Binding and GTPgammaS autoradiographic analysis of preproorphanin precursor peptide products at the ORL1 and opioid receptors. Utilizing agonist-stimulated GTPgammaS autoradiography, we analyzed the ability of preproorphanin FQ (ppOFQ) peptides to stimulate CHEMICAL binding in adult rat brain. Orphanin FQ (OFQ) stimulated CHEMICAL binding in a pattern similar to that described for [125I]-OFQ at the endogenous opioid receptor-like (ORL1) receptor. The ppOFQ peptides nocistatin and orphanin FQ2 (OFQ II(1-17)) had no effect, suggesting that they do not mediate their reported analgesic effects via a G(i/o)-coupled receptor (i.e. opioid or ORL1). Unlike OFQ II(1-17), high concentrations of its C-terminal extension, OFQ II(1-28), stimulated CHEMICAL binding in a GENE-like distribution and the effect was blocked by naloxone. To explore these observations, we evaluated the receptor binding profile of OFQ II(1-28) at the cloned ORL1 and mu opioid receptors. OFQ II(1-28) had no specific binding at either ORL1 or mu opioid receptors at concentrations up to 50 microM. This lack of affinity was not consistent with a mu-mediated effect, as suggested by preliminary observation using functional autoradiography in rat brain sections. Although behavioral studies suggest that OFQ II(1-28) possesses analgesic activity, this effect does not appear to be mediated via direct binding at the mu opioid receptor. Taken together, these findings support the view that (1) OFQ is the only ppOFQ peptide that binds to and activates the ORL1 receptor and (2) OFQ II(1-28) does not bind or stimulate CHEMICAL binding in cells expressing the mu opioid receptor. | DIRECT-REGULATOR |
| Binding and GTPgammaS autoradiographic analysis of preproorphanin precursor peptide products at the ORL1 and opioid receptors. Utilizing agonist-stimulated GTPgammaS autoradiography, we analyzed the ability of preproorphanin FQ (ppOFQ) peptides to stimulate [35S]-GTPgammaS binding in adult rat brain. Orphanin FQ (OFQ) stimulated [35S]-GTPgammaS binding in a pattern similar to that described for [125I]-OFQ at the endogenous opioid receptor-like (ORL1) receptor. The ppOFQ peptides nocistatin and orphanin FQ2 (OFQ II(1-17)) had no effect, suggesting that they do not mediate their reported analgesic effects via a G(i/o)-coupled receptor (i.e. opioid or ORL1). Unlike OFQ II(1-17), high concentrations of its C-terminal extension, OFQ II(1-28), stimulated [35S]-GTPgammaS binding in a GENE-like distribution and the effect was blocked by CHEMICAL. To explore these observations, we evaluated the receptor binding profile of OFQ II(1-28) at the cloned ORL1 and mu opioid receptors. OFQ II(1-28) had no specific binding at either ORL1 or mu opioid receptors at concentrations up to 50 microM. This lack of affinity was not consistent with a mu-mediated effect, as suggested by preliminary observation using functional autoradiography in rat brain sections. Although behavioral studies suggest that OFQ II(1-28) possesses analgesic activity, this effect does not appear to be mediated via direct binding at the mu opioid receptor. Taken together, these findings support the view that (1) OFQ is the only ppOFQ peptide that binds to and activates the ORL1 receptor and (2) OFQ II(1-28) does not bind or stimulate [35S]-GTPgammaS binding in cells expressing the mu opioid receptor. | INHIBITOR |
| Binding and CHEMICAL autoradiographic analysis of preproorphanin precursor peptide products at the GENE and opioid receptors. Utilizing agonist-stimulated CHEMICAL autoradiography, we analyzed the ability of preproorphanin FQ (ppOFQ) peptides to stimulate [35S]-GTPgammaS binding in adult rat brain. Orphanin FQ (OFQ) stimulated [35S]-GTPgammaS binding in a pattern similar to that described for [125I]-OFQ at the endogenous opioid receptor-like (ORL1) receptor. The ppOFQ peptides nocistatin and orphanin FQ2 (OFQ II(1-17)) had no effect, suggesting that they do not mediate their reported analgesic effects via a G(i/o)-coupled receptor (i.e. opioid or ORL1). Unlike OFQ II(1-17), high concentrations of its C-terminal extension, OFQ II(1-28), stimulated [35S]-GTPgammaS binding in a mu (mu) opioid receptor-like distribution and the effect was blocked by naloxone. To explore these observations, we evaluated the receptor binding profile of OFQ II(1-28) at the cloned GENE and mu opioid receptors. OFQ II(1-28) had no specific binding at either GENE or mu opioid receptors at concentrations up to 50 microM. This lack of affinity was not consistent with a mu-mediated effect, as suggested by preliminary observation using functional autoradiography in rat brain sections. Although behavioral studies suggest that OFQ II(1-28) possesses analgesic activity, this effect does not appear to be mediated via direct binding at the mu opioid receptor. Taken together, these findings support the view that (1) OFQ is the only ppOFQ peptide that binds to and activates the GENE receptor and (2) OFQ II(1-28) does not bind or stimulate [35S]-GTPgammaS binding in cells expressing the mu opioid receptor. | DIRECT-REGULATOR |
| Binding and CHEMICAL autoradiographic analysis of preproorphanin precursor peptide products at the ORL1 and GENE. Utilizing agonist-stimulated CHEMICAL autoradiography, we analyzed the ability of preproorphanin FQ (ppOFQ) peptides to stimulate [35S]-GTPgammaS binding in adult rat brain. Orphanin FQ (OFQ) stimulated [35S]-GTPgammaS binding in a pattern similar to that described for [125I]-OFQ at the endogenous opioid receptor-like (ORL1) receptor. The ppOFQ peptides nocistatin and orphanin FQ2 (OFQ II(1-17)) had no effect, suggesting that they do not mediate their reported analgesic effects via a G(i/o)-coupled receptor (i.e. opioid or ORL1). Unlike OFQ II(1-17), high concentrations of its C-terminal extension, OFQ II(1-28), stimulated [35S]-GTPgammaS binding in a mu (mu) opioid receptor-like distribution and the effect was blocked by naloxone. To explore these observations, we evaluated the receptor binding profile of OFQ II(1-28) at the cloned ORL1 and mu GENE. OFQ II(1-28) had no specific binding at either ORL1 or mu GENE at concentrations up to 50 microM. This lack of affinity was not consistent with a mu-mediated effect, as suggested by preliminary observation using functional autoradiography in rat brain sections. Although behavioral studies suggest that OFQ II(1-28) possesses analgesic activity, this effect does not appear to be mediated via direct binding at the mu opioid receptor. Taken together, these findings support the view that (1) OFQ is the only ppOFQ peptide that binds to and activates the ORL1 receptor and (2) OFQ II(1-28) does not bind or stimulate [35S]-GTPgammaS binding in cells expressing the mu opioid receptor. | DIRECT-REGULATOR |
| Binding and CHEMICAL autoradiographic analysis of GENE products at the ORL1 and opioid receptors. Utilizing agonist-stimulated CHEMICAL autoradiography, we analyzed the ability of preproorphanin FQ (ppOFQ) peptides to stimulate [35S]-GTPgammaS binding in adult rat brain. Orphanin FQ (OFQ) stimulated [35S]-GTPgammaS binding in a pattern similar to that described for [125I]-OFQ at the endogenous opioid receptor-like (ORL1) receptor. The ppOFQ peptides nocistatin and orphanin FQ2 (OFQ II(1-17)) had no effect, suggesting that they do not mediate their reported analgesic effects via a G(i/o)-coupled receptor (i.e. opioid or ORL1). Unlike OFQ II(1-17), high concentrations of its C-terminal extension, OFQ II(1-28), stimulated [35S]-GTPgammaS binding in a mu (mu) opioid receptor-like distribution and the effect was blocked by naloxone. To explore these observations, we evaluated the receptor binding profile of OFQ II(1-28) at the cloned ORL1 and mu opioid receptors. OFQ II(1-28) had no specific binding at either ORL1 or mu opioid receptors at concentrations up to 50 microM. This lack of affinity was not consistent with a mu-mediated effect, as suggested by preliminary observation using functional autoradiography in rat brain sections. Although behavioral studies suggest that OFQ II(1-28) possesses analgesic activity, this effect does not appear to be mediated via direct binding at the mu opioid receptor. Taken together, these findings support the view that (1) OFQ is the only ppOFQ peptide that binds to and activates the ORL1 receptor and (2) OFQ II(1-28) does not bind or stimulate [35S]-GTPgammaS binding in cells expressing the mu opioid receptor. | PART-OF |
| Blockade of LTC4 synthesis caused by additive inhibition of gIV-PLA2 phosphorylation: Effect of salmeterol and PDE4 inhibition in human eosinophils. BACKGROUND: Prior investigations have demonstrated that GENE stimulation is ineffective in inhibiting synthesis of eicosanoids in human eosinophils. This effect has been postulated to relate to density or structural differences in the GENE or its coupled G-protein. However, recent reports indicate that cAMP-specific PDE4 activity in eosinophils is 10-fold that of other inflammatory cells. We postulated that selective blockade of PDE4 in eosinophils would unmask the inhibitory effect of GENE stimulation and that this inhibition would result from decreased phosphor-ylation of cytosolic group IV-PLA(2) (gIV-PLA(2)). OBJECTIVE: To determine (a) whether PDE4 inhibition alone with rolipram blocked secretions of arachidonic acid (AA) and leukotriene C(4) (LTC(4)) caused by activation of eosinophils with formyl-met-leu-phe plus cytochalasin B (FMLP/B), (b) to determine if PDE4 inhibition plus GENE agonist act additively to augment endogenous cAMP concentration, and (c) to determine the mechanism by which additive inhibition of AA and LTC(4) synthesis is regulated by cAMP. METHODS: Human eosinophils were pretreated with buffer, salmeterol or rolipram (singly or combination) before FMLP/B activation. Release of AA and LTC(4), intracellular cAMP concentration, and phosphorylation and activation of gIV-PLA(2) were determined. RESULTS: CHEMICAL unmasked the inhibitory effect of GENE stimulation with salmeterol and significantly attenuated the stimulated release of AA and subsequent LTC(4). Inhibition corresponded to increased cAMP production caused by rolipram alone or rolipram plus salmeterol and blocked proportionately the phosphorylation and activation of gIV-PLA(2) in FMLP/B-activated eosinophils. CONCLUSIONS: Inhibition of PDE4 by rolipram unmasks beta(2)-adrenergic blockade of LTC(4) synthesis caused by FMLP/B. | REGULATOR |
| Blockade of LTC4 synthesis caused by additive inhibition of gIV-PLA2 phosphorylation: Effect of salmeterol and PDE4 inhibition in human eosinophils. BACKGROUND: Prior investigations have demonstrated that beta(2)-adrenoceptor stimulation is ineffective in inhibiting synthesis of eicosanoids in human eosinophils. This effect has been postulated to relate to density or structural differences in the beta(2)-adrenoceptor or its coupled G-protein. However, recent reports indicate that cAMP-specific PDE4 activity in eosinophils is 10-fold that of other inflammatory cells. We postulated that selective blockade of PDE4 in eosinophils would unmask the inhibitory effect of beta(2)-adrenoceptor stimulation and that this inhibition would result from decreased phosphor-ylation of cytosolic group IV-PLA(2) (gIV-PLA(2)). OBJECTIVE: To determine (a) whether PDE4 inhibition alone with CHEMICAL blocked secretions of arachidonic acid (AA) and leukotriene C(4) (LTC(4)) caused by activation of eosinophils with formyl-met-leu-phe plus cytochalasin B (FMLP/B), (b) to determine if PDE4 inhibition plus beta(2)-adrenoceptor agonist act additively to augment endogenous cAMP concentration, and (c) to determine the mechanism by which additive inhibition of AA and LTC(4) synthesis is regulated by cAMP. METHODS: Human eosinophils were pretreated with buffer, salmeterol or CHEMICAL (singly or combination) before FMLP/B activation. Release of AA and LTC(4), intracellular cAMP concentration, and phosphorylation and activation of gIV-PLA(2) were determined. RESULTS: CHEMICAL unmasked the inhibitory effect of beta(2)-adrenoceptor stimulation with salmeterol and significantly attenuated the stimulated release of AA and subsequent LTC(4). Inhibition corresponded to increased cAMP production caused by CHEMICAL alone or CHEMICAL plus salmeterol and blocked proportionately the phosphorylation and activation of gIV-PLA(2) in FMLP/B-activated eosinophils. CONCLUSIONS: Inhibition of PDE4 by CHEMICAL unmasks GENE blockade of LTC(4) synthesis caused by FMLP/B. | REGULATOR |
| Blockade of LTC4 synthesis caused by additive inhibition of gIV-PLA2 phosphorylation: Effect of CHEMICAL and PDE4 inhibition in human eosinophils. BACKGROUND: Prior investigations have demonstrated that GENE stimulation is ineffective in inhibiting synthesis of eicosanoids in human eosinophils. This effect has been postulated to relate to density or structural differences in the GENE or its coupled G-protein. However, recent reports indicate that cAMP-specific PDE4 activity in eosinophils is 10-fold that of other inflammatory cells. We postulated that selective blockade of PDE4 in eosinophils would unmask the inhibitory effect of GENE stimulation and that this inhibition would result from decreased phosphor-ylation of cytosolic group IV-PLA(2) (gIV-PLA(2)). OBJECTIVE: To determine (a) whether PDE4 inhibition alone with rolipram blocked secretions of arachidonic acid (AA) and leukotriene C(4) (LTC(4)) caused by activation of eosinophils with formyl-met-leu-phe plus cytochalasin B (FMLP/B), (b) to determine if PDE4 inhibition plus GENE agonist act additively to augment endogenous cAMP concentration, and (c) to determine the mechanism by which additive inhibition of AA and LTC(4) synthesis is regulated by cAMP. METHODS: Human eosinophils were pretreated with buffer, CHEMICAL or rolipram (singly or combination) before FMLP/B activation. Release of AA and LTC(4), intracellular cAMP concentration, and phosphorylation and activation of gIV-PLA(2) were determined. RESULTS: Rolipram unmasked the inhibitory effect of GENE stimulation with CHEMICAL and significantly attenuated the stimulated release of AA and subsequent LTC(4). Inhibition corresponded to increased cAMP production caused by rolipram alone or rolipram plus CHEMICAL and blocked proportionately the phosphorylation and activation of gIV-PLA(2) in FMLP/B-activated eosinophils. CONCLUSIONS: Inhibition of PDE4 by rolipram unmasks beta(2)-adrenergic blockade of LTC(4) synthesis caused by FMLP/B. | REGULATOR |
| Blockade of LTC4 synthesis caused by additive inhibition of gIV-PLA2 phosphorylation: Effect of salmeterol and PDE4 inhibition in human eosinophils. BACKGROUND: Prior investigations have demonstrated that beta(2)-adrenoceptor stimulation is ineffective in inhibiting synthesis of eicosanoids in human eosinophils. This effect has been postulated to relate to density or structural differences in the beta(2)-adrenoceptor or its coupled G-protein. However, recent reports indicate that cAMP-specific PDE4 activity in eosinophils is 10-fold that of other inflammatory cells. We postulated that selective blockade of PDE4 in eosinophils would unmask the inhibitory effect of beta(2)-adrenoceptor stimulation and that this inhibition would result from decreased phosphor-ylation of cytosolic group IV-PLA(2) (gIV-PLA(2)). OBJECTIVE: To determine (a) whether PDE4 inhibition alone with CHEMICAL blocked secretions of arachidonic acid (AA) and leukotriene C(4) (LTC(4)) caused by activation of eosinophils with formyl-met-leu-phe plus cytochalasin B (FMLP/B), (b) to determine if PDE4 inhibition plus beta(2)-adrenoceptor agonist act additively to augment endogenous cAMP concentration, and (c) to determine the mechanism by which additive inhibition of AA and LTC(4) synthesis is regulated by cAMP. METHODS: Human eosinophils were pretreated with buffer, salmeterol or CHEMICAL (singly or combination) before FMLP/B activation. Release of AA and LTC(4), intracellular cAMP concentration, and phosphorylation and activation of GENE were determined. RESULTS: CHEMICAL unmasked the inhibitory effect of beta(2)-adrenoceptor stimulation with salmeterol and significantly attenuated the stimulated release of AA and subsequent LTC(4). Inhibition corresponded to increased cAMP production caused by CHEMICAL alone or CHEMICAL plus salmeterol and blocked proportionately the phosphorylation and activation of GENE in FMLP/B-activated eosinophils. CONCLUSIONS: Inhibition of PDE4 by CHEMICAL unmasks beta(2)-adrenergic blockade of LTC(4) synthesis caused by FMLP/B. | INHIBITOR |
| Blockade of LTC4 synthesis caused by additive inhibition of gIV-PLA2 phosphorylation: Effect of CHEMICAL and PDE4 inhibition in human eosinophils. BACKGROUND: Prior investigations have demonstrated that beta(2)-adrenoceptor stimulation is ineffective in inhibiting synthesis of eicosanoids in human eosinophils. This effect has been postulated to relate to density or structural differences in the beta(2)-adrenoceptor or its coupled G-protein. However, recent reports indicate that cAMP-specific PDE4 activity in eosinophils is 10-fold that of other inflammatory cells. We postulated that selective blockade of PDE4 in eosinophils would unmask the inhibitory effect of beta(2)-adrenoceptor stimulation and that this inhibition would result from decreased phosphor-ylation of cytosolic group IV-PLA(2) (gIV-PLA(2)). OBJECTIVE: To determine (a) whether PDE4 inhibition alone with rolipram blocked secretions of arachidonic acid (AA) and leukotriene C(4) (LTC(4)) caused by activation of eosinophils with formyl-met-leu-phe plus cytochalasin B (FMLP/B), (b) to determine if PDE4 inhibition plus beta(2)-adrenoceptor agonist act additively to augment endogenous cAMP concentration, and (c) to determine the mechanism by which additive inhibition of AA and LTC(4) synthesis is regulated by cAMP. METHODS: Human eosinophils were pretreated with buffer, CHEMICAL or rolipram (singly or combination) before FMLP/B activation. Release of AA and LTC(4), intracellular cAMP concentration, and phosphorylation and activation of GENE were determined. RESULTS: Rolipram unmasked the inhibitory effect of beta(2)-adrenoceptor stimulation with CHEMICAL and significantly attenuated the stimulated release of AA and subsequent LTC(4). Inhibition corresponded to increased cAMP production caused by rolipram alone or rolipram plus CHEMICAL and blocked proportionately the phosphorylation and activation of GENE in FMLP/B-activated eosinophils. CONCLUSIONS: Inhibition of PDE4 by rolipram unmasks beta(2)-adrenergic blockade of LTC(4) synthesis caused by FMLP/B. | INHIBITOR |
| Blockade of LTC4 synthesis caused by additive inhibition of gIV-PLA2 phosphorylation: Effect of salmeterol and GENE inhibition in human eosinophils. BACKGROUND: Prior investigations have demonstrated that beta(2)-adrenoceptor stimulation is ineffective in inhibiting synthesis of eicosanoids in human eosinophils. This effect has been postulated to relate to density or structural differences in the beta(2)-adrenoceptor or its coupled G-protein. However, recent reports indicate that cAMP-specific GENE activity in eosinophils is 10-fold that of other inflammatory cells. We postulated that selective blockade of GENE in eosinophils would unmask the inhibitory effect of beta(2)-adrenoceptor stimulation and that this inhibition would result from decreased phosphor-ylation of cytosolic group IV-PLA(2) (gIV-PLA(2)). OBJECTIVE: To determine (a) whether GENE inhibition alone with CHEMICAL blocked secretions of arachidonic acid (AA) and leukotriene C(4) (LTC(4)) caused by activation of eosinophils with formyl-met-leu-phe plus cytochalasin B (FMLP/B), (b) to determine if GENE inhibition plus beta(2)-adrenoceptor agonist act additively to augment endogenous cAMP concentration, and (c) to determine the mechanism by which additive inhibition of AA and LTC(4) synthesis is regulated by cAMP. METHODS: Human eosinophils were pretreated with buffer, salmeterol or CHEMICAL (singly or combination) before FMLP/B activation. Release of AA and LTC(4), intracellular cAMP concentration, and phosphorylation and activation of gIV-PLA(2) were determined. RESULTS: CHEMICAL unmasked the inhibitory effect of beta(2)-adrenoceptor stimulation with salmeterol and significantly attenuated the stimulated release of AA and subsequent LTC(4). Inhibition corresponded to increased cAMP production caused by CHEMICAL alone or CHEMICAL plus salmeterol and blocked proportionately the phosphorylation and activation of gIV-PLA(2) in FMLP/B-activated eosinophils. CONCLUSIONS: Inhibition of GENE by CHEMICAL unmasks beta(2)-adrenergic blockade of LTC(4) synthesis caused by FMLP/B. | INHIBITOR |
| Blockade of CHEMICAL synthesis caused by additive inhibition of GENE phosphorylation: Effect of salmeterol and PDE4 inhibition in human eosinophils. BACKGROUND: Prior investigations have demonstrated that beta(2)-adrenoceptor stimulation is ineffective in inhibiting synthesis of eicosanoids in human eosinophils. This effect has been postulated to relate to density or structural differences in the beta(2)-adrenoceptor or its coupled G-protein. However, recent reports indicate that cAMP-specific PDE4 activity in eosinophils is 10-fold that of other inflammatory cells. We postulated that selective blockade of PDE4 in eosinophils would unmask the inhibitory effect of beta(2)-adrenoceptor stimulation and that this inhibition would result from decreased phosphor-ylation of cytosolic group IV-PLA(2) (gIV-PLA(2)). OBJECTIVE: To determine (a) whether PDE4 inhibition alone with rolipram blocked secretions of arachidonic acid (AA) and leukotriene C(4) (LTC(4)) caused by activation of eosinophils with formyl-met-leu-phe plus cytochalasin B (FMLP/B), (b) to determine if PDE4 inhibition plus beta(2)-adrenoceptor agonist act additively to augment endogenous cAMP concentration, and (c) to determine the mechanism by which additive inhibition of AA and LTC(4) synthesis is regulated by cAMP. METHODS: Human eosinophils were pretreated with buffer, salmeterol or rolipram (singly or combination) before FMLP/B activation. Release of AA and LTC(4), intracellular cAMP concentration, and phosphorylation and activation of gIV-PLA(2) were determined. RESULTS: Rolipram unmasked the inhibitory effect of beta(2)-adrenoceptor stimulation with salmeterol and significantly attenuated the stimulated release of AA and subsequent LTC(4). Inhibition corresponded to increased cAMP production caused by rolipram alone or rolipram plus salmeterol and blocked proportionately the phosphorylation and activation of gIV-PLA(2) in FMLP/B-activated eosinophils. CONCLUSIONS: Inhibition of PDE4 by rolipram unmasks beta(2)-adrenergic blockade of LTC(4) synthesis caused by FMLP/B. | PRODUCT-OF |
| A phase 1 study of tazarotene in adults with advanced cancer. Tazarotene is an acetylenic retinoid which is metabolised to CHEMICAL and which binds selectively to the GENE RARbeta and RARgamma. The safety, toxicity and pharmacokinetics of oral tazarotene were determined over 12 weeks of treatment in 34 patients with advanced cancer. Commonly seen toxicities were mucocutaneous symptoms, musculoskeletal pain and headache. Dose-limiting toxicities were hypercalcaemia, hypertriglyceridaemia and musculoskeletal pain. The maximum tolerated dose of tazarotene in this schedule is 25.2 mg day(-1). Plasma concentrations of CHEMICAL were found to peak rapidly within 1-3 h of dosing and thereafter declined quickly. The C(max) and AUC values on day 0, and weeks 2 and 4 were similar indicating no drug accumulation. The dose-normalised C(max) and AUC values at different dose levels and different study days appeared to be similar indicating linear pharmacokinetics. No objective responses were seen, although stable disease was seen in six out of eight evaluable patients receiving the three highest dose levels of tazarotene (16.8, 25.2 or 33.4 mg day(-1)). We conclude that oral tazarotene is well tolerated when administered daily for 12 weeks, has a favourable toxicity profile compared with other retinoids and merits further investigation as an anticancer therapy. | DIRECT-REGULATOR |
| A phase 1 study of tazarotene in adults with advanced cancer. Tazarotene is an acetylenic retinoid which is metabolised to CHEMICAL and which binds selectively to the retinoid receptors GENE and RARgamma. The safety, toxicity and pharmacokinetics of oral tazarotene were determined over 12 weeks of treatment in 34 patients with advanced cancer. Commonly seen toxicities were mucocutaneous symptoms, musculoskeletal pain and headache. Dose-limiting toxicities were hypercalcaemia, hypertriglyceridaemia and musculoskeletal pain. The maximum tolerated dose of tazarotene in this schedule is 25.2 mg day(-1). Plasma concentrations of CHEMICAL were found to peak rapidly within 1-3 h of dosing and thereafter declined quickly. The C(max) and AUC values on day 0, and weeks 2 and 4 were similar indicating no drug accumulation. The dose-normalised C(max) and AUC values at different dose levels and different study days appeared to be similar indicating linear pharmacokinetics. No objective responses were seen, although stable disease was seen in six out of eight evaluable patients receiving the three highest dose levels of tazarotene (16.8, 25.2 or 33.4 mg day(-1)). We conclude that oral tazarotene is well tolerated when administered daily for 12 weeks, has a favourable toxicity profile compared with other retinoids and merits further investigation as an anticancer therapy. | DIRECT-REGULATOR |
| A phase 1 study of tazarotene in adults with advanced cancer. Tazarotene is an acetylenic retinoid which is metabolised to CHEMICAL and which binds selectively to the retinoid receptors RARbeta and GENE. The safety, toxicity and pharmacokinetics of oral tazarotene were determined over 12 weeks of treatment in 34 patients with advanced cancer. Commonly seen toxicities were mucocutaneous symptoms, musculoskeletal pain and headache. Dose-limiting toxicities were hypercalcaemia, hypertriglyceridaemia and musculoskeletal pain. The maximum tolerated dose of tazarotene in this schedule is 25.2 mg day(-1). Plasma concentrations of CHEMICAL were found to peak rapidly within 1-3 h of dosing and thereafter declined quickly. The C(max) and AUC values on day 0, and weeks 2 and 4 were similar indicating no drug accumulation. The dose-normalised C(max) and AUC values at different dose levels and different study days appeared to be similar indicating linear pharmacokinetics. No objective responses were seen, although stable disease was seen in six out of eight evaluable patients receiving the three highest dose levels of tazarotene (16.8, 25.2 or 33.4 mg day(-1)). We conclude that oral tazarotene is well tolerated when administered daily for 12 weeks, has a favourable toxicity profile compared with other retinoids and merits further investigation as an anticancer therapy. | DIRECT-REGULATOR |
| A phase 1 study of tazarotene in adults with advanced cancer. CHEMICAL is an acetylenic retinoid which is metabolised to tazarotenic acid and which binds selectively to the GENE RARbeta and RARgamma. The safety, toxicity and pharmacokinetics of oral tazarotene were determined over 12 weeks of treatment in 34 patients with advanced cancer. Commonly seen toxicities were mucocutaneous symptoms, musculoskeletal pain and headache. Dose-limiting toxicities were hypercalcaemia, hypertriglyceridaemia and musculoskeletal pain. The maximum tolerated dose of tazarotene in this schedule is 25.2 mg day(-1). Plasma concentrations of tazarotenic acid were found to peak rapidly within 1-3 h of dosing and thereafter declined quickly. The C(max) and AUC values on day 0, and weeks 2 and 4 were similar indicating no drug accumulation. The dose-normalised C(max) and AUC values at different dose levels and different study days appeared to be similar indicating linear pharmacokinetics. No objective responses were seen, although stable disease was seen in six out of eight evaluable patients receiving the three highest dose levels of tazarotene (16.8, 25.2 or 33.4 mg day(-1)). We conclude that oral tazarotene is well tolerated when administered daily for 12 weeks, has a favourable toxicity profile compared with other retinoids and merits further investigation as an anticancer therapy. | DIRECT-REGULATOR |
| A phase 1 study of tazarotene in adults with advanced cancer. CHEMICAL is an acetylenic retinoid which is metabolised to tazarotenic acid and which binds selectively to the retinoid receptors GENE and RARgamma. The safety, toxicity and pharmacokinetics of oral tazarotene were determined over 12 weeks of treatment in 34 patients with advanced cancer. Commonly seen toxicities were mucocutaneous symptoms, musculoskeletal pain and headache. Dose-limiting toxicities were hypercalcaemia, hypertriglyceridaemia and musculoskeletal pain. The maximum tolerated dose of tazarotene in this schedule is 25.2 mg day(-1). Plasma concentrations of tazarotenic acid were found to peak rapidly within 1-3 h of dosing and thereafter declined quickly. The C(max) and AUC values on day 0, and weeks 2 and 4 were similar indicating no drug accumulation. The dose-normalised C(max) and AUC values at different dose levels and different study days appeared to be similar indicating linear pharmacokinetics. No objective responses were seen, although stable disease was seen in six out of eight evaluable patients receiving the three highest dose levels of tazarotene (16.8, 25.2 or 33.4 mg day(-1)). We conclude that oral tazarotene is well tolerated when administered daily for 12 weeks, has a favourable toxicity profile compared with other retinoids and merits further investigation as an anticancer therapy. | DIRECT-REGULATOR |
| A phase 1 study of tazarotene in adults with advanced cancer. CHEMICAL is an acetylenic retinoid which is metabolised to tazarotenic acid and which binds selectively to the retinoid receptors RARbeta and GENE. The safety, toxicity and pharmacokinetics of oral tazarotene were determined over 12 weeks of treatment in 34 patients with advanced cancer. Commonly seen toxicities were mucocutaneous symptoms, musculoskeletal pain and headache. Dose-limiting toxicities were hypercalcaemia, hypertriglyceridaemia and musculoskeletal pain. The maximum tolerated dose of tazarotene in this schedule is 25.2 mg day(-1). Plasma concentrations of tazarotenic acid were found to peak rapidly within 1-3 h of dosing and thereafter declined quickly. The C(max) and AUC values on day 0, and weeks 2 and 4 were similar indicating no drug accumulation. The dose-normalised C(max) and AUC values at different dose levels and different study days appeared to be similar indicating linear pharmacokinetics. No objective responses were seen, although stable disease was seen in six out of eight evaluable patients receiving the three highest dose levels of tazarotene (16.8, 25.2 or 33.4 mg day(-1)). We conclude that oral tazarotene is well tolerated when administered daily for 12 weeks, has a favourable toxicity profile compared with other retinoids and merits further investigation as an anticancer therapy. | DIRECT-REGULATOR |
| A phase 1 study of tazarotene in adults with advanced cancer. Tazarotene is an CHEMICAL which is metabolised to tazarotenic acid and which binds selectively to the GENE RARbeta and RARgamma. The safety, toxicity and pharmacokinetics of oral tazarotene were determined over 12 weeks of treatment in 34 patients with advanced cancer. Commonly seen toxicities were mucocutaneous symptoms, musculoskeletal pain and headache. Dose-limiting toxicities were hypercalcaemia, hypertriglyceridaemia and musculoskeletal pain. The maximum tolerated dose of tazarotene in this schedule is 25.2 mg day(-1). Plasma concentrations of tazarotenic acid were found to peak rapidly within 1-3 h of dosing and thereafter declined quickly. The C(max) and AUC values on day 0, and weeks 2 and 4 were similar indicating no drug accumulation. The dose-normalised C(max) and AUC values at different dose levels and different study days appeared to be similar indicating linear pharmacokinetics. No objective responses were seen, although stable disease was seen in six out of eight evaluable patients receiving the three highest dose levels of tazarotene (16.8, 25.2 or 33.4 mg day(-1)). We conclude that oral tazarotene is well tolerated when administered daily for 12 weeks, has a favourable toxicity profile compared with other retinoids and merits further investigation as an anticancer therapy. | DIRECT-REGULATOR |
| A phase 1 study of tazarotene in adults with advanced cancer. Tazarotene is an CHEMICAL which is metabolised to tazarotenic acid and which binds selectively to the retinoid receptors GENE and RARgamma. The safety, toxicity and pharmacokinetics of oral tazarotene were determined over 12 weeks of treatment in 34 patients with advanced cancer. Commonly seen toxicities were mucocutaneous symptoms, musculoskeletal pain and headache. Dose-limiting toxicities were hypercalcaemia, hypertriglyceridaemia and musculoskeletal pain. The maximum tolerated dose of tazarotene in this schedule is 25.2 mg day(-1). Plasma concentrations of tazarotenic acid were found to peak rapidly within 1-3 h of dosing and thereafter declined quickly. The C(max) and AUC values on day 0, and weeks 2 and 4 were similar indicating no drug accumulation. The dose-normalised C(max) and AUC values at different dose levels and different study days appeared to be similar indicating linear pharmacokinetics. No objective responses were seen, although stable disease was seen in six out of eight evaluable patients receiving the three highest dose levels of tazarotene (16.8, 25.2 or 33.4 mg day(-1)). We conclude that oral tazarotene is well tolerated when administered daily for 12 weeks, has a favourable toxicity profile compared with other retinoids and merits further investigation as an anticancer therapy. | DIRECT-REGULATOR |
| A phase 1 study of tazarotene in adults with advanced cancer. Tazarotene is an CHEMICAL which is metabolised to tazarotenic acid and which binds selectively to the retinoid receptors RARbeta and GENE. The safety, toxicity and pharmacokinetics of oral tazarotene were determined over 12 weeks of treatment in 34 patients with advanced cancer. Commonly seen toxicities were mucocutaneous symptoms, musculoskeletal pain and headache. Dose-limiting toxicities were hypercalcaemia, hypertriglyceridaemia and musculoskeletal pain. The maximum tolerated dose of tazarotene in this schedule is 25.2 mg day(-1). Plasma concentrations of tazarotenic acid were found to peak rapidly within 1-3 h of dosing and thereafter declined quickly. The C(max) and AUC values on day 0, and weeks 2 and 4 were similar indicating no drug accumulation. The dose-normalised C(max) and AUC values at different dose levels and different study days appeared to be similar indicating linear pharmacokinetics. No objective responses were seen, although stable disease was seen in six out of eight evaluable patients receiving the three highest dose levels of tazarotene (16.8, 25.2 or 33.4 mg day(-1)). We conclude that oral tazarotene is well tolerated when administered daily for 12 weeks, has a favourable toxicity profile compared with other retinoids and merits further investigation as an anticancer therapy. | DIRECT-REGULATOR |
| Anabolic effects of clenbuterol on skeletal muscle are mediated by GENE activation. The potent anabolic effects of the GENE agonist clenbuterol on skeletal muscle have been reported to be independent of actions on beta-adrenoceptors. In the present study clenbuterol, presented to rats in the diet (4 mg/kg), caused significant increases in gastrocnemius muscle mass, protein, and RNA content and a decrease in epididymal fat pad mass. These effects were not mimicked by oral administration of the GENE agonist salbutamol even at high dose (52 mg/kg diet), and the effects of clenbuterol were not inhibited by addition of CHEMICAL (200 mg/kg diet). However, the selective beta 2-antagonist ICI-118,551 (200 mg/kg diet) reversed the anabolic effects of clenbuterol, and a high dose of CHEMICAL (1,000 mg/kg diet) also inhibited these actions of clenbuterol. Furthermore, continuous infusion of salbutamol (1.15 mg.kg body wt-1.day-1) via miniosmotic pumps did cause significant increases in muscle mass, protein, and RNA content. These results indicate that the anabolic effects of clenbuterol are dependent on interaction with the GENE. However, a long duration of action appears to be required to induce the anabolic effects of beta 2-agonists. | NO-RELATIONSHIP |
| Anabolic effects of CHEMICAL on skeletal muscle are mediated by beta 2-adrenoceptor activation. The potent anabolic effects of the beta 2-adrenoceptor agonist CHEMICAL on skeletal muscle have been reported to be independent of actions on GENE. In the present study CHEMICAL, presented to rats in the diet (4 mg/kg), caused significant increases in gastrocnemius muscle mass, protein, and RNA content and a decrease in epididymal fat pad mass. These effects were not mimicked by oral administration of the beta 2-adrenoceptor agonist salbutamol even at high dose (52 mg/kg diet), and the effects of CHEMICAL were not inhibited by addition of DL-propranolol (200 mg/kg diet). However, the selective beta 2-antagonist ICI-118,551 (200 mg/kg diet) reversed the anabolic effects of CHEMICAL, and a high dose of DL-propranolol (1,000 mg/kg diet) also inhibited these actions of CHEMICAL. Furthermore, continuous infusion of salbutamol (1.15 mg.kg body wt-1.day-1) via miniosmotic pumps did cause significant increases in muscle mass, protein, and RNA content. These results indicate that the anabolic effects of CHEMICAL are dependent on interaction with the beta 2-adrenoceptor. However, a long duration of action appears to be required to induce the anabolic effects of beta 2-agonists. | NO-RELATIONSHIP |
| Anabolic effects of CHEMICAL on skeletal muscle are mediated by GENE activation. The potent anabolic effects of the GENE agonist CHEMICAL on skeletal muscle have been reported to be independent of actions on beta-adrenoceptors. In the present study CHEMICAL, presented to rats in the diet (4 mg/kg), caused significant increases in gastrocnemius muscle mass, protein, and RNA content and a decrease in epididymal fat pad mass. These effects were not mimicked by oral administration of the GENE agonist salbutamol even at high dose (52 mg/kg diet), and the effects of CHEMICAL were not inhibited by addition of DL-propranolol (200 mg/kg diet). However, the selective beta 2-antagonist ICI-118,551 (200 mg/kg diet) reversed the anabolic effects of CHEMICAL, and a high dose of DL-propranolol (1,000 mg/kg diet) also inhibited these actions of CHEMICAL. Furthermore, continuous infusion of salbutamol (1.15 mg.kg body wt-1.day-1) via miniosmotic pumps did cause significant increases in muscle mass, protein, and RNA content. These results indicate that the anabolic effects of CHEMICAL are dependent on interaction with the GENE. However, a long duration of action appears to be required to induce the anabolic effects of beta 2-agonists. | ACTIVATOR |
| Anabolic effects of clenbuterol on skeletal muscle are mediated by GENE activation. The potent anabolic effects of the GENE agonist clenbuterol on skeletal muscle have been reported to be independent of actions on beta-adrenoceptors. In the present study clenbuterol, presented to rats in the diet (4 mg/kg), caused significant increases in gastrocnemius muscle mass, protein, and RNA content and a decrease in epididymal fat pad mass. These effects were not mimicked by oral administration of the GENE agonist CHEMICAL even at high dose (52 mg/kg diet), and the effects of clenbuterol were not inhibited by addition of DL-propranolol (200 mg/kg diet). However, the selective beta 2-antagonist ICI-118,551 (200 mg/kg diet) reversed the anabolic effects of clenbuterol, and a high dose of DL-propranolol (1,000 mg/kg diet) also inhibited these actions of clenbuterol. Furthermore, continuous infusion of CHEMICAL (1.15 mg.kg body wt-1.day-1) via miniosmotic pumps did cause significant increases in muscle mass, protein, and RNA content. These results indicate that the anabolic effects of clenbuterol are dependent on interaction with the GENE. However, a long duration of action appears to be required to induce the anabolic effects of beta 2-agonists. | ACTIVATOR |
| Evidence that an alpha 2A-adrenoceptor subtype mediates antinociception in mice. In the hot-plate test in mice, the antinociceptive action of the GENE agonist, CHEMICAL, was abolished by the GENE antagonist, idazoxan, the potent alpha 2A-adrenoceptor antagonist, RX 821002 and the preferential alpha 2A-adrenoceptor antagonist, BRL 44408. In contrast, the preferential alpha 2B- (and alpha 2C)-adrenoceptor ligands ('antagonists'), ARC-239, BRL 41992 and prazosin were inactive. The preferential alpha 2A-adrenoceptor partial agonist, guanfacine, partially inhibited UK 14,304-induced antinociception. Further, guanfacine BRL 44408 reversibly elicited submaximal antinociception. It is concluded that alpha 2A-adrenoceptors mediate antinociception in mice. | ACTIVATOR |
| Evidence that an GENE subtype mediates antinociception in mice. In the hot-plate test in mice, the antinociceptive action of the alpha 2-adrenoceptor agonist, UK 14,304, was abolished by the alpha 2-adrenoceptor antagonist, idazoxan, the potent GENE antagonist, RX 821002 and the preferential GENE antagonist, BRL 44408. In contrast, the preferential alpha 2B- (and alpha 2C)-adrenoceptor ligands ('antagonists'), ARC-239, BRL 41992 and prazosin were inactive. The preferential GENE partial agonist, CHEMICAL, partially inhibited UK 14,304-induced antinociception. Further, CHEMICAL BRL 44408 reversibly elicited submaximal antinociception. It is concluded that alpha 2A-adrenoceptors mediate antinociception in mice. | ACTIVATOR |
| Evidence that an GENE subtype mediates antinociception in mice. In the hot-plate test in mice, the antinociceptive action of the alpha 2-adrenoceptor agonist, CHEMICAL, was abolished by the alpha 2-adrenoceptor antagonist, idazoxan, the potent GENE antagonist, RX 821002 and the preferential GENE antagonist, BRL 44408. In contrast, the preferential alpha 2B- (and alpha 2C)-adrenoceptor ligands ('antagonists'), ARC-239, BRL 41992 and prazosin were inactive. The preferential GENE partial agonist, guanfacine, partially inhibited CHEMICAL-induced antinociception. Further, guanfacine BRL 44408 reversibly elicited submaximal antinociception. It is concluded that alpha 2A-adrenoceptors mediate antinociception in mice. | ACTIVATOR |
| Evidence that an alpha 2A-adrenoceptor subtype mediates antinociception in mice. In the hot-plate test in mice, the antinociceptive action of the GENE agonist, UK 14,304, was abolished by the GENE antagonist, CHEMICAL, the potent alpha 2A-adrenoceptor antagonist, RX 821002 and the preferential alpha 2A-adrenoceptor antagonist, BRL 44408. In contrast, the preferential alpha 2B- (and alpha 2C)-adrenoceptor ligands ('antagonists'), ARC-239, BRL 41992 and prazosin were inactive. The preferential alpha 2A-adrenoceptor partial agonist, guanfacine, partially inhibited UK 14,304-induced antinociception. Further, guanfacine BRL 44408 reversibly elicited submaximal antinociception. It is concluded that alpha 2A-adrenoceptors mediate antinociception in mice. | INHIBITOR |
| Evidence that an GENE subtype mediates antinociception in mice. In the hot-plate test in mice, the antinociceptive action of the alpha 2-adrenoceptor agonist, UK 14,304, was abolished by the alpha 2-adrenoceptor antagonist, idazoxan, the potent GENE antagonist, CHEMICAL and the preferential GENE antagonist, BRL 44408. In contrast, the preferential alpha 2B- (and alpha 2C)-adrenoceptor ligands ('antagonists'), ARC-239, BRL 41992 and prazosin were inactive. The preferential GENE partial agonist, guanfacine, partially inhibited UK 14,304-induced antinociception. Further, guanfacine BRL 44408 reversibly elicited submaximal antinociception. It is concluded that alpha 2A-adrenoceptors mediate antinociception in mice. | INHIBITOR |
| Evidence that an GENE subtype mediates antinociception in mice. In the hot-plate test in mice, the antinociceptive action of the alpha 2-adrenoceptor agonist, UK 14,304, was abolished by the alpha 2-adrenoceptor antagonist, idazoxan, the potent GENE antagonist, RX 821002 and the preferential GENE antagonist, CHEMICAL. In contrast, the preferential alpha 2B- (and alpha 2C)-adrenoceptor ligands ('antagonists'), ARC-239, BRL 41992 and prazosin were inactive. The preferential GENE partial agonist, guanfacine, partially inhibited UK 14,304-induced antinociception. Further, guanfacine CHEMICAL reversibly elicited submaximal antinociception. It is concluded that alpha 2A-adrenoceptors mediate antinociception in mice. | INHIBITOR |
| Crystal structure of serine dehydratase from rat liver. GENE (L-serine dehydratase, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver GENE plays an important role in gluconeogenesis. Formation of pyruvate by GENE is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. GENE is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that GENE catalysis is not facilitated by forming the resonance-stabilized structure of the CHEMICAL as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | NO-RELATIONSHIP |
| Crystal structure of serine dehydratase from rat liver. GENE (L-serine dehydratase, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver GENE plays an important role in gluconeogenesis. Formation of pyruvate by GENE is a two-step reaction in which the CHEMICAL group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. GENE is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that GENE catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving CHEMICAL group of serine. | SUBSTRATE |
| Crystal structure of CHEMICAL dehydratase from rat liver. GENE (L-serine dehydratase, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver GENE plays an important role in gluconeogenesis. Formation of pyruvate by GENE is a two-step reaction in which the hydroxyl group of CHEMICAL is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. GENE is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that GENE catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of CHEMICAL. | SUBSTRATE |
| Crystal structure of serine dehydratase from rat liver. SDH (L-serine dehydratase, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver SDH plays an important role in gluconeogenesis. Formation of pyruvate by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with CHEMICAL, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of CHEMICAL is surrounded by a characteristic GENE ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of CHEMICAL participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound CHEMICAL suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | PART-OF |
| Crystal structure of serine dehydratase from rat liver. SDH (L-serine dehydratase, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver SDH plays an important role in gluconeogenesis. Formation of pyruvate by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic GENE ((168)CHEMICAL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | PART-OF |
| Crystal structure of serine dehydratase from rat liver. GENE (L-serine dehydratase, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver GENE plays an important role in gluconeogenesis. Formation of pyruvate by GENE is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. GENE is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with CHEMICAL, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of CHEMICAL is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of CHEMICAL participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound CHEMICAL suggest that GENE catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | NO-RELATIONSHIP |
| Crystal structure of serine dehydratase from rat liver. SDH (L-serine dehydratase, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver SDH plays an important role in gluconeogenesis. Formation of pyruvate by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The GENE crystallized with CHEMICAL (OMS) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The GENE contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | PART-OF |
| Crystal structure of serine dehydratase from rat liver. SDH (L-serine dehydratase, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver SDH plays an important role in gluconeogenesis. Formation of pyruvate by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The GENE crystallized with O-methylserine (CHEMICAL) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The GENE contained PLP-OMS aldimine in the active site, indicating that CHEMICAL can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | DIRECT-REGULATOR |
| Crystal structure of serine dehydratase from rat liver. SDH (L-serine dehydratase, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver SDH plays an important role in gluconeogenesis. Formation of pyruvate by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The GENE crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The GENE contained PLP-OMS CHEMICAL in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser CHEMICAL as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | PART-OF |
| Crystal structure of serine dehydratase from rat liver. SDH (L-serine dehydratase, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver SDH plays an important role in gluconeogenesis. Formation of pyruvate by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the CHEMICAL as seen in GENE. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | DIRECT-REGULATOR |
| Crystal structure of serine dehydratase from rat liver. GENE (L-serine dehydratase, EC 4.3.1.17) catalyzes the CHEMICAL (PLP)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver GENE plays an important role in gluconeogenesis. Formation of pyruvate by GENE is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. GENE is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that GENE catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | GENE-CHEMICAL |
| Crystal structure of serine dehydratase from rat liver. SDH (L-serine dehydratase, GENE) catalyzes the CHEMICAL (PLP)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver SDH plays an important role in gluconeogenesis. Formation of pyruvate by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | GENE-CHEMICAL |
| Crystal structure of serine dehydratase from rat liver. SDH GENE, EC 4.3.1.17) catalyzes the CHEMICAL (PLP)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver SDH plays an important role in gluconeogenesis. Formation of pyruvate by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | GENE-CHEMICAL |
| Crystal structure of serine dehydratase from rat liver. SDH (L-serine dehydratase, GENE) catalyzes the pyridoxal 5'-phosphate (CHEMICAL)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver SDH plays an important role in gluconeogenesis. Formation of pyruvate by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with CHEMICAL, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of CHEMICAL is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of CHEMICAL participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound CHEMICAL suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | SUBSTRATE |
| Crystal structure of serine dehydratase from rat liver. SDH GENE, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (CHEMICAL)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver SDH plays an important role in gluconeogenesis. Formation of pyruvate by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with CHEMICAL, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of CHEMICAL is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of CHEMICAL participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound CHEMICAL suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | SUBSTRATE |
| Crystal structure of serine dehydratase from rat liver. SDH (L-serine dehydratase, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver SDH plays an important role in gluconeogenesis. Formation of pyruvate by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The GENE crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The GENE contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with CHEMICAL, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of CHEMICAL is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of CHEMICAL participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound CHEMICAL suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | DIRECT-REGULATOR |
| Crystal structure of serine dehydratase from rat liver. GENE (L-serine dehydratase, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield CHEMICAL and ammonia. Liver GENE plays an important role in gluconeogenesis. Formation of CHEMICAL by GENE is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce CHEMICAL. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. GENE is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that GENE catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | PRODUCT-OF |
| Crystal structure of serine dehydratase from rat liver. SDH (L-serine dehydratase, GENE) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield CHEMICAL and ammonia. Liver SDH plays an important role in gluconeogenesis. Formation of CHEMICAL by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce CHEMICAL. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | PRODUCT-OF |
| Crystal structure of serine dehydratase from rat liver. SDH GENE, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield CHEMICAL and ammonia. Liver SDH plays an important role in gluconeogenesis. Formation of CHEMICAL by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce CHEMICAL. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | PRODUCT-OF |
| Crystal structure of serine dehydratase from rat liver. GENE (L-serine dehydratase, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield pyruvate and CHEMICAL. Liver GENE plays an important role in gluconeogenesis. Formation of pyruvate by GENE is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. GENE is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that GENE catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | PRODUCT-OF |
| Crystal structure of serine dehydratase from rat liver. SDH (L-serine dehydratase, GENE) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield pyruvate and CHEMICAL. Liver SDH plays an important role in gluconeogenesis. Formation of pyruvate by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | PRODUCT-OF |
| Crystal structure of serine dehydratase from rat liver. SDH GENE, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield pyruvate and CHEMICAL. Liver SDH plays an important role in gluconeogenesis. Formation of pyruvate by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | PRODUCT-OF |
| Crystal structure of serine dehydratase from rat liver. GENE (L-serine dehydratase, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of CHEMICAL to yield pyruvate and ammonia. Liver GENE plays an important role in gluconeogenesis. Formation of pyruvate by GENE is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. GENE is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that GENE catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | SUBSTRATE |
| Crystal structure of serine dehydratase from rat liver. SDH (L-serine dehydratase, GENE) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of CHEMICAL to yield pyruvate and ammonia. Liver SDH plays an important role in gluconeogenesis. Formation of pyruvate by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | SUBSTRATE |
| Crystal structure of serine dehydratase from rat liver. SDH GENE, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of CHEMICAL to yield pyruvate and ammonia. Liver SDH plays an important role in gluconeogenesis. Formation of pyruvate by SDH is a two-step reaction in which the hydroxyl group of serine is cleaved to produce aminoacrylate, and then the aminoacrylate is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. SDH is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that SDH catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | SUBSTRATE |
| Crystal structure of serine dehydratase from rat liver. GENE (L-serine dehydratase, EC 4.3.1.17) catalyzes the pyridoxal 5'-phosphate (PLP)-dependent dehydration of L-serine to yield pyruvate and ammonia. Liver GENE plays an important role in gluconeogenesis. Formation of pyruvate by GENE is a two-step reaction in which the hydroxyl group of serine is cleaved to produce CHEMICAL, and then the CHEMICAL is deaminated by nonenzymatic hydrolysis to produce pyruvate. The crystal structure of rat liver apo-SDH was determined by single isomorphous replacement at 2.8 A resolution. The holo-SDH crystallized with O-methylserine (OMS) was also determined at 2.6 A resolution by molecular replacement. GENE is composed of two domains, and each domain has a typical alphabeta-open structure. The active site is located in the cleft between the two domains. The holo-SDH contained PLP-OMS aldimine in the active site, indicating that OMS can form the Schiff base linkage with PLP, but the subsequent dehydration did not occur. Apo-SDH forms a dimer by inserting the small domain into the catalytic cleft of the partner subunit so that the active site is closed. Holo-SDH also forms a dimer by making contacts at the back of the clefts so that the dimerization does not close the catalytic cleft. The phosphate group of PLP is surrounded by a characteristic G-rich sequence ((168)GGGGL(172)) and forms hydrogen bonds with the amide groups of those amino acid residues, suggesting that the phosphate group can be protonated. N(1) of PLP participates in a hydrogen bond with Cys303, and similar hydrogen bonds with N(1) participating are seen in other beta-elimination enzymes. These hydrogen bonding schemes indicate that N(1) is not protonated, and thus, the pyridine ring cannot take a quinone-like structure. These characteristics of the bound PLP suggest that GENE catalysis is not facilitated by forming the resonance-stabilized structure of the PLP-Ser aldimine as seen in aminotransferases. A possible catalytic mechanism involves the phosphate group, surrounded by the characteristic sequence, acting as a general acid to donate a proton to the leaving hydroxyl group of serine. | PRODUCT-OF |
| Epidermal growth factor receptor autocrine signaling in RIE-1 cells transformed by the GENE oncogene enhances radiation resistance. Oncogenic forms of the small GTPase GENE increase the resistance of cells to killing by ionizing radiation (IR). Although not all of the signaling pathways for radioresistance are well defined, it is now clear that Ras-dependent signaling pathways involved in radioresistance include those mediated by phosphatidylinositol 3'-kinase (PI3-K) and Raf. Nevertheless, PI3-K and Raf together are not sufficient to reconstitute all of the resistance conferred by GENE, indicating that other effectors must also contribute. We show here that Ras-driven autocrine signaling through the epidermal growth factor receptor (EGFR) also contributes to radioresistance in Ras-transformed cells. Conditioned media (CM) collected from RIE-1 rat intestinal epithelial cells expressing oncogenic GENE increased the survival of irradiated cells. Ras-CM contains elevated levels of the EGFR ligand transforming growth factor alpha (TGF-alpha). Both Ras-CM and TGF-alpha stimulated EGFR phosphorylation, and exogenous TGF-alpha mimicked the effects of Ras-CM to increase radioresistance. Blocking EGFR signaling with the EGFR/HER-2 kinase inhibitor (KI) CHEMICAL decreased the postradiation survival of irradiated GENE-transformed cells and normal cells but had no effect on the survival of unirradiated cells. Ras-CM and TGF-alpha also increase PI3-K activity downstream of the EGFR and increase postradiation survival, both of which are abrogated by CHEMICAL. Thus, GENE utilizes autocrine signaling through EGFR to increase radioresistance, and the EGFR KI CHEMICAL acts as a radiosensitizer. The observation that Ras-transformed cells can be sensitized to killing by ionizing radiation with CHEMICAL demonstrates that EGFR KIs could potentially be used to radiosensitize tumors in which radioresistance is dependent on Ras-driven autocrine signaling through EGFR. | REGULATOR |
| Epidermal growth factor receptor autocrine signaling in RIE-1 cells transformed by the Ras oncogene enhances radiation resistance. Oncogenic forms of the small GTPase Ras increase the resistance of cells to killing by ionizing radiation (IR). Although not all of the signaling pathways for radioresistance are well defined, it is now clear that Ras-dependent signaling pathways involved in radioresistance include those mediated by phosphatidylinositol 3'-kinase (PI3-K) and Raf. Nevertheless, PI3-K and Raf together are not sufficient to reconstitute all of the resistance conferred by Ras, indicating that other effectors must also contribute. We show here that Ras-driven autocrine signaling through the epidermal growth factor receptor (EGFR) also contributes to radioresistance in Ras-transformed cells. Conditioned media (CM) collected from RIE-1 rat intestinal epithelial cells expressing oncogenic Ras increased the survival of irradiated cells. Ras-CM contains elevated levels of the GENE ligand transforming growth factor alpha (TGF-alpha). Both Ras-CM and TGF-alpha stimulated GENE phosphorylation, and exogenous TGF-alpha mimicked the effects of Ras-CM to increase radioresistance. Blocking GENE signaling with the EGFR/HER-2 kinase inhibitor (KI) CHEMICAL decreased the postradiation survival of irradiated Ras-transformed cells and normal cells but had no effect on the survival of unirradiated cells. Ras-CM and TGF-alpha also increase PI3-K activity downstream of the GENE and increase postradiation survival, both of which are abrogated by CHEMICAL. Thus, Ras utilizes autocrine signaling through GENE to increase radioresistance, and the GENE KI CHEMICAL acts as a radiosensitizer. The observation that Ras-transformed cells can be sensitized to killing by ionizing radiation with CHEMICAL demonstrates that GENE KIs could potentially be used to radiosensitize tumors in which radioresistance is dependent on Ras-driven autocrine signaling through GENE. | REGULATOR |
| Epidermal growth factor receptor autocrine signaling in RIE-1 cells transformed by the Ras oncogene enhances radiation resistance. Oncogenic forms of the small GTPase Ras increase the resistance of cells to killing by ionizing radiation (IR). Although not all of the signaling pathways for radioresistance are well defined, it is now clear that Ras-dependent signaling pathways involved in radioresistance include those mediated by phosphatidylinositol 3'-kinase (PI3-K) and Raf. Nevertheless, PI3-K and Raf together are not sufficient to reconstitute all of the resistance conferred by Ras, indicating that other effectors must also contribute. We show here that Ras-driven autocrine signaling through the epidermal growth factor receptor (EGFR) also contributes to radioresistance in Ras-transformed cells. Conditioned media (CM) collected from RIE-1 rat intestinal epithelial cells expressing oncogenic Ras increased the survival of irradiated cells. Ras-CM contains elevated levels of the EGFR ligand transforming growth factor alpha (TGF-alpha). Both Ras-CM and TGF-alpha stimulated EGFR phosphorylation, and exogenous TGF-alpha mimicked the effects of Ras-CM to increase radioresistance. Blocking EGFR signaling with the EGFR/GENE kinase inhibitor (KI) CHEMICAL decreased the postradiation survival of irradiated Ras-transformed cells and normal cells but had no effect on the survival of unirradiated cells. Ras-CM and TGF-alpha also increase PI3-K activity downstream of the EGFR and increase postradiation survival, both of which are abrogated by CHEMICAL. Thus, Ras utilizes autocrine signaling through EGFR to increase radioresistance, and the EGFR KI CHEMICAL acts as a radiosensitizer. The observation that Ras-transformed cells can be sensitized to killing by ionizing radiation with CHEMICAL demonstrates that EGFR KIs could potentially be used to radiosensitize tumors in which radioresistance is dependent on Ras-driven autocrine signaling through EGFR. | INHIBITOR |
| Epidermal growth factor receptor autocrine signaling in RIE-1 cells transformed by the Ras oncogene enhances radiation resistance. Oncogenic forms of the small GTPase Ras increase the resistance of cells to killing by ionizing radiation (IR). Although not all of the signaling pathways for radioresistance are well defined, it is now clear that Ras-dependent signaling pathways involved in radioresistance include those mediated by phosphatidylinositol 3'-kinase (PI3-K) and Raf. Nevertheless, GENE and Raf together are not sufficient to reconstitute all of the resistance conferred by Ras, indicating that other effectors must also contribute. We show here that Ras-driven autocrine signaling through the epidermal growth factor receptor (EGFR) also contributes to radioresistance in Ras-transformed cells. Conditioned media (CM) collected from RIE-1 rat intestinal epithelial cells expressing oncogenic Ras increased the survival of irradiated cells. Ras-CM contains elevated levels of the EGFR ligand transforming growth factor alpha (TGF-alpha). Both Ras-CM and TGF-alpha stimulated EGFR phosphorylation, and exogenous TGF-alpha mimicked the effects of Ras-CM to increase radioresistance. Blocking EGFR signaling with the EGFR/HER-2 kinase inhibitor (KI) CHEMICAL decreased the postradiation survival of irradiated Ras-transformed cells and normal cells but had no effect on the survival of unirradiated cells. Ras-CM and TGF-alpha also increase GENE activity downstream of the EGFR and increase postradiation survival, both of which are abrogated by CHEMICAL. Thus, Ras utilizes autocrine signaling through EGFR to increase radioresistance, and the EGFR KI CHEMICAL acts as a radiosensitizer. The observation that Ras-transformed cells can be sensitized to killing by ionizing radiation with CHEMICAL demonstrates that EGFR KIs could potentially be used to radiosensitize tumors in which radioresistance is dependent on Ras-driven autocrine signaling through EGFR. | INHIBITOR |
| Characterization of beta 3-adrenoceptor-mediated relaxation in rat abdominal aorta smooth muscle. The present study was carried out to characterize beta-adrenoceptor subtypes mediating relaxation of rat abdominal aorta smooth muscle. (-)-Isoprenaline and a nonconventional GENE agonist, CHEMICAL ((+/-)-CGP12177A), induced concentration-dependent relaxation of (-)-phenylephrine (0.3 microM) preconstricted spiral preparations. Pretreatment with a combination of (+/-)-2-hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2 -yl]phenoxy]propyl]amino]ethoxy]-benzamide methanesulfonate (CGP20712A, a selective beta(1)-adrenoceptor antagonist) and (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-buta nol hydrochloride (ICI-118,5511, a selective beta(2)-adrenoceptor antagonist) (0.1 microM for each) produced a 14-fold rightward shift of the concentration-response curve for (-)-isoprenaline; however, the relaxation in response to (+/-)-CGP12177A was unaffected by the blockade of beta(1)- and beta(2)-adrenoceptors. In the presence of CGP20712A and ICI-118,551 (0.1 microM for each), the concentration-response curves for (-)-isoprenaline and (+/-)-CGP12177A were shifted to the right by a nonselective beta(1)-, beta(2)- and GENE antagonist, (+/-)-bupranolol (3 and 10 microM). These results clearly suggest that beta(3)-adrenoceptors are involved in beta-adrenoceptor-mediated relaxation of rat abdominal aorta smooth muscle. | ACTIVATOR |
| Characterization of beta 3-adrenoceptor-mediated relaxation in rat abdominal aorta smooth muscle. The present study was carried out to characterize beta-adrenoceptor subtypes mediating relaxation of rat abdominal aorta smooth muscle. (-)-Isoprenaline and a nonconventional GENE agonist, (+/-)-[4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimida zol-2-one] hydrochloride (CHEMICAL), induced concentration-dependent relaxation of (-)-phenylephrine (0.3 microM) preconstricted spiral preparations. Pretreatment with a combination of (+/-)-2-hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2 -yl]phenoxy]propyl]amino]ethoxy]-benzamide methanesulfonate (CGP20712A, a selective beta(1)-adrenoceptor antagonist) and (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-buta nol hydrochloride (ICI-118,5511, a selective beta(2)-adrenoceptor antagonist) (0.1 microM for each) produced a 14-fold rightward shift of the concentration-response curve for (-)-isoprenaline; however, the relaxation in response to CHEMICAL was unaffected by the blockade of beta(1)- and beta(2)-adrenoceptors. In the presence of CGP20712A and ICI-118,551 (0.1 microM for each), the concentration-response curves for (-)-isoprenaline and CHEMICAL were shifted to the right by a nonselective beta(1)-, beta(2)- and GENE antagonist, (+/-)-bupranolol (3 and 10 microM). These results clearly suggest that beta(3)-adrenoceptors are involved in beta-adrenoceptor-mediated relaxation of rat abdominal aorta smooth muscle. | ACTIVATOR |
| Characterization of beta 3-adrenoceptor-mediated relaxation in rat abdominal aorta smooth muscle. The present study was carried out to characterize beta-adrenoceptor subtypes mediating relaxation of rat abdominal aorta smooth muscle. (-)-Isoprenaline and a nonconventional beta(3)-adrenoceptor agonist, (+/-)-[4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimida zol-2-one] hydrochloride ((+/-)-CGP12177A), induced concentration-dependent relaxation of (-)-phenylephrine (0.3 microM) preconstricted spiral preparations. Pretreatment with a combination of CHEMICAL (CGP20712A, a selective GENE antagonist) and (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-buta nol hydrochloride (ICI-118,5511, a selective beta(2)-adrenoceptor antagonist) (0.1 microM for each) produced a 14-fold rightward shift of the concentration-response curve for (-)-isoprenaline; however, the relaxation in response to (+/-)-CGP12177A was unaffected by the blockade of beta(1)- and beta(2)-adrenoceptors. In the presence of CGP20712A and ICI-118,551 (0.1 microM for each), the concentration-response curves for (-)-isoprenaline and (+/-)-CGP12177A were shifted to the right by a nonselective beta(1)-, beta(2)- and beta(3)-adrenoceptor antagonist, (+/-)-bupranolol (3 and 10 microM). These results clearly suggest that beta(3)-adrenoceptors are involved in beta-adrenoceptor-mediated relaxation of rat abdominal aorta smooth muscle. | INHIBITOR |
| Characterization of beta 3-adrenoceptor-mediated relaxation in rat abdominal aorta smooth muscle. The present study was carried out to characterize beta-adrenoceptor subtypes mediating relaxation of rat abdominal aorta smooth muscle. (-)-Isoprenaline and a nonconventional beta(3)-adrenoceptor agonist, (+/-)-[4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimida zol-2-one] hydrochloride ((+/-)-CGP12177A), induced concentration-dependent relaxation of (-)-phenylephrine (0.3 microM) preconstricted spiral preparations. Pretreatment with a combination of (+/-)-2-hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2 -yl]phenoxy]propyl]amino]ethoxy]-benzamide methanesulfonate (CHEMICAL, a selective GENE antagonist) and (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-buta nol hydrochloride (ICI-118,5511, a selective beta(2)-adrenoceptor antagonist) (0.1 microM for each) produced a 14-fold rightward shift of the concentration-response curve for (-)-isoprenaline; however, the relaxation in response to (+/-)-CGP12177A was unaffected by the blockade of beta(1)- and beta(2)-adrenoceptors. In the presence of CHEMICAL and ICI-118,551 (0.1 microM for each), the concentration-response curves for (-)-isoprenaline and (+/-)-CGP12177A were shifted to the right by a nonselective beta(1)-, beta(2)- and beta(3)-adrenoceptor antagonist, (+/-)-bupranolol (3 and 10 microM). These results clearly suggest that beta(3)-adrenoceptors are involved in beta-adrenoceptor-mediated relaxation of rat abdominal aorta smooth muscle. | INHIBITOR |
| Characterization of beta 3-adrenoceptor-mediated relaxation in rat abdominal aorta smooth muscle. The present study was carried out to characterize beta-adrenoceptor subtypes mediating relaxation of rat abdominal aorta smooth muscle. (-)-Isoprenaline and a nonconventional beta(3)-adrenoceptor agonist, (+/-)-[4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimida zol-2-one] hydrochloride ((+/-)-CGP12177A), induced concentration-dependent relaxation of (-)-phenylephrine (0.3 microM) preconstricted spiral preparations. Pretreatment with a combination of (+/-)-2-hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2 -yl]phenoxy]propyl]amino]ethoxy]-benzamide methanesulfonate (CGP20712A, a selective beta(1)-adrenoceptor antagonist) and CHEMICAL (ICI-118,5511, a selective GENE antagonist) (0.1 microM for each) produced a 14-fold rightward shift of the concentration-response curve for (-)-isoprenaline; however, the relaxation in response to (+/-)-CGP12177A was unaffected by the blockade of beta(1)- and beta(2)-adrenoceptors. In the presence of CGP20712A and ICI-118,551 (0.1 microM for each), the concentration-response curves for (-)-isoprenaline and (+/-)-CGP12177A were shifted to the right by a nonselective beta(1)-, beta(2)- and beta(3)-adrenoceptor antagonist, (+/-)-bupranolol (3 and 10 microM). These results clearly suggest that beta(3)-adrenoceptors are involved in beta-adrenoceptor-mediated relaxation of rat abdominal aorta smooth muscle. | INHIBITOR |
| Characterization of beta 3-adrenoceptor-mediated relaxation in rat abdominal aorta smooth muscle. The present study was carried out to characterize beta-adrenoceptor subtypes mediating relaxation of rat abdominal aorta smooth muscle. (-)-Isoprenaline and a nonconventional beta(3)-adrenoceptor agonist, (+/-)-[4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimida zol-2-one] hydrochloride ((+/-)-CGP12177A), induced concentration-dependent relaxation of (-)-phenylephrine (0.3 microM) preconstricted spiral preparations. Pretreatment with a combination of (+/-)-2-hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2 -yl]phenoxy]propyl]amino]ethoxy]-benzamide methanesulfonate (CGP20712A, a selective beta(1)-adrenoceptor antagonist) and (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-buta nol hydrochloride (CHEMICAL, a selective GENE antagonist) (0.1 microM for each) produced a 14-fold rightward shift of the concentration-response curve for (-)-isoprenaline; however, the relaxation in response to (+/-)-CGP12177A was unaffected by the blockade of beta(1)- and beta(2)-adrenoceptors. In the presence of CGP20712A and ICI-118,551 (0.1 microM for each), the concentration-response curves for (-)-isoprenaline and (+/-)-CGP12177A were shifted to the right by a nonselective beta(1)-, beta(2)- and beta(3)-adrenoceptor antagonist, (+/-)-bupranolol (3 and 10 microM). These results clearly suggest that beta(3)-adrenoceptors are involved in beta-adrenoceptor-mediated relaxation of rat abdominal aorta smooth muscle. | INHIBITOR |
| Use of the GENE as a reporter gene for non-invasive imaging of genetically modified cells. BACKGROUND: The GENE (NET) is a high-affinity transporter for CHEMICAL. Its expression is almost exclusively restricted to the sympathetic nervous system. In this study we evaluated whether the NET can be used as a reporter gene for non-invasive imaging of genetically modified cells with radiolabeled probes. METHODS: Human A431, HT1080 and murine CMS-5 cells were retrovirally transduced with bovine NET cDNA. Transduced and parental cells were incubated in vitro with [(131)I]meta-iodobenzylguanidine ([(131)I]MIBG). The specificity of tracer uptake was determined by adding the NET inhibitor imipramine. Rat PC12 cells served as positive controls. Parental and A431NET cells were xenotransplanted into nude mice and tumor uptake of [(123)I]MIBG in vivo was determined after tracer administration. RESULTS: In vitro stably transduced cells showed a 66- to 120-fold higher [(131)I]MIBG uptake than parental cells. Incubation with imipramine reduced [(131)I]MIBG uptake of transduced cells to the level found in parental cells. More than 70% of the initial radioactivity was retained in all transduced cell lines after 2 h incubation with tracer-free medium. [(131)I]MIBG uptake in PC12 cells, which express the NET endogenously, was 20- to 28-fold lower than in transduced cells. In vivo, A431NET tumors demonstrated a 33-fold higher [(123)I]MIBG uptake than parental tumors. Gamma camera images 24 h after tracer injection showed no tracer uptake in parental A431 tumors, but clear images of A431NET tumors. CONCLUSIONS: Transduction of tumor cells with NET cDNA causes highly specific uptake and significant retention of catecholamine analogs in vitro and in vivo. These characteristics make the NET suitable as a reporter gene for non-invasive monitoring of gene transfer. | SUBSTRATE |
| Use of the norepinephrine transporter as a reporter gene for non-invasive imaging of genetically modified cells. BACKGROUND: The norepinephrine transporter (GENE) is a high-affinity transporter for CHEMICAL. Its expression is almost exclusively restricted to the sympathetic nervous system. In this study we evaluated whether the GENE can be used as a reporter gene for non-invasive imaging of genetically modified cells with radiolabeled probes. METHODS: Human A431, HT1080 and murine CMS-5 cells were retrovirally transduced with bovine GENE cDNA. Transduced and parental cells were incubated in vitro with [(131)I]meta-iodobenzylguanidine ([(131)I]MIBG). The specificity of tracer uptake was determined by adding the GENE inhibitor imipramine. Rat PC12 cells served as positive controls. Parental and A431NET cells were xenotransplanted into nude mice and tumor uptake of [(123)I]MIBG in vivo was determined after tracer administration. RESULTS: In vitro stably transduced cells showed a 66- to 120-fold higher [(131)I]MIBG uptake than parental cells. Incubation with imipramine reduced [(131)I]MIBG uptake of transduced cells to the level found in parental cells. More than 70% of the initial radioactivity was retained in all transduced cell lines after 2 h incubation with tracer-free medium. [(131)I]MIBG uptake in PC12 cells, which express the GENE endogenously, was 20- to 28-fold lower than in transduced cells. In vivo, A431NET tumors demonstrated a 33-fold higher [(123)I]MIBG uptake than parental tumors. Gamma camera images 24 h after tracer injection showed no tracer uptake in parental A431 tumors, but clear images of A431NET tumors. CONCLUSIONS: Transduction of tumor cells with GENE cDNA causes highly specific uptake and significant retention of catecholamine analogs in vitro and in vivo. These characteristics make the GENE suitable as a reporter gene for non-invasive monitoring of gene transfer. | SUBSTRATE |
| Use of the norepinephrine transporter as a reporter gene for non-invasive imaging of genetically modified cells. BACKGROUND: The norepinephrine transporter (NET) is a high-affinity transporter for catecholamines. Its expression is almost exclusively restricted to the sympathetic nervous system. In this study we evaluated whether the GENE can be used as a reporter gene for non-invasive imaging of genetically modified cells with radiolabeled probes. METHODS: Human A431, HT1080 and murine CMS-5 cells were retrovirally transduced with bovine GENE cDNA. Transduced and parental cells were incubated in vitro with [(131)I]meta-iodobenzylguanidine ([(131)I]MIBG). The specificity of tracer uptake was determined by adding the GENE inhibitor CHEMICAL. Rat PC12 cells served as positive controls. Parental and A431NET cells were xenotransplanted into nude mice and tumor uptake of [(123)I]MIBG in vivo was determined after tracer administration. RESULTS: In vitro stably transduced cells showed a 66- to 120-fold higher [(131)I]MIBG uptake than parental cells. Incubation with CHEMICAL reduced [(131)I]MIBG uptake of transduced cells to the level found in parental cells. More than 70% of the initial radioactivity was retained in all transduced cell lines after 2 h incubation with tracer-free medium. [(131)I]MIBG uptake in PC12 cells, which express the GENE endogenously, was 20- to 28-fold lower than in transduced cells. In vivo, A431NET tumors demonstrated a 33-fold higher [(123)I]MIBG uptake than parental tumors. Gamma camera images 24 h after tracer injection showed no tracer uptake in parental A431 tumors, but clear images of A431NET tumors. CONCLUSIONS: Transduction of tumor cells with GENE cDNA causes highly specific uptake and significant retention of catecholamine analogs in vitro and in vivo. These characteristics make the GENE suitable as a reporter gene for non-invasive monitoring of gene transfer. | INHIBITOR |
| Use of the norepinephrine transporter as a reporter gene for non-invasive imaging of genetically modified cells. BACKGROUND: The norepinephrine transporter (NET) is a high-affinity transporter for catecholamines. Its expression is almost exclusively restricted to the sympathetic nervous system. In this study we evaluated whether the GENE can be used as a reporter gene for non-invasive imaging of genetically modified cells with radiolabeled probes. METHODS: Human A431, HT1080 and murine CMS-5 cells were retrovirally transduced with bovine GENE cDNA. Transduced and parental cells were incubated in vitro with [(131)I]meta-iodobenzylguanidine ([(131)I]MIBG). The specificity of tracer uptake was determined by adding the GENE inhibitor imipramine. Rat PC12 cells served as positive controls. Parental and A431NET cells were xenotransplanted into nude mice and tumor uptake of [(123)I]MIBG in vivo was determined after tracer administration. RESULTS: In vitro stably transduced cells showed a 66- to 120-fold higher CHEMICAL uptake than parental cells. Incubation with imipramine reduced CHEMICAL uptake of transduced cells to the level found in parental cells. More than 70% of the initial radioactivity was retained in all transduced cell lines after 2 h incubation with tracer-free medium. CHEMICAL uptake in PC12 cells, which express the GENE endogenously, was 20- to 28-fold lower than in transduced cells. In vivo, A431NET tumors demonstrated a 33-fold higher [(123)I]MIBG uptake than parental tumors. Gamma camera images 24 h after tracer injection showed no tracer uptake in parental A431 tumors, but clear images of A431NET tumors. CONCLUSIONS: Transduction of tumor cells with GENE cDNA causes highly specific uptake and significant retention of catecholamine analogs in vitro and in vivo. These characteristics make the GENE suitable as a reporter gene for non-invasive monitoring of gene transfer. | SUBSTRATE |
| Use of the norepinephrine transporter as a reporter gene for non-invasive imaging of genetically modified cells. BACKGROUND: The norepinephrine transporter (NET) is a high-affinity transporter for catecholamines. Its expression is almost exclusively restricted to the sympathetic nervous system. In this study we evaluated whether the GENE can be used as a reporter gene for non-invasive imaging of genetically modified cells with radiolabeled probes. METHODS: Human A431, HT1080 and murine CMS-5 cells were retrovirally transduced with bovine GENE cDNA. Transduced and parental cells were incubated in vitro with [(131)I]meta-iodobenzylguanidine ([(131)I]MIBG). The specificity of tracer uptake was determined by adding the GENE inhibitor imipramine. Rat PC12 cells served as positive controls. Parental and A431NET cells were xenotransplanted into nude mice and tumor uptake of CHEMICAL in vivo was determined after tracer administration. RESULTS: In vitro stably transduced cells showed a 66- to 120-fold higher [(131)I]MIBG uptake than parental cells. Incubation with imipramine reduced [(131)I]MIBG uptake of transduced cells to the level found in parental cells. More than 70% of the initial radioactivity was retained in all transduced cell lines after 2 h incubation with tracer-free medium. [(131)I]MIBG uptake in PC12 cells, which express the GENE endogenously, was 20- to 28-fold lower than in transduced cells. In vivo, A431GENE tumors demonstrated a 33-fold higher CHEMICAL uptake than parental tumors. Gamma camera images 24 h after tracer injection showed no tracer uptake in parental A431 tumors, but clear images of A431NET tumors. CONCLUSIONS: Transduction of tumor cells with GENE cDNA causes highly specific uptake and significant retention of catecholamine analogs in vitro and in vivo. These characteristics make the GENE suitable as a reporter gene for non-invasive monitoring of gene transfer. | SUBSTRATE |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, CHEMICAL, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, CHEMICAL) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (CHEMICAL, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, CHEMICAL, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, CHEMICAL, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | ACTIVATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, CHEMICAL, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | ACTIVATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, CHEMICAL, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | ACTIVATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, CHEMICAL, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, CHEMICAL, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (CHEMICAL, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, CHEMICAL, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, CHEMICAL, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, CHEMICAL, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, CHEMICAL, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, CHEMICAL, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, CHEMICAL, BRL 37344, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, CHEMICAL, CGP 20712, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CHEMICAL, SR 59230A, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, CHEMICAL, CGP 12177, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CHEMICAL, ICI 118551) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Comparative pharmacology of human beta-adrenergic receptor subtypes--characterization of stably transfected receptors in CHO cells. Although many beta1-receptor antagonists and beta2-receptor agonists have been used in pharmacotherapy for many years their pharmacological properties at all three known subtypes of beta-adrenergic receptors are not always well characterized. The aim of this study was, therefore, to provide comparative binding characteristics of agonists (epinephrine, norepinephrine, isoproterenol, fenoterol, salbutamol, salmeterol, terbutalin, formoterol, broxaterol) and antagonists (propranolol, alprenolol, atenolol, metoprolol, bisoprolol, carvedilol, pindolol, BRL 37344, CGP 20712, SR 59230A, CGP 12177, CHEMICAL) at all three subtypes of GENE in an identical cellular background. We generated Chinese hamster ovary (CHO) cells stably expressing the three beta-adrenergic receptor subtypes at comparable levels. We characterized these receptor subtypes and analyzed the affinity of routinely used drugs as well as experimental compounds in competition binding studies, using the non-selective antagonist 125I-cyanopindolol as a radioligand. Furthermore, we analyzed the beta-receptor-mediated adenylyl cyclase activity in isolated membranes from these cell lines. The results from our experiments show that all compounds exhibit distinct patterns of selectivity and activity at the three beta-receptor subtypes. In particular, a number of beta2- or beta3-receptor agonists that are inverse agonists at the other subtypes were identified. In addition, beta1-receptor antagonists with agonistic activity at beta2- and beta3-receptors were found. These specific mixtures of agonism, antagonism, and inverse agonism at different subtypes may have important implications for the therapeutic use of the respective compounds. | DIRECT-REGULATOR |
| Loss of beta-adrenoceptor response in myocytes overexpressing the Na+/Ca(2+)-exchanger. Increased Na+/Ca(2+)-exchanger (NCX) and altered beta-adrenoceptor (betaAR) responses are observed in failing human heart. To determine the possible interaction between these changes, we investigated the effect of NCX overexpression on responses to CHEMICAL in adult rat ventricular myocytes. Responses to CHEMICAL were largely mediated through the GENE in control myocytes. Adenovirally-mediated overexpression of NCX, at levels, which did not alter basal contraction of myocytes, markedly depressed the CHEMICAL concentration-response curve. Responses to CHEMICAL could be restored to normal by beta2AR blockade, suggesting a beta2AR-mediated inhibition of GENE signalling. Pertussis toxin normalised CHEMICAL responses in NCX cells, indicating that beta2AR effects were mediated by Gi. Negative-inotropic effects of high concentrations of ICI 118,551, previously shown to be due to beta2AR-Gi coupling, were increased in NCX cells. We conclude that NCX upregulation can markedly alter the consequences of betaAR stimulation and that this may contribute to the alterations in betaAR response seen in failing human heart. | REGULATOR |
| Loss of beta-adrenoceptor response in myocytes overexpressing the Na+/Ca(2+)-exchanger. Increased Na+/Ca(2+)-exchanger (NCX) and altered beta-adrenoceptor (betaAR) responses are observed in failing human heart. To determine the possible interaction between these changes, we investigated the effect of GENE overexpression on responses to CHEMICAL in adult rat ventricular myocytes. Responses to CHEMICAL were largely mediated through the beta1AR in control myocytes. Adenovirally-mediated overexpression of GENE, at levels, which did not alter basal contraction of myocytes, markedly depressed the CHEMICAL concentration-response curve. Responses to CHEMICAL could be restored to normal by beta2AR blockade, suggesting a beta2AR-mediated inhibition of beta1AR signalling. Pertussis toxin normalised CHEMICAL responses in GENE cells, indicating that beta2AR effects were mediated by Gi. Negative-inotropic effects of high concentrations of ICI 118,551, previously shown to be due to beta2AR-Gi coupling, were increased in GENE cells. We conclude that GENE upregulation can markedly alter the consequences of betaAR stimulation and that this may contribute to the alterations in betaAR response seen in failing human heart. | ACTIVATOR |
| Loss of beta-adrenoceptor response in myocytes overexpressing the Na+/Ca(2+)-exchanger. Increased Na+/Ca(2+)-exchanger (NCX) and altered beta-adrenoceptor (betaAR) responses are observed in failing human heart. To determine the possible interaction between these changes, we investigated the effect of NCX overexpression on responses to CHEMICAL in adult rat ventricular myocytes. Responses to CHEMICAL were largely mediated through the beta1AR in control myocytes. Adenovirally-mediated overexpression of NCX, at levels, which did not alter basal contraction of myocytes, markedly depressed the CHEMICAL concentration-response curve. Responses to CHEMICAL could be restored to normal by GENE blockade, suggesting a beta2AR-mediated inhibition of beta1AR signalling. Pertussis toxin normalised CHEMICAL responses in NCX cells, indicating that GENE effects were mediated by Gi. Negative-inotropic effects of high concentrations of ICI 118,551, previously shown to be due to beta2AR-Gi coupling, were increased in NCX cells. We conclude that NCX upregulation can markedly alter the consequences of betaAR stimulation and that this may contribute to the alterations in betaAR response seen in failing human heart. | ACTIVATOR |
| Manipulation of kinetic profiles in 2-aryl propionic acid cyclooxygenase inhibitors. The nonsteroidal anti-inflammatory drugs CHEMICAL and ibuprofen were modified in an attempt to alter the kinetics of inhibitor binding by GENE. Contrary to prior predictions, a halogen substituent is not sufficient to confer slow tight-binding behavior. Conversion of the carboxylate moiety of CHEMICAL to an ester or amide abolishes slow tight-binding behavior, regardless of halogenation state. | REGULATOR |
| Manipulation of kinetic profiles in 2-aryl propionic acid cyclooxygenase inhibitors. The nonsteroidal anti-inflammatory drugs flurbiprofen and CHEMICAL were modified in an attempt to alter the kinetics of inhibitor binding by GENE. Contrary to prior predictions, a halogen substituent is not sufficient to confer slow tight-binding behavior. Conversion of the carboxylate moiety of flurbiprofen to an ester or amide abolishes slow tight-binding behavior, regardless of halogenation state. | REGULATOR |
| Manipulation of kinetic profiles in CHEMICAL GENE inhibitors. The nonsteroidal anti-inflammatory drugs flurbiprofen and ibuprofen were modified in an attempt to alter the kinetics of inhibitor binding by COX-1. Contrary to prior predictions, a halogen substituent is not sufficient to confer slow tight-binding behavior. Conversion of the carboxylate moiety of flurbiprofen to an ester or amide abolishes slow tight-binding behavior, regardless of halogenation state. | INHIBITOR |
| Effects of the EGFR/HER2 kinase inhibitor CHEMICAL on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance. PURPOSE: Two members of the epidermal growth factor receptor family, EGFR and HER2, have been implicated in radioresistance in breast cancer and other malignancies. To gauge the potential clinical utility of targeting both EGFR and HER2 to control growth and radiosensitize human breast cancers, we examined the effect of a dual EGFR/HER2 inhibitor, CHEMICAL, on the proliferation and radiation response of either EGFR- or HER2-overexpressing human breast cancer cell lines. METHODS AND MATERIALS: Primary human breast cancer cell lines that endogenously overexpress EGFR or HER2 and luminal mammary epithelial H16N2 cells stably transfected with HER2 were evaluated for the effect of CHEMICAL on inhibition of ligand-induced or constitutive receptor phosphorylation, proliferation, radiosensitization, and inhibition of downstream signaling. RESULTS: CHEMICAL inhibited constitutive and/or ligand-induced EGFR or HER2 tyrosine phosphorylation of all five cell lines, which correlated with the antiproliferative response in all but one cell line. CHEMICAL radiosensitized EGFR-overexpressing cell lines, but HER2-overexpressing cells were unable to form colonies after brief exposure to CHEMICAL even in the absence of radiation, and thus could not be evaluated for radiosensitization. One cell line was resistant to the antiproliferative and radiosensitizing effects of CHEMICAL, despite receptor inhibition. Exploration of potential mechanisms of resistance in SUM185 cells revealed failure of CHEMICAL to inhibit downstream GENE and Akt activation, despite inhibition of HER2 phosphorylation. In contrast, sensitive HER2-overexpressing cell lines demonstrated inhibition of both GENE and Akt phosphorylation. CONCLUSION: CHEMICAL potently inhibits receptor phosphorylation in either EGFR- or HER2-overexpressing cell lines and has both antiproliferative and radiosensitizing effects. Resistance to CHEMICAL was not due to a lack of receptor inhibition, but rather with a lack of inhibition of GENE and Akt, suggesting that measurement of inhibition of crucial signaling pathways may better predict response than inhibition of receptor phosphorylation. The SUM185 cell line provides a valuable model for studying mechanisms of resistance of EGFR/HER2 inhibitor therapy. | NO-RELATIONSHIP |
| Effects of the EGFR/HER2 kinase inhibitor CHEMICAL on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance. PURPOSE: Two members of the epidermal growth factor receptor family, EGFR and HER2, have been implicated in radioresistance in breast cancer and other malignancies. To gauge the potential clinical utility of targeting both EGFR and HER2 to control growth and radiosensitize human breast cancers, we examined the effect of a dual EGFR/HER2 inhibitor, CHEMICAL, on the proliferation and radiation response of either EGFR- or HER2-overexpressing human breast cancer cell lines. METHODS AND MATERIALS: Primary human breast cancer cell lines that endogenously overexpress EGFR or HER2 and luminal mammary epithelial H16N2 cells stably transfected with HER2 were evaluated for the effect of CHEMICAL on inhibition of ligand-induced or constitutive receptor phosphorylation, proliferation, radiosensitization, and inhibition of downstream signaling. RESULTS: CHEMICAL inhibited constitutive and/or ligand-induced EGFR or HER2 tyrosine phosphorylation of all five cell lines, which correlated with the antiproliferative response in all but one cell line. CHEMICAL radiosensitized EGFR-overexpressing cell lines, but HER2-overexpressing cells were unable to form colonies after brief exposure to CHEMICAL even in the absence of radiation, and thus could not be evaluated for radiosensitization. One cell line was resistant to the antiproliferative and radiosensitizing effects of CHEMICAL, despite receptor inhibition. Exploration of potential mechanisms of resistance in SUM185 cells revealed failure of CHEMICAL to inhibit downstream ERK and GENE activation, despite inhibition of HER2 phosphorylation. In contrast, sensitive HER2-overexpressing cell lines demonstrated inhibition of both ERK and GENE phosphorylation. CONCLUSION: CHEMICAL potently inhibits receptor phosphorylation in either EGFR- or HER2-overexpressing cell lines and has both antiproliferative and radiosensitizing effects. Resistance to CHEMICAL was not due to a lack of receptor inhibition, but rather with a lack of inhibition of ERK and GENE, suggesting that measurement of inhibition of crucial signaling pathways may better predict response than inhibition of receptor phosphorylation. The SUM185 cell line provides a valuable model for studying mechanisms of resistance of EGFR/HER2 inhibitor therapy. | NO-RELATIONSHIP |
| Effects of the EGFR/HER2 kinase inhibitor GW572016 on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance. PURPOSE: Two members of the epidermal growth factor receptor family, GENE and HER2, have been implicated in radioresistance in breast cancer and other malignancies. To gauge the potential clinical utility of targeting both GENE and HER2 to control growth and radiosensitize human breast cancers, we examined the effect of a dual EGFR/HER2 inhibitor, GW572016, on the proliferation and radiation response of either EGFR- or HER2-overexpressing human breast cancer cell lines. METHODS AND MATERIALS: Primary human breast cancer cell lines that endogenously overexpress GENE or HER2 and luminal mammary epithelial H16N2 cells stably transfected with HER2 were evaluated for the effect of GW572016 on inhibition of ligand-induced or constitutive receptor phosphorylation, proliferation, radiosensitization, and inhibition of downstream signaling. RESULTS: GW572016 inhibited constitutive and/or ligand-induced GENE or HER2 CHEMICAL phosphorylation of all five cell lines, which correlated with the antiproliferative response in all but one cell line. GW572016 radiosensitized EGFR-overexpressing cell lines, but HER2-overexpressing cells were unable to form colonies after brief exposure to GW572016 even in the absence of radiation, and thus could not be evaluated for radiosensitization. One cell line was resistant to the antiproliferative and radiosensitizing effects of GW572016, despite receptor inhibition. Exploration of potential mechanisms of resistance in SUM185 cells revealed failure of GW572016 to inhibit downstream ERK and Akt activation, despite inhibition of HER2 phosphorylation. In contrast, sensitive HER2-overexpressing cell lines demonstrated inhibition of both ERK and Akt phosphorylation. CONCLUSION: GW572016 potently inhibits receptor phosphorylation in either EGFR- or HER2-overexpressing cell lines and has both antiproliferative and radiosensitizing effects. Resistance to GW572016 was not due to a lack of receptor inhibition, but rather with a lack of inhibition of ERK and Akt, suggesting that measurement of inhibition of crucial signaling pathways may better predict response than inhibition of receptor phosphorylation. The SUM185 cell line provides a valuable model for studying mechanisms of resistance of EGFR/HER2 inhibitor therapy. | PART-OF |
| Effects of the EGFR/HER2 kinase inhibitor GW572016 on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance. PURPOSE: Two members of the epidermal growth factor receptor family, EGFR and GENE, have been implicated in radioresistance in breast cancer and other malignancies. To gauge the potential clinical utility of targeting both EGFR and GENE to control growth and radiosensitize human breast cancers, we examined the effect of a dual EGFR/HER2 inhibitor, GW572016, on the proliferation and radiation response of either EGFR- or HER2-overexpressing human breast cancer cell lines. METHODS AND MATERIALS: Primary human breast cancer cell lines that endogenously overexpress EGFR or GENE and luminal mammary epithelial H16N2 cells stably transfected with GENE were evaluated for the effect of GW572016 on inhibition of ligand-induced or constitutive receptor phosphorylation, proliferation, radiosensitization, and inhibition of downstream signaling. RESULTS: GW572016 inhibited constitutive and/or ligand-induced EGFR or GENE CHEMICAL phosphorylation of all five cell lines, which correlated with the antiproliferative response in all but one cell line. GW572016 radiosensitized EGFR-overexpressing cell lines, but HER2-overexpressing cells were unable to form colonies after brief exposure to GW572016 even in the absence of radiation, and thus could not be evaluated for radiosensitization. One cell line was resistant to the antiproliferative and radiosensitizing effects of GW572016, despite receptor inhibition. Exploration of potential mechanisms of resistance in SUM185 cells revealed failure of GW572016 to inhibit downstream ERK and Akt activation, despite inhibition of GENE phosphorylation. In contrast, sensitive HER2-overexpressing cell lines demonstrated inhibition of both ERK and Akt phosphorylation. CONCLUSION: GW572016 potently inhibits receptor phosphorylation in either EGFR- or HER2-overexpressing cell lines and has both antiproliferative and radiosensitizing effects. Resistance to GW572016 was not due to a lack of receptor inhibition, but rather with a lack of inhibition of ERK and Akt, suggesting that measurement of inhibition of crucial signaling pathways may better predict response than inhibition of receptor phosphorylation. The SUM185 cell line provides a valuable model for studying mechanisms of resistance of EGFR/HER2 inhibitor therapy. | PART-OF |
| Effects of the EGFR/HER2 kinase inhibitor CHEMICAL on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance. PURPOSE: Two members of the epidermal growth factor receptor family, GENE and HER2, have been implicated in radioresistance in breast cancer and other malignancies. To gauge the potential clinical utility of targeting both GENE and HER2 to control growth and radiosensitize human breast cancers, we examined the effect of a dual EGFR/HER2 inhibitor, CHEMICAL, on the proliferation and radiation response of either EGFR- or HER2-overexpressing human breast cancer cell lines. METHODS AND MATERIALS: Primary human breast cancer cell lines that endogenously overexpress GENE or HER2 and luminal mammary epithelial H16N2 cells stably transfected with HER2 were evaluated for the effect of CHEMICAL on inhibition of ligand-induced or constitutive receptor phosphorylation, proliferation, radiosensitization, and inhibition of downstream signaling. RESULTS: CHEMICAL inhibited constitutive and/or ligand-induced GENE or HER2 tyrosine phosphorylation of all five cell lines, which correlated with the antiproliferative response in all but one cell line. CHEMICAL radiosensitized GENE-overexpressing cell lines, but HER2-overexpressing cells were unable to form colonies after brief exposure to CHEMICAL even in the absence of radiation, and thus could not be evaluated for radiosensitization. One cell line was resistant to the antiproliferative and radiosensitizing effects of CHEMICAL, despite receptor inhibition. Exploration of potential mechanisms of resistance in SUM185 cells revealed failure of CHEMICAL to inhibit downstream ERK and Akt activation, despite inhibition of HER2 phosphorylation. In contrast, sensitive HER2-overexpressing cell lines demonstrated inhibition of both ERK and Akt phosphorylation. CONCLUSION: CHEMICAL potently inhibits receptor phosphorylation in either EGFR- or HER2-overexpressing cell lines and has both antiproliferative and radiosensitizing effects. Resistance to CHEMICAL was not due to a lack of receptor inhibition, but rather with a lack of inhibition of ERK and Akt, suggesting that measurement of inhibition of crucial signaling pathways may better predict response than inhibition of receptor phosphorylation. The SUM185 cell line provides a valuable model for studying mechanisms of resistance of EGFR/HER2 inhibitor therapy. | INHIBITOR |
| Effects of the EGFR/HER2 kinase inhibitor CHEMICAL on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance. PURPOSE: Two members of the epidermal growth factor receptor family, EGFR and GENE, have been implicated in radioresistance in breast cancer and other malignancies. To gauge the potential clinical utility of targeting both EGFR and GENE to control growth and radiosensitize human breast cancers, we examined the effect of a dual EGFR/HER2 inhibitor, CHEMICAL, on the proliferation and radiation response of either EGFR- or HER2-overexpressing human breast cancer cell lines. METHODS AND MATERIALS: Primary human breast cancer cell lines that endogenously overexpress EGFR or GENE and luminal mammary epithelial H16N2 cells stably transfected with GENE were evaluated for the effect of CHEMICAL on inhibition of ligand-induced or constitutive receptor phosphorylation, proliferation, radiosensitization, and inhibition of downstream signaling. RESULTS: CHEMICAL inhibited constitutive and/or ligand-induced EGFR or GENE tyrosine phosphorylation of all five cell lines, which correlated with the antiproliferative response in all but one cell line. CHEMICAL radiosensitized EGFR-overexpressing cell lines, but GENE-overexpressing cells were unable to form colonies after brief exposure to CHEMICAL even in the absence of radiation, and thus could not be evaluated for radiosensitization. One cell line was resistant to the antiproliferative and radiosensitizing effects of CHEMICAL, despite receptor inhibition. Exploration of potential mechanisms of resistance in SUM185 cells revealed failure of CHEMICAL to inhibit downstream ERK and Akt activation, despite inhibition of GENE phosphorylation. In contrast, sensitive HER2-overexpressing cell lines demonstrated inhibition of both ERK and Akt phosphorylation. CONCLUSION: CHEMICAL potently inhibits receptor phosphorylation in either EGFR- or HER2-overexpressing cell lines and has both antiproliferative and radiosensitizing effects. Resistance to CHEMICAL was not due to a lack of receptor inhibition, but rather with a lack of inhibition of ERK and Akt, suggesting that measurement of inhibition of crucial signaling pathways may better predict response than inhibition of receptor phosphorylation. The SUM185 cell line provides a valuable model for studying mechanisms of resistance of EGFR/HER2 inhibitor therapy. | INHIBITOR |
| Effects of the EGFR/HER2 GENE inhibitor CHEMICAL on EGFR- and HER2-overexpressing breast cancer cell line proliferation, radiosensitization, and resistance. PURPOSE: Two members of the epidermal growth factor receptor family, EGFR and HER2, have been implicated in radioresistance in breast cancer and other malignancies. To gauge the potential clinical utility of targeting both EGFR and HER2 to control growth and radiosensitize human breast cancers, we examined the effect of a dual EGFR/HER2 inhibitor, CHEMICAL, on the proliferation and radiation response of either EGFR- or HER2-overexpressing human breast cancer cell lines. METHODS AND MATERIALS: Primary human breast cancer cell lines that endogenously overexpress EGFR or HER2 and luminal mammary epithelial H16N2 cells stably transfected with HER2 were evaluated for the effect of CHEMICAL on inhibition of ligand-induced or constitutive receptor phosphorylation, proliferation, radiosensitization, and inhibition of downstream signaling. RESULTS: CHEMICAL inhibited constitutive and/or ligand-induced EGFR or HER2 tyrosine phosphorylation of all five cell lines, which correlated with the antiproliferative response in all but one cell line. CHEMICAL radiosensitized EGFR-overexpressing cell lines, but HER2-overexpressing cells were unable to form colonies after brief exposure to CHEMICAL even in the absence of radiation, and thus could not be evaluated for radiosensitization. One cell line was resistant to the antiproliferative and radiosensitizing effects of CHEMICAL, despite receptor inhibition. Exploration of potential mechanisms of resistance in SUM185 cells revealed failure of CHEMICAL to inhibit downstream ERK and Akt activation, despite inhibition of HER2 phosphorylation. In contrast, sensitive HER2-overexpressing cell lines demonstrated inhibition of both ERK and Akt phosphorylation. CONCLUSION: CHEMICAL potently inhibits receptor phosphorylation in either EGFR- or HER2-overexpressing cell lines and has both antiproliferative and radiosensitizing effects. Resistance to CHEMICAL was not due to a lack of receptor inhibition, but rather with a lack of inhibition of ERK and Akt, suggesting that measurement of inhibition of crucial signaling pathways may better predict response than inhibition of receptor phosphorylation. The SUM185 cell line provides a valuable model for studying mechanisms of resistance of EGFR/HER2 inhibitor therapy. | INHIBITOR |
| CHEMICAL, but not leptin, regulates GENE in pancreatic islets: impact on glucose-stimulated insulin secretion. CHEMICAL, a drug widely used in the treatment of type 2 diabetes, has recently been shown to act on skeletal muscle and liver in part through the activation of GENE (AMPK). Whether metformin or the satiety factor leptin, which also stimulates AMPK in muscle, regulates this enzyme in pancreatic islets is unknown. We have recently shown that forced increases in AMPK activity inhibit insulin secretion from MIN6 cells (da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule SK, and Rutter GA. Biochem J 371: 761-774, 2003). Here, we explore whether 1) glucose, metformin, or leptin regulates AMPK activity in isolated islets from rodent and human and 2) whether changes in AMPK activity modulate insulin secretion from human islets. Increases in glucose concentration from 0 to 3 and from 3 to 17 mM inhibited AMPK activity in primary islets from mouse, rat, and human, confirming previous findings in insulinoma cells. Incubation with metformin (0.2-1 mM) activated AMPK in both human islets and MIN6 beta-cells in parallel with an inhibition of insulin secretion, whereas leptin (10-100 nM) was without effect in MIN6 cells. These studies demonstrate that AMPK activity is subject to regulation by both glucose and metformin in pancreatic islets and clonal beta-cells. The inhibitory effects of metformin on insulin secretion may therefore need to be considered with respect to the use of this drug for the treatment of type 2 diabetes. | REGULATOR |
| Metformin, but not leptin, regulates AMP-activated protein kinase in pancreatic islets: impact on glucose-stimulated insulin secretion. Metformin, a drug widely used in the treatment of type 2 diabetes, has recently been shown to act on skeletal muscle and liver in part through the activation of AMP-activated protein kinase (AMPK). Whether metformin or the satiety factor leptin, which also stimulates GENE in muscle, regulates this enzyme in pancreatic islets is unknown. We have recently shown that forced increases in GENE activity inhibit insulin secretion from MIN6 cells (da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule SK, and Rutter GA. Biochem J 371: 761-774, 2003). Here, we explore whether 1) CHEMICAL, metformin, or leptin regulates GENE activity in isolated islets from rodent and human and 2) whether changes in GENE activity modulate insulin secretion from human islets. Increases in CHEMICAL concentration from 0 to 3 and from 3 to 17 mM inhibited GENE activity in primary islets from mouse, rat, and human, confirming previous findings in insulinoma cells. Incubation with metformin (0.2-1 mM) activated GENE in both human islets and MIN6 beta-cells in parallel with an inhibition of insulin secretion, whereas leptin (10-100 nM) was without effect in MIN6 cells. These studies demonstrate that GENE activity is subject to regulation by both CHEMICAL and metformin in pancreatic islets and clonal beta-cells. The inhibitory effects of metformin on insulin secretion may therefore need to be considered with respect to the use of this drug for the treatment of type 2 diabetes. | REGULATOR |
| CHEMICAL, but not leptin, regulates AMP-activated protein kinase in pancreatic islets: impact on glucose-stimulated insulin secretion. CHEMICAL, a drug widely used in the treatment of type 2 diabetes, has recently been shown to act on skeletal muscle and liver in part through the activation of AMP-activated protein kinase (AMPK). Whether CHEMICAL or the satiety factor leptin, which also stimulates GENE in muscle, regulates this enzyme in pancreatic islets is unknown. We have recently shown that forced increases in GENE activity inhibit insulin secretion from MIN6 cells (da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule SK, and Rutter GA. Biochem J 371: 761-774, 2003). Here, we explore whether 1) glucose, CHEMICAL, or leptin regulates GENE activity in isolated islets from rodent and human and 2) whether changes in GENE activity modulate insulin secretion from human islets. Increases in glucose concentration from 0 to 3 and from 3 to 17 mM inhibited GENE activity in primary islets from mouse, rat, and human, confirming previous findings in insulinoma cells. Incubation with CHEMICAL (0.2-1 mM) activated GENE in both human islets and MIN6 beta-cells in parallel with an inhibition of insulin secretion, whereas leptin (10-100 nM) was without effect in MIN6 cells. These studies demonstrate that GENE activity is subject to regulation by both glucose and CHEMICAL in pancreatic islets and clonal beta-cells. The inhibitory effects of CHEMICAL on insulin secretion may therefore need to be considered with respect to the use of this drug for the treatment of type 2 diabetes. | REGULATOR |
| Metformin, but not leptin, regulates AMP-activated protein kinase in pancreatic islets: impact on CHEMICAL-stimulated GENE secretion. Metformin, a drug widely used in the treatment of type 2 diabetes, has recently been shown to act on skeletal muscle and liver in part through the activation of AMP-activated protein kinase (AMPK). Whether metformin or the satiety factor leptin, which also stimulates AMPK in muscle, regulates this enzyme in pancreatic islets is unknown. We have recently shown that forced increases in AMPK activity inhibit GENE secretion from MIN6 cells (da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule SK, and Rutter GA. Biochem J 371: 761-774, 2003). Here, we explore whether 1) CHEMICAL, metformin, or leptin regulates AMPK activity in isolated islets from rodent and human and 2) whether changes in AMPK activity modulate GENE secretion from human islets. Increases in CHEMICAL concentration from 0 to 3 and from 3 to 17 mM inhibited AMPK activity in primary islets from mouse, rat, and human, confirming previous findings in insulinoma cells. Incubation with metformin (0.2-1 mM) activated AMPK in both human islets and MIN6 beta-cells in parallel with an inhibition of GENE secretion, whereas leptin (10-100 nM) was without effect in MIN6 cells. These studies demonstrate that AMPK activity is subject to regulation by both CHEMICAL and metformin in pancreatic islets and clonal beta-cells. The inhibitory effects of metformin on GENE secretion may therefore need to be considered with respect to the use of this drug for the treatment of type 2 diabetes. | INDIRECT-UPREGULATOR |
| CHEMICAL, but not leptin, regulates AMP-activated protein kinase in pancreatic islets: impact on glucose-stimulated GENE secretion. CHEMICAL, a drug widely used in the treatment of type 2 diabetes, has recently been shown to act on skeletal muscle and liver in part through the activation of AMP-activated protein kinase (AMPK). Whether CHEMICAL or the satiety factor leptin, which also stimulates AMPK in muscle, regulates this enzyme in pancreatic islets is unknown. We have recently shown that forced increases in AMPK activity inhibit GENE secretion from MIN6 cells (da Silva Xavier G, Leclerc I, Varadi A, Tsuboi T, Moule SK, and Rutter GA. Biochem J 371: 761-774, 2003). Here, we explore whether 1) glucose, CHEMICAL, or leptin regulates AMPK activity in isolated islets from rodent and human and 2) whether changes in AMPK activity modulate GENE secretion from human islets. Increases in glucose concentration from 0 to 3 and from 3 to 17 mM inhibited AMPK activity in primary islets from mouse, rat, and human, confirming previous findings in insulinoma cells. Incubation with CHEMICAL (0.2-1 mM) activated AMPK in both human islets and MIN6 beta-cells in parallel with an inhibition of GENE secretion, whereas leptin (10-100 nM) was without effect in MIN6 cells. These studies demonstrate that AMPK activity is subject to regulation by both glucose and CHEMICAL in pancreatic islets and clonal beta-cells. The inhibitory effects of CHEMICAL on GENE secretion may therefore need to be considered with respect to the use of this drug for the treatment of type 2 diabetes. | GENE-CHEMICAL |
| A novel retinoic acid-responsive element regulates retinoic acid-induced BLR1 expression. The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. CHEMICAL is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by CHEMICAL. The RA-treated HL-60 cells used here expressed all CHEMICAL receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that RARalpha synergized with RXRalpha to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by CHEMICAL. Within this sequence DNase I footprinting revealed that CHEMICAL induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARalpha and RXRalpha. Without CHEMICAL there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by CHEMICAL. The ability of this cis-acting GENE to activate transcription in response to CHEMICAL also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from RA-treated cells indicated several prominent RARalpha binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. CHEMICAL upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel CHEMICAL response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains Oct1, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites. | ACTIVATOR |
| A novel retinoic acid-responsive element regulates retinoic acid-induced BLR1 expression. The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. CHEMICAL is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by CHEMICAL. The RA-treated HL-60 cells used here expressed all CHEMICAL receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that RARalpha synergized with RXRalpha to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by CHEMICAL. Within this sequence DNase I footprinting revealed that CHEMICAL induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARalpha and RXRalpha. Without CHEMICAL there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by CHEMICAL. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to CHEMICAL also depended on downstream sequences where an GENE (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from RA-treated cells indicated several prominent RARalpha binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. CHEMICAL upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel CHEMICAL response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains Oct1, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites. | DIRECT-REGULATOR |
| A novel retinoic acid-responsive element regulates retinoic acid-induced BLR1 expression. The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. CHEMICAL is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by CHEMICAL. The RA-treated HL-60 cells used here expressed all CHEMICAL receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that RARalpha synergized with RXRalpha to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by CHEMICAL. Within this sequence DNase I footprinting revealed that CHEMICAL induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARalpha and RXRalpha. Without CHEMICAL there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by CHEMICAL. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to CHEMICAL also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a GENE (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from RA-treated cells indicated several prominent RARalpha binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. CHEMICAL upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel CHEMICAL response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains Oct1, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites. | GENE-CHEMICAL |
| A novel retinoic acid-responsive element regulates retinoic acid-induced BLR1 expression. The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. CHEMICAL is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by CHEMICAL. The RA-treated HL-60 cells used here expressed all CHEMICAL receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that RARalpha synergized with RXRalpha to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by CHEMICAL. Within this sequence DNase I footprinting revealed that CHEMICAL induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARalpha and RXRalpha. Without CHEMICAL there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by CHEMICAL. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to CHEMICAL also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (GENE) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from RA-treated cells indicated several prominent RARalpha binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. CHEMICAL upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel CHEMICAL response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains Oct1, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites. | DIRECT-REGULATOR |
| A novel retinoic acid-responsive element regulates retinoic acid-induced BLR1 expression. The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. CHEMICAL is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by CHEMICAL. The RA-treated HL-60 cells used here expressed all CHEMICAL receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that RARalpha synergized with RXRalpha to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by CHEMICAL. Within this sequence DNase I footprinting revealed that CHEMICAL induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARalpha and RXRalpha. Without CHEMICAL there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by CHEMICAL. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to CHEMICAL also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a GENE (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from RA-treated cells indicated several prominent RARalpha binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. CHEMICAL upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel CHEMICAL response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains Oct1, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites. | GENE-CHEMICAL |
| A novel retinoic acid-responsive element regulates retinoic acid-induced BLR1 expression. The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. CHEMICAL is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by CHEMICAL. The RA-treated HL-60 cells used here expressed all CHEMICAL receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that RARalpha synergized with RXRalpha to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by CHEMICAL. Within this sequence DNase I footprinting revealed that CHEMICAL induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARalpha and RXRalpha. Without CHEMICAL there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by CHEMICAL. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to CHEMICAL also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (GENE) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from RA-treated cells indicated several prominent RARalpha binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. CHEMICAL upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel CHEMICAL response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains Oct1, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites. | ACTIVATOR |
| A novel retinoic acid-responsive element regulates retinoic acid-induced BLR1 expression. The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. CHEMICAL is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of GENE expression by CHEMICAL. The RA-treated HL-60 cells used here expressed all CHEMICAL receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that RARalpha synergized with RXRalpha to transcriptionally activate GENE expression. A 5'-flanking region capable of supporting RA-induced GENE activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by CHEMICAL. Within this sequence DNase I footprinting revealed that CHEMICAL induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARalpha and RXRalpha. Without CHEMICAL there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by CHEMICAL. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to CHEMICAL also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the GENE gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from RA-treated cells indicated several prominent RARalpha binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. CHEMICAL upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of GENE expression depends on a novel CHEMICAL response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains Oct1, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites. | GENE-CHEMICAL |
| A novel retinoic acid-responsive element regulates retinoic acid-induced BLR1 expression. The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. CHEMICAL is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by CHEMICAL. The RA-treated HL-60 cells used here expressed all CHEMICAL receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that RARalpha synergized with RXRalpha to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by CHEMICAL. Within this sequence DNase I footprinting revealed that CHEMICAL induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARalpha and RXRalpha. Without CHEMICAL there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by CHEMICAL. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to CHEMICAL also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from CHEMICAL-treated cells indicated several prominent RARalpha binding partners; among these, GENE, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. CHEMICAL upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel CHEMICAL response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains GENE, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites. | DIRECT-REGULATOR |
| A novel retinoic acid-responsive element regulates retinoic acid-induced BLR1 expression. The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. CHEMICAL is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by CHEMICAL. The RA-treated HL-60 cells used here expressed all CHEMICAL receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that RARalpha synergized with RXRalpha to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by CHEMICAL. Within this sequence DNase I footprinting revealed that CHEMICAL induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARalpha and RXRalpha. Without CHEMICAL there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by CHEMICAL. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to CHEMICAL also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from CHEMICAL-treated cells indicated several prominent RARalpha binding partners; among these, Oct1, GENE, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. CHEMICAL upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel CHEMICAL response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains Oct1, GENE, and CREB2 bound to their cognate downstream consensus binding sites. | DIRECT-REGULATOR |
| A novel retinoic acid-responsive element regulates retinoic acid-induced BLR1 expression. The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. CHEMICAL is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by CHEMICAL. The RA-treated HL-60 cells used here expressed all CHEMICAL receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that RARalpha synergized with RXRalpha to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by CHEMICAL. Within this sequence DNase I footprinting revealed that CHEMICAL induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARalpha and RXRalpha. Without CHEMICAL there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by CHEMICAL. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to CHEMICAL also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from CHEMICAL-treated cells indicated several prominent RARalpha binding partners; among these, Oct1, NFATc3, and GENE were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. CHEMICAL upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel CHEMICAL response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains Oct1, NFATc3, and GENE bound to their cognate downstream consensus binding sites. | DIRECT-REGULATOR |
| A novel retinoic acid-responsive element regulates retinoic acid-induced BLR1 expression. The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. CHEMICAL is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by CHEMICAL. The RA-treated HL-60 cells used here expressed all CHEMICAL receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that RARalpha synergized with RXRalpha to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by CHEMICAL. Within this sequence DNase I footprinting revealed that CHEMICAL induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARalpha and RXRalpha. Without CHEMICAL there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by CHEMICAL. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to CHEMICAL also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from RA-treated cells indicated several prominent RARalpha binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. CHEMICAL upregulated expression of these three factors. In sum the results of the present study indicate that CHEMICAL-induced expression of blr1 expression depends on a novel GENE. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains Oct1, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites. | GENE-CHEMICAL |
| A novel retinoic acid-responsive element regulates retinoic acid-induced BLR1 expression. The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. CHEMICAL is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by CHEMICAL. The RA-treated HL-60 cells used here expressed all CHEMICAL receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that RARalpha synergized with RXRalpha to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by CHEMICAL. Within this sequence DNase I footprinting revealed that CHEMICAL induced binding of a nuclear protein complex to an element containing two GENE. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARalpha and RXRalpha. Without CHEMICAL there was neither complex binding nor transcriptional activation. Both GENE were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by CHEMICAL. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to CHEMICAL also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from RA-treated cells indicated several prominent RARalpha binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. CHEMICAL upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel CHEMICAL response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GENE that bind RAR and RXR in a nuclear protein complex that also contains Oct1, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites. | DIRECT-REGULATOR |
| A novel retinoic acid-responsive element regulates retinoic acid-induced BLR1 expression. The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. CHEMICAL is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by CHEMICAL. The RA-treated HL-60 cells used here expressed all CHEMICAL receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that RARalpha synergized with RXRalpha to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by CHEMICAL. Within this sequence DNase I footprinting revealed that CHEMICAL induced binding of a GENE to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARalpha and RXRalpha. Without CHEMICAL there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by CHEMICAL. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to CHEMICAL also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from RA-treated cells indicated several prominent RARalpha binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. CHEMICAL upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel CHEMICAL response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a GENE that also contains Oct1, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites. | DIRECT-REGULATOR |
| A novel retinoic acid-responsive element regulates retinoic acid-induced BLR1 expression. The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. CHEMICAL is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by CHEMICAL. The RA-treated HL-60 cells used here expressed all CHEMICAL receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that GENE synergized with RXRalpha to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by CHEMICAL. Within this sequence DNase I footprinting revealed that CHEMICAL induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant GENE and RXRalpha. Without CHEMICAL there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by CHEMICAL. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to CHEMICAL also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from CHEMICAL-treated cells indicated several prominent GENE binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. CHEMICAL upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel CHEMICAL response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains Oct1, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites. | DIRECT-REGULATOR |
| A novel retinoic acid-responsive element regulates CHEMICAL-induced GENE expression. The mechanism of action of CHEMICAL (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. RA is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by RA. The RA-treated HL-60 cells used here expressed all RA receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that RARalpha synergized with RXRalpha to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by RA. Within this sequence DNase I footprinting revealed that RA induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARalpha and RXRalpha. Without RA there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by RA. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to RA also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from RA-treated cells indicated several prominent RARalpha binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. RA upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel RA response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains Oct1, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites. | INDIRECT-UPREGULATOR |
| A novel retinoic acid-responsive element regulates retinoic acid-induced BLR1 expression. The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. CHEMICAL is known to induce expression of the GENE (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by CHEMICAL. The RA-treated HL-60 cells used here expressed all CHEMICAL receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that RARalpha synergized with RXRalpha to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by CHEMICAL. Within this sequence DNase I footprinting revealed that CHEMICAL induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARalpha and RXRalpha. Without CHEMICAL there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by CHEMICAL. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to CHEMICAL also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from RA-treated cells indicated several prominent RARalpha binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. CHEMICAL upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel CHEMICAL response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains Oct1, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites. | INDIRECT-UPREGULATOR |
| A novel retinoic acid-responsive element regulates retinoic acid-induced GENE expression. The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. CHEMICAL is known to induce expression of the Burkitt's lymphoma receptor 1 (GENE) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by CHEMICAL. The RA-treated HL-60 cells used here expressed all CHEMICAL receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRgamma. Treatment with RAR- and RXR-selective ligands showed that RARalpha synergized with RXRalpha to transcriptionally activate blr1 expression. A 5'-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by CHEMICAL. Within this sequence DNase I footprinting revealed that CHEMICAL induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARalpha and RXRalpha. Without CHEMICAL there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by CHEMICAL. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to CHEMICAL also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from RA-treated cells indicated several prominent RARalpha binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. CHEMICAL upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel CHEMICAL response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains Oct1, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites. | INDIRECT-UPREGULATOR |
| The persistent membrane retention of desipramine causes lasting inhibition of norepinephrine transporter function. The present study examined the potential membrane retention of desipramine (DMI) following exposures of 293-hNET cells to DMI, and its effect on [3H]NE uptake. Incubation of cells with 500 nM DMI for 1 h or 1 day persistently inhibited the uptake of [3H]NE up to 7 days, despite daily repeated washing of cells with drug-free medium. Uptake inhibition was paralleled by persistent retention of DMI associated with cells, as determined by HPLC and by radiotracer experiments using CHEMICAL. CHEMICAL trapped in membranes was displaceable by the structurally unrelated GENE inhibitor, nisoxetine, in a concentration-dependent manner, implying interaction of retained CHEMICAL with the GENE. A similar cellular retention was observed following incubation of cells with nisoxetine. The results demonstrate that DMI and nisoxetine are persistently retained in cell membranes, at least partly in association with the GENE. The retention and slow diffusion of DMI and nisoxetine from membranes may contribute to their pharmacological and modulatory action on GENE. | DIRECT-REGULATOR |
| The persistent membrane retention of desipramine causes lasting inhibition of norepinephrine transporter function. The present study examined the potential membrane retention of desipramine (DMI) following exposures of 293-hNET cells to CHEMICAL, and its effect on [3H]NE uptake. Incubation of cells with 500 nM CHEMICAL for 1 h or 1 day persistently inhibited the uptake of [3H]NE up to 7 days, despite daily repeated washing of cells with drug-free medium. Uptake inhibition was paralleled by persistent retention of CHEMICAL associated with cells, as determined by HPLC and by radiotracer experiments using [3H]DMI. [3H]DMI trapped in membranes was displaceable by the structurally unrelated GENE inhibitor, nisoxetine, in a concentration-dependent manner, implying interaction of retained [3H]DMI with the GENE. A similar cellular retention was observed following incubation of cells with nisoxetine. The results demonstrate that CHEMICAL and nisoxetine are persistently retained in cell membranes, at least partly in association with the GENE. The retention and slow diffusion of CHEMICAL and nisoxetine from membranes may contribute to their pharmacological and modulatory action on GENE. | DIRECT-REGULATOR |
| The persistent membrane retention of desipramine causes lasting inhibition of norepinephrine transporter function. The present study examined the potential membrane retention of desipramine (DMI) following exposures of 293-hNET cells to DMI, and its effect on [3H]NE uptake. Incubation of cells with 500 nM DMI for 1 h or 1 day persistently inhibited the uptake of [3H]NE up to 7 days, despite daily repeated washing of cells with drug-free medium. Uptake inhibition was paralleled by persistent retention of DMI associated with cells, as determined by HPLC and by radiotracer experiments using [3H]DMI. [3H]DMI trapped in membranes was displaceable by the structurally unrelated GENE inhibitor, CHEMICAL, in a concentration-dependent manner, implying interaction of retained [3H]DMI with the GENE. A similar cellular retention was observed following incubation of cells with CHEMICAL. The results demonstrate that DMI and CHEMICAL are persistently retained in cell membranes, at least partly in association with the GENE. The retention and slow diffusion of DMI and CHEMICAL from membranes may contribute to their pharmacological and modulatory action on GENE. | DIRECT-REGULATOR |
| The persistent membrane retention of CHEMICAL causes lasting inhibition of GENE function. The present study examined the potential membrane retention of CHEMICAL (DMI) following exposures of 293-hNET cells to DMI, and its effect on [3H]NE uptake. Incubation of cells with 500 nM DMI for 1 h or 1 day persistently inhibited the uptake of [3H]NE up to 7 days, despite daily repeated washing of cells with drug-free medium. Uptake inhibition was paralleled by persistent retention of DMI associated with cells, as determined by HPLC and by radiotracer experiments using [3H]DMI. [3H]DMI trapped in membranes was displaceable by the structurally unrelated NET inhibitor, nisoxetine, in a concentration-dependent manner, implying interaction of retained [3H]DMI with the NET. A similar cellular retention was observed following incubation of cells with nisoxetine. The results demonstrate that DMI and nisoxetine are persistently retained in cell membranes, at least partly in association with the NET. The retention and slow diffusion of DMI and nisoxetine from membranes may contribute to their pharmacological and modulatory action on NET. | INHIBITOR |
| AT1-receptor antagonism in hypertension: what has been learned with irbesartan? CHEMICAL is a long-acting angiotensin II antagonist acting specifically at the level of the Type 1-receptor subtype (GENE-receptor). This compound lowers blood pressure dose-dependently in hypertensive patients and has a placebo-like tolerability. The antihypertensive efficacy of irbesartan is greatly enhanced by the coadministration of a diuretic, and fixed-dose combinations of irbesartan and hydrochlorothiazide are now available. Irbesartan-based treatment appears especially effective for high-risk patients, such as those with diabetes, renal disease and cardiac hypertrophy. In patients with Type 2 diabetes, irbesartan delays the development of nephropathy as well as the progression of renal failure. CHEMICAL may have antiatherosclerotic properties beyond those expected from blood pressure lowering per se: this AT1-blocker decreases the vascular oxidative stress and prevents the procoagulant as well as the pro-inflammatory effects of angiotensin II. CHEMICAL given alone or in combination with a diuretic therefore represents a rational approach to treat hypertensive patients. | INHIBITOR |
| AT1-receptor antagonism in hypertension: what has been learned with irbesartan? CHEMICAL is a long-acting GENE antagonist acting specifically at the level of the Type 1-receptor subtype (AT1-receptor). This compound lowers blood pressure dose-dependently in hypertensive patients and has a placebo-like tolerability. The antihypertensive efficacy of irbesartan is greatly enhanced by the coadministration of a diuretic, and fixed-dose combinations of irbesartan and hydrochlorothiazide are now available. Irbesartan-based treatment appears especially effective for high-risk patients, such as those with diabetes, renal disease and cardiac hypertrophy. In patients with Type 2 diabetes, irbesartan delays the development of nephropathy as well as the progression of renal failure. CHEMICAL may have antiatherosclerotic properties beyond those expected from blood pressure lowering per se: this AT1-blocker decreases the vascular oxidative stress and prevents the procoagulant as well as the pro-inflammatory effects of GENE. CHEMICAL given alone or in combination with a diuretic therefore represents a rational approach to treat hypertensive patients. | INHIBITOR |
| Binding of (-)-[3H]-CGP12177 at two sites in recombinant human beta 1-adrenoceptors and interaction with beta-blockers. To verify the hypothesis that the non-conventional partial agonist (-)-CGP12177 binds at two beta(1)-adrenoceptor sites, human GENE, expressed in CHO cells, were labelled with CHEMICAL. We compared the binding affinity and antagonist potency of 12 clinically used beta-blockers against the cyclic AMP-enhancing effects of (-)-isoprenaline and (-)-CGP12177.(-)-[(3)H]-CGP12177 bound to a high affinity site (H; K(H)=0.47 nM) and low affinity site (L); K(L)=235 nM). CHEMICAL dissociated from the GENE with a fast component (k(off)=0.45 min(-1)), consistent with the L-site, and a slow component (k(off)=0.017-0.033 min(-1)), consistent with the H-site. (-)-Isoprenaline and (-)-CGP12177 caused 96-fold and 12-fold maximal increases in cyclic AMP levels with -logEC(50)M of 8.2 and 7.6. (-)-CGP12177 antagonised the effects of (-)-isoprenaline with a pK(B) of 9.9. The beta-blockers antagonised the effects of (-)-isoprenaline more than the effects of (-)-CGP12177 with potency ratios: (-)-atenolol 1,000, (+/-)-metropolol 676, (-)-pindolol 631, (-)-timolol 589, (+/-)-carvedilol 204, (+/-)-oxprenolol 138, (+/-)-sotalol 132, (-)-propranolol 120, (+/-)-bisoprolol 95, (+/-)-alprenolol 81, (+/-)-nadolol 68 and (-)-bupranolol 56. In intact cells the binding constants of beta-blockers, estimated from competition with 3-5 nM CHEMICAL (binding to the H-site), correlated with the corresponding affinities estimated from antagonism of the (-)-isoprenaline effects. We conclude that CHEMICAL binds at two sites in the recombinant beta(1)-adrenoceptor. (-)-CGP12177 is an antagonist of catecholamine effects through the H-site and a non-conventional partial agonist through the L-site. beta-blockers are more potent antagonists through the H-site than the L-site. | DIRECT-REGULATOR |
| Binding of (-)-[3H]-CGP12177 at two sites in recombinant human beta 1-adrenoceptors and interaction with beta-blockers. To verify the hypothesis that the non-conventional partial agonist (-)-CGP12177 binds at two GENE sites, human beta(1)-adrenoceptors, expressed in CHO cells, were labelled with CHEMICAL. We compared the binding affinity and antagonist potency of 12 clinically used beta-blockers against the cyclic AMP-enhancing effects of (-)-isoprenaline and (-)-CGP12177.(-)-[(3)H]-CGP12177 bound to a high affinity site (H; K(H)=0.47 nM) and low affinity site (L); K(L)=235 nM). CHEMICAL dissociated from the beta(1)-adrenoceptors with a fast component (k(off)=0.45 min(-1)), consistent with the L-site, and a slow component (k(off)=0.017-0.033 min(-1)), consistent with the H-site. (-)-Isoprenaline and (-)-CGP12177 caused 96-fold and 12-fold maximal increases in cyclic AMP levels with -logEC(50)M of 8.2 and 7.6. (-)-CGP12177 antagonised the effects of (-)-isoprenaline with a pK(B) of 9.9. The beta-blockers antagonised the effects of (-)-isoprenaline more than the effects of (-)-CGP12177 with potency ratios: (-)-atenolol 1,000, (+/-)-metropolol 676, (-)-pindolol 631, (-)-timolol 589, (+/-)-carvedilol 204, (+/-)-oxprenolol 138, (+/-)-sotalol 132, (-)-propranolol 120, (+/-)-bisoprolol 95, (+/-)-alprenolol 81, (+/-)-nadolol 68 and (-)-bupranolol 56. In intact cells the binding constants of beta-blockers, estimated from competition with 3-5 nM CHEMICAL (binding to the H-site), correlated with the corresponding affinities estimated from antagonism of the (-)-isoprenaline effects. We conclude that CHEMICAL binds at two sites in the recombinant GENE. (-)-CGP12177 is an antagonist of catecholamine effects through the H-site and a non-conventional partial agonist through the L-site. beta-blockers are more potent antagonists through the H-site than the L-site. | DIRECT-REGULATOR |
| Binding of (-)-[3H]-CGP12177 at two sites in recombinant human beta 1-adrenoceptors and interaction with beta-blockers. To verify the hypothesis that the non-conventional partial agonist (-)-CGP12177 binds at two beta(1)-adrenoceptor sites, GENE, expressed in CHO cells, were labelled with CHEMICAL. We compared the binding affinity and antagonist potency of 12 clinically used beta-blockers against the cyclic AMP-enhancing effects of (-)-isoprenaline and (-)-CGP12177.(-)-[(3)H]-CGP12177 bound to a high affinity site (H; K(H)=0.47 nM) and low affinity site (L); K(L)=235 nM). CHEMICAL dissociated from the beta(1)-adrenoceptors with a fast component (k(off)=0.45 min(-1)), consistent with the L-site, and a slow component (k(off)=0.017-0.033 min(-1)), consistent with the H-site. (-)-Isoprenaline and (-)-CGP12177 caused 96-fold and 12-fold maximal increases in cyclic AMP levels with -logEC(50)M of 8.2 and 7.6. (-)-CGP12177 antagonised the effects of (-)-isoprenaline with a pK(B) of 9.9. The beta-blockers antagonised the effects of (-)-isoprenaline more than the effects of (-)-CGP12177 with potency ratios: (-)-atenolol 1,000, (+/-)-metropolol 676, (-)-pindolol 631, (-)-timolol 589, (+/-)-carvedilol 204, (+/-)-oxprenolol 138, (+/-)-sotalol 132, (-)-propranolol 120, (+/-)-bisoprolol 95, (+/-)-alprenolol 81, (+/-)-nadolol 68 and (-)-bupranolol 56. In intact cells the binding constants of beta-blockers, estimated from competition with 3-5 nM CHEMICAL (binding to the H-site), correlated with the corresponding affinities estimated from antagonism of the (-)-isoprenaline effects. We conclude that CHEMICAL binds at two sites in the recombinant beta(1)-adrenoceptor. (-)-CGP12177 is an antagonist of catecholamine effects through the H-site and a non-conventional partial agonist through the L-site. beta-blockers are more potent antagonists through the H-site than the L-site. | DIRECT-REGULATOR |
| Binding of (-)-[3H]-CGP12177 at two sites in recombinant human beta 1-adrenoceptors and interaction with beta-blockers. To verify the hypothesis that the non-conventional partial agonist CHEMICAL binds at two beta(1)-adrenoceptor sites, GENE, expressed in CHO cells, were labelled with (-)-[(3)H]-CGP12177. We compared the binding affinity and antagonist potency of 12 clinically used beta-blockers against the cyclic AMP-enhancing effects of (-)-isoprenaline and (-)-CGP12177.(-)-[(3)H]-CGP12177 bound to a high affinity site (H; K(H)=0.47 nM) and low affinity site (L); K(L)=235 nM). (-)-[(3)H]-CGP12177 dissociated from the beta(1)-adrenoceptors with a fast component (k(off)=0.45 min(-1)), consistent with the L-site, and a slow component (k(off)=0.017-0.033 min(-1)), consistent with the H-site. (-)-Isoprenaline and CHEMICAL caused 96-fold and 12-fold maximal increases in cyclic AMP levels with -logEC(50)M of 8.2 and 7.6. CHEMICAL antagonised the effects of (-)-isoprenaline with a pK(B) of 9.9. The beta-blockers antagonised the effects of (-)-isoprenaline more than the effects of CHEMICAL with potency ratios: (-)-atenolol 1,000, (+/-)-metropolol 676, (-)-pindolol 631, (-)-timolol 589, (+/-)-carvedilol 204, (+/-)-oxprenolol 138, (+/-)-sotalol 132, (-)-propranolol 120, (+/-)-bisoprolol 95, (+/-)-alprenolol 81, (+/-)-nadolol 68 and (-)-bupranolol 56. In intact cells the binding constants of beta-blockers, estimated from competition with 3-5 nM (-)-[(3)H]-CGP12177 (binding to the H-site), correlated with the corresponding affinities estimated from antagonism of the (-)-isoprenaline effects. We conclude that (-)-[(3)H]-CGP12177 binds at two sites in the recombinant beta(1)-adrenoceptor. CHEMICAL is an antagonist of catecholamine effects through the H-site and a non-conventional partial agonist through the L-site. beta-blockers are more potent antagonists through the H-site than the L-site. | DIRECT-REGULATOR |
| Binding of (-)-[3H]-CGP12177 at two sites in recombinant human beta 1-adrenoceptors and interaction with beta-blockers. To verify the hypothesis that the non-conventional partial agonist CHEMICAL binds at two GENE sites, human beta(1)-adrenoceptors, expressed in CHO cells, were labelled with (-)-[(3)H]-CGP12177. We compared the binding affinity and antagonist potency of 12 clinically used beta-blockers against the cyclic AMP-enhancing effects of (-)-isoprenaline and (-)-CGP12177.(-)-[(3)H]-CGP12177 bound to a high affinity site (H; K(H)=0.47 nM) and low affinity site (L); K(L)=235 nM). (-)-[(3)H]-CGP12177 dissociated from the beta(1)-adrenoceptors with a fast component (k(off)=0.45 min(-1)), consistent with the L-site, and a slow component (k(off)=0.017-0.033 min(-1)), consistent with the H-site. (-)-Isoprenaline and CHEMICAL caused 96-fold and 12-fold maximal increases in cyclic AMP levels with -logEC(50)M of 8.2 and 7.6. CHEMICAL antagonised the effects of (-)-isoprenaline with a pK(B) of 9.9. The beta-blockers antagonised the effects of (-)-isoprenaline more than the effects of CHEMICAL with potency ratios: (-)-atenolol 1,000, (+/-)-metropolol 676, (-)-pindolol 631, (-)-timolol 589, (+/-)-carvedilol 204, (+/-)-oxprenolol 138, (+/-)-sotalol 132, (-)-propranolol 120, (+/-)-bisoprolol 95, (+/-)-alprenolol 81, (+/-)-nadolol 68 and (-)-bupranolol 56. In intact cells the binding constants of beta-blockers, estimated from competition with 3-5 nM (-)-[(3)H]-CGP12177 (binding to the H-site), correlated with the corresponding affinities estimated from antagonism of the (-)-isoprenaline effects. We conclude that (-)-[(3)H]-CGP12177 binds at two sites in the recombinant GENE. CHEMICAL is an antagonist of catecholamine effects through the H-site and a non-conventional partial agonist through the L-site. beta-blockers are more potent antagonists through the H-site than the L-site. | DIRECT-REGULATOR |
| Binding of CHEMICAL at two sites in recombinant GENE and interaction with beta-blockers. To verify the hypothesis that the non-conventional partial agonist (-)-CGP12177 binds at two beta(1)-adrenoceptor sites, human beta(1)-adrenoceptors, expressed in CHO cells, were labelled with (-)-[(3)H]-CGP12177. We compared the binding affinity and antagonist potency of 12 clinically used beta-blockers against the cyclic AMP-enhancing effects of (-)-isoprenaline and (-)-CGP12177.(-)-[(3)H]-CGP12177 bound to a high affinity site (H; K(H)=0.47 nM) and low affinity site (L); K(L)=235 nM). (-)-[(3)H]-CGP12177 dissociated from the beta(1)-adrenoceptors with a fast component (k(off)=0.45 min(-1)), consistent with the L-site, and a slow component (k(off)=0.017-0.033 min(-1)), consistent with the H-site. (-)-Isoprenaline and (-)-CGP12177 caused 96-fold and 12-fold maximal increases in cyclic AMP levels with -logEC(50)M of 8.2 and 7.6. (-)-CGP12177 antagonised the effects of (-)-isoprenaline with a pK(B) of 9.9. The beta-blockers antagonised the effects of (-)-isoprenaline more than the effects of (-)-CGP12177 with potency ratios: (-)-atenolol 1,000, (+/-)-metropolol 676, (-)-pindolol 631, (-)-timolol 589, (+/-)-carvedilol 204, (+/-)-oxprenolol 138, (+/-)-sotalol 132, (-)-propranolol 120, (+/-)-bisoprolol 95, (+/-)-alprenolol 81, (+/-)-nadolol 68 and (-)-bupranolol 56. In intact cells the binding constants of beta-blockers, estimated from competition with 3-5 nM (-)-[(3)H]-CGP12177 (binding to the H-site), correlated with the corresponding affinities estimated from antagonism of the (-)-isoprenaline effects. We conclude that (-)-[(3)H]-CGP12177 binds at two sites in the recombinant beta(1)-adrenoceptor. (-)-CGP12177 is an antagonist of catecholamine effects through the H-site and a non-conventional partial agonist through the L-site. beta-blockers are more potent antagonists through the H-site than the L-site. | DIRECT-REGULATOR |
| Imiquimod, a Toll-like receptor-7 agonist, induces perforin in cytotoxic T lymphocytes in vitro. Imiquimod (IMQ), an activator of Toll-like receptor-7 (TLR-7), induces by several routes a profound anti-viral and anti-tumor effect in vivo. Physiologically, the immune system is using perforin-containing granules of cytotoxic T lymphocytes (CTL) towards the same biological purpose. This functional synergism prompted our current experiments addressing the question whether CHEMICAL may influence perforin-release and/or induce perforin in CTLs in vitro. In peripheral lymphocytes of healthy and diseased subjects, CHEMICAL induced a significant increase of perforin(+) CTLs within 12h in all experiments performed. This effect was most pronounced in CTLs of patients suffering from atopic dermatitis, a model disorder for subnormal perforin expression: as compared to perforin(+) CTLs detected at time point zero (100%), up to 270% of perforin(+) CTLs were induced by 2.5 microg/ml [corrected] CHEMICAL. GENE release from peripheral blood CTLs after PMA/ionomycin-stimulation was not influenced significantly by CHEMICAL. Thus, the biological activity of CHEMICAL appears to exceed its previously known functions, inasmuch as it boosts up significantly the perforin-granule system. | NO-RELATIONSHIP |
| CHEMICAL, a GENE agonist, induces perforin in cytotoxic T lymphocytes in vitro. CHEMICAL (IMQ), an activator of GENE (TLR-7), induces by several routes a profound anti-viral and anti-tumor effect in vivo. Physiologically, the immune system is using perforin-containing granules of cytotoxic T lymphocytes (CTL) towards the same biological purpose. This functional synergism prompted our current experiments addressing the question whether IMQ may influence perforin-release and/or induce perforin in CTLs in vitro. In peripheral lymphocytes of healthy and diseased subjects, IMQ induced a significant increase of perforin(+) CTLs within 12h in all experiments performed. This effect was most pronounced in CTLs of patients suffering from atopic dermatitis, a model disorder for subnormal perforin expression: as compared to perforin(+) CTLs detected at time point zero (100%), up to 270% of perforin(+) CTLs were induced by 2.5 microg/ml [corrected] IMQ. Perforin release from peripheral blood CTLs after PMA/ionomycin-stimulation was not influenced significantly by IMQ. Thus, the biological activity of IMQ appears to exceed its previously known functions, inasmuch as it boosts up significantly the perforin-granule system. | ACTIVATOR |
| CHEMICAL, a Toll-like receptor-7 agonist, induces perforin in cytotoxic T lymphocytes in vitro. CHEMICAL (IMQ), an activator of Toll-like receptor-7 (GENE), induces by several routes a profound anti-viral and anti-tumor effect in vivo. Physiologically, the immune system is using perforin-containing granules of cytotoxic T lymphocytes (CTL) towards the same biological purpose. This functional synergism prompted our current experiments addressing the question whether IMQ may influence perforin-release and/or induce perforin in CTLs in vitro. In peripheral lymphocytes of healthy and diseased subjects, IMQ induced a significant increase of perforin(+) CTLs within 12h in all experiments performed. This effect was most pronounced in CTLs of patients suffering from atopic dermatitis, a model disorder for subnormal perforin expression: as compared to perforin(+) CTLs detected at time point zero (100%), up to 270% of perforin(+) CTLs were induced by 2.5 microg/ml [corrected] IMQ. Perforin release from peripheral blood CTLs after PMA/ionomycin-stimulation was not influenced significantly by IMQ. Thus, the biological activity of IMQ appears to exceed its previously known functions, inasmuch as it boosts up significantly the perforin-granule system. | ACTIVATOR |
| Imiquimod, a GENE agonist, induces perforin in cytotoxic T lymphocytes in vitro. Imiquimod (CHEMICAL), an activator of GENE (TLR-7), induces by several routes a profound anti-viral and anti-tumor effect in vivo. Physiologically, the immune system is using perforin-containing granules of cytotoxic T lymphocytes (CTL) towards the same biological purpose. This functional synergism prompted our current experiments addressing the question whether CHEMICAL may influence perforin-release and/or induce perforin in CTLs in vitro. In peripheral lymphocytes of healthy and diseased subjects, CHEMICAL induced a significant increase of perforin(+) CTLs within 12h in all experiments performed. This effect was most pronounced in CTLs of patients suffering from atopic dermatitis, a model disorder for subnormal perforin expression: as compared to perforin(+) CTLs detected at time point zero (100%), up to 270% of perforin(+) CTLs were induced by 2.5 microg/ml [corrected] CHEMICAL. Perforin release from peripheral blood CTLs after PMA/ionomycin-stimulation was not influenced significantly by CHEMICAL. Thus, the biological activity of CHEMICAL appears to exceed its previously known functions, inasmuch as it boosts up significantly the perforin-granule system. | ACTIVATOR |
| Imiquimod, a Toll-like receptor-7 agonist, induces perforin in cytotoxic T lymphocytes in vitro. Imiquimod (CHEMICAL), an activator of Toll-like receptor-7 (GENE), induces by several routes a profound anti-viral and anti-tumor effect in vivo. Physiologically, the immune system is using perforin-containing granules of cytotoxic T lymphocytes (CTL) towards the same biological purpose. This functional synergism prompted our current experiments addressing the question whether CHEMICAL may influence perforin-release and/or induce perforin in CTLs in vitro. In peripheral lymphocytes of healthy and diseased subjects, CHEMICAL induced a significant increase of perforin(+) CTLs within 12h in all experiments performed. This effect was most pronounced in CTLs of patients suffering from atopic dermatitis, a model disorder for subnormal perforin expression: as compared to perforin(+) CTLs detected at time point zero (100%), up to 270% of perforin(+) CTLs were induced by 2.5 microg/ml [corrected] CHEMICAL. Perforin release from peripheral blood CTLs after PMA/ionomycin-stimulation was not influenced significantly by CHEMICAL. Thus, the biological activity of CHEMICAL appears to exceed its previously known functions, inasmuch as it boosts up significantly the perforin-granule system. | ACTIVATOR |
| CHEMICAL, a Toll-like receptor-7 agonist, induces GENE in cytotoxic T lymphocytes in vitro. CHEMICAL (IMQ), an activator of Toll-like receptor-7 (TLR-7), induces by several routes a profound anti-viral and anti-tumor effect in vivo. Physiologically, the immune system is using perforin-containing granules of cytotoxic T lymphocytes (CTL) towards the same biological purpose. This functional synergism prompted our current experiments addressing the question whether IMQ may influence perforin-release and/or induce GENE in CTLs in vitro. In peripheral lymphocytes of healthy and diseased subjects, IMQ induced a significant increase of perforin(+) CTLs within 12h in all experiments performed. This effect was most pronounced in CTLs of patients suffering from atopic dermatitis, a model disorder for subnormal GENE expression: as compared to perforin(+) CTLs detected at time point zero (100%), up to 270% of perforin(+) CTLs were induced by 2.5 microg/ml [corrected] IMQ. GENE release from peripheral blood CTLs after PMA/ionomycin-stimulation was not influenced significantly by IMQ. Thus, the biological activity of IMQ appears to exceed its previously known functions, inasmuch as it boosts up significantly the perforin-granule system. | ACTIVATOR |
| Mesenteric artery remodeling and effects of imidapril and CHEMICAL on it in spontaneously hypertensive rats. AIM: To investigate the remodeling of mesenteric artery and the expression of TGF-beta1, c-Jun in mesenteric artery and effects of imidapril and CHEMICAL on the remodeling in spontaneously hypertensive rats (SHR). METHODS: Thirty SHR (male/female, 21/9), aged 13 wk, were randomly divided into 3 groups (7 male rats and 3 female rats each group): SHR group, imidapril group (imidapril 3 mg/kg.d was given in drinking water for 14 wk), and CHEMICAL group (irbesartan 50 mg/kg.d was given in drinking water foe 14 wk). Ten homogeneous Wistar Kyoto rats, 5 males and 5 females, weighing 206+/-49 g, were selected as normal control group (WKY group). Systolic pressure was measured on d 1, 2, 4, 6, 8, 10, 12 and 14 during the experiment and the rats were killed at the end of the experiment. Angiotensin II (Ang II) level in plasma and mesenteric arteries was measured by radioimmunoassay. The morphology of the secondary branches of mesenteric artery were examined by light microscopy and electron microscopy. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression of transforming growth factor TGF-beta1 and c-Jun mRNA. RESULTS: Compared with imidapril group and CHEMICAL group, the blood pressure was remarkably increased in SHR group. GENE level in plasma and mesenteric arteries in SHR group was the same or lower than that in WKY group, and was higher in CHEMICAL group and lower in imidapril group. The remodeling of mesenteric arteries in SHR group was mostly obvious among the 4 groups. The ratio of TGF-beta1 absorbed light value to GAPDH absorbed light value in the SHR group was 0.887+/-0.019, which was significantly higher than that in WKY group, imidapril group, and CHEMICAL group with the ratios of 0.780+/-0.018, 0.803+/-0.005, and 0.847+/-0.017, respectively (P<0.01). GENE level in plasma and mesenteric arteries in imidapril group was significantly lower than that in CHEMICAL group (P<0.05). The c-Jun absorbed light value/GAPDH absorbed light value of mesenteric arteries in the SHR group was 0.850+/-0.015, which was significantly higher than that in the WKY, imidapril, and CHEMICAL groups (0.582+/-0.013, 0.743+/-0.012, and 0.789+/-0.013, respectively, P<0.01), and was significantly lower in imidapril group than in CHEMICAL group (P<0.05). CONCLUSION: Imidapril and CHEMICAL can not only control blood pressure but also inhibit mesenteric arteries remodeling and mRNA expression of TGF-beta1, c-Jun in SHR. Imidapril is more effective than CHEMICAL. | INDIRECT-DOWNREGULATOR |
| Mesenteric artery remodeling and effects of CHEMICAL and irbesartan on it in spontaneously hypertensive rats. AIM: To investigate the remodeling of mesenteric artery and the expression of TGF-beta1, GENE in mesenteric artery and effects of CHEMICAL and irbesartan on the remodeling in spontaneously hypertensive rats (SHR). METHODS: Thirty SHR (male/female, 21/9), aged 13 wk, were randomly divided into 3 groups (7 male rats and 3 female rats each group): SHR group, CHEMICAL group (imidapril 3 mg/kg.d was given in drinking water for 14 wk), and irbesartan group (irbesartan 50 mg/kg.d was given in drinking water foe 14 wk). Ten homogeneous Wistar Kyoto rats, 5 males and 5 females, weighing 206+/-49 g, were selected as normal control group (WKY group). Systolic pressure was measured on d 1, 2, 4, 6, 8, 10, 12 and 14 during the experiment and the rats were killed at the end of the experiment. Angiotensin II (Ang II) level in plasma and mesenteric arteries was measured by radioimmunoassay. The morphology of the secondary branches of mesenteric artery were examined by light microscopy and electron microscopy. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression of transforming growth factor TGF-beta1 and GENE mRNA. RESULTS: Compared with CHEMICAL group and irbesartan group, the blood pressure was remarkably increased in SHR group. Ang II level in plasma and mesenteric arteries in SHR group was the same or lower than that in WKY group, and was higher in irbesartan group and lower in CHEMICAL group. The remodeling of mesenteric arteries in SHR group was mostly obvious among the 4 groups. The ratio of TGF-beta1 absorbed light value to GAPDH absorbed light value in the SHR group was 0.887+/-0.019, which was significantly higher than that in WKY group, CHEMICAL group, and irbesartan group with the ratios of 0.780+/-0.018, 0.803+/-0.005, and 0.847+/-0.017, respectively (P<0.01). Ang II level in plasma and mesenteric arteries in CHEMICAL group was significantly lower than that in irbesartan group (P<0.05). The GENE absorbed light value/GAPDH absorbed light value of mesenteric arteries in the SHR group was 0.850+/-0.015, which was significantly higher than that in the WKY, CHEMICAL, and irbesartan groups (0.582+/-0.013, 0.743+/-0.012, and 0.789+/-0.013, respectively, P<0.01), and was significantly lower in CHEMICAL group than in irbesartan group (P<0.05). CONCLUSION: CHEMICAL and irbesartan can not only control blood pressure but also inhibit mesenteric arteries remodeling and mRNA expression of TGF-beta1, GENE in SHR. CHEMICAL is more effective than irbesartan. | GENE-CHEMICAL |
| Mesenteric artery remodeling and effects of CHEMICAL and irbesartan on it in spontaneously hypertensive rats. AIM: To investigate the remodeling of mesenteric artery and the expression of TGF-beta1, c-Jun in mesenteric artery and effects of CHEMICAL and irbesartan on the remodeling in spontaneously hypertensive rats (SHR). METHODS: Thirty SHR (male/female, 21/9), aged 13 wk, were randomly divided into 3 groups (7 male rats and 3 female rats each group): SHR group, CHEMICAL group (imidapril 3 mg/kg.d was given in drinking water for 14 wk), and irbesartan group (irbesartan 50 mg/kg.d was given in drinking water foe 14 wk). Ten homogeneous Wistar Kyoto rats, 5 males and 5 females, weighing 206+/-49 g, were selected as normal control group (WKY group). Systolic pressure was measured on d 1, 2, 4, 6, 8, 10, 12 and 14 during the experiment and the rats were killed at the end of the experiment. Angiotensin II (Ang II) level in plasma and mesenteric arteries was measured by radioimmunoassay. The morphology of the secondary branches of mesenteric artery were examined by light microscopy and electron microscopy. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression of transforming growth factor TGF-beta1 and c-Jun mRNA. RESULTS: Compared with CHEMICAL group and irbesartan group, the blood pressure was remarkably increased in SHR group. Ang II level in plasma and mesenteric arteries in SHR group was the same or lower than that in WKY group, and was higher in irbesartan group and lower in CHEMICAL group. The remodeling of mesenteric arteries in SHR group was mostly obvious among the 4 groups. The ratio of TGF-beta1 absorbed light value to GENE absorbed light value in the SHR group was 0.887+/-0.019, which was significantly higher than that in WKY group, CHEMICAL group, and irbesartan group with the ratios of 0.780+/-0.018, 0.803+/-0.005, and 0.847+/-0.017, respectively (P<0.01). Ang II level in plasma and mesenteric arteries in CHEMICAL group was significantly lower than that in irbesartan group (P<0.05). The c-Jun absorbed light value/GENE absorbed light value of mesenteric arteries in the SHR group was 0.850+/-0.015, which was significantly higher than that in the WKY, CHEMICAL, and irbesartan groups (0.582+/-0.013, 0.743+/-0.012, and 0.789+/-0.013, respectively, P<0.01), and was significantly lower in CHEMICAL group than in irbesartan group (P<0.05). CONCLUSION: CHEMICAL and irbesartan can not only control blood pressure but also inhibit mesenteric arteries remodeling and mRNA expression of TGF-beta1, c-Jun in SHR. CHEMICAL is more effective than irbesartan. | GENE-CHEMICAL |
| Mesenteric artery remodeling and effects of imidapril and CHEMICAL on it in spontaneously hypertensive rats. AIM: To investigate the remodeling of mesenteric artery and the expression of TGF-beta1, GENE in mesenteric artery and effects of imidapril and CHEMICAL on the remodeling in spontaneously hypertensive rats (SHR). METHODS: Thirty SHR (male/female, 21/9), aged 13 wk, were randomly divided into 3 groups (7 male rats and 3 female rats each group): SHR group, imidapril group (imidapril 3 mg/kg.d was given in drinking water for 14 wk), and CHEMICAL group (irbesartan 50 mg/kg.d was given in drinking water foe 14 wk). Ten homogeneous Wistar Kyoto rats, 5 males and 5 females, weighing 206+/-49 g, were selected as normal control group (WKY group). Systolic pressure was measured on d 1, 2, 4, 6, 8, 10, 12 and 14 during the experiment and the rats were killed at the end of the experiment. Angiotensin II (Ang II) level in plasma and mesenteric arteries was measured by radioimmunoassay. The morphology of the secondary branches of mesenteric artery were examined by light microscopy and electron microscopy. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression of transforming growth factor TGF-beta1 and GENE mRNA. RESULTS: Compared with imidapril group and CHEMICAL group, the blood pressure was remarkably increased in SHR group. Ang II level in plasma and mesenteric arteries in SHR group was the same or lower than that in WKY group, and was higher in CHEMICAL group and lower in imidapril group. The remodeling of mesenteric arteries in SHR group was mostly obvious among the 4 groups. The ratio of TGF-beta1 absorbed light value to GAPDH absorbed light value in the SHR group was 0.887+/-0.019, which was significantly higher than that in WKY group, imidapril group, and CHEMICAL group with the ratios of 0.780+/-0.018, 0.803+/-0.005, and 0.847+/-0.017, respectively (P<0.01). Ang II level in plasma and mesenteric arteries in imidapril group was significantly lower than that in CHEMICAL group (P<0.05). The GENE absorbed light value/GAPDH absorbed light value of mesenteric arteries in the SHR group was 0.850+/-0.015, which was significantly higher than that in the WKY, imidapril, and CHEMICAL groups (0.582+/-0.013, 0.743+/-0.012, and 0.789+/-0.013, respectively, P<0.01), and was significantly lower in imidapril group than in CHEMICAL group (P<0.05). CONCLUSION: Imidapril and CHEMICAL can not only control blood pressure but also inhibit mesenteric arteries remodeling and mRNA expression of TGF-beta1, GENE in SHR. Imidapril is more effective than CHEMICAL. | GENE-CHEMICAL |
| Mesenteric artery remodeling and effects of imidapril and CHEMICAL on it in spontaneously hypertensive rats. AIM: To investigate the remodeling of mesenteric artery and the expression of TGF-beta1, c-Jun in mesenteric artery and effects of imidapril and CHEMICAL on the remodeling in spontaneously hypertensive rats (SHR). METHODS: Thirty SHR (male/female, 21/9), aged 13 wk, were randomly divided into 3 groups (7 male rats and 3 female rats each group): SHR group, imidapril group (imidapril 3 mg/kg.d was given in drinking water for 14 wk), and CHEMICAL group (irbesartan 50 mg/kg.d was given in drinking water foe 14 wk). Ten homogeneous Wistar Kyoto rats, 5 males and 5 females, weighing 206+/-49 g, were selected as normal control group (WKY group). Systolic pressure was measured on d 1, 2, 4, 6, 8, 10, 12 and 14 during the experiment and the rats were killed at the end of the experiment. Angiotensin II (Ang II) level in plasma and mesenteric arteries was measured by radioimmunoassay. The morphology of the secondary branches of mesenteric artery were examined by light microscopy and electron microscopy. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression of transforming growth factor TGF-beta1 and c-Jun mRNA. RESULTS: Compared with imidapril group and CHEMICAL group, the blood pressure was remarkably increased in SHR group. Ang II level in plasma and mesenteric arteries in SHR group was the same or lower than that in WKY group, and was higher in CHEMICAL group and lower in imidapril group. The remodeling of mesenteric arteries in SHR group was mostly obvious among the 4 groups. The ratio of TGF-beta1 absorbed light value to GENE absorbed light value in the SHR group was 0.887+/-0.019, which was significantly higher than that in WKY group, imidapril group, and CHEMICAL group with the ratios of 0.780+/-0.018, 0.803+/-0.005, and 0.847+/-0.017, respectively (P<0.01). Ang II level in plasma and mesenteric arteries in imidapril group was significantly lower than that in CHEMICAL group (P<0.05). The c-Jun absorbed light value/GENE absorbed light value of mesenteric arteries in the SHR group was 0.850+/-0.015, which was significantly higher than that in the WKY, imidapril, and CHEMICAL groups (0.582+/-0.013, 0.743+/-0.012, and 0.789+/-0.013, respectively, P<0.01), and was significantly lower in imidapril group than in CHEMICAL group (P<0.05). CONCLUSION: Imidapril and CHEMICAL can not only control blood pressure but also inhibit mesenteric arteries remodeling and mRNA expression of TGF-beta1, c-Jun in SHR. Imidapril is more effective than CHEMICAL. | GENE-CHEMICAL |
| Mesenteric artery remodeling and effects of CHEMICAL and irbesartan on it in spontaneously hypertensive rats. AIM: To investigate the remodeling of mesenteric artery and the expression of GENE, c-Jun in mesenteric artery and effects of CHEMICAL and irbesartan on the remodeling in spontaneously hypertensive rats (SHR). METHODS: Thirty SHR (male/female, 21/9), aged 13 wk, were randomly divided into 3 groups (7 male rats and 3 female rats each group): SHR group, CHEMICAL group (imidapril 3 mg/kg.d was given in drinking water for 14 wk), and irbesartan group (irbesartan 50 mg/kg.d was given in drinking water foe 14 wk). Ten homogeneous Wistar Kyoto rats, 5 males and 5 females, weighing 206+/-49 g, were selected as normal control group (WKY group). Systolic pressure was measured on d 1, 2, 4, 6, 8, 10, 12 and 14 during the experiment and the rats were killed at the end of the experiment. Angiotensin II (Ang II) level in plasma and mesenteric arteries was measured by radioimmunoassay. The morphology of the secondary branches of mesenteric artery were examined by light microscopy and electron microscopy. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression of transforming growth factor GENE and c-Jun mRNA. RESULTS: Compared with CHEMICAL group and irbesartan group, the blood pressure was remarkably increased in SHR group. Ang II level in plasma and mesenteric arteries in SHR group was the same or lower than that in WKY group, and was higher in irbesartan group and lower in CHEMICAL group. The remodeling of mesenteric arteries in SHR group was mostly obvious among the 4 groups. The ratio of GENE absorbed light value to GAPDH absorbed light value in the SHR group was 0.887+/-0.019, which was significantly higher than that in WKY group, CHEMICAL group, and irbesartan group with the ratios of 0.780+/-0.018, 0.803+/-0.005, and 0.847+/-0.017, respectively (P<0.01). Ang II level in plasma and mesenteric arteries in CHEMICAL group was significantly lower than that in irbesartan group (P<0.05). The c-Jun absorbed light value/GAPDH absorbed light value of mesenteric arteries in the SHR group was 0.850+/-0.015, which was significantly higher than that in the WKY, CHEMICAL, and irbesartan groups (0.582+/-0.013, 0.743+/-0.012, and 0.789+/-0.013, respectively, P<0.01), and was significantly lower in CHEMICAL group than in irbesartan group (P<0.05). CONCLUSION: CHEMICAL and irbesartan can not only control blood pressure but also inhibit mesenteric arteries remodeling and mRNA expression of GENE, c-Jun in SHR. CHEMICAL is more effective than irbesartan. | GENE-CHEMICAL |
| Mesenteric artery remodeling and effects of imidapril and CHEMICAL on it in spontaneously hypertensive rats. AIM: To investigate the remodeling of mesenteric artery and the expression of GENE, c-Jun in mesenteric artery and effects of imidapril and CHEMICAL on the remodeling in spontaneously hypertensive rats (SHR). METHODS: Thirty SHR (male/female, 21/9), aged 13 wk, were randomly divided into 3 groups (7 male rats and 3 female rats each group): SHR group, imidapril group (imidapril 3 mg/kg.d was given in drinking water for 14 wk), and CHEMICAL group (irbesartan 50 mg/kg.d was given in drinking water foe 14 wk). Ten homogeneous Wistar Kyoto rats, 5 males and 5 females, weighing 206+/-49 g, were selected as normal control group (WKY group). Systolic pressure was measured on d 1, 2, 4, 6, 8, 10, 12 and 14 during the experiment and the rats were killed at the end of the experiment. Angiotensin II (Ang II) level in plasma and mesenteric arteries was measured by radioimmunoassay. The morphology of the secondary branches of mesenteric artery were examined by light microscopy and electron microscopy. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression of transforming growth factor GENE and c-Jun mRNA. RESULTS: Compared with imidapril group and CHEMICAL group, the blood pressure was remarkably increased in SHR group. Ang II level in plasma and mesenteric arteries in SHR group was the same or lower than that in WKY group, and was higher in CHEMICAL group and lower in imidapril group. The remodeling of mesenteric arteries in SHR group was mostly obvious among the 4 groups. The ratio of GENE absorbed light value to GAPDH absorbed light value in the SHR group was 0.887+/-0.019, which was significantly higher than that in WKY group, imidapril group, and CHEMICAL group with the ratios of 0.780+/-0.018, 0.803+/-0.005, and 0.847+/-0.017, respectively (P<0.01). Ang II level in plasma and mesenteric arteries in imidapril group was significantly lower than that in CHEMICAL group (P<0.05). The c-Jun absorbed light value/GAPDH absorbed light value of mesenteric arteries in the SHR group was 0.850+/-0.015, which was significantly higher than that in the WKY, imidapril, and CHEMICAL groups (0.582+/-0.013, 0.743+/-0.012, and 0.789+/-0.013, respectively, P<0.01), and was significantly lower in imidapril group than in CHEMICAL group (P<0.05). CONCLUSION: Imidapril and CHEMICAL can not only control blood pressure but also inhibit mesenteric arteries remodeling and mRNA expression of GENE, c-Jun in SHR. Imidapril is more effective than CHEMICAL. | GENE-CHEMICAL |
| Mesenteric artery remodeling and effects of CHEMICAL and irbesartan on it in spontaneously hypertensive rats. AIM: To investigate the remodeling of mesenteric artery and the expression of TGF-beta1, c-Jun in mesenteric artery and effects of CHEMICAL and irbesartan on the remodeling in spontaneously hypertensive rats (SHR). METHODS: Thirty SHR (male/female, 21/9), aged 13 wk, were randomly divided into 3 groups (7 male rats and 3 female rats each group): SHR group, CHEMICAL group (imidapril 3 mg/kg.d was given in drinking water for 14 wk), and irbesartan group (irbesartan 50 mg/kg.d was given in drinking water foe 14 wk). Ten homogeneous Wistar Kyoto rats, 5 males and 5 females, weighing 206+/-49 g, were selected as normal control group (WKY group). Systolic pressure was measured on d 1, 2, 4, 6, 8, 10, 12 and 14 during the experiment and the rats were killed at the end of the experiment. Angiotensin II (Ang II) level in plasma and mesenteric arteries was measured by radioimmunoassay. The morphology of the secondary branches of mesenteric artery were examined by light microscopy and electron microscopy. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression of transforming growth factor TGF-beta1 and c-Jun mRNA. RESULTS: Compared with CHEMICAL group and irbesartan group, the blood pressure was remarkably increased in SHR group. GENE level in plasma and mesenteric arteries in SHR group was the same or lower than that in WKY group, and was higher in irbesartan group and lower in CHEMICAL group. The remodeling of mesenteric arteries in SHR group was mostly obvious among the 4 groups. The ratio of TGF-beta1 absorbed light value to GAPDH absorbed light value in the SHR group was 0.887+/-0.019, which was significantly higher than that in WKY group, CHEMICAL group, and irbesartan group with the ratios of 0.780+/-0.018, 0.803+/-0.005, and 0.847+/-0.017, respectively (P<0.01). GENE level in plasma and mesenteric arteries in CHEMICAL group was significantly lower than that in irbesartan group (P<0.05). The c-Jun absorbed light value/GAPDH absorbed light value of mesenteric arteries in the SHR group was 0.850+/-0.015, which was significantly higher than that in the WKY, CHEMICAL, and irbesartan groups (0.582+/-0.013, 0.743+/-0.012, and 0.789+/-0.013, respectively, P<0.01), and was significantly lower in CHEMICAL group than in irbesartan group (P<0.05). CONCLUSION: CHEMICAL and irbesartan can not only control blood pressure but also inhibit mesenteric arteries remodeling and mRNA expression of TGF-beta1, c-Jun in SHR. CHEMICAL is more effective than irbesartan. | INDIRECT-DOWNREGULATOR |
| Mesenteric artery remodeling and effects of imidapril and irbesartan on it in spontaneously hypertensive rats. AIM: To investigate the remodeling of mesenteric artery and the expression of GENE, c-Jun in mesenteric artery and effects of imidapril and irbesartan on the remodeling in spontaneously hypertensive rats (SHR). METHODS: Thirty SHR (male/female, 21/9), aged 13 wk, were randomly divided into 3 groups (7 male rats and 3 female rats each group): SHR group, imidapril group (imidapril 3 mg/kg.d was given in drinking water for 14 wk), and irbesartan group (irbesartan 50 mg/kg.d was given in drinking water foe 14 wk). Ten homogeneous Wistar Kyoto rats, 5 males and 5 females, weighing 206+/-49 g, were selected as normal control group (WKY group). Systolic pressure was measured on d 1, 2, 4, 6, 8, 10, 12 and 14 during the experiment and the rats were killed at the end of the experiment. Angiotensin II (Ang II) level in plasma and mesenteric arteries was measured by radioimmunoassay. The morphology of the secondary branches of mesenteric artery were examined by light microscopy and electron microscopy. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression of transforming growth factor GENE and c-Jun mRNA. RESULTS: Compared with imidapril group and irbesartan group, the blood pressure was remarkably increased in SHR group. Ang II level in plasma and mesenteric arteries in SHR group was the same or lower than that in WKY group, and was higher in irbesartan group and lower in imidapril group. The remodeling of mesenteric arteries in SHR group was mostly obvious among the 4 groups. The ratio of GENE absorbed light value to GAPDH absorbed light value in the SHR group was 0.887+/-0.019, which was significantly higher than that in WKY group, imidapril group, and irbesartan group with the ratios of 0.780+/-0.018, 0.803+/-0.005, and 0.847+/-0.017, respectively (P<0.01). Ang II level in plasma and mesenteric arteries in imidapril group was significantly lower than that in irbesartan group (P<0.05). The c-Jun absorbed light value/GAPDH absorbed light value of mesenteric arteries in the SHR group was 0.850+/-0.015, which was significantly higher than that in the WKY, imidapril, and irbesartan groups (0.582+/-0.013, 0.743+/-0.012, and 0.789+/-0.013, respectively, P<0.01), and was significantly lower in imidapril group than in irbesartan group (P<0.05). CONCLUSION: CHEMICAL and irbesartan can not only control blood pressure but also inhibit mesenteric arteries remodeling and mRNA expression of GENE, c-Jun in SHR. CHEMICAL is more effective than irbesartan. | NO-RELATIONSHIP |
| Mesenteric artery remodeling and effects of imidapril and irbesartan on it in spontaneously hypertensive rats. AIM: To investigate the remodeling of mesenteric artery and the expression of TGF-beta1, GENE in mesenteric artery and effects of imidapril and irbesartan on the remodeling in spontaneously hypertensive rats (SHR). METHODS: Thirty SHR (male/female, 21/9), aged 13 wk, were randomly divided into 3 groups (7 male rats and 3 female rats each group): SHR group, imidapril group (imidapril 3 mg/kg.d was given in drinking water for 14 wk), and irbesartan group (irbesartan 50 mg/kg.d was given in drinking water foe 14 wk). Ten homogeneous Wistar Kyoto rats, 5 males and 5 females, weighing 206+/-49 g, were selected as normal control group (WKY group). Systolic pressure was measured on d 1, 2, 4, 6, 8, 10, 12 and 14 during the experiment and the rats were killed at the end of the experiment. Angiotensin II (Ang II) level in plasma and mesenteric arteries was measured by radioimmunoassay. The morphology of the secondary branches of mesenteric artery were examined by light microscopy and electron microscopy. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression of transforming growth factor TGF-beta1 and GENE mRNA. RESULTS: Compared with imidapril group and irbesartan group, the blood pressure was remarkably increased in SHR group. Ang II level in plasma and mesenteric arteries in SHR group was the same or lower than that in WKY group, and was higher in irbesartan group and lower in imidapril group. The remodeling of mesenteric arteries in SHR group was mostly obvious among the 4 groups. The ratio of TGF-beta1 absorbed light value to GAPDH absorbed light value in the SHR group was 0.887+/-0.019, which was significantly higher than that in WKY group, imidapril group, and irbesartan group with the ratios of 0.780+/-0.018, 0.803+/-0.005, and 0.847+/-0.017, respectively (P<0.01). Ang II level in plasma and mesenteric arteries in imidapril group was significantly lower than that in irbesartan group (P<0.05). The GENE absorbed light value/GAPDH absorbed light value of mesenteric arteries in the SHR group was 0.850+/-0.015, which was significantly higher than that in the WKY, imidapril, and irbesartan groups (0.582+/-0.013, 0.743+/-0.012, and 0.789+/-0.013, respectively, P<0.01), and was significantly lower in imidapril group than in irbesartan group (P<0.05). CONCLUSION: CHEMICAL and irbesartan can not only control blood pressure but also inhibit mesenteric arteries remodeling and mRNA expression of TGF-beta1, GENE in SHR. CHEMICAL is more effective than irbesartan. | NO-RELATIONSHIP |
| Clinical assessment of norepinephrine transporter blockade through biochemical and pharmacological profiles. BACKGROUND: To assess the sensitivity of biochemical, physiological, and pharmacological markers of peripheral norepinephrine (NE) transporter (NET) function, we chronically antagonized NET by a range of doses of CHEMICAL [(+)-N-methyl-3-(1-naphthalenyloxy)-2 thiophenepropanamine], which blocks the NE reuptake process. METHODS AND RESULTS: CHEMICAL was administered in a randomized, placebo-controlled study in 15 healthy volunteers. Plasma from CHEMICAL-treated subjects (ex vivo effect) dose-dependently decreased radioligand binding to GENE (maximum inhibition was 60%) (P=0.02). The dose of intravenous tyramine required to raise systolic blood pressure by 30 mm Hg (PD30) increased dose-dependently with CHEMICAL and was significant at the end of the 120-mg/d dosage (P<0.001). The plasma dihydoxyphenylglycol to NE (DHPG/NE) ratio was reduced significantly at 2 weeks of treatment with 80 mg/d CHEMICAL (11.3 at baseline, 3.4 at 240 mg/d, P<0.001). Plasma NE was significantly increased starting at 120 mg/d CHEMICAL. Urine results (corrected for 24-hour creatinine excretion) showed a dose-dependent change from the baseline urinary excretion for NE, DHPG, and the DHPG/NE ratio. The most sensitive measure, the DHPG/NE ratio, was significant at the 80-mg dose. Urinary NE excretion was significantly raised after 2 weeks of treatment with 80 mg/d CHEMICAL (P<0.001), the lowest dose used in the study. CONCLUSIONS: These findings suggest that the degree of NET blockade can be assessed with the plasma or urine DHPG/NE ratio and the pressor effect of tyramine. Also, the DHPG/NE ratio is more sensitive at the lower end of NET inhibition, whereas tyramine exhibits a linear relation, with NET inhibition commencing at a higher dose. | INHIBITOR |
| Clinical assessment of norepinephrine transporter blockade through biochemical and pharmacological profiles. BACKGROUND: To assess the sensitivity of biochemical, physiological, and pharmacological markers of peripheral norepinephrine (NE) transporter (NET) function, we chronically antagonized GENE by a range of doses of CHEMICAL [(+)-N-methyl-3-(1-naphthalenyloxy)-2 thiophenepropanamine], which blocks the NE reuptake process. METHODS AND RESULTS: CHEMICAL was administered in a randomized, placebo-controlled study in 15 healthy volunteers. Plasma from duloxetine-treated subjects (ex vivo effect) dose-dependently decreased radioligand binding to human GENE (maximum inhibition was 60%) (P=0.02). The dose of intravenous tyramine required to raise systolic blood pressure by 30 mm Hg (PD30) increased dose-dependently with CHEMICAL and was significant at the end of the 120-mg/d dosage (P<0.001). The plasma dihydoxyphenylglycol to NE (DHPG/NE) ratio was reduced significantly at 2 weeks of treatment with 80 mg/d CHEMICAL (11.3 at baseline, 3.4 at 240 mg/d, P<0.001). Plasma NE was significantly increased starting at 120 mg/d CHEMICAL. Urine results (corrected for 24-hour creatinine excretion) showed a dose-dependent change from the baseline urinary excretion for NE, DHPG, and the DHPG/NE ratio. The most sensitive measure, the DHPG/NE ratio, was significant at the 80-mg dose. Urinary NE excretion was significantly raised after 2 weeks of treatment with 80 mg/d CHEMICAL (P<0.001), the lowest dose used in the study. CONCLUSIONS: These findings suggest that the degree of GENE blockade can be assessed with the plasma or urine DHPG/NE ratio and the pressor effect of tyramine. Also, the DHPG/NE ratio is more sensitive at the lower end of GENE inhibition, whereas tyramine exhibits a linear relation, with GENE inhibition commencing at a higher dose. | INHIBITOR |
| Clinical assessment of norepinephrine transporter blockade through biochemical and pharmacological profiles. BACKGROUND: To assess the sensitivity of biochemical, physiological, and pharmacological markers of peripheral norepinephrine (NE) transporter (NET) function, we chronically antagonized GENE by a range of doses of duloxetine [CHEMICAL], which blocks the NE reuptake process. METHODS AND RESULTS: Duloxetine was administered in a randomized, placebo-controlled study in 15 healthy volunteers. Plasma from duloxetine-treated subjects (ex vivo effect) dose-dependently decreased radioligand binding to human GENE (maximum inhibition was 60%) (P=0.02). The dose of intravenous tyramine required to raise systolic blood pressure by 30 mm Hg (PD30) increased dose-dependently with duloxetine and was significant at the end of the 120-mg/d dosage (P<0.001). The plasma dihydoxyphenylglycol to NE (DHPG/NE) ratio was reduced significantly at 2 weeks of treatment with 80 mg/d duloxetine (11.3 at baseline, 3.4 at 240 mg/d, P<0.001). Plasma NE was significantly increased starting at 120 mg/d duloxetine. Urine results (corrected for 24-hour creatinine excretion) showed a dose-dependent change from the baseline urinary excretion for NE, DHPG, and the DHPG/NE ratio. The most sensitive measure, the DHPG/NE ratio, was significant at the 80-mg dose. Urinary NE excretion was significantly raised after 2 weeks of treatment with 80 mg/d duloxetine (P<0.001), the lowest dose used in the study. CONCLUSIONS: These findings suggest that the degree of GENE blockade can be assessed with the plasma or urine DHPG/NE ratio and the pressor effect of tyramine. Also, the DHPG/NE ratio is more sensitive at the lower end of GENE inhibition, whereas tyramine exhibits a linear relation, with GENE inhibition commencing at a higher dose. | INHIBITOR |
| Clinical assessment of norepinephrine transporter blockade through biochemical and pharmacological profiles. BACKGROUND: To assess the sensitivity of biochemical, physiological, and pharmacological markers of peripheral norepinephrine (NE) transporter (NET) function, we chronically antagonized GENE by a range of doses of duloxetine [(+)-N-methyl-3-(1-naphthalenyloxy)-2 thiophenepropanamine], which blocks the CHEMICAL reuptake process. METHODS AND RESULTS: Duloxetine was administered in a randomized, placebo-controlled study in 15 healthy volunteers. Plasma from duloxetine-treated subjects (ex vivo effect) dose-dependently decreased radioligand binding to human GENE (maximum inhibition was 60%) (P=0.02). The dose of intravenous tyramine required to raise systolic blood pressure by 30 mm Hg (PD30) increased dose-dependently with duloxetine and was significant at the end of the 120-mg/d dosage (P<0.001). The plasma dihydoxyphenylglycol to CHEMICAL (DHPG/NE) ratio was reduced significantly at 2 weeks of treatment with 80 mg/d duloxetine (11.3 at baseline, 3.4 at 240 mg/d, P<0.001). Plasma CHEMICAL was significantly increased starting at 120 mg/d duloxetine. Urine results (corrected for 24-hour creatinine excretion) showed a dose-dependent change from the baseline urinary excretion for CHEMICAL, DHPG, and the DHPG/NE ratio. The most sensitive measure, the DHPG/NE ratio, was significant at the 80-mg dose. Urinary CHEMICAL excretion was significantly raised after 2 weeks of treatment with 80 mg/d duloxetine (P<0.001), the lowest dose used in the study. CONCLUSIONS: These findings suggest that the degree of GENE blockade can be assessed with the plasma or urine DHPG/NE ratio and the pressor effect of tyramine. Also, the DHPG/NE ratio is more sensitive at the lower end of GENE inhibition, whereas tyramine exhibits a linear relation, with GENE inhibition commencing at a higher dose. | PRODUCT-OF |
| CHEMICAL increases apoptosis and ischaemia-reperfusion injury in the rat isolated heart. CHEMICAL, an antirheumatic gold compound, is an inhibitor of selenocysteine enzymes, such as thioredoxin reductase and GENE. These enzymes play an important role in protecting cardiac tissue from oxidative stress generated during ischaemia-reperfusion. CHEMICAL (100 mg/kg) was administered to rats and their hearts were subjected to an in vitro model of ischaemia-reperfusion. The activity of thioredoxin reductase and GENE was determined in liver and heart tissues in an attempt to correlate enzymatic activity with heart recovery after ischaemia-reperfusion. There was significantly less thioredoxin reductase activity in rat liver extracts, whereas the level of glutathione activity remained unchanged, demonstrating that the dose of auranofin used was able to selectively inhibit one of these enzyme systems. Rats administered auranofin displayed significantly impaired recovery from ischaemic insult. The end diastolic pressure was increased, whereas the rate pressure product was significantly decreased. The level of postischaemic apoptosis was also assessed by examining caspase-3 activity in tissue homogenates. CHEMICAL significantly increased the degree of postischaemic apoptosis, leading to poor postischaemic recovery. | INHIBITOR |
| CHEMICAL increases apoptosis and ischaemia-reperfusion injury in the rat isolated heart. CHEMICAL, an antirheumatic gold compound, is an inhibitor of GENE, such as thioredoxin reductase and glutathione peroxidase. These enzymes play an important role in protecting cardiac tissue from oxidative stress generated during ischaemia-reperfusion. CHEMICAL (100 mg/kg) was administered to rats and their hearts were subjected to an in vitro model of ischaemia-reperfusion. The activity of thioredoxin reductase and glutathione peroxidase was determined in liver and heart tissues in an attempt to correlate enzymatic activity with heart recovery after ischaemia-reperfusion. There was significantly less thioredoxin reductase activity in rat liver extracts, whereas the level of glutathione activity remained unchanged, demonstrating that the dose of auranofin used was able to selectively inhibit one of these enzyme systems. Rats administered auranofin displayed significantly impaired recovery from ischaemic insult. The end diastolic pressure was increased, whereas the rate pressure product was significantly decreased. The level of postischaemic apoptosis was also assessed by examining caspase-3 activity in tissue homogenates. CHEMICAL significantly increased the degree of postischaemic apoptosis, leading to poor postischaemic recovery. | INHIBITOR |
| CHEMICAL increases apoptosis and ischaemia-reperfusion injury in the rat isolated heart. CHEMICAL, an antirheumatic gold compound, is an inhibitor of selenocysteine enzymes, such as GENE and glutathione peroxidase. These enzymes play an important role in protecting cardiac tissue from oxidative stress generated during ischaemia-reperfusion. CHEMICAL (100 mg/kg) was administered to rats and their hearts were subjected to an in vitro model of ischaemia-reperfusion. The activity of GENE and glutathione peroxidase was determined in liver and heart tissues in an attempt to correlate enzymatic activity with heart recovery after ischaemia-reperfusion. There was significantly less GENE activity in rat liver extracts, whereas the level of glutathione activity remained unchanged, demonstrating that the dose of auranofin used was able to selectively inhibit one of these enzyme systems. Rats administered auranofin displayed significantly impaired recovery from ischaemic insult. The end diastolic pressure was increased, whereas the rate pressure product was significantly decreased. The level of postischaemic apoptosis was also assessed by examining caspase-3 activity in tissue homogenates. CHEMICAL significantly increased the degree of postischaemic apoptosis, leading to poor postischaemic recovery. | INHIBITOR |
| CHEMICAL and other main group metal compounds as antitumor agents. CHEMICAL has been the second metal to show activity against malignant tumors in humans soon after the establishment of platinum drugs in routine clinical practice. It has the unique property of inhibiting tumor growth as a simple cation, mainly because of its close resemblance to ferric iron. Even though its inability to shift between the trivalent and a divalent oxidation state precludes that CHEMICAL behaves as an iron analogue in every respect, it strongly interferes with cellular acquisition of iron from blood by competitive interaction with GENE and GENE receptor-mediated endocytosis. Furthermore, CHEMICAL also seems to affect intracellular availability of iron already taken up via this pathway, probably due to its inhibitory activity on vacuolar-type H(+)-ATPases. Apart from the consequences of iron deprivation, CHEMICAL exerts cytotoxic effects by direct interaction with the iron-dependent enzyme ribonucleotide reductase, resulting in reduced dNTP pools and inhibition of DNA synthesis. Both the abundance of GENE receptors and upregulation of ribonucleotide reductase render tumors susceptible to gallium-induced cytotoxicity. However, some experimental findings raise the question whether these effects resulting from the iron-mimicking properties of CHEMICAL are solely responsible for its antineoplastic activity or whether additional mechanisms are involved, such as antimitotic effects which result from its capability of inhibiting tubulin polymerization. The limitations experienced with CHEMICAL nitrate and CHEMICAL chloride, which call for a prolonged exposure to low steady-state CHEMICAL levels in blood in order to adequately exploit the affinity of CHEMICAL to tumor tissues and to avoid severe toxic effects, may be overcome by oral CHEMICAL complexes such as tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III) (gallium maltolate) or tris(8-quinolinolato)gallium(III) (KP46), which are currently being evaluated in clinical trials and show promise to initiate a revival of CHEMICAL in the clinical setting. These two investigational drugs, albeit differing in their complex stability, have both been developed with the intention of providing CHEMICAL in a form which allows sufficient intestinal absorption, but without altering its pharmacodynamic effects. CHEMICAL complexes based on other rationales are scarce and, with regard to the well-known antineoplastic potential of this metal, noticeably under-explored. With the recent approval of arsenic trioxide for the second-line treatment of acute promyelocytic leukemia, the clinical revival of arsenic compounds, which have been the mainstay of antileukemic therapy before the age of modern cancer chemotherapy, has already begun. Currently, strong efforts are being made to explore the activity spectrum in other (less rare) malignancies and to gain a deeper insight into the mode of action. Although this development is currently focusing on arsenic trioxide, it should be suited to stimulate investigations into the therapeutic potential of other arsenic compounds as well. | DIRECT-REGULATOR |
| CHEMICAL and other main group metal compounds as antitumor agents. CHEMICAL has been the second metal to show activity against malignant tumors in humans soon after the establishment of platinum drugs in routine clinical practice. It has the unique property of inhibiting tumor growth as a simple cation, mainly because of its close resemblance to ferric iron. Even though its inability to shift between the trivalent and a divalent oxidation state precludes that CHEMICAL behaves as an iron analogue in every respect, it strongly interferes with cellular acquisition of iron from blood by competitive interaction with transferrin and GENE-mediated endocytosis. Furthermore, CHEMICAL also seems to affect intracellular availability of iron already taken up via this pathway, probably due to its inhibitory activity on vacuolar-type H(+)-ATPases. Apart from the consequences of iron deprivation, CHEMICAL exerts cytotoxic effects by direct interaction with the iron-dependent enzyme ribonucleotide reductase, resulting in reduced dNTP pools and inhibition of DNA synthesis. Both the abundance of transferrin receptors and upregulation of ribonucleotide reductase render tumors susceptible to gallium-induced cytotoxicity. However, some experimental findings raise the question whether these effects resulting from the iron-mimicking properties of CHEMICAL are solely responsible for its antineoplastic activity or whether additional mechanisms are involved, such as antimitotic effects which result from its capability of inhibiting tubulin polymerization. The limitations experienced with CHEMICAL nitrate and CHEMICAL chloride, which call for a prolonged exposure to low steady-state CHEMICAL levels in blood in order to adequately exploit the affinity of CHEMICAL to tumor tissues and to avoid severe toxic effects, may be overcome by oral CHEMICAL complexes such as tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III) (gallium maltolate) or tris(8-quinolinolato)gallium(III) (KP46), which are currently being evaluated in clinical trials and show promise to initiate a revival of CHEMICAL in the clinical setting. These two investigational drugs, albeit differing in their complex stability, have both been developed with the intention of providing CHEMICAL in a form which allows sufficient intestinal absorption, but without altering its pharmacodynamic effects. CHEMICAL complexes based on other rationales are scarce and, with regard to the well-known antineoplastic potential of this metal, noticeably under-explored. With the recent approval of arsenic trioxide for the second-line treatment of acute promyelocytic leukemia, the clinical revival of arsenic compounds, which have been the mainstay of antileukemic therapy before the age of modern cancer chemotherapy, has already begun. Currently, strong efforts are being made to explore the activity spectrum in other (less rare) malignancies and to gain a deeper insight into the mode of action. Although this development is currently focusing on arsenic trioxide, it should be suited to stimulate investigations into the therapeutic potential of other arsenic compounds as well. | DIRECT-REGULATOR |
| Gallium and other main group metal compounds as antitumor agents. Gallium has been the second metal to show activity against malignant tumors in humans soon after the establishment of platinum drugs in routine clinical practice. It has the unique property of inhibiting tumor growth as a simple cation, mainly because of its close resemblance to ferric CHEMICAL. Even though its inability to shift between the trivalent and a divalent oxidation state precludes that gallium behaves as an CHEMICAL analogue in every respect, it strongly interferes with cellular acquisition of CHEMICAL from blood by competitive interaction with GENE and GENE receptor-mediated endocytosis. Furthermore, gallium also seems to affect intracellular availability of CHEMICAL already taken up via this pathway, probably due to its inhibitory activity on vacuolar-type H(+)-ATPases. Apart from the consequences of CHEMICAL deprivation, gallium exerts cytotoxic effects by direct interaction with the iron-dependent enzyme ribonucleotide reductase, resulting in reduced dNTP pools and inhibition of DNA synthesis. Both the abundance of GENE receptors and upregulation of ribonucleotide reductase render tumors susceptible to gallium-induced cytotoxicity. However, some experimental findings raise the question whether these effects resulting from the iron-mimicking properties of gallium are solely responsible for its antineoplastic activity or whether additional mechanisms are involved, such as antimitotic effects which result from its capability of inhibiting tubulin polymerization. The limitations experienced with gallium nitrate and gallium chloride, which call for a prolonged exposure to low steady-state gallium levels in blood in order to adequately exploit the affinity of gallium to tumor tissues and to avoid severe toxic effects, may be overcome by oral gallium complexes such as tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III) (gallium maltolate) or tris(8-quinolinolato)gallium(III) (KP46), which are currently being evaluated in clinical trials and show promise to initiate a revival of gallium in the clinical setting. These two investigational drugs, albeit differing in their complex stability, have both been developed with the intention of providing gallium in a form which allows sufficient intestinal absorption, but without altering its pharmacodynamic effects. Gallium complexes based on other rationales are scarce and, with regard to the well-known antineoplastic potential of this metal, noticeably under-explored. With the recent approval of arsenic trioxide for the second-line treatment of acute promyelocytic leukemia, the clinical revival of arsenic compounds, which have been the mainstay of antileukemic therapy before the age of modern cancer chemotherapy, has already begun. Currently, strong efforts are being made to explore the activity spectrum in other (less rare) malignancies and to gain a deeper insight into the mode of action. Although this development is currently focusing on arsenic trioxide, it should be suited to stimulate investigations into the therapeutic potential of other arsenic compounds as well. | REGULATOR |
| Gallium and other main group metal compounds as antitumor agents. Gallium has been the second metal to show activity against malignant tumors in humans soon after the establishment of platinum drugs in routine clinical practice. It has the unique property of inhibiting tumor growth as a simple cation, mainly because of its close resemblance to ferric CHEMICAL. Even though its inability to shift between the trivalent and a divalent oxidation state precludes that gallium behaves as an CHEMICAL analogue in every respect, it strongly interferes with cellular acquisition of CHEMICAL from blood by competitive interaction with transferrin and GENE-mediated endocytosis. Furthermore, gallium also seems to affect intracellular availability of CHEMICAL already taken up via this pathway, probably due to its inhibitory activity on vacuolar-type H(+)-ATPases. Apart from the consequences of CHEMICAL deprivation, gallium exerts cytotoxic effects by direct interaction with the iron-dependent enzyme ribonucleotide reductase, resulting in reduced dNTP pools and inhibition of DNA synthesis. Both the abundance of transferrin receptors and upregulation of ribonucleotide reductase render tumors susceptible to gallium-induced cytotoxicity. However, some experimental findings raise the question whether these effects resulting from the iron-mimicking properties of gallium are solely responsible for its antineoplastic activity or whether additional mechanisms are involved, such as antimitotic effects which result from its capability of inhibiting tubulin polymerization. The limitations experienced with gallium nitrate and gallium chloride, which call for a prolonged exposure to low steady-state gallium levels in blood in order to adequately exploit the affinity of gallium to tumor tissues and to avoid severe toxic effects, may be overcome by oral gallium complexes such as tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III) (gallium maltolate) or tris(8-quinolinolato)gallium(III) (KP46), which are currently being evaluated in clinical trials and show promise to initiate a revival of gallium in the clinical setting. These two investigational drugs, albeit differing in their complex stability, have both been developed with the intention of providing gallium in a form which allows sufficient intestinal absorption, but without altering its pharmacodynamic effects. Gallium complexes based on other rationales are scarce and, with regard to the well-known antineoplastic potential of this metal, noticeably under-explored. With the recent approval of arsenic trioxide for the second-line treatment of acute promyelocytic leukemia, the clinical revival of arsenic compounds, which have been the mainstay of antileukemic therapy before the age of modern cancer chemotherapy, has already begun. Currently, strong efforts are being made to explore the activity spectrum in other (less rare) malignancies and to gain a deeper insight into the mode of action. Although this development is currently focusing on arsenic trioxide, it should be suited to stimulate investigations into the therapeutic potential of other arsenic compounds as well. | SUBSTRATE |
| CHEMICAL and other main group metal compounds as antitumor agents. CHEMICAL has been the second metal to show activity against malignant tumors in humans soon after the establishment of platinum drugs in routine clinical practice. It has the unique property of inhibiting tumor growth as a simple cation, mainly because of its close resemblance to ferric iron. Even though its inability to shift between the trivalent and a divalent oxidation state precludes that CHEMICAL behaves as an iron analogue in every respect, it strongly interferes with cellular acquisition of iron from blood by competitive interaction with transferrin and transferrin receptor-mediated endocytosis. Furthermore, CHEMICAL also seems to affect intracellular availability of iron already taken up via this pathway, probably due to its inhibitory activity on vacuolar-type H(+)-ATPases. Apart from the consequences of iron deprivation, CHEMICAL exerts cytotoxic effects by direct interaction with the iron-dependent enzyme GENE, resulting in reduced dNTP pools and inhibition of DNA synthesis. Both the abundance of transferrin receptors and upregulation of GENE render tumors susceptible to gallium-induced cytotoxicity. However, some experimental findings raise the question whether these effects resulting from the iron-mimicking properties of CHEMICAL are solely responsible for its antineoplastic activity or whether additional mechanisms are involved, such as antimitotic effects which result from its capability of inhibiting tubulin polymerization. The limitations experienced with CHEMICAL nitrate and CHEMICAL chloride, which call for a prolonged exposure to low steady-state CHEMICAL levels in blood in order to adequately exploit the affinity of CHEMICAL to tumor tissues and to avoid severe toxic effects, may be overcome by oral CHEMICAL complexes such as tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III) (gallium maltolate) or tris(8-quinolinolato)gallium(III) (KP46), which are currently being evaluated in clinical trials and show promise to initiate a revival of CHEMICAL in the clinical setting. These two investigational drugs, albeit differing in their complex stability, have both been developed with the intention of providing CHEMICAL in a form which allows sufficient intestinal absorption, but without altering its pharmacodynamic effects. CHEMICAL complexes based on other rationales are scarce and, with regard to the well-known antineoplastic potential of this metal, noticeably under-explored. With the recent approval of arsenic trioxide for the second-line treatment of acute promyelocytic leukemia, the clinical revival of arsenic compounds, which have been the mainstay of antileukemic therapy before the age of modern cancer chemotherapy, has already begun. Currently, strong efforts are being made to explore the activity spectrum in other (less rare) malignancies and to gain a deeper insight into the mode of action. Although this development is currently focusing on arsenic trioxide, it should be suited to stimulate investigations into the therapeutic potential of other arsenic compounds as well. | DIRECT-REGULATOR |
| Gallium and other main group metal compounds as antitumor agents. Gallium has been the second metal to show activity against malignant tumors in humans soon after the establishment of platinum drugs in routine clinical practice. It has the unique property of inhibiting tumor growth as a simple cation, mainly because of its close resemblance to ferric CHEMICAL. Even though its inability to shift between the trivalent and a divalent oxidation state precludes that gallium behaves as an CHEMICAL analogue in every respect, it strongly interferes with cellular acquisition of CHEMICAL from blood by competitive interaction with transferrin and transferrin receptor-mediated endocytosis. Furthermore, gallium also seems to affect intracellular availability of CHEMICAL already taken up via this pathway, probably due to its inhibitory activity on vacuolar-type H(+)-ATPases. Apart from the consequences of CHEMICAL deprivation, gallium exerts cytotoxic effects by direct interaction with the CHEMICAL-dependent enzyme GENE, resulting in reduced dNTP pools and inhibition of DNA synthesis. Both the abundance of transferrin receptors and upregulation of GENE render tumors susceptible to gallium-induced cytotoxicity. However, some experimental findings raise the question whether these effects resulting from the iron-mimicking properties of gallium are solely responsible for its antineoplastic activity or whether additional mechanisms are involved, such as antimitotic effects which result from its capability of inhibiting tubulin polymerization. The limitations experienced with gallium nitrate and gallium chloride, which call for a prolonged exposure to low steady-state gallium levels in blood in order to adequately exploit the affinity of gallium to tumor tissues and to avoid severe toxic effects, may be overcome by oral gallium complexes such as tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III) (gallium maltolate) or tris(8-quinolinolato)gallium(III) (KP46), which are currently being evaluated in clinical trials and show promise to initiate a revival of gallium in the clinical setting. These two investigational drugs, albeit differing in their complex stability, have both been developed with the intention of providing gallium in a form which allows sufficient intestinal absorption, but without altering its pharmacodynamic effects. Gallium complexes based on other rationales are scarce and, with regard to the well-known antineoplastic potential of this metal, noticeably under-explored. With the recent approval of arsenic trioxide for the second-line treatment of acute promyelocytic leukemia, the clinical revival of arsenic compounds, which have been the mainstay of antileukemic therapy before the age of modern cancer chemotherapy, has already begun. Currently, strong efforts are being made to explore the activity spectrum in other (less rare) malignancies and to gain a deeper insight into the mode of action. Although this development is currently focusing on arsenic trioxide, it should be suited to stimulate investigations into the therapeutic potential of other arsenic compounds as well. | REGULATOR |
| CHEMICAL and other main group metal compounds as antitumor agents. CHEMICAL has been the second metal to show activity against malignant tumors in humans soon after the establishment of platinum drugs in routine clinical practice. It has the unique property of inhibiting tumor growth as a simple cation, mainly because of its close resemblance to ferric iron. Even though its inability to shift between the trivalent and a divalent oxidation state precludes that CHEMICAL behaves as an iron analogue in every respect, it strongly interferes with cellular acquisition of iron from blood by competitive interaction with transferrin and transferrin receptor-mediated endocytosis. Furthermore, CHEMICAL also seems to affect intracellular availability of iron already taken up via this pathway, probably due to its inhibitory activity on vacuolar-type H(+)-ATPases. Apart from the consequences of iron deprivation, CHEMICAL exerts cytotoxic effects by direct interaction with the iron-dependent enzyme ribonucleotide reductase, resulting in reduced dNTP pools and inhibition of DNA synthesis. Both the abundance of GENE and upregulation of ribonucleotide reductase render tumors susceptible to CHEMICAL-induced cytotoxicity. However, some experimental findings raise the question whether these effects resulting from the iron-mimicking properties of CHEMICAL are solely responsible for its antineoplastic activity or whether additional mechanisms are involved, such as antimitotic effects which result from its capability of inhibiting tubulin polymerization. The limitations experienced with CHEMICAL nitrate and CHEMICAL chloride, which call for a prolonged exposure to low steady-state CHEMICAL levels in blood in order to adequately exploit the affinity of CHEMICAL to tumor tissues and to avoid severe toxic effects, may be overcome by oral CHEMICAL complexes such as tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III) (gallium maltolate) or tris(8-quinolinolato)gallium(III) (KP46), which are currently being evaluated in clinical trials and show promise to initiate a revival of CHEMICAL in the clinical setting. These two investigational drugs, albeit differing in their complex stability, have both been developed with the intention of providing CHEMICAL in a form which allows sufficient intestinal absorption, but without altering its pharmacodynamic effects. CHEMICAL complexes based on other rationales are scarce and, with regard to the well-known antineoplastic potential of this metal, noticeably under-explored. With the recent approval of arsenic trioxide for the second-line treatment of acute promyelocytic leukemia, the clinical revival of arsenic compounds, which have been the mainstay of antileukemic therapy before the age of modern cancer chemotherapy, has already begun. Currently, strong efforts are being made to explore the activity spectrum in other (less rare) malignancies and to gain a deeper insight into the mode of action. Although this development is currently focusing on arsenic trioxide, it should be suited to stimulate investigations into the therapeutic potential of other arsenic compounds as well. | DIRECT-REGULATOR |
| CHEMICAL and other main group metal compounds as antitumor agents. CHEMICAL has been the second metal to show activity against malignant tumors in humans soon after the establishment of platinum drugs in routine clinical practice. It has the unique property of inhibiting tumor growth as a simple cation, mainly because of its close resemblance to ferric iron. Even though its inability to shift between the trivalent and a divalent oxidation state precludes that CHEMICAL behaves as an iron analogue in every respect, it strongly interferes with cellular acquisition of iron from blood by competitive interaction with transferrin and transferrin receptor-mediated endocytosis. Furthermore, CHEMICAL also seems to affect intracellular availability of iron already taken up via this pathway, probably due to its inhibitory activity on GENE. Apart from the consequences of iron deprivation, CHEMICAL exerts cytotoxic effects by direct interaction with the iron-dependent enzyme ribonucleotide reductase, resulting in reduced dNTP pools and inhibition of DNA synthesis. Both the abundance of transferrin receptors and upregulation of ribonucleotide reductase render tumors susceptible to gallium-induced cytotoxicity. However, some experimental findings raise the question whether these effects resulting from the iron-mimicking properties of CHEMICAL are solely responsible for its antineoplastic activity or whether additional mechanisms are involved, such as antimitotic effects which result from its capability of inhibiting tubulin polymerization. The limitations experienced with CHEMICAL nitrate and CHEMICAL chloride, which call for a prolonged exposure to low steady-state CHEMICAL levels in blood in order to adequately exploit the affinity of CHEMICAL to tumor tissues and to avoid severe toxic effects, may be overcome by oral CHEMICAL complexes such as tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III) (gallium maltolate) or tris(8-quinolinolato)gallium(III) (KP46), which are currently being evaluated in clinical trials and show promise to initiate a revival of CHEMICAL in the clinical setting. These two investigational drugs, albeit differing in their complex stability, have both been developed with the intention of providing CHEMICAL in a form which allows sufficient intestinal absorption, but without altering its pharmacodynamic effects. CHEMICAL complexes based on other rationales are scarce and, with regard to the well-known antineoplastic potential of this metal, noticeably under-explored. With the recent approval of arsenic trioxide for the second-line treatment of acute promyelocytic leukemia, the clinical revival of arsenic compounds, which have been the mainstay of antileukemic therapy before the age of modern cancer chemotherapy, has already begun. Currently, strong efforts are being made to explore the activity spectrum in other (less rare) malignancies and to gain a deeper insight into the mode of action. Although this development is currently focusing on arsenic trioxide, it should be suited to stimulate investigations into the therapeutic potential of other arsenic compounds as well. | INHIBITOR |
| Gallium and other main group metal compounds as antitumor agents. Gallium has been the second metal to show activity against malignant tumors in humans soon after the establishment of platinum drugs in routine clinical practice. It has the unique property of inhibiting tumor growth as a simple cation, mainly because of its close resemblance to ferric CHEMICAL. Even though its inability to shift between the trivalent and a divalent oxidation state precludes that gallium behaves as an CHEMICAL analogue in every respect, it strongly interferes with cellular acquisition of CHEMICAL from blood by competitive interaction with transferrin and transferrin receptor-mediated endocytosis. Furthermore, gallium also seems to affect intracellular availability of CHEMICAL already taken up via this pathway, probably due to its inhibitory activity on vacuolar-type H(+)-ATPases. Apart from the consequences of CHEMICAL deprivation, gallium exerts cytotoxic effects by direct interaction with the iron-dependent enzyme ribonucleotide reductase, resulting in reduced dNTP pools and inhibition of DNA synthesis. Both the abundance of transferrin receptors and upregulation of ribonucleotide reductase render tumors susceptible to gallium-induced cytotoxicity. However, some experimental findings raise the question whether these effects resulting from the CHEMICAL-mimicking properties of gallium are solely responsible for its antineoplastic activity or whether additional mechanisms are involved, such as antimitotic effects which result from its capability of inhibiting GENE polymerization. The limitations experienced with gallium nitrate and gallium chloride, which call for a prolonged exposure to low steady-state gallium levels in blood in order to adequately exploit the affinity of gallium to tumor tissues and to avoid severe toxic effects, may be overcome by oral gallium complexes such as tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III) (gallium maltolate) or tris(8-quinolinolato)gallium(III) (KP46), which are currently being evaluated in clinical trials and show promise to initiate a revival of gallium in the clinical setting. These two investigational drugs, albeit differing in their complex stability, have both been developed with the intention of providing gallium in a form which allows sufficient intestinal absorption, but without altering its pharmacodynamic effects. Gallium complexes based on other rationales are scarce and, with regard to the well-known antineoplastic potential of this metal, noticeably under-explored. With the recent approval of arsenic trioxide for the second-line treatment of acute promyelocytic leukemia, the clinical revival of arsenic compounds, which have been the mainstay of antileukemic therapy before the age of modern cancer chemotherapy, has already begun. Currently, strong efforts are being made to explore the activity spectrum in other (less rare) malignancies and to gain a deeper insight into the mode of action. Although this development is currently focusing on arsenic trioxide, it should be suited to stimulate investigations into the therapeutic potential of other arsenic compounds as well. | REGULATOR |
| CHEMICAL and other main group metal compounds as antitumor agents. CHEMICAL has been the second metal to show activity against malignant tumors in humans soon after the establishment of platinum drugs in routine clinical practice. It has the unique property of inhibiting tumor growth as a simple cation, mainly because of its close resemblance to ferric iron. Even though its inability to shift between the trivalent and a divalent oxidation state precludes that CHEMICAL behaves as an iron analogue in every respect, it strongly interferes with cellular acquisition of iron from blood by competitive interaction with transferrin and transferrin receptor-mediated endocytosis. Furthermore, CHEMICAL also seems to affect intracellular availability of iron already taken up via this pathway, probably due to its inhibitory activity on vacuolar-type H(+)-ATPases. Apart from the consequences of iron deprivation, CHEMICAL exerts cytotoxic effects by direct interaction with the iron-dependent enzyme ribonucleotide reductase, resulting in reduced dNTP pools and inhibition of DNA synthesis. Both the abundance of transferrin receptors and upregulation of ribonucleotide reductase render tumors susceptible to gallium-induced cytotoxicity. However, some experimental findings raise the question whether these effects resulting from the iron-mimicking properties of CHEMICAL are solely responsible for its antineoplastic activity or whether additional mechanisms are involved, such as antimitotic effects which result from its capability of inhibiting GENE polymerization. The limitations experienced with CHEMICAL nitrate and CHEMICAL chloride, which call for a prolonged exposure to low steady-state CHEMICAL levels in blood in order to adequately exploit the affinity of CHEMICAL to tumor tissues and to avoid severe toxic effects, may be overcome by oral CHEMICAL complexes such as tris(3-hydroxy-2-methyl-4H-pyran-4-onato)gallium(III) (gallium maltolate) or tris(8-quinolinolato)gallium(III) (KP46), which are currently being evaluated in clinical trials and show promise to initiate a revival of CHEMICAL in the clinical setting. These two investigational drugs, albeit differing in their complex stability, have both been developed with the intention of providing CHEMICAL in a form which allows sufficient intestinal absorption, but without altering its pharmacodynamic effects. CHEMICAL complexes based on other rationales are scarce and, with regard to the well-known antineoplastic potential of this metal, noticeably under-explored. With the recent approval of arsenic trioxide for the second-line treatment of acute promyelocytic leukemia, the clinical revival of arsenic compounds, which have been the mainstay of antileukemic therapy before the age of modern cancer chemotherapy, has already begun. Currently, strong efforts are being made to explore the activity spectrum in other (less rare) malignancies and to gain a deeper insight into the mode of action. Although this development is currently focusing on arsenic trioxide, it should be suited to stimulate investigations into the therapeutic potential of other arsenic compounds as well. | REGULATOR |
| The GENE is the binding site for the antiepileptic drug CHEMICAL. Here, we show that the GENE is the brain binding site of CHEMICAL (LEV), a new antiepileptic drug with a unique activity profile in animal models of seizure and epilepsy. The LEV-binding site is enriched in synaptic vesicles, and photoaffinity labeling of purified synaptic vesicles confirms that it has an apparent molecular mass of approximately 90 kDa. Brain membranes and purified synaptic vesicles from mice lacking SV2A do not bind a tritiated LEV derivative, indicating that SV2A is necessary for LEV binding. LEV and related compounds bind to SV2A expressed in fibroblasts, indicating that SV2A is sufficient for LEV binding. No binding was observed to the related isoforms SV2B and SV2C. Furthermore, there is a high degree of correlation between binding affinities of a series of LEV derivatives to SV2A in fibroblasts and to the LEV-binding site in brain. Finally, there is a strong correlation between the affinity of a compound for SV2A and its ability to protect against seizures in an audiogenic mouse animal model of epilepsy. These experimental results suggest that SV2A is the binding site of LEV in the brain and that LEV acts by modulating the function of SV2A, supporting previous indications that LEV possesses a mechanism of action distinct from that of other antiepileptic drugs. Further, these results indicate that proteins involved in vesicle exocytosis, and SV2 in particular, are promising targets for the development of new CNS drug therapies. | DIRECT-REGULATOR |
| The GENE is the binding site for the antiepileptic drug levetiracetam. Here, we show that the GENE is the brain binding site of levetiracetam (CHEMICAL), a new antiepileptic drug with a unique activity profile in animal models of seizure and epilepsy. The LEV-binding site is enriched in synaptic vesicles, and photoaffinity labeling of purified synaptic vesicles confirms that it has an apparent molecular mass of approximately 90 kDa. Brain membranes and purified synaptic vesicles from mice lacking SV2A do not bind a tritiated CHEMICAL derivative, indicating that SV2A is necessary for CHEMICAL binding. CHEMICAL and related compounds bind to SV2A expressed in fibroblasts, indicating that SV2A is sufficient for CHEMICAL binding. No binding was observed to the related isoforms SV2B and SV2C. Furthermore, there is a high degree of correlation between binding affinities of a series of CHEMICAL derivatives to SV2A in fibroblasts and to the LEV-binding site in brain. Finally, there is a strong correlation between the affinity of a compound for SV2A and its ability to protect against seizures in an audiogenic mouse animal model of epilepsy. These experimental results suggest that SV2A is the binding site of CHEMICAL in the brain and that CHEMICAL acts by modulating the function of SV2A, supporting previous indications that CHEMICAL possesses a mechanism of action distinct from that of other antiepileptic drugs. Further, these results indicate that proteins involved in vesicle exocytosis, and SV2 in particular, are promising targets for the development of new CNS drug therapies. | DIRECT-REGULATOR |
| The synaptic vesicle protein GENE is the binding site for the antiepileptic drug levetiracetam. Here, we show that the synaptic vesicle protein GENE is the brain binding site of levetiracetam (LEV), a new antiepileptic drug with a unique activity profile in animal models of seizure and epilepsy. The LEV-binding site is enriched in synaptic vesicles, and photoaffinity labeling of purified synaptic vesicles confirms that it has an apparent molecular mass of approximately 90 kDa. Brain membranes and purified synaptic vesicles from mice lacking GENE do not bind a tritiated CHEMICAL derivative, indicating that GENE is necessary for CHEMICAL binding. CHEMICAL and related compounds bind to GENE expressed in fibroblasts, indicating that GENE is sufficient for CHEMICAL binding. No binding was observed to the related isoforms SV2B and SV2C. Furthermore, there is a high degree of correlation between binding affinities of a series of CHEMICAL derivatives to GENE in fibroblasts and to the LEV-binding site in brain. Finally, there is a strong correlation between the affinity of a compound for GENE and its ability to protect against seizures in an audiogenic mouse animal model of epilepsy. These experimental results suggest that GENE is the binding site of CHEMICAL in the brain and that CHEMICAL acts by modulating the function of GENE, supporting previous indications that CHEMICAL possesses a mechanism of action distinct from that of other antiepileptic drugs. Further, these results indicate that proteins involved in vesicle exocytosis, and SV2 in particular, are promising targets for the development of new CNS drug therapies. | DIRECT-REGULATOR |
| Electrophysiological properties of mouse horizontal cell GABAA receptors. GABA-induced currents have been characterized in isolated horizontal cells from lower vertebrates but not in mammalian horizontal cells. Therefore horizontal cells were isolated after enzymatical and mechanical dissociation of the adult mouse retina and visually identified. We recorded from horizontal cell bodies using the whole cell and outside-out configuration of the patch-clamp technique. Extracellular application of CHEMICAL induced inward currents carried by chloride ions. GABA-evoked currents were completely and reversibly blocked by the competitive GABAA receptor antagonist bicuculline (IC50 = 1.7 microM), indicating expression of GABAA but not GABAC receptors. Their affinity for CHEMICAL was moderate (EC50 = 30 microM), and the Hill coefficient was 1.3, corresponding to two GENE. CHEMICAL responses were partially reduced by picrotoxin with differential effects on peak and steady-state current values. Zinc blocked the CHEMICAL response with an IC50 value of 7.3 microM in a noncompetitive manner. Furthermore, CHEMICAL receptors of horizontal cells were modulated by extracellular application of diazepam, zolpidem, methyl 6,7-dimethoxy-4-ethyl-beta-carboxylate, pentobarbital, and alphaxalone, thus showing typical pharmacological properties of CNS GABAA receptors. GABA-evoked single-channel currents were characterized by a main conductance state of 29.8 pS and two subconductance states (20.2 and 10.8 pS, respectively). Kinetic analysis of single-channel events within bursts revealed similar mean open and closed times for the main conductance and the 20.2-pS subconductance state, resulting in open probabilities of 44.6 and 42.7%, respectively. The ratio of open to closed times, however, was significantly different for the 10.8-pS subconductance state with an open probability of 57.2%. | REGULATOR |
| Electrophysiological properties of mouse horizontal cell GABAA receptors. GABA-induced currents have been characterized in isolated horizontal cells from lower vertebrates but not in mammalian horizontal cells. Therefore horizontal cells were isolated after enzymatical and mechanical dissociation of the adult mouse retina and visually identified. We recorded from horizontal cell bodies using the whole cell and outside-out configuration of the patch-clamp technique. Extracellular application of CHEMICAL induced inward currents carried by chloride ions. CHEMICAL-evoked currents were completely and reversibly blocked by the competitive GENE antagonist bicuculline (IC50 = 1.7 microM), indicating expression of GABAA but not GABAC receptors. Their affinity for CHEMICAL was moderate (EC50 = 30 microM), and the Hill coefficient was 1.3, corresponding to two CHEMICAL binding sites. CHEMICAL responses were partially reduced by picrotoxin with differential effects on peak and steady-state current values. Zinc blocked the CHEMICAL response with an IC50 value of 7.3 microM in a noncompetitive manner. Furthermore, CHEMICAL receptors of horizontal cells were modulated by extracellular application of diazepam, zolpidem, methyl 6,7-dimethoxy-4-ethyl-beta-carboxylate, pentobarbital, and alphaxalone, thus showing typical pharmacological properties of CNS GABAA receptors. GABA-evoked single-channel currents were characterized by a main conductance state of 29.8 pS and two subconductance states (20.2 and 10.8 pS, respectively). Kinetic analysis of single-channel events within bursts revealed similar mean open and closed times for the main conductance and the 20.2-pS subconductance state, resulting in open probabilities of 44.6 and 42.7%, respectively. The ratio of open to closed times, however, was significantly different for the 10.8-pS subconductance state with an open probability of 57.2%. | DIRECT-REGULATOR |
| Electrophysiological properties of mouse horizontal cell GABAA receptors. GABA-induced currents have been characterized in isolated horizontal cells from lower vertebrates but not in mammalian horizontal cells. Therefore horizontal cells were isolated after enzymatical and mechanical dissociation of the adult mouse retina and visually identified. We recorded from horizontal cell bodies using the whole cell and outside-out configuration of the patch-clamp technique. Extracellular application of GABA induced inward currents carried by chloride ions. GABA-evoked currents were completely and reversibly blocked by the competitive GABAA receptor antagonist bicuculline (IC50 = 1.7 microM), indicating expression of GABAA but not GABAC receptors. Their affinity for GABA was moderate (EC50 = 30 microM), and the Hill coefficient was 1.3, corresponding to two GABA binding sites. GABA responses were partially reduced by picrotoxin with differential effects on peak and steady-state current values. Zinc blocked the GABA response with an IC50 value of 7.3 microM in a noncompetitive manner. Furthermore, GENE of horizontal cells were modulated by extracellular application of CHEMICAL, zolpidem, methyl 6,7-dimethoxy-4-ethyl-beta-carboxylate, pentobarbital, and alphaxalone, thus showing typical pharmacological properties of CNS GABAA receptors. GABA-evoked single-channel currents were characterized by a main conductance state of 29.8 pS and two subconductance states (20.2 and 10.8 pS, respectively). Kinetic analysis of single-channel events within bursts revealed similar mean open and closed times for the main conductance and the 20.2-pS subconductance state, resulting in open probabilities of 44.6 and 42.7%, respectively. The ratio of open to closed times, however, was significantly different for the 10.8-pS subconductance state with an open probability of 57.2%. | REGULATOR |
| Electrophysiological properties of mouse horizontal cell GABAA receptors. GABA-induced currents have been characterized in isolated horizontal cells from lower vertebrates but not in mammalian horizontal cells. Therefore horizontal cells were isolated after enzymatical and mechanical dissociation of the adult mouse retina and visually identified. We recorded from horizontal cell bodies using the whole cell and outside-out configuration of the patch-clamp technique. Extracellular application of GABA induced inward currents carried by chloride ions. GABA-evoked currents were completely and reversibly blocked by the competitive GABAA receptor antagonist bicuculline (IC50 = 1.7 microM), indicating expression of GABAA but not GABAC receptors. Their affinity for GABA was moderate (EC50 = 30 microM), and the Hill coefficient was 1.3, corresponding to two GABA binding sites. GABA responses were partially reduced by picrotoxin with differential effects on peak and steady-state current values. Zinc blocked the GABA response with an IC50 value of 7.3 microM in a noncompetitive manner. Furthermore, GENE of horizontal cells were modulated by extracellular application of diazepam, CHEMICAL, methyl 6,7-dimethoxy-4-ethyl-beta-carboxylate, pentobarbital, and alphaxalone, thus showing typical pharmacological properties of CNS GABAA receptors. GABA-evoked single-channel currents were characterized by a main conductance state of 29.8 pS and two subconductance states (20.2 and 10.8 pS, respectively). Kinetic analysis of single-channel events within bursts revealed similar mean open and closed times for the main conductance and the 20.2-pS subconductance state, resulting in open probabilities of 44.6 and 42.7%, respectively. The ratio of open to closed times, however, was significantly different for the 10.8-pS subconductance state with an open probability of 57.2%. | REGULATOR |
| Electrophysiological properties of mouse horizontal cell GABAA receptors. GABA-induced currents have been characterized in isolated horizontal cells from lower vertebrates but not in mammalian horizontal cells. Therefore horizontal cells were isolated after enzymatical and mechanical dissociation of the adult mouse retina and visually identified. We recorded from horizontal cell bodies using the whole cell and outside-out configuration of the patch-clamp technique. Extracellular application of GABA induced inward currents carried by chloride ions. GABA-evoked currents were completely and reversibly blocked by the competitive GABAA receptor antagonist bicuculline (IC50 = 1.7 microM), indicating expression of GABAA but not GABAC receptors. Their affinity for GABA was moderate (EC50 = 30 microM), and the Hill coefficient was 1.3, corresponding to two GABA binding sites. GABA responses were partially reduced by picrotoxin with differential effects on peak and steady-state current values. Zinc blocked the GABA response with an IC50 value of 7.3 microM in a noncompetitive manner. Furthermore, GENE of horizontal cells were modulated by extracellular application of diazepam, zolpidem, CHEMICAL, pentobarbital, and alphaxalone, thus showing typical pharmacological properties of CNS GABAA receptors. GABA-evoked single-channel currents were characterized by a main conductance state of 29.8 pS and two subconductance states (20.2 and 10.8 pS, respectively). Kinetic analysis of single-channel events within bursts revealed similar mean open and closed times for the main conductance and the 20.2-pS subconductance state, resulting in open probabilities of 44.6 and 42.7%, respectively. The ratio of open to closed times, however, was significantly different for the 10.8-pS subconductance state with an open probability of 57.2%. | REGULATOR |
| Electrophysiological properties of mouse horizontal cell GABAA receptors. GABA-induced currents have been characterized in isolated horizontal cells from lower vertebrates but not in mammalian horizontal cells. Therefore horizontal cells were isolated after enzymatical and mechanical dissociation of the adult mouse retina and visually identified. We recorded from horizontal cell bodies using the whole cell and outside-out configuration of the patch-clamp technique. Extracellular application of GABA induced inward currents carried by chloride ions. GABA-evoked currents were completely and reversibly blocked by the competitive GABAA receptor antagonist bicuculline (IC50 = 1.7 microM), indicating expression of GABAA but not GABAC receptors. Their affinity for GABA was moderate (EC50 = 30 microM), and the Hill coefficient was 1.3, corresponding to two GABA binding sites. GABA responses were partially reduced by picrotoxin with differential effects on peak and steady-state current values. Zinc blocked the GABA response with an IC50 value of 7.3 microM in a noncompetitive manner. Furthermore, GENE of horizontal cells were modulated by extracellular application of diazepam, zolpidem, methyl 6,7-dimethoxy-4-ethyl-beta-carboxylate, CHEMICAL, and alphaxalone, thus showing typical pharmacological properties of CNS GABAA receptors. GABA-evoked single-channel currents were characterized by a main conductance state of 29.8 pS and two subconductance states (20.2 and 10.8 pS, respectively). Kinetic analysis of single-channel events within bursts revealed similar mean open and closed times for the main conductance and the 20.2-pS subconductance state, resulting in open probabilities of 44.6 and 42.7%, respectively. The ratio of open to closed times, however, was significantly different for the 10.8-pS subconductance state with an open probability of 57.2%. | REGULATOR |
| Electrophysiological properties of mouse horizontal cell GABAA receptors. GABA-induced currents have been characterized in isolated horizontal cells from lower vertebrates but not in mammalian horizontal cells. Therefore horizontal cells were isolated after enzymatical and mechanical dissociation of the adult mouse retina and visually identified. We recorded from horizontal cell bodies using the whole cell and outside-out configuration of the patch-clamp technique. Extracellular application of GABA induced inward currents carried by chloride ions. GABA-evoked currents were completely and reversibly blocked by the competitive GABAA receptor antagonist bicuculline (IC50 = 1.7 microM), indicating expression of GABAA but not GABAC receptors. Their affinity for GABA was moderate (EC50 = 30 microM), and the Hill coefficient was 1.3, corresponding to two GABA binding sites. GABA responses were partially reduced by picrotoxin with differential effects on peak and steady-state current values. Zinc blocked the GABA response with an IC50 value of 7.3 microM in a noncompetitive manner. Furthermore, GENE of horizontal cells were modulated by extracellular application of diazepam, zolpidem, methyl 6,7-dimethoxy-4-ethyl-beta-carboxylate, pentobarbital, and CHEMICAL, thus showing typical pharmacological properties of CNS GABAA receptors. GABA-evoked single-channel currents were characterized by a main conductance state of 29.8 pS and two subconductance states (20.2 and 10.8 pS, respectively). Kinetic analysis of single-channel events within bursts revealed similar mean open and closed times for the main conductance and the 20.2-pS subconductance state, resulting in open probabilities of 44.6 and 42.7%, respectively. The ratio of open to closed times, however, was significantly different for the 10.8-pS subconductance state with an open probability of 57.2%. | REGULATOR |
| Electrophysiological properties of mouse horizontal cell GABAA receptors. GABA-induced currents have been characterized in isolated horizontal cells from lower vertebrates but not in mammalian horizontal cells. Therefore horizontal cells were isolated after enzymatical and mechanical dissociation of the adult mouse retina and visually identified. We recorded from horizontal cell bodies using the whole cell and outside-out configuration of the patch-clamp technique. Extracellular application of GABA induced inward currents carried by chloride ions. GABA-evoked currents were completely and reversibly blocked by the competitive GENE antagonist CHEMICAL (IC50 = 1.7 microM), indicating expression of GABAA but not GABAC receptors. Their affinity for GABA was moderate (EC50 = 30 microM), and the Hill coefficient was 1.3, corresponding to two GABA binding sites. GABA responses were partially reduced by picrotoxin with differential effects on peak and steady-state current values. Zinc blocked the GABA response with an IC50 value of 7.3 microM in a noncompetitive manner. Furthermore, GABA receptors of horizontal cells were modulated by extracellular application of diazepam, zolpidem, methyl 6,7-dimethoxy-4-ethyl-beta-carboxylate, pentobarbital, and alphaxalone, thus showing typical pharmacological properties of CNS GABAA receptors. GABA-evoked single-channel currents were characterized by a main conductance state of 29.8 pS and two subconductance states (20.2 and 10.8 pS, respectively). Kinetic analysis of single-channel events within bursts revealed similar mean open and closed times for the main conductance and the 20.2-pS subconductance state, resulting in open probabilities of 44.6 and 42.7%, respectively. The ratio of open to closed times, however, was significantly different for the 10.8-pS subconductance state with an open probability of 57.2%. | INHIBITOR |
| Decreased GENE binding in the brain of depressed patients. The central histaminergic neuron system modulates the wakefulness, sleep-awake cycle, appetite control, learning and memory, and emotion. Previous studies have reported changes in neuronal histamine release and its metabolism under stress conditions in the mammalian brain. In this study, we examined, using positron emission tomography (PET) and CHEMICAL, whether the histaminergic neuron system is involved in human depression. Cerebral GENE (H(1)R) binding was measured in 10 patients with major depression and in 10 normal age-matched subjects using PET and CHEMICAL. Data were calculated by a graphical analysis on voxel-by-voxel and ROI (region of interests) basis. Binding potential (BP) values for CHEMICAL binding in the frontal and prefrontal cortices, and cingulate gyrus were significantly lower in the depressed patients than those in the normal control subjects. There was no area of the brain where CHEMICAL binding was significantly higher in the depressed patients than in the controls. ROI-based analysis also revealed that BP values for CHEMICAL binding in the frontal cortex and cingulate gyrus decreased in proportion to self-rating depressive scales scores. The results of this study demonstrate that depressed patients have decreased brain H(1)R binding and that this decrease correlates with the severity of depression symptoms. It is therefore suggested that the histaminergic neuron system plays an important role in the pathophysiology of depression and that its modulation may prove to be useful in the treatment of depression. | DIRECT-REGULATOR |
| Decreased histamine H1 receptor binding in the brain of depressed patients. The central histaminergic neuron system modulates the wakefulness, sleep-awake cycle, appetite control, learning and memory, and emotion. Previous studies have reported changes in neuronal histamine release and its metabolism under stress conditions in the mammalian brain. In this study, we examined, using positron emission tomography (PET) and CHEMICAL, whether the histaminergic neuron system is involved in human depression. Cerebral histamine H1 receptor (GENE) binding was measured in 10 patients with major depression and in 10 normal age-matched subjects using PET and CHEMICAL. Data were calculated by a graphical analysis on voxel-by-voxel and ROI (region of interests) basis. Binding potential (BP) values for CHEMICAL binding in the frontal and prefrontal cortices, and cingulate gyrus were significantly lower in the depressed patients than those in the normal control subjects. There was no area of the brain where CHEMICAL binding was significantly higher in the depressed patients than in the controls. ROI-based analysis also revealed that BP values for CHEMICAL binding in the frontal cortex and cingulate gyrus decreased in proportion to self-rating depressive scales scores. The results of this study demonstrate that depressed patients have decreased brain GENE binding and that this decrease correlates with the severity of depression symptoms. It is therefore suggested that the histaminergic neuron system plays an important role in the pathophysiology of depression and that its modulation may prove to be useful in the treatment of depression. | DIRECT-REGULATOR |
| Central effects of fexofenadine and cetirizine: measurement of psychomotor performance, subjective sleepiness, and brain GENE occupancy using CHEMICAL positron emission tomography. Histamine H1-receptor (H1R) antagonists, or antihistamines, often induce sedative side effects when used for the treatment of allergic disorders. This study compared the sedative profiles of the second-generation antihistamines, fexofenadine and cetirizine, using 3 different criteria: subjective sleepiness evaluated by the Stanford Sleepiness Scale, objective psychomotor tests (simple and choice reaction time tests and visual discrimination tests at 4 different exposure durations), and measurement of GENE occupancy (H1RO) in the brain. Subjective sleepiness and psychomotor performance were measured in 20 healthy Japanese volunteers at baseline and 90 min after administration of fexofenadine 120 mg or cetirizine 20 mg in a double-blind, placebo-controlled crossover study. Hydroxyzine 30 mg was included as a positive control. H1RO was measured using positron emission tomography (PET) with (11)C-doxepin in 12 of the 20 subjects, and a further 11 volunteers were recruited to act as controls. In psychomotor tests, fexofenadine was not significantly different from placebo and significantly less impairing than cetirizine on some tasks, as well as significantly less impairing than hydroxyzine on all tasks. For subjective sleepiness, fexofenadine was not significantly different from placebo, whereas cetirizine showed a trend toward increased sleepiness compared with fexofenadine and placebo. H1RO was negligible with fexofenadine (-0.1%) but moderately high with cetirizine (26.0%). In conclusion, fexofenadine 120 mg is distinguishable from cetirizine 20 mg, as assessed by H1RO and psychomotor testing. | DIRECT-REGULATOR |
| Central effects of fexofenadine and cetirizine: measurement of psychomotor performance, subjective sleepiness, and brain GENE occupancy using 11C-doxepin positron emission tomography. Histamine H1-receptor (H1R) antagonists, or CHEMICAL, often induce sedative side effects when used for the treatment of allergic disorders. This study compared the sedative profiles of the second-generation CHEMICAL, fexofenadine and cetirizine, using 3 different criteria: subjective sleepiness evaluated by the Stanford Sleepiness Scale, objective psychomotor tests (simple and choice reaction time tests and visual discrimination tests at 4 different exposure durations), and measurement of GENE occupancy (H1RO) in the brain. Subjective sleepiness and psychomotor performance were measured in 20 healthy Japanese volunteers at baseline and 90 min after administration of fexofenadine 120 mg or cetirizine 20 mg in a double-blind, placebo-controlled crossover study. Hydroxyzine 30 mg was included as a positive control. H1RO was measured using positron emission tomography (PET) with (11)C-doxepin in 12 of the 20 subjects, and a further 11 volunteers were recruited to act as controls. In psychomotor tests, fexofenadine was not significantly different from placebo and significantly less impairing than cetirizine on some tasks, as well as significantly less impairing than hydroxyzine on all tasks. For subjective sleepiness, fexofenadine was not significantly different from placebo, whereas cetirizine showed a trend toward increased sleepiness compared with fexofenadine and placebo. H1RO was negligible with fexofenadine (-0.1%) but moderately high with cetirizine (26.0%). In conclusion, fexofenadine 120 mg is distinguishable from cetirizine 20 mg, as assessed by H1RO and psychomotor testing. | DIRECT-REGULATOR |
| Central effects of CHEMICAL and cetirizine: measurement of psychomotor performance, subjective sleepiness, and brain GENE occupancy using 11C-doxepin positron emission tomography. Histamine H1-receptor (H1R) antagonists, or antihistamines, often induce sedative side effects when used for the treatment of allergic disorders. This study compared the sedative profiles of the second-generation antihistamines, CHEMICAL and cetirizine, using 3 different criteria: subjective sleepiness evaluated by the Stanford Sleepiness Scale, objective psychomotor tests (simple and choice reaction time tests and visual discrimination tests at 4 different exposure durations), and measurement of GENE occupancy (H1RO) in the brain. Subjective sleepiness and psychomotor performance were measured in 20 healthy Japanese volunteers at baseline and 90 min after administration of CHEMICAL 120 mg or cetirizine 20 mg in a double-blind, placebo-controlled crossover study. Hydroxyzine 30 mg was included as a positive control. H1RO was measured using positron emission tomography (PET) with (11)C-doxepin in 12 of the 20 subjects, and a further 11 volunteers were recruited to act as controls. In psychomotor tests, CHEMICAL was not significantly different from placebo and significantly less impairing than cetirizine on some tasks, as well as significantly less impairing than hydroxyzine on all tasks. For subjective sleepiness, CHEMICAL was not significantly different from placebo, whereas cetirizine showed a trend toward increased sleepiness compared with CHEMICAL and placebo. H1RO was negligible with CHEMICAL (-0.1%) but moderately high with cetirizine (26.0%). In conclusion, CHEMICAL 120 mg is distinguishable from cetirizine 20 mg, as assessed by H1RO and psychomotor testing. | DIRECT-REGULATOR |
| Central effects of fexofenadine and cetirizine: measurement of psychomotor performance, subjective sleepiness, and brain GENE occupancy using 11C-doxepin positron emission tomography. Histamine H1-receptor (H1R) antagonists, or antihistamines, often induce sedative side effects when used for the treatment of allergic disorders. This study compared the sedative profiles of the second-generation antihistamines, fexofenadine and CHEMICAL, using 3 different criteria: subjective sleepiness evaluated by the Stanford Sleepiness Scale, objective psychomotor tests (simple and choice reaction time tests and visual discrimination tests at 4 different exposure durations), and measurement of GENE occupancy (H1RO) in the brain. Subjective sleepiness and psychomotor performance were measured in 20 healthy Japanese volunteers at baseline and 90 min after administration of fexofenadine 120 mg or CHEMICAL 20 mg in a double-blind, placebo-controlled crossover study. Hydroxyzine 30 mg was included as a positive control. H1RO was measured using positron emission tomography (PET) with (11)C-doxepin in 12 of the 20 subjects, and a further 11 volunteers were recruited to act as controls. In psychomotor tests, fexofenadine was not significantly different from placebo and significantly less impairing than CHEMICAL on some tasks, as well as significantly less impairing than hydroxyzine on all tasks. For subjective sleepiness, fexofenadine was not significantly different from placebo, whereas CHEMICAL showed a trend toward increased sleepiness compared with fexofenadine and placebo. H1RO was negligible with fexofenadine (-0.1%) but moderately high with CHEMICAL (26.0%). In conclusion, fexofenadine 120 mg is distinguishable from CHEMICAL 20 mg, as assessed by H1RO and psychomotor testing. | DIRECT-REGULATOR |
| Central effects of fexofenadine and cetirizine: measurement of psychomotor performance, subjective sleepiness, and brain histamine H1-receptor occupancy using 11C-doxepin positron emission tomography. GENE (H1R) antagonists, or CHEMICAL, often induce sedative side effects when used for the treatment of allergic disorders. This study compared the sedative profiles of the second-generation CHEMICAL, fexofenadine and cetirizine, using 3 different criteria: subjective sleepiness evaluated by the Stanford Sleepiness Scale, objective psychomotor tests (simple and choice reaction time tests and visual discrimination tests at 4 different exposure durations), and measurement of histamine H1-receptor occupancy (H1RO) in the brain. Subjective sleepiness and psychomotor performance were measured in 20 healthy Japanese volunteers at baseline and 90 min after administration of fexofenadine 120 mg or cetirizine 20 mg in a double-blind, placebo-controlled crossover study. Hydroxyzine 30 mg was included as a positive control. H1RO was measured using positron emission tomography (PET) with (11)C-doxepin in 12 of the 20 subjects, and a further 11 volunteers were recruited to act as controls. In psychomotor tests, fexofenadine was not significantly different from placebo and significantly less impairing than cetirizine on some tasks, as well as significantly less impairing than hydroxyzine on all tasks. For subjective sleepiness, fexofenadine was not significantly different from placebo, whereas cetirizine showed a trend toward increased sleepiness compared with fexofenadine and placebo. H1RO was negligible with fexofenadine (-0.1%) but moderately high with cetirizine (26.0%). In conclusion, fexofenadine 120 mg is distinguishable from cetirizine 20 mg, as assessed by H1RO and psychomotor testing. | INHIBITOR |
| Central effects of fexofenadine and cetirizine: measurement of psychomotor performance, subjective sleepiness, and brain histamine H1-receptor occupancy using 11C-doxepin positron emission tomography. Histamine H1-receptor (GENE) antagonists, or CHEMICAL, often induce sedative side effects when used for the treatment of allergic disorders. This study compared the sedative profiles of the second-generation CHEMICAL, fexofenadine and cetirizine, using 3 different criteria: subjective sleepiness evaluated by the Stanford Sleepiness Scale, objective psychomotor tests (simple and choice reaction time tests and visual discrimination tests at 4 different exposure durations), and measurement of histamine H1-receptor occupancy (H1RO) in the brain. Subjective sleepiness and psychomotor performance were measured in 20 healthy Japanese volunteers at baseline and 90 min after administration of fexofenadine 120 mg or cetirizine 20 mg in a double-blind, placebo-controlled crossover study. Hydroxyzine 30 mg was included as a positive control. H1RO was measured using positron emission tomography (PET) with (11)C-doxepin in 12 of the 20 subjects, and a further 11 volunteers were recruited to act as controls. In psychomotor tests, fexofenadine was not significantly different from placebo and significantly less impairing than cetirizine on some tasks, as well as significantly less impairing than hydroxyzine on all tasks. For subjective sleepiness, fexofenadine was not significantly different from placebo, whereas cetirizine showed a trend toward increased sleepiness compared with fexofenadine and placebo. H1RO was negligible with fexofenadine (-0.1%) but moderately high with cetirizine (26.0%). In conclusion, fexofenadine 120 mg is distinguishable from cetirizine 20 mg, as assessed by H1RO and psychomotor testing. | INHIBITOR |
| A novel membrane sensor for GENE antagonist "CHEMICAL". The construction and general performance of thirteen new polymeric membrane sensors for the determination of CHEMICAL hydrochloride based on its ion exchange with reineckate, tetraphenylborate and tetraiodomercurate have been studied. The effects of membrane composition, type of plasticizer, pH value of sample solution and concentration of the analyte in the sensor internal solution have been thoroughly investigated. The novel sensor based on reineckate exchanger shows a stable, potentiometric response for CHEMICAL in the concentration range of 1 x 10(-2) - 2.5 x 10(-6) M at 25 degrees C that is independent of pH in the range of 2.0 - 4.5. The sensor possesses a Nernstian cationic slope of 62.3+/-0.7 mV/concentration decade and a lower detection limit of 1.3 x 10(-6) M with a fast response time of 20 - 40 s. Selectivity coefficients for a number of interfering ions and excipients relative to CHEMICAL were investigated. There is negligible interference from almost all studied cations, anions, and pharmaceutical excipients, however, citrizine that has a structure homologous to that of CHEMICAL was found to interfere. The determination of CHEMICAL in aqueous solution shows an average recovery of 99.83% with a mean relative standard deviation (RSD) of 0.5%. Direct potentiometric determination of CHEMICAL in tablets gave results that compare favorably with those obtained by standard spectrophotometric methods. Potentiometric titration of CHEMICAL with phosphomolybdic acid as a titrant has been monitored with the proposed sensor as an end point indicator electrode. | INHIBITOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. GENE (TS) continues to be a critical target for CHEMICAL (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent TS inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and TS is one target. Clinically, although overall response of colorectal cancer patients to a variety of TS inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of TS inhibitors will not only be based on measurement of the TS level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | REGULATOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. Thymidylate synthase (GENE) continues to be a critical target for CHEMICAL (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent GENE inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and GENE is one target. Clinically, although overall response of colorectal cancer patients to a variety of GENE inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of GENE inhibitors will not only be based on measurement of the GENE level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | REGULATOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. GENE (TS) continues to be a critical target for 5-fluorouracil (CHEMICAL) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent TS inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and TS is one target. Clinically, although overall response of colorectal cancer patients to a variety of TS inhibitors is similar, toxicity profiles are different. The availability of the CHEMICAL prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for CHEMICAL, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of TS inhibitors will not only be based on measurement of the TS level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | REGULATOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. Thymidylate synthase (GENE) continues to be a critical target for 5-fluorouracil (CHEMICAL) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent GENE inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and GENE is one target. Clinically, although overall response of colorectal cancer patients to a variety of GENE inhibitors is similar, toxicity profiles are different. The availability of the CHEMICAL prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for CHEMICAL, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of GENE inhibitors will not only be based on measurement of the GENE level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | REGULATOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. GENE (TS) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, CHEMICAL/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent TS inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and TS is one target. Clinically, although overall response of colorectal cancer patients to a variety of TS inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of TS inhibitors will not only be based on measurement of the TS level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | REGULATOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. Thymidylate synthase (GENE) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, CHEMICAL/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent GENE inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and GENE is one target. Clinically, although overall response of colorectal cancer patients to a variety of GENE inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of GENE inhibitors will not only be based on measurement of the GENE level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | REGULATOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. GENE (TS) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/CHEMICAL (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent TS inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and TS is one target. Clinically, although overall response of colorectal cancer patients to a variety of TS inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of TS inhibitors will not only be based on measurement of the TS level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | REGULATOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. Thymidylate synthase (GENE) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/CHEMICAL (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent GENE inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and GENE is one target. Clinically, although overall response of colorectal cancer patients to a variety of GENE inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of GENE inhibitors will not only be based on measurement of the GENE level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | REGULATOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. GENE (TS) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (CHEMICAL), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent TS inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and TS is one target. Clinically, although overall response of colorectal cancer patients to a variety of TS inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of TS inhibitors will not only be based on measurement of the TS level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | REGULATOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. Thymidylate synthase (GENE) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (CHEMICAL), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent GENE inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and GENE is one target. Clinically, although overall response of colorectal cancer patients to a variety of GENE inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of GENE inhibitors will not only be based on measurement of the GENE level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | REGULATOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. GENE (TS) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), CHEMICAL (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent TS inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and TS is one target. Clinically, although overall response of colorectal cancer patients to a variety of TS inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of TS inhibitors will not only be based on measurement of the TS level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | REGULATOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. Thymidylate synthase (GENE) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), CHEMICAL (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent GENE inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and GENE is one target. Clinically, although overall response of colorectal cancer patients to a variety of GENE inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of GENE inhibitors will not only be based on measurement of the GENE level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | REGULATOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. GENE (TS) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (CHEMICAL), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent TS inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and TS is one target. Clinically, although overall response of colorectal cancer patients to a variety of TS inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of TS inhibitors will not only be based on measurement of the TS level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | REGULATOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. Thymidylate synthase (GENE) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (CHEMICAL), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent GENE inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and GENE is one target. Clinically, although overall response of colorectal cancer patients to a variety of GENE inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of GENE inhibitors will not only be based on measurement of the GENE level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | REGULATOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. GENE (TS) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and CHEMICAL, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent TS inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and TS is one target. Clinically, although overall response of colorectal cancer patients to a variety of TS inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of TS inhibitors will not only be based on measurement of the TS level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | REGULATOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. Thymidylate synthase (GENE) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and CHEMICAL, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent GENE inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and GENE is one target. Clinically, although overall response of colorectal cancer patients to a variety of GENE inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of GENE inhibitors will not only be based on measurement of the GENE level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | REGULATOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. Thymidylate synthase (TS) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates CHEMICAL (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent GENE inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and GENE is one target. Clinically, although overall response of colorectal cancer patients to a variety of GENE inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of GENE inhibitors will not only be based on measurement of the GENE level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | INHIBITOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. Thymidylate synthase (TS) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (CHEMICAL, Tomudex) and AG337 (Thymitag) are more specific and potent GENE inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and GENE is one target. Clinically, although overall response of colorectal cancer patients to a variety of GENE inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of GENE inhibitors will not only be based on measurement of the GENE level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | INHIBITOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. Thymidylate synthase (TS) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, CHEMICAL) and AG337 (Thymitag) are more specific and potent GENE inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or CHEMICAL. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and GENE is one target. Clinically, although overall response of colorectal cancer patients to a variety of GENE inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of GENE inhibitors will not only be based on measurement of the GENE level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | INHIBITOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. Thymidylate synthase (TS) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and CHEMICAL (Thymitag) are more specific and potent GENE inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and GENE is one target. Clinically, although overall response of colorectal cancer patients to a variety of GENE inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of GENE inhibitors will not only be based on measurement of the GENE level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | INHIBITOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. Thymidylate synthase (TS) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (CHEMICAL) are more specific and potent GENE inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and GENE is one target. Clinically, although overall response of colorectal cancer patients to a variety of GENE inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of GENE inhibitors will not only be based on measurement of the GENE level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | INHIBITOR |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. GENE (TS) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of CHEMICAL, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent TS inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and TS is one target. Clinically, although overall response of colorectal cancer patients to a variety of TS inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of TS inhibitors will not only be based on measurement of the TS level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | PRODUCT-OF |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. Thymidylate synthase (GENE) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of CHEMICAL, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent GENE inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and GENE is one target. Clinically, although overall response of colorectal cancer patients to a variety of GENE inhibitors is similar, toxicity profiles are different. The availability of the 5-FU prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that thymidine phosphorylase, the activating enzyme for 5-FU, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of GENE inhibitors will not only be based on measurement of the GENE level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | PRODUCT-OF |
| Thymidylate synthase: a critical target in cancer therapy? For the last four decades, synthesis and testing of potentially active drugs (e.g., antimetabolites) have focused on structural modification of existing metabolites as precursors of DNA and RNA synthesis. In recent years, the focus has shifted to synthesis of target-specific agents. Thus, the current emphasis of drug development is directed at inhibiting specific target(s) expressed preferentially, if not exclusively, in tumor tissues, with the ultimate goal of improving the therapeutic efficacy and selectivity of these new agents. Preclinically, proof-of-principle studies were carried out in tumors with specific expression of the intended target. With the hope of translating preclinical findings to the design of implementation of clinical trials. Thymidylate synthase (TS) continues to be a critical target for 5-fluorouracil (5-FU) and its prodrugs, UFT/LV (Orzel), capecitabine (Xeloda), and S-1, primarily because this enzyme is essential for the synthesis of 2-deoxythymidine-5-monophosphate, a precursor for DNA synthesis. While fluoropyrimidine antimetabolites have other sites of action, antifolates ZD1694 (raltitrexed, Tomudex) and AG337 (Thymitag) are more specific and potent TS inhibitors. Thus, it is hoped that pronounced and sustained inhibition of this enzyme could result in downstream regulation of molecular markers associated with sensitivity and resistance to these agents. It is also critical to recognize that the degree and duration of inhibition of the target enzyme may depend on the expression level of the target enzyme, thymidylate synthase. Correlative studies in preclinical and clinical systems demonstrated a close relationship between the enzyme level (mRNA and protein) and response to therapy of colorectal cancer patients treated with fluoropyrimidine or Tomudex. However, significant overlap was demonstrated between responders and non-responders. These data are consistent with the hypothesis that prediction of response to anticancer drugs is multifactorial, and TS is one target. Clinically, although overall response of colorectal cancer patients to a variety of TS inhibitors is similar, toxicity profiles are different. The availability of the CHEMICAL prodrugs offers the possibility of greater therapeutic selectivity based on the demonstration that GENE, the activating enzyme for CHEMICAL, is expressed at a higher level in tumor tissue compared with normal tissue counterparts. It is likely that successful application of TS inhibitors will not only be based on measurement of the TS level in tumors vs. normal tissues, but on the delineation of the consequences of this inhibition on molecular markers associated with cellular proliferation, apoptosis and cell cycle regulation. | ACTIVATOR |
| [Pharmacological treatment of obesity]. The pharmacological treatment of obesity should be considered when cannot be achieved a 10% weight loss with diet therapy and physical activity. The drugs effective in obesity treatment may act by different mechanisms such as reduction in food intake, inhibition of fat absorption, increase of thermogenesis and stimulation of adipocyte apoptosis. At present, we only have two marketed drugs for obesity treatment. Sibutramine is an inhibitor of norepinephrine, dopamine and serotonina reuptake which inhibits food intake and increases thermogenesis. Sibutramine administration for a year can induce a weight loss of 4-7%. Its main side effects are hypertension, headache, insomnia and constipation. CHEMICAL is an inhibitor of GENE which is able to block the absorption of 30% of ingested fat. Its administration induces weight loss and reduction of ulterior weight regain. Also, this drug improves hypertension dyslipdaemia and helps to prevent diabetes in 52% of cases when administered over four years. The increase in frequency of stools and interference with vitamin absorption are its main side effects. Glucagon-like peptide 1, which increases insulin sensitivity and satiety, adiponectin and PPAR-gamma agonists which reduce insulin resistance and modulates adipocyte generation are the basis for future therapeutic approaches of obesity. Phosphatase inhibitors induce PPAR-gamma phosphorylation and UCP-1 expression leading to an increase in thermogenesis and reduction in appetite. | INHIBITOR |
| Viability assessment in sandwich-cultured rat hepatocytes after xenobiotic exposure. Troglitazone, bosentan and glibenclamide inhibit the bile salt export pump (Bsep) which transports taurocholate into bile. Sandwich-cultured rat hepatocytes maintain functional sodium taurocholate co-transporting polypeptide and Bsep transport proteins, and may be useful to study inhibition of transport by xenobiotics at concentrations below the lowest observable adverse effect level (LOAEL). The purpose of this study was to compare viability assessments determined with the neutral red, lactate dehydrogenase (LDH), alamar blue, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and propidium iodide assays in sandwich-cultured rat hepatocytes following exposure to xenobiotics known to inhibit Bsep, and to define the LOAEL for these xenobiotics in this system. The neutral red assay was not amenable to use in this model due to crystal formation on the collagen. Troglitazone decreased viability in every assay examined, with a LOAEL approximately 100 microM. CHEMICAL also decreased viability as measured by the GENE, MTT and propidium iodide assays, with a LOAEL approximately 200 microM; however, a significant decrease in viability was not observed with the alamar blue assay. Glibenclamide did not decrease viability with any assay at the xenobiotic concentrations examined in this study. Based on the results of this study, the GENE or propidium iodide assays would be the methods of choice to assess viability in sandwich-cultured rat hepatocytes after xenobiotic exposure. | INHIBITOR |
| Viability assessment in sandwich-cultured rat hepatocytes after xenobiotic exposure. CHEMICAL, bosentan and glibenclamide inhibit the GENE (Bsep) which transports taurocholate into bile. Sandwich-cultured rat hepatocytes maintain functional sodium taurocholate co-transporting polypeptide and Bsep transport proteins, and may be useful to study inhibition of transport by xenobiotics at concentrations below the lowest observable adverse effect level (LOAEL). The purpose of this study was to compare viability assessments determined with the neutral red, lactate dehydrogenase (LDH), alamar blue, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and propidium iodide assays in sandwich-cultured rat hepatocytes following exposure to xenobiotics known to inhibit Bsep, and to define the LOAEL for these xenobiotics in this system. The neutral red assay was not amenable to use in this model due to crystal formation on the collagen. CHEMICAL decreased viability in every assay examined, with a LOAEL approximately 100 microM. Bosentan also decreased viability as measured by the LDH, MTT and propidium iodide assays, with a LOAEL approximately 200 microM; however, a significant decrease in viability was not observed with the alamar blue assay. Glibenclamide did not decrease viability with any assay at the xenobiotic concentrations examined in this study. Based on the results of this study, the LDH or propidium iodide assays would be the methods of choice to assess viability in sandwich-cultured rat hepatocytes after xenobiotic exposure. | INHIBITOR |
| Viability assessment in sandwich-cultured rat hepatocytes after xenobiotic exposure. CHEMICAL, bosentan and glibenclamide inhibit the bile salt export pump (GENE) which transports taurocholate into bile. Sandwich-cultured rat hepatocytes maintain functional sodium taurocholate co-transporting polypeptide and GENE transport proteins, and may be useful to study inhibition of transport by xenobiotics at concentrations below the lowest observable adverse effect level (LOAEL). The purpose of this study was to compare viability assessments determined with the neutral red, lactate dehydrogenase (LDH), alamar blue, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and propidium iodide assays in sandwich-cultured rat hepatocytes following exposure to xenobiotics known to inhibit GENE, and to define the LOAEL for these xenobiotics in this system. The neutral red assay was not amenable to use in this model due to crystal formation on the collagen. CHEMICAL decreased viability in every assay examined, with a LOAEL approximately 100 microM. Bosentan also decreased viability as measured by the LDH, MTT and propidium iodide assays, with a LOAEL approximately 200 microM; however, a significant decrease in viability was not observed with the alamar blue assay. Glibenclamide did not decrease viability with any assay at the xenobiotic concentrations examined in this study. Based on the results of this study, the LDH or propidium iodide assays would be the methods of choice to assess viability in sandwich-cultured rat hepatocytes after xenobiotic exposure. | INHIBITOR |
| Viability assessment in sandwich-cultured rat hepatocytes after xenobiotic exposure. Troglitazone, CHEMICAL and glibenclamide inhibit the GENE (Bsep) which transports taurocholate into bile. Sandwich-cultured rat hepatocytes maintain functional sodium taurocholate co-transporting polypeptide and Bsep transport proteins, and may be useful to study inhibition of transport by xenobiotics at concentrations below the lowest observable adverse effect level (LOAEL). The purpose of this study was to compare viability assessments determined with the neutral red, lactate dehydrogenase (LDH), alamar blue, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and propidium iodide assays in sandwich-cultured rat hepatocytes following exposure to xenobiotics known to inhibit Bsep, and to define the LOAEL for these xenobiotics in this system. The neutral red assay was not amenable to use in this model due to crystal formation on the collagen. Troglitazone decreased viability in every assay examined, with a LOAEL approximately 100 microM. CHEMICAL also decreased viability as measured by the LDH, MTT and propidium iodide assays, with a LOAEL approximately 200 microM; however, a significant decrease in viability was not observed with the alamar blue assay. Glibenclamide did not decrease viability with any assay at the xenobiotic concentrations examined in this study. Based on the results of this study, the LDH or propidium iodide assays would be the methods of choice to assess viability in sandwich-cultured rat hepatocytes after xenobiotic exposure. | INHIBITOR |
| Viability assessment in sandwich-cultured rat hepatocytes after xenobiotic exposure. Troglitazone, CHEMICAL and glibenclamide inhibit the bile salt export pump (GENE) which transports taurocholate into bile. Sandwich-cultured rat hepatocytes maintain functional sodium taurocholate co-transporting polypeptide and GENE transport proteins, and may be useful to study inhibition of transport by xenobiotics at concentrations below the lowest observable adverse effect level (LOAEL). The purpose of this study was to compare viability assessments determined with the neutral red, lactate dehydrogenase (LDH), alamar blue, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and propidium iodide assays in sandwich-cultured rat hepatocytes following exposure to xenobiotics known to inhibit GENE, and to define the LOAEL for these xenobiotics in this system. The neutral red assay was not amenable to use in this model due to crystal formation on the collagen. Troglitazone decreased viability in every assay examined, with a LOAEL approximately 100 microM. CHEMICAL also decreased viability as measured by the LDH, MTT and propidium iodide assays, with a LOAEL approximately 200 microM; however, a significant decrease in viability was not observed with the alamar blue assay. Glibenclamide did not decrease viability with any assay at the xenobiotic concentrations examined in this study. Based on the results of this study, the LDH or propidium iodide assays would be the methods of choice to assess viability in sandwich-cultured rat hepatocytes after xenobiotic exposure. | INHIBITOR |
| Viability assessment in sandwich-cultured rat hepatocytes after xenobiotic exposure. Troglitazone, bosentan and CHEMICAL inhibit the GENE (Bsep) which transports taurocholate into bile. Sandwich-cultured rat hepatocytes maintain functional sodium taurocholate co-transporting polypeptide and Bsep transport proteins, and may be useful to study inhibition of transport by xenobiotics at concentrations below the lowest observable adverse effect level (LOAEL). The purpose of this study was to compare viability assessments determined with the neutral red, lactate dehydrogenase (LDH), alamar blue, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and propidium iodide assays in sandwich-cultured rat hepatocytes following exposure to xenobiotics known to inhibit Bsep, and to define the LOAEL for these xenobiotics in this system. The neutral red assay was not amenable to use in this model due to crystal formation on the collagen. Troglitazone decreased viability in every assay examined, with a LOAEL approximately 100 microM. Bosentan also decreased viability as measured by the LDH, MTT and propidium iodide assays, with a LOAEL approximately 200 microM; however, a significant decrease in viability was not observed with the alamar blue assay. CHEMICAL did not decrease viability with any assay at the xenobiotic concentrations examined in this study. Based on the results of this study, the LDH or propidium iodide assays would be the methods of choice to assess viability in sandwich-cultured rat hepatocytes after xenobiotic exposure. | INHIBITOR |
| Viability assessment in sandwich-cultured rat hepatocytes after xenobiotic exposure. Troglitazone, bosentan and CHEMICAL inhibit the bile salt export pump (GENE) which transports taurocholate into bile. Sandwich-cultured rat hepatocytes maintain functional sodium taurocholate co-transporting polypeptide and GENE transport proteins, and may be useful to study inhibition of transport by xenobiotics at concentrations below the lowest observable adverse effect level (LOAEL). The purpose of this study was to compare viability assessments determined with the neutral red, lactate dehydrogenase (LDH), alamar blue, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and propidium iodide assays in sandwich-cultured rat hepatocytes following exposure to xenobiotics known to inhibit GENE, and to define the LOAEL for these xenobiotics in this system. The neutral red assay was not amenable to use in this model due to crystal formation on the collagen. Troglitazone decreased viability in every assay examined, with a LOAEL approximately 100 microM. Bosentan also decreased viability as measured by the LDH, MTT and propidium iodide assays, with a LOAEL approximately 200 microM; however, a significant decrease in viability was not observed with the alamar blue assay. CHEMICAL did not decrease viability with any assay at the xenobiotic concentrations examined in this study. Based on the results of this study, the LDH or propidium iodide assays would be the methods of choice to assess viability in sandwich-cultured rat hepatocytes after xenobiotic exposure. | INHIBITOR |
| Viability assessment in sandwich-cultured rat hepatocytes after xenobiotic exposure. Troglitazone, bosentan and glibenclamide inhibit the GENE (Bsep) which transports CHEMICAL into bile. Sandwich-cultured rat hepatocytes maintain functional sodium CHEMICAL co-transporting polypeptide and Bsep transport proteins, and may be useful to study inhibition of transport by xenobiotics at concentrations below the lowest observable adverse effect level (LOAEL). The purpose of this study was to compare viability assessments determined with the neutral red, lactate dehydrogenase (LDH), alamar blue, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and propidium iodide assays in sandwich-cultured rat hepatocytes following exposure to xenobiotics known to inhibit Bsep, and to define the LOAEL for these xenobiotics in this system. The neutral red assay was not amenable to use in this model due to crystal formation on the collagen. Troglitazone decreased viability in every assay examined, with a LOAEL approximately 100 microM. Bosentan also decreased viability as measured by the LDH, MTT and propidium iodide assays, with a LOAEL approximately 200 microM; however, a significant decrease in viability was not observed with the alamar blue assay. Glibenclamide did not decrease viability with any assay at the xenobiotic concentrations examined in this study. Based on the results of this study, the LDH or propidium iodide assays would be the methods of choice to assess viability in sandwich-cultured rat hepatocytes after xenobiotic exposure. | SUBSTRATE |
| Viability assessment in sandwich-cultured rat hepatocytes after xenobiotic exposure. Troglitazone, bosentan and glibenclamide inhibit the bile salt export pump (GENE) which transports CHEMICAL into bile. Sandwich-cultured rat hepatocytes maintain functional sodium CHEMICAL co-transporting polypeptide and GENE transport proteins, and may be useful to study inhibition of transport by xenobiotics at concentrations below the lowest observable adverse effect level (LOAEL). The purpose of this study was to compare viability assessments determined with the neutral red, lactate dehydrogenase (LDH), alamar blue, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and propidium iodide assays in sandwich-cultured rat hepatocytes following exposure to xenobiotics known to inhibit GENE, and to define the LOAEL for these xenobiotics in this system. The neutral red assay was not amenable to use in this model due to crystal formation on the collagen. Troglitazone decreased viability in every assay examined, with a LOAEL approximately 100 microM. Bosentan also decreased viability as measured by the LDH, MTT and propidium iodide assays, with a LOAEL approximately 200 microM; however, a significant decrease in viability was not observed with the alamar blue assay. Glibenclamide did not decrease viability with any assay at the xenobiotic concentrations examined in this study. Based on the results of this study, the LDH or propidium iodide assays would be the methods of choice to assess viability in sandwich-cultured rat hepatocytes after xenobiotic exposure. | SUBSTRATE |
| Valdecoxib: assessment of cyclooxygenase-2 potency and selectivity. The discovery of a second isoform of cyclooxygenase (COX) led to the search for compounds that could selectively inhibit GENE in humans while sparing prostaglandin formation from COX-1. Celecoxib and rofecoxib were among the molecules developed from these efforts. We report here the pharmacological properties of a third selective GENE inhibitor, CHEMICAL, which is the most potent and in vitro selective of the marketed GENE inhibitors that we have studied. Recombinant human COX-1 and GENE were used to screen for new highly potent and in vitro selective GENE inhibitors and compare kinetic mechanisms of binding and enzyme inhibition with other COX inhibitors. CHEMICAL potently inhibits recombinant GENE, with an IC(50) of 0.005 microM; this compares with IC values of 0.05 microM for celecoxib, 0.5 microM for rofecoxib, and 5 microM for etoricoxib. Unique binding interactions of CHEMICAL with GENE translate into a fast rate of inactivation of GENE (110,000 M/s compared with 7000 M/s for rofecoxib and 80 M/s for etoricoxib). The overall saturation binding affinity for GENE of CHEMICAL is 2.6 nM (compared with 1.6 nM for celecoxib, 51 nM for rofecoxib, and 260 nM for etoricoxib), with a slow off-rate (t(1/2) approximately 98 min). CHEMICAL inhibits COX-1 in a competitive fashion only at very high concentrations (IC(50) = 150 microM). Collectively, these data provide a mechanistic basis for the potency and in vitro selectivity of CHEMICAL for GENE. CHEMICAL showed similar activity in the human whole-blood COX assay (COX-2 IC(50) = 0.24 microM; COX-1 IC(50) = 21.9 microM). We also determined whether this in vitro potency and selectivity translated to significant potency in vivo. In rats, CHEMICAL demonstrated marked potency in acute and chronic models of inflammation (air pouch ED(50) = 0.06 mg/kg; paw edema ED(50) = 5.9 mg/kg; adjuvant arthritis ED(50) = 0.03 mg/kg). In these same animals, COX-1 was spared at doses greater than 200 mg/kg. These data provide a basis for the observed potent anti-inflammatory activity of CHEMICAL in humans. | INHIBITOR |
| Valdecoxib: assessment of cyclooxygenase-2 potency and selectivity. The discovery of a second isoform of cyclooxygenase (COX) led to the search for compounds that could selectively inhibit GENE in humans while sparing prostaglandin formation from COX-1. CHEMICAL and rofecoxib were among the molecules developed from these efforts. We report here the pharmacological properties of a third selective GENE inhibitor, valdecoxib, which is the most potent and in vitro selective of the marketed GENE inhibitors that we have studied. Recombinant human COX-1 and GENE were used to screen for new highly potent and in vitro selective GENE inhibitors and compare kinetic mechanisms of binding and enzyme inhibition with other COX inhibitors. Valdecoxib potently inhibits recombinant GENE, with an IC(50) of 0.005 microM; this compares with IC values of 0.05 microM for CHEMICAL, 0.5 microM for rofecoxib, and 5 microM for etoricoxib. Unique binding interactions of valdecoxib with GENE translate into a fast rate of inactivation of GENE (110,000 M/s compared with 7000 M/s for rofecoxib and 80 M/s for etoricoxib). The overall saturation binding affinity for GENE of valdecoxib is 2.6 nM (compared with 1.6 nM for CHEMICAL, 51 nM for rofecoxib, and 260 nM for etoricoxib), with a slow off-rate (t(1/2) approximately 98 min). Valdecoxib inhibits COX-1 in a competitive fashion only at very high concentrations (IC(50) = 150 microM). Collectively, these data provide a mechanistic basis for the potency and in vitro selectivity of valdecoxib for GENE. Valdecoxib showed similar activity in the human whole-blood COX assay (COX-2 IC(50) = 0.24 microM; COX-1 IC(50) = 21.9 microM). We also determined whether this in vitro potency and selectivity translated to significant potency in vivo. In rats, valdecoxib demonstrated marked potency in acute and chronic models of inflammation (air pouch ED(50) = 0.06 mg/kg; paw edema ED(50) = 5.9 mg/kg; adjuvant arthritis ED(50) = 0.03 mg/kg). In these same animals, COX-1 was spared at doses greater than 200 mg/kg. These data provide a basis for the observed potent anti-inflammatory activity of valdecoxib in humans. | DIRECT-REGULATOR |
| Valdecoxib: assessment of cyclooxygenase-2 potency and selectivity. The discovery of a second isoform of cyclooxygenase (COX) led to the search for compounds that could selectively inhibit GENE in humans while sparing prostaglandin formation from COX-1. Celecoxib and CHEMICAL were among the molecules developed from these efforts. We report here the pharmacological properties of a third selective GENE inhibitor, valdecoxib, which is the most potent and in vitro selective of the marketed GENE inhibitors that we have studied. Recombinant human COX-1 and GENE were used to screen for new highly potent and in vitro selective GENE inhibitors and compare kinetic mechanisms of binding and enzyme inhibition with other COX inhibitors. Valdecoxib potently inhibits recombinant GENE, with an IC(50) of 0.005 microM; this compares with IC values of 0.05 microM for celecoxib, 0.5 microM for CHEMICAL, and 5 microM for etoricoxib. Unique binding interactions of valdecoxib with GENE translate into a fast rate of inactivation of GENE (110,000 M/s compared with 7000 M/s for CHEMICAL and 80 M/s for etoricoxib). The overall saturation binding affinity for GENE of valdecoxib is 2.6 nM (compared with 1.6 nM for celecoxib, 51 nM for CHEMICAL, and 260 nM for etoricoxib), with a slow off-rate (t(1/2) approximately 98 min). Valdecoxib inhibits COX-1 in a competitive fashion only at very high concentrations (IC(50) = 150 microM). Collectively, these data provide a mechanistic basis for the potency and in vitro selectivity of valdecoxib for GENE. Valdecoxib showed similar activity in the human whole-blood COX assay (COX-2 IC(50) = 0.24 microM; COX-1 IC(50) = 21.9 microM). We also determined whether this in vitro potency and selectivity translated to significant potency in vivo. In rats, valdecoxib demonstrated marked potency in acute and chronic models of inflammation (air pouch ED(50) = 0.06 mg/kg; paw edema ED(50) = 5.9 mg/kg; adjuvant arthritis ED(50) = 0.03 mg/kg). In these same animals, COX-1 was spared at doses greater than 200 mg/kg. These data provide a basis for the observed potent anti-inflammatory activity of valdecoxib in humans. | INHIBITOR |
| Valdecoxib: assessment of cyclooxygenase-2 potency and selectivity. The discovery of a second isoform of cyclooxygenase (COX) led to the search for compounds that could selectively inhibit GENE in humans while sparing prostaglandin formation from COX-1. Celecoxib and rofecoxib were among the molecules developed from these efforts. We report here the pharmacological properties of a third selective GENE inhibitor, valdecoxib, which is the most potent and in vitro selective of the marketed GENE inhibitors that we have studied. Recombinant human COX-1 and GENE were used to screen for new highly potent and in vitro selective GENE inhibitors and compare kinetic mechanisms of binding and enzyme inhibition with other COX inhibitors. Valdecoxib potently inhibits recombinant GENE, with an IC(50) of 0.005 microM; this compares with IC values of 0.05 microM for celecoxib, 0.5 microM for rofecoxib, and 5 microM for CHEMICAL. Unique binding interactions of valdecoxib with GENE translate into a fast rate of inactivation of GENE (110,000 M/s compared with 7000 M/s for rofecoxib and 80 M/s for etoricoxib). The overall saturation binding affinity for GENE of valdecoxib is 2.6 nM (compared with 1.6 nM for celecoxib, 51 nM for rofecoxib, and 260 nM for CHEMICAL), with a slow off-rate (t(1/2) approximately 98 min). Valdecoxib inhibits COX-1 in a competitive fashion only at very high concentrations (IC(50) = 150 microM). Collectively, these data provide a mechanistic basis for the potency and in vitro selectivity of valdecoxib for GENE. Valdecoxib showed similar activity in the human whole-blood COX assay (COX-2 IC(50) = 0.24 microM; COX-1 IC(50) = 21.9 microM). We also determined whether this in vitro potency and selectivity translated to significant potency in vivo. In rats, valdecoxib demonstrated marked potency in acute and chronic models of inflammation (air pouch ED(50) = 0.06 mg/kg; paw edema ED(50) = 5.9 mg/kg; adjuvant arthritis ED(50) = 0.03 mg/kg). In these same animals, COX-1 was spared at doses greater than 200 mg/kg. These data provide a basis for the observed potent anti-inflammatory activity of valdecoxib in humans. | DIRECT-REGULATOR |
| CHEMICAL: assessment of GENE potency and selectivity. The discovery of a second isoform of cyclooxygenase (COX) led to the search for compounds that could selectively inhibit COX-2 in humans while sparing prostaglandin formation from COX-1. Celecoxib and rofecoxib were among the molecules developed from these efforts. We report here the pharmacological properties of a third selective COX-2 inhibitor, valdecoxib, which is the most potent and in vitro selective of the marketed COX-2 inhibitors that we have studied. Recombinant human COX-1 and COX-2 were used to screen for new highly potent and in vitro selective COX-2 inhibitors and compare kinetic mechanisms of binding and enzyme inhibition with other COX inhibitors. CHEMICAL potently inhibits recombinant COX-2, with an IC(50) of 0.005 microM; this compares with IC values of 0.05 microM for celecoxib, 0.5 microM for rofecoxib, and 5 microM for etoricoxib. Unique binding interactions of valdecoxib with COX-2 translate into a fast rate of inactivation of COX-2 (110,000 M/s compared with 7000 M/s for rofecoxib and 80 M/s for etoricoxib). The overall saturation binding affinity for COX-2 of valdecoxib is 2.6 nM (compared with 1.6 nM for celecoxib, 51 nM for rofecoxib, and 260 nM for etoricoxib), with a slow off-rate (t(1/2) approximately 98 min). CHEMICAL inhibits COX-1 in a competitive fashion only at very high concentrations (IC(50) = 150 microM). Collectively, these data provide a mechanistic basis for the potency and in vitro selectivity of valdecoxib for COX-2. CHEMICAL showed similar activity in the human whole-blood COX assay (COX-2 IC(50) = 0.24 microM; COX-1 IC(50) = 21.9 microM). We also determined whether this in vitro potency and selectivity translated to significant potency in vivo. In rats, valdecoxib demonstrated marked potency in acute and chronic models of inflammation (air pouch ED(50) = 0.06 mg/kg; paw edema ED(50) = 5.9 mg/kg; adjuvant arthritis ED(50) = 0.03 mg/kg). In these same animals, COX-1 was spared at doses greater than 200 mg/kg. These data provide a basis for the observed potent anti-inflammatory activity of valdecoxib in humans. | REGULATOR |
| Valdecoxib: assessment of cyclooxygenase-2 potency and selectivity. The discovery of a second isoform of cyclooxygenase (COX) led to the search for compounds that could selectively inhibit COX-2 in humans while sparing prostaglandin formation from GENE. Celecoxib and rofecoxib were among the molecules developed from these efforts. We report here the pharmacological properties of a third selective COX-2 inhibitor, valdecoxib, which is the most potent and in vitro selective of the marketed COX-2 inhibitors that we have studied. Recombinant human GENE and COX-2 were used to screen for new highly potent and in vitro selective COX-2 inhibitors and compare kinetic mechanisms of binding and enzyme inhibition with other COX inhibitors. CHEMICAL potently inhibits recombinant COX-2, with an IC(50) of 0.005 microM; this compares with IC values of 0.05 microM for celecoxib, 0.5 microM for rofecoxib, and 5 microM for etoricoxib. Unique binding interactions of valdecoxib with COX-2 translate into a fast rate of inactivation of COX-2 (110,000 M/s compared with 7000 M/s for rofecoxib and 80 M/s for etoricoxib). The overall saturation binding affinity for COX-2 of valdecoxib is 2.6 nM (compared with 1.6 nM for celecoxib, 51 nM for rofecoxib, and 260 nM for etoricoxib), with a slow off-rate (t(1/2) approximately 98 min). CHEMICAL inhibits GENE in a competitive fashion only at very high concentrations (IC(50) = 150 microM). Collectively, these data provide a mechanistic basis for the potency and in vitro selectivity of valdecoxib for COX-2. CHEMICAL showed similar activity in the human whole-blood COX assay (COX-2 IC(50) = 0.24 microM; GENE IC(50) = 21.9 microM). We also determined whether this in vitro potency and selectivity translated to significant potency in vivo. In rats, valdecoxib demonstrated marked potency in acute and chronic models of inflammation (air pouch ED(50) = 0.06 mg/kg; paw edema ED(50) = 5.9 mg/kg; adjuvant arthritis ED(50) = 0.03 mg/kg). In these same animals, GENE was spared at doses greater than 200 mg/kg. These data provide a basis for the observed potent anti-inflammatory activity of valdecoxib in humans. | INHIBITOR |
| Valdecoxib: assessment of cyclooxygenase-2 potency and selectivity. The discovery of a second isoform of cyclooxygenase (COX) led to the search for compounds that could selectively inhibit COX-2 in humans while sparing prostaglandin formation from COX-1. Celecoxib and rofecoxib were among the molecules developed from these efforts. We report here the pharmacological properties of a third selective COX-2 inhibitor, valdecoxib, which is the most potent and in vitro selective of the marketed COX-2 inhibitors that we have studied. Recombinant human COX-1 and COX-2 were used to screen for new highly potent and in vitro selective COX-2 inhibitors and compare kinetic mechanisms of binding and enzyme inhibition with other COX inhibitors. CHEMICAL potently inhibits recombinant COX-2, with an IC(50) of 0.005 microM; this compares with IC values of 0.05 microM for celecoxib, 0.5 microM for rofecoxib, and 5 microM for etoricoxib. Unique binding interactions of valdecoxib with COX-2 translate into a fast rate of inactivation of COX-2 (110,000 M/s compared with 7000 M/s for rofecoxib and 80 M/s for etoricoxib). The overall saturation binding affinity for COX-2 of valdecoxib is 2.6 nM (compared with 1.6 nM for celecoxib, 51 nM for rofecoxib, and 260 nM for etoricoxib), with a slow off-rate (t(1/2) approximately 98 min). CHEMICAL inhibits COX-1 in a competitive fashion only at very high concentrations (IC(50) = 150 microM). Collectively, these data provide a mechanistic basis for the potency and in vitro selectivity of valdecoxib for COX-2. CHEMICAL showed similar activity in the GENE assay (COX-2 IC(50) = 0.24 microM; COX-1 IC(50) = 21.9 microM). We also determined whether this in vitro potency and selectivity translated to significant potency in vivo. In rats, valdecoxib demonstrated marked potency in acute and chronic models of inflammation (air pouch ED(50) = 0.06 mg/kg; paw edema ED(50) = 5.9 mg/kg; adjuvant arthritis ED(50) = 0.03 mg/kg). In these same animals, COX-1 was spared at doses greater than 200 mg/kg. These data provide a basis for the observed potent anti-inflammatory activity of valdecoxib in humans. | ACTIVATOR |
| Valdecoxib: assessment of cyclooxygenase-2 potency and selectivity. The discovery of a second isoform of cyclooxygenase (COX) led to the search for compounds that could selectively inhibit COX-2 in humans while sparing CHEMICAL formation from GENE. Celecoxib and rofecoxib were among the molecules developed from these efforts. We report here the pharmacological properties of a third selective COX-2 inhibitor, valdecoxib, which is the most potent and in vitro selective of the marketed COX-2 inhibitors that we have studied. Recombinant human GENE and COX-2 were used to screen for new highly potent and in vitro selective COX-2 inhibitors and compare kinetic mechanisms of binding and enzyme inhibition with other COX inhibitors. Valdecoxib potently inhibits recombinant COX-2, with an IC(50) of 0.005 microM; this compares with IC values of 0.05 microM for celecoxib, 0.5 microM for rofecoxib, and 5 microM for etoricoxib. Unique binding interactions of valdecoxib with COX-2 translate into a fast rate of inactivation of COX-2 (110,000 M/s compared with 7000 M/s for rofecoxib and 80 M/s for etoricoxib). The overall saturation binding affinity for COX-2 of valdecoxib is 2.6 nM (compared with 1.6 nM for celecoxib, 51 nM for rofecoxib, and 260 nM for etoricoxib), with a slow off-rate (t(1/2) approximately 98 min). Valdecoxib inhibits GENE in a competitive fashion only at very high concentrations (IC(50) = 150 microM). Collectively, these data provide a mechanistic basis for the potency and in vitro selectivity of valdecoxib for COX-2. Valdecoxib showed similar activity in the human whole-blood COX assay (COX-2 IC(50) = 0.24 microM; GENE IC(50) = 21.9 microM). We also determined whether this in vitro potency and selectivity translated to significant potency in vivo. In rats, valdecoxib demonstrated marked potency in acute and chronic models of inflammation (air pouch ED(50) = 0.06 mg/kg; paw edema ED(50) = 5.9 mg/kg; adjuvant arthritis ED(50) = 0.03 mg/kg). In these same animals, GENE was spared at doses greater than 200 mg/kg. These data provide a basis for the observed potent anti-inflammatory activity of valdecoxib in humans. | PRODUCT-OF |
| An angiotensin II AT1 receptor antagonist, CHEMICAL augments glucose uptake and GENE protein expression in 3T3-L1 adipocytes. Evidence has accumulated that some of the angiotensin II AT1 receptor antagonists have insulin-sensitizing property. We thus examined the effect of CHEMICAL on insulin action using 3T3-L1 adipocytes. With standard differentiation inducers, a higher dose of CHEMICAL effectively facilitated differentiation of 3T3-L1 preadipocytes. Treatment of both differentiating adipocytes and fully differentiated adipocytes with CHEMICAL caused a dose-dependent increase in mRNA levels for PPARgamma target genes such as aP2 and adiponectin. By contrast, CHEMICAL attenuated 11beta-hydroxysteroid dehydrogenase type 1 mRNA level in differentiated adipocytes. Of note, we demonstrated for the first time that CHEMICAL augmented GENE protein expression and 2-deoxy glucose uptake both in basal and insulin-stimulated state of adipocytes, which may contribute, at least partly, to its insulin-sensitizing ability. | INDIRECT-UPREGULATOR |
| An angiotensin II AT1 receptor antagonist, CHEMICAL augments glucose uptake and GLUT4 protein expression in 3T3-L1 adipocytes. Evidence has accumulated that some of the angiotensin II AT1 receptor antagonists have insulin-sensitizing property. We thus examined the effect of CHEMICAL on insulin action using 3T3-L1 adipocytes. With standard differentiation inducers, a higher dose of CHEMICAL effectively facilitated differentiation of 3T3-L1 preadipocytes. Treatment of both differentiating adipocytes and fully differentiated adipocytes with CHEMICAL caused a dose-dependent increase in mRNA levels for GENE target genes such as aP2 and adiponectin. By contrast, CHEMICAL attenuated 11beta-hydroxysteroid dehydrogenase type 1 mRNA level in differentiated adipocytes. Of note, we demonstrated for the first time that CHEMICAL augmented GLUT4 protein expression and 2-deoxy glucose uptake both in basal and insulin-stimulated state of adipocytes, which may contribute, at least partly, to its insulin-sensitizing ability. | INDIRECT-UPREGULATOR |
| An angiotensin II AT1 receptor antagonist, CHEMICAL augments glucose uptake and GLUT4 protein expression in 3T3-L1 adipocytes. Evidence has accumulated that some of the angiotensin II AT1 receptor antagonists have insulin-sensitizing property. We thus examined the effect of CHEMICAL on insulin action using 3T3-L1 adipocytes. With standard differentiation inducers, a higher dose of CHEMICAL effectively facilitated differentiation of 3T3-L1 preadipocytes. Treatment of both differentiating adipocytes and fully differentiated adipocytes with CHEMICAL caused a dose-dependent increase in mRNA levels for PPARgamma target genes such as GENE and adiponectin. By contrast, CHEMICAL attenuated 11beta-hydroxysteroid dehydrogenase type 1 mRNA level in differentiated adipocytes. Of note, we demonstrated for the first time that CHEMICAL augmented GLUT4 protein expression and 2-deoxy glucose uptake both in basal and insulin-stimulated state of adipocytes, which may contribute, at least partly, to its insulin-sensitizing ability. | INDIRECT-UPREGULATOR |
| An angiotensin II AT1 receptor antagonist, CHEMICAL augments glucose uptake and GLUT4 protein expression in 3T3-L1 adipocytes. Evidence has accumulated that some of the angiotensin II AT1 receptor antagonists have insulin-sensitizing property. We thus examined the effect of CHEMICAL on insulin action using 3T3-L1 adipocytes. With standard differentiation inducers, a higher dose of CHEMICAL effectively facilitated differentiation of 3T3-L1 preadipocytes. Treatment of both differentiating adipocytes and fully differentiated adipocytes with CHEMICAL caused a dose-dependent increase in mRNA levels for PPARgamma target genes such as aP2 and GENE. By contrast, CHEMICAL attenuated 11beta-hydroxysteroid dehydrogenase type 1 mRNA level in differentiated adipocytes. Of note, we demonstrated for the first time that CHEMICAL augmented GLUT4 protein expression and 2-deoxy glucose uptake both in basal and insulin-stimulated state of adipocytes, which may contribute, at least partly, to its insulin-sensitizing ability. | INDIRECT-UPREGULATOR |
| An angiotensin II AT1 receptor antagonist, CHEMICAL augments glucose uptake and GLUT4 protein expression in 3T3-L1 adipocytes. Evidence has accumulated that some of the angiotensin II AT1 receptor antagonists have insulin-sensitizing property. We thus examined the effect of CHEMICAL on insulin action using 3T3-L1 adipocytes. With standard differentiation inducers, a higher dose of CHEMICAL effectively facilitated differentiation of 3T3-L1 preadipocytes. Treatment of both differentiating adipocytes and fully differentiated adipocytes with CHEMICAL caused a dose-dependent increase in mRNA levels for PPARgamma target genes such as aP2 and adiponectin. By contrast, CHEMICAL attenuated GENE mRNA level in differentiated adipocytes. Of note, we demonstrated for the first time that CHEMICAL augmented GLUT4 protein expression and 2-deoxy glucose uptake both in basal and insulin-stimulated state of adipocytes, which may contribute, at least partly, to its insulin-sensitizing ability. | INDIRECT-DOWNREGULATOR |
| An GENE antagonist, CHEMICAL augments glucose uptake and GLUT4 protein expression in 3T3-L1 adipocytes. Evidence has accumulated that some of the GENE antagonists have insulin-sensitizing property. We thus examined the effect of CHEMICAL on insulin action using 3T3-L1 adipocytes. With standard differentiation inducers, a higher dose of CHEMICAL effectively facilitated differentiation of 3T3-L1 preadipocytes. Treatment of both differentiating adipocytes and fully differentiated adipocytes with CHEMICAL caused a dose-dependent increase in mRNA levels for PPARgamma target genes such as aP2 and adiponectin. By contrast, CHEMICAL attenuated 11beta-hydroxysteroid dehydrogenase type 1 mRNA level in differentiated adipocytes. Of note, we demonstrated for the first time that CHEMICAL augmented GLUT4 protein expression and 2-deoxy glucose uptake both in basal and insulin-stimulated state of adipocytes, which may contribute, at least partly, to its insulin-sensitizing ability. | INHIBITOR |
| An angiotensin II AT1 receptor antagonist, telmisartan augments CHEMICAL uptake and GENE protein expression in 3T3-L1 adipocytes. Evidence has accumulated that some of the angiotensin II AT1 receptor antagonists have insulin-sensitizing property. We thus examined the effect of telmisartan on insulin action using 3T3-L1 adipocytes. With standard differentiation inducers, a higher dose of telmisartan effectively facilitated differentiation of 3T3-L1 preadipocytes. Treatment of both differentiating adipocytes and fully differentiated adipocytes with telmisartan caused a dose-dependent increase in mRNA levels for PPARgamma target genes such as aP2 and adiponectin. By contrast, telmisartan attenuated 11beta-hydroxysteroid dehydrogenase type 1 mRNA level in differentiated adipocytes. Of note, we demonstrated for the first time that telmisartan augmented GENE protein expression and 2-deoxy CHEMICAL uptake both in basal and insulin-stimulated state of adipocytes, which may contribute, at least partly, to its insulin-sensitizing ability. | SUBSTRATE |
| An angiotensin II AT1 receptor antagonist, telmisartan augments glucose uptake and GENE protein expression in 3T3-L1 adipocytes. Evidence has accumulated that some of the angiotensin II AT1 receptor antagonists have insulin-sensitizing property. We thus examined the effect of telmisartan on insulin action using 3T3-L1 adipocytes. With standard differentiation inducers, a higher dose of telmisartan effectively facilitated differentiation of 3T3-L1 preadipocytes. Treatment of both differentiating adipocytes and fully differentiated adipocytes with telmisartan caused a dose-dependent increase in mRNA levels for PPARgamma target genes such as aP2 and adiponectin. By contrast, telmisartan attenuated 11beta-hydroxysteroid dehydrogenase type 1 mRNA level in differentiated adipocytes. Of note, we demonstrated for the first time that telmisartan augmented GENE protein expression and CHEMICAL uptake both in basal and insulin-stimulated state of adipocytes, which may contribute, at least partly, to its insulin-sensitizing ability. | SUBSTRATE |
| Pharmacogenetic differences in response to albuterol between Puerto Ricans and Mexicans with asthma. BACKGROUND: In the United States, Puerto Ricans and Mexicans have the highest and lowest asthma prevalence, morbidity, and mortality, respectively. Ethnic-specific differences in the response to drug treatment may contribute to differences in disease outcomes. Genetic variants at the beta(2)-adrenergic receptor (beta(2)AR) may modify asthma severity and albuterol responsiveness. We tested the association of beta(2)AR genotypes with asthma severity and bronchodilator response to albuterol in Puerto Ricans and Mexicans with asthma. METHODS: We used both family-based and cross-sectional tests of association with 8 beta(2)AR single nucleotide polymorphisms in 684 Puerto Rican and Mexican families. Regression analyses were used to determine the interaction between genotype, asthma severity, and bronchodilator drug responsiveness. RESULTS: Among Puerto Ricans with asthma, the arginine (Arg) 16 allele was associated with greater bronchodilator response using both family-based and cross-sectional tests (p = 0.00001-0.01). We found a strong interaction of baseline FEV(1) with the GENE (CHEMICAL) polymorphism in predicting bronchodilator response. Among Puerto Ricans with asthma with baseline FEV(1) < 80% of predicted, but not in those with FEV(1) > 80%, there was a very strong association between the Arg16 genotype and greater bronchodilator responsiveness. No association was observed between Arg16Gly genotypes and drug responsiveness among Mexicans with asthma. CONCLUSIONS: Ethnic-specific pharmacogenetic differences exist between Arg16Gly genotypes, asthma severity, and bronchodilator response in Puerto Ricans and Mexicans with asthma. These findings underscore the need for additional research on racial/ethnic differences in asthma morbidity and drug responsiveness. | PART-OF |
| Pharmacogenetic differences in response to CHEMICAL between Puerto Ricans and Mexicans with asthma. BACKGROUND: In the United States, Puerto Ricans and Mexicans have the highest and lowest asthma prevalence, morbidity, and mortality, respectively. Ethnic-specific differences in the response to drug treatment may contribute to differences in disease outcomes. Genetic variants at the GENE (beta(2)AR) may modify asthma severity and CHEMICAL responsiveness. We tested the association of beta(2)AR genotypes with asthma severity and bronchodilator response to CHEMICAL in Puerto Ricans and Mexicans with asthma. METHODS: We used both family-based and cross-sectional tests of association with 8 beta(2)AR single nucleotide polymorphisms in 684 Puerto Rican and Mexican families. Regression analyses were used to determine the interaction between genotype, asthma severity, and bronchodilator drug responsiveness. RESULTS: Among Puerto Ricans with asthma, the arginine (Arg) 16 allele was associated with greater bronchodilator response using both family-based and cross-sectional tests (p = 0.00001-0.01). We found a strong interaction of baseline FEV(1) with the Arg16Glycine (Gly) polymorphism in predicting bronchodilator response. Among Puerto Ricans with asthma with baseline FEV(1) < 80% of predicted, but not in those with FEV(1) > 80%, there was a very strong association between the Arg16 genotype and greater bronchodilator responsiveness. No association was observed between Arg16Gly genotypes and drug responsiveness among Mexicans with asthma. CONCLUSIONS: Ethnic-specific pharmacogenetic differences exist between Arg16Gly genotypes, asthma severity, and bronchodilator response in Puerto Ricans and Mexicans with asthma. These findings underscore the need for additional research on racial/ethnic differences in asthma morbidity and drug responsiveness. | REGULATOR |
| Pharmacogenetic differences in response to CHEMICAL between Puerto Ricans and Mexicans with asthma. BACKGROUND: In the United States, Puerto Ricans and Mexicans have the highest and lowest asthma prevalence, morbidity, and mortality, respectively. Ethnic-specific differences in the response to drug treatment may contribute to differences in disease outcomes. Genetic variants at the beta(2)-adrenergic receptor (GENE) may modify asthma severity and CHEMICAL responsiveness. We tested the association of GENE genotypes with asthma severity and bronchodilator response to CHEMICAL in Puerto Ricans and Mexicans with asthma. METHODS: We used both family-based and cross-sectional tests of association with 8 GENE single nucleotide polymorphisms in 684 Puerto Rican and Mexican families. Regression analyses were used to determine the interaction between genotype, asthma severity, and bronchodilator drug responsiveness. RESULTS: Among Puerto Ricans with asthma, the arginine (Arg) 16 allele was associated with greater bronchodilator response using both family-based and cross-sectional tests (p = 0.00001-0.01). We found a strong interaction of baseline FEV(1) with the Arg16Glycine (Gly) polymorphism in predicting bronchodilator response. Among Puerto Ricans with asthma with baseline FEV(1) < 80% of predicted, but not in those with FEV(1) > 80%, there was a very strong association between the Arg16 genotype and greater bronchodilator responsiveness. No association was observed between Arg16Gly genotypes and drug responsiveness among Mexicans with asthma. CONCLUSIONS: Ethnic-specific pharmacogenetic differences exist between Arg16Gly genotypes, asthma severity, and bronchodilator response in Puerto Ricans and Mexicans with asthma. These findings underscore the need for additional research on racial/ethnic differences in asthma morbidity and drug responsiveness. | REGULATOR |
| GENE inhibitors from Rhododendron collettianum and their structure-activity relationship (SAR) studies. A new coumarinolignoid 8'-epi-cleomiscosin A (1) together with the new glycoside 8-O-beta-D-glucopyranosyl-6-hydroxy-2-methyl-4H-1-benzopyrane-4-one (2) have been isolated from the aerial parts of Rhododendron collettianum and their structures determined on the basis of spectroscopic evidences. GENE inhibition study of these compounds and their structure-activity relationship (SAR) were also investigated. The compounds exhibited potent to mild inhibition activity against the enzyme. Especially, the compound 1 showed strong inhibition (IC50=1.33 microM) against the enzyme GENE, as compared to the standard GENE inhibitors CHEMICAL (IC50=16.67 microM) and L-mimosine (IC50=3.68 microM), indicating its potential used for the treatment of hyperpigmentation associated with the high production of melanocytes. | INHIBITOR |
| GENE inhibitors from Rhododendron collettianum and their structure-activity relationship (SAR) studies. A new coumarinolignoid 8'-epi-cleomiscosin A (1) together with the new glycoside 8-O-beta-D-glucopyranosyl-6-hydroxy-2-methyl-4H-1-benzopyrane-4-one (2) have been isolated from the aerial parts of Rhododendron collettianum and their structures determined on the basis of spectroscopic evidences. GENE inhibition study of these compounds and their structure-activity relationship (SAR) were also investigated. The compounds exhibited potent to mild inhibition activity against the enzyme. Especially, the compound 1 showed strong inhibition (IC50=1.33 microM) against the enzyme GENE, as compared to the standard GENE inhibitors kojic acid (IC50=16.67 microM) and CHEMICAL (IC50=3.68 microM), indicating its potential used for the treatment of hyperpigmentation associated with the high production of melanocytes. | INHIBITOR |
| In vivo activity of the potent oxytocin antagonist on uterine activity in the rat. Oxytocin antagonist (OTA), TT-235, was developed by our group and shown to inhibit either spontaneous or oxytocin-induced uterine contractions in primates. The purpose of the present study was to confirm the duration of TT-235 to block oxytocin-induced uterine contractions in estrous rats. In Experiment 1, the time-response of the three OTAs on uterine contractility was examined. The rats were anesthetized and cannulas were placed in the jugular vein for infusing vehicle (sterile saline), CHEMICAL, Antag II and TT-235. The uterine activity was monitored through a water-filled balloon-tipped cannula placed in the uterine horn. The uterine contractile activity was determined as the integrated area for 10 minutes. Each OTA was administered as a single bolus injection of 5 microg, followed by 100 mU of oxytocin 5 minutes later, also done as a single bolus. Oxytocin injection of the same dosage was repeated every hour for 5 hours. Experiment 2 determined the effect of the three OTAs on uterine GENE number (Rn) and binding affinity (Kd). Rats treated with either OTA or vehicle were sacrificed at 0.5 and 4 hours for receptor assay. In Experiment 1, CHEMICAL, Antag II and TT-235 inhibited the integrated uterine response to oxytocin at 5 minutes by 76%, 77% and 80%, respectively, compared to controls (p<0.05). Two hours after injecting CHEMICAL, inhibition of uterine contractility was 55% lower than controls (p<0.05). At 3 hours, uterine contractility was no longer affected in rats treated with CHEMICAL compared with controls. The suppressive uterine activity with Antag II continued up to 3 hours. However, uterine contractility remained lower (53%) in rats treated with TT-235 5 hours later. In Experiment 2, TT-235 induced a significant decrease (p<0.05) in GENE number and binding affinity at both 0.5 and 4 hours compared with controls. CHEMICAL and Antag II did not alter GENE number or binding affinity significantly at each time point studied compared with controls. In conclusion, TT-235 may inhibit the uterine response to oxytocin by decreasing GENE numbers and oxytocin binding affinity, which might explain the prolonged oxytocin antagonist activity of TT-235. | NO-RELATIONSHIP |
| In vivo activity of the potent oxytocin antagonist on uterine activity in the rat. Oxytocin antagonist (OTA), TT-235, was developed by our group and shown to inhibit either spontaneous or oxytocin-induced uterine contractions in primates. The purpose of the present study was to confirm the duration of TT-235 to block oxytocin-induced uterine contractions in estrous rats. In Experiment 1, the time-response of the three OTAs on uterine contractility was examined. The rats were anesthetized and cannulas were placed in the jugular vein for infusing vehicle (sterile saline), Antag I, CHEMICAL and TT-235. The uterine activity was monitored through a water-filled balloon-tipped cannula placed in the uterine horn. The uterine contractile activity was determined as the integrated area for 10 minutes. Each OTA was administered as a single bolus injection of 5 microg, followed by 100 mU of oxytocin 5 minutes later, also done as a single bolus. Oxytocin injection of the same dosage was repeated every hour for 5 hours. Experiment 2 determined the effect of the three OTAs on uterine GENE number (Rn) and binding affinity (Kd). Rats treated with either OTA or vehicle were sacrificed at 0.5 and 4 hours for receptor assay. In Experiment 1, Antag I, CHEMICAL and TT-235 inhibited the integrated uterine response to oxytocin at 5 minutes by 76%, 77% and 80%, respectively, compared to controls (p<0.05). Two hours after injecting Antag I, inhibition of uterine contractility was 55% lower than controls (p<0.05). At 3 hours, uterine contractility was no longer affected in rats treated with Antag I compared with controls. The suppressive uterine activity with CHEMICAL continued up to 3 hours. However, uterine contractility remained lower (53%) in rats treated with TT-235 5 hours later. In Experiment 2, TT-235 induced a significant decrease (p<0.05) in GENE number and binding affinity at both 0.5 and 4 hours compared with controls. Antag I and CHEMICAL did not alter GENE number or binding affinity significantly at each time point studied compared with controls. In conclusion, TT-235 may inhibit the uterine response to oxytocin by decreasing GENE numbers and oxytocin binding affinity, which might explain the prolonged oxytocin antagonist activity of TT-235. | NO-RELATIONSHIP |
| In vivo activity of the potent oxytocin antagonist on uterine activity in the rat. Oxytocin antagonist (OTA), CHEMICAL, was developed by our group and shown to inhibit either spontaneous or oxytocin-induced uterine contractions in primates. The purpose of the present study was to confirm the duration of CHEMICAL to block oxytocin-induced uterine contractions in estrous rats. In Experiment 1, the time-response of the three OTAs on uterine contractility was examined. The rats were anesthetized and cannulas were placed in the jugular vein for infusing vehicle (sterile saline), Antag I, Antag II and CHEMICAL. The uterine activity was monitored through a water-filled balloon-tipped cannula placed in the uterine horn. The uterine contractile activity was determined as the integrated area for 10 minutes. Each OTA was administered as a single bolus injection of 5 microg, followed by 100 mU of oxytocin 5 minutes later, also done as a single bolus. Oxytocin injection of the same dosage was repeated every hour for 5 hours. Experiment 2 determined the effect of the three OTAs on uterine GENE number (Rn) and binding affinity (Kd). Rats treated with either OTA or vehicle were sacrificed at 0.5 and 4 hours for receptor assay. In Experiment 1, Antag I, Antag II and CHEMICAL inhibited the integrated uterine response to oxytocin at 5 minutes by 76%, 77% and 80%, respectively, compared to controls (p<0.05). Two hours after injecting Antag I, inhibition of uterine contractility was 55% lower than controls (p<0.05). At 3 hours, uterine contractility was no longer affected in rats treated with Antag I compared with controls. The suppressive uterine activity with Antag II continued up to 3 hours. However, uterine contractility remained lower (53%) in rats treated with CHEMICAL 5 hours later. In Experiment 2, CHEMICAL induced a significant decrease (p<0.05) in GENE number and binding affinity at both 0.5 and 4 hours compared with controls. Antag I and Antag II did not alter GENE number or binding affinity significantly at each time point studied compared with controls. In conclusion, CHEMICAL may inhibit the uterine response to oxytocin by decreasing GENE numbers and oxytocin binding affinity, which might explain the prolonged oxytocin antagonist activity of CHEMICAL. | INDIRECT-DOWNREGULATOR |
| In vivo activity of the potent GENE antagonist on uterine activity in the rat. GENE antagonist (OTA), CHEMICAL, was developed by our group and shown to inhibit either spontaneous or oxytocin-induced uterine contractions in primates. The purpose of the present study was to confirm the duration of CHEMICAL to block oxytocin-induced uterine contractions in estrous rats. In Experiment 1, the time-response of the three OTAs on uterine contractility was examined. The rats were anesthetized and cannulas were placed in the jugular vein for infusing vehicle (sterile saline), Antag I, Antag II and CHEMICAL. The uterine activity was monitored through a water-filled balloon-tipped cannula placed in the uterine horn. The uterine contractile activity was determined as the integrated area for 10 minutes. Each OTA was administered as a single bolus injection of 5 microg, followed by 100 mU of GENE 5 minutes later, also done as a single bolus. GENE injection of the same dosage was repeated every hour for 5 hours. Experiment 2 determined the effect of the three OTAs on uterine GENE receptor number (Rn) and binding affinity (Kd). Rats treated with either OTA or vehicle were sacrificed at 0.5 and 4 hours for receptor assay. In Experiment 1, Antag I, Antag II and CHEMICAL inhibited the integrated uterine response to GENE at 5 minutes by 76%, 77% and 80%, respectively, compared to controls (p<0.05). Two hours after injecting Antag I, inhibition of uterine contractility was 55% lower than controls (p<0.05). At 3 hours, uterine contractility was no longer affected in rats treated with Antag I compared with controls. The suppressive uterine activity with Antag II continued up to 3 hours. However, uterine contractility remained lower (53%) in rats treated with CHEMICAL 5 hours later. In Experiment 2, CHEMICAL induced a significant decrease (p<0.05) in GENE receptor number and binding affinity at both 0.5 and 4 hours compared with controls. Antag I and Antag II did not alter GENE receptor number or binding affinity significantly at each time point studied compared with controls. In conclusion, CHEMICAL may inhibit the uterine response to GENE by decreasing GENE receptor numbers and GENE binding affinity, which might explain the prolonged GENE antagonist activity of CHEMICAL. | INHIBITOR |
| In vivo activity of the potent GENE antagonist on uterine activity in the rat. GENE antagonist (OTA), TT-235, was developed by our group and shown to inhibit either spontaneous or oxytocin-induced uterine contractions in primates. The purpose of the present study was to confirm the duration of TT-235 to block oxytocin-induced uterine contractions in estrous rats. In Experiment 1, the time-response of the three OTAs on uterine contractility was examined. The rats were anesthetized and cannulas were placed in the jugular vein for infusing vehicle (sterile saline), CHEMICAL, Antag II and TT-235. The uterine activity was monitored through a water-filled balloon-tipped cannula placed in the uterine horn. The uterine contractile activity was determined as the integrated area for 10 minutes. Each OTA was administered as a single bolus injection of 5 microg, followed by 100 mU of GENE 5 minutes later, also done as a single bolus. GENE injection of the same dosage was repeated every hour for 5 hours. Experiment 2 determined the effect of the three OTAs on uterine GENE receptor number (Rn) and binding affinity (Kd). Rats treated with either OTA or vehicle were sacrificed at 0.5 and 4 hours for receptor assay. In Experiment 1, CHEMICAL, Antag II and TT-235 inhibited the integrated uterine response to GENE at 5 minutes by 76%, 77% and 80%, respectively, compared to controls (p<0.05). Two hours after injecting CHEMICAL, inhibition of uterine contractility was 55% lower than controls (p<0.05). At 3 hours, uterine contractility was no longer affected in rats treated with CHEMICAL compared with controls. The suppressive uterine activity with Antag II continued up to 3 hours. However, uterine contractility remained lower (53%) in rats treated with TT-235 5 hours later. In Experiment 2, TT-235 induced a significant decrease (p<0.05) in GENE receptor number and binding affinity at both 0.5 and 4 hours compared with controls. CHEMICAL and Antag II did not alter GENE receptor number or binding affinity significantly at each time point studied compared with controls. In conclusion, TT-235 may inhibit the uterine response to GENE by decreasing GENE receptor numbers and GENE binding affinity, which might explain the prolonged GENE antagonist activity of TT-235. | NO-RELATIONSHIP |
| In vivo activity of the potent GENE antagonist on uterine activity in the rat. GENE antagonist (OTA), TT-235, was developed by our group and shown to inhibit either spontaneous or oxytocin-induced uterine contractions in primates. The purpose of the present study was to confirm the duration of TT-235 to block oxytocin-induced uterine contractions in estrous rats. In Experiment 1, the time-response of the three OTAs on uterine contractility was examined. The rats were anesthetized and cannulas were placed in the jugular vein for infusing vehicle (sterile saline), Antag I, CHEMICAL and TT-235. The uterine activity was monitored through a water-filled balloon-tipped cannula placed in the uterine horn. The uterine contractile activity was determined as the integrated area for 10 minutes. Each OTA was administered as a single bolus injection of 5 microg, followed by 100 mU of GENE 5 minutes later, also done as a single bolus. GENE injection of the same dosage was repeated every hour for 5 hours. Experiment 2 determined the effect of the three OTAs on uterine GENE receptor number (Rn) and binding affinity (Kd). Rats treated with either OTA or vehicle were sacrificed at 0.5 and 4 hours for receptor assay. In Experiment 1, Antag I, CHEMICAL and TT-235 inhibited the integrated uterine response to GENE at 5 minutes by 76%, 77% and 80%, respectively, compared to controls (p<0.05). Two hours after injecting Antag I, inhibition of uterine contractility was 55% lower than controls (p<0.05). At 3 hours, uterine contractility was no longer affected in rats treated with Antag I compared with controls. The suppressive uterine activity with CHEMICAL continued up to 3 hours. However, uterine contractility remained lower (53%) in rats treated with TT-235 5 hours later. In Experiment 2, TT-235 induced a significant decrease (p<0.05) in GENE receptor number and binding affinity at both 0.5 and 4 hours compared with controls. Antag I and CHEMICAL did not alter GENE receptor number or binding affinity significantly at each time point studied compared with controls. In conclusion, TT-235 may inhibit the uterine response to GENE by decreasing GENE receptor numbers and GENE binding affinity, which might explain the prolonged GENE antagonist activity of TT-235. | NO-RELATIONSHIP |
| In vivo activity of the potent oxytocin antagonist on uterine activity in the rat. GENE antagonist (OTA), CHEMICAL, was developed by our group and shown to inhibit either spontaneous or oxytocin-induced uterine contractions in primates. The purpose of the present study was to confirm the duration of CHEMICAL to block oxytocin-induced uterine contractions in estrous rats. In Experiment 1, the time-response of the three OTAs on uterine contractility was examined. The rats were anesthetized and cannulas were placed in the jugular vein for infusing vehicle (sterile saline), Antag I, Antag II and CHEMICAL. The uterine activity was monitored through a water-filled balloon-tipped cannula placed in the uterine horn. The uterine contractile activity was determined as the integrated area for 10 minutes. Each OTA was administered as a single bolus injection of 5 microg, followed by 100 mU of oxytocin 5 minutes later, also done as a single bolus. GENE injection of the same dosage was repeated every hour for 5 hours. Experiment 2 determined the effect of the three OTAs on uterine oxytocin receptor number (Rn) and binding affinity (Kd). Rats treated with either OTA or vehicle were sacrificed at 0.5 and 4 hours for receptor assay. In Experiment 1, Antag I, Antag II and CHEMICAL inhibited the integrated uterine response to oxytocin at 5 minutes by 76%, 77% and 80%, respectively, compared to controls (p<0.05). Two hours after injecting Antag I, inhibition of uterine contractility was 55% lower than controls (p<0.05). At 3 hours, uterine contractility was no longer affected in rats treated with Antag I compared with controls. The suppressive uterine activity with Antag II continued up to 3 hours. However, uterine contractility remained lower (53%) in rats treated with CHEMICAL 5 hours later. In Experiment 2, CHEMICAL induced a significant decrease (p<0.05) in oxytocin receptor number and binding affinity at both 0.5 and 4 hours compared with controls. Antag I and Antag II did not alter oxytocin receptor number or binding affinity significantly at each time point studied compared with controls. In conclusion, CHEMICAL may inhibit the uterine response to oxytocin by decreasing oxytocin receptor numbers and oxytocin binding affinity, which might explain the prolonged oxytocin antagonist activity of CHEMICAL. | INHIBITOR |
| Preclinical pharmacology of lumiracoxib: a novel selective inhibitor of cyclooxygenase-2. 1. This manuscript presents the preclinical profile of CHEMICAL, a novel cyclooxygenase-2 (COX-2) selective inhibitor. 2. CHEMICAL inhibited purified GENE and COX-2 with K(i) values of 3 and 0.06 microM, respectively. In cellular assays, CHEMICAL had an IC(50) of 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition of GENE at concentrations up to 30 microM (HEK 293 cells transfected with human COX-1). 3. In a human whole blood assay, IC(50) values for CHEMICAL were 0.13 microM for COX-2 and 67 microM for GENE (COX-1/COX-2 selectivity ratio 515). 4. CHEMICAL was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5. Ex vivo, CHEMICAL inhibited COX-1-derived thromboxane B(2) (TxB(2)) generation with an ID(50) of 33 mg kg(-1), whereas COX-2-derived production of prostaglandin E(2) (PGE(2)) in the lipopolysaccharide-stimulated rat air pouch was inhibited with an ID(50) value of 0.24 mg kg(-1). 6. Efficacy of CHEMICAL in rat models of hyperalgesia, oedema, pyresis and arthritis was dose-dependent and similar to diclofenac. However, consistent with its low GENE inhibitory activity, CHEMICAL at a dose of 100 mg kg(-1) orally caused no ulcers and was significantly less ulcerogenic than diclofenac (P<0.05). 7. CHEMICAL is a highly selective COX-2 inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with diclofenac, the reference NSAID, but with much improved gastrointestinal safety. | NO-RELATIONSHIP |
| Preclinical pharmacology of lumiracoxib: a novel selective inhibitor of GENE. 1. This manuscript presents the preclinical profile of CHEMICAL, a novel GENE (COX-2) selective inhibitor. 2. CHEMICAL inhibited purified COX-1 and COX-2 with K(i) values of 3 and 0.06 microM, respectively. In cellular assays, CHEMICAL had an IC(50) of 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition of COX-1 at concentrations up to 30 microM (HEK 293 cells transfected with human COX-1). 3. In a human whole blood assay, IC(50) values for CHEMICAL were 0.13 microM for COX-2 and 67 microM for COX-1 (COX-1/COX-2 selectivity ratio 515). 4. CHEMICAL was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5. Ex vivo, CHEMICAL inhibited COX-1-derived thromboxane B(2) (TxB(2)) generation with an ID(50) of 33 mg kg(-1), whereas COX-2-derived production of prostaglandin E(2) (PGE(2)) in the lipopolysaccharide-stimulated rat air pouch was inhibited with an ID(50) value of 0.24 mg kg(-1). 6. Efficacy of CHEMICAL in rat models of hyperalgesia, oedema, pyresis and arthritis was dose-dependent and similar to diclofenac. However, consistent with its low COX-1 inhibitory activity, CHEMICAL at a dose of 100 mg kg(-1) orally caused no ulcers and was significantly less ulcerogenic than diclofenac (P<0.05). 7. CHEMICAL is a highly selective COX-2 inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with diclofenac, the reference NSAID, but with much improved gastrointestinal safety. | INHIBITOR |
| Preclinical pharmacology of lumiracoxib: a novel selective inhibitor of cyclooxygenase-2. 1. This manuscript presents the preclinical profile of CHEMICAL, a novel cyclooxygenase-2 (GENE) selective inhibitor. 2. CHEMICAL inhibited purified COX-1 and GENE with K(i) values of 3 and 0.06 microM, respectively. In cellular assays, CHEMICAL had an IC(50) of 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition of COX-1 at concentrations up to 30 microM (HEK 293 cells transfected with human COX-1). 3. In a human whole blood assay, IC(50) values for CHEMICAL were 0.13 microM for GENE and 67 microM for COX-1 (COX-1/COX-2 selectivity ratio 515). 4. CHEMICAL was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5. Ex vivo, CHEMICAL inhibited COX-1-derived thromboxane B(2) (TxB(2)) generation with an ID(50) of 33 mg kg(-1), whereas COX-2-derived production of prostaglandin E(2) (PGE(2)) in the lipopolysaccharide-stimulated rat air pouch was inhibited with an ID(50) value of 0.24 mg kg(-1). 6. Efficacy of CHEMICAL in rat models of hyperalgesia, oedema, pyresis and arthritis was dose-dependent and similar to diclofenac. However, consistent with its low COX-1 inhibitory activity, CHEMICAL at a dose of 100 mg kg(-1) orally caused no ulcers and was significantly less ulcerogenic than diclofenac (P<0.05). 7. CHEMICAL is a highly selective GENE inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with diclofenac, the reference NSAID, but with much improved gastrointestinal safety. | INHIBITOR |
| Preclinical pharmacology of lumiracoxib: a novel selective inhibitor of cyclooxygenase-2. 1. This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor. 2. Lumiracoxib inhibited purified GENE and COX-2 with K(i) values of 3 and 0.06 microM, respectively. In cellular assays, lumiracoxib had an IC(50) of 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition of GENE at concentrations up to 30 microM (HEK 293 cells transfected with human COX-1). 3. In a human whole blood assay, IC(50) values for lumiracoxib were 0.13 microM for COX-2 and 67 microM for GENE (COX-1/COX-2 selectivity ratio 515). 4. Lumiracoxib was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5. Ex vivo, lumiracoxib inhibited COX-1-derived thromboxane B(2) (TxB(2)) generation with an ID(50) of 33 mg kg(-1), whereas COX-2-derived production of prostaglandin E(2) (PGE(2)) in the lipopolysaccharide-stimulated rat air pouch was inhibited with an ID(50) value of 0.24 mg kg(-1). 6. Efficacy of lumiracoxib in rat models of hyperalgesia, oedema, pyresis and arthritis was dose-dependent and similar to CHEMICAL. However, consistent with its low GENE inhibitory activity, lumiracoxib at a dose of 100 mg kg(-1) orally caused no ulcers and was significantly less ulcerogenic than CHEMICAL (P<0.05). 7. Lumiracoxib is a highly selective COX-2 inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with CHEMICAL, the reference NSAID, but with much improved gastrointestinal safety. | INHIBITOR |
| Preclinical pharmacology of lumiracoxib: a novel selective inhibitor of cyclooxygenase-2. 1. This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor. 2. Lumiracoxib inhibited purified COX-1 and GENE with K(i) values of 3 and 0.06 microM, respectively. In cellular assays, lumiracoxib had an IC(50) of 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition of COX-1 at concentrations up to 30 microM (HEK 293 cells transfected with human COX-1). 3. In a human whole blood assay, IC(50) values for lumiracoxib were 0.13 microM for GENE and 67 microM for COX-1 (COX-1/COX-2 selectivity ratio 515). 4. Lumiracoxib was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5. Ex vivo, lumiracoxib inhibited COX-1-derived thromboxane B(2) (TxB(2)) generation with an ID(50) of 33 mg kg(-1), whereas COX-2-derived production of prostaglandin E(2) (PGE(2)) in the lipopolysaccharide-stimulated rat air pouch was inhibited with an ID(50) value of 0.24 mg kg(-1). 6. Efficacy of lumiracoxib in rat models of hyperalgesia, oedema, pyresis and arthritis was dose-dependent and similar to CHEMICAL. However, consistent with its low COX-1 inhibitory activity, lumiracoxib at a dose of 100 mg kg(-1) orally caused no ulcers and was significantly less ulcerogenic than CHEMICAL (P<0.05). 7. Lumiracoxib is a highly selective GENE inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with CHEMICAL, the reference NSAID, but with much improved gastrointestinal safety. | INHIBITOR |
| Preclinical pharmacology of lumiracoxib: a novel selective inhibitor of cyclooxygenase-2. 1. This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor. 2. Lumiracoxib inhibited purified GENE and COX-2 with K(i) values of 3 and 0.06 microM, respectively. In cellular assays, lumiracoxib had an IC(50) of 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition of GENE at concentrations up to 30 microM (HEK 293 cells transfected with human COX-1). 3. In a human whole blood assay, IC(50) values for lumiracoxib were 0.13 microM for COX-2 and 67 microM for GENE (COX-1/COX-2 selectivity ratio 515). 4. Lumiracoxib was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5. Ex vivo, lumiracoxib inhibited GENE-derived CHEMICAL (TxB(2)) generation with an ID(50) of 33 mg kg(-1), whereas COX-2-derived production of prostaglandin E(2) (PGE(2)) in the lipopolysaccharide-stimulated rat air pouch was inhibited with an ID(50) value of 0.24 mg kg(-1). 6. Efficacy of lumiracoxib in rat models of hyperalgesia, oedema, pyresis and arthritis was dose-dependent and similar to diclofenac. However, consistent with its low GENE inhibitory activity, lumiracoxib at a dose of 100 mg kg(-1) orally caused no ulcers and was significantly less ulcerogenic than diclofenac (P<0.05). 7. Lumiracoxib is a highly selective COX-2 inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with diclofenac, the reference NSAID, but with much improved gastrointestinal safety. | PRODUCT-OF |
| Preclinical pharmacology of lumiracoxib: a novel selective inhibitor of cyclooxygenase-2. 1. This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor. 2. Lumiracoxib inhibited purified GENE and COX-2 with K(i) values of 3 and 0.06 microM, respectively. In cellular assays, lumiracoxib had an IC(50) of 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition of GENE at concentrations up to 30 microM (HEK 293 cells transfected with human COX-1). 3. In a human whole blood assay, IC(50) values for lumiracoxib were 0.13 microM for COX-2 and 67 microM for GENE (COX-1/COX-2 selectivity ratio 515). 4. Lumiracoxib was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5. Ex vivo, lumiracoxib inhibited GENE-derived thromboxane B(2) (CHEMICAL) generation with an ID(50) of 33 mg kg(-1), whereas COX-2-derived production of prostaglandin E(2) (PGE(2)) in the lipopolysaccharide-stimulated rat air pouch was inhibited with an ID(50) value of 0.24 mg kg(-1). 6. Efficacy of lumiracoxib in rat models of hyperalgesia, oedema, pyresis and arthritis was dose-dependent and similar to diclofenac. However, consistent with its low GENE inhibitory activity, lumiracoxib at a dose of 100 mg kg(-1) orally caused no ulcers and was significantly less ulcerogenic than diclofenac (P<0.05). 7. Lumiracoxib is a highly selective COX-2 inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with diclofenac, the reference NSAID, but with much improved gastrointestinal safety. | PRODUCT-OF |
| Preclinical pharmacology of lumiracoxib: a novel selective inhibitor of cyclooxygenase-2. 1. This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor. 2. Lumiracoxib inhibited purified COX-1 and GENE with K(i) values of 3 and 0.06 microM, respectively. In cellular assays, lumiracoxib had an IC(50) of 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition of COX-1 at concentrations up to 30 microM (HEK 293 cells transfected with human COX-1). 3. In a human whole blood assay, IC(50) values for lumiracoxib were 0.13 microM for GENE and 67 microM for COX-1 (COX-1/COX-2 selectivity ratio 515). 4. Lumiracoxib was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5. Ex vivo, lumiracoxib inhibited COX-1-derived thromboxane B(2) (TxB(2)) generation with an ID(50) of 33 mg kg(-1), whereas GENE-derived production of CHEMICAL (PGE(2)) in the lipopolysaccharide-stimulated rat air pouch was inhibited with an ID(50) value of 0.24 mg kg(-1). 6. Efficacy of lumiracoxib in rat models of hyperalgesia, oedema, pyresis and arthritis was dose-dependent and similar to diclofenac. However, consistent with its low COX-1 inhibitory activity, lumiracoxib at a dose of 100 mg kg(-1) orally caused no ulcers and was significantly less ulcerogenic than diclofenac (P<0.05). 7. Lumiracoxib is a highly selective GENE inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with diclofenac, the reference NSAID, but with much improved gastrointestinal safety. | PRODUCT-OF |
| Preclinical pharmacology of lumiracoxib: a novel selective inhibitor of cyclooxygenase-2. 1. This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor. 2. Lumiracoxib inhibited purified COX-1 and GENE with K(i) values of 3 and 0.06 microM, respectively. In cellular assays, lumiracoxib had an IC(50) of 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition of COX-1 at concentrations up to 30 microM (HEK 293 cells transfected with human COX-1). 3. In a human whole blood assay, IC(50) values for lumiracoxib were 0.13 microM for GENE and 67 microM for COX-1 (COX-1/COX-2 selectivity ratio 515). 4. Lumiracoxib was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5. Ex vivo, lumiracoxib inhibited COX-1-derived thromboxane B(2) (TxB(2)) generation with an ID(50) of 33 mg kg(-1), whereas GENE-derived production of prostaglandin E(2) (CHEMICAL) in the lipopolysaccharide-stimulated rat air pouch was inhibited with an ID(50) value of 0.24 mg kg(-1). 6. Efficacy of lumiracoxib in rat models of hyperalgesia, oedema, pyresis and arthritis was dose-dependent and similar to diclofenac. However, consistent with its low COX-1 inhibitory activity, lumiracoxib at a dose of 100 mg kg(-1) orally caused no ulcers and was significantly less ulcerogenic than diclofenac (P<0.05). 7. Lumiracoxib is a highly selective GENE inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with diclofenac, the reference NSAID, but with much improved gastrointestinal safety. | PRODUCT-OF |
| Cloning, sequencing, structural and molecular biological characterization of placental protein 20 (PP20)/human thiamin pyrophosphokinase (hTPK). Full-length cDNAs of placental protein 20 (PP20) were cloned by screening a human placental cDNA library, which encode a 243 amino acid protein, identical to human thiamin pyrophosphokinase (hTPK) as confirmed by protein sequence analysis. Genomic alignment showed that the PP20/hTPK gene contains 9 exons. It is abundantly expressed in placenta, as numerous EST clones were identified. As CHEMICAL metabolism deficiencies have been seen in placental infarcts previously, these indicate that GENE/hTPK may have a role in placental diseases. Analysis of the 1kb promoter region showed numerous putative transcription factor binding sites, which might be responsible for the ubiquitous PP20/hTPK expression. This may also be in accordance with the presence of the protein in tissues responsible for the regulation of the exquisite balance between cell division, differentiation and survival. TPK activity of the purified and recombinant protein was proved by mass spectrometry with electrospray ionization. By Western blot, PP20/hTPK was found in all human normal and tumorous adult and fetal tissues in nearly equal amounts, but not in sera. By immunohistochemical and immunofluorescent confocal imaging methods, diffuse labelling in the cytoplasm of the syncytiotrophoblasts and weak staining of the trophoblasts were observed, and the amount of PP20/hTPK decreased from the first trimester to the end of gestation. A 3D model of PP20/hTPK was computed (PDB No.: 1OLY) by homology modelling. A high degree of structural homology showed that the thiamin binding site was highly similar to that of the mouse enzyme, but highly different from the bacterial ones. Comparison of the catalytic centre sequences revealed differences, raising the possibility of designing new drugs which specifically inhibit bacterial and fungal enzymes without affecting PP20/hTPK and offering the possibility for safe antimicrobial therapy during pregnancy. | SUBSTRATE |
| Cloning, sequencing, structural and molecular biological characterization of placental protein 20 (PP20)/human thiamin pyrophosphokinase (hTPK). Full-length cDNAs of placental protein 20 (PP20) were cloned by screening a human placental cDNA library, which encode a 243 amino acid protein, identical to human thiamin pyrophosphokinase (hTPK) as confirmed by protein sequence analysis. Genomic alignment showed that the PP20/hTPK gene contains 9 exons. It is abundantly expressed in placenta, as numerous EST clones were identified. As CHEMICAL metabolism deficiencies have been seen in placental infarcts previously, these indicate that PP20/GENE may have a role in placental diseases. Analysis of the 1kb promoter region showed numerous putative transcription factor binding sites, which might be responsible for the ubiquitous PP20/hTPK expression. This may also be in accordance with the presence of the protein in tissues responsible for the regulation of the exquisite balance between cell division, differentiation and survival. TPK activity of the purified and recombinant protein was proved by mass spectrometry with electrospray ionization. By Western blot, PP20/hTPK was found in all human normal and tumorous adult and fetal tissues in nearly equal amounts, but not in sera. By immunohistochemical and immunofluorescent confocal imaging methods, diffuse labelling in the cytoplasm of the syncytiotrophoblasts and weak staining of the trophoblasts were observed, and the amount of PP20/hTPK decreased from the first trimester to the end of gestation. A 3D model of PP20/hTPK was computed (PDB No.: 1OLY) by homology modelling. A high degree of structural homology showed that the thiamin binding site was highly similar to that of the mouse enzyme, but highly different from the bacterial ones. Comparison of the catalytic centre sequences revealed differences, raising the possibility of designing new drugs which specifically inhibit bacterial and fungal enzymes without affecting PP20/hTPK and offering the possibility for safe antimicrobial therapy during pregnancy. | SUBSTRATE |
| Safety and tolerability of denufosol tetrasodium inhalation solution, a novel P2Y2 receptor agonist: results of a phase 1/phase 2 multicenter study in mild to moderate cystic fibrosis. CHEMICAL tetrasodium (INS37217) is a selective GENE agonist that stimulates ciliary beat frequency and Cl(-) secretion in normal and cystic fibrosis (CF) airway epithelia, and is being investigated as an inhaled treatment for CF. The Cl(-) secretory response is mediated via a non-CFTR pathway, and the driving force for Cl(-) secretion is enhanced by the effect of GENE activation to also inhibit epithelial Na(+) transport. CHEMICAL is metabolically more stable and better tolerated, and may enhance mucociliary clearance for a longer period of time than previously investigated GENE agonists. The goal of this phase 1/phase 2 study was to assess the safety and tolerability of single and repeated doses of aerosolized denufosol in subjects with CF. The study was a double-blind, placebo-controlled, multicenter comparison of ascending single doses of denufosol (10, 20, 40, and 60 mg, administered by inhalation via the Pari LC Star nebulizer) vs. placebo (normal saline), followed by a comparison of twice-daily administration of the maximum tolerated dose (MTD) of denufosol or placebo for 5 days. Thirty-seven adult (18 years of age or older) and 24 pediatric (5-17 years of age) subjects with CF were evaluated in five cohorts. Subjects were randomized in a 3:1 ratio to receive either denufosol or placebo within each cohort. The percent of subjects experiencing adverse events was similar between the denufosol and placebo groups. The most common adverse event in subjects receiving denufosol was chest tightness in adult subjects (39%) and cough in pediatric subjects (56%). Three (7%) subjects receiving denufosol and one (7%) subject receiving placebo experienced a serious adverse event. Forced expiratory volume in 1 sec (FEV(1)) profiles following dosing were similar across treatment groups, with some acute, reversible decline seen in both groups, most notably in subjects with lower lung function at baseline. In conclusion, doses up to 60 mg of denufosol inhalation solution were well-tolerated in most subjects. Some intolerability was noted among subjects with lower baseline lung function. Based on the results of this phase 1/phase 2 study, the Therapeutics Development Network (TDN) of the Cystic Fibrosis Foundation (CFF) and Inspire Pharmaceuticals, Inc., recently completed a multicenter, 28-day, phase 2 safety and efficacy clinical trial of denufosol inhalation solution in CF subjects with mild lung disease. | ACTIVATOR |
| Safety and tolerability of CHEMICAL inhalation solution, a novel GENE agonist: results of a phase 1/phase 2 multicenter study in mild to moderate cystic fibrosis. CHEMICAL (INS37217) is a selective P2Y(2) agonist that stimulates ciliary beat frequency and Cl(-) secretion in normal and cystic fibrosis (CF) airway epithelia, and is being investigated as an inhaled treatment for CF. The Cl(-) secretory response is mediated via a non-CFTR pathway, and the driving force for Cl(-) secretion is enhanced by the effect of P2Y(2) activation to also inhibit epithelial Na(+) transport. Denufosol is metabolically more stable and better tolerated, and may enhance mucociliary clearance for a longer period of time than previously investigated P2Y(2) agonists. The goal of this phase 1/phase 2 study was to assess the safety and tolerability of single and repeated doses of aerosolized denufosol in subjects with CF. The study was a double-blind, placebo-controlled, multicenter comparison of ascending single doses of denufosol (10, 20, 40, and 60 mg, administered by inhalation via the Pari LC Star nebulizer) vs. placebo (normal saline), followed by a comparison of twice-daily administration of the maximum tolerated dose (MTD) of denufosol or placebo for 5 days. Thirty-seven adult (18 years of age or older) and 24 pediatric (5-17 years of age) subjects with CF were evaluated in five cohorts. Subjects were randomized in a 3:1 ratio to receive either denufosol or placebo within each cohort. The percent of subjects experiencing adverse events was similar between the denufosol and placebo groups. The most common adverse event in subjects receiving denufosol was chest tightness in adult subjects (39%) and cough in pediatric subjects (56%). Three (7%) subjects receiving denufosol and one (7%) subject receiving placebo experienced a serious adverse event. Forced expiratory volume in 1 sec (FEV(1)) profiles following dosing were similar across treatment groups, with some acute, reversible decline seen in both groups, most notably in subjects with lower lung function at baseline. In conclusion, doses up to 60 mg of denufosol inhalation solution were well-tolerated in most subjects. Some intolerability was noted among subjects with lower baseline lung function. Based on the results of this phase 1/phase 2 study, the Therapeutics Development Network (TDN) of the Cystic Fibrosis Foundation (CFF) and Inspire Pharmaceuticals, Inc., recently completed a multicenter, 28-day, phase 2 safety and efficacy clinical trial of denufosol inhalation solution in CF subjects with mild lung disease. | ACTIVATOR |
| Safety and tolerability of denufosol tetrasodium inhalation solution, a novel P2Y2 receptor agonist: results of a phase 1/phase 2 multicenter study in mild to moderate cystic fibrosis. CHEMICAL (INS37217) is a selective GENE agonist that stimulates ciliary beat frequency and Cl(-) secretion in normal and cystic fibrosis (CF) airway epithelia, and is being investigated as an inhaled treatment for CF. The Cl(-) secretory response is mediated via a non-CFTR pathway, and the driving force for Cl(-) secretion is enhanced by the effect of GENE activation to also inhibit epithelial Na(+) transport. Denufosol is metabolically more stable and better tolerated, and may enhance mucociliary clearance for a longer period of time than previously investigated GENE agonists. The goal of this phase 1/phase 2 study was to assess the safety and tolerability of single and repeated doses of aerosolized denufosol in subjects with CF. The study was a double-blind, placebo-controlled, multicenter comparison of ascending single doses of denufosol (10, 20, 40, and 60 mg, administered by inhalation via the Pari LC Star nebulizer) vs. placebo (normal saline), followed by a comparison of twice-daily administration of the maximum tolerated dose (MTD) of denufosol or placebo for 5 days. Thirty-seven adult (18 years of age or older) and 24 pediatric (5-17 years of age) subjects with CF were evaluated in five cohorts. Subjects were randomized in a 3:1 ratio to receive either denufosol or placebo within each cohort. The percent of subjects experiencing adverse events was similar between the denufosol and placebo groups. The most common adverse event in subjects receiving denufosol was chest tightness in adult subjects (39%) and cough in pediatric subjects (56%). Three (7%) subjects receiving denufosol and one (7%) subject receiving placebo experienced a serious adverse event. Forced expiratory volume in 1 sec (FEV(1)) profiles following dosing were similar across treatment groups, with some acute, reversible decline seen in both groups, most notably in subjects with lower lung function at baseline. In conclusion, doses up to 60 mg of denufosol inhalation solution were well-tolerated in most subjects. Some intolerability was noted among subjects with lower baseline lung function. Based on the results of this phase 1/phase 2 study, the Therapeutics Development Network (TDN) of the Cystic Fibrosis Foundation (CFF) and Inspire Pharmaceuticals, Inc., recently completed a multicenter, 28-day, phase 2 safety and efficacy clinical trial of denufosol inhalation solution in CF subjects with mild lung disease. | ACTIVATOR |
| Safety and tolerability of denufosol tetrasodium inhalation solution, a novel P2Y2 receptor agonist: results of a phase 1/phase 2 multicenter study in mild to moderate cystic fibrosis. Denufosol tetrasodium (CHEMICAL) is a selective GENE agonist that stimulates ciliary beat frequency and Cl(-) secretion in normal and cystic fibrosis (CF) airway epithelia, and is being investigated as an inhaled treatment for CF. The Cl(-) secretory response is mediated via a non-CFTR pathway, and the driving force for Cl(-) secretion is enhanced by the effect of GENE activation to also inhibit epithelial Na(+) transport. Denufosol is metabolically more stable and better tolerated, and may enhance mucociliary clearance for a longer period of time than previously investigated GENE agonists. The goal of this phase 1/phase 2 study was to assess the safety and tolerability of single and repeated doses of aerosolized denufosol in subjects with CF. The study was a double-blind, placebo-controlled, multicenter comparison of ascending single doses of denufosol (10, 20, 40, and 60 mg, administered by inhalation via the Pari LC Star nebulizer) vs. placebo (normal saline), followed by a comparison of twice-daily administration of the maximum tolerated dose (MTD) of denufosol or placebo for 5 days. Thirty-seven adult (18 years of age or older) and 24 pediatric (5-17 years of age) subjects with CF were evaluated in five cohorts. Subjects were randomized in a 3:1 ratio to receive either denufosol or placebo within each cohort. The percent of subjects experiencing adverse events was similar between the denufosol and placebo groups. The most common adverse event in subjects receiving denufosol was chest tightness in adult subjects (39%) and cough in pediatric subjects (56%). Three (7%) subjects receiving denufosol and one (7%) subject receiving placebo experienced a serious adverse event. Forced expiratory volume in 1 sec (FEV(1)) profiles following dosing were similar across treatment groups, with some acute, reversible decline seen in both groups, most notably in subjects with lower lung function at baseline. In conclusion, doses up to 60 mg of denufosol inhalation solution were well-tolerated in most subjects. Some intolerability was noted among subjects with lower baseline lung function. Based on the results of this phase 1/phase 2 study, the Therapeutics Development Network (TDN) of the Cystic Fibrosis Foundation (CFF) and Inspire Pharmaceuticals, Inc., recently completed a multicenter, 28-day, phase 2 safety and efficacy clinical trial of denufosol inhalation solution in CF subjects with mild lung disease. | ACTIVATOR |
| Safety and tolerability of denufosol tetrasodium inhalation solution, a novel P2Y2 receptor agonist: results of a phase 1/phase 2 multicenter study in mild to moderate cystic fibrosis. Denufosol tetrasodium (INS37217) is a selective P2Y(2) agonist that stimulates ciliary beat frequency and CHEMICAL secretion in normal and cystic fibrosis (CF) airway epithelia, and is being investigated as an inhaled treatment for CF. The CHEMICAL secretory response is mediated via a non-GENE pathway, and the driving force for CHEMICAL secretion is enhanced by the effect of P2Y(2) activation to also inhibit epithelial Na(+) transport. Denufosol is metabolically more stable and better tolerated, and may enhance mucociliary clearance for a longer period of time than previously investigated P2Y(2) agonists. The goal of this phase 1/phase 2 study was to assess the safety and tolerability of single and repeated doses of aerosolized denufosol in subjects with CF. The study was a double-blind, placebo-controlled, multicenter comparison of ascending single doses of denufosol (10, 20, 40, and 60 mg, administered by inhalation via the Pari LC Star nebulizer) vs. placebo (normal saline), followed by a comparison of twice-daily administration of the maximum tolerated dose (MTD) of denufosol or placebo for 5 days. Thirty-seven adult (18 years of age or older) and 24 pediatric (5-17 years of age) subjects with CF were evaluated in five cohorts. Subjects were randomized in a 3:1 ratio to receive either denufosol or placebo within each cohort. The percent of subjects experiencing adverse events was similar between the denufosol and placebo groups. The most common adverse event in subjects receiving denufosol was chest tightness in adult subjects (39%) and cough in pediatric subjects (56%). Three (7%) subjects receiving denufosol and one (7%) subject receiving placebo experienced a serious adverse event. Forced expiratory volume in 1 sec (FEV(1)) profiles following dosing were similar across treatment groups, with some acute, reversible decline seen in both groups, most notably in subjects with lower lung function at baseline. In conclusion, doses up to 60 mg of denufosol inhalation solution were well-tolerated in most subjects. Some intolerability was noted among subjects with lower baseline lung function. Based on the results of this phase 1/phase 2 study, the Therapeutics Development Network (TDN) of the Cystic Fibrosis Foundation (CFF) and Inspire Pharmaceuticals, Inc., recently completed a multicenter, 28-day, phase 2 safety and efficacy clinical trial of denufosol inhalation solution in CF subjects with mild lung disease. | SUBSTRATE |
| The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan. In a previous study, we demonstrated that a dextromethorphan analog, dimemorfan, has neuroprotective effects. CHEMICAL and dimemorfan are high-affinity ligands at GENE. CHEMICAL has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan. Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with dimemorfan (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner. Dimemorfan pre-treatment also attenuated the KA-induced increases in c-fos/c-jun expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of dimemorfan were comparable to those of dextromethorphan. The anticonvulsant action of dextromethorphan or dimemorfan was significantly counteracted by a selective sigma1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or dimemorfan is, at least in part, related to sigma1 receptor-activated modulation of AP-1 transcription factors. We asked whether dimemorfan produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with dimemorfan showed no behavioral side effects. Our results suggest that dimemorfan is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions. | DIRECT-REGULATOR |
| The dextromethorphan analog CHEMICAL attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan. In a previous study, we demonstrated that a dextromethorphan analog, CHEMICAL, has neuroprotective effects. Dextromethorphan and CHEMICAL are high-affinity ligands at GENE. Dextromethorphan has moderate affinities for phencyclidine sites, while CHEMICAL has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of CHEMICAL. Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with CHEMICAL (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner. CHEMICAL pre-treatment also attenuated the KA-induced increases in c-fos/c-jun expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of CHEMICAL were comparable to those of dextromethorphan. The anticonvulsant action of dextromethorphan or CHEMICAL was significantly counteracted by a selective sigma1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or CHEMICAL is, at least in part, related to sigma1 receptor-activated modulation of AP-1 transcription factors. We asked whether CHEMICAL produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with CHEMICAL showed no behavioral side effects. Our results suggest that CHEMICAL is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions. | DIRECT-REGULATOR |
| The CHEMICAL analog dimemorfan attenuates kainate-induced seizures via GENE activation: comparison with the effects of CHEMICAL. In a previous study, we demonstrated that a CHEMICAL analog, dimemorfan, has neuroprotective effects. CHEMICAL and dimemorfan are high-affinity ligands at sigma1 receptors. CHEMICAL has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan. Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with dimemorfan (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner. Dimemorfan pre-treatment also attenuated the KA-induced increases in c-fos/c-jun expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of dimemorfan were comparable to those of CHEMICAL. The anticonvulsant action of CHEMICAL or dimemorfan was significantly counteracted by a selective GENE antagonist BD 1047, suggesting that the anticonvulsant action of CHEMICAL or dimemorfan is, at least in part, related to GENE-activated modulation of AP-1 transcription factors. We asked whether dimemorfan produces the behavioral side effects seen with CHEMICAL or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or CHEMICAL, while mice treated with dimemorfan showed no behavioral side effects. Our results suggest that dimemorfan is equipotent to CHEMICAL in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions. | ACTIVATOR |
| The CHEMICAL analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of CHEMICAL. In a previous study, we demonstrated that a CHEMICAL analog, dimemorfan, has neuroprotective effects. CHEMICAL and dimemorfan are high-affinity ligands at sigma1 receptors. CHEMICAL has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan. Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with dimemorfan (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner. Dimemorfan pre-treatment also attenuated the KA-induced increases in c-fos/c-jun expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of dimemorfan were comparable to those of CHEMICAL. The anticonvulsant action of CHEMICAL or dimemorfan was significantly counteracted by a selective sigma1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of CHEMICAL or dimemorfan is, at least in part, related to sigma1 receptor-activated modulation of GENE transcription factors. We asked whether dimemorfan produces the behavioral side effects seen with CHEMICAL or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or CHEMICAL, while mice treated with dimemorfan showed no behavioral side effects. Our results suggest that dimemorfan is equipotent to CHEMICAL in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions. | GENE-CHEMICAL |
| The dextromethorphan analog CHEMICAL attenuates kainate-induced seizures via GENE activation: comparison with the effects of dextromethorphan. In a previous study, we demonstrated that a dextromethorphan analog, CHEMICAL, has neuroprotective effects. Dextromethorphan and CHEMICAL are high-affinity ligands at sigma1 receptors. Dextromethorphan has moderate affinities for phencyclidine sites, while CHEMICAL has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of CHEMICAL. Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with CHEMICAL (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner. CHEMICAL pre-treatment also attenuated the KA-induced increases in c-fos/c-jun expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of CHEMICAL were comparable to those of dextromethorphan. The anticonvulsant action of dextromethorphan or CHEMICAL was significantly counteracted by a selective GENE antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or CHEMICAL is, at least in part, related to GENE-activated modulation of AP-1 transcription factors. We asked whether CHEMICAL produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with CHEMICAL showed no behavioral side effects. Our results suggest that CHEMICAL is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions. | ACTIVATOR |
| The dextromethorphan analog CHEMICAL attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan. In a previous study, we demonstrated that a dextromethorphan analog, CHEMICAL, has neuroprotective effects. Dextromethorphan and CHEMICAL are high-affinity ligands at sigma1 receptors. Dextromethorphan has moderate affinities for phencyclidine sites, while CHEMICAL has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of CHEMICAL. Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with CHEMICAL (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner. CHEMICAL pre-treatment also attenuated the KA-induced increases in c-fos/c-jun expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of CHEMICAL were comparable to those of dextromethorphan. The anticonvulsant action of dextromethorphan or CHEMICAL was significantly counteracted by a selective sigma1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or CHEMICAL is, at least in part, related to sigma1 receptor-activated modulation of GENE transcription factors. We asked whether CHEMICAL produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with CHEMICAL showed no behavioral side effects. Our results suggest that CHEMICAL is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions. | NO-RELATIONSHIP |
| The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan. In a previous study, we demonstrated that a dextromethorphan analog, dimemorfan, has neuroprotective effects. Dextromethorphan and dimemorfan are high-affinity ligands at sigma1 receptors. Dextromethorphan has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan. Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with dimemorfan (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner. Dimemorfan pre-treatment also attenuated the CHEMICAL-induced increases in c-fos/c-jun expression, GENE DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of dimemorfan were comparable to those of dextromethorphan. The anticonvulsant action of dextromethorphan or dimemorfan was significantly counteracted by a selective sigma1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or dimemorfan is, at least in part, related to sigma1 receptor-activated modulation of AP-1 transcription factors. We asked whether dimemorfan produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with dimemorfan showed no behavioral side effects. Our results suggest that dimemorfan is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions. | ACTIVATOR |
| The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan. In a previous study, we demonstrated that a dextromethorphan analog, dimemorfan, has neuroprotective effects. Dextromethorphan and dimemorfan are high-affinity ligands at sigma1 receptors. Dextromethorphan has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan. Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with dimemorfan (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner. Dimemorfan pre-treatment also attenuated the CHEMICAL-induced increases in GENE/c-jun expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of dimemorfan were comparable to those of dextromethorphan. The anticonvulsant action of dextromethorphan or dimemorfan was significantly counteracted by a selective sigma1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or dimemorfan is, at least in part, related to sigma1 receptor-activated modulation of AP-1 transcription factors. We asked whether dimemorfan produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with dimemorfan showed no behavioral side effects. Our results suggest that dimemorfan is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions. | INDIRECT-UPREGULATOR |
| The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan. In a previous study, we demonstrated that a dextromethorphan analog, dimemorfan, has neuroprotective effects. Dextromethorphan and dimemorfan are high-affinity ligands at sigma1 receptors. Dextromethorphan has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan. Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with dimemorfan (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner. Dimemorfan pre-treatment also attenuated the CHEMICAL-induced increases in c-fos/GENE expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of dimemorfan were comparable to those of dextromethorphan. The anticonvulsant action of dextromethorphan or dimemorfan was significantly counteracted by a selective sigma1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or dimemorfan is, at least in part, related to sigma1 receptor-activated modulation of AP-1 transcription factors. We asked whether dimemorfan produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with dimemorfan showed no behavioral side effects. Our results suggest that dimemorfan is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions. | INDIRECT-UPREGULATOR |
| The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan. In a previous study, we demonstrated that a dextromethorphan analog, dimemorfan, has neuroprotective effects. Dextromethorphan and dimemorfan are high-affinity ligands at sigma1 receptors. Dextromethorphan has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan. Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with dimemorfan (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner. CHEMICAL pre-treatment also attenuated the KA-induced increases in GENE/c-jun expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of dimemorfan were comparable to those of dextromethorphan. The anticonvulsant action of dextromethorphan or dimemorfan was significantly counteracted by a selective sigma1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or dimemorfan is, at least in part, related to sigma1 receptor-activated modulation of AP-1 transcription factors. We asked whether dimemorfan produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with dimemorfan showed no behavioral side effects. Our results suggest that dimemorfan is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions. | INDIRECT-DOWNREGULATOR |
| The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan. In a previous study, we demonstrated that a dextromethorphan analog, dimemorfan, has neuroprotective effects. Dextromethorphan and dimemorfan are high-affinity ligands at sigma1 receptors. Dextromethorphan has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan. Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with dimemorfan (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner. CHEMICAL pre-treatment also attenuated the KA-induced increases in c-fos/GENE expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of dimemorfan were comparable to those of dextromethorphan. The anticonvulsant action of dextromethorphan or dimemorfan was significantly counteracted by a selective sigma1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or dimemorfan is, at least in part, related to sigma1 receptor-activated modulation of AP-1 transcription factors. We asked whether dimemorfan produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with dimemorfan showed no behavioral side effects. Our results suggest that dimemorfan is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions. | INDIRECT-DOWNREGULATOR |
| The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan. In a previous study, we demonstrated that a dextromethorphan analog, dimemorfan, has neuroprotective effects. Dextromethorphan and dimemorfan are high-affinity ligands at sigma1 receptors. Dextromethorphan has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan. Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with dimemorfan (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner. CHEMICAL pre-treatment also attenuated the KA-induced increases in c-fos/c-jun expression, GENE DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of dimemorfan were comparable to those of dextromethorphan. The anticonvulsant action of dextromethorphan or dimemorfan was significantly counteracted by a selective sigma1 receptor antagonist BD 1047, suggesting that the anticonvulsant action of dextromethorphan or dimemorfan is, at least in part, related to sigma1 receptor-activated modulation of AP-1 transcription factors. We asked whether dimemorfan produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with dimemorfan showed no behavioral side effects. Our results suggest that dimemorfan is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions. | INDIRECT-DOWNREGULATOR |
| The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via GENE activation: comparison with the effects of dextromethorphan. In a previous study, we demonstrated that a dextromethorphan analog, dimemorfan, has neuroprotective effects. Dextromethorphan and dimemorfan are high-affinity ligands at sigma1 receptors. Dextromethorphan has moderate affinities for phencyclidine sites, while dimemorfan has very low affinities for such sites, suggesting that these sites are not essential for the anticonvulsant actions of dimemorfan. Kainate (KA) administration (10 mg kg(-1), i.p.) produced robust convulsions lasting 4-6 h in rats. Pre-treatment with dimemorfan (12 or 24 mg kg(-1)) reduced seizures in a dose-dependent manner. Dimemorfan pre-treatment also attenuated the KA-induced increases in c-fos/c-jun expression, activator protein (AP)-1 DNA-binding activity, and loss of cells in the CA1 and CA3 fields of the hippocampus. These effects of dimemorfan were comparable to those of dextromethorphan. The anticonvulsant action of dextromethorphan or dimemorfan was significantly counteracted by a selective GENE antagonist CHEMICAL, suggesting that the anticonvulsant action of dextromethorphan or dimemorfan is, at least in part, related to sigma1 receptor-activated modulation of AP-1 transcription factors. We asked whether dimemorfan produces the behavioral side effects seen with dextromethorphan or dextrorphan (a phencyclidine-like metabolite of dextromethorphan). Conditioned place preference and circling behaviors were significantly increased in mice treated with phencyclidine, dextrorphan or dextromethorphan, while mice treated with dimemorfan showed no behavioral side effects. Our results suggest that dimemorfan is equipotent to dextromethorphan in preventing KA-induced seizures, while it may lack behavioral effects, such as psychotomimetic reactions. | INHIBITOR |
| Binding domains of the GENE for the selective GENE antagonist barusiban in comparison to the agonists oxytocin and carbetocin. We have analyzed binding domains of the GENE for barusiban, a highly selective GENE antagonist, in comparison to the combined vasopressin V1A/oxytocin receptor antagonist atosiban and the agonists oxytocin and carbetocin. For this purpose, chimeric 'gain-in function' oxytocin/vasopressin V2 receptors were expressed in COS-7 cells. These recombinant receptors have been produced by transfer of domains from the GENE into the related vasopressin V2 receptor and have already been successfully employed for the identification of ligand binding domains at the GENE (Postina, R., Kojro, E., Fahrenholz, F., 1996. Separate agonist and peptide antagonist binding sites of the GENE defined by their transfer into the V2 vasopressin receptor. J. Biol. Chem. 271, 31593-31601). In displacement studies with 10 chimeric receptor constructs, the binding profile of barusiban was compared with the binding profiles of the ligands oxytocin, [Arg8]vasopressin, carbetocin, and atosiban. The binding profiles for the agonists oxytocin and carbetocin were found to be similar. For both agonists, important binding domains were the extracellular CHEMICAL-terminus (=E1) and the extracellular loops E2 and E3 from the GENE. For the vasopressin V1A/oxytocin receptor antagonist atosiban, none of the receptor constructs were able to provide a binding with higher affinity than the starting vasopressin V2 receptor. In contrast, the binding of barusiban was significantly improved when the transmembrane domains 1 and 2 were transferred from the GENE to the vasopressin V2 receptor. The binding domain of barusiban differs from the binding domain of the agonists and the nonselective GENE antagonist d(CH2)5[Tyr-(Me)2,Thr4,Orn8,Tyr9]vasotocin that has been used in previous studies. Overall, the data supported the concept of a central pocket site within the GENE. | PART-OF |
| Binding domains of the oxytocin receptor for the selective oxytocin receptor antagonist CHEMICAL in comparison to the agonists oxytocin and carbetocin. We have analyzed binding domains of the oxytocin receptor for CHEMICAL, a highly selective oxytocin receptor antagonist, in comparison to the combined vasopressin V1A/oxytocin receptor antagonist atosiban and the agonists oxytocin and carbetocin. For this purpose, chimeric 'gain-in function' oxytocin/vasopressin V2 receptors were expressed in COS-7 cells. These recombinant receptors have been produced by transfer of domains from the oxytocin receptor into the related GENE and have already been successfully employed for the identification of ligand binding domains at the oxytocin receptor (Postina, R., Kojro, E., Fahrenholz, F., 1996. Separate agonist and peptide antagonist binding sites of the oxytocin receptor defined by their transfer into the V2 vasopressin receptor. J. Biol. Chem. 271, 31593-31601). In displacement studies with 10 chimeric receptor constructs, the binding profile of CHEMICAL was compared with the binding profiles of the ligands oxytocin, [Arg8]vasopressin, carbetocin, and atosiban. The binding profiles for the agonists oxytocin and carbetocin were found to be similar. For both agonists, important binding domains were the extracellular N-terminus (=E1) and the extracellular loops E2 and E3 from the oxytocin receptor. For the vasopressin V1A/oxytocin receptor antagonist atosiban, none of the receptor constructs were able to provide a binding with higher affinity than the starting GENE. In contrast, the binding of CHEMICAL was significantly improved when the transmembrane domains 1 and 2 were transferred from the oxytocin receptor to the GENE. The binding domain of CHEMICAL differs from the binding domain of the agonists and the nonselective oxytocin receptor antagonist d(CH2)5[Tyr-(Me)2,Thr4,Orn8,Tyr9]vasotocin that has been used in previous studies. Overall, the data supported the concept of a central pocket site within the oxytocin receptor. | DIRECT-REGULATOR |
| Binding domains of the GENE for the selective GENE antagonist CHEMICAL in comparison to the agonists oxytocin and carbetocin. We have analyzed binding domains of the GENE for CHEMICAL, a highly selective GENE antagonist, in comparison to the combined vasopressin V1A/oxytocin receptor antagonist atosiban and the agonists oxytocin and carbetocin. For this purpose, chimeric 'gain-in function' oxytocin/vasopressin V2 receptors were expressed in COS-7 cells. These recombinant receptors have been produced by transfer of domains from the GENE into the related vasopressin V2 receptor and have already been successfully employed for the identification of ligand binding domains at the GENE (Postina, R., Kojro, E., Fahrenholz, F., 1996. Separate agonist and peptide antagonist binding sites of the GENE defined by their transfer into the V2 vasopressin receptor. J. Biol. Chem. 271, 31593-31601). In displacement studies with 10 chimeric receptor constructs, the binding profile of CHEMICAL was compared with the binding profiles of the ligands oxytocin, [Arg8]vasopressin, carbetocin, and atosiban. The binding profiles for the agonists oxytocin and carbetocin were found to be similar. For both agonists, important binding domains were the extracellular N-terminus (=E1) and the extracellular loops E2 and E3 from the GENE. For the vasopressin V1A/oxytocin receptor antagonist atosiban, none of the receptor constructs were able to provide a binding with higher affinity than the starting vasopressin V2 receptor. In contrast, the binding of CHEMICAL was significantly improved when the transmembrane domains 1 and 2 were transferred from the GENE to the vasopressin V2 receptor. The binding domain of CHEMICAL differs from the binding domain of the agonists and the nonselective GENE antagonist d(CH2)5[Tyr-(Me)2,Thr4,Orn8,Tyr9]vasotocin that has been used in previous studies. Overall, the data supported the concept of a central pocket site within the GENE. | INHIBITOR |
| Binding domains of the oxytocin receptor for the selective oxytocin receptor antagonist barusiban in comparison to the agonists oxytocin and carbetocin. We have analyzed binding domains of the oxytocin receptor for barusiban, a highly selective oxytocin receptor antagonist, in comparison to the combined vasopressin V1A/oxytocin receptor antagonist CHEMICAL and the agonists oxytocin and carbetocin. For this purpose, chimeric 'gain-in function' oxytocin/vasopressin V2 receptors were expressed in COS-7 cells. These recombinant receptors have been produced by transfer of domains from the oxytocin receptor into the related GENE and have already been successfully employed for the identification of ligand binding domains at the oxytocin receptor (Postina, R., Kojro, E., Fahrenholz, F., 1996. Separate agonist and peptide antagonist binding sites of the oxytocin receptor defined by their transfer into the V2 vasopressin receptor. J. Biol. Chem. 271, 31593-31601). In displacement studies with 10 chimeric receptor constructs, the binding profile of barusiban was compared with the binding profiles of the ligands oxytocin, [Arg8]vasopressin, carbetocin, and CHEMICAL. The binding profiles for the agonists oxytocin and carbetocin were found to be similar. For both agonists, important binding domains were the extracellular N-terminus (=E1) and the extracellular loops E2 and E3 from the oxytocin receptor. For the vasopressin V1A/oxytocin receptor antagonist CHEMICAL, none of the receptor constructs were able to provide a binding with higher affinity than the starting GENE. In contrast, the binding of barusiban was significantly improved when the transmembrane domains 1 and 2 were transferred from the oxytocin receptor to the GENE. The binding domain of barusiban differs from the binding domain of the agonists and the nonselective oxytocin receptor antagonist d(CH2)5[Tyr-(Me)2,Thr4,Orn8,Tyr9]vasotocin that has been used in previous studies. Overall, the data supported the concept of a central pocket site within the oxytocin receptor. | NO-RELATIONSHIP |
| Binding domains of the CHEMICAL receptor for the selective CHEMICAL receptor antagonist barusiban in comparison to the agonists CHEMICAL and carbetocin. We have analyzed binding domains of the CHEMICAL receptor for barusiban, a highly selective CHEMICAL receptor antagonist, in comparison to the combined GENE antagonist atosiban and the agonists CHEMICAL and carbetocin. For this purpose, chimeric 'gain-in function' oxytocin/vasopressin V2 receptors were expressed in COS-7 cells. These recombinant receptors have been produced by transfer of domains from the CHEMICAL receptor into the related vasopressin V2 receptor and have already been successfully employed for the identification of ligand binding domains at the CHEMICAL receptor (Postina, R., Kojro, E., Fahrenholz, F., 1996. Separate agonist and peptide antagonist binding sites of the CHEMICAL receptor defined by their transfer into the V2 vasopressin receptor. J. Biol. Chem. 271, 31593-31601). In displacement studies with 10 chimeric receptor constructs, the binding profile of barusiban was compared with the binding profiles of the ligands CHEMICAL, [Arg8]vasopressin, carbetocin, and atosiban. The binding profiles for the agonists CHEMICAL and carbetocin were found to be similar. For both agonists, important binding domains were the extracellular N-terminus (=E1) and the extracellular loops E2 and E3 from the CHEMICAL receptor. For the GENE antagonist atosiban, none of the receptor constructs were able to provide a binding with higher affinity than the starting vasopressin V2 receptor. In contrast, the binding of barusiban was significantly improved when the transmembrane domains 1 and 2 were transferred from the CHEMICAL receptor to the vasopressin V2 receptor. The binding domain of barusiban differs from the binding domain of the agonists and the nonselective CHEMICAL receptor antagonist d(CH2)5[Tyr-(Me)2,Thr4,Orn8,Tyr9]vasotocin that has been used in previous studies. Overall, the data supported the concept of a central pocket site within the CHEMICAL receptor. | INHIBITOR |
| Binding domains of the oxytocin receptor for the selective oxytocin receptor antagonist barusiban in comparison to the agonists oxytocin and CHEMICAL. We have analyzed binding domains of the oxytocin receptor for barusiban, a highly selective oxytocin receptor antagonist, in comparison to the combined GENE antagonist atosiban and the agonists oxytocin and CHEMICAL. For this purpose, chimeric 'gain-in function' oxytocin/vasopressin V2 receptors were expressed in COS-7 cells. These recombinant receptors have been produced by transfer of domains from the oxytocin receptor into the related vasopressin V2 receptor and have already been successfully employed for the identification of ligand binding domains at the oxytocin receptor (Postina, R., Kojro, E., Fahrenholz, F., 1996. Separate agonist and peptide antagonist binding sites of the oxytocin receptor defined by their transfer into the V2 vasopressin receptor. J. Biol. Chem. 271, 31593-31601). In displacement studies with 10 chimeric receptor constructs, the binding profile of barusiban was compared with the binding profiles of the ligands oxytocin, [Arg8]vasopressin, CHEMICAL, and atosiban. The binding profiles for the agonists oxytocin and CHEMICAL were found to be similar. For both agonists, important binding domains were the extracellular N-terminus (=E1) and the extracellular loops E2 and E3 from the oxytocin receptor. For the GENE antagonist atosiban, none of the receptor constructs were able to provide a binding with higher affinity than the starting vasopressin V2 receptor. In contrast, the binding of barusiban was significantly improved when the transmembrane domains 1 and 2 were transferred from the oxytocin receptor to the vasopressin V2 receptor. The binding domain of barusiban differs from the binding domain of the agonists and the nonselective oxytocin receptor antagonist d(CH2)5[Tyr-(Me)2,Thr4,Orn8,Tyr9]vasotocin that has been used in previous studies. Overall, the data supported the concept of a central pocket site within the oxytocin receptor. | ACTIVATOR |
| Binding domains of the CHEMICAL receptor for the selective GENE antagonist barusiban in comparison to the agonists CHEMICAL and carbetocin. We have analyzed binding domains of the CHEMICAL receptor for barusiban, a highly selective CHEMICAL receptor antagonist, in comparison to the combined vasopressin V1A/oxytocin receptor antagonist atosiban and the agonists CHEMICAL and carbetocin. For this purpose, chimeric 'gain-in function' oxytocin/vasopressin V2 receptors were expressed in COS-7 cells. These recombinant receptors have been produced by transfer of domains from the CHEMICAL receptor into the related vasopressin V2 receptor and have already been successfully employed for the identification of ligand binding domains at the CHEMICAL receptor (Postina, R., Kojro, E., Fahrenholz, F., 1996. Separate agonist and peptide antagonist binding sites of the CHEMICAL receptor defined by their transfer into the V2 vasopressin receptor. J. Biol. Chem. 271, 31593-31601). In displacement studies with 10 chimeric receptor constructs, the binding profile of barusiban was compared with the binding profiles of the ligands CHEMICAL, [Arg8]vasopressin, carbetocin, and atosiban. The binding profiles for the agonists CHEMICAL and carbetocin were found to be similar. For both agonists, important binding domains were the extracellular N-terminus (=E1) and the extracellular loops E2 and E3 from the CHEMICAL receptor. For the vasopressin V1A/oxytocin receptor antagonist atosiban, none of the receptor constructs were able to provide a binding with higher affinity than the starting vasopressin V2 receptor. In contrast, the binding of barusiban was significantly improved when the transmembrane domains 1 and 2 were transferred from the CHEMICAL receptor to the vasopressin V2 receptor. The binding domain of barusiban differs from the binding domain of the agonists and the nonselective CHEMICAL receptor antagonist d(CH2)5[Tyr-(Me)2,Thr4,Orn8,Tyr9]vasotocin that has been used in previous studies. Overall, the data supported the concept of a central pocket site within the CHEMICAL receptor. | ACTIVATOR |
| Binding domains of the GENE for the selective GENE antagonist barusiban in comparison to the agonists oxytocin and CHEMICAL. We have analyzed binding domains of the GENE for barusiban, a highly selective GENE antagonist, in comparison to the combined vasopressin V1A/oxytocin receptor antagonist atosiban and the agonists oxytocin and CHEMICAL. For this purpose, chimeric 'gain-in function' oxytocin/vasopressin V2 receptors were expressed in COS-7 cells. These recombinant receptors have been produced by transfer of domains from the GENE into the related vasopressin V2 receptor and have already been successfully employed for the identification of ligand binding domains at the GENE (Postina, R., Kojro, E., Fahrenholz, F., 1996. Separate agonist and peptide antagonist binding sites of the GENE defined by their transfer into the V2 vasopressin receptor. J. Biol. Chem. 271, 31593-31601). In displacement studies with 10 chimeric receptor constructs, the binding profile of barusiban was compared with the binding profiles of the ligands oxytocin, [Arg8]vasopressin, CHEMICAL, and atosiban. The binding profiles for the agonists oxytocin and CHEMICAL were found to be similar. For both agonists, important binding domains were the extracellular N-terminus (=E1) and the extracellular loops E2 and E3 from the GENE. For the vasopressin V1A/oxytocin receptor antagonist atosiban, none of the receptor constructs were able to provide a binding with higher affinity than the starting vasopressin V2 receptor. In contrast, the binding of barusiban was significantly improved when the transmembrane domains 1 and 2 were transferred from the GENE to the vasopressin V2 receptor. The binding domain of barusiban differs from the binding domain of the agonists and the nonselective GENE antagonist d(CH2)5[Tyr-(Me)2,Thr4,Orn8,Tyr9]vasotocin that has been used in previous studies. Overall, the data supported the concept of a central pocket site within the GENE. | ACTIVATOR |
| Binding domains of the GENE for the selective GENE antagonist barusiban in comparison to the agonists oxytocin and carbetocin. We have analyzed binding domains of the GENE for barusiban, a highly selective GENE antagonist, in comparison to the combined vasopressin V1A/oxytocin receptor antagonist atosiban and the agonists oxytocin and carbetocin. For this purpose, chimeric 'gain-in function' oxytocin/vasopressin V2 receptors were expressed in COS-7 cells. These recombinant receptors have been produced by transfer of domains from the GENE into the related vasopressin V2 receptor and have already been successfully employed for the identification of ligand binding domains at the GENE (Postina, R., Kojro, E., Fahrenholz, F., 1996. Separate agonist and peptide antagonist binding sites of the GENE defined by their transfer into the V2 vasopressin receptor. J. Biol. Chem. 271, 31593-31601). In displacement studies with 10 chimeric receptor constructs, the binding profile of barusiban was compared with the binding profiles of the ligands oxytocin, [Arg8]vasopressin, carbetocin, and atosiban. The binding profiles for the agonists oxytocin and carbetocin were found to be similar. For both agonists, important binding domains were the extracellular N-terminus (=E1) and the extracellular loops E2 and E3 from the GENE. For the vasopressin V1A/oxytocin receptor antagonist atosiban, none of the receptor constructs were able to provide a binding with higher affinity than the starting vasopressin V2 receptor. In contrast, the binding of barusiban was significantly improved when the transmembrane domains 1 and 2 were transferred from the GENE to the vasopressin V2 receptor. The binding domain of barusiban differs from the binding domain of the agonists and the nonselective GENE antagonist CHEMICAL that has been used in previous studies. Overall, the data supported the concept of a central pocket site within the GENE. | INHIBITOR |
| Binding domains of the oxytocin receptor for the selective oxytocin receptor antagonist barusiban in comparison to the agonists oxytocin and carbetocin. We have analyzed binding domains of the oxytocin receptor for barusiban, a highly selective oxytocin receptor antagonist, in comparison to the combined GENE antagonist CHEMICAL and the agonists oxytocin and carbetocin. For this purpose, chimeric 'gain-in function' oxytocin/vasopressin V2 receptors were expressed in COS-7 cells. These recombinant receptors have been produced by transfer of domains from the oxytocin receptor into the related vasopressin V2 receptor and have already been successfully employed for the identification of ligand binding domains at the oxytocin receptor (Postina, R., Kojro, E., Fahrenholz, F., 1996. Separate agonist and peptide antagonist binding sites of the oxytocin receptor defined by their transfer into the V2 vasopressin receptor. J. Biol. Chem. 271, 31593-31601). In displacement studies with 10 chimeric receptor constructs, the binding profile of barusiban was compared with the binding profiles of the ligands oxytocin, [Arg8]vasopressin, carbetocin, and CHEMICAL. The binding profiles for the agonists oxytocin and carbetocin were found to be similar. For both agonists, important binding domains were the extracellular N-terminus (=E1) and the extracellular loops E2 and E3 from the oxytocin receptor. For the GENE antagonist CHEMICAL, none of the receptor constructs were able to provide a binding with higher affinity than the starting vasopressin V2 receptor. In contrast, the binding of barusiban was significantly improved when the transmembrane domains 1 and 2 were transferred from the oxytocin receptor to the vasopressin V2 receptor. The binding domain of barusiban differs from the binding domain of the agonists and the nonselective oxytocin receptor antagonist d(CH2)5[Tyr-(Me)2,Thr4,Orn8,Tyr9]vasotocin that has been used in previous studies. Overall, the data supported the concept of a central pocket site within the oxytocin receptor. | INHIBITOR |
| Effect of 5-azacytidine and procainamide on GENE expression in Jurkat T cells. It has been observed that decrease of DNA methyltransferase 1 (DNMT1) activity is associated with low content of the CD3-zeta (zeta) chain in T cell receptor (TCR)/CD3 complex of T cells in systemic lupus erythematosus (SLE) patients. The GENE plays a pivotal role in intracellular signal transmission between TCR/CD3 complex and nuclei. The compounds 5'-azacytidine (AZC) and procainamide (PCA) belong to inhibitors of DNMT1, whose low activity correlates with increase in transcription of various genes. Using the reverse-transcription and real-time quantitative PCR (RQ-PCR) analysis, we indicated that CHEMICAL and PCA did not profoundly affect on GENE transcription in Jurkat T leukemia cells clone E6-1. However, the flowcytometric analysis revealed that CHEMICAL and PCA decreased intracellular contents of GENE in these cells in dose dependent manner. Our results suggest that decrease of DNMT1 activity may alter intracellular signal transmission without effect on transcription level of GENE. | NO-RELATIONSHIP |
| Effect of 5-azacytidine and procainamide on GENE expression in Jurkat T cells. It has been observed that decrease of DNA methyltransferase 1 (DNMT1) activity is associated with low content of the CD3-zeta (zeta) chain in T cell receptor (TCR)/CD3 complex of T cells in systemic lupus erythematosus (SLE) patients. The GENE plays a pivotal role in intracellular signal transmission between TCR/CD3 complex and nuclei. The compounds 5'-azacytidine (AZC) and procainamide (PCA) belong to inhibitors of DNMT1, whose low activity correlates with increase in transcription of various genes. Using the reverse-transcription and real-time quantitative PCR (RQ-PCR) analysis, we indicated that AZC and CHEMICAL did not profoundly affect on GENE transcription in Jurkat T leukemia cells clone E6-1. However, the flowcytometric analysis revealed that AZC and CHEMICAL decreased intracellular contents of GENE in these cells in dose dependent manner. Our results suggest that decrease of DNMT1 activity may alter intracellular signal transmission without effect on transcription level of GENE. | NO-RELATIONSHIP |
| Effect of 5-azacytidine and procainamide on CD3-zeta chain expression in Jurkat T cells. It has been observed that decrease of DNA methyltransferase 1 (DNMT1) activity is associated with low content of the CD3-zeta (zeta) chain in T cell receptor (TCR)/CD3 complex of T cells in systemic lupus erythematosus (SLE) patients. The CD3-zeta chain plays a pivotal role in intracellular signal transmission between TCR/CD3 complex and nuclei. The compounds CHEMICAL (AZC) and procainamide (PCA) belong to inhibitors of GENE, whose low activity correlates with increase in transcription of various genes. Using the reverse-transcription and real-time quantitative PCR (RQ-PCR) analysis, we indicated that AZC and PCA did not profoundly affect on CD3-zeta chain transcription in Jurkat T leukemia cells clone E6-1. However, the flowcytometric analysis revealed that AZC and PCA decreased intracellular contents of CD3-zeta chain in these cells in dose dependent manner. Our results suggest that decrease of GENE activity may alter intracellular signal transmission without effect on transcription level of CD3-zeta chain. | INHIBITOR |
| Effect of 5-azacytidine and procainamide on CD3-zeta chain expression in Jurkat T cells. It has been observed that decrease of DNA methyltransferase 1 (DNMT1) activity is associated with low content of the CD3-zeta (zeta) chain in T cell receptor (TCR)/CD3 complex of T cells in systemic lupus erythematosus (SLE) patients. The CD3-zeta chain plays a pivotal role in intracellular signal transmission between TCR/CD3 complex and nuclei. The compounds 5'-azacytidine (CHEMICAL) and procainamide (PCA) belong to inhibitors of GENE, whose low activity correlates with increase in transcription of various genes. Using the reverse-transcription and real-time quantitative PCR (RQ-PCR) analysis, we indicated that CHEMICAL and PCA did not profoundly affect on CD3-zeta chain transcription in Jurkat T leukemia cells clone E6-1. However, the flowcytometric analysis revealed that CHEMICAL and PCA decreased intracellular contents of CD3-zeta chain in these cells in dose dependent manner. Our results suggest that decrease of GENE activity may alter intracellular signal transmission without effect on transcription level of CD3-zeta chain. | INHIBITOR |
| Effect of 5-azacytidine and CHEMICAL on CD3-zeta chain expression in Jurkat T cells. It has been observed that decrease of DNA methyltransferase 1 (DNMT1) activity is associated with low content of the CD3-zeta (zeta) chain in T cell receptor (TCR)/CD3 complex of T cells in systemic lupus erythematosus (SLE) patients. The CD3-zeta chain plays a pivotal role in intracellular signal transmission between TCR/CD3 complex and nuclei. The compounds 5'-azacytidine (AZC) and CHEMICAL (PCA) belong to inhibitors of GENE, whose low activity correlates with increase in transcription of various genes. Using the reverse-transcription and real-time quantitative PCR (RQ-PCR) analysis, we indicated that AZC and PCA did not profoundly affect on CD3-zeta chain transcription in Jurkat T leukemia cells clone E6-1. However, the flowcytometric analysis revealed that AZC and PCA decreased intracellular contents of CD3-zeta chain in these cells in dose dependent manner. Our results suggest that decrease of GENE activity may alter intracellular signal transmission without effect on transcription level of CD3-zeta chain. | INHIBITOR |
| Effect of 5-azacytidine and procainamide on CD3-zeta chain expression in Jurkat T cells. It has been observed that decrease of DNA methyltransferase 1 (DNMT1) activity is associated with low content of the CD3-zeta (zeta) chain in T cell receptor (TCR)/CD3 complex of T cells in systemic lupus erythematosus (SLE) patients. The CD3-zeta chain plays a pivotal role in intracellular signal transmission between TCR/CD3 complex and nuclei. The compounds 5'-azacytidine (AZC) and procainamide (CHEMICAL) belong to inhibitors of GENE, whose low activity correlates with increase in transcription of various genes. Using the reverse-transcription and real-time quantitative PCR (RQ-PCR) analysis, we indicated that AZC and CHEMICAL did not profoundly affect on CD3-zeta chain transcription in Jurkat T leukemia cells clone E6-1. However, the flowcytometric analysis revealed that AZC and CHEMICAL decreased intracellular contents of CD3-zeta chain in these cells in dose dependent manner. Our results suggest that decrease of GENE activity may alter intracellular signal transmission without effect on transcription level of CD3-zeta chain. | INHIBITOR |
| Rapid quantitation of plasma 2'-deoxyuridine by high-performance liquid chromatography/atmospheric pressure chemical ionization mass spectrometry and its application to pharmacodynamic studies in cancer patients. A novel method employing high-performance liquid chromatograph-mass spectrometry (LC-MS) has been developed and validated for the quantitation of plasma 2'-deoxyuridine (UdR). It involves a plasma clean-up step with strong anion-exchange solid-phase extraction (SAX-SPE) followed by HPLC separation and atmospheric pressure chemical ionization mass spectrometry detection (APCI-MS) in a selected-ion monitoring (SIM) mode. The ionization conditions were optimised in negative ion mode to give the best intensity of the dominant formate adduct [M+HCOO]- at m/z 273. Retention times were 7.5 and 12.5 min for 2'-deoxyuridine and 5-iodo-2'-deoxyuridine, an iodinated analogue internal standard (IS), respectively. Peak area ratios of 2'-deoxyuridine to IS were used for regression analysis of the calibration curve. The latter was linear from 5 to 400 nmol/l using 1 ml sample volume of plasma. The average recovery was 81.5% and 78.6% for 2'-deoxyuridine and 5-iodo-deoxyuridine, respectively. The method provides sufficient sensitivity, precision, accuracy and selectivity for routine analysis of human plasma 2'-deoxyuridine concentration with the lowest limit of quantitation (LLOQ) of 5 nmol/l. Clinical studies in cancer patients treated with the new fluoropyrimidine analogue capecitabine (N4-pentoxycarbonyl-5'-5-fluorocytidine) have shown that plasma 2'-deoxyuridine was significantly elevated after 1 week of treatment, consistent with inhibition of thymidylate synthase (TS). These findings suggest that the mechanism of antiproliferative toxicity of capecitabine is at least partly due to GENE inhibitory activity of its active metabolite 5-fluoro-2'-deoxyuridine monophosphate (CHEMICAL). Monitoring of plasma UdR concentrations have the potential to help clinicians to guide scheduling of capecitabine or other GENE inhibitors in clinical trials. Marked differences of plasma 2'-deoxyuridine between human and rodents have also been confirmed. In conclusion, the LC-MS method developed is simple, highly selective and sensitive and permits pharmacodynamic studies of GENE inhibitors in several species. | INHIBITOR |
| Rapid quantitation of plasma 2'-deoxyuridine by high-performance liquid chromatography/atmospheric pressure chemical ionization mass spectrometry and its application to pharmacodynamic studies in cancer patients. A novel method employing high-performance liquid chromatograph-mass spectrometry (LC-MS) has been developed and validated for the quantitation of plasma 2'-deoxyuridine (UdR). It involves a plasma clean-up step with strong anion-exchange solid-phase extraction (SAX-SPE) followed by HPLC separation and atmospheric pressure chemical ionization mass spectrometry detection (APCI-MS) in a selected-ion monitoring (SIM) mode. The ionization conditions were optimised in negative ion mode to give the best intensity of the dominant formate adduct [M+HCOO]- at m/z 273. Retention times were 7.5 and 12.5 min for 2'-deoxyuridine and 5-iodo-2'-deoxyuridine, an iodinated analogue internal standard (IS), respectively. Peak area ratios of 2'-deoxyuridine to IS were used for regression analysis of the calibration curve. The latter was linear from 5 to 400 nmol/l using 1 ml sample volume of plasma. The average recovery was 81.5% and 78.6% for 2'-deoxyuridine and 5-iodo-deoxyuridine, respectively. The method provides sufficient sensitivity, precision, accuracy and selectivity for routine analysis of human plasma 2'-deoxyuridine concentration with the lowest limit of quantitation (LLOQ) of 5 nmol/l. Clinical studies in cancer patients treated with the new CHEMICAL analogue capecitabine (N4-pentoxycarbonyl-5'-5-fluorocytidine) have shown that plasma 2'-deoxyuridine was significantly elevated after 1 week of treatment, consistent with inhibition of GENE (TS). These findings suggest that the mechanism of antiproliferative toxicity of capecitabine is at least partly due to TS inhibitory activity of its active metabolite 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). Monitoring of plasma UdR concentrations have the potential to help clinicians to guide scheduling of capecitabine or other TS inhibitors in clinical trials. Marked differences of plasma 2'-deoxyuridine between human and rodents have also been confirmed. In conclusion, the LC-MS method developed is simple, highly selective and sensitive and permits pharmacodynamic studies of TS inhibitors in several species. | INHIBITOR |
| Rapid quantitation of plasma 2'-deoxyuridine by high-performance liquid chromatography/atmospheric pressure chemical ionization mass spectrometry and its application to pharmacodynamic studies in cancer patients. A novel method employing high-performance liquid chromatograph-mass spectrometry (LC-MS) has been developed and validated for the quantitation of plasma 2'-deoxyuridine (UdR). It involves a plasma clean-up step with strong anion-exchange solid-phase extraction (SAX-SPE) followed by HPLC separation and atmospheric pressure chemical ionization mass spectrometry detection (APCI-MS) in a selected-ion monitoring (SIM) mode. The ionization conditions were optimised in negative ion mode to give the best intensity of the dominant formate adduct [M+HCOO]- at m/z 273. Retention times were 7.5 and 12.5 min for 2'-deoxyuridine and 5-iodo-2'-deoxyuridine, an iodinated analogue internal standard (IS), respectively. Peak area ratios of 2'-deoxyuridine to IS were used for regression analysis of the calibration curve. The latter was linear from 5 to 400 nmol/l using 1 ml sample volume of plasma. The average recovery was 81.5% and 78.6% for 2'-deoxyuridine and 5-iodo-deoxyuridine, respectively. The method provides sufficient sensitivity, precision, accuracy and selectivity for routine analysis of human plasma 2'-deoxyuridine concentration with the lowest limit of quantitation (LLOQ) of 5 nmol/l. Clinical studies in cancer patients treated with the new CHEMICAL analogue capecitabine (N4-pentoxycarbonyl-5'-5-fluorocytidine) have shown that plasma 2'-deoxyuridine was significantly elevated after 1 week of treatment, consistent with inhibition of thymidylate synthase (GENE). These findings suggest that the mechanism of antiproliferative toxicity of capecitabine is at least partly due to GENE inhibitory activity of its active metabolite 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). Monitoring of plasma UdR concentrations have the potential to help clinicians to guide scheduling of capecitabine or other GENE inhibitors in clinical trials. Marked differences of plasma 2'-deoxyuridine between human and rodents have also been confirmed. In conclusion, the LC-MS method developed is simple, highly selective and sensitive and permits pharmacodynamic studies of GENE inhibitors in several species. | INHIBITOR |
| Rapid quantitation of plasma 2'-deoxyuridine by high-performance liquid chromatography/atmospheric pressure chemical ionization mass spectrometry and its application to pharmacodynamic studies in cancer patients. A novel method employing high-performance liquid chromatograph-mass spectrometry (LC-MS) has been developed and validated for the quantitation of plasma 2'-deoxyuridine (UdR). It involves a plasma clean-up step with strong anion-exchange solid-phase extraction (SAX-SPE) followed by HPLC separation and atmospheric pressure chemical ionization mass spectrometry detection (APCI-MS) in a selected-ion monitoring (SIM) mode. The ionization conditions were optimised in negative ion mode to give the best intensity of the dominant formate adduct [M+HCOO]- at m/z 273. Retention times were 7.5 and 12.5 min for 2'-deoxyuridine and 5-iodo-2'-deoxyuridine, an iodinated analogue internal standard (IS), respectively. Peak area ratios of 2'-deoxyuridine to IS were used for regression analysis of the calibration curve. The latter was linear from 5 to 400 nmol/l using 1 ml sample volume of plasma. The average recovery was 81.5% and 78.6% for 2'-deoxyuridine and 5-iodo-deoxyuridine, respectively. The method provides sufficient sensitivity, precision, accuracy and selectivity for routine analysis of human plasma 2'-deoxyuridine concentration with the lowest limit of quantitation (LLOQ) of 5 nmol/l. Clinical studies in cancer patients treated with the new fluoropyrimidine analogue CHEMICAL (N4-pentoxycarbonyl-5'-5-fluorocytidine) have shown that plasma 2'-deoxyuridine was significantly elevated after 1 week of treatment, consistent with inhibition of GENE (TS). These findings suggest that the mechanism of antiproliferative toxicity of CHEMICAL is at least partly due to TS inhibitory activity of its active metabolite 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). Monitoring of plasma UdR concentrations have the potential to help clinicians to guide scheduling of CHEMICAL or other TS inhibitors in clinical trials. Marked differences of plasma 2'-deoxyuridine between human and rodents have also been confirmed. In conclusion, the LC-MS method developed is simple, highly selective and sensitive and permits pharmacodynamic studies of TS inhibitors in several species. | INHIBITOR |
| Rapid quantitation of plasma 2'-deoxyuridine by high-performance liquid chromatography/atmospheric pressure chemical ionization mass spectrometry and its application to pharmacodynamic studies in cancer patients. A novel method employing high-performance liquid chromatograph-mass spectrometry (LC-MS) has been developed and validated for the quantitation of plasma 2'-deoxyuridine (UdR). It involves a plasma clean-up step with strong anion-exchange solid-phase extraction (SAX-SPE) followed by HPLC separation and atmospheric pressure chemical ionization mass spectrometry detection (APCI-MS) in a selected-ion monitoring (SIM) mode. The ionization conditions were optimised in negative ion mode to give the best intensity of the dominant formate adduct [M+HCOO]- at m/z 273. Retention times were 7.5 and 12.5 min for 2'-deoxyuridine and 5-iodo-2'-deoxyuridine, an iodinated analogue internal standard (IS), respectively. Peak area ratios of 2'-deoxyuridine to IS were used for regression analysis of the calibration curve. The latter was linear from 5 to 400 nmol/l using 1 ml sample volume of plasma. The average recovery was 81.5% and 78.6% for 2'-deoxyuridine and 5-iodo-deoxyuridine, respectively. The method provides sufficient sensitivity, precision, accuracy and selectivity for routine analysis of human plasma 2'-deoxyuridine concentration with the lowest limit of quantitation (LLOQ) of 5 nmol/l. Clinical studies in cancer patients treated with the new fluoropyrimidine analogue CHEMICAL (N4-pentoxycarbonyl-5'-5-fluorocytidine) have shown that plasma 2'-deoxyuridine was significantly elevated after 1 week of treatment, consistent with inhibition of thymidylate synthase (GENE). These findings suggest that the mechanism of antiproliferative toxicity of CHEMICAL is at least partly due to GENE inhibitory activity of its active metabolite 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). Monitoring of plasma UdR concentrations have the potential to help clinicians to guide scheduling of CHEMICAL or other GENE inhibitors in clinical trials. Marked differences of plasma 2'-deoxyuridine between human and rodents have also been confirmed. In conclusion, the LC-MS method developed is simple, highly selective and sensitive and permits pharmacodynamic studies of GENE inhibitors in several species. | INHIBITOR |
| Rapid quantitation of plasma 2'-deoxyuridine by high-performance liquid chromatography/atmospheric pressure chemical ionization mass spectrometry and its application to pharmacodynamic studies in cancer patients. A novel method employing high-performance liquid chromatograph-mass spectrometry (LC-MS) has been developed and validated for the quantitation of plasma 2'-deoxyuridine (UdR). It involves a plasma clean-up step with strong anion-exchange solid-phase extraction (SAX-SPE) followed by HPLC separation and atmospheric pressure chemical ionization mass spectrometry detection (APCI-MS) in a selected-ion monitoring (SIM) mode. The ionization conditions were optimised in negative ion mode to give the best intensity of the dominant formate adduct [M+HCOO]- at m/z 273. Retention times were 7.5 and 12.5 min for 2'-deoxyuridine and 5-iodo-2'-deoxyuridine, an iodinated analogue internal standard (IS), respectively. Peak area ratios of 2'-deoxyuridine to IS were used for regression analysis of the calibration curve. The latter was linear from 5 to 400 nmol/l using 1 ml sample volume of plasma. The average recovery was 81.5% and 78.6% for 2'-deoxyuridine and 5-iodo-deoxyuridine, respectively. The method provides sufficient sensitivity, precision, accuracy and selectivity for routine analysis of human plasma 2'-deoxyuridine concentration with the lowest limit of quantitation (LLOQ) of 5 nmol/l. Clinical studies in cancer patients treated with the new fluoropyrimidine analogue capecitabine (CHEMICAL) have shown that plasma 2'-deoxyuridine was significantly elevated after 1 week of treatment, consistent with inhibition of GENE (TS). These findings suggest that the mechanism of antiproliferative toxicity of capecitabine is at least partly due to TS inhibitory activity of its active metabolite 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). Monitoring of plasma UdR concentrations have the potential to help clinicians to guide scheduling of capecitabine or other TS inhibitors in clinical trials. Marked differences of plasma 2'-deoxyuridine between human and rodents have also been confirmed. In conclusion, the LC-MS method developed is simple, highly selective and sensitive and permits pharmacodynamic studies of TS inhibitors in several species. | INHIBITOR |
| Rapid quantitation of plasma 2'-deoxyuridine by high-performance liquid chromatography/atmospheric pressure chemical ionization mass spectrometry and its application to pharmacodynamic studies in cancer patients. A novel method employing high-performance liquid chromatograph-mass spectrometry (LC-MS) has been developed and validated for the quantitation of plasma 2'-deoxyuridine (UdR). It involves a plasma clean-up step with strong anion-exchange solid-phase extraction (SAX-SPE) followed by HPLC separation and atmospheric pressure chemical ionization mass spectrometry detection (APCI-MS) in a selected-ion monitoring (SIM) mode. The ionization conditions were optimised in negative ion mode to give the best intensity of the dominant formate adduct [M+HCOO]- at m/z 273. Retention times were 7.5 and 12.5 min for 2'-deoxyuridine and 5-iodo-2'-deoxyuridine, an iodinated analogue internal standard (IS), respectively. Peak area ratios of 2'-deoxyuridine to IS were used for regression analysis of the calibration curve. The latter was linear from 5 to 400 nmol/l using 1 ml sample volume of plasma. The average recovery was 81.5% and 78.6% for 2'-deoxyuridine and 5-iodo-deoxyuridine, respectively. The method provides sufficient sensitivity, precision, accuracy and selectivity for routine analysis of human plasma 2'-deoxyuridine concentration with the lowest limit of quantitation (LLOQ) of 5 nmol/l. Clinical studies in cancer patients treated with the new fluoropyrimidine analogue capecitabine (CHEMICAL) have shown that plasma 2'-deoxyuridine was significantly elevated after 1 week of treatment, consistent with inhibition of thymidylate synthase (GENE). These findings suggest that the mechanism of antiproliferative toxicity of capecitabine is at least partly due to GENE inhibitory activity of its active metabolite 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). Monitoring of plasma UdR concentrations have the potential to help clinicians to guide scheduling of capecitabine or other GENE inhibitors in clinical trials. Marked differences of plasma 2'-deoxyuridine between human and rodents have also been confirmed. In conclusion, the LC-MS method developed is simple, highly selective and sensitive and permits pharmacodynamic studies of GENE inhibitors in several species. | INHIBITOR |
| Rapid quantitation of plasma CHEMICAL by high-performance liquid chromatography/atmospheric pressure chemical ionization mass spectrometry and its application to pharmacodynamic studies in cancer patients. A novel method employing high-performance liquid chromatograph-mass spectrometry (LC-MS) has been developed and validated for the quantitation of plasma CHEMICAL (UdR). It involves a plasma clean-up step with strong anion-exchange solid-phase extraction (SAX-SPE) followed by HPLC separation and atmospheric pressure chemical ionization mass spectrometry detection (APCI-MS) in a selected-ion monitoring (SIM) mode. The ionization conditions were optimised in negative ion mode to give the best intensity of the dominant formate adduct [M+HCOO]- at m/z 273. Retention times were 7.5 and 12.5 min for CHEMICAL and 5-iodo-2'-deoxyuridine, an iodinated analogue internal standard (IS), respectively. Peak area ratios of CHEMICAL to IS were used for regression analysis of the calibration curve. The latter was linear from 5 to 400 nmol/l using 1 ml sample volume of plasma. The average recovery was 81.5% and 78.6% for CHEMICAL and 5-iodo-deoxyuridine, respectively. The method provides sufficient sensitivity, precision, accuracy and selectivity for routine analysis of human plasma CHEMICAL concentration with the lowest limit of quantitation (LLOQ) of 5 nmol/l. Clinical studies in cancer patients treated with the new fluoropyrimidine analogue capecitabine (N4-pentoxycarbonyl-5'-5-fluorocytidine) have shown that plasma CHEMICAL was significantly elevated after 1 week of treatment, consistent with inhibition of GENE (TS). These findings suggest that the mechanism of antiproliferative toxicity of capecitabine is at least partly due to TS inhibitory activity of its active metabolite 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). Monitoring of plasma UdR concentrations have the potential to help clinicians to guide scheduling of capecitabine or other TS inhibitors in clinical trials. Marked differences of plasma CHEMICAL between human and rodents have also been confirmed. In conclusion, the LC-MS method developed is simple, highly selective and sensitive and permits pharmacodynamic studies of TS inhibitors in several species. | INHIBITOR |
| Rapid quantitation of plasma CHEMICAL by high-performance liquid chromatography/atmospheric pressure chemical ionization mass spectrometry and its application to pharmacodynamic studies in cancer patients. A novel method employing high-performance liquid chromatograph-mass spectrometry (LC-MS) has been developed and validated for the quantitation of plasma CHEMICAL (UdR). It involves a plasma clean-up step with strong anion-exchange solid-phase extraction (SAX-SPE) followed by HPLC separation and atmospheric pressure chemical ionization mass spectrometry detection (APCI-MS) in a selected-ion monitoring (SIM) mode. The ionization conditions were optimised in negative ion mode to give the best intensity of the dominant formate adduct [M+HCOO]- at m/z 273. Retention times were 7.5 and 12.5 min for CHEMICAL and 5-iodo-2'-deoxyuridine, an iodinated analogue internal standard (IS), respectively. Peak area ratios of CHEMICAL to IS were used for regression analysis of the calibration curve. The latter was linear from 5 to 400 nmol/l using 1 ml sample volume of plasma. The average recovery was 81.5% and 78.6% for CHEMICAL and 5-iodo-deoxyuridine, respectively. The method provides sufficient sensitivity, precision, accuracy and selectivity for routine analysis of human plasma CHEMICAL concentration with the lowest limit of quantitation (LLOQ) of 5 nmol/l. Clinical studies in cancer patients treated with the new fluoropyrimidine analogue capecitabine (N4-pentoxycarbonyl-5'-5-fluorocytidine) have shown that plasma CHEMICAL was significantly elevated after 1 week of treatment, consistent with inhibition of thymidylate synthase (GENE). These findings suggest that the mechanism of antiproliferative toxicity of capecitabine is at least partly due to GENE inhibitory activity of its active metabolite 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). Monitoring of plasma UdR concentrations have the potential to help clinicians to guide scheduling of capecitabine or other GENE inhibitors in clinical trials. Marked differences of plasma CHEMICAL between human and rodents have also been confirmed. In conclusion, the LC-MS method developed is simple, highly selective and sensitive and permits pharmacodynamic studies of GENE inhibitors in several species. | INHIBITOR |
| Rapid quantitation of plasma 2'-deoxyuridine by high-performance liquid chromatography/atmospheric pressure chemical ionization mass spectrometry and its application to pharmacodynamic studies in cancer patients. A novel method employing high-performance liquid chromatograph-mass spectrometry (LC-MS) has been developed and validated for the quantitation of plasma 2'-deoxyuridine (UdR). It involves a plasma clean-up step with strong anion-exchange solid-phase extraction (SAX-SPE) followed by HPLC separation and atmospheric pressure chemical ionization mass spectrometry detection (APCI-MS) in a selected-ion monitoring (SIM) mode. The ionization conditions were optimised in negative ion mode to give the best intensity of the dominant formate adduct [M+HCOO]- at m/z 273. Retention times were 7.5 and 12.5 min for 2'-deoxyuridine and 5-iodo-2'-deoxyuridine, an iodinated analogue internal standard (IS), respectively. Peak area ratios of 2'-deoxyuridine to IS were used for regression analysis of the calibration curve. The latter was linear from 5 to 400 nmol/l using 1 ml sample volume of plasma. The average recovery was 81.5% and 78.6% for 2'-deoxyuridine and 5-iodo-deoxyuridine, respectively. The method provides sufficient sensitivity, precision, accuracy and selectivity for routine analysis of human plasma 2'-deoxyuridine concentration with the lowest limit of quantitation (LLOQ) of 5 nmol/l. Clinical studies in cancer patients treated with the new fluoropyrimidine analogue capecitabine (N4-pentoxycarbonyl-5'-5-fluorocytidine) have shown that plasma 2'-deoxyuridine was significantly elevated after 1 week of treatment, consistent with inhibition of thymidylate synthase (TS). These findings suggest that the mechanism of antiproliferative toxicity of capecitabine is at least partly due to GENE inhibitory activity of its active metabolite CHEMICAL (FdUMP). Monitoring of plasma UdR concentrations have the potential to help clinicians to guide scheduling of capecitabine or other GENE inhibitors in clinical trials. Marked differences of plasma 2'-deoxyuridine between human and rodents have also been confirmed. In conclusion, the LC-MS method developed is simple, highly selective and sensitive and permits pharmacodynamic studies of GENE inhibitors in several species. | INHIBITOR |
| Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in CHEMICAL mesylate-treated squamous carcinoma cells. CHEMICAL mesylate is a tyrosine GENE inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for CHEMICAL. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with CHEMICAL demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated GENE kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro GENE assay showed that CHEMICAL did not directly affect EGFR GENE activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein GENE (MAPK) activation. CHEMICAL stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation. Together, these results suggested that CHEMICAL affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, CHEMICAL primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR tyrosine GENE in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients. | NO-RELATIONSHIP |
| Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in CHEMICAL mesylate-treated squamous carcinoma cells. CHEMICAL mesylate is a tyrosine kinase inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for CHEMICAL. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the GENE antagonist cetuximab, which suggested direct involvement of GENE in this process. Western blot analysis of cells incubated with CHEMICAL demonstrated activation of GENE and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and GENE, but not Her2/ErbB2. An in vitro kinase assay showed that CHEMICAL did not directly affect GENE kinase activity, suggesting involvement of GENE-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation. CHEMICAL stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation. Together, these results suggested that CHEMICAL affects GENE activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, CHEMICAL primarily inhibits tyrosine kinases, it also stimulates the activity of GENE tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients. | REGULATOR |
| Induction of GENE and activation of EGF receptor in CHEMICAL-treated squamous carcinoma cells. CHEMICAL is a tyrosine kinase inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for imatinib. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with imatinib demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that imatinib did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation. Imatinib stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation. Together, these results suggested that imatinib affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, imatinib primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients. | ACTIVATOR |
| Induction of heparin-binding EGF-like growth factor and activation of GENE in CHEMICAL-treated squamous carcinoma cells. CHEMICAL is a tyrosine kinase inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for imatinib. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with imatinib demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that imatinib did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation. Imatinib stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation. Together, these results suggested that imatinib affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, imatinib primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients. | ACTIVATOR |
| Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in CHEMICAL mesylate-treated squamous carcinoma cells. CHEMICAL mesylate is a tyrosine kinase inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for CHEMICAL. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with CHEMICAL demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that CHEMICAL did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced CHEMICAL-mediated GENE (MAPK) activation. CHEMICAL stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation. Together, these results suggested that CHEMICAL affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, CHEMICAL primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients. | ACTIVATOR |
| Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in CHEMICAL mesylate-treated squamous carcinoma cells. CHEMICAL mesylate is a tyrosine kinase inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for CHEMICAL. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with CHEMICAL demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that CHEMICAL did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced CHEMICAL-mediated mitogen activated protein kinase (GENE) activation. CHEMICAL stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic GENE activation. Together, these results suggested that CHEMICAL affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, CHEMICAL primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients. | ACTIVATOR |
| Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in imatinib mesylate-treated squamous carcinoma cells. CHEMICAL mesylate is a tyrosine kinase inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for imatinib. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with imatinib demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that imatinib did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation. CHEMICAL stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic GENE activation. Together, these results suggested that imatinib affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, imatinib primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients. | ACTIVATOR |
| Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in CHEMICAL mesylate-treated squamous carcinoma cells. CHEMICAL mesylate is a GENE inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for CHEMICAL. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with CHEMICAL demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that CHEMICAL did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation. CHEMICAL stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation. Together, these results suggested that CHEMICAL affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, CHEMICAL primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR GENE in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients. | ACTIVATOR |
| Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in CHEMICAL mesylate-treated squamous carcinoma cells. CHEMICAL mesylate is a tyrosine kinase inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for CHEMICAL. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of CHEMICAL-induced changes in cell morphology and growth similar to changes associated with GENE (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with CHEMICAL demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that CHEMICAL did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation. CHEMICAL stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation. Together, these results suggested that CHEMICAL affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, CHEMICAL primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients. | ACTIVATOR |
| Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in imatinib mesylate-treated squamous carcinoma cells. CHEMICAL mesylate is a tyrosine kinase inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for imatinib. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with imatinib demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that imatinib did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation. CHEMICAL stimulated the rapid release of soluble GENE and the subsequent induction of membrane-bound GENE, which correlated with biphasic MAPK activation. Together, these results suggested that imatinib affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, imatinib primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients. | GENE-CHEMICAL |
| Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in imatinib mesylate-treated squamous carcinoma cells. CHEMICAL is a tyrosine kinase inhibitor of the ABL, platelet-derived growth factor receptor (GENE), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for imatinib. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with imatinib demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that imatinib did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation. Imatinib stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation. Together, these results suggested that imatinib affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, imatinib primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients. | INHIBITOR |
| Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in imatinib mesylate-treated squamous carcinoma cells. CHEMICAL is a tyrosine kinase inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and GENE kinases. Inhibition of BCR-ABL and GENE accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for imatinib. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with imatinib demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that imatinib did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation. Imatinib stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation. Together, these results suggested that imatinib affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, imatinib primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients. | INHIBITOR |
| Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in imatinib mesylate-treated squamous carcinoma cells. CHEMICAL is a tyrosine kinase inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit GENE. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for imatinib. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with imatinib demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that imatinib did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation. Imatinib stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation. Together, these results suggested that imatinib affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, imatinib primarily inhibits tyrosine GENE, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients. | INHIBITOR |
| Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in imatinib mesylate-treated squamous carcinoma cells. CHEMICAL is a GENE inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for imatinib. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with imatinib demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that imatinib did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation. Imatinib stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation. Together, these results suggested that imatinib affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, imatinib primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR GENE in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients. | INHIBITOR |
| Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in imatinib mesylate-treated squamous carcinoma cells. CHEMICAL is a tyrosine kinase inhibitor of the GENE, platelet-derived growth factor receptor (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for imatinib. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with imatinib demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that imatinib did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation. Imatinib stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation. Together, these results suggested that imatinib affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, imatinib primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients. | INHIBITOR |
| Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in imatinib mesylate-treated squamous carcinoma cells. CHEMICAL is a tyrosine kinase inhibitor of the ABL, GENE (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for imatinib. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with imatinib demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that imatinib did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation. Imatinib stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation. Together, these results suggested that imatinib affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, imatinib primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients. | INHIBITOR |
| Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in CHEMICAL mesylate-treated squamous carcinoma cells. CHEMICAL mesylate is a tyrosine kinase inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for CHEMICAL. Treatment of head and neck squamous carcinoma cells with clinically relevant concentrations of imatinib-induced changes in cell morphology and growth similar to changes associated with epidermal growth factor receptor (EGFR) activation. Imatinib-induced changes were blocked with the EGFR antagonist cetuximab, which suggested direct involvement of EGFR in this process. Western blot analysis of cells incubated with CHEMICAL demonstrated activation of EGFR and downstream signaling that was reduced by inhibition of mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1) and EGFR, but not Her2/ErbB2. An in vitro kinase assay showed that CHEMICAL did not directly affect EGFR kinase activity, suggesting involvement of EGFR-activating molecules. Inhibitors and neutralizing antibodies against heparin-binding epidermal growth factor-like growth factor (HB-EGF), and to a lesser extent transforming growth factor-alpha, reduced imatinib-mediated mitogen activated protein kinase (MAPK) activation. CHEMICAL stimulated the rapid release of soluble HB-EGF and the subsequent induction of membrane-bound HB-EGF, which correlated with biphasic MAPK activation. Together, these results suggested that CHEMICAL affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, CHEMICAL primarily inhibits GENE, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients. | INHIBITOR |
| Epithelioid gastrointestinal stromal tumor with GENE activating mutation and immunoreactivity. The authors report a unique case of an intra-abdominal, epithelioid mesenchymal tumor that had an activating mutation of GENE and a strong GENE immunoreactivity but lacked both c-kit mutation and c-kit protein (CD117) expression. IHC study showed that the tumor cells were diffusely and strongly positive for GENE, vimentin, CD34, and Bcl-2 but completely negative for CD117 as well as for muscle, epithelial, endothelial, endocrine, mesothelial, neural, and melanocytic cell markers. Molecular study revealed a mutation at the juxtamembrane domain of exon 12 in GENE gene with GTC to GAC transition at codon 561 (V561D), as shown in the previous mutational studies on gastrointestinal stromal tumor (GIST). This case likely represents an example of GIST with GENE activating mutation and GENE immunoreactivity without CD117 positivity, which has not been documented in the literature. CHEMICAL (imatinib mesylate [Gleevec]) might be an effective therapy in this case, since Gleevec targets both GENE and c-kit oncoproteins. | GENE-CHEMICAL |
| Epithelioid gastrointestinal stromal tumor with PDGFRA activating mutation and immunoreactivity. The authors report a unique case of an intra-abdominal, epithelioid mesenchymal tumor that had an activating mutation of PDGFRA and a strong PDGFRA immunoreactivity but lacked both GENE mutation and GENE protein (CD117) expression. IHC study showed that the tumor cells were diffusely and strongly positive for PDGFRA, vimentin, CD34, and Bcl-2 but completely negative for CD117 as well as for muscle, epithelial, endothelial, endocrine, mesothelial, neural, and melanocytic cell markers. Molecular study revealed a mutation at the juxtamembrane domain of exon 12 in PDGFRA gene with GTC to GAC transition at codon 561 (V561D), as shown in the previous mutational studies on gastrointestinal stromal tumor (GIST). This case likely represents an example of GIST with PDGFRA activating mutation and PDGFRA immunoreactivity without CD117 positivity, which has not been documented in the literature. CHEMICAL (imatinib mesylate [Gleevec]) might be an effective therapy in this case, since Gleevec targets both PDGFRA and GENE oncoproteins. | GENE-CHEMICAL |
| Epithelioid gastrointestinal stromal tumor with GENE activating mutation and immunoreactivity. The authors report a unique case of an intra-abdominal, epithelioid mesenchymal tumor that had an activating mutation of GENE and a strong GENE immunoreactivity but lacked both c-kit mutation and c-kit protein (CD117) expression. IHC study showed that the tumor cells were diffusely and strongly positive for GENE, vimentin, CD34, and Bcl-2 but completely negative for CD117 as well as for muscle, epithelial, endothelial, endocrine, mesothelial, neural, and melanocytic cell markers. Molecular study revealed a mutation at the juxtamembrane domain of exon 12 in GENE gene with GTC to GAC transition at codon 561 (V561D), as shown in the previous mutational studies on gastrointestinal stromal tumor (GIST). This case likely represents an example of GIST with GENE activating mutation and GENE immunoreactivity without CD117 positivity, which has not been documented in the literature. STI 571 (CHEMICAL [Gleevec]) might be an effective therapy in this case, since Gleevec targets both GENE and c-kit oncoproteins. | REGULATOR |
| Epithelioid gastrointestinal stromal tumor with PDGFRA activating mutation and immunoreactivity. The authors report a unique case of an intra-abdominal, epithelioid mesenchymal tumor that had an activating mutation of PDGFRA and a strong PDGFRA immunoreactivity but lacked both GENE mutation and GENE protein (CD117) expression. IHC study showed that the tumor cells were diffusely and strongly positive for PDGFRA, vimentin, CD34, and Bcl-2 but completely negative for CD117 as well as for muscle, epithelial, endothelial, endocrine, mesothelial, neural, and melanocytic cell markers. Molecular study revealed a mutation at the juxtamembrane domain of exon 12 in PDGFRA gene with GTC to GAC transition at codon 561 (V561D), as shown in the previous mutational studies on gastrointestinal stromal tumor (GIST). This case likely represents an example of GIST with PDGFRA activating mutation and PDGFRA immunoreactivity without CD117 positivity, which has not been documented in the literature. STI 571 (CHEMICAL [Gleevec]) might be an effective therapy in this case, since Gleevec targets both PDGFRA and GENE oncoproteins. | GENE-CHEMICAL |
| Epithelioid gastrointestinal stromal tumor with GENE activating mutation and immunoreactivity. The authors report a unique case of an intra-abdominal, epithelioid mesenchymal tumor that had an activating mutation of GENE and a strong GENE immunoreactivity but lacked both c-kit mutation and c-kit protein (CD117) expression. IHC study showed that the tumor cells were diffusely and strongly positive for GENE, vimentin, CD34, and Bcl-2 but completely negative for CD117 as well as for muscle, epithelial, endothelial, endocrine, mesothelial, neural, and melanocytic cell markers. Molecular study revealed a mutation at the juxtamembrane domain of exon 12 in GENE gene with GTC to GAC transition at codon 561 (V561D), as shown in the previous mutational studies on gastrointestinal stromal tumor (GIST). This case likely represents an example of GIST with GENE activating mutation and GENE immunoreactivity without CD117 positivity, which has not been documented in the literature. STI 571 (imatinib mesylate [CHEMICAL]) might be an effective therapy in this case, since CHEMICAL targets both GENE and c-kit oncoproteins. | REGULATOR |
| Epithelioid gastrointestinal stromal tumor with PDGFRA activating mutation and immunoreactivity. The authors report a unique case of an intra-abdominal, epithelioid mesenchymal tumor that had an activating mutation of PDGFRA and a strong PDGFRA immunoreactivity but lacked both GENE mutation and GENE protein (CD117) expression. IHC study showed that the tumor cells were diffusely and strongly positive for PDGFRA, vimentin, CD34, and Bcl-2 but completely negative for CD117 as well as for muscle, epithelial, endothelial, endocrine, mesothelial, neural, and melanocytic cell markers. Molecular study revealed a mutation at the juxtamembrane domain of exon 12 in PDGFRA gene with GTC to GAC transition at codon 561 (V561D), as shown in the previous mutational studies on gastrointestinal stromal tumor (GIST). This case likely represents an example of GIST with PDGFRA activating mutation and PDGFRA immunoreactivity without CD117 positivity, which has not been documented in the literature. STI 571 (imatinib mesylate [CHEMICAL]) might be an effective therapy in this case, since CHEMICAL targets both PDGFRA and GENE oncoproteins. | REGULATOR |
| Genetic polymorphism and activities of human lung alcohol and aldehyde dehydrogenases: implications for ethanol metabolism and cytotoxicity. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) exhibit genetic polymorphism and tissue specificity. ADH and ALDH isozyme phenotypes from 39 surgical Chinese lung specimens were identified by agarose isoelectric focusing. The identity of the lung GENE was further demonstrated by their characteristic pH-activity profiles for ethanol oxidation, Km values for NAD and ethanol, and inhibition by CHEMICAL or 1,10-phenanthroline. The beta 2 allele, coding for beta 2 polypeptide, was found to be predominant in the lung specimens studied. The ADH activities in the lungs with the homozygous phenotype ADH2 2-2 (exhibiting beta 2 beta 2) and ADH2 1-1 (exhibiting beta 1 beta 1) and the heterozygous phenotype ADH2 2-1 (exhibiting beta 2 beta 2, beta 2 beta 1, and beta 1 beta 1) were determined to be 999 +/- 77, 48 +/- 17, and 494 +/- 61 nmol/min/g tissue, respectively. Fifty-one percent of the specimens studied lacked the ALDH2 activity band on the isoelectric focusing gels. The activities in the lung tissues with the ALDH2-active phenotype and the inactive phenotype were determined to be 30 +/- 3 and 17 +/- 1 nmol/min/g tissue, respectively. These findings indicate that human pulmonary ethanol-metabolizing activities differ significantly with respect to genetic polymorphism at both the ADH2 and the ALDH2 loci. The results suggest that individuals with high Vmax beta 2-ADH and deficient in low-Km mitochondrial ALDH2, accounting for approximately 45% of the Chinese population, may end up with acetaldehyde accumulation during alcohol consumption, rendering them vulnerable to tissue injury caused by this highly reactive and toxic metabolite. | INHIBITOR |
| Genetic polymorphism and activities of human lung alcohol and aldehyde dehydrogenases: implications for ethanol metabolism and cytotoxicity. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) exhibit genetic polymorphism and tissue specificity. ADH and ALDH isozyme phenotypes from 39 surgical Chinese lung specimens were identified by agarose isoelectric focusing. The identity of the lung GENE was further demonstrated by their characteristic pH-activity profiles for ethanol oxidation, Km values for NAD and ethanol, and inhibition by 4-methylpyrazole or CHEMICAL. The beta 2 allele, coding for beta 2 polypeptide, was found to be predominant in the lung specimens studied. The ADH activities in the lungs with the homozygous phenotype ADH2 2-2 (exhibiting beta 2 beta 2) and ADH2 1-1 (exhibiting beta 1 beta 1) and the heterozygous phenotype ADH2 2-1 (exhibiting beta 2 beta 2, beta 2 beta 1, and beta 1 beta 1) were determined to be 999 +/- 77, 48 +/- 17, and 494 +/- 61 nmol/min/g tissue, respectively. Fifty-one percent of the specimens studied lacked the ALDH2 activity band on the isoelectric focusing gels. The activities in the lung tissues with the ALDH2-active phenotype and the inactive phenotype were determined to be 30 +/- 3 and 17 +/- 1 nmol/min/g tissue, respectively. These findings indicate that human pulmonary ethanol-metabolizing activities differ significantly with respect to genetic polymorphism at both the ADH2 and the ALDH2 loci. The results suggest that individuals with high Vmax beta 2-ADH and deficient in low-Km mitochondrial ALDH2, accounting for approximately 45% of the Chinese population, may end up with acetaldehyde accumulation during alcohol consumption, rendering them vulnerable to tissue injury caused by this highly reactive and toxic metabolite. | INHIBITOR |
| Genetic polymorphism and activities of human lung alcohol and aldehyde dehydrogenases: implications for ethanol metabolism and cytotoxicity. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) exhibit genetic polymorphism and tissue specificity. ADH and ALDH isozyme phenotypes from 39 surgical Chinese lung specimens were identified by agarose isoelectric focusing. The identity of the lung beta-ADHs was further demonstrated by their characteristic pH-activity profiles for ethanol oxidation, Km values for NAD and ethanol, and inhibition by 4-methylpyrazole or 1,10-phenanthroline. The beta 2 allele, coding for beta 2 polypeptide, was found to be predominant in the lung specimens studied. The ADH activities in the lungs with the homozygous phenotype ADH2 2-2 (exhibiting beta 2 beta 2) and ADH2 1-1 (exhibiting beta 1 beta 1) and the heterozygous phenotype ADH2 2-1 (exhibiting beta 2 beta 2, beta 2 beta 1, and beta 1 beta 1) were determined to be 999 +/- 77, 48 +/- 17, and 494 +/- 61 nmol/min/g tissue, respectively. Fifty-one percent of the specimens studied lacked the ALDH2 activity band on the isoelectric focusing gels. The activities in the lung tissues with the ALDH2-active phenotype and the inactive phenotype were determined to be 30 +/- 3 and 17 +/- 1 nmol/min/g tissue, respectively. These findings indicate that human pulmonary ethanol-metabolizing activities differ significantly with respect to genetic polymorphism at both the ADH2 and the ALDH2 loci. The results suggest that individuals with high Vmax GENE and deficient in low-Km mitochondrial ALDH2, accounting for approximately 45% of the Chinese population, may end up with CHEMICAL accumulation during alcohol consumption, rendering them vulnerable to tissue injury caused by this highly reactive and toxic metabolite. | PRODUCT-OF |
| Genetic polymorphism and activities of human lung alcohol and aldehyde dehydrogenases: implications for ethanol metabolism and cytotoxicity. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) exhibit genetic polymorphism and tissue specificity. ADH and ALDH isozyme phenotypes from 39 surgical Chinese lung specimens were identified by agarose isoelectric focusing. The identity of the lung beta-ADHs was further demonstrated by their characteristic pH-activity profiles for ethanol oxidation, Km values for NAD and ethanol, and inhibition by 4-methylpyrazole or 1,10-phenanthroline. The beta 2 allele, coding for beta 2 polypeptide, was found to be predominant in the lung specimens studied. The ADH activities in the lungs with the homozygous phenotype ADH2 2-2 (exhibiting beta 2 beta 2) and ADH2 1-1 (exhibiting beta 1 beta 1) and the heterozygous phenotype ADH2 2-1 (exhibiting beta 2 beta 2, beta 2 beta 1, and beta 1 beta 1) were determined to be 999 +/- 77, 48 +/- 17, and 494 +/- 61 nmol/min/g tissue, respectively. Fifty-one percent of the specimens studied lacked the GENE activity band on the isoelectric focusing gels. The activities in the lung tissues with the ALDH2-active phenotype and the inactive phenotype were determined to be 30 +/- 3 and 17 +/- 1 nmol/min/g tissue, respectively. These findings indicate that human pulmonary ethanol-metabolizing activities differ significantly with respect to genetic polymorphism at both the ADH2 and the GENE loci. The results suggest that individuals with high Vmax beta 2-ADH and deficient in low-Km mitochondrial GENE, accounting for approximately 45% of the Chinese population, may end up with CHEMICAL accumulation during alcohol consumption, rendering them vulnerable to tissue injury caused by this highly reactive and toxic metabolite. | PRODUCT-OF |
| Genetic polymorphism and activities of human lung alcohol and aldehyde dehydrogenases: implications for CHEMICAL metabolism and cytotoxicity. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) exhibit genetic polymorphism and tissue specificity. ADH and ALDH isozyme phenotypes from 39 surgical Chinese lung specimens were identified by agarose isoelectric focusing. The identity of the lung beta-ADHs was further demonstrated by their characteristic pH-activity profiles for CHEMICAL oxidation, Km values for NAD and CHEMICAL, and inhibition by 4-methylpyrazole or 1,10-phenanthroline. The beta 2 allele, coding for beta 2 polypeptide, was found to be predominant in the lung specimens studied. The ADH activities in the lungs with the homozygous phenotype GENE 2-2 (exhibiting beta 2 beta 2) and GENE 1-1 (exhibiting beta 1 beta 1) and the heterozygous phenotype GENE 2-1 (exhibiting beta 2 beta 2, beta 2 beta 1, and beta 1 beta 1) were determined to be 999 +/- 77, 48 +/- 17, and 494 +/- 61 nmol/min/g tissue, respectively. Fifty-one percent of the specimens studied lacked the ALDH2 activity band on the isoelectric focusing gels. The activities in the lung tissues with the ALDH2-active phenotype and the inactive phenotype were determined to be 30 +/- 3 and 17 +/- 1 nmol/min/g tissue, respectively. These findings indicate that human pulmonary CHEMICAL-metabolizing activities differ significantly with respect to genetic polymorphism at both the GENE and the ALDH2 loci. The results suggest that individuals with high Vmax beta 2-ADH and deficient in low-Km mitochondrial ALDH2, accounting for approximately 45% of the Chinese population, may end up with acetaldehyde accumulation during alcohol consumption, rendering them vulnerable to tissue injury caused by this highly reactive and toxic metabolite. | SUBSTRATE |
| Genetic polymorphism and activities of human lung alcohol and aldehyde dehydrogenases: implications for CHEMICAL metabolism and cytotoxicity. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) exhibit genetic polymorphism and tissue specificity. ADH and ALDH isozyme phenotypes from 39 surgical Chinese lung specimens were identified by agarose isoelectric focusing. The identity of the lung beta-ADHs was further demonstrated by their characteristic pH-activity profiles for CHEMICAL oxidation, Km values for NAD and CHEMICAL, and inhibition by 4-methylpyrazole or 1,10-phenanthroline. The beta 2 allele, coding for beta 2 polypeptide, was found to be predominant in the lung specimens studied. The ADH activities in the lungs with the homozygous phenotype ADH2 2-2 (exhibiting beta 2 beta 2) and ADH2 1-1 (exhibiting beta 1 beta 1) and the heterozygous phenotype ADH2 2-1 (exhibiting beta 2 beta 2, beta 2 beta 1, and beta 1 beta 1) were determined to be 999 +/- 77, 48 +/- 17, and 494 +/- 61 nmol/min/g tissue, respectively. Fifty-one percent of the specimens studied lacked the GENE activity band on the isoelectric focusing gels. The activities in the lung tissues with the ALDH2-active phenotype and the inactive phenotype were determined to be 30 +/- 3 and 17 +/- 1 nmol/min/g tissue, respectively. These findings indicate that human pulmonary CHEMICAL-metabolizing activities differ significantly with respect to genetic polymorphism at both the ADH2 and the GENE loci. The results suggest that individuals with high Vmax beta 2-ADH and deficient in low-Km mitochondrial GENE, accounting for approximately 45% of the Chinese population, may end up with acetaldehyde accumulation during alcohol consumption, rendering them vulnerable to tissue injury caused by this highly reactive and toxic metabolite. | SUBSTRATE |
| Genetic polymorphism and activities of human lung CHEMICAL and aldehyde dehydrogenases: implications for ethanol metabolism and cytotoxicity. CHEMICAL dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) exhibit genetic polymorphism and tissue specificity. ADH and ALDH isozyme phenotypes from 39 surgical Chinese lung specimens were identified by agarose isoelectric focusing. The identity of the lung beta-ADHs was further demonstrated by their characteristic pH-activity profiles for ethanol oxidation, Km values for NAD and ethanol, and inhibition by 4-methylpyrazole or 1,10-phenanthroline. The beta 2 allele, coding for beta 2 polypeptide, was found to be predominant in the lung specimens studied. The ADH activities in the lungs with the homozygous phenotype ADH2 2-2 (exhibiting beta 2 beta 2) and ADH2 1-1 (exhibiting beta 1 beta 1) and the heterozygous phenotype ADH2 2-1 (exhibiting beta 2 beta 2, beta 2 beta 1, and beta 1 beta 1) were determined to be 999 +/- 77, 48 +/- 17, and 494 +/- 61 nmol/min/g tissue, respectively. Fifty-one percent of the specimens studied lacked the ALDH2 activity band on the isoelectric focusing gels. The activities in the lung tissues with the ALDH2-active phenotype and the inactive phenotype were determined to be 30 +/- 3 and 17 +/- 1 nmol/min/g tissue, respectively. These findings indicate that human pulmonary ethanol-metabolizing activities differ significantly with respect to genetic polymorphism at both the ADH2 and the ALDH2 loci. The results suggest that individuals with high Vmax GENE and deficient in low-Km mitochondrial ALDH2, accounting for approximately 45% of the Chinese population, may end up with acetaldehyde accumulation during CHEMICAL consumption, rendering them vulnerable to tissue injury caused by this highly reactive and toxic metabolite. | SUBSTRATE |
| Genetic polymorphism and activities of human lung CHEMICAL and aldehyde dehydrogenases: implications for ethanol metabolism and cytotoxicity. CHEMICAL dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) exhibit genetic polymorphism and tissue specificity. ADH and ALDH isozyme phenotypes from 39 surgical Chinese lung specimens were identified by agarose isoelectric focusing. The identity of the lung beta-ADHs was further demonstrated by their characteristic pH-activity profiles for ethanol oxidation, Km values for NAD and ethanol, and inhibition by 4-methylpyrazole or 1,10-phenanthroline. The beta 2 allele, coding for beta 2 polypeptide, was found to be predominant in the lung specimens studied. The ADH activities in the lungs with the homozygous phenotype ADH2 2-2 (exhibiting beta 2 beta 2) and ADH2 1-1 (exhibiting beta 1 beta 1) and the heterozygous phenotype ADH2 2-1 (exhibiting beta 2 beta 2, beta 2 beta 1, and beta 1 beta 1) were determined to be 999 +/- 77, 48 +/- 17, and 494 +/- 61 nmol/min/g tissue, respectively. Fifty-one percent of the specimens studied lacked the GENE activity band on the isoelectric focusing gels. The activities in the lung tissues with the ALDH2-active phenotype and the inactive phenotype were determined to be 30 +/- 3 and 17 +/- 1 nmol/min/g tissue, respectively. These findings indicate that human pulmonary ethanol-metabolizing activities differ significantly with respect to genetic polymorphism at both the ADH2 and the GENE loci. The results suggest that individuals with high Vmax beta 2-ADH and deficient in low-Km mitochondrial GENE, accounting for approximately 45% of the Chinese population, may end up with acetaldehyde accumulation during CHEMICAL consumption, rendering them vulnerable to tissue injury caused by this highly reactive and toxic metabolite. | SUBSTRATE |
| Genetic polymorphism and activities of human lung alcohol and aldehyde dehydrogenases: implications for CHEMICAL metabolism and cytotoxicity. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) exhibit genetic polymorphism and tissue specificity. ADH and ALDH isozyme phenotypes from 39 surgical Chinese lung specimens were identified by agarose isoelectric focusing. The identity of the lung GENE was further demonstrated by their characteristic pH-activity profiles for CHEMICAL oxidation, Km values for NAD and CHEMICAL, and inhibition by 4-methylpyrazole or 1,10-phenanthroline. The beta 2 allele, coding for beta 2 polypeptide, was found to be predominant in the lung specimens studied. The ADH activities in the lungs with the homozygous phenotype ADH2 2-2 (exhibiting beta 2 beta 2) and ADH2 1-1 (exhibiting beta 1 beta 1) and the heterozygous phenotype ADH2 2-1 (exhibiting beta 2 beta 2, beta 2 beta 1, and beta 1 beta 1) were determined to be 999 +/- 77, 48 +/- 17, and 494 +/- 61 nmol/min/g tissue, respectively. Fifty-one percent of the specimens studied lacked the ALDH2 activity band on the isoelectric focusing gels. The activities in the lung tissues with the ALDH2-active phenotype and the inactive phenotype were determined to be 30 +/- 3 and 17 +/- 1 nmol/min/g tissue, respectively. These findings indicate that human pulmonary ethanol-metabolizing activities differ significantly with respect to genetic polymorphism at both the ADH2 and the ALDH2 loci. The results suggest that individuals with high Vmax beta 2-ADH and deficient in low-Km mitochondrial ALDH2, accounting for approximately 45% of the Chinese population, may end up with acetaldehyde accumulation during alcohol consumption, rendering them vulnerable to tissue injury caused by this highly reactive and toxic metabolite. | SUBSTRATE |
| CHEMICAL induces interleukin-18 production in human peripheral blood mononuclear cells. The effects of statins on immune response depend on the inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and leukocyte function-associated antigen (LFA)-1, which is a ligand of intercellular adhesion molecule (ICAM)-1. CHEMICAL, an HMG-CoA reductase inhibitor with mild inhibition of LFA-1, induced the production of interleukin (IL)-18, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in human peripheral blood mononuclear cells (PBMC). The GENE production is located upstream of the cytokine cascade activated by CHEMICAL. Moreover, CHEMICAL concentration-dependently inhibited the expression of ICAM-1 and induced the expression of CD40 on monocytes. In the presence of GENE, CHEMICAL suppressed the expression of ICAM-1 and CD40 as well as the production of IL-12, TNF-alpha and IFN-gamma in PBMC, contributing to the anti-inflammatory effect of CHEMICAL. The effects of CHEMICAL were abolished by the addition of the product of the HMG-CoA reductase, mevalonate, indicating the involvement of HMG-CoA reductase in the action of CHEMICAL. | GENE-CHEMICAL |
| CHEMICAL induces interleukin-18 production in human peripheral blood mononuclear cells. The effects of statins on immune response depend on the inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and leukocyte function-associated antigen (LFA)-1, which is a ligand of intercellular adhesion molecule (ICAM)-1. CHEMICAL, an GENE inhibitor with mild inhibition of LFA-1, induced the production of interleukin (IL)-18, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in human peripheral blood mononuclear cells (PBMC). The IL-18 production is located upstream of the cytokine cascade activated by CHEMICAL. Moreover, CHEMICAL concentration-dependently inhibited the expression of ICAM-1 and induced the expression of CD40 on monocytes. In the presence of IL-18, CHEMICAL suppressed the expression of ICAM-1 and CD40 as well as the production of IL-12, TNF-alpha and IFN-gamma in PBMC, contributing to the anti-inflammatory effect of CHEMICAL. The effects of CHEMICAL were abolished by the addition of the product of the GENE, mevalonate, indicating the involvement of GENE in the action of CHEMICAL. | REGULATOR |
| CHEMICAL induces interleukin-18 production in human peripheral blood mononuclear cells. The effects of statins on immune response depend on the inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and leukocyte function-associated antigen (LFA)-1, which is a ligand of intercellular adhesion molecule (ICAM)-1. CHEMICAL, an HMG-CoA reductase inhibitor with mild inhibition of LFA-1, induced the production of interleukin (IL)-18, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in human peripheral blood mononuclear cells (PBMC). The IL-18 production is located upstream of the GENE cascade activated by CHEMICAL. Moreover, CHEMICAL concentration-dependently inhibited the expression of ICAM-1 and induced the expression of CD40 on monocytes. In the presence of IL-18, CHEMICAL suppressed the expression of ICAM-1 and CD40 as well as the production of IL-12, TNF-alpha and IFN-gamma in PBMC, contributing to the anti-inflammatory effect of CHEMICAL. The effects of CHEMICAL were abolished by the addition of the product of the HMG-CoA reductase, mevalonate, indicating the involvement of HMG-CoA reductase in the action of CHEMICAL. | ACTIVATOR |
| CHEMICAL induces interleukin-18 production in human peripheral blood mononuclear cells. The effects of statins on immune response depend on the inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and leukocyte function-associated antigen (LFA)-1, which is a ligand of intercellular adhesion molecule (ICAM)-1. CHEMICAL, an HMG-CoA reductase inhibitor with mild inhibition of LFA-1, induced the production of interleukin (IL)-18, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in human peripheral blood mononuclear cells (PBMC). The IL-18 production is located upstream of the cytokine cascade activated by CHEMICAL. Moreover, CHEMICAL concentration-dependently inhibited the expression of ICAM-1 and induced the expression of CD40 on monocytes. In the presence of IL-18, CHEMICAL suppressed the expression of ICAM-1 and CD40 as well as the production of GENE, TNF-alpha and IFN-gamma in PBMC, contributing to the anti-inflammatory effect of CHEMICAL. The effects of CHEMICAL were abolished by the addition of the product of the HMG-CoA reductase, mevalonate, indicating the involvement of HMG-CoA reductase in the action of CHEMICAL. | GENE-CHEMICAL |
| CHEMICAL induces interleukin-18 production in human peripheral blood mononuclear cells. The effects of statins on immune response depend on the inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and leukocyte function-associated antigen (LFA)-1, which is a ligand of intercellular adhesion molecule (ICAM)-1. CHEMICAL, an HMG-CoA reductase inhibitor with mild inhibition of LFA-1, induced the production of interleukin (IL)-18, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in human peripheral blood mononuclear cells (PBMC). The IL-18 production is located upstream of the cytokine cascade activated by CHEMICAL. Moreover, CHEMICAL concentration-dependently inhibited the expression of ICAM-1 and induced the expression of CD40 on monocytes. In the presence of IL-18, CHEMICAL suppressed the expression of ICAM-1 and CD40 as well as the production of IL-12, GENE and IFN-gamma in PBMC, contributing to the anti-inflammatory effect of CHEMICAL. The effects of CHEMICAL were abolished by the addition of the product of the HMG-CoA reductase, mevalonate, indicating the involvement of HMG-CoA reductase in the action of CHEMICAL. | GENE-CHEMICAL |
| CHEMICAL induces interleukin-18 production in human peripheral blood mononuclear cells. The effects of statins on immune response depend on the inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and leukocyte function-associated antigen (LFA)-1, which is a ligand of intercellular adhesion molecule (ICAM)-1. CHEMICAL, an HMG-CoA reductase inhibitor with mild inhibition of LFA-1, induced the production of interleukin (IL)-18, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in human peripheral blood mononuclear cells (PBMC). The IL-18 production is located upstream of the cytokine cascade activated by CHEMICAL. Moreover, CHEMICAL concentration-dependently inhibited the expression of ICAM-1 and induced the expression of CD40 on monocytes. In the presence of IL-18, CHEMICAL suppressed the expression of ICAM-1 and CD40 as well as the production of IL-12, TNF-alpha and GENE in PBMC, contributing to the anti-inflammatory effect of CHEMICAL. The effects of CHEMICAL were abolished by the addition of the product of the HMG-CoA reductase, mevalonate, indicating the involvement of HMG-CoA reductase in the action of CHEMICAL. | INDIRECT-DOWNREGULATOR |
| CHEMICAL induces GENE production in human peripheral blood mononuclear cells. The effects of statins on immune response depend on the inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and leukocyte function-associated antigen (LFA)-1, which is a ligand of intercellular adhesion molecule (ICAM)-1. CHEMICAL, an HMG-CoA reductase inhibitor with mild inhibition of LFA-1, induced the production of interleukin (IL)-18, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in human peripheral blood mononuclear cells (PBMC). The IL-18 production is located upstream of the cytokine cascade activated by simvastatin. Moreover, simvastatin concentration-dependently inhibited the expression of ICAM-1 and induced the expression of CD40 on monocytes. In the presence of IL-18, simvastatin suppressed the expression of ICAM-1 and CD40 as well as the production of IL-12, TNF-alpha and IFN-gamma in PBMC, contributing to the anti-inflammatory effect of simvastatin. The effects of simvastatin were abolished by the addition of the product of the HMG-CoA reductase, mevalonate, indicating the involvement of HMG-CoA reductase in the action of simvastatin. | INDIRECT-UPREGULATOR |
| CHEMICAL induces interleukin-18 production in human peripheral blood mononuclear cells. The effects of statins on immune response depend on the inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and leukocyte function-associated antigen (LFA)-1, which is a ligand of intercellular adhesion molecule (ICAM)-1. CHEMICAL, an HMG-CoA reductase inhibitor with mild inhibition of LFA-1, induced the production of GENE, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in human peripheral blood mononuclear cells (PBMC). The IL-18 production is located upstream of the cytokine cascade activated by simvastatin. Moreover, simvastatin concentration-dependently inhibited the expression of ICAM-1 and induced the expression of CD40 on monocytes. In the presence of IL-18, simvastatin suppressed the expression of ICAM-1 and CD40 as well as the production of IL-12, TNF-alpha and IFN-gamma in PBMC, contributing to the anti-inflammatory effect of simvastatin. The effects of simvastatin were abolished by the addition of the product of the HMG-CoA reductase, mevalonate, indicating the involvement of HMG-CoA reductase in the action of simvastatin. | INDIRECT-UPREGULATOR |
| CHEMICAL induces interleukin-18 production in human peripheral blood mononuclear cells. The effects of statins on immune response depend on the inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and leukocyte function-associated antigen (LFA)-1, which is a ligand of intercellular adhesion molecule (ICAM)-1. CHEMICAL, an HMG-CoA reductase inhibitor with mild inhibition of LFA-1, induced the production of interleukin (IL)-18, GENE and interferon (IFN)-gamma in human peripheral blood mononuclear cells (PBMC). The IL-18 production is located upstream of the cytokine cascade activated by simvastatin. Moreover, simvastatin concentration-dependently inhibited the expression of ICAM-1 and induced the expression of CD40 on monocytes. In the presence of IL-18, simvastatin suppressed the expression of ICAM-1 and CD40 as well as the production of IL-12, TNF-alpha and IFN-gamma in PBMC, contributing to the anti-inflammatory effect of simvastatin. The effects of simvastatin were abolished by the addition of the product of the HMG-CoA reductase, mevalonate, indicating the involvement of HMG-CoA reductase in the action of simvastatin. | GENE-CHEMICAL |
| CHEMICAL induces interleukin-18 production in human peripheral blood mononuclear cells. The effects of statins on immune response depend on the inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and leukocyte function-associated antigen (LFA)-1, which is a ligand of intercellular adhesion molecule (ICAM)-1. CHEMICAL, an HMG-CoA reductase inhibitor with mild inhibition of LFA-1, induced the production of interleukin (IL)-18, tumor necrosis factor (TNF)-alpha and GENE in human peripheral blood mononuclear cells (PBMC). The IL-18 production is located upstream of the cytokine cascade activated by simvastatin. Moreover, simvastatin concentration-dependently inhibited the expression of ICAM-1 and induced the expression of CD40 on monocytes. In the presence of IL-18, simvastatin suppressed the expression of ICAM-1 and CD40 as well as the production of IL-12, TNF-alpha and IFN-gamma in PBMC, contributing to the anti-inflammatory effect of simvastatin. The effects of simvastatin were abolished by the addition of the product of the HMG-CoA reductase, mevalonate, indicating the involvement of HMG-CoA reductase in the action of simvastatin. | INDIRECT-UPREGULATOR |
| CHEMICAL induces interleukin-18 production in human peripheral blood mononuclear cells. The effects of statins on immune response depend on the inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and leukocyte function-associated antigen (LFA)-1, which is a ligand of intercellular adhesion molecule (ICAM)-1. CHEMICAL, an HMG-CoA reductase inhibitor with mild inhibition of LFA-1, induced the production of interleukin (IL)-18, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in human peripheral blood mononuclear cells (PBMC). The IL-18 production is located upstream of the cytokine cascade activated by CHEMICAL. Moreover, CHEMICAL concentration-dependently inhibited the expression of ICAM-1 and induced the expression of GENE on monocytes. In the presence of IL-18, CHEMICAL suppressed the expression of ICAM-1 and GENE as well as the production of IL-12, TNF-alpha and IFN-gamma in PBMC, contributing to the anti-inflammatory effect of CHEMICAL. The effects of CHEMICAL were abolished by the addition of the product of the HMG-CoA reductase, mevalonate, indicating the involvement of HMG-CoA reductase in the action of CHEMICAL. | INDIRECT-UPREGULATOR |
| CHEMICAL induces interleukin-18 production in human peripheral blood mononuclear cells. The effects of statins on immune response depend on the inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and leukocyte function-associated antigen (LFA)-1, which is a ligand of intercellular adhesion molecule (ICAM)-1. CHEMICAL, an HMG-CoA reductase inhibitor with mild inhibition of LFA-1, induced the production of interleukin (IL)-18, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in human peripheral blood mononuclear cells (PBMC). The IL-18 production is located upstream of the cytokine cascade activated by CHEMICAL. Moreover, CHEMICAL concentration-dependently inhibited the expression of GENE and induced the expression of CD40 on monocytes. In the presence of IL-18, CHEMICAL suppressed the expression of GENE and CD40 as well as the production of IL-12, TNF-alpha and IFN-gamma in PBMC, contributing to the anti-inflammatory effect of CHEMICAL. The effects of CHEMICAL were abolished by the addition of the product of the HMG-CoA reductase, mevalonate, indicating the involvement of HMG-CoA reductase in the action of CHEMICAL. | INDIRECT-DOWNREGULATOR |
| CHEMICAL induces interleukin-18 production in human peripheral blood mononuclear cells. The effects of statins on immune response depend on the inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and leukocyte function-associated antigen (LFA)-1, which is a ligand of intercellular adhesion molecule (ICAM)-1. CHEMICAL, an HMG-CoA reductase inhibitor with mild inhibition of GENE, induced the production of interleukin (IL)-18, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in human peripheral blood mononuclear cells (PBMC). The IL-18 production is located upstream of the cytokine cascade activated by simvastatin. Moreover, simvastatin concentration-dependently inhibited the expression of ICAM-1 and induced the expression of CD40 on monocytes. In the presence of IL-18, simvastatin suppressed the expression of ICAM-1 and CD40 as well as the production of IL-12, TNF-alpha and IFN-gamma in PBMC, contributing to the anti-inflammatory effect of simvastatin. The effects of simvastatin were abolished by the addition of the product of the HMG-CoA reductase, mevalonate, indicating the involvement of HMG-CoA reductase in the action of simvastatin. | INHIBITOR |
| Simvastatin induces interleukin-18 production in human peripheral blood mononuclear cells. The effects of statins on immune response depend on the inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase and leukocyte function-associated antigen (LFA)-1, which is a ligand of intercellular adhesion molecule (ICAM)-1. Simvastatin, an GENE inhibitor with mild inhibition of LFA-1, induced the production of interleukin (IL)-18, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma in human peripheral blood mononuclear cells (PBMC). The IL-18 production is located upstream of the cytokine cascade activated by simvastatin. Moreover, simvastatin concentration-dependently inhibited the expression of ICAM-1 and induced the expression of CD40 on monocytes. In the presence of IL-18, simvastatin suppressed the expression of ICAM-1 and CD40 as well as the production of IL-12, TNF-alpha and IFN-gamma in PBMC, contributing to the anti-inflammatory effect of simvastatin. The effects of simvastatin were abolished by the addition of the product of the GENE, CHEMICAL, indicating the involvement of GENE in the action of simvastatin. | GENE-CHEMICAL |
| COX-1 and GENE inhibition in horse blood by phenylbutazone, flunixin, CHEMICAL and meloxicam: an in vitro analysis. We report on the inhibitory activity of the NSAIDs meloxicam, CHEMICAL, phenylbutazone and flunixin, on blood cyclooxygenases in the horse using in vitro enzyme-linked assays. As expected, comparison of IC50 indicated that meloxicam and CHEMICAL are more selective inhibitors of GENE than phenylbutazone and flunixin; meloxicam was the most advantageous for horses of four NSAIDs examined. However at IC80, phenylbutazone (+134.4%) and flunixin (+29.7%) had greater GENE selectivity than at IC50, and meloxicam (-41.2%) and CHEMICAL (-12.9%) had lower GENE selectivity than at IC50. We therefore propose that the selectivity of NSAIDs should be assessed at the 80% as well as 50% inhibition level. | INHIBITOR |
| COX-1 and COX-2 inhibition in horse blood by phenylbutazone, flunixin, CHEMICAL and meloxicam: an in vitro analysis. We report on the inhibitory activity of the NSAIDs meloxicam, CHEMICAL, phenylbutazone and flunixin, on blood GENE in the horse using in vitro enzyme-linked assays. As expected, comparison of IC50 indicated that meloxicam and CHEMICAL are more selective inhibitors of COX-2 than phenylbutazone and flunixin; meloxicam was the most advantageous for horses of four NSAIDs examined. However at IC80, phenylbutazone (+134.4%) and flunixin (+29.7%) had greater COX-2 selectivity than at IC50, and meloxicam (-41.2%) and CHEMICAL (-12.9%) had lower COX-2 selectivity than at IC50. We therefore propose that the selectivity of NSAIDs should be assessed at the 80% as well as 50% inhibition level. | INHIBITOR |
| COX-1 and COX-2 inhibition in horse blood by CHEMICAL, flunixin, carprofen and meloxicam: an in vitro analysis. We report on the inhibitory activity of the NSAIDs meloxicam, carprofen, CHEMICAL and flunixin, on blood GENE in the horse using in vitro enzyme-linked assays. As expected, comparison of IC50 indicated that meloxicam and carprofen are more selective inhibitors of COX-2 than CHEMICAL and flunixin; meloxicam was the most advantageous for horses of four NSAIDs examined. However at IC80, CHEMICAL (+134.4%) and flunixin (+29.7%) had greater COX-2 selectivity than at IC50, and meloxicam (-41.2%) and carprofen (-12.9%) had lower COX-2 selectivity than at IC50. We therefore propose that the selectivity of NSAIDs should be assessed at the 80% as well as 50% inhibition level. | INHIBITOR |
| COX-1 and COX-2 inhibition in horse blood by phenylbutazone, CHEMICAL, carprofen and meloxicam: an in vitro analysis. We report on the inhibitory activity of the NSAIDs meloxicam, carprofen, phenylbutazone and CHEMICAL, on blood GENE in the horse using in vitro enzyme-linked assays. As expected, comparison of IC50 indicated that meloxicam and carprofen are more selective inhibitors of COX-2 than phenylbutazone and flunixin; meloxicam was the most advantageous for horses of four NSAIDs examined. However at IC80, phenylbutazone (+134.4%) and CHEMICAL (+29.7%) had greater COX-2 selectivity than at IC50, and meloxicam (-41.2%) and carprofen (-12.9%) had lower COX-2 selectivity than at IC50. We therefore propose that the selectivity of NSAIDs should be assessed at the 80% as well as 50% inhibition level. | INHIBITOR |
| GENE and COX-2 inhibition in horse blood by CHEMICAL, flunixin, carprofen and meloxicam: an in vitro analysis. We report on the inhibitory activity of the NSAIDs meloxicam, carprofen, CHEMICAL and flunixin, on blood cyclooxygenases in the horse using in vitro enzyme-linked assays. As expected, comparison of IC50 indicated that meloxicam and carprofen are more selective inhibitors of COX-2 than CHEMICAL and flunixin; meloxicam was the most advantageous for horses of four NSAIDs examined. However at IC80, CHEMICAL (+134.4%) and flunixin (+29.7%) had greater COX-2 selectivity than at IC50, and meloxicam (-41.2%) and carprofen (-12.9%) had lower COX-2 selectivity than at IC50. We therefore propose that the selectivity of NSAIDs should be assessed at the 80% as well as 50% inhibition level. | INHIBITOR |
| COX-1 and GENE inhibition in horse blood by CHEMICAL, flunixin, carprofen and meloxicam: an in vitro analysis. We report on the inhibitory activity of the NSAIDs meloxicam, carprofen, CHEMICAL and flunixin, on blood cyclooxygenases in the horse using in vitro enzyme-linked assays. As expected, comparison of IC50 indicated that meloxicam and carprofen are more selective inhibitors of GENE than CHEMICAL and flunixin; meloxicam was the most advantageous for horses of four NSAIDs examined. However at IC80, CHEMICAL (+134.4%) and flunixin (+29.7%) had greater GENE selectivity than at IC50, and meloxicam (-41.2%) and carprofen (-12.9%) had lower GENE selectivity than at IC50. We therefore propose that the selectivity of NSAIDs should be assessed at the 80% as well as 50% inhibition level. | INHIBITOR |
| GENE and COX-2 inhibition in horse blood by phenylbutazone, CHEMICAL, carprofen and meloxicam: an in vitro analysis. We report on the inhibitory activity of the NSAIDs meloxicam, carprofen, phenylbutazone and CHEMICAL, on blood cyclooxygenases in the horse using in vitro enzyme-linked assays. As expected, comparison of IC50 indicated that meloxicam and carprofen are more selective inhibitors of COX-2 than phenylbutazone and flunixin; meloxicam was the most advantageous for horses of four NSAIDs examined. However at IC80, phenylbutazone (+134.4%) and CHEMICAL (+29.7%) had greater COX-2 selectivity than at IC50, and meloxicam (-41.2%) and carprofen (-12.9%) had lower COX-2 selectivity than at IC50. We therefore propose that the selectivity of NSAIDs should be assessed at the 80% as well as 50% inhibition level. | INHIBITOR |
| COX-1 and GENE inhibition in horse blood by phenylbutazone, CHEMICAL, carprofen and meloxicam: an in vitro analysis. We report on the inhibitory activity of the NSAIDs meloxicam, carprofen, phenylbutazone and CHEMICAL, on blood cyclooxygenases in the horse using in vitro enzyme-linked assays. As expected, comparison of IC50 indicated that meloxicam and carprofen are more selective inhibitors of GENE than phenylbutazone and flunixin; meloxicam was the most advantageous for horses of four NSAIDs examined. However at IC80, phenylbutazone (+134.4%) and CHEMICAL (+29.7%) had greater GENE selectivity than at IC50, and meloxicam (-41.2%) and carprofen (-12.9%) had lower GENE selectivity than at IC50. We therefore propose that the selectivity of NSAIDs should be assessed at the 80% as well as 50% inhibition level. | INHIBITOR |
| GENE and COX-2 inhibition in horse blood by phenylbutazone, flunixin, CHEMICAL and meloxicam: an in vitro analysis. We report on the inhibitory activity of the NSAIDs meloxicam, CHEMICAL, phenylbutazone and flunixin, on blood cyclooxygenases in the horse using in vitro enzyme-linked assays. As expected, comparison of IC50 indicated that meloxicam and CHEMICAL are more selective inhibitors of COX-2 than phenylbutazone and flunixin; meloxicam was the most advantageous for horses of four NSAIDs examined. However at IC80, phenylbutazone (+134.4%) and flunixin (+29.7%) had greater COX-2 selectivity than at IC50, and meloxicam (-41.2%) and CHEMICAL (-12.9%) had lower COX-2 selectivity than at IC50. We therefore propose that the selectivity of NSAIDs should be assessed at the 80% as well as 50% inhibition level. | INHIBITOR |
| GENE and COX-2 inhibition in horse blood by phenylbutazone, flunixin, carprofen and CHEMICAL: an in vitro analysis. We report on the inhibitory activity of the NSAIDs CHEMICAL, carprofen, phenylbutazone and flunixin, on blood cyclooxygenases in the horse using in vitro enzyme-linked assays. As expected, comparison of IC50 indicated that CHEMICAL and carprofen are more selective inhibitors of COX-2 than phenylbutazone and flunixin; CHEMICAL was the most advantageous for horses of four NSAIDs examined. However at IC80, phenylbutazone (+134.4%) and flunixin (+29.7%) had greater COX-2 selectivity than at IC50, and CHEMICAL (-41.2%) and carprofen (-12.9%) had lower COX-2 selectivity than at IC50. We therefore propose that the selectivity of NSAIDs should be assessed at the 80% as well as 50% inhibition level. | INHIBITOR |
| COX-1 and GENE inhibition in horse blood by phenylbutazone, flunixin, carprofen and CHEMICAL: an in vitro analysis. We report on the inhibitory activity of the NSAIDs CHEMICAL, carprofen, phenylbutazone and flunixin, on blood cyclooxygenases in the horse using in vitro enzyme-linked assays. As expected, comparison of IC50 indicated that CHEMICAL and carprofen are more selective inhibitors of GENE than phenylbutazone and flunixin; CHEMICAL was the most advantageous for horses of four NSAIDs examined. However at IC80, phenylbutazone (+134.4%) and flunixin (+29.7%) had greater GENE selectivity than at IC50, and CHEMICAL (-41.2%) and carprofen (-12.9%) had lower GENE selectivity than at IC50. We therefore propose that the selectivity of NSAIDs should be assessed at the 80% as well as 50% inhibition level. | INHIBITOR |
| COX-1 and COX-2 inhibition in horse blood by phenylbutazone, flunixin, carprofen and meloxicam: an in vitro analysis. We report on the inhibitory activity of the NSAIDs CHEMICAL, carprofen, phenylbutazone and flunixin, on blood GENE in the horse using in vitro enzyme-linked assays. As expected, comparison of IC50 indicated that CHEMICAL and carprofen are more selective inhibitors of COX-2 than phenylbutazone and flunixin; CHEMICAL was the most advantageous for horses of four NSAIDs examined. However at IC80, phenylbutazone (+134.4%) and flunixin (+29.7%) had greater COX-2 selectivity than at IC50, and CHEMICAL (-41.2%) and carprofen (-12.9%) had lower COX-2 selectivity than at IC50. We therefore propose that the selectivity of NSAIDs should be assessed at the 80% as well as 50% inhibition level. | INHIBITOR |
| Carvedilol prevents cardiac hypertrophy and overexpression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in pressure-overloaded rat heart. The use of beta-blockers has emerged as a beneficial treatment for cardiac hypertrophy. Hypoxia-inducible factor-1alpha (HIF-1alpha) is tightly regulated in the ventricular myocardium. However, the expression of GENE in cardiac hypertrophy due to pressure overload and after treatment with beta-blocker is little known. To evaluate the effect of carvedilol on both myocardial GENE expression and cardiac hypertrophy, infra-renal aortic banding was performed for 4 weeks in adult Sprague-Dawley rats to induce cardiac hypertrophy. Carvedilol at 50 mg/kg body weight per day after surgery was given. Heart weight and the ratio of heart weight and body weight increased significantly after aortic banding for 4 weeks in the absence of drug treatment. Mean arterial pressure increased from 80 +/- 9 mmHg in the sham group to 94 +/-5 mmHg (p < 0.001) in the banding group. Echocardiography showed concentric hypertrophy after aortic banding. Mean arterial pressure decreased after treatment with carvedilol. The increased wall thickness and heart weight was reversed to normal by carvedilol. Western blot showed that GENE, vascular endothelial growth factor (VEGF) and brain natriuretic peptide (BNP) proteins were up-regulated and nerve growth factor-beta (NGF-beta) down-regulated in the banding group. Treatment with CHEMICAL, doxazosin, or N-acetylcysteine did not significantly affect GENE and VEGF proteins expression in the banding groups. Real-time polymerase chain reaction showed that mRNA of GENE, VEGF and BNP increased and mRNA of NGF-beta decreased in the banding group. Treatment with carvedilol reversed both protein and mRNA of GENE, VEGF, BNP, and NGF-beta to the baseline values. Increased immunohistochemical labeling of GENE, VEGF, and BNP in the ventricular myocardium was observed in the banding group and carvedilol again normalized the labeling. In conclusion, GENE, VEGF, and BNP mRNA and protein expression were up-regulated, while NGF-beta mRNA and protein was downregulated in the rat model of pressure-overloaded cardiac hypertrophy. Treatment with carvedilol is associated with a reversal of abnormal regulation of GENE, VEGF, BNP, and NGF-beta in the hypertrophic myocardium. | NO-RELATIONSHIP |
| Carvedilol prevents cardiac hypertrophy and overexpression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in pressure-overloaded rat heart. The use of beta-blockers has emerged as a beneficial treatment for cardiac hypertrophy. Hypoxia-inducible factor-1alpha (HIF-1alpha) is tightly regulated in the ventricular myocardium. However, the expression of HIF-1alpha in cardiac hypertrophy due to pressure overload and after treatment with beta-blocker is little known. To evaluate the effect of carvedilol on both myocardial HIF-1alpha expression and cardiac hypertrophy, infra-renal aortic banding was performed for 4 weeks in adult Sprague-Dawley rats to induce cardiac hypertrophy. Carvedilol at 50 mg/kg body weight per day after surgery was given. Heart weight and the ratio of heart weight and body weight increased significantly after aortic banding for 4 weeks in the absence of drug treatment. Mean arterial pressure increased from 80 +/- 9 mmHg in the sham group to 94 +/-5 mmHg (p < 0.001) in the banding group. Echocardiography showed concentric hypertrophy after aortic banding. Mean arterial pressure decreased after treatment with carvedilol. The increased wall thickness and heart weight was reversed to normal by carvedilol. Western blot showed that HIF-1alpha, vascular endothelial growth factor (VEGF) and brain natriuretic peptide (BNP) proteins were up-regulated and nerve growth factor-beta (NGF-beta) down-regulated in the banding group. Treatment with CHEMICAL, doxazosin, or N-acetylcysteine did not significantly affect HIF-1alpha and GENE proteins expression in the banding groups. Real-time polymerase chain reaction showed that mRNA of HIF-1alpha, GENE and BNP increased and mRNA of NGF-beta decreased in the banding group. Treatment with carvedilol reversed both protein and mRNA of HIF-1alpha, GENE, BNP, and NGF-beta to the baseline values. Increased immunohistochemical labeling of HIF-1alpha, GENE, and BNP in the ventricular myocardium was observed in the banding group and carvedilol again normalized the labeling. In conclusion, HIF-1alpha, GENE, and BNP mRNA and protein expression were up-regulated, while NGF-beta mRNA and protein was downregulated in the rat model of pressure-overloaded cardiac hypertrophy. Treatment with carvedilol is associated with a reversal of abnormal regulation of HIF-1alpha, GENE, BNP, and NGF-beta in the hypertrophic myocardium. | NO-RELATIONSHIP |
| Carvedilol prevents cardiac hypertrophy and overexpression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in pressure-overloaded rat heart. The use of beta-blockers has emerged as a beneficial treatment for cardiac hypertrophy. Hypoxia-inducible factor-1alpha (HIF-1alpha) is tightly regulated in the ventricular myocardium. However, the expression of GENE in cardiac hypertrophy due to pressure overload and after treatment with beta-blocker is little known. To evaluate the effect of carvedilol on both myocardial GENE expression and cardiac hypertrophy, infra-renal aortic banding was performed for 4 weeks in adult Sprague-Dawley rats to induce cardiac hypertrophy. Carvedilol at 50 mg/kg body weight per day after surgery was given. Heart weight and the ratio of heart weight and body weight increased significantly after aortic banding for 4 weeks in the absence of drug treatment. Mean arterial pressure increased from 80 +/- 9 mmHg in the sham group to 94 +/-5 mmHg (p < 0.001) in the banding group. Echocardiography showed concentric hypertrophy after aortic banding. Mean arterial pressure decreased after treatment with carvedilol. The increased wall thickness and heart weight was reversed to normal by carvedilol. Western blot showed that GENE, vascular endothelial growth factor (VEGF) and brain natriuretic peptide (BNP) proteins were up-regulated and nerve growth factor-beta (NGF-beta) down-regulated in the banding group. Treatment with valsartan, CHEMICAL, or N-acetylcysteine did not significantly affect GENE and VEGF proteins expression in the banding groups. Real-time polymerase chain reaction showed that mRNA of GENE, VEGF and BNP increased and mRNA of NGF-beta decreased in the banding group. Treatment with carvedilol reversed both protein and mRNA of GENE, VEGF, BNP, and NGF-beta to the baseline values. Increased immunohistochemical labeling of GENE, VEGF, and BNP in the ventricular myocardium was observed in the banding group and carvedilol again normalized the labeling. In conclusion, GENE, VEGF, and BNP mRNA and protein expression were up-regulated, while NGF-beta mRNA and protein was downregulated in the rat model of pressure-overloaded cardiac hypertrophy. Treatment with carvedilol is associated with a reversal of abnormal regulation of GENE, VEGF, BNP, and NGF-beta in the hypertrophic myocardium. | NO-RELATIONSHIP |
| Carvedilol prevents cardiac hypertrophy and overexpression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in pressure-overloaded rat heart. The use of beta-blockers has emerged as a beneficial treatment for cardiac hypertrophy. Hypoxia-inducible factor-1alpha (HIF-1alpha) is tightly regulated in the ventricular myocardium. However, the expression of HIF-1alpha in cardiac hypertrophy due to pressure overload and after treatment with beta-blocker is little known. To evaluate the effect of carvedilol on both myocardial HIF-1alpha expression and cardiac hypertrophy, infra-renal aortic banding was performed for 4 weeks in adult Sprague-Dawley rats to induce cardiac hypertrophy. Carvedilol at 50 mg/kg body weight per day after surgery was given. Heart weight and the ratio of heart weight and body weight increased significantly after aortic banding for 4 weeks in the absence of drug treatment. Mean arterial pressure increased from 80 +/- 9 mmHg in the sham group to 94 +/-5 mmHg (p < 0.001) in the banding group. Echocardiography showed concentric hypertrophy after aortic banding. Mean arterial pressure decreased after treatment with carvedilol. The increased wall thickness and heart weight was reversed to normal by carvedilol. Western blot showed that HIF-1alpha, vascular endothelial growth factor (VEGF) and brain natriuretic peptide (BNP) proteins were up-regulated and nerve growth factor-beta (NGF-beta) down-regulated in the banding group. Treatment with valsartan, CHEMICAL, or N-acetylcysteine did not significantly affect HIF-1alpha and GENE proteins expression in the banding groups. Real-time polymerase chain reaction showed that mRNA of HIF-1alpha, GENE and BNP increased and mRNA of NGF-beta decreased in the banding group. Treatment with carvedilol reversed both protein and mRNA of HIF-1alpha, GENE, BNP, and NGF-beta to the baseline values. Increased immunohistochemical labeling of HIF-1alpha, GENE, and BNP in the ventricular myocardium was observed in the banding group and carvedilol again normalized the labeling. In conclusion, HIF-1alpha, GENE, and BNP mRNA and protein expression were up-regulated, while NGF-beta mRNA and protein was downregulated in the rat model of pressure-overloaded cardiac hypertrophy. Treatment with carvedilol is associated with a reversal of abnormal regulation of HIF-1alpha, GENE, BNP, and NGF-beta in the hypertrophic myocardium. | NO-RELATIONSHIP |
| Carvedilol prevents cardiac hypertrophy and overexpression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in pressure-overloaded rat heart. The use of beta-blockers has emerged as a beneficial treatment for cardiac hypertrophy. Hypoxia-inducible factor-1alpha (HIF-1alpha) is tightly regulated in the ventricular myocardium. However, the expression of GENE in cardiac hypertrophy due to pressure overload and after treatment with beta-blocker is little known. To evaluate the effect of carvedilol on both myocardial GENE expression and cardiac hypertrophy, infra-renal aortic banding was performed for 4 weeks in adult Sprague-Dawley rats to induce cardiac hypertrophy. Carvedilol at 50 mg/kg body weight per day after surgery was given. Heart weight and the ratio of heart weight and body weight increased significantly after aortic banding for 4 weeks in the absence of drug treatment. Mean arterial pressure increased from 80 +/- 9 mmHg in the sham group to 94 +/-5 mmHg (p < 0.001) in the banding group. Echocardiography showed concentric hypertrophy after aortic banding. Mean arterial pressure decreased after treatment with carvedilol. The increased wall thickness and heart weight was reversed to normal by carvedilol. Western blot showed that GENE, vascular endothelial growth factor (VEGF) and brain natriuretic peptide (BNP) proteins were up-regulated and nerve growth factor-beta (NGF-beta) down-regulated in the banding group. Treatment with valsartan, doxazosin, or CHEMICAL did not significantly affect GENE and VEGF proteins expression in the banding groups. Real-time polymerase chain reaction showed that mRNA of GENE, VEGF and BNP increased and mRNA of NGF-beta decreased in the banding group. Treatment with carvedilol reversed both protein and mRNA of GENE, VEGF, BNP, and NGF-beta to the baseline values. Increased immunohistochemical labeling of GENE, VEGF, and BNP in the ventricular myocardium was observed in the banding group and carvedilol again normalized the labeling. In conclusion, GENE, VEGF, and BNP mRNA and protein expression were up-regulated, while NGF-beta mRNA and protein was downregulated in the rat model of pressure-overloaded cardiac hypertrophy. Treatment with carvedilol is associated with a reversal of abnormal regulation of GENE, VEGF, BNP, and NGF-beta in the hypertrophic myocardium. | NO-RELATIONSHIP |
| Carvedilol prevents cardiac hypertrophy and overexpression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in pressure-overloaded rat heart. The use of beta-blockers has emerged as a beneficial treatment for cardiac hypertrophy. Hypoxia-inducible factor-1alpha (HIF-1alpha) is tightly regulated in the ventricular myocardium. However, the expression of HIF-1alpha in cardiac hypertrophy due to pressure overload and after treatment with beta-blocker is little known. To evaluate the effect of carvedilol on both myocardial HIF-1alpha expression and cardiac hypertrophy, infra-renal aortic banding was performed for 4 weeks in adult Sprague-Dawley rats to induce cardiac hypertrophy. Carvedilol at 50 mg/kg body weight per day after surgery was given. Heart weight and the ratio of heart weight and body weight increased significantly after aortic banding for 4 weeks in the absence of drug treatment. Mean arterial pressure increased from 80 +/- 9 mmHg in the sham group to 94 +/-5 mmHg (p < 0.001) in the banding group. Echocardiography showed concentric hypertrophy after aortic banding. Mean arterial pressure decreased after treatment with carvedilol. The increased wall thickness and heart weight was reversed to normal by carvedilol. Western blot showed that HIF-1alpha, vascular endothelial growth factor (VEGF) and brain natriuretic peptide (BNP) proteins were up-regulated and nerve growth factor-beta (NGF-beta) down-regulated in the banding group. Treatment with valsartan, doxazosin, or CHEMICAL did not significantly affect HIF-1alpha and GENE proteins expression in the banding groups. Real-time polymerase chain reaction showed that mRNA of HIF-1alpha, GENE and BNP increased and mRNA of NGF-beta decreased in the banding group. Treatment with carvedilol reversed both protein and mRNA of HIF-1alpha, GENE, BNP, and NGF-beta to the baseline values. Increased immunohistochemical labeling of HIF-1alpha, GENE, and BNP in the ventricular myocardium was observed in the banding group and carvedilol again normalized the labeling. In conclusion, HIF-1alpha, GENE, and BNP mRNA and protein expression were up-regulated, while NGF-beta mRNA and protein was downregulated in the rat model of pressure-overloaded cardiac hypertrophy. Treatment with carvedilol is associated with a reversal of abnormal regulation of HIF-1alpha, GENE, BNP, and NGF-beta in the hypertrophic myocardium. | NO-RELATIONSHIP |
| CHEMICAL prevents cardiac hypertrophy and overexpression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in pressure-overloaded rat heart. The use of beta-blockers has emerged as a beneficial treatment for cardiac hypertrophy. Hypoxia-inducible factor-1alpha (HIF-1alpha) is tightly regulated in the ventricular myocardium. However, the expression of HIF-1alpha in cardiac hypertrophy due to pressure overload and after treatment with beta-blocker is little known. To evaluate the effect of CHEMICAL on both myocardial HIF-1alpha expression and cardiac hypertrophy, infra-renal aortic banding was performed for 4 weeks in adult Sprague-Dawley rats to induce cardiac hypertrophy. CHEMICAL at 50 mg/kg body weight per day after surgery was given. Heart weight and the ratio of heart weight and body weight increased significantly after aortic banding for 4 weeks in the absence of drug treatment. Mean arterial pressure increased from 80 +/- 9 mmHg in the sham group to 94 +/-5 mmHg (p < 0.001) in the banding group. Echocardiography showed concentric hypertrophy after aortic banding. Mean arterial pressure decreased after treatment with CHEMICAL. The increased wall thickness and heart weight was reversed to normal by CHEMICAL. Western blot showed that HIF-1alpha, vascular endothelial growth factor (VEGF) and brain natriuretic peptide (BNP) proteins were up-regulated and nerve growth factor-beta (NGF-beta) down-regulated in the banding group. Treatment with valsartan, doxazosin, or N-acetylcysteine did not significantly affect HIF-1alpha and VEGF proteins expression in the banding groups. Real-time polymerase chain reaction showed that mRNA of HIF-1alpha, VEGF and BNP increased and mRNA of GENE decreased in the banding group. Treatment with CHEMICAL reversed both protein and mRNA of HIF-1alpha, VEGF, BNP, and GENE to the baseline values. Increased immunohistochemical labeling of HIF-1alpha, VEGF, and BNP in the ventricular myocardium was observed in the banding group and CHEMICAL again normalized the labeling. In conclusion, HIF-1alpha, VEGF, and BNP mRNA and protein expression were up-regulated, while GENE mRNA and protein was downregulated in the rat model of pressure-overloaded cardiac hypertrophy. Treatment with CHEMICAL is associated with a reversal of abnormal regulation of HIF-1alpha, VEGF, BNP, and GENE in the hypertrophic myocardium. | INDIRECT-DOWNREGULATOR |
| CHEMICAL prevents cardiac hypertrophy and overexpression of GENE and vascular endothelial growth factor in pressure-overloaded rat heart. The use of beta-blockers has emerged as a beneficial treatment for cardiac hypertrophy. GENE (HIF-1alpha) is tightly regulated in the ventricular myocardium. However, the expression of HIF-1alpha in cardiac hypertrophy due to pressure overload and after treatment with beta-blocker is little known. To evaluate the effect of carvedilol on both myocardial HIF-1alpha expression and cardiac hypertrophy, infra-renal aortic banding was performed for 4 weeks in adult Sprague-Dawley rats to induce cardiac hypertrophy. CHEMICAL at 50 mg/kg body weight per day after surgery was given. Heart weight and the ratio of heart weight and body weight increased significantly after aortic banding for 4 weeks in the absence of drug treatment. Mean arterial pressure increased from 80 +/- 9 mmHg in the sham group to 94 +/-5 mmHg (p < 0.001) in the banding group. Echocardiography showed concentric hypertrophy after aortic banding. Mean arterial pressure decreased after treatment with carvedilol. The increased wall thickness and heart weight was reversed to normal by carvedilol. Western blot showed that HIF-1alpha, vascular endothelial growth factor (VEGF) and brain natriuretic peptide (BNP) proteins were up-regulated and nerve growth factor-beta (NGF-beta) down-regulated in the banding group. Treatment with valsartan, doxazosin, or N-acetylcysteine did not significantly affect HIF-1alpha and VEGF proteins expression in the banding groups. Real-time polymerase chain reaction showed that mRNA of HIF-1alpha, VEGF and BNP increased and mRNA of NGF-beta decreased in the banding group. Treatment with carvedilol reversed both protein and mRNA of HIF-1alpha, VEGF, BNP, and NGF-beta to the baseline values. Increased immunohistochemical labeling of HIF-1alpha, VEGF, and BNP in the ventricular myocardium was observed in the banding group and carvedilol again normalized the labeling. In conclusion, HIF-1alpha, VEGF, and BNP mRNA and protein expression were up-regulated, while NGF-beta mRNA and protein was downregulated in the rat model of pressure-overloaded cardiac hypertrophy. Treatment with carvedilol is associated with a reversal of abnormal regulation of HIF-1alpha, VEGF, BNP, and NGF-beta in the hypertrophic myocardium. | INDIRECT-DOWNREGULATOR |
| CHEMICAL prevents cardiac hypertrophy and overexpression of hypoxia-inducible factor-1alpha and GENE in pressure-overloaded rat heart. The use of beta-blockers has emerged as a beneficial treatment for cardiac hypertrophy. Hypoxia-inducible factor-1alpha (HIF-1alpha) is tightly regulated in the ventricular myocardium. However, the expression of HIF-1alpha in cardiac hypertrophy due to pressure overload and after treatment with beta-blocker is little known. To evaluate the effect of carvedilol on both myocardial HIF-1alpha expression and cardiac hypertrophy, infra-renal aortic banding was performed for 4 weeks in adult Sprague-Dawley rats to induce cardiac hypertrophy. CHEMICAL at 50 mg/kg body weight per day after surgery was given. Heart weight and the ratio of heart weight and body weight increased significantly after aortic banding for 4 weeks in the absence of drug treatment. Mean arterial pressure increased from 80 +/- 9 mmHg in the sham group to 94 +/-5 mmHg (p < 0.001) in the banding group. Echocardiography showed concentric hypertrophy after aortic banding. Mean arterial pressure decreased after treatment with carvedilol. The increased wall thickness and heart weight was reversed to normal by carvedilol. Western blot showed that HIF-1alpha, GENE (VEGF) and brain natriuretic peptide (BNP) proteins were up-regulated and nerve growth factor-beta (NGF-beta) down-regulated in the banding group. Treatment with valsartan, doxazosin, or N-acetylcysteine did not significantly affect HIF-1alpha and VEGF proteins expression in the banding groups. Real-time polymerase chain reaction showed that mRNA of HIF-1alpha, VEGF and BNP increased and mRNA of NGF-beta decreased in the banding group. Treatment with carvedilol reversed both protein and mRNA of HIF-1alpha, VEGF, BNP, and NGF-beta to the baseline values. Increased immunohistochemical labeling of HIF-1alpha, VEGF, and BNP in the ventricular myocardium was observed in the banding group and carvedilol again normalized the labeling. In conclusion, HIF-1alpha, VEGF, and BNP mRNA and protein expression were up-regulated, while NGF-beta mRNA and protein was downregulated in the rat model of pressure-overloaded cardiac hypertrophy. Treatment with carvedilol is associated with a reversal of abnormal regulation of HIF-1alpha, VEGF, BNP, and NGF-beta in the hypertrophic myocardium. | INDIRECT-UPREGULATOR |
| CHEMICAL prevents cardiac hypertrophy and overexpression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in pressure-overloaded rat heart. The use of beta-blockers has emerged as a beneficial treatment for cardiac hypertrophy. Hypoxia-inducible factor-1alpha (HIF-1alpha) is tightly regulated in the ventricular myocardium. However, the expression of GENE in cardiac hypertrophy due to pressure overload and after treatment with beta-blocker is little known. To evaluate the effect of CHEMICAL on both myocardial GENE expression and cardiac hypertrophy, infra-renal aortic banding was performed for 4 weeks in adult Sprague-Dawley rats to induce cardiac hypertrophy. CHEMICAL at 50 mg/kg body weight per day after surgery was given. Heart weight and the ratio of heart weight and body weight increased significantly after aortic banding for 4 weeks in the absence of drug treatment. Mean arterial pressure increased from 80 +/- 9 mmHg in the sham group to 94 +/-5 mmHg (p < 0.001) in the banding group. Echocardiography showed concentric hypertrophy after aortic banding. Mean arterial pressure decreased after treatment with CHEMICAL. The increased wall thickness and heart weight was reversed to normal by CHEMICAL. Western blot showed that GENE, vascular endothelial growth factor (VEGF) and brain natriuretic peptide (BNP) proteins were up-regulated and nerve growth factor-beta (NGF-beta) down-regulated in the banding group. Treatment with valsartan, doxazosin, or N-acetylcysteine did not significantly affect GENE and VEGF proteins expression in the banding groups. Real-time polymerase chain reaction showed that mRNA of GENE, VEGF and BNP increased and mRNA of NGF-beta decreased in the banding group. Treatment with CHEMICAL reversed both protein and mRNA of GENE, VEGF, BNP, and NGF-beta to the baseline values. Increased immunohistochemical labeling of GENE, VEGF, and BNP in the ventricular myocardium was observed in the banding group and CHEMICAL again normalized the labeling. In conclusion, GENE, VEGF, and BNP mRNA and protein expression were up-regulated, while NGF-beta mRNA and protein was downregulated in the rat model of pressure-overloaded cardiac hypertrophy. Treatment with CHEMICAL is associated with a reversal of abnormal regulation of GENE, VEGF, BNP, and NGF-beta in the hypertrophic myocardium. | INDIRECT-DOWNREGULATOR |
| CHEMICAL prevents cardiac hypertrophy and overexpression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in pressure-overloaded rat heart. The use of beta-blockers has emerged as a beneficial treatment for cardiac hypertrophy. Hypoxia-inducible factor-1alpha (HIF-1alpha) is tightly regulated in the ventricular myocardium. However, the expression of HIF-1alpha in cardiac hypertrophy due to pressure overload and after treatment with beta-blocker is little known. To evaluate the effect of CHEMICAL on both myocardial HIF-1alpha expression and cardiac hypertrophy, infra-renal aortic banding was performed for 4 weeks in adult Sprague-Dawley rats to induce cardiac hypertrophy. CHEMICAL at 50 mg/kg body weight per day after surgery was given. Heart weight and the ratio of heart weight and body weight increased significantly after aortic banding for 4 weeks in the absence of drug treatment. Mean arterial pressure increased from 80 +/- 9 mmHg in the sham group to 94 +/-5 mmHg (p < 0.001) in the banding group. Echocardiography showed concentric hypertrophy after aortic banding. Mean arterial pressure decreased after treatment with CHEMICAL. The increased wall thickness and heart weight was reversed to normal by CHEMICAL. Western blot showed that HIF-1alpha, vascular endothelial growth factor (VEGF) and brain natriuretic peptide (BNP) proteins were up-regulated and nerve growth factor-beta (NGF-beta) down-regulated in the banding group. Treatment with valsartan, doxazosin, or N-acetylcysteine did not significantly affect HIF-1alpha and GENE proteins expression in the banding groups. Real-time polymerase chain reaction showed that mRNA of HIF-1alpha, GENE and BNP increased and mRNA of NGF-beta decreased in the banding group. Treatment with CHEMICAL reversed both protein and mRNA of HIF-1alpha, GENE, BNP, and NGF-beta to the baseline values. Increased immunohistochemical labeling of HIF-1alpha, GENE, and BNP in the ventricular myocardium was observed in the banding group and CHEMICAL again normalized the labeling. In conclusion, HIF-1alpha, GENE, and BNP mRNA and protein expression were up-regulated, while NGF-beta mRNA and protein was downregulated in the rat model of pressure-overloaded cardiac hypertrophy. Treatment with CHEMICAL is associated with a reversal of abnormal regulation of HIF-1alpha, GENE, BNP, and NGF-beta in the hypertrophic myocardium. | INDIRECT-DOWNREGULATOR |
| CHEMICAL prevents cardiac hypertrophy and overexpression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in pressure-overloaded rat heart. The use of beta-blockers has emerged as a beneficial treatment for cardiac hypertrophy. Hypoxia-inducible factor-1alpha (HIF-1alpha) is tightly regulated in the ventricular myocardium. However, the expression of HIF-1alpha in cardiac hypertrophy due to pressure overload and after treatment with beta-blocker is little known. To evaluate the effect of CHEMICAL on both myocardial HIF-1alpha expression and cardiac hypertrophy, infra-renal aortic banding was performed for 4 weeks in adult Sprague-Dawley rats to induce cardiac hypertrophy. CHEMICAL at 50 mg/kg body weight per day after surgery was given. Heart weight and the ratio of heart weight and body weight increased significantly after aortic banding for 4 weeks in the absence of drug treatment. Mean arterial pressure increased from 80 +/- 9 mmHg in the sham group to 94 +/-5 mmHg (p < 0.001) in the banding group. Echocardiography showed concentric hypertrophy after aortic banding. Mean arterial pressure decreased after treatment with CHEMICAL. The increased wall thickness and heart weight was reversed to normal by CHEMICAL. Western blot showed that HIF-1alpha, vascular endothelial growth factor (VEGF) and brain natriuretic peptide (BNP) proteins were up-regulated and nerve growth factor-beta (NGF-beta) down-regulated in the banding group. Treatment with valsartan, doxazosin, or N-acetylcysteine did not significantly affect HIF-1alpha and VEGF proteins expression in the banding groups. Real-time polymerase chain reaction showed that mRNA of HIF-1alpha, VEGF and GENE increased and mRNA of NGF-beta decreased in the banding group. Treatment with CHEMICAL reversed both protein and mRNA of HIF-1alpha, VEGF, GENE, and NGF-beta to the baseline values. Increased immunohistochemical labeling of HIF-1alpha, VEGF, and GENE in the ventricular myocardium was observed in the banding group and CHEMICAL again normalized the labeling. In conclusion, HIF-1alpha, VEGF, and GENE mRNA and protein expression were up-regulated, while NGF-beta mRNA and protein was downregulated in the rat model of pressure-overloaded cardiac hypertrophy. Treatment with CHEMICAL is associated with a reversal of abnormal regulation of HIF-1alpha, VEGF, GENE, and NGF-beta in the hypertrophic myocardium. | INDIRECT-DOWNREGULATOR |
| CHEMICAL resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). CHEMICAL (STI571, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, BCR-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, CHEMICAL resistance has emerged. The reported mechanism of CHEMICAL resistance in GISTs involves missense mutation in the GENE of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of CHEMICAL resistance in GISTs, the imaging studies indicative of early development of CHEMICAL resistance, and the management of imatinib-resistant GISTs are discussed. | NO-RELATIONSHIP |
| CHEMICAL resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). CHEMICAL (STI571, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of GENE ABL, BCR-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, CHEMICAL resistance has emerged. The reported mechanism of CHEMICAL resistance in GISTs involves missense mutation in the kinase domain of GENE including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of CHEMICAL resistance in GISTs, the imaging studies indicative of early development of CHEMICAL resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| CHEMICAL resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). CHEMICAL (STI571, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, BCR-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, CHEMICAL resistance has emerged. The reported mechanism of CHEMICAL resistance in GISTs involves missense mutation in the kinase domain of KIT, including GENE, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of CHEMICAL resistance in GISTs, the imaging studies indicative of early development of CHEMICAL resistance, and the management of imatinib-resistant GISTs are discussed. | NO-RELATIONSHIP |
| CHEMICAL resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). CHEMICAL (STI571, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, BCR-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, CHEMICAL resistance has emerged. The reported mechanism of CHEMICAL resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, GENE, and Val654Ala. The established mechanisms and potential mechanisms of CHEMICAL resistance in GISTs, the imaging studies indicative of early development of CHEMICAL resistance, and the management of imatinib-resistant GISTs are discussed. | NO-RELATIONSHIP |
| CHEMICAL resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). CHEMICAL (STI571, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, BCR-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, CHEMICAL resistance has emerged. The reported mechanism of CHEMICAL resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and GENE. The established mechanisms and potential mechanisms of CHEMICAL resistance in GISTs, the imaging studies indicative of early development of CHEMICAL resistance, and the management of imatinib-resistant GISTs are discussed. | NO-RELATIONSHIP |
| CHEMICAL resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). CHEMICAL (STI571, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of GENE, ABL, BCR-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of GENE, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| CHEMICAL resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). CHEMICAL (STI571, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, GENE, BCR-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| CHEMICAL resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). CHEMICAL (STI571, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, GENE-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| CHEMICAL resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). CHEMICAL (STI571, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, BCR-ABL, GENE, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| CHEMICAL resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). CHEMICAL (STI571, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, BCR-ABL, PDGFRA, and GENE represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| Imatinib resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (CHEMICAL, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of GENE, ABL, BCR-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of GENE, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| Imatinib resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (CHEMICAL, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, GENE, BCR-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| Imatinib resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (CHEMICAL, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, GENE-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| Imatinib resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (CHEMICAL, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, BCR-ABL, GENE, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| Imatinib resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (CHEMICAL, Gleevec, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, BCR-ABL, PDGFRA, and GENE represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| Imatinib resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (STI571, CHEMICAL, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of GENE, ABL, BCR-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of GENE, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| Imatinib resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (STI571, CHEMICAL, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, GENE, BCR-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| Imatinib resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (STI571, CHEMICAL, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, GENE-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| Imatinib resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (STI571, CHEMICAL, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, BCR-ABL, GENE, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| Imatinib resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (STI571, CHEMICAL, Glivec; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, BCR-ABL, PDGFRA, and GENE represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| Imatinib resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (STI571, Gleevec, CHEMICAL; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of GENE, ABL, BCR-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of GENE, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| Imatinib resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (STI571, Gleevec, CHEMICAL; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, GENE, BCR-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| Imatinib resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (STI571, Gleevec, CHEMICAL; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, GENE-ABL, PDGFRA, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| Imatinib resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (STI571, Gleevec, CHEMICAL; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, BCR-ABL, GENE, and PDGFRB, represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| Imatinib resistance in gastrointestinal stromal tumors. Conventional chemotherapeutic drugs are ineffective in treatment of gastrointestinal stromal tumors (GISTs). Imatinib (STI571, Gleevec, CHEMICAL; Novartis Pharmaceuticals, East Hanover, NJ), a selective inhibitor of KIT, ABL, BCR-ABL, PDGFRA, and GENE represents a new paradigm of targeted cancer therapy and has revolutionized the treatment of patients with chronic myelogenous leukemia and GISTs. Unfortunately, imatinib resistance has emerged. The reported mechanism of imatinib resistance in GISTs involves missense mutation in the kinase domain of KIT, including Thr670Ile, Tyr823Asp, and Val654Ala. The established mechanisms and potential mechanisms of imatinib resistance in GISTs, the imaging studies indicative of early development of imatinib resistance, and the management of imatinib-resistant GISTs are discussed. | INHIBITOR |
| Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist. The histamine H(4) receptor (H(4)R) is involved in the chemotaxis of leukocytes and mast cells to sites of inflammation and is suggested to be a potential drug target for asthma and allergy. So far, selective H(4)R agonists have not been identified. In the present study, we therefore evaluated the human H(4)R (hH(4)R) for its interaction with various known histaminergic ligands. Almost all of the tested H(1)R and H(2)R antagonists, including several important therapeutics, displaced less than 30% of specific CHEMICAL binding to the GENE at concentrations up to 10 microM. Most of the tested H(2)R agonists and imidazole-based H(3)R ligands show micromolar-to-nanomolar range GENE affinity, and these ligands exert different intrinsic GENE activities, ranging from full agonists to inverse agonists. Interestingly, we identified 4-methylhistamine as a high-affinity H(4)R ligand (K(i) = 50 nM) that has a >100-fold selectivity for the GENE over the other histamine receptor subtypes. Moreover, 4-methylhistamine potently activated the GENE (pEC(50) = 7.4 +/- 0.1; alpha = 1), and this response was competitively antagonized by the selective H(4)R antagonist JNJ 7777120 [1-[(5-chloro-1H-indol-2-yl)-carbonyl]-4-methylpiperazine] (pA(2) = 7.8). The identification of 4-methylhistamine as a potent H(4)R agonist is of major importance for future studies to unravel the physiological roles of the H(4)R. | DIRECT-REGULATOR |
| Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist. The histamine H(4) receptor (H(4)R) is involved in the chemotaxis of leukocytes and mast cells to sites of inflammation and is suggested to be a potential drug target for asthma and allergy. So far, selective H(4)R agonists have not been identified. In the present study, we therefore evaluated the human H(4)R (hH(4)R) for its interaction with various known histaminergic ligands. Almost all of the tested H(1)R and H(2)R antagonists, including several important therapeutics, displaced less than 30% of specific [(3)H]histamine binding to the hH(4)R at concentrations up to 10 microM. Most of the tested H(2)R agonists and CHEMICAL-based GENE ligands show micromolar-to-nanomolar range hH(4)R affinity, and these ligands exert different intrinsic hH(4)R activities, ranging from full agonists to inverse agonists. Interestingly, we identified 4-methylhistamine as a high-affinity H(4)R ligand (K(i) = 50 nM) that has a >100-fold selectivity for the hH(4)R over the other histamine receptor subtypes. Moreover, 4-methylhistamine potently activated the hH(4)R (pEC(50) = 7.4 +/- 0.1; alpha = 1), and this response was competitively antagonized by the selective H(4)R antagonist JNJ 7777120 [1-[(5-chloro-1H-indol-2-yl)-carbonyl]-4-methylpiperazine] (pA(2) = 7.8). The identification of 4-methylhistamine as a potent H(4)R agonist is of major importance for future studies to unravel the physiological roles of the H(4)R. | DIRECT-REGULATOR |
| Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist. The histamine H(4) receptor (H(4)R) is involved in the chemotaxis of leukocytes and mast cells to sites of inflammation and is suggested to be a potential drug target for asthma and allergy. So far, selective H(4)R agonists have not been identified. In the present study, we therefore evaluated the human H(4)R (hH(4)R) for its interaction with various known histaminergic ligands. Almost all of the tested H(1)R and H(2)R antagonists, including several important therapeutics, displaced less than 30% of specific [(3)H]histamine binding to the GENE at concentrations up to 10 microM. Most of the tested H(2)R agonists and CHEMICAL-based H(3)R ligands show micromolar-to-nanomolar range GENE affinity, and these ligands exert different intrinsic GENE activities, ranging from full agonists to inverse agonists. Interestingly, we identified 4-methylhistamine as a high-affinity H(4)R ligand (K(i) = 50 nM) that has a >100-fold selectivity for the GENE over the other histamine receptor subtypes. Moreover, 4-methylhistamine potently activated the GENE (pEC(50) = 7.4 +/- 0.1; alpha = 1), and this response was competitively antagonized by the selective H(4)R antagonist JNJ 7777120 [1-[(5-chloro-1H-indol-2-yl)-carbonyl]-4-methylpiperazine] (pA(2) = 7.8). The identification of 4-methylhistamine as a potent H(4)R agonist is of major importance for future studies to unravel the physiological roles of the H(4)R. | DIRECT-REGULATOR |
| Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of CHEMICAL as the first potent and selective H4 receptor agonist. The histamine H(4) receptor (H(4)R) is involved in the chemotaxis of leukocytes and mast cells to sites of inflammation and is suggested to be a potential drug target for asthma and allergy. So far, selective GENE agonists have not been identified. In the present study, we therefore evaluated the human GENE (hH(4)R) for its interaction with various known histaminergic ligands. Almost all of the tested H(1)R and H(2)R antagonists, including several important therapeutics, displaced less than 30% of specific [(3)H]histamine binding to the hH(4)R at concentrations up to 10 microM. Most of the tested H(2)R agonists and imidazole-based H(3)R ligands show micromolar-to-nanomolar range hH(4)R affinity, and these ligands exert different intrinsic hH(4)R activities, ranging from full agonists to inverse agonists. Interestingly, we identified CHEMICAL as a high-affinity GENE ligand (K(i) = 50 nM) that has a >100-fold selectivity for the hH(4)R over the other histamine receptor subtypes. Moreover, CHEMICAL potently activated the hH(4)R (pEC(50) = 7.4 +/- 0.1; alpha = 1), and this response was competitively antagonized by the selective GENE antagonist JNJ 7777120 [1-[(5-chloro-1H-indol-2-yl)-carbonyl]-4-methylpiperazine] (pA(2) = 7.8). The identification of CHEMICAL as a potent GENE agonist is of major importance for future studies to unravel the physiological roles of the GENE. | ACTIVATOR |
| Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of CHEMICAL as the first potent and selective H4 receptor agonist. The histamine H(4) receptor (H(4)R) is involved in the chemotaxis of leukocytes and mast cells to sites of inflammation and is suggested to be a potential drug target for asthma and allergy. So far, selective H(4)R agonists have not been identified. In the present study, we therefore evaluated the human H(4)R (hH(4)R) for its interaction with various known histaminergic ligands. Almost all of the tested H(1)R and H(2)R antagonists, including several important therapeutics, displaced less than 30% of specific [(3)H]histamine binding to the GENE at concentrations up to 10 microM. Most of the tested H(2)R agonists and imidazole-based H(3)R ligands show micromolar-to-nanomolar range GENE affinity, and these ligands exert different intrinsic GENE activities, ranging from full agonists to inverse agonists. Interestingly, we identified CHEMICAL as a high-affinity H(4)R ligand (K(i) = 50 nM) that has a >100-fold selectivity for the GENE over the other histamine receptor subtypes. Moreover, CHEMICAL potently activated the GENE (pEC(50) = 7.4 +/- 0.1; alpha = 1), and this response was competitively antagonized by the selective H(4)R antagonist JNJ 7777120 [1-[(5-chloro-1H-indol-2-yl)-carbonyl]-4-methylpiperazine] (pA(2) = 7.8). The identification of CHEMICAL as a potent H(4)R agonist is of major importance for future studies to unravel the physiological roles of the H(4)R. | ACTIVATOR |
| Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of CHEMICAL as the first potent and selective H4 receptor agonist. The histamine H(4) receptor (H(4)R) is involved in the chemotaxis of leukocytes and mast cells to sites of inflammation and is suggested to be a potential drug target for asthma and allergy. So far, selective H(4)R agonists have not been identified. In the present study, we therefore evaluated the human H(4)R (hH(4)R) for its interaction with various known histaminergic ligands. Almost all of the tested H(1)R and H(2)R antagonists, including several important therapeutics, displaced less than 30% of specific [(3)H]histamine binding to the hH(4)R at concentrations up to 10 microM. Most of the tested H(2)R agonists and imidazole-based H(3)R ligands show micromolar-to-nanomolar range hH(4)R affinity, and these ligands exert different intrinsic hH(4)R activities, ranging from full agonists to inverse agonists. Interestingly, we identified CHEMICAL as a high-affinity H(4)R ligand (K(i) = 50 nM) that has a >100-fold selectivity for the hH(4)R over the other GENE subtypes. Moreover, CHEMICAL potently activated the hH(4)R (pEC(50) = 7.4 +/- 0.1; alpha = 1), and this response was competitively antagonized by the selective H(4)R antagonist JNJ 7777120 [1-[(5-chloro-1H-indol-2-yl)-carbonyl]-4-methylpiperazine] (pA(2) = 7.8). The identification of CHEMICAL as a potent H(4)R agonist is of major importance for future studies to unravel the physiological roles of the H(4)R. | DIRECT-REGULATOR |
| Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of CHEMICAL as the first potent and selective GENE agonist. The histamine H(4) receptor (H(4)R) is involved in the chemotaxis of leukocytes and mast cells to sites of inflammation and is suggested to be a potential drug target for asthma and allergy. So far, selective H(4)R agonists have not been identified. In the present study, we therefore evaluated the human H(4)R (hH(4)R) for its interaction with various known histaminergic ligands. Almost all of the tested H(1)R and H(2)R antagonists, including several important therapeutics, displaced less than 30% of specific [(3)H]histamine binding to the hH(4)R at concentrations up to 10 microM. Most of the tested H(2)R agonists and imidazole-based H(3)R ligands show micromolar-to-nanomolar range hH(4)R affinity, and these ligands exert different intrinsic hH(4)R activities, ranging from full agonists to inverse agonists. Interestingly, we identified CHEMICAL as a high-affinity H(4)R ligand (K(i) = 50 nM) that has a >100-fold selectivity for the hH(4)R over the other histamine receptor subtypes. Moreover, CHEMICAL potently activated the hH(4)R (pEC(50) = 7.4 +/- 0.1; alpha = 1), and this response was competitively antagonized by the selective H(4)R antagonist JNJ 7777120 [1-[(5-chloro-1H-indol-2-yl)-carbonyl]-4-methylpiperazine] (pA(2) = 7.8). The identification of CHEMICAL as a potent H(4)R agonist is of major importance for future studies to unravel the physiological roles of the H(4)R. | ACTIVATOR |
| Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist. The histamine H(4) receptor (H(4)R) is involved in the chemotaxis of leukocytes and mast cells to sites of inflammation and is suggested to be a potential drug target for asthma and allergy. So far, selective GENE agonists have not been identified. In the present study, we therefore evaluated the human GENE (hH(4)R) for its interaction with various known histaminergic ligands. Almost all of the tested H(1)R and H(2)R antagonists, including several important therapeutics, displaced less than 30% of specific [(3)H]histamine binding to the hH(4)R at concentrations up to 10 microM. Most of the tested H(2)R agonists and imidazole-based H(3)R ligands show micromolar-to-nanomolar range hH(4)R affinity, and these ligands exert different intrinsic hH(4)R activities, ranging from full agonists to inverse agonists. Interestingly, we identified 4-methylhistamine as a high-affinity GENE ligand (K(i) = 50 nM) that has a >100-fold selectivity for the hH(4)R over the other histamine receptor subtypes. Moreover, 4-methylhistamine potently activated the hH(4)R (pEC(50) = 7.4 +/- 0.1; alpha = 1), and this response was competitively antagonized by the selective GENE antagonist CHEMICAL [1-[(5-chloro-1H-indol-2-yl)-carbonyl]-4-methylpiperazine] (pA(2) = 7.8). The identification of 4-methylhistamine as a potent GENE agonist is of major importance for future studies to unravel the physiological roles of the GENE. | INHIBITOR |
| Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist. The histamine H(4) receptor (H(4)R) is involved in the chemotaxis of leukocytes and mast cells to sites of inflammation and is suggested to be a potential drug target for asthma and allergy. So far, selective GENE agonists have not been identified. In the present study, we therefore evaluated the human GENE (hH(4)R) for its interaction with various known histaminergic ligands. Almost all of the tested H(1)R and H(2)R antagonists, including several important therapeutics, displaced less than 30% of specific [(3)H]histamine binding to the hH(4)R at concentrations up to 10 microM. Most of the tested H(2)R agonists and imidazole-based H(3)R ligands show micromolar-to-nanomolar range hH(4)R affinity, and these ligands exert different intrinsic hH(4)R activities, ranging from full agonists to inverse agonists. Interestingly, we identified 4-methylhistamine as a high-affinity GENE ligand (K(i) = 50 nM) that has a >100-fold selectivity for the hH(4)R over the other histamine receptor subtypes. Moreover, 4-methylhistamine potently activated the hH(4)R (pEC(50) = 7.4 +/- 0.1; alpha = 1), and this response was competitively antagonized by the selective GENE antagonist JNJ 7777120 [CHEMICAL] (pA(2) = 7.8). The identification of 4-methylhistamine as a potent GENE agonist is of major importance for future studies to unravel the physiological roles of the GENE. | INHIBITOR |
| Novel agents that potentially inhibit irinotecan-induced diarrhea. Irinotecan (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Late-onset diarrhea appears to be associated with intestinal exposure to CHEMICAL (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CPT-11, which may bind to GENE and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CPT-11 and CHEMICAL may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of CHEMICAL. Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea. | DIRECT-REGULATOR |
| Novel agents that potentially inhibit irinotecan-induced diarrhea. Irinotecan (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 (CHEMICAL), the major active metabolite of CPT-11, which may bind to GENE and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CPT-11 and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea. | DIRECT-REGULATOR |
| Novel agents that potentially inhibit irinotecan-induced diarrhea. Irinotecan (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CHEMICAL administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CHEMICAL infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CHEMICAL, which may bind to GENE and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CHEMICAL and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CHEMICAL toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea. | DIRECT-REGULATOR |
| Novel agents that potentially inhibit irinotecan-induced diarrhea. Irinotecan (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of GENE activity, which can be eliminated by administration of CHEMICAL. Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CPT-11, which may bind to Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CPT-11 and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea. | INHIBITOR |
| Novel agents that potentially inhibit irinotecan-induced diarrhea. Irinotecan (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CHEMICAL administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CHEMICAL infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CHEMICAL, which may bind to Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CHEMICAL and SN-38 may also stimulate the production of pro-inflammatory GENE and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CHEMICAL toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea. | INDIRECT-UPREGULATOR |
| Novel agents that potentially inhibit irinotecan-induced diarrhea. Irinotecan (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Late-onset diarrhea appears to be associated with intestinal exposure to CHEMICAL (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CPT-11, which may bind to Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CPT-11 and CHEMICAL may also stimulate the production of pro-inflammatory GENE and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of CHEMICAL. Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea. | INDIRECT-UPREGULATOR |
| Novel agents that potentially inhibit irinotecan-induced diarrhea. Irinotecan (CPT-11, CHEMICAL) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting GENE (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CPT-11, which may bind to Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CPT-11 and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea. | INHIBITOR |
| Novel agents that potentially inhibit irinotecan-induced diarrhea. Irinotecan (CPT-11, CHEMICAL) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (GENE). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CPT-11, which may bind to GENE and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CPT-11 and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea. | INHIBITOR |
| Novel agents that potentially inhibit irinotecan-induced diarrhea. Irinotecan (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CHEMICAL administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CHEMICAL infusion and probably due to the inhibition of GENE activity, which can be eliminated by administration of atropine. Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CHEMICAL, which may bind to Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CHEMICAL and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CHEMICAL toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea. | INHIBITOR |
| Novel agents that potentially inhibit irinotecan-induced diarrhea. CHEMICAL (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting GENE (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CPT-11, which may bind to Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CPT-11 and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea. | INHIBITOR |
| Novel agents that potentially inhibit irinotecan-induced diarrhea. CHEMICAL (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (GENE). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CPT-11, which may bind to GENE and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CPT-11 and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea. | INHIBITOR |
| Novel agents that potentially inhibit irinotecan-induced diarrhea. Irinotecan (CHEMICAL, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting GENE (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CHEMICAL administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CHEMICAL infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CHEMICAL, which may bind to Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CHEMICAL and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CHEMICAL toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea. | INHIBITOR |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, CHEMICAL, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to GENE. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between PDXK and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either PDXK or GENE. | NO-RELATIONSHIP |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and CHEMICAL, the two latter derivatives being designed to bind to PDXK but not to GENE. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between PDXK and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either PDXK or GENE. | NO-RELATIONSHIP |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that CHEMICAL also interacts with GENE. To understand this interaction, we determined the crystal structure of GENE in complex with CHEMICAL, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to GENE but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of GENE rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between GENE and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either GENE or CDKs. | DIRECT-REGULATOR |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with GENE. To understand this interaction, we determined the crystal structure of GENE in complex with (R)-roscovitine, CHEMICAL, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to GENE but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of GENE rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between GENE and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either GENE or CDKs. | DIRECT-REGULATOR |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with GENE. To understand this interaction, we determined the crystal structure of GENE in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and CHEMICAL, the two latter derivatives being designed to bind to GENE but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of GENE rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between GENE and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either GENE or CDKs. | DIRECT-REGULATOR |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with GENE. To understand this interaction, we determined the crystal structure of GENE in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to GENE but not to CDKs. Structural analysis revealed that these three CHEMICAL bind similarly in the pyridoxal-binding site of GENE rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between GENE and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either GENE or CDKs. | DIRECT-REGULATOR |
| Crystal structure of CHEMICAL kinase in complex with roscovitine and derivatives. CHEMICAL kinase (PDXK) catalyzes the phosphorylation of CHEMICAL, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of CHEMICAL 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with GENE. To understand this interaction, we determined the crystal structure of GENE in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to GENE but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the CHEMICAL-binding site of GENE rather than in the anticipated ATP-binding site. The CHEMICAL pocket has thus an unexpected ability to accommodate molecules different from and larger than CHEMICAL. This work provides detailed structural information on the interactions between GENE and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either GENE or CDKs. | DIRECT-REGULATOR |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of CHEMICAL and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with GENE. To understand this interaction, we determined the crystal structure of GENE in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to GENE but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of GENE rather than in the anticipated CHEMICAL-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between GENE and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either GENE or CDKs. | DIRECT-REGULATOR |
| Crystal structure of GENE in complex with CHEMICAL and derivatives. GENE (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between PDXK and CHEMICAL and analogs. It could also aid in the design of CHEMICAL derivatives displaying strict selectivity for either PDXK or CDKs. | DIRECT-REGULATOR |
| Crystal structure of pyridoxal kinase in complex with CHEMICAL and derivatives. Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with GENE. To understand this interaction, we determined the crystal structure of GENE in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to GENE but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of GENE rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between GENE and CHEMICAL and analogs. It could also aid in the design of CHEMICAL derivatives displaying strict selectivity for either GENE or CDKs. | DIRECT-REGULATOR |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. GENE (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of CHEMICAL and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between PDXK and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either PDXK or CDKs. | REGULATOR |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. GENE (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and CHEMICAL. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between PDXK and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either PDXK or CDKs. | REGULATOR |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. Pyridoxal kinase (GENE) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and CHEMICAL. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with GENE. To understand this interaction, we determined the crystal structure of GENE in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to GENE but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of GENE rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between GENE and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either GENE or CDKs. | SUBSTRATE |
| Crystal structure of pyridoxal kinase in complex with CHEMICAL and derivatives. Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to GENE. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between PDXK and CHEMICAL and analogs. It could also aid in the design of CHEMICAL derivatives displaying strict selectivity for either PDXK or GENE. | REGULATOR |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. CHEMICAL (CYC202, Seliciclib) is a relatively selective inhibitor of GENE (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between PDXK and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either PDXK or CDKs. | INHIBITOR |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. CHEMICAL (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (GENE), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to GENE. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between PDXK and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either PDXK or GENE. | INHIBITOR |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CHEMICAL, Seliciclib) is a relatively selective inhibitor of GENE (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between PDXK and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either PDXK or CDKs. | INHIBITOR |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CHEMICAL, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (GENE), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to GENE. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between PDXK and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either PDXK or GENE. | INHIBITOR |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, CHEMICAL) is a relatively selective inhibitor of GENE (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between PDXK and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either PDXK or CDKs. | INHIBITOR |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. Pyridoxal kinase (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, CHEMICAL) is a relatively selective inhibitor of cyclin-dependent kinases (GENE), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to GENE. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between PDXK and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either PDXK or GENE. | INHIBITOR |
| Crystal structure of CHEMICAL kinase in complex with roscovitine and derivatives. GENE (PDXK) catalyzes the phosphorylation of CHEMICAL, pyridoxamine, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of CHEMICAL 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The CHEMICAL pocket has thus an unexpected ability to accommodate molecules different from and larger than CHEMICAL. This work provides detailed structural information on the interactions between PDXK and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either PDXK or CDKs. | SUBSTRATE |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. GENE (PDXK) catalyzes the phosphorylation of pyridoxal, CHEMICAL, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between PDXK and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either PDXK or CDKs. | SUBSTRATE |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. Pyridoxal kinase (GENE) catalyzes the phosphorylation of pyridoxal, CHEMICAL, and pyridoxine in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with GENE. To understand this interaction, we determined the crystal structure of GENE in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to GENE but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of GENE rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between GENE and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either GENE or CDKs. | SUBSTRATE |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. GENE (PDXK) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and CHEMICAL in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with PDXK. To understand this interaction, we determined the crystal structure of PDXK in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to PDXK but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of PDXK rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between PDXK and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either PDXK or CDKs. | SUBSTRATE |
| Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. Pyridoxal kinase (GENE) catalyzes the phosphorylation of pyridoxal, pyridoxamine, and CHEMICAL in the presence of ATP and Zn2+. This constitutes an essential step in the synthesis of pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, a cofactor for over 140 enzymes. (R)-Roscovitine (CYC202, Seliciclib) is a relatively selective inhibitor of cyclin-dependent kinases (CDKs), currently evaluated for the treatment of cancers, neurodegenerative disorders, renal diseases, and several viral infections. Affinity chromatography investigations have shown that (R)-roscovitine also interacts with GENE. To understand this interaction, we determined the crystal structure of GENE in complex with (R)-roscovitine, N6-methyl-(R)-roscovitine, and O6-(R)-roscovitine, the two latter derivatives being designed to bind to GENE but not to CDKs. Structural analysis revealed that these three roscovitines bind similarly in the pyridoxal-binding site of GENE rather than in the anticipated ATP-binding site. The pyridoxal pocket has thus an unexpected ability to accommodate molecules different from and larger than pyridoxal. This work provides detailed structural information on the interactions between GENE and roscovitine and analogs. It could also aid in the design of roscovitine derivatives displaying strict selectivity for either GENE or CDKs. | SUBSTRATE |
| GENE secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in GENE secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited by EGFR kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenylate cyclase activator, forskolin. The GENE secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation, but not by ERK inhibitor, CHEMICAL. The inhibition of ERK, moreover, did not cause attenuation in mucin secretion in response to cAMP and forskolin. The findings underline the role of EGFR as a convergence point in GENE secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in EGFR transactivation. | NO-RELATIONSHIP |
| Gastric GENE secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in gastric GENE secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on GENE secretion was inhibited by EGFR kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the GENE secretory responses to beta-adrenergic agonist-generated second messenger, CHEMICAL as well as adenylate cyclase activator, forskolin. The gastric GENE secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in GENE secretion in response to CHEMICAL and forskolin. The findings underline the role of EGFR as a convergence point in gastric GENE secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in EGFR transactivation. | GENE-CHEMICAL |
| Gastric GENE secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in gastric GENE secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on GENE secretion was inhibited by EGFR kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the GENE secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenylate cyclase activator, CHEMICAL. The gastric GENE secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in GENE secretion in response to cAMP and CHEMICAL. The findings underline the role of EGFR as a convergence point in gastric GENE secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in EGFR transactivation. | GENE-CHEMICAL |
| GENE secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in GENE secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, CHEMICAL, on mucin secretion was inhibited by EGFR kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenylate cyclase activator, forskolin. The GENE secretory responses to CHEMICAL, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in mucin secretion in response to cAMP and forskolin. The findings underline the role of EGFR as a convergence point in GENE secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in EGFR transactivation. | GENE-CHEMICAL |
| Gastric mucin secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in gastric mucin secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited by EGFR kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as GENE activator, CHEMICAL. The gastric mucin secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in mucin secretion in response to cAMP and CHEMICAL. The findings underline the role of EGFR as a convergence point in gastric mucin secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in EGFR transactivation. | ACTIVATOR |
| Gastric mucin secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in gastric mucin secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited by GENE kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenylate cyclase activator, forskolin. The gastric mucin secretory responses to isoproterenol, furthermore, were inhibited by CHEMICAL, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent GENE autophosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in mucin secretion in response to cAMP and forskolin. The findings underline the role of GENE as a convergence point in gastric mucin secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in GENE transactivation. | INHIBITOR |
| GENE secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in GENE secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited by EGFR kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenylate cyclase activator, forskolin. The GENE secretory responses to isoproterenol, furthermore, were inhibited by CHEMICAL, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in mucin secretion in response to cAMP and forskolin. The findings underline the role of EGFR as a convergence point in GENE secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in EGFR transactivation. | INHIBITOR |
| Gastric GENE secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in gastric GENE secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on GENE secretion was inhibited by EGFR kinase inhibitor, CHEMICAL, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the GENE secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenylate cyclase activator, forskolin. The gastric GENE secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in GENE secretion in response to cAMP and forskolin. The findings underline the role of EGFR as a convergence point in gastric GENE secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in EGFR transactivation. | INDIRECT-DOWNREGULATOR |
| Gastric GENE secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in gastric GENE secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on GENE secretion was inhibited by EGFR kinase inhibitor, PD153035, as well as CHEMICAL, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the GENE secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenylate cyclase activator, forskolin. The gastric GENE secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in GENE secretion in response to cAMP and forskolin. The findings underline the role of EGFR as a convergence point in gastric GENE secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in EGFR transactivation. | INDIRECT-DOWNREGULATOR |
| Gastric mucin secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor GENE. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in gastric mucin secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited by EGFR kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenylate cyclase activator, forskolin. The gastric mucin secretory responses to isoproterenol, furthermore, were inhibited by CHEMICAL, a selective inhibitor of GENE Src responsible for ligand-independent EGFR autophosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in mucin secretion in response to cAMP and forskolin. The findings underline the role of EGFR as a convergence point in gastric mucin secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in EGFR transactivation. | INHIBITOR |
| Gastric mucin secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in gastric mucin secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited by EGFR kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenylate cyclase activator, forskolin. The gastric mucin secretory responses to isoproterenol, furthermore, were inhibited by CHEMICAL, a selective inhibitor of tyrosine kinase GENE responsible for ligand-independent EGFR autophosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in mucin secretion in response to cAMP and forskolin. The findings underline the role of EGFR as a convergence point in gastric mucin secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for GENE kinase in EGFR transactivation. | INHIBITOR |
| Gastric mucin secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in gastric mucin secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited by EGFR kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenylate cyclase activator, forskolin. The gastric mucin secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation, but not by GENE inhibitor, CHEMICAL. The inhibition of GENE, moreover, did not cause attenuation in mucin secretion in response to cAMP and forskolin. The findings underline the role of EGFR as a convergence point in gastric mucin secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in EGFR transactivation. | INHIBITOR |
| Gastric mucin secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in gastric mucin secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited by EGFR kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the mucin secretory responses to beta-adrenergic agonist-generated second messenger, CHEMICAL as well as adenylate cyclase activator, forskolin. The gastric mucin secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation, but not by GENE inhibitor, PD98059. The inhibition of GENE, moreover, did not cause attenuation in mucin secretion in response to CHEMICAL and forskolin. The findings underline the role of EGFR as a convergence point in gastric mucin secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in EGFR transactivation. | NO-RELATIONSHIP |
| Gastric mucin secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in gastric mucin secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited by EGFR kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenylate cyclase activator, CHEMICAL. The gastric mucin secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation, but not by GENE inhibitor, PD98059. The inhibition of GENE, moreover, did not cause attenuation in mucin secretion in response to cAMP and CHEMICAL. The findings underline the role of EGFR as a convergence point in gastric mucin secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in EGFR transactivation. | NO-RELATIONSHIP |
| Gastric mucin secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in gastric mucin secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited by GENE kinase inhibitor, CHEMICAL, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenylate cyclase activator, forskolin. The gastric mucin secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent GENE autophosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in mucin secretion in response to cAMP and forskolin. The findings underline the role of GENE as a convergence point in gastric mucin secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in GENE transactivation. | INHIBITOR |
| Gastric mucin secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine GENE. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in gastric mucin secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited by EGFR GENE inhibitor, CHEMICAL, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenylate cyclase activator, forskolin. The gastric mucin secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine GENE Src responsible for ligand-independent EGFR autophosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in mucin secretion in response to cAMP and forskolin. The findings underline the role of EGFR as a convergence point in gastric mucin secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src GENE in EGFR transactivation. | INHIBITOR |
| Gastric mucin secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in gastric mucin secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited by EGFR kinase inhibitor, PD153035, as well as CHEMICAL, a specific inhibitor of GENE. Both inhibitors, moreover, blunted the mucin secretory responses to beta-adrenergic agonist-generated second messenger, cAMP as well as adenylate cyclase activator, forskolin. The gastric mucin secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in mucin secretion in response to cAMP and forskolin. The findings underline the role of EGFR as a convergence point in gastric mucin secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in EGFR transactivation. | INHIBITOR |
| Gastric mucin secretion in response to beta-adrenergic G protein-coupled receptor activation is mediated by SRC kinase-dependent epidermal growth factor receptor transactivation. In many systems, the integration of converging regulatory signals that relay on G protein-coupled receptor (GPCR) activation into functional cellular pathways requires the involvement of receptor tyrosine kinase. In this report, we provide evidence that activation of GPCR by beta-adrenergic agonist leading to stimulation in gastric mucin secretion requires epidermal growth factor receptor (EGFR) participation. Using [(3)H]glucosamine-labeled gastric mucosal cells, we show that stimulatory effect of beta-adrenergic agonist, isoproterenol, on mucin secretion was inhibited by EGFR kinase inhibitor, PD153035, as well as wortmannin, a specific inhibitor of PI3K. Both inhibitors, moreover, blunted the mucin secretory responses to beta-adrenergic agonist-generated second messenger, CHEMICAL as well as GENE activator, forskolin. The gastric mucin secretory responses to isoproterenol, furthermore, were inhibited by PP2, a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR autophosphorylation, but not by ERK inhibitor, PD98059. The inhibition of ERK, moreover, did not cause attenuation in mucin secretion in response to CHEMICAL and forskolin. The findings underline the role of EGFR as a convergence point in gastric mucin secretion triggered by beta-adrenergic GPCR activation, and demonstrate the requirement for Src kinase in EGFR transactivation. | ACTIVATOR |
| Losartan: a selective angiotensin II type 1 (AT1) receptor antagonist for the treatment of heart failure. CHEMICAL (COZAAR) is the prototype of a new class of potent and selective angiotensin II (AII) type 1 (AT(1)) receptor antagonists with the largest published preclinical and clinical data base. Since all of the AII antagonists are selective for the GENE, these drugs should exhibit similar cardiovascular effects. However, since the pharmacokinetic/pharmacodynamic profiles of these agents and their degree of affinity for the GENE differ, it is likely that differences in clinical profiles between these drugs exist and will require investigation. CHEMICAL (parent compound), has moderate affinity for the GENE (competitive inhibition). CHEMICAL is well-absorbed orally as an active drug and is rapidly converted via oxidation in the human liver to a more potent metabolite (designated E3174) with an affinity 20- to 30-times greater for the GENE (non-competitive inhibition). E3174 has a half-life of 6 - 9 h; elimination is via renal and hepatic routes. Antihypertensive and, in heart failure patients, haemodynamic activity is observed over a 24 h period with once daily dosing. Over 6 million patients have been treated for hypertension with continued excellent tolerability. Clinical experience in heart failure is growing, and recent data suggest an improved survival with losartan versus captopril, a drug from the angiotensin-converting-enzyme inhibitor class with proven benefit in this population. The current comprehensive losartan clinical end-point programme (4 large scale morbidity/mortality trials) should provide evidence regarding the efficacy of direct blockade of the GENE with losartan compared to standard therapy: 1) The CHEMICAL Heart Failure Survival Study - ELITE II, 2) The CHEMICAL Post-Myocardial Infarction Survival Study - OPTIMAAL, 3) The CHEMICAL Hypertension Survival Study - LIFE and 4) The CHEMICAL Renal Protection Study - RENAAL. | DIRECT-REGULATOR |
| Losartan: a selective angiotensin II type 1 (AT1) receptor antagonist for the treatment of heart failure. CHEMICAL (COZAAR) is the prototype of a new class of potent and selective angiotensin II (AII) type 1 (AT(1)) receptor antagonists with the largest published preclinical and clinical data base. Since all of the AII antagonists are selective for the AT(1) receptor, these drugs should exhibit similar cardiovascular effects. However, since the pharmacokinetic/pharmacodynamic profiles of these agents and their degree of affinity for the AT(1) receptor differ, it is likely that differences in clinical profiles between these drugs exist and will require investigation. CHEMICAL (parent compound), has moderate affinity for the AT(1) receptor (competitive inhibition). CHEMICAL is well-absorbed orally as an active drug and is rapidly converted via oxidation in the human liver to a more potent metabolite (designated E3174) with an affinity 20- to 30-times greater for the AT(1) receptor (non-competitive inhibition). E3174 has a half-life of 6 - 9 h; elimination is via renal and hepatic routes. Antihypertensive and, in heart failure patients, haemodynamic activity is observed over a 24 h period with once daily dosing. Over 6 million patients have been treated for hypertension with continued excellent tolerability. Clinical experience in heart failure is growing, and recent data suggest an improved survival with CHEMICAL versus captopril, a drug from the GENE inhibitor class with proven benefit in this population. The current comprehensive CHEMICAL clinical end-point programme (4 large scale morbidity/mortality trials) should provide evidence regarding the efficacy of direct blockade of the AT(1) receptor with CHEMICAL compared to standard therapy: 1) The CHEMICAL Heart Failure Survival Study - ELITE II, 2) The CHEMICAL Post-Myocardial Infarction Survival Study - OPTIMAAL, 3) The CHEMICAL Hypertension Survival Study - LIFE and 4) The CHEMICAL Renal Protection Study - RENAAL. | INHIBITOR |
| Losartan: a selective angiotensin II type 1 (AT1) receptor antagonist for the treatment of heart failure. Losartan (COZAAR) is the prototype of a new class of potent and selective angiotensin II (AII) type 1 (AT(1)) receptor antagonists with the largest published preclinical and clinical data base. Since all of the AII antagonists are selective for the AT(1) receptor, these drugs should exhibit similar cardiovascular effects. However, since the pharmacokinetic/pharmacodynamic profiles of these agents and their degree of affinity for the AT(1) receptor differ, it is likely that differences in clinical profiles between these drugs exist and will require investigation. Losartan (parent compound), has moderate affinity for the AT(1) receptor (competitive inhibition). Losartan is well-absorbed orally as an active drug and is rapidly converted via oxidation in the human liver to a more potent metabolite (designated E3174) with an affinity 20- to 30-times greater for the AT(1) receptor (non-competitive inhibition). E3174 has a half-life of 6 - 9 h; elimination is via renal and hepatic routes. Antihypertensive and, in heart failure patients, haemodynamic activity is observed over a 24 h period with once daily dosing. Over 6 million patients have been treated for hypertension with continued excellent tolerability. Clinical experience in heart failure is growing, and recent data suggest an improved survival with losartan versus CHEMICAL, a drug from the GENE inhibitor class with proven benefit in this population. The current comprehensive losartan clinical end-point programme (4 large scale morbidity/mortality trials) should provide evidence regarding the efficacy of direct blockade of the AT(1) receptor with losartan compared to standard therapy: 1) The Losartan Heart Failure Survival Study - ELITE II, 2) The Losartan Post-Myocardial Infarction Survival Study - OPTIMAAL, 3) The Losartan Hypertension Survival Study - LIFE and 4) The Losartan Renal Protection Study - RENAAL. | INHIBITOR |
| CHEMICAL: a selective GENE antagonist for the treatment of heart failure. CHEMICAL (COZAAR) is the prototype of a new class of potent and selective angiotensin II (AII) type 1 (AT(1)) receptor antagonists with the largest published preclinical and clinical data base. Since all of the AII antagonists are selective for the AT(1) receptor, these drugs should exhibit similar cardiovascular effects. However, since the pharmacokinetic/pharmacodynamic profiles of these agents and their degree of affinity for the AT(1) receptor differ, it is likely that differences in clinical profiles between these drugs exist and will require investigation. CHEMICAL (parent compound), has moderate affinity for the AT(1) receptor (competitive inhibition). CHEMICAL is well-absorbed orally as an active drug and is rapidly converted via oxidation in the human liver to a more potent metabolite (designated E3174) with an affinity 20- to 30-times greater for the AT(1) receptor (non-competitive inhibition). E3174 has a half-life of 6 - 9 h; elimination is via renal and hepatic routes. Antihypertensive and, in heart failure patients, haemodynamic activity is observed over a 24 h period with once daily dosing. Over 6 million patients have been treated for hypertension with continued excellent tolerability. Clinical experience in heart failure is growing, and recent data suggest an improved survival with losartan versus captopril, a drug from the angiotensin-converting-enzyme inhibitor class with proven benefit in this population. The current comprehensive losartan clinical end-point programme (4 large scale morbidity/mortality trials) should provide evidence regarding the efficacy of direct blockade of the AT(1) receptor with losartan compared to standard therapy: 1) The CHEMICAL Heart Failure Survival Study - ELITE II, 2) The CHEMICAL Post-Myocardial Infarction Survival Study - OPTIMAAL, 3) The CHEMICAL Hypertension Survival Study - LIFE and 4) The CHEMICAL Renal Protection Study - RENAAL. | INHIBITOR |
| Losartan: a selective angiotensin II type 1 (AT1) receptor antagonist for the treatment of heart failure. CHEMICAL (COZAAR) is the prototype of a new class of potent and selective GENE antagonists with the largest published preclinical and clinical data base. Since all of the AII antagonists are selective for the AT(1) receptor, these drugs should exhibit similar cardiovascular effects. However, since the pharmacokinetic/pharmacodynamic profiles of these agents and their degree of affinity for the AT(1) receptor differ, it is likely that differences in clinical profiles between these drugs exist and will require investigation. CHEMICAL (parent compound), has moderate affinity for the AT(1) receptor (competitive inhibition). CHEMICAL is well-absorbed orally as an active drug and is rapidly converted via oxidation in the human liver to a more potent metabolite (designated E3174) with an affinity 20- to 30-times greater for the AT(1) receptor (non-competitive inhibition). E3174 has a half-life of 6 - 9 h; elimination is via renal and hepatic routes. Antihypertensive and, in heart failure patients, haemodynamic activity is observed over a 24 h period with once daily dosing. Over 6 million patients have been treated for hypertension with continued excellent tolerability. Clinical experience in heart failure is growing, and recent data suggest an improved survival with losartan versus captopril, a drug from the angiotensin-converting-enzyme inhibitor class with proven benefit in this population. The current comprehensive losartan clinical end-point programme (4 large scale morbidity/mortality trials) should provide evidence regarding the efficacy of direct blockade of the AT(1) receptor with losartan compared to standard therapy: 1) The CHEMICAL Heart Failure Survival Study - ELITE II, 2) The CHEMICAL Post-Myocardial Infarction Survival Study - OPTIMAAL, 3) The CHEMICAL Hypertension Survival Study - LIFE and 4) The CHEMICAL Renal Protection Study - RENAAL. | INHIBITOR |
| Losartan: a selective angiotensin II type 1 (AT1) receptor antagonist for the treatment of heart failure. Losartan (CHEMICAL) is the prototype of a new class of potent and selective GENE antagonists with the largest published preclinical and clinical data base. Since all of the AII antagonists are selective for the AT(1) receptor, these drugs should exhibit similar cardiovascular effects. However, since the pharmacokinetic/pharmacodynamic profiles of these agents and their degree of affinity for the AT(1) receptor differ, it is likely that differences in clinical profiles between these drugs exist and will require investigation. Losartan (parent compound), has moderate affinity for the AT(1) receptor (competitive inhibition). Losartan is well-absorbed orally as an active drug and is rapidly converted via oxidation in the human liver to a more potent metabolite (designated E3174) with an affinity 20- to 30-times greater for the AT(1) receptor (non-competitive inhibition). E3174 has a half-life of 6 - 9 h; elimination is via renal and hepatic routes. Antihypertensive and, in heart failure patients, haemodynamic activity is observed over a 24 h period with once daily dosing. Over 6 million patients have been treated for hypertension with continued excellent tolerability. Clinical experience in heart failure is growing, and recent data suggest an improved survival with losartan versus captopril, a drug from the angiotensin-converting-enzyme inhibitor class with proven benefit in this population. The current comprehensive losartan clinical end-point programme (4 large scale morbidity/mortality trials) should provide evidence regarding the efficacy of direct blockade of the AT(1) receptor with losartan compared to standard therapy: 1) The Losartan Heart Failure Survival Study - ELITE II, 2) The Losartan Post-Myocardial Infarction Survival Study - OPTIMAAL, 3) The Losartan Hypertension Survival Study - LIFE and 4) The Losartan Renal Protection Study - RENAAL. | INHIBITOR |
| Effect of CHEMICAL on tumor necrosis factor production in endotoxic shock. Tumor necrosis factor (TNF) is a macrophage-derived mediator responsible for many of the pathophysiologic manifestations of endotoxic shock. We now demonstrate that CHEMICAL, a noncatechol inotrope, strongly inhibits lipopolysaccharide (LPS)-induced GENE production at concentrations readily achieved in vivo. This inhibition is apparent in murine macrophages, in macrophage cell lines, in vivo, and in cell lines containing a reporter gene construct that substitutes the chloramphenicol acetyl transferase (CAT) coding sequence for the GENE coding sequence and introns. Inhibition by CHEMICAL (like inhibition by pentoxifylline) is manifested at the level of mRNA accumulation, in contrast to inhibition caused by dexamethasone. Combined application of dexamethasone and CHEMICAL caused additive inhibition of GENE biosynthesis in vitro. Furthermore, treatment of mice with CHEMICAL immediately prior to endotoxin challenge led to significantly improved survival. These findings suggest that CHEMICAL possesses antiinflammatory as well as inotropic properties that may make it an appropriate agent for use in septic shock or other serious bacterial infections. Abrupt removal of CHEMICAL or pentoxifylline from the culture medium prior to LPS stimulation, however, caused significantly augmented GENE production. Therefore, CHEMICAL and other phosphodiesterase inhibitors may also enhance sensitivity to LPS during a period of time following discontinuation of therapy. | INDIRECT-UPREGULATOR |
| Effect of amrinone on tumor necrosis factor production in endotoxic shock. Tumor necrosis factor (TNF) is a macrophage-derived mediator responsible for many of the pathophysiologic manifestations of endotoxic shock. We now demonstrate that amrinone, a noncatechol inotrope, strongly inhibits lipopolysaccharide (LPS)-induced GENE production at concentrations readily achieved in vivo. This inhibition is apparent in murine macrophages, in macrophage cell lines, in vivo, and in cell lines containing a reporter gene construct that substitutes the chloramphenicol acetyl transferase (CAT) coding sequence for the GENE coding sequence and introns. Inhibition by amrinone (like inhibition by pentoxifylline) is manifested at the level of mRNA accumulation, in contrast to inhibition caused by dexamethasone. Combined application of dexamethasone and amrinone caused additive inhibition of GENE biosynthesis in vitro. Furthermore, treatment of mice with amrinone immediately prior to endotoxin challenge led to significantly improved survival. These findings suggest that amrinone possesses antiinflammatory as well as inotropic properties that may make it an appropriate agent for use in septic shock or other serious bacterial infections. Abrupt removal of amrinone or CHEMICAL from the culture medium prior to LPS stimulation, however, caused significantly augmented GENE production. Therefore, amrinone and other phosphodiesterase inhibitors may also enhance sensitivity to LPS during a period of time following discontinuation of therapy. | INDIRECT-UPREGULATOR |
| Effect of amrinone on tumor necrosis factor production in endotoxic shock. Tumor necrosis factor (TNF) is a macrophage-derived mediator responsible for many of the pathophysiologic manifestations of endotoxic shock. We now demonstrate that amrinone, a noncatechol inotrope, strongly inhibits lipopolysaccharide (LPS)-induced GENE production at concentrations readily achieved in vivo. This inhibition is apparent in murine macrophages, in macrophage cell lines, in vivo, and in cell lines containing a reporter gene construct that substitutes the chloramphenicol acetyl transferase (CAT) coding sequence for the GENE coding sequence and introns. Inhibition by amrinone (like inhibition by pentoxifylline) is manifested at the level of mRNA accumulation, in contrast to inhibition caused by CHEMICAL. Combined application of CHEMICAL and amrinone caused additive inhibition of GENE biosynthesis in vitro. Furthermore, treatment of mice with amrinone immediately prior to endotoxin challenge led to significantly improved survival. These findings suggest that amrinone possesses antiinflammatory as well as inotropic properties that may make it an appropriate agent for use in septic shock or other serious bacterial infections. Abrupt removal of amrinone or pentoxifylline from the culture medium prior to LPS stimulation, however, caused significantly augmented GENE production. Therefore, amrinone and other phosphodiesterase inhibitors may also enhance sensitivity to LPS during a period of time following discontinuation of therapy. | INDIRECT-DOWNREGULATOR |
| Age-dependent changes of pyridoxal phosphate synthesizing enzymes immunoreactivities and activities in the gerbil hippocampal CA1 region. In the present study, age-related changes of pyridoxal 5'-phosphate (PLP) synthesizing enzymes, pyridoxal kinase (PLK) and pyridoxine 5'-phosphate oxidase (PNPO), their protein contents and activities were examined in the gerbil hippocampus proper. Significant age-dependent changes in GENE and PNPO immunoreactivities were found in the CA1 region, but not in the CA2/3 region. In the postnatal month 1 (PM 1) group, GENE and PNPO immunoreactivities were detected mainly in the stratum pyramidale of the CA1 region. GENE and PNPO immunoreactivities and their protein contents were highest in the PM 6 group, showing that many CA1 pyramidal cells had strong GENE and PNPO immunoreactivities. Thereafter, GENE and PNPO immunoreactivities started to decrease and were very low at PM 24. Alterations in the change patterns in protein contents and total activities of GENE and PNPO corresponded to the immunohistochemical data, but their specific activities were not altered in any experimental group. Based on double immunofluorescence study, GENE and PNPO immunoreactive cells in the strata oriens and radiatum were identified as GABAergic cells. Therefore, decreases of GENE and PNPO in the hippocampal CA1 region of aged brains may be involved in aging processes related with CHEMICAL (GABA) function. | REGULATOR |
| Age-dependent changes of pyridoxal phosphate synthesizing enzymes immunoreactivities and activities in the gerbil hippocampal CA1 region. In the present study, age-related changes of pyridoxal 5'-phosphate (PLP) synthesizing enzymes, pyridoxal kinase (PLK) and pyridoxine 5'-phosphate oxidase (PNPO), their protein contents and activities were examined in the gerbil hippocampus proper. Significant age-dependent changes in PLK and GENE immunoreactivities were found in the CA1 region, but not in the CA2/3 region. In the postnatal month 1 (PM 1) group, PLK and GENE immunoreactivities were detected mainly in the stratum pyramidale of the CA1 region. PLK and GENE immunoreactivities and their protein contents were highest in the PM 6 group, showing that many CA1 pyramidal cells had strong PLK and GENE immunoreactivities. Thereafter, PLK and GENE immunoreactivities started to decrease and were very low at PM 24. Alterations in the change patterns in protein contents and total activities of PLK and GENE corresponded to the immunohistochemical data, but their specific activities were not altered in any experimental group. Based on double immunofluorescence study, PLK and GENE immunoreactive cells in the strata oriens and radiatum were identified as GABAergic cells. Therefore, decreases of PLK and GENE in the hippocampal CA1 region of aged brains may be involved in aging processes related with CHEMICAL (GABA) function. | REGULATOR |
| Age-dependent changes of pyridoxal phosphate synthesizing enzymes immunoreactivities and activities in the gerbil hippocampal CA1 region. In the present study, age-related changes of pyridoxal 5'-phosphate (PLP) synthesizing enzymes, pyridoxal kinase (PLK) and pyridoxine 5'-phosphate oxidase (PNPO), their protein contents and activities were examined in the gerbil hippocampus proper. Significant age-dependent changes in GENE and PNPO immunoreactivities were found in the CA1 region, but not in the CA2/3 region. In the postnatal month 1 (PM 1) group, GENE and PNPO immunoreactivities were detected mainly in the stratum pyramidale of the CA1 region. GENE and PNPO immunoreactivities and their protein contents were highest in the PM 6 group, showing that many CA1 pyramidal cells had strong GENE and PNPO immunoreactivities. Thereafter, GENE and PNPO immunoreactivities started to decrease and were very low at PM 24. Alterations in the change patterns in protein contents and total activities of GENE and PNPO corresponded to the immunohistochemical data, but their specific activities were not altered in any experimental group. Based on double immunofluorescence study, GENE and PNPO immunoreactive cells in the strata oriens and radiatum were identified as GABAergic cells. Therefore, decreases of GENE and PNPO in the hippocampal CA1 region of aged brains may be involved in aging processes related with gamma-aminobutyric acid (CHEMICAL) function. | REGULATOR |
| Age-dependent changes of pyridoxal phosphate synthesizing enzymes immunoreactivities and activities in the gerbil hippocampal CA1 region. In the present study, age-related changes of pyridoxal 5'-phosphate (PLP) synthesizing enzymes, pyridoxal kinase (PLK) and pyridoxine 5'-phosphate oxidase (PNPO), their protein contents and activities were examined in the gerbil hippocampus proper. Significant age-dependent changes in PLK and GENE immunoreactivities were found in the CA1 region, but not in the CA2/3 region. In the postnatal month 1 (PM 1) group, PLK and GENE immunoreactivities were detected mainly in the stratum pyramidale of the CA1 region. PLK and GENE immunoreactivities and their protein contents were highest in the PM 6 group, showing that many CA1 pyramidal cells had strong PLK and GENE immunoreactivities. Thereafter, PLK and GENE immunoreactivities started to decrease and were very low at PM 24. Alterations in the change patterns in protein contents and total activities of PLK and GENE corresponded to the immunohistochemical data, but their specific activities were not altered in any experimental group. Based on double immunofluorescence study, PLK and GENE immunoreactive cells in the strata oriens and radiatum were identified as GABAergic cells. Therefore, decreases of PLK and GENE in the hippocampal CA1 region of aged brains may be involved in aging processes related with gamma-aminobutyric acid (CHEMICAL) function. | REGULATOR |
| Age-dependent changes of pyridoxal phosphate synthesizing enzymes immunoreactivities and activities in the gerbil hippocampal CA1 region. In the present study, age-related changes of CHEMICAL (PLP) synthesizing enzymes, pyridoxal kinase (GENE) and pyridoxine 5'-phosphate oxidase (PNPO), their protein contents and activities were examined in the gerbil hippocampus proper. Significant age-dependent changes in GENE and PNPO immunoreactivities were found in the CA1 region, but not in the CA2/3 region. In the postnatal month 1 (PM 1) group, GENE and PNPO immunoreactivities were detected mainly in the stratum pyramidale of the CA1 region. GENE and PNPO immunoreactivities and their protein contents were highest in the PM 6 group, showing that many CA1 pyramidal cells had strong GENE and PNPO immunoreactivities. Thereafter, GENE and PNPO immunoreactivities started to decrease and were very low at PM 24. Alterations in the change patterns in protein contents and total activities of GENE and PNPO corresponded to the immunohistochemical data, but their specific activities were not altered in any experimental group. Based on double immunofluorescence study, GENE and PNPO immunoreactive cells in the strata oriens and radiatum were identified as GABAergic cells. Therefore, decreases of GENE and PNPO in the hippocampal CA1 region of aged brains may be involved in aging processes related with gamma-aminobutyric acid (GABA) function. | PRODUCT-OF |
| Age-dependent changes of pyridoxal phosphate synthesizing enzymes immunoreactivities and activities in the gerbil hippocampal CA1 region. In the present study, age-related changes of CHEMICAL (PLP) synthesizing enzymes, pyridoxal kinase (PLK) and GENE (PNPO), their protein contents and activities were examined in the gerbil hippocampus proper. Significant age-dependent changes in PLK and PNPO immunoreactivities were found in the CA1 region, but not in the CA2/3 region. In the postnatal month 1 (PM 1) group, PLK and PNPO immunoreactivities were detected mainly in the stratum pyramidale of the CA1 region. PLK and PNPO immunoreactivities and their protein contents were highest in the PM 6 group, showing that many CA1 pyramidal cells had strong PLK and PNPO immunoreactivities. Thereafter, PLK and PNPO immunoreactivities started to decrease and were very low at PM 24. Alterations in the change patterns in protein contents and total activities of PLK and PNPO corresponded to the immunohistochemical data, but their specific activities were not altered in any experimental group. Based on double immunofluorescence study, PLK and PNPO immunoreactive cells in the strata oriens and radiatum were identified as GABAergic cells. Therefore, decreases of PLK and PNPO in the hippocampal CA1 region of aged brains may be involved in aging processes related with gamma-aminobutyric acid (GABA) function. | PRODUCT-OF |
| Age-dependent changes of pyridoxal phosphate synthesizing enzymes immunoreactivities and activities in the gerbil hippocampal CA1 region. In the present study, age-related changes of CHEMICAL (PLP) synthesizing enzymes, pyridoxal kinase (PLK) and pyridoxine 5'-phosphate oxidase (GENE), their protein contents and activities were examined in the gerbil hippocampus proper. Significant age-dependent changes in PLK and GENE immunoreactivities were found in the CA1 region, but not in the CA2/3 region. In the postnatal month 1 (PM 1) group, PLK and GENE immunoreactivities were detected mainly in the stratum pyramidale of the CA1 region. PLK and GENE immunoreactivities and their protein contents were highest in the PM 6 group, showing that many CA1 pyramidal cells had strong PLK and GENE immunoreactivities. Thereafter, PLK and GENE immunoreactivities started to decrease and were very low at PM 24. Alterations in the change patterns in protein contents and total activities of PLK and GENE corresponded to the immunohistochemical data, but their specific activities were not altered in any experimental group. Based on double immunofluorescence study, PLK and GENE immunoreactive cells in the strata oriens and radiatum were identified as GABAergic cells. Therefore, decreases of PLK and GENE in the hippocampal CA1 region of aged brains may be involved in aging processes related with gamma-aminobutyric acid (GABA) function. | PRODUCT-OF |
| Age-dependent changes of pyridoxal phosphate synthesizing enzymes immunoreactivities and activities in the gerbil hippocampal CA1 region. In the present study, age-related changes of CHEMICAL (PLP) synthesizing enzymes, GENE (PLK) and pyridoxine 5'-phosphate oxidase (PNPO), their protein contents and activities were examined in the gerbil hippocampus proper. Significant age-dependent changes in PLK and PNPO immunoreactivities were found in the CA1 region, but not in the CA2/3 region. In the postnatal month 1 (PM 1) group, PLK and PNPO immunoreactivities were detected mainly in the stratum pyramidale of the CA1 region. PLK and PNPO immunoreactivities and their protein contents were highest in the PM 6 group, showing that many CA1 pyramidal cells had strong PLK and PNPO immunoreactivities. Thereafter, PLK and PNPO immunoreactivities started to decrease and were very low at PM 24. Alterations in the change patterns in protein contents and total activities of PLK and PNPO corresponded to the immunohistochemical data, but their specific activities were not altered in any experimental group. Based on double immunofluorescence study, PLK and PNPO immunoreactive cells in the strata oriens and radiatum were identified as GABAergic cells. Therefore, decreases of PLK and PNPO in the hippocampal CA1 region of aged brains may be involved in aging processes related with gamma-aminobutyric acid (GABA) function. | PRODUCT-OF |
| Age-dependent changes of pyridoxal phosphate synthesizing enzymes immunoreactivities and activities in the gerbil hippocampal CA1 region. In the present study, age-related changes of pyridoxal 5'-phosphate (CHEMICAL) synthesizing enzymes, pyridoxal kinase (GENE) and pyridoxine 5'-phosphate oxidase (PNPO), their protein contents and activities were examined in the gerbil hippocampus proper. Significant age-dependent changes in GENE and PNPO immunoreactivities were found in the CA1 region, but not in the CA2/3 region. In the postnatal month 1 (PM 1) group, GENE and PNPO immunoreactivities were detected mainly in the stratum pyramidale of the CA1 region. GENE and PNPO immunoreactivities and their protein contents were highest in the PM 6 group, showing that many CA1 pyramidal cells had strong GENE and PNPO immunoreactivities. Thereafter, GENE and PNPO immunoreactivities started to decrease and were very low at PM 24. Alterations in the change patterns in protein contents and total activities of GENE and PNPO corresponded to the immunohistochemical data, but their specific activities were not altered in any experimental group. Based on double immunofluorescence study, GENE and PNPO immunoreactive cells in the strata oriens and radiatum were identified as GABAergic cells. Therefore, decreases of GENE and PNPO in the hippocampal CA1 region of aged brains may be involved in aging processes related with gamma-aminobutyric acid (GABA) function. | PRODUCT-OF |
| Age-dependent changes of pyridoxal phosphate synthesizing enzymes immunoreactivities and activities in the gerbil hippocampal CA1 region. In the present study, age-related changes of pyridoxal 5'-phosphate (CHEMICAL) synthesizing enzymes, pyridoxal kinase (PLK) and GENE (PNPO), their protein contents and activities were examined in the gerbil hippocampus proper. Significant age-dependent changes in PLK and PNPO immunoreactivities were found in the CA1 region, but not in the CA2/3 region. In the postnatal month 1 (PM 1) group, PLK and PNPO immunoreactivities were detected mainly in the stratum pyramidale of the CA1 region. PLK and PNPO immunoreactivities and their protein contents were highest in the PM 6 group, showing that many CA1 pyramidal cells had strong PLK and PNPO immunoreactivities. Thereafter, PLK and PNPO immunoreactivities started to decrease and were very low at PM 24. Alterations in the change patterns in protein contents and total activities of PLK and PNPO corresponded to the immunohistochemical data, but their specific activities were not altered in any experimental group. Based on double immunofluorescence study, PLK and PNPO immunoreactive cells in the strata oriens and radiatum were identified as GABAergic cells. Therefore, decreases of PLK and PNPO in the hippocampal CA1 region of aged brains may be involved in aging processes related with gamma-aminobutyric acid (GABA) function. | PRODUCT-OF |
| Age-dependent changes of pyridoxal phosphate synthesizing enzymes immunoreactivities and activities in the gerbil hippocampal CA1 region. In the present study, age-related changes of pyridoxal 5'-phosphate (CHEMICAL) synthesizing enzymes, pyridoxal kinase (PLK) and pyridoxine 5'-phosphate oxidase (GENE), their protein contents and activities were examined in the gerbil hippocampus proper. Significant age-dependent changes in PLK and GENE immunoreactivities were found in the CA1 region, but not in the CA2/3 region. In the postnatal month 1 (PM 1) group, PLK and GENE immunoreactivities were detected mainly in the stratum pyramidale of the CA1 region. PLK and GENE immunoreactivities and their protein contents were highest in the PM 6 group, showing that many CA1 pyramidal cells had strong PLK and GENE immunoreactivities. Thereafter, PLK and GENE immunoreactivities started to decrease and were very low at PM 24. Alterations in the change patterns in protein contents and total activities of PLK and GENE corresponded to the immunohistochemical data, but their specific activities were not altered in any experimental group. Based on double immunofluorescence study, PLK and GENE immunoreactive cells in the strata oriens and radiatum were identified as GABAergic cells. Therefore, decreases of PLK and GENE in the hippocampal CA1 region of aged brains may be involved in aging processes related with gamma-aminobutyric acid (GABA) function. | PRODUCT-OF |
| Age-dependent changes of pyridoxal phosphate synthesizing enzymes immunoreactivities and activities in the gerbil hippocampal CA1 region. In the present study, age-related changes of pyridoxal 5'-phosphate (CHEMICAL) synthesizing enzymes, GENE (PLK) and pyridoxine 5'-phosphate oxidase (PNPO), their protein contents and activities were examined in the gerbil hippocampus proper. Significant age-dependent changes in PLK and PNPO immunoreactivities were found in the CA1 region, but not in the CA2/3 region. In the postnatal month 1 (PM 1) group, PLK and PNPO immunoreactivities were detected mainly in the stratum pyramidale of the CA1 region. PLK and PNPO immunoreactivities and their protein contents were highest in the PM 6 group, showing that many CA1 pyramidal cells had strong PLK and PNPO immunoreactivities. Thereafter, PLK and PNPO immunoreactivities started to decrease and were very low at PM 24. Alterations in the change patterns in protein contents and total activities of PLK and PNPO corresponded to the immunohistochemical data, but their specific activities were not altered in any experimental group. Based on double immunofluorescence study, PLK and PNPO immunoreactive cells in the strata oriens and radiatum were identified as GABAergic cells. Therefore, decreases of PLK and PNPO in the hippocampal CA1 region of aged brains may be involved in aging processes related with gamma-aminobutyric acid (GABA) function. | PRODUCT-OF |
| Functional characteristics of H+ -dependent nicotinate transport in primary cultures of astrocytes from rat cerebral cortex. In the present study, we report the characteristics of H(+)-coupled nicotinate transport in primary cultures of astrocytes from rat cerebral cortex. The [(3)H]nicotinate transport in rat astrocytes increased up to a pH 5.5. The nicotinic acid uptake at pH 6.0 was both energy-dependent and saturable with a Michaelis constant (K(t)) of 2.8+/-0.4 mM and the maximal uptake rate (V(max)) of 31+/-3.2 nmol/mg protein/10 min. This process was reduced by a protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone, and a typical monocarboxylate transporter (MCT) inhibitor, alpha-cyano-4-hydroxycinnamic acid, suggesting that nicotinate uptake by rat astrocytes is mediated by CHEMICAL-coupled GENE. [(3)H]Nicotinate transport in rat astrocytes was significantly inhibited by various monocarboxylic acids such as l-lactic acid and pyruvic acid with a relatively low affinity (K(i)>10 mM). On the other hand, the uptake process of l-lactic acid was also saturable with a high-affinity component (K(t)=0.27 mM) and a low-affinity component (K(t)=35.9 mM). Reverse transcription-PCR and Western blot analyses revealed that three MCT subtypes, MCT1/Slc16a1, MCT2/Slc16a7, and MCT4/Slc16a3, were expressed in these cells. Because l-lactate reduced to 67% of the nicotinate uptake even at 10mM, it is unlikely that nicotinate uptake in rat astrocytes is mediated by MCT1 and/or MCT2. These results provide biochemical evidence of a H(+)-coupled and saturable transport system, presumed to be a low-affinity monocarboxylate transporter MCT4 or other unknown H(+)-coupled GENE, for nicotinate in rat cerebrocortical astrocytes. | REGULATOR |
| Functional characteristics of H+ -dependent nicotinate transport in primary cultures of astrocytes from rat cerebral cortex. In the present study, we report the characteristics of H(+)-coupled nicotinate transport in primary cultures of astrocytes from rat cerebral cortex. The [(3)H]nicotinate transport in rat astrocytes increased up to a pH 5.5. The nicotinic acid uptake at pH 6.0 was both energy-dependent and saturable with a Michaelis constant (K(t)) of 2.8+/-0.4 mM and the maximal uptake rate (V(max)) of 31+/-3.2 nmol/mg protein/10 min. This process was reduced by a protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone, and a typical monocarboxylate transporter (MCT) inhibitor, alpha-cyano-4-hydroxycinnamic acid, suggesting that nicotinate uptake by rat astrocytes is mediated by H(+)-coupled monocarboxylate transport system. [(3)H]Nicotinate transport in rat astrocytes was significantly inhibited by various monocarboxylic acids such as l-lactic acid and pyruvic acid with a relatively low affinity (K(i)>10 mM). On the other hand, the uptake process of l-lactic acid was also saturable with a high-affinity component (K(t)=0.27 mM) and a low-affinity component (K(t)=35.9 mM). Reverse transcription-PCR and Western blot analyses revealed that three MCT subtypes, MCT1/Slc16a1, MCT2/Slc16a7, and MCT4/Slc16a3, were expressed in these cells. Because l-lactate reduced to 67% of the nicotinate uptake even at 10mM, it is unlikely that nicotinate uptake in rat astrocytes is mediated by MCT1 and/or MCT2. These results provide biochemical evidence of a CHEMICAL-coupled and saturable transport system, presumed to be a GENE MCT4 or other unknown H(+)-coupled monocarboxylate transport system, for nicotinate in rat cerebrocortical astrocytes. | REGULATOR |
| Functional characteristics of H+ -dependent nicotinate transport in primary cultures of astrocytes from rat cerebral cortex. In the present study, we report the characteristics of H(+)-coupled nicotinate transport in primary cultures of astrocytes from rat cerebral cortex. The [(3)H]nicotinate transport in rat astrocytes increased up to a pH 5.5. The nicotinic acid uptake at pH 6.0 was both energy-dependent and saturable with a Michaelis constant (K(t)) of 2.8+/-0.4 mM and the maximal uptake rate (V(max)) of 31+/-3.2 nmol/mg protein/10 min. This process was reduced by a protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone, and a typical monocarboxylate transporter (MCT) inhibitor, alpha-cyano-4-hydroxycinnamic acid, suggesting that nicotinate uptake by rat astrocytes is mediated by H(+)-coupled monocarboxylate transport system. [(3)H]Nicotinate transport in rat astrocytes was significantly inhibited by various monocarboxylic acids such as l-lactic acid and pyruvic acid with a relatively low affinity (K(i)>10 mM). On the other hand, the uptake process of l-lactic acid was also saturable with a high-affinity component (K(t)=0.27 mM) and a low-affinity component (K(t)=35.9 mM). Reverse transcription-PCR and Western blot analyses revealed that three MCT subtypes, MCT1/Slc16a1, MCT2/Slc16a7, and MCT4/Slc16a3, were expressed in these cells. Because l-lactate reduced to 67% of the nicotinate uptake even at 10mM, it is unlikely that nicotinate uptake in rat astrocytes is mediated by MCT1 and/or MCT2. These results provide biochemical evidence of a CHEMICAL-coupled and saturable transport system, presumed to be a low-affinity monocarboxylate transporter GENE or other unknown H(+)-coupled monocarboxylate transport system, for nicotinate in rat cerebrocortical astrocytes. | REGULATOR |
| Functional characteristics of H+ -dependent nicotinate transport in primary cultures of astrocytes from rat cerebral cortex. In the present study, we report the characteristics of H(+)-coupled nicotinate transport in primary cultures of astrocytes from rat cerebral cortex. The [(3)H]nicotinate transport in rat astrocytes increased up to a pH 5.5. The nicotinic acid uptake at pH 6.0 was both energy-dependent and saturable with a Michaelis constant (K(t)) of 2.8+/-0.4 mM and the maximal uptake rate (V(max)) of 31+/-3.2 nmol/mg protein/10 min. This process was reduced by a protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone, and a typical GENE (MCT) inhibitor, CHEMICAL, suggesting that nicotinate uptake by rat astrocytes is mediated by H(+)-coupled monocarboxylate transport system. [(3)H]Nicotinate transport in rat astrocytes was significantly inhibited by various monocarboxylic acids such as l-lactic acid and pyruvic acid with a relatively low affinity (K(i)>10 mM). On the other hand, the uptake process of l-lactic acid was also saturable with a high-affinity component (K(t)=0.27 mM) and a low-affinity component (K(t)=35.9 mM). Reverse transcription-PCR and Western blot analyses revealed that three MCT subtypes, MCT1/Slc16a1, MCT2/Slc16a7, and MCT4/Slc16a3, were expressed in these cells. Because l-lactate reduced to 67% of the nicotinate uptake even at 10mM, it is unlikely that nicotinate uptake in rat astrocytes is mediated by MCT1 and/or MCT2. These results provide biochemical evidence of a H(+)-coupled and saturable transport system, presumed to be a low-affinity GENE MCT4 or other unknown H(+)-coupled monocarboxylate transport system, for nicotinate in rat cerebrocortical astrocytes. | INHIBITOR |
| Functional characteristics of H+ -dependent nicotinate transport in primary cultures of astrocytes from rat cerebral cortex. In the present study, we report the characteristics of H(+)-coupled nicotinate transport in primary cultures of astrocytes from rat cerebral cortex. The [(3)H]nicotinate transport in rat astrocytes increased up to a pH 5.5. The nicotinic acid uptake at pH 6.0 was both energy-dependent and saturable with a Michaelis constant (K(t)) of 2.8+/-0.4 mM and the maximal uptake rate (V(max)) of 31+/-3.2 nmol/mg protein/10 min. This process was reduced by a protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone, and a typical monocarboxylate transporter (GENE) inhibitor, CHEMICAL, suggesting that nicotinate uptake by rat astrocytes is mediated by H(+)-coupled monocarboxylate transport system. [(3)H]Nicotinate transport in rat astrocytes was significantly inhibited by various monocarboxylic acids such as l-lactic acid and pyruvic acid with a relatively low affinity (K(i)>10 mM). On the other hand, the uptake process of l-lactic acid was also saturable with a high-affinity component (K(t)=0.27 mM) and a low-affinity component (K(t)=35.9 mM). Reverse transcription-PCR and Western blot analyses revealed that three GENE subtypes, MCT1/Slc16a1, MCT2/Slc16a7, and MCT4/Slc16a3, were expressed in these cells. Because l-lactate reduced to 67% of the nicotinate uptake even at 10mM, it is unlikely that nicotinate uptake in rat astrocytes is mediated by MCT1 and/or MCT2. These results provide biochemical evidence of a H(+)-coupled and saturable transport system, presumed to be a low-affinity monocarboxylate transporter MCT4 or other unknown H(+)-coupled monocarboxylate transport system, for nicotinate in rat cerebrocortical astrocytes. | INHIBITOR |
| Functional characteristics of H+ -dependent CHEMICAL transport in primary cultures of astrocytes from rat cerebral cortex. In the present study, we report the characteristics of H(+)-coupled CHEMICAL transport in primary cultures of astrocytes from rat cerebral cortex. The [(3)H]nicotinate transport in rat astrocytes increased up to a pH 5.5. The nicotinic acid uptake at pH 6.0 was both energy-dependent and saturable with a Michaelis constant (K(t)) of 2.8+/-0.4 mM and the maximal uptake rate (V(max)) of 31+/-3.2 nmol/mg protein/10 min. This process was reduced by a protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone, and a typical monocarboxylate transporter (MCT) inhibitor, alpha-cyano-4-hydroxycinnamic acid, suggesting that CHEMICAL uptake by rat astrocytes is mediated by H(+)-coupled GENE. [(3)H]Nicotinate transport in rat astrocytes was significantly inhibited by various monocarboxylic acids such as l-lactic acid and pyruvic acid with a relatively low affinity (K(i)>10 mM). On the other hand, the uptake process of l-lactic acid was also saturable with a high-affinity component (K(t)=0.27 mM) and a low-affinity component (K(t)=35.9 mM). Reverse transcription-PCR and Western blot analyses revealed that three MCT subtypes, MCT1/Slc16a1, MCT2/Slc16a7, and MCT4/Slc16a3, were expressed in these cells. Because l-lactate reduced to 67% of the CHEMICAL uptake even at 10mM, it is unlikely that CHEMICAL uptake in rat astrocytes is mediated by MCT1 and/or MCT2. These results provide biochemical evidence of a H(+)-coupled and saturable transport system, presumed to be a low-affinity monocarboxylate transporter MCT4 or other unknown H(+)-coupled GENE, for CHEMICAL in rat cerebrocortical astrocytes. | SUBSTRATE |
| Functional characteristics of H+ -dependent CHEMICAL transport in primary cultures of astrocytes from rat cerebral cortex. In the present study, we report the characteristics of H(+)-coupled CHEMICAL transport in primary cultures of astrocytes from rat cerebral cortex. The [(3)H]nicotinate transport in rat astrocytes increased up to a pH 5.5. The nicotinic acid uptake at pH 6.0 was both energy-dependent and saturable with a Michaelis constant (K(t)) of 2.8+/-0.4 mM and the maximal uptake rate (V(max)) of 31+/-3.2 nmol/mg protein/10 min. This process was reduced by a protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone, and a typical monocarboxylate transporter (MCT) inhibitor, alpha-cyano-4-hydroxycinnamic acid, suggesting that CHEMICAL uptake by rat astrocytes is mediated by H(+)-coupled monocarboxylate transport system. [(3)H]Nicotinate transport in rat astrocytes was significantly inhibited by various monocarboxylic acids such as l-lactic acid and pyruvic acid with a relatively low affinity (K(i)>10 mM). On the other hand, the uptake process of l-lactic acid was also saturable with a high-affinity component (K(t)=0.27 mM) and a low-affinity component (K(t)=35.9 mM). Reverse transcription-PCR and Western blot analyses revealed that three MCT subtypes, MCT1/Slc16a1, MCT2/Slc16a7, and MCT4/Slc16a3, were expressed in these cells. Because l-lactate reduced to 67% of the CHEMICAL uptake even at 10mM, it is unlikely that CHEMICAL uptake in rat astrocytes is mediated by GENE and/or MCT2. These results provide biochemical evidence of a H(+)-coupled and saturable transport system, presumed to be a low-affinity monocarboxylate transporter MCT4 or other unknown H(+)-coupled monocarboxylate transport system, for CHEMICAL in rat cerebrocortical astrocytes. | SUBSTRATE |
| Functional characteristics of H+ -dependent CHEMICAL transport in primary cultures of astrocytes from rat cerebral cortex. In the present study, we report the characteristics of H(+)-coupled CHEMICAL transport in primary cultures of astrocytes from rat cerebral cortex. The [(3)H]nicotinate transport in rat astrocytes increased up to a pH 5.5. The nicotinic acid uptake at pH 6.0 was both energy-dependent and saturable with a Michaelis constant (K(t)) of 2.8+/-0.4 mM and the maximal uptake rate (V(max)) of 31+/-3.2 nmol/mg protein/10 min. This process was reduced by a protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone, and a typical monocarboxylate transporter (MCT) inhibitor, alpha-cyano-4-hydroxycinnamic acid, suggesting that CHEMICAL uptake by rat astrocytes is mediated by H(+)-coupled monocarboxylate transport system. [(3)H]Nicotinate transport in rat astrocytes was significantly inhibited by various monocarboxylic acids such as l-lactic acid and pyruvic acid with a relatively low affinity (K(i)>10 mM). On the other hand, the uptake process of l-lactic acid was also saturable with a high-affinity component (K(t)=0.27 mM) and a low-affinity component (K(t)=35.9 mM). Reverse transcription-PCR and Western blot analyses revealed that three MCT subtypes, MCT1/Slc16a1, MCT2/Slc16a7, and MCT4/Slc16a3, were expressed in these cells. Because l-lactate reduced to 67% of the CHEMICAL uptake even at 10mM, it is unlikely that CHEMICAL uptake in rat astrocytes is mediated by MCT1 and/or GENE. These results provide biochemical evidence of a H(+)-coupled and saturable transport system, presumed to be a low-affinity monocarboxylate transporter MCT4 or other unknown H(+)-coupled monocarboxylate transport system, for CHEMICAL in rat cerebrocortical astrocytes. | SUBSTRATE |
| Functional characteristics of H+ -dependent CHEMICAL transport in primary cultures of astrocytes from rat cerebral cortex. In the present study, we report the characteristics of H(+)-coupled CHEMICAL transport in primary cultures of astrocytes from rat cerebral cortex. The [(3)H]nicotinate transport in rat astrocytes increased up to a pH 5.5. The nicotinic acid uptake at pH 6.0 was both energy-dependent and saturable with a Michaelis constant (K(t)) of 2.8+/-0.4 mM and the maximal uptake rate (V(max)) of 31+/-3.2 nmol/mg protein/10 min. This process was reduced by a protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone, and a typical monocarboxylate transporter (MCT) inhibitor, alpha-cyano-4-hydroxycinnamic acid, suggesting that CHEMICAL uptake by rat astrocytes is mediated by H(+)-coupled monocarboxylate transport system. [(3)H]Nicotinate transport in rat astrocytes was significantly inhibited by various monocarboxylic acids such as l-lactic acid and pyruvic acid with a relatively low affinity (K(i)>10 mM). On the other hand, the uptake process of l-lactic acid was also saturable with a high-affinity component (K(t)=0.27 mM) and a low-affinity component (K(t)=35.9 mM). Reverse transcription-PCR and Western blot analyses revealed that three MCT subtypes, MCT1/Slc16a1, MCT2/Slc16a7, and MCT4/Slc16a3, were expressed in these cells. Because l-lactate reduced to 67% of the CHEMICAL uptake even at 10mM, it is unlikely that CHEMICAL uptake in rat astrocytes is mediated by MCT1 and/or MCT2. These results provide biochemical evidence of a H(+)-coupled and saturable transport system, presumed to be a GENE MCT4 or other unknown H(+)-coupled monocarboxylate transport system, for CHEMICAL in rat cerebrocortical astrocytes. | SUBSTRATE |
| Functional characteristics of H+ -dependent CHEMICAL transport in primary cultures of astrocytes from rat cerebral cortex. In the present study, we report the characteristics of H(+)-coupled CHEMICAL transport in primary cultures of astrocytes from rat cerebral cortex. The [(3)H]nicotinate transport in rat astrocytes increased up to a pH 5.5. The nicotinic acid uptake at pH 6.0 was both energy-dependent and saturable with a Michaelis constant (K(t)) of 2.8+/-0.4 mM and the maximal uptake rate (V(max)) of 31+/-3.2 nmol/mg protein/10 min. This process was reduced by a protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone, and a typical monocarboxylate transporter (MCT) inhibitor, alpha-cyano-4-hydroxycinnamic acid, suggesting that CHEMICAL uptake by rat astrocytes is mediated by H(+)-coupled monocarboxylate transport system. [(3)H]Nicotinate transport in rat astrocytes was significantly inhibited by various monocarboxylic acids such as l-lactic acid and pyruvic acid with a relatively low affinity (K(i)>10 mM). On the other hand, the uptake process of l-lactic acid was also saturable with a high-affinity component (K(t)=0.27 mM) and a low-affinity component (K(t)=35.9 mM). Reverse transcription-PCR and Western blot analyses revealed that three MCT subtypes, MCT1/Slc16a1, MCT2/Slc16a7, and MCT4/Slc16a3, were expressed in these cells. Because l-lactate reduced to 67% of the CHEMICAL uptake even at 10mM, it is unlikely that CHEMICAL uptake in rat astrocytes is mediated by MCT1 and/or MCT2. These results provide biochemical evidence of a H(+)-coupled and saturable transport system, presumed to be a low-affinity monocarboxylate transporter GENE or other unknown H(+)-coupled monocarboxylate transport system, for CHEMICAL in rat cerebrocortical astrocytes. | SUBSTRATE |
| Functional characteristics of H+ -dependent CHEMICAL transport in primary cultures of astrocytes from rat cerebral cortex. In the present study, we report the characteristics of H(+)-coupled CHEMICAL transport in primary cultures of astrocytes from rat cerebral cortex. The [(3)H]nicotinate transport in rat astrocytes increased up to a pH 5.5. The nicotinic acid uptake at pH 6.0 was both energy-dependent and saturable with a Michaelis constant (K(t)) of 2.8+/-0.4 mM and the maximal uptake rate (V(max)) of 31+/-3.2 nmol/mg protein/10 min. This process was reduced by a protonophore, carbonylcyanide p-trifluoromethoxyphenylhydrazone, and a typical monocarboxylate transporter (MCT) inhibitor, alpha-cyano-4-hydroxycinnamic acid, suggesting that CHEMICAL uptake by rat astrocytes is mediated by GENE. [(3)H]Nicotinate transport in rat astrocytes was significantly inhibited by various monocarboxylic acids such as l-lactic acid and pyruvic acid with a relatively low affinity (K(i)>10 mM). On the other hand, the uptake process of l-lactic acid was also saturable with a high-affinity component (K(t)=0.27 mM) and a low-affinity component (K(t)=35.9 mM). Reverse transcription-PCR and Western blot analyses revealed that three MCT subtypes, MCT1/Slc16a1, MCT2/Slc16a7, and MCT4/Slc16a3, were expressed in these cells. Because l-lactate reduced to 67% of the CHEMICAL uptake even at 10mM, it is unlikely that CHEMICAL uptake in rat astrocytes is mediated by MCT1 and/or MCT2. These results provide biochemical evidence of a H(+)-coupled and saturable transport system, presumed to be a low-affinity monocarboxylate transporter MCT4 or other unknown GENE, for CHEMICAL in rat cerebrocortical astrocytes. | SUBSTRATE |
| A review of the structural and functional features of CHEMICAL, an angiotensin receptor blocker. The angiotensin II (A-II) type 1 (AT1) receptor-mediated effects of A-II play a key role in the pathophysiology of hypertension. Effective inhibition of A-II is provided by the latest class of antihypertensive medications, the GENE receptor blockers (ARBs). These orally available agents were developed around a common imidazole-based structural core. The most recent member of this drug class to be approved by the Food and Drug Administration, CHEMICAL, contains unique features that may explain its clinical efficacy. Key structural elements of CHEMICAL include a hydroxyalkyl substituent at the imidazole 4-position and a hydrolyzable ester group at the imidazole 5-position. Inter- and intramolecular hydrogen bonding involving these groups may contribute to the potentiation of antagonist activity. After oral administration, CHEMICAL is deesterified in the intestinal tract to produce the active metabolite olmesartan, which undergoes no additional metabolic change. The marked antihypertensive efficacy of CHEMICAL may result from a unique pharmacological interaction of the drug with the GENE receptor, resulting in a potent, long-lasting, dose-dependent blockade of A-II. This review article characterizes the structural features of olmesartan that may be responsible for its clinical efficacy. Inferential pharmacological studies compare and contrast the effects of olmesartan to those of other ARBs in comparable preclinical animal models. | REGULATOR |
| A review of the structural and functional features of olmesartan medoxomil, an angiotensin receptor blocker. The GENE-mediated effects of CHEMICAL play a key role in the pathophysiology of hypertension. Effective inhibition of CHEMICAL is provided by the latest class of antihypertensive medications, the AT1 receptor blockers (ARBs). These orally available agents were developed around a common imidazole-based structural core. The most recent member of this drug class to be approved by the Food and Drug Administration, olmesartan medoxomil, contains unique features that may explain its clinical efficacy. Key structural elements of olmesartan medoxomil include a hydroxyalkyl substituent at the imidazole 4-position and a hydrolyzable ester group at the imidazole 5-position. Inter- and intramolecular hydrogen bonding involving these groups may contribute to the potentiation of antagonist activity. After oral administration, olmesartan medoxomil is deesterified in the intestinal tract to produce the active metabolite olmesartan, which undergoes no additional metabolic change. The marked antihypertensive efficacy of olmesartan medoxomil may result from a unique pharmacological interaction of the drug with the AT1 receptor, resulting in a potent, long-lasting, dose-dependent blockade of CHEMICAL. This review article characterizes the structural features of olmesartan that may be responsible for its clinical efficacy. Inferential pharmacological studies compare and contrast the effects of olmesartan to those of other ARBs in comparable preclinical animal models. | REGULATOR |
| A review of the structural and functional features of CHEMICAL, an GENE blocker. The angiotensin II (A-II) type 1 (AT1) receptor-mediated effects of A-II play a key role in the pathophysiology of hypertension. Effective inhibition of A-II is provided by the latest class of antihypertensive medications, the AT1 receptor blockers (ARBs). These orally available agents were developed around a common imidazole-based structural core. The most recent member of this drug class to be approved by the Food and Drug Administration, CHEMICAL, contains unique features that may explain its clinical efficacy. Key structural elements of CHEMICAL include a hydroxyalkyl substituent at the imidazole 4-position and a hydrolyzable ester group at the imidazole 5-position. Inter- and intramolecular hydrogen bonding involving these groups may contribute to the potentiation of antagonist activity. After oral administration, CHEMICAL is deesterified in the intestinal tract to produce the active metabolite olmesartan, which undergoes no additional metabolic change. The marked antihypertensive efficacy of CHEMICAL may result from a unique pharmacological interaction of the drug with the AT1 receptor, resulting in a potent, long-lasting, dose-dependent blockade of A-II. This review article characterizes the structural features of olmesartan that may be responsible for its clinical efficacy. Inferential pharmacological studies compare and contrast the effects of olmesartan to those of other ARBs in comparable preclinical animal models. | INHIBITOR |
| A review of the structural and functional features of CHEMICAL, an angiotensin receptor blocker. The angiotensin II (A-II) type 1 (AT1) receptor-mediated effects of GENE play a key role in the pathophysiology of hypertension. Effective inhibition of GENE is provided by the latest class of antihypertensive medications, the AT1 receptor blockers (ARBs). These orally available agents were developed around a common imidazole-based structural core. The most recent member of this drug class to be approved by the Food and Drug Administration, CHEMICAL, contains unique features that may explain its clinical efficacy. Key structural elements of CHEMICAL include a hydroxyalkyl substituent at the imidazole 4-position and a hydrolyzable ester group at the imidazole 5-position. Inter- and intramolecular hydrogen bonding involving these groups may contribute to the potentiation of antagonist activity. After oral administration, CHEMICAL is deesterified in the intestinal tract to produce the active metabolite olmesartan, which undergoes no additional metabolic change. The marked antihypertensive efficacy of CHEMICAL may result from a unique pharmacological interaction of the drug with the AT1 receptor, resulting in a potent, long-lasting, dose-dependent blockade of GENE. This review article characterizes the structural features of olmesartan that may be responsible for its clinical efficacy. Inferential pharmacological studies compare and contrast the effects of olmesartan to those of other ARBs in comparable preclinical animal models. | INHIBITOR |
| Effects of granulocyte colony-stimulating factor (G-CSF) and GENE inhibitor (ONO-5046) on acid-induced lung injury in rats. It has been suggested that neutrophils play an important role in acid-aspirated lung injury. We examined the effects of the high dose of granulocyte-colony stimulating factor (G-CSF), which is capable of increasing peripheral neutrophils, and a specific GENE inhibitor (CHEMICAL) on acid lung injury in rats. Animals were anesthetized and normal saline (NS, 2 mL kg(-1)) or hydrochloric acid (HCl, 0.1 N 2 mL kg(-1)) was then instilled into trachea. Thirty minutes before HCl instillation, G-CSF (150 microg kg(-1)) was injected subcutaneously or CHEMICAL (10 mg kg(-1) h(-1)) was infused continuously into the right jugular vein. Animals were ventilated during the experiments. Five hours after HCl or NS instillation, bronchoalveolar lavage fluid (BALF) and lung tissue samples were obtained. Total nuclear cell count, absorbance, albumin, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, cytokine-induced neutrophil chemoattractant (CINC), GENE in BALF, wet-to-dry (W/D) ratio were measured. HCl aspiration markedly increased these values in BALF and W/D ratio. Both CHEMICAL and G-CSF attenuated the parameters increased by acid-induced lung injury in rats. The data suggests that neutrophils play an important role in acid-induced lung injury. However, high-dose G-CSF does not exacerbate acid-aspirated lung injury in rats, although this agent causes an increase in peripheral neutrophils. | INHIBITOR |
| Effects of GENE (G-CSF) and neutrophil elastase inhibitor (CHEMICAL) on acid-induced lung injury in rats. It has been suggested that neutrophils play an important role in acid-aspirated lung injury. We examined the effects of the high dose of granulocyte-colony stimulating factor (G-CSF), which is capable of increasing peripheral neutrophils, and a specific neutrophil elastase inhibitor (ONO-5046) on acid lung injury in rats. Animals were anesthetized and normal saline (NS, 2 mL kg(-1)) or hydrochloric acid (HCl, 0.1 N 2 mL kg(-1)) was then instilled into trachea. Thirty minutes before HCl instillation, G-CSF (150 microg kg(-1)) was injected subcutaneously or CHEMICAL (10 mg kg(-1) h(-1)) was infused continuously into the right jugular vein. Animals were ventilated during the experiments. Five hours after HCl or NS instillation, bronchoalveolar lavage fluid (BALF) and lung tissue samples were obtained. Total nuclear cell count, absorbance, albumin, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, cytokine-induced neutrophil chemoattractant (CINC), neutrophil elastase in BALF, wet-to-dry (W/D) ratio were measured. HCl aspiration markedly increased these values in BALF and W/D ratio. Both CHEMICAL and G-CSF attenuated the parameters increased by acid-induced lung injury in rats. The data suggests that neutrophils play an important role in acid-induced lung injury. However, high-dose G-CSF does not exacerbate acid-aspirated lung injury in rats, although this agent causes an increase in peripheral neutrophils. | INHIBITOR |
| Effects of granulocyte colony-stimulating factor (GENE) and neutrophil elastase inhibitor (CHEMICAL) on acid-induced lung injury in rats. It has been suggested that neutrophils play an important role in acid-aspirated lung injury. We examined the effects of the high dose of granulocyte-colony stimulating factor (G-CSF), which is capable of increasing peripheral neutrophils, and a specific neutrophil elastase inhibitor (ONO-5046) on acid lung injury in rats. Animals were anesthetized and normal saline (NS, 2 mL kg(-1)) or hydrochloric acid (HCl, 0.1 N 2 mL kg(-1)) was then instilled into trachea. Thirty minutes before HCl instillation, GENE (150 microg kg(-1)) was injected subcutaneously or CHEMICAL (10 mg kg(-1) h(-1)) was infused continuously into the right jugular vein. Animals were ventilated during the experiments. Five hours after HCl or NS instillation, bronchoalveolar lavage fluid (BALF) and lung tissue samples were obtained. Total nuclear cell count, absorbance, albumin, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, cytokine-induced neutrophil chemoattractant (CINC), neutrophil elastase in BALF, wet-to-dry (W/D) ratio were measured. HCl aspiration markedly increased these values in BALF and W/D ratio. Both CHEMICAL and GENE attenuated the parameters increased by acid-induced lung injury in rats. The data suggests that neutrophils play an important role in acid-induced lung injury. However, high-dose GENE does not exacerbate acid-aspirated lung injury in rats, although this agent causes an increase in peripheral neutrophils. | INHIBITOR |
| Guidance on the use of miglustat for treating patients with type 1 Gaucher disease. Type 1 Gaucher disease (GD) is a progressive lysosomal storage disorder due to an autosomal recessive deficiency of glucocerebrosidase. Clinical manifestations include anemia, thrombocytopenia, hepatosplenomegaly, and bone and pulmonary disease. Intravenous enzyme replacement (ERT) with imiglucerase is the accepted standard for treatment of symptomatic patients. More than 3,500 patients worldwide have received ERT with well-documented beneficial effects on the hematological, visceral, skeletal, and pulmonary manifestations, and with resultant improvement in health-related quality of life. CHEMICAL, an imino sugar that reversibly inhibits GENE and reduces intracellular substrate burden, is an oral treatment for patients with type 1 GD that was recently approved in the United States for symptomatic patients with mild to moderate clinical manifestations for whom ERT is not an option. Because responses to miglustat are slower and less robust than those observed with ERT, and because miglustat is associated with significant side effects, clinicians who care for patients with GD should become familiar with the limited indications for miglustat use and the circumstances when it may be prescribed appropriately. This review article and position statement represents the current opinion of American physicians with extensive expertise in GD regarding patient management in the context of the availability of standard imiglucerase treatment and the recent introduction of miglustat. | INHIBITOR |
| Guidance on the use of miglustat for treating patients with type 1 Gaucher disease. Type 1 Gaucher disease (GD) is a progressive lysosomal storage disorder due to an autosomal recessive deficiency of glucocerebrosidase. Clinical manifestations include anemia, thrombocytopenia, hepatosplenomegaly, and bone and pulmonary disease. Intravenous enzyme replacement (ERT) with imiglucerase is the accepted standard for treatment of symptomatic patients. More than 3,500 patients worldwide have received ERT with well-documented beneficial effects on the hematological, visceral, skeletal, and pulmonary manifestations, and with resultant improvement in health-related quality of life. Miglustat, an CHEMICAL that reversibly inhibits GENE and reduces intracellular substrate burden, is an oral treatment for patients with type 1 GD that was recently approved in the United States for symptomatic patients with mild to moderate clinical manifestations for whom ERT is not an option. Because responses to miglustat are slower and less robust than those observed with ERT, and because miglustat is associated with significant side effects, clinicians who care for patients with GD should become familiar with the limited indications for miglustat use and the circumstances when it may be prescribed appropriately. This review article and position statement represents the current opinion of American physicians with extensive expertise in GD regarding patient management in the context of the availability of standard imiglucerase treatment and the recent introduction of miglustat. | INHIBITOR |
| Nicotinic-receptor potentiator drugs, huprine X and CHEMICAL, increase ACh release by blocking AChE activity but not acting on GENE. The main goal of the present study was to analyse the effects of (+/-)-huprine X ((+/-)-HX) and CHEMICAL (GAL), with potentiating action on GENE, and huperzine A (HPA), devoid of nicotinic activity, on [3H]-acetylcholine ([3H]-ACh) release in striatal slices of rat brain. All compounds are non-covalent and reversible inhibitors of AChE. Addition of (+/-)-HX (0.01 microM), GAL (10 microM) and HPA (0.1 microM) to the superfusion medium decreased the release of the ACh neurotransmitter to a similar extent: 36%, 30% and 34%, respectively (P<0.01). This effect was reverted in the presence of atropine (ATR; 0.1 microM), which blocks the pre-synaptic muscarinic M2 receptor. After that, a wide range of concentrations of drugs, concomitantly with ATR (0.1 microM), was studied in the presence of haloperidol (HAL; 0.01 microM), a dopamine D2 antagonist. In these conditions, a dose-dependent increase of [3H]-ACh release was observed in the presence of (+/-)-HX, GAL and HPA. To test the role of GENE in the drugs' effects on [3H]-ACh release, mecamylamine (MEC) 100 microM was used to block such receptors. MEC alone significantly decreased neurotransmitter release by 18% (P<0.05), but no change was obtained in the presence of both ATR and MEC. Under these conditions, (+/-)-HX, GAL and HPA increased the release of [3H]-ACh by 37%, 25% and 38%, respectively (P<0.01). Taking into account all of these data, the present results suggest that the effects induced by (+/-)-HX and GAL nicotinic-receptor potentiators seem to be mainly due to their ability in inhibiting acetylcholinesterase activity, but not by interaction on the GENE. | NO-RELATIONSHIP |
| GENE potentiator drugs, huprine X and CHEMICAL, increase ACh release by blocking AChE activity but not acting on nicotinic receptors. The main goal of the present study was to analyse the effects of (+/-)-huprine X ((+/-)-HX) and CHEMICAL (GAL), with potentiating action on nicotinic receptors, and huperzine A (HPA), devoid of nicotinic activity, on [3H]-acetylcholine ([3H]-ACh) release in striatal slices of rat brain. All compounds are non-covalent and reversible inhibitors of AChE. Addition of (+/-)-HX (0.01 microM), GAL (10 microM) and HPA (0.1 microM) to the superfusion medium decreased the release of the ACh neurotransmitter to a similar extent: 36%, 30% and 34%, respectively (P<0.01). This effect was reverted in the presence of atropine (ATR; 0.1 microM), which blocks the pre-synaptic muscarinic M2 receptor. After that, a wide range of concentrations of drugs, concomitantly with ATR (0.1 microM), was studied in the presence of haloperidol (HAL; 0.01 microM), a dopamine D2 antagonist. In these conditions, a dose-dependent increase of [3H]-ACh release was observed in the presence of (+/-)-HX, GAL and HPA. To test the role of nicotinic receptors in the drugs' effects on [3H]-ACh release, mecamylamine (MEC) 100 microM was used to block such receptors. MEC alone significantly decreased neurotransmitter release by 18% (P<0.05), but no change was obtained in the presence of both ATR and MEC. Under these conditions, (+/-)-HX, GAL and HPA increased the release of [3H]-ACh by 37%, 25% and 38%, respectively (P<0.01). Taking into account all of these data, the present results suggest that the effects induced by (+/-)-HX and GAL nicotinic-receptor potentiators seem to be mainly due to their ability in inhibiting acetylcholinesterase activity, but not by interaction on the nicotinic receptors. | ACTIVATOR |
| Nicotinic-receptor potentiator drugs, huprine X and galantamine, increase ACh release by blocking AChE activity but not acting on nicotinic receptors. The main goal of the present study was to analyse the effects of (+/-)-huprine X ((+/-)-HX) and galantamine (GAL), with potentiating action on nicotinic receptors, and huperzine A (HPA), devoid of nicotinic activity, on [3H]-acetylcholine ([3H]-ACh) release in striatal slices of rat brain. All compounds are non-covalent and reversible inhibitors of AChE. Addition of (+/-)-HX (0.01 microM), GAL (10 microM) and HPA (0.1 microM) to the superfusion medium decreased the release of the ACh neurotransmitter to a similar extent: 36%, 30% and 34%, respectively (P<0.01). This effect was reverted in the presence of CHEMICAL (ATR; 0.1 microM), which blocks the pre-synaptic GENE. After that, a wide range of concentrations of drugs, concomitantly with ATR (0.1 microM), was studied in the presence of haloperidol (HAL; 0.01 microM), a dopamine D2 antagonist. In these conditions, a dose-dependent increase of [3H]-ACh release was observed in the presence of (+/-)-HX, GAL and HPA. To test the role of nicotinic receptors in the drugs' effects on [3H]-ACh release, mecamylamine (MEC) 100 microM was used to block such receptors. MEC alone significantly decreased neurotransmitter release by 18% (P<0.05), but no change was obtained in the presence of both ATR and MEC. Under these conditions, (+/-)-HX, GAL and HPA increased the release of [3H]-ACh by 37%, 25% and 38%, respectively (P<0.01). Taking into account all of these data, the present results suggest that the effects induced by (+/-)-HX and GAL nicotinic-receptor potentiators seem to be mainly due to their ability in inhibiting acetylcholinesterase activity, but not by interaction on the nicotinic receptors. | INHIBITOR |
| Nicotinic-receptor potentiator drugs, huprine X and galantamine, increase ACh release by blocking AChE activity but not acting on nicotinic receptors. The main goal of the present study was to analyse the effects of (+/-)-huprine X ((+/-)-HX) and galantamine (GAL), with potentiating action on nicotinic receptors, and huperzine A (HPA), devoid of nicotinic activity, on [3H]-acetylcholine ([3H]-ACh) release in striatal slices of rat brain. All compounds are non-covalent and reversible inhibitors of AChE. Addition of (+/-)-HX (0.01 microM), GAL (10 microM) and HPA (0.1 microM) to the superfusion medium decreased the release of the ACh neurotransmitter to a similar extent: 36%, 30% and 34%, respectively (P<0.01). This effect was reverted in the presence of atropine (CHEMICAL; 0.1 microM), which blocks the pre-synaptic GENE. After that, a wide range of concentrations of drugs, concomitantly with CHEMICAL (0.1 microM), was studied in the presence of haloperidol (HAL; 0.01 microM), a dopamine D2 antagonist. In these conditions, a dose-dependent increase of [3H]-ACh release was observed in the presence of (+/-)-HX, GAL and HPA. To test the role of nicotinic receptors in the drugs' effects on [3H]-ACh release, mecamylamine (MEC) 100 microM was used to block such receptors. MEC alone significantly decreased neurotransmitter release by 18% (P<0.05), but no change was obtained in the presence of both CHEMICAL and MEC. Under these conditions, (+/-)-HX, GAL and HPA increased the release of [3H]-ACh by 37%, 25% and 38%, respectively (P<0.01). Taking into account all of these data, the present results suggest that the effects induced by (+/-)-HX and GAL nicotinic-receptor potentiators seem to be mainly due to their ability in inhibiting acetylcholinesterase activity, but not by interaction on the nicotinic receptors. | INHIBITOR |
| Nicotinic-receptor potentiator drugs, huprine X and CHEMICAL, increase ACh release by blocking GENE activity but not acting on nicotinic receptors. The main goal of the present study was to analyse the effects of (+/-)-huprine X ((+/-)-HX) and CHEMICAL (GAL), with potentiating action on nicotinic receptors, and huperzine A (HPA), devoid of nicotinic activity, on [3H]-acetylcholine ([3H]-ACh) release in striatal slices of rat brain. All compounds are non-covalent and reversible inhibitors of GENE. Addition of (+/-)-HX (0.01 microM), GAL (10 microM) and HPA (0.1 microM) to the superfusion medium decreased the release of the ACh neurotransmitter to a similar extent: 36%, 30% and 34%, respectively (P<0.01). This effect was reverted in the presence of atropine (ATR; 0.1 microM), which blocks the pre-synaptic muscarinic M2 receptor. After that, a wide range of concentrations of drugs, concomitantly with ATR (0.1 microM), was studied in the presence of haloperidol (HAL; 0.01 microM), a dopamine D2 antagonist. In these conditions, a dose-dependent increase of [3H]-ACh release was observed in the presence of (+/-)-HX, GAL and HPA. To test the role of nicotinic receptors in the drugs' effects on [3H]-ACh release, mecamylamine (MEC) 100 microM was used to block such receptors. MEC alone significantly decreased neurotransmitter release by 18% (P<0.05), but no change was obtained in the presence of both ATR and MEC. Under these conditions, (+/-)-HX, GAL and HPA increased the release of [3H]-ACh by 37%, 25% and 38%, respectively (P<0.01). Taking into account all of these data, the present results suggest that the effects induced by (+/-)-HX and GAL nicotinic-receptor potentiators seem to be mainly due to their ability in inhibiting acetylcholinesterase activity, but not by interaction on the nicotinic receptors. | INHIBITOR |
| Nicotinic-receptor potentiator drugs, huprine X and galantamine, increase ACh release by blocking AChE activity but not acting on GENE. The main goal of the present study was to analyse the effects of (+/-)-huprine X ((+/-)-HX) and galantamine (GAL), with potentiating action on GENE, and huperzine A (HPA), devoid of nicotinic activity, on [3H]-acetylcholine ([3H]-ACh) release in striatal slices of rat brain. All compounds are non-covalent and reversible inhibitors of AChE. Addition of (+/-)-HX (0.01 microM), GAL (10 microM) and HPA (0.1 microM) to the superfusion medium decreased the release of the ACh neurotransmitter to a similar extent: 36%, 30% and 34%, respectively (P<0.01). This effect was reverted in the presence of atropine (ATR; 0.1 microM), which blocks the pre-synaptic muscarinic M2 receptor. After that, a wide range of concentrations of drugs, concomitantly with ATR (0.1 microM), was studied in the presence of haloperidol (HAL; 0.01 microM), a dopamine D2 antagonist. In these conditions, a dose-dependent increase of [3H]-ACh release was observed in the presence of (+/-)-HX, GAL and HPA. To test the role of GENE in the drugs' effects on [3H]-ACh release, CHEMICAL (MEC) 100 microM was used to block such receptors. MEC alone significantly decreased neurotransmitter release by 18% (P<0.05), but no change was obtained in the presence of both ATR and MEC. Under these conditions, (+/-)-HX, GAL and HPA increased the release of [3H]-ACh by 37%, 25% and 38%, respectively (P<0.01). Taking into account all of these data, the present results suggest that the effects induced by (+/-)-HX and GAL nicotinic-receptor potentiators seem to be mainly due to their ability in inhibiting acetylcholinesterase activity, but not by interaction on the GENE. | INHIBITOR |
| Nicotinic-receptor potentiator drugs, huprine X and galantamine, increase ACh release by blocking AChE activity but not acting on GENE. The main goal of the present study was to analyse the effects of (+/-)-huprine X ((+/-)-HX) and galantamine (GAL), with potentiating action on GENE, and huperzine A (HPA), devoid of nicotinic activity, on [3H]-acetylcholine ([3H]-ACh) release in striatal slices of rat brain. All compounds are non-covalent and reversible inhibitors of AChE. Addition of (+/-)-HX (0.01 microM), GAL (10 microM) and HPA (0.1 microM) to the superfusion medium decreased the release of the ACh neurotransmitter to a similar extent: 36%, 30% and 34%, respectively (P<0.01). This effect was reverted in the presence of atropine (ATR; 0.1 microM), which blocks the pre-synaptic muscarinic M2 receptor. After that, a wide range of concentrations of drugs, concomitantly with ATR (0.1 microM), was studied in the presence of haloperidol (HAL; 0.01 microM), a dopamine D2 antagonist. In these conditions, a dose-dependent increase of [3H]-ACh release was observed in the presence of (+/-)-HX, GAL and HPA. To test the role of GENE in the drugs' effects on [3H]-ACh release, mecamylamine (CHEMICAL) 100 microM was used to block such receptors. CHEMICAL alone significantly decreased neurotransmitter release by 18% (P<0.05), but no change was obtained in the presence of both ATR and CHEMICAL. Under these conditions, (+/-)-HX, GAL and HPA increased the release of [3H]-ACh by 37%, 25% and 38%, respectively (P<0.01). Taking into account all of these data, the present results suggest that the effects induced by (+/-)-HX and GAL nicotinic-receptor potentiators seem to be mainly due to their ability in inhibiting acetylcholinesterase activity, but not by interaction on the GENE. | NO-RELATIONSHIP |
| Nicotinic-receptor potentiator drugs, huprine X and galantamine, increase ACh release by blocking AChE activity but not acting on nicotinic receptors. The main goal of the present study was to analyse the effects of (+/-)-huprine X ((+/-)-HX) and galantamine (GAL), with potentiating action on nicotinic receptors, and huperzine A (HPA), devoid of nicotinic activity, on [3H]-acetylcholine ([3H]-ACh) release in striatal slices of rat brain. All compounds are non-covalent and reversible inhibitors of AChE. Addition of (+/-)-HX (0.01 microM), GAL (10 microM) and HPA (0.1 microM) to the superfusion medium decreased the release of the ACh neurotransmitter to a similar extent: 36%, 30% and 34%, respectively (P<0.01). This effect was reverted in the presence of atropine (ATR; 0.1 microM), which blocks the pre-synaptic muscarinic M2 receptor. After that, a wide range of concentrations of drugs, concomitantly with ATR (0.1 microM), was studied in the presence of CHEMICAL (HAL; 0.01 microM), a GENE antagonist. In these conditions, a dose-dependent increase of [3H]-ACh release was observed in the presence of (+/-)-HX, GAL and HPA. To test the role of nicotinic receptors in the drugs' effects on [3H]-ACh release, mecamylamine (MEC) 100 microM was used to block such receptors. MEC alone significantly decreased neurotransmitter release by 18% (P<0.05), but no change was obtained in the presence of both ATR and MEC. Under these conditions, (+/-)-HX, GAL and HPA increased the release of [3H]-ACh by 37%, 25% and 38%, respectively (P<0.01). Taking into account all of these data, the present results suggest that the effects induced by (+/-)-HX and GAL nicotinic-receptor potentiators seem to be mainly due to their ability in inhibiting acetylcholinesterase activity, but not by interaction on the nicotinic receptors. | INHIBITOR |
| Nicotinic-receptor potentiator drugs, huprine X and galantamine, increase ACh release by blocking AChE activity but not acting on nicotinic receptors. The main goal of the present study was to analyse the effects of (+/-)-huprine X ((+/-)-HX) and galantamine (GAL), with potentiating action on nicotinic receptors, and huperzine A (HPA), devoid of nicotinic activity, on [3H]-acetylcholine ([3H]-ACh) release in striatal slices of rat brain. All compounds are non-covalent and reversible inhibitors of AChE. Addition of (+/-)-HX (0.01 microM), GAL (10 microM) and HPA (0.1 microM) to the superfusion medium decreased the release of the ACh neurotransmitter to a similar extent: 36%, 30% and 34%, respectively (P<0.01). This effect was reverted in the presence of atropine (ATR; 0.1 microM), which blocks the pre-synaptic muscarinic M2 receptor. After that, a wide range of concentrations of drugs, concomitantly with ATR (0.1 microM), was studied in the presence of haloperidol (CHEMICAL; 0.01 microM), a GENE antagonist. In these conditions, a dose-dependent increase of [3H]-ACh release was observed in the presence of (+/-)-HX, GAL and HPA. To test the role of nicotinic receptors in the drugs' effects on [3H]-ACh release, mecamylamine (MEC) 100 microM was used to block such receptors. MEC alone significantly decreased neurotransmitter release by 18% (P<0.05), but no change was obtained in the presence of both ATR and MEC. Under these conditions, (+/-)-HX, GAL and HPA increased the release of [3H]-ACh by 37%, 25% and 38%, respectively (P<0.01). Taking into account all of these data, the present results suggest that the effects induced by (+/-)-HX and GAL nicotinic-receptor potentiators seem to be mainly due to their ability in inhibiting acetylcholinesterase activity, but not by interaction on the nicotinic receptors. | INHIBITOR |
| Rat hepatic stellate cells become retinoid unresponsive during activation. Hepatic stellate cells (HSC) play an essential role in fibrogenesis. Many stimuli cause HSC to activate, lose their Vitamin A and produce collagen. It is unclear whether Vitamin A loss causes activation, potentiates it or is simply an event in the cascade of activation changes. We determine if exogenous retinoids prevent the activation of freshly isolated rat HSC activated by plating on plastic. We also determine if retinoids: (1) reverse HSC activation; (2) maintain/restore HSC intracellular retinoid levels; (3) maintain expression of HSC nuclear receptors for CHEMICAL (RAR) in HSC that are becoming activated or are chronically activated. Markers of activation in freshly isolated HSC were decreased by either retinol or CHEMICAL without increases in HSC retinoid concentration. mRNA levels for GENE, RAR-beta and RAR-gamma, the nuclear receptors for CHEMICAL, decreased during activation of freshly isolated HSC even with retinoid supplementation. GENE, RAR-beta and RAR-gamma mRNA and RAR-beta protein was undetectable in chronically activated HSC and remained absent after CHEMICAL supplementation. Activation markers in chronically activated HSC were only slightly decreased after retinoid exposure. We conclude that exposure of HSC to extracellular retinoids diminishes some markers of activation but does not prevent HSC activation. | NO-RELATIONSHIP |
| Rat hepatic stellate cells become retinoid unresponsive during activation. Hepatic stellate cells (HSC) play an essential role in fibrogenesis. Many stimuli cause HSC to activate, lose their Vitamin A and produce collagen. It is unclear whether Vitamin A loss causes activation, potentiates it or is simply an event in the cascade of activation changes. We determine if exogenous retinoids prevent the activation of freshly isolated rat HSC activated by plating on plastic. We also determine if retinoids: (1) reverse HSC activation; (2) maintain/restore HSC intracellular retinoid levels; (3) maintain expression of HSC nuclear receptors for CHEMICAL (RAR) in HSC that are becoming activated or are chronically activated. Markers of activation in freshly isolated HSC were decreased by either retinol or CHEMICAL without increases in HSC retinoid concentration. mRNA levels for RAR-alpha, GENE and RAR-gamma, the nuclear receptors for CHEMICAL, decreased during activation of freshly isolated HSC even with retinoid supplementation. RAR-alpha, GENE and RAR-gamma mRNA and GENE protein was undetectable in chronically activated HSC and remained absent after CHEMICAL supplementation. Activation markers in chronically activated HSC were only slightly decreased after retinoid exposure. We conclude that exposure of HSC to extracellular retinoids diminishes some markers of activation but does not prevent HSC activation. | INDIRECT-DOWNREGULATOR |
| Rat hepatic stellate cells become retinoid unresponsive during activation. Hepatic stellate cells (HSC) play an essential role in fibrogenesis. Many stimuli cause HSC to activate, lose their Vitamin A and produce collagen. It is unclear whether Vitamin A loss causes activation, potentiates it or is simply an event in the cascade of activation changes. We determine if exogenous retinoids prevent the activation of freshly isolated rat HSC activated by plating on plastic. We also determine if retinoids: (1) reverse HSC activation; (2) maintain/restore HSC intracellular retinoid levels; (3) maintain expression of HSC nuclear receptors for CHEMICAL (RAR) in HSC that are becoming activated or are chronically activated. Markers of activation in freshly isolated HSC were decreased by either retinol or CHEMICAL without increases in HSC retinoid concentration. mRNA levels for RAR-alpha, RAR-beta and GENE, the nuclear receptors for CHEMICAL, decreased during activation of freshly isolated HSC even with retinoid supplementation. RAR-alpha, RAR-beta and GENE mRNA and RAR-beta protein was undetectable in chronically activated HSC and remained absent after CHEMICAL supplementation. Activation markers in chronically activated HSC were only slightly decreased after retinoid exposure. We conclude that exposure of HSC to extracellular retinoids diminishes some markers of activation but does not prevent HSC activation. | INDIRECT-DOWNREGULATOR |
| Rat hepatic stellate cells become retinoid unresponsive during activation. Hepatic stellate cells (HSC) play an essential role in fibrogenesis. Many stimuli cause HSC to activate, lose their Vitamin A and produce collagen. It is unclear whether Vitamin A loss causes activation, potentiates it or is simply an event in the cascade of activation changes. We determine if exogenous retinoids prevent the activation of freshly isolated rat HSC activated by plating on plastic. We also determine if retinoids: (1) reverse HSC activation; (2) maintain/restore HSC intracellular retinoid levels; (3) maintain expression of HSC GENE for CHEMICAL (RAR) in HSC that are becoming activated or are chronically activated. Markers of activation in freshly isolated HSC were decreased by either retinol or CHEMICAL without increases in HSC retinoid concentration. mRNA levels for RAR-alpha, RAR-beta and RAR-gamma, the GENE for CHEMICAL, decreased during activation of freshly isolated HSC even with retinoid supplementation. RAR-alpha, RAR-beta and RAR-gamma mRNA and RAR-beta protein was undetectable in chronically activated HSC and remained absent after CHEMICAL supplementation. Activation markers in chronically activated HSC were only slightly decreased after retinoid exposure. We conclude that exposure of HSC to extracellular retinoids diminishes some markers of activation but does not prevent HSC activation. | INDIRECT-DOWNREGULATOR |
| Rat hepatic stellate cells become CHEMICAL unresponsive during activation. Hepatic stellate cells (HSC) play an essential role in fibrogenesis. Many stimuli cause HSC to activate, lose their Vitamin A and produce collagen. It is unclear whether Vitamin A loss causes activation, potentiates it or is simply an event in the cascade of activation changes. We determine if exogenous retinoids prevent the activation of freshly isolated rat HSC activated by plating on plastic. We also determine if retinoids: (1) reverse HSC activation; (2) maintain/restore HSC intracellular CHEMICAL levels; (3) maintain expression of HSC nuclear receptors for retinoic acid (RAR) in HSC that are becoming activated or are chronically activated. Markers of activation in freshly isolated HSC were decreased by either retinol or retinoic acid without increases in HSC CHEMICAL concentration. mRNA levels for GENE, RAR-beta and RAR-gamma, the nuclear receptors for retinoic acid, decreased during activation of freshly isolated HSC even with CHEMICAL supplementation. GENE, RAR-beta and RAR-gamma mRNA and RAR-beta protein was undetectable in chronically activated HSC and remained absent after retinoic acid supplementation. Activation markers in chronically activated HSC were only slightly decreased after CHEMICAL exposure. We conclude that exposure of HSC to extracellular retinoids diminishes some markers of activation but does not prevent HSC activation. | INDIRECT-DOWNREGULATOR |
| Rat hepatic stellate cells become CHEMICAL unresponsive during activation. Hepatic stellate cells (HSC) play an essential role in fibrogenesis. Many stimuli cause HSC to activate, lose their Vitamin A and produce collagen. It is unclear whether Vitamin A loss causes activation, potentiates it or is simply an event in the cascade of activation changes. We determine if exogenous retinoids prevent the activation of freshly isolated rat HSC activated by plating on plastic. We also determine if retinoids: (1) reverse HSC activation; (2) maintain/restore HSC intracellular CHEMICAL levels; (3) maintain expression of HSC nuclear receptors for retinoic acid (RAR) in HSC that are becoming activated or are chronically activated. Markers of activation in freshly isolated HSC were decreased by either retinol or retinoic acid without increases in HSC CHEMICAL concentration. mRNA levels for RAR-alpha, GENE and RAR-gamma, the nuclear receptors for retinoic acid, decreased during activation of freshly isolated HSC even with CHEMICAL supplementation. RAR-alpha, GENE and RAR-gamma mRNA and GENE protein was undetectable in chronically activated HSC and remained absent after retinoic acid supplementation. Activation markers in chronically activated HSC were only slightly decreased after CHEMICAL exposure. We conclude that exposure of HSC to extracellular retinoids diminishes some markers of activation but does not prevent HSC activation. | NO-RELATIONSHIP |
| Rat hepatic stellate cells become CHEMICAL unresponsive during activation. Hepatic stellate cells (HSC) play an essential role in fibrogenesis. Many stimuli cause HSC to activate, lose their Vitamin A and produce collagen. It is unclear whether Vitamin A loss causes activation, potentiates it or is simply an event in the cascade of activation changes. We determine if exogenous retinoids prevent the activation of freshly isolated rat HSC activated by plating on plastic. We also determine if retinoids: (1) reverse HSC activation; (2) maintain/restore HSC intracellular CHEMICAL levels; (3) maintain expression of HSC nuclear receptors for retinoic acid (RAR) in HSC that are becoming activated or are chronically activated. Markers of activation in freshly isolated HSC were decreased by either retinol or retinoic acid without increases in HSC CHEMICAL concentration. mRNA levels for RAR-alpha, RAR-beta and GENE, the nuclear receptors for retinoic acid, decreased during activation of freshly isolated HSC even with CHEMICAL supplementation. RAR-alpha, RAR-beta and GENE mRNA and RAR-beta protein was undetectable in chronically activated HSC and remained absent after retinoic acid supplementation. Activation markers in chronically activated HSC were only slightly decreased after CHEMICAL exposure. We conclude that exposure of HSC to extracellular retinoids diminishes some markers of activation but does not prevent HSC activation. | INDIRECT-DOWNREGULATOR |
| Rat hepatic stellate cells become CHEMICAL unresponsive during activation. Hepatic stellate cells (HSC) play an essential role in fibrogenesis. Many stimuli cause HSC to activate, lose their Vitamin A and produce collagen. It is unclear whether Vitamin A loss causes activation, potentiates it or is simply an event in the cascade of activation changes. We determine if exogenous retinoids prevent the activation of freshly isolated rat HSC activated by plating on plastic. We also determine if retinoids: (1) reverse HSC activation; (2) maintain/restore HSC intracellular CHEMICAL levels; (3) maintain expression of HSC GENE for retinoic acid (RAR) in HSC that are becoming activated or are chronically activated. Markers of activation in freshly isolated HSC were decreased by either retinol or retinoic acid without increases in HSC CHEMICAL concentration. mRNA levels for RAR-alpha, RAR-beta and RAR-gamma, the GENE for retinoic acid, decreased during activation of freshly isolated HSC even with CHEMICAL supplementation. RAR-alpha, RAR-beta and RAR-gamma mRNA and RAR-beta protein was undetectable in chronically activated HSC and remained absent after retinoic acid supplementation. Activation markers in chronically activated HSC were only slightly decreased after CHEMICAL exposure. We conclude that exposure of HSC to extracellular retinoids diminishes some markers of activation but does not prevent HSC activation. | INDIRECT-DOWNREGULATOR |
| Protein kinase C potentiates homologous desensitization of the beta2-adrenoceptor in bovine tracheal smooth muscle. Preincubation (30 min) of bovine tracheal smooth muscle with various concentrations (0.1, 1 and 10 microM) of fenoterol decreased isoprenaline-induced maximal relaxation (E(max)) of CHEMICAL-contracted preparations in a concentration dependent fashion, indicating desensitization of the GENE. Preincubation with 1 microM of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) caused a small but significant decrease in isoprenaline-induced E(max), indicating activated PKC-mediated heterologous GENE desensitization. To investigate the capacity of activated PKC to regulate homologous desensitization, we incubated the smooth muscle strips with the combination of both 1 microM PMA and 1 microM fenoterol. This combined treatment synergistically decreased the isoprenaline-induced maximal relaxation, as compared to the individual effects of PMA and fenoterol alone, indicating a common pathway for heterologous and homologous desensitization. Moreover, the specific PKC-inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl) maleimide (GF 109203X) markedly increased the potency and E(max) of isoprenaline for all conditions used, including control conditions, and the synergistic effects of PMA and fenoterol were completely prevented. In conclusion, the present study demonstrates that homologous desensitization of the beta(2)-adrenergic receptor can be enhanced by PKC activation. For the first time we have provided evidence that this concept is functionally operative in airway smooth muscle, and it may explain the reduced bronchodilator response to GENE agonists in patients with asthma during a severe exacerbation. | ACTIVATOR |
| Protein kinase C potentiates homologous desensitization of the beta2-adrenoceptor in bovine tracheal smooth muscle. Preincubation (30 min) of bovine tracheal smooth muscle with various concentrations (0.1, 1 and 10 microM) of fenoterol decreased isoprenaline-induced maximal relaxation (E(max)) of methacholine-contracted preparations in a concentration dependent fashion, indicating desensitization of the beta(2)-adrenoceptor. Preincubation with 1 microM of the GENE (PKC) activator phorbol 12-myristate 13-acetate (CHEMICAL) caused a small but significant decrease in isoprenaline-induced E(max), indicating activated PKC-mediated heterologous beta(2)-adrenoceptor desensitization. To investigate the capacity of activated PKC to regulate homologous desensitization, we incubated the smooth muscle strips with the combination of both 1 microM CHEMICAL and 1 microM fenoterol. This combined treatment synergistically decreased the isoprenaline-induced maximal relaxation, as compared to the individual effects of CHEMICAL and fenoterol alone, indicating a common pathway for heterologous and homologous desensitization. Moreover, the specific PKC-inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl) maleimide (GF 109203X) markedly increased the potency and E(max) of isoprenaline for all conditions used, including control conditions, and the synergistic effects of CHEMICAL and fenoterol were completely prevented. In conclusion, the present study demonstrates that homologous desensitization of the beta(2)-adrenergic receptor can be enhanced by PKC activation. For the first time we have provided evidence that this concept is functionally operative in airway smooth muscle, and it may explain the reduced bronchodilator response to beta(2)-adrenoceptor agonists in patients with asthma during a severe exacerbation. | ACTIVATOR |
| Protein kinase C potentiates homologous desensitization of the beta2-adrenoceptor in bovine tracheal smooth muscle. Preincubation (30 min) of bovine tracheal smooth muscle with various concentrations (0.1, 1 and 10 microM) of fenoterol decreased isoprenaline-induced maximal relaxation (E(max)) of methacholine-contracted preparations in a concentration dependent fashion, indicating desensitization of the beta(2)-adrenoceptor. Preincubation with 1 microM of the protein kinase C (GENE) activator phorbol 12-myristate 13-acetate (CHEMICAL) caused a small but significant decrease in isoprenaline-induced E(max), indicating activated PKC-mediated heterologous beta(2)-adrenoceptor desensitization. To investigate the capacity of activated GENE to regulate homologous desensitization, we incubated the smooth muscle strips with the combination of both 1 microM CHEMICAL and 1 microM fenoterol. This combined treatment synergistically decreased the isoprenaline-induced maximal relaxation, as compared to the individual effects of CHEMICAL and fenoterol alone, indicating a common pathway for heterologous and homologous desensitization. Moreover, the specific PKC-inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl) maleimide (GF 109203X) markedly increased the potency and E(max) of isoprenaline for all conditions used, including control conditions, and the synergistic effects of CHEMICAL and fenoterol were completely prevented. In conclusion, the present study demonstrates that homologous desensitization of the beta(2)-adrenergic receptor can be enhanced by GENE activation. For the first time we have provided evidence that this concept is functionally operative in airway smooth muscle, and it may explain the reduced bronchodilator response to beta(2)-adrenoceptor agonists in patients with asthma during a severe exacerbation. | ACTIVATOR |
| Protein kinase C potentiates homologous desensitization of the beta2-adrenoceptor in bovine tracheal smooth muscle. Preincubation (30 min) of bovine tracheal smooth muscle with various concentrations (0.1, 1 and 10 microM) of fenoterol decreased isoprenaline-induced maximal relaxation (E(max)) of methacholine-contracted preparations in a concentration dependent fashion, indicating desensitization of the beta(2)-adrenoceptor. Preincubation with 1 microM of the GENE (PKC) activator CHEMICAL (PMA) caused a small but significant decrease in isoprenaline-induced E(max), indicating activated PKC-mediated heterologous beta(2)-adrenoceptor desensitization. To investigate the capacity of activated PKC to regulate homologous desensitization, we incubated the smooth muscle strips with the combination of both 1 microM PMA and 1 microM fenoterol. This combined treatment synergistically decreased the isoprenaline-induced maximal relaxation, as compared to the individual effects of PMA and fenoterol alone, indicating a common pathway for heterologous and homologous desensitization. Moreover, the specific PKC-inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl) maleimide (GF 109203X) markedly increased the potency and E(max) of isoprenaline for all conditions used, including control conditions, and the synergistic effects of PMA and fenoterol were completely prevented. In conclusion, the present study demonstrates that homologous desensitization of the beta(2)-adrenergic receptor can be enhanced by PKC activation. For the first time we have provided evidence that this concept is functionally operative in airway smooth muscle, and it may explain the reduced bronchodilator response to beta(2)-adrenoceptor agonists in patients with asthma during a severe exacerbation. | ACTIVATOR |
| Protein kinase C potentiates homologous desensitization of the beta2-adrenoceptor in bovine tracheal smooth muscle. Preincubation (30 min) of bovine tracheal smooth muscle with various concentrations (0.1, 1 and 10 microM) of fenoterol decreased isoprenaline-induced maximal relaxation (E(max)) of methacholine-contracted preparations in a concentration dependent fashion, indicating desensitization of the beta(2)-adrenoceptor. Preincubation with 1 microM of the protein kinase C (GENE) activator CHEMICAL (PMA) caused a small but significant decrease in isoprenaline-induced E(max), indicating activated PKC-mediated heterologous beta(2)-adrenoceptor desensitization. To investigate the capacity of activated GENE to regulate homologous desensitization, we incubated the smooth muscle strips with the combination of both 1 microM PMA and 1 microM fenoterol. This combined treatment synergistically decreased the isoprenaline-induced maximal relaxation, as compared to the individual effects of PMA and fenoterol alone, indicating a common pathway for heterologous and homologous desensitization. Moreover, the specific PKC-inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl) maleimide (GF 109203X) markedly increased the potency and E(max) of isoprenaline for all conditions used, including control conditions, and the synergistic effects of PMA and fenoterol were completely prevented. In conclusion, the present study demonstrates that homologous desensitization of the beta(2)-adrenergic receptor can be enhanced by GENE activation. For the first time we have provided evidence that this concept is functionally operative in airway smooth muscle, and it may explain the reduced bronchodilator response to beta(2)-adrenoceptor agonists in patients with asthma during a severe exacerbation. | ACTIVATOR |
| Protein kinase C potentiates homologous desensitization of the beta2-adrenoceptor in bovine tracheal smooth muscle. Preincubation (30 min) of bovine tracheal smooth muscle with various concentrations (0.1, 1 and 10 microM) of fenoterol decreased isoprenaline-induced maximal relaxation (E(max)) of methacholine-contracted preparations in a concentration dependent fashion, indicating desensitization of the GENE. Preincubation with 1 microM of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (CHEMICAL) caused a small but significant decrease in isoprenaline-induced E(max), indicating activated PKC-mediated heterologous GENE desensitization. To investigate the capacity of activated PKC to regulate homologous desensitization, we incubated the smooth muscle strips with the combination of both 1 microM CHEMICAL and 1 microM fenoterol. This combined treatment synergistically decreased the isoprenaline-induced maximal relaxation, as compared to the individual effects of CHEMICAL and fenoterol alone, indicating a common pathway for heterologous and homologous desensitization. Moreover, the specific PKC-inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl) maleimide (GF 109203X) markedly increased the potency and E(max) of isoprenaline for all conditions used, including control conditions, and the synergistic effects of CHEMICAL and fenoterol were completely prevented. In conclusion, the present study demonstrates that homologous desensitization of the beta(2)-adrenergic receptor can be enhanced by PKC activation. For the first time we have provided evidence that this concept is functionally operative in airway smooth muscle, and it may explain the reduced bronchodilator response to GENE agonists in patients with asthma during a severe exacerbation. | REGULATOR |
| Protein kinase C potentiates homologous desensitization of the beta2-adrenoceptor in bovine tracheal smooth muscle. Preincubation (30 min) of bovine tracheal smooth muscle with various concentrations (0.1, 1 and 10 microM) of CHEMICAL decreased isoprenaline-induced maximal relaxation (E(max)) of methacholine-contracted preparations in a concentration dependent fashion, indicating desensitization of the GENE. Preincubation with 1 microM of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) caused a small but significant decrease in isoprenaline-induced E(max), indicating activated PKC-mediated heterologous GENE desensitization. To investigate the capacity of activated PKC to regulate homologous desensitization, we incubated the smooth muscle strips with the combination of both 1 microM PMA and 1 microM CHEMICAL. This combined treatment synergistically decreased the isoprenaline-induced maximal relaxation, as compared to the individual effects of PMA and CHEMICAL alone, indicating a common pathway for heterologous and homologous desensitization. Moreover, the specific PKC-inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl) maleimide (GF 109203X) markedly increased the potency and E(max) of isoprenaline for all conditions used, including control conditions, and the synergistic effects of PMA and CHEMICAL were completely prevented. In conclusion, the present study demonstrates that homologous desensitization of the beta(2)-adrenergic receptor can be enhanced by PKC activation. For the first time we have provided evidence that this concept is functionally operative in airway smooth muscle, and it may explain the reduced bronchodilator response to GENE agonists in patients with asthma during a severe exacerbation. | REGULATOR |
| Protein kinase C potentiates homologous desensitization of the beta2-adrenoceptor in bovine tracheal smooth muscle. Preincubation (30 min) of bovine tracheal smooth muscle with various concentrations (0.1, 1 and 10 microM) of fenoterol decreased isoprenaline-induced maximal relaxation (E(max)) of methacholine-contracted preparations in a concentration dependent fashion, indicating desensitization of the GENE. Preincubation with 1 microM of the protein kinase C (PKC) activator CHEMICAL (PMA) caused a small but significant decrease in isoprenaline-induced E(max), indicating activated PKC-mediated heterologous GENE desensitization. To investigate the capacity of activated PKC to regulate homologous desensitization, we incubated the smooth muscle strips with the combination of both 1 microM PMA and 1 microM fenoterol. This combined treatment synergistically decreased the isoprenaline-induced maximal relaxation, as compared to the individual effects of PMA and fenoterol alone, indicating a common pathway for heterologous and homologous desensitization. Moreover, the specific PKC-inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl) maleimide (GF 109203X) markedly increased the potency and E(max) of isoprenaline for all conditions used, including control conditions, and the synergistic effects of PMA and fenoterol were completely prevented. In conclusion, the present study demonstrates that homologous desensitization of the beta(2)-adrenergic receptor can be enhanced by PKC activation. For the first time we have provided evidence that this concept is functionally operative in airway smooth muscle, and it may explain the reduced bronchodilator response to GENE agonists in patients with asthma during a severe exacerbation. | INHIBITOR |
| Protein kinase C potentiates homologous desensitization of the beta2-adrenoceptor in bovine tracheal smooth muscle. Preincubation (30 min) of bovine tracheal smooth muscle with various concentrations (0.1, 1 and 10 microM) of fenoterol decreased isoprenaline-induced maximal relaxation (E(max)) of methacholine-contracted preparations in a concentration dependent fashion, indicating desensitization of the beta(2)-adrenoceptor. Preincubation with 1 microM of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) caused a small but significant decrease in isoprenaline-induced E(max), indicating activated PKC-mediated heterologous beta(2)-adrenoceptor desensitization. To investigate the capacity of activated GENE to regulate homologous desensitization, we incubated the smooth muscle strips with the combination of both 1 microM PMA and 1 microM fenoterol. This combined treatment synergistically decreased the isoprenaline-induced maximal relaxation, as compared to the individual effects of PMA and fenoterol alone, indicating a common pathway for heterologous and homologous desensitization. Moreover, the specific GENE-inhibitor CHEMICAL (GF 109203X) markedly increased the potency and E(max) of isoprenaline for all conditions used, including control conditions, and the synergistic effects of PMA and fenoterol were completely prevented. In conclusion, the present study demonstrates that homologous desensitization of the beta(2)-adrenergic receptor can be enhanced by GENE activation. For the first time we have provided evidence that this concept is functionally operative in airway smooth muscle, and it may explain the reduced bronchodilator response to beta(2)-adrenoceptor agonists in patients with asthma during a severe exacerbation. | INHIBITOR |
| Protein kinase C potentiates homologous desensitization of the beta2-adrenoceptor in bovine tracheal smooth muscle. Preincubation (30 min) of bovine tracheal smooth muscle with various concentrations (0.1, 1 and 10 microM) of fenoterol decreased isoprenaline-induced maximal relaxation (E(max)) of methacholine-contracted preparations in a concentration dependent fashion, indicating desensitization of the beta(2)-adrenoceptor. Preincubation with 1 microM of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) caused a small but significant decrease in isoprenaline-induced E(max), indicating activated PKC-mediated heterologous beta(2)-adrenoceptor desensitization. To investigate the capacity of activated GENE to regulate homologous desensitization, we incubated the smooth muscle strips with the combination of both 1 microM PMA and 1 microM fenoterol. This combined treatment synergistically decreased the isoprenaline-induced maximal relaxation, as compared to the individual effects of PMA and fenoterol alone, indicating a common pathway for heterologous and homologous desensitization. Moreover, the specific GENE-inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl) maleimide (CHEMICAL) markedly increased the potency and E(max) of isoprenaline for all conditions used, including control conditions, and the synergistic effects of PMA and fenoterol were completely prevented. In conclusion, the present study demonstrates that homologous desensitization of the beta(2)-adrenergic receptor can be enhanced by GENE activation. For the first time we have provided evidence that this concept is functionally operative in airway smooth muscle, and it may explain the reduced bronchodilator response to beta(2)-adrenoceptor agonists in patients with asthma during a severe exacerbation. | INHIBITOR |
| Protein kinase C potentiates homologous desensitization of the beta2-adrenoceptor in bovine tracheal smooth muscle. Preincubation (30 min) of bovine tracheal smooth muscle with various concentrations (0.1, 1 and 10 microM) of fenoterol decreased isoprenaline-induced maximal relaxation (E(max)) of methacholine-contracted preparations in a concentration dependent fashion, indicating desensitization of the GENE. Preincubation with 1 microM of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) caused a small but significant decrease in CHEMICAL-induced E(max), indicating activated PKC-mediated heterologous GENE desensitization. To investigate the capacity of activated PKC to regulate homologous desensitization, we incubated the smooth muscle strips with the combination of both 1 microM PMA and 1 microM fenoterol. This combined treatment synergistically decreased the isoprenaline-induced maximal relaxation, as compared to the individual effects of PMA and fenoterol alone, indicating a common pathway for heterologous and homologous desensitization. Moreover, the specific PKC-inhibitor 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl) maleimide (GF 109203X) markedly increased the potency and E(max) of CHEMICAL for all conditions used, including control conditions, and the synergistic effects of PMA and fenoterol were completely prevented. In conclusion, the present study demonstrates that homologous desensitization of the beta(2)-adrenergic receptor can be enhanced by PKC activation. For the first time we have provided evidence that this concept is functionally operative in airway smooth muscle, and it may explain the reduced bronchodilator response to GENE agonists in patients with asthma during a severe exacerbation. | REGULATOR |
| Overview of monoclonal antibodies and small molecules targeting the epidermal growth factor receptor pathway in colorectal cancer. The epidermal growth factor receptor (EGFR) provides survival signals and is overexpressed in the majority of colorectal cancers. As more is learned about the molecular details of GENE signaling, antibodies can be designed to interfere with specific domains of the GENE molecule. In this review, we analyze preclinical and current clinical data on EGFR-targeting molecules and their potential role in the treatment of colorectal cancer. Cetuximab binds to domain III of GENE and hinders ligand binding. It is now approved by the US Food and Drug Administration for metastatic colorectal cancer treatment. Panitumumab is another widely studied anti-EGFR antibody with similar properties. Bispecific antibodies are modified immunoglobulin molecules containing 2 different binding specificities. These antibodies can redirect the immune response against tumor cells by tethering effector cells such as CD3e-expressing T cells or CD16-expressing natural killer cells and granulocytes to the surface of cancer cells. Tyrosine kinase inhibitors are CHEMICAL-derived, low molecular weight synthetic molecules that can block the intracellular tyrosine kinase domain of several receptors, including GENE, Erb2, and vascular endothelial growth factor receptor, and thereby inhibit ligand-induced receptor phosphorylation and abrogate the biologic effect of GENE signaling. The presence of skin rash and GENE gene amplification have been advanced as possible predictors of clinical effectiveness of targeted anti-EGFR therapies. | INHIBITOR |
| Overview of monoclonal antibodies and small molecules targeting the epidermal growth factor receptor pathway in colorectal cancer. The epidermal growth factor receptor (EGFR) provides survival signals and is overexpressed in the majority of colorectal cancers. As more is learned about the molecular details of EGFR signaling, antibodies can be designed to interfere with specific domains of the EGFR molecule. In this review, we analyze preclinical and current clinical data on EGFR-targeting molecules and their potential role in the treatment of colorectal cancer. Cetuximab binds to domain III of EGFR and hinders ligand binding. It is now approved by the US Food and Drug Administration for metastatic colorectal cancer treatment. Panitumumab is another widely studied anti-EGFR antibody with similar properties. Bispecific antibodies are modified immunoglobulin molecules containing 2 different binding specificities. These antibodies can redirect the immune response against tumor cells by tethering effector cells such as CD3e-expressing T cells or CD16-expressing natural killer cells and granulocytes to the surface of cancer cells. GENE inhibitors are CHEMICAL-derived, low molecular weight synthetic molecules that can block the intracellular tyrosine kinase domain of several receptors, including EGFR, Erb2, and vascular endothelial growth factor receptor, and thereby inhibit ligand-induced receptor phosphorylation and abrogate the biologic effect of EGFR signaling. The presence of skin rash and EGFR gene amplification have been advanced as possible predictors of clinical effectiveness of targeted anti-EGFR therapies. | INHIBITOR |
| Overview of monoclonal antibodies and small molecules targeting the epidermal growth factor receptor pathway in colorectal cancer. The epidermal growth factor receptor (EGFR) provides survival signals and is overexpressed in the majority of colorectal cancers. As more is learned about the molecular details of EGFR signaling, antibodies can be designed to interfere with specific domains of the EGFR molecule. In this review, we analyze preclinical and current clinical data on EGFR-targeting molecules and their potential role in the treatment of colorectal cancer. Cetuximab binds to domain III of EGFR and hinders ligand binding. It is now approved by the US Food and Drug Administration for metastatic colorectal cancer treatment. Panitumumab is another widely studied anti-EGFR antibody with similar properties. Bispecific antibodies are modified immunoglobulin molecules containing 2 different binding specificities. These antibodies can redirect the immune response against tumor cells by tethering effector cells such as CD3e-expressing T cells or CD16-expressing natural killer cells and granulocytes to the surface of cancer cells. Tyrosine kinase inhibitors are CHEMICAL-derived, low molecular weight synthetic molecules that can block the intracellular GENE of several receptors, including EGFR, Erb2, and vascular endothelial growth factor receptor, and thereby inhibit ligand-induced receptor phosphorylation and abrogate the biologic effect of EGFR signaling. The presence of skin rash and EGFR gene amplification have been advanced as possible predictors of clinical effectiveness of targeted anti-EGFR therapies. | INHIBITOR |
| Overview of monoclonal antibodies and small molecules targeting the epidermal growth factor receptor pathway in colorectal cancer. The epidermal growth factor receptor (EGFR) provides survival signals and is overexpressed in the majority of colorectal cancers. As more is learned about the molecular details of EGFR signaling, antibodies can be designed to interfere with specific domains of the EGFR molecule. In this review, we analyze preclinical and current clinical data on EGFR-targeting molecules and their potential role in the treatment of colorectal cancer. Cetuximab binds to domain III of EGFR and hinders ligand binding. It is now approved by the US Food and Drug Administration for metastatic colorectal cancer treatment. Panitumumab is another widely studied anti-EGFR antibody with similar properties. Bispecific antibodies are modified immunoglobulin molecules containing 2 different binding specificities. These antibodies can redirect the immune response against tumor cells by tethering effector cells such as CD3e-expressing T cells or CD16-expressing natural killer cells and granulocytes to the surface of cancer cells. Tyrosine kinase inhibitors are CHEMICAL-derived, low molecular weight synthetic molecules that can block the intracellular tyrosine kinase domain of several receptors, including EGFR, GENE, and vascular endothelial growth factor receptor, and thereby inhibit ligand-induced receptor phosphorylation and abrogate the biologic effect of EGFR signaling. The presence of skin rash and EGFR gene amplification have been advanced as possible predictors of clinical effectiveness of targeted anti-EGFR therapies. | INHIBITOR |
| Overview of monoclonal antibodies and small molecules targeting the epidermal growth factor receptor pathway in colorectal cancer. The epidermal growth factor receptor (EGFR) provides survival signals and is overexpressed in the majority of colorectal cancers. As more is learned about the molecular details of EGFR signaling, antibodies can be designed to interfere with specific domains of the EGFR molecule. In this review, we analyze preclinical and current clinical data on EGFR-targeting molecules and their potential role in the treatment of colorectal cancer. Cetuximab binds to domain III of EGFR and hinders ligand binding. It is now approved by the US Food and Drug Administration for metastatic colorectal cancer treatment. Panitumumab is another widely studied anti-EGFR antibody with similar properties. Bispecific antibodies are modified immunoglobulin molecules containing 2 different binding specificities. These antibodies can redirect the immune response against tumor cells by tethering effector cells such as CD3e-expressing T cells or CD16-expressing natural killer cells and granulocytes to the surface of cancer cells. Tyrosine kinase inhibitors are CHEMICAL-derived, low molecular weight synthetic molecules that can block the intracellular tyrosine kinase domain of several receptors, including EGFR, Erb2, and GENE, and thereby inhibit ligand-induced receptor phosphorylation and abrogate the biologic effect of EGFR signaling. The presence of skin rash and EGFR gene amplification have been advanced as possible predictors of clinical effectiveness of targeted anti-EGFR therapies. | INHIBITOR |
| Isolation and function of the amino acid transporter PAT1 (slc36a1) from rabbit and discrimination between transport via PAT1 and system IMINO in renal brush-border membrane vesicles. Reabsorption of amino acids is an important function of the renal proximal tubule. pH-dependent amino acid transport has been measured previously using rabbit renal brush-border membrane vesicles (BBMV). The purpose of this investigation was to determine whether this pH-dependent uptake represents H(+)/amino acid cotransport via a PAT1-like transport system. The GENE cDNA was isolated (2296bp including both 5' and 3' untranslated regions and poly(A) tail) and the open reading frame codes for a protein of 475 amino acids (92% identity to human PAT1). Rabbit PAT1 mRNA was found in all tissues investigated including kidney. When expressed heterologously in a mammalian cell line, GENE mediates pH-dependent, CHEMICAL-independent uptake of proline, glycine, l-alanine and alpha-(methylamino)isobutyric acid. Proline uptake was maximal at pH 5.0 (K(m) 2.2+/-0.7 mM). A transport system with identical characteristics (ion dependency, substrate specificity) was detected in rabbit renal BBMV where an overshoot was observed in the absence of Na+ but in the presence of an inwardly directed H+ gradient. In the presence of Na+ and under conditions in which PAT1 transport function was suppressed, a second proline uptake system was detected that exhibited functional characteristics similar to those of the IMINO system. The functional characteristics of GENE in either mammalian cells or renal BBMV suggest that PAT1 is the low-affinity transporter of proline, glycine and hydroxyproline believed to be defective in patients with iminoglycinuria. | NO-RELATIONSHIP |
| Isolation and function of the amino acid transporter PAT1 (slc36a1) from rabbit and discrimination between transport via PAT1 and system IMINO in renal brush-border membrane vesicles. Reabsorption of CHEMICAL is an important function of the renal proximal tubule. pH-dependent amino acid transport has been measured previously using rabbit renal brush-border membrane vesicles (BBMV). The purpose of this investigation was to determine whether this pH-dependent uptake represents H(+)/amino acid cotransport via a PAT1-like transport system. The rabbit PAT1 cDNA was isolated (2296bp including both 5' and 3' untranslated regions and poly(A) tail) and the open reading frame codes for a protein of 475 CHEMICAL (92% identity to GENE). Rabbit PAT1 mRNA was found in all tissues investigated including kidney. When expressed heterologously in a mammalian cell line, rabbit PAT1 mediates pH-dependent, Na(+)-independent uptake of proline, glycine, l-alanine and alpha-(methylamino)isobutyric acid. Proline uptake was maximal at pH 5.0 (K(m) 2.2+/-0.7 mM). A transport system with identical characteristics (ion dependency, substrate specificity) was detected in rabbit renal BBMV where an overshoot was observed in the absence of Na+ but in the presence of an inwardly directed H+ gradient. In the presence of Na+ and under conditions in which PAT1 transport function was suppressed, a second proline uptake system was detected that exhibited functional characteristics similar to those of the IMINO system. The functional characteristics of rabbit PAT1 in either mammalian cells or renal BBMV suggest that PAT1 is the low-affinity transporter of proline, glycine and hydroxyproline believed to be defective in patients with iminoglycinuria. | SUBSTRATE |
| Isolation and function of the amino acid transporter PAT1 (slc36a1) from rabbit and discrimination between transport via PAT1 and system IMINO in renal brush-border membrane vesicles. Reabsorption of amino acids is an important function of the renal proximal tubule. pH-dependent amino acid transport has been measured previously using rabbit renal brush-border membrane vesicles (BBMV). The purpose of this investigation was to determine whether this pH-dependent uptake represents H(+)/amino acid cotransport via a PAT1-like transport system. The GENE cDNA was isolated (2296bp including both 5' and 3' untranslated regions and poly(A) tail) and the open reading frame codes for a protein of 475 amino acids (92% identity to human PAT1). Rabbit PAT1 mRNA was found in all tissues investigated including kidney. When expressed heterologously in a mammalian cell line, GENE mediates pH-dependent, Na(+)-independent uptake of CHEMICAL, glycine, l-alanine and alpha-(methylamino)isobutyric acid. CHEMICAL uptake was maximal at pH 5.0 (K(m) 2.2+/-0.7 mM). A transport system with identical characteristics (ion dependency, substrate specificity) was detected in rabbit renal BBMV where an overshoot was observed in the absence of Na+ but in the presence of an inwardly directed H+ gradient. In the presence of Na+ and under conditions in which PAT1 transport function was suppressed, a second CHEMICAL uptake system was detected that exhibited functional characteristics similar to those of the IMINO system. The functional characteristics of GENE in either mammalian cells or renal BBMV suggest that PAT1 is the low-affinity transporter of CHEMICAL, glycine and hydroxyproline believed to be defective in patients with iminoglycinuria. | SUBSTRATE |
| Isolation and function of the amino acid transporter PAT1 (slc36a1) from rabbit and discrimination between transport via PAT1 and system IMINO in renal brush-border membrane vesicles. Reabsorption of amino acids is an important function of the renal proximal tubule. pH-dependent amino acid transport has been measured previously using rabbit renal brush-border membrane vesicles (BBMV). The purpose of this investigation was to determine whether this pH-dependent uptake represents H(+)/amino acid cotransport via a PAT1-like transport system. The GENE cDNA was isolated (2296bp including both 5' and 3' untranslated regions and poly(A) tail) and the open reading frame codes for a protein of 475 amino acids (92% identity to human PAT1). Rabbit PAT1 mRNA was found in all tissues investigated including kidney. When expressed heterologously in a mammalian cell line, GENE mediates pH-dependent, Na(+)-independent uptake of proline, CHEMICAL, l-alanine and alpha-(methylamino)isobutyric acid. Proline uptake was maximal at pH 5.0 (K(m) 2.2+/-0.7 mM). A transport system with identical characteristics (ion dependency, substrate specificity) was detected in rabbit renal BBMV where an overshoot was observed in the absence of Na+ but in the presence of an inwardly directed H+ gradient. In the presence of Na+ and under conditions in which PAT1 transport function was suppressed, a second proline uptake system was detected that exhibited functional characteristics similar to those of the IMINO system. The functional characteristics of GENE in either mammalian cells or renal BBMV suggest that PAT1 is the low-affinity transporter of proline, CHEMICAL and hydroxyproline believed to be defective in patients with iminoglycinuria. | SUBSTRATE |
| Isolation and function of the amino acid transporter PAT1 (slc36a1) from rabbit and discrimination between transport via PAT1 and system IMINO in renal brush-border membrane vesicles. Reabsorption of amino acids is an important function of the renal proximal tubule. pH-dependent amino acid transport has been measured previously using rabbit renal brush-border membrane vesicles (BBMV). The purpose of this investigation was to determine whether this pH-dependent uptake represents H(+)/amino acid cotransport via a PAT1-like transport system. The GENE cDNA was isolated (2296bp including both 5' and 3' untranslated regions and poly(A) tail) and the open reading frame codes for a protein of 475 amino acids (92% identity to human PAT1). Rabbit PAT1 mRNA was found in all tissues investigated including kidney. When expressed heterologously in a mammalian cell line, GENE mediates pH-dependent, Na(+)-independent uptake of proline, glycine, CHEMICAL and alpha-(methylamino)isobutyric acid. Proline uptake was maximal at pH 5.0 (K(m) 2.2+/-0.7 mM). A transport system with identical characteristics (ion dependency, substrate specificity) was detected in rabbit renal BBMV where an overshoot was observed in the absence of Na+ but in the presence of an inwardly directed H+ gradient. In the presence of Na+ and under conditions in which PAT1 transport function was suppressed, a second proline uptake system was detected that exhibited functional characteristics similar to those of the IMINO system. The functional characteristics of GENE in either mammalian cells or renal BBMV suggest that PAT1 is the low-affinity transporter of proline, glycine and hydroxyproline believed to be defective in patients with iminoglycinuria. | SUBSTRATE |
| Isolation and function of the amino acid transporter PAT1 (slc36a1) from rabbit and discrimination between transport via PAT1 and system IMINO in renal brush-border membrane vesicles. Reabsorption of amino acids is an important function of the renal proximal tubule. pH-dependent amino acid transport has been measured previously using rabbit renal brush-border membrane vesicles (BBMV). The purpose of this investigation was to determine whether this pH-dependent uptake represents H(+)/amino acid cotransport via a PAT1-like transport system. The GENE cDNA was isolated (2296bp including both 5' and 3' untranslated regions and poly(A) tail) and the open reading frame codes for a protein of 475 amino acids (92% identity to human PAT1). Rabbit PAT1 mRNA was found in all tissues investigated including kidney. When expressed heterologously in a mammalian cell line, GENE mediates pH-dependent, Na(+)-independent uptake of proline, glycine, l-alanine and CHEMICAL. Proline uptake was maximal at pH 5.0 (K(m) 2.2+/-0.7 mM). A transport system with identical characteristics (ion dependency, substrate specificity) was detected in rabbit renal BBMV where an overshoot was observed in the absence of Na+ but in the presence of an inwardly directed H+ gradient. In the presence of Na+ and under conditions in which PAT1 transport function was suppressed, a second proline uptake system was detected that exhibited functional characteristics similar to those of the IMINO system. The functional characteristics of GENE in either mammalian cells or renal BBMV suggest that PAT1 is the low-affinity transporter of proline, glycine and hydroxyproline believed to be defective in patients with iminoglycinuria. | SUBSTRATE |
| Isolation and function of the amino acid transporter GENE (slc36a1) from rabbit and discrimination between transport via GENE and system IMINO in renal brush-border membrane vesicles. Reabsorption of amino acids is an important function of the renal proximal tubule. pH-dependent amino acid transport has been measured previously using rabbit renal brush-border membrane vesicles (BBMV). The purpose of this investigation was to determine whether this pH-dependent uptake represents H(+)/amino acid cotransport via a PAT1-like transport system. The rabbit GENE cDNA was isolated (2296bp including both 5' and 3' untranslated regions and poly(A) tail) and the open reading frame codes for a protein of 475 amino acids (92% identity to human PAT1). Rabbit GENE mRNA was found in all tissues investigated including kidney. When expressed heterologously in a mammalian cell line, rabbit GENE mediates pH-dependent, Na(+)-independent uptake of CHEMICAL, glycine, l-alanine and alpha-(methylamino)isobutyric acid. CHEMICAL uptake was maximal at pH 5.0 (K(m) 2.2+/-0.7 mM). A transport system with identical characteristics (ion dependency, substrate specificity) was detected in rabbit renal BBMV where an overshoot was observed in the absence of Na+ but in the presence of an inwardly directed H+ gradient. In the presence of Na+ and under conditions in which GENE transport function was suppressed, a second CHEMICAL uptake system was detected that exhibited functional characteristics similar to those of the IMINO system. The functional characteristics of rabbit GENE in either mammalian cells or renal BBMV suggest that GENE is the low-affinity transporter of CHEMICAL, glycine and hydroxyproline believed to be defective in patients with iminoglycinuria. | SUBSTRATE |
| Isolation and function of the amino acid transporter GENE (slc36a1) from rabbit and discrimination between transport via GENE and system IMINO in renal brush-border membrane vesicles. Reabsorption of amino acids is an important function of the renal proximal tubule. pH-dependent amino acid transport has been measured previously using rabbit renal brush-border membrane vesicles (BBMV). The purpose of this investigation was to determine whether this pH-dependent uptake represents H(+)/amino acid cotransport via a PAT1-like transport system. The rabbit GENE cDNA was isolated (2296bp including both 5' and 3' untranslated regions and poly(A) tail) and the open reading frame codes for a protein of 475 amino acids (92% identity to human PAT1). Rabbit GENE mRNA was found in all tissues investigated including kidney. When expressed heterologously in a mammalian cell line, rabbit GENE mediates pH-dependent, Na(+)-independent uptake of proline, CHEMICAL, l-alanine and alpha-(methylamino)isobutyric acid. Proline uptake was maximal at pH 5.0 (K(m) 2.2+/-0.7 mM). A transport system with identical characteristics (ion dependency, substrate specificity) was detected in rabbit renal BBMV where an overshoot was observed in the absence of Na+ but in the presence of an inwardly directed H+ gradient. In the presence of Na+ and under conditions in which GENE transport function was suppressed, a second proline uptake system was detected that exhibited functional characteristics similar to those of the IMINO system. The functional characteristics of rabbit GENE in either mammalian cells or renal BBMV suggest that GENE is the low-affinity transporter of proline, CHEMICAL and hydroxyproline believed to be defective in patients with iminoglycinuria. | SUBSTRATE |
| Isolation and function of the amino acid transporter GENE (slc36a1) from rabbit and discrimination between transport via GENE and system IMINO in renal brush-border membrane vesicles. Reabsorption of amino acids is an important function of the renal proximal tubule. pH-dependent amino acid transport has been measured previously using rabbit renal brush-border membrane vesicles (BBMV). The purpose of this investigation was to determine whether this pH-dependent uptake represents H(+)/amino acid cotransport via a PAT1-like transport system. The rabbit GENE cDNA was isolated (2296bp including both 5' and 3' untranslated regions and poly(A) tail) and the open reading frame codes for a protein of 475 amino acids (92% identity to human PAT1). Rabbit GENE mRNA was found in all tissues investigated including kidney. When expressed heterologously in a mammalian cell line, rabbit GENE mediates pH-dependent, Na(+)-independent uptake of proline, glycine, l-alanine and alpha-(methylamino)isobutyric acid. Proline uptake was maximal at pH 5.0 (K(m) 2.2+/-0.7 mM). A transport system with identical characteristics (ion dependency, substrate specificity) was detected in rabbit renal BBMV where an overshoot was observed in the absence of Na+ but in the presence of an inwardly directed H+ gradient. In the presence of Na+ and under conditions in which GENE transport function was suppressed, a second proline uptake system was detected that exhibited functional characteristics similar to those of the IMINO system. The functional characteristics of rabbit GENE in either mammalian cells or renal BBMV suggest that GENE is the low-affinity transporter of proline, glycine and CHEMICAL believed to be defective in patients with iminoglycinuria. | SUBSTRATE |
| Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade. In this study, antidepressants with selectivity for the noradrenaline transporter (reboxetine and desipramine), or the serotonin transporter (fluoxetine and clomipramine) were examined in terms of their ability to promote an anti-inflammatory cytokine phenotype in human blood. In addition, we examined the ability of trimipramine; a tricyclic antidepressant that is devoid of monoamine reuptake inhibitory properties on cytokine production. Lipopolysaccharide (LPS) was used to stimulate monocyte-derived pro-inflammatory (IL-1beta, TNF-alpha, IL-12) and anti-inflammatory (IL-10) cytokines, whilst concanavalin A (Con A) was used to stimulate T-cell (Th(1): IFN-gamma and Th(2/3): IL-10) cytokines. All of the antidepressants suppressed IFN-gamma production in the 10-50 microM concentration range, irrespective of their preference for serotonin or noradrenaline transporters. This suppression of IFN-gamma production was paralleled by reduced T-cell proliferation, therefore we suggest that the ability of antidepressants to suppress IFN-gamma production may be related to their anti-proliferative properties. The fact that trimipramine also suppressed IFN-gamma production and T-cell proliferation indicates that these immunomodulatory actions of antidepressants are most likely unrelated to inhibition of monoamine reuptake. Interestingly, exposure to a lower concentration (1 microM) of the antidepressants tended to increase T-cell-derived GENE production, with significant effects elicited by the noradrenaline reuptake inhibitors CHEMICAL and desipramine. In contrast to the robust actions of antidepressants on T-cell derived cytokine production, they failed to induce any consistent change in LPS-induced monocyte cytokine production. Overall, our results indicate that IFN-gamma producing T-cells (Th(1) cells) are the major target for the immunomodulatory actions of antidepressants, and provide evidence questioning the relationship between the monoaminergic reuptake properties of antidepressants and their immunomodulatory effects. The potential clinical significance of the anti-inflammatory actions of antidepressants is discussed. | GENE-CHEMICAL |
| Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade. In this study, antidepressants with selectivity for the noradrenaline transporter (reboxetine and desipramine), or the serotonin transporter (fluoxetine and clomipramine) were examined in terms of their ability to promote an anti-inflammatory cytokine phenotype in human blood. In addition, we examined the ability of trimipramine; a tricyclic antidepressant that is devoid of monoamine reuptake inhibitory properties on cytokine production. Lipopolysaccharide (LPS) was used to stimulate monocyte-derived pro-inflammatory (IL-1beta, TNF-alpha, IL-12) and anti-inflammatory (IL-10) cytokines, whilst concanavalin A (Con A) was used to stimulate T-cell (Th(1): IFN-gamma and Th(2/3): IL-10) cytokines. All of the antidepressants suppressed IFN-gamma production in the 10-50 microM concentration range, irrespective of their preference for serotonin or noradrenaline transporters. This suppression of IFN-gamma production was paralleled by reduced T-cell proliferation, therefore we suggest that the ability of antidepressants to suppress IFN-gamma production may be related to their anti-proliferative properties. The fact that trimipramine also suppressed IFN-gamma production and T-cell proliferation indicates that these immunomodulatory actions of antidepressants are most likely unrelated to inhibition of monoamine reuptake. Interestingly, exposure to a lower concentration (1 microM) of the antidepressants tended to increase T-cell-derived GENE production, with significant effects elicited by the noradrenaline reuptake inhibitors reboxetine and CHEMICAL. In contrast to the robust actions of antidepressants on T-cell derived cytokine production, they failed to induce any consistent change in LPS-induced monocyte cytokine production. Overall, our results indicate that IFN-gamma producing T-cells (Th(1) cells) are the major target for the immunomodulatory actions of antidepressants, and provide evidence questioning the relationship between the monoaminergic reuptake properties of antidepressants and their immunomodulatory effects. The potential clinical significance of the anti-inflammatory actions of antidepressants is discussed. | GENE-CHEMICAL |
| Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade. In this study, antidepressants with selectivity for the GENE (CHEMICAL and desipramine), or the serotonin transporter (fluoxetine and clomipramine) were examined in terms of their ability to promote an anti-inflammatory cytokine phenotype in human blood. In addition, we examined the ability of trimipramine; a tricyclic antidepressant that is devoid of monoamine reuptake inhibitory properties on cytokine production. Lipopolysaccharide (LPS) was used to stimulate monocyte-derived pro-inflammatory (IL-1beta, TNF-alpha, IL-12) and anti-inflammatory (IL-10) cytokines, whilst concanavalin A (Con A) was used to stimulate T-cell (Th(1): IFN-gamma and Th(2/3): IL-10) cytokines. All of the antidepressants suppressed IFN-gamma production in the 10-50 microM concentration range, irrespective of their preference for serotonin or noradrenaline transporters. This suppression of IFN-gamma production was paralleled by reduced T-cell proliferation, therefore we suggest that the ability of antidepressants to suppress IFN-gamma production may be related to their anti-proliferative properties. The fact that trimipramine also suppressed IFN-gamma production and T-cell proliferation indicates that these immunomodulatory actions of antidepressants are most likely unrelated to inhibition of monoamine reuptake. Interestingly, exposure to a lower concentration (1 microM) of the antidepressants tended to increase T-cell-derived IL-10 production, with significant effects elicited by the noradrenaline reuptake inhibitors CHEMICAL and desipramine. In contrast to the robust actions of antidepressants on T-cell derived cytokine production, they failed to induce any consistent change in LPS-induced monocyte cytokine production. Overall, our results indicate that IFN-gamma producing T-cells (Th(1) cells) are the major target for the immunomodulatory actions of antidepressants, and provide evidence questioning the relationship between the monoaminergic reuptake properties of antidepressants and their immunomodulatory effects. The potential clinical significance of the anti-inflammatory actions of antidepressants is discussed. | REGULATOR |
| Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade. In this study, antidepressants with selectivity for the GENE (reboxetine and CHEMICAL), or the serotonin transporter (fluoxetine and clomipramine) were examined in terms of their ability to promote an anti-inflammatory cytokine phenotype in human blood. In addition, we examined the ability of trimipramine; a tricyclic antidepressant that is devoid of monoamine reuptake inhibitory properties on cytokine production. Lipopolysaccharide (LPS) was used to stimulate monocyte-derived pro-inflammatory (IL-1beta, TNF-alpha, IL-12) and anti-inflammatory (IL-10) cytokines, whilst concanavalin A (Con A) was used to stimulate T-cell (Th(1): IFN-gamma and Th(2/3): IL-10) cytokines. All of the antidepressants suppressed IFN-gamma production in the 10-50 microM concentration range, irrespective of their preference for serotonin or noradrenaline transporters. This suppression of IFN-gamma production was paralleled by reduced T-cell proliferation, therefore we suggest that the ability of antidepressants to suppress IFN-gamma production may be related to their anti-proliferative properties. The fact that trimipramine also suppressed IFN-gamma production and T-cell proliferation indicates that these immunomodulatory actions of antidepressants are most likely unrelated to inhibition of monoamine reuptake. Interestingly, exposure to a lower concentration (1 microM) of the antidepressants tended to increase T-cell-derived IL-10 production, with significant effects elicited by the noradrenaline reuptake inhibitors reboxetine and CHEMICAL. In contrast to the robust actions of antidepressants on T-cell derived cytokine production, they failed to induce any consistent change in LPS-induced monocyte cytokine production. Overall, our results indicate that IFN-gamma producing T-cells (Th(1) cells) are the major target for the immunomodulatory actions of antidepressants, and provide evidence questioning the relationship between the monoaminergic reuptake properties of antidepressants and their immunomodulatory effects. The potential clinical significance of the anti-inflammatory actions of antidepressants is discussed. | REGULATOR |
| Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade. In this study, antidepressants with selectivity for the noradrenaline transporter (reboxetine and desipramine), or the GENE (CHEMICAL and clomipramine) were examined in terms of their ability to promote an anti-inflammatory cytokine phenotype in human blood. In addition, we examined the ability of trimipramine; a tricyclic antidepressant that is devoid of monoamine reuptake inhibitory properties on cytokine production. Lipopolysaccharide (LPS) was used to stimulate monocyte-derived pro-inflammatory (IL-1beta, TNF-alpha, IL-12) and anti-inflammatory (IL-10) cytokines, whilst concanavalin A (Con A) was used to stimulate T-cell (Th(1): IFN-gamma and Th(2/3): IL-10) cytokines. All of the antidepressants suppressed IFN-gamma production in the 10-50 microM concentration range, irrespective of their preference for serotonin or noradrenaline transporters. This suppression of IFN-gamma production was paralleled by reduced T-cell proliferation, therefore we suggest that the ability of antidepressants to suppress IFN-gamma production may be related to their anti-proliferative properties. The fact that trimipramine also suppressed IFN-gamma production and T-cell proliferation indicates that these immunomodulatory actions of antidepressants are most likely unrelated to inhibition of monoamine reuptake. Interestingly, exposure to a lower concentration (1 microM) of the antidepressants tended to increase T-cell-derived IL-10 production, with significant effects elicited by the noradrenaline reuptake inhibitors reboxetine and desipramine. In contrast to the robust actions of antidepressants on T-cell derived cytokine production, they failed to induce any consistent change in LPS-induced monocyte cytokine production. Overall, our results indicate that IFN-gamma producing T-cells (Th(1) cells) are the major target for the immunomodulatory actions of antidepressants, and provide evidence questioning the relationship between the monoaminergic reuptake properties of antidepressants and their immunomodulatory effects. The potential clinical significance of the anti-inflammatory actions of antidepressants is discussed. | REGULATOR |
| Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade. In this study, antidepressants with selectivity for the noradrenaline transporter (reboxetine and desipramine), or the GENE (fluoxetine and CHEMICAL) were examined in terms of their ability to promote an anti-inflammatory cytokine phenotype in human blood. In addition, we examined the ability of trimipramine; a tricyclic antidepressant that is devoid of monoamine reuptake inhibitory properties on cytokine production. Lipopolysaccharide (LPS) was used to stimulate monocyte-derived pro-inflammatory (IL-1beta, TNF-alpha, IL-12) and anti-inflammatory (IL-10) cytokines, whilst concanavalin A (Con A) was used to stimulate T-cell (Th(1): IFN-gamma and Th(2/3): IL-10) cytokines. All of the antidepressants suppressed IFN-gamma production in the 10-50 microM concentration range, irrespective of their preference for serotonin or noradrenaline transporters. This suppression of IFN-gamma production was paralleled by reduced T-cell proliferation, therefore we suggest that the ability of antidepressants to suppress IFN-gamma production may be related to their anti-proliferative properties. The fact that trimipramine also suppressed IFN-gamma production and T-cell proliferation indicates that these immunomodulatory actions of antidepressants are most likely unrelated to inhibition of monoamine reuptake. Interestingly, exposure to a lower concentration (1 microM) of the antidepressants tended to increase T-cell-derived IL-10 production, with significant effects elicited by the noradrenaline reuptake inhibitors reboxetine and desipramine. In contrast to the robust actions of antidepressants on T-cell derived cytokine production, they failed to induce any consistent change in LPS-induced monocyte cytokine production. Overall, our results indicate that IFN-gamma producing T-cells (Th(1) cells) are the major target for the immunomodulatory actions of antidepressants, and provide evidence questioning the relationship between the monoaminergic reuptake properties of antidepressants and their immunomodulatory effects. The potential clinical significance of the anti-inflammatory actions of antidepressants is discussed. | REGULATOR |
| Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade. In this study, antidepressants with selectivity for the noradrenaline transporter (reboxetine and desipramine), or the serotonin transporter (fluoxetine and clomipramine) were examined in terms of their ability to promote an anti-inflammatory cytokine phenotype in human blood. In addition, we examined the ability of trimipramine; a tricyclic antidepressant that is devoid of monoamine reuptake inhibitory properties on cytokine production. Lipopolysaccharide (LPS) was used to stimulate monocyte-derived pro-inflammatory (IL-1beta, TNF-alpha, IL-12) and anti-inflammatory (IL-10) cytokines, whilst concanavalin A (Con A) was used to stimulate T-cell (Th(1): GENE and Th(2/3): IL-10) cytokines. All of the antidepressants suppressed GENE production in the 10-50 microM concentration range, irrespective of their preference for serotonin or noradrenaline transporters. This suppression of GENE production was paralleled by reduced T-cell proliferation, therefore we suggest that the ability of antidepressants to suppress GENE production may be related to their anti-proliferative properties. The fact that CHEMICAL also suppressed GENE production and T-cell proliferation indicates that these immunomodulatory actions of antidepressants are most likely unrelated to inhibition of monoamine reuptake. Interestingly, exposure to a lower concentration (1 microM) of the antidepressants tended to increase T-cell-derived IL-10 production, with significant effects elicited by the noradrenaline reuptake inhibitors reboxetine and desipramine. In contrast to the robust actions of antidepressants on T-cell derived cytokine production, they failed to induce any consistent change in LPS-induced monocyte cytokine production. Overall, our results indicate that GENE producing T-cells (Th(1) cells) are the major target for the immunomodulatory actions of antidepressants, and provide evidence questioning the relationship between the monoaminergic reuptake properties of antidepressants and their immunomodulatory effects. The potential clinical significance of the anti-inflammatory actions of antidepressants is discussed. | INDIRECT-DOWNREGULATOR |
| Effect of cyproheptadine on serum leptin levels. GENE is a 167 CHEMICAL protein encoded by the obesity gene that is synthesized in adipose tissue and interacts with receptors in the hypothalamus linked to the regulation of appetite and metabolism. It is known to suppress appetite and increase energy expenditure. Cyproheptadine is a piperidine antihistamine that increases appetite through its antiserotonergic effect on 5-HT2 receptors in the brain. Although both leptin and cyproheptadine are effective in controlling appetite, their interaction has not been addressed in clinical studies. This study evaluated serum leptin concentrations in patients who received cyproheptadine to treat a variety of disorders. Sixteen patients aged 7 to 71 years (mean, 26.25 years) were given cyproheptadine 2 to 6 mg/day for a minimum of 7 days. Body weight was measured and blood samples were obtained at baseline and after 1 week of treatment. Serum leptin levels were determined by leptin radioimmunoassay. The mean body weight at baseline (52.59 kg) did not differ significantly from that at 1 week after treatment (52.84 kg; P > .05), but the mean leptin level after 1 week of treatment with cyproheptadine (3.14 ng/mL) was 14.2% higher than that at baseline (2.75 ng/mL; P < .05). This increase may suggest that both leptin and cyproheptadine may affect appetite via similar receptors and that cyproheptadine does not impair leptin activity through these receptors. Further study will be necessary to clarify this relationship. | PART-OF |
| Effect of CHEMICAL on serum GENE levels. GENE is a 167 amino acid protein encoded by the obesity gene that is synthesized in adipose tissue and interacts with receptors in the hypothalamus linked to the regulation of appetite and metabolism. It is known to suppress appetite and increase energy expenditure. CHEMICAL is a piperidine antihistamine that increases appetite through its antiserotonergic effect on 5-HT2 receptors in the brain. Although both GENE and CHEMICAL are effective in controlling appetite, their interaction has not been addressed in clinical studies. This study evaluated serum GENE concentrations in patients who received CHEMICAL to treat a variety of disorders. Sixteen patients aged 7 to 71 years (mean, 26.25 years) were given CHEMICAL 2 to 6 mg/day for a minimum of 7 days. Body weight was measured and blood samples were obtained at baseline and after 1 week of treatment. Serum GENE levels were determined by GENE radioimmunoassay. The mean body weight at baseline (52.59 kg) did not differ significantly from that at 1 week after treatment (52.84 kg; P > .05), but the mean GENE level after 1 week of treatment with CHEMICAL (3.14 ng/mL) was 14.2% higher than that at baseline (2.75 ng/mL; P < .05). This increase may suggest that both GENE and CHEMICAL may affect appetite via similar receptors and that CHEMICAL does not impair GENE activity through these receptors. Further study will be necessary to clarify this relationship. | NO-RELATIONSHIP |
| Effect of cyproheptadine on serum leptin levels. Leptin is a 167 amino acid protein encoded by the obesity gene that is synthesized in adipose tissue and interacts with receptors in the hypothalamus linked to the regulation of appetite and metabolism. It is known to suppress appetite and increase energy expenditure. CHEMICAL is a piperidine antihistamine that increases appetite through its antiserotonergic effect on GENE receptors in the brain. Although both leptin and cyproheptadine are effective in controlling appetite, their interaction has not been addressed in clinical studies. This study evaluated serum leptin concentrations in patients who received cyproheptadine to treat a variety of disorders. Sixteen patients aged 7 to 71 years (mean, 26.25 years) were given cyproheptadine 2 to 6 mg/day for a minimum of 7 days. Body weight was measured and blood samples were obtained at baseline and after 1 week of treatment. Serum leptin levels were determined by leptin radioimmunoassay. The mean body weight at baseline (52.59 kg) did not differ significantly from that at 1 week after treatment (52.84 kg; P > .05), but the mean leptin level after 1 week of treatment with cyproheptadine (3.14 ng/mL) was 14.2% higher than that at baseline (2.75 ng/mL; P < .05). This increase may suggest that both leptin and cyproheptadine may affect appetite via similar receptors and that cyproheptadine does not impair leptin activity through these receptors. Further study will be necessary to clarify this relationship. | REGULATOR |
| Effect of cyproheptadine on serum leptin levels. Leptin is a 167 amino acid protein encoded by the obesity gene that is synthesized in adipose tissue and interacts with receptors in the hypothalamus linked to the regulation of appetite and metabolism. It is known to suppress appetite and increase energy expenditure. Cyproheptadine is a CHEMICAL antihistamine that increases appetite through its antiserotonergic effect on GENE receptors in the brain. Although both leptin and cyproheptadine are effective in controlling appetite, their interaction has not been addressed in clinical studies. This study evaluated serum leptin concentrations in patients who received cyproheptadine to treat a variety of disorders. Sixteen patients aged 7 to 71 years (mean, 26.25 years) were given cyproheptadine 2 to 6 mg/day for a minimum of 7 days. Body weight was measured and blood samples were obtained at baseline and after 1 week of treatment. Serum leptin levels were determined by leptin radioimmunoassay. The mean body weight at baseline (52.59 kg) did not differ significantly from that at 1 week after treatment (52.84 kg; P > .05), but the mean leptin level after 1 week of treatment with cyproheptadine (3.14 ng/mL) was 14.2% higher than that at baseline (2.75 ng/mL; P < .05). This increase may suggest that both leptin and cyproheptadine may affect appetite via similar receptors and that cyproheptadine does not impair leptin activity through these receptors. Further study will be necessary to clarify this relationship. | REGULATOR |
| Effect of cyproheptadine on serum leptin levels. Leptin is a 167 amino acid protein encoded by the obesity gene that is synthesized in adipose tissue and interacts with receptors in the hypothalamus linked to the regulation of appetite and metabolism. It is known to suppress appetite and increase energy expenditure. Cyproheptadine is a piperidine CHEMICAL that increases appetite through its antiserotonergic effect on GENE receptors in the brain. Although both leptin and cyproheptadine are effective in controlling appetite, their interaction has not been addressed in clinical studies. This study evaluated serum leptin concentrations in patients who received cyproheptadine to treat a variety of disorders. Sixteen patients aged 7 to 71 years (mean, 26.25 years) were given cyproheptadine 2 to 6 mg/day for a minimum of 7 days. Body weight was measured and blood samples were obtained at baseline and after 1 week of treatment. Serum leptin levels were determined by leptin radioimmunoassay. The mean body weight at baseline (52.59 kg) did not differ significantly from that at 1 week after treatment (52.84 kg; P > .05), but the mean leptin level after 1 week of treatment with cyproheptadine (3.14 ng/mL) was 14.2% higher than that at baseline (2.75 ng/mL; P < .05). This increase may suggest that both leptin and cyproheptadine may affect appetite via similar receptors and that cyproheptadine does not impair leptin activity through these receptors. Further study will be necessary to clarify this relationship. | REGULATOR |
| Comparison of captopril and enalapril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with GENE inhibitors in high dieted methionine mice. To examine the role of sulfhydryl (-SH) group in improvement of endothelial dysfunction with angiotensin-converting enzyme (ACE) inhibitors in experimental high dose of methionine dieted rats. We compared the effects of Captopril (an GENE inhibitor with -SH group), enalapril (an ACE-inhibitor without -SH group), CHEMICAL (only -SH group not GENE inhibitor) on endothelial dysfunction injured by methionine-induced hyperhomocysteinemia (HHcy) in rats. Male Sprague-Dawley rats were divided randomly into seven groups: control group, L-methionine group, low dose Captopril (15 mg/kg), middle dose Captopril (30 mg/kg), high dose Captopril (45 mg/kg), enalapril (20 mg/kg), CHEMICAL (200 mg/kg); control group were intragastric gavaged by water and others groups were intragastric gavaged by L-methionine and drugs in water one time every day. Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation of aortic rings were examined. Paraoxonase1 (PON1) and GENE activity, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) in serum were analyzed. It was found that a single intragastric gavage by L-methionine resulted in inhibition of endothelium-dependent relaxation, markedly increased the serum level of malondialdehyde and decreased the activity of PON1 and SOD, similarly decreased the level of NO in the serum; but had no effects on endothelium-independent relaxation and angiotensin-converting enzyme activity compared with the control group. Given the treatment with three doses of Captopril (15 approximately 45 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, and eliminated the increased level of malondialdehyde, the decreased level of NO, activity of PON1 and SOD in serum by single intragastric gavaged L-methionine. However, there were some significant differences among Captopril (30 mg/kg or 45 mg/kg), enalapril (20 mg/kg), and CHEMICAL particular in the activity of PON1 and GENE. These results suggested that Captopril can protect the vascular endothelium against the damages induced by L-methionine in rats, and the beneficial effects of Captopril may be related to attenuating the decrease in PON1 activity and NO levels. Furthermore, this protective effect may be concerned with the sulfhydryl group. | INHIBITOR |
| Comparison of captopril and enalapril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with ACE inhibitors in high dieted methionine mice. To examine the role of sulfhydryl (-SH) group in improvement of endothelial dysfunction with GENE (ACE) inhibitors in experimental high dose of methionine dieted rats. We compared the effects of Captopril (an ACE inhibitor with -SH group), enalapril (an ACE-inhibitor without -SH group), N-acetylcysteine (only -SH group not ACE inhibitor) on endothelial dysfunction injured by methionine-induced hyperhomocysteinemia (HHcy) in rats. Male Sprague-Dawley rats were divided randomly into seven groups: control group, CHEMICAL group, low dose Captopril (15 mg/kg), middle dose Captopril (30 mg/kg), high dose Captopril (45 mg/kg), enalapril (20 mg/kg), N-acetylcysteine (200 mg/kg); control group were intragastric gavaged by water and others groups were intragastric gavaged by CHEMICAL and drugs in water one time every day. Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation of aortic rings were examined. Paraoxonase1 (PON1) and ACE activity, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) in serum were analyzed. It was found that a single intragastric gavage by CHEMICAL resulted in inhibition of endothelium-dependent relaxation, markedly increased the serum level of malondialdehyde and decreased the activity of PON1 and SOD, similarly decreased the level of NO in the serum; but had no effects on endothelium-independent relaxation and GENE activity compared with the control group. Given the treatment with three doses of Captopril (15 approximately 45 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, and eliminated the increased level of malondialdehyde, the decreased level of NO, activity of PON1 and SOD in serum by single intragastric gavaged CHEMICAL. However, there were some significant differences among Captopril (30 mg/kg or 45 mg/kg), enalapril (20 mg/kg), and N-acetylcysteine particular in the activity of PON1 and ACE. These results suggested that Captopril can protect the vascular endothelium against the damages induced by CHEMICAL in rats, and the beneficial effects of Captopril may be related to attenuating the decrease in PON1 activity and NO levels. Furthermore, this protective effect may be concerned with the sulfhydryl group. | NO-RELATIONSHIP |
| Comparison of captopril and enalapril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with ACE inhibitors in high dieted methionine mice. To examine the role of sulfhydryl (-SH) group in improvement of endothelial dysfunction with angiotensin-converting enzyme (ACE) inhibitors in experimental high dose of methionine dieted rats. We compared the effects of CHEMICAL (an ACE inhibitor with -SH group), enalapril (an ACE-inhibitor without -SH group), N-acetylcysteine (only -SH group not ACE inhibitor) on endothelial dysfunction injured by methionine-induced hyperhomocysteinemia (HHcy) in rats. Male Sprague-Dawley rats were divided randomly into seven groups: control group, L-methionine group, low dose CHEMICAL (15 mg/kg), middle dose CHEMICAL (30 mg/kg), high dose CHEMICAL (45 mg/kg), enalapril (20 mg/kg), N-acetylcysteine (200 mg/kg); control group were intragastric gavaged by water and others groups were intragastric gavaged by L-methionine and drugs in water one time every day. Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation of aortic rings were examined. Paraoxonase1 (PON1) and ACE activity, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) in serum were analyzed. It was found that a single intragastric gavage by L-methionine resulted in inhibition of endothelium-dependent relaxation, markedly increased the serum level of malondialdehyde and decreased the activity of GENE and SOD, similarly decreased the level of NO in the serum; but had no effects on endothelium-independent relaxation and angiotensin-converting enzyme activity compared with the control group. Given the treatment with three doses of CHEMICAL (15 approximately 45 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, and eliminated the increased level of malondialdehyde, the decreased level of NO, activity of GENE and SOD in serum by single intragastric gavaged L-methionine. However, there were some significant differences among CHEMICAL (30 mg/kg or 45 mg/kg), enalapril (20 mg/kg), and N-acetylcysteine particular in the activity of GENE and ACE. These results suggested that CHEMICAL can protect the vascular endothelium against the damages induced by L-methionine in rats, and the beneficial effects of CHEMICAL may be related to attenuating the decrease in GENE activity and NO levels. Furthermore, this protective effect may be concerned with the sulfhydryl group. | GENE-CHEMICAL |
| Comparison of captopril and enalapril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with GENE inhibitors in high dieted methionine mice. To examine the role of sulfhydryl (-SH) group in improvement of endothelial dysfunction with angiotensin-converting enzyme (ACE) inhibitors in experimental high dose of methionine dieted rats. We compared the effects of CHEMICAL (an GENE inhibitor with -SH group), enalapril (an ACE-inhibitor without -SH group), N-acetylcysteine (only -SH group not GENE inhibitor) on endothelial dysfunction injured by methionine-induced hyperhomocysteinemia (HHcy) in rats. Male Sprague-Dawley rats were divided randomly into seven groups: control group, L-methionine group, low dose CHEMICAL (15 mg/kg), middle dose CHEMICAL (30 mg/kg), high dose CHEMICAL (45 mg/kg), enalapril (20 mg/kg), N-acetylcysteine (200 mg/kg); control group were intragastric gavaged by water and others groups were intragastric gavaged by L-methionine and drugs in water one time every day. Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation of aortic rings were examined. Paraoxonase1 (PON1) and GENE activity, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) in serum were analyzed. It was found that a single intragastric gavage by L-methionine resulted in inhibition of endothelium-dependent relaxation, markedly increased the serum level of malondialdehyde and decreased the activity of PON1 and SOD, similarly decreased the level of NO in the serum; but had no effects on endothelium-independent relaxation and angiotensin-converting enzyme activity compared with the control group. Given the treatment with three doses of CHEMICAL (15 approximately 45 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, and eliminated the increased level of malondialdehyde, the decreased level of NO, activity of PON1 and SOD in serum by single intragastric gavaged L-methionine. However, there were some significant differences among CHEMICAL (30 mg/kg or 45 mg/kg), enalapril (20 mg/kg), and N-acetylcysteine particular in the activity of PON1 and GENE. These results suggested that CHEMICAL can protect the vascular endothelium against the damages induced by L-methionine in rats, and the beneficial effects of CHEMICAL may be related to attenuating the decrease in PON1 activity and NO levels. Furthermore, this protective effect may be concerned with the sulfhydryl group. | INHIBITOR |
| Comparison of captopril and CHEMICAL to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with ACE inhibitors in high dieted methionine mice. To examine the role of sulfhydryl (-SH) group in improvement of endothelial dysfunction with angiotensin-converting enzyme (ACE) inhibitors in experimental high dose of methionine dieted rats. We compared the effects of Captopril (an ACE inhibitor with -SH group), CHEMICAL (an ACE-inhibitor without -SH group), N-acetylcysteine (only -SH group not ACE inhibitor) on endothelial dysfunction injured by methionine-induced hyperhomocysteinemia (HHcy) in rats. Male Sprague-Dawley rats were divided randomly into seven groups: control group, L-methionine group, low dose Captopril (15 mg/kg), middle dose Captopril (30 mg/kg), high dose Captopril (45 mg/kg), CHEMICAL (20 mg/kg), N-acetylcysteine (200 mg/kg); control group were intragastric gavaged by water and others groups were intragastric gavaged by L-methionine and drugs in water one time every day. Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation of aortic rings were examined. Paraoxonase1 (PON1) and ACE activity, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) in serum were analyzed. It was found that a single intragastric gavage by L-methionine resulted in inhibition of endothelium-dependent relaxation, markedly increased the serum level of malondialdehyde and decreased the activity of GENE and SOD, similarly decreased the level of NO in the serum; but had no effects on endothelium-independent relaxation and angiotensin-converting enzyme activity compared with the control group. Given the treatment with three doses of Captopril (15 approximately 45 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, and eliminated the increased level of malondialdehyde, the decreased level of NO, activity of GENE and SOD in serum by single intragastric gavaged L-methionine. However, there were some significant differences among Captopril (30 mg/kg or 45 mg/kg), CHEMICAL (20 mg/kg), and N-acetylcysteine particular in the activity of GENE and ACE. These results suggested that Captopril can protect the vascular endothelium against the damages induced by L-methionine in rats, and the beneficial effects of Captopril may be related to attenuating the decrease in GENE activity and NO levels. Furthermore, this protective effect may be concerned with the sulfhydryl group. | REGULATOR |
| Comparison of captopril and CHEMICAL to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with GENE inhibitors in high dieted methionine mice. To examine the role of sulfhydryl (-SH) group in improvement of endothelial dysfunction with angiotensin-converting enzyme (ACE) inhibitors in experimental high dose of methionine dieted rats. We compared the effects of Captopril (an GENE inhibitor with -SH group), CHEMICAL (an ACE-inhibitor without -SH group), N-acetylcysteine (only -SH group not GENE inhibitor) on endothelial dysfunction injured by methionine-induced hyperhomocysteinemia (HHcy) in rats. Male Sprague-Dawley rats were divided randomly into seven groups: control group, L-methionine group, low dose Captopril (15 mg/kg), middle dose Captopril (30 mg/kg), high dose Captopril (45 mg/kg), CHEMICAL (20 mg/kg), N-acetylcysteine (200 mg/kg); control group were intragastric gavaged by water and others groups were intragastric gavaged by L-methionine and drugs in water one time every day. Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation of aortic rings were examined. Paraoxonase1 (PON1) and GENE activity, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) in serum were analyzed. It was found that a single intragastric gavage by L-methionine resulted in inhibition of endothelium-dependent relaxation, markedly increased the serum level of malondialdehyde and decreased the activity of PON1 and SOD, similarly decreased the level of NO in the serum; but had no effects on endothelium-independent relaxation and angiotensin-converting enzyme activity compared with the control group. Given the treatment with three doses of Captopril (15 approximately 45 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, and eliminated the increased level of malondialdehyde, the decreased level of NO, activity of PON1 and SOD in serum by single intragastric gavaged L-methionine. However, there were some significant differences among Captopril (30 mg/kg or 45 mg/kg), CHEMICAL (20 mg/kg), and N-acetylcysteine particular in the activity of PON1 and GENE. These results suggested that Captopril can protect the vascular endothelium against the damages induced by L-methionine in rats, and the beneficial effects of Captopril may be related to attenuating the decrease in PON1 activity and NO levels. Furthermore, this protective effect may be concerned with the sulfhydryl group. | INHIBITOR |
| Comparison of captopril and enalapril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with ACE inhibitors in high dieted methionine mice. To examine the role of sulfhydryl (-SH) group in improvement of endothelial dysfunction with angiotensin-converting enzyme (ACE) inhibitors in experimental high dose of methionine dieted rats. We compared the effects of Captopril (an ACE inhibitor with -SH group), enalapril (an ACE-inhibitor without -SH group), CHEMICAL (only -SH group not ACE inhibitor) on endothelial dysfunction injured by methionine-induced hyperhomocysteinemia (HHcy) in rats. Male Sprague-Dawley rats were divided randomly into seven groups: control group, L-methionine group, low dose Captopril (15 mg/kg), middle dose Captopril (30 mg/kg), high dose Captopril (45 mg/kg), enalapril (20 mg/kg), CHEMICAL (200 mg/kg); control group were intragastric gavaged by water and others groups were intragastric gavaged by L-methionine and drugs in water one time every day. Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation of aortic rings were examined. Paraoxonase1 (PON1) and ACE activity, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) in serum were analyzed. It was found that a single intragastric gavage by L-methionine resulted in inhibition of endothelium-dependent relaxation, markedly increased the serum level of malondialdehyde and decreased the activity of GENE and SOD, similarly decreased the level of NO in the serum; but had no effects on endothelium-independent relaxation and angiotensin-converting enzyme activity compared with the control group. Given the treatment with three doses of Captopril (15 approximately 45 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, and eliminated the increased level of malondialdehyde, the decreased level of NO, activity of GENE and SOD in serum by single intragastric gavaged L-methionine. However, there were some significant differences among Captopril (30 mg/kg or 45 mg/kg), enalapril (20 mg/kg), and CHEMICAL particular in the activity of GENE and ACE. These results suggested that Captopril can protect the vascular endothelium against the damages induced by L-methionine in rats, and the beneficial effects of Captopril may be related to attenuating the decrease in GENE activity and NO levels. Furthermore, this protective effect may be concerned with the sulfhydryl group. | REGULATOR |
| Comparison of captopril and enalapril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with ACE inhibitors in high dieted methionine mice. To examine the role of sulfhydryl (-SH) group in improvement of endothelial dysfunction with angiotensin-converting enzyme (ACE) inhibitors in experimental high dose of methionine dieted rats. We compared the effects of CHEMICAL (an ACE inhibitor with -SH group), enalapril (an ACE-inhibitor without -SH group), N-acetylcysteine (only -SH group not ACE inhibitor) on endothelial dysfunction injured by methionine-induced hyperhomocysteinemia (HHcy) in rats. Male Sprague-Dawley rats were divided randomly into seven groups: control group, L-methionine group, low dose CHEMICAL (15 mg/kg), middle dose CHEMICAL (30 mg/kg), high dose CHEMICAL (45 mg/kg), enalapril (20 mg/kg), N-acetylcysteine (200 mg/kg); control group were intragastric gavaged by water and others groups were intragastric gavaged by L-methionine and drugs in water one time every day. Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation of aortic rings were examined. Paraoxonase1 (PON1) and ACE activity, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) in serum were analyzed. It was found that a single intragastric gavage by L-methionine resulted in inhibition of endothelium-dependent relaxation, markedly increased the serum level of malondialdehyde and decreased the activity of PON1 and GENE, similarly decreased the level of NO in the serum; but had no effects on endothelium-independent relaxation and angiotensin-converting enzyme activity compared with the control group. Given the treatment with three doses of CHEMICAL (15 approximately 45 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, and eliminated the increased level of malondialdehyde, the decreased level of NO, activity of PON1 and GENE in serum by single intragastric gavaged L-methionine. However, there were some significant differences among CHEMICAL (30 mg/kg or 45 mg/kg), enalapril (20 mg/kg), and N-acetylcysteine particular in the activity of PON1 and ACE. These results suggested that CHEMICAL can protect the vascular endothelium against the damages induced by L-methionine in rats, and the beneficial effects of CHEMICAL may be related to attenuating the decrease in PON1 activity and NO levels. Furthermore, this protective effect may be concerned with the sulfhydryl group. | GENE-CHEMICAL |
| Comparison of captopril and enalapril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with ACE inhibitors in high dieted methionine mice. To examine the role of sulfhydryl (-SH) group in improvement of endothelial dysfunction with angiotensin-converting enzyme (ACE) inhibitors in experimental high dose of methionine dieted rats. We compared the effects of Captopril (an ACE inhibitor with -SH group), enalapril (an ACE-inhibitor without -SH group), N-acetylcysteine (only -SH group not ACE inhibitor) on endothelial dysfunction injured by methionine-induced hyperhomocysteinemia (HHcy) in rats. Male Sprague-Dawley rats were divided randomly into seven groups: control group, CHEMICAL group, low dose Captopril (15 mg/kg), middle dose Captopril (30 mg/kg), high dose Captopril (45 mg/kg), enalapril (20 mg/kg), N-acetylcysteine (200 mg/kg); control group were intragastric gavaged by water and others groups were intragastric gavaged by CHEMICAL and drugs in water one time every day. Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation of aortic rings were examined. Paraoxonase1 (PON1) and ACE activity, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) in serum were analyzed. It was found that a single intragastric gavage by CHEMICAL resulted in inhibition of endothelium-dependent relaxation, markedly increased the serum level of malondialdehyde and decreased the activity of GENE and SOD, similarly decreased the level of NO in the serum; but had no effects on endothelium-independent relaxation and angiotensin-converting enzyme activity compared with the control group. Given the treatment with three doses of Captopril (15 approximately 45 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, and eliminated the increased level of malondialdehyde, the decreased level of NO, activity of GENE and SOD in serum by single intragastric gavaged CHEMICAL. However, there were some significant differences among Captopril (30 mg/kg or 45 mg/kg), enalapril (20 mg/kg), and N-acetylcysteine particular in the activity of GENE and ACE. These results suggested that Captopril can protect the vascular endothelium against the damages induced by CHEMICAL in rats, and the beneficial effects of Captopril may be related to attenuating the decrease in GENE activity and NO levels. Furthermore, this protective effect may be concerned with the sulfhydryl group. | INDIRECT-DOWNREGULATOR |
| Comparison of captopril and enalapril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with GENE inhibitors in high dieted methionine mice. To examine the role of sulfhydryl (-SH) group in improvement of endothelial dysfunction with angiotensin-converting enzyme (ACE) inhibitors in experimental high dose of methionine dieted rats. We compared the effects of Captopril (an GENE inhibitor with -CHEMICAL group), enalapril (an ACE-inhibitor without -SH group), N-acetylcysteine (only -SH group not GENE inhibitor) on endothelial dysfunction injured by methionine-induced hyperhomocysteinemia (HHcy) in rats. Male Sprague-Dawley rats were divided randomly into seven groups: control group, L-methionine group, low dose Captopril (15 mg/kg), middle dose Captopril (30 mg/kg), high dose Captopril (45 mg/kg), enalapril (20 mg/kg), N-acetylcysteine (200 mg/kg); control group were intragastric gavaged by water and others groups were intragastric gavaged by L-methionine and drugs in water one time every day. Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation of aortic rings were examined. Paraoxonase1 (PON1) and GENE activity, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) in serum were analyzed. It was found that a single intragastric gavage by L-methionine resulted in inhibition of endothelium-dependent relaxation, markedly increased the serum level of malondialdehyde and decreased the activity of PON1 and SOD, similarly decreased the level of NO in the serum; but had no effects on endothelium-independent relaxation and angiotensin-converting enzyme activity compared with the control group. Given the treatment with three doses of Captopril (15 approximately 45 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, and eliminated the increased level of malondialdehyde, the decreased level of NO, activity of PON1 and SOD in serum by single intragastric gavaged L-methionine. However, there were some significant differences among Captopril (30 mg/kg or 45 mg/kg), enalapril (20 mg/kg), and N-acetylcysteine particular in the activity of PON1 and GENE. These results suggested that Captopril can protect the vascular endothelium against the damages induced by L-methionine in rats, and the beneficial effects of Captopril may be related to attenuating the decrease in PON1 activity and NO levels. Furthermore, this protective effect may be concerned with the sulfhydryl group. | INHIBITOR |
| Comparison of captopril and enalapril to study the role of the CHEMICAL-group in improvement of endothelial dysfunction with GENE inhibitors in high dieted methionine mice. To examine the role of CHEMICAL (-SH) group in improvement of endothelial dysfunction with angiotensin-converting enzyme (ACE) inhibitors in experimental high dose of methionine dieted rats. We compared the effects of Captopril (an GENE inhibitor with -SH group), enalapril (an ACE-inhibitor without -SH group), N-acetylcysteine (only -SH group not GENE inhibitor) on endothelial dysfunction injured by methionine-induced hyperhomocysteinemia (HHcy) in rats. Male Sprague-Dawley rats were divided randomly into seven groups: control group, L-methionine group, low dose Captopril (15 mg/kg), middle dose Captopril (30 mg/kg), high dose Captopril (45 mg/kg), enalapril (20 mg/kg), N-acetylcysteine (200 mg/kg); control group were intragastric gavaged by water and others groups were intragastric gavaged by L-methionine and drugs in water one time every day. Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation of aortic rings were examined. Paraoxonase1 (PON1) and GENE activity, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) in serum were analyzed. It was found that a single intragastric gavage by L-methionine resulted in inhibition of endothelium-dependent relaxation, markedly increased the serum level of malondialdehyde and decreased the activity of PON1 and SOD, similarly decreased the level of NO in the serum; but had no effects on endothelium-independent relaxation and angiotensin-converting enzyme activity compared with the control group. Given the treatment with three doses of Captopril (15 approximately 45 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, and eliminated the increased level of malondialdehyde, the decreased level of NO, activity of PON1 and SOD in serum by single intragastric gavaged L-methionine. However, there were some significant differences among Captopril (30 mg/kg or 45 mg/kg), enalapril (20 mg/kg), and N-acetylcysteine particular in the activity of PON1 and GENE. These results suggested that Captopril can protect the vascular endothelium against the damages induced by L-methionine in rats, and the beneficial effects of Captopril may be related to attenuating the decrease in PON1 activity and NO levels. Furthermore, this protective effect may be concerned with the CHEMICAL group. | INHIBITOR |
| Comparison of captopril and enalapril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with ACE inhibitors in high dieted methionine mice. To examine the role of sulfhydryl (-SH) group in improvement of endothelial dysfunction with angiotensin-converting enzyme (ACE) inhibitors in experimental high dose of methionine dieted rats. We compared the effects of Captopril (an ACE inhibitor with -SH group), enalapril (an ACE-inhibitor without -SH group), N-acetylcysteine (only -SH group not ACE inhibitor) on endothelial dysfunction injured by methionine-induced hyperhomocysteinemia (HHcy) in rats. Male Sprague-Dawley rats were divided randomly into seven groups: control group, CHEMICAL group, low dose Captopril (15 mg/kg), middle dose Captopril (30 mg/kg), high dose Captopril (45 mg/kg), enalapril (20 mg/kg), N-acetylcysteine (200 mg/kg); control group were intragastric gavaged by water and others groups were intragastric gavaged by CHEMICAL and drugs in water one time every day. Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation of aortic rings were examined. Paraoxonase1 (PON1) and ACE activity, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) in serum were analyzed. It was found that a single intragastric gavage by CHEMICAL resulted in inhibition of endothelium-dependent relaxation, markedly increased the serum level of malondialdehyde and decreased the activity of PON1 and GENE, similarly decreased the level of NO in the serum; but had no effects on endothelium-independent relaxation and angiotensin-converting enzyme activity compared with the control group. Given the treatment with three doses of Captopril (15 approximately 45 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, and eliminated the increased level of malondialdehyde, the decreased level of NO, activity of PON1 and GENE in serum by single intragastric gavaged CHEMICAL. However, there were some significant differences among Captopril (30 mg/kg or 45 mg/kg), enalapril (20 mg/kg), and N-acetylcysteine particular in the activity of PON1 and ACE. These results suggested that Captopril can protect the vascular endothelium against the damages induced by CHEMICAL in rats, and the beneficial effects of Captopril may be related to attenuating the decrease in PON1 activity and NO levels. Furthermore, this protective effect may be concerned with the sulfhydryl group. | INHIBITOR |
| Preclinical and clinical development of the oral multikinase inhibitor CHEMICAL in cancer treatment. Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. CHEMICAL, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile. Further characterization showed that CHEMICAL suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, CHEMICAL demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, GENE, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, CHEMICAL showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral CHEMICAL as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of CHEMICAL in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for CHEMICAL and 0% for placebo. Stable disease was observed in 78% and 55% of patients on CHEMICAL and placebo, respectively. CHEMICAL significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of CHEMICAL by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated. | REGULATOR |
| Preclinical and clinical development of the oral multikinase inhibitor CHEMICAL in cancer treatment. Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. CHEMICAL, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile. Further characterization showed that CHEMICAL suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, CHEMICAL demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, GENE Flt-3, and c-KIT. Preclinically, CHEMICAL showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral CHEMICAL as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of CHEMICAL in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for CHEMICAL and 0% for placebo. Stable disease was observed in 78% and 55% of patients on CHEMICAL and placebo, respectively. CHEMICAL significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of CHEMICAL by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated. | REGULATOR |
| Preclinical and clinical development of the oral multikinase inhibitor CHEMICAL in cancer treatment. Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. CHEMICAL, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile. Further characterization showed that CHEMICAL suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, CHEMICAL demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta GENE, and c-KIT. Preclinically, CHEMICAL showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral CHEMICAL as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of CHEMICAL in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for CHEMICAL and 0% for placebo. Stable disease was observed in 78% and 55% of patients on CHEMICAL and placebo, respectively. CHEMICAL significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of CHEMICAL by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated. | REGULATOR |
| Preclinical and clinical development of the oral multikinase inhibitor CHEMICAL in cancer treatment. Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. CHEMICAL, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile. Further characterization showed that CHEMICAL suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, CHEMICAL demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and GENE. Preclinically, CHEMICAL showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral CHEMICAL as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of CHEMICAL in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for CHEMICAL and 0% for placebo. Stable disease was observed in 78% and 55% of patients on CHEMICAL and placebo, respectively. CHEMICAL significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of CHEMICAL by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated. | REGULATOR |
| Preclinical and clinical development of the oral multikinase inhibitor CHEMICAL in cancer treatment. Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. CHEMICAL, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile. Further characterization showed that CHEMICAL suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, CHEMICAL demonstrated significant activity against several GENE involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, CHEMICAL showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral CHEMICAL as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of CHEMICAL in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for CHEMICAL and 0% for placebo. Stable disease was observed in 78% and 55% of patients on CHEMICAL and placebo, respectively. CHEMICAL significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of CHEMICAL by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated. | REGULATOR |
| Preclinical and clinical development of the oral multikinase inhibitor CHEMICAL in cancer treatment. Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. CHEMICAL, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile. Further characterization showed that CHEMICAL suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, CHEMICAL demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including GENE, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, CHEMICAL showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral CHEMICAL as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of CHEMICAL in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for CHEMICAL and 0% for placebo. Stable disease was observed in 78% and 55% of patients on CHEMICAL and placebo, respectively. CHEMICAL significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of CHEMICAL by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated. | REGULATOR |
| Preclinical and clinical development of the oral multikinase inhibitor CHEMICAL in cancer treatment. Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. CHEMICAL, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile. Further characterization showed that CHEMICAL suppresses both wild-type and GENE mutant B-Raf activity in vitro. In addition, CHEMICAL demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, CHEMICAL showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral CHEMICAL as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of CHEMICAL in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for CHEMICAL and 0% for placebo. Stable disease was observed in 78% and 55% of patients on CHEMICAL and placebo, respectively. CHEMICAL significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of CHEMICAL by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated. | INHIBITOR |
| Preclinical and clinical development of the oral multikinase inhibitor CHEMICAL in cancer treatment. Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant GENE, or elevation of growth factor receptors. CHEMICAL, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile. Further characterization showed that CHEMICAL suppresses both wild-type and V599E mutant GENE activity in vitro. In addition, CHEMICAL demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, CHEMICAL showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral CHEMICAL as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of CHEMICAL in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for CHEMICAL and 0% for placebo. Stable disease was observed in 78% and 55% of patients on CHEMICAL and placebo, respectively. CHEMICAL significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of CHEMICAL by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated. | INHIBITOR |
| Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. CHEMICAL, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of GENE and its favorable kinase selectivity profile. Further characterization showed that sorafenib suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, sorafenib demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, sorafenib showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral sorafenib as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of sorafenib in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for sorafenib and 0% for placebo. Stable disease was observed in 78% and 55% of patients on sorafenib and placebo, respectively. CHEMICAL significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of sorafenib by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated. | INHIBITOR |
| Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. CHEMICAL, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable GENE selectivity profile. Further characterization showed that sorafenib suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, sorafenib demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, sorafenib showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral sorafenib as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of sorafenib in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for sorafenib and 0% for placebo. Stable disease was observed in 78% and 55% of patients on sorafenib and placebo, respectively. CHEMICAL significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of sorafenib by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated. | REGULATOR |
| Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. Sorafenib, which belongs chemically to a class that can be described as CHEMICAL, was selected for further pharmacologic characterization based on potent inhibition of GENE and its favorable kinase selectivity profile. Further characterization showed that sorafenib suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, sorafenib demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, sorafenib showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral sorafenib as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of sorafenib in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for sorafenib and 0% for placebo. Stable disease was observed in 78% and 55% of patients on sorafenib and placebo, respectively. Sorafenib significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of sorafenib by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated. | INHIBITOR |
| Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. Sorafenib, which belongs chemically to a class that can be described as CHEMICAL, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable GENE selectivity profile. Further characterization showed that sorafenib suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, sorafenib demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, sorafenib showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral sorafenib as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of sorafenib in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for sorafenib and 0% for placebo. Stable disease was observed in 78% and 55% of patients on sorafenib and placebo, respectively. Sorafenib significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of sorafenib by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated. | REGULATOR |
| A selective retinoid X receptor agonist CHEMICAL (LGD1069, targretin) inhibits angiogenesis and metastasis in solid tumours. The present study determined the influence of a retinoid X receptor agonist CHEMICAL on angiogenesis and metastasis in solid tumours. In the experimental lung metastasis xenograft models, treatment with CHEMICAL inhibited the development of the lung tumour nodule formation compared to control. In vivo angiogenesis assay utilising gelfoam sponges, CHEMICAL reduced angiogenesis in sponges containing GENE, epidermal growth factor and basic fibroblast growth factor to various extent. To determine the basis of these observations, human breast and non-small-cell lung cancer cells were subjected to migration and invasion assays in the presence of CHEMICAL. Our data showed that CHEMICAL decrease migration and invasiveness of tumour cells in a dose-dependent manner. Furthermore, CHEMICAL inhibited angiogenesis by directly inhibiting human umbilical vein endothelial cell growth and indirectly inhibiting tumour cell-mediated migration of human umbilical vein endothelial cells through Matrigel matrix. Analysis of tumour-conditioned medium indicated that CHEMICAL decreased the secretion of angiogenic factors and matrix metalloproteinases and increased the tissue inhibitor of matrix metalloproteinases. The ability of CHEMICAL to inhibit angiogenesis and metastasis was dependent on activation of its heterodimerisation partner peroxisome proliferator-activated receptor gamma. Collectively, our results suggest a role of CHEMICAL in treatment of angiogenesis and metastasis in solid tumours. | INHIBITOR |
| A selective retinoid X receptor agonist CHEMICAL (LGD1069, targretin) inhibits angiogenesis and metastasis in solid tumours. The present study determined the influence of a retinoid X receptor agonist CHEMICAL on angiogenesis and metastasis in solid tumours. In the experimental lung metastasis xenograft models, treatment with CHEMICAL inhibited the development of the lung tumour nodule formation compared to control. In vivo angiogenesis assay utilising gelfoam sponges, CHEMICAL reduced angiogenesis in sponges containing vascular endothelial growth factor, GENE and basic fibroblast growth factor to various extent. To determine the basis of these observations, human breast and non-small-cell lung cancer cells were subjected to migration and invasion assays in the presence of CHEMICAL. Our data showed that CHEMICAL decrease migration and invasiveness of tumour cells in a dose-dependent manner. Furthermore, CHEMICAL inhibited angiogenesis by directly inhibiting human umbilical vein endothelial cell growth and indirectly inhibiting tumour cell-mediated migration of human umbilical vein endothelial cells through Matrigel matrix. Analysis of tumour-conditioned medium indicated that CHEMICAL decreased the secretion of angiogenic factors and matrix metalloproteinases and increased the tissue inhibitor of matrix metalloproteinases. The ability of CHEMICAL to inhibit angiogenesis and metastasis was dependent on activation of its heterodimerisation partner peroxisome proliferator-activated receptor gamma. Collectively, our results suggest a role of CHEMICAL in treatment of angiogenesis and metastasis in solid tumours. | INHIBITOR |
| A selective retinoid X receptor agonist CHEMICAL (LGD1069, targretin) inhibits angiogenesis and metastasis in solid tumours. The present study determined the influence of a retinoid X receptor agonist CHEMICAL on angiogenesis and metastasis in solid tumours. In the experimental lung metastasis xenograft models, treatment with CHEMICAL inhibited the development of the lung tumour nodule formation compared to control. In vivo angiogenesis assay utilising gelfoam sponges, CHEMICAL reduced angiogenesis in sponges containing vascular endothelial growth factor, epidermal growth factor and basic GENE to various extent. To determine the basis of these observations, human breast and non-small-cell lung cancer cells were subjected to migration and invasion assays in the presence of CHEMICAL. Our data showed that CHEMICAL decrease migration and invasiveness of tumour cells in a dose-dependent manner. Furthermore, CHEMICAL inhibited angiogenesis by directly inhibiting human umbilical vein endothelial cell growth and indirectly inhibiting tumour cell-mediated migration of human umbilical vein endothelial cells through Matrigel matrix. Analysis of tumour-conditioned medium indicated that CHEMICAL decreased the secretion of angiogenic factors and matrix metalloproteinases and increased the tissue inhibitor of matrix metalloproteinases. The ability of CHEMICAL to inhibit angiogenesis and metastasis was dependent on activation of its heterodimerisation partner peroxisome proliferator-activated receptor gamma. Collectively, our results suggest a role of CHEMICAL in treatment of angiogenesis and metastasis in solid tumours. | INHIBITOR |
| A selective retinoid X receptor agonist CHEMICAL (LGD1069, targretin) inhibits angiogenesis and metastasis in solid tumours. The present study determined the influence of a retinoid X receptor agonist CHEMICAL on angiogenesis and metastasis in solid tumours. In the experimental lung metastasis xenograft models, treatment with CHEMICAL inhibited the development of the lung tumour nodule formation compared to control. In vivo angiogenesis assay utilising gelfoam sponges, CHEMICAL reduced angiogenesis in sponges containing vascular endothelial growth factor, epidermal growth factor and basic fibroblast growth factor to various extent. To determine the basis of these observations, human breast and non-small-cell lung cancer cells were subjected to migration and invasion assays in the presence of CHEMICAL. Our data showed that CHEMICAL decrease migration and invasiveness of tumour cells in a dose-dependent manner. Furthermore, CHEMICAL inhibited angiogenesis by directly inhibiting human umbilical vein endothelial cell growth and indirectly inhibiting tumour cell-mediated migration of human umbilical vein endothelial cells through Matrigel matrix. Analysis of tumour-conditioned medium indicated that CHEMICAL decreased the secretion of angiogenic factors and matrix metalloproteinases and increased the tissue inhibitor of matrix metalloproteinases. The ability of CHEMICAL to inhibit angiogenesis and metastasis was dependent on activation of its heterodimerisation partner GENE. Collectively, our results suggest a role of CHEMICAL in treatment of angiogenesis and metastasis in solid tumours. | ACTIVATOR |
| A selective retinoid X receptor agonist CHEMICAL (LGD1069, targretin) inhibits angiogenesis and metastasis in solid tumours. The present study determined the influence of a retinoid X receptor agonist CHEMICAL on angiogenesis and metastasis in solid tumours. In the experimental lung metastasis xenograft models, treatment with CHEMICAL inhibited the development of the lung tumour nodule formation compared to control. In vivo angiogenesis assay utilising gelfoam sponges, CHEMICAL reduced angiogenesis in sponges containing vascular endothelial growth factor, epidermal growth factor and basic fibroblast growth factor to various extent. To determine the basis of these observations, human breast and non-small-cell lung cancer cells were subjected to migration and invasion assays in the presence of CHEMICAL. Our data showed that CHEMICAL decrease migration and invasiveness of tumour cells in a dose-dependent manner. Furthermore, CHEMICAL inhibited angiogenesis by directly inhibiting human umbilical vein endothelial cell growth and indirectly inhibiting tumour cell-mediated migration of human umbilical vein endothelial cells through Matrigel matrix. Analysis of tumour-conditioned medium indicated that CHEMICAL decreased the secretion of angiogenic factors and GENE and increased the tissue inhibitor of GENE. The ability of CHEMICAL to inhibit angiogenesis and metastasis was dependent on activation of its heterodimerisation partner peroxisome proliferator-activated receptor gamma. Collectively, our results suggest a role of CHEMICAL in treatment of angiogenesis and metastasis in solid tumours. | INDIRECT-DOWNREGULATOR |
| A selective GENE agonist CHEMICAL (LGD1069, targretin) inhibits angiogenesis and metastasis in solid tumours. The present study determined the influence of a GENE agonist CHEMICAL on angiogenesis and metastasis in solid tumours. In the experimental lung metastasis xenograft models, treatment with CHEMICAL inhibited the development of the lung tumour nodule formation compared to control. In vivo angiogenesis assay utilising gelfoam sponges, CHEMICAL reduced angiogenesis in sponges containing vascular endothelial growth factor, epidermal growth factor and basic fibroblast growth factor to various extent. To determine the basis of these observations, human breast and non-small-cell lung cancer cells were subjected to migration and invasion assays in the presence of CHEMICAL. Our data showed that CHEMICAL decrease migration and invasiveness of tumour cells in a dose-dependent manner. Furthermore, CHEMICAL inhibited angiogenesis by directly inhibiting human umbilical vein endothelial cell growth and indirectly inhibiting tumour cell-mediated migration of human umbilical vein endothelial cells through Matrigel matrix. Analysis of tumour-conditioned medium indicated that CHEMICAL decreased the secretion of angiogenic factors and matrix metalloproteinases and increased the tissue inhibitor of matrix metalloproteinases. The ability of CHEMICAL to inhibit angiogenesis and metastasis was dependent on activation of its heterodimerisation partner peroxisome proliferator-activated receptor gamma. Collectively, our results suggest a role of CHEMICAL in treatment of angiogenesis and metastasis in solid tumours. | ACTIVATOR |
| A selective GENE agonist bexarotene (CHEMICAL, targretin) inhibits angiogenesis and metastasis in solid tumours. The present study determined the influence of a GENE agonist bexarotene on angiogenesis and metastasis in solid tumours. In the experimental lung metastasis xenograft models, treatment with bexarotene inhibited the development of the lung tumour nodule formation compared to control. In vivo angiogenesis assay utilising gelfoam sponges, bexarotene reduced angiogenesis in sponges containing vascular endothelial growth factor, epidermal growth factor and basic fibroblast growth factor to various extent. To determine the basis of these observations, human breast and non-small-cell lung cancer cells were subjected to migration and invasion assays in the presence of bexarotene. Our data showed that bexarotene decrease migration and invasiveness of tumour cells in a dose-dependent manner. Furthermore, bexarotene inhibited angiogenesis by directly inhibiting human umbilical vein endothelial cell growth and indirectly inhibiting tumour cell-mediated migration of human umbilical vein endothelial cells through Matrigel matrix. Analysis of tumour-conditioned medium indicated that bexarotene decreased the secretion of angiogenic factors and matrix metalloproteinases and increased the tissue inhibitor of matrix metalloproteinases. The ability of bexarotene to inhibit angiogenesis and metastasis was dependent on activation of its heterodimerisation partner peroxisome proliferator-activated receptor gamma. Collectively, our results suggest a role of bexarotene in treatment of angiogenesis and metastasis in solid tumours. | ACTIVATOR |
| A selective GENE agonist bexarotene (LGD1069, CHEMICAL) inhibits angiogenesis and metastasis in solid tumours. The present study determined the influence of a GENE agonist bexarotene on angiogenesis and metastasis in solid tumours. In the experimental lung metastasis xenograft models, treatment with bexarotene inhibited the development of the lung tumour nodule formation compared to control. In vivo angiogenesis assay utilising gelfoam sponges, bexarotene reduced angiogenesis in sponges containing vascular endothelial growth factor, epidermal growth factor and basic fibroblast growth factor to various extent. To determine the basis of these observations, human breast and non-small-cell lung cancer cells were subjected to migration and invasion assays in the presence of bexarotene. Our data showed that bexarotene decrease migration and invasiveness of tumour cells in a dose-dependent manner. Furthermore, bexarotene inhibited angiogenesis by directly inhibiting human umbilical vein endothelial cell growth and indirectly inhibiting tumour cell-mediated migration of human umbilical vein endothelial cells through Matrigel matrix. Analysis of tumour-conditioned medium indicated that bexarotene decreased the secretion of angiogenic factors and matrix metalloproteinases and increased the tissue inhibitor of matrix metalloproteinases. The ability of bexarotene to inhibit angiogenesis and metastasis was dependent on activation of its heterodimerisation partner peroxisome proliferator-activated receptor gamma. Collectively, our results suggest a role of bexarotene in treatment of angiogenesis and metastasis in solid tumours. | ACTIVATOR |
| Intrauterine pressure, ischemia markers, and experienced pain during administration of a CHEMICAL V1a receptor antagonist in spontaneous and vasopressin-induced dysmenorrhea. BACKGROUND: A model to study the effect of CHEMICAL V1a antagonist in dysmenorrhea. METHODS: A double-blind, randomized, placebo-controlled, cross-over trial was performed. Eight patients with primary dysmenorrhea and eight tuballigated, healthy subjects participated on days 1-2 of two consecutive menstruations. At each menstruation a bolus injection of 10 pmol/kg of CHEMICAL was administered before and during infusion of either 300 microg/min of atosiban or placebo. Intrauterine pressure was measured as area under the curve throughout the experiments. Ischemia markers in plasma and pain recorded by a visual analog scale were measured before and after each CHEMICAL injection as well as before and after the start of either atosiban or placebo infusion. RESULTS: CHEMICAL injections elevated area under the curve in both healthy volunteers and dysmenorrhea subjects. The vasopressin-induced rise in area under the curve was lower during atosiban administration than during infusion of placebo in both groups. None of the ischemia markers differed between or within groups at CHEMICAL injections or atosiban/placebo infusions. In subjects with dysmenorrhea the increase in pain following the administration of CHEMICAL was significantly lower during atosiban than during placebo infusion. Healthy volunteers experienced only slight discomfort after the CHEMICAL injections. CONCLUSIONS: Atosiban reduces vasopressin-induced intrauterine pressure in both healthy volunteers and dysmenorrheics, and reported pain in subjects with dysmenorrhea. The ischemia markers are not a useful biomarker index in women with dysmenorrhea. The dysmenorrhea pain evoked by CHEMICAL correlated poorly with area under the curve, which may suggest that the effect is mediated by more than one GENE. We conclude that this model with recordings in healthy women is useful in the evaluation of drug candidates for primary dysmenorrhea. | REGULATOR |
| Intrauterine pressure, ischemia markers, and experienced pain during administration of a GENE V1a receptor antagonist in spontaneous and vasopressin-induced dysmenorrhea. BACKGROUND: A model to study the effect of GENE V1a antagonist in dysmenorrhea. METHODS: A double-blind, randomized, placebo-controlled, cross-over trial was performed. Eight patients with primary dysmenorrhea and eight tuballigated, healthy subjects participated on days 1-2 of two consecutive menstruations. At each menstruation a bolus injection of 10 pmol/kg of GENE was administered before and during infusion of either 300 microg/min of CHEMICAL or placebo. Intrauterine pressure was measured as area under the curve throughout the experiments. Ischemia markers in plasma and pain recorded by a visual analog scale were measured before and after each GENE injection as well as before and after the start of either CHEMICAL or placebo infusion. RESULTS: GENE injections elevated area under the curve in both healthy volunteers and dysmenorrhea subjects. The vasopressin-induced rise in area under the curve was lower during CHEMICAL administration than during infusion of placebo in both groups. None of the ischemia markers differed between or within groups at GENE injections or atosiban/placebo infusions. In subjects with dysmenorrhea the increase in pain following the administration of GENE was significantly lower during CHEMICAL than during placebo infusion. Healthy volunteers experienced only slight discomfort after the GENE injections. CONCLUSIONS: CHEMICAL reduces vasopressin-induced intrauterine pressure in both healthy volunteers and dysmenorrheics, and reported pain in subjects with dysmenorrhea. The ischemia markers are not a useful biomarker index in women with dysmenorrhea. The dysmenorrhea pain evoked by GENE correlated poorly with area under the curve, which may suggest that the effect is mediated by more than one V1a-like receptor. We conclude that this model with recordings in healthy women is useful in the evaluation of drug candidates for primary dysmenorrhea. | GENE-CHEMICAL |
| GENE expression in resectable and unresectable pancreatic cancer: role as predictive or prognostic marker? BACKGROUND AND AIMS: GENE (TS) is an important enzyme for DNA synthesis and the target for CHEMICAL (5-FU). Its expression may determine the outcome of patients with gastrointestinal cancers. We examined the prognostic and predictive value of TS-protein expression in patients with ductal adenocarcinoma of the pancreas. METHODS: TS expression from 131 patients with ductal adenocarcinoma of the pancreas was analyzed by immunohistochemistry in paraffin-embedded primary tumour specimens or biopsies. RESULTS: The median disease-specific survival among all patients (n=131) was 13 months. The invasion depth, the presence of metastases, grading and Union Internationale Contre le Cancer [International Union Against Cancer] (UICC) stage were associated with survival. Among resected patients (n=98), a difference in median survival was seen in the group receiving postoperative adjuvant treatment (21.1 months) compared with the group treated by surgery alone (12.4 months) (p=0.025). Low- and high-TS immunoreactivity was present in 74 (56%) and 56 (43%) of the cancers, respectively. One sample was not evaluable. No difference in median survival was observed among low- and high-TS-expressing tumours. Among patients undergoing resection and receiving postoperative intra-arterial chemotherapy (n=23), a marked trend to a longer median survival was seen for the group with low-TS-expressing tumours compared with the corresponding high-TS group (25.0 vs 16.0 months) (p=0.3834). There was no difference in survival among all palliative treated patients with low- and high-TS-expressing tumours. CONCLUSION: Especially patients undergoing tumour resection with low-TS values seemed to have taken advantage from an intensified postoperative chemotherapeutic protocol. However due to the heterogeneous group of patients in the present report, larger trials of more homogenous patient populations will be necessary to confirm this hypothesis. | REGULATOR |
| Thymidylate synthase expression in resectable and unresectable pancreatic cancer: role as predictive or prognostic marker? BACKGROUND AND AIMS: Thymidylate synthase (GENE) is an important enzyme for DNA synthesis and the target for CHEMICAL (5-FU). Its expression may determine the outcome of patients with gastrointestinal cancers. We examined the prognostic and predictive value of TS-protein expression in patients with ductal adenocarcinoma of the pancreas. METHODS: GENE expression from 131 patients with ductal adenocarcinoma of the pancreas was analyzed by immunohistochemistry in paraffin-embedded primary tumour specimens or biopsies. RESULTS: The median disease-specific survival among all patients (n=131) was 13 months. The invasion depth, the presence of metastases, grading and Union Internationale Contre le Cancer [International Union Against Cancer] (UICC) stage were associated with survival. Among resected patients (n=98), a difference in median survival was seen in the group receiving postoperative adjuvant treatment (21.1 months) compared with the group treated by surgery alone (12.4 months) (p=0.025). Low- and high-TS immunoreactivity was present in 74 (56%) and 56 (43%) of the cancers, respectively. One sample was not evaluable. No difference in median survival was observed among low- and high-TS-expressing tumours. Among patients undergoing resection and receiving postoperative intra-arterial chemotherapy (n=23), a marked trend to a longer median survival was seen for the group with low-TS-expressing tumours compared with the corresponding high-TS group (25.0 vs 16.0 months) (p=0.3834). There was no difference in survival among all palliative treated patients with low- and high-TS-expressing tumours. CONCLUSION: Especially patients undergoing tumour resection with low-TS values seemed to have taken advantage from an intensified postoperative chemotherapeutic protocol. However due to the heterogeneous group of patients in the present report, larger trials of more homogenous patient populations will be necessary to confirm this hypothesis. | REGULATOR |
| GENE expression in resectable and unresectable pancreatic cancer: role as predictive or prognostic marker? BACKGROUND AND AIMS: GENE (TS) is an important enzyme for DNA synthesis and the target for 5-fluorouracil (CHEMICAL). Its expression may determine the outcome of patients with gastrointestinal cancers. We examined the prognostic and predictive value of TS-protein expression in patients with ductal adenocarcinoma of the pancreas. METHODS: TS expression from 131 patients with ductal adenocarcinoma of the pancreas was analyzed by immunohistochemistry in paraffin-embedded primary tumour specimens or biopsies. RESULTS: The median disease-specific survival among all patients (n=131) was 13 months. The invasion depth, the presence of metastases, grading and Union Internationale Contre le Cancer [International Union Against Cancer] (UICC) stage were associated with survival. Among resected patients (n=98), a difference in median survival was seen in the group receiving postoperative adjuvant treatment (21.1 months) compared with the group treated by surgery alone (12.4 months) (p=0.025). Low- and high-TS immunoreactivity was present in 74 (56%) and 56 (43%) of the cancers, respectively. One sample was not evaluable. No difference in median survival was observed among low- and high-TS-expressing tumours. Among patients undergoing resection and receiving postoperative intra-arterial chemotherapy (n=23), a marked trend to a longer median survival was seen for the group with low-TS-expressing tumours compared with the corresponding high-TS group (25.0 vs 16.0 months) (p=0.3834). There was no difference in survival among all palliative treated patients with low- and high-TS-expressing tumours. CONCLUSION: Especially patients undergoing tumour resection with low-TS values seemed to have taken advantage from an intensified postoperative chemotherapeutic protocol. However due to the heterogeneous group of patients in the present report, larger trials of more homogenous patient populations will be necessary to confirm this hypothesis. | REGULATOR |
| Thymidylate synthase expression in resectable and unresectable pancreatic cancer: role as predictive or prognostic marker? BACKGROUND AND AIMS: Thymidylate synthase (GENE) is an important enzyme for DNA synthesis and the target for 5-fluorouracil (CHEMICAL). Its expression may determine the outcome of patients with gastrointestinal cancers. We examined the prognostic and predictive value of TS-protein expression in patients with ductal adenocarcinoma of the pancreas. METHODS: GENE expression from 131 patients with ductal adenocarcinoma of the pancreas was analyzed by immunohistochemistry in paraffin-embedded primary tumour specimens or biopsies. RESULTS: The median disease-specific survival among all patients (n=131) was 13 months. The invasion depth, the presence of metastases, grading and Union Internationale Contre le Cancer [International Union Against Cancer] (UICC) stage were associated with survival. Among resected patients (n=98), a difference in median survival was seen in the group receiving postoperative adjuvant treatment (21.1 months) compared with the group treated by surgery alone (12.4 months) (p=0.025). Low- and high-TS immunoreactivity was present in 74 (56%) and 56 (43%) of the cancers, respectively. One sample was not evaluable. No difference in median survival was observed among low- and high-TS-expressing tumours. Among patients undergoing resection and receiving postoperative intra-arterial chemotherapy (n=23), a marked trend to a longer median survival was seen for the group with low-TS-expressing tumours compared with the corresponding high-TS group (25.0 vs 16.0 months) (p=0.3834). There was no difference in survival among all palliative treated patients with low- and high-TS-expressing tumours. CONCLUSION: Especially patients undergoing tumour resection with low-TS values seemed to have taken advantage from an intensified postoperative chemotherapeutic protocol. However due to the heterogeneous group of patients in the present report, larger trials of more homogenous patient populations will be necessary to confirm this hypothesis. | REGULATOR |
| Enzymatic and biochemical properties of a novel human serine dehydratase isoform. A cDNA clone similar to human serine dehydratase (SDH) is deposited in the GenBank/EMBL databases, but its structural and functional bases remain unknown. Despite the occurrence of mRNA, the expected protein level was found to be low in cultured cells. To learn about physicochemical properties of the protein, we expressed the cDNA in Escherichia coli, and compared the expressed protein with that of a hepatic GENE. The purified protein showed l-serine and l-threonine dehydratase activity, demonstrating to be an isoform of GENE. However, their Km and Vmax constants were different in a range of two-order. Removal of Pro128 from the hepatic GENE consisting of 328 residues, which is missing in the corresponding position of the isoform consisting of 329 residues, significantly changed the Michaelis constants and Kd value for pyridoxal 5'-phosphate, whereas addition of a CHEMICAL residue to the isoform was without effect. These findings suggest the difference in the structures of the active sites of the two enzymes. Another striking feature was that the expressed level of the isoform in E. coli was 7-fold lower than that of the hepatic GENE. Substitution of Val for Leu287 in the isoform dramatically increased the protein level. The high yield of the mutated isoform was also confirmed by the in vitro transcription and translation experiment. The poor expression of the isoform could be explained by the more stable secondary structure of the mRNA than that of the hepatic GENE mRNA. The present findings may provide a clue as to why the protein level in cultured cells is low. | PART-OF |
| Enzymatic and biochemical properties of a novel human serine dehydratase isoform. A cDNA clone similar to human serine dehydratase (SDH) is deposited in the GenBank/EMBL databases, but its structural and functional bases remain unknown. Despite the occurrence of mRNA, the expected protein level was found to be low in cultured cells. To learn about physicochemical properties of the protein, we expressed the cDNA in Escherichia coli, and compared the expressed protein with that of a hepatic GENE. The purified protein showed l-serine and l-threonine dehydratase activity, demonstrating to be an isoform of GENE. However, their Km and Vmax constants were different in a range of two-order. Removal of Pro128 from the hepatic GENE consisting of 328 residues, which is missing in the corresponding position of the isoform consisting of 329 residues, significantly changed the Michaelis constants and Kd value for CHEMICAL, whereas addition of a proline residue to the isoform was without effect. These findings suggest the difference in the structures of the active sites of the two enzymes. Another striking feature was that the expressed level of the isoform in E. coli was 7-fold lower than that of the hepatic GENE. Substitution of Val for Leu287 in the isoform dramatically increased the protein level. The high yield of the mutated isoform was also confirmed by the in vitro transcription and translation experiment. The poor expression of the isoform could be explained by the more stable secondary structure of the mRNA than that of the hepatic GENE mRNA. The present findings may provide a clue as to why the protein level in cultured cells is low. | DIRECT-REGULATOR |
| Multiple enzyme inhibitions by histamine H3 receptor antagonists as potential procognitive agents. Novel highly affine histamine H3 receptor ligands with additional inhibitory effects on the main histamine metabolizing enzyme in the brain, N-methyltransferase, chemically show structural elements of the GENE inhibitor CHEMICAL. H3 receptor antagonism, inhibition of metabolisation of neuronal histamine as well as inhibition of hydrolysis of acetylcholine are each one believed to improve reduced cognitive functions, which is useful for symptomatic treatment of Alzheimer's disease. Some of the new compounds proved in a slightly modified colorimetric Ellmann's assay to be potent inhibitors of GENE and of butyrylcholinesterase which is another catalytic enzyme hydrolysing acetylcholine. Some compounds with (sub)nanomolar activities on the histamine-related targets are also active in the nanomolar concentration range on both cholinesterase targets being 5- to 40-times more potent than CHEMICAL. Preliminary structure-activity relationships could already be drawn from the small number of compounds. The compounds acting as hybrid drugs simultaneously on four different targets to enhance cognitive functions via different pathways are promising lead structures for a new approach in the treatment of Alzheimer's disease. | INHIBITOR |
| Multiple enzyme inhibitions by histamine H3 receptor antagonists as potential procognitive agents. Novel highly affine histamine H3 receptor ligands with additional inhibitory effects on the main histamine metabolizing enzyme in the brain, N-methyltransferase, chemically show structural elements of the GENE inhibitor tacrine. H3 receptor antagonism, inhibition of metabolisation of neuronal histamine as well as inhibition of hydrolysis of CHEMICAL are each one believed to improve reduced cognitive functions, which is useful for symptomatic treatment of Alzheimer's disease. Some of the new compounds proved in a slightly modified colorimetric Ellmann's assay to be potent inhibitors of GENE and of butyrylcholinesterase which is another catalytic enzyme hydrolysing CHEMICAL. Some compounds with (sub)nanomolar activities on the histamine-related targets are also active in the nanomolar concentration range on both cholinesterase targets being 5- to 40-times more potent than tacrine. Preliminary structure-activity relationships could already be drawn from the small number of compounds. The compounds acting as hybrid drugs simultaneously on four different targets to enhance cognitive functions via different pathways are promising lead structures for a new approach in the treatment of Alzheimer's disease. | SUBSTRATE |
| Multiple enzyme inhibitions by histamine H3 receptor antagonists as potential procognitive agents. Novel highly affine histamine H3 receptor ligands with additional inhibitory effects on the main histamine metabolizing enzyme in the brain, N-methyltransferase, chemically show structural elements of the acetylcholinesterase inhibitor tacrine. H3 receptor antagonism, inhibition of metabolisation of neuronal histamine as well as inhibition of hydrolysis of CHEMICAL are each one believed to improve reduced cognitive functions, which is useful for symptomatic treatment of Alzheimer's disease. Some of the new compounds proved in a slightly modified colorimetric Ellmann's assay to be potent inhibitors of acetylcholinesterase and of GENE which is another catalytic enzyme hydrolysing CHEMICAL. Some compounds with (sub)nanomolar activities on the histamine-related targets are also active in the nanomolar concentration range on both cholinesterase targets being 5- to 40-times more potent than tacrine. Preliminary structure-activity relationships could already be drawn from the small number of compounds. The compounds acting as hybrid drugs simultaneously on four different targets to enhance cognitive functions via different pathways are promising lead structures for a new approach in the treatment of Alzheimer's disease. | SUBSTRATE |
| Multiple enzyme inhibitions by CHEMICAL H3 receptor antagonists as potential procognitive agents. Novel highly affine CHEMICAL H3 receptor ligands with additional inhibitory effects on the main CHEMICAL metabolizing enzyme in the brain, GENE, chemically show structural elements of the acetylcholinesterase inhibitor tacrine. H3 receptor antagonism, inhibition of metabolisation of neuronal CHEMICAL as well as inhibition of hydrolysis of acetylcholine are each one believed to improve reduced cognitive functions, which is useful for symptomatic treatment of Alzheimer's disease. Some of the new compounds proved in a slightly modified colorimetric Ellmann's assay to be potent inhibitors of acetylcholinesterase and of butyrylcholinesterase which is another catalytic enzyme hydrolysing acetylcholine. Some compounds with (sub)nanomolar activities on the histamine-related targets are also active in the nanomolar concentration range on both cholinesterase targets being 5- to 40-times more potent than tacrine. Preliminary structure-activity relationships could already be drawn from the small number of compounds. The compounds acting as hybrid drugs simultaneously on four different targets to enhance cognitive functions via different pathways are promising lead structures for a new approach in the treatment of Alzheimer's disease. | SUBSTRATE |
| Chemotherapy and targeted therapy combinations in advanced melanoma. For three decades, clinical trials with chemotherapy in melanoma have failed to show superiority of any one regimen over another. Dacarbazine remains the only "standard" agent. With response rates of <10% and median progression-free survival of 2 months or less in contemporary trials, there is a need to improve systemic therapy. Combination chemotherapy is associated with higher response rates than single-agent therapy but this has not translated into improved survival. An increasing number of potential therapeutic targets have been identified. For some, pharmacologic inhibitors are available, including CHEMICAL for GENE, farnesyltransferase inhibitors for NRAS, PD-0325901 for mitogen-activated protein kinase/extracellular signal-regulated kinase kinase, rapamycin analogues for mammalian target of rapamycin, and agents that inhibit either vascular endothelial growth factor or its receptors. Several multitargeted kinase inhibitors have potency against the fibroblast growth factor receptor, c-kit, and platelet-derived growth factor receptor. Small-molecule inhibitors of c-met and Akt are in preclinical development. Another class of agents indirectly affect aberrant signaling, including inhibitors of chaperones and proteasomes. Several targeted agents seem to enhance the cytotoxicity of chemotherapy in preclinical models. The mechanism by which signaling inhibition might synergize with chemotherapy requires more study so that rational combinations move forward. Very few targeted agents have been studied rigorously in this fashion. | INHIBITOR |
| Chemotherapy and targeted therapy combinations in advanced melanoma. For three decades, clinical trials with chemotherapy in melanoma have failed to show superiority of any one regimen over another. Dacarbazine remains the only "standard" agent. With response rates of <10% and median progression-free survival of 2 months or less in contemporary trials, there is a need to improve systemic therapy. Combination chemotherapy is associated with higher response rates than single-agent therapy but this has not translated into improved survival. An increasing number of potential therapeutic targets have been identified. For some, pharmacologic inhibitors are available, including sorafenib for BRAF, farnesyltransferase inhibitors for NRAS, CHEMICAL for GENE/extracellular signal-regulated kinase kinase, rapamycin analogues for mammalian target of rapamycin, and agents that inhibit either vascular endothelial growth factor or its receptors. Several multitargeted kinase inhibitors have potency against the fibroblast growth factor receptor, c-kit, and platelet-derived growth factor receptor. Small-molecule inhibitors of c-met and Akt are in preclinical development. Another class of agents indirectly affect aberrant signaling, including inhibitors of chaperones and proteasomes. Several targeted agents seem to enhance the cytotoxicity of chemotherapy in preclinical models. The mechanism by which signaling inhibition might synergize with chemotherapy requires more study so that rational combinations move forward. Very few targeted agents have been studied rigorously in this fashion. | INHIBITOR |
| Chemotherapy and targeted therapy combinations in advanced melanoma. For three decades, clinical trials with chemotherapy in melanoma have failed to show superiority of any one regimen over another. Dacarbazine remains the only "standard" agent. With response rates of <10% and median progression-free survival of 2 months or less in contemporary trials, there is a need to improve systemic therapy. Combination chemotherapy is associated with higher response rates than single-agent therapy but this has not translated into improved survival. An increasing number of potential therapeutic targets have been identified. For some, pharmacologic inhibitors are available, including sorafenib for BRAF, farnesyltransferase inhibitors for NRAS, CHEMICAL for mitogen-activated protein kinase/GENE, rapamycin analogues for mammalian target of rapamycin, and agents that inhibit either vascular endothelial growth factor or its receptors. Several multitargeted kinase inhibitors have potency against the fibroblast growth factor receptor, c-kit, and platelet-derived growth factor receptor. Small-molecule inhibitors of c-met and Akt are in preclinical development. Another class of agents indirectly affect aberrant signaling, including inhibitors of chaperones and proteasomes. Several targeted agents seem to enhance the cytotoxicity of chemotherapy in preclinical models. The mechanism by which signaling inhibition might synergize with chemotherapy requires more study so that rational combinations move forward. Very few targeted agents have been studied rigorously in this fashion. | INHIBITOR |
| Chemotherapy and targeted therapy combinations in advanced melanoma. For three decades, clinical trials with chemotherapy in melanoma have failed to show superiority of any one regimen over another. Dacarbazine remains the only "standard" agent. With response rates of <10% and median progression-free survival of 2 months or less in contemporary trials, there is a need to improve systemic therapy. Combination chemotherapy is associated with higher response rates than single-agent therapy but this has not translated into improved survival. An increasing number of potential therapeutic targets have been identified. For some, pharmacologic inhibitors are available, including sorafenib for BRAF, farnesyltransferase inhibitors for NRAS, PD-0325901 for mitogen-activated protein kinase/extracellular signal-regulated kinase kinase, CHEMICAL analogues for GENE, and agents that inhibit either vascular endothelial growth factor or its receptors. Several multitargeted kinase inhibitors have potency against the fibroblast growth factor receptor, c-kit, and platelet-derived growth factor receptor. Small-molecule inhibitors of c-met and Akt are in preclinical development. Another class of agents indirectly affect aberrant signaling, including inhibitors of chaperones and proteasomes. Several targeted agents seem to enhance the cytotoxicity of chemotherapy in preclinical models. The mechanism by which signaling inhibition might synergize with chemotherapy requires more study so that rational combinations move forward. Very few targeted agents have been studied rigorously in this fashion. | INHIBITOR |
| Lipid specific activation of the murine P4-ATPase Atp8a1 (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified Atp8a1 is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the GENE, Atp8a1 is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the CHEMICAL stereoisomer. Both flippase and Atp8a1 activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase. Activation of Atp8a1 is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate Atp8a1. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak Atp8a1 activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating Atp8a1 activity. These results indicate that the ATPase activity of the secretory granule Atp8a1 is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | NO-RELATIONSHIP |
| Lipid specific activation of the murine P4-ATPase GENE (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified GENE is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, GENE is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the CHEMICAL stereoisomer. Both flippase and GENE activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase. Activation of GENE is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate GENE. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak GENE activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating GENE activity. These results indicate that the ATPase activity of the secretory granule GENE is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | NO-RELATIONSHIP |
| Lipid specific activation of the murine P4-ATPase GENE (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified GENE is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, GENE is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer. Both flippase and GENE activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase. Activation of GENE is also reduced by these modifications; CHEMICAL, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate GENE. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak GENE activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating GENE activity. These results indicate that the ATPase activity of the secretory granule GENE is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | NO-RELATIONSHIP |
| Lipid specific activation of the murine P4-ATPase GENE (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified GENE is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, GENE is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer. Both flippase and GENE activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase. Activation of GENE is also reduced by these modifications; phosphatidylserine-O-methyl ester, CHEMICAL, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate GENE. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak GENE activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating GENE activity. These results indicate that the ATPase activity of the secretory granule GENE is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | NO-RELATIONSHIP |
| Lipid specific activation of the murine P4-ATPase GENE (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified GENE is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, GENE is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer. Both flippase and GENE activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase. Activation of GENE is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, CHEMICAL, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate GENE. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak GENE activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating GENE activity. These results indicate that the ATPase activity of the secretory granule GENE is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | NO-RELATIONSHIP |
| Lipid specific activation of the murine P4-ATPase GENE (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified GENE is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, GENE is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer. Both flippase and GENE activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase. Activation of GENE is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and CHEMICAL, which are not transported by the plasma membrane flippase, do not activate GENE. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak GENE activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating GENE activity. These results indicate that the ATPase activity of the secretory granule GENE is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | NO-RELATIONSHIP |
| Lipid specific activation of the murine P4-ATPase GENE (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified GENE is inactive in detergent micelles or in micelles containing CHEMICAL, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, GENE is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer. Both flippase and GENE activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase. Activation of GENE is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate GENE. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak GENE activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating GENE activity. These results indicate that the ATPase activity of the secretory granule GENE is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | NO-RELATIONSHIP |
| Lipid specific activation of the murine P4-ATPase GENE (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified GENE is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, GENE is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer. Both flippase and GENE activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase. Activation of GENE is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate GENE. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak GENE activators. However, CHEMICAL, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating GENE activity. These results indicate that the ATPase activity of the secretory granule GENE is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | NO-RELATIONSHIP |
| Lipid specific activation of the murine P4-ATPase GENE (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified GENE is inactive in detergent micelles or in micelles containing phosphatidylcholine, CHEMICAL, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, GENE is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer. Both flippase and GENE activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase. Activation of GENE is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate GENE. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak GENE activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating GENE activity. These results indicate that the ATPase activity of the secretory granule GENE is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | NO-RELATIONSHIP |
| Lipid specific activation of the murine P4-ATPase GENE (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified GENE is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or CHEMICAL, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, GENE is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer. Both flippase and GENE activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase. Activation of GENE is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate GENE. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak GENE activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating GENE activity. These results indicate that the ATPase activity of the secretory granule GENE is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | NO-RELATIONSHIP |
| Lipid specific activation of the murine P4-ATPase Atp8a1 (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "GENE" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to CHEMICAL, Ca(2+), and modification by sulfhydryl reagents. Although the GENE has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS GENE ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS GENE, a murine homologue of this enzyme was expressed in insect cells and purified. The purified Atp8a1 is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, Atp8a1 is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer. Both GENE and Atp8a1 activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS GENE. Activation of Atp8a1 is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane GENE, do not activate Atp8a1. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak Atp8a1 activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane GENE at a rate equivalent to PS, is incapable of activating Atp8a1 activity. These results indicate that the ATPase activity of the secretory granule Atp8a1 is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and CHEMICAL sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane GENE. | REGULATOR |
| Lipid specific activation of the murine P4-ATPase Atp8a1 (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "GENE" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, CHEMICAL, and modification by sulfhydryl reagents. Although the GENE has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS GENE ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS GENE, a murine homologue of this enzyme was expressed in insect cells and purified. The purified Atp8a1 is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, Atp8a1 is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer. Both GENE and Atp8a1 activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS GENE. Activation of Atp8a1 is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane GENE, do not activate Atp8a1. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak Atp8a1 activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane GENE at a rate equivalent to PS, is incapable of activating Atp8a1 activity. These results indicate that the ATPase activity of the secretory granule Atp8a1 is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane GENE. | REGULATOR |
| Lipid specific activation of the murine P4-ATPase Atp8a1 (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "GENE" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by CHEMICAL reagents. Although the GENE has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS GENE ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS GENE, a murine homologue of this enzyme was expressed in insect cells and purified. The purified Atp8a1 is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, Atp8a1 is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer. Both GENE and Atp8a1 activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS GENE. Activation of Atp8a1 is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane GENE, do not activate Atp8a1. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak Atp8a1 activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane GENE at a rate equivalent to PS, is incapable of activating Atp8a1 activity. These results indicate that the ATPase activity of the secretory granule Atp8a1 is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane GENE. | REGULATOR |
| Lipid specific activation of the murine P4-ATPase Atp8a1 (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified Atp8a1 is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the GENE, Atp8a1 is activated only by the naturally occurring CHEMICAL isomer of PS and not the sn-2,3-glycerol stereoisomer. Both flippase and Atp8a1 activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase. Activation of Atp8a1 is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate Atp8a1. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak Atp8a1 activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating Atp8a1 activity. These results indicate that the ATPase activity of the secretory granule Atp8a1 is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | ACTIVATOR |
| Lipid specific activation of the murine P4-ATPase GENE (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified GENE is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, GENE is activated only by the naturally occurring CHEMICAL isomer of PS and not the sn-2,3-glycerol stereoisomer. Both flippase and GENE activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase. Activation of GENE is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate GENE. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak GENE activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating GENE activity. These results indicate that the ATPase activity of the secretory granule GENE is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | ACTIVATOR |
| Lipid specific activation of the murine P4-ATPase GENE (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified GENE is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, GENE is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer. Both flippase and GENE activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase. Activation of GENE is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate GENE. Weakly translocated lipids (CHEMICAL, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak GENE activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating GENE activity. These results indicate that the ATPase activity of the secretory granule GENE is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | ACTIVATOR |
| Lipid specific activation of the murine P4-ATPase GENE (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified GENE is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, GENE is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer. Both flippase and GENE activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase. Activation of GENE is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate GENE. Weakly translocated lipids (PE, CHEMICAL, and phosphatidylhomoserine) are also weak GENE activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating GENE activity. These results indicate that the ATPase activity of the secretory granule GENE is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | ACTIVATOR |
| Lipid specific activation of the murine P4-ATPase GENE (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified GENE is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, GENE is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer. Both flippase and GENE activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase. Activation of GENE is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate GENE. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and CHEMICAL) are also weak GENE activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating GENE activity. These results indicate that the ATPase activity of the secretory granule GENE is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | ACTIVATOR |
| Lipid specific activation of the murine P4-ATPase Atp8a1 (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports CHEMICAL to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including CHEMICAL and other phospholipids. A candidate CHEMICAL flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of CHEMICAL asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a CHEMICAL flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified Atp8a1 is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by CHEMICAL. The selectivity for CHEMICAL is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane CHEMICAL transporter, Atp8a1 is activated only by the naturally occurring sn-1,2-glycerol isomer of CHEMICAL and not the sn-2,3-glycerol stereoisomer. Both flippase and Atp8a1 activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the CHEMICAL headgroup structure decrease recognition by the plasma membrane CHEMICAL flippase. Activation of Atp8a1 is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate Atp8a1. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak Atp8a1 activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to CHEMICAL, is incapable of activating Atp8a1 activity. These results indicate that the GENE activity of the secretory granule Atp8a1 is activated by phospholipids binding to a specific site whose properties (CHEMICAL selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | DIRECT-REGULATOR |
| Lipid specific activation of the murine P4-ATPase GENE (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports CHEMICAL to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including CHEMICAL and other phospholipids. A candidate CHEMICAL flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of CHEMICAL asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a CHEMICAL flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified GENE is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by CHEMICAL. The selectivity for CHEMICAL is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane CHEMICAL transporter, GENE is activated only by the naturally occurring sn-1,2-glycerol isomer of CHEMICAL and not the sn-2,3-glycerol stereoisomer. Both flippase and GENE activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the CHEMICAL headgroup structure decrease recognition by the plasma membrane CHEMICAL flippase. Activation of GENE is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate GENE. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak GENE activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to CHEMICAL, is incapable of activating GENE activity. These results indicate that the ATPase activity of the secretory granule GENE is activated by phospholipids binding to a specific site whose properties (CHEMICAL selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | DIRECT-REGULATOR |
| Lipid specific activation of the murine P4-ATPase GENE (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified GENE is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by CHEMICAL or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, GENE is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer. Both flippase and GENE activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase. Activation of GENE is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate GENE. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak GENE activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating GENE activity. These results indicate that the ATPase activity of the secretory granule GENE is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | NO-RELATIONSHIP |
| Lipid specific activation of the murine P4-ATPase GENE (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the flippase has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS flippase ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS flippase, a murine homologue of this enzyme was expressed in insect cells and purified. The purified GENE is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or CHEMICAL (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, GENE is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer. Both flippase and GENE activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS flippase. Activation of GENE is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane flippase, do not activate GENE. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak GENE activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane flippase at a rate equivalent to PS, is incapable of activating GENE activity. These results indicate that the ATPase activity of the secretory granule GENE is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane flippase. | ACTIVATOR |
| Lipid specific activation of the murine P4-ATPase Atp8a1 (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "flippase" selectively transports PS to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the GENE has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including PS and other phospholipids. A candidate PS GENE ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of PS asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a PS GENE, a murine homologue of this enzyme was expressed in insect cells and purified. The purified Atp8a1 is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by PS. The selectivity for PS is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane PS transporter, Atp8a1 is activated only by the naturally occurring sn-1,2-glycerol isomer of PS and not the sn-2,3-glycerol stereoisomer. Both GENE and Atp8a1 activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the PS headgroup structure decrease recognition by the plasma membrane PS GENE. Activation of Atp8a1 is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane GENE, do not activate Atp8a1. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak Atp8a1 activators. However, CHEMICAL, which is transported by the plasma membrane GENE at a rate equivalent to PS, is incapable of activating Atp8a1 activity. These results indicate that the ATPase activity of the secretory granule Atp8a1 is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane GENE. | REGULATOR |
| Lipid specific activation of the murine P4-ATPase Atp8a1 (ATPase II). The asymmetric transbilayer distribution of phosphatidylserine (PS) in the mammalian plasma membrane and secretory vesicles is maintained, in part, by an ATP-dependent transporter. This aminophospholipid "GENE" selectively transports CHEMICAL to the cytosolic leaflet of the bilayer and is sensitive to vanadate, Ca(2+), and modification by sulfhydryl reagents. Although the GENE has not been positively identified, a subfamily of P-type ATPases has been proposed to function as transporters of amphipaths, including CHEMICAL and other phospholipids. A candidate CHEMICAL GENE ATP8A1 (ATPase II), originally isolated from bovine secretory vesicles, is a member of this subfamily based on sequence homology to the founding member of the subfamily, the yeast protein Drs2, which has been linked to ribosomal assembly, the formation of Golgi-coated vesicles, and the maintenance of CHEMICAL asymmetry. To determine if ATP8A1 has biochemical characteristics consistent with a CHEMICAL GENE, a murine homologue of this enzyme was expressed in insect cells and purified. The purified Atp8a1 is inactive in detergent micelles or in micelles containing phosphatidylcholine, phosphatidic acid, or phosphatidylinositol, is minimally activated by phosphatidylglycerol or phosphatidylethanolamine (PE), and is maximally activated by CHEMICAL. The selectivity for CHEMICAL is dependent upon multiple elements of the lipid structure. Similar to the plasma membrane CHEMICAL transporter, Atp8a1 is activated only by the naturally occurring sn-1,2-glycerol isomer of CHEMICAL and not the sn-2,3-glycerol stereoisomer. Both GENE and Atp8a1 activities are insensitive to the stereochemistry of the serine headgroup. Most modifications of the CHEMICAL headgroup structure decrease recognition by the plasma membrane CHEMICAL GENE. Activation of Atp8a1 is also reduced by these modifications; phosphatidylserine-O-methyl ester, lysophosphatidylserine, glycerophosphoserine, and phosphoserine, which are not transported by the plasma membrane GENE, do not activate Atp8a1. Weakly translocated lipids (PE, phosphatidylhydroxypropionate, and phosphatidylhomoserine) are also weak Atp8a1 activators. However, N-methyl-phosphatidylserine, which is transported by the plasma membrane GENE at a rate equivalent to CHEMICAL, is incapable of activating Atp8a1 activity. These results indicate that the ATPase activity of the secretory granule Atp8a1 is activated by phospholipids binding to a specific site whose properties (PS selectivity, dependence upon glycerol but not serine, stereochemistry, and vanadate sensitivity) are similar to, but distinct from, the properties of the substrate binding site of the plasma membrane GENE. | DIRECT-REGULATOR |
| NMDA receptors are not alone: dynamic regulation of GENE structure and function by neuregulins and transient cholesterol-rich membrane domains leads to disease-specific nuances of glutamate-signalling. Glutamate receptors of the N-methyl-D-asparate (NMDA-) subtype are tetrameric allosteric and ligand-gated calcium channels. They are modulated by a variety of endogenous ligands and ions and play a pivotal role in memory-related signal transduction due to a voltage-dependent block by magnesium, which makes them Hebbian coincidence detectors. On the structural level NMDA receptors have an enormous flexibility due to seven genes (NR1, NR2A-D and NR3A-B), alternative splicing, RNA-editing and extensive posttranslational modifications, like phosphorylation and glycosylation. NMDA receptors are thought to be responsible for excitotoxicity and subsequent downstream events like neuroinflammation and apoptosis and thus have been implicated in many important human pathologies, ranging from amyotrophic lateral sclerosis, Alzheimer's and Parkinson' disease, depression, epilepsy, trauma and stroke to schizophrenia. This fundamental significance of GENE-related excitotoxicity is discussed in the context of the developing clinical success of CHEMICAL, but moreover set into relation to various proteomic and genetic markers of said diseases. The very complex localisational and functional regulation of NMDA receptors appears to be dependent on neuregulins and receptor tyrosine kinases in cholesterol-rich membrane domains (lipid rafts), calcium-related mitochondrial feedback-loops and subsynaptic structural elements like PSD-95 (post-synaptic density protein of 95 kD). The flexibility and multitude of interaction partners and possibilities of these highly dynamic molecular systems are discussed in terms of drug development strategies, in particular comparing high affinity and sub-type specific ligands to currently successful or promising therapies. | REGULATOR |
| Sorafenib: recent update on activity as a single agent and in combination with interferon-alpha2 in patients with advanced-stage renal cell carcinoma. Metastatic renal cell carcinoma does not respond favorably to conventional treatment strategies and is not very responsive to cytokine therapy. Therefore, novel targeted treatment approaches have been explored for patients with renal cancer who have chemotherapy-refractory disease. CHEMICAL (BAY 43-9006) is a small-molecule inhibitor that has been shown to target members of multiple classes of GENE that are known to be involved in tumor cell proliferation and tumor angiogenesis. These kinases include vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor, Flt-3, c-kit, and Raf kinases. Based on the significant improvement in progression-free survival, sorafenib received Food and Drug Administration approval in December 2005 for the treatment of renal cell carcinoma. In combination studies, sorafenib with other antitumor agents has demonstrated significant clinical activity in patients with renal cell carcinoma. As discussed in this mini-review, the clinical potency of sorafenib as a single agent or in combination with other antitumor agents is being evaluated in several ongoing clinical trials in patients with renal carcinoma. | INHIBITOR |
| Sorafenib: recent update on activity as a single agent and in combination with interferon-alpha2 in patients with advanced-stage renal cell carcinoma. Metastatic renal cell carcinoma does not respond favorably to conventional treatment strategies and is not very responsive to cytokine therapy. Therefore, novel targeted treatment approaches have been explored for patients with renal cancer who have chemotherapy-refractory disease. Sorafenib (CHEMICAL) is a small-molecule inhibitor that has been shown to target members of multiple classes of GENE that are known to be involved in tumor cell proliferation and tumor angiogenesis. These kinases include vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor, Flt-3, c-kit, and Raf kinases. Based on the significant improvement in progression-free survival, sorafenib received Food and Drug Administration approval in December 2005 for the treatment of renal cell carcinoma. In combination studies, sorafenib with other antitumor agents has demonstrated significant clinical activity in patients with renal cell carcinoma. As discussed in this mini-review, the clinical potency of sorafenib as a single agent or in combination with other antitumor agents is being evaluated in several ongoing clinical trials in patients with renal carcinoma. | INHIBITOR |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, CHEMICAL was able to inhibit NO production and inducible NO synthase (iNOS) expression via GENE (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both CHEMICAL solution prepared by bubbling pure CHEMICAL gas and NaSH, a CHEMICAL donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with CHEMICAL or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for CHEMICAL, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of CHEMICAL on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of CHEMICAL. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with CHEMICAL. Interestingly, the inhibitory effect of CHEMICAL on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that CHEMICAL can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | INDIRECT-DOWNREGULATOR |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, CHEMICAL was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (GENE) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both CHEMICAL solution prepared by bubbling pure CHEMICAL gas and NaSH, a CHEMICAL donor, dose dependently induced GENE expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with CHEMICAL or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for CHEMICAL, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of GENE expression by GENE small interfering RNA (siRNA) reversed the inhibitory effects of CHEMICAL on iNOS expression and NO production, GENE overexpression produced the same inhibitory effects of CHEMICAL. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with CHEMICAL. Interestingly, the inhibitory effect of CHEMICAL on NF-kappaB activation was reversed by the transient transfection with GENE siRNA, but was mimicked by either GENE gene transfection or treatment with carbon monoxide (CO), an end product of GENE. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that CHEMICAL can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | GENE-CHEMICAL |
| CHEMICAL inhibits nitric oxide production and nuclear factor-kappaB via GENE expression in RAW264.7 macrophages stimulated with lipopolysaccharide. CHEMICAL (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | GENE-CHEMICAL |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, CHEMICAL was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both CHEMICAL solution prepared by bubbling pure CHEMICAL gas and NaSH, a CHEMICAL donor, dose dependently induced HO-1 expression through the activation of the GENE (ERK). Pretreatment with CHEMICAL or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for CHEMICAL, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of CHEMICAL on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of CHEMICAL. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with CHEMICAL. Interestingly, the inhibitory effect of CHEMICAL on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that CHEMICAL can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | ACTIVATOR |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, CHEMICAL was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both CHEMICAL solution prepared by bubbling pure CHEMICAL gas and NaSH, a CHEMICAL donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (GENE). Pretreatment with CHEMICAL or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for CHEMICAL, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of CHEMICAL on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of CHEMICAL. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with CHEMICAL. Interestingly, the inhibitory effect of CHEMICAL on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that CHEMICAL can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | ACTIVATOR |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced GENE expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on GENE expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CHEMICAL treatment also inhibited LPS-induced NO production and GENE expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | INDIRECT-DOWNREGULATOR |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, CHEMICAL was able to inhibit NO production and GENE (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both CHEMICAL solution prepared by bubbling pure CHEMICAL gas and NaSH, a CHEMICAL donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with CHEMICAL or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for CHEMICAL, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of CHEMICAL on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of CHEMICAL. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with CHEMICAL. Interestingly, the inhibitory effect of CHEMICAL on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that CHEMICAL can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | INDIRECT-DOWNREGULATOR |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, CHEMICAL was able to inhibit NO production and inducible NO synthase (GENE) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both CHEMICAL solution prepared by bubbling pure CHEMICAL gas and NaSH, a CHEMICAL donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with CHEMICAL or NaHS significantly inhibited LPS-induced GENE expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for CHEMICAL, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of CHEMICAL on GENE expression and NO production, HO-1 overexpression produced the same inhibitory effects of CHEMICAL. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with CHEMICAL. Interestingly, the inhibitory effect of CHEMICAL on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and GENE expression via its inactivation of NF-kappaB. Collectively, our results suggest that CHEMICAL can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | INDIRECT-DOWNREGULATOR |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or CHEMICAL significantly inhibited LPS-induced GENE expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on GENE expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and GENE expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | INDIRECT-DOWNREGULATOR |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on GENE activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CHEMICAL treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of GENE. Collectively, our results suggest that H(2)S can inhibit NO production and GENE activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | INHIBITOR |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, CHEMICAL was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both CHEMICAL solution prepared by bubbling pure CHEMICAL gas and NaSH, a CHEMICAL donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with CHEMICAL or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for CHEMICAL, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of CHEMICAL on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of CHEMICAL. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with CHEMICAL. Interestingly, the inhibitory effect of CHEMICAL on GENE activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of GENE. Collectively, our results suggest that CHEMICAL can inhibit NO production and GENE activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | INHIBITOR |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing GENE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective GENE inhibitor CHEMICAL but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | INHIBITOR |
| CHEMICAL inhibits nitric oxide production and GENE via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. CHEMICAL (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | INHIBITOR |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the GENE inhibitor CHEMICAL. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | INHIBITOR |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, CHEMICAL was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both CHEMICAL solution prepared by bubbling pure CHEMICAL gas and NaSH, a CHEMICAL donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with CHEMICAL or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for CHEMICAL, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of CHEMICAL on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of CHEMICAL. In addition, LPS-induced nuclear factor GENE activation was diminished in RAW264.7 macrophages preincubated with CHEMICAL. Interestingly, the inhibitory effect of CHEMICAL on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that CHEMICAL can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | GENE-CHEMICAL |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced GENE expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of GENE expression by GENE small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, GENE overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with GENE siRNA, but was mimicked by either GENE gene transfection or treatment with CHEMICAL (CO), an end product of GENE. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | GENE-CHEMICAL |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced GENE expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of GENE expression by GENE small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, GENE overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with GENE siRNA, but was mimicked by either GENE gene transfection or treatment with carbon monoxide (CHEMICAL), an end product of GENE. CHEMICAL treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | GENE-CHEMICAL |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit CHEMICAL production and inducible CHEMICAL synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced GENE expression and CHEMICAL production. Moreover, CHEMICAL production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on GENE expression and CHEMICAL production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced CHEMICAL production and GENE expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit CHEMICAL production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | PRODUCT-OF |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (CHEMICAL), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (GENE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, CHEMICAL was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both CHEMICAL solution prepared by bubbling pure CHEMICAL gas and NaSH, a CHEMICAL donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with CHEMICAL or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing GENE mRNA was significantly reduced by the addition of L-Cys, a substrate for CHEMICAL, but enhanced by the selective GENE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of CHEMICAL on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of CHEMICAL. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with CHEMICAL. Interestingly, the inhibitory effect of CHEMICAL on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that CHEMICAL can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | PRODUCT-OF |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (CHEMICAL), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or GENE (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, CHEMICAL was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both CHEMICAL solution prepared by bubbling pure CHEMICAL gas and NaSH, a CHEMICAL donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with CHEMICAL or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for CHEMICAL, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of CHEMICAL on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of CHEMICAL. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with CHEMICAL. Interestingly, the inhibitory effect of CHEMICAL on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that CHEMICAL can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | PRODUCT-OF |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (CHEMICAL), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (GENE) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, CHEMICAL was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both CHEMICAL solution prepared by bubbling pure CHEMICAL gas and NaSH, a CHEMICAL donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with CHEMICAL or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for CHEMICAL, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the GENE inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of CHEMICAL on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of CHEMICAL. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with CHEMICAL. Interestingly, the inhibitory effect of CHEMICAL on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that CHEMICAL can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | PRODUCT-OF |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (CHEMICAL), a regulatory gaseous molecule that is endogenously synthesized by GENE (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, CHEMICAL was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both CHEMICAL solution prepared by bubbling pure CHEMICAL gas and NaSH, a CHEMICAL donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with CHEMICAL or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for CHEMICAL, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of CHEMICAL on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of CHEMICAL. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with CHEMICAL. Interestingly, the inhibitory effect of CHEMICAL on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that CHEMICAL can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | PRODUCT-OF |
| CHEMICAL inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. CHEMICAL (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (GENE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing GENE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective GENE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | PRODUCT-OF |
| CHEMICAL inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. CHEMICAL (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or GENE (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | PRODUCT-OF |
| CHEMICAL inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. CHEMICAL (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (GENE) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the GENE inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | PRODUCT-OF |
| CHEMICAL inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. CHEMICAL (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by GENE (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | PRODUCT-OF |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit CHEMICAL production and GENE (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and CHEMICAL production. Moreover, CHEMICAL production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and CHEMICAL production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced CHEMICAL production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit CHEMICAL production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | PRODUCT-OF |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (GENE) and/or cystathionine beta-synthase (CBS) from CHEMICAL (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing GENE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective GENE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | SUBSTRATE |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or GENE (CBS) from CHEMICAL (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | SUBSTRATE |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (GENE) from CHEMICAL (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the GENE inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | SUBSTRATE |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by GENE (CSE) and/or cystathionine beta-synthase (CBS) from CHEMICAL (L-Cys) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of L-Cys, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | SUBSTRATE |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (GENE) and/or cystathionine beta-synthase (CBS) from L-cysteine (CHEMICAL) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing GENE mRNA was significantly reduced by the addition of CHEMICAL, a substrate for H(2)S, but enhanced by the selective GENE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | SUBSTRATE |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or GENE (CBS) from L-cysteine (CHEMICAL) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of CHEMICAL, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | SUBSTRATE |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by cystathionine gamma-lyase (CSE) and/or cystathionine beta-synthase (GENE) from L-cysteine (CHEMICAL) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of CHEMICAL, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the GENE inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | SUBSTRATE |
| Hydrogen sulfide inhibits nitric oxide production and nuclear factor-kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with lipopolysaccharide. Hydrogen sulfide (H(2)S), a regulatory gaseous molecule that is endogenously synthesized by GENE (CSE) and/or cystathionine beta-synthase (CBS) from L-cysteine (CHEMICAL) metabolism, is a putative vasodilator, and its role in nitric oxide (NO) production is unexplored. Here, we show that at noncytotoxic concentrations, H(2)S was able to inhibit NO production and inducible NO synthase (iNOS) expression via heme oxygenase (HO-1) expression in RAW264.7 macrophages stimulated with lipopolysaccharide (LPS). Both H(2)S solution prepared by bubbling pure H(2)S gas and NaSH, a H(2)S donor, dose dependently induced HO-1 expression through the activation of the extracellular signal-regulated kinase (ERK). Pretreatment with H(2)S or NaHS significantly inhibited LPS-induced iNOS expression and NO production. Moreover, NO production in LPS-stimulated macrophages that are expressing CSE mRNA was significantly reduced by the addition of CHEMICAL, a substrate for H(2)S, but enhanced by the selective CSE inhibitor beta-cyano-L-alanine but not by the CBS inhibitor aminooxyacetic acid. While either blockage of HO activity by the HO inhibitor, tin protoporphyrin IX, or down-regulation of HO-1 expression by HO-1 small interfering RNA (siRNA) reversed the inhibitory effects of H(2)S on iNOS expression and NO production, HO-1 overexpression produced the same inhibitory effects of H(2)S. In addition, LPS-induced nuclear factor (NF)-kappaB activation was diminished in RAW264.7 macrophages preincubated with H(2)S. Interestingly, the inhibitory effect of H(2)S on NF-kappaB activation was reversed by the transient transfection with HO-1 siRNA, but was mimicked by either HO-1 gene transfection or treatment with carbon monoxide (CO), an end product of HO-1. CO treatment also inhibited LPS-induced NO production and iNOS expression via its inactivation of NF-kappaB. Collectively, our results suggest that H(2)S can inhibit NO production and NF-kappaB activation in LPS-stimulated macrophages through a mechanism that involves the action of HO-1/CO. | SUBSTRATE |
| Effect of chronic renal failure on GENE and argininosuccinate synthetase expression. BACKGROUND: L-arginine (L-arg) participates in numerous biological functions including CHEMICAL and nitric oxide synthesis. Sources of L-arg include dietary proteins and endogenous synthesis by argininosuccinate synthetase and argininosuccinate lyase. L-arg is converted to CHEMICAL by GENE I in the liver and GENE II in the kidney. Normally, the liver fully consumes L-arg for CHEMICAL generation and does not contribute to its circulating pool. Instead, much of the circulating L-arg is produced by the kidney. If true, plasma L-arg should be severely reduced in chronic renal failure (CRF); however, plasma L-arg is frequently unchanged in CRF. We hypothesized that preservation of plasma L-arg in CRF may be, partly, due to downregulation/inhibition of GENE. METHODS: Argininosuccinate synthetase, GENE I and II protein abundance and activity were measured in the liver and kidneys of rats 6 weeks after 5/6 nephrectomy or sham operation. In addition, GENE activity was measured in the presence of different CHEMICAL concentrations to simulate azotemia in vitro. RESULTS: Arginases I and II protein abundance as well as GENE activity in the liver, measured in the physiological buffer, were similar among the CRF and control groups. However, in vitro experiments simulating a uremic milieu revealed a marked concentration-dependent inhibition of GENE activity by CHEMICAL in the tissue lysates. CRF had no significant effect on argininosuccinate synthetase abundance in the kidney, liver, spleen or intestine. CONCLUSIONS: Although CRF does not change the abundance or intrinsic properties of GENE, the inherent rise in CHEMICAL concentration inhibits its enzymatic activity. The latter, in turn, attenuates L-arg catabolism and CHEMICAL production and, thereby, mitigates the fall in plasma L-arg. | PRODUCT-OF |
| Effect of chronic renal failure on arginase and argininosuccinate synthetase expression. BACKGROUND: L-arginine (L-arg) participates in numerous biological functions including CHEMICAL and nitric oxide synthesis. Sources of L-arg include dietary proteins and endogenous synthesis by argininosuccinate synthetase and argininosuccinate lyase. L-arg is converted to CHEMICAL by GENE in the liver and arginase II in the kidney. Normally, the liver fully consumes L-arg for CHEMICAL generation and does not contribute to its circulating pool. Instead, much of the circulating L-arg is produced by the kidney. If true, plasma L-arg should be severely reduced in chronic renal failure (CRF); however, plasma L-arg is frequently unchanged in CRF. We hypothesized that preservation of plasma L-arg in CRF may be, partly, due to downregulation/inhibition of arginase. METHODS: Argininosuccinate synthetase, GENE and II protein abundance and activity were measured in the liver and kidneys of rats 6 weeks after 5/6 nephrectomy or sham operation. In addition, arginase activity was measured in the presence of different CHEMICAL concentrations to simulate azotemia in vitro. RESULTS: Arginases I and II protein abundance as well as arginase activity in the liver, measured in the physiological buffer, were similar among the CRF and control groups. However, in vitro experiments simulating a uremic milieu revealed a marked concentration-dependent inhibition of arginase activity by CHEMICAL in the tissue lysates. CRF had no significant effect on argininosuccinate synthetase abundance in the kidney, liver, spleen or intestine. CONCLUSIONS: Although CRF does not change the abundance or intrinsic properties of arginase, the inherent rise in CHEMICAL concentration inhibits its enzymatic activity. The latter, in turn, attenuates L-arg catabolism and CHEMICAL production and, thereby, mitigates the fall in plasma L-arg. | PRODUCT-OF |
| Effect of chronic renal failure on arginase and argininosuccinate synthetase expression. BACKGROUND: L-arginine (L-arg) participates in numerous biological functions including CHEMICAL and nitric oxide synthesis. Sources of L-arg include dietary proteins and endogenous synthesis by argininosuccinate synthetase and argininosuccinate lyase. L-arg is converted to CHEMICAL by arginase I in the liver and GENE in the kidney. Normally, the liver fully consumes L-arg for CHEMICAL generation and does not contribute to its circulating pool. Instead, much of the circulating L-arg is produced by the kidney. If true, plasma L-arg should be severely reduced in chronic renal failure (CRF); however, plasma L-arg is frequently unchanged in CRF. We hypothesized that preservation of plasma L-arg in CRF may be, partly, due to downregulation/inhibition of arginase. METHODS: Argininosuccinate synthetase, arginase I and II protein abundance and activity were measured in the liver and kidneys of rats 6 weeks after 5/6 nephrectomy or sham operation. In addition, arginase activity was measured in the presence of different CHEMICAL concentrations to simulate azotemia in vitro. RESULTS: Arginases I and II protein abundance as well as arginase activity in the liver, measured in the physiological buffer, were similar among the CRF and control groups. However, in vitro experiments simulating a uremic milieu revealed a marked concentration-dependent inhibition of arginase activity by CHEMICAL in the tissue lysates. CRF had no significant effect on argininosuccinate synthetase abundance in the kidney, liver, spleen or intestine. CONCLUSIONS: Although CRF does not change the abundance or intrinsic properties of arginase, the inherent rise in CHEMICAL concentration inhibits its enzymatic activity. The latter, in turn, attenuates L-arg catabolism and CHEMICAL production and, thereby, mitigates the fall in plasma L-arg. | PRODUCT-OF |
| Effect of chronic renal failure on arginase and GENE expression. BACKGROUND: L-arginine (L-arg) participates in numerous biological functions including urea and nitric oxide synthesis. Sources of CHEMICAL include dietary proteins and endogenous synthesis by GENE and argininosuccinate lyase. CHEMICAL is converted to urea by arginase I in the liver and arginase II in the kidney. Normally, the liver fully consumes CHEMICAL for urea generation and does not contribute to its circulating pool. Instead, much of the circulating CHEMICAL is produced by the kidney. If true, plasma CHEMICAL should be severely reduced in chronic renal failure (CRF); however, plasma CHEMICAL is frequently unchanged in CRF. We hypothesized that preservation of plasma CHEMICAL in CRF may be, partly, due to downregulation/inhibition of arginase. METHODS: GENE, arginase I and II protein abundance and activity were measured in the liver and kidneys of rats 6 weeks after 5/6 nephrectomy or sham operation. In addition, arginase activity was measured in the presence of different urea concentrations to simulate azotemia in vitro. RESULTS: Arginases I and II protein abundance as well as arginase activity in the liver, measured in the physiological buffer, were similar among the CRF and control groups. However, in vitro experiments simulating a uremic milieu revealed a marked concentration-dependent inhibition of arginase activity by urea in the tissue lysates. CRF had no significant effect on GENE abundance in the kidney, liver, spleen or intestine. CONCLUSIONS: Although CRF does not change the abundance or intrinsic properties of arginase, the inherent rise in urea concentration inhibits its enzymatic activity. The latter, in turn, attenuates CHEMICAL catabolism and urea production and, thereby, mitigates the fall in plasma CHEMICAL. | PRODUCT-OF |
| Effect of chronic renal failure on arginase and argininosuccinate synthetase expression. BACKGROUND: L-arginine (L-arg) participates in numerous biological functions including urea and nitric oxide synthesis. Sources of CHEMICAL include dietary proteins and endogenous synthesis by argininosuccinate synthetase and GENE. CHEMICAL is converted to urea by arginase I in the liver and arginase II in the kidney. Normally, the liver fully consumes CHEMICAL for urea generation and does not contribute to its circulating pool. Instead, much of the circulating CHEMICAL is produced by the kidney. If true, plasma CHEMICAL should be severely reduced in chronic renal failure (CRF); however, plasma CHEMICAL is frequently unchanged in CRF. We hypothesized that preservation of plasma CHEMICAL in CRF may be, partly, due to downregulation/inhibition of arginase. METHODS: Argininosuccinate synthetase, arginase I and II protein abundance and activity were measured in the liver and kidneys of rats 6 weeks after 5/6 nephrectomy or sham operation. In addition, arginase activity was measured in the presence of different urea concentrations to simulate azotemia in vitro. RESULTS: Arginases I and II protein abundance as well as arginase activity in the liver, measured in the physiological buffer, were similar among the CRF and control groups. However, in vitro experiments simulating a uremic milieu revealed a marked concentration-dependent inhibition of arginase activity by urea in the tissue lysates. CRF had no significant effect on argininosuccinate synthetase abundance in the kidney, liver, spleen or intestine. CONCLUSIONS: Although CRF does not change the abundance or intrinsic properties of arginase, the inherent rise in urea concentration inhibits its enzymatic activity. The latter, in turn, attenuates CHEMICAL catabolism and urea production and, thereby, mitigates the fall in plasma CHEMICAL. | PRODUCT-OF |
| Effect of chronic renal failure on arginase and argininosuccinate synthetase expression. BACKGROUND: L-arginine (L-arg) participates in numerous biological functions including urea and nitric oxide synthesis. Sources of CHEMICAL include dietary proteins and endogenous synthesis by argininosuccinate synthetase and argininosuccinate lyase. CHEMICAL is converted to urea by GENE in the liver and arginase II in the kidney. Normally, the liver fully consumes CHEMICAL for urea generation and does not contribute to its circulating pool. Instead, much of the circulating CHEMICAL is produced by the kidney. If true, plasma CHEMICAL should be severely reduced in chronic renal failure (CRF); however, plasma CHEMICAL is frequently unchanged in CRF. We hypothesized that preservation of plasma CHEMICAL in CRF may be, partly, due to downregulation/inhibition of arginase. METHODS: Argininosuccinate synthetase, GENE and II protein abundance and activity were measured in the liver and kidneys of rats 6 weeks after 5/6 nephrectomy or sham operation. In addition, arginase activity was measured in the presence of different urea concentrations to simulate azotemia in vitro. RESULTS: Arginases I and II protein abundance as well as arginase activity in the liver, measured in the physiological buffer, were similar among the CRF and control groups. However, in vitro experiments simulating a uremic milieu revealed a marked concentration-dependent inhibition of arginase activity by urea in the tissue lysates. CRF had no significant effect on argininosuccinate synthetase abundance in the kidney, liver, spleen or intestine. CONCLUSIONS: Although CRF does not change the abundance or intrinsic properties of arginase, the inherent rise in urea concentration inhibits its enzymatic activity. The latter, in turn, attenuates CHEMICAL catabolism and urea production and, thereby, mitigates the fall in plasma CHEMICAL. | SUBSTRATE |
| Effect of chronic renal failure on arginase and argininosuccinate synthetase expression. BACKGROUND: L-arginine (L-arg) participates in numerous biological functions including urea and nitric oxide synthesis. Sources of CHEMICAL include dietary proteins and endogenous synthesis by argininosuccinate synthetase and argininosuccinate lyase. CHEMICAL is converted to urea by arginase I in the liver and GENE in the kidney. Normally, the liver fully consumes CHEMICAL for urea generation and does not contribute to its circulating pool. Instead, much of the circulating CHEMICAL is produced by the kidney. If true, plasma CHEMICAL should be severely reduced in chronic renal failure (CRF); however, plasma CHEMICAL is frequently unchanged in CRF. We hypothesized that preservation of plasma CHEMICAL in CRF may be, partly, due to downregulation/inhibition of arginase. METHODS: Argininosuccinate synthetase, arginase I and II protein abundance and activity were measured in the liver and kidneys of rats 6 weeks after 5/6 nephrectomy or sham operation. In addition, arginase activity was measured in the presence of different urea concentrations to simulate azotemia in vitro. RESULTS: Arginases I and II protein abundance as well as arginase activity in the liver, measured in the physiological buffer, were similar among the CRF and control groups. However, in vitro experiments simulating a uremic milieu revealed a marked concentration-dependent inhibition of arginase activity by urea in the tissue lysates. CRF had no significant effect on argininosuccinate synthetase abundance in the kidney, liver, spleen or intestine. CONCLUSIONS: Although CRF does not change the abundance or intrinsic properties of arginase, the inherent rise in urea concentration inhibits its enzymatic activity. The latter, in turn, attenuates CHEMICAL catabolism and urea production and, thereby, mitigates the fall in plasma CHEMICAL. | SUBSTRATE |
| Effect of chronic renal failure on GENE and argininosuccinate synthetase expression. BACKGROUND: L-arginine (L-arg) participates in numerous biological functions including urea and nitric oxide synthesis. Sources of CHEMICAL include dietary proteins and endogenous synthesis by argininosuccinate synthetase and argininosuccinate lyase. CHEMICAL is converted to urea by GENE I in the liver and GENE II in the kidney. Normally, the liver fully consumes CHEMICAL for urea generation and does not contribute to its circulating pool. Instead, much of the circulating CHEMICAL is produced by the kidney. If true, plasma CHEMICAL should be severely reduced in chronic renal failure (CRF); however, plasma CHEMICAL is frequently unchanged in CRF. We hypothesized that preservation of plasma CHEMICAL in CRF may be, partly, due to downregulation/inhibition of GENE. METHODS: Argininosuccinate synthetase, GENE I and II protein abundance and activity were measured in the liver and kidneys of rats 6 weeks after 5/6 nephrectomy or sham operation. In addition, GENE activity was measured in the presence of different urea concentrations to simulate azotemia in vitro. RESULTS: Arginases I and II protein abundance as well as GENE activity in the liver, measured in the physiological buffer, were similar among the CRF and control groups. However, in vitro experiments simulating a uremic milieu revealed a marked concentration-dependent inhibition of GENE activity by urea in the tissue lysates. CRF had no significant effect on argininosuccinate synthetase abundance in the kidney, liver, spleen or intestine. CONCLUSIONS: Although CRF does not change the abundance or intrinsic properties of GENE, the inherent rise in urea concentration inhibits its enzymatic activity. The latter, in turn, attenuates CHEMICAL catabolism and urea production and, thereby, mitigates the fall in plasma CHEMICAL. | SUBSTRATE |
| Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia. Hyponatremia is the most frequent electrolyte disorder encountered in hospitalized patients. It is a state of relative water excess due to stimulated arginine vasopressin (AVP) and fluid intake greater than obligatory losses. This kind of hyponatremia occurs in the syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, and liver cirrhosis. Fluid restriction is the presently recommended treatment for hyponatremia. However, fluid restriction may be very difficult for patients to achieve, is slow to work, and does not allow a graded therapeutic approach. More efficient and specific treatments of hyponatremia are needed. In this respect, pharmacologic research has yielded a number of compounds exhibiting antagonistic qualities at the vasopressin V2 receptor. Among these agents, peptidic derivatives of AVP turned out to have intrinsic antidiuretic properties in vivo when given over days or weeks. The development of such agents for use in patients has not been pursued. However, several promising nonpeptide, GENE antagonists have been described; these agents are CHEMICAL (lixivaptan), YM-087 (conivaptan), OPC-41061 (tolvaptan), and SR-121463. Prospective, randomized, placebo-controlled trials performed with these agents found that they corrected hyponatremia efficiently and safely. Most of the studies were conducted over a 4- to 28-day period. Long-term studies will be needed in the future to address such issues as the eventual benefit to patients and the effects of vasopressin antagonists on morbidity and mortality of patients with hyponatremia. | INHIBITOR |
| Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia. Hyponatremia is the most frequent electrolyte disorder encountered in hospitalized patients. It is a state of relative water excess due to stimulated arginine vasopressin (AVP) and fluid intake greater than obligatory losses. This kind of hyponatremia occurs in the syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, and liver cirrhosis. Fluid restriction is the presently recommended treatment for hyponatremia. However, fluid restriction may be very difficult for patients to achieve, is slow to work, and does not allow a graded therapeutic approach. More efficient and specific treatments of hyponatremia are needed. In this respect, pharmacologic research has yielded a number of compounds exhibiting antagonistic qualities at the vasopressin V2 receptor. Among these agents, peptidic derivatives of AVP turned out to have intrinsic antidiuretic properties in vivo when given over days or weeks. The development of such agents for use in patients has not been pursued. However, several promising nonpeptide, GENE antagonists have been described; these agents are VPA-985 (CHEMICAL), YM-087 (conivaptan), OPC-41061 (tolvaptan), and SR-121463. Prospective, randomized, placebo-controlled trials performed with these agents found that they corrected hyponatremia efficiently and safely. Most of the studies were conducted over a 4- to 28-day period. Long-term studies will be needed in the future to address such issues as the eventual benefit to patients and the effects of vasopressin antagonists on morbidity and mortality of patients with hyponatremia. | INHIBITOR |
| Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia. Hyponatremia is the most frequent electrolyte disorder encountered in hospitalized patients. It is a state of relative water excess due to stimulated arginine vasopressin (AVP) and fluid intake greater than obligatory losses. This kind of hyponatremia occurs in the syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, and liver cirrhosis. Fluid restriction is the presently recommended treatment for hyponatremia. However, fluid restriction may be very difficult for patients to achieve, is slow to work, and does not allow a graded therapeutic approach. More efficient and specific treatments of hyponatremia are needed. In this respect, pharmacologic research has yielded a number of compounds exhibiting antagonistic qualities at the vasopressin V2 receptor. Among these agents, peptidic derivatives of AVP turned out to have intrinsic antidiuretic properties in vivo when given over days or weeks. The development of such agents for use in patients has not been pursued. However, several promising nonpeptide, GENE antagonists have been described; these agents are VPA-985 (lixivaptan), CHEMICAL (conivaptan), OPC-41061 (tolvaptan), and SR-121463. Prospective, randomized, placebo-controlled trials performed with these agents found that they corrected hyponatremia efficiently and safely. Most of the studies were conducted over a 4- to 28-day period. Long-term studies will be needed in the future to address such issues as the eventual benefit to patients and the effects of vasopressin antagonists on morbidity and mortality of patients with hyponatremia. | INHIBITOR |
| Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia. Hyponatremia is the most frequent electrolyte disorder encountered in hospitalized patients. It is a state of relative water excess due to stimulated arginine vasopressin (AVP) and fluid intake greater than obligatory losses. This kind of hyponatremia occurs in the syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, and liver cirrhosis. Fluid restriction is the presently recommended treatment for hyponatremia. However, fluid restriction may be very difficult for patients to achieve, is slow to work, and does not allow a graded therapeutic approach. More efficient and specific treatments of hyponatremia are needed. In this respect, pharmacologic research has yielded a number of compounds exhibiting antagonistic qualities at the vasopressin V2 receptor. Among these agents, peptidic derivatives of AVP turned out to have intrinsic antidiuretic properties in vivo when given over days or weeks. The development of such agents for use in patients has not been pursued. However, several promising nonpeptide, GENE antagonists have been described; these agents are VPA-985 (lixivaptan), YM-087 (CHEMICAL), OPC-41061 (tolvaptan), and SR-121463. Prospective, randomized, placebo-controlled trials performed with these agents found that they corrected hyponatremia efficiently and safely. Most of the studies were conducted over a 4- to 28-day period. Long-term studies will be needed in the future to address such issues as the eventual benefit to patients and the effects of vasopressin antagonists on morbidity and mortality of patients with hyponatremia. | INHIBITOR |
| Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia. Hyponatremia is the most frequent electrolyte disorder encountered in hospitalized patients. It is a state of relative water excess due to stimulated arginine vasopressin (AVP) and fluid intake greater than obligatory losses. This kind of hyponatremia occurs in the syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, and liver cirrhosis. Fluid restriction is the presently recommended treatment for hyponatremia. However, fluid restriction may be very difficult for patients to achieve, is slow to work, and does not allow a graded therapeutic approach. More efficient and specific treatments of hyponatremia are needed. In this respect, pharmacologic research has yielded a number of compounds exhibiting antagonistic qualities at the vasopressin V2 receptor. Among these agents, peptidic derivatives of AVP turned out to have intrinsic antidiuretic properties in vivo when given over days or weeks. The development of such agents for use in patients has not been pursued. However, several promising nonpeptide, GENE antagonists have been described; these agents are VPA-985 (lixivaptan), YM-087 (conivaptan), CHEMICAL (tolvaptan), and SR-121463. Prospective, randomized, placebo-controlled trials performed with these agents found that they corrected hyponatremia efficiently and safely. Most of the studies were conducted over a 4- to 28-day period. Long-term studies will be needed in the future to address such issues as the eventual benefit to patients and the effects of vasopressin antagonists on morbidity and mortality of patients with hyponatremia. | INHIBITOR |
| Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia. Hyponatremia is the most frequent electrolyte disorder encountered in hospitalized patients. It is a state of relative water excess due to stimulated arginine vasopressin (AVP) and fluid intake greater than obligatory losses. This kind of hyponatremia occurs in the syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, and liver cirrhosis. Fluid restriction is the presently recommended treatment for hyponatremia. However, fluid restriction may be very difficult for patients to achieve, is slow to work, and does not allow a graded therapeutic approach. More efficient and specific treatments of hyponatremia are needed. In this respect, pharmacologic research has yielded a number of compounds exhibiting antagonistic qualities at the vasopressin V2 receptor. Among these agents, peptidic derivatives of AVP turned out to have intrinsic antidiuretic properties in vivo when given over days or weeks. The development of such agents for use in patients has not been pursued. However, several promising nonpeptide, GENE antagonists have been described; these agents are VPA-985 (lixivaptan), YM-087 (conivaptan), OPC-41061 (CHEMICAL), and SR-121463. Prospective, randomized, placebo-controlled trials performed with these agents found that they corrected hyponatremia efficiently and safely. Most of the studies were conducted over a 4- to 28-day period. Long-term studies will be needed in the future to address such issues as the eventual benefit to patients and the effects of vasopressin antagonists on morbidity and mortality of patients with hyponatremia. | INHIBITOR |
| Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia. Hyponatremia is the most frequent electrolyte disorder encountered in hospitalized patients. It is a state of relative water excess due to stimulated arginine vasopressin (AVP) and fluid intake greater than obligatory losses. This kind of hyponatremia occurs in the syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, and liver cirrhosis. Fluid restriction is the presently recommended treatment for hyponatremia. However, fluid restriction may be very difficult for patients to achieve, is slow to work, and does not allow a graded therapeutic approach. More efficient and specific treatments of hyponatremia are needed. In this respect, pharmacologic research has yielded a number of compounds exhibiting antagonistic qualities at the vasopressin V2 receptor. Among these agents, peptidic derivatives of AVP turned out to have intrinsic antidiuretic properties in vivo when given over days or weeks. The development of such agents for use in patients has not been pursued. However, several promising nonpeptide, GENE antagonists have been described; these agents are VPA-985 (lixivaptan), YM-087 (conivaptan), OPC-41061 (tolvaptan), and CHEMICAL. Prospective, randomized, placebo-controlled trials performed with these agents found that they corrected hyponatremia efficiently and safely. Most of the studies were conducted over a 4- to 28-day period. Long-term studies will be needed in the future to address such issues as the eventual benefit to patients and the effects of vasopressin antagonists on morbidity and mortality of patients with hyponatremia. | INHIBITOR |
| Sedation and GENE antagonism: studies in man with the enantiomers of chlorpheniramine and CHEMICAL. 1. The effects of 10 mg (+)- and (-)-chlorpheniramine and 5 mg (+)- and (-)-dimethindene on daytime sleep latencies, digit symbol substitution and subjective assessments of mood and well-being were studied in 6 healthy young adult humans. Each subject also took 5 mg triprolidine hydrochloride as an active control and two placebos. 2. Daytime sleep latencies were reduced with triprolidine, (+)-chlorpheniramine and (-)-dimethindene, and subjects also reported that they felt more sleepy after (+)-chlorpheniramine and (-)-dimethindene. Performance on digit symbol substitution was impaired with (+)-chlorpheniramine. 3. Changes in measures with (-)-chlorpheniramine and (+)-dimethindene were not different from changes with placebo. 4. In the present study, changes in measures of drowsiness and performance were limited to the enantiomers with high affinity for the GENE. These findings strongly suggest that sedation can arise from H1-receptor antagonism alone, and provide further support for the belief that the histaminergic system is concerned with the regulation of alertness in man. | INHIBITOR |
| Sedation and GENE antagonism: studies in man with the enantiomers of CHEMICAL and dimethindene. 1. The effects of 10 mg (+)- and (-)-chlorpheniramine and 5 mg (+)- and (-)-dimethindene on daytime sleep latencies, digit symbol substitution and subjective assessments of mood and well-being were studied in 6 healthy young adult humans. Each subject also took 5 mg triprolidine hydrochloride as an active control and two placebos. 2. Daytime sleep latencies were reduced with triprolidine, (+)-chlorpheniramine and (-)-dimethindene, and subjects also reported that they felt more sleepy after (+)-chlorpheniramine and (-)-dimethindene. Performance on digit symbol substitution was impaired with (+)-chlorpheniramine. 3. Changes in measures with (-)-chlorpheniramine and (+)-dimethindene were not different from changes with placebo. 4. In the present study, changes in measures of drowsiness and performance were limited to the enantiomers with high affinity for the GENE. These findings strongly suggest that sedation can arise from H1-receptor antagonism alone, and provide further support for the belief that the histaminergic system is concerned with the regulation of alertness in man. | INHIBITOR |
| Anti-clastogenic effect of beta-glucan extracted from barley towards chemically induced DNA damage in rodent cells. beta-Glucan (BG) was tested in vitro to determine its potential clastogenic and/or anti-clastogenic activity, and attempts were made to elucidate its possible mechanism of action by using combinations with an inhibitor of DNA polymerase. The study was carried out on cells deficient (CHO-k1) and cells proficient (HTC) in phases I and II enzymes, and the DNA damage was assessed by the chromosomal aberration assay. BG did not show a clastogenic effect, but was anti-clastogenic in both cell lines used, and at all concentrations tested (2.5, 5 and 10 microg/mL) in combination with damage inducing agents (methylmethane sulfonate in cell line CHO-k1, and methylmethane sulfonate or 2-aminoanthracene in cell line HTC). BG also showed a protective effect in the presence of a GENE inhibitor (CHEMICAL, Ara-C), demonstrating that BG does not act through an anti-mutagenic mechanism of action involving GENE. | INHIBITOR |
| Anti-clastogenic effect of beta-glucan extracted from barley towards chemically induced DNA damage in rodent cells. beta-Glucan (BG) was tested in vitro to determine its potential clastogenic and/or anti-clastogenic activity, and attempts were made to elucidate its possible mechanism of action by using combinations with an inhibitor of DNA polymerase. The study was carried out on cells deficient (CHO-k1) and cells proficient (HTC) in phases I and II enzymes, and the DNA damage was assessed by the chromosomal aberration assay. BG did not show a clastogenic effect, but was anti-clastogenic in both cell lines used, and at all concentrations tested (2.5, 5 and 10 microg/mL) in combination with damage inducing agents (methylmethane sulfonate in cell line CHO-k1, and methylmethane sulfonate or 2-aminoanthracene in cell line HTC). BG also showed a protective effect in the presence of a GENE inhibitor (cytosine arabinoside-3-phosphate, CHEMICAL), demonstrating that BG does not act through an anti-mutagenic mechanism of action involving GENE. | INHIBITOR |
| Association of DRD2 polymorphisms and chlorpromazine-induced extrapyramidal syndrome in Chinese schizophrenic patients. AIM: Extrapyramidal syndrome (EPS) is most commonly affected by typical antipsychotic drugs that have a high affinity with the D2 receptor. Recently, many research groups have reported on the positive relationship between the genetic variations in the DRD2 gene and the therapeutic response in schizophrenia patients as a result of the role of variations in the receptor in modulating receptor expression. In this study, we evaluate the role DRD2 plays in chlorpromazine-induced EPS in schizophrenic patients. METHODS: We identified seven SNP(single CHEMICAL polymorphism) (-141Cins>del, TaqIB, TaqID, GENE, rs6275, rs6277 and TaqIA) in the DRD2 gene in 146 schizophrenic inpatients (59 with EPS and 87 without EPS according to the Simpson-Angus Scale) treated with chlorpromazine after 8 weeks. The alleles of all loci were determined by PCR (polymerase chain reaction). RESULTS: Polymorphisms TaqID, GENE and rs6277 were not polymorphic in the population recruited in the present study. No statistical significance was found in the allele distribution of -141Cins>del, TaqIB, rs6275 and TaqIA or in the estimated haplotypes (constituted by TaqIB, rs6275 and TaqIA) in linkage disequilibrium between the two groups. CONCLUSION: Our results did not lend strong support to the view that the genetic variation of the DRD2 gene plays a major role in the individually variable adverse effect induced by chlorpromazine, at least in Chinese patients with schizophrenia. Our results confirmed a previous study on the relationship between DRD2 and EPS in Caucasians. | PART-OF |
| Association of GENE polymorphisms and chlorpromazine-induced extrapyramidal syndrome in Chinese schizophrenic patients. AIM: Extrapyramidal syndrome (EPS) is most commonly affected by typical antipsychotic drugs that have a high affinity with the D2 receptor. Recently, many research groups have reported on the positive relationship between the genetic variations in the GENE gene and the therapeutic response in schizophrenia patients as a result of the role of variations in the receptor in modulating receptor expression. In this study, we evaluate the role GENE plays in chlorpromazine-induced EPS in schizophrenic patients. METHODS: We identified seven SNP(single CHEMICAL polymorphism) (-141Cins>del, TaqIB, TaqID, Ser311Cys, rs6275, rs6277 and TaqIA) in the GENE gene in 146 schizophrenic inpatients (59 with EPS and 87 without EPS according to the Simpson-Angus Scale) treated with chlorpromazine after 8 weeks. The alleles of all loci were determined by PCR (polymerase chain reaction). RESULTS: Polymorphisms TaqID, Ser311Cys and rs6277 were not polymorphic in the population recruited in the present study. No statistical significance was found in the allele distribution of -141Cins>del, TaqIB, rs6275 and TaqIA or in the estimated haplotypes (constituted by TaqIB, rs6275 and TaqIA) in linkage disequilibrium between the two groups. CONCLUSION: Our results did not lend strong support to the view that the genetic variation of the GENE gene plays a major role in the individually variable adverse effect induced by chlorpromazine, at least in Chinese patients with schizophrenia. Our results confirmed a previous study on the relationship between GENE and EPS in Caucasians. | PART-OF |
| Association of GENE polymorphisms and chlorpromazine-induced extrapyramidal syndrome in Chinese schizophrenic patients. AIM: Extrapyramidal syndrome (EPS) is most commonly affected by typical antipsychotic drugs that have a high affinity with the D2 receptor. Recently, many research groups have reported on the positive relationship between the genetic variations in the GENE gene and the therapeutic response in schizophrenia patients as a result of the role of variations in the receptor in modulating receptor expression. In this study, we evaluate the role GENE plays in chlorpromazine-induced EPS in schizophrenic patients. METHODS: We identified seven SNP(single nucleotide polymorphism) (-141Cins>del, TaqIB, TaqID, Ser311Cys, rs6275, rs6277 and TaqIA) in the GENE gene in 146 schizophrenic inpatients (59 with EPS and 87 without EPS according to the Simpson-Angus Scale) treated with CHEMICAL after 8 weeks. The alleles of all loci were determined by PCR (polymerase chain reaction). RESULTS: Polymorphisms TaqID, Ser311Cys and rs6277 were not polymorphic in the population recruited in the present study. No statistical significance was found in the allele distribution of -141Cins>del, TaqIB, rs6275 and TaqIA or in the estimated haplotypes (constituted by TaqIB, rs6275 and TaqIA) in linkage disequilibrium between the two groups. CONCLUSION: Our results did not lend strong support to the view that the genetic variation of the GENE gene plays a major role in the individually variable adverse effect induced by CHEMICAL, at least in Chinese patients with schizophrenia. Our results confirmed a previous study on the relationship between GENE and EPS in Caucasians. | GENE-CHEMICAL |
| Activity-dependent cleavage of brain glutamic acid decarboxylase 65 by calpain. Previously, we reported that l-glutamic acid decarboxylase isoform 65 (GAD65) could be cleaved in vitro to release a stable truncated form which lacks amino acid 1-69 from the N-terminus, GAD65(Delta1-69). However, whether such a truncated form is also present under certain physiological conditions remains elusive. In the present study, we showed that, upon sustained neuronal stimulation, GENE could be cleaved into a truncated form in a rat synaptosomal preparation. This truncated form had similar electrophoretic mobility to purified recombinant human GAD65(Delta1-69). Furthermore, we demonstrated that this conversion was calcium dependent. Calcium-chelating reagents such as CHEMICAL and 1,2-bis-(o-aminphenoxy)-ethane-N,N,N',N'-tetra-acetic acid tetra-acetoxy-methyl ester prevented the cleavage of GENE. In addition, our data suggested that calpain, a calcium-dependent cysteine protease, is activated upon neuronal stimulation and could be responsible for the conversion of full-length GENE to truncated GENE in the brain. Moreover, calpain inhibitors such as calpain inhibitor I or calpastatin could block the cleavage. Results of our in vitro cleavage assay using purified calpain and immunopurified rat GENE also supported the idea that GENE could be directly cleaved by calpain. | INHIBITOR |
| Activity-dependent cleavage of brain glutamic acid decarboxylase 65 by calpain. Previously, we reported that l-glutamic acid decarboxylase isoform 65 (GAD65) could be cleaved in vitro to release a stable truncated form which lacks amino acid 1-69 from the N-terminus, GAD65(Delta1-69). However, whether such a truncated form is also present under certain physiological conditions remains elusive. In the present study, we showed that, upon sustained neuronal stimulation, GENE could be cleaved into a truncated form in a rat synaptosomal preparation. This truncated form had similar electrophoretic mobility to purified recombinant human GAD65(Delta1-69). Furthermore, we demonstrated that this conversion was calcium dependent. Calcium-chelating reagents such as EDTA and CHEMICAL prevented the cleavage of GENE. In addition, our data suggested that calpain, a calcium-dependent cysteine protease, is activated upon neuronal stimulation and could be responsible for the conversion of full-length GENE to truncated GENE in the brain. Moreover, calpain inhibitors such as calpain inhibitor I or calpastatin could block the cleavage. Results of our in vitro cleavage assay using purified calpain and immunopurified rat GENE also supported the idea that GENE could be directly cleaved by calpain. | GENE-CHEMICAL |
| Activity-dependent cleavage of brain glutamic acid decarboxylase 65 by calpain. Previously, we reported that l-glutamic acid decarboxylase isoform 65 (GAD65) could be cleaved in vitro to release a stable truncated form which lacks amino acid 1-69 from the CHEMICAL-terminus, GENE. However, whether such a truncated form is also present under certain physiological conditions remains elusive. In the present study, we showed that, upon sustained neuronal stimulation, GAD65 could be cleaved into a truncated form in a rat synaptosomal preparation. This truncated form had similar electrophoretic mobility to purified recombinant human GENE. Furthermore, we demonstrated that this conversion was calcium dependent. Calcium-chelating reagents such as EDTA and 1,2-bis-(o-aminphenoxy)-ethane-N,N,N',N'-tetra-acetic acid tetra-acetoxy-methyl ester prevented the cleavage of GAD65. In addition, our data suggested that calpain, a calcium-dependent cysteine protease, is activated upon neuronal stimulation and could be responsible for the conversion of full-length GAD65 to truncated GAD65 in the brain. Moreover, calpain inhibitors such as calpain inhibitor I or calpastatin could block the cleavage. Results of our in vitro cleavage assay using purified calpain and immunopurified rat GAD65 also supported the idea that GAD65 could be directly cleaved by calpain. | PART-OF |
| Therapeutic targets in melanoma: map kinase pathway. Recent progress in our understanding of the genetic alterations that occur in the pathogenesis of melanoma provides exciting opportunities for therapy. The most important signaling pathways in melanoma lie downstream of NRAS: the RAS-BRAF-MAPK pathway. A great deal of attention has been focused on the high mutation rate in the GENE oncogene, which approaches 60%, because GENE itself is an appealing drug substrate and because of the central contribution of GENE function to melanoma development that the mutation rate signifies. Agents that specifically target GENE, such as CHEMICAL, as well as new molecules that function both upstream and downstream of GENE, are being actively investigated. | REGULATOR |
| Reduction of cerebral infarct size by the AT1-receptor blocker CHEMICAL, the HMG-CoA reductase inhibitor rosuvastatin and their combination. An experimental study in rats. Our purpose was to test the impact of single and/or combined treatment with the GENE-receptor blocker CHEMICAL and the HMG-CoA reductase inhibitor rosuvastatin on infarct size and neuroscore in transient cerebral ischemia in rats. L-NAME was used to test whether any potential effect was due to activation of endothelial nitric oxide synthase (eNOS). Therefore, the middle cerebral artery was occluded for 1 h (MCAO) followed by 7 days reperfusion. Rats received CHEMICAL 2h before and daily after MCAO (pretreatment) or daily after MCAO (posttreatment); rosuvastatin was given daily for 7 days before MCAO without or with CHEMICAL pre- and posttreatment. In addition, CHEMICAL and rosuvastatin were combined with L-NAME. Infarct size and neuroscore at day 7 were compared to those of controls. As result, compared to controls (109+/-12 mm(3)) infarct size with CHEMICAL (pretreatment: 21+/-5 mm(3); posttreatment: 68+/-29 mm(3); P<0.05) or rosuvastatin (69+/-14 mm(3); P<0.05) was smaller. Combined treatment also reduced infarct size (pretreatment: 37+/-15 mm(3); posttreatment 57+/-20mm(3); P<0.05); but there was no benefit of combined treatment over CHEMICAL pretreatment alone. Compared to controls (2.08+/-0.28) only CHEMICAL pretreatment and combined treatment improved the neuroscore (0.97+/-0.05, 1.10+/-0.33; P<0.05). L-NAME abolished the reduction in infarct size and improvement in neuroscore. In conclusion, both, CHEMICAL or rosuvastatin treatment alone reduced infarct size in transient cerebral ischemia, and the best result was achieved with CHEMICAL pretreatment. Combined treatment was superior to rosuvastatin alone, but not to CHEMICAL. The therapeutic benefit of both agents was at least in parts mediated by eNOS-activation. | INHIBITOR |
| Reduction of cerebral infarct size by the AT1-receptor blocker candesartan, the GENE inhibitor CHEMICAL and their combination. An experimental study in rats. Our purpose was to test the impact of single and/or combined treatment with the AT(1)-receptor blocker candesartan and the GENE inhibitor CHEMICAL on infarct size and neuroscore in transient cerebral ischemia in rats. L-NAME was used to test whether any potential effect was due to activation of endothelial nitric oxide synthase (eNOS). Therefore, the middle cerebral artery was occluded for 1 h (MCAO) followed by 7 days reperfusion. Rats received candesartan 2h before and daily after MCAO (pretreatment) or daily after MCAO (posttreatment); CHEMICAL was given daily for 7 days before MCAO without or with candesartan pre- and posttreatment. In addition, candesartan and CHEMICAL were combined with L-NAME. Infarct size and neuroscore at day 7 were compared to those of controls. As result, compared to controls (109+/-12 mm(3)) infarct size with candesartan (pretreatment: 21+/-5 mm(3); posttreatment: 68+/-29 mm(3); P<0.05) or CHEMICAL (69+/-14 mm(3); P<0.05) was smaller. Combined treatment also reduced infarct size (pretreatment: 37+/-15 mm(3); posttreatment 57+/-20mm(3); P<0.05); but there was no benefit of combined treatment over candesartan pretreatment alone. Compared to controls (2.08+/-0.28) only candesartan pretreatment and combined treatment improved the neuroscore (0.97+/-0.05, 1.10+/-0.33; P<0.05). L-NAME abolished the reduction in infarct size and improvement in neuroscore. In conclusion, both, candesartan or CHEMICAL treatment alone reduced infarct size in transient cerebral ischemia, and the best result was achieved with candesartan pretreatment. Combined treatment was superior to CHEMICAL alone, but not to candesartan. The therapeutic benefit of both agents was at least in parts mediated by eNOS-activation. | INHIBITOR |
| Reduction of cerebral infarct size by the GENE-receptor blocker CHEMICAL, the HMG-CoA reductase inhibitor rosuvastatin and their combination. An experimental study in rats. Our purpose was to test the impact of single and/or combined treatment with the AT(1)-receptor blocker CHEMICAL and the HMG-CoA reductase inhibitor rosuvastatin on infarct size and neuroscore in transient cerebral ischemia in rats. L-NAME was used to test whether any potential effect was due to activation of endothelial nitric oxide synthase (eNOS). Therefore, the middle cerebral artery was occluded for 1 h (MCAO) followed by 7 days reperfusion. Rats received CHEMICAL 2h before and daily after MCAO (pretreatment) or daily after MCAO (posttreatment); rosuvastatin was given daily for 7 days before MCAO without or with CHEMICAL pre- and posttreatment. In addition, CHEMICAL and rosuvastatin were combined with L-NAME. Infarct size and neuroscore at day 7 were compared to those of controls. As result, compared to controls (109+/-12 mm(3)) infarct size with CHEMICAL (pretreatment: 21+/-5 mm(3); posttreatment: 68+/-29 mm(3); P<0.05) or rosuvastatin (69+/-14 mm(3); P<0.05) was smaller. Combined treatment also reduced infarct size (pretreatment: 37+/-15 mm(3); posttreatment 57+/-20mm(3); P<0.05); but there was no benefit of combined treatment over CHEMICAL pretreatment alone. Compared to controls (2.08+/-0.28) only CHEMICAL pretreatment and combined treatment improved the neuroscore (0.97+/-0.05, 1.10+/-0.33; P<0.05). L-NAME abolished the reduction in infarct size and improvement in neuroscore. In conclusion, both, CHEMICAL or rosuvastatin treatment alone reduced infarct size in transient cerebral ischemia, and the best result was achieved with CHEMICAL pretreatment. Combined treatment was superior to rosuvastatin alone, but not to CHEMICAL. The therapeutic benefit of both agents was at least in parts mediated by eNOS-activation. | INHIBITOR |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma. Diacylglycerol (DAG) acts as an allosteric activator of protein kinase C (PKC) and is converted to phosphatidic acid by DAG kinase (DGK). Therefore, DGK is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. gammaPKC directly associated with GENE through its accessory domain (AD), depending on Ca2+ as well as phosphatidylserine/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that gammaPKC phosphorylated Ser-776 and Ser-779 in the AD of GENE. The phosphorylation by gammaPKC resulted in activation of GENE because a GENE mutant in which Ser-776 and Ser-779 were substituted with CHEMICAL to mimic phosphorylation exhibited significantly higher activity compared with wild type GENE and an unphosphorylatable GENE mutant. Importantly, the interaction of the two kinases and the phosphorylation of GENE by gammaPKC could be confirmed in vivo, and overexpression of the AD of GENE inhibited re-translocation of gammaPKC. These results demonstrate that localization and activation of the functionally correlated kinases, gammaPKC and GENE, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of GENE and DAG signaling. | PART-OF |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma. Diacylglycerol (DAG) acts as an allosteric activator of protein kinase C (PKC) and is converted to phosphatidic acid by DAG kinase (DGK). Therefore, DGK is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. GENE directly associated with DGKgamma through its accessory domain (AD), depending on Ca2+ as well as phosphatidylserine/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that GENE CHEMICAL-776 and Ser-779 in the AD of DGKgamma. The phosphorylation by GENE resulted in activation of DGKgamma because a DGKgamma mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type DGKgamma and an unphosphorylatable DGKgamma mutant. Importantly, the interaction of the two kinases and the phosphorylation of DGKgamma by GENE could be confirmed in vivo, and overexpression of the AD of DGKgamma inhibited re-translocation of GENE. These results demonstrate that localization and activation of the functionally correlated kinases, GENE and DGKgamma, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of DGKgamma and DAG signaling. | PART-OF |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma. Diacylglycerol (DAG) acts as an allosteric activator of protein kinase C (PKC) and is converted to phosphatidic acid by DAG kinase (DGK). Therefore, DGK is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. gammaPKC directly associated with GENE through its accessory domain (AD), depending on Ca2+ as well as phosphatidylserine/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that gammaPKC phosphorylated Ser-776 and CHEMICAL-779 in the AD of GENE. The phosphorylation by gammaPKC resulted in activation of GENE because a GENE mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type GENE and an unphosphorylatable GENE mutant. Importantly, the interaction of the two kinases and the phosphorylation of GENE by gammaPKC could be confirmed in vivo, and overexpression of the AD of GENE inhibited re-translocation of gammaPKC. These results demonstrate that localization and activation of the functionally correlated kinases, gammaPKC and GENE, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of GENE and DAG signaling. | PART-OF |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma. Diacylglycerol (DAG) acts as an allosteric activator of protein kinase C (PKC) and is converted to phosphatidic acid by DAG kinase (DGK). Therefore, DGK is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. GENE directly associated with DGKgamma through its accessory domain (AD), depending on CHEMICAL as well as phosphatidylserine/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that GENE phosphorylated Ser-776 and Ser-779 in the AD of DGKgamma. The phosphorylation by GENE resulted in activation of DGKgamma because a DGKgamma mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type DGKgamma and an unphosphorylatable DGKgamma mutant. Importantly, the interaction of the two kinases and the phosphorylation of DGKgamma by GENE could be confirmed in vivo, and overexpression of the AD of DGKgamma inhibited re-translocation of GENE. These results demonstrate that localization and activation of the functionally correlated kinases, GENE and DGKgamma, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of DGKgamma and DAG signaling. | REGULATOR |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma. Diacylglycerol (DAG) acts as an allosteric activator of protein kinase C (PKC) and is converted to phosphatidic acid by DAG kinase (DGK). Therefore, DGK is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. gammaPKC directly associated with GENE through its accessory domain (AD), depending on CHEMICAL as well as phosphatidylserine/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that gammaPKC phosphorylated Ser-776 and Ser-779 in the AD of GENE. The phosphorylation by gammaPKC resulted in activation of GENE because a GENE mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type GENE and an unphosphorylatable GENE mutant. Importantly, the interaction of the two kinases and the phosphorylation of GENE by gammaPKC could be confirmed in vivo, and overexpression of the AD of GENE inhibited re-translocation of gammaPKC. These results demonstrate that localization and activation of the functionally correlated kinases, gammaPKC and GENE, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of GENE and DAG signaling. | PART-OF |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma. Diacylglycerol (DAG) acts as an allosteric activator of protein kinase C (PKC) and is converted to phosphatidic acid by DAG kinase (DGK). Therefore, DGK is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. GENE directly associated with DGKgamma through its accessory domain (AD), depending on Ca2+ as well as CHEMICAL/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that GENE phosphorylated Ser-776 and Ser-779 in the AD of DGKgamma. The phosphorylation by GENE resulted in activation of DGKgamma because a DGKgamma mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type DGKgamma and an unphosphorylatable DGKgamma mutant. Importantly, the interaction of the two kinases and the phosphorylation of DGKgamma by GENE could be confirmed in vivo, and overexpression of the AD of DGKgamma inhibited re-translocation of GENE. These results demonstrate that localization and activation of the functionally correlated kinases, GENE and DGKgamma, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of DGKgamma and DAG signaling. | REGULATOR |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma. Diacylglycerol (DAG) acts as an allosteric activator of protein kinase C (PKC) and is converted to phosphatidic acid by DAG kinase (DGK). Therefore, DGK is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. gammaPKC directly associated with GENE through its accessory domain (AD), depending on Ca2+ as well as CHEMICAL/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that gammaPKC phosphorylated Ser-776 and Ser-779 in the AD of GENE. The phosphorylation by gammaPKC resulted in activation of GENE because a GENE mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type GENE and an unphosphorylatable GENE mutant. Importantly, the interaction of the two kinases and the phosphorylation of GENE by gammaPKC could be confirmed in vivo, and overexpression of the AD of GENE inhibited re-translocation of gammaPKC. These results demonstrate that localization and activation of the functionally correlated kinases, gammaPKC and GENE, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of GENE and DAG signaling. | REGULATOR |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma. Diacylglycerol (DAG) acts as an allosteric activator of protein kinase C (PKC) and is converted to phosphatidic acid by DAG kinase (DGK). Therefore, DGK is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. GENE directly associated with DGKgamma through its accessory domain (AD), depending on Ca2+ as well as phosphatidylserine/CHEMICAL in vitro. Mass spectrometric analysis and mutation studies revealed that GENE phosphorylated Ser-776 and Ser-779 in the AD of DGKgamma. The phosphorylation by GENE resulted in activation of DGKgamma because a DGKgamma mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type DGKgamma and an unphosphorylatable DGKgamma mutant. Importantly, the interaction of the two kinases and the phosphorylation of DGKgamma by GENE could be confirmed in vivo, and overexpression of the AD of DGKgamma inhibited re-translocation of GENE. These results demonstrate that localization and activation of the functionally correlated kinases, GENE and DGKgamma, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of DGKgamma and DAG signaling. | REGULATOR |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma. Diacylglycerol (DAG) acts as an allosteric activator of protein kinase C (PKC) and is converted to phosphatidic acid by DAG kinase (DGK). Therefore, DGK is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. gammaPKC directly associated with GENE through its accessory domain (AD), depending on Ca2+ as well as phosphatidylserine/CHEMICAL in vitro. Mass spectrometric analysis and mutation studies revealed that gammaPKC phosphorylated Ser-776 and Ser-779 in the AD of GENE. The phosphorylation by gammaPKC resulted in activation of GENE because a GENE mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type GENE and an unphosphorylatable GENE mutant. Importantly, the interaction of the two kinases and the phosphorylation of GENE by gammaPKC could be confirmed in vivo, and overexpression of the AD of GENE inhibited re-translocation of gammaPKC. These results demonstrate that localization and activation of the functionally correlated kinases, gammaPKC and GENE, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of GENE and DAG signaling. | PART-OF |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with GENE gamma. CHEMICAL (DAG) acts as an allosteric activator of GENE (PKC) and is converted to phosphatidic acid by DAG kinase (DGK). Therefore, DGK is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. gammaPKC directly associated with DGKgamma through its accessory domain (AD), depending on Ca2+ as well as phosphatidylserine/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that gammaPKC phosphorylated Ser-776 and Ser-779 in the AD of DGKgamma. The phosphorylation by gammaPKC resulted in activation of DGKgamma because a DGKgamma mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type DGKgamma and an unphosphorylatable DGKgamma mutant. Importantly, the interaction of the two kinases and the phosphorylation of DGKgamma by gammaPKC could be confirmed in vivo, and overexpression of the AD of DGKgamma inhibited re-translocation of gammaPKC. These results demonstrate that localization and activation of the functionally correlated kinases, gammaPKC and DGKgamma, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of DGKgamma and DAG signaling. | ACTIVATOR |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma. CHEMICAL (DAG) acts as an allosteric activator of protein kinase C (GENE) and is converted to phosphatidic acid by DAG kinase (DGK). Therefore, DGK is thought to be a negative regulator of GENE activation. Here we show molecular mechanisms of functional coupling of the two kinases. gammaPKC directly associated with DGKgamma through its accessory domain (AD), depending on Ca2+ as well as phosphatidylserine/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that gammaPKC phosphorylated Ser-776 and Ser-779 in the AD of DGKgamma. The phosphorylation by gammaPKC resulted in activation of DGKgamma because a DGKgamma mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type DGKgamma and an unphosphorylatable DGKgamma mutant. Importantly, the interaction of the two kinases and the phosphorylation of DGKgamma by gammaPKC could be confirmed in vivo, and overexpression of the AD of DGKgamma inhibited re-translocation of gammaPKC. These results demonstrate that localization and activation of the functionally correlated kinases, gammaPKC and DGKgamma, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of DGKgamma and DAG signaling. | ACTIVATOR |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with GENE gamma. Diacylglycerol (CHEMICAL) acts as an allosteric activator of GENE (PKC) and is converted to phosphatidic acid by CHEMICAL kinase (DGK). Therefore, DGK is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. gammaPKC directly associated with DGKgamma through its accessory domain (AD), depending on Ca2+ as well as phosphatidylserine/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that gammaPKC phosphorylated Ser-776 and Ser-779 in the AD of DGKgamma. The phosphorylation by gammaPKC resulted in activation of DGKgamma because a DGKgamma mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type DGKgamma and an unphosphorylatable DGKgamma mutant. Importantly, the interaction of the two kinases and the phosphorylation of DGKgamma by gammaPKC could be confirmed in vivo, and overexpression of the AD of DGKgamma inhibited re-translocation of gammaPKC. These results demonstrate that localization and activation of the functionally correlated kinases, gammaPKC and DGKgamma, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of DGKgamma and CHEMICAL signaling. | ACTIVATOR |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma. Diacylglycerol (CHEMICAL) acts as an allosteric activator of protein kinase C (GENE) and is converted to phosphatidic acid by CHEMICAL kinase (DGK). Therefore, DGK is thought to be a negative regulator of GENE activation. Here we show molecular mechanisms of functional coupling of the two kinases. gammaPKC directly associated with DGKgamma through its accessory domain (AD), depending on Ca2+ as well as phosphatidylserine/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that gammaPKC phosphorylated Ser-776 and Ser-779 in the AD of DGKgamma. The phosphorylation by gammaPKC resulted in activation of DGKgamma because a DGKgamma mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type DGKgamma and an unphosphorylatable DGKgamma mutant. Importantly, the interaction of the two kinases and the phosphorylation of DGKgamma by gammaPKC could be confirmed in vivo, and overexpression of the AD of DGKgamma inhibited re-translocation of gammaPKC. These results demonstrate that localization and activation of the functionally correlated kinases, gammaPKC and DGKgamma, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of DGKgamma and CHEMICAL signaling. | ACTIVATOR |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma. Diacylglycerol (DAG) acts as an allosteric activator of protein kinase C (PKC) and is converted to CHEMICAL by GENE (DGK). Therefore, DGK is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. gammaPKC directly associated with DGKgamma through its accessory domain (AD), depending on Ca2+ as well as phosphatidylserine/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that gammaPKC phosphorylated Ser-776 and Ser-779 in the AD of DGKgamma. The phosphorylation by gammaPKC resulted in activation of DGKgamma because a DGKgamma mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type DGKgamma and an unphosphorylatable DGKgamma mutant. Importantly, the interaction of the two kinases and the phosphorylation of DGKgamma by gammaPKC could be confirmed in vivo, and overexpression of the AD of DGKgamma inhibited re-translocation of gammaPKC. These results demonstrate that localization and activation of the functionally correlated kinases, gammaPKC and DGKgamma, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of DGKgamma and DAG signaling. | PRODUCT-OF |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma. Diacylglycerol (DAG) acts as an allosteric activator of protein kinase C (PKC) and is converted to CHEMICAL by DAG kinase (GENE). Therefore, GENE is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. gammaPKC directly associated with DGKgamma through its accessory domain (AD), depending on Ca2+ as well as phosphatidylserine/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that gammaPKC phosphorylated Ser-776 and Ser-779 in the AD of DGKgamma. The phosphorylation by gammaPKC resulted in activation of DGKgamma because a DGKgamma mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type DGKgamma and an unphosphorylatable DGKgamma mutant. Importantly, the interaction of the two kinases and the phosphorylation of DGKgamma by gammaPKC could be confirmed in vivo, and overexpression of the AD of DGKgamma inhibited re-translocation of gammaPKC. These results demonstrate that localization and activation of the functionally correlated kinases, gammaPKC and DGKgamma, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of DGKgamma and DAG signaling. | PRODUCT-OF |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma. CHEMICAL (DAG) acts as an allosteric activator of protein kinase C (PKC) and is converted to phosphatidic acid by GENE (DGK). Therefore, DGK is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. gammaPKC directly associated with DGKgamma through its accessory domain (AD), depending on Ca2+ as well as phosphatidylserine/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that gammaPKC phosphorylated Ser-776 and Ser-779 in the AD of DGKgamma. The phosphorylation by gammaPKC resulted in activation of DGKgamma because a DGKgamma mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type DGKgamma and an unphosphorylatable DGKgamma mutant. Importantly, the interaction of the two kinases and the phosphorylation of DGKgamma by gammaPKC could be confirmed in vivo, and overexpression of the AD of DGKgamma inhibited re-translocation of gammaPKC. These results demonstrate that localization and activation of the functionally correlated kinases, gammaPKC and DGKgamma, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of DGKgamma and DAG signaling. | SUBSTRATE |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma. CHEMICAL (DAG) acts as an allosteric activator of protein kinase C (PKC) and is converted to phosphatidic acid by DAG kinase (GENE). Therefore, GENE is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. gammaPKC directly associated with DGKgamma through its accessory domain (AD), depending on Ca2+ as well as phosphatidylserine/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that gammaPKC phosphorylated Ser-776 and Ser-779 in the AD of DGKgamma. The phosphorylation by gammaPKC resulted in activation of DGKgamma because a DGKgamma mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type DGKgamma and an unphosphorylatable DGKgamma mutant. Importantly, the interaction of the two kinases and the phosphorylation of DGKgamma by gammaPKC could be confirmed in vivo, and overexpression of the AD of DGKgamma inhibited re-translocation of gammaPKC. These results demonstrate that localization and activation of the functionally correlated kinases, gammaPKC and DGKgamma, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of DGKgamma and DAG signaling. | SUBSTRATE |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma. Diacylglycerol (CHEMICAL) acts as an allosteric activator of protein kinase C (PKC) and is converted to phosphatidic acid by GENE (DGK). Therefore, DGK is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. gammaPKC directly associated with DGKgamma through its accessory domain (AD), depending on Ca2+ as well as phosphatidylserine/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that gammaPKC phosphorylated Ser-776 and Ser-779 in the AD of DGKgamma. The phosphorylation by gammaPKC resulted in activation of DGKgamma because a DGKgamma mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type DGKgamma and an unphosphorylatable DGKgamma mutant. Importantly, the interaction of the two kinases and the phosphorylation of DGKgamma by gammaPKC could be confirmed in vivo, and overexpression of the AD of DGKgamma inhibited re-translocation of gammaPKC. These results demonstrate that localization and activation of the functionally correlated kinases, gammaPKC and DGKgamma, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of DGKgamma and CHEMICAL signaling. | PRODUCT-OF |
| Phosphorylation and up-regulation of diacylglycerol kinase gamma via its interaction with protein kinase C gamma. Diacylglycerol (CHEMICAL) acts as an allosteric activator of protein kinase C (PKC) and is converted to phosphatidic acid by CHEMICAL kinase (GENE). Therefore, GENE is thought to be a negative regulator of PKC activation. Here we show molecular mechanisms of functional coupling of the two kinases. gammaPKC directly associated with DGKgamma through its accessory domain (AD), depending on Ca2+ as well as phosphatidylserine/diolein in vitro. Mass spectrometric analysis and mutation studies revealed that gammaPKC phosphorylated Ser-776 and Ser-779 in the AD of DGKgamma. The phosphorylation by gammaPKC resulted in activation of DGKgamma because a DGKgamma mutant in which Ser-776 and Ser-779 were substituted with glutamic acid to mimic phosphorylation exhibited significantly higher activity compared with wild type DGKgamma and an unphosphorylatable DGKgamma mutant. Importantly, the interaction of the two kinases and the phosphorylation of DGKgamma by gammaPKC could be confirmed in vivo, and overexpression of the AD of DGKgamma inhibited re-translocation of gammaPKC. These results demonstrate that localization and activation of the functionally correlated kinases, gammaPKC and DGKgamma, are spatio-temporally orchestrated by their direct association and phosphorylation, contributing to subtype-specific regulation of DGKgamma and CHEMICAL signaling. | ACTIVATOR |
| Differences in conformational stability between native and phosphorylated acetylcholinesterase as evidenced by a monoclonal antibody. Monoclonal antibody 25B1 generated against diisopropyl phosphorofluoridate inhibited fetal bovine serum acetylcholinesterase has been extensively characterized with respect to its anticholinesterase properties. This antibody demonstrated considerably different properties from previously reported inhibitory antibodies raised against acetylcholinesterase in terms of the degree of inhibition (greater than 98%), the high degree of specificity, and the stability of the antigen-antibody complex. Monoclonal antibody 25B1 appears to be directed against a conformational epitope located in close proximity to the catalytic center of the enzyme and was found to be most suitable for studying the stabilization of the active site of acetylcholinesterase against denaturation by heat or guanidine following phosphorylation by organophosphorus anticholinesterase compounds. This approach allowed the determination of stability rank order of various phosphorylated acetylcholinesterases. Among all the organophosphates tested, the combination of a methyl group and a negatively charged CHEMICAL attached to the P atom, CH3P(O)(O-)-GENE, conferred the greatest protection to the active site of aged or nonaged organophosphoryl conjugates of acetylcholinesterase. | PART-OF |
| Differences in conformational stability between native and phosphorylated acetylcholinesterase as evidenced by a monoclonal antibody. Monoclonal antibody 25B1 generated against diisopropyl phosphorofluoridate inhibited fetal bovine serum acetylcholinesterase has been extensively characterized with respect to its anticholinesterase properties. This antibody demonstrated considerably different properties from previously reported inhibitory antibodies raised against acetylcholinesterase in terms of the degree of inhibition (greater than 98%), the high degree of specificity, and the stability of the antigen-antibody complex. Monoclonal antibody 25B1 appears to be directed against a conformational epitope located in close proximity to the catalytic center of the enzyme and was found to be most suitable for studying the stabilization of the active site of acetylcholinesterase against denaturation by heat or guanidine following phosphorylation by organophosphorus anticholinesterase compounds. This approach allowed the determination of stability rank order of various phosphorylated acetylcholinesterases. Among all the organophosphates tested, the combination of a methyl group and a negatively charged oxygen attached to the CHEMICAL atom, CH3P(O)(O-)-GENE, conferred the greatest protection to the active site of aged or nonaged organophosphoryl conjugates of acetylcholinesterase. | PART-OF |
| Differences in conformational stability between native and phosphorylated acetylcholinesterase as evidenced by a monoclonal antibody. Monoclonal antibody 25B1 generated against diisopropyl phosphorofluoridate inhibited fetal bovine serum acetylcholinesterase has been extensively characterized with respect to its anticholinesterase properties. This antibody demonstrated considerably different properties from previously reported inhibitory antibodies raised against acetylcholinesterase in terms of the degree of inhibition (greater than 98%), the high degree of specificity, and the stability of the antigen-antibody complex. Monoclonal antibody 25B1 appears to be directed against a conformational epitope located in close proximity to the catalytic center of the enzyme and was found to be most suitable for studying the stabilization of the active site of acetylcholinesterase against denaturation by heat or guanidine following phosphorylation by organophosphorus anticholinesterase compounds. This approach allowed the determination of stability rank order of various phosphorylated acetylcholinesterases. Among all the organophosphates tested, the combination of a methyl group and a negatively charged oxygen attached to the P atom, CHEMICAL-GENE, conferred the greatest protection to the active site of aged or nonaged organophosphoryl conjugates of acetylcholinesterase. | PART-OF |
| Differences in conformational stability between native and phosphorylated GENE as evidenced by a monoclonal antibody. Monoclonal antibody 25B1 generated against diisopropyl phosphorofluoridate inhibited fetal bovine serum GENE has been extensively characterized with respect to its anticholinesterase properties. This antibody demonstrated considerably different properties from previously reported inhibitory antibodies raised against GENE in terms of the degree of inhibition (greater than 98%), the high degree of specificity, and the stability of the antigen-antibody complex. Monoclonal antibody 25B1 appears to be directed against a conformational epitope located in close proximity to the catalytic center of the enzyme and was found to be most suitable for studying the stabilization of the active site of GENE against denaturation by heat or guanidine following phosphorylation by organophosphorus anticholinesterase compounds. This approach allowed the determination of stability rank order of various phosphorylated acetylcholinesterases. Among all the organophosphates tested, the combination of a methyl group and a negatively charged oxygen attached to the P atom, CH3P(O)(O-)-AChE, conferred the greatest protection to the active site of aged or nonaged CHEMICAL conjugates of GENE. | DIRECT-REGULATOR |
| Differences in conformational stability between native and phosphorylated acetylcholinesterase as evidenced by a monoclonal antibody. Monoclonal antibody 25B1 generated against diisopropyl phosphorofluoridate inhibited fetal bovine serum acetylcholinesterase has been extensively characterized with respect to its anticholinesterase properties. This antibody demonstrated considerably different properties from previously reported inhibitory antibodies raised against acetylcholinesterase in terms of the degree of inhibition (greater than 98%), the high degree of specificity, and the stability of the antigen-antibody complex. Monoclonal antibody 25B1 appears to be directed against a conformational epitope located in close proximity to the catalytic center of the enzyme and was found to be most suitable for studying the stabilization of the active site of acetylcholinesterase against denaturation by heat or guanidine following phosphorylation by organophosphorus anticholinesterase compounds. This approach allowed the determination of stability rank order of various phosphorylated acetylcholinesterases. Among all the CHEMICAL tested, the combination of a methyl group and a negatively charged oxygen attached to the P atom, CH3P(O)(O-)-GENE, conferred the greatest protection to the active site of aged or nonaged organophosphoryl conjugates of acetylcholinesterase. | REGULATOR |
| Differences in conformational stability between native and phosphorylated GENE as evidenced by a monoclonal antibody. Monoclonal antibody 25B1 generated against diisopropyl phosphorofluoridate inhibited fetal bovine serum GENE has been extensively characterized with respect to its anticholinesterase properties. This antibody demonstrated considerably different properties from previously reported inhibitory antibodies raised against GENE in terms of the degree of inhibition (greater than 98%), the high degree of specificity, and the stability of the antigen-antibody complex. Monoclonal antibody 25B1 appears to be directed against a conformational epitope located in close proximity to the catalytic center of the enzyme and was found to be most suitable for studying the stabilization of the active site of GENE against denaturation by heat or CHEMICAL following phosphorylation by organophosphorus anticholinesterase compounds. This approach allowed the determination of stability rank order of various phosphorylated acetylcholinesterases. Among all the organophosphates tested, the combination of a methyl group and a negatively charged oxygen attached to the P atom, CH3P(O)(O-)-AChE, conferred the greatest protection to the active site of aged or nonaged organophosphoryl conjugates of GENE. | DIRECT-REGULATOR |
| Differences in conformational stability between native and phosphorylated acetylcholinesterase as evidenced by a monoclonal antibody. Monoclonal antibody 25B1 generated against CHEMICAL inhibited fetal GENE has been extensively characterized with respect to its anticholinesterase properties. This antibody demonstrated considerably different properties from previously reported inhibitory antibodies raised against acetylcholinesterase in terms of the degree of inhibition (greater than 98%), the high degree of specificity, and the stability of the antigen-antibody complex. Monoclonal antibody 25B1 appears to be directed against a conformational epitope located in close proximity to the catalytic center of the enzyme and was found to be most suitable for studying the stabilization of the active site of acetylcholinesterase against denaturation by heat or guanidine following phosphorylation by organophosphorus anticholinesterase compounds. This approach allowed the determination of stability rank order of various phosphorylated acetylcholinesterases. Among all the organophosphates tested, the combination of a methyl group and a negatively charged oxygen attached to the P atom, CH3P(O)(O-)-AChE, conferred the greatest protection to the active site of aged or nonaged organophosphoryl conjugates of acetylcholinesterase. | INHIBITOR |
| Effects of CHEMICAL deficiency and GENE C677T polymorphism on spontaneous and radiation-induced micronuclei in human lymphocytes. CHEMICAL plays a key role in the maintenance of genomic stability, providing methyl groups for the conversion of uracil to thymine and for DNA methylation. Besides dietary habits, CHEMICAL metabolism is influenced by genetic polymorphism. The C677T polymorphism of the methylene-tetrahydrofolate reductase (MTHFR) gene is associated with a reduction of catalytic activity and is suggested to modify cancer risk differently depending on folate status. In this work the effect of CHEMICAL deficiency on genome stability and radiosensitivity has been investigated in cultured lymphocytes of 12 subjects with different GENE genotype (four for each genotype). Cells were grown for 9 days with 12, 24 and 120 nM CHEMICAL and analyzed in a comprehensive micronucleus test coupled with centromere characterization by CREST immunostaining. In other experiments, cells were grown with various CHEMICAL concentrations, irradiated with 0.5 Gy of gamma rays and analyzed in the micronucleus test. The results obtained indicate that CHEMICAL deficiency induces to a comparable extent chromosome loss and breakage, irrespective of the GENE genotype. The effect of CHEMICAL was highly significant (P < 0.001) and explained >50% of variance of both types of micronuclei. Also nucleoplasmic bridges and buds were significantly increased under low folate supply; the increase in bridges was mainly observed in TT cells, highlighting a significant effect of the GENE genotype (P = 0.006) on this biomarker. CHEMICAL concentration significantly affected radiation-induced micronuclei (P < 0.001): the increased incidence of radiation-induced micronuclei with low CHEMICAL was mainly accounted for by carriers of the variant GENE allele (both homozygotes and heterozygotes), but the overall effect of genotype did not attain statistical significance. Treatment with ionizing radiations also increased the frequency of nucleoplasmic bridges. The effect of CHEMICAL level on this end-point was modulated by the GENE genotype (P for interaction = 0.02), with TT cells grown at low CHEMICAL concentration apparently resistant to the induction of radiation-induced bridges. Finally, the effect of in vitro folate deprivation on global DNA methylation was evaluated in lymphocytes of six homozygous subjects (three CC and three TT). The results obtained suggest that, under the conditions of this work, CHEMICAL deprivation is associated with global DNA hypermethylation. | GENE-CHEMICAL |
| Effects of folic acid deficiency and MTHFR GENE polymorphism on spontaneous and radiation-induced micronuclei in human lymphocytes. Folic acid plays a key role in the maintenance of genomic stability, providing methyl groups for the conversion of uracil to thymine and for DNA methylation. Besides dietary habits, folic acid metabolism is influenced by genetic polymorphism. The GENE polymorphism of the methylene-tetrahydrofolate reductase (MTHFR) gene is associated with a reduction of catalytic activity and is suggested to modify cancer risk differently depending on CHEMICAL status. In this work the effect of folic acid deficiency on genome stability and radiosensitivity has been investigated in cultured lymphocytes of 12 subjects with different MTHFR genotype (four for each genotype). Cells were grown for 9 days with 12, 24 and 120 nM folic acid and analyzed in a comprehensive micronucleus test coupled with centromere characterization by CREST immunostaining. In other experiments, cells were grown with various folic acid concentrations, irradiated with 0.5 Gy of gamma rays and analyzed in the micronucleus test. The results obtained indicate that folic acid deficiency induces to a comparable extent chromosome loss and breakage, irrespective of the MTHFR genotype. The effect of folic acid was highly significant (P < 0.001) and explained >50% of variance of both types of micronuclei. Also nucleoplasmic bridges and buds were significantly increased under low CHEMICAL supply; the increase in bridges was mainly observed in TT cells, highlighting a significant effect of the MTHFR genotype (P = 0.006) on this biomarker. Folic acid concentration significantly affected radiation-induced micronuclei (P < 0.001): the increased incidence of radiation-induced micronuclei with low folic acid was mainly accounted for by carriers of the variant MTHFR allele (both homozygotes and heterozygotes), but the overall effect of genotype did not attain statistical significance. Treatment with ionizing radiations also increased the frequency of nucleoplasmic bridges. The effect of folic acid level on this end-point was modulated by the MTHFR genotype (P for interaction = 0.02), with TT cells grown at low folic acid concentration apparently resistant to the induction of radiation-induced bridges. Finally, the effect of in vitro CHEMICAL deprivation on global DNA methylation was evaluated in lymphocytes of six homozygous subjects (three CC and three TT). The results obtained suggest that, under the conditions of this work, folic acid deprivation is associated with global DNA hypermethylation. | GENE-CHEMICAL |
| Effects of folic acid deficiency and MTHFR C677T polymorphism on spontaneous and radiation-induced micronuclei in human lymphocytes. Folic acid plays a key role in the maintenance of genomic stability, providing methyl groups for the conversion of uracil to thymine and for DNA methylation. Besides dietary habits, folic acid metabolism is influenced by genetic polymorphism. The C677T polymorphism of the GENE (MTHFR) gene is associated with a reduction of catalytic activity and is suggested to modify cancer risk differently depending on CHEMICAL status. In this work the effect of folic acid deficiency on genome stability and radiosensitivity has been investigated in cultured lymphocytes of 12 subjects with different MTHFR genotype (four for each genotype). Cells were grown for 9 days with 12, 24 and 120 nM folic acid and analyzed in a comprehensive micronucleus test coupled with centromere characterization by CREST immunostaining. In other experiments, cells were grown with various folic acid concentrations, irradiated with 0.5 Gy of gamma rays and analyzed in the micronucleus test. The results obtained indicate that folic acid deficiency induces to a comparable extent chromosome loss and breakage, irrespective of the MTHFR genotype. The effect of folic acid was highly significant (P < 0.001) and explained >50% of variance of both types of micronuclei. Also nucleoplasmic bridges and buds were significantly increased under low CHEMICAL supply; the increase in bridges was mainly observed in TT cells, highlighting a significant effect of the MTHFR genotype (P = 0.006) on this biomarker. Folic acid concentration significantly affected radiation-induced micronuclei (P < 0.001): the increased incidence of radiation-induced micronuclei with low folic acid was mainly accounted for by carriers of the variant MTHFR allele (both homozygotes and heterozygotes), but the overall effect of genotype did not attain statistical significance. Treatment with ionizing radiations also increased the frequency of nucleoplasmic bridges. The effect of folic acid level on this end-point was modulated by the MTHFR genotype (P for interaction = 0.02), with TT cells grown at low folic acid concentration apparently resistant to the induction of radiation-induced bridges. Finally, the effect of in vitro CHEMICAL deprivation on global DNA methylation was evaluated in lymphocytes of six homozygous subjects (three CC and three TT). The results obtained suggest that, under the conditions of this work, folic acid deprivation is associated with global DNA hypermethylation. | GENE-CHEMICAL |
| Effects of folic acid deficiency and GENE C677T polymorphism on spontaneous and radiation-induced micronuclei in human lymphocytes. Folic acid plays a key role in the maintenance of genomic stability, providing methyl groups for the conversion of uracil to thymine and for DNA methylation. Besides dietary habits, folic acid metabolism is influenced by genetic polymorphism. The C677T polymorphism of the methylene-tetrahydrofolate reductase (GENE) gene is associated with a reduction of catalytic activity and is suggested to modify cancer risk differently depending on CHEMICAL status. In this work the effect of folic acid deficiency on genome stability and radiosensitivity has been investigated in cultured lymphocytes of 12 subjects with different GENE genotype (four for each genotype). Cells were grown for 9 days with 12, 24 and 120 nM folic acid and analyzed in a comprehensive micronucleus test coupled with centromere characterization by CREST immunostaining. In other experiments, cells were grown with various folic acid concentrations, irradiated with 0.5 Gy of gamma rays and analyzed in the micronucleus test. The results obtained indicate that folic acid deficiency induces to a comparable extent chromosome loss and breakage, irrespective of the GENE genotype. The effect of folic acid was highly significant (P < 0.001) and explained >50% of variance of both types of micronuclei. Also nucleoplasmic bridges and buds were significantly increased under low CHEMICAL supply; the increase in bridges was mainly observed in TT cells, highlighting a significant effect of the GENE genotype (P = 0.006) on this biomarker. Folic acid concentration significantly affected radiation-induced micronuclei (P < 0.001): the increased incidence of radiation-induced micronuclei with low folic acid was mainly accounted for by carriers of the variant GENE allele (both homozygotes and heterozygotes), but the overall effect of genotype did not attain statistical significance. Treatment with ionizing radiations also increased the frequency of nucleoplasmic bridges. The effect of folic acid level on this end-point was modulated by the GENE genotype (P for interaction = 0.02), with TT cells grown at low folic acid concentration apparently resistant to the induction of radiation-induced bridges. Finally, the effect of in vitro CHEMICAL deprivation on global DNA methylation was evaluated in lymphocytes of six homozygous subjects (three CC and three TT). The results obtained suggest that, under the conditions of this work, folic acid deprivation is associated with global DNA hypermethylation. | GENE-CHEMICAL |
| Antifungal agents: mode of action in yeast cells. Different kinds of mycoses, especially invasive, have become an important public health problem as their incidence has increased dramatically in the last decades in relation to AIDS, hematological malignancies, transplant recipients and other immunosuppressed individuals. Management of fungal infections is markedly limited by problems of drug safety, resistance and effectiveness profile. Current therapy for invasive mycoses uses a relatively reduced number of antifungal drugs, such as amphotericin B, fluconazole and itraconazole. Other new antifungal agents from old and new chemical families, like voriconazole, posaconazole, ravuconazole, caspofungin and micafungin, have been introduced into the armamentarium for fungal infections management. This review is focused on the mode of action of those antifungal drugs used against pathogenic yeasts. The interaction of amphotericin B with ergosterol and other membrane sterols results in the production of aqueous pores of drug and the ergosterol biosynthetic pathway is the target of the allylamines, phenylmorpholines and CHEMICAL antifungal agents. The main molecular target of CHEMICAL antifungals is the GENE protein Erg11p/Cyp51p. Echinocandins, a new class of antifungal drugs, are fungal secondary metabolites that act against beta-1-3-D-glucan synthesis. The phenylmorpholines, of which amorolfine is the sole representative in human therapy, affect two targets in the ergosterol pathway: Erg24p (delta 14 reductase) and Erg2p (delta 8-delta 7 isomerase). The sordarins group are protein synthesis inhibitors that work by blocking the function of fungal translation elongation factor 2. Other protein inhibitors are zofimarin, BE31045, SCH57504, xylarin, hypoxysordarin and GR135402. In order to overcome the problems derived from the exploitation of CHEMICAL drugs, macrolides and echinocandins, novel targets were explored. Proposed antifungal drugs have been developed against potential targets like the N-myristylation of fungal proteins, with inhibitors like myristate and histidine analogues or myristoylpeptide derivatives, aminobenzothiazoles, quinolines and benzofurans. Polymerization of cell wall carbohydrates from uridine di-phospho sugars is another potential target. | REGULATOR |
| Antifungal agents: mode of action in yeast cells. Different kinds of mycoses, especially invasive, have become an important public health problem as their incidence has increased dramatically in the last decades in relation to AIDS, hematological malignancies, transplant recipients and other immunosuppressed individuals. Management of fungal infections is markedly limited by problems of drug safety, resistance and effectiveness profile. Current therapy for invasive mycoses uses a relatively reduced number of antifungal drugs, such as amphotericin B, fluconazole and itraconazole. Other new antifungal agents from old and new chemical families, like voriconazole, posaconazole, ravuconazole, caspofungin and micafungin, have been introduced into the armamentarium for fungal infections management. This review is focused on the mode of action of those antifungal drugs used against pathogenic yeasts. The interaction of amphotericin B with ergosterol and other membrane sterols results in the production of aqueous pores of drug and the ergosterol biosynthetic pathway is the target of the allylamines, phenylmorpholines and CHEMICAL antifungal agents. The main molecular target of CHEMICAL antifungals is the cytochrome P-450 protein GENE/Cyp51p. Echinocandins, a new class of antifungal drugs, are fungal secondary metabolites that act against beta-1-3-D-glucan synthesis. The phenylmorpholines, of which amorolfine is the sole representative in human therapy, affect two targets in the ergosterol pathway: Erg24p (delta 14 reductase) and Erg2p (delta 8-delta 7 isomerase). The sordarins group are protein synthesis inhibitors that work by blocking the function of fungal translation elongation factor 2. Other protein inhibitors are zofimarin, BE31045, SCH57504, xylarin, hypoxysordarin and GR135402. In order to overcome the problems derived from the exploitation of CHEMICAL drugs, macrolides and echinocandins, novel targets were explored. Proposed antifungal drugs have been developed against potential targets like the N-myristylation of fungal proteins, with inhibitors like myristate and histidine analogues or myristoylpeptide derivatives, aminobenzothiazoles, quinolines and benzofurans. Polymerization of cell wall carbohydrates from uridine di-phospho sugars is another potential target. | REGULATOR |
| Antifungal agents: mode of action in yeast cells. Different kinds of mycoses, especially invasive, have become an important public health problem as their incidence has increased dramatically in the last decades in relation to AIDS, hematological malignancies, transplant recipients and other immunosuppressed individuals. Management of fungal infections is markedly limited by problems of drug safety, resistance and effectiveness profile. Current therapy for invasive mycoses uses a relatively reduced number of antifungal drugs, such as amphotericin B, fluconazole and itraconazole. Other new antifungal agents from old and new chemical families, like voriconazole, posaconazole, ravuconazole, caspofungin and micafungin, have been introduced into the armamentarium for fungal infections management. This review is focused on the mode of action of those antifungal drugs used against pathogenic yeasts. The interaction of amphotericin B with ergosterol and other membrane sterols results in the production of aqueous pores of drug and the ergosterol biosynthetic pathway is the target of the allylamines, phenylmorpholines and CHEMICAL antifungal agents. The main molecular target of CHEMICAL antifungals is the cytochrome P-450 protein Erg11p/GENE. Echinocandins, a new class of antifungal drugs, are fungal secondary metabolites that act against beta-1-3-D-glucan synthesis. The phenylmorpholines, of which amorolfine is the sole representative in human therapy, affect two targets in the ergosterol pathway: Erg24p (delta 14 reductase) and Erg2p (delta 8-delta 7 isomerase). The sordarins group are protein synthesis inhibitors that work by blocking the function of fungal translation elongation factor 2. Other protein inhibitors are zofimarin, BE31045, SCH57504, xylarin, hypoxysordarin and GR135402. In order to overcome the problems derived from the exploitation of CHEMICAL drugs, macrolides and echinocandins, novel targets were explored. Proposed antifungal drugs have been developed against potential targets like the N-myristylation of fungal proteins, with inhibitors like myristate and histidine analogues or myristoylpeptide derivatives, aminobenzothiazoles, quinolines and benzofurans. Polymerization of cell wall carbohydrates from uridine di-phospho sugars is another potential target. | REGULATOR |
| Antifungal agents: mode of action in yeast cells. Different kinds of mycoses, especially invasive, have become an important public health problem as their incidence has increased dramatically in the last decades in relation to AIDS, hematological malignancies, transplant recipients and other immunosuppressed individuals. Management of fungal infections is markedly limited by problems of drug safety, resistance and effectiveness profile. Current therapy for invasive mycoses uses a relatively reduced number of antifungal drugs, such as amphotericin B, fluconazole and itraconazole. Other new antifungal agents from old and new chemical families, like voriconazole, posaconazole, ravuconazole, caspofungin and micafungin, have been introduced into the armamentarium for fungal infections management. This review is focused on the mode of action of those antifungal drugs used against pathogenic yeasts. The interaction of amphotericin B with ergosterol and other membrane sterols results in the production of aqueous pores of drug and the ergosterol biosynthetic pathway is the target of the allylamines, CHEMICAL and azole antifungal agents. The main molecular target of azole antifungals is the cytochrome P-450 protein Erg11p/Cyp51p. Echinocandins, a new class of antifungal drugs, are fungal secondary metabolites that act against beta-1-3-D-glucan synthesis. The CHEMICAL, of which amorolfine is the sole representative in human therapy, affect two targets in the ergosterol pathway: GENE (delta 14 reductase) and Erg2p (delta 8-delta 7 isomerase). The sordarins group are protein synthesis inhibitors that work by blocking the function of fungal translation elongation factor 2. Other protein inhibitors are zofimarin, BE31045, SCH57504, xylarin, hypoxysordarin and GR135402. In order to overcome the problems derived from the exploitation of azole drugs, macrolides and echinocandins, novel targets were explored. Proposed antifungal drugs have been developed against potential targets like the N-myristylation of fungal proteins, with inhibitors like myristate and histidine analogues or myristoylpeptide derivatives, aminobenzothiazoles, quinolines and benzofurans. Polymerization of cell wall carbohydrates from uridine di-phospho sugars is another potential target. | REGULATOR |
| Antifungal agents: mode of action in yeast cells. Different kinds of mycoses, especially invasive, have become an important public health problem as their incidence has increased dramatically in the last decades in relation to AIDS, hematological malignancies, transplant recipients and other immunosuppressed individuals. Management of fungal infections is markedly limited by problems of drug safety, resistance and effectiveness profile. Current therapy for invasive mycoses uses a relatively reduced number of antifungal drugs, such as amphotericin B, fluconazole and itraconazole. Other new antifungal agents from old and new chemical families, like voriconazole, posaconazole, ravuconazole, caspofungin and micafungin, have been introduced into the armamentarium for fungal infections management. This review is focused on the mode of action of those antifungal drugs used against pathogenic yeasts. The interaction of amphotericin B with ergosterol and other membrane sterols results in the production of aqueous pores of drug and the ergosterol biosynthetic pathway is the target of the allylamines, CHEMICAL and azole antifungal agents. The main molecular target of azole antifungals is the cytochrome P-450 protein Erg11p/Cyp51p. Echinocandins, a new class of antifungal drugs, are fungal secondary metabolites that act against beta-1-3-D-glucan synthesis. The CHEMICAL, of which amorolfine is the sole representative in human therapy, affect two targets in the ergosterol pathway: Erg24p (GENE) and Erg2p (delta 8-delta 7 isomerase). The sordarins group are protein synthesis inhibitors that work by blocking the function of fungal translation elongation factor 2. Other protein inhibitors are zofimarin, BE31045, SCH57504, xylarin, hypoxysordarin and GR135402. In order to overcome the problems derived from the exploitation of azole drugs, macrolides and echinocandins, novel targets were explored. Proposed antifungal drugs have been developed against potential targets like the N-myristylation of fungal proteins, with inhibitors like myristate and histidine analogues or myristoylpeptide derivatives, aminobenzothiazoles, quinolines and benzofurans. Polymerization of cell wall carbohydrates from uridine di-phospho sugars is another potential target. | REGULATOR |
| Antifungal agents: mode of action in yeast cells. Different kinds of mycoses, especially invasive, have become an important public health problem as their incidence has increased dramatically in the last decades in relation to AIDS, hematological malignancies, transplant recipients and other immunosuppressed individuals. Management of fungal infections is markedly limited by problems of drug safety, resistance and effectiveness profile. Current therapy for invasive mycoses uses a relatively reduced number of antifungal drugs, such as amphotericin B, fluconazole and itraconazole. Other new antifungal agents from old and new chemical families, like voriconazole, posaconazole, ravuconazole, caspofungin and micafungin, have been introduced into the armamentarium for fungal infections management. This review is focused on the mode of action of those antifungal drugs used against pathogenic yeasts. The interaction of amphotericin B with ergosterol and other membrane sterols results in the production of aqueous pores of drug and the ergosterol biosynthetic pathway is the target of the allylamines, CHEMICAL and azole antifungal agents. The main molecular target of azole antifungals is the cytochrome P-450 protein Erg11p/Cyp51p. Echinocandins, a new class of antifungal drugs, are fungal secondary metabolites that act against beta-1-3-D-glucan synthesis. The CHEMICAL, of which amorolfine is the sole representative in human therapy, affect two targets in the ergosterol pathway: Erg24p (delta 14 reductase) and GENE (delta 8-delta 7 isomerase). The sordarins group are protein synthesis inhibitors that work by blocking the function of fungal translation elongation factor 2. Other protein inhibitors are zofimarin, BE31045, SCH57504, xylarin, hypoxysordarin and GR135402. In order to overcome the problems derived from the exploitation of azole drugs, macrolides and echinocandins, novel targets were explored. Proposed antifungal drugs have been developed against potential targets like the N-myristylation of fungal proteins, with inhibitors like myristate and histidine analogues or myristoylpeptide derivatives, aminobenzothiazoles, quinolines and benzofurans. Polymerization of cell wall carbohydrates from uridine di-phospho sugars is another potential target. | REGULATOR |
| Antifungal agents: mode of action in yeast cells. Different kinds of mycoses, especially invasive, have become an important public health problem as their incidence has increased dramatically in the last decades in relation to AIDS, hematological malignancies, transplant recipients and other immunosuppressed individuals. Management of fungal infections is markedly limited by problems of drug safety, resistance and effectiveness profile. Current therapy for invasive mycoses uses a relatively reduced number of antifungal drugs, such as amphotericin B, fluconazole and itraconazole. Other new antifungal agents from old and new chemical families, like voriconazole, posaconazole, ravuconazole, caspofungin and micafungin, have been introduced into the armamentarium for fungal infections management. This review is focused on the mode of action of those antifungal drugs used against pathogenic yeasts. The interaction of amphotericin B with ergosterol and other membrane sterols results in the production of aqueous pores of drug and the ergosterol biosynthetic pathway is the target of the allylamines, CHEMICAL and azole antifungal agents. The main molecular target of azole antifungals is the cytochrome P-450 protein Erg11p/Cyp51p. Echinocandins, a new class of antifungal drugs, are fungal secondary metabolites that act against beta-1-3-D-glucan synthesis. The CHEMICAL, of which amorolfine is the sole representative in human therapy, affect two targets in the ergosterol pathway: Erg24p (delta 14 reductase) and Erg2p (GENE). The sordarins group are protein synthesis inhibitors that work by blocking the function of fungal translation elongation factor 2. Other protein inhibitors are zofimarin, BE31045, SCH57504, xylarin, hypoxysordarin and GR135402. In order to overcome the problems derived from the exploitation of azole drugs, macrolides and echinocandins, novel targets were explored. Proposed antifungal drugs have been developed against potential targets like the N-myristylation of fungal proteins, with inhibitors like myristate and histidine analogues or myristoylpeptide derivatives, aminobenzothiazoles, quinolines and benzofurans. Polymerization of cell wall carbohydrates from uridine di-phospho sugars is another potential target. | REGULATOR |
| Antifungal agents: mode of action in yeast cells. Different kinds of mycoses, especially invasive, have become an important public health problem as their incidence has increased dramatically in the last decades in relation to AIDS, hematological malignancies, transplant recipients and other immunosuppressed individuals. Management of fungal infections is markedly limited by problems of drug safety, resistance and effectiveness profile. Current therapy for invasive mycoses uses a relatively reduced number of antifungal drugs, such as amphotericin B, fluconazole and itraconazole. Other new antifungal agents from old and new chemical families, like voriconazole, posaconazole, ravuconazole, caspofungin and micafungin, have been introduced into the armamentarium for fungal infections management. This review is focused on the mode of action of those antifungal drugs used against pathogenic yeasts. The interaction of amphotericin B with ergosterol and other membrane sterols results in the production of aqueous pores of drug and the ergosterol biosynthetic pathway is the target of the allylamines, phenylmorpholines and azole antifungal agents. The main molecular target of azole antifungals is the cytochrome P-450 protein Erg11p/Cyp51p. Echinocandins, a new class of antifungal drugs, are fungal secondary metabolites that act against beta-1-3-D-glucan synthesis. The phenylmorpholines, of which CHEMICAL is the sole representative in human therapy, affect two targets in the ergosterol pathway: GENE (delta 14 reductase) and Erg2p (delta 8-delta 7 isomerase). The sordarins group are protein synthesis inhibitors that work by blocking the function of fungal translation elongation factor 2. Other protein inhibitors are zofimarin, BE31045, SCH57504, xylarin, hypoxysordarin and GR135402. In order to overcome the problems derived from the exploitation of azole drugs, macrolides and echinocandins, novel targets were explored. Proposed antifungal drugs have been developed against potential targets like the N-myristylation of fungal proteins, with inhibitors like myristate and histidine analogues or myristoylpeptide derivatives, aminobenzothiazoles, quinolines and benzofurans. Polymerization of cell wall carbohydrates from uridine di-phospho sugars is another potential target. | REGULATOR |
| Antifungal agents: mode of action in yeast cells. Different kinds of mycoses, especially invasive, have become an important public health problem as their incidence has increased dramatically in the last decades in relation to AIDS, hematological malignancies, transplant recipients and other immunosuppressed individuals. Management of fungal infections is markedly limited by problems of drug safety, resistance and effectiveness profile. Current therapy for invasive mycoses uses a relatively reduced number of antifungal drugs, such as amphotericin B, fluconazole and itraconazole. Other new antifungal agents from old and new chemical families, like voriconazole, posaconazole, ravuconazole, caspofungin and micafungin, have been introduced into the armamentarium for fungal infections management. This review is focused on the mode of action of those antifungal drugs used against pathogenic yeasts. The interaction of amphotericin B with ergosterol and other membrane sterols results in the production of aqueous pores of drug and the ergosterol biosynthetic pathway is the target of the allylamines, phenylmorpholines and azole antifungal agents. The main molecular target of azole antifungals is the cytochrome P-450 protein Erg11p/Cyp51p. Echinocandins, a new class of antifungal drugs, are fungal secondary metabolites that act against beta-1-3-D-glucan synthesis. The phenylmorpholines, of which CHEMICAL is the sole representative in human therapy, affect two targets in the ergosterol pathway: Erg24p (GENE) and Erg2p (delta 8-delta 7 isomerase). The sordarins group are protein synthesis inhibitors that work by blocking the function of fungal translation elongation factor 2. Other protein inhibitors are zofimarin, BE31045, SCH57504, xylarin, hypoxysordarin and GR135402. In order to overcome the problems derived from the exploitation of azole drugs, macrolides and echinocandins, novel targets were explored. Proposed antifungal drugs have been developed against potential targets like the N-myristylation of fungal proteins, with inhibitors like myristate and histidine analogues or myristoylpeptide derivatives, aminobenzothiazoles, quinolines and benzofurans. Polymerization of cell wall carbohydrates from uridine di-phospho sugars is another potential target. | REGULATOR |
| Antifungal agents: mode of action in yeast cells. Different kinds of mycoses, especially invasive, have become an important public health problem as their incidence has increased dramatically in the last decades in relation to AIDS, hematological malignancies, transplant recipients and other immunosuppressed individuals. Management of fungal infections is markedly limited by problems of drug safety, resistance and effectiveness profile. Current therapy for invasive mycoses uses a relatively reduced number of antifungal drugs, such as amphotericin B, fluconazole and itraconazole. Other new antifungal agents from old and new chemical families, like voriconazole, posaconazole, ravuconazole, caspofungin and micafungin, have been introduced into the armamentarium for fungal infections management. This review is focused on the mode of action of those antifungal drugs used against pathogenic yeasts. The interaction of amphotericin B with ergosterol and other membrane sterols results in the production of aqueous pores of drug and the ergosterol biosynthetic pathway is the target of the allylamines, phenylmorpholines and azole antifungal agents. The main molecular target of azole antifungals is the cytochrome P-450 protein Erg11p/Cyp51p. Echinocandins, a new class of antifungal drugs, are fungal secondary metabolites that act against beta-1-3-D-glucan synthesis. The phenylmorpholines, of which CHEMICAL is the sole representative in human therapy, affect two targets in the ergosterol pathway: Erg24p (delta 14 reductase) and GENE (delta 8-delta 7 isomerase). The sordarins group are protein synthesis inhibitors that work by blocking the function of fungal translation elongation factor 2. Other protein inhibitors are zofimarin, BE31045, SCH57504, xylarin, hypoxysordarin and GR135402. In order to overcome the problems derived from the exploitation of azole drugs, macrolides and echinocandins, novel targets were explored. Proposed antifungal drugs have been developed against potential targets like the N-myristylation of fungal proteins, with inhibitors like myristate and histidine analogues or myristoylpeptide derivatives, aminobenzothiazoles, quinolines and benzofurans. Polymerization of cell wall carbohydrates from uridine di-phospho sugars is another potential target. | REGULATOR |
| Antifungal agents: mode of action in yeast cells. Different kinds of mycoses, especially invasive, have become an important public health problem as their incidence has increased dramatically in the last decades in relation to AIDS, hematological malignancies, transplant recipients and other immunosuppressed individuals. Management of fungal infections is markedly limited by problems of drug safety, resistance and effectiveness profile. Current therapy for invasive mycoses uses a relatively reduced number of antifungal drugs, such as amphotericin B, fluconazole and itraconazole. Other new antifungal agents from old and new chemical families, like voriconazole, posaconazole, ravuconazole, caspofungin and micafungin, have been introduced into the armamentarium for fungal infections management. This review is focused on the mode of action of those antifungal drugs used against pathogenic yeasts. The interaction of amphotericin B with ergosterol and other membrane sterols results in the production of aqueous pores of drug and the ergosterol biosynthetic pathway is the target of the allylamines, phenylmorpholines and azole antifungal agents. The main molecular target of azole antifungals is the cytochrome P-450 protein Erg11p/Cyp51p. Echinocandins, a new class of antifungal drugs, are fungal secondary metabolites that act against beta-1-3-D-glucan synthesis. The phenylmorpholines, of which CHEMICAL is the sole representative in human therapy, affect two targets in the ergosterol pathway: Erg24p (delta 14 reductase) and Erg2p (GENE). The sordarins group are protein synthesis inhibitors that work by blocking the function of fungal translation elongation factor 2. Other protein inhibitors are zofimarin, BE31045, SCH57504, xylarin, hypoxysordarin and GR135402. In order to overcome the problems derived from the exploitation of azole drugs, macrolides and echinocandins, novel targets were explored. Proposed antifungal drugs have been developed against potential targets like the N-myristylation of fungal proteins, with inhibitors like myristate and histidine analogues or myristoylpeptide derivatives, aminobenzothiazoles, quinolines and benzofurans. Polymerization of cell wall carbohydrates from uridine di-phospho sugars is another potential target. | REGULATOR |
| Antifungal agents: mode of action in yeast cells. Different kinds of mycoses, especially invasive, have become an important public health problem as their incidence has increased dramatically in the last decades in relation to AIDS, hematological malignancies, transplant recipients and other immunosuppressed individuals. Management of fungal infections is markedly limited by problems of drug safety, resistance and effectiveness profile. Current therapy for invasive mycoses uses a relatively reduced number of antifungal drugs, such as amphotericin B, fluconazole and itraconazole. Other new antifungal agents from old and new chemical families, like voriconazole, posaconazole, ravuconazole, caspofungin and micafungin, have been introduced into the armamentarium for fungal infections management. This review is focused on the mode of action of those antifungal drugs used against pathogenic yeasts. The interaction of amphotericin B with ergosterol and other membrane sterols results in the production of aqueous pores of drug and the ergosterol biosynthetic pathway is the target of the allylamines, phenylmorpholines and azole antifungal agents. The main molecular target of azole antifungals is the cytochrome P-450 protein Erg11p/Cyp51p. Echinocandins, a new class of antifungal drugs, are fungal secondary metabolites that act against beta-1-3-D-glucan synthesis. The phenylmorpholines, of which amorolfine is the sole representative in human therapy, affect two targets in the ergosterol pathway: Erg24p (delta 14 reductase) and Erg2p (delta 8-delta 7 isomerase). The CHEMICAL group are protein synthesis inhibitors that work by blocking the function of GENE. Other protein inhibitors are zofimarin, BE31045, SCH57504, xylarin, hypoxysordarin and GR135402. In order to overcome the problems derived from the exploitation of azole drugs, macrolides and echinocandins, novel targets were explored. Proposed antifungal drugs have been developed against potential targets like the N-myristylation of fungal proteins, with inhibitors like myristate and histidine analogues or myristoylpeptide derivatives, aminobenzothiazoles, quinolines and benzofurans. Polymerization of cell wall carbohydrates from uridine di-phospho sugars is another potential target. | INHIBITOR |
| D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. Phospholipase C beta (PLC-beta)-coupled G protein-coupled receptor (GPCR) activities traditionally are assessed by measuring Ca2+ triggered by D-myo-inositol 1,4,5-trisphosphate (IP3), a PLC-beta hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of CHEMICAL production was also established using CHEMICAL binding proteins. The short lifetime of CHEMICAL makes this detection very challenging in measuring GENE responses. Indeed, this CHEMICAL rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that lithium chloride (LiCl) leads to D-myo-inositol 1-phosphate accumulation on GENE activation by inhibiting inositol monophosphatase, the final enzyme of the CHEMICAL metabolic cascade. We show here that IP1 can be used as a surrogate of CHEMICAL to monitor GENE activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GENE models. It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of PLC-beta activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | GENE-CHEMICAL |
| D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. Phospholipase C beta (PLC-beta)-coupled G protein-coupled receptor (GPCR) activities traditionally are assessed by measuring Ca2+ triggered by D-myo-inositol 1,4,5-trisphosphate (IP3), a PLC-beta hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of IP3 production was also established using IP3 binding proteins. The short lifetime of IP3 makes this detection very challenging in measuring GENE responses. Indeed, this IP3 rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that lithium chloride (LiCl) leads to D-myo-inositol 1-phosphate accumulation on GENE activation by inhibiting inositol monophosphatase, the final enzyme of the IP3 metabolic cascade. We show here that CHEMICAL can be used as a surrogate of IP3 to monitor GENE activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GENE models. It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of PLC-beta activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | ACTIVATOR |
| CHEMICAL as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor GENE activation. Phospholipase C beta (PLC-beta)-coupled GENE (GPCR) activities traditionally are assessed by measuring Ca2+ triggered by D-myo-inositol 1,4,5-trisphosphate (IP3), a PLC-beta hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of IP3 production was also established using IP3 binding proteins. The short lifetime of IP3 makes this detection very challenging in measuring GPCR responses. Indeed, this IP3 rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that lithium chloride (LiCl) leads to CHEMICAL accumulation on GPCR activation by inhibiting inositol monophosphatase, the final enzyme of the IP3 metabolic cascade. We show here that IP1 can be used as a surrogate of IP3 to monitor GPCR activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GPCR models. It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of PLC-beta activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | ACTIVATOR |
| D-myo-inositol 1-phosphate as a surrogate of CHEMICAL to monitor GENE activation. Phospholipase C beta (PLC-beta)-coupled GENE (GPCR) activities traditionally are assessed by measuring Ca2+ triggered by D-myo-inositol 1,4,5-trisphosphate (IP3), a PLC-beta hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of IP3 production was also established using IP3 binding proteins. The short lifetime of IP3 makes this detection very challenging in measuring GPCR responses. Indeed, this IP3 rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that lithium chloride (LiCl) leads to D-myo-inositol 1-phosphate accumulation on GPCR activation by inhibiting inositol monophosphatase, the final enzyme of the IP3 metabolic cascade. We show here that IP1 can be used as a surrogate of IP3 to monitor GPCR activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GPCR models. It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of PLC-beta activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | ACTIVATOR |
| D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. GENE (PLC-beta)-coupled G protein-coupled receptor (GPCR) activities traditionally are assessed by measuring Ca2+ triggered by CHEMICAL (IP3), a PLC-beta hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of IP3 production was also established using IP3 binding proteins. The short lifetime of IP3 makes this detection very challenging in measuring GPCR responses. Indeed, this IP3 rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that lithium chloride (LiCl) leads to D-myo-inositol 1-phosphate accumulation on GPCR activation by inhibiting inositol monophosphatase, the final enzyme of the IP3 metabolic cascade. We show here that IP1 can be used as a surrogate of IP3 to monitor GPCR activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GPCR models. It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of PLC-beta activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | ACTIVATOR |
| D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. Phospholipase C beta (GENE)-coupled G protein-coupled receptor (GPCR) activities traditionally are assessed by measuring Ca2+ triggered by CHEMICAL (IP3), a GENE hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of IP3 production was also established using IP3 binding proteins. The short lifetime of IP3 makes this detection very challenging in measuring GPCR responses. Indeed, this IP3 rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that lithium chloride (LiCl) leads to D-myo-inositol 1-phosphate accumulation on GPCR activation by inhibiting inositol monophosphatase, the final enzyme of the IP3 metabolic cascade. We show here that IP1 can be used as a surrogate of IP3 to monitor GPCR activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GPCR models. It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of GENE activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | SUBSTRATE |
| D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor GENE activation. Phospholipase C beta (PLC-beta)-coupled GENE (GPCR) activities traditionally are assessed by measuring Ca2+ triggered by CHEMICAL (IP3), a PLC-beta hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of IP3 production was also established using IP3 binding proteins. The short lifetime of IP3 makes this detection very challenging in measuring GPCR responses. Indeed, this IP3 rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that lithium chloride (LiCl) leads to D-myo-inositol 1-phosphate accumulation on GPCR activation by inhibiting inositol monophosphatase, the final enzyme of the IP3 metabolic cascade. We show here that IP1 can be used as a surrogate of IP3 to monitor GPCR activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GPCR models. It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of PLC-beta activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | ACTIVATOR |
| D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. Phospholipase C beta (PLC-beta)-coupled G protein-coupled receptor (GENE) activities traditionally are assessed by measuring Ca2+ triggered by CHEMICAL (IP3), a PLC-beta hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of IP3 production was also established using IP3 binding proteins. The short lifetime of IP3 makes this detection very challenging in measuring GENE responses. Indeed, this IP3 rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that lithium chloride (LiCl) leads to D-myo-inositol 1-phosphate accumulation on GENE activation by inhibiting inositol monophosphatase, the final enzyme of the IP3 metabolic cascade. We show here that IP1 can be used as a surrogate of IP3 to monitor GENE activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GENE models. It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of PLC-beta activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | ACTIVATOR |
| D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. Phospholipase C beta (PLC-beta)-coupled G protein-coupled receptor (GPCR) activities traditionally are assessed by measuring Ca2+ triggered by D-myo-inositol 1,4,5-trisphosphate (IP3), a PLC-beta hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of IP3 production was also established using IP3 binding proteins. The short lifetime of IP3 makes this detection very challenging in measuring GENE responses. Indeed, this IP3 rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that CHEMICAL (LiCl) leads to D-myo-inositol 1-phosphate accumulation on GENE activation by inhibiting inositol monophosphatase, the final enzyme of the IP3 metabolic cascade. We show here that IP1 can be used as a surrogate of IP3 to monitor GENE activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GENE models. It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of PLC-beta activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | ACTIVATOR |
| D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. Phospholipase C beta (PLC-beta)-coupled G protein-coupled receptor (GPCR) activities traditionally are assessed by measuring Ca2+ triggered by D-myo-inositol 1,4,5-trisphosphate (IP3), a PLC-beta hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of IP3 production was also established using IP3 binding proteins. The short lifetime of IP3 makes this detection very challenging in measuring GENE responses. Indeed, this IP3 rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that lithium chloride (CHEMICAL) leads to D-myo-inositol 1-phosphate accumulation on GENE activation by inhibiting inositol monophosphatase, the final enzyme of the IP3 metabolic cascade. We show here that IP1 can be used as a surrogate of IP3 to monitor GENE activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GENE models. It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of PLC-beta activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | ACTIVATOR |
| D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. Phospholipase C beta (PLC-beta)-coupled G protein-coupled receptor (GPCR) activities traditionally are assessed by measuring Ca2+ triggered by D-myo-inositol 1,4,5-trisphosphate (IP3), a PLC-beta hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of IP3 production was also established using IP3 binding proteins. The short lifetime of IP3 makes this detection very challenging in measuring GPCR responses. Indeed, this IP3 rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that CHEMICAL (LiCl) leads to D-myo-inositol 1-phosphate accumulation on GPCR activation by inhibiting GENE, the final enzyme of the IP3 metabolic cascade. We show here that IP1 can be used as a surrogate of IP3 to monitor GPCR activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GPCR models. It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of PLC-beta activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | INHIBITOR |
| D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. Phospholipase C beta (PLC-beta)-coupled G protein-coupled receptor (GPCR) activities traditionally are assessed by measuring Ca2+ triggered by D-myo-inositol 1,4,5-trisphosphate (IP3), a PLC-beta hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of IP3 production was also established using IP3 binding proteins. The short lifetime of IP3 makes this detection very challenging in measuring GPCR responses. Indeed, this IP3 rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that lithium chloride (CHEMICAL) leads to D-myo-inositol 1-phosphate accumulation on GPCR activation by inhibiting GENE, the final enzyme of the IP3 metabolic cascade. We show here that IP1 can be used as a surrogate of IP3 to monitor GPCR activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GPCR models. It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of PLC-beta activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | INHIBITOR |
| D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. Phospholipase C beta (PLC-beta)-coupled G protein-coupled receptor (GPCR) activities traditionally are assessed by measuring CHEMICAL triggered by D-myo-inositol 1,4,5-trisphosphate (IP3), a GENE hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of IP3 production was also established using IP3 binding proteins. The short lifetime of IP3 makes this detection very challenging in measuring GPCR responses. Indeed, this IP3 rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that lithium chloride (LiCl) leads to D-myo-inositol 1-phosphate accumulation on GPCR activation by inhibiting inositol monophosphatase, the final enzyme of the IP3 metabolic cascade. We show here that IP1 can be used as a surrogate of IP3 to monitor GPCR activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GPCR models. It has the advantage over the traditional CHEMICAL assay of allowing the measurement of inverse agonist activity as well as the analysis of GENE activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | ACTIVATOR |
| D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. GENE (PLC-beta)-coupled G protein-coupled receptor (GPCR) activities traditionally are assessed by measuring CHEMICAL triggered by D-myo-inositol 1,4,5-trisphosphate (IP3), a PLC-beta hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of IP3 production was also established using IP3 binding proteins. The short lifetime of IP3 makes this detection very challenging in measuring GPCR responses. Indeed, this IP3 rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that lithium chloride (LiCl) leads to D-myo-inositol 1-phosphate accumulation on GPCR activation by inhibiting inositol monophosphatase, the final enzyme of the IP3 metabolic cascade. We show here that IP1 can be used as a surrogate of IP3 to monitor GPCR activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GPCR models. It has the advantage over the traditional CHEMICAL assay of allowing the measurement of inverse agonist activity as well as the analysis of PLC-beta activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | REGULATOR |
| D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. Phospholipase C beta (PLC-beta)-coupled G protein-coupled receptor (GPCR) activities traditionally are assessed by measuring Ca2+ triggered by D-myo-inositol 1,4,5-trisphosphate (CHEMICAL), a GENE hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of CHEMICAL production was also established using CHEMICAL binding proteins. The short lifetime of CHEMICAL makes this detection very challenging in measuring GPCR responses. Indeed, this CHEMICAL rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that lithium chloride (LiCl) leads to D-myo-inositol 1-phosphate accumulation on GPCR activation by inhibiting inositol monophosphatase, the final enzyme of the CHEMICAL metabolic cascade. We show here that IP1 can be used as a surrogate of CHEMICAL to monitor GPCR activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GPCR models. It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of GENE activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | SUBSTRATE |
| D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. Phospholipase C beta (PLC-beta)-coupled G protein-coupled receptor (GPCR) activities traditionally are assessed by measuring Ca2+ triggered by D-myo-inositol 1,4,5-trisphosphate (IP3), a GENE hydrolysis product, or by measuring the production of CHEMICAL using cumbersome radioactive assays. A specific detection of IP3 production was also established using IP3 binding proteins. The short lifetime of IP3 makes this detection very challenging in measuring GPCR responses. Indeed, this IP3 rapidly enters the metabolic CHEMICAL cascade. It has been known for decades that lithium chloride (LiCl) leads to D-myo-inositol 1-phosphate accumulation on GPCR activation by inhibiting inositol monophosphatase, the final enzyme of the IP3 metabolic cascade. We show here that IP1 can be used as a surrogate of IP3 to monitor GPCR activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GPCR models. It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of GENE activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | PRODUCT-OF |
| CHEMICAL as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. Phospholipase C beta (PLC-beta)-coupled G protein-coupled receptor (GPCR) activities traditionally are assessed by measuring Ca2+ triggered by D-myo-inositol 1,4,5-trisphosphate (IP3), a PLC-beta hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of IP3 production was also established using IP3 binding proteins. The short lifetime of IP3 makes this detection very challenging in measuring GPCR responses. Indeed, this IP3 rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that lithium chloride (LiCl) leads to CHEMICAL accumulation on GPCR activation by inhibiting GENE, the final enzyme of the IP3 metabolic cascade. We show here that IP1 can be used as a surrogate of IP3 to monitor GPCR activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GPCR models. It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of PLC-beta activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | PRODUCT-OF |
| D-myo-inositol 1-phosphate as a surrogate of D-myo-inositol 1,4,5-tris phosphate to monitor G protein-coupled receptor activation. Phospholipase C beta (PLC-beta)-coupled G protein-coupled receptor (GPCR) activities traditionally are assessed by measuring Ca2+ triggered by D-myo-inositol 1,4,5-trisphosphate (IP3), a PLC-beta hydrolysis product, or by measuring the production of inositol phosphate using cumbersome radioactive assays. A specific detection of CHEMICAL production was also established using CHEMICAL binding proteins. The short lifetime of CHEMICAL makes this detection very challenging in measuring GPCR responses. Indeed, this CHEMICAL rapidly enters the metabolic inositol phosphate cascade. It has been known for decades that lithium chloride (LiCl) leads to D-myo-inositol 1-phosphate accumulation on GPCR activation by inhibiting GENE, the final enzyme of the CHEMICAL metabolic cascade. We show here that IP1 can be used as a surrogate of CHEMICAL to monitor GPCR activation. We developed a novel homogeneous time-resolved fluorescence (HTRF) assay that correlates perfectly with existing methods and is easily amenable to high-throughput screening. The IP-One assay was validated on various GPCR models. It has the advantage over the traditional Ca2+ assay of allowing the measurement of inverse agonist activity as well as the analysis of PLC-beta activity in any nontransfected primary cultures. Finally, the high assay specificity for D-myo-inositol 1 monophosphate (IP1(1)) opens new possibilities in developing selective assays to study the functional roles of the various isoforms of inositol phosphates. | PRODUCT-OF |
| Non-enzymatic interactions of glyoxylate with lysine, arginine, and glucosamine: a study of advanced non-enzymatic glycation like compounds. Glyoxylate is a 2 carbon aldo acid that is formed in hepatic tissue from glycolate. Once formed, the molecule can be converted to CHEMICAL by GENE (AGAT). In defects of AGAT, glyoxylate is transformed to oxalate, resulting in high levels of oxalate in the body. The objective of this study was 2-fold. First, it was to determine, if akin to D-glucose, D-fructose or DL-glyceraldehyde, glyoxylate was susceptible to non-enzymatic attack by amino containing molecules such as lysine, arginine or glucosamine. Second, if by virtue of its molecular structure and size, glyoxylate was as reactive a reagent in non-enzymatic reactions as DL-glyceraldehyde; i.e., a glycose that we previously demonstrated to be a more effective glycating agent than D-glucose or D-fructose. Using capillary electrophoresis (CE), high performance liquid chromatography and UV and fluorescence spectroscopy, glyoxylate was found to be a highly reactive precursor of advanced glycation like end products (AGLEs) and a more effective promoter of non-enzymatic end products than D-glucose, D-fructose or DL-glyceraldehyde. | PRODUCT-OF |
| Non-enzymatic interactions of glyoxylate with lysine, arginine, and glucosamine: a study of advanced non-enzymatic glycation like compounds. Glyoxylate is a 2 carbon aldo acid that is formed in hepatic tissue from glycolate. Once formed, the molecule can be converted to CHEMICAL by alanine-glyoxylate aminotransferase (GENE). In defects of GENE, glyoxylate is transformed to oxalate, resulting in high levels of oxalate in the body. The objective of this study was 2-fold. First, it was to determine, if akin to D-glucose, D-fructose or DL-glyceraldehyde, glyoxylate was susceptible to non-enzymatic attack by amino containing molecules such as lysine, arginine or glucosamine. Second, if by virtue of its molecular structure and size, glyoxylate was as reactive a reagent in non-enzymatic reactions as DL-glyceraldehyde; i.e., a glycose that we previously demonstrated to be a more effective glycating agent than D-glucose or D-fructose. Using capillary electrophoresis (CE), high performance liquid chromatography and UV and fluorescence spectroscopy, glyoxylate was found to be a highly reactive precursor of advanced glycation like end products (AGLEs) and a more effective promoter of non-enzymatic end products than D-glucose, D-fructose or DL-glyceraldehyde. | PRODUCT-OF |
| Cortisol metabolism in hypertension. Corticosteroids are critically involved in blood pressure regulation. Lack of adrenal steroids in Addison's disease causes life-threatening hypotension, whereas glucocorticoid excess in Cushing's syndrome invariably results in high blood pressure. At a pre-receptor level, glucocorticoid action is modulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). 11Beta-HSD1 activates CHEMICAL to cortisol to facilitate GENE (GR)-mediated action. By contrast, 11beta-HSD2 plays a pivotal role in aldosterone target tissues where it catalyses the opposite reaction (i.e. inactivation of cortisol to cortisone) to prevent activation of the mineralocorticoid receptor (MR) by cortisol. Mutations in the 11beta-HSD2 gene cause a rare form of inherited hypertension, the syndrome of apparent mineralocorticoid excess (AME), in which cortisol activates the MR resulting in severe hypertension and hypokalemia. Ingestion of competitive inhibitors of 11beta-HSD2 such as liquorice and carbenoxolone result in a similar but milder clinical phenotype. Epidemiological data suggests that polymorphic variability in the HSD11B2 gene determines salt sensitivity in the general population, which is a key predisposing factor to adult onset hypertension in some patients. Extrarenal sites of glucocorticoid action and metabolism that might impact on blood pressure include the vasculature and the central nervous system. Intriguingly, increased exposure to glucocorticoids during fetal life promotes high blood pressure in adulthood suggesting an early programming effect. Thus, metabolism and action in many peripheral tissues might contribute to the pathophysiology of human hypertension. | REGULATOR |
| Cortisol metabolism in hypertension. Corticosteroids are critically involved in blood pressure regulation. Lack of adrenal steroids in Addison's disease causes life-threatening hypotension, whereas glucocorticoid excess in Cushing's syndrome invariably results in high blood pressure. At a pre-receptor level, glucocorticoid action is modulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). 11Beta-HSD1 activates CHEMICAL to cortisol to facilitate glucocorticoid receptor (GENE)-mediated action. By contrast, 11beta-HSD2 plays a pivotal role in aldosterone target tissues where it catalyses the opposite reaction (i.e. inactivation of cortisol to cortisone) to prevent activation of the mineralocorticoid receptor (MR) by cortisol. Mutations in the 11beta-HSD2 gene cause a rare form of inherited hypertension, the syndrome of apparent mineralocorticoid excess (AME), in which cortisol activates the MR resulting in severe hypertension and hypokalemia. Ingestion of competitive inhibitors of 11beta-HSD2 such as liquorice and carbenoxolone result in a similar but milder clinical phenotype. Epidemiological data suggests that polymorphic variability in the HSD11B2 gene determines salt sensitivity in the general population, which is a key predisposing factor to adult onset hypertension in some patients. Extrarenal sites of glucocorticoid action and metabolism that might impact on blood pressure include the vasculature and the central nervous system. Intriguingly, increased exposure to glucocorticoids during fetal life promotes high blood pressure in adulthood suggesting an early programming effect. Thus, metabolism and action in many peripheral tissues might contribute to the pathophysiology of human hypertension. | REGULATOR |
| CHEMICAL metabolism in hypertension. Corticosteroids are critically involved in blood pressure regulation. Lack of adrenal steroids in Addison's disease causes life-threatening hypotension, whereas glucocorticoid excess in Cushing's syndrome invariably results in high blood pressure. At a pre-receptor level, glucocorticoid action is modulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). 11Beta-HSD1 activates cortisone to CHEMICAL to facilitate GENE (GR)-mediated action. By contrast, 11beta-HSD2 plays a pivotal role in aldosterone target tissues where it catalyses the opposite reaction (i.e. inactivation of CHEMICAL to cortisone) to prevent activation of the mineralocorticoid receptor (MR) by CHEMICAL. Mutations in the 11beta-HSD2 gene cause a rare form of inherited hypertension, the syndrome of apparent mineralocorticoid excess (AME), in which CHEMICAL activates the MR resulting in severe hypertension and hypokalemia. Ingestion of competitive inhibitors of 11beta-HSD2 such as liquorice and carbenoxolone result in a similar but milder clinical phenotype. Epidemiological data suggests that polymorphic variability in the HSD11B2 gene determines salt sensitivity in the general population, which is a key predisposing factor to adult onset hypertension in some patients. Extrarenal sites of glucocorticoid action and metabolism that might impact on blood pressure include the vasculature and the central nervous system. Intriguingly, increased exposure to glucocorticoids during fetal life promotes high blood pressure in adulthood suggesting an early programming effect. Thus, metabolism and action in many peripheral tissues might contribute to the pathophysiology of human hypertension. | REGULATOR |
| CHEMICAL metabolism in hypertension. Corticosteroids are critically involved in blood pressure regulation. Lack of adrenal steroids in Addison's disease causes life-threatening hypotension, whereas glucocorticoid excess in Cushing's syndrome invariably results in high blood pressure. At a pre-receptor level, glucocorticoid action is modulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). 11Beta-HSD1 activates cortisone to CHEMICAL to facilitate glucocorticoid receptor (GENE)-mediated action. By contrast, 11beta-HSD2 plays a pivotal role in aldosterone target tissues where it catalyses the opposite reaction (i.e. inactivation of CHEMICAL to cortisone) to prevent activation of the mineralocorticoid receptor (MR) by CHEMICAL. Mutations in the 11beta-HSD2 gene cause a rare form of inherited hypertension, the syndrome of apparent mineralocorticoid excess (AME), in which CHEMICAL activates the MR resulting in severe hypertension and hypokalemia. Ingestion of competitive inhibitors of 11beta-HSD2 such as liquorice and carbenoxolone result in a similar but milder clinical phenotype. Epidemiological data suggests that polymorphic variability in the HSD11B2 gene determines salt sensitivity in the general population, which is a key predisposing factor to adult onset hypertension in some patients. Extrarenal sites of glucocorticoid action and metabolism that might impact on blood pressure include the vasculature and the central nervous system. Intriguingly, increased exposure to glucocorticoids during fetal life promotes high blood pressure in adulthood suggesting an early programming effect. Thus, metabolism and action in many peripheral tissues might contribute to the pathophysiology of human hypertension. | REGULATOR |
| Cortisol metabolism in hypertension. Corticosteroids are critically involved in blood pressure regulation. Lack of adrenal steroids in Addison's disease causes life-threatening hypotension, whereas glucocorticoid excess in Cushing's syndrome invariably results in high blood pressure. At a pre-receptor level, glucocorticoid action is modulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). 11Beta-HSD1 activates cortisone to cortisol to facilitate glucocorticoid receptor (GR)-mediated action. By contrast, GENE plays a pivotal role in CHEMICAL target tissues where it catalyses the opposite reaction (i.e. inactivation of cortisol to cortisone) to prevent activation of the mineralocorticoid receptor (MR) by cortisol. Mutations in the GENE gene cause a rare form of inherited hypertension, the syndrome of apparent mineralocorticoid excess (AME), in which cortisol activates the MR resulting in severe hypertension and hypokalemia. Ingestion of competitive inhibitors of GENE such as liquorice and carbenoxolone result in a similar but milder clinical phenotype. Epidemiological data suggests that polymorphic variability in the HSD11B2 gene determines salt sensitivity in the general population, which is a key predisposing factor to adult onset hypertension in some patients. Extrarenal sites of glucocorticoid action and metabolism that might impact on blood pressure include the vasculature and the central nervous system. Intriguingly, increased exposure to glucocorticoids during fetal life promotes high blood pressure in adulthood suggesting an early programming effect. Thus, metabolism and action in many peripheral tissues might contribute to the pathophysiology of human hypertension. | REGULATOR |
| CHEMICAL metabolism in hypertension. Corticosteroids are critically involved in blood pressure regulation. Lack of adrenal steroids in Addison's disease causes life-threatening hypotension, whereas glucocorticoid excess in Cushing's syndrome invariably results in high blood pressure. At a pre-receptor level, glucocorticoid action is modulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). 11Beta-HSD1 activates cortisone to CHEMICAL to facilitate glucocorticoid receptor (GR)-mediated action. By contrast, 11beta-HSD2 plays a pivotal role in aldosterone target tissues where it catalyses the opposite reaction (i.e. inactivation of CHEMICAL to cortisone) to prevent activation of the GENE (MR) by CHEMICAL. Mutations in the 11beta-HSD2 gene cause a rare form of inherited hypertension, the syndrome of apparent mineralocorticoid excess (AME), in which CHEMICAL activates the MR resulting in severe hypertension and hypokalemia. Ingestion of competitive inhibitors of 11beta-HSD2 such as liquorice and carbenoxolone result in a similar but milder clinical phenotype. Epidemiological data suggests that polymorphic variability in the HSD11B2 gene determines salt sensitivity in the general population, which is a key predisposing factor to adult onset hypertension in some patients. Extrarenal sites of glucocorticoid action and metabolism that might impact on blood pressure include the vasculature and the central nervous system. Intriguingly, increased exposure to glucocorticoids during fetal life promotes high blood pressure in adulthood suggesting an early programming effect. Thus, metabolism and action in many peripheral tissues might contribute to the pathophysiology of human hypertension. | ACTIVATOR |
| CHEMICAL metabolism in hypertension. Corticosteroids are critically involved in blood pressure regulation. Lack of adrenal steroids in Addison's disease causes life-threatening hypotension, whereas glucocorticoid excess in Cushing's syndrome invariably results in high blood pressure. At a pre-receptor level, glucocorticoid action is modulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). 11Beta-HSD1 activates cortisone to CHEMICAL to facilitate glucocorticoid receptor (GR)-mediated action. By contrast, 11beta-HSD2 plays a pivotal role in aldosterone target tissues where it catalyses the opposite reaction (i.e. inactivation of CHEMICAL to cortisone) to prevent activation of the mineralocorticoid receptor (GENE) by CHEMICAL. Mutations in the 11beta-HSD2 gene cause a rare form of inherited hypertension, the syndrome of apparent mineralocorticoid excess (AME), in which CHEMICAL activates the GENE resulting in severe hypertension and hypokalemia. Ingestion of competitive inhibitors of 11beta-HSD2 such as liquorice and carbenoxolone result in a similar but milder clinical phenotype. Epidemiological data suggests that polymorphic variability in the HSD11B2 gene determines salt sensitivity in the general population, which is a key predisposing factor to adult onset hypertension in some patients. Extrarenal sites of glucocorticoid action and metabolism that might impact on blood pressure include the vasculature and the central nervous system. Intriguingly, increased exposure to glucocorticoids during fetal life promotes high blood pressure in adulthood suggesting an early programming effect. Thus, metabolism and action in many peripheral tissues might contribute to the pathophysiology of human hypertension. | ACTIVATOR |
| Cortisol metabolism in hypertension. Corticosteroids are critically involved in blood pressure regulation. Lack of adrenal steroids in Addison's disease causes life-threatening hypotension, whereas glucocorticoid excess in Cushing's syndrome invariably results in high blood pressure. At a pre-receptor level, glucocorticoid action is modulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). 11Beta-HSD1 activates cortisone to cortisol to facilitate glucocorticoid receptor (GR)-mediated action. By contrast, GENE plays a pivotal role in aldosterone target tissues where it catalyses the opposite reaction (i.e. inactivation of cortisol to cortisone) to prevent activation of the mineralocorticoid receptor (MR) by cortisol. Mutations in the GENE gene cause a rare form of inherited hypertension, the syndrome of apparent mineralocorticoid excess (AME), in which cortisol activates the MR resulting in severe hypertension and hypokalemia. Ingestion of competitive inhibitors of GENE such as liquorice and CHEMICAL result in a similar but milder clinical phenotype. Epidemiological data suggests that polymorphic variability in the HSD11B2 gene determines salt sensitivity in the general population, which is a key predisposing factor to adult onset hypertension in some patients. Extrarenal sites of glucocorticoid action and metabolism that might impact on blood pressure include the vasculature and the central nervous system. Intriguingly, increased exposure to glucocorticoids during fetal life promotes high blood pressure in adulthood suggesting an early programming effect. Thus, metabolism and action in many peripheral tissues might contribute to the pathophysiology of human hypertension. | INHIBITOR |
| CHEMICAL metabolism in hypertension. Corticosteroids are critically involved in blood pressure regulation. Lack of adrenal steroids in Addison's disease causes life-threatening hypotension, whereas glucocorticoid excess in Cushing's syndrome invariably results in high blood pressure. At a pre-receptor level, glucocorticoid action is modulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). GENE activates cortisone to CHEMICAL to facilitate glucocorticoid receptor (GR)-mediated action. By contrast, 11beta-HSD2 plays a pivotal role in aldosterone target tissues where it catalyses the opposite reaction (i.e. inactivation of CHEMICAL to cortisone) to prevent activation of the mineralocorticoid receptor (MR) by CHEMICAL. Mutations in the 11beta-HSD2 gene cause a rare form of inherited hypertension, the syndrome of apparent mineralocorticoid excess (AME), in which CHEMICAL activates the MR resulting in severe hypertension and hypokalemia. Ingestion of competitive inhibitors of 11beta-HSD2 such as liquorice and carbenoxolone result in a similar but milder clinical phenotype. Epidemiological data suggests that polymorphic variability in the HSD11B2 gene determines salt sensitivity in the general population, which is a key predisposing factor to adult onset hypertension in some patients. Extrarenal sites of glucocorticoid action and metabolism that might impact on blood pressure include the vasculature and the central nervous system. Intriguingly, increased exposure to glucocorticoids during fetal life promotes high blood pressure in adulthood suggesting an early programming effect. Thus, metabolism and action in many peripheral tissues might contribute to the pathophysiology of human hypertension. | ACTIVATOR |
| Cortisol metabolism in hypertension. Corticosteroids are critically involved in blood pressure regulation. Lack of adrenal steroids in Addison's disease causes life-threatening hypotension, whereas glucocorticoid excess in Cushing's syndrome invariably results in high blood pressure. At a pre-receptor level, glucocorticoid action is modulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). 11Beta-HSD1 activates CHEMICAL to cortisol to facilitate glucocorticoid receptor (GR)-mediated action. By contrast, GENE plays a pivotal role in aldosterone target tissues where it catalyses the opposite reaction (i.e. inactivation of cortisol to CHEMICAL) to prevent activation of the mineralocorticoid receptor (MR) by cortisol. Mutations in the GENE gene cause a rare form of inherited hypertension, the syndrome of apparent mineralocorticoid excess (AME), in which cortisol activates the MR resulting in severe hypertension and hypokalemia. Ingestion of competitive inhibitors of GENE such as liquorice and carbenoxolone result in a similar but milder clinical phenotype. Epidemiological data suggests that polymorphic variability in the HSD11B2 gene determines salt sensitivity in the general population, which is a key predisposing factor to adult onset hypertension in some patients. Extrarenal sites of glucocorticoid action and metabolism that might impact on blood pressure include the vasculature and the central nervous system. Intriguingly, increased exposure to glucocorticoids during fetal life promotes high blood pressure in adulthood suggesting an early programming effect. Thus, metabolism and action in many peripheral tissues might contribute to the pathophysiology of human hypertension. | GENE-CHEMICAL |
| Cortisol metabolism in hypertension. Corticosteroids are critically involved in blood pressure regulation. Lack of adrenal steroids in Addison's disease causes life-threatening hypotension, whereas glucocorticoid excess in Cushing's syndrome invariably results in high blood pressure. At a pre-receptor level, glucocorticoid action is modulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). GENE activates CHEMICAL to cortisol to facilitate glucocorticoid receptor (GR)-mediated action. By contrast, 11beta-HSD2 plays a pivotal role in aldosterone target tissues where it catalyses the opposite reaction (i.e. inactivation of cortisol to cortisone) to prevent activation of the mineralocorticoid receptor (MR) by cortisol. Mutations in the 11beta-HSD2 gene cause a rare form of inherited hypertension, the syndrome of apparent mineralocorticoid excess (AME), in which cortisol activates the MR resulting in severe hypertension and hypokalemia. Ingestion of competitive inhibitors of 11beta-HSD2 such as liquorice and carbenoxolone result in a similar but milder clinical phenotype. Epidemiological data suggests that polymorphic variability in the HSD11B2 gene determines salt sensitivity in the general population, which is a key predisposing factor to adult onset hypertension in some patients. Extrarenal sites of glucocorticoid action and metabolism that might impact on blood pressure include the vasculature and the central nervous system. Intriguingly, increased exposure to glucocorticoids during fetal life promotes high blood pressure in adulthood suggesting an early programming effect. Thus, metabolism and action in many peripheral tissues might contribute to the pathophysiology of human hypertension. | ACTIVATOR |
| CHEMICAL metabolism in hypertension. Corticosteroids are critically involved in blood pressure regulation. Lack of adrenal steroids in Addison's disease causes life-threatening hypotension, whereas glucocorticoid excess in Cushing's syndrome invariably results in high blood pressure. At a pre-receptor level, glucocorticoid action is modulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). 11Beta-HSD1 activates cortisone to CHEMICAL to facilitate glucocorticoid receptor (GR)-mediated action. By contrast, GENE plays a pivotal role in aldosterone target tissues where it catalyses the opposite reaction (i.e. inactivation of CHEMICAL to cortisone) to prevent activation of the mineralocorticoid receptor (MR) by CHEMICAL. Mutations in the GENE gene cause a rare form of inherited hypertension, the syndrome of apparent mineralocorticoid excess (AME), in which CHEMICAL activates the MR resulting in severe hypertension and hypokalemia. Ingestion of competitive inhibitors of GENE such as liquorice and carbenoxolone result in a similar but milder clinical phenotype. Epidemiological data suggests that polymorphic variability in the HSD11B2 gene determines salt sensitivity in the general population, which is a key predisposing factor to adult onset hypertension in some patients. Extrarenal sites of glucocorticoid action and metabolism that might impact on blood pressure include the vasculature and the central nervous system. Intriguingly, increased exposure to glucocorticoids during fetal life promotes high blood pressure in adulthood suggesting an early programming effect. Thus, metabolism and action in many peripheral tissues might contribute to the pathophysiology of human hypertension. | SUBSTRATE |
| PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. Dendritic cells (DCs) expressing CD1d, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma, indirectly regulates CD1d expression. Here we demonstrate that PPARgamma, turns on retinoic acid synthesis by inducing the expression of retinol and retinal metabolizing enzymes such as retinol dehydrogenase 10 and retinaldehyde dehydrogenase type 2 (RALDH2). PPARgamma-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans retinoic acid (ATRA) from retinol. CHEMICAL regulates gene expression via the activation of the GENE in human DCs, and RARalpha acutely regulates CD1d expression. The retinoic acid-induced elevated expression of CD1d is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to CD1d up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPARgamma-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression. | ACTIVATOR |
| PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. Dendritic cells (DCs) expressing CD1d, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma, indirectly regulates CD1d expression. Here we demonstrate that PPARgamma, turns on retinoic acid synthesis by inducing the expression of retinol and retinal metabolizing enzymes such as retinol dehydrogenase 10 and retinaldehyde dehydrogenase type 2 (RALDH2). PPARgamma-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans retinoic acid (ATRA) from retinol. CHEMICAL regulates gene expression via the activation of the retinoic acid receptor (RAR)alpha in human DCs, and GENE acutely regulates CD1d expression. The retinoic acid-induced elevated expression of CD1d is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to CD1d up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPARgamma-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression. | GENE-CHEMICAL |
| PPARgamma controls GENE expression by turning on retinoic acid synthesis in developing human dendritic cells. Dendritic cells (DCs) expressing GENE, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma, indirectly regulates GENE expression. Here we demonstrate that PPARgamma, turns on retinoic acid synthesis by inducing the expression of retinol and retinal metabolizing enzymes such as retinol dehydrogenase 10 and retinaldehyde dehydrogenase type 2 (RALDH2). PPARgamma-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans retinoic acid (ATRA) from retinol. CHEMICAL regulates gene expression via the activation of the retinoic acid receptor (RAR)alpha in human DCs, and RARalpha acutely regulates GENE expression. The retinoic acid-induced elevated expression of GENE is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to GENE up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPARgamma-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression. | GENE-CHEMICAL |
| PPARgamma controls GENE expression by turning on CHEMICAL synthesis in developing human dendritic cells. Dendritic cells (DCs) expressing GENE, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma, indirectly regulates GENE expression. Here we demonstrate that PPARgamma, turns on CHEMICAL synthesis by inducing the expression of retinol and retinal metabolizing enzymes such as retinol dehydrogenase 10 and retinaldehyde dehydrogenase type 2 (RALDH2). PPARgamma-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans CHEMICAL (ATRA) from retinol. ATRA regulates gene expression via the activation of the CHEMICAL receptor (RAR)alpha in human DCs, and RARalpha acutely regulates GENE expression. The CHEMICAL-induced elevated expression of GENE is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to GENE up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPARgamma-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression. | INDIRECT-UPREGULATOR |
| PPARgamma controls GENE expression by turning on retinoic acid synthesis in developing human dendritic cells. Dendritic cells (DCs) expressing GENE, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma, indirectly regulates GENE expression. Here we demonstrate that PPARgamma, turns on retinoic acid synthesis by inducing the expression of retinol and retinal metabolizing enzymes such as retinol dehydrogenase 10 and retinaldehyde dehydrogenase type 2 (RALDH2). PPARgamma-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans retinoic acid (ATRA) from retinol. ATRA regulates gene expression via the activation of the retinoic acid receptor (RAR)alpha in human DCs, and RARalpha acutely regulates GENE expression. The retinoic acid-induced elevated expression of GENE is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit CHEMICAL signaling leading to GENE up-regulation. These data show that regulation of CHEMICAL metabolism and signaling is part of the PPARgamma-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression. | PRODUCT-OF |
| PPARgamma controls CD1d expression by turning on CHEMICAL synthesis in developing human dendritic cells. Dendritic cells (DCs) expressing CD1d, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma, indirectly regulates CD1d expression. Here we demonstrate that PPARgamma, turns on CHEMICAL synthesis by inducing the expression of retinol and retinal metabolizing enzymes such as GENE and retinaldehyde dehydrogenase type 2 (RALDH2). PPARgamma-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans CHEMICAL (ATRA) from retinol. ATRA regulates gene expression via the activation of the CHEMICAL receptor (RAR)alpha in human DCs, and RARalpha acutely regulates CD1d expression. The retinoic acid-induced elevated expression of CD1d is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to CD1d up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPARgamma-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression. | PRODUCT-OF |
| PPARgamma controls CD1d expression by turning on CHEMICAL synthesis in developing human dendritic cells. Dendritic cells (DCs) expressing CD1d, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma, indirectly regulates CD1d expression. Here we demonstrate that PPARgamma, turns on CHEMICAL synthesis by inducing the expression of retinol and retinal metabolizing enzymes such as retinol dehydrogenase 10 and GENE (RALDH2). PPARgamma-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans CHEMICAL (ATRA) from retinol. ATRA regulates gene expression via the activation of the CHEMICAL receptor (RAR)alpha in human DCs, and RARalpha acutely regulates CD1d expression. The retinoic acid-induced elevated expression of CD1d is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to CD1d up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPARgamma-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression. | PRODUCT-OF |
| PPARgamma controls CD1d expression by turning on CHEMICAL synthesis in developing human dendritic cells. Dendritic cells (DCs) expressing CD1d, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma, indirectly regulates CD1d expression. Here we demonstrate that PPARgamma, turns on CHEMICAL synthesis by inducing the expression of retinol and retinal metabolizing enzymes such as retinol dehydrogenase 10 and retinaldehyde dehydrogenase type 2 (GENE). PPARgamma-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans CHEMICAL (ATRA) from retinol. ATRA regulates gene expression via the activation of the CHEMICAL receptor (RAR)alpha in human DCs, and RARalpha acutely regulates CD1d expression. The retinoic acid-induced elevated expression of CD1d is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to CD1d up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPARgamma-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression. | PRODUCT-OF |
| PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. Dendritic cells (DCs) expressing CD1d, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma, indirectly regulates CD1d expression. Here we demonstrate that PPARgamma, turns on retinoic acid synthesis by inducing the expression of CHEMICAL and retinal metabolizing enzymes such as GENE and retinaldehyde dehydrogenase type 2 (RALDH2). PPARgamma-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans retinoic acid (ATRA) from CHEMICAL. ATRA regulates gene expression via the activation of the retinoic acid receptor (RAR)alpha in human DCs, and RARalpha acutely regulates CD1d expression. The retinoic acid-induced elevated expression of CD1d is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to CD1d up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPARgamma-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression. | PRODUCT-OF |
| PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. Dendritic cells (DCs) expressing CD1d, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma, indirectly regulates CD1d expression. Here we demonstrate that PPARgamma, turns on retinoic acid synthesis by inducing the expression of CHEMICAL and retinal metabolizing enzymes such as CHEMICAL dehydrogenase 10 and GENE (RALDH2). PPARgamma-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans retinoic acid (ATRA) from CHEMICAL. ATRA regulates gene expression via the activation of the retinoic acid receptor (RAR)alpha in human DCs, and RARalpha acutely regulates CD1d expression. The retinoic acid-induced elevated expression of CD1d is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to CD1d up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPARgamma-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression. | SUBSTRATE |
| PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. Dendritic cells (DCs) expressing CD1d, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma, indirectly regulates CD1d expression. Here we demonstrate that PPARgamma, turns on retinoic acid synthesis by inducing the expression of CHEMICAL and retinal metabolizing enzymes such as CHEMICAL dehydrogenase 10 and retinaldehyde dehydrogenase type 2 (GENE). PPARgamma-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans retinoic acid (ATRA) from CHEMICAL. ATRA regulates gene expression via the activation of the retinoic acid receptor (RAR)alpha in human DCs, and RARalpha acutely regulates CD1d expression. The retinoic acid-induced elevated expression of CD1d is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to CD1d up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPARgamma-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression. | SUBSTRATE |
| PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. Dendritic cells (DCs) expressing CD1d, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma, indirectly regulates CD1d expression. Here we demonstrate that PPARgamma, turns on retinoic acid synthesis by inducing the expression of retinol and CHEMICAL metabolizing enzymes such as GENE and retinaldehyde dehydrogenase type 2 (RALDH2). PPARgamma-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans retinoic acid (ATRA) from retinol. ATRA regulates gene expression via the activation of the retinoic acid receptor (RAR)alpha in human DCs, and RARalpha acutely regulates CD1d expression. The retinoic acid-induced elevated expression of CD1d is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to CD1d up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPARgamma-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression. | SUBSTRATE |
| PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. Dendritic cells (DCs) expressing CD1d, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma, indirectly regulates CD1d expression. Here we demonstrate that PPARgamma, turns on retinoic acid synthesis by inducing the expression of retinol and CHEMICAL metabolizing enzymes such as retinol dehydrogenase 10 and GENE (RALDH2). PPARgamma-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans retinoic acid (ATRA) from retinol. ATRA regulates gene expression via the activation of the retinoic acid receptor (RAR)alpha in human DCs, and RARalpha acutely regulates CD1d expression. The retinoic acid-induced elevated expression of CD1d is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to CD1d up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPARgamma-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression. | SUBSTRATE |
| PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. Dendritic cells (DCs) expressing CD1d, a molecule responsible for lipid antigen presentation, are capable of enhancing natural killer T (iNKT) cell proliferation. The signals controlling CD1 expression and lipid antigen presentation are poorly defined. We have shown previously that stimulation of the lipid-activated transcription factor, peroxisome proliferator-activated receptor (PPAR)gamma, indirectly regulates CD1d expression. Here we demonstrate that PPARgamma, turns on retinoic acid synthesis by inducing the expression of retinol and CHEMICAL metabolizing enzymes such as retinol dehydrogenase 10 and retinaldehyde dehydrogenase type 2 (GENE). PPARgamma-regulated expression of these enzymes leads to an increase in the intracellular generation of all-trans retinoic acid (ATRA) from retinol. ATRA regulates gene expression via the activation of the retinoic acid receptor (RAR)alpha in human DCs, and RARalpha acutely regulates CD1d expression. The retinoic acid-induced elevated expression of CD1d is coupled to enhanced iNKT cell activation. Furthermore, in vivo relevant lipids such as oxidized low-density lipoprotein can also elicit retinoid signaling leading to CD1d up-regulation. These data show that regulation of retinoid metabolism and signaling is part of the PPARgamma-controlled transcriptional events in DCs. The uncovered mechanisms allow the DCs to respond to altered lipid homeostasis by changing CD1 gene expression. | SUBSTRATE |
| Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects. CONTEXT: CHEMICAL is a novel GENE and MT2 melatonin receptor selective agonist recently approved for insomnia treatment. Most approved insomnia medications have potential for abuse and cause motor and cognitive impairment. OBJECTIVE: To evaluate the potential for abuse, subjective effects, and motor and cognitive-impairing effects of ramelteon compared with triazolam, a classic benzodiazepine sedative-hypnotic drug. DESIGN: In this double-blind crossover study, each participant received oral doses of ramelteon (16, 80, or 160 mg), triazolam (0.25, 0.5, or 0.75 mg), and placebo during approximately 18 days. All participants received each treatment on different days. Most outcome measures were assessed at 0.5 hours before drug administration and repeatedly up to 24 hours after drug administration. SETTING: Residential research facility. PARTICIPANTS: Fourteen adults with histories of sedative abuse. MAIN OUTCOME MEASURES: Subject-rated measures included items relevant to potential for abuse (eg, drug liking, street value, and pharmacological classification), as well as assessments of a broad range of stimulant and sedative subjective effects. Observer-rated measures included assessments of sedation and impairment. Motor and cognitive performance measures included psychomotor and memory tasks and a standing balance task. RESULTS: Compared with placebo, ramelteon (16, 80, and 160 mg) showed no significant effect on any of the subjective effect measures, including those related to potential for abuse. In the pharmacological classification, 79% (11/14) of subjects identified the highest dose of ramelteon as placebo. Similarly, compared with placebo, ramelteon had no effect at any dose on any observer-rated or motor and cognitive performance measure. In contrast, triazolam showed dose-related effects on a wide range of subject-rated, observer-rated, and motor and cognitive performance measures, consistent with its profile as a sedative drug with abuse liability. CONCLUSION: CHEMICAL demonstrated no significant effects indicative of potential for abuse or motor and cognitive impairment at up to 20 times the recommended therapeutic dose and may represent a useful alternative to existing insomnia medications. | ACTIVATOR |
| Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects. CONTEXT: CHEMICAL is a novel MT1 and GENE selective agonist recently approved for insomnia treatment. Most approved insomnia medications have potential for abuse and cause motor and cognitive impairment. OBJECTIVE: To evaluate the potential for abuse, subjective effects, and motor and cognitive-impairing effects of ramelteon compared with triazolam, a classic benzodiazepine sedative-hypnotic drug. DESIGN: In this double-blind crossover study, each participant received oral doses of ramelteon (16, 80, or 160 mg), triazolam (0.25, 0.5, or 0.75 mg), and placebo during approximately 18 days. All participants received each treatment on different days. Most outcome measures were assessed at 0.5 hours before drug administration and repeatedly up to 24 hours after drug administration. SETTING: Residential research facility. PARTICIPANTS: Fourteen adults with histories of sedative abuse. MAIN OUTCOME MEASURES: Subject-rated measures included items relevant to potential for abuse (eg, drug liking, street value, and pharmacological classification), as well as assessments of a broad range of stimulant and sedative subjective effects. Observer-rated measures included assessments of sedation and impairment. Motor and cognitive performance measures included psychomotor and memory tasks and a standing balance task. RESULTS: Compared with placebo, ramelteon (16, 80, and 160 mg) showed no significant effect on any of the subjective effect measures, including those related to potential for abuse. In the pharmacological classification, 79% (11/14) of subjects identified the highest dose of ramelteon as placebo. Similarly, compared with placebo, ramelteon had no effect at any dose on any observer-rated or motor and cognitive performance measure. In contrast, triazolam showed dose-related effects on a wide range of subject-rated, observer-rated, and motor and cognitive performance measures, consistent with its profile as a sedative drug with abuse liability. CONCLUSION: CHEMICAL demonstrated no significant effects indicative of potential for abuse or motor and cognitive impairment at up to 20 times the recommended therapeutic dose and may represent a useful alternative to existing insomnia medications. | ACTIVATOR |
| Inhibition of cardiac voltage-gated sodium channels by grape polyphenols. BACKGROUND AND PURPOSE: The cardiovascular benefits of red wine consumption are often attributed to the antioxidant effects of its polyphenolic constituents, including quercetin, catechin and CHEMICAL. Inhibition of cardiac voltage-gated sodium channels (VGSCs) is antiarrhythmic and cardioprotective. As polyphenols may also modulate ion channels, and possess structural similarities to several antiarrhythmic GENE inhibitors, we hypothesised that GENE inhibition may contribute to cardioprotection by these polyphenols. EXPERIMENTAL APPROACH: The whole-cell voltage-clamp technique was used to record peak and late GENE currents (INa) from recombinant human heart NaV1.5 channels expressed in tsA201 cells. Right ventricular myocytes from rat heart were isolated and single myocytes were field-stimulated. Either calcium transients or contractility were measured using the calcium-sensitive dye Calcium-Green 1AM or video edge detection, respectively. KEY RESULTS: The red grape polyphenols quercetin, catechin and CHEMICAL blocked peak INa with IC50s of 19.4 microM, 76.8 microM and 77.3 microM, respectively. In contrast to lidocaine, CHEMICAL did not exhibit any frequency-dependence of peak INa block. Late INa induced by the GENE long QT mutant R1623Q was reduced by CHEMICAL and quercetin. CHEMICAL and quercetin also blocked late INa induced by the toxin, ATX II, with IC50s of 26.1 microM and 24.9 microM, respectively. In field-stimulated myocytes, ATXII-induced increases in diastolic calcium were prevented and reversed by CHEMICAL. ATXII-induced contractile dysfunction was delayed and reduced by CHEMICAL. CONCLUSIONS AND IMPLICATIONS: Our results indicate that several red grape polyphenols inhibit cardiac VGSCs and that this effect may contribute to the documented cardioprotective efficacy of red grape products. | INDIRECT-DOWNREGULATOR |
| Inhibition of cardiac voltage-gated sodium channels by grape polyphenols. BACKGROUND AND PURPOSE: The cardiovascular benefits of red wine consumption are often attributed to the antioxidant effects of its polyphenolic constituents, including quercetin, catechin and CHEMICAL. Inhibition of cardiac voltage-gated sodium channels (VGSCs) is antiarrhythmic and cardioprotective. As polyphenols may also modulate ion channels, and possess structural similarities to several antiarrhythmic VGSC inhibitors, we hypothesised that VGSC inhibition may contribute to cardioprotection by these polyphenols. EXPERIMENTAL APPROACH: The whole-cell voltage-clamp technique was used to record peak and late VGSC currents (INa) from recombinant human heart NaV1.5 channels expressed in tsA201 cells. Right ventricular myocytes from rat heart were isolated and single myocytes were field-stimulated. Either calcium transients or contractility were measured using the calcium-sensitive dye Calcium-Green 1AM or video edge detection, respectively. KEY RESULTS: The red grape polyphenols quercetin, catechin and CHEMICAL blocked peak INa with IC50s of 19.4 microM, 76.8 microM and 77.3 microM, respectively. In contrast to lidocaine, CHEMICAL did not exhibit any frequency-dependence of peak INa block. Late INa induced by the VGSC long QT mutant GENE was reduced by CHEMICAL and quercetin. CHEMICAL and quercetin also blocked late INa induced by the toxin, ATX II, with IC50s of 26.1 microM and 24.9 microM, respectively. In field-stimulated myocytes, ATXII-induced increases in diastolic calcium were prevented and reversed by CHEMICAL. ATXII-induced contractile dysfunction was delayed and reduced by CHEMICAL. CONCLUSIONS AND IMPLICATIONS: Our results indicate that several red grape polyphenols inhibit cardiac VGSCs and that this effect may contribute to the documented cardioprotective efficacy of red grape products. | INDIRECT-DOWNREGULATOR |
| Inhibition of cardiac voltage-gated sodium channels by grape polyphenols. BACKGROUND AND PURPOSE: The cardiovascular benefits of red wine consumption are often attributed to the antioxidant effects of its polyphenolic constituents, including CHEMICAL, catechin and resveratrol. Inhibition of cardiac voltage-gated sodium channels (VGSCs) is antiarrhythmic and cardioprotective. As polyphenols may also modulate ion channels, and possess structural similarities to several antiarrhythmic GENE inhibitors, we hypothesised that GENE inhibition may contribute to cardioprotection by these polyphenols. EXPERIMENTAL APPROACH: The whole-cell voltage-clamp technique was used to record peak and late GENE currents (INa) from recombinant human heart NaV1.5 channels expressed in tsA201 cells. Right ventricular myocytes from rat heart were isolated and single myocytes were field-stimulated. Either calcium transients or contractility were measured using the calcium-sensitive dye Calcium-Green 1AM or video edge detection, respectively. KEY RESULTS: The red grape polyphenols CHEMICAL, catechin and resveratrol blocked peak INa with IC50s of 19.4 microM, 76.8 microM and 77.3 microM, respectively. In contrast to lidocaine, resveratrol did not exhibit any frequency-dependence of peak INa block. Late INa induced by the GENE long QT mutant R1623Q was reduced by resveratrol and CHEMICAL. Resveratrol and CHEMICAL also blocked late INa induced by the toxin, ATX II, with IC50s of 26.1 microM and 24.9 microM, respectively. In field-stimulated myocytes, ATXII-induced increases in diastolic calcium were prevented and reversed by resveratrol. ATXII-induced contractile dysfunction was delayed and reduced by resveratrol. CONCLUSIONS AND IMPLICATIONS: Our results indicate that several red grape polyphenols inhibit cardiac VGSCs and that this effect may contribute to the documented cardioprotective efficacy of red grape products. | INHIBITOR |
| Inhibition of cardiac voltage-gated sodium channels by grape polyphenols. BACKGROUND AND PURPOSE: The cardiovascular benefits of red wine consumption are often attributed to the antioxidant effects of its polyphenolic constituents, including CHEMICAL, catechin and resveratrol. Inhibition of cardiac voltage-gated sodium channels (VGSCs) is antiarrhythmic and cardioprotective. As polyphenols may also modulate ion channels, and possess structural similarities to several antiarrhythmic VGSC inhibitors, we hypothesised that VGSC inhibition may contribute to cardioprotection by these polyphenols. EXPERIMENTAL APPROACH: The whole-cell voltage-clamp technique was used to record peak and late VGSC currents (INa) from recombinant human heart NaV1.5 channels expressed in tsA201 cells. Right ventricular myocytes from rat heart were isolated and single myocytes were field-stimulated. Either calcium transients or contractility were measured using the calcium-sensitive dye Calcium-Green 1AM or video edge detection, respectively. KEY RESULTS: The red grape polyphenols CHEMICAL, catechin and resveratrol blocked peak INa with IC50s of 19.4 microM, 76.8 microM and 77.3 microM, respectively. In contrast to lidocaine, resveratrol did not exhibit any frequency-dependence of peak INa block. Late INa induced by the VGSC long QT mutant GENE was reduced by resveratrol and CHEMICAL. Resveratrol and CHEMICAL also blocked late INa induced by the toxin, ATX II, with IC50s of 26.1 microM and 24.9 microM, respectively. In field-stimulated myocytes, ATXII-induced increases in diastolic calcium were prevented and reversed by resveratrol. ATXII-induced contractile dysfunction was delayed and reduced by resveratrol. CONCLUSIONS AND IMPLICATIONS: Our results indicate that several red grape polyphenols inhibit cardiac VGSCs and that this effect may contribute to the documented cardioprotective efficacy of red grape products. | INDIRECT-DOWNREGULATOR |
| Enhancement of radiosensitivity by GENE inhibitor, CHEMICAL and amrubicinol, in human lung adenocarcinoma A549 cells and kinetics of apoptosis and necrosis induction. The effects of CHEMICAL (AMR) and its active metabolite, amrubicinol (AMROH), on the sensitivity of human lung adenocarcinoma A549 cells to ionizing radiation were investigated in vitro. Further, the kinetics of apoptosis and necrosis induction were also analyzed. The cytocidal effects of X-ray irradiation on A549 cells resulted in a low level of radiosensitivity with a D0 value of 12 Gy. The slopes of the survival curves in the exponential phase were plotted on semilogarithmic paper for radiation combined with AMR (2.5 microg/ml) and AMROH (0.02 microg/ml) treatment, and were shown to be approximately parallel to treatment with irradiation alone. The initial shoulder-shape portion of the survival curve for radiation alone, indicating the repair of sublethal damage, was reduced as compared to that for sequential combined treatment with AMR or AMROH. Sequential treatments with AMR or AMROH prior to ionizing radiation resulted in an additive radio-enhancement effect that reduced not only survival, but also the shoulder width. Fractionated irradiation with 2 Gy per fraction of A549 cells was carried out in vitro similar to that commonly performed in clinical radiotherapy and the radio-resistance of the cells was shown to be inhibited by AMR and AMROH. Similar to AMR and AMROH, adriamycin and etoposide (VP-16) are DNA GENE inhibitors. The effects of these 4 agents on cells that received X-ray irradiation were compared and all of the agents exhibited comparable radio-enhancement effects. The induction of apoptosis was investigated at 48 and 72 h after administration of AMROH, radiation or combined treatment, and apoptosis was not significantly induced after any of the treatments. We also examined the induction of necrosis, and found that the incidence of necrosis following combined treatment was approximately 2 times higher than that with either of the single treatments. | INHIBITOR |
| Enhancement of radiosensitivity by GENE inhibitor, amrubicin and CHEMICAL, in human lung adenocarcinoma A549 cells and kinetics of apoptosis and necrosis induction. The effects of amrubicin (AMR) and its active metabolite, CHEMICAL (AMROH), on the sensitivity of human lung adenocarcinoma A549 cells to ionizing radiation were investigated in vitro. Further, the kinetics of apoptosis and necrosis induction were also analyzed. The cytocidal effects of X-ray irradiation on A549 cells resulted in a low level of radiosensitivity with a D0 value of 12 Gy. The slopes of the survival curves in the exponential phase were plotted on semilogarithmic paper for radiation combined with AMR (2.5 microg/ml) and AMROH (0.02 microg/ml) treatment, and were shown to be approximately parallel to treatment with irradiation alone. The initial shoulder-shape portion of the survival curve for radiation alone, indicating the repair of sublethal damage, was reduced as compared to that for sequential combined treatment with AMR or AMROH. Sequential treatments with AMR or AMROH prior to ionizing radiation resulted in an additive radio-enhancement effect that reduced not only survival, but also the shoulder width. Fractionated irradiation with 2 Gy per fraction of A549 cells was carried out in vitro similar to that commonly performed in clinical radiotherapy and the radio-resistance of the cells was shown to be inhibited by AMR and AMROH. Similar to AMR and AMROH, adriamycin and etoposide (VP-16) are DNA GENE inhibitors. The effects of these 4 agents on cells that received X-ray irradiation were compared and all of the agents exhibited comparable radio-enhancement effects. The induction of apoptosis was investigated at 48 and 72 h after administration of AMROH, radiation or combined treatment, and apoptosis was not significantly induced after any of the treatments. We also examined the induction of necrosis, and found that the incidence of necrosis following combined treatment was approximately 2 times higher than that with either of the single treatments. | INHIBITOR |
| Enhancement of radiosensitivity by topoisomerase II inhibitor, amrubicin and amrubicinol, in human lung adenocarcinoma A549 cells and kinetics of apoptosis and necrosis induction. The effects of amrubicin (AMR) and its active metabolite, amrubicinol (AMROH), on the sensitivity of human lung adenocarcinoma A549 cells to ionizing radiation were investigated in vitro. Further, the kinetics of apoptosis and necrosis induction were also analyzed. The cytocidal effects of X-ray irradiation on A549 cells resulted in a low level of radiosensitivity with a D0 value of 12 Gy. The slopes of the survival curves in the exponential phase were plotted on semilogarithmic paper for radiation combined with CHEMICAL (2.5 microg/ml) and AMROH (0.02 microg/ml) treatment, and were shown to be approximately parallel to treatment with irradiation alone. The initial shoulder-shape portion of the survival curve for radiation alone, indicating the repair of sublethal damage, was reduced as compared to that for sequential combined treatment with CHEMICAL or AMROH. Sequential treatments with CHEMICAL or AMROH prior to ionizing radiation resulted in an additive radio-enhancement effect that reduced not only survival, but also the shoulder width. Fractionated irradiation with 2 Gy per fraction of A549 cells was carried out in vitro similar to that commonly performed in clinical radiotherapy and the radio-resistance of the cells was shown to be inhibited by CHEMICAL and AMROH. Similar to CHEMICAL and AMROH, adriamycin and etoposide (VP-16) are GENE inhibitors. The effects of these 4 agents on cells that received X-ray irradiation were compared and all of the agents exhibited comparable radio-enhancement effects. The induction of apoptosis was investigated at 48 and 72 h after administration of AMROH, radiation or combined treatment, and apoptosis was not significantly induced after any of the treatments. We also examined the induction of necrosis, and found that the incidence of necrosis following combined treatment was approximately 2 times higher than that with either of the single treatments. | INHIBITOR |
| Enhancement of radiosensitivity by topoisomerase II inhibitor, amrubicin and amrubicinol, in human lung adenocarcinoma A549 cells and kinetics of apoptosis and necrosis induction. The effects of amrubicin (AMR) and its active metabolite, amrubicinol (AMROH), on the sensitivity of human lung adenocarcinoma A549 cells to ionizing radiation were investigated in vitro. Further, the kinetics of apoptosis and necrosis induction were also analyzed. The cytocidal effects of X-ray irradiation on A549 cells resulted in a low level of radiosensitivity with a D0 value of 12 Gy. The slopes of the survival curves in the exponential phase were plotted on semilogarithmic paper for radiation combined with AMR (2.5 microg/ml) and CHEMICAL (0.02 microg/ml) treatment, and were shown to be approximately parallel to treatment with irradiation alone. The initial shoulder-shape portion of the survival curve for radiation alone, indicating the repair of sublethal damage, was reduced as compared to that for sequential combined treatment with AMR or CHEMICAL. Sequential treatments with AMR or CHEMICAL prior to ionizing radiation resulted in an additive radio-enhancement effect that reduced not only survival, but also the shoulder width. Fractionated irradiation with 2 Gy per fraction of A549 cells was carried out in vitro similar to that commonly performed in clinical radiotherapy and the radio-resistance of the cells was shown to be inhibited by AMR and CHEMICAL. Similar to AMR and CHEMICAL, adriamycin and etoposide (VP-16) are GENE inhibitors. The effects of these 4 agents on cells that received X-ray irradiation were compared and all of the agents exhibited comparable radio-enhancement effects. The induction of apoptosis was investigated at 48 and 72 h after administration of CHEMICAL, radiation or combined treatment, and apoptosis was not significantly induced after any of the treatments. We also examined the induction of necrosis, and found that the incidence of necrosis following combined treatment was approximately 2 times higher than that with either of the single treatments. | INHIBITOR |
| Enhancement of radiosensitivity by topoisomerase II inhibitor, amrubicin and amrubicinol, in human lung adenocarcinoma A549 cells and kinetics of apoptosis and necrosis induction. The effects of amrubicin (AMR) and its active metabolite, amrubicinol (AMROH), on the sensitivity of human lung adenocarcinoma A549 cells to ionizing radiation were investigated in vitro. Further, the kinetics of apoptosis and necrosis induction were also analyzed. The cytocidal effects of X-ray irradiation on A549 cells resulted in a low level of radiosensitivity with a D0 value of 12 Gy. The slopes of the survival curves in the exponential phase were plotted on semilogarithmic paper for radiation combined with AMR (2.5 microg/ml) and AMROH (0.02 microg/ml) treatment, and were shown to be approximately parallel to treatment with irradiation alone. The initial shoulder-shape portion of the survival curve for radiation alone, indicating the repair of sublethal damage, was reduced as compared to that for sequential combined treatment with AMR or AMROH. Sequential treatments with AMR or AMROH prior to ionizing radiation resulted in an additive radio-enhancement effect that reduced not only survival, but also the shoulder width. Fractionated irradiation with 2 Gy per fraction of A549 cells was carried out in vitro similar to that commonly performed in clinical radiotherapy and the radio-resistance of the cells was shown to be inhibited by AMR and AMROH. Similar to AMR and AMROH, CHEMICAL and etoposide (VP-16) are GENE inhibitors. The effects of these 4 agents on cells that received X-ray irradiation were compared and all of the agents exhibited comparable radio-enhancement effects. The induction of apoptosis was investigated at 48 and 72 h after administration of AMROH, radiation or combined treatment, and apoptosis was not significantly induced after any of the treatments. We also examined the induction of necrosis, and found that the incidence of necrosis following combined treatment was approximately 2 times higher than that with either of the single treatments. | INHIBITOR |
| Enhancement of radiosensitivity by topoisomerase II inhibitor, amrubicin and amrubicinol, in human lung adenocarcinoma A549 cells and kinetics of apoptosis and necrosis induction. The effects of amrubicin (AMR) and its active metabolite, amrubicinol (AMROH), on the sensitivity of human lung adenocarcinoma A549 cells to ionizing radiation were investigated in vitro. Further, the kinetics of apoptosis and necrosis induction were also analyzed. The cytocidal effects of X-ray irradiation on A549 cells resulted in a low level of radiosensitivity with a D0 value of 12 Gy. The slopes of the survival curves in the exponential phase were plotted on semilogarithmic paper for radiation combined with AMR (2.5 microg/ml) and AMROH (0.02 microg/ml) treatment, and were shown to be approximately parallel to treatment with irradiation alone. The initial shoulder-shape portion of the survival curve for radiation alone, indicating the repair of sublethal damage, was reduced as compared to that for sequential combined treatment with AMR or AMROH. Sequential treatments with AMR or AMROH prior to ionizing radiation resulted in an additive radio-enhancement effect that reduced not only survival, but also the shoulder width. Fractionated irradiation with 2 Gy per fraction of A549 cells was carried out in vitro similar to that commonly performed in clinical radiotherapy and the radio-resistance of the cells was shown to be inhibited by AMR and AMROH. Similar to AMR and AMROH, adriamycin and CHEMICAL (VP-16) are GENE inhibitors. The effects of these 4 agents on cells that received X-ray irradiation were compared and all of the agents exhibited comparable radio-enhancement effects. The induction of apoptosis was investigated at 48 and 72 h after administration of AMROH, radiation or combined treatment, and apoptosis was not significantly induced after any of the treatments. We also examined the induction of necrosis, and found that the incidence of necrosis following combined treatment was approximately 2 times higher than that with either of the single treatments. | INHIBITOR |
| Enhancement of radiosensitivity by topoisomerase II inhibitor, amrubicin and amrubicinol, in human lung adenocarcinoma A549 cells and kinetics of apoptosis and necrosis induction. The effects of amrubicin (AMR) and its active metabolite, amrubicinol (AMROH), on the sensitivity of human lung adenocarcinoma A549 cells to ionizing radiation were investigated in vitro. Further, the kinetics of apoptosis and necrosis induction were also analyzed. The cytocidal effects of X-ray irradiation on A549 cells resulted in a low level of radiosensitivity with a D0 value of 12 Gy. The slopes of the survival curves in the exponential phase were plotted on semilogarithmic paper for radiation combined with AMR (2.5 microg/ml) and AMROH (0.02 microg/ml) treatment, and were shown to be approximately parallel to treatment with irradiation alone. The initial shoulder-shape portion of the survival curve for radiation alone, indicating the repair of sublethal damage, was reduced as compared to that for sequential combined treatment with AMR or AMROH. Sequential treatments with AMR or AMROH prior to ionizing radiation resulted in an additive radio-enhancement effect that reduced not only survival, but also the shoulder width. Fractionated irradiation with 2 Gy per fraction of A549 cells was carried out in vitro similar to that commonly performed in clinical radiotherapy and the radio-resistance of the cells was shown to be inhibited by AMR and AMROH. Similar to AMR and AMROH, adriamycin and etoposide (CHEMICAL) are GENE inhibitors. The effects of these 4 agents on cells that received X-ray irradiation were compared and all of the agents exhibited comparable radio-enhancement effects. The induction of apoptosis was investigated at 48 and 72 h after administration of AMROH, radiation or combined treatment, and apoptosis was not significantly induced after any of the treatments. We also examined the induction of necrosis, and found that the incidence of necrosis following combined treatment was approximately 2 times higher than that with either of the single treatments. | INHIBITOR |
| Interaction of nonsteroidal anti-inflammatory drugs (NSAID) with Helicobacter pylori in the stomach of humans and experimental animals. Helicobacter pylori (H. pylori) and non-steroidal anti-inflammatory drugs (NSAID) are major pathogenic factors in peptic ulcer disease but whether these two factors exert synergistic or antagonistic action on the gastric mucosa has been a subject of controversy. The classic concept states that there is an increased ulcer occurrence and bleeding in patients with both H. pylori infection and NSAID use. However, the question whether the H. pylori eradication therapy in NSAID users reduces the occurrence of peptic ulcer has not been fully addressed. Studies on secondary prevention of NSAID-associated ulcers in H. pylori patients have indicated that H. pylori eradication results in impaired ulcer healing with an effect on the rate of peptic ulcer occurrence. On the other hand, the treatment of H. pylori in patients with no prior history of chronic NSAID therapy has been shown to decrease the risk of peptic ulcer. Studies in experimental animals revealed for instance, that the H. pylori infection augments the gastric mucosal damage induced by NSAID in Mongolian gerbils. In rats with preexisting chromic gastric ulcers, H. pylori infection attenuated significantly the aspirin-induced inhibition of ulcer healing and accompanying fall in the gastric blood flow at the margin of these ulcers, suggesting negative interaction between CHEMICAL and H. pylori on ulcerogenesis. Accumulated evidence in humans and animals shows that both CHEMICAL and H. pylori upregulate the expression of cyclooxygenase (COX)-2 both at mRNA and protein levels at the ulcer margin, but failed to influence significantly that of GENE. It was, therefore, proposed that H. pylori may in fact, antagonize, aspirin-induced delay of ulcer healing due to suppression of acid secretion by the enhancement in PGE(2) possibly derived from COX-2 expression and activity and to the overexpression of growth factors such as TGF alpha and VEGF. The present review summarizes and further addresses the issue of the interaction between these two major ulcer risk factors determined in the stomach of humans and experimental animals. | NO-RELATIONSHIP |
| Interaction of nonsteroidal anti-inflammatory drugs (NSAID) with Helicobacter pylori in the stomach of humans and experimental animals. Helicobacter pylori (H. pylori) and non-steroidal anti-inflammatory drugs (NSAID) are major pathogenic factors in peptic ulcer disease but whether these two factors exert synergistic or antagonistic action on the gastric mucosa has been a subject of controversy. The classic concept states that there is an increased ulcer occurrence and bleeding in patients with both H. pylori infection and NSAID use. However, the question whether the H. pylori eradication therapy in NSAID users reduces the occurrence of peptic ulcer has not been fully addressed. Studies on secondary prevention of NSAID-associated ulcers in H. pylori patients have indicated that H. pylori eradication results in impaired ulcer healing with an effect on the rate of peptic ulcer occurrence. On the other hand, the treatment of H. pylori in patients with no prior history of chronic NSAID therapy has been shown to decrease the risk of peptic ulcer. Studies in experimental animals revealed for instance, that the H. pylori infection augments the gastric mucosal damage induced by NSAID in Mongolian gerbils. In rats with preexisting chromic gastric ulcers, H. pylori infection attenuated significantly the aspirin-induced inhibition of ulcer healing and accompanying fall in the gastric blood flow at the margin of these ulcers, suggesting negative interaction between CHEMICAL and H. pylori on ulcerogenesis. Accumulated evidence in humans and animals shows that both CHEMICAL and H. pylori upregulate the expression of cyclooxygenase (COX)-2 both at mRNA and protein levels at the ulcer margin, but failed to influence significantly that of COX-1. It was, therefore, proposed that H. pylori may in fact, antagonize, CHEMICAL-induced delay of ulcer healing due to suppression of acid secretion by the enhancement in PGE(2) possibly derived from GENE expression and activity and to the overexpression of growth factors such as TGF alpha and VEGF. The present review summarizes and further addresses the issue of the interaction between these two major ulcer risk factors determined in the stomach of humans and experimental animals. | GENE-CHEMICAL |
| Interaction of nonsteroidal anti-inflammatory drugs (NSAID) with Helicobacter pylori in the stomach of humans and experimental animals. Helicobacter pylori (H. pylori) and non-steroidal anti-inflammatory drugs (NSAID) are major pathogenic factors in peptic ulcer disease but whether these two factors exert synergistic or antagonistic action on the gastric mucosa has been a subject of controversy. The classic concept states that there is an increased ulcer occurrence and bleeding in patients with both H. pylori infection and NSAID use. However, the question whether the H. pylori eradication therapy in NSAID users reduces the occurrence of peptic ulcer has not been fully addressed. Studies on secondary prevention of NSAID-associated ulcers in H. pylori patients have indicated that H. pylori eradication results in impaired ulcer healing with an effect on the rate of peptic ulcer occurrence. On the other hand, the treatment of H. pylori in patients with no prior history of chronic NSAID therapy has been shown to decrease the risk of peptic ulcer. Studies in experimental animals revealed for instance, that the H. pylori infection augments the gastric mucosal damage induced by NSAID in Mongolian gerbils. In rats with preexisting chromic gastric ulcers, H. pylori infection attenuated significantly the aspirin-induced inhibition of ulcer healing and accompanying fall in the gastric blood flow at the margin of these ulcers, suggesting negative interaction between CHEMICAL and H. pylori on ulcerogenesis. Accumulated evidence in humans and animals shows that both CHEMICAL and H. pylori upregulate the expression of GENE both at mRNA and protein levels at the ulcer margin, but failed to influence significantly that of COX-1. It was, therefore, proposed that H. pylori may in fact, antagonize, aspirin-induced delay of ulcer healing due to suppression of acid secretion by the enhancement in PGE(2) possibly derived from COX-2 expression and activity and to the overexpression of growth factors such as TGF alpha and VEGF. The present review summarizes and further addresses the issue of the interaction between these two major ulcer risk factors determined in the stomach of humans and experimental animals. | INDIRECT-UPREGULATOR |
| Interaction of nonsteroidal anti-inflammatory drugs (NSAID) with Helicobacter pylori in the stomach of humans and experimental animals. Helicobacter pylori (H. pylori) and non-steroidal anti-inflammatory drugs (NSAID) are major pathogenic factors in peptic ulcer disease but whether these two factors exert synergistic or antagonistic action on the gastric mucosa has been a subject of controversy. The classic concept states that there is an increased ulcer occurrence and bleeding in patients with both H. pylori infection and NSAID use. However, the question whether the H. pylori eradication therapy in NSAID users reduces the occurrence of peptic ulcer has not been fully addressed. Studies on secondary prevention of NSAID-associated ulcers in H. pylori patients have indicated that H. pylori eradication results in impaired ulcer healing with an effect on the rate of peptic ulcer occurrence. On the other hand, the treatment of H. pylori in patients with no prior history of chronic NSAID therapy has been shown to decrease the risk of peptic ulcer. Studies in experimental animals revealed for instance, that the H. pylori infection augments the gastric mucosal damage induced by NSAID in Mongolian gerbils. In rats with preexisting chromic gastric ulcers, H. pylori infection attenuated significantly the aspirin-induced inhibition of ulcer healing and accompanying fall in the gastric blood flow at the margin of these ulcers, suggesting negative interaction between CHEMICAL and H. pylori on ulcerogenesis. Accumulated evidence in humans and animals shows that both CHEMICAL and H. pylori upregulate the expression of cyclooxygenase (COX)-2 both at mRNA and protein levels at the ulcer margin, but failed to influence significantly that of COX-1. It was, therefore, proposed that H. pylori may in fact, antagonize, CHEMICAL-induced delay of ulcer healing due to suppression of acid secretion by the enhancement in PGE(2) possibly derived from COX-2 expression and activity and to the overexpression of growth factors such as GENE and VEGF. The present review summarizes and further addresses the issue of the interaction between these two major ulcer risk factors determined in the stomach of humans and experimental animals. | INDIRECT-UPREGULATOR |
| Interaction of nonsteroidal anti-inflammatory drugs (NSAID) with Helicobacter pylori in the stomach of humans and experimental animals. Helicobacter pylori (H. pylori) and non-steroidal anti-inflammatory drugs (NSAID) are major pathogenic factors in peptic ulcer disease but whether these two factors exert synergistic or antagonistic action on the gastric mucosa has been a subject of controversy. The classic concept states that there is an increased ulcer occurrence and bleeding in patients with both H. pylori infection and NSAID use. However, the question whether the H. pylori eradication therapy in NSAID users reduces the occurrence of peptic ulcer has not been fully addressed. Studies on secondary prevention of NSAID-associated ulcers in H. pylori patients have indicated that H. pylori eradication results in impaired ulcer healing with an effect on the rate of peptic ulcer occurrence. On the other hand, the treatment of H. pylori in patients with no prior history of chronic NSAID therapy has been shown to decrease the risk of peptic ulcer. Studies in experimental animals revealed for instance, that the H. pylori infection augments the gastric mucosal damage induced by NSAID in Mongolian gerbils. In rats with preexisting chromic gastric ulcers, H. pylori infection attenuated significantly the aspirin-induced inhibition of ulcer healing and accompanying fall in the gastric blood flow at the margin of these ulcers, suggesting negative interaction between CHEMICAL and H. pylori on ulcerogenesis. Accumulated evidence in humans and animals shows that both CHEMICAL and H. pylori upregulate the expression of cyclooxygenase (COX)-2 both at mRNA and protein levels at the ulcer margin, but failed to influence significantly that of COX-1. It was, therefore, proposed that H. pylori may in fact, antagonize, CHEMICAL-induced delay of ulcer healing due to suppression of acid secretion by the enhancement in PGE(2) possibly derived from COX-2 expression and activity and to the overexpression of growth factors such as TGF alpha and GENE. The present review summarizes and further addresses the issue of the interaction between these two major ulcer risk factors determined in the stomach of humans and experimental animals. | INDIRECT-UPREGULATOR |
| Interaction of nonsteroidal anti-inflammatory drugs (NSAID) with Helicobacter pylori in the stomach of humans and experimental animals. Helicobacter pylori (H. pylori) and non-steroidal anti-inflammatory drugs (NSAID) are major pathogenic factors in peptic ulcer disease but whether these two factors exert synergistic or antagonistic action on the gastric mucosa has been a subject of controversy. The classic concept states that there is an increased ulcer occurrence and bleeding in patients with both H. pylori infection and NSAID use. However, the question whether the H. pylori eradication therapy in NSAID users reduces the occurrence of peptic ulcer has not been fully addressed. Studies on secondary prevention of NSAID-associated ulcers in H. pylori patients have indicated that H. pylori eradication results in impaired ulcer healing with an effect on the rate of peptic ulcer occurrence. On the other hand, the treatment of H. pylori in patients with no prior history of chronic NSAID therapy has been shown to decrease the risk of peptic ulcer. Studies in experimental animals revealed for instance, that the H. pylori infection augments the gastric mucosal damage induced by NSAID in Mongolian gerbils. In rats with preexisting chromic gastric ulcers, H. pylori infection attenuated significantly the aspirin-induced inhibition of ulcer healing and accompanying fall in the gastric blood flow at the margin of these ulcers, suggesting negative interaction between aspirin and H. pylori on ulcerogenesis. Accumulated evidence in humans and animals shows that both aspirin and H. pylori upregulate the expression of cyclooxygenase (COX)-2 both at mRNA and protein levels at the ulcer margin, but failed to influence significantly that of COX-1. It was, therefore, proposed that H. pylori may in fact, antagonize, aspirin-induced delay of ulcer healing due to suppression of acid secretion by the enhancement in CHEMICAL possibly derived from GENE expression and activity and to the overexpression of growth factors such as TGF alpha and VEGF. The present review summarizes and further addresses the issue of the interaction between these two major ulcer risk factors determined in the stomach of humans and experimental animals. | PRODUCT-OF |
| The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on CHEMICAL activity. CHEMICAL is a new-generation antifolate inhibitor of thymidylate synthase (TS) and a weaker inhibitor of glycinamide ribonucleotide transformylase (GARFT) required for de novo purine synthesis. Methylthioadenosine phosphorylase (MTAP) salvages purines by releasing adenine from methylthioadenosine and is often deleted in mesothelioma. The current study addresses the effect of MTAP on CHEMICAL activity using a highly potent transition state inhibitor of MTAP, MT-DADMe-Immucillin A (ImmA; K(i) = 86 pmol/L) in the MTAP(+) NCI-H28 and MTAP(-) NCI-H2052 mesothelioma cell lines. Based on selective nucleoside protection, GENE was found to be the primary CHEMICAL target in both cell lines with GARFT inhibition requiring 20- to 30-fold higher CHEMICAL concentrations. ImmA had no effect on CHEMICAL activity but, when thymidine was added, the CHEMICAL IC(50) decreased by a factor of approximately 3 in MTAP(+) H28 cells with no effect in MTAP(-) H2052 cells. Conversely, the transfection of MTAP into H2052 cells increased the CHEMICAL IC(50) by nearly 3-fold but only in the presence of thymidine; this was reversed by ImmA. An MTAP-specific short interfering RNA produced a 2-fold decrease in CHEMICAL IC(50) in MTAP(+) HeLa cells in the presence of thymidine. These data indicate that suppression of constitutive MTAP has no effect on CHEMICAL activity when the primary target is GENE. There is a modest salutary effect when the CHEMICAL target is GARFT alone. | REGULATOR |
| The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on CHEMICAL activity. CHEMICAL is a new-generation antifolate inhibitor of thymidylate synthase (TS) and a weaker inhibitor of glycinamide ribonucleotide transformylase (GARFT) required for de novo purine synthesis. Methylthioadenosine phosphorylase (MTAP) salvages purines by releasing adenine from methylthioadenosine and is often deleted in mesothelioma. The current study addresses the effect of MTAP on CHEMICAL activity using a highly potent transition state inhibitor of MTAP, MT-DADMe-Immucillin A (ImmA; K(i) = 86 pmol/L) in the MTAP(+) NCI-H28 and MTAP(-) NCI-H2052 mesothelioma cell lines. Based on selective nucleoside protection, TS was found to be the primary CHEMICAL target in both cell lines with GENE inhibition requiring 20- to 30-fold higher CHEMICAL concentrations. ImmA had no effect on CHEMICAL activity but, when thymidine was added, the CHEMICAL IC(50) decreased by a factor of approximately 3 in MTAP(+) H28 cells with no effect in MTAP(-) H2052 cells. Conversely, the transfection of MTAP into H2052 cells increased the CHEMICAL IC(50) by nearly 3-fold but only in the presence of thymidine; this was reversed by ImmA. An MTAP-specific short interfering RNA produced a 2-fold decrease in CHEMICAL IC(50) in MTAP(+) HeLa cells in the presence of thymidine. These data indicate that suppression of constitutive MTAP has no effect on CHEMICAL activity when the primary target is TS. There is a modest salutary effect when the CHEMICAL target is GENE alone. | REGULATOR |
| The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on pemetrexed activity. Pemetrexed is a new-generation antifolate inhibitor of thymidylate synthase (TS) and a weaker inhibitor of glycinamide ribonucleotide transformylase (GARFT) required for de novo purine synthesis. GENE (MTAP) salvages purines by releasing CHEMICAL from methylthioadenosine and is often deleted in mesothelioma. The current study addresses the effect of MTAP on pemetrexed activity using a highly potent transition state inhibitor of MTAP, MT-DADMe-Immucillin A (ImmA; K(i) = 86 pmol/L) in the MTAP(+) NCI-H28 and MTAP(-) NCI-H2052 mesothelioma cell lines. Based on selective nucleoside protection, TS was found to be the primary pemetrexed target in both cell lines with GARFT inhibition requiring 20- to 30-fold higher pemetrexed concentrations. ImmA had no effect on pemetrexed activity but, when thymidine was added, the pemetrexed IC(50) decreased by a factor of approximately 3 in MTAP(+) H28 cells with no effect in MTAP(-) H2052 cells. Conversely, the transfection of MTAP into H2052 cells increased the pemetrexed IC(50) by nearly 3-fold but only in the presence of thymidine; this was reversed by ImmA. An MTAP-specific short interfering RNA produced a 2-fold decrease in pemetrexed IC(50) in MTAP(+) HeLa cells in the presence of thymidine. These data indicate that suppression of constitutive MTAP has no effect on pemetrexed activity when the primary target is TS. There is a modest salutary effect when the pemetrexed target is GARFT alone. | SUBSTRATE |
| The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on pemetrexed activity. Pemetrexed is a new-generation antifolate inhibitor of thymidylate synthase (TS) and a weaker inhibitor of glycinamide ribonucleotide transformylase (GARFT) required for de novo purine synthesis. Methylthioadenosine phosphorylase (GENE) salvages purines by releasing CHEMICAL from methylthioadenosine and is often deleted in mesothelioma. The current study addresses the effect of GENE on pemetrexed activity using a highly potent transition state inhibitor of GENE, MT-DADMe-Immucillin A (ImmA; K(i) = 86 pmol/L) in the MTAP(+) NCI-H28 and MTAP(-) NCI-H2052 mesothelioma cell lines. Based on selective nucleoside protection, TS was found to be the primary pemetrexed target in both cell lines with GARFT inhibition requiring 20- to 30-fold higher pemetrexed concentrations. ImmA had no effect on pemetrexed activity but, when thymidine was added, the pemetrexed IC(50) decreased by a factor of approximately 3 in MTAP(+) H28 cells with no effect in MTAP(-) H2052 cells. Conversely, the transfection of GENE into H2052 cells increased the pemetrexed IC(50) by nearly 3-fold but only in the presence of thymidine; this was reversed by ImmA. An MTAP-specific short interfering RNA produced a 2-fold decrease in pemetrexed IC(50) in MTAP(+) HeLa cells in the presence of thymidine. These data indicate that suppression of constitutive GENE has no effect on pemetrexed activity when the primary target is TS. There is a modest salutary effect when the pemetrexed target is GARFT alone. | SUBSTRATE |
| The effect of a novel transition state inhibitor of CHEMICAL phosphorylase on pemetrexed activity. Pemetrexed is a new-generation antifolate inhibitor of thymidylate synthase (TS) and a weaker inhibitor of glycinamide ribonucleotide transformylase (GARFT) required for de novo purine synthesis. GENE (MTAP) salvages purines by releasing adenine from CHEMICAL and is often deleted in mesothelioma. The current study addresses the effect of MTAP on pemetrexed activity using a highly potent transition state inhibitor of MTAP, MT-DADMe-Immucillin A (ImmA; K(i) = 86 pmol/L) in the MTAP(+) NCI-H28 and MTAP(-) NCI-H2052 mesothelioma cell lines. Based on selective nucleoside protection, TS was found to be the primary pemetrexed target in both cell lines with GARFT inhibition requiring 20- to 30-fold higher pemetrexed concentrations. ImmA had no effect on pemetrexed activity but, when thymidine was added, the pemetrexed IC(50) decreased by a factor of approximately 3 in MTAP(+) H28 cells with no effect in MTAP(-) H2052 cells. Conversely, the transfection of MTAP into H2052 cells increased the pemetrexed IC(50) by nearly 3-fold but only in the presence of thymidine; this was reversed by ImmA. An MTAP-specific short interfering RNA produced a 2-fold decrease in pemetrexed IC(50) in MTAP(+) HeLa cells in the presence of thymidine. These data indicate that suppression of constitutive MTAP has no effect on pemetrexed activity when the primary target is TS. There is a modest salutary effect when the pemetrexed target is GARFT alone. | SUBSTRATE |
| The effect of a novel transition state inhibitor of CHEMICAL phosphorylase on pemetrexed activity. Pemetrexed is a new-generation antifolate inhibitor of thymidylate synthase (TS) and a weaker inhibitor of glycinamide ribonucleotide transformylase (GARFT) required for de novo purine synthesis. CHEMICAL phosphorylase (GENE) salvages purines by releasing adenine from CHEMICAL and is often deleted in mesothelioma. The current study addresses the effect of GENE on pemetrexed activity using a highly potent transition state inhibitor of GENE, MT-DADMe-Immucillin A (ImmA; K(i) = 86 pmol/L) in the MTAP(+) NCI-H28 and MTAP(-) NCI-H2052 mesothelioma cell lines. Based on selective nucleoside protection, TS was found to be the primary pemetrexed target in both cell lines with GARFT inhibition requiring 20- to 30-fold higher pemetrexed concentrations. ImmA had no effect on pemetrexed activity but, when thymidine was added, the pemetrexed IC(50) decreased by a factor of approximately 3 in MTAP(+) H28 cells with no effect in MTAP(-) H2052 cells. Conversely, the transfection of GENE into H2052 cells increased the pemetrexed IC(50) by nearly 3-fold but only in the presence of thymidine; this was reversed by ImmA. An MTAP-specific short interfering RNA produced a 2-fold decrease in pemetrexed IC(50) in MTAP(+) HeLa cells in the presence of thymidine. These data indicate that suppression of constitutive GENE has no effect on pemetrexed activity when the primary target is TS. There is a modest salutary effect when the pemetrexed target is GARFT alone. | SUBSTRATE |
| CHEMICAL and glinides exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that CHEMICAL and glinides additionally bind to GENE and exhibit GENE agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of GENE target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit GENE agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing GENE target gene expression. This dual mode of action of CHEMICAL and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and GENE. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, CHEMICAL, and other acidified sulfonamides may be promising leads in the development of new GENE agonists. In addition, we provide a unified concept of the GENE binding ability of seemingly disparate compound classes. | DIRECT-REGULATOR |
| Sulfonylureas and CHEMICAL exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and CHEMICAL additionally bind to GENE and exhibit GENE agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of GENE target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit GENE agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing GENE target gene expression. This dual mode of action of sulfonylureas and CHEMICAL may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and GENE. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. CHEMICAL, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new GENE agonists. In addition, we provide a unified concept of the GENE binding ability of seemingly disparate compound classes. | DIRECT-REGULATOR |
| CHEMICAL and glinides exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach. Most drugs currently employed in the treatment of type 2 diabetes either target the GENE stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that CHEMICAL and glinides additionally bind to PPARgamma and exhibit PPARgamma agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of PPARgamma target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit PPARgamma agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing PPARgamma target gene expression. This dual mode of action of CHEMICAL and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the GENE and PPARgamma. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, CHEMICAL, and other acidified sulfonamides may be promising leads in the development of new PPARgamma agonists. In addition, we provide a unified concept of the PPARgamma binding ability of seemingly disparate compound classes. | INHIBITOR |
| Sulfonylureas and CHEMICAL exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach. Most drugs currently employed in the treatment of type 2 diabetes either target the GENE stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and CHEMICAL additionally bind to PPARgamma and exhibit PPARgamma agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of PPARgamma target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit PPARgamma agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing PPARgamma target gene expression. This dual mode of action of sulfonylureas and CHEMICAL may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the GENE and PPARgamma. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. CHEMICAL, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new PPARgamma agonists. In addition, we provide a unified concept of the PPARgamma binding ability of seemingly disparate compound classes. | INHIBITOR |
| CHEMICAL and glinides exhibit GENE activity: a combined virtual screening and biological assay approach. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to PPARgamma and exhibit PPARgamma agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of PPARgamma target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit PPARgamma agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing PPARgamma target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and PPARgamma. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new PPARgamma agonists. In addition, we provide a unified concept of the PPARgamma binding ability of seemingly disparate compound classes. | ACTIVATOR |
| Sulfonylureas and CHEMICAL exhibit GENE activity: a combined virtual screening and biological assay approach. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and CHEMICAL additionally bind to PPARgamma and exhibit PPARgamma agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of PPARgamma target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit PPARgamma agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing PPARgamma target gene expression. This dual mode of action of sulfonylureas and CHEMICAL may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and PPARgamma. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. CHEMICAL, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new PPARgamma agonists. In addition, we provide a unified concept of the PPARgamma binding ability of seemingly disparate compound classes. | ACTIVATOR |
| Sulfonylureas and glinides exhibit GENE gamma activity: a combined virtual screening and biological assay approach. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the GENE (PPARgamma) improving insulin resistance (CHEMICAL). Our work shows that sulfonylureas and glinides additionally bind to PPARgamma and exhibit PPARgamma agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of PPARgamma target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit PPARgamma agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing PPARgamma target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and PPARgamma. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new PPARgamma agonists. In addition, we provide a unified concept of the PPARgamma binding ability of seemingly disparate compound classes. | REGULATOR |
| Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (GENE) improving insulin resistance (CHEMICAL). Our work shows that sulfonylureas and glinides additionally bind to GENE and exhibit GENE agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of GENE target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit GENE agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing GENE target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and GENE. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new GENE agonists. In addition, we provide a unified concept of the GENE binding ability of seemingly disparate compound classes. | REGULATOR |
| Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to GENE and exhibit GENE agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of GENE target genes. Among the measured compounds, CHEMICAL and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit GENE agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, CHEMICAL, is shown to be as potent as pioglitazone at inducing GENE target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and GENE. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new GENE agonists. In addition, we provide a unified concept of the GENE binding ability of seemingly disparate compound classes. | ACTIVATOR |
| Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to GENE and exhibit GENE agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of GENE target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit GENE agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as CHEMICAL at inducing GENE target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and GENE. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new GENE agonists. In addition, we provide a unified concept of the GENE binding ability of seemingly disparate compound classes. | REGULATOR |
| CHEMICAL and glinides exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating GENE release (CHEMICAL, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving GENE resistance (thiazolidinediones). Our work shows that CHEMICAL and glinides additionally bind to PPARgamma and exhibit PPARgamma agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of PPARgamma target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit PPARgamma agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing PPARgamma target gene expression. This dual mode of action of CHEMICAL and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and PPARgamma. Targeting both receptors could increase pancreatic GENE secretion and improve GENE resistance. Glinides, CHEMICAL, and other acidified sulfonamides may be promising leads in the development of new PPARgamma agonists. In addition, we provide a unified concept of the PPARgamma binding ability of seemingly disparate compound classes. | GENE-CHEMICAL |
| Sulfonylureas and CHEMICAL exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating GENE release (sulfonylureas, CHEMICAL), or target the peroxisome proliferator-activated receptor (PPARgamma) improving GENE resistance (thiazolidinediones). Our work shows that sulfonylureas and CHEMICAL additionally bind to PPARgamma and exhibit PPARgamma agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of PPARgamma target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit PPARgamma agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing PPARgamma target gene expression. This dual mode of action of sulfonylureas and CHEMICAL may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and PPARgamma. Targeting both receptors could increase pancreatic GENE secretion and improve GENE resistance. CHEMICAL, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new PPARgamma agonists. In addition, we provide a unified concept of the PPARgamma binding ability of seemingly disparate compound classes. | GENE-CHEMICAL |
| Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to GENE and exhibit GENE agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of GENE target genes. Among the measured compounds, gliquidone and CHEMICAL (two sulfonylureas), as well as nateglinide (a glinide), exhibit GENE agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing GENE target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and GENE. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new GENE agonists. In addition, we provide a unified concept of the GENE binding ability of seemingly disparate compound classes. | ACTIVATOR |
| Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to GENE and exhibit GENE agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of GENE target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as CHEMICAL (a glinide), exhibit GENE agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing GENE target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and GENE. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new GENE agonists. In addition, we provide a unified concept of the GENE binding ability of seemingly disparate compound classes. | ACTIVATOR |
| Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to GENE and exhibit GENE agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of GENE target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a CHEMICAL), exhibit GENE agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing GENE target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and GENE. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new GENE agonists. In addition, we provide a unified concept of the GENE binding ability of seemingly disparate compound classes. | ACTIVATOR |
| Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to GENE and exhibit GENE agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of GENE target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit GENE agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing GENE target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and GENE. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. CHEMICAL, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new GENE agonists. In addition, we provide a unified concept of the GENE binding ability of seemingly disparate compound classes. | ACTIVATOR |
| Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach. Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to GENE and exhibit GENE agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of GENE target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit GENE agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing GENE target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and GENE. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, sulfonylureas, and other CHEMICAL may be promising leads in the development of new GENE agonists. In addition, we provide a unified concept of the GENE binding ability of seemingly disparate compound classes. | ACTIVATOR |
| PGE(1) stimulation of HEK293 cells generates multiple contiguous domains with different [cAMP]: role of compartmentalized phosphodiesterases. There is a growing appreciation that the CHEMICAL (cAMP)-GENE (PKA) signaling pathway is organized to form transduction units that function to deliver specific messages. Such organization results in the local activation of PKA subsets through the generation of confined intracellular gradients of cAMP, but the mechanisms responsible for limiting the diffusion of cAMP largely remain to be clarified. In this study, by performing real-time imaging of cAMP, we show that prostaglandin 1 stimulation generates multiple contiguous, intracellular domains with different cAMP concentration in human embryonic kidney 293 cells. By using pharmacological and genetic manipulation of phosphodiesterases (PDEs), we demonstrate that compartmentalized PDE4B and PDE4D are responsible for selectively modulating the concentration of cAMP in individual subcellular compartments. We propose a model whereby compartmentalized PDEs, rather than representing an enzymatic barrier to cAMP diffusion, act as a sink to drain the second messenger from discrete locations, resulting in multiple and simultaneous domains with different cAMP concentrations irrespective of their distance from the site of cAMP synthesis. | REGULATOR |
| PGE(1) stimulation of HEK293 cells generates multiple contiguous domains with different [cAMP]: role of compartmentalized phosphodiesterases. There is a growing appreciation that the CHEMICAL (cAMP)-protein kinase A (GENE) signaling pathway is organized to form transduction units that function to deliver specific messages. Such organization results in the local activation of GENE subsets through the generation of confined intracellular gradients of cAMP, but the mechanisms responsible for limiting the diffusion of cAMP largely remain to be clarified. In this study, by performing real-time imaging of cAMP, we show that prostaglandin 1 stimulation generates multiple contiguous, intracellular domains with different cAMP concentration in human embryonic kidney 293 cells. By using pharmacological and genetic manipulation of phosphodiesterases (PDEs), we demonstrate that compartmentalized PDE4B and PDE4D are responsible for selectively modulating the concentration of cAMP in individual subcellular compartments. We propose a model whereby compartmentalized PDEs, rather than representing an enzymatic barrier to cAMP diffusion, act as a sink to drain the second messenger from discrete locations, resulting in multiple and simultaneous domains with different cAMP concentrations irrespective of their distance from the site of cAMP synthesis. | REGULATOR |
| PGE(1) stimulation of HEK293 cells generates multiple contiguous domains with different [cAMP]: role of compartmentalized phosphodiesterases. There is a growing appreciation that the cyclic adenosine monophosphate (CHEMICAL)-GENE (PKA) signaling pathway is organized to form transduction units that function to deliver specific messages. Such organization results in the local activation of PKA subsets through the generation of confined intracellular gradients of CHEMICAL, but the mechanisms responsible for limiting the diffusion of CHEMICAL largely remain to be clarified. In this study, by performing real-time imaging of CHEMICAL, we show that prostaglandin 1 stimulation generates multiple contiguous, intracellular domains with different CHEMICAL concentration in human embryonic kidney 293 cells. By using pharmacological and genetic manipulation of phosphodiesterases (PDEs), we demonstrate that compartmentalized PDE4B and PDE4D are responsible for selectively modulating the concentration of CHEMICAL in individual subcellular compartments. We propose a model whereby compartmentalized PDEs, rather than representing an enzymatic barrier to CHEMICAL diffusion, act as a sink to drain the second messenger from discrete locations, resulting in multiple and simultaneous domains with different CHEMICAL concentrations irrespective of their distance from the site of CHEMICAL synthesis. | REGULATOR |
| PGE(1) stimulation of HEK293 cells generates multiple contiguous domains with different [cAMP]: role of compartmentalized phosphodiesterases. There is a growing appreciation that the cyclic adenosine monophosphate (CHEMICAL)-protein kinase A (GENE) signaling pathway is organized to form transduction units that function to deliver specific messages. Such organization results in the local activation of GENE subsets through the generation of confined intracellular gradients of CHEMICAL, but the mechanisms responsible for limiting the diffusion of CHEMICAL largely remain to be clarified. In this study, by performing real-time imaging of CHEMICAL, we show that prostaglandin 1 stimulation generates multiple contiguous, intracellular domains with different CHEMICAL concentration in human embryonic kidney 293 cells. By using pharmacological and genetic manipulation of phosphodiesterases (PDEs), we demonstrate that compartmentalized PDE4B and PDE4D are responsible for selectively modulating the concentration of CHEMICAL in individual subcellular compartments. We propose a model whereby compartmentalized PDEs, rather than representing an enzymatic barrier to CHEMICAL diffusion, act as a sink to drain the second messenger from discrete locations, resulting in multiple and simultaneous domains with different CHEMICAL concentrations irrespective of their distance from the site of CHEMICAL synthesis. | REGULATOR |
| PGE(1) stimulation of HEK293 cells generates multiple contiguous domains with different [cAMP]: role of compartmentalized phosphodiesterases. There is a growing appreciation that the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway is organized to form transduction units that function to deliver specific messages. Such organization results in the local activation of PKA subsets through the generation of confined intracellular gradients of CHEMICAL, but the mechanisms responsible for limiting the diffusion of CHEMICAL largely remain to be clarified. In this study, by performing real-time imaging of CHEMICAL, we show that prostaglandin 1 stimulation generates multiple contiguous, intracellular domains with different CHEMICAL concentration in human embryonic kidney 293 cells. By using pharmacological and genetic manipulation of phosphodiesterases (PDEs), we demonstrate that compartmentalized GENE and PDE4D are responsible for selectively modulating the concentration of CHEMICAL in individual subcellular compartments. We propose a model whereby compartmentalized PDEs, rather than representing an enzymatic barrier to CHEMICAL diffusion, act as a sink to drain the second messenger from discrete locations, resulting in multiple and simultaneous domains with different CHEMICAL concentrations irrespective of their distance from the site of CHEMICAL synthesis. | REGULATOR |
| PGE(1) stimulation of HEK293 cells generates multiple contiguous domains with different [cAMP]: role of compartmentalized phosphodiesterases. There is a growing appreciation that the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway is organized to form transduction units that function to deliver specific messages. Such organization results in the local activation of PKA subsets through the generation of confined intracellular gradients of CHEMICAL, but the mechanisms responsible for limiting the diffusion of CHEMICAL largely remain to be clarified. In this study, by performing real-time imaging of CHEMICAL, we show that prostaglandin 1 stimulation generates multiple contiguous, intracellular domains with different CHEMICAL concentration in human embryonic kidney 293 cells. By using pharmacological and genetic manipulation of phosphodiesterases (PDEs), we demonstrate that compartmentalized PDE4B and GENE are responsible for selectively modulating the concentration of CHEMICAL in individual subcellular compartments. We propose a model whereby compartmentalized PDEs, rather than representing an enzymatic barrier to CHEMICAL diffusion, act as a sink to drain the second messenger from discrete locations, resulting in multiple and simultaneous domains with different CHEMICAL concentrations irrespective of their distance from the site of CHEMICAL synthesis. | REGULATOR |
| PGE(1) stimulation of HEK293 cells generates multiple contiguous domains with different [cAMP]: role of compartmentalized phosphodiesterases. There is a growing appreciation that the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway is organized to form transduction units that function to deliver specific messages. Such organization results in the local activation of PKA subsets through the generation of confined intracellular gradients of CHEMICAL, but the mechanisms responsible for limiting the diffusion of CHEMICAL largely remain to be clarified. In this study, by performing real-time imaging of CHEMICAL, we show that prostaglandin 1 stimulation generates multiple contiguous, intracellular domains with different CHEMICAL concentration in human embryonic kidney 293 cells. By using pharmacological and genetic manipulation of phosphodiesterases (PDEs), we demonstrate that compartmentalized PDE4B and PDE4D are responsible for selectively modulating the concentration of CHEMICAL in individual subcellular compartments. We propose a model whereby compartmentalized GENE, rather than representing an enzymatic barrier to CHEMICAL diffusion, act as a sink to drain the second messenger from discrete locations, resulting in multiple and simultaneous domains with different CHEMICAL concentrations irrespective of their distance from the site of CHEMICAL synthesis. | PART-OF |
| DNA topoisomerase IIalpha (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a 'functional amplicon' involving FAS, Her-2/neu and TOP2A genes. Fatty acid synthase (FAS), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in the de novo fatty acid biosynthesis, plays an active role in the development, maintenance, and enhancement of the malignant phenotype in a subset of breast carcinomas. We recently described that a molecular bi-directional cross-talk between FAS and the Her-2/neu (erbB-2) oncogene is taking place at the level of transcription, translation, and activity in breast cancer cells. Because Her-2/neu has been linked with altered sensitivity to cytotoxic drugs, we envisioned that FAS gene expression may represent a novel predictive molecular factor for breast cancer response to chemotherapy in a Her-2/neu-related manner. We herein evaluated whether chemotherapy-induced cell damage acts in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in breast cancer cells. To evaluate this option, FAS- and Her-2/neu-overexpressing SK-Br3 breast cancer cells were transiently transfected with a FAS promoter-reporter construct (FAS-Luciferase) harboring all the elements necessary for high level expression in cancer cells. SK-Br3 cells cultured in the presence of topoisomerase IIalpha (TOP2A) inhibitors doxorubicin and etopoxide (VP-16) demonstrated a 2- to 3-fold increase in GENE activity when compared with control cells growing in drug-free culture conditions. We failed to observe any significant activation of GENE following exposure to the anti-metabolite CHEMICAL, the alkylating drug cisplatin, or the microtubule interfering-agents paclitaxel and vincristine. Moreover, the up-regulatory effects of TOP2A inhibitors on the transcriptional activation of FAS gene expression were not significantly decreased when the GENE was damaged at the sterol regulatory element binding protein (SREBP)-binding site. Considering that FAS inhibition produces profound inhibition of DNA replication and S-phase progression in cancer cells, we finally asked whether a cross-talk between TOP2A and FAS could exhibit a Her-2/neu-related bi-directional nature. TOP2A protein levels were decreased during treatment with the anti-Her-2/neu antibody trastuzumab while, concomitantly, GENE activity and FAS protein expression were significantly reduced. Of note, when the expression levels of TOP2A protein were analyzed following exposure of SK-Br3 cells to increasing concentrations of the novel slow-binding FAS inhibitor C75, a dose-dependent reduction in TOP2A expression was observed. Although FAS gene is not physically located in the Her-2/neu-TOP2A amplicon, our present findings strongly suggest that a tight functional association between FAS, Her-2/neu and TOP2A genes is taking place in a subset of breast carcinoma cells. | NO-RELATIONSHIP |
| DNA topoisomerase IIalpha (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a 'functional amplicon' involving FAS, Her-2/neu and TOP2A genes. Fatty acid synthase (FAS), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in the de novo fatty acid biosynthesis, plays an active role in the development, maintenance, and enhancement of the malignant phenotype in a subset of breast carcinomas. We recently described that a molecular bi-directional cross-talk between FAS and the Her-2/neu (erbB-2) oncogene is taking place at the level of transcription, translation, and activity in breast cancer cells. Because Her-2/neu has been linked with altered sensitivity to cytotoxic drugs, we envisioned that FAS gene expression may represent a novel predictive molecular factor for breast cancer response to chemotherapy in a Her-2/neu-related manner. We herein evaluated whether chemotherapy-induced cell damage acts in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in breast cancer cells. To evaluate this option, FAS- and Her-2/neu-overexpressing SK-Br3 breast cancer cells were transiently transfected with a FAS promoter-reporter construct (FAS-Luciferase) harboring all the elements necessary for high level expression in cancer cells. SK-Br3 cells cultured in the presence of topoisomerase IIalpha (TOP2A) inhibitors doxorubicin and etopoxide (VP-16) demonstrated a 2- to 3-fold increase in GENE activity when compared with control cells growing in drug-free culture conditions. We failed to observe any significant activation of GENE following exposure to the anti-metabolite 5-fluorouracil, the alkylating drug CHEMICAL, or the microtubule interfering-agents paclitaxel and vincristine. Moreover, the up-regulatory effects of TOP2A inhibitors on the transcriptional activation of FAS gene expression were not significantly decreased when the GENE was damaged at the sterol regulatory element binding protein (SREBP)-binding site. Considering that FAS inhibition produces profound inhibition of DNA replication and S-phase progression in cancer cells, we finally asked whether a cross-talk between TOP2A and FAS could exhibit a Her-2/neu-related bi-directional nature. TOP2A protein levels were decreased during treatment with the anti-Her-2/neu antibody trastuzumab while, concomitantly, GENE activity and FAS protein expression were significantly reduced. Of note, when the expression levels of TOP2A protein were analyzed following exposure of SK-Br3 cells to increasing concentrations of the novel slow-binding FAS inhibitor C75, a dose-dependent reduction in TOP2A expression was observed. Although FAS gene is not physically located in the Her-2/neu-TOP2A amplicon, our present findings strongly suggest that a tight functional association between FAS, Her-2/neu and TOP2A genes is taking place in a subset of breast carcinoma cells. | NO-RELATIONSHIP |
| DNA topoisomerase IIalpha (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a 'functional amplicon' involving FAS, Her-2/neu and TOP2A genes. Fatty acid synthase (FAS), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in the de novo fatty acid biosynthesis, plays an active role in the development, maintenance, and enhancement of the malignant phenotype in a subset of breast carcinomas. We recently described that a molecular bi-directional cross-talk between FAS and the Her-2/neu (erbB-2) oncogene is taking place at the level of transcription, translation, and activity in breast cancer cells. Because Her-2/neu has been linked with altered sensitivity to cytotoxic drugs, we envisioned that FAS gene expression may represent a novel predictive molecular factor for breast cancer response to chemotherapy in a Her-2/neu-related manner. We herein evaluated whether chemotherapy-induced cell damage acts in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in breast cancer cells. To evaluate this option, FAS- and Her-2/neu-overexpressing SK-Br3 breast cancer cells were transiently transfected with a FAS promoter-reporter construct (FAS-Luciferase) harboring all the elements necessary for high level expression in cancer cells. SK-Br3 cells cultured in the presence of topoisomerase IIalpha (TOP2A) inhibitors doxorubicin and etopoxide (VP-16) demonstrated a 2- to 3-fold increase in GENE activity when compared with control cells growing in drug-free culture conditions. We failed to observe any significant activation of GENE following exposure to the anti-metabolite 5-fluorouracil, the alkylating drug cisplatin, or the microtubule interfering-agents CHEMICAL and vincristine. Moreover, the up-regulatory effects of TOP2A inhibitors on the transcriptional activation of FAS gene expression were not significantly decreased when the GENE was damaged at the sterol regulatory element binding protein (SREBP)-binding site. Considering that FAS inhibition produces profound inhibition of DNA replication and S-phase progression in cancer cells, we finally asked whether a cross-talk between TOP2A and FAS could exhibit a Her-2/neu-related bi-directional nature. TOP2A protein levels were decreased during treatment with the anti-Her-2/neu antibody trastuzumab while, concomitantly, GENE activity and FAS protein expression were significantly reduced. Of note, when the expression levels of TOP2A protein were analyzed following exposure of SK-Br3 cells to increasing concentrations of the novel slow-binding FAS inhibitor C75, a dose-dependent reduction in TOP2A expression was observed. Although FAS gene is not physically located in the Her-2/neu-TOP2A amplicon, our present findings strongly suggest that a tight functional association between FAS, Her-2/neu and TOP2A genes is taking place in a subset of breast carcinoma cells. | NO-RELATIONSHIP |
| DNA topoisomerase IIalpha (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a 'functional amplicon' involving FAS, Her-2/neu and TOP2A genes. Fatty acid synthase (FAS), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in the de novo fatty acid biosynthesis, plays an active role in the development, maintenance, and enhancement of the malignant phenotype in a subset of breast carcinomas. We recently described that a molecular bi-directional cross-talk between FAS and the Her-2/neu (erbB-2) oncogene is taking place at the level of transcription, translation, and activity in breast cancer cells. Because Her-2/neu has been linked with altered sensitivity to cytotoxic drugs, we envisioned that FAS gene expression may represent a novel predictive molecular factor for breast cancer response to chemotherapy in a Her-2/neu-related manner. We herein evaluated whether chemotherapy-induced cell damage acts in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in breast cancer cells. To evaluate this option, FAS- and Her-2/neu-overexpressing SK-Br3 breast cancer cells were transiently transfected with a FAS promoter-reporter construct (FAS-Luciferase) harboring all the elements necessary for high level expression in cancer cells. SK-Br3 cells cultured in the presence of topoisomerase IIalpha (TOP2A) inhibitors doxorubicin and etopoxide (VP-16) demonstrated a 2- to 3-fold increase in GENE activity when compared with control cells growing in drug-free culture conditions. We failed to observe any significant activation of GENE following exposure to the anti-metabolite 5-fluorouracil, the alkylating drug cisplatin, or the microtubule interfering-agents paclitaxel and CHEMICAL. Moreover, the up-regulatory effects of TOP2A inhibitors on the transcriptional activation of FAS gene expression were not significantly decreased when the GENE was damaged at the sterol regulatory element binding protein (SREBP)-binding site. Considering that FAS inhibition produces profound inhibition of DNA replication and S-phase progression in cancer cells, we finally asked whether a cross-talk between TOP2A and FAS could exhibit a Her-2/neu-related bi-directional nature. TOP2A protein levels were decreased during treatment with the anti-Her-2/neu antibody trastuzumab while, concomitantly, GENE activity and FAS protein expression were significantly reduced. Of note, when the expression levels of TOP2A protein were analyzed following exposure of SK-Br3 cells to increasing concentrations of the novel slow-binding FAS inhibitor C75, a dose-dependent reduction in TOP2A expression was observed. Although FAS gene is not physically located in the Her-2/neu-TOP2A amplicon, our present findings strongly suggest that a tight functional association between FAS, Her-2/neu and TOP2A genes is taking place in a subset of breast carcinoma cells. | NO-RELATIONSHIP |
| DNA topoisomerase IIalpha (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a 'functional amplicon' involving FAS, Her-2/neu and TOP2A genes. Fatty acid synthase (FAS), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in the de novo fatty acid biosynthesis, plays an active role in the development, maintenance, and enhancement of the malignant phenotype in a subset of breast carcinomas. We recently described that a molecular bi-directional cross-talk between FAS and the Her-2/neu (erbB-2) oncogene is taking place at the level of transcription, translation, and activity in breast cancer cells. Because Her-2/neu has been linked with altered sensitivity to cytotoxic drugs, we envisioned that FAS gene expression may represent a novel predictive molecular factor for breast cancer response to chemotherapy in a Her-2/neu-related manner. We herein evaluated whether chemotherapy-induced cell damage acts in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in breast cancer cells. To evaluate this option, FAS- and Her-2/neu-overexpressing SK-Br3 breast cancer cells were transiently transfected with a FAS promoter-reporter construct (FAS-Luciferase) harboring all the elements necessary for high level expression in cancer cells. SK-Br3 cells cultured in the presence of topoisomerase IIalpha (TOP2A) inhibitors CHEMICAL and etopoxide (VP-16) demonstrated a 2- to 3-fold increase in GENE activity when compared with control cells growing in drug-free culture conditions. We failed to observe any significant activation of GENE following exposure to the anti-metabolite 5-fluorouracil, the alkylating drug cisplatin, or the microtubule interfering-agents paclitaxel and vincristine. Moreover, the up-regulatory effects of TOP2A inhibitors on the transcriptional activation of FAS gene expression were not significantly decreased when the GENE was damaged at the sterol regulatory element binding protein (SREBP)-binding site. Considering that FAS inhibition produces profound inhibition of DNA replication and S-phase progression in cancer cells, we finally asked whether a cross-talk between TOP2A and FAS could exhibit a Her-2/neu-related bi-directional nature. TOP2A protein levels were decreased during treatment with the anti-Her-2/neu antibody trastuzumab while, concomitantly, GENE activity and FAS protein expression were significantly reduced. Of note, when the expression levels of TOP2A protein were analyzed following exposure of SK-Br3 cells to increasing concentrations of the novel slow-binding FAS inhibitor C75, a dose-dependent reduction in TOP2A expression was observed. Although FAS gene is not physically located in the Her-2/neu-TOP2A amplicon, our present findings strongly suggest that a tight functional association between FAS, Her-2/neu and TOP2A genes is taking place in a subset of breast carcinoma cells. | INHIBITOR |
| DNA topoisomerase IIalpha (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a 'functional amplicon' involving FAS, Her-2/neu and TOP2A genes. Fatty acid synthase (FAS), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in the de novo fatty acid biosynthesis, plays an active role in the development, maintenance, and enhancement of the malignant phenotype in a subset of breast carcinomas. We recently described that a molecular bi-directional cross-talk between FAS and the Her-2/neu (erbB-2) oncogene is taking place at the level of transcription, translation, and activity in breast cancer cells. Because Her-2/neu has been linked with altered sensitivity to cytotoxic drugs, we envisioned that FAS gene expression may represent a novel predictive molecular factor for breast cancer response to chemotherapy in a Her-2/neu-related manner. We herein evaluated whether chemotherapy-induced cell damage acts in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in breast cancer cells. To evaluate this option, FAS- and Her-2/neu-overexpressing SK-Br3 breast cancer cells were transiently transfected with a FAS promoter-reporter construct (FAS-Luciferase) harboring all the elements necessary for high level expression in cancer cells. SK-Br3 cells cultured in the presence of topoisomerase IIalpha (TOP2A) inhibitors doxorubicin and CHEMICAL (VP-16) demonstrated a 2- to 3-fold increase in GENE activity when compared with control cells growing in drug-free culture conditions. We failed to observe any significant activation of GENE following exposure to the anti-metabolite 5-fluorouracil, the alkylating drug cisplatin, or the microtubule interfering-agents paclitaxel and vincristine. Moreover, the up-regulatory effects of TOP2A inhibitors on the transcriptional activation of FAS gene expression were not significantly decreased when the GENE was damaged at the sterol regulatory element binding protein (SREBP)-binding site. Considering that FAS inhibition produces profound inhibition of DNA replication and S-phase progression in cancer cells, we finally asked whether a cross-talk between TOP2A and FAS could exhibit a Her-2/neu-related bi-directional nature. TOP2A protein levels were decreased during treatment with the anti-Her-2/neu antibody trastuzumab while, concomitantly, GENE activity and FAS protein expression were significantly reduced. Of note, when the expression levels of TOP2A protein were analyzed following exposure of SK-Br3 cells to increasing concentrations of the novel slow-binding FAS inhibitor C75, a dose-dependent reduction in TOP2A expression was observed. Although FAS gene is not physically located in the Her-2/neu-TOP2A amplicon, our present findings strongly suggest that a tight functional association between FAS, Her-2/neu and TOP2A genes is taking place in a subset of breast carcinoma cells. | ACTIVATOR |
| DNA topoisomerase IIalpha (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a 'functional amplicon' involving FAS, Her-2/neu and TOP2A genes. Fatty acid synthase (FAS), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in the de novo fatty acid biosynthesis, plays an active role in the development, maintenance, and enhancement of the malignant phenotype in a subset of breast carcinomas. We recently described that a molecular bi-directional cross-talk between FAS and the Her-2/neu (erbB-2) oncogene is taking place at the level of transcription, translation, and activity in breast cancer cells. Because Her-2/neu has been linked with altered sensitivity to cytotoxic drugs, we envisioned that FAS gene expression may represent a novel predictive molecular factor for breast cancer response to chemotherapy in a Her-2/neu-related manner. We herein evaluated whether chemotherapy-induced cell damage acts in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in breast cancer cells. To evaluate this option, FAS- and Her-2/neu-overexpressing SK-Br3 breast cancer cells were transiently transfected with a FAS promoter-reporter construct (FAS-Luciferase) harboring all the elements necessary for high level expression in cancer cells. SK-Br3 cells cultured in the presence of topoisomerase IIalpha (TOP2A) inhibitors doxorubicin and etopoxide (CHEMICAL) demonstrated a 2- to 3-fold increase in GENE activity when compared with control cells growing in drug-free culture conditions. We failed to observe any significant activation of GENE following exposure to the anti-metabolite 5-fluorouracil, the alkylating drug cisplatin, or the microtubule interfering-agents paclitaxel and vincristine. Moreover, the up-regulatory effects of TOP2A inhibitors on the transcriptional activation of FAS gene expression were not significantly decreased when the GENE was damaged at the sterol regulatory element binding protein (SREBP)-binding site. Considering that FAS inhibition produces profound inhibition of DNA replication and S-phase progression in cancer cells, we finally asked whether a cross-talk between TOP2A and FAS could exhibit a Her-2/neu-related bi-directional nature. TOP2A protein levels were decreased during treatment with the anti-Her-2/neu antibody trastuzumab while, concomitantly, GENE activity and FAS protein expression were significantly reduced. Of note, when the expression levels of TOP2A protein were analyzed following exposure of SK-Br3 cells to increasing concentrations of the novel slow-binding FAS inhibitor C75, a dose-dependent reduction in TOP2A expression was observed. Although FAS gene is not physically located in the Her-2/neu-TOP2A amplicon, our present findings strongly suggest that a tight functional association between FAS, Her-2/neu and TOP2A genes is taking place in a subset of breast carcinoma cells. | ACTIVATOR |
| DNA GENE (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a 'functional amplicon' involving FAS, Her-2/neu and TOP2A genes. Fatty acid synthase (FAS), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in the de novo fatty acid biosynthesis, plays an active role in the development, maintenance, and enhancement of the malignant phenotype in a subset of breast carcinomas. We recently described that a molecular bi-directional cross-talk between FAS and the Her-2/neu (erbB-2) oncogene is taking place at the level of transcription, translation, and activity in breast cancer cells. Because Her-2/neu has been linked with altered sensitivity to cytotoxic drugs, we envisioned that FAS gene expression may represent a novel predictive molecular factor for breast cancer response to chemotherapy in a Her-2/neu-related manner. We herein evaluated whether chemotherapy-induced cell damage acts in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in breast cancer cells. To evaluate this option, FAS- and Her-2/neu-overexpressing SK-Br3 breast cancer cells were transiently transfected with a FAS promoter-reporter construct (FAS-Luciferase) harboring all the elements necessary for high level expression in cancer cells. SK-Br3 cells cultured in the presence of GENE (TOP2A) inhibitors CHEMICAL and etopoxide (VP-16) demonstrated a 2- to 3-fold increase in FAS promoter activity when compared with control cells growing in drug-free culture conditions. We failed to observe any significant activation of FAS promoter following exposure to the anti-metabolite 5-fluorouracil, the alkylating drug cisplatin, or the microtubule interfering-agents paclitaxel and vincristine. Moreover, the up-regulatory effects of TOP2A inhibitors on the transcriptional activation of FAS gene expression were not significantly decreased when the FAS promoter was damaged at the sterol regulatory element binding protein (SREBP)-binding site. Considering that FAS inhibition produces profound inhibition of DNA replication and S-phase progression in cancer cells, we finally asked whether a cross-talk between TOP2A and FAS could exhibit a Her-2/neu-related bi-directional nature. TOP2A protein levels were decreased during treatment with the anti-Her-2/neu antibody trastuzumab while, concomitantly, FAS promoter activity and FAS protein expression were significantly reduced. Of note, when the expression levels of TOP2A protein were analyzed following exposure of SK-Br3 cells to increasing concentrations of the novel slow-binding FAS inhibitor C75, a dose-dependent reduction in TOP2A expression was observed. Although FAS gene is not physically located in the Her-2/neu-TOP2A amplicon, our present findings strongly suggest that a tight functional association between FAS, Her-2/neu and TOP2A genes is taking place in a subset of breast carcinoma cells. | INHIBITOR |
| DNA topoisomerase IIalpha (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a 'functional amplicon' involving FAS, Her-2/neu and GENE genes. Fatty acid synthase (FAS), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in the de novo fatty acid biosynthesis, plays an active role in the development, maintenance, and enhancement of the malignant phenotype in a subset of breast carcinomas. We recently described that a molecular bi-directional cross-talk between FAS and the Her-2/neu (erbB-2) oncogene is taking place at the level of transcription, translation, and activity in breast cancer cells. Because Her-2/neu has been linked with altered sensitivity to cytotoxic drugs, we envisioned that FAS gene expression may represent a novel predictive molecular factor for breast cancer response to chemotherapy in a Her-2/neu-related manner. We herein evaluated whether chemotherapy-induced cell damage acts in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in breast cancer cells. To evaluate this option, FAS- and Her-2/neu-overexpressing SK-Br3 breast cancer cells were transiently transfected with a FAS promoter-reporter construct (FAS-Luciferase) harboring all the elements necessary for high level expression in cancer cells. SK-Br3 cells cultured in the presence of topoisomerase IIalpha (GENE) inhibitors CHEMICAL and etopoxide (VP-16) demonstrated a 2- to 3-fold increase in FAS promoter activity when compared with control cells growing in drug-free culture conditions. We failed to observe any significant activation of FAS promoter following exposure to the anti-metabolite 5-fluorouracil, the alkylating drug cisplatin, or the microtubule interfering-agents paclitaxel and vincristine. Moreover, the up-regulatory effects of GENE inhibitors on the transcriptional activation of FAS gene expression were not significantly decreased when the FAS promoter was damaged at the sterol regulatory element binding protein (SREBP)-binding site. Considering that FAS inhibition produces profound inhibition of DNA replication and S-phase progression in cancer cells, we finally asked whether a cross-talk between GENE and FAS could exhibit a Her-2/neu-related bi-directional nature. GENE protein levels were decreased during treatment with the anti-Her-2/neu antibody trastuzumab while, concomitantly, FAS promoter activity and FAS protein expression were significantly reduced. Of note, when the expression levels of GENE protein were analyzed following exposure of SK-Br3 cells to increasing concentrations of the novel slow-binding FAS inhibitor C75, a dose-dependent reduction in GENE expression was observed. Although FAS gene is not physically located in the Her-2/neu-TOP2A amplicon, our present findings strongly suggest that a tight functional association between FAS, Her-2/neu and GENE genes is taking place in a subset of breast carcinoma cells. | INHIBITOR |
| DNA GENE (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a 'functional amplicon' involving FAS, Her-2/neu and TOP2A genes. Fatty acid synthase (FAS), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in the de novo fatty acid biosynthesis, plays an active role in the development, maintenance, and enhancement of the malignant phenotype in a subset of breast carcinomas. We recently described that a molecular bi-directional cross-talk between FAS and the Her-2/neu (erbB-2) oncogene is taking place at the level of transcription, translation, and activity in breast cancer cells. Because Her-2/neu has been linked with altered sensitivity to cytotoxic drugs, we envisioned that FAS gene expression may represent a novel predictive molecular factor for breast cancer response to chemotherapy in a Her-2/neu-related manner. We herein evaluated whether chemotherapy-induced cell damage acts in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in breast cancer cells. To evaluate this option, FAS- and Her-2/neu-overexpressing SK-Br3 breast cancer cells were transiently transfected with a FAS promoter-reporter construct (FAS-Luciferase) harboring all the elements necessary for high level expression in cancer cells. SK-Br3 cells cultured in the presence of GENE (TOP2A) inhibitors doxorubicin and CHEMICAL (VP-16) demonstrated a 2- to 3-fold increase in FAS promoter activity when compared with control cells growing in drug-free culture conditions. We failed to observe any significant activation of FAS promoter following exposure to the anti-metabolite 5-fluorouracil, the alkylating drug cisplatin, or the microtubule interfering-agents paclitaxel and vincristine. Moreover, the up-regulatory effects of TOP2A inhibitors on the transcriptional activation of FAS gene expression were not significantly decreased when the FAS promoter was damaged at the sterol regulatory element binding protein (SREBP)-binding site. Considering that FAS inhibition produces profound inhibition of DNA replication and S-phase progression in cancer cells, we finally asked whether a cross-talk between TOP2A and FAS could exhibit a Her-2/neu-related bi-directional nature. TOP2A protein levels were decreased during treatment with the anti-Her-2/neu antibody trastuzumab while, concomitantly, FAS promoter activity and FAS protein expression were significantly reduced. Of note, when the expression levels of TOP2A protein were analyzed following exposure of SK-Br3 cells to increasing concentrations of the novel slow-binding FAS inhibitor C75, a dose-dependent reduction in TOP2A expression was observed. Although FAS gene is not physically located in the Her-2/neu-TOP2A amplicon, our present findings strongly suggest that a tight functional association between FAS, Her-2/neu and TOP2A genes is taking place in a subset of breast carcinoma cells. | INHIBITOR |
| DNA topoisomerase IIalpha (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a 'functional amplicon' involving FAS, Her-2/neu and GENE genes. Fatty acid synthase (FAS), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in the de novo fatty acid biosynthesis, plays an active role in the development, maintenance, and enhancement of the malignant phenotype in a subset of breast carcinomas. We recently described that a molecular bi-directional cross-talk between FAS and the Her-2/neu (erbB-2) oncogene is taking place at the level of transcription, translation, and activity in breast cancer cells. Because Her-2/neu has been linked with altered sensitivity to cytotoxic drugs, we envisioned that FAS gene expression may represent a novel predictive molecular factor for breast cancer response to chemotherapy in a Her-2/neu-related manner. We herein evaluated whether chemotherapy-induced cell damage acts in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in breast cancer cells. To evaluate this option, FAS- and Her-2/neu-overexpressing SK-Br3 breast cancer cells were transiently transfected with a FAS promoter-reporter construct (FAS-Luciferase) harboring all the elements necessary for high level expression in cancer cells. SK-Br3 cells cultured in the presence of topoisomerase IIalpha (GENE) inhibitors doxorubicin and CHEMICAL (VP-16) demonstrated a 2- to 3-fold increase in FAS promoter activity when compared with control cells growing in drug-free culture conditions. We failed to observe any significant activation of FAS promoter following exposure to the anti-metabolite 5-fluorouracil, the alkylating drug cisplatin, or the microtubule interfering-agents paclitaxel and vincristine. Moreover, the up-regulatory effects of GENE inhibitors on the transcriptional activation of FAS gene expression were not significantly decreased when the FAS promoter was damaged at the sterol regulatory element binding protein (SREBP)-binding site. Considering that FAS inhibition produces profound inhibition of DNA replication and S-phase progression in cancer cells, we finally asked whether a cross-talk between GENE and FAS could exhibit a Her-2/neu-related bi-directional nature. GENE protein levels were decreased during treatment with the anti-Her-2/neu antibody trastuzumab while, concomitantly, FAS promoter activity and FAS protein expression were significantly reduced. Of note, when the expression levels of GENE protein were analyzed following exposure of SK-Br3 cells to increasing concentrations of the novel slow-binding FAS inhibitor C75, a dose-dependent reduction in GENE expression was observed. Although FAS gene is not physically located in the Her-2/neu-TOP2A amplicon, our present findings strongly suggest that a tight functional association between FAS, Her-2/neu and GENE genes is taking place in a subset of breast carcinoma cells. | INHIBITOR |
| DNA GENE (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a 'functional amplicon' involving FAS, Her-2/neu and TOP2A genes. Fatty acid synthase (FAS), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in the de novo fatty acid biosynthesis, plays an active role in the development, maintenance, and enhancement of the malignant phenotype in a subset of breast carcinomas. We recently described that a molecular bi-directional cross-talk between FAS and the Her-2/neu (erbB-2) oncogene is taking place at the level of transcription, translation, and activity in breast cancer cells. Because Her-2/neu has been linked with altered sensitivity to cytotoxic drugs, we envisioned that FAS gene expression may represent a novel predictive molecular factor for breast cancer response to chemotherapy in a Her-2/neu-related manner. We herein evaluated whether chemotherapy-induced cell damage acts in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in breast cancer cells. To evaluate this option, FAS- and Her-2/neu-overexpressing SK-Br3 breast cancer cells were transiently transfected with a FAS promoter-reporter construct (FAS-Luciferase) harboring all the elements necessary for high level expression in cancer cells. SK-Br3 cells cultured in the presence of GENE (TOP2A) inhibitors doxorubicin and etopoxide (CHEMICAL) demonstrated a 2- to 3-fold increase in FAS promoter activity when compared with control cells growing in drug-free culture conditions. We failed to observe any significant activation of FAS promoter following exposure to the anti-metabolite 5-fluorouracil, the alkylating drug cisplatin, or the microtubule interfering-agents paclitaxel and vincristine. Moreover, the up-regulatory effects of TOP2A inhibitors on the transcriptional activation of FAS gene expression were not significantly decreased when the FAS promoter was damaged at the sterol regulatory element binding protein (SREBP)-binding site. Considering that FAS inhibition produces profound inhibition of DNA replication and S-phase progression in cancer cells, we finally asked whether a cross-talk between TOP2A and FAS could exhibit a Her-2/neu-related bi-directional nature. TOP2A protein levels were decreased during treatment with the anti-Her-2/neu antibody trastuzumab while, concomitantly, FAS promoter activity and FAS protein expression were significantly reduced. Of note, when the expression levels of TOP2A protein were analyzed following exposure of SK-Br3 cells to increasing concentrations of the novel slow-binding FAS inhibitor C75, a dose-dependent reduction in TOP2A expression was observed. Although FAS gene is not physically located in the Her-2/neu-TOP2A amplicon, our present findings strongly suggest that a tight functional association between FAS, Her-2/neu and TOP2A genes is taking place in a subset of breast carcinoma cells. | INHIBITOR |
| DNA topoisomerase IIalpha (TOP2A) inhibitors up-regulate fatty acid synthase gene expression in SK-Br3 breast cancer cells: in vitro evidence for a 'functional amplicon' involving FAS, Her-2/neu and GENE genes. Fatty acid synthase (FAS), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in the de novo fatty acid biosynthesis, plays an active role in the development, maintenance, and enhancement of the malignant phenotype in a subset of breast carcinomas. We recently described that a molecular bi-directional cross-talk between FAS and the Her-2/neu (erbB-2) oncogene is taking place at the level of transcription, translation, and activity in breast cancer cells. Because Her-2/neu has been linked with altered sensitivity to cytotoxic drugs, we envisioned that FAS gene expression may represent a novel predictive molecular factor for breast cancer response to chemotherapy in a Her-2/neu-related manner. We herein evaluated whether chemotherapy-induced cell damage acts in an epigenetic fashion by inducing changes in the transcriptional activation of FAS gene in breast cancer cells. To evaluate this option, FAS- and Her-2/neu-overexpressing SK-Br3 breast cancer cells were transiently transfected with a FAS promoter-reporter construct (FAS-Luciferase) harboring all the elements necessary for high level expression in cancer cells. SK-Br3 cells cultured in the presence of topoisomerase IIalpha (GENE) inhibitors doxorubicin and etopoxide (CHEMICAL) demonstrated a 2- to 3-fold increase in FAS promoter activity when compared with control cells growing in drug-free culture conditions. We failed to observe any significant activation of FAS promoter following exposure to the anti-metabolite 5-fluorouracil, the alkylating drug cisplatin, or the microtubule interfering-agents paclitaxel and vincristine. Moreover, the up-regulatory effects of GENE inhibitors on the transcriptional activation of FAS gene expression were not significantly decreased when the FAS promoter was damaged at the sterol regulatory element binding protein (SREBP)-binding site. Considering that FAS inhibition produces profound inhibition of DNA replication and S-phase progression in cancer cells, we finally asked whether a cross-talk between GENE and FAS could exhibit a Her-2/neu-related bi-directional nature. GENE protein levels were decreased during treatment with the anti-Her-2/neu antibody trastuzumab while, concomitantly, FAS promoter activity and FAS protein expression were significantly reduced. Of note, when the expression levels of GENE protein were analyzed following exposure of SK-Br3 cells to increasing concentrations of the novel slow-binding FAS inhibitor C75, a dose-dependent reduction in GENE expression was observed. Although FAS gene is not physically located in the Her-2/neu-TOP2A amplicon, our present findings strongly suggest that a tight functional association between FAS, Her-2/neu and GENE genes is taking place in a subset of breast carcinoma cells. | INHIBITOR |
| CHEMICAL alters expression of endometrial GENE and their cofactors in new users of medroxyprogesterone acetate. OBJECTIVE: To evaluate the effect of mifepristone on the expression of endometrial GENE and their co-factors in depot medroxyprogesterone acetate (DMPA) users. DESIGN: A prospective, randomized, placebo-controlled trial. SETTING: Reproductive research center. PATIENT(S): Fifty healthy women with regular menstrual cycle. INTERVENTION(S): One hundred fifty milligrams of DMPA were given every 3 months. Two pills (25 mg each) of placebo or mifepristone were administered every 14 days during the DMPA therapy. Four endometrial biopsy specimens were obtained from each patient. MAIN OUTCOME MEASURE(S): The expression of estrogen receptor subtypes alpha and beta (ERalpha and ERbeta), progesterone receptors A and B (PRAB and PRB), and androgen receptor messenger RNA and protein was detected by real-time polymerase chain reaction and immunohistochemistry, respectively. Steroid receptor coactivator 1 (SRC-1), silencing mediator for retinoid and thyroid-hormone receptors, and cell proliferation were evaluated by immunohistochemistry. RESULT(S): The expression of endometrial ERalpha, PRAB, PRB, and SRC-1 was increased significantly after 1 week of mifepristone, but the increase was no longer seen after 10 weeks. A positive correlation between endometrial ERalpha, PRAB, PRB, and SRC-1 production and proliferation was demonstrated. CONCLUSION(S): Short-term exposure of mifepristone in new starters of DMPA increases the expression of endometrial ERalpha, PRAB, PRB, and SRC-1 and promotes cell proliferation. Prolonged exposure to mifepristone does not alter the suppression of these receptors that are caused by DMPA and continues to result in endometrial atrophy. | GENE-CHEMICAL |
| CHEMICAL alters expression of endometrial steroid receptors and their cofactors in new users of medroxyprogesterone acetate. OBJECTIVE: To evaluate the effect of CHEMICAL on the expression of endometrial steroid receptors and their co-factors in depot medroxyprogesterone acetate (DMPA) users. DESIGN: A prospective, randomized, placebo-controlled trial. SETTING: Reproductive research center. PATIENT(S): Fifty healthy women with regular menstrual cycle. INTERVENTION(S): One hundred fifty milligrams of DMPA were given every 3 months. Two pills (25 mg each) of placebo or CHEMICAL were administered every 14 days during the DMPA therapy. Four endometrial biopsy specimens were obtained from each patient. MAIN OUTCOME MEASURE(S): The expression of estrogen receptor subtypes alpha and beta (ERalpha and ERbeta), progesterone receptors A and B (PRAB and PRB), and androgen receptor messenger RNA and protein was detected by real-time polymerase chain reaction and immunohistochemistry, respectively. Steroid receptor coactivator 1 (SRC-1), silencing mediator for retinoid and thyroid-hormone receptors, and cell proliferation were evaluated by immunohistochemistry. RESULT(S): The expression of endometrial GENE, PRAB, PRB, and SRC-1 was increased significantly after 1 week of CHEMICAL, but the increase was no longer seen after 10 weeks. A positive correlation between endometrial GENE, PRAB, PRB, and SRC-1 production and proliferation was demonstrated. CONCLUSION(S): Short-term exposure of CHEMICAL in new starters of DMPA increases the expression of endometrial GENE, PRAB, PRB, and SRC-1 and promotes cell proliferation. Prolonged exposure to CHEMICAL does not alter the suppression of these receptors that are caused by DMPA and continues to result in endometrial atrophy. | INDIRECT-UPREGULATOR |
| CHEMICAL alters expression of endometrial steroid receptors and their cofactors in new users of medroxyprogesterone acetate. OBJECTIVE: To evaluate the effect of CHEMICAL on the expression of endometrial steroid receptors and their co-factors in depot medroxyprogesterone acetate (DMPA) users. DESIGN: A prospective, randomized, placebo-controlled trial. SETTING: Reproductive research center. PATIENT(S): Fifty healthy women with regular menstrual cycle. INTERVENTION(S): One hundred fifty milligrams of DMPA were given every 3 months. Two pills (25 mg each) of placebo or CHEMICAL were administered every 14 days during the DMPA therapy. Four endometrial biopsy specimens were obtained from each patient. MAIN OUTCOME MEASURE(S): The expression of estrogen receptor subtypes alpha and beta (ERalpha and ERbeta), progesterone receptors A and B (PRAB and PRB), and androgen receptor messenger RNA and protein was detected by real-time polymerase chain reaction and immunohistochemistry, respectively. Steroid receptor coactivator 1 (SRC-1), silencing mediator for retinoid and thyroid-hormone receptors, and cell proliferation were evaluated by immunohistochemistry. RESULT(S): The expression of endometrial ERalpha, GENE, PRB, and SRC-1 was increased significantly after 1 week of CHEMICAL, but the increase was no longer seen after 10 weeks. A positive correlation between endometrial ERalpha, GENE, PRB, and SRC-1 production and proliferation was demonstrated. CONCLUSION(S): Short-term exposure of CHEMICAL in new starters of DMPA increases the expression of endometrial ERalpha, GENE, PRB, and SRC-1 and promotes cell proliferation. Prolonged exposure to CHEMICAL does not alter the suppression of these receptors that are caused by DMPA and continues to result in endometrial atrophy. | INDIRECT-UPREGULATOR |
| CHEMICAL alters expression of endometrial steroid receptors and their cofactors in new users of medroxyprogesterone acetate. OBJECTIVE: To evaluate the effect of CHEMICAL on the expression of endometrial steroid receptors and their co-factors in depot medroxyprogesterone acetate (DMPA) users. DESIGN: A prospective, randomized, placebo-controlled trial. SETTING: Reproductive research center. PATIENT(S): Fifty healthy women with regular menstrual cycle. INTERVENTION(S): One hundred fifty milligrams of DMPA were given every 3 months. Two pills (25 mg each) of placebo or CHEMICAL were administered every 14 days during the DMPA therapy. Four endometrial biopsy specimens were obtained from each patient. MAIN OUTCOME MEASURE(S): The expression of estrogen receptor subtypes alpha and beta (ERalpha and ERbeta), progesterone receptors A and B (PRAB and PRB), and androgen receptor messenger RNA and protein was detected by real-time polymerase chain reaction and immunohistochemistry, respectively. Steroid receptor coactivator 1 (SRC-1), silencing mediator for retinoid and thyroid-hormone receptors, and cell proliferation were evaluated by immunohistochemistry. RESULT(S): The expression of endometrial ERalpha, PRAB, GENE, and SRC-1 was increased significantly after 1 week of CHEMICAL, but the increase was no longer seen after 10 weeks. A positive correlation between endometrial ERalpha, PRAB, GENE, and SRC-1 production and proliferation was demonstrated. CONCLUSION(S): Short-term exposure of CHEMICAL in new starters of DMPA increases the expression of endometrial ERalpha, PRAB, GENE, and SRC-1 and promotes cell proliferation. Prolonged exposure to CHEMICAL does not alter the suppression of these receptors that are caused by DMPA and continues to result in endometrial atrophy. | INDIRECT-UPREGULATOR |
| CHEMICAL alters expression of endometrial steroid receptors and their cofactors in new users of medroxyprogesterone acetate. OBJECTIVE: To evaluate the effect of CHEMICAL on the expression of endometrial steroid receptors and their co-factors in depot medroxyprogesterone acetate (DMPA) users. DESIGN: A prospective, randomized, placebo-controlled trial. SETTING: Reproductive research center. PATIENT(S): Fifty healthy women with regular menstrual cycle. INTERVENTION(S): One hundred fifty milligrams of DMPA were given every 3 months. Two pills (25 mg each) of placebo or CHEMICAL were administered every 14 days during the DMPA therapy. Four endometrial biopsy specimens were obtained from each patient. MAIN OUTCOME MEASURE(S): The expression of estrogen receptor subtypes alpha and beta (ERalpha and ERbeta), progesterone receptors A and B (PRAB and PRB), and androgen receptor messenger RNA and protein was detected by real-time polymerase chain reaction and immunohistochemistry, respectively. Steroid receptor coactivator 1 (SRC-1), silencing mediator for retinoid and thyroid-hormone receptors, and cell proliferation were evaluated by immunohistochemistry. RESULT(S): The expression of endometrial ERalpha, PRAB, PRB, and GENE was increased significantly after 1 week of CHEMICAL, but the increase was no longer seen after 10 weeks. A positive correlation between endometrial ERalpha, PRAB, PRB, and GENE production and proliferation was demonstrated. CONCLUSION(S): Short-term exposure of CHEMICAL in new starters of DMPA increases the expression of endometrial ERalpha, PRAB, PRB, and GENE and promotes cell proliferation. Prolonged exposure to CHEMICAL does not alter the suppression of these receptors that are caused by DMPA and continues to result in endometrial atrophy. | INDIRECT-UPREGULATOR |
| Characterization of the molecular mechanisms involved in the increased insulin secretion in rats with acute liver failure. To investigate the mechanism of hyperinsulinaemia in rats with acute liver failure induced by the administration of d-galactosamine (GalN), we focused on the role of polyprimidine tract-binding protein (PTB) in islet insulin synthesis. Recent reports indicate that GENE binds and stabilizes mRNA encoding insulin and insulin secretory granule proteins, including islet cell autoantigen 512 (ICA512), prohormone convertase 1/3 (PC1/3), and PC2. In the present study, glucose-stimulated insulin secretion was significantly increased in GalN-treated rats compared to controls. Levels of mRNA encoding insulin 1, ICA512, and PC1/3 were increased in the pancreatic islets of GalN-treated rats. This mRNA level elevation was not prevented by pretreatment with actinomycin D. When the PTB-binding site in insulin 1 mRNA was incubated with the islet cytosolic fraction, the RNA-protein complex level was increased in the cytosolic fraction obtained from GalN-treated rats compared to the level in control rats. The cytosolic fraction obtained from pancreatic islets obtained from CHEMICAL-treated rats had an increased GENE level compared to the levels obtained from the pancreatic islets of control rats. These findings suggest that, in rats with acute liver failure, cytosolic GENE binds and stabilizes mRNA encoding insulin and its secretory granule proteins. | INDIRECT-UPREGULATOR |
| Characterization of the molecular mechanisms involved in the increased GENE secretion in rats with acute liver failure. To investigate the mechanism of hyperinsulinaemia in rats with acute liver failure induced by the administration of d-galactosamine (GalN), we focused on the role of polyprimidine tract-binding protein (PTB) in islet GENE synthesis. Recent reports indicate that PTB binds and stabilizes mRNA encoding GENE and GENE secretory granule proteins, including islet cell autoantigen 512 (ICA512), prohormone convertase 1/3 (PC1/3), and PC2. In the present study, CHEMICAL-stimulated GENE secretion was significantly increased in GalN-treated rats compared to controls. Levels of mRNA encoding GENE 1, ICA512, and PC1/3 were increased in the pancreatic islets of GalN-treated rats. This mRNA level elevation was not prevented by pretreatment with actinomycin D. When the PTB-binding site in GENE 1 mRNA was incubated with the islet cytosolic fraction, the RNA-protein complex level was increased in the cytosolic fraction obtained from GalN-treated rats compared to the level in control rats. The cytosolic fraction obtained from pancreatic islets obtained from GalN-treated rats had an increased PTB level compared to the levels obtained from the pancreatic islets of control rats. These findings suggest that, in rats with acute liver failure, cytosolic PTB binds and stabilizes mRNA encoding GENE and its secretory granule proteins. | INDIRECT-UPREGULATOR |
| Characterization of the molecular mechanisms involved in the increased GENE secretion in rats with acute liver failure. To investigate the mechanism of hyperinsulinaemia in rats with acute liver failure induced by the administration of d-galactosamine (GalN), we focused on the role of polyprimidine tract-binding protein (PTB) in islet GENE synthesis. Recent reports indicate that PTB binds and stabilizes mRNA encoding GENE and GENE secretory granule proteins, including islet cell autoantigen 512 (ICA512), prohormone convertase 1/3 (PC1/3), and PC2. In the present study, glucose-stimulated GENE secretion was significantly increased in CHEMICAL-treated rats compared to controls. Levels of mRNA encoding GENE 1, ICA512, and PC1/3 were increased in the pancreatic islets of GalN-treated rats. This mRNA level elevation was not prevented by pretreatment with actinomycin D. When the PTB-binding site in GENE 1 mRNA was incubated with the islet cytosolic fraction, the RNA-protein complex level was increased in the cytosolic fraction obtained from GalN-treated rats compared to the level in control rats. The cytosolic fraction obtained from pancreatic islets obtained from GalN-treated rats had an increased PTB level compared to the levels obtained from the pancreatic islets of control rats. These findings suggest that, in rats with acute liver failure, cytosolic PTB binds and stabilizes mRNA encoding GENE and its secretory granule proteins. | INDIRECT-UPREGULATOR |
| Characterization of the molecular mechanisms involved in the increased insulin secretion in rats with acute liver failure. To investigate the mechanism of hyperinsulinaemia in rats with acute liver failure induced by the administration of d-galactosamine (GalN), we focused on the role of polyprimidine tract-binding protein (PTB) in islet insulin synthesis. Recent reports indicate that PTB binds and stabilizes mRNA encoding insulin and insulin secretory granule proteins, including islet cell autoantigen 512 (ICA512), prohormone convertase 1/3 (PC1/3), and PC2. In the present study, glucose-stimulated insulin secretion was significantly increased in GalN-treated rats compared to controls. Levels of mRNA encoding GENE, ICA512, and PC1/3 were increased in the pancreatic islets of CHEMICAL-treated rats. This mRNA level elevation was not prevented by pretreatment with actinomycin D. When the PTB-binding site in GENE mRNA was incubated with the islet cytosolic fraction, the RNA-protein complex level was increased in the cytosolic fraction obtained from GalN-treated rats compared to the level in control rats. The cytosolic fraction obtained from pancreatic islets obtained from GalN-treated rats had an increased PTB level compared to the levels obtained from the pancreatic islets of control rats. These findings suggest that, in rats with acute liver failure, cytosolic PTB binds and stabilizes mRNA encoding insulin and its secretory granule proteins. | INDIRECT-UPREGULATOR |
| Characterization of the molecular mechanisms involved in the increased insulin secretion in rats with acute liver failure. To investigate the mechanism of hyperinsulinaemia in rats with acute liver failure induced by the administration of d-galactosamine (GalN), we focused on the role of polyprimidine tract-binding protein (PTB) in islet insulin synthesis. Recent reports indicate that PTB binds and stabilizes mRNA encoding insulin and insulin secretory granule proteins, including islet cell autoantigen 512 (ICA512), prohormone convertase 1/3 (PC1/3), and PC2. In the present study, glucose-stimulated insulin secretion was significantly increased in GalN-treated rats compared to controls. Levels of mRNA encoding insulin 1, GENE, and PC1/3 were increased in the pancreatic islets of CHEMICAL-treated rats. This mRNA level elevation was not prevented by pretreatment with actinomycin D. When the PTB-binding site in insulin 1 mRNA was incubated with the islet cytosolic fraction, the RNA-protein complex level was increased in the cytosolic fraction obtained from GalN-treated rats compared to the level in control rats. The cytosolic fraction obtained from pancreatic islets obtained from GalN-treated rats had an increased PTB level compared to the levels obtained from the pancreatic islets of control rats. These findings suggest that, in rats with acute liver failure, cytosolic PTB binds and stabilizes mRNA encoding insulin and its secretory granule proteins. | INDIRECT-UPREGULATOR |
| Characterization of the molecular mechanisms involved in the increased insulin secretion in rats with acute liver failure. To investigate the mechanism of hyperinsulinaemia in rats with acute liver failure induced by the administration of d-galactosamine (GalN), we focused on the role of polyprimidine tract-binding protein (PTB) in islet insulin synthesis. Recent reports indicate that PTB binds and stabilizes mRNA encoding insulin and insulin secretory granule proteins, including islet cell autoantigen 512 (ICA512), prohormone convertase 1/3 (PC1/3), and PC2. In the present study, glucose-stimulated insulin secretion was significantly increased in GalN-treated rats compared to controls. Levels of mRNA encoding insulin 1, ICA512, and PC1/3 were increased in the pancreatic islets of GalN-treated rats. This mRNA level elevation was not prevented by pretreatment with actinomycin D. When the GENE in insulin 1 mRNA was incubated with the islet cytosolic fraction, the RNA-protein complex level was increased in the cytosolic fraction obtained from CHEMICAL-treated rats compared to the level in control rats. The cytosolic fraction obtained from pancreatic islets obtained from GalN-treated rats had an increased PTB level compared to the levels obtained from the pancreatic islets of control rats. These findings suggest that, in rats with acute liver failure, cytosolic PTB binds and stabilizes mRNA encoding insulin and its secretory granule proteins. | INDIRECT-UPREGULATOR |
| Cysteinyl leukotriene receptor 1 is involved in N-methyl-D-aspartate-mediated neuronal injury in mice. AIM: To determine whether cysteinyl leukotriene receptor 1 (CysLT1 receptor) is involved in N-methyl-D-aspartate (NMDA)-induced excitotoxic injury in the mouse brain. METHODS: Brain injury was induced by CHEMICAL microinjection (50-150 nmol in 0.5 microL) into the cerebral cortex. The changes in GENE expression 24 h after CHEMICAL injection and the effects of a GENE antagonist, pranlukast (0.01 and 0.1 mg/kg), an CHEMICAL receptor antagonist, ketamine (30 mg/kg), and an antioxidant, edaravone (9 mg/kg) were observed. RESULTS: In the NMDA-injured brain, the GENE mRNA, and protein expression were upregulated, and the receptor was mainly localized in the neurons and not in the astrocytes. Pranlukast, ketamine and edaravone decreased NMDA-induced injury; pranlukast (0.1 mg/kg) and ketamine inhibited the upregulated expression of the GENE. CONCLUSION: GENE expression in neurons is upregulated after CHEMICAL injection, and NMDA-induced responses are inhibited by GENE antagonists, indicating that the increased GENE is involved in CHEMICAL excitotoxicity. | INDIRECT-UPREGULATOR |
| GENE is involved in CHEMICAL-mediated neuronal injury in mice. AIM: To determine whether cysteinyl leukotriene receptor 1 (CysLT1 receptor) is involved in CHEMICAL (NMDA)-induced excitotoxic injury in the mouse brain. METHODS: Brain injury was induced by NMDA microinjection (50-150 nmol in 0.5 microL) into the cerebral cortex. The changes in CysLT1 receptor expression 24 h after NMDA injection and the effects of a CysLT1 receptor antagonist, pranlukast (0.01 and 0.1 mg/kg), an NMDA receptor antagonist, ketamine (30 mg/kg), and an antioxidant, edaravone (9 mg/kg) were observed. RESULTS: In the NMDA-injured brain, the CysLT1 receptor mRNA, and protein expression were upregulated, and the receptor was mainly localized in the neurons and not in the astrocytes. Pranlukast, ketamine and edaravone decreased NMDA-induced injury; pranlukast (0.1 mg/kg) and ketamine inhibited the upregulated expression of the CysLT1 receptor. CONCLUSION: CysLT1 receptor expression in neurons is upregulated after NMDA injection, and NMDA-induced responses are inhibited by CysLT1 receptor antagonists, indicating that the increased CysLT1 receptor is involved in NMDA excitotoxicity. | REGULATOR |
| Cysteinyl leukotriene receptor 1 is involved in N-methyl-D-aspartate-mediated neuronal injury in mice. AIM: To determine whether cysteinyl leukotriene receptor 1 (CysLT1 receptor) is involved in N-methyl-D-aspartate (NMDA)-induced excitotoxic injury in the mouse brain. METHODS: Brain injury was induced by NMDA microinjection (50-150 nmol in 0.5 microL) into the cerebral cortex. The changes in GENE expression 24 h after NMDA injection and the effects of a GENE antagonist, CHEMICAL (0.01 and 0.1 mg/kg), an NMDA receptor antagonist, ketamine (30 mg/kg), and an antioxidant, edaravone (9 mg/kg) were observed. RESULTS: In the NMDA-injured brain, the GENE mRNA, and protein expression were upregulated, and the receptor was mainly localized in the neurons and not in the astrocytes. CHEMICAL, ketamine and edaravone decreased NMDA-induced injury; CHEMICAL (0.1 mg/kg) and ketamine inhibited the upregulated expression of the GENE. CONCLUSION: GENE expression in neurons is upregulated after NMDA injection, and NMDA-induced responses are inhibited by GENE antagonists, indicating that the increased GENE is involved in NMDA excitotoxicity. | INHIBITOR |
| Cysteinyl leukotriene receptor 1 is involved in N-methyl-D-aspartate-mediated neuronal injury in mice. AIM: To determine whether cysteinyl leukotriene receptor 1 (CysLT1 receptor) is involved in N-methyl-D-aspartate (NMDA)-induced excitotoxic injury in the mouse brain. METHODS: Brain injury was induced by NMDA microinjection (50-150 nmol in 0.5 microL) into the cerebral cortex. The changes in GENE expression 24 h after NMDA injection and the effects of a GENE antagonist, pranlukast (0.01 and 0.1 mg/kg), an NMDA receptor antagonist, CHEMICAL (30 mg/kg), and an antioxidant, edaravone (9 mg/kg) were observed. RESULTS: In the NMDA-injured brain, the GENE mRNA, and protein expression were upregulated, and the receptor was mainly localized in the neurons and not in the astrocytes. Pranlukast, CHEMICAL and edaravone decreased NMDA-induced injury; pranlukast (0.1 mg/kg) and CHEMICAL inhibited the upregulated expression of the GENE. CONCLUSION: GENE expression in neurons is upregulated after NMDA injection, and NMDA-induced responses are inhibited by GENE antagonists, indicating that the increased GENE is involved in NMDA excitotoxicity. | INDIRECT-DOWNREGULATOR |
| Cysteinyl leukotriene receptor 1 is involved in N-methyl-D-aspartate-mediated neuronal injury in mice. AIM: To determine whether cysteinyl leukotriene receptor 1 (CysLT1 receptor) is involved in N-methyl-D-aspartate (NMDA)-induced excitotoxic injury in the mouse brain. METHODS: Brain injury was induced by NMDA microinjection (50-150 nmol in 0.5 microL) into the cerebral cortex. The changes in CysLT1 receptor expression 24 h after NMDA injection and the effects of a CysLT1 receptor antagonist, pranlukast (0.01 and 0.1 mg/kg), an GENE antagonist, CHEMICAL (30 mg/kg), and an antioxidant, edaravone (9 mg/kg) were observed. RESULTS: In the NMDA-injured brain, the CysLT1 receptor mRNA, and protein expression were upregulated, and the receptor was mainly localized in the neurons and not in the astrocytes. Pranlukast, CHEMICAL and edaravone decreased NMDA-induced injury; pranlukast (0.1 mg/kg) and CHEMICAL inhibited the upregulated expression of the CysLT1 receptor. CONCLUSION: CysLT1 receptor expression in neurons is upregulated after NMDA injection, and NMDA-induced responses are inhibited by CysLT1 receptor antagonists, indicating that the increased CysLT1 receptor is involved in NMDA excitotoxicity. | INHIBITOR |
| Bcl-2 phosphorylation has pathological significance in human breast cancer. The anti-apoptotic molecule, Bcl-2, is well known to play an important role in the chemoresistance of breast cancer. We have previously demonstrated that phosphorylation of GENE (FADD) at 194 CHEMICAL through c-jun NH2-terminal kinase (JNK) activation sensitizes breast cancer cells to chemotherapy through accelerating cell cycle arrest at G2/M, and that Bcl-2 phosphorylation downstream of JNK/FADD plays an important role in cell growth suppression by paclitaxel. In this study, the clinicopathological association of phosphorylated Bcl-2 (P-Bcl-2) with estrogen, progesterone, c-erbB-2 receptors, p53 expressions and phosphorylated FADD/JNK (P-FADD/JNK) was analyzed immunohistochemically using 107 human breast cancer specimens. Expression of P-Bcl-2 was found to significantly correlate with lymphatic invasion, lymph node metastasis, but not histological differentiation, tumor grade or vascular and fatty invasion. The positivity of P-Bcl-2 was also significantly correlated to that of P-FADD/JNK. Thus, P-Bcl-2 as well as the P-FADD/JNK parameter might be useful markers for cancer progression, independent of the hormone receptor status, in human breast cancers. | PART-OF |
| Bcl-2 phosphorylation has pathological significance in human breast cancer. The anti-apoptotic molecule, Bcl-2, is well known to play an important role in the chemoresistance of breast cancer. We have previously demonstrated that phosphorylation of Fas-associated death domain-containing protein (GENE) at 194 CHEMICAL through c-jun NH2-terminal kinase (JNK) activation sensitizes breast cancer cells to chemotherapy through accelerating cell cycle arrest at G2/M, and that Bcl-2 phosphorylation downstream of JNK/FADD plays an important role in cell growth suppression by paclitaxel. In this study, the clinicopathological association of phosphorylated Bcl-2 (P-Bcl-2) with estrogen, progesterone, c-erbB-2 receptors, p53 expressions and phosphorylated FADD/JNK (P-FADD/JNK) was analyzed immunohistochemically using 107 human breast cancer specimens. Expression of P-Bcl-2 was found to significantly correlate with lymphatic invasion, lymph node metastasis, but not histological differentiation, tumor grade or vascular and fatty invasion. The positivity of P-Bcl-2 was also significantly correlated to that of P-FADD/JNK. Thus, P-Bcl-2 as well as the P-FADD/JNK parameter might be useful markers for cancer progression, independent of the hormone receptor status, in human breast cancers. | PART-OF |
| GENE phosphorylation has pathological significance in human breast cancer. The anti-apoptotic molecule, GENE, is well known to play an important role in the chemoresistance of breast cancer. We have previously demonstrated that phosphorylation of Fas-associated death domain-containing protein (FADD) at 194 serine through c-jun NH2-terminal kinase (JNK) activation sensitizes breast cancer cells to chemotherapy through accelerating cell cycle arrest at G2/M, and that GENE phosphorylation downstream of JNK/FADD plays an important role in cell growth suppression by CHEMICAL. In this study, the clinicopathological association of phosphorylated GENE (P-Bcl-2) with estrogen, progesterone, c-erbB-2 receptors, p53 expressions and phosphorylated FADD/JNK (P-FADD/JNK) was analyzed immunohistochemically using 107 human breast cancer specimens. Expression of P-Bcl-2 was found to significantly correlate with lymphatic invasion, lymph node metastasis, but not histological differentiation, tumor grade or vascular and fatty invasion. The positivity of P-Bcl-2 was also significantly correlated to that of P-FADD/JNK. Thus, P-Bcl-2 as well as the P-FADD/JNK parameter might be useful markers for cancer progression, independent of the hormone receptor status, in human breast cancers. | ACTIVATOR |
| Bcl-2 phosphorylation has pathological significance in human breast cancer. The anti-apoptotic molecule, Bcl-2, is well known to play an important role in the chemoresistance of breast cancer. We have previously demonstrated that phosphorylation of GENE (FADD) at 194 serine through c-jun NH2-terminal kinase (JNK) activation sensitizes breast cancer cells to chemotherapy through accelerating cell cycle arrest at G2/M, and that Bcl-2 phosphorylation downstream of JNK/FADD plays an important role in cell growth suppression by CHEMICAL. In this study, the clinicopathological association of phosphorylated Bcl-2 (P-Bcl-2) with estrogen, progesterone, c-erbB-2 receptors, p53 expressions and phosphorylated FADD/JNK (P-FADD/JNK) was analyzed immunohistochemically using 107 human breast cancer specimens. Expression of P-Bcl-2 was found to significantly correlate with lymphatic invasion, lymph node metastasis, but not histological differentiation, tumor grade or vascular and fatty invasion. The positivity of P-Bcl-2 was also significantly correlated to that of P-FADD/JNK. Thus, P-Bcl-2 as well as the P-FADD/JNK parameter might be useful markers for cancer progression, independent of the hormone receptor status, in human breast cancers. | ACTIVATOR |
| Bcl-2 phosphorylation has pathological significance in human breast cancer. The anti-apoptotic molecule, Bcl-2, is well known to play an important role in the chemoresistance of breast cancer. We have previously demonstrated that phosphorylation of Fas-associated death domain-containing protein (GENE) at 194 serine through c-jun NH2-terminal kinase (JNK) activation sensitizes breast cancer cells to chemotherapy through accelerating cell cycle arrest at G2/M, and that Bcl-2 phosphorylation downstream of JNK/FADD plays an important role in cell growth suppression by CHEMICAL. In this study, the clinicopathological association of phosphorylated Bcl-2 (P-Bcl-2) with estrogen, progesterone, c-erbB-2 receptors, p53 expressions and phosphorylated FADD/JNK (P-FADD/JNK) was analyzed immunohistochemically using 107 human breast cancer specimens. Expression of P-Bcl-2 was found to significantly correlate with lymphatic invasion, lymph node metastasis, but not histological differentiation, tumor grade or vascular and fatty invasion. The positivity of P-Bcl-2 was also significantly correlated to that of P-FADD/JNK. Thus, P-Bcl-2 as well as the P-FADD/JNK parameter might be useful markers for cancer progression, independent of the hormone receptor status, in human breast cancers. | ACTIVATOR |
| Bcl-2 phosphorylation has pathological significance in human breast cancer. The anti-apoptotic molecule, Bcl-2, is well known to play an important role in the chemoresistance of breast cancer. We have previously demonstrated that phosphorylation of Fas-associated death domain-containing protein (FADD) at 194 serine through GENE (JNK) activation sensitizes breast cancer cells to chemotherapy through accelerating cell cycle arrest at G2/M, and that Bcl-2 phosphorylation downstream of JNK/FADD plays an important role in cell growth suppression by CHEMICAL. In this study, the clinicopathological association of phosphorylated Bcl-2 (P-Bcl-2) with estrogen, progesterone, c-erbB-2 receptors, p53 expressions and phosphorylated FADD/JNK (P-FADD/JNK) was analyzed immunohistochemically using 107 human breast cancer specimens. Expression of P-Bcl-2 was found to significantly correlate with lymphatic invasion, lymph node metastasis, but not histological differentiation, tumor grade or vascular and fatty invasion. The positivity of P-Bcl-2 was also significantly correlated to that of P-FADD/JNK. Thus, P-Bcl-2 as well as the P-FADD/JNK parameter might be useful markers for cancer progression, independent of the hormone receptor status, in human breast cancers. | ACTIVATOR |
| Bcl-2 phosphorylation has pathological significance in human breast cancer. The anti-apoptotic molecule, Bcl-2, is well known to play an important role in the chemoresistance of breast cancer. We have previously demonstrated that phosphorylation of Fas-associated death domain-containing protein (FADD) at 194 serine through c-jun NH2-terminal kinase (GENE) activation sensitizes breast cancer cells to chemotherapy through accelerating cell cycle arrest at G2/M, and that Bcl-2 phosphorylation downstream of JNK/FADD plays an important role in cell growth suppression by CHEMICAL. In this study, the clinicopathological association of phosphorylated Bcl-2 (P-Bcl-2) with estrogen, progesterone, c-erbB-2 receptors, p53 expressions and phosphorylated FADD/JNK (P-FADD/JNK) was analyzed immunohistochemically using 107 human breast cancer specimens. Expression of P-Bcl-2 was found to significantly correlate with lymphatic invasion, lymph node metastasis, but not histological differentiation, tumor grade or vascular and fatty invasion. The positivity of P-Bcl-2 was also significantly correlated to that of P-FADD/JNK. Thus, P-Bcl-2 as well as the P-FADD/JNK parameter might be useful markers for cancer progression, independent of the hormone receptor status, in human breast cancers. | ACTIVATOR |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. CHEMICAL (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. CHEMICAL produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the GENE mediated pressor response to B-HT 933, suggesting that carvedilol is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. CHEMICAL had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | NO-RELATIONSHIP |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. CHEMICAL (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of GENE. Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. CHEMICAL produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that carvedilol is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. CHEMICAL had no effect on the pressor response elicited by GENE, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | NO-RELATIONSHIP |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. Carvedilol (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the GENE mediated vasodepressor response to CHEMICAL in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. Carvedilol produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that carvedilol is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. Carvedilol had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | REGULATOR |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. Carvedilol (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. Carvedilol produced significant inhibition of the GENE mediated pressor response to CHEMICAL in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that carvedilol is also an GENE antagonist at antihypertensive doses. Carvedilol had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the GENE antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | ACTIVATOR |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. Carvedilol (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. Carvedilol produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the GENE mediated pressor response to CHEMICAL, suggesting that carvedilol is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. Carvedilol had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | NO-RELATIONSHIP |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. Carvedilol (0.3 mg/kg, iv) produced a significant inhibition of the GENE mediated positive chronotropic response to CHEMICAL. This same dose of carvedilol also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the GENE subtype. Carvedilol produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that carvedilol is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. Carvedilol had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | ACTIVATOR |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. Carvedilol (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. Carvedilol produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that carvedilol is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. Carvedilol had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the GENE activator, CHEMICAL, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a GENE antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | ACTIVATOR |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. Carvedilol (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. Carvedilol produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that carvedilol is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. Carvedilol had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, CHEMICAL, which is mediated through the opening of GENE and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | REGULATOR |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, CHEMICAL. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic CHEMICAL, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, CHEMICAL (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of CHEMICAL was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of CHEMICAL were chosen for mechanism of action studies in pithed rats. CHEMICAL (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of CHEMICAL also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, CHEMICAL blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. CHEMICAL produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that CHEMICAL is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. CHEMICAL had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of GENE and the subsequent translocation of extracellular calcium, was significantly inhibited by CHEMICAL (1 mg/kg, iv), suggesting that CHEMICAL is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of CHEMICAL was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by CHEMICAL may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that CHEMICAL, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, CHEMICAL. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic CHEMICAL, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, CHEMICAL (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of CHEMICAL was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of CHEMICAL were chosen for mechanism of action studies in pithed rats. CHEMICAL (0.3 mg/kg, iv) produced a significant inhibition of the GENE mediated positive chronotropic response to isoproterenol. This same dose of CHEMICAL also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, CHEMICAL blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the GENE subtype. CHEMICAL produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that CHEMICAL is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. CHEMICAL had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by CHEMICAL (1 mg/kg, iv), suggesting that CHEMICAL is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of CHEMICAL was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by CHEMICAL may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that CHEMICAL, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. CHEMICAL (0.3 mg/kg, iv) produced a significant inhibition of the GENE mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the GENE subtype. CHEMICAL produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that carvedilol is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. CHEMICAL had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, CHEMICAL. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic CHEMICAL, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, CHEMICAL (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of CHEMICAL was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of CHEMICAL were chosen for mechanism of action studies in pithed rats. CHEMICAL (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of CHEMICAL also inhibited, but to a lesser degree, the GENE mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, CHEMICAL blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. CHEMICAL produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that CHEMICAL is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. CHEMICAL had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by CHEMICAL (1 mg/kg, iv), suggesting that CHEMICAL is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of CHEMICAL was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by CHEMICAL may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that CHEMICAL, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. CHEMICAL (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. CHEMICAL produced significant inhibition of the GENE mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that carvedilol is also an GENE antagonist at antihypertensive doses. CHEMICAL had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the GENE antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, CHEMICAL. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic CHEMICAL, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, CHEMICAL (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of CHEMICAL was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of CHEMICAL were chosen for mechanism of action studies in pithed rats. CHEMICAL (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of CHEMICAL also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, CHEMICAL blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. CHEMICAL produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that CHEMICAL is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. CHEMICAL had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the GENE activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by CHEMICAL (1 mg/kg, iv), suggesting that CHEMICAL is also a GENE antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of CHEMICAL was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by CHEMICAL may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that CHEMICAL, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. Carvedilol (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. Carvedilol produced significant inhibition of the GENE mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that carvedilol is also an GENE antagonist at antihypertensive doses. Carvedilol had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the GENE antagonist, CHEMICAL (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. Carvedilol (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. Carvedilol produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that carvedilol is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. Carvedilol had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective GENE antagonist, CHEMICAL (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, CHEMICAL. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic CHEMICAL, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, CHEMICAL (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of CHEMICAL was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of CHEMICAL were chosen for mechanism of action studies in pithed rats. CHEMICAL (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of CHEMICAL also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, CHEMICAL blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. CHEMICAL produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that CHEMICAL is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. CHEMICAL had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent GENE and the subsequent translocation of extracellular calcium, was significantly inhibited by CHEMICAL (1 mg/kg, iv), suggesting that CHEMICAL is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of CHEMICAL was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by CHEMICAL may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that CHEMICAL, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of GENE in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol. The mechanism(s) responsible for arterial vasodilation observed following acute administration of CHEMICAL, a novel vasodilator/GENE antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. Carvedilol (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. Carvedilol produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that carvedilol is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. Carvedilol had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective GENE antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, CHEMICAL. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic CHEMICAL, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, CHEMICAL (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of CHEMICAL was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of CHEMICAL were chosen for mechanism of action studies in pithed rats. CHEMICAL (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of CHEMICAL also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, CHEMICAL blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. CHEMICAL produced significant inhibition of the GENE mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that CHEMICAL is also an GENE antagonist at antihypertensive doses. CHEMICAL had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the calcium channel activator, BAY-K-8644, which is mediated through the opening of voltage dependent calcium channels and the subsequent translocation of extracellular calcium, was significantly inhibited by CHEMICAL (1 mg/kg, iv), suggesting that CHEMICAL is also a calcium channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of CHEMICAL was nearly abolished by combined pretreatment of the rats with high doses of the GENE antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by CHEMICAL may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that CHEMICAL, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of calcium channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| Studies on the mechanism of arterial vasodilation produced by the novel antihypertensive agent, carvedilol. The mechanism(s) responsible for arterial vasodilation observed following acute administration of racemic carvedilol, a novel vasodilator/beta adrenoceptor antagonist, has been investigated in rats. In conscious spontaneously hypertensive rats, carvedilol (0.03-3.0 mg/kg, iv) produced a dose-dependent reduction in blood pressure with no significant effect on heart rate. Because cardiac output was relatively unaffected, the antihypertensive response of carvedilol was associated with a dose-dependent reduction in total peripheral vascular resistance. Submaximal antihypertensive doses of carvedilol were chosen for mechanism of action studies in pithed rats. Carvedilol (0.3 mg/kg, iv) produced a significant inhibition of the beta 1 adrenoceptor mediated positive chronotropic response to isoproterenol. This same dose of carvedilol also inhibited, but to a lesser degree, the beta 2 adrenoceptor mediated vasodepressor response to salbutamol in pithed rats whose blood pressure was elevated by a constant intravenous infusion of angiotensin II. Thus, carvedilol blocks both beta 1 and beta 2 adrenoceptors at antihypertensive doses, with modest selectivity being observed for the beta 1 adrenoceptor subtype. Carvedilol produced significant inhibition of the alpha 1 adrenoceptor mediated pressor response to cirazoline in the pithed rat, but had no effect on the alpha 2 adrenoceptor mediated pressor response to B-HT 933, suggesting that carvedilol is also an alpha 1 adrenoceptor antagonist at antihypertensive doses. Carvedilol had no effect on the pressor response elicited by angiotensin II, indicating a lack of nonspecific vasodilator activity. The vasopressor response to the CHEMICAL channel activator, BAY-K-8644, which is mediated through the opening of GENE and the subsequent translocation of extracellular CHEMICAL, was significantly inhibited by carvedilol (1 mg/kg, iv), suggesting that carvedilol is also a CHEMICAL channel antagonist, consistent with our previous in vitro studies. In anesthetized spontaneously hypertensive rats, the antihypertensive activity of carvedilol was nearly abolished by combined pretreatment of the rats with high doses of the alpha 1 adrenoceptor antagonist, prazosin (1 mg/kg, iv), and the nonselective beta adrenoceptor antagonist, propranolol (3 mg/kg, iv), suggesting that the majority of the antihypertensive response produced by carvedilol may be accounted for by blockade of beta and alpha 1 adrenoceptors. We therefore conclude that carvedilol, at antihypertensive doses, is an antagonist of beta 1, beta 2, and alpha 1 adrenoceptors, and also of CHEMICAL channels in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS) | GENE-CHEMICAL |
| Increased responsiveness of rat colonic splanchnic afferents to CHEMICAL after inflammation and recovery. 5-Hydroxytryptamine (5-HT) activates colonic splanchnic afferents, a mechanism by which it has been implicated in generating symptoms in postinfectious and postinflammatory states in humans. Here we compared mechanisms of colonic afferent activation by CHEMICAL and mechanical stimuli in normal and inflamed rat colon, and after recovery from inflammation. Colonic inflammation was induced in rats by dextran sulphate sodium. Single-fibre recordings of colonic lumbar splanchnic afferents revealed that 58% of endings responded to CHEMICAL (10(-4) m) in controls, 88% in acute inflammation (P<0.05) and 75% after 21 days recovery (P < 0.05 versus control). Maximal responses to CHEMICAL were also larger, and the estimated EC50 was reduced from 3.2 x 10(-6) to 8 x 10(-7) m in acute inflammation and recovered to 2 x 10(-6) m after recovery. Responsiveness to mechanical stimulation was unaffected. GENE antagonism with alosetron reduced responses to CHEMICAL in controls but not during inflammation. Responses to the mast cell degranulator 48/80 mimicked those to CHEMICAL in inflamed tissue but not in controls, and more 5-HT-containing mast cells were seen close to calcitonin gene-related peptide-containing fibres in inflamed serosa. We conclude that colonic serosal and mesenteric endings exhibit increased sensitivity to CHEMICAL in inflammation, with both an increase in proportion of responders and an increase in sensitivity, which is maintained after healing of inflammation. This is associated with alterations in the roles of 5-HT3 receptors and mast cells. | ACTIVATOR |
| Increased responsiveness of rat colonic splanchnic afferents to 5-HT after inflammation and recovery. 5-Hydroxytryptamine (5-HT) activates colonic splanchnic afferents, a mechanism by which it has been implicated in generating symptoms in postinfectious and postinflammatory states in humans. Here we compared mechanisms of colonic afferent activation by 5-HT and mechanical stimuli in normal and inflamed rat colon, and after recovery from inflammation. Colonic inflammation was induced in rats by dextran sulphate sodium. Single-fibre recordings of colonic lumbar splanchnic afferents revealed that 58% of endings responded to 5-HT (10(-4) m) in controls, 88% in acute inflammation (P<0.05) and 75% after 21 days recovery (P < 0.05 versus control). Maximal responses to 5-HT were also larger, and the estimated EC50 was reduced from 3.2 x 10(-6) to 8 x 10(-7) m in acute inflammation and recovered to 2 x 10(-6) m after recovery. Responsiveness to mechanical stimulation was unaffected. GENE antagonism with CHEMICAL reduced responses to 5-HT in controls but not during inflammation. Responses to the mast cell degranulator 48/80 mimicked those to 5-HT in inflamed tissue but not in controls, and more 5-HT-containing mast cells were seen close to calcitonin gene-related peptide-containing fibres in inflamed serosa. We conclude that colonic serosal and mesenteric endings exhibit increased sensitivity to 5-HT in inflammation, with both an increase in proportion of responders and an increase in sensitivity, which is maintained after healing of inflammation. This is associated with alterations in the roles of 5-HT3 receptors and mast cells. | INHIBITOR |
| The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle. Human progesterone receptor (PR) contains a motif that interacts with the SH3 domain of Src and mediates rapid activation of Src and downstream MAPK (Erk-1/-2) without relying on the transcriptional activity of the receptor. Here we investigated the role and intracellular location of this nontranscriptional activity of PR. CHEMICAL activation of Src/MAPK occurred outside the nucleus with the B isoform of PR that was distributed between the cytoplasm and nucleus, but not with PR-A that was predominantly nuclear. Breast cancer cells stably expressing wild-type PR-B or PR-B with disrupting point mutations in the SH3 domain binding motif (PR-BDeltaSH3) that do not affect the transcriptional activity of PR, were compared for effects of CHEMICAL on endogenous target gene expression and cell proliferation. CHEMICAL induction of the GENE gene, which lacks a progesterone response element, was dependent on PR activation of the Src/MAPK pathway, whereas induction of the Sgk (serum and glucocorticoid regulated kinase) gene that contains a functional progesterone response element was unaffected by mutations that interfere with PR activation of Src. CHEMICAL induction of cell cycle progression was also abrogated in cells expressing PR-BDeltaSH3, and no effect of CHEMICAL on GENE expression and cell cycle was observed in the presence of PR-A. These results highlight the importance of PR activation of the Src/MAPK signaling pathway for progesterone-induced transcription of select target genes and cell cycle progression. | NO-RELATIONSHIP |
| The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle. Human progesterone receptor (PR) contains a motif that interacts with the SH3 domain of Src and mediates rapid activation of Src and downstream MAPK (Erk-1/-2) without relying on the transcriptional activity of the receptor. Here we investigated the role and intracellular location of this nontranscriptional activity of PR. CHEMICAL activation of Src/MAPK occurred outside the nucleus with the B isoform of PR that was distributed between the cytoplasm and nucleus, but not with GENE that was predominantly nuclear. Breast cancer cells stably expressing wild-type PR-B or PR-B with disrupting point mutations in the SH3 domain binding motif (PR-BDeltaSH3) that do not affect the transcriptional activity of PR, were compared for effects of progestin on endogenous target gene expression and cell proliferation. CHEMICAL induction of the cyclin D1 gene, which lacks a progesterone response element, was dependent on PR activation of the Src/MAPK pathway, whereas induction of the Sgk (serum and glucocorticoid regulated kinase) gene that contains a functional progesterone response element was unaffected by mutations that interfere with PR activation of Src. CHEMICAL induction of cell cycle progression was also abrogated in cells expressing PR-BDeltaSH3, and no effect of progestin on cyclin D1 expression and cell cycle was observed in the presence of GENE. These results highlight the importance of PR activation of the Src/MAPK signaling pathway for progesterone-induced transcription of select target genes and cell cycle progression. | NO-RELATIONSHIP |
| The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle. Human progesterone receptor (PR) contains a motif that interacts with the SH3 domain of Src and mediates rapid activation of Src and downstream MAPK (Erk-1/-2) without relying on the transcriptional activity of the receptor. Here we investigated the role and intracellular location of this nontranscriptional activity of PR. CHEMICAL activation of Src/MAPK occurred outside the nucleus with the B isoform of PR that was distributed between the cytoplasm and nucleus, but not with PR-A that was predominantly nuclear. Breast cancer cells stably expressing wild-type PR-B or PR-B with disrupting point mutations in the SH3 domain binding motif (PR-BDeltaSH3) that do not affect the transcriptional activity of PR, were compared for effects of progestin on endogenous target gene expression and cell proliferation. CHEMICAL induction of the GENE gene, which lacks a progesterone response element, was dependent on PR activation of the Src/MAPK pathway, whereas induction of the Sgk (serum and glucocorticoid regulated kinase) gene that contains a functional progesterone response element was unaffected by mutations that interfere with PR activation of Src. CHEMICAL induction of cell cycle progression was also abrogated in cells expressing PR-BDeltaSH3, and no effect of progestin on GENE expression and cell cycle was observed in the presence of PR-A. These results highlight the importance of PR activation of the Src/MAPK signaling pathway for progesterone-induced transcription of select target genes and cell cycle progression. | INDIRECT-UPREGULATOR |
| The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle. Human progesterone receptor (PR) contains a motif that interacts with the SH3 domain of Src and mediates rapid activation of Src and downstream MAPK (Erk-1/-2) without relying on the transcriptional activity of the receptor. Here we investigated the role and intracellular location of this nontranscriptional activity of PR. CHEMICAL activation of Src/MAPK occurred outside the nucleus with the B isoform of PR that was distributed between the cytoplasm and nucleus, but not with PR-A that was predominantly nuclear. Breast cancer cells stably expressing wild-type PR-B or PR-B with disrupting point mutations in the SH3 domain binding motif (PR-BDeltaSH3) that do not affect the transcriptional activity of PR, were compared for effects of progestin on endogenous target gene expression and cell proliferation. CHEMICAL induction of the cyclin D1 gene, which lacks a progesterone response element, was dependent on PR activation of the Src/MAPK pathway, whereas induction of the GENE (serum and glucocorticoid regulated kinase) gene that contains a functional progesterone response element was unaffected by mutations that interfere with PR activation of Src. CHEMICAL induction of cell cycle progression was also abrogated in cells expressing PR-BDeltaSH3, and no effect of progestin on cyclin D1 expression and cell cycle was observed in the presence of PR-A. These results highlight the importance of PR activation of the Src/MAPK signaling pathway for progesterone-induced transcription of select target genes and cell cycle progression. | ACTIVATOR |
| The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle. Human progesterone receptor (PR) contains a motif that interacts with the SH3 domain of Src and mediates rapid activation of Src and downstream MAPK (Erk-1/-2) without relying on the transcriptional activity of the receptor. Here we investigated the role and intracellular location of this nontranscriptional activity of PR. CHEMICAL activation of Src/MAPK occurred outside the nucleus with the B isoform of PR that was distributed between the cytoplasm and nucleus, but not with PR-A that was predominantly nuclear. Breast cancer cells stably expressing wild-type PR-B or PR-B with disrupting point mutations in the SH3 domain binding motif (PR-BDeltaSH3) that do not affect the transcriptional activity of PR, were compared for effects of progestin on endogenous target gene expression and cell proliferation. CHEMICAL induction of the cyclin D1 gene, which lacks a progesterone response element, was dependent on PR activation of the Src/MAPK pathway, whereas induction of the Sgk (GENE) gene that contains a functional progesterone response element was unaffected by mutations that interfere with PR activation of Src. CHEMICAL induction of cell cycle progression was also abrogated in cells expressing PR-BDeltaSH3, and no effect of progestin on cyclin D1 expression and cell cycle was observed in the presence of PR-A. These results highlight the importance of PR activation of the Src/MAPK signaling pathway for progesterone-induced transcription of select target genes and cell cycle progression. | NO-RELATIONSHIP |
| The role of extranuclear signaling actions of GENE in mediating CHEMICAL regulation of gene expression and the cell cycle. Human CHEMICAL receptor (PR) contains a motif that interacts with the SH3 domain of Src and mediates rapid activation of Src and downstream MAPK (Erk-1/-2) without relying on the transcriptional activity of the receptor. Here we investigated the role and intracellular location of this nontranscriptional activity of PR. Progestin activation of Src/MAPK occurred outside the nucleus with the B isoform of PR that was distributed between the cytoplasm and nucleus, but not with PR-A that was predominantly nuclear. Breast cancer cells stably expressing wild-type PR-B or PR-B with disrupting point mutations in the SH3 domain binding motif (PR-BDeltaSH3) that do not affect the transcriptional activity of PR, were compared for effects of progestin on endogenous target gene expression and cell proliferation. Progestin induction of the cyclin D1 gene, which lacks a CHEMICAL response element, was dependent on PR activation of the Src/MAPK pathway, whereas induction of the Sgk (serum and glucocorticoid regulated kinase) gene that contains a functional CHEMICAL response element was unaffected by mutations that interfere with PR activation of Src. Progestin induction of cell cycle progression was also abrogated in cells expressing PR-BDeltaSH3, and no effect of progestin on cyclin D1 expression and cell cycle was observed in the presence of PR-A. These results highlight the importance of PR activation of the Src/MAPK signaling pathway for progesterone-induced transcription of select target genes and cell cycle progression. | REGULATOR |
| The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle. Human progesterone receptor (PR) contains a motif that interacts with the SH3 domain of Src and mediates rapid activation of Src and downstream MAPK (Erk-1/-2) without relying on the transcriptional activity of the receptor. Here we investigated the role and intracellular location of this nontranscriptional activity of PR. CHEMICAL activation of Src/MAPK occurred outside the nucleus with the GENE that was distributed between the cytoplasm and nucleus, but not with PR-A that was predominantly nuclear. Breast cancer cells stably expressing wild-type PR-B or PR-B with disrupting point mutations in the SH3 domain binding motif (PR-BDeltaSH3) that do not affect the transcriptional activity of PR, were compared for effects of progestin on endogenous target gene expression and cell proliferation. CHEMICAL induction of the cyclin D1 gene, which lacks a progesterone response element, was dependent on PR activation of the Src/MAPK pathway, whereas induction of the Sgk (serum and glucocorticoid regulated kinase) gene that contains a functional progesterone response element was unaffected by mutations that interfere with PR activation of Src. CHEMICAL induction of cell cycle progression was also abrogated in cells expressing PR-BDeltaSH3, and no effect of progestin on cyclin D1 expression and cell cycle was observed in the presence of PR-A. These results highlight the importance of PR activation of the Src/MAPK signaling pathway for progesterone-induced transcription of select target genes and cell cycle progression. | REGULATOR |
| The role of extranuclear signaling actions of CHEMICAL receptor in mediating CHEMICAL regulation of gene expression and the cell cycle. Human CHEMICAL receptor (PR) contains a motif that interacts with the SH3 domain of Src and mediates rapid activation of Src and downstream MAPK (Erk-1/-2) without relying on the transcriptional activity of the receptor. Here we investigated the role and intracellular location of this nontranscriptional activity of GENE. Progestin activation of Src/MAPK occurred outside the nucleus with the B isoform of GENE that was distributed between the cytoplasm and nucleus, but not with PR-A that was predominantly nuclear. Breast cancer cells stably expressing wild-type PR-B or PR-B with disrupting point mutations in the SH3 domain binding motif (PR-BDeltaSH3) that do not affect the transcriptional activity of GENE, were compared for effects of progestin on endogenous target gene expression and cell proliferation. Progestin induction of the cyclin D1 gene, which lacks a CHEMICAL response element, was dependent on GENE activation of the Src/MAPK pathway, whereas induction of the Sgk (serum and glucocorticoid regulated kinase) gene that contains a functional CHEMICAL response element was unaffected by mutations that interfere with GENE activation of Src. Progestin induction of cell cycle progression was also abrogated in cells expressing PR-BDeltaSH3, and no effect of progestin on cyclin D1 expression and cell cycle was observed in the presence of PR-A. These results highlight the importance of GENE activation of the Src/MAPK signaling pathway for CHEMICAL-induced transcription of select target genes and cell cycle progression. | REGULATOR |
| The role of extranuclear signaling actions of CHEMICAL receptor in mediating CHEMICAL regulation of gene expression and the cell cycle. Human CHEMICAL receptor (PR) contains a motif that interacts with the SH3 domain of GENE and mediates rapid activation of GENE and downstream MAPK (Erk-1/-2) without relying on the transcriptional activity of the receptor. Here we investigated the role and intracellular location of this nontranscriptional activity of PR. Progestin activation of Src/MAPK occurred outside the nucleus with the B isoform of PR that was distributed between the cytoplasm and nucleus, but not with PR-A that was predominantly nuclear. Breast cancer cells stably expressing wild-type PR-B or PR-B with disrupting point mutations in the SH3 domain binding motif (PR-BDeltaSH3) that do not affect the transcriptional activity of PR, were compared for effects of progestin on endogenous target gene expression and cell proliferation. Progestin induction of the cyclin D1 gene, which lacks a CHEMICAL response element, was dependent on PR activation of the Src/MAPK pathway, whereas induction of the Sgk (serum and glucocorticoid regulated kinase) gene that contains a functional CHEMICAL response element was unaffected by mutations that interfere with PR activation of GENE. Progestin induction of cell cycle progression was also abrogated in cells expressing PR-BDeltaSH3, and no effect of progestin on cyclin D1 expression and cell cycle was observed in the presence of PR-A. These results highlight the importance of PR activation of the GENE/MAPK signaling pathway for CHEMICAL-induced transcription of select target genes and cell cycle progression. | REGULATOR |
| The role of extranuclear signaling actions of CHEMICAL receptor in mediating CHEMICAL regulation of gene expression and the cell cycle. Human CHEMICAL receptor (PR) contains a motif that interacts with the SH3 domain of Src and mediates rapid activation of Src and downstream GENE (Erk-1/-2) without relying on the transcriptional activity of the receptor. Here we investigated the role and intracellular location of this nontranscriptional activity of PR. Progestin activation of Src/MAPK occurred outside the nucleus with the B isoform of PR that was distributed between the cytoplasm and nucleus, but not with PR-A that was predominantly nuclear. Breast cancer cells stably expressing wild-type PR-B or PR-B with disrupting point mutations in the SH3 domain binding motif (PR-BDeltaSH3) that do not affect the transcriptional activity of PR, were compared for effects of progestin on endogenous target gene expression and cell proliferation. Progestin induction of the cyclin D1 gene, which lacks a CHEMICAL response element, was dependent on PR activation of the Src/MAPK pathway, whereas induction of the Sgk (serum and glucocorticoid regulated kinase) gene that contains a functional CHEMICAL response element was unaffected by mutations that interfere with PR activation of Src. Progestin induction of cell cycle progression was also abrogated in cells expressing PR-BDeltaSH3, and no effect of progestin on cyclin D1 expression and cell cycle was observed in the presence of PR-A. These results highlight the importance of PR activation of the Src/GENE signaling pathway for CHEMICAL-induced transcription of select target genes and cell cycle progression. | ACTIVATOR |
| The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle. Human progesterone receptor (PR) contains a motif that interacts with the SH3 domain of GENE and mediates rapid activation of GENE and downstream MAPK (Erk-1/-2) without relying on the transcriptional activity of the receptor. Here we investigated the role and intracellular location of this nontranscriptional activity of PR. CHEMICAL activation of GENE/MAPK occurred outside the nucleus with the B isoform of PR that was distributed between the cytoplasm and nucleus, but not with PR-A that was predominantly nuclear. Breast cancer cells stably expressing wild-type PR-B or PR-B with disrupting point mutations in the SH3 domain binding motif (PR-BDeltaSH3) that do not affect the transcriptional activity of PR, were compared for effects of progestin on endogenous target gene expression and cell proliferation. CHEMICAL induction of the cyclin D1 gene, which lacks a progesterone response element, was dependent on PR activation of the Src/MAPK pathway, whereas induction of the Sgk (serum and glucocorticoid regulated kinase) gene that contains a functional progesterone response element was unaffected by mutations that interfere with PR activation of GENE. CHEMICAL induction of cell cycle progression was also abrogated in cells expressing PR-BDeltaSH3, and no effect of progestin on cyclin D1 expression and cell cycle was observed in the presence of PR-A. These results highlight the importance of PR activation of the Src/MAPK signaling pathway for progesterone-induced transcription of select target genes and cell cycle progression. | ACTIVATOR |
| The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle. Human progesterone receptor (PR) contains a motif that interacts with the SH3 domain of Src and mediates rapid activation of Src and downstream GENE (Erk-1/-2) without relying on the transcriptional activity of the receptor. Here we investigated the role and intracellular location of this nontranscriptional activity of PR. CHEMICAL activation of Src/GENE occurred outside the nucleus with the B isoform of PR that was distributed between the cytoplasm and nucleus, but not with PR-A that was predominantly nuclear. Breast cancer cells stably expressing wild-type PR-B or PR-B with disrupting point mutations in the SH3 domain binding motif (PR-BDeltaSH3) that do not affect the transcriptional activity of PR, were compared for effects of progestin on endogenous target gene expression and cell proliferation. CHEMICAL induction of the cyclin D1 gene, which lacks a progesterone response element, was dependent on PR activation of the Src/MAPK pathway, whereas induction of the Sgk (serum and glucocorticoid regulated kinase) gene that contains a functional progesterone response element was unaffected by mutations that interfere with PR activation of Src. CHEMICAL induction of cell cycle progression was also abrogated in cells expressing PR-BDeltaSH3, and no effect of progestin on cyclin D1 expression and cell cycle was observed in the presence of PR-A. These results highlight the importance of PR activation of the Src/MAPK signaling pathway for progesterone-induced transcription of select target genes and cell cycle progression. | ACTIVATOR |
| The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle. Human progesterone receptor (PR) contains a motif that interacts with the SH3 domain of Src and mediates rapid activation of Src and downstream MAPK (Erk-1/-2) without relying on the transcriptional activity of the receptor. Here we investigated the role and intracellular location of this nontranscriptional activity of GENE. CHEMICAL activation of Src/MAPK occurred outside the nucleus with the B isoform of GENE that was distributed between the cytoplasm and nucleus, but not with PR-A that was predominantly nuclear. Breast cancer cells stably expressing wild-type PR-B or PR-B with disrupting point mutations in the SH3 domain binding motif (PR-BDeltaSH3) that do not affect the transcriptional activity of GENE, were compared for effects of progestin on endogenous target gene expression and cell proliferation. CHEMICAL induction of the cyclin D1 gene, which lacks a progesterone response element, was dependent on GENE activation of the Src/MAPK pathway, whereas induction of the Sgk (serum and glucocorticoid regulated kinase) gene that contains a functional progesterone response element was unaffected by mutations that interfere with GENE activation of Src. CHEMICAL induction of cell cycle progression was also abrogated in cells expressing PR-BDeltaSH3, and no effect of progestin on cyclin D1 expression and cell cycle was observed in the presence of PR-A. These results highlight the importance of GENE activation of the Src/MAPK signaling pathway for progesterone-induced transcription of select target genes and cell cycle progression. | REGULATOR |
| Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy. Selected mutations in the human alpha4 or beta2 neuronal nicotinic acetylcholine receptor subunit genes cosegregate with a partial epilepsy syndrome known as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). To examine possible mechanisms underlying this inherited epilepsy, we engineered two ADNFLE mutations (Chrna4(S252F) and Chrna4(+L264)) in mice. Heterozygous ADNFLE mutant mice show persistent, abnormal cortical electroencephalograms with prominent delta and theta frequencies, exhibit frequent spontaneous seizures, and show an increased sensitivity to the proconvulsant action of nicotine. Relative to WT, electrophysiological recordings from ADNFLE mouse layer II/III cortical pyramidal cells reveal a >20-fold increase in nicotine-evoked inhibitory postsynaptic currents with no effect on excitatory postsynaptic currents. i.p. injection of a subthreshold dose of CHEMICAL, a use-dependent GENE antagonist, reduces cortical electroencephalogram delta power and transiently inhibits spontaneous seizure activity in ADNFLE mutant mice. Our studies suggest that the mechanism underlying ADNFLE seizures may involve inhibitory synchronization of cortical networks via activation of mutant alpha4-containing nicotinic acetylcholine receptors located on the presynaptic terminals and somatodendritic compartments of cortical GABAergic interneurons. | INHIBITOR |
| Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography. 2beta-carbomethoxy-3beta-(3'-((Z)-2-iodoethenyl)phenyl)nortropane (mZIENT, 1) and CHEMICAL (mZBrENT, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (GENE, DAT, and NET, respectively) using transfected cells. Both 1 and 2 have a high affinity for the GENE (Ki=0.2 nM) and are approximately 160 times more selective for the GENE than the DAT. Compound 2 has a significantly higher affinity for the NET than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with citalopram and methylphenidate demonstrated that this uptake is the result of preferential binding to the GENE. | DIRECT-REGULATOR |
| Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography. 2beta-carbomethoxy-3beta-(3'-((Z)-2-iodoethenyl)phenyl)nortropane (mZIENT, 1) and CHEMICAL (mZBrENT, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (SERT, GENE, and NET, respectively) using transfected cells. Both 1 and 2 have a high affinity for the SERT (Ki=0.2 nM) and are approximately 160 times more selective for the SERT than the GENE. Compound 2 has a significantly higher affinity for the NET than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with citalopram and methylphenidate demonstrated that this uptake is the result of preferential binding to the SERT. | DIRECT-REGULATOR |
| Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography. 2beta-carbomethoxy-3beta-(3'-((Z)-2-iodoethenyl)phenyl)nortropane (mZIENT, 1) and CHEMICAL (mZBrENT, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (SERT, DAT, and GENE, respectively) using transfected cells. Both 1 and 2 have a high affinity for the SERT (Ki=0.2 nM) and are approximately 160 times more selective for the SERT than the DAT. Compound 2 has a significantly higher affinity for the GENE than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with citalopram and methylphenidate demonstrated that this uptake is the result of preferential binding to the SERT. | DIRECT-REGULATOR |
| Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography. 2beta-carbomethoxy-3beta-(3'-((Z)-2-iodoethenyl)phenyl)nortropane (mZIENT, 1) and 2beta-carbomethoxy-3beta-(3'-((Z)-2-bromoethenyl)phenyl)nortropane (mZBrENT, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (SERT, DAT, and NET, respectively) using transfected cells. Both 1 and 2 have a high affinity for the GENE (Ki=0.2 nM) and are approximately 160 times more selective for the GENE than the DAT. Compound 2 has a significantly higher affinity for the NET than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with CHEMICAL and methylphenidate demonstrated that this uptake is the result of preferential binding to the GENE. | DIRECT-REGULATOR |
| Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography. 2beta-carbomethoxy-3beta-(3'-((Z)-2-iodoethenyl)phenyl)nortropane (mZIENT, 1) and 2beta-carbomethoxy-3beta-(3'-((Z)-2-bromoethenyl)phenyl)nortropane (mZBrENT, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (SERT, DAT, and NET, respectively) using transfected cells. Both 1 and 2 have a high affinity for the GENE (Ki=0.2 nM) and are approximately 160 times more selective for the GENE than the DAT. Compound 2 has a significantly higher affinity for the NET than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with citalopram and CHEMICAL demonstrated that this uptake is the result of preferential binding to the GENE. | DIRECT-REGULATOR |
| Synthesis, radiosynthesis, and biological evaluation of CHEMICAL: candidate radioligands for in vivo imaging of the GENE with positron emission tomography. 2beta-carbomethoxy-3beta-(3'-((Z)-2-iodoethenyl)phenyl)nortropane (mZIENT, 1) and 2beta-carbomethoxy-3beta-(3'-((Z)-2-bromoethenyl)phenyl)nortropane (mZBrENT, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (SERT, DAT, and NET, respectively) using transfected cells. Both 1 and 2 have a high affinity for the SERT (Ki=0.2 nM) and are approximately 160 times more selective for the SERT than the DAT. Compound 2 has a significantly higher affinity for the NET than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with citalopram and methylphenidate demonstrated that this uptake is the result of preferential binding to the SERT. | DIRECT-REGULATOR |
| Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography. CHEMICAL (mZIENT, 1) and 2beta-carbomethoxy-3beta-(3'-((Z)-2-bromoethenyl)phenyl)nortropane (mZBrENT, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (GENE, DAT, and NET, respectively) using transfected cells. Both 1 and 2 have a high affinity for the GENE (Ki=0.2 nM) and are approximately 160 times more selective for the GENE than the DAT. Compound 2 has a significantly higher affinity for the NET than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with citalopram and methylphenidate demonstrated that this uptake is the result of preferential binding to the GENE. | DIRECT-REGULATOR |
| Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography. CHEMICAL (mZIENT, 1) and 2beta-carbomethoxy-3beta-(3'-((Z)-2-bromoethenyl)phenyl)nortropane (mZBrENT, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (SERT, GENE, and NET, respectively) using transfected cells. Both 1 and 2 have a high affinity for the SERT (Ki=0.2 nM) and are approximately 160 times more selective for the SERT than the GENE. Compound 2 has a significantly higher affinity for the NET than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with citalopram and methylphenidate demonstrated that this uptake is the result of preferential binding to the SERT. | DIRECT-REGULATOR |
| Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography. CHEMICAL (mZIENT, 1) and 2beta-carbomethoxy-3beta-(3'-((Z)-2-bromoethenyl)phenyl)nortropane (mZBrENT, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (SERT, DAT, and GENE, respectively) using transfected cells. Both 1 and 2 have a high affinity for the SERT (Ki=0.2 nM) and are approximately 160 times more selective for the SERT than the DAT. Compound 2 has a significantly higher affinity for the GENE than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with citalopram and methylphenidate demonstrated that this uptake is the result of preferential binding to the SERT. | DIRECT-REGULATOR |
| Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography. 2beta-carbomethoxy-3beta-(3'-((Z)-2-iodoethenyl)phenyl)nortropane (mZIENT, 1) and 2beta-carbomethoxy-3beta-(3'-((Z)-2-bromoethenyl)phenyl)nortropane (CHEMICAL, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (GENE, DAT, and NET, respectively) using transfected cells. Both 1 and 2 have a high affinity for the GENE (Ki=0.2 nM) and are approximately 160 times more selective for the GENE than the DAT. Compound 2 has a significantly higher affinity for the NET than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with citalopram and methylphenidate demonstrated that this uptake is the result of preferential binding to the GENE. | DIRECT-REGULATOR |
| Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography. 2beta-carbomethoxy-3beta-(3'-((Z)-2-iodoethenyl)phenyl)nortropane (mZIENT, 1) and 2beta-carbomethoxy-3beta-(3'-((Z)-2-bromoethenyl)phenyl)nortropane (CHEMICAL, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (SERT, GENE, and NET, respectively) using transfected cells. Both 1 and 2 have a high affinity for the SERT (Ki=0.2 nM) and are approximately 160 times more selective for the SERT than the GENE. Compound 2 has a significantly higher affinity for the NET than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with citalopram and methylphenidate demonstrated that this uptake is the result of preferential binding to the SERT. | DIRECT-REGULATOR |
| Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography. 2beta-carbomethoxy-3beta-(3'-((Z)-2-iodoethenyl)phenyl)nortropane (mZIENT, 1) and 2beta-carbomethoxy-3beta-(3'-((Z)-2-bromoethenyl)phenyl)nortropane (CHEMICAL, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (SERT, DAT, and GENE, respectively) using transfected cells. Both 1 and 2 have a high affinity for the SERT (Ki=0.2 nM) and are approximately 160 times more selective for the SERT than the DAT. Compound 2 has a significantly higher affinity for the GENE than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with citalopram and methylphenidate demonstrated that this uptake is the result of preferential binding to the SERT. | DIRECT-REGULATOR |
| Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography. 2beta-carbomethoxy-3beta-(3'-((Z)-2-iodoethenyl)phenyl)nortropane (CHEMICAL, 1) and 2beta-carbomethoxy-3beta-(3'-((Z)-2-bromoethenyl)phenyl)nortropane (mZBrENT, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (GENE, DAT, and NET, respectively) using transfected cells. Both 1 and 2 have a high affinity for the GENE (Ki=0.2 nM) and are approximately 160 times more selective for the GENE than the DAT. Compound 2 has a significantly higher affinity for the NET than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with citalopram and methylphenidate demonstrated that this uptake is the result of preferential binding to the GENE. | DIRECT-REGULATOR |
| Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography. 2beta-carbomethoxy-3beta-(3'-((Z)-2-iodoethenyl)phenyl)nortropane (CHEMICAL, 1) and 2beta-carbomethoxy-3beta-(3'-((Z)-2-bromoethenyl)phenyl)nortropane (mZBrENT, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (SERT, GENE, and NET, respectively) using transfected cells. Both 1 and 2 have a high affinity for the SERT (Ki=0.2 nM) and are approximately 160 times more selective for the SERT than the GENE. Compound 2 has a significantly higher affinity for the NET than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with citalopram and methylphenidate demonstrated that this uptake is the result of preferential binding to the SERT. | DIRECT-REGULATOR |
| Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography. 2beta-carbomethoxy-3beta-(3'-((Z)-2-iodoethenyl)phenyl)nortropane (CHEMICAL, 1) and 2beta-carbomethoxy-3beta-(3'-((Z)-2-bromoethenyl)phenyl)nortropane (mZBrENT, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (SERT, DAT, and GENE, respectively) using transfected cells. Both 1 and 2 have a high affinity for the SERT (Ki=0.2 nM) and are approximately 160 times more selective for the SERT than the DAT. Compound 2 has a significantly higher affinity for the GENE than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [11C]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the SERT-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with citalopram and methylphenidate demonstrated that this uptake is the result of preferential binding to the SERT. | DIRECT-REGULATOR |
| Synthesis, radiosynthesis, and biological evaluation of carbon-11 labeled 2beta-carbomethoxy-3beta-(3'-((Z)-2-haloethenyl)phenyl)nortropanes: candidate radioligands for in vivo imaging of the serotonin transporter with positron emission tomography. 2beta-carbomethoxy-3beta-(3'-((Z)-2-iodoethenyl)phenyl)nortropane (mZIENT, 1) and 2beta-carbomethoxy-3beta-(3'-((Z)-2-bromoethenyl)phenyl)nortropane (mZBrENT, 2) were synthesized and evaluated for binding to the human serotonin, dopamine, and norepinephrine transporters (SERT, DAT, and NET, respectively) using transfected cells. Both 1 and 2 have a high affinity for the GENE (Ki=0.2 nM) and are approximately 160 times more selective for the GENE than the DAT. Compound 2 has a significantly higher affinity for the NET than 1, and this may be a result of the different size and electronegativity of the halogen atoms. MicroPET imaging in nonhuman primates with [CHEMICAL]1 and [11C]2 demonstrated that both tracers behave similarly in vivo with high uptake being observed in the GENE-rich brain regions and peak uptake being achieved in about 55 min postinjection. Chase studies with citalopram and methylphenidate demonstrated that this uptake is the result of preferential binding to the GENE. | DIRECT-REGULATOR |
| Pharmacokinetics of CHEMICAL plus hydrochlorothiazide combination in healthy subjects. BACKGROUND: Hypertension treatment guidelines recommend combination therapy with diuretics and other antihypertensive agents, including angiotensin II type 1 (AT1) receptor antagonists. This trial investigated the possibility of pharmacokinetic interactions between the GENE antagonist CHEMICAL and the thiazide diuretic hydrochlorothiazide in healthy subjects. METHODS: Twenty-four healthy normotensive adult male subjects underwent three consecutive 7-day treatment periods (A, B and C, respectively) during which they were randomised to receive: CHEMICAL 20 mg once daily (regimen A), hydrochlorothiazide 25 mg once daily (regimen B), or CHEMICAL 20 mg once daily plus hydrochlorothiazide 25 mg once daily (regimen C). Treatment periods were separated by washouts of 7-14 days. The primary pharmacokinetic parameters evaluated were: the area under the plasma concentration versus time curve at steady state (AUCss,tau), the maximum plasma concentration at steady state (Css,max), and the time at which Css,max occurred (tmax). RESULTS: Complete data sets from 17 subjects were available for pharmacokinetic analyses. Mean concentration versus time profiles were similar for monotherapy and combination treatment for both olmesartan (the active metabolite of olmesartan medoxomil) and hydrochlorothiazide. For olmesartan, comparison of monotherapy with combination therapy showed that for AUCss,tau and Css,max point estimates were close to unity, demonstrating bioequivalence. For hydrochlorothiazide, combination therapy resulted in decreases in AUCss,tau and Css,max of approximately 10% versus monotherapy; nevertheless, since 90% CIs were within the acceptance range, bioequivalence was proven. Median tmax values for olmesartan and hydrochlorothiazide for periods A, B and C were identical, indicating bioequivalence. Both CHEMICAL and hydrochlorothiazide were well tolerated. CONCLUSION: These results show that there is little or no potential for a clinically relevant pharmacokinetic interaction between CHEMICAL 20 mg and hydrochlorothiazide 25 mg, and therefore dosage adjustment should not be necessary when they are co-administered. | INHIBITOR |
| Effect of cromolyn on GENE interactions with RAGE and pancreatic cancer growth and invasion in mouse models. BACKGROUND: We previously found that GENE, a member of the S100 protein family, is expressed in more than 90% of pancreatic tumors and is associated with tumor growth and invasion. In the current study, we investigated the ability of the antiallergy drug, cromolyn, to block GENE function. METHODS: Interactions between cromolyn and GENE were investigated using a drug affinity column and by examining cromolyn's effects on coimmunoprecipitation of GENE and receptor for advanced glycation end-products (RAGE). The effects of cromolyn on cell growth, invasion, and nuclear factor-kappaB (NFkappaB) activity of pancreatic cancer cells with (BxPC-3 and MPanc-96) and without (Panc-1) endogenous GENE were investigated by cell proliferation assay, by cell invasion assay, and by luciferase reporter gene assay, respectively. The effects of cromolyn on tumor growth in vivo were investigated in three orthotopic models (n = 20 mice per model) by administration of cromolyn (5 mg/kg body weight, daily) with and without CHEMICAL (125 mg/kg body weight, biweekly), the drug currently used to treat pancreatic cancer. Tumor growth was assayed by reporter gene expression. All statistical tests were two-sided. RESULTS: GENE was retained on a cromolyn affinity column. Cromolyn blocked the coimmunoprecipitation of GENE and RAGE. In vitro, cromolyn (100 microM) inhibited S100P-stimulated Panc-1 cell proliferation (S100P, mean = 0.93 U, versus GENE + cromolyn, mean = 0.56 U, difference = 0.37 U; 95% confidence interval [CI] = 0.24 to 0.49 U; P = .001, n = 3), invasion (S100P, mean = 58.0%, versus GENE + cromolyn, mean = 9.4%, difference = 48.6%; 95% CI = 38.8% to 58.8%; P<.001, n = 3), and NFkappaB activity (S100P, mean = 14,460, versus GENE + cromolyn, mean = 7360 photons/s, difference = 7100 photons/s; 95% CI = 3689 to 10 510 photons/s; P = .005, n = 3). In vivo, cromolyn inhibited tumor growth in mice bearing tumor with endogenous GENE (BxPC-3: control, mean = 1.6 x 10(9) photons/s, versus cromolyn, mean = 4.4 x 10(8) photons/s, difference = 1.2 x 10(9) photons/s; 95% CI = 6.2 x 10(8) to 1.6 x 10(9) photons/s; P<.001, n = 5; MPanc-96: control, mean = 1.1 x 10(10) photons/s, versus cromolyn, mean = 4.8 x 10(9) photons/s, difference = 6.2 x 10(9) photons/s; 95% CI = 1.9 x 10(9) to 1.0 x 10(10) photons/s; P = .009, n = 5) and increased the effectiveness of CHEMICAL (BxPC-3: CHEMICAL, mean = 9.2 x 10(8) photons/s, versus combination, mean = 1.8 x 10(8) photons/s, difference = 7.4 x 10(8) photons/s; 95% CI = 4.5 x 10(8) to 1.0 x 10(9) photons/s; P<.001; MPanc-96: CHEMICAL, mean = 4.1 x 10(9) photons/s, versus combination, mean = 2.0 x 10(9) photons/s, difference = 2.1 x 10(9) photons/s; 95% CI = 4.4 x 10(8) to 3.8 x 10(9) photons/s; P<.001). However, cromolyn had no effect on growth of tumors lacking GENE (Panc-1). CONCLUSION: Cromolyn binds GENE, prevents activation of RAGE, inhibits tumor growth, and increases the effectiveness of CHEMICAL in experimental models. | REGULATOR |
| Biosynthesis of selenocysteine on its tRNA in eukaryotes. Selenocysteine (Sec) is cotranslationally inserted into protein in response to UGA codons and is the 21st amino acid in the genetic code. However, the means by which Sec is synthesized in eukaryotes is not known. Herein, comparative genomics and experimental analyses revealed that the mammalian Sec synthase (SecS) is the previously identified pyridoxal phosphate-containing protein known as the soluble liver antigen. SecS required selenophosphate and O-phosphoseryl-tRNA([Ser]Sec) as substrates to generate selenocysteyl-tRNA([Ser]Sec). Moreover, it was found that Sec was synthesized on the tRNA scaffold from selenide, ATP, and serine using tRNA([Ser]Sec), seryl-tRNA synthetase, O-phosphoseryl-tRNA([Ser]Sec) kinase, selenophosphate synthetase, and SecS. By identifying the pathway of Sec biosynthesis in mammals, this study not only functionally characterized SecS but also assigned the function of the O-phosphoseryl-tRNA([Ser]Sec) kinase. In addition, we found that selenophosphate synthetase 2 could synthesize CHEMICAL in vitro but GENE could not. Conservation of the overall pathway of Sec biosynthesis suggests that this pathway is also active in other eukaryotes and archaea that synthesize selenoproteins. | NO-RELATIONSHIP |
| Biosynthesis of selenocysteine on its tRNA in eukaryotes. Selenocysteine (Sec) is cotranslationally inserted into protein in response to UGA codons and is the 21st amino acid in the genetic code. However, the means by which Sec is synthesized in eukaryotes is not known. Herein, comparative genomics and experimental analyses revealed that the GENE (SecS) is the previously identified CHEMICAL-containing protein known as the soluble liver antigen. SecS required selenophosphate and O-phosphoseryl-tRNA([Ser]Sec) as substrates to generate selenocysteyl-tRNA([Ser]Sec). Moreover, it was found that Sec was synthesized on the tRNA scaffold from selenide, ATP, and serine using tRNA([Ser]Sec), seryl-tRNA synthetase, O-phosphoseryl-tRNA([Ser]Sec) kinase, selenophosphate synthetase, and SecS. By identifying the pathway of Sec biosynthesis in mammals, this study not only functionally characterized SecS but also assigned the function of the O-phosphoseryl-tRNA([Ser]Sec) kinase. In addition, we found that selenophosphate synthetase 2 could synthesize monoselenophosphate in vitro but selenophosphate synthetase 1 could not. Conservation of the overall pathway of Sec biosynthesis suggests that this pathway is also active in other eukaryotes and archaea that synthesize selenoproteins. | PART-OF |
| Biosynthesis of selenocysteine on its tRNA in eukaryotes. Selenocysteine (Sec) is cotranslationally inserted into protein in response to UGA codons and is the 21st amino acid in the genetic code. However, the means by which Sec is synthesized in eukaryotes is not known. Herein, comparative genomics and experimental analyses revealed that the mammalian Sec synthase (GENE) is the previously identified CHEMICAL-containing protein known as the soluble liver antigen. GENE required selenophosphate and O-phosphoseryl-tRNA([Ser]Sec) as substrates to generate selenocysteyl-tRNA([Ser]Sec). Moreover, it was found that Sec was synthesized on the tRNA scaffold from selenide, ATP, and serine using tRNA([Ser]Sec), seryl-tRNA synthetase, O-phosphoseryl-tRNA([Ser]Sec) kinase, selenophosphate synthetase, and GENE. By identifying the pathway of Sec biosynthesis in mammals, this study not only functionally characterized GENE but also assigned the function of the O-phosphoseryl-tRNA([Ser]Sec) kinase. In addition, we found that selenophosphate synthetase 2 could synthesize monoselenophosphate in vitro but selenophosphate synthetase 1 could not. Conservation of the overall pathway of Sec biosynthesis suggests that this pathway is also active in other eukaryotes and archaea that synthesize selenoproteins. | PART-OF |
| Biosynthesis of selenocysteine on its tRNA in eukaryotes. Selenocysteine (Sec) is cotranslationally inserted into protein in response to UGA codons and is the 21st amino acid in the genetic code. However, the means by which Sec is synthesized in eukaryotes is not known. Herein, comparative genomics and experimental analyses revealed that the mammalian Sec synthase (SecS) is the previously identified CHEMICAL-containing protein known as the GENE. SecS required selenophosphate and O-phosphoseryl-tRNA([Ser]Sec) as substrates to generate selenocysteyl-tRNA([Ser]Sec). Moreover, it was found that Sec was synthesized on the tRNA scaffold from selenide, ATP, and serine using tRNA([Ser]Sec), seryl-tRNA synthetase, O-phosphoseryl-tRNA([Ser]Sec) kinase, selenophosphate synthetase, and SecS. By identifying the pathway of Sec biosynthesis in mammals, this study not only functionally characterized SecS but also assigned the function of the O-phosphoseryl-tRNA([Ser]Sec) kinase. In addition, we found that selenophosphate synthetase 2 could synthesize monoselenophosphate in vitro but selenophosphate synthetase 1 could not. Conservation of the overall pathway of Sec biosynthesis suggests that this pathway is also active in other eukaryotes and archaea that synthesize selenoproteins. | PART-OF |
| Biosynthesis of selenocysteine on its tRNA in eukaryotes. Selenocysteine (Sec) is cotranslationally inserted into protein in response to UGA codons and is the 21st amino acid in the genetic code. However, the means by which Sec is synthesized in eukaryotes is not known. Herein, comparative genomics and experimental analyses revealed that the mammalian Sec synthase (SecS) is the previously identified pyridoxal phosphate-containing protein known as the soluble liver antigen. GENE required selenophosphate and O-phosphoseryl-tRNA([Ser]Sec) as substrates to generate CHEMICAL-tRNA([Ser]Sec). Moreover, it was found that Sec was synthesized on the tRNA scaffold from selenide, ATP, and serine using tRNA([Ser]Sec), seryl-tRNA synthetase, O-phosphoseryl-tRNA([Ser]Sec) kinase, selenophosphate synthetase, and GENE. By identifying the pathway of Sec biosynthesis in mammals, this study not only functionally characterized GENE but also assigned the function of the O-phosphoseryl-tRNA([Ser]Sec) kinase. In addition, we found that selenophosphate synthetase 2 could synthesize monoselenophosphate in vitro but selenophosphate synthetase 1 could not. Conservation of the overall pathway of Sec biosynthesis suggests that this pathway is also active in other eukaryotes and archaea that synthesize selenoproteins. | PRODUCT-OF |
| Biosynthesis of selenocysteine on its tRNA in eukaryotes. Selenocysteine (Sec) is cotranslationally inserted into protein in response to UGA codons and is the 21st amino acid in the genetic code. However, the means by which Sec is synthesized in eukaryotes is not known. Herein, comparative genomics and experimental analyses revealed that the mammalian Sec synthase (SecS) is the previously identified pyridoxal phosphate-containing protein known as the soluble liver antigen. SecS required selenophosphate and O-phosphoseryl-tRNA([Ser]Sec) as substrates to generate selenocysteyl-tRNA([Ser]Sec). Moreover, it was found that Sec was synthesized on the tRNA scaffold from selenide, ATP, and serine using tRNA([Ser]Sec), seryl-tRNA synthetase, O-phosphoseryl-tRNA([Ser]Sec) kinase, selenophosphate synthetase, and SecS. By identifying the pathway of Sec biosynthesis in mammals, this study not only functionally characterized SecS but also assigned the function of the O-phosphoseryl-tRNA([Ser]Sec) kinase. In addition, we found that GENE could synthesize CHEMICAL in vitro but selenophosphate synthetase 1 could not. Conservation of the overall pathway of Sec biosynthesis suggests that this pathway is also active in other eukaryotes and archaea that synthesize selenoproteins. | PRODUCT-OF |
| Biosynthesis of selenocysteine on its tRNA in eukaryotes. Selenocysteine (Sec) is cotranslationally inserted into protein in response to UGA codons and is the 21st amino acid in the genetic code. However, the means by which Sec is synthesized in eukaryotes is not known. Herein, comparative genomics and experimental analyses revealed that the mammalian Sec synthase (SecS) is the previously identified pyridoxal phosphate-containing protein known as the soluble liver antigen. GENE required selenophosphate and CHEMICAL-tRNA([Ser]Sec) as substrates to generate selenocysteyl-tRNA([Ser]Sec). Moreover, it was found that Sec was synthesized on the tRNA scaffold from selenide, ATP, and serine using tRNA([Ser]Sec), seryl-tRNA synthetase, O-phosphoseryl-tRNA([Ser]Sec) kinase, selenophosphate synthetase, and GENE. By identifying the pathway of Sec biosynthesis in mammals, this study not only functionally characterized GENE but also assigned the function of the O-phosphoseryl-tRNA([Ser]Sec) kinase. In addition, we found that selenophosphate synthetase 2 could synthesize monoselenophosphate in vitro but selenophosphate synthetase 1 could not. Conservation of the overall pathway of Sec biosynthesis suggests that this pathway is also active in other eukaryotes and archaea that synthesize selenoproteins. | SUBSTRATE |
| Biosynthesis of selenocysteine on its tRNA in eukaryotes. Selenocysteine (Sec) is cotranslationally inserted into protein in response to UGA codons and is the 21st amino acid in the genetic code. However, the means by which Sec is synthesized in eukaryotes is not known. Herein, comparative genomics and experimental analyses revealed that the mammalian Sec synthase (SecS) is the previously identified pyridoxal phosphate-containing protein known as the soluble liver antigen. GENE required CHEMICAL and O-phosphoseryl-tRNA([Ser]Sec) as substrates to generate selenocysteyl-tRNA([Ser]Sec). Moreover, it was found that Sec was synthesized on the tRNA scaffold from selenide, ATP, and serine using tRNA([Ser]Sec), seryl-tRNA synthetase, O-phosphoseryl-tRNA([Ser]Sec) kinase, CHEMICAL synthetase, and GENE. By identifying the pathway of Sec biosynthesis in mammals, this study not only functionally characterized GENE but also assigned the function of the O-phosphoseryl-tRNA([Ser]Sec) kinase. In addition, we found that CHEMICAL synthetase 2 could synthesize monoselenophosphate in vitro but CHEMICAL synthetase 1 could not. Conservation of the overall pathway of Sec biosynthesis suggests that this pathway is also active in other eukaryotes and archaea that synthesize selenoproteins. | SUBSTRATE |
| Effects of triflusal and aspirin in a rat model of cerebral ischemia. BACKGROUND AND PURPOSE: Neuroinflammation plays a critical role in the pathogenesis of cerebral ischemia. CHEMICAL, a selective cyclooxygenase-2, and its active metabolite 3-hydroxy-4-trifluoromethylbenzoic acid may inhibit apoptosis and inflammation after cerebral ischemia. An in vivo model of cerebral ischemia was used to investigate the effects of triflusal and aspirin treatment on infarct volume, and inflammation after cerebral ischemia in the rat. METHODS: Male Wistar rats were subjected to a permanent right-sided middle cerebral artery occlusion. Rats received oral administration of either triflusal or aspirin. After 3 days after surgery, immunostaining was used to detect neuroinflammatory cells and molecules, and infarct volumes were measured. RESULTS: Both triflusal and aspirin at a dose of 30 mg/kg but not 10 mg/kg significantly reduced infarct volume compared with vehicle treatment. Middle cerebral artery occlusion resulted in increased astrocyte and heat shock protein-27 (Hsp27) immunostaining in the ipsilateral cortex. CHEMICAL (30 mg/kg) or aspirin treatment (30 mg/kg) did not reduce the levels of GENE or Hsp27 immunostaining. CHEMICAL (30 mg/kg) also significantly decreased the protein levels of IL-Ibeta but not nuclear factor kappa B or tumor necrosis factor-alpha in the cortex ipsilateral to the middle cerebral artery occlusion. CONCLUSIONS: The results suggest that triflusal and aspirin appear to be equally neuroprotective against middle cerebral artery occlusion-induced cerebral ischemia. Therefore, strong rationale exists to continue the neuroprotective examination of triflusal in brain injury. | NO-RELATIONSHIP |
| Effects of triflusal and aspirin in a rat model of cerebral ischemia. BACKGROUND AND PURPOSE: Neuroinflammation plays a critical role in the pathogenesis of cerebral ischemia. CHEMICAL, a selective cyclooxygenase-2, and its active metabolite 3-hydroxy-4-trifluoromethylbenzoic acid may inhibit apoptosis and inflammation after cerebral ischemia. An in vivo model of cerebral ischemia was used to investigate the effects of triflusal and aspirin treatment on infarct volume, and inflammation after cerebral ischemia in the rat. METHODS: Male Wistar rats were subjected to a permanent right-sided middle cerebral artery occlusion. Rats received oral administration of either triflusal or aspirin. After 3 days after surgery, immunostaining was used to detect neuroinflammatory cells and molecules, and infarct volumes were measured. RESULTS: Both triflusal and aspirin at a dose of 30 mg/kg but not 10 mg/kg significantly reduced infarct volume compared with vehicle treatment. Middle cerebral artery occlusion resulted in increased astrocyte and heat shock protein-27 (Hsp27) immunostaining in the ipsilateral cortex. CHEMICAL (30 mg/kg) or aspirin treatment (30 mg/kg) did not reduce the levels of GFAP or GENE immunostaining. CHEMICAL (30 mg/kg) also significantly decreased the protein levels of IL-Ibeta but not nuclear factor kappa B or tumor necrosis factor-alpha in the cortex ipsilateral to the middle cerebral artery occlusion. CONCLUSIONS: The results suggest that triflusal and aspirin appear to be equally neuroprotective against middle cerebral artery occlusion-induced cerebral ischemia. Therefore, strong rationale exists to continue the neuroprotective examination of triflusal in brain injury. | NO-RELATIONSHIP |
| Effects of triflusal and CHEMICAL in a rat model of cerebral ischemia. BACKGROUND AND PURPOSE: Neuroinflammation plays a critical role in the pathogenesis of cerebral ischemia. Triflusal, a selective cyclooxygenase-2, and its active metabolite 3-hydroxy-4-trifluoromethylbenzoic acid may inhibit apoptosis and inflammation after cerebral ischemia. An in vivo model of cerebral ischemia was used to investigate the effects of triflusal and CHEMICAL treatment on infarct volume, and inflammation after cerebral ischemia in the rat. METHODS: Male Wistar rats were subjected to a permanent right-sided middle cerebral artery occlusion. Rats received oral administration of either triflusal or CHEMICAL. After 3 days after surgery, immunostaining was used to detect neuroinflammatory cells and molecules, and infarct volumes were measured. RESULTS: Both triflusal and CHEMICAL at a dose of 30 mg/kg but not 10 mg/kg significantly reduced infarct volume compared with vehicle treatment. Middle cerebral artery occlusion resulted in increased astrocyte and heat shock protein-27 (Hsp27) immunostaining in the ipsilateral cortex. Triflusal (30 mg/kg) or CHEMICAL treatment (30 mg/kg) did not reduce the levels of GENE or Hsp27 immunostaining. Triflusal (30 mg/kg) also significantly decreased the protein levels of IL-Ibeta but not nuclear factor kappa B or tumor necrosis factor-alpha in the cortex ipsilateral to the middle cerebral artery occlusion. CONCLUSIONS: The results suggest that triflusal and CHEMICAL appear to be equally neuroprotective against middle cerebral artery occlusion-induced cerebral ischemia. Therefore, strong rationale exists to continue the neuroprotective examination of triflusal in brain injury. | NO-RELATIONSHIP |
| Effects of triflusal and CHEMICAL in a rat model of cerebral ischemia. BACKGROUND AND PURPOSE: Neuroinflammation plays a critical role in the pathogenesis of cerebral ischemia. Triflusal, a selective cyclooxygenase-2, and its active metabolite 3-hydroxy-4-trifluoromethylbenzoic acid may inhibit apoptosis and inflammation after cerebral ischemia. An in vivo model of cerebral ischemia was used to investigate the effects of triflusal and CHEMICAL treatment on infarct volume, and inflammation after cerebral ischemia in the rat. METHODS: Male Wistar rats were subjected to a permanent right-sided middle cerebral artery occlusion. Rats received oral administration of either triflusal or CHEMICAL. After 3 days after surgery, immunostaining was used to detect neuroinflammatory cells and molecules, and infarct volumes were measured. RESULTS: Both triflusal and CHEMICAL at a dose of 30 mg/kg but not 10 mg/kg significantly reduced infarct volume compared with vehicle treatment. Middle cerebral artery occlusion resulted in increased astrocyte and heat shock protein-27 (Hsp27) immunostaining in the ipsilateral cortex. Triflusal (30 mg/kg) or CHEMICAL treatment (30 mg/kg) did not reduce the levels of GFAP or GENE immunostaining. Triflusal (30 mg/kg) also significantly decreased the protein levels of IL-Ibeta but not nuclear factor kappa B or tumor necrosis factor-alpha in the cortex ipsilateral to the middle cerebral artery occlusion. CONCLUSIONS: The results suggest that triflusal and CHEMICAL appear to be equally neuroprotective against middle cerebral artery occlusion-induced cerebral ischemia. Therefore, strong rationale exists to continue the neuroprotective examination of triflusal in brain injury. | NO-RELATIONSHIP |
| Effects of triflusal and aspirin in a rat model of cerebral ischemia. BACKGROUND AND PURPOSE: Neuroinflammation plays a critical role in the pathogenesis of cerebral ischemia. CHEMICAL, a selective cyclooxygenase-2, and its active metabolite 3-hydroxy-4-trifluoromethylbenzoic acid may inhibit apoptosis and inflammation after cerebral ischemia. An in vivo model of cerebral ischemia was used to investigate the effects of triflusal and aspirin treatment on infarct volume, and inflammation after cerebral ischemia in the rat. METHODS: Male Wistar rats were subjected to a permanent right-sided middle cerebral artery occlusion. Rats received oral administration of either triflusal or aspirin. After 3 days after surgery, immunostaining was used to detect neuroinflammatory cells and molecules, and infarct volumes were measured. RESULTS: Both triflusal and aspirin at a dose of 30 mg/kg but not 10 mg/kg significantly reduced infarct volume compared with vehicle treatment. Middle cerebral artery occlusion resulted in increased astrocyte and heat shock protein-27 (Hsp27) immunostaining in the ipsilateral cortex. CHEMICAL (30 mg/kg) or aspirin treatment (30 mg/kg) did not reduce the levels of GFAP or Hsp27 immunostaining. CHEMICAL (30 mg/kg) also significantly decreased the protein levels of IL-Ibeta but not GENE or tumor necrosis factor-alpha in the cortex ipsilateral to the middle cerebral artery occlusion. CONCLUSIONS: The results suggest that triflusal and aspirin appear to be equally neuroprotective against middle cerebral artery occlusion-induced cerebral ischemia. Therefore, strong rationale exists to continue the neuroprotective examination of triflusal in brain injury. | NO-RELATIONSHIP |
| Effects of triflusal and aspirin in a rat model of cerebral ischemia. BACKGROUND AND PURPOSE: Neuroinflammation plays a critical role in the pathogenesis of cerebral ischemia. CHEMICAL, a selective cyclooxygenase-2, and its active metabolite 3-hydroxy-4-trifluoromethylbenzoic acid may inhibit apoptosis and inflammation after cerebral ischemia. An in vivo model of cerebral ischemia was used to investigate the effects of triflusal and aspirin treatment on infarct volume, and inflammation after cerebral ischemia in the rat. METHODS: Male Wistar rats were subjected to a permanent right-sided middle cerebral artery occlusion. Rats received oral administration of either triflusal or aspirin. After 3 days after surgery, immunostaining was used to detect neuroinflammatory cells and molecules, and infarct volumes were measured. RESULTS: Both triflusal and aspirin at a dose of 30 mg/kg but not 10 mg/kg significantly reduced infarct volume compared with vehicle treatment. Middle cerebral artery occlusion resulted in increased astrocyte and heat shock protein-27 (Hsp27) immunostaining in the ipsilateral cortex. CHEMICAL (30 mg/kg) or aspirin treatment (30 mg/kg) did not reduce the levels of GFAP or Hsp27 immunostaining. CHEMICAL (30 mg/kg) also significantly decreased the protein levels of IL-Ibeta but not nuclear factor kappa B or GENE in the cortex ipsilateral to the middle cerebral artery occlusion. CONCLUSIONS: The results suggest that triflusal and aspirin appear to be equally neuroprotective against middle cerebral artery occlusion-induced cerebral ischemia. Therefore, strong rationale exists to continue the neuroprotective examination of triflusal in brain injury. | NO-RELATIONSHIP |
| Effects of triflusal and aspirin in a rat model of cerebral ischemia. BACKGROUND AND PURPOSE: Neuroinflammation plays a critical role in the pathogenesis of cerebral ischemia. CHEMICAL, a selective GENE, and its active metabolite 3-hydroxy-4-trifluoromethylbenzoic acid may inhibit apoptosis and inflammation after cerebral ischemia. An in vivo model of cerebral ischemia was used to investigate the effects of triflusal and aspirin treatment on infarct volume, and inflammation after cerebral ischemia in the rat. METHODS: Male Wistar rats were subjected to a permanent right-sided middle cerebral artery occlusion. Rats received oral administration of either triflusal or aspirin. After 3 days after surgery, immunostaining was used to detect neuroinflammatory cells and molecules, and infarct volumes were measured. RESULTS: Both triflusal and aspirin at a dose of 30 mg/kg but not 10 mg/kg significantly reduced infarct volume compared with vehicle treatment. Middle cerebral artery occlusion resulted in increased astrocyte and heat shock protein-27 (Hsp27) immunostaining in the ipsilateral cortex. CHEMICAL (30 mg/kg) or aspirin treatment (30 mg/kg) did not reduce the levels of GFAP or Hsp27 immunostaining. CHEMICAL (30 mg/kg) also significantly decreased the protein levels of IL-Ibeta but not nuclear factor kappa B or tumor necrosis factor-alpha in the cortex ipsilateral to the middle cerebral artery occlusion. CONCLUSIONS: The results suggest that triflusal and aspirin appear to be equally neuroprotective against middle cerebral artery occlusion-induced cerebral ischemia. Therefore, strong rationale exists to continue the neuroprotective examination of triflusal in brain injury. | REGULATOR |
| Effects of triflusal and aspirin in a rat model of cerebral ischemia. BACKGROUND AND PURPOSE: Neuroinflammation plays a critical role in the pathogenesis of cerebral ischemia. Triflusal, a selective GENE, and its active metabolite CHEMICAL may inhibit apoptosis and inflammation after cerebral ischemia. An in vivo model of cerebral ischemia was used to investigate the effects of triflusal and aspirin treatment on infarct volume, and inflammation after cerebral ischemia in the rat. METHODS: Male Wistar rats were subjected to a permanent right-sided middle cerebral artery occlusion. Rats received oral administration of either triflusal or aspirin. After 3 days after surgery, immunostaining was used to detect neuroinflammatory cells and molecules, and infarct volumes were measured. RESULTS: Both triflusal and aspirin at a dose of 30 mg/kg but not 10 mg/kg significantly reduced infarct volume compared with vehicle treatment. Middle cerebral artery occlusion resulted in increased astrocyte and heat shock protein-27 (Hsp27) immunostaining in the ipsilateral cortex. Triflusal (30 mg/kg) or aspirin treatment (30 mg/kg) did not reduce the levels of GFAP or Hsp27 immunostaining. Triflusal (30 mg/kg) also significantly decreased the protein levels of IL-Ibeta but not nuclear factor kappa B or tumor necrosis factor-alpha in the cortex ipsilateral to the middle cerebral artery occlusion. CONCLUSIONS: The results suggest that triflusal and aspirin appear to be equally neuroprotective against middle cerebral artery occlusion-induced cerebral ischemia. Therefore, strong rationale exists to continue the neuroprotective examination of triflusal in brain injury. | INHIBITOR |
| Effects of triflusal and aspirin in a rat model of cerebral ischemia. BACKGROUND AND PURPOSE: Neuroinflammation plays a critical role in the pathogenesis of cerebral ischemia. CHEMICAL, a selective cyclooxygenase-2, and its active metabolite 3-hydroxy-4-trifluoromethylbenzoic acid may inhibit apoptosis and inflammation after cerebral ischemia. An in vivo model of cerebral ischemia was used to investigate the effects of triflusal and aspirin treatment on infarct volume, and inflammation after cerebral ischemia in the rat. METHODS: Male Wistar rats were subjected to a permanent right-sided middle cerebral artery occlusion. Rats received oral administration of either triflusal or aspirin. After 3 days after surgery, immunostaining was used to detect neuroinflammatory cells and molecules, and infarct volumes were measured. RESULTS: Both triflusal and aspirin at a dose of 30 mg/kg but not 10 mg/kg significantly reduced infarct volume compared with vehicle treatment. Middle cerebral artery occlusion resulted in increased astrocyte and heat shock protein-27 (Hsp27) immunostaining in the ipsilateral cortex. CHEMICAL (30 mg/kg) or aspirin treatment (30 mg/kg) did not reduce the levels of GFAP or Hsp27 immunostaining. CHEMICAL (30 mg/kg) also significantly decreased the protein levels of GENE but not nuclear factor kappa B or tumor necrosis factor-alpha in the cortex ipsilateral to the middle cerebral artery occlusion. CONCLUSIONS: The results suggest that triflusal and aspirin appear to be equally neuroprotective against middle cerebral artery occlusion-induced cerebral ischemia. Therefore, strong rationale exists to continue the neuroprotective examination of triflusal in brain injury. | INDIRECT-DOWNREGULATOR |
| Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GENE, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GENE by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GENE reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by CHEMICAL (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GENE degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GENE by RNAi against GENE reduced surface GluR2 in neurons. Our results suggest that glutamate induces GENE degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GENE degradation may play an important role in regulating GluR2 surface expression. | NO-RELATIONSHIP |
| Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GENE, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GENE by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GENE reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CHEMICAL), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GENE degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GENE by RNAi against GENE reduced surface GluR2 in neurons. Our results suggest that glutamate induces GENE degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GENE degradation may play an important role in regulating GluR2 surface expression. | NO-RELATIONSHIP |
| Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GENE, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GENE by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GENE reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not CHEMICAL, an L-type Ca2+ channel blocker, prevented GENE degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GENE by RNAi against GENE reduced surface GluR2 in neurons. Our results suggest that glutamate induces GENE degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GENE degradation may play an important role in regulating GluR2 surface expression. | NO-RELATIONSHIP |
| CHEMICAL stimulates CHEMICAL receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The CHEMICAL receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that CHEMICAL stimulation caused a rapid reduction in protein levels of GRIP1, but not that of CHEMICAL receptor GENE, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GRIP1 by CHEMICAL was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GRIP1 reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GRIP1 degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GRIP1 by RNAi against GRIP1 reduced surface GluR2 in neurons. Our results suggest that CHEMICAL induces GRIP1 degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GRIP1 degradation may play an important role in regulating GluR2 surface expression. | NO-RELATIONSHIP |
| CHEMICAL stimulates CHEMICAL receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GENE. The CHEMICAL receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that CHEMICAL stimulation caused a rapid reduction in protein levels of GRIP1, but not that of CHEMICAL receptor (GluR) 1, GENE and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GRIP1 by CHEMICAL was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GRIP1 reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GRIP1 degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GENE, and knockdown of GRIP1 by RNAi against GRIP1 reduced surface GENE in neurons. Our results suggest that CHEMICAL induces GRIP1 degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GRIP1 degradation may play an important role in regulating GENE surface expression. | NO-RELATIONSHIP |
| CHEMICAL stimulates CHEMICAL receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The CHEMICAL receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that CHEMICAL stimulation caused a rapid reduction in protein levels of GRIP1, but not that of CHEMICAL receptor (GluR) 1, GluR2 and GENE (PICK1) in rat primary cortical neuron cultures. Down-regulation of GRIP1 by CHEMICAL was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GRIP1 reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GRIP1 degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GRIP1 by RNAi against GRIP1 reduced surface GluR2 in neurons. Our results suggest that CHEMICAL induces GRIP1 degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GRIP1 degradation may play an important role in regulating GluR2 surface expression. | NO-RELATIONSHIP |
| CHEMICAL stimulates CHEMICAL receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The CHEMICAL receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that CHEMICAL stimulation caused a rapid reduction in protein levels of GRIP1, but not that of CHEMICAL receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (GENE) in rat primary cortical neuron cultures. Down-regulation of GRIP1 by CHEMICAL was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GRIP1 reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GRIP1 degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GRIP1 by RNAi against GRIP1 reduced surface GluR2 in neurons. Our results suggest that CHEMICAL induces GRIP1 degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GRIP1 degradation may play an important role in regulating GluR2 surface expression. | NO-RELATIONSHIP |
| Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GENE. The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GRIP1, but not that of glutamate receptor (GluR) 1, GENE and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GRIP1 by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GRIP1 reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GRIP1 degradation. Furthermore, CHEMICAL prevented glutamate-stimulated reduction in surface amount of GENE, and knockdown of GRIP1 by RNAi against GRIP1 reduced surface GENE in neurons. Our results suggest that glutamate induces GRIP1 degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GRIP1 degradation may play an important role in regulating GENE surface expression. | INDIRECT-DOWNREGULATOR |
| Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GENE, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GENE by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (CHEMICAL), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GENE reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GENE degradation. Furthermore, CHEMICAL prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GENE by RNAi against GENE reduced surface GluR2 in neurons. Our results suggest that glutamate induces GENE degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GENE degradation may play an important role in regulating GluR2 surface expression. | INHIBITOR |
| CHEMICAL stimulates CHEMICAL receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The CHEMICAL receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that CHEMICAL stimulation caused a rapid reduction in protein levels of GRIP1, but not that of CHEMICAL receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GRIP1 by CHEMICAL was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a GENE inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GRIP1 reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GRIP1 degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GRIP1 by RNAi against GRIP1 reduced surface GluR2 in neurons. Our results suggest that CHEMICAL induces GRIP1 degradation by GENE through an NMDA receptor-Ca2+ pathway and that GRIP1 degradation may play an important role in regulating GluR2 surface expression. | INDIRECT-UPREGULATOR |
| CHEMICAL stimulates CHEMICAL receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The CHEMICAL receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that CHEMICAL stimulation caused a rapid reduction in protein levels of GRIP1, but not that of CHEMICAL receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GRIP1 by CHEMICAL was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GRIP1 reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GRIP1 degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GRIP1 by RNAi against GRIP1 reduced surface GluR2 in neurons. Our results suggest that CHEMICAL induces GRIP1 degradation by proteasome through an GENE-Ca2+ pathway and that GRIP1 degradation may play an important role in regulating GluR2 surface expression. | REGULATOR |
| CHEMICAL stimulates glutamate receptor interacting protein 1 degradation by GENE-proteasome system to regulate surface expression of GluR2. The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GRIP1, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GRIP1 by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of GENE. The GRIP1 reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GRIP1 degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GRIP1 by RNAi against GRIP1 reduced surface GluR2 in neurons. Our results suggest that glutamate induces GRIP1 degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GRIP1 degradation may play an important role in regulating GluR2 surface expression. | GENE-CHEMICAL |
| Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GENE, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GENE by glutamate was blocked by CHEMICAL (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GENE reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GENE degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GENE by RNAi against GENE reduced surface GluR2 in neurons. Our results suggest that glutamate induces GENE degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GENE degradation may play an important role in regulating GluR2 surface expression. | INHIBITOR |
| Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GENE, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GENE by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GENE reduction was inhibited by CHEMICAL, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GENE degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GENE by RNAi against GENE reduced surface GluR2 in neurons. Our results suggest that glutamate induces GENE degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GENE degradation may play an important role in regulating GluR2 surface expression. | INHIBITOR |
| Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GENE, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GENE by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GENE reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. CHEMICAL and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GENE degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GENE by RNAi against GENE reduced surface GluR2 in neurons. Our results suggest that glutamate induces GENE degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GENE degradation may play an important role in regulating GluR2 surface expression. | INDIRECT-UPREGULATOR |
| Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GENE, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GENE by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GENE reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and CHEMICAL (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GENE degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GENE by RNAi against GENE reduced surface GluR2 in neurons. Our results suggest that glutamate induces GENE degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GENE degradation may play an important role in regulating GluR2 surface expression. | INDIRECT-UPREGULATOR |
| Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GENE, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GENE by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GENE reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (CHEMICAL), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GENE degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GENE by RNAi against GENE reduced surface GluR2 in neurons. Our results suggest that glutamate induces GENE degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GENE degradation may play an important role in regulating GluR2 surface expression. | INDIRECT-UPREGULATOR |
| CHEMICAL stimulates CHEMICAL receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The CHEMICAL receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that CHEMICAL stimulation caused a rapid reduction in protein levels of GENE, but not that of CHEMICAL receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GENE by CHEMICAL was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GENE reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GENE degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GENE by RNAi against GENE reduced surface GluR2 in neurons. Our results suggest that CHEMICAL induces GENE degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GENE degradation may play an important role in regulating GluR2 surface expression. | GENE-CHEMICAL |
| CHEMICAL stimulates GENE degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The GENE (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GRIP1, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GRIP1 by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GRIP1 reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GRIP1 degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GRIP1 by RNAi against GRIP1 reduced surface GluR2 in neurons. Our results suggest that glutamate induces GRIP1 degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GRIP1 degradation may play an important role in regulating GluR2 surface expression. | INDIRECT-UPREGULATOR |
| Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GRIP1, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GRIP1 by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (CHEMICAL), a GENE inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GRIP1 reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GRIP1 degradation. Furthermore, CHEMICAL prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GRIP1 by RNAi against GRIP1 reduced surface GluR2 in neurons. Our results suggest that glutamate induces GRIP1 degradation by GENE through an NMDA receptor-Ca2+ pathway and that GRIP1 degradation may play an important role in regulating GluR2 surface expression. | INHIBITOR |
| Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GRIP1, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GRIP1 by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GRIP1 reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not CHEMICAL, an GENE blocker, prevented GRIP1 degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GRIP1 by RNAi against GRIP1 reduced surface GluR2 in neurons. Our results suggest that glutamate induces GRIP1 degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GRIP1 degradation may play an important role in regulating GluR2 surface expression. | INHIBITOR |
| Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GRIP1, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GRIP1 by glutamate was blocked by CHEMICAL (MG132), a GENE inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GRIP1 reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GRIP1 degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GRIP1 by RNAi against GRIP1 reduced surface GluR2 in neurons. Our results suggest that glutamate induces GRIP1 degradation by GENE through an NMDA receptor-Ca2+ pathway and that GRIP1 degradation may play an important role in regulating GluR2 surface expression. | INHIBITOR |
| Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GRIP1, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GRIP1 by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GRIP1 reduction was inhibited by CHEMICAL, an GENE antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GRIP1 degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GRIP1 by RNAi against GRIP1 reduced surface GluR2 in neurons. Our results suggest that glutamate induces GRIP1 degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GRIP1 degradation may play an important role in regulating GluR2 surface expression. | INHIBITOR |
| Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GRIP1, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GRIP1 by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GRIP1 reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by CHEMICAL (CNQX), an GENE antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GRIP1 degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GRIP1 by RNAi against GRIP1 reduced surface GluR2 in neurons. Our results suggest that glutamate induces GRIP1 degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GRIP1 degradation may play an important role in regulating GluR2 surface expression. | INHIBITOR |
| Glutamate stimulates glutamate receptor interacting protein 1 degradation by ubiquitin-proteasome system to regulate surface expression of GluR2. The glutamate receptor interacting protein 1 (GRIP1) is a scaffolding protein in postsynaptic density (PSD), tethering AMPA receptors to other signaling proteins. Here we report that glutamate stimulation caused a rapid reduction in protein levels of GRIP1, but not that of glutamate receptor (GluR) 1, GluR2 and protein interacting with C kinase 1 (PICK1) in rat primary cortical neuron cultures. Down-regulation of GRIP1 by glutamate was blocked by carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132), a proteasome inhibitor and by expression of K48R-ubiquitin, a dominant negative form of ubiquitin. The GRIP1 reduction was inhibited by MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CHEMICAL), an GENE antagonist. EGTA and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra acetic acid tetrakis (BAPTA), two Ca2+ chelators, but not nifedipine, an L-type Ca2+ channel blocker, prevented GRIP1 degradation. Furthermore, MG132 prevented glutamate-stimulated reduction in surface amount of GluR2, and knockdown of GRIP1 by RNAi against GRIP1 reduced surface GluR2 in neurons. Our results suggest that glutamate induces GRIP1 degradation by proteasome through an NMDA receptor-Ca2+ pathway and that GRIP1 degradation may play an important role in regulating GluR2 surface expression. | INHIBITOR |
| The inhibitory effect of the leukotriene receptor antagonist on leukotriene D4-induced MUC2/5AC gene expression and GENE secretion in human airway epithelial cells. OBJECTIVES: GENE gene expression and GENE production are markedly increased in inflammatory airway disorders such as asthma, chronic bronchitis and rhinosinusitis. Cytokines, lipopolysaccharides and other inflammatory mediators such as CHEMICAL and leukotriene are related to the secretion and production of GENE. However, the relationship of leukotrienes with GENE genes expression is not clear. The aim of this study is to evaluate MUC2/5AC gene expression and GENE secretion by the leukotriene receptor in human airway epithelial cells. METHODS: The effect of leukotriene D(4) and the leukotriene receptor antagonist, pranlukast hydrate (ONO-1078) on the regulation of MUC2/5AC gene expression and GENE secretion were observed in human airway NCI-H292 epithelial cells. The mRNA levels of MUC2/5AC and the amount of GENE were determined by reverse transcription-polymerase chain reaction (RT-PCR) and immunoassay. RESULTS: Leukotriene D(4) upregulated MUC2/5AC gene expression and GENE secretion in a dose dependent pattern. Pranlukast hydrate (ONO-1078, 100 microM) downregulated the leukotriene D(4)-induced MUC2/5AC gene expression and GENE secretion. CONCLUSION: These results suggest that the leukotriene receptor system is one of the mechanisms related to MUC2/5AC gene expression and GENE secretion in the human airway epithelium. | GENE-CHEMICAL |
| The inhibitory effect of the CHEMICAL receptor antagonist on CHEMICAL D4-induced MUC2/5AC gene expression and GENE secretion in human airway epithelial cells. OBJECTIVES: GENE gene expression and GENE production are markedly increased in inflammatory airway disorders such as asthma, chronic bronchitis and rhinosinusitis. Cytokines, lipopolysaccharides and other inflammatory mediators such as prostaglandin and CHEMICAL are related to the secretion and production of GENE. However, the relationship of leukotrienes with GENE genes expression is not clear. The aim of this study is to evaluate MUC2/5AC gene expression and GENE secretion by the CHEMICAL receptor in human airway epithelial cells. METHODS: The effect of CHEMICAL D(4) and the CHEMICAL receptor antagonist, pranlukast hydrate (ONO-1078) on the regulation of MUC2/5AC gene expression and GENE secretion were observed in human airway NCI-H292 epithelial cells. The mRNA levels of MUC2/5AC and the amount of GENE were determined by reverse transcription-polymerase chain reaction (RT-PCR) and immunoassay. RESULTS: CHEMICAL D(4) upregulated MUC2/5AC gene expression and GENE secretion in a dose dependent pattern. Pranlukast hydrate (ONO-1078, 100 microM) downregulated the CHEMICAL D(4)-induced MUC2/5AC gene expression and GENE secretion. CONCLUSION: These results suggest that the CHEMICAL receptor system is one of the mechanisms related to MUC2/5AC gene expression and GENE secretion in the human airway epithelium. | GENE-CHEMICAL |
| The inhibitory effect of the leukotriene receptor antagonist on leukotriene D4-induced MUC2/5AC gene expression and GENE secretion in human airway epithelial cells. OBJECTIVES: GENE gene expression and GENE production are markedly increased in inflammatory airway disorders such as asthma, chronic bronchitis and rhinosinusitis. Cytokines, lipopolysaccharides and other inflammatory mediators such as prostaglandin and leukotriene are related to the secretion and production of GENE. However, the relationship of CHEMICAL with GENE genes expression is not clear. The aim of this study is to evaluate MUC2/5AC gene expression and GENE secretion by the leukotriene receptor in human airway epithelial cells. METHODS: The effect of leukotriene D(4) and the leukotriene receptor antagonist, pranlukast hydrate (ONO-1078) on the regulation of MUC2/5AC gene expression and GENE secretion were observed in human airway NCI-H292 epithelial cells. The mRNA levels of MUC2/5AC and the amount of GENE were determined by reverse transcription-polymerase chain reaction (RT-PCR) and immunoassay. RESULTS: Leukotriene D(4) upregulated MUC2/5AC gene expression and GENE secretion in a dose dependent pattern. Pranlukast hydrate (ONO-1078, 100 microM) downregulated the leukotriene D(4)-induced MUC2/5AC gene expression and GENE secretion. CONCLUSION: These results suggest that the leukotriene receptor system is one of the mechanisms related to MUC2/5AC gene expression and GENE secretion in the human airway epithelium. | GENE-CHEMICAL |
| The inhibitory effect of the leukotriene receptor antagonist on leukotriene D4-induced GENE gene expression and mucin secretion in human airway epithelial cells. OBJECTIVES: Mucin gene expression and mucin production are markedly increased in inflammatory airway disorders such as asthma, chronic bronchitis and rhinosinusitis. Cytokines, lipopolysaccharides and other inflammatory mediators such as prostaglandin and leukotriene are related to the secretion and production of mucin. However, the relationship of leukotrienes with mucin genes expression is not clear. The aim of this study is to evaluate GENE gene expression and mucin secretion by the leukotriene receptor in human airway epithelial cells. METHODS: The effect of leukotriene D(4) and the leukotriene receptor antagonist, pranlukast hydrate (ONO-1078) on the regulation of GENE gene expression and mucin secretion were observed in human airway NCI-H292 epithelial cells. The mRNA levels of GENE and the amount of mucin were determined by reverse transcription-polymerase chain reaction (RT-PCR) and immunoassay. RESULTS: CHEMICAL upregulated GENE gene expression and mucin secretion in a dose dependent pattern. Pranlukast hydrate (ONO-1078, 100 microM) downregulated the leukotriene D(4)-induced GENE gene expression and mucin secretion. CONCLUSION: These results suggest that the leukotriene receptor system is one of the mechanisms related to GENE gene expression and mucin secretion in the human airway epithelium. | INDIRECT-UPREGULATOR |
| The inhibitory effect of the leukotriene receptor antagonist on leukotriene D4-induced MUC2/5AC gene expression and GENE secretion in human airway epithelial cells. OBJECTIVES: GENE gene expression and GENE production are markedly increased in inflammatory airway disorders such as asthma, chronic bronchitis and rhinosinusitis. Cytokines, lipopolysaccharides and other inflammatory mediators such as prostaglandin and leukotriene are related to the secretion and production of GENE. However, the relationship of leukotrienes with GENE genes expression is not clear. The aim of this study is to evaluate MUC2/5AC gene expression and GENE secretion by the leukotriene receptor in human airway epithelial cells. METHODS: The effect of leukotriene D(4) and the leukotriene receptor antagonist, pranlukast hydrate (ONO-1078) on the regulation of MUC2/5AC gene expression and GENE secretion were observed in human airway NCI-H292 epithelial cells. The mRNA levels of MUC2/5AC and the amount of GENE were determined by reverse transcription-polymerase chain reaction (RT-PCR) and immunoassay. RESULTS: CHEMICAL upregulated MUC2/5AC gene expression and GENE secretion in a dose dependent pattern. Pranlukast hydrate (ONO-1078, 100 microM) downregulated the leukotriene D(4)-induced MUC2/5AC gene expression and GENE secretion. CONCLUSION: These results suggest that the leukotriene receptor system is one of the mechanisms related to MUC2/5AC gene expression and GENE secretion in the human airway epithelium. | INDIRECT-UPREGULATOR |
| The inhibitory effect of the leukotriene receptor antagonist on CHEMICAL-induced MUC2/5AC gene expression and GENE secretion in human airway epithelial cells. OBJECTIVES: GENE gene expression and GENE production are markedly increased in inflammatory airway disorders such as asthma, chronic bronchitis and rhinosinusitis. Cytokines, lipopolysaccharides and other inflammatory mediators such as prostaglandin and leukotriene are related to the secretion and production of GENE. However, the relationship of leukotrienes with GENE genes expression is not clear. The aim of this study is to evaluate MUC2/5AC gene expression and GENE secretion by the leukotriene receptor in human airway epithelial cells. METHODS: The effect of leukotriene D(4) and the leukotriene receptor antagonist, pranlukast hydrate (ONO-1078) on the regulation of MUC2/5AC gene expression and GENE secretion were observed in human airway NCI-H292 epithelial cells. The mRNA levels of MUC2/5AC and the amount of GENE were determined by reverse transcription-polymerase chain reaction (RT-PCR) and immunoassay. RESULTS: Leukotriene D(4) upregulated MUC2/5AC gene expression and GENE secretion in a dose dependent pattern. Pranlukast hydrate (ONO-1078, 100 microM) downregulated the leukotriene D(4)-induced MUC2/5AC gene expression and GENE secretion. CONCLUSION: These results suggest that the leukotriene receptor system is one of the mechanisms related to MUC2/5AC gene expression and GENE secretion in the human airway epithelium. | INDIRECT-UPREGULATOR |
| The inhibitory effect of the leukotriene receptor antagonist on CHEMICAL-induced GENE gene expression and mucin secretion in human airway epithelial cells. OBJECTIVES: Mucin gene expression and mucin production are markedly increased in inflammatory airway disorders such as asthma, chronic bronchitis and rhinosinusitis. Cytokines, lipopolysaccharides and other inflammatory mediators such as prostaglandin and leukotriene are related to the secretion and production of mucin. However, the relationship of leukotrienes with mucin genes expression is not clear. The aim of this study is to evaluate GENE gene expression and mucin secretion by the leukotriene receptor in human airway epithelial cells. METHODS: The effect of leukotriene D(4) and the leukotriene receptor antagonist, pranlukast hydrate (ONO-1078) on the regulation of GENE gene expression and mucin secretion were observed in human airway NCI-H292 epithelial cells. The mRNA levels of GENE and the amount of mucin were determined by reverse transcription-polymerase chain reaction (RT-PCR) and immunoassay. RESULTS: Leukotriene D(4) upregulated GENE gene expression and mucin secretion in a dose dependent pattern. Pranlukast hydrate (ONO-1078, 100 microM) downregulated the leukotriene D(4)-induced GENE gene expression and mucin secretion. CONCLUSION: These results suggest that the leukotriene receptor system is one of the mechanisms related to GENE gene expression and mucin secretion in the human airway epithelium. | INDIRECT-UPREGULATOR |
| The inhibitory effect of the leukotriene receptor antagonist on leukotriene D4-induced GENE gene expression and mucin secretion in human airway epithelial cells. OBJECTIVES: Mucin gene expression and mucin production are markedly increased in inflammatory airway disorders such as asthma, chronic bronchitis and rhinosinusitis. Cytokines, lipopolysaccharides and other inflammatory mediators such as prostaglandin and leukotriene are related to the secretion and production of mucin. However, the relationship of leukotrienes with mucin genes expression is not clear. The aim of this study is to evaluate GENE gene expression and mucin secretion by the leukotriene receptor in human airway epithelial cells. METHODS: The effect of CHEMICAL and the leukotriene receptor antagonist, pranlukast hydrate (ONO-1078) on the regulation of GENE gene expression and mucin secretion were observed in human airway NCI-H292 epithelial cells. The mRNA levels of GENE and the amount of mucin were determined by reverse transcription-polymerase chain reaction (RT-PCR) and immunoassay. RESULTS: Leukotriene D(4) upregulated GENE gene expression and mucin secretion in a dose dependent pattern. Pranlukast hydrate (ONO-1078, 100 microM) downregulated the CHEMICAL-induced GENE gene expression and mucin secretion. CONCLUSION: These results suggest that the leukotriene receptor system is one of the mechanisms related to GENE gene expression and mucin secretion in the human airway epithelium. | GENE-CHEMICAL |
| The inhibitory effect of the leukotriene receptor antagonist on leukotriene D4-induced GENE gene expression and mucin secretion in human airway epithelial cells. OBJECTIVES: Mucin gene expression and mucin production are markedly increased in inflammatory airway disorders such as asthma, chronic bronchitis and rhinosinusitis. Cytokines, lipopolysaccharides and other inflammatory mediators such as prostaglandin and leukotriene are related to the secretion and production of mucin. However, the relationship of leukotrienes with mucin genes expression is not clear. The aim of this study is to evaluate GENE gene expression and mucin secretion by the leukotriene receptor in human airway epithelial cells. METHODS: The effect of leukotriene D(4) and the leukotriene receptor antagonist, pranlukast hydrate (ONO-1078) on the regulation of GENE gene expression and mucin secretion were observed in human airway NCI-H292 epithelial cells. The mRNA levels of GENE and the amount of mucin were determined by reverse transcription-polymerase chain reaction (RT-PCR) and immunoassay. RESULTS: Leukotriene D(4) upregulated GENE gene expression and mucin secretion in a dose dependent pattern. CHEMICAL (ONO-1078, 100 microM) downregulated the leukotriene D(4)-induced GENE gene expression and mucin secretion. CONCLUSION: These results suggest that the leukotriene receptor system is one of the mechanisms related to GENE gene expression and mucin secretion in the human airway epithelium. | INDIRECT-DOWNREGULATOR |
| The inhibitory effect of the leukotriene receptor antagonist on leukotriene D4-induced MUC2/5AC gene expression and GENE secretion in human airway epithelial cells. OBJECTIVES: GENE gene expression and GENE production are markedly increased in inflammatory airway disorders such as asthma, chronic bronchitis and rhinosinusitis. Cytokines, lipopolysaccharides and other inflammatory mediators such as prostaglandin and leukotriene are related to the secretion and production of GENE. However, the relationship of leukotrienes with GENE genes expression is not clear. The aim of this study is to evaluate MUC2/5AC gene expression and GENE secretion by the leukotriene receptor in human airway epithelial cells. METHODS: The effect of leukotriene D(4) and the leukotriene receptor antagonist, pranlukast hydrate (ONO-1078) on the regulation of MUC2/5AC gene expression and GENE secretion were observed in human airway NCI-H292 epithelial cells. The mRNA levels of MUC2/5AC and the amount of GENE were determined by reverse transcription-polymerase chain reaction (RT-PCR) and immunoassay. RESULTS: Leukotriene D(4) upregulated MUC2/5AC gene expression and GENE secretion in a dose dependent pattern. CHEMICAL (ONO-1078, 100 microM) downregulated the leukotriene D(4)-induced MUC2/5AC gene expression and GENE secretion. CONCLUSION: These results suggest that the leukotriene receptor system is one of the mechanisms related to MUC2/5AC gene expression and GENE secretion in the human airway epithelium. | INDIRECT-DOWNREGULATOR |
| The inhibitory effect of the leukotriene receptor antagonist on leukotriene D4-induced GENE gene expression and mucin secretion in human airway epithelial cells. OBJECTIVES: Mucin gene expression and mucin production are markedly increased in inflammatory airway disorders such as asthma, chronic bronchitis and rhinosinusitis. Cytokines, lipopolysaccharides and other inflammatory mediators such as prostaglandin and leukotriene are related to the secretion and production of mucin. However, the relationship of leukotrienes with mucin genes expression is not clear. The aim of this study is to evaluate GENE gene expression and mucin secretion by the leukotriene receptor in human airway epithelial cells. METHODS: The effect of leukotriene D(4) and the leukotriene receptor antagonist, pranlukast hydrate (ONO-1078) on the regulation of GENE gene expression and mucin secretion were observed in human airway NCI-H292 epithelial cells. The mRNA levels of GENE and the amount of mucin were determined by reverse transcription-polymerase chain reaction (RT-PCR) and immunoassay. RESULTS: Leukotriene D(4) upregulated GENE gene expression and mucin secretion in a dose dependent pattern. Pranlukast hydrate (CHEMICAL, 100 microM) downregulated the leukotriene D(4)-induced GENE gene expression and mucin secretion. CONCLUSION: These results suggest that the leukotriene receptor system is one of the mechanisms related to GENE gene expression and mucin secretion in the human airway epithelium. | INDIRECT-DOWNREGULATOR |
| The inhibitory effect of the leukotriene receptor antagonist on leukotriene D4-induced MUC2/5AC gene expression and GENE secretion in human airway epithelial cells. OBJECTIVES: GENE gene expression and GENE production are markedly increased in inflammatory airway disorders such as asthma, chronic bronchitis and rhinosinusitis. Cytokines, lipopolysaccharides and other inflammatory mediators such as prostaglandin and leukotriene are related to the secretion and production of GENE. However, the relationship of leukotrienes with GENE genes expression is not clear. The aim of this study is to evaluate MUC2/5AC gene expression and GENE secretion by the leukotriene receptor in human airway epithelial cells. METHODS: The effect of leukotriene D(4) and the leukotriene receptor antagonist, pranlukast hydrate (ONO-1078) on the regulation of MUC2/5AC gene expression and GENE secretion were observed in human airway NCI-H292 epithelial cells. The mRNA levels of MUC2/5AC and the amount of GENE were determined by reverse transcription-polymerase chain reaction (RT-PCR) and immunoassay. RESULTS: Leukotriene D(4) upregulated MUC2/5AC gene expression and GENE secretion in a dose dependent pattern. Pranlukast hydrate (CHEMICAL, 100 microM) downregulated the leukotriene D(4)-induced MUC2/5AC gene expression and GENE secretion. CONCLUSION: These results suggest that the leukotriene receptor system is one of the mechanisms related to MUC2/5AC gene expression and GENE secretion in the human airway epithelium. | INDIRECT-DOWNREGULATOR |
| The inhibitory effect of the GENE antagonist on leukotriene D4-induced MUC2/5AC gene expression and mucin secretion in human airway epithelial cells. OBJECTIVES: Mucin gene expression and mucin production are markedly increased in inflammatory airway disorders such as asthma, chronic bronchitis and rhinosinusitis. Cytokines, lipopolysaccharides and other inflammatory mediators such as prostaglandin and leukotriene are related to the secretion and production of mucin. However, the relationship of leukotrienes with mucin genes expression is not clear. The aim of this study is to evaluate MUC2/5AC gene expression and mucin secretion by the GENE in human airway epithelial cells. METHODS: The effect of leukotriene D(4) and the GENE antagonist, CHEMICAL (ONO-1078) on the regulation of MUC2/5AC gene expression and mucin secretion were observed in human airway NCI-H292 epithelial cells. The mRNA levels of MUC2/5AC and the amount of mucin were determined by reverse transcription-polymerase chain reaction (RT-PCR) and immunoassay. RESULTS: Leukotriene D(4) upregulated MUC2/5AC gene expression and mucin secretion in a dose dependent pattern. CHEMICAL (ONO-1078, 100 microM) downregulated the leukotriene D(4)-induced MUC2/5AC gene expression and mucin secretion. CONCLUSION: These results suggest that the GENE system is one of the mechanisms related to MUC2/5AC gene expression and mucin secretion in the human airway epithelium. | INHIBITOR |
| The inhibitory effect of the GENE antagonist on leukotriene D4-induced MUC2/5AC gene expression and mucin secretion in human airway epithelial cells. OBJECTIVES: Mucin gene expression and mucin production are markedly increased in inflammatory airway disorders such as asthma, chronic bronchitis and rhinosinusitis. Cytokines, lipopolysaccharides and other inflammatory mediators such as prostaglandin and leukotriene are related to the secretion and production of mucin. However, the relationship of leukotrienes with mucin genes expression is not clear. The aim of this study is to evaluate MUC2/5AC gene expression and mucin secretion by the GENE in human airway epithelial cells. METHODS: The effect of leukotriene D(4) and the GENE antagonist, pranlukast hydrate (CHEMICAL) on the regulation of MUC2/5AC gene expression and mucin secretion were observed in human airway NCI-H292 epithelial cells. The mRNA levels of MUC2/5AC and the amount of mucin were determined by reverse transcription-polymerase chain reaction (RT-PCR) and immunoassay. RESULTS: Leukotriene D(4) upregulated MUC2/5AC gene expression and mucin secretion in a dose dependent pattern. Pranlukast hydrate (ONO-1078, 100 microM) downregulated the leukotriene D(4)-induced MUC2/5AC gene expression and mucin secretion. CONCLUSION: These results suggest that the GENE system is one of the mechanisms related to MUC2/5AC gene expression and mucin secretion in the human airway epithelium. | INHIBITOR |
| Effect of isolated CHEMICAL supplementation on ABCA1-dependent cholesterol efflux potential in postmenopausal women. OBJECTIVE: Isoflavones may display beneficial health effects in postmenopausal women. We studied in a clinical trial whether isolated CHEMICAL treatment in postmenopausal women could affect reverse cholesterol transport as evaluated by adenosine triphosphate-binding cassette A1- (ABCA1), dependent cholesterol efflux from macrophages. In addition, various serum lipid and lipoprotein parameters were investigated. Furthermore, we separately assessed equol-producing and non-equol-producing women. DESIGN: Postmenopausal women (n=56) were treated with either CHEMICAL or placebo tablets for 3 months in a crossover design, separated by a 2-month washout period. Fifteen women were classified as equol producers, and 15 women were classified as non-equol producers. Serum samples were collected before and after each treatment period. [H]-Cholesterol-labeled J774 macrophage cells, with and without GENE up-regulation, were incubated with the samples, and ABCA1-dependent cholesterol efflux and serum lipid and lipoprotein levels were assessed. RESULTS: Serum promoted 3.1%+/-1.1% and 3.2%+/-1.1% cholesterol efflux from macrophages after CHEMICAL and placebo treatment, respectively. Thus, CHEMICAL supplementation did not affect ABCA1-dependent cholesterol efflux to serum. However, as a novel finding, CHEMICAL treatment increased a subclass of high-density lipoprotein, the pre-beta high-density lipoprotein levels by 18% without affecting any other serum lipid concentrations. ABCA1-facilitated cholesterol efflux and lipid parameters did not differ between equol-producing and non-equol-producing women. CONCLUSION: In postmenopausal women, isolated CHEMICAL treatment does not affect GENE-dependent cholesterol efflux potential from macrophages but increases circulating pre-beta high-density lipoprotein level, which could provide beneficial vascular effects. | NO-RELATIONSHIP |
| Effect of isolated CHEMICAL supplementation on ABCA1-dependent cholesterol efflux potential in postmenopausal women. OBJECTIVE: Isoflavones may display beneficial health effects in postmenopausal women. We studied in a clinical trial whether isolated CHEMICAL treatment in postmenopausal women could affect reverse cholesterol transport as evaluated by GENE- (ABCA1), dependent cholesterol efflux from macrophages. In addition, various serum lipid and lipoprotein parameters were investigated. Furthermore, we separately assessed equol-producing and non-equol-producing women. DESIGN: Postmenopausal women (n=56) were treated with either CHEMICAL or placebo tablets for 3 months in a crossover design, separated by a 2-month washout period. Fifteen women were classified as equol producers, and 15 women were classified as non-equol producers. Serum samples were collected before and after each treatment period. [H]-Cholesterol-labeled J774 macrophage cells, with and without ABCA1 up-regulation, were incubated with the samples, and ABCA1-dependent cholesterol efflux and serum lipid and lipoprotein levels were assessed. RESULTS: Serum promoted 3.1%+/-1.1% and 3.2%+/-1.1% cholesterol efflux from macrophages after CHEMICAL and placebo treatment, respectively. Thus, CHEMICAL supplementation did not affect ABCA1-dependent cholesterol efflux to serum. However, as a novel finding, CHEMICAL treatment increased a subclass of high-density lipoprotein, the pre-beta high-density lipoprotein levels by 18% without affecting any other serum lipid concentrations. ABCA1-facilitated cholesterol efflux and lipid parameters did not differ between equol-producing and non-equol-producing women. CONCLUSION: In postmenopausal women, isolated CHEMICAL treatment does not affect ABCA1-dependent cholesterol efflux potential from macrophages but increases circulating pre-beta high-density lipoprotein level, which could provide beneficial vascular effects. | REGULATOR |
| Effect of isolated CHEMICAL supplementation on ABCA1-dependent cholesterol efflux potential in postmenopausal women. OBJECTIVE: Isoflavones may display beneficial health effects in postmenopausal women. We studied in a clinical trial whether isolated CHEMICAL treatment in postmenopausal women could affect reverse cholesterol transport as evaluated by adenosine triphosphate-binding cassette A1- (ABCA1), dependent cholesterol efflux from macrophages. In addition, various serum lipid and lipoprotein parameters were investigated. Furthermore, we separately assessed equol-producing and non-equol-producing women. DESIGN: Postmenopausal women (n=56) were treated with either CHEMICAL or placebo tablets for 3 months in a crossover design, separated by a 2-month washout period. Fifteen women were classified as equol producers, and 15 women were classified as non-equol producers. Serum samples were collected before and after each treatment period. [H]-Cholesterol-labeled J774 macrophage cells, with and without ABCA1 up-regulation, were incubated with the samples, and ABCA1-dependent cholesterol efflux and serum lipid and lipoprotein levels were assessed. RESULTS: Serum promoted 3.1%+/-1.1% and 3.2%+/-1.1% cholesterol efflux from macrophages after CHEMICAL and placebo treatment, respectively. Thus, CHEMICAL supplementation did not affect ABCA1-dependent cholesterol efflux to serum. However, as a novel finding, CHEMICAL treatment increased a subclass of high-density lipoprotein, the GENE levels by 18% without affecting any other serum lipid concentrations. ABCA1-facilitated cholesterol efflux and lipid parameters did not differ between equol-producing and non-equol-producing women. CONCLUSION: In postmenopausal women, isolated CHEMICAL treatment does not affect ABCA1-dependent cholesterol efflux potential from macrophages but increases circulating GENE level, which could provide beneficial vascular effects. | INDIRECT-UPREGULATOR |
| Effect of isolated CHEMICAL supplementation on ABCA1-dependent cholesterol efflux potential in postmenopausal women. OBJECTIVE: Isoflavones may display beneficial health effects in postmenopausal women. We studied in a clinical trial whether isolated CHEMICAL treatment in postmenopausal women could affect reverse cholesterol transport as evaluated by adenosine triphosphate-binding cassette A1- (ABCA1), dependent cholesterol efflux from macrophages. In addition, various serum lipid and lipoprotein parameters were investigated. Furthermore, we separately assessed equol-producing and non-equol-producing women. DESIGN: Postmenopausal women (n=56) were treated with either CHEMICAL or placebo tablets for 3 months in a crossover design, separated by a 2-month washout period. Fifteen women were classified as equol producers, and 15 women were classified as non-equol producers. Serum samples were collected before and after each treatment period. [H]-Cholesterol-labeled J774 macrophage cells, with and without ABCA1 up-regulation, were incubated with the samples, and ABCA1-dependent cholesterol efflux and serum lipid and lipoprotein levels were assessed. RESULTS: Serum promoted 3.1%+/-1.1% and 3.2%+/-1.1% cholesterol efflux from macrophages after CHEMICAL and placebo treatment, respectively. Thus, CHEMICAL supplementation did not affect ABCA1-dependent cholesterol efflux to serum. However, as a novel finding, CHEMICAL treatment increased a subclass of GENE, the pre-beta GENE levels by 18% without affecting any other serum lipid concentrations. ABCA1-facilitated cholesterol efflux and lipid parameters did not differ between equol-producing and non-equol-producing women. CONCLUSION: In postmenopausal women, isolated CHEMICAL treatment does not affect ABCA1-dependent cholesterol efflux potential from macrophages but increases circulating pre-beta GENE level, which could provide beneficial vascular effects. | INDIRECT-UPREGULATOR |
| Effect of isolated isoflavone supplementation on ABCA1-dependent CHEMICAL efflux potential in postmenopausal women. OBJECTIVE: Isoflavones may display beneficial health effects in postmenopausal women. We studied in a clinical trial whether isolated isoflavone treatment in postmenopausal women could affect reverse CHEMICAL transport as evaluated by adenosine triphosphate-binding cassette A1- (ABCA1), dependent CHEMICAL efflux from macrophages. In addition, various serum lipid and lipoprotein parameters were investigated. Furthermore, we separately assessed equol-producing and non-equol-producing women. DESIGN: Postmenopausal women (n=56) were treated with either isoflavone or placebo tablets for 3 months in a crossover design, separated by a 2-month washout period. Fifteen women were classified as equol producers, and 15 women were classified as non-equol producers. Serum samples were collected before and after each treatment period. [H]-Cholesterol-labeled J774 macrophage cells, with and without GENE up-regulation, were incubated with the samples, and ABCA1-dependent CHEMICAL efflux and serum lipid and lipoprotein levels were assessed. RESULTS: Serum promoted 3.1%+/-1.1% and 3.2%+/-1.1% CHEMICAL efflux from macrophages after isoflavone and placebo treatment, respectively. Thus, isoflavone supplementation did not affect ABCA1-dependent CHEMICAL efflux to serum. However, as a novel finding, isoflavone treatment increased a subclass of high-density lipoprotein, the pre-beta high-density lipoprotein levels by 18% without affecting any other serum lipid concentrations. ABCA1-facilitated CHEMICAL efflux and lipid parameters did not differ between equol-producing and non-equol-producing women. CONCLUSION: In postmenopausal women, isolated isoflavone treatment does not affect GENE-dependent CHEMICAL efflux potential from macrophages but increases circulating pre-beta high-density lipoprotein level, which could provide beneficial vascular effects. | SUBSTRATE |
| Effect of isolated isoflavone supplementation on ABCA1-dependent CHEMICAL efflux potential in postmenopausal women. OBJECTIVE: Isoflavones may display beneficial health effects in postmenopausal women. We studied in a clinical trial whether isolated isoflavone treatment in postmenopausal women could affect reverse CHEMICAL transport as evaluated by GENE- (ABCA1), dependent CHEMICAL efflux from macrophages. In addition, various serum lipid and lipoprotein parameters were investigated. Furthermore, we separately assessed equol-producing and non-equol-producing women. DESIGN: Postmenopausal women (n=56) were treated with either isoflavone or placebo tablets for 3 months in a crossover design, separated by a 2-month washout period. Fifteen women were classified as equol producers, and 15 women were classified as non-equol producers. Serum samples were collected before and after each treatment period. [H]-Cholesterol-labeled J774 macrophage cells, with and without ABCA1 up-regulation, were incubated with the samples, and ABCA1-dependent CHEMICAL efflux and serum lipid and lipoprotein levels were assessed. RESULTS: Serum promoted 3.1%+/-1.1% and 3.2%+/-1.1% CHEMICAL efflux from macrophages after isoflavone and placebo treatment, respectively. Thus, isoflavone supplementation did not affect ABCA1-dependent CHEMICAL efflux to serum. However, as a novel finding, isoflavone treatment increased a subclass of high-density lipoprotein, the pre-beta high-density lipoprotein levels by 18% without affecting any other serum lipid concentrations. ABCA1-facilitated CHEMICAL efflux and lipid parameters did not differ between equol-producing and non-equol-producing women. CONCLUSION: In postmenopausal women, isolated isoflavone treatment does not affect ABCA1-dependent CHEMICAL efflux potential from macrophages but increases circulating pre-beta high-density lipoprotein level, which could provide beneficial vascular effects. | SUBSTRATE |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (BAY43-9006, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, GENE, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The CHEMICAL-resistant GENE(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | NO-RELATIONSHIP |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (BAY43-9006, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The CHEMICAL-resistant KIT(GENE) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | NO-RELATIONSHIP |
| The ability of CHEMICAL to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. CHEMICAL (BAY43-9006, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of CHEMICAL at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, GENE, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of CHEMICAL on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of CHEMICAL on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that CHEMICAL is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. CHEMICAL induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant GENE(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to CHEMICAL. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of CHEMICAL for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | NO-RELATIONSHIP |
| The ability of CHEMICAL to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. CHEMICAL (BAY43-9006, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of CHEMICAL at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of CHEMICAL on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of CHEMICAL on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that CHEMICAL is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. CHEMICAL induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(GENE) mutant, associated with systemic mastocytosis, was found to be resistant to CHEMICAL. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of CHEMICAL for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | NO-RELATIONSHIP |
| The ability of CHEMICAL to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine GENE are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. CHEMICAL (BAY43-9006, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine GENE from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of CHEMICAL at inhibiting mutants of the receptor tyrosine GENE PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of CHEMICAL on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of CHEMICAL on the activity of these GENE and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that CHEMICAL is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. CHEMICAL induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to CHEMICAL. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of CHEMICAL for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | REGULATOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. CHEMICAL (BAY43-9006, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against GENE from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the GENE PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. CHEMICAL induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | INHIBITOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. CHEMICAL (BAY43-9006, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the GENE (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. CHEMICAL induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | REGULATOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. CHEMICAL (BAY43-9006, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (GENE) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. CHEMICAL induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | REGULATOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. CHEMICAL (BAY43-9006, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and GENE (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. CHEMICAL induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | REGULATOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. CHEMICAL (BAY43-9006, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (GENE) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. CHEMICAL induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | REGULATOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (CHEMICAL, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against GENE from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the GENE PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | INHIBITOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (CHEMICAL, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the GENE (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | INHIBITOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (CHEMICAL, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (GENE) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | INHIBITOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (CHEMICAL, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and GENE (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | INHIBITOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (CHEMICAL, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (GENE) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | INHIBITOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (BAY43-9006, CHEMICAL) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against GENE from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the GENE PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | INHIBITOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (BAY43-9006, CHEMICAL) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the GENE (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | INHIBITOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (BAY43-9006, CHEMICAL) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (GENE) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | INHIBITOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (BAY43-9006, CHEMICAL) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and GENE (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | INHIBITOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (BAY43-9006, CHEMICAL) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (GENE) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | INHIBITOR |
| The ability of CHEMICAL to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. CHEMICAL (BAY43-9006, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against GENE from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of CHEMICAL at inhibiting mutants of the GENE PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of CHEMICAL on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of CHEMICAL on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that CHEMICAL is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. CHEMICAL induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to CHEMICAL. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of CHEMICAL for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | INHIBITOR |
| The ability of CHEMICAL to inhibit oncogenic GENE and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. CHEMICAL (BAY43-9006, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of CHEMICAL at inhibiting mutants of the receptor tyrosine kinases GENE, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of CHEMICAL on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of CHEMICAL on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that CHEMICAL is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. CHEMICAL induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to CHEMICAL. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of CHEMICAL for the treatment of myeloid malignancies expressing activated forms of GENE and FLT3. | INHIBITOR |
| The ability of CHEMICAL to inhibit oncogenic PDGFRbeta and GENE mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. CHEMICAL (BAY43-9006, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of CHEMICAL at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and GENE, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of CHEMICAL on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, GENE with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of CHEMICAL on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that CHEMICAL is a potent inhibitor of ETV6-PDGFRbeta and GENE mutants, including some of the mutants that confer resistance to PKC412 and other GENE inhibitors. CHEMICAL induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing GENE with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to CHEMICAL. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of CHEMICAL for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and GENE. | INHIBITOR |
| The ability of CHEMICAL to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. CHEMICAL (BAY43-9006, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of CHEMICAL at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of CHEMICAL on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of CHEMICAL on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that CHEMICAL is a potent inhibitor of GENE-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. CHEMICAL induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to CHEMICAL. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of CHEMICAL for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | INHIBITOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. CHEMICAL (BAY43-9006, Nexavar) is a small molecule GENE inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. CHEMICAL induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | INHIBITOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (CHEMICAL, Nexavar) is a small molecule GENE inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | INHIBITOR |
| The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (BAY43-9006, CHEMICAL) is a small molecule GENE inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3. | INHIBITOR |
| Glucocorticoids stimulate GENE upregulation in bovine mammary epithelium. Mammary epithelia produce an isotonic, low-Na(+) fluid that is rich in nutrients. Mechanisms that account for the low electrolyte concentration have not been elucidated, although amiloride-sensitive ion transport has been reported in some situations. We hypothesized that corticosteroid exposure modulates epithelial CHEMICAL channel (ENaC) expression and/or activity in bovine mammary epithelial cells. BME-UV cells were grown to confluent monolayers on permeable supports with a standard basolateral medium and apical medium of low-electrolyte, high-lactose composition that resembles the ionic composition of milk. Ion transport was assessed in modified Ussing flux chambers. Exposure to glucocorticoids (dexamethasone, cortisol, or prednisolone), but not aldosterone, increased short-circuit current (I(sc)), a sensitive measure of net ion transport, whereas apical exposure to amiloride or benzamil reduced corticosteroid-induced I(sc) close to basal levels. Quantitative RT-PCR indicated a glucocorticoid-induced increase in mRNA for beta- and gamma-ENaC, whereas alpha-ENaC mRNA expression was only mildly affected. Exposure to mifepristone (a glucocorticoid receptor antagonist), but not spironolactone (a mineralocorticoid receptor antagonist), precluded both the corticosteroid-induced elevation in amiloride-sensitive I(sc) and the induced changes in beta- and gamma-ENaC mRNA. We conclude that CHEMICAL movement across mammary epithelia is modulated by corticosteroids via a glucocorticoid receptor-mediated mechanism that regulates the expression of the beta- and gamma-subunits of GENE. GENE expression and activity could account for the low CHEMICAL concentration that is typical of milk. | SUBSTRATE |
| Glucocorticoids stimulate ENaC upregulation in bovine mammary epithelium. Mammary epithelia produce an isotonic, low-Na(+) fluid that is rich in nutrients. Mechanisms that account for the low electrolyte concentration have not been elucidated, although amiloride-sensitive ion transport has been reported in some situations. We hypothesized that corticosteroid exposure modulates epithelial CHEMICAL channel (ENaC) expression and/or activity in bovine mammary epithelial cells. BME-UV cells were grown to confluent monolayers on permeable supports with a standard basolateral medium and apical medium of low-electrolyte, high-lactose composition that resembles the ionic composition of milk. Ion transport was assessed in modified Ussing flux chambers. Exposure to glucocorticoids (dexamethasone, cortisol, or prednisolone), but not aldosterone, increased short-circuit current (I(sc)), a sensitive measure of net ion transport, whereas apical exposure to amiloride or benzamil reduced corticosteroid-induced I(sc) close to basal levels. Quantitative RT-PCR indicated a glucocorticoid-induced increase in mRNA for beta- and gamma-ENaC, whereas alpha-ENaC mRNA expression was only mildly affected. Exposure to mifepristone (a GENE antagonist), but not spironolactone (a mineralocorticoid receptor antagonist), precluded both the corticosteroid-induced elevation in amiloride-sensitive I(sc) and the induced changes in beta- and gamma-ENaC mRNA. We conclude that CHEMICAL movement across mammary epithelia is modulated by corticosteroids via a GENE-mediated mechanism that regulates the expression of the beta- and gamma-subunits of ENaC. ENaC expression and activity could account for the low CHEMICAL concentration that is typical of milk. | SUBSTRATE |
| Glucocorticoids stimulate ENaC upregulation in bovine mammary epithelium. Mammary epithelia produce an isotonic, low-Na(+) fluid that is rich in nutrients. Mechanisms that account for the low electrolyte concentration have not been elucidated, although amiloride-sensitive ion transport has been reported in some situations. We hypothesized that corticosteroid exposure modulates epithelial Na(+) channel (ENaC) expression and/or activity in bovine mammary epithelial cells. BME-UV cells were grown to confluent monolayers on permeable supports with a standard basolateral medium and apical medium of low-electrolyte, high-lactose composition that resembles the ionic composition of milk. Ion transport was assessed in modified Ussing flux chambers. Exposure to glucocorticoids (dexamethasone, cortisol, or prednisolone), but not aldosterone, increased short-circuit current (I(sc)), a sensitive measure of net ion transport, whereas apical exposure to amiloride or benzamil reduced corticosteroid-induced I(sc) close to basal levels. Quantitative RT-PCR indicated a glucocorticoid-induced increase in mRNA for beta- and gamma-ENaC, whereas alpha-ENaC mRNA expression was only mildly affected. Exposure to CHEMICAL (a GENE antagonist), but not spironolactone (a mineralocorticoid receptor antagonist), precluded both the corticosteroid-induced elevation in amiloride-sensitive I(sc) and the induced changes in beta- and gamma-ENaC mRNA. We conclude that Na(+) movement across mammary epithelia is modulated by corticosteroids via a glucocorticoid receptor-mediated mechanism that regulates the expression of the beta- and gamma-subunits of ENaC. ENaC expression and activity could account for the low Na(+) concentration that is typical of milk. | INHIBITOR |
| Glucocorticoids stimulate ENaC upregulation in bovine mammary epithelium. Mammary epithelia produce an isotonic, low-Na(+) fluid that is rich in nutrients. Mechanisms that account for the low electrolyte concentration have not been elucidated, although amiloride-sensitive ion transport has been reported in some situations. We hypothesized that corticosteroid exposure modulates epithelial Na(+) channel (ENaC) expression and/or activity in bovine mammary epithelial cells. BME-UV cells were grown to confluent monolayers on permeable supports with a standard basolateral medium and apical medium of low-electrolyte, high-lactose composition that resembles the ionic composition of milk. Ion transport was assessed in modified Ussing flux chambers. Exposure to glucocorticoids (dexamethasone, cortisol, or prednisolone), but not aldosterone, increased short-circuit current (I(sc)), a sensitive measure of net ion transport, whereas apical exposure to amiloride or benzamil reduced corticosteroid-induced I(sc) close to basal levels. Quantitative RT-PCR indicated a glucocorticoid-induced increase in mRNA for beta- and gamma-ENaC, whereas alpha-ENaC mRNA expression was only mildly affected. Exposure to mifepristone (a glucocorticoid receptor antagonist), but not CHEMICAL (a GENE antagonist), precluded both the corticosteroid-induced elevation in amiloride-sensitive I(sc) and the induced changes in beta- and gamma-ENaC mRNA. We conclude that Na(+) movement across mammary epithelia is modulated by corticosteroids via a glucocorticoid receptor-mediated mechanism that regulates the expression of the beta- and gamma-subunits of ENaC. ENaC expression and activity could account for the low Na(+) concentration that is typical of milk. | INHIBITOR |
| Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. It has been previously reported that aspirin inhibited the development of diabetic retinopathy in diabetic animals, raising the possibility that anti-inflammatory drugs may have beneficial effects on diabetic retinopathy. To further explore this, we compared effects of oral consumption of three different salicylate-based drugs (aspirin, sodium salicylate, and sulfasalazine) on the development of early stages of diabetic retinopathy in rats. These three drugs differ in their ability to inhibit cyclooxygenase but share an ability to inhibit nuclear factor-kappaB (NF-kappaB). Diabetes of 9-10 months duration significantly increased the number of TUNEL (transferase-mediated dUTP nick-end labeling)-positive capillary cells and acellular (degenerate) capillaries in the retinal vasculature, and all three salicylate-based drugs inhibited this cell death and formation of acellular capillaries without altering the severity of hyperglycemia. In short-term diabetes (2-4 months), all three CHEMICAL inhibited the diabetes-induced loss of neuronal cells from the ganglion cell layer. Oral aspirin (as a representative of the salicylate family) inhibited diabetes-induced increase in NF-kappaB DNA-binding affinity in electrophoretic mobility shift assay and transcription factor array in nuclear extract isolated from whole retina. All three CHEMICAL inhibited the diabetes-induced translocation of GENE (a subunit of NF-kappaB) into nuclei of retinal vascular endothelial cells of the isolated retinal vasculature, as well as of GENE and p65 into nuclei of cells in the ganglion cell layer and inner nuclear layer on whole-retinal sections. Sulfasalazine (also as a representative of the salicylates) inhibited the diabetes-induced upregulation of several inflammatory gene products, which are regulated by NF-kappaB, including vascular cell adhesion molecule, intracellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2 in whole-retinal lysate. CHEMICAL, in doses administrated in our experiments, inhibited NF-kappaB and perhaps other transcription factors in the retina, were well tolerated, and offered new tools to investigate and inhibit the development of diabetic retinopathy. | INDIRECT-DOWNREGULATOR |
| Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. It has been previously reported that aspirin inhibited the development of diabetic retinopathy in diabetic animals, raising the possibility that anti-inflammatory drugs may have beneficial effects on diabetic retinopathy. To further explore this, we compared effects of oral consumption of three different salicylate-based drugs (aspirin, sodium salicylate, and sulfasalazine) on the development of early stages of diabetic retinopathy in rats. These three drugs differ in their ability to inhibit cyclooxygenase but share an ability to inhibit nuclear factor-kappaB (NF-kappaB). Diabetes of 9-10 months duration significantly increased the number of TUNEL (transferase-mediated dUTP nick-end labeling)-positive capillary cells and acellular (degenerate) capillaries in the retinal vasculature, and all three salicylate-based drugs inhibited this cell death and formation of acellular capillaries without altering the severity of hyperglycemia. In short-term diabetes (2-4 months), all three CHEMICAL inhibited the diabetes-induced loss of neuronal cells from the ganglion cell layer. Oral aspirin (as a representative of the salicylate family) inhibited diabetes-induced increase in NF-kappaB DNA-binding affinity in electrophoretic mobility shift assay and transcription factor array in nuclear extract isolated from whole retina. All three CHEMICAL inhibited the diabetes-induced translocation of p50 (a subunit of NF-kappaB) into nuclei of retinal vascular endothelial cells of the isolated retinal vasculature, as well as of p50 and GENE into nuclei of cells in the ganglion cell layer and inner nuclear layer on whole-retinal sections. Sulfasalazine (also as a representative of the salicylates) inhibited the diabetes-induced upregulation of several inflammatory gene products, which are regulated by NF-kappaB, including vascular cell adhesion molecule, intracellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2 in whole-retinal lysate. CHEMICAL, in doses administrated in our experiments, inhibited NF-kappaB and perhaps other transcription factors in the retina, were well tolerated, and offered new tools to investigate and inhibit the development of diabetic retinopathy. | INHIBITOR |
| Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. It has been previously reported that CHEMICAL inhibited the development of diabetic retinopathy in diabetic animals, raising the possibility that anti-inflammatory drugs may have beneficial effects on diabetic retinopathy. To further explore this, we compared effects of oral consumption of three different salicylate-based drugs (aspirin, sodium salicylate, and sulfasalazine) on the development of early stages of diabetic retinopathy in rats. These three drugs differ in their ability to inhibit cyclooxygenase but share an ability to inhibit nuclear factor-kappaB (NF-kappaB). Diabetes of 9-10 months duration significantly increased the number of TUNEL (transferase-mediated dUTP nick-end labeling)-positive capillary cells and acellular (degenerate) capillaries in the retinal vasculature, and all three salicylate-based drugs inhibited this cell death and formation of acellular capillaries without altering the severity of hyperglycemia. In short-term diabetes (2-4 months), all three salicylates inhibited the diabetes-induced loss of neuronal cells from the ganglion cell layer. Oral CHEMICAL (as a representative of the salicylate family) inhibited diabetes-induced increase in GENE DNA-binding affinity in electrophoretic mobility shift assay and transcription factor array in nuclear extract isolated from whole retina. All three salicylates inhibited the diabetes-induced translocation of p50 (a subunit of NF-kappaB) into nuclei of retinal vascular endothelial cells of the isolated retinal vasculature, as well as of p50 and p65 into nuclei of cells in the ganglion cell layer and inner nuclear layer on whole-retinal sections. Sulfasalazine (also as a representative of the salicylates) inhibited the diabetes-induced upregulation of several inflammatory gene products, which are regulated by GENE, including vascular cell adhesion molecule, intracellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2 in whole-retinal lysate. Salicylates, in doses administrated in our experiments, inhibited GENE and perhaps other transcription factors in the retina, were well tolerated, and offered new tools to investigate and inhibit the development of diabetic retinopathy. | INDIRECT-DOWNREGULATOR |
| Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. It has been previously reported that aspirin inhibited the development of diabetic retinopathy in diabetic animals, raising the possibility that anti-inflammatory drugs may have beneficial effects on diabetic retinopathy. To further explore this, we compared effects of oral consumption of three different salicylate-based drugs (aspirin, sodium CHEMICAL, and sulfasalazine) on the development of early stages of diabetic retinopathy in rats. These three drugs differ in their ability to inhibit cyclooxygenase but share an ability to inhibit nuclear factor-kappaB (NF-kappaB). Diabetes of 9-10 months duration significantly increased the number of TUNEL (transferase-mediated dUTP nick-end labeling)-positive capillary cells and acellular (degenerate) capillaries in the retinal vasculature, and all three salicylate-based drugs inhibited this cell death and formation of acellular capillaries without altering the severity of hyperglycemia. In short-term diabetes (2-4 months), all three salicylates inhibited the diabetes-induced loss of neuronal cells from the ganglion cell layer. Oral aspirin (as a representative of the CHEMICAL family) inhibited diabetes-induced increase in GENE DNA-binding affinity in electrophoretic mobility shift assay and transcription factor array in nuclear extract isolated from whole retina. All three salicylates inhibited the diabetes-induced translocation of p50 (a subunit of NF-kappaB) into nuclei of retinal vascular endothelial cells of the isolated retinal vasculature, as well as of p50 and p65 into nuclei of cells in the ganglion cell layer and inner nuclear layer on whole-retinal sections. Sulfasalazine (also as a representative of the salicylates) inhibited the diabetes-induced upregulation of several inflammatory gene products, which are regulated by GENE, including vascular cell adhesion molecule, intracellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2 in whole-retinal lysate. Salicylates, in doses administrated in our experiments, inhibited GENE and perhaps other transcription factors in the retina, were well tolerated, and offered new tools to investigate and inhibit the development of diabetic retinopathy. | REGULATOR |
| Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. It has been previously reported that aspirin inhibited the development of diabetic retinopathy in diabetic animals, raising the possibility that anti-inflammatory drugs may have beneficial effects on diabetic retinopathy. To further explore this, we compared effects of oral consumption of three different salicylate-based drugs (aspirin, sodium salicylate, and sulfasalazine) on the development of early stages of diabetic retinopathy in rats. These three drugs differ in their ability to inhibit cyclooxygenase but share an ability to inhibit nuclear factor-kappaB (NF-kappaB). Diabetes of 9-10 months duration significantly increased the number of TUNEL (transferase-mediated dUTP nick-end labeling)-positive capillary cells and acellular (degenerate) capillaries in the retinal vasculature, and all three salicylate-based drugs inhibited this cell death and formation of acellular capillaries without altering the severity of hyperglycemia. In short-term diabetes (2-4 months), all three CHEMICAL inhibited the diabetes-induced loss of neuronal cells from the ganglion cell layer. Oral aspirin (as a representative of the salicylate family) inhibited diabetes-induced increase in GENE DNA-binding affinity in electrophoretic mobility shift assay and transcription factor array in nuclear extract isolated from whole retina. All three CHEMICAL inhibited the diabetes-induced translocation of p50 (a subunit of GENE) into nuclei of retinal vascular endothelial cells of the isolated retinal vasculature, as well as of p50 and p65 into nuclei of cells in the ganglion cell layer and inner nuclear layer on whole-retinal sections. Sulfasalazine (also as a representative of the salicylates) inhibited the diabetes-induced upregulation of several inflammatory gene products, which are regulated by GENE, including vascular cell adhesion molecule, intracellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2 in whole-retinal lysate. CHEMICAL, in doses administrated in our experiments, inhibited GENE and perhaps other transcription factors in the retina, were well tolerated, and offered new tools to investigate and inhibit the development of diabetic retinopathy. | INDIRECT-DOWNREGULATOR |
| Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. It has been previously reported that aspirin inhibited the development of diabetic retinopathy in diabetic animals, raising the possibility that anti-inflammatory drugs may have beneficial effects on diabetic retinopathy. To further explore this, we compared effects of oral consumption of three different salicylate-based drugs (aspirin, sodium salicylate, and sulfasalazine) on the development of early stages of diabetic retinopathy in rats. These three drugs differ in their ability to inhibit cyclooxygenase but share an ability to inhibit nuclear factor-kappaB (NF-kappaB). Diabetes of 9-10 months duration significantly increased the number of TUNEL (transferase-mediated dUTP nick-end labeling)-positive capillary cells and acellular (degenerate) capillaries in the retinal vasculature, and all three salicylate-based drugs inhibited this cell death and formation of acellular capillaries without altering the severity of hyperglycemia. In short-term diabetes (2-4 months), all three salicylates inhibited the diabetes-induced loss of neuronal cells from the ganglion cell layer. Oral aspirin (as a representative of the salicylate family) inhibited diabetes-induced increase in GENE DNA-binding affinity in electrophoretic mobility shift assay and transcription factor array in nuclear extract isolated from whole retina. All three salicylates inhibited the diabetes-induced translocation of p50 (a subunit of NF-kappaB) into nuclei of retinal vascular endothelial cells of the isolated retinal vasculature, as well as of p50 and p65 into nuclei of cells in the ganglion cell layer and inner nuclear layer on whole-retinal sections. CHEMICAL (also as a representative of the salicylates) inhibited the diabetes-induced upregulation of several inflammatory gene products, which are regulated by GENE, including vascular cell adhesion molecule, intracellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2 in whole-retinal lysate. Salicylates, in doses administrated in our experiments, inhibited GENE and perhaps other transcription factors in the retina, were well tolerated, and offered new tools to investigate and inhibit the development of diabetic retinopathy. | INDIRECT-DOWNREGULATOR |
| Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. It has been previously reported that aspirin inhibited the development of diabetic retinopathy in diabetic animals, raising the possibility that anti-inflammatory drugs may have beneficial effects on diabetic retinopathy. To further explore this, we compared effects of oral consumption of three different salicylate-based drugs (aspirin, sodium salicylate, and sulfasalazine) on the development of early stages of diabetic retinopathy in rats. These three drugs differ in their ability to inhibit cyclooxygenase but share an ability to inhibit nuclear factor-kappaB (NF-kappaB). Diabetes of 9-10 months duration significantly increased the number of TUNEL (transferase-mediated dUTP nick-end labeling)-positive capillary cells and acellular (degenerate) capillaries in the retinal vasculature, and all three salicylate-based drugs inhibited this cell death and formation of acellular capillaries without altering the severity of hyperglycemia. In short-term diabetes (2-4 months), all three salicylates inhibited the diabetes-induced loss of neuronal cells from the ganglion cell layer. Oral aspirin (as a representative of the salicylate family) inhibited diabetes-induced increase in NF-kappaB DNA-binding affinity in electrophoretic mobility shift assay and transcription factor array in nuclear extract isolated from whole retina. All three salicylates inhibited the diabetes-induced translocation of p50 (a subunit of NF-kappaB) into nuclei of retinal vascular endothelial cells of the isolated retinal vasculature, as well as of p50 and p65 into nuclei of cells in the ganglion cell layer and inner nuclear layer on whole-retinal sections. CHEMICAL (also as a representative of the salicylates) inhibited the diabetes-induced upregulation of several inflammatory gene products, which are regulated by NF-kappaB, including vascular cell adhesion molecule, GENE, inducible nitric oxide synthase, and cyclooxygenase-2 in whole-retinal lysate. Salicylates, in doses administrated in our experiments, inhibited NF-kappaB and perhaps other transcription factors in the retina, were well tolerated, and offered new tools to investigate and inhibit the development of diabetic retinopathy. | INDIRECT-DOWNREGULATOR |
| Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. It has been previously reported that aspirin inhibited the development of diabetic retinopathy in diabetic animals, raising the possibility that anti-inflammatory drugs may have beneficial effects on diabetic retinopathy. To further explore this, we compared effects of oral consumption of three different salicylate-based drugs (aspirin, sodium salicylate, and sulfasalazine) on the development of early stages of diabetic retinopathy in rats. These three drugs differ in their ability to inhibit cyclooxygenase but share an ability to inhibit nuclear factor-kappaB (NF-kappaB). Diabetes of 9-10 months duration significantly increased the number of TUNEL (transferase-mediated dUTP nick-end labeling)-positive capillary cells and acellular (degenerate) capillaries in the retinal vasculature, and all three salicylate-based drugs inhibited this cell death and formation of acellular capillaries without altering the severity of hyperglycemia. In short-term diabetes (2-4 months), all three salicylates inhibited the diabetes-induced loss of neuronal cells from the ganglion cell layer. Oral aspirin (as a representative of the salicylate family) inhibited diabetes-induced increase in NF-kappaB DNA-binding affinity in electrophoretic mobility shift assay and transcription factor array in nuclear extract isolated from whole retina. All three salicylates inhibited the diabetes-induced translocation of p50 (a subunit of NF-kappaB) into nuclei of retinal vascular endothelial cells of the isolated retinal vasculature, as well as of p50 and p65 into nuclei of cells in the ganglion cell layer and inner nuclear layer on whole-retinal sections. CHEMICAL (also as a representative of the salicylates) inhibited the diabetes-induced upregulation of several inflammatory gene products, which are regulated by NF-kappaB, including vascular cell adhesion molecule, intracellular adhesion molecule-1, GENE, and cyclooxygenase-2 in whole-retinal lysate. Salicylates, in doses administrated in our experiments, inhibited NF-kappaB and perhaps other transcription factors in the retina, were well tolerated, and offered new tools to investigate and inhibit the development of diabetic retinopathy. | INDIRECT-DOWNREGULATOR |
| Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. It has been previously reported that aspirin inhibited the development of diabetic retinopathy in diabetic animals, raising the possibility that anti-inflammatory drugs may have beneficial effects on diabetic retinopathy. To further explore this, we compared effects of oral consumption of three different salicylate-based drugs (aspirin, sodium salicylate, and sulfasalazine) on the development of early stages of diabetic retinopathy in rats. These three drugs differ in their ability to inhibit cyclooxygenase but share an ability to inhibit nuclear factor-kappaB (NF-kappaB). Diabetes of 9-10 months duration significantly increased the number of TUNEL (transferase-mediated dUTP nick-end labeling)-positive capillary cells and acellular (degenerate) capillaries in the retinal vasculature, and all three salicylate-based drugs inhibited this cell death and formation of acellular capillaries without altering the severity of hyperglycemia. In short-term diabetes (2-4 months), all three salicylates inhibited the diabetes-induced loss of neuronal cells from the ganglion cell layer. Oral aspirin (as a representative of the salicylate family) inhibited diabetes-induced increase in NF-kappaB DNA-binding affinity in electrophoretic mobility shift assay and transcription factor array in nuclear extract isolated from whole retina. All three salicylates inhibited the diabetes-induced translocation of p50 (a subunit of NF-kappaB) into nuclei of retinal vascular endothelial cells of the isolated retinal vasculature, as well as of p50 and p65 into nuclei of cells in the ganglion cell layer and inner nuclear layer on whole-retinal sections. CHEMICAL (also as a representative of the salicylates) inhibited the diabetes-induced upregulation of several inflammatory gene products, which are regulated by NF-kappaB, including vascular cell adhesion molecule, intracellular adhesion molecule-1, inducible nitric oxide synthase, and GENE in whole-retinal lysate. Salicylates, in doses administrated in our experiments, inhibited NF-kappaB and perhaps other transcription factors in the retina, were well tolerated, and offered new tools to investigate and inhibit the development of diabetic retinopathy. | INDIRECT-DOWNREGULATOR |
| Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. It has been previously reported that aspirin inhibited the development of diabetic retinopathy in diabetic animals, raising the possibility that anti-inflammatory drugs may have beneficial effects on diabetic retinopathy. To further explore this, we compared effects of oral consumption of three different salicylate-based drugs (aspirin, sodium salicylate, and sulfasalazine) on the development of early stages of diabetic retinopathy in rats. These three drugs differ in their ability to inhibit cyclooxygenase but share an ability to inhibit nuclear factor-kappaB (NF-kappaB). Diabetes of 9-10 months duration significantly increased the number of TUNEL (transferase-mediated dUTP nick-end labeling)-positive capillary cells and acellular (degenerate) capillaries in the retinal vasculature, and all three salicylate-based drugs inhibited this cell death and formation of acellular capillaries without altering the severity of hyperglycemia. In short-term diabetes (2-4 months), all three salicylates inhibited the diabetes-induced loss of neuronal cells from the ganglion cell layer. Oral aspirin (as a representative of the salicylate family) inhibited diabetes-induced increase in NF-kappaB DNA-binding affinity in electrophoretic mobility shift assay and transcription factor array in nuclear extract isolated from whole retina. All three salicylates inhibited the diabetes-induced translocation of p50 (a subunit of NF-kappaB) into nuclei of retinal vascular endothelial cells of the isolated retinal vasculature, as well as of p50 and p65 into nuclei of cells in the ganglion cell layer and inner nuclear layer on whole-retinal sections. Sulfasalazine (also as a representative of the salicylates) inhibited the diabetes-induced upregulation of several inflammatory gene products, which are regulated by NF-kappaB, including vascular cell adhesion molecule, intracellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2 in whole-retinal lysate. CHEMICAL, in doses administrated in our experiments, inhibited GENEB and perhaps other transcription factors in the retina, were well tolerated, and offered new tools to investigate and inhibit the development of diabetic retinopathy. | INHIBITOR |
| Localization of an 11 beta hydroxysteroid dehydrogenase activity to the distal nephron. Evidence for the existence of two species of dehydrogenase in the rat kidney. An 11 beta hydroxysteroid dehydrogenase (11 beta HSD) activity has been localized in the rat kidney by a histochemical technique which links steroid metabolism with the production of a color reaction. Oxidation of 11 beta-hydroxyandrostenedione was observed in cortical distal convoluted tubules and in medullary collecting ducts. Carbenoxolone abolished staining, no reaction was obtained with androstenedione hydroxylated at the 17 or 19 position, and oxidation of 11 beta-hydroxyandrostenedione was nicotinamide-adenine dinucleotide (NAD) dependent. These results demonstrate the presence of a dehydrogenase activity separate from the nicotinamide-adenine dinucleotide phosphate (NADP)-dependent 11 beta hydroxysteroid dehydrogenase recently purified and cloned from rat liver. We have named this activity 11 beta HSD2 to distinguish it from the CHEMICAL-dependent GENE. Histological studies showed that 11 beta HSD2 activity does not correlate with the immunocytochemical localization of the previously defined GENE enzyme, but rather the 11 beta HSD2 activity is localized in the distal tubules of the rat kidney. In this respect 11 beta HSD2 colocalizes with the mineralocorticoid receptor. No reaction product was obtained using cortisol or corticosterone as substrate with either NAD or CHEMICAL as cofactor. Furthermore incubation of tissue sections with 11 beta androstenedione in the presence of deoxycorticosterone completely inhibited cytochemical staining. We interpret these results as evidence of 20 reductase activity which uses the reduced cofactor at the expense of the color reaction. These results support the crucial role played by an 11 beta hydroxysteroid dehydrogenase in the local protection of type I receptors in mineralocorticoid selective tissues. | REGULATOR |
| Localization of an GENE activity to the distal nephron. Evidence for the existence of two species of dehydrogenase in the rat kidney. An GENE (11 beta HSD) activity has been localized in the rat kidney by a histochemical technique which links steroid metabolism with the production of a color reaction. Oxidation of 11 beta-hydroxyandrostenedione was observed in cortical distal convoluted tubules and in medullary collecting ducts. Carbenoxolone abolished staining, no reaction was obtained with androstenedione hydroxylated at the 17 or 19 position, and oxidation of 11 beta-hydroxyandrostenedione was nicotinamide-adenine dinucleotide (NAD) dependent. These results demonstrate the presence of a dehydrogenase activity separate from the CHEMICAL (NADP)-dependent GENE recently purified and cloned from rat liver. We have named this activity 11 beta HSD2 to distinguish it from the NADP-dependent 11 beta HSD. Histological studies showed that 11 beta HSD2 activity does not correlate with the immunocytochemical localization of the previously defined 11 beta HSD enzyme, but rather the 11 beta HSD2 activity is localized in the distal tubules of the rat kidney. In this respect 11 beta HSD2 colocalizes with the mineralocorticoid receptor. No reaction product was obtained using cortisol or corticosterone as substrate with either NAD or NADP as cofactor. Furthermore incubation of tissue sections with 11 beta androstenedione in the presence of deoxycorticosterone completely inhibited cytochemical staining. We interpret these results as evidence of 20 reductase activity which uses the reduced cofactor at the expense of the color reaction. These results support the crucial role played by an GENE in the local protection of type I receptors in mineralocorticoid selective tissues. | GENE-CHEMICAL |
| Localization of an GENE activity to the distal nephron. Evidence for the existence of two species of dehydrogenase in the rat kidney. An GENE (11 beta HSD) activity has been localized in the rat kidney by a histochemical technique which links steroid metabolism with the production of a color reaction. Oxidation of 11 beta-hydroxyandrostenedione was observed in cortical distal convoluted tubules and in medullary collecting ducts. Carbenoxolone abolished staining, no reaction was obtained with androstenedione hydroxylated at the 17 or 19 position, and oxidation of 11 beta-hydroxyandrostenedione was nicotinamide-adenine dinucleotide (NAD) dependent. These results demonstrate the presence of a dehydrogenase activity separate from the nicotinamide-adenine dinucleotide phosphate (CHEMICAL)-dependent GENE recently purified and cloned from rat liver. We have named this activity 11 beta HSD2 to distinguish it from the NADP-dependent 11 beta HSD. Histological studies showed that 11 beta HSD2 activity does not correlate with the immunocytochemical localization of the previously defined 11 beta HSD enzyme, but rather the 11 beta HSD2 activity is localized in the distal tubules of the rat kidney. In this respect 11 beta HSD2 colocalizes with the mineralocorticoid receptor. No reaction product was obtained using cortisol or corticosterone as substrate with either NAD or CHEMICAL as cofactor. Furthermore incubation of tissue sections with 11 beta androstenedione in the presence of deoxycorticosterone completely inhibited cytochemical staining. We interpret these results as evidence of 20 reductase activity which uses the reduced cofactor at the expense of the color reaction. These results support the crucial role played by an GENE in the local protection of type I receptors in mineralocorticoid selective tissues. | GENE-CHEMICAL |
| Effect of long-term fluoxetine treatment on the human serotonin transporter in Caco-2 cells. CHEMICAL is a selective serotonin reuptake inhibitor (SSRI) broadly used in the treatment of human mood disorders and gastrointestinal diseases involving the serotoninergic system. The effectiveness of this therapy depends on repeated long-term treatment. Most of the long-term studies in vivo of SSRI effects on serotoninergic activity have focused on their effects on autoreceptors or postsynaptic receptors. The chronic effect of SSRIs on the activity of the serotonin transporter (SERT) has been less studied and the results have been contradictory. The aim of this study was to determine the specific effect of long-term fluoxetine treatment on human serotonin transporter (hSERT) in vitro, by using the human enterocyte-like cell line Caco-2. Results show that fluoxetine diminished the 5-HT uptake in a concentration-dependent way and that this effect was reversible. CHEMICAL affected mainly the GENE transport rate by reducing the availability of the transporter in the membrane with no significant alteration of either the total GENE protein content or the GENE mRNA level. These results suggest that the effect of fluoxetine on the expression of GENE is post-translational and has shown itself to be independent of PKC and PKA activity. This study may be useful to clarify the effect of the long-term fluoxetine therapy in both gastrointestinal and central nervous system disorders. | NO-RELATIONSHIP |
| Effect of long-term CHEMICAL treatment on the human serotonin transporter in Caco-2 cells. CHEMICAL is a selective serotonin reuptake inhibitor (SSRI) broadly used in the treatment of human mood disorders and gastrointestinal diseases involving the serotoninergic system. The effectiveness of this therapy depends on repeated long-term treatment. Most of the long-term studies in vivo of SSRI effects on serotoninergic activity have focused on their effects on autoreceptors or postsynaptic receptors. The chronic effect of SSRIs on the activity of the serotonin transporter (SERT) has been less studied and the results have been contradictory. The aim of this study was to determine the specific effect of long-term CHEMICAL treatment on human serotonin transporter (hSERT) in vitro, by using the human enterocyte-like cell line Caco-2. Results show that CHEMICAL diminished the 5-HT uptake in a concentration-dependent way and that this effect was reversible. CHEMICAL affected mainly the hSERT transport rate by reducing the availability of the transporter in the membrane with no significant alteration of either the total hSERT protein content or the hSERT mRNA level. These results suggest that the effect of CHEMICAL on the expression of hSERT is post-translational and has shown itself to be independent of GENE and PKA activity. This study may be useful to clarify the effect of the long-term CHEMICAL therapy in both gastrointestinal and central nervous system disorders. | NO-RELATIONSHIP |
| Effect of long-term CHEMICAL treatment on the human serotonin transporter in Caco-2 cells. CHEMICAL is a selective serotonin reuptake inhibitor (SSRI) broadly used in the treatment of human mood disorders and gastrointestinal diseases involving the serotoninergic system. The effectiveness of this therapy depends on repeated long-term treatment. Most of the long-term studies in vivo of SSRI effects on serotoninergic activity have focused on their effects on autoreceptors or postsynaptic receptors. The chronic effect of SSRIs on the activity of the serotonin transporter (SERT) has been less studied and the results have been contradictory. The aim of this study was to determine the specific effect of long-term CHEMICAL treatment on human serotonin transporter (hSERT) in vitro, by using the human enterocyte-like cell line Caco-2. Results show that CHEMICAL diminished the 5-HT uptake in a concentration-dependent way and that this effect was reversible. CHEMICAL affected mainly the hSERT transport rate by reducing the availability of the transporter in the membrane with no significant alteration of either the total hSERT protein content or the hSERT mRNA level. These results suggest that the effect of CHEMICAL on the expression of hSERT is post-translational and has shown itself to be independent of PKC and GENE activity. This study may be useful to clarify the effect of the long-term CHEMICAL therapy in both gastrointestinal and central nervous system disorders. | NO-RELATIONSHIP |
| Roles played by lymphocyte function-associated antigen-1 in the regulation of lymphocytic cholinergic activity. Lymphocytes possess the essential components of a cholinergic system, including acetylcholine (ACh); choline acetyltransferase (ChAT), its synthesizing enzyme; and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). Stimulation of lymphocytes with phytohemagglutinin, which activates T cells via the T cell receptor/CD3 complex, enhances the synthesis and release of ACh and up-regulates expression of ChAT and M(5) mAChR mRNAs. In addition, activation of protein kinase C and increases in intracellular cAMP also enhance cholinergic activity in T cells, and lymphocyte function associated antigen-1 (LFA-1; CD11a/CD18) is an important mediator of leukocyte migration and T cell activation. Anti-CD11a monoclonal antibody (mAb) as well as antithymocyte globulin containing antibodies against CD2, CD7 and CD11a all increase ChAT activity, ACh synthesis and release, and expression of ChAT and M(5) mAChR mRNAs in T cells. The cholesterol-lowering drug CHEMICAL inhibits GENE signaling by binding to an allosteric site on CD11a (LFA-1 alpha chain), which leads to immunomodulation. We found that CHEMICAL abolishes anti-CD11a mAb-induced increases in lymphocytic cholinergic activity in a manner independent of its cholesterol-lowering activity. Collectively then, these results indicate that GENE contributes to the regulation of lymphocytic cholinergic activity via CD11a-mediated pathways and suggest that CHEMICAL exerts its immunosuppressive effects in part via modification of lymphocytic cholinergic activity. | INDIRECT-DOWNREGULATOR |
| Roles played by lymphocyte function-associated antigen-1 in the regulation of lymphocytic cholinergic activity. Lymphocytes possess the essential components of a cholinergic system, including acetylcholine (ACh); choline acetyltransferase (ChAT), its synthesizing enzyme; and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). Stimulation of lymphocytes with phytohemagglutinin, which activates T cells via the T cell receptor/CD3 complex, enhances the synthesis and release of ACh and up-regulates expression of ChAT and M(5) mAChR mRNAs. In addition, activation of protein kinase C and increases in intracellular cAMP also enhance cholinergic activity in T cells, and lymphocyte function associated antigen-1 (LFA-1; CD11a/CD18) is an important mediator of leukocyte migration and T cell activation. Anti-CD11a monoclonal antibody (mAb) as well as antithymocyte globulin containing antibodies against CD2, CD7 and GENE all increase ChAT activity, ACh synthesis and release, and expression of ChAT and M(5) mAChR mRNAs in T cells. The cholesterol-lowering drug CHEMICAL inhibits LFA-1 signaling by binding to an allosteric site on GENE (LFA-1 alpha chain), which leads to immunomodulation. We found that CHEMICAL abolishes anti-CD11a mAb-induced increases in lymphocytic cholinergic activity in a manner independent of its cholesterol-lowering activity. Collectively then, these results indicate that LFA-1 contributes to the regulation of lymphocytic cholinergic activity via GENE-mediated pathways and suggest that CHEMICAL exerts its immunosuppressive effects in part via modification of lymphocytic cholinergic activity. | REGULATOR |
| Roles played by lymphocyte function-associated antigen-1 in the regulation of lymphocytic cholinergic activity. Lymphocytes possess the essential components of a cholinergic system, including acetylcholine (ACh); choline acetyltransferase (ChAT), its synthesizing enzyme; and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). Stimulation of lymphocytes with phytohemagglutinin, which activates T cells via the T cell receptor/CD3 complex, enhances the synthesis and release of ACh and up-regulates expression of ChAT and M(5) mAChR mRNAs. In addition, activation of protein kinase C and increases in intracellular CHEMICAL also enhance cholinergic activity in T cells, and GENE (LFA-1; CD11a/CD18) is an important mediator of leukocyte migration and T cell activation. Anti-CD11a monoclonal antibody (mAb) as well as antithymocyte globulin containing antibodies against CD2, CD7 and CD11a all increase ChAT activity, ACh synthesis and release, and expression of ChAT and M(5) mAChR mRNAs in T cells. The cholesterol-lowering drug simvastatin inhibits LFA-1 signaling by binding to an allosteric site on CD11a (LFA-1 alpha chain), which leads to immunomodulation. We found that simvastatin abolishes anti-CD11a mAb-induced increases in lymphocytic cholinergic activity in a manner independent of its cholesterol-lowering activity. Collectively then, these results indicate that LFA-1 contributes to the regulation of lymphocytic cholinergic activity via CD11a-mediated pathways and suggest that simvastatin exerts its immunosuppressive effects in part via modification of lymphocytic cholinergic activity. | REGULATOR |
| Roles played by lymphocyte function-associated antigen-1 in the regulation of lymphocytic cholinergic activity. Lymphocytes possess the essential components of a cholinergic system, including acetylcholine (ACh); choline acetyltransferase (ChAT), its synthesizing enzyme; and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). Stimulation of lymphocytes with phytohemagglutinin, which activates T cells via the T cell receptor/CD3 complex, enhances the synthesis and release of ACh and up-regulates expression of ChAT and M(5) mAChR mRNAs. In addition, activation of protein kinase C and increases in intracellular CHEMICAL also enhance cholinergic activity in T cells, and lymphocyte function associated antigen-1 (GENE; CD11a/CD18) is an important mediator of leukocyte migration and T cell activation. Anti-CD11a monoclonal antibody (mAb) as well as antithymocyte globulin containing antibodies against CD2, CD7 and CD11a all increase ChAT activity, ACh synthesis and release, and expression of ChAT and M(5) mAChR mRNAs in T cells. The cholesterol-lowering drug simvastatin inhibits GENE signaling by binding to an allosteric site on CD11a (LFA-1 alpha chain), which leads to immunomodulation. We found that simvastatin abolishes anti-CD11a mAb-induced increases in lymphocytic cholinergic activity in a manner independent of its cholesterol-lowering activity. Collectively then, these results indicate that GENE contributes to the regulation of lymphocytic cholinergic activity via CD11a-mediated pathways and suggest that simvastatin exerts its immunosuppressive effects in part via modification of lymphocytic cholinergic activity. | REGULATOR |
| Roles played by lymphocyte function-associated antigen-1 in the regulation of lymphocytic cholinergic activity. Lymphocytes possess the essential components of a cholinergic system, including acetylcholine (ACh); choline acetyltransferase (ChAT), its synthesizing enzyme; and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). Stimulation of lymphocytes with phytohemagglutinin, which activates T cells via the T cell receptor/CD3 complex, enhances the synthesis and release of ACh and up-regulates expression of ChAT and M(5) mAChR mRNAs. In addition, activation of protein kinase C and increases in intracellular CHEMICAL also enhance cholinergic activity in T cells, and lymphocyte function associated antigen-1 (LFA-1; GENE/CD18) is an important mediator of leukocyte migration and T cell activation. Anti-CD11a monoclonal antibody (mAb) as well as antithymocyte globulin containing antibodies against CD2, CD7 and GENE all increase ChAT activity, ACh synthesis and release, and expression of ChAT and M(5) mAChR mRNAs in T cells. The cholesterol-lowering drug simvastatin inhibits LFA-1 signaling by binding to an allosteric site on GENE (LFA-1 alpha chain), which leads to immunomodulation. We found that simvastatin abolishes anti-CD11a mAb-induced increases in lymphocytic cholinergic activity in a manner independent of its cholesterol-lowering activity. Collectively then, these results indicate that LFA-1 contributes to the regulation of lymphocytic cholinergic activity via CD11a-mediated pathways and suggest that simvastatin exerts its immunosuppressive effects in part via modification of lymphocytic cholinergic activity. | REGULATOR |
| Roles played by lymphocyte function-associated antigen-1 in the regulation of lymphocytic cholinergic activity. Lymphocytes possess the essential components of a cholinergic system, including acetylcholine (ACh); choline acetyltransferase (ChAT), its synthesizing enzyme; and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). Stimulation of lymphocytes with phytohemagglutinin, which activates T cells via the T cell receptor/CD3 complex, enhances the synthesis and release of ACh and up-regulates expression of ChAT and M(5) mAChR mRNAs. In addition, activation of protein kinase C and increases in intracellular CHEMICAL also enhance cholinergic activity in T cells, and lymphocyte function associated antigen-1 (LFA-1; CD11a/GENE) is an important mediator of leukocyte migration and T cell activation. Anti-CD11a monoclonal antibody (mAb) as well as antithymocyte globulin containing antibodies against CD2, CD7 and CD11a all increase ChAT activity, ACh synthesis and release, and expression of ChAT and M(5) mAChR mRNAs in T cells. The cholesterol-lowering drug simvastatin inhibits LFA-1 signaling by binding to an allosteric site on CD11a (LFA-1 alpha chain), which leads to immunomodulation. We found that simvastatin abolishes anti-CD11a mAb-induced increases in lymphocytic cholinergic activity in a manner independent of its cholesterol-lowering activity. Collectively then, these results indicate that LFA-1 contributes to the regulation of lymphocytic cholinergic activity via CD11a-mediated pathways and suggest that simvastatin exerts its immunosuppressive effects in part via modification of lymphocytic cholinergic activity. | REGULATOR |
| Roles played by lymphocyte function-associated antigen-1 in the regulation of lymphocytic cholinergic activity. Lymphocytes possess the essential components of a cholinergic system, including acetylcholine (CHEMICAL); GENE (ChAT), its synthesizing enzyme; and both muscarinic and nicotinic CHEMICAL receptors (mAChRs and nAChRs, respectively). Stimulation of lymphocytes with phytohemagglutinin, which activates T cells via the T cell receptor/CD3 complex, enhances the synthesis and release of CHEMICAL and up-regulates expression of ChAT and M(5) mAChR mRNAs. In addition, activation of protein kinase C and increases in intracellular cAMP also enhance cholinergic activity in T cells, and lymphocyte function associated antigen-1 (LFA-1; CD11a/CD18) is an important mediator of leukocyte migration and T cell activation. Anti-CD11a monoclonal antibody (mAb) as well as antithymocyte globulin containing antibodies against CD2, CD7 and CD11a all increase ChAT activity, CHEMICAL synthesis and release, and expression of ChAT and M(5) mAChR mRNAs in T cells. The cholesterol-lowering drug simvastatin inhibits LFA-1 signaling by binding to an allosteric site on CD11a (LFA-1 alpha chain), which leads to immunomodulation. We found that simvastatin abolishes anti-CD11a mAb-induced increases in lymphocytic cholinergic activity in a manner independent of its cholesterol-lowering activity. Collectively then, these results indicate that LFA-1 contributes to the regulation of lymphocytic cholinergic activity via CD11a-mediated pathways and suggest that simvastatin exerts its immunosuppressive effects in part via modification of lymphocytic cholinergic activity. | PRODUCT-OF |
| Roles played by lymphocyte function-associated antigen-1 in the regulation of lymphocytic cholinergic activity. Lymphocytes possess the essential components of a cholinergic system, including acetylcholine (CHEMICAL); choline acetyltransferase (GENE), its synthesizing enzyme; and both muscarinic and nicotinic CHEMICAL receptors (mAChRs and nAChRs, respectively). Stimulation of lymphocytes with phytohemagglutinin, which activates T cells via the T cell receptor/CD3 complex, enhances the synthesis and release of CHEMICAL and up-regulates expression of GENE and M(5) mAChR mRNAs. In addition, activation of protein kinase C and increases in intracellular cAMP also enhance cholinergic activity in T cells, and lymphocyte function associated antigen-1 (LFA-1; CD11a/CD18) is an important mediator of leukocyte migration and T cell activation. Anti-CD11a monoclonal antibody (mAb) as well as antithymocyte globulin containing antibodies against CD2, CD7 and CD11a all increase GENE activity, CHEMICAL synthesis and release, and expression of GENE and M(5) mAChR mRNAs in T cells. The cholesterol-lowering drug simvastatin inhibits LFA-1 signaling by binding to an allosteric site on CD11a (LFA-1 alpha chain), which leads to immunomodulation. We found that simvastatin abolishes anti-CD11a mAb-induced increases in lymphocytic cholinergic activity in a manner independent of its cholesterol-lowering activity. Collectively then, these results indicate that LFA-1 contributes to the regulation of lymphocytic cholinergic activity via CD11a-mediated pathways and suggest that simvastatin exerts its immunosuppressive effects in part via modification of lymphocytic cholinergic activity. | PRODUCT-OF |
| Roles played by lymphocyte function-associated antigen-1 in the regulation of lymphocytic cholinergic activity. Lymphocytes possess the essential components of a cholinergic system, including CHEMICAL (ACh); GENE (ChAT), its synthesizing enzyme; and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). Stimulation of lymphocytes with phytohemagglutinin, which activates T cells via the T cell receptor/CD3 complex, enhances the synthesis and release of ACh and up-regulates expression of ChAT and M(5) mAChR mRNAs. In addition, activation of protein kinase C and increases in intracellular cAMP also enhance cholinergic activity in T cells, and lymphocyte function associated antigen-1 (LFA-1; CD11a/CD18) is an important mediator of leukocyte migration and T cell activation. Anti-CD11a monoclonal antibody (mAb) as well as antithymocyte globulin containing antibodies against CD2, CD7 and CD11a all increase ChAT activity, ACh synthesis and release, and expression of ChAT and M(5) mAChR mRNAs in T cells. The cholesterol-lowering drug simvastatin inhibits LFA-1 signaling by binding to an allosteric site on CD11a (LFA-1 alpha chain), which leads to immunomodulation. We found that simvastatin abolishes anti-CD11a mAb-induced increases in lymphocytic cholinergic activity in a manner independent of its cholesterol-lowering activity. Collectively then, these results indicate that LFA-1 contributes to the regulation of lymphocytic cholinergic activity via CD11a-mediated pathways and suggest that simvastatin exerts its immunosuppressive effects in part via modification of lymphocytic cholinergic activity. | PRODUCT-OF |
| Roles played by lymphocyte function-associated antigen-1 in the regulation of lymphocytic cholinergic activity. Lymphocytes possess the essential components of a cholinergic system, including CHEMICAL (ACh); choline acetyltransferase (GENE), its synthesizing enzyme; and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). Stimulation of lymphocytes with phytohemagglutinin, which activates T cells via the T cell receptor/CD3 complex, enhances the synthesis and release of ACh and up-regulates expression of GENE and M(5) mAChR mRNAs. In addition, activation of protein kinase C and increases in intracellular cAMP also enhance cholinergic activity in T cells, and lymphocyte function associated antigen-1 (LFA-1; CD11a/CD18) is an important mediator of leukocyte migration and T cell activation. Anti-CD11a monoclonal antibody (mAb) as well as antithymocyte globulin containing antibodies against CD2, CD7 and CD11a all increase GENE activity, ACh synthesis and release, and expression of GENE and M(5) mAChR mRNAs in T cells. The cholesterol-lowering drug simvastatin inhibits LFA-1 signaling by binding to an allosteric site on CD11a (LFA-1 alpha chain), which leads to immunomodulation. We found that simvastatin abolishes anti-CD11a mAb-induced increases in lymphocytic cholinergic activity in a manner independent of its cholesterol-lowering activity. Collectively then, these results indicate that LFA-1 contributes to the regulation of lymphocytic cholinergic activity via CD11a-mediated pathways and suggest that simvastatin exerts its immunosuppressive effects in part via modification of lymphocytic cholinergic activity. | PRODUCT-OF |
| Association of estrogen receptor-alpha and CHEMICAL receptor A expression with hormonal mammary carcinogenesis: role of the host microenvironment. INTRODUCTION: Medroxyprogesterone acetate (MPA) induces estrogen receptor (ER)-positive and CHEMICAL receptor (PR)-positive ductal invasive mammary carcinomas in BALB/c mice. We sought to reproduce this MPA cancer model in C57BL/6 mice because of their widespread use in genetic engineering. Within this experimental setting, we studied the carcinogenic effects of MPA, the morphologic changes in mammary glands that are induced by MPA and CHEMICAL, and the levels of GENE and PR expression in MPA-treated and progesterone-treated mammary glands. Finally, we evaluated whether the differences found between BALB/c and C57BL/6 mouse strains were due to intrinsic differences in epithelial cells. METHODS: The carcinogenic effect of MPA was evaluated in C57BL/6 mice using protocols proven to be carcinogenic in BALB/c mice. In addition, BALB/c and C57BL/6 females were treated with CHEMICAL or MPA for 1 or 2 months, and mammary glands were excised for histologic studies and for immunohistochemical and Western blot evaluation of GENE and PR. Hormone levels were determined by radioimmunoassay. Isolated mammary epithelial cells were transplanted into cleared fat pads of 21-day-old female Swiss nu/nu mice or control congenic animals. RESULTS: MPA failed to induce mammary carcinomas or significant morphologic changes in the mammary glands of C57BL/6 mice. The expression of ER-alpha and PR isoform A in virgin mice was surprisingly much higher in BALB/c than in C57BL/6 mammary glands, and both receptors were downregulated in progestin-treated BALB/c mice (P < 0.05). PR isoform B levels were low in virgin control mice and increased after progestin treatment in both strains. ER-beta expression followed a similar trend. No differences in hormone levels were found between strains. Surprisingly, the transplantation of the epithelial mammary gland cells of both strains into the cleared fat pads of Swiss (nu/nu) mice abolished the mammary gland morphologic differences and the GENE and PR differences between strains. CONCLUSION: C57BL/6 mammary glands are resistant to MPA-induced carcinogenesis and to hormone action. MPA and CHEMICAL have different effects on mammary glands. Low ER-alpha and PR-A levels in untreated mammary glands may be associated with a low-risk breast cancer profile. Although we cannot at this time rule out the participation of other, untested factors, our findings implicate the stroma as playing a crucial role in the strain-specific differential hormone receptor expression and hormone responsiveness. | GENE-CHEMICAL |
| Association of estrogen receptor-alpha and CHEMICAL receptor A expression with hormonal mammary carcinogenesis: role of the host microenvironment. INTRODUCTION: Medroxyprogesterone acetate (MPA) induces estrogen receptor (ER)-positive and CHEMICAL receptor (PR)-positive ductal invasive mammary carcinomas in BALB/c mice. We sought to reproduce this MPA cancer model in C57BL/6 mice because of their widespread use in genetic engineering. Within this experimental setting, we studied the carcinogenic effects of MPA, the morphologic changes in mammary glands that are induced by MPA and CHEMICAL, and the levels of ER and GENE expression in MPA-treated and progesterone-treated mammary glands. Finally, we evaluated whether the differences found between BALB/c and C57BL/6 mouse strains were due to intrinsic differences in epithelial cells. METHODS: The carcinogenic effect of MPA was evaluated in C57BL/6 mice using protocols proven to be carcinogenic in BALB/c mice. In addition, BALB/c and C57BL/6 females were treated with CHEMICAL or MPA for 1 or 2 months, and mammary glands were excised for histologic studies and for immunohistochemical and Western blot evaluation of ER and GENE. Hormone levels were determined by radioimmunoassay. Isolated mammary epithelial cells were transplanted into cleared fat pads of 21-day-old female Swiss nu/nu mice or control congenic animals. RESULTS: MPA failed to induce mammary carcinomas or significant morphologic changes in the mammary glands of C57BL/6 mice. The expression of ER-alpha and GENE isoform A in virgin mice was surprisingly much higher in BALB/c than in C57BL/6 mammary glands, and both receptors were downregulated in progestin-treated BALB/c mice (P < 0.05). GENE isoform B levels were low in virgin control mice and increased after progestin treatment in both strains. ER-beta expression followed a similar trend. No differences in hormone levels were found between strains. Surprisingly, the transplantation of the epithelial mammary gland cells of both strains into the cleared fat pads of Swiss (nu/nu) mice abolished the mammary gland morphologic differences and the ER and GENE differences between strains. CONCLUSION: C57BL/6 mammary glands are resistant to MPA-induced carcinogenesis and to hormone action. MPA and CHEMICAL have different effects on mammary glands. Low ER-alpha and PR-A levels in untreated mammary glands may be associated with a low-risk breast cancer profile. Although we cannot at this time rule out the participation of other, untested factors, our findings implicate the stroma as playing a crucial role in the strain-specific differential hormone receptor expression and hormone responsiveness. | GENE-CHEMICAL |
| Association of estrogen receptor-alpha and progesterone receptor A expression with hormonal mammary carcinogenesis: role of the host microenvironment. INTRODUCTION: Medroxyprogesterone acetate (MPA) induces estrogen receptor (ER)-positive and progesterone receptor (PR)-positive ductal invasive mammary carcinomas in BALB/c mice. We sought to reproduce this CHEMICAL cancer model in C57BL/6 mice because of their widespread use in genetic engineering. Within this experimental setting, we studied the carcinogenic effects of CHEMICAL, the morphologic changes in mammary glands that are induced by CHEMICAL and progesterone, and the levels of GENE and PR expression in MPA-treated and progesterone-treated mammary glands. Finally, we evaluated whether the differences found between BALB/c and C57BL/6 mouse strains were due to intrinsic differences in epithelial cells. METHODS: The carcinogenic effect of CHEMICAL was evaluated in C57BL/6 mice using protocols proven to be carcinogenic in BALB/c mice. In addition, BALB/c and C57BL/6 females were treated with progesterone or CHEMICAL for 1 or 2 months, and mammary glands were excised for histologic studies and for immunohistochemical and Western blot evaluation of GENE and PR. Hormone levels were determined by radioimmunoassay. Isolated mammary epithelial cells were transplanted into cleared fat pads of 21-day-old female Swiss nu/nu mice or control congenic animals. RESULTS: CHEMICAL failed to induce mammary carcinomas or significant morphologic changes in the mammary glands of C57BL/6 mice. The expression of ER-alpha and PR isoform A in virgin mice was surprisingly much higher in BALB/c than in C57BL/6 mammary glands, and both receptors were downregulated in progestin-treated BALB/c mice (P < 0.05). PR isoform B levels were low in virgin control mice and increased after progestin treatment in both strains. ER-beta expression followed a similar trend. No differences in hormone levels were found between strains. Surprisingly, the transplantation of the epithelial mammary gland cells of both strains into the cleared fat pads of Swiss (nu/nu) mice abolished the mammary gland morphologic differences and the GENE and PR differences between strains. CONCLUSION: C57BL/6 mammary glands are resistant to MPA-induced carcinogenesis and to hormone action. CHEMICAL and progesterone have different effects on mammary glands. Low ER-alpha and PR-A levels in untreated mammary glands may be associated with a low-risk breast cancer profile. Although we cannot at this time rule out the participation of other, untested factors, our findings implicate the stroma as playing a crucial role in the strain-specific differential hormone receptor expression and hormone responsiveness. | GENE-CHEMICAL |
| Association of estrogen receptor-alpha and progesterone receptor A expression with hormonal mammary carcinogenesis: role of the host microenvironment. INTRODUCTION: Medroxyprogesterone acetate (MPA) induces estrogen receptor (ER)-positive and progesterone receptor (PR)-positive ductal invasive mammary carcinomas in BALB/c mice. We sought to reproduce this CHEMICAL cancer model in C57BL/6 mice because of their widespread use in genetic engineering. Within this experimental setting, we studied the carcinogenic effects of CHEMICAL, the morphologic changes in mammary glands that are induced by CHEMICAL and progesterone, and the levels of ER and GENE expression in MPA-treated and progesterone-treated mammary glands. Finally, we evaluated whether the differences found between BALB/c and C57BL/6 mouse strains were due to intrinsic differences in epithelial cells. METHODS: The carcinogenic effect of CHEMICAL was evaluated in C57BL/6 mice using protocols proven to be carcinogenic in BALB/c mice. In addition, BALB/c and C57BL/6 females were treated with progesterone or CHEMICAL for 1 or 2 months, and mammary glands were excised for histologic studies and for immunohistochemical and Western blot evaluation of ER and GENE. Hormone levels were determined by radioimmunoassay. Isolated mammary epithelial cells were transplanted into cleared fat pads of 21-day-old female Swiss nu/nu mice or control congenic animals. RESULTS: CHEMICAL failed to induce mammary carcinomas or significant morphologic changes in the mammary glands of C57BL/6 mice. The expression of ER-alpha and GENE isoform A in virgin mice was surprisingly much higher in BALB/c than in C57BL/6 mammary glands, and both receptors were downregulated in progestin-treated BALB/c mice (P < 0.05). GENE isoform B levels were low in virgin control mice and increased after progestin treatment in both strains. ER-beta expression followed a similar trend. No differences in hormone levels were found between strains. Surprisingly, the transplantation of the epithelial mammary gland cells of both strains into the cleared fat pads of Swiss (nu/nu) mice abolished the mammary gland morphologic differences and the ER and GENE differences between strains. CONCLUSION: C57BL/6 mammary glands are resistant to MPA-induced carcinogenesis and to hormone action. CHEMICAL and progesterone have different effects on mammary glands. Low ER-alpha and PR-A levels in untreated mammary glands may be associated with a low-risk breast cancer profile. Although we cannot at this time rule out the participation of other, untested factors, our findings implicate the stroma as playing a crucial role in the strain-specific differential hormone receptor expression and hormone responsiveness. | GENE-CHEMICAL |
| Association of estrogen receptor-alpha and GENE A expression with hormonal mammary carcinogenesis: role of the host microenvironment. INTRODUCTION: Medroxyprogesterone acetate (CHEMICAL) induces estrogen receptor (ER)-positive and GENE (PR)-positive ductal invasive mammary carcinomas in BALB/c mice. We sought to reproduce this CHEMICAL cancer model in C57BL/6 mice because of their widespread use in genetic engineering. Within this experimental setting, we studied the carcinogenic effects of CHEMICAL, the morphologic changes in mammary glands that are induced by CHEMICAL and progesterone, and the levels of ER and PR expression in MPA-treated and progesterone-treated mammary glands. Finally, we evaluated whether the differences found between BALB/c and C57BL/6 mouse strains were due to intrinsic differences in epithelial cells. METHODS: The carcinogenic effect of CHEMICAL was evaluated in C57BL/6 mice using protocols proven to be carcinogenic in BALB/c mice. In addition, BALB/c and C57BL/6 females were treated with progesterone or CHEMICAL for 1 or 2 months, and mammary glands were excised for histologic studies and for immunohistochemical and Western blot evaluation of ER and PR. Hormone levels were determined by radioimmunoassay. Isolated mammary epithelial cells were transplanted into cleared fat pads of 21-day-old female Swiss nu/nu mice or control congenic animals. RESULTS: CHEMICAL failed to induce mammary carcinomas or significant morphologic changes in the mammary glands of C57BL/6 mice. The expression of ER-alpha and PR isoform A in virgin mice was surprisingly much higher in BALB/c than in C57BL/6 mammary glands, and both receptors were downregulated in progestin-treated BALB/c mice (P < 0.05). PR isoform B levels were low in virgin control mice and increased after progestin treatment in both strains. ER-beta expression followed a similar trend. No differences in hormone levels were found between strains. Surprisingly, the transplantation of the epithelial mammary gland cells of both strains into the cleared fat pads of Swiss (nu/nu) mice abolished the mammary gland morphologic differences and the ER and PR differences between strains. CONCLUSION: C57BL/6 mammary glands are resistant to MPA-induced carcinogenesis and to hormone action. CHEMICAL and progesterone have different effects on mammary glands. Low ER-alpha and PR-A levels in untreated mammary glands may be associated with a low-risk breast cancer profile. Although we cannot at this time rule out the participation of other, untested factors, our findings implicate the stroma as playing a crucial role in the strain-specific differential hormone receptor expression and hormone responsiveness. | INDIRECT-UPREGULATOR |
| Association of estrogen receptor-alpha and progesterone receptor A expression with hormonal mammary carcinogenesis: role of the host microenvironment. INTRODUCTION: Medroxyprogesterone acetate (MPA) induces estrogen receptor (ER)-positive and progesterone receptor (PR)-positive ductal invasive mammary carcinomas in BALB/c mice. We sought to reproduce this MPA cancer model in C57BL/6 mice because of their widespread use in genetic engineering. Within this experimental setting, we studied the carcinogenic effects of MPA, the morphologic changes in mammary glands that are induced by MPA and progesterone, and the levels of ER and PR expression in MPA-treated and progesterone-treated mammary glands. Finally, we evaluated whether the differences found between BALB/c and C57BL/6 mouse strains were due to intrinsic differences in epithelial cells. METHODS: The carcinogenic effect of MPA was evaluated in C57BL/6 mice using protocols proven to be carcinogenic in BALB/c mice. In addition, BALB/c and C57BL/6 females were treated with progesterone or MPA for 1 or 2 months, and mammary glands were excised for histologic studies and for immunohistochemical and Western blot evaluation of ER and PR. Hormone levels were determined by radioimmunoassay. Isolated mammary epithelial cells were transplanted into cleared fat pads of 21-day-old female Swiss nu/nu mice or control congenic animals. RESULTS: MPA failed to induce mammary carcinomas or significant morphologic changes in the mammary glands of C57BL/6 mice. The expression of ER-alpha and PR isoform A in virgin mice was surprisingly much higher in BALB/c than in C57BL/6 mammary glands, and both receptors were downregulated in progestin-treated BALB/c mice (P < 0.05). GENE levels were low in virgin control mice and increased after CHEMICAL treatment in both strains. ER-beta expression followed a similar trend. No differences in hormone levels were found between strains. Surprisingly, the transplantation of the epithelial mammary gland cells of both strains into the cleared fat pads of Swiss (nu/nu) mice abolished the mammary gland morphologic differences and the ER and PR differences between strains. CONCLUSION: C57BL/6 mammary glands are resistant to MPA-induced carcinogenesis and to hormone action. MPA and progesterone have different effects on mammary glands. Low ER-alpha and PR-A levels in untreated mammary glands may be associated with a low-risk breast cancer profile. Although we cannot at this time rule out the participation of other, untested factors, our findings implicate the stroma as playing a crucial role in the strain-specific differential hormone receptor expression and hormone responsiveness. | INDIRECT-UPREGULATOR |
| Association of estrogen receptor-alpha and progesterone receptor A expression with hormonal mammary carcinogenesis: role of the host microenvironment. INTRODUCTION: Medroxyprogesterone acetate (CHEMICAL) induces GENE (ER)-positive and progesterone receptor (PR)-positive ductal invasive mammary carcinomas in BALB/c mice. We sought to reproduce this CHEMICAL cancer model in C57BL/6 mice because of their widespread use in genetic engineering. Within this experimental setting, we studied the carcinogenic effects of CHEMICAL, the morphologic changes in mammary glands that are induced by CHEMICAL and progesterone, and the levels of ER and PR expression in MPA-treated and progesterone-treated mammary glands. Finally, we evaluated whether the differences found between BALB/c and C57BL/6 mouse strains were due to intrinsic differences in epithelial cells. METHODS: The carcinogenic effect of CHEMICAL was evaluated in C57BL/6 mice using protocols proven to be carcinogenic in BALB/c mice. In addition, BALB/c and C57BL/6 females were treated with progesterone or CHEMICAL for 1 or 2 months, and mammary glands were excised for histologic studies and for immunohistochemical and Western blot evaluation of ER and PR. Hormone levels were determined by radioimmunoassay. Isolated mammary epithelial cells were transplanted into cleared fat pads of 21-day-old female Swiss nu/nu mice or control congenic animals. RESULTS: CHEMICAL failed to induce mammary carcinomas or significant morphologic changes in the mammary glands of C57BL/6 mice. The expression of ER-alpha and PR isoform A in virgin mice was surprisingly much higher in BALB/c than in C57BL/6 mammary glands, and both receptors were downregulated in progestin-treated BALB/c mice (P < 0.05). PR isoform B levels were low in virgin control mice and increased after progestin treatment in both strains. ER-beta expression followed a similar trend. No differences in hormone levels were found between strains. Surprisingly, the transplantation of the epithelial mammary gland cells of both strains into the cleared fat pads of Swiss (nu/nu) mice abolished the mammary gland morphologic differences and the ER and PR differences between strains. CONCLUSION: C57BL/6 mammary glands are resistant to MPA-induced carcinogenesis and to hormone action. CHEMICAL and progesterone have different effects on mammary glands. Low ER-alpha and PR-A levels in untreated mammary glands may be associated with a low-risk breast cancer profile. Although we cannot at this time rule out the participation of other, untested factors, our findings implicate the stroma as playing a crucial role in the strain-specific differential hormone receptor expression and hormone responsiveness. | INDIRECT-UPREGULATOR |
| Association of estrogen receptor-alpha and progesterone receptor A expression with hormonal mammary carcinogenesis: role of the host microenvironment. INTRODUCTION: CHEMICAL (MPA) induces estrogen receptor (ER)-positive and progesterone receptor (GENE)-positive ductal invasive mammary carcinomas in BALB/c mice. We sought to reproduce this MPA cancer model in C57BL/6 mice because of their widespread use in genetic engineering. Within this experimental setting, we studied the carcinogenic effects of MPA, the morphologic changes in mammary glands that are induced by MPA and progesterone, and the levels of ER and GENE expression in MPA-treated and progesterone-treated mammary glands. Finally, we evaluated whether the differences found between BALB/c and C57BL/6 mouse strains were due to intrinsic differences in epithelial cells. METHODS: The carcinogenic effect of MPA was evaluated in C57BL/6 mice using protocols proven to be carcinogenic in BALB/c mice. In addition, BALB/c and C57BL/6 females were treated with progesterone or MPA for 1 or 2 months, and mammary glands were excised for histologic studies and for immunohistochemical and Western blot evaluation of ER and GENE. Hormone levels were determined by radioimmunoassay. Isolated mammary epithelial cells were transplanted into cleared fat pads of 21-day-old female Swiss nu/nu mice or control congenic animals. RESULTS: MPA failed to induce mammary carcinomas or significant morphologic changes in the mammary glands of C57BL/6 mice. The expression of ER-alpha and GENE isoform A in virgin mice was surprisingly much higher in BALB/c than in C57BL/6 mammary glands, and both receptors were downregulated in progestin-treated BALB/c mice (P < 0.05). GENE isoform B levels were low in virgin control mice and increased after progestin treatment in both strains. ER-beta expression followed a similar trend. No differences in hormone levels were found between strains. Surprisingly, the transplantation of the epithelial mammary gland cells of both strains into the cleared fat pads of Swiss (nu/nu) mice abolished the mammary gland morphologic differences and the ER and GENE differences between strains. CONCLUSION: C57BL/6 mammary glands are resistant to MPA-induced carcinogenesis and to hormone action. MPA and progesterone have different effects on mammary glands. Low ER-alpha and PR-A levels in untreated mammary glands may be associated with a low-risk breast cancer profile. Although we cannot at this time rule out the participation of other, untested factors, our findings implicate the stroma as playing a crucial role in the strain-specific differential hormone receptor expression and hormone responsiveness. | INDIRECT-UPREGULATOR |
| Association of estrogen receptor-alpha and progesterone receptor A expression with hormonal mammary carcinogenesis: role of the host microenvironment. INTRODUCTION: CHEMICAL (MPA) induces GENE (ER)-positive and progesterone receptor (PR)-positive ductal invasive mammary carcinomas in BALB/c mice. We sought to reproduce this MPA cancer model in C57BL/6 mice because of their widespread use in genetic engineering. Within this experimental setting, we studied the carcinogenic effects of MPA, the morphologic changes in mammary glands that are induced by MPA and progesterone, and the levels of ER and PR expression in MPA-treated and progesterone-treated mammary glands. Finally, we evaluated whether the differences found between BALB/c and C57BL/6 mouse strains were due to intrinsic differences in epithelial cells. METHODS: The carcinogenic effect of MPA was evaluated in C57BL/6 mice using protocols proven to be carcinogenic in BALB/c mice. In addition, BALB/c and C57BL/6 females were treated with progesterone or MPA for 1 or 2 months, and mammary glands were excised for histologic studies and for immunohistochemical and Western blot evaluation of ER and PR. Hormone levels were determined by radioimmunoassay. Isolated mammary epithelial cells were transplanted into cleared fat pads of 21-day-old female Swiss nu/nu mice or control congenic animals. RESULTS: MPA failed to induce mammary carcinomas or significant morphologic changes in the mammary glands of C57BL/6 mice. The expression of ER-alpha and PR isoform A in virgin mice was surprisingly much higher in BALB/c than in C57BL/6 mammary glands, and both receptors were downregulated in progestin-treated BALB/c mice (P < 0.05). PR isoform B levels were low in virgin control mice and increased after progestin treatment in both strains. ER-beta expression followed a similar trend. No differences in hormone levels were found between strains. Surprisingly, the transplantation of the epithelial mammary gland cells of both strains into the cleared fat pads of Swiss (nu/nu) mice abolished the mammary gland morphologic differences and the ER and PR differences between strains. CONCLUSION: C57BL/6 mammary glands are resistant to MPA-induced carcinogenesis and to hormone action. MPA and progesterone have different effects on mammary glands. Low ER-alpha and PR-A levels in untreated mammary glands may be associated with a low-risk breast cancer profile. Although we cannot at this time rule out the participation of other, untested factors, our findings implicate the stroma as playing a crucial role in the strain-specific differential hormone receptor expression and hormone responsiveness. | ACTIVATOR |
| Association of estrogen receptor-alpha and progesterone receptor A expression with hormonal mammary carcinogenesis: role of the host microenvironment. INTRODUCTION: CHEMICAL (MPA) induces estrogen receptor (GENE)-positive and progesterone receptor (PR)-positive ductal invasive mammary carcinomas in BALB/c mice. We sought to reproduce this MPA cancer model in C57BL/6 mice because of their widespread use in genetic engineering. Within this experimental setting, we studied the carcinogenic effects of MPA, the morphologic changes in mammary glands that are induced by MPA and progesterone, and the levels of GENE and PR expression in MPA-treated and progesterone-treated mammary glands. Finally, we evaluated whether the differences found between BALB/c and C57BL/6 mouse strains were due to intrinsic differences in epithelial cells. METHODS: The carcinogenic effect of MPA was evaluated in C57BL/6 mice using protocols proven to be carcinogenic in BALB/c mice. In addition, BALB/c and C57BL/6 females were treated with progesterone or MPA for 1 or 2 months, and mammary glands were excised for histologic studies and for immunohistochemical and Western blot evaluation of GENE and PR. Hormone levels were determined by radioimmunoassay. Isolated mammary epithelial cells were transplanted into cleared fat pads of 21-day-old female Swiss nu/nu mice or control congenic animals. RESULTS: MPA failed to induce mammary carcinomas or significant morphologic changes in the mammary glands of C57BL/6 mice. The expression of ER-alpha and PR isoform A in virgin mice was surprisingly much higher in BALB/c than in C57BL/6 mammary glands, and both receptors were downregulated in progestin-treated BALB/c mice (P < 0.05). PR isoform B levels were low in virgin control mice and increased after progestin treatment in both strains. ER-beta expression followed a similar trend. No differences in hormone levels were found between strains. Surprisingly, the transplantation of the epithelial mammary gland cells of both strains into the cleared fat pads of Swiss (nu/nu) mice abolished the mammary gland morphologic differences and the GENE and PR differences between strains. CONCLUSION: C57BL/6 mammary glands are resistant to MPA-induced carcinogenesis and to hormone action. MPA and progesterone have different effects on mammary glands. Low ER-alpha and PR-A levels in untreated mammary glands may be associated with a low-risk breast cancer profile. Although we cannot at this time rule out the participation of other, untested factors, our findings implicate the stroma as playing a crucial role in the strain-specific differential hormone receptor expression and hormone responsiveness. | INDIRECT-UPREGULATOR |
| Association of estrogen receptor-alpha and GENE A expression with hormonal mammary carcinogenesis: role of the host microenvironment. INTRODUCTION: CHEMICAL (MPA) induces estrogen receptor (ER)-positive and GENE (PR)-positive ductal invasive mammary carcinomas in BALB/c mice. We sought to reproduce this MPA cancer model in C57BL/6 mice because of their widespread use in genetic engineering. Within this experimental setting, we studied the carcinogenic effects of MPA, the morphologic changes in mammary glands that are induced by MPA and progesterone, and the levels of ER and PR expression in MPA-treated and progesterone-treated mammary glands. Finally, we evaluated whether the differences found between BALB/c and C57BL/6 mouse strains were due to intrinsic differences in epithelial cells. METHODS: The carcinogenic effect of MPA was evaluated in C57BL/6 mice using protocols proven to be carcinogenic in BALB/c mice. In addition, BALB/c and C57BL/6 females were treated with progesterone or MPA for 1 or 2 months, and mammary glands were excised for histologic studies and for immunohistochemical and Western blot evaluation of ER and PR. Hormone levels were determined by radioimmunoassay. Isolated mammary epithelial cells were transplanted into cleared fat pads of 21-day-old female Swiss nu/nu mice or control congenic animals. RESULTS: MPA failed to induce mammary carcinomas or significant morphologic changes in the mammary glands of C57BL/6 mice. The expression of ER-alpha and PR isoform A in virgin mice was surprisingly much higher in BALB/c than in C57BL/6 mammary glands, and both receptors were downregulated in progestin-treated BALB/c mice (P < 0.05). PR isoform B levels were low in virgin control mice and increased after progestin treatment in both strains. ER-beta expression followed a similar trend. No differences in hormone levels were found between strains. Surprisingly, the transplantation of the epithelial mammary gland cells of both strains into the cleared fat pads of Swiss (nu/nu) mice abolished the mammary gland morphologic differences and the ER and PR differences between strains. CONCLUSION: C57BL/6 mammary glands are resistant to MPA-induced carcinogenesis and to hormone action. MPA and progesterone have different effects on mammary glands. Low ER-alpha and PR-A levels in untreated mammary glands may be associated with a low-risk breast cancer profile. Although we cannot at this time rule out the participation of other, untested factors, our findings implicate the stroma as playing a crucial role in the strain-specific differential hormone receptor expression and hormone responsiveness. | INDIRECT-UPREGULATOR |
| Association of estrogen receptor-alpha and progesterone receptor A expression with hormonal mammary carcinogenesis: role of the host microenvironment. INTRODUCTION: Medroxyprogesterone acetate (MPA) induces estrogen receptor (ER)-positive and progesterone receptor (PR)-positive ductal invasive mammary carcinomas in BALB/c mice. We sought to reproduce this MPA cancer model in C57BL/6 mice because of their widespread use in genetic engineering. Within this experimental setting, we studied the carcinogenic effects of MPA, the morphologic changes in mammary glands that are induced by MPA and progesterone, and the levels of ER and PR expression in MPA-treated and progesterone-treated mammary glands. Finally, we evaluated whether the differences found between BALB/c and C57BL/6 mouse strains were due to intrinsic differences in epithelial cells. METHODS: The carcinogenic effect of MPA was evaluated in C57BL/6 mice using protocols proven to be carcinogenic in BALB/c mice. In addition, BALB/c and C57BL/6 females were treated with progesterone or MPA for 1 or 2 months, and mammary glands were excised for histologic studies and for immunohistochemical and Western blot evaluation of ER and PR. Hormone levels were determined by radioimmunoassay. Isolated mammary epithelial cells were transplanted into cleared fat pads of 21-day-old female Swiss nu/nu mice or control congenic animals. RESULTS: MPA failed to induce mammary carcinomas or significant morphologic changes in the mammary glands of C57BL/6 mice. The expression of GENE and PR isoform A in virgin mice was surprisingly much higher in BALB/c than in C57BL/6 mammary glands, and both receptors were downregulated in CHEMICAL-treated BALB/c mice (P < 0.05). PR isoform B levels were low in virgin control mice and increased after CHEMICAL treatment in both strains. ER-beta expression followed a similar trend. No differences in hormone levels were found between strains. Surprisingly, the transplantation of the epithelial mammary gland cells of both strains into the cleared fat pads of Swiss (nu/nu) mice abolished the mammary gland morphologic differences and the ER and PR differences between strains. CONCLUSION: C57BL/6 mammary glands are resistant to MPA-induced carcinogenesis and to hormone action. MPA and progesterone have different effects on mammary glands. Low GENE and PR-A levels in untreated mammary glands may be associated with a low-risk breast cancer profile. Although we cannot at this time rule out the participation of other, untested factors, our findings implicate the stroma as playing a crucial role in the strain-specific differential hormone receptor expression and hormone responsiveness. | INDIRECT-DOWNREGULATOR |
| Association of estrogen receptor-alpha and progesterone receptor A expression with hormonal mammary carcinogenesis: role of the host microenvironment. INTRODUCTION: Medroxyprogesterone acetate (MPA) induces estrogen receptor (ER)-positive and progesterone receptor (PR)-positive ductal invasive mammary carcinomas in BALB/c mice. We sought to reproduce this MPA cancer model in C57BL/6 mice because of their widespread use in genetic engineering. Within this experimental setting, we studied the carcinogenic effects of MPA, the morphologic changes in mammary glands that are induced by MPA and progesterone, and the levels of ER and PR expression in MPA-treated and progesterone-treated mammary glands. Finally, we evaluated whether the differences found between BALB/c and C57BL/6 mouse strains were due to intrinsic differences in epithelial cells. METHODS: The carcinogenic effect of MPA was evaluated in C57BL/6 mice using protocols proven to be carcinogenic in BALB/c mice. In addition, BALB/c and C57BL/6 females were treated with progesterone or MPA for 1 or 2 months, and mammary glands were excised for histologic studies and for immunohistochemical and Western blot evaluation of ER and PR. Hormone levels were determined by radioimmunoassay. Isolated mammary epithelial cells were transplanted into cleared fat pads of 21-day-old female Swiss nu/nu mice or control congenic animals. RESULTS: MPA failed to induce mammary carcinomas or significant morphologic changes in the mammary glands of C57BL/6 mice. The expression of ER-alpha and GENE in virgin mice was surprisingly much higher in BALB/c than in C57BL/6 mammary glands, and both receptors were downregulated in CHEMICAL-treated BALB/c mice (P < 0.05). PR isoform B levels were low in virgin control mice and increased after CHEMICAL treatment in both strains. ER-beta expression followed a similar trend. No differences in hormone levels were found between strains. Surprisingly, the transplantation of the epithelial mammary gland cells of both strains into the cleared fat pads of Swiss (nu/nu) mice abolished the mammary gland morphologic differences and the ER and PR differences between strains. CONCLUSION: C57BL/6 mammary glands are resistant to MPA-induced carcinogenesis and to hormone action. MPA and progesterone have different effects on mammary glands. Low ER-alpha and PR-A levels in untreated mammary glands may be associated with a low-risk breast cancer profile. Although we cannot at this time rule out the participation of other, untested factors, our findings implicate the stroma as playing a crucial role in the strain-specific differential hormone receptor expression and hormone responsiveness. | INDIRECT-DOWNREGULATOR |
| Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted CHEMICAL metabolism. Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or CHEMICAL metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with CHEMICAL metabolism also showed remarkable expression changes, including increased expression of GENE (HSD17beta7; involved in estradiol production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and CHEMICAL or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. | SUBSTRATE |
| Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted CHEMICAL metabolism. Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or CHEMICAL metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with CHEMICAL metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of GENE (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and CHEMICAL or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. | SUBSTRATE |
| Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant CHEMICAL signaling and disrupted steroid metabolism. Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either CHEMICAL signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by CHEMICAL, including GENE, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding CHEMICAL signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. | REGULATOR |
| Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant CHEMICAL signaling and disrupted steroid metabolism. Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either CHEMICAL signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by CHEMICAL, including X-inactive-specific transcript, GENE, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding CHEMICAL signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. | REGULATOR |
| Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant CHEMICAL signaling and disrupted steroid metabolism. Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either CHEMICAL signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by CHEMICAL, including X-inactive-specific transcript, anterior gradient-2, GENE, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding CHEMICAL signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. | REGULATOR |
| Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant CHEMICAL signaling and disrupted steroid metabolism. Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either CHEMICAL signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by CHEMICAL, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, GENE, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding CHEMICAL signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. | REGULATOR |
| Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant CHEMICAL signaling and disrupted steroid metabolism. Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either CHEMICAL signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by CHEMICAL, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, GENE, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding CHEMICAL signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. | REGULATOR |
| Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant CHEMICAL signaling and disrupted steroid metabolism. Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either CHEMICAL signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by CHEMICAL, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and GENE, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding CHEMICAL signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. | REGULATOR |
| Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism. Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. CHEMICAL-regulated genes including cytokeratin 1-19 and GENE were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. | INDIRECT-UPREGULATOR |
| Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism. Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. CHEMICAL-regulated genes including GENE and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. | INDIRECT-UPREGULATOR |
| Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism. Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. CHEMICAL-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although GENE was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. | GENE-CHEMICAL |
| Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism. Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of GENE (HSD17beta7; involved in CHEMICAL production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. | PRODUCT-OF |
| Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism. Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (GENE; involved in CHEMICAL production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. | PRODUCT-OF |
| Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism. Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of GENE (involved in CHEMICAL production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. | PRODUCT-OF |
| Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism. Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in CHEMICAL metabolism, such as GENE, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or CHEMICAL metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. | SUBSTRATE |
| Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism. Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in CHEMICAL metabolism, such as CHEMICAL adenosyltransferase-1a, GENE and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or CHEMICAL metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. | SUBSTRATE |
| Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism. Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p<0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17beta-hydroxysteroid dehydrogenase-7 (HSD17beta7; involved in estradiol production) and decreased expression of HSD17beta5 (involved in testosterone production). The expression of key genes important in CHEMICAL metabolism, such as CHEMICAL adenosyltransferase-1a, betaine-homocysteine methyltransferase and GENE, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or CHEMICAL metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood. | SUBSTRATE |
| A pilot study of IL-1 inhibition by anakinra in acute gout. CHEMICAL crystals stimulate monocytes and macrophages to release IL-1beta through the GENE component of the inflammasome. The effectiveness of IL-1 inhibition in hereditary autoinflammatory syndromes with mutations in the GENE protein suggested that IL-1 inhibition might also be effective in relieving the inflammatory manifestations of acute gout. The effectiveness of IL-1 inhibition was first evaluated in a mouse model of monosodium urate crystal-induced inflammation. IL-1 inhibition prevented peritoneal neutrophil accumulation but TNF blockade had no effect. Based on these findings, we performed a pilot, open-labeled study (trial registration number ISRCTN10862635) in 10 patients with gout who could not tolerate or had failed standard antiinflammatory therapies. All patients received 100 mg anakinra daily for 3 days. All 10 patients with acute gout responded rapidly to anakinra. No adverse effects were observed. IL-1 blockade appears to be an effective therapy for acute gouty arthritis. The clinical findings need to be confirmed in a controlled study. | SUBSTRATE |
| A pilot study of IL-1 inhibition by anakinra in acute gout. CHEMICAL crystals stimulate monocytes and macrophages to release GENE through the NALP3 component of the inflammasome. The effectiveness of IL-1 inhibition in hereditary autoinflammatory syndromes with mutations in the NALP3 protein suggested that IL-1 inhibition might also be effective in relieving the inflammatory manifestations of acute gout. The effectiveness of IL-1 inhibition was first evaluated in a mouse model of monosodium urate crystal-induced inflammation. IL-1 inhibition prevented peritoneal neutrophil accumulation but TNF blockade had no effect. Based on these findings, we performed a pilot, open-labeled study (trial registration number ISRCTN10862635) in 10 patients with gout who could not tolerate or had failed standard antiinflammatory therapies. All patients received 100 mg anakinra daily for 3 days. All 10 patients with acute gout responded rapidly to anakinra. No adverse effects were observed. IL-1 blockade appears to be an effective therapy for acute gouty arthritis. The clinical findings need to be confirmed in a controlled study. | GENE-CHEMICAL |
| Structural basis of inhibition of the human NAD+-dependent deacetylase SIRT5 by suramin. Sirtuins are NAD(+)-dependent protein deacetylases and are emerging as molecular targets for the development of pharmaceuticals to treat human metabolic and neurological diseases and cancer. To date, several GENE inhibitors and activators have been identified, but the structural mechanisms of how these compounds modulate GENE activity have not yet been determined. We identified suramin as a compound that binds to human SIRT5 and showed that it inhibits SIRT5 NAD(+)-dependent deacetylase activity with an IC(50) value of 22 microM. To provide insights into how GENE function is altered by inhibitors, we determined two crystal structures of SIRT5, one in complex with ADP-ribose, the other bound to suramin. Our structural studies provide a view of a synthetic inhibitory compound in a GENE active site revealing that suramin binds into the CHEMICAL, the product, and the substrate-binding site. Finally, our structures may enable the rational design of more potent inhibitors. | PART-OF |
| Structural basis of inhibition of the human NAD+-dependent deacetylase SIRT5 by CHEMICAL. Sirtuins are NAD(+)-dependent protein deacetylases and are emerging as molecular targets for the development of pharmaceuticals to treat human metabolic and neurological diseases and cancer. To date, several sirtuin inhibitors and activators have been identified, but the structural mechanisms of how these compounds modulate sirtuin activity have not yet been determined. We identified CHEMICAL as a compound that binds to GENE and showed that it inhibits SIRT5 NAD(+)-dependent deacetylase activity with an IC(50) value of 22 microM. To provide insights into how sirtuin function is altered by inhibitors, we determined two crystal structures of SIRT5, one in complex with ADP-ribose, the other bound to CHEMICAL. Our structural studies provide a view of a synthetic inhibitory compound in a sirtuin active site revealing that CHEMICAL binds into the NAD(+), the product, and the substrate-binding site. Finally, our structures may enable the rational design of more potent inhibitors. | DIRECT-REGULATOR |
| Structural basis of inhibition of the human NAD+-dependent deacetylase GENE by suramin. Sirtuins are NAD(+)-dependent protein deacetylases and are emerging as molecular targets for the development of pharmaceuticals to treat human metabolic and neurological diseases and cancer. To date, several sirtuin inhibitors and activators have been identified, but the structural mechanisms of how these compounds modulate sirtuin activity have not yet been determined. We identified suramin as a compound that binds to human GENE and showed that it inhibits GENE NAD(+)-dependent deacetylase activity with an IC(50) value of 22 microM. To provide insights into how sirtuin function is altered by inhibitors, we determined two crystal structures of GENE, one in complex with CHEMICAL-ribose, the other bound to suramin. Our structural studies provide a view of a synthetic inhibitory compound in a sirtuin active site revealing that suramin binds into the NAD(+), the product, and the substrate-binding site. Finally, our structures may enable the rational design of more potent inhibitors. | DIRECT-REGULATOR |
| Structural basis of inhibition of the human NAD+-dependent deacetylase GENE by CHEMICAL. Sirtuins are NAD(+)-dependent protein deacetylases and are emerging as molecular targets for the development of pharmaceuticals to treat human metabolic and neurological diseases and cancer. To date, several sirtuin inhibitors and activators have been identified, but the structural mechanisms of how these compounds modulate sirtuin activity have not yet been determined. We identified CHEMICAL as a compound that binds to human GENE and showed that it inhibits GENE NAD(+)-dependent deacetylase activity with an IC(50) value of 22 microM. To provide insights into how sirtuin function is altered by inhibitors, we determined two crystal structures of GENE, one in complex with ADP-ribose, the other bound to CHEMICAL. Our structural studies provide a view of a synthetic inhibitory compound in a sirtuin active site revealing that CHEMICAL binds into the NAD(+), the product, and the substrate-binding site. Finally, our structures may enable the rational design of more potent inhibitors. | DIRECT-REGULATOR |
| Structural basis of inhibition of the human NAD+-dependent deacetylase SIRT5 by CHEMICAL. Sirtuins are NAD(+)-dependent protein deacetylases and are emerging as molecular targets for the development of pharmaceuticals to treat human metabolic and neurological diseases and cancer. To date, several GENE inhibitors and activators have been identified, but the structural mechanisms of how these compounds modulate GENE activity have not yet been determined. We identified CHEMICAL as a compound that binds to human SIRT5 and showed that it inhibits SIRT5 NAD(+)-dependent deacetylase activity with an IC(50) value of 22 microM. To provide insights into how GENE function is altered by inhibitors, we determined two crystal structures of SIRT5, one in complex with ADP-ribose, the other bound to CHEMICAL. Our structural studies provide a view of a synthetic inhibitory compound in a GENE active site revealing that CHEMICAL binds into the NAD(+), the product, and the substrate-binding site. Finally, our structures may enable the rational design of more potent inhibitors. | ACTIVATOR |
| Structural basis of inhibition of the human NAD+-dependent deacetylase SIRT5 by CHEMICAL. Sirtuins are NAD(+)-dependent protein deacetylases and are emerging as molecular targets for the development of pharmaceuticals to treat human metabolic and neurological diseases and cancer. To date, several sirtuin inhibitors and activators have been identified, but the structural mechanisms of how these compounds modulate sirtuin activity have not yet been determined. We identified CHEMICAL as a compound that binds to human SIRT5 and showed that it inhibits GENE activity with an IC(50) value of 22 microM. To provide insights into how sirtuin function is altered by inhibitors, we determined two crystal structures of SIRT5, one in complex with ADP-ribose, the other bound to CHEMICAL. Our structural studies provide a view of a synthetic inhibitory compound in a sirtuin active site revealing that CHEMICAL binds into the NAD(+), the product, and the substrate-binding site. Finally, our structures may enable the rational design of more potent inhibitors. | INHIBITOR |
| Structural basis of inhibition of the GENE by CHEMICAL. Sirtuins are NAD(+)-dependent protein deacetylases and are emerging as molecular targets for the development of pharmaceuticals to treat human metabolic and neurological diseases and cancer. To date, several sirtuin inhibitors and activators have been identified, but the structural mechanisms of how these compounds modulate sirtuin activity have not yet been determined. We identified CHEMICAL as a compound that binds to human SIRT5 and showed that it inhibits SIRT5 NAD(+)-dependent deacetylase activity with an IC(50) value of 22 microM. To provide insights into how sirtuin function is altered by inhibitors, we determined two crystal structures of SIRT5, one in complex with ADP-ribose, the other bound to CHEMICAL. Our structural studies provide a view of a synthetic inhibitory compound in a sirtuin active site revealing that CHEMICAL binds into the NAD(+), the product, and the substrate-binding site. Finally, our structures may enable the rational design of more potent inhibitors. | INHIBITOR |
| Metabolic derangement of methionine and folate metabolism in mice deficient in GENE reductase. Hyperhomocyst(e)inemia is a metabolic derangement that is linked to the distribution of folate pools, which provide one-carbon units for biosynthesis of purines and thymidylate and for remethylation of homocysteine to form methionine. In humans, GENE deficiency results in the accumulation of CHEMICAL at the expense of folate derivatives required for purine and thymidylate biosynthesis. Complete ablation of GENE activity in mice results in embryonic lethality. Other mouse models for hyperhomocyst(e)inemia have normal or reduced levels of CHEMICAL and are not embryonic lethal, although they have decreased ratios of AdoMet/AdoHcy and impaired methylation. We have constructed a mouse model with a gene trap insertion in the Mtrr gene specifying GENE reductase, an enzyme essential for the activity of GENE. This model is a hypomorph, with reduced GENE reductase activity, thus avoiding the lethality associated with the absence of GENE activity. Mtrr(gt/gt) mice have increased plasma homocyst(e)ine, decreased plasma methionine, and increased tissue CHEMICAL. Unexpectedly, Mtrr(gt/gt) mice do not show decreases in the AdoMet/AdoHcy ratio in most tissues. The different metabolite profiles in the various genetic mouse models for hyperhomocyst(e)inemia may be useful in understanding biological effects of elevated homocyst(e)ine. | PRODUCT-OF |
| Metformin and CHEMICAL activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration. AMP-activated protein kinase (AMPK) acts as a cellular energy sensor: it responds to an increase in AMP concentration ([AMP]) or the AMP-to-ATP ratio (AMP/ATP). Metformin and CHEMICAL, which are biguanides, have been reported to increase GENE activity without increasing AMP/ATP. This study tests the hypothesis that these biguanides increase GENE activity in the heart by increasing cytosolic [AMP]. Groups of isolated rat hearts (n = 5-7 each) were perfused with Krebs-Henseleit buffer with or without 0.2 mM CHEMICAL or 10 mM metformin, and (31)P-NMR-measured phosphocreatine, ATP, and intracellular pH were used to calculate cytosolic [AMP]. At various times, hearts were freeze-clamped and assayed for GENE activity, phosphorylation of Thr(172) on AMPK-alpha, and phosphorylation of Ser(79) on acetyl-CoA carboxylase, an GENE target. In hearts treated with CHEMICAL for 18 min and then perfused for 20 min with Krebs-Henseleit buffer, [AMP] began to increase at 26 min and GENE activity was elevated at 36 min. In hearts treated with metformin, [AMP] was increased at 50 min and GENE activity, phosphorylated GENE, and phosphorylated acetyl-CoA carboxylase were elevated at 61 min. In metformin-treated hearts, HPLC-measured total AMP content and total AMP/ATP did not increase. In summary, CHEMICAL and metformin increase GENE activity and phosphorylation in the isolated heart. The increase in GENE activity was always preceded by and correlated with increased cytosolic [AMP]. Total AMP content and total AMP/ATP did not change. Cytosolic [AMP] reported metabolically active AMP, which triggered increased GENE activity, but measures of total AMP did not. | ACTIVATOR |
| CHEMICAL and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration. AMP-activated protein kinase (AMPK) acts as a cellular energy sensor: it responds to an increase in AMP concentration ([AMP]) or the AMP-to-ATP ratio (AMP/ATP). CHEMICAL and phenformin, which are biguanides, have been reported to increase GENE activity without increasing AMP/ATP. This study tests the hypothesis that these biguanides increase GENE activity in the heart by increasing cytosolic [AMP]. Groups of isolated rat hearts (n = 5-7 each) were perfused with Krebs-Henseleit buffer with or without 0.2 mM phenformin or 10 mM CHEMICAL, and (31)P-NMR-measured phosphocreatine, ATP, and intracellular pH were used to calculate cytosolic [AMP]. At various times, hearts were freeze-clamped and assayed for GENE activity, phosphorylation of Thr(172) on AMPK-alpha, and phosphorylation of Ser(79) on acetyl-CoA carboxylase, an GENE target. In hearts treated with phenformin for 18 min and then perfused for 20 min with Krebs-Henseleit buffer, [AMP] began to increase at 26 min and GENE activity was elevated at 36 min. In hearts treated with CHEMICAL, [AMP] was increased at 50 min and GENE activity, phosphorylated GENE, and phosphorylated acetyl-CoA carboxylase were elevated at 61 min. In metformin-treated hearts, HPLC-measured total AMP content and total AMP/ATP did not increase. In summary, phenformin and CHEMICAL increase GENE activity and phosphorylation in the isolated heart. The increase in GENE activity was always preceded by and correlated with increased cytosolic [AMP]. Total AMP content and total AMP/ATP did not change. Cytosolic [AMP] reported metabolically active AMP, which triggered increased GENE activity, but measures of total AMP did not. | ACTIVATOR |
| Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic CHEMICAL concentration. AMP-activated protein kinase (AMPK) acts as a cellular energy sensor: it responds to an increase in CHEMICAL concentration ([AMP]) or the AMP-to-ATP ratio (AMP/ATP). Metformin and phenformin, which are biguanides, have been reported to increase GENE activity without increasing AMP/ATP. This study tests the hypothesis that these biguanides increase GENE activity in the heart by increasing cytosolic [AMP]. Groups of isolated rat hearts (n = 5-7 each) were perfused with Krebs-Henseleit buffer with or without 0.2 mM phenformin or 10 mM metformin, and (31)P-NMR-measured phosphocreatine, ATP, and intracellular pH were used to calculate cytosolic [AMP]. At various times, hearts were freeze-clamped and assayed for GENE activity, phosphorylation of Thr(172) on AMPK-alpha, and phosphorylation of Ser(79) on acetyl-CoA carboxylase, an GENE target. In hearts treated with phenformin for 18 min and then perfused for 20 min with Krebs-Henseleit buffer, [AMP] began to increase at 26 min and GENE activity was elevated at 36 min. In hearts treated with metformin, [AMP] was increased at 50 min and GENE activity, phosphorylated GENE, and phosphorylated acetyl-CoA carboxylase were elevated at 61 min. In metformin-treated hearts, HPLC-measured total CHEMICAL content and total AMP/ATP did not increase. In summary, phenformin and metformin increase GENE activity and phosphorylation in the isolated heart. The increase in GENE activity was always preceded by and correlated with increased cytosolic [AMP]. Total CHEMICAL content and total AMP/ATP did not change. Cytosolic [AMP] reported metabolically active CHEMICAL, which triggered increased GENE activity, but measures of total CHEMICAL did not. | NO-RELATIONSHIP |
| Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration. AMP-activated protein kinase (AMPK) acts as a cellular energy sensor: it responds to an increase in AMP concentration ([AMP]) or the AMP-to-ATP ratio (AMP/ATP). Metformin and phenformin, which are CHEMICAL, have been reported to increase GENE activity without increasing AMP/ATP. This study tests the hypothesis that these CHEMICAL increase GENE activity in the heart by increasing cytosolic [AMP]. Groups of isolated rat hearts (n = 5-7 each) were perfused with Krebs-Henseleit buffer with or without 0.2 mM phenformin or 10 mM metformin, and (31)P-NMR-measured phosphocreatine, ATP, and intracellular pH were used to calculate cytosolic [AMP]. At various times, hearts were freeze-clamped and assayed for GENE activity, phosphorylation of Thr(172) on AMPK-alpha, and phosphorylation of Ser(79) on acetyl-CoA carboxylase, an GENE target. In hearts treated with phenformin for 18 min and then perfused for 20 min with Krebs-Henseleit buffer, [AMP] began to increase at 26 min and GENE activity was elevated at 36 min. In hearts treated with metformin, [AMP] was increased at 50 min and GENE activity, phosphorylated GENE, and phosphorylated acetyl-CoA carboxylase were elevated at 61 min. In metformin-treated hearts, HPLC-measured total AMP content and total AMP/ATP did not increase. In summary, phenformin and metformin increase GENE activity and phosphorylation in the isolated heart. The increase in GENE activity was always preceded by and correlated with increased cytosolic [AMP]. Total AMP content and total AMP/ATP did not change. Cytosolic [AMP] reported metabolically active AMP, which triggered increased GENE activity, but measures of total AMP did not. | ACTIVATOR |
| CHEMICAL and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration. AMP-activated protein kinase (AMPK) acts as a cellular energy sensor: it responds to an increase in AMP concentration ([AMP]) or the AMP-to-ATP ratio (AMP/ATP). CHEMICAL and phenformin, which are biguanides, have been reported to increase AMPK activity without increasing AMP/ATP. This study tests the hypothesis that these biguanides increase AMPK activity in the heart by increasing cytosolic [AMP]. Groups of isolated rat hearts (n = 5-7 each) were perfused with Krebs-Henseleit buffer with or without 0.2 mM phenformin or 10 mM CHEMICAL, and (31)P-NMR-measured phosphocreatine, ATP, and intracellular pH were used to calculate cytosolic [AMP]. At various times, hearts were freeze-clamped and assayed for AMPK activity, phosphorylation of Thr(172) on AMPK-alpha, and phosphorylation of Ser(79) on acetyl-CoA carboxylase, an AMPK target. In hearts treated with phenformin for 18 min and then perfused for 20 min with Krebs-Henseleit buffer, [AMP] began to increase at 26 min and AMPK activity was elevated at 36 min. In hearts treated with CHEMICAL, [AMP] was increased at 50 min and AMPK activity, phosphorylated AMPK, and GENE were elevated at 61 min. In metformin-treated hearts, HPLC-measured total AMP content and total AMP/ATP did not increase. In summary, phenformin and CHEMICAL increase AMPK activity and phosphorylation in the isolated heart. The increase in AMPK activity was always preceded by and correlated with increased cytosolic [AMP]. Total AMP content and total AMP/ATP did not change. Cytosolic [AMP] reported metabolically active AMP, which triggered increased AMPK activity, but measures of total AMP did not. | ACTIVATOR |
| CHEMICAL and phenformin activate GENE in the heart by increasing cytosolic AMP concentration. GENE (AMPK) acts as a cellular energy sensor: it responds to an increase in AMP concentration ([AMP]) or the AMP-to-ATP ratio (AMP/ATP). CHEMICAL and phenformin, which are biguanides, have been reported to increase AMPK activity without increasing AMP/ATP. This study tests the hypothesis that these biguanides increase AMPK activity in the heart by increasing cytosolic [AMP]. Groups of isolated rat hearts (n = 5-7 each) were perfused with Krebs-Henseleit buffer with or without 0.2 mM phenformin or 10 mM metformin, and (31)P-NMR-measured phosphocreatine, ATP, and intracellular pH were used to calculate cytosolic [AMP]. At various times, hearts were freeze-clamped and assayed for AMPK activity, phosphorylation of Thr(172) on AMPK-alpha, and phosphorylation of Ser(79) on acetyl-CoA carboxylase, an AMPK target. In hearts treated with phenformin for 18 min and then perfused for 20 min with Krebs-Henseleit buffer, [AMP] began to increase at 26 min and AMPK activity was elevated at 36 min. In hearts treated with metformin, [AMP] was increased at 50 min and AMPK activity, phosphorylated AMPK, and phosphorylated acetyl-CoA carboxylase were elevated at 61 min. In metformin-treated hearts, HPLC-measured total AMP content and total AMP/ATP did not increase. In summary, phenformin and metformin increase AMPK activity and phosphorylation in the isolated heart. The increase in AMPK activity was always preceded by and correlated with increased cytosolic [AMP]. Total AMP content and total AMP/ATP did not change. Cytosolic [AMP] reported metabolically active AMP, which triggered increased AMPK activity, but measures of total AMP did not. | ACTIVATOR |
| Metformin and CHEMICAL activate GENE in the heart by increasing cytosolic AMP concentration. GENE (AMPK) acts as a cellular energy sensor: it responds to an increase in AMP concentration ([AMP]) or the AMP-to-ATP ratio (AMP/ATP). Metformin and CHEMICAL, which are biguanides, have been reported to increase AMPK activity without increasing AMP/ATP. This study tests the hypothesis that these biguanides increase AMPK activity in the heart by increasing cytosolic [AMP]. Groups of isolated rat hearts (n = 5-7 each) were perfused with Krebs-Henseleit buffer with or without 0.2 mM CHEMICAL or 10 mM metformin, and (31)P-NMR-measured phosphocreatine, ATP, and intracellular pH were used to calculate cytosolic [AMP]. At various times, hearts were freeze-clamped and assayed for AMPK activity, phosphorylation of Thr(172) on AMPK-alpha, and phosphorylation of Ser(79) on acetyl-CoA carboxylase, an AMPK target. In hearts treated with CHEMICAL for 18 min and then perfused for 20 min with Krebs-Henseleit buffer, [AMP] began to increase at 26 min and AMPK activity was elevated at 36 min. In hearts treated with metformin, [AMP] was increased at 50 min and AMPK activity, phosphorylated AMPK, and phosphorylated acetyl-CoA carboxylase were elevated at 61 min. In metformin-treated hearts, HPLC-measured total AMP content and total AMP/ATP did not increase. In summary, CHEMICAL and metformin increase AMPK activity and phosphorylation in the isolated heart. The increase in AMPK activity was always preceded by and correlated with increased cytosolic [AMP]. Total AMP content and total AMP/ATP did not change. Cytosolic [AMP] reported metabolically active AMP, which triggered increased AMPK activity, but measures of total AMP did not. | ACTIVATOR |
| Characterization of GENE receptors in rat spinal cord via CHEMICAL binding and inhibition of [3H]-5-hydroxytryptamine release. The aim of the present study in rat spinal cord synaptosomes was to compare the pharmacological characteristics of the serotonin (5-HT)1B receptor defined by CHEMICAL [( 125I] ICYP) binding and the 5-HT autoreceptor defined by inhibition of [3H]-5-HT release. In Percoll gradient Fractions 3 and 4 of spinal cord synaptosomes, a single saturable binding site for [125I]ICYP with a maximum binding of 70 and 134 fmol/mg, respectively, was demonstrated in the presence of 30 microM isoproterenol. The Kd of 0.16 nM did not vary between fractions. Competition for [125I]ICYP binding by various 5-HT agonists and antagonists also indicated a single site model based on a Hill coefficient of approximately 1.0. The most potent compounds at displacing [125I]ICYP binding were RU 24969 (5-methoxy-3-[1,2,3,6-tetrahydropyridin-4-yl]-1H-indole), 5-carboxyamidotryptamine HCl, 5-methoxytryptamine, 5-HT and CGS 12066B (7-trifluoromethyl-4(4 methyl-1-pyrolo[1,2-a]-quinoxaline malate). [125I]ICYP binding was not altered by compounds with activity at 5-HT1A, 5-HT1C, 5-HT2, 5-HT3 or alpha-2 receptor sites. Similar to the pharmacological characteristics of the 5HT1B site defined by [125I]ICYP, compounds most active at inhibiting 15 mM K(+)-stimulated release of [3H]-5-HT were RU24969 = 5-carboxyamidotryptamine HCl = CGS 12066B greater than 5-methoxytryptamine greater than 5-HT. Compounds with activity at 5-HT1A, 5-HT1C, 5-HT2 or 5-HT3 sites were inactive. A correlation analysis of selective 5-HT1B compounds comparing the pKD for displacement of [125I]ICYP vs. the IC50 for inhibition of [3H]-5-HT release demonstrated the pharmacological similarity of the presynaptic inhibitory 5-HT autoreceptor and the 5-HT receptor site defined by [125I]ICYP binding in spinal cord synaptosomes (r = 0.791, P = .0193). Although [125I]ICYP binding was unaltered, alpha-2 agonists such as clonidine, norepinephrine and UK 14304 [5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline) as well as the alpha-2 antagonists rauwolscine and yohimbine also decreased the K(+)-stimulated release of [3H]-5-HT and phentolamine, an alpha-2 antagonist increased release. The action of these alpha-2 compounds to alter [3H]-5-HT release suggests the presence of heteroreceptors localized on 5-HT terminals in the spinal cord. These results point out that [125I]ICYP identifies the 5-HT1B receptor, and affinity of compounds for this site predicts action at the 5-HT1B autoreceptor.(ABSTRACT TRUNCATED AT 400 WORDS) | DIRECT-REGULATOR |
| Histamine H1 receptor involvement in prepulse inhibition and memory function: relevance for the antipsychotic actions of CHEMICAL. Histamine GENE blockade is one of the more prominent actions of the multi-receptor acting antipsychotic CHEMICAL. It is currently not known how much this GENE antagonism of CHEMICAL contributes to the therapeutic or adverse side effects of CHEMICAL. The current studies with Sprague-Dawley rats were conducted to determine the participation of histaminergic GENE receptor subtype in sensorimotor plasticity and memory function affected by CHEMICAL using tests of prepulse inhibition (PPI) and radial-arm maze choice accuracy. The PPI impairment caused by the glutamate antagonist dizocilpine (MK-801) was significantly attenuated by CHEMICAL. In the current project, we found that the selective GENE antagonist pyrilamine also reversed the dizocilpine-induced impairment in PPI of tactile startle with an auditory prepulse. In the radial-arm maze (RAM), pyrilamine, like CHEMICAL, impaired working memory and caused a significant dose-related slowing of response. Pyrilamine, however, decreased the number of reference memory errors. We have previously shown that nicotine effectively attenuates the clozapine-induced working memory impairment, but in the current study, nicotine did not significantly alter the effects of pyrilamine on the RAM. In summary, the therapeutic effect of CHEMICAL in reversing PPI impairment was mimicked by the GENE antagonist pyrilamine, while pyrilamine had a mixed effect on cognition. Pyrilamine impaired working memory but improved reference memory in rats. Thus, GENE antagonism seems to play a role in part of the beneficial actions of antipsychotics, such as CHEMICAL. | INHIBITOR |
| GENE involvement in prepulse inhibition and memory function: relevance for the antipsychotic actions of CHEMICAL. Histamine H(1) blockade is one of the more prominent actions of the multi-receptor acting antipsychotic CHEMICAL. It is currently not known how much this H(1) antagonism of CHEMICAL contributes to the therapeutic or adverse side effects of CHEMICAL. The current studies with Sprague-Dawley rats were conducted to determine the participation of histaminergic H(1) receptor subtype in sensorimotor plasticity and memory function affected by CHEMICAL using tests of prepulse inhibition (PPI) and radial-arm maze choice accuracy. The PPI impairment caused by the glutamate antagonist dizocilpine (MK-801) was significantly attenuated by CHEMICAL. In the current project, we found that the selective H(1) antagonist pyrilamine also reversed the dizocilpine-induced impairment in PPI of tactile startle with an auditory prepulse. In the radial-arm maze (RAM), pyrilamine, like CHEMICAL, impaired working memory and caused a significant dose-related slowing of response. Pyrilamine, however, decreased the number of reference memory errors. We have previously shown that nicotine effectively attenuates the clozapine-induced working memory impairment, but in the current study, nicotine did not significantly alter the effects of pyrilamine on the RAM. In summary, the therapeutic effect of CHEMICAL in reversing PPI impairment was mimicked by the H(1) antagonist pyrilamine, while pyrilamine had a mixed effect on cognition. Pyrilamine impaired working memory but improved reference memory in rats. Thus, H(1) antagonism seems to play a role in part of the beneficial actions of antipsychotics, such as CHEMICAL. | REGULATOR |
| Histamine H1 receptor involvement in prepulse inhibition and memory function: relevance for the antipsychotic actions of clozapine. Histamine GENE blockade is one of the more prominent actions of the multi-receptor acting antipsychotic clozapine. It is currently not known how much this GENE antagonism of clozapine contributes to the therapeutic or adverse side effects of clozapine. The current studies with Sprague-Dawley rats were conducted to determine the participation of histaminergic GENE receptor subtype in sensorimotor plasticity and memory function affected by clozapine using tests of prepulse inhibition (PPI) and radial-arm maze choice accuracy. The PPI impairment caused by the glutamate antagonist CHEMICAL (MK-801) was significantly attenuated by clozapine. In the current project, we found that the selective GENE antagonist pyrilamine also reversed the CHEMICAL-induced impairment in PPI of tactile startle with an auditory prepulse. In the radial-arm maze (RAM), pyrilamine, like clozapine, impaired working memory and caused a significant dose-related slowing of response. Pyrilamine, however, decreased the number of reference memory errors. We have previously shown that nicotine effectively attenuates the clozapine-induced working memory impairment, but in the current study, nicotine did not significantly alter the effects of pyrilamine on the RAM. In summary, the therapeutic effect of clozapine in reversing PPI impairment was mimicked by the GENE antagonist pyrilamine, while pyrilamine had a mixed effect on cognition. Pyrilamine impaired working memory but improved reference memory in rats. Thus, GENE antagonism seems to play a role in part of the beneficial actions of antipsychotics, such as clozapine. | INHIBITOR |
| Histamine H1 receptor involvement in prepulse inhibition and memory function: relevance for the antipsychotic actions of CHEMICAL. GENE blockade is one of the more prominent actions of the multi-receptor acting antipsychotic CHEMICAL. It is currently not known how much this H(1) antagonism of CHEMICAL contributes to the therapeutic or adverse side effects of CHEMICAL. The current studies with Sprague-Dawley rats were conducted to determine the participation of histaminergic H(1) receptor subtype in sensorimotor plasticity and memory function affected by CHEMICAL using tests of prepulse inhibition (PPI) and radial-arm maze choice accuracy. The PPI impairment caused by the glutamate antagonist dizocilpine (MK-801) was significantly attenuated by CHEMICAL. In the current project, we found that the selective H(1) antagonist pyrilamine also reversed the dizocilpine-induced impairment in PPI of tactile startle with an auditory prepulse. In the radial-arm maze (RAM), pyrilamine, like CHEMICAL, impaired working memory and caused a significant dose-related slowing of response. Pyrilamine, however, decreased the number of reference memory errors. We have previously shown that nicotine effectively attenuates the clozapine-induced working memory impairment, but in the current study, nicotine did not significantly alter the effects of pyrilamine on the RAM. In summary, the therapeutic effect of CHEMICAL in reversing PPI impairment was mimicked by the H(1) antagonist pyrilamine, while pyrilamine had a mixed effect on cognition. Pyrilamine impaired working memory but improved reference memory in rats. Thus, H(1) antagonism seems to play a role in part of the beneficial actions of antipsychotics, such as CHEMICAL. | INHIBITOR |
| Histamine H1 receptor involvement in prepulse inhibition and memory function: relevance for the antipsychotic actions of clozapine. Histamine GENE blockade is one of the more prominent actions of the multi-receptor acting antipsychotic clozapine. It is currently not known how much this GENE antagonism of clozapine contributes to the therapeutic or adverse side effects of clozapine. The current studies with Sprague-Dawley rats were conducted to determine the participation of histaminergic GENE receptor subtype in sensorimotor plasticity and memory function affected by clozapine using tests of prepulse inhibition (PPI) and radial-arm maze choice accuracy. The PPI impairment caused by the glutamate antagonist dizocilpine (MK-801) was significantly attenuated by clozapine. In the current project, we found that the selective GENE antagonist CHEMICAL also reversed the dizocilpine-induced impairment in PPI of tactile startle with an auditory prepulse. In the radial-arm maze (RAM), CHEMICAL, like clozapine, impaired working memory and caused a significant dose-related slowing of response. CHEMICAL, however, decreased the number of reference memory errors. We have previously shown that nicotine effectively attenuates the clozapine-induced working memory impairment, but in the current study, nicotine did not significantly alter the effects of CHEMICAL on the RAM. In summary, the therapeutic effect of clozapine in reversing PPI impairment was mimicked by the GENE antagonist CHEMICAL, while CHEMICAL had a mixed effect on cognition. CHEMICAL impaired working memory but improved reference memory in rats. Thus, GENE antagonism seems to play a role in part of the beneficial actions of antipsychotics, such as clozapine. | INHIBITOR |
| Inhibition of phosphatidylserine biosynthesis in developing rat brain by maternal exposure to CHEMICAL. Phosphatidylserine (PtdSer), major acidic phospholipids in neuronal membranes, participate in important cell signaling processes. The PtdSer in brain is highly enriched with docosahexaenoic acid (DHA; 22:6n-3), and the DHA status or CHEMICAL exposure has been shown to influence the PtdSer level. This study shows that CHEMICAL exposure during prenatal and developmental period significantly attenuates microsomal PtdSer biosynthetic activities and reduces PtdSer, particularly 18:0, 22:6-PtdSer, in developing rat brain cortices. Brain microsomes were incubated with deuterium labeled exogenous substrates in vitro and the products formed were detected by reversed phase HPLC-electrospray ionization mass spectrometry (ESI-MS). These in vitro bioassays showed that 1-stearoyl-2-docosahexaenoyl (18:0, 22:6) species is the best substrate for PtdSer synthesis from both phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn). The PtdSer biosynthetic activity of brain, especially for 18:0, 22:6-PtdSer production, was hampered significantly by maternal exposure to CHEMICAL. PtdSer levels were consistently reduced significantly in brain cortices of the pups from ethanol-exposed dams, due mainly to the depletion of 18:0, 22:6-PtdSer. The mRNA expression of GENE (PSS1) and PtdSer synthase 2 (PSS2) was not reduced by CHEMICAL. Similarly, the PSS1 enzyme level did not change after CHEMICAL exposure but PSS2 could not be probed with the antibody available currently. Degradation of PtdSer by mitochondrial PtdSer decarboxylation was not enhanced but also inhibited. Taken together, attenuated PtdSer biosynthetic activities are largely responsible for the PtdSer reduction observed in developing rat brains after maternal exposure to CHEMICAL. | NO-RELATIONSHIP |
| Inhibition of phosphatidylserine biosynthesis in developing rat brain by maternal exposure to CHEMICAL. Phosphatidylserine (PtdSer), major acidic phospholipids in neuronal membranes, participate in important cell signaling processes. The PtdSer in brain is highly enriched with docosahexaenoic acid (DHA; 22:6n-3), and the DHA status or CHEMICAL exposure has been shown to influence the PtdSer level. This study shows that CHEMICAL exposure during prenatal and developmental period significantly attenuates microsomal PtdSer biosynthetic activities and reduces PtdSer, particularly 18:0, 22:6-PtdSer, in developing rat brain cortices. Brain microsomes were incubated with deuterium labeled exogenous substrates in vitro and the products formed were detected by reversed phase HPLC-electrospray ionization mass spectrometry (ESI-MS). These in vitro bioassays showed that 1-stearoyl-2-docosahexaenoyl (18:0, 22:6) species is the best substrate for PtdSer synthesis from both phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn). The PtdSer biosynthetic activity of brain, especially for 18:0, 22:6-PtdSer production, was hampered significantly by maternal exposure to CHEMICAL. PtdSer levels were consistently reduced significantly in brain cortices of the pups from ethanol-exposed dams, due mainly to the depletion of 18:0, 22:6-PtdSer. The mRNA expression of PtdSer synthase 1 (GENE) and PtdSer synthase 2 (PSS2) was not reduced by CHEMICAL. Similarly, the GENE enzyme level did not change after CHEMICAL exposure but PSS2 could not be probed with the antibody available currently. Degradation of PtdSer by mitochondrial PtdSer decarboxylation was not enhanced but also inhibited. Taken together, attenuated PtdSer biosynthetic activities are largely responsible for the PtdSer reduction observed in developing rat brains after maternal exposure to CHEMICAL. | NO-RELATIONSHIP |
| Inhibition of phosphatidylserine biosynthesis in developing rat brain by maternal exposure to CHEMICAL. Phosphatidylserine (PtdSer), major acidic phospholipids in neuronal membranes, participate in important cell signaling processes. The PtdSer in brain is highly enriched with docosahexaenoic acid (DHA; 22:6n-3), and the DHA status or CHEMICAL exposure has been shown to influence the PtdSer level. This study shows that CHEMICAL exposure during prenatal and developmental period significantly attenuates microsomal PtdSer biosynthetic activities and reduces PtdSer, particularly 18:0, 22:6-PtdSer, in developing rat brain cortices. Brain microsomes were incubated with deuterium labeled exogenous substrates in vitro and the products formed were detected by reversed phase HPLC-electrospray ionization mass spectrometry (ESI-MS). These in vitro bioassays showed that 1-stearoyl-2-docosahexaenoyl (18:0, 22:6) species is the best substrate for PtdSer synthesis from both phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn). The PtdSer biosynthetic activity of brain, especially for 18:0, 22:6-PtdSer production, was hampered significantly by maternal exposure to CHEMICAL. PtdSer levels were consistently reduced significantly in brain cortices of the pups from ethanol-exposed dams, due mainly to the depletion of 18:0, 22:6-PtdSer. The mRNA expression of PtdSer synthase 1 (PSS1) and GENE (PSS2) was not reduced by CHEMICAL. Similarly, the PSS1 enzyme level did not change after CHEMICAL exposure but PSS2 could not be probed with the antibody available currently. Degradation of PtdSer by mitochondrial PtdSer decarboxylation was not enhanced but also inhibited. Taken together, attenuated PtdSer biosynthetic activities are largely responsible for the PtdSer reduction observed in developing rat brains after maternal exposure to CHEMICAL. | NO-RELATIONSHIP |
| Inhibition of phosphatidylserine biosynthesis in developing rat brain by maternal exposure to CHEMICAL. Phosphatidylserine (PtdSer), major acidic phospholipids in neuronal membranes, participate in important cell signaling processes. The PtdSer in brain is highly enriched with docosahexaenoic acid (DHA; 22:6n-3), and the DHA status or CHEMICAL exposure has been shown to influence the PtdSer level. This study shows that CHEMICAL exposure during prenatal and developmental period significantly attenuates microsomal PtdSer biosynthetic activities and reduces PtdSer, particularly 18:0, 22:6-PtdSer, in developing rat brain cortices. Brain microsomes were incubated with deuterium labeled exogenous substrates in vitro and the products formed were detected by reversed phase HPLC-electrospray ionization mass spectrometry (ESI-MS). These in vitro bioassays showed that 1-stearoyl-2-docosahexaenoyl (18:0, 22:6) species is the best substrate for PtdSer synthesis from both phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn). The PtdSer biosynthetic activity of brain, especially for 18:0, 22:6-PtdSer production, was hampered significantly by maternal exposure to CHEMICAL. PtdSer levels were consistently reduced significantly in brain cortices of the pups from ethanol-exposed dams, due mainly to the depletion of 18:0, 22:6-PtdSer. The mRNA expression of PtdSer synthase 1 (PSS1) and PtdSer synthase 2 (GENE) was not reduced by CHEMICAL. Similarly, the PSS1 enzyme level did not change after CHEMICAL exposure but GENE could not be probed with the antibody available currently. Degradation of PtdSer by mitochondrial PtdSer decarboxylation was not enhanced but also inhibited. Taken together, attenuated PtdSer biosynthetic activities are largely responsible for the PtdSer reduction observed in developing rat brains after maternal exposure to CHEMICAL. | NO-RELATIONSHIP |
| Regulation of gluconeogenesis by Kruppel-like factor 15. In the postabsorptive state, certain tissues, including the brain, require glucose as the sole source of energy. After an overnight fast, hepatic glycogen stores are depleted, and gluconeogenesis becomes essential for preventing life-threatening hypoglycemia. Mice with a targeted deletion of KLF15, a member of the Kruppel-like family of transcription factors, display severe hypoglycemia after an overnight (18 hr) fast. We provide evidence that defective amino acid catabolism promotes the development of fasting hypoglycemia in KLF15-/- mice by limiting gluconeogenic substrate availability. KLF15-/- liver and skeletal muscle show markedly reduced mRNA expression of amino acid-degrading enzymes. Furthermore, the enzymatic activity of GENE (ALT), which converts the critical gluconeogenic amino acid alanine into CHEMICAL, is decreased (approximately 50%) in KLF15-/- hepatocytes. Consistent with this observation, intraperitoneal injection of CHEMICAL, but not alanine, rescues fasting hypoglycemia in KLF15-/- mice. We conclude that KLF15 plays an important role in the regulation of gluconeogenesis. | PRODUCT-OF |
| Regulation of gluconeogenesis by Kruppel-like factor 15. In the postabsorptive state, certain tissues, including the brain, require glucose as the sole source of energy. After an overnight fast, hepatic glycogen stores are depleted, and gluconeogenesis becomes essential for preventing life-threatening hypoglycemia. Mice with a targeted deletion of KLF15, a member of the Kruppel-like family of transcription factors, display severe hypoglycemia after an overnight (18 hr) fast. We provide evidence that defective amino acid catabolism promotes the development of fasting hypoglycemia in KLF15-/- mice by limiting gluconeogenic substrate availability. KLF15-/- liver and skeletal muscle show markedly reduced mRNA expression of amino acid-degrading enzymes. Furthermore, the enzymatic activity of alanine aminotransferase (GENE), which converts the critical gluconeogenic amino acid alanine into CHEMICAL, is decreased (approximately 50%) in KLF15-/- hepatocytes. Consistent with this observation, intraperitoneal injection of CHEMICAL, but not alanine, rescues fasting hypoglycemia in KLF15-/- mice. We conclude that KLF15 plays an important role in the regulation of gluconeogenesis. | PRODUCT-OF |
| Regulation of gluconeogenesis by Kruppel-like factor 15. In the postabsorptive state, certain tissues, including the brain, require glucose as the sole source of energy. After an overnight fast, hepatic glycogen stores are depleted, and gluconeogenesis becomes essential for preventing life-threatening hypoglycemia. Mice with a targeted deletion of KLF15, a member of the Kruppel-like family of transcription factors, display severe hypoglycemia after an overnight (18 hr) fast. We provide evidence that defective CHEMICAL catabolism promotes the development of fasting hypoglycemia in KLF15-/- mice by limiting gluconeogenic substrate availability. KLF15-/- liver and skeletal muscle show markedly reduced mRNA expression of amino acid-degrading enzymes. Furthermore, the enzymatic activity of GENE (ALT), which converts the critical gluconeogenic CHEMICAL alanine into pyruvate, is decreased (approximately 50%) in KLF15-/- hepatocytes. Consistent with this observation, intraperitoneal injection of pyruvate, but not alanine, rescues fasting hypoglycemia in KLF15-/- mice. We conclude that KLF15 plays an important role in the regulation of gluconeogenesis. | SUBSTRATE |
| Regulation of gluconeogenesis by Kruppel-like factor 15. In the postabsorptive state, certain tissues, including the brain, require glucose as the sole source of energy. After an overnight fast, hepatic glycogen stores are depleted, and gluconeogenesis becomes essential for preventing life-threatening hypoglycemia. Mice with a targeted deletion of KLF15, a member of the Kruppel-like family of transcription factors, display severe hypoglycemia after an overnight (18 hr) fast. We provide evidence that defective CHEMICAL catabolism promotes the development of fasting hypoglycemia in KLF15-/- mice by limiting gluconeogenic substrate availability. KLF15-/- liver and skeletal muscle show markedly reduced mRNA expression of amino acid-degrading enzymes. Furthermore, the enzymatic activity of alanine aminotransferase (GENE), which converts the critical gluconeogenic CHEMICAL alanine into pyruvate, is decreased (approximately 50%) in KLF15-/- hepatocytes. Consistent with this observation, intraperitoneal injection of pyruvate, but not alanine, rescues fasting hypoglycemia in KLF15-/- mice. We conclude that KLF15 plays an important role in the regulation of gluconeogenesis. | SUBSTRATE |
| Regulation of gluconeogenesis by Kruppel-like factor 15. In the postabsorptive state, certain tissues, including the brain, require glucose as the sole source of energy. After an overnight fast, hepatic glycogen stores are depleted, and gluconeogenesis becomes essential for preventing life-threatening hypoglycemia. Mice with a targeted deletion of KLF15, a member of the Kruppel-like family of transcription factors, display severe hypoglycemia after an overnight (18 hr) fast. We provide evidence that defective amino acid catabolism promotes the development of fasting hypoglycemia in KLF15-/- mice by limiting gluconeogenic substrate availability. KLF15-/- liver and skeletal muscle show markedly reduced mRNA expression of amino acid-degrading enzymes. Furthermore, the enzymatic activity of GENE (ALT), which converts the critical gluconeogenic amino acid CHEMICAL into pyruvate, is decreased (approximately 50%) in KLF15-/- hepatocytes. Consistent with this observation, intraperitoneal injection of pyruvate, but not CHEMICAL, rescues fasting hypoglycemia in KLF15-/- mice. We conclude that KLF15 plays an important role in the regulation of gluconeogenesis. | SUBSTRATE |
| Regulation of gluconeogenesis by Kruppel-like factor 15. In the postabsorptive state, certain tissues, including the brain, require glucose as the sole source of energy. After an overnight fast, hepatic glycogen stores are depleted, and gluconeogenesis becomes essential for preventing life-threatening hypoglycemia. Mice with a targeted deletion of KLF15, a member of the Kruppel-like family of transcription factors, display severe hypoglycemia after an overnight (18 hr) fast. We provide evidence that defective amino acid catabolism promotes the development of fasting hypoglycemia in KLF15-/- mice by limiting gluconeogenic substrate availability. KLF15-/- liver and skeletal muscle show markedly reduced mRNA expression of amino acid-degrading enzymes. Furthermore, the enzymatic activity of CHEMICAL aminotransferase (GENE), which converts the critical gluconeogenic amino acid CHEMICAL into pyruvate, is decreased (approximately 50%) in KLF15-/- hepatocytes. Consistent with this observation, intraperitoneal injection of pyruvate, but not CHEMICAL, rescues fasting hypoglycemia in KLF15-/- mice. We conclude that KLF15 plays an important role in the regulation of gluconeogenesis. | SUBSTRATE |
| D-glucose stimulation of L-arginine transport and nitric oxide synthesis results from activation of mitogen-activated protein kinases p42/44 and Smad2 requiring functional type II TGF-beta receptors in human umbilical vein endothelium. Elevated extracellular D-glucose increases transforming growth factor beta1 (TGF-beta1) release from human umbilical vein endothelium (HUVEC). TGF-beta1, via TGF-beta receptors I (TbetaRI) and TbetaRII, activates Smad2 and mitogen-activated protein kinases p44 and p42 (p42/44(mapk)). We studied whether D-glucose-stimulation of L-arginine transport and nitric oxide synthesis involves TGF-beta1 in primary cultures of HUVEC. TGF-beta1 release was higher ( approximately 1.6-fold) in 25 mM (high) compared with 5 mM (normal) D-glucose. TGF-beta1 increases L-arginine transport (half maximal effect approximately 1.6 ng/ml) in normal D-glucose, but did not alter high D-glucose-increased L-arginine transport. TGF-beta1 and high D-glucose increased hCAT-1 mRNA expression ( approximately 8-fold) and maximal transport velocity (V(max)), CHEMICAL formation from L-[(3)H]arginine (index of NO synthesis) and endothelial NO synthase (eNOS) protein abundance, but did not alter GENE phosphorylation. TGF-beta1 and high D-glucose increased p42/44(mapk) and Smad2 phosphorylation, an effect blocked by PD-98059 (MEK1/2 inhibitor). However, TGF-beta1 and high D-glucose were ineffective in cells expressing a truncated, negative dominant TbetaRII. High D-glucose increases L-arginine transport and GENE expression following TbetaRII activation by TGF-beta1 involving p42/44(mapk) and Smad2 in HUVEC. Thus, TGF-beta1 could play a crucial role under conditions of hyperglycemia, such as gestational diabetes mellitus, which is associated with fetal endothelial dysfunction. | PRODUCT-OF |
| D-glucose stimulation of L-arginine transport and nitric oxide synthesis results from activation of mitogen-activated protein kinases p42/44 and Smad2 requiring functional type II TGF-beta receptors in human umbilical vein endothelium. Elevated extracellular D-glucose increases transforming growth factor beta1 (TGF-beta1) release from human umbilical vein endothelium (HUVEC). TGF-beta1, via TGF-beta receptors I (TbetaRI) and TbetaRII, activates Smad2 and mitogen-activated protein kinases p44 and p42 (p42/44(mapk)). We studied whether D-glucose-stimulation of L-arginine transport and nitric oxide synthesis involves TGF-beta1 in primary cultures of HUVEC. TGF-beta1 release was higher ( approximately 1.6-fold) in 25 mM (high) compared with 5 mM (normal) D-glucose. TGF-beta1 increases L-arginine transport (half maximal effect approximately 1.6 ng/ml) in normal D-glucose, but did not alter high D-glucose-increased L-arginine transport. TGF-beta1 and high D-glucose increased hCAT-1 mRNA expression ( approximately 8-fold) and maximal transport velocity (V(max)), L-[(3)H]citrulline formation from CHEMICAL (index of NO synthesis) and endothelial NO synthase (eNOS) protein abundance, but did not alter GENE phosphorylation. TGF-beta1 and high D-glucose increased p42/44(mapk) and Smad2 phosphorylation, an effect blocked by PD-98059 (MEK1/2 inhibitor). However, TGF-beta1 and high D-glucose were ineffective in cells expressing a truncated, negative dominant TbetaRII. High D-glucose increases L-arginine transport and GENE expression following TbetaRII activation by TGF-beta1 involving p42/44(mapk) and Smad2 in HUVEC. Thus, TGF-beta1 could play a crucial role under conditions of hyperglycemia, such as gestational diabetes mellitus, which is associated with fetal endothelial dysfunction. | SUBSTRATE |
| CHEMICAL stimulation of L-arginine transport and nitric oxide synthesis results from activation of mitogen-activated protein kinases p42/44 and Smad2 requiring functional GENE in human umbilical vein endothelium. Elevated extracellular CHEMICAL increases transforming growth factor beta1 (TGF-beta1) release from human umbilical vein endothelium (HUVEC). TGF-beta1, via TGF-beta receptors I (TbetaRI) and TbetaRII, activates Smad2 and mitogen-activated protein kinases p44 and p42 (p42/44(mapk)). We studied whether D-glucose-stimulation of L-arginine transport and nitric oxide synthesis involves TGF-beta1 in primary cultures of HUVEC. TGF-beta1 release was higher ( approximately 1.6-fold) in 25 mM (high) compared with 5 mM (normal) CHEMICAL. TGF-beta1 increases L-arginine transport (half maximal effect approximately 1.6 ng/ml) in normal CHEMICAL, but did not alter high D-glucose-increased L-arginine transport. TGF-beta1 and high CHEMICAL increased hCAT-1 mRNA expression ( approximately 8-fold) and maximal transport velocity (V(max)), L-[(3)H]citrulline formation from L-[(3)H]arginine (index of NO synthesis) and endothelial NO synthase (eNOS) protein abundance, but did not alter eNOS phosphorylation. TGF-beta1 and high CHEMICAL increased p42/44(mapk) and Smad2 phosphorylation, an effect blocked by PD-98059 (MEK1/2 inhibitor). However, TGF-beta1 and high CHEMICAL were ineffective in cells expressing a truncated, negative dominant TbetaRII. High CHEMICAL increases L-arginine transport and eNOS expression following TbetaRII activation by TGF-beta1 involving p42/44(mapk) and Smad2 in HUVEC. Thus, TGF-beta1 could play a crucial role under conditions of hyperglycemia, such as gestational diabetes mellitus, which is associated with fetal endothelial dysfunction. | REGULATOR |
| CHEMICAL stimulation of L-arginine transport and nitric oxide synthesis results from activation of mitogen-activated protein kinases p42/44 and Smad2 requiring functional type II TGF-beta receptors in human umbilical vein endothelium. Elevated extracellular CHEMICAL increases transforming growth factor beta1 (TGF-beta1) release from human umbilical vein endothelium (HUVEC). GENE, via TGF-beta receptors I (TbetaRI) and TbetaRII, activates Smad2 and mitogen-activated protein kinases p44 and p42 (p42/44(mapk)). We studied whether D-glucose-stimulation of L-arginine transport and nitric oxide synthesis involves GENE in primary cultures of HUVEC. GENE release was higher ( approximately 1.6-fold) in 25 mM (high) compared with 5 mM (normal) CHEMICAL. GENE increases L-arginine transport (half maximal effect approximately 1.6 ng/ml) in normal CHEMICAL, but did not alter high D-glucose-increased L-arginine transport. GENE and high CHEMICAL increased hCAT-1 mRNA expression ( approximately 8-fold) and maximal transport velocity (V(max)), L-[(3)H]citrulline formation from L-[(3)H]arginine (index of NO synthesis) and endothelial NO synthase (eNOS) protein abundance, but did not alter eNOS phosphorylation. GENE and high CHEMICAL increased p42/44(mapk) and Smad2 phosphorylation, an effect blocked by PD-98059 (MEK1/2 inhibitor). However, GENE and high CHEMICAL were ineffective in cells expressing a truncated, negative dominant TbetaRII. High CHEMICAL increases L-arginine transport and eNOS expression following TbetaRII activation by GENE involving p42/44(mapk) and Smad2 in HUVEC. Thus, GENE could play a crucial role under conditions of hyperglycemia, such as gestational diabetes mellitus, which is associated with fetal endothelial dysfunction. | GENE-CHEMICAL |
| CHEMICAL stimulation of L-arginine transport and nitric oxide synthesis results from activation of mitogen-activated protein kinases p42/44 and GENE requiring functional type II TGF-beta receptors in human umbilical vein endothelium. Elevated extracellular CHEMICAL increases transforming growth factor beta1 (TGF-beta1) release from human umbilical vein endothelium (HUVEC). TGF-beta1, via TGF-beta receptors I (TbetaRI) and TbetaRII, activates GENE and mitogen-activated protein kinases p44 and p42 (p42/44(mapk)). We studied whether D-glucose-stimulation of L-arginine transport and nitric oxide synthesis involves TGF-beta1 in primary cultures of HUVEC. TGF-beta1 release was higher ( approximately 1.6-fold) in 25 mM (high) compared with 5 mM (normal) CHEMICAL. TGF-beta1 increases L-arginine transport (half maximal effect approximately 1.6 ng/ml) in normal CHEMICAL, but did not alter high D-glucose-increased L-arginine transport. TGF-beta1 and high CHEMICAL increased hCAT-1 mRNA expression ( approximately 8-fold) and maximal transport velocity (V(max)), L-[(3)H]citrulline formation from L-[(3)H]arginine (index of NO synthesis) and endothelial NO synthase (eNOS) protein abundance, but did not alter eNOS phosphorylation. TGF-beta1 and high CHEMICAL increased p42/44(mapk) and GENE phosphorylation, an effect blocked by PD-98059 (MEK1/2 inhibitor). However, TGF-beta1 and high CHEMICAL were ineffective in cells expressing a truncated, negative dominant TbetaRII. High CHEMICAL increases L-arginine transport and eNOS expression following TbetaRII activation by TGF-beta1 involving p42/44(mapk) and GENE in HUVEC. Thus, TGF-beta1 could play a crucial role under conditions of hyperglycemia, such as gestational diabetes mellitus, which is associated with fetal endothelial dysfunction. | ACTIVATOR |
| CHEMICAL stimulation of L-arginine transport and nitric oxide synthesis results from activation of mitogen-activated protein kinases p42/44 and Smad2 requiring functional type II TGF-beta receptors in human umbilical vein endothelium. Elevated extracellular CHEMICAL increases transforming growth factor beta1 (TGF-beta1) release from human umbilical vein endothelium (HUVEC). TGF-beta1, via TGF-beta receptors I (TbetaRI) and GENE, activates Smad2 and mitogen-activated protein kinases p44 and p42 (p42/44(mapk)). We studied whether D-glucose-stimulation of L-arginine transport and nitric oxide synthesis involves TGF-beta1 in primary cultures of HUVEC. TGF-beta1 release was higher ( approximately 1.6-fold) in 25 mM (high) compared with 5 mM (normal) CHEMICAL. TGF-beta1 increases L-arginine transport (half maximal effect approximately 1.6 ng/ml) in normal CHEMICAL, but did not alter high D-glucose-increased L-arginine transport. TGF-beta1 and high CHEMICAL increased hCAT-1 mRNA expression ( approximately 8-fold) and maximal transport velocity (V(max)), L-[(3)H]citrulline formation from L-[(3)H]arginine (index of NO synthesis) and endothelial NO synthase (eNOS) protein abundance, but did not alter eNOS phosphorylation. TGF-beta1 and high CHEMICAL increased p42/44(mapk) and Smad2 phosphorylation, an effect blocked by PD-98059 (MEK1/2 inhibitor). However, TGF-beta1 and high CHEMICAL were ineffective in cells expressing a truncated, negative dominant GENE. High CHEMICAL increases L-arginine transport and eNOS expression following GENE activation by TGF-beta1 involving p42/44(mapk) and Smad2 in HUVEC. Thus, TGF-beta1 could play a crucial role under conditions of hyperglycemia, such as gestational diabetes mellitus, which is associated with fetal endothelial dysfunction. | NO-RELATIONSHIP |
| CHEMICAL stimulation of L-arginine transport and nitric oxide synthesis results from activation of mitogen-activated protein kinases p42/44 and Smad2 requiring functional type II TGF-beta receptors in human umbilical vein endothelium. Elevated extracellular CHEMICAL increases transforming growth factor beta1 (TGF-beta1) release from human umbilical vein endothelium (HUVEC). TGF-beta1, via TGF-beta receptors I (TbetaRI) and TbetaRII, activates Smad2 and mitogen-activated protein kinases p44 and p42 (p42/44(mapk)). We studied whether D-glucose-stimulation of L-arginine transport and nitric oxide synthesis involves TGF-beta1 in primary cultures of HUVEC. TGF-beta1 release was higher ( approximately 1.6-fold) in 25 mM (high) compared with 5 mM (normal) CHEMICAL. TGF-beta1 increases L-arginine transport (half maximal effect approximately 1.6 ng/ml) in normal CHEMICAL, but did not alter high D-glucose-increased L-arginine transport. TGF-beta1 and high CHEMICAL increased GENE mRNA expression ( approximately 8-fold) and maximal transport velocity (V(max)), L-[(3)H]citrulline formation from L-[(3)H]arginine (index of NO synthesis) and endothelial NO synthase (eNOS) protein abundance, but did not alter eNOS phosphorylation. TGF-beta1 and high CHEMICAL increased p42/44(mapk) and Smad2 phosphorylation, an effect blocked by PD-98059 (MEK1/2 inhibitor). However, TGF-beta1 and high CHEMICAL were ineffective in cells expressing a truncated, negative dominant TbetaRII. High CHEMICAL increases L-arginine transport and eNOS expression following TbetaRII activation by TGF-beta1 involving p42/44(mapk) and Smad2 in HUVEC. Thus, TGF-beta1 could play a crucial role under conditions of hyperglycemia, such as gestational diabetes mellitus, which is associated with fetal endothelial dysfunction. | INDIRECT-UPREGULATOR |
| CHEMICAL stimulation of L-arginine transport and nitric oxide synthesis results from activation of mitogen-activated protein kinases p42/44 and Smad2 requiring functional type II TGF-beta receptors in human umbilical vein endothelium. Elevated extracellular CHEMICAL increases transforming growth factor beta1 (TGF-beta1) release from human umbilical vein endothelium (HUVEC). TGF-beta1, via TGF-beta receptors I (TbetaRI) and TbetaRII, activates Smad2 and mitogen-activated protein kinases p44 and p42 (p42/44(mapk)). We studied whether D-glucose-stimulation of L-arginine transport and nitric oxide synthesis involves TGF-beta1 in primary cultures of HUVEC. TGF-beta1 release was higher ( approximately 1.6-fold) in 25 mM (high) compared with 5 mM (normal) CHEMICAL. TGF-beta1 increases L-arginine transport (half maximal effect approximately 1.6 ng/ml) in normal CHEMICAL, but did not alter high D-glucose-increased L-arginine transport. TGF-beta1 and high CHEMICAL increased hCAT-1 mRNA expression ( approximately 8-fold) and maximal transport velocity (V(max)), L-[(3)H]citrulline formation from L-[(3)H]arginine (index of NO synthesis) and endothelial NO synthase (eNOS) protein abundance, but did not alter GENE phosphorylation. TGF-beta1 and high CHEMICAL increased p42/44(mapk) and Smad2 phosphorylation, an effect blocked by PD-98059 (MEK1/2 inhibitor). However, TGF-beta1 and high CHEMICAL were ineffective in cells expressing a truncated, negative dominant TbetaRII. High CHEMICAL increases L-arginine transport and GENE expression following TbetaRII activation by TGF-beta1 involving p42/44(mapk) and Smad2 in HUVEC. Thus, TGF-beta1 could play a crucial role under conditions of hyperglycemia, such as gestational diabetes mellitus, which is associated with fetal endothelial dysfunction. | NO-RELATIONSHIP |
| CHEMICAL stimulation of L-arginine transport and nitric oxide synthesis results from activation of mitogen-activated protein kinases p42/44 and Smad2 requiring functional type II TGF-beta receptors in human umbilical vein endothelium. Elevated extracellular CHEMICAL increases GENE (TGF-beta1) release from human umbilical vein endothelium (HUVEC). TGF-beta1, via TGF-beta receptors I (TbetaRI) and TbetaRII, activates Smad2 and mitogen-activated protein kinases p44 and p42 (p42/44(mapk)). We studied whether D-glucose-stimulation of L-arginine transport and nitric oxide synthesis involves TGF-beta1 in primary cultures of HUVEC. TGF-beta1 release was higher ( approximately 1.6-fold) in 25 mM (high) compared with 5 mM (normal) CHEMICAL. TGF-beta1 increases L-arginine transport (half maximal effect approximately 1.6 ng/ml) in normal CHEMICAL, but did not alter high D-glucose-increased L-arginine transport. TGF-beta1 and high CHEMICAL increased hCAT-1 mRNA expression ( approximately 8-fold) and maximal transport velocity (V(max)), L-[(3)H]citrulline formation from L-[(3)H]arginine (index of NO synthesis) and endothelial NO synthase (eNOS) protein abundance, but did not alter eNOS phosphorylation. TGF-beta1 and high CHEMICAL increased p42/44(mapk) and Smad2 phosphorylation, an effect blocked by PD-98059 (MEK1/2 inhibitor). However, TGF-beta1 and high CHEMICAL were ineffective in cells expressing a truncated, negative dominant TbetaRII. High CHEMICAL increases L-arginine transport and eNOS expression following TbetaRII activation by TGF-beta1 involving p42/44(mapk) and Smad2 in HUVEC. Thus, TGF-beta1 could play a crucial role under conditions of hyperglycemia, such as gestational diabetes mellitus, which is associated with fetal endothelial dysfunction. | INDIRECT-UPREGULATOR |
| D-glucose stimulation of L-arginine transport and nitric oxide synthesis results from activation of mitogen-activated protein kinases p42/44 and GENE requiring functional type II TGF-beta receptors in human umbilical vein endothelium. Elevated extracellular D-glucose increases transforming growth factor beta1 (TGF-beta1) release from human umbilical vein endothelium (HUVEC). TGF-beta1, via TGF-beta receptors I (TbetaRI) and TbetaRII, activates GENE and mitogen-activated protein kinases p44 and p42 (p42/44(mapk)). We studied whether D-glucose-stimulation of L-arginine transport and nitric oxide synthesis involves TGF-beta1 in primary cultures of HUVEC. TGF-beta1 release was higher ( approximately 1.6-fold) in 25 mM (high) compared with 5 mM (normal) D-glucose. TGF-beta1 increases L-arginine transport (half maximal effect approximately 1.6 ng/ml) in normal D-glucose, but did not alter high D-glucose-increased L-arginine transport. TGF-beta1 and high D-glucose increased hCAT-1 mRNA expression ( approximately 8-fold) and maximal transport velocity (V(max)), L-[(3)H]citrulline formation from L-[(3)H]arginine (index of NO synthesis) and endothelial NO synthase (eNOS) protein abundance, but did not alter eNOS phosphorylation. TGF-beta1 and high D-glucose increased p42/44(mapk) and GENE phosphorylation, an effect blocked by CHEMICAL (MEK1/2 inhibitor). However, TGF-beta1 and high D-glucose were ineffective in cells expressing a truncated, negative dominant TbetaRII. High D-glucose increases L-arginine transport and eNOS expression following TbetaRII activation by TGF-beta1 involving p42/44(mapk) and GENE in HUVEC. Thus, TGF-beta1 could play a crucial role under conditions of hyperglycemia, such as gestational diabetes mellitus, which is associated with fetal endothelial dysfunction. | INHIBITOR |
| D-glucose stimulation of L-arginine transport and nitric oxide synthesis results from activation of mitogen-activated protein kinases p42/44 and Smad2 requiring functional type II TGF-beta receptors in human umbilical vein endothelium. Elevated extracellular D-glucose increases transforming growth factor beta1 (TGF-beta1) release from human umbilical vein endothelium (HUVEC). TGF-beta1, via TGF-beta receptors I (TbetaRI) and TbetaRII, activates Smad2 and mitogen-activated protein kinases p44 and p42 (p42/44(mapk)). We studied whether D-glucose-stimulation of L-arginine transport and nitric oxide synthesis involves TGF-beta1 in primary cultures of HUVEC. TGF-beta1 release was higher ( approximately 1.6-fold) in 25 mM (high) compared with 5 mM (normal) D-glucose. TGF-beta1 increases L-arginine transport (half maximal effect approximately 1.6 ng/ml) in normal D-glucose, but did not alter high D-glucose-increased L-arginine transport. TGF-beta1 and high D-glucose increased hCAT-1 mRNA expression ( approximately 8-fold) and maximal transport velocity (V(max)), L-[(3)H]citrulline formation from L-[(3)H]arginine (index of CHEMICAL synthesis) and GENE (eNOS) protein abundance, but did not alter eNOS phosphorylation. TGF-beta1 and high D-glucose increased p42/44(mapk) and Smad2 phosphorylation, an effect blocked by PD-98059 (MEK1/2 inhibitor). However, TGF-beta1 and high D-glucose were ineffective in cells expressing a truncated, negative dominant TbetaRII. High D-glucose increases L-arginine transport and eNOS expression following TbetaRII activation by TGF-beta1 involving p42/44(mapk) and Smad2 in HUVEC. Thus, TGF-beta1 could play a crucial role under conditions of hyperglycemia, such as gestational diabetes mellitus, which is associated with fetal endothelial dysfunction. | PRODUCT-OF |
| D-glucose stimulation of L-arginine transport and nitric oxide synthesis results from activation of mitogen-activated protein kinases p42/44 and Smad2 requiring functional type II TGF-beta receptors in human umbilical vein endothelium. Elevated extracellular D-glucose increases transforming growth factor beta1 (TGF-beta1) release from human umbilical vein endothelium (HUVEC). TGF-beta1, via TGF-beta receptors I (TbetaRI) and TbetaRII, activates Smad2 and mitogen-activated protein kinases p44 and p42 (p42/44(mapk)). We studied whether D-glucose-stimulation of L-arginine transport and nitric oxide synthesis involves TGF-beta1 in primary cultures of HUVEC. TGF-beta1 release was higher ( approximately 1.6-fold) in 25 mM (high) compared with 5 mM (normal) D-glucose. TGF-beta1 increases L-arginine transport (half maximal effect approximately 1.6 ng/ml) in normal D-glucose, but did not alter high D-glucose-increased L-arginine transport. TGF-beta1 and high D-glucose increased hCAT-1 mRNA expression ( approximately 8-fold) and maximal transport velocity (V(max)), L-[(3)H]citrulline formation from L-[(3)H]arginine (index of CHEMICAL synthesis) and endothelial CHEMICAL synthase (GENE) protein abundance, but did not alter GENE phosphorylation. TGF-beta1 and high D-glucose increased p42/44(mapk) and Smad2 phosphorylation, an effect blocked by PD-98059 (MEK1/2 inhibitor). However, TGF-beta1 and high D-glucose were ineffective in cells expressing a truncated, negative dominant TbetaRII. High D-glucose increases L-arginine transport and GENE expression following TbetaRII activation by TGF-beta1 involving p42/44(mapk) and Smad2 in HUVEC. Thus, TGF-beta1 could play a crucial role under conditions of hyperglycemia, such as gestational diabetes mellitus, which is associated with fetal endothelial dysfunction. | PRODUCT-OF |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of COX-2 via GENE activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a GENE ligand (CHEMICAL), induced COX-2 expression (protein and mRNA). Moreover stimulation of COX-2 promoter activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on COX-2 expression and on stimulation of COX-2 promoter activity by EPA and GLA suggest that GENE is implicated in COX-2 induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on COX-2 induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased GENE activity is necessary for the COX-2 induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of COX-2 in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | DIRECT-REGULATOR |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of GENE via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a PPARgamma ligand (roziglitazone), induced GENE expression (protein and mRNA). Moreover stimulation of GENE promoter activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of CHEMICAL and T0070907 (PPARgamma antagonists), on GENE expression and on stimulation of GENE promoter activity by EPA and GLA suggest that PPARgamma is implicated in GENE induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on GENE induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased PPARgamma activity is necessary for the GENE induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of GENE in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | INDIRECT-DOWNREGULATOR |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of COX-2 via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a PPARgamma ligand (roziglitazone), induced COX-2 expression (protein and mRNA). Moreover stimulation of GENE activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of CHEMICAL and T0070907 (PPARgamma antagonists), on COX-2 expression and on stimulation of GENE activity by EPA and GLA suggest that PPARgamma is implicated in COX-2 induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on COX-2 induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased PPARgamma activity is necessary for the COX-2 induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of COX-2 in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | INHIBITOR |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of GENE via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a PPARgamma ligand (roziglitazone), induced GENE expression (protein and mRNA). Moreover stimulation of GENE promoter activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and CHEMICAL (PPARgamma antagonists), on GENE expression and on stimulation of GENE promoter activity by EPA and GLA suggest that PPARgamma is implicated in GENE induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on GENE induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased PPARgamma activity is necessary for the GENE induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of GENE in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | GENE-CHEMICAL |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of COX-2 via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a PPARgamma ligand (roziglitazone), induced COX-2 expression (protein and mRNA). Moreover stimulation of GENE activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and CHEMICAL (PPARgamma antagonists), on COX-2 expression and on stimulation of GENE activity by EPA and GLA suggest that PPARgamma is implicated in COX-2 induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on COX-2 induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased PPARgamma activity is necessary for the COX-2 induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of COX-2 in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | INHIBITOR |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of COX-2 via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and CHEMICAL or a PPARgamma ligand (roziglitazone), induced COX-2 expression (protein and mRNA). Moreover stimulation of GENE activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on COX-2 expression and on stimulation of GENE activity by CHEMICAL and GLA suggest that PPARgamma is implicated in COX-2 induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on COX-2 induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased PPARgamma activity is necessary for the COX-2 induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of CHEMICAL, we suggest that induction of COX-2 in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | ACTIVATOR |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of COX-2 via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with CHEMICAL and EPA or a PPARgamma ligand (roziglitazone), induced COX-2 expression (protein and mRNA). Moreover stimulation of GENE activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on COX-2 expression and on stimulation of GENE activity by EPA and CHEMICAL suggest that PPARgamma is implicated in COX-2 induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on COX-2 induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased PPARgamma activity is necessary for the COX-2 induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of COX-2 in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | ACTIVATOR |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of GENE via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 CHEMICAL, gamma-linoleic acid (GLA) a n-6 CHEMICAL, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a PPARgamma ligand (roziglitazone), induced GENE expression (protein and mRNA). Moreover stimulation of GENE promoter activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on GENE expression and on stimulation of GENE promoter activity by EPA and GLA suggest that PPARgamma is implicated in GENE induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the CHEMICAL effects on GENE induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 CHEMICAL increased PPARgamma activity is necessary for the GENE induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of GENE in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | GENE-CHEMICAL |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of COX-2 via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a PPARgamma ligand (roziglitazone), induced COX-2 expression (protein and mRNA). Moreover stimulation of GENE activity was increased by those CHEMICAL or rosiglitazone. The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on COX-2 expression and on stimulation of GENE activity by EPA and GLA suggest that PPARgamma is implicated in COX-2 induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on COX-2 induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased PPARgamma activity is necessary for the COX-2 induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of COX-2 in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of CHEMICAL n-3 or n-6. | ACTIVATOR |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of COX-2 via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a PPARgamma ligand (roziglitazone), induced COX-2 expression (protein and mRNA). Moreover stimulation of GENE activity was increased by those PUFAs or CHEMICAL. The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on COX-2 expression and on stimulation of GENE activity by EPA and GLA suggest that PPARgamma is implicated in COX-2 induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on COX-2 induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased PPARgamma activity is necessary for the COX-2 induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of COX-2 in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | ACTIVATOR |
| CHEMICAL induce the expression of COX-2 via GENE activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a GENE ligand (roziglitazone), induced COX-2 expression (protein and mRNA). Moreover stimulation of COX-2 promoter activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on COX-2 expression and on stimulation of COX-2 promoter activity by EPA and GLA suggest that GENE is implicated in COX-2 induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on COX-2 induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased GENE activity is necessary for the COX-2 induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of COX-2 in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | ACTIVATOR |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of COX-2 via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a PPARgamma ligand (roziglitazone), induced COX-2 expression (protein and mRNA). Moreover stimulation of COX-2 promoter activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on COX-2 expression and on stimulation of COX-2 promoter activity by EPA and GLA suggest that PPARgamma is implicated in COX-2 induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on COX-2 induction, promoter activity and arachidonic acid mobilization suggesting involvement of CHEMICAL metabolites in GENE activation. These findings demonstrate that n-3 and n-6 PUFA increased PPARgamma activity is necessary for the COX-2 induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of COX-2 in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | ACTIVATOR |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of COX-2 via GENE activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a GENE ligand (roziglitazone), induced COX-2 expression (protein and mRNA). Moreover stimulation of COX-2 promoter activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on COX-2 expression and on stimulation of COX-2 promoter activity by EPA and GLA suggest that GENE is implicated in COX-2 induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on COX-2 induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that CHEMICAL increased GENE activity is necessary for the COX-2 induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of COX-2 in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | ACTIVATOR |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of GENE via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a PPARgamma ligand (roziglitazone), induced GENE expression (protein and mRNA). Moreover stimulation of GENE promoter activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on GENE expression and on stimulation of GENE promoter activity by EPA and GLA suggest that PPARgamma is implicated in GENE induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on GENE induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that CHEMICAL increased PPARgamma activity is necessary for the GENE induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of GENE in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | GENE-CHEMICAL |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of GENE via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a PPARgamma ligand (roziglitazone), induced GENE expression (protein and mRNA). Moreover stimulation of GENE promoter activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on GENE expression and on stimulation of GENE promoter activity by EPA and GLA suggest that PPARgamma is implicated in GENE induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on GENE induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased PPARgamma activity is necessary for the GENE induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of GENE in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of CHEMICAL or n-6. | REGULATOR |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of GENE via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with CHEMICAL and EPA or a PPARgamma ligand (roziglitazone), induced GENE expression (protein and mRNA). Moreover stimulation of GENE promoter activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on GENE expression and on stimulation of GENE promoter activity by EPA and CHEMICAL suggest that PPARgamma is implicated in GENE induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on GENE induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased PPARgamma activity is necessary for the GENE induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of GENE in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | INDIRECT-UPREGULATOR |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of GENE via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and CHEMICAL or a PPARgamma ligand (roziglitazone), induced GENE expression (protein and mRNA). Moreover stimulation of GENE promoter activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on GENE expression and on stimulation of GENE promoter activity by CHEMICAL and GLA suggest that PPARgamma is implicated in GENE induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on GENE induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased PPARgamma activity is necessary for the GENE induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of CHEMICAL, we suggest that induction of GENE in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | INDIRECT-UPREGULATOR |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of GENE via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a PPARgamma ligand (CHEMICAL), induced GENE expression (protein and mRNA). Moreover stimulation of GENE promoter activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on GENE expression and on stimulation of GENE promoter activity by EPA and GLA suggest that PPARgamma is implicated in GENE induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on GENE induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased PPARgamma activity is necessary for the GENE induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of GENE in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | INDIRECT-UPREGULATOR |
| CHEMICAL induce the expression of GENE via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a PPARgamma ligand (roziglitazone), induced GENE expression (protein and mRNA). Moreover stimulation of GENE promoter activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on GENE expression and on stimulation of GENE promoter activity by EPA and GLA suggest that PPARgamma is implicated in GENE induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on GENE induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased PPARgamma activity is necessary for the GENE induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of GENE in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | INDIRECT-UPREGULATOR |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of COX-2 via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a PPARgamma ligand (roziglitazone), induced COX-2 expression (protein and mRNA). Moreover stimulation of COX-2 promoter activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on COX-2 expression and on stimulation of COX-2 promoter activity by EPA and GLA suggest that PPARgamma is implicated in COX-2 induction. Finally, GENE inhibitor methyl CHEMICAL blocked the PUFA effects on COX-2 induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased PPARgamma activity is necessary for the COX-2 induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of COX-2 in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | INHIBITOR |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of GENE via PPARgamma activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a PPARgamma ligand (roziglitazone), induced GENE expression (protein and mRNA). Moreover stimulation of GENE promoter activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and T0070907 (PPARgamma antagonists), on GENE expression and on stimulation of GENE promoter activity by EPA and GLA suggest that PPARgamma is implicated in GENE induction. Finally, PLA2 inhibitor methyl CHEMICAL blocked the PUFA effects on GENE induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased PPARgamma activity is necessary for the GENE induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of GENE in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | INHIBITOR |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of COX-2 via GENE activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a GENE ligand (roziglitazone), induced COX-2 expression (protein and mRNA). Moreover stimulation of COX-2 promoter activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of CHEMICAL and T0070907 (GENE antagonists), on COX-2 expression and on stimulation of COX-2 promoter activity by EPA and GLA suggest that GENE is implicated in COX-2 induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on COX-2 induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased GENE activity is necessary for the COX-2 induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of COX-2 in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | INHIBITOR |
| n-3 and n-6 polyunsaturated fatty acids induce the expression of COX-2 via GENE activation in human keratinocyte HaCaT cells. Polyunsaturated fatty acids (PUFA) n-3 inhibit inflammation, in vivo and in vitro in keratinocytes. We examined in HaCaT keratinocyte cell line whether eicosapentaenoic acid (EPA) a n-3 PUFA, gamma-linoleic acid (GLA) a n-6 PUFA, and arachidic acid a saturated fatty acid, modulate expression of cyclooxygenase-2 (COX-2), an enzyme pivotal to skin inflammation and reparation. We demonstrate that only treatment of HaCaT with GLA and EPA or a GENE ligand (roziglitazone), induced COX-2 expression (protein and mRNA). Moreover stimulation of COX-2 promoter activity was increased by those PUFAs or rosiglitazone. The inhibitory effects of GW9662 and CHEMICAL (GENE antagonists), on COX-2 expression and on stimulation of COX-2 promoter activity by EPA and GLA suggest that GENE is implicated in COX-2 induction. Finally, PLA2 inhibitor methyl arachidonyl fluorophosphonate blocked the PUFA effects on COX-2 induction, promoter activity and arachidonic acid mobilization suggesting involvement of AA metabolites in PPAR activation. These findings demonstrate that n-3 and n-6 PUFA increased GENE activity is necessary for the COX-2 induction in HaCaT human keratinocyte cells. Given the anti-inflammatory properties of EPA, we suggest that induction of COX-2 in keratinocytes may be important in the anti-inflammatory and protective mechanism of action of PUFAs n-3 or n-6. | INHIBITOR |
Nebulized arformoterol in patients with COPD: a 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial. OBJECTIVE: The aim of this study was to assess the efficacy and tolerability of nebulized arformoterol tartrate (a selective, long-acting GENE agonist that is the [R,R] isomer of formoterol) and CHEMICAL versus placebo in patients with chronic obstructive pulmonary disease (COPD). METHODS: This 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial was conducted at 60 centers across the United States. Male and female patients aged >or=35 years with physician-diagnosed COPD received arformoterol (15 microg BID, 25 microg BID, or 50 microg QD via nebulizer), salmeterol (42 microg BID via metered dose inhaler), or placebo. Pulmonary function was assessed by spirometry; dyspnea, by the Transitional Dyspnea Index (TDI); and health status, by the St. George's Respiratory Questionnaire (SGRQ). Adverse events (AEs) were assessed by site personnel at all clinic visits (screening, first dose at week 0, and at weeks 3, 6, 9, 12, and follow-up). COPD exacerbations were defined as worsening respiratory status requiring a change in medication or an unscheduled provider visit. RESULTS: A total of 717 patients received study medication. The demographic composition of all treatment arms was similar. The mean age was 62.9 years, 58% were men, and mean baseline forced expiratory volume in 1 second (FEV(1)) was 1.2 L (41% predicted). Mean improvement in trough FEV(1) over 12 weeks was significantly greater with all 3 arformoterol doses (15 microg BID, +16.9%; 25 microg BID, +18.9%; 50 microg QD, +14.9%) and for salmeterol (+17.4%) relative to placebo (+6.0%; P < 0.001). There were significantly greater improvements in the mean percentage change in FEV(1) AUC(0-12h) from the predose value over 12 weeks (15 microg BID, 12.7%, 25 microg BID, 13.9%, 50 microg QD, 18.9%; salmeterol, 9.8%) versus placebo (2.7%; P | ACTIVATOR | |
Nebulized arformoterol in patients with COPD: a 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial. OBJECTIVE: The aim of this study was to assess the efficacy and tolerability of nebulized arformoterol tartrate (a selective, long-acting GENE agonist that is the CHEMICAL) and salmeterol xinafoate versus placebo in patients with chronic obstructive pulmonary disease (COPD). METHODS: This 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial was conducted at 60 centers across the United States. Male and female patients aged >or=35 years with physician-diagnosed COPD received arformoterol (15 microg BID, 25 microg BID, or 50 microg QD via nebulizer), salmeterol (42 microg BID via metered dose inhaler), or placebo. Pulmonary function was assessed by spirometry; dyspnea, by the Transitional Dyspnea Index (TDI); and health status, by the St. George's Respiratory Questionnaire (SGRQ). Adverse events (AEs) were assessed by site personnel at all clinic visits (screening, first dose at week 0, and at weeks 3, 6, 9, 12, and follow-up). COPD exacerbations were defined as worsening respiratory status requiring a change in medication or an unscheduled provider visit. RESULTS: A total of 717 patients received study medication. The demographic composition of all treatment arms was similar. The mean age was 62.9 years, 58% were men, and mean baseline forced expiratory volume in 1 second (FEV(1)) was 1.2 L (41% predicted). Mean improvement in trough FEV(1) over 12 weeks was significantly greater with all 3 arformoterol doses (15 microg BID, +16.9%; 25 microg BID, +18.9%; 50 microg QD, +14.9%) and for salmeterol (+17.4%) relative to placebo (+6.0%; P < 0.001). There were significantly greater improvements in the mean percentage change in FEV(1) AUC(0-12h) from the predose value over 12 weeks (15 microg BID, 12.7%, 25 microg BID, 13.9%, 50 microg QD, 18.9%; salmeterol, 9.8%) versus placebo (2.7%; P | ACTIVATOR | |
Nebulized arformoterol in patients with COPD: a 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial. OBJECTIVE: The aim of this study was to assess the efficacy and tolerability of nebulized CHEMICAL (a selective, long-acting GENE agonist that is the [R,R] isomer of formoterol) and salmeterol xinafoate versus placebo in patients with chronic obstructive pulmonary disease (COPD). METHODS: This 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial was conducted at 60 centers across the United States. Male and female patients aged >or=35 years with physician-diagnosed COPD received arformoterol (15 microg BID, 25 microg BID, or 50 microg QD via nebulizer), salmeterol (42 microg BID via metered dose inhaler), or placebo. Pulmonary function was assessed by spirometry; dyspnea, by the Transitional Dyspnea Index (TDI); and health status, by the St. George's Respiratory Questionnaire (SGRQ). Adverse events (AEs) were assessed by site personnel at all clinic visits (screening, first dose at week 0, and at weeks 3, 6, 9, 12, and follow-up). COPD exacerbations were defined as worsening respiratory status requiring a change in medication or an unscheduled provider visit. RESULTS: A total of 717 patients received study medication. The demographic composition of all treatment arms was similar. The mean age was 62.9 years, 58% were men, and mean baseline forced expiratory volume in 1 second (FEV(1)) was 1.2 L (41% predicted). Mean improvement in trough FEV(1) over 12 weeks was significantly greater with all 3 arformoterol doses (15 microg BID, +16.9%; 25 microg BID, +18.9%; 50 microg QD, +14.9%) and for salmeterol (+17.4%) relative to placebo (+6.0%; P < 0.001). There were significantly greater improvements in the mean percentage change in FEV(1) AUC(0-12h) from the predose value over 12 weeks (15 microg BID, 12.7%, 25 microg BID, 13.9%, 50 microg QD, 18.9%; salmeterol, 9.8%) versus placebo (2.7%; P | ACTIVATOR | |
| Discovery of acetyl-coenzyme A carboxylase 2 inhibitors: comparison of a fluorescence intensity-based phosphate assay and a fluorescence polarization-based ADP Assay for high-throughput screening. Acetyl-coenzyme A carboxylase (ACC) enzymes exist as two isoforms, GENE and ACC2, which play critical roles in fatty acid biosynthesis and oxidation. Though each isoform differs in tissue and subcellular localization, both catalyze the biotin- and ATP-dependent carboxylation of acetyl-coenzyme A to generate CHEMICAL, a key metabolite in the control of fatty acid synthesis and oxidation. The cytosolic GENE is expressed primarily in liver and adipose tissue, and uses CHEMICAL as a key building block in fatty acid biosynthesis. The mitochondrial ACC2 is primarily expressed in heart and skeletal muscle, where it is involved in the regulation of fatty acid oxidation. Inhibitors of ACC enzymes may therefore be useful therapeutics for diabetes, obesity, and metabolic syndrome. Two assay formats for these ATP-utilizing enzymes amenable to high-throughput screening are compared: a fluorescence intensity-based assay to detect inorganic phosphate and a fluorescence polarization-based assay to detect ADP. Acetyl-coenzyme A carboxylase inhibitors were identified by these high-throughput screening methods and were confirmed in a radiometric high performance liquid chromatography assay of CHEMICAL production. | PRODUCT-OF |
| Discovery of acetyl-coenzyme A carboxylase 2 inhibitors: comparison of a fluorescence intensity-based phosphate assay and a fluorescence polarization-based ADP Assay for high-throughput screening. Acetyl-coenzyme A carboxylase (ACC) enzymes exist as two isoforms, GENE and ACC2, which play critical roles in CHEMICAL biosynthesis and oxidation. Though each isoform differs in tissue and subcellular localization, both catalyze the biotin- and ATP-dependent carboxylation of acetyl-coenzyme A to generate malonyl-coenzyme A, a key metabolite in the control of CHEMICAL synthesis and oxidation. The cytosolic GENE is expressed primarily in liver and adipose tissue, and uses malonyl-coenzyme A as a key building block in CHEMICAL biosynthesis. The mitochondrial ACC2 is primarily expressed in heart and skeletal muscle, where it is involved in the regulation of CHEMICAL oxidation. Inhibitors of ACC enzymes may therefore be useful therapeutics for diabetes, obesity, and metabolic syndrome. Two assay formats for these ATP-utilizing enzymes amenable to high-throughput screening are compared: a fluorescence intensity-based assay to detect inorganic phosphate and a fluorescence polarization-based assay to detect ADP. Acetyl-coenzyme A carboxylase inhibitors were identified by these high-throughput screening methods and were confirmed in a radiometric high performance liquid chromatography assay of malonyl-coenzyme A production. | PRODUCT-OF |
| Discovery of acetyl-coenzyme A carboxylase 2 inhibitors: comparison of a fluorescence intensity-based phosphate assay and a fluorescence polarization-based ADP Assay for high-throughput screening. Acetyl-coenzyme A carboxylase (ACC) enzymes exist as two isoforms, ACC1 and GENE, which play critical roles in CHEMICAL biosynthesis and oxidation. Though each isoform differs in tissue and subcellular localization, both catalyze the biotin- and ATP-dependent carboxylation of acetyl-coenzyme A to generate malonyl-coenzyme A, a key metabolite in the control of CHEMICAL synthesis and oxidation. The cytosolic ACC1 is expressed primarily in liver and adipose tissue, and uses malonyl-coenzyme A as a key building block in CHEMICAL biosynthesis. The mitochondrial GENE is primarily expressed in heart and skeletal muscle, where it is involved in the regulation of CHEMICAL oxidation. Inhibitors of ACC enzymes may therefore be useful therapeutics for diabetes, obesity, and metabolic syndrome. Two assay formats for these ATP-utilizing enzymes amenable to high-throughput screening are compared: a fluorescence intensity-based assay to detect inorganic phosphate and a fluorescence polarization-based assay to detect ADP. Acetyl-coenzyme A carboxylase inhibitors were identified by these high-throughput screening methods and were confirmed in a radiometric high performance liquid chromatography assay of malonyl-coenzyme A production. | PRODUCT-OF |
| Discovery of acetyl-coenzyme A carboxylase 2 inhibitors: comparison of a fluorescence intensity-based phosphate assay and a fluorescence polarization-based ADP Assay for high-throughput screening. GENE (ACC) enzymes exist as two isoforms, ACC1 and ACC2, which play critical roles in CHEMICAL biosynthesis and oxidation. Though each isoform differs in tissue and subcellular localization, both catalyze the biotin- and ATP-dependent carboxylation of acetyl-coenzyme A to generate malonyl-coenzyme A, a key metabolite in the control of CHEMICAL synthesis and oxidation. The cytosolic ACC1 is expressed primarily in liver and adipose tissue, and uses malonyl-coenzyme A as a key building block in CHEMICAL biosynthesis. The mitochondrial ACC2 is primarily expressed in heart and skeletal muscle, where it is involved in the regulation of CHEMICAL oxidation. Inhibitors of ACC enzymes may therefore be useful therapeutics for diabetes, obesity, and metabolic syndrome. Two assay formats for these ATP-utilizing enzymes amenable to high-throughput screening are compared: a fluorescence intensity-based assay to detect inorganic phosphate and a fluorescence polarization-based assay to detect ADP. GENE inhibitors were identified by these high-throughput screening methods and were confirmed in a radiometric high performance liquid chromatography assay of malonyl-coenzyme A production. | PRODUCT-OF |
| Discovery of acetyl-coenzyme A carboxylase 2 inhibitors: comparison of a fluorescence intensity-based phosphate assay and a fluorescence polarization-based ADP Assay for high-throughput screening. Acetyl-coenzyme A carboxylase (GENE) enzymes exist as two isoforms, ACC1 and ACC2, which play critical roles in CHEMICAL biosynthesis and oxidation. Though each isoform differs in tissue and subcellular localization, both catalyze the biotin- and ATP-dependent carboxylation of acetyl-coenzyme A to generate malonyl-coenzyme A, a key metabolite in the control of CHEMICAL synthesis and oxidation. The cytosolic ACC1 is expressed primarily in liver and adipose tissue, and uses malonyl-coenzyme A as a key building block in CHEMICAL biosynthesis. The mitochondrial ACC2 is primarily expressed in heart and skeletal muscle, where it is involved in the regulation of CHEMICAL oxidation. Inhibitors of GENE enzymes may therefore be useful therapeutics for diabetes, obesity, and metabolic syndrome. Two assay formats for these ATP-utilizing enzymes amenable to high-throughput screening are compared: a fluorescence intensity-based assay to detect inorganic phosphate and a fluorescence polarization-based assay to detect ADP. Acetyl-coenzyme A carboxylase inhibitors were identified by these high-throughput screening methods and were confirmed in a radiometric high performance liquid chromatography assay of malonyl-coenzyme A production. | PRODUCT-OF |
| Retinoic acid is required for specification of the ventral eye field and for Rathke's pouch in the avian embryo. We have investigated the role of retinoic acid (RA) in eye development using the vitamin A deficient quail model system, which overcomes problems of retinoic acid synthesising enzyme redundancy in the embryo. In the absence of retinoic acid, the ventral optic stalk and ventral retina are missing, whereas the dorsal optic stalk and dorsal retina develop appropriately. Other ocular abnormalities observed were a thinner retina and the lack of differentiation of the lens. In an attempt to explain this, we studied the expression of various dorsally and ventrally expressed genes such as Pax2, Pax6, Tbx6, Vax2, Raldh1 and Raldh3 and noted that they were unchanged in their expression patterns. In contrast, the CHEMICAL catabolising enzymes GENE and Cyp26B1 which are known to be RA-responsive were not expressed at all in the developing eye. At much earlier stages, the expression domain of Shh in the prechordal plate was reduced, as was Nkx2.1 and we suggest a model whereby the eye field is specified according to the concentration of SHH protein that is present. We also describe another organ, Rathke's pouch which fails to develop in the absence of retinoic acid. We attribute this to the down-regulation of Bmp2, Shh and Fgf8 which are known to be involved in the induction of this structure. | SUBSTRATE |
| Retinoic acid is required for specification of the ventral eye field and for Rathke's pouch in the avian embryo. We have investigated the role of retinoic acid (RA) in eye development using the vitamin A deficient quail model system, which overcomes problems of retinoic acid synthesising enzyme redundancy in the embryo. In the absence of retinoic acid, the ventral optic stalk and ventral retina are missing, whereas the dorsal optic stalk and dorsal retina develop appropriately. Other ocular abnormalities observed were a thinner retina and the lack of differentiation of the lens. In an attempt to explain this, we studied the expression of various dorsally and ventrally expressed genes such as Pax2, Pax6, Tbx6, Vax2, Raldh1 and Raldh3 and noted that they were unchanged in their expression patterns. In contrast, the CHEMICAL catabolising enzymes Cyp26A1 and GENE which are known to be RA-responsive were not expressed at all in the developing eye. At much earlier stages, the expression domain of Shh in the prechordal plate was reduced, as was Nkx2.1 and we suggest a model whereby the eye field is specified according to the concentration of SHH protein that is present. We also describe another organ, Rathke's pouch which fails to develop in the absence of retinoic acid. We attribute this to the down-regulation of Bmp2, Shh and Fgf8 which are known to be involved in the induction of this structure. | SUBSTRATE |
| Biology of incretins: GLP-1 and GIP. This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The published literature was reviewed, with emphasis on recent advances in our understanding of the biology of GIP and GLP-1. GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet beta-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of beta-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue, and enhances bone formation via stimulation of osteoblast proliferation and inhibition of apoptosis. In contrast, GLP-1 exerts glucoregulatory actions via slowing of gastric emptying and CHEMICAL-dependent inhibition of GENE secretion. GLP-1 also promotes satiety and sustained GLP-1-receptor activation is associated with weight loss in both preclinical and clinical studies. The rapid degradation of both GIP and GLP-1 by the enzyme dipeptidyl peptidase-4 has led to the development of degradation-resistant GLP-1-receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. These agents decrease hemoglobin A1c (HbA1c) safely without weight gain in subjects with type 2 diabetes. GLP-1 and GIP integrate nutrient-derived signals to control food intake, energy absorption, and assimilation. Recently approved therapeutic agents based on potentiation of incretin action provide new physiologically based approaches for the treatment of type 2 diabetes. | INHIBITOR |
| Biology of incretins: GENE and GIP. This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The published literature was reviewed, with emphasis on recent advances in our understanding of the biology of GIP and GENE. GIP and GENE are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet beta-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of beta-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue, and enhances bone formation via stimulation of osteoblast proliferation and inhibition of apoptosis. In contrast, GENE exerts glucoregulatory actions via slowing of gastric emptying and CHEMICAL-dependent inhibition of glucagon secretion. GENE also promotes satiety and sustained GLP-1-receptor activation is associated with weight loss in both preclinical and clinical studies. The rapid degradation of both GIP and GENE by the enzyme dipeptidyl peptidase-4 has led to the development of degradation-resistant GLP-1-receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. These agents decrease hemoglobin A1c (HbA1c) safely without weight gain in subjects with type 2 diabetes. GENE and GIP integrate nutrient-derived signals to control food intake, energy absorption, and assimilation. Recently approved therapeutic agents based on potentiation of incretin action provide new physiologically based approaches for the treatment of type 2 diabetes. | REGULATOR |
| Biology of incretins: GLP-1 and GIP. This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The published literature was reviewed, with emphasis on recent advances in our understanding of the biology of GIP and GLP-1. GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet beta-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to CHEMICAL-dependent GENE secretion, induction of beta-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue, and enhances bone formation via stimulation of osteoblast proliferation and inhibition of apoptosis. In contrast, GLP-1 exerts glucoregulatory actions via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety and sustained GLP-1-receptor activation is associated with weight loss in both preclinical and clinical studies. The rapid degradation of both GIP and GLP-1 by the enzyme dipeptidyl peptidase-4 has led to the development of degradation-resistant GLP-1-receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. These agents decrease hemoglobin A1c (HbA1c) safely without weight gain in subjects with type 2 diabetes. GLP-1 and GIP integrate nutrient-derived signals to control food intake, energy absorption, and assimilation. Recently approved therapeutic agents based on potentiation of incretin action provide new physiologically based approaches for the treatment of type 2 diabetes. | GENE-CHEMICAL |
| CHEMICAL acts as a selective dopamine D2 receptor partial agonist. CHEMICAL has made a significant contribution to the treatment of schizophrenia and related disorders with an improved safety and tolerability profile, which has been attributed to its unique pharmacological profile. It has been claimed that partial agonism of the dopamine D(2) and 5-HT(1A) receptors and antagonism of the 5-HT(2) receptor contribute to the clinical profile of CHEMICAL, a so-called dopamine- and 5-HT stabiliser. However, recent studies have questioned the role of the 5-HT-mediated systems in the mechanism of action of CHEMICAL. This report reviews published and unpublished data that suggest that CHEMICAL acts as a selective partial agonist at the dopamine D(2) receptor and does not affect GENE at therapeutic doses. | NO-RELATIONSHIP |
| CHEMICAL acts as a selective dopamine D2 receptor partial agonist. CHEMICAL has made a significant contribution to the treatment of schizophrenia and related disorders with an improved safety and tolerability profile, which has been attributed to its unique pharmacological profile. It has been claimed that partial agonism of the dopamine D(2) and 5-HT(1A) receptors and antagonism of the GENE receptor contribute to the clinical profile of CHEMICAL, a so-called dopamine- and 5-HT stabiliser. However, recent studies have questioned the role of the 5-HT-mediated systems in the mechanism of action of CHEMICAL. This report reviews published and unpublished data that suggest that CHEMICAL acts as a selective partial agonist at the dopamine D(2) receptor and does not affect 5-HT receptors at therapeutic doses. | INHIBITOR |
| CHEMICAL acts as a selective dopamine D2 receptor partial agonist. CHEMICAL has made a significant contribution to the treatment of schizophrenia and related disorders with an improved safety and tolerability profile, which has been attributed to its unique pharmacological profile. It has been claimed that partial agonism of the dopamine D(2) and 5-HT(1A) receptors and antagonism of the 5-HT(2) receptor contribute to the clinical profile of CHEMICAL, a so-called dopamine- and 5-HT stabiliser. However, recent studies have questioned the role of the 5-HT-mediated systems in the mechanism of action of CHEMICAL. This report reviews published and unpublished data that suggest that CHEMICAL acts as a selective partial agonist at the GENE and does not affect 5-HT receptors at therapeutic doses. | ACTIVATOR |
| Pharmacological therapy of Cushing's syndrome: drugs and indications. OBJECTIVE: To review the main pharmacological properties and clinical applications of the drugs used in the medical therapy of Cushing's syndrome. DATA SOURCES: Search for articles were performed in the following dababases: MEDLINE, EMBASE, Cochrane Database of systematic Reviews and The Cochrane Central Register of Controlled Trials (CENTRAL). Search terms included Cushing's syndrome and drug therapy. DATA SYNTHESIS: Available data suggest that neuromodulatory compounds affect corticotropin (ACTH) or ACTH-releasing hormone (CRH) synthesis and release. They include serotonin antagonists, dopaminergic agonists, valproic acid, reserpine, somatostatin analogs and thiazolidinediones. These agents have been effective in a limited number of patients with ACTH-dependent Cushing's syndrome. Inhibitors of steroidogenesis reduce cortisol production by blocking one (metyrapone, trilostane) or several (aminoglutethimide, ketoconazole, fluconazole, etomidate) enzymes involved in steroid biosynthesis. Mitotane is a steroidogenesis inhibitor with adrenolitic properties. CHEMICAL blocks GENE activation without modifying cortisol synthesis. CONCLUSION: Agents that inhibit steroidogenesis are useful in all forms of Cushing's syndrome and are effective in about 70% of patients. Main indications for drug therapy include preparation for surgery, persistence or recurrence after surgery, while awaiting for the effect of radiation therapy, occult ectopic ACTH syndrome, severe hypercortisolism and malignancy related hypercortisolism. | INHIBITOR |
| Cannabinoid GENE in the paraventricular nucleus and central control of penile erection: immunocytochemistry, autoradiography and behavioral studies. [N-(piperidin-1-yl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide] (SR 141716A), a selective cannabinoid CB1 receptor antagonist, injected into the paraventricular nucleus of the hypothalamus (PVN) of male rats, induces penile erection. This effect is mediated by the release of glutamic acid, which in turn activates central oxytocinergic neurons mediating penile erection. Double immunofluorescence studies with selective antibodies against GENE, glutamic acid transporters (vesicular glutamate transporters 1 and 2 (VGlut1 and VGlut2), glutamic acid decarboxylase-67 (GAD67) and oxytocin itself, have shown that GENE in the PVN are located mainly in GABAergic terminals and fibers surrounding oxytocinergic cell bodies. As GABAergic synapses in the PVN impinge directly on oxytocinergic neurons or on excitatory glutamatergic synapses, which also impinge on oxytocinergic neurons, these results suggest that the blockade of GENE decreases GABA release in the PVN, increasing in turn glutamatergic neurotransmission to activate oxytocinergic neurons mediating penile erection. Autoradiography studies with CHEMICAL show that chronic treatment with SR 141716A for 15 days twice daily (1 mg/kg i.p.) significantly increases the density of GENE in the PVN. This increase occurs concomitantly with an almost twofold increase in the pro-erectile effect of SR 141716A injected into the PVN as compared with control rats. The present findings confirm that PVN GENE, localized mainly in GABAergic synapses that control in an inhibitory fashion excitatory synapses, exert an inhibitory control on penile erection, demonstrating for the first time that chronic blockade of GENE by SR 141716A increases the density of these receptors in the PVN. This increase is related to an enhanced pro-erectile effect of SR 141716A, which is still present 3 days after the end of the chronic treatment. | DIRECT-REGULATOR |
| Cannabinoid GENE in the paraventricular nucleus and central control of penile erection: immunocytochemistry, autoradiography and behavioral studies. [N-(piperidin-1-yl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide] (SR 141716A), a selective cannabinoid CB1 receptor antagonist, injected into the paraventricular nucleus of the hypothalamus (PVN) of male rats, induces penile erection. This effect is mediated by the release of glutamic acid, which in turn activates central oxytocinergic neurons mediating penile erection. Double immunofluorescence studies with selective antibodies against GENE, glutamic acid transporters (vesicular glutamate transporters 1 and 2 (VGlut1 and VGlut2), glutamic acid decarboxylase-67 (GAD67) and oxytocin itself, have shown that GENE in the PVN are located mainly in GABAergic terminals and fibers surrounding oxytocinergic cell bodies. As GABAergic synapses in the PVN impinge directly on oxytocinergic neurons or on excitatory glutamatergic synapses, which also impinge on oxytocinergic neurons, these results suggest that the blockade of GENE decreases GABA release in the PVN, increasing in turn glutamatergic neurotransmission to activate oxytocinergic neurons mediating penile erection. Autoradiography studies with [(3)H](-)-CP 55,940 show that chronic treatment with CHEMICAL for 15 days twice daily (1 mg/kg i.p.) significantly increases the density of GENE in the PVN. This increase occurs concomitantly with an almost twofold increase in the pro-erectile effect of CHEMICAL injected into the PVN as compared with control rats. The present findings confirm that PVN GENE, localized mainly in GABAergic synapses that control in an inhibitory fashion excitatory synapses, exert an inhibitory control on penile erection, demonstrating for the first time that chronic blockade of GENE by CHEMICAL increases the density of these receptors in the PVN. This increase is related to an enhanced pro-erectile effect of CHEMICAL, which is still present 3 days after the end of the chronic treatment. | ACTIVATOR |
| Cannabinoid CB1 receptors in the paraventricular nucleus and central control of penile erection: immunocytochemistry, autoradiography and behavioral studies. [N-(piperidin-1-yl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxyamide] (CHEMICAL), a selective GENE antagonist, injected into the paraventricular nucleus of the hypothalamus (PVN) of male rats, induces penile erection. This effect is mediated by the release of glutamic acid, which in turn activates central oxytocinergic neurons mediating penile erection. Double immunofluorescence studies with selective antibodies against CB1 receptors, glutamic acid transporters (vesicular glutamate transporters 1 and 2 (VGlut1 and VGlut2), glutamic acid decarboxylase-67 (GAD67) and oxytocin itself, have shown that CB1 receptors in the PVN are located mainly in GABAergic terminals and fibers surrounding oxytocinergic cell bodies. As GABAergic synapses in the PVN impinge directly on oxytocinergic neurons or on excitatory glutamatergic synapses, which also impinge on oxytocinergic neurons, these results suggest that the blockade of CB1 receptors decreases GABA release in the PVN, increasing in turn glutamatergic neurotransmission to activate oxytocinergic neurons mediating penile erection. Autoradiography studies with [(3)H](-)-CP 55,940 show that chronic treatment with CHEMICAL for 15 days twice daily (1 mg/kg i.p.) significantly increases the density of CB1 receptors in the PVN. This increase occurs concomitantly with an almost twofold increase in the pro-erectile effect of CHEMICAL injected into the PVN as compared with control rats. The present findings confirm that PVN CB1 receptors, localized mainly in GABAergic synapses that control in an inhibitory fashion excitatory synapses, exert an inhibitory control on penile erection, demonstrating for the first time that chronic blockade of CB1 receptors by CHEMICAL increases the density of these receptors in the PVN. This increase is related to an enhanced pro-erectile effect of CHEMICAL, which is still present 3 days after the end of the chronic treatment. | INHIBITOR |
| Cannabinoid CB1 receptors in the paraventricular nucleus and central control of penile erection: immunocytochemistry, autoradiography and behavioral studies. [CHEMICAL] (SR 141716A), a selective GENE antagonist, injected into the paraventricular nucleus of the hypothalamus (PVN) of male rats, induces penile erection. This effect is mediated by the release of glutamic acid, which in turn activates central oxytocinergic neurons mediating penile erection. Double immunofluorescence studies with selective antibodies against CB1 receptors, glutamic acid transporters (vesicular glutamate transporters 1 and 2 (VGlut1 and VGlut2), glutamic acid decarboxylase-67 (GAD67) and oxytocin itself, have shown that CB1 receptors in the PVN are located mainly in GABAergic terminals and fibers surrounding oxytocinergic cell bodies. As GABAergic synapses in the PVN impinge directly on oxytocinergic neurons or on excitatory glutamatergic synapses, which also impinge on oxytocinergic neurons, these results suggest that the blockade of CB1 receptors decreases GABA release in the PVN, increasing in turn glutamatergic neurotransmission to activate oxytocinergic neurons mediating penile erection. Autoradiography studies with [(3)H](-)-CP 55,940 show that chronic treatment with SR 141716A for 15 days twice daily (1 mg/kg i.p.) significantly increases the density of CB1 receptors in the PVN. This increase occurs concomitantly with an almost twofold increase in the pro-erectile effect of SR 141716A injected into the PVN as compared with control rats. The present findings confirm that PVN CB1 receptors, localized mainly in GABAergic synapses that control in an inhibitory fashion excitatory synapses, exert an inhibitory control on penile erection, demonstrating for the first time that chronic blockade of CB1 receptors by SR 141716A increases the density of these receptors in the PVN. This increase is related to an enhanced pro-erectile effect of SR 141716A, which is still present 3 days after the end of the chronic treatment. | INHIBITOR |
| Activation of human platelets by misfolded proteins. OBJECTIVE: Protein misfolding diseases result from the deposition of insoluble protein aggregates that often contain fibrils called amyloid. Amyloids are found in Alzheimer disease, atherosclerosis, diabetes mellitus, and systemic amyloidosis, which are diseases where platelet activation might be implicated. METHODS AND RESULTS: We induced amyloid properties in 6 unrelated proteins and found that all induced platelet aggregation in contrast to fresh controls. Amyloid-induced platelet aggregation was independent of CHEMICAL formation and ADP secretion but enhanced by feedback stimulation through these pathways. Treatments that raised cAMP (iloprost), sequestered Ca2+ (BAPTA-AM) or prevented amyloid-platelet interaction (sRAGE, tissue-type plasminogen activator [tPA]) induced almost complete inhibition. Modulation of the function of CD36 (CD36-/- mice), p38(MAPK) (SB203580), COX-1 (indomethacin), and glycoprotein Ib alpha (Nk-protease, 6D1 antibody) induced approximately 50% inhibition. Interference with fibrinogen binding (RGDS) revealed a major contribution of alphaIIb beta3-independent aggregation (agglutination). CONCLUSIONS: Protein misfolding resulting in the appearance of amyloid induces platelet aggregation. GENE activates platelets through 2 pathways: one is through CD36, p38(MAPK), CHEMICAL-mediated induction of aggregation; the other is through glycoprotein Ib alpha-mediated aggregation and agglutination. The platelet stimulating properties of amyloid might explain the enhanced platelet activation observed in many diseases accompanied by the appearance of misfolded proteins with amyloid. | REGULATOR |
| Activation of human platelets by misfolded proteins. OBJECTIVE: Protein misfolding diseases result from the deposition of insoluble protein aggregates that often contain fibrils called amyloid. Amyloids are found in Alzheimer disease, atherosclerosis, diabetes mellitus, and systemic amyloidosis, which are diseases where platelet activation might be implicated. METHODS AND RESULTS: We induced amyloid properties in 6 unrelated proteins and found that all induced platelet aggregation in contrast to fresh controls. Amyloid-induced platelet aggregation was independent of thromboxane A2 formation and ADP secretion but enhanced by feedback stimulation through these pathways. Treatments that raised cAMP (iloprost), sequestered Ca2+ (BAPTA-AM) or prevented amyloid-platelet interaction (sRAGE, tissue-type plasminogen activator [tPA]) induced almost complete inhibition. Modulation of the function of CD36 (CD36-/- mice), GENE(MAPK) (CHEMICAL), COX-1 (indomethacin), and glycoprotein Ib alpha (Nk-protease, 6D1 antibody) induced approximately 50% inhibition. Interference with fibrinogen binding (RGDS) revealed a major contribution of alphaIIb beta3-independent aggregation (agglutination). CONCLUSIONS: Protein misfolding resulting in the appearance of amyloid induces platelet aggregation. Amyloid activates platelets through 2 pathways: one is through CD36, p38(MAPK), thromboxane A2-mediated induction of aggregation; the other is through glycoprotein Ib alpha-mediated aggregation and agglutination. The platelet stimulating properties of amyloid might explain the enhanced platelet activation observed in many diseases accompanied by the appearance of misfolded proteins with amyloid. | REGULATOR |
| Activation of human platelets by misfolded proteins. OBJECTIVE: Protein misfolding diseases result from the deposition of insoluble protein aggregates that often contain fibrils called amyloid. Amyloids are found in Alzheimer disease, atherosclerosis, diabetes mellitus, and systemic amyloidosis, which are diseases where platelet activation might be implicated. METHODS AND RESULTS: We induced amyloid properties in 6 unrelated proteins and found that all induced platelet aggregation in contrast to fresh controls. Amyloid-induced platelet aggregation was independent of thromboxane A2 formation and ADP secretion but enhanced by feedback stimulation through these pathways. Treatments that raised cAMP (iloprost), sequestered Ca2+ (BAPTA-AM) or prevented amyloid-platelet interaction (sRAGE, tissue-type plasminogen activator [tPA]) induced almost complete inhibition. Modulation of the function of CD36 (CD36-/- mice), p38(GENE) (CHEMICAL), COX-1 (indomethacin), and glycoprotein Ib alpha (Nk-protease, 6D1 antibody) induced approximately 50% inhibition. Interference with fibrinogen binding (RGDS) revealed a major contribution of alphaIIb beta3-independent aggregation (agglutination). CONCLUSIONS: Protein misfolding resulting in the appearance of amyloid induces platelet aggregation. Amyloid activates platelets through 2 pathways: one is through CD36, p38(MAPK), thromboxane A2-mediated induction of aggregation; the other is through glycoprotein Ib alpha-mediated aggregation and agglutination. The platelet stimulating properties of amyloid might explain the enhanced platelet activation observed in many diseases accompanied by the appearance of misfolded proteins with amyloid. | REGULATOR |
| Activation of human platelets by misfolded proteins. OBJECTIVE: Protein misfolding diseases result from the deposition of insoluble protein aggregates that often contain fibrils called amyloid. Amyloids are found in Alzheimer disease, atherosclerosis, diabetes mellitus, and systemic amyloidosis, which are diseases where platelet activation might be implicated. METHODS AND RESULTS: We induced amyloid properties in 6 unrelated proteins and found that all induced platelet aggregation in contrast to fresh controls. Amyloid-induced platelet aggregation was independent of thromboxane A2 formation and ADP secretion but enhanced by feedback stimulation through these pathways. Treatments that raised cAMP (iloprost), sequestered Ca2+ (BAPTA-AM) or prevented amyloid-platelet interaction (sRAGE, tissue-type plasminogen activator [tPA]) induced almost complete inhibition. Modulation of the function of CD36 (CD36-/- mice), p38(MAPK) (SB203580), GENE (CHEMICAL), and glycoprotein Ib alpha (Nk-protease, 6D1 antibody) induced approximately 50% inhibition. Interference with fibrinogen binding (RGDS) revealed a major contribution of alphaIIb beta3-independent aggregation (agglutination). CONCLUSIONS: Protein misfolding resulting in the appearance of amyloid induces platelet aggregation. Amyloid activates platelets through 2 pathways: one is through CD36, p38(MAPK), thromboxane A2-mediated induction of aggregation; the other is through glycoprotein Ib alpha-mediated aggregation and agglutination. The platelet stimulating properties of amyloid might explain the enhanced platelet activation observed in many diseases accompanied by the appearance of misfolded proteins with amyloid. | REGULATOR |
| RDH12, a retinol dehydrogenase causing Leber's congenital amaurosis, is also involved in steroid metabolism. Three retinol dehydrogenases (RDHs) were tested for steroid converting abilities: human and murine RDH 12 and human RDH13. RDH12 is involved in retinal degeneration in Leber's congenital amaurosis (LCA). We show that murine Rdh12 and human RDH13 do not reveal activity towards the checked steroids, but that GENE reduces dihydrotestosterone to CHEMICAL, and is thus also involved in steroid metabolism. Furthermore, we analyzed both expression and subcellular localization of these enzymes. | PRODUCT-OF |
| Alteration of gastric functions and candidate genes associated with weight reduction in response to CHEMICAL. BACKGROUND & AIMS: It is unclear whether weight loss with the noradrenergic (norepinephrine) and serotonergic (5-hydroxytryptamine) reuptake inhibitor, CHEMICAL, is associated with altered stomach functions and whether genetics influence treatment response. METHODS: Forty-eight overweight and obese but otherwise healthy participants were randomized to placebo or CHEMICAL (15 mg/day for 12 weeks). At baseline and posttreatment we measured the following: gastric emptying for solids and liquids by scintigraphy, gastric volumes by single-photon emission computed tomography, maximum tolerated volume and 30-minute postnutrient challenge symptoms, and selected gastrointestinal hormones. All participants received structured behavior therapy for weight management. The influence of candidate gene polymorphisms involved in norepinephrine and 5-hydroxytryptamine or receptor function (phenylethanolamine N-methyltransferase, guanine nucleotide binding protein beta polypeptide 3, alpha2A adrenoreceptor, and solute carrier family 6 [neurotransmitter transporter, serotonin] member 4 [homo sapiens] [SLC6A4]) on weight loss and gastric functions was evaluated. RESULTS: The overall average weight loss posttreatment was 5.4 +/- 0.8 (SEM) kg with CHEMICAL and 0.9 +/- 0.9 kg with placebo (P < .001). The CHEMICAL group showed significant retardation in gastric emptying of solids (P = .03), reduced maximum tolerated volume (P = .03), and increased postprandial peptide YY compared with the placebo group. Obese females showed greater effects of CHEMICAL on weight loss and gastric emptying of solids and liquids. Gastric volumes and postchallenge symptoms were not significantly different in the 2 treatment groups. The LS/SS genotype of the promoter for GENE was associated with enhanced weight loss with CHEMICAL. CONCLUSIONS: Weight reduction with CHEMICAL is associated with altered gastric functions and increased peptide YY and is significantly associated with GENE genotype. The role of genetic variation in GENE on weight loss in response to CHEMICAL deserves further study. | GENE-CHEMICAL |
| Alteration of gastric functions and candidate genes associated with weight reduction in response to CHEMICAL. BACKGROUND & AIMS: It is unclear whether weight loss with the noradrenergic (norepinephrine) and serotonergic (5-hydroxytryptamine) reuptake inhibitor, CHEMICAL, is associated with altered stomach functions and whether genetics influence treatment response. METHODS: Forty-eight overweight and obese but otherwise healthy participants were randomized to placebo or CHEMICAL (15 mg/day for 12 weeks). At baseline and posttreatment we measured the following: gastric emptying for solids and liquids by scintigraphy, gastric volumes by single-photon emission computed tomography, maximum tolerated volume and 30-minute postnutrient challenge symptoms, and selected gastrointestinal hormones. All participants received structured behavior therapy for weight management. The influence of candidate gene polymorphisms involved in norepinephrine and 5-hydroxytryptamine or receptor function (phenylethanolamine N-methyltransferase, guanine nucleotide binding protein beta polypeptide 3, alpha2A adrenoreceptor, and solute carrier family 6 [neurotransmitter transporter, serotonin] member 4 [homo sapiens] [SLC6A4]) on weight loss and gastric functions was evaluated. RESULTS: The overall average weight loss posttreatment was 5.4 +/- 0.8 (SEM) kg with CHEMICAL and 0.9 +/- 0.9 kg with placebo (P < .001). The CHEMICAL group showed significant retardation in gastric emptying of solids (P = .03), reduced maximum tolerated volume (P = .03), and increased postprandial GENE compared with the placebo group. Obese females showed greater effects of CHEMICAL on weight loss and gastric emptying of solids and liquids. Gastric volumes and postchallenge symptoms were not significantly different in the 2 treatment groups. The LS/SS genotype of the promoter for SLC6A4 was associated with enhanced weight loss with CHEMICAL. CONCLUSIONS: Weight reduction with CHEMICAL is associated with altered gastric functions and increased GENE and is significantly associated with SLC6A4 genotype. The role of genetic variation in SLC6A4 on weight loss in response to CHEMICAL deserves further study. | INDIRECT-UPREGULATOR |
| Multiple GENE forms are produced by distinct starting points and alternative splicing of the CHEMICAL-terminal exons. 5'-RACE was performed on GENE mRNA and two new translation initiation ATG's were found. The first one is upstream of the previously designed initiation translation site localized in the rat calpastatin L-domain. The deduced protein sequence of this region is highly homologous to the XL-domain of calpastatin type I in other species. The other ATG has not previously been reported and is localized in exon 8, thus originating a calpastatin isoform constituted only by four repetitive inhibitory units without the XL-L-domains. Transcripts from the GENE gene are also subjected to multiple splicing events involving exons 4, 6, 8 in different combinations. A series of recombinant calpastatin forms was produced that differed in the exons present in the L-domain, and all the variants showed comparable inhibitory efficiency against calpain. It was concluded that the presence of the XL-domain in these isoforms is not relevant for the formation of the calpain/calpastatin complex in the absence of calcium, that is the interaction of calpastatin with inactive calpain. Using exon-specific antisera, specific calpastatin protein isoforms containing the XL-domain have been detected in rat brain homogenates. | PART-OF |
| An investigation of the absolute configuration of the potent GENE antagonist CHEMICAL using vibrational circular dichroism. CHEMICAL [(+)-1] is one of the most potent members of a class of chiral drug substances used to regulate the synthesis and release of histamine by the GENE, and as such, is an important biomarker for pharmaceutical companies conducting research in this field. In addition to overall structural features, the bioactivity of this molecule has also been found to be highly dependent on absolute stereochemistry, making the reliable assignment of this property a necessity. X-ray diffraction studies have provided conflicting data, leaving its three-dimensional structure uncertain. In view of this, its absolute configuration was investigated by vibrational circular dichroism. Results from this study provided independent assignment of this important molecule as the (1S,2S)-enantiomer. | INHIBITOR |
| Allosteric interaction of the neuromuscular blockers vecuronium and pancuronium with recombinant GENE. Neuromuscular blocking drugs produce muscle weakness by interaction with nicotinic-acetylcholine receptors. Cardiovascular side effects have been reported. In this study the neuromuscular blocking drug vecuronium and the controls gallamine and pancuronium slowed the rate of CHEMICAL induced [(3)H]N-methylscopolamine dissociation from Chinese hamster ovary cells expressing recombinant GENE K(off) values min(-1); vecuronium (125 nM), CHEMICAL 0.45+/-0.07+blocker 0.04+/-0.02; gallamine (21 nM), CHEMICAL 0.42+/-0.05+blocker 0.15+/-0.04; pancuronium(21 nM), CHEMICAL 0.36+/-0.03+blocker 0.03+/-0.01). These data indicate that vecuronium, gallamine and pancuronium interact with an allosteric site on the muscarinic M2 receptor (located on the heart) and this may explain some of their cardiac side effects. | DIRECT-REGULATOR |
| Allosteric interaction of the neuromuscular blockers vecuronium and pancuronium with recombinant GENE. Neuromuscular blocking drugs produce muscle weakness by interaction with nicotinic-acetylcholine receptors. Cardiovascular side effects have been reported. In this study the neuromuscular blocking drug vecuronium and the controls gallamine and pancuronium slowed the rate of atropine induced CHEMICAL dissociation from Chinese hamster ovary cells expressing recombinant GENE K(off) values min(-1); vecuronium (125 nM), atropine 0.45+/-0.07+blocker 0.04+/-0.02; gallamine (21 nM), atropine 0.42+/-0.05+blocker 0.15+/-0.04; pancuronium(21 nM), atropine 0.36+/-0.03+blocker 0.03+/-0.01). These data indicate that vecuronium, gallamine and pancuronium interact with an allosteric site on the muscarinic M2 receptor (located on the heart) and this may explain some of their cardiac side effects. | DIRECT-REGULATOR |
| Allosteric interaction of the neuromuscular blockers CHEMICAL and pancuronium with recombinant GENE. Neuromuscular blocking drugs produce muscle weakness by interaction with nicotinic-acetylcholine receptors. Cardiovascular side effects have been reported. In this study the neuromuscular blocking drug CHEMICAL and the controls gallamine and pancuronium slowed the rate of atropine induced [(3)H]N-methylscopolamine dissociation from Chinese hamster ovary cells expressing recombinant GENE K(off) values min(-1); CHEMICAL (125 nM), atropine 0.45+/-0.07+blocker 0.04+/-0.02; gallamine (21 nM), atropine 0.42+/-0.05+blocker 0.15+/-0.04; pancuronium(21 nM), atropine 0.36+/-0.03+blocker 0.03+/-0.01). These data indicate that CHEMICAL, gallamine and pancuronium interact with an allosteric site on the muscarinic M2 receptor (located on the heart) and this may explain some of their cardiac side effects. | INHIBITOR |
| Allosteric interaction of the neuromuscular blockers vecuronium and pancuronium with recombinant GENE. Neuromuscular blocking drugs produce muscle weakness by interaction with nicotinic-acetylcholine receptors. Cardiovascular side effects have been reported. In this study the neuromuscular blocking drug vecuronium and the controls CHEMICAL and pancuronium slowed the rate of atropine induced [(3)H]N-methylscopolamine dissociation from Chinese hamster ovary cells expressing recombinant GENE K(off) values min(-1); vecuronium (125 nM), atropine 0.45+/-0.07+blocker 0.04+/-0.02; CHEMICAL (21 nM), atropine 0.42+/-0.05+blocker 0.15+/-0.04; pancuronium(21 nM), atropine 0.36+/-0.03+blocker 0.03+/-0.01). These data indicate that vecuronium, CHEMICAL and pancuronium interact with an allosteric site on the muscarinic M2 receptor (located on the heart) and this may explain some of their cardiac side effects. | DIRECT-REGULATOR |
| Allosteric interaction of the neuromuscular blockers vecuronium and CHEMICAL with recombinant GENE. Neuromuscular blocking drugs produce muscle weakness by interaction with nicotinic-acetylcholine receptors. Cardiovascular side effects have been reported. In this study the neuromuscular blocking drug vecuronium and the controls gallamine and CHEMICAL slowed the rate of atropine induced [(3)H]N-methylscopolamine dissociation from Chinese hamster ovary cells expressing recombinant GENE K(off) values min(-1); vecuronium (125 nM), atropine 0.45+/-0.07+blocker 0.04+/-0.02; gallamine (21 nM), atropine 0.42+/-0.05+blocker 0.15+/-0.04; pancuronium(21 nM), atropine 0.36+/-0.03+blocker 0.03+/-0.01). These data indicate that vecuronium, gallamine and CHEMICAL interact with an allosteric site on the muscarinic M2 receptor (located on the heart) and this may explain some of their cardiac side effects. | DIRECT-REGULATOR |
| Allosteric interaction of the neuromuscular blockers CHEMICAL and pancuronium with recombinant human muscarinic M2 receptors. Neuromuscular blocking drugs produce muscle weakness by interaction with nicotinic-acetylcholine receptors. Cardiovascular side effects have been reported. In this study the neuromuscular blocking drug CHEMICAL and the controls gallamine and pancuronium slowed the rate of atropine induced [(3)H]N-methylscopolamine dissociation from Chinese hamster ovary cells expressing recombinant human muscarinic M2 receptors K(off) values min(-1); CHEMICAL (125 nM), atropine 0.45+/-0.07+blocker 0.04+/-0.02; gallamine (21 nM), atropine 0.42+/-0.05+blocker 0.15+/-0.04; pancuronium(21 nM), atropine 0.36+/-0.03+blocker 0.03+/-0.01). These data indicate that CHEMICAL, gallamine and pancuronium interact with an allosteric site on the GENE (located on the heart) and this may explain some of their cardiac side effects. | DIRECT-REGULATOR |
| Allosteric interaction of the neuromuscular blockers vecuronium and pancuronium with recombinant human muscarinic M2 receptors. Neuromuscular blocking drugs produce muscle weakness by interaction with nicotinic-acetylcholine receptors. Cardiovascular side effects have been reported. In this study the neuromuscular blocking drug vecuronium and the controls CHEMICAL and pancuronium slowed the rate of atropine induced [(3)H]N-methylscopolamine dissociation from Chinese hamster ovary cells expressing recombinant human muscarinic M2 receptors K(off) values min(-1); vecuronium (125 nM), atropine 0.45+/-0.07+blocker 0.04+/-0.02; CHEMICAL (21 nM), atropine 0.42+/-0.05+blocker 0.15+/-0.04; pancuronium(21 nM), atropine 0.36+/-0.03+blocker 0.03+/-0.01). These data indicate that vecuronium, CHEMICAL and pancuronium interact with an allosteric site on the GENE (located on the heart) and this may explain some of their cardiac side effects. | DIRECT-REGULATOR |
| Allosteric interaction of the neuromuscular blockers vecuronium and CHEMICAL with recombinant human muscarinic M2 receptors. Neuromuscular blocking drugs produce muscle weakness by interaction with nicotinic-acetylcholine receptors. Cardiovascular side effects have been reported. In this study the neuromuscular blocking drug vecuronium and the controls gallamine and CHEMICAL slowed the rate of atropine induced [(3)H]N-methylscopolamine dissociation from Chinese hamster ovary cells expressing recombinant human muscarinic M2 receptors K(off) values min(-1); vecuronium (125 nM), atropine 0.45+/-0.07+blocker 0.04+/-0.02; gallamine (21 nM), atropine 0.42+/-0.05+blocker 0.15+/-0.04; pancuronium(21 nM), atropine 0.36+/-0.03+blocker 0.03+/-0.01). These data indicate that vecuronium, gallamine and CHEMICAL interact with an allosteric site on the GENE (located on the heart) and this may explain some of their cardiac side effects. | DIRECT-REGULATOR |
| Hydrogen peroxide-mediated oxidative stress disrupts CHEMICAL binding on calmodulin: more evidence for oxidative stress in vitiligo. Patients with acute vitiligo have low epidermal catalase expression/activities and accumulate 10(-3) M H(2)O(2). One consequence of this severe oxidative stress is an altered CHEMICAL homeostasis in epidermal keratinocytes and melanocytes. Here, we show decreased epidermal GENE expression in acute vitiligo. Since 10(-3)M H(2)O(2) oxidises methionine and tryptophan residues in proteins, we examined CHEMICAL binding to GENE in the presence and absence of H(2)O(2) utilising (45)calcium. The results showed that all four CHEMICAL atoms exchanged per molecule of GENE. Since oxidised GENE looses its ability to activate CHEMICAL ATPase, enzyme activities were followed in full skin biopsies from lesional skin of patients with acute vitiligo (n=6) and healthy controls (n=6). The results yielded a 4-fold decrease of ATPase activities in the patients. Computer simulation of native and oxidised GENE confirmed the loss of all four CHEMICAL ions from their specific EF-hand domains. Taken together H(2)O(2)-mediated oxidation affects CHEMICAL binding in GENE leading to perturbed CHEMICAL homeostasis and perturbed l-phenylalanine-uptake in the epidermis of acute vitiligo. | DIRECT-REGULATOR |
| Hydrogen peroxide-mediated oxidative stress disrupts calcium binding on calmodulin: more evidence for oxidative stress in vitiligo. Patients with acute vitiligo have low epidermal catalase expression/activities and accumulate 10(-3) M CHEMICAL. One consequence of this severe oxidative stress is an altered calcium homeostasis in epidermal keratinocytes and melanocytes. Here, we show decreased epidermal GENE expression in acute vitiligo. Since 10(-3)M CHEMICAL oxidises methionine and tryptophan residues in proteins, we examined calcium binding to GENE in the presence and absence of CHEMICAL utilising (45)calcium. The results showed that all four calcium atoms exchanged per molecule of GENE. Since oxidised GENE looses its ability to activate calcium ATPase, enzyme activities were followed in full skin biopsies from lesional skin of patients with acute vitiligo (n=6) and healthy controls (n=6). The results yielded a 4-fold decrease of ATPase activities in the patients. Computer simulation of native and oxidised GENE confirmed the loss of all four calcium ions from their specific EF-hand domains. Taken together H(2)O(2)-mediated oxidation affects calcium binding in GENE leading to perturbed calcium homeostasis and perturbed l-phenylalanine-uptake in the epidermis of acute vitiligo. | REGULATOR |
| CHEMICAL-mediated oxidative stress disrupts calcium binding on GENE: more evidence for oxidative stress in vitiligo. Patients with acute vitiligo have low epidermal catalase expression/activities and accumulate 10(-3) M H(2)O(2). One consequence of this severe oxidative stress is an altered calcium homeostasis in epidermal keratinocytes and melanocytes. Here, we show decreased epidermal GENE expression in acute vitiligo. Since 10(-3)M H(2)O(2) oxidises methionine and tryptophan residues in proteins, we examined calcium binding to GENE in the presence and absence of H(2)O(2) utilising (45)calcium. The results showed that all four calcium atoms exchanged per molecule of GENE. Since oxidised GENE looses its ability to activate calcium ATPase, enzyme activities were followed in full skin biopsies from lesional skin of patients with acute vitiligo (n=6) and healthy controls (n=6). The results yielded a 4-fold decrease of ATPase activities in the patients. Computer simulation of native and oxidised GENE confirmed the loss of all four calcium ions from their specific EF-hand domains. Taken together H(2)O(2)-mediated oxidation affects calcium binding in GENE leading to perturbed calcium homeostasis and perturbed l-phenylalanine-uptake in the epidermis of acute vitiligo. | REGULATOR |
| Hydrogen peroxide-mediated oxidative stress disrupts calcium binding on calmodulin: more evidence for oxidative stress in vitiligo. Patients with acute vitiligo have low epidermal GENE expression/activities and accumulate 10(-3) M CHEMICAL. One consequence of this severe oxidative stress is an altered calcium homeostasis in epidermal keratinocytes and melanocytes. Here, we show decreased epidermal calmodulin expression in acute vitiligo. Since 10(-3)M CHEMICAL oxidises methionine and tryptophan residues in proteins, we examined calcium binding to calmodulin in the presence and absence of CHEMICAL utilising (45)calcium. The results showed that all four calcium atoms exchanged per molecule of calmodulin. Since oxidised calmodulin looses its ability to activate calcium ATPase, enzyme activities were followed in full skin biopsies from lesional skin of patients with acute vitiligo (n=6) and healthy controls (n=6). The results yielded a 4-fold decrease of ATPase activities in the patients. Computer simulation of native and oxidised calmodulin confirmed the loss of all four calcium ions from their specific EF-hand domains. Taken together H(2)O(2)-mediated oxidation affects calcium binding in calmodulin leading to perturbed calcium homeostasis and perturbed l-phenylalanine-uptake in the epidermis of acute vitiligo. | GENE-CHEMICAL |
| Characterization of the nitrosyl adduct of substrate-bound mouse cysteine dioxygenase by electron paramagnetic resonance: electronic structure of the active site and mechanistic implications. Mammalian cysteine dioxygenase (CDO) is a non-heme iron metalloenzyme that catalyzes the first committed step in oxidative cysteine catabolism. The active site coordination of GENE comprises a mononuclear iron ligated by the Nepsilon atoms of three protein-derived histidines, thus representing a new variant on the 2-histidine-1-carboxylate (2H1C) facial triad motif. Nitric oxide was used as a spectroscopic probe in investigating the order of substrate-O2 binding by EPR spectroscopy. In these experiments, GENE exhibits an ordered binding of l-cysteine prior to CHEMICAL (and presumably O2) similar to that observed for the 2H1C class of non-heme iron enzymes. Moreover, the GENE active site is essentially unreactive toward CHEMICAL in the absence of substrate, suggesting an obligate ordered binding of l-cysteine prior to CHEMICAL. Typically, addition of CHEMICAL to a mononuclear non-heme iron center results in the formation of an {FeNO}7 (S = 3/2) species characterized by an axial EPR spectrum with gx, gy, and gz values of approximately 4, approximately 4, and approximately 2, respectively. However, upon addition of CHEMICAL to GENE in the presence of substrate l-cysteine, a low-spin {FeNO}7 (S = 1/2) signal that accounts for approximately 85% of the iron within the enzyme develops. Similar {FeNO}7 (S = 1/2) EPR signals have been observed for a variety of octahedral mononuclear iron-nitrosyl synthetic complexes; however, this type of iron-nitrosyl species is not commonly observed for non-heme iron enzymes. Substitution of l-cysteine with isosteric substrate analogues cysteamine, 3-mercaptopropionic acid, and propane thiol did not produce any analogous {FeNO}7 signals (S = 1/2 or 3/2), thus reflecting the high substrate specificity of the enzyme observed by a number of researchers. The unusual {FeNO}7 (S = 1/2) electronic configuration adopted by the substrate-bound iron-nitrosyl GENE (termed {ES-NO}7) is a result of the bidentate thiol/amine coordination of l-cysteine in the NO-bound GENE active site. DFT computations were performed to further characterize this species. The DFT-predicted geometric parameters for {ES-NO}7 are in good agreement with the crystallographically determined substrate-bound active site configuration of GENE and are consistent with known iron-nitrosyl model complexes. Moreover, the computed EPR parameters (g and A values) are in excellent agreement with experimental results for this GENE species and those obtained from comparable synthetic {FeNO}7 (S = 1/2) iron-nitrosyl complexes. | DIRECT-REGULATOR |
| Characterization of the nitrosyl adduct of substrate-bound mouse cysteine dioxygenase by electron paramagnetic resonance: electronic structure of the active site and mechanistic implications. Mammalian cysteine dioxygenase (CDO) is a non-heme iron metalloenzyme that catalyzes the first committed step in oxidative cysteine catabolism. The active site coordination of GENE comprises a mononuclear iron ligated by the Nepsilon atoms of three protein-derived CHEMICAL, thus representing a new variant on the 2-histidine-1-carboxylate (2H1C) facial triad motif. Nitric oxide was used as a spectroscopic probe in investigating the order of substrate-O2 binding by EPR spectroscopy. In these experiments, GENE exhibits an ordered binding of l-cysteine prior to NO (and presumably O2) similar to that observed for the 2H1C class of non-heme iron enzymes. Moreover, the GENE active site is essentially unreactive toward NO in the absence of substrate, suggesting an obligate ordered binding of l-cysteine prior to NO. Typically, addition of NO to a mononuclear non-heme iron center results in the formation of an {FeNO}7 (S = 3/2) species characterized by an axial EPR spectrum with gx, gy, and gz values of approximately 4, approximately 4, and approximately 2, respectively. However, upon addition of NO to GENE in the presence of substrate l-cysteine, a low-spin {FeNO}7 (S = 1/2) signal that accounts for approximately 85% of the iron within the enzyme develops. Similar {FeNO}7 (S = 1/2) EPR signals have been observed for a variety of octahedral mononuclear iron-nitrosyl synthetic complexes; however, this type of iron-nitrosyl species is not commonly observed for non-heme iron enzymes. Substitution of l-cysteine with isosteric substrate analogues cysteamine, 3-mercaptopropionic acid, and propane thiol did not produce any analogous {FeNO}7 signals (S = 1/2 or 3/2), thus reflecting the high substrate specificity of the enzyme observed by a number of researchers. The unusual {FeNO}7 (S = 1/2) electronic configuration adopted by the substrate-bound iron-nitrosyl GENE (termed {ES-NO}7) is a result of the bidentate thiol/amine coordination of l-cysteine in the NO-bound GENE active site. DFT computations were performed to further characterize this species. The DFT-predicted geometric parameters for {ES-NO}7 are in good agreement with the crystallographically determined substrate-bound active site configuration of GENE and are consistent with known iron-nitrosyl model complexes. Moreover, the computed EPR parameters (g and A values) are in excellent agreement with experimental results for this GENE species and those obtained from comparable synthetic {FeNO}7 (S = 1/2) iron-nitrosyl complexes. | PART-OF |
| Characterization of the nitrosyl adduct of substrate-bound mouse cysteine dioxygenase by electron paramagnetic resonance: electronic structure of the active site and mechanistic implications. Mammalian cysteine dioxygenase (CDO) is a non-heme CHEMICAL metalloenzyme that catalyzes the first committed step in oxidative cysteine catabolism. The active site coordination of GENE comprises a mononuclear CHEMICAL ligated by the Nepsilon atoms of three protein-derived histidines, thus representing a new variant on the 2-histidine-1-carboxylate (2H1C) facial triad motif. Nitric oxide was used as a spectroscopic probe in investigating the order of substrate-O2 binding by EPR spectroscopy. In these experiments, GENE exhibits an ordered binding of l-cysteine prior to NO (and presumably O2) similar to that observed for the 2H1C class of non-heme CHEMICAL enzymes. Moreover, the GENE active site is essentially unreactive toward NO in the absence of substrate, suggesting an obligate ordered binding of l-cysteine prior to NO. Typically, addition of NO to a mononuclear non-heme CHEMICAL center results in the formation of an {FeNO}7 (S = 3/2) species characterized by an axial EPR spectrum with gx, gy, and gz values of approximately 4, approximately 4, and approximately 2, respectively. However, upon addition of NO to GENE in the presence of substrate l-cysteine, a low-spin {FeNO}7 (S = 1/2) signal that accounts for approximately 85% of the CHEMICAL within the enzyme develops. Similar {FeNO}7 (S = 1/2) EPR signals have been observed for a variety of octahedral mononuclear iron-nitrosyl synthetic complexes; however, this type of iron-nitrosyl species is not commonly observed for non-heme CHEMICAL enzymes. Substitution of l-cysteine with isosteric substrate analogues cysteamine, 3-mercaptopropionic acid, and propane thiol did not produce any analogous {FeNO}7 signals (S = 1/2 or 3/2), thus reflecting the high substrate specificity of the enzyme observed by a number of researchers. The unusual {FeNO}7 (S = 1/2) electronic configuration adopted by the substrate-bound iron-nitrosyl GENE (termed {ES-NO}7) is a result of the bidentate thiol/amine coordination of l-cysteine in the NO-bound GENE active site. DFT computations were performed to further characterize this species. The DFT-predicted geometric parameters for {ES-NO}7 are in good agreement with the crystallographically determined substrate-bound active site configuration of GENE and are consistent with known iron-nitrosyl model complexes. Moreover, the computed EPR parameters (g and A values) are in excellent agreement with experimental results for this GENE species and those obtained from comparable synthetic {FeNO}7 (S = 1/2) iron-nitrosyl complexes. | REGULATOR |
| Characterization of the nitrosyl adduct of substrate-bound mouse cysteine dioxygenase by electron paramagnetic resonance: electronic structure of the active site and mechanistic implications. Mammalian cysteine dioxygenase (CDO) is a non-heme iron metalloenzyme that catalyzes the first committed step in oxidative cysteine catabolism. The active site coordination of GENE comprises a mononuclear iron ligated by the Nepsilon atoms of three protein-derived histidines, thus representing a new variant on the 2-histidine-1-carboxylate (2H1C) facial triad motif. Nitric oxide was used as a spectroscopic probe in investigating the order of substrate-O2 binding by EPR spectroscopy. In these experiments, GENE exhibits an ordered binding of CHEMICAL prior to NO (and presumably O2) similar to that observed for the 2H1C class of non-heme iron enzymes. Moreover, the GENE active site is essentially unreactive toward NO in the absence of substrate, suggesting an obligate ordered binding of CHEMICAL prior to NO. Typically, addition of NO to a mononuclear non-heme iron center results in the formation of an {FeNO}7 (S = 3/2) species characterized by an axial EPR spectrum with gx, gy, and gz values of approximately 4, approximately 4, and approximately 2, respectively. However, upon addition of NO to GENE in the presence of substrate CHEMICAL, a low-spin {FeNO}7 (S = 1/2) signal that accounts for approximately 85% of the iron within the enzyme develops. Similar {FeNO}7 (S = 1/2) EPR signals have been observed for a variety of octahedral mononuclear iron-nitrosyl synthetic complexes; however, this type of iron-nitrosyl species is not commonly observed for non-heme iron enzymes. Substitution of CHEMICAL with isosteric substrate analogues cysteamine, 3-mercaptopropionic acid, and propane thiol did not produce any analogous {FeNO}7 signals (S = 1/2 or 3/2), thus reflecting the high substrate specificity of the enzyme observed by a number of researchers. The unusual {FeNO}7 (S = 1/2) electronic configuration adopted by the substrate-bound iron-nitrosyl GENE (termed {ES-NO}7) is a result of the bidentate thiol/amine coordination of CHEMICAL in the NO-bound GENE active site. DFT computations were performed to further characterize this species. The DFT-predicted geometric parameters for {ES-NO}7 are in good agreement with the crystallographically determined substrate-bound active site configuration of GENE and are consistent with known iron-nitrosyl model complexes. Moreover, the computed EPR parameters (g and A values) are in excellent agreement with experimental results for this GENE species and those obtained from comparable synthetic {FeNO}7 (S = 1/2) iron-nitrosyl complexes. | DIRECT-REGULATOR |
| Characterization of the nitrosyl adduct of substrate-bound mouse cysteine dioxygenase by electron paramagnetic resonance: electronic structure of the active site and mechanistic implications. Mammalian cysteine dioxygenase (CDO) is a non-heme iron metalloenzyme that catalyzes the first committed step in oxidative cysteine catabolism. The active site coordination of CDO comprises a mononuclear iron ligated by the Nepsilon atoms of three protein-derived histidines, thus representing a new variant on the 2-histidine-1-carboxylate (2H1C) facial triad motif. Nitric oxide was used as a spectroscopic probe in investigating the order of substrate-O2 binding by EPR spectroscopy. In these experiments, CDO exhibits an ordered binding of CHEMICAL prior to NO (and presumably O2) similar to that observed for the GENE. Moreover, the CDO active site is essentially unreactive toward NO in the absence of substrate, suggesting an obligate ordered binding of CHEMICAL prior to NO. Typically, addition of NO to a mononuclear non-heme iron center results in the formation of an {FeNO}7 (S = 3/2) species characterized by an axial EPR spectrum with gx, gy, and gz values of approximately 4, approximately 4, and approximately 2, respectively. However, upon addition of NO to CDO in the presence of substrate CHEMICAL, a low-spin {FeNO}7 (S = 1/2) signal that accounts for approximately 85% of the iron within the enzyme develops. Similar {FeNO}7 (S = 1/2) EPR signals have been observed for a variety of octahedral mononuclear iron-nitrosyl synthetic complexes; however, this type of iron-nitrosyl species is not commonly observed for non-heme iron enzymes. Substitution of CHEMICAL with isosteric substrate analogues cysteamine, 3-mercaptopropionic acid, and propane thiol did not produce any analogous {FeNO}7 signals (S = 1/2 or 3/2), thus reflecting the high substrate specificity of the enzyme observed by a number of researchers. The unusual {FeNO}7 (S = 1/2) electronic configuration adopted by the substrate-bound iron-nitrosyl CDO (termed {ES-NO}7) is a result of the bidentate thiol/amine coordination of CHEMICAL in the NO-bound CDO active site. DFT computations were performed to further characterize this species. The DFT-predicted geometric parameters for {ES-NO}7 are in good agreement with the crystallographically determined substrate-bound active site configuration of CDO and are consistent with known iron-nitrosyl model complexes. Moreover, the computed EPR parameters (g and A values) are in excellent agreement with experimental results for this CDO species and those obtained from comparable synthetic {FeNO}7 (S = 1/2) iron-nitrosyl complexes. | REGULATOR |
| Characterization of the nitrosyl adduct of substrate-bound mouse cysteine dioxygenase by electron paramagnetic resonance: electronic structure of the active site and mechanistic implications. Mammalian cysteine dioxygenase (CDO) is a non-heme iron metalloenzyme that catalyzes the first committed step in oxidative cysteine catabolism. The active site coordination of CDO comprises a mononuclear iron ligated by the Nepsilon atoms of three protein-derived histidines, thus representing a new variant on the 2-histidine-1-carboxylate (2H1C) facial triad motif. Nitric oxide was used as a spectroscopic probe in investigating the order of substrate-O2 binding by EPR spectroscopy. In these experiments, CDO exhibits an ordered binding of l-cysteine prior to CHEMICAL (and presumably O2) similar to that observed for the GENE. Moreover, the CDO active site is essentially unreactive toward CHEMICAL in the absence of substrate, suggesting an obligate ordered binding of l-cysteine prior to CHEMICAL. Typically, addition of CHEMICAL to a mononuclear non-heme iron center results in the formation of an {FeNO}7 (S = 3/2) species characterized by an axial EPR spectrum with gx, gy, and gz values of approximately 4, approximately 4, and approximately 2, respectively. However, upon addition of CHEMICAL to CDO in the presence of substrate l-cysteine, a low-spin {FeNO}7 (S = 1/2) signal that accounts for approximately 85% of the iron within the enzyme develops. Similar {FeNO}7 (S = 1/2) EPR signals have been observed for a variety of octahedral mononuclear iron-nitrosyl synthetic complexes; however, this type of iron-nitrosyl species is not commonly observed for non-heme iron enzymes. Substitution of l-cysteine with isosteric substrate analogues cysteamine, 3-mercaptopropionic acid, and propane thiol did not produce any analogous {FeNO}7 signals (S = 1/2 or 3/2), thus reflecting the high substrate specificity of the enzyme observed by a number of researchers. The unusual {FeNO}7 (S = 1/2) electronic configuration adopted by the substrate-bound iron-nitrosyl CDO (termed {ES-NO}7) is a result of the bidentate thiol/amine coordination of l-cysteine in the NO-bound CDO active site. DFT computations were performed to further characterize this species. The DFT-predicted geometric parameters for {ES-NO}7 are in good agreement with the crystallographically determined substrate-bound active site configuration of CDO and are consistent with known iron-nitrosyl model complexes. Moreover, the computed EPR parameters (g and A values) are in excellent agreement with experimental results for this CDO species and those obtained from comparable synthetic {FeNO}7 (S = 1/2) iron-nitrosyl complexes. | REGULATOR |
| Characterization of the nitrosyl adduct of substrate-bound mouse cysteine dioxygenase by electron paramagnetic resonance: electronic structure of the active site and mechanistic implications. Mammalian cysteine dioxygenase (CDO) is a non-heme iron metalloenzyme that catalyzes the first committed step in oxidative cysteine catabolism. The active site coordination of GENE comprises a mononuclear iron ligated by the Nepsilon atoms of three protein-derived histidines, thus representing a new variant on the 2-histidine-1-carboxylate (2H1C) facial triad motif. Nitric oxide was used as a spectroscopic probe in investigating the order of substrate-O2 binding by EPR spectroscopy. In these experiments, GENE exhibits an ordered binding of l-cysteine prior to NO (and presumably CHEMICAL) similar to that observed for the 2H1C class of non-heme iron enzymes. Moreover, the GENE active site is essentially unreactive toward NO in the absence of substrate, suggesting an obligate ordered binding of l-cysteine prior to NO. Typically, addition of NO to a mononuclear non-heme iron center results in the formation of an {FeNO}7 (S = 3/2) species characterized by an axial EPR spectrum with gx, gy, and gz values of approximately 4, approximately 4, and approximately 2, respectively. However, upon addition of NO to GENE in the presence of substrate l-cysteine, a low-spin {FeNO}7 (S = 1/2) signal that accounts for approximately 85% of the iron within the enzyme develops. Similar {FeNO}7 (S = 1/2) EPR signals have been observed for a variety of octahedral mononuclear iron-nitrosyl synthetic complexes; however, this type of iron-nitrosyl species is not commonly observed for non-heme iron enzymes. Substitution of l-cysteine with isosteric substrate analogues cysteamine, 3-mercaptopropionic acid, and propane thiol did not produce any analogous {FeNO}7 signals (S = 1/2 or 3/2), thus reflecting the high substrate specificity of the enzyme observed by a number of researchers. The unusual {FeNO}7 (S = 1/2) electronic configuration adopted by the substrate-bound iron-nitrosyl GENE (termed {ES-NO}7) is a result of the bidentate thiol/amine coordination of l-cysteine in the NO-bound GENE active site. DFT computations were performed to further characterize this species. The DFT-predicted geometric parameters for {ES-NO}7 are in good agreement with the crystallographically determined substrate-bound active site configuration of GENE and are consistent with known iron-nitrosyl model complexes. Moreover, the computed EPR parameters (g and A values) are in excellent agreement with experimental results for this GENE species and those obtained from comparable synthetic {FeNO}7 (S = 1/2) iron-nitrosyl complexes. | DIRECT-REGULATOR |
| Characterization of the nitrosyl adduct of substrate-bound mouse cysteine dioxygenase by electron paramagnetic resonance: electronic structure of the active site and mechanistic implications. Mammalian cysteine dioxygenase (CDO) is a non-heme iron metalloenzyme that catalyzes the first committed step in oxidative cysteine catabolism. The active site coordination of CDO comprises a mononuclear iron ligated by the Nepsilon atoms of three protein-derived histidines, thus representing a new variant on the 2-histidine-1-carboxylate (2H1C) facial triad motif. Nitric oxide was used as a spectroscopic probe in investigating the order of substrate-O2 binding by EPR spectroscopy. In these experiments, CDO exhibits an ordered binding of l-cysteine prior to NO (and presumably CHEMICAL) similar to that observed for the GENE. Moreover, the CDO active site is essentially unreactive toward NO in the absence of substrate, suggesting an obligate ordered binding of l-cysteine prior to NO. Typically, addition of NO to a mononuclear non-heme iron center results in the formation of an {FeNO}7 (S = 3/2) species characterized by an axial EPR spectrum with gx, gy, and gz values of approximately 4, approximately 4, and approximately 2, respectively. However, upon addition of NO to CDO in the presence of substrate l-cysteine, a low-spin {FeNO}7 (S = 1/2) signal that accounts for approximately 85% of the iron within the enzyme develops. Similar {FeNO}7 (S = 1/2) EPR signals have been observed for a variety of octahedral mononuclear iron-nitrosyl synthetic complexes; however, this type of iron-nitrosyl species is not commonly observed for non-heme iron enzymes. Substitution of l-cysteine with isosteric substrate analogues cysteamine, 3-mercaptopropionic acid, and propane thiol did not produce any analogous {FeNO}7 signals (S = 1/2 or 3/2), thus reflecting the high substrate specificity of the enzyme observed by a number of researchers. The unusual {FeNO}7 (S = 1/2) electronic configuration adopted by the substrate-bound iron-nitrosyl CDO (termed {ES-NO}7) is a result of the bidentate thiol/amine coordination of l-cysteine in the NO-bound CDO active site. DFT computations were performed to further characterize this species. The DFT-predicted geometric parameters for {ES-NO}7 are in good agreement with the crystallographically determined substrate-bound active site configuration of CDO and are consistent with known iron-nitrosyl model complexes. Moreover, the computed EPR parameters (g and A values) are in excellent agreement with experimental results for this CDO species and those obtained from comparable synthetic {FeNO}7 (S = 1/2) iron-nitrosyl complexes. | REGULATOR |
| Characterization of the CHEMICAL adduct of substrate-bound GENE by electron paramagnetic resonance: electronic structure of the active site and mechanistic implications. Mammalian cysteine dioxygenase (CDO) is a non-heme iron metalloenzyme that catalyzes the first committed step in oxidative cysteine catabolism. The active site coordination of CDO comprises a mononuclear iron ligated by the Nepsilon atoms of three protein-derived histidines, thus representing a new variant on the 2-histidine-1-carboxylate (2H1C) facial triad motif. Nitric oxide was used as a spectroscopic probe in investigating the order of substrate-O2 binding by EPR spectroscopy. In these experiments, CDO exhibits an ordered binding of l-cysteine prior to NO (and presumably O2) similar to that observed for the 2H1C class of non-heme iron enzymes. Moreover, the CDO active site is essentially unreactive toward NO in the absence of substrate, suggesting an obligate ordered binding of l-cysteine prior to NO. Typically, addition of NO to a mononuclear non-heme iron center results in the formation of an {FeNO}7 (S = 3/2) species characterized by an axial EPR spectrum with gx, gy, and gz values of approximately 4, approximately 4, and approximately 2, respectively. However, upon addition of NO to CDO in the presence of substrate l-cysteine, a low-spin {FeNO}7 (S = 1/2) signal that accounts for approximately 85% of the iron within the enzyme develops. Similar {FeNO}7 (S = 1/2) EPR signals have been observed for a variety of octahedral mononuclear iron-nitrosyl synthetic complexes; however, this type of iron-nitrosyl species is not commonly observed for non-heme iron enzymes. Substitution of l-cysteine with isosteric substrate analogues cysteamine, 3-mercaptopropionic acid, and propane thiol did not produce any analogous {FeNO}7 signals (S = 1/2 or 3/2), thus reflecting the high substrate specificity of the enzyme observed by a number of researchers. The unusual {FeNO}7 (S = 1/2) electronic configuration adopted by the substrate-bound iron-nitrosyl CDO (termed {ES-NO}7) is a result of the bidentate thiol/amine coordination of l-cysteine in the NO-bound CDO active site. DFT computations were performed to further characterize this species. The DFT-predicted geometric parameters for {ES-NO}7 are in good agreement with the crystallographically determined substrate-bound active site configuration of CDO and are consistent with known iron-nitrosyl model complexes. Moreover, the computed EPR parameters (g and A values) are in excellent agreement with experimental results for this CDO species and those obtained from comparable synthetic {FeNO}7 (S = 1/2) iron-nitrosyl complexes. | DIRECT-REGULATOR |
| Characterization of the nitrosyl adduct of substrate-bound mouse cysteine dioxygenase by electron paramagnetic resonance: electronic structure of the active site and mechanistic implications. GENE (CDO) is a non-heme CHEMICAL metalloenzyme that catalyzes the first committed step in oxidative cysteine catabolism. The active site coordination of CDO comprises a mononuclear CHEMICAL ligated by the Nepsilon atoms of three protein-derived histidines, thus representing a new variant on the 2-histidine-1-carboxylate (2H1C) facial triad motif. Nitric oxide was used as a spectroscopic probe in investigating the order of substrate-O2 binding by EPR spectroscopy. In these experiments, CDO exhibits an ordered binding of l-cysteine prior to NO (and presumably O2) similar to that observed for the 2H1C class of non-heme CHEMICAL enzymes. Moreover, the CDO active site is essentially unreactive toward NO in the absence of substrate, suggesting an obligate ordered binding of l-cysteine prior to NO. Typically, addition of NO to a mononuclear non-heme CHEMICAL center results in the formation of an {FeNO}7 (S = 3/2) species characterized by an axial EPR spectrum with gx, gy, and gz values of approximately 4, approximately 4, and approximately 2, respectively. However, upon addition of NO to CDO in the presence of substrate l-cysteine, a low-spin {FeNO}7 (S = 1/2) signal that accounts for approximately 85% of the CHEMICAL within the enzyme develops. Similar {FeNO}7 (S = 1/2) EPR signals have been observed for a variety of octahedral mononuclear iron-nitrosyl synthetic complexes; however, this type of iron-nitrosyl species is not commonly observed for non-heme CHEMICAL enzymes. Substitution of l-cysteine with isosteric substrate analogues cysteamine, 3-mercaptopropionic acid, and propane thiol did not produce any analogous {FeNO}7 signals (S = 1/2 or 3/2), thus reflecting the high substrate specificity of the enzyme observed by a number of researchers. The unusual {FeNO}7 (S = 1/2) electronic configuration adopted by the substrate-bound iron-nitrosyl CDO (termed {ES-NO}7) is a result of the bidentate thiol/amine coordination of l-cysteine in the NO-bound CDO active site. DFT computations were performed to further characterize this species. The DFT-predicted geometric parameters for {ES-NO}7 are in good agreement with the crystallographically determined substrate-bound active site configuration of CDO and are consistent with known iron-nitrosyl model complexes. Moreover, the computed EPR parameters (g and A values) are in excellent agreement with experimental results for this CDO species and those obtained from comparable synthetic {FeNO}7 (S = 1/2) iron-nitrosyl complexes. | SUBSTRATE |
| Characterization of the nitrosyl adduct of substrate-bound mouse CHEMICAL dioxygenase by electron paramagnetic resonance: electronic structure of the active site and mechanistic implications. GENE (CDO) is a non-heme iron metalloenzyme that catalyzes the first committed step in oxidative CHEMICAL catabolism. The active site coordination of CDO comprises a mononuclear iron ligated by the Nepsilon atoms of three protein-derived histidines, thus representing a new variant on the 2-histidine-1-carboxylate (2H1C) facial triad motif. Nitric oxide was used as a spectroscopic probe in investigating the order of substrate-O2 binding by EPR spectroscopy. In these experiments, CDO exhibits an ordered binding of l-cysteine prior to NO (and presumably O2) similar to that observed for the 2H1C class of non-heme iron enzymes. Moreover, the CDO active site is essentially unreactive toward NO in the absence of substrate, suggesting an obligate ordered binding of l-cysteine prior to NO. Typically, addition of NO to a mononuclear non-heme iron center results in the formation of an {FeNO}7 (S = 3/2) species characterized by an axial EPR spectrum with gx, gy, and gz values of approximately 4, approximately 4, and approximately 2, respectively. However, upon addition of NO to CDO in the presence of substrate l-cysteine, a low-spin {FeNO}7 (S = 1/2) signal that accounts for approximately 85% of the iron within the enzyme develops. Similar {FeNO}7 (S = 1/2) EPR signals have been observed for a variety of octahedral mononuclear iron-nitrosyl synthetic complexes; however, this type of iron-nitrosyl species is not commonly observed for non-heme iron enzymes. Substitution of l-cysteine with isosteric substrate analogues cysteamine, 3-mercaptopropionic acid, and propane thiol did not produce any analogous {FeNO}7 signals (S = 1/2 or 3/2), thus reflecting the high substrate specificity of the enzyme observed by a number of researchers. The unusual {FeNO}7 (S = 1/2) electronic configuration adopted by the substrate-bound iron-nitrosyl CDO (termed {ES-NO}7) is a result of the bidentate thiol/amine coordination of l-cysteine in the NO-bound CDO active site. DFT computations were performed to further characterize this species. The DFT-predicted geometric parameters for {ES-NO}7 are in good agreement with the crystallographically determined substrate-bound active site configuration of CDO and are consistent with known iron-nitrosyl model complexes. Moreover, the computed EPR parameters (g and A values) are in excellent agreement with experimental results for this CDO species and those obtained from comparable synthetic {FeNO}7 (S = 1/2) iron-nitrosyl complexes. | SUBSTRATE |
| Characterization of the nitrosyl adduct of substrate-bound mouse CHEMICAL dioxygenase by electron paramagnetic resonance: electronic structure of the active site and mechanistic implications. Mammalian CHEMICAL dioxygenase (GENE) is a non-heme iron metalloenzyme that catalyzes the first committed step in oxidative CHEMICAL catabolism. The active site coordination of GENE comprises a mononuclear iron ligated by the Nepsilon atoms of three protein-derived histidines, thus representing a new variant on the 2-histidine-1-carboxylate (2H1C) facial triad motif. Nitric oxide was used as a spectroscopic probe in investigating the order of substrate-O2 binding by EPR spectroscopy. In these experiments, GENE exhibits an ordered binding of l-cysteine prior to NO (and presumably O2) similar to that observed for the 2H1C class of non-heme iron enzymes. Moreover, the GENE active site is essentially unreactive toward NO in the absence of substrate, suggesting an obligate ordered binding of l-cysteine prior to NO. Typically, addition of NO to a mononuclear non-heme iron center results in the formation of an {FeNO}7 (S = 3/2) species characterized by an axial EPR spectrum with gx, gy, and gz values of approximately 4, approximately 4, and approximately 2, respectively. However, upon addition of NO to GENE in the presence of substrate l-cysteine, a low-spin {FeNO}7 (S = 1/2) signal that accounts for approximately 85% of the iron within the enzyme develops. Similar {FeNO}7 (S = 1/2) EPR signals have been observed for a variety of octahedral mononuclear iron-nitrosyl synthetic complexes; however, this type of iron-nitrosyl species is not commonly observed for non-heme iron enzymes. Substitution of l-cysteine with isosteric substrate analogues cysteamine, 3-mercaptopropionic acid, and propane thiol did not produce any analogous {FeNO}7 signals (S = 1/2 or 3/2), thus reflecting the high substrate specificity of the enzyme observed by a number of researchers. The unusual {FeNO}7 (S = 1/2) electronic configuration adopted by the substrate-bound iron-nitrosyl GENE (termed {ES-NO}7) is a result of the bidentate thiol/amine coordination of l-cysteine in the NO-bound GENE active site. DFT computations were performed to further characterize this species. The DFT-predicted geometric parameters for {ES-NO}7 are in good agreement with the crystallographically determined substrate-bound active site configuration of GENE and are consistent with known iron-nitrosyl model complexes. Moreover, the computed EPR parameters (g and A values) are in excellent agreement with experimental results for this GENE species and those obtained from comparable synthetic {FeNO}7 (S = 1/2) iron-nitrosyl complexes. | SUBSTRATE |
| Ligand-dependent transcriptional activities of four torafugu pufferfish Takifugu rubripes peroxisome proliferator-activated receptors. Structural and functional properties were investigated for four peroxisome proliferator-activated receptors (PPARs), PPARalpha1, GENE, PPARbeta, and PPARgamma, from torafugu pufferfish Takifugu rubripes and determined for their transcriptional activity by the reporter assay using reporter plasmids containing three copies of the acyl-CoA oxidase PPAR response element. Although torafugu PPARs showed a high similarity in the primary structure to other vertebrate counterparts, torafugu GENE and gamma contained additional sequences of 21 and 28 amino acids, respectively, as in the case of other teleost fish species when compared with African clawed frog counterparts. The transcriptional activity of torafugu PPARalpha1 was enhanced 4.5- and 11.5-fold by CHEMICAL and 5,8,11,14-eicosatetraynoic acid (ETYA) each at 10 microM, respectively, whereas that of GENE, 4.5- and 7.3-fold at the same concentration of the respective ligands, respectively. The activities of torafugu PPARalpha1 and alpha2 were also enhanced 5.6- and 6.3-fold by ETYA at 1 microM, respectively, but not by CHEMICAL at this concentration. Furthermore, the activities of the two torafugu PPARalphas were enhanced 4.3- and 7.6-fold by arachidonic acid, 4.4- and 5.2-fold by docosahexaenoic acid, and 6.7- and 8.0-fold by eicosapentaenoic acid each at 50 microM, respectively. On the other hand, the activities of torafugu PPARbeta and gamma were not changed by CHEMICAL, ETYA, rosiglitazone, nor PUFAs. These results suggest that the activities of torafugu PPARbeta and gamma require undefined ligands. Alternatively, the molecular mechanisms involved in their activation are different from those of other vertebrates. | NO-RELATIONSHIP |
| Ligand-dependent transcriptional activities of four torafugu pufferfish Takifugu rubripes peroxisome proliferator-activated receptors. Structural and functional properties were investigated for four peroxisome proliferator-activated receptors (PPARs), PPARalpha1, GENE, PPARbeta, and PPARgamma, from torafugu pufferfish Takifugu rubripes and determined for their transcriptional activity by the reporter assay using reporter plasmids containing three copies of the acyl-CoA oxidase PPAR response element. Although torafugu PPARs showed a high similarity in the primary structure to other vertebrate counterparts, torafugu GENE and gamma contained additional sequences of 21 and 28 amino acids, respectively, as in the case of other teleost fish species when compared with African clawed frog counterparts. The transcriptional activity of torafugu PPARalpha1 was enhanced 4.5- and 11.5-fold by Wy-14643 and CHEMICAL (ETYA) each at 10 microM, respectively, whereas that of GENE, 4.5- and 7.3-fold at the same concentration of the respective ligands, respectively. The activities of torafugu PPARalpha1 and alpha2 were also enhanced 5.6- and 6.3-fold by ETYA at 1 microM, respectively, but not by Wy-14643 at this concentration. Furthermore, the activities of the two torafugu PPARalphas were enhanced 4.3- and 7.6-fold by arachidonic acid, 4.4- and 5.2-fold by docosahexaenoic acid, and 6.7- and 8.0-fold by eicosapentaenoic acid each at 50 microM, respectively. On the other hand, the activities of torafugu PPARbeta and gamma were not changed by Wy-14643, ETYA, rosiglitazone, nor PUFAs. These results suggest that the activities of torafugu PPARbeta and gamma require undefined ligands. Alternatively, the molecular mechanisms involved in their activation are different from those of other vertebrates. | REGULATOR |
| Ligand-dependent transcriptional activities of four torafugu pufferfish Takifugu rubripes peroxisome proliferator-activated receptors. Structural and functional properties were investigated for four peroxisome proliferator-activated receptors (PPARs), PPARalpha1, GENE, PPARbeta, and PPARgamma, from torafugu pufferfish Takifugu rubripes and determined for their transcriptional activity by the reporter assay using reporter plasmids containing three copies of the acyl-CoA oxidase PPAR response element. Although torafugu PPARs showed a high similarity in the primary structure to other vertebrate counterparts, torafugu GENE and gamma contained additional sequences of 21 and 28 amino acids, respectively, as in the case of other teleost fish species when compared with African clawed frog counterparts. The transcriptional activity of torafugu PPARalpha1 was enhanced 4.5- and 11.5-fold by Wy-14643 and 5,8,11,14-eicosatetraynoic acid (CHEMICAL) each at 10 microM, respectively, whereas that of GENE, 4.5- and 7.3-fold at the same concentration of the respective ligands, respectively. The activities of torafugu PPARalpha1 and alpha2 were also enhanced 5.6- and 6.3-fold by CHEMICAL at 1 microM, respectively, but not by Wy-14643 at this concentration. Furthermore, the activities of the two torafugu PPARalphas were enhanced 4.3- and 7.6-fold by arachidonic acid, 4.4- and 5.2-fold by docosahexaenoic acid, and 6.7- and 8.0-fold by eicosapentaenoic acid each at 50 microM, respectively. On the other hand, the activities of torafugu PPARbeta and gamma were not changed by Wy-14643, CHEMICAL, rosiglitazone, nor PUFAs. These results suggest that the activities of torafugu PPARbeta and gamma require undefined ligands. Alternatively, the molecular mechanisms involved in their activation are different from those of other vertebrates. | DIRECT-REGULATOR |
| Ligand-dependent transcriptional activities of four torafugu pufferfish Takifugu rubripes peroxisome proliferator-activated receptors. Structural and functional properties were investigated for four peroxisome proliferator-activated receptors (PPARs), GENE, PPARalpha2, PPARbeta, and PPARgamma, from torafugu pufferfish Takifugu rubripes and determined for their transcriptional activity by the reporter assay using reporter plasmids containing three copies of the acyl-CoA oxidase PPAR response element. Although torafugu PPARs showed a high similarity in the primary structure to other vertebrate counterparts, torafugu PPARalpha2 and gamma contained additional sequences of 21 and 28 amino acids, respectively, as in the case of other teleost fish species when compared with African clawed frog counterparts. The transcriptional activity of torafugu GENE was enhanced 4.5- and 11.5-fold by CHEMICAL and 5,8,11,14-eicosatetraynoic acid (ETYA) each at 10 microM, respectively, whereas that of PPARalpha2, 4.5- and 7.3-fold at the same concentration of the respective ligands, respectively. The activities of torafugu GENE and alpha2 were also enhanced 5.6- and 6.3-fold by ETYA at 1 microM, respectively, but not by CHEMICAL at this concentration. Furthermore, the activities of the two torafugu PPARalphas were enhanced 4.3- and 7.6-fold by arachidonic acid, 4.4- and 5.2-fold by docosahexaenoic acid, and 6.7- and 8.0-fold by eicosapentaenoic acid each at 50 microM, respectively. On the other hand, the activities of torafugu PPARbeta and gamma were not changed by CHEMICAL, ETYA, rosiglitazone, nor PUFAs. These results suggest that the activities of torafugu PPARbeta and gamma require undefined ligands. Alternatively, the molecular mechanisms involved in their activation are different from those of other vertebrates. | NO-RELATIONSHIP |
| Ligand-dependent transcriptional activities of four torafugu pufferfish Takifugu rubripes peroxisome proliferator-activated receptors. Structural and functional properties were investigated for four peroxisome proliferator-activated receptors (PPARs), GENE, PPARalpha2, PPARbeta, and PPARgamma, from torafugu pufferfish Takifugu rubripes and determined for their transcriptional activity by the reporter assay using reporter plasmids containing three copies of the acyl-CoA oxidase PPAR response element. Although torafugu PPARs showed a high similarity in the primary structure to other vertebrate counterparts, torafugu PPARalpha2 and gamma contained additional sequences of 21 and 28 amino acids, respectively, as in the case of other teleost fish species when compared with African clawed frog counterparts. The transcriptional activity of torafugu GENE was enhanced 4.5- and 11.5-fold by Wy-14643 and CHEMICAL (ETYA) each at 10 microM, respectively, whereas that of PPARalpha2, 4.5- and 7.3-fold at the same concentration of the respective ligands, respectively. The activities of torafugu GENE and alpha2 were also enhanced 5.6- and 6.3-fold by ETYA at 1 microM, respectively, but not by Wy-14643 at this concentration. Furthermore, the activities of the two torafugu PPARalphas were enhanced 4.3- and 7.6-fold by arachidonic acid, 4.4- and 5.2-fold by docosahexaenoic acid, and 6.7- and 8.0-fold by eicosapentaenoic acid each at 50 microM, respectively. On the other hand, the activities of torafugu PPARbeta and gamma were not changed by Wy-14643, ETYA, rosiglitazone, nor PUFAs. These results suggest that the activities of torafugu PPARbeta and gamma require undefined ligands. Alternatively, the molecular mechanisms involved in their activation are different from those of other vertebrates. | ACTIVATOR |
| Ligand-dependent transcriptional activities of four torafugu pufferfish Takifugu rubripes peroxisome proliferator-activated receptors. Structural and functional properties were investigated for four peroxisome proliferator-activated receptors (PPARs), GENE, PPARalpha2, PPARbeta, and PPARgamma, from torafugu pufferfish Takifugu rubripes and determined for their transcriptional activity by the reporter assay using reporter plasmids containing three copies of the acyl-CoA oxidase PPAR response element. Although torafugu PPARs showed a high similarity in the primary structure to other vertebrate counterparts, torafugu PPARalpha2 and gamma contained additional sequences of 21 and 28 amino acids, respectively, as in the case of other teleost fish species when compared with African clawed frog counterparts. The transcriptional activity of torafugu GENE was enhanced 4.5- and 11.5-fold by Wy-14643 and 5,8,11,14-eicosatetraynoic acid (CHEMICAL) each at 10 microM, respectively, whereas that of PPARalpha2, 4.5- and 7.3-fold at the same concentration of the respective ligands, respectively. The activities of torafugu GENE and alpha2 were also enhanced 5.6- and 6.3-fold by CHEMICAL at 1 microM, respectively, but not by Wy-14643 at this concentration. Furthermore, the activities of the two torafugu PPARalphas were enhanced 4.3- and 7.6-fold by arachidonic acid, 4.4- and 5.2-fold by docosahexaenoic acid, and 6.7- and 8.0-fold by eicosapentaenoic acid each at 50 microM, respectively. On the other hand, the activities of torafugu PPARbeta and gamma were not changed by Wy-14643, CHEMICAL, rosiglitazone, nor PUFAs. These results suggest that the activities of torafugu PPARbeta and gamma require undefined ligands. Alternatively, the molecular mechanisms involved in their activation are different from those of other vertebrates. | NO-RELATIONSHIP |
| Ligand-dependent transcriptional activities of four torafugu pufferfish Takifugu rubripes peroxisome proliferator-activated receptors. Structural and functional properties were investigated for four peroxisome proliferator-activated receptors (PPARs), PPARalpha1, PPARalpha2, PPARbeta, and PPARgamma, from torafugu pufferfish Takifugu rubripes and determined for their transcriptional activity by the reporter assay using reporter plasmids containing three copies of the acyl-CoA oxidase PPAR response element. Although torafugu PPARs showed a high similarity in the primary structure to other vertebrate counterparts, torafugu PPARalpha2 and gamma contained additional sequences of 21 and 28 amino acids, respectively, as in the case of other teleost fish species when compared with African clawed frog counterparts. The transcriptional activity of torafugu PPARalpha1 was enhanced 4.5- and 11.5-fold by Wy-14643 and 5,8,11,14-eicosatetraynoic acid (ETYA) each at 10 microM, respectively, whereas that of PPARalpha2, 4.5- and 7.3-fold at the same concentration of the respective ligands, respectively. The activities of torafugu PPARalpha1 and alpha2 were also enhanced 5.6- and 6.3-fold by ETYA at 1 microM, respectively, but not by Wy-14643 at this concentration. Furthermore, the activities of the two GENE were enhanced 4.3- and 7.6-fold by CHEMICAL, 4.4- and 5.2-fold by docosahexaenoic acid, and 6.7- and 8.0-fold by eicosapentaenoic acid each at 50 microM, respectively. On the other hand, the activities of torafugu PPARbeta and gamma were not changed by Wy-14643, ETYA, rosiglitazone, nor PUFAs. These results suggest that the activities of torafugu PPARbeta and gamma require undefined ligands. Alternatively, the molecular mechanisms involved in their activation are different from those of other vertebrates. | ACTIVATOR |
| Ligand-dependent transcriptional activities of four torafugu pufferfish Takifugu rubripes peroxisome proliferator-activated receptors. Structural and functional properties were investigated for four peroxisome proliferator-activated receptors (PPARs), PPARalpha1, PPARalpha2, PPARbeta, and PPARgamma, from torafugu pufferfish Takifugu rubripes and determined for their transcriptional activity by the reporter assay using reporter plasmids containing three copies of the acyl-CoA oxidase PPAR response element. Although torafugu PPARs showed a high similarity in the primary structure to other vertebrate counterparts, torafugu PPARalpha2 and gamma contained additional sequences of 21 and 28 amino acids, respectively, as in the case of other teleost fish species when compared with African clawed frog counterparts. The transcriptional activity of torafugu PPARalpha1 was enhanced 4.5- and 11.5-fold by Wy-14643 and 5,8,11,14-eicosatetraynoic acid (ETYA) each at 10 microM, respectively, whereas that of PPARalpha2, 4.5- and 7.3-fold at the same concentration of the respective ligands, respectively. The activities of torafugu PPARalpha1 and alpha2 were also enhanced 5.6- and 6.3-fold by ETYA at 1 microM, respectively, but not by Wy-14643 at this concentration. Furthermore, the activities of the two GENE were enhanced 4.3- and 7.6-fold by arachidonic acid, 4.4- and 5.2-fold by CHEMICAL, and 6.7- and 8.0-fold by eicosapentaenoic acid each at 50 microM, respectively. On the other hand, the activities of torafugu PPARbeta and gamma were not changed by Wy-14643, ETYA, rosiglitazone, nor PUFAs. These results suggest that the activities of torafugu PPARbeta and gamma require undefined ligands. Alternatively, the molecular mechanisms involved in their activation are different from those of other vertebrates. | ACTIVATOR |
| Ligand-dependent transcriptional activities of four torafugu pufferfish Takifugu rubripes peroxisome proliferator-activated receptors. Structural and functional properties were investigated for four peroxisome proliferator-activated receptors (PPARs), PPARalpha1, PPARalpha2, PPARbeta, and PPARgamma, from torafugu pufferfish Takifugu rubripes and determined for their transcriptional activity by the reporter assay using reporter plasmids containing three copies of the acyl-CoA oxidase PPAR response element. Although torafugu PPARs showed a high similarity in the primary structure to other vertebrate counterparts, torafugu PPARalpha2 and gamma contained additional sequences of 21 and 28 amino acids, respectively, as in the case of other teleost fish species when compared with African clawed frog counterparts. The transcriptional activity of torafugu PPARalpha1 was enhanced 4.5- and 11.5-fold by Wy-14643 and 5,8,11,14-eicosatetraynoic acid (ETYA) each at 10 microM, respectively, whereas that of PPARalpha2, 4.5- and 7.3-fold at the same concentration of the respective ligands, respectively. The activities of torafugu PPARalpha1 and alpha2 were also enhanced 5.6- and 6.3-fold by ETYA at 1 microM, respectively, but not by Wy-14643 at this concentration. Furthermore, the activities of the two GENE were enhanced 4.3- and 7.6-fold by arachidonic acid, 4.4- and 5.2-fold by docosahexaenoic acid, and 6.7- and 8.0-fold by CHEMICAL each at 50 microM, respectively. On the other hand, the activities of torafugu PPARbeta and gamma were not changed by Wy-14643, ETYA, rosiglitazone, nor PUFAs. These results suggest that the activities of torafugu PPARbeta and gamma require undefined ligands. Alternatively, the molecular mechanisms involved in their activation are different from those of other vertebrates. | ACTIVATOR |
| Combination chemotherapy with a GENE antagonist (CHEMICAL) and melarsoprol in a mouse model of human African trypanosomiasis. Drug therapy for late-stage (encephalitic) human African trypanosomiasis (HAT) is currently very unsatisfactory with the most commonly used drug, melarsoprol, having a 5% overall mortality. There is evidence in a mouse model of HAT that Substance P (SP) receptor antagonism reduces the neuroinflammatory reaction to CNS trypanosome infection. In this study we investigated the effects of combination chemotherapy with melarsoprol and a humanised SP receptor antagonist CHEMICAL (EMEND) in this mouse model. The melarsoprol/aprepitant drug combination did not produce any clinical signs of illness in mice with CNS trypanosome infection. This lack of any additional or unexpected CNS toxicity in the mouse model of CNS HAT provides valuable safety data for the future possible use of this drug combination in patients with late-stage HAT. | INHIBITOR |
| Combination chemotherapy with a GENE antagonist (aprepitant) and CHEMICAL in a mouse model of human African trypanosomiasis. Drug therapy for late-stage (encephalitic) human African trypanosomiasis (HAT) is currently very unsatisfactory with the most commonly used drug, CHEMICAL, having a 5% overall mortality. There is evidence in a mouse model of HAT that Substance P (SP) receptor antagonism reduces the neuroinflammatory reaction to CNS trypanosome infection. In this study we investigated the effects of combination chemotherapy with CHEMICAL and a humanised SP receptor antagonist aprepitant (EMEND) in this mouse model. The melarsoprol/aprepitant drug combination did not produce any clinical signs of illness in mice with CNS trypanosome infection. This lack of any additional or unexpected CNS toxicity in the mouse model of CNS HAT provides valuable safety data for the future possible use of this drug combination in patients with late-stage HAT. | INHIBITOR |
| Combination chemotherapy with a substance P receptor antagonist (aprepitant) and melarsoprol in a mouse model of human African trypanosomiasis. Drug therapy for late-stage (encephalitic) human African trypanosomiasis (HAT) is currently very unsatisfactory with the most commonly used drug, melarsoprol, having a 5% overall mortality. There is evidence in a mouse model of HAT that Substance P (SP) receptor antagonism reduces the neuroinflammatory reaction to CNS trypanosome infection. In this study we investigated the effects of combination chemotherapy with melarsoprol and a GENE antagonist CHEMICAL (EMEND) in this mouse model. The melarsoprol/aprepitant drug combination did not produce any clinical signs of illness in mice with CNS trypanosome infection. This lack of any additional or unexpected CNS toxicity in the mouse model of CNS HAT provides valuable safety data for the future possible use of this drug combination in patients with late-stage HAT. | INHIBITOR |
| Combination chemotherapy with a substance P receptor antagonist (aprepitant) and melarsoprol in a mouse model of human African trypanosomiasis. Drug therapy for late-stage (encephalitic) human African trypanosomiasis (HAT) is currently very unsatisfactory with the most commonly used drug, melarsoprol, having a 5% overall mortality. There is evidence in a mouse model of HAT that Substance P (SP) receptor antagonism reduces the neuroinflammatory reaction to CNS trypanosome infection. In this study we investigated the effects of combination chemotherapy with melarsoprol and a GENE antagonist aprepitant (CHEMICAL) in this mouse model. The melarsoprol/aprepitant drug combination did not produce any clinical signs of illness in mice with CNS trypanosome infection. This lack of any additional or unexpected CNS toxicity in the mouse model of CNS HAT provides valuable safety data for the future possible use of this drug combination in patients with late-stage HAT. | INHIBITOR |
| Identification of the RLBP1 gene promoter. PURPOSE: Cellular retinaldehyde-binding protein (CRALBP), transcribed from the RLBP1 gene, is a GENE with 316 CHEMICAL found in the retinal pigment epithelium (RPE) and in retinal Muller cells. It is thought to play a critical role in the visual cycle by functioning as an acceptor of 11-cis-retinol from the isomerohydrolase reaction. The goal here was to evaluate the functional promoter of this gene. METHODS: 5' RACE analysis, promoter-reporter assays, and semiquantitative PCR with exon-specific primers were performed using human-derived RPE cells (ARPE-19 and D407) in culture to evaluate the 5' sequence flanking the RLBP1 gene. In addition, the murine, bovine, and porcine RLBP1 genes were evaluated in silico to identify likely proximal promoter/exon 1 sequences similar to the human gene. RESULTS: 5' RACE analysis revealed the presence of a previously undescribed exon in the RLBP1 gene. This was confirmed by analysis of the GenBank Human EST database, which revealed the presence of 18 sequences matching exon 1. Exon-specific PCR revealed that most CRALBP transcripts expressed in ARPE-19 cells contain both exon 1 and the final exon, suggesting that the primary promoter of CRALBP exists 5' of the newly identified exon 1. Highly homologous sequences in the murine, bovine, and porcine genes were also identified. Finally, promoter-reporter constructs revealed a minimal sequence necessary for promoter function and indicated significantly greater promoter activity compared with previously described RLBP1 promoters. CONCLUSIONS: The findings presented here suggest that CRALBP transcripts in RPE cells contain a noncoding exon in addition to a newly described promoter and, by definition, an additional intron. This finding sets the stage for a mechanistic understanding of the high degree of cell type-specific expression of RLBP1. | PART-OF |
| Identification of the RLBP1 gene promoter. PURPOSE: Cellular retinaldehyde-binding protein (CRALBP), transcribed from the RLBP1 gene, is a 36-kDa water-soluble protein with 316 amino acids found in the retinal pigment epithelium (RPE) and in retinal Muller cells. It is thought to play a critical role in the visual cycle by functioning as an acceptor of CHEMICAL from the GENE reaction. The goal here was to evaluate the functional promoter of this gene. METHODS: 5' RACE analysis, promoter-reporter assays, and semiquantitative PCR with exon-specific primers were performed using human-derived RPE cells (ARPE-19 and D407) in culture to evaluate the 5' sequence flanking the RLBP1 gene. In addition, the murine, bovine, and porcine RLBP1 genes were evaluated in silico to identify likely proximal promoter/exon 1 sequences similar to the human gene. RESULTS: 5' RACE analysis revealed the presence of a previously undescribed exon in the RLBP1 gene. This was confirmed by analysis of the GenBank Human EST database, which revealed the presence of 18 sequences matching exon 1. Exon-specific PCR revealed that most CRALBP transcripts expressed in ARPE-19 cells contain both exon 1 and the final exon, suggesting that the primary promoter of CRALBP exists 5' of the newly identified exon 1. Highly homologous sequences in the murine, bovine, and porcine genes were also identified. Finally, promoter-reporter constructs revealed a minimal sequence necessary for promoter function and indicated significantly greater promoter activity compared with previously described RLBP1 promoters. CONCLUSIONS: The findings presented here suggest that CRALBP transcripts in RPE cells contain a noncoding exon in addition to a newly described promoter and, by definition, an additional intron. This finding sets the stage for a mechanistic understanding of the high degree of cell type-specific expression of RLBP1. | GENE-CHEMICAL |
| Determination of dimethylarginine dimethylaminohydrolase activity in the kidney. Dimethylarginine dimethylaminohydrolase (DDAH) metabolizes asymmetric dimethylarginine to generate CHEMICAL and is present in large quantities in the kidney. We present a new study that optimizes the Prescott-Jones colorimetric assay to measure DDAH-dependent CHEMICAL generation in kidney homogenates. We found that the removal of urea with urease is necessary since urea also produces a positive reaction. Deproteinization with sulfosalicylic acid was found to be optimal and that protease inhibitors were not necessary. All assays were conducted in phosphate buffer, since other common additives can create false positive and false negative reactions. GENE or nitric oxide synthase isoenzymes were not found to influence CHEMICAL production. Our optimized CHEMICAL production assay to measure DDAH activity correlated closely with the direct measure of the rate of asymmetric dimethylarginine consumption. Using this assay, we found that both superoxide and nitric oxide inhibit renal cortical DDAH activity in vitro. | NO-RELATIONSHIP |
| Determination of dimethylarginine dimethylaminohydrolase activity in the kidney. Dimethylarginine dimethylaminohydrolase (DDAH) metabolizes asymmetric dimethylarginine to generate CHEMICAL and is present in large quantities in the kidney. We present a new study that optimizes the Prescott-Jones colorimetric assay to measure DDAH-dependent CHEMICAL generation in kidney homogenates. We found that the removal of urea with urease is necessary since urea also produces a positive reaction. Deproteinization with sulfosalicylic acid was found to be optimal and that protease inhibitors were not necessary. All assays were conducted in phosphate buffer, since other common additives can create false positive and false negative reactions. Arginase or GENE isoenzymes were not found to influence CHEMICAL production. Our optimized CHEMICAL production assay to measure DDAH activity correlated closely with the direct measure of the rate of asymmetric dimethylarginine consumption. Using this assay, we found that both superoxide and nitric oxide inhibit renal cortical DDAH activity in vitro. | NO-RELATIONSHIP |
| Determination of dimethylarginine dimethylaminohydrolase activity in the kidney. Dimethylarginine dimethylaminohydrolase (DDAH) metabolizes asymmetric dimethylarginine to generate L-citrulline and is present in large quantities in the kidney. We present a new study that optimizes the Prescott-Jones colorimetric assay to measure DDAH-dependent L-citrulline generation in kidney homogenates. We found that the removal of urea with urease is necessary since urea also produces a positive reaction. Deproteinization with sulfosalicylic acid was found to be optimal and that protease inhibitors were not necessary. All assays were conducted in phosphate buffer, since other common additives can create false positive and false negative reactions. Arginase or nitric oxide synthase isoenzymes were not found to influence L-citrulline production. Our optimized L-citrulline production assay to measure GENE activity correlated closely with the direct measure of the rate of asymmetric dimethylarginine consumption. Using this assay, we found that both CHEMICAL and nitric oxide inhibit renal cortical GENE activity in vitro. | INHIBITOR |
| Determination of dimethylarginine dimethylaminohydrolase activity in the kidney. Dimethylarginine dimethylaminohydrolase (DDAH) metabolizes asymmetric dimethylarginine to generate L-citrulline and is present in large quantities in the kidney. We present a new study that optimizes the Prescott-Jones colorimetric assay to measure DDAH-dependent L-citrulline generation in kidney homogenates. We found that the removal of urea with urease is necessary since urea also produces a positive reaction. Deproteinization with sulfosalicylic acid was found to be optimal and that protease inhibitors were not necessary. All assays were conducted in phosphate buffer, since other common additives can create false positive and false negative reactions. Arginase or CHEMICAL synthase isoenzymes were not found to influence L-citrulline production. Our optimized L-citrulline production assay to measure GENE activity correlated closely with the direct measure of the rate of asymmetric dimethylarginine consumption. Using this assay, we found that both superoxide and CHEMICAL inhibit renal cortical GENE activity in vitro. | INHIBITOR |
| Determination of dimethylarginine dimethylaminohydrolase activity in the kidney. Dimethylarginine dimethylaminohydrolase (DDAH) metabolizes asymmetric dimethylarginine to generate CHEMICAL and is present in large quantities in the kidney. We present a new study that optimizes the Prescott-Jones colorimetric assay to measure DDAH-dependent CHEMICAL generation in kidney homogenates. We found that the removal of urea with urease is necessary since urea also produces a positive reaction. Deproteinization with sulfosalicylic acid was found to be optimal and that protease inhibitors were not necessary. All assays were conducted in phosphate buffer, since other common additives can create false positive and false negative reactions. Arginase or nitric oxide synthase isoenzymes were not found to influence CHEMICAL production. Our optimized CHEMICAL production assay to measure GENE activity correlated closely with the direct measure of the rate of asymmetric dimethylarginine consumption. Using this assay, we found that both superoxide and nitric oxide inhibit renal cortical GENE activity in vitro. | PRODUCT-OF |
| Determination of dimethylarginine dimethylaminohydrolase activity in the kidney. GENE (DDAH) metabolizes asymmetric dimethylarginine to generate CHEMICAL and is present in large quantities in the kidney. We present a new study that optimizes the Prescott-Jones colorimetric assay to measure DDAH-dependent CHEMICAL generation in kidney homogenates. We found that the removal of urea with urease is necessary since urea also produces a positive reaction. Deproteinization with sulfosalicylic acid was found to be optimal and that protease inhibitors were not necessary. All assays were conducted in phosphate buffer, since other common additives can create false positive and false negative reactions. Arginase or nitric oxide synthase isoenzymes were not found to influence CHEMICAL production. Our optimized CHEMICAL production assay to measure DDAH activity correlated closely with the direct measure of the rate of asymmetric dimethylarginine consumption. Using this assay, we found that both superoxide and nitric oxide inhibit renal cortical DDAH activity in vitro. | PRODUCT-OF |
| Determination of CHEMICAL dimethylaminohydrolase activity in the kidney. CHEMICAL dimethylaminohydrolase (DDAH) metabolizes asymmetric CHEMICAL to generate L-citrulline and is present in large quantities in the kidney. We present a new study that optimizes the Prescott-Jones colorimetric assay to measure DDAH-dependent L-citrulline generation in kidney homogenates. We found that the removal of urea with urease is necessary since urea also produces a positive reaction. Deproteinization with sulfosalicylic acid was found to be optimal and that protease inhibitors were not necessary. All assays were conducted in phosphate buffer, since other common additives can create false positive and false negative reactions. Arginase or nitric oxide synthase isoenzymes were not found to influence L-citrulline production. Our optimized L-citrulline production assay to measure GENE activity correlated closely with the direct measure of the rate of asymmetric CHEMICAL consumption. Using this assay, we found that both superoxide and nitric oxide inhibit renal cortical GENE activity in vitro. | SUBSTRATE |
| Determination of dimethylarginine dimethylaminohydrolase activity in the kidney. Dimethylarginine dimethylaminohydrolase (DDAH) metabolizes asymmetric dimethylarginine to generate L-citrulline and is present in large quantities in the kidney. We present a new study that optimizes the Prescott-Jones colorimetric assay to measure DDAH-dependent L-citrulline generation in kidney homogenates. We found that the removal of CHEMICAL with GENE is necessary since CHEMICAL also produces a positive reaction. Deproteinization with sulfosalicylic acid was found to be optimal and that protease inhibitors were not necessary. All assays were conducted in phosphate buffer, since other common additives can create false positive and false negative reactions. Arginase or nitric oxide synthase isoenzymes were not found to influence L-citrulline production. Our optimized L-citrulline production assay to measure DDAH activity correlated closely with the direct measure of the rate of asymmetric dimethylarginine consumption. Using this assay, we found that both superoxide and nitric oxide inhibit renal cortical DDAH activity in vitro. | SUBSTRATE |
| Determination of CHEMICAL dimethylaminohydrolase activity in the kidney. GENE (DDAH) metabolizes asymmetric CHEMICAL to generate L-citrulline and is present in large quantities in the kidney. We present a new study that optimizes the Prescott-Jones colorimetric assay to measure DDAH-dependent L-citrulline generation in kidney homogenates. We found that the removal of urea with urease is necessary since urea also produces a positive reaction. Deproteinization with sulfosalicylic acid was found to be optimal and that protease inhibitors were not necessary. All assays were conducted in phosphate buffer, since other common additives can create false positive and false negative reactions. Arginase or nitric oxide synthase isoenzymes were not found to influence L-citrulline production. Our optimized L-citrulline production assay to measure DDAH activity correlated closely with the direct measure of the rate of asymmetric CHEMICAL consumption. Using this assay, we found that both superoxide and nitric oxide inhibit renal cortical DDAH activity in vitro. | SUBSTRATE |
| The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. OPINION STATEMENT: Treatment of early stage breast cancer requires a multimodality approach in order to eradicate residual cancer and prevent recurrent disease. Targeting the pathways that promote or sustain cancer cell growth and invasion is critical to the effective treatment of breast and other cancers. Overexpression of the family of HER receptors have been associated with a variety of malignancies; the first and best studied is the association of overexpression of the HER2/neu receptor with a more aggressive breast cancer phenotype and poorer survival. A humanized antibody to HER2/neu, trastuzumab, is now FDA approved for the treatment of early stage, GENE/neu overexpressing breast cancer sequenced with chemotherapy including CHEMICAL, cyclophosphamide, and paclitaxel. Additional international and national studies support the significant impact of trastuzumab on both disease free and overall survival in women with this aggressive form of breast cancer. Toxicity includes a low but clear risk of congestive heart failure, and the large phase III trials have helped to determine which patients are at higher risk for this complication. Non-anthracycline containing regimens are an alternative therapy associated with reduced cardiac toxicity. Trastuzumab therapy is now the standard of care for the treatment of early stage, HER2/neu positive breast cancer given in combination with one of several chemotherapy regimens. Ongoing questions include the appropriate duration of trastuzumab treatment as well as the optimal chemotherapy regimen and sequence. The next large phase III adjuvant trial for this subset of breast cancer is an international collaboration designed to evaluate the added or alternative benefit of an oral tyrosine kinase inhibitor targeting HER2/neu as well as the epidermal growth factor receptor (EGFR), lapatinib. Other trials are investigating differences in duration. Studies in the neoadjuvant setting should help to define markers of trastuzumab and lapatinib sensitivity and resistance. Preliminary data combining trastuzumab with the antiangiogenic antibody bevacizumab is encouraging; this combination will be tested in both early stage and late stage disease. | NO-RELATIONSHIP |
| The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. OPINION STATEMENT: Treatment of early stage breast cancer requires a multimodality approach in order to eradicate residual cancer and prevent recurrent disease. Targeting the pathways that promote or sustain cancer cell growth and invasion is critical to the effective treatment of breast and other cancers. Overexpression of the family of HER receptors have been associated with a variety of malignancies; the first and best studied is the association of overexpression of the HER2/neu receptor with a more aggressive breast cancer phenotype and poorer survival. A humanized antibody to HER2/neu, trastuzumab, is now FDA approved for the treatment of early stage, HER2/GENE overexpressing breast cancer sequenced with chemotherapy including CHEMICAL, cyclophosphamide, and paclitaxel. Additional international and national studies support the significant impact of trastuzumab on both disease free and overall survival in women with this aggressive form of breast cancer. Toxicity includes a low but clear risk of congestive heart failure, and the large phase III trials have helped to determine which patients are at higher risk for this complication. Non-anthracycline containing regimens are an alternative therapy associated with reduced cardiac toxicity. Trastuzumab therapy is now the standard of care for the treatment of early stage, HER2/neu positive breast cancer given in combination with one of several chemotherapy regimens. Ongoing questions include the appropriate duration of trastuzumab treatment as well as the optimal chemotherapy regimen and sequence. The next large phase III adjuvant trial for this subset of breast cancer is an international collaboration designed to evaluate the added or alternative benefit of an oral tyrosine kinase inhibitor targeting HER2/neu as well as the epidermal growth factor receptor (EGFR), lapatinib. Other trials are investigating differences in duration. Studies in the neoadjuvant setting should help to define markers of trastuzumab and lapatinib sensitivity and resistance. Preliminary data combining trastuzumab with the antiangiogenic antibody bevacizumab is encouraging; this combination will be tested in both early stage and late stage disease. | REGULATOR |
| The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. OPINION STATEMENT: Treatment of early stage breast cancer requires a multimodality approach in order to eradicate residual cancer and prevent recurrent disease. Targeting the pathways that promote or sustain cancer cell growth and invasion is critical to the effective treatment of breast and other cancers. Overexpression of the family of HER receptors have been associated with a variety of malignancies; the first and best studied is the association of overexpression of the HER2/neu receptor with a more aggressive breast cancer phenotype and poorer survival. A humanized antibody to HER2/neu, trastuzumab, is now FDA approved for the treatment of early stage, GENE/neu overexpressing breast cancer sequenced with chemotherapy including doxorubicin, CHEMICAL, and paclitaxel. Additional international and national studies support the significant impact of trastuzumab on both disease free and overall survival in women with this aggressive form of breast cancer. Toxicity includes a low but clear risk of congestive heart failure, and the large phase III trials have helped to determine which patients are at higher risk for this complication. Non-anthracycline containing regimens are an alternative therapy associated with reduced cardiac toxicity. Trastuzumab therapy is now the standard of care for the treatment of early stage, HER2/neu positive breast cancer given in combination with one of several chemotherapy regimens. Ongoing questions include the appropriate duration of trastuzumab treatment as well as the optimal chemotherapy regimen and sequence. The next large phase III adjuvant trial for this subset of breast cancer is an international collaboration designed to evaluate the added or alternative benefit of an oral tyrosine kinase inhibitor targeting HER2/neu as well as the epidermal growth factor receptor (EGFR), lapatinib. Other trials are investigating differences in duration. Studies in the neoadjuvant setting should help to define markers of trastuzumab and lapatinib sensitivity and resistance. Preliminary data combining trastuzumab with the antiangiogenic antibody bevacizumab is encouraging; this combination will be tested in both early stage and late stage disease. | REGULATOR |
| The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. OPINION STATEMENT: Treatment of early stage breast cancer requires a multimodality approach in order to eradicate residual cancer and prevent recurrent disease. Targeting the pathways that promote or sustain cancer cell growth and invasion is critical to the effective treatment of breast and other cancers. Overexpression of the family of HER receptors have been associated with a variety of malignancies; the first and best studied is the association of overexpression of the HER2/neu receptor with a more aggressive breast cancer phenotype and poorer survival. A humanized antibody to HER2/neu, trastuzumab, is now FDA approved for the treatment of early stage, HER2/GENE overexpressing breast cancer sequenced with chemotherapy including doxorubicin, CHEMICAL, and paclitaxel. Additional international and national studies support the significant impact of trastuzumab on both disease free and overall survival in women with this aggressive form of breast cancer. Toxicity includes a low but clear risk of congestive heart failure, and the large phase III trials have helped to determine which patients are at higher risk for this complication. Non-anthracycline containing regimens are an alternative therapy associated with reduced cardiac toxicity. Trastuzumab therapy is now the standard of care for the treatment of early stage, HER2/neu positive breast cancer given in combination with one of several chemotherapy regimens. Ongoing questions include the appropriate duration of trastuzumab treatment as well as the optimal chemotherapy regimen and sequence. The next large phase III adjuvant trial for this subset of breast cancer is an international collaboration designed to evaluate the added or alternative benefit of an oral tyrosine kinase inhibitor targeting HER2/neu as well as the epidermal growth factor receptor (EGFR), lapatinib. Other trials are investigating differences in duration. Studies in the neoadjuvant setting should help to define markers of trastuzumab and lapatinib sensitivity and resistance. Preliminary data combining trastuzumab with the antiangiogenic antibody bevacizumab is encouraging; this combination will be tested in both early stage and late stage disease. | REGULATOR |
| The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. OPINION STATEMENT: Treatment of early stage breast cancer requires a multimodality approach in order to eradicate residual cancer and prevent recurrent disease. Targeting the pathways that promote or sustain cancer cell growth and invasion is critical to the effective treatment of breast and other cancers. Overexpression of the family of HER receptors have been associated with a variety of malignancies; the first and best studied is the association of overexpression of the HER2/neu receptor with a more aggressive breast cancer phenotype and poorer survival. A humanized antibody to HER2/neu, trastuzumab, is now FDA approved for the treatment of early stage, GENE/neu overexpressing breast cancer sequenced with chemotherapy including doxorubicin, cyclophosphamide, and CHEMICAL. Additional international and national studies support the significant impact of trastuzumab on both disease free and overall survival in women with this aggressive form of breast cancer. Toxicity includes a low but clear risk of congestive heart failure, and the large phase III trials have helped to determine which patients are at higher risk for this complication. Non-anthracycline containing regimens are an alternative therapy associated with reduced cardiac toxicity. Trastuzumab therapy is now the standard of care for the treatment of early stage, HER2/neu positive breast cancer given in combination with one of several chemotherapy regimens. Ongoing questions include the appropriate duration of trastuzumab treatment as well as the optimal chemotherapy regimen and sequence. The next large phase III adjuvant trial for this subset of breast cancer is an international collaboration designed to evaluate the added or alternative benefit of an oral tyrosine kinase inhibitor targeting HER2/neu as well as the epidermal growth factor receptor (EGFR), lapatinib. Other trials are investigating differences in duration. Studies in the neoadjuvant setting should help to define markers of trastuzumab and lapatinib sensitivity and resistance. Preliminary data combining trastuzumab with the antiangiogenic antibody bevacizumab is encouraging; this combination will be tested in both early stage and late stage disease. | REGULATOR |
| The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. OPINION STATEMENT: Treatment of early stage breast cancer requires a multimodality approach in order to eradicate residual cancer and prevent recurrent disease. Targeting the pathways that promote or sustain cancer cell growth and invasion is critical to the effective treatment of breast and other cancers. Overexpression of the family of HER receptors have been associated with a variety of malignancies; the first and best studied is the association of overexpression of the HER2/neu receptor with a more aggressive breast cancer phenotype and poorer survival. A humanized antibody to HER2/neu, trastuzumab, is now FDA approved for the treatment of early stage, HER2/GENE overexpressing breast cancer sequenced with chemotherapy including doxorubicin, cyclophosphamide, and CHEMICAL. Additional international and national studies support the significant impact of trastuzumab on both disease free and overall survival in women with this aggressive form of breast cancer. Toxicity includes a low but clear risk of congestive heart failure, and the large phase III trials have helped to determine which patients are at higher risk for this complication. Non-anthracycline containing regimens are an alternative therapy associated with reduced cardiac toxicity. Trastuzumab therapy is now the standard of care for the treatment of early stage, HER2/neu positive breast cancer given in combination with one of several chemotherapy regimens. Ongoing questions include the appropriate duration of trastuzumab treatment as well as the optimal chemotherapy regimen and sequence. The next large phase III adjuvant trial for this subset of breast cancer is an international collaboration designed to evaluate the added or alternative benefit of an oral tyrosine kinase inhibitor targeting HER2/neu as well as the epidermal growth factor receptor (EGFR), lapatinib. Other trials are investigating differences in duration. Studies in the neoadjuvant setting should help to define markers of trastuzumab and lapatinib sensitivity and resistance. Preliminary data combining trastuzumab with the antiangiogenic antibody bevacizumab is encouraging; this combination will be tested in both early stage and late stage disease. | REGULATOR |
| The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. OPINION STATEMENT: Treatment of early stage breast cancer requires a multimodality approach in order to eradicate residual cancer and prevent recurrent disease. Targeting the pathways that promote or sustain cancer cell growth and invasion is critical to the effective treatment of breast and other cancers. Overexpression of the family of HER receptors have been associated with a variety of malignancies; the first and best studied is the association of overexpression of the HER2/neu receptor with a more aggressive breast cancer phenotype and poorer survival. A humanized antibody to HER2/neu, trastuzumab, is now FDA approved for the treatment of early stage, HER2/neu overexpressing breast cancer sequenced with chemotherapy including doxorubicin, cyclophosphamide, and paclitaxel. Additional international and national studies support the significant impact of trastuzumab on both disease free and overall survival in women with this aggressive form of breast cancer. Toxicity includes a low but clear risk of congestive heart failure, and the large phase III trials have helped to determine which patients are at higher risk for this complication. Non-anthracycline containing regimens are an alternative therapy associated with reduced cardiac toxicity. Trastuzumab therapy is now the standard of care for the treatment of early stage, HER2/neu positive breast cancer given in combination with one of several chemotherapy regimens. Ongoing questions include the appropriate duration of trastuzumab treatment as well as the optimal chemotherapy regimen and sequence. The next large phase III adjuvant trial for this subset of breast cancer is an international collaboration designed to evaluate the added or alternative benefit of an oral tyrosine kinase inhibitor targeting GENE/neu as well as the epidermal growth factor receptor (EGFR), CHEMICAL. Other trials are investigating differences in duration. Studies in the neoadjuvant setting should help to define markers of trastuzumab and CHEMICAL sensitivity and resistance. Preliminary data combining trastuzumab with the antiangiogenic antibody bevacizumab is encouraging; this combination will be tested in both early stage and late stage disease. | INHIBITOR |
| The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. OPINION STATEMENT: Treatment of early stage breast cancer requires a multimodality approach in order to eradicate residual cancer and prevent recurrent disease. Targeting the pathways that promote or sustain cancer cell growth and invasion is critical to the effective treatment of breast and other cancers. Overexpression of the family of HER receptors have been associated with a variety of malignancies; the first and best studied is the association of overexpression of the HER2/neu receptor with a more aggressive breast cancer phenotype and poorer survival. A humanized antibody to HER2/neu, trastuzumab, is now FDA approved for the treatment of early stage, HER2/neu overexpressing breast cancer sequenced with chemotherapy including doxorubicin, cyclophosphamide, and paclitaxel. Additional international and national studies support the significant impact of trastuzumab on both disease free and overall survival in women with this aggressive form of breast cancer. Toxicity includes a low but clear risk of congestive heart failure, and the large phase III trials have helped to determine which patients are at higher risk for this complication. Non-anthracycline containing regimens are an alternative therapy associated with reduced cardiac toxicity. Trastuzumab therapy is now the standard of care for the treatment of early stage, HER2/neu positive breast cancer given in combination with one of several chemotherapy regimens. Ongoing questions include the appropriate duration of trastuzumab treatment as well as the optimal chemotherapy regimen and sequence. The next large phase III adjuvant trial for this subset of breast cancer is an international collaboration designed to evaluate the added or alternative benefit of an oral tyrosine kinase inhibitor targeting HER2/GENE as well as the epidermal growth factor receptor (EGFR), CHEMICAL. Other trials are investigating differences in duration. Studies in the neoadjuvant setting should help to define markers of trastuzumab and CHEMICAL sensitivity and resistance. Preliminary data combining trastuzumab with the antiangiogenic antibody bevacizumab is encouraging; this combination will be tested in both early stage and late stage disease. | INHIBITOR |
| The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. OPINION STATEMENT: Treatment of early stage breast cancer requires a multimodality approach in order to eradicate residual cancer and prevent recurrent disease. Targeting the pathways that promote or sustain cancer cell growth and invasion is critical to the effective treatment of breast and other cancers. Overexpression of the family of HER receptors have been associated with a variety of malignancies; the first and best studied is the association of overexpression of the HER2/neu receptor with a more aggressive breast cancer phenotype and poorer survival. A humanized antibody to HER2/neu, trastuzumab, is now FDA approved for the treatment of early stage, HER2/neu overexpressing breast cancer sequenced with chemotherapy including doxorubicin, cyclophosphamide, and paclitaxel. Additional international and national studies support the significant impact of trastuzumab on both disease free and overall survival in women with this aggressive form of breast cancer. Toxicity includes a low but clear risk of congestive heart failure, and the large phase III trials have helped to determine which patients are at higher risk for this complication. Non-anthracycline containing regimens are an alternative therapy associated with reduced cardiac toxicity. Trastuzumab therapy is now the standard of care for the treatment of early stage, HER2/neu positive breast cancer given in combination with one of several chemotherapy regimens. Ongoing questions include the appropriate duration of trastuzumab treatment as well as the optimal chemotherapy regimen and sequence. The next large phase III adjuvant trial for this subset of breast cancer is an international collaboration designed to evaluate the added or alternative benefit of an oral tyrosine kinase inhibitor targeting HER2/neu as well as the GENE (EGFR), CHEMICAL. Other trials are investigating differences in duration. Studies in the neoadjuvant setting should help to define markers of trastuzumab and CHEMICAL sensitivity and resistance. Preliminary data combining trastuzumab with the antiangiogenic antibody bevacizumab is encouraging; this combination will be tested in both early stage and late stage disease. | REGULATOR |
| The role of trastuzumab in early stage breast cancer: current data and treatment recommendations. OPINION STATEMENT: Treatment of early stage breast cancer requires a multimodality approach in order to eradicate residual cancer and prevent recurrent disease. Targeting the pathways that promote or sustain cancer cell growth and invasion is critical to the effective treatment of breast and other cancers. Overexpression of the family of HER receptors have been associated with a variety of malignancies; the first and best studied is the association of overexpression of the HER2/neu receptor with a more aggressive breast cancer phenotype and poorer survival. A humanized antibody to HER2/neu, trastuzumab, is now FDA approved for the treatment of early stage, HER2/neu overexpressing breast cancer sequenced with chemotherapy including doxorubicin, cyclophosphamide, and paclitaxel. Additional international and national studies support the significant impact of trastuzumab on both disease free and overall survival in women with this aggressive form of breast cancer. Toxicity includes a low but clear risk of congestive heart failure, and the large phase III trials have helped to determine which patients are at higher risk for this complication. Non-anthracycline containing regimens are an alternative therapy associated with reduced cardiac toxicity. Trastuzumab therapy is now the standard of care for the treatment of early stage, HER2/neu positive breast cancer given in combination with one of several chemotherapy regimens. Ongoing questions include the appropriate duration of trastuzumab treatment as well as the optimal chemotherapy regimen and sequence. The next large phase III adjuvant trial for this subset of breast cancer is an international collaboration designed to evaluate the added or alternative benefit of an oral tyrosine kinase inhibitor targeting HER2/neu as well as the epidermal growth factor receptor (GENE), CHEMICAL. Other trials are investigating differences in duration. Studies in the neoadjuvant setting should help to define markers of trastuzumab and CHEMICAL sensitivity and resistance. Preliminary data combining trastuzumab with the antiangiogenic antibody bevacizumab is encouraging; this combination will be tested in both early stage and late stage disease. | REGULATOR |
| Stimulation of N-methyl-D-aspartate receptors modulates Jurkat T cell growth and adhesion to GENE. The aims of this study were to investigate the expression and the functional roles of N-methyl-d-aspartate (NMDA) receptors in leukemic Jurkat T cells. RT-PCR and immunofluorescence/confocal microscopy analysis showed that Jurkat T cells express the NR1 and NR2B subunits of the NMDA receptors. Exposure of Jurkat cells to either (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]cyclohepten-5,10-imine [(+)-MK 801] or D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5), two selective NMDA receptor antagonists, limited cell growth by inhibiting cell cycle progression and inducing apoptosis, whereas CHEMICAL (1 microM) and NMDA (10 microM) significantly increased (137.2+/-22.0%; P<0.01) Jurkat T cell adhesion to GENE. In conclusion, our results demonstrate that Jurkat T cells express NMDA receptors functionally active in controlling cell growth and adhesion to GENE. | REGULATOR |
| Stimulation of N-methyl-D-aspartate receptors modulates Jurkat T cell growth and adhesion to GENE. The aims of this study were to investigate the expression and the functional roles of N-methyl-d-aspartate (NMDA) receptors in leukemic Jurkat T cells. RT-PCR and immunofluorescence/confocal microscopy analysis showed that Jurkat T cells express the NR1 and NR2B subunits of the CHEMICAL receptors. Exposure of Jurkat cells to either (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]cyclohepten-5,10-imine [(+)-MK 801] or D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5), two selective CHEMICAL receptor antagonists, limited cell growth by inhibiting cell cycle progression and inducing apoptosis, whereas l-glutamate (1 microM) and CHEMICAL (10 microM) significantly increased (137.2+/-22.0%; P<0.01) Jurkat T cell adhesion to GENE. In conclusion, our results demonstrate that Jurkat T cells express CHEMICAL receptors functionally active in controlling cell growth and adhesion to GENE. | REGULATOR |
| Stimulation of N-methyl-D-aspartate receptors modulates Jurkat T cell growth and adhesion to fibronectin. The aims of this study were to investigate the expression and the functional roles of N-methyl-d-aspartate (NMDA) receptors in leukemic Jurkat T cells. RT-PCR and immunofluorescence/confocal microscopy analysis showed that Jurkat T cells express the NR1 and NR2B subunits of the NMDA receptors. Exposure of Jurkat cells to either CHEMICAL [(+)-MK 801] or D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5), two selective GENE antagonists, limited cell growth by inhibiting cell cycle progression and inducing apoptosis, whereas l-glutamate (1 microM) and NMDA (10 microM) significantly increased (137.2+/-22.0%; P<0.01) Jurkat T cell adhesion to fibronectin. In conclusion, our results demonstrate that Jurkat T cells express NMDA receptors functionally active in controlling cell growth and adhesion to fibronectin. | INHIBITOR |
| Stimulation of N-methyl-D-aspartate receptors modulates Jurkat T cell growth and adhesion to fibronectin. The aims of this study were to investigate the expression and the functional roles of N-methyl-d-aspartate (NMDA) receptors in leukemic Jurkat T cells. RT-PCR and immunofluorescence/confocal microscopy analysis showed that Jurkat T cells express the NR1 and NR2B subunits of the NMDA receptors. Exposure of Jurkat cells to either (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]cyclohepten-5,10-imine [CHEMICAL] or D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5), two selective GENE antagonists, limited cell growth by inhibiting cell cycle progression and inducing apoptosis, whereas l-glutamate (1 microM) and NMDA (10 microM) significantly increased (137.2+/-22.0%; P<0.01) Jurkat T cell adhesion to fibronectin. In conclusion, our results demonstrate that Jurkat T cells express NMDA receptors functionally active in controlling cell growth and adhesion to fibronectin. | INHIBITOR |
| Stimulation of N-methyl-D-aspartate receptors modulates Jurkat T cell growth and adhesion to fibronectin. The aims of this study were to investigate the expression and the functional roles of N-methyl-d-aspartate (NMDA) receptors in leukemic Jurkat T cells. RT-PCR and immunofluorescence/confocal microscopy analysis showed that Jurkat T cells express the NR1 and NR2B subunits of the NMDA receptors. Exposure of Jurkat cells to either (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]cyclohepten-5,10-imine [(+)-MK 801] or CHEMICAL (D-AP5), two selective GENE antagonists, limited cell growth by inhibiting cell cycle progression and inducing apoptosis, whereas l-glutamate (1 microM) and NMDA (10 microM) significantly increased (137.2+/-22.0%; P<0.01) Jurkat T cell adhesion to fibronectin. In conclusion, our results demonstrate that Jurkat T cells express NMDA receptors functionally active in controlling cell growth and adhesion to fibronectin. | INHIBITOR |
| Stimulation of N-methyl-D-aspartate receptors modulates Jurkat T cell growth and adhesion to fibronectin. The aims of this study were to investigate the expression and the functional roles of N-methyl-d-aspartate (NMDA) receptors in leukemic Jurkat T cells. RT-PCR and immunofluorescence/confocal microscopy analysis showed that Jurkat T cells express the NR1 and NR2B subunits of the NMDA receptors. Exposure of Jurkat cells to either (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]cyclohepten-5,10-imine [(+)-MK 801] or D-(-)-2-amino-5-phosphonopentanoic acid (CHEMICAL), two selective GENE antagonists, limited cell growth by inhibiting cell cycle progression and inducing apoptosis, whereas l-glutamate (1 microM) and NMDA (10 microM) significantly increased (137.2+/-22.0%; P<0.01) Jurkat T cell adhesion to fibronectin. In conclusion, our results demonstrate that Jurkat T cells express NMDA receptors functionally active in controlling cell growth and adhesion to fibronectin. | INHIBITOR |
| Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter. Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the hNET expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using hNET in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other hNET antagonists, such as CHEMICAL, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct hNET binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in GENE selectively disrupts CHEMICAL binding but not that of DVS. | INHIBITOR |
| Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter. Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the GENE expressed in membranes compared with whole cells when competing for CHEMICAL (NIS) binding. Using GENE in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other GENE antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct GENE binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in GENE transmembrane domain 3 selectively disrupts NIS binding but not that of DVS. | DIRECT-REGULATOR |
| Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter. Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the GENE expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (CHEMICAL) binding. Using GENE in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other GENE antagonists, such as CHEMICAL, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct GENE binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in GENE transmembrane domain 3 selectively disrupts CHEMICAL binding but not that of DVS. | DIRECT-REGULATOR |
| Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter. Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of CHEMICAL (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the GENE expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using GENE in transfected human embryonic kidney-293 cells, this difference in potency for CHEMICAL at sites labeled by [(3)H]NIS was found to distinguish CHEMICAL, the CHEMICAL analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other GENE antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct GENE binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in GENE transmembrane domain 3 selectively disrupts NIS binding but not that of CHEMICAL. | DIRECT-REGULATOR |
| Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter. Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the GENE expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using GENE in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by CHEMICAL was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other GENE antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct GENE binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in GENE transmembrane domain 3 selectively disrupts NIS binding but not that of DVS. | DIRECT-REGULATOR |
| Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter. Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the GENE expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using GENE in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog CHEMICAL (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other GENE antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct GENE binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in GENE transmembrane domain 3 selectively disrupts NIS binding but not that of DVS. | INHIBITOR |
| Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter. Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the GENE expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using GENE in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (CHEMICAL), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other GENE antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct GENE binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in GENE transmembrane domain 3 selectively disrupts NIS binding but not that of DVS. | DIRECT-REGULATOR |
| Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter. Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the GENE expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using GENE in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), CHEMICAL, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other GENE antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct GENE binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in GENE transmembrane domain 3 selectively disrupts NIS binding but not that of DVS. | DIRECT-REGULATOR |
| Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter. Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the GENE expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using GENE in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the CHEMICAL analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other GENE antagonists, such as NIS, mazindol, tricyclic antidepressants, and CHEMICAL. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct GENE binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in GENE transmembrane domain 3 selectively disrupts NIS binding but not that of DVS. | INHIBITOR |
| Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter. Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the GENE expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using GENE in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog CHEMICAL (RTI-55) from other GENE antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct GENE binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in GENE transmembrane domain 3 selectively disrupts NIS binding but not that of DVS. | INHIBITOR |
| Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter. Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the GENE expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using GENE in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (CHEMICAL) from other GENE antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct GENE binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in GENE transmembrane domain 3 selectively disrupts NIS binding but not that of DVS. | INHIBITOR |
| Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter. Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the GENE expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using GENE in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other GENE antagonists, such as NIS, CHEMICAL, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct GENE binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in GENE transmembrane domain 3 selectively disrupts NIS binding but not that of DVS. | INHIBITOR |
| CHEMICAL identifies novel antagonist binding determinants in the human norepinephrine transporter. CHEMICAL (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (GENE and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the GENE expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using GENE in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other GENE antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct GENE binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in GENE transmembrane domain 3 selectively disrupts NIS binding but not that of DVS. | INHIBITOR |
| CHEMICAL identifies novel antagonist binding determinants in the human norepinephrine transporter. CHEMICAL (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and GENE, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the hNET expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using hNET in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other hNET antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct hNET binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in hNET transmembrane domain 3 selectively disrupts NIS binding but not that of DVS. | INHIBITOR |
| Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter. Desvenlafaxine succinate (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the GENE expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using GENE in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other GENE antagonists, such as NIS, mazindol, CHEMICAL antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct GENE binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in GENE transmembrane domain 3 selectively disrupts NIS binding but not that of DVS. | INHIBITOR |
| CHEMICAL identifies novel antagonist binding determinants in the GENE. CHEMICAL (DVS) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and hSERT, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of DVS (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the hNET expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using hNET in transfected human embryonic kidney-293 cells, this difference in potency for DVS at sites labeled by [(3)H]NIS was found to distinguish DVS, the DVS analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other hNET antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct hNET binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in hNET transmembrane domain 3 selectively disrupts NIS binding but not that of DVS. | INHIBITOR |
| Desvenlafaxine succinate identifies novel antagonist binding determinants in the human norepinephrine transporter. Desvenlafaxine succinate (CHEMICAL) is a recently introduced antagonist of the human norepinephrine and serotonin transporters (hNET and GENE, respectively), currently in clinical development for use in the treatment of major depressive disorder and vasomotor symptoms associated with menopause. Initial evaluation of the pharmacological properties of CHEMICAL (J Pharmacol Exp Ther 318:657-665, 2006) revealed significantly reduced potency for the hNET expressed in membranes compared with whole cells when competing for [(3)H]nisoxetine (NIS) binding. Using hNET in transfected human embryonic kidney-293 cells, this difference in potency for CHEMICAL at sites labeled by [(3)H]NIS was found to distinguish CHEMICAL, the CHEMICAL analog rac-(1-[1-(3-chloro-phenyl)-2-(4-methylpiperazin-1-yl)-ethyl]cyclohexanol (WY-46824), methylphenidate, and the cocaine analog 3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester (RTI-55) from other hNET antagonists, such as NIS, mazindol, tricyclic antidepressants, and cocaine. These differences seem not to arise from preparation-specific perturbations of ligand intrinsic affinity or antagonist-specific surface trafficking but rather from protein conformational alterations that perturb the relationships between distinct hNET binding sites. In an initial search for molecular features that differentially define antagonist binding determinants, we document that Val148 in hNET transmembrane domain 3 selectively disrupts NIS binding but not that of CHEMICAL. | INHIBITOR |
| [Lipoprotein(a): a link between thrombogenesis and atherogenesis]. INTRODUCTION: It is well known that numerous mechanisms of thrombogenesis can participate in every stage of atherosclerotic disease. The discovery of GENE lipoprotein and its structural similarity with plasminogen suggests another pathogenic link between atherogenesis and thrombogenesis. SOME CHARACTERISTICS OF LP(A) LIPOPROTEIN: This lipoprotein is present in the whole human population in a wide range of plasma concentrations. It has numerous different isoforms. Its synthesis occurs in the liver, but it is practically metabolically independent from other lipoproteins. Today, GENE lipoprotein is considered to be an independent risk factor for heart and brain ischemic disease. FIBRINOLYTIC MECHANISMS: The primary role of the fibrinolytic mechanism is to prevent thrombus Jormation during circulation and to remove already formed ones. Plasmin has a central role in this process, due to the inactive proenzyme plasminogen. Its basic activators are tissue-type plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA). The most important inhibitors of plasminogen are alpha2-antiplasmin and plasminogen activator inhibitors 1 and 2 (PA-1 and PAI-2). Structural similarity of GENE and plasminogen The apo(a) and plasminogen genes are very closely linked on the long arm of chromosome 6. Because of that they are structuraly very similar and they have a cross immunological reactivity. Their common elements are so-called "kringle" structures. The key difference in structure of GENE and plasminogen is replacement of CHEMICAL with Ser at position 560. This prevents splitting of apo(a) by plasminogen activators. LP(A) AND FIBRINOLYSIS: GENE lipoprotein inhibits activation of plasminogen by streptokinase. It is also a competitive inhibitor of plasminogen for its binding to plasminogen receptors. Furthermore, it successfully achieves competitive inhibition of plasminogen for binding to tetranectin and thrombospondin. Also, GENE inhibits activation of transforming growth factor alpha (TGF-alpha). It positively correlates with PAI-1 and it is assumed that it promotes release of tissue factor pathway inhibitor (17FPI) from endothelial cell surfaces. CONCLUSION: In regulation of the hemostatic system via apolipoprotein(a) antifibrinolytic effects, GENE lipoprotein ojfers a molecular solution to the link between thrombogenesis and atherogenesis. | PART-OF |
| [Lipoprotein(a): a link between thrombogenesis and atherogenesis]. INTRODUCTION: It is well known that numerous mechanisms of thrombogenesis can participate in every stage of atherosclerotic disease. The discovery of Lp(a) lipoprotein and its structural similarity with GENE suggests another pathogenic link between atherogenesis and thrombogenesis. SOME CHARACTERISTICS OF LP(A) LIPOPROTEIN: This lipoprotein is present in the whole human population in a wide range of plasma concentrations. It has numerous different isoforms. Its synthesis occurs in the liver, but it is practically metabolically independent from other lipoproteins. Today, Lp(a) lipoprotein is considered to be an independent risk factor for heart and brain ischemic disease. FIBRINOLYTIC MECHANISMS: The primary role of the fibrinolytic mechanism is to prevent thrombus Jormation during circulation and to remove already formed ones. Plasmin has a central role in this process, due to the inactive proenzyme GENE. Its basic activators are tissue-type GENE activator (t-PA) and urokinase GENE activator (u-PA). The most important inhibitors of GENE are alpha2-antiplasmin and GENE activator inhibitors 1 and 2 (PA-1 and PAI-2). Structural similarity of Lp(a) and GENE The apo(a) and GENE genes are very closely linked on the long arm of chromosome 6. Because of that they are structuraly very similar and they have a cross immunological reactivity. Their common elements are so-called "kringle" structures. The key difference in structure of Lp(a) and GENE is replacement of CHEMICAL with Ser at position 560. This prevents splitting of apo(a) by GENE activators. LP(A) AND FIBRINOLYSIS: Lp(a) lipoprotein inhibits activation of GENE by streptokinase. It is also a competitive inhibitor of GENE for its binding to GENE receptors. Furthermore, it successfully achieves competitive inhibition of GENE for binding to tetranectin and thrombospondin. Also, Lp(a) inhibits activation of transforming growth factor alpha (TGF-alpha). It positively correlates with PAI-1 and it is assumed that it promotes release of tissue factor pathway inhibitor (17FPI) from endothelial cell surfaces. CONCLUSION: In regulation of the hemostatic system via apolipoprotein(a) antifibrinolytic effects, Lp(a) lipoprotein ojfers a molecular solution to the link between thrombogenesis and atherogenesis. | PART-OF |
| [Lipoprotein(a): a link between thrombogenesis and atherogenesis]. INTRODUCTION: It is well known that numerous mechanisms of thrombogenesis can participate in every stage of atherosclerotic disease. The discovery of GENE lipoprotein and its structural similarity with plasminogen suggests another pathogenic link between atherogenesis and thrombogenesis. SOME CHARACTERISTICS OF LP(A) LIPOPROTEIN: This lipoprotein is present in the whole human population in a wide range of plasma concentrations. It has numerous different isoforms. Its synthesis occurs in the liver, but it is practically metabolically independent from other lipoproteins. Today, GENE lipoprotein is considered to be an independent risk factor for heart and brain ischemic disease. FIBRINOLYTIC MECHANISMS: The primary role of the fibrinolytic mechanism is to prevent thrombus Jormation during circulation and to remove already formed ones. Plasmin has a central role in this process, due to the inactive proenzyme plasminogen. Its basic activators are tissue-type plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA). The most important inhibitors of plasminogen are alpha2-antiplasmin and plasminogen activator inhibitors 1 and 2 (PA-1 and PAI-2). Structural similarity of GENE and plasminogen The apo(a) and plasminogen genes are very closely linked on the long arm of chromosome 6. Because of that they are structuraly very similar and they have a cross immunological reactivity. Their common elements are so-called "kringle" structures. The key difference in structure of GENE and plasminogen is replacement of Arg with CHEMICAL at position 560. This prevents splitting of apo(a) by plasminogen activators. LP(A) AND FIBRINOLYSIS: GENE lipoprotein inhibits activation of plasminogen by streptokinase. It is also a competitive inhibitor of plasminogen for its binding to plasminogen receptors. Furthermore, it successfully achieves competitive inhibition of plasminogen for binding to tetranectin and thrombospondin. Also, GENE inhibits activation of transforming growth factor alpha (TGF-alpha). It positively correlates with PAI-1 and it is assumed that it promotes release of tissue factor pathway inhibitor (17FPI) from endothelial cell surfaces. CONCLUSION: In regulation of the hemostatic system via apolipoprotein(a) antifibrinolytic effects, GENE lipoprotein ojfers a molecular solution to the link between thrombogenesis and atherogenesis. | PART-OF |
| [Lipoprotein(a): a link between thrombogenesis and atherogenesis]. INTRODUCTION: It is well known that numerous mechanisms of thrombogenesis can participate in every stage of atherosclerotic disease. The discovery of Lp(a) lipoprotein and its structural similarity with GENE suggests another pathogenic link between atherogenesis and thrombogenesis. SOME CHARACTERISTICS OF LP(A) LIPOPROTEIN: This lipoprotein is present in the whole human population in a wide range of plasma concentrations. It has numerous different isoforms. Its synthesis occurs in the liver, but it is practically metabolically independent from other lipoproteins. Today, Lp(a) lipoprotein is considered to be an independent risk factor for heart and brain ischemic disease. FIBRINOLYTIC MECHANISMS: The primary role of the fibrinolytic mechanism is to prevent thrombus Jormation during circulation and to remove already formed ones. Plasmin has a central role in this process, due to the inactive proenzyme GENE. Its basic activators are tissue-type GENE activator (t-PA) and urokinase GENE activator (u-PA). The most important inhibitors of GENE are alpha2-antiplasmin and GENE activator inhibitors 1 and 2 (PA-1 and PAI-2). Structural similarity of Lp(a) and GENE The apo(a) and GENE genes are very closely linked on the long arm of chromosome 6. Because of that they are structuraly very similar and they have a cross immunological reactivity. Their common elements are so-called "kringle" structures. The key difference in structure of Lp(a) and GENE is replacement of Arg with CHEMICAL at position 560. This prevents splitting of apo(a) by GENE activators. LP(A) AND FIBRINOLYSIS: Lp(a) lipoprotein inhibits activation of GENE by streptokinase. It is also a competitive inhibitor of GENE for its binding to GENE receptors. Furthermore, it successfully achieves competitive inhibition of GENE for binding to tetranectin and thrombospondin. Also, Lp(a) inhibits activation of transforming growth factor alpha (TGF-alpha). It positively correlates with PAI-1 and it is assumed that it promotes release of tissue factor pathway inhibitor (17FPI) from endothelial cell surfaces. CONCLUSION: In regulation of the hemostatic system via apolipoprotein(a) antifibrinolytic effects, Lp(a) lipoprotein ojfers a molecular solution to the link between thrombogenesis and atherogenesis. | PART-OF |
| Sunitinib, sorafenib and mTOR inhibitors in renal cancer. Understanding the alterations in cellular protein interactions and their relations to genetic mutations that cause renal cell carcinoma (RCC) provides a unique opportunity for the development of disease-specific therapy for patients with advanced forms of this disease. There is substantial evidence of an association between mutation on von Hippel-Lindau (VHL) gene and the earliest stages of tumorigenesis of RCC. The main consequence of VHL loss is the upregulation of downstream proangiogenic factors leading to highly vascular tumors. Overexpression of hypoxia inducible factor (HIF) is also caused by the mammalian target of rapamycin (mTOR), a key component of signaling pathways inside the cell, involved in cell proliferation. The inhibition of proangiogenic factors and mTOR was the main idea behind the development of new targeted agents in advanced RCC. Since December 2005, 3 targeted agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced RCC: sorafenib, sunitinib and temsirolimus. CHEMICAL and sunitinib are synthetic, orally active agents shown to directly inhibit vascular endothelial growth factor receptors -2 and -3 (GENE, VEGFR-3) and platelet-derived growth factor receptor beta (PDGFR-beta), while temsirolimus is an mTOR inhibitor. Recent clinical studies form the basis for new guidelines for the treatment of advanced RCC: sorafenib should be used as a second-line treatment, sunitinib as the first-line therapy for good and intermediate-risk patients, and temsirolimus should be considered as first-line treatment for poor-risk patients. Future approaches to targeted therapy should focus on optimizing the use of current active drugs, exploring their combinations or investigating their sequential use. In addition, it is important to define the mechanisms of resistance on their use and to further investigate biomarkers and enhance treatment efficacy for the individual patients. The development of these targeted therapies represents an exciting step forward in the treatment of advanced RCC. | INHIBITOR |
| Sunitinib, sorafenib and mTOR inhibitors in renal cancer. Understanding the alterations in cellular protein interactions and their relations to genetic mutations that cause renal cell carcinoma (RCC) provides a unique opportunity for the development of disease-specific therapy for patients with advanced forms of this disease. There is substantial evidence of an association between mutation on von Hippel-Lindau (VHL) gene and the earliest stages of tumorigenesis of RCC. The main consequence of VHL loss is the upregulation of downstream proangiogenic factors leading to highly vascular tumors. Overexpression of hypoxia inducible factor (HIF) is also caused by the mammalian target of rapamycin (mTOR), a key component of signaling pathways inside the cell, involved in cell proliferation. The inhibition of proangiogenic factors and mTOR was the main idea behind the development of new targeted agents in advanced RCC. Since December 2005, 3 targeted agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced RCC: sorafenib, sunitinib and temsirolimus. CHEMICAL and sunitinib are synthetic, orally active agents shown to directly inhibit vascular endothelial growth factor receptors -2 and -3 (VEGFR-2, GENE) and platelet-derived growth factor receptor beta (PDGFR-beta), while temsirolimus is an mTOR inhibitor. Recent clinical studies form the basis for new guidelines for the treatment of advanced RCC: sorafenib should be used as a second-line treatment, sunitinib as the first-line therapy for good and intermediate-risk patients, and temsirolimus should be considered as first-line treatment for poor-risk patients. Future approaches to targeted therapy should focus on optimizing the use of current active drugs, exploring their combinations or investigating their sequential use. In addition, it is important to define the mechanisms of resistance on their use and to further investigate biomarkers and enhance treatment efficacy for the individual patients. The development of these targeted therapies represents an exciting step forward in the treatment of advanced RCC. | INHIBITOR |
| Sunitinib, sorafenib and mTOR inhibitors in renal cancer. Understanding the alterations in cellular protein interactions and their relations to genetic mutations that cause renal cell carcinoma (RCC) provides a unique opportunity for the development of disease-specific therapy for patients with advanced forms of this disease. There is substantial evidence of an association between mutation on von Hippel-Lindau (VHL) gene and the earliest stages of tumorigenesis of RCC. The main consequence of VHL loss is the upregulation of downstream proangiogenic factors leading to highly vascular tumors. Overexpression of hypoxia inducible factor (HIF) is also caused by the mammalian target of rapamycin (mTOR), a key component of signaling pathways inside the cell, involved in cell proliferation. The inhibition of proangiogenic factors and mTOR was the main idea behind the development of new targeted agents in advanced RCC. Since December 2005, 3 targeted agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced RCC: sorafenib, sunitinib and temsirolimus. CHEMICAL and sunitinib are synthetic, orally active agents shown to directly inhibit vascular endothelial growth factor receptors -2 and -3 (VEGFR-2, VEGFR-3) and GENE (PDGFR-beta), while temsirolimus is an mTOR inhibitor. Recent clinical studies form the basis for new guidelines for the treatment of advanced RCC: sorafenib should be used as a second-line treatment, sunitinib as the first-line therapy for good and intermediate-risk patients, and temsirolimus should be considered as first-line treatment for poor-risk patients. Future approaches to targeted therapy should focus on optimizing the use of current active drugs, exploring their combinations or investigating their sequential use. In addition, it is important to define the mechanisms of resistance on their use and to further investigate biomarkers and enhance treatment efficacy for the individual patients. The development of these targeted therapies represents an exciting step forward in the treatment of advanced RCC. | INHIBITOR |
| Sunitinib, sorafenib and mTOR inhibitors in renal cancer. Understanding the alterations in cellular protein interactions and their relations to genetic mutations that cause renal cell carcinoma (RCC) provides a unique opportunity for the development of disease-specific therapy for patients with advanced forms of this disease. There is substantial evidence of an association between mutation on von Hippel-Lindau (VHL) gene and the earliest stages of tumorigenesis of RCC. The main consequence of VHL loss is the upregulation of downstream proangiogenic factors leading to highly vascular tumors. Overexpression of hypoxia inducible factor (HIF) is also caused by the mammalian target of rapamycin (mTOR), a key component of signaling pathways inside the cell, involved in cell proliferation. The inhibition of proangiogenic factors and mTOR was the main idea behind the development of new targeted agents in advanced RCC. Since December 2005, 3 targeted agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced RCC: sorafenib, sunitinib and temsirolimus. CHEMICAL and sunitinib are synthetic, orally active agents shown to directly inhibit vascular endothelial growth factor receptors -2 and -3 (VEGFR-2, VEGFR-3) and platelet-derived growth factor receptor beta (GENE), while temsirolimus is an mTOR inhibitor. Recent clinical studies form the basis for new guidelines for the treatment of advanced RCC: sorafenib should be used as a second-line treatment, sunitinib as the first-line therapy for good and intermediate-risk patients, and temsirolimus should be considered as first-line treatment for poor-risk patients. Future approaches to targeted therapy should focus on optimizing the use of current active drugs, exploring their combinations or investigating their sequential use. In addition, it is important to define the mechanisms of resistance on their use and to further investigate biomarkers and enhance treatment efficacy for the individual patients. The development of these targeted therapies represents an exciting step forward in the treatment of advanced RCC. | INHIBITOR |
| CHEMICAL, sorafenib and mTOR inhibitors in renal cancer. Understanding the alterations in cellular protein interactions and their relations to genetic mutations that cause renal cell carcinoma (RCC) provides a unique opportunity for the development of disease-specific therapy for patients with advanced forms of this disease. There is substantial evidence of an association between mutation on von Hippel-Lindau (VHL) gene and the earliest stages of tumorigenesis of RCC. The main consequence of VHL loss is the upregulation of downstream proangiogenic factors leading to highly vascular tumors. Overexpression of hypoxia inducible factor (HIF) is also caused by the mammalian target of rapamycin (mTOR), a key component of signaling pathways inside the cell, involved in cell proliferation. The inhibition of proangiogenic factors and mTOR was the main idea behind the development of new targeted agents in advanced RCC. Since December 2005, 3 targeted agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced RCC: sorafenib, CHEMICAL and temsirolimus. Sorafenib and CHEMICAL are synthetic, orally active agents shown to directly inhibit vascular endothelial growth factor receptors -2 and -3 (GENE, VEGFR-3) and platelet-derived growth factor receptor beta (PDGFR-beta), while temsirolimus is an mTOR inhibitor. Recent clinical studies form the basis for new guidelines for the treatment of advanced RCC: sorafenib should be used as a second-line treatment, CHEMICAL as the first-line therapy for good and intermediate-risk patients, and temsirolimus should be considered as first-line treatment for poor-risk patients. Future approaches to targeted therapy should focus on optimizing the use of current active drugs, exploring their combinations or investigating their sequential use. In addition, it is important to define the mechanisms of resistance on their use and to further investigate biomarkers and enhance treatment efficacy for the individual patients. The development of these targeted therapies represents an exciting step forward in the treatment of advanced RCC. | INHIBITOR |
| CHEMICAL, sorafenib and mTOR inhibitors in renal cancer. Understanding the alterations in cellular protein interactions and their relations to genetic mutations that cause renal cell carcinoma (RCC) provides a unique opportunity for the development of disease-specific therapy for patients with advanced forms of this disease. There is substantial evidence of an association between mutation on von Hippel-Lindau (VHL) gene and the earliest stages of tumorigenesis of RCC. The main consequence of VHL loss is the upregulation of downstream proangiogenic factors leading to highly vascular tumors. Overexpression of hypoxia inducible factor (HIF) is also caused by the mammalian target of rapamycin (mTOR), a key component of signaling pathways inside the cell, involved in cell proliferation. The inhibition of proangiogenic factors and mTOR was the main idea behind the development of new targeted agents in advanced RCC. Since December 2005, 3 targeted agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced RCC: sorafenib, CHEMICAL and temsirolimus. Sorafenib and CHEMICAL are synthetic, orally active agents shown to directly inhibit vascular endothelial growth factor receptors -2 and -3 (VEGFR-2, GENE) and platelet-derived growth factor receptor beta (PDGFR-beta), while temsirolimus is an mTOR inhibitor. Recent clinical studies form the basis for new guidelines for the treatment of advanced RCC: sorafenib should be used as a second-line treatment, CHEMICAL as the first-line therapy for good and intermediate-risk patients, and temsirolimus should be considered as first-line treatment for poor-risk patients. Future approaches to targeted therapy should focus on optimizing the use of current active drugs, exploring their combinations or investigating their sequential use. In addition, it is important to define the mechanisms of resistance on their use and to further investigate biomarkers and enhance treatment efficacy for the individual patients. The development of these targeted therapies represents an exciting step forward in the treatment of advanced RCC. | INHIBITOR |
| CHEMICAL, sorafenib and mTOR inhibitors in renal cancer. Understanding the alterations in cellular protein interactions and their relations to genetic mutations that cause renal cell carcinoma (RCC) provides a unique opportunity for the development of disease-specific therapy for patients with advanced forms of this disease. There is substantial evidence of an association between mutation on von Hippel-Lindau (VHL) gene and the earliest stages of tumorigenesis of RCC. The main consequence of VHL loss is the upregulation of downstream proangiogenic factors leading to highly vascular tumors. Overexpression of hypoxia inducible factor (HIF) is also caused by the mammalian target of rapamycin (mTOR), a key component of signaling pathways inside the cell, involved in cell proliferation. The inhibition of proangiogenic factors and mTOR was the main idea behind the development of new targeted agents in advanced RCC. Since December 2005, 3 targeted agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced RCC: sorafenib, CHEMICAL and temsirolimus. Sorafenib and CHEMICAL are synthetic, orally active agents shown to directly inhibit vascular endothelial growth factor receptors -2 and -3 (VEGFR-2, VEGFR-3) and GENE (PDGFR-beta), while temsirolimus is an mTOR inhibitor. Recent clinical studies form the basis for new guidelines for the treatment of advanced RCC: sorafenib should be used as a second-line treatment, CHEMICAL as the first-line therapy for good and intermediate-risk patients, and temsirolimus should be considered as first-line treatment for poor-risk patients. Future approaches to targeted therapy should focus on optimizing the use of current active drugs, exploring their combinations or investigating their sequential use. In addition, it is important to define the mechanisms of resistance on their use and to further investigate biomarkers and enhance treatment efficacy for the individual patients. The development of these targeted therapies represents an exciting step forward in the treatment of advanced RCC. | INHIBITOR |
| CHEMICAL, sorafenib and mTOR inhibitors in renal cancer. Understanding the alterations in cellular protein interactions and their relations to genetic mutations that cause renal cell carcinoma (RCC) provides a unique opportunity for the development of disease-specific therapy for patients with advanced forms of this disease. There is substantial evidence of an association between mutation on von Hippel-Lindau (VHL) gene and the earliest stages of tumorigenesis of RCC. The main consequence of VHL loss is the upregulation of downstream proangiogenic factors leading to highly vascular tumors. Overexpression of hypoxia inducible factor (HIF) is also caused by the mammalian target of rapamycin (mTOR), a key component of signaling pathways inside the cell, involved in cell proliferation. The inhibition of proangiogenic factors and mTOR was the main idea behind the development of new targeted agents in advanced RCC. Since December 2005, 3 targeted agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced RCC: sorafenib, CHEMICAL and temsirolimus. Sorafenib and CHEMICAL are synthetic, orally active agents shown to directly inhibit vascular endothelial growth factor receptors -2 and -3 (VEGFR-2, VEGFR-3) and platelet-derived growth factor receptor beta (GENE), while temsirolimus is an mTOR inhibitor. Recent clinical studies form the basis for new guidelines for the treatment of advanced RCC: sorafenib should be used as a second-line treatment, CHEMICAL as the first-line therapy for good and intermediate-risk patients, and temsirolimus should be considered as first-line treatment for poor-risk patients. Future approaches to targeted therapy should focus on optimizing the use of current active drugs, exploring their combinations or investigating their sequential use. In addition, it is important to define the mechanisms of resistance on their use and to further investigate biomarkers and enhance treatment efficacy for the individual patients. The development of these targeted therapies represents an exciting step forward in the treatment of advanced RCC. | INHIBITOR |
| Sunitinib, sorafenib and GENE inhibitors in renal cancer. Understanding the alterations in cellular protein interactions and their relations to genetic mutations that cause renal cell carcinoma (RCC) provides a unique opportunity for the development of disease-specific therapy for patients with advanced forms of this disease. There is substantial evidence of an association between mutation on von Hippel-Lindau (VHL) gene and the earliest stages of tumorigenesis of RCC. The main consequence of VHL loss is the upregulation of downstream proangiogenic factors leading to highly vascular tumors. Overexpression of hypoxia inducible factor (HIF) is also caused by the mammalian target of rapamycin (mTOR), a key component of signaling pathways inside the cell, involved in cell proliferation. The inhibition of proangiogenic factors and GENE was the main idea behind the development of new targeted agents in advanced RCC. Since December 2005, 3 targeted agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced RCC: sorafenib, sunitinib and CHEMICAL. Sorafenib and sunitinib are synthetic, orally active agents shown to directly inhibit vascular endothelial growth factor receptors -2 and -3 (VEGFR-2, VEGFR-3) and platelet-derived growth factor receptor beta (PDGFR-beta), while CHEMICAL is an GENE inhibitor. Recent clinical studies form the basis for new guidelines for the treatment of advanced RCC: sorafenib should be used as a second-line treatment, sunitinib as the first-line therapy for good and intermediate-risk patients, and CHEMICAL should be considered as first-line treatment for poor-risk patients. Future approaches to targeted therapy should focus on optimizing the use of current active drugs, exploring their combinations or investigating their sequential use. In addition, it is important to define the mechanisms of resistance on their use and to further investigate biomarkers and enhance treatment efficacy for the individual patients. The development of these targeted therapies represents an exciting step forward in the treatment of advanced RCC. | INHIBITOR |
| Management of psoriasis: the position of retinoid drugs. Oral synthetic CHEMICAL have been established as effective systemic therapy for psoriasis since their introduction for clinical use in the 1970s; a compound for topical use, tazarotene has been recently marketed. Despite the demonstrated clinical success of retinoid therapy in psoriasis, its mechanism of action has not been fully elucidated, and investigators are confronted with two paradoxes. One is that the binding of CHEMICAL to nuclear GENE (RARs) does not match their therapeutic efficacy: acitretin activates the three receptor subtypes, RAR-alpha, -beta and -gamma, without measurable receptor binding, whereas tazarotene preferentially binds to and activates RAR-beta and -gamma in preference to RAR-alpha. The other is that there is already increased formation of retinoic acid in the psoriatic lesion. Answering these questions should result in better use of these drugs in the treatment of psoriasis. Oral administration of acitretin remains one of the first therapeutic choices for severe psoriasis, particularly in association with ultraviolet light therapy, of which it may decrease the carcinogenic risk. Topical tazarotene is suitable for moderate plaque psoriasis. Its efficacy and tolerability can be enhanced by the addition of topical corticosteroids; its irritative potential is counterbalanced by a sustained therapeutic effect after the treatment is stopped. | DIRECT-REGULATOR |
| Management of psoriasis: the position of retinoid drugs. Oral synthetic CHEMICAL have been established as effective systemic therapy for psoriasis since their introduction for clinical use in the 1970s; a compound for topical use, tazarotene has been recently marketed. Despite the demonstrated clinical success of retinoid therapy in psoriasis, its mechanism of action has not been fully elucidated, and investigators are confronted with two paradoxes. One is that the binding of CHEMICAL to nuclear retinoic acid receptors (GENE) does not match their therapeutic efficacy: acitretin activates the three receptor subtypes, RAR-alpha, -beta and -gamma, without measurable receptor binding, whereas tazarotene preferentially binds to and activates RAR-beta and -gamma in preference to RAR-alpha. The other is that there is already increased formation of retinoic acid in the psoriatic lesion. Answering these questions should result in better use of these drugs in the treatment of psoriasis. Oral administration of acitretin remains one of the first therapeutic choices for severe psoriasis, particularly in association with ultraviolet light therapy, of which it may decrease the carcinogenic risk. Topical tazarotene is suitable for moderate plaque psoriasis. Its efficacy and tolerability can be enhanced by the addition of topical corticosteroids; its irritative potential is counterbalanced by a sustained therapeutic effect after the treatment is stopped. | DIRECT-REGULATOR |
| Management of psoriasis: the position of retinoid drugs. Oral synthetic retinoids have been established as effective systemic therapy for psoriasis since their introduction for clinical use in the 1970s; a compound for topical use, CHEMICAL has been recently marketed. Despite the demonstrated clinical success of retinoid therapy in psoriasis, its mechanism of action has not been fully elucidated, and investigators are confronted with two paradoxes. One is that the binding of retinoids to nuclear retinoic acid receptors (RARs) does not match their therapeutic efficacy: acitretin activates the three receptor subtypes, GENE, -beta and -gamma, without measurable receptor binding, whereas CHEMICAL preferentially binds to and activates RAR-beta and -gamma in preference to GENE. The other is that there is already increased formation of retinoic acid in the psoriatic lesion. Answering these questions should result in better use of these drugs in the treatment of psoriasis. Oral administration of acitretin remains one of the first therapeutic choices for severe psoriasis, particularly in association with ultraviolet light therapy, of which it may decrease the carcinogenic risk. Topical CHEMICAL is suitable for moderate plaque psoriasis. Its efficacy and tolerability can be enhanced by the addition of topical corticosteroids; its irritative potential is counterbalanced by a sustained therapeutic effect after the treatment is stopped. | DIRECT-REGULATOR |
| Comprehensive review of CHEMICAL, a second-generation monoamine oxidase inhibitor, for the treatment of Parkinson's disease. BACKGROUND: Inhibitors of monoamine oxidase (MAO) with selectivity and specificity for MAO type B (MAO-B) prolong the duration of action of both endogenously and exogenously derived dopamine. CHEMICAL [N-propargyl-l(R)-aminoindan] is a second-generation propargylamine pharmacophore that selectively and irreversibly inhibits brain GENE and is specifically designed for the treatment of Parkinson's disease (PD). OBJECTIVE: The aim of this study was to review the pharmacology, tolerability, and clinical efficacy of CHEMICAL in the treatment of PD. METHODS: MEDLINE (1966-April 2007), the Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts (1970-April 2007) were searched for original research and review articles published in English. The search terms were monoamine oxidase, neuroprotection, Parkinson disease, propargylamine, CHEMICAL, and selegiline. The reference lists of articles were also consulted, as was information provided by the manufacturer of CHEMICAL. RESULTS: Data from 63 clinical and laboratory studies were analyzed. Based on the results from those studies, we concluded that CHEMICAL PO QD, at the therapeutic dosage range of 0.5 to 1 rag/d, is effective and well tolerated and completely, selectively, and specifically inhibited GENE. Pharmacologically, CHEMICAL was found to be < or =10-fold more potent than selegiline and was not metabolized to amphetamine derivatives. CHEMICAL was effective both as monotherapy in early PD and as adjunctive treatment in patients with advancing PD and motor fluctuations. As monotherapy, CHEMICAL provided modest yet clinically meaningful benefit. A randomized, double-blind, placebo-controlled study found that, after 26 weeks of treatment, the adjusted effect size for total Unified Parkinson's Disease Rating Scale score was -4.20 (95% CI, -5.66 to -2.73) for CHEMICAL 1 mg/d versus placebo (P < 0.001). Preliminary long-term data from an open-label study suggest a sustained therapeutic advantage when CHEMICAL is initiated early (before the need for dopaminergic agents) rather than later. In patients with more advanced disease who received treatment with dopaminergic agents, CHEMICAL and entacapone were associated with reductions of "off" time significantly greater than placebo (-1.18 and -1.2 vs 0.4 hour; both, P < or = 0.001). CHEMICAL was well tolerated in younger (aged <;70 years) and older (aged > or =70 years) patients with early or advanced PD. Pharmacologically, CHEMICAL has the potential to augment the vasopressor effects of diet-derived tyramine (ie, the "cheese reaction"). However, clinical challenge studies of tyramine have found this unlikely to occur even with ingestion of supraphysiologic amounts of tyramine. In experimental models, CHEMICAL has been found to have neuroprotective properties that may be independent of GENE inhibition. CONCLUSIONS: Based on this review, CHEMICAL has been found to be well tolerated and effective in the treatment of early PD and as adjunctive treatment in motor fluctuations. Whether CHEMICAL is associated with clinically significant neuroprotection (ie, disease modification) in PD is the subject of ongoing clinical trials. | INHIBITOR |
| Comprehensive review of rasagiline, a second-generation monoamine oxidase inhibitor, for the treatment of Parkinson's disease. BACKGROUND: Inhibitors of monoamine oxidase (MAO) with selectivity and specificity for MAO type B (MAO-B) prolong the duration of action of both endogenously and exogenously derived dopamine. Rasagiline [CHEMICAL] is a second-generation propargylamine pharmacophore that selectively and irreversibly inhibits brain GENE and is specifically designed for the treatment of Parkinson's disease (PD). OBJECTIVE: The aim of this study was to review the pharmacology, tolerability, and clinical efficacy of rasagiline in the treatment of PD. METHODS: MEDLINE (1966-April 2007), the Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts (1970-April 2007) were searched for original research and review articles published in English. The search terms were monoamine oxidase, neuroprotection, Parkinson disease, propargylamine, rasagiline, and selegiline. The reference lists of articles were also consulted, as was information provided by the manufacturer of rasagiline. RESULTS: Data from 63 clinical and laboratory studies were analyzed. Based on the results from those studies, we concluded that rasagiline PO QD, at the therapeutic dosage range of 0.5 to 1 rag/d, is effective and well tolerated and completely, selectively, and specifically inhibited GENE. Pharmacologically, rasagiline was found to be < or =10-fold more potent than selegiline and was not metabolized to amphetamine derivatives. Rasagiline was effective both as monotherapy in early PD and as adjunctive treatment in patients with advancing PD and motor fluctuations. As monotherapy, rasagiline provided modest yet clinically meaningful benefit. A randomized, double-blind, placebo-controlled study found that, after 26 weeks of treatment, the adjusted effect size for total Unified Parkinson's Disease Rating Scale score was -4.20 (95% CI, -5.66 to -2.73) for rasagiline 1 mg/d versus placebo (P < 0.001). Preliminary long-term data from an open-label study suggest a sustained therapeutic advantage when rasagiline is initiated early (before the need for dopaminergic agents) rather than later. In patients with more advanced disease who received treatment with dopaminergic agents, rasagiline and entacapone were associated with reductions of "off" time significantly greater than placebo (-1.18 and -1.2 vs 0.4 hour; both, P < or = 0.001). Rasagiline was well tolerated in younger (aged <;70 years) and older (aged > or =70 years) patients with early or advanced PD. Pharmacologically, rasagiline has the potential to augment the vasopressor effects of diet-derived tyramine (ie, the "cheese reaction"). However, clinical challenge studies of tyramine have found this unlikely to occur even with ingestion of supraphysiologic amounts of tyramine. In experimental models, rasagiline has been found to have neuroprotective properties that may be independent of GENE inhibition. CONCLUSIONS: Based on this review, rasagiline has been found to be well tolerated and effective in the treatment of early PD and as adjunctive treatment in motor fluctuations. Whether rasagiline is associated with clinically significant neuroprotection (ie, disease modification) in PD is the subject of ongoing clinical trials. | INHIBITOR |
| Comprehensive review of rasagiline, a second-generation monoamine oxidase inhibitor, for the treatment of Parkinson's disease. BACKGROUND: Inhibitors of monoamine oxidase (MAO) with selectivity and specificity for MAO type B (MAO-B) prolong the duration of action of both endogenously and exogenously derived dopamine. Rasagiline [N-propargyl-l(R)-aminoindan] is a second-generation CHEMICAL pharmacophore that selectively and irreversibly inhibits brain GENE and is specifically designed for the treatment of Parkinson's disease (PD). OBJECTIVE: The aim of this study was to review the pharmacology, tolerability, and clinical efficacy of rasagiline in the treatment of PD. METHODS: MEDLINE (1966-April 2007), the Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts (1970-April 2007) were searched for original research and review articles published in English. The search terms were monoamine oxidase, neuroprotection, Parkinson disease, CHEMICAL, rasagiline, and selegiline. The reference lists of articles were also consulted, as was information provided by the manufacturer of rasagiline. RESULTS: Data from 63 clinical and laboratory studies were analyzed. Based on the results from those studies, we concluded that rasagiline PO QD, at the therapeutic dosage range of 0.5 to 1 rag/d, is effective and well tolerated and completely, selectively, and specifically inhibited GENE. Pharmacologically, rasagiline was found to be < or =10-fold more potent than selegiline and was not metabolized to amphetamine derivatives. Rasagiline was effective both as monotherapy in early PD and as adjunctive treatment in patients with advancing PD and motor fluctuations. As monotherapy, rasagiline provided modest yet clinically meaningful benefit. A randomized, double-blind, placebo-controlled study found that, after 26 weeks of treatment, the adjusted effect size for total Unified Parkinson's Disease Rating Scale score was -4.20 (95% CI, -5.66 to -2.73) for rasagiline 1 mg/d versus placebo (P < 0.001). Preliminary long-term data from an open-label study suggest a sustained therapeutic advantage when rasagiline is initiated early (before the need for dopaminergic agents) rather than later. In patients with more advanced disease who received treatment with dopaminergic agents, rasagiline and entacapone were associated with reductions of "off" time significantly greater than placebo (-1.18 and -1.2 vs 0.4 hour; both, P < or = 0.001). Rasagiline was well tolerated in younger (aged <;70 years) and older (aged > or =70 years) patients with early or advanced PD. Pharmacologically, rasagiline has the potential to augment the vasopressor effects of diet-derived tyramine (ie, the "cheese reaction"). However, clinical challenge studies of tyramine have found this unlikely to occur even with ingestion of supraphysiologic amounts of tyramine. In experimental models, rasagiline has been found to have neuroprotective properties that may be independent of GENE inhibition. CONCLUSIONS: Based on this review, rasagiline has been found to be well tolerated and effective in the treatment of early PD and as adjunctive treatment in motor fluctuations. Whether rasagiline is associated with clinically significant neuroprotection (ie, disease modification) in PD is the subject of ongoing clinical trials. | INHIBITOR |
| Comprehensive review of CHEMICAL, a second-generation GENE inhibitor, for the treatment of Parkinson's disease. BACKGROUND: Inhibitors of GENE (MAO) with selectivity and specificity for MAO type B (MAO-B) prolong the duration of action of both endogenously and exogenously derived dopamine. CHEMICAL [N-propargyl-l(R)-aminoindan] is a second-generation propargylamine pharmacophore that selectively and irreversibly inhibits brain MAO-B and is specifically designed for the treatment of Parkinson's disease (PD). OBJECTIVE: The aim of this study was to review the pharmacology, tolerability, and clinical efficacy of CHEMICAL in the treatment of PD. METHODS: MEDLINE (1966-April 2007), the Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts (1970-April 2007) were searched for original research and review articles published in English. The search terms were GENE, neuroprotection, Parkinson disease, propargylamine, CHEMICAL, and selegiline. The reference lists of articles were also consulted, as was information provided by the manufacturer of CHEMICAL. RESULTS: Data from 63 clinical and laboratory studies were analyzed. Based on the results from those studies, we concluded that CHEMICAL PO QD, at the therapeutic dosage range of 0.5 to 1 rag/d, is effective and well tolerated and completely, selectively, and specifically inhibited MAO-B. Pharmacologically, CHEMICAL was found to be < or =10-fold more potent than selegiline and was not metabolized to amphetamine derivatives. CHEMICAL was effective both as monotherapy in early PD and as adjunctive treatment in patients with advancing PD and motor fluctuations. As monotherapy, CHEMICAL provided modest yet clinically meaningful benefit. A randomized, double-blind, placebo-controlled study found that, after 26 weeks of treatment, the adjusted effect size for total Unified Parkinson's Disease Rating Scale score was -4.20 (95% CI, -5.66 to -2.73) for CHEMICAL 1 mg/d versus placebo (P < 0.001). Preliminary long-term data from an open-label study suggest a sustained therapeutic advantage when CHEMICAL is initiated early (before the need for dopaminergic agents) rather than later. In patients with more advanced disease who received treatment with dopaminergic agents, CHEMICAL and entacapone were associated with reductions of "off" time significantly greater than placebo (-1.18 and -1.2 vs 0.4 hour; both, P < or = 0.001). CHEMICAL was well tolerated in younger (aged <;70 years) and older (aged > or =70 years) patients with early or advanced PD. Pharmacologically, CHEMICAL has the potential to augment the vasopressor effects of diet-derived tyramine (ie, the "cheese reaction"). However, clinical challenge studies of tyramine have found this unlikely to occur even with ingestion of supraphysiologic amounts of tyramine. In experimental models, CHEMICAL has been found to have neuroprotective properties that may be independent of MAO-B inhibition. CONCLUSIONS: Based on this review, CHEMICAL has been found to be well tolerated and effective in the treatment of early PD and as adjunctive treatment in motor fluctuations. Whether CHEMICAL is associated with clinically significant neuroprotection (ie, disease modification) in PD is the subject of ongoing clinical trials. | INHIBITOR |
| Mutation of Gly721 alters DNA topoisomerase I active site architecture and sensitivity to camptothecin. DNA topoisomerase I (Top1p) catalyzes the relaxation of supercoiled DNA via a concerted mechanism of DNA strand cleavage and religation. GENE is the cellular target of the anti-cancer drug camptothecin (CPT), which reversibly stabilizes a covalent enzyme-DNA intermediate. GENE clamps around duplex DNA, wherein the core and C-terminal domains are connected by extended alpha-helices (linker domain), which position the active site Tyr of the C-terminal domain within the catalytic pocket. The physical connection of the linker with the GENE clamp as well as linker flexibility affect enzyme sensitivity to CPT. Crystallographic data reveal that a conserved CHEMICAL residue (located at the juncture between the linker and C-terminal domains) is at one end of a short alpha-helix, which extends to the active site Tyr covalently linked to the DNA. In the presence of drug, the linker is rigid and this alpha-helix extends to include CHEMICAL and the preceding Leu. We report that mutation of this conserved CHEMICAL in yeast GENE alters enzyme sensitivity to CPT. Mutating CHEMICAL to Asp, Glu, Asn, Gln, Leu, or Ala enhanced enzyme CPT sensitivity, with the acidic residues inducing the greatest increase in drug sensitivity in vivo and in vitro. By contrast, Val or Phe substituents rendered the enzyme CPT-resistant. Mutation-induced alterations in enzyme architecture preceding the active site Tyr suggest these structural transitions modulate enzyme sensitivity to CPT, while enhancing the rate of DNA cleavage. We postulate that this conserved CHEMICAL residue provides a flexible hinge within the GENE catalytic pocket to facilitate linker dynamics and the structural alterations that accompany drug binding of the covalent enzyme-DNA intermediate. | PART-OF |
| Mutation of Gly721 alters DNA topoisomerase I active site architecture and sensitivity to camptothecin. DNA topoisomerase I (Top1p) catalyzes the relaxation of supercoiled DNA via a concerted mechanism of DNA strand cleavage and religation. GENE is the cellular target of the anti-cancer drug camptothecin (CPT), which reversibly stabilizes a covalent enzyme-DNA intermediate. GENE clamps around duplex DNA, wherein the core and CHEMICAL-terminal domains are connected by extended alpha-helices (linker domain), which position the active site Tyr of the C-terminal domain within the catalytic pocket. The physical connection of the linker with the GENE clamp as well as linker flexibility affect enzyme sensitivity to CPT. Crystallographic data reveal that a conserved Gly residue (located at the juncture between the linker and C-terminal domains) is at one end of a short alpha-helix, which extends to the active site Tyr covalently linked to the DNA. In the presence of drug, the linker is rigid and this alpha-helix extends to include Gly and the preceding Leu. We report that mutation of this conserved Gly in yeast GENE alters enzyme sensitivity to CPT. Mutating Gly to Asp, Glu, Asn, Gln, Leu, or Ala enhanced enzyme CPT sensitivity, with the acidic residues inducing the greatest increase in drug sensitivity in vivo and in vitro. By contrast, Val or Phe substituents rendered the enzyme CPT-resistant. Mutation-induced alterations in enzyme architecture preceding the active site Tyr suggest these structural transitions modulate enzyme sensitivity to CPT, while enhancing the rate of DNA cleavage. We postulate that this conserved Gly residue provides a flexible hinge within the GENE catalytic pocket to facilitate linker dynamics and the structural alterations that accompany drug binding of the covalent enzyme-DNA intermediate. | PART-OF |
| Mutation of Gly721 alters DNA topoisomerase I active site architecture and sensitivity to camptothecin. DNA topoisomerase I (Top1p) catalyzes the relaxation of supercoiled DNA via a concerted mechanism of DNA strand cleavage and religation. Top1p is the cellular target of the anti-cancer drug camptothecin (CPT), which reversibly stabilizes a covalent enzyme-DNA intermediate. Top1p clamps around duplex DNA, wherein the core and CHEMICAL-terminal domains are connected by extended GENE (linker domain), which position the active site Tyr of the C-terminal domain within the catalytic pocket. The physical connection of the linker with the Top1p clamp as well as linker flexibility affect enzyme sensitivity to CPT. Crystallographic data reveal that a conserved Gly residue (located at the juncture between the linker and C-terminal domains) is at one end of a short alpha-helix, which extends to the active site Tyr covalently linked to the DNA. In the presence of drug, the linker is rigid and this alpha-helix extends to include Gly and the preceding Leu. We report that mutation of this conserved Gly in yeast Top1p alters enzyme sensitivity to CPT. Mutating Gly to Asp, Glu, Asn, Gln, Leu, or Ala enhanced enzyme CPT sensitivity, with the acidic residues inducing the greatest increase in drug sensitivity in vivo and in vitro. By contrast, Val or Phe substituents rendered the enzyme CPT-resistant. Mutation-induced alterations in enzyme architecture preceding the active site Tyr suggest these structural transitions modulate enzyme sensitivity to CPT, while enhancing the rate of DNA cleavage. We postulate that this conserved Gly residue provides a flexible hinge within the Top1p catalytic pocket to facilitate linker dynamics and the structural alterations that accompany drug binding of the covalent enzyme-DNA intermediate. | PART-OF |
| Mutation of Gly721 alters DNA topoisomerase I active site architecture and sensitivity to camptothecin. DNA topoisomerase I (Top1p) catalyzes the relaxation of supercoiled DNA via a concerted mechanism of DNA strand cleavage and religation. Top1p is the cellular target of the anti-cancer drug camptothecin (CPT), which reversibly stabilizes a covalent enzyme-DNA intermediate. Top1p clamps around duplex DNA, wherein the core and CHEMICAL-terminal domains are connected by extended alpha-helices (GENE), which position the active site Tyr of the C-terminal domain within the catalytic pocket. The physical connection of the linker with the Top1p clamp as well as linker flexibility affect enzyme sensitivity to CPT. Crystallographic data reveal that a conserved Gly residue (located at the juncture between the linker and C-terminal domains) is at one end of a short alpha-helix, which extends to the active site Tyr covalently linked to the DNA. In the presence of drug, the linker is rigid and this alpha-helix extends to include Gly and the preceding Leu. We report that mutation of this conserved Gly in yeast Top1p alters enzyme sensitivity to CPT. Mutating Gly to Asp, Glu, Asn, Gln, Leu, or Ala enhanced enzyme CPT sensitivity, with the acidic residues inducing the greatest increase in drug sensitivity in vivo and in vitro. By contrast, Val or Phe substituents rendered the enzyme CPT-resistant. Mutation-induced alterations in enzyme architecture preceding the active site Tyr suggest these structural transitions modulate enzyme sensitivity to CPT, while enhancing the rate of DNA cleavage. We postulate that this conserved Gly residue provides a flexible hinge within the Top1p catalytic pocket to facilitate linker dynamics and the structural alterations that accompany drug binding of the covalent enzyme-DNA intermediate. | PART-OF |
| Mutation of Gly721 alters DNA topoisomerase I active site architecture and sensitivity to camptothecin. DNA topoisomerase I (Top1p) catalyzes the relaxation of supercoiled DNA via a concerted mechanism of DNA strand cleavage and religation. Top1p is the cellular target of the anti-cancer drug camptothecin (CPT), which reversibly stabilizes a covalent enzyme-DNA intermediate. Top1p clamps around duplex DNA, wherein the core and C-terminal domains are connected by extended alpha-helices (linker domain), which position the active site Tyr of the C-terminal domain within the catalytic pocket. The physical connection of the linker with the Top1p clamp as well as linker flexibility affect enzyme sensitivity to CPT. Crystallographic data reveal that a conserved CHEMICAL residue (located at the juncture between the linker and C-terminal domains) is at one end of a short alpha-helix, which extends to the active site Tyr covalently linked to the DNA. In the presence of drug, the linker is rigid and this alpha-helix extends to include CHEMICAL and the preceding Leu. We report that mutation of this conserved CHEMICAL in GENE alters enzyme sensitivity to CPT. Mutating CHEMICAL to Asp, Glu, Asn, Gln, Leu, or Ala enhanced enzyme CPT sensitivity, with the acidic residues inducing the greatest increase in drug sensitivity in vivo and in vitro. By contrast, Val or Phe substituents rendered the enzyme CPT-resistant. Mutation-induced alterations in enzyme architecture preceding the active site Tyr suggest these structural transitions modulate enzyme sensitivity to CPT, while enhancing the rate of DNA cleavage. We postulate that this conserved CHEMICAL residue provides a flexible hinge within the Top1p catalytic pocket to facilitate linker dynamics and the structural alterations that accompany drug binding of the covalent enzyme-DNA intermediate. | PART-OF |
| Mutation of Gly721 alters DNA topoisomerase I active site architecture and sensitivity to camptothecin. DNA topoisomerase I (Top1p) catalyzes the relaxation of supercoiled DNA via a concerted mechanism of DNA strand cleavage and religation. GENE is the cellular target of the anti-cancer drug camptothecin (CPT), which reversibly stabilizes a covalent enzyme-DNA intermediate. GENE clamps around duplex DNA, wherein the core and C-terminal domains are connected by extended alpha-helices (linker domain), which position the active site CHEMICAL of the C-terminal domain within the catalytic pocket. The physical connection of the linker with the GENE clamp as well as linker flexibility affect enzyme sensitivity to CPT. Crystallographic data reveal that a conserved Gly residue (located at the juncture between the linker and C-terminal domains) is at one end of a short alpha-helix, which extends to the active site CHEMICAL covalently linked to the DNA. In the presence of drug, the linker is rigid and this alpha-helix extends to include Gly and the preceding Leu. We report that mutation of this conserved Gly in yeast GENE alters enzyme sensitivity to CPT. Mutating Gly to Asp, Glu, Asn, Gln, Leu, or Ala enhanced enzyme CPT sensitivity, with the acidic residues inducing the greatest increase in drug sensitivity in vivo and in vitro. By contrast, Val or Phe substituents rendered the enzyme CPT-resistant. Mutation-induced alterations in enzyme architecture preceding the active site CHEMICAL suggest these structural transitions modulate enzyme sensitivity to CPT, while enhancing the rate of DNA cleavage. We postulate that this conserved Gly residue provides a flexible hinge within the GENE catalytic pocket to facilitate linker dynamics and the structural alterations that accompany drug binding of the covalent enzyme-DNA intermediate. | PART-OF |
| Mutation of Gly721 alters DNA topoisomerase I active site architecture and sensitivity to camptothecin. DNA topoisomerase I (Top1p) catalyzes the relaxation of supercoiled DNA via a concerted mechanism of DNA strand cleavage and religation. Top1p is the cellular target of the anti-cancer drug camptothecin (CPT), which reversibly stabilizes a covalent enzyme-DNA intermediate. Top1p clamps around duplex DNA, wherein the core and C-terminal domains are connected by extended GENE (linker domain), which position the active site CHEMICAL of the C-terminal domain within the catalytic pocket. The physical connection of the linker with the Top1p clamp as well as linker flexibility affect enzyme sensitivity to CPT. Crystallographic data reveal that a conserved Gly residue (located at the juncture between the linker and C-terminal domains) is at one end of a short alpha-helix, which extends to the active site CHEMICAL covalently linked to the DNA. In the presence of drug, the linker is rigid and this alpha-helix extends to include Gly and the preceding Leu. We report that mutation of this conserved Gly in yeast Top1p alters enzyme sensitivity to CPT. Mutating Gly to Asp, Glu, Asn, Gln, Leu, or Ala enhanced enzyme CPT sensitivity, with the acidic residues inducing the greatest increase in drug sensitivity in vivo and in vitro. By contrast, Val or Phe substituents rendered the enzyme CPT-resistant. Mutation-induced alterations in enzyme architecture preceding the active site CHEMICAL suggest these structural transitions modulate enzyme sensitivity to CPT, while enhancing the rate of DNA cleavage. We postulate that this conserved Gly residue provides a flexible hinge within the Top1p catalytic pocket to facilitate linker dynamics and the structural alterations that accompany drug binding of the covalent enzyme-DNA intermediate. | PART-OF |
| Mutation of Gly721 alters DNA topoisomerase I active site architecture and sensitivity to camptothecin. DNA topoisomerase I (Top1p) catalyzes the relaxation of supercoiled DNA via a concerted mechanism of DNA strand cleavage and religation. Top1p is the cellular target of the anti-cancer drug camptothecin (CPT), which reversibly stabilizes a covalent enzyme-DNA intermediate. Top1p clamps around duplex DNA, wherein the core and C-terminal domains are connected by extended alpha-helices (linker domain), which position the active site Tyr of the C-terminal domain within the catalytic pocket. The physical connection of the linker with the Top1p clamp as well as linker flexibility affect enzyme sensitivity to CPT. Crystallographic data reveal that a conserved CHEMICAL residue (located at the juncture between the linker and C-terminal domains) is at one end of a short GENE, which extends to the active site Tyr covalently linked to the DNA. In the presence of drug, the linker is rigid and this GENE extends to include CHEMICAL and the preceding Leu. We report that mutation of this conserved CHEMICAL in yeast Top1p alters enzyme sensitivity to CPT. Mutating CHEMICAL to Asp, Glu, Asn, Gln, Leu, or Ala enhanced enzyme CPT sensitivity, with the acidic residues inducing the greatest increase in drug sensitivity in vivo and in vitro. By contrast, Val or Phe substituents rendered the enzyme CPT-resistant. Mutation-induced alterations in enzyme architecture preceding the active site Tyr suggest these structural transitions modulate enzyme sensitivity to CPT, while enhancing the rate of DNA cleavage. We postulate that this conserved CHEMICAL residue provides a flexible hinge within the Top1p catalytic pocket to facilitate linker dynamics and the structural alterations that accompany drug binding of the covalent enzyme-DNA intermediate. | PART-OF |
| Mutation of Gly721 alters DNA topoisomerase I active site architecture and sensitivity to camptothecin. DNA topoisomerase I (Top1p) catalyzes the relaxation of supercoiled DNA via a concerted mechanism of DNA strand cleavage and religation. Top1p is the cellular target of the anti-cancer drug camptothecin (CPT), which reversibly stabilizes a covalent enzyme-DNA intermediate. Top1p clamps around duplex DNA, wherein the core and C-terminal domains are connected by extended alpha-helices (linker domain), which position the active site Tyr of the C-terminal domain within the catalytic pocket. The physical connection of the linker with the Top1p clamp as well as linker flexibility affect enzyme sensitivity to CPT. Crystallographic data reveal that a conserved Gly residue (located at the juncture between the linker and CHEMICAL-terminal domains) is at one end of a short GENE, which extends to the active site Tyr covalently linked to the DNA. In the presence of drug, the linker is rigid and this GENE extends to include Gly and the preceding Leu. We report that mutation of this conserved Gly in yeast Top1p alters enzyme sensitivity to CPT. Mutating Gly to Asp, Glu, Asn, Gln, Leu, or Ala enhanced enzyme CPT sensitivity, with the acidic residues inducing the greatest increase in drug sensitivity in vivo and in vitro. By contrast, Val or Phe substituents rendered the enzyme CPT-resistant. Mutation-induced alterations in enzyme architecture preceding the active site Tyr suggest these structural transitions modulate enzyme sensitivity to CPT, while enhancing the rate of DNA cleavage. We postulate that this conserved Gly residue provides a flexible hinge within the Top1p catalytic pocket to facilitate linker dynamics and the structural alterations that accompany drug binding of the covalent enzyme-DNA intermediate. | PART-OF |
| Mutation of Gly721 alters DNA topoisomerase I active site architecture and sensitivity to camptothecin. DNA topoisomerase I (Top1p) catalyzes the relaxation of supercoiled DNA via a concerted mechanism of DNA strand cleavage and religation. Top1p is the cellular target of the anti-cancer drug camptothecin (CPT), which reversibly stabilizes a covalent enzyme-DNA intermediate. Top1p clamps around duplex DNA, wherein the core and C-terminal domains are connected by extended alpha-helices (linker domain), which position the active site CHEMICAL of the C-terminal domain within the catalytic pocket. The physical connection of the linker with the Top1p clamp as well as linker flexibility affect enzyme sensitivity to CPT. Crystallographic data reveal that a conserved Gly residue (located at the juncture between the linker and C-terminal domains) is at one end of a short GENE, which extends to the active site CHEMICAL covalently linked to the DNA. In the presence of drug, the linker is rigid and this GENE extends to include Gly and the preceding Leu. We report that mutation of this conserved Gly in yeast Top1p alters enzyme sensitivity to CPT. Mutating Gly to Asp, Glu, Asn, Gln, Leu, or Ala enhanced enzyme CPT sensitivity, with the acidic residues inducing the greatest increase in drug sensitivity in vivo and in vitro. By contrast, Val or Phe substituents rendered the enzyme CPT-resistant. Mutation-induced alterations in enzyme architecture preceding the active site CHEMICAL suggest these structural transitions modulate enzyme sensitivity to CPT, while enhancing the rate of DNA cleavage. We postulate that this conserved Gly residue provides a flexible hinge within the Top1p catalytic pocket to facilitate linker dynamics and the structural alterations that accompany drug binding of the covalent enzyme-DNA intermediate. | PART-OF |
| Mutation of Gly721 alters DNA topoisomerase I active site architecture and sensitivity to camptothecin. DNA topoisomerase I (Top1p) catalyzes the relaxation of supercoiled DNA via a concerted mechanism of DNA strand cleavage and religation. Top1p is the cellular target of the anti-cancer drug camptothecin (CPT), which reversibly stabilizes a covalent enzyme-DNA intermediate. Top1p clamps around duplex DNA, wherein the core and C-terminal domains are connected by extended alpha-helices (linker domain), which position the active site Tyr of the C-terminal domain within the catalytic pocket. The physical connection of the linker with the Top1p clamp as well as linker flexibility affect enzyme sensitivity to CPT. Crystallographic data reveal that a conserved Gly residue (located at the juncture between the linker and C-terminal domains) is at one end of a short GENE, which extends to the active site Tyr covalently linked to the DNA. In the presence of drug, the linker is rigid and this GENE extends to include Gly and the preceding CHEMICAL. We report that mutation of this conserved Gly in yeast Top1p alters enzyme sensitivity to CPT. Mutating Gly to Asp, Glu, Asn, Gln, CHEMICAL, or Ala enhanced enzyme CPT sensitivity, with the acidic residues inducing the greatest increase in drug sensitivity in vivo and in vitro. By contrast, Val or Phe substituents rendered the enzyme CPT-resistant. Mutation-induced alterations in enzyme architecture preceding the active site Tyr suggest these structural transitions modulate enzyme sensitivity to CPT, while enhancing the rate of DNA cleavage. We postulate that this conserved Gly residue provides a flexible hinge within the Top1p catalytic pocket to facilitate linker dynamics and the structural alterations that accompany drug binding of the covalent enzyme-DNA intermediate. | PART-OF |
| Mutation of Gly721 alters DNA topoisomerase I active site architecture and sensitivity to CHEMICAL. DNA topoisomerase I (Top1p) catalyzes the relaxation of supercoiled DNA via a concerted mechanism of DNA strand cleavage and religation. GENE is the cellular target of the anti-cancer drug CHEMICAL (CPT), which reversibly stabilizes a covalent enzyme-DNA intermediate. GENE clamps around duplex DNA, wherein the core and C-terminal domains are connected by extended alpha-helices (linker domain), which position the active site Tyr of the C-terminal domain within the catalytic pocket. The physical connection of the linker with the GENE clamp as well as linker flexibility affect enzyme sensitivity to CPT. Crystallographic data reveal that a conserved Gly residue (located at the juncture between the linker and C-terminal domains) is at one end of a short alpha-helix, which extends to the active site Tyr covalently linked to the DNA. In the presence of drug, the linker is rigid and this alpha-helix extends to include Gly and the preceding Leu. We report that mutation of this conserved Gly in yeast GENE alters enzyme sensitivity to CPT. Mutating Gly to Asp, Glu, Asn, Gln, Leu, or Ala enhanced enzyme CPT sensitivity, with the acidic residues inducing the greatest increase in drug sensitivity in vivo and in vitro. By contrast, Val or Phe substituents rendered the enzyme CPT-resistant. Mutation-induced alterations in enzyme architecture preceding the active site Tyr suggest these structural transitions modulate enzyme sensitivity to CPT, while enhancing the rate of DNA cleavage. We postulate that this conserved Gly residue provides a flexible hinge within the GENE catalytic pocket to facilitate linker dynamics and the structural alterations that accompany drug binding of the covalent enzyme-DNA intermediate. | REGULATOR |
| Mutation of Gly721 alters DNA topoisomerase I active site architecture and sensitivity to camptothecin. DNA topoisomerase I (Top1p) catalyzes the relaxation of supercoiled DNA via a concerted mechanism of DNA strand cleavage and religation. GENE is the cellular target of the anti-cancer drug camptothecin (CHEMICAL), which reversibly stabilizes a covalent enzyme-DNA intermediate. GENE clamps around duplex DNA, wherein the core and C-terminal domains are connected by extended alpha-helices (linker domain), which position the active site Tyr of the C-terminal domain within the catalytic pocket. The physical connection of the linker with the GENE clamp as well as linker flexibility affect enzyme sensitivity to CHEMICAL. Crystallographic data reveal that a conserved Gly residue (located at the juncture between the linker and C-terminal domains) is at one end of a short alpha-helix, which extends to the active site Tyr covalently linked to the DNA. In the presence of drug, the linker is rigid and this alpha-helix extends to include Gly and the preceding Leu. We report that mutation of this conserved Gly in yeast GENE alters enzyme sensitivity to CHEMICAL. Mutating Gly to Asp, Glu, Asn, Gln, Leu, or Ala enhanced enzyme CHEMICAL sensitivity, with the acidic residues inducing the greatest increase in drug sensitivity in vivo and in vitro. By contrast, Val or Phe substituents rendered the enzyme CPT-resistant. Mutation-induced alterations in enzyme architecture preceding the active site Tyr suggest these structural transitions modulate enzyme sensitivity to CHEMICAL, while enhancing the rate of DNA cleavage. We postulate that this conserved Gly residue provides a flexible hinge within the GENE catalytic pocket to facilitate linker dynamics and the structural alterations that accompany drug binding of the covalent enzyme-DNA intermediate. | REGULATOR |
| Mutation of Gly721 alters GENE active site architecture and sensitivity to CHEMICAL. GENE (Top1p) catalyzes the relaxation of supercoiled DNA via a concerted mechanism of DNA strand cleavage and religation. Top1p is the cellular target of the anti-cancer drug CHEMICAL (CPT), which reversibly stabilizes a covalent enzyme-DNA intermediate. Top1p clamps around duplex DNA, wherein the core and C-terminal domains are connected by extended alpha-helices (linker domain), which position the active site Tyr of the C-terminal domain within the catalytic pocket. The physical connection of the linker with the Top1p clamp as well as linker flexibility affect enzyme sensitivity to CPT. Crystallographic data reveal that a conserved Gly residue (located at the juncture between the linker and C-terminal domains) is at one end of a short alpha-helix, which extends to the active site Tyr covalently linked to the DNA. In the presence of drug, the linker is rigid and this alpha-helix extends to include Gly and the preceding Leu. We report that mutation of this conserved Gly in yeast Top1p alters enzyme sensitivity to CPT. Mutating Gly to Asp, Glu, Asn, Gln, Leu, or Ala enhanced enzyme CPT sensitivity, with the acidic residues inducing the greatest increase in drug sensitivity in vivo and in vitro. By contrast, Val or Phe substituents rendered the enzyme CPT-resistant. Mutation-induced alterations in enzyme architecture preceding the active site Tyr suggest these structural transitions modulate enzyme sensitivity to CPT, while enhancing the rate of DNA cleavage. We postulate that this conserved Gly residue provides a flexible hinge within the Top1p catalytic pocket to facilitate linker dynamics and the structural alterations that accompany drug binding of the covalent enzyme-DNA intermediate. | REGULATOR |
| Mutation of Gly721 alters DNA topoisomerase I active site architecture and sensitivity to camptothecin. DNA topoisomerase I (Top1p) catalyzes the relaxation of supercoiled DNA via a concerted mechanism of DNA strand cleavage and religation. Top1p is the cellular target of the anti-cancer drug camptothecin (CPT), which reversibly stabilizes a covalent enzyme-DNA intermediate. Top1p clamps around duplex DNA, wherein the core and C-terminal domains are connected by extended alpha-helices (linker domain), which position the active site Tyr of the C-terminal domain within the catalytic pocket. The physical connection of the linker with the Top1p clamp as well as linker flexibility affect enzyme sensitivity to CHEMICAL. Crystallographic data reveal that a conserved Gly residue (located at the juncture between the linker and C-terminal domains) is at one end of a short alpha-helix, which extends to the active site Tyr covalently linked to the DNA. In the presence of drug, the linker is rigid and this alpha-helix extends to include Gly and the preceding Leu. We report that mutation of this conserved Gly in GENE alters enzyme sensitivity to CHEMICAL. Mutating Gly to Asp, Glu, Asn, Gln, Leu, or Ala enhanced enzyme CHEMICAL sensitivity, with the acidic residues inducing the greatest increase in drug sensitivity in vivo and in vitro. By contrast, Val or Phe substituents rendered the enzyme CPT-resistant. Mutation-induced alterations in enzyme architecture preceding the active site Tyr suggest these structural transitions modulate enzyme sensitivity to CHEMICAL, while enhancing the rate of DNA cleavage. We postulate that this conserved Gly residue provides a flexible hinge within the Top1p catalytic pocket to facilitate linker dynamics and the structural alterations that accompany drug binding of the covalent enzyme-DNA intermediate. | REGULATOR |
| Characterization of the substrate mimic bound to engineered prostacyclin synthase in solution using high-resolution NMR spectroscopy and mutagenesis: implication of the molecular mechanism in biosynthesis of prostacyclin. High-resolution NMR spectroscopy was used to determine the docking of a substrate (prostaglandin H2) mimic (U46619) to the engineered prostacyclin (PGI2) synthase (PGIS) in solution. The binding of U46619 to the GENE protein was demonstrated by 1D NMR titration, and the significant perturbation of the chemical shifts of protons at CHEMICAL, H2C, and H20 of U46619 were observed upon U46619 binding to the engineered GENE in a concentration-dependent manner. The detailed conformational change and 3D structure of the PGIS-bound U46619 were further demonstrated by 2D 1H NMR experiments using the transferred NOE technique. The distances between the protons H20 and H2, H18 and H2, and H18 and H4 are shorter following their binding to the GENE in solution-down to within 5 A. These shorter distances resulted in a widely open conformation, where the triangle shape of the unbound U46619 changed to a more compact conformation with an oval shape. The bound conformation of U46619 fits the crystal structure of the GENE substrate binding pocket considerably better than that of the unbound U46619. The residues important to the substrate binding in the active site pocket of GENE were also predicted. For example, Trp282 could be one of the most important residues and is suspected to play a role in the determination of specific catalytic function, which has been established by the docking studies using the NMR structure of the PGIS-bound form of U46619 and the GENE crystal structure. These studies have provided the structural information for the interaction of the GENE with its substrate mimic. The noted conformational changes where the C-6 position is closer to the C-9 position of U46619 provided the first experimental data for understanding the molecular mechanism of the catalytic function of GENE in the isomerization of PGH2 to prostacyclin. | PART-OF |
| Characterization of the substrate mimic bound to engineered prostacyclin synthase in solution using high-resolution NMR spectroscopy and mutagenesis: implication of the molecular mechanism in biosynthesis of prostacyclin. High-resolution NMR spectroscopy was used to determine the docking of a substrate (prostaglandin H2) mimic (U46619) to the engineered prostacyclin (PGI2) synthase (PGIS) in solution. The binding of U46619 to the GENE protein was demonstrated by 1D NMR titration, and the significant perturbation of the chemical shifts of protons at C-11, CHEMICAL, and H20 of U46619 were observed upon U46619 binding to the engineered GENE in a concentration-dependent manner. The detailed conformational change and 3D structure of the PGIS-bound U46619 were further demonstrated by 2D 1H NMR experiments using the transferred NOE technique. The distances between the protons H20 and H2, H18 and H2, and H18 and H4 are shorter following their binding to the GENE in solution-down to within 5 A. These shorter distances resulted in a widely open conformation, where the triangle shape of the unbound U46619 changed to a more compact conformation with an oval shape. The bound conformation of U46619 fits the crystal structure of the GENE substrate binding pocket considerably better than that of the unbound U46619. The residues important to the substrate binding in the active site pocket of GENE were also predicted. For example, Trp282 could be one of the most important residues and is suspected to play a role in the determination of specific catalytic function, which has been established by the docking studies using the NMR structure of the PGIS-bound form of U46619 and the GENE crystal structure. These studies have provided the structural information for the interaction of the GENE with its substrate mimic. The noted conformational changes where the C-6 position is closer to the C-9 position of U46619 provided the first experimental data for understanding the molecular mechanism of the catalytic function of GENE in the isomerization of PGH2 to prostacyclin. | PART-OF |
| Characterization of the substrate mimic bound to engineered prostacyclin synthase in solution using high-resolution NMR spectroscopy and mutagenesis: implication of the molecular mechanism in biosynthesis of prostacyclin. High-resolution NMR spectroscopy was used to determine the docking of a substrate (prostaglandin H2) mimic (U46619) to the engineered prostacyclin (PGI2) synthase (PGIS) in solution. The binding of U46619 to the GENE protein was demonstrated by 1D NMR titration, and the significant perturbation of the chemical shifts of protons at C-11, H2C, and CHEMICAL of U46619 were observed upon U46619 binding to the engineered GENE in a concentration-dependent manner. The detailed conformational change and 3D structure of the PGIS-bound U46619 were further demonstrated by 2D 1H NMR experiments using the transferred NOE technique. The distances between the protons CHEMICAL and H2, H18 and H2, and H18 and H4 are shorter following their binding to the GENE in solution-down to within 5 A. These shorter distances resulted in a widely open conformation, where the triangle shape of the unbound U46619 changed to a more compact conformation with an oval shape. The bound conformation of U46619 fits the crystal structure of the GENE substrate binding pocket considerably better than that of the unbound U46619. The residues important to the substrate binding in the active site pocket of GENE were also predicted. For example, Trp282 could be one of the most important residues and is suspected to play a role in the determination of specific catalytic function, which has been established by the docking studies using the NMR structure of the PGIS-bound form of U46619 and the GENE crystal structure. These studies have provided the structural information for the interaction of the GENE with its substrate mimic. The noted conformational changes where the C-6 position is closer to the C-9 position of U46619 provided the first experimental data for understanding the molecular mechanism of the catalytic function of GENE in the isomerization of PGH2 to prostacyclin. | PART-OF |
| Characterization of the substrate mimic bound to engineered prostacyclin synthase in solution using high-resolution NMR spectroscopy and mutagenesis: implication of the molecular mechanism in biosynthesis of prostacyclin. High-resolution NMR spectroscopy was used to determine the docking of a substrate (prostaglandin H2) mimic (U46619) to the engineered prostacyclin (PGI2) synthase (PGIS) in solution. The binding of CHEMICAL to the GENE protein was demonstrated by 1D NMR titration, and the significant perturbation of the chemical shifts of protons at C-11, H2C, and H20 of CHEMICAL were observed upon CHEMICAL binding to the engineered GENE in a concentration-dependent manner. The detailed conformational change and 3D structure of the PGIS-bound CHEMICAL were further demonstrated by 2D 1H NMR experiments using the transferred NOE technique. The distances between the protons H20 and H2, H18 and H2, and H18 and H4 are shorter following their binding to the GENE in solution-down to within 5 A. These shorter distances resulted in a widely open conformation, where the triangle shape of the unbound CHEMICAL changed to a more compact conformation with an oval shape. The bound conformation of CHEMICAL fits the crystal structure of the GENE substrate binding pocket considerably better than that of the unbound CHEMICAL. The residues important to the substrate binding in the active site pocket of GENE were also predicted. For example, Trp282 could be one of the most important residues and is suspected to play a role in the determination of specific catalytic function, which has been established by the docking studies using the NMR structure of the PGIS-bound form of CHEMICAL and the GENE crystal structure. These studies have provided the structural information for the interaction of the GENE with its substrate mimic. The noted conformational changes where the C-6 position is closer to the C-9 position of CHEMICAL provided the first experimental data for understanding the molecular mechanism of the catalytic function of GENE in the isomerization of PGH2 to prostacyclin. | DIRECT-REGULATOR |
| Characterization of the substrate mimic bound to engineered prostacyclin synthase in solution using high-resolution NMR spectroscopy and mutagenesis: implication of the molecular mechanism in biosynthesis of prostacyclin. High-resolution NMR spectroscopy was used to determine the docking of a substrate (prostaglandin H2) mimic (U46619) to the engineered prostacyclin (PGI2) synthase (PGIS) in solution. The binding of U46619 to the GENE protein was demonstrated by 1D NMR titration, and the significant perturbation of the chemical shifts of protons at C-11, H2C, and H20 of U46619 were observed upon U46619 binding to the engineered GENE in a concentration-dependent manner. The detailed conformational change and 3D structure of the PGIS-bound U46619 were further demonstrated by 2D 1H NMR experiments using the transferred NOE technique. The distances between the protons H20 and CHEMICAL, H18 and CHEMICAL, and H18 and H4 are shorter following their binding to the GENE in solution-down to within 5 A. These shorter distances resulted in a widely open conformation, where the triangle shape of the unbound U46619 changed to a more compact conformation with an oval shape. The bound conformation of U46619 fits the crystal structure of the GENE substrate binding pocket considerably better than that of the unbound U46619. The residues important to the substrate binding in the active site pocket of GENE were also predicted. For example, Trp282 could be one of the most important residues and is suspected to play a role in the determination of specific catalytic function, which has been established by the docking studies using the NMR structure of the PGIS-bound form of U46619 and the GENE crystal structure. These studies have provided the structural information for the interaction of the GENE with its substrate mimic. The noted conformational changes where the C-6 position is closer to the C-9 position of U46619 provided the first experimental data for understanding the molecular mechanism of the catalytic function of GENE in the isomerization of PGH2 to prostacyclin. | PART-OF |
| Characterization of the substrate mimic bound to engineered prostacyclin synthase in solution using high-resolution NMR spectroscopy and mutagenesis: implication of the molecular mechanism in biosynthesis of prostacyclin. High-resolution NMR spectroscopy was used to determine the docking of a substrate (prostaglandin H2) mimic (U46619) to the engineered prostacyclin (PGI2) synthase (PGIS) in solution. The binding of U46619 to the GENE protein was demonstrated by 1D NMR titration, and the significant perturbation of the chemical shifts of protons at C-11, H2C, and H20 of U46619 were observed upon U46619 binding to the engineered GENE in a concentration-dependent manner. The detailed conformational change and 3D structure of the PGIS-bound U46619 were further demonstrated by 2D 1H NMR experiments using the transferred NOE technique. The distances between the protons H20 and H2, CHEMICAL and H2, and CHEMICAL and H4 are shorter following their binding to the GENE in solution-down to within 5 A. These shorter distances resulted in a widely open conformation, where the triangle shape of the unbound U46619 changed to a more compact conformation with an oval shape. The bound conformation of U46619 fits the crystal structure of the GENE substrate binding pocket considerably better than that of the unbound U46619. The residues important to the substrate binding in the active site pocket of GENE were also predicted. For example, Trp282 could be one of the most important residues and is suspected to play a role in the determination of specific catalytic function, which has been established by the docking studies using the NMR structure of the PGIS-bound form of U46619 and the GENE crystal structure. These studies have provided the structural information for the interaction of the GENE with its substrate mimic. The noted conformational changes where the C-6 position is closer to the C-9 position of U46619 provided the first experimental data for understanding the molecular mechanism of the catalytic function of GENE in the isomerization of PGH2 to prostacyclin. | DIRECT-REGULATOR |
| Characterization of the substrate mimic bound to engineered prostacyclin synthase in solution using high-resolution NMR spectroscopy and mutagenesis: implication of the molecular mechanism in biosynthesis of prostacyclin. High-resolution NMR spectroscopy was used to determine the docking of a substrate (prostaglandin H2) mimic (U46619) to the engineered prostacyclin (PGI2) synthase (PGIS) in solution. The binding of U46619 to the GENE protein was demonstrated by 1D NMR titration, and the significant perturbation of the chemical shifts of protons at C-11, H2C, and H20 of U46619 were observed upon U46619 binding to the engineered GENE in a concentration-dependent manner. The detailed conformational change and 3D structure of the PGIS-bound U46619 were further demonstrated by 2D 1H NMR experiments using the transferred NOE technique. The distances between the protons H20 and H2, H18 and H2, and H18 and CHEMICAL are shorter following their binding to the GENE in solution-down to within 5 A. These shorter distances resulted in a widely open conformation, where the triangle shape of the unbound U46619 changed to a more compact conformation with an oval shape. The bound conformation of U46619 fits the crystal structure of the GENE substrate binding pocket considerably better than that of the unbound U46619. The residues important to the substrate binding in the active site pocket of GENE were also predicted. For example, Trp282 could be one of the most important residues and is suspected to play a role in the determination of specific catalytic function, which has been established by the docking studies using the NMR structure of the PGIS-bound form of U46619 and the GENE crystal structure. These studies have provided the structural information for the interaction of the GENE with its substrate mimic. The noted conformational changes where the C-6 position is closer to the C-9 position of U46619 provided the first experimental data for understanding the molecular mechanism of the catalytic function of GENE in the isomerization of PGH2 to prostacyclin. | DIRECT-REGULATOR |
| Characterization of the substrate mimic bound to engineered prostacyclin synthase in solution using high-resolution NMR spectroscopy and mutagenesis: implication of the molecular mechanism in biosynthesis of prostacyclin. High-resolution NMR spectroscopy was used to determine the docking of a substrate (prostaglandin H2) mimic (CHEMICAL) to the engineered GENE (PGIS) in solution. The binding of CHEMICAL to the PGIS protein was demonstrated by 1D NMR titration, and the significant perturbation of the chemical shifts of protons at C-11, H2C, and H20 of CHEMICAL were observed upon CHEMICAL binding to the engineered PGIS in a concentration-dependent manner. The detailed conformational change and 3D structure of the PGIS-bound CHEMICAL were further demonstrated by 2D 1H NMR experiments using the transferred NOE technique. The distances between the protons H20 and H2, H18 and H2, and H18 and H4 are shorter following their binding to the PGIS in solution-down to within 5 A. These shorter distances resulted in a widely open conformation, where the triangle shape of the unbound CHEMICAL changed to a more compact conformation with an oval shape. The bound conformation of CHEMICAL fits the crystal structure of the PGIS substrate binding pocket considerably better than that of the unbound CHEMICAL. The residues important to the substrate binding in the active site pocket of PGIS were also predicted. For example, Trp282 could be one of the most important residues and is suspected to play a role in the determination of specific catalytic function, which has been established by the docking studies using the NMR structure of the PGIS-bound form of CHEMICAL and the PGIS crystal structure. These studies have provided the structural information for the interaction of the PGIS with its substrate mimic. The noted conformational changes where the C-6 position is closer to the C-9 position of CHEMICAL provided the first experimental data for understanding the molecular mechanism of the catalytic function of PGIS in the isomerization of PGH2 to prostacyclin. | DIRECT-REGULATOR |
| Characterization of the substrate mimic bound to engineered prostacyclin synthase in solution using high-resolution NMR spectroscopy and mutagenesis: implication of the molecular mechanism in biosynthesis of prostacyclin. High-resolution NMR spectroscopy was used to determine the docking of a substrate (CHEMICAL) mimic (U46619) to the engineered GENE (PGIS) in solution. The binding of U46619 to the PGIS protein was demonstrated by 1D NMR titration, and the significant perturbation of the chemical shifts of protons at C-11, H2C, and H20 of U46619 were observed upon U46619 binding to the engineered PGIS in a concentration-dependent manner. The detailed conformational change and 3D structure of the PGIS-bound U46619 were further demonstrated by 2D 1H NMR experiments using the transferred NOE technique. The distances between the protons H20 and H2, H18 and H2, and H18 and H4 are shorter following their binding to the PGIS in solution-down to within 5 A. These shorter distances resulted in a widely open conformation, where the triangle shape of the unbound U46619 changed to a more compact conformation with an oval shape. The bound conformation of U46619 fits the crystal structure of the PGIS substrate binding pocket considerably better than that of the unbound U46619. The residues important to the substrate binding in the active site pocket of PGIS were also predicted. For example, Trp282 could be one of the most important residues and is suspected to play a role in the determination of specific catalytic function, which has been established by the docking studies using the NMR structure of the PGIS-bound form of U46619 and the PGIS crystal structure. These studies have provided the structural information for the interaction of the PGIS with its substrate mimic. The noted conformational changes where the C-6 position is closer to the C-9 position of U46619 provided the first experimental data for understanding the molecular mechanism of the catalytic function of PGIS in the isomerization of PGH2 to prostacyclin. | INHIBITOR |
| Characterization of the substrate mimic bound to engineered prostacyclin synthase in solution using high-resolution NMR spectroscopy and mutagenesis: implication of the molecular mechanism in biosynthesis of prostacyclin. High-resolution NMR spectroscopy was used to determine the docking of a substrate (CHEMICAL) mimic (U46619) to the engineered prostacyclin (PGI2) synthase (GENE) in solution. The binding of U46619 to the GENE protein was demonstrated by 1D NMR titration, and the significant perturbation of the chemical shifts of protons at C-11, H2C, and H20 of U46619 were observed upon U46619 binding to the engineered GENE in a concentration-dependent manner. The detailed conformational change and 3D structure of the PGIS-bound U46619 were further demonstrated by 2D 1H NMR experiments using the transferred NOE technique. The distances between the protons H20 and H2, H18 and H2, and H18 and H4 are shorter following their binding to the GENE in solution-down to within 5 A. These shorter distances resulted in a widely open conformation, where the triangle shape of the unbound U46619 changed to a more compact conformation with an oval shape. The bound conformation of U46619 fits the crystal structure of the GENE substrate binding pocket considerably better than that of the unbound U46619. The residues important to the substrate binding in the active site pocket of GENE were also predicted. For example, Trp282 could be one of the most important residues and is suspected to play a role in the determination of specific catalytic function, which has been established by the docking studies using the NMR structure of the PGIS-bound form of U46619 and the GENE crystal structure. These studies have provided the structural information for the interaction of the GENE with its substrate mimic. The noted conformational changes where the C-6 position is closer to the C-9 position of U46619 provided the first experimental data for understanding the molecular mechanism of the catalytic function of GENE in the isomerization of PGH2 to prostacyclin. | DIRECT-REGULATOR |
| Current and future prospects for anticoagulant therapy: inhibitors of GENE and factor IIa. Indirect systemic and direct oral GENE and direct oral factor IIa inhibitors with improved pharmacologic profiles compared with heparins and vitamin K antagonists are currently in clinical development. This overview focuses on the indirect antithrombin dependent pentasaccharide derivatives of idraparinux and on the most advanced oral direct inhibitors to GENE (CHEMICAL and apixaban) and IIa (dabigatran). Specifically, the results of dose-finding studies for the prevention of venous thromboembolism after elective orthopedic surgery, the results of dose-finding studies for treatment of acute venous thromboembolism including prolonged prophylaxis of recurrent events, and the designs of ongoing clinical trials are reviewed. | INHIBITOR |
| Current and future prospects for anticoagulant therapy: inhibitors of GENE and factor IIa. Indirect systemic and direct oral GENE and direct oral factor IIa inhibitors with improved pharmacologic profiles compared with heparins and vitamin K antagonists are currently in clinical development. This overview focuses on the indirect antithrombin dependent pentasaccharide derivatives of idraparinux and on the most advanced oral direct inhibitors to GENE (rivaroxaban and CHEMICAL) and IIa (dabigatran). Specifically, the results of dose-finding studies for the prevention of venous thromboembolism after elective orthopedic surgery, the results of dose-finding studies for treatment of acute venous thromboembolism including prolonged prophylaxis of recurrent events, and the designs of ongoing clinical trials are reviewed. | INHIBITOR |
| Triple pharmacological blockade of the renin-angiotensin-aldosterone system in nondiabetic CKD: an open-label crossover randomized controlled trial. BACKGROUND: Agents inhibiting the renin-angiotensin-aldosterone (RAAS) system have an important role in slowing the progression of chronic kidney disease. We evaluated the hypothesis that the addition of an aldosterone receptor antagonist to an angiotensin-converting enzyme (ACE) inhibitor and angiotensin II type 1 (AT-1) receptor blocker (ARB) (triple RAAS blockade) may provide an additional benefit compared with an GENE inhibitor and ARB (double RAAS blockade). DESIGN: Randomized open controlled crossover study. SETTING & PARTICIPANTS: 18 whites (7 women, 11 men) from the Outpatient Department of Nephrology with chronic nondiabetic proteinuric kidney diseases, mean age 42.4 +/- 1.9 years (SEM). INTERVENTIONS: In the 8-week run-in period, all participants received the GENE inhibitor CHEMICAL (5 mg), the ARB telmisartan (80 mg), and the diuretic hydrochlorothiazide (12.5 mg) as double RAAS blockade to achieve the target blood pressure of less than 130/80 mm Hg. Participants were then randomly assigned to 2 treatment sequences, either the addition of spironolactone (25 mg) (triple RAAS blockade) through 8 weeks followed by double RAAS blockade through 8 weeks (sequence 1) or double RAAS blockade followed by triple RAAS blockade (sequence 2). MAIN OUTCOME MEASURES: 24-hour urine protein excretion (primary end point) and markers of tubular injury and fibrosis (secondary end points). Analysis was performed using analysis of variance for repeated measurements. RESULTS: At baseline, mean serum creatinine level was 1.16 +/- 0.09 mg/dL (103 +/- 8 micromol/L), estimated glomerular filtration rate was 107.8 mL/min (95% confidence interval, 93 to 140.9 [1.8 mL/s; 95% confidence interval, 1.55 to 2.35; Cockcroft-Gault formula), and 24-hour mean proteinuria was 0.97 +/- 0.18 g. Mean urine protein excretion was 0.7 g/24 h (95% confidence interval, 0.48 to 0.92) less after triple RAAS blockade than after double RAAS blockade (P = 0.01), without change in blood pressure. Urine excretion of N-acetyl-beta-d-glucosaminidase (P = 0.02) and amino-terminal propeptide of type III procollagen (P = 0.05) also significantly decreased. Potassium levels increased significantly after triple therapy (P = 0.02). However, no patient was withdrawn because of adverse effects. LIMITATIONS: Absence of blinding, small sample size, short treatment period, absence of histological assessment. CONCLUSIONS: Administration of an aldosterone receptor antagonist in addition to double RAAS blockade with an GENE inhibitor and ARB may slow the progression of chronic kidney disease. Additional studies are necessary to confirm this result. | INHIBITOR |
| Porcine GENE and TLR7 are both activated by a selective TLR7 ligand, imiquimod. Toll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors (PRR), which are utilized by the innate immune system to recognize microbial components, known as pathogen-associated molecular patterns (PAMP). We cloned and characterized porcine TLR7 and GENE genes from pig lymph node tissue. Sequence analysis showed that the aa sequence identities of porcine TLR7 with human, mouse and bovine TLR7 are 85, 78 and 90%, respectively, whereas porcine GENE aa sequence identities with human, mouse and bovine GENE are 73, 69 and 79%, respectively. Both porcine TLR7 and GENE proteins were expressed in cell lines and were N-glycosylated. The stimulatory activity of TLR7 and GENE ligands to porcine and human TLR7 and GENE in transiently transfected Cos-7 and 293T cells were analyzed using a NF-kappaB reporter assay. Two CHEMICAL molecules, imiquimod and gardiquimod, markedly activated both porcine TLR7 and GENE whereas only human TLR7, but not GENE, was activated by the ligands. Therefore, receptor specificity for porcine GENE is clearly species specific. We further showed that porcine TLR7 and GENE are located intracellularly and are mainly within the endoplasmic reticulum. Moreover, activation of transfected cells and porcine PBMC by TLR7 ligands was inhibited by bafilomycin A(1) indicating the requirement of endosomal/lysosomal acidification for activation of the receptors. | NO-RELATIONSHIP |
| Porcine GENE and TLR7 are both activated by a selective TLR7 ligand, CHEMICAL. Toll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors (PRR), which are utilized by the innate immune system to recognize microbial components, known as pathogen-associated molecular patterns (PAMP). We cloned and characterized porcine TLR7 and GENE genes from pig lymph node tissue. Sequence analysis showed that the aa sequence identities of porcine TLR7 with human, mouse and bovine TLR7 are 85, 78 and 90%, respectively, whereas porcine GENE aa sequence identities with human, mouse and bovine GENE are 73, 69 and 79%, respectively. Both porcine TLR7 and GENE proteins were expressed in cell lines and were N-glycosylated. The stimulatory activity of TLR7 and GENE ligands to porcine and human TLR7 and GENE in transiently transfected Cos-7 and 293T cells were analyzed using a NF-kappaB reporter assay. Two imidazoquinoline molecules, CHEMICAL and gardiquimod, markedly activated both porcine TLR7 and GENE whereas only human TLR7, but not GENE, was activated by the ligands. Therefore, receptor specificity for porcine GENE is clearly species specific. We further showed that porcine TLR7 and GENE are located intracellularly and are mainly within the endoplasmic reticulum. Moreover, activation of transfected cells and porcine PBMC by TLR7 ligands was inhibited by bafilomycin A(1) indicating the requirement of endosomal/lysosomal acidification for activation of the receptors. | NO-RELATIONSHIP |
| Porcine GENE and TLR7 are both activated by a selective TLR7 ligand, imiquimod. Toll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors (PRR), which are utilized by the innate immune system to recognize microbial components, known as pathogen-associated molecular patterns (PAMP). We cloned and characterized porcine TLR7 and GENE genes from pig lymph node tissue. Sequence analysis showed that the aa sequence identities of porcine TLR7 with human, mouse and bovine TLR7 are 85, 78 and 90%, respectively, whereas porcine GENE aa sequence identities with human, mouse and bovine GENE are 73, 69 and 79%, respectively. Both porcine TLR7 and GENE proteins were expressed in cell lines and were N-glycosylated. The stimulatory activity of TLR7 and GENE ligands to porcine and human TLR7 and GENE in transiently transfected Cos-7 and 293T cells were analyzed using a NF-kappaB reporter assay. Two imidazoquinoline molecules, imiquimod and CHEMICAL, markedly activated both porcine TLR7 and GENE whereas only human TLR7, but not GENE, was activated by the ligands. Therefore, receptor specificity for porcine GENE is clearly species specific. We further showed that porcine TLR7 and GENE are located intracellularly and are mainly within the endoplasmic reticulum. Moreover, activation of transfected cells and porcine PBMC by TLR7 ligands was inhibited by bafilomycin A(1) indicating the requirement of endosomal/lysosomal acidification for activation of the receptors. | NO-RELATIONSHIP |
| Porcine TLR8 and TLR7 are both activated by a selective TLR7 ligand, imiquimod. Toll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors (PRR), which are utilized by the innate immune system to recognize microbial components, known as pathogen-associated molecular patterns (PAMP). We cloned and characterized GENE and TLR8 genes from pig lymph node tissue. Sequence analysis showed that the aa sequence identities of GENE with human, mouse and bovine TLR7 are 85, 78 and 90%, respectively, whereas porcine TLR8 aa sequence identities with human, mouse and bovine TLR8 are 73, 69 and 79%, respectively. Both GENE and TLR8 proteins were expressed in cell lines and were CHEMICAL-glycosylated. The stimulatory activity of TLR7 and TLR8 ligands to porcine and human TLR7 and TLR8 in transiently transfected Cos-7 and 293T cells were analyzed using a NF-kappaB reporter assay. Two imidazoquinoline molecules, imiquimod and gardiquimod, markedly activated both GENE and TLR8 whereas only human TLR7, but not TLR8, was activated by the ligands. Therefore, receptor specificity for porcine TLR8 is clearly species specific. We further showed that GENE and TLR8 are located intracellularly and are mainly within the endoplasmic reticulum. Moreover, activation of transfected cells and porcine PBMC by TLR7 ligands was inhibited by bafilomycin A(1) indicating the requirement of endosomal/lysosomal acidification for activation of the receptors. | PART-OF |
| Porcine GENE and TLR7 are both activated by a selective TLR7 ligand, imiquimod. Toll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors (PRR), which are utilized by the innate immune system to recognize microbial components, known as pathogen-associated molecular patterns (PAMP). We cloned and characterized porcine TLR7 and GENE genes from pig lymph node tissue. Sequence analysis showed that the aa sequence identities of porcine TLR7 with human, mouse and bovine TLR7 are 85, 78 and 90%, respectively, whereas porcine GENE aa sequence identities with human, mouse and bovine GENE are 73, 69 and 79%, respectively. Both porcine TLR7 and GENE proteins were expressed in cell lines and were CHEMICAL-glycosylated. The stimulatory activity of TLR7 and GENE ligands to porcine and human TLR7 and GENE in transiently transfected Cos-7 and 293T cells were analyzed using a NF-kappaB reporter assay. Two imidazoquinoline molecules, imiquimod and gardiquimod, markedly activated both porcine TLR7 and GENE whereas only human TLR7, but not GENE, was activated by the ligands. Therefore, receptor specificity for porcine GENE is clearly species specific. We further showed that porcine TLR7 and GENE are located intracellularly and are mainly within the endoplasmic reticulum. Moreover, activation of transfected cells and porcine PBMC by TLR7 ligands was inhibited by bafilomycin A(1) indicating the requirement of endosomal/lysosomal acidification for activation of the receptors. | PART-OF |
| Porcine TLR8 and TLR7 are both activated by a selective TLR7 ligand, imiquimod. Toll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors (PRR), which are utilized by the innate immune system to recognize microbial components, known as pathogen-associated molecular patterns (PAMP). We cloned and characterized GENE and TLR8 genes from pig lymph node tissue. Sequence analysis showed that the aa sequence identities of GENE with human, mouse and bovine TLR7 are 85, 78 and 90%, respectively, whereas porcine TLR8 aa sequence identities with human, mouse and bovine TLR8 are 73, 69 and 79%, respectively. Both GENE and TLR8 proteins were expressed in cell lines and were N-glycosylated. The stimulatory activity of TLR7 and TLR8 ligands to porcine and human TLR7 and TLR8 in transiently transfected Cos-7 and 293T cells were analyzed using a NF-kappaB reporter assay. Two CHEMICAL molecules, imiquimod and gardiquimod, markedly activated both GENE and TLR8 whereas only human TLR7, but not TLR8, was activated by the ligands. Therefore, receptor specificity for porcine TLR8 is clearly species specific. We further showed that GENE and TLR8 are located intracellularly and are mainly within the endoplasmic reticulum. Moreover, activation of transfected cells and porcine PBMC by TLR7 ligands was inhibited by bafilomycin A(1) indicating the requirement of endosomal/lysosomal acidification for activation of the receptors. | ACTIVATOR |
| Porcine TLR8 and TLR7 are both activated by a selective TLR7 ligand, imiquimod. Toll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors (PRR), which are utilized by the innate immune system to recognize microbial components, known as pathogen-associated molecular patterns (PAMP). We cloned and characterized porcine TLR7 and TLR8 genes from pig lymph node tissue. Sequence analysis showed that the aa sequence identities of porcine TLR7 with human, mouse and bovine TLR7 are 85, 78 and 90%, respectively, whereas porcine TLR8 aa sequence identities with human, mouse and bovine TLR8 are 73, 69 and 79%, respectively. Both porcine TLR7 and TLR8 proteins were expressed in cell lines and were N-glycosylated. The stimulatory activity of TLR7 and TLR8 ligands to porcine and GENE and TLR8 in transiently transfected Cos-7 and 293T cells were analyzed using a NF-kappaB reporter assay. Two CHEMICAL molecules, imiquimod and gardiquimod, markedly activated both porcine TLR7 and TLR8 whereas only GENE, but not TLR8, was activated by the ligands. Therefore, receptor specificity for porcine TLR8 is clearly species specific. We further showed that porcine TLR7 and TLR8 are located intracellularly and are mainly within the endoplasmic reticulum. Moreover, activation of transfected cells and porcine PBMC by TLR7 ligands was inhibited by bafilomycin A(1) indicating the requirement of endosomal/lysosomal acidification for activation of the receptors. | ACTIVATOR |
| Porcine TLR8 and TLR7 are both activated by a selective TLR7 ligand, CHEMICAL. Toll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors (PRR), which are utilized by the innate immune system to recognize microbial components, known as pathogen-associated molecular patterns (PAMP). We cloned and characterized GENE and TLR8 genes from pig lymph node tissue. Sequence analysis showed that the aa sequence identities of GENE with human, mouse and bovine TLR7 are 85, 78 and 90%, respectively, whereas porcine TLR8 aa sequence identities with human, mouse and bovine TLR8 are 73, 69 and 79%, respectively. Both GENE and TLR8 proteins were expressed in cell lines and were N-glycosylated. The stimulatory activity of TLR7 and TLR8 ligands to porcine and human TLR7 and TLR8 in transiently transfected Cos-7 and 293T cells were analyzed using a NF-kappaB reporter assay. Two imidazoquinoline molecules, CHEMICAL and gardiquimod, markedly activated both GENE and TLR8 whereas only human TLR7, but not TLR8, was activated by the ligands. Therefore, receptor specificity for porcine TLR8 is clearly species specific. We further showed that GENE and TLR8 are located intracellularly and are mainly within the endoplasmic reticulum. Moreover, activation of transfected cells and porcine PBMC by TLR7 ligands was inhibited by bafilomycin A(1) indicating the requirement of endosomal/lysosomal acidification for activation of the receptors. | ACTIVATOR |
| Porcine TLR8 and TLR7 are both activated by a selective TLR7 ligand, CHEMICAL. Toll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors (PRR), which are utilized by the innate immune system to recognize microbial components, known as pathogen-associated molecular patterns (PAMP). We cloned and characterized porcine TLR7 and TLR8 genes from pig lymph node tissue. Sequence analysis showed that the aa sequence identities of porcine TLR7 with human, mouse and bovine TLR7 are 85, 78 and 90%, respectively, whereas porcine TLR8 aa sequence identities with human, mouse and bovine TLR8 are 73, 69 and 79%, respectively. Both porcine TLR7 and TLR8 proteins were expressed in cell lines and were N-glycosylated. The stimulatory activity of TLR7 and TLR8 ligands to porcine and GENE and TLR8 in transiently transfected Cos-7 and 293T cells were analyzed using a NF-kappaB reporter assay. Two imidazoquinoline molecules, CHEMICAL and gardiquimod, markedly activated both porcine TLR7 and TLR8 whereas only GENE, but not TLR8, was activated by the ligands. Therefore, receptor specificity for porcine TLR8 is clearly species specific. We further showed that porcine TLR7 and TLR8 are located intracellularly and are mainly within the endoplasmic reticulum. Moreover, activation of transfected cells and porcine PBMC by TLR7 ligands was inhibited by bafilomycin A(1) indicating the requirement of endosomal/lysosomal acidification for activation of the receptors. | ACTIVATOR |
| Porcine TLR8 and TLR7 are both activated by a selective TLR7 ligand, imiquimod. Toll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors (PRR), which are utilized by the innate immune system to recognize microbial components, known as pathogen-associated molecular patterns (PAMP). We cloned and characterized GENE and TLR8 genes from pig lymph node tissue. Sequence analysis showed that the aa sequence identities of GENE with human, mouse and bovine TLR7 are 85, 78 and 90%, respectively, whereas porcine TLR8 aa sequence identities with human, mouse and bovine TLR8 are 73, 69 and 79%, respectively. Both GENE and TLR8 proteins were expressed in cell lines and were N-glycosylated. The stimulatory activity of TLR7 and TLR8 ligands to porcine and human TLR7 and TLR8 in transiently transfected Cos-7 and 293T cells were analyzed using a NF-kappaB reporter assay. Two imidazoquinoline molecules, imiquimod and CHEMICAL, markedly activated both GENE and TLR8 whereas only human TLR7, but not TLR8, was activated by the ligands. Therefore, receptor specificity for porcine TLR8 is clearly species specific. We further showed that GENE and TLR8 are located intracellularly and are mainly within the endoplasmic reticulum. Moreover, activation of transfected cells and porcine PBMC by TLR7 ligands was inhibited by bafilomycin A(1) indicating the requirement of endosomal/lysosomal acidification for activation of the receptors. | ACTIVATOR |
| Porcine TLR8 and TLR7 are both activated by a selective TLR7 ligand, imiquimod. Toll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors (PRR), which are utilized by the innate immune system to recognize microbial components, known as pathogen-associated molecular patterns (PAMP). We cloned and characterized porcine TLR7 and TLR8 genes from pig lymph node tissue. Sequence analysis showed that the aa sequence identities of porcine TLR7 with human, mouse and bovine TLR7 are 85, 78 and 90%, respectively, whereas porcine TLR8 aa sequence identities with human, mouse and bovine TLR8 are 73, 69 and 79%, respectively. Both porcine TLR7 and TLR8 proteins were expressed in cell lines and were N-glycosylated. The stimulatory activity of TLR7 and TLR8 ligands to porcine and GENE and TLR8 in transiently transfected Cos-7 and 293T cells were analyzed using a NF-kappaB reporter assay. Two imidazoquinoline molecules, imiquimod and CHEMICAL, markedly activated both porcine TLR7 and TLR8 whereas only GENE, but not TLR8, was activated by the ligands. Therefore, receptor specificity for porcine TLR8 is clearly species specific. We further showed that porcine TLR7 and TLR8 are located intracellularly and are mainly within the endoplasmic reticulum. Moreover, activation of transfected cells and porcine PBMC by TLR7 ligands was inhibited by bafilomycin A(1) indicating the requirement of endosomal/lysosomal acidification for activation of the receptors. | ACTIVATOR |
| Porcine TLR8 and GENE are both activated by a selective GENE ligand, CHEMICAL. Toll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors (PRR), which are utilized by the innate immune system to recognize microbial components, known as pathogen-associated molecular patterns (PAMP). We cloned and characterized porcine GENE and TLR8 genes from pig lymph node tissue. Sequence analysis showed that the aa sequence identities of porcine GENE with human, mouse and bovine GENE are 85, 78 and 90%, respectively, whereas porcine TLR8 aa sequence identities with human, mouse and bovine TLR8 are 73, 69 and 79%, respectively. Both porcine GENE and TLR8 proteins were expressed in cell lines and were N-glycosylated. The stimulatory activity of GENE and TLR8 ligands to porcine and human GENE and TLR8 in transiently transfected Cos-7 and 293T cells were analyzed using a NF-kappaB reporter assay. Two imidazoquinoline molecules, CHEMICAL and gardiquimod, markedly activated both porcine GENE and TLR8 whereas only human GENE, but not TLR8, was activated by the ligands. Therefore, receptor specificity for porcine TLR8 is clearly species specific. We further showed that porcine GENE and TLR8 are located intracellularly and are mainly within the endoplasmic reticulum. Moreover, activation of transfected cells and porcine PBMC by GENE ligands was inhibited by bafilomycin A(1) indicating the requirement of endosomal/lysosomal acidification for activation of the receptors. | DIRECT-REGULATOR |
| Porcine TLR8 and GENE are both activated by a selective GENE ligand, imiquimod. Toll-like receptors (TLRs) are a family of highly conserved germline-encoded pattern-recognition receptors (PRR), which are utilized by the innate immune system to recognize microbial components, known as pathogen-associated molecular patterns (PAMP). We cloned and characterized porcine GENE and TLR8 genes from pig lymph node tissue. Sequence analysis showed that the aa sequence identities of porcine GENE with human, mouse and bovine GENE are 85, 78 and 90%, respectively, whereas porcine TLR8 aa sequence identities with human, mouse and bovine TLR8 are 73, 69 and 79%, respectively. Both porcine GENE and TLR8 proteins were expressed in cell lines and were N-glycosylated. The stimulatory activity of GENE and TLR8 ligands to porcine and human GENE and TLR8 in transiently transfected Cos-7 and 293T cells were analyzed using a NF-kappaB reporter assay. Two imidazoquinoline molecules, imiquimod and gardiquimod, markedly activated both porcine GENE and TLR8 whereas only human GENE, but not TLR8, was activated by the ligands. Therefore, receptor specificity for porcine TLR8 is clearly species specific. We further showed that porcine GENE and TLR8 are located intracellularly and are mainly within the endoplasmic reticulum. Moreover, activation of transfected cells and porcine PBMC by GENE ligands was inhibited by CHEMICAL indicating the requirement of endosomal/lysosomal acidification for activation of the receptors. | INHIBITOR |
| High-affinity blockade of voltage-operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues. BACKGROUND AND PURPOSE: Voltage-operated sodium channels constitute major target sites for local anaesthetic-like action. The clinical use of local anaesthetics is still limited by severe side effects, in particular, arrhythmias and convulsions. These side effects render the search for new local anaesthetics a matter of high interest. EXPERIMENTAL APPROACH: We have investigated the effects of three halogenated structural analogues of propofol on voltage-operated human skeletal muscle sodium channels (Na(V)1.4) and the effect of one compound (4-chloropropofol) on neuronal sodium channels (Na(V)1.2) heterologously expressed in human embryonic kidney cell line 293. KEY RESULTS: 4-Iodo-, 4-bromo- and 4-chloropropofol reversibly suppressed depolarization-induced whole-cell sodium inward currents with high potency. The IC(50) for block of resting channels at -150 mV was 2.3, 3.9 and 11.3 microM in GENE, respectively, and 29.2 microM for 4-chloropropofol in Na(V)1.2. Membrane depolarization inducing inactivation strongly increased the blocking potency of all compounds. Estimated affinities for the fast-inactivated channel state were 81 nM, 312 nM and 227 nM for CHEMICAL, 4-bromopropofol and 4-chloropropofol in GENE, and 450 nM for 4-chloropropofol in Na(V)1.2. Recovery from fast inactivation was prolonged in the presence of drug leading to an accumulation of block during repetitive stimulation at high frequencies (100 Hz). CONCLUSIONS AND IMPLICATIONS: Halogenated propofol analogues constitute a novel class of sodium channel-blocking drugs possessing almost 100-fold higher potency compared with the local anaesthetic and anti-arrhythmic drug lidocaine. Preferential drug binding to inactivated channel states suggests that halogenated propofol analogues might be especially effective in suppressing ectopic discharges in a variety of pathological conditions. | DIRECT-REGULATOR |
| High-affinity blockade of voltage-operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues. BACKGROUND AND PURPOSE: Voltage-operated sodium channels constitute major target sites for local anaesthetic-like action. The clinical use of local anaesthetics is still limited by severe side effects, in particular, arrhythmias and convulsions. These side effects render the search for new local anaesthetics a matter of high interest. EXPERIMENTAL APPROACH: We have investigated the effects of three halogenated structural analogues of propofol on voltage-operated human skeletal muscle sodium channels (Na(V)1.4) and the effect of one compound (4-chloropropofol) on neuronal sodium channels (Na(V)1.2) heterologously expressed in human embryonic kidney cell line 293. KEY RESULTS: 4-Iodo-, 4-bromo- and 4-chloropropofol reversibly suppressed depolarization-induced whole-cell sodium inward currents with high potency. The IC(50) for block of resting channels at -150 mV was 2.3, 3.9 and 11.3 microM in GENE, respectively, and 29.2 microM for 4-chloropropofol in Na(V)1.2. Membrane depolarization inducing inactivation strongly increased the blocking potency of all compounds. Estimated affinities for the fast-inactivated channel state were 81 nM, 312 nM and 227 nM for 4-iodopropofol, CHEMICAL and 4-chloropropofol in GENE, and 450 nM for 4-chloropropofol in Na(V)1.2. Recovery from fast inactivation was prolonged in the presence of drug leading to an accumulation of block during repetitive stimulation at high frequencies (100 Hz). CONCLUSIONS AND IMPLICATIONS: Halogenated propofol analogues constitute a novel class of sodium channel-blocking drugs possessing almost 100-fold higher potency compared with the local anaesthetic and anti-arrhythmic drug lidocaine. Preferential drug binding to inactivated channel states suggests that halogenated propofol analogues might be especially effective in suppressing ectopic discharges in a variety of pathological conditions. | DIRECT-REGULATOR |
| High-affinity blockade of voltage-operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues. BACKGROUND AND PURPOSE: Voltage-operated sodium channels constitute major target sites for local anaesthetic-like action. The clinical use of local anaesthetics is still limited by severe side effects, in particular, arrhythmias and convulsions. These side effects render the search for new local anaesthetics a matter of high interest. EXPERIMENTAL APPROACH: We have investigated the effects of three halogenated structural analogues of propofol on voltage-operated human skeletal muscle sodium channels (Na(V)1.4) and the effect of one compound (4-chloropropofol) on neuronal sodium channels (Na(V)1.2) heterologously expressed in human embryonic kidney cell line 293. KEY RESULTS: 4-Iodo-, 4-bromo- and CHEMICAL reversibly suppressed depolarization-induced whole-cell sodium inward currents with high potency. The IC(50) for block of resting channels at -150 mV was 2.3, 3.9 and 11.3 microM in GENE, respectively, and 29.2 microM for CHEMICAL in Na(V)1.2. Membrane depolarization inducing inactivation strongly increased the blocking potency of all compounds. Estimated affinities for the fast-inactivated channel state were 81 nM, 312 nM and 227 nM for 4-iodopropofol, 4-bromopropofol and CHEMICAL in GENE, and 450 nM for CHEMICAL in Na(V)1.2. Recovery from fast inactivation was prolonged in the presence of drug leading to an accumulation of block during repetitive stimulation at high frequencies (100 Hz). CONCLUSIONS AND IMPLICATIONS: Halogenated propofol analogues constitute a novel class of sodium channel-blocking drugs possessing almost 100-fold higher potency compared with the local anaesthetic and anti-arrhythmic drug lidocaine. Preferential drug binding to inactivated channel states suggests that halogenated propofol analogues might be especially effective in suppressing ectopic discharges in a variety of pathological conditions. | DIRECT-REGULATOR |
| High-affinity blockade of voltage-operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues. BACKGROUND AND PURPOSE: Voltage-operated sodium channels constitute major target sites for local anaesthetic-like action. The clinical use of local anaesthetics is still limited by severe side effects, in particular, arrhythmias and convulsions. These side effects render the search for new local anaesthetics a matter of high interest. EXPERIMENTAL APPROACH: We have investigated the effects of three halogenated structural analogues of propofol on voltage-operated human skeletal muscle sodium channels (Na(V)1.4) and the effect of one compound (4-chloropropofol) on neuronal sodium channels (Na(V)1.2) heterologously expressed in human embryonic kidney cell line 293. KEY RESULTS: 4-Iodo-, 4-bromo- and CHEMICAL reversibly suppressed depolarization-induced whole-cell sodium inward currents with high potency. The IC(50) for block of resting channels at -150 mV was 2.3, 3.9 and 11.3 microM in Na(V)1.4, respectively, and 29.2 microM for CHEMICAL in GENE. Membrane depolarization inducing inactivation strongly increased the blocking potency of all compounds. Estimated affinities for the fast-inactivated channel state were 81 nM, 312 nM and 227 nM for 4-iodopropofol, 4-bromopropofol and CHEMICAL in Na(V)1.4, and 450 nM for CHEMICAL in GENE. Recovery from fast inactivation was prolonged in the presence of drug leading to an accumulation of block during repetitive stimulation at high frequencies (100 Hz). CONCLUSIONS AND IMPLICATIONS: Halogenated propofol analogues constitute a novel class of sodium channel-blocking drugs possessing almost 100-fold higher potency compared with the local anaesthetic and anti-arrhythmic drug lidocaine. Preferential drug binding to inactivated channel states suggests that halogenated propofol analogues might be especially effective in suppressing ectopic discharges in a variety of pathological conditions. | DIRECT-REGULATOR |
| High-affinity blockade of voltage-operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues. BACKGROUND AND PURPOSE: Voltage-operated sodium channels constitute major target sites for local anaesthetic-like action. The clinical use of local anaesthetics is still limited by severe side effects, in particular, arrhythmias and convulsions. These side effects render the search for new local anaesthetics a matter of high interest. EXPERIMENTAL APPROACH: We have investigated the effects of three halogenated structural analogues of propofol on voltage-operated human skeletal muscle sodium channels (Na(V)1.4) and the effect of one compound (4-chloropropofol) on neuronal sodium channels (Na(V)1.2) heterologously expressed in human embryonic kidney cell line 293. KEY RESULTS: 4-Iodo-, 4-bromo- and 4-chloropropofol reversibly suppressed depolarization-induced whole-cell sodium inward currents with high potency. The IC(50) for block of resting channels at -150 mV was 2.3, 3.9 and 11.3 microM in Na(V)1.4, respectively, and 29.2 microM for 4-chloropropofol in Na(V)1.2. Membrane depolarization inducing inactivation strongly increased the blocking potency of all compounds. Estimated affinities for the fast-inactivated channel state were 81 nM, 312 nM and 227 nM for 4-iodopropofol, 4-bromopropofol and 4-chloropropofol in Na(V)1.4, and 450 nM for 4-chloropropofol in Na(V)1.2. Recovery from fast inactivation was prolonged in the presence of drug leading to an accumulation of block during repetitive stimulation at high frequencies (100 Hz). CONCLUSIONS AND IMPLICATIONS: Halogenated propofol analogues constitute a novel class of GENE-blocking drugs possessing almost 100-fold higher potency compared with the local anaesthetic and anti-arrhythmic drug CHEMICAL. Preferential drug binding to inactivated channel states suggests that halogenated propofol analogues might be especially effective in suppressing ectopic discharges in a variety of pathological conditions. | INHIBITOR |
| High-affinity blockade of GENE by CHEMICAL analogues. BACKGROUND AND PURPOSE: Voltage-operated sodium channels constitute major target sites for local anaesthetic-like action. The clinical use of local anaesthetics is still limited by severe side effects, in particular, arrhythmias and convulsions. These side effects render the search for new local anaesthetics a matter of high interest. EXPERIMENTAL APPROACH: We have investigated the effects of three halogenated structural analogues of propofol on voltage-operated human skeletal muscle sodium channels (Na(V)1.4) and the effect of one compound (4-chloropropofol) on neuronal sodium channels (Na(V)1.2) heterologously expressed in human embryonic kidney cell line 293. KEY RESULTS: 4-Iodo-, 4-bromo- and 4-chloropropofol reversibly suppressed depolarization-induced whole-cell sodium inward currents with high potency. The IC(50) for block of resting channels at -150 mV was 2.3, 3.9 and 11.3 microM in Na(V)1.4, respectively, and 29.2 microM for 4-chloropropofol in Na(V)1.2. Membrane depolarization inducing inactivation strongly increased the blocking potency of all compounds. Estimated affinities for the fast-inactivated channel state were 81 nM, 312 nM and 227 nM for 4-iodopropofol, 4-bromopropofol and 4-chloropropofol in Na(V)1.4, and 450 nM for 4-chloropropofol in Na(V)1.2. Recovery from fast inactivation was prolonged in the presence of drug leading to an accumulation of block during repetitive stimulation at high frequencies (100 Hz). CONCLUSIONS AND IMPLICATIONS: CHEMICAL analogues constitute a novel class of sodium channel-blocking drugs possessing almost 100-fold higher potency compared with the local anaesthetic and anti-arrhythmic drug lidocaine. Preferential drug binding to inactivated channel states suggests that CHEMICAL analogues might be especially effective in suppressing ectopic discharges in a variety of pathological conditions. | INHIBITOR |
| High-affinity blockade of voltage-operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues. BACKGROUND AND PURPOSE: Voltage-operated sodium channels constitute major target sites for local anaesthetic-like action. The clinical use of local anaesthetics is still limited by severe side effects, in particular, arrhythmias and convulsions. These side effects render the search for new local anaesthetics a matter of high interest. EXPERIMENTAL APPROACH: We have investigated the effects of three halogenated structural analogues of propofol on voltage-operated human skeletal muscle sodium channels (Na(V)1.4) and the effect of one compound (4-chloropropofol) on neuronal sodium channels (Na(V)1.2) heterologously expressed in human embryonic kidney cell line 293. KEY RESULTS: 4-Iodo-, 4-bromo- and 4-chloropropofol reversibly suppressed depolarization-induced whole-cell sodium inward currents with high potency. The IC(50) for block of resting channels at -150 mV was 2.3, 3.9 and 11.3 microM in Na(V)1.4, respectively, and 29.2 microM for 4-chloropropofol in Na(V)1.2. Membrane depolarization inducing inactivation strongly increased the blocking potency of all compounds. Estimated affinities for the fast-inactivated channel state were 81 nM, 312 nM and 227 nM for 4-iodopropofol, 4-bromopropofol and 4-chloropropofol in Na(V)1.4, and 450 nM for 4-chloropropofol in Na(V)1.2. Recovery from fast inactivation was prolonged in the presence of drug leading to an accumulation of block during repetitive stimulation at high frequencies (100 Hz). CONCLUSIONS AND IMPLICATIONS: CHEMICAL analogues constitute a novel class of GENE-blocking drugs possessing almost 100-fold higher potency compared with the local anaesthetic and anti-arrhythmic drug lidocaine. Preferential drug binding to inactivated channel states suggests that halogenated propofol analogues might be especially effective in suppressing ectopic discharges in a variety of pathological conditions. | INHIBITOR |
| Irbesartan: a review of its use in hypertension and diabetic nephropathy. CHEMICAL (Aprovel, Avapro, Irbetan, Karvea), an GENE antagonist, is approved in many countries worldwide for the treatment of hypertension. It is also approved in some regions for the treatment of nephropathy in patients with hypertension and type 2 diabetes mellitus. In adults with essential hypertension, irbesartan is effective at reducing blood pressure (BP) over a 24-hour period with once-daily administration. CHEMICAL also slows the progression of renal disease in hypertensive patients with type 2 diabetes, with this effect partly independent of its BP-lowering effect. In addition, irbesartan was generally well tolerated in clinical trials. Thus, irbesartan is a useful treatment option for patients with hypertension, including those with type 2 diabetes and nephropathy. | INHIBITOR |
| Irbesartan: a review of its use in hypertension and diabetic nephropathy. Irbesartan (CHEMICAL, Avapro, Irbetan, Karvea), an GENE antagonist, is approved in many countries worldwide for the treatment of hypertension. It is also approved in some regions for the treatment of nephropathy in patients with hypertension and type 2 diabetes mellitus. In adults with essential hypertension, irbesartan is effective at reducing blood pressure (BP) over a 24-hour period with once-daily administration. Irbesartan also slows the progression of renal disease in hypertensive patients with type 2 diabetes, with this effect partly independent of its BP-lowering effect. In addition, irbesartan was generally well tolerated in clinical trials. Thus, irbesartan is a useful treatment option for patients with hypertension, including those with type 2 diabetes and nephropathy. | INHIBITOR |
| Irbesartan: a review of its use in hypertension and diabetic nephropathy. Irbesartan (Aprovel, CHEMICAL, Irbetan, Karvea), an GENE antagonist, is approved in many countries worldwide for the treatment of hypertension. It is also approved in some regions for the treatment of nephropathy in patients with hypertension and type 2 diabetes mellitus. In adults with essential hypertension, irbesartan is effective at reducing blood pressure (BP) over a 24-hour period with once-daily administration. Irbesartan also slows the progression of renal disease in hypertensive patients with type 2 diabetes, with this effect partly independent of its BP-lowering effect. In addition, irbesartan was generally well tolerated in clinical trials. Thus, irbesartan is a useful treatment option for patients with hypertension, including those with type 2 diabetes and nephropathy. | INHIBITOR |
| Irbesartan: a review of its use in hypertension and diabetic nephropathy. Irbesartan (Aprovel, Avapro, CHEMICAL, Karvea), an GENE antagonist, is approved in many countries worldwide for the treatment of hypertension. It is also approved in some regions for the treatment of nephropathy in patients with hypertension and type 2 diabetes mellitus. In adults with essential hypertension, irbesartan is effective at reducing blood pressure (BP) over a 24-hour period with once-daily administration. Irbesartan also slows the progression of renal disease in hypertensive patients with type 2 diabetes, with this effect partly independent of its BP-lowering effect. In addition, irbesartan was generally well tolerated in clinical trials. Thus, irbesartan is a useful treatment option for patients with hypertension, including those with type 2 diabetes and nephropathy. | INHIBITOR |
| Irbesartan: a review of its use in hypertension and diabetic nephropathy. Irbesartan (Aprovel, Avapro, Irbetan, CHEMICAL), an GENE antagonist, is approved in many countries worldwide for the treatment of hypertension. It is also approved in some regions for the treatment of nephropathy in patients with hypertension and type 2 diabetes mellitus. In adults with essential hypertension, irbesartan is effective at reducing blood pressure (BP) over a 24-hour period with once-daily administration. Irbesartan also slows the progression of renal disease in hypertensive patients with type 2 diabetes, with this effect partly independent of its BP-lowering effect. In addition, irbesartan was generally well tolerated in clinical trials. Thus, irbesartan is a useful treatment option for patients with hypertension, including those with type 2 diabetes and nephropathy. | INHIBITOR |
| DNA damage and homologous recombination signaling induced by thymidylate deprivation. DNA damage is accepted as a consequence of thymidylate deprivation induced by chemotherapeutic inhibitors of thymidylate synthase (TS), but the types of damage and signaling responses remain incompletely understood. Thymidylate deprivation increases dUTP and uracil in DNA, which is removed by base excision repair (BER). Because BER requires a synthesis step, strand break intermediates presumably accumulate. Thymidylate deprivation also induces cell cycle arrest during replication. Homologous recombination (HR) is a means of repairing persistent BER intermediates and collapsed replication forks. There are also intimate links between HR and S-phase checkpoint pathways. In this study, the goals were to determine the involvement of HR-associated proteins and DNA damage signaling responses to thymidylate deprivation. When GENE, which is a central component of HR, was depleted by siRNA cells were sensitized to CHEMICAL (RTX), which specifically inhibits TS. To our knowledge, this is the first demonstration in mammalian cells that depletion of GENE causes sensitivity to thymidylate deprivation. Activation of DNA damage signaling responses was examined following treatment with RTX. Phosphorylation of replication protein A (RPA2 subunit) and formation of damage-induced foci were strikingly evident following IC(50) doses of RTX. Induction was much more striking following RTX treatment than with hydroxyurea, which is commonly used to inhibit replication. RTX treatment also induced foci of GENE, gamma-H2AX, phospho-Chk1, and phospho-NBS1, although the extent of co-localization with RPA2 foci varied. Collectively, the results suggest that HR and S-phase checkpoint signaling processes are invoked by thymidylate deprivation and influence cellular resistance to thymidylate deprivation. | REGULATOR |
| DNA damage and homologous recombination signaling induced by thymidylate deprivation. DNA damage is accepted as a consequence of thymidylate deprivation induced by chemotherapeutic inhibitors of thymidylate synthase (TS), but the types of damage and signaling responses remain incompletely understood. Thymidylate deprivation increases dUTP and uracil in DNA, which is removed by base excision repair (BER). Because BER requires a synthesis step, strand break intermediates presumably accumulate. Thymidylate deprivation also induces cell cycle arrest during replication. Homologous recombination (HR) is a means of repairing persistent BER intermediates and collapsed replication forks. There are also intimate links between HR and S-phase checkpoint pathways. In this study, the goals were to determine the involvement of HR-associated proteins and DNA damage signaling responses to thymidylate deprivation. When GENE, which is a central component of HR, was depleted by siRNA cells were sensitized to raltitrexed (CHEMICAL), which specifically inhibits TS. To our knowledge, this is the first demonstration in mammalian cells that depletion of GENE causes sensitivity to thymidylate deprivation. Activation of DNA damage signaling responses was examined following treatment with CHEMICAL. Phosphorylation of replication protein A (RPA2 subunit) and formation of damage-induced foci were strikingly evident following IC(50) doses of CHEMICAL. Induction was much more striking following CHEMICAL treatment than with hydroxyurea, which is commonly used to inhibit replication. CHEMICAL treatment also induced foci of GENE, gamma-H2AX, phospho-Chk1, and phospho-NBS1, although the extent of co-localization with RPA2 foci varied. Collectively, the results suggest that HR and S-phase checkpoint signaling processes are invoked by thymidylate deprivation and influence cellular resistance to thymidylate deprivation. | INDIRECT-UPREGULATOR |
| DNA damage and homologous recombination signaling induced by thymidylate deprivation. DNA damage is accepted as a consequence of thymidylate deprivation induced by chemotherapeutic inhibitors of thymidylate synthase (TS), but the types of damage and signaling responses remain incompletely understood. Thymidylate deprivation increases dUTP and uracil in DNA, which is removed by base excision repair (BER). Because BER requires a synthesis step, strand break intermediates presumably accumulate. Thymidylate deprivation also induces cell cycle arrest during replication. Homologous recombination (HR) is a means of repairing persistent BER intermediates and collapsed replication forks. There are also intimate links between HR and S-phase checkpoint pathways. In this study, the goals were to determine the involvement of HR-associated proteins and DNA damage signaling responses to thymidylate deprivation. When RAD51, which is a central component of HR, was depleted by siRNA cells were sensitized to raltitrexed (RTX), which specifically inhibits TS. To our knowledge, this is the first demonstration in mammalian cells that depletion of RAD51 causes sensitivity to thymidylate deprivation. Activation of DNA damage signaling responses was examined following treatment with CHEMICAL. Phosphorylation of replication protein A (RPA2 subunit) and formation of damage-induced foci were strikingly evident following IC(50) doses of CHEMICAL. Induction was much more striking following CHEMICAL treatment than with hydroxyurea, which is commonly used to inhibit replication. CHEMICAL treatment also induced foci of RAD51, gamma-H2AX, phospho-Chk1, and phospho-NBS1, although the extent of co-localization with GENE foci varied. Collectively, the results suggest that HR and S-phase checkpoint signaling processes are invoked by thymidylate deprivation and influence cellular resistance to thymidylate deprivation. | INDIRECT-UPREGULATOR |
| DNA damage and homologous recombination signaling induced by thymidylate deprivation. DNA damage is accepted as a consequence of thymidylate deprivation induced by chemotherapeutic inhibitors of thymidylate synthase (TS), but the types of damage and signaling responses remain incompletely understood. Thymidylate deprivation increases dUTP and uracil in DNA, which is removed by base excision repair (BER). Because BER requires a synthesis step, strand break intermediates presumably accumulate. Thymidylate deprivation also induces cell cycle arrest during replication. Homologous recombination (HR) is a means of repairing persistent BER intermediates and collapsed replication forks. There are also intimate links between HR and S-phase checkpoint pathways. In this study, the goals were to determine the involvement of HR-associated proteins and DNA damage signaling responses to thymidylate deprivation. When RAD51, which is a central component of HR, was depleted by siRNA cells were sensitized to raltitrexed (RTX), which specifically inhibits TS. To our knowledge, this is the first demonstration in mammalian cells that depletion of RAD51 causes sensitivity to thymidylate deprivation. Activation of DNA damage signaling responses was examined following treatment with CHEMICAL. Phosphorylation of GENE (RPA2 subunit) and formation of damage-induced foci were strikingly evident following IC(50) doses of CHEMICAL. Induction was much more striking following CHEMICAL treatment than with hydroxyurea, which is commonly used to inhibit replication. CHEMICAL treatment also induced foci of RAD51, gamma-H2AX, phospho-Chk1, and phospho-NBS1, although the extent of co-localization with RPA2 foci varied. Collectively, the results suggest that HR and S-phase checkpoint signaling processes are invoked by thymidylate deprivation and influence cellular resistance to thymidylate deprivation. | ACTIVATOR |
| DNA damage and homologous recombination signaling induced by thymidylate deprivation. DNA damage is accepted as a consequence of thymidylate deprivation induced by chemotherapeutic inhibitors of thymidylate synthase (TS), but the types of damage and signaling responses remain incompletely understood. Thymidylate deprivation increases dUTP and uracil in DNA, which is removed by base excision repair (BER). Because BER requires a synthesis step, strand break intermediates presumably accumulate. Thymidylate deprivation also induces cell cycle arrest during replication. Homologous recombination (HR) is a means of repairing persistent BER intermediates and collapsed replication forks. There are also intimate links between HR and S-phase checkpoint pathways. In this study, the goals were to determine the involvement of HR-associated proteins and DNA damage signaling responses to thymidylate deprivation. When RAD51, which is a central component of HR, was depleted by siRNA cells were sensitized to raltitrexed (RTX), which specifically inhibits TS. To our knowledge, this is the first demonstration in mammalian cells that depletion of RAD51 causes sensitivity to thymidylate deprivation. Activation of DNA damage signaling responses was examined following treatment with CHEMICAL. Phosphorylation of replication protein A (RPA2 subunit) and formation of damage-induced foci were strikingly evident following IC(50) doses of CHEMICAL. Induction was much more striking following CHEMICAL treatment than with hydroxyurea, which is commonly used to inhibit replication. CHEMICAL treatment also induced foci of RAD51, GENE, phospho-Chk1, and phospho-NBS1, although the extent of co-localization with RPA2 foci varied. Collectively, the results suggest that HR and S-phase checkpoint signaling processes are invoked by thymidylate deprivation and influence cellular resistance to thymidylate deprivation. | INDIRECT-UPREGULATOR |
| DNA damage and homologous recombination signaling induced by thymidylate deprivation. DNA damage is accepted as a consequence of thymidylate deprivation induced by chemotherapeutic inhibitors of thymidylate synthase (TS), but the types of damage and signaling responses remain incompletely understood. Thymidylate deprivation increases dUTP and uracil in DNA, which is removed by base excision repair (BER). Because BER requires a synthesis step, strand break intermediates presumably accumulate. Thymidylate deprivation also induces cell cycle arrest during replication. Homologous recombination (HR) is a means of repairing persistent BER intermediates and collapsed replication forks. There are also intimate links between HR and S-phase checkpoint pathways. In this study, the goals were to determine the involvement of HR-associated proteins and DNA damage signaling responses to thymidylate deprivation. When RAD51, which is a central component of HR, was depleted by siRNA cells were sensitized to raltitrexed (RTX), which specifically inhibits TS. To our knowledge, this is the first demonstration in mammalian cells that depletion of RAD51 causes sensitivity to thymidylate deprivation. Activation of DNA damage signaling responses was examined following treatment with CHEMICAL. Phosphorylation of replication protein A (RPA2 subunit) and formation of damage-induced foci were strikingly evident following IC(50) doses of CHEMICAL. Induction was much more striking following CHEMICAL treatment than with hydroxyurea, which is commonly used to inhibit replication. CHEMICAL treatment also induced foci of RAD51, gamma-H2AX, GENE, and phospho-NBS1, although the extent of co-localization with RPA2 foci varied. Collectively, the results suggest that HR and S-phase checkpoint signaling processes are invoked by thymidylate deprivation and influence cellular resistance to thymidylate deprivation. | INDIRECT-UPREGULATOR |
| DNA damage and homologous recombination signaling induced by thymidylate deprivation. DNA damage is accepted as a consequence of thymidylate deprivation induced by chemotherapeutic inhibitors of thymidylate synthase (TS), but the types of damage and signaling responses remain incompletely understood. Thymidylate deprivation increases dUTP and uracil in DNA, which is removed by base excision repair (BER). Because BER requires a synthesis step, strand break intermediates presumably accumulate. Thymidylate deprivation also induces cell cycle arrest during replication. Homologous recombination (HR) is a means of repairing persistent BER intermediates and collapsed replication forks. There are also intimate links between HR and S-phase checkpoint pathways. In this study, the goals were to determine the involvement of HR-associated proteins and DNA damage signaling responses to thymidylate deprivation. When RAD51, which is a central component of HR, was depleted by siRNA cells were sensitized to raltitrexed (RTX), which specifically inhibits TS. To our knowledge, this is the first demonstration in mammalian cells that depletion of RAD51 causes sensitivity to thymidylate deprivation. Activation of DNA damage signaling responses was examined following treatment with CHEMICAL. Phosphorylation of replication protein A (RPA2 subunit) and formation of damage-induced foci were strikingly evident following IC(50) doses of CHEMICAL. Induction was much more striking following CHEMICAL treatment than with hydroxyurea, which is commonly used to inhibit replication. CHEMICAL treatment also induced foci of RAD51, gamma-H2AX, phospho-Chk1, and GENE, although the extent of co-localization with RPA2 foci varied. Collectively, the results suggest that HR and S-phase checkpoint signaling processes are invoked by thymidylate deprivation and influence cellular resistance to thymidylate deprivation. | INDIRECT-UPREGULATOR |
| DNA damage and homologous recombination signaling induced by thymidylate deprivation. DNA damage is accepted as a consequence of thymidylate deprivation induced by chemotherapeutic inhibitors of thymidylate synthase (TS), but the types of damage and signaling responses remain incompletely understood. Thymidylate deprivation increases dUTP and uracil in DNA, which is removed by base excision repair (BER). Because BER requires a synthesis step, strand break intermediates presumably accumulate. Thymidylate deprivation also induces cell cycle arrest during replication. Homologous recombination (HR) is a means of repairing persistent BER intermediates and collapsed replication forks. There are also intimate links between HR and S-phase checkpoint pathways. In this study, the goals were to determine the involvement of HR-associated proteins and DNA damage signaling responses to thymidylate deprivation. When RAD51, which is a central component of HR, was depleted by siRNA cells were sensitized to raltitrexed (CHEMICAL), which specifically inhibits GENE. To our knowledge, this is the first demonstration in mammalian cells that depletion of RAD51 causes sensitivity to thymidylate deprivation. Activation of DNA damage signaling responses was examined following treatment with CHEMICAL. Phosphorylation of replication protein A (RPA2 subunit) and formation of damage-induced foci were strikingly evident following IC(50) doses of CHEMICAL. Induction was much more striking following CHEMICAL treatment than with hydroxyurea, which is commonly used to inhibit replication. CHEMICAL treatment also induced foci of RAD51, gamma-H2AX, phospho-Chk1, and phospho-NBS1, although the extent of co-localization with RPA2 foci varied. Collectively, the results suggest that HR and S-phase checkpoint signaling processes are invoked by thymidylate deprivation and influence cellular resistance to thymidylate deprivation. | INHIBITOR |
| DNA damage and homologous recombination signaling induced by CHEMICAL deprivation. DNA damage is accepted as a consequence of CHEMICAL deprivation induced by chemotherapeutic inhibitors of GENE (TS), but the types of damage and signaling responses remain incompletely understood. CHEMICAL deprivation increases dUTP and uracil in DNA, which is removed by base excision repair (BER). Because BER requires a synthesis step, strand break intermediates presumably accumulate. CHEMICAL deprivation also induces cell cycle arrest during replication. Homologous recombination (HR) is a means of repairing persistent BER intermediates and collapsed replication forks. There are also intimate links between HR and S-phase checkpoint pathways. In this study, the goals were to determine the involvement of HR-associated proteins and DNA damage signaling responses to CHEMICAL deprivation. When RAD51, which is a central component of HR, was depleted by siRNA cells were sensitized to raltitrexed (RTX), which specifically inhibits TS. To our knowledge, this is the first demonstration in mammalian cells that depletion of RAD51 causes sensitivity to CHEMICAL deprivation. Activation of DNA damage signaling responses was examined following treatment with RTX. Phosphorylation of replication protein A (RPA2 subunit) and formation of damage-induced foci were strikingly evident following IC(50) doses of RTX. Induction was much more striking following RTX treatment than with hydroxyurea, which is commonly used to inhibit replication. RTX treatment also induced foci of RAD51, gamma-H2AX, phospho-Chk1, and phospho-NBS1, although the extent of co-localization with RPA2 foci varied. Collectively, the results suggest that HR and S-phase checkpoint signaling processes are invoked by CHEMICAL deprivation and influence cellular resistance to CHEMICAL deprivation. | INHIBITOR |
| DNA damage and homologous recombination signaling induced by CHEMICAL deprivation. DNA damage is accepted as a consequence of CHEMICAL deprivation induced by chemotherapeutic inhibitors of CHEMICAL synthase (GENE), but the types of damage and signaling responses remain incompletely understood. CHEMICAL deprivation increases dUTP and uracil in DNA, which is removed by base excision repair (BER). Because BER requires a synthesis step, strand break intermediates presumably accumulate. CHEMICAL deprivation also induces cell cycle arrest during replication. Homologous recombination (HR) is a means of repairing persistent BER intermediates and collapsed replication forks. There are also intimate links between HR and S-phase checkpoint pathways. In this study, the goals were to determine the involvement of HR-associated proteins and DNA damage signaling responses to CHEMICAL deprivation. When RAD51, which is a central component of HR, was depleted by siRNA cells were sensitized to raltitrexed (RTX), which specifically inhibits GENE. To our knowledge, this is the first demonstration in mammalian cells that depletion of RAD51 causes sensitivity to CHEMICAL deprivation. Activation of DNA damage signaling responses was examined following treatment with RTX. Phosphorylation of replication protein A (RPA2 subunit) and formation of damage-induced foci were strikingly evident following IC(50) doses of RTX. Induction was much more striking following RTX treatment than with hydroxyurea, which is commonly used to inhibit replication. RTX treatment also induced foci of RAD51, gamma-H2AX, phospho-Chk1, and phospho-NBS1, although the extent of co-localization with RPA2 foci varied. Collectively, the results suggest that HR and S-phase checkpoint signaling processes are invoked by CHEMICAL deprivation and influence cellular resistance to CHEMICAL deprivation. | INHIBITOR |
| Adipose tissue as a source of nicotinamide N-methyltransferase and homocysteine. Nicotinamide N-methyltransferase (NNMT) catalyses the conversion of nicotinamide to 1-methylnicotinamide and plays an important role in hepatic detoxification reactions. Here we show that, in addition to the liver, 3T3-L1 adipocytes as well as human and murine adipose tissue explants express high amounts of enzymatically active GENE. GENE mRNA levels and enzyme activity increased in 3T3-L1 cells in a differentiation-dependent manner. Homocysteine, the atherogenic product of the NNMT-catalyzed reaction, was secreted from 3T3-L1 cells or adipose tissue cultures. Homocysteine release increased during 3T3-L1 differentiation and was reduced when adipose tissue was treated with the GENE inhibitor 1-methylnicotinamide. Nicotinic acid (NA), a widely used drug to lower elevated plasma lipid levels, induced GENE enzyme activity in white adipose tissue of mice. In tissue culture nicotinamide treatment led to an increase in adipose tissue homocysteine secretion. These data support the concept that adipose tissue GENE contributes to the increased plasma homocysteine levels in patients treated with CHEMICAL. | REGULATOR |
| Adipose tissue as a source of nicotinamide N-methyltransferase and homocysteine. Nicotinamide N-methyltransferase (NNMT) catalyses the conversion of nicotinamide to 1-methylnicotinamide and plays an important role in hepatic detoxification reactions. Here we show that, in addition to the liver, 3T3-L1 adipocytes as well as human and murine adipose tissue explants express high amounts of enzymatically active GENE. GENE mRNA levels and enzyme activity increased in 3T3-L1 cells in a differentiation-dependent manner. Homocysteine, the atherogenic product of the NNMT-catalyzed reaction, was secreted from 3T3-L1 cells or adipose tissue cultures. Homocysteine release increased during 3T3-L1 differentiation and was reduced when adipose tissue was treated with the GENE inhibitor 1-methylnicotinamide. CHEMICAL (NA), a widely used drug to lower elevated plasma lipid levels, induced GENE enzyme activity in white adipose tissue of mice. In tissue culture nicotinamide treatment led to an increase in adipose tissue homocysteine secretion. These data support the concept that adipose tissue GENE contributes to the increased plasma homocysteine levels in patients treated with NA. | ACTIVATOR |
| Adipose tissue as a source of nicotinamide N-methyltransferase and homocysteine. Nicotinamide N-methyltransferase (NNMT) catalyses the conversion of nicotinamide to CHEMICAL and plays an important role in hepatic detoxification reactions. Here we show that, in addition to the liver, 3T3-L1 adipocytes as well as human and murine adipose tissue explants express high amounts of enzymatically active GENE. GENE mRNA levels and enzyme activity increased in 3T3-L1 cells in a differentiation-dependent manner. Homocysteine, the atherogenic product of the NNMT-catalyzed reaction, was secreted from 3T3-L1 cells or adipose tissue cultures. Homocysteine release increased during 3T3-L1 differentiation and was reduced when adipose tissue was treated with the GENE inhibitor CHEMICAL. Nicotinic acid (NA), a widely used drug to lower elevated plasma lipid levels, induced GENE enzyme activity in white adipose tissue of mice. In tissue culture nicotinamide treatment led to an increase in adipose tissue homocysteine secretion. These data support the concept that adipose tissue GENE contributes to the increased plasma homocysteine levels in patients treated with NA. | PRODUCT-OF |
| Adipose tissue as a source of nicotinamide N-methyltransferase and homocysteine. GENE (NNMT) catalyses the conversion of nicotinamide to CHEMICAL and plays an important role in hepatic detoxification reactions. Here we show that, in addition to the liver, 3T3-L1 adipocytes as well as human and murine adipose tissue explants express high amounts of enzymatically active NNMT. NNMT mRNA levels and enzyme activity increased in 3T3-L1 cells in a differentiation-dependent manner. Homocysteine, the atherogenic product of the NNMT-catalyzed reaction, was secreted from 3T3-L1 cells or adipose tissue cultures. Homocysteine release increased during 3T3-L1 differentiation and was reduced when adipose tissue was treated with the NNMT inhibitor CHEMICAL. Nicotinic acid (NA), a widely used drug to lower elevated plasma lipid levels, induced NNMT enzyme activity in white adipose tissue of mice. In tissue culture nicotinamide treatment led to an increase in adipose tissue homocysteine secretion. These data support the concept that adipose tissue NNMT contributes to the increased plasma homocysteine levels in patients treated with NA. | PRODUCT-OF |
| Adipose tissue as a source of nicotinamide N-methyltransferase and CHEMICAL. Nicotinamide N-methyltransferase (NNMT) catalyses the conversion of nicotinamide to 1-methylnicotinamide and plays an important role in hepatic detoxification reactions. Here we show that, in addition to the liver, 3T3-L1 adipocytes as well as human and murine adipose tissue explants express high amounts of enzymatically active GENE. GENE mRNA levels and enzyme activity increased in 3T3-L1 cells in a differentiation-dependent manner. CHEMICAL, the atherogenic product of the NNMT-catalyzed reaction, was secreted from 3T3-L1 cells or adipose tissue cultures. CHEMICAL release increased during 3T3-L1 differentiation and was reduced when adipose tissue was treated with the GENE inhibitor 1-methylnicotinamide. Nicotinic acid (NA), a widely used drug to lower elevated plasma lipid levels, induced GENE enzyme activity in white adipose tissue of mice. In tissue culture nicotinamide treatment led to an increase in adipose tissue CHEMICAL secretion. These data support the concept that adipose tissue GENE contributes to the increased plasma CHEMICAL levels in patients treated with NA. | PRODUCT-OF |
| Adipose tissue as a source of nicotinamide N-methyltransferase and homocysteine. Nicotinamide N-methyltransferase (NNMT) catalyses the conversion of nicotinamide to 1-methylnicotinamide and plays an important role in hepatic detoxification reactions. Here we show that, in addition to the liver, 3T3-L1 adipocytes as well as human and murine adipose tissue explants express high amounts of enzymatically active GENE. GENE mRNA levels and enzyme activity increased in 3T3-L1 cells in a differentiation-dependent manner. CHEMICAL, the atherogenic product of the GENE-catalyzed reaction, was secreted from 3T3-L1 cells or adipose tissue cultures. CHEMICAL release increased during 3T3-L1 differentiation and was reduced when adipose tissue was treated with the GENE inhibitor 1-methylnicotinamide. Nicotinic acid (NA), a widely used drug to lower elevated plasma lipid levels, induced GENE enzyme activity in white adipose tissue of mice. In tissue culture nicotinamide treatment led to an increase in adipose tissue homocysteine secretion. These data support the concept that adipose tissue GENE contributes to the increased plasma homocysteine levels in patients treated with NA. | PRODUCT-OF |
| Adipose tissue as a source of CHEMICAL N-methyltransferase and homocysteine. GENE (NNMT) catalyses the conversion of CHEMICAL to 1-methylnicotinamide and plays an important role in hepatic detoxification reactions. Here we show that, in addition to the liver, 3T3-L1 adipocytes as well as human and murine adipose tissue explants express high amounts of enzymatically active NNMT. NNMT mRNA levels and enzyme activity increased in 3T3-L1 cells in a differentiation-dependent manner. Homocysteine, the atherogenic product of the NNMT-catalyzed reaction, was secreted from 3T3-L1 cells or adipose tissue cultures. Homocysteine release increased during 3T3-L1 differentiation and was reduced when adipose tissue was treated with the NNMT inhibitor 1-methylnicotinamide. Nicotinic acid (NA), a widely used drug to lower elevated plasma lipid levels, induced NNMT enzyme activity in white adipose tissue of mice. In tissue culture CHEMICAL treatment led to an increase in adipose tissue homocysteine secretion. These data support the concept that adipose tissue NNMT contributes to the increased plasma homocysteine levels in patients treated with NA. | SUBSTRATE |
| Adipose tissue as a source of CHEMICAL N-methyltransferase and homocysteine. CHEMICAL N-methyltransferase (GENE) catalyses the conversion of CHEMICAL to 1-methylnicotinamide and plays an important role in hepatic detoxification reactions. Here we show that, in addition to the liver, 3T3-L1 adipocytes as well as human and murine adipose tissue explants express high amounts of enzymatically active GENE. GENE mRNA levels and enzyme activity increased in 3T3-L1 cells in a differentiation-dependent manner. Homocysteine, the atherogenic product of the NNMT-catalyzed reaction, was secreted from 3T3-L1 cells or adipose tissue cultures. Homocysteine release increased during 3T3-L1 differentiation and was reduced when adipose tissue was treated with the GENE inhibitor 1-methylnicotinamide. Nicotinic acid (NA), a widely used drug to lower elevated plasma lipid levels, induced GENE enzyme activity in white adipose tissue of mice. In tissue culture CHEMICAL treatment led to an increase in adipose tissue homocysteine secretion. These data support the concept that adipose tissue GENE contributes to the increased plasma homocysteine levels in patients treated with NA. | SUBSTRATE |
| Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. The L-type calcium channel (GENE) isoforms Ca(v)1.2 and Ca(v)1.3 display similar 1,4-dihydropyridine (CHEMICAL) binding properties and are both expressed in mammalian brain. Recent work implicates Ca(v)1.3 channels as interesting drug targets, but no isoform-selective modulators exist. It is also unknown to what extent Ca(v)1.1 and Ca(v)1.4 contribute to L-type-specific CHEMICAL binding activity in brain. To address this question and to determine whether DHPs can discriminate between Ca(v)1.2 and Ca(v)1.3 binding pockets, we combined radioreceptor assays and quantitative polymerase chain reaction (qPCR). We bred double mutants (Ca(v)-DM) from mice expressing mutant Ca(v)1.2 channels [Ca(v)1.2DHP(-/-)] lacking high affinity for DHPs and from Ca(v)1.3 knockouts [Ca(v)1.3(-/-)]. (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) and Ca(v)-DM brains was reduced to 15.1 and 4.4% of wild type, respectively, indicating that Ca(v)1.3 accounts for 10.7% of brain LTCCs. qPCR revealed that Ca(v)1.1 and Ca(v)1.4 alpha(1) subunits comprised 0.08% of the GENE transcripts in mouse whole brain, suggesting that they cannot account for the residual binding. Instead, this could be explained by low-affinity binding (127-fold K(d) increase) to the mutated Ca(v)1.2 channels. Inhibition of (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) (predominantly Ca(v)1.3) and wild-type (predominantly Ca(v)1.2) brain membranes by unlabeled DHPs revealed a 3- to 4-fold selectivity of nitrendipine and nifedipine for the Ca(v)1.2 binding pocket, a finding further confirmed with heterologously expressed channels. This suggests that small differences in their binding pockets may allow development of isoform-selective modulators for LTCCs and that, because of their very low expression, Ca(v)1.1 and Ca(v)1.4 are unlikely to serve as drug targets to treat CNS diseases. | DIRECT-REGULATOR |
| Expression and 1,4-dihydropyridine-binding properties of brain GENE isoforms. The GENE (LTCC) isoforms Ca(v)1.2 and Ca(v)1.3 display similar 1,4-dihydropyridine (CHEMICAL) binding properties and are both expressed in mammalian brain. Recent work implicates Ca(v)1.3 channels as interesting drug targets, but no isoform-selective modulators exist. It is also unknown to what extent Ca(v)1.1 and Ca(v)1.4 contribute to L-type-specific CHEMICAL binding activity in brain. To address this question and to determine whether DHPs can discriminate between Ca(v)1.2 and Ca(v)1.3 binding pockets, we combined radioreceptor assays and quantitative polymerase chain reaction (qPCR). We bred double mutants (Ca(v)-DM) from mice expressing mutant Ca(v)1.2 channels [Ca(v)1.2DHP(-/-)] lacking high affinity for DHPs and from Ca(v)1.3 knockouts [Ca(v)1.3(-/-)]. (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) and Ca(v)-DM brains was reduced to 15.1 and 4.4% of wild type, respectively, indicating that Ca(v)1.3 accounts for 10.7% of brain LTCCs. qPCR revealed that Ca(v)1.1 and Ca(v)1.4 alpha(1) subunits comprised 0.08% of the LTCC transcripts in mouse whole brain, suggesting that they cannot account for the residual binding. Instead, this could be explained by low-affinity binding (127-fold K(d) increase) to the mutated Ca(v)1.2 channels. Inhibition of (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) (predominantly Ca(v)1.3) and wild-type (predominantly Ca(v)1.2) brain membranes by unlabeled DHPs revealed a 3- to 4-fold selectivity of nitrendipine and nifedipine for the Ca(v)1.2 binding pocket, a finding further confirmed with heterologously expressed channels. This suggests that small differences in their binding pockets may allow development of isoform-selective modulators for LTCCs and that, because of their very low expression, Ca(v)1.1 and Ca(v)1.4 are unlikely to serve as drug targets to treat CNS diseases. | DIRECT-REGULATOR |
| Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. The L-type calcium channel (LTCC) isoforms GENE and Ca(v)1.3 display similar 1,4-dihydropyridine (CHEMICAL) binding properties and are both expressed in mammalian brain. Recent work implicates Ca(v)1.3 channels as interesting drug targets, but no isoform-selective modulators exist. It is also unknown to what extent Ca(v)1.1 and Ca(v)1.4 contribute to L-type-specific CHEMICAL binding activity in brain. To address this question and to determine whether DHPs can discriminate between GENE and Ca(v)1.3 binding pockets, we combined radioreceptor assays and quantitative polymerase chain reaction (qPCR). We bred double mutants (Ca(v)-DM) from mice expressing mutant GENE channels [Ca(v)1.2DHP(-/-)] lacking high affinity for DHPs and from Ca(v)1.3 knockouts [Ca(v)1.3(-/-)]. (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) and Ca(v)-DM brains was reduced to 15.1 and 4.4% of wild type, respectively, indicating that Ca(v)1.3 accounts for 10.7% of brain LTCCs. qPCR revealed that Ca(v)1.1 and Ca(v)1.4 alpha(1) subunits comprised 0.08% of the LTCC transcripts in mouse whole brain, suggesting that they cannot account for the residual binding. Instead, this could be explained by low-affinity binding (127-fold K(d) increase) to the mutated GENE channels. Inhibition of (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) (predominantly Ca(v)1.3) and wild-type (predominantly Ca(v)1.2) brain membranes by unlabeled DHPs revealed a 3- to 4-fold selectivity of nitrendipine and nifedipine for the GENE binding pocket, a finding further confirmed with heterologously expressed channels. This suggests that small differences in their binding pockets may allow development of isoform-selective modulators for LTCCs and that, because of their very low expression, Ca(v)1.1 and Ca(v)1.4 are unlikely to serve as drug targets to treat CNS diseases. | DIRECT-REGULATOR |
| Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. The L-type calcium channel (LTCC) isoforms Ca(v)1.2 and GENE display similar 1,4-dihydropyridine (CHEMICAL) binding properties and are both expressed in mammalian brain. Recent work implicates GENE channels as interesting drug targets, but no isoform-selective modulators exist. It is also unknown to what extent Ca(v)1.1 and Ca(v)1.4 contribute to L-type-specific CHEMICAL binding activity in brain. To address this question and to determine whether DHPs can discriminate between Ca(v)1.2 and GENE binding pockets, we combined radioreceptor assays and quantitative polymerase chain reaction (qPCR). We bred double mutants (Ca(v)-DM) from mice expressing mutant Ca(v)1.2 channels [Ca(v)1.2DHP(-/-)] lacking high affinity for DHPs and from GENE knockouts [Ca(v)1.3(-/-)]. (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) and Ca(v)-DM brains was reduced to 15.1 and 4.4% of wild type, respectively, indicating that GENE accounts for 10.7% of brain LTCCs. qPCR revealed that Ca(v)1.1 and Ca(v)1.4 alpha(1) subunits comprised 0.08% of the LTCC transcripts in mouse whole brain, suggesting that they cannot account for the residual binding. Instead, this could be explained by low-affinity binding (127-fold K(d) increase) to the mutated Ca(v)1.2 channels. Inhibition of (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) (predominantly Ca(v)1.3) and wild-type (predominantly Ca(v)1.2) brain membranes by unlabeled DHPs revealed a 3- to 4-fold selectivity of nitrendipine and nifedipine for the Ca(v)1.2 binding pocket, a finding further confirmed with heterologously expressed channels. This suggests that small differences in their binding pockets may allow development of isoform-selective modulators for LTCCs and that, because of their very low expression, Ca(v)1.1 and Ca(v)1.4 are unlikely to serve as drug targets to treat CNS diseases. | DIRECT-REGULATOR |
| Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. The L-type calcium channel (LTCC) isoforms Ca(v)1.2 and GENE display similar 1,4-dihydropyridine (DHP) binding properties and are both expressed in mammalian brain. Recent work implicates GENE channels as interesting drug targets, but no isoform-selective modulators exist. It is also unknown to what extent Ca(v)1.1 and Ca(v)1.4 contribute to L-type-specific DHP binding activity in brain. To address this question and to determine whether DHPs can discriminate between Ca(v)1.2 and GENE binding pockets, we combined radioreceptor assays and quantitative polymerase chain reaction (qPCR). We bred double mutants (Ca(v)-DM) from mice expressing mutant Ca(v)1.2 channels [Ca(v)1.2DHP(-/-)] lacking high affinity for DHPs and from GENE knockouts [Ca(v)1.3(-/-)]. CHEMICAL binding to Ca(v)1.2DHP(-/-) and Ca(v)-DM brains was reduced to 15.1 and 4.4% of wild type, respectively, indicating that GENE accounts for 10.7% of brain LTCCs. qPCR revealed that Ca(v)1.1 and Ca(v)1.4 alpha(1) subunits comprised 0.08% of the LTCC transcripts in mouse whole brain, suggesting that they cannot account for the residual binding. Instead, this could be explained by low-affinity binding (127-fold K(d) increase) to the mutated Ca(v)1.2 channels. Inhibition of CHEMICAL binding to Ca(v)1.2DHP(-/-) (predominantly GENE) and wild-type (predominantly Ca(v)1.2) brain membranes by unlabeled DHPs revealed a 3- to 4-fold selectivity of nitrendipine and nifedipine for the Ca(v)1.2 binding pocket, a finding further confirmed with heterologously expressed channels. This suggests that small differences in their binding pockets may allow development of isoform-selective modulators for LTCCs and that, because of their very low expression, Ca(v)1.1 and Ca(v)1.4 are unlikely to serve as drug targets to treat CNS diseases. | DIRECT-REGULATOR |
| Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. The L-type calcium channel (LTCC) isoforms GENE and Ca(v)1.3 display similar 1,4-dihydropyridine (DHP) binding properties and are both expressed in mammalian brain. Recent work implicates Ca(v)1.3 channels as interesting drug targets, but no isoform-selective modulators exist. It is also unknown to what extent Ca(v)1.1 and Ca(v)1.4 contribute to L-type-specific DHP binding activity in brain. To address this question and to determine whether DHPs can discriminate between GENE and Ca(v)1.3 binding pockets, we combined radioreceptor assays and quantitative polymerase chain reaction (qPCR). We bred double mutants (Ca(v)-DM) from mice expressing mutant GENE channels [Ca(v)1.2DHP(-/-)] lacking high affinity for DHPs and from Ca(v)1.3 knockouts [Ca(v)1.3(-/-)]. CHEMICAL binding to Ca(v)1.2DHP(-/-) and Ca(v)-DM brains was reduced to 15.1 and 4.4% of wild type, respectively, indicating that Ca(v)1.3 accounts for 10.7% of brain LTCCs. qPCR revealed that Ca(v)1.1 and Ca(v)1.4 alpha(1) subunits comprised 0.08% of the LTCC transcripts in mouse whole brain, suggesting that they cannot account for the residual binding. Instead, this could be explained by low-affinity binding (127-fold K(d) increase) to the mutated GENE channels. Inhibition of CHEMICAL binding to Ca(v)1.2DHP(-/-) (predominantly Ca(v)1.3) and wild-type (predominantly GENE) brain membranes by unlabeled DHPs revealed a 3- to 4-fold selectivity of nitrendipine and nifedipine for the GENE binding pocket, a finding further confirmed with heterologously expressed channels. This suggests that small differences in their binding pockets may allow development of isoform-selective modulators for LTCCs and that, because of their very low expression, Ca(v)1.1 and Ca(v)1.4 are unlikely to serve as drug targets to treat CNS diseases. | DIRECT-REGULATOR |
| Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. The L-type calcium channel (LTCC) isoforms GENE and Ca(v)1.3 display similar 1,4-dihydropyridine (DHP) binding properties and are both expressed in mammalian brain. Recent work implicates Ca(v)1.3 channels as interesting drug targets, but no isoform-selective modulators exist. It is also unknown to what extent Ca(v)1.1 and Ca(v)1.4 contribute to L-type-specific DHP binding activity in brain. To address this question and to determine whether DHPs can discriminate between GENE and Ca(v)1.3 binding pockets, we combined radioreceptor assays and quantitative polymerase chain reaction (qPCR). We bred double mutants (Ca(v)-DM) from mice expressing mutant GENE channels [Ca(v)1.2DHP(-/-)] lacking high affinity for DHPs and from Ca(v)1.3 knockouts [Ca(v)1.3(-/-)]. (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) and Ca(v)-DM brains was reduced to 15.1 and 4.4% of wild type, respectively, indicating that Ca(v)1.3 accounts for 10.7% of brain LTCCs. qPCR revealed that Ca(v)1.1 and Ca(v)1.4 alpha(1) subunits comprised 0.08% of the LTCC transcripts in mouse whole brain, suggesting that they cannot account for the residual binding. Instead, this could be explained by low-affinity binding (127-fold K(d) increase) to the mutated GENE channels. Inhibition of (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) (predominantly Ca(v)1.3) and wild-type (predominantly Ca(v)1.2) brain membranes by unlabeled DHPs revealed a 3- to 4-fold selectivity of CHEMICAL and nifedipine for the GENE binding pocket, a finding further confirmed with heterologously expressed channels. This suggests that small differences in their binding pockets may allow development of isoform-selective modulators for LTCCs and that, because of their very low expression, Ca(v)1.1 and Ca(v)1.4 are unlikely to serve as drug targets to treat CNS diseases. | DIRECT-REGULATOR |
| Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. The L-type calcium channel (LTCC) isoforms GENE and Ca(v)1.3 display similar 1,4-dihydropyridine (DHP) binding properties and are both expressed in mammalian brain. Recent work implicates Ca(v)1.3 channels as interesting drug targets, but no isoform-selective modulators exist. It is also unknown to what extent Ca(v)1.1 and Ca(v)1.4 contribute to L-type-specific DHP binding activity in brain. To address this question and to determine whether DHPs can discriminate between GENE and Ca(v)1.3 binding pockets, we combined radioreceptor assays and quantitative polymerase chain reaction (qPCR). We bred double mutants (Ca(v)-DM) from mice expressing mutant GENE channels [Ca(v)1.2DHP(-/-)] lacking high affinity for DHPs and from Ca(v)1.3 knockouts [Ca(v)1.3(-/-)]. (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) and Ca(v)-DM brains was reduced to 15.1 and 4.4% of wild type, respectively, indicating that Ca(v)1.3 accounts for 10.7% of brain LTCCs. qPCR revealed that Ca(v)1.1 and Ca(v)1.4 alpha(1) subunits comprised 0.08% of the LTCC transcripts in mouse whole brain, suggesting that they cannot account for the residual binding. Instead, this could be explained by low-affinity binding (127-fold K(d) increase) to the mutated GENE channels. Inhibition of (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) (predominantly Ca(v)1.3) and wild-type (predominantly Ca(v)1.2) brain membranes by unlabeled DHPs revealed a 3- to 4-fold selectivity of nitrendipine and CHEMICAL for the GENE binding pocket, a finding further confirmed with heterologously expressed channels. This suggests that small differences in their binding pockets may allow development of isoform-selective modulators for LTCCs and that, because of their very low expression, Ca(v)1.1 and Ca(v)1.4 are unlikely to serve as drug targets to treat CNS diseases. | DIRECT-REGULATOR |
| Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. The L-type calcium channel (LTCC) isoforms Ca(v)1.2 and Ca(v)1.3 display similar 1,4-dihydropyridine (DHP) binding properties and are both expressed in mammalian brain. Recent work implicates Ca(v)1.3 channels as interesting drug targets, but no isoform-selective modulators exist. It is also unknown to what extent Ca(v)1.1 and Ca(v)1.4 contribute to L-type-specific DHP binding activity in brain. To address this question and to determine whether DHPs can discriminate between Ca(v)1.2 and Ca(v)1.3 binding pockets, we combined radioreceptor assays and quantitative polymerase chain reaction (qPCR). We bred double mutants (Ca(v)-DM) from mice expressing mutant Ca(v)1.2 channels [Ca(v)1.2DHP(-/-)] lacking high affinity for DHPs and from Ca(v)1.3 knockouts [Ca(v)1.3(-/-)]. CHEMICAL binding to Ca(v)1.2DHP(-/-) and GENE-DM brains was reduced to 15.1 and 4.4% of wild type, respectively, indicating that Ca(v)1.3 accounts for 10.7% of brain LTCCs. qPCR revealed that Ca(v)1.1 and Ca(v)1.4 alpha(1) subunits comprised 0.08% of the LTCC transcripts in mouse whole brain, suggesting that they cannot account for the residual binding. Instead, this could be explained by low-affinity binding (127-fold K(d) increase) to the mutated Ca(v)1.2 channels. Inhibition of CHEMICAL binding to Ca(v)1.2DHP(-/-) (predominantly Ca(v)1.3) and wild-type (predominantly Ca(v)1.2) brain membranes by unlabeled DHPs revealed a 3- to 4-fold selectivity of nitrendipine and nifedipine for the Ca(v)1.2 binding pocket, a finding further confirmed with heterologously expressed channels. This suggests that small differences in their binding pockets may allow development of isoform-selective modulators for LTCCs and that, because of their very low expression, Ca(v)1.1 and Ca(v)1.4 are unlikely to serve as drug targets to treat CNS diseases. | DIRECT-REGULATOR |
| Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. The L-type calcium channel (LTCC) isoforms Ca(v)1.2 and Ca(v)1.3 display similar 1,4-dihydropyridine (DHP) binding properties and are both expressed in mammalian brain. Recent work implicates Ca(v)1.3 channels as interesting drug targets, but no isoform-selective modulators exist. It is also unknown to what extent Ca(v)1.1 and Ca(v)1.4 contribute to L-type-specific DHP binding activity in brain. To address this question and to determine whether DHPs can discriminate between Ca(v)1.2 and Ca(v)1.3 binding pockets, we combined radioreceptor assays and quantitative polymerase chain reaction (qPCR). We bred double mutants (Ca(v)-DM) from mice expressing mutant Ca(v)1.2 channels [Ca(v)1.2DHP(-/-)] lacking high affinity for DHPs and from Ca(v)1.3 knockouts [Ca(v)1.3(-/-)]. CHEMICAL binding to Ca(v)1.2DHP(-/-) and Ca(v)-DM brains was reduced to 15.1 and 4.4% of wild type, respectively, indicating that Ca(v)1.3 accounts for 10.7% of brain GENE. qPCR revealed that Ca(v)1.1 and Ca(v)1.4 alpha(1) subunits comprised 0.08% of the LTCC transcripts in mouse whole brain, suggesting that they cannot account for the residual binding. Instead, this could be explained by low-affinity binding (127-fold K(d) increase) to the mutated Ca(v)1.2 channels. Inhibition of CHEMICAL binding to Ca(v)1.2DHP(-/-) (predominantly Ca(v)1.3) and wild-type (predominantly Ca(v)1.2) brain membranes by unlabeled DHPs revealed a 3- to 4-fold selectivity of nitrendipine and nifedipine for the Ca(v)1.2 binding pocket, a finding further confirmed with heterologously expressed channels. This suggests that small differences in their binding pockets may allow development of isoform-selective modulators for GENE and that, because of their very low expression, Ca(v)1.1 and Ca(v)1.4 are unlikely to serve as drug targets to treat CNS diseases. | DIRECT-REGULATOR |
| Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. The L-type calcium channel (GENE) isoforms Ca(v)1.2 and Ca(v)1.3 display similar CHEMICAL (DHP) binding properties and are both expressed in mammalian brain. Recent work implicates Ca(v)1.3 channels as interesting drug targets, but no isoform-selective modulators exist. It is also unknown to what extent Ca(v)1.1 and Ca(v)1.4 contribute to L-type-specific DHP binding activity in brain. To address this question and to determine whether DHPs can discriminate between Ca(v)1.2 and Ca(v)1.3 binding pockets, we combined radioreceptor assays and quantitative polymerase chain reaction (qPCR). We bred double mutants (Ca(v)-DM) from mice expressing mutant Ca(v)1.2 channels [Ca(v)1.2DHP(-/-)] lacking high affinity for DHPs and from Ca(v)1.3 knockouts [Ca(v)1.3(-/-)]. (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) and Ca(v)-DM brains was reduced to 15.1 and 4.4% of wild type, respectively, indicating that Ca(v)1.3 accounts for 10.7% of brain LTCCs. qPCR revealed that Ca(v)1.1 and Ca(v)1.4 alpha(1) subunits comprised 0.08% of the GENE transcripts in mouse whole brain, suggesting that they cannot account for the residual binding. Instead, this could be explained by low-affinity binding (127-fold K(d) increase) to the mutated Ca(v)1.2 channels. Inhibition of (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) (predominantly Ca(v)1.3) and wild-type (predominantly Ca(v)1.2) brain membranes by unlabeled DHPs revealed a 3- to 4-fold selectivity of nitrendipine and nifedipine for the Ca(v)1.2 binding pocket, a finding further confirmed with heterologously expressed channels. This suggests that small differences in their binding pockets may allow development of isoform-selective modulators for LTCCs and that, because of their very low expression, Ca(v)1.1 and Ca(v)1.4 are unlikely to serve as drug targets to treat CNS diseases. | DIRECT-REGULATOR |
| Expression and 1,4-dihydropyridine-binding properties of brain GENE isoforms. The GENE (LTCC) isoforms Ca(v)1.2 and Ca(v)1.3 display similar CHEMICAL (DHP) binding properties and are both expressed in mammalian brain. Recent work implicates Ca(v)1.3 channels as interesting drug targets, but no isoform-selective modulators exist. It is also unknown to what extent Ca(v)1.1 and Ca(v)1.4 contribute to L-type-specific DHP binding activity in brain. To address this question and to determine whether DHPs can discriminate between Ca(v)1.2 and Ca(v)1.3 binding pockets, we combined radioreceptor assays and quantitative polymerase chain reaction (qPCR). We bred double mutants (Ca(v)-DM) from mice expressing mutant Ca(v)1.2 channels [Ca(v)1.2DHP(-/-)] lacking high affinity for DHPs and from Ca(v)1.3 knockouts [Ca(v)1.3(-/-)]. (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) and Ca(v)-DM brains was reduced to 15.1 and 4.4% of wild type, respectively, indicating that Ca(v)1.3 accounts for 10.7% of brain LTCCs. qPCR revealed that Ca(v)1.1 and Ca(v)1.4 alpha(1) subunits comprised 0.08% of the LTCC transcripts in mouse whole brain, suggesting that they cannot account for the residual binding. Instead, this could be explained by low-affinity binding (127-fold K(d) increase) to the mutated Ca(v)1.2 channels. Inhibition of (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) (predominantly Ca(v)1.3) and wild-type (predominantly Ca(v)1.2) brain membranes by unlabeled DHPs revealed a 3- to 4-fold selectivity of nitrendipine and nifedipine for the Ca(v)1.2 binding pocket, a finding further confirmed with heterologously expressed channels. This suggests that small differences in their binding pockets may allow development of isoform-selective modulators for LTCCs and that, because of their very low expression, Ca(v)1.1 and Ca(v)1.4 are unlikely to serve as drug targets to treat CNS diseases. | DIRECT-REGULATOR |
| Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. The L-type calcium channel (LTCC) isoforms GENE and Ca(v)1.3 display similar CHEMICAL (DHP) binding properties and are both expressed in mammalian brain. Recent work implicates Ca(v)1.3 channels as interesting drug targets, but no isoform-selective modulators exist. It is also unknown to what extent Ca(v)1.1 and Ca(v)1.4 contribute to L-type-specific DHP binding activity in brain. To address this question and to determine whether DHPs can discriminate between GENE and Ca(v)1.3 binding pockets, we combined radioreceptor assays and quantitative polymerase chain reaction (qPCR). We bred double mutants (Ca(v)-DM) from mice expressing mutant GENE channels [Ca(v)1.2DHP(-/-)] lacking high affinity for DHPs and from Ca(v)1.3 knockouts [Ca(v)1.3(-/-)]. (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) and Ca(v)-DM brains was reduced to 15.1 and 4.4% of wild type, respectively, indicating that Ca(v)1.3 accounts for 10.7% of brain LTCCs. qPCR revealed that Ca(v)1.1 and Ca(v)1.4 alpha(1) subunits comprised 0.08% of the LTCC transcripts in mouse whole brain, suggesting that they cannot account for the residual binding. Instead, this could be explained by low-affinity binding (127-fold K(d) increase) to the mutated GENE channels. Inhibition of (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) (predominantly Ca(v)1.3) and wild-type (predominantly Ca(v)1.2) brain membranes by unlabeled DHPs revealed a 3- to 4-fold selectivity of nitrendipine and nifedipine for the GENE binding pocket, a finding further confirmed with heterologously expressed channels. This suggests that small differences in their binding pockets may allow development of isoform-selective modulators for LTCCs and that, because of their very low expression, Ca(v)1.1 and Ca(v)1.4 are unlikely to serve as drug targets to treat CNS diseases. | DIRECT-REGULATOR |
| Expression and 1,4-dihydropyridine-binding properties of brain L-type calcium channel isoforms. The L-type calcium channel (LTCC) isoforms Ca(v)1.2 and GENE display similar CHEMICAL (DHP) binding properties and are both expressed in mammalian brain. Recent work implicates GENE channels as interesting drug targets, but no isoform-selective modulators exist. It is also unknown to what extent Ca(v)1.1 and Ca(v)1.4 contribute to L-type-specific DHP binding activity in brain. To address this question and to determine whether DHPs can discriminate between Ca(v)1.2 and GENE binding pockets, we combined radioreceptor assays and quantitative polymerase chain reaction (qPCR). We bred double mutants (Ca(v)-DM) from mice expressing mutant Ca(v)1.2 channels [Ca(v)1.2DHP(-/-)] lacking high affinity for DHPs and from GENE knockouts [Ca(v)1.3(-/-)]. (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) and Ca(v)-DM brains was reduced to 15.1 and 4.4% of wild type, respectively, indicating that GENE accounts for 10.7% of brain LTCCs. qPCR revealed that Ca(v)1.1 and Ca(v)1.4 alpha(1) subunits comprised 0.08% of the LTCC transcripts in mouse whole brain, suggesting that they cannot account for the residual binding. Instead, this could be explained by low-affinity binding (127-fold K(d) increase) to the mutated Ca(v)1.2 channels. Inhibition of (+)-[(3)H]isradipine binding to Ca(v)1.2DHP(-/-) (predominantly Ca(v)1.3) and wild-type (predominantly Ca(v)1.2) brain membranes by unlabeled DHPs revealed a 3- to 4-fold selectivity of nitrendipine and nifedipine for the Ca(v)1.2 binding pocket, a finding further confirmed with heterologously expressed channels. This suggests that small differences in their binding pockets may allow development of isoform-selective modulators for LTCCs and that, because of their very low expression, Ca(v)1.1 and Ca(v)1.4 are unlikely to serve as drug targets to treat CNS diseases. | DIRECT-REGULATOR |
| Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. The detailed molecular mechanism of action of second-generation BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor bosutinib employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of bosutinib targets comprised of over 45 novel tyrosine and serine/threonine kinases. We have found clear differences in the target patterns of bosutinib in primary CML cells versus the K562 cell line. A comparison of bosutinib with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. CHEMICAL did not inhibit GENE or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo bosutinib is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the mid-nanomolar range. Finally, bosutinib is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation. | NO-RELATIONSHIP |
| Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. The detailed molecular mechanism of action of second-generation BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor bosutinib employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of bosutinib targets comprised of over 45 novel tyrosine and serine/threonine kinases. We have found clear differences in the target patterns of bosutinib in primary CML cells versus the K562 cell line. A comparison of bosutinib with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. CHEMICAL did not inhibit KIT or GENE, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo bosutinib is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the mid-nanomolar range. Finally, bosutinib is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation. | NO-RELATIONSHIP |
| Global target profile of the kinase inhibitor CHEMICAL in primary chronic myeloid leukemia cells. The detailed molecular mechanism of action of second-generation BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor CHEMICAL employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of CHEMICAL targets comprised of over 45 novel tyrosine and serine/threonine kinases. We have found clear differences in the target patterns of CHEMICAL in primary CML cells versus the K562 cell line. A comparison of CHEMICAL with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, GENE and TEC family kinases. CHEMICAL did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo CHEMICAL is inactive against GENE T315I, we found this clinically important mutant to be enzymatically inhibited in the mid-nanomolar range. Finally, CHEMICAL is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation. | NO-RELATIONSHIP |
| Global target profile of the kinase inhibitor CHEMICAL in primary chronic myeloid leukemia cells. The detailed molecular mechanism of action of second-generation BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor CHEMICAL employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of CHEMICAL targets comprised of over 45 novel tyrosine and serine/threonine kinases. We have found clear differences in the target patterns of CHEMICAL in primary CML cells versus the K562 cell line. A comparison of CHEMICAL with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. CHEMICAL did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo CHEMICAL is inactive against ABL GENE, we found this clinically important mutant to be enzymatically inhibited in the mid-nanomolar range. Finally, CHEMICAL is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation. | NO-RELATIONSHIP |
| Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. The detailed molecular mechanism of action of second-generation BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor bosutinib employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of bosutinib targets comprised of over 45 novel tyrosine and serine/threonine kinases. We have found clear differences in the target patterns of bosutinib in primary CML cells versus the K562 cell line. A comparison of bosutinib with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. CHEMICAL did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked GENE. Although in vivo bosutinib is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the mid-nanomolar range. Finally, bosutinib is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation. | REGULATOR |
| Global target profile of the GENE inhibitor bosutinib in primary chronic myeloid leukemia cells. The detailed molecular mechanism of action of second-generation BCR-ABL tyrosine GENE inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor bosutinib employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro GENE assays against a large recombinant GENE panel. The combined strategy resulted in a global survey of bosutinib targets comprised of over 45 novel tyrosine and serine/threonine kinases. We have found clear differences in the target patterns of bosutinib in primary CML cells versus the K562 cell line. A comparison of bosutinib with CHEMICAL across the whole GENE panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. Bosutinib did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo bosutinib is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the mid-nanomolar range. Finally, bosutinib is the first GENE inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation. | DIRECT-REGULATOR |
| Global target profile of the GENE inhibitor CHEMICAL in primary chronic myeloid leukemia cells. The detailed molecular mechanism of action of second-generation BCR-ABL tyrosine GENE inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor CHEMICAL employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro GENE assays against a large recombinant GENE panel. The combined strategy resulted in a global survey of CHEMICAL targets comprised of over 45 novel tyrosine and serine/threonine kinases. We have found clear differences in the target patterns of CHEMICAL in primary CML cells versus the K562 cell line. A comparison of CHEMICAL with dasatinib across the whole GENE panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. CHEMICAL did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo CHEMICAL is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the mid-nanomolar range. Finally, CHEMICAL is the first GENE inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation. | INHIBITOR |
| Global target profile of the kinase inhibitor CHEMICAL in primary chronic myeloid leukemia cells. The detailed molecular mechanism of action of second-generation BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor CHEMICAL employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of CHEMICAL targets comprised of over 45 novel tyrosine and serine/threonine kinases. We have found clear differences in the target patterns of CHEMICAL in primary CML cells versus the K562 cell line. A comparison of CHEMICAL with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. CHEMICAL did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo CHEMICAL is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the mid-nanomolar range. Finally, CHEMICAL is the first kinase inhibitor shown to target GENE, recently implicated in myeloid leukemia cell proliferation. | INHIBITOR |
| Global target profile of the kinase inhibitor CHEMICAL in primary chronic myeloid leukemia cells. The detailed molecular mechanism of action of second-generation BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual GENE/ABL inhibitor CHEMICAL employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of CHEMICAL targets comprised of over 45 novel tyrosine and serine/threonine kinases. We have found clear differences in the target patterns of CHEMICAL in primary CML cells versus the K562 cell line. A comparison of CHEMICAL with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the GENE, ABL and TEC family kinases. CHEMICAL did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo CHEMICAL is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the mid-nanomolar range. Finally, CHEMICAL is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation. | INHIBITOR |
| The effect of estramustine derivatives on microtubule assembly in vitro depends on the charge of the substituent. Estramustine, and derivatives of estramustine with a charged substituent at position 17 on the estrogen moiety, have been investigated for their effects on bovine brain microtubules in vitro. The negatively charged estramustine phosphate has been found previously to be a microtubule-associated protein (MAP)-dependent microtubule inhibitor [Wallin M, Deinum J and Friden B, FEBS Lett 179: 289-293, 1985]. In the present study the binding of estramustine phosphate to MAP2 and tau was investigated. Both these GENE were found to have two to three binding sites for estramustine phosphate which is compatible with the reported number of basic amino acid repeats of these GENE, considered to be the ultimate tubulin binding domains. The Kd for the binding of estramustine phosphate to MAP2 was estimated to be 20 microM at 4 degrees, and for the binding of tau, 200 microM. The rate of dissociation was very low (T1/2 greater than 2 hr), which indicates that the binding of estramustine phosphate may stabilize the protein-drug complex by changing the protein conformation. Two new negatively charged estramustine derivatives, estramustine sulphate and estramustine glucuronide, were found to be similar MAP-dependent microtubule inhibitors. The concentration for 50% inhibition of assembly was 100 microM for the sulphate derivative, the same as found previously for estramustine phosphate, and 250 microM for the more bulky estramustine glucuronide. A positively charged derivative, CHEMICAL, did not inhibit microtubule assembly or alter the composition of the coassembled GENE. The morphology of the microtubules was, however, affected. The uncharged estramustine bound to both tubulin and GENE, but no effects were seen on microtubule assembly, the composition of coassembled GENE or the microtubule morphology. Our results suggest that only negatively charged estramustine derivatives have a MAP-dependent microtubule inhibitory effect. The two new negatively charged derivatives could therefore be valuable tools in the study of tubulin-MAP interactions. The results also confirm that these interactions between tubulin and GENE are mainly electrostatic. | NO-RELATIONSHIP |
| The effect of CHEMICAL derivatives on microtubule assembly in vitro depends on the charge of the substituent. CHEMICAL, and derivatives of CHEMICAL with a charged substituent at position 17 on the estrogen moiety, have been investigated for their effects on bovine brain microtubules in vitro. The negatively charged CHEMICAL phosphate has been found previously to be a microtubule-associated protein (MAP)-dependent microtubule inhibitor [Wallin M, Deinum J and Friden B, FEBS Lett 179: 289-293, 1985]. In the present study the binding of CHEMICAL phosphate to MAP2 and tau was investigated. Both these GENE were found to have two to three binding sites for CHEMICAL phosphate which is compatible with the reported number of basic amino acid repeats of these GENE, considered to be the ultimate tubulin binding domains. The Kd for the binding of CHEMICAL phosphate to MAP2 was estimated to be 20 microM at 4 degrees, and for the binding of tau, 200 microM. The rate of dissociation was very low (T1/2 greater than 2 hr), which indicates that the binding of CHEMICAL phosphate may stabilize the protein-drug complex by changing the protein conformation. Two new negatively charged CHEMICAL derivatives, CHEMICAL sulphate and CHEMICAL glucuronide, were found to be similar MAP-dependent microtubule inhibitors. The concentration for 50% inhibition of assembly was 100 microM for the sulphate derivative, the same as found previously for CHEMICAL phosphate, and 250 microM for the more bulky CHEMICAL glucuronide. A positively charged derivative, CHEMICAL sarcosinate, did not inhibit microtubule assembly or alter the composition of the coassembled GENE. The morphology of the microtubules was, however, affected. The uncharged CHEMICAL bound to both tubulin and GENE, but no effects were seen on microtubule assembly, the composition of coassembled GENE or the microtubule morphology. Our results suggest that only negatively charged CHEMICAL derivatives have a MAP-dependent microtubule inhibitory effect. The two new negatively charged derivatives could therefore be valuable tools in the study of tubulin-MAP interactions. The results also confirm that these interactions between tubulin and GENE are mainly electrostatic. | DIRECT-REGULATOR |
| The effect of estramustine derivatives on microtubule assembly in vitro depends on the charge of the substituent. Estramustine, and derivatives of estramustine with a charged substituent at position 17 on the estrogen moiety, have been investigated for their effects on bovine brain microtubules in vitro. The negatively charged estramustine phosphate has been found previously to be a microtubule-associated protein (MAP)-dependent microtubule inhibitor [Wallin M, Deinum J and Friden B, FEBS Lett 179: 289-293, 1985]. In the present study the binding of estramustine phosphate to MAP2 and tau was investigated. Both these GENE were found to have two to three binding sites for estramustine phosphate which is compatible with the reported number of basic CHEMICAL repeats of these GENE, considered to be the ultimate tubulin binding domains. The Kd for the binding of estramustine phosphate to MAP2 was estimated to be 20 microM at 4 degrees, and for the binding of tau, 200 microM. The rate of dissociation was very low (T1/2 greater than 2 hr), which indicates that the binding of estramustine phosphate may stabilize the protein-drug complex by changing the protein conformation. Two new negatively charged estramustine derivatives, estramustine sulphate and estramustine glucuronide, were found to be similar MAP-dependent microtubule inhibitors. The concentration for 50% inhibition of assembly was 100 microM for the sulphate derivative, the same as found previously for estramustine phosphate, and 250 microM for the more bulky estramustine glucuronide. A positively charged derivative, estramustine sarcosinate, did not inhibit microtubule assembly or alter the composition of the coassembled GENE. The morphology of the microtubules was, however, affected. The uncharged estramustine bound to both tubulin and GENE, but no effects were seen on microtubule assembly, the composition of coassembled GENE or the microtubule morphology. Our results suggest that only negatively charged estramustine derivatives have a MAP-dependent microtubule inhibitory effect. The two new negatively charged derivatives could therefore be valuable tools in the study of tubulin-MAP interactions. The results also confirm that these interactions between tubulin and GENE are mainly electrostatic. | PART-OF |
| The effect of estramustine derivatives on microtubule assembly in vitro depends on the charge of the substituent. Estramustine, and derivatives of estramustine with a charged substituent at position 17 on the estrogen moiety, have been investigated for their effects on bovine brain microtubules in vitro. The negatively charged estramustine phosphate has been found previously to be a microtubule-associated protein (MAP)-dependent microtubule inhibitor [Wallin M, Deinum J and Friden B, FEBS Lett 179: 289-293, 1985]. In the present study the binding of estramustine phosphate to MAP2 and tau was investigated. Both these MAPs were found to have two to three binding sites for estramustine phosphate which is compatible with the reported number of basic CHEMICAL repeats of these MAPs, considered to be the ultimate GENE binding domains. The Kd for the binding of estramustine phosphate to MAP2 was estimated to be 20 microM at 4 degrees, and for the binding of tau, 200 microM. The rate of dissociation was very low (T1/2 greater than 2 hr), which indicates that the binding of estramustine phosphate may stabilize the protein-drug complex by changing the protein conformation. Two new negatively charged estramustine derivatives, estramustine sulphate and estramustine glucuronide, were found to be similar MAP-dependent microtubule inhibitors. The concentration for 50% inhibition of assembly was 100 microM for the sulphate derivative, the same as found previously for estramustine phosphate, and 250 microM for the more bulky estramustine glucuronide. A positively charged derivative, estramustine sarcosinate, did not inhibit microtubule assembly or alter the composition of the coassembled MAPs. The morphology of the microtubules was, however, affected. The uncharged estramustine bound to both GENE and MAPs, but no effects were seen on microtubule assembly, the composition of coassembled MAPs or the microtubule morphology. Our results suggest that only negatively charged estramustine derivatives have a MAP-dependent microtubule inhibitory effect. The two new negatively charged derivatives could therefore be valuable tools in the study of tubulin-MAP interactions. The results also confirm that these interactions between GENE and MAPs are mainly electrostatic. | PART-OF |
| The effect of estramustine derivatives on microtubule assembly in vitro depends on the charge of the substituent. Estramustine, and derivatives of estramustine with a charged substituent at position 17 on the estrogen moiety, have been investigated for their effects on bovine brain microtubules in vitro. The negatively charged CHEMICAL has been found previously to be a microtubule-associated protein (MAP)-dependent microtubule inhibitor [Wallin M, Deinum J and Friden B, FEBS Lett 179: 289-293, 1985]. In the present study the binding of CHEMICAL to MAP2 and tau was investigated. Both these GENE were found to have two to three binding sites for CHEMICAL which is compatible with the reported number of basic amino acid repeats of these GENE, considered to be the ultimate tubulin binding domains. The Kd for the binding of CHEMICAL to MAP2 was estimated to be 20 microM at 4 degrees, and for the binding of tau, 200 microM. The rate of dissociation was very low (T1/2 greater than 2 hr), which indicates that the binding of CHEMICAL may stabilize the protein-drug complex by changing the protein conformation. Two new negatively charged estramustine derivatives, estramustine sulphate and estramustine glucuronide, were found to be similar MAP-dependent microtubule inhibitors. The concentration for 50% inhibition of assembly was 100 microM for the sulphate derivative, the same as found previously for CHEMICAL, and 250 microM for the more bulky estramustine glucuronide. A positively charged derivative, estramustine sarcosinate, did not inhibit microtubule assembly or alter the composition of the coassembled GENE. The morphology of the microtubules was, however, affected. The uncharged estramustine bound to both tubulin and GENE, but no effects were seen on microtubule assembly, the composition of coassembled GENE or the microtubule morphology. Our results suggest that only negatively charged estramustine derivatives have a MAP-dependent microtubule inhibitory effect. The two new negatively charged derivatives could therefore be valuable tools in the study of tubulin-MAP interactions. The results also confirm that these interactions between tubulin and GENE are mainly electrostatic. | DIRECT-REGULATOR |
| The effect of estramustine derivatives on microtubule assembly in vitro depends on the charge of the substituent. Estramustine, and derivatives of estramustine with a charged substituent at position 17 on the estrogen moiety, have been investigated for their effects on bovine brain microtubules in vitro. The negatively charged CHEMICAL has been found previously to be a microtubule-associated protein (MAP)-dependent microtubule inhibitor [Wallin M, Deinum J and Friden B, FEBS Lett 179: 289-293, 1985]. In the present study the binding of CHEMICAL to GENE and tau was investigated. Both these MAPs were found to have two to three binding sites for CHEMICAL which is compatible with the reported number of basic amino acid repeats of these MAPs, considered to be the ultimate tubulin binding domains. The Kd for the binding of CHEMICAL to GENE was estimated to be 20 microM at 4 degrees, and for the binding of tau, 200 microM. The rate of dissociation was very low (T1/2 greater than 2 hr), which indicates that the binding of CHEMICAL may stabilize the protein-drug complex by changing the protein conformation. Two new negatively charged estramustine derivatives, estramustine sulphate and estramustine glucuronide, were found to be similar MAP-dependent microtubule inhibitors. The concentration for 50% inhibition of assembly was 100 microM for the sulphate derivative, the same as found previously for CHEMICAL, and 250 microM for the more bulky estramustine glucuronide. A positively charged derivative, estramustine sarcosinate, did not inhibit microtubule assembly or alter the composition of the coassembled MAPs. The morphology of the microtubules was, however, affected. The uncharged estramustine bound to both tubulin and MAPs, but no effects were seen on microtubule assembly, the composition of coassembled MAPs or the microtubule morphology. Our results suggest that only negatively charged estramustine derivatives have a MAP-dependent microtubule inhibitory effect. The two new negatively charged derivatives could therefore be valuable tools in the study of tubulin-MAP interactions. The results also confirm that these interactions between tubulin and MAPs are mainly electrostatic. | DIRECT-REGULATOR |
| The effect of CHEMICAL derivatives on microtubule assembly in vitro depends on the charge of the substituent. CHEMICAL, and derivatives of CHEMICAL with a charged substituent at position 17 on the estrogen moiety, have been investigated for their effects on bovine brain microtubules in vitro. The negatively charged CHEMICAL phosphate has been found previously to be a microtubule-associated protein (MAP)-dependent microtubule inhibitor [Wallin M, Deinum J and Friden B, FEBS Lett 179: 289-293, 1985]. In the present study the binding of CHEMICAL phosphate to MAP2 and tau was investigated. Both these MAPs were found to have two to three binding sites for CHEMICAL phosphate which is compatible with the reported number of basic amino acid repeats of these MAPs, considered to be the ultimate GENE binding domains. The Kd for the binding of CHEMICAL phosphate to MAP2 was estimated to be 20 microM at 4 degrees, and for the binding of tau, 200 microM. The rate of dissociation was very low (T1/2 greater than 2 hr), which indicates that the binding of CHEMICAL phosphate may stabilize the protein-drug complex by changing the protein conformation. Two new negatively charged CHEMICAL derivatives, CHEMICAL sulphate and CHEMICAL glucuronide, were found to be similar MAP-dependent microtubule inhibitors. The concentration for 50% inhibition of assembly was 100 microM for the sulphate derivative, the same as found previously for CHEMICAL phosphate, and 250 microM for the more bulky CHEMICAL glucuronide. A positively charged derivative, CHEMICAL sarcosinate, did not inhibit microtubule assembly or alter the composition of the coassembled MAPs. The morphology of the microtubules was, however, affected. The uncharged CHEMICAL bound to both GENE and MAPs, but no effects were seen on microtubule assembly, the composition of coassembled MAPs or the microtubule morphology. Our results suggest that only negatively charged CHEMICAL derivatives have a MAP-dependent microtubule inhibitory effect. The two new negatively charged derivatives could therefore be valuable tools in the study of tubulin-MAP interactions. The results also confirm that these interactions between GENE and MAPs are mainly electrostatic. | DIRECT-REGULATOR |
| The effect of CHEMICAL derivatives on microtubule assembly in vitro depends on the charge of the substituent. CHEMICAL, and derivatives of CHEMICAL with a charged substituent at position 17 on the estrogen moiety, have been investigated for their effects on bovine brain microtubules in vitro. The negatively charged CHEMICAL phosphate has been found previously to be a microtubule-associated protein (MAP)-dependent microtubule inhibitor [Wallin M, Deinum J and Friden B, FEBS Lett 179: 289-293, 1985]. In the present study the binding of CHEMICAL phosphate to MAP2 and tau was investigated. Both these MAPs were found to have two to three binding sites for CHEMICAL phosphate which is compatible with the reported number of basic amino acid repeats of these MAPs, considered to be the ultimate tubulin binding domains. The Kd for the binding of CHEMICAL phosphate to MAP2 was estimated to be 20 microM at 4 degrees, and for the binding of tau, 200 microM. The rate of dissociation was very low (T1/2 greater than 2 hr), which indicates that the binding of CHEMICAL phosphate may stabilize the protein-drug complex by changing the protein conformation. Two new negatively charged CHEMICAL derivatives, CHEMICAL sulphate and CHEMICAL glucuronide, were found to be similar MAP-dependent microtubule inhibitors. The concentration for 50% inhibition of assembly was 100 microM for the sulphate derivative, the same as found previously for CHEMICAL phosphate, and 250 microM for the more bulky CHEMICAL glucuronide. A positively charged derivative, CHEMICAL sarcosinate, did not inhibit microtubule assembly or alter the composition of the coassembled MAPs. The morphology of the microtubules was, however, affected. The uncharged CHEMICAL bound to both tubulin and MAPs, but no effects were seen on microtubule assembly, the composition of coassembled MAPs or the microtubule morphology. Our results suggest that only negatively charged CHEMICAL derivatives have a GENE-dependent microtubule inhibitory effect. The two new negatively charged derivatives could therefore be valuable tools in the study of tubulin-MAP interactions. The results also confirm that these interactions between tubulin and MAPs are mainly electrostatic. | INHIBITOR |
| The effect of estramustine derivatives on microtubule assembly in vitro depends on the charge of the substituent. Estramustine, and derivatives of estramustine with a charged substituent at position 17 on the estrogen moiety, have been investigated for their effects on bovine brain microtubules in vitro. The negatively charged CHEMICAL has been found previously to be a GENE (MAP)-dependent microtubule inhibitor [Wallin M, Deinum J and Friden B, FEBS Lett 179: 289-293, 1985]. In the present study the binding of CHEMICAL to MAP2 and tau was investigated. Both these MAPs were found to have two to three binding sites for CHEMICAL which is compatible with the reported number of basic amino acid repeats of these MAPs, considered to be the ultimate tubulin binding domains. The Kd for the binding of CHEMICAL to MAP2 was estimated to be 20 microM at 4 degrees, and for the binding of tau, 200 microM. The rate of dissociation was very low (T1/2 greater than 2 hr), which indicates that the binding of CHEMICAL may stabilize the protein-drug complex by changing the protein conformation. Two new negatively charged estramustine derivatives, estramustine sulphate and estramustine glucuronide, were found to be similar MAP-dependent microtubule inhibitors. The concentration for 50% inhibition of assembly was 100 microM for the sulphate derivative, the same as found previously for CHEMICAL, and 250 microM for the more bulky estramustine glucuronide. A positively charged derivative, estramustine sarcosinate, did not inhibit microtubule assembly or alter the composition of the coassembled MAPs. The morphology of the microtubules was, however, affected. The uncharged estramustine bound to both tubulin and MAPs, but no effects were seen on microtubule assembly, the composition of coassembled MAPs or the microtubule morphology. Our results suggest that only negatively charged estramustine derivatives have a MAP-dependent microtubule inhibitory effect. The two new negatively charged derivatives could therefore be valuable tools in the study of tubulin-MAP interactions. The results also confirm that these interactions between tubulin and MAPs are mainly electrostatic. | INHIBITOR |
| The effect of estramustine derivatives on microtubule assembly in vitro depends on the charge of the substituent. Estramustine, and derivatives of estramustine with a charged substituent at position 17 on the estrogen moiety, have been investigated for their effects on bovine brain microtubules in vitro. The negatively charged CHEMICAL has been found previously to be a microtubule-associated protein (GENE)-dependent microtubule inhibitor [Wallin M, Deinum J and Friden B, FEBS Lett 179: 289-293, 1985]. In the present study the binding of CHEMICAL to MAP2 and tau was investigated. Both these MAPs were found to have two to three binding sites for CHEMICAL which is compatible with the reported number of basic amino acid repeats of these MAPs, considered to be the ultimate tubulin binding domains. The Kd for the binding of CHEMICAL to MAP2 was estimated to be 20 microM at 4 degrees, and for the binding of tau, 200 microM. The rate of dissociation was very low (T1/2 greater than 2 hr), which indicates that the binding of CHEMICAL may stabilize the protein-drug complex by changing the protein conformation. Two new negatively charged estramustine derivatives, estramustine sulphate and estramustine glucuronide, were found to be similar MAP-dependent microtubule inhibitors. The concentration for 50% inhibition of assembly was 100 microM for the sulphate derivative, the same as found previously for CHEMICAL, and 250 microM for the more bulky estramustine glucuronide. A positively charged derivative, estramustine sarcosinate, did not inhibit microtubule assembly or alter the composition of the coassembled MAPs. The morphology of the microtubules was, however, affected. The uncharged estramustine bound to both tubulin and MAPs, but no effects were seen on microtubule assembly, the composition of coassembled MAPs or the microtubule morphology. Our results suggest that only negatively charged estramustine derivatives have a MAP-dependent microtubule inhibitory effect. The two new negatively charged derivatives could therefore be valuable tools in the study of tubulin-MAP interactions. The results also confirm that these interactions between tubulin and MAPs are mainly electrostatic. | INHIBITOR |
| The effect of estramustine derivatives on microtubule assembly in vitro depends on the charge of the substituent. Estramustine, and derivatives of estramustine with a charged substituent at position 17 on the estrogen moiety, have been investigated for their effects on bovine brain microtubules in vitro. The negatively charged estramustine phosphate has been found previously to be a microtubule-associated protein (MAP)-dependent microtubule inhibitor [Wallin M, Deinum J and Friden B, FEBS Lett 179: 289-293, 1985]. In the present study the binding of estramustine phosphate to MAP2 and tau was investigated. Both these MAPs were found to have two to three binding sites for estramustine phosphate which is compatible with the reported number of basic amino acid repeats of these MAPs, considered to be the ultimate tubulin binding domains. The Kd for the binding of estramustine phosphate to MAP2 was estimated to be 20 microM at 4 degrees, and for the binding of tau, 200 microM. The rate of dissociation was very low (T1/2 greater than 2 hr), which indicates that the binding of estramustine phosphate may stabilize the protein-drug complex by changing the protein conformation. Two new negatively charged estramustine derivatives, CHEMICAL and estramustine glucuronide, were found to be similar GENE-dependent microtubule inhibitors. The concentration for 50% inhibition of assembly was 100 microM for the sulphate derivative, the same as found previously for estramustine phosphate, and 250 microM for the more bulky estramustine glucuronide. A positively charged derivative, estramustine sarcosinate, did not inhibit microtubule assembly or alter the composition of the coassembled MAPs. The morphology of the microtubules was, however, affected. The uncharged estramustine bound to both tubulin and MAPs, but no effects were seen on microtubule assembly, the composition of coassembled MAPs or the microtubule morphology. Our results suggest that only negatively charged estramustine derivatives have a MAP-dependent microtubule inhibitory effect. The two new negatively charged derivatives could therefore be valuable tools in the study of tubulin-MAP interactions. The results also confirm that these interactions between tubulin and MAPs are mainly electrostatic. | INHIBITOR |
| The effect of estramustine derivatives on microtubule assembly in vitro depends on the charge of the substituent. Estramustine, and derivatives of estramustine with a charged substituent at position 17 on the estrogen moiety, have been investigated for their effects on bovine brain microtubules in vitro. The negatively charged estramustine phosphate has been found previously to be a microtubule-associated protein (MAP)-dependent microtubule inhibitor [Wallin M, Deinum J and Friden B, FEBS Lett 179: 289-293, 1985]. In the present study the binding of estramustine phosphate to MAP2 and tau was investigated. Both these MAPs were found to have two to three binding sites for estramustine phosphate which is compatible with the reported number of basic amino acid repeats of these MAPs, considered to be the ultimate tubulin binding domains. The Kd for the binding of estramustine phosphate to MAP2 was estimated to be 20 microM at 4 degrees, and for the binding of tau, 200 microM. The rate of dissociation was very low (T1/2 greater than 2 hr), which indicates that the binding of estramustine phosphate may stabilize the protein-drug complex by changing the protein conformation. Two new negatively charged estramustine derivatives, estramustine sulphate and CHEMICAL, were found to be similar GENE-dependent microtubule inhibitors. The concentration for 50% inhibition of assembly was 100 microM for the sulphate derivative, the same as found previously for estramustine phosphate, and 250 microM for the more bulky CHEMICAL. A positively charged derivative, estramustine sarcosinate, did not inhibit microtubule assembly or alter the composition of the coassembled MAPs. The morphology of the microtubules was, however, affected. The uncharged estramustine bound to both tubulin and MAPs, but no effects were seen on microtubule assembly, the composition of coassembled MAPs or the microtubule morphology. Our results suggest that only negatively charged estramustine derivatives have a MAP-dependent microtubule inhibitory effect. The two new negatively charged derivatives could therefore be valuable tools in the study of tubulin-MAP interactions. The results also confirm that these interactions between tubulin and MAPs are mainly electrostatic. | INHIBITOR |
| Analysis of coenzyme binding by human placental 3 beta-hydroxy-5-ene-steroid dehydrogenase and steroid 5----4-ene-isomerase using 5'-[p-(fluorosulfonyl)benzoyl]adenosine, an affinity labeling cofactor analog. 3 beta-Hydroxy-5-ene-steroid dehydrogenase and steroid 5----4-ene-isomerase copurify as a single, homogeneous protein from human placental microsomes. Affinity alkylation with 2 alpha-bromoacetoxyprogesterone suggests that the dehydrogenase and isomerase substrate steroids bind at different sites on the same protein. However, the coenzyme, NADH, completely abolishes the alkylation of both enzyme activities by the progestin analog [Thomas J .L., Myers R. P., Rosik L. O. and Strickler R. C., J. Steroid Biochem. 36 (1990) 117-123]. Unlike bacterial GENE, the human isomerase reaction is stimulated by CHEMICAL (NADH, NAD+). The affinity labeling nucleotide analog, 5'-[p-(fluorosulfonyl)benzoyl]adenosine (FSA), inactivates the dehydrogenase and isomerase activities at similar rates in an irreversible manner which follows first order kinetics with respect to both time and alkylator concentration (0.2-0.6 mM). FSA is a cofactor site-directed reagent that binds with similar affinity as a competitive inhibitor of NAD+ reduction by dehydrogenase (Ki = 162 microM) or as a stimulator of isomerase (Km = 153 microM). Parallel plots derived from Kitz and Wilson analysis indicate that FSA inactivates the two enzyme activities with equal alkylation efficiency (k3/Ki = 1/slope = 0.51/mol-s for both). The 3 beta-hydroxysteroid substrate, pregnenolone, protects isomerase as well as dehydrogenase from inactivation by FSA. These observations are evidence for a single cofactor binding region which services both enzyme activities. | ACTIVATOR |
| Analysis of coenzyme binding by human placental 3 beta-hydroxy-5-ene-steroid dehydrogenase and steroid 5----4-ene-isomerase using 5'-[p-(fluorosulfonyl)benzoyl]adenosine, an affinity labeling cofactor analog. 3 beta-Hydroxy-5-ene-steroid dehydrogenase and steroid 5----4-ene-isomerase copurify as a single, homogeneous protein from human placental microsomes. Affinity alkylation with 2 alpha-bromoacetoxyprogesterone suggests that the dehydrogenase and isomerase substrate steroids bind at different sites on the same protein. However, the coenzyme, CHEMICAL, completely abolishes the alkylation of both enzyme activities by the progestin analog [Thomas J .L., Myers R. P., Rosik L. O. and Strickler R. C., J. Steroid Biochem. 36 (1990) 117-123]. Unlike bacterial GENE, the human isomerase reaction is stimulated by diphosphopyridine nucleotides (CHEMICAL, NAD+). The affinity labeling nucleotide analog, 5'-[p-(fluorosulfonyl)benzoyl]adenosine (FSA), inactivates the dehydrogenase and isomerase activities at similar rates in an irreversible manner which follows first order kinetics with respect to both time and alkylator concentration (0.2-0.6 mM). FSA is a cofactor site-directed reagent that binds with similar affinity as a competitive inhibitor of NAD+ reduction by dehydrogenase (Ki = 162 microM) or as a stimulator of isomerase (Km = 153 microM). Parallel plots derived from Kitz and Wilson analysis indicate that FSA inactivates the two enzyme activities with equal alkylation efficiency (k3/Ki = 1/slope = 0.51/mol-s for both). The 3 beta-hydroxysteroid substrate, pregnenolone, protects isomerase as well as dehydrogenase from inactivation by FSA. These observations are evidence for a single cofactor binding region which services both enzyme activities. | ACTIVATOR |
| Analysis of coenzyme binding by human placental 3 beta-hydroxy-5-ene-steroid dehydrogenase and steroid 5----4-ene-isomerase using 5'-[p-(fluorosulfonyl)benzoyl]adenosine, an affinity labeling cofactor analog. 3 beta-Hydroxy-5-ene-steroid dehydrogenase and steroid 5----4-ene-isomerase copurify as a single, homogeneous protein from human placental microsomes. Affinity alkylation with 2 alpha-bromoacetoxyprogesterone suggests that the dehydrogenase and isomerase substrate steroids bind at different sites on the same protein. However, the coenzyme, NADH, completely abolishes the alkylation of both enzyme activities by the progestin analog [Thomas J .L., Myers R. P., Rosik L. O. and Strickler R. C., J. Steroid Biochem. 36 (1990) 117-123]. Unlike bacterial GENE, the human isomerase reaction is stimulated by diphosphopyridine nucleotides (NADH, CHEMICAL). The affinity labeling nucleotide analog, 5'-[p-(fluorosulfonyl)benzoyl]adenosine (FSA), inactivates the dehydrogenase and isomerase activities at similar rates in an irreversible manner which follows first order kinetics with respect to both time and alkylator concentration (0.2-0.6 mM). FSA is a cofactor site-directed reagent that binds with similar affinity as a competitive inhibitor of CHEMICAL reduction by dehydrogenase (Ki = 162 microM) or as a stimulator of isomerase (Km = 153 microM). Parallel plots derived from Kitz and Wilson analysis indicate that FSA inactivates the two enzyme activities with equal alkylation efficiency (k3/Ki = 1/slope = 0.51/mol-s for both). The 3 beta-hydroxysteroid substrate, pregnenolone, protects isomerase as well as dehydrogenase from inactivation by FSA. These observations are evidence for a single cofactor binding region which services both enzyme activities. | ACTIVATOR |
| Analysis of coenzyme binding by human placental 3 beta-hydroxy-5-ene-steroid GENE and steroid 5----4-ene-isomerase using 5'-[p-(fluorosulfonyl)benzoyl]adenosine, an affinity labeling cofactor analog. 3 beta-Hydroxy-5-ene-steroid GENE and steroid 5----4-ene-isomerase copurify as a single, homogeneous protein from human placental microsomes. Affinity alkylation with 2 alpha-bromoacetoxyprogesterone suggests that the GENE and isomerase substrate steroids bind at different sites on the same protein. However, the coenzyme, NADH, completely abolishes the alkylation of both enzyme activities by the progestin analog [Thomas J .L., Myers R. P., Rosik L. O. and Strickler R. C., J. Steroid Biochem. 36 (1990) 117-123]. Unlike bacterial 3-keto-5-ene-steroid isomerase, the human isomerase reaction is stimulated by diphosphopyridine nucleotides (NADH, NAD+). The affinity labeling nucleotide analog, 5'-[p-(fluorosulfonyl)benzoyl]adenosine (FSA), inactivates the GENE and isomerase activities at similar rates in an irreversible manner which follows first order kinetics with respect to both time and alkylator concentration (0.2-0.6 mM). FSA is a cofactor site-directed reagent that binds with similar affinity as a competitive inhibitor of NAD+ reduction by GENE (Ki = 162 microM) or as a stimulator of isomerase (Km = 153 microM). Parallel plots derived from Kitz and Wilson analysis indicate that FSA inactivates the two enzyme activities with equal alkylation efficiency (k3/Ki = 1/slope = 0.51/mol-s for both). The CHEMICAL substrate, pregnenolone, protects isomerase as well as GENE from inactivation by FSA. These observations are evidence for a single cofactor binding region which services both enzyme activities. | SUBSTRATE |
| Analysis of coenzyme binding by human placental 3 beta-hydroxy-5-ene-steroid GENE and steroid 5----4-ene-isomerase using 5'-[p-(fluorosulfonyl)benzoyl]adenosine, an affinity labeling cofactor analog. 3 beta-Hydroxy-5-ene-steroid GENE and steroid 5----4-ene-isomerase copurify as a single, homogeneous protein from human placental microsomes. Affinity alkylation with 2 alpha-bromoacetoxyprogesterone suggests that the GENE and isomerase substrate steroids bind at different sites on the same protein. However, the coenzyme, NADH, completely abolishes the alkylation of both enzyme activities by the progestin analog [Thomas J .L., Myers R. P., Rosik L. O. and Strickler R. C., J. Steroid Biochem. 36 (1990) 117-123]. Unlike bacterial 3-keto-5-ene-steroid isomerase, the human isomerase reaction is stimulated by diphosphopyridine nucleotides (NADH, NAD+). The affinity labeling nucleotide analog, 5'-[p-(fluorosulfonyl)benzoyl]adenosine (FSA), inactivates the GENE and isomerase activities at similar rates in an irreversible manner which follows first order kinetics with respect to both time and alkylator concentration (0.2-0.6 mM). FSA is a cofactor site-directed reagent that binds with similar affinity as a competitive inhibitor of NAD+ reduction by GENE (Ki = 162 microM) or as a stimulator of isomerase (Km = 153 microM). Parallel plots derived from Kitz and Wilson analysis indicate that FSA inactivates the two enzyme activities with equal alkylation efficiency (k3/Ki = 1/slope = 0.51/mol-s for both). The 3 beta-hydroxysteroid substrate, CHEMICAL, protects isomerase as well as GENE from inactivation by FSA. These observations are evidence for a single cofactor binding region which services both enzyme activities. | SUBSTRATE |
| Analysis of coenzyme binding by GENE and steroid 5----4-ene-isomerase using CHEMICAL, an affinity labeling cofactor analog. 3 beta-Hydroxy-5-ene-steroid dehydrogenase and steroid 5----4-ene-isomerase copurify as a single, homogeneous protein from human placental microsomes. Affinity alkylation with 2 alpha-bromoacetoxyprogesterone suggests that the dehydrogenase and isomerase substrate steroids bind at different sites on the same protein. However, the coenzyme, NADH, completely abolishes the alkylation of both enzyme activities by the progestin analog [Thomas J .L., Myers R. P., Rosik L. O. and Strickler R. C., J. Steroid Biochem. 36 (1990) 117-123]. Unlike bacterial 3-keto-5-ene-steroid isomerase, the human isomerase reaction is stimulated by diphosphopyridine nucleotides (NADH, NAD+). The affinity labeling nucleotide analog, CHEMICAL (FSA), inactivates the dehydrogenase and isomerase activities at similar rates in an irreversible manner which follows first order kinetics with respect to both time and alkylator concentration (0.2-0.6 mM). FSA is a cofactor site-directed reagent that binds with similar affinity as a competitive inhibitor of NAD+ reduction by dehydrogenase (Ki = 162 microM) or as a stimulator of isomerase (Km = 153 microM). Parallel plots derived from Kitz and Wilson analysis indicate that FSA inactivates the two enzyme activities with equal alkylation efficiency (k3/Ki = 1/slope = 0.51/mol-s for both). The 3 beta-hydroxysteroid substrate, pregnenolone, protects isomerase as well as dehydrogenase from inactivation by FSA. These observations are evidence for a single cofactor binding region which services both enzyme activities. | DIRECT-REGULATOR |
| Analysis of coenzyme binding by human placental 3 beta-hydroxy-5-ene-steroid dehydrogenase and GENE using CHEMICAL, an affinity labeling cofactor analog. 3 beta-Hydroxy-5-ene-steroid dehydrogenase and GENE copurify as a single, homogeneous protein from human placental microsomes. Affinity alkylation with 2 alpha-bromoacetoxyprogesterone suggests that the dehydrogenase and isomerase substrate steroids bind at different sites on the same protein. However, the coenzyme, NADH, completely abolishes the alkylation of both enzyme activities by the progestin analog [Thomas J .L., Myers R. P., Rosik L. O. and Strickler R. C., J. Steroid Biochem. 36 (1990) 117-123]. Unlike bacterial 3-keto-5-ene-steroid isomerase, the human isomerase reaction is stimulated by diphosphopyridine nucleotides (NADH, NAD+). The affinity labeling nucleotide analog, CHEMICAL (FSA), inactivates the dehydrogenase and isomerase activities at similar rates in an irreversible manner which follows first order kinetics with respect to both time and alkylator concentration (0.2-0.6 mM). FSA is a cofactor site-directed reagent that binds with similar affinity as a competitive inhibitor of NAD+ reduction by dehydrogenase (Ki = 162 microM) or as a stimulator of isomerase (Km = 153 microM). Parallel plots derived from Kitz and Wilson analysis indicate that FSA inactivates the two enzyme activities with equal alkylation efficiency (k3/Ki = 1/slope = 0.51/mol-s for both). The 3 beta-hydroxysteroid substrate, pregnenolone, protects isomerase as well as dehydrogenase from inactivation by FSA. These observations are evidence for a single cofactor binding region which services both enzyme activities. | DIRECT-REGULATOR |
| Analysis of coenzyme binding by human placental 3 beta-hydroxy-5-ene-steroid GENE and steroid 5----4-ene-isomerase using 5'-[p-(fluorosulfonyl)benzoyl]adenosine, an affinity labeling cofactor analog. 3 beta-Hydroxy-5-ene-steroid GENE and steroid 5----4-ene-isomerase copurify as a single, homogeneous protein from human placental microsomes. Affinity alkylation with 2 alpha-bromoacetoxyprogesterone suggests that the GENE and isomerase substrate steroids bind at different sites on the same protein. However, the coenzyme, NADH, completely abolishes the alkylation of both enzyme activities by the progestin analog [Thomas J .L., Myers R. P., Rosik L. O. and Strickler R. C., J. Steroid Biochem. 36 (1990) 117-123]. Unlike bacterial 3-keto-5-ene-steroid isomerase, the human isomerase reaction is stimulated by diphosphopyridine nucleotides (NADH, NAD+). The affinity labeling CHEMICAL analog, 5'-[p-(fluorosulfonyl)benzoyl]adenosine (FSA), inactivates the GENE and isomerase activities at similar rates in an irreversible manner which follows first order kinetics with respect to both time and alkylator concentration (0.2-0.6 mM). FSA is a cofactor site-directed reagent that binds with similar affinity as a competitive inhibitor of NAD+ reduction by GENE (Ki = 162 microM) or as a stimulator of isomerase (Km = 153 microM). Parallel plots derived from Kitz and Wilson analysis indicate that FSA inactivates the two enzyme activities with equal alkylation efficiency (k3/Ki = 1/slope = 0.51/mol-s for both). The 3 beta-hydroxysteroid substrate, pregnenolone, protects isomerase as well as GENE from inactivation by FSA. These observations are evidence for a single cofactor binding region which services both enzyme activities. | INHIBITOR |
| Analysis of coenzyme binding by human placental 3 beta-hydroxy-5-ene-steroid GENE and steroid 5----4-ene-isomerase using CHEMICAL, an affinity labeling cofactor analog. 3 beta-Hydroxy-5-ene-steroid GENE and steroid 5----4-ene-isomerase copurify as a single, homogeneous protein from human placental microsomes. Affinity alkylation with 2 alpha-bromoacetoxyprogesterone suggests that the GENE and isomerase substrate steroids bind at different sites on the same protein. However, the coenzyme, NADH, completely abolishes the alkylation of both enzyme activities by the progestin analog [Thomas J .L., Myers R. P., Rosik L. O. and Strickler R. C., J. Steroid Biochem. 36 (1990) 117-123]. Unlike bacterial 3-keto-5-ene-steroid isomerase, the human isomerase reaction is stimulated by diphosphopyridine nucleotides (NADH, NAD+). The affinity labeling nucleotide analog, CHEMICAL (FSA), inactivates the GENE and isomerase activities at similar rates in an irreversible manner which follows first order kinetics with respect to both time and alkylator concentration (0.2-0.6 mM). FSA is a cofactor site-directed reagent that binds with similar affinity as a competitive inhibitor of NAD+ reduction by GENE (Ki = 162 microM) or as a stimulator of isomerase (Km = 153 microM). Parallel plots derived from Kitz and Wilson analysis indicate that FSA inactivates the two enzyme activities with equal alkylation efficiency (k3/Ki = 1/slope = 0.51/mol-s for both). The 3 beta-hydroxysteroid substrate, pregnenolone, protects isomerase as well as GENE from inactivation by FSA. These observations are evidence for a single cofactor binding region which services both enzyme activities. | ACTIVATOR |
| Analysis of coenzyme binding by human placental 3 beta-hydroxy-5-ene-steroid GENE and steroid 5----4-ene-isomerase using 5'-[p-(fluorosulfonyl)benzoyl]adenosine, an affinity labeling cofactor analog. 3 beta-Hydroxy-5-ene-steroid GENE and steroid 5----4-ene-isomerase copurify as a single, homogeneous protein from human placental microsomes. Affinity alkylation with 2 alpha-bromoacetoxyprogesterone suggests that the GENE and isomerase substrate steroids bind at different sites on the same protein. However, the coenzyme, NADH, completely abolishes the alkylation of both enzyme activities by the progestin analog [Thomas J .L., Myers R. P., Rosik L. O. and Strickler R. C., J. Steroid Biochem. 36 (1990) 117-123]. Unlike bacterial 3-keto-5-ene-steroid isomerase, the human isomerase reaction is stimulated by diphosphopyridine nucleotides (NADH, NAD+). The affinity labeling nucleotide analog, 5'-[p-(fluorosulfonyl)benzoyl]adenosine (CHEMICAL), inactivates the GENE and isomerase activities at similar rates in an irreversible manner which follows first order kinetics with respect to both time and alkylator concentration (0.2-0.6 mM). CHEMICAL is a cofactor site-directed reagent that binds with similar affinity as a competitive inhibitor of NAD+ reduction by GENE (Ki = 162 microM) or as a stimulator of isomerase (Km = 153 microM). Parallel plots derived from Kitz and Wilson analysis indicate that CHEMICAL inactivates the two enzyme activities with equal alkylation efficiency (k3/Ki = 1/slope = 0.51/mol-s for both). The 3 beta-hydroxysteroid substrate, pregnenolone, protects isomerase as well as GENE from inactivation by CHEMICAL. These observations are evidence for a single cofactor binding region which services both enzyme activities. | DIRECT-REGULATOR |
| Analysis of coenzyme binding by human placental 3 beta-hydroxy-5-ene-steroid GENE and steroid 5----4-ene-isomerase using 5'-[p-(fluorosulfonyl)benzoyl]adenosine, an affinity labeling cofactor analog. 3 beta-Hydroxy-5-ene-steroid GENE and steroid 5----4-ene-isomerase copurify as a single, homogeneous protein from human placental microsomes. Affinity alkylation with 2 alpha-bromoacetoxyprogesterone suggests that the GENE and isomerase substrate steroids bind at different sites on the same protein. However, the coenzyme, NADH, completely abolishes the alkylation of both enzyme activities by the progestin analog [Thomas J .L., Myers R. P., Rosik L. O. and Strickler R. C., J. Steroid Biochem. 36 (1990) 117-123]. Unlike bacterial 3-keto-5-ene-steroid isomerase, the human isomerase reaction is stimulated by diphosphopyridine nucleotides (NADH, NAD+). The affinity labeling nucleotide analog, 5'-[p-(fluorosulfonyl)benzoyl]adenosine (FSA), inactivates the GENE and isomerase activities at similar rates in an irreversible manner which follows first order kinetics with respect to both time and alkylator concentration (0.2-0.6 mM). FSA is a cofactor site-directed reagent that binds with similar affinity as a competitive inhibitor of CHEMICAL reduction by GENE (Ki = 162 microM) or as a stimulator of isomerase (Km = 153 microM). Parallel plots derived from Kitz and Wilson analysis indicate that FSA inactivates the two enzyme activities with equal alkylation efficiency (k3/Ki = 1/slope = 0.51/mol-s for both). The 3 beta-hydroxysteroid substrate, pregnenolone, protects isomerase as well as GENE from inactivation by FSA. These observations are evidence for a single cofactor binding region which services both enzyme activities. | SUBSTRATE |
| Analysis of coenzyme binding by human placental 3 beta-hydroxy-5-ene-steroid GENE and steroid 5----4-ene-isomerase using 5'-[p-(fluorosulfonyl)benzoyl]adenosine, an affinity labeling cofactor analog. 3 beta-Hydroxy-5-ene-steroid GENE and steroid 5----4-ene-isomerase copurify as a single, homogeneous protein from human placental microsomes. Affinity alkylation with 2 alpha-bromoacetoxyprogesterone suggests that the GENE and isomerase substrate CHEMICAL bind at different sites on the same protein. However, the coenzyme, NADH, completely abolishes the alkylation of both enzyme activities by the progestin analog [Thomas J .L., Myers R. P., Rosik L. O. and Strickler R. C., J. Steroid Biochem. 36 (1990) 117-123]. Unlike bacterial 3-keto-5-ene-steroid isomerase, the human isomerase reaction is stimulated by diphosphopyridine nucleotides (NADH, NAD+). The affinity labeling nucleotide analog, 5'-[p-(fluorosulfonyl)benzoyl]adenosine (FSA), inactivates the GENE and isomerase activities at similar rates in an irreversible manner which follows first order kinetics with respect to both time and alkylator concentration (0.2-0.6 mM). FSA is a cofactor site-directed reagent that binds with similar affinity as a competitive inhibitor of NAD+ reduction by GENE (Ki = 162 microM) or as a stimulator of isomerase (Km = 153 microM). Parallel plots derived from Kitz and Wilson analysis indicate that FSA inactivates the two enzyme activities with equal alkylation efficiency (k3/Ki = 1/slope = 0.51/mol-s for both). The 3 beta-hydroxysteroid substrate, pregnenolone, protects isomerase as well as GENE from inactivation by FSA. These observations are evidence for a single cofactor binding region which services both enzyme activities. | DIRECT-REGULATOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (CHEMICAL, Sutent) specific for GENE kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | DIRECT-REGULATOR |
| Tyrosine GENE blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of GENE blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others GENE inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic GENE, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (CHEMICAL, Sutent) specific for VEGF receptor GENE, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT GENE. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine GENE blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, CHEMICAL) specific for GENE kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | DIRECT-REGULATOR |
| Tyrosine GENE blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of GENE blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others GENE inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic GENE, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, CHEMICAL) specific for VEGF receptor GENE, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT GENE. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine GENE blockers for cancer treatment. | DIRECT-REGULATOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, CHEMICAL (Nilotinib) and INNO-406 (NS-187) specific for GENE kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | DIRECT-REGULATOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (CHEMICAL) and INNO-406 (NS-187) specific for GENE kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | DIRECT-REGULATOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and CHEMICAL (NS-187) specific for GENE kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | PART-OF |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (CHEMICAL) specific for GENE kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | DIRECT-REGULATOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following GENE blockers for treatment of various human tumors are in clinical development: CHEMICAL (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following GENE blockers for treatment of various human tumors are in clinical development: Lapatinib (CHEMICAL, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following GENE blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, CHEMICAL, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following GENE blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, CHEMICAL), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following GENE blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), CHEMICAL (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following GENE blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CHEMICAL), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following GENE blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), CHEMICAL (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following GENE blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (CHEMICAL), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following GENE blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), CHEMICAL (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following GENE blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (CHEMICAL/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following GENE blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/CHEMICAL), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following GENE blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), CHEMICAL (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following GENE blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (CHEMICAL, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following GENE blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, CHEMICAL), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include CHEMICAL (BMS-354825) specific for GENE non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include CHEMICAL (BMS-354825) specific for ABL GENE, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following GENE blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and CHEMICAL (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following GENE blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (CHEMICAL, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following GENE blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, CHEMICAL). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine GENE blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of GENE blockers is CHEMICAL (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others GENE inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic GENE, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor GENE, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT GENE. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine GENE blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is CHEMICAL (Imatinib mesylate, Gleevec, STI571), the inhibitor of GENE/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is CHEMICAL (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/GENE oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine GENE blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of GENE blockers is Imatinib (CHEMICAL, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others GENE inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic GENE, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor GENE, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT GENE. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine GENE blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (CHEMICAL, Gleevec, STI571), the inhibitor of GENE/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (CHEMICAL, Gleevec, STI571), the inhibitor of Bcr/GENE oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine GENE blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of GENE blockers is Imatinib (Imatinib mesylate, CHEMICAL, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others GENE inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic GENE, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor GENE, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT GENE. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine GENE blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, CHEMICAL, STI571), the inhibitor of GENE/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, CHEMICAL, STI571), the inhibitor of Bcr/GENE oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine GENE blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of GENE blockers is Imatinib (Imatinib mesylate, Gleevec, CHEMICAL), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of CHEMICAL for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others GENE inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic GENE, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor GENE, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT GENE. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine GENE blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, CHEMICAL), the inhibitor of GENE/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of CHEMICAL for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, CHEMICAL), the inhibitor of Bcr/GENE oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of CHEMICAL for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (CHEMICAL) specific for GENE non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, CHEMICAL (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for GENE kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | DIRECT-REGULATOR |
| Tyrosine GENE blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of GENE blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others GENE inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic GENE, CHEMICAL (Iressa), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor GENE, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT GENE. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine GENE blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (CHEMICAL), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for GENE kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | INHIBITOR |
| Tyrosine GENE blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of GENE blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others GENE inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic GENE, Gefitinib (CHEMICAL), Erlotinib (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor GENE, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT GENE. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine GENE blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), CHEMICAL (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for GENE kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | DIRECT-REGULATOR |
| Tyrosine GENE blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of GENE blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others GENE inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic GENE, Gefitinib (Iressa), CHEMICAL (OSI-774, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor GENE, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT GENE. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine GENE blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (CHEMICAL, Tarceva) and Sunitinib (SU 11248, Sutent) specific for GENE kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | DIRECT-REGULATOR |
| Tyrosine GENE blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of GENE blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others GENE inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic GENE, Gefitinib (Iressa), Erlotinib (CHEMICAL, Tarceva) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor GENE, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT GENE. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine GENE blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, CHEMICAL) and Sunitinib (SU 11248, Sutent) specific for GENE kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | DIRECT-REGULATOR |
| Tyrosine GENE blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of GENE blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others GENE inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic GENE, Gefitinib (Iressa), Erlotinib (OSI-774, CHEMICAL) and Sunitinib (SU 11248, Sutent) specific for VEGF receptor GENE, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT GENE. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine GENE blockers for cancer treatment. | INHIBITOR |
| Tyrosine kinase blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of kinase blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others kinase inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic kinase, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and CHEMICAL (SU 11248, Sutent) specific for GENE kinase, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT kinase. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment. | DIRECT-REGULATOR |
| Tyrosine GENE blockers: new hope for successful cancer therapy. Tyrosine kinases (TKs) are attractive targets for cancer therapy, as quite often their abnormal signaling has been linked with tumor development and growth. Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair, apoptosis, and cell proliferation. During the last few years, thorough analysis of the mechanism underlying tyrosine kinase's activity led to novel cancer therapy using TKs blockers. These drugs are remarkably effective in the treatment of various human tumors including head and neck, gastric, prostate and breast cancer and leukemias. The most successful example of GENE blockers is Imatinib (Imatinib mesylate, Gleevec, STI571), the inhibitor of Bcr/Abl oncoprotein, which has become a first-line therapy for chronic myelogenous leukemia. The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed. Others GENE inhibitors used recently in cancer therapy include Dasatinib (BMS-354825) specific for ABL non-receptor cytoplasmic GENE, Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva) and CHEMICAL (SU 11248, Sutent) specific for VEGF receptor GENE, AMN107 (Nilotinib) and INNO-406 (NS-187) specific for c-KIT GENE. The following TK blockers for treatment of various human tumors are in clinical development: Lapatinib (Lapatinib ditosylate, Tykerb, GW-572016), Canertinib (CI-1033), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava). Herein, we discuss the chemistry, biological activity and clinical potential of new drugs with tyrosine GENE blockers for cancer treatment. | DIRECT-REGULATOR |
| Transdermal selegiline for the treatment of major depressive disorder. Non-selective inhibition of monoamine oxidase (MAO) enzymes (ie, isoforms A and B) in the brain are associated with clinically significant antidepressant effects. In the US, the selegiline transdermal system (STS; EMSAM) is the first antidepressant transdermal delivery system to receive Food and Drug Administration (FDA) approved labeling for the treatment of major depressive disorder (MDD). Currently, the use of orally administered GENE inhibitor antidepressants (eg, phenelzine, tranylcypromine) is limited by the risk of CHEMICAL-provoked events (eg, acute hypertension and headache, also known as the "cheese reaction") when combined with dietary CHEMICAL. The selegiline transdermal system is the only MAOI available in the US for the treatment of MDD that does not require dietary restriction at the clinically effective dose of 6 mg/24 hours. Delivery of selegiline transdermally (EMSAM((R))) bypasses hepatic first pass metabolism, thereby avoiding significant inhibition of gastrointestinal and hepatic MAO-A activity (ie, reduced risk of tyramine-provoked events) while still providing sufficient levels of selegiline in the brain to produce an antidepressant effect. At dosages of 6-12 mg/24 hours, EMSAM has been shown to improve symptoms of depression, have good tolerability, and have high rates of medication adherence. However, at higher doses of EMSAM (ie, 9 mg/24 hours or more), dietary restriction of CHEMICAL intake is recommended. The introduction of EMSAM overcomes many of the safety concerns affiliated with the conventional oral GENE inhibitors and EMSAM may be considered another strategy for the treatment of MDD, especially in patients who cannot tolerate oral antidepressants, are poorly adherent, who present with atypical depressive symptoms, or have failed other antidepressants. | REGULATOR |
| Transdermal selegiline for the treatment of major depressive disorder. Non-selective inhibition of monoamine oxidase (MAO) enzymes (ie, isoforms A and B) in the brain are associated with clinically significant antidepressant effects. In the US, the selegiline transdermal system (STS; EMSAM) is the first antidepressant transdermal delivery system to receive Food and Drug Administration (FDA) approved labeling for the treatment of major depressive disorder (MDD). Currently, the use of orally administered GENE inhibitor antidepressants (eg, CHEMICAL, tranylcypromine) is limited by the risk of tyramine-provoked events (eg, acute hypertension and headache, also known as the "cheese reaction") when combined with dietary tyramine. The selegiline transdermal system is the only MAOI available in the US for the treatment of MDD that does not require dietary restriction at the clinically effective dose of 6 mg/24 hours. Delivery of selegiline transdermally (EMSAM((R))) bypasses hepatic first pass metabolism, thereby avoiding significant inhibition of gastrointestinal and hepatic MAO-A activity (ie, reduced risk of tyramine-provoked events) while still providing sufficient levels of selegiline in the brain to produce an antidepressant effect. At dosages of 6-12 mg/24 hours, EMSAM has been shown to improve symptoms of depression, have good tolerability, and have high rates of medication adherence. However, at higher doses of EMSAM (ie, 9 mg/24 hours or more), dietary restriction of tyramine intake is recommended. The introduction of EMSAM overcomes many of the safety concerns affiliated with the conventional oral GENE inhibitors and EMSAM may be considered another strategy for the treatment of MDD, especially in patients who cannot tolerate oral antidepressants, are poorly adherent, who present with atypical depressive symptoms, or have failed other antidepressants. | INHIBITOR |
| Transdermal selegiline for the treatment of major depressive disorder. Non-selective inhibition of monoamine oxidase (MAO) enzymes (ie, isoforms A and B) in the brain are associated with clinically significant antidepressant effects. In the US, the selegiline transdermal system (STS; EMSAM) is the first antidepressant transdermal delivery system to receive Food and Drug Administration (FDA) approved labeling for the treatment of major depressive disorder (MDD). Currently, the use of orally administered GENE inhibitor antidepressants (eg, phenelzine, CHEMICAL) is limited by the risk of tyramine-provoked events (eg, acute hypertension and headache, also known as the "cheese reaction") when combined with dietary tyramine. The selegiline transdermal system is the only MAOI available in the US for the treatment of MDD that does not require dietary restriction at the clinically effective dose of 6 mg/24 hours. Delivery of selegiline transdermally (EMSAM((R))) bypasses hepatic first pass metabolism, thereby avoiding significant inhibition of gastrointestinal and hepatic MAO-A activity (ie, reduced risk of tyramine-provoked events) while still providing sufficient levels of selegiline in the brain to produce an antidepressant effect. At dosages of 6-12 mg/24 hours, EMSAM has been shown to improve symptoms of depression, have good tolerability, and have high rates of medication adherence. However, at higher doses of EMSAM (ie, 9 mg/24 hours or more), dietary restriction of tyramine intake is recommended. The introduction of EMSAM overcomes many of the safety concerns affiliated with the conventional oral GENE inhibitors and EMSAM may be considered another strategy for the treatment of MDD, especially in patients who cannot tolerate oral antidepressants, are poorly adherent, who present with atypical depressive symptoms, or have failed other antidepressants. | INHIBITOR |
| Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents. CHEMICAL (Strattera(R)) is a selective norepinephrine (noradrenaline) reuptake inhibitor that is not classified as a stimulant, and is indicated for use in patients with attention-deficit hyperactivity disorder (ADHD). CHEMICAL is effective and generally well tolerated. It is significantly more effective than placebo and standard current therapy and does not differ significantly from or is noninferior to immediate-release methylphenidate; however, it is significantly less effective than the extended-release methylphenidate formulation OROS(R) methylphenidate (hereafter referred to as osmotically released methylphenidate) and extended-release mixed amfetamine salts. CHEMICAL can be administered either as a single daily dose or split into two evenly divided doses, has a negligible risk of abuse or misuse, and is not a controlled substance in the US. CHEMICAL is particularly useful for patients at risk of substance abuse, as well as those who have co-morbid anxiety or tics, or who do not wish to take a controlled substance. Thus, atomoxetine is a useful option in the treatment of ADHD in children and adolescents. The mechanism of action of atomoxetine is unclear, but is thought to be related to its selective inhibition of presynaptic norepinephrine reuptake in the prefrontal cortex. CHEMICAL has a high affinity and selectivity for norepinephrine transporters, but little or no affinity for various GENE. CHEMICAL has a demonstrated ability to selectively inhibit norepinephrine uptake in humans and animals, and studies have shown that it preferentially binds to areas of known high distribution of noradrenergic neurons, such as the fronto-cortical subsystem. CHEMICAL was generally associated with statistically, but not clinically, significant increases in both heart rate and blood pressure in pediatric patients with ADHD. While there was an initial loss in expected height and weight among atomoxetine recipients, this eventually returned to normal in the longer term. Data suggest that atomoxetine is unlikely to have any abuse potential. CHEMICAL appeared less likely than methylphenidate to exacerbate disordered sleep in pediatric patients with ADHD. CHEMICAL is rapidly absorbed, and demonstrates dose-proportional increases in plasma exposure. It undergoes extensive biotransformation, which is affected by poor metabolism by cytochrome P450 (CYP) 2D6 in a small percentage of the population; these patients have greater exposure to and slower elimination of atomoxetine than extensive metabolizers. Patients with hepatic insufficiency show an increase in atomoxetine exposure. CYP2D6 inhibitors, such as paroxetine, are associated with changes in atomoxetine pharmacokinetics similar to those observed among poor CYP2D6 metabolizers. Once- or twice-daily atomoxetine was effective in the short-term treatment of ADHD in children and adolescents, as observed in several well designed placebo-controlled trials. CHEMICAL also demonstrated efficacy in the longer term treatment of these patients. A single morning dose was shown to be effective into the evening, and discontinuation of atomoxetine was not associated with symptom rebound. CHEMICAL efficacy did not appear to differ between children and adolescents. Stimulant-naive patients also responded well to atomoxetine treatment. CHEMICAL did not differ significantly from or was noninferior to immediate-release methylphenidate in children and adolescents with ADHD with regard to efficacy, and was significantly more effective than standard current therapy (any combination of medicines [excluding atomoxetine] and/or behavioral counseling, or no treatment). However, atomoxetine was significantly less effective than osmotically released methylphenidate and extended-release mixed amfetamine salts. The efficacy of atomoxetine did not appear to be affected by the presence of co-morbid disorders, and symptoms of the co-morbid disorders were not affected or were improved by atomoxetine administration. Health-related quality of life (HR-QOL) appeared to be positively affected by atomoxetine in both short- and long-term studies; atomoxetine also improved HR-QOL to a greater extent than standard current therapy. CHEMICAL was generally well tolerated in children and adolescents with ADHD. Common adverse events included headache, abdominal pain, decreased appetite, vomiting, somnolence, and nausea. The majority of adverse events were mild or moderate; there was a very low incidence of serious adverse events. Few patients discontinued atomoxetine treatment because of adverse events. CHEMICAL discontinuation appeared to be well tolerated, with a low incidence of discontinuation-emergent adverse events. CHEMICAL appeared better tolerated among extensive CYP2D6 metabolizers than among poor metabolizers. Slight differences were evident in the adverse event profiles of atomoxetine and stimulants, both immediate- and extended-release. Somnolence appeared more common among atomoxetine recipients and insomnia appeared more common among stimulant recipients. A black-box warning for suicidal ideation has been published in the US prescribing information, based on findings from a meta-analysis showing that atomoxetine is associated with a significantly higher incidence of suicidal ideation than placebo. Rarely, atomoxetine may also be associated with serious liver injury; postmarketing data show that three patients have had liver-related adverse events deemed probably related to atomoxetine treatment. Treatment algorithms involving the initial use of atomoxetine appear cost effective versus algorithms involving initial methylphenidate (immediate- or extended-release), dexamfetamine, tricyclic antidepressants, or no treatment in stimulant-naive, -failed, and -contraindicated children and adolescents with ADHD. The incremental cost per quality-adjusted life-year is below commonly accepted cost-effectiveness thresholds, as shown in several Markov model analyses conducted from the perspective of various European countries, with a time horizon of 1 year. | NO-RELATIONSHIP |
| Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents. CHEMICAL (Strattera(R)) is a selective norepinephrine (noradrenaline) reuptake inhibitor that is not classified as a stimulant, and is indicated for use in patients with attention-deficit hyperactivity disorder (ADHD). CHEMICAL is effective and generally well tolerated. It is significantly more effective than placebo and standard current therapy and does not differ significantly from or is noninferior to immediate-release methylphenidate; however, it is significantly less effective than the extended-release methylphenidate formulation OROS(R) methylphenidate (hereafter referred to as osmotically released methylphenidate) and extended-release mixed amfetamine salts. CHEMICAL can be administered either as a single daily dose or split into two evenly divided doses, has a negligible risk of abuse or misuse, and is not a controlled substance in the US. CHEMICAL is particularly useful for patients at risk of substance abuse, as well as those who have co-morbid anxiety or tics, or who do not wish to take a controlled substance. Thus, atomoxetine is a useful option in the treatment of ADHD in children and adolescents. The mechanism of action of atomoxetine is unclear, but is thought to be related to its selective inhibition of presynaptic norepinephrine reuptake in the prefrontal cortex. CHEMICAL has a high affinity and selectivity for GENE, but little or no affinity for various neurotransmitter receptors. CHEMICAL has a demonstrated ability to selectively inhibit norepinephrine uptake in humans and animals, and studies have shown that it preferentially binds to areas of known high distribution of noradrenergic neurons, such as the fronto-cortical subsystem. CHEMICAL was generally associated with statistically, but not clinically, significant increases in both heart rate and blood pressure in pediatric patients with ADHD. While there was an initial loss in expected height and weight among atomoxetine recipients, this eventually returned to normal in the longer term. Data suggest that atomoxetine is unlikely to have any abuse potential. CHEMICAL appeared less likely than methylphenidate to exacerbate disordered sleep in pediatric patients with ADHD. CHEMICAL is rapidly absorbed, and demonstrates dose-proportional increases in plasma exposure. It undergoes extensive biotransformation, which is affected by poor metabolism by cytochrome P450 (CYP) 2D6 in a small percentage of the population; these patients have greater exposure to and slower elimination of atomoxetine than extensive metabolizers. Patients with hepatic insufficiency show an increase in atomoxetine exposure. CYP2D6 inhibitors, such as paroxetine, are associated with changes in atomoxetine pharmacokinetics similar to those observed among poor CYP2D6 metabolizers. Once- or twice-daily atomoxetine was effective in the short-term treatment of ADHD in children and adolescents, as observed in several well designed placebo-controlled trials. CHEMICAL also demonstrated efficacy in the longer term treatment of these patients. A single morning dose was shown to be effective into the evening, and discontinuation of atomoxetine was not associated with symptom rebound. CHEMICAL efficacy did not appear to differ between children and adolescents. Stimulant-naive patients also responded well to atomoxetine treatment. CHEMICAL did not differ significantly from or was noninferior to immediate-release methylphenidate in children and adolescents with ADHD with regard to efficacy, and was significantly more effective than standard current therapy (any combination of medicines [excluding atomoxetine] and/or behavioral counseling, or no treatment). However, atomoxetine was significantly less effective than osmotically released methylphenidate and extended-release mixed amfetamine salts. The efficacy of atomoxetine did not appear to be affected by the presence of co-morbid disorders, and symptoms of the co-morbid disorders were not affected or were improved by atomoxetine administration. Health-related quality of life (HR-QOL) appeared to be positively affected by atomoxetine in both short- and long-term studies; atomoxetine also improved HR-QOL to a greater extent than standard current therapy. CHEMICAL was generally well tolerated in children and adolescents with ADHD. Common adverse events included headache, abdominal pain, decreased appetite, vomiting, somnolence, and nausea. The majority of adverse events were mild or moderate; there was a very low incidence of serious adverse events. Few patients discontinued atomoxetine treatment because of adverse events. CHEMICAL discontinuation appeared to be well tolerated, with a low incidence of discontinuation-emergent adverse events. CHEMICAL appeared better tolerated among extensive CYP2D6 metabolizers than among poor metabolizers. Slight differences were evident in the adverse event profiles of atomoxetine and stimulants, both immediate- and extended-release. Somnolence appeared more common among atomoxetine recipients and insomnia appeared more common among stimulant recipients. A black-box warning for suicidal ideation has been published in the US prescribing information, based on findings from a meta-analysis showing that atomoxetine is associated with a significantly higher incidence of suicidal ideation than placebo. Rarely, atomoxetine may also be associated with serious liver injury; postmarketing data show that three patients have had liver-related adverse events deemed probably related to atomoxetine treatment. Treatment algorithms involving the initial use of atomoxetine appear cost effective versus algorithms involving initial methylphenidate (immediate- or extended-release), dexamfetamine, tricyclic antidepressants, or no treatment in stimulant-naive, -failed, and -contraindicated children and adolescents with ADHD. The incremental cost per quality-adjusted life-year is below commonly accepted cost-effectiveness thresholds, as shown in several Markov model analyses conducted from the perspective of various European countries, with a time horizon of 1 year. | DIRECT-REGULATOR |
| Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents. Atomoxetine (Strattera(R)) is a selective norepinephrine (noradrenaline) reuptake inhibitor that is not classified as a stimulant, and is indicated for use in patients with attention-deficit hyperactivity disorder (ADHD). Atomoxetine is effective and generally well tolerated. It is significantly more effective than placebo and standard current therapy and does not differ significantly from or is noninferior to immediate-release methylphenidate; however, it is significantly less effective than the extended-release methylphenidate formulation OROS(R) methylphenidate (hereafter referred to as osmotically released methylphenidate) and extended-release mixed amfetamine salts. Atomoxetine can be administered either as a single daily dose or split into two evenly divided doses, has a negligible risk of abuse or misuse, and is not a controlled substance in the US. Atomoxetine is particularly useful for patients at risk of substance abuse, as well as those who have co-morbid anxiety or tics, or who do not wish to take a controlled substance. Thus, atomoxetine is a useful option in the treatment of ADHD in children and adolescents. The mechanism of action of atomoxetine is unclear, but is thought to be related to its selective inhibition of presynaptic norepinephrine reuptake in the prefrontal cortex. Atomoxetine has a high affinity and selectivity for norepinephrine transporters, but little or no affinity for various neurotransmitter receptors. Atomoxetine has a demonstrated ability to selectively inhibit norepinephrine uptake in humans and animals, and studies have shown that it preferentially binds to areas of known high distribution of noradrenergic neurons, such as the fronto-cortical subsystem. Atomoxetine was generally associated with statistically, but not clinically, significant increases in both heart rate and blood pressure in pediatric patients with ADHD. While there was an initial loss in expected height and weight among atomoxetine recipients, this eventually returned to normal in the longer term. Data suggest that atomoxetine is unlikely to have any abuse potential. Atomoxetine appeared less likely than methylphenidate to exacerbate disordered sleep in pediatric patients with ADHD. Atomoxetine is rapidly absorbed, and demonstrates dose-proportional increases in plasma exposure. It undergoes extensive biotransformation, which is affected by poor metabolism by cytochrome P450 (CYP) 2D6 in a small percentage of the population; these patients have greater exposure to and slower elimination of atomoxetine than extensive metabolizers. Patients with hepatic insufficiency show an increase in atomoxetine exposure. GENE inhibitors, such as CHEMICAL, are associated with changes in atomoxetine pharmacokinetics similar to those observed among poor GENE metabolizers. Once- or twice-daily atomoxetine was effective in the short-term treatment of ADHD in children and adolescents, as observed in several well designed placebo-controlled trials. Atomoxetine also demonstrated efficacy in the longer term treatment of these patients. A single morning dose was shown to be effective into the evening, and discontinuation of atomoxetine was not associated with symptom rebound. Atomoxetine efficacy did not appear to differ between children and adolescents. Stimulant-naive patients also responded well to atomoxetine treatment. Atomoxetine did not differ significantly from or was noninferior to immediate-release methylphenidate in children and adolescents with ADHD with regard to efficacy, and was significantly more effective than standard current therapy (any combination of medicines [excluding atomoxetine] and/or behavioral counseling, or no treatment). However, atomoxetine was significantly less effective than osmotically released methylphenidate and extended-release mixed amfetamine salts. The efficacy of atomoxetine did not appear to be affected by the presence of co-morbid disorders, and symptoms of the co-morbid disorders were not affected or were improved by atomoxetine administration. Health-related quality of life (HR-QOL) appeared to be positively affected by atomoxetine in both short- and long-term studies; atomoxetine also improved HR-QOL to a greater extent than standard current therapy. Atomoxetine was generally well tolerated in children and adolescents with ADHD. Common adverse events included headache, abdominal pain, decreased appetite, vomiting, somnolence, and nausea. The majority of adverse events were mild or moderate; there was a very low incidence of serious adverse events. Few patients discontinued atomoxetine treatment because of adverse events. Atomoxetine discontinuation appeared to be well tolerated, with a low incidence of discontinuation-emergent adverse events. Atomoxetine appeared better tolerated among extensive GENE metabolizers than among poor metabolizers. Slight differences were evident in the adverse event profiles of atomoxetine and stimulants, both immediate- and extended-release. Somnolence appeared more common among atomoxetine recipients and insomnia appeared more common among stimulant recipients. A black-box warning for suicidal ideation has been published in the US prescribing information, based on findings from a meta-analysis showing that atomoxetine is associated with a significantly higher incidence of suicidal ideation than placebo. Rarely, atomoxetine may also be associated with serious liver injury; postmarketing data show that three patients have had liver-related adverse events deemed probably related to atomoxetine treatment. Treatment algorithms involving the initial use of atomoxetine appear cost effective versus algorithms involving initial methylphenidate (immediate- or extended-release), dexamfetamine, tricyclic antidepressants, or no treatment in stimulant-naive, -failed, and -contraindicated children and adolescents with ADHD. The incremental cost per quality-adjusted life-year is below commonly accepted cost-effectiveness thresholds, as shown in several Markov model analyses conducted from the perspective of various European countries, with a time horizon of 1 year. | INHIBITOR |
| Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents. CHEMICAL (Strattera(R)) is a selective norepinephrine (noradrenaline) reuptake inhibitor that is not classified as a stimulant, and is indicated for use in patients with attention-deficit hyperactivity disorder (ADHD). CHEMICAL is effective and generally well tolerated. It is significantly more effective than placebo and standard current therapy and does not differ significantly from or is noninferior to immediate-release methylphenidate; however, it is significantly less effective than the extended-release methylphenidate formulation OROS(R) methylphenidate (hereafter referred to as osmotically released methylphenidate) and extended-release mixed amfetamine salts. CHEMICAL can be administered either as a single daily dose or split into two evenly divided doses, has a negligible risk of abuse or misuse, and is not a controlled substance in the US. CHEMICAL is particularly useful for patients at risk of substance abuse, as well as those who have co-morbid anxiety or tics, or who do not wish to take a controlled substance. Thus, CHEMICAL is a useful option in the treatment of ADHD in children and adolescents. The mechanism of action of CHEMICAL is unclear, but is thought to be related to its selective inhibition of presynaptic norepinephrine reuptake in the prefrontal cortex. CHEMICAL has a high affinity and selectivity for norepinephrine transporters, but little or no affinity for various neurotransmitter receptors. CHEMICAL has a demonstrated ability to selectively inhibit norepinephrine uptake in humans and animals, and studies have shown that it preferentially binds to areas of known high distribution of noradrenergic neurons, such as the fronto-cortical subsystem. CHEMICAL was generally associated with statistically, but not clinically, significant increases in both heart rate and blood pressure in pediatric patients with ADHD. While there was an initial loss in expected height and weight among CHEMICAL recipients, this eventually returned to normal in the longer term. Data suggest that CHEMICAL is unlikely to have any abuse potential. CHEMICAL appeared less likely than methylphenidate to exacerbate disordered sleep in pediatric patients with ADHD. CHEMICAL is rapidly absorbed, and demonstrates dose-proportional increases in plasma exposure. It undergoes extensive biotransformation, which is affected by poor metabolism by GENE in a small percentage of the population; these patients have greater exposure to and slower elimination of CHEMICAL than extensive metabolizers. Patients with hepatic insufficiency show an increase in CHEMICAL exposure. CYP2D6 inhibitors, such as paroxetine, are associated with changes in CHEMICAL pharmacokinetics similar to those observed among poor CYP2D6 metabolizers. Once- or twice-daily CHEMICAL was effective in the short-term treatment of ADHD in children and adolescents, as observed in several well designed placebo-controlled trials. CHEMICAL also demonstrated efficacy in the longer term treatment of these patients. A single morning dose was shown to be effective into the evening, and discontinuation of CHEMICAL was not associated with symptom rebound. CHEMICAL efficacy did not appear to differ between children and adolescents. Stimulant-naive patients also responded well to CHEMICAL treatment. CHEMICAL did not differ significantly from or was noninferior to immediate-release methylphenidate in children and adolescents with ADHD with regard to efficacy, and was significantly more effective than standard current therapy (any combination of medicines [excluding atomoxetine] and/or behavioral counseling, or no treatment). However, CHEMICAL was significantly less effective than osmotically released methylphenidate and extended-release mixed amfetamine salts. The efficacy of CHEMICAL did not appear to be affected by the presence of co-morbid disorders, and symptoms of the co-morbid disorders were not affected or were improved by CHEMICAL administration. Health-related quality of life (HR-QOL) appeared to be positively affected by CHEMICAL in both short- and long-term studies; CHEMICAL also improved HR-QOL to a greater extent than standard current therapy. CHEMICAL was generally well tolerated in children and adolescents with ADHD. Common adverse events included headache, abdominal pain, decreased appetite, vomiting, somnolence, and nausea. The majority of adverse events were mild or moderate; there was a very low incidence of serious adverse events. Few patients discontinued CHEMICAL treatment because of adverse events. CHEMICAL discontinuation appeared to be well tolerated, with a low incidence of discontinuation-emergent adverse events. CHEMICAL appeared better tolerated among extensive CYP2D6 metabolizers than among poor metabolizers. Slight differences were evident in the adverse event profiles of CHEMICAL and stimulants, both immediate- and extended-release. Somnolence appeared more common among CHEMICAL recipients and insomnia appeared more common among stimulant recipients. A black-box warning for suicidal ideation has been published in the US prescribing information, based on findings from a meta-analysis showing that CHEMICAL is associated with a significantly higher incidence of suicidal ideation than placebo. Rarely, CHEMICAL may also be associated with serious liver injury; postmarketing data show that three patients have had liver-related adverse events deemed probably related to CHEMICAL treatment. Treatment algorithms involving the initial use of CHEMICAL appear cost effective versus algorithms involving initial methylphenidate (immediate- or extended-release), dexamfetamine, tricyclic antidepressants, or no treatment in stimulant-naive, -failed, and -contraindicated children and adolescents with ADHD. The incremental cost per quality-adjusted life-year is below commonly accepted cost-effectiveness thresholds, as shown in several Markov model analyses conducted from the perspective of various European countries, with a time horizon of 1 year. | SUBSTRATE |
| Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents. CHEMICAL (Strattera(R)) is a selective norepinephrine (noradrenaline) reuptake inhibitor that is not classified as a stimulant, and is indicated for use in patients with attention-deficit hyperactivity disorder (ADHD). CHEMICAL is effective and generally well tolerated. It is significantly more effective than placebo and standard current therapy and does not differ significantly from or is noninferior to immediate-release methylphenidate; however, it is significantly less effective than the extended-release methylphenidate formulation OROS(R) methylphenidate (hereafter referred to as osmotically released methylphenidate) and extended-release mixed amfetamine salts. CHEMICAL can be administered either as a single daily dose or split into two evenly divided doses, has a negligible risk of abuse or misuse, and is not a controlled substance in the US. CHEMICAL is particularly useful for patients at risk of substance abuse, as well as those who have co-morbid anxiety or tics, or who do not wish to take a controlled substance. Thus, CHEMICAL is a useful option in the treatment of ADHD in children and adolescents. The mechanism of action of CHEMICAL is unclear, but is thought to be related to its selective inhibition of presynaptic norepinephrine reuptake in the prefrontal cortex. CHEMICAL has a high affinity and selectivity for norepinephrine transporters, but little or no affinity for various neurotransmitter receptors. CHEMICAL has a demonstrated ability to selectively inhibit norepinephrine uptake in humans and animals, and studies have shown that it preferentially binds to areas of known high distribution of noradrenergic neurons, such as the fronto-cortical subsystem. CHEMICAL was generally associated with statistically, but not clinically, significant increases in both heart rate and blood pressure in pediatric patients with ADHD. While there was an initial loss in expected height and weight among CHEMICAL recipients, this eventually returned to normal in the longer term. Data suggest that CHEMICAL is unlikely to have any abuse potential. CHEMICAL appeared less likely than methylphenidate to exacerbate disordered sleep in pediatric patients with ADHD. CHEMICAL is rapidly absorbed, and demonstrates dose-proportional increases in plasma exposure. It undergoes extensive biotransformation, which is affected by poor metabolism by cytochrome P450 (CYP) 2D6 in a small percentage of the population; these patients have greater exposure to and slower elimination of CHEMICAL than extensive metabolizers. Patients with hepatic insufficiency show an increase in CHEMICAL exposure. GENE inhibitors, such as paroxetine, are associated with changes in CHEMICAL pharmacokinetics similar to those observed among poor GENE metabolizers. Once- or twice-daily CHEMICAL was effective in the short-term treatment of ADHD in children and adolescents, as observed in several well designed placebo-controlled trials. CHEMICAL also demonstrated efficacy in the longer term treatment of these patients. A single morning dose was shown to be effective into the evening, and discontinuation of CHEMICAL was not associated with symptom rebound. CHEMICAL efficacy did not appear to differ between children and adolescents. Stimulant-naive patients also responded well to CHEMICAL treatment. CHEMICAL did not differ significantly from or was noninferior to immediate-release methylphenidate in children and adolescents with ADHD with regard to efficacy, and was significantly more effective than standard current therapy (any combination of medicines [excluding atomoxetine] and/or behavioral counseling, or no treatment). However, CHEMICAL was significantly less effective than osmotically released methylphenidate and extended-release mixed amfetamine salts. The efficacy of CHEMICAL did not appear to be affected by the presence of co-morbid disorders, and symptoms of the co-morbid disorders were not affected or were improved by CHEMICAL administration. Health-related quality of life (HR-QOL) appeared to be positively affected by CHEMICAL in both short- and long-term studies; CHEMICAL also improved HR-QOL to a greater extent than standard current therapy. CHEMICAL was generally well tolerated in children and adolescents with ADHD. Common adverse events included headache, abdominal pain, decreased appetite, vomiting, somnolence, and nausea. The majority of adverse events were mild or moderate; there was a very low incidence of serious adverse events. Few patients discontinued CHEMICAL treatment because of adverse events. CHEMICAL discontinuation appeared to be well tolerated, with a low incidence of discontinuation-emergent adverse events. CHEMICAL appeared better tolerated among extensive GENE metabolizers than among poor metabolizers. Slight differences were evident in the adverse event profiles of CHEMICAL and stimulants, both immediate- and extended-release. Somnolence appeared more common among CHEMICAL recipients and insomnia appeared more common among stimulant recipients. A black-box warning for suicidal ideation has been published in the US prescribing information, based on findings from a meta-analysis showing that CHEMICAL is associated with a significantly higher incidence of suicidal ideation than placebo. Rarely, CHEMICAL may also be associated with serious liver injury; postmarketing data show that three patients have had liver-related adverse events deemed probably related to CHEMICAL treatment. Treatment algorithms involving the initial use of CHEMICAL appear cost effective versus algorithms involving initial methylphenidate (immediate- or extended-release), dexamfetamine, tricyclic antidepressants, or no treatment in stimulant-naive, -failed, and -contraindicated children and adolescents with ADHD. The incremental cost per quality-adjusted life-year is below commonly accepted cost-effectiveness thresholds, as shown in several Markov model analyses conducted from the perspective of various European countries, with a time horizon of 1 year. | NO-RELATIONSHIP |
| Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents. CHEMICAL (Strattera(R)) is a selective norepinephrine (noradrenaline) reuptake inhibitor that is not classified as a stimulant, and is indicated for use in patients with attention-deficit hyperactivity disorder (ADHD). CHEMICAL is effective and generally well tolerated. It is significantly more effective than placebo and standard current therapy and does not differ significantly from or is noninferior to immediate-release methylphenidate; however, it is significantly less effective than the extended-release methylphenidate formulation OROS(R) methylphenidate (hereafter referred to as osmotically released methylphenidate) and extended-release mixed amfetamine salts. CHEMICAL can be administered either as a single daily dose or split into two evenly divided doses, has a negligible risk of abuse or misuse, and is not a controlled substance in the US. CHEMICAL is particularly useful for patients at risk of substance abuse, as well as those who have co-morbid anxiety or tics, or who do not wish to take a controlled substance. Thus, atomoxetine is a useful option in the treatment of ADHD in children and adolescents. The mechanism of action of atomoxetine is unclear, but is thought to be related to its selective inhibition of presynaptic norepinephrine reuptake in the prefrontal cortex. CHEMICAL has a high affinity and selectivity for norepinephrine transporters, but little or no affinity for various neurotransmitter receptors. CHEMICAL has a demonstrated ability to selectively inhibit norepinephrine uptake in humans and animals, and studies have shown that it preferentially binds to areas of known high distribution of noradrenergic neurons, such as the fronto-cortical subsystem. CHEMICAL was generally associated with statistically, but not clinically, significant increases in both heart rate and blood pressure in pediatric patients with ADHD. While there was an initial loss in expected height and weight among atomoxetine recipients, this eventually returned to normal in the longer term. Data suggest that atomoxetine is unlikely to have any abuse potential. CHEMICAL appeared less likely than methylphenidate to exacerbate disordered sleep in pediatric patients with ADHD. CHEMICAL is rapidly absorbed, and demonstrates dose-proportional increases in plasma exposure. It undergoes extensive biotransformation, which is affected by poor metabolism by cytochrome P450 (CYP) 2D6 in a small percentage of the population; these patients have greater exposure to and slower elimination of atomoxetine than extensive metabolizers. Patients with hepatic insufficiency show an increase in atomoxetine exposure. GENE inhibitors, such as paroxetine, are associated with changes in atomoxetine pharmacokinetics similar to those observed among poor GENE metabolizers. Once- or twice-daily atomoxetine was effective in the short-term treatment of ADHD in children and adolescents, as observed in several well designed placebo-controlled trials. CHEMICAL also demonstrated efficacy in the longer term treatment of these patients. A single morning dose was shown to be effective into the evening, and discontinuation of atomoxetine was not associated with symptom rebound. CHEMICAL efficacy did not appear to differ between children and adolescents. Stimulant-naive patients also responded well to atomoxetine treatment. CHEMICAL did not differ significantly from or was noninferior to immediate-release methylphenidate in children and adolescents with ADHD with regard to efficacy, and was significantly more effective than standard current therapy (any combination of medicines [excluding atomoxetine] and/or behavioral counseling, or no treatment). However, atomoxetine was significantly less effective than osmotically released methylphenidate and extended-release mixed amfetamine salts. The efficacy of atomoxetine did not appear to be affected by the presence of co-morbid disorders, and symptoms of the co-morbid disorders were not affected or were improved by atomoxetine administration. Health-related quality of life (HR-QOL) appeared to be positively affected by atomoxetine in both short- and long-term studies; atomoxetine also improved HR-QOL to a greater extent than standard current therapy. CHEMICAL was generally well tolerated in children and adolescents with ADHD. Common adverse events included headache, abdominal pain, decreased appetite, vomiting, somnolence, and nausea. The majority of adverse events were mild or moderate; there was a very low incidence of serious adverse events. Few patients discontinued atomoxetine treatment because of adverse events. CHEMICAL discontinuation appeared to be well tolerated, with a low incidence of discontinuation-emergent adverse events. CHEMICAL appeared better tolerated among extensive GENE metabolizers than among poor metabolizers. Slight differences were evident in the adverse event profiles of atomoxetine and stimulants, both immediate- and extended-release. Somnolence appeared more common among atomoxetine recipients and insomnia appeared more common among stimulant recipients. A black-box warning for suicidal ideation has been published in the US prescribing information, based on findings from a meta-analysis showing that atomoxetine is associated with a significantly higher incidence of suicidal ideation than placebo. Rarely, atomoxetine may also be associated with serious liver injury; postmarketing data show that three patients have had liver-related adverse events deemed probably related to atomoxetine treatment. Treatment algorithms involving the initial use of atomoxetine appear cost effective versus algorithms involving initial methylphenidate (immediate- or extended-release), dexamfetamine, tricyclic antidepressants, or no treatment in stimulant-naive, -failed, and -contraindicated children and adolescents with ADHD. The incremental cost per quality-adjusted life-year is below commonly accepted cost-effectiveness thresholds, as shown in several Markov model analyses conducted from the perspective of various European countries, with a time horizon of 1 year. | DIRECT-REGULATOR |
| Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics. Mammalian glutamate dehydrogenase (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of l-glutamate to 2-oxoglutarate using NAD(P)(+) as coenzyme. Unlike its counterparts from other animal kingdoms, mammalian GENE is regulated by a host of ligands. The recently discovered hyperinsulinism/hyperammonemia disorder showed that the loss of allosteric inhibition of GENE by GTP causes excessive secretion of insulin. Subsequent studies demonstrated that wild-type and hyperinsulinemia/hyperammonemia forms of GENE are inhibited by the green tea polyphenols, epigallocatechin gallate and epicatechin gallate. This was followed by high throughput studies that identified more stable inhibitors, including hexachlorophene, GW5074, and bithionol. Shown here are the structures of GENE complexed with these three compounds. CHEMICAL forms a ring around the internal cavity in GENE through aromatic stacking interactions between the drug and GENE as well as between the drug molecules themselves. In contrast, GW5074 and bithionol both bind as pairs of stacked compounds at hexameric 2-fold axes between the dimers of subunits. The internal core of GENE contracts when the catalytic cleft closes during enzymatic turnover. None of the drugs cause conformational changes in the contact residues, but all bind to key interfaces involved in this contraction process. Therefore, it seems likely that the drugs inhibit enzymatic turnover by inhibiting this transition. Indeed, this expansion/contraction process may play a major role in the inter-subunit communication and allosteric regulation observed in GENE. | DIRECT-REGULATOR |
| Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics. GENE (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of l-glutamate to 2-oxoglutarate using CHEMICAL as coenzyme. Unlike its counterparts from other animal kingdoms, mammalian GDH is regulated by a host of ligands. The recently discovered hyperinsulinism/hyperammonemia disorder showed that the loss of allosteric inhibition of GDH by GTP causes excessive secretion of insulin. Subsequent studies demonstrated that wild-type and hyperinsulinemia/hyperammonemia forms of GDH are inhibited by the green tea polyphenols, epigallocatechin gallate and epicatechin gallate. This was followed by high throughput studies that identified more stable inhibitors, including hexachlorophene, GW5074, and bithionol. Shown here are the structures of GDH complexed with these three compounds. Hexachlorophene forms a ring around the internal cavity in GDH through aromatic stacking interactions between the drug and GDH as well as between the drug molecules themselves. In contrast, GW5074 and bithionol both bind as pairs of stacked compounds at hexameric 2-fold axes between the dimers of subunits. The internal core of GDH contracts when the catalytic cleft closes during enzymatic turnover. None of the drugs cause conformational changes in the contact residues, but all bind to key interfaces involved in this contraction process. Therefore, it seems likely that the drugs inhibit enzymatic turnover by inhibiting this transition. Indeed, this expansion/contraction process may play a major role in the inter-subunit communication and allosteric regulation observed in GDH. | SUBSTRATE |
| Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics. Mammalian glutamate dehydrogenase (GENE) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of l-glutamate to 2-oxoglutarate using CHEMICAL as coenzyme. Unlike its counterparts from other animal kingdoms, mammalian GENE is regulated by a host of ligands. The recently discovered hyperinsulinism/hyperammonemia disorder showed that the loss of allosteric inhibition of GENE by GTP causes excessive secretion of insulin. Subsequent studies demonstrated that wild-type and hyperinsulinemia/hyperammonemia forms of GENE are inhibited by the green tea polyphenols, epigallocatechin gallate and epicatechin gallate. This was followed by high throughput studies that identified more stable inhibitors, including hexachlorophene, GW5074, and bithionol. Shown here are the structures of GENE complexed with these three compounds. Hexachlorophene forms a ring around the internal cavity in GENE through aromatic stacking interactions between the drug and GENE as well as between the drug molecules themselves. In contrast, GW5074 and bithionol both bind as pairs of stacked compounds at hexameric 2-fold axes between the dimers of subunits. The internal core of GENE contracts when the catalytic cleft closes during enzymatic turnover. None of the drugs cause conformational changes in the contact residues, but all bind to key interfaces involved in this contraction process. Therefore, it seems likely that the drugs inhibit enzymatic turnover by inhibiting this transition. Indeed, this expansion/contraction process may play a major role in the inter-subunit communication and allosteric regulation observed in GENE. | SUBSTRATE |
| Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics. Mammalian glutamate dehydrogenase (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of l-glutamate to 2-oxoglutarate using NAD(P)(+) as coenzyme. Unlike its counterparts from other animal kingdoms, mammalian GDH is regulated by a host of ligands. The recently discovered hyperinsulinism/hyperammonemia disorder showed that the loss of allosteric inhibition of GDH by CHEMICAL causes excessive secretion of GENE. Subsequent studies demonstrated that wild-type and hyperinsulinemia/hyperammonemia forms of GDH are inhibited by the green tea polyphenols, epigallocatechin gallate and epicatechin gallate. This was followed by high throughput studies that identified more stable inhibitors, including hexachlorophene, GW5074, and bithionol. Shown here are the structures of GDH complexed with these three compounds. Hexachlorophene forms a ring around the internal cavity in GDH through aromatic stacking interactions between the drug and GDH as well as between the drug molecules themselves. In contrast, GW5074 and bithionol both bind as pairs of stacked compounds at hexameric 2-fold axes between the dimers of subunits. The internal core of GDH contracts when the catalytic cleft closes during enzymatic turnover. None of the drugs cause conformational changes in the contact residues, but all bind to key interfaces involved in this contraction process. Therefore, it seems likely that the drugs inhibit enzymatic turnover by inhibiting this transition. Indeed, this expansion/contraction process may play a major role in the inter-subunit communication and allosteric regulation observed in GDH. | GENE-CHEMICAL |
| Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics. Mammalian glutamate dehydrogenase (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of l-glutamate to 2-oxoglutarate using NAD(P)(+) as coenzyme. Unlike its counterparts from other animal kingdoms, mammalian GENE is regulated by a host of ligands. The recently discovered hyperinsulinism/hyperammonemia disorder showed that the loss of allosteric inhibition of GENE by GTP causes excessive secretion of insulin. Subsequent studies demonstrated that wild-type and hyperinsulinemia/hyperammonemia forms of GENE are inhibited by the green tea polyphenols, CHEMICAL and epicatechin gallate. This was followed by high throughput studies that identified more stable inhibitors, including hexachlorophene, GW5074, and bithionol. Shown here are the structures of GENE complexed with these three compounds. Hexachlorophene forms a ring around the internal cavity in GENE through aromatic stacking interactions between the drug and GENE as well as between the drug molecules themselves. In contrast, GW5074 and bithionol both bind as pairs of stacked compounds at hexameric 2-fold axes between the dimers of subunits. The internal core of GENE contracts when the catalytic cleft closes during enzymatic turnover. None of the drugs cause conformational changes in the contact residues, but all bind to key interfaces involved in this contraction process. Therefore, it seems likely that the drugs inhibit enzymatic turnover by inhibiting this transition. Indeed, this expansion/contraction process may play a major role in the inter-subunit communication and allosteric regulation observed in GENE. | INHIBITOR |
| Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics. Mammalian glutamate dehydrogenase (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of l-glutamate to 2-oxoglutarate using NAD(P)(+) as coenzyme. Unlike its counterparts from other animal kingdoms, mammalian GENE is regulated by a host of ligands. The recently discovered hyperinsulinism/hyperammonemia disorder showed that the loss of allosteric inhibition of GENE by GTP causes excessive secretion of insulin. Subsequent studies demonstrated that wild-type and hyperinsulinemia/hyperammonemia forms of GENE are inhibited by the green tea polyphenols, epigallocatechin gallate and CHEMICAL. This was followed by high throughput studies that identified more stable inhibitors, including hexachlorophene, GW5074, and bithionol. Shown here are the structures of GENE complexed with these three compounds. Hexachlorophene forms a ring around the internal cavity in GENE through aromatic stacking interactions between the drug and GENE as well as between the drug molecules themselves. In contrast, GW5074 and bithionol both bind as pairs of stacked compounds at hexameric 2-fold axes between the dimers of subunits. The internal core of GENE contracts when the catalytic cleft closes during enzymatic turnover. None of the drugs cause conformational changes in the contact residues, but all bind to key interfaces involved in this contraction process. Therefore, it seems likely that the drugs inhibit enzymatic turnover by inhibiting this transition. Indeed, this expansion/contraction process may play a major role in the inter-subunit communication and allosteric regulation observed in GENE. | INHIBITOR |
| Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics. Mammalian glutamate dehydrogenase (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of l-glutamate to 2-oxoglutarate using NAD(P)(+) as coenzyme. Unlike its counterparts from other animal kingdoms, mammalian GENE is regulated by a host of ligands. The recently discovered hyperinsulinism/hyperammonemia disorder showed that the loss of allosteric inhibition of GENE by CHEMICAL causes excessive secretion of insulin. Subsequent studies demonstrated that wild-type and hyperinsulinemia/hyperammonemia forms of GENE are inhibited by the green tea polyphenols, epigallocatechin gallate and epicatechin gallate. This was followed by high throughput studies that identified more stable inhibitors, including hexachlorophene, GW5074, and bithionol. Shown here are the structures of GENE complexed with these three compounds. Hexachlorophene forms a ring around the internal cavity in GENE through aromatic stacking interactions between the drug and GENE as well as between the drug molecules themselves. In contrast, GW5074 and bithionol both bind as pairs of stacked compounds at hexameric 2-fold axes between the dimers of subunits. The internal core of GENE contracts when the catalytic cleft closes during enzymatic turnover. None of the drugs cause conformational changes in the contact residues, but all bind to key interfaces involved in this contraction process. Therefore, it seems likely that the drugs inhibit enzymatic turnover by inhibiting this transition. Indeed, this expansion/contraction process may play a major role in the inter-subunit communication and allosteric regulation observed in GENE. | INHIBITOR |
| Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics. GENE (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of l-glutamate to CHEMICAL using NAD(P)(+) as coenzyme. Unlike its counterparts from other animal kingdoms, mammalian GDH is regulated by a host of ligands. The recently discovered hyperinsulinism/hyperammonemia disorder showed that the loss of allosteric inhibition of GDH by GTP causes excessive secretion of insulin. Subsequent studies demonstrated that wild-type and hyperinsulinemia/hyperammonemia forms of GDH are inhibited by the green tea polyphenols, epigallocatechin gallate and epicatechin gallate. This was followed by high throughput studies that identified more stable inhibitors, including hexachlorophene, GW5074, and bithionol. Shown here are the structures of GDH complexed with these three compounds. Hexachlorophene forms a ring around the internal cavity in GDH through aromatic stacking interactions between the drug and GDH as well as between the drug molecules themselves. In contrast, GW5074 and bithionol both bind as pairs of stacked compounds at hexameric 2-fold axes between the dimers of subunits. The internal core of GDH contracts when the catalytic cleft closes during enzymatic turnover. None of the drugs cause conformational changes in the contact residues, but all bind to key interfaces involved in this contraction process. Therefore, it seems likely that the drugs inhibit enzymatic turnover by inhibiting this transition. Indeed, this expansion/contraction process may play a major role in the inter-subunit communication and allosteric regulation observed in GDH. | PRODUCT-OF |
| Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics. Mammalian glutamate dehydrogenase (GENE) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of l-glutamate to CHEMICAL using NAD(P)(+) as coenzyme. Unlike its counterparts from other animal kingdoms, mammalian GENE is regulated by a host of ligands. The recently discovered hyperinsulinism/hyperammonemia disorder showed that the loss of allosteric inhibition of GENE by GTP causes excessive secretion of insulin. Subsequent studies demonstrated that wild-type and hyperinsulinemia/hyperammonemia forms of GENE are inhibited by the green tea polyphenols, epigallocatechin gallate and epicatechin gallate. This was followed by high throughput studies that identified more stable inhibitors, including hexachlorophene, GW5074, and bithionol. Shown here are the structures of GENE complexed with these three compounds. Hexachlorophene forms a ring around the internal cavity in GENE through aromatic stacking interactions between the drug and GENE as well as between the drug molecules themselves. In contrast, GW5074 and bithionol both bind as pairs of stacked compounds at hexameric 2-fold axes between the dimers of subunits. The internal core of GENE contracts when the catalytic cleft closes during enzymatic turnover. None of the drugs cause conformational changes in the contact residues, but all bind to key interfaces involved in this contraction process. Therefore, it seems likely that the drugs inhibit enzymatic turnover by inhibiting this transition. Indeed, this expansion/contraction process may play a major role in the inter-subunit communication and allosteric regulation observed in GENE. | PRODUCT-OF |
| Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics. GENE (GDH) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of CHEMICAL to 2-oxoglutarate using NAD(P)(+) as coenzyme. Unlike its counterparts from other animal kingdoms, mammalian GDH is regulated by a host of ligands. The recently discovered hyperinsulinism/hyperammonemia disorder showed that the loss of allosteric inhibition of GDH by GTP causes excessive secretion of insulin. Subsequent studies demonstrated that wild-type and hyperinsulinemia/hyperammonemia forms of GDH are inhibited by the green tea polyphenols, epigallocatechin gallate and epicatechin gallate. This was followed by high throughput studies that identified more stable inhibitors, including hexachlorophene, GW5074, and bithionol. Shown here are the structures of GDH complexed with these three compounds. Hexachlorophene forms a ring around the internal cavity in GDH through aromatic stacking interactions between the drug and GDH as well as between the drug molecules themselves. In contrast, GW5074 and bithionol both bind as pairs of stacked compounds at hexameric 2-fold axes between the dimers of subunits. The internal core of GDH contracts when the catalytic cleft closes during enzymatic turnover. None of the drugs cause conformational changes in the contact residues, but all bind to key interfaces involved in this contraction process. Therefore, it seems likely that the drugs inhibit enzymatic turnover by inhibiting this transition. Indeed, this expansion/contraction process may play a major role in the inter-subunit communication and allosteric regulation observed in GDH. | SUBSTRATE |
| Novel inhibitors complexed with glutamate dehydrogenase: allosteric regulation by control of protein dynamics. Mammalian glutamate dehydrogenase (GENE) is a homohexameric enzyme that catalyzes the reversible oxidative deamination of CHEMICAL to 2-oxoglutarate using NAD(P)(+) as coenzyme. Unlike its counterparts from other animal kingdoms, mammalian GENE is regulated by a host of ligands. The recently discovered hyperinsulinism/hyperammonemia disorder showed that the loss of allosteric inhibition of GENE by GTP causes excessive secretion of insulin. Subsequent studies demonstrated that wild-type and hyperinsulinemia/hyperammonemia forms of GENE are inhibited by the green tea polyphenols, epigallocatechin gallate and epicatechin gallate. This was followed by high throughput studies that identified more stable inhibitors, including hexachlorophene, GW5074, and bithionol. Shown here are the structures of GENE complexed with these three compounds. Hexachlorophene forms a ring around the internal cavity in GENE through aromatic stacking interactions between the drug and GENE as well as between the drug molecules themselves. In contrast, GW5074 and bithionol both bind as pairs of stacked compounds at hexameric 2-fold axes between the dimers of subunits. The internal core of GENE contracts when the catalytic cleft closes during enzymatic turnover. None of the drugs cause conformational changes in the contact residues, but all bind to key interfaces involved in this contraction process. Therefore, it seems likely that the drugs inhibit enzymatic turnover by inhibiting this transition. Indeed, this expansion/contraction process may play a major role in the inter-subunit communication and allosteric regulation observed in GENE. | SUBSTRATE |
| The effect of a peripheral block on inflammation-induced prostaglandin E2 and cyclooxygenase expression in rats. BACKGROUND: Peripheral inflammatory pain is associated with an upregulation of spinal cord COX-2 (cyclooxygenase-2), with a subsequent increase in central prostaglandin E2 (PGE2) levels associated with the development of hyperalgesia. In this study, we evaluated the effect of CHEMICAL administered via a nerve block or via a systemic route on the spinal expression of PGE2 and GENE in a model of peripheral inflammation in rats. METHODS: All rats randomly received three injections: 1) a left subcutaneous hindpaw injection (0.2 mL with either carrageenan 2% w/v or saline), 2) a left sciatic block (0.2 mL with either CHEMICAL 0.5% or saline), and 3) a systemic injection (subcutaneous interscapular with 0.2 mL with either CHEMICAL 0.5% or saline). Local edema, thermal, and mechanical hyperalgesia as well as cerebrospinal fluid PGE2 concentration and COX-1 and COX-2 expression in the spinal cord in dorsal root ganglions were measured. RESULTS: We confirmed that a CHEMICAL block attenuates hyperalgesia and local inflammation in a model of inflammatory pain. This effect was associated with an inhibition of the increase in COX-2 expression induced by peripheral inflammation in dorsal root ganglions and cord. The subsequent production of PGE2 in cerebrospinal fluid was also impaired. Systemic CHEMICAL did not modify either the hyperalgesia and local inflammation or GENE expression. CONCLUSION: These results constitute a key element strongly suggesting that local anesthetics act at a different level when administered systematically or via a nerve block. | NO-RELATIONSHIP |
| The effect of a peripheral block on inflammation-induced CHEMICAL and cyclooxygenase expression in rats. BACKGROUND: Peripheral inflammatory pain is associated with an upregulation of spinal cord GENE (cyclooxygenase-2), with a subsequent increase in central CHEMICAL (PGE2) levels associated with the development of hyperalgesia. In this study, we evaluated the effect of bupivacaine administered via a nerve block or via a systemic route on the spinal expression of PGE2 and COX in a model of peripheral inflammation in rats. METHODS: All rats randomly received three injections: 1) a left subcutaneous hindpaw injection (0.2 mL with either carrageenan 2% w/v or saline), 2) a left sciatic block (0.2 mL with either bupivacaine 0.5% or saline), and 3) a systemic injection (subcutaneous interscapular with 0.2 mL with either bupivacaine 0.5% or saline). Local edema, thermal, and mechanical hyperalgesia as well as cerebrospinal fluid PGE2 concentration and COX-1 and GENE expression in the spinal cord in dorsal root ganglions were measured. RESULTS: We confirmed that a bupivacaine block attenuates hyperalgesia and local inflammation in a model of inflammatory pain. This effect was associated with an inhibition of the increase in GENE expression induced by peripheral inflammation in dorsal root ganglions and cord. The subsequent production of PGE2 in cerebrospinal fluid was also impaired. Systemic bupivacaine did not modify either the hyperalgesia and local inflammation or COX expression. CONCLUSION: These results constitute a key element strongly suggesting that local anesthetics act at a different level when administered systematically or via a nerve block. | PRODUCT-OF |
| The effect of a peripheral block on inflammation-induced CHEMICAL and cyclooxygenase expression in rats. BACKGROUND: Peripheral inflammatory pain is associated with an upregulation of spinal cord COX-2 (GENE), with a subsequent increase in central CHEMICAL (PGE2) levels associated with the development of hyperalgesia. In this study, we evaluated the effect of bupivacaine administered via a nerve block or via a systemic route on the spinal expression of PGE2 and COX in a model of peripheral inflammation in rats. METHODS: All rats randomly received three injections: 1) a left subcutaneous hindpaw injection (0.2 mL with either carrageenan 2% w/v or saline), 2) a left sciatic block (0.2 mL with either bupivacaine 0.5% or saline), and 3) a systemic injection (subcutaneous interscapular with 0.2 mL with either bupivacaine 0.5% or saline). Local edema, thermal, and mechanical hyperalgesia as well as cerebrospinal fluid PGE2 concentration and COX-1 and COX-2 expression in the spinal cord in dorsal root ganglions were measured. RESULTS: We confirmed that a bupivacaine block attenuates hyperalgesia and local inflammation in a model of inflammatory pain. This effect was associated with an inhibition of the increase in COX-2 expression induced by peripheral inflammation in dorsal root ganglions and cord. The subsequent production of PGE2 in cerebrospinal fluid was also impaired. Systemic bupivacaine did not modify either the hyperalgesia and local inflammation or COX expression. CONCLUSION: These results constitute a key element strongly suggesting that local anesthetics act at a different level when administered systematically or via a nerve block. | PRODUCT-OF |
| The effect of a peripheral block on inflammation-induced prostaglandin E2 and cyclooxygenase expression in rats. BACKGROUND: Peripheral inflammatory pain is associated with an upregulation of spinal cord GENE (cyclooxygenase-2), with a subsequent increase in central prostaglandin E2 (CHEMICAL) levels associated with the development of hyperalgesia. In this study, we evaluated the effect of bupivacaine administered via a nerve block or via a systemic route on the spinal expression of CHEMICAL and COX in a model of peripheral inflammation in rats. METHODS: All rats randomly received three injections: 1) a left subcutaneous hindpaw injection (0.2 mL with either carrageenan 2% w/v or saline), 2) a left sciatic block (0.2 mL with either bupivacaine 0.5% or saline), and 3) a systemic injection (subcutaneous interscapular with 0.2 mL with either bupivacaine 0.5% or saline). Local edema, thermal, and mechanical hyperalgesia as well as cerebrospinal fluid CHEMICAL concentration and COX-1 and GENE expression in the spinal cord in dorsal root ganglions were measured. RESULTS: We confirmed that a bupivacaine block attenuates hyperalgesia and local inflammation in a model of inflammatory pain. This effect was associated with an inhibition of the increase in GENE expression induced by peripheral inflammation in dorsal root ganglions and cord. The subsequent production of CHEMICAL in cerebrospinal fluid was also impaired. Systemic bupivacaine did not modify either the hyperalgesia and local inflammation or COX expression. CONCLUSION: These results constitute a key element strongly suggesting that local anesthetics act at a different level when administered systematically or via a nerve block. | PRODUCT-OF |
| The effect of a peripheral block on inflammation-induced prostaglandin E2 and cyclooxygenase expression in rats. BACKGROUND: Peripheral inflammatory pain is associated with an upregulation of spinal cord COX-2 (GENE), with a subsequent increase in central prostaglandin E2 (CHEMICAL) levels associated with the development of hyperalgesia. In this study, we evaluated the effect of bupivacaine administered via a nerve block or via a systemic route on the spinal expression of CHEMICAL and COX in a model of peripheral inflammation in rats. METHODS: All rats randomly received three injections: 1) a left subcutaneous hindpaw injection (0.2 mL with either carrageenan 2% w/v or saline), 2) a left sciatic block (0.2 mL with either bupivacaine 0.5% or saline), and 3) a systemic injection (subcutaneous interscapular with 0.2 mL with either bupivacaine 0.5% or saline). Local edema, thermal, and mechanical hyperalgesia as well as cerebrospinal fluid CHEMICAL concentration and COX-1 and COX-2 expression in the spinal cord in dorsal root ganglions were measured. RESULTS: We confirmed that a bupivacaine block attenuates hyperalgesia and local inflammation in a model of inflammatory pain. This effect was associated with an inhibition of the increase in COX-2 expression induced by peripheral inflammation in dorsal root ganglions and cord. The subsequent production of CHEMICAL in cerebrospinal fluid was also impaired. Systemic bupivacaine did not modify either the hyperalgesia and local inflammation or COX expression. CONCLUSION: These results constitute a key element strongly suggesting that local anesthetics act at a different level when administered systematically or via a nerve block. | PRODUCT-OF |
| Two pharmacologically distinct GENE subtypes in the contraction of rabbit aorta: each subtype couples with a different Ca2+ signalling mechanism and plays a different physiological role. Using the GENE subtype-selective antagonists chlorethylclonidine (CEC), CHEMICAL, and 5-methyl-urapidil, we have examined the possible heterogeneity in the GENE populations in rabbit aorta. The GENE alkylating agent CEC selectively inhibited the phasic component of the norepinephrine-induced contractile response, with little effect on the tonic component. The GENE occupancy-response relationship defined by the phenoxybenzamine inactivation method was rectangular hyperbolic for the tonic response, whereas that for the phasic response was linear, indicating the different degree of receptor reserve for the two responses. Radioligand binding studies with the nonselective GENE antagonist radioligand 125I-BE2254 showed that 73-87% of the binding sites in rabbit aorta are CEC sensitive and they are predominantly low affinity sites both for CHEMICAL (pKd = 8.1) and for 5-methylurapidil (pKd = 7.1). Moreover, alpha 1-adrenoceptor-mediated phosphatidylinositol (PI) hydrolysis was CEC sensitive, and fractional inactivation of alpha 1 receptors with CEC showed equivalent increments in the reduction of PI hydrolysis and phasic contractile response, suggesting that both responses are linearly related to the CEC-sensitive receptor sites. The Schild plots for the competitive antagonists CHEMICAL and 5-methyl-urapidil against alpha 1a-adrenoceptor-selective agonist methoxamine-induced contraction were linear and had slopes not significantly different from unity, with a pA2 of 9.07 +/- 0.07 (n = 5) for CHEMICAL and 9.09 +/- 0.05 (n = 3) for 5-methyl-urapidil. However, the Schilod plots for these antagonists against norepinephrine were curvilinear. Computer-assisted analysis of these curvilinear Schild plots in a two-receptor system indicated that GENE populations responsible for the constrictive response are predominantly (approximately 80-90%) low affinity sites for the two antagonists (pKd approximately 8.1 for CHEMICAL and pKd approximately 7.1 for 5-methyl-urapidil) and a small population (approximately 10-20%) are high affinity sites (pKd approximately 9.1 for both CHEMICAL and 5-methyl-urapidil), which was in good agreement with radioligand binding studies.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| Two pharmacologically distinct GENE subtypes in the contraction of rabbit aorta: each subtype couples with a different Ca2+ signalling mechanism and plays a different physiological role. Using the GENE subtype-selective antagonists chlorethylclonidine (CEC), WB4101, and CHEMICAL, we have examined the possible heterogeneity in the GENE populations in rabbit aorta. The GENE alkylating agent CEC selectively inhibited the phasic component of the norepinephrine-induced contractile response, with little effect on the tonic component. The GENE occupancy-response relationship defined by the phenoxybenzamine inactivation method was rectangular hyperbolic for the tonic response, whereas that for the phasic response was linear, indicating the different degree of receptor reserve for the two responses. Radioligand binding studies with the nonselective GENE antagonist radioligand 125I-BE2254 showed that 73-87% of the binding sites in rabbit aorta are CEC sensitive and they are predominantly low affinity sites both for WB4101 (pKd = 8.1) and for 5-methylurapidil (pKd = 7.1). Moreover, alpha 1-adrenoceptor-mediated phosphatidylinositol (PI) hydrolysis was CEC sensitive, and fractional inactivation of alpha 1 receptors with CEC showed equivalent increments in the reduction of PI hydrolysis and phasic contractile response, suggesting that both responses are linearly related to the CEC-sensitive receptor sites. The Schild plots for the competitive antagonists WB4101 and CHEMICAL against alpha 1a-adrenoceptor-selective agonist methoxamine-induced contraction were linear and had slopes not significantly different from unity, with a pA2 of 9.07 +/- 0.07 (n = 5) for WB4101 and 9.09 +/- 0.05 (n = 3) for CHEMICAL. However, the Schilod plots for these antagonists against norepinephrine were curvilinear. Computer-assisted analysis of these curvilinear Schild plots in a two-receptor system indicated that GENE populations responsible for the constrictive response are predominantly (approximately 80-90%) low affinity sites for the two antagonists (pKd approximately 8.1 for WB4101 and pKd approximately 7.1 for 5-methyl-urapidil) and a small population (approximately 10-20%) are high affinity sites (pKd approximately 9.1 for both WB4101 and CHEMICAL), which was in good agreement with radioligand binding studies.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| Two pharmacologically distinct GENE subtypes in the contraction of rabbit aorta: each subtype couples with a different Ca2+ signalling mechanism and plays a different physiological role. Using the GENE subtype-selective antagonists chlorethylclonidine (CEC), WB4101, and 5-methyl-urapidil, we have examined the possible heterogeneity in the GENE populations in rabbit aorta. The GENE alkylating agent CEC selectively inhibited the phasic component of the norepinephrine-induced contractile response, with little effect on the tonic component. The GENE occupancy-response relationship defined by the phenoxybenzamine inactivation method was rectangular hyperbolic for the tonic response, whereas that for the phasic response was linear, indicating the different degree of receptor reserve for the two responses. Radioligand binding studies with the nonselective GENE antagonist radioligand CHEMICAL showed that 73-87% of the binding sites in rabbit aorta are CEC sensitive and they are predominantly low affinity sites both for WB4101 (pKd = 8.1) and for 5-methylurapidil (pKd = 7.1). Moreover, alpha 1-adrenoceptor-mediated phosphatidylinositol (PI) hydrolysis was CEC sensitive, and fractional inactivation of alpha 1 receptors with CEC showed equivalent increments in the reduction of PI hydrolysis and phasic contractile response, suggesting that both responses are linearly related to the CEC-sensitive receptor sites. The Schild plots for the competitive antagonists WB4101 and 5-methyl-urapidil against alpha 1a-adrenoceptor-selective agonist methoxamine-induced contraction were linear and had slopes not significantly different from unity, with a pA2 of 9.07 +/- 0.07 (n = 5) for WB4101 and 9.09 +/- 0.05 (n = 3) for 5-methyl-urapidil. However, the Schilod plots for these antagonists against norepinephrine were curvilinear. Computer-assisted analysis of these curvilinear Schild plots in a two-receptor system indicated that GENE populations responsible for the constrictive response are predominantly (approximately 80-90%) low affinity sites for the two antagonists (pKd approximately 8.1 for WB4101 and pKd approximately 7.1 for 5-methyl-urapidil) and a small population (approximately 10-20%) are high affinity sites (pKd approximately 9.1 for both WB4101 and 5-methyl-urapidil), which was in good agreement with radioligand binding studies.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| Two pharmacologically distinct GENE subtypes in the contraction of rabbit aorta: each subtype couples with a different Ca2+ signalling mechanism and plays a different physiological role. Using the GENE subtype-selective antagonists chlorethylclonidine (CEC), WB4101, and 5-methyl-urapidil, we have examined the possible heterogeneity in the GENE populations in rabbit aorta. The GENE alkylating agent CHEMICAL selectively inhibited the phasic component of the norepinephrine-induced contractile response, with little effect on the tonic component. The GENE occupancy-response relationship defined by the phenoxybenzamine inactivation method was rectangular hyperbolic for the tonic response, whereas that for the phasic response was linear, indicating the different degree of receptor reserve for the two responses. Radioligand binding studies with the nonselective GENE antagonist radioligand 125I-BE2254 showed that 73-87% of the binding sites in rabbit aorta are CHEMICAL sensitive and they are predominantly low affinity sites both for WB4101 (pKd = 8.1) and for 5-methylurapidil (pKd = 7.1). Moreover, alpha 1-adrenoceptor-mediated phosphatidylinositol (PI) hydrolysis was CHEMICAL sensitive, and fractional inactivation of alpha 1 receptors with CHEMICAL showed equivalent increments in the reduction of PI hydrolysis and phasic contractile response, suggesting that both responses are linearly related to the CEC-sensitive receptor sites. The Schild plots for the competitive antagonists WB4101 and 5-methyl-urapidil against alpha 1a-adrenoceptor-selective agonist methoxamine-induced contraction were linear and had slopes not significantly different from unity, with a pA2 of 9.07 +/- 0.07 (n = 5) for WB4101 and 9.09 +/- 0.05 (n = 3) for 5-methyl-urapidil. However, the Schilod plots for these antagonists against norepinephrine were curvilinear. Computer-assisted analysis of these curvilinear Schild plots in a two-receptor system indicated that GENE populations responsible for the constrictive response are predominantly (approximately 80-90%) low affinity sites for the two antagonists (pKd approximately 8.1 for WB4101 and pKd approximately 7.1 for 5-methyl-urapidil) and a small population (approximately 10-20%) are high affinity sites (pKd approximately 9.1 for both WB4101 and 5-methyl-urapidil), which was in good agreement with radioligand binding studies.(ABSTRACT TRUNCATED AT 400 WORDS) | ACTIVATOR |
| Two pharmacologically distinct GENE subtypes in the contraction of rabbit aorta: each subtype couples with a different Ca2+ signalling mechanism and plays a different physiological role. Using the GENE subtype-selective antagonists chlorethylclonidine (CEC), WB4101, and 5-methyl-urapidil, we have examined the possible heterogeneity in the GENE populations in rabbit aorta. The GENE alkylating agent CEC selectively inhibited the phasic component of the norepinephrine-induced contractile response, with little effect on the tonic component. The GENE occupancy-response relationship defined by the phenoxybenzamine inactivation method was rectangular hyperbolic for the tonic response, whereas that for the phasic response was linear, indicating the different degree of receptor reserve for the two responses. Radioligand binding studies with the nonselective GENE antagonist radioligand 125I-BE2254 showed that 73-87% of the binding sites in rabbit aorta are CEC sensitive and they are predominantly low affinity sites both for WB4101 (pKd = 8.1) and for CHEMICAL (pKd = 7.1). Moreover, alpha 1-adrenoceptor-mediated phosphatidylinositol (PI) hydrolysis was CEC sensitive, and fractional inactivation of alpha 1 receptors with CEC showed equivalent increments in the reduction of PI hydrolysis and phasic contractile response, suggesting that both responses are linearly related to the CEC-sensitive receptor sites. The Schild plots for the competitive antagonists WB4101 and 5-methyl-urapidil against alpha 1a-adrenoceptor-selective agonist methoxamine-induced contraction were linear and had slopes not significantly different from unity, with a pA2 of 9.07 +/- 0.07 (n = 5) for WB4101 and 9.09 +/- 0.05 (n = 3) for 5-methyl-urapidil. However, the Schilod plots for these antagonists against norepinephrine were curvilinear. Computer-assisted analysis of these curvilinear Schild plots in a two-receptor system indicated that GENE populations responsible for the constrictive response are predominantly (approximately 80-90%) low affinity sites for the two antagonists (pKd approximately 8.1 for WB4101 and pKd approximately 7.1 for 5-methyl-urapidil) and a small population (approximately 10-20%) are high affinity sites (pKd approximately 9.1 for both WB4101 and 5-methyl-urapidil), which was in good agreement with radioligand binding studies.(ABSTRACT TRUNCATED AT 400 WORDS) | DIRECT-REGULATOR |
| Two pharmacologically distinct alpha 1-adrenoceptor subtypes in the contraction of rabbit aorta: each subtype couples with a different Ca2+ signalling mechanism and plays a different physiological role. Using the alpha 1-adrenoceptor subtype-selective antagonists chlorethylclonidine (CEC), WB4101, and 5-methyl-urapidil, we have examined the possible heterogeneity in the alpha 1-adrenoceptor populations in rabbit aorta. The alpha 1-adrenoceptor alkylating agent CEC selectively inhibited the phasic component of the norepinephrine-induced contractile response, with little effect on the tonic component. The alpha 1-adrenoceptor occupancy-response relationship defined by the phenoxybenzamine inactivation method was rectangular hyperbolic for the tonic response, whereas that for the phasic response was linear, indicating the different degree of receptor reserve for the two responses. Radioligand binding studies with the nonselective alpha 1-adrenoceptor antagonist radioligand 125I-BE2254 showed that 73-87% of the binding sites in rabbit aorta are CEC sensitive and they are predominantly low affinity sites both for WB4101 (pKd = 8.1) and for 5-methylurapidil (pKd = 7.1). Moreover, alpha 1-adrenoceptor-mediated phosphatidylinositol (PI) hydrolysis was CEC sensitive, and fractional inactivation of alpha 1 receptors with CEC showed equivalent increments in the reduction of PI hydrolysis and phasic contractile response, suggesting that both responses are linearly related to the CEC-sensitive receptor sites. The Schild plots for the competitive antagonists WB4101 and 5-methyl-urapidil against GENE-selective agonist CHEMICAL-induced contraction were linear and had slopes not significantly different from unity, with a pA2 of 9.07 +/- 0.07 (n = 5) for WB4101 and 9.09 +/- 0.05 (n = 3) for 5-methyl-urapidil. However, the Schilod plots for these antagonists against norepinephrine were curvilinear. Computer-assisted analysis of these curvilinear Schild plots in a two-receptor system indicated that alpha 1-adrenoceptor populations responsible for the constrictive response are predominantly (approximately 80-90%) low affinity sites for the two antagonists (pKd approximately 8.1 for WB4101 and pKd approximately 7.1 for 5-methyl-urapidil) and a small population (approximately 10-20%) are high affinity sites (pKd approximately 9.1 for both WB4101 and 5-methyl-urapidil), which was in good agreement with radioligand binding studies.(ABSTRACT TRUNCATED AT 400 WORDS) | ACTIVATOR |
| Two pharmacologically distinct alpha 1-adrenoceptor subtypes in the contraction of rabbit aorta: each subtype couples with a different Ca2+ signalling mechanism and plays a different physiological role. Using the alpha 1-adrenoceptor subtype-selective antagonists chlorethylclonidine (CEC), CHEMICAL, and 5-methyl-urapidil, we have examined the possible heterogeneity in the alpha 1-adrenoceptor populations in rabbit aorta. The alpha 1-adrenoceptor alkylating agent CEC selectively inhibited the phasic component of the norepinephrine-induced contractile response, with little effect on the tonic component. The alpha 1-adrenoceptor occupancy-response relationship defined by the phenoxybenzamine inactivation method was rectangular hyperbolic for the tonic response, whereas that for the phasic response was linear, indicating the different degree of receptor reserve for the two responses. Radioligand binding studies with the nonselective alpha 1-adrenoceptor antagonist radioligand 125I-BE2254 showed that 73-87% of the binding sites in rabbit aorta are CEC sensitive and they are predominantly low affinity sites both for CHEMICAL (pKd = 8.1) and for 5-methylurapidil (pKd = 7.1). Moreover, alpha 1-adrenoceptor-mediated phosphatidylinositol (PI) hydrolysis was CEC sensitive, and fractional inactivation of alpha 1 receptors with CEC showed equivalent increments in the reduction of PI hydrolysis and phasic contractile response, suggesting that both responses are linearly related to the CEC-sensitive receptor sites. The Schild plots for the competitive antagonists CHEMICAL and 5-methyl-urapidil against GENE-selective agonist methoxamine-induced contraction were linear and had slopes not significantly different from unity, with a pA2 of 9.07 +/- 0.07 (n = 5) for CHEMICAL and 9.09 +/- 0.05 (n = 3) for 5-methyl-urapidil. However, the Schilod plots for these antagonists against norepinephrine were curvilinear. Computer-assisted analysis of these curvilinear Schild plots in a two-receptor system indicated that alpha 1-adrenoceptor populations responsible for the constrictive response are predominantly (approximately 80-90%) low affinity sites for the two antagonists (pKd approximately 8.1 for CHEMICAL and pKd approximately 7.1 for 5-methyl-urapidil) and a small population (approximately 10-20%) are high affinity sites (pKd approximately 9.1 for both CHEMICAL and 5-methyl-urapidil), which was in good agreement with radioligand binding studies.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| Two pharmacologically distinct alpha 1-adrenoceptor subtypes in the contraction of rabbit aorta: each subtype couples with a different Ca2+ signalling mechanism and plays a different physiological role. Using the alpha 1-adrenoceptor subtype-selective antagonists chlorethylclonidine (CEC), WB4101, and CHEMICAL, we have examined the possible heterogeneity in the alpha 1-adrenoceptor populations in rabbit aorta. The alpha 1-adrenoceptor alkylating agent CEC selectively inhibited the phasic component of the norepinephrine-induced contractile response, with little effect on the tonic component. The alpha 1-adrenoceptor occupancy-response relationship defined by the phenoxybenzamine inactivation method was rectangular hyperbolic for the tonic response, whereas that for the phasic response was linear, indicating the different degree of receptor reserve for the two responses. Radioligand binding studies with the nonselective alpha 1-adrenoceptor antagonist radioligand 125I-BE2254 showed that 73-87% of the binding sites in rabbit aorta are CEC sensitive and they are predominantly low affinity sites both for WB4101 (pKd = 8.1) and for 5-methylurapidil (pKd = 7.1). Moreover, alpha 1-adrenoceptor-mediated phosphatidylinositol (PI) hydrolysis was CEC sensitive, and fractional inactivation of alpha 1 receptors with CEC showed equivalent increments in the reduction of PI hydrolysis and phasic contractile response, suggesting that both responses are linearly related to the CEC-sensitive receptor sites. The Schild plots for the competitive antagonists WB4101 and CHEMICAL against GENE-selective agonist methoxamine-induced contraction were linear and had slopes not significantly different from unity, with a pA2 of 9.07 +/- 0.07 (n = 5) for WB4101 and 9.09 +/- 0.05 (n = 3) for CHEMICAL. However, the Schilod plots for these antagonists against norepinephrine were curvilinear. Computer-assisted analysis of these curvilinear Schild plots in a two-receptor system indicated that alpha 1-adrenoceptor populations responsible for the constrictive response are predominantly (approximately 80-90%) low affinity sites for the two antagonists (pKd approximately 8.1 for WB4101 and pKd approximately 7.1 for 5-methyl-urapidil) and a small population (approximately 10-20%) are high affinity sites (pKd approximately 9.1 for both WB4101 and 5-methyl-urapidil), which was in good agreement with radioligand binding studies.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| Two pharmacologically distinct GENE subtypes in the contraction of rabbit aorta: each subtype couples with a different Ca2+ signalling mechanism and plays a different physiological role. Using the GENE subtype-selective antagonists CHEMICAL (CEC), WB4101, and 5-methyl-urapidil, we have examined the possible heterogeneity in the GENE populations in rabbit aorta. The GENE alkylating agent CEC selectively inhibited the phasic component of the norepinephrine-induced contractile response, with little effect on the tonic component. The GENE occupancy-response relationship defined by the phenoxybenzamine inactivation method was rectangular hyperbolic for the tonic response, whereas that for the phasic response was linear, indicating the different degree of receptor reserve for the two responses. Radioligand binding studies with the nonselective GENE antagonist radioligand 125I-BE2254 showed that 73-87% of the binding sites in rabbit aorta are CEC sensitive and they are predominantly low affinity sites both for WB4101 (pKd = 8.1) and for 5-methylurapidil (pKd = 7.1). Moreover, alpha 1-adrenoceptor-mediated phosphatidylinositol (PI) hydrolysis was CEC sensitive, and fractional inactivation of alpha 1 receptors with CEC showed equivalent increments in the reduction of PI hydrolysis and phasic contractile response, suggesting that both responses are linearly related to the CEC-sensitive receptor sites. The Schild plots for the competitive antagonists WB4101 and 5-methyl-urapidil against alpha 1a-adrenoceptor-selective agonist methoxamine-induced contraction were linear and had slopes not significantly different from unity, with a pA2 of 9.07 +/- 0.07 (n = 5) for WB4101 and 9.09 +/- 0.05 (n = 3) for 5-methyl-urapidil. However, the Schilod plots for these antagonists against norepinephrine were curvilinear. Computer-assisted analysis of these curvilinear Schild plots in a two-receptor system indicated that GENE populations responsible for the constrictive response are predominantly (approximately 80-90%) low affinity sites for the two antagonists (pKd approximately 8.1 for WB4101 and pKd approximately 7.1 for 5-methyl-urapidil) and a small population (approximately 10-20%) are high affinity sites (pKd approximately 9.1 for both WB4101 and 5-methyl-urapidil), which was in good agreement with radioligand binding studies.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| CHEMICAL for the treatment of pulmonary arterial hypertension. CHEMICAL is an GENE antagonist (ERA) that was recently approved for treatment of pulmonary arterial hypertension (PAH). Endothelin (ET) is a potent vasoconstrictor with mitogenic, hypertrophic and pro-inflammatory properties that is upregulated in pulmonary hypertensive diseases. The biologic effects of ET are mediated by 2 cell surface receptors termed ET(A) and ET(B). ET(A) mediates the vasoconstrictor effect of ET on vascular smooth muscle, whereas ET(B) is expressed primarily on vascular endothelial cells where it induces nitric oxide synthesis and acts to clear ET from the circulation. CHEMICAL is the first ET(A) selective ERA approved for use in the US. Recently published clinical trials in patients with PAH demonstrate improvement in functional capacity and pulmonary hemodynamics similar to other ET(A) selective and non-selective ERAs. Its once daily dosing and lower incidence of serum aminotransferase elevation offer potential advantages over other ERAs, but further experience with this agent is needed to fully understand its long-term efficacy and safety. This review discusses the endothelin family of proteins and receptors and their role in the pathophysiology of pulmonary hypertensive diseases. It also examines the development process, safety profile and clinical trials that have resulted in ambrisentan being approved for treatment of PAH. | INHIBITOR |
| CHEMICAL for the treatment of pulmonary arterial hypertension. CHEMICAL is an endothelin receptor antagonist (ERA) that was recently approved for treatment of pulmonary arterial hypertension (PAH). Endothelin (ET) is a potent vasoconstrictor with mitogenic, hypertrophic and pro-inflammatory properties that is upregulated in pulmonary hypertensive diseases. The biologic effects of ET are mediated by 2 cell surface receptors termed GENE and ET(B). GENE mediates the vasoconstrictor effect of ET on vascular smooth muscle, whereas ET(B) is expressed primarily on vascular endothelial cells where it induces nitric oxide synthesis and acts to clear ET from the circulation. CHEMICAL is the first GENE selective ERA approved for use in the US. Recently published clinical trials in patients with PAH demonstrate improvement in functional capacity and pulmonary hemodynamics similar to other GENE selective and non-selective ERAs. Its once daily dosing and lower incidence of serum aminotransferase elevation offer potential advantages over other ERAs, but further experience with this agent is needed to fully understand its long-term efficacy and safety. This review discusses the endothelin family of proteins and receptors and their role in the pathophysiology of pulmonary hypertensive diseases. It also examines the development process, safety profile and clinical trials that have resulted in ambrisentan being approved for treatment of PAH. | REGULATOR |
| Design, synthesis, and in-vivo evaluation of 4,5-diaryloxazole as novel nonsteroidal anti-inflammatory drug. A series of 4,5-diaryloxazole analogs were designed and the interaction between CHEMICAL and GENE studied by the docking method to improve the biological activity and reduce the gastrointestinal side effects of CHEMICAL. Finally, 3-(4-(4-fluorophenyl)-5-(4-aminosulfonyl-3-fluorophenyl)-oxazole-2-yl) propanoic acid (NC-2142), the best candidate, was selected for synthesis and bioassay based on the screening result. NC-2142 could lower the tumefaction rates of back metatarsus in rats, as well as reduce the writhing times in mice. NC-2142 produced fewer gastric lesions than CHEMICAL. After the aminosulfonyl group was introduced into the benzene ring of CHEMICAL, its analgesic and anti-inflammatory activities remained unchanged, and it reduced the number of gastric lesions. This provided a feasible method for further structure modification and optimization of CHEMICAL. | DIRECT-REGULATOR |
| Breast cancer and steroid metabolizing enzymes: the role of progestogens. It is well documented that breast tissue, both normal and cancerous, contains all the enzymatic systems necessary for the bioformation and metabolic transformation of estrogens, androgens and progesterone. These include sulfatases, aromatase, hydroxysteroid-dehydrogenases, sulfotransferases, hydroxylases and glucuronidases. The control of these enzymes plays an important role in the development and pathogenesis of hormone-dependent breast cancer. As discussed in this review, various progestogens including dydrogesterone and its 20alpha-dihydro-derivative, medrogestone, CHEMICAL, nomegestrol acetate and norelgestromin can reduce intratissular levels of estradiol in breast cancer by blocking GENE and 17beta-hydroxysteroid-dehydrogenase type 1 activities. A possible correlation has been postulated between breast cell proliferation and estrogen sulfotransferase activity. Progesterone is largely transformed in the breast; normal breast produces mainly 4-ene derivatives, whereas 5alpha-derivatives are most common in breast cancer tissue. It has been suggested that this specific conversion of progesterone may be involved in breast carcinogenesis. In conclusion, treatment with anti-aromatases combined with anti-sulfatase or 17beta-hydroxysteroid-dehydrogenase type 1 could provide new therapeutic possibilities in the treatment of patients with hormone-dependent breast cancer. | INHIBITOR |
| Breast cancer and steroid metabolizing enzymes: the role of progestogens. It is well documented that breast tissue, both normal and cancerous, contains all the enzymatic systems necessary for the bioformation and metabolic transformation of estrogens, androgens and progesterone. These include sulfatases, aromatase, hydroxysteroid-dehydrogenases, sulfotransferases, hydroxylases and glucuronidases. The control of these enzymes plays an important role in the development and pathogenesis of hormone-dependent breast cancer. As discussed in this review, various progestogens including dydrogesterone and its 20alpha-dihydro-derivative, medrogestone, CHEMICAL, nomegestrol acetate and norelgestromin can reduce intratissular levels of estradiol in breast cancer by blocking sulfatase and GENE activities. A possible correlation has been postulated between breast cell proliferation and estrogen sulfotransferase activity. Progesterone is largely transformed in the breast; normal breast produces mainly 4-ene derivatives, whereas 5alpha-derivatives are most common in breast cancer tissue. It has been suggested that this specific conversion of progesterone may be involved in breast carcinogenesis. In conclusion, treatment with anti-aromatases combined with anti-sulfatase or GENE could provide new therapeutic possibilities in the treatment of patients with hormone-dependent breast cancer. | INHIBITOR |
| Breast cancer and steroid metabolizing enzymes: the role of progestogens. It is well documented that breast tissue, both normal and cancerous, contains all the enzymatic systems necessary for the bioformation and metabolic transformation of estrogens, androgens and progesterone. These include sulfatases, aromatase, hydroxysteroid-dehydrogenases, sulfotransferases, hydroxylases and glucuronidases. The control of these enzymes plays an important role in the development and pathogenesis of hormone-dependent breast cancer. As discussed in this review, various progestogens including dydrogesterone and its 20alpha-dihydro-derivative, medrogestone, promegestone, CHEMICAL and norelgestromin can reduce intratissular levels of estradiol in breast cancer by blocking GENE and 17beta-hydroxysteroid-dehydrogenase type 1 activities. A possible correlation has been postulated between breast cell proliferation and estrogen sulfotransferase activity. Progesterone is largely transformed in the breast; normal breast produces mainly 4-ene derivatives, whereas 5alpha-derivatives are most common in breast cancer tissue. It has been suggested that this specific conversion of progesterone may be involved in breast carcinogenesis. In conclusion, treatment with anti-aromatases combined with anti-sulfatase or 17beta-hydroxysteroid-dehydrogenase type 1 could provide new therapeutic possibilities in the treatment of patients with hormone-dependent breast cancer. | INHIBITOR |
| Breast cancer and steroid metabolizing enzymes: the role of progestogens. It is well documented that breast tissue, both normal and cancerous, contains all the enzymatic systems necessary for the bioformation and metabolic transformation of estrogens, androgens and progesterone. These include sulfatases, aromatase, hydroxysteroid-dehydrogenases, sulfotransferases, hydroxylases and glucuronidases. The control of these enzymes plays an important role in the development and pathogenesis of hormone-dependent breast cancer. As discussed in this review, various progestogens including dydrogesterone and its 20alpha-dihydro-derivative, medrogestone, promegestone, CHEMICAL and norelgestromin can reduce intratissular levels of estradiol in breast cancer by blocking sulfatase and GENE activities. A possible correlation has been postulated between breast cell proliferation and estrogen sulfotransferase activity. Progesterone is largely transformed in the breast; normal breast produces mainly 4-ene derivatives, whereas 5alpha-derivatives are most common in breast cancer tissue. It has been suggested that this specific conversion of progesterone may be involved in breast carcinogenesis. In conclusion, treatment with anti-aromatases combined with anti-sulfatase or GENE could provide new therapeutic possibilities in the treatment of patients with hormone-dependent breast cancer. | INHIBITOR |
| Breast cancer and steroid metabolizing enzymes: the role of progestogens. It is well documented that breast tissue, both normal and cancerous, contains all the enzymatic systems necessary for the bioformation and metabolic transformation of estrogens, androgens and progesterone. These include sulfatases, aromatase, hydroxysteroid-dehydrogenases, sulfotransferases, hydroxylases and glucuronidases. The control of these enzymes plays an important role in the development and pathogenesis of hormone-dependent breast cancer. As discussed in this review, various progestogens including dydrogesterone and its 20alpha-dihydro-derivative, medrogestone, promegestone, nomegestrol acetate and CHEMICAL can reduce intratissular levels of estradiol in breast cancer by blocking GENE and 17beta-hydroxysteroid-dehydrogenase type 1 activities. A possible correlation has been postulated between breast cell proliferation and estrogen sulfotransferase activity. Progesterone is largely transformed in the breast; normal breast produces mainly 4-ene derivatives, whereas 5alpha-derivatives are most common in breast cancer tissue. It has been suggested that this specific conversion of progesterone may be involved in breast carcinogenesis. In conclusion, treatment with anti-aromatases combined with anti-sulfatase or 17beta-hydroxysteroid-dehydrogenase type 1 could provide new therapeutic possibilities in the treatment of patients with hormone-dependent breast cancer. | INHIBITOR |
| Breast cancer and steroid metabolizing enzymes: the role of progestogens. It is well documented that breast tissue, both normal and cancerous, contains all the enzymatic systems necessary for the bioformation and metabolic transformation of estrogens, androgens and progesterone. These include sulfatases, aromatase, hydroxysteroid-dehydrogenases, sulfotransferases, hydroxylases and glucuronidases. The control of these enzymes plays an important role in the development and pathogenesis of hormone-dependent breast cancer. As discussed in this review, various progestogens including dydrogesterone and its 20alpha-dihydro-derivative, medrogestone, promegestone, nomegestrol acetate and CHEMICAL can reduce intratissular levels of estradiol in breast cancer by blocking sulfatase and GENE activities. A possible correlation has been postulated between breast cell proliferation and estrogen sulfotransferase activity. Progesterone is largely transformed in the breast; normal breast produces mainly 4-ene derivatives, whereas 5alpha-derivatives are most common in breast cancer tissue. It has been suggested that this specific conversion of progesterone may be involved in breast carcinogenesis. In conclusion, treatment with anti-aromatases combined with anti-sulfatase or GENE could provide new therapeutic possibilities in the treatment of patients with hormone-dependent breast cancer. | INHIBITOR |
| Breast cancer and steroid metabolizing enzymes: the role of CHEMICAL. It is well documented that breast tissue, both normal and cancerous, contains all the enzymatic systems necessary for the bioformation and metabolic transformation of estrogens, androgens and progesterone. These include sulfatases, aromatase, hydroxysteroid-dehydrogenases, sulfotransferases, hydroxylases and glucuronidases. The control of these enzymes plays an important role in the development and pathogenesis of hormone-dependent breast cancer. As discussed in this review, various CHEMICAL including dydrogesterone and its 20alpha-dihydro-derivative, medrogestone, promegestone, nomegestrol acetate and norelgestromin can reduce intratissular levels of estradiol in breast cancer by blocking GENE and 17beta-hydroxysteroid-dehydrogenase type 1 activities. A possible correlation has been postulated between breast cell proliferation and estrogen sulfotransferase activity. Progesterone is largely transformed in the breast; normal breast produces mainly 4-ene derivatives, whereas 5alpha-derivatives are most common in breast cancer tissue. It has been suggested that this specific conversion of progesterone may be involved in breast carcinogenesis. In conclusion, treatment with anti-aromatases combined with anti-sulfatase or 17beta-hydroxysteroid-dehydrogenase type 1 could provide new therapeutic possibilities in the treatment of patients with hormone-dependent breast cancer. | INHIBITOR |
| Breast cancer and steroid metabolizing enzymes: the role of CHEMICAL. It is well documented that breast tissue, both normal and cancerous, contains all the enzymatic systems necessary for the bioformation and metabolic transformation of estrogens, androgens and progesterone. These include sulfatases, aromatase, hydroxysteroid-dehydrogenases, sulfotransferases, hydroxylases and glucuronidases. The control of these enzymes plays an important role in the development and pathogenesis of hormone-dependent breast cancer. As discussed in this review, various CHEMICAL including dydrogesterone and its 20alpha-dihydro-derivative, medrogestone, promegestone, nomegestrol acetate and norelgestromin can reduce intratissular levels of estradiol in breast cancer by blocking sulfatase and GENE activities. A possible correlation has been postulated between breast cell proliferation and estrogen sulfotransferase activity. Progesterone is largely transformed in the breast; normal breast produces mainly 4-ene derivatives, whereas 5alpha-derivatives are most common in breast cancer tissue. It has been suggested that this specific conversion of progesterone may be involved in breast carcinogenesis. In conclusion, treatment with anti-aromatases combined with anti-sulfatase or GENE could provide new therapeutic possibilities in the treatment of patients with hormone-dependent breast cancer. | INHIBITOR |
| Breast cancer and steroid metabolizing enzymes: the role of progestogens. It is well documented that breast tissue, both normal and cancerous, contains all the enzymatic systems necessary for the bioformation and metabolic transformation of estrogens, androgens and progesterone. These include sulfatases, aromatase, hydroxysteroid-dehydrogenases, sulfotransferases, hydroxylases and glucuronidases. The control of these enzymes plays an important role in the development and pathogenesis of hormone-dependent breast cancer. As discussed in this review, various progestogens including CHEMICAL and its 20alpha-dihydro-derivative, medrogestone, promegestone, nomegestrol acetate and norelgestromin can reduce intratissular levels of estradiol in breast cancer by blocking GENE and 17beta-hydroxysteroid-dehydrogenase type 1 activities. A possible correlation has been postulated between breast cell proliferation and estrogen sulfotransferase activity. Progesterone is largely transformed in the breast; normal breast produces mainly 4-ene derivatives, whereas 5alpha-derivatives are most common in breast cancer tissue. It has been suggested that this specific conversion of progesterone may be involved in breast carcinogenesis. In conclusion, treatment with anti-aromatases combined with anti-sulfatase or 17beta-hydroxysteroid-dehydrogenase type 1 could provide new therapeutic possibilities in the treatment of patients with hormone-dependent breast cancer. | INHIBITOR |
| Breast cancer and steroid metabolizing enzymes: the role of progestogens. It is well documented that breast tissue, both normal and cancerous, contains all the enzymatic systems necessary for the bioformation and metabolic transformation of estrogens, androgens and progesterone. These include sulfatases, aromatase, hydroxysteroid-dehydrogenases, sulfotransferases, hydroxylases and glucuronidases. The control of these enzymes plays an important role in the development and pathogenesis of hormone-dependent breast cancer. As discussed in this review, various progestogens including CHEMICAL and its 20alpha-dihydro-derivative, medrogestone, promegestone, nomegestrol acetate and norelgestromin can reduce intratissular levels of estradiol in breast cancer by blocking sulfatase and GENE activities. A possible correlation has been postulated between breast cell proliferation and estrogen sulfotransferase activity. Progesterone is largely transformed in the breast; normal breast produces mainly 4-ene derivatives, whereas 5alpha-derivatives are most common in breast cancer tissue. It has been suggested that this specific conversion of progesterone may be involved in breast carcinogenesis. In conclusion, treatment with anti-aromatases combined with anti-sulfatase or GENE could provide new therapeutic possibilities in the treatment of patients with hormone-dependent breast cancer. | INHIBITOR |
| Breast cancer and steroid metabolizing enzymes: the role of progestogens. It is well documented that breast tissue, both normal and cancerous, contains all the enzymatic systems necessary for the bioformation and metabolic transformation of estrogens, androgens and progesterone. These include sulfatases, aromatase, hydroxysteroid-dehydrogenases, sulfotransferases, hydroxylases and glucuronidases. The control of these enzymes plays an important role in the development and pathogenesis of hormone-dependent breast cancer. As discussed in this review, various progestogens including dydrogesterone and its 20alpha-dihydro-derivative, CHEMICAL, promegestone, nomegestrol acetate and norelgestromin can reduce intratissular levels of estradiol in breast cancer by blocking GENE and 17beta-hydroxysteroid-dehydrogenase type 1 activities. A possible correlation has been postulated between breast cell proliferation and estrogen sulfotransferase activity. Progesterone is largely transformed in the breast; normal breast produces mainly 4-ene derivatives, whereas 5alpha-derivatives are most common in breast cancer tissue. It has been suggested that this specific conversion of progesterone may be involved in breast carcinogenesis. In conclusion, treatment with anti-aromatases combined with anti-sulfatase or 17beta-hydroxysteroid-dehydrogenase type 1 could provide new therapeutic possibilities in the treatment of patients with hormone-dependent breast cancer. | INHIBITOR |
| Breast cancer and steroid metabolizing enzymes: the role of progestogens. It is well documented that breast tissue, both normal and cancerous, contains all the enzymatic systems necessary for the bioformation and metabolic transformation of estrogens, androgens and progesterone. These include sulfatases, aromatase, hydroxysteroid-dehydrogenases, sulfotransferases, hydroxylases and glucuronidases. The control of these enzymes plays an important role in the development and pathogenesis of hormone-dependent breast cancer. As discussed in this review, various progestogens including dydrogesterone and its 20alpha-dihydro-derivative, CHEMICAL, promegestone, nomegestrol acetate and norelgestromin can reduce intratissular levels of estradiol in breast cancer by blocking sulfatase and GENE activities. A possible correlation has been postulated between breast cell proliferation and estrogen sulfotransferase activity. Progesterone is largely transformed in the breast; normal breast produces mainly 4-ene derivatives, whereas 5alpha-derivatives are most common in breast cancer tissue. It has been suggested that this specific conversion of progesterone may be involved in breast carcinogenesis. In conclusion, treatment with anti-aromatases combined with anti-sulfatase or GENE could provide new therapeutic possibilities in the treatment of patients with hormone-dependent breast cancer. | INHIBITOR |
| Breast cancer and steroid metabolizing enzymes: the role of progestogens. It is well documented that breast tissue, both normal and cancerous, contains all the enzymatic systems necessary for the bioformation and metabolic transformation of estrogens, androgens and progesterone. These include sulfatases, aromatase, hydroxysteroid-dehydrogenases, sulfotransferases, hydroxylases and glucuronidases. The control of these enzymes plays an important role in the development and pathogenesis of hormone-dependent breast cancer. As discussed in this review, various progestogens including dydrogesterone and its 20alpha-dihydro-derivative, medrogestone, promegestone, nomegestrol acetate and norelgestromin can reduce intratissular levels of CHEMICAL in breast cancer by blocking GENE and 17beta-hydroxysteroid-dehydrogenase type 1 activities. A possible correlation has been postulated between breast cell proliferation and estrogen sulfotransferase activity. Progesterone is largely transformed in the breast; normal breast produces mainly 4-ene derivatives, whereas 5alpha-derivatives are most common in breast cancer tissue. It has been suggested that this specific conversion of progesterone may be involved in breast carcinogenesis. In conclusion, treatment with anti-aromatases combined with anti-sulfatase or 17beta-hydroxysteroid-dehydrogenase type 1 could provide new therapeutic possibilities in the treatment of patients with hormone-dependent breast cancer. | PRODUCT-OF |
| Breast cancer and steroid metabolizing enzymes: the role of progestogens. It is well documented that breast tissue, both normal and cancerous, contains all the enzymatic systems necessary for the bioformation and metabolic transformation of estrogens, androgens and progesterone. These include sulfatases, aromatase, hydroxysteroid-dehydrogenases, sulfotransferases, hydroxylases and glucuronidases. The control of these enzymes plays an important role in the development and pathogenesis of hormone-dependent breast cancer. As discussed in this review, various progestogens including dydrogesterone and its 20alpha-dihydro-derivative, medrogestone, promegestone, nomegestrol acetate and norelgestromin can reduce intratissular levels of CHEMICAL in breast cancer by blocking sulfatase and GENE activities. A possible correlation has been postulated between breast cell proliferation and estrogen sulfotransferase activity. Progesterone is largely transformed in the breast; normal breast produces mainly 4-ene derivatives, whereas 5alpha-derivatives are most common in breast cancer tissue. It has been suggested that this specific conversion of progesterone may be involved in breast carcinogenesis. In conclusion, treatment with anti-aromatases combined with anti-sulfatase or GENE could provide new therapeutic possibilities in the treatment of patients with hormone-dependent breast cancer. | PRODUCT-OF |
| Combination therapy with mitiglinide and voglibose improves glycemic control in type 2 diabetic patients on hemodialysis. OBJECTIVE: CHEMICAL, a rapid- and short-acting insulinotropic GENE ligand, exhibits hypoglycemic action unlike other sulfonylureas. The efficacy of the combination of mitiglinide and alpha-glucosidase inhibitors for diabetic patients on hemodialysis (HD) has not been prospectively evaluated; therefore, we evaluated the efficacy and safety of mitiglinide in these patients. RESEARCH DESIGN AND METHODS: We performed an open-label randomized study with 36 type 2 diabetics with poor glycemic control on HD and receiving daily doses of voglibose (0.9 mg). The patients were randomly assigned to two groups: a combination-therapy group (mitiglinide group), mitiglinide initial dose 7.5 - 15 mg titrated to 30 mg daily and constant daily dose 0.9 mg of voglibose, and a monotherapy group (control group), constant daily dose 0.9 mg of voglibose alone. The efficacy of the treatment was determined by monitoring plasma glucose, hemoglobin A1c (Hb(A1c)), and glycated albumin (GA) levels and using homeostasis model assessment of insulin resistance (HOMA-IR). Safety and tolerance were determined by monitoring clinical and laboratory parameters. RESULTS: The final dose of mitiglinide was 22.9 +/- 8.9 (mean +/- s.d.) mg (0.41 mg/kg) daily. CHEMICAL reduced fasting plasma glucose and GA levels after 4 weeks and Hb(A1c) levels after 8 weeks. Triglyceride levels and HOMA-IR values also decreased significantly after mitiglinide treatment. No significant changes in blood pressure levels or serious adverse effects such as hypoglycemia or liver impairment were observed. CONCLUSIONS: This study suggests a combination therapy of mitiglinide and voglibose may have potential for the treatment of diabetics on HD. Due to the small sample size used, further studies should be performed, particularly to assess the safety of mitiglinide treatment. | DIRECT-REGULATOR |
| Combination therapy with mitiglinide and voglibose improves glycemic control in type 2 diabetic patients on hemodialysis. OBJECTIVE: Mitiglinide, a rapid- and short-acting insulinotropic GENE ligand, exhibits hypoglycemic action unlike other CHEMICAL. The efficacy of the combination of mitiglinide and alpha-glucosidase inhibitors for diabetic patients on hemodialysis (HD) has not been prospectively evaluated; therefore, we evaluated the efficacy and safety of mitiglinide in these patients. RESEARCH DESIGN AND METHODS: We performed an open-label randomized study with 36 type 2 diabetics with poor glycemic control on HD and receiving daily doses of voglibose (0.9 mg). The patients were randomly assigned to two groups: a combination-therapy group (mitiglinide group), mitiglinide initial dose 7.5 - 15 mg titrated to 30 mg daily and constant daily dose 0.9 mg of voglibose, and a monotherapy group (control group), constant daily dose 0.9 mg of voglibose alone. The efficacy of the treatment was determined by monitoring plasma glucose, hemoglobin A1c (Hb(A1c)), and glycated albumin (GA) levels and using homeostasis model assessment of insulin resistance (HOMA-IR). Safety and tolerance were determined by monitoring clinical and laboratory parameters. RESULTS: The final dose of mitiglinide was 22.9 +/- 8.9 (mean +/- s.d.) mg (0.41 mg/kg) daily. Mitiglinide reduced fasting plasma glucose and GA levels after 4 weeks and Hb(A1c) levels after 8 weeks. Triglyceride levels and HOMA-IR values also decreased significantly after mitiglinide treatment. No significant changes in blood pressure levels or serious adverse effects such as hypoglycemia or liver impairment were observed. CONCLUSIONS: This study suggests a combination therapy of mitiglinide and voglibose may have potential for the treatment of diabetics on HD. Due to the small sample size used, further studies should be performed, particularly to assess the safety of mitiglinide treatment. | DIRECT-REGULATOR |
| Combination therapy with mitiglinide and voglibose improves glycemic control in type 2 diabetic patients on hemodialysis. OBJECTIVE: CHEMICAL, a rapid- and short-acting insulinotropic sulfonylurea receptor ligand, exhibits hypoglycemic action unlike other sulfonylureas. The efficacy of the combination of mitiglinide and alpha-glucosidase inhibitors for diabetic patients on hemodialysis (HD) has not been prospectively evaluated; therefore, we evaluated the efficacy and safety of mitiglinide in these patients. RESEARCH DESIGN AND METHODS: We performed an open-label randomized study with 36 type 2 diabetics with poor glycemic control on HD and receiving daily doses of voglibose (0.9 mg). The patients were randomly assigned to two groups: a combination-therapy group (mitiglinide group), mitiglinide initial dose 7.5 - 15 mg titrated to 30 mg daily and constant daily dose 0.9 mg of voglibose, and a monotherapy group (control group), constant daily dose 0.9 mg of voglibose alone. The efficacy of the treatment was determined by monitoring plasma glucose, hemoglobin A1c (Hb(A1c)), and glycated albumin (GA) levels and using homeostasis model assessment of insulin resistance (HOMA-IR). Safety and tolerance were determined by monitoring clinical and laboratory parameters. RESULTS: The final dose of mitiglinide was 22.9 +/- 8.9 (mean +/- s.d.) mg (0.41 mg/kg) daily. CHEMICAL reduced fasting plasma glucose and GENE levels after 4 weeks and Hb(A1c) levels after 8 weeks. Triglyceride levels and HOMA-IR values also decreased significantly after mitiglinide treatment. No significant changes in blood pressure levels or serious adverse effects such as hypoglycemia or liver impairment were observed. CONCLUSIONS: This study suggests a combination therapy of mitiglinide and voglibose may have potential for the treatment of diabetics on HD. Due to the small sample size used, further studies should be performed, particularly to assess the safety of mitiglinide treatment. | INDIRECT-DOWNREGULATOR |
| Combination therapy with mitiglinide and voglibose improves glycemic control in type 2 diabetic patients on hemodialysis. OBJECTIVE: CHEMICAL, a rapid- and short-acting insulinotropic sulfonylurea receptor ligand, exhibits hypoglycemic action unlike other sulfonylureas. The efficacy of the combination of mitiglinide and alpha-glucosidase inhibitors for diabetic patients on hemodialysis (HD) has not been prospectively evaluated; therefore, we evaluated the efficacy and safety of mitiglinide in these patients. RESEARCH DESIGN AND METHODS: We performed an open-label randomized study with 36 type 2 diabetics with poor glycemic control on HD and receiving daily doses of voglibose (0.9 mg). The patients were randomly assigned to two groups: a combination-therapy group (mitiglinide group), mitiglinide initial dose 7.5 - 15 mg titrated to 30 mg daily and constant daily dose 0.9 mg of voglibose, and a monotherapy group (control group), constant daily dose 0.9 mg of voglibose alone. The efficacy of the treatment was determined by monitoring plasma glucose, hemoglobin A1c (Hb(A1c)), and glycated albumin (GA) levels and using homeostasis model assessment of insulin resistance (HOMA-IR). Safety and tolerance were determined by monitoring clinical and laboratory parameters. RESULTS: The final dose of mitiglinide was 22.9 +/- 8.9 (mean +/- s.d.) mg (0.41 mg/kg) daily. CHEMICAL reduced fasting plasma glucose and GA levels after 4 weeks and GENE levels after 8 weeks. Triglyceride levels and HOMA-IR values also decreased significantly after mitiglinide treatment. No significant changes in blood pressure levels or serious adverse effects such as hypoglycemia or liver impairment were observed. CONCLUSIONS: This study suggests a combination therapy of mitiglinide and voglibose may have potential for the treatment of diabetics on HD. Due to the small sample size used, further studies should be performed, particularly to assess the safety of mitiglinide treatment. | INDIRECT-DOWNREGULATOR |
| A fluorescence resonance energy transfer-based M2 muscarinic receptor sensor reveals rapid kinetics of allosteric modulation. Allosteric modulators have been identified for several G protein-coupled receptors, most notably muscarinic receptors. To study their mechanism of action, we made use of a recently developed technique to generate fluorescence resonance energy transfer (FRET)-based sensors to monitor G protein-coupled receptor activation. Cyan fluorescent protein was fused to the CHEMICAL terminus of the GENE, and a specific binding sequence for the small fluorescent compound fluorescein arsenical hairpin binder, FlAsH, was inserted into the third intracellular loop; the latter site was labeled in intact cells by incubation with FlAsH. We then measured FRET between the donor cyan fluorescent protein and the acceptor FlAsH in intact cells and monitored its changes in real time. Agonists such as acetylcholine and carbachol induced rapid changes in FRET, indicative of agonist-induced conformational changes. Removal of the agonists or addition of an antagonist caused a reversal of this signal with rate constants between 400 and 1100 ms. The allosteric ligands gallamine and dimethyl-W84 caused no changes in FRET when given alone, but increased FRET when given in the presence of an agonist, compatible with an inactivation of the receptors. The kinetics of these effects were very rapid, with rate constants of 80-100 ms and approximately 200 ms for saturating concentrations of gallamine and dimethyl-W84, respectively. Because these speeds are significantly faster than the responses to antagonists, these data indicate that gallamine and dimethyl-W84 are allosteric ligands and actively induce a conformation of the M(2) receptor with a reduced affinity for its agonists. | PART-OF |
| A fluorescence resonance energy transfer-based M2 muscarinic receptor sensor reveals rapid kinetics of allosteric modulation. Allosteric modulators have been identified for several G protein-coupled receptors, most notably muscarinic receptors. To study their mechanism of action, we made use of a recently developed technique to generate fluorescence resonance energy transfer (FRET)-based sensors to monitor G protein-coupled receptor activation. Cyan fluorescent protein was fused to the C terminus of the GENE, and a specific binding sequence for the small fluorescent compound CHEMICAL arsenical hairpin binder, FlAsH, was inserted into the third intracellular loop; the latter site was labeled in intact cells by incubation with FlAsH. We then measured FRET between the donor cyan fluorescent protein and the acceptor FlAsH in intact cells and monitored its changes in real time. Agonists such as acetylcholine and carbachol induced rapid changes in FRET, indicative of agonist-induced conformational changes. Removal of the agonists or addition of an antagonist caused a reversal of this signal with rate constants between 400 and 1100 ms. The allosteric ligands gallamine and dimethyl-W84 caused no changes in FRET when given alone, but increased FRET when given in the presence of an agonist, compatible with an inactivation of the receptors. The kinetics of these effects were very rapid, with rate constants of 80-100 ms and approximately 200 ms for saturating concentrations of gallamine and dimethyl-W84, respectively. Because these speeds are significantly faster than the responses to antagonists, these data indicate that gallamine and dimethyl-W84 are allosteric ligands and actively induce a conformation of the M(2) receptor with a reduced affinity for its agonists. | DIRECT-REGULATOR |
| A fluorescence resonance energy transfer-based M2 muscarinic receptor sensor reveals rapid kinetics of allosteric modulation. Allosteric modulators have been identified for several G protein-coupled receptors, most notably muscarinic receptors. To study their mechanism of action, we made use of a recently developed technique to generate fluorescence resonance energy transfer (FRET)-based sensors to monitor G protein-coupled receptor activation. Cyan fluorescent protein was fused to the C terminus of the M(2) muscarinic receptor, and a specific binding sequence for the small fluorescent compound fluorescein arsenical hairpin binder, FlAsH, was inserted into the third intracellular loop; the latter site was labeled in intact cells by incubation with FlAsH. We then measured FRET between the donor cyan fluorescent protein and the acceptor FlAsH in intact cells and monitored its changes in real time. Agonists such as acetylcholine and carbachol induced rapid changes in FRET, indicative of agonist-induced conformational changes. Removal of the agonists or addition of an antagonist caused a reversal of this signal with rate constants between 400 and 1100 ms. The allosteric ligands CHEMICAL and dimethyl-W84 caused no changes in FRET when given alone, but increased FRET when given in the presence of an agonist, compatible with an inactivation of the receptors. The kinetics of these effects were very rapid, with rate constants of 80-100 ms and approximately 200 ms for saturating concentrations of CHEMICAL and dimethyl-W84, respectively. Because these speeds are significantly faster than the responses to antagonists, these data indicate that CHEMICAL and dimethyl-W84 are allosteric ligands and actively induce a conformation of the GENE with a reduced affinity for its agonists. | DIRECT-REGULATOR |
| A fluorescence resonance energy transfer-based M2 muscarinic receptor sensor reveals rapid kinetics of allosteric modulation. Allosteric modulators have been identified for several G protein-coupled receptors, most notably muscarinic receptors. To study their mechanism of action, we made use of a recently developed technique to generate fluorescence resonance energy transfer (FRET)-based sensors to monitor G protein-coupled receptor activation. Cyan fluorescent protein was fused to the C terminus of the M(2) muscarinic receptor, and a specific binding sequence for the small fluorescent compound fluorescein arsenical hairpin binder, FlAsH, was inserted into the third intracellular loop; the latter site was labeled in intact cells by incubation with FlAsH. We then measured FRET between the donor cyan fluorescent protein and the acceptor FlAsH in intact cells and monitored its changes in real time. Agonists such as acetylcholine and carbachol induced rapid changes in FRET, indicative of agonist-induced conformational changes. Removal of the agonists or addition of an antagonist caused a reversal of this signal with rate constants between 400 and 1100 ms. The allosteric ligands gallamine and CHEMICAL caused no changes in FRET when given alone, but increased FRET when given in the presence of an agonist, compatible with an inactivation of the receptors. The kinetics of these effects were very rapid, with rate constants of 80-100 ms and approximately 200 ms for saturating concentrations of gallamine and CHEMICAL, respectively. Because these speeds are significantly faster than the responses to antagonists, these data indicate that gallamine and CHEMICAL are allosteric ligands and actively induce a conformation of the GENE with a reduced affinity for its agonists. | DIRECT-REGULATOR |
| A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons. CHEMICAL is a nonsteroidal anti-inflammatory drug widely used to relieve pain and inflammation in many disorders via inhibition of cyclooxygenases. Recently, we have demonstrated that CHEMICAL inhibits intracellular signaling of RhoA and promotes significant axonal growth and functional recovery following spinal cord lesions in rodents. In addition, another study suggests that CHEMICAL reduces generation of amyloid-beta42 peptide via inactivation of RhoA signaling, although it may also regulate amyloid-beta42 formation by direct inhibition of the gamma-secretase complex. The molecular mechanisms by which CHEMICAL inhibits the RhoA signal in neurons, however, remain unclear. Here, we report that the transcription factor GENE (PPARgamma) is essential for coupling CHEMICAL to RhoA inhibition and subsequent neurite growth promotion in neurons. CHEMICAL activates PPARgamma in neuron-like PC12 and B104 cells. Activation of PPARgamma with traditional agonists mimics the RhoA-inhibiting properties of CHEMICAL in PC12 cells and, like CHEMICAL, promotes neurite elongation in primary cultured neurons exposed to axonal growth inhibitors. Protein knockdown with small interfering RNA specific for PPARgamma blocks RhoA suppression of PPARgamma agonists in PC12 cells. Moreover, the effect of CHEMICAL on RhoA activity and neurite growth in neuronal cultures is prevented by selective PPARgamma inhibition. These findings support that PPARgamma plays an essential role in mediating the RhoA-inhibiting effect of CHEMICAL. Elucidation of the novel molecular mechanisms linking CHEMICAL to RhoA inhibition may provide additional therapeutic targets to the disorders characterized by RhoA activation, including spinal cord injuries and Alzheimer's disease. | REGULATOR |
| A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons. CHEMICAL is a nonsteroidal anti-inflammatory drug widely used to relieve pain and inflammation in many disorders via inhibition of cyclooxygenases. Recently, we have demonstrated that CHEMICAL inhibits intracellular signaling of RhoA and promotes significant axonal growth and functional recovery following spinal cord lesions in rodents. In addition, another study suggests that CHEMICAL reduces generation of amyloid-beta42 peptide via inactivation of RhoA signaling, although it may also regulate amyloid-beta42 formation by direct inhibition of the gamma-secretase complex. The molecular mechanisms by which CHEMICAL inhibits the RhoA signal in neurons, however, remain unclear. Here, we report that the transcription factor peroxisome proliferator-activated receptor gamma (GENE) is essential for coupling CHEMICAL to RhoA inhibition and subsequent neurite growth promotion in neurons. CHEMICAL activates GENE in neuron-like PC12 and B104 cells. Activation of GENE with traditional agonists mimics the RhoA-inhibiting properties of CHEMICAL in PC12 cells and, like CHEMICAL, promotes neurite elongation in primary cultured neurons exposed to axonal growth inhibitors. Protein knockdown with small interfering RNA specific for GENE blocks RhoA suppression of GENE agonists in PC12 cells. Moreover, the effect of CHEMICAL on RhoA activity and neurite growth in neuronal cultures is prevented by selective GENE inhibition. These findings support that GENE plays an essential role in mediating the RhoA-inhibiting effect of CHEMICAL. Elucidation of the novel molecular mechanisms linking CHEMICAL to RhoA inhibition may provide additional therapeutic targets to the disorders characterized by RhoA activation, including spinal cord injuries and Alzheimer's disease. | REGULATOR |
| A molecular mechanism for ibuprofen-mediated GENE inhibition in neurons. CHEMICAL is a nonsteroidal anti-inflammatory drug widely used to relieve pain and inflammation in many disorders via inhibition of cyclooxygenases. Recently, we have demonstrated that CHEMICAL inhibits intracellular signaling of GENE and promotes significant axonal growth and functional recovery following spinal cord lesions in rodents. In addition, another study suggests that CHEMICAL reduces generation of amyloid-beta42 peptide via inactivation of GENE signaling, although it may also regulate amyloid-beta42 formation by direct inhibition of the gamma-secretase complex. The molecular mechanisms by which CHEMICAL inhibits the GENE signal in neurons, however, remain unclear. Here, we report that the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for coupling CHEMICAL to GENE inhibition and subsequent neurite growth promotion in neurons. CHEMICAL activates PPARgamma in neuron-like PC12 and B104 cells. Activation of PPARgamma with traditional agonists mimics the RhoA-inhibiting properties of CHEMICAL in PC12 cells and, like CHEMICAL, promotes neurite elongation in primary cultured neurons exposed to axonal growth inhibitors. Protein knockdown with small interfering RNA specific for PPARgamma blocks GENE suppression of PPARgamma agonists in PC12 cells. Moreover, the effect of CHEMICAL on GENE activity and neurite growth in neuronal cultures is prevented by selective PPARgamma inhibition. These findings support that PPARgamma plays an essential role in mediating the RhoA-inhibiting effect of CHEMICAL. Elucidation of the novel molecular mechanisms linking CHEMICAL to GENE inhibition may provide additional therapeutic targets to the disorders characterized by GENE activation, including spinal cord injuries and Alzheimer's disease. | REGULATOR |
| A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons. CHEMICAL is a nonsteroidal anti-inflammatory drug widely used to relieve pain and inflammation in many disorders via inhibition of cyclooxygenases. Recently, we have demonstrated that ibuprofen inhibits intracellular signaling of RhoA and promotes significant axonal growth and functional recovery following spinal cord lesions in rodents. In addition, another study suggests that ibuprofen reduces generation of amyloid-beta42 peptide via inactivation of RhoA signaling, although it may also regulate amyloid-beta42 formation by direct inhibition of the gamma-secretase complex. The molecular mechanisms by which ibuprofen inhibits the RhoA signal in neurons, however, remain unclear. Here, we report that the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for coupling ibuprofen to RhoA inhibition and subsequent neurite growth promotion in neurons. CHEMICAL activates GENE in neuron-like PC12 and B104 cells. Activation of GENE with traditional agonists mimics the RhoA-inhibiting properties of ibuprofen in PC12 cells and, like ibuprofen, promotes neurite elongation in primary cultured neurons exposed to axonal growth inhibitors. Protein knockdown with small interfering RNA specific for GENE blocks RhoA suppression of GENE agonists in PC12 cells. Moreover, the effect of ibuprofen on RhoA activity and neurite growth in neuronal cultures is prevented by selective GENE inhibition. These findings support that GENE plays an essential role in mediating the RhoA-inhibiting effect of ibuprofen. Elucidation of the novel molecular mechanisms linking ibuprofen to RhoA inhibition may provide additional therapeutic targets to the disorders characterized by RhoA activation, including spinal cord injuries and Alzheimer's disease. | ACTIVATOR |
| A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons. CHEMICAL is a nonsteroidal anti-inflammatory drug widely used to relieve pain and inflammation in many disorders via inhibition of cyclooxygenases. Recently, we have demonstrated that CHEMICAL inhibits intracellular signaling of RhoA and promotes significant axonal growth and functional recovery following spinal cord lesions in rodents. In addition, another study suggests that CHEMICAL reduces generation of GENE peptide via inactivation of RhoA signaling, although it may also regulate GENE formation by direct inhibition of the gamma-secretase complex. The molecular mechanisms by which CHEMICAL inhibits the RhoA signal in neurons, however, remain unclear. Here, we report that the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for coupling CHEMICAL to RhoA inhibition and subsequent neurite growth promotion in neurons. CHEMICAL activates PPARgamma in neuron-like PC12 and B104 cells. Activation of PPARgamma with traditional agonists mimics the RhoA-inhibiting properties of CHEMICAL in PC12 cells and, like CHEMICAL, promotes neurite elongation in primary cultured neurons exposed to axonal growth inhibitors. Protein knockdown with small interfering RNA specific for PPARgamma blocks RhoA suppression of PPARgamma agonists in PC12 cells. Moreover, the effect of CHEMICAL on RhoA activity and neurite growth in neuronal cultures is prevented by selective PPARgamma inhibition. These findings support that PPARgamma plays an essential role in mediating the RhoA-inhibiting effect of CHEMICAL. Elucidation of the novel molecular mechanisms linking CHEMICAL to RhoA inhibition may provide additional therapeutic targets to the disorders characterized by RhoA activation, including spinal cord injuries and Alzheimer's disease. | GENE-CHEMICAL |
| A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons. CHEMICAL is a nonsteroidal anti-inflammatory drug widely used to relieve pain and inflammation in many disorders via inhibition of GENE. Recently, we have demonstrated that ibuprofen inhibits intracellular signaling of RhoA and promotes significant axonal growth and functional recovery following spinal cord lesions in rodents. In addition, another study suggests that ibuprofen reduces generation of amyloid-beta42 peptide via inactivation of RhoA signaling, although it may also regulate amyloid-beta42 formation by direct inhibition of the gamma-secretase complex. The molecular mechanisms by which ibuprofen inhibits the RhoA signal in neurons, however, remain unclear. Here, we report that the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for coupling ibuprofen to RhoA inhibition and subsequent neurite growth promotion in neurons. CHEMICAL activates PPARgamma in neuron-like PC12 and B104 cells. Activation of PPARgamma with traditional agonists mimics the RhoA-inhibiting properties of ibuprofen in PC12 cells and, like ibuprofen, promotes neurite elongation in primary cultured neurons exposed to axonal growth inhibitors. Protein knockdown with small interfering RNA specific for PPARgamma blocks RhoA suppression of PPARgamma agonists in PC12 cells. Moreover, the effect of ibuprofen on RhoA activity and neurite growth in neuronal cultures is prevented by selective PPARgamma inhibition. These findings support that PPARgamma plays an essential role in mediating the RhoA-inhibiting effect of ibuprofen. Elucidation of the novel molecular mechanisms linking ibuprofen to RhoA inhibition may provide additional therapeutic targets to the disorders characterized by RhoA activation, including spinal cord injuries and Alzheimer's disease. | INHIBITOR |
| A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons. CHEMICAL is a nonsteroidal anti-inflammatory drug widely used to relieve pain and inflammation in many disorders via inhibition of cyclooxygenases. Recently, we have demonstrated that CHEMICAL inhibits intracellular signaling of RhoA and promotes significant axonal growth and functional recovery following spinal cord lesions in rodents. In addition, another study suggests that CHEMICAL reduces generation of amyloid-beta42 peptide via inactivation of RhoA signaling, although it may also regulate amyloid-beta42 formation by direct inhibition of the GENE. The molecular mechanisms by which CHEMICAL inhibits the RhoA signal in neurons, however, remain unclear. Here, we report that the transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for coupling CHEMICAL to RhoA inhibition and subsequent neurite growth promotion in neurons. CHEMICAL activates PPARgamma in neuron-like PC12 and B104 cells. Activation of PPARgamma with traditional agonists mimics the RhoA-inhibiting properties of CHEMICAL in PC12 cells and, like CHEMICAL, promotes neurite elongation in primary cultured neurons exposed to axonal growth inhibitors. Protein knockdown with small interfering RNA specific for PPARgamma blocks RhoA suppression of PPARgamma agonists in PC12 cells. Moreover, the effect of CHEMICAL on RhoA activity and neurite growth in neuronal cultures is prevented by selective PPARgamma inhibition. These findings support that PPARgamma plays an essential role in mediating the RhoA-inhibiting effect of CHEMICAL. Elucidation of the novel molecular mechanisms linking CHEMICAL to RhoA inhibition may provide additional therapeutic targets to the disorders characterized by RhoA activation, including spinal cord injuries and Alzheimer's disease. | INHIBITOR |
| Comparative efficacy and safety of the novel oral anticoagulants CHEMICAL, rivaroxaban and apixaban in preclinical and clinical development. Therapeutic oral anticoagulation is still commonly achieved by administration of warfarin or other vitamin K antagonists that are associated with an untoward pharmacokinetic / pharmacodynamic (PK/PD) profile leading to a high incidence of bleeding complications or therapeutic failure. Hence, there is an unmet medical need of novel easy-to-use oral anticoagulants with improved efficacy and safety. Recent developments include the identification of non-peptidic small-molecules that selectively inhibit certain serine proteases within the coagulation cascade. Of these, the GENE inhibitor CHEMICAL and factor Xa inhibitor rivaroxaban have recently been licensed for thromboprophylaxis after orthopaedic surgery mainly in Europe. In addition, the factor Xa inhibitor apixaban is in late-stage clinical development. Each drug is prescribed at fixed doses without the need of anticoagulant monitoring. Phase III trials in orthopaedic patients essentially resulted in non-inferior efficacy of CHEMICAL and superior efficacy of rivaroxaban over enoxaparin without any marked differences of drug safety, while apixaban data is still controversial. However, alterations of rivaroxaban and apixaban pharmacokinetics upon interactions with inhibitors and inducers of CYP3A4 or P-glycoprotein may complicate the use of these compounds in daily practice, whereas CHEMICAL elimination largely depends on renal function. Hence, this review reports PK/PD, efficacy and safety data of CHEMICAL, rivaroxaban and apixaban throughout preclinical and clinical development. | INHIBITOR |
| Comparative efficacy and safety of the novel oral anticoagulants dabigatran, CHEMICAL and apixaban in preclinical and clinical development. Therapeutic oral anticoagulation is still commonly achieved by administration of warfarin or other vitamin K antagonists that are associated with an untoward pharmacokinetic / pharmacodynamic (PK/PD) profile leading to a high incidence of bleeding complications or therapeutic failure. Hence, there is an unmet medical need of novel easy-to-use oral anticoagulants with improved efficacy and safety. Recent developments include the identification of non-peptidic small-molecules that selectively inhibit certain serine proteases within the coagulation cascade. Of these, the thrombin inhibitor dabigatran and GENE inhibitor CHEMICAL have recently been licensed for thromboprophylaxis after orthopaedic surgery mainly in Europe. In addition, the GENE inhibitor apixaban is in late-stage clinical development. Each drug is prescribed at fixed doses without the need of anticoagulant monitoring. Phase III trials in orthopaedic patients essentially resulted in non-inferior efficacy of dabigatran and superior efficacy of CHEMICAL over enoxaparin without any marked differences of drug safety, while apixaban data is still controversial. However, alterations of CHEMICAL and apixaban pharmacokinetics upon interactions with inhibitors and inducers of CYP3A4 or P-glycoprotein may complicate the use of these compounds in daily practice, whereas dabigatran elimination largely depends on renal function. Hence, this review reports PK/PD, efficacy and safety data of dabigatran, CHEMICAL and apixaban throughout preclinical and clinical development. | INHIBITOR |
| Comparative efficacy and safety of the novel oral anticoagulants dabigatran, rivaroxaban and CHEMICAL in preclinical and clinical development. Therapeutic oral anticoagulation is still commonly achieved by administration of warfarin or other vitamin K antagonists that are associated with an untoward pharmacokinetic / pharmacodynamic (PK/PD) profile leading to a high incidence of bleeding complications or therapeutic failure. Hence, there is an unmet medical need of novel easy-to-use oral anticoagulants with improved efficacy and safety. Recent developments include the identification of non-peptidic small-molecules that selectively inhibit certain serine proteases within the coagulation cascade. Of these, the thrombin inhibitor dabigatran and GENE inhibitor rivaroxaban have recently been licensed for thromboprophylaxis after orthopaedic surgery mainly in Europe. In addition, the GENE inhibitor CHEMICAL is in late-stage clinical development. Each drug is prescribed at fixed doses without the need of anticoagulant monitoring. Phase III trials in orthopaedic patients essentially resulted in non-inferior efficacy of dabigatran and superior efficacy of rivaroxaban over enoxaparin without any marked differences of drug safety, while CHEMICAL data is still controversial. However, alterations of rivaroxaban and CHEMICAL pharmacokinetics upon interactions with inhibitors and inducers of CYP3A4 or P-glycoprotein may complicate the use of these compounds in daily practice, whereas dabigatran elimination largely depends on renal function. Hence, this review reports PK/PD, efficacy and safety data of dabigatran, rivaroxaban and CHEMICAL throughout preclinical and clinical development. | INHIBITOR |
| CHEMICAL directly inhibits matrix metalloproteinase-2 activity in continuous ambulatory peritoneal dialysis therapy. BACKGROUND: Matrix metalloproteinase (MMP)-2 plays an important role in tissue remodeling related to inflammation during continuous ambulatory peritoneal dialysis (CAPD) therapy. But its inhibitors were not applied clinically. We determined whether an angiotensin-converting enzyme (ACE) inhibitor, CHEMICAL, inhibits GENE activity in peritoneal effluents from patients on CAPD, and simulated molecular models of the GENE-CHEMICAL complex. METHODS: The inhibitory effect of CHEMICAL on GENE activity was measured in peritoneal effluents from 17 patients on CAPD. Molecular models of the MMP-2-captopril complex were simulated by 1000 iterations of random docking and energy minimization. RESULTS: CHEMICAL directly inhibited GENE activity in peritoneal effluents from patients on CAPD (IC50; 48 micromol/l), and that CHEMICAL binding to the GENE active site could be formed in each complex model without molecular distortion. CONCLUSION: ACE inhibitors, such as CHEMICAL, may be applied as important compounds for GENE inhibition in inflammation caused by CAPD. | INHIBITOR |
| CHEMICAL directly inhibits matrix metalloproteinase-2 activity in continuous ambulatory peritoneal dialysis therapy. BACKGROUND: Matrix metalloproteinase (MMP)-2 plays an important role in tissue remodeling related to inflammation during continuous ambulatory peritoneal dialysis (CAPD) therapy. But its inhibitors were not applied clinically. We determined whether an GENE (ACE) inhibitor, CHEMICAL, inhibits MMP-2 activity in peritoneal effluents from patients on CAPD, and simulated molecular models of the MMP-2-captopril complex. METHODS: The inhibitory effect of CHEMICAL on MMP-2 activity was measured in peritoneal effluents from 17 patients on CAPD. Molecular models of the MMP-2-captopril complex were simulated by 1000 iterations of random docking and energy minimization. RESULTS: CHEMICAL directly inhibited MMP-2 activity in peritoneal effluents from patients on CAPD (IC50; 48 micromol/l), and that CHEMICAL binding to the MMP-2 active site could be formed in each complex model without molecular distortion. CONCLUSION: ACE inhibitors, such as CHEMICAL, may be applied as important compounds for MMP-2 inhibition in inflammation caused by CAPD. | INHIBITOR |
| CHEMICAL directly inhibits matrix metalloproteinase-2 activity in continuous ambulatory peritoneal dialysis therapy. BACKGROUND: Matrix metalloproteinase (MMP)-2 plays an important role in tissue remodeling related to inflammation during continuous ambulatory peritoneal dialysis (CAPD) therapy. But its inhibitors were not applied clinically. We determined whether an angiotensin-converting enzyme (GENE) inhibitor, CHEMICAL, inhibits MMP-2 activity in peritoneal effluents from patients on CAPD, and simulated molecular models of the MMP-2-captopril complex. METHODS: The inhibitory effect of CHEMICAL on MMP-2 activity was measured in peritoneal effluents from 17 patients on CAPD. Molecular models of the MMP-2-captopril complex were simulated by 1000 iterations of random docking and energy minimization. RESULTS: CHEMICAL directly inhibited MMP-2 activity in peritoneal effluents from patients on CAPD (IC50; 48 micromol/l), and that CHEMICAL binding to the MMP-2 active site could be formed in each complex model without molecular distortion. CONCLUSION: GENE inhibitors, such as CHEMICAL, may be applied as important compounds for MMP-2 inhibition in inflammation caused by CAPD. | INHIBITOR |
| CHEMICAL directly inhibits matrix metalloproteinase-2 activity in continuous ambulatory peritoneal dialysis therapy. BACKGROUND: Matrix metalloproteinase (MMP)-2 plays an important role in tissue remodeling related to inflammation during continuous ambulatory peritoneal dialysis (CAPD) therapy. But its inhibitors were not applied clinically. We determined whether an angiotensin-converting enzyme (ACE) inhibitor, captopril, inhibits GENE activity in peritoneal effluents from patients on CAPD, and simulated molecular models of the MMP-2-captopril complex. METHODS: The inhibitory effect of captopril on GENE activity was measured in peritoneal effluents from 17 patients on CAPD. Molecular models of the MMP-2-captopril complex were simulated by 1000 iterations of random docking and energy minimization. RESULTS: CHEMICAL directly inhibited GENE activity in peritoneal effluents from patients on CAPD (IC50; 48 micromol/l), and that captopril binding to the GENE active site could be formed in each complex model without molecular distortion. CONCLUSION: ACE inhibitors, such as captopril, may be applied as important compounds for GENE inhibition in inflammation caused by CAPD. | INHIBITOR |
| CHEMICAL directly inhibits GENE activity in continuous ambulatory peritoneal dialysis therapy. BACKGROUND: Matrix metalloproteinase (MMP)-2 plays an important role in tissue remodeling related to inflammation during continuous ambulatory peritoneal dialysis (CAPD) therapy. But its inhibitors were not applied clinically. We determined whether an angiotensin-converting enzyme (ACE) inhibitor, captopril, inhibits MMP-2 activity in peritoneal effluents from patients on CAPD, and simulated molecular models of the MMP-2-captopril complex. METHODS: The inhibitory effect of captopril on MMP-2 activity was measured in peritoneal effluents from 17 patients on CAPD. Molecular models of the MMP-2-captopril complex were simulated by 1000 iterations of random docking and energy minimization. RESULTS: CHEMICAL directly inhibited MMP-2 activity in peritoneal effluents from patients on CAPD (IC50; 48 micromol/l), and that captopril binding to the MMP-2 active site could be formed in each complex model without molecular distortion. CONCLUSION: ACE inhibitors, such as captopril, may be applied as important compounds for MMP-2 inhibition in inflammation caused by CAPD. | INHIBITOR |
| Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel. The biguanides, phenformin and CHEMICAL, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of GENE and the current natively expressed in vascular smooth muscle cells (VSMCs). Phenformin but not CHEMICAL inhibits a number of variants of GENE including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC50=0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known GENE blocker PNU 37883A. Additionally, phenformin inhibited the current elicited through the Kir6.2DeltaC26 (functional without SUR) channel with an IC50 of 1.78 mM. Phenformin reduced the open probability of Kir6.1/SUR2B channels by approximately 90% in inside-out patches. These findings suggest that phenformin interacts directly with the pore-forming Kir6.0 subunit however the sulphonylurea receptor is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A. | NO-RELATIONSHIP |
| Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel. The biguanides, phenformin and CHEMICAL, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of K(ATP) and the current natively expressed in vascular smooth muscle cells (VSMCs). Phenformin but not CHEMICAL inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (GENE/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC50=0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known K(ATP) blocker PNU 37883A. Additionally, phenformin inhibited the current elicited through the Kir6.2DeltaC26 (functional without SUR) channel with an IC50 of 1.78 mM. Phenformin reduced the open probability of Kir6.1/SUR2B channels by approximately 90% in inside-out patches. These findings suggest that phenformin interacts directly with the pore-forming Kir6.0 subunit however the sulphonylurea receptor is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A. | NO-RELATIONSHIP |
| Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel. The biguanides, phenformin and CHEMICAL, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of K(ATP) and the current natively expressed in vascular smooth muscle cells (VSMCs). Phenformin but not CHEMICAL inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/GENE and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC50=0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known K(ATP) blocker PNU 37883A. Additionally, phenformin inhibited the current elicited through the Kir6.2DeltaC26 (functional without SUR) channel with an IC50 of 1.78 mM. Phenformin reduced the open probability of Kir6.1/SUR2B channels by approximately 90% in inside-out patches. These findings suggest that phenformin interacts directly with the pore-forming Kir6.0 subunit however the sulphonylurea receptor is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A. | NO-RELATIONSHIP |
| Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel. The biguanides, phenformin and CHEMICAL, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of K(ATP) and the current natively expressed in vascular smooth muscle cells (VSMCs). Phenformin but not CHEMICAL inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and GENE/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC50=0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known K(ATP) blocker PNU 37883A. Additionally, phenformin inhibited the current elicited through the Kir6.2DeltaC26 (functional without SUR) channel with an IC50 of 1.78 mM. Phenformin reduced the open probability of Kir6.1/SUR2B channels by approximately 90% in inside-out patches. These findings suggest that phenformin interacts directly with the pore-forming Kir6.0 subunit however the sulphonylurea receptor is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A. | NO-RELATIONSHIP |
| Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel. The biguanides, phenformin and CHEMICAL, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of K(ATP) and the current natively expressed in vascular smooth muscle cells (VSMCs). Phenformin but not CHEMICAL inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/GENE). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC50=0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known K(ATP) blocker PNU 37883A. Additionally, phenformin inhibited the current elicited through the Kir6.2DeltaC26 (functional without SUR) channel with an IC50 of 1.78 mM. Phenformin reduced the open probability of Kir6.1/SUR2B channels by approximately 90% in inside-out patches. These findings suggest that phenformin interacts directly with the pore-forming Kir6.0 subunit however the sulphonylurea receptor is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A. | NO-RELATIONSHIP |
| CHEMICAL has a direct inhibitory effect on the ATP-sensitive potassium channel. The biguanides, CHEMICAL and metformin, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of K(ATP) and the current natively expressed in vascular smooth muscle cells (VSMCs). CHEMICAL but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC50=0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known K(ATP) blocker PNU 37883A. Additionally, CHEMICAL inhibited the current elicited through the Kir6.2DeltaC26 (functional without SUR) channel with an IC50 of 1.78 mM. CHEMICAL reduced the open probability of Kir6.1/SUR2B channels by approximately 90% in inside-out patches. These findings suggest that CHEMICAL interacts directly with the pore-forming GENE subunit however the sulphonylurea receptor is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A. | DIRECT-REGULATOR |
| CHEMICAL has a direct inhibitory effect on the ATP-sensitive potassium channel. The biguanides, CHEMICAL and metformin, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of K(ATP) and the current natively expressed in vascular smooth muscle cells (VSMCs). CHEMICAL but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC50=0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known K(ATP) blocker PNU 37883A. Additionally, CHEMICAL inhibited the current elicited through the Kir6.2DeltaC26 (functional without GENE) channel with an IC50 of 1.78 mM. CHEMICAL reduced the open probability of Kir6.1/SUR2B channels by approximately 90% in inside-out patches. These findings suggest that CHEMICAL interacts directly with the pore-forming Kir6.0 subunit however the sulphonylurea receptor is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A. | NO-RELATIONSHIP |
| CHEMICAL has a direct inhibitory effect on the ATP-sensitive potassium channel. The biguanides, CHEMICAL and metformin, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of K(ATP) and the current natively expressed in vascular smooth muscle cells (VSMCs). CHEMICAL but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC50=0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known K(ATP) blocker PNU 37883A. Additionally, CHEMICAL inhibited the current elicited through the Kir6.2DeltaC26 (functional without SUR) channel with an IC50 of 1.78 mM. CHEMICAL reduced the open probability of Kir6.1/SUR2B channels by approximately 90% in inside-out patches. These findings suggest that CHEMICAL interacts directly with the pore-forming Kir6.0 subunit however the GENE is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A. | DIRECT-REGULATOR |
| CHEMICAL has a direct inhibitory effect on the ATP-sensitive potassium channel. The biguanides, phenformin and metformin, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of K(ATP) and the current natively expressed in vascular smooth muscle cells (VSMCs). CHEMICAL but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC50=0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known K(ATP) blocker PNU 37883A. Additionally, phenformin inhibited the current elicited through the Kir6.2DeltaC26 (functional without SUR) channel with an IC50 of 1.78 mM. CHEMICAL reduced the open probability of GENE/SUR2B channels by approximately 90% in inside-out patches. These findings suggest that phenformin interacts directly with the pore-forming Kir6.0 subunit however the sulphonylurea receptor is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A. | INHIBITOR |
| CHEMICAL has a direct inhibitory effect on the ATP-sensitive potassium channel. The biguanides, phenformin and metformin, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of K(ATP) and the current natively expressed in vascular smooth muscle cells (VSMCs). CHEMICAL but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC50=0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known K(ATP) blocker PNU 37883A. Additionally, phenformin inhibited the current elicited through the Kir6.2DeltaC26 (functional without SUR) channel with an IC50 of 1.78 mM. CHEMICAL reduced the open probability of Kir6.1/GENE channels by approximately 90% in inside-out patches. These findings suggest that phenformin interacts directly with the pore-forming Kir6.0 subunit however the sulphonylurea receptor is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A. | INHIBITOR |
| CHEMICAL has a direct inhibitory effect on the ATP-sensitive potassium channel. The biguanides, phenformin and metformin, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of GENE and the current natively expressed in vascular smooth muscle cells (VSMCs). CHEMICAL but not metformin inhibits a number of variants of GENE including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC50=0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known GENE blocker PNU 37883A. Additionally, phenformin inhibited the current elicited through the Kir6.2DeltaC26 (functional without SUR) channel with an IC50 of 1.78 mM. CHEMICAL reduced the open probability of Kir6.1/SUR2B channels by approximately 90% in inside-out patches. These findings suggest that phenformin interacts directly with the pore-forming Kir6.0 subunit however the sulphonylurea receptor is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A. | INHIBITOR |
| CHEMICAL has a direct inhibitory effect on the ATP-sensitive potassium channel. The biguanides, phenformin and metformin, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of K(ATP) and the current natively expressed in vascular smooth muscle cells (VSMCs). CHEMICAL but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and GENE/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC50=0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known K(ATP) blocker PNU 37883A. Additionally, phenformin inhibited the current elicited through the Kir6.2DeltaC26 (functional without SUR) channel with an IC50 of 1.78 mM. CHEMICAL reduced the open probability of Kir6.1/SUR2B channels by approximately 90% in inside-out patches. These findings suggest that phenformin interacts directly with the pore-forming Kir6.0 subunit however the sulphonylurea receptor is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A. | REGULATOR |
| CHEMICAL has a direct inhibitory effect on the ATP-sensitive potassium channel. The biguanides, phenformin and metformin, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of K(ATP) and the current natively expressed in vascular smooth muscle cells (VSMCs). CHEMICAL but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/GENE). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC50=0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known K(ATP) blocker PNU 37883A. Additionally, phenformin inhibited the current elicited through the Kir6.2DeltaC26 (functional without SUR) channel with an IC50 of 1.78 mM. CHEMICAL reduced the open probability of Kir6.1/SUR2B channels by approximately 90% in inside-out patches. These findings suggest that phenformin interacts directly with the pore-forming Kir6.0 subunit however the sulphonylurea receptor is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A. | REGULATOR |
| CHEMICAL has a direct inhibitory effect on the GENE. The biguanides, phenformin and metformin, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of K(ATP) and the current natively expressed in vascular smooth muscle cells (VSMCs). CHEMICAL but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC50=0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known K(ATP) blocker PNU 37883A. Additionally, phenformin inhibited the current elicited through the Kir6.2DeltaC26 (functional without SUR) channel with an IC50 of 1.78 mM. CHEMICAL reduced the open probability of Kir6.1/SUR2B channels by approximately 90% in inside-out patches. These findings suggest that phenformin interacts directly with the pore-forming Kir6.0 subunit however the sulphonylurea receptor is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A. | INHIBITOR |
| Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel. The biguanides, phenformin and metformin, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of GENE and the current natively expressed in vascular smooth muscle cells (VSMCs). Phenformin but not metformin inhibits a number of variants of GENE including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC50=0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known GENE blocker CHEMICAL. Additionally, phenformin inhibited the current elicited through the Kir6.2DeltaC26 (functional without SUR) channel with an IC50 of 1.78 mM. Phenformin reduced the open probability of Kir6.1/SUR2B channels by approximately 90% in inside-out patches. These findings suggest that phenformin interacts directly with the pore-forming Kir6.0 subunit however the sulphonylurea receptor is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of CHEMICAL. | INHIBITOR |
| CHEMICAL has a direct inhibitory effect on the ATP-sensitive potassium channel. The biguanides, CHEMICAL and metformin, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K+ channel (K(ATP)) regulation in cell lines expressing the cloned components of K(ATP) and the current natively expressed in vascular smooth muscle cells (VSMCs). CHEMICAL but not metformin inhibits a number of variants of K(ATP) including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic beta-cells (Kir6.2/SUR1). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC50=0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known K(ATP) blocker PNU 37883A. Additionally, CHEMICAL inhibited the current elicited through the GENE (functional without SUR) channel with an IC50 of 1.78 mM. CHEMICAL reduced the open probability of Kir6.1/SUR2B channels by approximately 90% in inside-out patches. These findings suggest that CHEMICAL interacts directly with the pore-forming Kir6.0 subunit however the sulphonylurea receptor is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A. | INHIBITOR |
| Comparison of the pharmacological effects of CHEMICAL and doxercalciferol on the factors involved in mineral homeostasis. Vitamin D receptor agonists (VDRAs) directly suppress parathyroid hormone (PTH) mRNA expression. Different VDRAs are known to have differential effects on serum calcium (Ca), which may also affect serum PTH levels since serum Ca regulates PTH secretion mediated by the Ca-sensing receptor (CaSR). In this study, we compared the effects of CHEMICAL and doxercalciferol on regulating serum Ca and PTH, and also the expression of PTH, GENE, and CaSR mRNA. The 5/6 nephrectomized (NX) Sprague-Dawley rats on a normal or hyperphosphatemia-inducing diet were treated with vehicle, CHEMICAL, or doxercalciferol for two weeks. Both drugs at the tested doses (0.042-0.33 mug/kg) suppressed PTH mRNA expression and serum PTH effectively in the 5/6 NX rats, but CHEMICAL was less potent in raising serum Ca than doxercalciferol. In pig parathyroid cells, CHEMICAL and the active form of doxercalciferol induced GENE translocation from the cytoplasm into the nucleus, suppressed PTH mRNA expression and inhibited cell proliferation in a similar manner, although CHEMICAL induced the expression of CaSR mRNA more effectively. The multiple effects of VDRAs on modulating serum Ca, parathyroid cell proliferation, and the expression of CaSR and PTH mRNA reflect the complex involvement of the vitamin D axis in regulating the mineral homeostasis system. | GENE-CHEMICAL |
| Comparison of the pharmacological effects of paricalcitol and CHEMICAL on the factors involved in mineral homeostasis. Vitamin D receptor agonists (VDRAs) directly suppress parathyroid hormone (PTH) mRNA expression. Different VDRAs are known to have differential effects on serum calcium (Ca), which may also affect serum PTH levels since serum Ca regulates PTH secretion mediated by the Ca-sensing receptor (CaSR). In this study, we compared the effects of paricalcitol and CHEMICAL on regulating serum Ca and PTH, and also the expression of PTH, GENE, and CaSR mRNA. The 5/6 nephrectomized (NX) Sprague-Dawley rats on a normal or hyperphosphatemia-inducing diet were treated with vehicle, paricalcitol, or CHEMICAL for two weeks. Both drugs at the tested doses (0.042-0.33 mug/kg) suppressed PTH mRNA expression and serum PTH effectively in the 5/6 NX rats, but paricalcitol was less potent in raising serum Ca than CHEMICAL. In pig parathyroid cells, paricalcitol and the active form of CHEMICAL induced GENE translocation from the cytoplasm into the nucleus, suppressed PTH mRNA expression and inhibited cell proliferation in a similar manner, although paricalcitol induced the expression of CaSR mRNA more effectively. The multiple effects of VDRAs on modulating serum Ca, parathyroid cell proliferation, and the expression of CaSR and PTH mRNA reflect the complex involvement of the vitamin D axis in regulating the mineral homeostasis system. | GENE-CHEMICAL |
| Comparison of the pharmacological effects of paricalcitol and doxercalciferol on the factors involved in mineral homeostasis. Vitamin D receptor agonists (VDRAs) directly suppress parathyroid hormone (PTH) mRNA expression. Different VDRAs are known to have differential effects on serum calcium (Ca), which may also affect serum PTH levels since serum CHEMICAL regulates PTH secretion mediated by the GENE (CaSR). In this study, we compared the effects of paricalcitol and doxercalciferol on regulating serum CHEMICAL and PTH, and also the expression of PTH, VDR, and CaSR mRNA. The 5/6 nephrectomized (NX) Sprague-Dawley rats on a normal or hyperphosphatemia-inducing diet were treated with vehicle, paricalcitol, or doxercalciferol for two weeks. Both drugs at the tested doses (0.042-0.33 mug/kg) suppressed PTH mRNA expression and serum PTH effectively in the 5/6 NX rats, but paricalcitol was less potent in raising serum CHEMICAL than doxercalciferol. In pig parathyroid cells, paricalcitol and the active form of doxercalciferol induced VDR translocation from the cytoplasm into the nucleus, suppressed PTH mRNA expression and inhibited cell proliferation in a similar manner, although paricalcitol induced the expression of CaSR mRNA more effectively. The multiple effects of VDRAs on modulating serum CHEMICAL, parathyroid cell proliferation, and the expression of CaSR and PTH mRNA reflect the complex involvement of the vitamin D axis in regulating the mineral homeostasis system. | REGULATOR |
| Comparison of the pharmacological effects of paricalcitol and doxercalciferol on the factors involved in mineral homeostasis. Vitamin D receptor agonists (VDRAs) directly suppress parathyroid hormone (PTH) mRNA expression. Different VDRAs are known to have differential effects on serum calcium (Ca), which may also affect serum PTH levels since serum CHEMICAL regulates PTH secretion mediated by the Ca-sensing receptor (GENE). In this study, we compared the effects of paricalcitol and doxercalciferol on regulating serum CHEMICAL and PTH, and also the expression of PTH, VDR, and GENE mRNA. The 5/6 nephrectomized (NX) Sprague-Dawley rats on a normal or hyperphosphatemia-inducing diet were treated with vehicle, paricalcitol, or doxercalciferol for two weeks. Both drugs at the tested doses (0.042-0.33 mug/kg) suppressed PTH mRNA expression and serum PTH effectively in the 5/6 NX rats, but paricalcitol was less potent in raising serum CHEMICAL than doxercalciferol. In pig parathyroid cells, paricalcitol and the active form of doxercalciferol induced VDR translocation from the cytoplasm into the nucleus, suppressed PTH mRNA expression and inhibited cell proliferation in a similar manner, although paricalcitol induced the expression of GENE mRNA more effectively. The multiple effects of VDRAs on modulating serum CHEMICAL, parathyroid cell proliferation, and the expression of GENE and PTH mRNA reflect the complex involvement of the vitamin D axis in regulating the mineral homeostasis system. | REGULATOR |
| Comparison of the pharmacological effects of CHEMICAL and doxercalciferol on the factors involved in mineral homeostasis. Vitamin D receptor agonists (VDRAs) directly suppress parathyroid hormone (PTH) mRNA expression. Different VDRAs are known to have differential effects on serum calcium (Ca), which may also affect serum PTH levels since serum Ca regulates PTH secretion mediated by the Ca-sensing receptor (CaSR). In this study, we compared the effects of CHEMICAL and doxercalciferol on regulating serum Ca and PTH, and also the expression of PTH, VDR, and GENE mRNA. The 5/6 nephrectomized (NX) Sprague-Dawley rats on a normal or hyperphosphatemia-inducing diet were treated with vehicle, CHEMICAL, or doxercalciferol for two weeks. Both drugs at the tested doses (0.042-0.33 mug/kg) suppressed PTH mRNA expression and serum PTH effectively in the 5/6 NX rats, but CHEMICAL was less potent in raising serum Ca than doxercalciferol. In pig parathyroid cells, CHEMICAL and the active form of doxercalciferol induced VDR translocation from the cytoplasm into the nucleus, suppressed PTH mRNA expression and inhibited cell proliferation in a similar manner, although CHEMICAL induced the expression of GENE mRNA more effectively. The multiple effects of VDRAs on modulating serum Ca, parathyroid cell proliferation, and the expression of GENE and PTH mRNA reflect the complex involvement of the vitamin D axis in regulating the mineral homeostasis system. | INDIRECT-UPREGULATOR |
| Comparison of the pharmacological effects of paricalcitol and doxercalciferol on the factors involved in mineral homeostasis. Vitamin D receptor agonists (VDRAs) directly suppress parathyroid hormone (PTH) mRNA expression. Different VDRAs are known to have differential effects on serum calcium (Ca), which may also affect serum GENE levels since serum CHEMICAL regulates GENE secretion mediated by the Ca-sensing receptor (CaSR). In this study, we compared the effects of paricalcitol and doxercalciferol on regulating serum CHEMICAL and GENE, and also the expression of GENE, VDR, and CaSR mRNA. The 5/6 nephrectomized (NX) Sprague-Dawley rats on a normal or hyperphosphatemia-inducing diet were treated with vehicle, paricalcitol, or doxercalciferol for two weeks. Both drugs at the tested doses (0.042-0.33 mug/kg) suppressed GENE mRNA expression and serum GENE effectively in the 5/6 NX rats, but paricalcitol was less potent in raising serum CHEMICAL than doxercalciferol. In pig parathyroid cells, paricalcitol and the active form of doxercalciferol induced VDR translocation from the cytoplasm into the nucleus, suppressed GENE mRNA expression and inhibited cell proliferation in a similar manner, although paricalcitol induced the expression of CaSR mRNA more effectively. The multiple effects of VDRAs on modulating serum CHEMICAL, parathyroid cell proliferation, and the expression of CaSR and GENE mRNA reflect the complex involvement of the vitamin D axis in regulating the mineral homeostasis system. | GENE-CHEMICAL |
| Comparison of the pharmacological effects of CHEMICAL and doxercalciferol on the factors involved in mineral homeostasis. Vitamin D receptor agonists (VDRAs) directly suppress parathyroid hormone (PTH) mRNA expression. Different VDRAs are known to have differential effects on serum calcium (Ca), which may also affect serum GENE levels since serum Ca regulates GENE secretion mediated by the Ca-sensing receptor (CaSR). In this study, we compared the effects of CHEMICAL and doxercalciferol on regulating serum Ca and GENE, and also the expression of GENE, VDR, and CaSR mRNA. The 5/6 nephrectomized (NX) Sprague-Dawley rats on a normal or hyperphosphatemia-inducing diet were treated with vehicle, CHEMICAL, or doxercalciferol for two weeks. Both drugs at the tested doses (0.042-0.33 mug/kg) suppressed GENE mRNA expression and serum GENE effectively in the 5/6 NX rats, but CHEMICAL was less potent in raising serum Ca than doxercalciferol. In pig parathyroid cells, CHEMICAL and the active form of doxercalciferol induced VDR translocation from the cytoplasm into the nucleus, suppressed GENE mRNA expression and inhibited cell proliferation in a similar manner, although CHEMICAL induced the expression of CaSR mRNA more effectively. The multiple effects of VDRAs on modulating serum Ca, parathyroid cell proliferation, and the expression of CaSR and GENE mRNA reflect the complex involvement of the vitamin D axis in regulating the mineral homeostasis system. | INDIRECT-DOWNREGULATOR |
| Comparison of the pharmacological effects of paricalcitol and CHEMICAL on the factors involved in mineral homeostasis. Vitamin D receptor agonists (VDRAs) directly suppress parathyroid hormone (PTH) mRNA expression. Different VDRAs are known to have differential effects on serum calcium (Ca), which may also affect serum GENE levels since serum Ca regulates GENE secretion mediated by the Ca-sensing receptor (CaSR). In this study, we compared the effects of paricalcitol and CHEMICAL on regulating serum Ca and GENE, and also the expression of GENE, VDR, and CaSR mRNA. The 5/6 nephrectomized (NX) Sprague-Dawley rats on a normal or hyperphosphatemia-inducing diet were treated with vehicle, paricalcitol, or CHEMICAL for two weeks. Both drugs at the tested doses (0.042-0.33 mug/kg) suppressed GENE mRNA expression and serum GENE effectively in the 5/6 NX rats, but paricalcitol was less potent in raising serum Ca than CHEMICAL. In pig parathyroid cells, paricalcitol and the active form of CHEMICAL induced VDR translocation from the cytoplasm into the nucleus, suppressed GENE mRNA expression and inhibited cell proliferation in a similar manner, although paricalcitol induced the expression of CaSR mRNA more effectively. The multiple effects of VDRAs on modulating serum Ca, parathyroid cell proliferation, and the expression of CaSR and GENE mRNA reflect the complex involvement of the vitamin D axis in regulating the mineral homeostasis system. | INDIRECT-DOWNREGULATOR |
| Identification of a primary target of thalidomide teratogenicity. Half a century ago, thalidomide was widely prescribed to pregnant women as a sedative but was found to be teratogenic, causing multiple birth defects. Today, thalidomide is still used in the treatment of leprosy and multiple myeloma, although how it causes limb malformation and other developmental defects is unknown. Here, we identified cereblon (CRBN) as a thalidomide-binding protein. GENE forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. CHEMICAL initiates its teratogenic effects by binding to GENE and inhibiting the associated ubiquitin ligase activity. This study reveals a basis for thalidomide teratogenicity and may contribute to the development of new thalidomide derivatives without teratogenic activity. | DIRECT-REGULATOR |
| Identification of a primary target of thalidomide teratogenicity. Half a century ago, thalidomide was widely prescribed to pregnant women as a sedative but was found to be teratogenic, causing multiple birth defects. Today, thalidomide is still used in the treatment of leprosy and multiple myeloma, although how it causes limb malformation and other developmental defects is unknown. Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 GENE complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. CHEMICAL initiates its teratogenic effects by binding to CRBN and inhibiting the associated GENE activity. This study reveals a basis for thalidomide teratogenicity and may contribute to the development of new thalidomide derivatives without teratogenic activity. | INHIBITOR |
| New standards in hypertension and cardiovascular risk management: focus on telmisartan. Blockade of the renin-angiotensin system is an important approach in managing high blood pressure, and has increasingly been shown to affect cardiovascular disease processes mediated by angiotensin II throughout the cardiovascular and renal continua. CHEMICAL is an GENE blocker (ARB) displaying unique pharmacologic properties, including a longer half life than any other ARB, that result in large and sustained reductions of blood pressure. In patients with mild-to-moderate hypertension, telmisartan has proved superior to other antihypertensive agents (valsartan, losartan, ramipril, perindopril, and atenolol) in controlling blood pressure particularly towards the end of the dosing interval. There is also clinical evidence that telmisartan reduces left ventricular hypertrophy, reduces arterial stiffness and the recurrence of atrial fibrillation, and confers renoprotection. The ONgoing CHEMICAL Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study has demonstrated that telmisartan has similar cardiovascular protective effects to ramipril in a large, high-risk patient population but was better tolerated. The powerful and sustained blood pressure control apparent in clinical trials, together with cardiovascular protection and tolerability demonstrated in ONTARGET means that telmisartan may be a preferred option for patients with hypertension. | INHIBITOR |
| Jostling for position: optimizing linker location in the design of estrogen receptor-targeting PROTACs. Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to ER antagonists. It has been shown that in most of these resistant tumor cells, the ER is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an ER agonist, promoting tumor growth. This suggests that targeted ER degradation may provide an effective therapeutic approach for breast cancers, even those that are resistant to conventional therapies. With this in mind, we previously demonstrated that proteolysis targeting chimeras (PROTACs) effectively induce degradation of the ER as a proof-of-concept experiment. Herein we further refined the PROTAC approach to target the ER for degradation. The ER-targeting PROTACs are composed of an CHEMICAL on one end and a hypoxia-inducing factor 1alpha (HIF-1alpha)-derived synthetic pentapeptide on the other. The pentapeptide is recognized by an E3 ubiquitin ligase called the von Hippel Lindau tumor suppressor protein (pVHL), thereby recruiting the ER to this E3 ligase for ubiquitination and degradation. Specifically, the pentapeptide is attached at three different locations on CHEMICAL to generate three different PROTAC types. With the pentapeptide linked through the C7alpha position of CHEMICAL, the resulting PROTAC shows the most effective ER degradation and highest affinity for the GENE. This result provides an opportunity to develop a novel type of ER antagonist that may overcome the resistance of breast tumors to conventional drugs such as tamoxifen and fulvestrant (Faslodex). | DIRECT-REGULATOR |
| Jostling for position: optimizing linker location in the design of estrogen receptor-targeting PROTACs. Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to GENE antagonists. It has been shown that in most of these resistant tumor cells, the GENE is expressed and continues to regulate tumor growth. Recent studies indicate that tamoxifen initially acts as an antagonist, but later functions as an GENE agonist, promoting tumor growth. This suggests that targeted GENE degradation may provide an effective therapeutic approach for breast cancers, even those that are resistant to conventional therapies. With this in mind, we previously demonstrated that proteolysis targeting chimeras (PROTACs) effectively induce degradation of the GENE as a proof-of-concept experiment. Herein we further refined the PROTAC approach to target the GENE for degradation. The GENE-targeting PROTACs are composed of an CHEMICAL on one end and a hypoxia-inducing factor 1alpha (HIF-1alpha)-derived synthetic pentapeptide on the other. The pentapeptide is recognized by an E3 ubiquitin ligase called the von Hippel Lindau tumor suppressor protein (pVHL), thereby recruiting the GENE to this E3 ligase for ubiquitination and degradation. Specifically, the pentapeptide is attached at three different locations on CHEMICAL to generate three different PROTAC types. With the pentapeptide linked through the C7alpha position of CHEMICAL, the resulting PROTAC shows the most effective GENE degradation and highest affinity for the estrogen receptor. This result provides an opportunity to develop a novel type of GENE antagonist that may overcome the resistance of breast tumors to conventional drugs such as tamoxifen and fulvestrant (Faslodex). | REGULATOR |
| Jostling for position: optimizing linker location in the design of estrogen receptor-targeting PROTACs. Estrogen receptor-alpha (ER) antagonists have been widely used for breast cancer therapy. Despite initial responsiveness, hormone-sensitive ER-positive cancer cells eventually develop resistance to GENE antagonists. It has been shown that in most of these resistant tumor cells, the GENE is expressed and continues to regulate tumor growth. Recent studies indicate that CHEMICAL initially acts as an antagonist, but later functions as an GENE agonist, promoting tumor growth. This suggests that targeted GENE degradation may provide an effective therapeutic approach for breast cancers, even those that are resistant to conventional therapies. With this in mind, we previously demonstrated that proteolysis targeting chimeras (PROTACs) effectively induce degradation of the GENE as a proof-of-concept experiment. Herein we further refined the PROTAC approach to target the GENE for degradation. The ER-targeting PROTACs are composed of an estradiol on one end and a hypoxia-inducing factor 1alpha (HIF-1alpha)-derived synthetic pentapeptide on the other. The pentapeptide is recognized by an E3 ubiquitin ligase called the von Hippel Lindau tumor suppressor protein (pVHL), thereby recruiting the GENE to this E3 ligase for ubiquitination and degradation. Specifically, the pentapeptide is attached at three different locations on estradiol to generate three different PROTAC types. With the pentapeptide linked through the C7alpha position of estradiol, the resulting PROTAC shows the most effective GENE degradation and highest affinity for the estrogen receptor. This result provides an opportunity to develop a novel type of GENE antagonist that may overcome the resistance of breast tumors to conventional drugs such as CHEMICAL and fulvestrant (Faslodex). | INHIBITOR |
| The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. BACKGROUND AND PURPOSE: There are two important properties of receptor-ligand interactions: affinity (the ability of the ligand to bind to the receptor) and efficacy (the ability of the receptor-ligand complex to induce a response). Ligands are classified as agonists or antagonists depending on whether or not they have efficacy. In theory, it is possible to develop selective agonists based on selective affinity, selective intrinsic efficacy or both. This study examined the affinity and intrinsic efficacy of 31 beta-adrenoceptor agonists at the three human beta-adrenoceptors to determine whether the current agonists are subtype selective because of affinity or intrinsic efficacy. EXPERIMENTAL APPROACH: Stable clonal CHO-K1 cell lines, transfected with either the human beta(1), GENE or beta(3)-adrenoceptor, were used, and whole-cell [(3)H]-CGP 12177 radioligand binding and [(3)H]-cAMP accumulation were measured. KEY RESULTS: Several agonists were found to be highly subtype selective because of selective affinity (e.g. salmeterol and formoterol, for the beta(2)-adrenoceptor over the beta(1) or beta(3)), while others (e.g. isoprenaline) had little affinity-selectivity. However, the intrinsic efficacy of salmeterol, formoterol and isoprenaline was similar across all three receptor subtypes. Other ligands (e.g. denopamine for beta(1); clenbuterol, AZ 40140d, CHEMICAL for GENE) were found to have subtype-selective intrinsic efficacy. Several ligands appeared to activate two agonist conformations of the beta(1)- and beta(3)-adrenoceptors. CONCLUSIONS AND IMPLICATIONS: There are agonists with subtype selectivity based upon both selective affinity and selective intrinsic efficacy. Therefore, there is scope to develop better selective agonists based upon both selective affinity and selective intrinsic efficacy. | DIRECT-REGULATOR |
| The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. BACKGROUND AND PURPOSE: There are two important properties of receptor-ligand interactions: affinity (the ability of the ligand to bind to the receptor) and efficacy (the ability of the receptor-ligand complex to induce a response). Ligands are classified as agonists or antagonists depending on whether or not they have efficacy. In theory, it is possible to develop selective agonists based on selective affinity, selective intrinsic efficacy or both. This study examined the affinity and intrinsic efficacy of 31 beta-adrenoceptor agonists at the three human beta-adrenoceptors to determine whether the current agonists are subtype selective because of affinity or intrinsic efficacy. EXPERIMENTAL APPROACH: Stable clonal CHO-K1 cell lines, transfected with either the human GENE, beta(2) or beta(3)-adrenoceptor, were used, and whole-cell [(3)H]-CGP 12177 radioligand binding and [(3)H]-cAMP accumulation were measured. KEY RESULTS: Several agonists were found to be highly subtype selective because of selective affinity (e.g. salmeterol and formoterol, for the beta(2)-adrenoceptor over the GENE or beta(3)), while others (e.g. isoprenaline) had little affinity-selectivity. However, the intrinsic efficacy of salmeterol, formoterol and isoprenaline was similar across all three receptor subtypes. Other ligands (e.g. CHEMICAL for GENE; clenbuterol, AZ 40140d, salbutamol for beta(2)) were found to have subtype-selective intrinsic efficacy. Several ligands appeared to activate two agonist conformations of the beta(1)- and beta(3)-adrenoceptors. CONCLUSIONS AND IMPLICATIONS: There are agonists with subtype selectivity based upon both selective affinity and selective intrinsic efficacy. Therefore, there is scope to develop better selective agonists based upon both selective affinity and selective intrinsic efficacy. | DIRECT-REGULATOR |
| The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. BACKGROUND AND PURPOSE: There are two important properties of receptor-ligand interactions: affinity (the ability of the ligand to bind to the receptor) and efficacy (the ability of the receptor-ligand complex to induce a response). Ligands are classified as agonists or antagonists depending on whether or not they have efficacy. In theory, it is possible to develop selective agonists based on selective affinity, selective intrinsic efficacy or both. This study examined the affinity and intrinsic efficacy of 31 beta-adrenoceptor agonists at the three human beta-adrenoceptors to determine whether the current agonists are subtype selective because of affinity or intrinsic efficacy. EXPERIMENTAL APPROACH: Stable clonal CHO-K1 cell lines, transfected with either the human beta(1), GENE or beta(3)-adrenoceptor, were used, and whole-cell [(3)H]-CGP 12177 radioligand binding and [(3)H]-cAMP accumulation were measured. KEY RESULTS: Several agonists were found to be highly subtype selective because of selective affinity (e.g. salmeterol and formoterol, for the beta(2)-adrenoceptor over the beta(1) or beta(3)), while others (e.g. isoprenaline) had little affinity-selectivity. However, the intrinsic efficacy of salmeterol, formoterol and isoprenaline was similar across all three receptor subtypes. Other ligands (e.g. denopamine for beta(1); CHEMICAL, AZ 40140d, salbutamol for GENE) were found to have subtype-selective intrinsic efficacy. Several ligands appeared to activate two agonist conformations of the beta(1)- and beta(3)-adrenoceptors. CONCLUSIONS AND IMPLICATIONS: There are agonists with subtype selectivity based upon both selective affinity and selective intrinsic efficacy. Therefore, there is scope to develop better selective agonists based upon both selective affinity and selective intrinsic efficacy. | DIRECT-REGULATOR |
| The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. BACKGROUND AND PURPOSE: There are two important properties of receptor-ligand interactions: affinity (the ability of the ligand to bind to the receptor) and efficacy (the ability of the receptor-ligand complex to induce a response). Ligands are classified as agonists or antagonists depending on whether or not they have efficacy. In theory, it is possible to develop selective agonists based on selective affinity, selective intrinsic efficacy or both. This study examined the affinity and intrinsic efficacy of 31 beta-adrenoceptor agonists at the three human beta-adrenoceptors to determine whether the current agonists are subtype selective because of affinity or intrinsic efficacy. EXPERIMENTAL APPROACH: Stable clonal CHO-K1 cell lines, transfected with either the human beta(1), GENE or beta(3)-adrenoceptor, were used, and whole-cell [(3)H]-CGP 12177 radioligand binding and [(3)H]-cAMP accumulation were measured. KEY RESULTS: Several agonists were found to be highly subtype selective because of selective affinity (e.g. salmeterol and formoterol, for the beta(2)-adrenoceptor over the beta(1) or beta(3)), while others (e.g. isoprenaline) had little affinity-selectivity. However, the intrinsic efficacy of salmeterol, formoterol and isoprenaline was similar across all three receptor subtypes. Other ligands (e.g. denopamine for beta(1); clenbuterol, CHEMICAL, salbutamol for GENE) were found to have subtype-selective intrinsic efficacy. Several ligands appeared to activate two agonist conformations of the beta(1)- and beta(3)-adrenoceptors. CONCLUSIONS AND IMPLICATIONS: There are agonists with subtype selectivity based upon both selective affinity and selective intrinsic efficacy. Therefore, there is scope to develop better selective agonists based upon both selective affinity and selective intrinsic efficacy. | DIRECT-REGULATOR |
| The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. BACKGROUND AND PURPOSE: There are two important properties of receptor-ligand interactions: affinity (the ability of the ligand to bind to the receptor) and efficacy (the ability of the receptor-ligand complex to induce a response). Ligands are classified as agonists or antagonists depending on whether or not they have efficacy. In theory, it is possible to develop selective agonists based on selective affinity, selective intrinsic efficacy or both. This study examined the affinity and intrinsic efficacy of 31 beta-adrenoceptor agonists at the three human beta-adrenoceptors to determine whether the current agonists are subtype selective because of affinity or intrinsic efficacy. EXPERIMENTAL APPROACH: Stable clonal CHO-K1 cell lines, transfected with either the human beta(1), beta(2) or beta(3)-adrenoceptor, were used, and whole-cell [(3)H]-CGP 12177 radioligand binding and [(3)H]-cAMP accumulation were measured. KEY RESULTS: Several agonists were found to be highly subtype selective because of selective affinity (e.g. CHEMICAL and formoterol, for the GENE over the beta(1) or beta(3)), while others (e.g. isoprenaline) had little affinity-selectivity. However, the intrinsic efficacy of CHEMICAL, formoterol and isoprenaline was similar across all three receptor subtypes. Other ligands (e.g. denopamine for beta(1); clenbuterol, AZ 40140d, salbutamol for beta(2)) were found to have subtype-selective intrinsic efficacy. Several ligands appeared to activate two agonist conformations of the beta(1)- and beta(3)-adrenoceptors. CONCLUSIONS AND IMPLICATIONS: There are agonists with subtype selectivity based upon both selective affinity and selective intrinsic efficacy. Therefore, there is scope to develop better selective agonists based upon both selective affinity and selective intrinsic efficacy. | DIRECT-REGULATOR |
| The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. BACKGROUND AND PURPOSE: There are two important properties of receptor-ligand interactions: affinity (the ability of the ligand to bind to the receptor) and efficacy (the ability of the receptor-ligand complex to induce a response). Ligands are classified as agonists or antagonists depending on whether or not they have efficacy. In theory, it is possible to develop selective agonists based on selective affinity, selective intrinsic efficacy or both. This study examined the affinity and intrinsic efficacy of 31 beta-adrenoceptor agonists at the three human beta-adrenoceptors to determine whether the current agonists are subtype selective because of affinity or intrinsic efficacy. EXPERIMENTAL APPROACH: Stable clonal CHO-K1 cell lines, transfected with either the human GENE, beta(2) or beta(3)-adrenoceptor, were used, and whole-cell [(3)H]-CGP 12177 radioligand binding and [(3)H]-cAMP accumulation were measured. KEY RESULTS: Several agonists were found to be highly subtype selective because of selective affinity (e.g. CHEMICAL and formoterol, for the beta(2)-adrenoceptor over the GENE or beta(3)), while others (e.g. isoprenaline) had little affinity-selectivity. However, the intrinsic efficacy of CHEMICAL, formoterol and isoprenaline was similar across all three receptor subtypes. Other ligands (e.g. denopamine for beta(1); clenbuterol, AZ 40140d, salbutamol for beta(2)) were found to have subtype-selective intrinsic efficacy. Several ligands appeared to activate two agonist conformations of the beta(1)- and beta(3)-adrenoceptors. CONCLUSIONS AND IMPLICATIONS: There are agonists with subtype selectivity based upon both selective affinity and selective intrinsic efficacy. Therefore, there is scope to develop better selective agonists based upon both selective affinity and selective intrinsic efficacy. | DIRECT-REGULATOR |
| The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. BACKGROUND AND PURPOSE: There are two important properties of receptor-ligand interactions: affinity (the ability of the ligand to bind to the receptor) and efficacy (the ability of the receptor-ligand complex to induce a response). Ligands are classified as agonists or antagonists depending on whether or not they have efficacy. In theory, it is possible to develop selective agonists based on selective affinity, selective intrinsic efficacy or both. This study examined the affinity and intrinsic efficacy of 31 beta-adrenoceptor agonists at the three human beta-adrenoceptors to determine whether the current agonists are subtype selective because of affinity or intrinsic efficacy. EXPERIMENTAL APPROACH: Stable clonal CHO-K1 cell lines, transfected with either the human beta(1), beta(2) or beta(3)-adrenoceptor, were used, and whole-cell [(3)H]-CGP 12177 radioligand binding and [(3)H]-cAMP accumulation were measured. KEY RESULTS: Several agonists were found to be highly subtype selective because of selective affinity (e.g. salmeterol and CHEMICAL, for the GENE over the beta(1) or beta(3)), while others (e.g. isoprenaline) had little affinity-selectivity. However, the intrinsic efficacy of salmeterol, CHEMICAL and isoprenaline was similar across all three receptor subtypes. Other ligands (e.g. denopamine for beta(1); clenbuterol, AZ 40140d, salbutamol for beta(2)) were found to have subtype-selective intrinsic efficacy. Several ligands appeared to activate two agonist conformations of the beta(1)- and beta(3)-adrenoceptors. CONCLUSIONS AND IMPLICATIONS: There are agonists with subtype selectivity based upon both selective affinity and selective intrinsic efficacy. Therefore, there is scope to develop better selective agonists based upon both selective affinity and selective intrinsic efficacy. | DIRECT-REGULATOR |
| The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. BACKGROUND AND PURPOSE: There are two important properties of receptor-ligand interactions: affinity (the ability of the ligand to bind to the receptor) and efficacy (the ability of the receptor-ligand complex to induce a response). Ligands are classified as agonists or antagonists depending on whether or not they have efficacy. In theory, it is possible to develop selective agonists based on selective affinity, selective intrinsic efficacy or both. This study examined the affinity and intrinsic efficacy of 31 beta-adrenoceptor agonists at the three human beta-adrenoceptors to determine whether the current agonists are subtype selective because of affinity or intrinsic efficacy. EXPERIMENTAL APPROACH: Stable clonal CHO-K1 cell lines, transfected with either the human beta(1), beta(2) or beta(3)-adrenoceptor, were used, and whole-cell [(3)H]-CGP 12177 radioligand binding and [(3)H]-cAMP accumulation were measured. KEY RESULTS: Several agonists were found to be highly subtype selective because of selective affinity (e.g. salmeterol and CHEMICAL, for the beta(2)-adrenoceptor over the beta(1) or GENE), while others (e.g. isoprenaline) had little affinity-selectivity. However, the intrinsic efficacy of salmeterol, CHEMICAL and isoprenaline was similar across all three receptor subtypes. Other ligands (e.g. denopamine for beta(1); clenbuterol, AZ 40140d, salbutamol for beta(2)) were found to have subtype-selective intrinsic efficacy. Several ligands appeared to activate two agonist conformations of the beta(1)- and beta(3)-adrenoceptors. CONCLUSIONS AND IMPLICATIONS: There are agonists with subtype selectivity based upon both selective affinity and selective intrinsic efficacy. Therefore, there is scope to develop better selective agonists based upon both selective affinity and selective intrinsic efficacy. | DIRECT-REGULATOR |
| The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. BACKGROUND AND PURPOSE: There are two important properties of receptor-ligand interactions: affinity (the ability of the ligand to bind to the receptor) and efficacy (the ability of the receptor-ligand complex to induce a response). Ligands are classified as agonists or antagonists depending on whether or not they have efficacy. In theory, it is possible to develop selective agonists based on selective affinity, selective intrinsic efficacy or both. This study examined the affinity and intrinsic efficacy of 31 beta-adrenoceptor agonists at the three human beta-adrenoceptors to determine whether the current agonists are subtype selective because of affinity or intrinsic efficacy. EXPERIMENTAL APPROACH: Stable clonal CHO-K1 cell lines, transfected with either the human beta(1), beta(2) or beta(3)-adrenoceptor, were used, and whole-cell [(3)H]-CGP 12177 radioligand binding and [(3)H]-cAMP accumulation were measured. KEY RESULTS: Several agonists were found to be highly subtype selective because of selective affinity (e.g. salmeterol and formoterol, for the GENE over the beta(1) or beta(3)), while others (e.g. CHEMICAL) had little affinity-selectivity. However, the intrinsic efficacy of salmeterol, formoterol and CHEMICAL was similar across all three receptor subtypes. Other ligands (e.g. denopamine for beta(1); clenbuterol, AZ 40140d, salbutamol for beta(2)) were found to have subtype-selective intrinsic efficacy. Several ligands appeared to activate two agonist conformations of the beta(1)- and beta(3)-adrenoceptors. CONCLUSIONS AND IMPLICATIONS: There are agonists with subtype selectivity based upon both selective affinity and selective intrinsic efficacy. Therefore, there is scope to develop better selective agonists based upon both selective affinity and selective intrinsic efficacy. | DIRECT-REGULATOR |
| The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. BACKGROUND AND PURPOSE: There are two important properties of receptor-ligand interactions: affinity (the ability of the ligand to bind to the receptor) and efficacy (the ability of the receptor-ligand complex to induce a response). Ligands are classified as agonists or antagonists depending on whether or not they have efficacy. In theory, it is possible to develop selective agonists based on selective affinity, selective intrinsic efficacy or both. This study examined the affinity and intrinsic efficacy of 31 beta-adrenoceptor agonists at the three human beta-adrenoceptors to determine whether the current agonists are subtype selective because of affinity or intrinsic efficacy. EXPERIMENTAL APPROACH: Stable clonal CHO-K1 cell lines, transfected with either the human GENE, beta(2) or beta(3)-adrenoceptor, were used, and whole-cell [(3)H]-CGP 12177 radioligand binding and [(3)H]-cAMP accumulation were measured. KEY RESULTS: Several agonists were found to be highly subtype selective because of selective affinity (e.g. salmeterol and formoterol, for the beta(2)-adrenoceptor over the GENE or beta(3)), while others (e.g. CHEMICAL) had little affinity-selectivity. However, the intrinsic efficacy of salmeterol, formoterol and CHEMICAL was similar across all three receptor subtypes. Other ligands (e.g. denopamine for beta(1); clenbuterol, AZ 40140d, salbutamol for beta(2)) were found to have subtype-selective intrinsic efficacy. Several ligands appeared to activate two agonist conformations of the beta(1)- and beta(3)-adrenoceptors. CONCLUSIONS AND IMPLICATIONS: There are agonists with subtype selectivity based upon both selective affinity and selective intrinsic efficacy. Therefore, there is scope to develop better selective agonists based upon both selective affinity and selective intrinsic efficacy. | DIRECT-REGULATOR |
| The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. BACKGROUND AND PURPOSE: There are two important properties of receptor-ligand interactions: affinity (the ability of the ligand to bind to the receptor) and efficacy (the ability of the receptor-ligand complex to induce a response). Ligands are classified as agonists or antagonists depending on whether or not they have efficacy. In theory, it is possible to develop selective agonists based on selective affinity, selective intrinsic efficacy or both. This study examined the affinity and intrinsic efficacy of 31 beta-adrenoceptor agonists at the three human beta-adrenoceptors to determine whether the current agonists are subtype selective because of affinity or intrinsic efficacy. EXPERIMENTAL APPROACH: Stable clonal CHO-K1 cell lines, transfected with either the human beta(1), beta(2) or beta(3)-adrenoceptor, were used, and whole-cell [(3)H]-CGP 12177 radioligand binding and [(3)H]-cAMP accumulation were measured. KEY RESULTS: Several agonists were found to be highly subtype selective because of selective affinity (e.g. salmeterol and formoterol, for the beta(2)-adrenoceptor over the beta(1) or GENE), while others (e.g. CHEMICAL) had little affinity-selectivity. However, the intrinsic efficacy of salmeterol, formoterol and CHEMICAL was similar across all three receptor subtypes. Other ligands (e.g. denopamine for beta(1); clenbuterol, AZ 40140d, salbutamol for beta(2)) were found to have subtype-selective intrinsic efficacy. Several ligands appeared to activate two agonist conformations of the beta(1)- and beta(3)-adrenoceptors. CONCLUSIONS AND IMPLICATIONS: There are agonists with subtype selectivity based upon both selective affinity and selective intrinsic efficacy. Therefore, there is scope to develop better selective agonists based upon both selective affinity and selective intrinsic efficacy. | DIRECT-REGULATOR |
| Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. Rasagiline (N-propargyl-1-(R)-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO)-B inhibitor, anti-Parkinsonian drug. Rasagiline is effective as monotherapy or adjunct to L-Dopa for patients with early and late Parkinson's disease (PD). Its S-isomer, TVP1022 is thousand times less potent as an MAO-B inhibitor. However, both compounds have similar molecular mechanisms of neuroprotection in neuronal cell cultures and animal neurodegenerative models, indicating that the neuroprotective effect of rasagiline does not depend on inhibition of MAO-B, but rather is associated with the CHEMICAL moiety, which promotes mitochondrial viability and stabilizes permeability transition by regulating GENE family proteins. Novel findings demonstrated that the major metabolite of rasagiline, 1-(R)-aminoindan has antioxidant and neuroprotective capabilities and thus, may contribute to the overt activity of its parent compound, rasagiline. This paper will review the earlier and present studies in the development of rasagiline for treatment of PD and discuss its pharmacology and applicable mechanism of action. | GENE-CHEMICAL |
| CHEMICAL: a novel anti-Parkinsonian GENE inhibitor with neuroprotective activity. CHEMICAL (N-propargyl-1-(R)-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO)-B inhibitor, anti-Parkinsonian drug. CHEMICAL is effective as monotherapy or adjunct to L-Dopa for patients with early and late Parkinson's disease (PD). Its S-isomer, TVP1022 is thousand times less potent as an MAO-B inhibitor. However, both compounds have similar molecular mechanisms of neuroprotection in neuronal cell cultures and animal neurodegenerative models, indicating that the neuroprotective effect of rasagiline does not depend on inhibition of MAO-B, but rather is associated with the N-propargyl moiety, which promotes mitochondrial viability and stabilizes permeability transition by regulating Bcl-2 family proteins. Novel findings demonstrated that the major metabolite of rasagiline, 1-(R)-aminoindan has antioxidant and neuroprotective capabilities and thus, may contribute to the overt activity of its parent compound, rasagiline. This paper will review the earlier and present studies in the development of rasagiline for treatment of PD and discuss its pharmacology and applicable mechanism of action. | INHIBITOR |
| Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. CHEMICAL (N-propargyl-1-(R)-aminoindan) is a novel, highly potent irreversible GENE inhibitor, anti-Parkinsonian drug. CHEMICAL is effective as monotherapy or adjunct to L-Dopa for patients with early and late Parkinson's disease (PD). Its S-isomer, TVP1022 is thousand times less potent as an MAO-B inhibitor. However, both compounds have similar molecular mechanisms of neuroprotection in neuronal cell cultures and animal neurodegenerative models, indicating that the neuroprotective effect of rasagiline does not depend on inhibition of MAO-B, but rather is associated with the N-propargyl moiety, which promotes mitochondrial viability and stabilizes permeability transition by regulating Bcl-2 family proteins. Novel findings demonstrated that the major metabolite of rasagiline, 1-(R)-aminoindan has antioxidant and neuroprotective capabilities and thus, may contribute to the overt activity of its parent compound, rasagiline. This paper will review the earlier and present studies in the development of rasagiline for treatment of PD and discuss its pharmacology and applicable mechanism of action. | INHIBITOR |
| Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. Rasagiline (CHEMICAL) is a novel, highly potent irreversible GENE inhibitor, anti-Parkinsonian drug. Rasagiline is effective as monotherapy or adjunct to L-Dopa for patients with early and late Parkinson's disease (PD). Its S-isomer, TVP1022 is thousand times less potent as an MAO-B inhibitor. However, both compounds have similar molecular mechanisms of neuroprotection in neuronal cell cultures and animal neurodegenerative models, indicating that the neuroprotective effect of rasagiline does not depend on inhibition of MAO-B, but rather is associated with the N-propargyl moiety, which promotes mitochondrial viability and stabilizes permeability transition by regulating Bcl-2 family proteins. Novel findings demonstrated that the major metabolite of rasagiline, 1-(R)-aminoindan has antioxidant and neuroprotective capabilities and thus, may contribute to the overt activity of its parent compound, rasagiline. This paper will review the earlier and present studies in the development of rasagiline for treatment of PD and discuss its pharmacology and applicable mechanism of action. | INHIBITOR |
| Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. Rasagiline (N-propargyl-1-(R)-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO)-B inhibitor, anti-Parkinsonian drug. Rasagiline is effective as monotherapy or adjunct to L-Dopa for patients with early and late Parkinson's disease (PD). Its S-isomer, CHEMICAL is thousand times less potent as an GENE inhibitor. However, both compounds have similar molecular mechanisms of neuroprotection in neuronal cell cultures and animal neurodegenerative models, indicating that the neuroprotective effect of rasagiline does not depend on inhibition of GENE, but rather is associated with the N-propargyl moiety, which promotes mitochondrial viability and stabilizes permeability transition by regulating Bcl-2 family proteins. Novel findings demonstrated that the major metabolite of rasagiline, 1-(R)-aminoindan has antioxidant and neuroprotective capabilities and thus, may contribute to the overt activity of its parent compound, rasagiline. This paper will review the earlier and present studies in the development of rasagiline for treatment of PD and discuss its pharmacology and applicable mechanism of action. | INHIBITOR |
| Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. CHEMICAL (N-propargyl-1-(R)-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO)-B inhibitor, anti-Parkinsonian drug. CHEMICAL is effective as monotherapy or adjunct to L-Dopa for patients with early and late Parkinson's disease (PD). Its S-isomer, TVP1022 is thousand times less potent as an GENE inhibitor. However, both compounds have similar molecular mechanisms of neuroprotection in neuronal cell cultures and animal neurodegenerative models, indicating that the neuroprotective effect of CHEMICAL does not depend on inhibition of GENE, but rather is associated with the N-propargyl moiety, which promotes mitochondrial viability and stabilizes permeability transition by regulating Bcl-2 family proteins. Novel findings demonstrated that the major metabolite of CHEMICAL, 1-(R)-aminoindan has antioxidant and neuroprotective capabilities and thus, may contribute to the overt activity of its parent compound, CHEMICAL. This paper will review the earlier and present studies in the development of CHEMICAL for treatment of PD and discuss its pharmacology and applicable mechanism of action. | NO-RELATIONSHIP |
| Resistance to thyroid hormone due to a novel thyroid hormone receptor mutant in a patient with hypothyroidism secondary to lingual thyroid and functional characterization of the mutant receptor. BACKGROUND: We describe a rare case of congenital hypothyroidism and an extremely high serum thyrotropin (TSH) level caused by a combination of resistance to thyroid hormone (RTH) and a lingual thyroid. As the RTH mutant, R316C, was new, the optimum dose of CHEMICAL was unclear. To aid in assessment of the therapy, we characterized the mutant R316C thyroid hormone receptor (TR) and compared it with a common mutant, R316H, using in vitro studies. SUMMARY: The patient was a newborn female having severe hypothyroidism with a free thyroxine level of 0.36 ng/dL and a serum GENE level of 177 microU/mL. A scintiscan showed ectopic lingual thyroid tissue without a normal thyroid gland. Supplementation with CHEMICAL at a dose of >350 microg/day did not normalize the serum GENE level; however, the patient showed normal growth and intelligence at 14 years of age. Consistent with the results of a computer analysis, the binding of R316C to triiodothyronine (T3) was significantly decreased to 38% that of the wild type. Electrophoretic mobility shift assay demonstrated that like R316H, R316C did not form a homodimer, but formed a heterodimer with RXR. However, a glutathione-S-transferase pull-down assay showed reduced binding of R316C with NCoR in the absence of T3 and impaired release in the presence of T3. In addition, transient transfection experiments demonstrated that unlike R316H, R316C had severe impairment of transcriptional activity on genes both positively and negatively regulated by thyroid hormone. It also had a clear dominant negative effect on genes negatively, but not positively, regulated by thyroid hormone, including the TSH-releasing hormone and TSHbeta genes. CONCLUSION: This is the first reported case of a R316C TR mutation. The characteristics of the R316C mutant differed from those of the R316H mutant. Our findings suggest that R316C causes reduced association with and impaired release of NCoR, resulting in RTH predominantly at the pituitary level, and that slightly elevated serum GENE level with high dose of CHEMICAL might be optimum for normal growth. | NO-RELATIONSHIP |
| Resistance to thyroid hormone due to a novel thyroid hormone receptor mutant in a patient with hypothyroidism secondary to lingual thyroid and functional characterization of the mutant receptor. BACKGROUND: We describe a rare case of congenital hypothyroidism and an extremely high serum thyrotropin (TSH) level caused by a combination of resistance to thyroid hormone (RTH) and a lingual thyroid. As the RTH mutant, GENE, was new, the optimum dose of levothyroxine was unclear. To aid in assessment of the therapy, we characterized the mutant GENE thyroid hormone receptor (TR) and compared it with a common mutant, R316H, using in vitro studies. SUMMARY: The patient was a newborn female having severe hypothyroidism with a free thyroxine level of 0.36 ng/dL and a serum TSH level of 177 microU/mL. A scintiscan showed ectopic lingual thyroid tissue without a normal thyroid gland. Supplementation with levothyroxine at a dose of >350 microg/day did not normalize the serum TSH level; however, the patient showed normal growth and intelligence at 14 years of age. Consistent with the results of a computer analysis, the binding of GENE to triiodothyronine (CHEMICAL) was significantly decreased to 38% that of the wild type. Electrophoretic mobility shift assay demonstrated that like R316H, GENE did not form a homodimer, but formed a heterodimer with RXR. However, a glutathione-S-transferase pull-down assay showed reduced binding of GENE with NCoR in the absence of CHEMICAL and impaired release in the presence of CHEMICAL. In addition, transient transfection experiments demonstrated that unlike R316H, GENE had severe impairment of transcriptional activity on genes both positively and negatively regulated by thyroid hormone. It also had a clear dominant negative effect on genes negatively, but not positively, regulated by thyroid hormone, including the TSH-releasing hormone and TSHbeta genes. CONCLUSION: This is the first reported case of a GENE TR mutation. The characteristics of the GENE mutant differed from those of the R316H mutant. Our findings suggest that GENE causes reduced association with and impaired release of NCoR, resulting in RTH predominantly at the pituitary level, and that slightly elevated serum TSH level with high dose of levothyroxine might be optimum for normal growth. | DIRECT-REGULATOR |
| Resistance to thyroid hormone due to a novel thyroid hormone receptor mutant in a patient with hypothyroidism secondary to lingual thyroid and functional characterization of the mutant receptor. BACKGROUND: We describe a rare case of congenital hypothyroidism and an extremely high serum thyrotropin (TSH) level caused by a combination of resistance to thyroid hormone (RTH) and a lingual thyroid. As the RTH mutant, GENE, was new, the optimum dose of levothyroxine was unclear. To aid in assessment of the therapy, we characterized the mutant GENE thyroid hormone receptor (TR) and compared it with a common mutant, R316H, using in vitro studies. SUMMARY: The patient was a newborn female having severe hypothyroidism with a free thyroxine level of 0.36 ng/dL and a serum TSH level of 177 microU/mL. A scintiscan showed ectopic lingual thyroid tissue without a normal thyroid gland. Supplementation with levothyroxine at a dose of >350 microg/day did not normalize the serum TSH level; however, the patient showed normal growth and intelligence at 14 years of age. Consistent with the results of a computer analysis, the binding of GENE to CHEMICAL (T3) was significantly decreased to 38% that of the wild type. Electrophoretic mobility shift assay demonstrated that like R316H, GENE did not form a homodimer, but formed a heterodimer with RXR. However, a glutathione-S-transferase pull-down assay showed reduced binding of GENE with NCoR in the absence of T3 and impaired release in the presence of T3. In addition, transient transfection experiments demonstrated that unlike R316H, GENE had severe impairment of transcriptional activity on genes both positively and negatively regulated by thyroid hormone. It also had a clear dominant negative effect on genes negatively, but not positively, regulated by thyroid hormone, including the TSH-releasing hormone and TSHbeta genes. CONCLUSION: This is the first reported case of a GENE TR mutation. The characteristics of the GENE mutant differed from those of the R316H mutant. Our findings suggest that GENE causes reduced association with and impaired release of NCoR, resulting in RTH predominantly at the pituitary level, and that slightly elevated serum TSH level with high dose of levothyroxine might be optimum for normal growth. | DIRECT-REGULATOR |
| Resistance to thyroid hormone due to a novel thyroid hormone receptor mutant in a patient with hypothyroidism secondary to lingual thyroid and functional characterization of the mutant receptor. BACKGROUND: We describe a rare case of congenital hypothyroidism and an extremely high serum thyrotropin (TSH) level caused by a combination of resistance to thyroid hormone (RTH) and a lingual thyroid. As the RTH mutant, R316C, was new, the optimum dose of levothyroxine was unclear. To aid in assessment of the therapy, we characterized the mutant R316C thyroid hormone receptor (TR) and compared it with a common mutant, R316H, using in vitro studies. SUMMARY: The patient was a newborn female having severe hypothyroidism with a free thyroxine level of 0.36 ng/dL and a serum TSH level of 177 microU/mL. A scintiscan showed ectopic lingual thyroid tissue without a normal thyroid gland. Supplementation with levothyroxine at a dose of >350 microg/day did not normalize the serum TSH level; however, the patient showed normal growth and intelligence at 14 years of age. Consistent with the results of a computer analysis, the binding of R316C to triiodothyronine (T3) was significantly decreased to 38% that of the wild type. Electrophoretic mobility shift assay demonstrated that like R316H, R316C did not form a homodimer, but formed a heterodimer with RXR. However, a glutathione-S-transferase pull-down assay showed reduced binding of R316C with GENE in the absence of CHEMICAL and impaired release in the presence of CHEMICAL. In addition, transient transfection experiments demonstrated that unlike R316H, R316C had severe impairment of transcriptional activity on genes both positively and negatively regulated by thyroid hormone. It also had a clear dominant negative effect on genes negatively, but not positively, regulated by thyroid hormone, including the TSH-releasing hormone and TSHbeta genes. CONCLUSION: This is the first reported case of a R316C TR mutation. The characteristics of the R316C mutant differed from those of the R316H mutant. Our findings suggest that R316C causes reduced association with and impaired release of GENE, resulting in RTH predominantly at the pituitary level, and that slightly elevated serum TSH level with high dose of levothyroxine might be optimum for normal growth. | GENE-CHEMICAL |
| Selective cyclooxygenase-2 (COX-2) inhibitors and breast cancer risk. BACKGROUND: Recent epidemiologic and laboratory studies have suggested that non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of breast cancer through inhibition of cyclooxygenase-2 (COX-2). METHODS: We conducted a case-control study to measure the association between selective cox-2 inhibitors, particularly celecoxib, CHEMICAL, valdecoxib and non-specific NSAID subgroups, and breast cancer risk. Between 2003 and 2006, a total of 18,368 incident breast cancer cases were identified in the Ingenix/Lab Rx insurance database, which contains clinical encounter and drug prescription data. Four controls per case were randomly selected, matched on age and time in database. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. RESULTS: Breast cancer risk was inversely associated with both non-specific NSAID and selective GENE inhibitor use. Greater than 12 months' duration of use of Celecoxib at a standard dose (200mg/day) was associated with a 16% decrease in breast cancer risk (OR=0.84, 95% CI=0.73, 0.97). We observed the greatest risk reduction in association with >2 years of CHEMICAL exposure (OR=0.54, 95% CI=0.37, 0.80). Acetaminophen, a compound with less biological plausibility for chemoprevention, showed no significant association with the risk of developing breast cancer. CONCLUSION: Consistent with animal models and laboratory investigations, higher doses of selective GENE inhibitors were more protective against breast cancer than non-specific NSAIDs. With exposure to CHEMICAL, a selective GENE inhibitor, breast cancer risk reduction was appreciable (46%), suggesting a possible role for selective GENE inhibitors in breast cancer prophylaxis. | INHIBITOR |
| Selective cyclooxygenase-2 (COX-2) inhibitors and breast cancer risk. BACKGROUND: Recent epidemiologic and laboratory studies have suggested that non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of breast cancer through inhibition of cyclooxygenase-2 (COX-2). METHODS: We conducted a case-control study to measure the association between selective GENE inhibitors, particularly CHEMICAL, rofecoxib, valdecoxib and non-specific NSAID subgroups, and breast cancer risk. Between 2003 and 2006, a total of 18,368 incident breast cancer cases were identified in the Ingenix/Lab Rx insurance database, which contains clinical encounter and drug prescription data. Four controls per case were randomly selected, matched on age and time in database. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. RESULTS: Breast cancer risk was inversely associated with both non-specific NSAID and selective COX-2 inhibitor use. Greater than 12 months' duration of use of CHEMICAL at a standard dose (200mg/day) was associated with a 16% decrease in breast cancer risk (OR=0.84, 95% CI=0.73, 0.97). We observed the greatest risk reduction in association with >2 years of rofecoxib exposure (OR=0.54, 95% CI=0.37, 0.80). Acetaminophen, a compound with less biological plausibility for chemoprevention, showed no significant association with the risk of developing breast cancer. CONCLUSION: Consistent with animal models and laboratory investigations, higher doses of selective COX-2 inhibitors were more protective against breast cancer than non-specific NSAIDs. With exposure to rofecoxib, a selective COX-2 inhibitor, breast cancer risk reduction was appreciable (46%), suggesting a possible role for selective COX-2 inhibitors in breast cancer prophylaxis. | INHIBITOR |
| Selective cyclooxygenase-2 (COX-2) inhibitors and breast cancer risk. BACKGROUND: Recent epidemiologic and laboratory studies have suggested that non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of breast cancer through inhibition of cyclooxygenase-2 (COX-2). METHODS: We conducted a case-control study to measure the association between selective GENE inhibitors, particularly celecoxib, rofecoxib, CHEMICAL and non-specific NSAID subgroups, and breast cancer risk. Between 2003 and 2006, a total of 18,368 incident breast cancer cases were identified in the Ingenix/Lab Rx insurance database, which contains clinical encounter and drug prescription data. Four controls per case were randomly selected, matched on age and time in database. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. RESULTS: Breast cancer risk was inversely associated with both non-specific NSAID and selective COX-2 inhibitor use. Greater than 12 months' duration of use of Celecoxib at a standard dose (200mg/day) was associated with a 16% decrease in breast cancer risk (OR=0.84, 95% CI=0.73, 0.97). We observed the greatest risk reduction in association with >2 years of rofecoxib exposure (OR=0.54, 95% CI=0.37, 0.80). Acetaminophen, a compound with less biological plausibility for chemoprevention, showed no significant association with the risk of developing breast cancer. CONCLUSION: Consistent with animal models and laboratory investigations, higher doses of selective COX-2 inhibitors were more protective against breast cancer than non-specific NSAIDs. With exposure to rofecoxib, a selective COX-2 inhibitor, breast cancer risk reduction was appreciable (46%), suggesting a possible role for selective COX-2 inhibitors in breast cancer prophylaxis. | INHIBITOR |
| Selective GENE (COX-2) inhibitors and breast cancer risk. BACKGROUND: Recent epidemiologic and laboratory studies have suggested that non-CHEMICAL anti-inflammatory drugs (NSAIDs) may reduce the risk of breast cancer through inhibition of GENE (COX-2). METHODS: We conducted a case-control study to measure the association between selective cox-2 inhibitors, particularly celecoxib, rofecoxib, valdecoxib and non-specific NSAID subgroups, and breast cancer risk. Between 2003 and 2006, a total of 18,368 incident breast cancer cases were identified in the Ingenix/Lab Rx insurance database, which contains clinical encounter and drug prescription data. Four controls per case were randomly selected, matched on age and time in database. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. RESULTS: Breast cancer risk was inversely associated with both non-specific NSAID and selective COX-2 inhibitor use. Greater than 12 months' duration of use of Celecoxib at a standard dose (200mg/day) was associated with a 16% decrease in breast cancer risk (OR=0.84, 95% CI=0.73, 0.97). We observed the greatest risk reduction in association with >2 years of rofecoxib exposure (OR=0.54, 95% CI=0.37, 0.80). Acetaminophen, a compound with less biological plausibility for chemoprevention, showed no significant association with the risk of developing breast cancer. CONCLUSION: Consistent with animal models and laboratory investigations, higher doses of selective COX-2 inhibitors were more protective against breast cancer than non-specific NSAIDs. With exposure to rofecoxib, a selective COX-2 inhibitor, breast cancer risk reduction was appreciable (46%), suggesting a possible role for selective COX-2 inhibitors in breast cancer prophylaxis. | INHIBITOR |
| Selective cyclooxygenase-2 (COX-2) inhibitors and breast cancer risk. BACKGROUND: Recent epidemiologic and laboratory studies have suggested that non-CHEMICAL anti-inflammatory drugs (NSAIDs) may reduce the risk of breast cancer through inhibition of cyclooxygenase-2 (GENE). METHODS: We conducted a case-control study to measure the association between selective cox-2 inhibitors, particularly celecoxib, rofecoxib, valdecoxib and non-specific NSAID subgroups, and breast cancer risk. Between 2003 and 2006, a total of 18,368 incident breast cancer cases were identified in the Ingenix/Lab Rx insurance database, which contains clinical encounter and drug prescription data. Four controls per case were randomly selected, matched on age and time in database. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. RESULTS: Breast cancer risk was inversely associated with both non-specific NSAID and selective GENE inhibitor use. Greater than 12 months' duration of use of Celecoxib at a standard dose (200mg/day) was associated with a 16% decrease in breast cancer risk (OR=0.84, 95% CI=0.73, 0.97). We observed the greatest risk reduction in association with >2 years of rofecoxib exposure (OR=0.54, 95% CI=0.37, 0.80). Acetaminophen, a compound with less biological plausibility for chemoprevention, showed no significant association with the risk of developing breast cancer. CONCLUSION: Consistent with animal models and laboratory investigations, higher doses of selective GENE inhibitors were more protective against breast cancer than non-specific NSAIDs. With exposure to rofecoxib, a selective GENE inhibitor, breast cancer risk reduction was appreciable (46%), suggesting a possible role for selective GENE inhibitors in breast cancer prophylaxis. | INHIBITOR |
| Barrel rotation in rats induced by SMS 201-995: suppression by CHEMICAL. Intracerebroventricular administration of SMS 201-995 (5 micrograms/rat), a somatostatin analogue, induced barrel rotation in rats. Pretreatment with CHEMICAL (40 micrograms/100 g b. wt., IP) 3 days or 7 days prior to the injection of SMS 201-995 significantly inhibited the response rate of barrel rotation induced by SMS 201-995, but not that induced by GENE (1 microgram/rat, ICV). The suppressive effect of CHEMICAL on barrel rotation could be partially countered by MK-329, a selective peripheral CCK (CCK-A) receptor antagonist. Desulfated cerulein did not affect the barrel rotation induced by SMS 201-995. These findings suggest that CHEMICAL specifically suppresses the barrel rotation evoked by SMS 201-995 in a long-lasting manner possibly acting through CCK-A receptor. | NO-RELATIONSHIP |
| Barrel rotation in rats induced by SMS 201-995: suppression by ceruletide. Intracerebroventricular administration of CHEMICAL (5 micrograms/rat), a somatostatin analogue, induced barrel rotation in rats. Pretreatment with ceruletide (40 micrograms/100 g b. wt., IP) 3 days or 7 days prior to the injection of CHEMICAL significantly inhibited the response rate of barrel rotation induced by CHEMICAL, but not that induced by arginine-vasopressin (1 microgram/rat, ICV). The suppressive effect of ceruletide on barrel rotation could be partially countered by MK-329, a selective peripheral CCK (CCK-A) receptor antagonist. Desulfated cerulein did not affect the barrel rotation induced by CHEMICAL. These findings suggest that ceruletide specifically suppresses the barrel rotation evoked by CHEMICAL in a long-lasting manner possibly acting through GENE. | REGULATOR |
| Barrel rotation in rats induced by SMS 201-995: suppression by ceruletide. Intracerebroventricular administration of CHEMICAL (5 micrograms/rat), a GENE analogue, induced barrel rotation in rats. Pretreatment with ceruletide (40 micrograms/100 g b. wt., IP) 3 days or 7 days prior to the injection of CHEMICAL significantly inhibited the response rate of barrel rotation induced by CHEMICAL, but not that induced by arginine-vasopressin (1 microgram/rat, ICV). The suppressive effect of ceruletide on barrel rotation could be partially countered by MK-329, a selective peripheral CCK (CCK-A) receptor antagonist. Desulfated cerulein did not affect the barrel rotation induced by CHEMICAL. These findings suggest that ceruletide specifically suppresses the barrel rotation evoked by CHEMICAL in a long-lasting manner possibly acting through CCK-A receptor. | REGULATOR |
| Barrel rotation in rats induced by SMS 201-995: suppression by CHEMICAL. Intracerebroventricular administration of SMS 201-995 (5 micrograms/rat), a somatostatin analogue, induced barrel rotation in rats. Pretreatment with CHEMICAL (40 micrograms/100 g b. wt., IP) 3 days or 7 days prior to the injection of SMS 201-995 significantly inhibited the response rate of barrel rotation induced by SMS 201-995, but not that induced by arginine-vasopressin (1 microgram/rat, ICV). The suppressive effect of CHEMICAL on barrel rotation could be partially countered by MK-329, a selective peripheral GENE (CCK-A) receptor antagonist. Desulfated cerulein did not affect the barrel rotation induced by SMS 201-995. These findings suggest that CHEMICAL specifically suppresses the barrel rotation evoked by SMS 201-995 in a long-lasting manner possibly acting through CCK-A receptor. | INHIBITOR |
| Barrel rotation in rats induced by SMS 201-995: suppression by CHEMICAL. Intracerebroventricular administration of SMS 201-995 (5 micrograms/rat), a somatostatin analogue, induced barrel rotation in rats. Pretreatment with CHEMICAL (40 micrograms/100 g b. wt., IP) 3 days or 7 days prior to the injection of SMS 201-995 significantly inhibited the response rate of barrel rotation induced by SMS 201-995, but not that induced by arginine-vasopressin (1 microgram/rat, ICV). The suppressive effect of CHEMICAL on barrel rotation could be partially countered by MK-329, a selective peripheral CCK GENE antagonist. Desulfated cerulein did not affect the barrel rotation induced by SMS 201-995. These findings suggest that CHEMICAL specifically suppresses the barrel rotation evoked by SMS 201-995 in a long-lasting manner possibly acting through CCK-A receptor. | INHIBITOR |
| Barrel rotation in rats induced by SMS 201-995: suppression by CHEMICAL. Intracerebroventricular administration of SMS 201-995 (5 micrograms/rat), a somatostatin analogue, induced barrel rotation in rats. Pretreatment with CHEMICAL (40 micrograms/100 g b. wt., IP) 3 days or 7 days prior to the injection of SMS 201-995 significantly inhibited the response rate of barrel rotation induced by SMS 201-995, but not that induced by arginine-vasopressin (1 microgram/rat, ICV). The suppressive effect of CHEMICAL on barrel rotation could be partially countered by MK-329, a selective peripheral CCK (CCK-A) receptor antagonist. Desulfated cerulein did not affect the barrel rotation induced by SMS 201-995. These findings suggest that CHEMICAL specifically suppresses the barrel rotation evoked by SMS 201-995 in a long-lasting manner possibly acting through GENE. | REGULATOR |
| Barrel rotation in rats induced by SMS 201-995: suppression by ceruletide. Intracerebroventricular administration of SMS 201-995 (5 micrograms/rat), a somatostatin analogue, induced barrel rotation in rats. Pretreatment with ceruletide (40 micrograms/100 g b. wt., IP) 3 days or 7 days prior to the injection of SMS 201-995 significantly inhibited the response rate of barrel rotation induced by SMS 201-995, but not that induced by arginine-vasopressin (1 microgram/rat, ICV). The suppressive effect of ceruletide on barrel rotation could be partially countered by CHEMICAL, a selective peripheral GENE (CCK-A) receptor antagonist. Desulfated cerulein did not affect the barrel rotation induced by SMS 201-995. These findings suggest that ceruletide specifically suppresses the barrel rotation evoked by SMS 201-995 in a long-lasting manner possibly acting through CCK-A receptor. | INHIBITOR |
| Barrel rotation in rats induced by SMS 201-995: suppression by ceruletide. Intracerebroventricular administration of SMS 201-995 (5 micrograms/rat), a somatostatin analogue, induced barrel rotation in rats. Pretreatment with ceruletide (40 micrograms/100 g b. wt., IP) 3 days or 7 days prior to the injection of SMS 201-995 significantly inhibited the response rate of barrel rotation induced by SMS 201-995, but not that induced by arginine-vasopressin (1 microgram/rat, ICV). The suppressive effect of ceruletide on barrel rotation could be partially countered by CHEMICAL, a selective peripheral CCK GENE antagonist. Desulfated cerulein did not affect the barrel rotation induced by SMS 201-995. These findings suggest that ceruletide specifically suppresses the barrel rotation evoked by SMS 201-995 in a long-lasting manner possibly acting through CCK-A receptor. | INHIBITOR |
| Effects of the histamine H1 antagonist CHEMICAL on rat fetal palate development. BACKGROUND: The effects of histamine H1 antagonist CHEMICAL on rat palate development were characterized following in utero exposure. METHODS: To identify the optimum dose for inducing cleft palate, pregnant rats were administered 30, 60, or 90 mg/kg CHEMICAL on Gestation Days 11 to 14. Fetal palate gene expression was also assessed after 90 mg/kg CHEMICAL at 8, 15 and 30 hours post-dose on Gestation Day 14 using microarray and qRT-PCR. RESULTS: Rats in the 60- and 90-mg/kg groups exhibited adverse clinical signs and body weight loss. Rats in the 90-mg/kg group also demonstrated increases in late resorptions and decreases in fetal weight. Effects in the low-dose group were limited to decreases in body weight gain. Fetal assessment on Gestation Day 21 revealed that findings were limited to the 60- and 90-mg/kg groups, and included cleft palate (80% of litters for both groups), high arched palate, small nose, micrognathia, high domed head, digits shortened/absent and small limb. The fetal incidence of cleft palate was higher at 90 mg/kg, thus this dose was selected to assess palate gene expression. The altered genes associated with CHEMICAL-induced cleft palate included Wnt5a, GENE, Bmp4, Fgf10, Fgfr2, Msx1, and Insig1 but the magnitude of the change was relatively small (1.5- to 2-fold). CONCLUSIONS: Expression of several genes involved in palate, limb and digit development was altered in the fetal palate following in utero exposure to CHEMICAL. The subtle perturbation and interplay of these genes may have profound effects on the dynamics of fetal palate development. | REGULATOR |
| Effects of the histamine H1 antagonist CHEMICAL on rat fetal palate development. BACKGROUND: The effects of histamine H1 antagonist CHEMICAL on rat palate development were characterized following in utero exposure. METHODS: To identify the optimum dose for inducing cleft palate, pregnant rats were administered 30, 60, or 90 mg/kg CHEMICAL on Gestation Days 11 to 14. Fetal palate gene expression was also assessed after 90 mg/kg CHEMICAL at 8, 15 and 30 hours post-dose on Gestation Day 14 using microarray and qRT-PCR. RESULTS: Rats in the 60- and 90-mg/kg groups exhibited adverse clinical signs and body weight loss. Rats in the 90-mg/kg group also demonstrated increases in late resorptions and decreases in fetal weight. Effects in the low-dose group were limited to decreases in body weight gain. Fetal assessment on Gestation Day 21 revealed that findings were limited to the 60- and 90-mg/kg groups, and included cleft palate (80% of litters for both groups), high arched palate, small nose, micrognathia, high domed head, digits shortened/absent and small limb. The fetal incidence of cleft palate was higher at 90 mg/kg, thus this dose was selected to assess palate gene expression. The altered genes associated with CHEMICAL-induced cleft palate included Wnt5a, Bmp2, GENE, Fgf10, Fgfr2, Msx1, and Insig1 but the magnitude of the change was relatively small (1.5- to 2-fold). CONCLUSIONS: Expression of several genes involved in palate, limb and digit development was altered in the fetal palate following in utero exposure to CHEMICAL. The subtle perturbation and interplay of these genes may have profound effects on the dynamics of fetal palate development. | REGULATOR |
| Effects of the histamine H1 antagonist CHEMICAL on rat fetal palate development. BACKGROUND: The effects of histamine H1 antagonist CHEMICAL on rat palate development were characterized following in utero exposure. METHODS: To identify the optimum dose for inducing cleft palate, pregnant rats were administered 30, 60, or 90 mg/kg CHEMICAL on Gestation Days 11 to 14. Fetal palate gene expression was also assessed after 90 mg/kg CHEMICAL at 8, 15 and 30 hours post-dose on Gestation Day 14 using microarray and qRT-PCR. RESULTS: Rats in the 60- and 90-mg/kg groups exhibited adverse clinical signs and body weight loss. Rats in the 90-mg/kg group also demonstrated increases in late resorptions and decreases in fetal weight. Effects in the low-dose group were limited to decreases in body weight gain. Fetal assessment on Gestation Day 21 revealed that findings were limited to the 60- and 90-mg/kg groups, and included cleft palate (80% of litters for both groups), high arched palate, small nose, micrognathia, high domed head, digits shortened/absent and small limb. The fetal incidence of cleft palate was higher at 90 mg/kg, thus this dose was selected to assess palate gene expression. The altered genes associated with CHEMICAL-induced cleft palate included Wnt5a, Bmp2, Bmp4, GENE, Fgfr2, Msx1, and Insig1 but the magnitude of the change was relatively small (1.5- to 2-fold). CONCLUSIONS: Expression of several genes involved in palate, limb and digit development was altered in the fetal palate following in utero exposure to CHEMICAL. The subtle perturbation and interplay of these genes may have profound effects on the dynamics of fetal palate development. | REGULATOR |
| Effects of the histamine H1 antagonist CHEMICAL on rat fetal palate development. BACKGROUND: The effects of histamine H1 antagonist CHEMICAL on rat palate development were characterized following in utero exposure. METHODS: To identify the optimum dose for inducing cleft palate, pregnant rats were administered 30, 60, or 90 mg/kg CHEMICAL on Gestation Days 11 to 14. Fetal palate gene expression was also assessed after 90 mg/kg CHEMICAL at 8, 15 and 30 hours post-dose on Gestation Day 14 using microarray and qRT-PCR. RESULTS: Rats in the 60- and 90-mg/kg groups exhibited adverse clinical signs and body weight loss. Rats in the 90-mg/kg group also demonstrated increases in late resorptions and decreases in fetal weight. Effects in the low-dose group were limited to decreases in body weight gain. Fetal assessment on Gestation Day 21 revealed that findings were limited to the 60- and 90-mg/kg groups, and included cleft palate (80% of litters for both groups), high arched palate, small nose, micrognathia, high domed head, digits shortened/absent and small limb. The fetal incidence of cleft palate was higher at 90 mg/kg, thus this dose was selected to assess palate gene expression. The altered genes associated with CHEMICAL-induced cleft palate included Wnt5a, Bmp2, Bmp4, Fgf10, GENE, Msx1, and Insig1 but the magnitude of the change was relatively small (1.5- to 2-fold). CONCLUSIONS: Expression of several genes involved in palate, limb and digit development was altered in the fetal palate following in utero exposure to CHEMICAL. The subtle perturbation and interplay of these genes may have profound effects on the dynamics of fetal palate development. | REGULATOR |
| Effects of the histamine H1 antagonist CHEMICAL on rat fetal palate development. BACKGROUND: The effects of histamine H1 antagonist CHEMICAL on rat palate development were characterized following in utero exposure. METHODS: To identify the optimum dose for inducing cleft palate, pregnant rats were administered 30, 60, or 90 mg/kg CHEMICAL on Gestation Days 11 to 14. Fetal palate gene expression was also assessed after 90 mg/kg CHEMICAL at 8, 15 and 30 hours post-dose on Gestation Day 14 using microarray and qRT-PCR. RESULTS: Rats in the 60- and 90-mg/kg groups exhibited adverse clinical signs and body weight loss. Rats in the 90-mg/kg group also demonstrated increases in late resorptions and decreases in fetal weight. Effects in the low-dose group were limited to decreases in body weight gain. Fetal assessment on Gestation Day 21 revealed that findings were limited to the 60- and 90-mg/kg groups, and included cleft palate (80% of litters for both groups), high arched palate, small nose, micrognathia, high domed head, digits shortened/absent and small limb. The fetal incidence of cleft palate was higher at 90 mg/kg, thus this dose was selected to assess palate gene expression. The altered genes associated with CHEMICAL-induced cleft palate included Wnt5a, Bmp2, Bmp4, Fgf10, Fgfr2, GENE, and Insig1 but the magnitude of the change was relatively small (1.5- to 2-fold). CONCLUSIONS: Expression of several genes involved in palate, limb and digit development was altered in the fetal palate following in utero exposure to CHEMICAL. The subtle perturbation and interplay of these genes may have profound effects on the dynamics of fetal palate development. | REGULATOR |
| Effects of the histamine H1 antagonist CHEMICAL on rat fetal palate development. BACKGROUND: The effects of histamine H1 antagonist CHEMICAL on rat palate development were characterized following in utero exposure. METHODS: To identify the optimum dose for inducing cleft palate, pregnant rats were administered 30, 60, or 90 mg/kg CHEMICAL on Gestation Days 11 to 14. Fetal palate gene expression was also assessed after 90 mg/kg CHEMICAL at 8, 15 and 30 hours post-dose on Gestation Day 14 using microarray and qRT-PCR. RESULTS: Rats in the 60- and 90-mg/kg groups exhibited adverse clinical signs and body weight loss. Rats in the 90-mg/kg group also demonstrated increases in late resorptions and decreases in fetal weight. Effects in the low-dose group were limited to decreases in body weight gain. Fetal assessment on Gestation Day 21 revealed that findings were limited to the 60- and 90-mg/kg groups, and included cleft palate (80% of litters for both groups), high arched palate, small nose, micrognathia, high domed head, digits shortened/absent and small limb. The fetal incidence of cleft palate was higher at 90 mg/kg, thus this dose was selected to assess palate gene expression. The altered genes associated with CHEMICAL-induced cleft palate included Wnt5a, Bmp2, Bmp4, Fgf10, Fgfr2, Msx1, and GENE but the magnitude of the change was relatively small (1.5- to 2-fold). CONCLUSIONS: Expression of several genes involved in palate, limb and digit development was altered in the fetal palate following in utero exposure to CHEMICAL. The subtle perturbation and interplay of these genes may have profound effects on the dynamics of fetal palate development. | INDIRECT-UPREGULATOR |
| Effects of the histamine H1 antagonist CHEMICAL on rat fetal palate development. BACKGROUND: The effects of histamine H1 antagonist CHEMICAL on rat palate development were characterized following in utero exposure. METHODS: To identify the optimum dose for inducing cleft palate, pregnant rats were administered 30, 60, or 90 mg/kg CHEMICAL on Gestation Days 11 to 14. Fetal palate gene expression was also assessed after 90 mg/kg CHEMICAL at 8, 15 and 30 hours post-dose on Gestation Day 14 using microarray and qRT-PCR. RESULTS: Rats in the 60- and 90-mg/kg groups exhibited adverse clinical signs and body weight loss. Rats in the 90-mg/kg group also demonstrated increases in late resorptions and decreases in fetal weight. Effects in the low-dose group were limited to decreases in body weight gain. Fetal assessment on Gestation Day 21 revealed that findings were limited to the 60- and 90-mg/kg groups, and included cleft palate (80% of litters for both groups), high arched palate, small nose, micrognathia, high domed head, digits shortened/absent and small limb. The fetal incidence of cleft palate was higher at 90 mg/kg, thus this dose was selected to assess palate gene expression. The altered genes associated with CHEMICAL-induced cleft palate included GENE, Bmp2, Bmp4, Fgf10, Fgfr2, Msx1, and Insig1 but the magnitude of the change was relatively small (1.5- to 2-fold). CONCLUSIONS: Expression of several genes involved in palate, limb and digit development was altered in the fetal palate following in utero exposure to CHEMICAL. The subtle perturbation and interplay of these genes may have profound effects on the dynamics of fetal palate development. | REGULATOR |
| Effects of the GENE antagonist CHEMICAL on rat fetal palate development. BACKGROUND: The effects of GENE antagonist CHEMICAL on rat palate development were characterized following in utero exposure. METHODS: To identify the optimum dose for inducing cleft palate, pregnant rats were administered 30, 60, or 90 mg/kg CHEMICAL on Gestation Days 11 to 14. Fetal palate gene expression was also assessed after 90 mg/kg CHEMICAL at 8, 15 and 30 hours post-dose on Gestation Day 14 using microarray and qRT-PCR. RESULTS: Rats in the 60- and 90-mg/kg groups exhibited adverse clinical signs and body weight loss. Rats in the 90-mg/kg group also demonstrated increases in late resorptions and decreases in fetal weight. Effects in the low-dose group were limited to decreases in body weight gain. Fetal assessment on Gestation Day 21 revealed that findings were limited to the 60- and 90-mg/kg groups, and included cleft palate (80% of litters for both groups), high arched palate, small nose, micrognathia, high domed head, digits shortened/absent and small limb. The fetal incidence of cleft palate was higher at 90 mg/kg, thus this dose was selected to assess palate gene expression. The altered genes associated with chlorcyclizine-induced cleft palate included Wnt5a, Bmp2, Bmp4, Fgf10, Fgfr2, Msx1, and Insig1 but the magnitude of the change was relatively small (1.5- to 2-fold). CONCLUSIONS: Expression of several genes involved in palate, limb and digit development was altered in the fetal palate following in utero exposure to CHEMICAL. The subtle perturbation and interplay of these genes may have profound effects on the dynamics of fetal palate development. | INHIBITOR |
| GABA(A) receptors as molecular targets of general anesthetics: identification of binding sites provides clues to allosteric modulation. PURPOSE: The purpose of this review is to summarize current knowledge of detailed biochemical evidence for the role of gamma-aminobutyric acid type A receptors (GABA(A)-Rs) in the mechanisms of general anesthesia. PRINCIPAL FINDINGS: With the knowledge that all general anesthetics positively modulate GABA(A)-R-mediated inhibitory transmission, site-directed mutagenesis comparing sequences of GABA(A)-R subunits of varying sensitivity led to identification of amino acid residues in the transmembrane domain that are critical for the drug actions in vitro. Using a photo incorporable analogue of the general anesthetic, R(+)etomidate, we identified two transmembrane CHEMICAL that were affinity labelled in purified GENE. Homology protein structural modelling positions these two residues, alphaM1-11' and betaM3-4', close to each other in a single type of intersubunit etomidate binding pocket at the beta/alpha interface. This position would be appropriate for modulation of agonist channel gating. Overall, available information suggests that these two etomidate binding residues are allosterically coupled to sites of action of steroids, barbiturates, volatile agents, and propofol, but not alcohols. Residue alpha/betaM2-15' is probably not a binding site but allosterically coupled to action of volatile agents, alcohols, and intravenous agents, and alpha/betaM1-(-2') is coupled to action of intravenous agents. CONCLUSIONS: Establishment of a coherent and consistent structural model of the GABA(A)-R lends support to the conclusion that general anesthetics can modulate function by binding to appropriate domains on the protein. Genetic engineering of mice with mutation in some of these GABA(A)-R residues are insensitive to general anesthetics in vivo, suggesting that further analysis of these domains could lead to development of more potent and specific drugs. | DIRECT-REGULATOR |
| GABA(A) receptors as molecular targets of general anesthetics: identification of binding sites provides clues to allosteric modulation. PURPOSE: The purpose of this review is to summarize current knowledge of detailed biochemical evidence for the role of gamma-aminobutyric acid type A receptors (GABA(A)-Rs) in the mechanisms of general anesthesia. PRINCIPAL FINDINGS: With the knowledge that all general anesthetics positively modulate GENE-mediated inhibitory transmission, site-directed mutagenesis comparing sequences of GENE subunits of varying sensitivity led to identification of CHEMICAL residues in the transmembrane domain that are critical for the drug actions in vitro. Using a photo incorporable analogue of the general anesthetic, R(+)etomidate, we identified two transmembrane amino acids that were affinity labelled in purified bovine brain GENE. Homology protein structural modelling positions these two residues, alphaM1-11' and betaM3-4', close to each other in a single type of intersubunit etomidate binding pocket at the beta/alpha interface. This position would be appropriate for modulation of agonist channel gating. Overall, available information suggests that these two etomidate binding residues are allosterically coupled to sites of action of steroids, barbiturates, volatile agents, and propofol, but not alcohols. Residue alpha/betaM2-15' is probably not a binding site but allosterically coupled to action of volatile agents, alcohols, and intravenous agents, and alpha/betaM1-(-2') is coupled to action of intravenous agents. CONCLUSIONS: Establishment of a coherent and consistent structural model of the GENE lends support to the conclusion that general anesthetics can modulate function by binding to appropriate domains on the protein. Genetic engineering of mice with mutation in some of these GENE residues are insensitive to general anesthetics in vivo, suggesting that further analysis of these domains could lead to development of more potent and specific drugs. | PART-OF |
| GABA(A) receptors as molecular targets of general anesthetics: identification of binding sites provides clues to allosteric modulation. PURPOSE: The purpose of this review is to summarize current knowledge of detailed biochemical evidence for the role of gamma-aminobutyric acid type A receptors (GABA(A)-Rs) in the mechanisms of general anesthesia. PRINCIPAL FINDINGS: With the knowledge that all general anesthetics positively modulate GABA(A)-R-mediated inhibitory transmission, site-directed mutagenesis comparing sequences of GABA(A)-R subunits of varying sensitivity led to identification of amino acid residues in the transmembrane domain that are critical for the drug actions in vitro. Using a photo incorporable analogue of the general anesthetic, CHEMICAL, we identified two transmembrane amino acids that were affinity labelled in purified GENE. Homology protein structural modelling positions these two residues, alphaM1-11' and betaM3-4', close to each other in a single type of intersubunit etomidate binding pocket at the beta/alpha interface. This position would be appropriate for modulation of agonist channel gating. Overall, available information suggests that these two etomidate binding residues are allosterically coupled to sites of action of steroids, barbiturates, volatile agents, and propofol, but not alcohols. Residue alpha/betaM2-15' is probably not a binding site but allosterically coupled to action of volatile agents, alcohols, and intravenous agents, and alpha/betaM1-(-2') is coupled to action of intravenous agents. CONCLUSIONS: Establishment of a coherent and consistent structural model of the GABA(A)-R lends support to the conclusion that general anesthetics can modulate function by binding to appropriate domains on the protein. Genetic engineering of mice with mutation in some of these GABA(A)-R residues are insensitive to general anesthetics in vivo, suggesting that further analysis of these domains could lead to development of more potent and specific drugs. | DIRECT-REGULATOR |
| Role of extracellular calcium and GENE in prolactin secretion induced by hyposmolarity, thyrotropin-releasing hormone, and high K+ in GH4C1 cells. The mechanism by which 30% medium hyposmolarity induces PRL secretion by GH4C1 cells was compared with that induced by 100 nmol/l TRH or 30 mmol/l K+. Removing medium Ca2+, blocking Ca2+ channels with 50 mumol/l verapamil, or inhibiting GENE activation with 20 mumol/l trifluoperazine, 10 mumol/l chlorpromazine or 10 mumol/l pimozide almost completely blocked hyposmolarity-induced secretion. The smooth muscle relaxant, W-7, which is believed relatively specific in inhibiting the CHEMICAL-GENE interaction, depressed hyposmolarity-induced PRL secretion in a dose-dependent manner (r = -0.991, p less than 0.01). The above drugs also blocked or decreased high K(+)-induced secretion, but had much less effect on TRH-induced secretion. Secretion induced by TRH, hyposmolarity, or high K+ was optimal at pH 7.3-7.65 and was significantly depressed at pH 6.0 or 8.0, indicating that release of hormone induced by all 3 stimuli is due to an active cell process requiring a physiologic extracellular pH and is not produced by nonspecific cell toxicity. The data suggest hyposmolarity and high K+ may share some similarities in their mechanism of stimulating secretion, which is different from that of TRH. | DIRECT-REGULATOR |
| Role of extracellular calcium and GENE in prolactin secretion induced by hyposmolarity, thyrotropin-releasing hormone, and high K+ in GH4C1 cells. The mechanism by which 30% medium hyposmolarity induces PRL secretion by GH4C1 cells was compared with that induced by 100 nmol/l TRH or 30 mmol/l K+. Removing medium Ca2+, blocking Ca2+ channels with 50 mumol/l verapamil, or inhibiting GENE activation with 20 mumol/l trifluoperazine, 10 mumol/l chlorpromazine or 10 mumol/l pimozide almost completely blocked hyposmolarity-induced secretion. The smooth muscle relaxant, CHEMICAL, which is believed relatively specific in inhibiting the Ca2(+)-GENE interaction, depressed hyposmolarity-induced PRL secretion in a dose-dependent manner (r = -0.991, p less than 0.01). The above drugs also blocked or decreased high K(+)-induced secretion, but had much less effect on TRH-induced secretion. Secretion induced by TRH, hyposmolarity, or high K+ was optimal at pH 7.3-7.65 and was significantly depressed at pH 6.0 or 8.0, indicating that release of hormone induced by all 3 stimuli is due to an active cell process requiring a physiologic extracellular pH and is not produced by nonspecific cell toxicity. The data suggest hyposmolarity and high K+ may share some similarities in their mechanism of stimulating secretion, which is different from that of TRH. | INHIBITOR |
| Role of extracellular CHEMICAL and calmodulin in GENE secretion induced by hyposmolarity, thyrotropin-releasing hormone, and high K+ in GH4C1 cells. The mechanism by which 30% medium hyposmolarity induces PRL secretion by GH4C1 cells was compared with that induced by 100 nmol/l TRH or 30 mmol/l K+. Removing medium Ca2+, blocking Ca2+ channels with 50 mumol/l verapamil, or inhibiting calmodulin activation with 20 mumol/l trifluoperazine, 10 mumol/l chlorpromazine or 10 mumol/l pimozide almost completely blocked hyposmolarity-induced secretion. The smooth muscle relaxant, W-7, which is believed relatively specific in inhibiting the Ca2(+)-calmodulin interaction, depressed hyposmolarity-induced PRL secretion in a dose-dependent manner (r = -0.991, p less than 0.01). The above drugs also blocked or decreased high K(+)-induced secretion, but had much less effect on TRH-induced secretion. Secretion induced by TRH, hyposmolarity, or high K+ was optimal at pH 7.3-7.65 and was significantly depressed at pH 6.0 or 8.0, indicating that release of hormone induced by all 3 stimuli is due to an active cell process requiring a physiologic extracellular pH and is not produced by nonspecific cell toxicity. The data suggest hyposmolarity and high K+ may share some similarities in their mechanism of stimulating secretion, which is different from that of TRH. | GENE-CHEMICAL |
| Role of extracellular calcium and calmodulin in prolactin secretion induced by hyposmolarity, thyrotropin-releasing hormone, and high K+ in GH4C1 cells. The mechanism by which 30% medium hyposmolarity induces GENE secretion by GH4C1 cells was compared with that induced by 100 nmol/l TRH or 30 mmol/l K+. Removing medium Ca2+, blocking Ca2+ channels with 50 mumol/l verapamil, or inhibiting calmodulin activation with 20 mumol/l trifluoperazine, 10 mumol/l chlorpromazine or 10 mumol/l pimozide almost completely blocked hyposmolarity-induced secretion. The smooth muscle relaxant, CHEMICAL, which is believed relatively specific in inhibiting the Ca2(+)-calmodulin interaction, depressed hyposmolarity-induced GENE secretion in a dose-dependent manner (r = -0.991, p less than 0.01). The above drugs also blocked or decreased high K(+)-induced secretion, but had much less effect on TRH-induced secretion. Secretion induced by TRH, hyposmolarity, or high K+ was optimal at pH 7.3-7.65 and was significantly depressed at pH 6.0 or 8.0, indicating that release of hormone induced by all 3 stimuli is due to an active cell process requiring a physiologic extracellular pH and is not produced by nonspecific cell toxicity. The data suggest hyposmolarity and high K+ may share some similarities in their mechanism of stimulating secretion, which is different from that of TRH. | INDIRECT-DOWNREGULATOR |
| Role of extracellular calcium and calmodulin in prolactin secretion induced by hyposmolarity, thyrotropin-releasing hormone, and high K+ in GH4C1 cells. The mechanism by which 30% medium hyposmolarity induces PRL secretion by GH4C1 cells was compared with that induced by 100 nmol/l TRH or 30 mmol/l K+. Removing medium Ca2+, blocking GENE with 50 mumol/l CHEMICAL, or inhibiting calmodulin activation with 20 mumol/l trifluoperazine, 10 mumol/l chlorpromazine or 10 mumol/l pimozide almost completely blocked hyposmolarity-induced secretion. The smooth muscle relaxant, W-7, which is believed relatively specific in inhibiting the Ca2(+)-calmodulin interaction, depressed hyposmolarity-induced PRL secretion in a dose-dependent manner (r = -0.991, p less than 0.01). The above drugs also blocked or decreased high K(+)-induced secretion, but had much less effect on TRH-induced secretion. Secretion induced by TRH, hyposmolarity, or high K+ was optimal at pH 7.3-7.65 and was significantly depressed at pH 6.0 or 8.0, indicating that release of hormone induced by all 3 stimuli is due to an active cell process requiring a physiologic extracellular pH and is not produced by nonspecific cell toxicity. The data suggest hyposmolarity and high K+ may share some similarities in their mechanism of stimulating secretion, which is different from that of TRH. | INHIBITOR |
| Role of extracellular calcium and GENE in prolactin secretion induced by hyposmolarity, thyrotropin-releasing hormone, and high K+ in GH4C1 cells. The mechanism by which 30% medium hyposmolarity induces PRL secretion by GH4C1 cells was compared with that induced by 100 nmol/l TRH or 30 mmol/l K+. Removing medium Ca2+, blocking Ca2+ channels with 50 mumol/l verapamil, or inhibiting GENE activation with 20 mumol/l CHEMICAL, 10 mumol/l chlorpromazine or 10 mumol/l pimozide almost completely blocked hyposmolarity-induced secretion. The smooth muscle relaxant, W-7, which is believed relatively specific in inhibiting the Ca2(+)-calmodulin interaction, depressed hyposmolarity-induced PRL secretion in a dose-dependent manner (r = -0.991, p less than 0.01). The above drugs also blocked or decreased high K(+)-induced secretion, but had much less effect on TRH-induced secretion. Secretion induced by TRH, hyposmolarity, or high K+ was optimal at pH 7.3-7.65 and was significantly depressed at pH 6.0 or 8.0, indicating that release of hormone induced by all 3 stimuli is due to an active cell process requiring a physiologic extracellular pH and is not produced by nonspecific cell toxicity. The data suggest hyposmolarity and high K+ may share some similarities in their mechanism of stimulating secretion, which is different from that of TRH. | ACTIVATOR |
| Role of extracellular calcium and GENE in prolactin secretion induced by hyposmolarity, thyrotropin-releasing hormone, and high K+ in GH4C1 cells. The mechanism by which 30% medium hyposmolarity induces PRL secretion by GH4C1 cells was compared with that induced by 100 nmol/l TRH or 30 mmol/l K+. Removing medium Ca2+, blocking Ca2+ channels with 50 mumol/l verapamil, or inhibiting GENE activation with 20 mumol/l trifluoperazine, 10 mumol/l CHEMICAL or 10 mumol/l pimozide almost completely blocked hyposmolarity-induced secretion. The smooth muscle relaxant, W-7, which is believed relatively specific in inhibiting the Ca2(+)-calmodulin interaction, depressed hyposmolarity-induced PRL secretion in a dose-dependent manner (r = -0.991, p less than 0.01). The above drugs also blocked or decreased high K(+)-induced secretion, but had much less effect on TRH-induced secretion. Secretion induced by TRH, hyposmolarity, or high K+ was optimal at pH 7.3-7.65 and was significantly depressed at pH 6.0 or 8.0, indicating that release of hormone induced by all 3 stimuli is due to an active cell process requiring a physiologic extracellular pH and is not produced by nonspecific cell toxicity. The data suggest hyposmolarity and high K+ may share some similarities in their mechanism of stimulating secretion, which is different from that of TRH. | INHIBITOR |
| Role of extracellular calcium and GENE in prolactin secretion induced by hyposmolarity, thyrotropin-releasing hormone, and high K+ in GH4C1 cells. The mechanism by which 30% medium hyposmolarity induces PRL secretion by GH4C1 cells was compared with that induced by 100 nmol/l TRH or 30 mmol/l K+. Removing medium Ca2+, blocking Ca2+ channels with 50 mumol/l verapamil, or inhibiting GENE activation with 20 mumol/l trifluoperazine, 10 mumol/l chlorpromazine or 10 mumol/l CHEMICAL almost completely blocked hyposmolarity-induced secretion. The smooth muscle relaxant, W-7, which is believed relatively specific in inhibiting the Ca2(+)-calmodulin interaction, depressed hyposmolarity-induced PRL secretion in a dose-dependent manner (r = -0.991, p less than 0.01). The above drugs also blocked or decreased high K(+)-induced secretion, but had much less effect on TRH-induced secretion. Secretion induced by TRH, hyposmolarity, or high K+ was optimal at pH 7.3-7.65 and was significantly depressed at pH 6.0 or 8.0, indicating that release of hormone induced by all 3 stimuli is due to an active cell process requiring a physiologic extracellular pH and is not produced by nonspecific cell toxicity. The data suggest hyposmolarity and high K+ may share some similarities in their mechanism of stimulating secretion, which is different from that of TRH. | INHIBITOR |
| Use of (Gyro) Gy and CHEMICAL synthase transgenic mice to study functions of CHEMICAL. The polyamines putrescine, spermidine, and CHEMICAL are essential for mammalian cell growth, -differentiation, and cell death and have important physiological roles in all tissues. Many of the properties of polyamines that can be demonstrated in vitro are common to all three molecules with differences only in potency. Loss of any of the enzymes needed to make either putrescine or spermidine (which also -prevent the production of spermine) is lethal, but male mice lacking CHEMICAL synthase (SpmS) due to a deletion of part of the X chromosome are viable on the B6C3H background. These mice are termed Gyro (Gy) due to their circling behavior. They have a variety of abnormalities including deafness, neurological problems, small size, and a tendency to early death. They can therefore be used to evaluate the physiological function(s) uniquely provided by CHEMICAL. They also provide a potential animal model for Snyder-Robinson syndrome (SRS), a rare human inherited disease due to a loss of SpmS activity. An essential control in experiments using Gy mice is to demonstrate that the abnormal phenotypes exhibited by these mice are abolished by providing replacement CHEMICAL and this can be accomplished by breeding with CAG-GENE mice that express SpmS from a ubiquitous promoter. Techniques for identifying, characterizing, and using these mouse strains and limitations of this approach are described in this chapter. | PRODUCT-OF |
| Use of (Gyro) Gy and CHEMICAL synthase transgenic mice to study functions of CHEMICAL. The polyamines putrescine, spermidine, and CHEMICAL are essential for mammalian cell growth, -differentiation, and cell death and have important physiological roles in all tissues. Many of the properties of polyamines that can be demonstrated in vitro are common to all three molecules with differences only in potency. Loss of any of the enzymes needed to make either putrescine or spermidine (which also -prevent the production of spermine) is lethal, but male mice lacking CHEMICAL synthase (SpmS) due to a deletion of part of the X chromosome are viable on the B6C3H background. These mice are termed Gyro (Gy) due to their circling behavior. They have a variety of abnormalities including deafness, neurological problems, small size, and a tendency to early death. They can therefore be used to evaluate the physiological function(s) uniquely provided by CHEMICAL. They also provide a potential animal model for Snyder-Robinson syndrome (SRS), a rare human inherited disease due to a loss of GENE activity. An essential control in experiments using Gy mice is to demonstrate that the abnormal phenotypes exhibited by these mice are abolished by providing replacement CHEMICAL and this can be accomplished by breeding with CAG-SMS mice that express GENE from a ubiquitous promoter. Techniques for identifying, characterizing, and using these mouse strains and limitations of this approach are described in this chapter. | PRODUCT-OF |
| CHEMICAL (XL184), a novel GENE and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase GENE and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. CHEMICAL (XL184) is a small-molecule kinase inhibitor with potent activity toward GENE and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with CHEMICAL inhibited GENE and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, CHEMICAL dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with CHEMICAL did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target GENE. Collectively, these data suggest that CHEMICAL is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated GENE and VEGFR signaling. | GENE-CHEMICAL |
| CHEMICAL (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of GENE, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. CHEMICAL (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and GENE receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with CHEMICAL inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, CHEMICAL dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with CHEMICAL did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of GENE signaling that do not target MET. Collectively, these data suggest that CHEMICAL is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | INHIBITOR |
| CHEMICAL (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. CHEMICAL (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with CHEMICAL inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, CHEMICAL dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with CHEMICAL did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that CHEMICAL is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and GENE signaling. | GENE-CHEMICAL |
| CHEMICAL (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine GENE MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. CHEMICAL (XL184) is a small-molecule GENE inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | INHIBITOR |
| CHEMICAL (XL184), a novel GENE and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase GENE and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. CHEMICAL (XL184) is a small-molecule kinase inhibitor with potent activity toward GENE and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited GENE and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target GENE. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated GENE and VEGFR signaling. | INHIBITOR |
| CHEMICAL (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. CHEMICAL (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and GENE (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | INHIBITOR |
| CHEMICAL (XL184), a novel MET and GENE inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. CHEMICAL (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (GENE), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and GENE phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | INHIBITOR |
| CHEMICAL (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. CHEMICAL (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other GENE that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | REGULATOR |
| CHEMICAL (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. CHEMICAL (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including GENE, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | REGULATOR |
| CHEMICAL (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. CHEMICAL (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, GENE, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | REGULATOR |
| CHEMICAL (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. CHEMICAL (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, GENE, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | REGULATOR |
| CHEMICAL (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. CHEMICAL (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and GENE. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | REGULATOR |
| Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine GENE MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (CHEMICAL) is a small-molecule GENE inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | INHIBITOR |
| Cabozantinib (XL184), a novel GENE and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase GENE and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (CHEMICAL) is a small-molecule kinase inhibitor with potent activity toward GENE and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited GENE and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target GENE. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated GENE and VEGFR signaling. | INHIBITOR |
| Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (CHEMICAL) is a small-molecule kinase inhibitor with potent activity toward MET and GENE (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | INHIBITOR |
| Cabozantinib (XL184), a novel MET and GENE inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (CHEMICAL) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (GENE), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and GENE phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | INHIBITOR |
| Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (CHEMICAL) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other GENE that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | INHIBITOR |
| Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (CHEMICAL) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including GENE, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | INHIBITOR |
| Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (CHEMICAL) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, GENE, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | INHIBITOR |
| Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (CHEMICAL) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, GENE, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | INHIBITOR |
| Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (CHEMICAL) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and GENE. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | INHIBITOR |
| CHEMICAL (XL184), a novel MET and GENE inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. CHEMICAL (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with CHEMICAL inhibited MET and GENE phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, CHEMICAL dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with CHEMICAL did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that CHEMICAL is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling. | INHIBITOR |
| CHEMICAL suppresses osteoclastogenesis induced by GENE and cancer cells through inhibition of inflammatory pathways: a new use for an old drug. BACKGROUND AND PURPOSE: Most patients with cancer die not because of the tumour in the primary site, but because it has spread to other sites. Common tumours, such as breast, multiple myeloma, and prostate tumours, frequently metastasize to the bone. To search for an inhibitor of cancer-induced bone loss, we investigated the effect of thiocolchicoside, a semi-synthetic colchicoside derived from the plant Gloriosa superba and clinically used as a muscle relaxant, on osteoclastogenesis induced by receptor activator of NF-kappaB ligand (RANKL) and tumour cells. EXPERIMENTAL APPROACH: We used RAW 264.7 (murine macrophage) cells, a well-established system for osteoclastogenesis, and evaluated the effect of thiocolchicoside on RANKL-induced NF-kappaB signalling and osteoclastogenesis as well as on osteoclastogenesis induced by tumour cells. KEY RESULTS: CHEMICAL suppressed osteoclastogenesis induced by GENE, and by breast cancer and multiple myeloma cells. Inhibition of the NF-kappaB pathway was responsible for this effect since the colchicoside inhibited RANKL-induced NF-kappaB activation, activation of IkappaB kinase (IKK) and suppressed inhibitor of NF-kappaBalpha (IkappaBalpha) phosphorylation and degradation, an inhibitor of NF-kappaB. Furthermore, an inhibitor of the IkappaBalpha kinase gamma or NF-kappaB essential modulator, the regulatory component of the IKK complex, demonstrated that the NF-kappaB signalling pathway is mandatory for osteoclastogenesis induced by GENE. CONCLUSIONS AND IMPLICATIONS: Together, these data suggest that thiocolchicoside significantly suppressed osteoclastogenesis induced by GENE and tumour cells via the NF-kappaB signalling pathway. Thus, thiocolchicoside, a drug that has been used for almost half a century to treat muscle pain, may also be considered as a new treatment for bone loss. | INDIRECT-DOWNREGULATOR |
| Thiocolchicoside suppresses osteoclastogenesis induced by RANKL and cancer cells through inhibition of inflammatory pathways: a new use for an old drug. BACKGROUND AND PURPOSE: Most patients with cancer die not because of the tumour in the primary site, but because it has spread to other sites. Common tumours, such as breast, multiple myeloma, and prostate tumours, frequently metastasize to the bone. To search for an inhibitor of cancer-induced bone loss, we investigated the effect of thiocolchicoside, a semi-synthetic CHEMICAL derived from the plant Gloriosa superba and clinically used as a muscle relaxant, on osteoclastogenesis induced by receptor activator of GENE ligand (RANKL) and tumour cells. EXPERIMENTAL APPROACH: We used RAW 264.7 (murine macrophage) cells, a well-established system for osteoclastogenesis, and evaluated the effect of thiocolchicoside on RANKL-induced GENE signalling and osteoclastogenesis as well as on osteoclastogenesis induced by tumour cells. KEY RESULTS: Thiocolchicoside suppressed osteoclastogenesis induced by RANKL, and by breast cancer and multiple myeloma cells. Inhibition of the GENE pathway was responsible for this effect since the CHEMICAL inhibited RANKL-induced GENE activation, activation of IkappaB kinase (IKK) and suppressed inhibitor of NF-kappaBalpha (IkappaBalpha) phosphorylation and degradation, an inhibitor of GENE. Furthermore, an inhibitor of the IkappaBalpha kinase gamma or GENE essential modulator, the regulatory component of the IKK complex, demonstrated that the GENE signalling pathway is mandatory for osteoclastogenesis induced by RANKL. CONCLUSIONS AND IMPLICATIONS: Together, these data suggest that thiocolchicoside significantly suppressed osteoclastogenesis induced by RANKL and tumour cells via the GENE signalling pathway. Thus, thiocolchicoside, a drug that has been used for almost half a century to treat muscle pain, may also be considered as a new treatment for bone loss. | INHIBITOR |
| Thiocolchicoside suppresses osteoclastogenesis induced by RANKL and cancer cells through inhibition of inflammatory pathways: a new use for an old drug. BACKGROUND AND PURPOSE: Most patients with cancer die not because of the tumour in the primary site, but because it has spread to other sites. Common tumours, such as breast, multiple myeloma, and prostate tumours, frequently metastasize to the bone. To search for an inhibitor of cancer-induced bone loss, we investigated the effect of thiocolchicoside, a semi-synthetic CHEMICAL derived from the plant Gloriosa superba and clinically used as a muscle relaxant, on osteoclastogenesis induced by receptor activator of NF-kappaB ligand (RANKL) and tumour cells. EXPERIMENTAL APPROACH: We used RAW 264.7 (murine macrophage) cells, a well-established system for osteoclastogenesis, and evaluated the effect of thiocolchicoside on RANKL-induced NF-kappaB signalling and osteoclastogenesis as well as on osteoclastogenesis induced by tumour cells. KEY RESULTS: Thiocolchicoside suppressed osteoclastogenesis induced by RANKL, and by breast cancer and multiple myeloma cells. Inhibition of the NF-kappaB pathway was responsible for this effect since the CHEMICAL inhibited RANKL-induced NF-kappaB activation, activation of GENE (IKK) and suppressed inhibitor of NF-kappaBalpha (IkappaBalpha) phosphorylation and degradation, an inhibitor of NF-kappaB. Furthermore, an inhibitor of the IkappaBalpha kinase gamma or NF-kappaB essential modulator, the regulatory component of the IKK complex, demonstrated that the NF-kappaB signalling pathway is mandatory for osteoclastogenesis induced by RANKL. CONCLUSIONS AND IMPLICATIONS: Together, these data suggest that thiocolchicoside significantly suppressed osteoclastogenesis induced by RANKL and tumour cells via the NF-kappaB signalling pathway. Thus, thiocolchicoside, a drug that has been used for almost half a century to treat muscle pain, may also be considered as a new treatment for bone loss. | ACTIVATOR |
| Thiocolchicoside suppresses osteoclastogenesis induced by RANKL and cancer cells through inhibition of inflammatory pathways: a new use for an old drug. BACKGROUND AND PURPOSE: Most patients with cancer die not because of the tumour in the primary site, but because it has spread to other sites. Common tumours, such as breast, multiple myeloma, and prostate tumours, frequently metastasize to the bone. To search for an inhibitor of cancer-induced bone loss, we investigated the effect of thiocolchicoside, a semi-synthetic CHEMICAL derived from the plant Gloriosa superba and clinically used as a muscle relaxant, on osteoclastogenesis induced by receptor activator of NF-kappaB ligand (RANKL) and tumour cells. EXPERIMENTAL APPROACH: We used RAW 264.7 (murine macrophage) cells, a well-established system for osteoclastogenesis, and evaluated the effect of thiocolchicoside on RANKL-induced NF-kappaB signalling and osteoclastogenesis as well as on osteoclastogenesis induced by tumour cells. KEY RESULTS: Thiocolchicoside suppressed osteoclastogenesis induced by RANKL, and by breast cancer and multiple myeloma cells. Inhibition of the NF-kappaB pathway was responsible for this effect since the CHEMICAL inhibited RANKL-induced NF-kappaB activation, activation of IkappaB kinase (GENE) and suppressed inhibitor of NF-kappaBalpha (IkappaBalpha) phosphorylation and degradation, an inhibitor of NF-kappaB. Furthermore, an inhibitor of the IkappaBalpha kinase gamma or NF-kappaB essential modulator, the regulatory component of the GENE complex, demonstrated that the NF-kappaB signalling pathway is mandatory for osteoclastogenesis induced by RANKL. CONCLUSIONS AND IMPLICATIONS: Together, these data suggest that thiocolchicoside significantly suppressed osteoclastogenesis induced by RANKL and tumour cells via the NF-kappaB signalling pathway. Thus, thiocolchicoside, a drug that has been used for almost half a century to treat muscle pain, may also be considered as a new treatment for bone loss. | INHIBITOR |
| Thiocolchicoside suppresses osteoclastogenesis induced by RANKL and cancer cells through inhibition of inflammatory pathways: a new use for an old drug. BACKGROUND AND PURPOSE: Most patients with cancer die not because of the tumour in the primary site, but because it has spread to other sites. Common tumours, such as breast, multiple myeloma, and prostate tumours, frequently metastasize to the bone. To search for an inhibitor of cancer-induced bone loss, we investigated the effect of thiocolchicoside, a semi-synthetic CHEMICAL derived from the plant Gloriosa superba and clinically used as a muscle relaxant, on osteoclastogenesis induced by receptor activator of NF-kappaB ligand (RANKL) and tumour cells. EXPERIMENTAL APPROACH: We used RAW 264.7 (murine macrophage) cells, a well-established system for osteoclastogenesis, and evaluated the effect of thiocolchicoside on RANKL-induced NF-kappaB signalling and osteoclastogenesis as well as on osteoclastogenesis induced by tumour cells. KEY RESULTS: Thiocolchicoside suppressed osteoclastogenesis induced by RANKL, and by breast cancer and multiple myeloma cells. Inhibition of the NF-kappaB pathway was responsible for this effect since the CHEMICAL inhibited RANKL-induced NF-kappaB activation, activation of IkappaB kinase (IKK) and suppressed inhibitor of GENE (IkappaBalpha) phosphorylation and degradation, an inhibitor of NF-kappaB. Furthermore, an inhibitor of the IkappaBalpha kinase gamma or NF-kappaB essential modulator, the regulatory component of the IKK complex, demonstrated that the NF-kappaB signalling pathway is mandatory for osteoclastogenesis induced by RANKL. CONCLUSIONS AND IMPLICATIONS: Together, these data suggest that thiocolchicoside significantly suppressed osteoclastogenesis induced by RANKL and tumour cells via the NF-kappaB signalling pathway. Thus, thiocolchicoside, a drug that has been used for almost half a century to treat muscle pain, may also be considered as a new treatment for bone loss. | INHIBITOR |
| Thiocolchicoside suppresses osteoclastogenesis induced by RANKL and cancer cells through inhibition of inflammatory pathways: a new use for an old drug. BACKGROUND AND PURPOSE: Most patients with cancer die not because of the tumour in the primary site, but because it has spread to other sites. Common tumours, such as breast, multiple myeloma, and prostate tumours, frequently metastasize to the bone. To search for an inhibitor of cancer-induced bone loss, we investigated the effect of thiocolchicoside, a semi-synthetic CHEMICAL derived from the plant Gloriosa superba and clinically used as a muscle relaxant, on osteoclastogenesis induced by receptor activator of NF-kappaB ligand (RANKL) and tumour cells. EXPERIMENTAL APPROACH: We used RAW 264.7 (murine macrophage) cells, a well-established system for osteoclastogenesis, and evaluated the effect of thiocolchicoside on RANKL-induced NF-kappaB signalling and osteoclastogenesis as well as on osteoclastogenesis induced by tumour cells. KEY RESULTS: Thiocolchicoside suppressed osteoclastogenesis induced by RANKL, and by breast cancer and multiple myeloma cells. Inhibition of the NF-kappaB pathway was responsible for this effect since the CHEMICAL inhibited RANKL-induced NF-kappaB activation, activation of IkappaB kinase (IKK) and suppressed inhibitor of NF-kappaBalpha (GENE) phosphorylation and degradation, an inhibitor of NF-kappaB. Furthermore, an inhibitor of the GENE kinase gamma or NF-kappaB essential modulator, the regulatory component of the IKK complex, demonstrated that the NF-kappaB signalling pathway is mandatory for osteoclastogenesis induced by RANKL. CONCLUSIONS AND IMPLICATIONS: Together, these data suggest that thiocolchicoside significantly suppressed osteoclastogenesis induced by RANKL and tumour cells via the NF-kappaB signalling pathway. Thus, thiocolchicoside, a drug that has been used for almost half a century to treat muscle pain, may also be considered as a new treatment for bone loss. | INHIBITOR |
| Thiocolchicoside suppresses osteoclastogenesis induced by GENE and cancer cells through inhibition of inflammatory pathways: a new use for an old drug. BACKGROUND AND PURPOSE: Most patients with cancer die not because of the tumour in the primary site, but because it has spread to other sites. Common tumours, such as breast, multiple myeloma, and prostate tumours, frequently metastasize to the bone. To search for an inhibitor of cancer-induced bone loss, we investigated the effect of thiocolchicoside, a semi-synthetic CHEMICAL derived from the plant Gloriosa superba and clinically used as a muscle relaxant, on osteoclastogenesis induced by receptor activator of NF-kappaB ligand (RANKL) and tumour cells. EXPERIMENTAL APPROACH: We used RAW 264.7 (murine macrophage) cells, a well-established system for osteoclastogenesis, and evaluated the effect of thiocolchicoside on RANKL-induced NF-kappaB signalling and osteoclastogenesis as well as on osteoclastogenesis induced by tumour cells. KEY RESULTS: Thiocolchicoside suppressed osteoclastogenesis induced by GENE, and by breast cancer and multiple myeloma cells. Inhibition of the NF-kappaB pathway was responsible for this effect since the CHEMICAL inhibited GENE-induced NF-kappaB activation, activation of IkappaB kinase (IKK) and suppressed inhibitor of NF-kappaBalpha (IkappaBalpha) phosphorylation and degradation, an inhibitor of NF-kappaB. Furthermore, an inhibitor of the IkappaBalpha kinase gamma or NF-kappaB essential modulator, the regulatory component of the IKK complex, demonstrated that the NF-kappaB signalling pathway is mandatory for osteoclastogenesis induced by GENE. CONCLUSIONS AND IMPLICATIONS: Together, these data suggest that thiocolchicoside significantly suppressed osteoclastogenesis induced by GENE and tumour cells via the NF-kappaB signalling pathway. Thus, thiocolchicoside, a drug that has been used for almost half a century to treat muscle pain, may also be considered as a new treatment for bone loss. | INHIBITOR |
| CHEMICAL suppresses osteoclastogenesis induced by RANKL and cancer cells through inhibition of inflammatory pathways: a new use for an old drug. BACKGROUND AND PURPOSE: Most patients with cancer die not because of the tumour in the primary site, but because it has spread to other sites. Common tumours, such as breast, multiple myeloma, and prostate tumours, frequently metastasize to the bone. To search for an inhibitor of cancer-induced bone loss, we investigated the effect of CHEMICAL, a semi-synthetic colchicoside derived from the plant Gloriosa superba and clinically used as a muscle relaxant, on osteoclastogenesis induced by receptor activator of GENE ligand (RANKL) and tumour cells. EXPERIMENTAL APPROACH: We used RAW 264.7 (murine macrophage) cells, a well-established system for osteoclastogenesis, and evaluated the effect of CHEMICAL on RANKL-induced GENE signalling and osteoclastogenesis as well as on osteoclastogenesis induced by tumour cells. KEY RESULTS: CHEMICAL suppressed osteoclastogenesis induced by RANKL, and by breast cancer and multiple myeloma cells. Inhibition of the GENE pathway was responsible for this effect since the colchicoside inhibited RANKL-induced GENE activation, activation of IkappaB kinase (IKK) and suppressed inhibitor of NF-kappaBalpha (IkappaBalpha) phosphorylation and degradation, an inhibitor of GENE. Furthermore, an inhibitor of the IkappaBalpha kinase gamma or GENE essential modulator, the regulatory component of the IKK complex, demonstrated that the GENE signalling pathway is mandatory for osteoclastogenesis induced by RANKL. CONCLUSIONS AND IMPLICATIONS: Together, these data suggest that CHEMICAL significantly suppressed osteoclastogenesis induced by RANKL and tumour cells via the GENE signalling pathway. Thus, CHEMICAL, a drug that has been used for almost half a century to treat muscle pain, may also be considered as a new treatment for bone loss. | REGULATOR |
| Endothelial nitric oxide synthase genotypes and haplotypes modify the responses to CHEMICAL in patients with erectile dysfunction. Erectile dysfunction (ED) is usually treated with CHEMICAL. Although genetic polymorphisms in the endothelial nitric oxide synthase (eNOS) gene may impair endogenous NO formation, there is little information about how GENE polymorphisms and haplotypes affect the responses to CHEMICAL. We studied 118 patients; 63 patients had ED secondary to radical prostatectomy (PED) and 55 had organic, clinical ED. GENE genotypes for three GENE polymorphisms (T(-786)C, rs2070744; a variable number of tandem repeats (VNTR) in intron 4; and Glu298Asp, rs1799983) were determined, and GENE haplotypes were estimated using PHASE 2.1. The clinical responses to CHEMICAL were evaluated and the patients were classified as good responders (GR) or poor responders (PR) when their changes in five-item version of International Index for Erectile Function questionnaire were above or below the median value. The TC/CC genotypes and the C allele for the T(-786)C polymorphism were more common in GR, compared with PR patients with PED. However, the 4b4a/4a4a genotypes and the 4a allele for the VNTR polymorphism in intron 4 were more common in GR, compared with PR patients with clinical ED. The C-4a-Glu haplotype was more common in GR than in PR patients with PED. Conversely, the T-4b-Asp haplotype was less common in GR than in PR patients with PED. No other significant differences were found. Our findings show evidence that GENE polymorphisms affect the responses of PED and clinical ED patients to CHEMICAL. | GENE-CHEMICAL |
| GENE genotypes and haplotypes modify the responses to CHEMICAL in patients with erectile dysfunction. Erectile dysfunction (ED) is usually treated with CHEMICAL. Although genetic polymorphisms in the endothelial nitric oxide synthase (eNOS) gene may impair endogenous NO formation, there is little information about how eNOS polymorphisms and haplotypes affect the responses to CHEMICAL. We studied 118 patients; 63 patients had ED secondary to radical prostatectomy (PED) and 55 had organic, clinical ED. eNOS genotypes for three eNOS polymorphisms (T(-786)C, rs2070744; a variable number of tandem repeats (VNTR) in intron 4; and Glu298Asp, rs1799983) were determined, and eNOS haplotypes were estimated using PHASE 2.1. The clinical responses to CHEMICAL were evaluated and the patients were classified as good responders (GR) or poor responders (PR) when their changes in five-item version of International Index for Erectile Function questionnaire were above or below the median value. The TC/CC genotypes and the C allele for the T(-786)C polymorphism were more common in GR, compared with PR patients with PED. However, the 4b4a/4a4a genotypes and the 4a allele for the VNTR polymorphism in intron 4 were more common in GR, compared with PR patients with clinical ED. The C-4a-Glu haplotype was more common in GR than in PR patients with PED. Conversely, the T-4b-Asp haplotype was less common in GR than in PR patients with PED. No other significant differences were found. Our findings show evidence that eNOS polymorphisms affect the responses of PED and clinical ED patients to CHEMICAL. | GENE-CHEMICAL |
| Endothelial nitric oxide synthase genotypes and haplotypes modify the responses to sildenafil in patients with erectile dysfunction. Erectile dysfunction (ED) is usually treated with sildenafil. Although genetic polymorphisms in the endothelial nitric oxide synthase (GENE) gene may impair endogenous CHEMICAL formation, there is little information about how GENE polymorphisms and haplotypes affect the responses to sildenafil. We studied 118 patients; 63 patients had ED secondary to radical prostatectomy (PED) and 55 had organic, clinical ED. GENE genotypes for three GENE polymorphisms (T(-786)C, rs2070744; a variable number of tandem repeats (VNTR) in intron 4; and Glu298Asp, rs1799983) were determined, and GENE haplotypes were estimated using PHASE 2.1. The clinical responses to sildenafil were evaluated and the patients were classified as good responders (GR) or poor responders (PR) when their changes in five-item version of International Index for Erectile Function questionnaire were above or below the median value. The TC/CC genotypes and the C allele for the T(-786)C polymorphism were more common in GR, compared with PR patients with PED. However, the 4b4a/4a4a genotypes and the 4a allele for the VNTR polymorphism in intron 4 were more common in GR, compared with PR patients with clinical ED. The C-4a-Glu haplotype was more common in GR than in PR patients with PED. Conversely, the T-4b-Asp haplotype was less common in GR than in PR patients with PED. CHEMICAL other significant differences were found. Our findings show evidence that GENE polymorphisms affect the responses of PED and clinical ED patients to sildenafil. | PRODUCT-OF |
| GENE genotypes and haplotypes modify the responses to sildenafil in patients with erectile dysfunction. Erectile dysfunction (ED) is usually treated with sildenafil. Although genetic polymorphisms in the GENE (eNOS) gene may impair endogenous CHEMICAL formation, there is little information about how eNOS polymorphisms and haplotypes affect the responses to sildenafil. We studied 118 patients; 63 patients had ED secondary to radical prostatectomy (PED) and 55 had organic, clinical ED. eNOS genotypes for three eNOS polymorphisms (T(-786)C, rs2070744; a variable number of tandem repeats (VNTR) in intron 4; and Glu298Asp, rs1799983) were determined, and eNOS haplotypes were estimated using PHASE 2.1. The clinical responses to sildenafil were evaluated and the patients were classified as good responders (GR) or poor responders (PR) when their changes in five-item version of International Index for Erectile Function questionnaire were above or below the median value. The TC/CC genotypes and the C allele for the T(-786)C polymorphism were more common in GR, compared with PR patients with PED. However, the 4b4a/4a4a genotypes and the 4a allele for the VNTR polymorphism in intron 4 were more common in GR, compared with PR patients with clinical ED. The C-4a-Glu haplotype was more common in GR than in PR patients with PED. Conversely, the T-4b-Asp haplotype was less common in GR than in PR patients with PED. CHEMICAL other significant differences were found. Our findings show evidence that eNOS polymorphisms affect the responses of PED and clinical ED patients to sildenafil. | PRODUCT-OF |
| CHEMICAL induces the expression of cyclooxygenase-2 and inducible nitric oxide synthase. Nuclear factor-κB (NF-κB) is a transcription factor that mediates the inducible expression of a variety of genes involved in immune and inflammatory responses. GENE activation induces numerous proinflammatory gene products including cytokines, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). The divalent heavy metal CHEMICAL has been used for thousands of years. Although CHEMICAL is clearly toxic to most mammalian organ systems, especially the immune system, exposure has still increased in some areas of the world. However, the underlying toxic mechanism is not clearly identified. Here, we report biochemical evidence that CHEMICAL alone induces GENE activation, resulting in the induced expression of COX-2 and iNOS. The results suggest that CHEMICAL can induce inflammatory diseases by lowering host defense. | ACTIVATOR |
| CHEMICAL induces the expression of cyclooxygenase-2 and inducible nitric oxide synthase. Nuclear factor-κB (NF-κB) is a transcription factor that mediates the inducible expression of a variety of genes involved in immune and inflammatory responses. NF-κB activation induces numerous proinflammatory gene products including cytokines, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). The divalent heavy metal CHEMICAL has been used for thousands of years. Although CHEMICAL is clearly toxic to most mammalian organ systems, especially the immune system, exposure has still increased in some areas of the world. However, the underlying toxic mechanism is not clearly identified. Here, we report biochemical evidence that CHEMICAL alone induces NF-κB activation, resulting in the induced expression of GENE and iNOS. The results suggest that CHEMICAL can induce inflammatory diseases by lowering host defense. | INDIRECT-UPREGULATOR |
| CHEMICAL induces the expression of cyclooxygenase-2 and inducible nitric oxide synthase. Nuclear factor-κB (NF-κB) is a transcription factor that mediates the inducible expression of a variety of genes involved in immune and inflammatory responses. NF-κB activation induces numerous proinflammatory gene products including cytokines, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). The divalent heavy metal CHEMICAL has been used for thousands of years. Although CHEMICAL is clearly toxic to most mammalian organ systems, especially the immune system, exposure has still increased in some areas of the world. However, the underlying toxic mechanism is not clearly identified. Here, we report biochemical evidence that CHEMICAL alone induces NF-κB activation, resulting in the induced expression of COX-2 and GENE. The results suggest that CHEMICAL can induce inflammatory diseases by lowering host defense. | INDIRECT-UPREGULATOR |
| CHEMICAL induces the expression of GENE and inducible nitric oxide synthase. Nuclear factor-κB (NF-κB) is a transcription factor that mediates the inducible expression of a variety of genes involved in immune and inflammatory responses. NF-κB activation induces numerous proinflammatory gene products including cytokines, GENE (COX-2), and inducible nitric oxide synthase (iNOS). The divalent heavy metal mercury has been used for thousands of years. Although mercury is clearly toxic to most mammalian organ systems, especially the immune system, exposure has still increased in some areas of the world. However, the underlying toxic mechanism is not clearly identified. Here, we report biochemical evidence that mercury alone induces NF-κB activation, resulting in the induced expression of COX-2 and iNOS. The results suggest that mercury can induce inflammatory diseases by lowering host defense. | INDIRECT-UPREGULATOR |
| CHEMICAL induces the expression of cyclooxygenase-2 and GENE. Nuclear factor-κB (NF-κB) is a transcription factor that mediates the inducible expression of a variety of genes involved in immune and inflammatory responses. NF-κB activation induces numerous proinflammatory gene products including cytokines, cyclooxygenase-2 (COX-2), and GENE (iNOS). The divalent heavy metal mercury has been used for thousands of years. Although mercury is clearly toxic to most mammalian organ systems, especially the immune system, exposure has still increased in some areas of the world. However, the underlying toxic mechanism is not clearly identified. Here, we report biochemical evidence that mercury alone induces NF-κB activation, resulting in the induced expression of COX-2 and iNOS. The results suggest that mercury can induce inflammatory diseases by lowering host defense. | INDIRECT-UPREGULATOR |
| Pharmacological evidence of functional inhibitory metabotrophic glutamate receptors on mouse arousal-related cholinergic laterodorsal tegmental neurons. Cholinergic neurons of the pontine laterodorsal tegmentum (LDT) are importantly involved in neurobiological mechanisms governing states of arousal such as sleep and wakefulness as well as other appetitive behaviors, such as drug-seeking. Accordingly, mechanisms controlling their excitability are important to elucidate if we are to understand how these LDT neurons generate arousal states. Glutamate mediates the vast majority of excitatory synaptic transmission in the vertebrate CNS and while presence of glutamate input in the LDT has been shown and ionotropic responses to glutamate have been reported in the LDT, characterization of metabotropic responses is lacking. Therefore, electrophysiological responses and changes in levels of intracellular Ca(2+) in mouse cholinergic LDT neurons following application of specific mGluR agonists and antagonists were examined. Unexpectedly, both the GENEspecific agonist, CHEMICAL, and the group II mGluR (mGlu(2/3)) agonist, LY379268 (LY), induced a TTX-insensitive outward current/hyperpolarization. Both outward currents were significantly reduced by the mGluR antagonist MCPG and the CHPG-induced current was blocked by the specific GENE antagonist MTEP. Concurrent Ca(2+)imaging revealed that while CHEMICAL actions did include release of Ca(2+) from CPA/thapsigargin-sensitive intracellular stores, actions of LY did not. Both CHPG- and LY-induced outward currents were mediated by a TEA-sensitive potassium conductance. The large-conductance, Ca(2+)-dependent potassium (BK) channel blocker, iberiotoxin, attenuated CHEMICAL actions. Consistent with actions on the BK conductance, CHEMICAL enhanced the amplitude of the fast component of the after hyperpolarizing potential, concurrent with a reduction in the firing rate. We conclude that stimulation of GENE and group II (mGluR(2/3)) elicits postsynaptically-mediated outward currents/hyperpolarizations in cholinergic LDT neurons. Effects of glutamatergic input would be, thus, expected not only to be excitation via stimulation of ionotropic glutamate receptors and mGluR(1), but also inhibition via actions at GENE and mGluR(2/3) on these neurons. As these two processes counteract each other, these surprising findings necessitate revision of predictions regarding the net level of excitation generated by glutamate input to cholinergic LDT cells and, by extension, the functional outcome of glutamate transmission on processes which these neurons regulate. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. | ACTIVATOR |
| Pharmacological evidence of functional inhibitory metabotrophic glutamate receptors on mouse arousal-related cholinergic laterodorsal tegmental neurons. Cholinergic neurons of the pontine laterodorsal tegmentum (LDT) are importantly involved in neurobiological mechanisms governing states of arousal such as sleep and wakefulness as well as other appetitive behaviors, such as drug-seeking. Accordingly, mechanisms controlling their excitability are important to elucidate if we are to understand how these LDT neurons generate arousal states. Glutamate mediates the vast majority of excitatory synaptic transmission in the vertebrate CNS and while presence of glutamate input in the LDT has been shown and ionotropic responses to glutamate have been reported in the LDT, characterization of metabotropic responses is lacking. Therefore, electrophysiological responses and changes in levels of intracellular Ca(2+) in mouse cholinergic LDT neurons following application of specific mGluR agonists and antagonists were examined. Unexpectedly, both the mGluR(5)specific agonist, CHPG, and the GENE (mGlu(2/3)) agonist, CHEMICAL (LY), induced a TTX-insensitive outward current/hyperpolarization. Both outward currents were significantly reduced by the mGluR antagonist MCPG and the CHPG-induced current was blocked by the specific mGluR(5) antagonist MTEP. Concurrent Ca(2+)imaging revealed that while CHPG actions did include release of Ca(2+) from CPA/thapsigargin-sensitive intracellular stores, actions of LY did not. Both CHPG- and LY-induced outward currents were mediated by a TEA-sensitive potassium conductance. The large-conductance, Ca(2+)-dependent potassium (BK) channel blocker, iberiotoxin, attenuated CHPG actions. Consistent with actions on the BK conductance, CHPG enhanced the amplitude of the fast component of the after hyperpolarizing potential, concurrent with a reduction in the firing rate. We conclude that stimulation of mGluR(5) and group II (mGluR(2/3)) elicits postsynaptically-mediated outward currents/hyperpolarizations in cholinergic LDT neurons. Effects of glutamatergic input would be, thus, expected not only to be excitation via stimulation of ionotropic glutamate receptors and mGluR(1), but also inhibition via actions at mGluR(5) and mGluR(2/3) on these neurons. As these two processes counteract each other, these surprising findings necessitate revision of predictions regarding the net level of excitation generated by glutamate input to cholinergic LDT cells and, by extension, the functional outcome of glutamate transmission on processes which these neurons regulate. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. | ACTIVATOR |
| Pharmacological evidence of functional inhibitory metabotrophic glutamate receptors on mouse arousal-related cholinergic laterodorsal tegmental neurons. Cholinergic neurons of the pontine laterodorsal tegmentum (LDT) are importantly involved in neurobiological mechanisms governing states of arousal such as sleep and wakefulness as well as other appetitive behaviors, such as drug-seeking. Accordingly, mechanisms controlling their excitability are important to elucidate if we are to understand how these LDT neurons generate arousal states. Glutamate mediates the vast majority of excitatory synaptic transmission in the vertebrate CNS and while presence of glutamate input in the LDT has been shown and ionotropic responses to glutamate have been reported in the LDT, characterization of metabotropic responses is lacking. Therefore, electrophysiological responses and changes in levels of intracellular Ca(2+) in mouse cholinergic LDT neurons following application of specific GENE agonists and antagonists were examined. Unexpectedly, both the mGluR(5)specific agonist, CHPG, and the group II GENE (mGlu(2/3)) agonist, LY379268 (LY), induced a TTX-insensitive outward current/hyperpolarization. Both outward currents were significantly reduced by the GENE antagonist CHEMICAL and the CHPG-induced current was blocked by the specific mGluR(5) antagonist MTEP. Concurrent Ca(2+)imaging revealed that while CHPG actions did include release of Ca(2+) from CPA/thapsigargin-sensitive intracellular stores, actions of LY did not. Both CHPG- and LY-induced outward currents were mediated by a TEA-sensitive potassium conductance. The large-conductance, Ca(2+)-dependent potassium (BK) channel blocker, iberiotoxin, attenuated CHPG actions. Consistent with actions on the BK conductance, CHPG enhanced the amplitude of the fast component of the after hyperpolarizing potential, concurrent with a reduction in the firing rate. We conclude that stimulation of mGluR(5) and group II (mGluR(2/3)) elicits postsynaptically-mediated outward currents/hyperpolarizations in cholinergic LDT neurons. Effects of glutamatergic input would be, thus, expected not only to be excitation via stimulation of ionotropic glutamate receptors and mGluR(1), but also inhibition via actions at mGluR(5) and mGluR(2/3) on these neurons. As these two processes counteract each other, these surprising findings necessitate revision of predictions regarding the net level of excitation generated by glutamate input to cholinergic LDT cells and, by extension, the functional outcome of glutamate transmission on processes which these neurons regulate. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. | INHIBITOR |
| Pharmacological evidence of functional inhibitory metabotrophic glutamate receptors on mouse arousal-related cholinergic laterodorsal tegmental neurons. Cholinergic neurons of the pontine laterodorsal tegmentum (LDT) are importantly involved in neurobiological mechanisms governing states of arousal such as sleep and wakefulness as well as other appetitive behaviors, such as drug-seeking. Accordingly, mechanisms controlling their excitability are important to elucidate if we are to understand how these LDT neurons generate arousal states. Glutamate mediates the vast majority of excitatory synaptic transmission in the vertebrate CNS and while presence of glutamate input in the LDT has been shown and ionotropic responses to glutamate have been reported in the LDT, characterization of metabotropic responses is lacking. Therefore, electrophysiological responses and changes in levels of intracellular Ca(2+) in mouse cholinergic LDT neurons following application of specific mGluR agonists and antagonists were examined. Unexpectedly, both the mGluR(5)specific agonist, CHPG, and the group II mGluR (mGlu(2/3)) agonist, LY379268 (LY), induced a TTX-insensitive outward current/hyperpolarization. Both outward currents were significantly reduced by the mGluR antagonist MCPG and the CHPG-induced current was blocked by the specific GENE antagonist CHEMICAL. Concurrent Ca(2+)imaging revealed that while CHPG actions did include release of Ca(2+) from CPA/thapsigargin-sensitive intracellular stores, actions of LY did not. Both CHPG- and LY-induced outward currents were mediated by a TEA-sensitive potassium conductance. The large-conductance, Ca(2+)-dependent potassium (BK) channel blocker, iberiotoxin, attenuated CHPG actions. Consistent with actions on the BK conductance, CHPG enhanced the amplitude of the fast component of the after hyperpolarizing potential, concurrent with a reduction in the firing rate. We conclude that stimulation of GENE and group II (mGluR(2/3)) elicits postsynaptically-mediated outward currents/hyperpolarizations in cholinergic LDT neurons. Effects of glutamatergic input would be, thus, expected not only to be excitation via stimulation of ionotropic glutamate receptors and mGluR(1), but also inhibition via actions at GENE and mGluR(2/3) on these neurons. As these two processes counteract each other, these surprising findings necessitate revision of predictions regarding the net level of excitation generated by glutamate input to cholinergic LDT cells and, by extension, the functional outcome of glutamate transmission on processes which these neurons regulate. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. | INHIBITOR |
| A potent GENE inhibitor is selectively cytotoxic in melanomas with high levels of replicative stress. There are few effective treatments for metastatic melanoma. Checkpoint kinase 1 (Chk1) inhibitors are being trialled for their efficacy in enhancing conventional chemotherapeutic agents, but their effectiveness as single agents is not known. We have examined the effectiveness of two novel GENE selective inhibitors, CHEMICAL and AR678, in a panel of melanoma cell lines and normal cell types. We demonstrate that these drugs display single-agent activity, with IC50s in the low nanomolar range. The drugs produce cytotoxic effects in cell lines that are most sensitive to these drugs, whereas normal cells are only sensitive to these drugs at the higher concentrations where they have cytostatic activity. The cytotoxic effect is the consequence of inhibition of S-phase GENE, which drives cells prematurely from late S phase into an aberrant mitosis and results in either failure of cytokinesis or cell death through an apoptotic mechanism. The sensitivity to the GENE inhibitors was correlated with the level of endogenous DNA damage indicating replicative stress. GENE inhibitors are viable single-agent therapies that target melanoma cells with high levels of endogenous DNA damage. This sensitivity suggests that GENE is a critical component of an adaptation to replicative stress in these cells. It also suggests that markers of DNA damage may be useful in identifying the melanomas and potentially other tumour types that are more likely to be sensitive to GENE inhibitors as single agents. | INHIBITOR |
| A potent GENE inhibitor is selectively cytotoxic in melanomas with high levels of replicative stress. There are few effective treatments for metastatic melanoma. Checkpoint kinase 1 (Chk1) inhibitors are being trialled for their efficacy in enhancing conventional chemotherapeutic agents, but their effectiveness as single agents is not known. We have examined the effectiveness of two novel GENE selective inhibitors, AR323 and CHEMICAL, in a panel of melanoma cell lines and normal cell types. We demonstrate that these drugs display single-agent activity, with IC50s in the low nanomolar range. The drugs produce cytotoxic effects in cell lines that are most sensitive to these drugs, whereas normal cells are only sensitive to these drugs at the higher concentrations where they have cytostatic activity. The cytotoxic effect is the consequence of inhibition of S-phase GENE, which drives cells prematurely from late S phase into an aberrant mitosis and results in either failure of cytokinesis or cell death through an apoptotic mechanism. The sensitivity to the GENE inhibitors was correlated with the level of endogenous DNA damage indicating replicative stress. GENE inhibitors are viable single-agent therapies that target melanoma cells with high levels of endogenous DNA damage. This sensitivity suggests that GENE is a critical component of an adaptation to replicative stress in these cells. It also suggests that markers of DNA damage may be useful in identifying the melanomas and potentially other tumour types that are more likely to be sensitive to GENE inhibitors as single agents. | INHIBITOR |
| CHEMICAL inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. BACKGROUND & AIMS: CHEMICAL reduces the incidence of and mortality from colorectal cancer (CRC) by unknown mechanisms. Cancer cells have defects in signaling via the mechanistic target of rapamycin (mTOR), which regulates proliferation. We investigated whether CHEMICAL affects adenosine monophosphate-activated protein kinase (AMPK) and mTOR signaling in CRC cells. METHODS: The effects of CHEMICAL on mTOR signaling, the ribosomal protein S6, S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) were examined in CRC cells by immunoblotting. Phosphorylation of GENE was measured; the effects of loss of AMPKalpha on the aspirin-induced effects of mTOR were determined using small interfering RNA (siRNA) in CRC cells and in AMPK(alpha1/alpha2-/-) mouse embryonic fibroblasts. LC3 and ULK1 were used as markers of autophagy. We analyzed rectal mucosa samples from patients given 600 mg CHEMICAL, once daily for 1 week. RESULTS: CHEMICAL reduced mTOR signaling in CRC cells by inhibiting the mTOR effectors S6K1 and 4E-BP1. CHEMICAL changed nucleotide ratios and activated GENE in CRC cells. mTOR was still inhibited by CHEMICAL in CRC cells after siRNA knockdown of AMPKalpha, indicating AMPK-dependent and GENE-independent mechanisms of CHEMICAL-induced inhibition of mTOR. CHEMICAL induced autophagy, a feature of mTOR inhibition. CHEMICAL and metformin (an activator of AMPK) increased inhibition of mTOR and Akt, as well as autophagy in CRC cells. Rectal mucosal samples from patients given CHEMICAL had reduced phosphorylation of S6K1 and S6. CONCLUSIONS: CHEMICAL is an inhibitor of mTOR and an activator of GENE, targeting regulators of intracellular energy homeostasis and metabolism. These could contribute to its protective effects against development of CRC. | NO-RELATIONSHIP |
| Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. BACKGROUND & AIMS: Aspirin reduces the incidence of and mortality from colorectal cancer (CRC) by unknown mechanisms. Cancer cells have defects in signaling via the mechanistic target of rapamycin (mTOR), which regulates proliferation. We investigated whether aspirin affects adenosine monophosphate-activated protein kinase (AMPK) and mTOR signaling in CRC cells. METHODS: The effects of aspirin on mTOR signaling, the ribosomal protein S6, S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) were examined in CRC cells by immunoblotting. Phosphorylation of GENE was measured; the effects of loss of AMPKalpha on the aspirin-induced effects of mTOR were determined using small interfering RNA (siRNA) in CRC cells and in AMPK(alpha1/alpha2-/-) mouse embryonic fibroblasts. LC3 and ULK1 were used as markers of autophagy. We analyzed rectal mucosa samples from patients given 600 mg aspirin, once daily for 1 week. RESULTS: Aspirin reduced mTOR signaling in CRC cells by inhibiting the mTOR effectors S6K1 and 4E-BP1. Aspirin changed nucleotide ratios and activated GENE in CRC cells. mTOR was still inhibited by aspirin in CRC cells after siRNA knockdown of AMPKalpha, indicating AMPK-dependent and AMPK-independent mechanisms of aspirin-induced inhibition of mTOR. Aspirin induced autophagy, a feature of mTOR inhibition. Aspirin and CHEMICAL (an activator of GENE) increased inhibition of mTOR and Akt, as well as autophagy in CRC cells. Rectal mucosal samples from patients given aspirin had reduced phosphorylation of S6K1 and S6. CONCLUSIONS: Aspirin is an inhibitor of mTOR and an activator of GENE, targeting regulators of intracellular energy homeostasis and metabolism. These could contribute to its protective effects against development of CRC. | ACTIVATOR |
| CHEMICAL inhibits mTOR signaling, activates GENE, and induces autophagy in colorectal cancer cells. BACKGROUND & AIMS: CHEMICAL reduces the incidence of and mortality from colorectal cancer (CRC) by unknown mechanisms. Cancer cells have defects in signaling via the mechanistic target of rapamycin (mTOR), which regulates proliferation. We investigated whether aspirin affects adenosine monophosphate-activated protein kinase (AMPK) and mTOR signaling in CRC cells. METHODS: The effects of aspirin on mTOR signaling, the ribosomal protein S6, S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) were examined in CRC cells by immunoblotting. Phosphorylation of AMPK was measured; the effects of loss of AMPKalpha on the aspirin-induced effects of mTOR were determined using small interfering RNA (siRNA) in CRC cells and in AMPK(alpha1/alpha2-/-) mouse embryonic fibroblasts. LC3 and ULK1 were used as markers of autophagy. We analyzed rectal mucosa samples from patients given 600 mg aspirin, once daily for 1 week. RESULTS: CHEMICAL reduced mTOR signaling in CRC cells by inhibiting the mTOR effectors S6K1 and 4E-BP1. CHEMICAL changed nucleotide ratios and activated AMPK in CRC cells. mTOR was still inhibited by aspirin in CRC cells after siRNA knockdown of AMPKalpha, indicating AMPK-dependent and AMPK-independent mechanisms of aspirin-induced inhibition of mTOR. CHEMICAL induced autophagy, a feature of mTOR inhibition. CHEMICAL and metformin (an activator of AMPK) increased inhibition of mTOR and Akt, as well as autophagy in CRC cells. Rectal mucosal samples from patients given aspirin had reduced phosphorylation of S6K1 and S6. CONCLUSIONS: CHEMICAL is an inhibitor of mTOR and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism. These could contribute to its protective effects against development of CRC. | ACTIVATOR |
| CHEMICAL inhibits GENE signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. BACKGROUND & AIMS: CHEMICAL reduces the incidence of and mortality from colorectal cancer (CRC) by unknown mechanisms. Cancer cells have defects in signaling via the mechanistic target of rapamycin (mTOR), which regulates proliferation. We investigated whether aspirin affects adenosine monophosphate-activated protein kinase (AMPK) and GENE signaling in CRC cells. METHODS: The effects of aspirin on GENE signaling, the ribosomal protein S6, S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) were examined in CRC cells by immunoblotting. Phosphorylation of AMPK was measured; the effects of loss of AMPKalpha on the aspirin-induced effects of GENE were determined using small interfering RNA (siRNA) in CRC cells and in AMPK(alpha1/alpha2-/-) mouse embryonic fibroblasts. LC3 and ULK1 were used as markers of autophagy. We analyzed rectal mucosa samples from patients given 600 mg aspirin, once daily for 1 week. RESULTS: CHEMICAL reduced GENE signaling in CRC cells by inhibiting the GENE effectors S6K1 and 4E-BP1. CHEMICAL changed nucleotide ratios and activated AMPK in CRC cells. GENE was still inhibited by aspirin in CRC cells after siRNA knockdown of AMPKalpha, indicating AMPK-dependent and AMPK-independent mechanisms of aspirin-induced inhibition of GENE. CHEMICAL induced autophagy, a feature of GENE inhibition. CHEMICAL and metformin (an activator of AMPK) increased inhibition of GENE and Akt, as well as autophagy in CRC cells. Rectal mucosal samples from patients given aspirin had reduced phosphorylation of S6K1 and S6. CONCLUSIONS: CHEMICAL is an inhibitor of GENE and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism. These could contribute to its protective effects against development of CRC. | INHIBITOR |
| Aspirin inhibits GENE signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. BACKGROUND & AIMS: Aspirin reduces the incidence of and mortality from colorectal cancer (CRC) by unknown mechanisms. Cancer cells have defects in signaling via the mechanistic target of rapamycin (mTOR), which regulates proliferation. We investigated whether aspirin affects adenosine monophosphate-activated protein kinase (AMPK) and GENE signaling in CRC cells. METHODS: The effects of aspirin on GENE signaling, the ribosomal protein S6, S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) were examined in CRC cells by immunoblotting. Phosphorylation of AMPK was measured; the effects of loss of AMPKalpha on the aspirin-induced effects of GENE were determined using small interfering RNA (siRNA) in CRC cells and in AMPK(alpha1/alpha2-/-) mouse embryonic fibroblasts. LC3 and ULK1 were used as markers of autophagy. We analyzed rectal mucosa samples from patients given 600 mg aspirin, once daily for 1 week. RESULTS: Aspirin reduced GENE signaling in CRC cells by inhibiting the GENE effectors S6K1 and 4E-BP1. Aspirin changed nucleotide ratios and activated AMPK in CRC cells. GENE was still inhibited by aspirin in CRC cells after siRNA knockdown of AMPKalpha, indicating AMPK-dependent and AMPK-independent mechanisms of aspirin-induced inhibition of GENE. Aspirin induced autophagy, a feature of GENE inhibition. Aspirin and CHEMICAL (an activator of AMPK) increased inhibition of GENE and Akt, as well as autophagy in CRC cells. Rectal mucosal samples from patients given aspirin had reduced phosphorylation of S6K1 and S6. CONCLUSIONS: Aspirin is an inhibitor of GENE and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism. These could contribute to its protective effects against development of CRC. | INHIBITOR |
| Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. BACKGROUND & AIMS: Aspirin reduces the incidence of and mortality from colorectal cancer (CRC) by unknown mechanisms. Cancer cells have defects in signaling via the mechanistic target of rapamycin (mTOR), which regulates proliferation. We investigated whether aspirin affects adenosine monophosphate-activated protein kinase (AMPK) and mTOR signaling in CRC cells. METHODS: The effects of aspirin on mTOR signaling, the ribosomal protein S6, S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) were examined in CRC cells by immunoblotting. Phosphorylation of AMPK was measured; the effects of loss of AMPKalpha on the aspirin-induced effects of mTOR were determined using small interfering RNA (siRNA) in CRC cells and in AMPK(alpha1/alpha2-/-) mouse embryonic fibroblasts. LC3 and ULK1 were used as markers of autophagy. We analyzed rectal mucosa samples from patients given 600 mg aspirin, once daily for 1 week. RESULTS: Aspirin reduced mTOR signaling in CRC cells by inhibiting the mTOR effectors S6K1 and 4E-BP1. Aspirin changed nucleotide ratios and activated AMPK in CRC cells. mTOR was still inhibited by aspirin in CRC cells after siRNA knockdown of AMPKalpha, indicating AMPK-dependent and AMPK-independent mechanisms of aspirin-induced inhibition of mTOR. Aspirin induced autophagy, a feature of mTOR inhibition. Aspirin and CHEMICAL (an activator of AMPK) increased inhibition of mTOR and GENE, as well as autophagy in CRC cells. Rectal mucosal samples from patients given aspirin had reduced phosphorylation of S6K1 and S6. CONCLUSIONS: Aspirin is an inhibitor of mTOR and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism. These could contribute to its protective effects against development of CRC. | INHIBITOR |
| CHEMICAL inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. BACKGROUND & AIMS: CHEMICAL reduces the incidence of and mortality from colorectal cancer (CRC) by unknown mechanisms. Cancer cells have defects in signaling via the mechanistic target of rapamycin (mTOR), which regulates proliferation. We investigated whether CHEMICAL affects adenosine monophosphate-activated protein kinase (AMPK) and mTOR signaling in CRC cells. METHODS: The effects of CHEMICAL on mTOR signaling, the ribosomal protein S6, S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) were examined in CRC cells by immunoblotting. Phosphorylation of AMPK was measured; the effects of loss of AMPKalpha on the aspirin-induced effects of mTOR were determined using small interfering RNA (siRNA) in CRC cells and in AMPK(alpha1/alpha2-/-) mouse embryonic fibroblasts. LC3 and ULK1 were used as markers of autophagy. We analyzed rectal mucosa samples from patients given 600 mg CHEMICAL, once daily for 1 week. RESULTS: CHEMICAL reduced mTOR signaling in CRC cells by inhibiting the mTOR effectors GENE and 4E-BP1. CHEMICAL changed nucleotide ratios and activated AMPK in CRC cells. mTOR was still inhibited by CHEMICAL in CRC cells after siRNA knockdown of AMPKalpha, indicating AMPK-dependent and AMPK-independent mechanisms of aspirin-induced inhibition of mTOR. CHEMICAL induced autophagy, a feature of mTOR inhibition. CHEMICAL and metformin (an activator of AMPK) increased inhibition of mTOR and Akt, as well as autophagy in CRC cells. Rectal mucosal samples from patients given CHEMICAL had reduced phosphorylation of GENE and S6. CONCLUSIONS: CHEMICAL is an inhibitor of mTOR and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism. These could contribute to its protective effects against development of CRC. | INHIBITOR |
| CHEMICAL inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. BACKGROUND & AIMS: CHEMICAL reduces the incidence of and mortality from colorectal cancer (CRC) by unknown mechanisms. Cancer cells have defects in signaling via the mechanistic target of rapamycin (mTOR), which regulates proliferation. We investigated whether CHEMICAL affects adenosine monophosphate-activated protein kinase (AMPK) and mTOR signaling in CRC cells. METHODS: The effects of CHEMICAL on mTOR signaling, the ribosomal protein GENE, GENE kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) were examined in CRC cells by immunoblotting. Phosphorylation of AMPK was measured; the effects of loss of AMPKalpha on the aspirin-induced effects of mTOR were determined using small interfering RNA (siRNA) in CRC cells and in AMPK(alpha1/alpha2-/-) mouse embryonic fibroblasts. LC3 and ULK1 were used as markers of autophagy. We analyzed rectal mucosa samples from patients given 600 mg CHEMICAL, once daily for 1 week. RESULTS: CHEMICAL reduced mTOR signaling in CRC cells by inhibiting the mTOR effectors S6K1 and 4E-BP1. CHEMICAL changed nucleotide ratios and activated AMPK in CRC cells. mTOR was still inhibited by CHEMICAL in CRC cells after siRNA knockdown of AMPKalpha, indicating AMPK-dependent and AMPK-independent mechanisms of aspirin-induced inhibition of mTOR. CHEMICAL induced autophagy, a feature of mTOR inhibition. CHEMICAL and metformin (an activator of AMPK) increased inhibition of mTOR and Akt, as well as autophagy in CRC cells. Rectal mucosal samples from patients given CHEMICAL had reduced phosphorylation of S6K1 and GENE. CONCLUSIONS: CHEMICAL is an inhibitor of mTOR and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism. These could contribute to its protective effects against development of CRC. | INHIBITOR |
| CHEMICAL inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. BACKGROUND & AIMS: CHEMICAL reduces the incidence of and mortality from colorectal cancer (CRC) by unknown mechanisms. Cancer cells have defects in signaling via the mechanistic target of rapamycin (mTOR), which regulates proliferation. We investigated whether aspirin affects adenosine monophosphate-activated protein kinase (AMPK) and mTOR signaling in CRC cells. METHODS: The effects of aspirin on mTOR signaling, the ribosomal protein S6, S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) were examined in CRC cells by immunoblotting. Phosphorylation of AMPK was measured; the effects of loss of AMPKalpha on the aspirin-induced effects of mTOR were determined using small interfering RNA (siRNA) in CRC cells and in AMPK(alpha1/alpha2-/-) mouse embryonic fibroblasts. LC3 and ULK1 were used as markers of autophagy. We analyzed rectal mucosa samples from patients given 600 mg aspirin, once daily for 1 week. RESULTS: CHEMICAL reduced mTOR signaling in CRC cells by inhibiting the mTOR effectors GENE and 4E-BP1. CHEMICAL changed nucleotide ratios and activated AMPK in CRC cells. mTOR was still inhibited by aspirin in CRC cells after siRNA knockdown of AMPKalpha, indicating AMPK-dependent and AMPK-independent mechanisms of aspirin-induced inhibition of mTOR. CHEMICAL induced autophagy, a feature of mTOR inhibition. CHEMICAL and metformin (an activator of AMPK) increased inhibition of mTOR and Akt, as well as autophagy in CRC cells. Rectal mucosal samples from patients given aspirin had reduced phosphorylation of GENE and S6. CONCLUSIONS: CHEMICAL is an inhibitor of mTOR and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism. These could contribute to its protective effects against development of CRC. | INHIBITOR |
| CHEMICAL inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. BACKGROUND & AIMS: CHEMICAL reduces the incidence of and mortality from colorectal cancer (CRC) by unknown mechanisms. Cancer cells have defects in signaling via the mechanistic target of rapamycin (mTOR), which regulates proliferation. We investigated whether aspirin affects adenosine monophosphate-activated protein kinase (AMPK) and mTOR signaling in CRC cells. METHODS: The effects of aspirin on mTOR signaling, the ribosomal protein S6, S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) were examined in CRC cells by immunoblotting. Phosphorylation of AMPK was measured; the effects of loss of AMPKalpha on the aspirin-induced effects of mTOR were determined using small interfering RNA (siRNA) in CRC cells and in AMPK(alpha1/alpha2-/-) mouse embryonic fibroblasts. LC3 and ULK1 were used as markers of autophagy. We analyzed rectal mucosa samples from patients given 600 mg aspirin, once daily for 1 week. RESULTS: CHEMICAL reduced mTOR signaling in CRC cells by inhibiting the mTOR effectors S6K1 and GENE. CHEMICAL changed nucleotide ratios and activated AMPK in CRC cells. mTOR was still inhibited by aspirin in CRC cells after siRNA knockdown of AMPKalpha, indicating AMPK-dependent and AMPK-independent mechanisms of aspirin-induced inhibition of mTOR. CHEMICAL induced autophagy, a feature of mTOR inhibition. CHEMICAL and metformin (an activator of AMPK) increased inhibition of mTOR and Akt, as well as autophagy in CRC cells. Rectal mucosal samples from patients given aspirin had reduced phosphorylation of S6K1 and S6. CONCLUSIONS: CHEMICAL is an inhibitor of mTOR and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism. These could contribute to its protective effects against development of CRC. | INHIBITOR |
| CHEMICAL inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. BACKGROUND & AIMS: CHEMICAL reduces the incidence of and mortality from colorectal cancer (CRC) by unknown mechanisms. Cancer cells have defects in signaling via the mechanistic target of rapamycin (mTOR), which regulates proliferation. We investigated whether aspirin affects adenosine monophosphate-activated protein kinase (AMPK) and mTOR signaling in CRC cells. METHODS: The effects of aspirin on mTOR signaling, the ribosomal protein S6, S6 kinase 1 (S6K1), and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) were examined in CRC cells by immunoblotting. Phosphorylation of AMPK was measured; the effects of loss of AMPKalpha on the aspirin-induced effects of mTOR were determined using small interfering RNA (siRNA) in CRC cells and in AMPK(alpha1/alpha2-/-) mouse embryonic fibroblasts. LC3 and ULK1 were used as markers of autophagy. We analyzed rectal mucosa samples from patients given 600 mg aspirin, once daily for 1 week. RESULTS: CHEMICAL reduced mTOR signaling in CRC cells by inhibiting the mTOR effectors S6K1 and 4E-BP1. CHEMICAL changed nucleotide ratios and activated AMPK in CRC cells. mTOR was still inhibited by aspirin in CRC cells after siRNA knockdown of AMPKalpha, indicating AMPK-dependent and AMPK-independent mechanisms of aspirin-induced inhibition of mTOR. CHEMICAL induced autophagy, a feature of mTOR inhibition. CHEMICAL and metformin (an activator of AMPK) increased inhibition of mTOR and GENE, as well as autophagy in CRC cells. Rectal mucosal samples from patients given aspirin had reduced phosphorylation of S6K1 and S6. CONCLUSIONS: CHEMICAL is an inhibitor of mTOR and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism. These could contribute to its protective effects against development of CRC. | INHIBITOR |
| Oncogenic GENE expression is associated with derangement of the cAMP/PKA pathway and CHEMICAL-reversible alterations of mitochondrial dynamics and respiration. The Warburg effect in cancer cells has been proposed to involve several mechanisms, including adaptation to hypoxia, oncogenes activation or loss of oncosuppressors and impaired mitochondrial function. In previous papers, it has been shown that GENE transformed mouse cells are much more sensitive as compared with normal cells to glucose withdrawal (undergoing apoptosis) and present a high glycolytic rate and a strong reduction of mitochondrial complex I. Recent observations suggest that transformed cells have a derangement in the cyclic adenosine monophosphate/cAMP-dependent protein kinase (cAMP/PKA) pathway, which is known to regulate several mitochondrial functions. Herein, the derangement of the cAMP/PKA pathway and its impact on transformation-linked changes of mitochondrial functions is investigated. Exogenous stimulation of PKA activity, achieved by CHEMICAL treatment, protected K-ras-transformed cells from apoptosis induced by glucose deprivation, enhanced complex I activity, intracellular adenosine triphosphate (ATP) levels, mitochondrial fusion and decreased intracellular reactive oxygen species (ROS) levels. Several of these effects were almost completely prevented by inhibiting the PKA activity. Short-time treatment with compounds favoring mitochondrial fusion strongly decreased the cellular ROS levels especially in transformed cells. These findings support the notion that glucose shortage-induced apoptosis, specific of K-ras-transformed cells, is associated to a derangement of PKA signaling that leads to mitochondrial complex I decrease, reduction of ATP formation, prevalence of mitochondrial fission over fusion, and thereby opening new approaches for development of anticancer drugs. | GENE-CHEMICAL |
| Oncogenic GENE expression is associated with derangement of the cAMP/PKA pathway and forskolin-reversible alterations of mitochondrial dynamics and respiration. The Warburg effect in cancer cells has been proposed to involve several mechanisms, including adaptation to hypoxia, oncogenes activation or loss of oncosuppressors and impaired mitochondrial function. In previous papers, it has been shown that GENE transformed mouse cells are much more sensitive as compared with normal cells to CHEMICAL withdrawal (undergoing apoptosis) and present a high glycolytic rate and a strong reduction of mitochondrial complex I. Recent observations suggest that transformed cells have a derangement in the cyclic adenosine monophosphate/cAMP-dependent protein kinase (cAMP/PKA) pathway, which is known to regulate several mitochondrial functions. Herein, the derangement of the cAMP/PKA pathway and its impact on transformation-linked changes of mitochondrial functions is investigated. Exogenous stimulation of PKA activity, achieved by forskolin treatment, protected K-ras-transformed cells from apoptosis induced by CHEMICAL deprivation, enhanced complex I activity, intracellular adenosine triphosphate (ATP) levels, mitochondrial fusion and decreased intracellular reactive oxygen species (ROS) levels. Several of these effects were almost completely prevented by inhibiting the PKA activity. Short-time treatment with compounds favoring mitochondrial fusion strongly decreased the cellular ROS levels especially in transformed cells. These findings support the notion that CHEMICAL shortage-induced apoptosis, specific of GENE-transformed cells, is associated to a derangement of PKA signaling that leads to mitochondrial complex I decrease, reduction of ATP formation, prevalence of mitochondrial fission over fusion, and thereby opening new approaches for development of anticancer drugs. | REGULATOR |
| Oncogenic K-ras expression is associated with derangement of the cAMP/GENE pathway and CHEMICAL-reversible alterations of mitochondrial dynamics and respiration. The Warburg effect in cancer cells has been proposed to involve several mechanisms, including adaptation to hypoxia, oncogenes activation or loss of oncosuppressors and impaired mitochondrial function. In previous papers, it has been shown that K-ras transformed mouse cells are much more sensitive as compared with normal cells to glucose withdrawal (undergoing apoptosis) and present a high glycolytic rate and a strong reduction of mitochondrial complex I. Recent observations suggest that transformed cells have a derangement in the cyclic adenosine monophosphate/cAMP-dependent protein kinase (cAMP/PKA) pathway, which is known to regulate several mitochondrial functions. Herein, the derangement of the cAMP/PKA pathway and its impact on transformation-linked changes of mitochondrial functions is investigated. Exogenous stimulation of GENE activity, achieved by CHEMICAL treatment, protected K-ras-transformed cells from apoptosis induced by glucose deprivation, enhanced complex I activity, intracellular adenosine triphosphate (ATP) levels, mitochondrial fusion and decreased intracellular reactive oxygen species (ROS) levels. Several of these effects were almost completely prevented by inhibiting the GENE activity. Short-time treatment with compounds favoring mitochondrial fusion strongly decreased the cellular ROS levels especially in transformed cells. These findings support the notion that glucose shortage-induced apoptosis, specific of K-ras-transformed cells, is associated to a derangement of GENE signaling that leads to mitochondrial complex I decrease, reduction of ATP formation, prevalence of mitochondrial fission over fusion, and thereby opening new approaches for development of anticancer drugs. | REGULATOR |
| Oncogenic K-ras expression is associated with derangement of the cAMP/PKA pathway and forskolin-reversible alterations of mitochondrial dynamics and respiration. The Warburg effect in cancer cells has been proposed to involve several mechanisms, including adaptation to hypoxia, oncogenes activation or loss of oncosuppressors and impaired mitochondrial function. In previous papers, it has been shown that K-ras transformed mouse cells are much more sensitive as compared with normal cells to glucose withdrawal (undergoing apoptosis) and present a high glycolytic rate and a strong reduction of mitochondrial GENE. Recent observations suggest that transformed cells have a derangement in the cyclic adenosine monophosphate/cAMP-dependent protein kinase (cAMP/PKA) pathway, which is known to regulate several mitochondrial functions. Herein, the derangement of the cAMP/PKA pathway and its impact on transformation-linked changes of mitochondrial functions is investigated. Exogenous stimulation of PKA activity, achieved by CHEMICAL treatment, protected K-ras-transformed cells from apoptosis induced by glucose deprivation, enhanced GENE activity, intracellular adenosine triphosphate (ATP) levels, mitochondrial fusion and decreased intracellular reactive oxygen species (ROS) levels. Several of these effects were almost completely prevented by inhibiting the PKA activity. Short-time treatment with compounds favoring mitochondrial fusion strongly decreased the cellular ROS levels especially in transformed cells. These findings support the notion that glucose shortage-induced apoptosis, specific of K-ras-transformed cells, is associated to a derangement of PKA signaling that leads to mitochondrial GENE decrease, reduction of ATP formation, prevalence of mitochondrial fission over fusion, and thereby opening new approaches for development of anticancer drugs. | ACTIVATOR |
| CHEMICAL inhibits myofibroblast differentiation in nasal polyp-derived fibroblasts via the GENE pathway. The purposes of this study were to determine whether berberine has any effect on phenotype changes and extracellular matrix (ECM) production in nasal polyp-derived fibroblasts (NPDFs) and to investigate the underlying molecular mechanism. NPDFs were pre-treated with berberine prior to induction by transforming growth factor (TGF)-β1. The expression of α-smooth muscle actin (SMA) and collagen type I mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of α-SMA protein and collagen type I was determined by western blotting and/or immunofluorescent staining. The total soluble collagen production was analysed by the SirCol collagen assay. The expression of several signaling molecules of the TGF-β1 pathway was evaluated by western blot analysis. In TGF-β1-induced NPDFs, berberine significantly inhibited the expression of α-SMA and collagen type I mRNA and reduced α-SMA and collagen protein levels. CHEMICAL only suppressed the expression of pp38 among the evaluated signaling molecules. SB203580 (a specific inhibitor of GENE kinase) markedly suppressed the increased expression of collagen type I and α-SMA in TGF-β1-induced NPDFs. CHEMICAL exerts suppressive effects on phenotype changes and ECM production in NPDFs via GENE signaling pathway interference. The findings provide new therapeutic options for ECM production in nasal polyps. | REGULATOR |
| Berberine inhibits myofibroblast differentiation in nasal polyp-derived fibroblasts via the p38 pathway. The purposes of this study were to determine whether berberine has any effect on phenotype changes and extracellular matrix (ECM) production in nasal polyp-derived fibroblasts (NPDFs) and to investigate the underlying molecular mechanism. NPDFs were pre-treated with berberine prior to induction by transforming growth factor (TGF)-β1. The expression of α-smooth muscle actin (SMA) and GENE mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of α-SMA protein and GENE was determined by western blotting and/or immunofluorescent staining. The total soluble collagen production was analysed by the SirCol collagen assay. The expression of several signaling molecules of the TGF-β1 pathway was evaluated by western blot analysis. In TGF-β1-induced NPDFs, berberine significantly inhibited the expression of α-SMA and GENE mRNA and reduced α-SMA and collagen protein levels. Berberine only suppressed the expression of pp38 among the evaluated signaling molecules. CHEMICAL (a specific inhibitor of p38 kinase) markedly suppressed the increased expression of GENE and α-SMA in TGF-β1-induced NPDFs. Berberine exerts suppressive effects on phenotype changes and ECM production in NPDFs via p38 signaling pathway interference. The findings provide new therapeutic options for ECM production in nasal polyps. | INDIRECT-DOWNREGULATOR |
| Berberine inhibits myofibroblast differentiation in nasal polyp-derived fibroblasts via the p38 pathway. The purposes of this study were to determine whether berberine has any effect on phenotype changes and extracellular matrix (ECM) production in nasal polyp-derived fibroblasts (NPDFs) and to investigate the underlying molecular mechanism. NPDFs were pre-treated with berberine prior to induction by transforming growth factor (TGF)-β1. The expression of α-smooth muscle actin (SMA) and collagen type I mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of GENE protein and collagen type I was determined by western blotting and/or immunofluorescent staining. The total soluble collagen production was analysed by the SirCol collagen assay. The expression of several signaling molecules of the TGF-β1 pathway was evaluated by western blot analysis. In TGF-β1-induced NPDFs, berberine significantly inhibited the expression of GENE and collagen type I mRNA and reduced GENE and collagen protein levels. Berberine only suppressed the expression of pp38 among the evaluated signaling molecules. CHEMICAL (a specific inhibitor of p38 kinase) markedly suppressed the increased expression of collagen type I and GENE in TGF-β1-induced NPDFs. Berberine exerts suppressive effects on phenotype changes and ECM production in NPDFs via p38 signaling pathway interference. The findings provide new therapeutic options for ECM production in nasal polyps. | INDIRECT-DOWNREGULATOR |
| Berberine inhibits myofibroblast differentiation in nasal polyp-derived fibroblasts via the p38 pathway. The purposes of this study were to determine whether berberine has any effect on phenotype changes and extracellular matrix (ECM) production in nasal polyp-derived fibroblasts (NPDFs) and to investigate the underlying molecular mechanism. NPDFs were pre-treated with berberine prior to induction by transforming growth factor (TGF)-β1. The expression of α-smooth muscle actin (SMA) and collagen type I mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of α-SMA protein and collagen type I was determined by western blotting and/or immunofluorescent staining. The total soluble collagen production was analysed by the SirCol collagen assay. The expression of several signaling molecules of the GENE pathway was evaluated by western blot analysis. In TGF-β1-induced NPDFs, berberine significantly inhibited the expression of α-SMA and collagen type I mRNA and reduced α-SMA and collagen protein levels. Berberine only suppressed the expression of pp38 among the evaluated signaling molecules. CHEMICAL (a specific inhibitor of p38 kinase) markedly suppressed the increased expression of collagen type I and α-SMA in GENE-induced NPDFs. Berberine exerts suppressive effects on phenotype changes and ECM production in NPDFs via p38 signaling pathway interference. The findings provide new therapeutic options for ECM production in nasal polyps. | GENE-CHEMICAL |
| CHEMICAL inhibits myofibroblast differentiation in nasal polyp-derived fibroblasts via the p38 pathway. The purposes of this study were to determine whether CHEMICAL has any effect on phenotype changes and extracellular matrix (ECM) production in nasal polyp-derived fibroblasts (NPDFs) and to investigate the underlying molecular mechanism. NPDFs were pre-treated with CHEMICAL prior to induction by transforming growth factor (TGF)-β1. The expression of α-smooth muscle actin (SMA) and collagen type I mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of α-SMA protein and collagen type I was determined by western blotting and/or immunofluorescent staining. The total soluble collagen production was analysed by the SirCol collagen assay. The expression of several signaling molecules of the GENE pathway was evaluated by western blot analysis. In GENE-induced NPDFs, CHEMICAL significantly inhibited the expression of α-SMA and collagen type I mRNA and reduced α-SMA and collagen protein levels. CHEMICAL only suppressed the expression of pp38 among the evaluated signaling molecules. SB203580 (a specific inhibitor of p38 kinase) markedly suppressed the increased expression of collagen type I and α-SMA in TGF-β1-induced NPDFs. CHEMICAL exerts suppressive effects on phenotype changes and ECM production in NPDFs via p38 signaling pathway interference. The findings provide new therapeutic options for ECM production in nasal polyps. | GENE-CHEMICAL |
| CHEMICAL inhibits myofibroblast differentiation in nasal polyp-derived fibroblasts via the p38 pathway. The purposes of this study were to determine whether CHEMICAL has any effect on phenotype changes and extracellular matrix (ECM) production in nasal polyp-derived fibroblasts (NPDFs) and to investigate the underlying molecular mechanism. NPDFs were pre-treated with CHEMICAL prior to induction by transforming growth factor (TGF)-β1. The expression of α-smooth muscle actin (SMA) and collagen type I mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of GENE protein and collagen type I was determined by western blotting and/or immunofluorescent staining. The total soluble collagen production was analysed by the SirCol collagen assay. The expression of several signaling molecules of the TGF-β1 pathway was evaluated by western blot analysis. In TGF-β1-induced NPDFs, CHEMICAL significantly inhibited the expression of GENE and collagen type I mRNA and reduced GENE and collagen protein levels. CHEMICAL only suppressed the expression of pp38 among the evaluated signaling molecules. SB203580 (a specific inhibitor of p38 kinase) markedly suppressed the increased expression of collagen type I and GENE in TGF-β1-induced NPDFs. CHEMICAL exerts suppressive effects on phenotype changes and ECM production in NPDFs via p38 signaling pathway interference. The findings provide new therapeutic options for ECM production in nasal polyps. | INDIRECT-DOWNREGULATOR |
| CHEMICAL inhibits myofibroblast differentiation in nasal polyp-derived fibroblasts via the p38 pathway. The purposes of this study were to determine whether CHEMICAL has any effect on phenotype changes and extracellular matrix (ECM) production in nasal polyp-derived fibroblasts (NPDFs) and to investigate the underlying molecular mechanism. NPDFs were pre-treated with CHEMICAL prior to induction by transforming growth factor (TGF)-β1. The expression of α-smooth muscle actin (SMA) and GENE mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of α-SMA protein and GENE was determined by western blotting and/or immunofluorescent staining. The total soluble collagen production was analysed by the SirCol collagen assay. The expression of several signaling molecules of the TGF-β1 pathway was evaluated by western blot analysis. In TGF-β1-induced NPDFs, CHEMICAL significantly inhibited the expression of α-SMA and GENE mRNA and reduced α-SMA and collagen protein levels. CHEMICAL only suppressed the expression of pp38 among the evaluated signaling molecules. SB203580 (a specific inhibitor of p38 kinase) markedly suppressed the increased expression of GENE and α-SMA in TGF-β1-induced NPDFs. CHEMICAL exerts suppressive effects on phenotype changes and ECM production in NPDFs via p38 signaling pathway interference. The findings provide new therapeutic options for ECM production in nasal polyps. | INDIRECT-DOWNREGULATOR |
| CHEMICAL inhibits myofibroblast differentiation in nasal polyp-derived fibroblasts via the p38 pathway. The purposes of this study were to determine whether CHEMICAL has any effect on phenotype changes and extracellular matrix (ECM) production in nasal polyp-derived fibroblasts (NPDFs) and to investigate the underlying molecular mechanism. NPDFs were pre-treated with CHEMICAL prior to induction by transforming growth factor (TGF)-β1. The expression of α-smooth muscle actin (SMA) and GENE type I mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of α-SMA protein and GENE type I was determined by western blotting and/or immunofluorescent staining. The total soluble GENE production was analysed by the SirCol GENE assay. The expression of several signaling molecules of the TGF-β1 pathway was evaluated by western blot analysis. In TGF-β1-induced NPDFs, CHEMICAL significantly inhibited the expression of α-SMA and GENE type I mRNA and reduced α-SMA and GENE protein levels. CHEMICAL only suppressed the expression of pp38 among the evaluated signaling molecules. SB203580 (a specific inhibitor of p38 kinase) markedly suppressed the increased expression of GENE type I and α-SMA in TGF-β1-induced NPDFs. CHEMICAL exerts suppressive effects on phenotype changes and ECM production in NPDFs via p38 signaling pathway interference. The findings provide new therapeutic options for ECM production in nasal polyps. | GENE-CHEMICAL |
| CHEMICAL inhibits myofibroblast differentiation in nasal polyp-derived fibroblasts via the p38 pathway. The purposes of this study were to determine whether berberine has any effect on phenotype changes and extracellular matrix (ECM) production in nasal polyp-derived fibroblasts (NPDFs) and to investigate the underlying molecular mechanism. NPDFs were pre-treated with berberine prior to induction by transforming growth factor (TGF)-β1. The expression of α-smooth muscle actin (SMA) and collagen type I mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of α-SMA protein and collagen type I was determined by western blotting and/or immunofluorescent staining. The total soluble collagen production was analysed by the SirCol collagen assay. The expression of several signaling molecules of the TGF-β1 pathway was evaluated by western blot analysis. In TGF-β1-induced NPDFs, berberine significantly inhibited the expression of α-SMA and collagen type I mRNA and reduced α-SMA and collagen protein levels. CHEMICAL only suppressed the expression of GENE among the evaluated signaling molecules. SB203580 (a specific inhibitor of p38 kinase) markedly suppressed the increased expression of collagen type I and α-SMA in TGF-β1-induced NPDFs. CHEMICAL exerts suppressive effects on phenotype changes and ECM production in NPDFs via p38 signaling pathway interference. The findings provide new therapeutic options for ECM production in nasal polyps. | INDIRECT-DOWNREGULATOR |
| Berberine inhibits myofibroblast differentiation in nasal polyp-derived fibroblasts via the GENE pathway. The purposes of this study were to determine whether berberine has any effect on phenotype changes and extracellular matrix (ECM) production in nasal polyp-derived fibroblasts (NPDFs) and to investigate the underlying molecular mechanism. NPDFs were pre-treated with berberine prior to induction by transforming growth factor (TGF)-β1. The expression of α-smooth muscle actin (SMA) and collagen type I mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of α-SMA protein and collagen type I was determined by western blotting and/or immunofluorescent staining. The total soluble collagen production was analysed by the SirCol collagen assay. The expression of several signaling molecules of the TGF-β1 pathway was evaluated by western blot analysis. In TGF-β1-induced NPDFs, berberine significantly inhibited the expression of α-SMA and collagen type I mRNA and reduced α-SMA and collagen protein levels. Berberine only suppressed the expression of pp38 among the evaluated signaling molecules. CHEMICAL (a specific inhibitor of GENE kinase) markedly suppressed the increased expression of collagen type I and α-SMA in TGF-β1-induced NPDFs. Berberine exerts suppressive effects on phenotype changes and ECM production in NPDFs via GENE signaling pathway interference. The findings provide new therapeutic options for ECM production in nasal polyps. | INHIBITOR |
| Berberine inhibits myofibroblast differentiation in nasal polyp-derived fibroblasts via the p38 pathway. The purposes of this study were to determine whether berberine has any effect on phenotype changes and extracellular matrix (ECM) production in nasal polyp-derived fibroblasts (NPDFs) and to investigate the underlying molecular mechanism. NPDFs were pre-treated with berberine prior to induction by transforming growth factor (TGF)-β1. The expression of α-smooth muscle actin (SMA) and collagen type I mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of α-SMA protein and collagen type I was determined by western blotting and/or immunofluorescent staining. The total soluble collagen production was analysed by the SirCol collagen assay. The expression of several signaling molecules of the TGF-β1 pathway was evaluated by western blot analysis. In TGF-β1-induced NPDFs, berberine significantly inhibited the expression of α-SMA and collagen type I mRNA and reduced α-SMA and collagen protein levels. Berberine only suppressed the expression of pp38 among the evaluated signaling molecules. CHEMICAL (a specific inhibitor of p38 GENE) markedly suppressed the increased expression of collagen type I and α-SMA in TGF-β1-induced NPDFs. Berberine exerts suppressive effects on phenotype changes and ECM production in NPDFs via p38 signaling pathway interference. The findings provide new therapeutic options for ECM production in nasal polyps. | INHIBITOR |
| Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous GENE and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. GENE mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. CHEMICAL and pomalidomide inhibited autoubiquitination of GENE in HEK293T cells expressing thalidomide-binding competent wild-type GENE, but not thalidomide-binding defective GENE(YW/AA). Overexpression of GENE wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in GENE, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, GENE protein was undetectable. Our biophysical, biochemical and gene silencing studies show that GENE is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide. | NO-RELATIONSHIP |
| Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and CHEMICAL. Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, CHEMICAL, bound endogenous GENE and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. GENE mediated antiproliferative activities of lenalidomide and CHEMICAL in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and CHEMICAL inhibited autoubiquitination of GENE in HEK293T cells expressing thalidomide-binding competent wild-type GENE, but not thalidomide-binding defective GENE(YW/AA). Overexpression of GENE wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in GENE, while in DF15R myeloma cells resistant to both CHEMICAL and lenalidomide, GENE protein was undetectable. Our biophysical, biochemical and gene silencing studies show that GENE is a proximate, therapeutically important molecular target of lenalidomide and CHEMICAL. | DIRECT-REGULATOR |
| Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and CHEMICAL. Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, CHEMICAL, bound endogenous CRBN and recombinant CRBN-GENE (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and CHEMICAL in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and CHEMICAL inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both CHEMICAL and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and CHEMICAL. | DIRECT-REGULATOR |
| Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and CHEMICAL. Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, CHEMICAL, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (GENE) complexes. CRBN mediated antiproliferative activities of lenalidomide and CHEMICAL in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and CHEMICAL inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both CHEMICAL and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and CHEMICAL. | DIRECT-REGULATOR |
| Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. CHEMICAL and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of CHEMICAL. Our studies demonstrate that CHEMICAL, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous GENE and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. GENE mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of GENE in HEK293T cells expressing CHEMICAL-binding competent wild-type GENE, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of GENE wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in GENE, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, GENE protein was undetectable. Our biophysical, biochemical and gene silencing studies show that GENE is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide. | DIRECT-REGULATOR |
| Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. CHEMICAL and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of CHEMICAL. Our studies demonstrate that CHEMICAL, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-GENE (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide. | DIRECT-REGULATOR |
| Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. CHEMICAL and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of CHEMICAL. Our studies demonstrate that CHEMICAL, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (GENE) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide. | DIRECT-REGULATOR |
| Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of CHEMICAL and pomalidomide. Thalidomide and the immunomodulatory drug, CHEMICAL, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, CHEMICAL and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-GENE (DDB1) complexes. CRBN mediated antiproliferative activities of CHEMICAL and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. CHEMICAL and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for CHEMICAL resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and CHEMICAL, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of CHEMICAL and pomalidomide. | DIRECT-REGULATOR |
| Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of CHEMICAL and pomalidomide. Thalidomide and the immunomodulatory drug, CHEMICAL, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, CHEMICAL and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (GENE) complexes. CRBN mediated antiproliferative activities of CHEMICAL and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. CHEMICAL and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for CHEMICAL resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and CHEMICAL, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of CHEMICAL and pomalidomide. | DIRECT-REGULATOR |
| GENE is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and CHEMICAL. Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, CHEMICAL, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and CHEMICAL in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and CHEMICAL inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both CHEMICAL and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and CHEMICAL. | REGULATOR |
| GENE is a direct protein target for immunomodulatory and antiproliferative activities of CHEMICAL and pomalidomide. Thalidomide and the immunomodulatory drug, CHEMICAL, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, CHEMICAL and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of CHEMICAL and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. CHEMICAL and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for CHEMICAL resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and CHEMICAL, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of CHEMICAL and pomalidomide. | REGULATOR |
| GENE is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. CHEMICAL and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein GENE (CRBN) has been identified as the primary teratogenic target of CHEMICAL. Our studies demonstrate that CHEMICAL, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide. | REGULATOR |
| Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of CHEMICAL and pomalidomide. Thalidomide and the immunomodulatory drug, CHEMICAL, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, CHEMICAL and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of CHEMICAL and pomalidomide in myeloma cells, as well as CHEMICAL- and pomalidomide-induced GENE production in T cells. CHEMICAL and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for CHEMICAL resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and CHEMICAL, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of CHEMICAL and pomalidomide. | INDIRECT-UPREGULATOR |
| Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and CHEMICAL. Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, CHEMICAL, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and CHEMICAL in myeloma cells, as well as lenalidomide- and CHEMICAL-induced GENE production in T cells. Lenalidomide and CHEMICAL inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both CHEMICAL and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and CHEMICAL. | INDIRECT-UPREGULATOR |
| Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and CHEMICAL. Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, CHEMICAL, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and CHEMICAL in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and CHEMICAL inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified CHEMICAL-mediated reductions in c-myc and IRF4 expression and increases in p21(GENE) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both CHEMICAL and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and CHEMICAL. | INDIRECT-UPREGULATOR |
| Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and CHEMICAL. Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, CHEMICAL, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and CHEMICAL in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and CHEMICAL inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified CHEMICAL-mediated reductions in c-myc and IRF4 expression and increases in GENE(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both CHEMICAL and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and CHEMICAL. | INDIRECT-UPREGULATOR |
| Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and CHEMICAL. Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, CHEMICAL, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and CHEMICAL in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and CHEMICAL inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified CHEMICAL-mediated reductions in GENE and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both CHEMICAL and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and CHEMICAL. | INDIRECT-DOWNREGULATOR |
| Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and CHEMICAL. Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, CHEMICAL, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and CHEMICAL in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and CHEMICAL inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified CHEMICAL-mediated reductions in c-myc and GENE expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both CHEMICAL and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and CHEMICAL. | INDIRECT-DOWNREGULATOR |
| Evaluation of food-drug interaction of guava leaf tea. Guava leaf tea (GLT) contains guava leaf polyphenol (Gvpp), which regulates the absorption of dietary carbohydrate from the intestines. Borderline diabetics, who are at high risk of development of diabetes, take GLT to suppress a rapid increase of blood sugar level after meals. However, patients with diabetes in whom diabetic drugs or warfarin as a blood thinner are prescribed also take GLT with the expectation of glycemic control. Therefore, we studied whether GLT had potential for inhibition or induction of cytochrome P450 (CYP) and an influence on the action of warfarin. Extract of guava leaf (GvEx) consists of carbohydrate and CHEMICAL, which are Gvpp, quercetin, and ellagic acid. These CHEMICAL, but not GvEx, showed a certain level of inhibition of human-cDNA-expressed GENE. In a comparison of GLT and grapefruit juice, GLT showed weaker inhibition of CYP activities and of midazolam 1'-hydroxylation than grapefruit juice. Furthermore, neither liver weight nor CYP3A expression in the liver was changed in rats that received GvEx for 90 days compared with the control group. When rats were concomitantly treated with GLT and warfarin, the prolongation of clotting time of blood by warfarin was not influenced. These data suggest that GLT is unlikely to interact with drugs. | INHIBITOR |
| CHEMICAL in the treatment of non-small-cell lung cancer. INTRODUCTION: Recent progress in identifying distinct subsets of lung cancer, based on critical driver mutations, has led to increasingly focused efforts in the development of selectively targeted therapies. The fusion oncogene, echinoderm microtubule-associated protein-like 4 - anaplastic lymphoma kinase (EML4-ALK), is present in approximately 5% of non-small-cell lung cancer (NSCLC) tumors. CHEMICAL is an oral tyrosine kinase inhibitor (TKI), which silences the protein product of the ALK fusion gene and has recently been approved for the treatment of NSCLC aberrantly expressing ALK. Emerging data suggest that CHEMICAL may also have activity in other subsets of lung cancer, including tumors demonstrating amplification or mutation of the GENE oncogene, or translocation of the ROS1 oncogene. AREAS COVERED: This paper gives an overview of the molecular pathogenesis of ALK-associated NSCLC. It also reviews the pharmacokinetic and pharmacodynamic data on CHEMICAL and outlines the preclinical and clinical studies leading to the approval of CHEMICAL. In addition, it discusses its role in the treatment of NSCLC expressing ALK. EXPERT OPINION: CHEMICAL represents the newest example of a focused strategy for drug development in lung cancer, based on identification and targeted inhibition of critical tumor-specific driver mutations. CHEMICAL has demonstrated efficacy against ALK-rearranged NSCLC, and has potential for broader application in select subsets of lung cancer. | GENE-CHEMICAL |
| CHEMICAL in the treatment of non-small-cell lung cancer. INTRODUCTION: Recent progress in identifying distinct subsets of lung cancer, based on critical driver mutations, has led to increasingly focused efforts in the development of selectively targeted therapies. The fusion oncogene, echinoderm microtubule-associated protein-like 4 - anaplastic lymphoma kinase (EML4-ALK), is present in approximately 5% of non-small-cell lung cancer (NSCLC) tumors. CHEMICAL is an oral tyrosine kinase inhibitor (TKI), which silences the protein product of the ALK fusion gene and has recently been approved for the treatment of NSCLC aberrantly expressing ALK. Emerging data suggest that CHEMICAL may also have activity in other subsets of lung cancer, including tumors demonstrating amplification or mutation of the MET oncogene, or translocation of the GENE oncogene. AREAS COVERED: This paper gives an overview of the molecular pathogenesis of ALK-associated NSCLC. It also reviews the pharmacokinetic and pharmacodynamic data on CHEMICAL and outlines the preclinical and clinical studies leading to the approval of CHEMICAL. In addition, it discusses its role in the treatment of NSCLC expressing ALK. EXPERT OPINION: CHEMICAL represents the newest example of a focused strategy for drug development in lung cancer, based on identification and targeted inhibition of critical tumor-specific driver mutations. CHEMICAL has demonstrated efficacy against ALK-rearranged NSCLC, and has potential for broader application in select subsets of lung cancer. | GENE-CHEMICAL |
| CHEMICAL in the treatment of non-small-cell lung cancer. INTRODUCTION: Recent progress in identifying distinct subsets of lung cancer, based on critical driver mutations, has led to increasingly focused efforts in the development of selectively targeted therapies. The fusion oncogene, echinoderm microtubule-associated protein-like 4 - anaplastic lymphoma kinase (EML4-ALK), is present in approximately 5% of non-small-cell lung cancer (NSCLC) tumors. CHEMICAL is an oral tyrosine kinase inhibitor (TKI), which silences the protein product of the GENE fusion gene and has recently been approved for the treatment of NSCLC aberrantly expressing GENE. Emerging data suggest that crizotinib may also have activity in other subsets of lung cancer, including tumors demonstrating amplification or mutation of the MET oncogene, or translocation of the ROS1 oncogene. AREAS COVERED: This paper gives an overview of the molecular pathogenesis of ALK-associated NSCLC. It also reviews the pharmacokinetic and pharmacodynamic data on crizotinib and outlines the preclinical and clinical studies leading to the approval of crizotinib. In addition, it discusses its role in the treatment of NSCLC expressing GENE. EXPERT OPINION: CHEMICAL represents the newest example of a focused strategy for drug development in lung cancer, based on identification and targeted inhibition of critical tumor-specific driver mutations. CHEMICAL has demonstrated efficacy against GENE-rearranged NSCLC, and has potential for broader application in select subsets of lung cancer. | REGULATOR |
| CHEMICAL in the treatment of non-small-cell lung cancer. INTRODUCTION: Recent progress in identifying distinct subsets of lung cancer, based on critical driver mutations, has led to increasingly focused efforts in the development of selectively targeted therapies. The fusion oncogene, echinoderm microtubule-associated protein-like 4 - anaplastic lymphoma kinase (EML4-ALK), is present in approximately 5% of non-small-cell lung cancer (NSCLC) tumors. CHEMICAL is an oral GENE inhibitor (TKI), which silences the protein product of the ALK fusion gene and has recently been approved for the treatment of NSCLC aberrantly expressing ALK. Emerging data suggest that crizotinib may also have activity in other subsets of lung cancer, including tumors demonstrating amplification or mutation of the MET oncogene, or translocation of the ROS1 oncogene. AREAS COVERED: This paper gives an overview of the molecular pathogenesis of ALK-associated NSCLC. It also reviews the pharmacokinetic and pharmacodynamic data on crizotinib and outlines the preclinical and clinical studies leading to the approval of crizotinib. In addition, it discusses its role in the treatment of NSCLC expressing ALK. EXPERT OPINION: CHEMICAL represents the newest example of a focused strategy for drug development in lung cancer, based on identification and targeted inhibition of critical tumor-specific driver mutations. CHEMICAL has demonstrated efficacy against ALK-rearranged NSCLC, and has potential for broader application in select subsets of lung cancer. | INHIBITOR |
| Central adenosinergic system involvement in ethanol-induced motor incoordination in mice. To clarify if the behavioral interaction between CHEMICAL and GENE reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. GENE agonists, N6-(R-phenylisopropyl)adenosine (R-PIA), N6-(S-phenylisopropyl)adenosine, 5'-(N-cyclopropyl)-carboxamidoadenosine, antagonists, theophylline and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. GENE agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of GENE modulation of this effect of CHEMICAL and confirmed our previous reports in which GENE agonists and antagonists were given i.p. Enprofylline, a weak GENE antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain GENE receptor mechanism(s) in ethanol-adenosine interactions. Results from R-PIA and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of GENE A1 subtype. However, 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of GENE A2. No effect of CHEMICAL on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest GENE receptor activation adequate to produce behavioral interaction with CHEMICAL. There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of CHEMICAL-GENE interaction.(ABSTRACT TRUNCATED AT 250 WORDS) | DIRECT-REGULATOR |
| Central adenosinergic system involvement in ethanol-induced motor incoordination in mice. To clarify if the behavioral interaction between ethanol and adenosine reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. adenosine agonists, N6-(R-phenylisopropyl)adenosine (R-PIA), CHEMICAL, 5'-(N-cyclopropyl)-carboxamidoadenosine, antagonists, theophylline and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. Adenosine agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of adenosine modulation of this effect of ethanol and confirmed our previous reports in which adenosine agonists and antagonists were given i.p. Enprofylline, a weak adenosine antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain adenosine receptor mechanism(s) in ethanol-adenosine interactions. Results from R-PIA and CHEMICAL experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of GENE subtype. However, 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of adenosine A2. No effect of ethanol on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest adenosine receptor activation adequate to produce behavioral interaction with ethanol. There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.(ABSTRACT TRUNCATED AT 250 WORDS) | REGULATOR |
| Central adenosinergic system involvement in ethanol-induced motor incoordination in mice. To clarify if the behavioral interaction between CHEMICAL and adenosine reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. adenosine agonists, N6-(R-phenylisopropyl)adenosine (R-PIA), N6-(S-phenylisopropyl)adenosine, 5'-(N-cyclopropyl)-carboxamidoadenosine, antagonists, theophylline and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. Adenosine agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of adenosine modulation of this effect of CHEMICAL and confirmed our previous reports in which adenosine agonists and antagonists were given i.p. Enprofylline, a weak adenosine antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain GENE mechanism(s) in CHEMICAL-adenosine interactions. Results from R-PIA and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of adenosine A1 subtype. However, 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of adenosine A2. No effect of CHEMICAL on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest GENE activation adequate to produce behavioral interaction with CHEMICAL. There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.(ABSTRACT TRUNCATED AT 250 WORDS) | REGULATOR |
| Central adenosinergic system involvement in ethanol-induced motor incoordination in mice. To clarify if the behavioral interaction between ethanol and adenosine reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. adenosine agonists, N6-(R-phenylisopropyl)adenosine (R-PIA), N6-(S-phenylisopropyl)adenosine, CHEMICAL, antagonists, theophylline and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. Adenosine agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of adenosine modulation of this effect of ethanol and confirmed our previous reports in which adenosine agonists and antagonists were given i.p. Enprofylline, a weak adenosine antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain adenosine receptor mechanism(s) in ethanol-adenosine interactions. Results from R-PIA and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of adenosine A1 subtype. However, CHEMICAL data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of GENE. No effect of ethanol on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest adenosine receptor activation adequate to produce behavioral interaction with ethanol. There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.(ABSTRACT TRUNCATED AT 250 WORDS) | REGULATOR |
| Central adenosinergic system involvement in ethanol-induced motor incoordination in mice. To clarify if the behavioral interaction between ethanol and adenosine reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. adenosine agonists, N6-(R-phenylisopropyl)adenosine (R-PIA), N6-(S-phenylisopropyl)adenosine, 5'-(N-cyclopropyl)-carboxamidoadenosine, antagonists, theophylline and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. Adenosine agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of adenosine modulation of this effect of ethanol and confirmed our previous reports in which adenosine agonists and antagonists were given i.p. CHEMICAL, a weak adenosine antagonist but potent inhibitor of GENE, did not alter ethanol's motor incoordination, further supporting involvement of brain adenosine receptor mechanism(s) in ethanol-adenosine interactions. Results from R-PIA and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of adenosine A1 subtype. However, 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of adenosine A2. No effect of ethanol on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest adenosine receptor activation adequate to produce behavioral interaction with ethanol. There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.(ABSTRACT TRUNCATED AT 250 WORDS) | INHIBITOR |
| Central adenosinergic system involvement in ethanol-induced motor incoordination in mice. To clarify if the behavioral interaction between ethanol and GENE reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. GENE agonists, CHEMICAL (R-PIA), N6-(S-phenylisopropyl)adenosine, 5'-(N-cyclopropyl)-carboxamidoadenosine, antagonists, theophylline and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. GENE agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of GENE modulation of this effect of ethanol and confirmed our previous reports in which GENE agonists and antagonists were given i.p. Enprofylline, a weak GENE antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain GENE receptor mechanism(s) in ethanol-adenosine interactions. Results from R-PIA and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of GENE A1 subtype. However, 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of GENE A2. No effect of ethanol on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest GENE receptor activation adequate to produce behavioral interaction with ethanol. There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.(ABSTRACT TRUNCATED AT 250 WORDS) | ACTIVATOR |
| Central adenosinergic system involvement in ethanol-induced motor incoordination in mice. To clarify if the behavioral interaction between ethanol and GENE reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. GENE agonists, N6-(R-phenylisopropyl)adenosine (CHEMICAL), N6-(S-phenylisopropyl)adenosine, 5'-(N-cyclopropyl)-carboxamidoadenosine, antagonists, theophylline and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. GENE agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of GENE modulation of this effect of ethanol and confirmed our previous reports in which GENE agonists and antagonists were given i.p. Enprofylline, a weak GENE antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain GENE receptor mechanism(s) in ethanol-adenosine interactions. Results from CHEMICAL and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of GENE A1 subtype. However, 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of GENE A2. No effect of ethanol on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest GENE receptor activation adequate to produce behavioral interaction with ethanol. There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.(ABSTRACT TRUNCATED AT 250 WORDS) | ACTIVATOR |
| Central adenosinergic system involvement in ethanol-induced motor incoordination in mice. To clarify if the behavioral interaction between ethanol and GENE reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. GENE agonists, N6-(R-phenylisopropyl)adenosine (R-PIA), CHEMICAL, 5'-(N-cyclopropyl)-carboxamidoadenosine, antagonists, theophylline and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. GENE agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of GENE modulation of this effect of ethanol and confirmed our previous reports in which GENE agonists and antagonists were given i.p. Enprofylline, a weak GENE antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain GENE receptor mechanism(s) in ethanol-adenosine interactions. Results from R-PIA and CHEMICAL experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of GENE A1 subtype. However, 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of GENE A2. No effect of ethanol on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest GENE receptor activation adequate to produce behavioral interaction with ethanol. There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.(ABSTRACT TRUNCATED AT 250 WORDS) | ACTIVATOR |
| Central adenosinergic system involvement in ethanol-induced motor incoordination in mice. To clarify if the behavioral interaction between ethanol and GENE reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. GENE agonists, N6-(R-phenylisopropyl)adenosine (R-PIA), N6-(S-phenylisopropyl)adenosine, CHEMICAL, antagonists, theophylline and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. GENE agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of GENE modulation of this effect of ethanol and confirmed our previous reports in which GENE agonists and antagonists were given i.p. Enprofylline, a weak GENE antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain GENE receptor mechanism(s) in ethanol-adenosine interactions. Results from R-PIA and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of GENE A1 subtype. However, CHEMICAL data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of GENE A2. No effect of ethanol on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest GENE receptor activation adequate to produce behavioral interaction with ethanol. There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.(ABSTRACT TRUNCATED AT 250 WORDS) | ACTIVATOR |
| Central adenosinergic system involvement in ethanol-induced motor incoordination in mice. To clarify if the behavioral interaction between ethanol and GENE reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. GENE agonists, N6-(R-phenylisopropyl)adenosine (R-PIA), N6-(S-phenylisopropyl)adenosine, 5'-(N-cyclopropyl)-carboxamidoadenosine, antagonists, CHEMICAL and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. GENE agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of GENE modulation of this effect of ethanol and confirmed our previous reports in which GENE agonists and antagonists were given i.p. Enprofylline, a weak GENE antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain GENE receptor mechanism(s) in ethanol-adenosine interactions. Results from R-PIA and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of GENE A1 subtype. However, 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of GENE A2. No effect of ethanol on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest GENE receptor activation adequate to produce behavioral interaction with ethanol. There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.(ABSTRACT TRUNCATED AT 250 WORDS) | INHIBITOR |
| Central adenosinergic system involvement in ethanol-induced motor incoordination in mice. To clarify if the behavioral interaction between ethanol and GENE reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. GENE agonists, N6-(R-phenylisopropyl)adenosine (R-PIA), N6-(S-phenylisopropyl)adenosine, 5'-(N-cyclopropyl)-carboxamidoadenosine, antagonists, theophylline and CHEMICAL as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. GENE agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of GENE modulation of this effect of ethanol and confirmed our previous reports in which GENE agonists and antagonists were given i.p. Enprofylline, a weak GENE antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain GENE receptor mechanism(s) in ethanol-adenosine interactions. Results from R-PIA and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of GENE A1 subtype. However, 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of GENE A2. No effect of ethanol on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest GENE receptor activation adequate to produce behavioral interaction with ethanol. There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.(ABSTRACT TRUNCATED AT 250 WORDS) | ACTIVATOR |
| Central adenosinergic system involvement in ethanol-induced motor incoordination in mice. To clarify if the behavioral interaction between ethanol and GENE reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. GENE agonists, N6-(R-phenylisopropyl)adenosine (R-PIA), N6-(S-phenylisopropyl)adenosine, 5'-(N-cyclopropyl)-carboxamidoadenosine, antagonists, theophylline and 8-p-(sulfophenyl)theophylline as well as CHEMICAL on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. GENE agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of GENE modulation of this effect of ethanol and confirmed our previous reports in which GENE agonists and antagonists were given i.p. CHEMICAL, a weak GENE antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain GENE receptor mechanism(s) in ethanol-adenosine interactions. Results from R-PIA and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of GENE A1 subtype. However, 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of GENE A2. No effect of ethanol on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest GENE receptor activation adequate to produce behavioral interaction with ethanol. There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.(ABSTRACT TRUNCATED AT 250 WORDS) | INHIBITOR |
| Central adenosinergic system involvement in ethanol-induced motor incoordination in mice. To clarify if the behavioral interaction between ethanol and GENE reported previously occur centrally or due to a peripheral hemodynamic change, the effect of i.c.v. GENE agonists, N6-(R-phenylisopropyl)adenosine (R-PIA), N6-(S-phenylisopropyl)adenosine, 5'-(N-cyclopropyl)-carboxamidoadenosine, antagonists, theophylline and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. GENE agonists and antagonists dose dependently accentuated and attenuated, respectively, ethanol-induced motor incoordination, thereby suggesting a central mechanism of GENE modulation of this effect of ethanol and confirmed our previous reports in which GENE agonists and antagonists were given i.p. CHEMICAL, a weak GENE antagonist but potent inhibitor of cyclic AMP phosphodiesterase, did not alter ethanol's motor incoordination, further supporting involvement of brain GENE receptor mechanism(s) in ethanol-adenosine interactions. Results from R-PIA and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer, suggesting predominance of GENE A1 subtype. However, 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of GENE A2. No effect of ethanol on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest GENE receptor activation adequate to produce behavioral interaction with ethanol. There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.(ABSTRACT TRUNCATED AT 250 WORDS) | INHIBITOR |
| GENE and NF-κB signal pathway cross-talk is mediated through TAK1 and SMAD7 in a subset of head and neck cancers. Transforming growth factor-beta (TGF-β) has a dual role in epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC). Attenuation of canonical GENE signaling enhances de novo tumor development, whereas GENE overexpression and signaling paradoxically promotes malignant progression. We recently observed that TGF-β-induced growth arrest response is attenuated, in association with aberrant activation of nuclear factor-κB (NF-κB), a transcription factor, which promotes malignant progression in HNSCC. However, what role cross-talk between components of the GENE and NF-κB pathways plays in altered activation of these pathways has not been established. Here, we show GENE receptor II and TGF-β-activated kinase 1 (TAK1) are predominantly expressed in a subset of HNSCC tumors with nuclear activation of NF-κB family member RELA (p65). Further, TGF-β1 treatment induced sequential phosphorylation of TAK1, IKK, IκBα and RELA in human HNSCC lines. TAK1 enhances TGF-β-induced NF-κB activation, as TAK1 siRNA knockdown decreased TGF-β1-induced phosphorylation of IKK, IκB and RELA, degradation of IκBα, RELA nuclear translocation and DNA binding, and NF-κB-induced reporter and target gene transcription. Functionally, TAK1 siRNA inhibited cell proliferation, migration and invasion. CHEMICAL, a TAK1 inhibitor and anti-inflammatory compound used in traditional Chinese medicine, also decreased TGF-β1-induced phosphorylation of TAK1 and RELA, and suppressed basal, TGF-β1- and tumor necrosis factor-alpha (TNF-α)-induced NF-κB reporter gene activity. CHEMICAL also inhibited cell proliferation, while increasing sub-G0 DNA fragmentation and Annexin V markers of apoptosis. Furthermore, GENE and RELA activation promoted SMAD7 expression. In turn, SMAD7 preferentially suppressed TGF-β-induced SMAD and NF-κB reporters when compared with constitutive or TNF-α-induced NF-κB reporter gene activation. Thus, cross-talk by GENE via TAK1 and NF-κB promotes the malignant phenotype of HNSCC. Moreover, NF-κB may contribute to the downstream attenuation of canonical GENE signaling through increased SMAD7 expression. CHEMICAL highlights the therapeutic potential of agents targeting TAK1 as a key node in this pro-oncogenic GENE-NF-κB signal pathway. | GENE-CHEMICAL |
| TGF-β and GENE signal pathway cross-talk is mediated through TAK1 and SMAD7 in a subset of head and neck cancers. Transforming growth factor-beta (TGF-β) has a dual role in epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC). Attenuation of canonical TGF-β signaling enhances de novo tumor development, whereas TGF-β overexpression and signaling paradoxically promotes malignant progression. We recently observed that TGF-β-induced growth arrest response is attenuated, in association with aberrant activation of nuclear factor-κB (NF-κB), a transcription factor, which promotes malignant progression in HNSCC. However, what role cross-talk between components of the TGF-β and GENE pathways plays in altered activation of these pathways has not been established. Here, we show TGF-β receptor II and TGF-β-activated kinase 1 (TAK1) are predominantly expressed in a subset of HNSCC tumors with nuclear activation of GENE family member RELA (p65). Further, TGF-β1 treatment induced sequential phosphorylation of TAK1, IKK, IκBα and RELA in human HNSCC lines. TAK1 enhances TGF-β-induced GENE activation, as TAK1 siRNA knockdown decreased TGF-β1-induced phosphorylation of IKK, IκB and RELA, degradation of IκBα, RELA nuclear translocation and DNA binding, and NF-κB-induced reporter and target gene transcription. Functionally, TAK1 siRNA inhibited cell proliferation, migration and invasion. CHEMICAL, a TAK1 inhibitor and anti-inflammatory compound used in traditional Chinese medicine, also decreased TGF-β1-induced phosphorylation of TAK1 and RELA, and suppressed basal, TGF-β1- and tumor necrosis factor-alpha (TNF-α)-induced GENE reporter gene activity. CHEMICAL also inhibited cell proliferation, while increasing sub-G0 DNA fragmentation and Annexin V markers of apoptosis. Furthermore, TGF-β and RELA activation promoted SMAD7 expression. In turn, SMAD7 preferentially suppressed TGF-β-induced SMAD and GENE reporters when compared with constitutive or TNF-α-induced GENE reporter gene activation. Thus, cross-talk by TGF-β via TAK1 and GENE promotes the malignant phenotype of HNSCC. Moreover, GENE may contribute to the downstream attenuation of canonical TGF-β signaling through increased SMAD7 expression. CHEMICAL highlights the therapeutic potential of agents targeting TAK1 as a key node in this pro-oncogenic TGF-β-GENE signal pathway. | INHIBITOR |
| TGF-β and NF-κB signal pathway cross-talk is mediated through TAK1 and SMAD7 in a subset of head and neck cancers. Transforming growth factor-beta (TGF-β) has a dual role in epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC). Attenuation of canonical TGF-β signaling enhances de novo tumor development, whereas TGF-β overexpression and signaling paradoxically promotes malignant progression. We recently observed that TGF-β-induced growth arrest response is attenuated, in association with aberrant activation of nuclear factor-κB (NF-κB), a transcription factor, which promotes malignant progression in HNSCC. However, what role cross-talk between components of the TGF-β and NF-κB pathways plays in altered activation of these pathways has not been established. Here, we show TGF-β receptor II and TGF-β-activated kinase 1 (TAK1) are predominantly expressed in a subset of HNSCC tumors with nuclear activation of NF-κB family member RELA (p65). Further, TGF-β1 treatment induced sequential phosphorylation of TAK1, IKK, IκBα and RELA in human HNSCC lines. TAK1 enhances TGF-β-induced NF-κB activation, as TAK1 siRNA knockdown decreased TGF-β1-induced phosphorylation of IKK, IκB and RELA, degradation of IκBα, RELA nuclear translocation and DNA binding, and NF-κB-induced reporter and target gene transcription. Functionally, TAK1 siRNA inhibited cell proliferation, migration and invasion. CHEMICAL, a TAK1 inhibitor and anti-inflammatory compound used in traditional Chinese medicine, also decreased TGF-β1-induced phosphorylation of TAK1 and RELA, and suppressed basal, TGF-β1- and tumor necrosis factor-alpha (TNF-α)-induced NF-κB reporter gene activity. CHEMICAL also inhibited cell proliferation, while increasing sub-G0 DNA fragmentation and GENE markers of apoptosis. Furthermore, TGF-β and RELA activation promoted SMAD7 expression. In turn, SMAD7 preferentially suppressed TGF-β-induced SMAD and NF-κB reporters when compared with constitutive or TNF-α-induced NF-κB reporter gene activation. Thus, cross-talk by TGF-β via TAK1 and NF-κB promotes the malignant phenotype of HNSCC. Moreover, NF-κB may contribute to the downstream attenuation of canonical TGF-β signaling through increased SMAD7 expression. CHEMICAL highlights the therapeutic potential of agents targeting TAK1 as a key node in this pro-oncogenic TGF-β-NF-κB signal pathway. | INDIRECT-UPREGULATOR |
| TGF-β and NF-κB signal pathway cross-talk is mediated through TAK1 and SMAD7 in a subset of head and neck cancers. Transforming growth factor-beta (TGF-β) has a dual role in epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC). Attenuation of canonical TGF-β signaling enhances de novo tumor development, whereas TGF-β overexpression and signaling paradoxically promotes malignant progression. We recently observed that TGF-β-induced growth arrest response is attenuated, in association with aberrant activation of nuclear factor-κB (NF-κB), a transcription factor, which promotes malignant progression in HNSCC. However, what role cross-talk between components of the TGF-β and NF-κB pathways plays in altered activation of these pathways has not been established. Here, we show TGF-β receptor II and TGF-β-activated kinase 1 (TAK1) are predominantly expressed in a subset of HNSCC tumors with nuclear activation of NF-κB family member RELA (p65). Further, GENE treatment induced sequential phosphorylation of TAK1, IKK, IκBα and RELA in human HNSCC lines. TAK1 enhances TGF-β-induced NF-κB activation, as TAK1 siRNA knockdown decreased TGF-β1-induced phosphorylation of IKK, IκB and RELA, degradation of IκBα, RELA nuclear translocation and DNA binding, and NF-κB-induced reporter and target gene transcription. Functionally, TAK1 siRNA inhibited cell proliferation, migration and invasion. CHEMICAL, a TAK1 inhibitor and anti-inflammatory compound used in traditional Chinese medicine, also decreased GENE-induced phosphorylation of TAK1 and RELA, and suppressed basal, TGF-β1- and tumor necrosis factor-alpha (TNF-α)-induced NF-κB reporter gene activity. CHEMICAL also inhibited cell proliferation, while increasing sub-G0 DNA fragmentation and Annexin V markers of apoptosis. Furthermore, TGF-β and RELA activation promoted SMAD7 expression. In turn, SMAD7 preferentially suppressed TGF-β-induced SMAD and NF-κB reporters when compared with constitutive or TNF-α-induced NF-κB reporter gene activation. Thus, cross-talk by TGF-β via TAK1 and NF-κB promotes the malignant phenotype of HNSCC. Moreover, NF-κB may contribute to the downstream attenuation of canonical TGF-β signaling through increased SMAD7 expression. CHEMICAL highlights the therapeutic potential of agents targeting TAK1 as a key node in this pro-oncogenic TGF-β-NF-κB signal pathway. | INHIBITOR |
| TGF-β and NF-κB signal pathway cross-talk is mediated through TAK1 and SMAD7 in a subset of head and neck cancers. Transforming growth factor-beta (TGF-β) has a dual role in epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC). Attenuation of canonical TGF-β signaling enhances de novo tumor development, whereas TGF-β overexpression and signaling paradoxically promotes malignant progression. We recently observed that TGF-β-induced growth arrest response is attenuated, in association with aberrant activation of nuclear factor-κB (NF-κB), a transcription factor, which promotes malignant progression in HNSCC. However, what role cross-talk between components of the TGF-β and NF-κB pathways plays in altered activation of these pathways has not been established. Here, we show TGF-β receptor II and TGF-β-activated kinase 1 (TAK1) are predominantly expressed in a subset of HNSCC tumors with nuclear activation of NF-κB family member RELA (p65). Further, TGF-β1 treatment induced sequential phosphorylation of TAK1, IKK, IκBα and RELA in human HNSCC lines. TAK1 enhances TGF-β-induced NF-κB activation, as TAK1 siRNA knockdown decreased TGF-β1-induced phosphorylation of IKK, IκB and RELA, degradation of IκBα, RELA nuclear translocation and DNA binding, and NF-κB-induced reporter and target gene transcription. Functionally, TAK1 siRNA inhibited cell proliferation, migration and invasion. CHEMICAL, a TAK1 inhibitor and anti-inflammatory compound used in traditional Chinese medicine, also decreased TGF-β1-induced phosphorylation of TAK1 and RELA, and suppressed basal, TGF-β1- and GENE (TNF-α)-induced NF-κB reporter gene activity. CHEMICAL also inhibited cell proliferation, while increasing sub-G0 DNA fragmentation and Annexin V markers of apoptosis. Furthermore, TGF-β and RELA activation promoted SMAD7 expression. In turn, SMAD7 preferentially suppressed TGF-β-induced SMAD and NF-κB reporters when compared with constitutive or TNF-α-induced NF-κB reporter gene activation. Thus, cross-talk by TGF-β via TAK1 and NF-κB promotes the malignant phenotype of HNSCC. Moreover, NF-κB may contribute to the downstream attenuation of canonical TGF-β signaling through increased SMAD7 expression. CHEMICAL highlights the therapeutic potential of agents targeting TAK1 as a key node in this pro-oncogenic TGF-β-NF-κB signal pathway. | INHIBITOR |
| TGF-β and NF-κB signal pathway cross-talk is mediated through GENE and SMAD7 in a subset of head and neck cancers. Transforming growth factor-beta (TGF-β) has a dual role in epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC). Attenuation of canonical TGF-β signaling enhances de novo tumor development, whereas TGF-β overexpression and signaling paradoxically promotes malignant progression. We recently observed that TGF-β-induced growth arrest response is attenuated, in association with aberrant activation of nuclear factor-κB (NF-κB), a transcription factor, which promotes malignant progression in HNSCC. However, what role cross-talk between components of the TGF-β and NF-κB pathways plays in altered activation of these pathways has not been established. Here, we show TGF-β receptor II and TGF-β-activated kinase 1 (TAK1) are predominantly expressed in a subset of HNSCC tumors with nuclear activation of NF-κB family member RELA (p65). Further, TGF-β1 treatment induced sequential phosphorylation of GENE, IKK, IκBα and RELA in human HNSCC lines. GENE enhances TGF-β-induced NF-κB activation, as GENE siRNA knockdown decreased TGF-β1-induced phosphorylation of IKK, IκB and RELA, degradation of IκBα, RELA nuclear translocation and DNA binding, and NF-κB-induced reporter and target gene transcription. Functionally, GENE siRNA inhibited cell proliferation, migration and invasion. CHEMICAL, a GENE inhibitor and anti-inflammatory compound used in traditional Chinese medicine, also decreased TGF-β1-induced phosphorylation of GENE and RELA, and suppressed basal, TGF-β1- and tumor necrosis factor-alpha (TNF-α)-induced NF-κB reporter gene activity. CHEMICAL also inhibited cell proliferation, while increasing sub-G0 DNA fragmentation and Annexin V markers of apoptosis. Furthermore, TGF-β and RELA activation promoted SMAD7 expression. In turn, SMAD7 preferentially suppressed TGF-β-induced SMAD and NF-κB reporters when compared with constitutive or TNF-α-induced NF-κB reporter gene activation. Thus, cross-talk by TGF-β via GENE and NF-κB promotes the malignant phenotype of HNSCC. Moreover, NF-κB may contribute to the downstream attenuation of canonical TGF-β signaling through increased SMAD7 expression. CHEMICAL highlights the therapeutic potential of agents targeting GENE as a key node in this pro-oncogenic TGF-β-NF-κB signal pathway. | INHIBITOR |
| TGF-β and NF-κB signal pathway cross-talk is mediated through TAK1 and SMAD7 in a subset of head and neck cancers. Transforming growth factor-beta (TGF-β) has a dual role in epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC). Attenuation of canonical TGF-β signaling enhances de novo tumor development, whereas TGF-β overexpression and signaling paradoxically promotes malignant progression. We recently observed that TGF-β-induced growth arrest response is attenuated, in association with aberrant activation of nuclear factor-κB (NF-κB), a transcription factor, which promotes malignant progression in HNSCC. However, what role cross-talk between components of the TGF-β and NF-κB pathways plays in altered activation of these pathways has not been established. Here, we show TGF-β receptor II and TGF-β-activated kinase 1 (TAK1) are predominantly expressed in a subset of HNSCC tumors with nuclear activation of NF-κB family member GENE (p65). Further, TGF-β1 treatment induced sequential phosphorylation of TAK1, IKK, IκBα and GENE in human HNSCC lines. TAK1 enhances TGF-β-induced NF-κB activation, as TAK1 siRNA knockdown decreased TGF-β1-induced phosphorylation of IKK, IκB and GENE, degradation of IκBα, GENE nuclear translocation and DNA binding, and NF-κB-induced reporter and target gene transcription. Functionally, TAK1 siRNA inhibited cell proliferation, migration and invasion. CHEMICAL, a TAK1 inhibitor and anti-inflammatory compound used in traditional Chinese medicine, also decreased TGF-β1-induced phosphorylation of TAK1 and GENE, and suppressed basal, TGF-β1- and tumor necrosis factor-alpha (TNF-α)-induced NF-κB reporter gene activity. CHEMICAL also inhibited cell proliferation, while increasing sub-G0 DNA fragmentation and Annexin V markers of apoptosis. Furthermore, TGF-β and GENE activation promoted SMAD7 expression. In turn, SMAD7 preferentially suppressed TGF-β-induced SMAD and NF-κB reporters when compared with constitutive or TNF-α-induced NF-κB reporter gene activation. Thus, cross-talk by TGF-β via TAK1 and NF-κB promotes the malignant phenotype of HNSCC. Moreover, NF-κB may contribute to the downstream attenuation of canonical TGF-β signaling through increased SMAD7 expression. CHEMICAL highlights the therapeutic potential of agents targeting TAK1 as a key node in this pro-oncogenic TGF-β-NF-κB signal pathway. | INHIBITOR |
| The atypical antidepressant mianserin exhibits agonist activity at kappa-opioid receptors. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of CHEMICAL binding and MAPK phosphorylation. KEY RESULTS: Mianserin displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In CHEMICAL assays, mianserin selectively activated kappa-opioid receptors. The agonist activity was antagonized by the selective kappa-opioid blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed kappa-opioid agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing kappa-opioid receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full kappa-opioid agonists (-)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full GENE agonists in CHEMICAL assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, mianserin directly activates kappa-opioid receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | ACTIVATOR |
| The atypical antidepressant mianserin exhibits agonist activity at GENE. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of CHEMICAL binding and MAPK phosphorylation. KEY RESULTS: Mianserin displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In CHEMICAL assays, mianserin selectively activated GENE. The agonist activity was antagonized by the selective kappa-opioid blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed kappa-opioid agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing GENE and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full kappa-opioid agonists (-)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full kappa-opioid receptor agonists in CHEMICAL assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, mianserin directly activates GENE, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | DIRECT-REGULATOR |
| The atypical antidepressant mianserin exhibits agonist activity at GENE receptors. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and MAPK phosphorylation. KEY RESULTS: Mianserin displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, mianserin selectively activated GENE receptors. The agonist activity was antagonized by the selective GENE blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed GENE agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing GENE receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated CHEMICAL binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full GENE agonists (-)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full GENE receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, mianserin directly activates GENE receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | DIRECT-REGULATOR |
| The atypical antidepressant mianserin exhibits agonist activity at GENE. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and MAPK phosphorylation. KEY RESULTS: CHEMICAL displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, mianserin selectively activated GENE. The agonist activity was antagonized by the selective kappa-opioid blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed kappa-opioid agonist activity. CHEMICAL and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing GENE and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full kappa-opioid agonists (-)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full kappa-opioid receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, mianserin directly activates GENE, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | DIRECT-REGULATOR |
| The atypical antidepressant mianserin exhibits agonist activity at GENE. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and MAPK phosphorylation. KEY RESULTS: Mianserin displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, mianserin selectively activated GENE. The agonist activity was antagonized by the selective kappa-opioid blocker nor-binaltorphimine (nor-BNI). The mianserin analogue CHEMICAL also displayed kappa-opioid agonist activity. Mianserin and CHEMICAL increased ERK1/2 phosphorylation in CHO cells expressing GENE and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full kappa-opioid agonists (-)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full kappa-opioid receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, mianserin directly activates GENE, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | REGULATOR |
| The atypical antidepressant mianserin exhibits agonist activity at GENE. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and MAPK phosphorylation. KEY RESULTS: Mianserin displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, mianserin selectively activated GENE. The agonist activity was antagonized by the selective kappa-opioid blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed kappa-opioid agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing GENE and C6 cells, and these effects were antagonized by CHEMICAL. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full kappa-opioid agonists (-)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full kappa-opioid receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, mianserin directly activates GENE, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | INHIBITOR |
| The atypical antidepressant CHEMICAL exhibits agonist activity at GENE receptors. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant CHEMICAL at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of CHEMICAL were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and MAPK phosphorylation. KEY RESULTS: CHEMICAL displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, CHEMICAL selectively activated GENE receptors. The agonist activity was antagonized by the selective GENE blocker nor-binaltorphimine (nor-BNI). The CHEMICAL analogue mirtazapine also displayed GENE agonist activity. CHEMICAL and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing GENE receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, CHEMICAL stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full GENE agonists (-)-U50,488 and dynorphin A. When combined, CHEMICAL antagonized the effects of the full GENE receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, CHEMICAL directly activates GENE receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | ACTIVATOR |
| The atypical antidepressant mianserin exhibits agonist activity at GENE receptors. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and MAPK phosphorylation. KEY RESULTS: Mianserin displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, mianserin selectively activated GENE receptors. The agonist activity was antagonized by the selective GENE blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed GENE agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing GENE receptors and C6 cells, and these effects were antagonized by CHEMICAL. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgammaS binding in a CHEMICAL-sensitive manner with maximal effects lower than those of the full GENE agonists (-)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full GENE receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, mianserin directly activates GENE receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | REGULATOR |
| The atypical antidepressant mianserin exhibits agonist activity at kappa-opioid receptors. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and MAPK phosphorylation. KEY RESULTS: Mianserin displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, mianserin selectively activated kappa-opioid receptors. The agonist activity was antagonized by the selective kappa-opioid blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed kappa-opioid agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing kappa-opioid receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full kappa-opioid agonists (-)-U50,488 and CHEMICAL. When combined, mianserin antagonized the effects of the full kappa-opioid receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of GENE MAPK and ERK1/2 phosphorylation by CHEMICAL. CONCLUSIONS AND IMPLICATIONS: In different cell systems, mianserin directly activates kappa-opioid receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | ACTIVATOR |
| The atypical antidepressant mianserin exhibits agonist activity at kappa-opioid receptors. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and GENE phosphorylation. KEY RESULTS: Mianserin displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, mianserin selectively activated kappa-opioid receptors. The agonist activity was antagonized by the selective kappa-opioid blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed kappa-opioid agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing kappa-opioid receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full kappa-opioid agonists (-)-U50,488 and CHEMICAL. When combined, mianserin antagonized the effects of the full kappa-opioid receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 GENE and ERK1/2 phosphorylation by CHEMICAL. CONCLUSIONS AND IMPLICATIONS: In different cell systems, mianserin directly activates kappa-opioid receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | ACTIVATOR |
| The atypical antidepressant CHEMICAL exhibits agonist activity at GENE. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant CHEMICAL at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of CHEMICAL were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and MAPK phosphorylation. KEY RESULTS: CHEMICAL displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, CHEMICAL selectively activated GENE. The agonist activity was antagonized by the selective kappa-opioid blocker nor-binaltorphimine (nor-BNI). The CHEMICAL analogue mirtazapine also displayed kappa-opioid agonist activity. CHEMICAL and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing GENE and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, CHEMICAL stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full kappa-opioid agonists (-)-U50,488 and dynorphin A. When combined, CHEMICAL antagonized the effects of the full kappa-opioid receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, CHEMICAL directly activates GENE, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | ACTIVATOR |
| The atypical antidepressant mianserin exhibits agonist activity at GENE receptors. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and MAPK phosphorylation. KEY RESULTS: Mianserin displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, mianserin selectively activated GENE receptors. The agonist activity was antagonized by the selective GENE blocker CHEMICAL (nor-BNI). The mianserin analogue mirtazapine also displayed GENE agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing GENE receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full GENE agonists (-)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full GENE receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, mianserin directly activates GENE receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | INHIBITOR |
| The atypical antidepressant CHEMICAL exhibits agonist activity at kappa-opioid receptors. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant CHEMICAL at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of CHEMICAL were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and MAPK phosphorylation. KEY RESULTS: CHEMICAL displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, CHEMICAL selectively activated kappa-opioid receptors. The agonist activity was antagonized by the selective kappa-opioid blocker nor-binaltorphimine (nor-BNI). The CHEMICAL analogue mirtazapine also displayed kappa-opioid agonist activity. CHEMICAL and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing kappa-opioid receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, CHEMICAL stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full kappa-opioid agonists (-)-U50,488 and dynorphin A. When combined, CHEMICAL antagonized the effects of the full kappa-opioid receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of GENE MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, CHEMICAL directly activates kappa-opioid receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | INDIRECT-DOWNREGULATOR |
| The atypical antidepressant CHEMICAL exhibits agonist activity at kappa-opioid receptors. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant CHEMICAL at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of CHEMICAL were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and GENE phosphorylation. KEY RESULTS: CHEMICAL displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, CHEMICAL selectively activated kappa-opioid receptors. The agonist activity was antagonized by the selective kappa-opioid blocker nor-binaltorphimine (nor-BNI). The CHEMICAL analogue mirtazapine also displayed kappa-opioid agonist activity. CHEMICAL and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing kappa-opioid receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, CHEMICAL stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full kappa-opioid agonists (-)-U50,488 and dynorphin A. When combined, CHEMICAL antagonized the effects of the full kappa-opioid receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 GENE and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, CHEMICAL directly activates kappa-opioid receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | ACTIVATOR |
| The atypical antidepressant mianserin exhibits agonist activity at kappa-opioid receptors. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that CHEMICAL antidepressants act as agonists at distinct GENE. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native GENE. EXPERIMENTAL APPROACH: Effects of mianserin were examined in CHO cells transfected with human GENE, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and MAPK phosphorylation. KEY RESULTS: Mianserin displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, mianserin selectively activated kappa-opioid receptors. The agonist activity was antagonized by the selective kappa-opioid blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed kappa-opioid agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing kappa-opioid receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full kappa-opioid agonists (-)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full kappa-opioid receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, mianserin directly activates kappa-opioid receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | ACTIVATOR |
| The atypical antidepressant mianserin exhibits agonist activity at GENE receptors. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and MAPK phosphorylation. KEY RESULTS: Mianserin displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, mianserin selectively activated GENE receptors. The agonist activity was antagonized by the selective GENE blocker nor-binaltorphimine (nor-BNI). The mianserin analogue CHEMICAL also displayed GENE agonist activity. Mianserin and CHEMICAL increased ERK1/2 phosphorylation in CHO cells expressing GENE receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full GENE agonists (-)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full GENE receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, mianserin directly activates GENE receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | ACTIVATOR |
| The atypical antidepressant mianserin exhibits agonist activity at GENE receptors. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and MAPK phosphorylation. KEY RESULTS: Mianserin displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, mianserin selectively activated GENE receptors. The agonist activity was antagonized by the selective GENE blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed GENE agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing GENE receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full GENE agonists CHEMICAL and dynorphin A. When combined, mianserin antagonized the effects of the full GENE receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, mianserin directly activates GENE receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | ACTIVATOR |
| The atypical antidepressant mianserin exhibits agonist activity at GENE receptors. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and MAPK phosphorylation. KEY RESULTS: Mianserin displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, mianserin selectively activated GENE receptors. The agonist activity was antagonized by the selective GENE blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed GENE agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing GENE receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full GENE agonists (-)-U50,488 and CHEMICAL. When combined, mianserin antagonized the effects of the full GENE receptor agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by CHEMICAL. CONCLUSIONS AND IMPLICATIONS: In different cell systems, mianserin directly activates GENE receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | ACTIVATOR |
| The atypical antidepressant CHEMICAL exhibits agonist activity at kappa-opioid receptors. BACKGROUND AND PURPOSE: Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant CHEMICAL at cloned and native opioid receptors. EXPERIMENTAL APPROACH: Effects of CHEMICAL were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [(35)S]GTPgammaS binding and MAPK phosphorylation. KEY RESULTS: CHEMICAL displayed 12- and 18-fold higher affinity for kappa- than micro- and delta-opioid receptors respectively. In [(35)S]GTPgammaS assays, CHEMICAL selectively activated kappa-opioid receptors. The agonist activity was antagonized by the selective kappa-opioid blocker nor-binaltorphimine (nor-BNI). The CHEMICAL analogue mirtazapine also displayed kappa-opioid agonist activity. CHEMICAL and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing kappa-opioid receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, CHEMICAL stimulated [35S]GTPgammaS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full kappa-opioid agonists (-)-U50,488 and dynorphin A. When combined, CHEMICAL antagonized the effects of the full GENE agonists in [(35)S]GTPgammaS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A. CONCLUSIONS AND IMPLICATIONS: In different cell systems, CHEMICAL directly activates kappa-opioid receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants. | INHIBITOR |
| CHEMICAL restores cognitive deficits and improves amyloid and Tau pathologies in a senescence-accelerated mouse model. Ageing is associated with a deterioration of cognitive performance and with increased risk of neurodegenerative disorders. Hypertension is the most-prevalent modifiable risk factor for cardiovascular morbidity and mortality worldwide, and clinical data suggest that hypertension is a risk factor for Alzheimer's disease (AD). In the present study we tested whether CHEMICAL, a GENE antagonist commonly used as antihypertensive drug, could ameliorate the cognitive impairments and increases in AD-related markers shown by the senescence-accelerated mouse prone-8 (SAMP8). CHEMICAL administration (5 mg/kg for 3 weeks) to 6-month-old SAMP8 mice attenuated cognitive memory impairments shown by these mice in the novel object recognition test. In the hippocampus of SAMP8 mice it has been found increases in Aβ(42) levels, the principal constituent of amyloid plaques observed in AD, accompanied by both an increased expression of the cleaving enzyme BACE1 and a decreased expression of the degrading enzyme IDE. All these effects were reversed by CHEMICAL treatment. Tau hyperphosphorylation (PHF-1 epitope) shown by SAMP8 mice at this age was also decreased in the hippocampus of propranolol-treated mice, an effect probably related to a decrease in JNK1 expression. Interestingly, CHEMICAL also phosphorylated Akt in SAMP8 mice, which was associated with an increase of glycogen synthase kinase-3β phosphorylation, contributing therefore to the reductions in Tau hyperphosphorylation. Synaptic pathology in SAMP8 mice, as shown by decreases in synaptophysin and BDNF, was also counteracted by CHEMICAL treatment. Overall, CHEMICAL might be beneficial in age-related brain dysfunction and could be an emerging candidate for the treatment of other neurodegenerative diseases. This article is part of a Special Issue entitled 'Cognitive Enhancers'. | INHIBITOR |
| Anti-inflammatory trends of 1, 3-diphenyl-2-propen-1-one derivatives. CHEMICAL (1, 3-Diphenyl-2-propen-1-one) are constituted by a three carbon α, β-unsaturated carbonyl system. The biosynthesis of flavonoids and isoflavonoids is initiated by CHEMICAL. Notable pharmacological activities of CHEMICAL and its derivatives include anti-inflammatory, antifungal, antibacterial, antimalarial, antituberculosis, antitumor, antimicrobial and antiviral effects respectively. Owing to simplicity of the chemical structures and a huge variety of pharmacological actions exhibited, the entities derived from CHEMICAL are subjected to extensive consideration. This review article is an effort to sum up the anti-inflammatory activities of chalcone derived chemical entities. Effect of CHEMICAL on lipid peroxidation, GENE(HO-1), cyclooxygenase (COX), interleukin 5 (IL-5), nitric oxide (NO) and expression of cell adhesion molecules (CAM) is summarized stepwise. | GENE-CHEMICAL |
| Anti-inflammatory trends of 1, 3-diphenyl-2-propen-1-one derivatives. CHEMICAL (1, 3-Diphenyl-2-propen-1-one) are constituted by a three carbon α, β-unsaturated carbonyl system. The biosynthesis of flavonoids and isoflavonoids is initiated by CHEMICAL. Notable pharmacological activities of CHEMICAL and its derivatives include anti-inflammatory, antifungal, antibacterial, antimalarial, antituberculosis, antitumor, antimicrobial and antiviral effects respectively. Owing to simplicity of the chemical structures and a huge variety of pharmacological actions exhibited, the entities derived from CHEMICAL are subjected to extensive consideration. This review article is an effort to sum up the anti-inflammatory activities of chalcone derived chemical entities. Effect of CHEMICAL on lipid peroxidation, heme oxygenase 1(GENE), cyclooxygenase (COX), interleukin 5 (IL-5), nitric oxide (NO) and expression of cell adhesion molecules (CAM) is summarized stepwise. | GENE-CHEMICAL |
| Anti-inflammatory trends of 1, 3-diphenyl-2-propen-1-one derivatives. CHEMICAL (1, 3-Diphenyl-2-propen-1-one) are constituted by a three carbon α, β-unsaturated carbonyl system. The biosynthesis of flavonoids and isoflavonoids is initiated by CHEMICAL. Notable pharmacological activities of CHEMICAL and its derivatives include anti-inflammatory, antifungal, antibacterial, antimalarial, antituberculosis, antitumor, antimicrobial and antiviral effects respectively. Owing to simplicity of the chemical structures and a huge variety of pharmacological actions exhibited, the entities derived from CHEMICAL are subjected to extensive consideration. This review article is an effort to sum up the anti-inflammatory activities of chalcone derived chemical entities. Effect of CHEMICAL on lipid peroxidation, heme oxygenase 1(HO-1), GENE (COX), interleukin 5 (IL-5), nitric oxide (NO) and expression of cell adhesion molecules (CAM) is summarized stepwise. | GENE-CHEMICAL |
| Anti-inflammatory trends of 1, 3-diphenyl-2-propen-1-one derivatives. CHEMICAL (1, 3-Diphenyl-2-propen-1-one) are constituted by a three carbon α, β-unsaturated carbonyl system. The biosynthesis of flavonoids and isoflavonoids is initiated by CHEMICAL. Notable pharmacological activities of CHEMICAL and its derivatives include anti-inflammatory, antifungal, antibacterial, antimalarial, antituberculosis, antitumor, antimicrobial and antiviral effects respectively. Owing to simplicity of the chemical structures and a huge variety of pharmacological actions exhibited, the entities derived from CHEMICAL are subjected to extensive consideration. This review article is an effort to sum up the anti-inflammatory activities of chalcone derived chemical entities. Effect of CHEMICAL on lipid peroxidation, heme oxygenase 1(HO-1), cyclooxygenase (GENE), interleukin 5 (IL-5), nitric oxide (NO) and expression of cell adhesion molecules (CAM) is summarized stepwise. | GENE-CHEMICAL |
| Anti-inflammatory trends of 1, 3-diphenyl-2-propen-1-one derivatives. CHEMICAL (1, 3-Diphenyl-2-propen-1-one) are constituted by a three carbon α, β-unsaturated carbonyl system. The biosynthesis of flavonoids and isoflavonoids is initiated by CHEMICAL. Notable pharmacological activities of CHEMICAL and its derivatives include anti-inflammatory, antifungal, antibacterial, antimalarial, antituberculosis, antitumor, antimicrobial and antiviral effects respectively. Owing to simplicity of the chemical structures and a huge variety of pharmacological actions exhibited, the entities derived from CHEMICAL are subjected to extensive consideration. This review article is an effort to sum up the anti-inflammatory activities of chalcone derived chemical entities. Effect of CHEMICAL on lipid peroxidation, heme oxygenase 1(HO-1), cyclooxygenase (COX), GENE (IL-5), nitric oxide (NO) and expression of cell adhesion molecules (CAM) is summarized stepwise. | GENE-CHEMICAL |
| Anti-inflammatory trends of 1, 3-diphenyl-2-propen-1-one derivatives. CHEMICAL (1, 3-Diphenyl-2-propen-1-one) are constituted by a three carbon α, β-unsaturated carbonyl system. The biosynthesis of flavonoids and isoflavonoids is initiated by CHEMICAL. Notable pharmacological activities of CHEMICAL and its derivatives include anti-inflammatory, antifungal, antibacterial, antimalarial, antituberculosis, antitumor, antimicrobial and antiviral effects respectively. Owing to simplicity of the chemical structures and a huge variety of pharmacological actions exhibited, the entities derived from CHEMICAL are subjected to extensive consideration. This review article is an effort to sum up the anti-inflammatory activities of chalcone derived chemical entities. Effect of CHEMICAL on lipid peroxidation, heme oxygenase 1(HO-1), cyclooxygenase (COX), interleukin 5 (GENE), nitric oxide (NO) and expression of cell adhesion molecules (CAM) is summarized stepwise. | GENE-CHEMICAL |
| CHEMICAL generation and liver X receptor-dependent reverse cholesterol transport: not all roads lead to Rome. Cell cholesterol metabolism is a tightly regulated process, dependent in part on activation of nuclear liver X receptors (LXRs) to increase expression of genes mediating removal of excess cholesterol from cells in the reverse cholesterol transport pathway. LXRs are thought to be activated predominantly by oxysterols generated enzymatically from cholesterol in different cell organelles. Defects resulting in slowed release of cholesterol from late endosomes and lysosomes or reduction in sterol-27-hydroxylase activity lead to specific blocks in CHEMICAL production and impaired LXR-dependent gene activation. This block does not appear to be compensated by CHEMICAL production in other cell compartments. The purpose of this review is to summarize current knowledge about oxysterol-dependent activation by GENE of genes involved in reverse cholesterol transport, and what these defects of cell cholesterol homeostasis can teach us about the critical pathways of CHEMICAL generation for expression of GENE-dependent genes. | GENE-CHEMICAL |
| Oxysterol generation and liver X receptor-dependent reverse cholesterol transport: not all roads lead to Rome. Cell cholesterol metabolism is a tightly regulated process, dependent in part on activation of nuclear liver X receptors (LXRs) to increase expression of genes mediating removal of excess cholesterol from cells in the reverse cholesterol transport pathway. GENE are thought to be activated predominantly by CHEMICAL generated enzymatically from cholesterol in different cell organelles. Defects resulting in slowed release of cholesterol from late endosomes and lysosomes or reduction in sterol-27-hydroxylase activity lead to specific blocks in oxysterol production and impaired LXR-dependent gene activation. This block does not appear to be compensated by oxysterol production in other cell compartments. The purpose of this review is to summarize current knowledge about oxysterol-dependent activation by LXR of genes involved in reverse cholesterol transport, and what these defects of cell cholesterol homeostasis can teach us about the critical pathways of oxysterol generation for expression of LXR-dependent genes. | ACTIVATOR |
| CHEMICAL generation and liver X receptor-dependent reverse cholesterol transport: not all roads lead to Rome. Cell cholesterol metabolism is a tightly regulated process, dependent in part on activation of nuclear liver X receptors (LXRs) to increase expression of genes mediating removal of excess cholesterol from cells in the reverse cholesterol transport pathway. LXRs are thought to be activated predominantly by oxysterols generated enzymatically from cholesterol in different cell organelles. Defects resulting in slowed release of cholesterol from late endosomes and lysosomes or reduction in GENE activity lead to specific blocks in CHEMICAL production and impaired LXR-dependent gene activation. This block does not appear to be compensated by CHEMICAL production in other cell compartments. The purpose of this review is to summarize current knowledge about oxysterol-dependent activation by LXR of genes involved in reverse cholesterol transport, and what these defects of cell cholesterol homeostasis can teach us about the critical pathways of CHEMICAL generation for expression of LXR-dependent genes. | PRODUCT-OF |
| Cresyl saligenin phosphate makes multiple adducts on free histidine, but does not form an adduct on histidine 438 of human butyrylcholinesterase. Cresyl saligenin phosphate (CBDP) is a suspected causative agent of "aerotoxic syndrome", affecting pilots, crew members and passengers. CBDP is produced in vivo from ortho-containing isomers of tricresyl phosphate (TCP), a component of jet engine lubricants and hydraulic fluids. CBDP irreversibly inhibits butyrylcholinesterase (BChE) in human plasma by forming adducts on the active site serine (Ser-198). Inhibited GENE undergoes aging to release saligenin and o-cresol. The active site histidine (His-438) was hypothesized to abstract o-hydroxybenzyl moiety from the initial adduct on Ser-198. Our goal was to test this hypothesis. Mass spectral analysis of CBDP-inhibited GENE digested with Glu-C showed an o-hydroxybenzyl adduct (+106amu) on CHEMICAL 499, a residue far from the active site, but not on His-438. Nevertheless, the nitrogen of the imidazole ring of free l-histidine formed a variety of adducts upon reaction with CBDP, including the o-hydroxybenzyl adduct, suggesting that histidine-CBDP adducts may form on other proteins. | PART-OF |
| Cresyl saligenin phosphate makes multiple adducts on free histidine, but does not form an adduct on histidine 438 of human butyrylcholinesterase. Cresyl saligenin phosphate (CBDP) is a suspected causative agent of "aerotoxic syndrome", affecting pilots, crew members and passengers. CBDP is produced in vivo from ortho-containing isomers of tricresyl phosphate (TCP), a component of jet engine lubricants and hydraulic fluids. CBDP irreversibly inhibits butyrylcholinesterase (BChE) in human plasma by forming adducts on the active site serine (Ser-198). Inhibited GENE undergoes aging to release saligenin and o-cresol. The active site histidine (His-438) was hypothesized to abstract o-hydroxybenzyl moiety from the initial adduct on Ser-198. Our goal was to test this hypothesis. Mass spectral analysis of CBDP-inhibited GENE digested with Glu-C showed an o-hydroxybenzyl adduct (+106amu) on lysine 499, a residue far from the active site, but not on CHEMICAL-438. Nevertheless, the nitrogen of the imidazole ring of free l-histidine formed a variety of adducts upon reaction with CBDP, including the o-hydroxybenzyl adduct, suggesting that histidine-CBDP adducts may form on other proteins. | NO-RELATIONSHIP |
| Cresyl saligenin phosphate makes multiple adducts on free CHEMICAL, but does not form an adduct on CHEMICAL 438 of GENE. Cresyl saligenin phosphate (CBDP) is a suspected causative agent of "aerotoxic syndrome", affecting pilots, crew members and passengers. CBDP is produced in vivo from ortho-containing isomers of tricresyl phosphate (TCP), a component of jet engine lubricants and hydraulic fluids. CBDP irreversibly inhibits butyrylcholinesterase (BChE) in human plasma by forming adducts on the active site serine (Ser-198). Inhibited BChE undergoes aging to release saligenin and o-cresol. The active site CHEMICAL (His-438) was hypothesized to abstract o-hydroxybenzyl moiety from the initial adduct on Ser-198. Our goal was to test this hypothesis. Mass spectral analysis of CBDP-inhibited BChE digested with Glu-C showed an o-hydroxybenzyl adduct (+106amu) on lysine 499, a residue far from the active site, but not on His-438. Nevertheless, the nitrogen of the imidazole ring of free l-histidine formed a variety of adducts upon reaction with CBDP, including the o-hydroxybenzyl adduct, suggesting that histidine-CBDP adducts may form on other proteins. | PART-OF |
| Cresyl saligenin phosphate makes multiple adducts on free histidine, but does not form an adduct on histidine 438 of human GENE. Cresyl saligenin phosphate (CBDP) is a suspected causative agent of "aerotoxic syndrome", affecting pilots, crew members and passengers. CBDP is produced in vivo from ortho-containing isomers of tricresyl phosphate (TCP), a component of jet engine lubricants and hydraulic fluids. CBDP irreversibly inhibits GENE (BChE) in human plasma by forming adducts on the active site CHEMICAL (Ser-198). Inhibited BChE undergoes aging to release saligenin and o-cresol. The active site histidine (His-438) was hypothesized to abstract o-hydroxybenzyl moiety from the initial adduct on Ser-198. Our goal was to test this hypothesis. Mass spectral analysis of CBDP-inhibited BChE digested with Glu-C showed an o-hydroxybenzyl adduct (+106amu) on lysine 499, a residue far from the active site, but not on His-438. Nevertheless, the nitrogen of the imidazole ring of free l-histidine formed a variety of adducts upon reaction with CBDP, including the o-hydroxybenzyl adduct, suggesting that histidine-CBDP adducts may form on other proteins. | PART-OF |
| Cresyl saligenin phosphate makes multiple adducts on free histidine, but does not form an adduct on histidine 438 of human butyrylcholinesterase. Cresyl saligenin phosphate (CBDP) is a suspected causative agent of "aerotoxic syndrome", affecting pilots, crew members and passengers. CBDP is produced in vivo from ortho-containing isomers of tricresyl phosphate (TCP), a component of jet engine lubricants and hydraulic fluids. CBDP irreversibly inhibits butyrylcholinesterase (GENE) in human plasma by forming adducts on the active site CHEMICAL (Ser-198). Inhibited GENE undergoes aging to release saligenin and o-cresol. The active site histidine (His-438) was hypothesized to abstract o-hydroxybenzyl moiety from the initial adduct on Ser-198. Our goal was to test this hypothesis. Mass spectral analysis of CBDP-inhibited GENE digested with Glu-C showed an o-hydroxybenzyl adduct (+106amu) on lysine 499, a residue far from the active site, but not on His-438. Nevertheless, the nitrogen of the imidazole ring of free l-histidine formed a variety of adducts upon reaction with CBDP, including the o-hydroxybenzyl adduct, suggesting that histidine-CBDP adducts may form on other proteins. | PART-OF |
| Cresyl saligenin phosphate makes multiple adducts on free histidine, but does not form an adduct on histidine 438 of human GENE. Cresyl saligenin phosphate (CBDP) is a suspected causative agent of "aerotoxic syndrome", affecting pilots, crew members and passengers. CBDP is produced in vivo from ortho-containing isomers of tricresyl phosphate (TCP), a component of jet engine lubricants and hydraulic fluids. CBDP irreversibly inhibits GENE (BChE) in human plasma by forming adducts on the active site serine (CHEMICAL-198). Inhibited BChE undergoes aging to release saligenin and o-cresol. The active site histidine (His-438) was hypothesized to abstract o-hydroxybenzyl moiety from the initial adduct on Ser-198. Our goal was to test this hypothesis. Mass spectral analysis of CBDP-inhibited BChE digested with Glu-C showed an o-hydroxybenzyl adduct (+106amu) on lysine 499, a residue far from the active site, but not on His-438. Nevertheless, the nitrogen of the imidazole ring of free l-histidine formed a variety of adducts upon reaction with CBDP, including the o-hydroxybenzyl adduct, suggesting that histidine-CBDP adducts may form on other proteins. | PART-OF |
| Cresyl saligenin phosphate makes multiple adducts on free histidine, but does not form an adduct on histidine 438 of human butyrylcholinesterase. Cresyl saligenin phosphate (CBDP) is a suspected causative agent of "aerotoxic syndrome", affecting pilots, crew members and passengers. CBDP is produced in vivo from ortho-containing isomers of tricresyl phosphate (TCP), a component of jet engine lubricants and hydraulic fluids. CBDP irreversibly inhibits butyrylcholinesterase (GENE) in human plasma by forming adducts on the active site serine (CHEMICAL-198). Inhibited GENE undergoes aging to release saligenin and o-cresol. The active site histidine (His-438) was hypothesized to abstract o-hydroxybenzyl moiety from the initial adduct on Ser-198. Our goal was to test this hypothesis. Mass spectral analysis of CBDP-inhibited GENE digested with Glu-C showed an o-hydroxybenzyl adduct (+106amu) on lysine 499, a residue far from the active site, but not on His-438. Nevertheless, the nitrogen of the imidazole ring of free l-histidine formed a variety of adducts upon reaction with CBDP, including the o-hydroxybenzyl adduct, suggesting that histidine-CBDP adducts may form on other proteins. | PART-OF |
| Cresyl saligenin phosphate makes multiple adducts on free histidine, but does not form an adduct on histidine 438 of human butyrylcholinesterase. Cresyl saligenin phosphate (CBDP) is a suspected causative agent of "aerotoxic syndrome", affecting pilots, crew members and passengers. CBDP is produced in vivo from ortho-containing isomers of tricresyl phosphate (TCP), a component of jet engine lubricants and hydraulic fluids. CBDP irreversibly inhibits butyrylcholinesterase (BChE) in human plasma by forming adducts on the active site serine (Ser-198). Inhibited GENE undergoes aging to release saligenin and o-cresol. The active site histidine (His-438) was hypothesized to abstract CHEMICAL moiety from the initial adduct on Ser-198. Our goal was to test this hypothesis. Mass spectral analysis of CBDP-inhibited GENE digested with Glu-C showed an CHEMICAL adduct (+106amu) on lysine 499, a residue far from the active site, but not on His-438. Nevertheless, the nitrogen of the imidazole ring of free l-histidine formed a variety of adducts upon reaction with CBDP, including the CHEMICAL adduct, suggesting that histidine-CBDP adducts may form on other proteins. | DIRECT-REGULATOR |
| Cresyl saligenin phosphate makes multiple adducts on free histidine, but does not form an adduct on histidine 438 of human butyrylcholinesterase. Cresyl saligenin phosphate (CBDP) is a suspected causative agent of "aerotoxic syndrome", affecting pilots, crew members and passengers. CBDP is produced in vivo from ortho-containing isomers of tricresyl phosphate (TCP), a component of jet engine lubricants and hydraulic fluids. CBDP irreversibly inhibits butyrylcholinesterase (BChE) in human plasma by forming adducts on the active site serine (Ser-198). Inhibited GENE undergoes aging to release saligenin and o-cresol. The active site histidine (His-438) was hypothesized to abstract o-hydroxybenzyl moiety from the initial adduct on Ser-198. Our goal was to test this hypothesis. Mass spectral analysis of CBDP-inhibited GENE digested with CHEMICAL-C showed an o-hydroxybenzyl adduct (+106amu) on lysine 499, a residue far from the active site, but not on His-438. Nevertheless, the nitrogen of the imidazole ring of free l-histidine formed a variety of adducts upon reaction with CBDP, including the o-hydroxybenzyl adduct, suggesting that histidine-CBDP adducts may form on other proteins. | PART-OF |
| CHEMICAL makes multiple adducts on free histidine, but does not form an adduct on histidine 438 of GENE. CHEMICAL (CBDP) is a suspected causative agent of "aerotoxic syndrome", affecting pilots, crew members and passengers. CBDP is produced in vivo from ortho-containing isomers of tricresyl phosphate (TCP), a component of jet engine lubricants and hydraulic fluids. CBDP irreversibly inhibits butyrylcholinesterase (BChE) in human plasma by forming adducts on the active site serine (Ser-198). Inhibited BChE undergoes aging to release saligenin and o-cresol. The active site histidine (His-438) was hypothesized to abstract o-hydroxybenzyl moiety from the initial adduct on Ser-198. Our goal was to test this hypothesis. Mass spectral analysis of CBDP-inhibited BChE digested with Glu-C showed an o-hydroxybenzyl adduct (+106amu) on lysine 499, a residue far from the active site, but not on His-438. Nevertheless, the nitrogen of the imidazole ring of free l-histidine formed a variety of adducts upon reaction with CBDP, including the o-hydroxybenzyl adduct, suggesting that histidine-CBDP adducts may form on other proteins. | NO-RELATIONSHIP |
| Cresyl saligenin phosphate makes multiple adducts on free histidine, but does not form an adduct on histidine 438 of human butyrylcholinesterase. Cresyl saligenin phosphate (CBDP) is a suspected causative agent of "aerotoxic syndrome", affecting pilots, crew members and passengers. CHEMICAL is produced in vivo from ortho-containing isomers of tricresyl phosphate (TCP), a component of jet engine lubricants and hydraulic fluids. CHEMICAL irreversibly inhibits butyrylcholinesterase (BChE) in human plasma by forming adducts on the active site serine (Ser-198). Inhibited GENE undergoes aging to release saligenin and o-cresol. The active site histidine (His-438) was hypothesized to abstract o-hydroxybenzyl moiety from the initial adduct on Ser-198. Our goal was to test this hypothesis. Mass spectral analysis of CHEMICAL-inhibited GENE digested with Glu-C showed an o-hydroxybenzyl adduct (+106amu) on lysine 499, a residue far from the active site, but not on His-438. Nevertheless, the nitrogen of the imidazole ring of free l-histidine formed a variety of adducts upon reaction with CHEMICAL, including the o-hydroxybenzyl adduct, suggesting that histidine-CBDP adducts may form on other proteins. | INHIBITOR |
| Cresyl saligenin phosphate makes multiple adducts on free histidine, but does not form an adduct on histidine 438 of human GENE. Cresyl saligenin phosphate (CBDP) is a suspected causative agent of "aerotoxic syndrome", affecting pilots, crew members and passengers. CHEMICAL is produced in vivo from ortho-containing isomers of tricresyl phosphate (TCP), a component of jet engine lubricants and hydraulic fluids. CHEMICAL irreversibly inhibits GENE (BChE) in human plasma by forming adducts on the active site serine (Ser-198). Inhibited BChE undergoes aging to release saligenin and o-cresol. The active site histidine (His-438) was hypothesized to abstract o-hydroxybenzyl moiety from the initial adduct on Ser-198. Our goal was to test this hypothesis. Mass spectral analysis of CBDP-inhibited BChE digested with Glu-C showed an o-hydroxybenzyl adduct (+106amu) on lysine 499, a residue far from the active site, but not on His-438. Nevertheless, the nitrogen of the imidazole ring of free l-histidine formed a variety of adducts upon reaction with CHEMICAL, including the o-hydroxybenzyl adduct, suggesting that histidine-CBDP adducts may form on other proteins. | INHIBITOR |
| Vitamin E deficiency impairs the somatostatinergic receptor-effector system and leads to phosphotyrosine phosphatase overactivation and cell death in the rat hippocampus. Vitamin E plays an essential role in maintaining the structure and function of the nervous system, and its deficiency, commonly associated with fat malabsorption diseases, may reduce neuronal survival. We previously demonstrated that the somatostatinergic system, implicated in neuronal survival control, can be modulated by CHEMICAL in the rat dentate gyrus, increasing GENE phosphorylation. To gain a better understanding of the molecular actions of tocopherols and examine the link among vitamin E, somatostatin and neuronal survival, we have investigated the effects of a deficiency and subsequent administration of tocopherol on the somatostatin signaling pathway and neuronal survival in the rat hippocampus. No changes in somatostatin expression were detected in vitamin-E-deficient rats. These rats, however, showed a significant increase in the somatostatin receptor density and dissociation constant, which correlated with a significant increase in the protein levels of somatostatin receptors. Nevertheless, vitamin E deficiency impaired the ability of the somatostatin receptors to couple to the effectors adenylyl cyclase and phosphotyrosine phosphatase by diminishing Gi protein functionality. Furthermore, vitamin E deficiency significantly increased phosphotyrosine phosphatase activity and PTPη expression, as well as PKCδ activation, and decreased extracellular-signal-regulated kinase phosphorylation. All these changes were accompanied by an increase in neuronal cell death. Subsequent CHEMICAL administration partially or completely reversed all these values to control levels. Altogether, our results prove the importance of vitamin E homeostasis in the somatostatin receptor-effector system and suggest a possible mechanism by which this vitamin may regulate the neuronal cell survival in the adult hippocampus. | ACTIVATOR |
| CCAAT/Enhancer-binding protein-homologous protein sensitizes to CHEMICAL by modulating p21 and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma cells. CHEMICAL, vascular endothelial cell growth factor receptor inhibitor, suppresses hypoxia-induced angiogenesis, growth, proliferation, and metastasis in cancer cells. CCAAT/enhancer-binding protein-homologous protein (CHOP) has pivotal roles in regulation of growth and survival. In the present study, we evaluated the effects of CHEMICAL on cell survival, p21, and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma (ATC) cells. Moreover, we investigated the roles of CHOP in cell survival under condition of CHEMICAL treatment in FRO ATC cells. After CHEMICAL treatment, cell viability, GENE, and caspase-3 protein levels were not changed. p53 and p27 protein levels decreased while p21 protein levels increased. Phospho-Akt protein levels were not altered. In SU5416-treated situation, cell viability was not different before and after administration of either p21 siRNA or LY294002 whereas it was lessened after co-administration of p21 siRNA and LY294002. Compared to CHEMICAL treatment alone, cell viability was reduced with CHOP plasmid but it was unchanged with CHOP siRNA. GENE and caspase-3 protein levels with CHOP plasmid were elevated whereas the protein levels with CHOP siRNA were similar. While CHOP plasmid transfection diminished p21 and phospho-Akt protein levels, CHOP siRNA transfection did not alter the protein levels. In conclusion, these results suggest that CHOP may sensitize FRO ATC cells to CHEMICAL thereby inhibiting cell survival by modulating p21 and PI3K/Akt signal pathway. Furthermore, these findings imply that CHOP may be a possible candidate as the chemosensitizing factor for induction of cytotoxicity in ATC cells exposed to CHEMICAL. | NO-RELATIONSHIP |
| CCAAT/Enhancer-binding protein-homologous protein sensitizes to CHEMICAL by modulating p21 and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma cells. CHEMICAL, vascular endothelial cell growth factor receptor inhibitor, suppresses hypoxia-induced angiogenesis, growth, proliferation, and metastasis in cancer cells. CCAAT/enhancer-binding protein-homologous protein (CHOP) has pivotal roles in regulation of growth and survival. In the present study, we evaluated the effects of CHEMICAL on cell survival, p21, and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma (ATC) cells. Moreover, we investigated the roles of CHOP in cell survival under condition of CHEMICAL treatment in FRO ATC cells. After CHEMICAL treatment, cell viability, PARP-1, and GENE protein levels were not changed. p53 and p27 protein levels decreased while p21 protein levels increased. Phospho-Akt protein levels were not altered. In SU5416-treated situation, cell viability was not different before and after administration of either p21 siRNA or LY294002 whereas it was lessened after co-administration of p21 siRNA and LY294002. Compared to CHEMICAL treatment alone, cell viability was reduced with CHOP plasmid but it was unchanged with CHOP siRNA. PARP-1 and GENE protein levels with CHOP plasmid were elevated whereas the protein levels with CHOP siRNA were similar. While CHOP plasmid transfection diminished p21 and phospho-Akt protein levels, CHOP siRNA transfection did not alter the protein levels. In conclusion, these results suggest that CHOP may sensitize FRO ATC cells to CHEMICAL thereby inhibiting cell survival by modulating p21 and PI3K/Akt signal pathway. Furthermore, these findings imply that CHOP may be a possible candidate as the chemosensitizing factor for induction of cytotoxicity in ATC cells exposed to CHEMICAL. | NO-RELATIONSHIP |
| GENE sensitizes to CHEMICAL by modulating p21 and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma cells. CHEMICAL, vascular endothelial cell growth factor receptor inhibitor, suppresses hypoxia-induced angiogenesis, growth, proliferation, and metastasis in cancer cells. CCAAT/enhancer-binding protein-homologous protein (CHOP) has pivotal roles in regulation of growth and survival. In the present study, we evaluated the effects of CHEMICAL on cell survival, p21, and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma (ATC) cells. Moreover, we investigated the roles of CHOP in cell survival under condition of CHEMICAL treatment in FRO ATC cells. After CHEMICAL treatment, cell viability, PARP-1, and caspase-3 protein levels were not changed. p53 and p27 protein levels decreased while p21 protein levels increased. Phospho-Akt protein levels were not altered. In SU5416-treated situation, cell viability was not different before and after administration of either p21 siRNA or LY294002 whereas it was lessened after co-administration of p21 siRNA and LY294002. Compared to CHEMICAL treatment alone, cell viability was reduced with CHOP plasmid but it was unchanged with CHOP siRNA. PARP-1 and caspase-3 protein levels with CHOP plasmid were elevated whereas the protein levels with CHOP siRNA were similar. While CHOP plasmid transfection diminished p21 and phospho-Akt protein levels, CHOP siRNA transfection did not alter the protein levels. In conclusion, these results suggest that CHOP may sensitize FRO ATC cells to CHEMICAL thereby inhibiting cell survival by modulating p21 and PI3K/Akt signal pathway. Furthermore, these findings imply that CHOP may be a possible candidate as the chemosensitizing factor for induction of cytotoxicity in ATC cells exposed to CHEMICAL. | REGULATOR |
| CCAAT/Enhancer-binding protein-homologous protein sensitizes to CHEMICAL by modulating GENE and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma cells. CHEMICAL, vascular endothelial cell growth factor receptor inhibitor, suppresses hypoxia-induced angiogenesis, growth, proliferation, and metastasis in cancer cells. CCAAT/enhancer-binding protein-homologous protein (CHOP) has pivotal roles in regulation of growth and survival. In the present study, we evaluated the effects of CHEMICAL on cell survival, GENE, and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma (ATC) cells. Moreover, we investigated the roles of CHOP in cell survival under condition of CHEMICAL treatment in FRO ATC cells. After CHEMICAL treatment, cell viability, PARP-1, and caspase-3 protein levels were not changed. p53 and p27 protein levels decreased while GENE protein levels increased. Phospho-Akt protein levels were not altered. In SU5416-treated situation, cell viability was not different before and after administration of either GENE siRNA or LY294002 whereas it was lessened after co-administration of GENE siRNA and LY294002. Compared to CHEMICAL treatment alone, cell viability was reduced with CHOP plasmid but it was unchanged with CHOP siRNA. PARP-1 and caspase-3 protein levels with CHOP plasmid were elevated whereas the protein levels with CHOP siRNA were similar. While CHOP plasmid transfection diminished GENE and phospho-Akt protein levels, CHOP siRNA transfection did not alter the protein levels. In conclusion, these results suggest that CHOP may sensitize FRO ATC cells to CHEMICAL thereby inhibiting cell survival by modulating GENE and PI3K/Akt signal pathway. Furthermore, these findings imply that CHOP may be a possible candidate as the chemosensitizing factor for induction of cytotoxicity in ATC cells exposed to CHEMICAL. | GENE-CHEMICAL |
| CCAAT/Enhancer-binding protein-homologous protein sensitizes to CHEMICAL by modulating p21 and GENE/Akt signal pathway in FRO anaplastic thyroid carcinoma cells. CHEMICAL, vascular endothelial cell growth factor receptor inhibitor, suppresses hypoxia-induced angiogenesis, growth, proliferation, and metastasis in cancer cells. CCAAT/enhancer-binding protein-homologous protein (CHOP) has pivotal roles in regulation of growth and survival. In the present study, we evaluated the effects of CHEMICAL on cell survival, p21, and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma (ATC) cells. Moreover, we investigated the roles of CHOP in cell survival under condition of CHEMICAL treatment in FRO ATC cells. After CHEMICAL treatment, cell viability, PARP-1, and caspase-3 protein levels were not changed. p53 and p27 protein levels decreased while p21 protein levels increased. Phospho-Akt protein levels were not altered. In SU5416-treated situation, cell viability was not different before and after administration of either p21 siRNA or LY294002 whereas it was lessened after co-administration of p21 siRNA and LY294002. Compared to CHEMICAL treatment alone, cell viability was reduced with CHOP plasmid but it was unchanged with CHOP siRNA. PARP-1 and caspase-3 protein levels with CHOP plasmid were elevated whereas the protein levels with CHOP siRNA were similar. While CHOP plasmid transfection diminished p21 and phospho-Akt protein levels, CHOP siRNA transfection did not alter the protein levels. In conclusion, these results suggest that CHOP may sensitize FRO ATC cells to CHEMICAL thereby inhibiting cell survival by modulating p21 and PI3K/Akt signal pathway. Furthermore, these findings imply that CHOP may be a possible candidate as the chemosensitizing factor for induction of cytotoxicity in ATC cells exposed to CHEMICAL. | REGULATOR |
| CCAAT/Enhancer-binding protein-homologous protein sensitizes to CHEMICAL by modulating p21 and PI3K/GENE signal pathway in FRO anaplastic thyroid carcinoma cells. CHEMICAL, vascular endothelial cell growth factor receptor inhibitor, suppresses hypoxia-induced angiogenesis, growth, proliferation, and metastasis in cancer cells. CCAAT/enhancer-binding protein-homologous protein (CHOP) has pivotal roles in regulation of growth and survival. In the present study, we evaluated the effects of CHEMICAL on cell survival, p21, and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma (ATC) cells. Moreover, we investigated the roles of CHOP in cell survival under condition of CHEMICAL treatment in FRO ATC cells. After CHEMICAL treatment, cell viability, PARP-1, and caspase-3 protein levels were not changed. p53 and p27 protein levels decreased while p21 protein levels increased. Phospho-Akt protein levels were not altered. In SU5416-treated situation, cell viability was not different before and after administration of either p21 siRNA or LY294002 whereas it was lessened after co-administration of p21 siRNA and LY294002. Compared to CHEMICAL treatment alone, cell viability was reduced with CHOP plasmid but it was unchanged with CHOP siRNA. PARP-1 and caspase-3 protein levels with CHOP plasmid were elevated whereas the protein levels with CHOP siRNA were similar. While CHOP plasmid transfection diminished p21 and phospho-Akt protein levels, CHOP siRNA transfection did not alter the protein levels. In conclusion, these results suggest that CHOP may sensitize FRO ATC cells to CHEMICAL thereby inhibiting cell survival by modulating p21 and PI3K/Akt signal pathway. Furthermore, these findings imply that CHOP may be a possible candidate as the chemosensitizing factor for induction of cytotoxicity in ATC cells exposed to CHEMICAL. | REGULATOR |
| CCAAT/Enhancer-binding protein-homologous protein sensitizes to CHEMICAL by modulating p21 and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma cells. CHEMICAL, vascular endothelial cell growth factor receptor inhibitor, suppresses hypoxia-induced angiogenesis, growth, proliferation, and metastasis in cancer cells. CCAAT/enhancer-binding protein-homologous protein (CHOP) has pivotal roles in regulation of growth and survival. In the present study, we evaluated the effects of CHEMICAL on cell survival, p21, and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma (ATC) cells. Moreover, we investigated the roles of GENE in cell survival under condition of CHEMICAL treatment in FRO ATC cells. After CHEMICAL treatment, cell viability, PARP-1, and caspase-3 protein levels were not changed. p53 and p27 protein levels decreased while p21 protein levels increased. Phospho-Akt protein levels were not altered. In SU5416-treated situation, cell viability was not different before and after administration of either p21 siRNA or LY294002 whereas it was lessened after co-administration of p21 siRNA and LY294002. Compared to CHEMICAL treatment alone, cell viability was reduced with GENE plasmid but it was unchanged with GENE siRNA. PARP-1 and caspase-3 protein levels with GENE plasmid were elevated whereas the protein levels with GENE siRNA were similar. While GENE plasmid transfection diminished p21 and phospho-Akt protein levels, GENE siRNA transfection did not alter the protein levels. In conclusion, these results suggest that GENE may sensitize FRO ATC cells to CHEMICAL thereby inhibiting cell survival by modulating p21 and PI3K/Akt signal pathway. Furthermore, these findings imply that GENE may be a possible candidate as the chemosensitizing factor for induction of cytotoxicity in ATC cells exposed to CHEMICAL. | REGULATOR |
| Cholinergic modulation by opioid receptor ligands: potential application to Alzheimer's disease. Morphinans have a storied history in medicinal chemistry as pain management drugs but have received attention as modulators of cholinergic signaling for the treatment of Alzheimer's Disease (AD). CHEMICAL is a reversible, competitive acetylcholinesterase (AChE) inhibitor and allosteric potentiating ligand of GENE (nAChR-APL) that shares many common structural elements with morphinan-based opioids. The structurally diverse opioids codeine and eseroline, like galantamine, are also nAChR-APL that have greatly diminished affinity for AChE, representing potential lead compounds for selective nAChR-APL development. In accordance with the emerging repurposing trend of evaluating known compounds for novel pharmacological activity, ongoing research on augmentation of cholinergic signaling that has been aided by the use of opioids will be reviewed. | DIRECT-REGULATOR |
| Cholinergic modulation by opioid receptor ligands: potential application to Alzheimer's disease. Morphinans have a storied history in medicinal chemistry as pain management drugs but have received attention as modulators of cholinergic signaling for the treatment of Alzheimer's Disease (AD). CHEMICAL is a reversible, competitive acetylcholinesterase (AChE) inhibitor and allosteric potentiating ligand of nicotinic acetylcholine receptors (GENE-APL) that shares many common structural elements with morphinan-based opioids. The structurally diverse opioids codeine and eseroline, like galantamine, are also nAChR-APL that have greatly diminished affinity for AChE, representing potential lead compounds for selective nAChR-APL development. In accordance with the emerging repurposing trend of evaluating known compounds for novel pharmacological activity, ongoing research on augmentation of cholinergic signaling that has been aided by the use of opioids will be reviewed. | DIRECT-REGULATOR |
| Cholinergic modulation by opioid receptor ligands: potential application to Alzheimer's disease. Morphinans have a storied history in medicinal chemistry as pain management drugs but have received attention as modulators of cholinergic signaling for the treatment of Alzheimer's Disease (AD). Galantamine is a reversible, competitive acetylcholinesterase (AChE) inhibitor and allosteric potentiating ligand of nicotinic acetylcholine receptors (nAChR-APL) that shares many common structural elements with morphinan-based opioids. The structurally diverse opioids CHEMICAL and eseroline, like galantamine, are also GENE-APL that have greatly diminished affinity for AChE, representing potential lead compounds for selective nAChR-APL development. In accordance with the emerging repurposing trend of evaluating known compounds for novel pharmacological activity, ongoing research on augmentation of cholinergic signaling that has been aided by the use of opioids will be reviewed. | REGULATOR |
| Cholinergic modulation by opioid receptor ligands: potential application to Alzheimer's disease. Morphinans have a storied history in medicinal chemistry as pain management drugs but have received attention as modulators of cholinergic signaling for the treatment of Alzheimer's Disease (AD). Galantamine is a reversible, competitive acetylcholinesterase (AChE) inhibitor and allosteric potentiating ligand of nicotinic acetylcholine receptors (nAChR-APL) that shares many common structural elements with morphinan-based opioids. The structurally diverse opioids CHEMICAL and eseroline, like galantamine, are also nAChR-APL that have greatly diminished affinity for GENE, representing potential lead compounds for selective nAChR-APL development. In accordance with the emerging repurposing trend of evaluating known compounds for novel pharmacological activity, ongoing research on augmentation of cholinergic signaling that has been aided by the use of opioids will be reviewed. | DIRECT-REGULATOR |
| Cholinergic modulation by opioid receptor ligands: potential application to Alzheimer's disease. Morphinans have a storied history in medicinal chemistry as pain management drugs but have received attention as modulators of cholinergic signaling for the treatment of Alzheimer's Disease (AD). Galantamine is a reversible, competitive acetylcholinesterase (AChE) inhibitor and allosteric potentiating ligand of nicotinic acetylcholine receptors (nAChR-APL) that shares many common structural elements with morphinan-based opioids. The structurally diverse opioids codeine and CHEMICAL, like galantamine, are also GENE-APL that have greatly diminished affinity for AChE, representing potential lead compounds for selective nAChR-APL development. In accordance with the emerging repurposing trend of evaluating known compounds for novel pharmacological activity, ongoing research on augmentation of cholinergic signaling that has been aided by the use of opioids will be reviewed. | INHIBITOR |
| Cholinergic modulation by opioid receptor ligands: potential application to Alzheimer's disease. Morphinans have a storied history in medicinal chemistry as pain management drugs but have received attention as modulators of cholinergic signaling for the treatment of Alzheimer's Disease (AD). Galantamine is a reversible, competitive acetylcholinesterase (AChE) inhibitor and allosteric potentiating ligand of nicotinic acetylcholine receptors (nAChR-APL) that shares many common structural elements with morphinan-based opioids. The structurally diverse opioids codeine and CHEMICAL, like galantamine, are also nAChR-APL that have greatly diminished affinity for GENE, representing potential lead compounds for selective nAChR-APL development. In accordance with the emerging repurposing trend of evaluating known compounds for novel pharmacological activity, ongoing research on augmentation of cholinergic signaling that has been aided by the use of opioids will be reviewed. | DIRECT-REGULATOR |
| Cholinergic modulation by opioid receptor ligands: potential application to Alzheimer's disease. Morphinans have a storied history in medicinal chemistry as pain management drugs but have received attention as modulators of cholinergic signaling for the treatment of Alzheimer's Disease (AD). CHEMICAL is a reversible, competitive acetylcholinesterase (AChE) inhibitor and allosteric potentiating ligand of nicotinic acetylcholine receptors (nAChR-APL) that shares many common structural elements with morphinan-based opioids. The structurally diverse opioids codeine and eseroline, like CHEMICAL, are also nAChR-APL that have greatly diminished affinity for GENE, representing potential lead compounds for selective nAChR-APL development. In accordance with the emerging repurposing trend of evaluating known compounds for novel pharmacological activity, ongoing research on augmentation of cholinergic signaling that has been aided by the use of opioids will be reviewed. | DIRECT-REGULATOR |
| Cholinergic modulation by opioid receptor ligands: potential application to Alzheimer's disease. Morphinans have a storied history in medicinal chemistry as pain management drugs but have received attention as modulators of cholinergic signaling for the treatment of Alzheimer's Disease (AD). CHEMICAL is a reversible, competitive GENE (AChE) inhibitor and allosteric potentiating ligand of nicotinic acetylcholine receptors (nAChR-APL) that shares many common structural elements with morphinan-based opioids. The structurally diverse opioids codeine and eseroline, like galantamine, are also nAChR-APL that have greatly diminished affinity for AChE, representing potential lead compounds for selective nAChR-APL development. In accordance with the emerging repurposing trend of evaluating known compounds for novel pharmacological activity, ongoing research on augmentation of cholinergic signaling that has been aided by the use of opioids will be reviewed. | INHIBITOR |
| Abnormal uterine bleeding and dysfunctional uterine bleeding in pediatric and adolescent gynecology. Abnormal uterine bleeding (AUB), which is defined as excessively heavy, prolonged and/or frequent bleeding of uterine origin, is a frequent cause of visits to the Emergency Department and/or health care provider. While there are many etiologies of AUB, the one most likely among otherwise healthy adolescents is dysfunctional uterine bleeding (DUB), which is characterizing any AUB when all possible underlying pathologic causes have been previously excluded. The most common cause of DUB in adolescence is anovulation, which is very frequent in the first 2-3 post-menarchal years and is associated with immaturity of the hypothalamic - pituitary - ovarian axis. Management of AUB is based on the underlying etiology and the severity of the bleeding and primary goals are prevention of complications, such as anemia and reestablishment of regular cyclical bleeding, while the management of DUB can in part be directed by the amount of flow, the degree of associated anemia, as well as patient and family comfort with different treatment modalities. Treatment options for DUB are: combined oral contraceptives (COCs), progestogens, non steroidal anti inflammatory drugs (NSAIDs), tranexamic acid (anti-fibrinolytic), GENE analogues, CHEMICAL and Levonorgestrel releasing intra uterine system (LNG IUS). | INHIBITOR |
| Abnormal uterine bleeding and dysfunctional uterine bleeding in pediatric and adolescent gynecology. Abnormal uterine bleeding (AUB), which is defined as excessively heavy, prolonged and/or frequent bleeding of uterine origin, is a frequent cause of visits to the Emergency Department and/or health care provider. While there are many etiologies of AUB, the one most likely among otherwise healthy adolescents is dysfunctional uterine bleeding (DUB), which is characterizing any AUB when all possible underlying pathologic causes have been previously excluded. The most common cause of DUB in adolescence is anovulation, which is very frequent in the first 2-3 post-menarchal years and is associated with immaturity of the hypothalamic - pituitary - ovarian axis. Management of AUB is based on the underlying etiology and the severity of the bleeding and primary goals are prevention of complications, such as anemia and reestablishment of regular cyclical bleeding, while the management of DUB can in part be directed by the amount of flow, the degree of associated anemia, as well as patient and family comfort with different treatment modalities. Treatment options for DUB are: combined oral contraceptives (COCs), progestogens, non steroidal anti inflammatory drugs (NSAIDs), tranexamic acid (anti-fibrinolytic), GENE analogues, Danazol and CHEMICAL releasing intra uterine system (LNG IUS). | REGULATOR |
| Role of CHEMICAL receptors on the modulation of NADPH-diaphorase-positive cell number in supraoptic and paraventricular nuclei of ovariectomised female rats. Modulation of the nitric oxide producing system (demonstrated via the NADPH-diaphorase histochemical reaction) by oestradiol has been established in several structures of the rat brain. The present study aimed to explore the possible regulation of NADPH-diaphorase activity by oestradiol in neurones of the supraoptic (SON) and paraventricular (PVN) nuclei and the role of CHEMICAL receptors (ERα and ERβ) in this regulation. Adult ovariectomised rats were divided into six groups and injected either with vehicle or a single dose of oestradiol, a selective ERα agonist-PPT [4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol], a selective ERβ agonist-DPN [2,3-bis(4-hydroxyphenyl)-propionitrile], a selective ERα antagonist-MPP [1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride] or a selective ERβ antagonist-PHTPP (4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol). The number of NADPH-diaphorase positive elements in the SON and the PVN was modulated by both GENE but, depending on the nucleus, ERα and ERβ ligands induced different effects. These results suggest that the regulation of nitrergic system by GENE may play a role in the control of CHEMICAL-dependent physiological mechanisms regulated by the SON and the PVN. | REGULATOR |
| Role of oestrogen receptors on the modulation of NADPH-diaphorase-positive cell number in supraoptic and paraventricular nuclei of ovariectomised female rats. Modulation of the nitric oxide producing system (demonstrated via the NADPH-diaphorase histochemical reaction) by oestradiol has been established in several structures of the rat brain. The present study aimed to explore the possible regulation of NADPH-diaphorase activity by oestradiol in neurones of the supraoptic (SON) and paraventricular (PVN) nuclei and the role of oestrogen receptors (ERα and ERβ) in this regulation. Adult ovariectomised rats were divided into six groups and injected either with vehicle or a single dose of oestradiol, a selective ERα agonist-PPT [4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol], a selective GENE agonist-CHEMICAL [2,3-bis(4-hydroxyphenyl)-propionitrile], a selective ERα antagonist-MPP [1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride] or a selective GENE antagonist-PHTPP (4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol). The number of NADPH-diaphorase positive elements in the SON and the PVN was modulated by both ERs but, depending on the nucleus, ERα and GENE ligands induced different effects. These results suggest that the regulation of nitrergic system by ERs may play a role in the control of oestrogen-dependent physiological mechanisms regulated by the SON and the PVN. | ACTIVATOR |
| Role of oestrogen receptors on the modulation of NADPH-diaphorase-positive cell number in supraoptic and paraventricular nuclei of ovariectomised female rats. Modulation of the nitric oxide producing system (demonstrated via the NADPH-diaphorase histochemical reaction) by oestradiol has been established in several structures of the rat brain. The present study aimed to explore the possible regulation of NADPH-diaphorase activity by oestradiol in neurones of the supraoptic (SON) and paraventricular (PVN) nuclei and the role of oestrogen receptors (ERα and ERβ) in this regulation. Adult ovariectomised rats were divided into six groups and injected either with vehicle or a single dose of oestradiol, a selective ERα agonist-PPT [4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol], a selective GENE agonist-DPN [CHEMICAL], a selective ERα antagonist-MPP [1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride] or a selective GENE antagonist-PHTPP (4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol). The number of NADPH-diaphorase positive elements in the SON and the PVN was modulated by both ERs but, depending on the nucleus, ERα and GENE ligands induced different effects. These results suggest that the regulation of nitrergic system by ERs may play a role in the control of oestrogen-dependent physiological mechanisms regulated by the SON and the PVN. | ACTIVATOR |
| Role of oestrogen receptors on the modulation of NADPH-diaphorase-positive cell number in supraoptic and paraventricular nuclei of ovariectomised female rats. Modulation of the nitric oxide producing system (demonstrated via the NADPH-diaphorase histochemical reaction) by oestradiol has been established in several structures of the rat brain. The present study aimed to explore the possible regulation of NADPH-diaphorase activity by oestradiol in neurones of the supraoptic (SON) and paraventricular (PVN) nuclei and the role of oestrogen receptors (ERα and ERβ) in this regulation. Adult ovariectomised rats were divided into six groups and injected either with vehicle or a single dose of oestradiol, a selective GENE agonist-CHEMICAL [4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol], a selective ERβ agonist-DPN [2,3-bis(4-hydroxyphenyl)-propionitrile], a selective GENE antagonist-MPP [1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride] or a selective ERβ antagonist-PHTPP (4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol). The number of NADPH-diaphorase positive elements in the SON and the PVN was modulated by both ERs but, depending on the nucleus, GENE and ERβ ligands induced different effects. These results suggest that the regulation of nitrergic system by ERs may play a role in the control of oestrogen-dependent physiological mechanisms regulated by the SON and the PVN. | ACTIVATOR |
| Role of oestrogen receptors on the modulation of NADPH-diaphorase-positive cell number in supraoptic and paraventricular nuclei of ovariectomised female rats. Modulation of the nitric oxide producing system (demonstrated via the NADPH-diaphorase histochemical reaction) by oestradiol has been established in several structures of the rat brain. The present study aimed to explore the possible regulation of NADPH-diaphorase activity by oestradiol in neurones of the supraoptic (SON) and paraventricular (PVN) nuclei and the role of oestrogen receptors (ERα and ERβ) in this regulation. Adult ovariectomised rats were divided into six groups and injected either with vehicle or a single dose of oestradiol, a selective GENE agonist-PPT [CHEMICAL], a selective ERβ agonist-DPN [2,3-bis(4-hydroxyphenyl)-propionitrile], a selective GENE antagonist-MPP [1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride] or a selective ERβ antagonist-PHTPP (4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol). The number of NADPH-diaphorase positive elements in the SON and the PVN was modulated by both ERs but, depending on the nucleus, GENE and ERβ ligands induced different effects. These results suggest that the regulation of nitrergic system by ERs may play a role in the control of oestrogen-dependent physiological mechanisms regulated by the SON and the PVN. | ACTIVATOR |
| Role of oestrogen receptors on the modulation of NADPH-diaphorase-positive cell number in supraoptic and paraventricular nuclei of ovariectomised female rats. Modulation of the nitric oxide producing system (demonstrated via the NADPH-diaphorase histochemical reaction) by oestradiol has been established in several structures of the rat brain. The present study aimed to explore the possible regulation of NADPH-diaphorase activity by oestradiol in neurones of the supraoptic (SON) and paraventricular (PVN) nuclei and the role of oestrogen receptors (ERα and ERβ) in this regulation. Adult ovariectomised rats were divided into six groups and injected either with vehicle or a single dose of oestradiol, a selective GENE agonist-PPT [4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol], a selective ERβ agonist-DPN [2,3-bis(4-hydroxyphenyl)-propionitrile], a selective GENE antagonist-CHEMICAL [1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride] or a selective ERβ antagonist-PHTPP (4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol). The number of NADPH-diaphorase positive elements in the SON and the PVN was modulated by both ERs but, depending on the nucleus, GENE and ERβ ligands induced different effects. These results suggest that the regulation of nitrergic system by ERs may play a role in the control of oestrogen-dependent physiological mechanisms regulated by the SON and the PVN. | INHIBITOR |
| Role of oestrogen receptors on the modulation of NADPH-diaphorase-positive cell number in supraoptic and paraventricular nuclei of ovariectomised female rats. Modulation of the nitric oxide producing system (demonstrated via the NADPH-diaphorase histochemical reaction) by oestradiol has been established in several structures of the rat brain. The present study aimed to explore the possible regulation of NADPH-diaphorase activity by oestradiol in neurones of the supraoptic (SON) and paraventricular (PVN) nuclei and the role of oestrogen receptors (ERα and ERβ) in this regulation. Adult ovariectomised rats were divided into six groups and injected either with vehicle or a single dose of oestradiol, a selective GENE agonist-PPT [4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol], a selective ERβ agonist-DPN [2,3-bis(4-hydroxyphenyl)-propionitrile], a selective GENE antagonist-MPP [CHEMICAL]-1H-pyrazole dihydrochloride] or a selective ERβ antagonist-PHTPP (4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol). The number of NADPH-diaphorase positive elements in the SON and the PVN was modulated by both ERs but, depending on the nucleus, GENE and ERβ ligands induced different effects. These results suggest that the regulation of nitrergic system by ERs may play a role in the control of oestrogen-dependent physiological mechanisms regulated by the SON and the PVN. | INHIBITOR |
| Role of oestrogen receptors on the modulation of NADPH-diaphorase-positive cell number in supraoptic and paraventricular nuclei of ovariectomised female rats. Modulation of the nitric oxide producing system (demonstrated via the NADPH-diaphorase histochemical reaction) by oestradiol has been established in several structures of the rat brain. The present study aimed to explore the possible regulation of NADPH-diaphorase activity by oestradiol in neurones of the supraoptic (SON) and paraventricular (PVN) nuclei and the role of oestrogen receptors (ERα and ERβ) in this regulation. Adult ovariectomised rats were divided into six groups and injected either with vehicle or a single dose of oestradiol, a selective GENE agonist-PPT [4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol], a selective ERβ agonist-DPN [2,3-bis(4-hydroxyphenyl)-propionitrile], a selective GENE antagonist-MPP [1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-CHEMICAL] or a selective ERβ antagonist-PHTPP (4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol). The number of NADPH-diaphorase positive elements in the SON and the PVN was modulated by both ERs but, depending on the nucleus, GENE and ERβ ligands induced different effects. These results suggest that the regulation of nitrergic system by ERs may play a role in the control of oestrogen-dependent physiological mechanisms regulated by the SON and the PVN. | INHIBITOR |
| Role of oestrogen receptors on the modulation of NADPH-diaphorase-positive cell number in supraoptic and paraventricular nuclei of ovariectomised female rats. Modulation of the nitric oxide producing system (demonstrated via the NADPH-diaphorase histochemical reaction) by oestradiol has been established in several structures of the rat brain. The present study aimed to explore the possible regulation of NADPH-diaphorase activity by oestradiol in neurones of the supraoptic (SON) and paraventricular (PVN) nuclei and the role of oestrogen receptors (ERα and ERβ) in this regulation. Adult ovariectomised rats were divided into six groups and injected either with vehicle or a single dose of oestradiol, a selective ERα agonist-PPT [4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol], a selective GENE agonist-DPN [2,3-bis(4-hydroxyphenyl)-propionitrile], a selective ERα antagonist-MPP [1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride] or a selective GENE antagonist-CHEMICAL (4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol). The number of NADPH-diaphorase positive elements in the SON and the PVN was modulated by both ERs but, depending on the nucleus, ERα and GENE ligands induced different effects. These results suggest that the regulation of nitrergic system by ERs may play a role in the control of oestrogen-dependent physiological mechanisms regulated by the SON and the PVN. | INHIBITOR |
| Role of oestrogen receptors on the modulation of NADPH-diaphorase-positive cell number in supraoptic and paraventricular nuclei of ovariectomised female rats. Modulation of the nitric oxide producing system (demonstrated via the NADPH-diaphorase histochemical reaction) by oestradiol has been established in several structures of the rat brain. The present study aimed to explore the possible regulation of NADPH-diaphorase activity by oestradiol in neurones of the supraoptic (SON) and paraventricular (PVN) nuclei and the role of oestrogen receptors (ERα and ERβ) in this regulation. Adult ovariectomised rats were divided into six groups and injected either with vehicle or a single dose of oestradiol, a selective ERα agonist-PPT [4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol], a selective GENE agonist-DPN [2,3-bis(4-hydroxyphenyl)-propionitrile], a selective ERα antagonist-MPP [1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride] or a selective GENE antagonist-PHTPP (CHEMICAL). The number of NADPH-diaphorase positive elements in the SON and the PVN was modulated by both ERs but, depending on the nucleus, ERα and GENE ligands induced different effects. These results suggest that the regulation of nitrergic system by ERs may play a role in the control of oestrogen-dependent physiological mechanisms regulated by the SON and the PVN. | INHIBITOR |
| Role of oestrogen receptors on the modulation of NADPH-diaphorase-positive cell number in supraoptic and paraventricular nuclei of ovariectomised female rats. Modulation of the CHEMICAL producing system (demonstrated via the GENE histochemical reaction) by oestradiol has been established in several structures of the rat brain. The present study aimed to explore the possible regulation of GENE activity by oestradiol in neurones of the supraoptic (SON) and paraventricular (PVN) nuclei and the role of oestrogen receptors (ERα and ERβ) in this regulation. Adult ovariectomised rats were divided into six groups and injected either with vehicle or a single dose of oestradiol, a selective ERα agonist-PPT [4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol], a selective ERβ agonist-DPN [2,3-bis(4-hydroxyphenyl)-propionitrile], a selective ERα antagonist-MPP [1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride] or a selective ERβ antagonist-PHTPP (4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol). The number of GENE positive elements in the SON and the PVN was modulated by both ERs but, depending on the nucleus, ERα and ERβ ligands induced different effects. These results suggest that the regulation of nitrergic system by ERs may play a role in the control of oestrogen-dependent physiological mechanisms regulated by the SON and the PVN. | PRODUCT-OF |
| Human plasma-derived BuChE as a stoichiometric bioscavenger for treatment of nerve agent poisoning. Potent organophosphorous (OP) agents, such as VX, are hazardous by absorption through the skin and are resistant to conventional pharmacological antidotal treatments. The residence time of a stoichiometric bioscavenger, human butyrylcholinesterase (GENE), in the plasma more closely matches that of VX than do the residence times of conventional therapy drugs (CHEMICAL, anti-muscarinic, anticonvulsant). Intramuscular (i.m.) GENE afforded almost complete protection when administered prior to the onset of observable cholinergic signs of VX poisoning, but once signs of poisoning became evident the efficacy of i.m. GENE decreased. A combination of nerve agent therapy drugs (oxime, anti-muscarinic, anticonvulsant) with GENE (i.m.) protected 100% (8/8) of guinea-pigs from a lethal dose of VX (0.74mg/kg) to 48h, even when administered on signs of poisoning. Survival was presumed to be due to immediate alleviation of the cholinergic crisis by the conventional pharmacological treatment drugs, in conjunction with bioscavenger that prevented further absorbed agent reaching the AChE targets. Evidence to support this proposed mechanism of action was obtained from PKPD experiments in which multiple blood samples and microdialysate samples were collected from individual conscious ambulatory animals. Plasma concentrations of intramuscularly-administered atropine, diazepam and HI-6 reached a peak within 15min and were eliminated rapidly within 4h. Plasma concentrations of GENE administered by the i.m. route took approximately 24h to reach a peak, but were well-maintained over the subsequent 7days. Thus, the pharmacological therapy rapidly treated the initial signs of poisoning, whilst the bioscavenger provided prolonged protection by neutralising further nerve agent entering the bloodstream and preventing it from reaching the target organs. | REGULATOR |
| Human plasma-derived BuChE as a stoichiometric bioscavenger for treatment of nerve agent poisoning. Potent organophosphorous (OP) agents, such as VX, are hazardous by absorption through the skin and are resistant to conventional pharmacological antidotal treatments. The residence time of a stoichiometric bioscavenger, GENE (huBuChE), in the plasma more closely matches that of VX than do the residence times of conventional therapy drugs (CHEMICAL, anti-muscarinic, anticonvulsant). Intramuscular (i.m.) huBuChE afforded almost complete protection when administered prior to the onset of observable cholinergic signs of VX poisoning, but once signs of poisoning became evident the efficacy of i.m. huBuChE decreased. A combination of nerve agent therapy drugs (oxime, anti-muscarinic, anticonvulsant) with huBuChE (i.m.) protected 100% (8/8) of guinea-pigs from a lethal dose of VX (0.74mg/kg) to 48h, even when administered on signs of poisoning. Survival was presumed to be due to immediate alleviation of the cholinergic crisis by the conventional pharmacological treatment drugs, in conjunction with bioscavenger that prevented further absorbed agent reaching the AChE targets. Evidence to support this proposed mechanism of action was obtained from PKPD experiments in which multiple blood samples and microdialysate samples were collected from individual conscious ambulatory animals. Plasma concentrations of intramuscularly-administered atropine, diazepam and HI-6 reached a peak within 15min and were eliminated rapidly within 4h. Plasma concentrations of huBuChE administered by the i.m. route took approximately 24h to reach a peak, but were well-maintained over the subsequent 7days. Thus, the pharmacological therapy rapidly treated the initial signs of poisoning, whilst the bioscavenger provided prolonged protection by neutralising further nerve agent entering the bloodstream and preventing it from reaching the target organs. | REGULATOR |
| Verrucarin A sensitizes TRAIL-induced apoptosis via the upregulation of DR5 in an eIF2α/CHOP-dependent manner. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. However, resistance to GENE in some cancers remains a current problem in recent. The protein-folding compartment of the endoplasmic reticulum (ER) is particularly sensitive to disturbances, which, if severe, may trigger apoptosis. Therefore, we examined whether CHEMICAL (VA) sensitize GENE-induced apoptosis in cancer cells by induction of ER stress. We first found that VA induces a major molecule of ER stress, CCAAT/enhancer binding protein homologous protein (CHOP)-dependent DR5 induction and subsequently increases TRAIL-induced cleavage of caspases and PARP in TRAIL-resistant Hep3B cells. Importantly, the transient knockdown using siRNA for CHOP abrogated VA-induced DR5 expression and attenuated TRAIL-induced apoptosis. Treatment with VA also increased the levels of phosphorylation of eukaryotic translation initiation factor-2α (eIF2α), which is a common cellular response of ER stress. Furthermore, salubrinal, a specific eIF2α phosphorylation-inducing agent, increased CHOP and DR5 expression in the presence of VA. In contrast, transfection of mutant-eIF2α significantly reversed VA-induced apoptosis with downregulation of CHOP-dependent DR5 expression. Therefore, VA-induced eIF2α phosphorylation seemed to be important for CHOP and DR5 upregulation and TRAIL-induced apoptosis. In addition, generation of reactive oxygen species (ROS) is an effector molecular in sensitization of VA-induced ER stress. We concluded that VA triggers TRAIL-induced apoptosis by eIF2α/CHOP-dependent DR5 induction via ROS generation. | REGULATOR |
| Verrucarin A sensitizes TRAIL-induced apoptosis via the upregulation of DR5 in an eIF2α/CHOP-dependent manner. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. However, resistance to TRAIL in some cancers remains a current problem in recent. The protein-folding compartment of the endoplasmic reticulum (ER) is particularly sensitive to disturbances, which, if severe, may trigger apoptosis. Therefore, we examined whether verrucarin A (VA) sensitize TRAIL-induced apoptosis in cancer cells by induction of ER stress. We first found that VA induces a major molecule of ER stress, CCAAT/enhancer binding protein homologous protein (CHOP)-dependent DR5 induction and subsequently increases TRAIL-induced cleavage of caspases and PARP in TRAIL-resistant Hep3B cells. Importantly, the transient knockdown using siRNA for CHOP abrogated VA-induced DR5 expression and attenuated TRAIL-induced apoptosis. Treatment with VA also increased the levels of phosphorylation of eukaryotic translation initiation factor-2α (eIF2α), which is a common cellular response of ER stress. Furthermore, CHEMICAL, a specific GENE phosphorylation-inducing agent, increased CHOP and DR5 expression in the presence of VA. In contrast, transfection of mutant-eIF2α significantly reversed VA-induced apoptosis with downregulation of CHOP-dependent DR5 expression. Therefore, VA-induced GENE phosphorylation seemed to be important for CHOP and DR5 upregulation and TRAIL-induced apoptosis. In addition, generation of reactive oxygen species (ROS) is an effector molecular in sensitization of VA-induced ER stress. We concluded that VA triggers TRAIL-induced apoptosis by eIF2α/CHOP-dependent DR5 induction via ROS generation. | ACTIVATOR |
| Verrucarin A sensitizes TRAIL-induced apoptosis via the upregulation of DR5 in an eIF2α/CHOP-dependent manner. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. However, resistance to TRAIL in some cancers remains a current problem in recent. The protein-folding compartment of the endoplasmic reticulum (ER) is particularly sensitive to disturbances, which, if severe, may trigger apoptosis. Therefore, we examined whether verrucarin A (VA) sensitize TRAIL-induced apoptosis in cancer cells by induction of ER stress. We first found that VA induces a major molecule of ER stress, CCAAT/enhancer binding protein homologous protein (CHOP)-dependent DR5 induction and subsequently increases TRAIL-induced cleavage of caspases and PARP in TRAIL-resistant Hep3B cells. Importantly, the transient knockdown using siRNA for GENE abrogated VA-induced DR5 expression and attenuated TRAIL-induced apoptosis. Treatment with VA also increased the levels of phosphorylation of eukaryotic translation initiation factor-2α (eIF2α), which is a common cellular response of ER stress. Furthermore, CHEMICAL, a specific eIF2α phosphorylation-inducing agent, increased GENE and DR5 expression in the presence of VA. In contrast, transfection of mutant-eIF2α significantly reversed VA-induced apoptosis with downregulation of CHOP-dependent DR5 expression. Therefore, VA-induced eIF2α phosphorylation seemed to be important for GENE and DR5 upregulation and TRAIL-induced apoptosis. In addition, generation of reactive oxygen species (ROS) is an effector molecular in sensitization of VA-induced ER stress. We concluded that VA triggers TRAIL-induced apoptosis by eIF2α/CHOP-dependent DR5 induction via ROS generation. | INDIRECT-UPREGULATOR |
| Verrucarin A sensitizes TRAIL-induced apoptosis via the upregulation of GENE in an eIF2α/CHOP-dependent manner. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. However, resistance to TRAIL in some cancers remains a current problem in recent. The protein-folding compartment of the endoplasmic reticulum (ER) is particularly sensitive to disturbances, which, if severe, may trigger apoptosis. Therefore, we examined whether verrucarin A (VA) sensitize TRAIL-induced apoptosis in cancer cells by induction of ER stress. We first found that VA induces a major molecule of ER stress, CCAAT/enhancer binding protein homologous protein (CHOP)-dependent GENE induction and subsequently increases TRAIL-induced cleavage of caspases and PARP in TRAIL-resistant Hep3B cells. Importantly, the transient knockdown using siRNA for CHOP abrogated VA-induced GENE expression and attenuated TRAIL-induced apoptosis. Treatment with VA also increased the levels of phosphorylation of eukaryotic translation initiation factor-2α (eIF2α), which is a common cellular response of ER stress. Furthermore, CHEMICAL, a specific eIF2α phosphorylation-inducing agent, increased CHOP and GENE expression in the presence of VA. In contrast, transfection of mutant-eIF2α significantly reversed VA-induced apoptosis with downregulation of CHOP-dependent GENE expression. Therefore, VA-induced eIF2α phosphorylation seemed to be important for CHOP and GENE upregulation and TRAIL-induced apoptosis. In addition, generation of reactive oxygen species (ROS) is an effector molecular in sensitization of VA-induced ER stress. We concluded that VA triggers TRAIL-induced apoptosis by eIF2α/CHOP-dependent GENE induction via ROS generation. | INDIRECT-UPREGULATOR |
| CHEMICAL sensitizes TRAIL-induced apoptosis via the upregulation of GENE in an eIF2α/CHOP-dependent manner. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. However, resistance to TRAIL in some cancers remains a current problem in recent. The protein-folding compartment of the endoplasmic reticulum (ER) is particularly sensitive to disturbances, which, if severe, may trigger apoptosis. Therefore, we examined whether verrucarin A (VA) sensitize TRAIL-induced apoptosis in cancer cells by induction of ER stress. We first found that VA induces a major molecule of ER stress, CCAAT/enhancer binding protein homologous protein (CHOP)-dependent GENE induction and subsequently increases TRAIL-induced cleavage of caspases and PARP in TRAIL-resistant Hep3B cells. Importantly, the transient knockdown using siRNA for CHOP abrogated VA-induced GENE expression and attenuated TRAIL-induced apoptosis. Treatment with VA also increased the levels of phosphorylation of eukaryotic translation initiation factor-2α (eIF2α), which is a common cellular response of ER stress. Furthermore, salubrinal, a specific eIF2α phosphorylation-inducing agent, increased CHOP and GENE expression in the presence of VA. In contrast, transfection of mutant-eIF2α significantly reversed VA-induced apoptosis with downregulation of CHOP-dependent GENE expression. Therefore, VA-induced eIF2α phosphorylation seemed to be important for CHOP and GENE upregulation and TRAIL-induced apoptosis. In addition, generation of reactive oxygen species (ROS) is an effector molecular in sensitization of VA-induced ER stress. We concluded that VA triggers TRAIL-induced apoptosis by eIF2α/CHOP-dependent GENE induction via ROS generation. | ACTIVATOR |
| CHEMICAL sensitizes TRAIL-induced apoptosis via the upregulation of DR5 in an GENE/CHOP-dependent manner. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. However, resistance to TRAIL in some cancers remains a current problem in recent. The protein-folding compartment of the endoplasmic reticulum (ER) is particularly sensitive to disturbances, which, if severe, may trigger apoptosis. Therefore, we examined whether verrucarin A (VA) sensitize TRAIL-induced apoptosis in cancer cells by induction of ER stress. We first found that VA induces a major molecule of ER stress, CCAAT/enhancer binding protein homologous protein (CHOP)-dependent DR5 induction and subsequently increases TRAIL-induced cleavage of caspases and PARP in TRAIL-resistant Hep3B cells. Importantly, the transient knockdown using siRNA for CHOP abrogated VA-induced DR5 expression and attenuated TRAIL-induced apoptosis. Treatment with VA also increased the levels of phosphorylation of eukaryotic translation initiation factor-2α (eIF2α), which is a common cellular response of ER stress. Furthermore, salubrinal, a specific GENE phosphorylation-inducing agent, increased CHOP and DR5 expression in the presence of VA. In contrast, transfection of mutant-eIF2α significantly reversed VA-induced apoptosis with downregulation of CHOP-dependent DR5 expression. Therefore, VA-induced GENE phosphorylation seemed to be important for CHOP and DR5 upregulation and TRAIL-induced apoptosis. In addition, generation of reactive oxygen species (ROS) is an effector molecular in sensitization of VA-induced ER stress. We concluded that VA triggers TRAIL-induced apoptosis by eIF2α/CHOP-dependent DR5 induction via ROS generation. | ACTIVATOR |
| CHEMICAL sensitizes TRAIL-induced apoptosis via the upregulation of DR5 in an eIF2α/GENE-dependent manner. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. However, resistance to TRAIL in some cancers remains a current problem in recent. The protein-folding compartment of the endoplasmic reticulum (ER) is particularly sensitive to disturbances, which, if severe, may trigger apoptosis. Therefore, we examined whether verrucarin A (VA) sensitize TRAIL-induced apoptosis in cancer cells by induction of ER stress. We first found that VA induces a major molecule of ER stress, CCAAT/enhancer binding protein homologous protein (CHOP)-dependent DR5 induction and subsequently increases TRAIL-induced cleavage of caspases and PARP in TRAIL-resistant Hep3B cells. Importantly, the transient knockdown using siRNA for GENE abrogated VA-induced DR5 expression and attenuated TRAIL-induced apoptosis. Treatment with VA also increased the levels of phosphorylation of eukaryotic translation initiation factor-2α (eIF2α), which is a common cellular response of ER stress. Furthermore, salubrinal, a specific eIF2α phosphorylation-inducing agent, increased GENE and DR5 expression in the presence of VA. In contrast, transfection of mutant-eIF2α significantly reversed VA-induced apoptosis with downregulation of CHOP-dependent DR5 expression. Therefore, VA-induced eIF2α phosphorylation seemed to be important for GENE and DR5 upregulation and TRAIL-induced apoptosis. In addition, generation of reactive oxygen species (ROS) is an effector molecular in sensitization of VA-induced ER stress. We concluded that VA triggers TRAIL-induced apoptosis by eIF2α/CHOP-dependent DR5 induction via ROS generation. | REGULATOR |
| Microtubule network is required for insulin-induced signal transduction and actin remodeling. Both microtubule and actin are required for insulin-induced glucose uptake. However, the roles of these two cytoskeletons and their relationship in insulin action still remain unclear. In this work, we examined the morphological change of microtubule/actin and their involvement in insulin signal transduction using rat skeletal muscle cells. Insulin rapidly led to microtubule clustering from ventral to dorsal surface of the cell. Microtubule filaments were rearranged to create space where new actin structures formed. Disruption of microtubule prevented insulin-induced actin remodeling and distal insulin signal transduction, with reduction in surface glucose transporter isoform 4 (GLUT4) and glucose uptake. Though microtubule mediated actin remodeling through PKCζ, reorganization of microtubule depended on CHEMICAL phosphorylation of GENE, the mechanism is different from insulin-induced actin remodeling, which relied on the activity of PI3-kinase and PKCζ. We propose that microtubule network is required for insulin-induced signal transduction and actin remodeling in skeletal muscle cells. | PART-OF |
| Microtubule network is required for insulin-induced signal transduction and actin remodeling. Both microtubule and actin are required for insulin-induced CHEMICAL uptake. However, the roles of these two cytoskeletons and their relationship in insulin action still remain unclear. In this work, we examined the morphological change of microtubule/actin and their involvement in insulin signal transduction using rat skeletal muscle cells. Insulin rapidly led to microtubule clustering from ventral to dorsal surface of the cell. Microtubule filaments were rearranged to create space where new actin structures formed. Disruption of microtubule prevented insulin-induced actin remodeling and distal insulin signal transduction, with reduction in surface GENE (GLUT4) and CHEMICAL uptake. Though microtubule mediated actin remodeling through PKCζ, reorganization of microtubule depended on tyrosine phosphorylation of insulin receptor, the mechanism is different from insulin-induced actin remodeling, which relied on the activity of PI3-kinase and PKCζ. We propose that microtubule network is required for insulin-induced signal transduction and actin remodeling in skeletal muscle cells. | SUBSTRATE |
| Microtubule network is required for insulin-induced signal transduction and actin remodeling. Both microtubule and actin are required for insulin-induced CHEMICAL uptake. However, the roles of these two cytoskeletons and their relationship in insulin action still remain unclear. In this work, we examined the morphological change of microtubule/actin and their involvement in insulin signal transduction using rat skeletal muscle cells. Insulin rapidly led to microtubule clustering from ventral to dorsal surface of the cell. Microtubule filaments were rearranged to create space where new actin structures formed. Disruption of microtubule prevented insulin-induced actin remodeling and distal insulin signal transduction, with reduction in surface CHEMICAL transporter isoform 4 (GENE) and CHEMICAL uptake. Though microtubule mediated actin remodeling through PKCζ, reorganization of microtubule depended on tyrosine phosphorylation of insulin receptor, the mechanism is different from insulin-induced actin remodeling, which relied on the activity of PI3-kinase and PKCζ. We propose that microtubule network is required for insulin-induced signal transduction and actin remodeling in skeletal muscle cells. | SUBSTRATE |
| Quantitative analysis of the interaction of constitutive androstane receptor with chemicals and steroid receptor coactivator 1 using surface plasmon resonance biosensor systems: a case study of the Baikal seal (Pusa sibirica) and the mouse. The constitutive androstane receptor (CAR) not only displays a high basal transcriptional activity but also acts as a ligand-dependent transcriptional factor. It is known that CAR exhibits different ligand profiles across species. However, the mechanisms underlying CAR activation by chemicals and the species-specific responses are not fully understood. The objectives of this study are to establish a high-throughput tool to screen CAR ligands and to clarify how CAR proteins from the Baikal seal (bsCAR) and the mouse (mCAR) interact with chemicals and steroid receptor coactivator 1 (SRC1). We developed the surface plasmon resonance (SPR) system to assess quantitatively the interaction of CAR with potential ligands and SRC1. The ligand-binding domain (LBD) of bsCAR and mCAR was synthesized in a wheat germ cell-free system. The purified CAR LBD was then immobilized on the sensor chip for the SPR assay, and the kinetics of direct interaction of GENE with ligand candidates was measured. Androstanol and CHEMICAL, estrone, 17β-estradiol, TCPOBOP, and CITCO showed compound-specific but similar affinities for both GENE. The CAR-SRC1 interaction was ligand dependent but exhibited a different ligand profile between the seal and the mouse. The results of SRC1 interaction assay accounted for those of our previous in vitro CAR-mediated transactivation assay. In silico analyses also supported the results of CAR-SRC1 interaction; there is little structural difference in the ligand-binding pocket of bsCAR and mCAR, but there is a distinct discrimination in the helix 11 and 12 of these receptors, suggesting that the interaction of ligand-bound CAR and SRC1 is critical for determining species-specific and ligand-dependent transactivation over the basal activity. The SPR assays demonstrated a potential as a high-throughput screening tool of CAR ligands. | DIRECT-REGULATOR |
| Quantitative analysis of the interaction of constitutive androstane receptor with chemicals and steroid receptor coactivator 1 using surface plasmon resonance biosensor systems: a case study of the Baikal seal (Pusa sibirica) and the mouse. The constitutive androstane receptor (CAR) not only displays a high basal transcriptional activity but also acts as a ligand-dependent transcriptional factor. It is known that CAR exhibits different ligand profiles across species. However, the mechanisms underlying CAR activation by chemicals and the species-specific responses are not fully understood. The objectives of this study are to establish a high-throughput tool to screen CAR ligands and to clarify how CAR proteins from the Baikal seal (bsCAR) and the mouse (mCAR) interact with chemicals and steroid receptor coactivator 1 (SRC1). We developed the surface plasmon resonance (SPR) system to assess quantitatively the interaction of CAR with potential ligands and SRC1. The ligand-binding domain (LBD) of bsCAR and mCAR was synthesized in a wheat germ cell-free system. The purified CAR LBD was then immobilized on the sensor chip for the SPR assay, and the kinetics of direct interaction of GENE with ligand candidates was measured. Androstanol and androstenol, CHEMICAL, 17β-estradiol, TCPOBOP, and CITCO showed compound-specific but similar affinities for both GENE. The CAR-SRC1 interaction was ligand dependent but exhibited a different ligand profile between the seal and the mouse. The results of SRC1 interaction assay accounted for those of our previous in vitro CAR-mediated transactivation assay. In silico analyses also supported the results of CAR-SRC1 interaction; there is little structural difference in the ligand-binding pocket of bsCAR and mCAR, but there is a distinct discrimination in the helix 11 and 12 of these receptors, suggesting that the interaction of ligand-bound CAR and SRC1 is critical for determining species-specific and ligand-dependent transactivation over the basal activity. The SPR assays demonstrated a potential as a high-throughput screening tool of CAR ligands. | DIRECT-REGULATOR |
| Quantitative analysis of the interaction of constitutive androstane receptor with chemicals and steroid receptor coactivator 1 using surface plasmon resonance biosensor systems: a case study of the Baikal seal (Pusa sibirica) and the mouse. The constitutive androstane receptor (CAR) not only displays a high basal transcriptional activity but also acts as a ligand-dependent transcriptional factor. It is known that CAR exhibits different ligand profiles across species. However, the mechanisms underlying CAR activation by chemicals and the species-specific responses are not fully understood. The objectives of this study are to establish a high-throughput tool to screen CAR ligands and to clarify how CAR proteins from the Baikal seal (bsCAR) and the mouse (mCAR) interact with chemicals and steroid receptor coactivator 1 (SRC1). We developed the surface plasmon resonance (SPR) system to assess quantitatively the interaction of CAR with potential ligands and SRC1. The ligand-binding domain (LBD) of bsCAR and mCAR was synthesized in a wheat germ cell-free system. The purified CAR LBD was then immobilized on the sensor chip for the SPR assay, and the kinetics of direct interaction of GENE with ligand candidates was measured. Androstanol and androstenol, estrone, CHEMICAL, TCPOBOP, and CITCO showed compound-specific but similar affinities for both GENE. The CAR-SRC1 interaction was ligand dependent but exhibited a different ligand profile between the seal and the mouse. The results of SRC1 interaction assay accounted for those of our previous in vitro CAR-mediated transactivation assay. In silico analyses also supported the results of CAR-SRC1 interaction; there is little structural difference in the ligand-binding pocket of bsCAR and mCAR, but there is a distinct discrimination in the helix 11 and 12 of these receptors, suggesting that the interaction of ligand-bound CAR and SRC1 is critical for determining species-specific and ligand-dependent transactivation over the basal activity. The SPR assays demonstrated a potential as a high-throughput screening tool of CAR ligands. | DIRECT-REGULATOR |
| Quantitative analysis of the interaction of constitutive androstane receptor with chemicals and steroid receptor coactivator 1 using surface plasmon resonance biosensor systems: a case study of the Baikal seal (Pusa sibirica) and the mouse. The constitutive androstane receptor (CAR) not only displays a high basal transcriptional activity but also acts as a ligand-dependent transcriptional factor. It is known that CAR exhibits different ligand profiles across species. However, the mechanisms underlying CAR activation by chemicals and the species-specific responses are not fully understood. The objectives of this study are to establish a high-throughput tool to screen CAR ligands and to clarify how CAR proteins from the Baikal seal (bsCAR) and the mouse (mCAR) interact with chemicals and steroid receptor coactivator 1 (SRC1). We developed the surface plasmon resonance (SPR) system to assess quantitatively the interaction of CAR with potential ligands and SRC1. The ligand-binding domain (LBD) of bsCAR and mCAR was synthesized in a wheat germ cell-free system. The purified CAR LBD was then immobilized on the sensor chip for the SPR assay, and the kinetics of direct interaction of GENE with ligand candidates was measured. Androstanol and androstenol, estrone, 17β-estradiol, CHEMICAL, and CITCO showed compound-specific but similar affinities for both GENE. The CAR-SRC1 interaction was ligand dependent but exhibited a different ligand profile between the seal and the mouse. The results of SRC1 interaction assay accounted for those of our previous in vitro CAR-mediated transactivation assay. In silico analyses also supported the results of CAR-SRC1 interaction; there is little structural difference in the ligand-binding pocket of bsCAR and mCAR, but there is a distinct discrimination in the helix 11 and 12 of these receptors, suggesting that the interaction of ligand-bound CAR and SRC1 is critical for determining species-specific and ligand-dependent transactivation over the basal activity. The SPR assays demonstrated a potential as a high-throughput screening tool of CAR ligands. | DIRECT-REGULATOR |
| Quantitative analysis of the interaction of constitutive androstane receptor with chemicals and steroid receptor coactivator 1 using surface plasmon resonance biosensor systems: a case study of the Baikal seal (Pusa sibirica) and the mouse. The constitutive androstane receptor (CAR) not only displays a high basal transcriptional activity but also acts as a ligand-dependent transcriptional factor. It is known that CAR exhibits different ligand profiles across species. However, the mechanisms underlying CAR activation by chemicals and the species-specific responses are not fully understood. The objectives of this study are to establish a high-throughput tool to screen CAR ligands and to clarify how CAR proteins from the Baikal seal (bsCAR) and the mouse (mCAR) interact with chemicals and steroid receptor coactivator 1 (SRC1). We developed the surface plasmon resonance (SPR) system to assess quantitatively the interaction of CAR with potential ligands and SRC1. The ligand-binding domain (LBD) of bsCAR and mCAR was synthesized in a wheat germ cell-free system. The purified CAR LBD was then immobilized on the sensor chip for the SPR assay, and the kinetics of direct interaction of GENE with ligand candidates was measured. Androstanol and androstenol, estrone, 17β-estradiol, TCPOBOP, and CHEMICAL showed compound-specific but similar affinities for both GENE. The CAR-SRC1 interaction was ligand dependent but exhibited a different ligand profile between the seal and the mouse. The results of SRC1 interaction assay accounted for those of our previous in vitro CAR-mediated transactivation assay. In silico analyses also supported the results of CAR-SRC1 interaction; there is little structural difference in the ligand-binding pocket of bsCAR and mCAR, but there is a distinct discrimination in the helix 11 and 12 of these receptors, suggesting that the interaction of ligand-bound CAR and SRC1 is critical for determining species-specific and ligand-dependent transactivation over the basal activity. The SPR assays demonstrated a potential as a high-throughput screening tool of CAR ligands. | DIRECT-REGULATOR |
| Quantitative analysis of the interaction of constitutive androstane receptor with chemicals and steroid receptor coactivator 1 using surface plasmon resonance biosensor systems: a case study of the Baikal seal (Pusa sibirica) and the mouse. The constitutive androstane receptor (CAR) not only displays a high basal transcriptional activity but also acts as a ligand-dependent transcriptional factor. It is known that CAR exhibits different ligand profiles across species. However, the mechanisms underlying CAR activation by chemicals and the species-specific responses are not fully understood. The objectives of this study are to establish a high-throughput tool to screen CAR ligands and to clarify how CAR proteins from the Baikal seal (bsCAR) and the mouse (mCAR) interact with chemicals and steroid receptor coactivator 1 (SRC1). We developed the surface plasmon resonance (SPR) system to assess quantitatively the interaction of CAR with potential ligands and SRC1. The ligand-binding domain (LBD) of bsCAR and mCAR was synthesized in a wheat germ cell-free system. The purified CAR LBD was then immobilized on the sensor chip for the SPR assay, and the kinetics of direct interaction of GENE with ligand candidates was measured. CHEMICAL and androstenol, estrone, 17β-estradiol, TCPOBOP, and CITCO showed compound-specific but similar affinities for both GENE. The CAR-SRC1 interaction was ligand dependent but exhibited a different ligand profile between the seal and the mouse. The results of SRC1 interaction assay accounted for those of our previous in vitro CAR-mediated transactivation assay. In silico analyses also supported the results of CAR-SRC1 interaction; there is little structural difference in the ligand-binding pocket of bsCAR and mCAR, but there is a distinct discrimination in the helix 11 and 12 of these receptors, suggesting that the interaction of ligand-bound CAR and SRC1 is critical for determining species-specific and ligand-dependent transactivation over the basal activity. The SPR assays demonstrated a potential as a high-throughput screening tool of CAR ligands. | DIRECT-REGULATOR |
| GENE blockade impairs the muscarinic conversion of sub-threshold transient depression into long-lasting LTD in the hippocampus-prefrontal cortex pathway in vivo: correlation with gamma oscillations. Cholinergic fibers from the brainstem and basal forebrain innervate the medial prefrontal cortex (mPFC) modulating neuronal activity and synaptic plasticity responses to hippocampal inputs. Here, we investigated the muscarinic and glutamatergic modulation of long-term depression (LTD) in the intact projections from CA1 to mPFC in vivo. Cortical-evoked responses were recorded in urethane-anesthetized rats for 30 min during baseline and 4 h following LTD. In order to test the potentiating effects of pilocarpine (PILO), independent groups of rats received either a microinjection of CHEMICAL (40 nmol; i.c.v.) or vehicle, immediately before or 20 min after a sub-threshold LTD protocol (600 pulses, 1 Hz; LFS600). Other groups received either an infusion of the selective GENE antagonist (AP7; 10 nmol; intra-mPFC) or vehicle, 10 min prior to CHEMICAL preceding LFS600, or prior to a supra-threshold LTD protocol (900 pulses, 1 Hz; LFS900). Our results show that CHEMICAL converts a transient cortical depression induced by LFS600 into a robust LTD, stable for at least 4 h. When applied after LFS600, CHEMICAL does not change either mPFC basal neurotransmission or late LTD. Our data also indicate that GENE pre-activation is essential to the muscarinic enhancement of mPFC synaptic depression, since AP7 microinjection into the mPFC blocked the conversion of transient depression into long-lasting LTD produced by CHEMICAL. In addition, AP7 effectively blocked the long-lasting LTD induced by LFS900. Therefore, our findings suggest that the glutamatergic co-activation of prefrontal neurons is important for the effects of CHEMICAL on mPFC synaptic depression, which could play an important role in the control of executive and emotional functions. | INHIBITOR |
| GENE blockade impairs the muscarinic conversion of sub-threshold transient depression into long-lasting LTD in the hippocampus-prefrontal cortex pathway in vivo: correlation with gamma oscillations. Cholinergic fibers from the brainstem and basal forebrain innervate the medial prefrontal cortex (mPFC) modulating neuronal activity and synaptic plasticity responses to hippocampal inputs. Here, we investigated the muscarinic and glutamatergic modulation of long-term depression (LTD) in the intact projections from CA1 to mPFC in vivo. Cortical-evoked responses were recorded in urethane-anesthetized rats for 30 min during baseline and 4 h following LTD. In order to test the potentiating effects of pilocarpine (PILO), independent groups of rats received either a microinjection of PILO (40 nmol; i.c.v.) or vehicle, immediately before or 20 min after a sub-threshold LTD protocol (600 pulses, 1 Hz; LFS600). Other groups received either an infusion of the selective GENE antagonist (AP7; 10 nmol; intra-mPFC) or vehicle, 10 min prior to PILO preceding LFS600, or prior to a supra-threshold LTD protocol (900 pulses, 1 Hz; LFS900). Our results show that PILO converts a transient cortical depression induced by LFS600 into a robust LTD, stable for at least 4 h. When applied after LFS600, PILO does not change either mPFC basal neurotransmission or late LTD. Our data also indicate that GENE pre-activation is essential to the muscarinic enhancement of mPFC synaptic depression, since CHEMICAL microinjection into the mPFC blocked the conversion of transient depression into long-lasting LTD produced by PILO. In addition, CHEMICAL effectively blocked the long-lasting LTD induced by LFS900. Therefore, our findings suggest that the glutamatergic co-activation of prefrontal neurons is important for the effects of PILO on mPFC synaptic depression, which could play an important role in the control of executive and emotional functions. | INHIBITOR |
| Metabolism of triethylenetetramine and 1,12-diamino-3,6,9-triazadodecane by the spermidine/spermine-N(1)-acetyltransferase and thialysine acetyltransferase. Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that CHEMICAL is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of CHEMICAL is increased in GENE-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize CHEMICAL at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of CHEMICAL to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by GENE in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of CHEMICAL and SpmTrien, SSAT2 is the main acetylator of CHEMICAL, whereas SpmTrien is primarily acetylated by GENE. | SUBSTRATE |
| Metabolism of triethylenetetramine and 1,12-diamino-3,6,9-triazadodecane by the spermidine/spermine-N(1)-acetyltransferase and thialysine acetyltransferase. Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that CHEMICAL is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of CHEMICAL is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize CHEMICAL at the same rate as the wild-type mice, indicating the existence of another GENE respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of CHEMICAL to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of CHEMICAL and SpmTrien, SSAT2 is the main acetylator of CHEMICAL, whereas SpmTrien is primarily acetylated by SSAT1. | SUBSTRATE |
| Metabolism of triethylenetetramine and 1,12-diamino-3,6,9-triazadodecane by the spermidine/spermine-N(1)-acetyltransferase and thialysine acetyltransferase. Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that CHEMICAL is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of CHEMICAL is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize CHEMICAL at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of GENE in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of CHEMICAL to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant GENE and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of CHEMICAL and SpmTrien, GENE is the main acetylator of CHEMICAL, whereas SpmTrien is primarily acetylated by SSAT1. | SUBSTRATE |
| Metabolism of triethylenetetramine and CHEMICAL by the spermidine/spermine-N(1)-acetyltransferase and thialysine acetyltransferase. Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, CHEMICAL(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by GENE in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by GENE. | SUBSTRATE |
| Metabolism of triethylenetetramine and CHEMICAL by the spermidine/spermine-N(1)-acetyltransferase and thialysine acetyltransferase. Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, CHEMICAL(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of GENE and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by SSAT1. | SUBSTRATE |
| Metabolism of triethylenetetramine and 1,12-diamino-3,6,9-triazadodecane by the spermidine/spermine-N(1)-acetyltransferase and thialysine acetyltransferase. Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(CHEMICAL), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by GENE in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and CHEMICAL, SSAT2 is the main acetylator of TETA, whereas CHEMICAL is primarily acetylated by GENE. | SUBSTRATE |
| Metabolism of triethylenetetramine and 1,12-diamino-3,6,9-triazadodecane by the spermidine/spermine-N(1)-acetyltransferase and thialysine acetyltransferase. Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(CHEMICAL), a charge-deficient spermine analog, was an extremely poor substrate of GENE and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and CHEMICAL, SSAT2 is the main acetylator of TETA, whereas CHEMICAL is primarily acetylated by SSAT1. | SUBSTRATE |
| Metabolism of triethylenetetramine and 1,12-diamino-3,6,9-triazadodecane by the spermidine/spermine-N(1)-acetyltransferase and thialysine acetyltransferase. Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient CHEMICAL analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by GENE in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by GENE. | SUBSTRATE |
| Metabolism of triethylenetetramine and 1,12-diamino-3,6,9-triazadodecane by the spermidine/spermine-N(1)-acetyltransferase and thialysine acetyltransferase. Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient CHEMICAL analog, was an extremely poor substrate of GENE and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by SSAT1. | SUBSTRATE |
| Metabolism of CHEMICAL and 1,12-diamino-3,6,9-triazadodecane by the spermidine/spermine-N(1)-acetyltransferase and GENE. CHEMICAL (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (SSAT1) and by GENE (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by SSAT1. | SUBSTRATE |
| Metabolism of CHEMICAL and 1,12-diamino-3,6,9-triazadodecane by the GENE and thialysine acetyltransferase. CHEMICAL (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme GENE (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by SSAT1. | SUBSTRATE |
| Metabolism of triethylenetetramine and CHEMICAL by the spermidine/spermine-N(1)-acetyltransferase and GENE. Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (SSAT1) and by GENE (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by SSAT1. | SUBSTRATE |
| Metabolism of triethylenetetramine and CHEMICAL by the GENE and thialysine acetyltransferase. Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme GENE (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by SSAT1. | SUBSTRATE |
| Metabolism of triethylenetetramine and 1,12-diamino-3,6,9-triazadodecane by the GENE and thialysine acetyltransferase. Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that CHEMICAL is metabolized in vitro by polyamine catabolic enzyme GENE (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of CHEMICAL is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize CHEMICAL at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of CHEMICAL to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of CHEMICAL and SpmTrien, SSAT2 is the main acetylator of CHEMICAL, whereas SpmTrien is primarily acetylated by SSAT1. | SUBSTRATE |
| Metabolism of triethylenetetramine and 1,12-diamino-3,6,9-triazadodecane by the spermidine/spermine-N(1)-acetyltransferase and GENE. Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that CHEMICAL is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (SSAT1) and by GENE (SSAT2) to its monoacetylated derivative (MAT). The acetylation of CHEMICAL is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize CHEMICAL at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of CHEMICAL to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of CHEMICAL and SpmTrien, SSAT2 is the main acetylator of CHEMICAL, whereas SpmTrien is primarily acetylated by SSAT1. | SUBSTRATE |
| Metabolism of triethylenetetramine and 1,12-diamino-3,6,9-triazadodecane by the GENE and thialysine acetyltransferase. Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of CHEMICAL spermidine. We recently showed that TETA is metabolized in vitro by CHEMICAL catabolic enzyme GENE (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by SSAT1. | SUBSTRATE |
| Metabolism of triethylenetetramine and 1,12-diamino-3,6,9-triazadodecane by the spermidine/spermine-N(1)-acetyltransferase and thialysine acetyltransferase. Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of CHEMICAL spermidine. We recently showed that TETA is metabolized in vitro by CHEMICAL catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (GENE) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by GENE in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by GENE. | SUBSTRATE |
| In vitro metabolism of the 5-hydroxytryptamine1B receptor antagonist elzasonan. The metabolism of elzasonan has been examined in vitro using hepatic microsomes from human and recombinant heterologously expressed P450 enzymes (rCYP). Metabolism occurs primarily via oxidative N-demethylation to form M4 and oxidation reactions to form elzasonan N-oxide (M5) and CHEMICAL metabolite (M3). Additionally, elzasonan was shown to be metabolized to the novel cyclized indole metabolite (M6) which undergoes subsequent oxidation to form the iminium ion metabolite (M3a). The rCYP data was normalized relative to the levels of each CYP form in native human liver microsomes to better assess the contribution of each rCYP in the metabolism of elzasonan. Results demonstrated the involvement of CYP3A4 in the pathways leading to M3a, M3, M5 and M6 and CYP2C8 in the formation of M4. Kinetic constants for the formation of M3 were determined and correlation and inhibition studies suggested that CYP3A4 is primarily responsible for the formation of M3 and CYP2C19 plays a very minor role in its formation. GENE has shown to be an essential component in P450 3A4 catalyzed CHEMICAL formation and provides insights on the disconnect between human liver microsomes data and that of rCYP. Furthermore, rCYP3A4 containing b5 are useful models for predicting the rates for liver microsomes P450-dependent drug oxidations and should be utilized routinely. | PRODUCT-OF |
| In vitro metabolism of the GENE receptor antagonist CHEMICAL. The metabolism of CHEMICAL has been examined in vitro using hepatic microsomes from human and recombinant heterologously expressed P450 enzymes (rCYP). Metabolism occurs primarily via oxidative N-demethylation to form M4 and oxidation reactions to form CHEMICAL N-oxide (M5) and 5-hydroxyelzasonan metabolite (M3). Additionally, CHEMICAL was shown to be metabolized to the novel cyclized indole metabolite (M6) which undergoes subsequent oxidation to form the iminium ion metabolite (M3a). The rCYP data was normalized relative to the levels of each CYP form in native human liver microsomes to better assess the contribution of each rCYP in the metabolism of CHEMICAL. Results demonstrated the involvement of CYP3A4 in the pathways leading to M3a, M3, M5 and M6 and CYP2C8 in the formation of M4. Kinetic constants for the formation of M3 were determined and correlation and inhibition studies suggested that CYP3A4 is primarily responsible for the formation of M3 and CYP2C19 plays a very minor role in its formation. Cytochrome b5 has shown to be an essential component in P450 3A4 catalyzed 5-hydroxyelzasonan formation and provides insights on the disconnect between human liver microsomes data and that of rCYP. Furthermore, rCYP3A4 containing b5 are useful models for predicting the rates for liver microsomes P450-dependent drug oxidations and should be utilized routinely. | INHIBITOR |
| In vitro metabolism of the 5-hydroxytryptamine1B receptor antagonist elzasonan. The metabolism of elzasonan has been examined in vitro using hepatic microsomes from human and recombinant heterologously expressed P450 enzymes (rCYP). Metabolism occurs primarily via oxidative N-demethylation to form M4 and oxidation reactions to form elzasonan N-oxide (M5) and CHEMICAL metabolite (M3). Additionally, elzasonan was shown to be metabolized to the novel cyclized indole metabolite (M6) which undergoes subsequent oxidation to form the iminium ion metabolite (M3a). The rCYP data was normalized relative to the levels of each CYP form in native human liver microsomes to better assess the contribution of each rCYP in the metabolism of elzasonan. Results demonstrated the involvement of CYP3A4 in the pathways leading to M3a, M3, M5 and M6 and CYP2C8 in the formation of M4. Kinetic constants for the formation of M3 were determined and correlation and inhibition studies suggested that CYP3A4 is primarily responsible for the formation of M3 and CYP2C19 plays a very minor role in its formation. Cytochrome b5 has shown to be an essential component in GENE catalyzed CHEMICAL formation and provides insights on the disconnect between human liver microsomes data and that of rCYP. Furthermore, rCYP3A4 containing b5 are useful models for predicting the rates for liver microsomes P450-dependent drug oxidations and should be utilized routinely. | PRODUCT-OF |
| In vitro metabolism of the 5-hydroxytryptamine1B receptor antagonist CHEMICAL. The metabolism of CHEMICAL has been examined in vitro using hepatic microsomes from human and recombinant heterologously expressed P450 enzymes (rCYP). Metabolism occurs primarily via oxidative N-demethylation to form M4 and oxidation reactions to form CHEMICAL N-oxide (M5) and 5-hydroxyelzasonan metabolite (M3). Additionally, CHEMICAL was shown to be metabolized to the novel cyclized indole metabolite (M6) which undergoes subsequent oxidation to form the iminium ion metabolite (M3a). The GENE data was normalized relative to the levels of each CYP form in native human liver microsomes to better assess the contribution of each GENE in the metabolism of CHEMICAL. Results demonstrated the involvement of CYP3A4 in the pathways leading to M3a, M3, M5 and M6 and CYP2C8 in the formation of M4. Kinetic constants for the formation of M3 were determined and correlation and inhibition studies suggested that CYP3A4 is primarily responsible for the formation of M3 and CYP2C19 plays a very minor role in its formation. Cytochrome b5 has shown to be an essential component in P450 3A4 catalyzed 5-hydroxyelzasonan formation and provides insights on the disconnect between human liver microsomes data and that of GENE. Furthermore, rCYP3A4 containing b5 are useful models for predicting the rates for liver microsomes P450-dependent drug oxidations and should be utilized routinely. | SUBSTRATE |
| Effective phagocytosis of low Her2 tumor cell lines with engineered, aglycosylated IgG displaying high FcγRIIa affinity and selectivity. Glycans anchored to residue N297 of the antibody IgG Fc domain are critical in mediating binding toward FcγRs to direct both adaptive and innate immune responses. However, using a full length bacterial IgG display system, we have isolated aglycosylated Fc domains with mutations that confer up to a 160-fold increase in the affinity toward the low affinity FcγRIIa-R131 allele as well as high selectivity against binding to the remarkably homologous human inhibitory receptor, FcγRIIb. The mutant Fc domain (GENE) contained a total of 5 CHEMICAL substitutions that conferred an activating to inhibitory ratio of 25 (A/I ratio; FcyRIIa-R131:FcγRIIb). Incorporation of this engineered Fc into trastuzumab, an anti-Her2 antibody, resulted in a 75% increase in tumor cell phagocytosis by macrophages compared to that of the parental glycosylated trastuzumab with both medium and low Her2-expressing cancer cells. A mathematical model has been developed to help explain how receptor affinity and the A/I ratio relate to improved antibody dependent cell-mediated phagocytosis. Our model provides guidelines for the future engineering of Fc domains with enhanced effector function. | PART-OF |
| Effective phagocytosis of low Her2 tumor cell lines with engineered, aglycosylated IgG displaying high FcγRIIa affinity and selectivity. Glycans anchored to residue N297 of the antibody IgG Fc domain are critical in mediating binding toward FcγRs to direct both adaptive and innate immune responses. However, using a full length bacterial IgG display system, we have isolated aglycosylated Fc domains with mutations that confer up to a 160-fold increase in the affinity toward the low affinity FcγRIIa-R131 allele as well as high selectivity against binding to the remarkably homologous human inhibitory receptor, FcγRIIb. The mutant Fc domain (AglycoT-Fc1004) contained a total of 5 CHEMICAL substitutions that conferred an activating to inhibitory ratio of 25 (A/I ratio; GENE-R131:FcγRIIb). Incorporation of this engineered Fc into trastuzumab, an anti-Her2 antibody, resulted in a 75% increase in tumor cell phagocytosis by macrophages compared to that of the parental glycosylated trastuzumab with both medium and low Her2-expressing cancer cells. A mathematical model has been developed to help explain how receptor affinity and the A/I ratio relate to improved antibody dependent cell-mediated phagocytosis. Our model provides guidelines for the future engineering of Fc domains with enhanced effector function. | PART-OF |
| Effective phagocytosis of low Her2 tumor cell lines with engineered, aglycosylated IgG displaying high FcγRIIa affinity and selectivity. Glycans anchored to residue N297 of the antibody IgG Fc domain are critical in mediating binding toward FcγRs to direct both adaptive and innate immune responses. However, using a full length bacterial IgG display system, we have isolated aglycosylated Fc domains with mutations that confer up to a 160-fold increase in the affinity toward the low affinity FcγRIIa-R131 allele as well as high selectivity against binding to the remarkably homologous human inhibitory receptor, GENE. The mutant Fc domain (AglycoT-Fc1004) contained a total of 5 CHEMICAL substitutions that conferred an activating to inhibitory ratio of 25 (A/I ratio; FcyRIIa-R131:GENE). Incorporation of this engineered Fc into trastuzumab, an anti-Her2 antibody, resulted in a 75% increase in tumor cell phagocytosis by macrophages compared to that of the parental glycosylated trastuzumab with both medium and low Her2-expressing cancer cells. A mathematical model has been developed to help explain how receptor affinity and the A/I ratio relate to improved antibody dependent cell-mediated phagocytosis. Our model provides guidelines for the future engineering of Fc domains with enhanced effector function. | PART-OF |
| Effective phagocytosis of low Her2 tumor cell lines with engineered, aglycosylated IgG displaying high FcγRIIa affinity and selectivity. Glycans anchored to residue N297 of the antibody IgG GENE are critical in mediating binding toward FcγRs to direct both adaptive and innate immune responses. However, using a full length bacterial IgG display system, we have isolated aglycosylated Fc domains with mutations that confer up to a 160-fold increase in the affinity toward the low affinity FcγRIIa-R131 allele as well as high selectivity against binding to the remarkably homologous human inhibitory receptor, FcγRIIb. The mutant GENE (AglycoT-Fc1004) contained a total of 5 CHEMICAL substitutions that conferred an activating to inhibitory ratio of 25 (A/I ratio; FcyRIIa-R131:FcγRIIb). Incorporation of this engineered Fc into trastuzumab, an anti-Her2 antibody, resulted in a 75% increase in tumor cell phagocytosis by macrophages compared to that of the parental glycosylated trastuzumab with both medium and low Her2-expressing cancer cells. A mathematical model has been developed to help explain how receptor affinity and the A/I ratio relate to improved antibody dependent cell-mediated phagocytosis. Our model provides guidelines for the future engineering of Fc domains with enhanced effector function. | PART-OF |
| Exposure to valproic acid inhibits chondrogenesis and osteogenesis in mid-organogenesis mouse limbs. In utero exposure to valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, causes neural tube, heart, and limb defects. Valpromide (VPD), the amide derivative of VPA, does not inhibit GENE activity and is a weak teratogen in vivo. The detailed mechanism of action of VPA as a teratogen is not known. The goal of this study was to test the hypothesis that VPA disrupts regulation of the expression of genes that are critical in chondrogenesis and osteogenesis during limb development. Murine gestation day-12 embryonic forelimbs were excised and exposed to VPA or CHEMICAL in a limb bud culture system. VPA caused a significant concentration- dependent increase in limb abnormalities, which was correlated with its GENE inhibitory effect. The signaling of both Sox9 and Runx2, key regulators of chondrogenesis, was downregulated by VPA. In contrast, CHEMICAL had little effect on limb morphology and no significant effect on GENE activity or the expression of marker genes. Thus, VPA exposure dysregulated the expression of target genes directly involved in chondrogenesis and osteogenesis in the developing limb. Disturbances in these signaling pathways are likely to be a consequence of GENE inhibition because CHEMICAL did not affect their expressions. | NO-RELATIONSHIP |
| Exposure to valproic acid inhibits chondrogenesis and osteogenesis in mid-organogenesis mouse limbs. In utero exposure to valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, causes neural tube, heart, and limb defects. CHEMICAL (VPD), the amide derivative of VPA, does not inhibit GENE activity and is a weak teratogen in vivo. The detailed mechanism of action of VPA as a teratogen is not known. The goal of this study was to test the hypothesis that VPA disrupts regulation of the expression of genes that are critical in chondrogenesis and osteogenesis during limb development. Murine gestation day-12 embryonic forelimbs were excised and exposed to VPA or VPD in a limb bud culture system. VPA caused a significant concentration- dependent increase in limb abnormalities, which was correlated with its GENE inhibitory effect. The signaling of both Sox9 and Runx2, key regulators of chondrogenesis, was downregulated by VPA. In contrast, VPD had little effect on limb morphology and no significant effect on GENE activity or the expression of marker genes. Thus, VPA exposure dysregulated the expression of target genes directly involved in chondrogenesis and osteogenesis in the developing limb. Disturbances in these signaling pathways are likely to be a consequence of GENE inhibition because VPD did not affect their expressions. | NO-RELATIONSHIP |
| Exposure to valproic acid inhibits chondrogenesis and osteogenesis in mid-organogenesis mouse limbs. In utero exposure to valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, causes neural tube, heart, and limb defects. Valpromide (VPD), the CHEMICAL derivative of VPA, does not inhibit GENE activity and is a weak teratogen in vivo. The detailed mechanism of action of VPA as a teratogen is not known. The goal of this study was to test the hypothesis that VPA disrupts regulation of the expression of genes that are critical in chondrogenesis and osteogenesis during limb development. Murine gestation day-12 embryonic forelimbs were excised and exposed to VPA or VPD in a limb bud culture system. VPA caused a significant concentration- dependent increase in limb abnormalities, which was correlated with its GENE inhibitory effect. The signaling of both Sox9 and Runx2, key regulators of chondrogenesis, was downregulated by VPA. In contrast, VPD had little effect on limb morphology and no significant effect on GENE activity or the expression of marker genes. Thus, VPA exposure dysregulated the expression of target genes directly involved in chondrogenesis and osteogenesis in the developing limb. Disturbances in these signaling pathways are likely to be a consequence of GENE inhibition because VPD did not affect their expressions. | NO-RELATIONSHIP |
| Exposure to valproic acid inhibits chondrogenesis and osteogenesis in mid-organogenesis mouse limbs. In utero exposure to valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, causes neural tube, heart, and limb defects. Valpromide (VPD), the amide derivative of CHEMICAL, does not inhibit GENE activity and is a weak teratogen in vivo. The detailed mechanism of action of CHEMICAL as a teratogen is not known. The goal of this study was to test the hypothesis that CHEMICAL disrupts regulation of the expression of genes that are critical in chondrogenesis and osteogenesis during limb development. Murine gestation day-12 embryonic forelimbs were excised and exposed to CHEMICAL or VPD in a limb bud culture system. CHEMICAL caused a significant concentration- dependent increase in limb abnormalities, which was correlated with its GENE inhibitory effect. The signaling of both Sox9 and Runx2, key regulators of chondrogenesis, was downregulated by CHEMICAL. In contrast, VPD had little effect on limb morphology and no significant effect on GENE activity or the expression of marker genes. Thus, CHEMICAL exposure dysregulated the expression of target genes directly involved in chondrogenesis and osteogenesis in the developing limb. Disturbances in these signaling pathways are likely to be a consequence of GENE inhibition because VPD did not affect their expressions. | INHIBITOR |
| Exposure to valproic acid inhibits chondrogenesis and osteogenesis in mid-organogenesis mouse limbs. In utero exposure to valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, causes neural tube, heart, and limb defects. Valpromide (VPD), the amide derivative of CHEMICAL, does not inhibit HDAC activity and is a weak teratogen in vivo. The detailed mechanism of action of CHEMICAL as a teratogen is not known. The goal of this study was to test the hypothesis that CHEMICAL disrupts regulation of the expression of genes that are critical in chondrogenesis and osteogenesis during limb development. Murine gestation day-12 embryonic forelimbs were excised and exposed to CHEMICAL or VPD in a limb bud culture system. CHEMICAL caused a significant concentration- dependent increase in limb abnormalities, which was correlated with its HDAC inhibitory effect. The signaling of both GENE and Runx2, key regulators of chondrogenesis, was downregulated by CHEMICAL. In contrast, VPD had little effect on limb morphology and no significant effect on HDAC activity or the expression of marker genes. Thus, CHEMICAL exposure dysregulated the expression of target genes directly involved in chondrogenesis and osteogenesis in the developing limb. Disturbances in these signaling pathways are likely to be a consequence of HDAC inhibition because VPD did not affect their expressions. | INDIRECT-DOWNREGULATOR |
| Exposure to valproic acid inhibits chondrogenesis and osteogenesis in mid-organogenesis mouse limbs. In utero exposure to valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, causes neural tube, heart, and limb defects. Valpromide (VPD), the amide derivative of CHEMICAL, does not inhibit HDAC activity and is a weak teratogen in vivo. The detailed mechanism of action of CHEMICAL as a teratogen is not known. The goal of this study was to test the hypothesis that CHEMICAL disrupts regulation of the expression of genes that are critical in chondrogenesis and osteogenesis during limb development. Murine gestation day-12 embryonic forelimbs were excised and exposed to CHEMICAL or VPD in a limb bud culture system. CHEMICAL caused a significant concentration- dependent increase in limb abnormalities, which was correlated with its HDAC inhibitory effect. The signaling of both Sox9 and GENE, key regulators of chondrogenesis, was downregulated by CHEMICAL. In contrast, VPD had little effect on limb morphology and no significant effect on HDAC activity or the expression of marker genes. Thus, CHEMICAL exposure dysregulated the expression of target genes directly involved in chondrogenesis and osteogenesis in the developing limb. Disturbances in these signaling pathways are likely to be a consequence of HDAC inhibition because VPD did not affect their expressions. | INDIRECT-DOWNREGULATOR |
| Exposure to CHEMICAL inhibits chondrogenesis and osteogenesis in mid-organogenesis mouse limbs. In utero exposure to CHEMICAL (VPA), a GENE (HDAC) inhibitor, causes neural tube, heart, and limb defects. Valpromide (VPD), the amide derivative of VPA, does not inhibit HDAC activity and is a weak teratogen in vivo. The detailed mechanism of action of VPA as a teratogen is not known. The goal of this study was to test the hypothesis that VPA disrupts regulation of the expression of genes that are critical in chondrogenesis and osteogenesis during limb development. Murine gestation day-12 embryonic forelimbs were excised and exposed to VPA or VPD in a limb bud culture system. VPA caused a significant concentration- dependent increase in limb abnormalities, which was correlated with its HDAC inhibitory effect. The signaling of both Sox9 and Runx2, key regulators of chondrogenesis, was downregulated by VPA. In contrast, VPD had little effect on limb morphology and no significant effect on HDAC activity or the expression of marker genes. Thus, VPA exposure dysregulated the expression of target genes directly involved in chondrogenesis and osteogenesis in the developing limb. Disturbances in these signaling pathways are likely to be a consequence of HDAC inhibition because VPD did not affect their expressions. | INHIBITOR |
| Exposure to CHEMICAL inhibits chondrogenesis and osteogenesis in mid-organogenesis mouse limbs. In utero exposure to CHEMICAL (VPA), a histone deacetylase (GENE) inhibitor, causes neural tube, heart, and limb defects. Valpromide (VPD), the amide derivative of VPA, does not inhibit GENE activity and is a weak teratogen in vivo. The detailed mechanism of action of VPA as a teratogen is not known. The goal of this study was to test the hypothesis that VPA disrupts regulation of the expression of genes that are critical in chondrogenesis and osteogenesis during limb development. Murine gestation day-12 embryonic forelimbs were excised and exposed to VPA or VPD in a limb bud culture system. VPA caused a significant concentration- dependent increase in limb abnormalities, which was correlated with its GENE inhibitory effect. The signaling of both Sox9 and Runx2, key regulators of chondrogenesis, was downregulated by VPA. In contrast, VPD had little effect on limb morphology and no significant effect on GENE activity or the expression of marker genes. Thus, VPA exposure dysregulated the expression of target genes directly involved in chondrogenesis and osteogenesis in the developing limb. Disturbances in these signaling pathways are likely to be a consequence of GENE inhibition because VPD did not affect their expressions. | INHIBITOR |
| Exposure to valproic acid inhibits chondrogenesis and osteogenesis in mid-organogenesis mouse limbs. In utero exposure to valproic acid (CHEMICAL), a GENE (HDAC) inhibitor, causes neural tube, heart, and limb defects. Valpromide (VPD), the amide derivative of CHEMICAL, does not inhibit HDAC activity and is a weak teratogen in vivo. The detailed mechanism of action of CHEMICAL as a teratogen is not known. The goal of this study was to test the hypothesis that CHEMICAL disrupts regulation of the expression of genes that are critical in chondrogenesis and osteogenesis during limb development. Murine gestation day-12 embryonic forelimbs were excised and exposed to CHEMICAL or VPD in a limb bud culture system. CHEMICAL caused a significant concentration- dependent increase in limb abnormalities, which was correlated with its HDAC inhibitory effect. The signaling of both Sox9 and Runx2, key regulators of chondrogenesis, was downregulated by CHEMICAL. In contrast, VPD had little effect on limb morphology and no significant effect on HDAC activity or the expression of marker genes. Thus, CHEMICAL exposure dysregulated the expression of target genes directly involved in chondrogenesis and osteogenesis in the developing limb. Disturbances in these signaling pathways are likely to be a consequence of HDAC inhibition because VPD did not affect their expressions. | INHIBITOR |
| Tumor necrosis factor-alpha potentiates the cytotoxicity of amiodarone in Hepa1c1c7 cells: roles of caspase activation and oxidative stress. Amiodarone (AMD), a class III antiarrhythmic drug, causes idiosyncratic hepatotoxicity in human patients. We demonstrated previously that tumor necrosis factor-alpha (TNF-α) plays an important role in a rat model of AMD-induced hepatotoxicity under inflammatory stress. In this study, we developed a model in vitro to study the roles of caspase activation and oxidative stress in TNF potentiation of CHEMICAL cytotoxicity. CHEMICAL caused cell death in Hepa1c1c7 cells, and TNF cotreatment potentiated its toxicity. Activation of GENE 9 and 3/7 was observed in AMD/TNF-cotreated cells, and caspase inhibitors provided minor protection from cytotoxicity. Intracellular reactive oxygen species (ROS) generation and lipid peroxidation were observed after treatment with CHEMICAL and were further elevated by TNF cotreatment. Adding water-soluble antioxidants (trolox, N-acetylcysteine, glutathione, or ascorbate) produced only minor attenuation of AMD/TNF-induced cytotoxicity and did not influence the effect of CHEMICAL alone. On the other hand, α-tocopherol (TOCO), which reduced lipid peroxidation and ROS generation, prevented CHEMICAL toxicity and caused pronounced reduction in cytotoxicity from AMD/TNF cotreatment. α-TOCO plus a pancaspase inhibitor completely abolished AMD/TNF-induced cytotoxicity. In summary, activation of GENE and oxidative stress were observed after CHEMICAL/TNF cotreatment, and caspase inhibitors and a lipid-soluble free-radical scavenger attenuated AMD/TNF-induced cytotoxicity. | ACTIVATOR |
| Tumor necrosis factor-alpha potentiates the cytotoxicity of amiodarone in Hepa1c1c7 cells: roles of caspase activation and oxidative stress. Amiodarone (AMD), a class III antiarrhythmic drug, causes idiosyncratic hepatotoxicity in human patients. We demonstrated previously that tumor necrosis factor-alpha (TNF-α) plays an important role in a rat model of AMD-induced hepatotoxicity under inflammatory stress. In this study, we developed a model in vitro to study the roles of caspase activation and oxidative stress in TNF potentiation of AMD cytotoxicity. AMD caused cell death in Hepa1c1c7 cells, and TNF cotreatment potentiated its toxicity. Activation of caspases 9 and 3/7 was observed in AMD/TNF-cotreated cells, and caspase inhibitors provided minor protection from cytotoxicity. Intracellular reactive oxygen species (ROS) generation and lipid peroxidation were observed after treatment with AMD and were further elevated by TNF cotreatment. Adding water-soluble antioxidants (trolox, N-acetylcysteine, glutathione, or ascorbate) produced only minor attenuation of AMD/TNF-induced cytotoxicity and did not influence the effect of AMD alone. On the other hand, α-tocopherol (TOCO), which reduced lipid peroxidation and ROS generation, prevented AMD toxicity and caused pronounced reduction in cytotoxicity from AMD/TNF cotreatment. CHEMICAL plus a GENE inhibitor completely abolished AMD/TNF-induced cytotoxicity. In summary, activation of caspases and oxidative stress were observed after AMD/TNF cotreatment, and caspase inhibitors and a lipid-soluble free-radical scavenger attenuated AMD/TNF-induced cytotoxicity. | INHIBITOR |
| Amino acid residues at the N- and C-termini are essential for the folding of active human butyrylcholinesterase polypeptide. Human serum butyrylcholinesterase (HuBChE) is currently the most suitable bioscavenger for the prophylaxis of highly toxic organophosphate (OP) nerve agents. A dose of 200mg of GENE is envisioned as a prophylactic treatment that can protect humans from an exposure of up to 2×LD50 of soman. The limited availability and administration of multiple doses of this stoichiometric bioscavenger make this pretreatment difficult. Thus, the goal of this study was to produce a smaller enzymatically active GENE polypeptide (HBP) that could bind to nerve agents with high affinity thereby reducing the dose of enzyme. Studies have indicated that the three-dimensional structure and the domains of GENE (CHEMICAL pocket, lip of the active center gorge, and the anionic substrate-binding domain) that are critical for the binding of substrate are also essential for the selectivity and binding of inhibitors including OPs. Therefore, we designed three HBPs by deleting some N- and C-terminal residues of GENE by maintaining the folds of the active site core that includes the three active site residues (S198, E325, and H438). HBP-4 that lacks 45 residues from C-terminus but known to have BChE activity was used as a control. The cDNAs for the HBPs containing signal sequences were synthesized, cloned into different mammalian expression vectors, and recombinant polypeptides were transiently expressed in different cell lines. No BChE activity was detected in the culture media of cells transfected with any of the newly designed HBPs, and the inactive polypeptides remained inside the cells. Only enzymatically active HBP-4 was secreted into the culture medium. These results suggest that residues at the N- and C-termini are required for the folding and/or maintenance of HBP into an active stable, conformation. | PART-OF |
| CHEMICAL residues at the N- and C-termini are essential for the folding of active GENE polypeptide. Human serum butyrylcholinesterase (HuBChE) is currently the most suitable bioscavenger for the prophylaxis of highly toxic organophosphate (OP) nerve agents. A dose of 200mg of HuBChE is envisioned as a prophylactic treatment that can protect humans from an exposure of up to 2×LD50 of soman. The limited availability and administration of multiple doses of this stoichiometric bioscavenger make this pretreatment difficult. Thus, the goal of this study was to produce a smaller enzymatically active HuBChE polypeptide (HBP) that could bind to nerve agents with high affinity thereby reducing the dose of enzyme. Studies have indicated that the three-dimensional structure and the domains of HuBChE (acyl pocket, lip of the active center gorge, and the anionic substrate-binding domain) that are critical for the binding of substrate are also essential for the selectivity and binding of inhibitors including OPs. Therefore, we designed three HBPs by deleting some N- and C-terminal residues of HuBChE by maintaining the folds of the active site core that includes the three active site residues (S198, E325, and H438). HBP-4 that lacks 45 residues from C-terminus but known to have BChE activity was used as a control. The cDNAs for the HBPs containing signal sequences were synthesized, cloned into different mammalian expression vectors, and recombinant polypeptides were transiently expressed in different cell lines. No BChE activity was detected in the culture media of cells transfected with any of the newly designed HBPs, and the inactive polypeptides remained inside the cells. Only enzymatically active HBP-4 was secreted into the culture medium. These results suggest that residues at the N- and C-termini are required for the folding and/or maintenance of HBP into an active stable, conformation. | PART-OF |
| Amino acid residues at the N- and C-termini are essential for the folding of active human butyrylcholinesterase polypeptide. Human serum butyrylcholinesterase (GENE) is currently the most suitable bioscavenger for the prophylaxis of highly toxic CHEMICAL (OP) nerve agents. A dose of 200mg of GENE is envisioned as a prophylactic treatment that can protect humans from an exposure of up to 2×LD50 of soman. The limited availability and administration of multiple doses of this stoichiometric bioscavenger make this pretreatment difficult. Thus, the goal of this study was to produce a smaller enzymatically active GENE polypeptide (HBP) that could bind to nerve agents with high affinity thereby reducing the dose of enzyme. Studies have indicated that the three-dimensional structure and the domains of GENE (acyl pocket, lip of the active center gorge, and the anionic substrate-binding domain) that are critical for the binding of substrate are also essential for the selectivity and binding of inhibitors including OPs. Therefore, we designed three HBPs by deleting some N- and C-terminal residues of GENE by maintaining the folds of the active site core that includes the three active site residues (S198, E325, and H438). HBP-4 that lacks 45 residues from C-terminus but known to have BChE activity was used as a control. The cDNAs for the HBPs containing signal sequences were synthesized, cloned into different mammalian expression vectors, and recombinant polypeptides were transiently expressed in different cell lines. No BChE activity was detected in the culture media of cells transfected with any of the newly designed HBPs, and the inactive polypeptides remained inside the cells. Only enzymatically active HBP-4 was secreted into the culture medium. These results suggest that residues at the N- and C-termini are required for the folding and/or maintenance of HBP into an active stable, conformation. | REGULATOR |
| Amino acid residues at the N- and C-termini are essential for the folding of active human butyrylcholinesterase polypeptide. GENE (HuBChE) is currently the most suitable bioscavenger for the prophylaxis of highly toxic CHEMICAL (OP) nerve agents. A dose of 200mg of HuBChE is envisioned as a prophylactic treatment that can protect humans from an exposure of up to 2×LD50 of soman. The limited availability and administration of multiple doses of this stoichiometric bioscavenger make this pretreatment difficult. Thus, the goal of this study was to produce a smaller enzymatically active HuBChE polypeptide (HBP) that could bind to nerve agents with high affinity thereby reducing the dose of enzyme. Studies have indicated that the three-dimensional structure and the domains of HuBChE (acyl pocket, lip of the active center gorge, and the anionic substrate-binding domain) that are critical for the binding of substrate are also essential for the selectivity and binding of inhibitors including OPs. Therefore, we designed three HBPs by deleting some N- and C-terminal residues of HuBChE by maintaining the folds of the active site core that includes the three active site residues (S198, E325, and H438). HBP-4 that lacks 45 residues from C-terminus but known to have BChE activity was used as a control. The cDNAs for the HBPs containing signal sequences were synthesized, cloned into different mammalian expression vectors, and recombinant polypeptides were transiently expressed in different cell lines. No BChE activity was detected in the culture media of cells transfected with any of the newly designed HBPs, and the inactive polypeptides remained inside the cells. Only enzymatically active HBP-4 was secreted into the culture medium. These results suggest that residues at the N- and C-termini are required for the folding and/or maintenance of HBP into an active stable, conformation. | REGULATOR |
| Claudin-3 and claudin-4 regulate sensitivity to CHEMICAL by controlling expression of the copper and CHEMICAL influx transporter GENE. Claudin-3 (CLDN3) and claudin-4 (CLDN4) are the major structural molecules that form tight junctions (TJs) between epithelial cells. We found that knockdown of the expression of either CLDN3 or CLDN4 produced marked changes in the phenotype of ovarian cancer cells, including an increase in resistance to CHEMICAL (cDDP). The effect of CLND3 and CLDN4 on cDDP cytotoxicity, cDDP cellular accumulation, and DNA adduct formation was compared in the CLDN3- and CLDN4-expressing parental human ovarian carcinoma 2008 cells and CLDN3 and CLDN4 knockdown sublines (CLDN3KD and CLDN4KD, respectively). Knockdown of CLDN3 or CLDN4 rendered human ovarian carcinoma 2008 cells resistant to cDDP in both in vitro culture and in vivo xenograft model. The net accumulation of platinum (Pt) and the Pt-DNA adduct levels were reduced in CLDN3KD and CLDN4KD cells. The endogenous mRNA levels of copper influx transporter GENE were found to be significantly reduced in the knockdown cells, and exogenous expression of GENE restored their sensitivity to cDDP. Reexpression of an shRNAi-resistant CLDN3 or CLDN4 up-regulated GENE levels, reversed the cDDP resistance, and enhanced TJ formation in the knockdown cells. Baseline copper (Cu) level, Cu uptake, and Cu cytotoxicity were also reduced in CLDN3KD and CLDN4KD cells. Cu-dependent tyrosinase activity was also markedly reduced in both types of CLDN knockdown cells when incubated with the substrate l-DOPA. These results indicate that CLDN3 and CLDN4 affect sensitivity of the ovarian cancer cells to the cytotoxic effect of cDDP by regulating expression of the Cu transporter GENE. | GENE-CHEMICAL |
| Claudin-3 and claudin-4 regulate sensitivity to CHEMICAL by controlling expression of the GENE CTR1. Claudin-3 (CLDN3) and claudin-4 (CLDN4) are the major structural molecules that form tight junctions (TJs) between epithelial cells. We found that knockdown of the expression of either CLDN3 or CLDN4 produced marked changes in the phenotype of ovarian cancer cells, including an increase in resistance to CHEMICAL (cDDP). The effect of CLND3 and CLDN4 on cDDP cytotoxicity, cDDP cellular accumulation, and DNA adduct formation was compared in the CLDN3- and CLDN4-expressing parental human ovarian carcinoma 2008 cells and CLDN3 and CLDN4 knockdown sublines (CLDN3KD and CLDN4KD, respectively). Knockdown of CLDN3 or CLDN4 rendered human ovarian carcinoma 2008 cells resistant to cDDP in both in vitro culture and in vivo xenograft model. The net accumulation of platinum (Pt) and the Pt-DNA adduct levels were reduced in CLDN3KD and CLDN4KD cells. The endogenous mRNA levels of copper influx transporter CTR1 were found to be significantly reduced in the knockdown cells, and exogenous expression of CTR1 restored their sensitivity to cDDP. Reexpression of an shRNAi-resistant CLDN3 or CLDN4 up-regulated CTR1 levels, reversed the cDDP resistance, and enhanced TJ formation in the knockdown cells. Baseline copper (Cu) level, Cu uptake, and Cu cytotoxicity were also reduced in CLDN3KD and CLDN4KD cells. Cu-dependent tyrosinase activity was also markedly reduced in both types of CLDN knockdown cells when incubated with the substrate l-DOPA. These results indicate that CLDN3 and CLDN4 affect sensitivity of the ovarian cancer cells to the cytotoxic effect of cDDP by regulating expression of the Cu transporter CTR1. | GENE-CHEMICAL |
| GENE and claudin-4 regulate sensitivity to CHEMICAL by controlling expression of the copper and CHEMICAL influx transporter CTR1. GENE (CLDN3) and claudin-4 (CLDN4) are the major structural molecules that form tight junctions (TJs) between epithelial cells. We found that knockdown of the expression of either CLDN3 or CLDN4 produced marked changes in the phenotype of ovarian cancer cells, including an increase in resistance to CHEMICAL (cDDP). The effect of CLND3 and CLDN4 on cDDP cytotoxicity, cDDP cellular accumulation, and DNA adduct formation was compared in the CLDN3- and CLDN4-expressing parental human ovarian carcinoma 2008 cells and CLDN3 and CLDN4 knockdown sublines (CLDN3KD and CLDN4KD, respectively). Knockdown of CLDN3 or CLDN4 rendered human ovarian carcinoma 2008 cells resistant to cDDP in both in vitro culture and in vivo xenograft model. The net accumulation of platinum (Pt) and the Pt-DNA adduct levels were reduced in CLDN3KD and CLDN4KD cells. The endogenous mRNA levels of copper influx transporter CTR1 were found to be significantly reduced in the knockdown cells, and exogenous expression of CTR1 restored their sensitivity to cDDP. Reexpression of an shRNAi-resistant CLDN3 or CLDN4 up-regulated CTR1 levels, reversed the cDDP resistance, and enhanced TJ formation in the knockdown cells. Baseline copper (Cu) level, Cu uptake, and Cu cytotoxicity were also reduced in CLDN3KD and CLDN4KD cells. Cu-dependent tyrosinase activity was also markedly reduced in both types of CLDN knockdown cells when incubated with the substrate l-DOPA. These results indicate that CLDN3 and CLDN4 affect sensitivity of the ovarian cancer cells to the cytotoxic effect of cDDP by regulating expression of the Cu transporter CTR1. | REGULATOR |
| Claudin-3 and GENE regulate sensitivity to CHEMICAL by controlling expression of the copper and CHEMICAL influx transporter CTR1. Claudin-3 (CLDN3) and GENE (CLDN4) are the major structural molecules that form tight junctions (TJs) between epithelial cells. We found that knockdown of the expression of either CLDN3 or CLDN4 produced marked changes in the phenotype of ovarian cancer cells, including an increase in resistance to CHEMICAL (cDDP). The effect of CLND3 and CLDN4 on cDDP cytotoxicity, cDDP cellular accumulation, and DNA adduct formation was compared in the CLDN3- and CLDN4-expressing parental human ovarian carcinoma 2008 cells and CLDN3 and CLDN4 knockdown sublines (CLDN3KD and CLDN4KD, respectively). Knockdown of CLDN3 or CLDN4 rendered human ovarian carcinoma 2008 cells resistant to cDDP in both in vitro culture and in vivo xenograft model. The net accumulation of platinum (Pt) and the Pt-DNA adduct levels were reduced in CLDN3KD and CLDN4KD cells. The endogenous mRNA levels of copper influx transporter CTR1 were found to be significantly reduced in the knockdown cells, and exogenous expression of CTR1 restored their sensitivity to cDDP. Reexpression of an shRNAi-resistant CLDN3 or CLDN4 up-regulated CTR1 levels, reversed the cDDP resistance, and enhanced TJ formation in the knockdown cells. Baseline copper (Cu) level, Cu uptake, and Cu cytotoxicity were also reduced in CLDN3KD and CLDN4KD cells. Cu-dependent tyrosinase activity was also markedly reduced in both types of CLDN knockdown cells when incubated with the substrate l-DOPA. These results indicate that CLDN3 and CLDN4 affect sensitivity of the ovarian cancer cells to the cytotoxic effect of cDDP by regulating expression of the Cu transporter CTR1. | REGULATOR |
| Claudin-3 and claudin-4 regulate sensitivity to cisplatin by controlling expression of the copper and cisplatin influx transporter CTR1. Claudin-3 (CLDN3) and claudin-4 (CLDN4) are the major structural molecules that form tight junctions (TJs) between epithelial cells. We found that knockdown of the expression of either CLDN3 or CLDN4 produced marked changes in the phenotype of ovarian cancer cells, including an increase in resistance to cisplatin (cDDP). The effect of CLND3 and CLDN4 on cDDP cytotoxicity, cDDP cellular accumulation, and DNA adduct formation was compared in the CLDN3- and CLDN4-expressing parental human ovarian carcinoma 2008 cells and CLDN3 and CLDN4 knockdown sublines (CLDN3KD and CLDN4KD, respectively). Knockdown of CLDN3 or CLDN4 rendered human ovarian carcinoma 2008 cells resistant to cDDP in both in vitro culture and in vivo xenograft model. The net accumulation of platinum (Pt) and the Pt-DNA adduct levels were reduced in CLDN3KD and CLDN4KD cells. The endogenous mRNA levels of copper influx transporter CTR1 were found to be significantly reduced in the knockdown cells, and exogenous expression of CTR1 restored their sensitivity to cDDP. Reexpression of an shRNAi-resistant CLDN3 or CLDN4 up-regulated CTR1 levels, reversed the cDDP resistance, and enhanced TJ formation in the knockdown cells. Baseline copper (Cu) level, CHEMICAL uptake, and CHEMICAL cytotoxicity were also reduced in CLDN3KD and CLDN4KD cells. CHEMICAL-dependent GENE activity was also markedly reduced in both types of CLDN knockdown cells when incubated with the substrate l-DOPA. These results indicate that CLDN3 and CLDN4 affect sensitivity of the ovarian cancer cells to the cytotoxic effect of cDDP by regulating expression of the CHEMICAL transporter CTR1. | SUBSTRATE |
| Claudin-3 and claudin-4 regulate sensitivity to cisplatin by controlling expression of the copper and cisplatin influx transporter CTR1. Claudin-3 (CLDN3) and claudin-4 (CLDN4) are the major structural molecules that form tight junctions (TJs) between epithelial cells. We found that knockdown of the expression of either CLDN3 or CLDN4 produced marked changes in the phenotype of ovarian cancer cells, including an increase in resistance to cisplatin (cDDP). The effect of CLND3 and CLDN4 on cDDP cytotoxicity, cDDP cellular accumulation, and DNA adduct formation was compared in the CLDN3- and CLDN4-expressing parental human ovarian carcinoma 2008 cells and CLDN3 and CLDN4 knockdown sublines (CLDN3KD and CLDN4KD, respectively). Knockdown of CLDN3 or CLDN4 rendered human ovarian carcinoma 2008 cells resistant to cDDP in both in vitro culture and in vivo xenograft model. The net accumulation of platinum (Pt) and the Pt-DNA adduct levels were reduced in CLDN3KD and CLDN4KD cells. The endogenous mRNA levels of copper influx transporter CTR1 were found to be significantly reduced in the knockdown cells, and exogenous expression of CTR1 restored their sensitivity to cDDP. Reexpression of an shRNAi-resistant CLDN3 or CLDN4 up-regulated CTR1 levels, reversed the cDDP resistance, and enhanced TJ formation in the knockdown cells. Baseline copper (Cu) level, Cu uptake, and Cu cytotoxicity were also reduced in CLDN3KD and CLDN4KD cells. Cu-dependent GENE activity was also markedly reduced in both types of CLDN knockdown cells when incubated with the substrate CHEMICAL. These results indicate that CLDN3 and CLDN4 affect sensitivity of the ovarian cancer cells to the cytotoxic effect of cDDP by regulating expression of the Cu transporter CTR1. | SUBSTRATE |
| Regulation of hepatic phase II metabolism in pregnant mice. Phase II enzymes, including Ugts, Sults, and Gsts, are critical for the disposition and detoxification of endo- and xenobiotics. In this study, the mRNA and protein expression of major phase II enzymes, as well as key regulatory transcription factors, were quantified in livers of time-matched pregnant and virgin control C57BL/6 mice on gestation days (GD) 7, 11, 14, 17, and postnatal days (PND) 1, 15, and 30. Compared with virgin controls, the mRNA expression of Ugt1a1, 1a6, 1a9, 2a3, 2b1, 2b34, and 2b35 decreased 40 to 80% in pregnant dams. Protein expression of GENE also decreased and corresponded with reduced in vitro glucuronidation of CHEMICAL in S9 fractions from livers of pregnant mice. Similar to Ugts levels, Gsta1 and a4 mRNAs were reduced in pregnant dams in mid to late gestation; however no change in protein expression was observed. Conversely, Sult1a1, 2a1/2, and 3a1 mRNAs increased 100 to 500% at various time points in pregnant and lactating mice and corresponded with enhanced in vitro sulfation of acetaminophen in liver S9 fractions. Coinciding with maximal decreases in Ugts as well as increases in Sults, the expression of transcription factors CAR, PPARα, and PXR and their target genes were downregulated, whereas ERα mRNA was upregulated. Collectively, these data demonstrate altered regulation of hepatic phase II metabolism in mice during pregnancy and suggest that CAR, PPARα, PXR, and ERα signaling pathways may be candidate signaling pathways responsible for these changes. | SUBSTRATE |
| Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling. Results showed that CHEMICAL increased nuclear levels of Nrf2, and both CHEMICAL and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (alpha-SMA), fibronectin and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, CHEMICAL and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as GENE, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of CHEMICAL on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of CHEMICAL. Finally, CHEMICAL suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, CHEMICAL attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that CHEMICAL could be used to treat renal fibrosis. | NO-RELATIONSHIP |
| Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling. Results showed that CHEMICAL increased nuclear levels of Nrf2, and both CHEMICAL and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (alpha-SMA), fibronectin and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, CHEMICAL and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, GENE and glutathione S-transferase (GST) did not reverse the inhibitory effect of CHEMICAL on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of CHEMICAL. Finally, CHEMICAL suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, CHEMICAL attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that CHEMICAL could be used to treat renal fibrosis. | NO-RELATIONSHIP |
| Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling. Results showed that CHEMICAL increased nuclear levels of Nrf2, and both CHEMICAL and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (alpha-SMA), fibronectin and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, CHEMICAL and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and GENE (GST) did not reverse the inhibitory effect of CHEMICAL on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of CHEMICAL. Finally, CHEMICAL suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, CHEMICAL attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that CHEMICAL could be used to treat renal fibrosis. | NO-RELATIONSHIP |
| Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling. Results showed that CHEMICAL increased nuclear levels of Nrf2, and both CHEMICAL and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (alpha-SMA), fibronectin and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, CHEMICAL and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GENE) did not reverse the inhibitory effect of CHEMICAL on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of CHEMICAL. Finally, CHEMICAL suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, CHEMICAL attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that CHEMICAL could be used to treat renal fibrosis. | NO-RELATIONSHIP |
| Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling. Results showed that CHEMICAL increased nuclear levels of Nrf2, and both CHEMICAL and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (alpha-SMA), fibronectin and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, CHEMICAL and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the GENE (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of CHEMICAL on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of CHEMICAL. Finally, CHEMICAL suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, CHEMICAL attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that CHEMICAL could be used to treat renal fibrosis. | NO-RELATIONSHIP |
| Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling. Results showed that CHEMICAL increased nuclear levels of Nrf2, and both CHEMICAL and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (alpha-SMA), fibronectin and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, CHEMICAL and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (GENE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of CHEMICAL on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of CHEMICAL. Finally, CHEMICAL suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, CHEMICAL attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that CHEMICAL could be used to treat renal fibrosis. | NO-RELATIONSHIP |
| Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that GENE protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates GENE, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling. Results showed that CHEMICAL increased nuclear levels of GENE, and both CHEMICAL and adenovirus-mediated overexpression of GENE (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (alpha-SMA), fibronectin and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, CHEMICAL and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of GENE expression. However, downregulation of the antioxidant response element (ARE)-driven GENE target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of CHEMICAL on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of CHEMICAL. Finally, CHEMICAL suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of GENE and phospho-Smad3, respectively. In summary, CHEMICAL attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that CHEMICAL could be used to treat renal fibrosis. | INDIRECT-UPREGULATOR |
| Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. GENE plays a key role in the development of renal fibrosis. Suppressing the GENE signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting GENE signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of GENE signaling. Results showed that CHEMICAL increased nuclear levels of Nrf2, and both CHEMICAL and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (alpha-SMA), fibronectin and type 1 collagen expression in GENE-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, CHEMICAL and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of CHEMICAL on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of CHEMICAL. Finally, CHEMICAL suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, CHEMICAL attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that CHEMICAL could be used to treat renal fibrosis. | INDIRECT-DOWNREGULATOR |
| CHEMICAL attenuates renal fibrosis via GENE-mediated inhibition of transforming growth factor-beta/Smad signaling. TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling. Results showed that DMF increased nuclear levels of Nrf2, and both DMF and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (alpha-SMA), fibronectin and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, DMF and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of DMF on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of DMF. Finally, DMF suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, DMF attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that DMF could be used to treat renal fibrosis. | REGULATOR |
| Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling. Results showed that CHEMICAL increased nuclear levels of Nrf2, and both CHEMICAL and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased GENE, alpha-smooth muscle actin (alpha-SMA), fibronectin and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, CHEMICAL and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of CHEMICAL on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of CHEMICAL. Finally, CHEMICAL suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, CHEMICAL attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that CHEMICAL could be used to treat renal fibrosis. | INDIRECT-DOWNREGULATOR |
| Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling. Results showed that CHEMICAL increased nuclear levels of Nrf2, and both CHEMICAL and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, GENE (alpha-SMA), fibronectin and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, CHEMICAL and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of CHEMICAL on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of CHEMICAL. Finally, CHEMICAL suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, CHEMICAL attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that CHEMICAL could be used to treat renal fibrosis. | INDIRECT-DOWNREGULATOR |
| Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling. Results showed that CHEMICAL increased nuclear levels of Nrf2, and both CHEMICAL and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (GENE), fibronectin and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, CHEMICAL and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of CHEMICAL on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of CHEMICAL. Finally, CHEMICAL suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and GENE, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, CHEMICAL attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that CHEMICAL could be used to treat renal fibrosis. | INDIRECT-DOWNREGULATOR |
| Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling. Results showed that CHEMICAL increased nuclear levels of Nrf2, and both CHEMICAL and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (alpha-SMA), GENE and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, CHEMICAL and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of CHEMICAL on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of CHEMICAL. Finally, CHEMICAL suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, GENE and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, CHEMICAL attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that CHEMICAL could be used to treat renal fibrosis. | INDIRECT-DOWNREGULATOR |
| Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling. Results showed that CHEMICAL increased nuclear levels of Nrf2, and both CHEMICAL and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (alpha-SMA), fibronectin and GENE expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, CHEMICAL and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of CHEMICAL on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of CHEMICAL. Finally, CHEMICAL suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, fibronectin and GENE expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, CHEMICAL attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that CHEMICAL could be used to treat renal fibrosis. | INDIRECT-DOWNREGULATOR |
| CHEMICAL attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/GENE signaling. TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling. Results showed that DMF increased nuclear levels of Nrf2, and both DMF and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (alpha-SMA), fibronectin and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, DMF and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of DMF on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of DMF. Finally, DMF suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, DMF attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that DMF could be used to treat renal fibrosis. | INHIBITOR |
| CHEMICAL attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of GENE/Smad signaling. TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling. Results showed that DMF increased nuclear levels of Nrf2, and both DMF and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (alpha-SMA), fibronectin and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, DMF and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of DMF on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of DMF. Finally, DMF suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, DMF attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that DMF could be used to treat renal fibrosis. | INHIBITOR |
| Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling. Results showed that CHEMICAL increased nuclear levels of Nrf2, and both CHEMICAL and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (alpha-SMA), fibronectin and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, CHEMICAL and Ad-Nrf2 repressed TGF-beta-stimulated Smad3 activity by inhibiting Smad3 phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of CHEMICAL on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of CHEMICAL. Finally, CHEMICAL suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and GENE, respectively. In summary, CHEMICAL attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/Smad3 signaling in an ARE-independent manner, suggesting that CHEMICAL could be used to treat renal fibrosis. | INDIRECT-DOWNREGULATOR |
| Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. TGF-beta plays a key role in the development of renal fibrosis. Suppressing the TGF-beta signaling pathway is a possible therapeutic approach for preventing this disease, and reports have suggested that Nrf2 protects against renal fibrosis by inhibiting TGF-beta signaling. This study examines whether dimethylfumarate (DMF), which stimulates Nrf2, prevents renal fibrosis via the Nrf2-mediated suppression of TGF-beta signaling. Results showed that CHEMICAL increased nuclear levels of Nrf2, and both CHEMICAL and adenovirus-mediated overexpression of Nrf2 (Ad-Nrf2) decreased PAI-1, alpha-smooth muscle actin (alpha-SMA), fibronectin and type 1 collagen expression in TGF-beta-treated rat mesangial cells (RMCs) and renal fibroblast cells (NRK-49F). Additionally, CHEMICAL and Ad-Nrf2 repressed TGF-beta-stimulated GENE activity by inhibiting GENE phosphorylation, which was restored by siRNA-mediated knockdown of Nrf2 expression. However, downregulation of the antioxidant response element (ARE)-driven Nrf2 target genes such as NQO1, HO-1 and glutathione S-transferase (GST) did not reverse the inhibitory effect of CHEMICAL on TGF-beta-induced upregulation of profibrotic genes or extracellular matrix proteins, suggesting an ARE-independent anti-fibrotic activity of CHEMICAL. Finally, CHEMICAL suppressed unilateral ureteral obstruction (UUO)-induced renal fibrosis and alpha-SMA, fibronectin and type 1 collagen expression in the obstructed kidneys from UUO mice, along with increased and decreased expression of Nrf2 and phospho-Smad3, respectively. In summary, CHEMICAL attenuated renal fibrosis via the Nrf2-mediated inhibition of TGF-beta/GENE signaling in an ARE-independent manner, suggesting that CHEMICAL could be used to treat renal fibrosis. | INHIBITOR |
| The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with Met-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while GENE (OCN) was augmented in CCL3(-/-) and CHEMICAL-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. | INDIRECT-UPREGULATOR |
| The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with Met-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (GENE) was augmented in CCL3(-/-) and CHEMICAL-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. | INDIRECT-UPREGULATOR |
| The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with Met-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (GENE) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and CHEMICAL-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. | INDIRECT-UPREGULATOR |
| The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with Met-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and GENE was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and CHEMICAL-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. | INDIRECT-UPREGULATOR |
| The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with Met-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers GENE (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and CHEMICAL-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. | INDIRECT-UPREGULATOR |
| The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of GENE (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with CHEMICAL-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and Met-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. | INDIRECT-DOWNREGULATOR |
| The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (GENE), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with CHEMICAL-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and Met-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. | INDIRECT-DOWNREGULATOR |
| The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand GENE, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with CHEMICAL-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and Met-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. | INDIRECT-DOWNREGULATOR |
| The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, GENE (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with CHEMICAL-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and Met-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. | INDIRECT-DOWNREGULATOR |
| The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (GENE) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with CHEMICAL-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and Met-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. | INDIRECT-DOWNREGULATOR |
| The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/GENE (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with CHEMICAL-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and Met-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. | INDIRECT-DOWNREGULATOR |
| The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (GENE) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with CHEMICAL-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and Met-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. | INDIRECT-DOWNREGULATOR |
| The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with Met-RANTES. CHEMICAL-RANTES treatment also reduced the levels of GENE and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and Met-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. | INDIRECT-DOWNREGULATOR |
| The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with Met-RANTES. CHEMICAL-RANTES treatment also reduced the levels of cathepsin K and GENE (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and Met-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. | INDIRECT-DOWNREGULATOR |
| The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with Met-RANTES. CHEMICAL-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (GENE). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and Met-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. | INDIRECT-DOWNREGULATOR |
| The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that GENE down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with CHEMICAL-RANTES (an antagonist of GENE and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with Met-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and Met-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. | INHIBITOR |
| The effect of CCL3 and GENE in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of GENE and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with CHEMICAL-RANTES (an antagonist of CCR5 and GENE). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with Met-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and Met-RANTES-treated mice. Altogether, these findings show that GENE is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. | INHIBITOR |
| Human ether-a-go-go-related gene channel blockers and its structural analysis for drug design. The human ether-a-go-go-related gene (hERG) is a K+ channel protein mainly expressed in the heart and the nervous systems and its blockade by non-cardiovascular acting drugs resulted in tachycardia and sudden death. In this present review, we have focused the physicochemical properties responsible for the GENE blocking activity of structurally different compounds. The reported research works showed that the hydrophobicity on the van der Waals (vdW) surface of the molecules (aroused from the aromatic ring) necessary for the GENE blocking activity along with topological and electronic properties. The quinolizidine alkaloids (natural products) such as oxymatrine, sophoridine, sophocarpine and CHEMICAL carry the common molecular structure of O=C=N-C-C-C-N that possessed positive ionotropic effect and GENE blocking activity. Acehytisine hydrochloride (previously named Guangfu base A) was isolated from the root of Aconitum coreanum (Levl.), is an anti-arrhythmic drug in phase IV clinical trial. The isoquinoline alkaloid, neferine (Nef) induces a concentration-dependent decrease in current amplitude (IC50 of 7.419 MM). Most of these natural product compounds contain non-flexible aromatic structures but have significant activity due to the presence of optimum hydrophobicity. Recent research works revealed that Eag and GENE channels are expressed by a variety of cancer cell lines and tissues. The Eag channel showed an oncogenic potential while GENE channels are associated with more aggressive tumors and have a role in mediating invasion. This review concluded that the consideration of physicochemical properties necessary for the GENE blocking activity will guide to develop novel drugs with less cardiotoxicity. | INHIBITOR |
| Human ether-a-go-go-related gene channel blockers and its structural analysis for drug design. The human ether-a-go-go-related gene (hERG) is a K+ channel protein mainly expressed in the heart and the nervous systems and its blockade by non-cardiovascular acting drugs resulted in tachycardia and sudden death. In this present review, we have focused the physicochemical properties responsible for the GENE blocking activity of structurally different compounds. The reported research works showed that the hydrophobicity on the van der Waals (vdW) surface of the molecules (aroused from the aromatic ring) necessary for the GENE blocking activity along with topological and electronic properties. The quinolizidine alkaloids (natural products) such as oxymatrine, sophoridine, sophocarpine and matrine carry the common molecular structure of CHEMICAL that possessed positive ionotropic effect and GENE blocking activity. Acehytisine hydrochloride (previously named Guangfu base A) was isolated from the root of Aconitum coreanum (Levl.), is an anti-arrhythmic drug in phase IV clinical trial. The isoquinoline alkaloid, neferine (Nef) induces a concentration-dependent decrease in current amplitude (IC50 of 7.419 MM). Most of these natural product compounds contain non-flexible aromatic structures but have significant activity due to the presence of optimum hydrophobicity. Recent research works revealed that Eag and GENE channels are expressed by a variety of cancer cell lines and tissues. The Eag channel showed an oncogenic potential while GENE channels are associated with more aggressive tumors and have a role in mediating invasion. This review concluded that the consideration of physicochemical properties necessary for the GENE blocking activity will guide to develop novel drugs with less cardiotoxicity. | ACTIVATOR |
| Human ether-a-go-go-related gene channel blockers and its structural analysis for drug design. The human ether-a-go-go-related gene (hERG) is a K+ channel protein mainly expressed in the heart and the nervous systems and its blockade by non-cardiovascular acting drugs resulted in tachycardia and sudden death. In this present review, we have focused the physicochemical properties responsible for the GENE blocking activity of structurally different compounds. The reported research works showed that the hydrophobicity on the van der Waals (vdW) surface of the molecules (aroused from the aromatic ring) necessary for the GENE blocking activity along with topological and electronic properties. The CHEMICAL (natural products) such as oxymatrine, sophoridine, sophocarpine and matrine carry the common molecular structure of O=C=N-C-C-C-N that possessed positive ionotropic effect and GENE blocking activity. Acehytisine hydrochloride (previously named Guangfu base A) was isolated from the root of Aconitum coreanum (Levl.), is an anti-arrhythmic drug in phase IV clinical trial. The isoquinoline alkaloid, neferine (Nef) induces a concentration-dependent decrease in current amplitude (IC50 of 7.419 MM). Most of these natural product compounds contain non-flexible aromatic structures but have significant activity due to the presence of optimum hydrophobicity. Recent research works revealed that Eag and GENE channels are expressed by a variety of cancer cell lines and tissues. The Eag channel showed an oncogenic potential while GENE channels are associated with more aggressive tumors and have a role in mediating invasion. This review concluded that the consideration of physicochemical properties necessary for the GENE blocking activity will guide to develop novel drugs with less cardiotoxicity. | INHIBITOR |
| Human ether-a-go-go-related gene channel blockers and its structural analysis for drug design. The human ether-a-go-go-related gene (hERG) is a K+ channel protein mainly expressed in the heart and the nervous systems and its blockade by non-cardiovascular acting drugs resulted in tachycardia and sudden death. In this present review, we have focused the physicochemical properties responsible for the GENE blocking activity of structurally different compounds. The reported research works showed that the hydrophobicity on the van der Waals (vdW) surface of the molecules (aroused from the aromatic ring) necessary for the GENE blocking activity along with topological and electronic properties. The quinolizidine alkaloids (natural products) such as CHEMICAL, sophoridine, sophocarpine and matrine carry the common molecular structure of O=C=N-C-C-C-N that possessed positive ionotropic effect and GENE blocking activity. Acehytisine hydrochloride (previously named Guangfu base A) was isolated from the root of Aconitum coreanum (Levl.), is an anti-arrhythmic drug in phase IV clinical trial. The isoquinoline alkaloid, neferine (Nef) induces a concentration-dependent decrease in current amplitude (IC50 of 7.419 MM). Most of these natural product compounds contain non-flexible aromatic structures but have significant activity due to the presence of optimum hydrophobicity. Recent research works revealed that Eag and GENE channels are expressed by a variety of cancer cell lines and tissues. The Eag channel showed an oncogenic potential while GENE channels are associated with more aggressive tumors and have a role in mediating invasion. This review concluded that the consideration of physicochemical properties necessary for the GENE blocking activity will guide to develop novel drugs with less cardiotoxicity. | INHIBITOR |
| Human ether-a-go-go-related gene channel blockers and its structural analysis for drug design. The human ether-a-go-go-related gene (hERG) is a K+ channel protein mainly expressed in the heart and the nervous systems and its blockade by non-cardiovascular acting drugs resulted in tachycardia and sudden death. In this present review, we have focused the physicochemical properties responsible for the GENE blocking activity of structurally different compounds. The reported research works showed that the hydrophobicity on the van der Waals (vdW) surface of the molecules (aroused from the aromatic ring) necessary for the GENE blocking activity along with topological and electronic properties. The quinolizidine alkaloids (natural products) such as oxymatrine, CHEMICAL, sophocarpine and matrine carry the common molecular structure of O=C=N-C-C-C-N that possessed positive ionotropic effect and GENE blocking activity. Acehytisine hydrochloride (previously named Guangfu base A) was isolated from the root of Aconitum coreanum (Levl.), is an anti-arrhythmic drug in phase IV clinical trial. The isoquinoline alkaloid, neferine (Nef) induces a concentration-dependent decrease in current amplitude (IC50 of 7.419 MM). Most of these natural product compounds contain non-flexible aromatic structures but have significant activity due to the presence of optimum hydrophobicity. Recent research works revealed that Eag and GENE channels are expressed by a variety of cancer cell lines and tissues. The Eag channel showed an oncogenic potential while GENE channels are associated with more aggressive tumors and have a role in mediating invasion. This review concluded that the consideration of physicochemical properties necessary for the GENE blocking activity will guide to develop novel drugs with less cardiotoxicity. | INHIBITOR |
| Human ether-a-go-go-related gene channel blockers and its structural analysis for drug design. The human ether-a-go-go-related gene (hERG) is a K+ channel protein mainly expressed in the heart and the nervous systems and its blockade by non-cardiovascular acting drugs resulted in tachycardia and sudden death. In this present review, we have focused the physicochemical properties responsible for the GENE blocking activity of structurally different compounds. The reported research works showed that the hydrophobicity on the van der Waals (vdW) surface of the molecules (aroused from the aromatic ring) necessary for the GENE blocking activity along with topological and electronic properties. The quinolizidine alkaloids (natural products) such as oxymatrine, sophoridine, CHEMICAL and matrine carry the common molecular structure of O=C=N-C-C-C-N that possessed positive ionotropic effect and GENE blocking activity. Acehytisine hydrochloride (previously named Guangfu base A) was isolated from the root of Aconitum coreanum (Levl.), is an anti-arrhythmic drug in phase IV clinical trial. The isoquinoline alkaloid, neferine (Nef) induces a concentration-dependent decrease in current amplitude (IC50 of 7.419 MM). Most of these natural product compounds contain non-flexible aromatic structures but have significant activity due to the presence of optimum hydrophobicity. Recent research works revealed that Eag and GENE channels are expressed by a variety of cancer cell lines and tissues. The Eag channel showed an oncogenic potential while GENE channels are associated with more aggressive tumors and have a role in mediating invasion. This review concluded that the consideration of physicochemical properties necessary for the GENE blocking activity will guide to develop novel drugs with less cardiotoxicity. | INHIBITOR |
| Multifunctional targets of dietary CHEMICAL in disease: a case for the GENE network and energy metabolism. Chronic, non-acute inflammation is behind conditions that represent most of the disease burden in humans and is clearly linked to immune and metabolic mechanisms. The convergence of pathways involving the immune response, oxidative stress, increased circulating lipids and aberrant insulin signaling results in CCL2-associated macrophage recruitment and altered energy metabolism. The CCL2/CCR2 pathway and the energy sensor AMP-activated protein kinase (AMPK) are attractive therapeutic targets as a part of preventive management of disease. Several effects of CHEMICAL are useful in this scenario, including a reduction in the activities of cytokines and modulation of cellular metabolism through histone deacetylase inhibitors, AMPK activators, calorie-restriction mimetics or epigenetic regulators. Research is currently underway to develop orally active drugs with these effects, but it is convenient to examine more closely what we are eating. If a lack of relevance in terms of toxicity and substantial effectiveness are confirmed, plant-derived components may provide useful druggable components and dietary supplements. We consider therapeutic actions as a combination of synergistic and/or antagonistic interactions in a multi-target strategy. Hence, improvement in food through enrichment with CHEMICAL with demonstrated activity may represent a major advance in the design of diets with both industrial and sanitary value. | REGULATOR |
| Multifunctional targets of dietary CHEMICAL in disease: a case for the chemokine network and energy metabolism. Chronic, non-acute inflammation is behind conditions that represent most of the disease burden in humans and is clearly linked to immune and metabolic mechanisms. The convergence of pathways involving the immune response, oxidative stress, increased circulating lipids and aberrant insulin signaling results in CCL2-associated macrophage recruitment and altered energy metabolism. The CCL2/CCR2 pathway and the energy sensor AMP-activated protein kinase (AMPK) are attractive therapeutic targets as a part of preventive management of disease. Several effects of CHEMICAL are useful in this scenario, including a reduction in the activities of cytokines and modulation of cellular metabolism through histone deacetylase inhibitors, GENE activators, calorie-restriction mimetics or epigenetic regulators. Research is currently underway to develop orally active drugs with these effects, but it is convenient to examine more closely what we are eating. If a lack of relevance in terms of toxicity and substantial effectiveness are confirmed, plant-derived components may provide useful druggable components and dietary supplements. We consider therapeutic actions as a combination of synergistic and/or antagonistic interactions in a multi-target strategy. Hence, improvement in food through enrichment with CHEMICAL with demonstrated activity may represent a major advance in the design of diets with both industrial and sanitary value. | ACTIVATOR |
| Multifunctional targets of dietary CHEMICAL in disease: a case for the chemokine network and energy metabolism. Chronic, non-acute inflammation is behind conditions that represent most of the disease burden in humans and is clearly linked to immune and metabolic mechanisms. The convergence of pathways involving the immune response, oxidative stress, increased circulating lipids and aberrant insulin signaling results in CCL2-associated macrophage recruitment and altered energy metabolism. The CCL2/CCR2 pathway and the energy sensor AMP-activated protein kinase (AMPK) are attractive therapeutic targets as a part of preventive management of disease. Several effects of CHEMICAL are useful in this scenario, including a reduction in the activities of GENE and modulation of cellular metabolism through histone deacetylase inhibitors, AMPK activators, calorie-restriction mimetics or epigenetic regulators. Research is currently underway to develop orally active drugs with these effects, but it is convenient to examine more closely what we are eating. If a lack of relevance in terms of toxicity and substantial effectiveness are confirmed, plant-derived components may provide useful druggable components and dietary supplements. We consider therapeutic actions as a combination of synergistic and/or antagonistic interactions in a multi-target strategy. Hence, improvement in food through enrichment with CHEMICAL with demonstrated activity may represent a major advance in the design of diets with both industrial and sanitary value. | INHIBITOR |
| Multifunctional targets of dietary CHEMICAL in disease: a case for the chemokine network and energy metabolism. Chronic, non-acute inflammation is behind conditions that represent most of the disease burden in humans and is clearly linked to immune and metabolic mechanisms. The convergence of pathways involving the immune response, oxidative stress, increased circulating lipids and aberrant insulin signaling results in CCL2-associated macrophage recruitment and altered energy metabolism. The CCL2/CCR2 pathway and the energy sensor AMP-activated protein kinase (AMPK) are attractive therapeutic targets as a part of preventive management of disease. Several effects of CHEMICAL are useful in this scenario, including a reduction in the activities of cytokines and modulation of cellular metabolism through GENE inhibitors, AMPK activators, calorie-restriction mimetics or epigenetic regulators. Research is currently underway to develop orally active drugs with these effects, but it is convenient to examine more closely what we are eating. If a lack of relevance in terms of toxicity and substantial effectiveness are confirmed, plant-derived components may provide useful druggable components and dietary supplements. We consider therapeutic actions as a combination of synergistic and/or antagonistic interactions in a multi-target strategy. Hence, improvement in food through enrichment with CHEMICAL with demonstrated activity may represent a major advance in the design of diets with both industrial and sanitary value. | INHIBITOR |
| Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use GENE as a metastatic inducer of MDA-MB-231 cells to investigate the effect of CHEMICAL on cell migration and invasion. CHEMICAL suppressed GENE-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. CHEMICAL abrogated EGF-induced phosphorylation of GENE receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that CHEMICAL inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of CHEMICAL as a potent anti-metastatic agent in MDA-MB-231 cells. | INHIBITOR |
| Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of NFD on cell migration and invasion. NFD suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced GENE expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. NFD abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the EGFR inhibitor CHEMICAL inhibited EGF-induced GENE expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that NFD inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of GENE expression. These results provide a novel mechanism to explain the role of NFD as a potent anti-metastatic agent in MDA-MB-231 cells. | INDIRECT-DOWNREGULATOR |
| Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of CHEMICAL on cell migration and invasion. CHEMICAL suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. CHEMICAL abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific GENE inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that CHEMICAL inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent GENE/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of CHEMICAL as a potent anti-metastatic agent in MDA-MB-231 cells. | REGULATOR |
| Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of CHEMICAL on cell migration and invasion. CHEMICAL suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. CHEMICAL abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that CHEMICAL inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/GENE signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of CHEMICAL as a potent anti-metastatic agent in MDA-MB-231 cells. | REGULATOR |
| Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of CHEMICAL on cell migration and invasion. CHEMICAL suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced GENE expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. CHEMICAL abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced GENE expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that CHEMICAL inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of GENE expression. These results provide a novel mechanism to explain the role of CHEMICAL as a potent anti-metastatic agent in MDA-MB-231 cells. | INDIRECT-DOWNREGULATOR |
| Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of CHEMICAL on cell migration and invasion. CHEMICAL suppressed EGF-mediated protein levels of GENE and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. CHEMICAL abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that CHEMICAL inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of CHEMICAL as a potent anti-metastatic agent in MDA-MB-231 cells. | INDIRECT-DOWNREGULATOR |
| Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of CHEMICAL on cell migration and invasion. CHEMICAL suppressed EGF-mediated protein levels of c-Jun and GENE, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. CHEMICAL abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that CHEMICAL inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of CHEMICAL as a potent anti-metastatic agent in MDA-MB-231 cells. | INDIRECT-DOWNREGULATOR |
| Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of NFD on cell migration and invasion. NFD suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. NFD abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific GENE inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the EGFR inhibitor CHEMICAL inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that GENE/Akt activation occur downstream of EGFR activation. These findings suggest that NFD inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of NFD as a potent anti-metastatic agent in MDA-MB-231 cells. | ACTIVATOR |
| Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of NFD on cell migration and invasion. NFD suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. NFD abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the EGFR inhibitor CHEMICAL inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/GENE activation occur downstream of EGFR activation. These findings suggest that NFD inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of NFD as a potent anti-metastatic agent in MDA-MB-231 cells. | ACTIVATOR |
| Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of NFD on cell migration and invasion. NFD suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. NFD abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the GENE inhibitor CHEMICAL inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of GENE activation. These findings suggest that NFD inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of NFD as a potent anti-metastatic agent in MDA-MB-231 cells. | INHIBITOR |
| Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use GENE as a metastatic inducer of MDA-MB-231 cells to investigate the effect of NFD on cell migration and invasion. NFD suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. NFD abrogated EGF-induced phosphorylation of GENE receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the EGFR inhibitor CHEMICAL inhibited GENE-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that NFD inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of NFD as a potent anti-metastatic agent in MDA-MB-231 cells. | INHIBITOR |
| Inhibition of GENE/EGFR activation with CHEMICAL blocks migration and invasion of MDA-MB-231 cells. CHEMICAL (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use GENE as a metastatic inducer of MDA-MB-231 cells to investigate the effect of NFD on cell migration and invasion. NFD suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. NFD abrogated EGF-induced phosphorylation of GENE receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that NFD inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of NFD as a potent anti-metastatic agent in MDA-MB-231 cells. | ACTIVATOR |
| Inhibition of EGF/GENE activation with CHEMICAL blocks migration and invasion of MDA-MB-231 cells. CHEMICAL (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of NFD on cell migration and invasion. NFD suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. NFD abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the GENE inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of GENE activation. These findings suggest that NFD inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of NFD as a potent anti-metastatic agent in MDA-MB-231 cells. | ACTIVATOR |
| Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of CHEMICAL on cell migration and invasion. CHEMICAL suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. CHEMICAL abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the GENE inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of GENE activation. These findings suggest that CHEMICAL inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via GENE-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of CHEMICAL as a potent anti-metastatic agent in MDA-MB-231 cells. | REGULATOR |
| Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of CHEMICAL on cell migration and invasion. CHEMICAL suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. CHEMICAL abrogated EGF-induced phosphorylation of GENE (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that CHEMICAL inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of CHEMICAL as a potent anti-metastatic agent in MDA-MB-231 cells. | INHIBITOR |
| Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of CHEMICAL on cell migration and invasion. CHEMICAL suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. CHEMICAL abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and GENE (PI3K)/Akt. The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that CHEMICAL inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of CHEMICAL as a potent anti-metastatic agent in MDA-MB-231 cells. | INHIBITOR |
| Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of NFD on cell migration and invasion. NFD suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. NFD abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific GENE inhibitor, CHEMICAL, blocked significantly EGF-induced cell migration and invasion. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that NFD inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of NFD as a potent anti-metastatic agent in MDA-MB-231 cells. | INHIBITOR |
| Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use GENE as a metastatic inducer of MDA-MB-231 cells to investigate the effect of NFD on cell migration and invasion. NFD suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. NFD abrogated EGF-induced phosphorylation of GENE receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific PI3K inhibitor, CHEMICAL, blocked significantly GENE-induced cell migration and invasion. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that NFD inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of NFD as a potent anti-metastatic agent in MDA-MB-231 cells. | INHIBITOR |
| A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the research field. Herein, we report the identification and characterization of CHEMICAL (ESI-09), a novel noncyclic nucleotide EPAC antagonist that is capable of specifically blocking intracellular EPAC-mediated Rap1 activation and Akt phosphorylation, as well as EPAC-mediated GENE secretion in pancreatic β cells. Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells. Our studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer. | INDIRECT-DOWNREGULATOR |
| A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the research field. Herein, we report the identification and characterization of 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile (CHEMICAL), a novel noncyclic nucleotide EPAC antagonist that is capable of specifically blocking intracellular EPAC-mediated Rap1 activation and Akt phosphorylation, as well as EPAC-mediated GENE secretion in pancreatic β cells. Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells. Our studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer. | INHIBITOR |
| A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the research field. Herein, we report the identification and characterization of 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile (ESI-09), a novel noncyclic CHEMICAL EPAC antagonist that is capable of specifically blocking intracellular EPAC-mediated Rap1 activation and Akt phosphorylation, as well as EPAC-mediated GENE secretion in pancreatic β cells. Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells. Our studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer. | GENE-CHEMICAL |
| A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating GENE activity represents a significant unmet need within the research field. Herein, we report the identification and characterization of CHEMICAL (ESI-09), a novel noncyclic nucleotide GENE antagonist that is capable of specifically blocking intracellular GENE-mediated Rap1 activation and Akt phosphorylation, as well as EPAC-mediated insulin secretion in pancreatic β cells. Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells. Our studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer. | INHIBITOR |
| A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the research field. Herein, we report the identification and characterization of CHEMICAL (ESI-09), a novel noncyclic nucleotide EPAC antagonist that is capable of specifically blocking intracellular EPAC-mediated GENE activation and Akt phosphorylation, as well as EPAC-mediated insulin secretion in pancreatic β cells. Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells. Our studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer. | INHIBITOR |
| A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the research field. Herein, we report the identification and characterization of CHEMICAL (ESI-09), a novel noncyclic nucleotide EPAC antagonist that is capable of specifically blocking intracellular EPAC-mediated Rap1 activation and GENE phosphorylation, as well as EPAC-mediated insulin secretion in pancreatic β cells. Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells. Our studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer. | INHIBITOR |
| A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating GENE activity represents a significant unmet need within the research field. Herein, we report the identification and characterization of 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile (CHEMICAL), a novel noncyclic nucleotide GENE antagonist that is capable of specifically blocking intracellular GENE-mediated Rap1 activation and Akt phosphorylation, as well as EPAC-mediated insulin secretion in pancreatic β cells. Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells. Our studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer. | INHIBITOR |
| A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the research field. Herein, we report the identification and characterization of 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile (CHEMICAL), a novel noncyclic nucleotide EPAC antagonist that is capable of specifically blocking intracellular EPAC-mediated GENE activation and Akt phosphorylation, as well as EPAC-mediated insulin secretion in pancreatic β cells. Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells. Our studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer. | INHIBITOR |
| A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the research field. Herein, we report the identification and characterization of 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile (CHEMICAL), a novel noncyclic nucleotide EPAC antagonist that is capable of specifically blocking intracellular EPAC-mediated Rap1 activation and GENE phosphorylation, as well as EPAC-mediated insulin secretion in pancreatic β cells. Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells. Our studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer. | INHIBITOR |
| A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating GENE activity represents a significant unmet need within the research field. Herein, we report the identification and characterization of 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile (ESI-09), a novel noncyclic CHEMICAL GENE antagonist that is capable of specifically blocking intracellular GENE-mediated Rap1 activation and Akt phosphorylation, as well as EPAC-mediated insulin secretion in pancreatic β cells. Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells. Our studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer. | INHIBITOR |
| A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the research field. Herein, we report the identification and characterization of 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile (ESI-09), a novel noncyclic CHEMICAL EPAC antagonist that is capable of specifically blocking intracellular EPAC-mediated GENE activation and Akt phosphorylation, as well as EPAC-mediated insulin secretion in pancreatic β cells. Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells. Our studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer. | INHIBITOR |
| A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the research field. Herein, we report the identification and characterization of 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile (ESI-09), a novel noncyclic CHEMICAL EPAC antagonist that is capable of specifically blocking intracellular EPAC-mediated Rap1 activation and GENE phosphorylation, as well as EPAC-mediated insulin secretion in pancreatic β cells. Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells. Our studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer. | INHIBITOR |
| CHEMICAL directly inhibits ghrelin secretion through AMP-activated protein kinase in rat primary gastric cells. The antidiabetic drug CHEMICAL causes weight loss in both diabetic and non-diabetic individuals. CHEMICAL treatment is also associated with lower circulating levels of the orexigenic hormone ghrelin. To test whether CHEMICAL directly affects ghrelin cells, rat primary stomach cells were treated with CHEMICAL and the levels of ghrelin secretion, proghrelin gene expression and activation of adenosine monophosphate-activated protein kinase (AMPK) were examined. CHEMICAL significantly reduced ghrelin secretion and proghrelin mRNA production and both these effects were blocked by co-incubation with the GENE inhibitor compound C. Furthermore, the GENE activator 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) significantly inhibited ghrelin secretion. Additionally, ghrelin cells were shown to express GENE. Finally, CHEMICAL treatment caused a significant increase in the level of phosphorylated (active) GENE. Our results show that CHEMICAL directly inhibits stomach ghrelin production and secretion through GENE. This reduction in ghrelin secretion may be one of the key components in Metformin's mechanism of weight loss. | ACTIVATOR |
| CHEMICAL directly inhibits ghrelin secretion through GENE in rat primary gastric cells. The antidiabetic drug CHEMICAL causes weight loss in both diabetic and non-diabetic individuals. CHEMICAL treatment is also associated with lower circulating levels of the orexigenic hormone ghrelin. To test whether CHEMICAL directly affects ghrelin cells, rat primary stomach cells were treated with CHEMICAL and the levels of ghrelin secretion, proghrelin gene expression and activation of adenosine monophosphate-activated protein kinase (AMPK) were examined. CHEMICAL significantly reduced ghrelin secretion and proghrelin mRNA production and both these effects were blocked by co-incubation with the AMPK inhibitor compound C. Furthermore, the AMPK activator 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) significantly inhibited ghrelin secretion. Additionally, ghrelin cells were shown to express AMPK. Finally, CHEMICAL treatment caused a significant increase in the level of phosphorylated (active) AMPK. Our results show that CHEMICAL directly inhibits stomach ghrelin production and secretion through AMPK. This reduction in ghrelin secretion may be one of the key components in Metformin's mechanism of weight loss. | INHIBITOR |
| Metformin directly inhibits ghrelin secretion through AMP-activated protein kinase in rat primary gastric cells. The antidiabetic drug Metformin causes weight loss in both diabetic and non-diabetic individuals. Metformin treatment is also associated with lower circulating levels of the orexigenic hormone ghrelin. To test whether Metformin directly affects ghrelin cells, rat primary stomach cells were treated with Metformin and the levels of ghrelin secretion, proghrelin gene expression and activation of adenosine monophosphate-activated protein kinase (AMPK) were examined. Metformin significantly reduced ghrelin secretion and proghrelin mRNA production and both these effects were blocked by co-incubation with the GENE inhibitor compound C. Furthermore, the GENE activator CHEMICAL (AICAR) significantly inhibited ghrelin secretion. Additionally, ghrelin cells were shown to express GENE. Finally, Metformin treatment caused a significant increase in the level of phosphorylated (active) GENE. Our results show that Metformin directly inhibits stomach ghrelin production and secretion through GENE. This reduction in ghrelin secretion may be one of the key components in Metformin's mechanism of weight loss. | ACTIVATOR |
| Metformin directly inhibits ghrelin secretion through AMP-activated protein kinase in rat primary gastric cells. The antidiabetic drug Metformin causes weight loss in both diabetic and non-diabetic individuals. Metformin treatment is also associated with lower circulating levels of the orexigenic hormone ghrelin. To test whether Metformin directly affects ghrelin cells, rat primary stomach cells were treated with Metformin and the levels of ghrelin secretion, proghrelin gene expression and activation of adenosine monophosphate-activated protein kinase (AMPK) were examined. Metformin significantly reduced ghrelin secretion and proghrelin mRNA production and both these effects were blocked by co-incubation with the GENE inhibitor compound C. Furthermore, the GENE activator 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (CHEMICAL) significantly inhibited ghrelin secretion. Additionally, ghrelin cells were shown to express GENE. Finally, Metformin treatment caused a significant increase in the level of phosphorylated (active) GENE. Our results show that Metformin directly inhibits stomach ghrelin production and secretion through GENE. This reduction in ghrelin secretion may be one of the key components in Metformin's mechanism of weight loss. | ACTIVATOR |
| CHEMICAL directly inhibits ghrelin secretion through AMP-activated protein kinase in rat primary gastric cells. The antidiabetic drug CHEMICAL causes weight loss in both diabetic and non-diabetic individuals. CHEMICAL treatment is also associated with lower circulating levels of the orexigenic hormone ghrelin. To test whether CHEMICAL directly affects ghrelin cells, rat primary stomach cells were treated with CHEMICAL and the levels of ghrelin secretion, proghrelin gene expression and activation of adenosine monophosphate-activated protein kinase (AMPK) were examined. CHEMICAL significantly reduced ghrelin secretion and proghrelin mRNA production and both these effects were blocked by co-incubation with the AMPK inhibitor compound C. Furthermore, the AMPK activator 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) significantly inhibited ghrelin secretion. Additionally, ghrelin cells were shown to express AMPK. Finally, CHEMICAL treatment caused a significant increase in the level of GENE. Our results show that CHEMICAL directly inhibits stomach ghrelin production and secretion through AMPK. This reduction in ghrelin secretion may be one of the key components in Metformin's mechanism of weight loss. | INDIRECT-UPREGULATOR |
| Metformin directly inhibits GENE secretion through AMP-activated protein kinase in rat primary gastric cells. The antidiabetic drug Metformin causes weight loss in both diabetic and non-diabetic individuals. Metformin treatment is also associated with lower circulating levels of the orexigenic hormone GENE. To test whether Metformin directly affects GENE cells, rat primary stomach cells were treated with Metformin and the levels of GENE secretion, proghrelin gene expression and activation of adenosine monophosphate-activated protein kinase (AMPK) were examined. Metformin significantly reduced GENE secretion and proghrelin mRNA production and both these effects were blocked by co-incubation with the AMPK inhibitor CHEMICAL. Furthermore, the AMPK activator 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) significantly inhibited GENE secretion. Additionally, GENE cells were shown to express AMPK. Finally, Metformin treatment caused a significant increase in the level of phosphorylated (active) AMPK. Our results show that Metformin directly inhibits stomach GENE production and secretion through AMPK. This reduction in GENE secretion may be one of the key components in Metformin's mechanism of weight loss. | INDIRECT-DOWNREGULATOR |
| Metformin directly inhibits ghrelin secretion through AMP-activated protein kinase in rat primary gastric cells. The antidiabetic drug Metformin causes weight loss in both diabetic and non-diabetic individuals. Metformin treatment is also associated with lower circulating levels of the orexigenic hormone ghrelin. To test whether Metformin directly affects ghrelin cells, rat primary stomach cells were treated with Metformin and the levels of ghrelin secretion, GENE gene expression and activation of adenosine monophosphate-activated protein kinase (AMPK) were examined. Metformin significantly reduced ghrelin secretion and GENE mRNA production and both these effects were blocked by co-incubation with the AMPK inhibitor CHEMICAL. Furthermore, the AMPK activator 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) significantly inhibited ghrelin secretion. Additionally, ghrelin cells were shown to express AMPK. Finally, Metformin treatment caused a significant increase in the level of phosphorylated (active) AMPK. Our results show that Metformin directly inhibits stomach ghrelin production and secretion through AMPK. This reduction in ghrelin secretion may be one of the key components in Metformin's mechanism of weight loss. | INHIBITOR |
| CHEMICAL directly inhibits GENE secretion through AMP-activated protein kinase in rat primary gastric cells. The antidiabetic drug CHEMICAL causes weight loss in both diabetic and non-diabetic individuals. CHEMICAL treatment is also associated with lower circulating levels of the orexigenic hormone GENE. To test whether CHEMICAL directly affects GENE cells, rat primary stomach cells were treated with CHEMICAL and the levels of GENE secretion, proghrelin gene expression and activation of adenosine monophosphate-activated protein kinase (AMPK) were examined. CHEMICAL significantly reduced GENE secretion and proghrelin mRNA production and both these effects were blocked by co-incubation with the AMPK inhibitor compound C. Furthermore, the AMPK activator 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) significantly inhibited GENE secretion. Additionally, GENE cells were shown to express AMPK. Finally, CHEMICAL treatment caused a significant increase in the level of phosphorylated (active) AMPK. Our results show that CHEMICAL directly inhibits stomach GENE production and secretion through AMPK. This reduction in GENE secretion may be one of the key components in Metformin's mechanism of weight loss. | GENE-CHEMICAL |
| CHEMICAL directly inhibits ghrelin secretion through AMP-activated protein kinase in rat primary gastric cells. The antidiabetic drug CHEMICAL causes weight loss in both diabetic and non-diabetic individuals. CHEMICAL treatment is also associated with lower circulating levels of the GENE ghrelin. To test whether CHEMICAL directly affects ghrelin cells, rat primary stomach cells were treated with CHEMICAL and the levels of ghrelin secretion, proghrelin gene expression and activation of adenosine monophosphate-activated protein kinase (AMPK) were examined. CHEMICAL significantly reduced ghrelin secretion and proghrelin mRNA production and both these effects were blocked by co-incubation with the AMPK inhibitor compound C. Furthermore, the AMPK activator 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) significantly inhibited ghrelin secretion. Additionally, ghrelin cells were shown to express AMPK. Finally, CHEMICAL treatment caused a significant increase in the level of phosphorylated (active) AMPK. Our results show that CHEMICAL directly inhibits stomach ghrelin production and secretion through AMPK. This reduction in ghrelin secretion may be one of the key components in Metformin's mechanism of weight loss. | INDIRECT-DOWNREGULATOR |
| CHEMICAL directly inhibits ghrelin secretion through AMP-activated protein kinase in rat primary gastric cells. The antidiabetic drug CHEMICAL causes weight loss in both diabetic and non-diabetic individuals. CHEMICAL treatment is also associated with lower circulating levels of the orexigenic hormone ghrelin. To test whether CHEMICAL directly affects ghrelin cells, rat primary stomach cells were treated with CHEMICAL and the levels of ghrelin secretion, GENE gene expression and activation of adenosine monophosphate-activated protein kinase (AMPK) were examined. CHEMICAL significantly reduced ghrelin secretion and GENE mRNA production and both these effects were blocked by co-incubation with the AMPK inhibitor compound C. Furthermore, the AMPK activator 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) significantly inhibited ghrelin secretion. Additionally, ghrelin cells were shown to express AMPK. Finally, CHEMICAL treatment caused a significant increase in the level of phosphorylated (active) AMPK. Our results show that CHEMICAL directly inhibits stomach ghrelin production and secretion through AMPK. This reduction in ghrelin secretion may be one of the key components in Metformin's mechanism of weight loss. | INDIRECT-DOWNREGULATOR |
| Metformin directly inhibits GENE secretion through AMP-activated protein kinase in rat primary gastric cells. The antidiabetic drug Metformin causes weight loss in both diabetic and non-diabetic individuals. Metformin treatment is also associated with lower circulating levels of the orexigenic hormone GENE. To test whether Metformin directly affects GENE cells, rat primary stomach cells were treated with Metformin and the levels of GENE secretion, proghrelin gene expression and activation of adenosine monophosphate-activated protein kinase (AMPK) were examined. Metformin significantly reduced GENE secretion and proghrelin mRNA production and both these effects were blocked by co-incubation with the AMPK inhibitor compound C. Furthermore, the AMPK activator 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (CHEMICAL) significantly inhibited GENE secretion. Additionally, GENE cells were shown to express AMPK. Finally, Metformin treatment caused a significant increase in the level of phosphorylated (active) AMPK. Our results show that Metformin directly inhibits stomach GENE production and secretion through AMPK. This reduction in GENE secretion may be one of the key components in Metformin's mechanism of weight loss. | INDIRECT-DOWNREGULATOR |
| Metformin directly inhibits ghrelin secretion through AMP-activated protein kinase in rat primary gastric cells. The antidiabetic drug Metformin causes weight loss in both diabetic and non-diabetic individuals. Metformin treatment is also associated with lower circulating levels of the orexigenic hormone ghrelin. To test whether Metformin directly affects ghrelin cells, rat primary stomach cells were treated with Metformin and the levels of ghrelin secretion, proghrelin gene expression and activation of adenosine monophosphate-activated protein kinase (AMPK) were examined. Metformin significantly reduced ghrelin secretion and proghrelin mRNA production and both these effects were blocked by co-incubation with the GENE inhibitor CHEMICAL. Furthermore, the GENE activator 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) significantly inhibited ghrelin secretion. Additionally, ghrelin cells were shown to express GENE. Finally, Metformin treatment caused a significant increase in the level of phosphorylated (active) GENE. Our results show that Metformin directly inhibits stomach ghrelin production and secretion through GENE. This reduction in ghrelin secretion may be one of the key components in Metformin's mechanism of weight loss. | INHIBITOR |
| Fungicide CHEMICAL and environmental pollutant dioxin induce the GENE transporter in bovine mammary epithelial cells by the arylhydrocarbon receptor signaling pathway. The molecular mechanisms by which environmental pollutants including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or widely used imidazole fungicide CHEMICAL display their toxic effects in vertebrates are still not well understood. Using computer analysis, we recently identified nuclear aryl hydrocarbon receptor (AhR) binding sites termed "dioxin response elements" (DREs) in the 5'-untranslated region (5'-UTR) of efflux transporter GENE (Accession No. EU570105) from the bovine mammary gland. As these regulatory motifs mediate regulation of target genes by AhR agonists including TCDD and CHEMICAL, we have systematically investigated the effect of both contaminants on functional GENE transport activity in primary bovine mammary epithelial cells. TCDD or CHEMICAL doubled ABCG2-mediated Hoechst H33342 secretion. This effect was almost completely reversed by specific GENE inhibitor Ko143. In further mechanistic studies, we showed that this induction was due to binding of activated AhR to DRE sequences in the GENE 5'-UTR. Receptor binding was significantly reduced by specific AhR antagonist salicyl amide. Induction of AhR by TCDD and CHEMICAL resulted in a time- and dose-dependent increase of GENE gene expression and transporter protein levels. As GENE represents the main mammary transporter for xenobiotics including drugs and toxins, exposure to prevalent AhR agonists may enhance transporter-mediated secretion of potential harmful compounds into milk. Through identification of mammary GENE as a novel target gene of pesticide CHEMICAL and dioxin, our results may therefore help to improve the protection of breast-feeding infants and the consumer of dairy products. | REGULATOR |
| Fungicide prochloraz and environmental pollutant CHEMICAL induce the GENE transporter in bovine mammary epithelial cells by the arylhydrocarbon receptor signaling pathway. The molecular mechanisms by which environmental pollutants including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or widely used imidazole fungicide prochloraz display their toxic effects in vertebrates are still not well understood. Using computer analysis, we recently identified nuclear aryl hydrocarbon receptor (AhR) binding sites termed "dioxin response elements" (DREs) in the 5'-untranslated region (5'-UTR) of efflux transporter GENE (Accession No. EU570105) from the bovine mammary gland. As these regulatory motifs mediate regulation of target genes by AhR agonists including TCDD and prochloraz, we have systematically investigated the effect of both contaminants on functional GENE transport activity in primary bovine mammary epithelial cells. TCDD or prochloraz doubled ABCG2-mediated Hoechst H33342 secretion. This effect was almost completely reversed by specific GENE inhibitor Ko143. In further mechanistic studies, we showed that this induction was due to binding of activated AhR to DRE sequences in the GENE 5'-UTR. Receptor binding was significantly reduced by specific AhR antagonist salicyl amide. Induction of AhR by TCDD and prochloraz resulted in a time- and dose-dependent increase of GENE gene expression and transporter protein levels. As GENE represents the main mammary transporter for xenobiotics including drugs and toxins, exposure to prevalent AhR agonists may enhance transporter-mediated secretion of potential harmful compounds into milk. Through identification of mammary GENE as a novel target gene of pesticide prochloraz and CHEMICAL, our results may therefore help to improve the protection of breast-feeding infants and the consumer of dairy products. | REGULATOR |
| Fungicide prochloraz and environmental pollutant dioxin induce the GENE transporter in bovine mammary epithelial cells by the arylhydrocarbon receptor signaling pathway. The molecular mechanisms by which environmental pollutants including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or widely used imidazole fungicide prochloraz display their toxic effects in vertebrates are still not well understood. Using computer analysis, we recently identified nuclear aryl hydrocarbon receptor (AhR) binding sites termed "dioxin response elements" (DREs) in the 5'-untranslated region (5'-UTR) of efflux transporter GENE (Accession No. EU570105) from the bovine mammary gland. As these regulatory motifs mediate regulation of target genes by AhR agonists including CHEMICAL and prochloraz, we have systematically investigated the effect of both contaminants on functional GENE transport activity in primary bovine mammary epithelial cells. CHEMICAL or prochloraz doubled GENE-mediated Hoechst H33342 secretion. This effect was almost completely reversed by specific GENE inhibitor Ko143. In further mechanistic studies, we showed that this induction was due to binding of activated AhR to DRE sequences in the GENE 5'-UTR. Receptor binding was significantly reduced by specific AhR antagonist salicyl amide. Induction of AhR by CHEMICAL and prochloraz resulted in a time- and dose-dependent increase of GENE gene expression and transporter protein levels. As GENE represents the main mammary transporter for xenobiotics including drugs and toxins, exposure to prevalent AhR agonists may enhance transporter-mediated secretion of potential harmful compounds into milk. Through identification of mammary GENE as a novel target gene of pesticide prochloraz and dioxin, our results may therefore help to improve the protection of breast-feeding infants and the consumer of dairy products. | REGULATOR |
| Fungicide CHEMICAL and environmental pollutant dioxin induce the ABCG2 transporter in bovine mammary epithelial cells by the GENE signaling pathway. The molecular mechanisms by which environmental pollutants including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or widely used imidazole fungicide CHEMICAL display their toxic effects in vertebrates are still not well understood. Using computer analysis, we recently identified nuclear aryl hydrocarbon receptor (AhR) binding sites termed "dioxin response elements" (DREs) in the 5'-untranslated region (5'-UTR) of efflux transporter ABCG2 (Accession No. EU570105) from the bovine mammary gland. As these regulatory motifs mediate regulation of target genes by AhR agonists including TCDD and CHEMICAL, we have systematically investigated the effect of both contaminants on functional ABCG2 transport activity in primary bovine mammary epithelial cells. TCDD or CHEMICAL doubled ABCG2-mediated Hoechst H33342 secretion. This effect was almost completely reversed by specific ABCG2 inhibitor Ko143. In further mechanistic studies, we showed that this induction was due to binding of activated AhR to DRE sequences in the ABCG2 5'-UTR. Receptor binding was significantly reduced by specific AhR antagonist salicyl amide. Induction of AhR by TCDD and CHEMICAL resulted in a time- and dose-dependent increase of ABCG2 gene expression and transporter protein levels. As ABCG2 represents the main mammary transporter for xenobiotics including drugs and toxins, exposure to prevalent AhR agonists may enhance transporter-mediated secretion of potential harmful compounds into milk. Through identification of mammary ABCG2 as a novel target gene of pesticide CHEMICAL and dioxin, our results may therefore help to improve the protection of breast-feeding infants and the consumer of dairy products. | REGULATOR |
| Fungicide prochloraz and environmental pollutant CHEMICAL induce the ABCG2 transporter in bovine mammary epithelial cells by the GENE signaling pathway. The molecular mechanisms by which environmental pollutants including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or widely used imidazole fungicide prochloraz display their toxic effects in vertebrates are still not well understood. Using computer analysis, we recently identified nuclear aryl hydrocarbon receptor (AhR) binding sites termed "dioxin response elements" (DREs) in the 5'-untranslated region (5'-UTR) of efflux transporter ABCG2 (Accession No. EU570105) from the bovine mammary gland. As these regulatory motifs mediate regulation of target genes by AhR agonists including TCDD and prochloraz, we have systematically investigated the effect of both contaminants on functional ABCG2 transport activity in primary bovine mammary epithelial cells. TCDD or prochloraz doubled ABCG2-mediated Hoechst H33342 secretion. This effect was almost completely reversed by specific ABCG2 inhibitor Ko143. In further mechanistic studies, we showed that this induction was due to binding of activated AhR to DRE sequences in the ABCG2 5'-UTR. Receptor binding was significantly reduced by specific AhR antagonist salicyl amide. Induction of AhR by TCDD and prochloraz resulted in a time- and dose-dependent increase of ABCG2 gene expression and transporter protein levels. As ABCG2 represents the main mammary transporter for xenobiotics including drugs and toxins, exposure to prevalent AhR agonists may enhance transporter-mediated secretion of potential harmful compounds into milk. Through identification of mammary ABCG2 as a novel target gene of pesticide prochloraz and CHEMICAL, our results may therefore help to improve the protection of breast-feeding infants and the consumer of dairy products. | ACTIVATOR |
| Fungicide prochloraz and environmental pollutant dioxin induce the ABCG2 transporter in bovine mammary epithelial cells by the arylhydrocarbon receptor signaling pathway. The molecular mechanisms by which environmental pollutants including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or widely used imidazole fungicide prochloraz display their toxic effects in vertebrates are still not well understood. Using computer analysis, we recently identified nuclear aryl hydrocarbon receptor (AhR) binding sites termed "dioxin response elements" (DREs) in the 5'-untranslated region (5'-UTR) of efflux transporter ABCG2 (Accession No. EU570105) from the bovine mammary gland. As these regulatory motifs mediate regulation of target genes by GENE agonists including CHEMICAL and prochloraz, we have systematically investigated the effect of both contaminants on functional ABCG2 transport activity in primary bovine mammary epithelial cells. CHEMICAL or prochloraz doubled ABCG2-mediated Hoechst H33342 secretion. This effect was almost completely reversed by specific ABCG2 inhibitor Ko143. In further mechanistic studies, we showed that this induction was due to binding of activated GENE to DRE sequences in the ABCG2 5'-UTR. Receptor binding was significantly reduced by specific GENE antagonist salicyl amide. Induction of GENE by CHEMICAL and prochloraz resulted in a time- and dose-dependent increase of ABCG2 gene expression and transporter protein levels. As ABCG2 represents the main mammary transporter for xenobiotics including drugs and toxins, exposure to prevalent GENE agonists may enhance transporter-mediated secretion of potential harmful compounds into milk. Through identification of mammary ABCG2 as a novel target gene of pesticide prochloraz and dioxin, our results may therefore help to improve the protection of breast-feeding infants and the consumer of dairy products. | ACTIVATOR |
| Fungicide CHEMICAL and environmental pollutant dioxin induce the ABCG2 transporter in bovine mammary epithelial cells by the arylhydrocarbon receptor signaling pathway. The molecular mechanisms by which environmental pollutants including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or widely used imidazole fungicide CHEMICAL display their toxic effects in vertebrates are still not well understood. Using computer analysis, we recently identified nuclear aryl hydrocarbon receptor (AhR) binding sites termed "dioxin response elements" (DREs) in the 5'-untranslated region (5'-UTR) of efflux transporter ABCG2 (Accession No. EU570105) from the bovine mammary gland. As these regulatory motifs mediate regulation of target genes by GENE agonists including TCDD and CHEMICAL, we have systematically investigated the effect of both contaminants on functional ABCG2 transport activity in primary bovine mammary epithelial cells. TCDD or CHEMICAL doubled ABCG2-mediated Hoechst H33342 secretion. This effect was almost completely reversed by specific ABCG2 inhibitor Ko143. In further mechanistic studies, we showed that this induction was due to binding of activated GENE to DRE sequences in the ABCG2 5'-UTR. Receptor binding was significantly reduced by specific GENE antagonist salicyl amide. Induction of GENE by TCDD and CHEMICAL resulted in a time- and dose-dependent increase of ABCG2 gene expression and transporter protein levels. As ABCG2 represents the main mammary transporter for xenobiotics including drugs and toxins, exposure to prevalent GENE agonists may enhance transporter-mediated secretion of potential harmful compounds into milk. Through identification of mammary ABCG2 as a novel target gene of pesticide CHEMICAL and dioxin, our results may therefore help to improve the protection of breast-feeding infants and the consumer of dairy products. | ACTIVATOR |
| Fungicide prochloraz and environmental pollutant dioxin induce the GENE transporter in bovine mammary epithelial cells by the arylhydrocarbon receptor signaling pathway. The molecular mechanisms by which environmental pollutants including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or widely used imidazole fungicide prochloraz display their toxic effects in vertebrates are still not well understood. Using computer analysis, we recently identified nuclear aryl hydrocarbon receptor (AhR) binding sites termed "dioxin response elements" (DREs) in the 5'-untranslated region (5'-UTR) of efflux transporter GENE (Accession No. EU570105) from the bovine mammary gland. As these regulatory motifs mediate regulation of target genes by AhR agonists including TCDD and prochloraz, we have systematically investigated the effect of both contaminants on functional GENE transport activity in primary bovine mammary epithelial cells. TCDD or prochloraz doubled ABCG2-mediated Hoechst H33342 secretion. This effect was almost completely reversed by specific GENE inhibitor CHEMICAL. In further mechanistic studies, we showed that this induction was due to binding of activated AhR to DRE sequences in the GENE 5'-UTR. Receptor binding was significantly reduced by specific AhR antagonist salicyl amide. Induction of AhR by TCDD and prochloraz resulted in a time- and dose-dependent increase of GENE gene expression and transporter protein levels. As GENE represents the main mammary transporter for xenobiotics including drugs and toxins, exposure to prevalent AhR agonists may enhance transporter-mediated secretion of potential harmful compounds into milk. Through identification of mammary GENE as a novel target gene of pesticide prochloraz and dioxin, our results may therefore help to improve the protection of breast-feeding infants and the consumer of dairy products. | INHIBITOR |
| Fungicide prochloraz and environmental pollutant dioxin induce the ABCG2 transporter in bovine mammary epithelial cells by the arylhydrocarbon receptor signaling pathway. The molecular mechanisms by which environmental pollutants including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or widely used imidazole fungicide prochloraz display their toxic effects in vertebrates are still not well understood. Using computer analysis, we recently identified nuclear aryl hydrocarbon receptor (AhR) binding sites termed "dioxin response elements" (DREs) in the 5'-untranslated region (5'-UTR) of efflux transporter ABCG2 (Accession No. EU570105) from the bovine mammary gland. As these regulatory motifs mediate regulation of target genes by GENE agonists including TCDD and prochloraz, we have systematically investigated the effect of both contaminants on functional ABCG2 transport activity in primary bovine mammary epithelial cells. TCDD or prochloraz doubled ABCG2-mediated Hoechst H33342 secretion. This effect was almost completely reversed by specific ABCG2 inhibitor Ko143. In further mechanistic studies, we showed that this induction was due to binding of activated GENE to DRE sequences in the ABCG2 5'-UTR. Receptor binding was significantly reduced by specific GENE antagonist CHEMICAL. Induction of GENE by TCDD and prochloraz resulted in a time- and dose-dependent increase of ABCG2 gene expression and transporter protein levels. As ABCG2 represents the main mammary transporter for xenobiotics including drugs and toxins, exposure to prevalent GENE agonists may enhance transporter-mediated secretion of potential harmful compounds into milk. Through identification of mammary ABCG2 as a novel target gene of pesticide prochloraz and dioxin, our results may therefore help to improve the protection of breast-feeding infants and the consumer of dairy products. | INHIBITOR |
| Fungicide prochloraz and environmental pollutant dioxin induce the GENE transporter in bovine mammary epithelial cells by the arylhydrocarbon receptor signaling pathway. The molecular mechanisms by which environmental pollutants including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or widely used imidazole fungicide prochloraz display their toxic effects in vertebrates are still not well understood. Using computer analysis, we recently identified nuclear aryl hydrocarbon receptor (AhR) binding sites termed "dioxin response elements" (DREs) in the 5'-untranslated region (5'-UTR) of efflux transporter GENE (Accession No. EU570105) from the bovine mammary gland. As these regulatory motifs mediate regulation of target genes by AhR agonists including TCDD and prochloraz, we have systematically investigated the effect of both contaminants on functional GENE transport activity in primary bovine mammary epithelial cells. TCDD or prochloraz doubled GENE-mediated CHEMICAL secretion. This effect was almost completely reversed by specific GENE inhibitor Ko143. In further mechanistic studies, we showed that this induction was due to binding of activated AhR to DRE sequences in the GENE 5'-UTR. Receptor binding was significantly reduced by specific AhR antagonist salicyl amide. Induction of AhR by TCDD and prochloraz resulted in a time- and dose-dependent increase of GENE gene expression and transporter protein levels. As GENE represents the main mammary transporter for xenobiotics including drugs and toxins, exposure to prevalent AhR agonists may enhance transporter-mediated secretion of potential harmful compounds into milk. Through identification of mammary GENE as a novel target gene of pesticide prochloraz and dioxin, our results may therefore help to improve the protection of breast-feeding infants and the consumer of dairy products. | PRODUCT-OF |
| Effects of silver nanoparticles on the liver and hepatocytes in vitro. With the increasing use and incorporation of nanoparticles (NPs) into consumer products, screening for potential toxicity is necessary to ensure customer safety. NPs have been shown to translocate to the bloodstream following inhalation and ingestion, and such studies demonstrate that the liver is an important organ for accumulation. Silver (Ag) NPs are highly relevant for human exposure due to their use in food contact materials, dietary supplements, and antibacterial wound treatments. Due to the large number of different NPs already used in various products and being developed for new applications, it is essential that relevant, quick, and cheap methods of in vitro risk assessment suitable for these new materials are established. Therefore, this study used a simple hepatocytes model combined with an in vivo injection model to simulate the passage of a small amount of NPs into the bloodstream following exposure, e.g., via ingestion or inhalation, and examined the potential of CHEMICAL NPs of 20 nm diameter to cause toxicity, inflammation, and oxidative stress in the liver following in vivo exposures of female Wistar rats via iv injection to 50 μg of NPs and in vitro exposures using the human hepatocyte cell line C3A. We found that CHEMICAL NPs were highly cytotoxic to hepatocytes (LC(50) GENE: 2.5 μg/cm(2)) and affected hepatocyte homeostasis by reducing albumin release. At sublethal concentrations with normal cell or tissue morphology, CHEMICAL NPs were detected in cytoplasm and nuclei of hepatocytes. We observed similar effects of CHEMICAL NPs on inflammatory mediator expression in vitro and in vivo with increase of interleukin-8 (IL-8)/macrophage inflammatory protein 2, IL-1RI, and tumor necrosis factor-α expression in both models and increased IL-8 protein release in vitro. This article presents evidence of the potential toxicity and inflammogenic potential of CHEMICAL NPs in the liver following ingestion. In addition, the similarities between in vitro and in vivo responses are striking and encouraging for future reduction, refinement, and replacement of animal studies by the use of hepatocyte cell lines in particle risk assessment. | REGULATOR |
| Effects of silver nanoparticles on the liver and hepatocytes in vitro. With the increasing use and incorporation of nanoparticles (NPs) into consumer products, screening for potential toxicity is necessary to ensure customer safety. NPs have been shown to translocate to the bloodstream following inhalation and ingestion, and such studies demonstrate that the liver is an important organ for accumulation. Silver (Ag) NPs are highly relevant for human exposure due to their use in food contact materials, dietary supplements, and antibacterial wound treatments. Due to the large number of different NPs already used in various products and being developed for new applications, it is essential that relevant, quick, and cheap methods of in vitro risk assessment suitable for these new materials are established. Therefore, this study used a simple hepatocytes model combined with an in vivo injection model to simulate the passage of a small amount of NPs into the bloodstream following exposure, e.g., via ingestion or inhalation, and examined the potential of CHEMICAL NPs of 20 nm diameter to cause toxicity, inflammation, and oxidative stress in the liver following in vivo exposures of female Wistar rats via iv injection to 50 μg of NPs and in vitro exposures using the human hepatocyte cell line C3A. We found that CHEMICAL NPs were highly cytotoxic to hepatocytes (LC(50) lactate dehydrogenase: 2.5 μg/cm(2)) and affected hepatocyte homeostasis by reducing albumin release. At sublethal concentrations with normal cell or tissue morphology, CHEMICAL NPs were detected in cytoplasm and nuclei of hepatocytes. We observed similar effects of CHEMICAL NPs on inflammatory mediator expression in vitro and in vivo with increase of GENE (IL-8)/macrophage inflammatory protein 2, IL-1RI, and tumor necrosis factor-α expression in both models and increased IL-8 protein release in vitro. This article presents evidence of the potential toxicity and inflammogenic potential of CHEMICAL NPs in the liver following ingestion. In addition, the similarities between in vitro and in vivo responses are striking and encouraging for future reduction, refinement, and replacement of animal studies by the use of hepatocyte cell lines in particle risk assessment. | INDIRECT-UPREGULATOR |
| Effects of silver nanoparticles on the liver and hepatocytes in vitro. With the increasing use and incorporation of nanoparticles (NPs) into consumer products, screening for potential toxicity is necessary to ensure customer safety. NPs have been shown to translocate to the bloodstream following inhalation and ingestion, and such studies demonstrate that the liver is an important organ for accumulation. Silver (Ag) NPs are highly relevant for human exposure due to their use in food contact materials, dietary supplements, and antibacterial wound treatments. Due to the large number of different NPs already used in various products and being developed for new applications, it is essential that relevant, quick, and cheap methods of in vitro risk assessment suitable for these new materials are established. Therefore, this study used a simple hepatocytes model combined with an in vivo injection model to simulate the passage of a small amount of NPs into the bloodstream following exposure, e.g., via ingestion or inhalation, and examined the potential of CHEMICAL NPs of 20 nm diameter to cause toxicity, inflammation, and oxidative stress in the liver following in vivo exposures of female Wistar rats via iv injection to 50 μg of NPs and in vitro exposures using the human hepatocyte cell line C3A. We found that CHEMICAL NPs were highly cytotoxic to hepatocytes (LC(50) lactate dehydrogenase: 2.5 μg/cm(2)) and affected hepatocyte homeostasis by reducing albumin release. At sublethal concentrations with normal cell or tissue morphology, CHEMICAL NPs were detected in cytoplasm and nuclei of hepatocytes. We observed similar effects of CHEMICAL NPs on inflammatory mediator expression in vitro and in vivo with increase of interleukin-8 (GENE)/macrophage inflammatory protein 2, IL-1RI, and tumor necrosis factor-α expression in both models and increased GENE protein release in vitro. This article presents evidence of the potential toxicity and inflammogenic potential of CHEMICAL NPs in the liver following ingestion. In addition, the similarities between in vitro and in vivo responses are striking and encouraging for future reduction, refinement, and replacement of animal studies by the use of hepatocyte cell lines in particle risk assessment. | INDIRECT-UPREGULATOR |
| Effects of silver nanoparticles on the liver and hepatocytes in vitro. With the increasing use and incorporation of nanoparticles (NPs) into consumer products, screening for potential toxicity is necessary to ensure customer safety. NPs have been shown to translocate to the bloodstream following inhalation and ingestion, and such studies demonstrate that the liver is an important organ for accumulation. Silver (Ag) NPs are highly relevant for human exposure due to their use in food contact materials, dietary supplements, and antibacterial wound treatments. Due to the large number of different NPs already used in various products and being developed for new applications, it is essential that relevant, quick, and cheap methods of in vitro risk assessment suitable for these new materials are established. Therefore, this study used a simple hepatocytes model combined with an in vivo injection model to simulate the passage of a small amount of NPs into the bloodstream following exposure, e.g., via ingestion or inhalation, and examined the potential of CHEMICAL NPs of 20 nm diameter to cause toxicity, inflammation, and oxidative stress in the liver following in vivo exposures of female Wistar rats via iv injection to 50 μg of NPs and in vitro exposures using the human hepatocyte cell line C3A. We found that CHEMICAL NPs were highly cytotoxic to hepatocytes (LC(50) lactate dehydrogenase: 2.5 μg/cm(2)) and affected hepatocyte homeostasis by reducing albumin release. At sublethal concentrations with normal cell or tissue morphology, CHEMICAL NPs were detected in cytoplasm and nuclei of hepatocytes. We observed similar effects of CHEMICAL NPs on inflammatory mediator expression in vitro and in vivo with increase of interleukin-8 (IL-8)/GENE, IL-1RI, and tumor necrosis factor-α expression in both models and increased IL-8 protein release in vitro. This article presents evidence of the potential toxicity and inflammogenic potential of CHEMICAL NPs in the liver following ingestion. In addition, the similarities between in vitro and in vivo responses are striking and encouraging for future reduction, refinement, and replacement of animal studies by the use of hepatocyte cell lines in particle risk assessment. | INDIRECT-UPREGULATOR |
| Effects of silver nanoparticles on the liver and hepatocytes in vitro. With the increasing use and incorporation of nanoparticles (NPs) into consumer products, screening for potential toxicity is necessary to ensure customer safety. NPs have been shown to translocate to the bloodstream following inhalation and ingestion, and such studies demonstrate that the liver is an important organ for accumulation. Silver (Ag) NPs are highly relevant for human exposure due to their use in food contact materials, dietary supplements, and antibacterial wound treatments. Due to the large number of different NPs already used in various products and being developed for new applications, it is essential that relevant, quick, and cheap methods of in vitro risk assessment suitable for these new materials are established. Therefore, this study used a simple hepatocytes model combined with an in vivo injection model to simulate the passage of a small amount of NPs into the bloodstream following exposure, e.g., via ingestion or inhalation, and examined the potential of CHEMICAL NPs of 20 nm diameter to cause toxicity, inflammation, and oxidative stress in the liver following in vivo exposures of female Wistar rats via iv injection to 50 μg of NPs and in vitro exposures using the human hepatocyte cell line C3A. We found that CHEMICAL NPs were highly cytotoxic to hepatocytes (LC(50) lactate dehydrogenase: 2.5 μg/cm(2)) and affected hepatocyte homeostasis by reducing albumin release. At sublethal concentrations with normal cell or tissue morphology, CHEMICAL NPs were detected in cytoplasm and nuclei of hepatocytes. We observed similar effects of CHEMICAL NPs on inflammatory mediator expression in vitro and in vivo with increase of interleukin-8 (IL-8)/macrophage inflammatory protein 2, GENE, and tumor necrosis factor-α expression in both models and increased IL-8 protein release in vitro. This article presents evidence of the potential toxicity and inflammogenic potential of CHEMICAL NPs in the liver following ingestion. In addition, the similarities between in vitro and in vivo responses are striking and encouraging for future reduction, refinement, and replacement of animal studies by the use of hepatocyte cell lines in particle risk assessment. | INDIRECT-UPREGULATOR |
| Effects of silver nanoparticles on the liver and hepatocytes in vitro. With the increasing use and incorporation of nanoparticles (NPs) into consumer products, screening for potential toxicity is necessary to ensure customer safety. NPs have been shown to translocate to the bloodstream following inhalation and ingestion, and such studies demonstrate that the liver is an important organ for accumulation. Silver (Ag) NPs are highly relevant for human exposure due to their use in food contact materials, dietary supplements, and antibacterial wound treatments. Due to the large number of different NPs already used in various products and being developed for new applications, it is essential that relevant, quick, and cheap methods of in vitro risk assessment suitable for these new materials are established. Therefore, this study used a simple hepatocytes model combined with an in vivo injection model to simulate the passage of a small amount of NPs into the bloodstream following exposure, e.g., via ingestion or inhalation, and examined the potential of CHEMICAL NPs of 20 nm diameter to cause toxicity, inflammation, and oxidative stress in the liver following in vivo exposures of female Wistar rats via iv injection to 50 μg of NPs and in vitro exposures using the human hepatocyte cell line C3A. We found that CHEMICAL NPs were highly cytotoxic to hepatocytes (LC(50) lactate dehydrogenase: 2.5 μg/cm(2)) and affected hepatocyte homeostasis by reducing albumin release. At sublethal concentrations with normal cell or tissue morphology, CHEMICAL NPs were detected in cytoplasm and nuclei of hepatocytes. We observed similar effects of CHEMICAL NPs on inflammatory mediator expression in vitro and in vivo with increase of interleukin-8 (IL-8)/macrophage inflammatory protein 2, IL-1RI, and GENE expression in both models and increased IL-8 protein release in vitro. This article presents evidence of the potential toxicity and inflammogenic potential of CHEMICAL NPs in the liver following ingestion. In addition, the similarities between in vitro and in vivo responses are striking and encouraging for future reduction, refinement, and replacement of animal studies by the use of hepatocyte cell lines in particle risk assessment. | INDIRECT-UPREGULATOR |
| Effects of silver nanoparticles on the liver and hepatocytes in vitro. With the increasing use and incorporation of nanoparticles (NPs) into consumer products, screening for potential toxicity is necessary to ensure customer safety. NPs have been shown to translocate to the bloodstream following inhalation and ingestion, and such studies demonstrate that the liver is an important organ for accumulation. Silver (Ag) NPs are highly relevant for human exposure due to their use in food contact materials, dietary supplements, and antibacterial wound treatments. Due to the large number of different NPs already used in various products and being developed for new applications, it is essential that relevant, quick, and cheap methods of in vitro risk assessment suitable for these new materials are established. Therefore, this study used a simple hepatocytes model combined with an in vivo injection model to simulate the passage of a small amount of NPs into the bloodstream following exposure, e.g., via ingestion or inhalation, and examined the potential of CHEMICAL NPs of 20 nm diameter to cause toxicity, inflammation, and oxidative stress in the liver following in vivo exposures of female Wistar rats via iv injection to 50 μg of NPs and in vitro exposures using the human hepatocyte cell line C3A. We found that CHEMICAL NPs were highly cytotoxic to hepatocytes (LC(50) lactate dehydrogenase: 2.5 μg/cm(2)) and affected hepatocyte homeostasis by reducing GENE release. At sublethal concentrations with normal cell or tissue morphology, CHEMICAL NPs were detected in cytoplasm and nuclei of hepatocytes. We observed similar effects of CHEMICAL NPs on inflammatory mediator expression in vitro and in vivo with increase of interleukin-8 (IL-8)/macrophage inflammatory protein 2, IL-1RI, and tumor necrosis factor-α expression in both models and increased IL-8 protein release in vitro. This article presents evidence of the potential toxicity and inflammogenic potential of CHEMICAL NPs in the liver following ingestion. In addition, the similarities between in vitro and in vivo responses are striking and encouraging for future reduction, refinement, and replacement of animal studies by the use of hepatocyte cell lines in particle risk assessment. | INDIRECT-DOWNREGULATOR |
| Extracellular loop II modulates CHEMICAL sensitivity of the prostaglandin EP3 receptor. Unlike the majority of G protein-coupled receptors, the prostaglandin E(2) (PGE(2)) E-prostanoid 3 (EP3) receptor binds agonist with high affinity that is insensitive to the presence of guanosine 5[prime]-O-(3-thio)triphosphate (GTPγS). We report the identification of mutations that confer GTPγS sensitivity to agonist binding. Seven point mutations were introduced into the conserved motif in the second extracellular loop (ECII) of EP3, resulting in acquisition of GTP-sensitive agonist binding. One receptor mutation W203A was studied in detail. Loss of agonist binding was observed on intact human embryonic kidney 293 cells expressing the W203A receptor, conditions where high CHEMICAL levels are present; however, high affinity binding [(3)H]PGE(2) was observed in broken cell preparations washed free of CHEMICAL. The [(3)H]PGE(2) binding of W203A in broken cell membrane fractions was inhibited by addition of GTPγS (IC(50) 21 ± 1.8 nM). Taken together, these results suggest that the wild-type EP3 receptor displays unusual characteristics of the complex coupled equilibria between agonist-receptor and receptor-G protein interaction. Moreover, mutation of GENE can alter this coupled equilibrium from CHEMICAL-insensitive agonist binding to more conventional GTP-sensitive binding. This suggests that for the mutant receptors, GENE plays a critical role in linking the agonist bound receptor conformation to the G protein nucleotide bound state. | NO-RELATIONSHIP |
| Extracellular loop II modulates GTP sensitivity of the prostaglandin EP3 receptor. Unlike the majority of G protein-coupled receptors, the GENE binds agonist with high affinity that is insensitive to the presence of CHEMICAL (GTPγS). We report the identification of mutations that confer GTPγS sensitivity to agonist binding. Seven point mutations were introduced into the conserved motif in the second extracellular loop (ECII) of EP3, resulting in acquisition of GTP-sensitive agonist binding. One receptor mutation W203A was studied in detail. Loss of agonist binding was observed on intact human embryonic kidney 293 cells expressing the W203A receptor, conditions where high GTP levels are present; however, high affinity binding [(3)H]PGE(2) was observed in broken cell preparations washed free of GTP. The [(3)H]PGE(2) binding of W203A in broken cell membrane fractions was inhibited by addition of GTPγS (IC(50) 21 ± 1.8 nM). Taken together, these results suggest that the wild-type EP3 receptor displays unusual characteristics of the complex coupled equilibria between agonist-receptor and receptor-G protein interaction. Moreover, mutation of ECII can alter this coupled equilibrium from GTP-insensitive agonist binding to more conventional GTP-sensitive binding. This suggests that for the mutant receptors, ECII plays a critical role in linking the agonist bound receptor conformation to the G protein nucleotide bound state. | NO-RELATIONSHIP |
| Extracellular loop II modulates GTP sensitivity of the prostaglandin EP3 receptor. Unlike the majority of G protein-coupled receptors, the GENE binds agonist with high affinity that is insensitive to the presence of guanosine 5[prime]-O-(3-thio)triphosphate (CHEMICAL). We report the identification of mutations that confer CHEMICAL sensitivity to agonist binding. Seven point mutations were introduced into the conserved motif in the second extracellular loop (ECII) of EP3, resulting in acquisition of GTP-sensitive agonist binding. One receptor mutation W203A was studied in detail. Loss of agonist binding was observed on intact human embryonic kidney 293 cells expressing the W203A receptor, conditions where high GTP levels are present; however, high affinity binding [(3)H]PGE(2) was observed in broken cell preparations washed free of GTP. The [(3)H]PGE(2) binding of W203A in broken cell membrane fractions was inhibited by addition of CHEMICAL (IC(50) 21 ± 1.8 nM). Taken together, these results suggest that the wild-type EP3 receptor displays unusual characteristics of the complex coupled equilibria between agonist-receptor and receptor-G protein interaction. Moreover, mutation of ECII can alter this coupled equilibrium from GTP-insensitive agonist binding to more conventional GTP-sensitive binding. This suggests that for the mutant receptors, ECII plays a critical role in linking the agonist bound receptor conformation to the G protein nucleotide bound state. | NO-RELATIONSHIP |
| Extracellular loop II modulates GTP sensitivity of the prostaglandin EP3 receptor. Unlike the majority of G protein-coupled receptors, the prostaglandin E(2) (PGE(2)) E-prostanoid 3 (EP3) receptor binds agonist with high affinity that is insensitive to the presence of guanosine 5[prime]-O-(3-thio)triphosphate (GTPγS). We report the identification of mutations that confer GTPγS sensitivity to agonist binding. Seven point mutations were introduced into the conserved motif in the second extracellular loop (ECII) of EP3, resulting in acquisition of GTP-sensitive agonist binding. One receptor mutation GENE was studied in detail. Loss of agonist binding was observed on intact human embryonic kidney 293 cells expressing the GENE receptor, conditions where high GTP levels are present; however, high affinity binding CHEMICAL was observed in broken cell preparations washed free of GTP. The CHEMICAL binding of GENE in broken cell membrane fractions was inhibited by addition of GTPγS (IC(50) 21 ± 1.8 nM). Taken together, these results suggest that the wild-type EP3 receptor displays unusual characteristics of the complex coupled equilibria between agonist-receptor and receptor-G protein interaction. Moreover, mutation of ECII can alter this coupled equilibrium from GTP-insensitive agonist binding to more conventional GTP-sensitive binding. This suggests that for the mutant receptors, ECII plays a critical role in linking the agonist bound receptor conformation to the G protein nucleotide bound state. | DIRECT-REGULATOR |
| Extracellular loop II modulates GTP sensitivity of the prostaglandin EP3 receptor. Unlike the majority of G protein-coupled receptors, the prostaglandin E(2) (PGE(2)) E-prostanoid 3 (EP3) receptor binds agonist with high affinity that is insensitive to the presence of guanosine 5[prime]-O-(3-thio)triphosphate (GTPγS). We report the identification of mutations that confer CHEMICAL sensitivity to agonist binding. Seven point mutations were introduced into the conserved motif in the second extracellular loop (ECII) of EP3, resulting in acquisition of GTP-sensitive agonist binding. One receptor mutation GENE was studied in detail. Loss of agonist binding was observed on intact human embryonic kidney 293 cells expressing the GENE receptor, conditions where high GTP levels are present; however, high affinity binding [(3)H]PGE(2) was observed in broken cell preparations washed free of GTP. The [(3)H]PGE(2) binding of GENE in broken cell membrane fractions was inhibited by addition of CHEMICAL (IC(50) 21 ± 1.8 nM). Taken together, these results suggest that the wild-type EP3 receptor displays unusual characteristics of the complex coupled equilibria between agonist-receptor and receptor-G protein interaction. Moreover, mutation of ECII can alter this coupled equilibrium from GTP-insensitive agonist binding to more conventional GTP-sensitive binding. This suggests that for the mutant receptors, ECII plays a critical role in linking the agonist bound receptor conformation to the G protein nucleotide bound state. | INHIBITOR |
| Extracellular loop II modulates GTP sensitivity of the prostaglandin EP3 receptor. Unlike the majority of G protein-coupled receptors, the prostaglandin E(2) (PGE(2)) E-prostanoid 3 (EP3) receptor binds agonist with high affinity that is insensitive to the presence of guanosine 5[prime]-O-(3-thio)triphosphate (GTPγS). We report the identification of mutations that confer GTPγS sensitivity to agonist binding. Seven point mutations were introduced into the conserved motif in the second extracellular loop (ECII) of EP3, resulting in acquisition of GTP-sensitive agonist binding. One receptor mutation W203A was studied in detail. Loss of agonist binding was observed on intact human embryonic kidney 293 cells expressing the W203A receptor, conditions where high GTP levels are present; however, high affinity binding [(3)H]PGE(2) was observed in broken cell preparations washed free of GTP. The [(3)H]PGE(2) binding of W203A in broken cell membrane fractions was inhibited by addition of GTPγS (IC(50) 21 ± 1.8 nM). Taken together, these results suggest that the wild-type EP3 receptor displays unusual characteristics of the complex coupled equilibria between agonist-receptor and receptor-G protein interaction. Moreover, mutation of ECII can alter this coupled equilibrium from GTP-insensitive agonist binding to more conventional GTP-sensitive binding. This suggests that for the mutant receptors, ECII plays a critical role in linking the agonist bound receptor conformation to the GENE CHEMICAL bound state. | DIRECT-REGULATOR |
| GENE modulates CHEMICAL sensitivity of the prostaglandin EP3 receptor. Unlike the majority of G protein-coupled receptors, the prostaglandin E(2) (PGE(2)) E-prostanoid 3 (EP3) receptor binds agonist with high affinity that is insensitive to the presence of guanosine 5[prime]-O-(3-thio)triphosphate (GTPγS). We report the identification of mutations that confer GTPγS sensitivity to agonist binding. Seven point mutations were introduced into the conserved motif in the second extracellular loop (ECII) of EP3, resulting in acquisition of GTP-sensitive agonist binding. One receptor mutation W203A was studied in detail. Loss of agonist binding was observed on intact human embryonic kidney 293 cells expressing the W203A receptor, conditions where high CHEMICAL levels are present; however, high affinity binding [(3)H]PGE(2) was observed in broken cell preparations washed free of CHEMICAL. The [(3)H]PGE(2) binding of W203A in broken cell membrane fractions was inhibited by addition of GTPγS (IC(50) 21 ± 1.8 nM). Taken together, these results suggest that the wild-type EP3 receptor displays unusual characteristics of the complex coupled equilibria between agonist-receptor and receptor-G protein interaction. Moreover, mutation of ECII can alter this coupled equilibrium from GTP-insensitive agonist binding to more conventional GTP-sensitive binding. This suggests that for the mutant receptors, ECII plays a critical role in linking the agonist bound receptor conformation to the G protein nucleotide bound state. | REGULATOR |
| Extracellular loop II modulates CHEMICAL sensitivity of the GENE. Unlike the majority of G protein-coupled receptors, the prostaglandin E(2) (PGE(2)) E-prostanoid 3 (EP3) receptor binds agonist with high affinity that is insensitive to the presence of guanosine 5[prime]-O-(3-thio)triphosphate (GTPγS). We report the identification of mutations that confer GTPγS sensitivity to agonist binding. Seven point mutations were introduced into the conserved motif in the second extracellular loop (ECII) of EP3, resulting in acquisition of GTP-sensitive agonist binding. One receptor mutation W203A was studied in detail. Loss of agonist binding was observed on intact human embryonic kidney 293 cells expressing the W203A receptor, conditions where high CHEMICAL levels are present; however, high affinity binding [(3)H]PGE(2) was observed in broken cell preparations washed free of CHEMICAL. The [(3)H]PGE(2) binding of W203A in broken cell membrane fractions was inhibited by addition of GTPγS (IC(50) 21 ± 1.8 nM). Taken together, these results suggest that the wild-type EP3 receptor displays unusual characteristics of the complex coupled equilibria between agonist-receptor and receptor-G protein interaction. Moreover, mutation of ECII can alter this coupled equilibrium from GTP-insensitive agonist binding to more conventional GTP-sensitive binding. This suggests that for the mutant receptors, ECII plays a critical role in linking the agonist bound receptor conformation to the G protein nucleotide bound state. | REGULATOR |
| Extracellular loop II modulates CHEMICAL sensitivity of the prostaglandin EP3 receptor. Unlike the majority of G protein-coupled receptors, the prostaglandin E(2) (PGE(2)) E-prostanoid 3 (EP3) receptor binds agonist with high affinity that is insensitive to the presence of guanosine 5[prime]-O-(3-thio)triphosphate (GTPγS). We report the identification of mutations that confer GTPγS sensitivity to agonist binding. Seven point mutations were introduced into the conserved motif in the GENE (ECII) of EP3, resulting in acquisition of CHEMICAL-sensitive agonist binding. One receptor mutation W203A was studied in detail. Loss of agonist binding was observed on intact human embryonic kidney 293 cells expressing the W203A receptor, conditions where high CHEMICAL levels are present; however, high affinity binding [(3)H]PGE(2) was observed in broken cell preparations washed free of CHEMICAL. The [(3)H]PGE(2) binding of W203A in broken cell membrane fractions was inhibited by addition of GTPγS (IC(50) 21 ± 1.8 nM). Taken together, these results suggest that the wild-type EP3 receptor displays unusual characteristics of the complex coupled equilibria between agonist-receptor and receptor-G protein interaction. Moreover, mutation of ECII can alter this coupled equilibrium from GTP-insensitive agonist binding to more conventional GTP-sensitive binding. This suggests that for the mutant receptors, ECII plays a critical role in linking the agonist bound receptor conformation to the G protein nucleotide bound state. | REGULATOR |
| Extracellular loop II modulates CHEMICAL sensitivity of the prostaglandin GENE receptor. Unlike the majority of G protein-coupled receptors, the prostaglandin E(2) (PGE(2)) E-prostanoid 3 (EP3) receptor binds agonist with high affinity that is insensitive to the presence of guanosine 5[prime]-O-(3-thio)triphosphate (GTPγS). We report the identification of mutations that confer GTPγS sensitivity to agonist binding. Seven point mutations were introduced into the conserved motif in the second extracellular loop (ECII) of GENE, resulting in acquisition of CHEMICAL-sensitive agonist binding. One receptor mutation W203A was studied in detail. Loss of agonist binding was observed on intact human embryonic kidney 293 cells expressing the W203A receptor, conditions where high CHEMICAL levels are present; however, high affinity binding [(3)H]PGE(2) was observed in broken cell preparations washed free of CHEMICAL. The [(3)H]PGE(2) binding of W203A in broken cell membrane fractions was inhibited by addition of GTPγS (IC(50) 21 ± 1.8 nM). Taken together, these results suggest that the wild-type GENE receptor displays unusual characteristics of the complex coupled equilibria between agonist-receptor and receptor-G protein interaction. Moreover, mutation of ECII can alter this coupled equilibrium from GTP-insensitive agonist binding to more conventional GTP-sensitive binding. This suggests that for the mutant receptors, ECII plays a critical role in linking the agonist bound receptor conformation to the G protein nucleotide bound state. | REGULATOR |
| Extracellular loop II modulates CHEMICAL sensitivity of the prostaglandin EP3 receptor. Unlike the majority of G protein-coupled receptors, the prostaglandin E(2) (PGE(2)) E-prostanoid 3 (EP3) receptor binds agonist with high affinity that is insensitive to the presence of guanosine 5[prime]-O-(3-thio)triphosphate (GTPγS). We report the identification of mutations that confer GTPγS sensitivity to agonist binding. Seven point mutations were introduced into the conserved motif in the second extracellular loop (ECII) of EP3, resulting in acquisition of GTP-sensitive agonist binding. One receptor mutation GENE was studied in detail. Loss of agonist binding was observed on intact human embryonic kidney 293 cells expressing the GENE receptor, conditions where high CHEMICAL levels are present; however, high affinity binding [(3)H]PGE(2) was observed in broken cell preparations washed free of CHEMICAL. The [(3)H]PGE(2) binding of GENE in broken cell membrane fractions was inhibited by addition of GTPγS (IC(50) 21 ± 1.8 nM). Taken together, these results suggest that the wild-type EP3 receptor displays unusual characteristics of the complex coupled equilibria between agonist-receptor and receptor-G protein interaction. Moreover, mutation of ECII can alter this coupled equilibrium from GTP-insensitive agonist binding to more conventional GTP-sensitive binding. This suggests that for the mutant receptors, ECII plays a critical role in linking the agonist bound receptor conformation to the G protein nucleotide bound state. | PRODUCT-OF |
| Phosphoinositide-dependent kinase-1 and protein kinase Cδ contribute to endothelin-1 constriction and elevated blood pressure in intermittent hypoxia. Obstructive sleep apnea (OSA) is associated with cardiovascular complications including hypertension. Previous findings from our laboratory indicate that exposure to intermittent hypoxia (IH), to mimic sleep apnea, increases blood pressure in rats. IH also increases endothelin-1 (ET-1) constrictor sensitivity in a protein kinase C (PKC) δ-dependent manner in mesenteric arteries. Because phosphoinositide-dependent kinase-1 (PDK-1) regulates PKCδ activity, we hypothesized that GENE contributes to the augmented ET-1 constrictor sensitivity and elevated blood pressure following IH. Male Sprague-Dawley rats were exposed to either sham or IH (cycles between 21% O(2)/0% CO(2) and 5% O(2)/5% CO(2)) conditions for 7 h/day for 14 or 21 days. The contribution of PKCδ and GENE to ET-1-mediated vasoconstriction was assessed in mesenteric arteries using pharmacological inhibitors. Constrictor sensitivity to ET-1 was enhanced in arteries from IH-exposed rats. Inhibition of PKCδ or GENE blunted ET-1 constriction in arteries from IH but not sham group rats. Western analysis revealed similar levels of total and phosphorylated GENE in arteries from sham and IH group rats but decreased protein-protein interaction between PKCδ and GENE in arteries from IH- compared with sham-exposed rats. Blood pressure was increased in rats exposed to IH, and treatment with the GENE inhibitor CHEMICAL [2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}-acetamide] (33 mg/day) lowered blood pressure in IH but not sham group rats. Our results suggest that exposure to IH unmasks a role for GENE in regulating ET-1 constrictor sensitivity and blood pressure that is not present under normal conditions. These novel findings suggest that GENE may be a uniquely effective antihypertensive therapy for OSA patients. | INHIBITOR |
| Phosphoinositide-dependent kinase-1 and protein kinase Cδ contribute to endothelin-1 constriction and elevated blood pressure in intermittent hypoxia. Obstructive sleep apnea (OSA) is associated with cardiovascular complications including hypertension. Previous findings from our laboratory indicate that exposure to intermittent hypoxia (IH), to mimic sleep apnea, increases blood pressure in rats. IH also increases endothelin-1 (ET-1) constrictor sensitivity in a protein kinase C (PKC) δ-dependent manner in mesenteric arteries. Because phosphoinositide-dependent kinase-1 (PDK-1) regulates PKCδ activity, we hypothesized that GENE contributes to the augmented ET-1 constrictor sensitivity and elevated blood pressure following IH. Male Sprague-Dawley rats were exposed to either sham or IH (cycles between 21% O(2)/0% CO(2) and 5% O(2)/5% CO(2)) conditions for 7 h/day for 14 or 21 days. The contribution of PKCδ and GENE to ET-1-mediated vasoconstriction was assessed in mesenteric arteries using pharmacological inhibitors. Constrictor sensitivity to ET-1 was enhanced in arteries from IH-exposed rats. Inhibition of PKCδ or GENE blunted ET-1 constriction in arteries from IH but not sham group rats. Western analysis revealed similar levels of total and phosphorylated GENE in arteries from sham and IH group rats but decreased protein-protein interaction between PKCδ and GENE in arteries from IH- compared with sham-exposed rats. Blood pressure was increased in rats exposed to IH, and treatment with the GENE inhibitor OSU-03012 [CHEMICAL] (33 mg/day) lowered blood pressure in IH but not sham group rats. Our results suggest that exposure to IH unmasks a role for GENE in regulating ET-1 constrictor sensitivity and blood pressure that is not present under normal conditions. These novel findings suggest that GENE may be a uniquely effective antihypertensive therapy for OSA patients. | INHIBITOR |
| Intercellular adhesion molecule-2 is involved in apical ectoplasmic specialization dynamics during spermatogenesis in the rat. In this study, we investigated the role of intercellular adhesion molecule-2 (ICAM2) in the testis. GENE is a cell adhesion protein having important roles in cell migration, especially during inflammation when leukocytes cross the endothelium. Herein, we showed GENE to be expressed by germ and Sertoli cells in the rat testis. When a monospecific antibody was used for immunolocalization experiments, GENE was found to surround the heads of elongating/elongated spermatids in all stages of the seminiferous epithelial cycle. To determine whether GENE is a constituent of apical ectoplasmic specialization (ES), co-immunoprecipitation and dual immunofluorescence staining were performed. Interestingly, GENE was found to associate with β1-integrin, nectin-3, afadin, Src, proline-rich tyrosine kinase 2, annexin II, and actin. Following CHEMICAL treatment, GENE was found to be upregulated during restructuring of the seminiferous epithelium, with round spermatids becoming increasingly immunoreactive for GENE by 6-16 h. Interestingly, there was a loss in the binding of GENE to actin during CHEMICAL-induced germ cell loss, suggesting that a loss of ICAM2-actin interactions might have facilitated junction restructuring. Taken collectively, these results illustrate that GENE plays an important role in apical ES dynamics during spermatogenesis. | REGULATOR |
| Intercellular adhesion molecule-2 is involved in apical ectoplasmic specialization dynamics during spermatogenesis in the rat. In this study, we investigated the role of intercellular adhesion molecule-2 (ICAM2) in the testis. ICAM2 is a cell adhesion protein having important roles in cell migration, especially during inflammation when leukocytes cross the endothelium. Herein, we showed ICAM2 to be expressed by germ and Sertoli cells in the rat testis. When a monospecific antibody was used for immunolocalization experiments, ICAM2 was found to surround the heads of elongating/elongated spermatids in all stages of the seminiferous epithelial cycle. To determine whether ICAM2 is a constituent of apical ectoplasmic specialization (ES), co-immunoprecipitation and dual immunofluorescence staining were performed. Interestingly, ICAM2 was found to associate with β1-integrin, nectin-3, afadin, Src, proline-rich tyrosine kinase 2, annexin II, and GENE. Following CHEMICAL treatment, ICAM2 was found to be upregulated during restructuring of the seminiferous epithelium, with round spermatids becoming increasingly immunoreactive for ICAM2 by 6-16 h. Interestingly, there was a loss in the binding of ICAM2 to GENE during CHEMICAL-induced germ cell loss, suggesting that a loss of ICAM2-actin interactions might have facilitated junction restructuring. Taken collectively, these results illustrate that ICAM2 plays an important role in apical ES dynamics during spermatogenesis. | DIRECT-REGULATOR |
| The catalytic competence of cytochrome P450 in the synthesis of serotonin from 5-methoxytryptamine in the brain: an in vitro study. Brain serotonin has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. The aim of present study was to identify rat cytochrome P450 (CYP) isoforms which can catalyze the O-demethylation of 5-methoxytryptamine to serotonin, and to find out whether that alternative pathway of serotonin synthesis may take place in the brain. The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type CYP2D6 or the allelic variant 2D6*4*4). Of the rat CYP isoforms studied, GENE isoforms were the most efficient in catalyzing the O-demethylation of 5-methoxytryptamine to serotonin, but they were less effective than the human isoform CYP2D6. Microsomes from different brain regions were capable of metabolizing 5-methoxytryptamine to serotonin. The reaction was inhibited by the specific GENE inhibitors CHEMICAL and fluoxetine. Human liver microsomes of the wild-type CYP2D6 metabolized 5-methoxytryptamine to serotonin more effectively than did the defective CYP2D6*4*4 ones. The obtained results indicate that rat brain GENE isoforms catalyze the formation of serotonin from 5-methoxytryptamine, and that the deficit or genetic defect of GENE may affect serotonin metabolism in the brain. The results are discussed in the context of their possible physiological and pharmacological significance in vivo. | INHIBITOR |
| The catalytic competence of cytochrome P450 in the synthesis of serotonin from 5-methoxytryptamine in the brain: an in vitro study. Brain serotonin has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. The aim of present study was to identify rat cytochrome P450 (CYP) isoforms which can catalyze the O-demethylation of 5-methoxytryptamine to serotonin, and to find out whether that alternative pathway of serotonin synthesis may take place in the brain. The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type CYP2D6 or the allelic variant 2D6*4*4). Of the rat CYP isoforms studied, GENE isoforms were the most efficient in catalyzing the O-demethylation of 5-methoxytryptamine to serotonin, but they were less effective than the human isoform CYP2D6. Microsomes from different brain regions were capable of metabolizing 5-methoxytryptamine to serotonin. The reaction was inhibited by the specific GENE inhibitors quinine and CHEMICAL. Human liver microsomes of the wild-type CYP2D6 metabolized 5-methoxytryptamine to serotonin more effectively than did the defective CYP2D6*4*4 ones. The obtained results indicate that rat brain GENE isoforms catalyze the formation of serotonin from 5-methoxytryptamine, and that the deficit or genetic defect of GENE may affect serotonin metabolism in the brain. The results are discussed in the context of their possible physiological and pharmacological significance in vivo. | INHIBITOR |
| The catalytic competence of cytochrome P450 in the synthesis of CHEMICAL from 5-methoxytryptamine in the brain: an in vitro study. Brain CHEMICAL has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. The aim of present study was to identify rat cytochrome P450 (CYP) isoforms which can catalyze the O-demethylation of 5-methoxytryptamine to CHEMICAL, and to find out whether that alternative pathway of CHEMICAL synthesis may take place in the brain. The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type CYP2D6 or the allelic variant 2D6*4*4). Of the rat CYP isoforms studied, GENE isoforms were the most efficient in catalyzing the O-demethylation of 5-methoxytryptamine to CHEMICAL, but they were less effective than the human isoform CYP2D6. Microsomes from different brain regions were capable of metabolizing 5-methoxytryptamine to CHEMICAL. The reaction was inhibited by the specific GENE inhibitors quinine and fluoxetine. Human liver microsomes of the wild-type CYP2D6 metabolized 5-methoxytryptamine to CHEMICAL more effectively than did the defective CYP2D6*4*4 ones. The obtained results indicate that rat brain GENE isoforms catalyze the formation of CHEMICAL from 5-methoxytryptamine, and that the deficit or genetic defect of GENE may affect CHEMICAL metabolism in the brain. The results are discussed in the context of their possible physiological and pharmacological significance in vivo. | PRODUCT-OF |
| The catalytic competence of cytochrome P450 in the synthesis of CHEMICAL from 5-methoxytryptamine in the brain: an in vitro study. Brain CHEMICAL has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. The aim of present study was to identify rat cytochrome P450 (CYP) isoforms which can catalyze the O-demethylation of 5-methoxytryptamine to CHEMICAL, and to find out whether that alternative pathway of CHEMICAL synthesis may take place in the brain. The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type CYP2D6 or the allelic variant 2D6*4*4). Of the rat CYP isoforms studied, CYP2D isoforms were the most efficient in catalyzing the O-demethylation of 5-methoxytryptamine to CHEMICAL, but they were less effective than the GENE. Microsomes from different brain regions were capable of metabolizing 5-methoxytryptamine to CHEMICAL. The reaction was inhibited by the specific CYP2D inhibitors quinine and fluoxetine. Human liver microsomes of the wild-type CYP2D6 metabolized 5-methoxytryptamine to CHEMICAL more effectively than did the defective CYP2D6*4*4 ones. The obtained results indicate that rat brain CYP2D isoforms catalyze the formation of CHEMICAL from 5-methoxytryptamine, and that the deficit or genetic defect of CYP2D may affect CHEMICAL metabolism in the brain. The results are discussed in the context of their possible physiological and pharmacological significance in vivo. | PRODUCT-OF |
| The catalytic competence of GENE in the synthesis of CHEMICAL from 5-methoxytryptamine in the brain: an in vitro study. Brain CHEMICAL has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. The aim of present study was to identify rat GENE (CYP) isoforms which can catalyze the O-demethylation of 5-methoxytryptamine to CHEMICAL, and to find out whether that alternative pathway of CHEMICAL synthesis may take place in the brain. The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type CYP2D6 or the allelic variant 2D6*4*4). Of the rat CYP isoforms studied, CYP2D isoforms were the most efficient in catalyzing the O-demethylation of 5-methoxytryptamine to CHEMICAL, but they were less effective than the human isoform CYP2D6. Microsomes from different brain regions were capable of metabolizing 5-methoxytryptamine to CHEMICAL. The reaction was inhibited by the specific CYP2D inhibitors quinine and fluoxetine. Human liver microsomes of the wild-type CYP2D6 metabolized 5-methoxytryptamine to CHEMICAL more effectively than did the defective CYP2D6*4*4 ones. The obtained results indicate that rat brain CYP2D isoforms catalyze the formation of CHEMICAL from 5-methoxytryptamine, and that the deficit or genetic defect of CYP2D may affect CHEMICAL metabolism in the brain. The results are discussed in the context of their possible physiological and pharmacological significance in vivo. | PRODUCT-OF |
| The catalytic competence of cytochrome P450 in the synthesis of CHEMICAL from 5-methoxytryptamine in the brain: an in vitro study. Brain CHEMICAL has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. The aim of present study was to identify rat cytochrome P450 (CYP) isoforms which can catalyze the O-demethylation of 5-methoxytryptamine to CHEMICAL, and to find out whether that alternative pathway of CHEMICAL synthesis may take place in the brain. The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type GENE or the allelic variant 2D6*4*4). Of the rat CYP isoforms studied, CYP2D isoforms were the most efficient in catalyzing the O-demethylation of 5-methoxytryptamine to CHEMICAL, but they were less effective than the human isoform GENE. Microsomes from different brain regions were capable of metabolizing 5-methoxytryptamine to CHEMICAL. The reaction was inhibited by the specific CYP2D inhibitors quinine and fluoxetine. Human liver microsomes of the wild-type GENE metabolized 5-methoxytryptamine to CHEMICAL more effectively than did the defective CYP2D6*4*4 ones. The obtained results indicate that rat brain CYP2D isoforms catalyze the formation of CHEMICAL from 5-methoxytryptamine, and that the deficit or genetic defect of CYP2D may affect CHEMICAL metabolism in the brain. The results are discussed in the context of their possible physiological and pharmacological significance in vivo. | PRODUCT-OF |
| The catalytic competence of cytochrome P450 in the synthesis of CHEMICAL from 5-methoxytryptamine in the brain: an in vitro study. Brain CHEMICAL has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. The aim of present study was to identify rat cytochrome P450 (CYP) isoforms which can catalyze the O-demethylation of 5-methoxytryptamine to CHEMICAL, and to find out whether that alternative pathway of CHEMICAL synthesis may take place in the brain. The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type CYP2D6 or the allelic variant 2D6*4*4). Of the rat CYP isoforms studied, CYP2D isoforms were the most efficient in catalyzing the O-demethylation of 5-methoxytryptamine to CHEMICAL, but they were less effective than the human isoform CYP2D6. Microsomes from different brain regions were capable of metabolizing 5-methoxytryptamine to CHEMICAL. The reaction was inhibited by the specific CYP2D inhibitors quinine and fluoxetine. Human liver microsomes of the wild-type CYP2D6 metabolized 5-methoxytryptamine to CHEMICAL more effectively than did the defective CYP2D6*4*4 ones. The obtained results indicate that GENE isoforms catalyze the formation of CHEMICAL from 5-methoxytryptamine, and that the deficit or genetic defect of CYP2D may affect CHEMICAL metabolism in the brain. The results are discussed in the context of their possible physiological and pharmacological significance in vivo. | PRODUCT-OF |
| The catalytic competence of cytochrome P450 in the synthesis of serotonin from 5-methoxytryptamine in the brain: an in vitro study. Brain serotonin has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. The aim of present study was to identify rat cytochrome P450 (CYP) isoforms which can catalyze the O-demethylation of 5-methoxytryptamine to serotonin, and to find out whether that alternative pathway of serotonin synthesis may take place in the brain. The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type CYP2D6 or the allelic variant 2D6*4*4). Of the rat CYP isoforms studied, GENE isoforms were the most efficient in catalyzing the CHEMICAL-demethylation of 5-methoxytryptamine to serotonin, but they were less effective than the human isoform CYP2D6. Microsomes from different brain regions were capable of metabolizing 5-methoxytryptamine to serotonin. The reaction was inhibited by the specific GENE inhibitors quinine and fluoxetine. Human liver microsomes of the wild-type CYP2D6 metabolized 5-methoxytryptamine to serotonin more effectively than did the defective CYP2D6*4*4 ones. The obtained results indicate that rat brain GENE isoforms catalyze the formation of serotonin from 5-methoxytryptamine, and that the deficit or genetic defect of GENE may affect serotonin metabolism in the brain. The results are discussed in the context of their possible physiological and pharmacological significance in vivo. | SUBSTRATE |
| The catalytic competence of cytochrome P450 in the synthesis of serotonin from 5-methoxytryptamine in the brain: an in vitro study. Brain serotonin has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. The aim of present study was to identify rat cytochrome P450 (CYP) isoforms which can catalyze the O-demethylation of 5-methoxytryptamine to serotonin, and to find out whether that alternative pathway of serotonin synthesis may take place in the brain. The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type CYP2D6 or the allelic variant 2D6*4*4). Of the rat CYP isoforms studied, CYP2D isoforms were the most efficient in catalyzing the CHEMICAL-demethylation of 5-methoxytryptamine to serotonin, but they were less effective than the GENE. Microsomes from different brain regions were capable of metabolizing 5-methoxytryptamine to serotonin. The reaction was inhibited by the specific CYP2D inhibitors quinine and fluoxetine. Human liver microsomes of the wild-type CYP2D6 metabolized 5-methoxytryptamine to serotonin more effectively than did the defective CYP2D6*4*4 ones. The obtained results indicate that rat brain CYP2D isoforms catalyze the formation of serotonin from 5-methoxytryptamine, and that the deficit or genetic defect of CYP2D may affect serotonin metabolism in the brain. The results are discussed in the context of their possible physiological and pharmacological significance in vivo. | SUBSTRATE |
| The catalytic competence of cytochrome P450 in the synthesis of serotonin from CHEMICAL in the brain: an in vitro study. Brain serotonin has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. The aim of present study was to identify rat cytochrome P450 (CYP) isoforms which can catalyze the O-demethylation of CHEMICAL to serotonin, and to find out whether that alternative pathway of serotonin synthesis may take place in the brain. The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type CYP2D6 or the allelic variant 2D6*4*4). Of the rat CYP isoforms studied, GENE isoforms were the most efficient in catalyzing the O-demethylation of CHEMICAL to serotonin, but they were less effective than the human isoform CYP2D6. Microsomes from different brain regions were capable of metabolizing CHEMICAL to serotonin. The reaction was inhibited by the specific GENE inhibitors quinine and fluoxetine. Human liver microsomes of the wild-type CYP2D6 metabolized CHEMICAL to serotonin more effectively than did the defective CYP2D6*4*4 ones. The obtained results indicate that rat brain GENE isoforms catalyze the formation of serotonin from CHEMICAL, and that the deficit or genetic defect of GENE may affect serotonin metabolism in the brain. The results are discussed in the context of their possible physiological and pharmacological significance in vivo. | SUBSTRATE |
| The catalytic competence of cytochrome P450 in the synthesis of serotonin from CHEMICAL in the brain: an in vitro study. Brain serotonin has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. The aim of present study was to identify rat cytochrome P450 (CYP) isoforms which can catalyze the O-demethylation of CHEMICAL to serotonin, and to find out whether that alternative pathway of serotonin synthesis may take place in the brain. The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type CYP2D6 or the allelic variant 2D6*4*4). Of the rat CYP isoforms studied, CYP2D isoforms were the most efficient in catalyzing the O-demethylation of CHEMICAL to serotonin, but they were less effective than the GENE. Microsomes from different brain regions were capable of metabolizing CHEMICAL to serotonin. The reaction was inhibited by the specific CYP2D inhibitors quinine and fluoxetine. Human liver microsomes of the wild-type CYP2D6 metabolized CHEMICAL to serotonin more effectively than did the defective CYP2D6*4*4 ones. The obtained results indicate that rat brain CYP2D isoforms catalyze the formation of serotonin from CHEMICAL, and that the deficit or genetic defect of CYP2D may affect serotonin metabolism in the brain. The results are discussed in the context of their possible physiological and pharmacological significance in vivo. | SUBSTRATE |
| The catalytic competence of GENE in the synthesis of serotonin from CHEMICAL in the brain: an in vitro study. Brain serotonin has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. The aim of present study was to identify rat GENE (CYP) isoforms which can catalyze the O-demethylation of CHEMICAL to serotonin, and to find out whether that alternative pathway of serotonin synthesis may take place in the brain. The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type CYP2D6 or the allelic variant 2D6*4*4). Of the rat CYP isoforms studied, CYP2D isoforms were the most efficient in catalyzing the O-demethylation of CHEMICAL to serotonin, but they were less effective than the human isoform CYP2D6. Microsomes from different brain regions were capable of metabolizing CHEMICAL to serotonin. The reaction was inhibited by the specific CYP2D inhibitors quinine and fluoxetine. Human liver microsomes of the wild-type CYP2D6 metabolized CHEMICAL to serotonin more effectively than did the defective CYP2D6*4*4 ones. The obtained results indicate that rat brain CYP2D isoforms catalyze the formation of serotonin from CHEMICAL, and that the deficit or genetic defect of CYP2D may affect serotonin metabolism in the brain. The results are discussed in the context of their possible physiological and pharmacological significance in vivo. | SUBSTRATE |
| The catalytic competence of cytochrome P450 in the synthesis of serotonin from CHEMICAL in the brain: an in vitro study. Brain serotonin has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. The aim of present study was to identify rat cytochrome P450 (CYP) isoforms which can catalyze the O-demethylation of CHEMICAL to serotonin, and to find out whether that alternative pathway of serotonin synthesis may take place in the brain. The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type GENE or the allelic variant 2D6*4*4). Of the rat CYP isoforms studied, CYP2D isoforms were the most efficient in catalyzing the O-demethylation of CHEMICAL to serotonin, but they were less effective than the human isoform GENE. Microsomes from different brain regions were capable of metabolizing CHEMICAL to serotonin. The reaction was inhibited by the specific CYP2D inhibitors quinine and fluoxetine. Human liver microsomes of the wild-type GENE metabolized CHEMICAL to serotonin more effectively than did the defective CYP2D6*4*4 ones. The obtained results indicate that rat brain CYP2D isoforms catalyze the formation of serotonin from CHEMICAL, and that the deficit or genetic defect of CYP2D may affect serotonin metabolism in the brain. The results are discussed in the context of their possible physiological and pharmacological significance in vivo. | SUBSTRATE |
| The catalytic competence of cytochrome P450 in the synthesis of serotonin from CHEMICAL in the brain: an in vitro study. Brain serotonin has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. The aim of present study was to identify rat cytochrome P450 (CYP) isoforms which can catalyze the O-demethylation of CHEMICAL to serotonin, and to find out whether that alternative pathway of serotonin synthesis may take place in the brain. The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type CYP2D6 or the allelic variant 2D6*4*4). Of the rat CYP isoforms studied, CYP2D isoforms were the most efficient in catalyzing the O-demethylation of CHEMICAL to serotonin, but they were less effective than the human isoform CYP2D6. Microsomes from different brain regions were capable of metabolizing CHEMICAL to serotonin. The reaction was inhibited by the specific CYP2D inhibitors quinine and fluoxetine. Human liver microsomes of the wild-type CYP2D6 metabolized CHEMICAL to serotonin more effectively than did the defective CYP2D6*4*4 ones. The obtained results indicate that GENE isoforms catalyze the formation of serotonin from CHEMICAL, and that the deficit or genetic defect of CYP2D may affect serotonin metabolism in the brain. The results are discussed in the context of their possible physiological and pharmacological significance in vivo. | SUBSTRATE |
| Estrogen receptor signaling as a target for novel breast cancer therapeutics. In breast cancer (BC) epithelial cells, the mitogenic action of CHEMICAL is transduced through binding to two receptors, GENE and ERβ, which act as transcription factors. Anti-estrogens (AEs) and aromatase inhibitors (AIs) are used clinically to arrest the estrogen-dependent growth of BC. In the case of AE or AI resistance, Herceptin or lapatinib may be used to inhibit growth factors. Estrogen effects are mediated not only through nuclear ERs but also through cytoplasmic/membrane ERs and G-protein-coupled ERs. These estrogen-binding systems associate with various proteins that direct cell cycle signaling, proliferation and survival. The partners of nuclear ER include SRC1-3, HDACs and ERβ itself as well as newly identified proteins, such as E6-AP, LKB1, PELP1, PAX-2 and FOXA1. The partners of extra-nuclear GENE include PI3K and the tyrosine kinase Src. These various factors are all potential targets for therapeutic intervention. In addition, BC proliferation is enhanced by insulin and EGF, which stimulate signaling through the MAPK and PI3K/AKT pathways by activation of the IGF-1R and EGFR axes, respectively. These pathways are tightly interconnected with ER-activated signaling, and membrane GENE forms complexes with Src and PI3K. Chemokine-mediated signaling also modulates the estrogen response. Inhibiting these pathways with specific inhibitors or activating some of the pathways by gene manipulation may be therapeutically valuable for arresting BC cell cycle progression and for inducing apoptosis to antagonize hormone-resistance. Here, we review some newly identified putatively targetable ER partners and highlight the need to develop tumor-targeting drug carrier systems affecting both the tumor cells and the tumor environment. | DIRECT-REGULATOR |
| Estrogen receptor signaling as a target for novel breast cancer therapeutics. In breast cancer (BC) epithelial cells, the mitogenic action of CHEMICAL is transduced through binding to two receptors, ERα and GENE, which act as transcription factors. Anti-estrogens (AEs) and aromatase inhibitors (AIs) are used clinically to arrest the estrogen-dependent growth of BC. In the case of AE or AI resistance, Herceptin or lapatinib may be used to inhibit growth factors. Estrogen effects are mediated not only through nuclear ERs but also through cytoplasmic/membrane ERs and G-protein-coupled ERs. These estrogen-binding systems associate with various proteins that direct cell cycle signaling, proliferation and survival. The partners of nuclear ER include SRC1-3, HDACs and GENE itself as well as newly identified proteins, such as E6-AP, LKB1, PELP1, PAX-2 and FOXA1. The partners of extra-nuclear ERα include PI3K and the tyrosine kinase Src. These various factors are all potential targets for therapeutic intervention. In addition, BC proliferation is enhanced by insulin and EGF, which stimulate signaling through the MAPK and PI3K/AKT pathways by activation of the IGF-1R and EGFR axes, respectively. These pathways are tightly interconnected with ER-activated signaling, and membrane ERα forms complexes with Src and PI3K. Chemokine-mediated signaling also modulates the estrogen response. Inhibiting these pathways with specific inhibitors or activating some of the pathways by gene manipulation may be therapeutically valuable for arresting BC cell cycle progression and for inducing apoptosis to antagonize hormone-resistance. Here, we review some newly identified putatively targetable ER partners and highlight the need to develop tumor-targeting drug carrier systems affecting both the tumor cells and the tumor environment. | DIRECT-REGULATOR |
| CHEMICAL receptor signaling as a target for novel breast cancer therapeutics. In breast cancer (BC) epithelial cells, the mitogenic action of estradiol is transduced through binding to two receptors, ERα and ERβ, which act as transcription factors. Anti-estrogens (AEs) and aromatase inhibitors (AIs) are used clinically to arrest the estrogen-dependent growth of BC. In the case of AE or AI resistance, Herceptin or lapatinib may be used to inhibit growth factors. CHEMICAL effects are mediated not only through nuclear GENE but also through cytoplasmic/membrane GENE and G-protein-coupled GENE. These estrogen-binding systems associate with various proteins that direct cell cycle signaling, proliferation and survival. The partners of nuclear ER include SRC1-3, HDACs and ERβ itself as well as newly identified proteins, such as E6-AP, LKB1, PELP1, PAX-2 and FOXA1. The partners of extra-nuclear ERα include PI3K and the tyrosine kinase Src. These various factors are all potential targets for therapeutic intervention. In addition, BC proliferation is enhanced by insulin and EGF, which stimulate signaling through the MAPK and PI3K/AKT pathways by activation of the IGF-1R and EGFR axes, respectively. These pathways are tightly interconnected with ER-activated signaling, and membrane ERα forms complexes with Src and PI3K. Chemokine-mediated signaling also modulates the estrogen response. Inhibiting these pathways with specific inhibitors or activating some of the pathways by gene manipulation may be therapeutically valuable for arresting BC cell cycle progression and for inducing apoptosis to antagonize hormone-resistance. Here, we review some newly identified putatively targetable ER partners and highlight the need to develop tumor-targeting drug carrier systems affecting both the tumor cells and the tumor environment. | REGULATOR |
| CHEMICAL receptor signaling as a target for novel breast cancer therapeutics. In breast cancer (BC) epithelial cells, the mitogenic action of estradiol is transduced through binding to two receptors, ERα and ERβ, which act as transcription factors. Anti-estrogens (AEs) and aromatase inhibitors (AIs) are used clinically to arrest the estrogen-dependent growth of BC. In the case of AE or AI resistance, Herceptin or lapatinib may be used to inhibit growth factors. CHEMICAL effects are mediated not only through nuclear ERs but also through cytoplasmic/membrane ERs and GENE-coupled ERs. These estrogen-binding systems associate with various proteins that direct cell cycle signaling, proliferation and survival. The partners of nuclear ER include SRC1-3, HDACs and ERβ itself as well as newly identified proteins, such as E6-AP, LKB1, PELP1, PAX-2 and FOXA1. The partners of extra-nuclear ERα include PI3K and the tyrosine kinase Src. These various factors are all potential targets for therapeutic intervention. In addition, BC proliferation is enhanced by insulin and EGF, which stimulate signaling through the MAPK and PI3K/AKT pathways by activation of the IGF-1R and EGFR axes, respectively. These pathways are tightly interconnected with ER-activated signaling, and membrane ERα forms complexes with Src and PI3K. Chemokine-mediated signaling also modulates the estrogen response. Inhibiting these pathways with specific inhibitors or activating some of the pathways by gene manipulation may be therapeutically valuable for arresting BC cell cycle progression and for inducing apoptosis to antagonize hormone-resistance. Here, we review some newly identified putatively targetable ER partners and highlight the need to develop tumor-targeting drug carrier systems affecting both the tumor cells and the tumor environment. | REGULATOR |
| Toosendanin induces apoptosis through suppression of GENE signaling pathway in HL-60 cells. Toosendanin (TSN), a triterpenoid isolated from Melia toosendan Sieb. et Zucc., has been found to suppress proliferation and induce apoptosis in a variety of human cancer cells. However, the mechanism how CHEMICAL induces apoptosis remains poorly understood. In this study, we examined the effects of CHEMICAL on the growth, cell cycle arrest, induction of apoptosis and the involved signaling pathway in human promyelocytic leukemia HL-60 cells. Proliferation of HL-60 cells was inhibited in a dose-dependent manner with the IC(50 (48 h)) of 28 ng/mL. The growth inhibition was due primarily to the S phase arrest and cell apoptosis. Cell apoptosis induced by CHEMICAL was confirmed by Annexin V-FITC/propidium iodide staining. The increase of the pro-apoptotic protein Bax, cleaved PARP and caspase-3, and the decrease of anti-apoptotic protein Bcl-2 were observed. Western blot analysis indicated that CHEMICAL inhibits the CDC42/MEKK1/JNK pathway. Taken together, our study suggested, for the first time, that the pro-apoptotic effects of CHEMICAL on HL-60 cells were mediated through GENE signaling pathway. | REGULATOR |
| CHEMICAL induces apoptosis through suppression of GENE signaling pathway in HL-60 cells. CHEMICAL (TSN), a triterpenoid isolated from Melia toosendan Sieb. et Zucc., has been found to suppress proliferation and induce apoptosis in a variety of human cancer cells. However, the mechanism how TSN induces apoptosis remains poorly understood. In this study, we examined the effects of TSN on the growth, cell cycle arrest, induction of apoptosis and the involved signaling pathway in human promyelocytic leukemia HL-60 cells. Proliferation of HL-60 cells was inhibited in a dose-dependent manner with the IC(50 (48 h)) of 28 ng/mL. The growth inhibition was due primarily to the S phase arrest and cell apoptosis. Cell apoptosis induced by TSN was confirmed by Annexin V-FITC/propidium iodide staining. The increase of the pro-apoptotic protein Bax, cleaved PARP and caspase-3, and the decrease of anti-apoptotic protein Bcl-2 were observed. Western blot analysis indicated that TSN inhibits the CDC42/MEKK1/JNK pathway. Taken together, our study suggested, for the first time, that the pro-apoptotic effects of TSN on HL-60 cells were mediated through GENE signaling pathway. | INHIBITOR |
| Toosendanin induces apoptosis through suppression of JNK signaling pathway in HL-60 cells. Toosendanin (TSN), a triterpenoid isolated from Melia toosendan Sieb. et Zucc., has been found to suppress proliferation and induce apoptosis in a variety of human cancer cells. However, the mechanism how CHEMICAL induces apoptosis remains poorly understood. In this study, we examined the effects of CHEMICAL on the growth, cell cycle arrest, induction of apoptosis and the involved signaling pathway in human promyelocytic leukemia HL-60 cells. Proliferation of HL-60 cells was inhibited in a dose-dependent manner with the IC(50 (48 h)) of 28 ng/mL. The growth inhibition was due primarily to the S phase arrest and cell apoptosis. Cell apoptosis induced by CHEMICAL was confirmed by Annexin V-FITC/propidium iodide staining. The increase of the pro-apoptotic protein Bax, cleaved PARP and caspase-3, and the decrease of anti-apoptotic protein Bcl-2 were observed. Western blot analysis indicated that CHEMICAL inhibits the GENE/MEKK1/JNK pathway. Taken together, our study suggested, for the first time, that the pro-apoptotic effects of CHEMICAL on HL-60 cells were mediated through JNK signaling pathway. | INHIBITOR |
| Toosendanin induces apoptosis through suppression of JNK signaling pathway in HL-60 cells. Toosendanin (TSN), a triterpenoid isolated from Melia toosendan Sieb. et Zucc., has been found to suppress proliferation and induce apoptosis in a variety of human cancer cells. However, the mechanism how CHEMICAL induces apoptosis remains poorly understood. In this study, we examined the effects of CHEMICAL on the growth, cell cycle arrest, induction of apoptosis and the involved signaling pathway in human promyelocytic leukemia HL-60 cells. Proliferation of HL-60 cells was inhibited in a dose-dependent manner with the IC(50 (48 h)) of 28 ng/mL. The growth inhibition was due primarily to the S phase arrest and cell apoptosis. Cell apoptosis induced by CHEMICAL was confirmed by Annexin V-FITC/propidium iodide staining. The increase of the pro-apoptotic protein Bax, cleaved PARP and caspase-3, and the decrease of anti-apoptotic protein Bcl-2 were observed. Western blot analysis indicated that CHEMICAL inhibits the CDC42/GENE/JNK pathway. Taken together, our study suggested, for the first time, that the pro-apoptotic effects of CHEMICAL on HL-60 cells were mediated through JNK signaling pathway. | INHIBITOR |
| Novel insights on the effect of CHEMICAL in a murine colitis model. Studies showed that CHEMICAL has a positive influence on symptoms of ulcerative colitis. In the present study, we explored the effect of CHEMICAL treatment using different routes of administration in the dextran sodium sulfate (DSS) colitis mouse model. We also investigated the effects of cotinine, a major metabolite of CHEMICAL, in the model. C57BL6 adult male mice were given DSS solution freely in the drinking water for seven consecutive days, and tap water was given thereafter. Disease severity, length of the colon, colon tissue histology, and inflammatory markers, including colonic myeloperoxidase activity and colonic GENE levels, were evaluated. The effect of CHEMICAL and cotinine treatments via various different routes of administration were examined the DSS model. In addition, we measured the plasma levels of CHEMICAL and cotinine in our treatment protocols. Administration of low, but not high, doses of oral CHEMICAL in DSS-treated mice resulted in a significant decrease in disease severity, histologic damage scores, as well as colonic level of GENE. However, the anti-inflammatory effect of CHEMICAL was not seen after chronic s.c. or minipump infusion of the drug. Differences in plasma levels of CHEMICAL and cotinine do not seem to account for this lack of effect. Finally, oral cotinine alone failed to show a significant effect in the DSS model of colitis. These results highlight that dose and route of administration play a critical role in the protective effect of CHEMICAL in the DSS mouse colitis model. | INDIRECT-DOWNREGULATOR |
| The S349T mutation of SQSTM1 links Keap1/Nrf2 signalling to Paget's disease of bone. Mutations affecting the Sequestosome 1 (SQSTM1) gene commonly occur in patients with the skeletal disorder Paget's disease of bone (PDB), a condition characterised by defective osteoclast differentiation and function. Whilst most mutations cluster within the ubiquitin-associated (UBA) domain of the SQSTM1 protein, and are associated with dysregulated NFκB signalling, several non-UBA domain mutations have also been identified. Keap1 is a SQSTM1-interacting protein that regulates the levels and activity of the Nrf2 transcription factor. This in turn controls the expression of numerous cytoprotective genes that contribute to the cell's capacity to defend itself against chemical and oxidative stress, through binding to the antioxidant response element (ARE). The PDB-associated S349T mutation maps to the Keap1-interacting region (KIR) of SQSTM1, however the effects of PDB mutant SQSTM1 on Keap1 function have not been investigated. Here we show that unlike other SQSTM1 mutations, the S349T mutation results in neither impaired ubiquitin-binding function in pull-down assays, nor dysregulated NFκB signalling in luciferase reporter assays. Keap1 is expressed in differentiating osteoclast-like cells and the S349T mutation selectively impairs the SQSTM1-Keap1 interaction in co-immunoprecipitations, which molecular modelling indicates results from effects on critical CHEMICAL bonds required to stabilise the GENE-Keap1 complex. Further, S349T mutant SQSTM1, but not other PDB-associated mutants, showed reduced ability to activate Nrf2 signalling as assessed by ARE-luciferase reporter assays. Thus, SQSTM1-mediated dysregulation of the Keap1-Nrf2 axis, which could potentially lead to aberrant production of oxidative response genes, may contribute to disease aetiology in a subset of PDB patients. | PART-OF |
| The S349T mutation of SQSTM1 links Keap1/Nrf2 signalling to Paget's disease of bone. Mutations affecting the Sequestosome 1 (SQSTM1) gene commonly occur in patients with the skeletal disorder Paget's disease of bone (PDB), a condition characterised by defective osteoclast differentiation and function. Whilst most mutations cluster within the ubiquitin-associated (UBA) domain of the SQSTM1 protein, and are associated with dysregulated NFκB signalling, several non-UBA domain mutations have also been identified. GENE is a SQSTM1-interacting protein that regulates the levels and activity of the Nrf2 transcription factor. This in turn controls the expression of numerous cytoprotective genes that contribute to the cell's capacity to defend itself against chemical and oxidative stress, through binding to the antioxidant response element (ARE). The PDB-associated S349T mutation maps to the Keap1-interacting region (KIR) of SQSTM1, however the effects of PDB mutant SQSTM1 on GENE function have not been investigated. Here we show that unlike other SQSTM1 mutations, the S349T mutation results in neither impaired ubiquitin-binding function in pull-down assays, nor dysregulated NFκB signalling in luciferase reporter assays. GENE is expressed in differentiating osteoclast-like cells and the S349T mutation selectively impairs the SQSTM1-Keap1 interaction in co-immunoprecipitations, which molecular modelling indicates results from effects on critical CHEMICAL bonds required to stabilise the KIR-GENE complex. Further, S349T mutant SQSTM1, but not other PDB-associated mutants, showed reduced ability to activate Nrf2 signalling as assessed by ARE-luciferase reporter assays. Thus, SQSTM1-mediated dysregulation of the Keap1-Nrf2 axis, which could potentially lead to aberrant production of oxidative response genes, may contribute to disease aetiology in a subset of PDB patients. | DIRECT-REGULATOR |
| GENE suppresses postischemic CHEMICAL intolerance and neuronal damage through hypothalamic brain-derived neurotrophic factor. GENE (a CHEMICAL-sensing neuropeptide in the hypothalamus) and brain-derived neurotrophic factor (BDNF; a member of the neurotrophin family) play roles in many physiologic functions, including regulation of CHEMICAL metabolism. We previously showed that the development of postischemic CHEMICAL intolerance is one of the triggers of ischemic neuronal damage. The aim of this study was to determine whether there was an interaction between orexin-A and BDNF functions in the hypothalamus after cerebral ischemic stress. Male ddY mice were subjected to 2 hours of middle cerebral artery occlusion (MCAO). Neuronal damage was estimated by histologic and behavioral analyses. Expression of protein levels was analyzed by Western blot. Small interfering RNA directed BDNF, orexin-A, and SB334867 [N-(2-methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea; a specific orexin-1 receptor antagonist] were administered directly into the hypothalamus. The level of hypothalamic orexin-A, detected by immunohistochemistry, was decreased on day 1 after MCAO. Intrahypothalamic administration of orexin-A (1 or 5 pmol/mouse) significantly and dose-dependently suppressed the development of postischemic CHEMICAL intolerance on day 1 and development of neuronal damage on day 3. The MCAO-induced decrease in insulin receptor levels in the liver and skeletal muscle on day 1 was recovered to control levels by orexin-A, and this effect of orexin-A was reversed by the administration of SB334867 as well as by hypothalamic BDNF knockdown. These results suggest that suppression of postischemic CHEMICAL intolerance by orexin-A assists in the prevention of cerebral ischemic neuronal damage. In addition, hypothalamic BDNF may play an important role in this effect of orexin-A. | SUBSTRATE |
| Orexin-A suppresses postischemic glucose intolerance and neuronal damage through hypothalamic brain-derived neurotrophic factor. Orexin-A (a glucose-sensing neuropeptide in the hypothalamus) and brain-derived neurotrophic factor (BDNF; a member of the neurotrophin family) play roles in many physiologic functions, including regulation of glucose metabolism. We previously showed that the development of postischemic glucose intolerance is one of the triggers of ischemic neuronal damage. The aim of this study was to determine whether there was an interaction between GENE and BDNF functions in the hypothalamus after cerebral ischemic stress. Male ddY mice were subjected to 2 hours of middle cerebral artery occlusion (MCAO). Neuronal damage was estimated by histologic and behavioral analyses. Expression of protein levels was analyzed by Western blot. Small interfering RNA directed BDNF, GENE, and CHEMICAL [N-(2-methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea; a specific orexin-1 receptor antagonist] were administered directly into the hypothalamus. The level of hypothalamic GENE, detected by immunohistochemistry, was decreased on day 1 after MCAO. Intrahypothalamic administration of GENE (1 or 5 pmol/mouse) significantly and dose-dependently suppressed the development of postischemic glucose intolerance on day 1 and development of neuronal damage on day 3. The MCAO-induced decrease in insulin receptor levels in the liver and skeletal muscle on day 1 was recovered to control levels by GENE, and this effect of GENE was reversed by the administration of CHEMICAL as well as by hypothalamic BDNF knockdown. These results suggest that suppression of postischemic glucose intolerance by GENE assists in the prevention of cerebral ischemic neuronal damage. In addition, hypothalamic BDNF may play an important role in this effect of GENE. | INDIRECT-DOWNREGULATOR |
| Orexin-A suppresses postischemic glucose intolerance and neuronal damage through hypothalamic brain-derived neurotrophic factor. Orexin-A (a glucose-sensing neuropeptide in the hypothalamus) and brain-derived neurotrophic factor (BDNF; a member of the neurotrophin family) play roles in many physiologic functions, including regulation of glucose metabolism. We previously showed that the development of postischemic glucose intolerance is one of the triggers of ischemic neuronal damage. The aim of this study was to determine whether there was an interaction between orexin-A and BDNF functions in the hypothalamus after cerebral ischemic stress. Male ddY mice were subjected to 2 hours of middle cerebral artery occlusion (MCAO). Neuronal damage was estimated by histologic and behavioral analyses. Expression of protein levels was analyzed by Western blot. Small interfering RNA directed BDNF, orexin-A, and CHEMICAL [N-(2-methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea; a specific orexin-1 receptor antagonist] were administered directly into the hypothalamus. The level of hypothalamic orexin-A, detected by immunohistochemistry, was decreased on day 1 after MCAO. Intrahypothalamic administration of orexin-A (1 or 5 pmol/mouse) significantly and dose-dependently suppressed the development of postischemic glucose intolerance on day 1 and development of neuronal damage on day 3. The MCAO-induced decrease in GENE levels in the liver and skeletal muscle on day 1 was recovered to control levels by orexin-A, and this effect of orexin-A was reversed by the administration of CHEMICAL as well as by hypothalamic BDNF knockdown. These results suggest that suppression of postischemic glucose intolerance by orexin-A assists in the prevention of cerebral ischemic neuronal damage. In addition, hypothalamic BDNF may play an important role in this effect of orexin-A. | INDIRECT-DOWNREGULATOR |
| Orexin-A suppresses postischemic glucose intolerance and neuronal damage through hypothalamic brain-derived neurotrophic factor. Orexin-A (a glucose-sensing neuropeptide in the hypothalamus) and brain-derived neurotrophic factor (BDNF; a member of the neurotrophin family) play roles in many physiologic functions, including regulation of glucose metabolism. We previously showed that the development of postischemic glucose intolerance is one of the triggers of ischemic neuronal damage. The aim of this study was to determine whether there was an interaction between orexin-A and BDNF functions in the hypothalamus after cerebral ischemic stress. Male ddY mice were subjected to 2 hours of middle cerebral artery occlusion (MCAO). Neuronal damage was estimated by histologic and behavioral analyses. Expression of protein levels was analyzed by Western blot. Small interfering RNA directed BDNF, orexin-A, and CHEMICAL [N-(2-methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea; a specific GENE antagonist] were administered directly into the hypothalamus. The level of hypothalamic orexin-A, detected by immunohistochemistry, was decreased on day 1 after MCAO. Intrahypothalamic administration of orexin-A (1 or 5 pmol/mouse) significantly and dose-dependently suppressed the development of postischemic glucose intolerance on day 1 and development of neuronal damage on day 3. The MCAO-induced decrease in insulin receptor levels in the liver and skeletal muscle on day 1 was recovered to control levels by orexin-A, and this effect of orexin-A was reversed by the administration of CHEMICAL as well as by hypothalamic BDNF knockdown. These results suggest that suppression of postischemic glucose intolerance by orexin-A assists in the prevention of cerebral ischemic neuronal damage. In addition, hypothalamic BDNF may play an important role in this effect of orexin-A. | INHIBITOR |
| Orexin-A suppresses postischemic glucose intolerance and neuronal damage through hypothalamic brain-derived neurotrophic factor. Orexin-A (a glucose-sensing neuropeptide in the hypothalamus) and brain-derived neurotrophic factor (BDNF; a member of the neurotrophin family) play roles in many physiologic functions, including regulation of glucose metabolism. We previously showed that the development of postischemic glucose intolerance is one of the triggers of ischemic neuronal damage. The aim of this study was to determine whether there was an interaction between orexin-A and BDNF functions in the hypothalamus after cerebral ischemic stress. Male ddY mice were subjected to 2 hours of middle cerebral artery occlusion (MCAO). Neuronal damage was estimated by histologic and behavioral analyses. Expression of protein levels was analyzed by Western blot. Small interfering RNA directed BDNF, orexin-A, and SB334867 [CHEMICAL; a specific GENE antagonist] were administered directly into the hypothalamus. The level of hypothalamic orexin-A, detected by immunohistochemistry, was decreased on day 1 after MCAO. Intrahypothalamic administration of orexin-A (1 or 5 pmol/mouse) significantly and dose-dependently suppressed the development of postischemic glucose intolerance on day 1 and development of neuronal damage on day 3. The MCAO-induced decrease in insulin receptor levels in the liver and skeletal muscle on day 1 was recovered to control levels by orexin-A, and this effect of orexin-A was reversed by the administration of SB334867 as well as by hypothalamic BDNF knockdown. These results suggest that suppression of postischemic glucose intolerance by orexin-A assists in the prevention of cerebral ischemic neuronal damage. In addition, hypothalamic BDNF may play an important role in this effect of orexin-A. | INHIBITOR |
| Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1. Mesalamine (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon. Knowledge about the molecular and cellular targets of CHEMICAL is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking. We sought to identify molecular pathways interfered by CHEMICAL, using CRC cell lines with different genetic background. Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29). Filtering and analysis of data identified three oncogenic pathways interfered by CHEMICAL: MAPK/ERK pathway, cell adhesion and GENE/Wnt signaling. PAK1 emerged as a consensus target of CHEMICAL, orchestrating these pathways. We further investigated the effect of CHEMICAL on cell adhesion. CHEMICAL increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement. Moreover, CHEMICAL treatment restored membranous expression of adhesion molecules E-cadherin and GENE. Role of PAK1 as a mediator of mesalamine activity was validated in vitro and in vivo. Inhibition of PAK1 by RNA interference also increased cell adhesion. PAK1 expression was elevated in APC(min) polyps and CHEMICAL treatment reduced its expression. Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of PAK1 in APC(min) polyposis. We propose that inhibition of PAK1 expression by CHEMICAL can impede with neoplastic progression in colorectal carcinogenesis. The mechanism of PAK1 inhibition and induction of membranous translocation of adhesion proteins by CHEMICAL might be independent of its known anti-inflammatory action. | INDIRECT-DOWNREGULATOR |
| Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1. Mesalamine (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon. Knowledge about the molecular and cellular targets of CHEMICAL is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking. We sought to identify molecular pathways interfered by CHEMICAL, using CRC cell lines with different genetic background. Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29). Filtering and analysis of data identified three oncogenic pathways interfered by CHEMICAL: MAPK/ERK pathway, cell adhesion and β-catenin/GENE signaling. PAK1 emerged as a consensus target of CHEMICAL, orchestrating these pathways. We further investigated the effect of CHEMICAL on cell adhesion. CHEMICAL increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement. Moreover, CHEMICAL treatment restored membranous expression of adhesion molecules E-cadherin and β-catenin. Role of PAK1 as a mediator of mesalamine activity was validated in vitro and in vivo. Inhibition of PAK1 by RNA interference also increased cell adhesion. PAK1 expression was elevated in APC(min) polyps and CHEMICAL treatment reduced its expression. Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of PAK1 in APC(min) polyposis. We propose that inhibition of PAK1 expression by CHEMICAL can impede with neoplastic progression in colorectal carcinogenesis. The mechanism of PAK1 inhibition and induction of membranous translocation of adhesion proteins by CHEMICAL might be independent of its known anti-inflammatory action. | GENE-CHEMICAL |
| Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1. Mesalamine (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon. Knowledge about the molecular and cellular targets of CHEMICAL is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking. We sought to identify molecular pathways interfered by CHEMICAL, using CRC cell lines with different genetic background. Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29). Filtering and analysis of data identified three oncogenic pathways interfered by CHEMICAL: GENE/ERK pathway, cell adhesion and β-catenin/Wnt signaling. PAK1 emerged as a consensus target of CHEMICAL, orchestrating these pathways. We further investigated the effect of CHEMICAL on cell adhesion. CHEMICAL increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement. Moreover, CHEMICAL treatment restored membranous expression of adhesion molecules E-cadherin and β-catenin. Role of PAK1 as a mediator of mesalamine activity was validated in vitro and in vivo. Inhibition of PAK1 by RNA interference also increased cell adhesion. PAK1 expression was elevated in APC(min) polyps and CHEMICAL treatment reduced its expression. Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of PAK1 in APC(min) polyposis. We propose that inhibition of PAK1 expression by CHEMICAL can impede with neoplastic progression in colorectal carcinogenesis. The mechanism of PAK1 inhibition and induction of membranous translocation of adhesion proteins by CHEMICAL might be independent of its known anti-inflammatory action. | REGULATOR |
| Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1. Mesalamine (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon. Knowledge about the molecular and cellular targets of CHEMICAL is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking. We sought to identify molecular pathways interfered by CHEMICAL, using CRC cell lines with different genetic background. Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29). Filtering and analysis of data identified three oncogenic pathways interfered by CHEMICAL: MAPK/GENE pathway, cell adhesion and β-catenin/Wnt signaling. PAK1 emerged as a consensus target of CHEMICAL, orchestrating these pathways. We further investigated the effect of CHEMICAL on cell adhesion. CHEMICAL increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement. Moreover, CHEMICAL treatment restored membranous expression of adhesion molecules E-cadherin and β-catenin. Role of PAK1 as a mediator of mesalamine activity was validated in vitro and in vivo. Inhibition of PAK1 by RNA interference also increased cell adhesion. PAK1 expression was elevated in APC(min) polyps and CHEMICAL treatment reduced its expression. Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of PAK1 in APC(min) polyposis. We propose that inhibition of PAK1 expression by CHEMICAL can impede with neoplastic progression in colorectal carcinogenesis. The mechanism of PAK1 inhibition and induction of membranous translocation of adhesion proteins by CHEMICAL might be independent of its known anti-inflammatory action. | REGULATOR |
| Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1. Mesalamine (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon. Knowledge about the molecular and cellular targets of CHEMICAL is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking. We sought to identify molecular pathways interfered by CHEMICAL, using CRC cell lines with different genetic background. Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29). Filtering and analysis of data identified three oncogenic pathways interfered by 5-ASA: MAPK/ERK pathway, cell adhesion and β-catenin/Wnt signaling. GENE emerged as a consensus target of CHEMICAL, orchestrating these pathways. We further investigated the effect of CHEMICAL on cell adhesion. CHEMICAL increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement. Moreover, CHEMICAL treatment restored membranous expression of adhesion molecules E-cadherin and β-catenin. Role of GENE as a mediator of mesalamine activity was validated in vitro and in vivo. Inhibition of GENE by RNA interference also increased cell adhesion. GENE expression was elevated in APC(min) polyps and CHEMICAL treatment reduced its expression. Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of GENE in APC(min) polyposis. We propose that inhibition of GENE expression by CHEMICAL can impede with neoplastic progression in colorectal carcinogenesis. The mechanism of GENE inhibition and induction of membranous translocation of adhesion proteins by CHEMICAL might be independent of its known anti-inflammatory action. | REGULATOR |
| CHEMICAL modulates intercellular adhesion through inhibition of p-21 activated kinase-1. CHEMICAL (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon. Knowledge about the molecular and cellular targets of 5-ASA is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking. We sought to identify molecular pathways interfered by 5-ASA, using CRC cell lines with different genetic background. Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29). Filtering and analysis of data identified three oncogenic pathways interfered by 5-ASA: MAPK/ERK pathway, cell adhesion and β-catenin/Wnt signaling. GENE emerged as a consensus target of 5-ASA, orchestrating these pathways. We further investigated the effect of 5-ASA on cell adhesion. 5-ASA increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement. Moreover, 5-ASA treatment restored membranous expression of adhesion molecules E-cadherin and β-catenin. Role of GENE as a mediator of CHEMICAL activity was validated in vitro and in vivo. Inhibition of GENE by RNA interference also increased cell adhesion. GENE expression was elevated in APC(min) polyps and 5-ASA treatment reduced its expression. Our data demonstrates novel pharmacological mechanism of CHEMICAL in modulation of cell adhesion and role of GENE in APC(min) polyposis. We propose that inhibition of GENE expression by 5-ASA can impede with neoplastic progression in colorectal carcinogenesis. The mechanism of GENE inhibition and induction of membranous translocation of adhesion proteins by 5-ASA might be independent of its known anti-inflammatory action. | REGULATOR |
| Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1. Mesalamine (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon. Knowledge about the molecular and cellular targets of CHEMICAL is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking. We sought to identify molecular pathways interfered by CHEMICAL, using CRC cell lines with different genetic background. Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29). Filtering and analysis of data identified three oncogenic pathways interfered by 5-ASA: MAPK/ERK pathway, cell adhesion and β-catenin/Wnt signaling. PAK1 emerged as a consensus target of CHEMICAL, orchestrating these pathways. We further investigated the effect of CHEMICAL on cell adhesion. CHEMICAL increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement. Moreover, CHEMICAL treatment restored membranous expression of adhesion molecules GENE and β-catenin. Role of PAK1 as a mediator of mesalamine activity was validated in vitro and in vivo. Inhibition of PAK1 by RNA interference also increased cell adhesion. PAK1 expression was elevated in APC(min) polyps and CHEMICAL treatment reduced its expression. Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of PAK1 in APC(min) polyposis. We propose that inhibition of PAK1 expression by CHEMICAL can impede with neoplastic progression in colorectal carcinogenesis. The mechanism of PAK1 inhibition and induction of membranous translocation of adhesion proteins by CHEMICAL might be independent of its known anti-inflammatory action. | INDIRECT-DOWNREGULATOR |
| CHEMICAL modulates intercellular adhesion through inhibition of GENE. CHEMICAL (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon. Knowledge about the molecular and cellular targets of 5-ASA is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking. We sought to identify molecular pathways interfered by 5-ASA, using CRC cell lines with different genetic background. Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29). Filtering and analysis of data identified three oncogenic pathways interfered by 5-ASA: MAPK/ERK pathway, cell adhesion and β-catenin/Wnt signaling. PAK1 emerged as a consensus target of 5-ASA, orchestrating these pathways. We further investigated the effect of 5-ASA on cell adhesion. 5-ASA increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement. Moreover, 5-ASA treatment restored membranous expression of adhesion molecules E-cadherin and β-catenin. Role of PAK1 as a mediator of mesalamine activity was validated in vitro and in vivo. Inhibition of PAK1 by RNA interference also increased cell adhesion. PAK1 expression was elevated in APC(min) polyps and 5-ASA treatment reduced its expression. Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of PAK1 in APC(min) polyposis. We propose that inhibition of PAK1 expression by 5-ASA can impede with neoplastic progression in colorectal carcinogenesis. The mechanism of PAK1 inhibition and induction of membranous translocation of adhesion proteins by 5-ASA might be independent of its known anti-inflammatory action. | INHIBITOR |
| Cholestatic effect of epigallocatechin gallate in rats is mediated via decreased expression of Mrp2. Epigallocatechin gallate (EGCG) has been shown to be protective in various experimental models of liver injury, although opposite effects have also been reported. Since its effect on biliary physiology has not been thoroughly investigated, the present study evaluated effect of CHEMICAL on bile flow and bile acid homeostasis in rats. Compared to controls, CHEMICAL treatment decreased bile flow by 23%. Hepatic paracellular permeability and biliary bile acid excretion were not altered by CHEMICAL administration, but biliary glutathione excretion was reduced by 70%. Accordingly, the main glutathione transporter on the hepatocyte canalicular membrane, multidrug resistance-associated protein 2 (Mrp2), was significantly decreased at the protein level. CHEMICAL administration also doubled plasma bile acid levels compared to controls. While protein levels of the main hepatic bile acid transporters were unchanged, the rate-limiting enzyme in the bile acid synthesis, GENE, was significantly increased by CHEMICAL. Enhanced bile acid synthesis in these animals was also confirmed by a 2-fold increase in plasma marker 7α-hydroxy-4-cholesten-3-one. In contrast, CHEMICAL markedly downregulated major bile acid transporters (Asbt and Ostα) and regulatory molecules (Shp and Fgf15) in the ileum. When CHEMICAL was coadministered with ethinylestradiol, a potent cholestatic agent, it did not show any additional effect on the induced cholestasis. This study shows ability of CHEMICAL to raise plasma bile acid concentrations, mainly through GENE upregulation, and to decrease bile production through reduction in Mrp2-mediated bile acid-independent bile flow. In conclusion, our data demonstrate that under certain conditions CHEMICAL may induce cholestasis. | INDIRECT-UPREGULATOR |
| Cholestatic effect of epigallocatechin gallate in rats is mediated via decreased expression of Mrp2. Epigallocatechin gallate (EGCG) has been shown to be protective in various experimental models of liver injury, although opposite effects have also been reported. Since its effect on biliary physiology has not been thoroughly investigated, the present study evaluated effect of CHEMICAL on bile flow and bile acid homeostasis in rats. Compared to controls, CHEMICAL treatment decreased bile flow by 23%. Hepatic paracellular permeability and biliary bile acid excretion were not altered by CHEMICAL administration, but biliary glutathione excretion was reduced by 70%. Accordingly, the main glutathione transporter on the hepatocyte canalicular membrane, multidrug resistance-associated protein 2 (Mrp2), was significantly decreased at the protein level. CHEMICAL administration also doubled plasma bile acid levels compared to controls. While protein levels of the main hepatic GENE were unchanged, the rate-limiting enzyme in the bile acid synthesis, Cyp7a1, was significantly increased by CHEMICAL. Enhanced bile acid synthesis in these animals was also confirmed by a 2-fold increase in plasma marker 7α-hydroxy-4-cholesten-3-one. In contrast, CHEMICAL markedly downregulated major GENE (Asbt and Ostα) and regulatory molecules (Shp and Fgf15) in the ileum. When CHEMICAL was coadministered with ethinylestradiol, a potent cholestatic agent, it did not show any additional effect on the induced cholestasis. This study shows ability of CHEMICAL to raise plasma bile acid concentrations, mainly through Cyp7a1 upregulation, and to decrease bile production through reduction in Mrp2-mediated bile acid-independent bile flow. In conclusion, our data demonstrate that under certain conditions CHEMICAL may induce cholestasis. | INDIRECT-DOWNREGULATOR |
| Cholestatic effect of epigallocatechin gallate in rats is mediated via decreased expression of Mrp2. Epigallocatechin gallate (EGCG) has been shown to be protective in various experimental models of liver injury, although opposite effects have also been reported. Since its effect on biliary physiology has not been thoroughly investigated, the present study evaluated effect of CHEMICAL on bile flow and bile acid homeostasis in rats. Compared to controls, CHEMICAL treatment decreased bile flow by 23%. Hepatic paracellular permeability and biliary bile acid excretion were not altered by CHEMICAL administration, but biliary glutathione excretion was reduced by 70%. Accordingly, the main glutathione transporter on the hepatocyte canalicular membrane, multidrug resistance-associated protein 2 (Mrp2), was significantly decreased at the protein level. CHEMICAL administration also doubled plasma bile acid levels compared to controls. While protein levels of the main hepatic bile acid transporters were unchanged, the rate-limiting enzyme in the bile acid synthesis, Cyp7a1, was significantly increased by CHEMICAL. Enhanced bile acid synthesis in these animals was also confirmed by a 2-fold increase in plasma marker 7α-hydroxy-4-cholesten-3-one. In contrast, CHEMICAL markedly downregulated major bile acid transporters (GENE and Ostα) and regulatory molecules (Shp and Fgf15) in the ileum. When CHEMICAL was coadministered with ethinylestradiol, a potent cholestatic agent, it did not show any additional effect on the induced cholestasis. This study shows ability of CHEMICAL to raise plasma bile acid concentrations, mainly through Cyp7a1 upregulation, and to decrease bile production through reduction in Mrp2-mediated bile acid-independent bile flow. In conclusion, our data demonstrate that under certain conditions CHEMICAL may induce cholestasis. | INDIRECT-DOWNREGULATOR |
| Cholestatic effect of epigallocatechin gallate in rats is mediated via decreased expression of Mrp2. Epigallocatechin gallate (EGCG) has been shown to be protective in various experimental models of liver injury, although opposite effects have also been reported. Since its effect on biliary physiology has not been thoroughly investigated, the present study evaluated effect of CHEMICAL on bile flow and bile acid homeostasis in rats. Compared to controls, CHEMICAL treatment decreased bile flow by 23%. Hepatic paracellular permeability and biliary bile acid excretion were not altered by CHEMICAL administration, but biliary glutathione excretion was reduced by 70%. Accordingly, the main glutathione transporter on the hepatocyte canalicular membrane, multidrug resistance-associated protein 2 (Mrp2), was significantly decreased at the protein level. CHEMICAL administration also doubled plasma bile acid levels compared to controls. While protein levels of the main hepatic bile acid transporters were unchanged, the rate-limiting enzyme in the bile acid synthesis, Cyp7a1, was significantly increased by CHEMICAL. Enhanced bile acid synthesis in these animals was also confirmed by a 2-fold increase in plasma marker 7α-hydroxy-4-cholesten-3-one. In contrast, CHEMICAL markedly downregulated major bile acid transporters (Asbt and GENE) and regulatory molecules (Shp and Fgf15) in the ileum. When CHEMICAL was coadministered with ethinylestradiol, a potent cholestatic agent, it did not show any additional effect on the induced cholestasis. This study shows ability of CHEMICAL to raise plasma bile acid concentrations, mainly through Cyp7a1 upregulation, and to decrease bile production through reduction in Mrp2-mediated bile acid-independent bile flow. In conclusion, our data demonstrate that under certain conditions CHEMICAL may induce cholestasis. | INDIRECT-DOWNREGULATOR |
| Cholestatic effect of epigallocatechin gallate in rats is mediated via decreased expression of Mrp2. Epigallocatechin gallate (EGCG) has been shown to be protective in various experimental models of liver injury, although opposite effects have also been reported. Since its effect on biliary physiology has not been thoroughly investigated, the present study evaluated effect of CHEMICAL on bile flow and bile acid homeostasis in rats. Compared to controls, CHEMICAL treatment decreased bile flow by 23%. Hepatic paracellular permeability and biliary bile acid excretion were not altered by CHEMICAL administration, but biliary glutathione excretion was reduced by 70%. Accordingly, the main glutathione transporter on the hepatocyte canalicular membrane, multidrug resistance-associated protein 2 (Mrp2), was significantly decreased at the protein level. CHEMICAL administration also doubled plasma bile acid levels compared to controls. While protein levels of the main hepatic bile acid transporters were unchanged, the rate-limiting enzyme in the bile acid synthesis, Cyp7a1, was significantly increased by CHEMICAL. Enhanced bile acid synthesis in these animals was also confirmed by a 2-fold increase in plasma marker 7α-hydroxy-4-cholesten-3-one. In contrast, CHEMICAL markedly downregulated major bile acid transporters (Asbt and Ostα) and regulatory molecules (GENE and Fgf15) in the ileum. When CHEMICAL was coadministered with ethinylestradiol, a potent cholestatic agent, it did not show any additional effect on the induced cholestasis. This study shows ability of CHEMICAL to raise plasma bile acid concentrations, mainly through Cyp7a1 upregulation, and to decrease bile production through reduction in Mrp2-mediated bile acid-independent bile flow. In conclusion, our data demonstrate that under certain conditions CHEMICAL may induce cholestasis. | INDIRECT-DOWNREGULATOR |
| Cholestatic effect of epigallocatechin gallate in rats is mediated via decreased expression of Mrp2. Epigallocatechin gallate (EGCG) has been shown to be protective in various experimental models of liver injury, although opposite effects have also been reported. Since its effect on biliary physiology has not been thoroughly investigated, the present study evaluated effect of CHEMICAL on bile flow and bile acid homeostasis in rats. Compared to controls, CHEMICAL treatment decreased bile flow by 23%. Hepatic paracellular permeability and biliary bile acid excretion were not altered by CHEMICAL administration, but biliary glutathione excretion was reduced by 70%. Accordingly, the main glutathione transporter on the hepatocyte canalicular membrane, multidrug resistance-associated protein 2 (Mrp2), was significantly decreased at the protein level. CHEMICAL administration also doubled plasma bile acid levels compared to controls. While protein levels of the main hepatic bile acid transporters were unchanged, the rate-limiting enzyme in the bile acid synthesis, Cyp7a1, was significantly increased by CHEMICAL. Enhanced bile acid synthesis in these animals was also confirmed by a 2-fold increase in plasma marker 7α-hydroxy-4-cholesten-3-one. In contrast, CHEMICAL markedly downregulated major bile acid transporters (Asbt and Ostα) and regulatory molecules (Shp and GENE) in the ileum. When CHEMICAL was coadministered with ethinylestradiol, a potent cholestatic agent, it did not show any additional effect on the induced cholestasis. This study shows ability of CHEMICAL to raise plasma bile acid concentrations, mainly through Cyp7a1 upregulation, and to decrease bile production through reduction in Mrp2-mediated bile acid-independent bile flow. In conclusion, our data demonstrate that under certain conditions CHEMICAL may induce cholestasis. | INDIRECT-DOWNREGULATOR |
| Serotonin receptors of type 6 (5-HT6): from neuroscience to clinical pharmacology. The serotonin (5-HT) receptors of type 6 (GENE) are quite different from all other 5-HT receptors, as they include a short third cytoplasmatic loop and a long CHEMICAL-terminal tail, and one intron located in the middle of the third cytoplasmatic loop. A lot of controversies still exist regarding their binding affinity, effects of GENE ligands on brain catecholamines, behavioral syndromes regulated by them, and brain distribution. In spite of the lack of information on metabolic pattern of the various compounds, some of GENE receptor ligands entered the clinical development as potential anti-dementia, antipsychotic, antidepressant and anti-obese drugs. The present paper is a comprehensive review on the state of art of the GENE receptors, while highlighting the potential clinical applications of GENE receptor agonists/antagonists. | PART-OF |
| Serotonin receptors of type 6 (5-HT6): from neuroscience to clinical pharmacology. The GENE of type 6 (5-HT6) are quite different from all other 5-HT receptors, as they include a short third cytoplasmatic loop and a long CHEMICAL-terminal tail, and one intron located in the middle of the third cytoplasmatic loop. A lot of controversies still exist regarding their binding affinity, effects of 5-HT6 ligands on brain catecholamines, behavioral syndromes regulated by them, and brain distribution. In spite of the lack of information on metabolic pattern of the various compounds, some of 5-HT6 receptor ligands entered the clinical development as potential anti-dementia, antipsychotic, antidepressant and anti-obese drugs. The present paper is a comprehensive review on the state of art of the 5-HT6 receptors, while highlighting the potential clinical applications of 5-HT6 receptor agonists/antagonists. | PART-OF |
| Expression of cAMP-responsive element binding proteins (CREBs) in fast- and slow-twitch muscles: A signaling pathway to account for the synaptic expression of collagen-tailed subunit (ColQ) of acetylcholinesterase at the rat neuromuscular junction. The gene encoding the collagen-tailed subunit (ColQ) of acetylcholinesterase (AChE) contains two distinct promoters that drive the production of two ColQ mRNAs, ColQ-1 and GENE, in slow- and fast-twitch muscles, respectively. GENE is expressed at the neuromuscular junction (NMJ) in fast-twitch muscle, and this expression depends on trophic factors supplied by motor neurons signaling via a cAMP-dependent pathway in muscle. To further elucidate the molecular basis of ColQ-1a's synaptic expression, here we investigated the expression and localization of cAMP-responsive element binding protein (CREB) at the synaptic and extra-synaptic regions of fast- and slow-twitch muscles from adult rats. The total amount of active, phosphorylated CREB (P-CREB) present in slow-twitch soleus muscle was higher than that in fast-twitch tibialis muscle, but P-CREB was predominantly expressed in the fast-twitch muscle at NMJs. In contrast, P-CREB was detected in both synaptic and extra-synaptic regions of slow-twitch muscle. These results reveal, for the first time, the differential distribution of P-CREB in fast- and slow-twitch muscles, which might support the crucial role of CHEMICAL-dependent signaling in controlling the synapse-specific expression of GENE in fast-twitch muscles. | REGULATOR |
| CHEMICAL inhibits LPS plus IFN-γ-induced inflammatory response in astrocytes primary cultures. A large body of evidence suggests that the inflammatory reaction plays an important role in the pathogenesis of neurodegenerative diseases. Our previous studies described the neuroprotective effects of CHEMICAL in lipopolysaccharide (LPS)-induced inflammatory models, in which CHEMICAL was shown to prevent mesencephalic neuron death and ameliorate cognitive ability animals. To further investigate the protective effect and underlying mechanism of CHEMICAL, astrocytes were pretreated with low (0.1mM) and high dose (0.5mM) CHEMICAL for 1h prior to LPS plus interferon-γ stimulation. Biochemical analyses showed that NO and ROS production and GENE activity were significantly reduced by CHEMICAL. Data at transcriptional level also demonstrated that CHEMICAL potently attenuated gene expressions involved in inflammation, such as GENE, COX-2 and TLR4. In addition, our exploration further revealed that the suppressive action of CHEMICAL on inflammation was mediated via inhibiting nuclear factor-κB (NF-κB) activation. Collectively, these results suggest that CHEMICAL can exert inhibitory effects on the inflammatory reaction in astrocytes and that inactivation of NF-κB could be the major determinant for its anti-inflammatory mechanism. Therefore, CHEMICAL may potentially be a highly effective therapeutic agent in treating neurodegenerative diseases associated with inflammation. | INDIRECT-DOWNREGULATOR |
| CHEMICAL inhibits LPS plus IFN-γ-induced inflammatory response in astrocytes primary cultures. A large body of evidence suggests that the inflammatory reaction plays an important role in the pathogenesis of neurodegenerative diseases. Our previous studies described the neuroprotective effects of CHEMICAL in lipopolysaccharide (LPS)-induced inflammatory models, in which CHEMICAL was shown to prevent mesencephalic neuron death and ameliorate cognitive ability animals. To further investigate the protective effect and underlying mechanism of CHEMICAL, astrocytes were pretreated with low (0.1mM) and high dose (0.5mM) CHEMICAL for 1h prior to LPS plus interferon-γ stimulation. Biochemical analyses showed that NO and ROS production and iNOS activity were significantly reduced by CHEMICAL. Data at transcriptional level also demonstrated that CHEMICAL potently attenuated gene expressions involved in inflammation, such as iNOS, GENE and TLR4. In addition, our exploration further revealed that the suppressive action of CHEMICAL on inflammation was mediated via inhibiting nuclear factor-κB (NF-κB) activation. Collectively, these results suggest that CHEMICAL can exert inhibitory effects on the inflammatory reaction in astrocytes and that inactivation of NF-κB could be the major determinant for its anti-inflammatory mechanism. Therefore, CHEMICAL may potentially be a highly effective therapeutic agent in treating neurodegenerative diseases associated with inflammation. | INDIRECT-DOWNREGULATOR |
| CHEMICAL inhibits LPS plus IFN-γ-induced inflammatory response in astrocytes primary cultures. A large body of evidence suggests that the inflammatory reaction plays an important role in the pathogenesis of neurodegenerative diseases. Our previous studies described the neuroprotective effects of CHEMICAL in lipopolysaccharide (LPS)-induced inflammatory models, in which CHEMICAL was shown to prevent mesencephalic neuron death and ameliorate cognitive ability animals. To further investigate the protective effect and underlying mechanism of CHEMICAL, astrocytes were pretreated with low (0.1mM) and high dose (0.5mM) CHEMICAL for 1h prior to LPS plus interferon-γ stimulation. Biochemical analyses showed that NO and ROS production and iNOS activity were significantly reduced by CHEMICAL. Data at transcriptional level also demonstrated that CHEMICAL potently attenuated gene expressions involved in inflammation, such as iNOS, COX-2 and GENE. In addition, our exploration further revealed that the suppressive action of CHEMICAL on inflammation was mediated via inhibiting nuclear factor-κB (NF-κB) activation. Collectively, these results suggest that CHEMICAL can exert inhibitory effects on the inflammatory reaction in astrocytes and that inactivation of NF-κB could be the major determinant for its anti-inflammatory mechanism. Therefore, CHEMICAL may potentially be a highly effective therapeutic agent in treating neurodegenerative diseases associated with inflammation. | INDIRECT-DOWNREGULATOR |
| CHEMICAL inhibits LPS plus IFN-γ-induced inflammatory response in astrocytes primary cultures. A large body of evidence suggests that the inflammatory reaction plays an important role in the pathogenesis of neurodegenerative diseases. Our previous studies described the neuroprotective effects of CHEMICAL in lipopolysaccharide (LPS)-induced inflammatory models, in which CHEMICAL was shown to prevent mesencephalic neuron death and ameliorate cognitive ability animals. To further investigate the protective effect and underlying mechanism of CHEMICAL, astrocytes were pretreated with low (0.1mM) and high dose (0.5mM) CHEMICAL for 1h prior to LPS plus interferon-γ stimulation. Biochemical analyses showed that NO and ROS production and iNOS activity were significantly reduced by CHEMICAL. Data at transcriptional level also demonstrated that CHEMICAL potently attenuated gene expressions involved in inflammation, such as iNOS, COX-2 and TLR4. In addition, our exploration further revealed that the suppressive action of CHEMICAL on inflammation was mediated via inhibiting nuclear factor-κB (GENE) activation. Collectively, these results suggest that CHEMICAL can exert inhibitory effects on the inflammatory reaction in astrocytes and that inactivation of GENE could be the major determinant for its anti-inflammatory mechanism. Therefore, CHEMICAL may potentially be a highly effective therapeutic agent in treating neurodegenerative diseases associated with inflammation. | INHIBITOR |
| CHEMICAL inhibits LPS plus IFN-γ-induced inflammatory response in astrocytes primary cultures. A large body of evidence suggests that the inflammatory reaction plays an important role in the pathogenesis of neurodegenerative diseases. Our previous studies described the neuroprotective effects of CHEMICAL in lipopolysaccharide (LPS)-induced inflammatory models, in which CHEMICAL was shown to prevent mesencephalic neuron death and ameliorate cognitive ability animals. To further investigate the protective effect and underlying mechanism of CHEMICAL, astrocytes were pretreated with low (0.1mM) and high dose (0.5mM) CHEMICAL for 1h prior to LPS plus interferon-γ stimulation. Biochemical analyses showed that NO and ROS production and iNOS activity were significantly reduced by CHEMICAL. Data at transcriptional level also demonstrated that CHEMICAL potently attenuated gene expressions involved in inflammation, such as iNOS, COX-2 and TLR4. In addition, our exploration further revealed that the suppressive action of CHEMICAL on inflammation was mediated via inhibiting GENE (NF-κB) activation. Collectively, these results suggest that CHEMICAL can exert inhibitory effects on the inflammatory reaction in astrocytes and that inactivation of NF-κB could be the major determinant for its anti-inflammatory mechanism. Therefore, CHEMICAL may potentially be a highly effective therapeutic agent in treating neurodegenerative diseases associated with inflammation. | INHIBITOR |
| CHEMICAL inhibits LPS plus GENE-induced inflammatory response in astrocytes primary cultures. A large body of evidence suggests that the inflammatory reaction plays an important role in the pathogenesis of neurodegenerative diseases. Our previous studies described the neuroprotective effects of catalpol in lipopolysaccharide (LPS)-induced inflammatory models, in which catalpol was shown to prevent mesencephalic neuron death and ameliorate cognitive ability animals. To further investigate the protective effect and underlying mechanism of catalpol, astrocytes were pretreated with low (0.1mM) and high dose (0.5mM) catalpol for 1h prior to LPS plus interferon-γ stimulation. Biochemical analyses showed that NO and ROS production and iNOS activity were significantly reduced by catalpol. Data at transcriptional level also demonstrated that catalpol potently attenuated gene expressions involved in inflammation, such as iNOS, COX-2 and TLR4. In addition, our exploration further revealed that the suppressive action of catalpol on inflammation was mediated via inhibiting nuclear factor-κB (NF-κB) activation. Collectively, these results suggest that catalpol can exert inhibitory effects on the inflammatory reaction in astrocytes and that inactivation of NF-κB could be the major determinant for its anti-inflammatory mechanism. Therefore, catalpol may potentially be a highly effective therapeutic agent in treating neurodegenerative diseases associated with inflammation. | INHIBITOR |
| GENE inhibitory effect by dammarane-type triterpenes from hydrolyzate of total Gynostemma pentaphyllum CHEMICAL. GENE (PTP1B) is an important factor in non-insulin-dependent diabetes mellitus (type-2 diabetes), and a promising target for treatment of diabetes and obesity. Therefore, the aim of this study is to investigate the inhibitory activities of constituents (three new together with twelve known triterpenes compounds) isolated from the hydrolyzate of total CHEMICAL from Gynostemma pentaphyllum. Their structures were accomplished mainly base on the spectroscopic methods, and then were further confirmed by X-ray crystal diffraction. All the compounds were evaluated for inhibitory activity against PTP1B. Current data suggested that the compounds 1, 3, 12, 13 and 14 were considered to be potential as antidiabetic agents, in which they could significantly inhibit the PTP1B enzyme activity in a dose-dependent manner. | INHIBITOR |
| GENE inhibitory effect by CHEMICAL-type triterpenes from hydrolyzate of total Gynostemma pentaphyllum saponins. GENE (PTP1B) is an important factor in non-insulin-dependent diabetes mellitus (type-2 diabetes), and a promising target for treatment of diabetes and obesity. Therefore, the aim of this study is to investigate the inhibitory activities of constituents (three new together with twelve known triterpenes compounds) isolated from the hydrolyzate of total saponins from Gynostemma pentaphyllum. Their structures were accomplished mainly base on the spectroscopic methods, and then were further confirmed by X-ray crystal diffraction. All the compounds were evaluated for inhibitory activity against PTP1B. Current data suggested that the compounds 1, 3, 12, 13 and 14 were considered to be potential as antidiabetic agents, in which they could significantly inhibit the PTP1B enzyme activity in a dose-dependent manner. | INHIBITOR |
| GENE inhibitory effect by dammarane-type CHEMICAL from hydrolyzate of total Gynostemma pentaphyllum saponins. GENE (PTP1B) is an important factor in non-insulin-dependent diabetes mellitus (type-2 diabetes), and a promising target for treatment of diabetes and obesity. Therefore, the aim of this study is to investigate the inhibitory activities of constituents (three new together with twelve known CHEMICAL compounds) isolated from the hydrolyzate of total saponins from Gynostemma pentaphyllum. Their structures were accomplished mainly base on the spectroscopic methods, and then were further confirmed by X-ray crystal diffraction. All the compounds were evaluated for inhibitory activity against PTP1B. Current data suggested that the compounds 1, 3, 12, 13 and 14 were considered to be potential as antidiabetic agents, in which they could significantly inhibit the PTP1B enzyme activity in a dose-dependent manner. | INHIBITOR |
| Disrupted cytoskeletal homeostasis, astrogliosis and apoptotic cell death in the cerebellum of preweaning rats injected with diphenyl ditelluride. In the present report 15 day-old rats were injected with 0.3μmol of diphenyl ditelluride (PhTe)(2)/kg body weight and parameters of neurodegeneration were analyzed in slices from cerebellum 3 and 6 days afterwards. The earlier responses, at day 3 after injection, included hyperphosphorylation of intermediate filament (IF) proteins from astrocyte (glial fibrillary acidic protein - GFAP - and vimentin) and neuron (low-, medium- and high molecular weight neurofilament subunits: NF-L, NF-M and NF-H); increased mitogen-activated protein kinase (MAPK) (Erk and p38MAPK) and cAMP-dependent protein kinase (PKA) activities. Also, reactive astrogliosis takes part of the early responses to the insult with CHEMICAL, evidenced by upregulated GFAP in Western blot, PCR and immunofluorescence analysis. Six days after CHEMICAL injection we found persistent astrogliosis, increased propidium iodide (PI) positive cells in NeuN positive population evidenced by flow cytometry and reduced immunofluorescence for NeuN, suggesting that the in vivo exposure to CHEMICAL progressed to neuronal death. Moreover, activated caspase 3 suggested apoptotic neuronal death. Neurodegeneration was related with decreased [(3)H]glutamate uptake and decreased Akt immunoreactivity, however GENE (Ser9) was not altered in CHEMICAL injected rat. Therefore, the present results show that the earlier cerebellar responses to CHEMICAL include disruption of cytoskeletal homeostasis that could be related with MAPK and PKA activation and reactive astrogliosis. Akt inhibition observed at this time could also play a role in the neuronal death evidenced afterwards. The later events of the neurodegenerative process are characterized by persistent astrogliosis and activation of apoptotic neuronal death through caspase 3 mediated mechanisms, which could be related with glutamate excitotoxicity. The progression of these responses are therefore likely to be critical for the outcome of the neurodegeneration provoked by CHEMICAL in rat cerebellum. | NO-RELATIONSHIP |
| Disrupted cytoskeletal homeostasis, astrogliosis and apoptotic cell death in the cerebellum of preweaning rats injected with diphenyl ditelluride. In the present report 15 day-old rats were injected with 0.3μmol of diphenyl ditelluride (PhTe)(2)/kg body weight and parameters of neurodegeneration were analyzed in slices from cerebellum 3 and 6 days afterwards. The earlier responses, at day 3 after injection, included hyperphosphorylation of intermediate filament (IF) proteins from astrocyte (glial fibrillary acidic protein - GFAP - and vimentin) and neuron (low-, medium- and high molecular weight neurofilament subunits: NF-L, NF-M and NF-H); increased mitogen-activated protein kinase (MAPK) (Erk and p38MAPK) and cAMP-dependent protein kinase (PKA) activities. Also, reactive astrogliosis takes part of the early responses to the insult with (PhTe)(2), evidenced by upregulated GFAP in Western blot, PCR and immunofluorescence analysis. Six days after (PhTe)(2) injection we found persistent astrogliosis, increased propidium iodide (PI) positive cells in NeuN positive population evidenced by flow cytometry and reduced immunofluorescence for NeuN, suggesting that the in vivo exposure to (PhTe)(2) progressed to neuronal death. Moreover, activated caspase 3 suggested apoptotic neuronal death. Neurodegeneration was related with decreased [(3)H]glutamate uptake and decreased Akt immunoreactivity, however GENE (CHEMICAL9) was not altered in (PhTe)(2) injected rat. Therefore, the present results show that the earlier cerebellar responses to (PhTe)(2) include disruption of cytoskeletal homeostasis that could be related with MAPK and PKA activation and reactive astrogliosis. Akt inhibition observed at this time could also play a role in the neuronal death evidenced afterwards. The later events of the neurodegenerative process are characterized by persistent astrogliosis and activation of apoptotic neuronal death through caspase 3 mediated mechanisms, which could be related with glutamate excitotoxicity. The progression of these responses are therefore likely to be critical for the outcome of the neurodegeneration provoked by (PhTe)(2) in rat cerebellum. | NO-RELATIONSHIP |
| Disrupted cytoskeletal homeostasis, astrogliosis and apoptotic cell death in the cerebellum of preweaning rats injected with diphenyl ditelluride. In the present report 15 day-old rats were injected with 0.3μmol of diphenyl ditelluride (PhTe)(2)/kg body weight and parameters of neurodegeneration were analyzed in slices from cerebellum 3 and 6 days afterwards. The earlier responses, at day 3 after injection, included hyperphosphorylation of intermediate filament (IF) proteins from astrocyte (glial fibrillary acidic protein - GFAP - and vimentin) and neuron (low-, medium- and high molecular weight neurofilament subunits: NF-L, NF-M and NF-H); increased mitogen-activated protein kinase (MAPK) (Erk and p38MAPK) and cAMP-dependent protein kinase (PKA) activities. Also, reactive astrogliosis takes part of the early responses to the insult with CHEMICAL, evidenced by upregulated GFAP in Western blot, PCR and immunofluorescence analysis. Six days after CHEMICAL injection we found persistent astrogliosis, increased propidium iodide (PI) positive cells in NeuN positive population evidenced by flow cytometry and reduced immunofluorescence for NeuN, suggesting that the in vivo exposure to CHEMICAL progressed to neuronal death. Moreover, activated caspase 3 suggested apoptotic neuronal death. Neurodegeneration was related with decreased [(3)H]glutamate uptake and decreased Akt immunoreactivity, however phospho-GSK-3-β (Ser9) was not altered in CHEMICAL injected rat. Therefore, the present results show that the earlier cerebellar responses to CHEMICAL include disruption of cytoskeletal homeostasis that could be related with GENE and PKA activation and reactive astrogliosis. Akt inhibition observed at this time could also play a role in the neuronal death evidenced afterwards. The later events of the neurodegenerative process are characterized by persistent astrogliosis and activation of apoptotic neuronal death through caspase 3 mediated mechanisms, which could be related with glutamate excitotoxicity. The progression of these responses are therefore likely to be critical for the outcome of the neurodegeneration provoked by CHEMICAL in rat cerebellum. | ACTIVATOR |
| Disrupted cytoskeletal homeostasis, astrogliosis and apoptotic cell death in the cerebellum of preweaning rats injected with diphenyl ditelluride. In the present report 15 day-old rats were injected with 0.3μmol of diphenyl ditelluride (PhTe)(2)/kg body weight and parameters of neurodegeneration were analyzed in slices from cerebellum 3 and 6 days afterwards. The earlier responses, at day 3 after injection, included hyperphosphorylation of intermediate filament (IF) proteins from astrocyte (glial fibrillary acidic protein - GFAP - and vimentin) and neuron (low-, medium- and high molecular weight neurofilament subunits: NF-L, NF-M and NF-H); increased mitogen-activated protein kinase (MAPK) (Erk and p38MAPK) and cAMP-dependent protein kinase (PKA) activities. Also, reactive astrogliosis takes part of the early responses to the insult with CHEMICAL, evidenced by upregulated GFAP in Western blot, PCR and immunofluorescence analysis. Six days after CHEMICAL injection we found persistent astrogliosis, increased propidium iodide (PI) positive cells in NeuN positive population evidenced by flow cytometry and reduced immunofluorescence for NeuN, suggesting that the in vivo exposure to CHEMICAL progressed to neuronal death. Moreover, activated caspase 3 suggested apoptotic neuronal death. Neurodegeneration was related with decreased [(3)H]glutamate uptake and decreased Akt immunoreactivity, however phospho-GSK-3-β (Ser9) was not altered in CHEMICAL injected rat. Therefore, the present results show that the earlier cerebellar responses to CHEMICAL include disruption of cytoskeletal homeostasis that could be related with MAPK and GENE activation and reactive astrogliosis. Akt inhibition observed at this time could also play a role in the neuronal death evidenced afterwards. The later events of the neurodegenerative process are characterized by persistent astrogliosis and activation of apoptotic neuronal death through caspase 3 mediated mechanisms, which could be related with glutamate excitotoxicity. The progression of these responses are therefore likely to be critical for the outcome of the neurodegeneration provoked by CHEMICAL in rat cerebellum. | ACTIVATOR |
| Disrupted cytoskeletal homeostasis, astrogliosis and apoptotic cell death in the cerebellum of preweaning rats injected with diphenyl ditelluride. In the present report 15 day-old rats were injected with 0.3μmol of diphenyl ditelluride (PhTe)(2)/kg body weight and parameters of neurodegeneration were analyzed in slices from cerebellum 3 and 6 days afterwards. The earlier responses, at day 3 after injection, included hyperphosphorylation of intermediate filament (IF) proteins from astrocyte (glial fibrillary acidic protein - GENE - and vimentin) and neuron (low-, medium- and high molecular weight neurofilament subunits: NF-L, NF-M and NF-H); increased mitogen-activated protein kinase (MAPK) (Erk and p38MAPK) and cAMP-dependent protein kinase (PKA) activities. Also, reactive astrogliosis takes part of the early responses to the insult with CHEMICAL, evidenced by upregulated GENE in Western blot, PCR and immunofluorescence analysis. Six days after CHEMICAL injection we found persistent astrogliosis, increased propidium iodide (PI) positive cells in NeuN positive population evidenced by flow cytometry and reduced immunofluorescence for NeuN, suggesting that the in vivo exposure to CHEMICAL progressed to neuronal death. Moreover, activated caspase 3 suggested apoptotic neuronal death. Neurodegeneration was related with decreased [(3)H]glutamate uptake and decreased Akt immunoreactivity, however phospho-GSK-3-β (Ser9) was not altered in CHEMICAL injected rat. Therefore, the present results show that the earlier cerebellar responses to CHEMICAL include disruption of cytoskeletal homeostasis that could be related with MAPK and PKA activation and reactive astrogliosis. Akt inhibition observed at this time could also play a role in the neuronal death evidenced afterwards. The later events of the neurodegenerative process are characterized by persistent astrogliosis and activation of apoptotic neuronal death through caspase 3 mediated mechanisms, which could be related with glutamate excitotoxicity. The progression of these responses are therefore likely to be critical for the outcome of the neurodegeneration provoked by CHEMICAL in rat cerebellum. | ACTIVATOR |
| Disrupted cytoskeletal homeostasis, astrogliosis and apoptotic cell death in the cerebellum of preweaning rats injected with diphenyl ditelluride. In the present report 15 day-old rats were injected with 0.3μmol of diphenyl ditelluride (PhTe)(2)/kg body weight and parameters of neurodegeneration were analyzed in slices from cerebellum 3 and 6 days afterwards. The earlier responses, at day 3 after injection, included hyperphosphorylation of intermediate filament (IF) proteins from astrocyte (glial fibrillary acidic protein - GFAP - and vimentin) and neuron (low-, medium- and high molecular weight neurofilament subunits: NF-L, NF-M and NF-H); increased mitogen-activated protein kinase (MAPK) (Erk and p38MAPK) and cAMP-dependent protein kinase (PKA) activities. Also, reactive astrogliosis takes part of the early responses to the insult with CHEMICAL, evidenced by upregulated GFAP in Western blot, PCR and immunofluorescence analysis. Six days after CHEMICAL injection we found persistent astrogliosis, increased propidium iodide (PI) positive cells in GENE positive population evidenced by flow cytometry and reduced immunofluorescence for GENE, suggesting that the in vivo exposure to CHEMICAL progressed to neuronal death. Moreover, activated caspase 3 suggested apoptotic neuronal death. Neurodegeneration was related with decreased [(3)H]glutamate uptake and decreased Akt immunoreactivity, however phospho-GSK-3-β (Ser9) was not altered in CHEMICAL injected rat. Therefore, the present results show that the earlier cerebellar responses to CHEMICAL include disruption of cytoskeletal homeostasis that could be related with MAPK and PKA activation and reactive astrogliosis. Akt inhibition observed at this time could also play a role in the neuronal death evidenced afterwards. The later events of the neurodegenerative process are characterized by persistent astrogliosis and activation of apoptotic neuronal death through caspase 3 mediated mechanisms, which could be related with glutamate excitotoxicity. The progression of these responses are therefore likely to be critical for the outcome of the neurodegeneration provoked by CHEMICAL in rat cerebellum. | INDIRECT-DOWNREGULATOR |
| Disrupted cytoskeletal homeostasis, astrogliosis and apoptotic cell death in the cerebellum of preweaning rats injected with diphenyl ditelluride. In the present report 15 day-old rats were injected with 0.3μmol of diphenyl ditelluride (PhTe)(2)/kg body weight and parameters of neurodegeneration were analyzed in slices from cerebellum 3 and 6 days afterwards. The earlier responses, at day 3 after injection, included hyperphosphorylation of intermediate filament (IF) proteins from astrocyte (glial fibrillary acidic protein - GFAP - and vimentin) and neuron (low-, medium- and high molecular weight neurofilament subunits: NF-L, NF-M and NF-H); increased mitogen-activated protein kinase (MAPK) (Erk and p38MAPK) and cAMP-dependent protein kinase (PKA) activities. Also, reactive astrogliosis takes part of the early responses to the insult with CHEMICAL, evidenced by upregulated GFAP in Western blot, PCR and immunofluorescence analysis. Six days after CHEMICAL injection we found persistent astrogliosis, increased propidium iodide (PI) positive cells in NeuN positive population evidenced by flow cytometry and reduced immunofluorescence for NeuN, suggesting that the in vivo exposure to CHEMICAL progressed to neuronal death. Moreover, activated caspase 3 suggested apoptotic neuronal death. Neurodegeneration was related with decreased [(3)H]glutamate uptake and decreased GENE immunoreactivity, however phospho-GSK-3-β (Ser9) was not altered in CHEMICAL injected rat. Therefore, the present results show that the earlier cerebellar responses to CHEMICAL include disruption of cytoskeletal homeostasis that could be related with MAPK and PKA activation and reactive astrogliosis. GENE inhibition observed at this time could also play a role in the neuronal death evidenced afterwards. The later events of the neurodegenerative process are characterized by persistent astrogliosis and activation of apoptotic neuronal death through caspase 3 mediated mechanisms, which could be related with glutamate excitotoxicity. The progression of these responses are therefore likely to be critical for the outcome of the neurodegeneration provoked by CHEMICAL in rat cerebellum. | INHIBITOR |
| Profluorogenic reductase substrate for rapid, selective, and sensitive visualization and detection of human cancer cells that overexpress NQO1. Achieving the vision of identifying and quantifying cancer-related events and targets for future personalized oncology is predicated on the existence of synthetically accessible and economically viable probe molecules fully able to report the presence of these events and targets in a rapid and highly selective and sensitive fashion. Delineated here are the design and evaluation of a newly synthesized turn-on probe whose intense fluorescent reporter signature is revealed only through probe activation by a specific intracellular enzyme present in tumor cells of multiple origins. Quenching of molecular probe fluorescence is achieved through unique photoinduced electron transfer between the naphthalimide dye reporter and a covalently attached, quinone-based enzyme substrate. Fluorescence of the reporter dye is turned on by rapid removal of the CHEMICAL quencher, an event that immediately occurs only after highly selective, two-electron reduction of the sterically and conformationally restricted CHEMICAL substrate by the cancer-associated GENE (hNQO1). Successes of the approach include rapid differentiation of NQO1-expressing and -nonexpressing cancer cell lines via the unaided eye, flow cytometry, fluorescence imaging, and two-photon microscopy. The potential for use of the turn-on probe in longer-term cellular studies is indicated by its lack of influence on cell viability and its in vitro stability. | SUBSTRATE |
| Profluorogenic reductase substrate for rapid, selective, and sensitive visualization and detection of human cancer cells that overexpress NQO1. Achieving the vision of identifying and quantifying cancer-related events and targets for future personalized oncology is predicated on the existence of synthetically accessible and economically viable probe molecules fully able to report the presence of these events and targets in a rapid and highly selective and sensitive fashion. Delineated here are the design and evaluation of a newly synthesized turn-on probe whose intense fluorescent reporter signature is revealed only through probe activation by a specific intracellular enzyme present in tumor cells of multiple origins. Quenching of molecular probe fluorescence is achieved through unique photoinduced electron transfer between the naphthalimide dye reporter and a covalently attached, quinone-based enzyme substrate. Fluorescence of the reporter dye is turned on by rapid removal of the CHEMICAL quencher, an event that immediately occurs only after highly selective, two-electron reduction of the sterically and conformationally restricted CHEMICAL substrate by the cancer-associated human NAD(P)H:quinone oxidoreductase isozyme 1 (GENE). Successes of the approach include rapid differentiation of NQO1-expressing and -nonexpressing cancer cell lines via the unaided eye, flow cytometry, fluorescence imaging, and two-photon microscopy. The potential for use of the turn-on probe in longer-term cellular studies is indicated by its lack of influence on cell viability and its in vitro stability. | SUBSTRATE |
| Synthesis, biological evaluation, and molecular modeling of CHEMICAL derivatives as potent GENE inhibitors with anti-heart-failure activity in vivo. Novel CHEMICAL (GL) derivatives were designed and synthesized by introducing various amine or amino acid residues into the carbohydrate chain and at C-30. Their inhibitory effects on high-mobility group box 1 (HMGB1) were evaluated using a cell-based lipopolysaccharide (LPS) induced tumor necrosis factor α (TNF-α) release study. Compounds 10, 12, 18-20, 23, and 24, which had substituents introduced at C-30, demonstrated moderate HMGB1 inhibition with ED₅₀ values ranging from 337 to 141 μM, which are values comparable to that of the leading GL compound (1) (ED₅₀ = 70 μM). Compounds 23 and 24 emerged as novel and interesting HMGB1 inhibitors. These compounds were able to extend the survival of mice with chronic heart failure (CHF) and acute heart failure (AHF), respectively. In addition, molecular modeling studies were performed to support the biological data. | INHIBITOR |
| Further exploration of M₁ allosteric agonists: subtle structural changes abolish M₁ allosteric agonism and result in pan-mAChR orthosteric antagonism. This letter describes the further exploration of two series of M(1) allosteric agonists, TBPB and VU0357017, previously reported from our lab. Within the CHEMICAL scaffold, either electronic or steric perturbations to the central piperidine ring led to a loss of selective M(1) allosteric agonism and afforded pan-GENE antagonism, which was demonstrated to be mediated via the orthosteric site. Additional SAR around a related M(1) allosteric agonist family (VU0357017) identified similar, subtle 'molecular switches' that modulated modes of pharmacology from allosteric agonism to pan-mAChR orthosteric antagonism. Therefore, all of these ligands are best classified as bi-topic ligands that possess high affinity binding at an allosteric site to engender selective M(1) activation, but all bind, at higher concentrations, to the orthosteric ACh site, leading to non-selective orthosteric site binding and GENE antagonism. | INHIBITOR |
| Further exploration of M₁ allosteric agonists: subtle structural changes abolish M₁ allosteric agonism and result in pan-mAChR orthosteric antagonism. This letter describes the further exploration of two series of M(1) allosteric agonists, TBPB and VU0357017, previously reported from our lab. Within the TPBP scaffold, either electronic or steric perturbations to the central CHEMICAL ring led to a loss of selective M(1) allosteric agonism and afforded pan-GENE antagonism, which was demonstrated to be mediated via the orthosteric site. Additional SAR around a related M(1) allosteric agonist family (VU0357017) identified similar, subtle 'molecular switches' that modulated modes of pharmacology from allosteric agonism to pan-mAChR orthosteric antagonism. Therefore, all of these ligands are best classified as bi-topic ligands that possess high affinity binding at an allosteric site to engender selective M(1) activation, but all bind, at higher concentrations, to the orthosteric ACh site, leading to non-selective orthosteric site binding and GENE antagonism. | INHIBITOR |
| Further exploration of M₁ allosteric agonists: subtle structural changes abolish M₁ allosteric agonism and result in pan-mAChR orthosteric antagonism. This letter describes the further exploration of two series of M(1) allosteric agonists, TBPB and CHEMICAL, previously reported from our lab. Within the TPBP scaffold, either electronic or steric perturbations to the central piperidine ring led to a loss of selective M(1) allosteric agonism and afforded pan-mAChR antagonism, which was demonstrated to be mediated via the orthosteric site. Additional SAR around a related M(1) allosteric agonist family (CHEMICAL) identified similar, subtle 'molecular switches' that modulated modes of pharmacology from allosteric agonism to pan-GENE orthosteric antagonism. Therefore, all of these ligands are best classified as bi-topic ligands that possess high affinity binding at an allosteric site to engender selective M(1) activation, but all bind, at higher concentrations, to the orthosteric ACh site, leading to non-selective orthosteric site binding and GENE antagonism. | ACTIVATOR |
| Effects of single or repeated silymarin administration on pharmacokinetics of CHEMICAL and its major metabolite, 9-hydroxyrisperidone in rats. 1. The interactions between herbal dietary supplements and therapeutic drugs have emerged as an important issue and P-glycoprotein (P-gp) has been reported as one of the significant factors of these interactions. 2. The objective of this article is to examine the effects of single and repeated administrations of silymarin on pharmacokinetics of a GENE substrate, CHEMICAL, and its major metabolite, 9-hydroxyrisperidone, in rats. 3. To determine the plasma levels of CHEMICAL and 9-hydroxyrisperidone in rats, a HPLC method was developed using a liquid-liquid acid back extraction. When CHEMICAL (6 mg/kg) was co-administered with silymarin (40 mg/kg) to rats orally, the C(max) of 9-hydroxyrisperidone was significantly increased to1.3-fold (p < 0.05), while the other pharmacokinetic parameters did not show any significant differences. Expanding the experiment where rats were repeatedly administered with silymarin for 5 days prior to giving CHEMICAL, the C(max) of CHEMICAL and 9-hydroxyrisperidone were significantly increased to 2.4-fold (p < 0.001) and 1.7-fold (p < 0.001), respectively, and the AUC(0-t), as well to 1.7-fold (p < 0.05) and 2.1-fold (p < 0.01), respectively. 4. The repeated exposures of silymarin, compared to single administration of silymarin, increased oral bioavailability and affected the pharmacokinetics of CHEMICAL and 9-hydroxyrisperidone, by inhibiting GENE. | SUBSTRATE |
| Effects of single or repeated silymarin administration on pharmacokinetics of risperidone and its major metabolite, CHEMICAL in rats. 1. The interactions between herbal dietary supplements and therapeutic drugs have emerged as an important issue and P-glycoprotein (P-gp) has been reported as one of the significant factors of these interactions. 2. The objective of this article is to examine the effects of single and repeated administrations of silymarin on pharmacokinetics of a GENE substrate, risperidone, and its major metabolite, CHEMICAL, in rats. 3. To determine the plasma levels of risperidone and CHEMICAL in rats, a HPLC method was developed using a liquid-liquid acid back extraction. When risperidone (6 mg/kg) was co-administered with silymarin (40 mg/kg) to rats orally, the C(max) of CHEMICAL was significantly increased to1.3-fold (p < 0.05), while the other pharmacokinetic parameters did not show any significant differences. Expanding the experiment where rats were repeatedly administered with silymarin for 5 days prior to giving risperidone, the C(max) of risperidone and CHEMICAL were significantly increased to 2.4-fold (p < 0.001) and 1.7-fold (p < 0.001), respectively, and the AUC(0-t), as well to 1.7-fold (p < 0.05) and 2.1-fold (p < 0.01), respectively. 4. The repeated exposures of silymarin, compared to single administration of silymarin, increased oral bioavailability and affected the pharmacokinetics of risperidone and CHEMICAL, by inhibiting GENE. | SUBSTRATE |
| Design, synthesis and structure-activity relationship of new GENE analogues containing proline derivatives in position 2. In this study, we present the synthesis and pharmacological properties of new analogues of GENE modified in the CHEMICAL-terminal part of the molecule with proline derivatives: indoline-2-carboxylic acid (Ica) and (2S,4R)-4-(naphthalene-2-ylmethyl)pyrrolidine-2-carboxylic acid. All the peptides were tested for pressor, antidiuretic and in vitro uterotonic activities. We also determined their binding affinity to the human oxytocin receptor. The Ica(2) substitution resulted in two moderately potent and selective antioxytocic agents: [Mpa(1), Ica(2), D-Arg(8)]VP and [Mpa(1),Ica(2),Val(4),D-Arg(8)]VP (pA(2) = 7.09 and 7.50, respectively). On the other hand, peptides modified with (2S,4R)-4-(naphthalene-2-ylmethyl)pyrrolidine-2-carboxylic acid, apart from their moderate antioxytocic activity, turned out to be weak antagonists of the pressor response to GENE. The results of this study provide useful information about the structure-activity relationship of GENE analogues and can help to design compounds with desired biological properties. | PART-OF |
| Design, synthesis and structure-activity relationship of new GENE analogues containing proline derivatives in position 2. In this study, we present the synthesis and pharmacological properties of new analogues of GENE modified in the N-terminal part of the molecule with proline derivatives: indoline-2-carboxylic acid (Ica) and CHEMICAL. All the peptides were tested for pressor, antidiuretic and in vitro uterotonic activities. We also determined their binding affinity to the human oxytocin receptor. The Ica(2) substitution resulted in two moderately potent and selective antioxytocic agents: [Mpa(1), Ica(2), D-Arg(8)]VP and [Mpa(1),Ica(2),Val(4),D-Arg(8)]VP (pA(2) = 7.09 and 7.50, respectively). On the other hand, peptides modified with CHEMICAL, apart from their moderate antioxytocic activity, turned out to be weak antagonists of the pressor response to GENE. The results of this study provide useful information about the structure-activity relationship of GENE analogues and can help to design compounds with desired biological properties. | INHIBITOR |
| Liver X Receptors and female reproduction: when cholesterol meets fertility! The role of cholesterol in female reproductive physiology has been suspected for a long time, while the molecular bases were unknown. Cholesterol is the precursor of ovarian steroid biosynthesis and is also essential for fertility. In the uterus, cholesterol is essential to achieve correct contractions at term, but an excessive uterine cholesterol concentration has been associated with contractility defects. GENE and LXR β are nuclear receptors activated by CHEMICAL, oxidized derivatives of cholesterol. Since their discovery, the role of LXR in the control of cholesterol homeostasis has been widely described. Beyond their cholesterol-lowering role, more recent data have linked these nuclear receptors to various physiological processes. In particular, they control ovarian endocrine and exocrine functions, as well as uterine contractility. Their contribution to female reproductive cancers will also be discussed. This review will try to enlighten on the LXR as a molecular link between dietary cholesterol and reproductive diseases in women. In the future, a better comprehension of the various physiological processes regulated by the LXR will help to develop new ligands to prevent or to cure these pathologies in women. | ACTIVATOR |
| Liver X Receptors and female reproduction: when cholesterol meets fertility! The role of cholesterol in female reproductive physiology has been suspected for a long time, while the molecular bases were unknown. Cholesterol is the precursor of ovarian steroid biosynthesis and is also essential for fertility. In the uterus, cholesterol is essential to achieve correct contractions at term, but an excessive uterine cholesterol concentration has been associated with contractility defects. Liver X Receptor (LXR) α and GENE are nuclear receptors activated by CHEMICAL, oxidized derivatives of cholesterol. Since their discovery, the role of LXR in the control of cholesterol homeostasis has been widely described. Beyond their cholesterol-lowering role, more recent data have linked these nuclear receptors to various physiological processes. In particular, they control ovarian endocrine and exocrine functions, as well as uterine contractility. Their contribution to female reproductive cancers will also be discussed. This review will try to enlighten on the LXR as a molecular link between dietary cholesterol and reproductive diseases in women. In the future, a better comprehension of the various physiological processes regulated by the LXR will help to develop new ligands to prevent or to cure these pathologies in women. | ACTIVATOR |
| GENE regulates GnRH-induced FSHβ gene expression. The regulation of gonadotropin synthesis by CHEMICAL plays an essential role in the neuroendocrine control of reproduction. The known signaling mechanisms involved in gonadotropin synthesis have been expanding. For example, involvement of GENE in LHβ induction by CHEMICAL has been discovered. We examined the role of GENE in FSHβ gene expression in LβT2 gonadotrope cells. CHEMICAL caused a sustained increase in nuclear GENE levels, which was significantly reduced by c-Jun N-terminal kinase (JNK) inhibition. Small interfering RNA-mediated knockdown of GENE mRNA demonstrated that induction of FSHβ mRNA by CHEMICAL depended on GENE and that regulation of FSHβ by GENE occurred independently of the JNK-c-jun pathway. β-Catenin depletion had no impact on FSHβ mRNA stability. In LβT2 cells transfected with FSHβ promoter luciferase fusion constructs, CHEMICAL responsiveness was conferred by the proximal promoter (-944/-1) and was markedly decreased by GENE knockdown. However, none of the T-cell factor/lymphoid enhancer factor binding sites in that region were required for promoter activation by CHEMICAL. Chromatin immunoprecipitation further corroborated the absence of direct interaction between GENE and the 1.8-kb FSHβ promoter. To elucidate the mechanism for the GENE effect, we analyzed approximately 1 billion reads of next-generation RNA sequencing GENE knockdown assays and selected the nuclear cofactor breast cancer metastasis-suppressor 1-like (Brms1L) as one candidate for further study. Subsequent experiments confirmed that Brms1L mRNA expression was decreased by GENE knockdown as well as by JNK inhibition. Furthermore, knockdown of Brms1L significantly attenuated GnRH-induced FSHβ expression. Thus, our findings indicate that the expression of Brms1L depends on GENE activity and contributes to FSHβ induction by CHEMICAL. | GENE-CHEMICAL |
| β-catenin regulates CHEMICAL-induced GENE gene expression. The regulation of gonadotropin synthesis by CHEMICAL plays an essential role in the neuroendocrine control of reproduction. The known signaling mechanisms involved in gonadotropin synthesis have been expanding. For example, involvement of β-catenin in LHβ induction by CHEMICAL has been discovered. We examined the role of β-catenin in GENE gene expression in LβT2 gonadotrope cells. CHEMICAL caused a sustained increase in nuclear β-catenin levels, which was significantly reduced by c-Jun N-terminal kinase (JNK) inhibition. Small interfering RNA-mediated knockdown of β-catenin mRNA demonstrated that induction of GENE mRNA by CHEMICAL depended on β-catenin and that regulation of GENE by β-catenin occurred independently of the JNK-c-jun pathway. β-Catenin depletion had no impact on GENE mRNA stability. In LβT2 cells transfected with GENE promoter luciferase fusion constructs, CHEMICAL responsiveness was conferred by the proximal promoter (-944/-1) and was markedly decreased by β-catenin knockdown. However, none of the T-cell factor/lymphoid enhancer factor binding sites in that region were required for promoter activation by CHEMICAL. Chromatin immunoprecipitation further corroborated the absence of direct interaction between β-catenin and the 1.8-kb GENE promoter. To elucidate the mechanism for the β-catenin effect, we analyzed approximately 1 billion reads of next-generation RNA sequencing β-catenin knockdown assays and selected the nuclear cofactor breast cancer metastasis-suppressor 1-like (Brms1L) as one candidate for further study. Subsequent experiments confirmed that Brms1L mRNA expression was decreased by β-catenin knockdown as well as by JNK inhibition. Furthermore, knockdown of Brms1L significantly attenuated GnRH-induced GENE expression. Thus, our findings indicate that the expression of Brms1L depends on β-catenin activity and contributes to GENE induction by CHEMICAL. | INDIRECT-UPREGULATOR |
| Doxorubicin decreases paraquat accumulation and toxicity in Caco-2 cells. P-glycoprotein (P-gp) is an efflux pump belonging to the ATP-binding cassette transporter superfamily expressed in several organs. Considering its potential protective effects, the induction of de novo synthesis of P-gp could be used therapeutically in the treatment of intoxications by its substrates. The herbicide paraquat (PQ) is a P-gp substrate responsible for thousands of fatal intoxications worldwide that still lacks an effective antidote. The aim of the present work was to evaluate the effectiveness of such an antidote by testing whether doxorubicin (DOX), a known P-gp inducer, could efficiently protect Caco-2 cells against PQ cytotoxicity, 6 h after the incubation with the herbicide, reflecting a real-life intoxication scenario. Cytotoxicity was evaluated by the MTT assay and PQ intracellular concentrations were measured by gas chromatography-ion trap-mass spectrometry (GC-IT-MS). Also, the CHEMICAL modulatory effect on choline uptake transport system was assessed by measuring the uptake of [³H]-choline. The results show that CHEMICAL exerts protective effects against PQ cytotoxicity, preventing the intracellular accumulation of the herbicide. These protective effects were not completely prevented by the incubation with the UIC2 antibody, a specific P-gp inhibitor, suggesting the involvement of alternative protection mechanisms. In fact, CHEMICAL also efficiently inhibited the choline transport system that influences PQ cellular uptake. In conclusion, in this cellular model, CHEMICAL effectively protects against PQ toxicity by inducing P-gp and through the interaction with the GENE, suggesting that compounds presenting this double feature of promoting the efflux and limiting the uptake of PQ could be used as effective antidotes to treat intoxications. | REGULATOR |
| Doxorubicin decreases paraquat accumulation and toxicity in Caco-2 cells. P-glycoprotein (P-gp) is an efflux pump belonging to the ATP-binding cassette transporter superfamily expressed in several organs. Considering its potential protective effects, the induction of de novo synthesis of GENE could be used therapeutically in the treatment of intoxications by its substrates. The herbicide paraquat (PQ) is a GENE substrate responsible for thousands of fatal intoxications worldwide that still lacks an effective antidote. The aim of the present work was to evaluate the effectiveness of such an antidote by testing whether doxorubicin (DOX), a known GENE inducer, could efficiently protect Caco-2 cells against PQ cytotoxicity, 6 h after the incubation with the herbicide, reflecting a real-life intoxication scenario. Cytotoxicity was evaluated by the MTT assay and PQ intracellular concentrations were measured by gas chromatography-ion trap-mass spectrometry (GC-IT-MS). Also, the CHEMICAL modulatory effect on choline uptake transport system was assessed by measuring the uptake of [³H]-choline. The results show that CHEMICAL exerts protective effects against PQ cytotoxicity, preventing the intracellular accumulation of the herbicide. These protective effects were not completely prevented by the incubation with the UIC2 antibody, a specific GENE inhibitor, suggesting the involvement of alternative protection mechanisms. In fact, CHEMICAL also efficiently inhibited the choline transport system that influences PQ cellular uptake. In conclusion, in this cellular model, CHEMICAL effectively protects against PQ toxicity by inducing GENE and through the interaction with the choline transporter, suggesting that compounds presenting this double feature of promoting the efflux and limiting the uptake of PQ could be used as effective antidotes to treat intoxications. | INDIRECT-UPREGULATOR |
| CHEMICAL decreases paraquat accumulation and toxicity in Caco-2 cells. P-glycoprotein (P-gp) is an efflux pump belonging to the ATP-binding cassette transporter superfamily expressed in several organs. Considering its potential protective effects, the induction of de novo synthesis of GENE could be used therapeutically in the treatment of intoxications by its substrates. The herbicide paraquat (PQ) is a GENE substrate responsible for thousands of fatal intoxications worldwide that still lacks an effective antidote. The aim of the present work was to evaluate the effectiveness of such an antidote by testing whether CHEMICAL (DOX), a known GENE inducer, could efficiently protect Caco-2 cells against PQ cytotoxicity, 6 h after the incubation with the herbicide, reflecting a real-life intoxication scenario. Cytotoxicity was evaluated by the MTT assay and PQ intracellular concentrations were measured by gas chromatography-ion trap-mass spectrometry (GC-IT-MS). Also, the DOX modulatory effect on choline uptake transport system was assessed by measuring the uptake of [³H]-choline. The results show that DOX exerts protective effects against PQ cytotoxicity, preventing the intracellular accumulation of the herbicide. These protective effects were not completely prevented by the incubation with the UIC2 antibody, a specific GENE inhibitor, suggesting the involvement of alternative protection mechanisms. In fact, DOX also efficiently inhibited the choline transport system that influences PQ cellular uptake. In conclusion, in this cellular model, DOX effectively protects against PQ toxicity by inducing GENE and through the interaction with the choline transporter, suggesting that compounds presenting this double feature of promoting the efflux and limiting the uptake of PQ could be used as effective antidotes to treat intoxications. | ACTIVATOR |
| Doxorubicin decreases CHEMICAL accumulation and toxicity in Caco-2 cells. P-glycoprotein (P-gp) is an efflux pump belonging to the ATP-binding cassette transporter superfamily expressed in several organs. Considering its potential protective effects, the induction of de novo synthesis of GENE could be used therapeutically in the treatment of intoxications by its substrates. The herbicide CHEMICAL (PQ) is a GENE substrate responsible for thousands of fatal intoxications worldwide that still lacks an effective antidote. The aim of the present work was to evaluate the effectiveness of such an antidote by testing whether doxorubicin (DOX), a known GENE inducer, could efficiently protect Caco-2 cells against PQ cytotoxicity, 6 h after the incubation with the herbicide, reflecting a real-life intoxication scenario. Cytotoxicity was evaluated by the MTT assay and PQ intracellular concentrations were measured by gas chromatography-ion trap-mass spectrometry (GC-IT-MS). Also, the DOX modulatory effect on choline uptake transport system was assessed by measuring the uptake of [³H]-choline. The results show that DOX exerts protective effects against PQ cytotoxicity, preventing the intracellular accumulation of the herbicide. These protective effects were not completely prevented by the incubation with the UIC2 antibody, a specific GENE inhibitor, suggesting the involvement of alternative protection mechanisms. In fact, DOX also efficiently inhibited the choline transport system that influences PQ cellular uptake. In conclusion, in this cellular model, DOX effectively protects against PQ toxicity by inducing GENE and through the interaction with the choline transporter, suggesting that compounds presenting this double feature of promoting the efflux and limiting the uptake of PQ could be used as effective antidotes to treat intoxications. | SUBSTRATE |
| The selective SYK inhibitor CHEMICAL (PRT062607) inhibits B cell signaling and function in vitro and in vivo and augments the activity of fludarabine in chronic lymphocytic leukemia. GENE (BCR) associated kinases including spleen tyrosine kinase (SYK) contribute to the pathogenesis of B-cell malignancies. SYK is persistently phosphorylated in a subset of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), and SYK inhibition results in abrogation of downstream kinase activity and apoptosis. CHEMICAL (also known as PRT062607) is a novel, highly selective, and orally bioavailable small molecule SYK inhibitor (SYK IC(50) = 1 nM) with anti-SYK activity that is at least 80-fold greater than its affinity for other kinases. We evaluated the preclinical characteristics of CHEMICAL in models of NHL and CLL. CHEMICAL successfully inhibited SYK-mediated GENE signaling and decreased cell viability in NHL and CLL. Oral dosing in mice prevented BCR-mediated splenomegaly and significantly inhibited NHL tumor growth in a xenograft model. In addition, combination treatment of primary CLL cells with CHEMICAL plus fludarabine produced synergistic enhancement of activity at nanomolar concentrations. Our findings support the ongoing development of CHEMICAL as a therapeutic agent for B-cell malignancies. A dose finding study in healthy volunteers has been completed. | INHIBITOR |
| The selective GENE inhibitor CHEMICAL (PRT062607) inhibits B cell signaling and function in vitro and in vivo and augments the activity of fludarabine in chronic lymphocytic leukemia. B-cell receptor (BCR) associated kinases including spleen tyrosine kinase (SYK) contribute to the pathogenesis of B-cell malignancies. GENE is persistently phosphorylated in a subset of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), and GENE inhibition results in abrogation of downstream kinase activity and apoptosis. CHEMICAL (also known as PRT062607) is a novel, highly selective, and orally bioavailable small molecule GENE inhibitor (SYK IC(50) = 1 nM) with anti-SYK activity that is at least 80-fold greater than its affinity for other kinases. We evaluated the preclinical characteristics of CHEMICAL in models of NHL and CLL. CHEMICAL successfully inhibited SYK-mediated B-cell receptor signaling and decreased cell viability in NHL and CLL. Oral dosing in mice prevented BCR-mediated splenomegaly and significantly inhibited NHL tumor growth in a xenograft model. In addition, combination treatment of primary CLL cells with CHEMICAL plus fludarabine produced synergistic enhancement of activity at nanomolar concentrations. Our findings support the ongoing development of CHEMICAL as a therapeutic agent for B-cell malignancies. A dose finding study in healthy volunteers has been completed. | INHIBITOR |
| The selective GENE inhibitor P505-15 (CHEMICAL) inhibits B cell signaling and function in vitro and in vivo and augments the activity of fludarabine in chronic lymphocytic leukemia. B-cell receptor (BCR) associated kinases including spleen tyrosine kinase (SYK) contribute to the pathogenesis of B-cell malignancies. GENE is persistently phosphorylated in a subset of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), and GENE inhibition results in abrogation of downstream kinase activity and apoptosis. P505-15 (also known as PRT062607) is a novel, highly selective, and orally bioavailable small molecule GENE inhibitor (SYK IC(50) = 1 nM) with anti-SYK activity that is at least 80-fold greater than its affinity for other kinases. We evaluated the preclinical characteristics of P505-15 in models of NHL and CLL. P505-15 successfully inhibited SYK-mediated B-cell receptor signaling and decreased cell viability in NHL and CLL. Oral dosing in mice prevented BCR-mediated splenomegaly and significantly inhibited NHL tumor growth in a xenograft model. In addition, combination treatment of primary CLL cells with P505-15 plus fludarabine produced synergistic enhancement of activity at nanomolar concentrations. Our findings support the ongoing development of P505-15 as a therapeutic agent for B-cell malignancies. A dose finding study in healthy volunteers has been completed. | INHIBITOR |
| The fidelity of transcription: GENE (RPO21) mutations that increase transcriptional slippage in S. cerevisiae. The fidelity of RNA synthesis depends on both accurate template-mediated nucleotide selection and proper maintenance of register between template and RNA. Loss of register, or transcriptional slippage, is particularly likely on homopolymeric runs in the template. Transcriptional slippage can alter the coding capacity of mRNAs and is used as a regulatory mechanism. Here we describe mutations in the largest subunit of Saccharomyces cerevisiae RNA polymerase II that substantially increase the level of transcriptional slippage. Alleles of GENE (RPO21) with elevated slippage rates were identified among CHEMICAL-sensitive mutants and were also isolated using a slippage-dependent reporter gene. Biochemical characterization of polymerase II isolated from these mutants confirms elevated levels of transcriptional slippage. | REGULATOR |
| The fidelity of transcription: RPB1 (RPO21) mutations that increase transcriptional slippage in S. cerevisiae. The fidelity of RNA synthesis depends on both accurate template-mediated nucleotide selection and proper maintenance of register between template and RNA. Loss of register, or transcriptional slippage, is particularly likely on homopolymeric runs in the template. Transcriptional slippage can alter the coding capacity of mRNAs and is used as a regulatory mechanism. Here we describe mutations in the largest subunit of Saccharomyces cerevisiae RNA polymerase II that substantially increase the level of transcriptional slippage. Alleles of RPB1 (GENE) with elevated slippage rates were identified among CHEMICAL-sensitive mutants and were also isolated using a slippage-dependent reporter gene. Biochemical characterization of polymerase II isolated from these mutants confirms elevated levels of transcriptional slippage. | REGULATOR |
| Aryl hydrocarbon receptor is a target of 17-Allylamino-17-demethoxygeldanamycin and enhances its anticancer activity in lung adenocarcinoma cells. We have demonstrated that aryl hydrocarbon receptor (AhR) is overexpressed in lung adenocarcinoma (AD). GENE is usually associated with heat shock protein 90 (Hsp90) in the cytoplasm. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, is currently under evaluation for its anticancer activity in clinical trials. Here we investigated whether GENE plays a role in 17-AAG-mediated anticancer activity by functioning as a downstream target or by modulating its anticancer efficacy. GENE expression in lung AD cells was modulated by siRNA interference or overexpression. Tumor growth was determined with colony formation in vitro or in vivo. Anticancer activity of CHEMICAL was determined by measuring cell viability, cell cycle distribution, and expression of cell cycle regulators. Proteins and mRNA levels were examined by immunoblotting and the real-time reverse transcription-polymerase chain reaction, respectively. In this study, GENE overexpression positively modulated growth of lung AD cells, at least partially, via RelA-dependent mechanisms. Although treatment with CHEMICAL reduced GENE levels and AhR-regulated gene expression in lung AD cells, GENE expression increased anticancer activity of CHEMICAL. In addition, CHEMICAL treatment reduced cell viability, CDK2, CDK4, cyclin E, cyclin D1, and phosphorylated Rb levels in AhR-expressing lung AD cells. NAD(P)H:quinone oxidoreductase (NQO1), which is regulated by GENE, was shown to increase anticancer activity of CHEMICAL in cells. Knockdown of NQO1 expression attenuated the reduction of cell cycle regulators by CHEMICAL treatment in GENE overexpressed cells. We demonstrated that GENE protein not only functions as a downstream target of CHEMICAL, but also enhances anticancer activity of CHEMICAL in lung AD cells. | INDIRECT-UPREGULATOR |
| GENE is a target of CHEMICAL and enhances its anticancer activity in lung adenocarcinoma cells. We have demonstrated that aryl hydrocarbon receptor (AhR) is overexpressed in lung adenocarcinoma (AD). AhR is usually associated with heat shock protein 90 (Hsp90) in the cytoplasm. CHEMICAL (17-AAG), an Hsp90 inhibitor, is currently under evaluation for its anticancer activity in clinical trials. Here we investigated whether AhR plays a role in 17-AAG-mediated anticancer activity by functioning as a downstream target or by modulating its anticancer efficacy. AhR expression in lung AD cells was modulated by siRNA interference or overexpression. Tumor growth was determined with colony formation in vitro or in vivo. Anticancer activity of 17-AAG was determined by measuring cell viability, cell cycle distribution, and expression of cell cycle regulators. Proteins and mRNA levels were examined by immunoblotting and the real-time reverse transcription-polymerase chain reaction, respectively. In this study, AhR overexpression positively modulated growth of lung AD cells, at least partially, via RelA-dependent mechanisms. Although treatment with 17-AAG reduced AhR levels and AhR-regulated gene expression in lung AD cells, AhR expression increased anticancer activity of 17-AAG. In addition, 17-AAG treatment reduced cell viability, CDK2, CDK4, cyclin E, cyclin D1, and phosphorylated Rb levels in AhR-expressing lung AD cells. NAD(P)H:quinone oxidoreductase (NQO1), which is regulated by AhR, was shown to increase anticancer activity of 17-AAG in cells. Knockdown of NQO1 expression attenuated the reduction of cell cycle regulators by 17-AAG treatment in AhR overexpressed cells. We demonstrated that AhR protein not only functions as a downstream target of 17-AAG, but also enhances anticancer activity of 17-AAG in lung AD cells. | REGULATOR |
| Aryl hydrocarbon receptor is a target of 17-Allylamino-17-demethoxygeldanamycin and enhances its anticancer activity in lung adenocarcinoma cells. We have demonstrated that aryl hydrocarbon receptor (AhR) is overexpressed in lung adenocarcinoma (AD). AhR is usually associated with heat shock protein 90 (Hsp90) in the cytoplasm. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, is currently under evaluation for its anticancer activity in clinical trials. Here we investigated whether AhR plays a role in 17-AAG-mediated anticancer activity by functioning as a downstream target or by modulating its anticancer efficacy. AhR expression in lung AD cells was modulated by siRNA interference or overexpression. Tumor growth was determined with colony formation in vitro or in vivo. Anticancer activity of CHEMICAL was determined by measuring cell viability, cell cycle distribution, and expression of cell cycle regulators. Proteins and mRNA levels were examined by immunoblotting and the real-time reverse transcription-polymerase chain reaction, respectively. In this study, AhR overexpression positively modulated growth of lung AD cells, at least partially, via RelA-dependent mechanisms. Although treatment with CHEMICAL reduced AhR levels and AhR-regulated gene expression in lung AD cells, AhR expression increased anticancer activity of CHEMICAL. In addition, CHEMICAL treatment reduced cell viability, GENE, CDK4, cyclin E, cyclin D1, and phosphorylated Rb levels in AhR-expressing lung AD cells. NAD(P)H:quinone oxidoreductase (NQO1), which is regulated by AhR, was shown to increase anticancer activity of CHEMICAL in cells. Knockdown of NQO1 expression attenuated the reduction of cell cycle regulators by CHEMICAL treatment in AhR overexpressed cells. We demonstrated that AhR protein not only functions as a downstream target of CHEMICAL, but also enhances anticancer activity of CHEMICAL in lung AD cells. | INDIRECT-DOWNREGULATOR |
| Aryl hydrocarbon receptor is a target of 17-Allylamino-17-demethoxygeldanamycin and enhances its anticancer activity in lung adenocarcinoma cells. We have demonstrated that aryl hydrocarbon receptor (AhR) is overexpressed in lung adenocarcinoma (AD). AhR is usually associated with heat shock protein 90 (Hsp90) in the cytoplasm. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, is currently under evaluation for its anticancer activity in clinical trials. Here we investigated whether AhR plays a role in 17-AAG-mediated anticancer activity by functioning as a downstream target or by modulating its anticancer efficacy. AhR expression in lung AD cells was modulated by siRNA interference or overexpression. Tumor growth was determined with colony formation in vitro or in vivo. Anticancer activity of CHEMICAL was determined by measuring cell viability, cell cycle distribution, and expression of cell cycle regulators. Proteins and mRNA levels were examined by immunoblotting and the real-time reverse transcription-polymerase chain reaction, respectively. In this study, AhR overexpression positively modulated growth of lung AD cells, at least partially, via RelA-dependent mechanisms. Although treatment with CHEMICAL reduced AhR levels and AhR-regulated gene expression in lung AD cells, AhR expression increased anticancer activity of CHEMICAL. In addition, CHEMICAL treatment reduced cell viability, CDK2, GENE, cyclin E, cyclin D1, and phosphorylated Rb levels in AhR-expressing lung AD cells. NAD(P)H:quinone oxidoreductase (NQO1), which is regulated by AhR, was shown to increase anticancer activity of CHEMICAL in cells. Knockdown of NQO1 expression attenuated the reduction of cell cycle regulators by CHEMICAL treatment in AhR overexpressed cells. We demonstrated that AhR protein not only functions as a downstream target of CHEMICAL, but also enhances anticancer activity of CHEMICAL in lung AD cells. | INDIRECT-DOWNREGULATOR |
| Aryl hydrocarbon receptor is a target of 17-Allylamino-17-demethoxygeldanamycin and enhances its anticancer activity in lung adenocarcinoma cells. We have demonstrated that aryl hydrocarbon receptor (AhR) is overexpressed in lung adenocarcinoma (AD). AhR is usually associated with heat shock protein 90 (Hsp90) in the cytoplasm. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, is currently under evaluation for its anticancer activity in clinical trials. Here we investigated whether AhR plays a role in 17-AAG-mediated anticancer activity by functioning as a downstream target or by modulating its anticancer efficacy. AhR expression in lung AD cells was modulated by siRNA interference or overexpression. Tumor growth was determined with colony formation in vitro or in vivo. Anticancer activity of CHEMICAL was determined by measuring cell viability, cell cycle distribution, and expression of cell cycle regulators. Proteins and mRNA levels were examined by immunoblotting and the real-time reverse transcription-polymerase chain reaction, respectively. In this study, AhR overexpression positively modulated growth of lung AD cells, at least partially, via RelA-dependent mechanisms. Although treatment with CHEMICAL reduced AhR levels and AhR-regulated gene expression in lung AD cells, AhR expression increased anticancer activity of CHEMICAL. In addition, CHEMICAL treatment reduced cell viability, CDK2, CDK4, GENE, cyclin D1, and phosphorylated Rb levels in AhR-expressing lung AD cells. NAD(P)H:quinone oxidoreductase (NQO1), which is regulated by AhR, was shown to increase anticancer activity of CHEMICAL in cells. Knockdown of NQO1 expression attenuated the reduction of cell cycle regulators by CHEMICAL treatment in AhR overexpressed cells. We demonstrated that AhR protein not only functions as a downstream target of CHEMICAL, but also enhances anticancer activity of CHEMICAL in lung AD cells. | INDIRECT-DOWNREGULATOR |
| Aryl hydrocarbon receptor is a target of 17-Allylamino-17-demethoxygeldanamycin and enhances its anticancer activity in lung adenocarcinoma cells. We have demonstrated that aryl hydrocarbon receptor (AhR) is overexpressed in lung adenocarcinoma (AD). AhR is usually associated with heat shock protein 90 (Hsp90) in the cytoplasm. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, is currently under evaluation for its anticancer activity in clinical trials. Here we investigated whether AhR plays a role in 17-AAG-mediated anticancer activity by functioning as a downstream target or by modulating its anticancer efficacy. AhR expression in lung AD cells was modulated by siRNA interference or overexpression. Tumor growth was determined with colony formation in vitro or in vivo. Anticancer activity of CHEMICAL was determined by measuring cell viability, cell cycle distribution, and expression of cell cycle regulators. Proteins and mRNA levels were examined by immunoblotting and the real-time reverse transcription-polymerase chain reaction, respectively. In this study, AhR overexpression positively modulated growth of lung AD cells, at least partially, via RelA-dependent mechanisms. Although treatment with CHEMICAL reduced AhR levels and AhR-regulated gene expression in lung AD cells, AhR expression increased anticancer activity of CHEMICAL. In addition, CHEMICAL treatment reduced cell viability, CDK2, CDK4, cyclin E, GENE, and phosphorylated Rb levels in AhR-expressing lung AD cells. NAD(P)H:quinone oxidoreductase (NQO1), which is regulated by AhR, was shown to increase anticancer activity of CHEMICAL in cells. Knockdown of NQO1 expression attenuated the reduction of cell cycle regulators by CHEMICAL treatment in AhR overexpressed cells. We demonstrated that AhR protein not only functions as a downstream target of CHEMICAL, but also enhances anticancer activity of CHEMICAL in lung AD cells. | INDIRECT-DOWNREGULATOR |
| Aryl hydrocarbon receptor is a target of 17-Allylamino-17-demethoxygeldanamycin and enhances its anticancer activity in lung adenocarcinoma cells. We have demonstrated that aryl hydrocarbon receptor (AhR) is overexpressed in lung adenocarcinoma (AD). AhR is usually associated with heat shock protein 90 (Hsp90) in the cytoplasm. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, is currently under evaluation for its anticancer activity in clinical trials. Here we investigated whether AhR plays a role in 17-AAG-mediated anticancer activity by functioning as a downstream target or by modulating its anticancer efficacy. AhR expression in lung AD cells was modulated by siRNA interference or overexpression. Tumor growth was determined with colony formation in vitro or in vivo. Anticancer activity of CHEMICAL was determined by measuring cell viability, cell cycle distribution, and expression of cell cycle regulators. Proteins and mRNA levels were examined by immunoblotting and the real-time reverse transcription-polymerase chain reaction, respectively. In this study, AhR overexpression positively modulated growth of lung AD cells, at least partially, via RelA-dependent mechanisms. Although treatment with CHEMICAL reduced AhR levels and AhR-regulated gene expression in lung AD cells, AhR expression increased anticancer activity of CHEMICAL. In addition, CHEMICAL treatment reduced cell viability, CDK2, CDK4, cyclin E, cyclin D1, and GENE levels in AhR-expressing lung AD cells. NAD(P)H:quinone oxidoreductase (NQO1), which is regulated by AhR, was shown to increase anticancer activity of CHEMICAL in cells. Knockdown of NQO1 expression attenuated the reduction of cell cycle regulators by CHEMICAL treatment in AhR overexpressed cells. We demonstrated that AhR protein not only functions as a downstream target of CHEMICAL, but also enhances anticancer activity of CHEMICAL in lung AD cells. | INDIRECT-DOWNREGULATOR |
| Aryl hydrocarbon receptor is a target of CHEMICAL and enhances its anticancer activity in lung adenocarcinoma cells. We have demonstrated that aryl hydrocarbon receptor (AhR) is overexpressed in lung adenocarcinoma (AD). AhR is usually associated with heat shock protein 90 (Hsp90) in the cytoplasm. CHEMICAL (17-AAG), an GENE inhibitor, is currently under evaluation for its anticancer activity in clinical trials. Here we investigated whether AhR plays a role in 17-AAG-mediated anticancer activity by functioning as a downstream target or by modulating its anticancer efficacy. AhR expression in lung AD cells was modulated by siRNA interference or overexpression. Tumor growth was determined with colony formation in vitro or in vivo. Anticancer activity of 17-AAG was determined by measuring cell viability, cell cycle distribution, and expression of cell cycle regulators. Proteins and mRNA levels were examined by immunoblotting and the real-time reverse transcription-polymerase chain reaction, respectively. In this study, AhR overexpression positively modulated growth of lung AD cells, at least partially, via RelA-dependent mechanisms. Although treatment with 17-AAG reduced AhR levels and AhR-regulated gene expression in lung AD cells, AhR expression increased anticancer activity of 17-AAG. In addition, 17-AAG treatment reduced cell viability, CDK2, CDK4, cyclin E, cyclin D1, and phosphorylated Rb levels in AhR-expressing lung AD cells. NAD(P)H:quinone oxidoreductase (NQO1), which is regulated by AhR, was shown to increase anticancer activity of 17-AAG in cells. Knockdown of NQO1 expression attenuated the reduction of cell cycle regulators by 17-AAG treatment in AhR overexpressed cells. We demonstrated that AhR protein not only functions as a downstream target of 17-AAG, but also enhances anticancer activity of 17-AAG in lung AD cells. | INHIBITOR |
| Aryl hydrocarbon receptor is a target of 17-Allylamino-17-demethoxygeldanamycin and enhances its anticancer activity in lung adenocarcinoma cells. We have demonstrated that aryl hydrocarbon receptor (AhR) is overexpressed in lung adenocarcinoma (AD). AhR is usually associated with heat shock protein 90 (Hsp90) in the cytoplasm. 17-Allylamino-17-demethoxygeldanamycin (CHEMICAL), an GENE inhibitor, is currently under evaluation for its anticancer activity in clinical trials. Here we investigated whether AhR plays a role in 17-AAG-mediated anticancer activity by functioning as a downstream target or by modulating its anticancer efficacy. AhR expression in lung AD cells was modulated by siRNA interference or overexpression. Tumor growth was determined with colony formation in vitro or in vivo. Anticancer activity of CHEMICAL was determined by measuring cell viability, cell cycle distribution, and expression of cell cycle regulators. Proteins and mRNA levels were examined by immunoblotting and the real-time reverse transcription-polymerase chain reaction, respectively. In this study, AhR overexpression positively modulated growth of lung AD cells, at least partially, via RelA-dependent mechanisms. Although treatment with CHEMICAL reduced AhR levels and AhR-regulated gene expression in lung AD cells, AhR expression increased anticancer activity of CHEMICAL. In addition, CHEMICAL treatment reduced cell viability, CDK2, CDK4, cyclin E, cyclin D1, and phosphorylated Rb levels in AhR-expressing lung AD cells. NAD(P)H:quinone oxidoreductase (NQO1), which is regulated by AhR, was shown to increase anticancer activity of CHEMICAL in cells. Knockdown of NQO1 expression attenuated the reduction of cell cycle regulators by CHEMICAL treatment in AhR overexpressed cells. We demonstrated that AhR protein not only functions as a downstream target of CHEMICAL, but also enhances anticancer activity of CHEMICAL in lung AD cells. | INHIBITOR |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and GENE (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four GENE proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). GENE did not significantly contribute to CHEMICAL monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | NO-RELATIONSHIP |
| Pharmacogenomics of CHEMICAL metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. CHEMICAL (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the GENE substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to CHEMICAL. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of CHEMICAL metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. CHEMICAL (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of GENE (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three GENE proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate GENE activity toward dFdC, and therefore would not contribute to interindividual variability in response to CHEMICAL. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of GENE (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (CHEMICAL), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three GENE proteins showed similar K(m) and V(max) for CHEMICAL and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for CHEMICAL deamination. All four DCK proteins yielded comparable metabolic activity for CHEMICAL and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate GENE activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (GENE and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (CHEMICAL), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for CHEMICAL and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for CHEMICAL deamination. All four DCK proteins yielded comparable metabolic activity for CHEMICAL and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the GENE substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and GENE) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (CHEMICAL), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for CHEMICAL and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for CHEMICAL deamination. All four DCK proteins yielded comparable metabolic activity for CHEMICAL and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and GENE (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (CHEMICAL), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for CHEMICAL and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for CHEMICAL deamination. All four GENE proteins yielded comparable metabolic activity for CHEMICAL and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). GENE did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (GENE, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (CHEMICAL), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for CHEMICAL and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for CHEMICAL deamination. All four DCK proteins yielded comparable metabolic activity for CHEMICAL and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, GENE, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (CHEMICAL), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for CHEMICAL and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for CHEMICAL deamination. All four DCK proteins yielded comparable metabolic activity for CHEMICAL and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and GENE) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (CHEMICAL), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for CHEMICAL and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for CHEMICAL deamination. All four DCK proteins yielded comparable metabolic activity for CHEMICAL and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of GENE (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), CHEMICAL, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three GENE proteins showed similar K(m) and V(max) for Ara-C and CHEMICAL deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and CHEMICAL monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of CHEMICAL monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate GENE activity toward CHEMICAL, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward CHEMICAL monophosphorylation may be relevant to CHEMICAL clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (GENE and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), CHEMICAL, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and CHEMICAL deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and CHEMICAL monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of CHEMICAL monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the GENE substitution does not significantly modulate CDA activity toward CHEMICAL, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward CHEMICAL monophosphorylation may be relevant to CHEMICAL clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and GENE) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), CHEMICAL, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and CHEMICAL deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and CHEMICAL monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of CHEMICAL monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward CHEMICAL, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward CHEMICAL monophosphorylation may be relevant to CHEMICAL clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and GENE (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), CHEMICAL, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and CHEMICAL deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four GENE proteins yielded comparable metabolic activity for Ara-C and CHEMICAL monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of CHEMICAL monophosphorylation due to a 40% decrease in K(m) (P < 0.05). GENE did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward CHEMICAL, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward CHEMICAL monophosphorylation may be relevant to CHEMICAL clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (GENE, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), CHEMICAL, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and CHEMICAL deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and CHEMICAL monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of CHEMICAL monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward CHEMICAL, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward CHEMICAL monophosphorylation may be relevant to CHEMICAL clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, GENE, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), CHEMICAL, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and CHEMICAL deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and CHEMICAL monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of CHEMICAL monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward CHEMICAL, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward CHEMICAL monophosphorylation may be relevant to CHEMICAL clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and GENE) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), CHEMICAL, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and CHEMICAL deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and CHEMICAL monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of CHEMICAL monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward CHEMICAL, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward CHEMICAL monophosphorylation may be relevant to CHEMICAL clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of GENE (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite CHEMICAL (dFdU) as substrates. All three GENE proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate GENE activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (GENE and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite CHEMICAL (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the GENE substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and GENE) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite CHEMICAL (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and GENE (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite CHEMICAL (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four GENE proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). GENE did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (GENE, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite CHEMICAL (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, GENE, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite CHEMICAL (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and GENE) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite CHEMICAL (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of GENE (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (CHEMICAL) as substrates. All three GENE proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to CHEMICAL monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate GENE activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. CHEMICAL (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (GENE), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and GENE (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four GENE proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). GENE did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in GENE and deoxycytidine kinase. CHEMICAL (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by GENE (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and GENE. CHEMICAL (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and GENE (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in GENE and deoxycytidine kinase. Gemcitabine (CHEMICAL, 2',2'-difluorodeoxycytidine) is metabolized by GENE (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), CHEMICAL, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and CHEMICAL deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and CHEMICAL monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of CHEMICAL monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward CHEMICAL, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward CHEMICAL monophosphorylation may be relevant to CHEMICAL clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and GENE. Gemcitabine (CHEMICAL, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and GENE (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), CHEMICAL, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and CHEMICAL deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and CHEMICAL monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of CHEMICAL monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward CHEMICAL, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward CHEMICAL monophosphorylation may be relevant to CHEMICAL clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, CHEMICAL) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (GENE), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and GENE (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four GENE proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). GENE did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in GENE and deoxycytidine kinase. Gemcitabine (dFdC, CHEMICAL) is metabolized by GENE (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, CHEMICAL) is metabolized by cytidine deaminase (GENE) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of GENE (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three GENE proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate GENE activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and GENE. Gemcitabine (dFdC, CHEMICAL) is metabolized by cytidine deaminase (CDA) and GENE (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of GENE (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for CHEMICAL (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three GENE proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate GENE activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (GENE and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for CHEMICAL (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the GENE substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and GENE) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for CHEMICAL (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and GENE (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for CHEMICAL (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four GENE proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). GENE did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (GENE, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for CHEMICAL (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, GENE, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for CHEMICAL (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and GENE) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for CHEMICAL (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. | SUBSTRATE |
| Discovery of CHEMICAL based TNIK inhibitors. A series of compounds based on a CHEMICAL scaffold that are potent and selective inhibitors of GENE (TNIK) activity are described. These compounds were used as tools to test the importance of TNIK kinase activity in signaling and proliferation in Wnt-activated colorectal cancer cells. The results indicate that pharmacological inhibition of TNIK kinase activity has minimal effects on either Wnt/TCF4/β-catenin-driven transcription or viability. The findings suggest that the kinase activity of TNIK may be less important to Wnt signaling than other aspects of TNIK function, such as its putative role in stabilizing the TCF4/β-catenin transcriptional complex. | INHIBITOR |
| Discovery of CHEMICAL based GENE inhibitors. A series of compounds based on a CHEMICAL scaffold that are potent and selective inhibitors of Traf2- and Nck-interacting kinase (GENE) activity are described. These compounds were used as tools to test the importance of GENE kinase activity in signaling and proliferation in Wnt-activated colorectal cancer cells. The results indicate that pharmacological inhibition of GENE kinase activity has minimal effects on either Wnt/TCF4/β-catenin-driven transcription or viability. The findings suggest that the kinase activity of GENE may be less important to Wnt signaling than other aspects of GENE function, such as its putative role in stabilizing the TCF4/β-catenin transcriptional complex. | INHIBITOR |
| Boron-based inhibitors of acyl protein thioesterases 1 and 2. Ras proteins are of importance in cell proliferation, and hence their mutated forms play causative roles in many kinds of cancer in different tissues. Inhibition of the Ras-depalmitoylating enzyme acyl protein thioesterases APT1 and -2 is a new approach to modulating the Ras cycle. Here we present CHEMICAL and borinic acid derivatives as a new class of potent and nontoxic GENE inhibitors. These compounds were detected by extensive library screening using chemical arrays and turned out to inhibit human APT1 and -2 in a competitive mode. Furthermore, one of the molecules was demonstrated to inhibit Erk1/2 phosphorylation significantly. | INHIBITOR |
| Boron-based inhibitors of acyl protein thioesterases 1 and 2. Ras proteins are of importance in cell proliferation, and hence their mutated forms play causative roles in many kinds of cancer in different tissues. Inhibition of the Ras-depalmitoylating enzyme acyl protein thioesterases APT1 and -2 is a new approach to modulating the Ras cycle. Here we present boronic and CHEMICAL derivatives as a new class of potent and nontoxic GENE inhibitors. These compounds were detected by extensive library screening using chemical arrays and turned out to inhibit human APT1 and -2 in a competitive mode. Furthermore, one of the molecules was demonstrated to inhibit Erk1/2 phosphorylation significantly. | INHIBITOR |
| CHEMICAL-based inhibitors of GENE. Ras proteins are of importance in cell proliferation, and hence their mutated forms play causative roles in many kinds of cancer in different tissues. Inhibition of the Ras-depalmitoylating enzyme acyl protein thioesterases APT1 and -2 is a new approach to modulating the Ras cycle. Here we present boronic and borinic acid derivatives as a new class of potent and nontoxic APT inhibitors. These compounds were detected by extensive library screening using chemical arrays and turned out to inhibit human APT1 and -2 in a competitive mode. Furthermore, one of the molecules was demonstrated to inhibit Erk1/2 phosphorylation significantly. | INHIBITOR |
| Phytoestrogen genistein protects against endothelial barrier dysfunction in vascular endothelial cells through PKA-mediated suppression of RhoA signaling. The soy-derived phytoestrogen genistein has received attention for its potential to improve vascular function, but its mechanism remains unclear. Here, we report that genistein at physiologically relevant concentrations (0.1-10 μM) significantly inhibited thrombin-induced increase in endothelial monolayer permeability. CHEMICAL also reduced the formation of stress fibers by GENE and suppressed thrombin-induced phosphorylation of myosin light chain (MLC) on Ser(19)/Thr(18) in endothelial cells (ECs). CHEMICAL had no effect on resting intracellular [Ca(2+)] or GENE-induced increase in Ca(2+) mobilization. Addition of the inhibitors of endothelial nitric oxide synthase or estrogen receptor did not alter the protective effect of genistein. RhoA is a small GTPase that plays an important role in actin-myosin contraction and endothelial barrier dysfunction. RhoA inhibitor blocked the protective effect of genistein on endothelial permeability and also ablated thrombin-induced MLC-phosphorylation in ECs. Inhibition of PKA significantly attenuated the effect of genistein on thrombin-induced EC permeability, MLC phosphorylation, and RhoA membrane translocation in ECs. Furthermore, GENE diminished cAMP production in ECs, which were prevented by treatment with genistein. These findings demonstrated that genistein improves thrombin-induced endothelial barrier dysfunction in ECs through PKA-mediated suppression of RhoA signaling. | NO-RELATIONSHIP |
| Phytoestrogen genistein protects against endothelial barrier dysfunction in vascular endothelial cells through PKA-mediated suppression of RhoA signaling. The soy-derived phytoestrogen genistein has received attention for its potential to improve vascular function, but its mechanism remains unclear. Here, we report that genistein at physiologically relevant concentrations (0.1-10 μM) significantly inhibited thrombin-induced increase in endothelial monolayer permeability. Genistein also reduced the formation of stress fibers by thrombin and suppressed thrombin-induced phosphorylation of GENE (MLC) on CHEMICAL(19)/Thr(18) in endothelial cells (ECs). Genistein had no effect on resting intracellular [Ca(2+)] or thrombin-induced increase in Ca(2+) mobilization. Addition of the inhibitors of endothelial nitric oxide synthase or estrogen receptor did not alter the protective effect of genistein. RhoA is a small GTPase that plays an important role in actin-myosin contraction and endothelial barrier dysfunction. RhoA inhibitor blocked the protective effect of genistein on endothelial permeability and also ablated thrombin-induced MLC-phosphorylation in ECs. Inhibition of PKA significantly attenuated the effect of genistein on thrombin-induced EC permeability, MLC phosphorylation, and RhoA membrane translocation in ECs. Furthermore, thrombin diminished cAMP production in ECs, which were prevented by treatment with genistein. These findings demonstrated that genistein improves thrombin-induced endothelial barrier dysfunction in ECs through PKA-mediated suppression of RhoA signaling. | PART-OF |
| Phytoestrogen genistein protects against endothelial barrier dysfunction in vascular endothelial cells through PKA-mediated suppression of RhoA signaling. The soy-derived phytoestrogen genistein has received attention for its potential to improve vascular function, but its mechanism remains unclear. Here, we report that genistein at physiologically relevant concentrations (0.1-10 μM) significantly inhibited thrombin-induced increase in endothelial monolayer permeability. Genistein also reduced the formation of stress fibers by thrombin and suppressed thrombin-induced phosphorylation of myosin light chain (GENE) on CHEMICAL(19)/Thr(18) in endothelial cells (ECs). Genistein had no effect on resting intracellular [Ca(2+)] or thrombin-induced increase in Ca(2+) mobilization. Addition of the inhibitors of endothelial nitric oxide synthase or estrogen receptor did not alter the protective effect of genistein. RhoA is a small GTPase that plays an important role in actin-myosin contraction and endothelial barrier dysfunction. RhoA inhibitor blocked the protective effect of genistein on endothelial permeability and also ablated thrombin-induced MLC-phosphorylation in ECs. Inhibition of PKA significantly attenuated the effect of genistein on thrombin-induced EC permeability, GENE phosphorylation, and RhoA membrane translocation in ECs. Furthermore, thrombin diminished cAMP production in ECs, which were prevented by treatment with genistein. These findings demonstrated that genistein improves thrombin-induced endothelial barrier dysfunction in ECs through PKA-mediated suppression of RhoA signaling. | PART-OF |
| Phytoestrogen genistein protects against endothelial barrier dysfunction in vascular endothelial cells through PKA-mediated suppression of RhoA signaling. The soy-derived phytoestrogen genistein has received attention for its potential to improve vascular function, but its mechanism remains unclear. Here, we report that genistein at physiologically relevant concentrations (0.1-10 μM) significantly inhibited thrombin-induced increase in endothelial monolayer permeability. Genistein also reduced the formation of stress fibers by thrombin and suppressed thrombin-induced phosphorylation of GENE (MLC) on Ser(19)/CHEMICAL(18) in endothelial cells (ECs). Genistein had no effect on resting intracellular [Ca(2+)] or thrombin-induced increase in Ca(2+) mobilization. Addition of the inhibitors of endothelial nitric oxide synthase or estrogen receptor did not alter the protective effect of genistein. RhoA is a small GTPase that plays an important role in actin-myosin contraction and endothelial barrier dysfunction. RhoA inhibitor blocked the protective effect of genistein on endothelial permeability and also ablated thrombin-induced MLC-phosphorylation in ECs. Inhibition of PKA significantly attenuated the effect of genistein on thrombin-induced EC permeability, MLC phosphorylation, and RhoA membrane translocation in ECs. Furthermore, thrombin diminished cAMP production in ECs, which were prevented by treatment with genistein. These findings demonstrated that genistein improves thrombin-induced endothelial barrier dysfunction in ECs through PKA-mediated suppression of RhoA signaling. | PART-OF |
| Phytoestrogen genistein protects against endothelial barrier dysfunction in vascular endothelial cells through PKA-mediated suppression of RhoA signaling. The soy-derived phytoestrogen genistein has received attention for its potential to improve vascular function, but its mechanism remains unclear. Here, we report that genistein at physiologically relevant concentrations (0.1-10 μM) significantly inhibited thrombin-induced increase in endothelial monolayer permeability. Genistein also reduced the formation of stress fibers by thrombin and suppressed thrombin-induced phosphorylation of myosin light chain (GENE) on Ser(19)/CHEMICAL(18) in endothelial cells (ECs). Genistein had no effect on resting intracellular [Ca(2+)] or thrombin-induced increase in Ca(2+) mobilization. Addition of the inhibitors of endothelial nitric oxide synthase or estrogen receptor did not alter the protective effect of genistein. RhoA is a small GTPase that plays an important role in actin-myosin contraction and endothelial barrier dysfunction. RhoA inhibitor blocked the protective effect of genistein on endothelial permeability and also ablated thrombin-induced MLC-phosphorylation in ECs. Inhibition of PKA significantly attenuated the effect of genistein on thrombin-induced EC permeability, GENE phosphorylation, and RhoA membrane translocation in ECs. Furthermore, thrombin diminished cAMP production in ECs, which were prevented by treatment with genistein. These findings demonstrated that genistein improves thrombin-induced endothelial barrier dysfunction in ECs through PKA-mediated suppression of RhoA signaling. | PART-OF |
| Phytoestrogen CHEMICAL protects against endothelial barrier dysfunction in vascular endothelial cells through PKA-mediated suppression of GENE signaling. The soy-derived phytoestrogen CHEMICAL has received attention for its potential to improve vascular function, but its mechanism remains unclear. Here, we report that CHEMICAL at physiologically relevant concentrations (0.1-10 μM) significantly inhibited thrombin-induced increase in endothelial monolayer permeability. CHEMICAL also reduced the formation of stress fibers by thrombin and suppressed thrombin-induced phosphorylation of myosin light chain (MLC) on Ser(19)/Thr(18) in endothelial cells (ECs). CHEMICAL had no effect on resting intracellular [Ca(2+)] or thrombin-induced increase in Ca(2+) mobilization. Addition of the inhibitors of endothelial nitric oxide synthase or estrogen receptor did not alter the protective effect of CHEMICAL. GENE is a small GTPase that plays an important role in actin-myosin contraction and endothelial barrier dysfunction. GENE inhibitor blocked the protective effect of CHEMICAL on endothelial permeability and also ablated thrombin-induced MLC-phosphorylation in ECs. Inhibition of PKA significantly attenuated the effect of CHEMICAL on thrombin-induced EC permeability, MLC phosphorylation, and GENE membrane translocation in ECs. Furthermore, thrombin diminished cAMP production in ECs, which were prevented by treatment with CHEMICAL. These findings demonstrated that CHEMICAL improves thrombin-induced endothelial barrier dysfunction in ECs through PKA-mediated suppression of GENE signaling. | INDIRECT-DOWNREGULATOR |
| Phytoestrogen CHEMICAL protects against endothelial barrier dysfunction in vascular endothelial cells through GENE-mediated suppression of RhoA signaling. The soy-derived phytoestrogen CHEMICAL has received attention for its potential to improve vascular function, but its mechanism remains unclear. Here, we report that CHEMICAL at physiologically relevant concentrations (0.1-10 μM) significantly inhibited thrombin-induced increase in endothelial monolayer permeability. CHEMICAL also reduced the formation of stress fibers by thrombin and suppressed thrombin-induced phosphorylation of myosin light chain (MLC) on Ser(19)/Thr(18) in endothelial cells (ECs). CHEMICAL had no effect on resting intracellular [Ca(2+)] or thrombin-induced increase in Ca(2+) mobilization. Addition of the inhibitors of endothelial nitric oxide synthase or estrogen receptor did not alter the protective effect of CHEMICAL. RhoA is a small GTPase that plays an important role in actin-myosin contraction and endothelial barrier dysfunction. RhoA inhibitor blocked the protective effect of CHEMICAL on endothelial permeability and also ablated thrombin-induced MLC-phosphorylation in ECs. Inhibition of GENE significantly attenuated the effect of CHEMICAL on thrombin-induced EC permeability, MLC phosphorylation, and RhoA membrane translocation in ECs. Furthermore, thrombin diminished cAMP production in ECs, which were prevented by treatment with CHEMICAL. These findings demonstrated that CHEMICAL improves thrombin-induced endothelial barrier dysfunction in ECs through PKA-mediated suppression of RhoA signaling. | INHIBITOR |
| Phytoestrogen CHEMICAL protects against endothelial barrier dysfunction in vascular endothelial cells through PKA-mediated suppression of RhoA signaling. The soy-derived phytoestrogen CHEMICAL has received attention for its potential to improve vascular function, but its mechanism remains unclear. Here, we report that CHEMICAL at physiologically relevant concentrations (0.1-10 μM) significantly inhibited thrombin-induced increase in endothelial monolayer permeability. CHEMICAL also reduced the formation of stress fibers by thrombin and suppressed thrombin-induced phosphorylation of myosin light chain (MLC) on Ser(19)/Thr(18) in endothelial cells (ECs). CHEMICAL had no effect on resting intracellular [Ca(2+)] or thrombin-induced increase in Ca(2+) mobilization. Addition of the inhibitors of endothelial nitric oxide synthase or estrogen receptor did not alter the protective effect of CHEMICAL. RhoA is a small GTPase that plays an important role in actin-myosin contraction and endothelial barrier dysfunction. RhoA inhibitor blocked the protective effect of CHEMICAL on endothelial permeability and also ablated thrombin-induced MLC-phosphorylation in ECs. Inhibition of PKA significantly attenuated the effect of CHEMICAL on thrombin-induced EC permeability, GENE phosphorylation, and RhoA membrane translocation in ECs. Furthermore, thrombin diminished cAMP production in ECs, which were prevented by treatment with CHEMICAL. These findings demonstrated that CHEMICAL improves thrombin-induced endothelial barrier dysfunction in ECs through PKA-mediated suppression of RhoA signaling. | INHIBITOR |
| Phytoestrogen genistein protects against endothelial barrier dysfunction in vascular endothelial cells through PKA-mediated suppression of RhoA signaling. The soy-derived phytoestrogen genistein has received attention for its potential to improve vascular function, but its mechanism remains unclear. Here, we report that genistein at physiologically relevant concentrations (0.1-10 μM) significantly inhibited thrombin-induced increase in endothelial monolayer permeability. CHEMICAL also reduced the formation of stress fibers by thrombin and suppressed thrombin-induced phosphorylation of GENE (MLC) on Ser(19)/Thr(18) in endothelial cells (ECs). CHEMICAL had no effect on resting intracellular [Ca(2+)] or thrombin-induced increase in Ca(2+) mobilization. Addition of the inhibitors of endothelial nitric oxide synthase or estrogen receptor did not alter the protective effect of genistein. RhoA is a small GTPase that plays an important role in actin-myosin contraction and endothelial barrier dysfunction. RhoA inhibitor blocked the protective effect of genistein on endothelial permeability and also ablated thrombin-induced MLC-phosphorylation in ECs. Inhibition of PKA significantly attenuated the effect of genistein on thrombin-induced EC permeability, MLC phosphorylation, and RhoA membrane translocation in ECs. Furthermore, thrombin diminished cAMP production in ECs, which were prevented by treatment with genistein. These findings demonstrated that genistein improves thrombin-induced endothelial barrier dysfunction in ECs through PKA-mediated suppression of RhoA signaling. | INHIBITOR |
| Phytoestrogen genistein protects against endothelial barrier dysfunction in vascular endothelial cells through PKA-mediated suppression of RhoA signaling. The soy-derived phytoestrogen genistein has received attention for its potential to improve vascular function, but its mechanism remains unclear. Here, we report that genistein at physiologically relevant concentrations (0.1-10 μM) significantly inhibited thrombin-induced increase in endothelial monolayer permeability. CHEMICAL also reduced the formation of stress fibers by thrombin and suppressed thrombin-induced phosphorylation of myosin light chain (GENE) on Ser(19)/Thr(18) in endothelial cells (ECs). CHEMICAL had no effect on resting intracellular [Ca(2+)] or thrombin-induced increase in Ca(2+) mobilization. Addition of the inhibitors of endothelial nitric oxide synthase or estrogen receptor did not alter the protective effect of genistein. RhoA is a small GTPase that plays an important role in actin-myosin contraction and endothelial barrier dysfunction. RhoA inhibitor blocked the protective effect of genistein on endothelial permeability and also ablated thrombin-induced MLC-phosphorylation in ECs. Inhibition of PKA significantly attenuated the effect of genistein on thrombin-induced EC permeability, GENE phosphorylation, and RhoA membrane translocation in ECs. Furthermore, thrombin diminished cAMP production in ECs, which were prevented by treatment with genistein. These findings demonstrated that genistein improves thrombin-induced endothelial barrier dysfunction in ECs through PKA-mediated suppression of RhoA signaling. | INHIBITOR |
| Evaluation of drug interactions of CHEMICAL (a GPR119 agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of CHEMICAL, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by CHEMICAL, and a clinical drug interaction study investigated the effect of CHEMICAL (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, CHEMICAL demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, CHEMICAL inhibited BCRP and GENE, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with CHEMICAL, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, CHEMICAL did not inhibit GENE based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by CHEMICAL. | NO-RELATIONSHIP |
| Evaluation of drug interactions of CHEMICAL (a GPR119 agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of CHEMICAL, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by CHEMICAL, and a clinical drug interaction study investigated the effect of CHEMICAL (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, CHEMICAL demonstrated little/weak inhibition (IC50 values >30 μM) towards GENE (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, CHEMICAL inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with CHEMICAL, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, CHEMICAL did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by CHEMICAL. | INHIBITOR |
| Evaluation of drug interactions of CHEMICAL (a GPR119 agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of CHEMICAL, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by CHEMICAL, and a clinical drug interaction study investigated the effect of CHEMICAL (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, CHEMICAL demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (GENE, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, CHEMICAL inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with CHEMICAL, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, CHEMICAL did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by CHEMICAL. | INHIBITOR |
| Evaluation of drug interactions of CHEMICAL (a GPR119 agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of CHEMICAL, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by CHEMICAL, and a clinical drug interaction study investigated the effect of CHEMICAL (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, CHEMICAL demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, GENE, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, CHEMICAL inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with CHEMICAL, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, CHEMICAL did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by CHEMICAL. | INHIBITOR |
| Evaluation of drug interactions of CHEMICAL (a GPR119 agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of CHEMICAL, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by CHEMICAL, and a clinical drug interaction study investigated the effect of CHEMICAL (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, CHEMICAL demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, GENE, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, CHEMICAL inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with CHEMICAL, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, CHEMICAL did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by CHEMICAL. | INHIBITOR |
| Evaluation of drug interactions of CHEMICAL (a GPR119 agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of CHEMICAL, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by CHEMICAL, and a clinical drug interaction study investigated the effect of CHEMICAL (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, CHEMICAL demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, GENE, 3A4), Pgp, OATP1B3, or OCT2. However, CHEMICAL inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with CHEMICAL, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, CHEMICAL did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by CHEMICAL. | INHIBITOR |
| Evaluation of drug interactions of CHEMICAL (a GPR119 agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of CHEMICAL, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by CHEMICAL, and a clinical drug interaction study investigated the effect of CHEMICAL (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, CHEMICAL demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, GENE), Pgp, OATP1B3, or OCT2. However, CHEMICAL inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with CHEMICAL, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, CHEMICAL did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by CHEMICAL. | INHIBITOR |
| Evaluation of drug interactions of CHEMICAL (a GPR119 agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of CHEMICAL, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by CHEMICAL, and a clinical drug interaction study investigated the effect of CHEMICAL (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, CHEMICAL demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), GENE, OATP1B3, or OCT2. However, CHEMICAL inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with CHEMICAL, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, CHEMICAL did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by CHEMICAL. | INHIBITOR |
| Evaluation of drug interactions of CHEMICAL (a GPR119 agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of CHEMICAL, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by CHEMICAL, and a clinical drug interaction study investigated the effect of CHEMICAL (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, CHEMICAL demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, GENE, or OCT2. However, CHEMICAL inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with CHEMICAL, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, CHEMICAL did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by CHEMICAL. | INHIBITOR |
| Evaluation of drug interactions of CHEMICAL (a GPR119 agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of CHEMICAL, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by CHEMICAL, and a clinical drug interaction study investigated the effect of CHEMICAL (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, CHEMICAL demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or GENE. However, CHEMICAL inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with CHEMICAL, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, CHEMICAL did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by CHEMICAL. | INHIBITOR |
| Evaluation of drug interactions of CHEMICAL (a GPR119 agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of CHEMICAL, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by CHEMICAL, and a clinical drug interaction study investigated the effect of CHEMICAL (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, CHEMICAL demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, CHEMICAL inhibited GENE and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with CHEMICAL, which is consistent with an inhibitory effect on intestinal GENE and CYP3A4. In contrast, CHEMICAL did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by CHEMICAL. | INHIBITOR |
| Evaluation of drug interactions of CHEMICAL (a GPR119 agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of CHEMICAL, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by CHEMICAL, and a clinical drug interaction study investigated the effect of CHEMICAL (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, CHEMICAL demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, CHEMICAL inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with CHEMICAL, which is consistent with an inhibitory effect on intestinal BCRP and GENE. In contrast, CHEMICAL did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by CHEMICAL. | INHIBITOR |
| Evaluation of drug interactions of GSK1292263 (a GPR119 agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of GSK1292263, a novel GPR119 agonist, with the GENE inhibitors CHEMICAL and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by GSK1292263, and a clinical drug interaction study investigated the effect of GSK1292263 (300 mg BID) on the pharmacokinetic profile of CHEMICAL (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, GSK1292263 demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, GSK1292263 inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of CHEMICAL [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with GSK1292263, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, GSK1292263 did not inhibit OATP1B1 based on the lack of changes in CHEMICAL acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with CHEMICAL and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by GSK1292263. | INHIBITOR |
| Evaluation of drug interactions of CHEMICAL (a GPR119 agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of CHEMICAL, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of GENE and CYP enzymes by CHEMICAL, and a clinical drug interaction study investigated the effect of CHEMICAL (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, CHEMICAL demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, CHEMICAL inhibited BCRP and OATP1B1, which are GENE involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with CHEMICAL, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, CHEMICAL did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of GENE and enzymes by CHEMICAL. | INHIBITOR |
| Evaluation of drug interactions of GSK1292263 (a GPR119 agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of GSK1292263, a novel GPR119 agonist, with the GENE inhibitors simvastatin and CHEMICAL. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by GSK1292263, and a clinical drug interaction study investigated the effect of GSK1292263 (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and CHEMICAL (10 mg single dose). 3. In vitro, GSK1292263 demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, GSK1292263 inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and CHEMICAL [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with GSK1292263, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, GSK1292263 did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by GSK1292263. | INHIBITOR |
| Evaluation of drug interactions of CHEMICAL (a GPR119 agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of CHEMICAL, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and GENE enzymes by CHEMICAL, and a clinical drug interaction study investigated the effect of CHEMICAL (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, CHEMICAL demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, CHEMICAL inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with CHEMICAL, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, CHEMICAL did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by CHEMICAL. | INHIBITOR |
| Evaluation of drug interactions of CHEMICAL (a GENE agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of CHEMICAL, a novel GENE agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by CHEMICAL, and a clinical drug interaction study investigated the effect of CHEMICAL (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, CHEMICAL demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, CHEMICAL inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with CHEMICAL, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, CHEMICAL did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by CHEMICAL. | ACTIVATOR |
| CHEMICAL toxicity and detoxification in ascomycetous fungi. In the last couple of decades fungal infections have become a significant clinical problem. A major interest into fungal CHEMICAL action has been provoked since research has proven that CHEMICAL hormones are toxic to fungi and affect the host/fungus relationship. CHEMICAL hormones were found to differ in their antifungal activity in ascomycetous fungi Hortaea werneckii, Saccharomyces cerevisiae and Aspergillus oryzae. Dehydroepiandrosterone was shown to be the strongest inhibitor of growth in all three varieties of fungi followed by androstenedione and testosterone. For their protection, fungi use several mechanisms to lower the toxic effects of steroids. The efficiency of biotransformation in detoxification depended on the microorganism and CHEMICAL substrate used. Biotransformation was a relatively slow process as it also depended on the growth phase of the fungus. In addition to biotransformation, CHEMICAL extrusion out of the cells contributed to the lowering of the active intracellular CHEMICAL concentration. Plasma membrane Pdr5 transporter was found to be the most effective, followed by Snq2 transporter and vacuolar transporters Ybt1 and Ycf1. Proteins GENE and Dan1 were not found to be involved in CHEMICAL import. The research of possible targets of CHEMICAL hormone action in fungi suggests that CHEMICAL hormones inhibit ergosterol biosynthesis in S. cerevisiae and H. werneckii. Results of this inhibition caused changes in the sterol content of the cellular membrane. The presence of CHEMICAL hormones most probably causes the degradation of the Tat2 permease and impairment of tryptophan import. | NO-RELATIONSHIP |
| CHEMICAL toxicity and detoxification in ascomycetous fungi. In the last couple of decades fungal infections have become a significant clinical problem. A major interest into fungal CHEMICAL action has been provoked since research has proven that CHEMICAL hormones are toxic to fungi and affect the host/fungus relationship. CHEMICAL hormones were found to differ in their antifungal activity in ascomycetous fungi Hortaea werneckii, Saccharomyces cerevisiae and Aspergillus oryzae. Dehydroepiandrosterone was shown to be the strongest inhibitor of growth in all three varieties of fungi followed by androstenedione and testosterone. For their protection, fungi use several mechanisms to lower the toxic effects of steroids. The efficiency of biotransformation in detoxification depended on the microorganism and CHEMICAL substrate used. Biotransformation was a relatively slow process as it also depended on the growth phase of the fungus. In addition to biotransformation, CHEMICAL extrusion out of the cells contributed to the lowering of the active intracellular CHEMICAL concentration. Plasma membrane Pdr5 transporter was found to be the most effective, followed by Snq2 transporter and vacuolar transporters Ybt1 and Ycf1. Proteins Aus1 and GENE were not found to be involved in CHEMICAL import. The research of possible targets of CHEMICAL hormone action in fungi suggests that CHEMICAL hormones inhibit ergosterol biosynthesis in S. cerevisiae and H. werneckii. Results of this inhibition caused changes in the sterol content of the cellular membrane. The presence of CHEMICAL hormones most probably causes the degradation of the Tat2 permease and impairment of tryptophan import. | NO-RELATIONSHIP |
| CHEMICAL toxicity and detoxification in ascomycetous fungi. In the last couple of decades fungal infections have become a significant clinical problem. A major interest into fungal CHEMICAL action has been provoked since research has proven that CHEMICAL hormones are toxic to fungi and affect the host/fungus relationship. CHEMICAL hormones were found to differ in their antifungal activity in ascomycetous fungi Hortaea werneckii, Saccharomyces cerevisiae and Aspergillus oryzae. Dehydroepiandrosterone was shown to be the strongest inhibitor of growth in all three varieties of fungi followed by androstenedione and testosterone. For their protection, fungi use several mechanisms to lower the toxic effects of steroids. The efficiency of biotransformation in detoxification depended on the microorganism and CHEMICAL substrate used. Biotransformation was a relatively slow process as it also depended on the growth phase of the fungus. In addition to biotransformation, CHEMICAL extrusion out of the cells contributed to the lowering of the active intracellular CHEMICAL concentration. Plasma membrane Pdr5 transporter was found to be the most effective, followed by Snq2 transporter and vacuolar transporters Ybt1 and Ycf1. Proteins Aus1 and Dan1 were not found to be involved in CHEMICAL import. The research of possible targets of CHEMICAL hormone action in fungi suggests that CHEMICAL hormones inhibit ergosterol biosynthesis in S. cerevisiae and H. werneckii. Results of this inhibition caused changes in the sterol content of the cellular membrane. The presence of CHEMICAL hormones most probably causes the degradation of the GENE permease and impairment of tryptophan import. | SUBSTRATE |
| Cell-cycle and DNA damage regulation of the DNA mismatch repair protein GENE occurs at the transcriptional and post-transcriptional level. DNA mismatch repair during replication is a conserved process essential for maintaining genomic stability. Mismatch repair is also implicated in cell-cycle arrest and apoptosis after DNA damage. Because yeast and human mismatch repair systems are well conserved, we have employed the budding yeast Saccharomyces cerevisiae to understand the regulation and function of the mismatch repair gene GENE. Using a luciferase-based transcriptional reporter, we defined a 218-bp region upstream of GENE that contains cell-cycle and DNA damage responsive elements. The 5' end of the GENE transcript was mapped by primer extension and was found to encode a small upstream open reading frame (uORF). Mutagenesis of the uORF start codon or of the uORF stop codon, which creates a continuous reading frame with GENE, increased GENE steady-state protein levels ∼2-fold. Furthermore, we found that the cell-cycle transcription factors Swi6, Swi4, and Mbp1-along with SCB/MCB cell-cycle binding sites upstream of MSH2-are all required for full basal expression of GENE. Mutagenesis of the cell-cycle boxes resulted in a minor reduction in basal GENE levels and a 3-fold defect in mismatch repair. Disruption of the cell-cycle boxes also affected growth in a DNA polymerase-defective strain background where mismatch repair is essential, particularly in the presence of the DNA damaging agent methyl methane sulfonate (MMS). Promoter replacements conferring constitutive expression of GENE revealed that the transcriptional induction in response to CHEMICAL is required to maintain induced levels of GENE. Turnover experiments confirmed an elevated rate of degradation in the presence of CHEMICAL. Taken together, the data show that the DNA damage regulation of GENE occurs at the transcriptional and post-transcriptional levels. The transcriptional and translational control elements identified are conserved in mammalian cells, underscoring the use of yeast as a model system to examine the regulation of GENE. | GENE-CHEMICAL |
| Inhibition of Th1/Th17 responses via suppression of STAT1 and STAT3 activation contributes to the amelioration of murine experimental colitis by a natural flavonoid glucoside CHEMICAL. Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the intestine which involves overproduction of pro-inflammatory cytokines and excessive functions of inflammatory cells. However, current treatments for IBD may have potential adverse effects including steroid dependence, infections and lymphoma. Therefore new therapies or drug candidates for the treatment of IBD are desperately needed. In the present study we found that CHEMICAL, a major bioactive compound from plants in Epimedium family, exerted protective effect on intestinal inflammation in mice induced by dextran sulfate sodium. Oral administration of CHEMICAL significantly attenuated the disease progression and alleviated the pathological changes of colitis. It also inhibited the production of pro-inflammatory cytokines and expression of p-p65, p-STAT1 and p-STAT3 in colon tissues. Further study showed that CHEMICAL dose-dependently inhibited the proliferation and activation of T lymphocytes, and suppressed pro-inflammatory GENE levels of activated T cells. Moreover, CHEMICAL treatment inhibited the phosphorylations of STAT1 and STAT3 in CD4(+) T cells, which were the crucial transcription factors for Th1 and Th17 respectively. Taken together, these results indicate that CHEMICAL is a potential therapeutic agent for IBD. | INDIRECT-DOWNREGULATOR |
| Inhibition of Th1/Th17 responses via suppression of GENE and STAT3 activation contributes to the amelioration of murine experimental colitis by a natural flavonoid glucoside CHEMICAL. Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the intestine which involves overproduction of pro-inflammatory cytokines and excessive functions of inflammatory cells. However, current treatments for IBD may have potential adverse effects including steroid dependence, infections and lymphoma. Therefore new therapies or drug candidates for the treatment of IBD are desperately needed. In the present study we found that CHEMICAL, a major bioactive compound from plants in Epimedium family, exerted protective effect on intestinal inflammation in mice induced by dextran sulfate sodium. Oral administration of CHEMICAL significantly attenuated the disease progression and alleviated the pathological changes of colitis. It also inhibited the production of pro-inflammatory cytokines and expression of p-p65, p-STAT1 and p-STAT3 in colon tissues. Further study showed that CHEMICAL dose-dependently inhibited the proliferation and activation of T lymphocytes, and suppressed pro-inflammatory cytokine levels of activated T cells. Moreover, CHEMICAL treatment inhibited the phosphorylations of GENE and STAT3 in CD4(+) T cells, which were the crucial transcription factors for Th1 and Th17 respectively. Taken together, these results indicate that CHEMICAL is a potential therapeutic agent for IBD. | INHIBITOR |
| Inhibition of Th1/Th17 responses via suppression of STAT1 and GENE activation contributes to the amelioration of murine experimental colitis by a natural flavonoid glucoside CHEMICAL. Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the intestine which involves overproduction of pro-inflammatory cytokines and excessive functions of inflammatory cells. However, current treatments for IBD may have potential adverse effects including steroid dependence, infections and lymphoma. Therefore new therapies or drug candidates for the treatment of IBD are desperately needed. In the present study we found that CHEMICAL, a major bioactive compound from plants in Epimedium family, exerted protective effect on intestinal inflammation in mice induced by dextran sulfate sodium. Oral administration of CHEMICAL significantly attenuated the disease progression and alleviated the pathological changes of colitis. It also inhibited the production of pro-inflammatory cytokines and expression of p-p65, p-STAT1 and p-STAT3 in colon tissues. Further study showed that CHEMICAL dose-dependently inhibited the proliferation and activation of T lymphocytes, and suppressed pro-inflammatory cytokine levels of activated T cells. Moreover, CHEMICAL treatment inhibited the phosphorylations of STAT1 and GENE in CD4(+) T cells, which were the crucial transcription factors for Th1 and Th17 respectively. Taken together, these results indicate that CHEMICAL is a potential therapeutic agent for IBD. | INHIBITOR |
| Inhibition of Th1/Th17 responses via suppression of GENE and STAT3 activation contributes to the amelioration of murine experimental colitis by a natural CHEMICAL glucoside icariin. Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the intestine which involves overproduction of pro-inflammatory cytokines and excessive functions of inflammatory cells. However, current treatments for IBD may have potential adverse effects including steroid dependence, infections and lymphoma. Therefore new therapies or drug candidates for the treatment of IBD are desperately needed. In the present study we found that icariin, a major bioactive compound from plants in Epimedium family, exerted protective effect on intestinal inflammation in mice induced by dextran sulfate sodium. Oral administration of icariin significantly attenuated the disease progression and alleviated the pathological changes of colitis. It also inhibited the production of pro-inflammatory cytokines and expression of p-p65, p-STAT1 and p-STAT3 in colon tissues. Further study showed that icariin dose-dependently inhibited the proliferation and activation of T lymphocytes, and suppressed pro-inflammatory cytokine levels of activated T cells. Moreover, icariin treatment inhibited the phosphorylations of GENE and STAT3 in CD4(+) T cells, which were the crucial transcription factors for Th1 and Th17 respectively. Taken together, these results indicate that icariin is a potential therapeutic agent for IBD. | INHIBITOR |
| Inhibition of Th1/Th17 responses via suppression of STAT1 and GENE activation contributes to the amelioration of murine experimental colitis by a natural CHEMICAL glucoside icariin. Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the intestine which involves overproduction of pro-inflammatory cytokines and excessive functions of inflammatory cells. However, current treatments for IBD may have potential adverse effects including steroid dependence, infections and lymphoma. Therefore new therapies or drug candidates for the treatment of IBD are desperately needed. In the present study we found that icariin, a major bioactive compound from plants in Epimedium family, exerted protective effect on intestinal inflammation in mice induced by dextran sulfate sodium. Oral administration of icariin significantly attenuated the disease progression and alleviated the pathological changes of colitis. It also inhibited the production of pro-inflammatory cytokines and expression of p-p65, p-STAT1 and p-STAT3 in colon tissues. Further study showed that icariin dose-dependently inhibited the proliferation and activation of T lymphocytes, and suppressed pro-inflammatory cytokine levels of activated T cells. Moreover, icariin treatment inhibited the phosphorylations of STAT1 and GENE in CD4(+) T cells, which were the crucial transcription factors for Th1 and Th17 respectively. Taken together, these results indicate that icariin is a potential therapeutic agent for IBD. | INHIBITOR |
| Stimulatory effect of GENE on theca-interstitial cell proliferation and cell cycle regulatory proteins through MTORC1 dependent pathway. The present study examined the effect of insulin-mediated activation of the mammalian target of CHEMICAL complex 1 (MTORC1) signaling network on the proliferation of primary culture of theca-interstitial (T-I) cells. Our results show that GENE treatment increased proliferation of the T-I cells through the MTORC1-dependent signaling pathway by increasing cell cycle regulatory proteins. Inhibition of ERK1/2 signaling caused partial reduction of insulin-induced phosphorylation of RPS6KB1 and RPS6 whereas inhibition of PI3-kinase signaling completely blocked the GENE response. Pharmacological inhibition of MTORC1 with CHEMICAL abrogated the GENE-induced phosphorylation of EIF4EBP1, RPS6KB1 and its downstream effector, RPS6. These results were further confirmed by demonstrating that knockdown of Mtor using siRNA reduced the insulin-stimulated MTORC1 signaling. Furthermore, insulin-stimulated T-I cell proliferation and the expression of cell cycle regulatory proteins CDK4, CCND3 and PCNA were also blocked by CHEMICAL. Taken together, the present studies show that GENE stimulates cell proliferation and cell cycle regulatory proteins in T-I cells via activation of the MTORC1 signaling pathway. | INHIBITOR |
| Stimulatory effect of insulin on theca-interstitial cell proliferation and GENE through MTORC1 dependent pathway. The present study examined the effect of insulin-mediated activation of the mammalian target of CHEMICAL complex 1 (MTORC1) signaling network on the proliferation of primary culture of theca-interstitial (T-I) cells. Our results show that insulin treatment increased proliferation of the T-I cells through the MTORC1-dependent signaling pathway by increasing GENE. Inhibition of ERK1/2 signaling caused partial reduction of insulin-induced phosphorylation of RPS6KB1 and RPS6 whereas inhibition of PI3-kinase signaling completely blocked the insulin response. Pharmacological inhibition of MTORC1 with CHEMICAL abrogated the insulin-induced phosphorylation of EIF4EBP1, RPS6KB1 and its downstream effector, RPS6. These results were further confirmed by demonstrating that knockdown of Mtor using siRNA reduced the insulin-stimulated MTORC1 signaling. Furthermore, insulin-stimulated T-I cell proliferation and the expression of GENE CDK4, CCND3 and PCNA were also blocked by CHEMICAL. Taken together, the present studies show that insulin stimulates cell proliferation and GENE in T-I cells via activation of the MTORC1 signaling pathway. | INDIRECT-DOWNREGULATOR |
| Stimulatory effect of insulin on theca-interstitial cell proliferation and cell cycle regulatory proteins through MTORC1 dependent pathway. The present study examined the effect of insulin-mediated activation of the mammalian target of CHEMICAL complex 1 (MTORC1) signaling network on the proliferation of primary culture of theca-interstitial (T-I) cells. Our results show that insulin treatment increased proliferation of the T-I cells through the MTORC1-dependent signaling pathway by increasing cell cycle regulatory proteins. Inhibition of ERK1/2 signaling caused partial reduction of insulin-induced phosphorylation of RPS6KB1 and RPS6 whereas inhibition of PI3-kinase signaling completely blocked the insulin response. Pharmacological inhibition of MTORC1 with CHEMICAL abrogated the insulin-induced phosphorylation of EIF4EBP1, RPS6KB1 and its downstream effector, RPS6. These results were further confirmed by demonstrating that knockdown of Mtor using siRNA reduced the insulin-stimulated MTORC1 signaling. Furthermore, insulin-stimulated T-I cell proliferation and the expression of cell cycle regulatory proteins GENE, CCND3 and PCNA were also blocked by CHEMICAL. Taken together, the present studies show that insulin stimulates cell proliferation and cell cycle regulatory proteins in T-I cells via activation of the MTORC1 signaling pathway. | INDIRECT-DOWNREGULATOR |
| Stimulatory effect of insulin on theca-interstitial cell proliferation and cell cycle regulatory proteins through MTORC1 dependent pathway. The present study examined the effect of insulin-mediated activation of the mammalian target of CHEMICAL complex 1 (MTORC1) signaling network on the proliferation of primary culture of theca-interstitial (T-I) cells. Our results show that insulin treatment increased proliferation of the T-I cells through the MTORC1-dependent signaling pathway by increasing cell cycle regulatory proteins. Inhibition of ERK1/2 signaling caused partial reduction of insulin-induced phosphorylation of RPS6KB1 and RPS6 whereas inhibition of PI3-kinase signaling completely blocked the insulin response. Pharmacological inhibition of MTORC1 with CHEMICAL abrogated the insulin-induced phosphorylation of EIF4EBP1, RPS6KB1 and its downstream effector, RPS6. These results were further confirmed by demonstrating that knockdown of Mtor using siRNA reduced the insulin-stimulated MTORC1 signaling. Furthermore, insulin-stimulated T-I cell proliferation and the expression of cell cycle regulatory proteins CDK4, GENE and PCNA were also blocked by CHEMICAL. Taken together, the present studies show that insulin stimulates cell proliferation and cell cycle regulatory proteins in T-I cells via activation of the MTORC1 signaling pathway. | INDIRECT-DOWNREGULATOR |
| Stimulatory effect of insulin on theca-interstitial cell proliferation and cell cycle regulatory proteins through MTORC1 dependent pathway. The present study examined the effect of insulin-mediated activation of the mammalian target of CHEMICAL complex 1 (MTORC1) signaling network on the proliferation of primary culture of theca-interstitial (T-I) cells. Our results show that insulin treatment increased proliferation of the T-I cells through the MTORC1-dependent signaling pathway by increasing cell cycle regulatory proteins. Inhibition of ERK1/2 signaling caused partial reduction of insulin-induced phosphorylation of RPS6KB1 and RPS6 whereas inhibition of PI3-kinase signaling completely blocked the insulin response. Pharmacological inhibition of MTORC1 with CHEMICAL abrogated the insulin-induced phosphorylation of EIF4EBP1, RPS6KB1 and its downstream effector, RPS6. These results were further confirmed by demonstrating that knockdown of Mtor using siRNA reduced the insulin-stimulated MTORC1 signaling. Furthermore, insulin-stimulated T-I cell proliferation and the expression of cell cycle regulatory proteins CDK4, CCND3 and GENE were also blocked by CHEMICAL. Taken together, the present studies show that insulin stimulates cell proliferation and cell cycle regulatory proteins in T-I cells via activation of the MTORC1 signaling pathway. | INDIRECT-DOWNREGULATOR |
| Stimulatory effect of insulin on theca-interstitial cell proliferation and cell cycle regulatory proteins through GENE dependent pathway. The present study examined the effect of insulin-mediated activation of the mammalian target of CHEMICAL complex 1 (MTORC1) signaling network on the proliferation of primary culture of theca-interstitial (T-I) cells. Our results show that insulin treatment increased proliferation of the T-I cells through the MTORC1-dependent signaling pathway by increasing cell cycle regulatory proteins. Inhibition of ERK1/2 signaling caused partial reduction of insulin-induced phosphorylation of RPS6KB1 and RPS6 whereas inhibition of PI3-kinase signaling completely blocked the insulin response. Pharmacological inhibition of GENE with CHEMICAL abrogated the insulin-induced phosphorylation of EIF4EBP1, RPS6KB1 and its downstream effector, RPS6. These results were further confirmed by demonstrating that knockdown of Mtor using siRNA reduced the insulin-stimulated GENE signaling. Furthermore, insulin-stimulated T-I cell proliferation and the expression of cell cycle regulatory proteins CDK4, CCND3 and PCNA were also blocked by CHEMICAL. Taken together, the present studies show that insulin stimulates cell proliferation and cell cycle regulatory proteins in T-I cells via activation of the GENE signaling pathway. | INHIBITOR |
| Stimulatory effect of insulin on theca-interstitial cell proliferation and cell cycle regulatory proteins through MTORC1 dependent pathway. The present study examined the effect of insulin-mediated activation of the mammalian target of CHEMICAL complex 1 (MTORC1) signaling network on the proliferation of primary culture of theca-interstitial (T-I) cells. Our results show that insulin treatment increased proliferation of the T-I cells through the MTORC1-dependent signaling pathway by increasing cell cycle regulatory proteins. Inhibition of ERK1/2 signaling caused partial reduction of insulin-induced phosphorylation of RPS6KB1 and RPS6 whereas inhibition of PI3-kinase signaling completely blocked the insulin response. Pharmacological inhibition of MTORC1 with CHEMICAL abrogated the insulin-induced phosphorylation of GENE, RPS6KB1 and its downstream effector, RPS6. These results were further confirmed by demonstrating that knockdown of Mtor using siRNA reduced the insulin-stimulated MTORC1 signaling. Furthermore, insulin-stimulated T-I cell proliferation and the expression of cell cycle regulatory proteins CDK4, CCND3 and PCNA were also blocked by CHEMICAL. Taken together, the present studies show that insulin stimulates cell proliferation and cell cycle regulatory proteins in T-I cells via activation of the MTORC1 signaling pathway. | INHIBITOR |
| Stimulatory effect of insulin on theca-interstitial cell proliferation and cell cycle regulatory proteins through MTORC1 dependent pathway. The present study examined the effect of insulin-mediated activation of the mammalian target of CHEMICAL complex 1 (MTORC1) signaling network on the proliferation of primary culture of theca-interstitial (T-I) cells. Our results show that insulin treatment increased proliferation of the T-I cells through the MTORC1-dependent signaling pathway by increasing cell cycle regulatory proteins. Inhibition of ERK1/2 signaling caused partial reduction of insulin-induced phosphorylation of GENE and RPS6 whereas inhibition of PI3-kinase signaling completely blocked the insulin response. Pharmacological inhibition of MTORC1 with CHEMICAL abrogated the insulin-induced phosphorylation of EIF4EBP1, GENE and its downstream effector, RPS6. These results were further confirmed by demonstrating that knockdown of Mtor using siRNA reduced the insulin-stimulated MTORC1 signaling. Furthermore, insulin-stimulated T-I cell proliferation and the expression of cell cycle regulatory proteins CDK4, CCND3 and PCNA were also blocked by CHEMICAL. Taken together, the present studies show that insulin stimulates cell proliferation and cell cycle regulatory proteins in T-I cells via activation of the MTORC1 signaling pathway. | INHIBITOR |
| Stimulatory effect of insulin on theca-interstitial cell proliferation and cell cycle regulatory proteins through MTORC1 dependent pathway. The present study examined the effect of insulin-mediated activation of the mammalian target of CHEMICAL complex 1 (MTORC1) signaling network on the proliferation of primary culture of theca-interstitial (T-I) cells. Our results show that insulin treatment increased proliferation of the T-I cells through the MTORC1-dependent signaling pathway by increasing cell cycle regulatory proteins. Inhibition of ERK1/2 signaling caused partial reduction of insulin-induced phosphorylation of RPS6KB1 and GENE whereas inhibition of PI3-kinase signaling completely blocked the insulin response. Pharmacological inhibition of MTORC1 with CHEMICAL abrogated the insulin-induced phosphorylation of EIF4EBP1, RPS6KB1 and its downstream effector, GENE. These results were further confirmed by demonstrating that knockdown of Mtor using siRNA reduced the insulin-stimulated MTORC1 signaling. Furthermore, insulin-stimulated T-I cell proliferation and the expression of cell cycle regulatory proteins CDK4, CCND3 and PCNA were also blocked by CHEMICAL. Taken together, the present studies show that insulin stimulates cell proliferation and cell cycle regulatory proteins in T-I cells via activation of the MTORC1 signaling pathway. | INHIBITOR |
| The conserved PHD1-PHD2 domain of ZFP-1/AF10 is a discrete functional module essential for viability in Caenorhabditis elegans. Plant homeodomain (PHD)-type zinc fingers play an important role in recognizing chromatin modifications and recruiting regulatory proteins to specific genes. A specific module containing a conventional PHD finger followed by an extended PHD finger exists in the mammalian GENE protein, among a few others. GENE has mostly been studied in the context of the leukemic MLL-AF10 fusion protein, which lacks the CHEMICAL-terminal PHD fingers of GENE. Although this domain of GENE is the most conserved region of the protein, its biological significance has not been elucidated. In this study, we used genetic and biochemical approaches to examine the PHD1-PHD2 region of the Caenorhabditis elegans ortholog of GENE, zinc finger protein 1 (ZFP-1). We demonstrate that the PHD1-PHD2 region is essential for viability and that the first PHD finger contributes to the preferred binding of PHD1-PHD2 to lysine 4-methylated histone H3 tails. Moreover, we show that ZFP-1 localization peaks overlap with H3K4 methylation-enriched promoters of actively expressed genes genomewide and that H3K4 methylation is important for ZFP-1 localization to promoters in the embryo. We predict that the essential biological role of the PHD1-PHD2 module of ZFP-1/AF10 is connected to the regulation of actively expressed genes during early development. | PART-OF |
| The conserved GENE domain of ZFP-1/AF10 is a discrete functional module essential for viability in Caenorhabditis elegans. Plant homeodomain (PHD)-type zinc fingers play an important role in recognizing chromatin modifications and recruiting regulatory proteins to specific genes. A specific module containing a conventional PHD finger followed by an extended PHD finger exists in the mammalian AF10 protein, among a few others. AF10 has mostly been studied in the context of the leukemic MLL-AF10 fusion protein, which lacks the N-terminal PHD fingers of AF10. Although this domain of AF10 is the most conserved region of the protein, its biological significance has not been elucidated. In this study, we used genetic and biochemical approaches to examine the GENE region of the Caenorhabditis elegans ortholog of AF10, zinc finger protein 1 (ZFP-1). We demonstrate that the GENE region is essential for viability and that the first PHD finger contributes to the preferred binding of GENE to CHEMICAL 4-methylated histone H3 tails. Moreover, we show that ZFP-1 localization peaks overlap with H3K4 methylation-enriched promoters of actively expressed genes genomewide and that H3K4 methylation is important for ZFP-1 localization to promoters in the embryo. We predict that the essential biological role of the GENE module of ZFP-1/AF10 is connected to the regulation of actively expressed genes during early development. | PART-OF |
| Synthesis and evaluation of 8-oxoadenine derivatives as potent Toll-like receptor 7 agonists with high water solubility. We report the discovery of novel series of highly potent GENE agonists based on 8-oxoadenines, 1 and 2 by introducing and optimizing various CHEMICAL onto the N(9)-position of the adenine moiety. The introduction of the amino group resulted in not only improved water solubility but also enhanced GENE agonistic activity. In particular compound 20 (DSR-6434) indicated an optimal balance between the agonistic potency and high water solubility. It also demonstrated a strong antitumor effect in vivo by intravenous administration in a tumor bearing mice model. | INHIBITOR |
| Synthesis and evaluation of 8-oxoadenine derivatives as potent Toll-like receptor 7 agonists with high water solubility. We report the discovery of novel series of highly potent GENE agonists based on 8-oxoadenines, 1 and 2 by introducing and optimizing various tertiary amines onto the CHEMICAL(9)-position of the adenine moiety. The introduction of the amino group resulted in not only improved water solubility but also enhanced GENE agonistic activity. In particular compound 20 (DSR-6434) indicated an optimal balance between the agonistic potency and high water solubility. It also demonstrated a strong antitumor effect in vivo by intravenous administration in a tumor bearing mice model. | REGULATOR |
| Synthesis and evaluation of 8-oxoadenine derivatives as potent Toll-like receptor 7 agonists with high water solubility. We report the discovery of novel series of highly potent GENE agonists based on 8-oxoadenines, 1 and 2 by introducing and optimizing various tertiary amines onto the N(9)-position of the CHEMICAL moiety. The introduction of the amino group resulted in not only improved water solubility but also enhanced GENE agonistic activity. In particular compound 20 (DSR-6434) indicated an optimal balance between the agonistic potency and high water solubility. It also demonstrated a strong antitumor effect in vivo by intravenous administration in a tumor bearing mice model. | ACTIVATOR |
| Synthesis and evaluation of 8-oxoadenine derivatives as potent Toll-like receptor 7 agonists with high water solubility. We report the discovery of novel series of highly potent GENE agonists based on 8-oxoadenines, 1 and 2 by introducing and optimizing various tertiary amines onto the N(9)-position of the adenine moiety. The introduction of the CHEMICAL group resulted in not only improved water solubility but also enhanced GENE agonistic activity. In particular compound 20 (DSR-6434) indicated an optimal balance between the agonistic potency and high water solubility. It also demonstrated a strong antitumor effect in vivo by intravenous administration in a tumor bearing mice model. | ACTIVATOR |
| Synthesis and evaluation of 8-oxoadenine derivatives as potent Toll-like receptor 7 agonists with high water solubility. We report the discovery of novel series of highly potent GENE agonists based on CHEMICAL, 1 and 2 by introducing and optimizing various tertiary amines onto the N(9)-position of the adenine moiety. The introduction of the amino group resulted in not only improved water solubility but also enhanced GENE agonistic activity. In particular compound 20 (DSR-6434) indicated an optimal balance between the agonistic potency and high water solubility. It also demonstrated a strong antitumor effect in vivo by intravenous administration in a tumor bearing mice model. | ACTIVATOR |
| Synthesis and evaluation of CHEMICAL derivatives as potent GENE agonists with high water solubility. We report the discovery of novel series of highly potent TLR7 agonists based on 8-oxoadenines, 1 and 2 by introducing and optimizing various tertiary amines onto the N(9)-position of the adenine moiety. The introduction of the amino group resulted in not only improved water solubility but also enhanced TLR7 agonistic activity. In particular compound 20 (DSR-6434) indicated an optimal balance between the agonistic potency and high water solubility. It also demonstrated a strong antitumor effect in vivo by intravenous administration in a tumor bearing mice model. | ACTIVATOR |
| Discovery of liver-targeted inhibitors of stearoyl-CoA desaturase (SCD1). Inhibitors based on a CHEMICAL scaffold were discovered for stearoyl-coenzyme A (CoA) desaturase 1 (GENE) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model. Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties. After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles. Responding to concerns about target localization and potential mechanism-based side effects, an initial effort was also made to improve liver concentration in an available rat PK model. An advanced compound 17m with a 5-carboxy-2-thiazole substructure appended to the spirocyclic piperidine scaffold was developed which satisfied the in vitro and in vivo requirements for more detailed studies. | INHIBITOR |
| Discovery of liver-targeted inhibitors of stearoyl-CoA desaturase (SCD1). Inhibitors based on a CHEMICAL scaffold were discovered for GENE (SCD1) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model. Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties. After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles. Responding to concerns about target localization and potential mechanism-based side effects, an initial effort was also made to improve liver concentration in an available rat PK model. An advanced compound 17m with a 5-carboxy-2-thiazole substructure appended to the spirocyclic piperidine scaffold was developed which satisfied the in vitro and in vivo requirements for more detailed studies. | INHIBITOR |
| Development of hypoxia-inducible factor (HIF)-1α inhibitors: effect of ortho-carborane substituents on HIF transcriptional activity under hypoxia. A series of substituted ortho-carboranylphenoxyacetanilides were synthesized and evaluated for their ability to inhibit hypoxia-induced HIF-1 transcriptional activity using a cell-based reporter assay in HeLa cells expressing the HRE-dependent firefly luciferase reporter construct (HRE-Luc) and constitutively expressing CMV-driven Renilla luciferase reporter, and their ability to inhibit cell growth (GI(50)) using the MTT assay. Among the compounds synthesized, 1g and 1l showed significant inhibition of hypoxia-induced HIF-1 transcriptional activity (IC(50): 1.9 ± 0.4 and 1.4 ± 0.2 μM, respectively). Both compounds suppressed HIF-1α accumulation in a concentration-dependent manner. The porcine heart malate dehydrogenase (MDH) refolding assay revealed that compound 1l inhibited GENE chaperone activity (IC(50): 6.80 ± 0.25 μM) and this inhibition activity was higher than that of CHEMICAL (IC(50): 10.9 ± 0.63 μM). | INHIBITOR |
| CHEMICAL and raisanberine alleviate intermittent hypoxia induced abnormal GENE and 3β-HSD and low testosterone by suppressing endoplasmic reticulum stress and activated p66Shc in rat testes. We hypothesized that hypoxia induced testicular damage is mediated by an activated NADPH oxidase (NOX), therefore, APO (apocynin) an inhibitor of NOX and raisanberine (RS), a calcium influx inhibitor were tested if they could attenuate hypoxic toxicity to the testis. Male Sprague-Dawley rats were exposed to hypoxia (10±0.5% O2) for 17d and intervened with APO and RS in the last 6d. Histological changes and expression of pro-inflammation factors were evaluated in vivo. Biomarkers in isolated Leydig cells incubated with H2O2 were also assayed in vitro. Hypoxic rats displayed lower serum testosterone and higher LH and FSH. Upregulation of p22/p47(phox), NOX2, MMP9, PERK and p66Shc was associated with downregulation of GENE, 3β-HSD and Cx43 in the hypoxia testis, revealed by Western blot and immunohistochemical assay, respectively. APO and RS at least partially normalize hypoxia caused male hypogonadism by suppressing ER stress, and p66Shc in testes. | GENE-CHEMICAL |
| CHEMICAL and raisanberine alleviate intermittent hypoxia induced abnormal StAR and GENE and low testosterone by suppressing endoplasmic reticulum stress and activated p66Shc in rat testes. We hypothesized that hypoxia induced testicular damage is mediated by an activated NADPH oxidase (NOX), therefore, APO (apocynin) an inhibitor of NOX and raisanberine (RS), a calcium influx inhibitor were tested if they could attenuate hypoxic toxicity to the testis. Male Sprague-Dawley rats were exposed to hypoxia (10±0.5% O2) for 17d and intervened with APO and RS in the last 6d. Histological changes and expression of pro-inflammation factors were evaluated in vivo. Biomarkers in isolated Leydig cells incubated with H2O2 were also assayed in vitro. Hypoxic rats displayed lower serum testosterone and higher LH and FSH. Upregulation of p22/p47(phox), NOX2, MMP9, PERK and p66Shc was associated with downregulation of StAR, GENE and Cx43 in the hypoxia testis, revealed by Western blot and immunohistochemical assay, respectively. APO and RS at least partially normalize hypoxia caused male hypogonadism by suppressing ER stress, and p66Shc in testes. | GENE-CHEMICAL |
| Apocynin and CHEMICAL alleviate intermittent hypoxia induced abnormal GENE and 3β-HSD and low testosterone by suppressing endoplasmic reticulum stress and activated p66Shc in rat testes. We hypothesized that hypoxia induced testicular damage is mediated by an activated NADPH oxidase (NOX), therefore, APO (apocynin) an inhibitor of NOX and CHEMICAL (RS), a calcium influx inhibitor were tested if they could attenuate hypoxic toxicity to the testis. Male Sprague-Dawley rats were exposed to hypoxia (10±0.5% O2) for 17d and intervened with APO and RS in the last 6d. Histological changes and expression of pro-inflammation factors were evaluated in vivo. Biomarkers in isolated Leydig cells incubated with H2O2 were also assayed in vitro. Hypoxic rats displayed lower serum testosterone and higher LH and FSH. Upregulation of p22/p47(phox), NOX2, MMP9, PERK and p66Shc was associated with downregulation of GENE, 3β-HSD and Cx43 in the hypoxia testis, revealed by Western blot and immunohistochemical assay, respectively. APO and RS at least partially normalize hypoxia caused male hypogonadism by suppressing ER stress, and p66Shc in testes. | GENE-CHEMICAL |
| CHEMICAL and raisanberine alleviate intermittent hypoxia induced abnormal StAR and 3β-HSD and low testosterone by suppressing endoplasmic reticulum stress and activated GENE in rat testes. We hypothesized that hypoxia induced testicular damage is mediated by an activated NADPH oxidase (NOX), therefore, APO (apocynin) an inhibitor of NOX and raisanberine (RS), a calcium influx inhibitor were tested if they could attenuate hypoxic toxicity to the testis. Male Sprague-Dawley rats were exposed to hypoxia (10±0.5% O2) for 17d and intervened with APO and RS in the last 6d. Histological changes and expression of pro-inflammation factors were evaluated in vivo. Biomarkers in isolated Leydig cells incubated with H2O2 were also assayed in vitro. Hypoxic rats displayed lower serum testosterone and higher LH and FSH. Upregulation of p22/p47(phox), NOX2, MMP9, PERK and GENE was associated with downregulation of StAR, 3β-HSD and Cx43 in the hypoxia testis, revealed by Western blot and immunohistochemical assay, respectively. APO and RS at least partially normalize hypoxia caused male hypogonadism by suppressing ER stress, and GENE in testes. | INDIRECT-UPREGULATOR |
| Apocynin and CHEMICAL alleviate intermittent hypoxia induced abnormal StAR and 3β-HSD and low testosterone by suppressing endoplasmic reticulum stress and activated GENE in rat testes. We hypothesized that hypoxia induced testicular damage is mediated by an activated NADPH oxidase (NOX), therefore, APO (apocynin) an inhibitor of NOX and CHEMICAL (RS), a calcium influx inhibitor were tested if they could attenuate hypoxic toxicity to the testis. Male Sprague-Dawley rats were exposed to hypoxia (10±0.5% O2) for 17d and intervened with APO and RS in the last 6d. Histological changes and expression of pro-inflammation factors were evaluated in vivo. Biomarkers in isolated Leydig cells incubated with H2O2 were also assayed in vitro. Hypoxic rats displayed lower serum testosterone and higher LH and FSH. Upregulation of p22/p47(phox), NOX2, MMP9, PERK and GENE was associated with downregulation of StAR, 3β-HSD and Cx43 in the hypoxia testis, revealed by Western blot and immunohistochemical assay, respectively. APO and RS at least partially normalize hypoxia caused male hypogonadism by suppressing ER stress, and GENE in testes. | ACTIVATOR |
| Apocynin and raisanberine alleviate intermittent hypoxia induced abnormal StAR and 3β-HSD and low testosterone by suppressing endoplasmic reticulum stress and activated p66Shc in rat testes. We hypothesized that hypoxia induced testicular damage is mediated by an activated NADPH oxidase (NOX), therefore, CHEMICAL (apocynin) an inhibitor of GENE and raisanberine (RS), a calcium influx inhibitor were tested if they could attenuate hypoxic toxicity to the testis. Male Sprague-Dawley rats were exposed to hypoxia (10±0.5% O2) for 17d and intervened with CHEMICAL and RS in the last 6d. Histological changes and expression of pro-inflammation factors were evaluated in vivo. Biomarkers in isolated Leydig cells incubated with H2O2 were also assayed in vitro. Hypoxic rats displayed lower serum testosterone and higher LH and FSH. Upregulation of p22/p47(phox), NOX2, MMP9, PERK and p66Shc was associated with downregulation of StAR, 3β-HSD and Cx43 in the hypoxia testis, revealed by Western blot and immunohistochemical assay, respectively. CHEMICAL and RS at least partially normalize hypoxia caused male hypogonadism by suppressing ER stress, and p66Shc in testes. | INHIBITOR |
| CHEMICAL and raisanberine alleviate intermittent hypoxia induced abnormal StAR and 3β-HSD and low testosterone by suppressing endoplasmic reticulum stress and activated p66Shc in rat testes. We hypothesized that hypoxia induced testicular damage is mediated by an activated NADPH oxidase (NOX), therefore, APO (CHEMICAL) an inhibitor of GENE and raisanberine (RS), a calcium influx inhibitor were tested if they could attenuate hypoxic toxicity to the testis. Male Sprague-Dawley rats were exposed to hypoxia (10±0.5% O2) for 17d and intervened with APO and RS in the last 6d. Histological changes and expression of pro-inflammation factors were evaluated in vivo. Biomarkers in isolated Leydig cells incubated with H2O2 were also assayed in vitro. Hypoxic rats displayed lower serum testosterone and higher LH and FSH. Upregulation of p22/p47(phox), NOX2, MMP9, PERK and p66Shc was associated with downregulation of StAR, 3β-HSD and Cx43 in the hypoxia testis, revealed by Western blot and immunohistochemical assay, respectively. APO and RS at least partially normalize hypoxia caused male hypogonadism by suppressing ER stress, and p66Shc in testes. | INHIBITOR |
| Apocynin and raisanberine alleviate intermittent hypoxia induced abnormal StAR and 3β-HSD and low testosterone by suppressing endoplasmic reticulum stress and activated GENE in rat testes. We hypothesized that hypoxia induced testicular damage is mediated by an activated NADPH oxidase (NOX), therefore, CHEMICAL (apocynin) an inhibitor of NOX and raisanberine (RS), a calcium influx inhibitor were tested if they could attenuate hypoxic toxicity to the testis. Male Sprague-Dawley rats were exposed to hypoxia (10±0.5% O2) for 17d and intervened with CHEMICAL and RS in the last 6d. Histological changes and expression of pro-inflammation factors were evaluated in vivo. Biomarkers in isolated Leydig cells incubated with H2O2 were also assayed in vitro. Hypoxic rats displayed lower serum testosterone and higher LH and FSH. Upregulation of p22/p47(phox), NOX2, MMP9, PERK and GENE was associated with downregulation of StAR, 3β-HSD and Cx43 in the hypoxia testis, revealed by Western blot and immunohistochemical assay, respectively. CHEMICAL and RS at least partially normalize hypoxia caused male hypogonadism by suppressing ER stress, and GENE in testes. | INDIRECT-DOWNREGULATOR |
| Apocynin and CHEMICAL alleviate intermittent hypoxia induced abnormal StAR and GENE and low testosterone by suppressing endoplasmic reticulum stress and activated p66Shc in rat testes. We hypothesized that hypoxia induced testicular damage is mediated by an activated NADPH oxidase (NOX), therefore, APO (apocynin) an inhibitor of NOX and CHEMICAL (RS), a calcium influx inhibitor were tested if they could attenuate hypoxic toxicity to the testis. Male Sprague-Dawley rats were exposed to hypoxia (10±0.5% O2) for 17d and intervened with APO and RS in the last 6d. Histological changes and expression of pro-inflammation factors were evaluated in vivo. Biomarkers in isolated Leydig cells incubated with H2O2 were also assayed in vitro. Hypoxic rats displayed lower serum testosterone and higher LH and FSH. Upregulation of p22/p47(phox), NOX2, MMP9, PERK and p66Shc was associated with downregulation of StAR, GENE and Cx43 in the hypoxia testis, revealed by Western blot and immunohistochemical assay, respectively. APO and RS at least partially normalize hypoxia caused male hypogonadism by suppressing ER stress, and p66Shc in testes. | GENE-CHEMICAL |
| Arsenic suppresses cell survival via Pirh2-mediated proteasomal degradation of ΔNp63 protein. Transcription factor p63, a member of the p53 family, shares a high degree of sequence similarity with p53. Because of transcription from two distinct promoters, the p63 gene encodes two isoforms, GENE and ΔNp63. Although GENE acts as a tumor suppressor, ΔNp63 functions as an oncogene and is often overexpressed in squamous cell carcinomas. Thus, therapeutic agents targeting ΔNp63 might be used to manage tumors that overexpress ΔNp63. Here we found that CHEMICAL, a frontline agent for acute promyelocytic leukemia, inhibits ΔNp63 but not GENE expression in time- and dose-dependent manners. In addition, we found that CHEMICAL decreases the stability of ΔNp63 protein via a proteasome-dependent pathway but has little effect on the level of ΔNp63 transcript. Furthermore, we found that CHEMICAL activates the Pirh2 promoter and consequently induces Pirh2 expression. Consistent with this, we found that knockdown of Pirh2 inhibits, whereas ectopic expression of Pirh2 enhances, arsenic-induced degradation of ΔNp63 protein. Importantly, we found that knockdown of ΔNp63 sensitizes, whereas ectopic expression of ΔNp63 inhibits, growth suppression induced by arsenic. Together, these data suggest that arsenic degrades ΔNp63 protein at least in part via Pirh2-dependent proteolysis and that inhibition of ΔNp63 expression facilitates tumor cells to arsenic-induced death. | NO-RELATIONSHIP |
| Arsenic suppresses cell survival via Pirh2-mediated proteasomal degradation of GENE protein. Transcription factor p63, a member of the p53 family, shares a high degree of sequence similarity with p53. Because of transcription from two distinct promoters, the p63 gene encodes two isoforms, TAp63 and GENE. Although TAp63 acts as a tumor suppressor, GENE functions as an oncogene and is often overexpressed in squamous cell carcinomas. Thus, therapeutic agents targeting GENE might be used to manage tumors that overexpress GENE. Here we found that CHEMICAL, a frontline agent for acute promyelocytic leukemia, inhibits GENE but not TAp63 expression in time- and dose-dependent manners. In addition, we found that CHEMICAL decreases the stability of GENE protein via a proteasome-dependent pathway but has little effect on the level of GENE transcript. Furthermore, we found that CHEMICAL activates the Pirh2 promoter and consequently induces Pirh2 expression. Consistent with this, we found that knockdown of Pirh2 inhibits, whereas ectopic expression of Pirh2 enhances, arsenic-induced degradation of GENE protein. Importantly, we found that knockdown of GENE sensitizes, whereas ectopic expression of GENE inhibits, growth suppression induced by arsenic. Together, these data suggest that arsenic degrades GENE protein at least in part via Pirh2-dependent proteolysis and that inhibition of GENE expression facilitates tumor cells to arsenic-induced death. | NO-RELATIONSHIP |
| CHEMICAL suppresses cell survival via Pirh2-mediated proteasomal degradation of GENE protein. Transcription factor p63, a member of the p53 family, shares a high degree of sequence similarity with p53. Because of transcription from two distinct promoters, the p63 gene encodes two isoforms, TAp63 and GENE. Although TAp63 acts as a tumor suppressor, GENE functions as an oncogene and is often overexpressed in squamous cell carcinomas. Thus, therapeutic agents targeting GENE might be used to manage tumors that overexpress GENE. Here we found that arsenic trioxide, a frontline agent for acute promyelocytic leukemia, inhibits GENE but not TAp63 expression in time- and dose-dependent manners. In addition, we found that arsenic trioxide decreases the stability of GENE protein via a proteasome-dependent pathway but has little effect on the level of GENE transcript. Furthermore, we found that arsenic trioxide activates the Pirh2 promoter and consequently induces Pirh2 expression. Consistent with this, we found that knockdown of Pirh2 inhibits, whereas ectopic expression of Pirh2 enhances, arsenic-induced degradation of GENE protein. Importantly, we found that knockdown of GENE sensitizes, whereas ectopic expression of GENE inhibits, growth suppression induced by arsenic. Together, these data suggest that arsenic degrades GENE protein at least in part via Pirh2-dependent proteolysis and that inhibition of GENE expression facilitates tumor cells to arsenic-induced death. | GENE-CHEMICAL |
| CHEMICAL suppresses cell survival via Pirh2-mediated proteasomal degradation of ΔNp63 protein. Transcription factor p63, a member of the p53 family, shares a high degree of sequence similarity with p53. Because of transcription from two distinct promoters, the p63 gene encodes two isoforms, TAp63 and ΔNp63. Although TAp63 acts as a tumor suppressor, ΔNp63 functions as an oncogene and is often overexpressed in squamous cell carcinomas. Thus, therapeutic agents targeting ΔNp63 might be used to manage tumors that overexpress ΔNp63. Here we found that CHEMICAL trioxide, a frontline agent for acute promyelocytic leukemia, inhibits ΔNp63 but not TAp63 expression in time- and dose-dependent manners. In addition, we found that CHEMICAL trioxide decreases the stability of ΔNp63 protein via a proteasome-dependent pathway but has little effect on the level of ΔNp63 transcript. Furthermore, we found that CHEMICAL trioxide activates the GENE promoter and consequently induces GENE expression. Consistent with this, we found that knockdown of GENE inhibits, whereas ectopic expression of GENE enhances, arsenic-induced degradation of ΔNp63 protein. Importantly, we found that knockdown of ΔNp63 sensitizes, whereas ectopic expression of ΔNp63 inhibits, growth suppression induced by CHEMICAL. Together, these data suggest that CHEMICAL degrades ΔNp63 protein at least in part via GENE-dependent proteolysis and that inhibition of ΔNp63 expression facilitates tumor cells to arsenic-induced death. | GENE-CHEMICAL |
| Arsenic suppresses cell survival via Pirh2-mediated proteasomal degradation of ΔNp63 protein. Transcription factor p63, a member of the p53 family, shares a high degree of sequence similarity with p53. Because of transcription from two distinct promoters, the p63 gene encodes two isoforms, TAp63 and ΔNp63. Although TAp63 acts as a tumor suppressor, ΔNp63 functions as an oncogene and is often overexpressed in squamous cell carcinomas. Thus, therapeutic agents targeting ΔNp63 might be used to manage tumors that overexpress ΔNp63. Here we found that CHEMICAL, a frontline agent for acute promyelocytic leukemia, inhibits ΔNp63 but not TAp63 expression in time- and dose-dependent manners. In addition, we found that CHEMICAL decreases the stability of ΔNp63 protein via a GENE-dependent pathway but has little effect on the level of ΔNp63 transcript. Furthermore, we found that CHEMICAL activates the Pirh2 promoter and consequently induces Pirh2 expression. Consistent with this, we found that knockdown of Pirh2 inhibits, whereas ectopic expression of Pirh2 enhances, arsenic-induced degradation of ΔNp63 protein. Importantly, we found that knockdown of ΔNp63 sensitizes, whereas ectopic expression of ΔNp63 inhibits, growth suppression induced by arsenic. Together, these data suggest that arsenic degrades ΔNp63 protein at least in part via Pirh2-dependent proteolysis and that inhibition of ΔNp63 expression facilitates tumor cells to arsenic-induced death. | REGULATOR |
| CHEMICAL suppresses cell survival via GENE-mediated proteasomal degradation of ΔNp63 protein. Transcription factor p63, a member of the p53 family, shares a high degree of sequence similarity with p53. Because of transcription from two distinct promoters, the p63 gene encodes two isoforms, TAp63 and ΔNp63. Although TAp63 acts as a tumor suppressor, ΔNp63 functions as an oncogene and is often overexpressed in squamous cell carcinomas. Thus, therapeutic agents targeting ΔNp63 might be used to manage tumors that overexpress ΔNp63. Here we found that arsenic trioxide, a frontline agent for acute promyelocytic leukemia, inhibits ΔNp63 but not TAp63 expression in time- and dose-dependent manners. In addition, we found that arsenic trioxide decreases the stability of ΔNp63 protein via a proteasome-dependent pathway but has little effect on the level of ΔNp63 transcript. Furthermore, we found that arsenic trioxide activates the GENE promoter and consequently induces GENE expression. Consistent with this, we found that knockdown of GENE inhibits, whereas ectopic expression of GENE enhances, arsenic-induced degradation of ΔNp63 protein. Importantly, we found that knockdown of ΔNp63 sensitizes, whereas ectopic expression of ΔNp63 inhibits, growth suppression induced by arsenic. Together, these data suggest that arsenic degrades ΔNp63 protein at least in part via Pirh2-dependent proteolysis and that inhibition of ΔNp63 expression facilitates tumor cells to arsenic-induced death. | REGULATOR |
| Arsenic suppresses cell survival via Pirh2-mediated proteasomal degradation of ΔNp63 protein. Transcription factor p63, a member of the p53 family, shares a high degree of sequence similarity with p53. Because of transcription from two distinct promoters, the p63 gene encodes two isoforms, TAp63 and ΔNp63. Although TAp63 acts as a tumor suppressor, ΔNp63 functions as an oncogene and is often overexpressed in squamous cell carcinomas. Thus, therapeutic agents targeting ΔNp63 might be used to manage tumors that overexpress ΔNp63. Here we found that CHEMICAL, a frontline agent for acute promyelocytic leukemia, inhibits ΔNp63 but not TAp63 expression in time- and dose-dependent manners. In addition, we found that CHEMICAL decreases the stability of ΔNp63 protein via a proteasome-dependent pathway but has little effect on the level of ΔNp63 transcript. Furthermore, we found that CHEMICAL activates the GENE and consequently induces Pirh2 expression. Consistent with this, we found that knockdown of Pirh2 inhibits, whereas ectopic expression of Pirh2 enhances, arsenic-induced degradation of ΔNp63 protein. Importantly, we found that knockdown of ΔNp63 sensitizes, whereas ectopic expression of ΔNp63 inhibits, growth suppression induced by arsenic. Together, these data suggest that arsenic degrades ΔNp63 protein at least in part via Pirh2-dependent proteolysis and that inhibition of ΔNp63 expression facilitates tumor cells to arsenic-induced death. | ACTIVATOR |
| Arsenic suppresses cell survival via Pirh2-mediated proteasomal degradation of ΔNp63 protein. Transcription factor p63, a member of the p53 family, shares a high degree of sequence similarity with p53. Because of transcription from two distinct promoters, the p63 gene encodes two isoforms, TAp63 and ΔNp63. Although TAp63 acts as a tumor suppressor, ΔNp63 functions as an oncogene and is often overexpressed in squamous cell carcinomas. Thus, therapeutic agents targeting ΔNp63 might be used to manage tumors that overexpress ΔNp63. Here we found that CHEMICAL, a frontline agent for acute promyelocytic leukemia, inhibits ΔNp63 but not TAp63 expression in time- and dose-dependent manners. In addition, we found that CHEMICAL decreases the stability of ΔNp63 protein via a proteasome-dependent pathway but has little effect on the level of ΔNp63 transcript. Furthermore, we found that CHEMICAL activates the GENE promoter and consequently induces GENE expression. Consistent with this, we found that knockdown of GENE inhibits, whereas ectopic expression of GENE enhances, arsenic-induced degradation of ΔNp63 protein. Importantly, we found that knockdown of ΔNp63 sensitizes, whereas ectopic expression of ΔNp63 inhibits, growth suppression induced by arsenic. Together, these data suggest that arsenic degrades ΔNp63 protein at least in part via Pirh2-dependent proteolysis and that inhibition of ΔNp63 expression facilitates tumor cells to arsenic-induced death. | INDIRECT-UPREGULATOR |
| CHEMICAL, isolated from dietary mugwort (Artemisia princeps), induces G2/M cell cycle arrest by inactivating cdc25C-cdc2 via ATM-Chk1/2 activation. CHEMICAL, a flavonoid derived from Artemisia princeps (Japanese mugwort), has been shown to inhibit the growth of several human cancer cells, However, the exact mechanism for the cytotoxic effect of jaceosidin is not completely understood. In this study, we investigated the molecular mechanism involved in the antiproliferative effect of jaceosidin in human endometrial cancer cells. We demonstrated that jaceosidin is a more potent inhibitor of cell growth than cisplatin in human endometrial cancer cells. In contrast, jaceosidin-induced cytotoxicity in normal endometrial cells was lower than that observed for cisplatin. CHEMICAL induced G2/M phase cell cycle arrest and modulated the levels of GENE and p-Cdc2 in Hec1A cells. Knockdown of p21 using specific siRNAs partially abrogated jaceosidin-induced cell growth inhibition. Additional mechanistic studies revealed that jaceosidin treatment resulted in an increase in phosphorylation of Cdc25C and ATM-Chk1/2. Ku55933, an ATM inhibitor, reversed jaceosidin-induced cell growth inhibition, in part. Moreover, jaceosidin treatment resulted in phosphorylation of ERK, and pretreatment with the ERK inhibitor, PD98059, attenuated cell growth inhibition by jaceosidin. These data suggest that jaceosidin, isolated from Japanese mugwort, modulates the ERK/ATM/Chk1/2 pathway, leading to inactivation of the Cdc2-cyclin B1 complex, followed by G2/M cell cycle arrest in endometrial cancer cells. | GENE-CHEMICAL |
| CHEMICAL, isolated from dietary mugwort (Artemisia princeps), induces G2/M cell cycle arrest by inactivating cdc25C-cdc2 via ATM-Chk1/2 activation. CHEMICAL, a flavonoid derived from Artemisia princeps (Japanese mugwort), has been shown to inhibit the growth of several human cancer cells, However, the exact mechanism for the cytotoxic effect of jaceosidin is not completely understood. In this study, we investigated the molecular mechanism involved in the antiproliferative effect of jaceosidin in human endometrial cancer cells. We demonstrated that jaceosidin is a more potent inhibitor of cell growth than cisplatin in human endometrial cancer cells. In contrast, jaceosidin-induced cytotoxicity in normal endometrial cells was lower than that observed for cisplatin. CHEMICAL induced G2/M phase cell cycle arrest and modulated the levels of cyclin B and GENE in Hec1A cells. Knockdown of p21 using specific siRNAs partially abrogated jaceosidin-induced cell growth inhibition. Additional mechanistic studies revealed that jaceosidin treatment resulted in an increase in phosphorylation of Cdc25C and ATM-Chk1/2. Ku55933, an ATM inhibitor, reversed jaceosidin-induced cell growth inhibition, in part. Moreover, jaceosidin treatment resulted in phosphorylation of ERK, and pretreatment with the ERK inhibitor, PD98059, attenuated cell growth inhibition by jaceosidin. These data suggest that jaceosidin, isolated from Japanese mugwort, modulates the ERK/ATM/Chk1/2 pathway, leading to inactivation of the Cdc2-cyclin B1 complex, followed by G2/M cell cycle arrest in endometrial cancer cells. | GENE-CHEMICAL |
| CHEMICAL, isolated from dietary mugwort (Artemisia princeps), induces G2/M cell cycle arrest by inactivating cdc25C-cdc2 via ATM-Chk1/2 activation. CHEMICAL, a flavonoid derived from Artemisia princeps (Japanese mugwort), has been shown to inhibit the growth of several human cancer cells, However, the exact mechanism for the cytotoxic effect of CHEMICAL is not completely understood. In this study, we investigated the molecular mechanism involved in the antiproliferative effect of CHEMICAL in human endometrial cancer cells. We demonstrated that CHEMICAL is a more potent inhibitor of cell growth than cisplatin in human endometrial cancer cells. In contrast, jaceosidin-induced cytotoxicity in normal endometrial cells was lower than that observed for cisplatin. CHEMICAL induced G2/M phase cell cycle arrest and modulated the levels of cyclin B and p-Cdc2 in Hec1A cells. Knockdown of p21 using specific siRNAs partially abrogated jaceosidin-induced cell growth inhibition. Additional mechanistic studies revealed that CHEMICAL treatment resulted in an increase in phosphorylation of Cdc25C and ATM-Chk1/2. Ku55933, an ATM inhibitor, reversed jaceosidin-induced cell growth inhibition, in part. Moreover, CHEMICAL treatment resulted in phosphorylation of GENE, and pretreatment with the GENE inhibitor, PD98059, attenuated cell growth inhibition by CHEMICAL. These data suggest that CHEMICAL, isolated from Japanese mugwort, modulates the ERK/ATM/Chk1/2 pathway, leading to inactivation of the Cdc2-cyclin B1 complex, followed by G2/M cell cycle arrest in endometrial cancer cells. | ACTIVATOR |
| CHEMICAL, isolated from dietary mugwort (Artemisia princeps), induces G2/M cell cycle arrest by inactivating cdc25C-cdc2 via ATM-Chk1/2 activation. CHEMICAL, a flavonoid derived from Artemisia princeps (Japanese mugwort), has been shown to inhibit the growth of several human cancer cells, However, the exact mechanism for the cytotoxic effect of CHEMICAL is not completely understood. In this study, we investigated the molecular mechanism involved in the antiproliferative effect of CHEMICAL in human endometrial cancer cells. We demonstrated that CHEMICAL is a more potent inhibitor of cell growth than cisplatin in human endometrial cancer cells. In contrast, jaceosidin-induced cytotoxicity in normal endometrial cells was lower than that observed for cisplatin. CHEMICAL induced G2/M phase cell cycle arrest and modulated the levels of cyclin B and p-Cdc2 in Hec1A cells. Knockdown of p21 using specific siRNAs partially abrogated jaceosidin-induced cell growth inhibition. Additional mechanistic studies revealed that CHEMICAL treatment resulted in an increase in phosphorylation of Cdc25C and ATM-Chk1/2. Ku55933, an GENE inhibitor, reversed jaceosidin-induced cell growth inhibition, in part. Moreover, CHEMICAL treatment resulted in phosphorylation of ERK, and pretreatment with the ERK inhibitor, PD98059, attenuated cell growth inhibition by CHEMICAL. These data suggest that CHEMICAL, isolated from Japanese mugwort, modulates the ERK/GENE/Chk1/2 pathway, leading to inactivation of the Cdc2-cyclin B1 complex, followed by G2/M cell cycle arrest in endometrial cancer cells. | REGULATOR |
| CHEMICAL, isolated from dietary mugwort (Artemisia princeps), induces G2/M cell cycle arrest by inactivating cdc25C-cdc2 via ATM-Chk1/2 activation. CHEMICAL, a flavonoid derived from Artemisia princeps (Japanese mugwort), has been shown to inhibit the growth of several human cancer cells, However, the exact mechanism for the cytotoxic effect of CHEMICAL is not completely understood. In this study, we investigated the molecular mechanism involved in the antiproliferative effect of CHEMICAL in human endometrial cancer cells. We demonstrated that CHEMICAL is a more potent inhibitor of cell growth than cisplatin in human endometrial cancer cells. In contrast, jaceosidin-induced cytotoxicity in normal endometrial cells was lower than that observed for cisplatin. CHEMICAL induced G2/M phase cell cycle arrest and modulated the levels of cyclin B and p-Cdc2 in Hec1A cells. Knockdown of p21 using specific siRNAs partially abrogated jaceosidin-induced cell growth inhibition. Additional mechanistic studies revealed that CHEMICAL treatment resulted in an increase in phosphorylation of GENE and ATM-Chk1/2. Ku55933, an ATM inhibitor, reversed jaceosidin-induced cell growth inhibition, in part. Moreover, CHEMICAL treatment resulted in phosphorylation of ERK, and pretreatment with the ERK inhibitor, PD98059, attenuated cell growth inhibition by CHEMICAL. These data suggest that CHEMICAL, isolated from Japanese mugwort, modulates the ERK/ATM/Chk1/2 pathway, leading to inactivation of the Cdc2-cyclin B1 complex, followed by G2/M cell cycle arrest in endometrial cancer cells. | ACTIVATOR |
| CHEMICAL, isolated from dietary mugwort (Artemisia princeps), induces G2/M cell cycle arrest by inactivating GENE-cdc2 via ATM-Chk1/2 activation. CHEMICAL, a flavonoid derived from Artemisia princeps (Japanese mugwort), has been shown to inhibit the growth of several human cancer cells, However, the exact mechanism for the cytotoxic effect of jaceosidin is not completely understood. In this study, we investigated the molecular mechanism involved in the antiproliferative effect of jaceosidin in human endometrial cancer cells. We demonstrated that jaceosidin is a more potent inhibitor of cell growth than cisplatin in human endometrial cancer cells. In contrast, jaceosidin-induced cytotoxicity in normal endometrial cells was lower than that observed for cisplatin. CHEMICAL induced G2/M phase cell cycle arrest and modulated the levels of cyclin B and p-Cdc2 in Hec1A cells. Knockdown of p21 using specific siRNAs partially abrogated jaceosidin-induced cell growth inhibition. Additional mechanistic studies revealed that jaceosidin treatment resulted in an increase in phosphorylation of Cdc25C and ATM-Chk1/2. Ku55933, an ATM inhibitor, reversed jaceosidin-induced cell growth inhibition, in part. Moreover, jaceosidin treatment resulted in phosphorylation of ERK, and pretreatment with the ERK inhibitor, PD98059, attenuated cell growth inhibition by jaceosidin. These data suggest that jaceosidin, isolated from Japanese mugwort, modulates the ERK/ATM/Chk1/2 pathway, leading to inactivation of the Cdc2-cyclin B1 complex, followed by G2/M cell cycle arrest in endometrial cancer cells. | INHIBITOR |
| CHEMICAL, isolated from dietary mugwort (Artemisia princeps), induces G2/M cell cycle arrest by inactivating cdc25C-GENE via ATM-Chk1/2 activation. CHEMICAL, a flavonoid derived from Artemisia princeps (Japanese mugwort), has been shown to inhibit the growth of several human cancer cells, However, the exact mechanism for the cytotoxic effect of jaceosidin is not completely understood. In this study, we investigated the molecular mechanism involved in the antiproliferative effect of jaceosidin in human endometrial cancer cells. We demonstrated that jaceosidin is a more potent inhibitor of cell growth than cisplatin in human endometrial cancer cells. In contrast, jaceosidin-induced cytotoxicity in normal endometrial cells was lower than that observed for cisplatin. CHEMICAL induced G2/M phase cell cycle arrest and modulated the levels of cyclin B and p-Cdc2 in Hec1A cells. Knockdown of p21 using specific siRNAs partially abrogated jaceosidin-induced cell growth inhibition. Additional mechanistic studies revealed that jaceosidin treatment resulted in an increase in phosphorylation of Cdc25C and ATM-Chk1/2. Ku55933, an ATM inhibitor, reversed jaceosidin-induced cell growth inhibition, in part. Moreover, jaceosidin treatment resulted in phosphorylation of ERK, and pretreatment with the ERK inhibitor, PD98059, attenuated cell growth inhibition by jaceosidin. These data suggest that jaceosidin, isolated from Japanese mugwort, modulates the ERK/ATM/Chk1/2 pathway, leading to inactivation of the Cdc2-cyclin B1 complex, followed by G2/M cell cycle arrest in endometrial cancer cells. | INHIBITOR |
| Jaceosidin, isolated from dietary mugwort (Artemisia princeps), induces G2/M cell cycle arrest by inactivating cdc25C-cdc2 via ATM-Chk1/2 activation. Jaceosidin, a flavonoid derived from Artemisia princeps (Japanese mugwort), has been shown to inhibit the growth of several human cancer cells, However, the exact mechanism for the cytotoxic effect of jaceosidin is not completely understood. In this study, we investigated the molecular mechanism involved in the antiproliferative effect of jaceosidin in human endometrial cancer cells. We demonstrated that jaceosidin is a more potent inhibitor of cell growth than cisplatin in human endometrial cancer cells. In contrast, jaceosidin-induced cytotoxicity in normal endometrial cells was lower than that observed for cisplatin. Jaceosidin induced G2/M phase cell cycle arrest and modulated the levels of cyclin B and p-Cdc2 in Hec1A cells. Knockdown of p21 using specific siRNAs partially abrogated jaceosidin-induced cell growth inhibition. Additional mechanistic studies revealed that jaceosidin treatment resulted in an increase in phosphorylation of Cdc25C and ATM-Chk1/2. Ku55933, an ATM inhibitor, reversed jaceosidin-induced cell growth inhibition, in part. Moreover, jaceosidin treatment resulted in phosphorylation of GENE, and pretreatment with the GENE inhibitor, CHEMICAL, attenuated cell growth inhibition by jaceosidin. These data suggest that jaceosidin, isolated from Japanese mugwort, modulates the ERK/ATM/Chk1/2 pathway, leading to inactivation of the Cdc2-cyclin B1 complex, followed by G2/M cell cycle arrest in endometrial cancer cells. | INHIBITOR |
| CHEMICAL, isolated from dietary mugwort (Artemisia princeps), induces G2/M cell cycle arrest by inactivating cdc25C-cdc2 via ATM-Chk1/2 activation. CHEMICAL, a flavonoid derived from Artemisia princeps (Japanese mugwort), has been shown to inhibit the growth of several human cancer cells, However, the exact mechanism for the cytotoxic effect of CHEMICAL is not completely understood. In this study, we investigated the molecular mechanism involved in the antiproliferative effect of CHEMICAL in human endometrial cancer cells. We demonstrated that CHEMICAL is a more potent inhibitor of cell growth than cisplatin in human endometrial cancer cells. In contrast, jaceosidin-induced cytotoxicity in normal endometrial cells was lower than that observed for cisplatin. CHEMICAL induced G2/M phase cell cycle arrest and modulated the levels of cyclin B and p-Cdc2 in Hec1A cells. Knockdown of p21 using specific siRNAs partially abrogated jaceosidin-induced cell growth inhibition. Additional mechanistic studies revealed that CHEMICAL treatment resulted in an increase in phosphorylation of Cdc25C and ATM-Chk1/2. Ku55933, an ATM inhibitor, reversed jaceosidin-induced cell growth inhibition, in part. Moreover, CHEMICAL treatment resulted in phosphorylation of ERK, and pretreatment with the ERK inhibitor, PD98059, attenuated cell growth inhibition by CHEMICAL. These data suggest that CHEMICAL, isolated from Japanese mugwort, modulates the ERK/ATM/Chk1/2 pathway, leading to inactivation of the GENE-cyclin B1 complex, followed by G2/M cell cycle arrest in endometrial cancer cells. | INHIBITOR |
| CHEMICAL, isolated from dietary mugwort (Artemisia princeps), induces G2/M cell cycle arrest by inactivating cdc25C-cdc2 via ATM-Chk1/2 activation. CHEMICAL, a flavonoid derived from Artemisia princeps (Japanese mugwort), has been shown to inhibit the growth of several human cancer cells, However, the exact mechanism for the cytotoxic effect of CHEMICAL is not completely understood. In this study, we investigated the molecular mechanism involved in the antiproliferative effect of CHEMICAL in human endometrial cancer cells. We demonstrated that CHEMICAL is a more potent inhibitor of cell growth than cisplatin in human endometrial cancer cells. In contrast, jaceosidin-induced cytotoxicity in normal endometrial cells was lower than that observed for cisplatin. CHEMICAL induced G2/M phase cell cycle arrest and modulated the levels of cyclin B and p-Cdc2 in Hec1A cells. Knockdown of p21 using specific siRNAs partially abrogated jaceosidin-induced cell growth inhibition. Additional mechanistic studies revealed that CHEMICAL treatment resulted in an increase in phosphorylation of Cdc25C and ATM-Chk1/2. Ku55933, an ATM inhibitor, reversed jaceosidin-induced cell growth inhibition, in part. Moreover, CHEMICAL treatment resulted in phosphorylation of ERK, and pretreatment with the ERK inhibitor, PD98059, attenuated cell growth inhibition by CHEMICAL. These data suggest that CHEMICAL, isolated from Japanese mugwort, modulates the ERK/ATM/Chk1/2 pathway, leading to inactivation of the Cdc2-GENE complex, followed by G2/M cell cycle arrest in endometrial cancer cells. | INHIBITOR |
| Electrical Stimuli Release CHEMICAL to Increase GENE Translocation and Glucose Uptake via PI3Kγ-Akt-AS160 in Skeletal Muscle Cells. Skeletal muscle glucose uptake in response to exercise is preserved in insulin-resistant conditions, but the signals involved are debated. CHEMICAL is released from skeletal muscle by contractile activity and can autocrinely signal through purinergic receptors, and we hypothesized it may influence glucose uptake. Electrical stimulation, CHEMICAL, and insulin each increased fluorescent 2-NBD-Glucose (2-NBDG) uptake in primary myotubes, but only electrical stimulation and ATP-dependent 2-NBDG uptake were inhibited by adenosine-phosphate phosphatase and by purinergic receptor blockade (suramin). Electrical stimulation transiently elevated extracellular CHEMICAL and caused Akt phosphorylation that was additive to insulin and inhibited by suramin. Exogenous CHEMICAL transiently activated Akt and, inhibiting phosphatidylinositol 3-kinase (PI3K) or Akt as well as dominant-negative Akt mutant, reduced ATP-dependent 2-NBDG uptake and Akt phosphorylation. ATP-dependent 2-NBDG uptake was also inhibited by the G protein βγ subunit-interacting peptide βark-ct and by the phosphatidylinositol 3-kinase-γ (PI3Kγ) inhibitor AS605240. CHEMICAL caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160/Rab8A reduced by dominant-negative Akt or PI3Kγ kinase-dead mutants, and potentiated by myristoylated PI3Kγ. CHEMICAL stimulated 2-NBDG uptake in normal and insulin-resistant adult muscle fibers, resembling the reported effect of exercise. Hence, the ATP-induced pathway may be tapped to bypass insulin resistance. | ACTIVATOR |
| Electrical Stimuli Release CHEMICAL to Increase GLUT4 Translocation and Glucose Uptake via GENE-Akt-AS160 in Skeletal Muscle Cells. Skeletal muscle glucose uptake in response to exercise is preserved in insulin-resistant conditions, but the signals involved are debated. CHEMICAL is released from skeletal muscle by contractile activity and can autocrinely signal through purinergic receptors, and we hypothesized it may influence glucose uptake. Electrical stimulation, CHEMICAL, and insulin each increased fluorescent 2-NBD-Glucose (2-NBDG) uptake in primary myotubes, but only electrical stimulation and ATP-dependent 2-NBDG uptake were inhibited by adenosine-phosphate phosphatase and by purinergic receptor blockade (suramin). Electrical stimulation transiently elevated extracellular CHEMICAL and caused Akt phosphorylation that was additive to insulin and inhibited by suramin. Exogenous CHEMICAL transiently activated Akt and, inhibiting phosphatidylinositol 3-kinase (PI3K) or Akt as well as dominant-negative Akt mutant, reduced ATP-dependent 2-NBDG uptake and Akt phosphorylation. ATP-dependent 2-NBDG uptake was also inhibited by the G protein βγ subunit-interacting peptide βark-ct and by the phosphatidylinositol 3-kinase-γ (PI3Kγ) inhibitor AS605240. CHEMICAL caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160/Rab8A reduced by dominant-negative Akt or GENE kinase-dead mutants, and potentiated by myristoylated GENE. CHEMICAL stimulated 2-NBDG uptake in normal and insulin-resistant adult muscle fibers, resembling the reported effect of exercise. Hence, the ATP-induced pathway may be tapped to bypass insulin resistance. | ACTIVATOR |
| Electrical Stimuli Release CHEMICAL to Increase GLUT4 Translocation and Glucose Uptake via PI3Kγ-GENE-AS160 in Skeletal Muscle Cells. Skeletal muscle glucose uptake in response to exercise is preserved in insulin-resistant conditions, but the signals involved are debated. CHEMICAL is released from skeletal muscle by contractile activity and can autocrinely signal through purinergic receptors, and we hypothesized it may influence glucose uptake. Electrical stimulation, CHEMICAL, and insulin each increased fluorescent 2-NBD-Glucose (2-NBDG) uptake in primary myotubes, but only electrical stimulation and ATP-dependent 2-NBDG uptake were inhibited by adenosine-phosphate phosphatase and by purinergic receptor blockade (suramin). Electrical stimulation transiently elevated extracellular CHEMICAL and caused GENE phosphorylation that was additive to insulin and inhibited by suramin. Exogenous CHEMICAL transiently activated GENE and, inhibiting phosphatidylinositol 3-kinase (PI3K) or GENE as well as dominant-negative GENE mutant, reduced ATP-dependent 2-NBDG uptake and GENE phosphorylation. ATP-dependent 2-NBDG uptake was also inhibited by the G protein βγ subunit-interacting peptide βark-ct and by the phosphatidylinositol 3-kinase-γ (PI3Kγ) inhibitor AS605240. CHEMICAL caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160/Rab8A reduced by dominant-negative GENE or PI3Kγ kinase-dead mutants, and potentiated by myristoylated PI3Kγ. CHEMICAL stimulated 2-NBDG uptake in normal and insulin-resistant adult muscle fibers, resembling the reported effect of exercise. Hence, the ATP-induced pathway may be tapped to bypass insulin resistance. | ACTIVATOR |
| Electrical Stimuli Release CHEMICAL to Increase GLUT4 Translocation and Glucose Uptake via PI3Kγ-Akt-GENE in Skeletal Muscle Cells. Skeletal muscle glucose uptake in response to exercise is preserved in insulin-resistant conditions, but the signals involved are debated. CHEMICAL is released from skeletal muscle by contractile activity and can autocrinely signal through purinergic receptors, and we hypothesized it may influence glucose uptake. Electrical stimulation, CHEMICAL, and insulin each increased fluorescent 2-NBD-Glucose (2-NBDG) uptake in primary myotubes, but only electrical stimulation and ATP-dependent 2-NBDG uptake were inhibited by adenosine-phosphate phosphatase and by purinergic receptor blockade (suramin). Electrical stimulation transiently elevated extracellular CHEMICAL and caused Akt phosphorylation that was additive to insulin and inhibited by suramin. Exogenous CHEMICAL transiently activated Akt and, inhibiting phosphatidylinositol 3-kinase (PI3K) or Akt as well as dominant-negative Akt mutant, reduced ATP-dependent 2-NBDG uptake and Akt phosphorylation. ATP-dependent 2-NBDG uptake was also inhibited by the G protein βγ subunit-interacting peptide βark-ct and by the phosphatidylinositol 3-kinase-γ (PI3Kγ) inhibitor AS605240. CHEMICAL caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160/Rab8A reduced by dominant-negative Akt or PI3Kγ kinase-dead mutants, and potentiated by myristoylated PI3Kγ. CHEMICAL stimulated 2-NBDG uptake in normal and insulin-resistant adult muscle fibers, resembling the reported effect of exercise. Hence, the ATP-induced pathway may be tapped to bypass insulin resistance. | REGULATOR |
| Electrical Stimuli Release CHEMICAL to Increase GLUT4 Translocation and Glucose Uptake via PI3Kγ-Akt-AS160 in Skeletal Muscle Cells. Skeletal muscle glucose uptake in response to exercise is preserved in insulin-resistant conditions, but the signals involved are debated. CHEMICAL is released from skeletal muscle by contractile activity and can autocrinely signal through GENE, and we hypothesized it may influence glucose uptake. Electrical stimulation, CHEMICAL, and insulin each increased fluorescent 2-NBD-Glucose (2-NBDG) uptake in primary myotubes, but only electrical stimulation and ATP-dependent 2-NBDG uptake were inhibited by adenosine-phosphate phosphatase and by purinergic receptor blockade (suramin). Electrical stimulation transiently elevated extracellular CHEMICAL and caused Akt phosphorylation that was additive to insulin and inhibited by suramin. Exogenous CHEMICAL transiently activated Akt and, inhibiting phosphatidylinositol 3-kinase (PI3K) or Akt as well as dominant-negative Akt mutant, reduced ATP-dependent 2-NBDG uptake and Akt phosphorylation. ATP-dependent 2-NBDG uptake was also inhibited by the G protein βγ subunit-interacting peptide βark-ct and by the phosphatidylinositol 3-kinase-γ (PI3Kγ) inhibitor AS605240. CHEMICAL caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160/Rab8A reduced by dominant-negative Akt or PI3Kγ kinase-dead mutants, and potentiated by myristoylated PI3Kγ. CHEMICAL stimulated 2-NBDG uptake in normal and insulin-resistant adult muscle fibers, resembling the reported effect of exercise. Hence, the ATP-induced pathway may be tapped to bypass insulin resistance. | REGULATOR |
| Electrical Stimuli Release ATP to Increase GLUT4 Translocation and Glucose Uptake via PI3Kγ-Akt-AS160 in Skeletal Muscle Cells. Skeletal muscle glucose uptake in response to exercise is preserved in insulin-resistant conditions, but the signals involved are debated. ATP is released from skeletal muscle by contractile activity and can autocrinely signal through purinergic receptors, and we hypothesized it may influence glucose uptake. Electrical stimulation, ATP, and insulin each increased fluorescent 2-NBD-Glucose (2-NBDG) uptake in primary myotubes, but only electrical stimulation and ATP-dependent 2-NBDG uptake were inhibited by GENE and by purinergic receptor blockade (CHEMICAL). Electrical stimulation transiently elevated extracellular ATP and caused Akt phosphorylation that was additive to insulin and inhibited by CHEMICAL. Exogenous ATP transiently activated Akt and, inhibiting phosphatidylinositol 3-kinase (PI3K) or Akt as well as dominant-negative Akt mutant, reduced ATP-dependent 2-NBDG uptake and Akt phosphorylation. ATP-dependent 2-NBDG uptake was also inhibited by the G protein βγ subunit-interacting peptide βark-ct and by the phosphatidylinositol 3-kinase-γ (PI3Kγ) inhibitor AS605240. ATP caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160/Rab8A reduced by dominant-negative Akt or PI3Kγ kinase-dead mutants, and potentiated by myristoylated PI3Kγ. ATP stimulated 2-NBDG uptake in normal and insulin-resistant adult muscle fibers, resembling the reported effect of exercise. Hence, the ATP-induced pathway may be tapped to bypass insulin resistance. | INHIBITOR |
| Electrical Stimuli Release ATP to Increase GLUT4 Translocation and Glucose Uptake via PI3Kγ-Akt-AS160 in Skeletal Muscle Cells. Skeletal muscle glucose uptake in response to exercise is preserved in insulin-resistant conditions, but the signals involved are debated. ATP is released from skeletal muscle by contractile activity and can autocrinely signal through purinergic receptors, and we hypothesized it may influence glucose uptake. Electrical stimulation, ATP, and insulin each increased fluorescent 2-NBD-Glucose (2-NBDG) uptake in primary myotubes, but only electrical stimulation and ATP-dependent 2-NBDG uptake were inhibited by adenosine-phosphate phosphatase and by GENE blockade (CHEMICAL). Electrical stimulation transiently elevated extracellular ATP and caused Akt phosphorylation that was additive to insulin and inhibited by CHEMICAL. Exogenous ATP transiently activated Akt and, inhibiting phosphatidylinositol 3-kinase (PI3K) or Akt as well as dominant-negative Akt mutant, reduced ATP-dependent 2-NBDG uptake and Akt phosphorylation. ATP-dependent 2-NBDG uptake was also inhibited by the G protein βγ subunit-interacting peptide βark-ct and by the phosphatidylinositol 3-kinase-γ (PI3Kγ) inhibitor AS605240. ATP caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160/Rab8A reduced by dominant-negative Akt or PI3Kγ kinase-dead mutants, and potentiated by myristoylated PI3Kγ. ATP stimulated 2-NBDG uptake in normal and insulin-resistant adult muscle fibers, resembling the reported effect of exercise. Hence, the ATP-induced pathway may be tapped to bypass insulin resistance. | INHIBITOR |
| Electrical Stimuli Release ATP to Increase GLUT4 Translocation and Glucose Uptake via PI3Kγ-Akt-AS160 in Skeletal Muscle Cells. Skeletal muscle glucose uptake in response to exercise is preserved in insulin-resistant conditions, but the signals involved are debated. ATP is released from skeletal muscle by contractile activity and can autocrinely signal through purinergic receptors, and we hypothesized it may influence glucose uptake. Electrical stimulation, ATP, and insulin each increased fluorescent 2-NBD-Glucose (2-NBDG) uptake in primary myotubes, but only electrical stimulation and ATP-dependent 2-NBDG uptake were inhibited by adenosine-phosphate phosphatase and by purinergic receptor blockade (suramin). Electrical stimulation transiently elevated extracellular ATP and caused GENE phosphorylation that was additive to insulin and inhibited by CHEMICAL. Exogenous ATP transiently activated GENE and, inhibiting phosphatidylinositol 3-kinase (PI3K) or GENE as well as dominant-negative GENE mutant, reduced ATP-dependent 2-NBDG uptake and GENE phosphorylation. ATP-dependent 2-NBDG uptake was also inhibited by the G protein βγ subunit-interacting peptide βark-ct and by the phosphatidylinositol 3-kinase-γ (PI3Kγ) inhibitor AS605240. ATP caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160/Rab8A reduced by dominant-negative GENE or PI3Kγ kinase-dead mutants, and potentiated by myristoylated PI3Kγ. ATP stimulated 2-NBDG uptake in normal and insulin-resistant adult muscle fibers, resembling the reported effect of exercise. Hence, the ATP-induced pathway may be tapped to bypass insulin resistance. | INHIBITOR |
| Electrical Stimuli Release ATP to Increase GLUT4 Translocation and Glucose Uptake via PI3Kγ-Akt-AS160 in Skeletal Muscle Cells. Skeletal muscle glucose uptake in response to exercise is preserved in insulin-resistant conditions, but the signals involved are debated. ATP is released from skeletal muscle by contractile activity and can autocrinely signal through purinergic receptors, and we hypothesized it may influence glucose uptake. Electrical stimulation, ATP, and insulin each increased fluorescent 2-NBD-Glucose (2-NBDG) uptake in primary myotubes, but only electrical stimulation and ATP-dependent 2-NBDG uptake were inhibited by adenosine-phosphate phosphatase and by purinergic receptor blockade (suramin). Electrical stimulation transiently elevated extracellular ATP and caused Akt phosphorylation that was additive to insulin and inhibited by suramin. Exogenous ATP transiently activated Akt and, inhibiting phosphatidylinositol 3-kinase (PI3K) or Akt as well as dominant-negative Akt mutant, reduced ATP-dependent 2-NBDG uptake and Akt phosphorylation. ATP-dependent 2-NBDG uptake was also inhibited by the G protein βγ subunit-interacting peptide βark-ct and by the GENE (PI3Kγ) inhibitor CHEMICAL. ATP caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160/Rab8A reduced by dominant-negative Akt or PI3Kγ kinase-dead mutants, and potentiated by myristoylated PI3Kγ. ATP stimulated 2-NBDG uptake in normal and insulin-resistant adult muscle fibers, resembling the reported effect of exercise. Hence, the ATP-induced pathway may be tapped to bypass insulin resistance. | INHIBITOR |
| Electrical Stimuli Release ATP to Increase GLUT4 Translocation and Glucose Uptake via PI3Kγ-Akt-AS160 in Skeletal Muscle Cells. Skeletal muscle glucose uptake in response to exercise is preserved in insulin-resistant conditions, but the signals involved are debated. ATP is released from skeletal muscle by contractile activity and can autocrinely signal through purinergic receptors, and we hypothesized it may influence glucose uptake. Electrical stimulation, ATP, and insulin each increased fluorescent 2-NBD-Glucose (2-NBDG) uptake in primary myotubes, but only electrical stimulation and ATP-dependent 2-NBDG uptake were inhibited by adenosine-phosphate phosphatase and by purinergic receptor blockade (suramin). Electrical stimulation transiently elevated extracellular ATP and caused Akt phosphorylation that was additive to insulin and inhibited by suramin. Exogenous ATP transiently activated Akt and, inhibiting phosphatidylinositol 3-kinase (PI3K) or Akt as well as dominant-negative Akt mutant, reduced ATP-dependent 2-NBDG uptake and Akt phosphorylation. ATP-dependent 2-NBDG uptake was also inhibited by the G protein βγ subunit-interacting peptide βark-ct and by the phosphatidylinositol 3-kinase-γ (GENE) inhibitor CHEMICAL. ATP caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160/Rab8A reduced by dominant-negative Akt or GENE kinase-dead mutants, and potentiated by myristoylated GENE. ATP stimulated 2-NBDG uptake in normal and insulin-resistant adult muscle fibers, resembling the reported effect of exercise. Hence, the ATP-induced pathway may be tapped to bypass insulin resistance. | INHIBITOR |
| Electrical Stimuli Release ATP to Increase GENE Translocation and CHEMICAL Uptake via PI3Kγ-Akt-AS160 in Skeletal Muscle Cells. Skeletal muscle glucose uptake in response to exercise is preserved in insulin-resistant conditions, but the signals involved are debated. ATP is released from skeletal muscle by contractile activity and can autocrinely signal through purinergic receptors, and we hypothesized it may influence glucose uptake. Electrical stimulation, ATP, and insulin each increased fluorescent 2-NBD-Glucose (2-NBDG) uptake in primary myotubes, but only electrical stimulation and ATP-dependent 2-NBDG uptake were inhibited by adenosine-phosphate phosphatase and by purinergic receptor blockade (suramin). Electrical stimulation transiently elevated extracellular ATP and caused Akt phosphorylation that was additive to insulin and inhibited by suramin. Exogenous ATP transiently activated Akt and, inhibiting phosphatidylinositol 3-kinase (PI3K) or Akt as well as dominant-negative Akt mutant, reduced ATP-dependent 2-NBDG uptake and Akt phosphorylation. ATP-dependent 2-NBDG uptake was also inhibited by the G protein βγ subunit-interacting peptide βark-ct and by the phosphatidylinositol 3-kinase-γ (PI3Kγ) inhibitor AS605240. ATP caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160/Rab8A reduced by dominant-negative Akt or PI3Kγ kinase-dead mutants, and potentiated by myristoylated PI3Kγ. ATP stimulated 2-NBDG uptake in normal and insulin-resistant adult muscle fibers, resembling the reported effect of exercise. Hence, the ATP-induced pathway may be tapped to bypass insulin resistance. | SUBSTRATE |
| The COP9 signalosome interacts with and regulates interferon regulatory factor 5 protein stability. The transcription factor interferon regulatory factor 5 (IRF5) exerts crucial functions in the regulation of host immunity against extracellular pathogens, DNA damage-induced apoptosis, death receptor signaling, and macrophage polarization. Tight regulation of GENE is thus warranted for an efficient response toward extracellular stressors and for limiting autoimmune and inflammatory responses. Here we report that the COP9 signalosome (CSN), a general modulator of diverse cellular and developmental processes, associates constitutively with GENE and promotes its protein stability. The constitutive CSN/IRF5 interaction was identified using proteomics and confirmed by endogenous immunoprecipitations. The CSN/IRF5 interaction occurred on the CHEMICAL and amino termini of GENE; a single internal deletion from amino acids 455 to 466 (Δ455-466) was found to significantly reduce GENE protein stability. CSN subunit 3 (CSN3) was identified as a direct interacting partner of GENE, and knockdown of this subunit with small interfering RNAs resulted in enhanced degradation. Degradation was further augmented by knockdown of CSN1 and CSN3 together. The ubiquitin E1 inhibitor UBEI-41 or the proteasome inhibitor MG132 prevented GENE degradation, supporting the idea that its stability is regulated by the ubiquitin-proteasome system. Importantly, activation of GENE by the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resulted in enhanced degradation via loss of the CSN/IRF5 interaction. This study defines CSN to be a new interacting partner of GENE that controls its stability. | PART-OF |
| The COP9 signalosome interacts with and regulates interferon regulatory factor 5 protein stability. The transcription factor interferon regulatory factor 5 (IRF5) exerts crucial functions in the regulation of host immunity against extracellular pathogens, DNA damage-induced apoptosis, death receptor signaling, and macrophage polarization. Tight regulation of GENE is thus warranted for an efficient response toward extracellular stressors and for limiting autoimmune and inflammatory responses. Here we report that the COP9 signalosome (CSN), a general modulator of diverse cellular and developmental processes, associates constitutively with GENE and promotes its protein stability. The constitutive CSN/IRF5 interaction was identified using proteomics and confirmed by endogenous immunoprecipitations. The CSN/IRF5 interaction occurred on the carboxyl and CHEMICAL termini of GENE; a single internal deletion from CHEMICAL acids 455 to 466 (Δ455-466) was found to significantly reduce GENE protein stability. CSN subunit 3 (CSN3) was identified as a direct interacting partner of GENE, and knockdown of this subunit with small interfering RNAs resulted in enhanced degradation. Degradation was further augmented by knockdown of CSN1 and CSN3 together. The ubiquitin E1 inhibitor UBEI-41 or the proteasome inhibitor MG132 prevented GENE degradation, supporting the idea that its stability is regulated by the ubiquitin-proteasome system. Importantly, activation of GENE by the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resulted in enhanced degradation via loss of the CSN/IRF5 interaction. This study defines CSN to be a new interacting partner of GENE that controls its stability. | PART-OF |
| The COP9 signalosome interacts with and regulates interferon regulatory factor 5 protein stability. The transcription factor interferon regulatory factor 5 (IRF5) exerts crucial functions in the regulation of host immunity against extracellular pathogens, DNA damage-induced apoptosis, death receptor signaling, and macrophage polarization. Tight regulation of GENE is thus warranted for an efficient response toward extracellular stressors and for limiting autoimmune and inflammatory responses. Here we report that the COP9 signalosome (CSN), a general modulator of diverse cellular and developmental processes, associates constitutively with GENE and promotes its protein stability. The constitutive CSN/IRF5 interaction was identified using proteomics and confirmed by endogenous immunoprecipitations. The CSN/IRF5 interaction occurred on the carboxyl and amino termini of IRF5; a single internal deletion from CHEMICAL 455 to 466 (Δ455-466) was found to significantly reduce GENE protein stability. CSN subunit 3 (CSN3) was identified as a direct interacting partner of GENE, and knockdown of this subunit with small interfering RNAs resulted in enhanced degradation. Degradation was further augmented by knockdown of CSN1 and CSN3 together. The ubiquitin E1 inhibitor UBEI-41 or the proteasome inhibitor MG132 prevented GENE degradation, supporting the idea that its stability is regulated by the ubiquitin-proteasome system. Importantly, activation of GENE by the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resulted in enhanced degradation via loss of the CSN/IRF5 interaction. This study defines CSN to be a new interacting partner of GENE that controls its stability. | PART-OF |
| Structure-based design, synthesis and evaluation of novel CHEMICAL derivatives as telomerase inhibitors and potential for cancer polypharmacology. A series of CHEMICAL derivatives were synthesized and evaluated for telomerase inhibition, GENE expression and suppression of cancer cell growth in vitro. All of the compounds tested, except for compounds 4, 7, 16, 24, 27 and 28 were selected by the NCI screening system. Among them, compounds 16, 39, and 40 repressed GENE expression without greatly affecting cell growth, suggesting for the selectivity toward GENE expression. Taken together, our findings indicated that the analysis of cytotoxicity and telomerase inhibition might provide information applicable for further developing potential telomerase and polypharmacological targeting strategy. | INHIBITOR |
| Structure-based design, synthesis and evaluation of novel CHEMICAL derivatives as GENE inhibitors and potential for cancer polypharmacology. A series of CHEMICAL derivatives were synthesized and evaluated for GENE inhibition, hTERT expression and suppression of cancer cell growth in vitro. All of the compounds tested, except for compounds 4, 7, 16, 24, 27 and 28 were selected by the NCI screening system. Among them, compounds 16, 39, and 40 repressed hTERT expression without greatly affecting cell growth, suggesting for the selectivity toward hTERT expression. Taken together, our findings indicated that the analysis of cytotoxicity and GENE inhibition might provide information applicable for further developing potential GENE and polypharmacological targeting strategy. | INHIBITOR |
| Trichostatin A inhibits transforming growth factor-β-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced NF-E2-related factor 2-antioxidant response element signaling. Trichostatin A (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by CHEMICAL on transforming growth factor-β (TGF-β)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with TGF-β in the presence of CHEMICAL, the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (Nrf2-ARE) activator sulforaphane, or small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin (α-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H(2)O(2), intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with CHEMICAL and the Nrf2-ARE activator resulted in increased inhibition of the TGF-β-induced myofibroblast differentiation as compared with treatment with DPI or NAC. Furthermore, CHEMICAL also decreased cellular ROS and H(2)O(2) accumulation induced by TGF-β, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, CHEMICAL induced GENE nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas GENE knockdown by RNA interference blocked the inhibition of CHEMICAL on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that CHEMICAL inhibits TGF-β-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling. | GENE-CHEMICAL |
| Trichostatin A inhibits transforming growth factor-β-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced NF-E2-related factor 2-antioxidant response element signaling. Trichostatin A (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by CHEMICAL on GENE (TGF-β)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with TGF-β in the presence of CHEMICAL, the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (Nrf2-ARE) activator sulforaphane, or small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin (α-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H(2)O(2), intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with CHEMICAL and the Nrf2-ARE activator resulted in increased inhibition of the TGF-β-induced myofibroblast differentiation as compared with treatment with DPI or NAC. Furthermore, CHEMICAL also decreased cellular ROS and H(2)O(2) accumulation induced by TGF-β, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, CHEMICAL induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of CHEMICAL on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that CHEMICAL inhibits TGF-β-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling. | REGULATOR |
| Trichostatin A inhibits transforming growth factor-β-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced NF-E2-related factor 2-antioxidant response element signaling. Trichostatin A (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by TSA on transforming growth factor-β (TGF-β)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with GENE in the presence of TSA, the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (Nrf2-ARE) activator sulforaphane, or small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin (α-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H(2)O(2), intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with TSA and the Nrf2-ARE activator resulted in increased inhibition of the GENE-induced myofibroblast differentiation as compared with treatment with CHEMICAL or NAC. Furthermore, TSA also decreased cellular ROS and H(2)O(2) accumulation induced by GENE, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, TSA induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of TSA on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that TSA inhibits TGF-β-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling. | GENE-CHEMICAL |
| Trichostatin A inhibits transforming growth factor-β-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced NF-E2-related factor 2-antioxidant response element signaling. Trichostatin A (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by TSA on transforming growth factor-β (TGF-β)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with GENE in the presence of TSA, the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (Nrf2-ARE) activator sulforaphane, or small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin (α-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H(2)O(2), intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with TSA and the Nrf2-ARE activator resulted in increased inhibition of the GENE-induced myofibroblast differentiation as compared with treatment with DPI or CHEMICAL. Furthermore, TSA also decreased cellular ROS and H(2)O(2) accumulation induced by GENE, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, TSA induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of TSA on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that TSA inhibits TGF-β-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling. | GENE-CHEMICAL |
| Trichostatin A inhibits transforming growth factor-β-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced NF-E2-related factor 2-antioxidant response element signaling. Trichostatin A (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by TSA on transforming growth factor-β (TGF-β)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with TGF-β in the presence of TSA, the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), the antioxidant N-acetyl-cysteine (NAC), the GENE-antioxidant response element (Nrf2-ARE) activator CHEMICAL, or small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin (α-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H(2)O(2), intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with TSA and the Nrf2-ARE activator resulted in increased inhibition of the TGF-β-induced myofibroblast differentiation as compared with treatment with DPI or NAC. Furthermore, TSA also decreased cellular ROS and H(2)O(2) accumulation induced by TGF-β, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, TSA induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of TSA on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that TSA inhibits TGF-β-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling. | ACTIVATOR |
| Trichostatin A inhibits transforming growth factor-β-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced NF-E2-related factor 2-antioxidant response element signaling. Trichostatin A (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by TSA on transforming growth factor-β (TGF-β)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with TGF-β in the presence of TSA, the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-GENE (Nrf2-ARE) activator CHEMICAL, or small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin (α-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H(2)O(2), intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with TSA and the Nrf2-ARE activator resulted in increased inhibition of the TGF-β-induced myofibroblast differentiation as compared with treatment with DPI or NAC. Furthermore, TSA also decreased cellular ROS and H(2)O(2) accumulation induced by TGF-β, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, TSA induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of TSA on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that TSA inhibits TGF-β-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling. | ACTIVATOR |
| Trichostatin A inhibits transforming growth factor-β-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced NF-E2-related factor 2-antioxidant response element signaling. Trichostatin A (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by TSA on transforming growth factor-β (TGF-β)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with TGF-β in the presence of TSA, the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (GENE-ARE) activator CHEMICAL, or small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin (α-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H(2)O(2), intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with TSA and the Nrf2-ARE activator resulted in increased inhibition of the TGF-β-induced myofibroblast differentiation as compared with treatment with DPI or NAC. Furthermore, TSA also decreased cellular ROS and H(2)O(2) accumulation induced by TGF-β, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, TSA induced GENE nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas GENE knockdown by RNA interference blocked the inhibition of TSA on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that TSA inhibits TGF-β-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling. | ACTIVATOR |
| Trichostatin A inhibits transforming growth factor-β-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced NF-E2-related factor 2-antioxidant response element signaling. Trichostatin A (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by TSA on transforming growth factor-β (TGF-β)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with TGF-β in the presence of TSA, the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (Nrf2-GENE) activator CHEMICAL, or small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin (α-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H(2)O(2), intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with TSA and the Nrf2-ARE activator resulted in increased inhibition of the TGF-β-induced myofibroblast differentiation as compared with treatment with DPI or NAC. Furthermore, TSA also decreased cellular ROS and H(2)O(2) accumulation induced by TGF-β, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, TSA induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of TSA on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that TSA inhibits TGF-β-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling. | ACTIVATOR |
| Trichostatin A inhibits transforming growth factor-β-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced NF-E2-related factor 2-antioxidant response element signaling. Trichostatin A (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by CHEMICAL on transforming growth factor-β (TGF-β)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with TGF-β in the presence of CHEMICAL, the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (Nrf2-ARE) activator sulforaphane, or small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin (α-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H(2)O(2), intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with CHEMICAL and the Nrf2-ARE activator resulted in increased inhibition of the TGF-β-induced myofibroblast differentiation as compared with treatment with DPI or NAC. Furthermore, CHEMICAL also decreased cellular ROS and H(2)O(2) accumulation induced by TGF-β, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, CHEMICAL induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of CHEMICAL on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that CHEMICAL inhibits TGF-β-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-GENE signaling. | ACTIVATOR |
| CHEMICAL inhibits transforming growth factor-β-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced GENE-antioxidant response element signaling. CHEMICAL (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by TSA on transforming growth factor-β (TGF-β)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with TGF-β in the presence of TSA, the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (Nrf2-ARE) activator sulforaphane, or small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin (α-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H(2)O(2), intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with TSA and the Nrf2-ARE activator resulted in increased inhibition of the TGF-β-induced myofibroblast differentiation as compared with treatment with DPI or NAC. Furthermore, TSA also decreased cellular ROS and H(2)O(2) accumulation induced by TGF-β, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, TSA induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of TSA on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that TSA inhibits TGF-β-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling. | INDIRECT-UPREGULATOR |
| CHEMICAL inhibits transforming growth factor-β-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced NF-E2-related factor 2-GENE signaling. CHEMICAL (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by TSA on transforming growth factor-β (TGF-β)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with TGF-β in the presence of TSA, the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (Nrf2-ARE) activator sulforaphane, or small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin (α-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H(2)O(2), intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with TSA and the Nrf2-ARE activator resulted in increased inhibition of the TGF-β-induced myofibroblast differentiation as compared with treatment with DPI or NAC. Furthermore, TSA also decreased cellular ROS and H(2)O(2) accumulation induced by TGF-β, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, TSA induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of TSA on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that TSA inhibits TGF-β-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling. | ACTIVATOR |
| Trichostatin A inhibits transforming growth factor-β-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced NF-E2-related factor 2-antioxidant response element signaling. Trichostatin A (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by CHEMICAL on transforming growth factor-β (TGF-β)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with GENE in the presence of CHEMICAL, the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (Nrf2-ARE) activator sulforaphane, or small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin (α-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H(2)O(2), intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with CHEMICAL and the Nrf2-ARE activator resulted in increased inhibition of the TGF-β-induced myofibroblast differentiation as compared with treatment with DPI or NAC. Furthermore, CHEMICAL also decreased cellular ROS and H(2)O(2) accumulation induced by GENE, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, CHEMICAL induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of CHEMICAL on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that CHEMICAL inhibits GENE-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling. | INHIBITOR |
| Trichostatin A inhibits transforming growth factor-β-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced NF-E2-related factor 2-antioxidant response element signaling. Trichostatin A (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by TSA on transforming growth factor-β (TGF-β)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with TGF-β in the presence of TSA, the GENE inhibitor CHEMICAL (DPI), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (Nrf2-ARE) activator sulforaphane, or small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin (α-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H(2)O(2), intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with TSA and the Nrf2-ARE activator resulted in increased inhibition of the TGF-β-induced myofibroblast differentiation as compared with treatment with DPI or NAC. Furthermore, TSA also decreased cellular ROS and H(2)O(2) accumulation induced by TGF-β, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, TSA induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of TSA on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that TSA inhibits TGF-β-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling. | INHIBITOR |
| Trichostatin A inhibits transforming growth factor-β-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced NF-E2-related factor 2-antioxidant response element signaling. Trichostatin A (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by TSA on transforming growth factor-β (TGF-β)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with TGF-β in the presence of TSA, the GENE inhibitor diphenyleneiodonium (CHEMICAL), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (Nrf2-ARE) activator sulforaphane, or small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin (α-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H(2)O(2), intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with TSA and the Nrf2-ARE activator resulted in increased inhibition of the TGF-β-induced myofibroblast differentiation as compared with treatment with CHEMICAL or NAC. Furthermore, TSA also decreased cellular ROS and H(2)O(2) accumulation induced by TGF-β, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, TSA induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of TSA on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that TSA inhibits TGF-β-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling. | INHIBITOR |
| CHEMICAL inhibits GENE-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced NF-E2-related factor 2-antioxidant response element signaling. CHEMICAL (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by TSA on GENE (TGF-β)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with TGF-β in the presence of TSA, the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (Nrf2-ARE) activator sulforaphane, or small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin (α-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H(2)O(2), intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with TSA and the Nrf2-ARE activator resulted in increased inhibition of the TGF-β-induced myofibroblast differentiation as compared with treatment with DPI or NAC. Furthermore, TSA also decreased cellular ROS and H(2)O(2) accumulation induced by TGF-β, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, TSA induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of TSA on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that TSA inhibits TGF-β-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling. | INHIBITOR |
| Cannabinoid discrimination and antagonism by CB(1) neutral and inverse agonist antagonists. Cannabinoid receptor 1 (CB(1)) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB(1) neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the CB(1) inverse agonist SR141716A (rimonabant) and the CB(1) neutral antagonist CHEMICAL were compared for their ability to modify GENE-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB(1) full agonist AM4054. Results indicate that AM4054 serves as an effective CB(1) discriminative stimulus, with an onset and time course of action comparable with that of the CB(1) agonist Δ(9)-tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist CHEMICAL produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that rimonabant and CHEMICAL produce highly similar antagonist effects, as evident in comparable pA(2) values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB(1) neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB(1) receptors. | REGULATOR |
| Cannabinoid discrimination and antagonism by CB(1) neutral and inverse agonist antagonists. Cannabinoid receptor 1 (CB(1)) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB(1) neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the CB(1) inverse agonist CHEMICAL (rimonabant) and the CB(1) neutral antagonist AM4113 were compared for their ability to modify GENE-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB(1) full agonist AM4054. Results indicate that AM4054 serves as an effective CB(1) discriminative stimulus, with an onset and time course of action comparable with that of the CB(1) agonist Δ(9)-tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA(2) values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB(1) neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB(1) receptors. | REGULATOR |
| Cannabinoid discrimination and antagonism by CB(1) neutral and inverse agonist antagonists. Cannabinoid receptor 1 (CB(1)) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB(1) neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the CB(1) inverse agonist SR141716A (CHEMICAL) and the CB(1) neutral antagonist AM4113 were compared for their ability to modify GENE-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB(1) full agonist AM4054. Results indicate that AM4054 serves as an effective CB(1) discriminative stimulus, with an onset and time course of action comparable with that of the CB(1) agonist Δ(9)-tetrahydrocannabinol, and that the inverse agonist CHEMICAL and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that CHEMICAL and AM4113 produce highly similar antagonist effects, as evident in comparable pA(2) values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB(1) neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB(1) receptors. | REGULATOR |
| Cannabinoid discrimination and antagonism by GENE neutral and inverse agonist antagonists. Cannabinoid receptor 1 (CB(1)) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of GENE neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the GENE inverse agonist SR141716A (rimonabant) and the GENE neutral antagonist AM4113 were compared for their ability to modify GENE receptor-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel GENE full agonist CHEMICAL. Results indicate that CHEMICAL serves as an effective GENE discriminative stimulus, with an onset and time course of action comparable with that of the GENE agonist Δ(9)-tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the CHEMICAL dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of CHEMICAL. Schild analyses further show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA(2) values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for GENE neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at GENE receptors. | ACTIVATOR |
| Cannabinoid discrimination and antagonism by GENE neutral and inverse agonist antagonists. Cannabinoid receptor 1 (CB(1)) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of GENE neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the GENE inverse agonist SR141716A (rimonabant) and the GENE neutral antagonist AM4113 were compared for their ability to modify GENE receptor-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel GENE full agonist AM4054. Results indicate that AM4054 serves as an effective GENE discriminative stimulus, with an onset and time course of action comparable with that of the GENE agonist CHEMICAL, and that the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA(2) values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for GENE neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at GENE receptors. | ACTIVATOR |
| Cannabinoid discrimination and antagonism by GENE neutral and inverse agonist antagonists. Cannabinoid receptor 1 (CB(1)) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of GENE neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the GENE inverse agonist SR141716A (rimonabant) and the GENE neutral antagonist AM4113 were compared for their ability to modify GENE receptor-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel GENE full agonist AM4054. Results indicate that AM4054 serves as an effective GENE discriminative stimulus, with an onset and time course of action comparable with that of the GENE agonist Δ(9)-tetrahydrocannabinol, and that the inverse agonist CHEMICAL and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that CHEMICAL and AM4113 produce highly similar antagonist effects, as evident in comparable pA(2) values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for GENE neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at GENE receptors. | ACTIVATOR |
| Cannabinoid discrimination and antagonism by GENE neutral and inverse agonist antagonists. Cannabinoid receptor 1 (CB(1)) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of GENE neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the GENE inverse agonist CHEMICAL (rimonabant) and the GENE neutral antagonist AM4113 were compared for their ability to modify GENE receptor-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel GENE full agonist AM4054. Results indicate that AM4054 serves as an effective GENE discriminative stimulus, with an onset and time course of action comparable with that of the GENE agonist Δ(9)-tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA(2) values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for GENE neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at GENE receptors. | ACTIVATOR |
| Cannabinoid discrimination and antagonism by CB(1) neutral and inverse agonist antagonists. GENE (CB(1)) inverse agonists (e.g., CHEMICAL) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB(1) neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the CB(1) inverse agonist SR141716A (rimonabant) and the CB(1) neutral antagonist AM4113 were compared for their ability to modify CB(1) receptor-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB(1) full agonist AM4054. Results indicate that AM4054 serves as an effective CB(1) discriminative stimulus, with an onset and time course of action comparable with that of the CB(1) agonist Δ(9)-tetrahydrocannabinol, and that the inverse agonist CHEMICAL and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that CHEMICAL and AM4113 produce highly similar antagonist effects, as evident in comparable pA(2) values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB(1) neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB(1) receptors. | ACTIVATOR |
| Cannabinoid discrimination and antagonism by GENE neutral and inverse agonist antagonists. Cannabinoid receptor 1 (CB(1)) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of GENE neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the GENE inverse agonist SR141716A (rimonabant) and the GENE neutral antagonist CHEMICAL were compared for their ability to modify GENE receptor-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel GENE full agonist AM4054. Results indicate that AM4054 serves as an effective GENE discriminative stimulus, with an onset and time course of action comparable with that of the GENE agonist Δ(9)-tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist CHEMICAL produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that rimonabant and CHEMICAL produce highly similar antagonist effects, as evident in comparable pA(2) values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for GENE neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at GENE receptors. | INHIBITOR |
| Marked decline in beta cell function during pregnancy leads to the development of CHEMICAL intolerance in Japanese women. The aim of this study is to investigate CHEMICAL metabolism longitudinally during pregnancy to explore mechanisms underlying gestational diabetes mellitus (GDM). We reviewed a total of 62 pregnant Japanese women who underwent a 75g oral CHEMICAL tolerance test (OGTT) twice during pregnancy (median: early, 13; late, 28 weeks' gestation) because of positive GDM screening. All showed normal OGTT results in early pregnancy. Based on late OGTT, 15 had GDM (late-onset GDM) and 47 normal CHEMICAL tolerance (NGT). In early pregnancy, there were no significant differences in GENE sensitivity (insulin sensitivity index derived from OGTT [ISOGTT] and homeostasis model assessment for GENE resistance [HOMA-IR]) and GENE secretion (a ratio of the total area-under-the-insulin-curve to the total area-under-the-CHEMICAL-curve [AUCins/glu] and insulinogenic index [IGI]) between the NGT and late-onset GDM groups. In each group, GENE sensitivity significantly decreased from early to late pregnancy, most in the late-onset GDM group (each p < 0.05). The GENE secretion showed no significant changes with advancing pregnancy in both of the groups, although late-onset GDM showed significantly lower IGI compared with NGT in late OGTT (p < 0.05). When assessed beta cell function by OGTT-derived disposition index (i.e. GENE Secretion-Sensitivity Index-2 and IGI/fasting insulin), the indices significantly decreased from early to late pregnancy in the both groups (each p < 0.05). Women with late-onset GDM showed significantly lower indices compared with NGT (each p < 0.05). The failure of beta cell to compensate for decreased GENE sensitivity could contribute to the development of the late-onset GDM. | GENE-CHEMICAL |
| New oral anticoagulants: comparative pharmacology with vitamin K antagonists. New oral anticoagulants (OACs) that directly inhibit Factor Xa (FXa) or GENE have been developed for the long-term prevention of thromboembolic disorders. These novel agents provide numerous benefits over older vitamin K antagonists (VKAs) due to major pharmacological differences. VKAs are economical and very well characterized, but have important limitations that can outweigh these advantages, such as slow onset of action, narrow therapeutic window and unpredictable anticoagulant effect. VKA-associated dietary precautions, monitoring and dosing adjustments to maintain international normalized ratio (INR) within therapeutic range, and bridging therapy, are inconvenient for patients, expensive, and may result in inappropriate use of VKA therapy. This may lead to increased bleeding risk or reduced anticoagulation and increased risk of thrombotic events. The new OACs have rapid onset of action, low potential for food and drug interactions, and predictable anticoagulant effect that removes the need for routine monitoring. FXa inhibitors, e.g. rivaroxaban and apixaban, are potent, oral direct inhibitors of prothrombinase-bound, clot-associated or free FXa. Both agents have a rapid onset of action, a wide therapeutic window, little or no interaction with food and other drugs, minimal inter-patient variability, and display similar pharmacokinetics in different patient populations. Since both are substrates, co-administration of rivaroxaban and apixaban with strong cytochrome P450 (CYP) 3A4 and permeability glycoprotein (P-gp) inhibitors and inducers can result in substantial changes in plasma concentrations due to altered clearance rates; consequently, their concomitant use is contraindicated and caution is required when used concomitantly with strong CYP3A4 and P-gp inducers. Although parenteral oral direct GENE inhibitors (DTIs), such as argatroban and bivalirudin, have been on the market for years, DTIs such as dabigatran are novel synthetic GENE antagonists. CHEMICAL etexilate is a low-molecular-weight non-active pro-drug that is administered orally and converted rapidly to its active form, dabigatran--a potent, competitive and reversible DTI. CHEMICAL has an advantage over the indirect GENE inhibitors, unfractionated heparin and low-molecular-weight heparin, in that it inhibits free and fibrin-bound GENE. The reversible binding of dabigatran may provide safer and more predictable anticoagulant treatment than seen with irreversible, non-covalent GENE inhibitors, e.g. hirudin. CHEMICAL shows a very low potential for drug-drug interactions. However, co-administration of dabigatran etexilate with other anticoagulants and antiplatelet agents can increase the bleeding risk. Although the new agents are pharmacologically better than VKAs--particularly in terms of fixed dosing, rapid onset of action, no INR monitoring and lower risk of drug interactions--there are some differences between them: the bioavailability of dabigatran is lower than rivaroxaban and apixaban, and so the dabigatran dosage required is higher; lower protein binding of dabigatran reduces the variability related to albuminaemia. The risk of metabolic drug-drug interactions also appears to differ between OACs: VKAs > rivaroxaban > apixaban > dabigatran. The convenience of the new OACs has translated into improvements in efficacy and safety as shown in phase III randomized trials. The new anticoagulants so far offer the greatest promise and opportunity for the replacement of VKAs. | INHIBITOR |
| New oral anticoagulants: comparative pharmacology with vitamin K antagonists. New oral anticoagulants (OACs) that directly inhibit Factor Xa (FXa) or thrombin have been developed for the long-term prevention of thromboembolic disorders. These novel agents provide numerous benefits over older vitamin K antagonists (VKAs) due to major pharmacological differences. VKAs are economical and very well characterized, but have important limitations that can outweigh these advantages, such as slow onset of action, narrow therapeutic window and unpredictable anticoagulant effect. VKA-associated dietary precautions, monitoring and dosing adjustments to maintain international normalized ratio (INR) within therapeutic range, and bridging therapy, are inconvenient for patients, expensive, and may result in inappropriate use of VKA therapy. This may lead to increased bleeding risk or reduced anticoagulation and increased risk of thrombotic events. The new OACs have rapid onset of action, low potential for food and drug interactions, and predictable anticoagulant effect that removes the need for routine monitoring. FXa inhibitors, e.g. rivaroxaban and apixaban, are potent, oral direct inhibitors of prothrombinase-bound, clot-associated or free FXa. Both agents have a rapid onset of action, a wide therapeutic window, little or no interaction with food and other drugs, minimal inter-patient variability, and display similar pharmacokinetics in different patient populations. Since both are substrates, co-administration of rivaroxaban and apixaban with strong cytochrome P450 (CYP) 3A4 and permeability glycoprotein (P-gp) inhibitors and inducers can result in substantial changes in plasma concentrations due to altered clearance rates; consequently, their concomitant use is contraindicated and caution is required when used concomitantly with strong CYP3A4 and P-gp inducers. Although parenteral oral direct thrombin inhibitors (DTIs), such as argatroban and bivalirudin, have been on the market for years, DTIs such as dabigatran are novel synthetic thrombin antagonists. CHEMICAL etexilate is a low-molecular-weight non-active pro-drug that is administered orally and converted rapidly to its active form, dabigatran--a potent, competitive and reversible DTI. CHEMICAL has an advantage over the indirect thrombin inhibitors, unfractionated heparin and low-molecular-weight heparin, in that it inhibits free and GENE-bound thrombin. The reversible binding of dabigatran may provide safer and more predictable anticoagulant treatment than seen with irreversible, non-covalent thrombin inhibitors, e.g. hirudin. CHEMICAL shows a very low potential for drug-drug interactions. However, co-administration of dabigatran etexilate with other anticoagulants and antiplatelet agents can increase the bleeding risk. Although the new agents are pharmacologically better than VKAs--particularly in terms of fixed dosing, rapid onset of action, no INR monitoring and lower risk of drug interactions--there are some differences between them: the bioavailability of dabigatran is lower than rivaroxaban and apixaban, and so the dabigatran dosage required is higher; lower protein binding of dabigatran reduces the variability related to albuminaemia. The risk of metabolic drug-drug interactions also appears to differ between OACs: VKAs > rivaroxaban > apixaban > dabigatran. The convenience of the new OACs has translated into improvements in efficacy and safety as shown in phase III randomized trials. The new anticoagulants so far offer the greatest promise and opportunity for the replacement of VKAs. | INHIBITOR |
| New oral anticoagulants: comparative pharmacology with vitamin K antagonists. New oral anticoagulants (OACs) that directly inhibit Factor Xa (FXa) or thrombin have been developed for the long-term prevention of thromboembolic disorders. These novel agents provide numerous benefits over older vitamin K antagonists (VKAs) due to major pharmacological differences. VKAs are economical and very well characterized, but have important limitations that can outweigh these advantages, such as slow onset of action, narrow therapeutic window and unpredictable anticoagulant effect. VKA-associated dietary precautions, monitoring and dosing adjustments to maintain international normalized ratio (INR) within therapeutic range, and bridging therapy, are inconvenient for patients, expensive, and may result in inappropriate use of VKA therapy. This may lead to increased bleeding risk or reduced anticoagulation and increased risk of thrombotic events. The new OACs have rapid onset of action, low potential for food and drug interactions, and predictable anticoagulant effect that removes the need for routine monitoring. GENE inhibitors, e.g. CHEMICAL and apixaban, are potent, oral direct inhibitors of prothrombinase-bound, clot-associated or free GENE. Both agents have a rapid onset of action, a wide therapeutic window, little or no interaction with food and other drugs, minimal inter-patient variability, and display similar pharmacokinetics in different patient populations. Since both are substrates, co-administration of CHEMICAL and apixaban with strong cytochrome P450 (CYP) 3A4 and permeability glycoprotein (P-gp) inhibitors and inducers can result in substantial changes in plasma concentrations due to altered clearance rates; consequently, their concomitant use is contraindicated and caution is required when used concomitantly with strong CYP3A4 and P-gp inducers. Although parenteral oral direct thrombin inhibitors (DTIs), such as argatroban and bivalirudin, have been on the market for years, DTIs such as dabigatran are novel synthetic thrombin antagonists. Dabigatran etexilate is a low-molecular-weight non-active pro-drug that is administered orally and converted rapidly to its active form, dabigatran--a potent, competitive and reversible DTI. Dabigatran has an advantage over the indirect thrombin inhibitors, unfractionated heparin and low-molecular-weight heparin, in that it inhibits free and fibrin-bound thrombin. The reversible binding of dabigatran may provide safer and more predictable anticoagulant treatment than seen with irreversible, non-covalent thrombin inhibitors, e.g. hirudin. Dabigatran shows a very low potential for drug-drug interactions. However, co-administration of dabigatran etexilate with other anticoagulants and antiplatelet agents can increase the bleeding risk. Although the new agents are pharmacologically better than VKAs--particularly in terms of fixed dosing, rapid onset of action, no INR monitoring and lower risk of drug interactions--there are some differences between them: the bioavailability of dabigatran is lower than CHEMICAL and apixaban, and so the dabigatran dosage required is higher; lower protein binding of dabigatran reduces the variability related to albuminaemia. The risk of metabolic drug-drug interactions also appears to differ between OACs: VKAs > CHEMICAL > apixaban > dabigatran. The convenience of the new OACs has translated into improvements in efficacy and safety as shown in phase III randomized trials. The new anticoagulants so far offer the greatest promise and opportunity for the replacement of VKAs. | INHIBITOR |
| New oral anticoagulants: comparative pharmacology with vitamin K antagonists. New oral anticoagulants (OACs) that directly inhibit Factor Xa (FXa) or thrombin have been developed for the long-term prevention of thromboembolic disorders. These novel agents provide numerous benefits over older vitamin K antagonists (VKAs) due to major pharmacological differences. VKAs are economical and very well characterized, but have important limitations that can outweigh these advantages, such as slow onset of action, narrow therapeutic window and unpredictable anticoagulant effect. VKA-associated dietary precautions, monitoring and dosing adjustments to maintain international normalized ratio (INR) within therapeutic range, and bridging therapy, are inconvenient for patients, expensive, and may result in inappropriate use of VKA therapy. This may lead to increased bleeding risk or reduced anticoagulation and increased risk of thrombotic events. The new OACs have rapid onset of action, low potential for food and drug interactions, and predictable anticoagulant effect that removes the need for routine monitoring. FXa inhibitors, e.g. CHEMICAL and apixaban, are potent, oral direct inhibitors of GENE-bound, clot-associated or free FXa. Both agents have a rapid onset of action, a wide therapeutic window, little or no interaction with food and other drugs, minimal inter-patient variability, and display similar pharmacokinetics in different patient populations. Since both are substrates, co-administration of CHEMICAL and apixaban with strong cytochrome P450 (CYP) 3A4 and permeability glycoprotein (P-gp) inhibitors and inducers can result in substantial changes in plasma concentrations due to altered clearance rates; consequently, their concomitant use is contraindicated and caution is required when used concomitantly with strong CYP3A4 and P-gp inducers. Although parenteral oral direct thrombin inhibitors (DTIs), such as argatroban and bivalirudin, have been on the market for years, DTIs such as dabigatran are novel synthetic thrombin antagonists. Dabigatran etexilate is a low-molecular-weight non-active pro-drug that is administered orally and converted rapidly to its active form, dabigatran--a potent, competitive and reversible DTI. Dabigatran has an advantage over the indirect thrombin inhibitors, unfractionated heparin and low-molecular-weight heparin, in that it inhibits free and fibrin-bound thrombin. The reversible binding of dabigatran may provide safer and more predictable anticoagulant treatment than seen with irreversible, non-covalent thrombin inhibitors, e.g. hirudin. Dabigatran shows a very low potential for drug-drug interactions. However, co-administration of dabigatran etexilate with other anticoagulants and antiplatelet agents can increase the bleeding risk. Although the new agents are pharmacologically better than VKAs--particularly in terms of fixed dosing, rapid onset of action, no INR monitoring and lower risk of drug interactions--there are some differences between them: the bioavailability of dabigatran is lower than CHEMICAL and apixaban, and so the dabigatran dosage required is higher; lower protein binding of dabigatran reduces the variability related to albuminaemia. The risk of metabolic drug-drug interactions also appears to differ between OACs: VKAs > CHEMICAL > apixaban > dabigatran. The convenience of the new OACs has translated into improvements in efficacy and safety as shown in phase III randomized trials. The new anticoagulants so far offer the greatest promise and opportunity for the replacement of VKAs. | INHIBITOR |
| New oral anticoagulants: comparative pharmacology with vitamin K antagonists. New oral anticoagulants (OACs) that directly inhibit Factor Xa (FXa) or thrombin have been developed for the long-term prevention of thromboembolic disorders. These novel agents provide numerous benefits over older vitamin K antagonists (VKAs) due to major pharmacological differences. VKAs are economical and very well characterized, but have important limitations that can outweigh these advantages, such as slow onset of action, narrow therapeutic window and unpredictable anticoagulant effect. VKA-associated dietary precautions, monitoring and dosing adjustments to maintain international normalized ratio (INR) within therapeutic range, and bridging therapy, are inconvenient for patients, expensive, and may result in inappropriate use of VKA therapy. This may lead to increased bleeding risk or reduced anticoagulation and increased risk of thrombotic events. The new OACs have rapid onset of action, low potential for food and drug interactions, and predictable anticoagulant effect that removes the need for routine monitoring. GENE inhibitors, e.g. rivaroxaban and CHEMICAL, are potent, oral direct inhibitors of prothrombinase-bound, clot-associated or free GENE. Both agents have a rapid onset of action, a wide therapeutic window, little or no interaction with food and other drugs, minimal inter-patient variability, and display similar pharmacokinetics in different patient populations. Since both are substrates, co-administration of rivaroxaban and CHEMICAL with strong cytochrome P450 (CYP) 3A4 and permeability glycoprotein (P-gp) inhibitors and inducers can result in substantial changes in plasma concentrations due to altered clearance rates; consequently, their concomitant use is contraindicated and caution is required when used concomitantly with strong CYP3A4 and P-gp inducers. Although parenteral oral direct thrombin inhibitors (DTIs), such as argatroban and bivalirudin, have been on the market for years, DTIs such as dabigatran are novel synthetic thrombin antagonists. Dabigatran etexilate is a low-molecular-weight non-active pro-drug that is administered orally and converted rapidly to its active form, dabigatran--a potent, competitive and reversible DTI. Dabigatran has an advantage over the indirect thrombin inhibitors, unfractionated heparin and low-molecular-weight heparin, in that it inhibits free and fibrin-bound thrombin. The reversible binding of dabigatran may provide safer and more predictable anticoagulant treatment than seen with irreversible, non-covalent thrombin inhibitors, e.g. hirudin. Dabigatran shows a very low potential for drug-drug interactions. However, co-administration of dabigatran etexilate with other anticoagulants and antiplatelet agents can increase the bleeding risk. Although the new agents are pharmacologically better than VKAs--particularly in terms of fixed dosing, rapid onset of action, no INR monitoring and lower risk of drug interactions--there are some differences between them: the bioavailability of dabigatran is lower than rivaroxaban and CHEMICAL, and so the dabigatran dosage required is higher; lower protein binding of dabigatran reduces the variability related to albuminaemia. The risk of metabolic drug-drug interactions also appears to differ between OACs: VKAs > rivaroxaban > CHEMICAL > dabigatran. The convenience of the new OACs has translated into improvements in efficacy and safety as shown in phase III randomized trials. The new anticoagulants so far offer the greatest promise and opportunity for the replacement of VKAs. | INHIBITOR |
| New oral anticoagulants: comparative pharmacology with vitamin K antagonists. New oral anticoagulants (OACs) that directly inhibit Factor Xa (FXa) or thrombin have been developed for the long-term prevention of thromboembolic disorders. These novel agents provide numerous benefits over older vitamin K antagonists (VKAs) due to major pharmacological differences. VKAs are economical and very well characterized, but have important limitations that can outweigh these advantages, such as slow onset of action, narrow therapeutic window and unpredictable anticoagulant effect. VKA-associated dietary precautions, monitoring and dosing adjustments to maintain international normalized ratio (INR) within therapeutic range, and bridging therapy, are inconvenient for patients, expensive, and may result in inappropriate use of VKA therapy. This may lead to increased bleeding risk or reduced anticoagulation and increased risk of thrombotic events. The new OACs have rapid onset of action, low potential for food and drug interactions, and predictable anticoagulant effect that removes the need for routine monitoring. FXa inhibitors, e.g. rivaroxaban and CHEMICAL, are potent, oral direct inhibitors of GENE-bound, clot-associated or free FXa. Both agents have a rapid onset of action, a wide therapeutic window, little or no interaction with food and other drugs, minimal inter-patient variability, and display similar pharmacokinetics in different patient populations. Since both are substrates, co-administration of rivaroxaban and CHEMICAL with strong cytochrome P450 (CYP) 3A4 and permeability glycoprotein (P-gp) inhibitors and inducers can result in substantial changes in plasma concentrations due to altered clearance rates; consequently, their concomitant use is contraindicated and caution is required when used concomitantly with strong CYP3A4 and P-gp inducers. Although parenteral oral direct thrombin inhibitors (DTIs), such as argatroban and bivalirudin, have been on the market for years, DTIs such as dabigatran are novel synthetic thrombin antagonists. Dabigatran etexilate is a low-molecular-weight non-active pro-drug that is administered orally and converted rapidly to its active form, dabigatran--a potent, competitive and reversible DTI. Dabigatran has an advantage over the indirect thrombin inhibitors, unfractionated heparin and low-molecular-weight heparin, in that it inhibits free and fibrin-bound thrombin. The reversible binding of dabigatran may provide safer and more predictable anticoagulant treatment than seen with irreversible, non-covalent thrombin inhibitors, e.g. hirudin. Dabigatran shows a very low potential for drug-drug interactions. However, co-administration of dabigatran etexilate with other anticoagulants and antiplatelet agents can increase the bleeding risk. Although the new agents are pharmacologically better than VKAs--particularly in terms of fixed dosing, rapid onset of action, no INR monitoring and lower risk of drug interactions--there are some differences between them: the bioavailability of dabigatran is lower than rivaroxaban and CHEMICAL, and so the dabigatran dosage required is higher; lower protein binding of dabigatran reduces the variability related to albuminaemia. The risk of metabolic drug-drug interactions also appears to differ between OACs: VKAs > rivaroxaban > CHEMICAL > dabigatran. The convenience of the new OACs has translated into improvements in efficacy and safety as shown in phase III randomized trials. The new anticoagulants so far offer the greatest promise and opportunity for the replacement of VKAs. | INHIBITOR |
| New oral anticoagulants: comparative pharmacology with vitamin K antagonists. New oral anticoagulants (OACs) that directly inhibit Factor Xa (FXa) or GENE have been developed for the long-term prevention of thromboembolic disorders. These novel agents provide numerous benefits over older vitamin K antagonists (VKAs) due to major pharmacological differences. VKAs are economical and very well characterized, but have important limitations that can outweigh these advantages, such as slow onset of action, narrow therapeutic window and unpredictable anticoagulant effect. VKA-associated dietary precautions, monitoring and dosing adjustments to maintain international normalized ratio (INR) within therapeutic range, and bridging therapy, are inconvenient for patients, expensive, and may result in inappropriate use of VKA therapy. This may lead to increased bleeding risk or reduced anticoagulation and increased risk of thrombotic events. The new OACs have rapid onset of action, low potential for food and drug interactions, and predictable anticoagulant effect that removes the need for routine monitoring. FXa inhibitors, e.g. rivaroxaban and apixaban, are potent, oral direct inhibitors of prothrombinase-bound, clot-associated or free FXa. Both agents have a rapid onset of action, a wide therapeutic window, little or no interaction with food and other drugs, minimal inter-patient variability, and display similar pharmacokinetics in different patient populations. Since both are substrates, co-administration of rivaroxaban and apixaban with strong cytochrome P450 (CYP) 3A4 and permeability glycoprotein (P-gp) inhibitors and inducers can result in substantial changes in plasma concentrations due to altered clearance rates; consequently, their concomitant use is contraindicated and caution is required when used concomitantly with strong CYP3A4 and P-gp inducers. Although parenteral oral direct GENE inhibitors (DTIs), such as CHEMICAL and bivalirudin, have been on the market for years, DTIs such as dabigatran are novel synthetic GENE antagonists. Dabigatran etexilate is a low-molecular-weight non-active pro-drug that is administered orally and converted rapidly to its active form, dabigatran--a potent, competitive and reversible DTI. Dabigatran has an advantage over the indirect GENE inhibitors, unfractionated heparin and low-molecular-weight heparin, in that it inhibits free and fibrin-bound GENE. The reversible binding of dabigatran may provide safer and more predictable anticoagulant treatment than seen with irreversible, non-covalent GENE inhibitors, e.g. hirudin. Dabigatran shows a very low potential for drug-drug interactions. However, co-administration of dabigatran etexilate with other anticoagulants and antiplatelet agents can increase the bleeding risk. Although the new agents are pharmacologically better than VKAs--particularly in terms of fixed dosing, rapid onset of action, no INR monitoring and lower risk of drug interactions--there are some differences between them: the bioavailability of dabigatran is lower than rivaroxaban and apixaban, and so the dabigatran dosage required is higher; lower protein binding of dabigatran reduces the variability related to albuminaemia. The risk of metabolic drug-drug interactions also appears to differ between OACs: VKAs > rivaroxaban > apixaban > dabigatran. The convenience of the new OACs has translated into improvements in efficacy and safety as shown in phase III randomized trials. The new anticoagulants so far offer the greatest promise and opportunity for the replacement of VKAs. | INHIBITOR |
| Fluorescence lifetime analysis and effect of magnesium ions on binding of CHEMICAL to human aldehyde dehydrogenase 1. Aldehyde dehydrogenase 1 (ALDH1A1) catalyzes the oxidation of toxic aldehydes to carboxylic acids. Physiologic levels of Mg(2+) ions decrease GENE activity in part by increasing CHEMICAL binding affinity to the enzyme. By using time-resolved fluorescence spectroscopy, we have resolved the fluorescent lifetimes (τ) of free CHEMICAL in solution (τ=0.4 ns) and two enzyme-bound CHEMICAL states (τ=2.0 ns and τ=7.7 ns). We used this technique to investigate the effects of Mg(2+) ions on the ALDH1A1-NADH binding characteristics and enzyme catalysis. From the resolved free and bound CHEMICAL fluorescence signatures, the KD values for both CHEMICAL conformations in ALDH1A1 ranged from about 24 μM to 1 μM for Mg(2+) ion concentrations of 0-6000 μM, respectively. The rate constants for dissociation of the enzyme-NADH complex ranged from 0.03 s(-1) (6000 μM Mg(2+)) to 0.30s(-1) (0 μM Mg(2+)) as determined by addition of excess NAD(+) to prevent re-association of CHEMICAL and resolving the real-time CHEMICAL fluorescence signal. During the initial reaction of enzyme with NAD(+) and butyraldehyde, there was an immediate rise in the CHEMICAL fluorescence, due to the formation of bound CHEMICAL complexes, with a constant steady-state rate of production of free CHEMICAL. As the Mg(2+) ion concentration was increased, there was a consistent decrease of the enzyme catalytic turnover from 0.31 s(-1) (0 μM Mg(2+)) to 0.050 s(-1) (6000 μM Mg(2+)) and a distinct shift in steady-state conformational population from one that favors the GENE-CHEMICAL complex with the shorter fluorescence lifetime (33% excess) in the absence of magnesium ion to one that favors the ALDH1-NADH complex with the longer fluorescence lifetime (13% excess) at 6000 μM Mg(2+). This shift in conformational population at higher Mg(2+) ion concentrations and to lower enzyme activity may be due to longer residence time of the CHEMICAL in the GENE pocket. The results from monitoring enzyme catalysis in the absence of magnesium suggests that the ALDH1-NADH complex with the shorter fluorescence lifetime is the form initially produced, and the complex with the longer fluorescence lifetime is produced through isomerization. | DIRECT-REGULATOR |
| Fluorescence lifetime analysis and effect of magnesium ions on binding of CHEMICAL to human aldehyde dehydrogenase 1. Aldehyde dehydrogenase 1 (ALDH1A1) catalyzes the oxidation of toxic aldehydes to carboxylic acids. Physiologic levels of Mg(2+) ions decrease ALDH1 activity in part by increasing CHEMICAL binding affinity to the enzyme. By using time-resolved fluorescence spectroscopy, we have resolved the fluorescent lifetimes (τ) of free CHEMICAL in solution (τ=0.4 ns) and two enzyme-bound CHEMICAL states (τ=2.0 ns and τ=7.7 ns). We used this technique to investigate the effects of Mg(2+) ions on the ALDH1A1-NADH binding characteristics and enzyme catalysis. From the resolved free and bound CHEMICAL fluorescence signatures, the KD values for both CHEMICAL conformations in GENE ranged from about 24 μM to 1 μM for Mg(2+) ion concentrations of 0-6000 μM, respectively. The rate constants for dissociation of the enzyme-NADH complex ranged from 0.03 s(-1) (6000 μM Mg(2+)) to 0.30s(-1) (0 μM Mg(2+)) as determined by addition of excess NAD(+) to prevent re-association of CHEMICAL and resolving the real-time CHEMICAL fluorescence signal. During the initial reaction of enzyme with NAD(+) and butyraldehyde, there was an immediate rise in the CHEMICAL fluorescence, due to the formation of bound CHEMICAL complexes, with a constant steady-state rate of production of free CHEMICAL. As the Mg(2+) ion concentration was increased, there was a consistent decrease of the enzyme catalytic turnover from 0.31 s(-1) (0 μM Mg(2+)) to 0.050 s(-1) (6000 μM Mg(2+)) and a distinct shift in steady-state conformational population from one that favors the ALDH1-NADH complex with the shorter fluorescence lifetime (33% excess) in the absence of magnesium ion to one that favors the ALDH1-NADH complex with the longer fluorescence lifetime (13% excess) at 6000 μM Mg(2+). This shift in conformational population at higher Mg(2+) ion concentrations and to lower enzyme activity may be due to longer residence time of the CHEMICAL in the ALDH1 pocket. The results from monitoring enzyme catalysis in the absence of magnesium suggests that the ALDH1-NADH complex with the shorter fluorescence lifetime is the form initially produced, and the complex with the longer fluorescence lifetime is produced through isomerization. | DIRECT-REGULATOR |
| Fluorescence lifetime analysis and effect of magnesium ions on binding of CHEMICAL to GENE. Aldehyde dehydrogenase 1 (ALDH1A1) catalyzes the oxidation of toxic aldehydes to carboxylic acids. Physiologic levels of Mg(2+) ions decrease ALDH1 activity in part by increasing CHEMICAL binding affinity to the enzyme. By using time-resolved fluorescence spectroscopy, we have resolved the fluorescent lifetimes (τ) of free CHEMICAL in solution (τ=0.4 ns) and two enzyme-bound CHEMICAL states (τ=2.0 ns and τ=7.7 ns). We used this technique to investigate the effects of Mg(2+) ions on the ALDH1A1-NADH binding characteristics and enzyme catalysis. From the resolved free and bound CHEMICAL fluorescence signatures, the KD values for both CHEMICAL conformations in ALDH1A1 ranged from about 24 μM to 1 μM for Mg(2+) ion concentrations of 0-6000 μM, respectively. The rate constants for dissociation of the enzyme-NADH complex ranged from 0.03 s(-1) (6000 μM Mg(2+)) to 0.30s(-1) (0 μM Mg(2+)) as determined by addition of excess NAD(+) to prevent re-association of CHEMICAL and resolving the real-time CHEMICAL fluorescence signal. During the initial reaction of enzyme with NAD(+) and butyraldehyde, there was an immediate rise in the CHEMICAL fluorescence, due to the formation of bound CHEMICAL complexes, with a constant steady-state rate of production of free CHEMICAL. As the Mg(2+) ion concentration was increased, there was a consistent decrease of the enzyme catalytic turnover from 0.31 s(-1) (0 μM Mg(2+)) to 0.050 s(-1) (6000 μM Mg(2+)) and a distinct shift in steady-state conformational population from one that favors the ALDH1-NADH complex with the shorter fluorescence lifetime (33% excess) in the absence of magnesium ion to one that favors the ALDH1-NADH complex with the longer fluorescence lifetime (13% excess) at 6000 μM Mg(2+). This shift in conformational population at higher Mg(2+) ion concentrations and to lower enzyme activity may be due to longer residence time of the CHEMICAL in the ALDH1 pocket. The results from monitoring enzyme catalysis in the absence of magnesium suggests that the ALDH1-NADH complex with the shorter fluorescence lifetime is the form initially produced, and the complex with the longer fluorescence lifetime is produced through isomerization. | DIRECT-REGULATOR |
| Fluorescence lifetime analysis and effect of magnesium ions on binding of NADH to human aldehyde dehydrogenase 1. Aldehyde dehydrogenase 1 (ALDH1A1) catalyzes the oxidation of toxic aldehydes to carboxylic acids. Physiologic levels of CHEMICAL ions decrease ALDH1 activity in part by increasing NADH binding affinity to the enzyme. By using time-resolved fluorescence spectroscopy, we have resolved the fluorescent lifetimes (τ) of free NADH in solution (τ=0.4 ns) and two enzyme-bound NADH states (τ=2.0 ns and τ=7.7 ns). We used this technique to investigate the effects of CHEMICAL ions on the ALDH1A1-NADH binding characteristics and enzyme catalysis. From the resolved free and bound NADH fluorescence signatures, the KD values for both NADH conformations in GENE ranged from about 24 μM to 1 μM for CHEMICAL ion concentrations of 0-6000 μM, respectively. The rate constants for dissociation of the enzyme-NADH complex ranged from 0.03 s(-1) (6000 μM Mg(2+)) to 0.30s(-1) (0 μM Mg(2+)) as determined by addition of excess NAD(+) to prevent re-association of NADH and resolving the real-time NADH fluorescence signal. During the initial reaction of enzyme with NAD(+) and butyraldehyde, there was an immediate rise in the NADH fluorescence, due to the formation of bound NADH complexes, with a constant steady-state rate of production of free NADH. As the CHEMICAL ion concentration was increased, there was a consistent decrease of the enzyme catalytic turnover from 0.31 s(-1) (0 μM Mg(2+)) to 0.050 s(-1) (6000 μM Mg(2+)) and a distinct shift in steady-state conformational population from one that favors the ALDH1-NADH complex with the shorter fluorescence lifetime (33% excess) in the absence of magnesium ion to one that favors the ALDH1-NADH complex with the longer fluorescence lifetime (13% excess) at 6000 μM CHEMICAL. This shift in conformational population at higher CHEMICAL ion concentrations and to lower enzyme activity may be due to longer residence time of the NADH in the ALDH1 pocket. The results from monitoring enzyme catalysis in the absence of magnesium suggests that the ALDH1-NADH complex with the shorter fluorescence lifetime is the form initially produced, and the complex with the longer fluorescence lifetime is produced through isomerization. | DIRECT-REGULATOR |
| Fluorescence lifetime analysis and effect of magnesium ions on binding of NADH to human aldehyde dehydrogenase 1. Aldehyde dehydrogenase 1 (ALDH1A1) catalyzes the oxidation of toxic aldehydes to carboxylic acids. Physiologic levels of CHEMICAL ions decrease GENE activity in part by increasing NADH binding affinity to the enzyme. By using time-resolved fluorescence spectroscopy, we have resolved the fluorescent lifetimes (τ) of free NADH in solution (τ=0.4 ns) and two enzyme-bound NADH states (τ=2.0 ns and τ=7.7 ns). We used this technique to investigate the effects of CHEMICAL ions on the ALDH1A1-NADH binding characteristics and enzyme catalysis. From the resolved free and bound NADH fluorescence signatures, the KD values for both NADH conformations in ALDH1A1 ranged from about 24 μM to 1 μM for CHEMICAL ion concentrations of 0-6000 μM, respectively. The rate constants for dissociation of the enzyme-NADH complex ranged from 0.03 s(-1) (6000 μM Mg(2+)) to 0.30s(-1) (0 μM Mg(2+)) as determined by addition of excess NAD(+) to prevent re-association of NADH and resolving the real-time NADH fluorescence signal. During the initial reaction of enzyme with NAD(+) and butyraldehyde, there was an immediate rise in the NADH fluorescence, due to the formation of bound NADH complexes, with a constant steady-state rate of production of free NADH. As the CHEMICAL ion concentration was increased, there was a consistent decrease of the enzyme catalytic turnover from 0.31 s(-1) (0 μM Mg(2+)) to 0.050 s(-1) (6000 μM Mg(2+)) and a distinct shift in steady-state conformational population from one that favors the ALDH1-NADH complex with the shorter fluorescence lifetime (33% excess) in the absence of magnesium ion to one that favors the ALDH1-NADH complex with the longer fluorescence lifetime (13% excess) at 6000 μM CHEMICAL. This shift in conformational population at higher CHEMICAL ion concentrations and to lower enzyme activity may be due to longer residence time of the NADH in the GENE pocket. The results from monitoring enzyme catalysis in the absence of magnesium suggests that the ALDH1-NADH complex with the shorter fluorescence lifetime is the form initially produced, and the complex with the longer fluorescence lifetime is produced through isomerization. | GENE-CHEMICAL |
| Fluorescence lifetime analysis and effect of magnesium ions on binding of NADH to human aldehyde dehydrogenase 1. GENE (ALDH1A1) catalyzes the oxidation of toxic aldehydes to CHEMICAL. Physiologic levels of Mg(2+) ions decrease ALDH1 activity in part by increasing NADH binding affinity to the enzyme. By using time-resolved fluorescence spectroscopy, we have resolved the fluorescent lifetimes (τ) of free NADH in solution (τ=0.4 ns) and two enzyme-bound NADH states (τ=2.0 ns and τ=7.7 ns). We used this technique to investigate the effects of Mg(2+) ions on the ALDH1A1-NADH binding characteristics and enzyme catalysis. From the resolved free and bound NADH fluorescence signatures, the KD values for both NADH conformations in ALDH1A1 ranged from about 24 μM to 1 μM for Mg(2+) ion concentrations of 0-6000 μM, respectively. The rate constants for dissociation of the enzyme-NADH complex ranged from 0.03 s(-1) (6000 μM Mg(2+)) to 0.30s(-1) (0 μM Mg(2+)) as determined by addition of excess NAD(+) to prevent re-association of NADH and resolving the real-time NADH fluorescence signal. During the initial reaction of enzyme with NAD(+) and butyraldehyde, there was an immediate rise in the NADH fluorescence, due to the formation of bound NADH complexes, with a constant steady-state rate of production of free NADH. As the Mg(2+) ion concentration was increased, there was a consistent decrease of the enzyme catalytic turnover from 0.31 s(-1) (0 μM Mg(2+)) to 0.050 s(-1) (6000 μM Mg(2+)) and a distinct shift in steady-state conformational population from one that favors the ALDH1-NADH complex with the shorter fluorescence lifetime (33% excess) in the absence of magnesium ion to one that favors the ALDH1-NADH complex with the longer fluorescence lifetime (13% excess) at 6000 μM Mg(2+). This shift in conformational population at higher Mg(2+) ion concentrations and to lower enzyme activity may be due to longer residence time of the NADH in the ALDH1 pocket. The results from monitoring enzyme catalysis in the absence of magnesium suggests that the ALDH1-NADH complex with the shorter fluorescence lifetime is the form initially produced, and the complex with the longer fluorescence lifetime is produced through isomerization. | PRODUCT-OF |
| Fluorescence lifetime analysis and effect of magnesium ions on binding of NADH to human aldehyde dehydrogenase 1. Aldehyde dehydrogenase 1 (GENE) catalyzes the oxidation of toxic aldehydes to CHEMICAL. Physiologic levels of Mg(2+) ions decrease ALDH1 activity in part by increasing NADH binding affinity to the enzyme. By using time-resolved fluorescence spectroscopy, we have resolved the fluorescent lifetimes (τ) of free NADH in solution (τ=0.4 ns) and two enzyme-bound NADH states (τ=2.0 ns and τ=7.7 ns). We used this technique to investigate the effects of Mg(2+) ions on the ALDH1A1-NADH binding characteristics and enzyme catalysis. From the resolved free and bound NADH fluorescence signatures, the KD values for both NADH conformations in GENE ranged from about 24 μM to 1 μM for Mg(2+) ion concentrations of 0-6000 μM, respectively. The rate constants for dissociation of the enzyme-NADH complex ranged from 0.03 s(-1) (6000 μM Mg(2+)) to 0.30s(-1) (0 μM Mg(2+)) as determined by addition of excess NAD(+) to prevent re-association of NADH and resolving the real-time NADH fluorescence signal. During the initial reaction of enzyme with NAD(+) and butyraldehyde, there was an immediate rise in the NADH fluorescence, due to the formation of bound NADH complexes, with a constant steady-state rate of production of free NADH. As the Mg(2+) ion concentration was increased, there was a consistent decrease of the enzyme catalytic turnover from 0.31 s(-1) (0 μM Mg(2+)) to 0.050 s(-1) (6000 μM Mg(2+)) and a distinct shift in steady-state conformational population from one that favors the ALDH1-NADH complex with the shorter fluorescence lifetime (33% excess) in the absence of magnesium ion to one that favors the ALDH1-NADH complex with the longer fluorescence lifetime (13% excess) at 6000 μM Mg(2+). This shift in conformational population at higher Mg(2+) ion concentrations and to lower enzyme activity may be due to longer residence time of the NADH in the ALDH1 pocket. The results from monitoring enzyme catalysis in the absence of magnesium suggests that the ALDH1-NADH complex with the shorter fluorescence lifetime is the form initially produced, and the complex with the longer fluorescence lifetime is produced through isomerization. | PRODUCT-OF |
| Fluorescence lifetime analysis and effect of magnesium ions on binding of NADH to human aldehyde dehydrogenase 1. GENE (ALDH1A1) catalyzes the oxidation of toxic CHEMICAL to carboxylic acids. Physiologic levels of Mg(2+) ions decrease ALDH1 activity in part by increasing NADH binding affinity to the enzyme. By using time-resolved fluorescence spectroscopy, we have resolved the fluorescent lifetimes (τ) of free NADH in solution (τ=0.4 ns) and two enzyme-bound NADH states (τ=2.0 ns and τ=7.7 ns). We used this technique to investigate the effects of Mg(2+) ions on the ALDH1A1-NADH binding characteristics and enzyme catalysis. From the resolved free and bound NADH fluorescence signatures, the KD values for both NADH conformations in ALDH1A1 ranged from about 24 μM to 1 μM for Mg(2+) ion concentrations of 0-6000 μM, respectively. The rate constants for dissociation of the enzyme-NADH complex ranged from 0.03 s(-1) (6000 μM Mg(2+)) to 0.30s(-1) (0 μM Mg(2+)) as determined by addition of excess NAD(+) to prevent re-association of NADH and resolving the real-time NADH fluorescence signal. During the initial reaction of enzyme with NAD(+) and butyraldehyde, there was an immediate rise in the NADH fluorescence, due to the formation of bound NADH complexes, with a constant steady-state rate of production of free NADH. As the Mg(2+) ion concentration was increased, there was a consistent decrease of the enzyme catalytic turnover from 0.31 s(-1) (0 μM Mg(2+)) to 0.050 s(-1) (6000 μM Mg(2+)) and a distinct shift in steady-state conformational population from one that favors the ALDH1-NADH complex with the shorter fluorescence lifetime (33% excess) in the absence of magnesium ion to one that favors the ALDH1-NADH complex with the longer fluorescence lifetime (13% excess) at 6000 μM Mg(2+). This shift in conformational population at higher Mg(2+) ion concentrations and to lower enzyme activity may be due to longer residence time of the NADH in the ALDH1 pocket. The results from monitoring enzyme catalysis in the absence of magnesium suggests that the ALDH1-NADH complex with the shorter fluorescence lifetime is the form initially produced, and the complex with the longer fluorescence lifetime is produced through isomerization. | SUBSTRATE |
| Fluorescence lifetime analysis and effect of magnesium ions on binding of NADH to human aldehyde dehydrogenase 1. Aldehyde dehydrogenase 1 (GENE) catalyzes the oxidation of toxic CHEMICAL to carboxylic acids. Physiologic levels of Mg(2+) ions decrease ALDH1 activity in part by increasing NADH binding affinity to the enzyme. By using time-resolved fluorescence spectroscopy, we have resolved the fluorescent lifetimes (τ) of free NADH in solution (τ=0.4 ns) and two enzyme-bound NADH states (τ=2.0 ns and τ=7.7 ns). We used this technique to investigate the effects of Mg(2+) ions on the ALDH1A1-NADH binding characteristics and enzyme catalysis. From the resolved free and bound NADH fluorescence signatures, the KD values for both NADH conformations in GENE ranged from about 24 μM to 1 μM for Mg(2+) ion concentrations of 0-6000 μM, respectively. The rate constants for dissociation of the enzyme-NADH complex ranged from 0.03 s(-1) (6000 μM Mg(2+)) to 0.30s(-1) (0 μM Mg(2+)) as determined by addition of excess NAD(+) to prevent re-association of NADH and resolving the real-time NADH fluorescence signal. During the initial reaction of enzyme with NAD(+) and butyraldehyde, there was an immediate rise in the NADH fluorescence, due to the formation of bound NADH complexes, with a constant steady-state rate of production of free NADH. As the Mg(2+) ion concentration was increased, there was a consistent decrease of the enzyme catalytic turnover from 0.31 s(-1) (0 μM Mg(2+)) to 0.050 s(-1) (6000 μM Mg(2+)) and a distinct shift in steady-state conformational population from one that favors the ALDH1-NADH complex with the shorter fluorescence lifetime (33% excess) in the absence of magnesium ion to one that favors the ALDH1-NADH complex with the longer fluorescence lifetime (13% excess) at 6000 μM Mg(2+). This shift in conformational population at higher Mg(2+) ion concentrations and to lower enzyme activity may be due to longer residence time of the NADH in the ALDH1 pocket. The results from monitoring enzyme catalysis in the absence of magnesium suggests that the ALDH1-NADH complex with the shorter fluorescence lifetime is the form initially produced, and the complex with the longer fluorescence lifetime is produced through isomerization. | SUBSTRATE |
| CHEMICAL induces Alzheimer's disease-like pathologies in vitro and in vivo. The pathologic mechanisms of Alzheimer's disease (AD) have not been fully uncovered. CHEMICAL, a ubiquitous dietary pollutant and by-product of oxidative stress, can induce cytotoxicity in neurons, which might play an important role in the etiology of AD. Here, we examined the effects of CHEMICAL on the AD pathologies in vitro and in vivo. We found CHEMICAL induced HT22 cells death in concentration- and time-dependent manners. Interestingly, CHEMICAL increased proteins' levels of amyloid precursor protein (GENE), β-secretase (BACE-1) and the amyloid β-peptide transporter receptor for advanced glycation end products, and decreased A-disintegrin and metalloprotease (ADAM) 10 levels. In vivo, chronic oral exposure to CHEMICAL (2.5 mg/kg/day by intragastric gavage for 8 weeks) induced mild cognitive declination and pyknosis/atrophy of hippocampal neurons. The activity of superoxide dismutase was down-regulated while the level of malondialdehyde was up-regulated in rat brain. Moreover, CHEMICAL resulted in activation of astrocytes, up-regulation of BACE-1 in cortex and down-regulation of ADAM-10 in hippocampus and cortex. Taken together, our findings suggest that exposure to CHEMICAL induces AD-like pathology in vitro and in vivo. Scavenging CHEMICAL might be beneficial for the therapy of AD. | INDIRECT-UPREGULATOR |
| CHEMICAL induces Alzheimer's disease-like pathologies in vitro and in vivo. The pathologic mechanisms of Alzheimer's disease (AD) have not been fully uncovered. CHEMICAL, a ubiquitous dietary pollutant and by-product of oxidative stress, can induce cytotoxicity in neurons, which might play an important role in the etiology of AD. Here, we examined the effects of CHEMICAL on the AD pathologies in vitro and in vivo. We found CHEMICAL induced HT22 cells death in concentration- and time-dependent manners. Interestingly, CHEMICAL increased proteins' levels of amyloid precursor protein (APP), β-secretase (BACE-1) and the amyloid β-peptide transporter receptor for advanced glycation end products, and decreased A-disintegrin and metalloprotease (ADAM) 10 levels. In vivo, chronic oral exposure to CHEMICAL (2.5 mg/kg/day by intragastric gavage for 8 weeks) induced mild cognitive declination and pyknosis/atrophy of hippocampal neurons. The activity of superoxide dismutase was down-regulated while the level of malondialdehyde was up-regulated in rat brain. Moreover, CHEMICAL resulted in activation of astrocytes, up-regulation of GENE in cortex and down-regulation of ADAM-10 in hippocampus and cortex. Taken together, our findings suggest that exposure to CHEMICAL induces AD-like pathology in vitro and in vivo. Scavenging CHEMICAL might be beneficial for the therapy of AD. | INDIRECT-UPREGULATOR |
| CHEMICAL induces Alzheimer's disease-like pathologies in vitro and in vivo. The pathologic mechanisms of Alzheimer's disease (AD) have not been fully uncovered. CHEMICAL, a ubiquitous dietary pollutant and by-product of oxidative stress, can induce cytotoxicity in neurons, which might play an important role in the etiology of AD. Here, we examined the effects of CHEMICAL on the AD pathologies in vitro and in vivo. We found CHEMICAL induced HT22 cells death in concentration- and time-dependent manners. Interestingly, CHEMICAL increased proteins' levels of GENE (APP), β-secretase (BACE-1) and the amyloid β-peptide transporter receptor for advanced glycation end products, and decreased A-disintegrin and metalloprotease (ADAM) 10 levels. In vivo, chronic oral exposure to CHEMICAL (2.5 mg/kg/day by intragastric gavage for 8 weeks) induced mild cognitive declination and pyknosis/atrophy of hippocampal neurons. The activity of superoxide dismutase was down-regulated while the level of malondialdehyde was up-regulated in rat brain. Moreover, CHEMICAL resulted in activation of astrocytes, up-regulation of BACE-1 in cortex and down-regulation of ADAM-10 in hippocampus and cortex. Taken together, our findings suggest that exposure to CHEMICAL induces AD-like pathology in vitro and in vivo. Scavenging CHEMICAL might be beneficial for the therapy of AD. | INDIRECT-UPREGULATOR |
| CHEMICAL induces Alzheimer's disease-like pathologies in vitro and in vivo. The pathologic mechanisms of Alzheimer's disease (AD) have not been fully uncovered. CHEMICAL, a ubiquitous dietary pollutant and by-product of oxidative stress, can induce cytotoxicity in neurons, which might play an important role in the etiology of AD. Here, we examined the effects of CHEMICAL on the AD pathologies in vitro and in vivo. We found CHEMICAL induced HT22 cells death in concentration- and time-dependent manners. Interestingly, CHEMICAL increased proteins' levels of amyloid precursor protein (APP), GENE (BACE-1) and the amyloid β-peptide transporter receptor for advanced glycation end products, and decreased A-disintegrin and metalloprotease (ADAM) 10 levels. In vivo, chronic oral exposure to CHEMICAL (2.5 mg/kg/day by intragastric gavage for 8 weeks) induced mild cognitive declination and pyknosis/atrophy of hippocampal neurons. The activity of superoxide dismutase was down-regulated while the level of malondialdehyde was up-regulated in rat brain. Moreover, CHEMICAL resulted in activation of astrocytes, up-regulation of BACE-1 in cortex and down-regulation of ADAM-10 in hippocampus and cortex. Taken together, our findings suggest that exposure to CHEMICAL induces AD-like pathology in vitro and in vivo. Scavenging CHEMICAL might be beneficial for the therapy of AD. | INDIRECT-UPREGULATOR |
| CHEMICAL induces Alzheimer's disease-like pathologies in vitro and in vivo. The pathologic mechanisms of Alzheimer's disease (AD) have not been fully uncovered. CHEMICAL, a ubiquitous dietary pollutant and by-product of oxidative stress, can induce cytotoxicity in neurons, which might play an important role in the etiology of AD. Here, we examined the effects of CHEMICAL on the AD pathologies in vitro and in vivo. We found CHEMICAL induced HT22 cells death in concentration- and time-dependent manners. Interestingly, CHEMICAL increased proteins' levels of amyloid precursor protein (APP), β-secretase (BACE-1) and the GENE receptor for advanced glycation end products, and decreased A-disintegrin and metalloprotease (ADAM) 10 levels. In vivo, chronic oral exposure to CHEMICAL (2.5 mg/kg/day by intragastric gavage for 8 weeks) induced mild cognitive declination and pyknosis/atrophy of hippocampal neurons. The activity of superoxide dismutase was down-regulated while the level of malondialdehyde was up-regulated in rat brain. Moreover, CHEMICAL resulted in activation of astrocytes, up-regulation of BACE-1 in cortex and down-regulation of ADAM-10 in hippocampus and cortex. Taken together, our findings suggest that exposure to CHEMICAL induces AD-like pathology in vitro and in vivo. Scavenging CHEMICAL might be beneficial for the therapy of AD. | INDIRECT-UPREGULATOR |
| CHEMICAL induces Alzheimer's disease-like pathologies in vitro and in vivo. The pathologic mechanisms of Alzheimer's disease (AD) have not been fully uncovered. CHEMICAL, a ubiquitous dietary pollutant and by-product of oxidative stress, can induce cytotoxicity in neurons, which might play an important role in the etiology of AD. Here, we examined the effects of CHEMICAL on the AD pathologies in vitro and in vivo. We found CHEMICAL induced HT22 cells death in concentration- and time-dependent manners. Interestingly, CHEMICAL increased proteins' levels of amyloid precursor protein (APP), β-secretase (BACE-1) and the amyloid β-peptide transporter GENE, and decreased A-disintegrin and metalloprotease (ADAM) 10 levels. In vivo, chronic oral exposure to CHEMICAL (2.5 mg/kg/day by intragastric gavage for 8 weeks) induced mild cognitive declination and pyknosis/atrophy of hippocampal neurons. The activity of superoxide dismutase was down-regulated while the level of malondialdehyde was up-regulated in rat brain. Moreover, CHEMICAL resulted in activation of astrocytes, up-regulation of BACE-1 in cortex and down-regulation of ADAM-10 in hippocampus and cortex. Taken together, our findings suggest that exposure to CHEMICAL induces AD-like pathology in vitro and in vivo. Scavenging CHEMICAL might be beneficial for the therapy of AD. | INDIRECT-UPREGULATOR |
| CHEMICAL induces Alzheimer's disease-like pathologies in vitro and in vivo. The pathologic mechanisms of Alzheimer's disease (AD) have not been fully uncovered. CHEMICAL, a ubiquitous dietary pollutant and by-product of oxidative stress, can induce cytotoxicity in neurons, which might play an important role in the etiology of AD. Here, we examined the effects of CHEMICAL on the AD pathologies in vitro and in vivo. We found CHEMICAL induced HT22 cells death in concentration- and time-dependent manners. Interestingly, CHEMICAL increased proteins' levels of amyloid precursor protein (APP), β-secretase (BACE-1) and the amyloid β-peptide transporter receptor for advanced glycation end products, and decreased A-disintegrin and metalloprotease (ADAM) 10 levels. In vivo, chronic oral exposure to CHEMICAL (2.5 mg/kg/day by intragastric gavage for 8 weeks) induced mild cognitive declination and pyknosis/atrophy of hippocampal neurons. The activity of superoxide dismutase was down-regulated while the level of malondialdehyde was up-regulated in rat brain. Moreover, CHEMICAL resulted in activation of astrocytes, up-regulation of BACE-1 in cortex and down-regulation of GENE in hippocampus and cortex. Taken together, our findings suggest that exposure to CHEMICAL induces AD-like pathology in vitro and in vivo. Scavenging CHEMICAL might be beneficial for the therapy of AD. | INDIRECT-DOWNREGULATOR |
| CHEMICAL induces Alzheimer's disease-like pathologies in vitro and in vivo. The pathologic mechanisms of Alzheimer's disease (AD) have not been fully uncovered. CHEMICAL, a ubiquitous dietary pollutant and by-product of oxidative stress, can induce cytotoxicity in neurons, which might play an important role in the etiology of AD. Here, we examined the effects of CHEMICAL on the AD pathologies in vitro and in vivo. We found CHEMICAL induced HT22 cells death in concentration- and time-dependent manners. Interestingly, CHEMICAL increased proteins' levels of amyloid precursor protein (APP), β-secretase (BACE-1) and the amyloid β-peptide transporter receptor for advanced glycation end products, and decreased GENE levels. In vivo, chronic oral exposure to CHEMICAL (2.5 mg/kg/day by intragastric gavage for 8 weeks) induced mild cognitive declination and pyknosis/atrophy of hippocampal neurons. The activity of superoxide dismutase was down-regulated while the level of malondialdehyde was up-regulated in rat brain. Moreover, CHEMICAL resulted in activation of astrocytes, up-regulation of BACE-1 in cortex and down-regulation of ADAM-10 in hippocampus and cortex. Taken together, our findings suggest that exposure to CHEMICAL induces AD-like pathology in vitro and in vivo. Scavenging CHEMICAL might be beneficial for the therapy of AD. | INDIRECT-DOWNREGULATOR |
| Membrane-initiated CHEMICAL signaling in immortalized hypothalamic N-38 neurons. Regulation of sexual reproduction by CHEMICAL involves the activation of GENE (ERs) in the hypothalamus. Of the two classical ERs involved in reproduction, ERα appears to be the critical isoform. The role of ERα in reproduction has been found to involve a nuclear ERα that induces a genomic mechanism of action. More recently, a plasma membrane ERα has been shown to trigger signaling pathways involved in reproduction. Mechanisms underlying membrane-initiated CHEMICAL signaling are emerging, including evidence that activation of plasma membrane ERα involves receptor trafficking. The present study examined the insertion of ERα into the plasma membrane of N-38 neurons, an immortalized murine hypothalamic cell line. We identified, using western blotting and PCR that N-38 neurons express full-length 66kDa ERα and a 52kDa ERα spliced variant missing the fourth exon - ERαΔ4. Using surface biotinylation, we observed that treatment of N-38 neurons with CHEMICAL or with a membrane impermeant CHEMICAL elevated plasma membrane ERα protein levels, indicating that membrane signaling increased receptor insertion into the cell membrane. Insertion of ERα was blocked by the ER antagonist ICI 182,780 or with the protein kinase C (PKC) pathway inhibitor bisindolylmaleimide (BIS). Downstream membrane-initiated signaling was confirmed by CHEMICAL activation of PKC-theta (PKCθ) and the release of intracellular calcium. These results indicate that membrane ERα levels in N-38 neurons are dynamically autoregulated by CHEMICAL. | ACTIVATOR |
| Membrane-initiated CHEMICAL signaling in immortalized hypothalamic N-38 neurons. Regulation of sexual reproduction by CHEMICAL involves the activation of estrogen receptors (GENE) in the hypothalamus. Of the two classical GENE involved in reproduction, ERα appears to be the critical isoform. The role of ERα in reproduction has been found to involve a nuclear ERα that induces a genomic mechanism of action. More recently, a plasma membrane ERα has been shown to trigger signaling pathways involved in reproduction. Mechanisms underlying membrane-initiated CHEMICAL signaling are emerging, including evidence that activation of plasma membrane ERα involves receptor trafficking. The present study examined the insertion of ERα into the plasma membrane of N-38 neurons, an immortalized murine hypothalamic cell line. We identified, using western blotting and PCR that N-38 neurons express full-length 66kDa ERα and a 52kDa ERα spliced variant missing the fourth exon - ERαΔ4. Using surface biotinylation, we observed that treatment of N-38 neurons with CHEMICAL or with a membrane impermeant CHEMICAL elevated plasma membrane ERα protein levels, indicating that membrane signaling increased receptor insertion into the cell membrane. Insertion of ERα was blocked by the ER antagonist ICI 182,780 or with the protein kinase C (PKC) pathway inhibitor bisindolylmaleimide (BIS). Downstream membrane-initiated signaling was confirmed by CHEMICAL activation of PKC-theta (PKCθ) and the release of intracellular calcium. These results indicate that membrane ERα levels in N-38 neurons are dynamically autoregulated by CHEMICAL. | ACTIVATOR |
| Membrane-initiated CHEMICAL signaling in immortalized hypothalamic N-38 neurons. Regulation of sexual reproduction by CHEMICAL involves the activation of estrogen receptors (ERs) in the hypothalamus. Of the two classical ERs involved in reproduction, GENE appears to be the critical isoform. The role of GENE in reproduction has been found to involve a nuclear GENE that induces a genomic mechanism of action. More recently, a plasma membrane GENE has been shown to trigger signaling pathways involved in reproduction. Mechanisms underlying membrane-initiated CHEMICAL signaling are emerging, including evidence that activation of plasma membrane GENE involves receptor trafficking. The present study examined the insertion of GENE into the plasma membrane of N-38 neurons, an immortalized murine hypothalamic cell line. We identified, using western blotting and PCR that N-38 neurons express full-length 66kDa GENE and a 52kDa GENE spliced variant missing the fourth exon - ERαΔ4. Using surface biotinylation, we observed that treatment of N-38 neurons with CHEMICAL or with a membrane impermeant CHEMICAL elevated plasma membrane GENE protein levels, indicating that membrane signaling increased receptor insertion into the cell membrane. Insertion of GENE was blocked by the ER antagonist ICI 182,780 or with the protein kinase C (PKC) pathway inhibitor bisindolylmaleimide (BIS). Downstream membrane-initiated signaling was confirmed by CHEMICAL activation of PKC-theta (PKCθ) and the release of intracellular calcium. These results indicate that membrane GENE levels in N-38 neurons are dynamically autoregulated by CHEMICAL. | GENE-CHEMICAL |
| Membrane-initiated estradiol signaling in immortalized hypothalamic N-38 neurons. Regulation of sexual reproduction by estradiol involves the activation of estrogen receptors (ERs) in the hypothalamus. Of the two classical ERs involved in reproduction, GENE appears to be the critical isoform. The role of GENE in reproduction has been found to involve a nuclear GENE that induces a genomic mechanism of action. More recently, a plasma membrane GENE has been shown to trigger signaling pathways involved in reproduction. Mechanisms underlying membrane-initiated estradiol signaling are emerging, including evidence that activation of plasma membrane GENE involves receptor trafficking. The present study examined the insertion of GENE into the plasma membrane of N-38 neurons, an immortalized murine hypothalamic cell line. We identified, using western blotting and PCR that N-38 neurons express full-length 66kDa GENE and a 52kDa GENE spliced variant missing the fourth exon - ERαΔ4. Using surface biotinylation, we observed that treatment of N-38 neurons with estradiol or with a membrane impermeant estradiol elevated plasma membrane GENE protein levels, indicating that membrane signaling increased receptor insertion into the cell membrane. Insertion of GENE was blocked by the ER antagonist CHEMICAL or with the protein kinase C (PKC) pathway inhibitor bisindolylmaleimide (BIS). Downstream membrane-initiated signaling was confirmed by estradiol activation of PKC-theta (PKCθ) and the release of intracellular calcium. These results indicate that membrane GENE levels in N-38 neurons are dynamically autoregulated by estradiol. | INHIBITOR |
| Membrane-initiated estradiol signaling in immortalized hypothalamic N-38 neurons. Regulation of sexual reproduction by estradiol involves the activation of estrogen receptors (ERs) in the hypothalamus. Of the two classical ERs involved in reproduction, GENE appears to be the critical isoform. The role of GENE in reproduction has been found to involve a nuclear GENE that induces a genomic mechanism of action. More recently, a plasma membrane GENE has been shown to trigger signaling pathways involved in reproduction. Mechanisms underlying membrane-initiated estradiol signaling are emerging, including evidence that activation of plasma membrane GENE involves receptor trafficking. The present study examined the insertion of GENE into the plasma membrane of N-38 neurons, an immortalized murine hypothalamic cell line. We identified, using western blotting and PCR that N-38 neurons express full-length 66kDa GENE and a 52kDa GENE spliced variant missing the fourth exon - ERαΔ4. Using surface biotinylation, we observed that treatment of N-38 neurons with estradiol or with a membrane impermeant estradiol elevated plasma membrane GENE protein levels, indicating that membrane signaling increased receptor insertion into the cell membrane. Insertion of GENE was blocked by the ER antagonist ICI 182,780 or with the protein kinase C (PKC) pathway inhibitor CHEMICAL (BIS). Downstream membrane-initiated signaling was confirmed by estradiol activation of PKC-theta (PKCθ) and the release of intracellular calcium. These results indicate that membrane GENE levels in N-38 neurons are dynamically autoregulated by estradiol. | INHIBITOR |
| Membrane-initiated estradiol signaling in immortalized hypothalamic N-38 neurons. Regulation of sexual reproduction by estradiol involves the activation of estrogen receptors (ERs) in the hypothalamus. Of the two classical ERs involved in reproduction, ERα appears to be the critical isoform. The role of ERα in reproduction has been found to involve a nuclear ERα that induces a genomic mechanism of action. More recently, a plasma membrane ERα has been shown to trigger signaling pathways involved in reproduction. Mechanisms underlying membrane-initiated estradiol signaling are emerging, including evidence that activation of plasma membrane ERα involves receptor trafficking. The present study examined the insertion of ERα into the plasma membrane of N-38 neurons, an immortalized murine hypothalamic cell line. We identified, using western blotting and PCR that N-38 neurons express full-length 66kDa ERα and a 52kDa ERα spliced variant missing the fourth exon - ERαΔ4. Using surface biotinylation, we observed that treatment of N-38 neurons with estradiol or with a membrane impermeant estradiol elevated plasma membrane ERα protein levels, indicating that membrane signaling increased receptor insertion into the cell membrane. Insertion of ERα was blocked by the ER antagonist ICI 182,780 or with the GENE (PKC) pathway inhibitor CHEMICAL (BIS). Downstream membrane-initiated signaling was confirmed by estradiol activation of PKC-theta (PKCθ) and the release of intracellular calcium. These results indicate that membrane ERα levels in N-38 neurons are dynamically autoregulated by estradiol. | INHIBITOR |
| Membrane-initiated estradiol signaling in immortalized hypothalamic N-38 neurons. Regulation of sexual reproduction by estradiol involves the activation of estrogen receptors (ERs) in the hypothalamus. Of the two classical ERs involved in reproduction, ERα appears to be the critical isoform. The role of ERα in reproduction has been found to involve a nuclear ERα that induces a genomic mechanism of action. More recently, a plasma membrane ERα has been shown to trigger signaling pathways involved in reproduction. Mechanisms underlying membrane-initiated estradiol signaling are emerging, including evidence that activation of plasma membrane ERα involves receptor trafficking. The present study examined the insertion of ERα into the plasma membrane of N-38 neurons, an immortalized murine hypothalamic cell line. We identified, using western blotting and PCR that N-38 neurons express full-length 66kDa ERα and a 52kDa ERα spliced variant missing the fourth exon - ERαΔ4. Using surface biotinylation, we observed that treatment of N-38 neurons with estradiol or with a membrane impermeant estradiol elevated plasma membrane ERα protein levels, indicating that membrane signaling increased receptor insertion into the cell membrane. Insertion of ERα was blocked by the ER antagonist ICI 182,780 or with the protein kinase C (GENE) pathway inhibitor CHEMICAL (BIS). Downstream membrane-initiated signaling was confirmed by estradiol activation of PKC-theta (PKCθ) and the release of intracellular calcium. These results indicate that membrane ERα levels in N-38 neurons are dynamically autoregulated by estradiol. | INHIBITOR |
| Membrane-initiated estradiol signaling in immortalized hypothalamic N-38 neurons. Regulation of sexual reproduction by estradiol involves the activation of estrogen receptors (ERs) in the hypothalamus. Of the two classical ERs involved in reproduction, GENE appears to be the critical isoform. The role of GENE in reproduction has been found to involve a nuclear GENE that induces a genomic mechanism of action. More recently, a plasma membrane GENE has been shown to trigger signaling pathways involved in reproduction. Mechanisms underlying membrane-initiated estradiol signaling are emerging, including evidence that activation of plasma membrane GENE involves receptor trafficking. The present study examined the insertion of GENE into the plasma membrane of N-38 neurons, an immortalized murine hypothalamic cell line. We identified, using western blotting and PCR that N-38 neurons express full-length 66kDa GENE and a 52kDa GENE spliced variant missing the fourth exon - ERαΔ4. Using surface biotinylation, we observed that treatment of N-38 neurons with estradiol or with a membrane impermeant estradiol elevated plasma membrane GENE protein levels, indicating that membrane signaling increased receptor insertion into the cell membrane. Insertion of GENE was blocked by the ER antagonist ICI 182,780 or with the protein kinase C (PKC) pathway inhibitor bisindolylmaleimide (CHEMICAL). Downstream membrane-initiated signaling was confirmed by estradiol activation of PKC-theta (PKCθ) and the release of intracellular calcium. These results indicate that membrane GENE levels in N-38 neurons are dynamically autoregulated by estradiol. | INHIBITOR |
| Membrane-initiated estradiol signaling in immortalized hypothalamic N-38 neurons. Regulation of sexual reproduction by estradiol involves the activation of estrogen receptors (ERs) in the hypothalamus. Of the two classical ERs involved in reproduction, ERα appears to be the critical isoform. The role of ERα in reproduction has been found to involve a nuclear ERα that induces a genomic mechanism of action. More recently, a plasma membrane ERα has been shown to trigger signaling pathways involved in reproduction. Mechanisms underlying membrane-initiated estradiol signaling are emerging, including evidence that activation of plasma membrane ERα involves receptor trafficking. The present study examined the insertion of ERα into the plasma membrane of N-38 neurons, an immortalized murine hypothalamic cell line. We identified, using western blotting and PCR that N-38 neurons express full-length 66kDa ERα and a 52kDa ERα spliced variant missing the fourth exon - ERαΔ4. Using surface biotinylation, we observed that treatment of N-38 neurons with estradiol or with a membrane impermeant estradiol elevated plasma membrane ERα protein levels, indicating that membrane signaling increased receptor insertion into the cell membrane. Insertion of ERα was blocked by the ER antagonist ICI 182,780 or with the GENE (PKC) pathway inhibitor bisindolylmaleimide (CHEMICAL). Downstream membrane-initiated signaling was confirmed by estradiol activation of PKC-theta (PKCθ) and the release of intracellular calcium. These results indicate that membrane ERα levels in N-38 neurons are dynamically autoregulated by estradiol. | INHIBITOR |
| Membrane-initiated estradiol signaling in immortalized hypothalamic N-38 neurons. Regulation of sexual reproduction by estradiol involves the activation of estrogen receptors (ERs) in the hypothalamus. Of the two classical ERs involved in reproduction, ERα appears to be the critical isoform. The role of ERα in reproduction has been found to involve a nuclear ERα that induces a genomic mechanism of action. More recently, a plasma membrane ERα has been shown to trigger signaling pathways involved in reproduction. Mechanisms underlying membrane-initiated estradiol signaling are emerging, including evidence that activation of plasma membrane ERα involves receptor trafficking. The present study examined the insertion of ERα into the plasma membrane of N-38 neurons, an immortalized murine hypothalamic cell line. We identified, using western blotting and PCR that N-38 neurons express full-length 66kDa ERα and a 52kDa ERα spliced variant missing the fourth exon - ERαΔ4. Using surface biotinylation, we observed that treatment of N-38 neurons with estradiol or with a membrane impermeant estradiol elevated plasma membrane ERα protein levels, indicating that membrane signaling increased receptor insertion into the cell membrane. Insertion of ERα was blocked by the ER antagonist ICI 182,780 or with the protein kinase C (GENE) pathway inhibitor bisindolylmaleimide (CHEMICAL). Downstream membrane-initiated signaling was confirmed by estradiol activation of PKC-theta (PKCθ) and the release of intracellular calcium. These results indicate that membrane ERα levels in N-38 neurons are dynamically autoregulated by estradiol. | INHIBITOR |
| Membrane-initiated estradiol signaling in immortalized hypothalamic N-38 neurons. Regulation of sexual reproduction by estradiol involves the activation of estrogen receptors (ERs) in the hypothalamus. Of the two classical ERs involved in reproduction, ERα appears to be the critical isoform. The role of ERα in reproduction has been found to involve a nuclear ERα that induces a genomic mechanism of action. More recently, a plasma membrane ERα has been shown to trigger signaling pathways involved in reproduction. Mechanisms underlying membrane-initiated estradiol signaling are emerging, including evidence that activation of plasma membrane ERα involves receptor trafficking. The present study examined the insertion of ERα into the plasma membrane of N-38 neurons, an immortalized murine hypothalamic cell line. We identified, using western blotting and PCR that N-38 neurons express full-length 66kDa ERα and a 52kDa ERα spliced variant missing the fourth exon - ERαΔ4. Using surface biotinylation, we observed that treatment of N-38 neurons with estradiol or with a membrane impermeant estradiol elevated plasma membrane ERα protein levels, indicating that membrane signaling increased receptor insertion into the cell membrane. Insertion of ERα was blocked by the GENE antagonist CHEMICAL or with the protein kinase C (PKC) pathway inhibitor bisindolylmaleimide (BIS). Downstream membrane-initiated signaling was confirmed by estradiol activation of PKC-theta (PKCθ) and the release of intracellular calcium. These results indicate that membrane ERα levels in N-38 neurons are dynamically autoregulated by estradiol. | INHIBITOR |
| Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson's disease. Consumption of coffee is associated with reduced risk of Parkinson's disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of α-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if CHEMICAL has an effect in the MPTP model of PD. Mice fed a diet containing CHEMICAL for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with CHEMICAL treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with CHEMICAL. In cultured primary microglia and astrocytes, CHEMICAL had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NFκB activation, iNOS induction, and nitric oxide production. CHEMICAL also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, MPP(+)-induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by CHEMICAL. These findings indicate that the neuroprotective effect of CHEMICAL against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of GENE. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD. | REGULATOR |
| Neuroprotective and anti-inflammatory properties of a coffee component in the CHEMICAL model of Parkinson's disease. Consumption of coffee is associated with reduced risk of Parkinson's disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of α-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if EHT has an effect in the CHEMICAL model of PD. Mice fed a diet containing EHT for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following CHEMICAL challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with EHT treatment. The neuroinflammatory response to CHEMICAL was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with EHT. In cultured primary microglia and astrocytes, EHT had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NFκB activation, iNOS induction, and nitric oxide production. EHT also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, MPP(+)-induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by EHT. These findings indicate that the neuroprotective effect of EHT against CHEMICAL is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of GENE. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD. | GENE-CHEMICAL |
| Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson's disease. Consumption of coffee is associated with reduced risk of Parkinson's disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is CHEMICAL (EHT), which ameliorates the phenotype of GENE transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if EHT has an effect in the MPTP model of PD. Mice fed a diet containing EHT for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with EHT treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with EHT. In cultured primary microglia and astrocytes, EHT had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NFκB activation, iNOS induction, and nitric oxide production. EHT also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, MPP(+)-induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by EHT. These findings indicate that the neuroprotective effect of EHT against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of PP2A. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD. | INDIRECT-DOWNREGULATOR |
| Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson's disease. Consumption of coffee is associated with reduced risk of Parkinson's disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (CHEMICAL), which ameliorates the phenotype of GENE transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if CHEMICAL has an effect in the MPTP model of PD. Mice fed a diet containing CHEMICAL for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with CHEMICAL treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with CHEMICAL. In cultured primary microglia and astrocytes, CHEMICAL had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NFκB activation, iNOS induction, and nitric oxide production. CHEMICAL also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, MPP(+)-induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by CHEMICAL. These findings indicate that the neuroprotective effect of CHEMICAL against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of PP2A. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD. | INDIRECT-DOWNREGULATOR |
| Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson's disease. Consumption of coffee is associated with reduced risk of Parkinson's disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of α-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if CHEMICAL has an effect in the MPTP model of PD. Mice fed a diet containing CHEMICAL for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and GENE content were also less pronounced with CHEMICAL treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with CHEMICAL. In cultured primary microglia and astrocytes, CHEMICAL had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NFκB activation, iNOS induction, and nitric oxide production. CHEMICAL also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, MPP(+)-induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by CHEMICAL. These findings indicate that the neuroprotective effect of CHEMICAL against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of PP2A. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD. | INDIRECT-DOWNREGULATOR |
| Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson's disease. Consumption of coffee is associated with reduced risk of Parkinson's disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of α-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if CHEMICAL has an effect in the MPTP model of PD. Mice fed a diet containing CHEMICAL for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with CHEMICAL treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with CHEMICAL. In cultured primary microglia and astrocytes, CHEMICAL had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NFκB activation, iNOS induction, and nitric oxide production. CHEMICAL also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, MPP(+)-induced demethylation of GENE (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by CHEMICAL. These findings indicate that the neuroprotective effect of CHEMICAL against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of PP2A. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD. | INDIRECT-DOWNREGULATOR |
| Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson's disease. Consumption of coffee is associated with reduced risk of Parkinson's disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of α-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if EHT has an effect in the MPTP model of PD. Mice fed a diet containing EHT for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with EHT treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with EHT. In cultured primary microglia and astrocytes, EHT had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NFκB activation, iNOS induction, and nitric oxide production. EHT also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, CHEMICAL-induced demethylation of GENE (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by EHT. These findings indicate that the neuroprotective effect of EHT against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of PP2A. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD. | REGULATOR |
| Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson's disease. Consumption of coffee is associated with reduced risk of Parkinson's disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of α-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if EHT has an effect in the MPTP model of PD. Mice fed a diet containing EHT for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with EHT treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with EHT. In cultured primary microglia and astrocytes, EHT had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NFκB activation, iNOS induction, and nitric oxide production. EHT also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, CHEMICAL-induced demethylation of phosphoprotein phosphatase 2A (GENE), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by EHT. These findings indicate that the neuroprotective effect of EHT against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of GENE. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD. | REGULATOR |
| Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson's disease. Consumption of coffee is associated with reduced risk of Parkinson's disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of α-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if CHEMICAL has an effect in the MPTP model of PD. Mice fed a diet containing CHEMICAL for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with CHEMICAL treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and GENE activation were significantly prevented with CHEMICAL. In cultured primary microglia and astrocytes, CHEMICAL had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NFκB activation, iNOS induction, and nitric oxide production. CHEMICAL also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, MPP(+)-induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by CHEMICAL. These findings indicate that the neuroprotective effect of CHEMICAL against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of PP2A. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD. | INHIBITOR |
| Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson's disease. Consumption of coffee is associated with reduced risk of Parkinson's disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of α-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if CHEMICAL has an effect in the MPTP model of PD. Mice fed a diet containing CHEMICAL for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with CHEMICAL treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with CHEMICAL. In cultured primary microglia and astrocytes, CHEMICAL had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced GENE activation, iNOS induction, and nitric oxide production. CHEMICAL also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, MPP(+)-induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by CHEMICAL. These findings indicate that the neuroprotective effect of CHEMICAL against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of PP2A. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD. | INHIBITOR |
| Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson's disease. Consumption of coffee is associated with reduced risk of Parkinson's disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of α-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if CHEMICAL has an effect in the MPTP model of PD. Mice fed a diet containing CHEMICAL for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with CHEMICAL treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with CHEMICAL. In cultured primary microglia and astrocytes, CHEMICAL had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NFκB activation, GENE induction, and nitric oxide production. CHEMICAL also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, MPP(+)-induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by CHEMICAL. These findings indicate that the neuroprotective effect of CHEMICAL against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of PP2A. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD. | INDIRECT-DOWNREGULATOR |
| Hydrogen sulfide, the next potent preventive and therapeutic agent in aging and age-associated diseases. Hydrogen sulfide (H(2)S) is the third endogenous signaling gasotransmitter, following nitric oxide and carbon monoxide. It is physiologically generated by cystathionine-γ-lyase, cystathionine-β-synthase, and 3-mercaptopyruvate sulfurtransferase. CHEMICAL has been gaining increasing attention as an important endogenous signaling molecule because of its significant effects on the cardiovascular and nervous systems. Substantial evidence shows that CHEMICAL is involved in aging by inhibiting free-radical reactions, activating SIRT1, and probably interacting with the age-related gene GENE. Moreover, CHEMICAL has been shown to have therapeutic potential in age-associated diseases. This article provides an overview of the physiological functions and effects of CHEMICAL in aging and age-associated diseases, and proposes the potential health and therapeutic benefits of CHEMICAL. | REGULATOR |
| Hydrogen sulfide, the next potent preventive and therapeutic agent in aging and age-associated diseases. Hydrogen sulfide (H(2)S) is the third endogenous signaling gasotransmitter, following nitric oxide and carbon monoxide. It is physiologically generated by cystathionine-γ-lyase, cystathionine-β-synthase, and 3-mercaptopyruvate sulfurtransferase. CHEMICAL has been gaining increasing attention as an important endogenous signaling molecule because of its significant effects on the cardiovascular and nervous systems. Substantial evidence shows that CHEMICAL is involved in aging by inhibiting free-radical reactions, activating GENE, and probably interacting with the age-related gene Klotho. Moreover, CHEMICAL has been shown to have therapeutic potential in age-associated diseases. This article provides an overview of the physiological functions and effects of CHEMICAL in aging and age-associated diseases, and proposes the potential health and therapeutic benefits of CHEMICAL. | ACTIVATOR |
| Induction of GENE through p38 MAPK/Nrf2 signaling pathway by ethanol extract of Inula helenium L. reduces inflammation in LPS-activated RAW 264.7 cells and CLP-induced septic mice. High mobility group box 1 (HMGB1) plays a crucial mediator in the pathogenesis of many inflammatory diseases. We recently proposed that heme oxygenase-1 (HO-1) negatively regulates HMGB1 in inflammatory conditions. We investigated whether ethanol extract of Inula helenium L. (EIH) activates p38 MAPK/Nrf2/HO-1 pathways in RAW264.7 cells and reduces inflammation in CLP-induced septic mice. EIH induced expression of GENE protein in a time- and concentration-dependent manner. EIH significantly diminished GENE expression in siNrf2 RNA-transfected cells. As expected, the inhibited expression of iNOS/NO, COX-2/PGE2, HMGB1 release by EIH in LPS-activated RAW264.7 cells was significantly reversed by siHO-1RNA transfection. Furthermore, EIH not only inhibited NF-κB luciferase activity, phosphorylation of IκBα in LPS-activated cells but also significantly suppressed expression of adhesion molecules (ICAM-1 and VCAM-1) in TNF-α activated human umbilical vein endothelial cells. The induction of GENE by EIH was inhibited by SB203580 but not by CHEMICAL, PD98059, nor LY294002. Most importantly, administration of EIH significantly reduced not only increase in blood HMGB1, ALT, AST, BUN, creatinine levels but also decrease macrophage infiltrate in the liver of septic mice, which were reversed by ZnPPIX, a GENE inhibitor. We concluded that EIH has anti-inflammatory effect via the induction of p38 MAPK-dependent GENE signaling pathway. | NO-RELATIONSHIP |
| Induction of GENE through p38 MAPK/Nrf2 signaling pathway by ethanol extract of Inula helenium L. reduces inflammation in LPS-activated RAW 264.7 cells and CLP-induced septic mice. High mobility group box 1 (HMGB1) plays a crucial mediator in the pathogenesis of many inflammatory diseases. We recently proposed that heme oxygenase-1 (HO-1) negatively regulates HMGB1 in inflammatory conditions. We investigated whether ethanol extract of Inula helenium L. (EIH) activates p38 MAPK/Nrf2/HO-1 pathways in RAW264.7 cells and reduces inflammation in CLP-induced septic mice. EIH induced expression of GENE protein in a time- and concentration-dependent manner. EIH significantly diminished GENE expression in siNrf2 RNA-transfected cells. As expected, the inhibited expression of iNOS/NO, COX-2/PGE2, HMGB1 release by EIH in LPS-activated RAW264.7 cells was significantly reversed by siHO-1RNA transfection. Furthermore, EIH not only inhibited NF-κB luciferase activity, phosphorylation of IκBα in LPS-activated cells but also significantly suppressed expression of adhesion molecules (ICAM-1 and VCAM-1) in TNF-α activated human umbilical vein endothelial cells. The induction of GENE by EIH was inhibited by SB203580 but not by SP600125, CHEMICAL, nor LY294002. Most importantly, administration of EIH significantly reduced not only increase in blood HMGB1, ALT, AST, BUN, creatinine levels but also decrease macrophage infiltrate in the liver of septic mice, which were reversed by ZnPPIX, a GENE inhibitor. We concluded that EIH has anti-inflammatory effect via the induction of p38 MAPK-dependent GENE signaling pathway. | NO-RELATIONSHIP |
| Induction of GENE through p38 MAPK/Nrf2 signaling pathway by ethanol extract of Inula helenium L. reduces inflammation in LPS-activated RAW 264.7 cells and CLP-induced septic mice. High mobility group box 1 (HMGB1) plays a crucial mediator in the pathogenesis of many inflammatory diseases. We recently proposed that heme oxygenase-1 (HO-1) negatively regulates HMGB1 in inflammatory conditions. We investigated whether ethanol extract of Inula helenium L. (EIH) activates p38 MAPK/Nrf2/HO-1 pathways in RAW264.7 cells and reduces inflammation in CLP-induced septic mice. EIH induced expression of GENE protein in a time- and concentration-dependent manner. EIH significantly diminished GENE expression in siNrf2 RNA-transfected cells. As expected, the inhibited expression of iNOS/NO, COX-2/PGE2, HMGB1 release by EIH in LPS-activated RAW264.7 cells was significantly reversed by siHO-1RNA transfection. Furthermore, EIH not only inhibited NF-κB luciferase activity, phosphorylation of IκBα in LPS-activated cells but also significantly suppressed expression of adhesion molecules (ICAM-1 and VCAM-1) in TNF-α activated human umbilical vein endothelial cells. The induction of GENE by EIH was inhibited by SB203580 but not by SP600125, PD98059, nor CHEMICAL. Most importantly, administration of EIH significantly reduced not only increase in blood HMGB1, ALT, AST, BUN, creatinine levels but also decrease macrophage infiltrate in the liver of septic mice, which were reversed by ZnPPIX, a GENE inhibitor. We concluded that EIH has anti-inflammatory effect via the induction of p38 MAPK-dependent GENE signaling pathway. | NO-RELATIONSHIP |
| Induction of GENE through p38 MAPK/Nrf2 signaling pathway by CHEMICAL extract of Inula helenium L. reduces inflammation in LPS-activated RAW 264.7 cells and CLP-induced septic mice. High mobility group box 1 (HMGB1) plays a crucial mediator in the pathogenesis of many inflammatory diseases. We recently proposed that heme oxygenase-1 (HO-1) negatively regulates HMGB1 in inflammatory conditions. We investigated whether CHEMICAL extract of Inula helenium L. (EIH) activates p38 MAPK/Nrf2/HO-1 pathways in RAW264.7 cells and reduces inflammation in CLP-induced septic mice. EIH induced expression of GENE protein in a time- and concentration-dependent manner. EIH significantly diminished GENE expression in siNrf2 RNA-transfected cells. As expected, the inhibited expression of iNOS/NO, COX-2/PGE2, HMGB1 release by EIH in LPS-activated RAW264.7 cells was significantly reversed by siHO-1RNA transfection. Furthermore, EIH not only inhibited NF-κB luciferase activity, phosphorylation of IκBα in LPS-activated cells but also significantly suppressed expression of adhesion molecules (ICAM-1 and VCAM-1) in TNF-α activated human umbilical vein endothelial cells. The induction of GENE by EIH was inhibited by SB203580 but not by SP600125, PD98059, nor LY294002. Most importantly, administration of EIH significantly reduced not only increase in blood HMGB1, ALT, AST, BUN, creatinine levels but also decrease macrophage infiltrate in the liver of septic mice, which were reversed by ZnPPIX, a GENE inhibitor. We concluded that EIH has anti-inflammatory effect via the induction of p38 MAPK-dependent GENE signaling pathway. | ACTIVATOR |
| Induction of HO-1 through GENE MAPK/Nrf2 signaling pathway by CHEMICAL extract of Inula helenium L. reduces inflammation in LPS-activated RAW 264.7 cells and CLP-induced septic mice. High mobility group box 1 (HMGB1) plays a crucial mediator in the pathogenesis of many inflammatory diseases. We recently proposed that heme oxygenase-1 (HO-1) negatively regulates HMGB1 in inflammatory conditions. We investigated whether CHEMICAL extract of Inula helenium L. (EIH) activates GENE MAPK/Nrf2/HO-1 pathways in RAW264.7 cells and reduces inflammation in CLP-induced septic mice. EIH induced expression of HO-1 protein in a time- and concentration-dependent manner. EIH significantly diminished HO-1 expression in siNrf2 RNA-transfected cells. As expected, the inhibited expression of iNOS/NO, COX-2/PGE2, HMGB1 release by EIH in LPS-activated RAW264.7 cells was significantly reversed by siHO-1RNA transfection. Furthermore, EIH not only inhibited NF-κB luciferase activity, phosphorylation of IκBα in LPS-activated cells but also significantly suppressed expression of adhesion molecules (ICAM-1 and VCAM-1) in TNF-α activated human umbilical vein endothelial cells. The induction of HO-1 by EIH was inhibited by SB203580 but not by SP600125, PD98059, nor LY294002. Most importantly, administration of EIH significantly reduced not only increase in blood HMGB1, ALT, AST, BUN, creatinine levels but also decrease macrophage infiltrate in the liver of septic mice, which were reversed by ZnPPIX, a HO-1 inhibitor. We concluded that EIH has anti-inflammatory effect via the induction of GENE MAPK-dependent HO-1 signaling pathway. | ACTIVATOR |
| Induction of HO-1 through p38 GENE/Nrf2 signaling pathway by CHEMICAL extract of Inula helenium L. reduces inflammation in LPS-activated RAW 264.7 cells and CLP-induced septic mice. High mobility group box 1 (HMGB1) plays a crucial mediator in the pathogenesis of many inflammatory diseases. We recently proposed that heme oxygenase-1 (HO-1) negatively regulates HMGB1 in inflammatory conditions. We investigated whether CHEMICAL extract of Inula helenium L. (EIH) activates p38 MAPK/Nrf2/HO-1 pathways in RAW264.7 cells and reduces inflammation in CLP-induced septic mice. EIH induced expression of HO-1 protein in a time- and concentration-dependent manner. EIH significantly diminished HO-1 expression in siNrf2 RNA-transfected cells. As expected, the inhibited expression of iNOS/NO, COX-2/PGE2, HMGB1 release by EIH in LPS-activated RAW264.7 cells was significantly reversed by siHO-1RNA transfection. Furthermore, EIH not only inhibited NF-κB luciferase activity, phosphorylation of IκBα in LPS-activated cells but also significantly suppressed expression of adhesion molecules (ICAM-1 and VCAM-1) in TNF-α activated human umbilical vein endothelial cells. The induction of HO-1 by EIH was inhibited by SB203580 but not by SP600125, PD98059, nor LY294002. Most importantly, administration of EIH significantly reduced not only increase in blood HMGB1, ALT, AST, BUN, creatinine levels but also decrease macrophage infiltrate in the liver of septic mice, which were reversed by ZnPPIX, a HO-1 inhibitor. We concluded that EIH has anti-inflammatory effect via the induction of p38 MAPK-dependent HO-1 signaling pathway. | ACTIVATOR |
| Induction of GENE through p38 MAPK/Nrf2 signaling pathway by ethanol extract of Inula helenium L. reduces inflammation in LPS-activated RAW 264.7 cells and CLP-induced septic mice. High mobility group box 1 (HMGB1) plays a crucial mediator in the pathogenesis of many inflammatory diseases. We recently proposed that heme oxygenase-1 (HO-1) negatively regulates HMGB1 in inflammatory conditions. We investigated whether ethanol extract of Inula helenium L. (EIH) activates p38 MAPK/Nrf2/HO-1 pathways in RAW264.7 cells and reduces inflammation in CLP-induced septic mice. EIH induced expression of GENE protein in a time- and concentration-dependent manner. EIH significantly diminished GENE expression in siNrf2 RNA-transfected cells. As expected, the inhibited expression of iNOS/NO, COX-2/PGE2, HMGB1 release by EIH in LPS-activated RAW264.7 cells was significantly reversed by siHO-1RNA transfection. Furthermore, EIH not only inhibited NF-κB luciferase activity, phosphorylation of IκBα in LPS-activated cells but also significantly suppressed expression of adhesion molecules (ICAM-1 and VCAM-1) in TNF-α activated human umbilical vein endothelial cells. The induction of GENE by EIH was inhibited by CHEMICAL but not by SP600125, PD98059, nor LY294002. Most importantly, administration of EIH significantly reduced not only increase in blood HMGB1, ALT, AST, BUN, creatinine levels but also decrease macrophage infiltrate in the liver of septic mice, which were reversed by ZnPPIX, a GENE inhibitor. We concluded that EIH has anti-inflammatory effect via the induction of p38 MAPK-dependent GENE signaling pathway. | INHIBITOR |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1. FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary CHEMICAL by a mechanism that involves the GENE (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis. | REGULATOR |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1. FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary CHEMICAL by a mechanism that involves the farnesoid X receptor (GENE), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis. | REGULATOR |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1. FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary bile acids by a mechanism that involves the GENE (FXR), a CHEMICAL-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis. | ACTIVATOR |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1. FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (GENE), a CHEMICAL-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis. | ACTIVATOR |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and GENE, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that GENE exhibits 10-fold higher specific activity than FMO1. GENE overexpression in mice significantly increases plasma TMAO levels while silencing GENE decreases TMAO levels. In both humans and mice, hepatic GENE expression is reduced in males compared to females. In mice, this reduction in GENE expression is due primarily to downregulation by androgens. GENE expression is induced by dietary CHEMICAL by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that GENE and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis. | INDIRECT-UPREGULATOR |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and GENE, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that GENE exhibits 10-fold higher specific activity than FMO1. GENE overexpression in mice significantly increases plasma TMAO levels while silencing GENE decreases TMAO levels. In both humans and mice, hepatic GENE expression is reduced in males compared to females. In mice, this reduction in GENE expression is due primarily to downregulation by CHEMICAL. GENE expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that GENE and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis. | GENE-CHEMICAL |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating CHEMICAL levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and GENE, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to CHEMICAL. Further, we show that GENE exhibits 10-fold higher specific activity than FMO1. GENE overexpression in mice significantly increases plasma CHEMICAL levels while silencing GENE decreases CHEMICAL levels. In both humans and mice, hepatic GENE expression is reduced in males compared to females. In mice, this reduction in GENE expression is due primarily to downregulation by androgens. GENE expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that GENE and CHEMICAL are significantly correlated, and CHEMICAL levels explain 11% of the variation in atherosclerosis. | PRODUCT-OF |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating CHEMICAL levels. We demonstrate that two GENE family members, FMO1 and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to CHEMICAL. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1. FMO3 overexpression in mice significantly increases plasma CHEMICAL levels while silencing FMO3 decreases CHEMICAL levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and CHEMICAL are significantly correlated, and CHEMICAL levels explain 11% of the variation in atherosclerosis. | PRODUCT-OF |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating CHEMICAL levels. We demonstrate that two flavin mono-oxygenase family members, GENE and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to CHEMICAL. Further, we show that FMO3 exhibits 10-fold higher specific activity than GENE. FMO3 overexpression in mice significantly increases plasma CHEMICAL levels while silencing FMO3 decreases CHEMICAL levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and CHEMICAL are significantly correlated, and CHEMICAL levels explain 11% of the variation in atherosclerosis. | PRODUCT-OF |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two GENE family members, FMO1 and FMO3, oxidize CHEMICAL (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1. FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis. | SUBSTRATE |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, GENE and FMO3, oxidize CHEMICAL (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than GENE. FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis. | SUBSTRATE |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and GENE, oxidize CHEMICAL (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that GENE exhibits 10-fold higher specific activity than FMO1. GENE overexpression in mice significantly increases plasma TMAO levels while silencing GENE decreases TMAO levels. In both humans and mice, hepatic GENE expression is reduced in males compared to females. In mice, this reduction in GENE expression is due primarily to downregulation by androgens. GENE expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that GENE and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis. | SUBSTRATE |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two GENE family members, FMO1 and FMO3, oxidize trimethylamine (CHEMICAL), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1. FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis. | SUBSTRATE |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, GENE and FMO3, oxidize trimethylamine (CHEMICAL), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than GENE. FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis. | SUBSTRATE |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and GENE, oxidize trimethylamine (CHEMICAL), derived from gut flora metabolism of choline, to TMAO. Further, we show that GENE exhibits 10-fold higher specific activity than FMO1. GENE overexpression in mice significantly increases plasma TMAO levels while silencing GENE decreases TMAO levels. In both humans and mice, hepatic GENE expression is reduced in males compared to females. In mice, this reduction in GENE expression is due primarily to downregulation by androgens. GENE expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that GENE and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis. | SUBSTRATE |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two GENE family members, FMO1 and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of CHEMICAL, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1. FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis. | SUBSTRATE |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, GENE and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of CHEMICAL, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than GENE. FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis. | SUBSTRATE |
| Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and GENE, oxidize trimethylamine (TMA), derived from gut flora metabolism of CHEMICAL, to TMAO. Further, we show that GENE exhibits 10-fold higher specific activity than FMO1. GENE overexpression in mice significantly increases plasma TMAO levels while silencing GENE decreases TMAO levels. In both humans and mice, hepatic GENE expression is reduced in males compared to females. In mice, this reduction in GENE expression is due primarily to downregulation by androgens. GENE expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that GENE and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis. | SUBSTRATE |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other CHEMICAL, including Δ(5)-androstenediol, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to GENE (ERα) and ERβ. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of ERα and ERβ. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these CHEMICAL and SERMs in regulating responses mediated by ERα and ERβ a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other CHEMICAL, including Δ(5)-androstenediol, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to estrogen receptor-α (GENE) and ERβ. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of GENE and ERβ. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these CHEMICAL and SERMs in regulating responses mediated by GENE and ERβ a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other CHEMICAL, including Δ(5)-androstenediol, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to estrogen receptor-α (ERα) and GENE. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of ERα and GENE. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these CHEMICAL and SERMs in regulating responses mediated by ERα and GENE a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including CHEMICAL, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to GENE (ERα) and ERβ. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of ERα and ERβ. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by ERα and ERβ a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including CHEMICAL, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to estrogen receptor-α (GENE) and ERβ. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of GENE and ERβ. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by GENE and ERβ a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including CHEMICAL, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to estrogen receptor-α (ERα) and GENE. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of ERα and GENE. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by ERα and GENE a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Δ(5)-androstenediol, CHEMICAL and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to GENE (ERα) and ERβ. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of ERα and ERβ. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by ERα and ERβ a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Δ(5)-androstenediol, CHEMICAL and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to estrogen receptor-α (GENE) and ERβ. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of GENE and ERβ. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by GENE and ERβ a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Δ(5)-androstenediol, CHEMICAL and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to estrogen receptor-α (ERα) and GENE. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of ERα and GENE. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by ERα and GENE a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Δ(5)-androstenediol, 5α-androstanediol and CHEMICAL, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to GENE (ERα) and ERβ. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of ERα and ERβ. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by ERα and ERβ a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Δ(5)-androstenediol, 5α-androstanediol and CHEMICAL, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to estrogen receptor-α (GENE) and ERβ. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of GENE and ERβ. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by GENE and ERβ a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Δ(5)-androstenediol, 5α-androstanediol and CHEMICAL, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to estrogen receptor-α (ERα) and GENE. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of ERα and GENE. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by ERα and GENE a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Δ(5)-androstenediol, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a CHEMICAL and a C19 methyl group, also mediate physiological responses through binding to GENE (ERα) and ERβ. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of ERα and ERβ. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by ERα and ERβ a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Δ(5)-androstenediol, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a CHEMICAL and a C19 methyl group, also mediate physiological responses through binding to estrogen receptor-α (GENE) and ERβ. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of GENE and ERβ. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by GENE and ERβ a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Δ(5)-androstenediol, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a CHEMICAL and a C19 methyl group, also mediate physiological responses through binding to estrogen receptor-α (ERα) and GENE. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of ERα and GENE. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by ERα and GENE a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 CHEMICAL group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Δ(5)-androstenediol, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 CHEMICAL group, also mediate physiological responses through binding to GENE (ERα) and ERβ. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of ERα and ERβ. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by ERα and ERβ a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 CHEMICAL group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Δ(5)-androstenediol, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 CHEMICAL group, also mediate physiological responses through binding to estrogen receptor-α (GENE) and ERβ. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of GENE and ERβ. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by GENE and ERβ a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 CHEMICAL group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Δ(5)-androstenediol, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 CHEMICAL group, also mediate physiological responses through binding to estrogen receptor-α (ERα) and GENE. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of ERα and GENE. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by ERα and GENE a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | DIRECT-REGULATOR |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological CHEMICAL in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the CHEMICAL receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Δ(5)-androstenediol, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to CHEMICAL receptor-α (ERα) and ERβ. Moreover, selective CHEMICAL response modulators (SERMs) with diverse structures also regulate transcription of GENE and ERβ. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by GENE and ERβ a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | GENE-CHEMICAL |
| What are the physiological estrogens? Estradiol (E2) is the principal physiological CHEMICAL in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the CHEMICAL receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Δ(5)-androstenediol, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to CHEMICAL receptor-α (ERα) and GENE. Moreover, selective CHEMICAL response modulators (SERMs) with diverse structures also regulate transcription of ERα and GENE. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by ERα and GENE a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. | GENE-CHEMICAL |
| Synthesis of CHEMICAL derivatives: discovery of a potent and selective GENE inhibitor for the treatment of Alzheimer's disease. Phosphodiesterase type 5 (PDE5) mediates the degradation of cGMP in a variety of tissues including brain. Recent studies have demonstrated the importance of the nitric oxide/cGMP/cAMP-responsive element-binding protein (CREB) pathway to the process of learning and memory. Thus, PDE5 inhibitors (PDE5Is) are thought to be promising new therapeutic agents for the treatment of Alzheimer's disease (AD), a neurodegenerative disorder characterized by memory loss. To explore this possibility, a series of CHEMICAL derivatives were synthesized and evaluated. We found that compound 7a selectively inhibits PDE5 with an IC(50) of 0.27 nM and readily crosses the blood brain barrier. In an in vivo mouse model of AD, compound 7a rescues synaptic and memory defects. Quinoline-based, CNS-permeant PDE5Is have potential for AD therapeutic development. | INHIBITOR |
| Synthesis of quinoline derivatives: discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer's disease. Phosphodiesterase type 5 (GENE) mediates the degradation of CHEMICAL in a variety of tissues including brain. Recent studies have demonstrated the importance of the nitric oxide/cGMP/cAMP-responsive element-binding protein (CREB) pathway to the process of learning and memory. Thus, GENE inhibitors (PDE5Is) are thought to be promising new therapeutic agents for the treatment of Alzheimer's disease (AD), a neurodegenerative disorder characterized by memory loss. To explore this possibility, a series of quinoline derivatives were synthesized and evaluated. We found that compound 7a selectively inhibits GENE with an IC(50) of 0.27 nM and readily crosses the blood brain barrier. In an in vivo mouse model of AD, compound 7a rescues synaptic and memory defects. Quinoline-based, CNS-permeant PDE5Is have potential for AD therapeutic development. | SUBSTRATE |
| Synthesis of quinoline derivatives: discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer's disease. GENE (PDE5) mediates the degradation of CHEMICAL in a variety of tissues including brain. Recent studies have demonstrated the importance of the nitric oxide/cGMP/cAMP-responsive element-binding protein (CREB) pathway to the process of learning and memory. Thus, PDE5 inhibitors (PDE5Is) are thought to be promising new therapeutic agents for the treatment of Alzheimer's disease (AD), a neurodegenerative disorder characterized by memory loss. To explore this possibility, a series of quinoline derivatives were synthesized and evaluated. We found that compound 7a selectively inhibits PDE5 with an IC(50) of 0.27 nM and readily crosses the blood brain barrier. In an in vivo mouse model of AD, compound 7a rescues synaptic and memory defects. Quinoline-based, CNS-permeant PDE5Is have potential for AD therapeutic development. | SUBSTRATE |
| Fragment-based design, synthesis, and biological evaluation of N-substituted-5-(4-isopropylthiophenol)-2-hydroxynicotinamide derivatives as novel GENE inhibitors. We have previously reported a nanomolar inhibitor of antiapoptotic GENE protein, 3-thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1). S1 plays its function by binding to the BH3 groove of GENE. Basing on this spacial structural characteristic, we developed a novel class of GENE inhibitor using fragment-based drug discovery approach. By dissecting S1, we identified the compound 4 with a 2-hydroxypyridine core as the starting fragment. In the following molecular growth, we used the ligand efficiency evaluation and fit quality score to assess the fragments. A novel potent compound, CHEMICAL (12c), which binds GENE with an IC(50) value of 54 nM was obtained. Compound 12c demonstrated a better aqueous solubility than S1. | DIRECT-REGULATOR |
| Fragment-based design, synthesis, and biological evaluation of N-substituted-5-(4-isopropylthiophenol)-2-hydroxynicotinamide derivatives as novel GENE inhibitors. We have previously reported a nanomolar inhibitor of antiapoptotic GENE protein, CHEMICAL (S1). S1 plays its function by binding to the BH3 groove of GENE. Basing on this spacial structural characteristic, we developed a novel class of GENE inhibitor using fragment-based drug discovery approach. By dissecting S1, we identified the compound 4 with a 2-hydroxypyridine core as the starting fragment. In the following molecular growth, we used the ligand efficiency evaluation and fit quality score to assess the fragments. A novel potent compound, N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide (12c), which binds GENE with an IC(50) value of 54 nM was obtained. Compound 12c demonstrated a better aqueous solubility than S1. | INHIBITOR |
| Fragment-based design, synthesis, and biological evaluation of CHEMICAL derivatives as novel GENE inhibitors. We have previously reported a nanomolar inhibitor of antiapoptotic GENE protein, 3-thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1). S1 plays its function by binding to the BH3 groove of GENE. Basing on this spacial structural characteristic, we developed a novel class of GENE inhibitor using fragment-based drug discovery approach. By dissecting S1, we identified the compound 4 with a 2-hydroxypyridine core as the starting fragment. In the following molecular growth, we used the ligand efficiency evaluation and fit quality score to assess the fragments. A novel potent compound, N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide (12c), which binds GENE with an IC(50) value of 54 nM was obtained. Compound 12c demonstrated a better aqueous solubility than S1. | INHIBITOR |
| CHEMICAL clearance, distribution, metabolism, and excretion in monkeys following intravenous administration. CHEMICAL, a polyethylene glycol (PEG)ylated peptide-based erythropoiesis-stimulating agent, stimulates the GENE dimer that governs erythropoiesis. Studies were designed to determine the erythropoietic response, pharmacokinetics (PK), tissue distribution, metabolism, and excretion of peginesatide in nonhuman primates following a single i.v. dose. The PK profile of peginesatide (0.1-5 mg/kg) is characterized by low, dose-dependent plasma clearance; small volume of distribution; and long half-life. The peginesatide PK profile following a single i.v. dose is consistent with the sustained erythropoiesis. Biodistribution quantitative whole-body autoradiography demonstrated high peginesatide levels in bone marrow (i.e., primary hematopoietic site) as well as other known hematopoietic sites persisting through at least 3 weeks at 2.1 mg/kg. Microautoradiography analysis at 48 hours postdose revealed uniform and high distribution of radioactivity in the bone marrow and splenic red pulp with less extensive distribution in the renal cortex (glomeruli, associated ducts, interstitial cells). Radioactivity in the kidney was most prominent in the outer medullary and papillary interstitium. At 2 weeks after dosing, cumulative radioactivity recovery in the urine and feces was 60 and 7% of the administered dose, respectively, with most of the radioactivity associated with the parent molecule. In conclusion, the PK characteristics are consistent with a PEGylated peptide of a 45-kDa molecular mass, specifically low volume of distribution and long half-life. Drug was localized principally to hematopoietic sites, and nonspecific tissue retention was not observed. The nonhuman primate data indicate that peginesatide is metabolically stable and primarily excreted in the urine. | ACTIVATOR |
| Peginesatide clearance, distribution, metabolism, and excretion in monkeys following intravenous administration. Peginesatide, a CHEMICAL (PEG)ylated peptide-based erythropoiesis-stimulating agent, stimulates the GENE dimer that governs erythropoiesis. Studies were designed to determine the erythropoietic response, pharmacokinetics (PK), tissue distribution, metabolism, and excretion of peginesatide in nonhuman primates following a single i.v. dose. The PK profile of peginesatide (0.1-5 mg/kg) is characterized by low, dose-dependent plasma clearance; small volume of distribution; and long half-life. The peginesatide PK profile following a single i.v. dose is consistent with the sustained erythropoiesis. Biodistribution quantitative whole-body autoradiography demonstrated high peginesatide levels in bone marrow (i.e., primary hematopoietic site) as well as other known hematopoietic sites persisting through at least 3 weeks at 2.1 mg/kg. Microautoradiography analysis at 48 hours postdose revealed uniform and high distribution of radioactivity in the bone marrow and splenic red pulp with less extensive distribution in the renal cortex (glomeruli, associated ducts, interstitial cells). Radioactivity in the kidney was most prominent in the outer medullary and papillary interstitium. At 2 weeks after dosing, cumulative radioactivity recovery in the urine and feces was 60 and 7% of the administered dose, respectively, with most of the radioactivity associated with the parent molecule. In conclusion, the PK characteristics are consistent with a PEGylated peptide of a 45-kDa molecular mass, specifically low volume of distribution and long half-life. Drug was localized principally to hematopoietic sites, and nonspecific tissue retention was not observed. The nonhuman primate data indicate that peginesatide is metabolically stable and primarily excreted in the urine. | ACTIVATOR |
| Peginesatide clearance, distribution, metabolism, and excretion in monkeys following intravenous administration. Peginesatide, a polyethylene glycol (CHEMICAL)ylated peptide-based erythropoiesis-stimulating agent, stimulates the GENE dimer that governs erythropoiesis. Studies were designed to determine the erythropoietic response, pharmacokinetics (PK), tissue distribution, metabolism, and excretion of peginesatide in nonhuman primates following a single i.v. dose. The PK profile of peginesatide (0.1-5 mg/kg) is characterized by low, dose-dependent plasma clearance; small volume of distribution; and long half-life. The peginesatide PK profile following a single i.v. dose is consistent with the sustained erythropoiesis. Biodistribution quantitative whole-body autoradiography demonstrated high peginesatide levels in bone marrow (i.e., primary hematopoietic site) as well as other known hematopoietic sites persisting through at least 3 weeks at 2.1 mg/kg. Microautoradiography analysis at 48 hours postdose revealed uniform and high distribution of radioactivity in the bone marrow and splenic red pulp with less extensive distribution in the renal cortex (glomeruli, associated ducts, interstitial cells). Radioactivity in the kidney was most prominent in the outer medullary and papillary interstitium. At 2 weeks after dosing, cumulative radioactivity recovery in the urine and feces was 60 and 7% of the administered dose, respectively, with most of the radioactivity associated with the parent molecule. In conclusion, the PK characteristics are consistent with a PEGylated peptide of a 45-kDa molecular mass, specifically low volume of distribution and long half-life. Drug was localized principally to hematopoietic sites, and nonspecific tissue retention was not observed. The nonhuman primate data indicate that peginesatide is metabolically stable and primarily excreted in the urine. | PART-OF |
| Comparison of orientation and rotational motion of skeletal muscle cross-bridges containing phosphorylated and dephosphorylated myosin regulatory light chain. Calcium binding to thin filaments is a major element controlling active force generation in striated muscles. Recent evidence suggests that processes other than Ca(2+) binding, such as phosphorylation of myosin regulatory light chain (RLC) also controls contraction of vertebrate striated muscle (Cooke, R. (2011) Biophys. Rev. 3, 33-45). Electron paramagnetic resonance (EPR) studies using CHEMICAL analog spin label probes showed that dephosphorylated myosin heads are highly ordered in the relaxed fibers and have very low GENE activity. This ordered structure of myosin cross-bridges disappears with the phosphorylation of RLC (Stewart, M. (2010) Proc. Natl. Acad. Sci. U.S.A. 107, 430-435). The slower GENE activity in the dephosporylated moiety has been defined as a new super-relaxed state (SRX). It can be observed in both skeletal and cardiac muscle fibers (Hooijman, P., Stewart, M. A., and Cooke, R. (2011) Biophys. J. 100, 1969-1976). Given the importance of the finding that suggests a novel pathway of regulation of skeletal muscle, we aim to examine the effects of phosphorylation on cross-bridge orientation and rotational motion. We find that: (i) relaxed cross-bridges, but not active ones, are statistically better ordered in muscle where the RLC is dephosporylated compared with phosphorylated RLC; (ii) relaxed phosphorylated and dephosphorylated cross-bridges rotate equally slowly; and (iii) active phosphorylated cross-bridges rotate considerably faster than dephosphorylated ones during isometric contraction but the duty cycle remained the same, suggesting that both phosphorylated and dephosphorylated muscles develop the same isometric tension at full Ca(2+) saturation. A simple theory was developed to account for this fact. | DIRECT-REGULATOR |
| Comparison of orientation and rotational motion of skeletal muscle cross-bridges containing phosphorylated and GENE regulatory light chain. Calcium binding to thin filaments is a major element controlling active force generation in striated muscles. Recent evidence suggests that processes other than Ca(2+) binding, such as phosphorylation of myosin regulatory light chain (RLC) also controls contraction of vertebrate striated muscle (Cooke, R. (2011) Biophys. Rev. 3, 33-45). Electron paramagnetic resonance (EPR) studies using CHEMICAL analog spin label probes showed that GENE heads are highly ordered in the relaxed fibers and have very low ATPase activity. This ordered structure of myosin cross-bridges disappears with the phosphorylation of RLC (Stewart, M. (2010) Proc. Natl. Acad. Sci. U.S.A. 107, 430-435). The slower ATPase activity in the dephosporylated moiety has been defined as a new super-relaxed state (SRX). It can be observed in both skeletal and cardiac muscle fibers (Hooijman, P., Stewart, M. A., and Cooke, R. (2011) Biophys. J. 100, 1969-1976). Given the importance of the finding that suggests a novel pathway of regulation of skeletal muscle, we aim to examine the effects of phosphorylation on cross-bridge orientation and rotational motion. We find that: (i) relaxed cross-bridges, but not active ones, are statistically better ordered in muscle where the RLC is dephosporylated compared with phosphorylated RLC; (ii) relaxed phosphorylated and dephosphorylated cross-bridges rotate equally slowly; and (iii) active phosphorylated cross-bridges rotate considerably faster than dephosphorylated ones during isometric contraction but the duty cycle remained the same, suggesting that both phosphorylated and dephosphorylated muscles develop the same isometric tension at full Ca(2+) saturation. A simple theory was developed to account for this fact. | DIRECT-REGULATOR |
| LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation. There has been much recent interest in lysophosphatidic acid (LPA) signaling through one of its receptors, LPA1, in fibrotic diseases, but the mechanisms by which LPA-LPA1 signaling promotes pathological fibrosis remain to be fully elucidated. Using a mouse peritoneal fibrosis model, we demonstrate central roles for CHEMICAL and LPA1 in fibroblast proliferation. Genetic deletion or pharmacological antagonism of LPA1 protected mice from peritoneal fibrosis, blunting the increases in peritoneal collagen by 65.4 and 52.9%, respectively, compared to control animals and demonstrated that peritoneal fibroblast proliferation was highly LPA1 dependent. Activation of LPA1 on mesothelial cells induced these cells to express connective tissue growth factor (CTGF), driving fibroblast proliferation in a paracrine fashion. Activation of mesothelial cell LPA1 induced CTGF expression by inducing cytoskeleton reorganization in these cells, causing nuclear translocation of myocardin-related transcription factor (MRTF)-A and MRTF-B. Pharmacological inhibition of MRTF-induced transcription also diminished CTGF expression and fibrosis in the peritoneal fibrosis model, mitigating the increase in peritoneal collagen content by 57.9% compared to controls. LPA1-induced cytoskeleton reorganization therefore makes a previously unrecognized but critically important contribution to the profibrotic activities of CHEMICAL by driving GENE-dependent CTGF expression, which, in turn, drives fibroblast proliferation.-Sakai, N., Chun, J., Duffield, J. S., Wada, T., Luster, A. D., Tager, A. M. LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation. | REGULATOR |
| LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation. There has been much recent interest in lysophosphatidic acid (LPA) signaling through one of its receptors, GENE, in fibrotic diseases, but the mechanisms by which CHEMICAL-GENE signaling promotes pathological fibrosis remain to be fully elucidated. Using a mouse peritoneal fibrosis model, we demonstrate central roles for CHEMICAL and GENE in fibroblast proliferation. Genetic deletion or pharmacological antagonism of GENE protected mice from peritoneal fibrosis, blunting the increases in peritoneal collagen by 65.4 and 52.9%, respectively, compared to control animals and demonstrated that peritoneal fibroblast proliferation was highly GENE dependent. Activation of GENE on mesothelial cells induced these cells to express connective tissue growth factor (CTGF), driving fibroblast proliferation in a paracrine fashion. Activation of mesothelial cell GENE induced CTGF expression by inducing cytoskeleton reorganization in these cells, causing nuclear translocation of myocardin-related transcription factor (MRTF)-A and MRTF-B. Pharmacological inhibition of MRTF-induced transcription also diminished CTGF expression and fibrosis in the peritoneal fibrosis model, mitigating the increase in peritoneal collagen content by 57.9% compared to controls. LPA1-induced cytoskeleton reorganization therefore makes a previously unrecognized but critically important contribution to the profibrotic activities of CHEMICAL by driving MRTF-dependent CTGF expression, which, in turn, drives fibroblast proliferation.-Sakai, N., Chun, J., Duffield, J. S., Wada, T., Luster, A. D., Tager, A. M. LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation. | REGULATOR |
| LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation. There has been much recent interest in CHEMICAL (LPA) signaling through one of its receptors, GENE, in fibrotic diseases, but the mechanisms by which LPA-LPA1 signaling promotes pathological fibrosis remain to be fully elucidated. Using a mouse peritoneal fibrosis model, we demonstrate central roles for LPA and GENE in fibroblast proliferation. Genetic deletion or pharmacological antagonism of GENE protected mice from peritoneal fibrosis, blunting the increases in peritoneal collagen by 65.4 and 52.9%, respectively, compared to control animals and demonstrated that peritoneal fibroblast proliferation was highly GENE dependent. Activation of GENE on mesothelial cells induced these cells to express connective tissue growth factor (CTGF), driving fibroblast proliferation in a paracrine fashion. Activation of mesothelial cell GENE induced CTGF expression by inducing cytoskeleton reorganization in these cells, causing nuclear translocation of myocardin-related transcription factor (MRTF)-A and MRTF-B. Pharmacological inhibition of MRTF-induced transcription also diminished CTGF expression and fibrosis in the peritoneal fibrosis model, mitigating the increase in peritoneal collagen content by 57.9% compared to controls. LPA1-induced cytoskeleton reorganization therefore makes a previously unrecognized but critically important contribution to the profibrotic activities of LPA by driving MRTF-dependent CTGF expression, which, in turn, drives fibroblast proliferation.-Sakai, N., Chun, J., Duffield, J. S., Wada, T., Luster, A. D., Tager, A. M. LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation. | REGULATOR |
| LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation. There has been much recent interest in lysophosphatidic acid (LPA) signaling through one of its receptors, LPA1, in fibrotic diseases, but the mechanisms by which LPA-LPA1 signaling promotes pathological fibrosis remain to be fully elucidated. Using a mouse peritoneal fibrosis model, we demonstrate central roles for CHEMICAL and LPA1 in fibroblast proliferation. Genetic deletion or pharmacological antagonism of LPA1 protected mice from peritoneal fibrosis, blunting the increases in peritoneal collagen by 65.4 and 52.9%, respectively, compared to control animals and demonstrated that peritoneal fibroblast proliferation was highly LPA1 dependent. Activation of LPA1 on mesothelial cells induced these cells to express connective tissue growth factor (CTGF), driving fibroblast proliferation in a paracrine fashion. Activation of mesothelial cell LPA1 induced GENE expression by inducing cytoskeleton reorganization in these cells, causing nuclear translocation of myocardin-related transcription factor (MRTF)-A and MRTF-B. Pharmacological inhibition of MRTF-induced transcription also diminished GENE expression and fibrosis in the peritoneal fibrosis model, mitigating the increase in peritoneal collagen content by 57.9% compared to controls. LPA1-induced cytoskeleton reorganization therefore makes a previously unrecognized but critically important contribution to the profibrotic activities of CHEMICAL by driving MRTF-dependent GENE expression, which, in turn, drives fibroblast proliferation.-Sakai, N., Chun, J., Duffield, J. S., Wada, T., Luster, A. D., Tager, A. M. LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation. | GENE-CHEMICAL |
| Cooperative effects for GENE differ between styrene and its metabolites. Abstract 1. Cooperative interactions are frequently observed in the metabolism of drugs and pollutants by cytochrome P450s; nevertheless, the molecular determinants for cooperativity remain elusive. Previously, we demonstrated that steady-state styrene metabolism by GENE exhibits positive cooperativity. 2. We hypothesized that styrene metabolites have lower affinity than styrene toward GENE and limited ability to induce cooperative effects during metabolism. To test the hypothesis, we determined the potency and mechanism of inhibition for styrene and its metabolites toward oxidation of 4-nitrophenol using GENE Supersomes® and human liver microsomes. 3. Styrene inhibited the reaction through a mixed cooperative mechanism with high affinity for the catalytic site (67 µM) and lower affinity for the cooperative site (1100 µM), while increasing substrate turnover at high concentrations. Styrene oxide and CHEMICAL possessed similar affinity for GENE. Styrene oxide behaved cooperatively like styrene, but CHEMICAL decreased turnover at high concentrations. Styrene glycol was a very poor competitive inhibitor. Among all compounds, there was a positive correlation with binding and hydrophobicity. 4. Taken together, these findings for GENE further validate contributions of cooperative mechanisms to metabolic processes, demonstrate the role of molecular structure on those mechanisms and underscore the potential for heterotropic cooperative effects between different compounds. | DIRECT-REGULATOR |
| Cooperative effects for GENE differ between CHEMICAL and its metabolites. Abstract 1. Cooperative interactions are frequently observed in the metabolism of drugs and pollutants by cytochrome P450s; nevertheless, the molecular determinants for cooperativity remain elusive. Previously, we demonstrated that steady-state CHEMICAL metabolism by GENE exhibits positive cooperativity. 2. We hypothesized that CHEMICAL metabolites have lower affinity than CHEMICAL toward GENE and limited ability to induce cooperative effects during metabolism. To test the hypothesis, we determined the potency and mechanism of inhibition for CHEMICAL and its metabolites toward oxidation of 4-nitrophenol using GENE Supersomes® and human liver microsomes. 3. CHEMICAL inhibited the reaction through a mixed cooperative mechanism with high affinity for the catalytic site (67 µM) and lower affinity for the cooperative site (1100 µM), while increasing substrate turnover at high concentrations. CHEMICAL oxide and 4-vinylphenol possessed similar affinity for GENE. CHEMICAL oxide behaved cooperatively like CHEMICAL, but 4-vinylphenol decreased turnover at high concentrations. CHEMICAL glycol was a very poor competitive inhibitor. Among all compounds, there was a positive correlation with binding and hydrophobicity. 4. Taken together, these findings for GENE further validate contributions of cooperative mechanisms to metabolic processes, demonstrate the role of molecular structure on those mechanisms and underscore the potential for heterotropic cooperative effects between different compounds. | DIRECT-REGULATOR |
| Cooperative effects for GENE differ between styrene and its metabolites. Abstract 1. Cooperative interactions are frequently observed in the metabolism of drugs and pollutants by cytochrome P450s; nevertheless, the molecular determinants for cooperativity remain elusive. Previously, we demonstrated that steady-state styrene metabolism by GENE exhibits positive cooperativity. 2. We hypothesized that styrene metabolites have lower affinity than styrene toward GENE and limited ability to induce cooperative effects during metabolism. To test the hypothesis, we determined the potency and mechanism of inhibition for styrene and its metabolites toward oxidation of 4-nitrophenol using GENE Supersomes® and human liver microsomes. 3. Styrene inhibited the reaction through a mixed cooperative mechanism with high affinity for the catalytic site (67 µM) and lower affinity for the cooperative site (1100 µM), while increasing substrate turnover at high concentrations. CHEMICAL and 4-vinylphenol possessed similar affinity for GENE. CHEMICAL behaved cooperatively like styrene, but 4-vinylphenol decreased turnover at high concentrations. Styrene glycol was a very poor competitive inhibitor. Among all compounds, there was a positive correlation with binding and hydrophobicity. 4. Taken together, these findings for GENE further validate contributions of cooperative mechanisms to metabolic processes, demonstrate the role of molecular structure on those mechanisms and underscore the potential for heterotropic cooperative effects between different compounds. | DIRECT-REGULATOR |
| Nuclear receptors in bile acid metabolism. CHEMICAL are signaling molecules that activate nuclear receptors, such as farnesoid X receptor, pregnane X receptor, GENE, and vitamin D receptor, and play a critical role in the regulation of lipid, glucose, energy, and drug metabolism. These xenobiotic/endobiotic-sensing nuclear receptors regulate phase I oxidation, phase II conjugation, and phase III transport in bile acid and drug metabolism in the digestive system. Integration of bile acid metabolism with drug metabolism controls absorption, transport, and metabolism of nutrients and drugs to maintain metabolic homeostasis and also protects against liver injury, inflammation, and related metabolic diseases, such as nonalcoholic fatty liver disease, diabetes, and obesity. Bile-acid-based drugs targeting nuclear receptors are in clinical trials for treating cholestatic liver diseases and fatty liver disease. | ACTIVATOR |
| Nuclear receptors in bile acid metabolism. CHEMICAL are signaling molecules that activate nuclear receptors, such as farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, and GENE, and play a critical role in the regulation of lipid, glucose, energy, and drug metabolism. These xenobiotic/endobiotic-sensing nuclear receptors regulate phase I oxidation, phase II conjugation, and phase III transport in bile acid and drug metabolism in the digestive system. Integration of bile acid metabolism with drug metabolism controls absorption, transport, and metabolism of nutrients and drugs to maintain metabolic homeostasis and also protects against liver injury, inflammation, and related metabolic diseases, such as nonalcoholic fatty liver disease, diabetes, and obesity. Bile-acid-based drugs targeting nuclear receptors are in clinical trials for treating cholestatic liver diseases and fatty liver disease. | ACTIVATOR |
| GENE in bile acid metabolism. CHEMICAL are signaling molecules that activate GENE, such as farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, and vitamin D receptor, and play a critical role in the regulation of lipid, glucose, energy, and drug metabolism. These xenobiotic/endobiotic-sensing GENE regulate phase I oxidation, phase II conjugation, and phase III transport in bile acid and drug metabolism in the digestive system. Integration of bile acid metabolism with drug metabolism controls absorption, transport, and metabolism of nutrients and drugs to maintain metabolic homeostasis and also protects against liver injury, inflammation, and related metabolic diseases, such as nonalcoholic fatty liver disease, diabetes, and obesity. Bile-acid-based drugs targeting GENE are in clinical trials for treating cholestatic liver diseases and fatty liver disease. | ACTIVATOR |
| Nuclear receptors in bile acid metabolism. CHEMICAL are signaling molecules that activate nuclear receptors, such as GENE, pregnane X receptor, constitutive androstane receptor, and vitamin D receptor, and play a critical role in the regulation of lipid, glucose, energy, and drug metabolism. These xenobiotic/endobiotic-sensing nuclear receptors regulate phase I oxidation, phase II conjugation, and phase III transport in bile acid and drug metabolism in the digestive system. Integration of bile acid metabolism with drug metabolism controls absorption, transport, and metabolism of nutrients and drugs to maintain metabolic homeostasis and also protects against liver injury, inflammation, and related metabolic diseases, such as nonalcoholic fatty liver disease, diabetes, and obesity. Bile-acid-based drugs targeting nuclear receptors are in clinical trials for treating cholestatic liver diseases and fatty liver disease. | ACTIVATOR |
| Nuclear receptors in bile acid metabolism. CHEMICAL are signaling molecules that activate nuclear receptors, such as farnesoid X receptor, GENE, constitutive androstane receptor, and vitamin D receptor, and play a critical role in the regulation of lipid, glucose, energy, and drug metabolism. These xenobiotic/endobiotic-sensing nuclear receptors regulate phase I oxidation, phase II conjugation, and phase III transport in bile acid and drug metabolism in the digestive system. Integration of bile acid metabolism with drug metabolism controls absorption, transport, and metabolism of nutrients and drugs to maintain metabolic homeostasis and also protects against liver injury, inflammation, and related metabolic diseases, such as nonalcoholic fatty liver disease, diabetes, and obesity. Bile-acid-based drugs targeting nuclear receptors are in clinical trials for treating cholestatic liver diseases and fatty liver disease. | ACTIVATOR |
| RANKL targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting NF-κB activation and down regulating inflammatory cytokines. Peptides designed from osteoprotegerin (OPG) have previously been shown to inhibit receptor activator of NF-κB ligand (RANKL) and prevent bone loss without significantly inhibiting inflammation. The objective of this study was to develop a novel peptide with dual inhibitory activity against bone loss and inflammation using site-directed mutagenesis. Out of the three putative sites (i.e., Tyr70-Asp78, Tyr82-Glu96, and Leu113-Arg122) available on OPG for RANKL binding, Leu113-Arg122 was used as a template for peptide synthesis. Peptide mutants of the template sequence (112YLEIEFCLKHR122) were synthesized and initially screened for their inhibitory effect on RANK-RANKL binding by competitive ELISA. The most active peptide was further evaluated in vitro for RANKL induced osteoclastogenesis in mouse macrophage cells, and in vivo for Freund's complete adjuvant induced arthritis (AIA) in Lewis rats. The efficacy of the candidate peptide was compared with that of the standard drug celecoxib. The peptide CHEMICAL (YLEIEFSLKHR), obtained by direct substitution of cysteine with a serine residue in the template sequence, significantly (p<0.05) inhibited GENE-RANKL binding, and RANKL induced TRAP activity and formation of multinucleated osteoclasts without any cytotoxicity. Administration of CHEMICAL peptide at the dose of 30mg/kg (i.p.) ameliorated both bone loss and inflammation in AIA rats. To elucidate the mechanism for inhibition of inflammation in arthritic rats, serum and tissue cytokines (TNF-α, IL-1β, and IL-6) were analyzed by ELISA and RT-PCR methods. Results confirmed that CHEMICAL peptide inhibited pro-inflammatory cytokines in the sera and hind paw tissues of AIA rats through its suppressive effect on RANKL induced nuclear translocation of NF-κB. The results obtained in this study substantiate the therapeutic benefit of this novel peptide in the prevention of bone loss and inflammation in rheumatoid arthritis with reduced side effects. | INHIBITOR |
| GENE targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting NF-κB activation and down regulating inflammatory cytokines. Peptides designed from osteoprotegerin (OPG) have previously been shown to inhibit receptor activator of NF-κB ligand (RANKL) and prevent bone loss without significantly inhibiting inflammation. The objective of this study was to develop a novel peptide with dual inhibitory activity against bone loss and inflammation using site-directed mutagenesis. Out of the three putative sites (i.e., Tyr70-Asp78, Tyr82-Glu96, and Leu113-Arg122) available on OPG for GENE binding, Leu113-Arg122 was used as a template for peptide synthesis. Peptide mutants of the template sequence (112YLEIEFCLKHR122) were synthesized and initially screened for their inhibitory effect on RANK-RANKL binding by competitive ELISA. The most active peptide was further evaluated in vitro for GENE induced osteoclastogenesis in mouse macrophage cells, and in vivo for Freund's complete adjuvant induced arthritis (AIA) in Lewis rats. The efficacy of the candidate peptide was compared with that of the standard drug celecoxib. The peptide CHEMICAL (YLEIEFSLKHR), obtained by direct substitution of cysteine with a serine residue in the template sequence, significantly (p<0.05) inhibited RANK-GENE binding, and GENE induced TRAP activity and formation of multinucleated osteoclasts without any cytotoxicity. Administration of CHEMICAL peptide at the dose of 30mg/kg (i.p.) ameliorated both bone loss and inflammation in AIA rats. To elucidate the mechanism for inhibition of inflammation in arthritic rats, serum and tissue cytokines (TNF-α, IL-1β, and IL-6) were analyzed by ELISA and RT-PCR methods. Results confirmed that CHEMICAL peptide inhibited pro-inflammatory cytokines in the sera and hind paw tissues of AIA rats through its suppressive effect on GENE induced nuclear translocation of NF-κB. The results obtained in this study substantiate the therapeutic benefit of this novel peptide in the prevention of bone loss and inflammation in rheumatoid arthritis with reduced side effects. | INHIBITOR |
| RANKL targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting NF-κB activation and down regulating inflammatory cytokines. Peptides designed from osteoprotegerin (OPG) have previously been shown to inhibit receptor activator of NF-κB ligand (RANKL) and prevent bone loss without significantly inhibiting inflammation. The objective of this study was to develop a novel peptide with dual inhibitory activity against bone loss and inflammation using site-directed mutagenesis. Out of the three putative sites (i.e., Tyr70-Asp78, Tyr82-Glu96, and Leu113-Arg122) available on OPG for RANKL binding, Leu113-Arg122 was used as a template for peptide synthesis. Peptide mutants of the template sequence (112YLEIEFCLKHR122) were synthesized and initially screened for their inhibitory effect on RANK-RANKL binding by competitive ELISA. The most active peptide was further evaluated in vitro for RANKL induced osteoclastogenesis in mouse macrophage cells, and in vivo for Freund's complete adjuvant induced arthritis (AIA) in Lewis rats. The efficacy of the candidate peptide was compared with that of the standard drug celecoxib. The peptide YR-11 (YLEIEFSLKHR), obtained by direct substitution of CHEMICAL with a serine residue in the template sequence, significantly (p<0.05) inhibited GENE-RANKL binding, and RANKL induced TRAP activity and formation of multinucleated osteoclasts without any cytotoxicity. Administration of YR-11 peptide at the dose of 30mg/kg (i.p.) ameliorated both bone loss and inflammation in AIA rats. To elucidate the mechanism for inhibition of inflammation in arthritic rats, serum and tissue cytokines (TNF-α, IL-1β, and IL-6) were analyzed by ELISA and RT-PCR methods. Results confirmed that YR-11 peptide inhibited pro-inflammatory cytokines in the sera and hind paw tissues of AIA rats through its suppressive effect on RANKL induced nuclear translocation of NF-κB. The results obtained in this study substantiate the therapeutic benefit of this novel peptide in the prevention of bone loss and inflammation in rheumatoid arthritis with reduced side effects. | PART-OF |
| GENE targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting NF-κB activation and down regulating inflammatory cytokines. Peptides designed from osteoprotegerin (OPG) have previously been shown to inhibit receptor activator of NF-κB ligand (RANKL) and prevent bone loss without significantly inhibiting inflammation. The objective of this study was to develop a novel peptide with dual inhibitory activity against bone loss and inflammation using site-directed mutagenesis. Out of the three putative sites (i.e., Tyr70-Asp78, Tyr82-Glu96, and Leu113-Arg122) available on OPG for GENE binding, Leu113-Arg122 was used as a template for peptide synthesis. Peptide mutants of the template sequence (112YLEIEFCLKHR122) were synthesized and initially screened for their inhibitory effect on RANK-RANKL binding by competitive ELISA. The most active peptide was further evaluated in vitro for GENE induced osteoclastogenesis in mouse macrophage cells, and in vivo for Freund's complete adjuvant induced arthritis (AIA) in Lewis rats. The efficacy of the candidate peptide was compared with that of the standard drug celecoxib. The peptide YR-11 (YLEIEFSLKHR), obtained by direct substitution of CHEMICAL with a serine residue in the template sequence, significantly (p<0.05) inhibited RANK-GENE binding, and GENE induced TRAP activity and formation of multinucleated osteoclasts without any cytotoxicity. Administration of YR-11 peptide at the dose of 30mg/kg (i.p.) ameliorated both bone loss and inflammation in AIA rats. To elucidate the mechanism for inhibition of inflammation in arthritic rats, serum and tissue cytokines (TNF-α, IL-1β, and IL-6) were analyzed by ELISA and RT-PCR methods. Results confirmed that YR-11 peptide inhibited pro-inflammatory cytokines in the sera and hind paw tissues of AIA rats through its suppressive effect on GENE induced nuclear translocation of NF-κB. The results obtained in this study substantiate the therapeutic benefit of this novel peptide in the prevention of bone loss and inflammation in rheumatoid arthritis with reduced side effects. | PART-OF |
| RANKL targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting NF-κB activation and down regulating inflammatory cytokines. Peptides designed from osteoprotegerin (OPG) have previously been shown to inhibit receptor activator of NF-κB ligand (RANKL) and prevent bone loss without significantly inhibiting inflammation. The objective of this study was to develop a novel peptide with dual inhibitory activity against bone loss and inflammation using site-directed mutagenesis. Out of the three putative sites (i.e., Tyr70-Asp78, Tyr82-Glu96, and Leu113-Arg122) available on OPG for RANKL binding, Leu113-Arg122 was used as a template for peptide synthesis. Peptide mutants of the template sequence (112YLEIEFCLKHR122) were synthesized and initially screened for their inhibitory effect on RANK-RANKL binding by competitive ELISA. The most active peptide was further evaluated in vitro for RANKL induced osteoclastogenesis in mouse macrophage cells, and in vivo for Freund's complete adjuvant induced arthritis (AIA) in Lewis rats. The efficacy of the candidate peptide was compared with that of the standard drug celecoxib. The peptide YR-11 (YLEIEFSLKHR), obtained by direct substitution of cysteine with a CHEMICAL residue in the template sequence, significantly (p<0.05) inhibited GENE-RANKL binding, and RANKL induced TRAP activity and formation of multinucleated osteoclasts without any cytotoxicity. Administration of YR-11 peptide at the dose of 30mg/kg (i.p.) ameliorated both bone loss and inflammation in AIA rats. To elucidate the mechanism for inhibition of inflammation in arthritic rats, serum and tissue cytokines (TNF-α, IL-1β, and IL-6) were analyzed by ELISA and RT-PCR methods. Results confirmed that YR-11 peptide inhibited pro-inflammatory cytokines in the sera and hind paw tissues of AIA rats through its suppressive effect on RANKL induced nuclear translocation of NF-κB. The results obtained in this study substantiate the therapeutic benefit of this novel peptide in the prevention of bone loss and inflammation in rheumatoid arthritis with reduced side effects. | PART-OF |
| GENE targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting NF-κB activation and down regulating inflammatory cytokines. Peptides designed from osteoprotegerin (OPG) have previously been shown to inhibit receptor activator of NF-κB ligand (RANKL) and prevent bone loss without significantly inhibiting inflammation. The objective of this study was to develop a novel peptide with dual inhibitory activity against bone loss and inflammation using site-directed mutagenesis. Out of the three putative sites (i.e., Tyr70-Asp78, Tyr82-Glu96, and Leu113-Arg122) available on OPG for GENE binding, Leu113-Arg122 was used as a template for peptide synthesis. Peptide mutants of the template sequence (112YLEIEFCLKHR122) were synthesized and initially screened for their inhibitory effect on RANK-RANKL binding by competitive ELISA. The most active peptide was further evaluated in vitro for GENE induced osteoclastogenesis in mouse macrophage cells, and in vivo for Freund's complete adjuvant induced arthritis (AIA) in Lewis rats. The efficacy of the candidate peptide was compared with that of the standard drug celecoxib. The peptide YR-11 (YLEIEFSLKHR), obtained by direct substitution of cysteine with a CHEMICAL residue in the template sequence, significantly (p<0.05) inhibited RANK-GENE binding, and GENE induced TRAP activity and formation of multinucleated osteoclasts without any cytotoxicity. Administration of YR-11 peptide at the dose of 30mg/kg (i.p.) ameliorated both bone loss and inflammation in AIA rats. To elucidate the mechanism for inhibition of inflammation in arthritic rats, serum and tissue cytokines (TNF-α, IL-1β, and IL-6) were analyzed by ELISA and RT-PCR methods. Results confirmed that YR-11 peptide inhibited pro-inflammatory cytokines in the sera and hind paw tissues of AIA rats through its suppressive effect on GENE induced nuclear translocation of NF-κB. The results obtained in this study substantiate the therapeutic benefit of this novel peptide in the prevention of bone loss and inflammation in rheumatoid arthritis with reduced side effects. | PART-OF |
| RANKL targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting GENE activation and down regulating inflammatory cytokines. Peptides designed from osteoprotegerin (OPG) have previously been shown to inhibit receptor activator of GENE ligand (RANKL) and prevent bone loss without significantly inhibiting inflammation. The objective of this study was to develop a novel peptide with dual inhibitory activity against bone loss and inflammation using site-directed mutagenesis. Out of the three putative sites (i.e., Tyr70-Asp78, Tyr82-Glu96, and Leu113-Arg122) available on OPG for RANKL binding, Leu113-Arg122 was used as a template for peptide synthesis. Peptide mutants of the template sequence (112YLEIEFCLKHR122) were synthesized and initially screened for their inhibitory effect on RANK-RANKL binding by competitive ELISA. The most active peptide was further evaluated in vitro for RANKL induced osteoclastogenesis in mouse macrophage cells, and in vivo for Freund's complete adjuvant induced arthritis (AIA) in Lewis rats. The efficacy of the candidate peptide was compared with that of the standard drug celecoxib. The peptide CHEMICAL (YLEIEFSLKHR), obtained by direct substitution of cysteine with a serine residue in the template sequence, significantly (p<0.05) inhibited RANK-RANKL binding, and RANKL induced TRAP activity and formation of multinucleated osteoclasts without any cytotoxicity. Administration of CHEMICAL peptide at the dose of 30mg/kg (i.p.) ameliorated both bone loss and inflammation in AIA rats. To elucidate the mechanism for inhibition of inflammation in arthritic rats, serum and tissue cytokines (TNF-α, IL-1β, and IL-6) were analyzed by ELISA and RT-PCR methods. Results confirmed that CHEMICAL peptide inhibited pro-inflammatory cytokines in the sera and hind paw tissues of AIA rats through its suppressive effect on RANKL induced nuclear translocation of GENE. The results obtained in this study substantiate the therapeutic benefit of this novel peptide in the prevention of bone loss and inflammation in rheumatoid arthritis with reduced side effects. | INDIRECT-DOWNREGULATOR |
| RANKL targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting NF-κB activation and down regulating inflammatory cytokines. Peptides designed from osteoprotegerin (OPG) have previously been shown to inhibit receptor activator of NF-κB ligand (RANKL) and prevent bone loss without significantly inhibiting inflammation. The objective of this study was to develop a novel peptide with dual inhibitory activity against bone loss and inflammation using site-directed mutagenesis. Out of the three putative sites (i.e., Tyr70-Asp78, Tyr82-Glu96, and Leu113-Arg122) available on OPG for RANKL binding, Leu113-Arg122 was used as a template for peptide synthesis. Peptide mutants of the template sequence (112YLEIEFCLKHR122) were synthesized and initially screened for their inhibitory effect on RANK-RANKL binding by competitive ELISA. The most active peptide was further evaluated in vitro for RANKL induced osteoclastogenesis in mouse macrophage cells, and in vivo for Freund's complete adjuvant induced arthritis (AIA) in Lewis rats. The efficacy of the candidate peptide was compared with that of the standard drug celecoxib. The peptide CHEMICAL (YLEIEFSLKHR), obtained by direct substitution of cysteine with a serine residue in the template sequence, significantly (p<0.05) inhibited RANK-RANKL binding, and RANKL induced GENE activity and formation of multinucleated osteoclasts without any cytotoxicity. Administration of CHEMICAL peptide at the dose of 30mg/kg (i.p.) ameliorated both bone loss and inflammation in AIA rats. To elucidate the mechanism for inhibition of inflammation in arthritic rats, serum and tissue cytokines (TNF-α, IL-1β, and IL-6) were analyzed by ELISA and RT-PCR methods. Results confirmed that CHEMICAL peptide inhibited pro-inflammatory cytokines in the sera and hind paw tissues of AIA rats through its suppressive effect on RANKL induced nuclear translocation of NF-κB. The results obtained in this study substantiate the therapeutic benefit of this novel peptide in the prevention of bone loss and inflammation in rheumatoid arthritis with reduced side effects. | INHIBITOR |
| RANKL targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting NF-κB activation and down regulating inflammatory cytokines. Peptides designed from osteoprotegerin (OPG) have previously been shown to inhibit receptor activator of NF-κB ligand (RANKL) and prevent bone loss without significantly inhibiting inflammation. The objective of this study was to develop a novel peptide with dual inhibitory activity against bone loss and inflammation using site-directed mutagenesis. Out of the three putative sites (i.e., Tyr70-Asp78, Tyr82-Glu96, and Leu113-Arg122) available on OPG for RANKL binding, Leu113-Arg122 was used as a template for peptide synthesis. Peptide mutants of the template sequence (112YLEIEFCLKHR122) were synthesized and initially screened for their inhibitory effect on RANK-RANKL binding by competitive ELISA. The most active peptide was further evaluated in vitro for RANKL induced osteoclastogenesis in mouse macrophage cells, and in vivo for Freund's complete adjuvant induced arthritis (AIA) in Lewis rats. The efficacy of the candidate peptide was compared with that of the standard drug celecoxib. The peptide YR-11 (YLEIEFSLKHR), obtained by direct substitution of CHEMICAL with a serine residue in the template sequence, significantly (p<0.05) inhibited RANK-RANKL binding, and RANKL induced GENE activity and formation of multinucleated osteoclasts without any cytotoxicity. Administration of YR-11 peptide at the dose of 30mg/kg (i.p.) ameliorated both bone loss and inflammation in AIA rats. To elucidate the mechanism for inhibition of inflammation in arthritic rats, serum and tissue cytokines (TNF-α, IL-1β, and IL-6) were analyzed by ELISA and RT-PCR methods. Results confirmed that YR-11 peptide inhibited pro-inflammatory cytokines in the sera and hind paw tissues of AIA rats through its suppressive effect on RANKL induced nuclear translocation of NF-κB. The results obtained in this study substantiate the therapeutic benefit of this novel peptide in the prevention of bone loss and inflammation in rheumatoid arthritis with reduced side effects. | PART-OF |
| RANKL targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting NF-κB activation and down regulating inflammatory cytokines. Peptides designed from osteoprotegerin (OPG) have previously been shown to inhibit receptor activator of NF-κB ligand (RANKL) and prevent bone loss without significantly inhibiting inflammation. The objective of this study was to develop a novel peptide with dual inhibitory activity against bone loss and inflammation using site-directed mutagenesis. Out of the three putative sites (i.e., Tyr70-Asp78, Tyr82-Glu96, and Leu113-Arg122) available on OPG for RANKL binding, Leu113-Arg122 was used as a template for peptide synthesis. Peptide mutants of the template sequence (112YLEIEFCLKHR122) were synthesized and initially screened for their inhibitory effect on RANK-RANKL binding by competitive ELISA. The most active peptide was further evaluated in vitro for RANKL induced osteoclastogenesis in mouse macrophage cells, and in vivo for Freund's complete adjuvant induced arthritis (AIA) in Lewis rats. The efficacy of the candidate peptide was compared with that of the standard drug celecoxib. The peptide YR-11 (YLEIEFSLKHR), obtained by direct substitution of cysteine with a CHEMICAL residue in the template sequence, significantly (p<0.05) inhibited RANK-RANKL binding, and RANKL induced GENE activity and formation of multinucleated osteoclasts without any cytotoxicity. Administration of YR-11 peptide at the dose of 30mg/kg (i.p.) ameliorated both bone loss and inflammation in AIA rats. To elucidate the mechanism for inhibition of inflammation in arthritic rats, serum and tissue cytokines (TNF-α, IL-1β, and IL-6) were analyzed by ELISA and RT-PCR methods. Results confirmed that YR-11 peptide inhibited pro-inflammatory cytokines in the sera and hind paw tissues of AIA rats through its suppressive effect on RANKL induced nuclear translocation of NF-κB. The results obtained in this study substantiate the therapeutic benefit of this novel peptide in the prevention of bone loss and inflammation in rheumatoid arthritis with reduced side effects. | PART-OF |
| RANKL targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting NF-κB activation and down regulating inflammatory GENE. Peptides designed from osteoprotegerin (OPG) have previously been shown to inhibit receptor activator of NF-κB ligand (RANKL) and prevent bone loss without significantly inhibiting inflammation. The objective of this study was to develop a novel peptide with dual inhibitory activity against bone loss and inflammation using site-directed mutagenesis. Out of the three putative sites (i.e., Tyr70-Asp78, Tyr82-Glu96, and Leu113-Arg122) available on OPG for RANKL binding, Leu113-Arg122 was used as a template for peptide synthesis. Peptide mutants of the template sequence (112YLEIEFCLKHR122) were synthesized and initially screened for their inhibitory effect on RANK-RANKL binding by competitive ELISA. The most active peptide was further evaluated in vitro for RANKL induced osteoclastogenesis in mouse macrophage cells, and in vivo for Freund's complete adjuvant induced arthritis (AIA) in Lewis rats. The efficacy of the candidate peptide was compared with that of the standard drug celecoxib. The peptide CHEMICAL (YLEIEFSLKHR), obtained by direct substitution of cysteine with a serine residue in the template sequence, significantly (p<0.05) inhibited RANK-RANKL binding, and RANKL induced TRAP activity and formation of multinucleated osteoclasts without any cytotoxicity. Administration of CHEMICAL peptide at the dose of 30mg/kg (i.p.) ameliorated both bone loss and inflammation in AIA rats. To elucidate the mechanism for inhibition of inflammation in arthritic rats, serum and tissue GENE (TNF-α, IL-1β, and IL-6) were analyzed by ELISA and RT-PCR methods. Results confirmed that CHEMICAL peptide inhibited pro-inflammatory GENE in the sera and hind paw tissues of AIA rats through its suppressive effect on RANKL induced nuclear translocation of NF-κB. The results obtained in this study substantiate the therapeutic benefit of this novel peptide in the prevention of bone loss and inflammation in rheumatoid arthritis with reduced side effects. | INDIRECT-DOWNREGULATOR |
| Activation of Rac1 GTPase by nanoparticulate structures in human macrophages. Inflammatory activation of alveolar macrophages by ambient particles can be facilitated via Toll-like receptors (TLR). The action of TLR agonists and antagonists has been reported to depend on the formation of nanoparticulate structures. Aim of the present study was to identify the signaling pathways induced by nanoparticulate structures in human macrophages, which might be critical for inflammatory cell activation. METHODS: Studies were performed in primary human alveolar macrophages or in differentiated THP-1 macrophages. CHEMICAL nanoparticles were prepared by Stöber synthesis and characterized by dynamic light scattering and scanning electron microscopy. Mycobacterial DNA was isolated from Mycobacterium bovis BCG, and nanoparticle formation was assessed by atomic force microscopy and dynamic light scattering. GENE polymerization was measured by phalloidin-TRITC staining, and cell activation was determined by reverse transcription quantitative PCR analysis, L929 cytotoxicity assay (cytokine induction), and pull-down assays (Rho GTPases). RESULTS: In contrast to immune stimulatory sequence ISS 1018, BCG DNA spontaneously formed nanoparticulate structures and induced GENE polymerization as did synthetic CHEMICAL nanoparticles. Co-incubation with CHEMICAL nanoparticles amplified the responsiveness of macrophages toward the TLR9 ligand ISS 1018. The activation of Rac1 was induced by CHEMICAL nanoparticles as well as BCG DNA and is suggested as the critical signaling event inducing both cytoskeleton changes as well as inflammatory cell activation. CONCLUSION: Nanoparticles can induce signaling pathways, which amplify an inflammatory response in macrophages. | REGULATOR |
| Activation of GENE GTPase by nanoparticulate structures in human macrophages. Inflammatory activation of alveolar macrophages by ambient particles can be facilitated via Toll-like receptors (TLR). The action of TLR agonists and antagonists has been reported to depend on the formation of nanoparticulate structures. Aim of the present study was to identify the signaling pathways induced by nanoparticulate structures in human macrophages, which might be critical for inflammatory cell activation. METHODS: Studies were performed in primary human alveolar macrophages or in differentiated THP-1 macrophages. CHEMICAL nanoparticles were prepared by Stöber synthesis and characterized by dynamic light scattering and scanning electron microscopy. Mycobacterial DNA was isolated from Mycobacterium bovis BCG, and nanoparticle formation was assessed by atomic force microscopy and dynamic light scattering. Actin polymerization was measured by phalloidin-TRITC staining, and cell activation was determined by reverse transcription quantitative PCR analysis, L929 cytotoxicity assay (cytokine induction), and pull-down assays (Rho GTPases). RESULTS: In contrast to immune stimulatory sequence ISS 1018, BCG DNA spontaneously formed nanoparticulate structures and induced actin polymerization as did synthetic CHEMICAL nanoparticles. Co-incubation with CHEMICAL nanoparticles amplified the responsiveness of macrophages toward the TLR9 ligand ISS 1018. The activation of GENE was induced by CHEMICAL nanoparticles as well as BCG DNA and is suggested as the critical signaling event inducing both cytoskeleton changes as well as inflammatory cell activation. CONCLUSION: Nanoparticles can induce signaling pathways, which amplify an inflammatory response in macrophages. | ACTIVATOR |
| Enhancing macrocyclic diterpenes as multidrug-resistance reversers: structure-activity studies on jolkinol D derivatives. The phytochemical study of Euphorbia piscatoria yielded jolkinol D (1) in a large amount, whose derivatization gave rise to 12 ester derivatives (2-13) and hydrolysis to compound 14. The in vitro modulation of GENE of compounds 1-14 was evaluated through a combination of transport and chemosensitivity assays, using the L5178 mouse T lymphoma cell line transfected with the human MDR1 gene. Apart from jolkinol D, all derivatives (2-14) showed potential as MDR reversal agents. In this small library of novel bioactive macrocyclic CHEMICAL derivatives, designed to evaluate structure-activity relationships essential in overcoming multidrug resistance (MDR), some correlations between MDR reversal and molecular weight, accessible solvent areas, and octanol/water partition coefficient were identified that can contribute to the development of new selective GENE reversal agents. | INHIBITOR |
| Osteoblasts survive the arsenic trioxide treatment by activation of ATM-mediated pathway. Arsenic trioxide (ATO) is widely used in tumor treatment, but excessive arsenic exposure can have adverse effects. We recently found that, in primary osteoblasts, CHEMICAL produces oxidative stress and causes DNA tailing, but does not induce apoptosis. We further examined the signaling pathway by which osteoblasts survive CHEMICAL treatment, and found that they were arrested at G2/M phase of the cell cycle at 30h and overrode the G2/M boundary at 48h. After treatment for 30h, there was increased Cdc2 phosphorylation and expression of Wee1, a Cdc2 kinase, and expression of the cell cycle inhibitor, p21(waf1/cip1), which interacts with Cdc2. Furthermore, levels of the phosphatase Cdc25C, which activates Cdc2, were decreased, while the ratio of its phosphorylated/inactivated form to the total amount was increased. Moreover, phosphorylation/activation of the checkpoint kinases Chk1, Chk2 and p53 levels were increased, as were levels of activated GENE and γ-H2AX. The cell viability was decreased as an GENE inhibitor was added. Additionally, these effects of CHEMICAL on γ-H2AX, Chk1, Chk2, p53, and p21(waf1/cip1) were reduced by an GENE inhibitor. These findings suggest that G2/M phase arrest of osteoblasts is mediated by Chk1/Chk2 activation via an ATM-dependent pathway by which osteoblasts survive. | INHIBITOR |
| Osteoblasts survive the CHEMICAL treatment by activation of GENE-mediated pathway. CHEMICAL (ATO) is widely used in tumor treatment, but excessive arsenic exposure can have adverse effects. We recently found that, in primary osteoblasts, ATO produces oxidative stress and causes DNA tailing, but does not induce apoptosis. We further examined the signaling pathway by which osteoblasts survive ATO treatment, and found that they were arrested at G2/M phase of the cell cycle at 30h and overrode the G2/M boundary at 48h. After treatment for 30h, there was increased Cdc2 phosphorylation and expression of Wee1, a Cdc2 kinase, and expression of the cell cycle inhibitor, p21(waf1/cip1), which interacts with Cdc2. Furthermore, levels of the phosphatase Cdc25C, which activates Cdc2, were decreased, while the ratio of its phosphorylated/inactivated form to the total amount was increased. Moreover, phosphorylation/activation of the checkpoint kinases Chk1, Chk2 and p53 levels were increased, as were levels of activated GENE and γ-H2AX. The cell viability was decreased as an GENE inhibitor was added. Additionally, these effects of ATO on γ-H2AX, Chk1, Chk2, p53, and p21(waf1/cip1) were reduced by an GENE inhibitor. These findings suggest that G2/M phase arrest of osteoblasts is mediated by Chk1/Chk2 activation via an ATM-dependent pathway by which osteoblasts survive. | ACTIVATOR |
| Osteoblasts survive the arsenic trioxide treatment by activation of ATM-mediated pathway. Arsenic trioxide (ATO) is widely used in tumor treatment, but excessive arsenic exposure can have adverse effects. We recently found that, in primary osteoblasts, CHEMICAL produces oxidative stress and causes DNA tailing, but does not induce apoptosis. We further examined the signaling pathway by which osteoblasts survive CHEMICAL treatment, and found that they were arrested at G2/M phase of the cell cycle at 30h and overrode the G2/M boundary at 48h. After treatment for 30h, there was increased Cdc2 phosphorylation and expression of Wee1, a Cdc2 kinase, and expression of the cell cycle inhibitor, p21(waf1/cip1), which interacts with Cdc2. Furthermore, levels of the phosphatase Cdc25C, which activates Cdc2, were decreased, while the ratio of its phosphorylated/inactivated form to the total amount was increased. Moreover, phosphorylation/activation of the checkpoint kinases GENE, Chk2 and p53 levels were increased, as were levels of activated ATM and γ-H2AX. The cell viability was decreased as an ATM inhibitor was added. Additionally, these effects of CHEMICAL on γ-H2AX, GENE, Chk2, p53, and p21(waf1/cip1) were reduced by an ATM inhibitor. These findings suggest that G2/M phase arrest of osteoblasts is mediated by Chk1/Chk2 activation via an ATM-dependent pathway by which osteoblasts survive. | REGULATOR |
| Osteoblasts survive the arsenic trioxide treatment by activation of ATM-mediated pathway. Arsenic trioxide (ATO) is widely used in tumor treatment, but excessive arsenic exposure can have adverse effects. We recently found that, in primary osteoblasts, CHEMICAL produces oxidative stress and causes DNA tailing, but does not induce apoptosis. We further examined the signaling pathway by which osteoblasts survive CHEMICAL treatment, and found that they were arrested at G2/M phase of the cell cycle at 30h and overrode the G2/M boundary at 48h. After treatment for 30h, there was increased Cdc2 phosphorylation and expression of Wee1, a Cdc2 kinase, and expression of the cell cycle inhibitor, p21(waf1/cip1), which interacts with Cdc2. Furthermore, levels of the phosphatase Cdc25C, which activates Cdc2, were decreased, while the ratio of its phosphorylated/inactivated form to the total amount was increased. Moreover, phosphorylation/activation of the checkpoint kinases Chk1, GENE and p53 levels were increased, as were levels of activated ATM and γ-H2AX. The cell viability was decreased as an ATM inhibitor was added. Additionally, these effects of CHEMICAL on γ-H2AX, Chk1, GENE, p53, and p21(waf1/cip1) were reduced by an ATM inhibitor. These findings suggest that G2/M phase arrest of osteoblasts is mediated by Chk1/Chk2 activation via an ATM-dependent pathway by which osteoblasts survive. | REGULATOR |
| Osteoblasts survive the arsenic trioxide treatment by activation of ATM-mediated pathway. Arsenic trioxide (ATO) is widely used in tumor treatment, but excessive arsenic exposure can have adverse effects. We recently found that, in primary osteoblasts, CHEMICAL produces oxidative stress and causes DNA tailing, but does not induce apoptosis. We further examined the signaling pathway by which osteoblasts survive CHEMICAL treatment, and found that they were arrested at G2/M phase of the cell cycle at 30h and overrode the G2/M boundary at 48h. After treatment for 30h, there was increased Cdc2 phosphorylation and expression of Wee1, a Cdc2 kinase, and expression of the cell cycle inhibitor, p21(waf1/cip1), which interacts with Cdc2. Furthermore, levels of the phosphatase Cdc25C, which activates Cdc2, were decreased, while the ratio of its phosphorylated/inactivated form to the total amount was increased. Moreover, phosphorylation/activation of the checkpoint kinases Chk1, Chk2 and GENE levels were increased, as were levels of activated ATM and γ-H2AX. The cell viability was decreased as an ATM inhibitor was added. Additionally, these effects of CHEMICAL on γ-H2AX, Chk1, Chk2, GENE, and p21(waf1/cip1) were reduced by an ATM inhibitor. These findings suggest that G2/M phase arrest of osteoblasts is mediated by Chk1/Chk2 activation via an ATM-dependent pathway by which osteoblasts survive. | REGULATOR |
| Osteoblasts survive the arsenic trioxide treatment by activation of ATM-mediated pathway. Arsenic trioxide (ATO) is widely used in tumor treatment, but excessive arsenic exposure can have adverse effects. We recently found that, in primary osteoblasts, CHEMICAL produces oxidative stress and causes DNA tailing, but does not induce apoptosis. We further examined the signaling pathway by which osteoblasts survive CHEMICAL treatment, and found that they were arrested at G2/M phase of the cell cycle at 30h and overrode the G2/M boundary at 48h. After treatment for 30h, there was increased Cdc2 phosphorylation and expression of Wee1, a Cdc2 kinase, and expression of the cell cycle inhibitor, p21(waf1/cip1), which interacts with Cdc2. Furthermore, levels of the phosphatase Cdc25C, which activates Cdc2, were decreased, while the ratio of its phosphorylated/inactivated form to the total amount was increased. Moreover, phosphorylation/activation of the checkpoint kinases Chk1, Chk2 and p53 levels were increased, as were levels of activated ATM and γ-H2AX. The cell viability was decreased as an ATM inhibitor was added. Additionally, these effects of CHEMICAL on γ-H2AX, Chk1, Chk2, p53, and GENE(waf1/cip1) were reduced by an ATM inhibitor. These findings suggest that G2/M phase arrest of osteoblasts is mediated by Chk1/Chk2 activation via an ATM-dependent pathway by which osteoblasts survive. | REGULATOR |
| Osteoblasts survive the arsenic trioxide treatment by activation of ATM-mediated pathway. Arsenic trioxide (ATO) is widely used in tumor treatment, but excessive arsenic exposure can have adverse effects. We recently found that, in primary osteoblasts, CHEMICAL produces oxidative stress and causes DNA tailing, but does not induce apoptosis. We further examined the signaling pathway by which osteoblasts survive CHEMICAL treatment, and found that they were arrested at G2/M phase of the cell cycle at 30h and overrode the G2/M boundary at 48h. After treatment for 30h, there was increased Cdc2 phosphorylation and expression of Wee1, a Cdc2 kinase, and expression of the cell cycle inhibitor, p21(waf1/cip1), which interacts with Cdc2. Furthermore, levels of the phosphatase Cdc25C, which activates Cdc2, were decreased, while the ratio of its phosphorylated/inactivated form to the total amount was increased. Moreover, phosphorylation/activation of the checkpoint kinases Chk1, Chk2 and p53 levels were increased, as were levels of activated ATM and γ-H2AX. The cell viability was decreased as an ATM inhibitor was added. Additionally, these effects of CHEMICAL on γ-H2AX, Chk1, Chk2, p53, and p21(GENE/cip1) were reduced by an ATM inhibitor. These findings suggest that G2/M phase arrest of osteoblasts is mediated by Chk1/Chk2 activation via an ATM-dependent pathway by which osteoblasts survive. | REGULATOR |
| Osteoblasts survive the arsenic trioxide treatment by activation of ATM-mediated pathway. Arsenic trioxide (ATO) is widely used in tumor treatment, but excessive arsenic exposure can have adverse effects. We recently found that, in primary osteoblasts, CHEMICAL produces oxidative stress and causes DNA tailing, but does not induce apoptosis. We further examined the signaling pathway by which osteoblasts survive CHEMICAL treatment, and found that they were arrested at G2/M phase of the cell cycle at 30h and overrode the G2/M boundary at 48h. After treatment for 30h, there was increased Cdc2 phosphorylation and expression of Wee1, a Cdc2 kinase, and expression of the cell cycle inhibitor, p21(waf1/cip1), which interacts with Cdc2. Furthermore, levels of the phosphatase Cdc25C, which activates Cdc2, were decreased, while the ratio of its phosphorylated/inactivated form to the total amount was increased. Moreover, phosphorylation/activation of the checkpoint kinases Chk1, Chk2 and p53 levels were increased, as were levels of activated ATM and γ-H2AX. The cell viability was decreased as an ATM inhibitor was added. Additionally, these effects of CHEMICAL on γ-H2AX, Chk1, Chk2, p53, and p21(waf1/GENE) were reduced by an ATM inhibitor. These findings suggest that G2/M phase arrest of osteoblasts is mediated by Chk1/Chk2 activation via an ATM-dependent pathway by which osteoblasts survive. | REGULATOR |
| Osteoblasts survive the arsenic trioxide treatment by activation of ATM-mediated pathway. Arsenic trioxide (ATO) is widely used in tumor treatment, but excessive arsenic exposure can have adverse effects. We recently found that, in primary osteoblasts, CHEMICAL produces oxidative stress and causes DNA tailing, but does not induce apoptosis. We further examined the signaling pathway by which osteoblasts survive CHEMICAL treatment, and found that they were arrested at G2/M phase of the cell cycle at 30h and overrode the G2/M boundary at 48h. After treatment for 30h, there was increased Cdc2 phosphorylation and expression of Wee1, a Cdc2 kinase, and expression of the cell cycle inhibitor, p21(waf1/cip1), which interacts with Cdc2. Furthermore, levels of the phosphatase Cdc25C, which activates Cdc2, were decreased, while the ratio of its phosphorylated/inactivated form to the total amount was increased. Moreover, phosphorylation/activation of the checkpoint kinases Chk1, Chk2 and p53 levels were increased, as were levels of activated ATM and γ-H2AX. The cell viability was decreased as an ATM inhibitor was added. Additionally, these effects of CHEMICAL on γ-GENE, Chk1, Chk2, p53, and p21(waf1/cip1) were reduced by an ATM inhibitor. These findings suggest that G2/M phase arrest of osteoblasts is mediated by Chk1/Chk2 activation via an ATM-dependent pathway by which osteoblasts survive. | REGULATOR |
| Dietary relevant mixtures of phytoestrogens inhibit adipocyte differentiation in vitro. Phytoestrogens (PEs) are naturally occurring plant components, with the ability to induce biological responses in vertebrates by mimicking or modulating the action of endogenous hormones. Single isoflavones have been shown to affect adipocyte differentiation, but knowledge on the effect of dietary relevant mixtures of PEs, including for instance lignans, is lacking. In the current study dietary relevant mixtures of isoflavones and their metabolites, lignans and their metabolites, coumestrol, and a mixture containing all of them, were examined for effects on adipogenesis in 3T3-L1 adipocytes, as well as tested for their GENE activating abilities. The results showed that mixtures of CHEMICAL parent compounds and metabolites, respectively, a mixture of lignan metabolites, as well as coumestrol concentration-dependently inhibited adipocyte differentiation. Furthermore, a mixture of CHEMICAL parent compounds, and a mixture of CHEMICAL metabolites were found to have GENE activating abilities. These results suggest that PEs can affect pathways known to play a role in obesity development, and indicate that the inhibitory effect on adipocyte differentiation does not appear to be strictly associated with GENE activation/inhibition. The current study support the hypothesis that compounds with endocrine activity can affect pathways playing a role in the development obesity and obesity related diseases. | ACTIVATOR |
| Evaluation of suppressive and pro-resolving effects of EPA and DHA in human primary monocytes and T-helper cells. Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both CHEMICAL, but DHA to a lesser extent compared with EPA, selectively and dose-dependently reduced the percentage of cytokine-expressing Th cells in a peroxisome proliferator-activated receptor (PPAR)γ-dependent fashion, whereas the expression of the cell surface marker GENE was unaltered on activated T cells. In monocytes, both EPA and DHA increased interleukin (IL)-10 without affecting tumor necrosis factor (TNF)-α and IL-6. Cellular incorporation of EPA and DHA occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, EPA and DHA gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that EPA and DHA do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. | GENE-CHEMICAL |
| Evaluation of suppressive and pro-resolving effects of EPA and CHEMICAL in human primary monocytes and T-helper cells. Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both fatty acids, but CHEMICAL to a lesser extent compared with EPA, selectively and dose-dependently reduced the percentage of cytokine-expressing Th cells in a peroxisome proliferator-activated receptor (PPAR)γ-dependent fashion, whereas the expression of the cell surface marker GENE was unaltered on activated T cells. In monocytes, both EPA and CHEMICAL increased interleukin (IL)-10 without affecting tumor necrosis factor (TNF)-α and IL-6. Cellular incorporation of EPA and CHEMICAL occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, EPA and CHEMICAL gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that EPA and CHEMICAL do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. | GENE-CHEMICAL |
| Evaluation of suppressive and pro-resolving effects of CHEMICAL and DHA in human primary monocytes and T-helper cells. Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both fatty acids, but DHA to a lesser extent compared with CHEMICAL, selectively and dose-dependently reduced the percentage of cytokine-expressing Th cells in a peroxisome proliferator-activated receptor (PPAR)γ-dependent fashion, whereas the expression of the cell surface marker GENE was unaltered on activated T cells. In monocytes, both CHEMICAL and DHA increased interleukin (IL)-10 without affecting tumor necrosis factor (TNF)-α and IL-6. Cellular incorporation of CHEMICAL and DHA occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, CHEMICAL and DHA gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that CHEMICAL and DHA do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. | GENE-CHEMICAL |
| Evaluation of suppressive and pro-resolving effects of CHEMICAL and DHA in human primary monocytes and T-helper cells. Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both fatty acids, but DHA to a lesser extent compared with CHEMICAL, selectively and dose-dependently reduced the percentage of cytokine-expressing Th cells in a peroxisome proliferator-activated receptor (PPAR)γ-dependent fashion, whereas the expression of the cell surface marker CD69 was unaltered on activated T cells. In monocytes, both CHEMICAL and DHA increased interleukin (IL)-10 without affecting GENE and IL-6. Cellular incorporation of CHEMICAL and DHA occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, CHEMICAL and DHA gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that CHEMICAL and DHA do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. | NO-RELATIONSHIP |
| Evaluation of suppressive and pro-resolving effects of CHEMICAL and DHA in human primary monocytes and T-helper cells. Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both fatty acids, but DHA to a lesser extent compared with CHEMICAL, selectively and dose-dependently reduced the percentage of cytokine-expressing Th cells in a peroxisome proliferator-activated receptor (PPAR)γ-dependent fashion, whereas the expression of the cell surface marker CD69 was unaltered on activated T cells. In monocytes, both CHEMICAL and DHA increased interleukin (IL)-10 without affecting tumor necrosis factor (TNF)-α and GENE. Cellular incorporation of CHEMICAL and DHA occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, CHEMICAL and DHA gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that CHEMICAL and DHA do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. | NO-RELATIONSHIP |
| Evaluation of suppressive and pro-resolving effects of EPA and CHEMICAL in human primary monocytes and T-helper cells. Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both fatty acids, but CHEMICAL to a lesser extent compared with EPA, selectively and dose-dependently reduced the percentage of cytokine-expressing Th cells in a peroxisome proliferator-activated receptor (PPAR)γ-dependent fashion, whereas the expression of the cell surface marker CD69 was unaltered on activated T cells. In monocytes, both EPA and CHEMICAL increased interleukin (IL)-10 without affecting GENE and IL-6. Cellular incorporation of EPA and CHEMICAL occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, EPA and CHEMICAL gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that EPA and CHEMICAL do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. | NO-RELATIONSHIP |
| Evaluation of suppressive and pro-resolving effects of EPA and CHEMICAL in human primary monocytes and T-helper cells. Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both fatty acids, but CHEMICAL to a lesser extent compared with EPA, selectively and dose-dependently reduced the percentage of cytokine-expressing Th cells in a peroxisome proliferator-activated receptor (PPAR)γ-dependent fashion, whereas the expression of the cell surface marker CD69 was unaltered on activated T cells. In monocytes, both EPA and CHEMICAL increased interleukin (IL)-10 without affecting tumor necrosis factor (TNF)-α and GENE. Cellular incorporation of EPA and CHEMICAL occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, EPA and CHEMICAL gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that EPA and CHEMICAL do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. | NO-RELATIONSHIP |
| Evaluation of suppressive and pro-resolving effects of EPA and DHA in human primary monocytes and T-helper cells. Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both CHEMICAL, but DHA to a lesser extent compared with EPA, selectively and dose-dependently reduced the percentage of cytokine-expressing Th cells in a GENE-dependent fashion, whereas the expression of the cell surface marker CD69 was unaltered on activated T cells. In monocytes, both EPA and DHA increased interleukin (IL)-10 without affecting tumor necrosis factor (TNF)-α and IL-6. Cellular incorporation of EPA and DHA occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, EPA and DHA gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that EPA and DHA do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. | REGULATOR |
| Evaluation of suppressive and pro-resolving effects of EPA and CHEMICAL in human primary monocytes and T-helper cells. Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both fatty acids, but CHEMICAL to a lesser extent compared with EPA, selectively and dose-dependently reduced the percentage of cytokine-expressing Th cells in a GENE-dependent fashion, whereas the expression of the cell surface marker CD69 was unaltered on activated T cells. In monocytes, both EPA and CHEMICAL increased interleukin (IL)-10 without affecting tumor necrosis factor (TNF)-α and IL-6. Cellular incorporation of EPA and CHEMICAL occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, EPA and CHEMICAL gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that EPA and CHEMICAL do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. | REGULATOR |
| Evaluation of suppressive and pro-resolving effects of CHEMICAL and DHA in human primary monocytes and T-helper cells. Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both fatty acids, but DHA to a lesser extent compared with CHEMICAL, selectively and dose-dependently reduced the percentage of cytokine-expressing Th cells in a GENE-dependent fashion, whereas the expression of the cell surface marker CD69 was unaltered on activated T cells. In monocytes, both CHEMICAL and DHA increased interleukin (IL)-10 without affecting tumor necrosis factor (TNF)-α and IL-6. Cellular incorporation of CHEMICAL and DHA occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, CHEMICAL and DHA gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that CHEMICAL and DHA do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. | REGULATOR |
| Evaluation of suppressive and pro-resolving effects of CHEMICAL and DHA in human primary monocytes and T-helper cells. Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both fatty acids, but DHA to a lesser extent compared with CHEMICAL, selectively and dose-dependently reduced the percentage of cytokine-expressing Th cells in a peroxisome proliferator-activated receptor (PPAR)γ-dependent fashion, whereas the expression of the cell surface marker CD69 was unaltered on activated T cells. In monocytes, both CHEMICAL and DHA increased GENE without affecting tumor necrosis factor (TNF)-α and IL-6. Cellular incorporation of CHEMICAL and DHA occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, CHEMICAL and DHA gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that CHEMICAL and DHA do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. | INDIRECT-UPREGULATOR |
| Evaluation of suppressive and pro-resolving effects of EPA and CHEMICAL in human primary monocytes and T-helper cells. Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both fatty acids, but CHEMICAL to a lesser extent compared with EPA, selectively and dose-dependently reduced the percentage of cytokine-expressing Th cells in a peroxisome proliferator-activated receptor (PPAR)γ-dependent fashion, whereas the expression of the cell surface marker CD69 was unaltered on activated T cells. In monocytes, both EPA and CHEMICAL increased GENE without affecting tumor necrosis factor (TNF)-α and IL-6. Cellular incorporation of EPA and CHEMICAL occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, EPA and CHEMICAL gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that EPA and CHEMICAL do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. | INDIRECT-UPREGULATOR |
| Evaluation of suppressive and pro-resolving effects of EPA and DHA in human primary monocytes and T-helper cells. Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both CHEMICAL, but DHA to a lesser extent compared with EPA, selectively and dose-dependently reduced the percentage of GENE-expressing Th cells in a peroxisome proliferator-activated receptor (PPAR)γ-dependent fashion, whereas the expression of the cell surface marker CD69 was unaltered on activated T cells. In monocytes, both EPA and DHA increased interleukin (IL)-10 without affecting tumor necrosis factor (TNF)-α and IL-6. Cellular incorporation of EPA and DHA occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, EPA and DHA gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that EPA and DHA do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. | INDIRECT-DOWNREGULATOR |
| Evaluation of suppressive and pro-resolving effects of EPA and CHEMICAL in human primary monocytes and T-helper cells. Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both fatty acids, but CHEMICAL to a lesser extent compared with EPA, selectively and dose-dependently reduced the percentage of GENE-expressing Th cells in a peroxisome proliferator-activated receptor (PPAR)γ-dependent fashion, whereas the expression of the cell surface marker CD69 was unaltered on activated T cells. In monocytes, both EPA and CHEMICAL increased interleukin (IL)-10 without affecting tumor necrosis factor (TNF)-α and IL-6. Cellular incorporation of EPA and CHEMICAL occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, EPA and CHEMICAL gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that EPA and CHEMICAL do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. | INDIRECT-DOWNREGULATOR |
| Evaluation of suppressive and pro-resolving effects of CHEMICAL and DHA in human primary monocytes and T-helper cells. Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both fatty acids, but DHA to a lesser extent compared with CHEMICAL, selectively and dose-dependently reduced the percentage of GENE-expressing Th cells in a peroxisome proliferator-activated receptor (PPAR)γ-dependent fashion, whereas the expression of the cell surface marker CD69 was unaltered on activated T cells. In monocytes, both CHEMICAL and DHA increased interleukin (IL)-10 without affecting tumor necrosis factor (TNF)-α and IL-6. Cellular incorporation of CHEMICAL and DHA occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, CHEMICAL and DHA gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that CHEMICAL and DHA do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. | INDIRECT-DOWNREGULATOR |
| In vitro permeability analysis, pharmacokinetic and brain distribution study in mice of CHEMICAL, isoimperatorin and cnidilin in Radix Angelicae Dahuricae. Coumarins are important constituents of Radix Angelicae Dahuricae, a well-known traditional Chinese medicine possess several known bioactivities with potentials in the treatment of central nervous system diseases. By using an HPLC-MS/MS method, we analyzed the in vivo plasma and brain pharmacokinetics of three ingredients of coumarins, including CHEMICAL, isoimperatorin and cnidilin in mice after oral administration of Dahuricae extract at doses of 800mg/kg. The biosamples were prepared using acetonitrile precipitation and the separation was achieved on an XDB-C18 column by gradient elution. The BBB permeability and P-gp-mediated efflux were further examined in Madin Canine kidney cells transfected with full length cDNA for human multidrug resistance gene1 (MDCKII-MDR1). Our results demonstrate that the method has excellent and satisfactory selectivity, sensitivity, linearity, precision, and accuracy for simultaneous determination of CHEMICAL, isoimperatorin and cnidilin. The pharmacokinetics parameters were determined by using noncompartmental analyses, including the AUC(0-t) in plasma (1695.22, 1326.45 and 636.98mg*h/L), the AUC(0-t) in brain (1812.35, 2125.17 and 1145.83ng*h/g) as well as the T1/2 in plasma (0.66, 0.82, 0.97h) and brain (0.96, 1.1, 0.99h) for CHEMICAL, isoimperatorin and cnidilin, respectively, suggesting that the three coumarins could easily pass through the BBB in vivo. In the in vitro model we observed high permeability of CHEMICAL and isoimperatorin with the GENE-mediated efflux ratios of 0.53 and 0.06, as well as medium permeability of cnidilin with 0.82. All data suggest that these three coumarins have high BBB permeability and have pharmacokinetic potentials for the treatment of central nervous system diseases. | SUBSTRATE |
| In vitro permeability analysis, pharmacokinetic and brain distribution study in mice of imperatorin, CHEMICAL and cnidilin in Radix Angelicae Dahuricae. Coumarins are important constituents of Radix Angelicae Dahuricae, a well-known traditional Chinese medicine possess several known bioactivities with potentials in the treatment of central nervous system diseases. By using an HPLC-MS/MS method, we analyzed the in vivo plasma and brain pharmacokinetics of three ingredients of coumarins, including imperatorin, CHEMICAL and cnidilin in mice after oral administration of Dahuricae extract at doses of 800mg/kg. The biosamples were prepared using acetonitrile precipitation and the separation was achieved on an XDB-C18 column by gradient elution. The BBB permeability and P-gp-mediated efflux were further examined in Madin Canine kidney cells transfected with full length cDNA for human multidrug resistance gene1 (MDCKII-MDR1). Our results demonstrate that the method has excellent and satisfactory selectivity, sensitivity, linearity, precision, and accuracy for simultaneous determination of imperatorin, CHEMICAL and cnidilin. The pharmacokinetics parameters were determined by using noncompartmental analyses, including the AUC(0-t) in plasma (1695.22, 1326.45 and 636.98mg*h/L), the AUC(0-t) in brain (1812.35, 2125.17 and 1145.83ng*h/g) as well as the T1/2 in plasma (0.66, 0.82, 0.97h) and brain (0.96, 1.1, 0.99h) for imperatorin, CHEMICAL and cnidilin, respectively, suggesting that the three coumarins could easily pass through the BBB in vivo. In the in vitro model we observed high permeability of imperatorin and CHEMICAL with the GENE-mediated efflux ratios of 0.53 and 0.06, as well as medium permeability of cnidilin with 0.82. All data suggest that these three coumarins have high BBB permeability and have pharmacokinetic potentials for the treatment of central nervous system diseases. | SUBSTRATE |
| In vitro permeability analysis, pharmacokinetic and brain distribution study in mice of imperatorin, isoimperatorin and CHEMICAL in Radix Angelicae Dahuricae. Coumarins are important constituents of Radix Angelicae Dahuricae, a well-known traditional Chinese medicine possess several known bioactivities with potentials in the treatment of central nervous system diseases. By using an HPLC-MS/MS method, we analyzed the in vivo plasma and brain pharmacokinetics of three ingredients of coumarins, including imperatorin, isoimperatorin and CHEMICAL in mice after oral administration of Dahuricae extract at doses of 800mg/kg. The biosamples were prepared using acetonitrile precipitation and the separation was achieved on an XDB-C18 column by gradient elution. The BBB permeability and P-gp-mediated efflux were further examined in Madin Canine kidney cells transfected with full length cDNA for human multidrug resistance gene1 (MDCKII-MDR1). Our results demonstrate that the method has excellent and satisfactory selectivity, sensitivity, linearity, precision, and accuracy for simultaneous determination of imperatorin, isoimperatorin and CHEMICAL. The pharmacokinetics parameters were determined by using noncompartmental analyses, including the AUC(0-t) in plasma (1695.22, 1326.45 and 636.98mg*h/L), the AUC(0-t) in brain (1812.35, 2125.17 and 1145.83ng*h/g) as well as the T1/2 in plasma (0.66, 0.82, 0.97h) and brain (0.96, 1.1, 0.99h) for imperatorin, isoimperatorin and CHEMICAL, respectively, suggesting that the three coumarins could easily pass through the BBB in vivo. In the in vitro model we observed high permeability of imperatorin and isoimperatorin with the GENE-mediated efflux ratios of 0.53 and 0.06, as well as medium permeability of CHEMICAL with 0.82. All data suggest that these three coumarins have high BBB permeability and have pharmacokinetic potentials for the treatment of central nervous system diseases. | SUBSTRATE |
| Involvement of Src and the GENE cytoskeleton in the antitumorigenic action of adenosine dialdehyde. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of CHEMICAL and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, AdOx disrupted GENE cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of CHEMICAL or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of GENE cytoskeleton, and a change of the colocalization pattern between GENE and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the GENE cytoskeleton and Src kinase activity. | GENE-CHEMICAL |
| Involvement of GENE and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of CHEMICAL and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic GENE and its kinase activity. Interestingly, AdOx disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of GENE and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of CHEMICAL or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on GENE, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and GENE. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and GENE kinase activity. | GENE-CHEMICAL |
| Involvement of GENE and the actin cytoskeleton in the antitumorigenic action of CHEMICAL. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with CHEMICAL (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic GENE and its kinase activity. Interestingly, AdOx disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of GENE and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on GENE, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and GENE. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and GENE kinase activity. | REGULATOR |
| Involvement of Src and the GENE cytoskeleton in the antitumorigenic action of CHEMICAL. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with CHEMICAL (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, AdOx disrupted GENE cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of GENE cytoskeleton, and a change of the colocalization pattern between GENE and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the GENE cytoskeleton and Src kinase activity. | INHIBITOR |
| Involvement of Src and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of CHEMICAL and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic Src and its GENE activity. Interestingly, AdOx disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of CHEMICAL or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that CHEMICAL/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src GENE activity. | REGULATOR |
| Involvement of GENE and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that CHEMICAL was capable of indirectly diminishing the phosphorylation of oncogenic GENE and its kinase activity. Interestingly, CHEMICAL disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of GENE and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on GENE, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and GENE. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and GENE kinase activity. | INHIBITOR |
| Involvement of Src and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that CHEMICAL was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, CHEMICAL disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and GENE/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity. | INDIRECT-DOWNREGULATOR |
| Involvement of Src and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that CHEMICAL was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, CHEMICAL disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/GENE, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity. | INDIRECT-DOWNREGULATOR |
| Involvement of Src and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that CHEMICAL was capable of indirectly diminishing the phosphorylation of oncogenic Src and its GENE activity. Interestingly, CHEMICAL disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src GENE activity. | INHIBITOR |
| Involvement of Src and the GENE cytoskeleton in the antitumorigenic action of adenosine dialdehyde. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that CHEMICAL was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, CHEMICAL disrupted GENE cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of GENE cytoskeleton, and a change of the colocalization pattern between GENE and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the GENE cytoskeleton and Src kinase activity. | INHIBITOR |
| Involvement of Src and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, AdOx disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of GENE by specific siRNA or another type of inhibitor, CHEMICAL (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity. | INHIBITOR |
| Involvement of Src and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, AdOx disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of GENE by specific siRNA or another type of inhibitor, 3-deazaadenosine (CHEMICAL), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity. | INHIBITOR |
| Involvement of Src and the actin cytoskeleton in the antitumorigenic action of CHEMICAL. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with CHEMICAL (AdOx), an inhibitor of transmethylation-suppressive GENE (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, AdOx disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity. | INHIBITOR |
| Involvement of Src and the actin cytoskeleton in the antitumorigenic action of CHEMICAL. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with CHEMICAL (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (GENE), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, AdOx disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of GENE by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity. | INHIBITOR |
| Involvement of Src and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (CHEMICAL), an inhibitor of transmethylation-suppressive GENE (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that CHEMICAL was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, CHEMICAL disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity. | INHIBITOR |
| Involvement of Src and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (CHEMICAL), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (GENE), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that CHEMICAL was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, CHEMICAL disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of GENE by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity. | INHIBITOR |
| Involvement of Src and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive GENE (SAHH), enhanced the level of CHEMICAL and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, AdOx disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of CHEMICAL or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity. | GENE-CHEMICAL |
| Involvement of Src and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (GENE), enhanced the level of CHEMICAL and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, AdOx disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of CHEMICAL or inhibition of GENE by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity. | PRODUCT-OF |
| Synthesis of derivatives of CHEMICAL and their inhibitory activities against matrix metalloproteinase-1 (MMP-1). A series of GENE inhibitors have been identified based upon a CHEMICAL scaffold using structure-based drug design methods. The best compound in the series showed an IC50 value of 0.4 μM. A docking study was conducted for compound (S)-10n in order to investigate its binding interactions with GENE. The structure-activity relationships (SAR) were also briefly discussed. Useful SAR was established which provides important guidelines for the design of future generations of potent inhibitors against GENE. | INHIBITOR |
| Synthesis of derivatives of CHEMICAL and their inhibitory activities against GENE (MMP-1). A series of MMP-1 inhibitors have been identified based upon a CHEMICAL scaffold using structure-based drug design methods. The best compound in the series showed an IC50 value of 0.4 μM. A docking study was conducted for compound (S)-10n in order to investigate its binding interactions with MMP-1. The structure-activity relationships (SAR) were also briefly discussed. Useful SAR was established which provides important guidelines for the design of future generations of potent inhibitors against MMP-1. | INHIBITOR |
| Synthesis and biological evaluation of some novel resveratrol amide derivatives as potential anti-tumor agents. Three series of novel resveratrol amide derivatives (1a-q, 2a-h, 3a-l) were synthesized and evaluated for their biological activities. All compounds were characterized by (1)H NMR, (13)C NMR, MS and elemental analysis. Furthermore, compound 3e was also characterized by X-ray crystallography. All the compounds were evaluated for their anti-tumor activity against MCF-7, A549 and B16-F10 tumor cell lines as well as GENE (COX-2)-derived CHEMICAL (PGE2) inhibitory activity of murine macrophage RAW 264.7 cell line. Among them, compounds 1c, 1g and 3e displayed the most potent COX-2 inhibitory activity with the IC50 values of 1.02, 1.27 and 1.98 μM, respectively. Molecular docking studies were performed to position compounds 1c and 3e into the active site of COX-2 to determine the probable binding modes. | INHIBITOR |
| Synthesis and biological evaluation of some novel resveratrol amide derivatives as potential anti-tumor agents. Three series of novel resveratrol amide derivatives (1a-q, 2a-h, 3a-l) were synthesized and evaluated for their biological activities. All compounds were characterized by (1)H NMR, (13)C NMR, MS and elemental analysis. Furthermore, compound 3e was also characterized by X-ray crystallography. All the compounds were evaluated for their anti-tumor activity against MCF-7, A549 and B16-F10 tumor cell lines as well as cyclooxygenase-2 (GENE)-derived CHEMICAL (PGE2) inhibitory activity of murine macrophage RAW 264.7 cell line. Among them, compounds 1c, 1g and 3e displayed the most potent GENE inhibitory activity with the IC50 values of 1.02, 1.27 and 1.98 μM, respectively. Molecular docking studies were performed to position compounds 1c and 3e into the active site of GENE to determine the probable binding modes. | INHIBITOR |
| Synthesis and biological evaluation of some novel resveratrol amide derivatives as potential anti-tumor agents. Three series of novel resveratrol amide derivatives (1a-q, 2a-h, 3a-l) were synthesized and evaluated for their biological activities. All compounds were characterized by (1)H NMR, (13)C NMR, MS and elemental analysis. Furthermore, compound 3e was also characterized by X-ray crystallography. All the compounds were evaluated for their anti-tumor activity against MCF-7, A549 and B16-F10 tumor cell lines as well as GENE (COX-2)-derived prostaglandin E2 (CHEMICAL) inhibitory activity of murine macrophage RAW 264.7 cell line. Among them, compounds 1c, 1g and 3e displayed the most potent COX-2 inhibitory activity with the IC50 values of 1.02, 1.27 and 1.98 μM, respectively. Molecular docking studies were performed to position compounds 1c and 3e into the active site of COX-2 to determine the probable binding modes. | INHIBITOR |
| Synthesis and biological evaluation of some novel resveratrol amide derivatives as potential anti-tumor agents. Three series of novel resveratrol amide derivatives (1a-q, 2a-h, 3a-l) were synthesized and evaluated for their biological activities. All compounds were characterized by (1)H NMR, (13)C NMR, MS and elemental analysis. Furthermore, compound 3e was also characterized by X-ray crystallography. All the compounds were evaluated for their anti-tumor activity against MCF-7, A549 and B16-F10 tumor cell lines as well as cyclooxygenase-2 (GENE)-derived prostaglandin E2 (CHEMICAL) inhibitory activity of murine macrophage RAW 264.7 cell line. Among them, compounds 1c, 1g and 3e displayed the most potent GENE inhibitory activity with the IC50 values of 1.02, 1.27 and 1.98 μM, respectively. Molecular docking studies were performed to position compounds 1c and 3e into the active site of GENE to determine the probable binding modes. | INHIBITOR |
| Bioactives and nutraceutical phytochemicals naturally occurring in virgin olive oil. The case study of the Nocellara del Belice Italian olive cultivar. This work reports on the composition and bionutritional value of organic virgin olive oil from the Nocellara del Belice variety, one cultivated in the olive areas of the Sicily region, Italy. Destoned oils obtained by processing olives with a destoning-based procedure were compared with conventional oils. This innovative technique, consisting in removing the stone from fruits prior to processing, strongly enhanced the already high-quality level of the conventional product. An in-depth analytical investigation from 2008 to 2010 showed how this innovative olive extraction process led to an excellent peculiar final product, mainly attributable to the improved biophenol and volatile composition, as well as higher concentrations of the lipophilic and vitamin antioxidants (tocopherols and tocotrienols). It had higher levels of CHEMICAL (p-HPEA-EDA), a nutraceutical compound exerting actions against GENE and COX2 (cycloxygenases). Its head-space aroma displayed new volatile phytomolecules and also had higher levels of green volatiles from the lipoxygenase (LOX)-pathway (one having as precursors the polyunsaturated fatty acids containing a cis-cis-1,4-pentadiene system). Among the other bioactives, we highlight its significant levels of trans-β-carotene and xanthophylls (lutein, violaxanthin, neoxanthin and other carotenoids). Its enhanced nutritional value was also attributable to the increased intensity of valuable tasting notes. | REGULATOR |
| Bioactives and nutraceutical phytochemicals naturally occurring in virgin olive oil. The case study of the Nocellara del Belice Italian olive cultivar. This work reports on the composition and bionutritional value of organic virgin olive oil from the Nocellara del Belice variety, one cultivated in the olive areas of the Sicily region, Italy. Destoned oils obtained by processing olives with a destoning-based procedure were compared with conventional oils. This innovative technique, consisting in removing the stone from fruits prior to processing, strongly enhanced the already high-quality level of the conventional product. An in-depth analytical investigation from 2008 to 2010 showed how this innovative olive extraction process led to an excellent peculiar final product, mainly attributable to the improved biophenol and volatile composition, as well as higher concentrations of the lipophilic and vitamin antioxidants (tocopherols and tocotrienols). It had higher levels of CHEMICAL (p-HPEA-EDA), a nutraceutical compound exerting actions against COX1 and GENE (cycloxygenases). Its head-space aroma displayed new volatile phytomolecules and also had higher levels of green volatiles from the lipoxygenase (LOX)-pathway (one having as precursors the polyunsaturated fatty acids containing a cis-cis-1,4-pentadiene system). Among the other bioactives, we highlight its significant levels of trans-β-carotene and xanthophylls (lutein, violaxanthin, neoxanthin and other carotenoids). Its enhanced nutritional value was also attributable to the increased intensity of valuable tasting notes. | REGULATOR |
| Bioactives and nutraceutical phytochemicals naturally occurring in virgin olive oil. The case study of the Nocellara del Belice Italian olive cultivar. This work reports on the composition and bionutritional value of organic virgin olive oil from the Nocellara del Belice variety, one cultivated in the olive areas of the Sicily region, Italy. Destoned oils obtained by processing olives with a destoning-based procedure were compared with conventional oils. This innovative technique, consisting in removing the stone from fruits prior to processing, strongly enhanced the already high-quality level of the conventional product. An in-depth analytical investigation from 2008 to 2010 showed how this innovative olive extraction process led to an excellent peculiar final product, mainly attributable to the improved biophenol and volatile composition, as well as higher concentrations of the lipophilic and vitamin antioxidants (tocopherols and tocotrienols). It had higher levels of CHEMICAL (p-HPEA-EDA), a nutraceutical compound exerting actions against COX1 and COX2 (GENE). Its head-space aroma displayed new volatile phytomolecules and also had higher levels of green volatiles from the lipoxygenase (LOX)-pathway (one having as precursors the polyunsaturated fatty acids containing a cis-cis-1,4-pentadiene system). Among the other bioactives, we highlight its significant levels of trans-β-carotene and xanthophylls (lutein, violaxanthin, neoxanthin and other carotenoids). Its enhanced nutritional value was also attributable to the increased intensity of valuable tasting notes. | REGULATOR |
| Bioactives and nutraceutical phytochemicals naturally occurring in virgin olive oil. The case study of the Nocellara del Belice Italian olive cultivar. This work reports on the composition and bionutritional value of organic virgin olive oil from the Nocellara del Belice variety, one cultivated in the olive areas of the Sicily region, Italy. Destoned oils obtained by processing olives with a destoning-based procedure were compared with conventional oils. This innovative technique, consisting in removing the stone from fruits prior to processing, strongly enhanced the already high-quality level of the conventional product. An in-depth analytical investigation from 2008 to 2010 showed how this innovative olive extraction process led to an excellent peculiar final product, mainly attributable to the improved biophenol and volatile composition, as well as higher concentrations of the lipophilic and vitamin antioxidants (tocopherols and tocotrienols). It had higher levels of oleocanthal (CHEMICAL), a nutraceutical compound exerting actions against GENE and COX2 (cycloxygenases). Its head-space aroma displayed new volatile phytomolecules and also had higher levels of green volatiles from the lipoxygenase (LOX)-pathway (one having as precursors the polyunsaturated fatty acids containing a cis-cis-1,4-pentadiene system). Among the other bioactives, we highlight its significant levels of trans-β-carotene and xanthophylls (lutein, violaxanthin, neoxanthin and other carotenoids). Its enhanced nutritional value was also attributable to the increased intensity of valuable tasting notes. | REGULATOR |
| Bioactives and nutraceutical phytochemicals naturally occurring in virgin olive oil. The case study of the Nocellara del Belice Italian olive cultivar. This work reports on the composition and bionutritional value of organic virgin olive oil from the Nocellara del Belice variety, one cultivated in the olive areas of the Sicily region, Italy. Destoned oils obtained by processing olives with a destoning-based procedure were compared with conventional oils. This innovative technique, consisting in removing the stone from fruits prior to processing, strongly enhanced the already high-quality level of the conventional product. An in-depth analytical investigation from 2008 to 2010 showed how this innovative olive extraction process led to an excellent peculiar final product, mainly attributable to the improved biophenol and volatile composition, as well as higher concentrations of the lipophilic and vitamin antioxidants (tocopherols and tocotrienols). It had higher levels of oleocanthal (CHEMICAL), a nutraceutical compound exerting actions against COX1 and GENE (cycloxygenases). Its head-space aroma displayed new volatile phytomolecules and also had higher levels of green volatiles from the lipoxygenase (LOX)-pathway (one having as precursors the polyunsaturated fatty acids containing a cis-cis-1,4-pentadiene system). Among the other bioactives, we highlight its significant levels of trans-β-carotene and xanthophylls (lutein, violaxanthin, neoxanthin and other carotenoids). Its enhanced nutritional value was also attributable to the increased intensity of valuable tasting notes. | REGULATOR |
| Bioactives and nutraceutical phytochemicals naturally occurring in virgin olive oil. The case study of the Nocellara del Belice Italian olive cultivar. This work reports on the composition and bionutritional value of organic virgin olive oil from the Nocellara del Belice variety, one cultivated in the olive areas of the Sicily region, Italy. Destoned oils obtained by processing olives with a destoning-based procedure were compared with conventional oils. This innovative technique, consisting in removing the stone from fruits prior to processing, strongly enhanced the already high-quality level of the conventional product. An in-depth analytical investigation from 2008 to 2010 showed how this innovative olive extraction process led to an excellent peculiar final product, mainly attributable to the improved biophenol and volatile composition, as well as higher concentrations of the lipophilic and vitamin antioxidants (tocopherols and tocotrienols). It had higher levels of oleocanthal (CHEMICAL), a nutraceutical compound exerting actions against COX1 and COX2 (GENE). Its head-space aroma displayed new volatile phytomolecules and also had higher levels of green volatiles from the lipoxygenase (LOX)-pathway (one having as precursors the polyunsaturated fatty acids containing a cis-cis-1,4-pentadiene system). Among the other bioactives, we highlight its significant levels of trans-β-carotene and xanthophylls (lutein, violaxanthin, neoxanthin and other carotenoids). Its enhanced nutritional value was also attributable to the increased intensity of valuable tasting notes. | REGULATOR |
| Bioactives and nutraceutical phytochemicals naturally occurring in virgin olive oil. The case study of the Nocellara del Belice Italian olive cultivar. This work reports on the composition and bionutritional value of organic virgin olive oil from the Nocellara del Belice variety, one cultivated in the olive areas of the Sicily region, Italy. Destoned oils obtained by processing olives with a destoning-based procedure were compared with conventional oils. This innovative technique, consisting in removing the stone from fruits prior to processing, strongly enhanced the already high-quality level of the conventional product. An in-depth analytical investigation from 2008 to 2010 showed how this innovative olive extraction process led to an excellent peculiar final product, mainly attributable to the improved biophenol and volatile composition, as well as higher concentrations of the lipophilic and vitamin antioxidants (tocopherols and tocotrienols). It had higher levels of oleocanthal (p-HPEA-EDA), a nutraceutical compound exerting actions against COX1 and COX2 (cycloxygenases). Its head-space aroma displayed new volatile phytomolecules and also had higher levels of green volatiles from the GENE (LOX)-pathway (one having as precursors the CHEMICAL containing a cis-cis-1,4-pentadiene system). Among the other bioactives, we highlight its significant levels of trans-β-carotene and xanthophylls (lutein, violaxanthin, neoxanthin and other carotenoids). Its enhanced nutritional value was also attributable to the increased intensity of valuable tasting notes. | PRODUCT-OF |
| Bioactives and nutraceutical phytochemicals naturally occurring in virgin olive oil. The case study of the Nocellara del Belice Italian olive cultivar. This work reports on the composition and bionutritional value of organic virgin olive oil from the Nocellara del Belice variety, one cultivated in the olive areas of the Sicily region, Italy. Destoned oils obtained by processing olives with a destoning-based procedure were compared with conventional oils. This innovative technique, consisting in removing the stone from fruits prior to processing, strongly enhanced the already high-quality level of the conventional product. An in-depth analytical investigation from 2008 to 2010 showed how this innovative olive extraction process led to an excellent peculiar final product, mainly attributable to the improved biophenol and volatile composition, as well as higher concentrations of the lipophilic and vitamin antioxidants (tocopherols and tocotrienols). It had higher levels of oleocanthal (p-HPEA-EDA), a nutraceutical compound exerting actions against COX1 and COX2 (cycloxygenases). Its head-space aroma displayed new volatile phytomolecules and also had higher levels of green volatiles from the lipoxygenase (GENE)-pathway (one having as precursors the CHEMICAL containing a cis-cis-1,4-pentadiene system). Among the other bioactives, we highlight its significant levels of trans-β-carotene and xanthophylls (lutein, violaxanthin, neoxanthin and other carotenoids). Its enhanced nutritional value was also attributable to the increased intensity of valuable tasting notes. | PRODUCT-OF |
| Bioactives and nutraceutical phytochemicals naturally occurring in virgin olive oil. The case study of the Nocellara del Belice Italian olive cultivar. This work reports on the composition and bionutritional value of organic virgin olive oil from the Nocellara del Belice variety, one cultivated in the olive areas of the Sicily region, Italy. Destoned oils obtained by processing olives with a destoning-based procedure were compared with conventional oils. This innovative technique, consisting in removing the stone from fruits prior to processing, strongly enhanced the already high-quality level of the conventional product. An in-depth analytical investigation from 2008 to 2010 showed how this innovative olive extraction process led to an excellent peculiar final product, mainly attributable to the improved biophenol and volatile composition, as well as higher concentrations of the lipophilic and vitamin antioxidants (tocopherols and tocotrienols). It had higher levels of oleocanthal (p-HPEA-EDA), a nutraceutical compound exerting actions against COX1 and COX2 (cycloxygenases). Its head-space aroma displayed new volatile phytomolecules and also had higher levels of green volatiles from the GENE (LOX)-pathway (one having as precursors the polyunsaturated fatty acids containing a CHEMICAL system). Among the other bioactives, we highlight its significant levels of trans-β-carotene and xanthophylls (lutein, violaxanthin, neoxanthin and other carotenoids). Its enhanced nutritional value was also attributable to the increased intensity of valuable tasting notes. | GENE-CHEMICAL |
| Bioactives and nutraceutical phytochemicals naturally occurring in virgin olive oil. The case study of the Nocellara del Belice Italian olive cultivar. This work reports on the composition and bionutritional value of organic virgin olive oil from the Nocellara del Belice variety, one cultivated in the olive areas of the Sicily region, Italy. Destoned oils obtained by processing olives with a destoning-based procedure were compared with conventional oils. This innovative technique, consisting in removing the stone from fruits prior to processing, strongly enhanced the already high-quality level of the conventional product. An in-depth analytical investigation from 2008 to 2010 showed how this innovative olive extraction process led to an excellent peculiar final product, mainly attributable to the improved biophenol and volatile composition, as well as higher concentrations of the lipophilic and vitamin antioxidants (tocopherols and tocotrienols). It had higher levels of oleocanthal (p-HPEA-EDA), a nutraceutical compound exerting actions against COX1 and COX2 (cycloxygenases). Its head-space aroma displayed new volatile phytomolecules and also had higher levels of green volatiles from the lipoxygenase (GENE)-pathway (one having as precursors the polyunsaturated fatty acids containing a CHEMICAL system). Among the other bioactives, we highlight its significant levels of trans-β-carotene and xanthophylls (lutein, violaxanthin, neoxanthin and other carotenoids). Its enhanced nutritional value was also attributable to the increased intensity of valuable tasting notes. | PRODUCT-OF |
| The contrasting activity of CHEMICAL versus chlorido ruthenium and osmium arene azo- and imino-pyridine anticancer complexes: control of cell selectivity, cross-resistance, GENE dependence, and apoptosis pathway. Organometallic half-sandwich complexes [M(p-cymene)(azo/imino-pyridine)X](+) where M = Ru(II) or Os(II) and X ═ Cl or I, exhibit potent antiproliferative activity toward a range of cancer cells. Not only are the CHEMICAL complexes more potent than the chlorido analogues, but they are not cross-resistant with the clinical platinum drugs cisplatin and oxaliplatin. They are also more selective for cancer cells versus normal cells (fibroblasts) and show high accumulation in cell membranes. They arrest cell growth in G1 phase in contrast to cisplatin (S phase) with a high incidence of late-stage apoptosis. The CHEMICAL complexes retain potency in GENE mutant colon cells. All complexes activate caspase 3. In general, antiproliferative activity is greatly enhanced by low levels of the glutathione synthase inhibitor l-buthionine sulfoxime. The work illustrates how subtle changes to the design of low-spin d(6) metal complexes can lead to major changes in cellular metabolism and to potent complexes with novel mechanisms of anticancer activity. | REGULATOR |
| The contrasting activity of iodido versus CHEMICAL and osmium arene azo- and imino-pyridine anticancer complexes: control of cell selectivity, cross-resistance, GENE dependence, and apoptosis pathway. Organometallic half-sandwich complexes [M(p-cymene)(azo/imino-pyridine)X](+) where M = Ru(II) or Os(II) and X ═ Cl or I, exhibit potent antiproliferative activity toward a range of cancer cells. Not only are the iodido complexes more potent than the chlorido analogues, but they are not cross-resistant with the clinical platinum drugs cisplatin and oxaliplatin. They are also more selective for cancer cells versus normal cells (fibroblasts) and show high accumulation in cell membranes. They arrest cell growth in G1 phase in contrast to cisplatin (S phase) with a high incidence of late-stage apoptosis. The iodido complexes retain potency in GENE mutant colon cells. All complexes activate caspase 3. In general, antiproliferative activity is greatly enhanced by low levels of the glutathione synthase inhibitor l-buthionine sulfoxime. The work illustrates how subtle changes to the design of low-spin d(6) metal complexes can lead to major changes in cellular metabolism and to potent complexes with novel mechanisms of anticancer activity. | REGULATOR |
| The contrasting activity of iodido versus chlorido ruthenium and CHEMICAL anticancer complexes: control of cell selectivity, cross-resistance, GENE dependence, and apoptosis pathway. Organometallic half-sandwich complexes [M(p-cymene)(azo/imino-pyridine)X](+) where M = Ru(II) or Os(II) and X ═ Cl or I, exhibit potent antiproliferative activity toward a range of cancer cells. Not only are the iodido complexes more potent than the chlorido analogues, but they are not cross-resistant with the clinical platinum drugs cisplatin and oxaliplatin. They are also more selective for cancer cells versus normal cells (fibroblasts) and show high accumulation in cell membranes. They arrest cell growth in G1 phase in contrast to cisplatin (S phase) with a high incidence of late-stage apoptosis. The iodido complexes retain potency in GENE mutant colon cells. All complexes activate caspase 3. In general, antiproliferative activity is greatly enhanced by low levels of the glutathione synthase inhibitor l-buthionine sulfoxime. The work illustrates how subtle changes to the design of low-spin d(6) metal complexes can lead to major changes in cellular metabolism and to potent complexes with novel mechanisms of anticancer activity. | REGULATOR |
| The contrasting activity of iodido versus chlorido ruthenium and osmium arene azo- and imino-pyridine anticancer complexes: control of cell selectivity, cross-resistance, p53 dependence, and apoptosis pathway. Organometallic half-sandwich complexes [M(p-cymene)(azo/imino-pyridine)X](+) where M = Ru(II) or Os(II) and X ═ Cl or I, exhibit potent antiproliferative activity toward a range of cancer cells. Not only are the iodido complexes more potent than the chlorido analogues, but they are not cross-resistant with the clinical platinum drugs cisplatin and oxaliplatin. They are also more selective for cancer cells versus normal cells (fibroblasts) and show high accumulation in cell membranes. They arrest cell growth in G1 phase in contrast to cisplatin (S phase) with a high incidence of late-stage apoptosis. The iodido complexes retain potency in p53 mutant colon cells. All complexes activate caspase 3. In general, antiproliferative activity is greatly enhanced by low levels of the GENE inhibitor CHEMICAL. The work illustrates how subtle changes to the design of low-spin d(6) metal complexes can lead to major changes in cellular metabolism and to potent complexes with novel mechanisms of anticancer activity. | INHIBITOR |
| Zinc-dependent lysosomal enlargement in TRPML1-deficient cells involves MTF-1 transcription factor and ZnT4 (Slc30a4) transporter. CHEMICAL is critical for a multitude of cellular processes, including gene expression, secretion and enzymatic activities. Cellular CHEMICAL is controlled by zinc-chelating proteins and by CHEMICAL transporters. The recent identification of CHEMICAL permeability of the lysosomal ion channel GENE (transient receptor potential mucolipin 1), and the evidence of abnormal CHEMICAL levels in cells deficient in GENE, suggested a role for TRPML1 in CHEMICAL transport. In the present study we provide new evidence for such a role and identify additional cellular components responsible for it. In agreement with the previously published data, an acute siRNA (small interfering RNA)-driven GENE KD (knockdown) leads to the build-up of large cytoplasmic vesicles positive for LysoTracker™ and CHEMICAL staining, when cells are exposed to high concentrations of CHEMICAL. We now show that lysosomal enlargement and CHEMICAL build-up in TRPML1-KD cells exposed to CHEMICAL are ameliorated by KD of the zinc-sensitive transcription factor MTF-1 (metal-regulatory-element-binding transcription factor-1) or the CHEMICAL transporter ZnT4. GENE KD is associated with a build-up of cytoplasmic CHEMICAL and with enhanced transcriptional response of mRNA for MT2a (metallothionein 2a). GENE KD did not suppress lysosomal secretion, but it did delay CHEMICAL leak from the lysosomes into the cytoplasm. These results underscore a role for TRPML1 in CHEMICAL metabolism. Furthermore, they suggest that GENE works in concert with ZnT4 to regulate CHEMICAL translocation between the cytoplasm and lysosomes. | PRODUCT-OF |
| Zinc-dependent lysosomal enlargement in TRPML1-deficient cells involves MTF-1 transcription factor and ZnT4 (Slc30a4) transporter. CHEMICAL is critical for a multitude of cellular processes, including gene expression, secretion and enzymatic activities. Cellular CHEMICAL is controlled by zinc-chelating proteins and by CHEMICAL transporters. The recent identification of CHEMICAL permeability of the lysosomal ion channel TRPML1 (GENE), and the evidence of abnormal CHEMICAL levels in cells deficient in TRPML1, suggested a role for TRPML1 in CHEMICAL transport. In the present study we provide new evidence for such a role and identify additional cellular components responsible for it. In agreement with the previously published data, an acute siRNA (small interfering RNA)-driven TRPML1 KD (knockdown) leads to the build-up of large cytoplasmic vesicles positive for LysoTracker™ and CHEMICAL staining, when cells are exposed to high concentrations of CHEMICAL. We now show that lysosomal enlargement and CHEMICAL build-up in TRPML1-KD cells exposed to CHEMICAL are ameliorated by KD of the zinc-sensitive transcription factor MTF-1 (metal-regulatory-element-binding transcription factor-1) or the CHEMICAL transporter ZnT4. TRPML1 KD is associated with a build-up of cytoplasmic CHEMICAL and with enhanced transcriptional response of mRNA for MT2a (metallothionein 2a). TRPML1 KD did not suppress lysosomal secretion, but it did delay CHEMICAL leak from the lysosomes into the cytoplasm. These results underscore a role for TRPML1 in CHEMICAL metabolism. Furthermore, they suggest that TRPML1 works in concert with ZnT4 to regulate CHEMICAL translocation between the cytoplasm and lysosomes. | SUBSTRATE |
| Zinc-dependent lysosomal enlargement in TRPML1-deficient cells involves MTF-1 transcription factor and ZnT4 (Slc30a4) transporter. CHEMICAL is critical for a multitude of cellular processes, including gene expression, secretion and enzymatic activities. Cellular CHEMICAL is controlled by GENE and by CHEMICAL transporters. The recent identification of CHEMICAL permeability of the lysosomal ion channel TRPML1 (transient receptor potential mucolipin 1), and the evidence of abnormal CHEMICAL levels in cells deficient in TRPML1, suggested a role for TRPML1 in CHEMICAL transport. In the present study we provide new evidence for such a role and identify additional cellular components responsible for it. In agreement with the previously published data, an acute siRNA (small interfering RNA)-driven TRPML1 KD (knockdown) leads to the build-up of large cytoplasmic vesicles positive for LysoTracker™ and CHEMICAL staining, when cells are exposed to high concentrations of CHEMICAL. We now show that lysosomal enlargement and CHEMICAL build-up in TRPML1-KD cells exposed to CHEMICAL are ameliorated by KD of the zinc-sensitive transcription factor MTF-1 (metal-regulatory-element-binding transcription factor-1) or the CHEMICAL transporter ZnT4. TRPML1 KD is associated with a build-up of cytoplasmic CHEMICAL and with enhanced transcriptional response of mRNA for MT2a (metallothionein 2a). TRPML1 KD did not suppress lysosomal secretion, but it did delay CHEMICAL leak from the lysosomes into the cytoplasm. These results underscore a role for TRPML1 in CHEMICAL metabolism. Furthermore, they suggest that TRPML1 works in concert with ZnT4 to regulate CHEMICAL translocation between the cytoplasm and lysosomes. | REGULATOR |
| Zinc-dependent lysosomal enlargement in TRPML1-deficient cells involves MTF-1 transcription factor and ZnT4 (Slc30a4) transporter. CHEMICAL is critical for a multitude of cellular processes, including gene expression, secretion and enzymatic activities. Cellular CHEMICAL is controlled by zinc-chelating proteins and by GENE. The recent identification of CHEMICAL permeability of the lysosomal ion channel TRPML1 (transient receptor potential mucolipin 1), and the evidence of abnormal CHEMICAL levels in cells deficient in TRPML1, suggested a role for TRPML1 in CHEMICAL transport. In the present study we provide new evidence for such a role and identify additional cellular components responsible for it. In agreement with the previously published data, an acute siRNA (small interfering RNA)-driven TRPML1 KD (knockdown) leads to the build-up of large cytoplasmic vesicles positive for LysoTracker™ and CHEMICAL staining, when cells are exposed to high concentrations of CHEMICAL. We now show that lysosomal enlargement and CHEMICAL build-up in TRPML1-KD cells exposed to CHEMICAL are ameliorated by KD of the zinc-sensitive transcription factor MTF-1 (metal-regulatory-element-binding transcription factor-1) or the CHEMICAL transporter ZnT4. TRPML1 KD is associated with a build-up of cytoplasmic CHEMICAL and with enhanced transcriptional response of mRNA for MT2a (metallothionein 2a). TRPML1 KD did not suppress lysosomal secretion, but it did delay CHEMICAL leak from the lysosomes into the cytoplasm. These results underscore a role for TRPML1 in CHEMICAL metabolism. Furthermore, they suggest that TRPML1 works in concert with ZnT4 to regulate CHEMICAL translocation between the cytoplasm and lysosomes. | REGULATOR |
| Zinc-dependent lysosomal enlargement in TRPML1-deficient cells involves MTF-1 transcription factor and GENE (Slc30a4) transporter. CHEMICAL is critical for a multitude of cellular processes, including gene expression, secretion and enzymatic activities. Cellular CHEMICAL is controlled by zinc-chelating proteins and by CHEMICAL transporters. The recent identification of CHEMICAL permeability of the lysosomal ion channel TRPML1 (transient receptor potential mucolipin 1), and the evidence of abnormal CHEMICAL levels in cells deficient in TRPML1, suggested a role for TRPML1 in CHEMICAL transport. In the present study we provide new evidence for such a role and identify additional cellular components responsible for it. In agreement with the previously published data, an acute siRNA (small interfering RNA)-driven TRPML1 KD (knockdown) leads to the build-up of large cytoplasmic vesicles positive for LysoTracker™ and CHEMICAL staining, when cells are exposed to high concentrations of CHEMICAL. We now show that lysosomal enlargement and CHEMICAL build-up in TRPML1-KD cells exposed to CHEMICAL are ameliorated by KD of the zinc-sensitive transcription factor MTF-1 (metal-regulatory-element-binding transcription factor-1) or the CHEMICAL transporter GENE. TRPML1 KD is associated with a build-up of cytoplasmic CHEMICAL and with enhanced transcriptional response of mRNA for MT2a (metallothionein 2a). TRPML1 KD did not suppress lysosomal secretion, but it did delay CHEMICAL leak from the lysosomes into the cytoplasm. These results underscore a role for TRPML1 in CHEMICAL metabolism. Furthermore, they suggest that TRPML1 works in concert with GENE to regulate CHEMICAL translocation between the cytoplasm and lysosomes. | SUBSTRATE |
| Evaluation of in vivo anti-hyperglycemic and antioxidant potentials of CHEMICAL and sandalwood oil. Sandalwood finds numerous mentions across diverse traditional medicinal systems in use worldwide. The objective of this study was to evaluate the in vivo anti-hyperglycemic and antioxidant potential of sandalwood oil and its major constituent CHEMICAL. The in vivo anti-hyperglycemic experiment was conducted in alloxan-induced diabetic male Swiss albino mice models. The in vivo antioxidant experiment was performed in d-galactose mediated oxidative stress induced male Swiss albino mice models. Intraperitoneal administration of CHEMICAL (100mg/kg BW) and sandalwood oil (1g/kg BW) for an week modulated parameters such as body weight, blood glucose, serum bilirubin, liver glycogen, and lipid peroxides contents to normoglycemic levels in the alloxan-induced diabetic mice. Similarly, intraperitoneal administration of CHEMICAL (100mg/kg BW) and sandalwood oil (1g/kg BW) for two weeks modulated parameters such as serum aminotransferases, alkaline phosphatase, bilirubin, superoxide dismutase, GENE, free sulfhydryl, protein carbonyl, nitric oxide, liver lipid peroxide contents, and antioxidant capacity in d-galactose mediated oxidative stress induced mice. Besides, it was observed that the beneficial effects of CHEMICAL were well complimented, differentially by other constituents present in sandalwood oil, thus indicating synergism in biological activity of this traditionally used bioresource. | GENE-CHEMICAL |
| Evaluation of in vivo anti-hyperglycemic and antioxidant potentials of CHEMICAL and sandalwood oil. Sandalwood finds numerous mentions across diverse traditional medicinal systems in use worldwide. The objective of this study was to evaluate the in vivo anti-hyperglycemic and antioxidant potential of sandalwood oil and its major constituent CHEMICAL. The in vivo anti-hyperglycemic experiment was conducted in alloxan-induced diabetic male Swiss albino mice models. The in vivo antioxidant experiment was performed in d-galactose mediated oxidative stress induced male Swiss albino mice models. Intraperitoneal administration of CHEMICAL (100mg/kg BW) and sandalwood oil (1g/kg BW) for an week modulated parameters such as body weight, blood glucose, serum bilirubin, liver glycogen, and lipid peroxides contents to normoglycemic levels in the alloxan-induced diabetic mice. Similarly, intraperitoneal administration of CHEMICAL (100mg/kg BW) and sandalwood oil (1g/kg BW) for two weeks modulated parameters such as serum GENE, alkaline phosphatase, bilirubin, superoxide dismutase, catalase, free sulfhydryl, protein carbonyl, nitric oxide, liver lipid peroxide contents, and antioxidant capacity in d-galactose mediated oxidative stress induced mice. Besides, it was observed that the beneficial effects of CHEMICAL were well complimented, differentially by other constituents present in sandalwood oil, thus indicating synergism in biological activity of this traditionally used bioresource. | GENE-CHEMICAL |
| Evaluation of in vivo anti-hyperglycemic and antioxidant potentials of CHEMICAL and sandalwood oil. Sandalwood finds numerous mentions across diverse traditional medicinal systems in use worldwide. The objective of this study was to evaluate the in vivo anti-hyperglycemic and antioxidant potential of sandalwood oil and its major constituent CHEMICAL. The in vivo anti-hyperglycemic experiment was conducted in alloxan-induced diabetic male Swiss albino mice models. The in vivo antioxidant experiment was performed in d-galactose mediated oxidative stress induced male Swiss albino mice models. Intraperitoneal administration of CHEMICAL (100mg/kg BW) and sandalwood oil (1g/kg BW) for an week modulated parameters such as body weight, blood glucose, serum bilirubin, liver glycogen, and lipid peroxides contents to normoglycemic levels in the alloxan-induced diabetic mice. Similarly, intraperitoneal administration of CHEMICAL (100mg/kg BW) and sandalwood oil (1g/kg BW) for two weeks modulated parameters such as serum aminotransferases, GENE, bilirubin, superoxide dismutase, catalase, free sulfhydryl, protein carbonyl, nitric oxide, liver lipid peroxide contents, and antioxidant capacity in d-galactose mediated oxidative stress induced mice. Besides, it was observed that the beneficial effects of CHEMICAL were well complimented, differentially by other constituents present in sandalwood oil, thus indicating synergism in biological activity of this traditionally used bioresource. | GENE-CHEMICAL |
| Evaluation of in vivo anti-hyperglycemic and antioxidant potentials of CHEMICAL and sandalwood oil. Sandalwood finds numerous mentions across diverse traditional medicinal systems in use worldwide. The objective of this study was to evaluate the in vivo anti-hyperglycemic and antioxidant potential of sandalwood oil and its major constituent CHEMICAL. The in vivo anti-hyperglycemic experiment was conducted in alloxan-induced diabetic male Swiss albino mice models. The in vivo antioxidant experiment was performed in d-galactose mediated oxidative stress induced male Swiss albino mice models. Intraperitoneal administration of CHEMICAL (100mg/kg BW) and sandalwood oil (1g/kg BW) for an week modulated parameters such as body weight, blood glucose, serum bilirubin, liver glycogen, and lipid peroxides contents to normoglycemic levels in the alloxan-induced diabetic mice. Similarly, intraperitoneal administration of CHEMICAL (100mg/kg BW) and sandalwood oil (1g/kg BW) for two weeks modulated parameters such as serum aminotransferases, alkaline phosphatase, bilirubin, GENE, catalase, free sulfhydryl, protein carbonyl, nitric oxide, liver lipid peroxide contents, and antioxidant capacity in d-galactose mediated oxidative stress induced mice. Besides, it was observed that the beneficial effects of CHEMICAL were well complimented, differentially by other constituents present in sandalwood oil, thus indicating synergism in biological activity of this traditionally used bioresource. | GENE-CHEMICAL |
| Serum amyloid A upsurge precedes standard biomarkers of hepatotoxicity in ritodrine-injected mice. The tocolytic agent ritodrine acts on the β2-adrenoceptor and is an effective treatment option for preterm labor. However, several adverse effects of ritodrine therapy, including liver damage, have been noted. To elucidate the underlying mechanisms of ritodrine-induced adverse effects, development of sensitive biomarkers of these adverse events is necessary. Here, we report the development and analysis of an animal model of ritodrine-induced liver damage. Female mice received daily ritodrine injections for 2 weeks; liver samples were then collected and subjected to DNA microarray analysis. Ritodrine significantly altered the expression of genes related to steroid and lipid metabolism, as well as the metabolism of ritodrine itself. Importantly, expression of the acute-phase reactant serum amyloid A (SAA) significantly increased after ritodrine injection, with values indicating the largest fold-change. This large increase in blood GENE levels serves as a more sensitive biomarker than conventional liver enzymes, such as aspartate aminotransferase and alanine aminotransferase. The increase in GENE expression is specific to ritodrine-induced liver damage, because GENE expression was not induced by other hepatotoxic drugs such as CHEMICAL, valproic acid, or metformin. Our in vitro studies showed that cyclic adenosine 3',5'-monophosphate (cAMP) accumulation was not a primary cause of the ritodrine-induced GENE increase. Instead, GENE expression was enhanced by indirect phosphorylation of the signal transducer and activator of transcription-3 (STAT3) mediated by interleukin-6. Therefore, our study provides a method for sensitive and early detection of hepatic injury, and may thus help preclude serious liver damage due to ritodrine use in preterm labor. | NO-RELATIONSHIP |
| Serum amyloid A upsurge precedes standard biomarkers of hepatotoxicity in ritodrine-injected mice. The tocolytic agent ritodrine acts on the β2-adrenoceptor and is an effective treatment option for preterm labor. However, several adverse effects of ritodrine therapy, including liver damage, have been noted. To elucidate the underlying mechanisms of ritodrine-induced adverse effects, development of sensitive biomarkers of these adverse events is necessary. Here, we report the development and analysis of an animal model of ritodrine-induced liver damage. Female mice received daily ritodrine injections for 2 weeks; liver samples were then collected and subjected to DNA microarray analysis. Ritodrine significantly altered the expression of genes related to steroid and lipid metabolism, as well as the metabolism of ritodrine itself. Importantly, expression of the acute-phase reactant serum amyloid A (SAA) significantly increased after ritodrine injection, with values indicating the largest fold-change. This large increase in blood GENE levels serves as a more sensitive biomarker than conventional liver enzymes, such as aspartate aminotransferase and alanine aminotransferase. The increase in GENE expression is specific to ritodrine-induced liver damage, because GENE expression was not induced by other hepatotoxic drugs such as acetaminophen, CHEMICAL, or metformin. Our in vitro studies showed that cyclic adenosine 3',5'-monophosphate (cAMP) accumulation was not a primary cause of the ritodrine-induced GENE increase. Instead, GENE expression was enhanced by indirect phosphorylation of the signal transducer and activator of transcription-3 (STAT3) mediated by interleukin-6. Therefore, our study provides a method for sensitive and early detection of hepatic injury, and may thus help preclude serious liver damage due to ritodrine use in preterm labor. | NO-RELATIONSHIP |
| Serum amyloid A upsurge precedes standard biomarkers of hepatotoxicity in ritodrine-injected mice. The tocolytic agent ritodrine acts on the β2-adrenoceptor and is an effective treatment option for preterm labor. However, several adverse effects of ritodrine therapy, including liver damage, have been noted. To elucidate the underlying mechanisms of ritodrine-induced adverse effects, development of sensitive biomarkers of these adverse events is necessary. Here, we report the development and analysis of an animal model of ritodrine-induced liver damage. Female mice received daily ritodrine injections for 2 weeks; liver samples were then collected and subjected to DNA microarray analysis. Ritodrine significantly altered the expression of genes related to steroid and lipid metabolism, as well as the metabolism of ritodrine itself. Importantly, expression of the acute-phase reactant serum amyloid A (SAA) significantly increased after ritodrine injection, with values indicating the largest fold-change. This large increase in blood GENE levels serves as a more sensitive biomarker than conventional liver enzymes, such as aspartate aminotransferase and alanine aminotransferase. The increase in GENE expression is specific to ritodrine-induced liver damage, because GENE expression was not induced by other hepatotoxic drugs such as acetaminophen, valproic acid, or CHEMICAL. Our in vitro studies showed that cyclic adenosine 3',5'-monophosphate (cAMP) accumulation was not a primary cause of the ritodrine-induced GENE increase. Instead, GENE expression was enhanced by indirect phosphorylation of the signal transducer and activator of transcription-3 (STAT3) mediated by interleukin-6. Therefore, our study provides a method for sensitive and early detection of hepatic injury, and may thus help preclude serious liver damage due to ritodrine use in preterm labor. | NO-RELATIONSHIP |
| Serum amyloid A upsurge precedes standard biomarkers of hepatotoxicity in ritodrine-injected mice. The tocolytic agent ritodrine acts on the β2-adrenoceptor and is an effective treatment option for preterm labor. However, several adverse effects of ritodrine therapy, including liver damage, have been noted. To elucidate the underlying mechanisms of ritodrine-induced adverse effects, development of sensitive biomarkers of these adverse events is necessary. Here, we report the development and analysis of an animal model of ritodrine-induced liver damage. Female mice received daily ritodrine injections for 2 weeks; liver samples were then collected and subjected to DNA microarray analysis. Ritodrine significantly altered the expression of genes related to steroid and lipid metabolism, as well as the metabolism of ritodrine itself. Importantly, expression of the acute-phase reactant serum amyloid A (SAA) significantly increased after ritodrine injection, with values indicating the largest fold-change. This large increase in blood GENE levels serves as a more sensitive biomarker than conventional liver enzymes, such as aspartate aminotransferase and alanine aminotransferase. The increase in GENE expression is specific to ritodrine-induced liver damage, because GENE expression was not induced by other hepatotoxic drugs such as acetaminophen, valproic acid, or metformin. Our in vitro studies showed that CHEMICAL (cAMP) accumulation was not a primary cause of the ritodrine-induced GENE increase. Instead, GENE expression was enhanced by indirect phosphorylation of the signal transducer and activator of transcription-3 (STAT3) mediated by interleukin-6. Therefore, our study provides a method for sensitive and early detection of hepatic injury, and may thus help preclude serious liver damage due to ritodrine use in preterm labor. | NO-RELATIONSHIP |
| Serum amyloid A upsurge precedes standard biomarkers of hepatotoxicity in ritodrine-injected mice. The tocolytic agent ritodrine acts on the β2-adrenoceptor and is an effective treatment option for preterm labor. However, several adverse effects of ritodrine therapy, including liver damage, have been noted. To elucidate the underlying mechanisms of ritodrine-induced adverse effects, development of sensitive biomarkers of these adverse events is necessary. Here, we report the development and analysis of an animal model of ritodrine-induced liver damage. Female mice received daily ritodrine injections for 2 weeks; liver samples were then collected and subjected to DNA microarray analysis. Ritodrine significantly altered the expression of genes related to steroid and lipid metabolism, as well as the metabolism of ritodrine itself. Importantly, expression of the acute-phase reactant serum amyloid A (SAA) significantly increased after ritodrine injection, with values indicating the largest fold-change. This large increase in blood GENE levels serves as a more sensitive biomarker than conventional liver enzymes, such as aspartate aminotransferase and alanine aminotransferase. The increase in GENE expression is specific to ritodrine-induced liver damage, because GENE expression was not induced by other hepatotoxic drugs such as acetaminophen, valproic acid, or metformin. Our in vitro studies showed that cyclic adenosine 3',5'-monophosphate (CHEMICAL) accumulation was not a primary cause of the ritodrine-induced GENE increase. Instead, GENE expression was enhanced by indirect phosphorylation of the signal transducer and activator of transcription-3 (STAT3) mediated by interleukin-6. Therefore, our study provides a method for sensitive and early detection of hepatic injury, and may thus help preclude serious liver damage due to ritodrine use in preterm labor. | NO-RELATIONSHIP |
| Serum amyloid A upsurge precedes standard biomarkers of hepatotoxicity in ritodrine-injected mice. The tocolytic agent CHEMICAL acts on the GENE and is an effective treatment option for preterm labor. However, several adverse effects of CHEMICAL therapy, including liver damage, have been noted. To elucidate the underlying mechanisms of ritodrine-induced adverse effects, development of sensitive biomarkers of these adverse events is necessary. Here, we report the development and analysis of an animal model of ritodrine-induced liver damage. Female mice received daily CHEMICAL injections for 2 weeks; liver samples were then collected and subjected to DNA microarray analysis. CHEMICAL significantly altered the expression of genes related to steroid and lipid metabolism, as well as the metabolism of CHEMICAL itself. Importantly, expression of the acute-phase reactant serum amyloid A (SAA) significantly increased after CHEMICAL injection, with values indicating the largest fold-change. This large increase in blood SAA levels serves as a more sensitive biomarker than conventional liver enzymes, such as aspartate aminotransferase and alanine aminotransferase. The increase in SAA expression is specific to ritodrine-induced liver damage, because SAA expression was not induced by other hepatotoxic drugs such as acetaminophen, valproic acid, or metformin. Our in vitro studies showed that cyclic adenosine 3',5'-monophosphate (cAMP) accumulation was not a primary cause of the ritodrine-induced SAA increase. Instead, SAA expression was enhanced by indirect phosphorylation of the signal transducer and activator of transcription-3 (STAT3) mediated by interleukin-6. Therefore, our study provides a method for sensitive and early detection of hepatic injury, and may thus help preclude serious liver damage due to CHEMICAL use in preterm labor. | REGULATOR |
| Serum amyloid A upsurge precedes standard biomarkers of hepatotoxicity in ritodrine-injected mice. The tocolytic agent CHEMICAL acts on the β2-adrenoceptor and is an effective treatment option for preterm labor. However, several adverse effects of CHEMICAL therapy, including liver damage, have been noted. To elucidate the underlying mechanisms of ritodrine-induced adverse effects, development of sensitive biomarkers of these adverse events is necessary. Here, we report the development and analysis of an animal model of ritodrine-induced liver damage. Female mice received daily CHEMICAL injections for 2 weeks; liver samples were then collected and subjected to DNA microarray analysis. CHEMICAL significantly altered the expression of genes related to steroid and lipid metabolism, as well as the metabolism of CHEMICAL itself. Importantly, expression of the acute-phase reactant GENE (SAA) significantly increased after CHEMICAL injection, with values indicating the largest fold-change. This large increase in blood SAA levels serves as a more sensitive biomarker than conventional liver enzymes, such as aspartate aminotransferase and alanine aminotransferase. The increase in SAA expression is specific to ritodrine-induced liver damage, because SAA expression was not induced by other hepatotoxic drugs such as acetaminophen, valproic acid, or metformin. Our in vitro studies showed that cyclic adenosine 3',5'-monophosphate (cAMP) accumulation was not a primary cause of the ritodrine-induced SAA increase. Instead, SAA expression was enhanced by indirect phosphorylation of the signal transducer and activator of transcription-3 (STAT3) mediated by interleukin-6. Therefore, our study provides a method for sensitive and early detection of hepatic injury, and may thus help preclude serious liver damage due to CHEMICAL use in preterm labor. | INDIRECT-UPREGULATOR |
| Serum amyloid A upsurge precedes standard biomarkers of hepatotoxicity in ritodrine-injected mice. The tocolytic agent CHEMICAL acts on the β2-adrenoceptor and is an effective treatment option for preterm labor. However, several adverse effects of CHEMICAL therapy, including liver damage, have been noted. To elucidate the underlying mechanisms of ritodrine-induced adverse effects, development of sensitive biomarkers of these adverse events is necessary. Here, we report the development and analysis of an animal model of ritodrine-induced liver damage. Female mice received daily CHEMICAL injections for 2 weeks; liver samples were then collected and subjected to DNA microarray analysis. CHEMICAL significantly altered the expression of genes related to steroid and lipid metabolism, as well as the metabolism of CHEMICAL itself. Importantly, expression of the acute-phase reactant serum amyloid A (GENE) significantly increased after CHEMICAL injection, with values indicating the largest fold-change. This large increase in blood GENE levels serves as a more sensitive biomarker than conventional liver enzymes, such as aspartate aminotransferase and alanine aminotransferase. The increase in GENE expression is specific to ritodrine-induced liver damage, because GENE expression was not induced by other hepatotoxic drugs such as acetaminophen, valproic acid, or metformin. Our in vitro studies showed that cyclic adenosine 3',5'-monophosphate (cAMP) accumulation was not a primary cause of the ritodrine-induced GENE increase. Instead, GENE expression was enhanced by indirect phosphorylation of the signal transducer and activator of transcription-3 (STAT3) mediated by interleukin-6. Therefore, our study provides a method for sensitive and early detection of hepatic injury, and may thus help preclude serious liver damage due to CHEMICAL use in preterm labor. | INDIRECT-UPREGULATOR |
| GENE upsurge precedes standard biomarkers of hepatotoxicity in CHEMICAL-injected mice. The tocolytic agent CHEMICAL acts on the β2-adrenoceptor and is an effective treatment option for preterm labor. However, several adverse effects of CHEMICAL therapy, including liver damage, have been noted. To elucidate the underlying mechanisms of ritodrine-induced adverse effects, development of sensitive biomarkers of these adverse events is necessary. Here, we report the development and analysis of an animal model of ritodrine-induced liver damage. Female mice received daily CHEMICAL injections for 2 weeks; liver samples were then collected and subjected to DNA microarray analysis. CHEMICAL significantly altered the expression of genes related to steroid and lipid metabolism, as well as the metabolism of CHEMICAL itself. Importantly, expression of the acute-phase reactant serum amyloid A (SAA) significantly increased after CHEMICAL injection, with values indicating the largest fold-change. This large increase in blood SAA levels serves as a more sensitive biomarker than conventional liver enzymes, such as aspartate aminotransferase and alanine aminotransferase. The increase in SAA expression is specific to ritodrine-induced liver damage, because SAA expression was not induced by other hepatotoxic drugs such as acetaminophen, valproic acid, or metformin. Our in vitro studies showed that cyclic adenosine 3',5'-monophosphate (cAMP) accumulation was not a primary cause of the ritodrine-induced SAA increase. Instead, SAA expression was enhanced by indirect phosphorylation of the signal transducer and activator of transcription-3 (STAT3) mediated by interleukin-6. Therefore, our study provides a method for sensitive and early detection of hepatic injury, and may thus help preclude serious liver damage due to CHEMICAL use in preterm labor. | GENE-CHEMICAL |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, GENE inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of CHEMICAL versus most species of Enterobacteriaceae depending on the presence or absence of GENE enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of CHEMICAL (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of CHEMICAL versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of CHEMICAL. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to CHEMICAL. Like CHEMICAL, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus GENE-producing Gram-negative bacilli that are not inhibited by CHEMICAL alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of CHEMICAL versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | NO-RELATIONSHIP |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C GENE and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the CHEMICAL bicyclic ring system, and avibactam has been shown to bond covalently to GENE. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | INHIBITOR |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. CHEMICAL (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C GENE and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of CHEMICAL closely resembles portions of the cephem bicyclic ring system, and CHEMICAL has been shown to bond covalently to GENE. Very little is known about the potential for CHEMICAL to select for resistance. The addition of CHEMICAL greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of CHEMICAL also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of CHEMICAL does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of CHEMICAL follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of CHEMICAL increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, CHEMICAL is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, CHEMICAL serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | DIRECT-REGULATOR |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of CHEMICAL versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of CHEMICAL (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of CHEMICAL versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of CHEMICAL. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to CHEMICAL. Like CHEMICAL, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by CHEMICAL alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of CHEMICAL versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for CHEMICAL-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing GENE (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | REGULATOR |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of CHEMICAL versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of CHEMICAL (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of CHEMICAL versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of CHEMICAL. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to CHEMICAL. Like CHEMICAL, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by CHEMICAL alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of CHEMICAL versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for CHEMICAL-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (GENE), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | REGULATOR |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of CHEMICAL versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of CHEMICAL (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of CHEMICAL versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of CHEMICAL. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to CHEMICAL. Like CHEMICAL, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by CHEMICAL alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of CHEMICAL versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for CHEMICAL-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), GENE (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | REGULATOR |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of CHEMICAL versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of CHEMICAL (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of CHEMICAL versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of CHEMICAL. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to CHEMICAL. Like CHEMICAL, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by CHEMICAL alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of CHEMICAL versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for CHEMICAL-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (GENE) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | REGULATOR |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of CHEMICAL versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of CHEMICAL (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of CHEMICAL versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of CHEMICAL. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to CHEMICAL. Like CHEMICAL, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by CHEMICAL alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of CHEMICAL versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for CHEMICAL-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or GENE. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | REGULATOR |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. CHEMICAL (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of CHEMICAL closely resembles portions of the cephem bicyclic ring system, and CHEMICAL has been shown to bond covalently to β-lactamases. Very little is known about the potential for CHEMICAL to select for resistance. The addition of CHEMICAL greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of CHEMICAL also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of CHEMICAL does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of CHEMICAL follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of CHEMICAL increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, CHEMICAL is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, CHEMICAL serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-CHEMICAL include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing GENE (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | NO-RELATIONSHIP |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. CHEMICAL (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of CHEMICAL closely resembles portions of the cephem bicyclic ring system, and CHEMICAL has been shown to bond covalently to β-lactamases. Very little is known about the potential for CHEMICAL to select for resistance. The addition of CHEMICAL greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of CHEMICAL also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of CHEMICAL does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of CHEMICAL follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of CHEMICAL increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, CHEMICAL is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, CHEMICAL serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-CHEMICAL include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (GENE), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | NO-RELATIONSHIP |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. CHEMICAL (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of CHEMICAL closely resembles portions of the cephem bicyclic ring system, and CHEMICAL has been shown to bond covalently to β-lactamases. Very little is known about the potential for CHEMICAL to select for resistance. The addition of CHEMICAL greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of CHEMICAL also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of CHEMICAL does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of CHEMICAL follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of CHEMICAL increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, CHEMICAL is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, CHEMICAL serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-CHEMICAL include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), GENE (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | NO-RELATIONSHIP |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. CHEMICAL (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of CHEMICAL closely resembles portions of the cephem bicyclic ring system, and CHEMICAL has been shown to bond covalently to β-lactamases. Very little is known about the potential for CHEMICAL to select for resistance. The addition of CHEMICAL greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of CHEMICAL also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of CHEMICAL does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of CHEMICAL follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of CHEMICAL increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, CHEMICAL is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, CHEMICAL serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-CHEMICAL include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (GENE) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | NO-RELATIONSHIP |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. CHEMICAL (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of CHEMICAL closely resembles portions of the cephem bicyclic ring system, and CHEMICAL has been shown to bond covalently to β-lactamases. Very little is known about the potential for CHEMICAL to select for resistance. The addition of CHEMICAL greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of CHEMICAL also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of CHEMICAL does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of CHEMICAL follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of CHEMICAL increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, CHEMICAL is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, CHEMICAL serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-CHEMICAL include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or GENE. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | NO-RELATIONSHIP |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. CHEMICAL (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, GENE inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of CHEMICAL closely resembles portions of the cephem bicyclic ring system, and CHEMICAL has been shown to bond covalently to β-lactamases. Very little is known about the potential for CHEMICAL to select for resistance. The addition of CHEMICAL greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of GENE enzyme(s). Against Pseudomonas aeruginosa, the addition of CHEMICAL also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of CHEMICAL does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of CHEMICAL follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of CHEMICAL increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, CHEMICAL is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-CHEMICAL is rapidly bactericidal versus GENE-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, CHEMICAL serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | INHIBITOR |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Avibactam (formerly CHEMICAL, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some GENE enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | INHIBITOR |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Avibactam (formerly CHEMICAL, AVE1330A) is a synthetic non-β-lactam, GENE inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of GENE enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | INHIBITOR |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. CHEMICAL (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some GENE enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | INHIBITOR |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. CHEMICAL (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of CHEMICAL closely resembles portions of the cephem bicyclic ring system, and CHEMICAL has been shown to bond covalently to β-lactamases. Very little is known about the potential for CHEMICAL to select for resistance. The addition of CHEMICAL greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of CHEMICAL also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of CHEMICAL does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of CHEMICAL follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of CHEMICAL increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, CHEMICAL is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, CHEMICAL serves to broaden the spectrum of ceftazidime versus GENE-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum GENE (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | NO-RELATIONSHIP |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of CHEMICAL versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of CHEMICAL (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of CHEMICAL versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of CHEMICAL. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to CHEMICAL. Like CHEMICAL, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by CHEMICAL alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of CHEMICAL versus GENE-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum GENE (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | REGULATOR |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Avibactam (formerly NXL104, CHEMICAL) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some GENE enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | INHIBITOR |
| Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Avibactam (formerly NXL104, CHEMICAL) is a synthetic non-β-lactam, GENE inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of GENE enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. | INHIBITOR |
| Apelin inhibits diet-induced obesity by enhancing lymphatic and blood vessel integrity. Angiogenesis is tightly associated with the outgrowth of adipose tissue, leading to obesity, which is a risk factor for type 2 diabetes and hypertension, mainly because expanding adipose tissue requires an increased nutrient supply from blood vessels. Therefore, induction of vessel abnormality by adipokines has been well studied, whereas how altered vascular function promotes obesity is relatively unexplored. Also, surviving Prox1 heterozygous mice showed abnormal lymphatic patterning and adult-onset obesity, indicating that accumulation of adipocytes could be closely linked with lymphatic function. Here we propose a new anti-obesity strategy based on enhancement of lymphatic and blood vessel integrity with apelin. Apelin-knockout mice given a high-fat diet showed an obese phenotype associated with abnormal lymphatic and blood vessel enlargement. Fatty acids present in the high-fat diet induced hyperpermeability of endothelial cells, causing adipocyte differentiation, whereas apelin promoted vascular stabilization. Moreover, treatment of high-fat-diet-fed apelin-knockout mice with a selective GENE inhibitor, CHEMICAL, improved vascular function, and also attenuated obesity. Finally, apelin transgenic mice showed decreased subcutaneous adipose tissue owing to inhibition of high-fat-diet-induced hyperpermeability of vessels. These results indicate that apelin inhibits high-fat-diet-induced obesity by enhancing vessel integrity. Apelin could serve as a therapeutic target for treating obesity and related diseases. | INHIBITOR |
| Activation of the anti-cancer agent upamostat by the mARC enzyme system. Abstract 1. CHEMICAL (Mesupron®) is a new small molecule GENE inhibitor. The drug candidate was developed to inhibit the urokinase-type plasminogen activator (uPA) system, which plays a major role in tumor invasion and metastasis. CHEMICAL is currently in clinical development as an anti-metastatic and non-cytotoxic agent against pancreatic and breast cancer. 2. CHEMICAL is the orally available amidoxime- (i.e. hydroxyamidine-) prodrug of the pharmacologically active form, WX-UK1. In this study, the reductive enzymatic activation of upamostat to its corresponding amidine WX-UK1 was analyzed. 3. The recently discovered molybdenum enzyme "mitochondrial Amidoxime Reducing Component" (mARC) catalyses together with its electron transport proteins cytochrome b(5) and NADH cytochrome b(5) reductase the reduction of N-hydroxylated prodrugs. In vitro biotransformation assays with porcine subcellular fractions and the reconstituted human enzymes demonstrate an mARC-dependent N-reduction of upamostat. | INHIBITOR |
| Activation of the anti-cancer agent upamostat by the mARC enzyme system. Abstract 1. Upamostat (CHEMICAL®) is a new small molecule GENE inhibitor. The drug candidate was developed to inhibit the urokinase-type plasminogen activator (uPA) system, which plays a major role in tumor invasion and metastasis. Upamostat is currently in clinical development as an anti-metastatic and non-cytotoxic agent against pancreatic and breast cancer. 2. Upamostat is the orally available amidoxime- (i.e. hydroxyamidine-) prodrug of the pharmacologically active form, WX-UK1. In this study, the reductive enzymatic activation of upamostat to its corresponding amidine WX-UK1 was analyzed. 3. The recently discovered molybdenum enzyme "mitochondrial Amidoxime Reducing Component" (mARC) catalyses together with its electron transport proteins cytochrome b(5) and NADH cytochrome b(5) reductase the reduction of N-hydroxylated prodrugs. In vitro biotransformation assays with porcine subcellular fractions and the reconstituted human enzymes demonstrate an mARC-dependent N-reduction of upamostat. | INHIBITOR |
| A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of GENE and the SAGA coactivator complex. Although many functions and targets have been attributed to the histone and protein deacetylase SIRT1, a comprehensive analysis of SIRT1 binding proteins yielding a high-confidence interaction map has not been established. Using a comparative statistical analysis of binding partners, we have assembled a high-confidence SIRT1 interactome. Employing this method, we identified the deubiquitinating enzyme ubiquitin-specific protease 22 (USP22), a component of the deubiquitinating module (DUBm) of the SAGA transcriptional coactivating complex, as a SIRT1-interacting partner. We found that this interaction is highly specific, requires the ZnF-UBP domain of GENE, and is disrupted by the inactivating H363Y mutation within SIRT1. Moreover, we show that GENE is acetylated on multiple CHEMICAL residues and that alteration of a single CHEMICAL (K129) within the ZnF-UBP domain is sufficient to alter interaction of the DUBm with the core SAGA complex. Furthermore, USP22-mediated recruitment of SIRT1 activity promotes the deacetylation of individual SAGA complex components. Our results indicate an important role of SIRT1-mediated deacetylation in regulating the formation of DUBm subcomplexes within the larger SAGA complex. | PART-OF |
| A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex. Although many functions and targets have been attributed to the histone and protein deacetylase SIRT1, a comprehensive analysis of SIRT1 binding proteins yielding a high-confidence interaction map has not been established. Using a comparative statistical analysis of binding partners, we have assembled a high-confidence SIRT1 interactome. Employing this method, we identified the deubiquitinating enzyme ubiquitin-specific protease 22 (USP22), a component of the deubiquitinating module (DUBm) of the SAGA transcriptional coactivating complex, as a SIRT1-interacting partner. We found that this interaction is highly specific, requires the GENE of USP22, and is disrupted by the inactivating H363Y mutation within SIRT1. Moreover, we show that USP22 is acetylated on multiple CHEMICAL residues and that alteration of a single CHEMICAL (K129) within the GENE is sufficient to alter interaction of the DUBm with the core SAGA complex. Furthermore, USP22-mediated recruitment of SIRT1 activity promotes the deacetylation of individual SAGA complex components. Our results indicate an important role of SIRT1-mediated deacetylation in regulating the formation of DUBm subcomplexes within the larger SAGA complex. | PART-OF |
| Characterization of cytosolic glutathione peroxidase and phospholipid-hydroperoxide glutathione peroxidase genes in rainbow trout (Oncorhynchus mykiss) and their modulation by in vitro CHEMICAL exposure. CHEMICAL (Se) is an oligonutrient with both essential biological functions and recognized harmful effects. As the selenocysteine (SeCys) amino acid, CHEMICAL is integrated in several Se-containing proteins (selenoproteins), many of which are fundamental for cell homeostasis. Nevertheless, CHEMICAL may exert toxic effects at levels marginally above those required, mainly through the generation of reactive oxygen species (ROS). The CHEMICAL chemical speciation can strongly affect the bioavailability of this metal and its impact on metabolism, dictating the levels that can be beneficial or detrimental towards an organism. Glutathione peroxidase (GPxs) is the largest and the most studied selenoprotein family. Cytosolic glutathione peroxidase (cGPx, GPx1) and phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) are widely distributed throughout tissues, and play a pivotal role in regulating the oxidative status in the cell. In this study we have cloned GENE and GPx4 genes in rainbow trout (Oncorhynchus mykiss). The constitutive mRNA expression of these GPx genes was examined in 18 trout tissues and their responsiveness to Se availability was analysed using a rainbow trout liver cell line (RTL). An inorganic (sodium selenite, Na2SeO3) and organic (selenocysteine, Cys-Se-Se-Cys) selenocompound have been used as Se sources. GENE activity was also tested to verify the impact of transcript changes on the enzymatic function of these molecules. To understand if the results obtained from the transcript expression analysis were due to Se bioavailability or generation of ROS, the cytoxicity of the two selenocompounds was tested by measuring the impact of Se on cell membrane integrity. Lastly, Se availability was quantified by mass spectrophotometry to determine the amount of Se in the cell culture media, the Se background due to the foetal calf serum supplement and the contribution from the two selenocompounds used in the treatments. Three isoforms of genes for both GENE (GPx1a, 1b1 and 1b2) and GPx4 (GPx4a1, a2 and b) have been identified. The discovery of a third gene encoding for GENE and GPx4 hints that salmonids may have the biggest selenoproteome amongst all vertebrates. Transcripts of GPx4 genes were more highly expressed in most tissues examined in vivo (except blood, head kidney and spleen), whereas those of the GENE genes were more responsive to CHEMICAL exposure in vitro, especially to the organic form. Interestingly, GPx1a was the most sensitive to CHEMICAL availability in non stressful conditions, whereas GPx1b1 and GPx1b2 were highly induced by exposure to CHEMICAL levels that had some toxic effects on the cells. Although the different concentrations tested of the two selenocompounds modulate GENE transcript expression to various degrees, no significant change of GENE enzymatic activity was detectable. Our results lead us to conclude that trout GENE transcripts expression level may represent a sensitive biomarker for CHEMICAL intake, helping to evaluate if CHEMICAL concentration and chemical speciation impact on cell homeostasis. | REGULATOR |
| Characterization of cytosolic glutathione peroxidase and phospholipid-hydroperoxide glutathione peroxidase genes in rainbow trout (Oncorhynchus mykiss) and their modulation by in vitro CHEMICAL exposure. CHEMICAL (Se) is an oligonutrient with both essential biological functions and recognized harmful effects. As the selenocysteine (SeCys) amino acid, CHEMICAL is integrated in several Se-containing proteins (selenoproteins), many of which are fundamental for cell homeostasis. Nevertheless, CHEMICAL may exert toxic effects at levels marginally above those required, mainly through the generation of reactive oxygen species (ROS). The CHEMICAL chemical speciation can strongly affect the bioavailability of this metal and its impact on metabolism, dictating the levels that can be beneficial or detrimental towards an organism. Glutathione peroxidase (GPxs) is the largest and the most studied selenoprotein family. Cytosolic glutathione peroxidase (cGPx, GPx1) and phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) are widely distributed throughout tissues, and play a pivotal role in regulating the oxidative status in the cell. In this study we have cloned GPx1 and GPx4 genes in rainbow trout (Oncorhynchus mykiss). The constitutive mRNA expression of these GPx genes was examined in 18 trout tissues and their responsiveness to Se availability was analysed using a rainbow trout liver cell line (RTL). An inorganic (sodium selenite, Na2SeO3) and organic (selenocysteine, Cys-Se-Se-Cys) selenocompound have been used as Se sources. GPx1 activity was also tested to verify the impact of transcript changes on the enzymatic function of these molecules. To understand if the results obtained from the transcript expression analysis were due to Se bioavailability or generation of ROS, the cytoxicity of the two selenocompounds was tested by measuring the impact of Se on cell membrane integrity. Lastly, Se availability was quantified by mass spectrophotometry to determine the amount of Se in the cell culture media, the Se background due to the foetal calf serum supplement and the contribution from the two selenocompounds used in the treatments. Three isoforms of genes for both GPx1 (GPx1a, 1b1 and 1b2) and GPx4 (GPx4a1, a2 and b) have been identified. The discovery of a third gene encoding for GPx1 and GPx4 hints that salmonids may have the biggest selenoproteome amongst all vertebrates. Transcripts of GPx4 genes were more highly expressed in most tissues examined in vivo (except blood, head kidney and spleen), whereas those of the GPx1 genes were more responsive to CHEMICAL exposure in vitro, especially to the organic form. Interestingly, GENE was the most sensitive to CHEMICAL availability in non stressful conditions, whereas GPx1b1 and GPx1b2 were highly induced by exposure to CHEMICAL levels that had some toxic effects on the cells. Although the different concentrations tested of the two selenocompounds modulate GPx1 transcript expression to various degrees, no significant change of GPx1 enzymatic activity was detectable. Our results lead us to conclude that trout GPx1 transcripts expression level may represent a sensitive biomarker for CHEMICAL intake, helping to evaluate if CHEMICAL concentration and chemical speciation impact on cell homeostasis. | REGULATOR |
| Characterization of GENE and phospholipid-hydroperoxide glutathione peroxidase genes in rainbow trout (Oncorhynchus mykiss) and their modulation by in vitro CHEMICAL exposure. CHEMICAL (Se) is an oligonutrient with both essential biological functions and recognized harmful effects. As the selenocysteine (SeCys) amino acid, CHEMICAL is integrated in several Se-containing proteins (selenoproteins), many of which are fundamental for cell homeostasis. Nevertheless, CHEMICAL may exert toxic effects at levels marginally above those required, mainly through the generation of reactive oxygen species (ROS). The CHEMICAL chemical speciation can strongly affect the bioavailability of this metal and its impact on metabolism, dictating the levels that can be beneficial or detrimental towards an organism. Glutathione peroxidase (GPxs) is the largest and the most studied selenoprotein family. GENE (cGPx, GPx1) and phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) are widely distributed throughout tissues, and play a pivotal role in regulating the oxidative status in the cell. In this study we have cloned GPx1 and GPx4 genes in rainbow trout (Oncorhynchus mykiss). The constitutive mRNA expression of these GPx genes was examined in 18 trout tissues and their responsiveness to Se availability was analysed using a rainbow trout liver cell line (RTL). An inorganic (sodium selenite, Na2SeO3) and organic (selenocysteine, Cys-Se-Se-Cys) selenocompound have been used as Se sources. GPx1 activity was also tested to verify the impact of transcript changes on the enzymatic function of these molecules. To understand if the results obtained from the transcript expression analysis were due to Se bioavailability or generation of ROS, the cytoxicity of the two selenocompounds was tested by measuring the impact of Se on cell membrane integrity. Lastly, Se availability was quantified by mass spectrophotometry to determine the amount of Se in the cell culture media, the Se background due to the foetal calf serum supplement and the contribution from the two selenocompounds used in the treatments. Three isoforms of genes for both GPx1 (GPx1a, 1b1 and 1b2) and GPx4 (GPx4a1, a2 and b) have been identified. The discovery of a third gene encoding for GPx1 and GPx4 hints that salmonids may have the biggest selenoproteome amongst all vertebrates. Transcripts of GPx4 genes were more highly expressed in most tissues examined in vivo (except blood, head kidney and spleen), whereas those of the GPx1 genes were more responsive to CHEMICAL exposure in vitro, especially to the organic form. Interestingly, GPx1a was the most sensitive to CHEMICAL availability in non stressful conditions, whereas GPx1b1 and GPx1b2 were highly induced by exposure to CHEMICAL levels that had some toxic effects on the cells. Although the different concentrations tested of the two selenocompounds modulate GPx1 transcript expression to various degrees, no significant change of GPx1 enzymatic activity was detectable. Our results lead us to conclude that trout GPx1 transcripts expression level may represent a sensitive biomarker for CHEMICAL intake, helping to evaluate if CHEMICAL concentration and chemical speciation impact on cell homeostasis. | REGULATOR |
| Characterization of cytosolic glutathione peroxidase and GENE genes in rainbow trout (Oncorhynchus mykiss) and their modulation by in vitro CHEMICAL exposure. CHEMICAL (Se) is an oligonutrient with both essential biological functions and recognized harmful effects. As the selenocysteine (SeCys) amino acid, CHEMICAL is integrated in several Se-containing proteins (selenoproteins), many of which are fundamental for cell homeostasis. Nevertheless, CHEMICAL may exert toxic effects at levels marginally above those required, mainly through the generation of reactive oxygen species (ROS). The CHEMICAL chemical speciation can strongly affect the bioavailability of this metal and its impact on metabolism, dictating the levels that can be beneficial or detrimental towards an organism. Glutathione peroxidase (GPxs) is the largest and the most studied selenoprotein family. Cytosolic glutathione peroxidase (cGPx, GPx1) and phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) are widely distributed throughout tissues, and play a pivotal role in regulating the oxidative status in the cell. In this study we have cloned GPx1 and GPx4 genes in rainbow trout (Oncorhynchus mykiss). The constitutive mRNA expression of these GPx genes was examined in 18 trout tissues and their responsiveness to Se availability was analysed using a rainbow trout liver cell line (RTL). An inorganic (sodium selenite, Na2SeO3) and organic (selenocysteine, Cys-Se-Se-Cys) selenocompound have been used as Se sources. GPx1 activity was also tested to verify the impact of transcript changes on the enzymatic function of these molecules. To understand if the results obtained from the transcript expression analysis were due to Se bioavailability or generation of ROS, the cytoxicity of the two selenocompounds was tested by measuring the impact of Se on cell membrane integrity. Lastly, Se availability was quantified by mass spectrophotometry to determine the amount of Se in the cell culture media, the Se background due to the foetal calf serum supplement and the contribution from the two selenocompounds used in the treatments. Three isoforms of genes for both GPx1 (GPx1a, 1b1 and 1b2) and GPx4 (GPx4a1, a2 and b) have been identified. The discovery of a third gene encoding for GPx1 and GPx4 hints that salmonids may have the biggest selenoproteome amongst all vertebrates. Transcripts of GPx4 genes were more highly expressed in most tissues examined in vivo (except blood, head kidney and spleen), whereas those of the GPx1 genes were more responsive to CHEMICAL exposure in vitro, especially to the organic form. Interestingly, GPx1a was the most sensitive to CHEMICAL availability in non stressful conditions, whereas GPx1b1 and GPx1b2 were highly induced by exposure to CHEMICAL levels that had some toxic effects on the cells. Although the different concentrations tested of the two selenocompounds modulate GPx1 transcript expression to various degrees, no significant change of GPx1 enzymatic activity was detectable. Our results lead us to conclude that trout GPx1 transcripts expression level may represent a sensitive biomarker for CHEMICAL intake, helping to evaluate if CHEMICAL concentration and chemical speciation impact on cell homeostasis. | REGULATOR |
| Characterization of cytosolic glutathione peroxidase and phospholipid-hydroperoxide glutathione peroxidase genes in rainbow trout (Oncorhynchus mykiss) and their modulation by in vitro CHEMICAL exposure. CHEMICAL (Se) is an oligonutrient with both essential biological functions and recognized harmful effects. As the selenocysteine (SeCys) amino acid, CHEMICAL is integrated in several Se-containing proteins (selenoproteins), many of which are fundamental for cell homeostasis. Nevertheless, CHEMICAL may exert toxic effects at levels marginally above those required, mainly through the generation of reactive oxygen species (ROS). The CHEMICAL chemical speciation can strongly affect the bioavailability of this metal and its impact on metabolism, dictating the levels that can be beneficial or detrimental towards an organism. Glutathione peroxidase (GPxs) is the largest and the most studied selenoprotein family. Cytosolic glutathione peroxidase (cGPx, GPx1) and phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) are widely distributed throughout tissues, and play a pivotal role in regulating the oxidative status in the cell. In this study we have cloned GPx1 and GPx4 genes in rainbow trout (Oncorhynchus mykiss). The constitutive mRNA expression of these GPx genes was examined in 18 trout tissues and their responsiveness to Se availability was analysed using a rainbow trout liver cell line (RTL). An inorganic (sodium selenite, Na2SeO3) and organic (selenocysteine, Cys-Se-Se-Cys) selenocompound have been used as Se sources. GPx1 activity was also tested to verify the impact of transcript changes on the enzymatic function of these molecules. To understand if the results obtained from the transcript expression analysis were due to Se bioavailability or generation of ROS, the cytoxicity of the two selenocompounds was tested by measuring the impact of Se on cell membrane integrity. Lastly, Se availability was quantified by mass spectrophotometry to determine the amount of Se in the cell culture media, the Se background due to the foetal calf serum supplement and the contribution from the two selenocompounds used in the treatments. Three isoforms of genes for both GPx1 (GPx1a, 1b1 and 1b2) and GPx4 (GPx4a1, a2 and b) have been identified. The discovery of a third gene encoding for GPx1 and GPx4 hints that salmonids may have the biggest selenoproteome amongst all vertebrates. Transcripts of GPx4 genes were more highly expressed in most tissues examined in vivo (except blood, head kidney and spleen), whereas those of the GPx1 genes were more responsive to CHEMICAL exposure in vitro, especially to the organic form. Interestingly, GPx1a was the most sensitive to CHEMICAL availability in non stressful conditions, whereas GENE and GPx1b2 were highly induced by exposure to CHEMICAL levels that had some toxic effects on the cells. Although the different concentrations tested of the two selenocompounds modulate GPx1 transcript expression to various degrees, no significant change of GPx1 enzymatic activity was detectable. Our results lead us to conclude that trout GPx1 transcripts expression level may represent a sensitive biomarker for CHEMICAL intake, helping to evaluate if CHEMICAL concentration and chemical speciation impact on cell homeostasis. | REGULATOR |
| Characterization of cytosolic glutathione peroxidase and phospholipid-hydroperoxide glutathione peroxidase genes in rainbow trout (Oncorhynchus mykiss) and their modulation by in vitro CHEMICAL exposure. CHEMICAL (Se) is an oligonutrient with both essential biological functions and recognized harmful effects. As the selenocysteine (SeCys) amino acid, CHEMICAL is integrated in several Se-containing proteins (selenoproteins), many of which are fundamental for cell homeostasis. Nevertheless, CHEMICAL may exert toxic effects at levels marginally above those required, mainly through the generation of reactive oxygen species (ROS). The CHEMICAL chemical speciation can strongly affect the bioavailability of this metal and its impact on metabolism, dictating the levels that can be beneficial or detrimental towards an organism. Glutathione peroxidase (GPxs) is the largest and the most studied selenoprotein family. Cytosolic glutathione peroxidase (cGPx, GPx1) and phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) are widely distributed throughout tissues, and play a pivotal role in regulating the oxidative status in the cell. In this study we have cloned GPx1 and GPx4 genes in rainbow trout (Oncorhynchus mykiss). The constitutive mRNA expression of these GPx genes was examined in 18 trout tissues and their responsiveness to Se availability was analysed using a rainbow trout liver cell line (RTL). An inorganic (sodium selenite, Na2SeO3) and organic (selenocysteine, Cys-Se-Se-Cys) selenocompound have been used as Se sources. GPx1 activity was also tested to verify the impact of transcript changes on the enzymatic function of these molecules. To understand if the results obtained from the transcript expression analysis were due to Se bioavailability or generation of ROS, the cytoxicity of the two selenocompounds was tested by measuring the impact of Se on cell membrane integrity. Lastly, Se availability was quantified by mass spectrophotometry to determine the amount of Se in the cell culture media, the Se background due to the foetal calf serum supplement and the contribution from the two selenocompounds used in the treatments. Three isoforms of genes for both GPx1 (GPx1a, 1b1 and 1b2) and GPx4 (GPx4a1, a2 and b) have been identified. The discovery of a third gene encoding for GPx1 and GPx4 hints that salmonids may have the biggest selenoproteome amongst all vertebrates. Transcripts of GPx4 genes were more highly expressed in most tissues examined in vivo (except blood, head kidney and spleen), whereas those of the GPx1 genes were more responsive to CHEMICAL exposure in vitro, especially to the organic form. Interestingly, GPx1a was the most sensitive to CHEMICAL availability in non stressful conditions, whereas GPx1b1 and GENE were highly induced by exposure to CHEMICAL levels that had some toxic effects on the cells. Although the different concentrations tested of the two selenocompounds modulate GPx1 transcript expression to various degrees, no significant change of GPx1 enzymatic activity was detectable. Our results lead us to conclude that trout GPx1 transcripts expression level may represent a sensitive biomarker for CHEMICAL intake, helping to evaluate if CHEMICAL concentration and chemical speciation impact on cell homeostasis. | REGULATOR |
| Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by Trolox. While manganese (Mn) is essential for proper central nervous system (CNS) development, excessive CHEMICAL exposure may lead to neurotoxicity. CHEMICAL preferentially accumulates in the basal ganglia, and in adults it may cause Parkinson's disease-like disorder. Compared to adults, younger individuals accumulate greater CHEMICAL levels in the CNS and are more vulnerable to its toxicity. Moreover, the mechanisms mediating developmental Mn-induced neurotoxicity are not completely understood. The present study investigated the developmental neurotoxicity elicited by CHEMICAL exposure (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 to PN27 in rats. Neurochemical analyses were carried out on PN29, with a particular focus on striatal alterations in intracellular signaling pathways (MAPKs, Akt and DARPP-32), oxidative stress generation and cell death. Motor alterations were evaluated later in life at 3, 4 or 5 weeks of age. CHEMICAL exposure (20 mg/kg) increased p38(MAPK) and Akt phosphorylation, but decreased DARPP-32-Thr-34 phosphorylation. CHEMICAL (10 and 20 mg/kg) increased caspase activity and F(2)-isoprostane production (a biological marker of lipid peroxidation). Paralleling the changes in striatal biochemical parameters, CHEMICAL (20 mg/kg) also caused motor impairment, evidenced by increased falling latency in the rotarod test, decreased distance traveled and motor speed in the open-field test. Notably, the antioxidant Trolox™ reversed the CHEMICAL (20 mg/kg)-dependent augmentation in p38(MAPK) phosphorylation and reduced the CHEMICAL (20 mg/kg)-induced caspase activity and F(2)-isoprostane production. Trolox™ also reversed the Mn-induced motor coordination deficits. These findings are the first to show that long-term exposure to CHEMICAL during a critical period of neurodevelopment causes motor coordination dysfunction with parallel increment in oxidative stress markers, GENE(MAPK) phosphorylation and caspase activity in the striatum. Moreover, we establish Trolox™ as a potential neuroprotective agent given its efficacy in reversing the Mn-induced neurodevelopmental effects. | ACTIVATOR |
| Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by Trolox. While manganese (Mn) is essential for proper central nervous system (CNS) development, excessive CHEMICAL exposure may lead to neurotoxicity. CHEMICAL preferentially accumulates in the basal ganglia, and in adults it may cause Parkinson's disease-like disorder. Compared to adults, younger individuals accumulate greater CHEMICAL levels in the CNS and are more vulnerable to its toxicity. Moreover, the mechanisms mediating developmental Mn-induced neurotoxicity are not completely understood. The present study investigated the developmental neurotoxicity elicited by CHEMICAL exposure (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 to PN27 in rats. Neurochemical analyses were carried out on PN29, with a particular focus on striatal alterations in intracellular signaling pathways (MAPKs, Akt and DARPP-32), oxidative stress generation and cell death. Motor alterations were evaluated later in life at 3, 4 or 5 weeks of age. CHEMICAL exposure (20 mg/kg) increased p38(MAPK) and Akt phosphorylation, but decreased DARPP-32-Thr-34 phosphorylation. CHEMICAL (10 and 20 mg/kg) increased caspase activity and F(2)-isoprostane production (a biological marker of lipid peroxidation). Paralleling the changes in striatal biochemical parameters, CHEMICAL (20 mg/kg) also caused motor impairment, evidenced by increased falling latency in the rotarod test, decreased distance traveled and motor speed in the open-field test. Notably, the antioxidant Trolox™ reversed the CHEMICAL (20 mg/kg)-dependent augmentation in p38(MAPK) phosphorylation and reduced the CHEMICAL (20 mg/kg)-induced caspase activity and F(2)-isoprostane production. Trolox™ also reversed the Mn-induced motor coordination deficits. These findings are the first to show that long-term exposure to CHEMICAL during a critical period of neurodevelopment causes motor coordination dysfunction with parallel increment in oxidative stress markers, p38(GENE) phosphorylation and caspase activity in the striatum. Moreover, we establish Trolox™ as a potential neuroprotective agent given its efficacy in reversing the Mn-induced neurodevelopmental effects. | ACTIVATOR |
| Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by Trolox. While manganese (Mn) is essential for proper central nervous system (CNS) development, excessive CHEMICAL exposure may lead to neurotoxicity. CHEMICAL preferentially accumulates in the basal ganglia, and in adults it may cause Parkinson's disease-like disorder. Compared to adults, younger individuals accumulate greater CHEMICAL levels in the CNS and are more vulnerable to its toxicity. Moreover, the mechanisms mediating developmental Mn-induced neurotoxicity are not completely understood. The present study investigated the developmental neurotoxicity elicited by CHEMICAL exposure (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 to PN27 in rats. Neurochemical analyses were carried out on PN29, with a particular focus on striatal alterations in intracellular signaling pathways (MAPKs, Akt and DARPP-32), oxidative stress generation and cell death. Motor alterations were evaluated later in life at 3, 4 or 5 weeks of age. CHEMICAL exposure (20 mg/kg) increased p38(MAPK) and Akt phosphorylation, but decreased DARPP-32-Thr-34 phosphorylation. CHEMICAL (10 and 20 mg/kg) increased GENE activity and F(2)-isoprostane production (a biological marker of lipid peroxidation). Paralleling the changes in striatal biochemical parameters, CHEMICAL (20 mg/kg) also caused motor impairment, evidenced by increased falling latency in the rotarod test, decreased distance traveled and motor speed in the open-field test. Notably, the antioxidant Trolox™ reversed the CHEMICAL (20 mg/kg)-dependent augmentation in p38(MAPK) phosphorylation and reduced the CHEMICAL (20 mg/kg)-induced GENE activity and F(2)-isoprostane production. Trolox™ also reversed the Mn-induced motor coordination deficits. These findings are the first to show that long-term exposure to CHEMICAL during a critical period of neurodevelopment causes motor coordination dysfunction with parallel increment in oxidative stress markers, p38(MAPK) phosphorylation and GENE activity in the striatum. Moreover, we establish Trolox™ as a potential neuroprotective agent given its efficacy in reversing the Mn-induced neurodevelopmental effects. | ACTIVATOR |
| Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by Trolox. While manganese (Mn) is essential for proper central nervous system (CNS) development, excessive CHEMICAL exposure may lead to neurotoxicity. CHEMICAL preferentially accumulates in the basal ganglia, and in adults it may cause Parkinson's disease-like disorder. Compared to adults, younger individuals accumulate greater CHEMICAL levels in the CNS and are more vulnerable to its toxicity. Moreover, the mechanisms mediating developmental Mn-induced neurotoxicity are not completely understood. The present study investigated the developmental neurotoxicity elicited by CHEMICAL exposure (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 to PN27 in rats. Neurochemical analyses were carried out on PN29, with a particular focus on striatal alterations in intracellular signaling pathways (MAPKs, GENE and DARPP-32), oxidative stress generation and cell death. Motor alterations were evaluated later in life at 3, 4 or 5 weeks of age. CHEMICAL exposure (20 mg/kg) increased p38(MAPK) and GENE phosphorylation, but decreased DARPP-32-Thr-34 phosphorylation. CHEMICAL (10 and 20 mg/kg) increased caspase activity and F(2)-isoprostane production (a biological marker of lipid peroxidation). Paralleling the changes in striatal biochemical parameters, CHEMICAL (20 mg/kg) also caused motor impairment, evidenced by increased falling latency in the rotarod test, decreased distance traveled and motor speed in the open-field test. Notably, the antioxidant Trolox™ reversed the CHEMICAL (20 mg/kg)-dependent augmentation in p38(MAPK) phosphorylation and reduced the CHEMICAL (20 mg/kg)-induced caspase activity and F(2)-isoprostane production. Trolox™ also reversed the Mn-induced motor coordination deficits. These findings are the first to show that long-term exposure to CHEMICAL during a critical period of neurodevelopment causes motor coordination dysfunction with parallel increment in oxidative stress markers, p38(MAPK) phosphorylation and caspase activity in the striatum. Moreover, we establish Trolox™ as a potential neuroprotective agent given its efficacy in reversing the Mn-induced neurodevelopmental effects. | GENE-CHEMICAL |
| Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by Trolox. While manganese (Mn) is essential for proper central nervous system (CNS) development, excessive CHEMICAL exposure may lead to neurotoxicity. CHEMICAL preferentially accumulates in the basal ganglia, and in adults it may cause Parkinson's disease-like disorder. Compared to adults, younger individuals accumulate greater CHEMICAL levels in the CNS and are more vulnerable to its toxicity. Moreover, the mechanisms mediating developmental Mn-induced neurotoxicity are not completely understood. The present study investigated the developmental neurotoxicity elicited by CHEMICAL exposure (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 to PN27 in rats. Neurochemical analyses were carried out on PN29, with a particular focus on striatal alterations in intracellular signaling pathways (MAPKs, Akt and DARPP-32), oxidative stress generation and cell death. Motor alterations were evaluated later in life at 3, 4 or 5 weeks of age. CHEMICAL exposure (20 mg/kg) increased p38(MAPK) and Akt phosphorylation, but decreased GENE-Thr-34 phosphorylation. CHEMICAL (10 and 20 mg/kg) increased caspase activity and F(2)-isoprostane production (a biological marker of lipid peroxidation). Paralleling the changes in striatal biochemical parameters, CHEMICAL (20 mg/kg) also caused motor impairment, evidenced by increased falling latency in the rotarod test, decreased distance traveled and motor speed in the open-field test. Notably, the antioxidant Trolox™ reversed the CHEMICAL (20 mg/kg)-dependent augmentation in p38(MAPK) phosphorylation and reduced the CHEMICAL (20 mg/kg)-induced caspase activity and F(2)-isoprostane production. Trolox™ also reversed the Mn-induced motor coordination deficits. These findings are the first to show that long-term exposure to CHEMICAL during a critical period of neurodevelopment causes motor coordination dysfunction with parallel increment in oxidative stress markers, p38(MAPK) phosphorylation and caspase activity in the striatum. Moreover, we establish Trolox™ as a potential neuroprotective agent given its efficacy in reversing the Mn-induced neurodevelopmental effects. | INHIBITOR |
| Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by CHEMICAL. While manganese (Mn) is essential for proper central nervous system (CNS) development, excessive Mn exposure may lead to neurotoxicity. Mn preferentially accumulates in the basal ganglia, and in adults it may cause Parkinson's disease-like disorder. Compared to adults, younger individuals accumulate greater Mn levels in the CNS and are more vulnerable to its toxicity. Moreover, the mechanisms mediating developmental Mn-induced neurotoxicity are not completely understood. The present study investigated the developmental neurotoxicity elicited by Mn exposure (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 to PN27 in rats. Neurochemical analyses were carried out on PN29, with a particular focus on striatal alterations in intracellular signaling pathways (MAPKs, Akt and DARPP-32), oxidative stress generation and cell death. Motor alterations were evaluated later in life at 3, 4 or 5 weeks of age. Mn exposure (20 mg/kg) increased p38(MAPK) and Akt phosphorylation, but decreased DARPP-32-Thr-34 phosphorylation. Mn (10 and 20 mg/kg) increased caspase activity and F(2)-isoprostane production (a biological marker of lipid peroxidation). Paralleling the changes in striatal biochemical parameters, Mn (20 mg/kg) also caused motor impairment, evidenced by increased falling latency in the rotarod test, decreased distance traveled and motor speed in the open-field test. Notably, the antioxidant CHEMICAL™ reversed the Mn (20 mg/kg)-dependent augmentation in GENE(MAPK) phosphorylation and reduced the Mn (20 mg/kg)-induced caspase activity and F(2)-isoprostane production. Trolox™ also reversed the Mn-induced motor coordination deficits. These findings are the first to show that long-term exposure to Mn during a critical period of neurodevelopment causes motor coordination dysfunction with parallel increment in oxidative stress markers, p38(MAPK) phosphorylation and caspase activity in the striatum. Moreover, we establish Trolox™ as a potential neuroprotective agent given its efficacy in reversing the Mn-induced neurodevelopmental effects. | INHIBITOR |
| Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by CHEMICAL. While manganese (Mn) is essential for proper central nervous system (CNS) development, excessive Mn exposure may lead to neurotoxicity. Mn preferentially accumulates in the basal ganglia, and in adults it may cause Parkinson's disease-like disorder. Compared to adults, younger individuals accumulate greater Mn levels in the CNS and are more vulnerable to its toxicity. Moreover, the mechanisms mediating developmental Mn-induced neurotoxicity are not completely understood. The present study investigated the developmental neurotoxicity elicited by Mn exposure (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 to PN27 in rats. Neurochemical analyses were carried out on PN29, with a particular focus on striatal alterations in intracellular signaling pathways (MAPKs, Akt and DARPP-32), oxidative stress generation and cell death. Motor alterations were evaluated later in life at 3, 4 or 5 weeks of age. Mn exposure (20 mg/kg) increased p38(MAPK) and Akt phosphorylation, but decreased DARPP-32-Thr-34 phosphorylation. Mn (10 and 20 mg/kg) increased caspase activity and F(2)-isoprostane production (a biological marker of lipid peroxidation). Paralleling the changes in striatal biochemical parameters, Mn (20 mg/kg) also caused motor impairment, evidenced by increased falling latency in the rotarod test, decreased distance traveled and motor speed in the open-field test. Notably, the antioxidant CHEMICAL™ reversed the Mn (20 mg/kg)-dependent augmentation in p38(GENE) phosphorylation and reduced the Mn (20 mg/kg)-induced caspase activity and F(2)-isoprostane production. Trolox™ also reversed the Mn-induced motor coordination deficits. These findings are the first to show that long-term exposure to Mn during a critical period of neurodevelopment causes motor coordination dysfunction with parallel increment in oxidative stress markers, p38(MAPK) phosphorylation and caspase activity in the striatum. Moreover, we establish Trolox™ as a potential neuroprotective agent given its efficacy in reversing the Mn-induced neurodevelopmental effects. | INHIBITOR |
| Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by CHEMICAL. While manganese (Mn) is essential for proper central nervous system (CNS) development, excessive Mn exposure may lead to neurotoxicity. Mn preferentially accumulates in the basal ganglia, and in adults it may cause Parkinson's disease-like disorder. Compared to adults, younger individuals accumulate greater Mn levels in the CNS and are more vulnerable to its toxicity. Moreover, the mechanisms mediating developmental Mn-induced neurotoxicity are not completely understood. The present study investigated the developmental neurotoxicity elicited by Mn exposure (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 to PN27 in rats. Neurochemical analyses were carried out on PN29, with a particular focus on striatal alterations in intracellular signaling pathways (MAPKs, Akt and DARPP-32), oxidative stress generation and cell death. Motor alterations were evaluated later in life at 3, 4 or 5 weeks of age. Mn exposure (20 mg/kg) increased p38(MAPK) and Akt phosphorylation, but decreased DARPP-32-Thr-34 phosphorylation. Mn (10 and 20 mg/kg) increased GENE activity and F(2)-isoprostane production (a biological marker of lipid peroxidation). Paralleling the changes in striatal biochemical parameters, Mn (20 mg/kg) also caused motor impairment, evidenced by increased falling latency in the rotarod test, decreased distance traveled and motor speed in the open-field test. Notably, the antioxidant CHEMICAL™ reversed the Mn (20 mg/kg)-dependent augmentation in p38(MAPK) phosphorylation and reduced the Mn (20 mg/kg)-induced GENE activity and F(2)-isoprostane production. Trolox™ also reversed the Mn-induced motor coordination deficits. These findings are the first to show that long-term exposure to Mn during a critical period of neurodevelopment causes motor coordination dysfunction with parallel increment in oxidative stress markers, p38(MAPK) phosphorylation and GENE activity in the striatum. Moreover, we establish Trolox™ as a potential neuroprotective agent given its efficacy in reversing the Mn-induced neurodevelopmental effects. | INHIBITOR |
| Nocapyrones H-J, 3,6-Disubstituted α-Pyrones from the Marine Actinomycete Nocardiopsis sp. KMF-001. Three new 3,6-disubstituted α-pyrones, nocapyrones H-J (1-3), were isolated from the marine actinomycete Nocardiopsis sp. KMF-001. Their structures were assigned to be 3-alkylated 6-(1-methyl-1-propenyl)-2H-pyran-2-ones on the basis of UV, MS, NMR, and high resolution (HR)-FAB-MS analyses. CHEMICAL (1) reduced the pro-inflammatory factor such as nitric oxide (NO), prostaglandin E2 (PGE2) and GENE (IL-1β). Moreover, nocapyrone H showed 5.82% stronger inhibitory effect on NO production than chrysin at a concentration of 10 µm in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. | INDIRECT-DOWNREGULATOR |
| Nocapyrones H-J, 3,6-Disubstituted α-Pyrones from the Marine Actinomycete Nocardiopsis sp. KMF-001. Three new 3,6-disubstituted α-pyrones, nocapyrones H-J (1-3), were isolated from the marine actinomycete Nocardiopsis sp. KMF-001. Their structures were assigned to be 3-alkylated 6-(1-methyl-1-propenyl)-2H-pyran-2-ones on the basis of UV, MS, NMR, and high resolution (HR)-FAB-MS analyses. CHEMICAL (1) reduced the pro-inflammatory factor such as nitric oxide (NO), prostaglandin E2 (PGE2) and interleukin-1β (GENE). Moreover, nocapyrone H showed 5.82% stronger inhibitory effect on NO production than chrysin at a concentration of 10 µm in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. | INDIRECT-DOWNREGULATOR |
| Investigating the enteroenteric recirculation of CHEMICAL, a GENE inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats. The study described here investigated the impact of intestinal excretion (IE; excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on CHEMICAL pharmacokinetics and disposition. The experimental approaches involve integrating CHEMICAL elimination pathways with pharmacokinetic profiles obtained from bile duct-cannulated (BDC) rats and dogs receiving i.v. doses together with oral administration of activated charcoal (AC). Additionally, the role of P-gp (P-glycoprotein; abcb1) and BCRP (breast cancer resistance protein; abcg2) in CHEMICAL disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats. Approximately 20-50% of an CHEMICAL i.v. dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC). The fecal elimination, IC, and systemic clearance of CHEMICAL were increased upon AC administration in both BDC rats and dogs and were decreased in BDC rats dosed with GF-120918, a dual BCRP and P-gp inhibitor). BCRP appeared to play a more important role for absorption and intestinal and renal elimination of CHEMICAL than P-gp in transporter-KO rats after oral and i.v. dosing, which led to a higher level of active renal excretion in rat than other species. These data demonstrate that CHEMICAL undergoes IE, EER, and RTR that are facilitated by efflux transporters. Intestinal reabsorption of CHEMICAL could be interrupted by AC even at 3 hours post-drug dose in dogs (late charcoal effect). This study demonstrates that the intestine is an organ for direct clearance and redistribution of CHEMICAL. The IE, EER, and RTR contribute to overall pharmacokinetic profiles of CHEMICAL. IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on CHEMICAL disposition. | INHIBITOR |
| Investigating the enteroenteric recirculation of apixaban, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats. The study described here investigated the impact of intestinal excretion (IE; excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on apixaban pharmacokinetics and disposition. The experimental approaches involve integrating apixaban elimination pathways with pharmacokinetic profiles obtained from bile duct-cannulated (BDC) rats and dogs receiving i.v. doses together with oral administration of activated charcoal (AC). Additionally, the role of P-gp (P-glycoprotein; abcb1) and GENE (breast cancer resistance protein; abcg2) in apixaban disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats. Approximately 20-50% of an apixaban i.v. dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC). The fecal elimination, IC, and systemic clearance of apixaban were increased upon AC administration in both BDC rats and dogs and were decreased in BDC rats dosed with CHEMICAL, a dual GENE and P-gp inhibitor). GENE appeared to play a more important role for absorption and intestinal and renal elimination of apixaban than P-gp in transporter-KO rats after oral and i.v. dosing, which led to a higher level of active renal excretion in rat than other species. These data demonstrate that apixaban undergoes IE, EER, and RTR that are facilitated by efflux transporters. Intestinal reabsorption of apixaban could be interrupted by AC even at 3 hours post-drug dose in dogs (late charcoal effect). This study demonstrates that the intestine is an organ for direct clearance and redistribution of apixaban. The IE, EER, and RTR contribute to overall pharmacokinetic profiles of apixaban. IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on apixaban disposition. | INHIBITOR |
| Investigating the enteroenteric recirculation of apixaban, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats. The study described here investigated the impact of intestinal excretion (IE; excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on apixaban pharmacokinetics and disposition. The experimental approaches involve integrating apixaban elimination pathways with pharmacokinetic profiles obtained from bile duct-cannulated (BDC) rats and dogs receiving i.v. doses together with oral administration of activated charcoal (AC). Additionally, the role of GENE (P-glycoprotein; abcb1) and BCRP (breast cancer resistance protein; abcg2) in apixaban disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats. Approximately 20-50% of an apixaban i.v. dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC). The fecal elimination, IC, and systemic clearance of apixaban were increased upon AC administration in both BDC rats and dogs and were decreased in BDC rats dosed with CHEMICAL, a dual BCRP and GENE inhibitor). BCRP appeared to play a more important role for absorption and intestinal and renal elimination of apixaban than GENE in transporter-KO rats after oral and i.v. dosing, which led to a higher level of active renal excretion in rat than other species. These data demonstrate that apixaban undergoes IE, EER, and RTR that are facilitated by efflux transporters. Intestinal reabsorption of apixaban could be interrupted by AC even at 3 hours post-drug dose in dogs (late charcoal effect). This study demonstrates that the intestine is an organ for direct clearance and redistribution of apixaban. The IE, EER, and RTR contribute to overall pharmacokinetic profiles of apixaban. IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on apixaban disposition. | INHIBITOR |
| Investigating the enteroenteric recirculation of CHEMICAL, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats. The study described here investigated the impact of intestinal excretion (IE; excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on CHEMICAL pharmacokinetics and disposition. The experimental approaches involve integrating CHEMICAL elimination pathways with pharmacokinetic profiles obtained from bile duct-cannulated (BDC) rats and dogs receiving i.v. doses together with oral administration of activated charcoal (AC). Additionally, the role of P-gp (P-glycoprotein; abcb1) and GENE (breast cancer resistance protein; abcg2) in CHEMICAL disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats. Approximately 20-50% of an CHEMICAL i.v. dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC). The fecal elimination, IC, and systemic clearance of CHEMICAL were increased upon AC administration in both BDC rats and dogs and were decreased in BDC rats dosed with GF-120918, a dual GENE and P-gp inhibitor). GENE appeared to play a more important role for absorption and intestinal and renal elimination of CHEMICAL than P-gp in transporter-KO rats after oral and i.v. dosing, which led to a higher level of active renal excretion in rat than other species. These data demonstrate that CHEMICAL undergoes IE, EER, and RTR that are facilitated by efflux transporters. Intestinal reabsorption of CHEMICAL could be interrupted by AC even at 3 hours post-drug dose in dogs (late charcoal effect). This study demonstrates that the intestine is an organ for direct clearance and redistribution of CHEMICAL. The IE, EER, and RTR contribute to overall pharmacokinetic profiles of CHEMICAL. IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on CHEMICAL disposition. | SUBSTRATE |
| Investigating the enteroenteric recirculation of CHEMICAL, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats. The study described here investigated the impact of intestinal excretion (IE; excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on CHEMICAL pharmacokinetics and disposition. The experimental approaches involve integrating CHEMICAL elimination pathways with pharmacokinetic profiles obtained from bile duct-cannulated (BDC) rats and dogs receiving i.v. doses together with oral administration of activated charcoal (AC). Additionally, the role of GENE (P-glycoprotein; abcb1) and BCRP (breast cancer resistance protein; abcg2) in CHEMICAL disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats. Approximately 20-50% of an CHEMICAL i.v. dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC). The fecal elimination, IC, and systemic clearance of CHEMICAL were increased upon AC administration in both BDC rats and dogs and were decreased in BDC rats dosed with GF-120918, a dual BCRP and GENE inhibitor). BCRP appeared to play a more important role for absorption and intestinal and renal elimination of CHEMICAL than GENE in transporter-KO rats after oral and i.v. dosing, which led to a higher level of active renal excretion in rat than other species. These data demonstrate that CHEMICAL undergoes IE, EER, and RTR that are facilitated by efflux transporters. Intestinal reabsorption of CHEMICAL could be interrupted by AC even at 3 hours post-drug dose in dogs (late charcoal effect). This study demonstrates that the intestine is an organ for direct clearance and redistribution of CHEMICAL. The IE, EER, and RTR contribute to overall pharmacokinetic profiles of CHEMICAL. IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on CHEMICAL disposition. | SUBSTRATE |
| Cloning, Characterization, and Sulfonamide and Thiol Inhibition Studies of an α-Carbonic Anhydrase from Trypanosoma cruzi, the Causative Agent of Chagas Disease. An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO(2) hydration reaction, being similar kinetically to the human (h) isoform GENE, although it is devoid of the CHEMICAL64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo. | PART-OF |
| Cloning, Characterization, and Sulfonamide and Thiol Inhibition Studies of an α-Carbonic Anhydrase from Trypanosoma cruzi, the Causative Agent of Chagas Disease. An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO(2) hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of CHEMICAL and some 5-mercapto-1,3,4-thiadiazoles were investigated as GENE inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo. | INHIBITOR |
| Cloning, Characterization, and Sulfonamide and Thiol Inhibition Studies of an α-Carbonic Anhydrase from Trypanosoma cruzi, the Causative Agent of Chagas Disease. An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO(2) hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some CHEMICAL were investigated as GENE inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo. | INHIBITOR |
| Cloning, Characterization, and CHEMICAL and Thiol Inhibition Studies of an GENE from Trypanosoma cruzi, the Causative Agent of Chagas Disease. An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO(2) hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo. | INHIBITOR |
| Cloning, Characterization, and Sulfonamide and CHEMICAL Inhibition Studies of an GENE from Trypanosoma cruzi, the Causative Agent of Chagas Disease. An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO(2) hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo. | INHIBITOR |
| Cloning, Characterization, and Sulfonamide and Thiol Inhibition Studies of an α-Carbonic Anhydrase from Trypanosoma cruzi, the Causative Agent of Chagas Disease. An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CHEMICAL hydration reaction, being similar kinetically to the human (h) isoform GENE, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo. | GENE-CHEMICAL |
| Cloning, Characterization, and Sulfonamide and Thiol Inhibition Studies of an α-Carbonic Anhydrase from Trypanosoma cruzi, the Causative Agent of Chagas Disease. An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (GENE) has a very high catalytic activity for the CHEMICAL hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as GENE inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo. | GENE-CHEMICAL |
| The increased number of Leydig cells by di(2-ethylhexyl) phthalate comes from the differentiation of stem cells into Leydig cell lineage in the adult rat testis. The objective of the present study is to determine whether di(2-ethylhexyl) phthalate (DEHP) exposure at adulthood increases rat Leydig cell number and to investigate the possible mechanism. 90-day-old Long-Evans rats were randomly divided into 3 groups, and were gavaged with the corn oil (control) or 10 or 750mg/kg CHEMICAL daily for 7 days, and then received an intraperitoneal injection of 75mg/kg ethane dimethanesulfonate (EDS) to eliminate Leydig cells. Serum testosterone concentrations were assessed by RIA, and the mRNA levels of Leydig cell genes were measured by qPCR. EDS eliminated all Leydig cells in the control testis on day 4 post-EDS, as judged by undetectable serum testosterone level and no 3β-hydroxysteroid dehydrogenase positive (3β-HSD(pos)) cells in the interstitium. However, in DEHP-treated groups, there were detectable serum testosterone concentrations and some oval-shaped 3β-HSD(pos) cells in the interstitium. These 3β-HSD(pos) cells were not stained by the antibody against 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a marker for Leydig cells at a more advanced stage. The disappearance of mRNAs of Leydig cell biomarkers including Lhcgr, Cyp11a1, Cyp17a1, GENE and Hsd11b1 in the control testis was observed on day 4 post-EDS. However, there were detectable concentrations of Lhcgr, Cyp11a1 and Cyp17a1 mRNAs but undetectable concentrations of GENE, Hsd17b3 and Hsd11b1 in the CHEMICAL-treated testes, indicating that these 3β-HSD(pos) cells were newly formed progenitor Leydig cells. The mRNA level for nestin (Nes, biomarker for stem Leydig cells) was significantly increased in the control testis on day 4 post-EDS, but not in the CHEMICAL treated testes, suggesting that these nestin positive stem cells were differentiated into progenitor Leydig cells in the DEHP-treated testes. The present study suggests that CHEMICAL increases the differentiation of stem cells into progenitor Leydig cells. | NO-RELATIONSHIP |
| The increased number of Leydig cells by di(2-ethylhexyl) phthalate comes from the differentiation of stem cells into Leydig cell lineage in the adult rat testis. The objective of the present study is to determine whether di(2-ethylhexyl) phthalate (DEHP) exposure at adulthood increases rat Leydig cell number and to investigate the possible mechanism. 90-day-old Long-Evans rats were randomly divided into 3 groups, and were gavaged with the corn oil (control) or 10 or 750mg/kg CHEMICAL daily for 7 days, and then received an intraperitoneal injection of 75mg/kg ethane dimethanesulfonate (EDS) to eliminate Leydig cells. Serum testosterone concentrations were assessed by RIA, and the mRNA levels of Leydig cell genes were measured by qPCR. EDS eliminated all Leydig cells in the control testis on day 4 post-EDS, as judged by undetectable serum testosterone level and no 3β-hydroxysteroid dehydrogenase positive (3β-HSD(pos)) cells in the interstitium. However, in DEHP-treated groups, there were detectable serum testosterone concentrations and some oval-shaped 3β-HSD(pos) cells in the interstitium. These 3β-HSD(pos) cells were not stained by the antibody against 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a marker for Leydig cells at a more advanced stage. The disappearance of mRNAs of Leydig cell biomarkers including Lhcgr, Cyp11a1, Cyp17a1, Insl3 and Hsd11b1 in the control testis was observed on day 4 post-EDS. However, there were detectable concentrations of Lhcgr, Cyp11a1 and Cyp17a1 mRNAs but undetectable concentrations of Insl3, GENE and Hsd11b1 in the CHEMICAL-treated testes, indicating that these 3β-HSD(pos) cells were newly formed progenitor Leydig cells. The mRNA level for nestin (Nes, biomarker for stem Leydig cells) was significantly increased in the control testis on day 4 post-EDS, but not in the CHEMICAL treated testes, suggesting that these nestin positive stem cells were differentiated into progenitor Leydig cells in the DEHP-treated testes. The present study suggests that CHEMICAL increases the differentiation of stem cells into progenitor Leydig cells. | NO-RELATIONSHIP |
| The increased number of Leydig cells by di(2-ethylhexyl) phthalate comes from the differentiation of stem cells into Leydig cell lineage in the adult rat testis. The objective of the present study is to determine whether di(2-ethylhexyl) phthalate (DEHP) exposure at adulthood increases rat Leydig cell number and to investigate the possible mechanism. 90-day-old Long-Evans rats were randomly divided into 3 groups, and were gavaged with the corn oil (control) or 10 or 750mg/kg CHEMICAL daily for 7 days, and then received an intraperitoneal injection of 75mg/kg ethane dimethanesulfonate (EDS) to eliminate Leydig cells. Serum testosterone concentrations were assessed by RIA, and the mRNA levels of Leydig cell genes were measured by qPCR. EDS eliminated all Leydig cells in the control testis on day 4 post-EDS, as judged by undetectable serum testosterone level and no 3β-hydroxysteroid dehydrogenase positive (3β-HSD(pos)) cells in the interstitium. However, in DEHP-treated groups, there were detectable serum testosterone concentrations and some oval-shaped 3β-HSD(pos) cells in the interstitium. These 3β-HSD(pos) cells were not stained by the antibody against 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a marker for Leydig cells at a more advanced stage. The disappearance of mRNAs of Leydig cell biomarkers including Lhcgr, Cyp11a1, Cyp17a1, Insl3 and GENE in the control testis was observed on day 4 post-EDS. However, there were detectable concentrations of Lhcgr, Cyp11a1 and Cyp17a1 mRNAs but undetectable concentrations of Insl3, Hsd17b3 and GENE in the CHEMICAL-treated testes, indicating that these 3β-HSD(pos) cells were newly formed progenitor Leydig cells. The mRNA level for nestin (Nes, biomarker for stem Leydig cells) was significantly increased in the control testis on day 4 post-EDS, but not in the CHEMICAL treated testes, suggesting that these nestin positive stem cells were differentiated into progenitor Leydig cells in the DEHP-treated testes. The present study suggests that CHEMICAL increases the differentiation of stem cells into progenitor Leydig cells. | INDIRECT-DOWNREGULATOR |
| The increased number of Leydig cells by di(2-ethylhexyl) phthalate comes from the differentiation of stem cells into Leydig cell lineage in the adult rat testis. The objective of the present study is to determine whether di(2-ethylhexyl) phthalate (DEHP) exposure at adulthood increases rat Leydig cell number and to investigate the possible mechanism. 90-day-old Long-Evans rats were randomly divided into 3 groups, and were gavaged with the corn oil (control) or 10 or 750mg/kg CHEMICAL daily for 7 days, and then received an intraperitoneal injection of 75mg/kg ethane dimethanesulfonate (EDS) to eliminate Leydig cells. Serum testosterone concentrations were assessed by RIA, and the mRNA levels of Leydig cell genes were measured by qPCR. EDS eliminated all Leydig cells in the control testis on day 4 post-EDS, as judged by undetectable serum testosterone level and no 3β-hydroxysteroid dehydrogenase positive (3β-HSD(pos)) cells in the interstitium. However, in DEHP-treated groups, there were detectable serum testosterone concentrations and some oval-shaped 3β-HSD(pos) cells in the interstitium. These 3β-HSD(pos) cells were not stained by the antibody against 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a marker for Leydig cells at a more advanced stage. The disappearance of mRNAs of Leydig cell biomarkers including Lhcgr, Cyp11a1, Cyp17a1, Insl3 and Hsd11b1 in the control testis was observed on day 4 post-EDS. However, there were detectable concentrations of Lhcgr, Cyp11a1 and Cyp17a1 mRNAs but undetectable concentrations of Insl3, Hsd17b3 and Hsd11b1 in the DEHP-treated testes, indicating that these 3β-HSD(pos) cells were newly formed progenitor Leydig cells. The mRNA level for GENE (Nes, biomarker for stem Leydig cells) was significantly increased in the control testis on day 4 post-EDS, but not in the CHEMICAL treated testes, suggesting that these GENE positive stem cells were differentiated into progenitor Leydig cells in the DEHP-treated testes. The present study suggests that CHEMICAL increases the differentiation of stem cells into progenitor Leydig cells. | NO-RELATIONSHIP |
| The increased number of Leydig cells by di(2-ethylhexyl) phthalate comes from the differentiation of stem cells into Leydig cell lineage in the adult rat testis. The objective of the present study is to determine whether di(2-ethylhexyl) phthalate (DEHP) exposure at adulthood increases rat Leydig cell number and to investigate the possible mechanism. 90-day-old Long-Evans rats were randomly divided into 3 groups, and were gavaged with the corn oil (control) or 10 or 750mg/kg CHEMICAL daily for 7 days, and then received an intraperitoneal injection of 75mg/kg ethane dimethanesulfonate (EDS) to eliminate Leydig cells. Serum testosterone concentrations were assessed by RIA, and the mRNA levels of Leydig cell genes were measured by qPCR. EDS eliminated all Leydig cells in the control testis on day 4 post-EDS, as judged by undetectable serum testosterone level and no 3β-hydroxysteroid dehydrogenase positive (3β-HSD(pos)) cells in the interstitium. However, in DEHP-treated groups, there were detectable serum testosterone concentrations and some oval-shaped 3β-HSD(pos) cells in the interstitium. These 3β-HSD(pos) cells were not stained by the antibody against 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a marker for Leydig cells at a more advanced stage. The disappearance of mRNAs of Leydig cell biomarkers including Lhcgr, Cyp11a1, Cyp17a1, Insl3 and Hsd11b1 in the control testis was observed on day 4 post-EDS. However, there were detectable concentrations of Lhcgr, Cyp11a1 and Cyp17a1 mRNAs but undetectable concentrations of Insl3, Hsd17b3 and Hsd11b1 in the DEHP-treated testes, indicating that these 3β-HSD(pos) cells were newly formed progenitor Leydig cells. The mRNA level for nestin (GENE, biomarker for stem Leydig cells) was significantly increased in the control testis on day 4 post-EDS, but not in the CHEMICAL treated testes, suggesting that these nestin positive stem cells were differentiated into progenitor Leydig cells in the DEHP-treated testes. The present study suggests that CHEMICAL increases the differentiation of stem cells into progenitor Leydig cells. | NO-RELATIONSHIP |
| The increased number of Leydig cells by di(2-ethylhexyl) phthalate comes from the differentiation of stem cells into Leydig cell lineage in the adult rat testis. The objective of the present study is to determine whether di(2-ethylhexyl) phthalate (DEHP) exposure at adulthood increases rat Leydig cell number and to investigate the possible mechanism. 90-day-old Long-Evans rats were randomly divided into 3 groups, and were gavaged with the corn oil (control) or 10 or 750mg/kg CHEMICAL daily for 7 days, and then received an intraperitoneal injection of 75mg/kg ethane dimethanesulfonate (EDS) to eliminate Leydig cells. Serum testosterone concentrations were assessed by RIA, and the mRNA levels of Leydig cell genes were measured by qPCR. EDS eliminated all Leydig cells in the control testis on day 4 post-EDS, as judged by undetectable serum testosterone level and no 3β-hydroxysteroid dehydrogenase positive (3β-HSD(pos)) cells in the interstitium. However, in DEHP-treated groups, there were detectable serum testosterone concentrations and some oval-shaped 3β-HSD(pos) cells in the interstitium. These 3β-HSD(pos) cells were not stained by the antibody against 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a marker for Leydig cells at a more advanced stage. The disappearance of mRNAs of Leydig cell biomarkers including GENE, Cyp11a1, Cyp17a1, Insl3 and Hsd11b1 in the control testis was observed on day 4 post-EDS. However, there were detectable concentrations of GENE, Cyp11a1 and Cyp17a1 mRNAs but undetectable concentrations of Insl3, Hsd17b3 and Hsd11b1 in the CHEMICAL-treated testes, indicating that these 3β-HSD(pos) cells were newly formed progenitor Leydig cells. The mRNA level for nestin (Nes, biomarker for stem Leydig cells) was significantly increased in the control testis on day 4 post-EDS, but not in the CHEMICAL treated testes, suggesting that these nestin positive stem cells were differentiated into progenitor Leydig cells in the DEHP-treated testes. The present study suggests that CHEMICAL increases the differentiation of stem cells into progenitor Leydig cells. | INDIRECT-DOWNREGULATOR |
| The increased number of Leydig cells by di(2-ethylhexyl) phthalate comes from the differentiation of stem cells into Leydig cell lineage in the adult rat testis. The objective of the present study is to determine whether di(2-ethylhexyl) phthalate (DEHP) exposure at adulthood increases rat Leydig cell number and to investigate the possible mechanism. 90-day-old Long-Evans rats were randomly divided into 3 groups, and were gavaged with the corn oil (control) or 10 or 750mg/kg CHEMICAL daily for 7 days, and then received an intraperitoneal injection of 75mg/kg ethane dimethanesulfonate (EDS) to eliminate Leydig cells. Serum testosterone concentrations were assessed by RIA, and the mRNA levels of Leydig cell genes were measured by qPCR. EDS eliminated all Leydig cells in the control testis on day 4 post-EDS, as judged by undetectable serum testosterone level and no 3β-hydroxysteroid dehydrogenase positive (3β-HSD(pos)) cells in the interstitium. However, in DEHP-treated groups, there were detectable serum testosterone concentrations and some oval-shaped 3β-HSD(pos) cells in the interstitium. These 3β-HSD(pos) cells were not stained by the antibody against 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a marker for Leydig cells at a more advanced stage. The disappearance of mRNAs of Leydig cell biomarkers including Lhcgr, GENE, Cyp17a1, Insl3 and Hsd11b1 in the control testis was observed on day 4 post-EDS. However, there were detectable concentrations of Lhcgr, GENE and Cyp17a1 mRNAs but undetectable concentrations of Insl3, Hsd17b3 and Hsd11b1 in the CHEMICAL-treated testes, indicating that these 3β-HSD(pos) cells were newly formed progenitor Leydig cells. The mRNA level for nestin (Nes, biomarker for stem Leydig cells) was significantly increased in the control testis on day 4 post-EDS, but not in the CHEMICAL treated testes, suggesting that these nestin positive stem cells were differentiated into progenitor Leydig cells in the DEHP-treated testes. The present study suggests that CHEMICAL increases the differentiation of stem cells into progenitor Leydig cells. | INDIRECT-DOWNREGULATOR |
| The increased number of Leydig cells by di(2-ethylhexyl) phthalate comes from the differentiation of stem cells into Leydig cell lineage in the adult rat testis. The objective of the present study is to determine whether di(2-ethylhexyl) phthalate (DEHP) exposure at adulthood increases rat Leydig cell number and to investigate the possible mechanism. 90-day-old Long-Evans rats were randomly divided into 3 groups, and were gavaged with the corn oil (control) or 10 or 750mg/kg CHEMICAL daily for 7 days, and then received an intraperitoneal injection of 75mg/kg ethane dimethanesulfonate (EDS) to eliminate Leydig cells. Serum testosterone concentrations were assessed by RIA, and the mRNA levels of Leydig cell genes were measured by qPCR. EDS eliminated all Leydig cells in the control testis on day 4 post-EDS, as judged by undetectable serum testosterone level and no 3β-hydroxysteroid dehydrogenase positive (3β-HSD(pos)) cells in the interstitium. However, in DEHP-treated groups, there were detectable serum testosterone concentrations and some oval-shaped 3β-HSD(pos) cells in the interstitium. These 3β-HSD(pos) cells were not stained by the antibody against 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a marker for Leydig cells at a more advanced stage. The disappearance of mRNAs of Leydig cell biomarkers including Lhcgr, Cyp11a1, GENE, Insl3 and Hsd11b1 in the control testis was observed on day 4 post-EDS. However, there were detectable concentrations of Lhcgr, Cyp11a1 and GENE mRNAs but undetectable concentrations of Insl3, Hsd17b3 and Hsd11b1 in the CHEMICAL-treated testes, indicating that these 3β-HSD(pos) cells were newly formed progenitor Leydig cells. The mRNA level for nestin (Nes, biomarker for stem Leydig cells) was significantly increased in the control testis on day 4 post-EDS, but not in the CHEMICAL treated testes, suggesting that these nestin positive stem cells were differentiated into progenitor Leydig cells in the DEHP-treated testes. The present study suggests that CHEMICAL increases the differentiation of stem cells into progenitor Leydig cells. | INDIRECT-DOWNREGULATOR |
| The increased number of Leydig cells by di(2-ethylhexyl) phthalate comes from the differentiation of stem cells into Leydig cell lineage in the adult rat testis. The objective of the present study is to determine whether di(2-ethylhexyl) phthalate (DEHP) exposure at adulthood increases rat Leydig cell number and to investigate the possible mechanism. 90-day-old Long-Evans rats were randomly divided into 3 groups, and were gavaged with the corn oil (control) or 10 or 750mg/kg DEHP daily for 7 days, and then received an intraperitoneal injection of 75mg/kg ethane dimethanesulfonate (EDS) to eliminate Leydig cells. Serum testosterone concentrations were assessed by RIA, and the mRNA levels of Leydig cell genes were measured by qPCR. CHEMICAL eliminated all Leydig cells in the control testis on day 4 post-EDS, as judged by undetectable serum testosterone level and no 3β-hydroxysteroid dehydrogenase positive (3β-HSD(pos)) cells in the interstitium. However, in DEHP-treated groups, there were detectable serum testosterone concentrations and some oval-shaped 3β-HSD(pos) cells in the interstitium. These 3β-HSD(pos) cells were not stained by the antibody against 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a marker for Leydig cells at a more advanced stage. The disappearance of mRNAs of Leydig cell biomarkers including Lhcgr, Cyp11a1, Cyp17a1, Insl3 and Hsd11b1 in the control testis was observed on day 4 post-EDS. However, there were detectable concentrations of Lhcgr, Cyp11a1 and Cyp17a1 mRNAs but undetectable concentrations of Insl3, Hsd17b3 and Hsd11b1 in the DEHP-treated testes, indicating that these 3β-HSD(pos) cells were newly formed progenitor Leydig cells. The mRNA level for GENE (Nes, biomarker for stem Leydig cells) was significantly increased in the control testis on day 4 post-CHEMICAL, but not in the DEHP treated testes, suggesting that these GENE positive stem cells were differentiated into progenitor Leydig cells in the DEHP-treated testes. The present study suggests that DEHP increases the differentiation of stem cells into progenitor Leydig cells. | INDIRECT-UPREGULATOR |
| The increased number of Leydig cells by di(2-ethylhexyl) phthalate comes from the differentiation of stem cells into Leydig cell lineage in the adult rat testis. The objective of the present study is to determine whether di(2-ethylhexyl) phthalate (DEHP) exposure at adulthood increases rat Leydig cell number and to investigate the possible mechanism. 90-day-old Long-Evans rats were randomly divided into 3 groups, and were gavaged with the corn oil (control) or 10 or 750mg/kg DEHP daily for 7 days, and then received an intraperitoneal injection of 75mg/kg ethane dimethanesulfonate (EDS) to eliminate Leydig cells. Serum testosterone concentrations were assessed by RIA, and the mRNA levels of Leydig cell genes were measured by qPCR. CHEMICAL eliminated all Leydig cells in the control testis on day 4 post-EDS, as judged by undetectable serum testosterone level and no 3β-hydroxysteroid dehydrogenase positive (3β-HSD(pos)) cells in the interstitium. However, in DEHP-treated groups, there were detectable serum testosterone concentrations and some oval-shaped 3β-HSD(pos) cells in the interstitium. These 3β-HSD(pos) cells were not stained by the antibody against 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a marker for Leydig cells at a more advanced stage. The disappearance of mRNAs of Leydig cell biomarkers including Lhcgr, Cyp11a1, Cyp17a1, Insl3 and Hsd11b1 in the control testis was observed on day 4 post-EDS. However, there were detectable concentrations of Lhcgr, Cyp11a1 and Cyp17a1 mRNAs but undetectable concentrations of Insl3, Hsd17b3 and Hsd11b1 in the DEHP-treated testes, indicating that these 3β-HSD(pos) cells were newly formed progenitor Leydig cells. The mRNA level for nestin (GENE, biomarker for stem Leydig cells) was significantly increased in the control testis on day 4 post-CHEMICAL, but not in the DEHP treated testes, suggesting that these nestin positive stem cells were differentiated into progenitor Leydig cells in the DEHP-treated testes. The present study suggests that DEHP increases the differentiation of stem cells into progenitor Leydig cells. | INDIRECT-UPREGULATOR |
| CHEMICAL pulse frequency-dependent stimulation of FSHβ transcription is mediated via activation of PKA and CREB. Expression of pituitary GENE and LH, under the control of pulsatile CHEMICAL, is essential for fertility. cAMP response element-binding protein (CREB) has been implicated in the regulation of FSHβ gene expression, but the molecular mechanisms by which pulsatile CHEMICAL regulates CREB activation remain poorly understood. We hypothesized that CREB is activated by a distinct signaling pathway in response to pulsatile CHEMICAL in a frequency-dependent manner to dictate the FSHβ transcriptional response. CHEMICAL stimulation of CREB phosphorylation (pCREB) in the gonadotrope-derived LβT2 cell line was attenuated by a protein kinase A (PKA) inhibitor, H89. A dominant negative PKA (DNPKA) reduced GnRH-stimulated pCREB and markedly decreased CHEMICAL stimulation of FSHβ mRNA and FSHβLUC activity, but had little effect on LHβLUC activity, indicating relative specificity of this pathway. In perifusion studies, FSHβ mRNA levels and FSHβLUC activities were increased by pulsatile CHEMICAL, with significantly greater increases at low compared with high pulse frequencies. DNPKA markedly reduced these GnRH-stimulated FSHβ responses at both low and high pulse frequencies. Correlating with FSHβ activation, both PKA activity and levels of pCREB were increased to a greater extent by low compared with high CHEMICAL pulse frequencies, and the induction of pCREB was also attenuated by overexpression of DNPKA at both low and high pulse frequencies. Taken together, these data indicate that a PKA-mediated signaling pathway mediates CHEMICAL activation of CREB at low-pulse frequencies, playing a significant role in the decoding of the hypothalamic CHEMICAL signal to result in frequency-dependent FSHβ activation. | GENE-CHEMICAL |
| CHEMICAL pulse frequency-dependent stimulation of FSHβ transcription is mediated via activation of PKA and CREB. Expression of pituitary FSH and GENE, under the control of pulsatile CHEMICAL, is essential for fertility. cAMP response element-binding protein (CREB) has been implicated in the regulation of FSHβ gene expression, but the molecular mechanisms by which pulsatile CHEMICAL regulates CREB activation remain poorly understood. We hypothesized that CREB is activated by a distinct signaling pathway in response to pulsatile CHEMICAL in a frequency-dependent manner to dictate the FSHβ transcriptional response. CHEMICAL stimulation of CREB phosphorylation (pCREB) in the gonadotrope-derived LβT2 cell line was attenuated by a protein kinase A (PKA) inhibitor, H89. A dominant negative PKA (DNPKA) reduced GnRH-stimulated pCREB and markedly decreased CHEMICAL stimulation of FSHβ mRNA and FSHβLUC activity, but had little effect on LHβLUC activity, indicating relative specificity of this pathway. In perifusion studies, FSHβ mRNA levels and FSHβLUC activities were increased by pulsatile CHEMICAL, with significantly greater increases at low compared with high pulse frequencies. DNPKA markedly reduced these GnRH-stimulated FSHβ responses at both low and high pulse frequencies. Correlating with FSHβ activation, both PKA activity and levels of pCREB were increased to a greater extent by low compared with high CHEMICAL pulse frequencies, and the induction of pCREB was also attenuated by overexpression of DNPKA at both low and high pulse frequencies. Taken together, these data indicate that a PKA-mediated signaling pathway mediates CHEMICAL activation of CREB at low-pulse frequencies, playing a significant role in the decoding of the hypothalamic CHEMICAL signal to result in frequency-dependent FSHβ activation. | GENE-CHEMICAL |
| CHEMICAL pulse frequency-dependent stimulation of GENE transcription is mediated via activation of PKA and CREB. Expression of pituitary FSH and LH, under the control of pulsatile CHEMICAL, is essential for fertility. cAMP response element-binding protein (CREB) has been implicated in the regulation of GENE gene expression, but the molecular mechanisms by which pulsatile CHEMICAL regulates CREB activation remain poorly understood. We hypothesized that CREB is activated by a distinct signaling pathway in response to pulsatile CHEMICAL in a frequency-dependent manner to dictate the GENE transcriptional response. CHEMICAL stimulation of CREB phosphorylation (pCREB) in the gonadotrope-derived LβT2 cell line was attenuated by a protein kinase A (PKA) inhibitor, H89. A dominant negative PKA (DNPKA) reduced GnRH-stimulated pCREB and markedly decreased CHEMICAL stimulation of GENE mRNA and FSHβLUC activity, but had little effect on LHβLUC activity, indicating relative specificity of this pathway. In perifusion studies, GENE mRNA levels and FSHβLUC activities were increased by pulsatile CHEMICAL, with significantly greater increases at low compared with high pulse frequencies. DNPKA markedly reduced these GnRH-stimulated GENE responses at both low and high pulse frequencies. Correlating with GENE activation, both PKA activity and levels of pCREB were increased to a greater extent by low compared with high CHEMICAL pulse frequencies, and the induction of pCREB was also attenuated by overexpression of DNPKA at both low and high pulse frequencies. Taken together, these data indicate that a PKA-mediated signaling pathway mediates CHEMICAL activation of CREB at low-pulse frequencies, playing a significant role in the decoding of the hypothalamic CHEMICAL signal to result in frequency-dependent GENE activation. | GENE-CHEMICAL |
| CHEMICAL pulse frequency-dependent stimulation of FSHβ transcription is mediated via activation of PKA and CREB. Expression of pituitary FSH and LH, under the control of pulsatile CHEMICAL, is essential for fertility. cAMP response element-binding protein (CREB) has been implicated in the regulation of FSHβ gene expression, but the molecular mechanisms by which pulsatile CHEMICAL regulates CREB activation remain poorly understood. We hypothesized that CREB is activated by a distinct signaling pathway in response to pulsatile CHEMICAL in a frequency-dependent manner to dictate the FSHβ transcriptional response. CHEMICAL stimulation of CREB phosphorylation (pCREB) in the gonadotrope-derived LβT2 cell line was attenuated by a protein kinase A (PKA) inhibitor, H89. A dominant negative PKA (DNPKA) reduced GnRH-stimulated pCREB and markedly decreased CHEMICAL stimulation of FSHβ mRNA and FSHβLUC activity, but had little effect on GENELUC activity, indicating relative specificity of this pathway. In perifusion studies, FSHβ mRNA levels and FSHβLUC activities were increased by pulsatile CHEMICAL, with significantly greater increases at low compared with high pulse frequencies. DNPKA markedly reduced these GnRH-stimulated FSHβ responses at both low and high pulse frequencies. Correlating with FSHβ activation, both PKA activity and levels of pCREB were increased to a greater extent by low compared with high CHEMICAL pulse frequencies, and the induction of pCREB was also attenuated by overexpression of DNPKA at both low and high pulse frequencies. Taken together, these data indicate that a PKA-mediated signaling pathway mediates CHEMICAL activation of CREB at low-pulse frequencies, playing a significant role in the decoding of the hypothalamic CHEMICAL signal to result in frequency-dependent FSHβ activation. | NO-RELATIONSHIP |
| CHEMICAL pulse frequency-dependent stimulation of FSHβ transcription is mediated via activation of PKA and CREB. Expression of pituitary FSH and LH, under the control of pulsatile CHEMICAL, is essential for fertility. cAMP response element-binding protein (CREB) has been implicated in the regulation of FSHβ gene expression, but the molecular mechanisms by which pulsatile CHEMICAL regulates CREB activation remain poorly understood. We hypothesized that CREB is activated by a distinct signaling pathway in response to pulsatile CHEMICAL in a frequency-dependent manner to dictate the FSHβ transcriptional response. CHEMICAL stimulation of CREB phosphorylation (pCREB) in the gonadotrope-derived LβT2 cell line was attenuated by a protein kinase A (PKA) inhibitor, H89. A dominant negative PKA (DNPKA) reduced CHEMICAL-stimulated GENE and markedly decreased CHEMICAL stimulation of FSHβ mRNA and FSHβLUC activity, but had little effect on LHβLUC activity, indicating relative specificity of this pathway. In perifusion studies, FSHβ mRNA levels and FSHβLUC activities were increased by pulsatile CHEMICAL, with significantly greater increases at low compared with high pulse frequencies. DNPKA markedly reduced these GnRH-stimulated FSHβ responses at both low and high pulse frequencies. Correlating with FSHβ activation, both PKA activity and levels of GENE were increased to a greater extent by low compared with high CHEMICAL pulse frequencies, and the induction of GENE was also attenuated by overexpression of DNPKA at both low and high pulse frequencies. Taken together, these data indicate that a PKA-mediated signaling pathway mediates CHEMICAL activation of CREB at low-pulse frequencies, playing a significant role in the decoding of the hypothalamic CHEMICAL signal to result in frequency-dependent FSHβ activation. | INDIRECT-UPREGULATOR |
| CHEMICAL pulse frequency-dependent stimulation of FSHβ transcription is mediated via activation of PKA and GENE. Expression of pituitary FSH and LH, under the control of pulsatile CHEMICAL, is essential for fertility. cAMP response element-binding protein (CREB) has been implicated in the regulation of FSHβ gene expression, but the molecular mechanisms by which pulsatile CHEMICAL regulates GENE activation remain poorly understood. We hypothesized that GENE is activated by a distinct signaling pathway in response to pulsatile CHEMICAL in a frequency-dependent manner to dictate the FSHβ transcriptional response. CHEMICAL stimulation of GENE phosphorylation (pCREB) in the gonadotrope-derived LβT2 cell line was attenuated by a protein kinase A (PKA) inhibitor, H89. A dominant negative PKA (DNPKA) reduced GnRH-stimulated pCREB and markedly decreased CHEMICAL stimulation of FSHβ mRNA and FSHβLUC activity, but had little effect on LHβLUC activity, indicating relative specificity of this pathway. In perifusion studies, FSHβ mRNA levels and FSHβLUC activities were increased by pulsatile CHEMICAL, with significantly greater increases at low compared with high pulse frequencies. DNPKA markedly reduced these GnRH-stimulated FSHβ responses at both low and high pulse frequencies. Correlating with FSHβ activation, both PKA activity and levels of pCREB were increased to a greater extent by low compared with high CHEMICAL pulse frequencies, and the induction of pCREB was also attenuated by overexpression of DNPKA at both low and high pulse frequencies. Taken together, these data indicate that a PKA-mediated signaling pathway mediates CHEMICAL activation of GENE at low-pulse frequencies, playing a significant role in the decoding of the hypothalamic CHEMICAL signal to result in frequency-dependent FSHβ activation. | ACTIVATOR |
| CHEMICAL pulse frequency-dependent stimulation of FSHβ transcription is mediated via activation of GENE and CREB. Expression of pituitary FSH and LH, under the control of pulsatile CHEMICAL, is essential for fertility. cAMP response element-binding protein (CREB) has been implicated in the regulation of FSHβ gene expression, but the molecular mechanisms by which pulsatile CHEMICAL regulates CREB activation remain poorly understood. We hypothesized that CREB is activated by a distinct signaling pathway in response to pulsatile CHEMICAL in a frequency-dependent manner to dictate the FSHβ transcriptional response. CHEMICAL stimulation of CREB phosphorylation (pCREB) in the gonadotrope-derived LβT2 cell line was attenuated by a protein kinase A (PKA) inhibitor, H89. A dominant negative GENE (DNPKA) reduced GnRH-stimulated pCREB and markedly decreased CHEMICAL stimulation of FSHβ mRNA and FSHβLUC activity, but had little effect on LHβLUC activity, indicating relative specificity of this pathway. In perifusion studies, FSHβ mRNA levels and FSHβLUC activities were increased by pulsatile CHEMICAL, with significantly greater increases at low compared with high pulse frequencies. DNPKA markedly reduced these GnRH-stimulated FSHβ responses at both low and high pulse frequencies. Correlating with FSHβ activation, both GENE activity and levels of pCREB were increased to a greater extent by low compared with high CHEMICAL pulse frequencies, and the induction of pCREB was also attenuated by overexpression of DNPKA at both low and high pulse frequencies. Taken together, these data indicate that a PKA-mediated signaling pathway mediates CHEMICAL activation of CREB at low-pulse frequencies, playing a significant role in the decoding of the hypothalamic CHEMICAL signal to result in frequency-dependent FSHβ activation. | ACTIVATOR |
| GnRH pulse frequency-dependent stimulation of FSHβ transcription is mediated via activation of PKA and GENE. Expression of pituitary FSH and LH, under the control of pulsatile GnRH, is essential for fertility. cAMP response element-binding protein (CREB) has been implicated in the regulation of FSHβ gene expression, but the molecular mechanisms by which pulsatile GnRH regulates GENE activation remain poorly understood. We hypothesized that GENE is activated by a distinct signaling pathway in response to pulsatile GnRH in a frequency-dependent manner to dictate the FSHβ transcriptional response. GnRH stimulation of GENE phosphorylation (pCREB) in the gonadotrope-derived LβT2 cell line was attenuated by a protein kinase A (PKA) inhibitor, CHEMICAL. A dominant negative PKA (DNPKA) reduced GnRH-stimulated pCREB and markedly decreased GnRH stimulation of FSHβ mRNA and FSHβLUC activity, but had little effect on LHβLUC activity, indicating relative specificity of this pathway. In perifusion studies, FSHβ mRNA levels and FSHβLUC activities were increased by pulsatile GnRH, with significantly greater increases at low compared with high pulse frequencies. DNPKA markedly reduced these GnRH-stimulated FSHβ responses at both low and high pulse frequencies. Correlating with FSHβ activation, both PKA activity and levels of pCREB were increased to a greater extent by low compared with high GnRH pulse frequencies, and the induction of pCREB was also attenuated by overexpression of DNPKA at both low and high pulse frequencies. Taken together, these data indicate that a PKA-mediated signaling pathway mediates GnRH activation of GENE at low-pulse frequencies, playing a significant role in the decoding of the hypothalamic GnRH signal to result in frequency-dependent FSHβ activation. | INHIBITOR |
| GnRH pulse frequency-dependent stimulation of FSHβ transcription is mediated via activation of PKA and CREB. Expression of pituitary FSH and LH, under the control of pulsatile GnRH, is essential for fertility. cAMP response element-binding protein (CREB) has been implicated in the regulation of FSHβ gene expression, but the molecular mechanisms by which pulsatile GnRH regulates CREB activation remain poorly understood. We hypothesized that CREB is activated by a distinct signaling pathway in response to pulsatile GnRH in a frequency-dependent manner to dictate the FSHβ transcriptional response. GnRH stimulation of CREB phosphorylation (GENE) in the gonadotrope-derived LβT2 cell line was attenuated by a protein kinase A (PKA) inhibitor, CHEMICAL. A dominant negative PKA (DNPKA) reduced GnRH-stimulated GENE and markedly decreased GnRH stimulation of FSHβ mRNA and FSHβLUC activity, but had little effect on LHβLUC activity, indicating relative specificity of this pathway. In perifusion studies, FSHβ mRNA levels and FSHβLUC activities were increased by pulsatile GnRH, with significantly greater increases at low compared with high pulse frequencies. DNPKA markedly reduced these GnRH-stimulated FSHβ responses at both low and high pulse frequencies. Correlating with FSHβ activation, both PKA activity and levels of GENE were increased to a greater extent by low compared with high GnRH pulse frequencies, and the induction of GENE was also attenuated by overexpression of DNPKA at both low and high pulse frequencies. Taken together, these data indicate that a PKA-mediated signaling pathway mediates GnRH activation of CREB at low-pulse frequencies, playing a significant role in the decoding of the hypothalamic GnRH signal to result in frequency-dependent FSHβ activation. | INHIBITOR |
| GnRH pulse frequency-dependent stimulation of FSHβ transcription is mediated via activation of PKA and CREB. Expression of pituitary FSH and LH, under the control of pulsatile GnRH, is essential for fertility. cAMP response element-binding protein (CREB) has been implicated in the regulation of FSHβ gene expression, but the molecular mechanisms by which pulsatile GnRH regulates CREB activation remain poorly understood. We hypothesized that CREB is activated by a distinct signaling pathway in response to pulsatile GnRH in a frequency-dependent manner to dictate the FSHβ transcriptional response. GnRH stimulation of CREB phosphorylation (pCREB) in the gonadotrope-derived LβT2 cell line was attenuated by a GENE (PKA) inhibitor, CHEMICAL. A dominant negative PKA (DNPKA) reduced GnRH-stimulated pCREB and markedly decreased GnRH stimulation of FSHβ mRNA and FSHβLUC activity, but had little effect on LHβLUC activity, indicating relative specificity of this pathway. In perifusion studies, FSHβ mRNA levels and FSHβLUC activities were increased by pulsatile GnRH, with significantly greater increases at low compared with high pulse frequencies. DNPKA markedly reduced these GnRH-stimulated FSHβ responses at both low and high pulse frequencies. Correlating with FSHβ activation, both PKA activity and levels of pCREB were increased to a greater extent by low compared with high GnRH pulse frequencies, and the induction of pCREB was also attenuated by overexpression of DNPKA at both low and high pulse frequencies. Taken together, these data indicate that a PKA-mediated signaling pathway mediates GnRH activation of CREB at low-pulse frequencies, playing a significant role in the decoding of the hypothalamic GnRH signal to result in frequency-dependent FSHβ activation. | INHIBITOR |
| GnRH pulse frequency-dependent stimulation of FSHβ transcription is mediated via activation of GENE and CREB. Expression of pituitary FSH and LH, under the control of pulsatile GnRH, is essential for fertility. cAMP response element-binding protein (CREB) has been implicated in the regulation of FSHβ gene expression, but the molecular mechanisms by which pulsatile GnRH regulates CREB activation remain poorly understood. We hypothesized that CREB is activated by a distinct signaling pathway in response to pulsatile GnRH in a frequency-dependent manner to dictate the FSHβ transcriptional response. GnRH stimulation of CREB phosphorylation (pCREB) in the gonadotrope-derived LβT2 cell line was attenuated by a protein kinase A (GENE) inhibitor, CHEMICAL. A dominant negative GENE (DNPKA) reduced GnRH-stimulated pCREB and markedly decreased GnRH stimulation of FSHβ mRNA and FSHβLUC activity, but had little effect on LHβLUC activity, indicating relative specificity of this pathway. In perifusion studies, FSHβ mRNA levels and FSHβLUC activities were increased by pulsatile GnRH, with significantly greater increases at low compared with high pulse frequencies. DNPKA markedly reduced these GnRH-stimulated FSHβ responses at both low and high pulse frequencies. Correlating with FSHβ activation, both GENE activity and levels of pCREB were increased to a greater extent by low compared with high GnRH pulse frequencies, and the induction of pCREB was also attenuated by overexpression of DNPKA at both low and high pulse frequencies. Taken together, these data indicate that a PKA-mediated signaling pathway mediates GnRH activation of CREB at low-pulse frequencies, playing a significant role in the decoding of the hypothalamic GnRH signal to result in frequency-dependent FSHβ activation. | INHIBITOR |
| CHEMICAL alleviates hepatocyte steatosis through activating AMPK signaling pathway. CHEMICAL, an effective compound derived from foxtail-like sophora herb and seed, has been reported that it can alleviate non-alcoholic steatohepatitis (NASH) in rats and affect GENE synthesis. Meanwhile, adipocytokines could adjust hepatic lipid metabolism through AMPK signaling pathway. In the work presented here, primary hepatocytes were isolated from specific pathogen-free male SD rats and incubated with 200 μmol/L oleic acid for 24h to induce steatotic model, then treated with sophocarpine for 72 h. Oil red staining was performed to evaluate steatosis, total RNA and protein of primary hepatocytes were extracted for real-time RT-PCR and western blot analysis. A cluster of aberrances were observed in the model group, including hepatocyte steatosis, increased leptin and decreased adiponectin mRNA expressions. While sophocarpine treatment resulted in: significant improvement of steatosis (>50% decrease), decrease of leptin expression (<0.57-fold) and increase of adiponectin expression (>1.48-fold). Moreover, compared with the model group, sophocarpine could significantly increase P-AMPKα (>5.82-fold), AMPKα (>1.29-fold) and ACC (>3.27-fold) protein expressions, and reduce P-ACC (<0.30-fold) and HNF-4α (<0.20-fold) protein expression. The mRNA expression of Srebp-1c was downregulated significantly simultaneously (<0.68-fold). We concluded that sophocarpine could alleviate hepatocyte steatosis and the potential mechanism might be the activated signaling pathway of AMPK. | GENE-CHEMICAL |
| CHEMICAL alleviates hepatocyte steatosis through activating GENE signaling pathway. CHEMICAL, an effective compound derived from foxtail-like sophora herb and seed, has been reported that it can alleviate non-alcoholic steatohepatitis (NASH) in rats and affect adipocytokine synthesis. Meanwhile, adipocytokines could adjust hepatic lipid metabolism through GENE signaling pathway. In the work presented here, primary hepatocytes were isolated from specific pathogen-free male SD rats and incubated with 200 μmol/L oleic acid for 24h to induce steatotic model, then treated with CHEMICAL for 72 h. Oil red staining was performed to evaluate steatosis, total RNA and protein of primary hepatocytes were extracted for real-time RT-PCR and western blot analysis. A cluster of aberrances were observed in the model group, including hepatocyte steatosis, increased leptin and decreased adiponectin mRNA expressions. While CHEMICAL treatment resulted in: significant improvement of steatosis (>50% decrease), decrease of leptin expression (<0.57-fold) and increase of adiponectin expression (>1.48-fold). Moreover, compared with the model group, CHEMICAL could significantly increase P-AMPKα (>5.82-fold), AMPKα (>1.29-fold) and ACC (>3.27-fold) protein expressions, and reduce P-ACC (<0.30-fold) and HNF-4α (<0.20-fold) protein expression. The mRNA expression of Srebp-1c was downregulated significantly simultaneously (<0.68-fold). We concluded that CHEMICAL could alleviate hepatocyte steatosis and the potential mechanism might be the activated signaling pathway of GENE. | ACTIVATOR |
| CHEMICAL alleviates hepatocyte steatosis through activating AMPK signaling pathway. CHEMICAL, an effective compound derived from foxtail-like sophora herb and seed, has been reported that it can alleviate non-alcoholic steatohepatitis (NASH) in rats and affect adipocytokine synthesis. Meanwhile, adipocytokines could adjust hepatic lipid metabolism through AMPK signaling pathway. In the work presented here, primary hepatocytes were isolated from specific pathogen-free male SD rats and incubated with 200 μmol/L oleic acid for 24h to induce steatotic model, then treated with CHEMICAL for 72 h. Oil red staining was performed to evaluate steatosis, total RNA and protein of primary hepatocytes were extracted for real-time RT-PCR and western blot analysis. A cluster of aberrances were observed in the model group, including hepatocyte steatosis, increased leptin and decreased adiponectin mRNA expressions. While CHEMICAL treatment resulted in: significant improvement of steatosis (>50% decrease), decrease of leptin expression (<0.57-fold) and increase of adiponectin expression (>1.48-fold). Moreover, compared with the model group, CHEMICAL could significantly increase P-AMPKα (>5.82-fold), AMPKα (>1.29-fold) and GENE (>3.27-fold) protein expressions, and reduce P-ACC (<0.30-fold) and HNF-4α (<0.20-fold) protein expression. The mRNA expression of Srebp-1c was downregulated significantly simultaneously (<0.68-fold). We concluded that CHEMICAL could alleviate hepatocyte steatosis and the potential mechanism might be the activated signaling pathway of AMPK. | INDIRECT-UPREGULATOR |
| CHEMICAL alleviates hepatocyte steatosis through activating AMPK signaling pathway. CHEMICAL, an effective compound derived from foxtail-like sophora herb and seed, has been reported that it can alleviate non-alcoholic steatohepatitis (NASH) in rats and affect adipocytokine synthesis. Meanwhile, adipocytokines could adjust hepatic lipid metabolism through AMPK signaling pathway. In the work presented here, primary hepatocytes were isolated from specific pathogen-free male SD rats and incubated with 200 μmol/L oleic acid for 24h to induce steatotic model, then treated with CHEMICAL for 72 h. Oil red staining was performed to evaluate steatosis, total RNA and protein of primary hepatocytes were extracted for real-time RT-PCR and western blot analysis. A cluster of aberrances were observed in the model group, including hepatocyte steatosis, increased leptin and decreased adiponectin mRNA expressions. While CHEMICAL treatment resulted in: significant improvement of steatosis (>50% decrease), decrease of leptin expression (<0.57-fold) and increase of adiponectin expression (>1.48-fold). Moreover, compared with the model group, CHEMICAL could significantly increase GENE (>5.82-fold), AMPKα (>1.29-fold) and ACC (>3.27-fold) protein expressions, and reduce P-ACC (<0.30-fold) and HNF-4α (<0.20-fold) protein expression. The mRNA expression of Srebp-1c was downregulated significantly simultaneously (<0.68-fold). We concluded that CHEMICAL could alleviate hepatocyte steatosis and the potential mechanism might be the activated signaling pathway of AMPK. | INDIRECT-UPREGULATOR |
| CHEMICAL alleviates hepatocyte steatosis through activating AMPK signaling pathway. CHEMICAL, an effective compound derived from foxtail-like sophora herb and seed, has been reported that it can alleviate non-alcoholic steatohepatitis (NASH) in rats and affect adipocytokine synthesis. Meanwhile, adipocytokines could adjust hepatic lipid metabolism through AMPK signaling pathway. In the work presented here, primary hepatocytes were isolated from specific pathogen-free male SD rats and incubated with 200 μmol/L oleic acid for 24h to induce steatotic model, then treated with CHEMICAL for 72 h. Oil red staining was performed to evaluate steatosis, total RNA and protein of primary hepatocytes were extracted for real-time RT-PCR and western blot analysis. A cluster of aberrances were observed in the model group, including hepatocyte steatosis, increased leptin and decreased adiponectin mRNA expressions. While CHEMICAL treatment resulted in: significant improvement of steatosis (>50% decrease), decrease of leptin expression (<0.57-fold) and increase of adiponectin expression (>1.48-fold). Moreover, compared with the model group, CHEMICAL could significantly increase P-AMPKα (>5.82-fold), GENE (>1.29-fold) and ACC (>3.27-fold) protein expressions, and reduce P-ACC (<0.30-fold) and HNF-4α (<0.20-fold) protein expression. The mRNA expression of Srebp-1c was downregulated significantly simultaneously (<0.68-fold). We concluded that CHEMICAL could alleviate hepatocyte steatosis and the potential mechanism might be the activated signaling pathway of AMPK. | INDIRECT-UPREGULATOR |
| CHEMICAL alleviates hepatocyte steatosis through activating AMPK signaling pathway. CHEMICAL, an effective compound derived from foxtail-like sophora herb and seed, has been reported that it can alleviate non-alcoholic steatohepatitis (NASH) in rats and affect adipocytokine synthesis. Meanwhile, adipocytokines could adjust hepatic lipid metabolism through AMPK signaling pathway. In the work presented here, primary hepatocytes were isolated from specific pathogen-free male SD rats and incubated with 200 μmol/L oleic acid for 24h to induce steatotic model, then treated with CHEMICAL for 72 h. Oil red staining was performed to evaluate steatosis, total RNA and protein of primary hepatocytes were extracted for real-time RT-PCR and western blot analysis. A cluster of aberrances were observed in the model group, including hepatocyte steatosis, increased leptin and decreased GENE mRNA expressions. While CHEMICAL treatment resulted in: significant improvement of steatosis (>50% decrease), decrease of leptin expression (<0.57-fold) and increase of GENE expression (>1.48-fold). Moreover, compared with the model group, CHEMICAL could significantly increase P-AMPKα (>5.82-fold), AMPKα (>1.29-fold) and ACC (>3.27-fold) protein expressions, and reduce P-ACC (<0.30-fold) and HNF-4α (<0.20-fold) protein expression. The mRNA expression of Srebp-1c was downregulated significantly simultaneously (<0.68-fold). We concluded that CHEMICAL could alleviate hepatocyte steatosis and the potential mechanism might be the activated signaling pathway of AMPK. | INDIRECT-UPREGULATOR |
| CHEMICAL alleviates hepatocyte steatosis through activating AMPK signaling pathway. CHEMICAL, an effective compound derived from foxtail-like sophora herb and seed, has been reported that it can alleviate non-alcoholic steatohepatitis (NASH) in rats and affect adipocytokine synthesis. Meanwhile, adipocytokines could adjust hepatic lipid metabolism through AMPK signaling pathway. In the work presented here, primary hepatocytes were isolated from specific pathogen-free male SD rats and incubated with 200 μmol/L oleic acid for 24h to induce steatotic model, then treated with CHEMICAL for 72 h. Oil red staining was performed to evaluate steatosis, total RNA and protein of primary hepatocytes were extracted for real-time RT-PCR and western blot analysis. A cluster of aberrances were observed in the model group, including hepatocyte steatosis, increased leptin and decreased adiponectin mRNA expressions. While CHEMICAL treatment resulted in: significant improvement of steatosis (>50% decrease), decrease of leptin expression (<0.57-fold) and increase of adiponectin expression (>1.48-fold). Moreover, compared with the model group, CHEMICAL could significantly increase P-AMPKα (>5.82-fold), AMPKα (>1.29-fold) and ACC (>3.27-fold) protein expressions, and reduce GENE (<0.30-fold) and HNF-4α (<0.20-fold) protein expression. The mRNA expression of Srebp-1c was downregulated significantly simultaneously (<0.68-fold). We concluded that CHEMICAL could alleviate hepatocyte steatosis and the potential mechanism might be the activated signaling pathway of AMPK. | INDIRECT-DOWNREGULATOR |
| CHEMICAL alleviates hepatocyte steatosis through activating AMPK signaling pathway. CHEMICAL, an effective compound derived from foxtail-like sophora herb and seed, has been reported that it can alleviate non-alcoholic steatohepatitis (NASH) in rats and affect adipocytokine synthesis. Meanwhile, adipocytokines could adjust hepatic lipid metabolism through AMPK signaling pathway. In the work presented here, primary hepatocytes were isolated from specific pathogen-free male SD rats and incubated with 200 μmol/L oleic acid for 24h to induce steatotic model, then treated with CHEMICAL for 72 h. Oil red staining was performed to evaluate steatosis, total RNA and protein of primary hepatocytes were extracted for real-time RT-PCR and western blot analysis. A cluster of aberrances were observed in the model group, including hepatocyte steatosis, increased leptin and decreased adiponectin mRNA expressions. While CHEMICAL treatment resulted in: significant improvement of steatosis (>50% decrease), decrease of leptin expression (<0.57-fold) and increase of adiponectin expression (>1.48-fold). Moreover, compared with the model group, CHEMICAL could significantly increase P-AMPKα (>5.82-fold), AMPKα (>1.29-fold) and ACC (>3.27-fold) protein expressions, and reduce P-ACC (<0.30-fold) and GENE (<0.20-fold) protein expression. The mRNA expression of Srebp-1c was downregulated significantly simultaneously (<0.68-fold). We concluded that CHEMICAL could alleviate hepatocyte steatosis and the potential mechanism might be the activated signaling pathway of AMPK. | INDIRECT-DOWNREGULATOR |
| CHEMICAL alleviates hepatocyte steatosis through activating AMPK signaling pathway. CHEMICAL, an effective compound derived from foxtail-like sophora herb and seed, has been reported that it can alleviate non-alcoholic steatohepatitis (NASH) in rats and affect adipocytokine synthesis. Meanwhile, adipocytokines could adjust hepatic lipid metabolism through AMPK signaling pathway. In the work presented here, primary hepatocytes were isolated from specific pathogen-free male SD rats and incubated with 200 μmol/L oleic acid for 24h to induce steatotic model, then treated with CHEMICAL for 72 h. Oil red staining was performed to evaluate steatosis, total RNA and protein of primary hepatocytes were extracted for real-time RT-PCR and western blot analysis. A cluster of aberrances were observed in the model group, including hepatocyte steatosis, increased GENE and decreased adiponectin mRNA expressions. While CHEMICAL treatment resulted in: significant improvement of steatosis (>50% decrease), decrease of GENE expression (<0.57-fold) and increase of adiponectin expression (>1.48-fold). Moreover, compared with the model group, CHEMICAL could significantly increase P-AMPKα (>5.82-fold), AMPKα (>1.29-fold) and ACC (>3.27-fold) protein expressions, and reduce P-ACC (<0.30-fold) and HNF-4α (<0.20-fold) protein expression. The mRNA expression of Srebp-1c was downregulated significantly simultaneously (<0.68-fold). We concluded that CHEMICAL could alleviate hepatocyte steatosis and the potential mechanism might be the activated signaling pathway of AMPK. | INDIRECT-DOWNREGULATOR |
| Site dependent intestinal absorption of darunavir and its interaction with ketoconazole. The expression of GENE increases from proximal to distal parts of the small intestine, whereas for P450 enzymes the expression is reported to be highest in duodenum and jejunum, decreasing to more distal sites. To evaluate to what extent the regional differences in expression of GENE and P450 enzymes affect the absorption of a dual substrate, we investigated the transport of darunavir across different small intestinal segments (duodenum, proximal jejunum and ileum). Moreover, the effect of ketoconazole on the intestinal absorption of darunavir was explored, since these drugs are commonly co-administered. Performing the rat in situ intestinal perfusion technique with mesenteric blood sampling, we found no significant differences in the transport of darunavir at the different intestinal segments. The involvement of GENE in the absorption of darunavir was clearly shown by coperfusion of darunavir with the GENE inhibitor CHEMICAL. In presence of CHEMICAL, a 2.2-, 4.2- and 5.7-fold increase in Papp values were measured for duodenum, proximal jejunum and ileum, respectively. Involvement of P450 mediated metabolism in the absorption of darunavir could not be demonstrated in this rat model. Upon studying the drug-drug interaction of darunavir with ketoconazole, data were indicative for an inhibitory effect of ketoconazole on GENE as the main mechanism for the increased transport of darunavir across the small intestine. | INHIBITOR |
| Site dependent intestinal absorption of darunavir and its interaction with CHEMICAL. The expression of GENE increases from proximal to distal parts of the small intestine, whereas for P450 enzymes the expression is reported to be highest in duodenum and jejunum, decreasing to more distal sites. To evaluate to what extent the regional differences in expression of GENE and P450 enzymes affect the absorption of a dual substrate, we investigated the transport of darunavir across different small intestinal segments (duodenum, proximal jejunum and ileum). Moreover, the effect of CHEMICAL on the intestinal absorption of darunavir was explored, since these drugs are commonly co-administered. Performing the rat in situ intestinal perfusion technique with mesenteric blood sampling, we found no significant differences in the transport of darunavir at the different intestinal segments. The involvement of GENE in the absorption of darunavir was clearly shown by coperfusion of darunavir with the GENE inhibitor zosuquidar. In presence of zosuquidar, a 2.2-, 4.2- and 5.7-fold increase in Papp values were measured for duodenum, proximal jejunum and ileum, respectively. Involvement of P450 mediated metabolism in the absorption of darunavir could not be demonstrated in this rat model. Upon studying the drug-drug interaction of darunavir with CHEMICAL, data were indicative for an inhibitory effect of CHEMICAL on GENE as the main mechanism for the increased transport of darunavir across the small intestine. | INHIBITOR |
| Site dependent intestinal absorption of CHEMICAL and its interaction with ketoconazole. The expression of GENE increases from proximal to distal parts of the small intestine, whereas for P450 enzymes the expression is reported to be highest in duodenum and jejunum, decreasing to more distal sites. To evaluate to what extent the regional differences in expression of GENE and P450 enzymes affect the absorption of a dual substrate, we investigated the transport of CHEMICAL across different small intestinal segments (duodenum, proximal jejunum and ileum). Moreover, the effect of ketoconazole on the intestinal absorption of CHEMICAL was explored, since these drugs are commonly co-administered. Performing the rat in situ intestinal perfusion technique with mesenteric blood sampling, we found no significant differences in the transport of CHEMICAL at the different intestinal segments. The involvement of GENE in the absorption of CHEMICAL was clearly shown by coperfusion of CHEMICAL with the GENE inhibitor zosuquidar. In presence of zosuquidar, a 2.2-, 4.2- and 5.7-fold increase in Papp values were measured for duodenum, proximal jejunum and ileum, respectively. Involvement of P450 mediated metabolism in the absorption of CHEMICAL could not be demonstrated in this rat model. Upon studying the drug-drug interaction of CHEMICAL with ketoconazole, data were indicative for an inhibitory effect of ketoconazole on GENE as the main mechanism for the increased transport of CHEMICAL across the small intestine. | SUBSTRATE |
| Site dependent intestinal absorption of CHEMICAL and its interaction with ketoconazole. The expression of P-gp increases from proximal to distal parts of the small intestine, whereas for GENE enzymes the expression is reported to be highest in duodenum and jejunum, decreasing to more distal sites. To evaluate to what extent the regional differences in expression of P-gp and GENE enzymes affect the absorption of a dual substrate, we investigated the transport of CHEMICAL across different small intestinal segments (duodenum, proximal jejunum and ileum). Moreover, the effect of ketoconazole on the intestinal absorption of CHEMICAL was explored, since these drugs are commonly co-administered. Performing the rat in situ intestinal perfusion technique with mesenteric blood sampling, we found no significant differences in the transport of CHEMICAL at the different intestinal segments. The involvement of P-gp in the absorption of CHEMICAL was clearly shown by coperfusion of CHEMICAL with the P-gp inhibitor zosuquidar. In presence of zosuquidar, a 2.2-, 4.2- and 5.7-fold increase in Papp values were measured for duodenum, proximal jejunum and ileum, respectively. Involvement of GENE mediated metabolism in the absorption of CHEMICAL could not be demonstrated in this rat model. Upon studying the drug-drug interaction of CHEMICAL with ketoconazole, data were indicative for an inhibitory effect of ketoconazole on P-gp as the main mechanism for the increased transport of CHEMICAL across the small intestine. | SUBSTRATE |
| Site dependent intestinal absorption of CHEMICAL and its interaction with ketoconazole. The expression of P-gp increases from proximal to distal parts of the small intestine, whereas for GENE the expression is reported to be highest in duodenum and jejunum, decreasing to more distal sites. To evaluate to what extent the regional differences in expression of P-gp and GENE affect the absorption of a dual substrate, we investigated the transport of CHEMICAL across different small intestinal segments (duodenum, proximal jejunum and ileum). Moreover, the effect of ketoconazole on the intestinal absorption of CHEMICAL was explored, since these drugs are commonly co-administered. Performing the rat in situ intestinal perfusion technique with mesenteric blood sampling, we found no significant differences in the transport of CHEMICAL at the different intestinal segments. The involvement of P-gp in the absorption of CHEMICAL was clearly shown by coperfusion of CHEMICAL with the P-gp inhibitor zosuquidar. In presence of zosuquidar, a 2.2-, 4.2- and 5.7-fold increase in Papp values were measured for duodenum, proximal jejunum and ileum, respectively. Involvement of P450 mediated metabolism in the absorption of CHEMICAL could not be demonstrated in this rat model. Upon studying the drug-drug interaction of CHEMICAL with ketoconazole, data were indicative for an inhibitory effect of ketoconazole on P-gp as the main mechanism for the increased transport of CHEMICAL across the small intestine. | SUBSTRATE |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CHEMICAL effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CHEMICAL prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of GENE, iNOS, and TNF-α. Furthermore, CFB, CFE and CHEMICAL suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CHEMICAL effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CHEMICAL prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, GENE, and TNF-α. Furthermore, CFB, CFE and CHEMICAL suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CHEMICAL effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CHEMICAL prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and GENE. Furthermore, CFB, CFE and CHEMICAL suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, CHEMICAL and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including GENE (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, CHEMICAL and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (GENE), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of GENE, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, CHEMICAL and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), GENE (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, CHEMICAL and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (GENE), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, GENE, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, CHEMICAL and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and GENE (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, CHEMICAL and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (GENE). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and CHEMICAL fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including GENE (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and CHEMICAL fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (GENE), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of GENE, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and CHEMICAL fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), GENE (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and CHEMICAL fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (GENE), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, GENE, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and CHEMICAL fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and GENE (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and CHEMICAL fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (GENE). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% CHEMICAL C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including GENE (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% CHEMICAL C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (GENE), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of GENE, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% CHEMICAL C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), GENE (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% CHEMICAL C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (GENE), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, GENE, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% CHEMICAL C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and GENE (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% CHEMICAL C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (GENE). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, CHEMICAL (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including GENE (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, CHEMICAL (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (GENE), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of GENE, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, CHEMICAL (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), GENE (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, CHEMICAL (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (GENE), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, GENE, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, CHEMICAL (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and GENE (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, CHEMICAL (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (GENE). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CHEMICAL) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including GENE (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CHEMICAL effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CHEMICAL prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CHEMICAL suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CHEMICAL) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), GENE (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CHEMICAL effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CHEMICAL prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CHEMICAL suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CHEMICAL) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and GENE (TNF- α). Moreover, CFB, CFE and CHEMICAL effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CHEMICAL prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CHEMICAL suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CHEMICAL) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (GENE). Moreover, CFB, CFE and CHEMICAL effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CHEMICAL prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CHEMICAL suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. | INDIRECT-DOWNREGULATOR |
| Interaction of silymarin CHEMICAL with GENE. GENE (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin CHEMICAL on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin CHEMICAL investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of CHEMICAL at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. | SUBSTRATE |
| Interaction of silymarin CHEMICAL with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin CHEMICAL on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin CHEMICAL investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on GENE isoform specificity and concentrations of CHEMICAL at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with GENE substrates in patients. | REGULATOR |
| Interaction of silymarin CHEMICAL with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin CHEMICAL on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, GENE- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin CHEMICAL investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of CHEMICAL at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. | INHIBITOR |
| Interaction of silymarin CHEMICAL with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin CHEMICAL on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and GENE-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin CHEMICAL investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of CHEMICAL at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. | INHIBITOR |
| Interaction of silymarin CHEMICAL with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin CHEMICAL on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and GENE-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin CHEMICAL investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of CHEMICAL at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. | INHIBITOR |
| Interaction of silymarin flavonolignans with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. GENE-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), CHEMICAL (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, CHEMICAL, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. | INHIBITOR |
| Interaction of silymarin flavonolignans with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, GENE-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), CHEMICAL (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, CHEMICAL, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. | INHIBITOR |
| Interaction of silymarin flavonolignans with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and GENE-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), CHEMICAL (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, CHEMICAL, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. | INHIBITOR |
| Interaction of silymarin flavonolignans with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. GENE-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), CHEMICAL (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and CHEMICAL (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. | INHIBITOR |
| Interaction of silymarin flavonolignans with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, GENE-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), CHEMICAL (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and CHEMICAL (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. | INHIBITOR |
| Interaction of silymarin flavonolignans with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and GENE-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), CHEMICAL (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and CHEMICAL (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. | INHIBITOR |
| Interaction of silymarin flavonolignans with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. GENE-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and CHEMICAL (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. | INHIBITOR |
| Interaction of silymarin flavonolignans with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, GENE-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and CHEMICAL (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. | INHIBITOR |
| Interaction of silymarin flavonolignans with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and GENE-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and CHEMICAL (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. | INHIBITOR |
| Interaction of silymarin flavonolignans with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), CHEMICAL (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, CHEMICAL, and silybin B (100 µM) significantly inhibited GENE-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on GENE isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with GENE substrates in patients. | INHIBITOR |
| Interaction of silymarin flavonolignans with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), CHEMICAL (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and CHEMICAL (100 µM) significantly inhibited GENE-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on GENE isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with GENE substrates in patients. | INHIBITOR |
| Interaction of silymarin flavonolignans with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, GENE- and OATP1B3-mediated CHEMICAL uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited OATP-mediated CHEMICAL and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. | SUBSTRATE |
| Interaction of silymarin flavonolignans with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and GENE-mediated CHEMICAL uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited OATP-mediated CHEMICAL and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. | SUBSTRATE |
| Interaction of silymarin flavonolignans with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and GENE-mediated CHEMICAL uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. | SUBSTRATE |
| Interaction of silymarin flavonolignans with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated CHEMICAL uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited GENE-mediated CHEMICAL and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on GENE isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with GENE substrates in patients. | SUBSTRATE |
| Interaction of silymarin flavonolignans with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited GENE-mediated estradiol-17β-glucuronide and CHEMICAL uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on GENE isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with GENE substrates in patients. | SUBSTRATE |
| Oxidation of tertiary amine-derivatized surfaces to control protein adhesion. Selective oxidation of ω-tertiary amine self-assembled thiol monolayers to CHEMICAL is shown to transform the adhesion of model proteins GENE and fibrinogen upon them. Efficient preparation of both secondary and tertiary linker amides as judged by X-ray photoelectron spectroscopy (XPS) and water droplet contact angle was achieved with an improved amide bond formation on gold quartz crystal microbalance (QCM) sensors using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium (HATU). Oxidation with hydrogen peroxide was similarly assessed, and adhesion of GENE and fibrinogen from phosphate buffered saline was then assayed by QCM and imaged by AFM. Tertiary amine-functionalized sensors adsorbed multilayers of aggregated GENE, whereas CHEMICAL and triethylene glycol-terminated monolayers are consistent with small protein aggregates. The surface containing a dimethylamine N-oxide headgroup and ethyl secondary amide linker showed the largest difference in adsorption of both proteins. Oxidation of tertiary amine decorated surfaces therefore holds the potential for selective deposition of proteins and cells through masking and other patterning techniques. | DIRECT-REGULATOR |
| Oxidation of tertiary amine-derivatized surfaces to control protein adhesion. Selective oxidation of ω-tertiary amine self-assembled thiol monolayers to CHEMICAL is shown to transform the adhesion of model proteins lysozyme and GENE upon them. Efficient preparation of both secondary and tertiary linker amides as judged by X-ray photoelectron spectroscopy (XPS) and water droplet contact angle was achieved with an improved amide bond formation on gold quartz crystal microbalance (QCM) sensors using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium (HATU). Oxidation with hydrogen peroxide was similarly assessed, and adhesion of lysozyme and GENE from phosphate buffered saline was then assayed by QCM and imaged by AFM. Tertiary amine-functionalized sensors adsorbed multilayers of aggregated lysozyme, whereas CHEMICAL and triethylene glycol-terminated monolayers are consistent with small protein aggregates. The surface containing a dimethylamine N-oxide headgroup and ethyl secondary amide linker showed the largest difference in adsorption of both proteins. Oxidation of tertiary amine decorated surfaces therefore holds the potential for selective deposition of proteins and cells through masking and other patterning techniques. | DIRECT-REGULATOR |
| Oxidation of tertiary amine-derivatized surfaces to control protein adhesion. Selective oxidation of ω-tertiary amine self-assembled thiol monolayers to tertiary amine N-oxides is shown to transform the adhesion of model proteins GENE and fibrinogen upon them. Efficient preparation of both secondary and tertiary linker amides as judged by X-ray photoelectron spectroscopy (XPS) and water droplet contact angle was achieved with an improved amide bond formation on gold quartz crystal microbalance (QCM) sensors using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium (HATU). Oxidation with hydrogen peroxide was similarly assessed, and adhesion of GENE and fibrinogen from phosphate buffered saline was then assayed by QCM and imaged by AFM. Tertiary amine-functionalized sensors adsorbed multilayers of aggregated GENE, whereas tertiary amine N-oxides and CHEMICAL-terminated monolayers are consistent with small protein aggregates. The surface containing a dimethylamine N-oxide headgroup and ethyl secondary amide linker showed the largest difference in adsorption of both proteins. Oxidation of tertiary amine decorated surfaces therefore holds the potential for selective deposition of proteins and cells through masking and other patterning techniques. | REGULATOR |
| Oxidation of tertiary amine-derivatized surfaces to control protein adhesion. Selective oxidation of CHEMICAL self-assembled thiol monolayers to tertiary amine N-oxides is shown to transform the adhesion of model proteins GENE and fibrinogen upon them. Efficient preparation of both secondary and tertiary linker amides as judged by X-ray photoelectron spectroscopy (XPS) and water droplet contact angle was achieved with an improved amide bond formation on gold quartz crystal microbalance (QCM) sensors using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium (HATU). Oxidation with hydrogen peroxide was similarly assessed, and adhesion of GENE and fibrinogen from phosphate buffered saline was then assayed by QCM and imaged by AFM. Tertiary amine-functionalized sensors adsorbed multilayers of aggregated GENE, whereas tertiary amine N-oxides and triethylene glycol-terminated monolayers are consistent with small protein aggregates. The surface containing a dimethylamine N-oxide headgroup and ethyl secondary amide linker showed the largest difference in adsorption of both proteins. Oxidation of tertiary amine decorated surfaces therefore holds the potential for selective deposition of proteins and cells through masking and other patterning techniques. | REGULATOR |
| Oxidation of tertiary amine-derivatized surfaces to control protein adhesion. Selective oxidation of CHEMICAL self-assembled thiol monolayers to tertiary amine N-oxides is shown to transform the adhesion of model proteins lysozyme and GENE upon them. Efficient preparation of both secondary and tertiary linker amides as judged by X-ray photoelectron spectroscopy (XPS) and water droplet contact angle was achieved with an improved amide bond formation on gold quartz crystal microbalance (QCM) sensors using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium (HATU). Oxidation with hydrogen peroxide was similarly assessed, and adhesion of lysozyme and GENE from phosphate buffered saline was then assayed by QCM and imaged by AFM. Tertiary amine-functionalized sensors adsorbed multilayers of aggregated lysozyme, whereas tertiary amine N-oxides and triethylene glycol-terminated monolayers are consistent with small protein aggregates. The surface containing a dimethylamine N-oxide headgroup and ethyl secondary amide linker showed the largest difference in adsorption of both proteins. Oxidation of tertiary amine decorated surfaces therefore holds the potential for selective deposition of proteins and cells through masking and other patterning techniques. | REGULATOR |
| Oxidation of tertiary amine-derivatized surfaces to control protein adhesion. Selective oxidation of ω-tertiary amine self-assembled CHEMICAL monolayers to tertiary amine N-oxides is shown to transform the adhesion of model proteins GENE and fibrinogen upon them. Efficient preparation of both secondary and tertiary linker amides as judged by X-ray photoelectron spectroscopy (XPS) and water droplet contact angle was achieved with an improved amide bond formation on gold quartz crystal microbalance (QCM) sensors using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium (HATU). Oxidation with hydrogen peroxide was similarly assessed, and adhesion of GENE and fibrinogen from phosphate buffered saline was then assayed by QCM and imaged by AFM. Tertiary amine-functionalized sensors adsorbed multilayers of aggregated GENE, whereas tertiary amine N-oxides and triethylene glycol-terminated monolayers are consistent with small protein aggregates. The surface containing a dimethylamine N-oxide headgroup and ethyl secondary amide linker showed the largest difference in adsorption of both proteins. Oxidation of tertiary amine decorated surfaces therefore holds the potential for selective deposition of proteins and cells through masking and other patterning techniques. | DIRECT-REGULATOR |
| Oxidation of tertiary amine-derivatized surfaces to control protein adhesion. Selective oxidation of ω-tertiary amine self-assembled CHEMICAL monolayers to tertiary amine N-oxides is shown to transform the adhesion of model proteins lysozyme and GENE upon them. Efficient preparation of both secondary and tertiary linker amides as judged by X-ray photoelectron spectroscopy (XPS) and water droplet contact angle was achieved with an improved amide bond formation on gold quartz crystal microbalance (QCM) sensors using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium (HATU). Oxidation with hydrogen peroxide was similarly assessed, and adhesion of lysozyme and GENE from phosphate buffered saline was then assayed by QCM and imaged by AFM. Tertiary amine-functionalized sensors adsorbed multilayers of aggregated lysozyme, whereas tertiary amine N-oxides and triethylene glycol-terminated monolayers are consistent with small protein aggregates. The surface containing a dimethylamine N-oxide headgroup and ethyl secondary amide linker showed the largest difference in adsorption of both proteins. Oxidation of tertiary amine decorated surfaces therefore holds the potential for selective deposition of proteins and cells through masking and other patterning techniques. | DIRECT-REGULATOR |
| Oxidation of tertiary amine-derivatized surfaces to control protein adhesion. Selective oxidation of ω-tertiary amine self-assembled thiol monolayers to tertiary amine N-oxides is shown to transform the adhesion of model proteins GENE and fibrinogen upon them. Efficient preparation of both secondary and tertiary linker amides as judged by X-ray photoelectron spectroscopy (XPS) and water droplet contact angle was achieved with an improved amide bond formation on gold quartz crystal microbalance (QCM) sensors using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium (HATU). Oxidation with CHEMICAL was similarly assessed, and adhesion of GENE and fibrinogen from phosphate buffered saline was then assayed by QCM and imaged by AFM. Tertiary amine-functionalized sensors adsorbed multilayers of aggregated GENE, whereas tertiary amine N-oxides and triethylene glycol-terminated monolayers are consistent with small protein aggregates. The surface containing a dimethylamine N-oxide headgroup and ethyl secondary amide linker showed the largest difference in adsorption of both proteins. Oxidation of tertiary amine decorated surfaces therefore holds the potential for selective deposition of proteins and cells through masking and other patterning techniques. | REGULATOR |
| Oxidation of tertiary amine-derivatized surfaces to control protein adhesion. Selective oxidation of ω-tertiary amine self-assembled thiol monolayers to tertiary amine N-oxides is shown to transform the adhesion of model proteins lysozyme and GENE upon them. Efficient preparation of both secondary and tertiary linker amides as judged by X-ray photoelectron spectroscopy (XPS) and water droplet contact angle was achieved with an improved amide bond formation on gold quartz crystal microbalance (QCM) sensors using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium (HATU). Oxidation with CHEMICAL was similarly assessed, and adhesion of lysozyme and GENE from phosphate buffered saline was then assayed by QCM and imaged by AFM. Tertiary amine-functionalized sensors adsorbed multilayers of aggregated lysozyme, whereas tertiary amine N-oxides and triethylene glycol-terminated monolayers are consistent with small protein aggregates. The surface containing a dimethylamine N-oxide headgroup and ethyl secondary amide linker showed the largest difference in adsorption of both proteins. Oxidation of tertiary amine decorated surfaces therefore holds the potential for selective deposition of proteins and cells through masking and other patterning techniques. | REGULATOR |
| Neuroprotective effects of mercaptoethylleonurine and mercaptoethylguanidine analogs on hydrogen peroxide-induced apoptosis in human neuronal SH-SY5Y cells. A series of mercaptoethylleonurine and mercaptoethylguanidine derivatives were designed and synthesized. Their neuroprotective effects toward H2O2-induced apoptosis were investigated in human SH-SY5Y cells. The results from these studies identified several potent compounds, with compound 8k emerging as the most effective. Further investigation demonstrated that 8k reduced CHEMICAL-induced activation of mitochondrial apoptosis by inhibiting the expression of GENE and elevating the expression of Bcl-2. Moreover, the molecular mechanism underlying the observed neuroprotective effects of 8k was exerted via the Akt and JNK pathways. Compound 8k can be a lead compound for further discovery of neuroprotective medicine. | INDIRECT-DOWNREGULATOR |
| Neuroprotective effects of mercaptoethylleonurine and mercaptoethylguanidine analogs on hydrogen peroxide-induced apoptosis in human neuronal SH-SY5Y cells. A series of mercaptoethylleonurine and mercaptoethylguanidine derivatives were designed and synthesized. Their neuroprotective effects toward H2O2-induced apoptosis were investigated in human SH-SY5Y cells. The results from these studies identified several potent compounds, with compound 8k emerging as the most effective. Further investigation demonstrated that 8k reduced CHEMICAL-induced activation of mitochondrial apoptosis by inhibiting the expression of Bax and elevating the expression of GENE. Moreover, the molecular mechanism underlying the observed neuroprotective effects of 8k was exerted via the Akt and JNK pathways. Compound 8k can be a lead compound for further discovery of neuroprotective medicine. | INDIRECT-UPREGULATOR |
| Effects of induced hyperinsulinaemia with and without hyperglycaemia on measures of cardiac vagal control. AIMS/HYPOTHESIS: We examined the effects of serum insulin levels on vagal control over the heart and tested the hypothesis that higher fasting insulin levels are associated with lower vagal control. We also examined whether experimentally induced increases in insulin by beta cell secretagogues, including glucagon-like peptide-1 (GLP-1), will decrease vagal control. METHODS: Respiration and ECGs were recorded for 130 healthy participants undergoing clamps. Three variables of cardiac vagal effects (the root mean square of successive differences [rMSSD] in the interbeat interval of the heart rate [IBI], heart-rate variability [HRV] caused by peak-valley respiratory sinus arrhythmia [pvRSA], and high-frequency power [HF]) and heart rate (HR) were obtained at seven time points during the clamps, characterised by increasing levels of insulin (achieved by administering insulin plus glucose, glucose only, glucose and GLP-1, and glucose and GLP-1 combined with arginine). RESULTS: Serum insulin level was positively associated with HR at all time points during the clamps except the first-phase hyperglycaemic clamp. GENE levels were negatively correlated with variables of vagal control, reaching significance for rMSSD and log(10)HF, but not for pvRSA, during the last four phases of the hyperglycaemic clamp (hyperglycaemic second phase, GLP-1 first and second phases, and CHEMICAL). These associations disappeared when adjusted for age, BMI and insulin sensitivity. Administration of the beta cell secretagogues GLP-1 and CHEMICAL led to a significant increase in HR, but this was not paired with a significant reduction in HRV measures. CONCLUSION/INTERPRETATION: Experimentally induced hyperinsulinaemia is not correlated with cardiac vagal control or HR when adjusting for age, BMI and insulin sensitivity index. Our findings suggest that exposure to a GLP-1 during hyperglycaemia leads to a small acute increase in HR but not to an acute decrease in cardiac vagal control. | GENE-CHEMICAL |
| Effects of induced hyperinsulinaemia with and without hyperglycaemia on measures of cardiac vagal control. AIMS/HYPOTHESIS: We examined the effects of serum GENE levels on vagal control over the heart and tested the hypothesis that higher fasting GENE levels are associated with lower vagal control. We also examined whether experimentally induced increases in GENE by beta cell secretagogues, including glucagon-like peptide-1 (GLP-1), will decrease vagal control. METHODS: Respiration and ECGs were recorded for 130 healthy participants undergoing clamps. Three variables of cardiac vagal effects (the root mean square of successive differences [rMSSD] in the interbeat interval of the heart rate [IBI], heart-rate variability [HRV] caused by peak-valley respiratory sinus arrhythmia [pvRSA], and high-frequency power [HF]) and heart rate (HR) were obtained at seven time points during the clamps, characterised by increasing levels of GENE (achieved by administering GENE plus CHEMICAL, CHEMICAL only, CHEMICAL and GLP-1, and CHEMICAL and GLP-1 combined with arginine). RESULTS: Serum GENE level was positively associated with HR at all time points during the clamps except the first-phase hyperglycaemic clamp. GENE levels were negatively correlated with variables of vagal control, reaching significance for rMSSD and log(10)HF, but not for pvRSA, during the last four phases of the hyperglycaemic clamp (hyperglycaemic second phase, GLP-1 first and second phases, and arginine). These associations disappeared when adjusted for age, BMI and GENE sensitivity. Administration of the beta cell secretagogues GLP-1 and arginine led to a significant increase in HR, but this was not paired with a significant reduction in HRV measures. CONCLUSION/INTERPRETATION: Experimentally induced hyperinsulinaemia is not correlated with cardiac vagal control or HR when adjusting for age, BMI and GENE sensitivity index. Our findings suggest that exposure to a GLP-1 during hyperglycaemia leads to a small acute increase in HR but not to an acute decrease in cardiac vagal control. | GENE-CHEMICAL |
| Effects of induced hyperinsulinaemia with and without hyperglycaemia on measures of cardiac vagal control. AIMS/HYPOTHESIS: We examined the effects of serum GENE levels on vagal control over the heart and tested the hypothesis that higher fasting GENE levels are associated with lower vagal control. We also examined whether experimentally induced increases in GENE by beta cell secretagogues, including glucagon-like peptide-1 (GLP-1), will decrease vagal control. METHODS: Respiration and ECGs were recorded for 130 healthy participants undergoing clamps. Three variables of cardiac vagal effects (the root mean square of successive differences [rMSSD] in the interbeat interval of the heart rate [IBI], heart-rate variability [HRV] caused by peak-valley respiratory sinus arrhythmia [pvRSA], and high-frequency power [HF]) and heart rate (HR) were obtained at seven time points during the clamps, characterised by increasing levels of GENE (achieved by administering GENE plus glucose, glucose only, glucose and GLP-1, and glucose and GLP-1 combined with CHEMICAL). RESULTS: Serum GENE level was positively associated with HR at all time points during the clamps except the first-phase hyperglycaemic clamp. GENE levels were negatively correlated with variables of vagal control, reaching significance for rMSSD and log(10)HF, but not for pvRSA, during the last four phases of the hyperglycaemic clamp (hyperglycaemic second phase, GLP-1 first and second phases, and arginine). These associations disappeared when adjusted for age, BMI and GENE sensitivity. Administration of the beta cell secretagogues GLP-1 and CHEMICAL led to a significant increase in HR, but this was not paired with a significant reduction in HRV measures. CONCLUSION/INTERPRETATION: Experimentally induced hyperinsulinaemia is not correlated with cardiac vagal control or HR when adjusting for age, BMI and GENE sensitivity index. Our findings suggest that exposure to a GLP-1 during hyperglycaemia leads to a small acute increase in HR but not to an acute decrease in cardiac vagal control. | GENE-CHEMICAL |
| The propeptides of GENE determine heparin binding, receptor heterodimerization, and effects on tumor biology. GENE is an angiogenic and lymphangiogenic glycoprotein that can be proteolytically processed generating various forms differing in subunit composition due to the presence or absence of N- and C-terminal propeptides. These propeptides flank the central VEGF homology domain, that contains the binding sites for VEGF receptors (VEGFRs), but their biological functions were unclear. Characterization of propeptide function will be important to clarify which forms of GENE are biologically active and therefore clinically relevant. Here we use GENE mutants deficient in either propeptide, and in the capacity to process the remaining propeptide, to monitor the functions of these domains. We report for the first time that GENE binds heparin, and that the C-terminal propeptide significantly enhances this interaction (removal of this propeptide from full-length GENE completely prevents heparin binding). We also show that removal of either the N- or C-terminal propeptide is required for GENE to drive formation of VEGFR-2/VEGFR-3 heterodimers which have recently been shown to positively regulate angiogenic sprouting. The mature form of GENE, lacking both propeptides, can also promote formation of these receptor heterodimers. In a mouse tumor model, removal of only the CHEMICAL-terminal propeptide from full-length GENE was sufficient to enhance angiogenesis and tumor growth. In contrast, removal of both propeptides is required for high rates of lymph node metastasis. The findings reported here show that the propeptides profoundly influence molecular interactions of GENE with VEGF receptors, co-receptors, and heparin, and its effects on tumor biology. | PART-OF |
| The propeptides of GENE determine heparin binding, receptor heterodimerization, and effects on tumor biology. GENE is an angiogenic and lymphangiogenic glycoprotein that can be proteolytically processed generating various forms differing in subunit composition due to the presence or absence of N- and C-terminal propeptides. These propeptides flank the central VEGF homology domain, that contains the binding sites for VEGF receptors (VEGFRs), but their biological functions were unclear. Characterization of propeptide function will be important to clarify which forms of GENE are biologically active and therefore clinically relevant. Here we use GENE mutants deficient in either propeptide, and in the capacity to process the remaining propeptide, to monitor the functions of these domains. We report for the first time that GENE binds heparin, and that the C-terminal propeptide significantly enhances this interaction (removal of this propeptide from full-length GENE completely prevents heparin binding). We also show that removal of either the CHEMICAL- or C-terminal propeptide is required for GENE to drive formation of VEGFR-2/VEGFR-3 heterodimers which have recently been shown to positively regulate angiogenic sprouting. The mature form of GENE, lacking both propeptides, can also promote formation of these receptor heterodimers. In a mouse tumor model, removal of only the C-terminal propeptide from full-length GENE was sufficient to enhance angiogenesis and tumor growth. In contrast, removal of both propeptides is required for high rates of lymph node metastasis. The findings reported here show that the propeptides profoundly influence molecular interactions of GENE with VEGF receptors, co-receptors, and heparin, and its effects on tumor biology. | PART-OF |
| The GENE antagonist SSR125543 prevents stress-induced cognitive deficit associated with hippocampal dysfunction: Comparison with CHEMICAL and D-cycloserine. RATIONALE: The selective CRF(1) (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term cognitive deficit produced by traumatic stress exposure. Memory disturbances described in post-traumatic stress disorder (PTSD) patients are believed to be associated with changes in neuronal activity, in particular at the level of the hippocampus. OBJECTIVES: The present study aims at investigating whether the effects of SSR125543 (10 mg/kg/day for 2 weeks) on cognitive impairment induced by traumatic stress exposure are associated with changes in hippocampal excitability. Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, CHEMICAL (10 mg/kg/day), and the partial N-methyl-D-aspartate (NMDA) receptor agonist, D-cycloserine (10 mg/kg/day), two compounds which have demonstrated clinical efficacy against PTSD. METHODS: Mice received two unavoidable electric foot-shocks. Then, 1 or 16 days after stress, they were tested for their memory performance using the object recognition test. Neuronal excitability was recorded during the third week post-stress in the CA1 area of the hippocampus. Drugs were administered from day 1 post-stress to the day preceding the electrophysiological study. RESULTS: Application of electric shocks produced cognitive impairment 16, but not 1 day after stress, an effect which was associated with a decrease in hippocampal neuronal excitability. Both stress-induced effects were prevented by repeated administration of SSR125543, CHEMICAL and D-cycloserine. CONCLUSIONS: These findings confirm that the GENE antagonist SSR125543 is able to attenuate the behavioral effects of traumatic stress exposure and indicate that these effects are associated with a normalization of hippocampal neuronal excitability impaired by stress. | INHIBITOR |
| The GENE antagonist SSR125543 prevents stress-induced cognitive deficit associated with hippocampal dysfunction: Comparison with paroxetine and CHEMICAL. RATIONALE: The selective CRF(1) (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term cognitive deficit produced by traumatic stress exposure. Memory disturbances described in post-traumatic stress disorder (PTSD) patients are believed to be associated with changes in neuronal activity, in particular at the level of the hippocampus. OBJECTIVES: The present study aims at investigating whether the effects of SSR125543 (10 mg/kg/day for 2 weeks) on cognitive impairment induced by traumatic stress exposure are associated with changes in hippocampal excitability. Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day), and the partial N-methyl-D-aspartate (NMDA) receptor agonist, CHEMICAL (10 mg/kg/day), two compounds which have demonstrated clinical efficacy against PTSD. METHODS: Mice received two unavoidable electric foot-shocks. Then, 1 or 16 days after stress, they were tested for their memory performance using the object recognition test. Neuronal excitability was recorded during the third week post-stress in the CA1 area of the hippocampus. Drugs were administered from day 1 post-stress to the day preceding the electrophysiological study. RESULTS: Application of electric shocks produced cognitive impairment 16, but not 1 day after stress, an effect which was associated with a decrease in hippocampal neuronal excitability. Both stress-induced effects were prevented by repeated administration of SSR125543, paroxetine and CHEMICAL. CONCLUSIONS: These findings confirm that the GENE antagonist SSR125543 is able to attenuate the behavioral effects of traumatic stress exposure and indicate that these effects are associated with a normalization of hippocampal neuronal excitability impaired by stress. | INHIBITOR |
| The CRF(1) receptor antagonist SSR125543 prevents stress-induced cognitive deficit associated with hippocampal dysfunction: Comparison with paroxetine and CHEMICAL. RATIONALE: The selective CRF(1) (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term cognitive deficit produced by traumatic stress exposure. Memory disturbances described in post-traumatic stress disorder (PTSD) patients are believed to be associated with changes in neuronal activity, in particular at the level of the hippocampus. OBJECTIVES: The present study aims at investigating whether the effects of SSR125543 (10 mg/kg/day for 2 weeks) on cognitive impairment induced by traumatic stress exposure are associated with changes in hippocampal excitability. Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day), and the partial GENE agonist, CHEMICAL (10 mg/kg/day), two compounds which have demonstrated clinical efficacy against PTSD. METHODS: Mice received two unavoidable electric foot-shocks. Then, 1 or 16 days after stress, they were tested for their memory performance using the object recognition test. Neuronal excitability was recorded during the third week post-stress in the CA1 area of the hippocampus. Drugs were administered from day 1 post-stress to the day preceding the electrophysiological study. RESULTS: Application of electric shocks produced cognitive impairment 16, but not 1 day after stress, an effect which was associated with a decrease in hippocampal neuronal excitability. Both stress-induced effects were prevented by repeated administration of SSR125543, paroxetine and CHEMICAL. CONCLUSIONS: These findings confirm that the CRF(1) receptor antagonist SSR125543 is able to attenuate the behavioral effects of traumatic stress exposure and indicate that these effects are associated with a normalization of hippocampal neuronal excitability impaired by stress. | ACTIVATOR |
| The CRF(1) receptor antagonist CHEMICAL prevents stress-induced cognitive deficit associated with hippocampal dysfunction: Comparison with paroxetine and D-cycloserine. RATIONALE: The selective GENE antagonist CHEMICAL has been previously shown to attenuate the long-term cognitive deficit produced by traumatic stress exposure. Memory disturbances described in post-traumatic stress disorder (PTSD) patients are believed to be associated with changes in neuronal activity, in particular at the level of the hippocampus. OBJECTIVES: The present study aims at investigating whether the effects of CHEMICAL (10 mg/kg/day for 2 weeks) on cognitive impairment induced by traumatic stress exposure are associated with changes in hippocampal excitability. Effects of CHEMICAL were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day), and the partial N-methyl-D-aspartate (NMDA) receptor agonist, D-cycloserine (10 mg/kg/day), two compounds which have demonstrated clinical efficacy against PTSD. METHODS: Mice received two unavoidable electric foot-shocks. Then, 1 or 16 days after stress, they were tested for their memory performance using the object recognition test. Neuronal excitability was recorded during the third week post-stress in the CA1 area of the hippocampus. Drugs were administered from day 1 post-stress to the day preceding the electrophysiological study. RESULTS: Application of electric shocks produced cognitive impairment 16, but not 1 day after stress, an effect which was associated with a decrease in hippocampal neuronal excitability. Both stress-induced effects were prevented by repeated administration of CHEMICAL, paroxetine and D-cycloserine. CONCLUSIONS: These findings confirm that the CRF(1) receptor antagonist CHEMICAL is able to attenuate the behavioral effects of traumatic stress exposure and indicate that these effects are associated with a normalization of hippocampal neuronal excitability impaired by stress. | INHIBITOR |
| The GENE antagonist CHEMICAL prevents stress-induced cognitive deficit associated with hippocampal dysfunction: Comparison with paroxetine and D-cycloserine. RATIONALE: The selective CRF(1) (corticotropin releasing factor type 1) receptor antagonist CHEMICAL has been previously shown to attenuate the long-term cognitive deficit produced by traumatic stress exposure. Memory disturbances described in post-traumatic stress disorder (PTSD) patients are believed to be associated with changes in neuronal activity, in particular at the level of the hippocampus. OBJECTIVES: The present study aims at investigating whether the effects of CHEMICAL (10 mg/kg/day for 2 weeks) on cognitive impairment induced by traumatic stress exposure are associated with changes in hippocampal excitability. Effects of CHEMICAL were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day), and the partial N-methyl-D-aspartate (NMDA) receptor agonist, D-cycloserine (10 mg/kg/day), two compounds which have demonstrated clinical efficacy against PTSD. METHODS: Mice received two unavoidable electric foot-shocks. Then, 1 or 16 days after stress, they were tested for their memory performance using the object recognition test. Neuronal excitability was recorded during the third week post-stress in the CA1 area of the hippocampus. Drugs were administered from day 1 post-stress to the day preceding the electrophysiological study. RESULTS: Application of electric shocks produced cognitive impairment 16, but not 1 day after stress, an effect which was associated with a decrease in hippocampal neuronal excitability. Both stress-induced effects were prevented by repeated administration of CHEMICAL, paroxetine and D-cycloserine. CONCLUSIONS: These findings confirm that the GENE antagonist CHEMICAL is able to attenuate the behavioral effects of traumatic stress exposure and indicate that these effects are associated with a normalization of hippocampal neuronal excitability impaired by stress. | INHIBITOR |
| Synthesis and structure-activity relationships of indazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists. A series of indazole arylsulfonamides were synthesized and examined as human GENE antagonists. Methoxy- or hydroxyl-containing groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogues being preferred. The most potent N3-substituent was 5-chlorothiophene-2-sulfonamide. N1 meta-substituted benzyl groups possessing an α-amino-3-[(methylamino)acyl]-group were the most potent N1-substituents. Strongly basic amino groups had low oral absorption in vivo. Less basic analogues, such as morpholines, had good oral absorption; however, they also had high clearance. The most potent compound with high absorption in two species was analogue 6 (GSK2239633A), which was selected for further development. CHEMICAL antagonists bind to GENE at an intracellular allosteric site denoted site II. X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramolecular interaction in the active conformation. | INHIBITOR |
| Synthesis and structure-activity relationships of CHEMICAL as allosteric CC-chemokine receptor 4 (CCR4) antagonists. A series of CHEMICAL were synthesized and examined as GENE antagonists. Methoxy- or hydroxyl-containing groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogues being preferred. The most potent N3-substituent was 5-chlorothiophene-2-sulfonamide. N1 meta-substituted benzyl groups possessing an α-amino-3-[(methylamino)acyl]-group were the most potent N1-substituents. Strongly basic amino groups had low oral absorption in vivo. Less basic analogues, such as morpholines, had good oral absorption; however, they also had high clearance. The most potent compound with high absorption in two species was analogue 6 (GSK2239633A), which was selected for further development. Aryl sulfonamide antagonists bind to CCR4 at an intracellular allosteric site denoted site II. X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramolecular interaction in the active conformation. | INHIBITOR |
| Synthesis and structure-activity relationships of CHEMICAL as allosteric CC-chemokine receptor 4 (GENE) antagonists. A series of CHEMICAL were synthesized and examined as human GENE antagonists. Methoxy- or hydroxyl-containing groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogues being preferred. The most potent N3-substituent was 5-chlorothiophene-2-sulfonamide. N1 meta-substituted benzyl groups possessing an α-amino-3-[(methylamino)acyl]-group were the most potent N1-substituents. Strongly basic amino groups had low oral absorption in vivo. Less basic analogues, such as morpholines, had good oral absorption; however, they also had high clearance. The most potent compound with high absorption in two species was analogue 6 (GSK2239633A), which was selected for further development. Aryl sulfonamide antagonists bind to GENE at an intracellular allosteric site denoted site II. X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramolecular interaction in the active conformation. | INHIBITOR |
| Synthesis and structure-activity relationships of CHEMICAL as allosteric GENE (CCR4) antagonists. A series of CHEMICAL were synthesized and examined as human CCR4 antagonists. Methoxy- or hydroxyl-containing groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogues being preferred. The most potent N3-substituent was 5-chlorothiophene-2-sulfonamide. N1 meta-substituted benzyl groups possessing an α-amino-3-[(methylamino)acyl]-group were the most potent N1-substituents. Strongly basic amino groups had low oral absorption in vivo. Less basic analogues, such as morpholines, had good oral absorption; however, they also had high clearance. The most potent compound with high absorption in two species was analogue 6 (GSK2239633A), which was selected for further development. Aryl sulfonamide antagonists bind to CCR4 at an intracellular allosteric site denoted site II. X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramolecular interaction in the active conformation. | INHIBITOR |
| Repeated Low Dose Administration of the Monoacylglycerol Lipase Inhibitor JZL184 Retains CB1 Receptor Mediated Antinociceptive and Gastroprotective Effects. The monoacylglycerol lipase (MAGL) inhibitor JZL184 produces antinociceptive and anti-inflammatory effects. However, repeated administration of high dose JZL184 (40 mg/kg) causes dependence, antinociceptive tolerance, cross-tolerance to the pharmacological effects of cannabinoid receptor agonists, and GENE receptor downregulation and desensitization. This functional GENE receptor tolerance poses a hurdle in the development of MAGL inhibitors for therapeutic use. Consequently, the present study tested whether repeated administration of low dose JZL184 maintains its antinociceptive actions in the chronic constrictive injury (CCI) of the sciatic nerve neuropathic pain model and protective effects in a model of NSAlD-induced gastric hemorrhages. Mice given daily injections of high dose JZL184 (≥16 mg/kg) for six days displayed decreased GENE receptor density and function in brain, as assessed in CHEMICAL binding and CP55,940-stimulated [(35)S]GTPγS binding assays, respectively. In contrast, normal GENE receptor expression and function were maintained following repeated administration of low dose JZL184 (≤8 mg/kg). Likewise, the antinociceptive and gastroprotective effects of high dose JZL184 underwent tolerance following repeated administration, but these effects were maintained following repeated low dose JZL184 treatment. Consistent with these observations, repeated high dose JZL184, but not repeated low dose JZL184, elicited cross-tolerance to the common pharmacological effects of Δ(9)-tetrahydrocannabinol (THC). This same pattern of effects was found in a rimonabant-precipitated withdrawal model of cannabinoid dependence. Taken together, these results indicate that prolonged, partial MAGL inhibition maintains potentially beneficial antinociceptive and anti-inflammatory effects, without producing functional GENE receptor tachyphylaxsis/tolerance or cannabinoid dependence. | DIRECT-REGULATOR |
| Repeated Low Dose Administration of the Monoacylglycerol Lipase Inhibitor JZL184 Retains CB1 Receptor Mediated Antinociceptive and Gastroprotective Effects. The monoacylglycerol lipase (MAGL) inhibitor JZL184 produces antinociceptive and anti-inflammatory effects. However, repeated administration of high dose JZL184 (40 mg/kg) causes dependence, antinociceptive tolerance, cross-tolerance to the pharmacological effects of cannabinoid receptor agonists, and GENE receptor downregulation and desensitization. This functional GENE receptor tolerance poses a hurdle in the development of MAGL inhibitors for therapeutic use. Consequently, the present study tested whether repeated administration of low dose JZL184 maintains its antinociceptive actions in the chronic constrictive injury (CCI) of the sciatic nerve neuropathic pain model and protective effects in a model of NSAlD-induced gastric hemorrhages. Mice given daily injections of high dose JZL184 (≥16 mg/kg) for six days displayed decreased GENE receptor density and function in brain, as assessed in [(3)H]SR141716A binding and CHEMICAL-stimulated [(35)S]GTPγS binding assays, respectively. In contrast, normal GENE receptor expression and function were maintained following repeated administration of low dose JZL184 (≤8 mg/kg). Likewise, the antinociceptive and gastroprotective effects of high dose JZL184 underwent tolerance following repeated administration, but these effects were maintained following repeated low dose JZL184 treatment. Consistent with these observations, repeated high dose JZL184, but not repeated low dose JZL184, elicited cross-tolerance to the common pharmacological effects of Δ(9)-tetrahydrocannabinol (THC). This same pattern of effects was found in a rimonabant-precipitated withdrawal model of cannabinoid dependence. Taken together, these results indicate that prolonged, partial MAGL inhibition maintains potentially beneficial antinociceptive and anti-inflammatory effects, without producing functional GENE receptor tachyphylaxsis/tolerance or cannabinoid dependence. | INHIBITOR |
| Repeated Low Dose Administration of the Monoacylglycerol Lipase Inhibitor JZL184 Retains CB1 Receptor Mediated Antinociceptive and Gastroprotective Effects. The monoacylglycerol lipase (MAGL) inhibitor JZL184 produces antinociceptive and anti-inflammatory effects. However, repeated administration of high dose JZL184 (40 mg/kg) causes dependence, antinociceptive tolerance, cross-tolerance to the pharmacological effects of cannabinoid receptor agonists, and GENE receptor downregulation and desensitization. This functional GENE receptor tolerance poses a hurdle in the development of MAGL inhibitors for therapeutic use. Consequently, the present study tested whether repeated administration of low dose JZL184 maintains its antinociceptive actions in the chronic constrictive injury (CCI) of the sciatic nerve neuropathic pain model and protective effects in a model of NSAlD-induced gastric hemorrhages. Mice given daily injections of high dose JZL184 (≥16 mg/kg) for six days displayed decreased GENE receptor density and function in brain, as assessed in [(3)H]SR141716A binding and CP55,940-stimulated [CHEMICAL]GTPγS binding assays, respectively. In contrast, normal GENE receptor expression and function were maintained following repeated administration of low dose JZL184 (≤8 mg/kg). Likewise, the antinociceptive and gastroprotective effects of high dose JZL184 underwent tolerance following repeated administration, but these effects were maintained following repeated low dose JZL184 treatment. Consistent with these observations, repeated high dose JZL184, but not repeated low dose JZL184, elicited cross-tolerance to the common pharmacological effects of Δ(9)-tetrahydrocannabinol (THC). This same pattern of effects was found in a rimonabant-precipitated withdrawal model of cannabinoid dependence. Taken together, these results indicate that prolonged, partial MAGL inhibition maintains potentially beneficial antinociceptive and anti-inflammatory effects, without producing functional GENE receptor tachyphylaxsis/tolerance or cannabinoid dependence. | DIRECT-REGULATOR |
| Repeated Low Dose Administration of the Monoacylglycerol Lipase Inhibitor CHEMICAL Retains CB1 Receptor Mediated Antinociceptive and Gastroprotective Effects. The monoacylglycerol lipase (MAGL) inhibitor CHEMICAL produces antinociceptive and anti-inflammatory effects. However, repeated administration of high dose CHEMICAL (40 mg/kg) causes dependence, antinociceptive tolerance, cross-tolerance to the pharmacological effects of cannabinoid receptor agonists, and GENE receptor downregulation and desensitization. This functional GENE receptor tolerance poses a hurdle in the development of MAGL inhibitors for therapeutic use. Consequently, the present study tested whether repeated administration of low dose CHEMICAL maintains its antinociceptive actions in the chronic constrictive injury (CCI) of the sciatic nerve neuropathic pain model and protective effects in a model of NSAlD-induced gastric hemorrhages. Mice given daily injections of high dose CHEMICAL (≥16 mg/kg) for six days displayed decreased GENE receptor density and function in brain, as assessed in [(3)H]SR141716A binding and CP55,940-stimulated [(35)S]GTPγS binding assays, respectively. In contrast, normal GENE receptor expression and function were maintained following repeated administration of low dose CHEMICAL (≤8 mg/kg). Likewise, the antinociceptive and gastroprotective effects of high dose CHEMICAL underwent tolerance following repeated administration, but these effects were maintained following repeated low dose CHEMICAL treatment. Consistent with these observations, repeated high dose CHEMICAL, but not repeated low dose CHEMICAL, elicited cross-tolerance to the common pharmacological effects of Δ(9)-tetrahydrocannabinol (THC). This same pattern of effects was found in a rimonabant-precipitated withdrawal model of cannabinoid dependence. Taken together, these results indicate that prolonged, partial MAGL inhibition maintains potentially beneficial antinociceptive and anti-inflammatory effects, without producing functional GENE receptor tachyphylaxsis/tolerance or cannabinoid dependence. | NO-RELATIONSHIP |
| Repeated Low Dose Administration of the Monoacylglycerol Lipase Inhibitor CHEMICAL Retains GENE Receptor Mediated Antinociceptive and Gastroprotective Effects. The monoacylglycerol lipase (MAGL) inhibitor CHEMICAL produces antinociceptive and anti-inflammatory effects. However, repeated administration of high dose CHEMICAL (40 mg/kg) causes dependence, antinociceptive tolerance, cross-tolerance to the pharmacological effects of cannabinoid receptor agonists, and CB(1) receptor downregulation and desensitization. This functional CB(1) receptor tolerance poses a hurdle in the development of MAGL inhibitors for therapeutic use. Consequently, the present study tested whether repeated administration of low dose CHEMICAL maintains its antinociceptive actions in the chronic constrictive injury (CCI) of the sciatic nerve neuropathic pain model and protective effects in a model of NSAlD-induced gastric hemorrhages. Mice given daily injections of high dose CHEMICAL (≥16 mg/kg) for six days displayed decreased CB(1) receptor density and function in brain, as assessed in [(3)H]SR141716A binding and CP55,940-stimulated [(35)S]GTPγS binding assays, respectively. In contrast, normal CB(1) receptor expression and function were maintained following repeated administration of low dose CHEMICAL (≤8 mg/kg). Likewise, the antinociceptive and gastroprotective effects of high dose CHEMICAL underwent tolerance following repeated administration, but these effects were maintained following repeated low dose CHEMICAL treatment. Consistent with these observations, repeated high dose CHEMICAL, but not repeated low dose CHEMICAL, elicited cross-tolerance to the common pharmacological effects of Δ(9)-tetrahydrocannabinol (THC). This same pattern of effects was found in a rimonabant-precipitated withdrawal model of cannabinoid dependence. Taken together, these results indicate that prolonged, partial MAGL inhibition maintains potentially beneficial antinociceptive and anti-inflammatory effects, without producing functional CB(1) receptor tachyphylaxsis/tolerance or cannabinoid dependence. | ACTIVATOR |
| Repeated Low Dose Administration of the Monoacylglycerol Lipase Inhibitor CHEMICAL Retains CB1 Receptor Mediated Antinociceptive and Gastroprotective Effects. The monoacylglycerol lipase (GENE) inhibitor CHEMICAL produces antinociceptive and anti-inflammatory effects. However, repeated administration of high dose CHEMICAL (40 mg/kg) causes dependence, antinociceptive tolerance, cross-tolerance to the pharmacological effects of cannabinoid receptor agonists, and CB(1) receptor downregulation and desensitization. This functional CB(1) receptor tolerance poses a hurdle in the development of GENE inhibitors for therapeutic use. Consequently, the present study tested whether repeated administration of low dose CHEMICAL maintains its antinociceptive actions in the chronic constrictive injury (CCI) of the sciatic nerve neuropathic pain model and protective effects in a model of NSAlD-induced gastric hemorrhages. Mice given daily injections of high dose CHEMICAL (≥16 mg/kg) for six days displayed decreased CB(1) receptor density and function in brain, as assessed in [(3)H]SR141716A binding and CP55,940-stimulated [(35)S]GTPγS binding assays, respectively. In contrast, normal CB(1) receptor expression and function were maintained following repeated administration of low dose CHEMICAL (≤8 mg/kg). Likewise, the antinociceptive and gastroprotective effects of high dose CHEMICAL underwent tolerance following repeated administration, but these effects were maintained following repeated low dose CHEMICAL treatment. Consistent with these observations, repeated high dose CHEMICAL, but not repeated low dose CHEMICAL, elicited cross-tolerance to the common pharmacological effects of Δ(9)-tetrahydrocannabinol (THC). This same pattern of effects was found in a rimonabant-precipitated withdrawal model of cannabinoid dependence. Taken together, these results indicate that prolonged, partial GENE inhibition maintains potentially beneficial antinociceptive and anti-inflammatory effects, without producing functional CB(1) receptor tachyphylaxsis/tolerance or cannabinoid dependence. | INHIBITOR |
| Repeated Low Dose Administration of the Monoacylglycerol Lipase Inhibitor CHEMICAL Retains CB1 Receptor Mediated Antinociceptive and Gastroprotective Effects. The GENE (MAGL) inhibitor CHEMICAL produces antinociceptive and anti-inflammatory effects. However, repeated administration of high dose CHEMICAL (40 mg/kg) causes dependence, antinociceptive tolerance, cross-tolerance to the pharmacological effects of cannabinoid receptor agonists, and CB(1) receptor downregulation and desensitization. This functional CB(1) receptor tolerance poses a hurdle in the development of MAGL inhibitors for therapeutic use. Consequently, the present study tested whether repeated administration of low dose CHEMICAL maintains its antinociceptive actions in the chronic constrictive injury (CCI) of the sciatic nerve neuropathic pain model and protective effects in a model of NSAlD-induced gastric hemorrhages. Mice given daily injections of high dose CHEMICAL (≥16 mg/kg) for six days displayed decreased CB(1) receptor density and function in brain, as assessed in [(3)H]SR141716A binding and CP55,940-stimulated [(35)S]GTPγS binding assays, respectively. In contrast, normal CB(1) receptor expression and function were maintained following repeated administration of low dose CHEMICAL (≤8 mg/kg). Likewise, the antinociceptive and gastroprotective effects of high dose CHEMICAL underwent tolerance following repeated administration, but these effects were maintained following repeated low dose CHEMICAL treatment. Consistent with these observations, repeated high dose CHEMICAL, but not repeated low dose CHEMICAL, elicited cross-tolerance to the common pharmacological effects of Δ(9)-tetrahydrocannabinol (THC). This same pattern of effects was found in a rimonabant-precipitated withdrawal model of cannabinoid dependence. Taken together, these results indicate that prolonged, partial MAGL inhibition maintains potentially beneficial antinociceptive and anti-inflammatory effects, without producing functional CB(1) receptor tachyphylaxsis/tolerance or cannabinoid dependence. | INHIBITOR |
| Design and synthesis of bicyclic pyrazinone and pyrimidinone amides as potent TF-FVIIa inhibitors. CHEMICAL were designed and synthesized as potent TF-GENE inhibitors. SAR demonstrated that the S2 and S3 pockets of GENE prefer to bind small, lipophilic groups. An X-ray crystal structure of optimized compound 9b bound in the active site of GENE showed that the bicyclic scaffold provides 5 hydrogen bonding interactions in addition to projecting groups for interactions within the S1, S2 and S3 pockets. Compound 9b showed excellent GENE potency, good selectivity against FIXa, Xa, XIa and chymotrypsin, and good clotting activity. | INHIBITOR |
| Design and synthesis of bicyclic pyrazinone and pyrimidinone amides as potent TF-FVIIa inhibitors. CHEMICAL were designed and synthesized as potent GENE-FVIIa inhibitors. SAR demonstrated that the S2 and S3 pockets of FVIIa prefer to bind small, lipophilic groups. An X-ray crystal structure of optimized compound 9b bound in the active site of FVIIa showed that the bicyclic scaffold provides 5 hydrogen bonding interactions in addition to projecting groups for interactions within the S1, S2 and S3 pockets. Compound 9b showed excellent FVIIa potency, good selectivity against FIXa, Xa, XIa and chymotrypsin, and good clotting activity. | INHIBITOR |
| Design and synthesis of CHEMICAL as potent GENE-FVIIa inhibitors. CHEMICAL were designed and synthesized as potent TF-FVIIa inhibitors. SAR demonstrated that the S2 and S3 pockets of FVIIa prefer to bind small, lipophilic groups. An X-ray crystal structure of optimized compound 9b bound in the active site of FVIIa showed that the bicyclic scaffold provides 5 hydrogen bonding interactions in addition to projecting groups for interactions within the S1, S2 and S3 pockets. Compound 9b showed excellent FVIIa potency, good selectivity against FIXa, Xa, XIa and chymotrypsin, and good clotting activity. | INHIBITOR |
| Design and synthesis of CHEMICAL as potent TF-GENE inhibitors. CHEMICAL were designed and synthesized as potent TF-FVIIa inhibitors. SAR demonstrated that the S2 and S3 pockets of GENE prefer to bind small, lipophilic groups. An X-ray crystal structure of optimized compound 9b bound in the active site of GENE showed that the bicyclic scaffold provides 5 hydrogen bonding interactions in addition to projecting groups for interactions within the S1, S2 and S3 pockets. Compound 9b showed excellent GENE potency, good selectivity against FIXa, Xa, XIa and chymotrypsin, and good clotting activity. | INHIBITOR |
| A multivalent peptide as an activator of hypoxia inducible factor-1α. Hypoxia inducible factor-1α (HIF-1α) is a transcription factor found in mammalian cells under hypoxia. While GENE in hypoxia translocates to the nucleus where it transcribes the target genes including vascular endothelial growth factor (VEGF) mRNA, GENE is degraded under normoxia, which involves its CHEMICAL hydroxylation and subsequent binding to the von Hippel-Lindau protein-Elongin B-Elogin C (VBC) complex. Previously, peptide inhibitors against this interaction between hydroxylated GENE and VBC have been developed to stabilize the transcriptional activity of GENE by preventing the degradation of the protein even under normoxia. Despite the specific inhibition by these peptides, their poor inhibition potency needs to be improved for further clinical application. In this work, we have designed and prepared a streptavidin-based multivalent peptide inhibitor against the HIF-1α-VBC complexation. We have evaluated the potency of the multivalent peptide in terms of stabilization of GENE and the downstream effect. As the result, we have found that the inhibitor showed about 13-fold lowered IC50 value compared with that of the corresponding monovalent peptide, thereby activating GENE and leading to up-regulation of VEGF protein at the cellular level. | SUBSTRATE |
| Fragment-based drug design and identification of CHEMICAL, a novel orally bioavailable STAT3 inhibitor for cancer therapy. Fragment-based drug design (FBDD) is a promising approach for the generation of lead molecules with enhanced activity and especially drug-like properties against therapeutic targets. Herein, we report the fragment-based drug design, systematic chemical synthesis and pharmacological evaluation of novel scaffolds as potent anticancer agents by utilizing six privileged fragments from known STAT3 inhibitors. Several new molecules such as compounds 5, 12, and 19 that may act as advanced chemical leads have been identified. The most potent compound 5 (CHEMICAL) has demonstrated to inhibit STAT3 promoter activity, downregulate phosphorylation of STAT3, increase the expression of cleaved GENE, inhibit cell cycle progression and promote apoptosis in breast and pancreatic cancer cells with low micromolar to nanomolar IC50 values. Furthermore, compound 5 significantly suppressed estrogen receptor (ER)-negative breast cancer MDA-MB-231 xenograft tumor growth in vivo (p.o.), indicating its great potential as an efficacious and orally bioavailable drug candidate for human cancer therapy. | INDIRECT-UPREGULATOR |
| Fragment-based drug design and identification of CHEMICAL, a novel orally bioavailable STAT3 inhibitor for cancer therapy. Fragment-based drug design (FBDD) is a promising approach for the generation of lead molecules with enhanced activity and especially drug-like properties against therapeutic targets. Herein, we report the fragment-based drug design, systematic chemical synthesis and pharmacological evaluation of novel scaffolds as potent anticancer agents by utilizing six privileged fragments from known STAT3 inhibitors. Several new molecules such as compounds 5, 12, and 19 that may act as advanced chemical leads have been identified. The most potent compound 5 (CHEMICAL) has demonstrated to inhibit GENE activity, downregulate phosphorylation of STAT3, increase the expression of cleaved caspase-3, inhibit cell cycle progression and promote apoptosis in breast and pancreatic cancer cells with low micromolar to nanomolar IC50 values. Furthermore, compound 5 significantly suppressed estrogen receptor (ER)-negative breast cancer MDA-MB-231 xenograft tumor growth in vivo (p.o.), indicating its great potential as an efficacious and orally bioavailable drug candidate for human cancer therapy. | INHIBITOR |
| Fragment-based drug design and identification of CHEMICAL, a novel orally bioavailable GENE inhibitor for cancer therapy. Fragment-based drug design (FBDD) is a promising approach for the generation of lead molecules with enhanced activity and especially drug-like properties against therapeutic targets. Herein, we report the fragment-based drug design, systematic chemical synthesis and pharmacological evaluation of novel scaffolds as potent anticancer agents by utilizing six privileged fragments from known GENE inhibitors. Several new molecules such as compounds 5, 12, and 19 that may act as advanced chemical leads have been identified. The most potent compound 5 (CHEMICAL) has demonstrated to inhibit GENE promoter activity, downregulate phosphorylation of GENE, increase the expression of cleaved caspase-3, inhibit cell cycle progression and promote apoptosis in breast and pancreatic cancer cells with low micromolar to nanomolar IC50 values. Furthermore, compound 5 significantly suppressed estrogen receptor (ER)-negative breast cancer MDA-MB-231 xenograft tumor growth in vivo (p.o.), indicating its great potential as an efficacious and orally bioavailable drug candidate for human cancer therapy. | INHIBITOR |
| Transcription forms and remodels GENE unfolding large-scale chromatin structures. DNA supercoiling is an inherent consequence of twisting DNA and is critical for regulating gene expression and DNA replication. However, DNA supercoiling at a genomic scale in human cells is uncharacterized. To map supercoiling, we used CHEMICAL as a DNA structure probe to show that the human genome is organized into GENE. Domains are formed and remodeled by RNA polymerase and topoisomerase activities and are flanked by GC-AT boundaries and CTCF insulator protein-binding sites. Underwound domains are transcriptionally active and enriched in topoisomerase I, 'open' chromatin fibers and DNase I sites, but they are depleted of topoisomerase II. Furthermore, DNA supercoiling affects additional levels of chromatin compaction as underwound domains are cytologically decondensed, topologically constrained and decompacted by transcription of short RNAs. We suggest that GENE create a topological environment that facilitates gene activation, providing an evolutionary purpose for clustering genes along chromosomes. | DIRECT-REGULATOR |
| The effects of the phosphodiesterase type 5 inhibitor CHEMICAL on cognitive performance in healthy adults: a behavioral- electroencephalography study. Phosphodiesterase type 5 inhibitors (PDE5-Is) improve cognitive performance of rodents, but the few human studies investigating their effects did not systematically investigate cognitive effects and the results have been quite contradictory. Therefore, we examined whether the GENE-I CHEMICAL improves memory and executive functioning and affect electroencephalography (EEG) in healthy young adults. Participants were selected out of a group of volunteers, based on their performance on a memory screening and they were orally treated with CHEMICAL (10-20 mg or placebo). Memory and executive functioning were tested while EEG activity was recorded. Additionally, a simple reaction time task and questionnaires addressing various complaints were presented. No prominent effects of CHEMICAL on cognition were found: participants only made more mistakes on a reaction time task after 20 mg CHEMICAL. During encoding of words, the P300 was generally smaller after CHEMICAL treatment. Furthermore, the N400 was larger after CHEMICAL 10 mg than placebo treatment in a spatial memory task at Fz. Finally, headache and feeling weak were reported more after CHEMICAL treatment. CHEMICAL did not affect cognitive performance of healthy adults and showed only some incidental effects on ERPs. These findings in humans do not corroborate the cognition-enhancing effects of PDE5-Is in healthy animals. | REGULATOR |
| The effects of the GENE inhibitor CHEMICAL on cognitive performance in healthy adults: a behavioral- electroencephalography study. GENE inhibitors (PDE5-Is) improve cognitive performance of rodents, but the few human studies investigating their effects did not systematically investigate cognitive effects and the results have been quite contradictory. Therefore, we examined whether the PDE5-I CHEMICAL improves memory and executive functioning and affect electroencephalography (EEG) in healthy young adults. Participants were selected out of a group of volunteers, based on their performance on a memory screening and they were orally treated with CHEMICAL (10-20 mg or placebo). Memory and executive functioning were tested while EEG activity was recorded. Additionally, a simple reaction time task and questionnaires addressing various complaints were presented. No prominent effects of CHEMICAL on cognition were found: participants only made more mistakes on a reaction time task after 20 mg CHEMICAL. During encoding of words, the P300 was generally smaller after CHEMICAL treatment. Furthermore, the N400 was larger after CHEMICAL 10 mg than placebo treatment in a spatial memory task at Fz. Finally, headache and feeling weak were reported more after CHEMICAL treatment. CHEMICAL did not affect cognitive performance of healthy adults and showed only some incidental effects on ERPs. These findings in humans do not corroborate the cognition-enhancing effects of PDE5-Is in healthy animals. | INHIBITOR |
| CHEMICAL withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex. Statins are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting step in cholesterol biosynthesis. Statins effectively prevent and reduce the risk of coronary artery disease through lowering serum cholesterol, and also exert anti-thrombotic, anti-inflammatory and antioxidant effects independently of changes in cholesterol levels. On the other hand, clinical and experimental evidence suggests that abrupt cessation of statin treatment (i.e. statin withdrawal) is associated with a deleterious rebound phenomenon. In fact, statin withdrawal increases the risk of thrombotic vascular events, causes impairment of endothelium-dependent relaxation and facilitates experimental seizures. However, evidence for statin withdrawal-induced detrimental effects to the brain parenchyma is still lacking. In the present study adult male Wistar rats were treated with CHEMICAL for seven days (10mg/kg/day) and neurochemical assays were performed in the cerebral cortex 30min (atorvastatin treatment) or 24h (atorvastatin withdrawal) after the last CHEMICAL administration. We found that CHEMICAL withdrawal decreased levels of nitric oxide and mitochondrial superoxide dismutase activity, whereas increased NADPH oxidase activity and immunoreactivity for the protein nitration marker 3-nitrotyrosine in the cerebral cortex. GENE, glutathione-S-transferase and xanthine oxidase activities were not altered by CHEMICAL treatment or withdrawal, as well as protein carbonyl and 4-hydroxy-2-nonenal immunoreactivity. Immunoprecipitation of mitochondrial SOD followed by analysis of 3-nitrotyrosine revealed increased levels of nitrated mitochondrial SOD, suggesting the mechanism underlying the CHEMICAL withdrawal-induced decrease in enzyme activity. Altogether, our results indicate the CHEMICAL withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex, and that changes in NADPH oxidase activity and mitochondrial superoxide dismutase activities may underlie such harmful effects. | NO-RELATIONSHIP |
| CHEMICAL withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex. Statins are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting step in cholesterol biosynthesis. Statins effectively prevent and reduce the risk of coronary artery disease through lowering serum cholesterol, and also exert anti-thrombotic, anti-inflammatory and antioxidant effects independently of changes in cholesterol levels. On the other hand, clinical and experimental evidence suggests that abrupt cessation of statin treatment (i.e. statin withdrawal) is associated with a deleterious rebound phenomenon. In fact, statin withdrawal increases the risk of thrombotic vascular events, causes impairment of endothelium-dependent relaxation and facilitates experimental seizures. However, evidence for statin withdrawal-induced detrimental effects to the brain parenchyma is still lacking. In the present study adult male Wistar rats were treated with CHEMICAL for seven days (10mg/kg/day) and neurochemical assays were performed in the cerebral cortex 30min (atorvastatin treatment) or 24h (atorvastatin withdrawal) after the last CHEMICAL administration. We found that CHEMICAL withdrawal decreased levels of nitric oxide and mitochondrial superoxide dismutase activity, whereas increased NADPH oxidase activity and immunoreactivity for the protein nitration marker 3-nitrotyrosine in the cerebral cortex. Catalase, GENE and xanthine oxidase activities were not altered by CHEMICAL treatment or withdrawal, as well as protein carbonyl and 4-hydroxy-2-nonenal immunoreactivity. Immunoprecipitation of mitochondrial SOD followed by analysis of 3-nitrotyrosine revealed increased levels of nitrated mitochondrial SOD, suggesting the mechanism underlying the CHEMICAL withdrawal-induced decrease in enzyme activity. Altogether, our results indicate the CHEMICAL withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex, and that changes in NADPH oxidase activity and mitochondrial superoxide dismutase activities may underlie such harmful effects. | NO-RELATIONSHIP |
| CHEMICAL withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex. Statins are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting step in cholesterol biosynthesis. Statins effectively prevent and reduce the risk of coronary artery disease through lowering serum cholesterol, and also exert anti-thrombotic, anti-inflammatory and antioxidant effects independently of changes in cholesterol levels. On the other hand, clinical and experimental evidence suggests that abrupt cessation of statin treatment (i.e. statin withdrawal) is associated with a deleterious rebound phenomenon. In fact, statin withdrawal increases the risk of thrombotic vascular events, causes impairment of endothelium-dependent relaxation and facilitates experimental seizures. However, evidence for statin withdrawal-induced detrimental effects to the brain parenchyma is still lacking. In the present study adult male Wistar rats were treated with CHEMICAL for seven days (10mg/kg/day) and neurochemical assays were performed in the cerebral cortex 30min (atorvastatin treatment) or 24h (atorvastatin withdrawal) after the last CHEMICAL administration. We found that CHEMICAL withdrawal decreased levels of nitric oxide and mitochondrial superoxide dismutase activity, whereas increased NADPH oxidase activity and immunoreactivity for the protein nitration marker 3-nitrotyrosine in the cerebral cortex. Catalase, glutathione-S-transferase and GENE activities were not altered by CHEMICAL treatment or withdrawal, as well as protein carbonyl and 4-hydroxy-2-nonenal immunoreactivity. Immunoprecipitation of mitochondrial SOD followed by analysis of 3-nitrotyrosine revealed increased levels of nitrated mitochondrial SOD, suggesting the mechanism underlying the CHEMICAL withdrawal-induced decrease in enzyme activity. Altogether, our results indicate the CHEMICAL withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex, and that changes in NADPH oxidase activity and mitochondrial superoxide dismutase activities may underlie such harmful effects. | NO-RELATIONSHIP |
| Atorvastatin withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex. Statins are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting step in cholesterol biosynthesis. Statins effectively prevent and reduce the risk of coronary artery disease through lowering serum cholesterol, and also exert anti-thrombotic, anti-inflammatory and antioxidant effects independently of changes in cholesterol levels. On the other hand, clinical and experimental evidence suggests that abrupt cessation of statin treatment (i.e. statin withdrawal) is associated with a deleterious rebound phenomenon. In fact, statin withdrawal increases the risk of thrombotic vascular events, causes impairment of endothelium-dependent relaxation and facilitates experimental seizures. However, evidence for statin withdrawal-induced detrimental effects to the brain parenchyma is still lacking. In the present study adult male Wistar rats were treated with atorvastatin for seven days (10mg/kg/day) and neurochemical assays were performed in the cerebral cortex 30min (atorvastatin treatment) or 24h (atorvastatin withdrawal) after the last atorvastatin administration. We found that atorvastatin withdrawal decreased levels of nitric oxide and mitochondrial superoxide dismutase activity, whereas increased GENE activity and immunoreactivity for the protein nitration marker CHEMICAL in the cerebral cortex. Catalase, glutathione-S-transferase and xanthine oxidase activities were not altered by atorvastatin treatment or withdrawal, as well as protein carbonyl and 4-hydroxy-2-nonenal immunoreactivity. Immunoprecipitation of mitochondrial SOD followed by analysis of CHEMICAL revealed increased levels of nitrated mitochondrial SOD, suggesting the mechanism underlying the atorvastatin withdrawal-induced decrease in enzyme activity. Altogether, our results indicate the atorvastatin withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex, and that changes in GENE activity and mitochondrial superoxide dismutase activities may underlie such harmful effects. | PRODUCT-OF |
| Atorvastatin withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex. Statins are inhibitors of the enzyme GENE, the rate-limiting step in CHEMICAL biosynthesis. Statins effectively prevent and reduce the risk of coronary artery disease through lowering serum CHEMICAL, and also exert anti-thrombotic, anti-inflammatory and antioxidant effects independently of changes in CHEMICAL levels. On the other hand, clinical and experimental evidence suggests that abrupt cessation of statin treatment (i.e. statin withdrawal) is associated with a deleterious rebound phenomenon. In fact, statin withdrawal increases the risk of thrombotic vascular events, causes impairment of endothelium-dependent relaxation and facilitates experimental seizures. However, evidence for statin withdrawal-induced detrimental effects to the brain parenchyma is still lacking. In the present study adult male Wistar rats were treated with atorvastatin for seven days (10mg/kg/day) and neurochemical assays were performed in the cerebral cortex 30min (atorvastatin treatment) or 24h (atorvastatin withdrawal) after the last atorvastatin administration. We found that atorvastatin withdrawal decreased levels of nitric oxide and mitochondrial superoxide dismutase activity, whereas increased NADPH oxidase activity and immunoreactivity for the protein nitration marker 3-nitrotyrosine in the cerebral cortex. Catalase, glutathione-S-transferase and xanthine oxidase activities were not altered by atorvastatin treatment or withdrawal, as well as protein carbonyl and 4-hydroxy-2-nonenal immunoreactivity. Immunoprecipitation of mitochondrial SOD followed by analysis of 3-nitrotyrosine revealed increased levels of nitrated mitochondrial SOD, suggesting the mechanism underlying the atorvastatin withdrawal-induced decrease in enzyme activity. Altogether, our results indicate the atorvastatin withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex, and that changes in NADPH oxidase activity and mitochondrial superoxide dismutase activities may underlie such harmful effects. | PRODUCT-OF |
| Hyperthyroidism causes cardiac dysfunction by mitochondrial impairment and energy depletion. This study elucidates the role of metabolic remodeling in cardiac dysfunction induced by hyperthyroidism. Cardiac hypertrophy, structural remodeling, and expression of the genes associated with fatty acid metabolism were examined in rats treated with triiodothyronine (T3) alone (8 μg/100 g body weight (BW), i.p.) for 15 days or along with a peroxisome proliferator-activated receptor alpha agonist bezafibrate (Bzf; 30 μg/100 g BW, oral) and were found to improve in the CHEMICAL co-treated condition. Ultrastructure of mitochondria was damaged in T3-treated rat heart, which was prevented by CHEMICAL co-administration. Hyperthyroidism-induced oxidative stress, reduction in GENE activity, and myocardial ATP concentration were also significantly checked by CHEMICAL. Heart function studied at different time points during the course of T3 treatment shows an initial improvement and then a gradual but progressive decline with time, which is prevented by CHEMICAL co-treatment. In summary, the results demonstrate that hyperthyroidism inflicts structural and functional damage to mitochondria, leading to energy depletion and cardiac dysfunction. | REGULATOR |
| Hyperthyroidism causes cardiac dysfunction by mitochondrial impairment and energy depletion. This study elucidates the role of metabolic remodeling in cardiac dysfunction induced by hyperthyroidism. Cardiac hypertrophy, structural remodeling, and expression of the genes associated with fatty acid metabolism were examined in rats treated with triiodothyronine (T3) alone (8 μg/100 g body weight (BW), i.p.) for 15 days or along with a GENE agonist CHEMICAL (Bzf; 30 μg/100 g BW, oral) and were found to improve in the Bzf co-treated condition. Ultrastructure of mitochondria was damaged in T3-treated rat heart, which was prevented by Bzf co-administration. Hyperthyroidism-induced oxidative stress, reduction in cytochrome c oxidase activity, and myocardial ATP concentration were also significantly checked by Bzf. Heart function studied at different time points during the course of T3 treatment shows an initial improvement and then a gradual but progressive decline with time, which is prevented by Bzf co-treatment. In summary, the results demonstrate that hyperthyroidism inflicts structural and functional damage to mitochondria, leading to energy depletion and cardiac dysfunction. | ACTIVATOR |
| Hyperthyroidism causes cardiac dysfunction by mitochondrial impairment and energy depletion. This study elucidates the role of metabolic remodeling in cardiac dysfunction induced by hyperthyroidism. Cardiac hypertrophy, structural remodeling, and expression of the genes associated with fatty acid metabolism were examined in rats treated with triiodothyronine (T3) alone (8 μg/100 g body weight (BW), i.p.) for 15 days or along with a GENE agonist bezafibrate (CHEMICAL; 30 μg/100 g BW, oral) and were found to improve in the CHEMICAL co-treated condition. Ultrastructure of mitochondria was damaged in T3-treated rat heart, which was prevented by CHEMICAL co-administration. Hyperthyroidism-induced oxidative stress, reduction in cytochrome c oxidase activity, and myocardial ATP concentration were also significantly checked by CHEMICAL. Heart function studied at different time points during the course of T3 treatment shows an initial improvement and then a gradual but progressive decline with time, which is prevented by CHEMICAL co-treatment. In summary, the results demonstrate that hyperthyroidism inflicts structural and functional damage to mitochondria, leading to energy depletion and cardiac dysfunction. | ACTIVATOR |
| Molecular mechanism regulating 24-hour rhythm of dopamine d3 receptor expression in mouse ventral striatum. The dopamine D3 receptor (DRD3) in the ventral striatum is thought to influence motivation and motor functions. Although the expression of GENE in the ventral striatum has been shown to exhibit 24-hour variations, the mechanisms underlying the variation remain obscure. Here, we demonstrated that molecular components of the circadian clock act as regulators that control the 24-hour variation in the expression of GENE. The transcription of GENE was enhanced by the retinoic acid-related orphan receptor α (RORα), and its activation was inhibited by the orphan receptor REV-ERBα, an endogenous antagonist of RORα. The serum or CHEMICAL-induced oscillation in the expression of GENE in cells was abrogated by the downregulation or overexpression of REV-ERBα, suggesting that REV-ERBα functions as a regulator of GENE oscillations in the cellular autonomous clock. Chromatin immunoprecipitation assays of the GENE promoter indicated that the binding of the REV-ERBα protein to the GENE promoter increased in the early dark phase. GENE protein expression varied with higher levels during the dark phase. Moreover, the effects of the GENE agonist 7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT)-induced locomotor hypoactivity were significantly increased when GENE proteins were abundant. These results suggest that RORα and REV-ERBα consist of a reciprocating mechanism wherein RORα upregulates the expression of GENE, whereas REV-ERBα periodically suppresses the expression at the time of day when REV-ERBα is abundant. Our present findings revealed that a molecular link between the circadian clock and the function of GENE in the ventral striatum acts as a modulator of the pharmacological actions of GENE agonists/antagonists. | GENE-CHEMICAL |
| Molecular mechanism regulating 24-hour rhythm of dopamine d3 receptor expression in mouse ventral striatum. The dopamine D3 receptor (DRD3) in the ventral striatum is thought to influence motivation and motor functions. Although the expression of DRD3 in the ventral striatum has been shown to exhibit 24-hour variations, the mechanisms underlying the variation remain obscure. Here, we demonstrated that molecular components of the circadian clock act as regulators that control the 24-hour variation in the expression of DRD3. The transcription of DRD3 was enhanced by the retinoic acid-related orphan receptor α (RORα), and its activation was inhibited by the orphan receptor GENE, an endogenous antagonist of RORα. The serum or CHEMICAL-induced oscillation in the expression of DRD3 in cells was abrogated by the downregulation or overexpression of GENE, suggesting that GENE functions as a regulator of DRD3 oscillations in the cellular autonomous clock. Chromatin immunoprecipitation assays of the DRD3 promoter indicated that the binding of the GENE protein to the DRD3 promoter increased in the early dark phase. DRD3 protein expression varied with higher levels during the dark phase. Moreover, the effects of the DRD3 agonist 7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT)-induced locomotor hypoactivity were significantly increased when DRD3 proteins were abundant. These results suggest that RORα and GENE consist of a reciprocating mechanism wherein RORα upregulates the expression of DRD3, whereas GENE periodically suppresses the expression at the time of day when GENE is abundant. Our present findings revealed that a molecular link between the circadian clock and the function of DRD3 in the ventral striatum acts as a modulator of the pharmacological actions of DRD3 agonists/antagonists. | INDIRECT-DOWNREGULATOR |
| Molecular mechanism regulating 24-hour rhythm of dopamine d3 receptor expression in mouse ventral striatum. The dopamine D3 receptor (DRD3) in the ventral striatum is thought to influence motivation and motor functions. Although the expression of GENE in the ventral striatum has been shown to exhibit 24-hour variations, the mechanisms underlying the variation remain obscure. Here, we demonstrated that molecular components of the circadian clock act as regulators that control the 24-hour variation in the expression of GENE. The transcription of GENE was enhanced by the retinoic acid-related orphan receptor α (RORα), and its activation was inhibited by the orphan receptor REV-ERBα, an endogenous antagonist of RORα. The serum or dexamethasone-induced oscillation in the expression of GENE in cells was abrogated by the downregulation or overexpression of REV-ERBα, suggesting that REV-ERBα functions as a regulator of GENE oscillations in the cellular autonomous clock. Chromatin immunoprecipitation assays of the GENE promoter indicated that the binding of the REV-ERBα protein to the GENE promoter increased in the early dark phase. GENE protein expression varied with higher levels during the dark phase. Moreover, the effects of the GENE agonist CHEMICAL (7-OH-DPAT)-induced locomotor hypoactivity were significantly increased when GENE proteins were abundant. These results suggest that RORα and REV-ERBα consist of a reciprocating mechanism wherein RORα upregulates the expression of GENE, whereas REV-ERBα periodically suppresses the expression at the time of day when REV-ERBα is abundant. Our present findings revealed that a molecular link between the circadian clock and the function of GENE in the ventral striatum acts as a modulator of the pharmacological actions of GENE agonists/antagonists. | ACTIVATOR |
| Molecular mechanism regulating 24-hour rhythm of dopamine d3 receptor expression in mouse ventral striatum. The dopamine D3 receptor (DRD3) in the ventral striatum is thought to influence motivation and motor functions. Although the expression of GENE in the ventral striatum has been shown to exhibit 24-hour variations, the mechanisms underlying the variation remain obscure. Here, we demonstrated that molecular components of the circadian clock act as regulators that control the 24-hour variation in the expression of GENE. The transcription of GENE was enhanced by the retinoic acid-related orphan receptor α (RORα), and its activation was inhibited by the orphan receptor REV-ERBα, an endogenous antagonist of RORα. The serum or dexamethasone-induced oscillation in the expression of GENE in cells was abrogated by the downregulation or overexpression of REV-ERBα, suggesting that REV-ERBα functions as a regulator of GENE oscillations in the cellular autonomous clock. Chromatin immunoprecipitation assays of the GENE promoter indicated that the binding of the REV-ERBα protein to the GENE promoter increased in the early dark phase. GENE protein expression varied with higher levels during the dark phase. Moreover, the effects of the GENE agonist 7-hydroxy-N,N-dipropyl-2-aminotetralin (CHEMICAL)-induced locomotor hypoactivity were significantly increased when GENE proteins were abundant. These results suggest that RORα and REV-ERBα consist of a reciprocating mechanism wherein RORα upregulates the expression of GENE, whereas REV-ERBα periodically suppresses the expression at the time of day when REV-ERBα is abundant. Our present findings revealed that a molecular link between the circadian clock and the function of GENE in the ventral striatum acts as a modulator of the pharmacological actions of GENE agonists/antagonists. | ACTIVATOR |
| Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist IKM-159: asymmetric synthesis, neuroactivity, and structural characterization. IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. By employment of (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, CHEMICAL and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with CHEMICAL, whereas the (2S)-counterpart was inactive in both assays. Racemic IKM-159 was crystallized with the ligand-binding domain of GENE, and the structure revealed a complex containing CHEMICAL at the glutamate binding site. CHEMICAL locks the GENE in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors. | DIRECT-REGULATOR |
| Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist IKM-159: asymmetric synthesis, neuroactivity, and structural characterization. IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. By employment of (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2R)-IKM-159, whereas the (2S)-counterpart was inactive in both assays. CHEMICAL was crystallized with the ligand-binding domain of GENE, and the structure revealed a complex containing (2R)-IKM-159 at the glutamate binding site. (2R)-IKM-159 locks the GENE in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors. | DIRECT-REGULATOR |
| Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist IKM-159: asymmetric synthesis, neuroactivity, and structural characterization. IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. By employment of (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, CHEMICAL and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with CHEMICAL, whereas the (2S)-counterpart was inactive in both assays. Racemic IKM-159 was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing CHEMICAL at the glutamate binding site. CHEMICAL locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of GENE. | INHIBITOR |
| Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid GENE antagonist CHEMICAL: asymmetric synthesis, neuroactivity, and structural characterization. CHEMICAL was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of CHEMICAL was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of CHEMICAL prepared by enantioselective asymmetric synthesis. By employment of (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2R)-IKM-159, whereas the (2S)-counterpart was inactive in both assays. Racemic CHEMICAL was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2R)-IKM-159 at the glutamate binding site. (2R)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors. | INHIBITOR |
| Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist IKM-159: asymmetric synthesis, neuroactivity, and structural characterization. CHEMICAL was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as GENE-selective antagonists. However, it was not known which enantiomer of CHEMICAL was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of CHEMICAL prepared by enantioselective asymmetric synthesis. By employment of (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2R)-IKM-159, whereas the (2S)-counterpart was inactive in both assays. Racemic CHEMICAL was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2R)-IKM-159 at the glutamate binding site. (2R)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors. | INHIBITOR |
| Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist IKM-159: asymmetric synthesis, neuroactivity, and structural characterization. IKM-159 was developed and identified as a member of a new class of heterotricyclic CHEMICAL analogues that act as GENE-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. By employment of (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2R)-IKM-159, whereas the (2S)-counterpart was inactive in both assays. Racemic IKM-159 was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2R)-IKM-159 at the CHEMICAL binding site. (2R)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors. | INHIBITOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, CHEMICAL, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, CHEMICAL, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | DIRECT-REGULATOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, CHEMICAL, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | DIRECT-REGULATOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, CHEMICAL, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, CHEMICAL, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | DIRECT-REGULATOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, CHEMICAL, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | DIRECT-REGULATOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, CHEMICAL, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | DIRECT-REGULATOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, CHEMICAL, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, CHEMICAL, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | INHIBITOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, CHEMICAL, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | DIRECT-REGULATOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, CHEMICAL, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | DIRECT-REGULATOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, CHEMICAL, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | DIRECT-REGULATOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, CHEMICAL, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, CHEMICAL, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | INHIBITOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and CHEMICAL were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | DIRECT-REGULATOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, CHEMICAL, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | DIRECT-REGULATOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, CHEMICAL, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | INHIBITOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by CHEMICAL, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | DIRECT-REGULATOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, CHEMICAL, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | INHIBITOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, CHEMICAL, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | INHIBITOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, CHEMICAL, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | INHIBITOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, CHEMICAL, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | INHIBITOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, CHEMICAL, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | INHIBITOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of CHEMICAL, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, CHEMICAL, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | INHIBITOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, CHEMICAL, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | INHIBITOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and CHEMICAL were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. Coumarin 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, CHEMICAL, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | DIRECT-REGULATOR |
| Binding of Diverse Environmental Chemicals with Human Cytochromes GENE, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with GENE than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for GENE. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with GENE. CHEMICAL 7-hydroxylation, catalyzed by GENE, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of GENE, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of GENE. The metabolism of chemicals by GENE during the assays explained why some of the chemicals that bound well were poor inhibitors of GENE. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of GENE with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that GENE, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. | SUBSTRATE |
| Discovery of a Novel Selective PPARγ Ligand with Partial Agonist Binding Properties by Integrated in Silico/in Vitro Work Flow. Full agonists to the GENE, such as CHEMICAL, have been associated with a series of undesired side effects, such as weight gain, fluid retention, cardiac hypertrophy, and hepatotoxicity. Nevertheless, PPARγ is involved in the expression of genes that control glucose and lipid metabolism and is an important target for drugs against type 2 diabetes, dyslipidemia, atherosclerosis, and cardiovascular disease. In an effort to identify novel PPARγ ligands with an improved pharmacological profile, emphasis has shifted to selective ligands with partial agonist binding properties. Toward this end we applied an integrated in silico/in vitro workflow, based on pharmacophore- and structure-based virtual screening of the ZINC library, coupled with competitive binding and transactivation assays, and adipocyte differentiation and gene expression studies. Hit compound 9 was identified as the most potent ligand (IC50 = 0.3 μM) and a relatively poor inducer of adipocyte differentiation. The binding mode of compound 9 was confirmed by molecular dynamics simulation, and the calculated free energy of binding was -8.4 kcal/mol. A novel functional group, the carbonitrile group, was identified to be a key substituent in the ligand-protein interactions. Further studies on the transcriptional regulation properties of compound 9 revealed a gene regulatory profile that was to a large extent unique, however functionally closer to that of a partial agonist. | ACTIVATOR |
| Structural Characterization of an LPA1 Second Extracellular Loop Mimetic with a Self-Assembling Coiled-Coil Folding Constraint. G protein-coupled receptor (GPCR) structures are of interest as a means to understand biological signal transduction and as tools for therapeutic discovery. The growing number of GPCR crystal structures demonstrates that the extracellular loops (EL) connecting the membrane-spanning helices show tremendous structural variability relative to the more structurally-conserved seven transmembrane α-helical domains. The EL of the LPA(1) receptor have not yet been conclusively resolved, and bear limited sequence identity to known structures. This study involved development of a peptide to characterize the intrinsic structure of the LPA(1) GPCR second EL. The loop was embedded between two helices that assemble into a coiled-coil, which served as a receptor-mimetic folding constraint (LPA(1)-CC-EL2 peptide). The ensemble of structures from multi-dimensional NMR experiments demonstrated that a robust coiled-coil formed without noticeable deformation due to the GENE sequence. In contrast, the GENE sequence showed well-defined structure only near its CHEMICAL-terminal residues. The NMR ensemble was combined with a computational model of the LPA(1) receptor that had previously been validated. The resulting hybrid models were evaluated using docking. Nine different hybrid models interacted with LPA 18:1 as expected, based on prior mutagenesis studies, and one was additionally consistent with antagonist affinity trends. | PART-OF |
| The (R)-omeprazole hydroxylation index reflects CYP2C19 activity in healthy Japanese volunteers. PURPOSE: CHEMICAL has (R)- and (S)-enantiomers, which exhibit different pharmacokinetics (PK) among patients with GENE genotype groups. The aim of this study was to investigate whether the 1-point, 4-h postdose (R)-omeprazole hydroxylation index (HI) of racemic omeprazole reflects the three CYP2C19 genotype groups in Japanese individuals. METHODS: Ninety healthy Japanese individuals were enrolled and classified into the three different CYP2C19 genotype groups: homozygous extensive metabolizers (hmEMs; n = 34), heterozygous EMs (htEMs; n = 44), and poor metabolizers (PMs; n = 12). Blood samples were drawn 4 h after the intake of an oral dose of omeprazole 40 mg, and plasma levels of omeprazole and its metabolites were analyzed by high-performance liquid chromatography (HPLC) using a chiral column. RESULTS: Mean plasma concentrations of (R)- and (S)-omeprazole in PMs were significantly higher than those in hmEMs and htEMs, and similar results were obtained in the case of omeprazole sulfone. Additionally, there was a significant difference in plasma concentrations of (R)-5-hydroxyomeprazole among CYP2C19 genotype groups, whereas no significant differences were observed in that of (S)-5-hydroxyomeprazole. Similarly, (R)-omeprazole HI in hmEMs, htEMs, and PMs were 5.6, 3.1, and 0.3, respectively, which were significantly different, but no significant difference was present in the (S)-omeprazole HI. CONCLUSION: Our findings demonstrate that (R)-omeprazole HI correlated better with CYP2C19 genotype groups than racemic-omeprazole HI, and these results may be useful for classification among patients in CYP2C19 genotype groups prior to omeprazole treatment. | REGULATOR |
| The CHEMICAL hydroxylation index reflects GENE activity in healthy Japanese volunteers. PURPOSE: Omeprazole has (R)- and (S)-enantiomers, which exhibit different pharmacokinetics (PK) among patients with cytochrome P450 (CYP) 2C19 genotype groups. The aim of this study was to investigate whether the 1-point, 4-h postdose CHEMICAL hydroxylation index (HI) of racemic omeprazole reflects the three GENE genotype groups in Japanese individuals. METHODS: Ninety healthy Japanese individuals were enrolled and classified into the three different GENE genotype groups: homozygous extensive metabolizers (hmEMs; n = 34), heterozygous EMs (htEMs; n = 44), and poor metabolizers (PMs; n = 12). Blood samples were drawn 4 h after the intake of an oral dose of omeprazole 40 mg, and plasma levels of omeprazole and its metabolites were analyzed by high-performance liquid chromatography (HPLC) using a chiral column. RESULTS: Mean plasma concentrations of (R)- and (S)-omeprazole in PMs were significantly higher than those in hmEMs and htEMs, and similar results were obtained in the case of omeprazole sulfone. Additionally, there was a significant difference in plasma concentrations of (R)-5-hydroxyomeprazole among GENE genotype groups, whereas no significant differences were observed in that of (S)-5-hydroxyomeprazole. Similarly, CHEMICAL HI in hmEMs, htEMs, and PMs were 5.6, 3.1, and 0.3, respectively, which were significantly different, but no significant difference was present in the (S)-omeprazole HI. CONCLUSION: Our findings demonstrate that CHEMICAL HI correlated better with GENE genotype groups than racemic-omeprazole HI, and these results may be useful for classification among patients in GENE genotype groups prior to omeprazole treatment. | SUBSTRATE |
| The (R)-omeprazole hydroxylation index reflects GENE activity in healthy Japanese volunteers. PURPOSE: Omeprazole has (R)- and (S)-enantiomers, which exhibit different pharmacokinetics (PK) among patients with cytochrome P450 (CYP) 2C19 genotype groups. The aim of this study was to investigate whether the 1-point, 4-h postdose (R)-omeprazole hydroxylation index (HI) of racemic omeprazole reflects the three GENE genotype groups in Japanese individuals. METHODS: Ninety healthy Japanese individuals were enrolled and classified into the three different GENE genotype groups: homozygous extensive metabolizers (hmEMs; n = 34), heterozygous EMs (htEMs; n = 44), and poor metabolizers (PMs; n = 12). Blood samples were drawn 4 h after the intake of an oral dose of omeprazole 40 mg, and plasma levels of omeprazole and its metabolites were analyzed by high-performance liquid chromatography (HPLC) using a chiral column. RESULTS: Mean plasma concentrations of (R)- and (S)-omeprazole in PMs were significantly higher than those in hmEMs and htEMs, and similar results were obtained in the case of omeprazole sulfone. Additionally, there was a significant difference in plasma concentrations of CHEMICAL among GENE genotype groups, whereas no significant differences were observed in that of (S)-5-hydroxyomeprazole. Similarly, (R)-omeprazole HI in hmEMs, htEMs, and PMs were 5.6, 3.1, and 0.3, respectively, which were significantly different, but no significant difference was present in the (S)-omeprazole HI. CONCLUSION: Our findings demonstrate that (R)-omeprazole HI correlated better with GENE genotype groups than racemic-omeprazole HI, and these results may be useful for classification among patients in GENE genotype groups prior to omeprazole treatment. | GENE-CHEMICAL |
| The (R)-omeprazole hydroxylation index reflects GENE activity in healthy Japanese volunteers. PURPOSE: Omeprazole has (R)- and (S)-enantiomers, which exhibit different pharmacokinetics (PK) among patients with cytochrome P450 (CYP) 2C19 genotype groups. The aim of this study was to investigate whether the 1-point, 4-h postdose (R)-omeprazole hydroxylation index (HI) of racemic omeprazole reflects the three GENE genotype groups in Japanese individuals. METHODS: Ninety healthy Japanese individuals were enrolled and classified into the three different GENE genotype groups: homozygous extensive metabolizers (hmEMs; n = 34), heterozygous EMs (htEMs; n = 44), and poor metabolizers (PMs; n = 12). Blood samples were drawn 4 h after the intake of an oral dose of omeprazole 40 mg, and plasma levels of omeprazole and its metabolites were analyzed by high-performance liquid chromatography (HPLC) using a chiral column. RESULTS: Mean plasma concentrations of (R)- and (S)-omeprazole in PMs were significantly higher than those in hmEMs and htEMs, and similar results were obtained in the case of omeprazole sulfone. Additionally, there was a significant difference in plasma concentrations of (R)-5-hydroxyomeprazole among GENE genotype groups, whereas no significant differences were observed in that of CHEMICAL. Similarly, (R)-omeprazole HI in hmEMs, htEMs, and PMs were 5.6, 3.1, and 0.3, respectively, which were significantly different, but no significant difference was present in the (S)-omeprazole HI. CONCLUSION: Our findings demonstrate that (R)-omeprazole HI correlated better with GENE genotype groups than racemic-omeprazole HI, and these results may be useful for classification among patients in GENE genotype groups prior to omeprazole treatment. | NO-RELATIONSHIP |
| The (R)-omeprazole hydroxylation index reflects GENE activity in healthy Japanese volunteers. PURPOSE: Omeprazole has (R)- and (S)-enantiomers, which exhibit different pharmacokinetics (PK) among patients with cytochrome P450 (CYP) 2C19 genotype groups. The aim of this study was to investigate whether the 1-point, 4-h postdose (R)-omeprazole hydroxylation index (HI) of racemic omeprazole reflects the three GENE genotype groups in Japanese individuals. METHODS: Ninety healthy Japanese individuals were enrolled and classified into the three different GENE genotype groups: homozygous extensive metabolizers (hmEMs; n = 34), heterozygous EMs (htEMs; n = 44), and poor metabolizers (PMs; n = 12). Blood samples were drawn 4 h after the intake of an oral dose of omeprazole 40 mg, and plasma levels of omeprazole and its metabolites were analyzed by high-performance liquid chromatography (HPLC) using a chiral column. RESULTS: Mean plasma concentrations of (R)- and (S)-omeprazole in PMs were significantly higher than those in hmEMs and htEMs, and similar results were obtained in the case of omeprazole sulfone. Additionally, there was a significant difference in plasma concentrations of (R)-5-hydroxyomeprazole among GENE genotype groups, whereas no significant differences were observed in that of (S)-5-hydroxyomeprazole. Similarly, (R)-omeprazole HI in hmEMs, htEMs, and PMs were 5.6, 3.1, and 0.3, respectively, which were significantly different, but no significant difference was present in the (S)-omeprazole HI. CONCLUSION: Our findings demonstrate that (R)-omeprazole HI correlated better with GENE genotype groups than CHEMICAL HI, and these results may be useful for classification among patients in GENE genotype groups prior to omeprazole treatment. | GENE-CHEMICAL |
| Induction of xenobiotic receptors, transporters, and drug metabolizing enzymes by CHEMICAL. Perturbations of the expression of transporters and drug-metabolizing enzymes (DMEs) by opioids can be the locus of deleterious drug-drug interactions (DDIs). Many transporters and DMEs are regulated by xenobiotic receptors [XRs; e.g., pregnane X receptor (PXR), constitutive androstane receptor (CAR), and Aryl hydrocarbon receptor (AhR)]; however, there is a paucity of information regarding the influence of opioids on XRs. The objective of this study was to determine the influence of CHEMICAL administration (15 mg/kg intraperitoneally twice daily for 8 days) on liver expression of XRs, transporters, and DMEs in rats. Microarray, quantitative real-time polymerase chain reaction and immunoblotting analyses were used to identify significantly regulated genes. Three XRs (e.g., GENE, CAR, and AhR), 27 transporters (e.g., ABCB1 and SLC22A8), and 19 DMEs (e.g., CYP2B2 and CYP3A1) were regulated (P < 0.05) with fold changes ranging from -46.3 to 17.1. Using MetaCore (computational platform), we identified a unique gene-network of transporters and DMEs assembled around GENE, CAR, and AhR. Therefore, a series of transactivation/translocation assays were conducted to determine whether the observed changes of transporters/DMEs are mediated by direct activation of GENE, CAR, or AhR by CHEMICAL or its major metabolites (noroxycodone and oxymorphone). Neither CHEMICAL nor its metabolites activated GENE, CAR, or AhR. Taken together, these findings identify a signature hepatic gene-network associated with repeated CHEMICAL administration in rats and demonstrate that CHEMICAL alters the expression of many transporters and DMEs (without direct activation of GENE, CAR, and AhR), which could lead to undesirable DDIs after coadministration of substrates of these transporters/DMEs with CHEMICAL. | NO-RELATIONSHIP |
| Induction of xenobiotic receptors, transporters, and drug metabolizing enzymes by CHEMICAL. Perturbations of the expression of transporters and drug-metabolizing enzymes (DMEs) by opioids can be the locus of deleterious drug-drug interactions (DDIs). Many transporters and DMEs are regulated by xenobiotic receptors [XRs; e.g., pregnane X receptor (PXR), constitutive androstane receptor (CAR), and Aryl hydrocarbon receptor (AhR)]; however, there is a paucity of information regarding the influence of opioids on XRs. The objective of this study was to determine the influence of CHEMICAL administration (15 mg/kg intraperitoneally twice daily for 8 days) on liver expression of XRs, transporters, and DMEs in rats. Microarray, quantitative real-time polymerase chain reaction and immunoblotting analyses were used to identify significantly regulated genes. Three XRs (e.g., PXR, GENE, and AhR), 27 transporters (e.g., ABCB1 and SLC22A8), and 19 DMEs (e.g., CYP2B2 and CYP3A1) were regulated (P < 0.05) with fold changes ranging from -46.3 to 17.1. Using MetaCore (computational platform), we identified a unique gene-network of transporters and DMEs assembled around PXR, GENE, and AhR. Therefore, a series of transactivation/translocation assays were conducted to determine whether the observed changes of transporters/DMEs are mediated by direct activation of PXR, GENE, or AhR by CHEMICAL or its major metabolites (noroxycodone and oxymorphone). Neither CHEMICAL nor its metabolites activated PXR, GENE, or AhR. Taken together, these findings identify a signature hepatic gene-network associated with repeated CHEMICAL administration in rats and demonstrate that CHEMICAL alters the expression of many transporters and DMEs (without direct activation of PXR, GENE, and AhR), which could lead to undesirable DDIs after coadministration of substrates of these transporters/DMEs with CHEMICAL. | NO-RELATIONSHIP |
| Induction of xenobiotic receptors, transporters, and drug metabolizing enzymes by CHEMICAL. Perturbations of the expression of transporters and drug-metabolizing enzymes (DMEs) by opioids can be the locus of deleterious drug-drug interactions (DDIs). Many transporters and DMEs are regulated by xenobiotic receptors [XRs; e.g., pregnane X receptor (PXR), constitutive androstane receptor (CAR), and Aryl hydrocarbon receptor (AhR)]; however, there is a paucity of information regarding the influence of opioids on XRs. The objective of this study was to determine the influence of CHEMICAL administration (15 mg/kg intraperitoneally twice daily for 8 days) on liver expression of XRs, transporters, and DMEs in rats. Microarray, quantitative real-time polymerase chain reaction and immunoblotting analyses were used to identify significantly regulated genes. Three XRs (e.g., PXR, CAR, and AhR), 27 transporters (e.g., ABCB1 and SLC22A8), and 19 DMEs (e.g., CYP2B2 and CYP3A1) were regulated (P < 0.05) with fold changes ranging from -46.3 to 17.1. Using MetaCore (computational platform), we identified a unique gene-network of transporters and DMEs assembled around PXR, CAR, and GENE. Therefore, a series of transactivation/translocation assays were conducted to determine whether the observed changes of transporters/DMEs are mediated by direct activation of PXR, CAR, or GENE by CHEMICAL or its major metabolites (noroxycodone and oxymorphone). Neither CHEMICAL nor its metabolites activated PXR, CAR, or GENE. Taken together, these findings identify a signature hepatic gene-network associated with repeated CHEMICAL administration in rats and demonstrate that CHEMICAL alters the expression of many transporters and DMEs (without direct activation of PXR, CAR, and AhR), which could lead to undesirable DDIs after coadministration of substrates of these transporters/DMEs with CHEMICAL. | NO-RELATIONSHIP |
| Induction of GENE, transporters, and drug metabolizing enzymes by CHEMICAL. Perturbations of the expression of transporters and drug-metabolizing enzymes (DMEs) by opioids can be the locus of deleterious drug-drug interactions (DDIs). Many transporters and DMEs are regulated by GENE [XRs; e.g., pregnane X receptor (PXR), constitutive androstane receptor (CAR), and Aryl hydrocarbon receptor (AhR)]; however, there is a paucity of information regarding the influence of opioids on XRs. The objective of this study was to determine the influence of CHEMICAL administration (15 mg/kg intraperitoneally twice daily for 8 days) on liver expression of XRs, transporters, and DMEs in rats. Microarray, quantitative real-time polymerase chain reaction and immunoblotting analyses were used to identify significantly regulated genes. Three XRs (e.g., PXR, CAR, and AhR), 27 transporters (e.g., ABCB1 and SLC22A8), and 19 DMEs (e.g., CYP2B2 and CYP3A1) were regulated (P < 0.05) with fold changes ranging from -46.3 to 17.1. Using MetaCore (computational platform), we identified a unique gene-network of transporters and DMEs assembled around PXR, CAR, and AhR. Therefore, a series of transactivation/translocation assays were conducted to determine whether the observed changes of transporters/DMEs are mediated by direct activation of PXR, CAR, or AhR by CHEMICAL or its major metabolites (noroxycodone and oxymorphone). Neither CHEMICAL nor its metabolites activated PXR, CAR, or AhR. Taken together, these findings identify a signature hepatic gene-network associated with repeated CHEMICAL administration in rats and demonstrate that CHEMICAL alters the expression of many transporters and DMEs (without direct activation of PXR, CAR, and AhR), which could lead to undesirable DDIs after coadministration of substrates of these transporters/DMEs with CHEMICAL. | ACTIVATOR |
| Vitamin A and retinoid signaling: genomic and non-genomic effects. Vitamin A or retinol is arguably the most multifunctional vitamin in the human body as it is essential from embryogenesis to adulthood. The pleiotropic effects of vitamin A are exerted mainly by one active metabolite, CHEMICAL (atRA), which regulates the expression of a battery of target genes through several families of GENE (RARs, RXRs and PPARβ/δ), polymorphic retinoic acid (RA) response elements and multiple coregulators. It also involves extra nuclear and non-transcriptional effects such as the activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of several actors of RA signaling. However, vitamin A itself proved recently to be active and RARs to be present in the cytosol to regulate translation and cell plasticity. All these new concepts expand the scope of the biologic functions of vitamin A and RA. | REGULATOR |
| Vitamin A and retinoid signaling: genomic and non-genomic effects. Vitamin A or retinol is arguably the most multifunctional vitamin in the human body as it is essential from embryogenesis to adulthood. The pleiotropic effects of vitamin A are exerted mainly by one active metabolite, CHEMICAL (atRA), which regulates the expression of a battery of target genes through several families of nuclear receptors (GENE, RXRs and PPARβ/δ), polymorphic retinoic acid (RA) response elements and multiple coregulators. It also involves extra nuclear and non-transcriptional effects such as the activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of several actors of RA signaling. However, vitamin A itself proved recently to be active and GENE to be present in the cytosol to regulate translation and cell plasticity. All these new concepts expand the scope of the biologic functions of vitamin A and RA. | REGULATOR |
| Vitamin A and retinoid signaling: genomic and non-genomic effects. Vitamin A or retinol is arguably the most multifunctional vitamin in the human body as it is essential from embryogenesis to adulthood. The pleiotropic effects of vitamin A are exerted mainly by one active metabolite, CHEMICAL (atRA), which regulates the expression of a battery of target genes through several families of nuclear receptors (RARs, GENE and PPARβ/δ), polymorphic retinoic acid (RA) response elements and multiple coregulators. It also involves extra nuclear and non-transcriptional effects such as the activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of several actors of RA signaling. However, vitamin A itself proved recently to be active and RARs to be present in the cytosol to regulate translation and cell plasticity. All these new concepts expand the scope of the biologic functions of vitamin A and RA. | REGULATOR |
| Vitamin A and retinoid signaling: genomic and non-genomic effects. Vitamin A or retinol is arguably the most multifunctional vitamin in the human body as it is essential from embryogenesis to adulthood. The pleiotropic effects of vitamin A are exerted mainly by one active metabolite, CHEMICAL (atRA), which regulates the expression of a battery of target genes through several families of nuclear receptors (RARs, RXRs and PPARβ/δ), GENE and multiple coregulators. It also involves extra nuclear and non-transcriptional effects such as the activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of several actors of RA signaling. However, vitamin A itself proved recently to be active and RARs to be present in the cytosol to regulate translation and cell plasticity. All these new concepts expand the scope of the biologic functions of vitamin A and RA. | REGULATOR |
| Vitamin A and retinoid signaling: genomic and non-genomic effects. Vitamin A or retinol is arguably the most multifunctional vitamin in the human body as it is essential from embryogenesis to adulthood. The pleiotropic effects of vitamin A are exerted mainly by one active metabolite, all-trans retinoic acid (CHEMICAL), which regulates the expression of a battery of target genes through several families of GENE (RARs, RXRs and PPARβ/δ), polymorphic retinoic acid (RA) response elements and multiple coregulators. It also involves extra nuclear and non-transcriptional effects such as the activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of several actors of RA signaling. However, vitamin A itself proved recently to be active and RARs to be present in the cytosol to regulate translation and cell plasticity. All these new concepts expand the scope of the biologic functions of vitamin A and RA. | REGULATOR |
| Vitamin A and retinoid signaling: genomic and non-genomic effects. Vitamin A or retinol is arguably the most multifunctional vitamin in the human body as it is essential from embryogenesis to adulthood. The pleiotropic effects of vitamin A are exerted mainly by one active metabolite, all-trans retinoic acid (CHEMICAL), which regulates the expression of a battery of target genes through several families of nuclear receptors (GENE, RXRs and PPARβ/δ), polymorphic retinoic acid (RA) response elements and multiple coregulators. It also involves extra nuclear and non-transcriptional effects such as the activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of several actors of RA signaling. However, vitamin A itself proved recently to be active and GENE to be present in the cytosol to regulate translation and cell plasticity. All these new concepts expand the scope of the biologic functions of vitamin A and RA. | REGULATOR |
| Vitamin A and retinoid signaling: genomic and non-genomic effects. Vitamin A or retinol is arguably the most multifunctional vitamin in the human body as it is essential from embryogenesis to adulthood. The pleiotropic effects of vitamin A are exerted mainly by one active metabolite, all-trans retinoic acid (CHEMICAL), which regulates the expression of a battery of target genes through several families of nuclear receptors (RARs, GENE and PPARβ/δ), polymorphic retinoic acid (RA) response elements and multiple coregulators. It also involves extra nuclear and non-transcriptional effects such as the activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of several actors of RA signaling. However, vitamin A itself proved recently to be active and RARs to be present in the cytosol to regulate translation and cell plasticity. All these new concepts expand the scope of the biologic functions of vitamin A and RA. | REGULATOR |
| Vitamin A and retinoid signaling: genomic and non-genomic effects. Vitamin A or retinol is arguably the most multifunctional vitamin in the human body as it is essential from embryogenesis to adulthood. The pleiotropic effects of vitamin A are exerted mainly by one active metabolite, all-trans retinoic acid (CHEMICAL), which regulates the expression of a battery of target genes through several families of nuclear receptors (RARs, RXRs and PPARβ/δ), GENE and multiple coregulators. It also involves extra nuclear and non-transcriptional effects such as the activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of several actors of RA signaling. However, vitamin A itself proved recently to be active and RARs to be present in the cytosol to regulate translation and cell plasticity. All these new concepts expand the scope of the biologic functions of vitamin A and RA. | REGULATOR |
| Effect of GENE on Renal Fibrosis by Regulating MMP-9 and TIMP1 in kk-ay Diabetic Nephropathy Mice. MicroRNAs (miRs) play important roles in initiation and progression of many pathologic processes. However, the roles of miRs in diabetic nephropathy remain unclear. This study was to determine whether GENE was involved in diabetic nephropathy and to explore the relationship between GENE and MMP9/TIMP1 expression in diabetic nephropathy. In situ hybridization studies showed that GENE was primarily localized and distributed in cortical glomerular and renal tubular cells in diabetic kk-ay kidney. Real-time quantitative RT-PCR demonstrated that the expression of GENE was significantly increased in kk-ay mice, compared with control C57BL mice. Interestingly, GENE expression positively correlated with urine albumin CHEMICAL ratio (ACR), TIMP1, collagen IV (ColIV), and fibronectin (FN); while negatively correlated with CHEMICAL clearance ratio (Ccr) and MMP-9 protein. Importantly, antagomir-21 not only ameliorated Ccr and ACR but also decreased TIMP1, ColIV, and FN proteins. In conclusion, our data demonstrate that GENE contributes to renal fibrosis by mediating MMP9/TIMP1 and that inhibition of GENE may be a novel target for diabetic nephropathy. | GENE-CHEMICAL |
| Modification of the Catalytic Function of Human Hydroxysteroid Sulfotransferase GENE by Formation of CHEMICAL Bonds. The human cytosolic sulfotransferase GENE catalyzes the sulfation of a broad range of xenobiotics, as well as endogenous hydroxysteroids and bile acids. Reversible modulation of the catalytic activity of this enzyme could play important roles in its physiologic functions. Whereas other mammalian sulfotransferases are known to be reversibly altered by changes in their redox environment, this has not been previously shown for GENE. We have examined the hypothesis that the formation of CHEMICAL bonds in GENE can reversibly regulate the catalytic function of the enzyme. Three thiol oxidants were used as model compounds to investigate their effects on homogeneous preparations of hSULT2A1: glutathione CHEMICAL, 5,5'-dithiobis(2-nitrobenzoic acid), and 1,1'-azobis(N,N-dimethylformamide) (diamide). Examination of the effects of CHEMICAL bond formation with these agents indicated that the activity of the enzyme is reversibly altered. Studies on the kinetics of the hSULT2A1-catalyzed sulfation of dehydroepiandrosterone (DHEA) showed the effects of CHEMICAL bond formation on the substrate inhibition characteristics of the enzyme. The effects of these agents on the binding of substrates and products, liquid chromatography-mass spectrometry identification of the disulfides formed, and structural modeling of the modified enzyme were examined. Our results indicate that conformational changes at cysteines near the nucleotide binding site affect the binding of both the nucleotide and DHEA to the enzyme, with the specific effects dependent on the structure of the resulting CHEMICAL. Thus, the formation of CHEMICAL bonds in GENE is a potentially important reversible mechanism for alterations in the rates of sulfation of both endogenous and xenobiotic substrates. | PART-OF |
| Modification of the Catalytic Function of GENE by Formation of CHEMICAL Bonds. The human cytosolic sulfotransferase hSULT2A1 catalyzes the sulfation of a broad range of xenobiotics, as well as endogenous hydroxysteroids and bile acids. Reversible modulation of the catalytic activity of this enzyme could play important roles in its physiologic functions. Whereas other mammalian sulfotransferases are known to be reversibly altered by changes in their redox environment, this has not been previously shown for hSULT2A1. We have examined the hypothesis that the formation of disulfide bonds in hSULT2A1 can reversibly regulate the catalytic function of the enzyme. Three thiol oxidants were used as model compounds to investigate their effects on homogeneous preparations of hSULT2A1: glutathione disulfide, 5,5'-dithiobis(2-nitrobenzoic acid), and 1,1'-azobis(N,N-dimethylformamide) (diamide). Examination of the effects of disulfide bond formation with these agents indicated that the activity of the enzyme is reversibly altered. Studies on the kinetics of the hSULT2A1-catalyzed sulfation of dehydroepiandrosterone (DHEA) showed the effects of disulfide bond formation on the substrate inhibition characteristics of the enzyme. The effects of these agents on the binding of substrates and products, liquid chromatography-mass spectrometry identification of the disulfides formed, and structural modeling of the modified enzyme were examined. Our results indicate that conformational changes at cysteines near the nucleotide binding site affect the binding of both the nucleotide and DHEA to the enzyme, with the specific effects dependent on the structure of the resulting disulfide. Thus, the formation of disulfide bonds in hSULT2A1 is a potentially important reversible mechanism for alterations in the rates of sulfation of both endogenous and xenobiotic substrates. | PART-OF |
| Modification of the Catalytic Function of Human Hydroxysteroid Sulfotransferase GENE by Formation of Disulfide Bonds. The human cytosolic sulfotransferase GENE catalyzes the sulfation of a broad range of xenobiotics, as well as endogenous hydroxysteroids and bile acids. Reversible modulation of the catalytic activity of this enzyme could play important roles in its physiologic functions. Whereas other mammalian sulfotransferases are known to be reversibly altered by changes in their redox environment, this has not been previously shown for GENE. We have examined the hypothesis that the formation of disulfide bonds in GENE can reversibly regulate the catalytic function of the enzyme. Three thiol oxidants were used as model compounds to investigate their effects on homogeneous preparations of hSULT2A1: glutathione disulfide, 5,5'-dithiobis(2-nitrobenzoic acid), and 1,1'-azobis(N,N-dimethylformamide) (diamide). Examination of the effects of disulfide bond formation with these agents indicated that the activity of the enzyme is reversibly altered. Studies on the kinetics of the GENE-catalyzed sulfation of CHEMICAL (DHEA) showed the effects of disulfide bond formation on the substrate inhibition characteristics of the enzyme. The effects of these agents on the binding of substrates and products, liquid chromatography-mass spectrometry identification of the disulfides formed, and structural modeling of the modified enzyme were examined. Our results indicate that conformational changes at cysteines near the nucleotide binding site affect the binding of both the nucleotide and DHEA to the enzyme, with the specific effects dependent on the structure of the resulting disulfide. Thus, the formation of disulfide bonds in GENE is a potentially important reversible mechanism for alterations in the rates of sulfation of both endogenous and xenobiotic substrates. | SUBSTRATE |
| Modification of the Catalytic Function of Human Hydroxysteroid Sulfotransferase GENE by Formation of Disulfide Bonds. The human cytosolic sulfotransferase GENE catalyzes the sulfation of a broad range of xenobiotics, as well as endogenous hydroxysteroids and bile acids. Reversible modulation of the catalytic activity of this enzyme could play important roles in its physiologic functions. Whereas other mammalian sulfotransferases are known to be reversibly altered by changes in their redox environment, this has not been previously shown for GENE. We have examined the hypothesis that the formation of disulfide bonds in GENE can reversibly regulate the catalytic function of the enzyme. Three thiol oxidants were used as model compounds to investigate their effects on homogeneous preparations of hSULT2A1: glutathione disulfide, 5,5'-dithiobis(2-nitrobenzoic acid), and 1,1'-azobis(N,N-dimethylformamide) (diamide). Examination of the effects of disulfide bond formation with these agents indicated that the activity of the enzyme is reversibly altered. Studies on the kinetics of the GENE-catalyzed sulfation of dehydroepiandrosterone (CHEMICAL) showed the effects of disulfide bond formation on the substrate inhibition characteristics of the enzyme. The effects of these agents on the binding of substrates and products, liquid chromatography-mass spectrometry identification of the disulfides formed, and structural modeling of the modified enzyme were examined. Our results indicate that conformational changes at cysteines near the nucleotide binding site affect the binding of both the nucleotide and CHEMICAL to the enzyme, with the specific effects dependent on the structure of the resulting disulfide. Thus, the formation of disulfide bonds in GENE is a potentially important reversible mechanism for alterations in the rates of sulfation of both endogenous and xenobiotic substrates. | SUBSTRATE |
| Modification of the Catalytic Function of Human Hydroxysteroid Sulfotransferase hSULT2A1 by Formation of Disulfide Bonds. The GENE catalyzes the sulfation of a broad range of xenobiotics, as well as endogenous CHEMICAL and bile acids. Reversible modulation of the catalytic activity of this enzyme could play important roles in its physiologic functions. Whereas other mammalian sulfotransferases are known to be reversibly altered by changes in their redox environment, this has not been previously shown for hSULT2A1. We have examined the hypothesis that the formation of disulfide bonds in hSULT2A1 can reversibly regulate the catalytic function of the enzyme. Three thiol oxidants were used as model compounds to investigate their effects on homogeneous preparations of hSULT2A1: glutathione disulfide, 5,5'-dithiobis(2-nitrobenzoic acid), and 1,1'-azobis(N,N-dimethylformamide) (diamide). Examination of the effects of disulfide bond formation with these agents indicated that the activity of the enzyme is reversibly altered. Studies on the kinetics of the hSULT2A1-catalyzed sulfation of dehydroepiandrosterone (DHEA) showed the effects of disulfide bond formation on the substrate inhibition characteristics of the enzyme. The effects of these agents on the binding of substrates and products, liquid chromatography-mass spectrometry identification of the disulfides formed, and structural modeling of the modified enzyme were examined. Our results indicate that conformational changes at cysteines near the nucleotide binding site affect the binding of both the nucleotide and DHEA to the enzyme, with the specific effects dependent on the structure of the resulting disulfide. Thus, the formation of disulfide bonds in hSULT2A1 is a potentially important reversible mechanism for alterations in the rates of sulfation of both endogenous and xenobiotic substrates. | SUBSTRATE |
| Modification of the Catalytic Function of Human Hydroxysteroid Sulfotransferase hSULT2A1 by Formation of Disulfide Bonds. The GENE catalyzes the sulfation of a broad range of xenobiotics, as well as endogenous hydroxysteroids and CHEMICAL. Reversible modulation of the catalytic activity of this enzyme could play important roles in its physiologic functions. Whereas other mammalian sulfotransferases are known to be reversibly altered by changes in their redox environment, this has not been previously shown for hSULT2A1. We have examined the hypothesis that the formation of disulfide bonds in hSULT2A1 can reversibly regulate the catalytic function of the enzyme. Three thiol oxidants were used as model compounds to investigate their effects on homogeneous preparations of hSULT2A1: glutathione disulfide, 5,5'-dithiobis(2-nitrobenzoic acid), and 1,1'-azobis(N,N-dimethylformamide) (diamide). Examination of the effects of disulfide bond formation with these agents indicated that the activity of the enzyme is reversibly altered. Studies on the kinetics of the hSULT2A1-catalyzed sulfation of dehydroepiandrosterone (DHEA) showed the effects of disulfide bond formation on the substrate inhibition characteristics of the enzyme. The effects of these agents on the binding of substrates and products, liquid chromatography-mass spectrometry identification of the disulfides formed, and structural modeling of the modified enzyme were examined. Our results indicate that conformational changes at cysteines near the nucleotide binding site affect the binding of both the nucleotide and DHEA to the enzyme, with the specific effects dependent on the structure of the resulting disulfide. Thus, the formation of disulfide bonds in hSULT2A1 is a potentially important reversible mechanism for alterations in the rates of sulfation of both endogenous and xenobiotic substrates. | SUBSTRATE |
| Synthesis of novel estrogen receptor antagonists using metal-catalyzed coupling reactions and characterization of their biological activity. Estrogen receptor (ER) antagonists are valuable in the treatment of ER-positive human breast cancer. In this study, we designed and synthesized nine new derivatives of 17β-estradiol (E2) with a bulky side chain attached to its C-7α position, and determined their GENE antagonistic activity using in vitro bioassays. Four of the derivatives showed a strong inhibition of ERα transactivation activity in a luciferase reporter assay and blocked ERα interactions with coactivators. Similarly, these derivatives also strongly inhibited the growth of the ERα-positive human breast cancer cells. Computational docking analysis was conducted to model the interaction of these antagonists with the human ERα and showed that they could tightly bind to the ERα in a manner similar to that of CHEMICAL, a pure GENE antagonist. These results provide an example that attachment of a bulky side chain to the C-7α position of E2 can produce GENE antagonists with GENE affinity comparable to that of CHEMICAL. | INHIBITOR |
| Discovery of 7-methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole (TASP0382088): a potent and selective transforming growth factor-β type I receptor inhibitor as a topical drug for alopecia. CHEMICAL 11 (TASP0382088) was synthesized and evaluated as transforming growth factor-β (TGF-β) type I receptor (also known as GENE or ALK5) inhibitor. Compound 11, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC50=4.8 nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50=17 nM). The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11. Furthermore, the topical application of 3% 11 lotion significantly inhibited Smad2 phosphorylation in mouse skin at 8 h after application (71% inhibition, compared with vehicle-treated animals). | INHIBITOR |
| Discovery of 7-methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole (TASP0382088): a potent and selective transforming growth factor-β type I receptor inhibitor as a topical drug for alopecia. CHEMICAL 11 (TASP0382088) was synthesized and evaluated as transforming growth factor-β (TGF-β) type I receptor (also known as activin receptor-like kinase 5 or GENE) inhibitor. Compound 11, a potent and selective GENE inhibitor, exhibited good enzyme inhibitory activity (IC50=4.8 nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50=17 nM). The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11. Furthermore, the topical application of 3% 11 lotion significantly inhibited Smad2 phosphorylation in mouse skin at 8 h after application (71% inhibition, compared with vehicle-treated animals). | INHIBITOR |
| Discovery of 7-methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole (TASP0382088): a potent and selective transforming growth factor-β type I receptor inhibitor as a topical drug for alopecia. CHEMICAL 11 (TASP0382088) was synthesized and evaluated as GENE (also known as activin receptor-like kinase 5 or ALK5) inhibitor. Compound 11, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC50=4.8 nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50=17 nM). The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11. Furthermore, the topical application of 3% 11 lotion significantly inhibited Smad2 phosphorylation in mouse skin at 8 h after application (71% inhibition, compared with vehicle-treated animals). | INHIBITOR |
| Discovery of 7-methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole (TASP0382088): a potent and selective transforming growth factor-β type I receptor inhibitor as a topical drug for alopecia. 7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole 11 (CHEMICAL) was synthesized and evaluated as transforming growth factor-β (TGF-β) type I receptor (also known as GENE or ALK5) inhibitor. Compound 11, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC50=4.8 nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50=17 nM). The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11. Furthermore, the topical application of 3% 11 lotion significantly inhibited Smad2 phosphorylation in mouse skin at 8 h after application (71% inhibition, compared with vehicle-treated animals). | INHIBITOR |
| Discovery of 7-methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole (TASP0382088): a potent and selective transforming growth factor-β type I receptor inhibitor as a topical drug for alopecia. 7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole 11 (CHEMICAL) was synthesized and evaluated as transforming growth factor-β (TGF-β) type I receptor (also known as activin receptor-like kinase 5 or GENE) inhibitor. Compound 11, a potent and selective GENE inhibitor, exhibited good enzyme inhibitory activity (IC50=4.8 nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50=17 nM). The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11. Furthermore, the topical application of 3% 11 lotion significantly inhibited Smad2 phosphorylation in mouse skin at 8 h after application (71% inhibition, compared with vehicle-treated animals). | INHIBITOR |
| Discovery of 7-methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole (TASP0382088): a potent and selective transforming growth factor-β type I receptor inhibitor as a topical drug for alopecia. 7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole 11 (CHEMICAL) was synthesized and evaluated as GENE (also known as activin receptor-like kinase 5 or ALK5) inhibitor. Compound 11, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC50=4.8 nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50=17 nM). The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11. Furthermore, the topical application of 3% 11 lotion significantly inhibited Smad2 phosphorylation in mouse skin at 8 h after application (71% inhibition, compared with vehicle-treated animals). | INHIBITOR |
| Discovery of CHEMICAL (TASP0382088): a potent and selective GENE inhibitor as a topical drug for alopecia. 7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole 11 (TASP0382088) was synthesized and evaluated as transforming growth factor-β (TGF-β) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitor. Compound 11, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC50=4.8 nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50=17 nM). The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11. Furthermore, the topical application of 3% 11 lotion significantly inhibited Smad2 phosphorylation in mouse skin at 8 h after application (71% inhibition, compared with vehicle-treated animals). | INHIBITOR |
| Discovery of 7-methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole (CHEMICAL): a potent and selective GENE inhibitor as a topical drug for alopecia. 7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole 11 (TASP0382088) was synthesized and evaluated as transforming growth factor-β (TGF-β) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitor. Compound 11, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC50=4.8 nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50=17 nM). The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11. Furthermore, the topical application of 3% 11 lotion significantly inhibited Smad2 phosphorylation in mouse skin at 8 h after application (71% inhibition, compared with vehicle-treated animals). | INHIBITOR |
| ARF represses CHEMICAL receptor transactivation in prostate cancer. CHEMICAL receptor (AR) signaling is essential for prostate cancer (PCa) development in humans. The initiation of prostate malignancy and progression to a castration-resistant stage are largely contributed by the modulation of GENE activity through its coregulatory proteins. We and others previously reported that p14 alternative reading frame (ARF) expression is positively correlated with the disease progression and severity of PCa. Here, we provide evidence that p14ARF physically interacts with GENE and functions as an GENE corespressor in both an androgen-dependent and CHEMICAL-independent manner. Endogenous ARF (p14ARF in human and p19ARF in mouse) and GENE colocalize in both human PCa cells in vitro and PCa tissues of mouse and human in vivo. Overexpression of p14ARF in PCa cells significantly attenuates the activities of CHEMICAL response region (ARR2)-probasin and prostate-specific antigen (PSA) promoters. The forced expression of p14ARF in cells resulted in a suppression of PSA and NK transcription factor locus 1 (NKX3.1) expression. Conversely, knockdown of endogenous p14ARF in human PCa cells with short hairpin RNA enhanced GENE transactivation activities in a dose-dependent and p53-independent manner. Furthermore, we demonstrated that p14ARF binds to both the N-terminal domain and the ligand-binding domain of GENE, and the human double minute 2 (HDM2)-binding motif of p14ARF is required for the interaction of p14ARF and GENE proteins. p14ARF perturbs the androgen-induced interaction between the N terminus and C terminus of GENE. Most importantly, we observed that the expression of PSA is reversely correlated with p14ARF in human prostate tissues. Taken together, our results reveal a novel function of ARF in modulation of GENE transactivation in PCa. | NO-RELATIONSHIP |
| ARF represses androgen receptor transactivation in prostate cancer. Androgen receptor (AR) signaling is essential for prostate cancer (PCa) development in humans. The initiation of prostate malignancy and progression to a castration-resistant stage are largely contributed by the modulation of GENE activity through its coregulatory proteins. We and others previously reported that p14 alternative reading frame (ARF) expression is positively correlated with the disease progression and severity of PCa. Here, we provide evidence that p14ARF physically interacts with GENE and functions as an GENE corespressor in both an androgen-dependent and androgen-independent manner. Endogenous ARF (p14ARF in human and p19ARF in mouse) and GENE colocalize in both human PCa cells in vitro and PCa tissues of mouse and human in vivo. Overexpression of p14ARF in PCa cells significantly attenuates the activities of androgen response region (ARR2)-probasin and prostate-specific antigen (PSA) promoters. The forced expression of p14ARF in cells resulted in a suppression of PSA and NK transcription factor locus 1 (NKX3.1) expression. Conversely, knockdown of endogenous p14ARF in human PCa cells with short hairpin RNA enhanced GENE transactivation activities in a dose-dependent and p53-independent manner. Furthermore, we demonstrated that p14ARF binds to both the CHEMICAL-terminal domain and the ligand-binding domain of GENE, and the human double minute 2 (HDM2)-binding motif of p14ARF is required for the interaction of p14ARF and GENE proteins. p14ARF perturbs the androgen-induced interaction between the CHEMICAL terminus and C terminus of GENE. Most importantly, we observed that the expression of PSA is reversely correlated with p14ARF in human prostate tissues. Taken together, our results reveal a novel function of ARF in modulation of GENE transactivation in PCa. | PART-OF |
| ARF represses androgen receptor transactivation in prostate cancer. Androgen receptor (AR) signaling is essential for prostate cancer (PCa) development in humans. The initiation of prostate malignancy and progression to a castration-resistant stage are largely contributed by the modulation of GENE activity through its coregulatory proteins. We and others previously reported that p14 alternative reading frame (ARF) expression is positively correlated with the disease progression and severity of PCa. Here, we provide evidence that p14ARF physically interacts with GENE and functions as an GENE corespressor in both an androgen-dependent and androgen-independent manner. Endogenous ARF (p14ARF in human and p19ARF in mouse) and GENE colocalize in both human PCa cells in vitro and PCa tissues of mouse and human in vivo. Overexpression of p14ARF in PCa cells significantly attenuates the activities of androgen response region (ARR2)-probasin and prostate-specific antigen (PSA) promoters. The forced expression of p14ARF in cells resulted in a suppression of PSA and NK transcription factor locus 1 (NKX3.1) expression. Conversely, knockdown of endogenous p14ARF in human PCa cells with short hairpin RNA enhanced GENE transactivation activities in a dose-dependent and p53-independent manner. Furthermore, we demonstrated that p14ARF binds to both the N-terminal domain and the ligand-binding domain of GENE, and the human double minute 2 (HDM2)-binding motif of p14ARF is required for the interaction of p14ARF and GENE proteins. p14ARF perturbs the androgen-induced interaction between the N terminus and CHEMICAL terminus of GENE. Most importantly, we observed that the expression of PSA is reversely correlated with p14ARF in human prostate tissues. Taken together, our results reveal a novel function of ARF in modulation of GENE transactivation in PCa. | PART-OF |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (GENE, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by CHEMICAL (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by CHEMICAL, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both CHEMICAL. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | GENE-CHEMICAL |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, GENE, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by CHEMICAL (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by CHEMICAL, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both CHEMICAL. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | GENE-CHEMICAL |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, GENE, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by CHEMICAL (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by CHEMICAL, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both CHEMICAL. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | GENE-CHEMICAL |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, GENE) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by CHEMICAL (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by CHEMICAL, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both CHEMICAL. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | GENE-CHEMICAL |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (GENE, ABCG5/8, HMGCoA, ACAT) produced by CHEMICAL (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by CHEMICAL, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced GENE expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both CHEMICAL. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | PRODUCT-OF |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, GENE, HMGCoA, ACAT) produced by CHEMICAL (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by CHEMICAL, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both CHEMICAL. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | PRODUCT-OF |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, GENE, ACAT) produced by CHEMICAL (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by CHEMICAL, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both CHEMICAL. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate GENE activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | REGULATOR |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, GENE) produced by CHEMICAL (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by CHEMICAL, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both CHEMICAL. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While GENE expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | PRODUCT-OF |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (GENE, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (CHEMICAL/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | GENE-CHEMICAL |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, GENE, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (CHEMICAL/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | GENE-CHEMICAL |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, GENE, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (CHEMICAL/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | GENE-CHEMICAL |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, GENE) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (CHEMICAL/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | GENE-CHEMICAL |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (GENE, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (CHEMICAL/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced GENE expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | PRODUCT-OF |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, GENE, HMGCoA, ACAT) produced by 7-ketosterols (CHEMICAL/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | PRODUCT-OF |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, GENE, ACAT) produced by 7-ketosterols (CHEMICAL/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate GENE activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | PRODUCT-OF |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, GENE) produced by 7-ketosterols (CHEMICAL/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While GENE expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | PRODUCT-OF |
| Relative expression of CHEMICAL transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by CHEMICAL oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (GENE, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to CHEMICAL absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (stigmasterol/CHEMICAL) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | SUBSTRATE |
| Relative expression of CHEMICAL transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by CHEMICAL oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, GENE, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to CHEMICAL absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (stigmasterol/CHEMICAL) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | SUBSTRATE |
| Relative expression of CHEMICAL transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by CHEMICAL oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, GENE, TNFα) and the influence of gene expression transporters and enzymes related to CHEMICAL absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (stigmasterol/CHEMICAL) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | SUBSTRATE |
| Relative expression of CHEMICAL transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by CHEMICAL oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, GENE) and the influence of gene expression transporters and enzymes related to CHEMICAL absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (stigmasterol/CHEMICAL) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | SUBSTRATE |
| Relative expression of CHEMICAL transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by CHEMICAL oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to CHEMICAL absorption and metabolism (GENE, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (stigmasterol/CHEMICAL) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced GENE expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | SUBSTRATE |
| Relative expression of CHEMICAL transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by CHEMICAL oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to CHEMICAL absorption and metabolism (NPC1L1, GENE, HMGCoA, ACAT) produced by 7-ketosterols (stigmasterol/CHEMICAL) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | SUBSTRATE |
| Relative expression of CHEMICAL transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by CHEMICAL oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to CHEMICAL absorption and metabolism (NPC1L1, ABCG5/8, GENE, ACAT) produced by 7-ketosterols (stigmasterol/CHEMICAL) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate GENE activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | SUBSTRATE |
| Relative expression of CHEMICAL transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by CHEMICAL oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to CHEMICAL absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, GENE) produced by 7-ketosterols (stigmasterol/CHEMICAL) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While GENE expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | SUBSTRATE |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by CHEMICAL (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by CHEMICAL, showing a greater influence upon GENE expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both CHEMICAL. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | GENE-CHEMICAL |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed CHEMICAL to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with GENE induced changes in ABCG expression levels after CHEMICAL-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of CHEMICAL is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | GENE-CHEMICAL |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed CHEMICAL to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in GENE expression levels after CHEMICAL-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of CHEMICAL is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | GENE-CHEMICAL |
| Relative expression of cGENE and inflammation markers through the induction of CHEMICAL-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the CHEMICAL internalization. | ACTIVATOR |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, GENE, ACAT) produced by 7-ketosterols (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [CHEMICAL]i, which also could mediate GENE activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | REGULATOR |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by CHEMICAL (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by CHEMICAL, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, GENE was up-regulated by both CHEMICAL. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | INDIRECT-UPREGULATOR |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by CHEMICAL (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only GENE were down-regulated by CHEMICAL, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both CHEMICAL. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | INDIRECT-DOWNREGULATOR |
| Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than CHEMICAL. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced GENE expression only in CHEMICAL-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. | INDIRECT-DOWNREGULATOR |
| CHEMICAL treatment alters the extracellular adenine nucleotide hydrolysis in platelets and lymphocytes of adult rats. This study evaluated the effects of CHEMICAL on ectonucleotidase activities such as NTPDase (nucleoside triphosphate diphosphohydrolase), Ecto-NPP (nucleotide pyrophosphatase/phosphodiesterase), 5'-nucleotidase and adenosine deaminase (ADA) in platelets and lymphocytes of rats, as well as in the profile of platelet aggregation. Animals were divided into five groups: I (control); II (oil); III (caffeic acid 10mg/kg); IV (caffeic acid 50mg/kg); and V (caffeic acid 100mg/kg). Animals were treated with CHEMICAL diluted in oil for 30days. In platelets, CHEMICAL decreased the ATP hydrolysis and increased ADP hydrolysis in groups III, IV and V when compared to control (P<0.05). The 5'-nucleotidase activity was decreased, while E-NPP and GENE activities were increased in platelets of rats of groups III, IV and V (P<0.05). CHEMICAL reduced significantly the platelet aggregation in the animals of groups III, IV and V in relation to group I (P<0.05). In lymphocytes, the NTPDase and GENE activities were increased in all groups treated with CHEMICAL when compared to control (P<0.05). These findings demonstrated that the enzymes were altered in tissues by CHEMICAL and this compound decreased the platelet aggregation suggesting that CHEMICAL should be considered a potentially therapeutic agent in disorders related to the purinergic system. | ACTIVATOR |
| CHEMICAL treatment alters the extracellular adenine nucleotide hydrolysis in platelets and lymphocytes of adult rats. This study evaluated the effects of CHEMICAL on ectonucleotidase activities such as GENE (nucleoside triphosphate diphosphohydrolase), Ecto-NPP (nucleotide pyrophosphatase/phosphodiesterase), 5'-nucleotidase and adenosine deaminase (ADA) in platelets and lymphocytes of rats, as well as in the profile of platelet aggregation. Animals were divided into five groups: I (control); II (oil); III (caffeic acid 10mg/kg); IV (caffeic acid 50mg/kg); and V (caffeic acid 100mg/kg). Animals were treated with CHEMICAL diluted in oil for 30days. In platelets, CHEMICAL decreased the ATP hydrolysis and increased ADP hydrolysis in groups III, IV and V when compared to control (P<0.05). The 5'-nucleotidase activity was decreased, while E-NPP and ADA activities were increased in platelets of rats of groups III, IV and V (P<0.05). CHEMICAL reduced significantly the platelet aggregation in the animals of groups III, IV and V in relation to group I (P<0.05). In lymphocytes, the GENE and ADA activities were increased in all groups treated with CHEMICAL when compared to control (P<0.05). These findings demonstrated that the enzymes were altered in tissues by CHEMICAL and this compound decreased the platelet aggregation suggesting that CHEMICAL should be considered a potentially therapeutic agent in disorders related to the purinergic system. | ACTIVATOR |
| Mutant B-RAF-Mcl-1 survival signaling depends on the GENE transcription factor. Approximately 50% of melanomas depend on mutant B-RAF for proliferation, metastasis and survival. The inhibition of oncogenic B-RAF with highly targeted compounds has produced remarkable albeit short-lived clinical responses in B-RAF mutant melanoma patients. Reactivation of signaling downstream of B-RAF is frequently associated with acquired resistance to B-RAF inhibitors, and the identification of B-RAF targets may provide new strategies for managing melanoma. Oncogenic B-RAF(V600E) is known to promote the stabilizing phosphorylation of the anti-apoptotic protein Mcl-1, implicated in melanoma survival and chemoresistance. We now show that B-RAF(V600E) signaling also induces the transcription of Mcl-1 in melanocytes and melanoma. We demonstrate that activation of GENE CHEMICAL-727 and tyrosine-705 phosphorylations is promoted by B-RAF(V600E) activity and that the Mcl-1 promoter is dependent on a STAT consensus-site for B-RAF-mediated activation. Consequently, suppression of GENE activity disrupted B-RAF(V600E)-mediated induction of Mcl-1 and reduced melanoma cell survival. We propose that GENE has a central role in the survival and contributes to chemoresistance of B-RAF(V600E) melanoma.Oncogene advance online publication, 4 March 2013; doi:10.1038/onc.2013.45. | PART-OF |
| Mutant B-RAF-Mcl-1 survival signaling depends on the GENE transcription factor. Approximately 50% of melanomas depend on mutant B-RAF for proliferation, metastasis and survival. The inhibition of oncogenic B-RAF with highly targeted compounds has produced remarkable albeit short-lived clinical responses in B-RAF mutant melanoma patients. Reactivation of signaling downstream of B-RAF is frequently associated with acquired resistance to B-RAF inhibitors, and the identification of B-RAF targets may provide new strategies for managing melanoma. Oncogenic B-RAF(V600E) is known to promote the stabilizing phosphorylation of the anti-apoptotic protein Mcl-1, implicated in melanoma survival and chemoresistance. We now show that B-RAF(V600E) signaling also induces the transcription of Mcl-1 in melanocytes and melanoma. We demonstrate that activation of GENE serine-727 and CHEMICAL-705 phosphorylations is promoted by B-RAF(V600E) activity and that the Mcl-1 promoter is dependent on a STAT consensus-site for B-RAF-mediated activation. Consequently, suppression of GENE activity disrupted B-RAF(V600E)-mediated induction of Mcl-1 and reduced melanoma cell survival. We propose that GENE has a central role in the survival and contributes to chemoresistance of B-RAF(V600E) melanoma.Oncogene advance online publication, 4 March 2013; doi:10.1038/onc.2013.45. | PART-OF |
| Aldehyde oxidase importance in vivo in xenobiotic metabolism: CHEMICAL nitroreduction in mice. Aldehyde oxidase (AOX) metabolizes many xenobiotics in vitro, but its importance in vivo is usually unknown relative to cytochrome P450s (CYPs) and other detoxification systems. Currently, the most important insecticides are neonicotinoids, which are metabolized in vitro by AOX on reduction of the nitroimino group and by CYPs via oxidation reactions. The goal of this study was to establish the relative importance of AOX and CYPs in vivo using the mouse model. The procedure was to reduce liver AOX activity by providing tungsten or hydralazine in the drinking water or to use the AOX-deficient DBA/2 mouse strain. None of these approaches reduced GENE activity measured in vitro with an isozyme nonspecific substrate. Liver AOX activity was reduced by 45% with tungsten and 61% with hydralazine and 81% in AOX-deficient mice relative to controls. When mice were treated ip with the major neonicotinoid CHEMICAL (IMI), metabolism by GENE oxidation reactions was not appreciably affected, whereas the AOX-generated nitrosoguanidine metabolite was decreased by 30% with tungsten and 56% with hydralazine and 86% in the AOX-deficient mice. The other IMI nitroreduction metabolite, desnitro-IMI, was decreased by 55%, 65%, and 81% with tungsten, hydralazine, and in the AOX-deficient mice, respectively. Thus, decreasing liver AOX activity by three quite different procedures gave a corresponding decrease for in vivo reductive metabolites in the liver of IMI-treated mice. Possible AOX involvement in IMI metabolism in insects was evaluated using AOX-expressing and AOX-deficient Drosophila, but no differences were found in IMI nitroreduction or sensitivity between the two strains. This is the first study to establish the in vivo relevance of AOX in neonicotinoid metabolism in mammals and one of the first for xenobiotics in general. | NO-RELATIONSHIP |
| Aldehyde oxidase importance in vivo in xenobiotic metabolism: imidacloprid nitroreduction in mice. Aldehyde oxidase (AOX) metabolizes many xenobiotics in vitro, but its importance in vivo is usually unknown relative to cytochrome P450s (CYPs) and other detoxification systems. Currently, the most important insecticides are neonicotinoids, which are metabolized in vitro by AOX on reduction of the nitroimino group and by CYPs via oxidation reactions. The goal of this study was to establish the relative importance of AOX and CYPs in vivo using the mouse model. The procedure was to reduce liver AOX activity by providing tungsten or hydralazine in the drinking water or to use the AOX-deficient DBA/2 mouse strain. None of these approaches reduced GENE activity measured in vitro with an isozyme nonspecific substrate. Liver AOX activity was reduced by 45% with tungsten and 61% with hydralazine and 81% in AOX-deficient mice relative to controls. When mice were treated ip with the major neonicotinoid imidacloprid (CHEMICAL), metabolism by GENE oxidation reactions was not appreciably affected, whereas the AOX-generated nitrosoguanidine metabolite was decreased by 30% with tungsten and 56% with hydralazine and 86% in the AOX-deficient mice. The other CHEMICAL nitroreduction metabolite, desnitro-IMI, was decreased by 55%, 65%, and 81% with tungsten, hydralazine, and in the AOX-deficient mice, respectively. Thus, decreasing liver AOX activity by three quite different procedures gave a corresponding decrease for in vivo reductive metabolites in the liver of IMI-treated mice. Possible AOX involvement in CHEMICAL metabolism in insects was evaluated using AOX-expressing and AOX-deficient Drosophila, but no differences were found in CHEMICAL nitroreduction or sensitivity between the two strains. This is the first study to establish the in vivo relevance of AOX in neonicotinoid metabolism in mammals and one of the first for xenobiotics in general. | SUBSTRATE |
| Aldehyde oxidase importance in vivo in xenobiotic metabolism: imidacloprid nitroreduction in mice. Aldehyde oxidase (AOX) metabolizes many xenobiotics in vitro, but its importance in vivo is usually unknown relative to cytochrome P450s (CYPs) and other detoxification systems. Currently, the most important insecticides are neonicotinoids, which are metabolized in vitro by GENE on reduction of the nitroimino group and by CYPs via oxidation reactions. The goal of this study was to establish the relative importance of GENE and CYPs in vivo using the mouse model. The procedure was to reduce liver GENE activity by providing CHEMICAL or hydralazine in the drinking water or to use the AOX-deficient DBA/2 mouse strain. None of these approaches reduced CYP activity measured in vitro with an isozyme nonspecific substrate. Liver GENE activity was reduced by 45% with CHEMICAL and 61% with hydralazine and 81% in AOX-deficient mice relative to controls. When mice were treated ip with the major neonicotinoid imidacloprid (IMI), metabolism by CYP oxidation reactions was not appreciably affected, whereas the AOX-generated nitrosoguanidine metabolite was decreased by 30% with CHEMICAL and 56% with hydralazine and 86% in the AOX-deficient mice. The other IMI nitroreduction metabolite, desnitro-IMI, was decreased by 55%, 65%, and 81% with CHEMICAL, hydralazine, and in the AOX-deficient mice, respectively. Thus, decreasing liver GENE activity by three quite different procedures gave a corresponding decrease for in vivo reductive metabolites in the liver of IMI-treated mice. Possible GENE involvement in IMI metabolism in insects was evaluated using AOX-expressing and AOX-deficient Drosophila, but no differences were found in IMI nitroreduction or sensitivity between the two strains. This is the first study to establish the in vivo relevance of GENE in neonicotinoid metabolism in mammals and one of the first for xenobiotics in general. | GENE-CHEMICAL |
| Aldehyde oxidase importance in vivo in xenobiotic metabolism: imidacloprid nitroreduction in mice. Aldehyde oxidase (AOX) metabolizes many xenobiotics in vitro, but its importance in vivo is usually unknown relative to cytochrome P450s (CYPs) and other detoxification systems. Currently, the most important insecticides are neonicotinoids, which are metabolized in vitro by GENE on reduction of the nitroimino group and by CYPs via oxidation reactions. The goal of this study was to establish the relative importance of GENE and CYPs in vivo using the mouse model. The procedure was to reduce liver GENE activity by providing tungsten or CHEMICAL in the drinking water or to use the AOX-deficient DBA/2 mouse strain. None of these approaches reduced CYP activity measured in vitro with an isozyme nonspecific substrate. Liver GENE activity was reduced by 45% with tungsten and 61% with CHEMICAL and 81% in AOX-deficient mice relative to controls. When mice were treated ip with the major neonicotinoid imidacloprid (IMI), metabolism by CYP oxidation reactions was not appreciably affected, whereas the AOX-generated nitrosoguanidine metabolite was decreased by 30% with tungsten and 56% with CHEMICAL and 86% in the AOX-deficient mice. The other IMI nitroreduction metabolite, desnitro-IMI, was decreased by 55%, 65%, and 81% with tungsten, CHEMICAL, and in the AOX-deficient mice, respectively. Thus, decreasing liver GENE activity by three quite different procedures gave a corresponding decrease for in vivo reductive metabolites in the liver of IMI-treated mice. Possible GENE involvement in IMI metabolism in insects was evaluated using AOX-expressing and AOX-deficient Drosophila, but no differences were found in IMI nitroreduction or sensitivity between the two strains. This is the first study to establish the in vivo relevance of GENE in neonicotinoid metabolism in mammals and one of the first for xenobiotics in general. | INHIBITOR |
| Aldehyde oxidase importance in vivo in xenobiotic metabolism: imidacloprid nitroreduction in mice. Aldehyde oxidase (AOX) metabolizes many xenobiotics in vitro, but its importance in vivo is usually unknown relative to cytochrome P450s (CYPs) and other detoxification systems. Currently, the most important insecticides are neonicotinoids, which are metabolized in vitro by GENE on reduction of the nitroimino group and by CYPs via oxidation reactions. The goal of this study was to establish the relative importance of GENE and CYPs in vivo using the mouse model. The procedure was to reduce liver GENE activity by providing tungsten or hydralazine in the drinking water or to use the AOX-deficient DBA/2 mouse strain. None of these approaches reduced CYP activity measured in vitro with an isozyme nonspecific substrate. Liver GENE activity was reduced by 45% with tungsten and 61% with hydralazine and 81% in AOX-deficient mice relative to controls. When mice were treated ip with the major neonicotinoid imidacloprid (IMI), metabolism by CYP oxidation reactions was not appreciably affected, whereas the GENE-generated CHEMICAL metabolite was decreased by 30% with tungsten and 56% with hydralazine and 86% in the AOX-deficient mice. The other IMI nitroreduction metabolite, desnitro-IMI, was decreased by 55%, 65%, and 81% with tungsten, hydralazine, and in the AOX-deficient mice, respectively. Thus, decreasing liver GENE activity by three quite different procedures gave a corresponding decrease for in vivo reductive metabolites in the liver of IMI-treated mice. Possible GENE involvement in IMI metabolism in insects was evaluated using AOX-expressing and AOX-deficient Drosophila, but no differences were found in IMI nitroreduction or sensitivity between the two strains. This is the first study to establish the in vivo relevance of GENE in neonicotinoid metabolism in mammals and one of the first for xenobiotics in general. | PRODUCT-OF |
| Aldehyde oxidase importance in vivo in xenobiotic metabolism: imidacloprid nitroreduction in mice. Aldehyde oxidase (AOX) metabolizes many xenobiotics in vitro, but its importance in vivo is usually unknown relative to cytochrome P450s (CYPs) and other detoxification systems. Currently, the most important insecticides are neonicotinoids, which are metabolized in vitro by GENE on reduction of the nitroimino group and by CYPs via oxidation reactions. The goal of this study was to establish the relative importance of GENE and CYPs in vivo using the mouse model. The procedure was to reduce liver GENE activity by providing tungsten or hydralazine in the drinking water or to use the AOX-deficient DBA/2 mouse strain. None of these approaches reduced CYP activity measured in vitro with an isozyme nonspecific substrate. Liver GENE activity was reduced by 45% with tungsten and 61% with hydralazine and 81% in AOX-deficient mice relative to controls. When mice were treated ip with the major neonicotinoid imidacloprid (IMI), metabolism by CYP oxidation reactions was not appreciably affected, whereas the AOX-generated nitrosoguanidine metabolite was decreased by 30% with tungsten and 56% with hydralazine and 86% in the AOX-deficient mice. The other CHEMICAL nitroreduction metabolite, desnitro-IMI, was decreased by 55%, 65%, and 81% with tungsten, hydralazine, and in the AOX-deficient mice, respectively. Thus, decreasing liver GENE activity by three quite different procedures gave a corresponding decrease for in vivo reductive metabolites in the liver of IMI-treated mice. Possible GENE involvement in CHEMICAL metabolism in insects was evaluated using AOX-expressing and AOX-deficient Drosophila, but no differences were found in CHEMICAL nitroreduction or sensitivity between the two strains. This is the first study to establish the in vivo relevance of GENE in neonicotinoid metabolism in mammals and one of the first for xenobiotics in general. | SUBSTRATE |
| Aldehyde oxidase importance in vivo in xenobiotic metabolism: imidacloprid nitroreduction in mice. Aldehyde oxidase (AOX) metabolizes many xenobiotics in vitro, but its importance in vivo is usually unknown relative to cytochrome P450s (CYPs) and other detoxification systems. Currently, the most important insecticides are neonicotinoids, which are metabolized in vitro by GENE on reduction of the nitroimino group and by CYPs via oxidation reactions. The goal of this study was to establish the relative importance of GENE and CYPs in vivo using the mouse model. The procedure was to reduce liver GENE activity by providing tungsten or hydralazine in the drinking water or to use the AOX-deficient DBA/2 mouse strain. None of these approaches reduced CYP activity measured in vitro with an isozyme nonspecific substrate. Liver GENE activity was reduced by 45% with tungsten and 61% with hydralazine and 81% in AOX-deficient mice relative to controls. When mice were treated ip with the major CHEMICAL imidacloprid (IMI), metabolism by CYP oxidation reactions was not appreciably affected, whereas the AOX-generated nitrosoguanidine metabolite was decreased by 30% with tungsten and 56% with hydralazine and 86% in the AOX-deficient mice. The other IMI nitroreduction metabolite, desnitro-IMI, was decreased by 55%, 65%, and 81% with tungsten, hydralazine, and in the AOX-deficient mice, respectively. Thus, decreasing liver GENE activity by three quite different procedures gave a corresponding decrease for in vivo reductive metabolites in the liver of IMI-treated mice. Possible GENE involvement in IMI metabolism in insects was evaluated using AOX-expressing and AOX-deficient Drosophila, but no differences were found in IMI nitroreduction or sensitivity between the two strains. This is the first study to establish the in vivo relevance of GENE in CHEMICAL metabolism in mammals and one of the first for xenobiotics in general. | SUBSTRATE |
| Aldehyde oxidase importance in vivo in xenobiotic metabolism: imidacloprid nitroreduction in mice. Aldehyde oxidase (AOX) metabolizes many xenobiotics in vitro, but its importance in vivo is usually unknown relative to cytochrome P450s (CYPs) and other detoxification systems. Currently, the most important insecticides are CHEMICAL, which are metabolized in vitro by GENE on reduction of the nitroimino group and by CYPs via oxidation reactions. The goal of this study was to establish the relative importance of GENE and CYPs in vivo using the mouse model. The procedure was to reduce liver GENE activity by providing tungsten or hydralazine in the drinking water or to use the AOX-deficient DBA/2 mouse strain. None of these approaches reduced CYP activity measured in vitro with an isozyme nonspecific substrate. Liver GENE activity was reduced by 45% with tungsten and 61% with hydralazine and 81% in AOX-deficient mice relative to controls. When mice were treated ip with the major neonicotinoid imidacloprid (IMI), metabolism by CYP oxidation reactions was not appreciably affected, whereas the AOX-generated nitrosoguanidine metabolite was decreased by 30% with tungsten and 56% with hydralazine and 86% in the AOX-deficient mice. The other IMI nitroreduction metabolite, desnitro-IMI, was decreased by 55%, 65%, and 81% with tungsten, hydralazine, and in the AOX-deficient mice, respectively. Thus, decreasing liver GENE activity by three quite different procedures gave a corresponding decrease for in vivo reductive metabolites in the liver of IMI-treated mice. Possible GENE involvement in IMI metabolism in insects was evaluated using AOX-expressing and AOX-deficient Drosophila, but no differences were found in IMI nitroreduction or sensitivity between the two strains. This is the first study to establish the in vivo relevance of GENE in neonicotinoid metabolism in mammals and one of the first for xenobiotics in general. | SUBSTRATE |
| Aldehyde oxidase importance in vivo in xenobiotic metabolism: imidacloprid nitroreduction in mice. Aldehyde oxidase (AOX) metabolizes many xenobiotics in vitro, but its importance in vivo is usually unknown relative to cytochrome P450s (CYPs) and other detoxification systems. Currently, the most important insecticides are CHEMICAL, which are metabolized in vitro by AOX on reduction of the nitroimino group and by GENE via oxidation reactions. The goal of this study was to establish the relative importance of AOX and GENE in vivo using the mouse model. The procedure was to reduce liver AOX activity by providing tungsten or hydralazine in the drinking water or to use the AOX-deficient DBA/2 mouse strain. None of these approaches reduced CYP activity measured in vitro with an isozyme nonspecific substrate. Liver AOX activity was reduced by 45% with tungsten and 61% with hydralazine and 81% in AOX-deficient mice relative to controls. When mice were treated ip with the major neonicotinoid imidacloprid (IMI), metabolism by CYP oxidation reactions was not appreciably affected, whereas the AOX-generated nitrosoguanidine metabolite was decreased by 30% with tungsten and 56% with hydralazine and 86% in the AOX-deficient mice. The other IMI nitroreduction metabolite, desnitro-IMI, was decreased by 55%, 65%, and 81% with tungsten, hydralazine, and in the AOX-deficient mice, respectively. Thus, decreasing liver AOX activity by three quite different procedures gave a corresponding decrease for in vivo reductive metabolites in the liver of IMI-treated mice. Possible AOX involvement in IMI metabolism in insects was evaluated using AOX-expressing and AOX-deficient Drosophila, but no differences were found in IMI nitroreduction or sensitivity between the two strains. This is the first study to establish the in vivo relevance of AOX in neonicotinoid metabolism in mammals and one of the first for xenobiotics in general. | SUBSTRATE |
| Aldehyde oxidase importance in vivo in xenobiotic metabolism: imidacloprid nitroreduction in mice. Aldehyde oxidase (AOX) metabolizes many xenobiotics in vitro, but its importance in vivo is usually unknown relative to cytochrome P450s (CYPs) and other detoxification systems. Currently, the most important insecticides are neonicotinoids, which are metabolized in vitro by GENE on reduction of the CHEMICAL group and by CYPs via oxidation reactions. The goal of this study was to establish the relative importance of GENE and CYPs in vivo using the mouse model. The procedure was to reduce liver GENE activity by providing tungsten or hydralazine in the drinking water or to use the AOX-deficient DBA/2 mouse strain. None of these approaches reduced CYP activity measured in vitro with an isozyme nonspecific substrate. Liver GENE activity was reduced by 45% with tungsten and 61% with hydralazine and 81% in AOX-deficient mice relative to controls. When mice were treated ip with the major neonicotinoid imidacloprid (IMI), metabolism by CYP oxidation reactions was not appreciably affected, whereas the AOX-generated nitrosoguanidine metabolite was decreased by 30% with tungsten and 56% with hydralazine and 86% in the AOX-deficient mice. The other IMI nitroreduction metabolite, desnitro-IMI, was decreased by 55%, 65%, and 81% with tungsten, hydralazine, and in the AOX-deficient mice, respectively. Thus, decreasing liver GENE activity by three quite different procedures gave a corresponding decrease for in vivo reductive metabolites in the liver of IMI-treated mice. Possible GENE involvement in IMI metabolism in insects was evaluated using AOX-expressing and AOX-deficient Drosophila, but no differences were found in IMI nitroreduction or sensitivity between the two strains. This is the first study to establish the in vivo relevance of GENE in neonicotinoid metabolism in mammals and one of the first for xenobiotics in general. | SUBSTRATE |
| Non-front-fanged colubroid snakes: A current evidence-based analysis of medical significance. Non-front-fanged colubroid snakes (NFFC; formerly and artificially taxonomically assembled as "colubrids") comprise about 70% of extant snake species and include several taxa now known to cause lethal or life threatening envenoming in humans. Although the medical risks of bites by only a handful of species have been documented, a growing number of NFFC are implicated in medically significant bites. The majority of these snakes have oral products (Duvernoy's secretions, or venoms) with unknown biomedical properties and their potential for causing harm in humans is unknown. Increasingly, multiple NFFC species are entering the commercial snake trade posing an uncertain risk. Published case reports describing NFFC bites were assessed for evidence-based value, clinical detail and verified species identification. These data were subjected to meta-analysis and a hazard index was generated for select taxa. Cases on which we consulted or personally treated were included and subjected to the same assessment criteria. Cases involving approximately 120 species met the selection criteria, and a small subset designated Hazard Level 1 (most hazardous), contained 5 species with lethal potential. Recommended management of these cases included antivenom for 3 species, Dispholidus typus, Rhabdophis tiginis, Rhabdophis subminiatus, whereas others in this subset without commercially available antivenoms (Thelotornis spp.) were treated with plasma/erythrocyte replacement therapy and supportive care. Heparin, antifibrinolytics and/or plasmapheresis/exchange transfusion have been used in the management of some Hazard Level 1 envenomings, but evidence-based analysis positively contraindicates the use of any of these interventions. Hazard Level 2/3 species were involved in cases containing mixed quality data that implicated these taxa (e.g. Boiga irregularis, Philodryas olfersii, Malpolon monspessulanus) with bites that caused rare systemic effects. Recommended management may include use of GENE inhibitors (e.g. CHEMICAL) and wound care on a case-by-case basis. Hazard level 3 species comprised a larger group capable of producing significant local effects only, often associated with a protracted bite (eg Heterodon nasicus, Borikenophis (Alsophis) portoricensis, Platyceps (Coluber) rhodorachis). Management is restricted to wound care. Bites by Hazard level 4 species comprised the majority of surveyed taxa and these showed only minor effects of no clinical importance. This study has produced a comprehensive evidence-based listing of NFFC snakes tabulated against medical significance of bites, together with best-practice management recommendations. This analysis assumes increasing importance, as there is growing exposure to lesser-known NFFC snakes, particularly in captive collections that may uncover further species of significance in the future. Careful and accurate documentation of bites by verified species of NFFC snakes is required to increase the evidence base and establish the best medical management approach for each species. | INHIBITOR |
| Anti-adipogenic diarylheptanoids from Alnus hirsuta f. sibirica on 3T3-L1 cells. A new diarylheptanoid, (5S)-hydroxy-1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)-hepta-1E-en-3-one (1), was isolated along with seventeen known diarylheptanoids (2-18) from the methanol extract of Alnus hirsuta f. sibirica leaves using bioactivity-guided fractionation. Among the isolated compounds, compounds 1 and 2 and 4-12 reduced lipid accumulation dose-dependently in 3T3-L1 preadipocytes. Of the compounds active in the present assay system, the most potent compound 7, CHEMICAL, significantly suppressed the induction of peroxisome proliferator activated receptor γ (PPARγ and GENE (C/EBPα) protein expression, and inhibited adipocyte differentiation induced by troglitazone, a PPARγ agonist. It was demonstrated that compound 7 has anti-adipogenic activity mediated by the regulation of PPARγ dependent pathways. | INDIRECT-DOWNREGULATOR |
| Anti-adipogenic diarylheptanoids from Alnus hirsuta f. sibirica on 3T3-L1 cells. A new diarylheptanoid, (5S)-hydroxy-1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)-hepta-1E-en-3-one (1), was isolated along with seventeen known diarylheptanoids (2-18) from the methanol extract of Alnus hirsuta f. sibirica leaves using bioactivity-guided fractionation. Among the isolated compounds, compounds 1 and 2 and 4-12 reduced lipid accumulation dose-dependently in 3T3-L1 preadipocytes. Of the compounds active in the present assay system, the most potent compound 7, CHEMICAL, significantly suppressed the induction of peroxisome proliferator activated receptor γ (PPARγ and CCAAT/enhancer binding protein α (GENE) protein expression, and inhibited adipocyte differentiation induced by troglitazone, a PPARγ agonist. It was demonstrated that compound 7 has anti-adipogenic activity mediated by the regulation of PPARγ dependent pathways. | INDIRECT-DOWNREGULATOR |
| Anti-adipogenic diarylheptanoids from Alnus hirsuta f. sibirica on 3T3-L1 cells. A new diarylheptanoid, (5S)-hydroxy-1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)-hepta-1E-en-3-one (1), was isolated along with seventeen known diarylheptanoids (2-18) from the methanol extract of Alnus hirsuta f. sibirica leaves using bioactivity-guided fractionation. Among the isolated compounds, compounds 1 and 2 and 4-12 reduced lipid accumulation dose-dependently in 3T3-L1 preadipocytes. Of the compounds active in the present assay system, the most potent compound 7, CHEMICAL, significantly suppressed the induction of GENE (PPARγ and CCAAT/enhancer binding protein α (C/EBPα) protein expression, and inhibited adipocyte differentiation induced by troglitazone, a PPARγ agonist. It was demonstrated that compound 7 has anti-adipogenic activity mediated by the regulation of PPARγ dependent pathways. | INDIRECT-DOWNREGULATOR |
| Anti-adipogenic diarylheptanoids from Alnus hirsuta f. sibirica on 3T3-L1 cells. A new diarylheptanoid, (5S)-hydroxy-1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)-hepta-1E-en-3-one (1), was isolated along with seventeen known diarylheptanoids (2-18) from the methanol extract of Alnus hirsuta f. sibirica leaves using bioactivity-guided fractionation. Among the isolated compounds, compounds 1 and 2 and 4-12 reduced lipid accumulation dose-dependently in 3T3-L1 preadipocytes. Of the compounds active in the present assay system, the most potent compound 7, CHEMICAL, significantly suppressed the induction of peroxisome proliferator activated receptor γ (GENE and CCAAT/enhancer binding protein α (C/EBPα) protein expression, and inhibited adipocyte differentiation induced by troglitazone, a GENE agonist. It was demonstrated that compound 7 has anti-adipogenic activity mediated by the regulation of GENE dependent pathways. | INHIBITOR |
| Anti-adipogenic diarylheptanoids from Alnus hirsuta f. sibirica on 3T3-L1 cells. A new diarylheptanoid, (5S)-hydroxy-1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)-hepta-1E-en-3-one (1), was isolated along with seventeen known diarylheptanoids (2-18) from the methanol extract of Alnus hirsuta f. sibirica leaves using bioactivity-guided fractionation. Among the isolated compounds, compounds 1 and 2 and 4-12 reduced lipid accumulation dose-dependently in 3T3-L1 preadipocytes. Of the compounds active in the present assay system, the most potent compound 7, platyphyllonol-5-O-β-d-xylopyranoside, significantly suppressed the induction of peroxisome proliferator activated receptor γ (PPARγ and CCAAT/enhancer binding protein α (C/EBPα) protein expression, and inhibited adipocyte differentiation induced by CHEMICAL, a GENE agonist. It was demonstrated that compound 7 has anti-adipogenic activity mediated by the regulation of GENE dependent pathways. | ACTIVATOR |
| Benzenesulfonamides: a unique class of chemokine receptor type 4 inhibitors. The interaction of GENE with CXCL12 (SDF-1) plays a critical role in cancer metastasis by facilitating the homing of tumor cells to metastatic sites. Based on our previously published work on GENE antagonists, we have synthesized a series of CHEMICAL that inhibit the GENE/CXCL12 interaction. Analogue bioactivities were assessed with binding affinity and Matrigel invasion assays. Computer modeling was employed to evaluate a selection of the new analogues docked into the GENE X-ray structure and to rationalize discrepancies between the affinity and Matrigel in vitro assays. A lead compound displays nanomolar potency in the binding affinity assay (IC(50)=8.0 nM) and the Matrigel invasion assay (100 % blockade of invasion at 10 nM). These data demonstrate that benzenesulfonamides are a unique class of GENE inhibitors with high potency. | INHIBITOR |
| Benzenesulfonamides: a unique class of chemokine receptor type 4 inhibitors. The interaction of CXCR4 with GENE (SDF-1) plays a critical role in cancer metastasis by facilitating the homing of tumor cells to metastatic sites. Based on our previously published work on CXCR4 antagonists, we have synthesized a series of CHEMICAL that inhibit the CXCR4/GENE interaction. Analogue bioactivities were assessed with binding affinity and Matrigel invasion assays. Computer modeling was employed to evaluate a selection of the new analogues docked into the CXCR4 X-ray structure and to rationalize discrepancies between the affinity and Matrigel in vitro assays. A lead compound displays nanomolar potency in the binding affinity assay (IC(50)=8.0 nM) and the Matrigel invasion assay (100 % blockade of invasion at 10 nM). These data demonstrate that benzenesulfonamides are a unique class of CXCR4 inhibitors with high potency. | INHIBITOR |
| Benzenesulfonamides: a unique class of chemokine receptor type 4 inhibitors. The interaction of GENE with CXCL12 (SDF-1) plays a critical role in cancer metastasis by facilitating the homing of tumor cells to metastatic sites. Based on our previously published work on GENE antagonists, we have synthesized a series of aryl sulfonamides that inhibit the CXCR4/CXCL12 interaction. Analogue bioactivities were assessed with binding affinity and Matrigel invasion assays. Computer modeling was employed to evaluate a selection of the new analogues docked into the GENE X-ray structure and to rationalize discrepancies between the affinity and Matrigel in vitro assays. A lead compound displays nanomolar potency in the binding affinity assay (IC(50)=8.0 nM) and the Matrigel invasion assay (100 % blockade of invasion at 10 nM). These data demonstrate that CHEMICAL are a unique class of GENE inhibitors with high potency. | INHIBITOR |
| CHEMICAL: a unique class of GENE inhibitors. The interaction of CXCR4 with CXCL12 (SDF-1) plays a critical role in cancer metastasis by facilitating the homing of tumor cells to metastatic sites. Based on our previously published work on CXCR4 antagonists, we have synthesized a series of aryl sulfonamides that inhibit the CXCR4/CXCL12 interaction. Analogue bioactivities were assessed with binding affinity and Matrigel invasion assays. Computer modeling was employed to evaluate a selection of the new analogues docked into the CXCR4 X-ray structure and to rationalize discrepancies between the affinity and Matrigel in vitro assays. A lead compound displays nanomolar potency in the binding affinity assay (IC(50)=8.0 nM) and the Matrigel invasion assay (100 % blockade of invasion at 10 nM). These data demonstrate that benzenesulfonamides are a unique class of CXCR4 inhibitors with high potency. | INHIBITOR |
| Measurement of Transport Activities of CHEMICAL in GENE and Multidrug Resistance-Associated Proteins Using LC-MS/MS. A method has been developed for the measurement of transport activities in membrane vesicles obtained from Sf9 cells for 3β-hydroxy-Δ(5)-bile acids by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Calibration curves for the bile acids were linear over the range of 10 to 2000 pmol/mL, and the detection limit was less than 1 pmol/mL for 3β-hydroxy-Δ(5)-bile acids using selected reaction monitoring analysis. The analytical method was applied to measurements of transport activities in membrane vesicles obtained from human multidrug resistance-associated protein 2-, 3-, and human bile salt export pump-expressing Sf9 cells for conjugated 3β-hydroxy-Δ(5)-bile acids. The present study demonstrated that human multidrug resistance-associated protein 3 vesicles accepted conjugated 3β-hydroxy-Δ(5)-bile acids along with common bile acids such as glycocholic acid and taurolithocholic acid 3-sulfate. | SUBSTRATE |
| Measurement of Transport Activities of CHEMICAL in Bile Salt Export Pump and GENE Using LC-MS/MS. A method has been developed for the measurement of transport activities in membrane vesicles obtained from Sf9 cells for 3β-hydroxy-Δ(5)-bile acids by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Calibration curves for the bile acids were linear over the range of 10 to 2000 pmol/mL, and the detection limit was less than 1 pmol/mL for 3β-hydroxy-Δ(5)-bile acids using selected reaction monitoring analysis. The analytical method was applied to measurements of transport activities in membrane vesicles obtained from human multidrug resistance-associated protein 2-, 3-, and human bile salt export pump-expressing Sf9 cells for conjugated 3β-hydroxy-Δ(5)-bile acids. The present study demonstrated that human multidrug resistance-associated protein 3 vesicles accepted conjugated 3β-hydroxy-Δ(5)-bile acids along with common bile acids such as glycocholic acid and taurolithocholic acid 3-sulfate. | SUBSTRATE |
| Measurement of Transport Activities of 3β-Hydroxy-Δ(5)-bile Acids in Bile Salt Export Pump and Multidrug Resistance-Associated Proteins Using LC-MS/MS. A method has been developed for the measurement of transport activities in membrane vesicles obtained from Sf9 cells for CHEMICAL by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Calibration curves for the bile acids were linear over the range of 10 to 2000 pmol/mL, and the detection limit was less than 1 pmol/mL for CHEMICAL using selected reaction monitoring analysis. The analytical method was applied to measurements of transport activities in membrane vesicles obtained from human multidrug resistance-associated protein 2-, 3-, and GENE-expressing Sf9 cells for conjugated CHEMICAL. The present study demonstrated that human multidrug resistance-associated protein 3 vesicles accepted conjugated CHEMICAL along with common bile acids such as glycocholic acid and taurolithocholic acid 3-sulfate. | SUBSTRATE |
| Measurement of Transport Activities of 3β-Hydroxy-Δ(5)-bile Acids in Bile Salt Export Pump and Multidrug Resistance-Associated Proteins Using LC-MS/MS. A method has been developed for the measurement of transport activities in membrane vesicles obtained from Sf9 cells for CHEMICAL by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Calibration curves for the bile acids were linear over the range of 10 to 2000 pmol/mL, and the detection limit was less than 1 pmol/mL for CHEMICAL using selected reaction monitoring analysis. The analytical method was applied to measurements of transport activities in membrane vesicles obtained from human multidrug resistance-associated protein 2-, 3-, and human bile salt export pump-expressing Sf9 cells for conjugated CHEMICAL. The present study demonstrated that GENE vesicles accepted conjugated CHEMICAL along with common bile acids such as glycocholic acid and taurolithocholic acid 3-sulfate. | SUBSTRATE |
| Measurement of Transport Activities of 3β-Hydroxy-Δ(5)-bile Acids in Bile Salt Export Pump and Multidrug Resistance-Associated Proteins Using LC-MS/MS. A method has been developed for the measurement of transport activities in membrane vesicles obtained from Sf9 cells for 3β-hydroxy-Δ(5)-bile acids by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Calibration curves for the CHEMICAL were linear over the range of 10 to 2000 pmol/mL, and the detection limit was less than 1 pmol/mL for 3β-hydroxy-Δ(5)-bile acids using selected reaction monitoring analysis. The analytical method was applied to measurements of transport activities in membrane vesicles obtained from human multidrug resistance-associated protein 2-, 3-, and human bile salt export pump-expressing Sf9 cells for conjugated 3β-hydroxy-Δ(5)-bile acids. The present study demonstrated that GENE vesicles accepted conjugated 3β-hydroxy-Δ(5)-bile acids along with common CHEMICAL such as glycocholic acid and taurolithocholic acid 3-sulfate. | SUBSTRATE |
| Measurement of Transport Activities of 3β-Hydroxy-Δ(5)-bile Acids in Bile Salt Export Pump and Multidrug Resistance-Associated Proteins Using LC-MS/MS. A method has been developed for the measurement of transport activities in membrane vesicles obtained from Sf9 cells for 3β-hydroxy-Δ(5)-bile acids by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Calibration curves for the bile acids were linear over the range of 10 to 2000 pmol/mL, and the detection limit was less than 1 pmol/mL for 3β-hydroxy-Δ(5)-bile acids using selected reaction monitoring analysis. The analytical method was applied to measurements of transport activities in membrane vesicles obtained from human multidrug resistance-associated protein 2-, 3-, and human bile salt export pump-expressing Sf9 cells for conjugated 3β-hydroxy-Δ(5)-bile acids. The present study demonstrated that GENE vesicles accepted conjugated 3β-hydroxy-Δ(5)-bile acids along with common bile acids such as CHEMICAL and taurolithocholic acid 3-sulfate. | SUBSTRATE |
| Measurement of Transport Activities of 3β-Hydroxy-Δ(5)-bile Acids in Bile Salt Export Pump and Multidrug Resistance-Associated Proteins Using LC-MS/MS. A method has been developed for the measurement of transport activities in membrane vesicles obtained from Sf9 cells for 3β-hydroxy-Δ(5)-bile acids by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Calibration curves for the bile acids were linear over the range of 10 to 2000 pmol/mL, and the detection limit was less than 1 pmol/mL for 3β-hydroxy-Δ(5)-bile acids using selected reaction monitoring analysis. The analytical method was applied to measurements of transport activities in membrane vesicles obtained from human multidrug resistance-associated protein 2-, 3-, and human bile salt export pump-expressing Sf9 cells for conjugated 3β-hydroxy-Δ(5)-bile acids. The present study demonstrated that GENE vesicles accepted conjugated 3β-hydroxy-Δ(5)-bile acids along with common bile acids such as glycocholic acid and CHEMICAL. | SUBSTRATE |
| An Intracellular Domain Fragment of the p75 Neurotrophin Receptor (p75NTR) Enhances Tropomyosin Receptor Kinase A (TrkA) Receptor Function. Facilitation of nerve growth factor (NGF) signaling by the p75 neurotrophin receptor (p75(NTR)) is critical for neuronal survival and differentiation. However, the interaction between GENE and TrkA receptors required for this activity is not understood. Here, we report that a specific 29-CHEMICAL peptide derived from the intracellular domain fragment of GENE interacts with and potentiates binding of NGF to TrkA-expressing cells, leading to increased neurite outgrowth in sympathetic neurons as a result of enhanced Erk1/2 and Akt signaling. An endogenous intracellular domain fragment of GENE (p75(ICD)) containing these 29 amino acids is produced by regulated proteolysis of the full-length receptor. We demonstrate that generation of this fragment is a requirement for GENE to facilitate TrkA signaling in neurons and propose that the juxtamembrane region of p75(ICD) acts to cause a conformational change within the extracellular domain of TrkA. This finding provides new insight into the mechanism by which GENE and TrkA interact to enhance neurotrophic signaling. | PART-OF |
| An Intracellular Domain Fragment of the p75 Neurotrophin Receptor (p75NTR) Enhances Tropomyosin Receptor Kinase A (TrkA) Receptor Function. Facilitation of nerve growth factor (NGF) signaling by the p75 neurotrophin receptor (p75(NTR)) is critical for neuronal survival and differentiation. However, the interaction between GENE and TrkA receptors required for this activity is not understood. Here, we report that a specific 29-amino acid peptide derived from the intracellular domain fragment of GENE interacts with and potentiates binding of NGF to TrkA-expressing cells, leading to increased neurite outgrowth in sympathetic neurons as a result of enhanced Erk1/2 and Akt signaling. An endogenous intracellular domain fragment of GENE (p75(ICD)) containing these 29 CHEMICAL is produced by regulated proteolysis of the full-length receptor. We demonstrate that generation of this fragment is a requirement for GENE to facilitate TrkA signaling in neurons and propose that the juxtamembrane region of p75(ICD) acts to cause a conformational change within the extracellular domain of TrkA. This finding provides new insight into the mechanism by which GENE and TrkA interact to enhance neurotrophic signaling. | PART-OF |
| An Intracellular Domain Fragment of the p75 Neurotrophin Receptor (p75NTR) Enhances Tropomyosin Receptor Kinase A (TrkA) Receptor Function. Facilitation of nerve growth factor (NGF) signaling by the p75 neurotrophin receptor (p75(NTR)) is critical for neuronal survival and differentiation. However, the interaction between p75(NTR) and TrkA receptors required for this activity is not understood. Here, we report that a specific 29-amino acid peptide derived from the intracellular domain fragment of p75(NTR) interacts with and potentiates binding of NGF to TrkA-expressing cells, leading to increased neurite outgrowth in sympathetic neurons as a result of enhanced Erk1/2 and Akt signaling. An endogenous intracellular domain fragment of p75(NTR) (GENE) containing these 29 CHEMICAL is produced by regulated proteolysis of the full-length receptor. We demonstrate that generation of this fragment is a requirement for p75(NTR) to facilitate TrkA signaling in neurons and propose that the juxtamembrane region of GENE acts to cause a conformational change within the extracellular domain of TrkA. This finding provides new insight into the mechanism by which p75(NTR) and TrkA interact to enhance neurotrophic signaling. | PART-OF |
| Synthesis and evaluation of 3-(benzylthio)-5-(1H-indol-3-yl)-1,2,4-triazol-4-amines as GENE inhibitory anticancer agents. A series of substituted CHEMICAL has been synthesised and tested in vitro as potential pro-apoptotic GENE-inhibitory anticancer agents. Synthesis of the target compounds was readily accomplished in good yields through a cyclisation reaction between indole-3-carboxylic acid hydrazide and carbon disulfide under basic conditions, followed by S-benzylation. Active compounds, such as the nitrobenzyl analogue 6c, were found to exhibit sub-micromolar IC50 values in GENE expressing human cancer cell lines. Molecular modelling and ELISA studies further implicated anti-apoptotic GENE as a candidate molecular target underpinning anticancer activity. | INHIBITOR |
| Synthesis and evaluation of 3-(benzylthio)-5-(1H-indol-3-yl)-1,2,4-triazol-4-amines as GENE inhibitory anticancer agents. A series of substituted 3-(benzylthio)-5-(1H-indol-3-yl)-4H-1,2,4-triazol-4-amines has been synthesised and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents. Synthesis of the target compounds was readily accomplished in good yields through a cyclisation reaction between indole-3-carboxylic acid hydrazide and carbon disulfide under basic conditions, followed by S-benzylation. Active compounds, such as the CHEMICAL analogue 6c, were found to exhibit sub-micromolar IC50 values in GENE expressing human cancer cell lines. Molecular modelling and ELISA studies further implicated anti-apoptotic GENE as a candidate molecular target underpinning anticancer activity. | INHIBITOR |
| Synthesis and evaluation of CHEMICAL as GENE inhibitory anticancer agents. A series of substituted 3-(benzylthio)-5-(1H-indol-3-yl)-4H-1,2,4-triazol-4-amines has been synthesised and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents. Synthesis of the target compounds was readily accomplished in good yields through a cyclisation reaction between indole-3-carboxylic acid hydrazide and carbon disulfide under basic conditions, followed by S-benzylation. Active compounds, such as the nitrobenzyl analogue 6c, were found to exhibit sub-micromolar IC50 values in GENE expressing human cancer cell lines. Molecular modelling and ELISA studies further implicated anti-apoptotic GENE as a candidate molecular target underpinning anticancer activity. | INHIBITOR |
| Effect of CHEMICAL pretreatment on arsenic-induced oxidative stress in male Wistar rats. Humans are commonly exposed to CHEMICAL, one of the most important lifestyle chemicals. The occurrence of high levels of arsenic in the groundwater of the southeast region of Asia has received much attention in the past decade and has become a global health concern. Predominant occurrence of both these chemicals and ease of their human exposure led us to investigate the effect of CHEMICAL, a major tobacco alkaloid, on arsenic toxicity. Adult male rats were pre-exposed to two different doses of CHEMICAL (0.75 and 3 mg/kg, intraperitoneally) for 7 days followed by 30 days of arsenic exposure (50 ppm sodium arsenite in drinking water). CHEMICAL pre-exposure resulted in an increased brain arsenic accumulation and a decreased liver arsenic concentration. Arsenic also caused a significant oxidative stress in the blood, brain and liver of the exposed rats. GENE, a phase II enzyme, was inhibited by both arsenic and CHEMICAL but no such inhibition was noted in arsenic-treated animals pre-exposed to CHEMICAL. Upon CHEMICAL pre-exposure, brain acetylcholinesterase increased, while monoamine oxidase (MAO) decreased. The toxic effects of MAO significantly attenuated with CHEMICAL pre-exposure. The present study suggests that CHEMICAL may not be the major contributing factor for the previously reported synergistic toxic interaction between tobacco and arsenic. CHEMICAL pre-exposure in arsenic-exposed animals revealed interesting toxicokinetics and oxidative stress modulating interactions in the brain and liver of rats, which requires further exploration. | INHIBITOR |
| Effect of nicotine pretreatment on arsenic-induced oxidative stress in male Wistar rats. Humans are commonly exposed to nicotine, one of the most important lifestyle chemicals. The occurrence of high levels of CHEMICAL in the groundwater of the southeast region of Asia has received much attention in the past decade and has become a global health concern. Predominant occurrence of both these chemicals and ease of their human exposure led us to investigate the effect of nicotine, a major tobacco alkaloid, on CHEMICAL toxicity. Adult male rats were pre-exposed to two different doses of nicotine (0.75 and 3 mg/kg, intraperitoneally) for 7 days followed by 30 days of CHEMICAL exposure (50 ppm sodium arsenite in drinking water). Nicotine pre-exposure resulted in an increased brain CHEMICAL accumulation and a decreased liver CHEMICAL concentration. CHEMICAL also caused a significant oxidative stress in the blood, brain and liver of the exposed rats. GENE, a phase II enzyme, was inhibited by both CHEMICAL and nicotine but no such inhibition was noted in CHEMICAL-treated animals pre-exposed to nicotine. Upon nicotine pre-exposure, brain acetylcholinesterase increased, while monoamine oxidase (MAO) decreased. The toxic effects of MAO significantly attenuated with nicotine pre-exposure. The present study suggests that nicotine may not be the major contributing factor for the previously reported synergistic toxic interaction between tobacco and CHEMICAL. Nicotine pre-exposure in arsenic-exposed animals revealed interesting toxicokinetics and oxidative stress modulating interactions in the brain and liver of rats, which requires further exploration. | INHIBITOR |
| Effect of CHEMICAL pretreatment on arsenic-induced oxidative stress in male Wistar rats. Humans are commonly exposed to CHEMICAL, one of the most important lifestyle chemicals. The occurrence of high levels of arsenic in the groundwater of the southeast region of Asia has received much attention in the past decade and has become a global health concern. Predominant occurrence of both these chemicals and ease of their human exposure led us to investigate the effect of CHEMICAL, a major tobacco alkaloid, on arsenic toxicity. Adult male rats were pre-exposed to two different doses of CHEMICAL (0.75 and 3 mg/kg, intraperitoneally) for 7 days followed by 30 days of arsenic exposure (50 ppm sodium arsenite in drinking water). CHEMICAL pre-exposure resulted in an increased brain arsenic accumulation and a decreased liver arsenic concentration. Arsenic also caused a significant oxidative stress in the blood, brain and liver of the exposed rats. Glutathione-S-transferase, a phase II enzyme, was inhibited by both arsenic and CHEMICAL but no such inhibition was noted in arsenic-treated animals pre-exposed to CHEMICAL. Upon CHEMICAL pre-exposure, brain GENE increased, while monoamine oxidase (MAO) decreased. The toxic effects of MAO significantly attenuated with CHEMICAL pre-exposure. The present study suggests that CHEMICAL may not be the major contributing factor for the previously reported synergistic toxic interaction between tobacco and arsenic. CHEMICAL pre-exposure in arsenic-exposed animals revealed interesting toxicokinetics and oxidative stress modulating interactions in the brain and liver of rats, which requires further exploration. | INDIRECT-UPREGULATOR |
| Effect of CHEMICAL pretreatment on arsenic-induced oxidative stress in male Wistar rats. Humans are commonly exposed to CHEMICAL, one of the most important lifestyle chemicals. The occurrence of high levels of arsenic in the groundwater of the southeast region of Asia has received much attention in the past decade and has become a global health concern. Predominant occurrence of both these chemicals and ease of their human exposure led us to investigate the effect of CHEMICAL, a major tobacco alkaloid, on arsenic toxicity. Adult male rats were pre-exposed to two different doses of CHEMICAL (0.75 and 3 mg/kg, intraperitoneally) for 7 days followed by 30 days of arsenic exposure (50 ppm sodium arsenite in drinking water). CHEMICAL pre-exposure resulted in an increased brain arsenic accumulation and a decreased liver arsenic concentration. Arsenic also caused a significant oxidative stress in the blood, brain and liver of the exposed rats. Glutathione-S-transferase, a phase II enzyme, was inhibited by both arsenic and CHEMICAL but no such inhibition was noted in arsenic-treated animals pre-exposed to CHEMICAL. Upon CHEMICAL pre-exposure, brain acetylcholinesterase increased, while GENE (MAO) decreased. The toxic effects of MAO significantly attenuated with CHEMICAL pre-exposure. The present study suggests that CHEMICAL may not be the major contributing factor for the previously reported synergistic toxic interaction between tobacco and arsenic. CHEMICAL pre-exposure in arsenic-exposed animals revealed interesting toxicokinetics and oxidative stress modulating interactions in the brain and liver of rats, which requires further exploration. | INDIRECT-DOWNREGULATOR |
| Effect of CHEMICAL pretreatment on arsenic-induced oxidative stress in male Wistar rats. Humans are commonly exposed to CHEMICAL, one of the most important lifestyle chemicals. The occurrence of high levels of arsenic in the groundwater of the southeast region of Asia has received much attention in the past decade and has become a global health concern. Predominant occurrence of both these chemicals and ease of their human exposure led us to investigate the effect of CHEMICAL, a major tobacco alkaloid, on arsenic toxicity. Adult male rats were pre-exposed to two different doses of CHEMICAL (0.75 and 3 mg/kg, intraperitoneally) for 7 days followed by 30 days of arsenic exposure (50 ppm sodium arsenite in drinking water). CHEMICAL pre-exposure resulted in an increased brain arsenic accumulation and a decreased liver arsenic concentration. Arsenic also caused a significant oxidative stress in the blood, brain and liver of the exposed rats. Glutathione-S-transferase, a phase II enzyme, was inhibited by both arsenic and CHEMICAL but no such inhibition was noted in arsenic-treated animals pre-exposed to CHEMICAL. Upon CHEMICAL pre-exposure, brain acetylcholinesterase increased, while monoamine oxidase (GENE) decreased. The toxic effects of GENE significantly attenuated with CHEMICAL pre-exposure. The present study suggests that CHEMICAL may not be the major contributing factor for the previously reported synergistic toxic interaction between tobacco and arsenic. CHEMICAL pre-exposure in arsenic-exposed animals revealed interesting toxicokinetics and oxidative stress modulating interactions in the brain and liver of rats, which requires further exploration. | INDIRECT-DOWNREGULATOR |
| Developing Predictive Approaches to Characterize Adaptive Responses of the Reproductive Endocrine Axis to Aromatase Inhibition: II. Computational Modeling. Endocrine-disrupting chemicals can affect reproduction and development in humans and wildlife. We developed a computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose-response and time-course (DRTC) behaviors for endocrine effects of the aromatase inhibitor, fadrozole (FAD). The model describes adaptive responses to endocrine stress involving regulated secretion of a generic gonadotropin (LH/FSH) from the hypothalamic-pituitary complex. For model development, we used plasma 17β-estradiol (E2) concentrations and ovarian cytochrome P450 (CYP) 19A aromatase mRNA data from two time-course experiments, each of which included both an exposure and a depuration phase, and plasma E2 data from a third 4-day study. Model parameters were estimated using E2 concentrations for 0, 0.5, and 3 µg/l CHEMICAL exposure concentrations, and good fits to these data were obtained. The model accurately predicted GENE mRNA fold changes for controls and three CHEMICAL doses (0, 0.5, and 3 µg/l) and plasma E2 dose response from the 4-day study. Comparing the model-predicted DRTC with experimental data provided insight into how the feedback control mechanisms in the HPG axis mediate these changes: specifically, adaptive changes in plasma E2 levels occurring during exposure and "overshoot" occurring postexposure. This study demonstrates the value of mechanistic modeling to examine and predict dynamic behaviors in perturbed systems. As this work progresses, we will obtain a refined understanding of how adaptive responses within the vertebrate HPG axis affect DRTC behaviors for aromatase inhibitors and other types of endocrine-active chemicals and apply that knowledge in support of risk assessments. | GENE-CHEMICAL |
| Developing Predictive Approaches to Characterize Adaptive Responses of the Reproductive Endocrine Axis to GENE Inhibition: II. Computational Modeling. Endocrine-disrupting chemicals can affect reproduction and development in humans and wildlife. We developed a computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose-response and time-course (DRTC) behaviors for endocrine effects of the GENE inhibitor, CHEMICAL (FAD). The model describes adaptive responses to endocrine stress involving regulated secretion of a generic gonadotropin (LH/FSH) from the hypothalamic-pituitary complex. For model development, we used plasma 17β-estradiol (E2) concentrations and ovarian cytochrome P450 (CYP) 19A GENE mRNA data from two time-course experiments, each of which included both an exposure and a depuration phase, and plasma E2 data from a third 4-day study. Model parameters were estimated using E2 concentrations for 0, 0.5, and 3 µg/l FAD exposure concentrations, and good fits to these data were obtained. The model accurately predicted CYP19A mRNA fold changes for controls and three FAD doses (0, 0.5, and 3 µg/l) and plasma E2 dose response from the 4-day study. Comparing the model-predicted DRTC with experimental data provided insight into how the feedback control mechanisms in the HPG axis mediate these changes: specifically, adaptive changes in plasma E2 levels occurring during exposure and "overshoot" occurring postexposure. This study demonstrates the value of mechanistic modeling to examine and predict dynamic behaviors in perturbed systems. As this work progresses, we will obtain a refined understanding of how adaptive responses within the vertebrate HPG axis affect DRTC behaviors for GENE inhibitors and other types of endocrine-active chemicals and apply that knowledge in support of risk assessments. | INHIBITOR |
| Developing Predictive Approaches to Characterize Adaptive Responses of the Reproductive Endocrine Axis to GENE Inhibition: II. Computational Modeling. Endocrine-disrupting chemicals can affect reproduction and development in humans and wildlife. We developed a computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose-response and time-course (DRTC) behaviors for endocrine effects of the GENE inhibitor, fadrozole (CHEMICAL). The model describes adaptive responses to endocrine stress involving regulated secretion of a generic gonadotropin (LH/FSH) from the hypothalamic-pituitary complex. For model development, we used plasma 17β-estradiol (E2) concentrations and ovarian cytochrome P450 (CYP) 19A GENE mRNA data from two time-course experiments, each of which included both an exposure and a depuration phase, and plasma E2 data from a third 4-day study. Model parameters were estimated using E2 concentrations for 0, 0.5, and 3 µg/l CHEMICAL exposure concentrations, and good fits to these data were obtained. The model accurately predicted CYP19A mRNA fold changes for controls and three CHEMICAL doses (0, 0.5, and 3 µg/l) and plasma E2 dose response from the 4-day study. Comparing the model-predicted DRTC with experimental data provided insight into how the feedback control mechanisms in the HPG axis mediate these changes: specifically, adaptive changes in plasma E2 levels occurring during exposure and "overshoot" occurring postexposure. This study demonstrates the value of mechanistic modeling to examine and predict dynamic behaviors in perturbed systems. As this work progresses, we will obtain a refined understanding of how adaptive responses within the vertebrate HPG axis affect DRTC behaviors for GENE inhibitors and other types of endocrine-active chemicals and apply that knowledge in support of risk assessments. | INHIBITOR |
| Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of GENE. The transient receptor potential ankyrin 1 (TRPA1) nonselective cation channel has a conserved function as a noxious chemical sensor throughout much of Metazoa. Electrophilic chemicals activate both insect and vertebrate GENE via covalent modification of CHEMICAL residues in the amino-terminal region. Although naturally occurring electrophilic plant compounds, such as mustard oil and cinnamaldehyde, are GENE agonists, it is unknown whether arthropod-produced electrophiles activate mammalian GENE. We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human GENE channel. We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type GENE or GENE with three serine-substituted cysteines crucial for electrophile activation (C621S, C641S, C665S). We found that pBQN activates GENE starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline. Activation by pBQN required reactivity with CHEMICAL residues, but ones that are distinct from those previously reported to be the key targets of electrophiles. The current reduction we found at higher pBQN concentrations was a cysteine-dependent desensitization of GENE, and did not require prior activation. The cysteines required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium)ethyl methanesulfonate failed to cause desensitization (despite large activation). Interestingly, following pBQN desensitization, wild-type GENE had dramatically reduced response to the nonelectrophile agonist carvacrol, whereas the triple CHEMICAL mutant GENE retained its full response. Our results suggest that modification of multiple CHEMICAL residues by electrophilic compounds can generate both activation and desensitization of the GENE channel. | PART-OF |
| Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of GENE. The transient receptor potential ankyrin 1 (TRPA1) nonselective cation channel has a conserved function as a noxious chemical sensor throughout much of Metazoa. Electrophilic chemicals activate both insect and vertebrate GENE via covalent modification of cysteine residues in the CHEMICAL-terminal region. Although naturally occurring electrophilic plant compounds, such as mustard oil and cinnamaldehyde, are GENE agonists, it is unknown whether arthropod-produced electrophiles activate mammalian GENE. We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human GENE channel. We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type GENE or GENE with three serine-substituted cysteines crucial for electrophile activation (C621S, C641S, C665S). We found that pBQN activates GENE starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline. Activation by pBQN required reactivity with cysteine residues, but ones that are distinct from those previously reported to be the key targets of electrophiles. The current reduction we found at higher pBQN concentrations was a cysteine-dependent desensitization of GENE, and did not require prior activation. The cysteines required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium)ethyl methanesulfonate failed to cause desensitization (despite large activation). Interestingly, following pBQN desensitization, wild-type GENE had dramatically reduced response to the nonelectrophile agonist carvacrol, whereas the triple cysteine mutant GENE retained its full response. Our results suggest that modification of multiple cysteine residues by electrophilic compounds can generate both activation and desensitization of the GENE channel. | PART-OF |
| Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of GENE. The transient receptor potential ankyrin 1 (TRPA1) nonselective cation channel has a conserved function as a noxious chemical sensor throughout much of Metazoa. Electrophilic chemicals activate both insect and vertebrate GENE via covalent modification of cysteine residues in the amino-terminal region. Although naturally occurring electrophilic plant compounds, such as mustard oil and cinnamaldehyde, are GENE agonists, it is unknown whether arthropod-produced electrophiles activate mammalian GENE. We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human GENE channel. We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type GENE or GENE with three CHEMICAL-substituted cysteines crucial for electrophile activation (C621S, C641S, C665S). We found that pBQN activates GENE starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline. Activation by pBQN required reactivity with cysteine residues, but ones that are distinct from those previously reported to be the key targets of electrophiles. The current reduction we found at higher pBQN concentrations was a cysteine-dependent desensitization of GENE, and did not require prior activation. The cysteines required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium)ethyl methanesulfonate failed to cause desensitization (despite large activation). Interestingly, following pBQN desensitization, wild-type GENE had dramatically reduced response to the nonelectrophile agonist carvacrol, whereas the triple cysteine mutant GENE retained its full response. Our results suggest that modification of multiple cysteine residues by electrophilic compounds can generate both activation and desensitization of the GENE channel. | PART-OF |
| Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of TRPA1. The transient receptor potential ankyrin 1 (TRPA1) nonselective cation channel has a conserved function as a noxious chemical sensor throughout much of Metazoa. Electrophilic chemicals activate both insect and vertebrate TRPA1 via covalent modification of cysteine residues in the amino-terminal region. Although naturally occurring electrophilic plant compounds, such as mustard oil and cinnamaldehyde, are TRPA1 agonists, it is unknown whether arthropod-produced electrophiles activate mammalian TRPA1. We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human TRPA1 channel. We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type TRPA1 or TRPA1 with three CHEMICAL-substituted cysteines crucial for electrophile activation (GENE, C641S, C665S). We found that pBQN activates TRPA1 starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline. Activation by pBQN required reactivity with cysteine residues, but ones that are distinct from those previously reported to be the key targets of electrophiles. The current reduction we found at higher pBQN concentrations was a cysteine-dependent desensitization of TRPA1, and did not require prior activation. The cysteines required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium)ethyl methanesulfonate failed to cause desensitization (despite large activation). Interestingly, following pBQN desensitization, wild-type TRPA1 had dramatically reduced response to the nonelectrophile agonist carvacrol, whereas the triple cysteine mutant TRPA1 retained its full response. Our results suggest that modification of multiple cysteine residues by electrophilic compounds can generate both activation and desensitization of the TRPA1 channel. | PART-OF |
| Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of TRPA1. The transient receptor potential ankyrin 1 (TRPA1) nonselective cation channel has a conserved function as a noxious chemical sensor throughout much of Metazoa. Electrophilic chemicals activate both insect and vertebrate TRPA1 via covalent modification of cysteine residues in the amino-terminal region. Although naturally occurring electrophilic plant compounds, such as mustard oil and cinnamaldehyde, are TRPA1 agonists, it is unknown whether arthropod-produced electrophiles activate mammalian TRPA1. We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human TRPA1 channel. We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type TRPA1 or TRPA1 with three CHEMICAL-substituted cysteines crucial for electrophile activation (C621S, GENE, C665S). We found that pBQN activates TRPA1 starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline. Activation by pBQN required reactivity with cysteine residues, but ones that are distinct from those previously reported to be the key targets of electrophiles. The current reduction we found at higher pBQN concentrations was a cysteine-dependent desensitization of TRPA1, and did not require prior activation. The cysteines required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium)ethyl methanesulfonate failed to cause desensitization (despite large activation). Interestingly, following pBQN desensitization, wild-type TRPA1 had dramatically reduced response to the nonelectrophile agonist carvacrol, whereas the triple cysteine mutant TRPA1 retained its full response. Our results suggest that modification of multiple cysteine residues by electrophilic compounds can generate both activation and desensitization of the TRPA1 channel. | PART-OF |
| Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of TRPA1. The transient receptor potential ankyrin 1 (TRPA1) nonselective cation channel has a conserved function as a noxious chemical sensor throughout much of Metazoa. Electrophilic chemicals activate both insect and vertebrate TRPA1 via covalent modification of cysteine residues in the amino-terminal region. Although naturally occurring electrophilic plant compounds, such as mustard oil and cinnamaldehyde, are TRPA1 agonists, it is unknown whether arthropod-produced electrophiles activate mammalian TRPA1. We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human TRPA1 channel. We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type TRPA1 or TRPA1 with three CHEMICAL-substituted cysteines crucial for electrophile activation (C621S, C641S, GENE). We found that pBQN activates TRPA1 starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline. Activation by pBQN required reactivity with cysteine residues, but ones that are distinct from those previously reported to be the key targets of electrophiles. The current reduction we found at higher pBQN concentrations was a cysteine-dependent desensitization of TRPA1, and did not require prior activation. The cysteines required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium)ethyl methanesulfonate failed to cause desensitization (despite large activation). Interestingly, following pBQN desensitization, wild-type TRPA1 had dramatically reduced response to the nonelectrophile agonist carvacrol, whereas the triple cysteine mutant TRPA1 retained its full response. Our results suggest that modification of multiple cysteine residues by electrophilic compounds can generate both activation and desensitization of the TRPA1 channel. | PART-OF |
| Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of GENE. The transient receptor potential ankyrin 1 (TRPA1) nonselective cation channel has a conserved function as a noxious chemical sensor throughout much of Metazoa. Electrophilic chemicals activate both insect and vertebrate GENE via covalent modification of cysteine residues in the amino-terminal region. Although naturally occurring electrophilic plant compounds, such as mustard oil and cinnamaldehyde, are GENE agonists, it is unknown whether arthropod-produced electrophiles activate mammalian GENE. We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human GENE channel. We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type GENE or GENE with three serine-substituted CHEMICAL crucial for electrophile activation (C621S, C641S, C665S). We found that pBQN activates GENE starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline. Activation by pBQN required reactivity with cysteine residues, but ones that are distinct from those previously reported to be the key targets of electrophiles. The current reduction we found at higher pBQN concentrations was a cysteine-dependent desensitization of GENE, and did not require prior activation. The CHEMICAL required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium)ethyl methanesulfonate failed to cause desensitization (despite large activation). Interestingly, following pBQN desensitization, wild-type GENE had dramatically reduced response to the nonelectrophile agonist carvacrol, whereas the triple cysteine mutant GENE retained its full response. Our results suggest that modification of multiple cysteine residues by electrophilic compounds can generate both activation and desensitization of the GENE channel. | REGULATOR |
| Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of TRPA1. The transient receptor potential ankyrin 1 (TRPA1) nonselective cation channel has a conserved function as a noxious chemical sensor throughout much of Metazoa. Electrophilic chemicals activate both insect and vertebrate TRPA1 via covalent modification of cysteine residues in the amino-terminal region. Although naturally occurring electrophilic plant compounds, such as mustard oil and cinnamaldehyde, are TRPA1 agonists, it is unknown whether arthropod-produced electrophiles activate mammalian TRPA1. We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human TRPA1 channel. We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type TRPA1 or TRPA1 with three serine-substituted CHEMICAL crucial for electrophile activation (GENE, C641S, C665S). We found that pBQN activates TRPA1 starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline. Activation by pBQN required reactivity with cysteine residues, but ones that are distinct from those previously reported to be the key targets of electrophiles. The current reduction we found at higher pBQN concentrations was a cysteine-dependent desensitization of TRPA1, and did not require prior activation. The CHEMICAL required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium)ethyl methanesulfonate failed to cause desensitization (despite large activation). Interestingly, following pBQN desensitization, wild-type TRPA1 had dramatically reduced response to the nonelectrophile agonist carvacrol, whereas the triple cysteine mutant TRPA1 retained its full response. Our results suggest that modification of multiple cysteine residues by electrophilic compounds can generate both activation and desensitization of the TRPA1 channel. | REGULATOR |
| Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of TRPA1. The transient receptor potential ankyrin 1 (TRPA1) nonselective cation channel has a conserved function as a noxious chemical sensor throughout much of Metazoa. Electrophilic chemicals activate both insect and vertebrate TRPA1 via covalent modification of cysteine residues in the amino-terminal region. Although naturally occurring electrophilic plant compounds, such as mustard oil and cinnamaldehyde, are TRPA1 agonists, it is unknown whether arthropod-produced electrophiles activate mammalian TRPA1. We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human TRPA1 channel. We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type TRPA1 or TRPA1 with three serine-substituted CHEMICAL crucial for electrophile activation (C621S, GENE, C665S). We found that pBQN activates TRPA1 starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline. Activation by pBQN required reactivity with cysteine residues, but ones that are distinct from those previously reported to be the key targets of electrophiles. The current reduction we found at higher pBQN concentrations was a cysteine-dependent desensitization of TRPA1, and did not require prior activation. The CHEMICAL required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium)ethyl methanesulfonate failed to cause desensitization (despite large activation). Interestingly, following pBQN desensitization, wild-type TRPA1 had dramatically reduced response to the nonelectrophile agonist carvacrol, whereas the triple cysteine mutant TRPA1 retained its full response. Our results suggest that modification of multiple cysteine residues by electrophilic compounds can generate both activation and desensitization of the TRPA1 channel. | REGULATOR |
| Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of TRPA1. The transient receptor potential ankyrin 1 (TRPA1) nonselective cation channel has a conserved function as a noxious chemical sensor throughout much of Metazoa. Electrophilic chemicals activate both insect and vertebrate TRPA1 via covalent modification of cysteine residues in the amino-terminal region. Although naturally occurring electrophilic plant compounds, such as mustard oil and cinnamaldehyde, are TRPA1 agonists, it is unknown whether arthropod-produced electrophiles activate mammalian TRPA1. We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human TRPA1 channel. We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type TRPA1 or TRPA1 with three serine-substituted CHEMICAL crucial for electrophile activation (C621S, C641S, GENE). We found that pBQN activates TRPA1 starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline. Activation by pBQN required reactivity with cysteine residues, but ones that are distinct from those previously reported to be the key targets of electrophiles. The current reduction we found at higher pBQN concentrations was a cysteine-dependent desensitization of TRPA1, and did not require prior activation. The CHEMICAL required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium)ethyl methanesulfonate failed to cause desensitization (despite large activation). Interestingly, following pBQN desensitization, wild-type TRPA1 had dramatically reduced response to the nonelectrophile agonist carvacrol, whereas the triple cysteine mutant TRPA1 retained its full response. Our results suggest that modification of multiple cysteine residues by electrophilic compounds can generate both activation and desensitization of the TRPA1 channel. | REGULATOR |
| Benzoquinone Reveals a CHEMICAL-Dependent Desensitization Mechanism of GENE. The transient receptor potential ankyrin 1 (TRPA1) nonselective cation channel has a conserved function as a noxious chemical sensor throughout much of Metazoa. Electrophilic chemicals activate both insect and vertebrate GENE via covalent modification of cysteine residues in the amino-terminal region. Although naturally occurring electrophilic plant compounds, such as mustard oil and cinnamaldehyde, are GENE agonists, it is unknown whether arthropod-produced electrophiles activate mammalian GENE. We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human GENE channel. We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type GENE or GENE with three serine-substituted cysteines crucial for electrophile activation (C621S, C641S, C665S). We found that pBQN activates GENE starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline. Activation by pBQN required reactivity with cysteine residues, but ones that are distinct from those previously reported to be the key targets of electrophiles. The current reduction we found at higher pBQN concentrations was a cysteine-dependent desensitization of GENE, and did not require prior activation. The cysteines required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium)ethyl methanesulfonate failed to cause desensitization (despite large activation). Interestingly, following pBQN desensitization, wild-type GENE had dramatically reduced response to the nonelectrophile agonist carvacrol, whereas the triple cysteine mutant GENE retained its full response. Our results suggest that modification of multiple cysteine residues by electrophilic compounds can generate both activation and desensitization of the GENE channel. | REGULATOR |
| CHEMICAL Reveals a Cysteine-Dependent Desensitization Mechanism of GENE. The transient receptor potential ankyrin 1 (TRPA1) nonselective cation channel has a conserved function as a noxious chemical sensor throughout much of Metazoa. Electrophilic chemicals activate both insect and vertebrate GENE via covalent modification of cysteine residues in the amino-terminal region. Although naturally occurring electrophilic plant compounds, such as mustard oil and cinnamaldehyde, are GENE agonists, it is unknown whether arthropod-produced electrophiles activate mammalian GENE. We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human GENE channel. We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type GENE or GENE with three serine-substituted cysteines crucial for electrophile activation (C621S, C641S, C665S). We found that pBQN activates GENE starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline. Activation by pBQN required reactivity with cysteine residues, but ones that are distinct from those previously reported to be the key targets of electrophiles. The current reduction we found at higher pBQN concentrations was a cysteine-dependent desensitization of GENE, and did not require prior activation. The cysteines required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium)ethyl methanesulfonate failed to cause desensitization (despite large activation). Interestingly, following pBQN desensitization, wild-type GENE had dramatically reduced response to the nonelectrophile agonist carvacrol, whereas the triple cysteine mutant GENE retained its full response. Our results suggest that modification of multiple cysteine residues by electrophilic compounds can generate both activation and desensitization of the GENE channel. | REGULATOR |
| Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of GENE. The transient receptor potential ankyrin 1 (TRPA1) nonselective cation channel has a conserved function as a noxious chemical sensor throughout much of Metazoa. Electrophilic chemicals activate both insect and vertebrate GENE via covalent modification of cysteine residues in the amino-terminal region. Although naturally occurring electrophilic plant compounds, such as mustard oil and cinnamaldehyde, are GENE agonists, it is unknown whether arthropod-produced electrophiles activate mammalian GENE. We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human GENE channel. We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type GENE or GENE with three serine-substituted cysteines crucial for electrophile activation (C621S, C641S, C665S). We found that CHEMICAL activates GENE starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline. Activation by CHEMICAL required reactivity with cysteine residues, but ones that are distinct from those previously reported to be the key targets of electrophiles. The current reduction we found at higher CHEMICAL concentrations was a cysteine-dependent desensitization of GENE, and did not require prior activation. The cysteines required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium)ethyl methanesulfonate failed to cause desensitization (despite large activation). Interestingly, following CHEMICAL desensitization, wild-type GENE had dramatically reduced response to the nonelectrophile agonist carvacrol, whereas the triple cysteine mutant GENE retained its full response. Our results suggest that modification of multiple cysteine residues by electrophilic compounds can generate both activation and desensitization of the GENE channel. | ACTIVATOR |
| Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of GENE. The transient receptor potential ankyrin 1 (TRPA1) nonselective cation channel has a conserved function as a noxious chemical sensor throughout much of Metazoa. Electrophilic chemicals activate both insect and vertebrate GENE via covalent modification of cysteine residues in the amino-terminal region. Although naturally occurring electrophilic plant compounds, such as mustard oil and cinnamaldehyde, are GENE agonists, it is unknown whether arthropod-produced electrophiles activate mammalian GENE. We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human GENE channel. We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type GENE or GENE with three serine-substituted cysteines crucial for electrophile activation (C621S, C641S, C665S). We found that pBQN activates GENE starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline. Activation by pBQN required reactivity with cysteine residues, but ones that are distinct from those previously reported to be the key targets of electrophiles. The current reduction we found at higher pBQN concentrations was a cysteine-dependent desensitization of GENE, and did not require prior activation. The cysteines required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium)ethyl methanesulfonate failed to cause desensitization (despite large activation). Interestingly, following pBQN desensitization, wild-type GENE had dramatically reduced response to the nonelectrophile agonist CHEMICAL, whereas the triple cysteine mutant GENE retained its full response. Our results suggest that modification of multiple cysteine residues by electrophilic compounds can generate both activation and desensitization of the GENE channel. | ACTIVATOR |
| Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of GENE. The transient receptor potential ankyrin 1 (TRPA1) nonselective cation channel has a conserved function as a noxious chemical sensor throughout much of Metazoa. Electrophilic chemicals activate both insect and vertebrate GENE via covalent modification of cysteine residues in the amino-terminal region. Although naturally occurring electrophilic plant compounds, such as mustard oil and CHEMICAL, are GENE agonists, it is unknown whether arthropod-produced electrophiles activate mammalian GENE. We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human GENE channel. We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type GENE or GENE with three serine-substituted cysteines crucial for electrophile activation (C621S, C641S, C665S). We found that pBQN activates GENE starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline. Activation by pBQN required reactivity with cysteine residues, but ones that are distinct from those previously reported to be the key targets of electrophiles. The current reduction we found at higher pBQN concentrations was a cysteine-dependent desensitization of GENE, and did not require prior activation. The cysteines required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium)ethyl methanesulfonate failed to cause desensitization (despite large activation). Interestingly, following pBQN desensitization, wild-type GENE had dramatically reduced response to the nonelectrophile agonist carvacrol, whereas the triple cysteine mutant GENE retained its full response. Our results suggest that modification of multiple cysteine residues by electrophilic compounds can generate both activation and desensitization of the GENE channel. | ACTIVATOR |
| Synthesis and in-silico studies of some CHEMICAL derivatives as potential GENE inhibitors. The synthesis of several 4-phenyl-5-pyridin-4-yl-2,3-dihydro-3H-1,2,4-triazole-3-thiones possessing N-2 Mannich bases or S-alkyl substituents, is reported. Several of them exhibited a low nanomolar COX enzyme inhibition activity. Most of the compounds showed inhibition of edema was similar to that evoked by celocoxib in animal model. Molecular docking studies of the compounds into the binding sites of COX-1 and COX-2 allowed us to shed light on the binding mode of these novel COX inhibitors. | INHIBITOR |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the CHEMICAL-nitrosylation of GENE, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of GENE, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized GENE. This effect appeared to be due to both competition between S-nitrosocysteine and GENE for the Trx system and direct modulation by S-nitrosocysteine of Trx reductase activity. Our findings that NO/SNO target both Prx and Trx reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | PART-OF |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the S-nitrosylation of GENE, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic CHEMICAL (Cys-52 and Cys-173) and disrupted the oligomeric structure of GENE, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized GENE. This effect appeared to be due to both competition between S-nitrosocysteine and GENE for the Trx system and direct modulation by S-nitrosocysteine of Trx reductase activity. Our findings that NO/SNO target both Prx and Trx reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | PART-OF |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the S-nitrosylation of Prx1, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic CHEMICAL (Cys-52 and Cys-173) and disrupted the oligomeric structure of Prx1, leading to loss of GENE activity. A highly potent inhibition of the GENE catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized Prx1. This effect appeared to be due to both competition between S-nitrosocysteine and Prx1 for the Trx system and direct modulation by S-nitrosocysteine of Trx reductase activity. Our findings that NO/SNO target both Prx and Trx reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | PART-OF |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the S-nitrosylation of GENE, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (CHEMICAL-52 and Cys-173) and disrupted the oligomeric structure of GENE, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized GENE. This effect appeared to be due to both competition between S-nitrosocysteine and GENE for the Trx system and direct modulation by S-nitrosocysteine of Trx reductase activity. Our findings that NO/SNO target both Prx and Trx reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | PART-OF |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the S-nitrosylation of Prx1, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (CHEMICAL-52 and Cys-173) and disrupted the oligomeric structure of Prx1, leading to loss of GENE activity. A highly potent inhibition of the GENE catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized Prx1. This effect appeared to be due to both competition between S-nitrosocysteine and Prx1 for the Trx system and direct modulation by S-nitrosocysteine of Trx reductase activity. Our findings that NO/SNO target both Prx and Trx reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | PART-OF |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the S-nitrosylation of Prx1, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of Prx1, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized Prx1. This effect appeared to be due to both competition between S-nitrosocysteine and Prx1 for the Trx system and direct modulation by S-nitrosocysteine of Trx reductase activity. Our findings that NO/CHEMICAL target both GENE and Trx reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | REGULATOR |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the S-nitrosylation of Prx1, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of Prx1, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized Prx1. This effect appeared to be due to both competition between S-nitrosocysteine and Prx1 for the Trx system and direct modulation by S-nitrosocysteine of GENE activity. Our findings that NO/CHEMICAL target both Prx and GENE may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | REGULATOR |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, CHEMICAL/SNO donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the S-nitrosylation of GENE, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of GENE, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized GENE. This effect appeared to be due to both competition between S-nitrosocysteine and GENE for the Trx system and direct modulation by S-nitrosocysteine of Trx reductase activity. Our findings that NO/SNO target both Prx and Trx reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | REGULATOR |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/CHEMICAL donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the S-nitrosylation of GENE, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of GENE, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized GENE. This effect appeared to be due to both competition between S-nitrosocysteine and GENE for the Trx system and direct modulation by S-nitrosocysteine of Trx reductase activity. Our findings that NO/SNO target both Prx and Trx reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | REGULATOR |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as CHEMICAL and S-nitrosoglutathione readily induced the S-nitrosylation of GENE, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of GENE, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, CHEMICAL (10 μm) effectively blocked the Trx-mediated regeneration of oxidized GENE. This effect appeared to be due to both competition between CHEMICAL and GENE for the Trx system and direct modulation by CHEMICAL of Trx reductase activity. Our findings that NO/SNO target both Prx and Trx reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | GENE-CHEMICAL |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as S-nitrosocysteine and CHEMICAL readily induced the S-nitrosylation of GENE, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of GENE, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized GENE. This effect appeared to be due to both competition between S-nitrosocysteine and GENE for the Trx system and direct modulation by S-nitrosocysteine of Trx reductase activity. Our findings that NO/SNO target both Prx and Trx reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | REGULATOR |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the S-nitrosylation of Prx1, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of Prx1, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by CHEMICAL/SNO was seen in assays employing the coupled GENE-Trx system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized Prx1. This effect appeared to be due to both competition between S-nitrosocysteine and Prx1 for the Trx system and direct modulation by S-nitrosocysteine of Trx reductase activity. Our findings that NO/SNO target both GENE and Trx reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | INHIBITOR |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the S-nitrosylation of Prx1, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of Prx1, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by CHEMICAL/SNO was seen in assays employing the coupled Prx-GENE system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized Prx1. This effect appeared to be due to both competition between S-nitrosocysteine and Prx1 for the GENE system and direct modulation by S-nitrosocysteine of GENE reductase activity. Our findings that NO/SNO target both Prx and GENE reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | INHIBITOR |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the S-nitrosylation of Prx1, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of Prx1, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by NO/CHEMICAL was seen in assays employing the coupled Prx-GENE system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized Prx1. This effect appeared to be due to both competition between S-nitrosocysteine and Prx1 for the GENE system and direct modulation by S-nitrosocysteine of GENE reductase activity. Our findings that NO/SNO target both Prx and GENE reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | INHIBITOR |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as CHEMICAL and S-nitrosoglutathione readily induced the S-nitrosylation of Prx1, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of Prx1, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, CHEMICAL (10 μm) effectively blocked the Trx-mediated regeneration of oxidized Prx1. This effect appeared to be due to both competition between CHEMICAL and Prx1 for the GENE system and direct modulation by CHEMICAL of GENE reductase activity. Our findings that NO/SNO target both Prx and GENE reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | REGULATOR |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as CHEMICAL and S-nitrosoglutathione readily induced the S-nitrosylation of Prx1, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of Prx1, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, CHEMICAL (10 μm) effectively blocked the Trx-mediated regeneration of oxidized Prx1. This effect appeared to be due to both competition between CHEMICAL and Prx1 for the Trx system and direct modulation by CHEMICAL of GENE activity. Our findings that NO/SNO target both Prx and GENE may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | REGULATOR |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the S-nitrosylation of Prx1, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of Prx1, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized Prx1. This effect appeared to be due to both competition between S-nitrosocysteine and Prx1 for the Trx system and direct modulation by S-nitrosocysteine of GENE activity. Our findings that CHEMICAL/SNO target both Prx and GENE may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | REGULATOR |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the S-nitrosylation of Prx1, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of Prx1, leading to loss of GENE activity. A highly potent inhibition of the GENE catalytic reaction by CHEMICAL/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized Prx1. This effect appeared to be due to both competition between S-nitrosocysteine and Prx1 for the Trx system and direct modulation by S-nitrosocysteine of Trx reductase activity. Our findings that NO/SNO target both Prx and Trx reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | INHIBITOR |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the S-nitrosylation of Prx1, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of Prx1, leading to loss of GENE activity. A highly potent inhibition of the GENE catalytic reaction by NO/CHEMICAL was seen in assays employing the coupled Prx-Trx system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized Prx1. This effect appeared to be due to both competition between S-nitrosocysteine and Prx1 for the Trx system and direct modulation by S-nitrosocysteine of Trx reductase activity. Our findings that NO/SNO target both Prx and Trx reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | INHIBITOR |
| Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as CHEMICAL and S-nitrosoglutathione readily induced the S-nitrosylation of Prx1, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of Prx1, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, CHEMICAL (10 μm) effectively blocked the Trx-mediated regeneration of GENE. This effect appeared to be due to both competition between CHEMICAL and Prx1 for the Trx system and direct modulation by CHEMICAL of Trx reductase activity. Our findings that NO/SNO target both Prx and Trx reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. | INDIRECT-DOWNREGULATOR |
| Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. CHEMICAL treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and GENE content. CK significantly inhibited DMN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and GENE content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited DMN-induced increases in matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor-α (TNF-α) mRNA, and GENE type I and α-smooth muscle actin protein. DMN-induced cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. | GENE-CHEMICAL |
| Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. CHEMICAL treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited CHEMICAL-induced increases in serum GENE (ALT) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited DMN-induced increases in matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor-α (TNF-α) mRNA, and collagen type I and α-smooth muscle actin protein. DMN-induced cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. | ACTIVATOR |
| Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. CHEMICAL treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited CHEMICAL-induced increases in serum alanine aminotransferase (GENE) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited DMN-induced increases in matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor-α (TNF-α) mRNA, and collagen type I and α-smooth muscle actin protein. DMN-induced cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. | ACTIVATOR |
| Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. CHEMICAL treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited CHEMICAL-induced increases in serum alanine aminotransferase (ALT) and GENE (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited DMN-induced increases in matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor-α (TNF-α) mRNA, and collagen type I and α-smooth muscle actin protein. DMN-induced cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. | ACTIVATOR |
| Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. CHEMICAL treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited CHEMICAL-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (GENE) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited DMN-induced increases in matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor-α (TNF-α) mRNA, and collagen type I and α-smooth muscle actin protein. DMN-induced cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. | ACTIVATOR |
| Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. CHEMICAL treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited DMN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited DMN-induced increases in matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor-α (TNF-α) mRNA, and collagen type I and α-smooth muscle actin protein. CHEMICAL-induced cyclooxygenase-2 (COX-2) expression and GENE (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. | ACTIVATOR |
| Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. CHEMICAL treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited DMN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited DMN-induced increases in matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor-α (TNF-α) mRNA, and collagen type I and α-smooth muscle actin protein. CHEMICAL-induced cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (GENE) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. | ACTIVATOR |
| Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. CHEMICAL treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited DMN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited CHEMICAL-induced increases in GENE (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor-α (TNF-α) mRNA, and collagen type I and α-smooth muscle actin protein. DMN-induced cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. | INDIRECT-UPREGULATOR |
| Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. CHEMICAL treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited DMN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited CHEMICAL-induced increases in matrix metalloproteinase-13 (GENE), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor-α (TNF-α) mRNA, and collagen type I and α-smooth muscle actin protein. DMN-induced cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. | INDIRECT-UPREGULATOR |
| Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. CHEMICAL treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited DMN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited CHEMICAL-induced increases in matrix metalloproteinase-13 (MMP-13), GENE (TIMP-1), and tumor necrosis factor-α (TNF-α) mRNA, and collagen type I and α-smooth muscle actin protein. DMN-induced cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. | INDIRECT-UPREGULATOR |
| Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. CHEMICAL treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited DMN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited CHEMICAL-induced increases in matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (GENE), and tumor necrosis factor-α (TNF-α) mRNA, and collagen type I and α-smooth muscle actin protein. DMN-induced cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. | INDIRECT-UPREGULATOR |
| Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. CHEMICAL treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited DMN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited CHEMICAL-induced increases in matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and GENE (TNF-α) mRNA, and collagen type I and α-smooth muscle actin protein. DMN-induced cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. | INDIRECT-UPREGULATOR |
| Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. CHEMICAL treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited DMN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited CHEMICAL-induced increases in matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor-α (GENE) mRNA, and collagen type I and α-smooth muscle actin protein. DMN-induced cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. | INDIRECT-UPREGULATOR |
| Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. CHEMICAL treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited DMN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited CHEMICAL-induced increases in matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor-α (TNF-α) mRNA, and GENE and α-smooth muscle actin protein. DMN-induced cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. | INDIRECT-UPREGULATOR |
| Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. CHEMICAL treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited DMN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited CHEMICAL-induced increases in matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor-α (TNF-α) mRNA, and collagen type I and GENE protein. DMN-induced cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. | INDIRECT-UPREGULATOR |
| Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. CHEMICAL treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited DMN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited DMN-induced increases in matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor-α (TNF-α) mRNA, and collagen type I and α-smooth muscle actin protein. CHEMICAL-induced GENE (COX-2) expression and nuclear factor-kappa B (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. | INDIRECT-UPREGULATOR |
| Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. CHEMICAL treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited DMN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited DMN-induced increases in matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor-α (TNF-α) mRNA, and collagen type I and α-smooth muscle actin protein. CHEMICAL-induced cyclooxygenase-2 (GENE) expression and nuclear factor-kappa B (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. | INDIRECT-UPREGULATOR |
| Cadmium telluride quantum dots cause oxidative stress leading to extrinsic and intrinsic apoptosis in hepatocellular carcinoma HepG2 cells. The mechanisms of toxicity related to human hepatocellular carcinoma HepG2 cell exposures to cadmium telluride quantum dots (CdTe-QDs) were investigated. CdTe-QDs caused cytotoxicity in HepG2 cells in a dose- and time-dependent manner. Treated cells showed an increase in reactive oxygen species (ROS). Altered antioxidant levels were demonstrated by depletion of reduced glutathione (GSH), a decreased ratio of reduced glutathione to oxidized glutathione (GSH/GSSG) and an increased NF-E2-related Factor 2 (Nrf2) activation. Enzyme assays showed that superoxide dismutase (SOD) activity was elevated whereas catalase (CAT) and glutathione-S-transferase (GST) activities were depressed. Further analyses revealed that CHEMICAL-QD exposure resulted in apoptosis, indicated by changes in levels of GENE activity, poly ADP-ribose polymerase (PARP) cleavage and phosphatidylserine externalization. Extrinsic apoptotic pathway markers such as Fas levels and caspase-8 activity increased as a result of CdTe-QD exposure. Involvement of the intrinsic/mitochondrial apoptotic pathway was indicated by decreased levels of B-cell lymphoma 2 (Bcl2) protein and mitochondrial cytochrome c, and by increased levels of mitochondrial Bcl-2-associated X protein (Bax) and cytosolic cytochrome c. Further, mitogen-activated protein kinases (MAPKs) such as c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinases (Erk1/2), and p38 were all activated. Our findings reveal that CdTe-QDs cause oxidative stress, interfere with antioxidant defenses and activate protein kinases, leading to apoptosis via both extrinsic and intrinsic pathways. Since the effects of CdTe-QDs on selected biomarkers were similar or greater compared to those of CdCl2 at equivalent concentrations of cadmium, the study suggests that the toxicity of CdTe-QDs arises from a combination of the effects of cadmium and ROS generated from the NPs. | REGULATOR |
| Cadmium telluride quantum dots cause oxidative stress leading to extrinsic and intrinsic apoptosis in hepatocellular carcinoma HepG2 cells. The mechanisms of toxicity related to human hepatocellular carcinoma HepG2 cell exposures to cadmium telluride quantum dots (CdTe-QDs) were investigated. CdTe-QDs caused cytotoxicity in HepG2 cells in a dose- and time-dependent manner. Treated cells showed an increase in reactive oxygen species (ROS). Altered antioxidant levels were demonstrated by depletion of reduced glutathione (GSH), a decreased ratio of reduced glutathione to oxidized glutathione (GSH/GSSG) and an increased NF-E2-related Factor 2 (Nrf2) activation. Enzyme assays showed that superoxide dismutase (SOD) activity was elevated whereas catalase (CAT) and glutathione-S-transferase (GST) activities were depressed. Further analyses revealed that CHEMICAL-QD exposure resulted in apoptosis, indicated by changes in levels of caspase-3 activity, GENE (PARP) cleavage and phosphatidylserine externalization. Extrinsic apoptotic pathway markers such as Fas levels and caspase-8 activity increased as a result of CdTe-QD exposure. Involvement of the intrinsic/mitochondrial apoptotic pathway was indicated by decreased levels of B-cell lymphoma 2 (Bcl2) protein and mitochondrial cytochrome c, and by increased levels of mitochondrial Bcl-2-associated X protein (Bax) and cytosolic cytochrome c. Further, mitogen-activated protein kinases (MAPKs) such as c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinases (Erk1/2), and p38 were all activated. Our findings reveal that CdTe-QDs cause oxidative stress, interfere with antioxidant defenses and activate protein kinases, leading to apoptosis via both extrinsic and intrinsic pathways. Since the effects of CdTe-QDs on selected biomarkers were similar or greater compared to those of CdCl2 at equivalent concentrations of cadmium, the study suggests that the toxicity of CdTe-QDs arises from a combination of the effects of cadmium and ROS generated from the NPs. | GENE-CHEMICAL |
| Cadmium telluride quantum dots cause oxidative stress leading to extrinsic and intrinsic apoptosis in hepatocellular carcinoma HepG2 cells. The mechanisms of toxicity related to human hepatocellular carcinoma HepG2 cell exposures to cadmium telluride quantum dots (CdTe-QDs) were investigated. CdTe-QDs caused cytotoxicity in HepG2 cells in a dose- and time-dependent manner. Treated cells showed an increase in reactive oxygen species (ROS). Altered antioxidant levels were demonstrated by depletion of reduced glutathione (GSH), a decreased ratio of reduced glutathione to oxidized glutathione (GSH/GSSG) and an increased NF-E2-related Factor 2 (Nrf2) activation. Enzyme assays showed that superoxide dismutase (SOD) activity was elevated whereas catalase (CAT) and glutathione-S-transferase (GST) activities were depressed. Further analyses revealed that CHEMICAL-QD exposure resulted in apoptosis, indicated by changes in levels of caspase-3 activity, poly ADP-ribose polymerase (GENE) cleavage and phosphatidylserine externalization. Extrinsic apoptotic pathway markers such as Fas levels and caspase-8 activity increased as a result of CdTe-QD exposure. Involvement of the intrinsic/mitochondrial apoptotic pathway was indicated by decreased levels of B-cell lymphoma 2 (Bcl2) protein and mitochondrial cytochrome c, and by increased levels of mitochondrial Bcl-2-associated X protein (Bax) and cytosolic cytochrome c. Further, mitogen-activated protein kinases (MAPKs) such as c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinases (Erk1/2), and p38 were all activated. Our findings reveal that CdTe-QDs cause oxidative stress, interfere with antioxidant defenses and activate protein kinases, leading to apoptosis via both extrinsic and intrinsic pathways. Since the effects of CdTe-QDs on selected biomarkers were similar or greater compared to those of CdCl2 at equivalent concentrations of cadmium, the study suggests that the toxicity of CdTe-QDs arises from a combination of the effects of cadmium and ROS generated from the NPs. | GENE-CHEMICAL |
| Cadmium telluride quantum dots cause oxidative stress leading to extrinsic and intrinsic apoptosis in hepatocellular carcinoma HepG2 cells. The mechanisms of toxicity related to human hepatocellular carcinoma HepG2 cell exposures to cadmium telluride quantum dots (CdTe-QDs) were investigated. CdTe-QDs caused cytotoxicity in HepG2 cells in a dose- and time-dependent manner. Treated cells showed an increase in reactive oxygen species (ROS). Altered antioxidant levels were demonstrated by depletion of reduced glutathione (GSH), a decreased ratio of reduced glutathione to oxidized glutathione (GSH/GSSG) and an increased NF-E2-related Factor 2 (Nrf2) activation. Enzyme assays showed that superoxide dismutase (SOD) activity was elevated whereas catalase (CAT) and glutathione-S-transferase (GST) activities were depressed. Further analyses revealed that CdTe-QD exposure resulted in apoptosis, indicated by changes in levels of caspase-3 activity, poly ADP-ribose polymerase (PARP) cleavage and phosphatidylserine externalization. Extrinsic apoptotic pathway markers such as Fas levels and GENE activity increased as a result of CHEMICAL-QD exposure. Involvement of the intrinsic/mitochondrial apoptotic pathway was indicated by decreased levels of B-cell lymphoma 2 (Bcl2) protein and mitochondrial cytochrome c, and by increased levels of mitochondrial Bcl-2-associated X protein (Bax) and cytosolic cytochrome c. Further, mitogen-activated protein kinases (MAPKs) such as c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinases (Erk1/2), and p38 were all activated. Our findings reveal that CdTe-QDs cause oxidative stress, interfere with antioxidant defenses and activate protein kinases, leading to apoptosis via both extrinsic and intrinsic pathways. Since the effects of CdTe-QDs on selected biomarkers were similar or greater compared to those of CdCl2 at equivalent concentrations of cadmium, the study suggests that the toxicity of CdTe-QDs arises from a combination of the effects of cadmium and ROS generated from the NPs. | ACTIVATOR |
| Cadmium telluride quantum dots cause oxidative stress leading to extrinsic and intrinsic apoptosis in hepatocellular carcinoma HepG2 cells. The mechanisms of toxicity related to human hepatocellular carcinoma HepG2 cell exposures to cadmium telluride quantum dots (CdTe-QDs) were investigated. CdTe-QDs caused cytotoxicity in HepG2 cells in a dose- and time-dependent manner. Treated cells showed an increase in reactive oxygen species (ROS). Altered antioxidant levels were demonstrated by depletion of reduced glutathione (GSH), a decreased ratio of reduced glutathione to oxidized glutathione (GSH/GSSG) and an increased NF-E2-related Factor 2 (Nrf2) activation. Enzyme assays showed that superoxide dismutase (SOD) activity was elevated whereas catalase (CAT) and glutathione-S-transferase (GST) activities were depressed. Further analyses revealed that CdTe-QD exposure resulted in apoptosis, indicated by changes in levels of caspase-3 activity, poly ADP-ribose polymerase (PARP) cleavage and phosphatidylserine externalization. Extrinsic apoptotic pathway markers such as Fas levels and caspase-8 activity increased as a result of CdTe-QD exposure. Involvement of the intrinsic/mitochondrial apoptotic pathway was indicated by decreased levels of B-cell lymphoma 2 (Bcl2) protein and mitochondrial cytochrome c, and by increased levels of mitochondrial Bcl-2-associated X protein (Bax) and cytosolic cytochrome c. Further, mitogen-activated protein GENE (MAPKs) such as c-Jun N-terminal GENE (JNK), extracellular signal-regulated GENE (Erk1/2), and p38 were all activated. Our findings reveal that CHEMICAL-QDs cause oxidative stress, interfere with antioxidant defenses and activate protein GENE, leading to apoptosis via both extrinsic and intrinsic pathways. Since the effects of CdTe-QDs on selected biomarkers were similar or greater compared to those of CdCl2 at equivalent concentrations of cadmium, the study suggests that the toxicity of CdTe-QDs arises from a combination of the effects of cadmium and ROS generated from the NPs. | ACTIVATOR |
| Cadmium telluride quantum dots cause oxidative stress leading to extrinsic and intrinsic apoptosis in hepatocellular carcinoma HepG2 cells. The mechanisms of toxicity related to human hepatocellular carcinoma HepG2 cell exposures to cadmium telluride quantum dots (CdTe-QDs) were investigated. CdTe-QDs caused cytotoxicity in HepG2 cells in a dose- and time-dependent manner. Treated cells showed an increase in reactive oxygen species (ROS). Altered antioxidant levels were demonstrated by depletion of reduced glutathione (GSH), a decreased ratio of reduced glutathione to oxidized glutathione (GSH/GSSG) and an increased NF-E2-related Factor 2 (Nrf2) activation. Enzyme assays showed that superoxide dismutase (SOD) activity was elevated whereas catalase (CAT) and glutathione-S-transferase (GST) activities were depressed. Further analyses revealed that CdTe-QD exposure resulted in apoptosis, indicated by changes in levels of caspase-3 activity, poly ADP-ribose polymerase (PARP) cleavage and phosphatidylserine externalization. Extrinsic apoptotic pathway markers such as GENE levels and caspase-8 activity increased as a result of CHEMICAL-QD exposure. Involvement of the intrinsic/mitochondrial apoptotic pathway was indicated by decreased levels of B-cell lymphoma 2 (Bcl2) protein and mitochondrial cytochrome c, and by increased levels of mitochondrial Bcl-2-associated X protein (Bax) and cytosolic cytochrome c. Further, mitogen-activated protein kinases (MAPKs) such as c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinases (Erk1/2), and p38 were all activated. Our findings reveal that CdTe-QDs cause oxidative stress, interfere with antioxidant defenses and activate protein kinases, leading to apoptosis via both extrinsic and intrinsic pathways. Since the effects of CdTe-QDs on selected biomarkers were similar or greater compared to those of CdCl2 at equivalent concentrations of cadmium, the study suggests that the toxicity of CdTe-QDs arises from a combination of the effects of cadmium and ROS generated from the NPs. | INDIRECT-UPREGULATOR |
| Anti-apoptotic cardioprotective effects of GENE gene silencing against ischemia-reperfusion injury: Use of deoxycholic acid-modified low molecular weight CHEMICAL as a cardiac siRNA-carrier. The cardiomyocyte apoptosis plays a critical role in the development of myocardial injury after ischemia and reperfusion. Thus, alteration of the major apoptosis-regulatory factors during myocardial ischemia-reperfusion is expected to have favorable cardioprotective effects. Herein, we report ischemic-reperfused myocardial infarction (MI) repair with siRNA against Src homology region 2 domain-containing tyrosine phosphatase-1 (SHP-1), which is known as a key factor involved in regulating the progress of apoptosis in many cell types. A low molecular weight CHEMICAL modified with deoxycholic acid (PEI1.8-DA)-based delivery strategy was suggested for the cardiac application of GENE siRNA to overcome the poor gene delivery efficiency to myocardium due to the highly charged structures of the compact cardiac muscles. The PEI1.8-DA conjugates formed stable nanocomplexes with GENE siRNA via electrostatic and hydrophobic interactions. The PEI1.8-DA/SHP-1 siRNA polyplexes effectively silenced GENE gene expression in cardiomyocytes, leading to a significant inhibition of cardiomyocyte apoptosis under hypoxia. In comparison to conventional gene carriers, relatively large amounts of siRNA molecules remained after treatment with the PEI1.8-DA/SHP-1 siRNA polyplexes. Cardiac administration of the PEI1.8-DA/SHP-1 siRNA polyplexes resulted in substantial improvement in GENE gene silencing, which can be explained by the enhancement of cardiac delivery efficiency of the PEI1.8-DA conjugates. In addition, in vivo treatment with the PEI1.8-DA/SHP-1 siRNA polyplexes induced a highly significant reduction in myocardial apoptosis and infarct size in rat MI models. These results demonstrate that the PEI1.8-DA/SHP-1 siRNA polyplex formulation is a useful system for efficient gene delivery into the compact myocardium that provides a fundamental advantage in treating ischemic-reperfused MI. | REGULATOR |
| Anti-apoptotic cardioprotective effects of GENE gene silencing against ischemia-reperfusion injury: Use of deoxycholic acid-modified low molecular weight polyethyleneimine as a cardiac siRNA-carrier. The cardiomyocyte apoptosis plays a critical role in the development of myocardial injury after ischemia and reperfusion. Thus, alteration of the major apoptosis-regulatory factors during myocardial ischemia-reperfusion is expected to have favorable cardioprotective effects. Herein, we report ischemic-reperfused myocardial infarction (MI) repair with siRNA against Src homology region 2 domain-containing tyrosine phosphatase-1 (SHP-1), which is known as a key factor involved in regulating the progress of apoptosis in many cell types. A low molecular weight polyethyleneimine modified with CHEMICAL (PEI1.8-DA)-based delivery strategy was suggested for the cardiac application of GENE siRNA to overcome the poor gene delivery efficiency to myocardium due to the highly charged structures of the compact cardiac muscles. The PEI1.8-DA conjugates formed stable nanocomplexes with GENE siRNA via electrostatic and hydrophobic interactions. The PEI1.8-DA/SHP-1 siRNA polyplexes effectively silenced GENE gene expression in cardiomyocytes, leading to a significant inhibition of cardiomyocyte apoptosis under hypoxia. In comparison to conventional gene carriers, relatively large amounts of siRNA molecules remained after treatment with the PEI1.8-DA/SHP-1 siRNA polyplexes. Cardiac administration of the PEI1.8-DA/SHP-1 siRNA polyplexes resulted in substantial improvement in GENE gene silencing, which can be explained by the enhancement of cardiac delivery efficiency of the PEI1.8-DA conjugates. In addition, in vivo treatment with the PEI1.8-DA/SHP-1 siRNA polyplexes induced a highly significant reduction in myocardial apoptosis and infarct size in rat MI models. These results demonstrate that the PEI1.8-DA/SHP-1 siRNA polyplex formulation is a useful system for efficient gene delivery into the compact myocardium that provides a fundamental advantage in treating ischemic-reperfused MI. | REGULATOR |
| Neuroprotective Effects of CHEMICAL on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson's Disease Model in Mice. CHEMICAL, an active component of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep is well-known for its anti-oxidative and neuroprotective activities. Although anti-Parkinson's disease activity of CHEMICAL was reported in both of in vivo and in vitro model, detailed mechanisms are not clarified. In this study, we addressed that CHEMICAL attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits, dopaminergic neuronal degeneration and dopamine depletion. CHEMICAL administration enhanced glutathione (GSH) activity, glial cell line-derived neurotrophic factor (GDNF) expression and PI3K/Akt pathway activation, which might ameliorate MPTP injection-induced progressive elevation of reactive oxygen species (ROS) formation in mice. In addition to the effect on ROS, CHEMICAL ameliorated MPTP-reduced lysosome-associated membrane protein type 2A (Lamp 2A) expression. Taken together, our data demonstrate that CHEMICAL attenuates MPTP-induced dopaminergic neuronal degeneration via modulating GENE expression, PI3K/Akt pathway and GSH activation, which subsequently ameliorate MPTP-induced ROS formation and decrease of Lamp 2A expression. Copyright © 2013 John Wiley & Sons, Ltd. | GENE-CHEMICAL |
| Neuroprotective Effects of Puerarin on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson's Disease Model in Mice. Puerarin, an active component of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep is well-known for its anti-oxidative and neuroprotective activities. Although anti-Parkinson's disease activity of puerarin was reported in both of in vivo and in vitro model, detailed mechanisms are not clarified. In this study, we addressed that puerarin attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits, dopaminergic neuronal degeneration and dopamine depletion. Puerarin administration enhanced glutathione (GSH) activity, glial cell line-derived neurotrophic factor (GDNF) expression and PI3K/Akt pathway activation, which might ameliorate CHEMICAL injection-induced progressive elevation of reactive oxygen species (ROS) formation in mice. In addition to the effect on ROS, puerarin ameliorated MPTP-reduced lysosome-associated membrane protein type 2A (Lamp 2A) expression. Taken together, our data demonstrate that puerarin attenuates CHEMICAL-induced dopaminergic neuronal degeneration via modulating GENE expression, PI3K/Akt pathway and GSH activation, which subsequently ameliorate MPTP-induced ROS formation and decrease of Lamp 2A expression. Copyright © 2013 John Wiley & Sons, Ltd. | GENE-CHEMICAL |
| Neuroprotective Effects of CHEMICAL on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson's Disease Model in Mice. CHEMICAL, an active component of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep is well-known for its anti-oxidative and neuroprotective activities. Although anti-Parkinson's disease activity of CHEMICAL was reported in both of in vivo and in vitro model, detailed mechanisms are not clarified. In this study, we addressed that CHEMICAL attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits, dopaminergic neuronal degeneration and dopamine depletion. CHEMICAL administration enhanced glutathione (GSH) activity, glial cell line-derived neurotrophic factor (GDNF) expression and PI3K/Akt pathway activation, which might ameliorate MPTP injection-induced progressive elevation of reactive oxygen species (ROS) formation in mice. In addition to the effect on ROS, CHEMICAL ameliorated MPTP-reduced lysosome-associated membrane protein type 2A (Lamp 2A) expression. Taken together, our data demonstrate that CHEMICAL attenuates MPTP-induced dopaminergic neuronal degeneration via modulating GDNF expression, GENE/Akt pathway and GSH activation, which subsequently ameliorate MPTP-induced ROS formation and decrease of Lamp 2A expression. Copyright © 2013 John Wiley & Sons, Ltd. | REGULATOR |
| Neuroprotective Effects of CHEMICAL on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson's Disease Model in Mice. CHEMICAL, an active component of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep is well-known for its anti-oxidative and neuroprotective activities. Although anti-Parkinson's disease activity of CHEMICAL was reported in both of in vivo and in vitro model, detailed mechanisms are not clarified. In this study, we addressed that CHEMICAL attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits, dopaminergic neuronal degeneration and dopamine depletion. CHEMICAL administration enhanced glutathione (GSH) activity, glial cell line-derived neurotrophic factor (GDNF) expression and PI3K/Akt pathway activation, which might ameliorate MPTP injection-induced progressive elevation of reactive oxygen species (ROS) formation in mice. In addition to the effect on ROS, CHEMICAL ameliorated MPTP-reduced lysosome-associated membrane protein type 2A (Lamp 2A) expression. Taken together, our data demonstrate that CHEMICAL attenuates MPTP-induced dopaminergic neuronal degeneration via modulating GDNF expression, PI3K/GENE pathway and GSH activation, which subsequently ameliorate MPTP-induced ROS formation and decrease of Lamp 2A expression. Copyright © 2013 John Wiley & Sons, Ltd. | REGULATOR |
| Neuroprotective Effects of Puerarin on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson's Disease Model in Mice. Puerarin, an active component of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep is well-known for its anti-oxidative and neuroprotective activities. Although anti-Parkinson's disease activity of puerarin was reported in both of in vivo and in vitro model, detailed mechanisms are not clarified. In this study, we addressed that puerarin attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits, dopaminergic neuronal degeneration and dopamine depletion. Puerarin administration enhanced glutathione (GSH) activity, glial cell line-derived neurotrophic factor (GDNF) expression and PI3K/Akt pathway activation, which might ameliorate CHEMICAL injection-induced progressive elevation of reactive oxygen species (ROS) formation in mice. In addition to the effect on ROS, puerarin ameliorated MPTP-reduced lysosome-associated membrane protein type 2A (Lamp 2A) expression. Taken together, our data demonstrate that puerarin attenuates CHEMICAL-induced dopaminergic neuronal degeneration via modulating GDNF expression, GENE/Akt pathway and GSH activation, which subsequently ameliorate MPTP-induced ROS formation and decrease of Lamp 2A expression. Copyright © 2013 John Wiley & Sons, Ltd. | REGULATOR |
| Neuroprotective Effects of Puerarin on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson's Disease Model in Mice. Puerarin, an active component of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep is well-known for its anti-oxidative and neuroprotective activities. Although anti-Parkinson's disease activity of puerarin was reported in both of in vivo and in vitro model, detailed mechanisms are not clarified. In this study, we addressed that puerarin attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits, dopaminergic neuronal degeneration and dopamine depletion. Puerarin administration enhanced glutathione (GSH) activity, glial cell line-derived neurotrophic factor (GDNF) expression and PI3K/Akt pathway activation, which might ameliorate CHEMICAL injection-induced progressive elevation of reactive oxygen species (ROS) formation in mice. In addition to the effect on ROS, puerarin ameliorated MPTP-reduced lysosome-associated membrane protein type 2A (Lamp 2A) expression. Taken together, our data demonstrate that puerarin attenuates CHEMICAL-induced dopaminergic neuronal degeneration via modulating GDNF expression, PI3K/GENE pathway and GSH activation, which subsequently ameliorate MPTP-induced ROS formation and decrease of Lamp 2A expression. Copyright © 2013 John Wiley & Sons, Ltd. | REGULATOR |
| Neuroprotective Effects of CHEMICAL on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson's Disease Model in Mice. CHEMICAL, an active component of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep is well-known for its anti-oxidative and neuroprotective activities. Although anti-Parkinson's disease activity of puerarin was reported in both of in vivo and in vitro model, detailed mechanisms are not clarified. In this study, we addressed that puerarin attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits, dopaminergic neuronal degeneration and dopamine depletion. CHEMICAL administration enhanced glutathione (GSH) activity, GENE (GDNF) expression and PI3K/Akt pathway activation, which might ameliorate MPTP injection-induced progressive elevation of reactive oxygen species (ROS) formation in mice. In addition to the effect on ROS, puerarin ameliorated MPTP-reduced lysosome-associated membrane protein type 2A (Lamp 2A) expression. Taken together, our data demonstrate that puerarin attenuates MPTP-induced dopaminergic neuronal degeneration via modulating GDNF expression, PI3K/Akt pathway and GSH activation, which subsequently ameliorate MPTP-induced ROS formation and decrease of Lamp 2A expression. Copyright © 2013 John Wiley & Sons, Ltd. | ACTIVATOR |
| Neuroprotective Effects of CHEMICAL on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson's Disease Model in Mice. CHEMICAL, an active component of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep is well-known for its anti-oxidative and neuroprotective activities. Although anti-Parkinson's disease activity of CHEMICAL was reported in both of in vivo and in vitro model, detailed mechanisms are not clarified. In this study, we addressed that CHEMICAL attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits, dopaminergic neuronal degeneration and dopamine depletion. CHEMICAL administration enhanced glutathione (GSH) activity, glial cell line-derived neurotrophic factor (GDNF) expression and PI3K/Akt pathway activation, which might ameliorate MPTP injection-induced progressive elevation of reactive oxygen species (ROS) formation in mice. In addition to the effect on ROS, CHEMICAL ameliorated MPTP-reduced lysosome-associated membrane protein type 2A (GENE) expression. Taken together, our data demonstrate that CHEMICAL attenuates MPTP-induced dopaminergic neuronal degeneration via modulating GDNF expression, PI3K/Akt pathway and GSH activation, which subsequently ameliorate MPTP-induced ROS formation and decrease of GENE expression. Copyright © 2013 John Wiley & Sons, Ltd. | INDIRECT-DOWNREGULATOR |
| Neuroprotective Effects of Puerarin on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson's Disease Model in Mice. Puerarin, an active component of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep is well-known for its anti-oxidative and neuroprotective activities. Although anti-Parkinson's disease activity of puerarin was reported in both of in vivo and in vitro model, detailed mechanisms are not clarified. In this study, we addressed that puerarin attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits, dopaminergic neuronal degeneration and dopamine depletion. Puerarin administration enhanced glutathione (GSH) activity, glial cell line-derived neurotrophic factor (GDNF) expression and PI3K/Akt pathway activation, which might ameliorate CHEMICAL injection-induced progressive elevation of reactive oxygen species (ROS) formation in mice. In addition to the effect on ROS, puerarin ameliorated CHEMICAL-reduced GENE (Lamp 2A) expression. Taken together, our data demonstrate that puerarin attenuates MPTP-induced dopaminergic neuronal degeneration via modulating GDNF expression, PI3K/Akt pathway and GSH activation, which subsequently ameliorate MPTP-induced ROS formation and decrease of Lamp 2A expression. Copyright © 2013 John Wiley & Sons, Ltd. | INDIRECT-DOWNREGULATOR |
| Neuroprotective Effects of Puerarin on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson's Disease Model in Mice. Puerarin, an active component of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep is well-known for its anti-oxidative and neuroprotective activities. Although anti-Parkinson's disease activity of puerarin was reported in both of in vivo and in vitro model, detailed mechanisms are not clarified. In this study, we addressed that puerarin attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits, dopaminergic neuronal degeneration and dopamine depletion. Puerarin administration enhanced glutathione (GSH) activity, glial cell line-derived neurotrophic factor (GDNF) expression and PI3K/Akt pathway activation, which might ameliorate CHEMICAL injection-induced progressive elevation of reactive oxygen species (ROS) formation in mice. In addition to the effect on ROS, puerarin ameliorated CHEMICAL-reduced lysosome-associated membrane protein type 2A (GENE) expression. Taken together, our data demonstrate that puerarin attenuates MPTP-induced dopaminergic neuronal degeneration via modulating GDNF expression, PI3K/Akt pathway and GSH activation, which subsequently ameliorate MPTP-induced ROS formation and decrease of GENE expression. Copyright © 2013 John Wiley & Sons, Ltd. | INDIRECT-DOWNREGULATOR |
| Efficient induction of apoptosis in HeLa cells by a novel cationic porphycene photosensitizer. In the present study we analyze the photobiological properties of 2,7,12-tris(α-pyridinio-p-tolyl)-17-(p-(methoxymethyl)phenyl) porphycene (Py3MeO-TBPo) in Hela cells, in order to assess its potential as a new photosensitizer for photodynamic therapy of cultured tumor cells. Using 0.5 μM CHEMICAL, flow cytometry studies demonstrated an increase of intracellular drug levels related to the incubation time, reaching a maximum at 18 h. LysoTracker(®) Green (LTG) and MitoTracker(®) Green (MTG) probes were used to identify the subcellular localization. Upon exposure to ultraviolet excitation, red porphycene fluorescence was detected as red granules in the cytoplasm that colocalized with LTG. No significant toxic effects were detected for CHEMICAL in the dark at concentrations below 1 μM. In contrast, CHEMICAL combined with red-light irradiation induced concentration- and fluence-dependent HeLa cells inactivation. Besides, all photodynamic protocols assayed induced a clear effect of cell detachment inhibition after trypsin treatment. Both apoptotic and necrotic cell death mechanisms can occur in HeLa cells depending on the experimental protocol. After 18 h incubation with 0.5 μM CHEMICAL and subsequent red light irradiation (3.6 J/cm(2)), a high number of cells die by apoptosis, as evaluated by morphological alterations, immunofluorescent relocalization of GENE from cytosol to mitochondria, and TUNEL assay. Likewise, immunofluorescence techniques showed that cytochrome c is released from mitochondria into cytosol in cells undergoing apoptosis, which occurs immediately after relocation of GENE in mitochondria. The highest amount of apoptosis appeared 24 h after treatment (70%) and this cell death occurred without cell detachment to the substrate. In contrast, with 0.75 μM CHEMICAL and 3.6 J/cm(2) irradiation, morphological changes showed a preferential necrotic cell death. Singlet oxygen was identified as the cytotoxic agent involved in cell photoinactivation. Moreover, cell cultures pre-exposed to the singlet oxygen scavenger sodium azide showed pronounced protection against the loss of viability induced by CHEMICAL and light. Different changes in distribution and organization of cytoskeletal elements (microtubules and actin microfilaments) as well as the protein vinculin, after apoptotic and necrotic photodynamic treatments have been analyzed. Neither of these two cell death mechanisms (apoptosis or necrosis) induced cell detachment. In summary, CHEMICAL appears to meet the requirements for further scrutiny as a very good photosensitizer for photodynamic therapy: it is water soluble, has a high absorption in the red spectral region (where light penetration in tissue is higher), and is able to induce effective high apoptotic rate (70%) related to the more widely studied photosensitizers. | REGULATOR |
| Addition of artificial salt bridge by Ile646Lys mutation in GENE coiled-coil domain regulates 6-helical bundle formation. HIV entry is mediated by the envelope glycoproteins gp120 and GENE. The GENE subunit contains several functional domains: the CHEMICAL-terminal heptad repeat (NHR) domains fold a triple stranded coiled-coil forming a meta-stable prefusion intermediate. C-terminal heptad repeat (CHR) subsequently folds onto the hydrophobic grooves of the NHR coiled-coil to form a stable 6-helix bundle, which juxtaposes the viral and cellular membranes for fusion. The C34 which has 34 amino acid residues is known as the core structure in CHR. A highly anti-HIV peptide inhibitor derived from C34 was designed. An artificial salt bridge was added in the 6-helical bundle by substitution of lysine for Ile646. With a cholesterol modification at C-terminal, the inhibitor containing I646K mutation represented higher anti-viral activity than C34-cholesterol combination without mutation. | PART-OF |
| Cytotoxic mechanism of Piper gaudichaudianum Kunth essential oil and its major compound CHEMICAL. Piper gaudichaudianum Kunth is used in popular medicine as anti-inflamatory and against liver disorders. One of the most studied components of the plant is the essential oil for which chemical analysis revealed (E)-nerolidol as major compound. Recently, we have shown that P. gaudichaudianum essential oil possesses strong cytotoxic effects in mammalian V79 cells. The aim of this study was to analyze the cytotoxicity and mutagenicity of P. gaudichaudianum essential oil and CHEMICAL using Saccharomyces cerevisiae as model study. Treatment of the XV185-14c and N123 strains with essential oil and CHEMICAL led to cytotoxicity but did not induce mutagenicity. Our results revealed an important role of base excision repair (BER) as the GENE, ntg2, apn1 and apn2 mutants showed pronounced sensitivity to essential oil and CHEMICAL. In the absence of superoxide dismutase (in sod1Δ mutant strain) sensitivity to the essential oil and CHEMICAL increased indicating that this oil and CHEMICAL are generating reactive oxygen species (ROS). The ROS production was confirmed by DCF-DA probing assay in Sod-deficient strains. From this, we conclude that the observed cytotoxicity to P. gaudichaudianum essential oil and CHEMICAL is mainly related to ROS and DNA single strand breaks generated by the presence of oxidative lesions. | REGULATOR |
| Cytotoxic mechanism of Piper gaudichaudianum Kunth essential oil and its major compound CHEMICAL. Piper gaudichaudianum Kunth is used in popular medicine as anti-inflamatory and against liver disorders. One of the most studied components of the plant is the essential oil for which chemical analysis revealed (E)-nerolidol as major compound. Recently, we have shown that P. gaudichaudianum essential oil possesses strong cytotoxic effects in mammalian V79 cells. The aim of this study was to analyze the cytotoxicity and mutagenicity of P. gaudichaudianum essential oil and CHEMICAL using Saccharomyces cerevisiae as model study. Treatment of the XV185-14c and N123 strains with essential oil and CHEMICAL led to cytotoxicity but did not induce mutagenicity. Our results revealed an important role of base excision repair (BER) as the ntg1, GENE, apn1 and apn2 mutants showed pronounced sensitivity to essential oil and CHEMICAL. In the absence of superoxide dismutase (in sod1Δ mutant strain) sensitivity to the essential oil and CHEMICAL increased indicating that this oil and CHEMICAL are generating reactive oxygen species (ROS). The ROS production was confirmed by DCF-DA probing assay in Sod-deficient strains. From this, we conclude that the observed cytotoxicity to P. gaudichaudianum essential oil and CHEMICAL is mainly related to ROS and DNA single strand breaks generated by the presence of oxidative lesions. | REGULATOR |
| Cytotoxic mechanism of Piper gaudichaudianum Kunth essential oil and its major compound CHEMICAL. Piper gaudichaudianum Kunth is used in popular medicine as anti-inflamatory and against liver disorders. One of the most studied components of the plant is the essential oil for which chemical analysis revealed (E)-nerolidol as major compound. Recently, we have shown that P. gaudichaudianum essential oil possesses strong cytotoxic effects in mammalian V79 cells. The aim of this study was to analyze the cytotoxicity and mutagenicity of P. gaudichaudianum essential oil and CHEMICAL using Saccharomyces cerevisiae as model study. Treatment of the XV185-14c and N123 strains with essential oil and CHEMICAL led to cytotoxicity but did not induce mutagenicity. Our results revealed an important role of base excision repair (BER) as the ntg1, ntg2, GENE and apn2 mutants showed pronounced sensitivity to essential oil and CHEMICAL. In the absence of superoxide dismutase (in sod1Δ mutant strain) sensitivity to the essential oil and CHEMICAL increased indicating that this oil and CHEMICAL are generating reactive oxygen species (ROS). The ROS production was confirmed by DCF-DA probing assay in Sod-deficient strains. From this, we conclude that the observed cytotoxicity to P. gaudichaudianum essential oil and CHEMICAL is mainly related to ROS and DNA single strand breaks generated by the presence of oxidative lesions. | REGULATOR |
| Cytotoxic mechanism of Piper gaudichaudianum Kunth essential oil and its major compound CHEMICAL. Piper gaudichaudianum Kunth is used in popular medicine as anti-inflamatory and against liver disorders. One of the most studied components of the plant is the essential oil for which chemical analysis revealed (E)-nerolidol as major compound. Recently, we have shown that P. gaudichaudianum essential oil possesses strong cytotoxic effects in mammalian V79 cells. The aim of this study was to analyze the cytotoxicity and mutagenicity of P. gaudichaudianum essential oil and CHEMICAL using Saccharomyces cerevisiae as model study. Treatment of the XV185-14c and N123 strains with essential oil and CHEMICAL led to cytotoxicity but did not induce mutagenicity. Our results revealed an important role of base excision repair (BER) as the ntg1, ntg2, apn1 and GENE mutants showed pronounced sensitivity to essential oil and CHEMICAL. In the absence of superoxide dismutase (in sod1Δ mutant strain) sensitivity to the essential oil and CHEMICAL increased indicating that this oil and CHEMICAL are generating reactive oxygen species (ROS). The ROS production was confirmed by DCF-DA probing assay in Sod-deficient strains. From this, we conclude that the observed cytotoxicity to P. gaudichaudianum essential oil and CHEMICAL is mainly related to ROS and DNA single strand breaks generated by the presence of oxidative lesions. | REGULATOR |
| Metabolism Studies of Unformulated Internally [3H]-labeled siRNAs in Mice. Absorption, distribution, metabolism, and excretion properties of two unformulated model siRNAs were determined using a single internal [(3)H]-radiolabeling procedure, where the full-length oligonucleotides were radiolabeled by Br/(3)H-exchange. Tissue distribution, excretion, and mass balance of radioactivity were investigated in male CD-1 mice, following a single intravenous administration of the [(3)H]-siRNAs, at a target dose level of 5 mg/kg. Quantitative whole-body autoradiography (QWBA) and liquid scintillation counting techniques were used to determine tissue distribution. Radiochromatogram profiles were determined in plasma, tissue extracts and urine. Metabolites were separated by liquid chromatography and identified by radiodetection and high-resolution accurate mass spectrometry. In general, there was little difference in the distribution of total radiolabeled components after administration of the two unformulated [(3)H]-siRNAs. The radioactivity was rapidly and widely distributed throughout the body, and remained detectable in all tissues investigated at later time points (24 and 48 hours for [CHEMICAL]-GENE and [(3)H]-SSB siRNA, respectively). After an initial rapid decline, concentrations of total radiolabeled components in dried blood declined at a much slower rate. A nearly complete mass balance was obtained for the [(3)H]-SSB siRNA and renal excretion was the main route of elimination (38%). The metabolism of the two model siRNAs was rapid and extensive. Five minutes after administration, no parent compound could be detected in plasma. Instead, radiolabeled nucleosides resulting from nuclease hydrolysis were observed. In the metabolism profiles obtained from various tissues only radiolabeled nucleosides were found, suggesting that siRNAs are rapidly metabolized and that the distribution pattern of total radiolabeled components can be ascribed to small molecular weight metabolites. | REGULATOR |
| Metabolism Studies of Unformulated Internally [3H]-labeled siRNAs in Mice. Absorption, distribution, metabolism, and excretion properties of two unformulated model siRNAs were determined using a single internal [(3)H]-radiolabeling procedure, where the full-length oligonucleotides were radiolabeled by Br/(3)H-exchange. Tissue distribution, excretion, and mass balance of radioactivity were investigated in male CD-1 mice, following a single intravenous administration of the [(3)H]-siRNAs, at a target dose level of 5 mg/kg. Quantitative whole-body autoradiography (QWBA) and liquid scintillation counting techniques were used to determine tissue distribution. Radiochromatogram profiles were determined in plasma, tissue extracts and urine. Metabolites were separated by liquid chromatography and identified by radiodetection and high-resolution accurate mass spectrometry. In general, there was little difference in the distribution of total radiolabeled components after administration of the two unformulated [(3)H]-siRNAs. The radioactivity was rapidly and widely distributed throughout the body, and remained detectable in all tissues investigated at later time points (24 and 48 hours for [(3)H]-MRP4 and [(3)H]-SSB siRNA, respectively). After an initial rapid decline, concentrations of total radiolabeled components in dried blood declined at a much slower rate. A nearly complete mass balance was obtained for the [(3)H]-SSB siRNA and renal excretion was the main route of elimination (38%). The metabolism of the two model siRNAs was rapid and extensive. Five minutes after administration, no parent compound could be detected in plasma. Instead, radiolabeled CHEMICAL resulting from GENE hydrolysis were observed. In the metabolism profiles obtained from various tissues only radiolabeled CHEMICAL were found, suggesting that siRNAs are rapidly metabolized and that the distribution pattern of total radiolabeled components can be ascribed to small molecular weight metabolites. | PRODUCT-OF |
| Chemical genetic analyses of quantitative changes in GENE activity during the human cell cycle. Cyclin-dependent kinase 1 (Cdk1) controls cell proliferation and is inhibited by promising anticancer agents, but its mode of action and the consequences of its inhibition are incompletely understood. GENE promotes S- and M-phases during the cell-cycle but also suppresses endoreduplication, which is associated with polyploidy and genome instability. The complexity of GENE regulation has made it difficult to determine whether these different roles require different thresholds of kinase activity and whether the surge of activity as inhibitory phosphates are removed at mitotic onset is essential for cell proliferation. Here, we have used chemical genetics in a human cell line to address these issues. We rescued cells lethally depleted of endogenous GENE with an exogenous GENE conferring sensitivity to one ATP analogue inhibitor (1NMPP1) and resistance to another (RO3306). At no 1NMPP1 concentration was mitosis in rescued clones prevented without also inducing endoreduplication, suggesting that these two key roles for GENE are not simply controlled by different GENE activity thresholds. We also rescued CHEMICAL-resistant clones using exogenous GENE without inhibitory phosphorylation sites, indicating that the mitotic surge of GENE activity is dispensable for cell proliferation. These results suggest that the basic mammalian cycle requires at least some qualitative changes in GENE activity and that quantitative increases in activity need not be rapid. Furthermore, the viability of cells that are unable to undergo rapid GENE activation, and the strong association between endoreduplication and impaired proliferation, may place restrictions on the therapeutic use of a GENE inhibitors. | NO-RELATIONSHIP |
| Chemical genetic analyses of quantitative changes in GENE activity during the human cell cycle. Cyclin-dependent kinase 1 (Cdk1) controls cell proliferation and is inhibited by promising anticancer agents, but its mode of action and the consequences of its inhibition are incompletely understood. GENE promotes S- and M-phases during the cell-cycle but also suppresses endoreduplication, which is associated with polyploidy and genome instability. The complexity of GENE regulation has made it difficult to determine whether these different roles require different thresholds of kinase activity and whether the surge of activity as inhibitory phosphates are removed at mitotic onset is essential for cell proliferation. Here, we have used chemical genetics in a human cell line to address these issues. We rescued cells lethally depleted of endogenous GENE with an exogenous GENE conferring sensitivity to one ATP analogue inhibitor (CHEMICAL) and resistance to another (RO3306). At no CHEMICAL concentration was mitosis in rescued clones prevented without also inducing endoreduplication, suggesting that these two key roles for GENE are not simply controlled by different GENE activity thresholds. We also rescued RO3306-resistant clones using exogenous GENE without inhibitory phosphorylation sites, indicating that the mitotic surge of GENE activity is dispensable for cell proliferation. These results suggest that the basic mammalian cycle requires at least some qualitative changes in GENE activity and that quantitative increases in activity need not be rapid. Furthermore, the viability of cells that are unable to undergo rapid GENE activation, and the strong association between endoreduplication and impaired proliferation, may place restrictions on the therapeutic use of a GENE inhibitors. | INHIBITOR |
| Exploring the effect of N-substitution in nor-lobelane on the interaction with VMAT2: discovery of a potential clinical candidate for treatment of methamphetamine abuse. A series of CHEMICAL-substituted lobelane analogues was synthesized and evaluated for their [(3)H]dihydrotetrabenazine binding affinity at the GENE and for their inhibition of vesicular [(3)H]dopamine uptake. Compound 19a, which contains an N-1,2(R)-dihydroxypropyl group, had been identified as a potential clinical candidate for the treatment of methamphetamine abuse. | DIRECT-REGULATOR |
| Exploring the effect of N-substitution in nor-lobelane on the interaction with VMAT2: discovery of a potential clinical candidate for treatment of methamphetamine abuse. A series of N-substituted CHEMICAL analogues was synthesized and evaluated for their [(3)H]dihydrotetrabenazine binding affinity at the GENE and for their inhibition of vesicular [(3)H]dopamine uptake. Compound 19a, which contains an N-1,2(R)-dihydroxypropyl group, had been identified as a potential clinical candidate for the treatment of methamphetamine abuse. | DIRECT-REGULATOR |
| Exploring the effect of N-substitution in nor-lobelane on the interaction with VMAT2: discovery of a potential clinical candidate for treatment of methamphetamine abuse. A series of N-substituted lobelane analogues was synthesized and evaluated for their CHEMICAL binding affinity at the GENE and for their inhibition of vesicular [(3)H]dopamine uptake. Compound 19a, which contains an N-1,2(R)-dihydroxypropyl group, had been identified as a potential clinical candidate for the treatment of methamphetamine abuse. | DIRECT-REGULATOR |
| Exploring the effect of N-substitution in CHEMICAL on the interaction with GENE: discovery of a potential clinical candidate for treatment of methamphetamine abuse. A series of N-substituted lobelane analogues was synthesized and evaluated for their [(3)H]dihydrotetrabenazine binding affinity at the vesicular monoamine transporter and for their inhibition of vesicular [(3)H]dopamine uptake. Compound 19a, which contains an N-1,2(R)-dihydroxypropyl group, had been identified as a potential clinical candidate for the treatment of methamphetamine abuse. | DIRECT-REGULATOR |
| Exploring the effect of CHEMICAL-substitution in nor-lobelane on the interaction with GENE: discovery of a potential clinical candidate for treatment of methamphetamine abuse. A series of N-substituted lobelane analogues was synthesized and evaluated for their [(3)H]dihydrotetrabenazine binding affinity at the vesicular monoamine transporter and for their inhibition of vesicular [(3)H]dopamine uptake. Compound 19a, which contains an N-1,2(R)-dihydroxypropyl group, had been identified as a potential clinical candidate for the treatment of methamphetamine abuse. | DIRECT-REGULATOR |
| Exploring the effect of N-substitution in nor-lobelane on the interaction with VMAT2: discovery of a potential clinical candidate for treatment of methamphetamine abuse. A series of N-substituted lobelane analogues was synthesized and evaluated for their [(3)H]dihydrotetrabenazine binding affinity at the GENE and for their inhibition of vesicular CHEMICAL uptake. Compound 19a, which contains an N-1,2(R)-dihydroxypropyl group, had been identified as a potential clinical candidate for the treatment of methamphetamine abuse. | SUBSTRATE |
| The pre-clinical absorption, distribution, metabolism and excretion properties of CHEMICAL, an orally bioavailable antagonist of the hedgehog signal transduction pathway. Abstract 1. CHEMICAL is a novel semisynthetic cyclopamine derivative that is a potent and selective Smoothened inhibitor that blocks the hedgehog signal transduction pathway. 2. The in vivo clearance of CHEMICAL is low in mouse and dog and moderate in monkey. The volume of distribution is high across species. Oral bioavailability ranges from moderate in monkey to high in mouse and dog. Predicted human clearance using simple allometry is low (24 L h(-1)), predicted volume of distribution is high (469 L) and predicted half-life is long (20 h). 3. CHEMICAL is highly bound to plasma proteins and has minimal interaction with GENE. 4. In vitro metabolic stability ranges from stable to moderately stable. Twelve oxidative metabolites were detected in mouse, rat, dog, monkey and human liver microsome incubations and none were unique to human. 5. CHEMICAL is not a potent reversible inhibitor of CYP1A2, 2C8, 2C9 or 3A4 (testosterone). CHEMICAL is a moderate inhibitor of CYP2C19, 2D6 and 3A4 (midazolam) with KI values of 19, 16 and 4.5 µM, respectively. CHEMICAL is both a substrate and inhibitor (IC50 = 1.9 µM) of P-glycoprotein. 6. In summary, CHEMICAL has desirable pre-clinical absorption, distribution, metabolism and excretion properties. | NO-RELATIONSHIP |
| The pre-clinical absorption, distribution, metabolism and excretion properties of CHEMICAL, an orally bioavailable antagonist of the hedgehog signal transduction pathway. Abstract 1. CHEMICAL is a novel semisynthetic cyclopamine derivative that is a potent and selective Smoothened inhibitor that blocks the hedgehog signal transduction pathway. 2. The in vivo clearance of CHEMICAL is low in mouse and dog and moderate in monkey. The volume of distribution is high across species. Oral bioavailability ranges from moderate in monkey to high in mouse and dog. Predicted human clearance using simple allometry is low (24 L h(-1)), predicted volume of distribution is high (469 L) and predicted half-life is long (20 h). 3. CHEMICAL is highly bound to plasma proteins and has minimal interaction with human α-1-acid glycoprotein. 4. In vitro metabolic stability ranges from stable to moderately stable. Twelve oxidative metabolites were detected in mouse, rat, dog, monkey and human liver microsome incubations and none were unique to human. 5. CHEMICAL is not a potent reversible inhibitor of CYP1A2, 2C8, 2C9 or 3A4 (testosterone). CHEMICAL is a moderate inhibitor of CYP2C19, 2D6 and 3A4 (midazolam) with KI values of 19, 16 and 4.5 µM, respectively. CHEMICAL is both a substrate and inhibitor (IC50 = 1.9 µM) of GENE. 6. In summary, CHEMICAL has desirable pre-clinical absorption, distribution, metabolism and excretion properties. | INHIBITOR |
| Lorcaserin: a review of its use in chronic weight management. Oral CHEMICAL (BELVIQ(®)), a selective serotonin GENE receptor agonist, is indicated in the US as an adjunct to diet and exercise in the chronic weight management of obese adults, or overweight adults with at least one weight-related comorbidity (e.g. dyslipidaemia, hypertension, type 2 diabetes). This article reviews the pharmacological properties, therapeutic efficacy and tolerability of oral CHEMICAL in this patient population. In three large randomized, double-blind, multicentre studies, oral CHEMICAL was more effective than placebo in the management of obese and overweight adults with or without type 2 diabetes mellitus. Following 12 months' therapy, significantly higher proportions of CHEMICAL than placebo recipients achieved a ≥5 and ≥10 % reduction from baseline in their bodyweight and a significant between-group difference favouring CHEMICAL over placebo was observed for the change from baseline in bodyweight. Moreover, among patients who had achieved a ≥5 % reduction in their bodyweight after 12 months' therapy with CHEMICAL, a significantly higher proportion who received CHEMICAL for a further 12 months than those who switched to placebo maintained ≥5 % weight loss at 24 months. In general, oral CHEMICAL was well tolerated in clinical studies, with hypoglycaemia and headache the most frequently reported adverse events in those with or without type 2 diabetes, respectively. According to a pooled analysis, the risk of US-FDA-defined valvulopathy with CHEMICAL is generally low and not statistically significantly different from placebo. From these and other data, the FDA has concluded that CHEMICAL is unlikely to elevate the risk of valvulopathy. | ACTIVATOR |
| Lorcaserin: a review of its use in chronic weight management. Oral lorcaserin (CHEMICAL(®)), a selective serotonin GENE receptor agonist, is indicated in the US as an adjunct to diet and exercise in the chronic weight management of obese adults, or overweight adults with at least one weight-related comorbidity (e.g. dyslipidaemia, hypertension, type 2 diabetes). This article reviews the pharmacological properties, therapeutic efficacy and tolerability of oral lorcaserin in this patient population. In three large randomized, double-blind, multicentre studies, oral lorcaserin was more effective than placebo in the management of obese and overweight adults with or without type 2 diabetes mellitus. Following 12 months' therapy, significantly higher proportions of lorcaserin than placebo recipients achieved a ≥5 and ≥10 % reduction from baseline in their bodyweight and a significant between-group difference favouring lorcaserin over placebo was observed for the change from baseline in bodyweight. Moreover, among patients who had achieved a ≥5 % reduction in their bodyweight after 12 months' therapy with lorcaserin, a significantly higher proportion who received lorcaserin for a further 12 months than those who switched to placebo maintained ≥5 % weight loss at 24 months. In general, oral lorcaserin was well tolerated in clinical studies, with hypoglycaemia and headache the most frequently reported adverse events in those with or without type 2 diabetes, respectively. According to a pooled analysis, the risk of US-FDA-defined valvulopathy with lorcaserin is generally low and not statistically significantly different from placebo. From these and other data, the FDA has concluded that lorcaserin is unlikely to elevate the risk of valvulopathy. | ACTIVATOR |
| Design, Synthesis, Biological Evaluation, and Docking Studies of (S)-Phenylalanine Derivatives with a 2-Cyanopyrrolidine Moiety as Potent Dipeptidyl Peptidase 4 Inhibitors. A novel series of (S)-phenylalanine derivatives with a 2-cyanopyrrolidine moiety were designed and synthesized through a rational drug design strategy. Biological evaluation revealed that most tested compounds were potent dipeptidyl peptidase 4 (DPP-4) inhibitors, among them, the CHEMICAL derivative 11h displayed the most potent GENE inhibitory activity with an IC50 value of 0.247 μM. In addition, molecular docking analysis of the representative compounds 11h, 11k, and 15a were performed, which not only revealed the impact of binding modes on GENE inhibitory activity, but also provided additional methodological values for design and optimization. © 2013 John Wiley & Sons A/S. | INHIBITOR |
| Design, Synthesis, Biological Evaluation, and Docking Studies of (S)-Phenylalanine Derivatives with a CHEMICAL Moiety as Potent GENE Inhibitors. A novel series of (S)-phenylalanine derivatives with a CHEMICAL moiety were designed and synthesized through a rational drug design strategy. Biological evaluation revealed that most tested compounds were potent dipeptidyl peptidase 4 (DPP-4) inhibitors, among them, the cyclopropyl-substituted phenylalanine derivative 11h displayed the most potent DPP-4 inhibitory activity with an IC50 value of 0.247 μM. In addition, molecular docking analysis of the representative compounds 11h, 11k, and 15a were performed, which not only revealed the impact of binding modes on DPP-4 inhibitory activity, but also provided additional methodological values for design and optimization. © 2013 John Wiley & Sons A/S. | INHIBITOR |
| Design, Synthesis, Biological Evaluation, and Docking Studies of CHEMICAL Derivatives with a 2-Cyanopyrrolidine Moiety as Potent GENE Inhibitors. A novel series of (S)-phenylalanine derivatives with a 2-cyanopyrrolidine moiety were designed and synthesized through a rational drug design strategy. Biological evaluation revealed that most tested compounds were potent dipeptidyl peptidase 4 (DPP-4) inhibitors, among them, the cyclopropyl-substituted phenylalanine derivative 11h displayed the most potent DPP-4 inhibitory activity with an IC50 value of 0.247 μM. In addition, molecular docking analysis of the representative compounds 11h, 11k, and 15a were performed, which not only revealed the impact of binding modes on DPP-4 inhibitory activity, but also provided additional methodological values for design and optimization. © 2013 John Wiley & Sons A/S. | INHIBITOR |
| Bioimaging real-time PXR-dependent mdr1a gene regulation in mdr1a.fLUC reporter mice. The MDR1 gene encodes P-glycoprotein, a transmembrane drug efflux transporter that confers multidrug resistance in cancer cells and affects drug pharmacokinetics by virtue of its expression in the liver, kidney, and colon. Nuclear receptors SXR and GENE are possible master regulators of xenobiotic-inducible MDR1 expression in drug processing organs, but the mechanism of MDR1 regulation has yet to be directly demonstrated in vivo. Moreover, it has previously been impossible to determine the sustained or cumulative effect of repeated doses of xenobiotics on in vivo MDR1 expression. We previously reported a mouse model containing firefly luciferase (fLUC) knocked into the mdr1a genomic locus, allowing non-invasive bioimaging of intestinal mdr1a gene expression in live animals. In the current study, we crossed mdr1a.fLUC mice into the pxr knockout (pxr(-/-)) genetic background and injected mice with pregnenolone-16α-carbonitrile (PCN), a strong PXR ligand, and two therapeutically relevant taxanes, paclitaxel and docetaxel. All three agents induced mdr1a.fLUC expression (bioluminescence), but only PCN and docetaxel appeared to act primarily via PXR. Luminescence returned to baseline by 24-48 hrs after drug injection and was re-inducible over two additional rounds of drug dosing in pxr(+/+) mice. CHEMICAL, a GENE ligand, modestly induced mdr1a.fLUC in pxr(+/+) and pxr(-/-) strains, consistent with CAR's minor role in mdr1a regulation. Collectively, these results demonstrate that the mdr1a.fLUC bioimaging model can capture changes in mdr1 gene expression under conditions of repeated xenobiotic treatment in vivo and that it can be used to probe the mechanism of gene regulation in response to different xenobiotic agents. | DIRECT-REGULATOR |
| Bioimaging real-time PXR-dependent mdr1a gene regulation in mdr1a.fLUC reporter mice. The MDR1 gene encodes P-glycoprotein, a transmembrane drug efflux transporter that confers multidrug resistance in cancer cells and affects drug pharmacokinetics by virtue of its expression in the liver, kidney, and colon. Nuclear receptors SXR and CAR are possible master regulators of xenobiotic-inducible MDR1 expression in drug processing organs, but the mechanism of MDR1 regulation has yet to be directly demonstrated in vivo. Moreover, it has previously been impossible to determine the sustained or cumulative effect of repeated doses of xenobiotics on in vivo MDR1 expression. We previously reported a mouse model containing firefly luciferase (fLUC) knocked into the mdr1a genomic locus, allowing non-invasive bioimaging of intestinal mdr1a gene expression in live animals. In the current study, we crossed mdr1a.fLUC mice into the pxr knockout (pxr(-/-)) genetic background and injected mice with CHEMICAL (PCN), a strong GENE ligand, and two therapeutically relevant taxanes, paclitaxel and docetaxel. All three agents induced mdr1a.fLUC expression (bioluminescence), but only PCN and docetaxel appeared to act primarily via GENE. Luminescence returned to baseline by 24-48 hrs after drug injection and was re-inducible over two additional rounds of drug dosing in pxr(+/+) mice. TCPOBOP, a CAR ligand, modestly induced mdr1a.fLUC in pxr(+/+) and pxr(-/-) strains, consistent with CAR's minor role in mdr1a regulation. Collectively, these results demonstrate that the mdr1a.fLUC bioimaging model can capture changes in mdr1 gene expression under conditions of repeated xenobiotic treatment in vivo and that it can be used to probe the mechanism of gene regulation in response to different xenobiotic agents. | DIRECT-REGULATOR |
| Bioimaging real-time PXR-dependent mdr1a gene regulation in mdr1a.fLUC reporter mice. The MDR1 gene encodes P-glycoprotein, a transmembrane drug efflux transporter that confers multidrug resistance in cancer cells and affects drug pharmacokinetics by virtue of its expression in the liver, kidney, and colon. Nuclear receptors SXR and CAR are possible master regulators of xenobiotic-inducible MDR1 expression in drug processing organs, but the mechanism of MDR1 regulation has yet to be directly demonstrated in vivo. Moreover, it has previously been impossible to determine the sustained or cumulative effect of repeated doses of xenobiotics on in vivo MDR1 expression. We previously reported a mouse model containing firefly luciferase (fLUC) knocked into the mdr1a genomic locus, allowing non-invasive bioimaging of intestinal mdr1a gene expression in live animals. In the current study, we crossed mdr1a.fLUC mice into the pxr knockout (pxr(-/-)) genetic background and injected mice with pregnenolone-16α-carbonitrile (CHEMICAL), a strong GENE ligand, and two therapeutically relevant taxanes, paclitaxel and docetaxel. All three agents induced mdr1a.fLUC expression (bioluminescence), but only CHEMICAL and docetaxel appeared to act primarily via GENE. Luminescence returned to baseline by 24-48 hrs after drug injection and was re-inducible over two additional rounds of drug dosing in pxr(+/+) mice. TCPOBOP, a CAR ligand, modestly induced mdr1a.fLUC in pxr(+/+) and pxr(-/-) strains, consistent with CAR's minor role in mdr1a regulation. Collectively, these results demonstrate that the mdr1a.fLUC bioimaging model can capture changes in mdr1 gene expression under conditions of repeated xenobiotic treatment in vivo and that it can be used to probe the mechanism of gene regulation in response to different xenobiotic agents. | DIRECT-REGULATOR |
| Bioimaging real-time PXR-dependent GENE gene regulation in mdr1a.fLUC reporter mice. The MDR1 gene encodes P-glycoprotein, a transmembrane drug efflux transporter that confers multidrug resistance in cancer cells and affects drug pharmacokinetics by virtue of its expression in the liver, kidney, and colon. Nuclear receptors SXR and CAR are possible master regulators of xenobiotic-inducible MDR1 expression in drug processing organs, but the mechanism of MDR1 regulation has yet to be directly demonstrated in vivo. Moreover, it has previously been impossible to determine the sustained or cumulative effect of repeated doses of xenobiotics on in vivo MDR1 expression. We previously reported a mouse model containing firefly luciferase (fLUC) knocked into the GENE genomic locus, allowing non-invasive bioimaging of intestinal GENE gene expression in live animals. In the current study, we crossed mdr1a.fLUC mice into the pxr knockout (pxr(-/-)) genetic background and injected mice with pregnenolone-16α-carbonitrile (PCN), a strong PXR ligand, and two therapeutically relevant taxanes, paclitaxel and docetaxel. All three agents induced GENE.fLUC expression (bioluminescence), but only CHEMICAL and docetaxel appeared to act primarily via PXR. Luminescence returned to baseline by 24-48 hrs after drug injection and was re-inducible over two additional rounds of drug dosing in pxr(+/+) mice. TCPOBOP, a CAR ligand, modestly induced mdr1a.fLUC in pxr(+/+) and pxr(-/-) strains, consistent with CAR's minor role in GENE regulation. Collectively, these results demonstrate that the mdr1a.fLUC bioimaging model can capture changes in mdr1 gene expression under conditions of repeated xenobiotic treatment in vivo and that it can be used to probe the mechanism of gene regulation in response to different xenobiotic agents. | REGULATOR |
| Bioimaging real-time PXR-dependent GENE gene regulation in mdr1a.fLUC reporter mice. The MDR1 gene encodes P-glycoprotein, a transmembrane drug efflux transporter that confers multidrug resistance in cancer cells and affects drug pharmacokinetics by virtue of its expression in the liver, kidney, and colon. Nuclear receptors SXR and CAR are possible master regulators of xenobiotic-inducible MDR1 expression in drug processing organs, but the mechanism of MDR1 regulation has yet to be directly demonstrated in vivo. Moreover, it has previously been impossible to determine the sustained or cumulative effect of repeated doses of xenobiotics on in vivo MDR1 expression. We previously reported a mouse model containing firefly luciferase (fLUC) knocked into the GENE genomic locus, allowing non-invasive bioimaging of intestinal GENE gene expression in live animals. In the current study, we crossed mdr1a.fLUC mice into the pxr knockout (pxr(-/-)) genetic background and injected mice with pregnenolone-16α-carbonitrile (PCN), a strong PXR ligand, and two therapeutically relevant taxanes, paclitaxel and CHEMICAL. All three agents induced GENE.fLUC expression (bioluminescence), but only PCN and CHEMICAL appeared to act primarily via PXR. Luminescence returned to baseline by 24-48 hrs after drug injection and was re-inducible over two additional rounds of drug dosing in pxr(+/+) mice. TCPOBOP, a CAR ligand, modestly induced mdr1a.fLUC in pxr(+/+) and pxr(-/-) strains, consistent with CAR's minor role in GENE regulation. Collectively, these results demonstrate that the mdr1a.fLUC bioimaging model can capture changes in mdr1 gene expression under conditions of repeated xenobiotic treatment in vivo and that it can be used to probe the mechanism of gene regulation in response to different xenobiotic agents. | INDIRECT-UPREGULATOR |
| Bioimaging real-time PXR-dependent GENE gene regulation in mdr1a.fLUC reporter mice. The MDR1 gene encodes P-glycoprotein, a transmembrane drug efflux transporter that confers multidrug resistance in cancer cells and affects drug pharmacokinetics by virtue of its expression in the liver, kidney, and colon. Nuclear receptors SXR and CAR are possible master regulators of xenobiotic-inducible MDR1 expression in drug processing organs, but the mechanism of MDR1 regulation has yet to be directly demonstrated in vivo. Moreover, it has previously been impossible to determine the sustained or cumulative effect of repeated doses of xenobiotics on in vivo MDR1 expression. We previously reported a mouse model containing firefly luciferase (fLUC) knocked into the GENE genomic locus, allowing non-invasive bioimaging of intestinal GENE gene expression in live animals. In the current study, we crossed mdr1a.fLUC mice into the pxr knockout (pxr(-/-)) genetic background and injected mice with pregnenolone-16α-carbonitrile (PCN), a strong PXR ligand, and two therapeutically relevant taxanes, paclitaxel and docetaxel. All three agents induced mdr1a.fLUC expression (bioluminescence), but only PCN and docetaxel appeared to act primarily via PXR. Luminescence returned to baseline by 24-48 hrs after drug injection and was re-inducible over two additional rounds of drug dosing in pxr(+/+) mice. CHEMICAL, a CAR ligand, modestly induced mdr1a.fLUC in pxr(+/+) and pxr(-/-) strains, consistent with CAR's minor role in GENE regulation. Collectively, these results demonstrate that the mdr1a.fLUC bioimaging model can capture changes in mdr1 gene expression under conditions of repeated xenobiotic treatment in vivo and that it can be used to probe the mechanism of gene regulation in response to different xenobiotic agents. | GENE-CHEMICAL |
| Bioimaging real-time PXR-dependent mdr1a gene regulation in mdr1a.fLUC reporter mice. The MDR1 gene encodes P-glycoprotein, a transmembrane drug efflux transporter that confers multidrug resistance in cancer cells and affects drug pharmacokinetics by virtue of its expression in the liver, kidney, and colon. Nuclear receptors SXR and CAR are possible master regulators of xenobiotic-inducible MDR1 expression in drug processing organs, but the mechanism of MDR1 regulation has yet to be directly demonstrated in vivo. Moreover, it has previously been impossible to determine the sustained or cumulative effect of repeated doses of xenobiotics on in vivo MDR1 expression. We previously reported a mouse model containing firefly luciferase (fLUC) knocked into the mdr1a genomic locus, allowing non-invasive bioimaging of intestinal mdr1a gene expression in live animals. In the current study, we crossed mdr1a.fLUC mice into the pxr knockout (pxr(-/-)) genetic background and injected mice with pregnenolone-16α-carbonitrile (PCN), a strong GENE ligand, and two therapeutically relevant taxanes, paclitaxel and CHEMICAL. All three agents induced mdr1a.fLUC expression (bioluminescence), but only PCN and CHEMICAL appeared to act primarily via GENE. Luminescence returned to baseline by 24-48 hrs after drug injection and was re-inducible over two additional rounds of drug dosing in pxr(+/+) mice. TCPOBOP, a CAR ligand, modestly induced mdr1a.fLUC in pxr(+/+) and pxr(-/-) strains, consistent with CAR's minor role in mdr1a regulation. Collectively, these results demonstrate that the mdr1a.fLUC bioimaging model can capture changes in mdr1 gene expression under conditions of repeated xenobiotic treatment in vivo and that it can be used to probe the mechanism of gene regulation in response to different xenobiotic agents. | REGULATOR |
| CHEMICAL attenuates mast cell-mediated allergic inflammation. A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. In this study, we investigated anti-allergic inflammatory effect of CHEMICAL and underlying mechanisms of action using in vitro and in vivo models. CHEMICAL inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1). CHEMICAL decreased expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-8. The inhibitory effect of CHEMICAL on theses pro-inflammatory cytokines was related with GENE N-terminal kinases, and p38 mitogen-activated protein kinase, nuclear factor-κB, and caspase-1. Furthermore, CHEMICAL attenuated IgE-mediated passive cutaneous anaphylaxis and the expression of histamine receptor 1 at the inflamed tissue. The inhibitory effects of CHEMICAL were more potent than cromolyn, a known anti-allergic drug. Our results showed that CHEMICAL down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory cytokines. In light of in vitro and in vivo anti-allergic inflammatory effects, CHEMICAL could be a beneficial anti-allergic inflammatory agent. | INHIBITOR |
| CHEMICAL attenuates mast cell-mediated allergic inflammation. A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. In this study, we investigated anti-allergic inflammatory effect of CHEMICAL and underlying mechanisms of action using in vitro and in vivo models. CHEMICAL inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1). CHEMICAL decreased expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-8. The inhibitory effect of CHEMICAL on theses pro-inflammatory cytokines was related with c-Jun GENE, and p38 mitogen-activated protein kinase, nuclear factor-κB, and caspase-1. Furthermore, CHEMICAL attenuated IgE-mediated passive cutaneous anaphylaxis and the expression of histamine receptor 1 at the inflamed tissue. The inhibitory effects of CHEMICAL were more potent than cromolyn, a known anti-allergic drug. Our results showed that CHEMICAL down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory cytokines. In light of in vitro and in vivo anti-allergic inflammatory effects, CHEMICAL could be a beneficial anti-allergic inflammatory agent. | GENE-CHEMICAL |
| CHEMICAL attenuates mast cell-mediated allergic inflammation. A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. In this study, we investigated anti-allergic inflammatory effect of CHEMICAL and underlying mechanisms of action using in vitro and in vivo models. CHEMICAL inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1). CHEMICAL decreased expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-8. The inhibitory effect of CHEMICAL on theses pro-inflammatory cytokines was related with c-Jun N-terminal kinases, and GENE mitogen-activated protein kinase, nuclear factor-κB, and caspase-1. Furthermore, CHEMICAL attenuated IgE-mediated passive cutaneous anaphylaxis and the expression of histamine receptor 1 at the inflamed tissue. The inhibitory effects of CHEMICAL were more potent than cromolyn, a known anti-allergic drug. Our results showed that CHEMICAL down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory cytokines. In light of in vitro and in vivo anti-allergic inflammatory effects, CHEMICAL could be a beneficial anti-allergic inflammatory agent. | INHIBITOR |
| CHEMICAL attenuates mast cell-mediated allergic inflammation. A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. In this study, we investigated anti-allergic inflammatory effect of CHEMICAL and underlying mechanisms of action using in vitro and in vivo models. CHEMICAL inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1). CHEMICAL decreased expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-8. The inhibitory effect of CHEMICAL on theses pro-inflammatory cytokines was related with c-Jun N-terminal kinases, and p38 GENE, nuclear factor-κB, and caspase-1. Furthermore, CHEMICAL attenuated IgE-mediated passive cutaneous anaphylaxis and the expression of histamine receptor 1 at the inflamed tissue. The inhibitory effects of CHEMICAL were more potent than cromolyn, a known anti-allergic drug. Our results showed that CHEMICAL down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory cytokines. In light of in vitro and in vivo anti-allergic inflammatory effects, CHEMICAL could be a beneficial anti-allergic inflammatory agent. | INHIBITOR |
| CHEMICAL attenuates mast cell-mediated allergic inflammation. A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. In this study, we investigated anti-allergic inflammatory effect of CHEMICAL and underlying mechanisms of action using in vitro and in vivo models. CHEMICAL inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1). CHEMICAL decreased expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-8. The inhibitory effect of CHEMICAL on theses pro-inflammatory cytokines was related with c-Jun N-terminal kinases, and p38 mitogen-activated protein kinase, GENE, and caspase-1. Furthermore, CHEMICAL attenuated IgE-mediated passive cutaneous anaphylaxis and the expression of histamine receptor 1 at the inflamed tissue. The inhibitory effects of CHEMICAL were more potent than cromolyn, a known anti-allergic drug. Our results showed that CHEMICAL down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory cytokines. In light of in vitro and in vivo anti-allergic inflammatory effects, CHEMICAL could be a beneficial anti-allergic inflammatory agent. | INHIBITOR |
| CHEMICAL attenuates mast cell-mediated allergic inflammation. A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. In this study, we investigated anti-allergic inflammatory effect of CHEMICAL and underlying mechanisms of action using in vitro and in vivo models. CHEMICAL inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1). CHEMICAL decreased expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-8. The inhibitory effect of CHEMICAL on theses pro-inflammatory cytokines was related with c-Jun N-terminal kinases, and p38 mitogen-activated protein kinase, nuclear factor-κB, and GENE. Furthermore, CHEMICAL attenuated IgE-mediated passive cutaneous anaphylaxis and the expression of histamine receptor 1 at the inflamed tissue. The inhibitory effects of CHEMICAL were more potent than cromolyn, a known anti-allergic drug. Our results showed that CHEMICAL down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory cytokines. In light of in vitro and in vivo anti-allergic inflammatory effects, CHEMICAL could be a beneficial anti-allergic inflammatory agent. | INHIBITOR |
| CHEMICAL attenuates mast cell-mediated allergic inflammation. A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. In this study, we investigated anti-allergic inflammatory effect of CHEMICAL and underlying mechanisms of action using in vitro and in vivo models. CHEMICAL inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1). CHEMICAL decreased expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-8. The inhibitory effect of CHEMICAL on theses pro-inflammatory cytokines was related with c-Jun N-terminal kinases, and p38 mitogen-activated protein kinase, nuclear factor-κB, and caspase-1. Furthermore, CHEMICAL attenuated GENE-mediated passive cutaneous anaphylaxis and the expression of histamine receptor 1 at the inflamed tissue. The inhibitory effects of CHEMICAL were more potent than cromolyn, a known anti-allergic drug. Our results showed that CHEMICAL down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory cytokines. In light of in vitro and in vivo anti-allergic inflammatory effects, CHEMICAL could be a beneficial anti-allergic inflammatory agent. | INHIBITOR |
| CHEMICAL attenuates mast cell-mediated allergic inflammation. A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. In this study, we investigated anti-allergic inflammatory effect of galangin and underlying mechanisms of action using in vitro and in vivo models. CHEMICAL inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1). CHEMICAL decreased expression of pro-inflammatory GENE, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-8. The inhibitory effect of galangin on theses pro-inflammatory GENE was related with c-Jun N-terminal kinases, and p38 mitogen-activated protein kinase, nuclear factor-κB, and caspase-1. Furthermore, galangin attenuated IgE-mediated passive cutaneous anaphylaxis and the expression of histamine receptor 1 at the inflamed tissue. The inhibitory effects of galangin were more potent than cromolyn, a known anti-allergic drug. Our results showed that galangin down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory GENE. In light of in vitro and in vivo anti-allergic inflammatory effects, galangin could be a beneficial anti-allergic inflammatory agent. | INDIRECT-DOWNREGULATOR |
| CHEMICAL attenuates mast cell-mediated allergic inflammation. A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. In this study, we investigated anti-allergic inflammatory effect of galangin and underlying mechanisms of action using in vitro and in vivo models. CHEMICAL inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1). CHEMICAL decreased expression of pro-inflammatory cytokines, such as GENE, interleukin (IL)-6, IL-1β, and IL-8. The inhibitory effect of galangin on theses pro-inflammatory cytokines was related with c-Jun N-terminal kinases, and p38 mitogen-activated protein kinase, nuclear factor-κB, and caspase-1. Furthermore, galangin attenuated IgE-mediated passive cutaneous anaphylaxis and the expression of histamine receptor 1 at the inflamed tissue. The inhibitory effects of galangin were more potent than cromolyn, a known anti-allergic drug. Our results showed that galangin down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory cytokines. In light of in vitro and in vivo anti-allergic inflammatory effects, galangin could be a beneficial anti-allergic inflammatory agent. | INDIRECT-DOWNREGULATOR |
| CHEMICAL attenuates mast cell-mediated allergic inflammation. A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. In this study, we investigated anti-allergic inflammatory effect of galangin and underlying mechanisms of action using in vitro and in vivo models. CHEMICAL inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1). CHEMICAL decreased expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, GENE (IL)-6, IL-1β, and IL-8. The inhibitory effect of galangin on theses pro-inflammatory cytokines was related with c-Jun N-terminal kinases, and p38 mitogen-activated protein kinase, nuclear factor-κB, and caspase-1. Furthermore, galangin attenuated IgE-mediated passive cutaneous anaphylaxis and the expression of histamine receptor 1 at the inflamed tissue. The inhibitory effects of galangin were more potent than cromolyn, a known anti-allergic drug. Our results showed that galangin down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory cytokines. In light of in vitro and in vivo anti-allergic inflammatory effects, galangin could be a beneficial anti-allergic inflammatory agent. | INDIRECT-DOWNREGULATOR |
| CHEMICAL attenuates mast cell-mediated allergic inflammation. A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. In this study, we investigated anti-allergic inflammatory effect of galangin and underlying mechanisms of action using in vitro and in vivo models. CHEMICAL inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1). CHEMICAL decreased expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin GENE, IL-1β, and IL-8. The inhibitory effect of galangin on theses pro-inflammatory cytokines was related with c-Jun N-terminal kinases, and p38 mitogen-activated protein kinase, nuclear factor-κB, and caspase-1. Furthermore, galangin attenuated IgE-mediated passive cutaneous anaphylaxis and the expression of histamine receptor 1 at the inflamed tissue. The inhibitory effects of galangin were more potent than cromolyn, a known anti-allergic drug. Our results showed that galangin down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory cytokines. In light of in vitro and in vivo anti-allergic inflammatory effects, galangin could be a beneficial anti-allergic inflammatory agent. | INDIRECT-DOWNREGULATOR |
| CHEMICAL attenuates mast cell-mediated allergic inflammation. A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. In this study, we investigated anti-allergic inflammatory effect of galangin and underlying mechanisms of action using in vitro and in vivo models. CHEMICAL inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1). CHEMICAL decreased expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, GENE, and IL-8. The inhibitory effect of galangin on theses pro-inflammatory cytokines was related with c-Jun N-terminal kinases, and p38 mitogen-activated protein kinase, nuclear factor-κB, and caspase-1. Furthermore, galangin attenuated IgE-mediated passive cutaneous anaphylaxis and the expression of histamine receptor 1 at the inflamed tissue. The inhibitory effects of galangin were more potent than cromolyn, a known anti-allergic drug. Our results showed that galangin down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory cytokines. In light of in vitro and in vivo anti-allergic inflammatory effects, galangin could be a beneficial anti-allergic inflammatory agent. | INDIRECT-DOWNREGULATOR |
| CHEMICAL attenuates mast cell-mediated allergic inflammation. A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. In this study, we investigated anti-allergic inflammatory effect of galangin and underlying mechanisms of action using in vitro and in vivo models. CHEMICAL inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1). CHEMICAL decreased expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and GENE. The inhibitory effect of galangin on theses pro-inflammatory cytokines was related with c-Jun N-terminal kinases, and p38 mitogen-activated protein kinase, nuclear factor-κB, and caspase-1. Furthermore, galangin attenuated IgE-mediated passive cutaneous anaphylaxis and the expression of histamine receptor 1 at the inflamed tissue. The inhibitory effects of galangin were more potent than cromolyn, a known anti-allergic drug. Our results showed that galangin down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory cytokines. In light of in vitro and in vivo anti-allergic inflammatory effects, galangin could be a beneficial anti-allergic inflammatory agent. | INDIRECT-DOWNREGULATOR |
| CHEMICAL attenuates mast cell-mediated allergic inflammation. A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. In this study, we investigated anti-allergic inflammatory effect of CHEMICAL and underlying mechanisms of action using in vitro and in vivo models. CHEMICAL inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1). CHEMICAL decreased expression of pro-inflammatory GENE, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-8. The inhibitory effect of CHEMICAL on theses pro-inflammatory GENE was related with c-Jun N-terminal kinases, and p38 mitogen-activated protein kinase, nuclear factor-κB, and caspase-1. Furthermore, CHEMICAL attenuated IgE-mediated passive cutaneous anaphylaxis and the expression of histamine receptor 1 at the inflamed tissue. The inhibitory effects of CHEMICAL were more potent than cromolyn, a known anti-allergic drug. Our results showed that CHEMICAL down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory GENE. In light of in vitro and in vivo anti-allergic inflammatory effects, CHEMICAL could be a beneficial anti-allergic inflammatory agent. | INDIRECT-DOWNREGULATOR |
| CHEMICAL attenuates mast cell-mediated allergic inflammation. A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. In this study, we investigated anti-allergic inflammatory effect of CHEMICAL and underlying mechanisms of action using in vitro and in vivo models. CHEMICAL inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1). CHEMICAL decreased expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-8. The inhibitory effect of CHEMICAL on theses pro-inflammatory cytokines was related with c-Jun N-terminal kinases, and p38 mitogen-activated protein kinase, nuclear factor-κB, and caspase-1. Furthermore, CHEMICAL attenuated IgE-mediated passive cutaneous anaphylaxis and the expression of GENE at the inflamed tissue. The inhibitory effects of CHEMICAL were more potent than cromolyn, a known anti-allergic drug. Our results showed that CHEMICAL down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory cytokines. In light of in vitro and in vivo anti-allergic inflammatory effects, CHEMICAL could be a beneficial anti-allergic inflammatory agent. | INDIRECT-DOWNREGULATOR |
| Aberrant activation of M phase proteins by cell proliferation-evoking carcinogens after 28-day administration in rats. We have previously reported that hepatocarcinogens increase liver cells expressing p21(Cip1), a G1 checkpoint protein and M phase proteins after 28-day treatment in rats. This study aimed to identify early prediction markers of carcinogens available in many target organs after 28-day treatment in rats. Immunohistochemical analysis was performed on Ki-67, p21(Cip1) and M phase proteins [nuclear Cdc2, phospho-Histone H3 (p-Histone H3), Aurora B and heterochromatin protein 1α (HP1α)] with carcinogens targeting different organs. Carcinogens targeting thyroid (sulfadimethoxine; SDM), urinary bladder (phenylethyl isothiocyanate), forestomach (butylated hydroxyanisole; BHA), glandular stomach (catechol; CC), and colon (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and chenodeoxycholic acid) were examined using a non-carcinogenic toxicant (caprolactam) and carcinogens targeting other organs as negative controls. All carcinogens increased Ki-67(+), nuclear Cdc2(+), p-Histone H3(+) or Aurora B(+) carcinogenic target cells, except for both colon carcinogens, which did not increase cell proliferation. On the other hand, p21(Cip1+) cells increased with SDM and CC. GENE responded only to CHEMICAL. Results revealed carcinogens evoking cell proliferation concurrently induced cell cycle arrest at M phase or showing chromosomal instability reflecting aberration in cell cycle regulation, irrespective of target organs, after 28-day treatment. Therefore, M phase proteins may be early prediction markers of carcinogens evoking cell proliferation in many target organs. | ACTIVATOR |
| CHEMICAL attenuates metastasis via both ERK and PI3K/Akt pathways in HGF-treated liver cancer HepG2 cells. Hepatocyte growth factor (HGF), and its receptor, c-Met activation has recently been shown to play important roles in cancer invasion and metastasis in a wide variety of tumor cells. We use HGF as an invasive inducer of human HepG2 cells to investigate the effect of four flavones including apigenin, tricetin, tangeretin, and CHEMICAL on HGF/c-Met-mediated tumor invasion and metastasis. Among them, CHEMICAL markedly inhibited HGF-induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and transwell-chamber invasion/migration assay under non-cytotoxic concentrations. Data also showed CHEMICAL inhibited HGF-induced cell scattering and cytoskeleton changed such as filopodia and lamellipodia. Furthermore, CHEMICAL could inhibit HGF-induced the membrane localization of phosphorylated c-Met, ERK2, and Akt, but not phosphorylated JNK1/2 and GENE. Next, CHEMICAL significantly decreased the levels of phospho-ERK2 and phospho-Akt in ERK2 or Akt siRNA-transfected cells concomitantly with a marked reduction on cell invasion and migration. In conclusion, CHEMICAL attenuates HGF-induced HepG2 cells metastasis involving both ERK and PI3K/Akt pathways and are potentially useful as anti-metastatic agents for the treatment of hepatoma. | NO-RELATIONSHIP |
| CHEMICAL attenuates metastasis via both ERK and PI3K/Akt pathways in HGF-treated liver cancer HepG2 cells. Hepatocyte growth factor (HGF), and its receptor, c-Met activation has recently been shown to play important roles in cancer invasion and metastasis in a wide variety of tumor cells. We use HGF as an invasive inducer of human HepG2 cells to investigate the effect of four flavones including apigenin, tricetin, tangeretin, and CHEMICAL on HGF/c-Met-mediated tumor invasion and metastasis. Among them, CHEMICAL markedly inhibited HGF-induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and transwell-chamber invasion/migration assay under non-cytotoxic concentrations. Data also showed CHEMICAL inhibited HGF-induced cell scattering and cytoskeleton changed such as filopodia and lamellipodia. Furthermore, CHEMICAL could inhibit HGF-induced the membrane localization of phosphorylated c-Met, ERK2, and Akt, but not phosphorylated JNK1/2 and p38. Next, CHEMICAL significantly decreased the levels of GENE and phospho-Akt in ERK2 or Akt siRNA-transfected cells concomitantly with a marked reduction on cell invasion and migration. In conclusion, CHEMICAL attenuates HGF-induced HepG2 cells metastasis involving both ERK and PI3K/Akt pathways and are potentially useful as anti-metastatic agents for the treatment of hepatoma. | INDIRECT-DOWNREGULATOR |
| CHEMICAL attenuates metastasis via both ERK and PI3K/Akt pathways in HGF-treated liver cancer HepG2 cells. Hepatocyte growth factor (HGF), and its receptor, c-Met activation has recently been shown to play important roles in cancer invasion and metastasis in a wide variety of tumor cells. We use HGF as an invasive inducer of human HepG2 cells to investigate the effect of four flavones including apigenin, tricetin, tangeretin, and CHEMICAL on HGF/c-Met-mediated tumor invasion and metastasis. Among them, CHEMICAL markedly inhibited HGF-induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and transwell-chamber invasion/migration assay under non-cytotoxic concentrations. Data also showed CHEMICAL inhibited HGF-induced cell scattering and cytoskeleton changed such as filopodia and lamellipodia. Furthermore, CHEMICAL could inhibit HGF-induced the membrane localization of phosphorylated c-Met, ERK2, and Akt, but not phosphorylated JNK1/2 and p38. Next, CHEMICAL significantly decreased the levels of phospho-ERK2 and GENE in ERK2 or Akt siRNA-transfected cells concomitantly with a marked reduction on cell invasion and migration. In conclusion, CHEMICAL attenuates HGF-induced HepG2 cells metastasis involving both ERK and PI3K/Akt pathways and are potentially useful as anti-metastatic agents for the treatment of hepatoma. | INDIRECT-DOWNREGULATOR |
| CHEMICAL attenuates metastasis via both ERK and PI3K/Akt pathways in HGF-treated liver cancer HepG2 cells. Hepatocyte growth factor (HGF), and its receptor, c-Met activation has recently been shown to play important roles in cancer invasion and metastasis in a wide variety of tumor cells. We use HGF as an invasive inducer of human HepG2 cells to investigate the effect of four flavones including apigenin, tricetin, tangeretin, and CHEMICAL on HGF/c-Met-mediated tumor invasion and metastasis. Among them, CHEMICAL markedly inhibited HGF-induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and transwell-chamber invasion/migration assay under non-cytotoxic concentrations. Data also showed CHEMICAL inhibited HGF-induced cell scattering and cytoskeleton changed such as filopodia and lamellipodia. Furthermore, CHEMICAL could inhibit HGF-induced the membrane localization of phosphorylated c-Met, GENE, and Akt, but not phosphorylated JNK1/2 and p38. Next, CHEMICAL significantly decreased the levels of phospho-ERK2 and phospho-Akt in GENE or Akt siRNA-transfected cells concomitantly with a marked reduction on cell invasion and migration. In conclusion, CHEMICAL attenuates HGF-induced HepG2 cells metastasis involving both ERK and PI3K/Akt pathways and are potentially useful as anti-metastatic agents for the treatment of hepatoma. | INHIBITOR |
| CHEMICAL attenuates metastasis via both ERK and PI3K/Akt pathways in HGF-treated liver cancer HepG2 cells. Hepatocyte growth factor (HGF), and its receptor, c-Met activation has recently been shown to play important roles in cancer invasion and metastasis in a wide variety of tumor cells. We use HGF as an invasive inducer of human HepG2 cells to investigate the effect of four flavones including apigenin, tricetin, tangeretin, and CHEMICAL on HGF/c-Met-mediated tumor invasion and metastasis. Among them, CHEMICAL markedly inhibited HGF-induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and transwell-chamber invasion/migration assay under non-cytotoxic concentrations. Data also showed CHEMICAL inhibited HGF-induced cell scattering and cytoskeleton changed such as filopodia and lamellipodia. Furthermore, CHEMICAL could inhibit HGF-induced the membrane localization of phosphorylated c-Met, ERK2, and GENE, but not phosphorylated JNK1/2 and p38. Next, CHEMICAL significantly decreased the levels of phospho-ERK2 and phospho-Akt in ERK2 or GENE siRNA-transfected cells concomitantly with a marked reduction on cell invasion and migration. In conclusion, CHEMICAL attenuates HGF-induced HepG2 cells metastasis involving both ERK and PI3K/Akt pathways and are potentially useful as anti-metastatic agents for the treatment of hepatoma. | INHIBITOR |
| CHEMICAL attenuates metastasis via both GENE and PI3K/Akt pathways in HGF-treated liver cancer HepG2 cells. Hepatocyte growth factor (HGF), and its receptor, c-Met activation has recently been shown to play important roles in cancer invasion and metastasis in a wide variety of tumor cells. We use HGF as an invasive inducer of human HepG2 cells to investigate the effect of four flavones including apigenin, tricetin, tangeretin, and nobiletin on HGF/c-Met-mediated tumor invasion and metastasis. Among them, nobiletin markedly inhibited HGF-induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and transwell-chamber invasion/migration assay under non-cytotoxic concentrations. Data also showed nobiletin inhibited HGF-induced cell scattering and cytoskeleton changed such as filopodia and lamellipodia. Furthermore, nobiletin could inhibit HGF-induced the membrane localization of phosphorylated c-Met, ERK2, and Akt, but not phosphorylated JNK1/2 and p38. Next, nobiletin significantly decreased the levels of phospho-ERK2 and phospho-Akt in ERK2 or Akt siRNA-transfected cells concomitantly with a marked reduction on cell invasion and migration. In conclusion, nobiletin attenuates HGF-induced HepG2 cells metastasis involving both GENE and PI3K/Akt pathways and are potentially useful as anti-metastatic agents for the treatment of hepatoma. | REGULATOR |
| CHEMICAL attenuates metastasis via both ERK and GENE/Akt pathways in HGF-treated liver cancer HepG2 cells. Hepatocyte growth factor (HGF), and its receptor, c-Met activation has recently been shown to play important roles in cancer invasion and metastasis in a wide variety of tumor cells. We use HGF as an invasive inducer of human HepG2 cells to investigate the effect of four flavones including apigenin, tricetin, tangeretin, and nobiletin on HGF/c-Met-mediated tumor invasion and metastasis. Among them, nobiletin markedly inhibited HGF-induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and transwell-chamber invasion/migration assay under non-cytotoxic concentrations. Data also showed nobiletin inhibited HGF-induced cell scattering and cytoskeleton changed such as filopodia and lamellipodia. Furthermore, nobiletin could inhibit HGF-induced the membrane localization of phosphorylated c-Met, ERK2, and Akt, but not phosphorylated JNK1/2 and p38. Next, nobiletin significantly decreased the levels of phospho-ERK2 and phospho-Akt in ERK2 or Akt siRNA-transfected cells concomitantly with a marked reduction on cell invasion and migration. In conclusion, nobiletin attenuates HGF-induced HepG2 cells metastasis involving both ERK and PI3K/Akt pathways and are potentially useful as anti-metastatic agents for the treatment of hepatoma. | REGULATOR |
| CHEMICAL attenuates metastasis via both ERK and PI3K/Akt pathways in HGF-treated liver cancer HepG2 cells. Hepatocyte growth factor (HGF), and its receptor, c-Met activation has recently been shown to play important roles in cancer invasion and metastasis in a wide variety of tumor cells. We use GENE as an invasive inducer of human HepG2 cells to investigate the effect of four flavones including apigenin, tricetin, tangeretin, and CHEMICAL on HGF/c-Met-mediated tumor invasion and metastasis. Among them, CHEMICAL markedly inhibited HGF-induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and transwell-chamber invasion/migration assay under non-cytotoxic concentrations. Data also showed CHEMICAL inhibited HGF-induced cell scattering and cytoskeleton changed such as filopodia and lamellipodia. Furthermore, CHEMICAL could inhibit HGF-induced the membrane localization of phosphorylated c-Met, ERK2, and Akt, but not phosphorylated JNK1/2 and p38. Next, CHEMICAL significantly decreased the levels of phospho-ERK2 and phospho-Akt in ERK2 or Akt siRNA-transfected cells concomitantly with a marked reduction on cell invasion and migration. In conclusion, CHEMICAL attenuates GENE-induced HepG2 cells metastasis involving both ERK and PI3K/Akt pathways and are potentially useful as anti-metastatic agents for the treatment of hepatoma. | INHIBITOR |
| CHEMICAL attenuates metastasis via both ERK and PI3K/Akt pathways in HGF-treated liver cancer HepG2 cells. Hepatocyte growth factor (HGF), and its receptor, c-Met activation has recently been shown to play important roles in cancer invasion and metastasis in a wide variety of tumor cells. We use HGF as an invasive inducer of human HepG2 cells to investigate the effect of four flavones including apigenin, tricetin, tangeretin, and CHEMICAL on HGF/c-Met-mediated tumor invasion and metastasis. Among them, CHEMICAL markedly inhibited HGF-induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and transwell-chamber invasion/migration assay under non-cytotoxic concentrations. Data also showed CHEMICAL inhibited HGF-induced cell scattering and cytoskeleton changed such as filopodia and lamellipodia. Furthermore, CHEMICAL could inhibit HGF-induced the membrane localization of phosphorylated c-Met, ERK2, and Akt, but not phosphorylated JNK1/2 and p38. Next, CHEMICAL significantly decreased the levels of phospho-ERK2 and phospho-Akt in ERK2 or Akt siRNA-transfected cells concomitantly with a marked reduction on cell invasion and migration. In conclusion, CHEMICAL attenuates HGF-induced HepG2 cells metastasis involving both ERK and GENE/Akt pathways and are potentially useful as anti-metastatic agents for the treatment of hepatoma. | REGULATOR |
| CHEMICAL attenuates metastasis via both ERK and PI3K/Akt pathways in HGF-treated liver cancer HepG2 cells. Hepatocyte growth factor (HGF), and its receptor, GENE activation has recently been shown to play important roles in cancer invasion and metastasis in a wide variety of tumor cells. We use HGF as an invasive inducer of human HepG2 cells to investigate the effect of four flavones including apigenin, tricetin, tangeretin, and CHEMICAL on HGF/c-Met-mediated tumor invasion and metastasis. Among them, CHEMICAL markedly inhibited HGF-induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and transwell-chamber invasion/migration assay under non-cytotoxic concentrations. Data also showed CHEMICAL inhibited HGF-induced cell scattering and cytoskeleton changed such as filopodia and lamellipodia. Furthermore, CHEMICAL could inhibit HGF-induced the membrane localization of phosphorylated GENE, ERK2, and Akt, but not phosphorylated JNK1/2 and p38. Next, CHEMICAL significantly decreased the levels of phospho-ERK2 and phospho-Akt in ERK2 or Akt siRNA-transfected cells concomitantly with a marked reduction on cell invasion and migration. In conclusion, CHEMICAL attenuates HGF-induced HepG2 cells metastasis involving both ERK and PI3K/Akt pathways and are potentially useful as anti-metastatic agents for the treatment of hepatoma. | INHIBITOR |
| T-Cells from HLA-B*57:01+ Human Subjects Are Activated with CHEMICAL through Two Independent Pathways and Induce Cell Death by Multiple Mechanisms. Susceptibility to CHEMICAL hypersensitivity has been attributed to possession of the specific human leukocyte antigen allele HLA-B*57:01. HLA-B*57:01-restricted activation of CD8+ T-cells provides a link between the genetic association and the iatrogenic disease. The objectives of this study were to characterize the functionality of drug-responsive CD8+ T-cell clones generated from HLA-B*57:01+ drug-naive subjects and to explore the relationship between CHEMICAL accumulation in antigen presenting cells and the T-cell response. Seventy-four CD8+ clones expressing different Vβ receptors were shown to proliferate and kill target cells via different mechanisms when exposed to CHEMICAL. Certain clones were activated with CHEMICAL in the absence of antigen presenting cells. Analysis of the remaining clones revealed two pathways of drug-dependent T-cell activation. Overnight incubation of antigen presenting cells with CHEMICAL, followed by repeated washing to remove soluble drug, activated approximately 50% of the clones, and the response was blocked by glutaraldehyde fixation. In contrast, a 1 h antigen presenting cell pulse did not activate any of the clones. Accumulation of CHEMICAL in antigen presenting cells was rapid (less than 1 h), and the intracellular concentrations were maintained for 16 h. However, intracellular CHEMICAL was not detectable by mass spectrometry after pulsing. These data suggest that T-cells can be activated by CHEMICAL through a direct interaction with surface and intracellular major histocompatibility complex (MHC) molecules. With the former, CHEMICAL seemingly participates in the GENE T-cell receptor binding interaction. In contrast, the latter pathway likely involves GENE binding peptides displayed as a consequence of CHEMICAL exposure, but not CHEMICAL itself. | NO-RELATIONSHIP |
| T-Cells from HLA-B*57:01+ Human Subjects Are Activated with CHEMICAL through Two Independent Pathways and Induce Cell Death by Multiple Mechanisms. Susceptibility to CHEMICAL hypersensitivity has been attributed to possession of the specific human leukocyte antigen allele HLA-B*57:01. HLA-B*57:01-restricted activation of CD8+ T-cells provides a link between the genetic association and the iatrogenic disease. The objectives of this study were to characterize the functionality of drug-responsive CD8+ T-cell clones generated from HLA-B*57:01+ drug-naive subjects and to explore the relationship between CHEMICAL accumulation in antigen presenting cells and the T-cell response. Seventy-four CD8+ clones expressing different Vβ receptors were shown to proliferate and kill target cells via different mechanisms when exposed to CHEMICAL. Certain clones were activated with CHEMICAL in the absence of antigen presenting cells. Analysis of the remaining clones revealed two pathways of drug-dependent T-cell activation. Overnight incubation of antigen presenting cells with CHEMICAL, followed by repeated washing to remove soluble drug, activated approximately 50% of the clones, and the response was blocked by glutaraldehyde fixation. In contrast, a 1 h antigen presenting cell pulse did not activate any of the clones. Accumulation of CHEMICAL in antigen presenting cells was rapid (less than 1 h), and the intracellular concentrations were maintained for 16 h. However, intracellular CHEMICAL was not detectable by mass spectrometry after pulsing. These data suggest that T-cells can be activated by CHEMICAL through a direct interaction with surface and intracellular GENE (MHC) molecules. With the former, CHEMICAL seemingly participates in the MHC T-cell receptor binding interaction. In contrast, the latter pathway likely involves MHC binding peptides displayed as a consequence of CHEMICAL exposure, but not CHEMICAL itself. | NO-RELATIONSHIP |
| T-Cells from HLA-B*57:01+ Human Subjects Are Activated with CHEMICAL through Two Independent Pathways and Induce Cell Death by Multiple Mechanisms. Susceptibility to CHEMICAL hypersensitivity has been attributed to possession of the specific human leukocyte antigen allele HLA-B*57:01. HLA-B*57:01-restricted activation of CD8+ T-cells provides a link between the genetic association and the iatrogenic disease. The objectives of this study were to characterize the functionality of drug-responsive CD8+ T-cell clones generated from HLA-B*57:01+ drug-naive subjects and to explore the relationship between CHEMICAL accumulation in antigen presenting cells and the T-cell response. Seventy-four CD8+ clones expressing different Vβ receptors were shown to proliferate and kill target cells via different mechanisms when exposed to CHEMICAL. Certain clones were activated with CHEMICAL in the absence of antigen presenting cells. Analysis of the remaining clones revealed two pathways of drug-dependent T-cell activation. Overnight incubation of antigen presenting cells with CHEMICAL, followed by repeated washing to remove soluble drug, activated approximately 50% of the clones, and the response was blocked by glutaraldehyde fixation. In contrast, a 1 h antigen presenting cell pulse did not activate any of the clones. Accumulation of CHEMICAL in antigen presenting cells was rapid (less than 1 h), and the intracellular concentrations were maintained for 16 h. However, intracellular CHEMICAL was not detectable by mass spectrometry after pulsing. These data suggest that T-cells can be activated by CHEMICAL through a direct interaction with surface and intracellular major histocompatibility complex (MHC) molecules. With the former, CHEMICAL seemingly participates in the MHC GENE binding interaction. In contrast, the latter pathway likely involves MHC binding peptides displayed as a consequence of CHEMICAL exposure, but not CHEMICAL itself. | NO-RELATIONSHIP |
| T-Cells from HLA-B*57:01+ Human Subjects Are Activated with CHEMICAL through Two Independent Pathways and Induce Cell Death by Multiple Mechanisms. Susceptibility to CHEMICAL hypersensitivity has been attributed to possession of the specific human leukocyte antigen allele HLA-B*57:01. HLA-B*57:01-restricted activation of CD8+ T-cells provides a link between the genetic association and the iatrogenic disease. The objectives of this study were to characterize the functionality of drug-responsive CD8+ T-cell clones generated from HLA-B*57:01+ drug-naive subjects and to explore the relationship between CHEMICAL accumulation in antigen presenting cells and the T-cell response. Seventy-four CD8+ clones expressing different GENE were shown to proliferate and kill target cells via different mechanisms when exposed to CHEMICAL. Certain clones were activated with CHEMICAL in the absence of antigen presenting cells. Analysis of the remaining clones revealed two pathways of drug-dependent T-cell activation. Overnight incubation of antigen presenting cells with CHEMICAL, followed by repeated washing to remove soluble drug, activated approximately 50% of the clones, and the response was blocked by glutaraldehyde fixation. In contrast, a 1 h antigen presenting cell pulse did not activate any of the clones. Accumulation of CHEMICAL in antigen presenting cells was rapid (less than 1 h), and the intracellular concentrations were maintained for 16 h. However, intracellular CHEMICAL was not detectable by mass spectrometry after pulsing. These data suggest that T-cells can be activated by CHEMICAL through a direct interaction with surface and intracellular major histocompatibility complex (MHC) molecules. With the former, CHEMICAL seemingly participates in the MHC T-cell receptor binding interaction. In contrast, the latter pathway likely involves MHC binding peptides displayed as a consequence of CHEMICAL exposure, but not CHEMICAL itself. | NO-RELATIONSHIP |
| Potential diagnostic applications of side chain oxysterols analysis in plasma and cerebrospinal fluid. The neurospecific CHEMICAL 24-hydroxylase converts excess brain CHEMICAL into 24S-hydroxycholesterol (24OHC) which, via the liver X receptor (LXR), can increase the expression and synthesis of astrocyte ApoE. 24OHC effluxes directly from brain into plasma where it is considered an indicator of brain CHEMICAL turnover. It is reduced in neurodegenerative disease states proportionally to the severity of disease and the degree of brain atrophy. In the early phases of active disease, a higher rate of turnover may result in transitory increases in plasma 24OHC. Less than 1% of the total brain excretion of 24OHC occurs via the cerebrospinal fluid (CSF) whereas almost all 27-hydroxycholesterol (27OHC) excretion is dependent on the function of the blood-cerebrospinal fluid barrier. Iincreased CSF oxysterols were found in patients with neurodegenerative and neuroinflammatory diseases in the presence of barrier dysfunction. In neurodegeneration, free CHEMICAL released from dying cells may engulf neurons. CHEMICAL also increases Amyloid β (Aβ) deposition and tau pathology. ApoE, 24OHC, tau and soluble APP were correlated in Alzheimer disease (AD) samples. Excess of CHEMICAL converted into 24OHC may up-regulate ApoE synthesis which is a scavenger for GENE and Tau. In AD this protective mechanism seems to be inefficient, probably due to the presence of high concentrations of 27OHC, microvascular dysfunction and the decreased efficiency of ApoE4 as lipid transporter and GENE scavenger. 24OHC itself was cytotoxic. Analysis of side chain oxysterols in the CSF is likely to provided useful information about CHEMICAL metabolism and ApoE function in the pathogenesis of AD. | SUBSTRATE |
| Potential diagnostic applications of side chain oxysterols analysis in plasma and cerebrospinal fluid. The neurospecific CHEMICAL 24-hydroxylase converts excess brain CHEMICAL into 24S-hydroxycholesterol (24OHC) which, via the liver X receptor (LXR), can increase the expression and synthesis of astrocyte ApoE. 24OHC effluxes directly from brain into plasma where it is considered an indicator of brain CHEMICAL turnover. It is reduced in neurodegenerative disease states proportionally to the severity of disease and the degree of brain atrophy. In the early phases of active disease, a higher rate of turnover may result in transitory increases in plasma 24OHC. Less than 1% of the total brain excretion of 24OHC occurs via the cerebrospinal fluid (CSF) whereas almost all 27-hydroxycholesterol (27OHC) excretion is dependent on the function of the blood-cerebrospinal fluid barrier. Iincreased CSF oxysterols were found in patients with neurodegenerative and neuroinflammatory diseases in the presence of barrier dysfunction. In neurodegeneration, free CHEMICAL released from dying cells may engulf neurons. CHEMICAL also increases Amyloid β (Aβ) deposition and tau pathology. ApoE, 24OHC, tau and soluble APP were correlated in Alzheimer disease (AD) samples. Excess of CHEMICAL converted into 24OHC may up-regulate ApoE synthesis which is a scavenger for Aβ and GENE. In AD this protective mechanism seems to be inefficient, probably due to the presence of high concentrations of 27OHC, microvascular dysfunction and the decreased efficiency of ApoE4 as lipid transporter and Aβ scavenger. 24OHC itself was cytotoxic. Analysis of side chain oxysterols in the CSF is likely to provided useful information about CHEMICAL metabolism and ApoE function in the pathogenesis of AD. | SUBSTRATE |
| Potential diagnostic applications of side chain oxysterols analysis in plasma and cerebrospinal fluid. The neurospecific CHEMICAL 24-hydroxylase converts excess brain CHEMICAL into 24S-hydroxycholesterol (24OHC) which, via the liver X receptor (LXR), can increase the expression and synthesis of astrocyte GENE. 24OHC effluxes directly from brain into plasma where it is considered an indicator of brain CHEMICAL turnover. It is reduced in neurodegenerative disease states proportionally to the severity of disease and the degree of brain atrophy. In the early phases of active disease, a higher rate of turnover may result in transitory increases in plasma 24OHC. Less than 1% of the total brain excretion of 24OHC occurs via the cerebrospinal fluid (CSF) whereas almost all 27-hydroxycholesterol (27OHC) excretion is dependent on the function of the blood-cerebrospinal fluid barrier. Iincreased CSF oxysterols were found in patients with neurodegenerative and neuroinflammatory diseases in the presence of barrier dysfunction. In neurodegeneration, free CHEMICAL released from dying cells may engulf neurons. CHEMICAL also increases Amyloid β (Aβ) deposition and tau pathology. GENE, 24OHC, tau and soluble APP were correlated in Alzheimer disease (AD) samples. Excess of CHEMICAL converted into 24OHC may up-regulate GENE synthesis which is a scavenger for Aβ and Tau. In AD this protective mechanism seems to be inefficient, probably due to the presence of high concentrations of 27OHC, microvascular dysfunction and the decreased efficiency of ApoE4 as lipid transporter and Aβ scavenger. 24OHC itself was cytotoxic. Analysis of side chain oxysterols in the CSF is likely to provided useful information about CHEMICAL metabolism and GENE function in the pathogenesis of AD. | PRODUCT-OF |
| Potential diagnostic applications of side chain oxysterols analysis in plasma and cerebrospinal fluid. The neurospecific cholesterol 24-hydroxylase converts excess brain cholesterol into 24S-hydroxycholesterol (24OHC) which, via the liver X receptor (LXR), can increase the expression and synthesis of astrocyte GENE. CHEMICAL effluxes directly from brain into plasma where it is considered an indicator of brain cholesterol turnover. It is reduced in neurodegenerative disease states proportionally to the severity of disease and the degree of brain atrophy. In the early phases of active disease, a higher rate of turnover may result in transitory increases in plasma CHEMICAL. Less than 1% of the total brain excretion of CHEMICAL occurs via the cerebrospinal fluid (CSF) whereas almost all 27-hydroxycholesterol (27OHC) excretion is dependent on the function of the blood-cerebrospinal fluid barrier. Iincreased CSF oxysterols were found in patients with neurodegenerative and neuroinflammatory diseases in the presence of barrier dysfunction. In neurodegeneration, free cholesterol released from dying cells may engulf neurons. Cholesterol also increases Amyloid β (Aβ) deposition and tau pathology. GENE, CHEMICAL, tau and soluble APP were correlated in Alzheimer disease (AD) samples. Excess of cholesterol converted into CHEMICAL may up-regulate GENE synthesis which is a scavenger for Aβ and Tau. In AD this protective mechanism seems to be inefficient, probably due to the presence of high concentrations of 27OHC, microvascular dysfunction and the decreased efficiency of ApoE4 as lipid transporter and Aβ scavenger. CHEMICAL itself was cytotoxic. Analysis of side chain oxysterols in the CSF is likely to provided useful information about cholesterol metabolism and GENE function in the pathogenesis of AD. | PRODUCT-OF |
| Potential diagnostic applications of side chain oxysterols analysis in plasma and cerebrospinal fluid. The neurospecific cholesterol 24-hydroxylase converts excess brain cholesterol into 24S-hydroxycholesterol (24OHC) which, via the liver X receptor (LXR), can increase the expression and synthesis of astrocyte ApoE. 24OHC effluxes directly from brain into plasma where it is considered an indicator of brain cholesterol turnover. It is reduced in neurodegenerative disease states proportionally to the severity of disease and the degree of brain atrophy. In the early phases of active disease, a higher rate of turnover may result in transitory increases in plasma 24OHC. Less than 1% of the total brain excretion of 24OHC occurs via the cerebrospinal fluid (CSF) whereas almost all 27-hydroxycholesterol (27OHC) excretion is dependent on the function of the blood-cerebrospinal fluid barrier. Iincreased CSF oxysterols were found in patients with neurodegenerative and neuroinflammatory diseases in the presence of barrier dysfunction. In neurodegeneration, free cholesterol released from dying cells may engulf neurons. CHEMICAL also increases GENE (Aβ) deposition and tau pathology. ApoE, 24OHC, tau and soluble APP were correlated in Alzheimer disease (AD) samples. Excess of cholesterol converted into 24OHC may up-regulate ApoE synthesis which is a scavenger for Aβ and Tau. In AD this protective mechanism seems to be inefficient, probably due to the presence of high concentrations of 27OHC, microvascular dysfunction and the decreased efficiency of ApoE4 as lipid transporter and Aβ scavenger. 24OHC itself was cytotoxic. Analysis of side chain oxysterols in the CSF is likely to provided useful information about cholesterol metabolism and ApoE function in the pathogenesis of AD. | INDIRECT-UPREGULATOR |
| Potential diagnostic applications of side chain oxysterols analysis in plasma and cerebrospinal fluid. The neurospecific cholesterol 24-hydroxylase converts excess brain cholesterol into 24S-hydroxycholesterol (24OHC) which, via the liver X receptor (LXR), can increase the expression and synthesis of astrocyte ApoE. 24OHC effluxes directly from brain into plasma where it is considered an indicator of brain cholesterol turnover. It is reduced in neurodegenerative disease states proportionally to the severity of disease and the degree of brain atrophy. In the early phases of active disease, a higher rate of turnover may result in transitory increases in plasma 24OHC. Less than 1% of the total brain excretion of 24OHC occurs via the cerebrospinal fluid (CSF) whereas almost all 27-hydroxycholesterol (27OHC) excretion is dependent on the function of the blood-cerebrospinal fluid barrier. Iincreased CSF oxysterols were found in patients with neurodegenerative and neuroinflammatory diseases in the presence of barrier dysfunction. In neurodegeneration, free cholesterol released from dying cells may engulf neurons. CHEMICAL also increases Amyloid β (Aβ) deposition and GENE pathology. ApoE, 24OHC, GENE and soluble APP were correlated in Alzheimer disease (AD) samples. Excess of cholesterol converted into 24OHC may up-regulate ApoE synthesis which is a scavenger for Aβ and GENE. In AD this protective mechanism seems to be inefficient, probably due to the presence of high concentrations of 27OHC, microvascular dysfunction and the decreased efficiency of ApoE4 as lipid transporter and Aβ scavenger. 24OHC itself was cytotoxic. Analysis of side chain oxysterols in the CSF is likely to provided useful information about cholesterol metabolism and ApoE function in the pathogenesis of AD. | INDIRECT-UPREGULATOR |
| Loss of Calcium/Calmodulin-Dependent Protein Kinase II Activity in Cortical Astrocytes Decreases Glutamate Uptake and Induces Neurotoxic Release of ATP. The extent of calcium/calmodulin-dependent protein kinase II (CaMKII) inactivation in the brain following ischemia correlates with the extent of damage. We have previously shown that a loss of CaMKII activity in neurons is detrimental to neuronal viability by inducing excitotoxic glutamate release. In the current study, we extend these findings to show that the ability of astrocytes to buffer extracellular glutamate is reduced when CaMKII is inhibited. Furthermore, CaMKII inhibition in astrocytes is associated with the rapid onset of intracellular CHEMICAL oscillations. Surprisingly, this rapid CHEMICAL influx is blocked by the N-type CHEMICAL channel antagonist, omega-conotoxin. While the function of GENE within astrocytes is controversial, these voltage-gated CHEMICAL channels have been linked to CHEMICAL-dependent vesicular gliotransmitter release. When extracellular glutamate and ATP levels are measured following CaMKII inhibition within our enriched astrocyte cultures, no alterations in glutamate levels are observed, whereas ATP levels in the extracellular environment significantly increase. Extracellular ATP accumulation associated with CaMKII inhibition contributes both to CHEMICAL oscillations within astrocytes and ultimately cortical neuron toxicity. Thus, a loss of CaMKII signaling within astrocytes dysregulates glutamate uptake and supports ATP release, two processes that would compromise neuronal survival following ischemic/excitotoxic insults. | SUBSTRATE |
| Loss of Calcium/Calmodulin-Dependent Protein Kinase II Activity in Cortical Astrocytes Decreases Glutamate Uptake and Induces Neurotoxic Release of ATP. The extent of calcium/calmodulin-dependent protein kinase II (CaMKII) inactivation in the brain following ischemia correlates with the extent of damage. We have previously shown that a loss of CaMKII activity in neurons is detrimental to neuronal viability by inducing excitotoxic glutamate release. In the current study, we extend these findings to show that the ability of astrocytes to buffer extracellular glutamate is reduced when CaMKII is inhibited. Furthermore, CaMKII inhibition in astrocytes is associated with the rapid onset of intracellular CHEMICAL oscillations. Surprisingly, this rapid CHEMICAL influx is blocked by the N-type CHEMICAL channel antagonist, omega-conotoxin. While the function of N-type CHEMICAL channels within astrocytes is controversial, these GENE have been linked to CHEMICAL-dependent vesicular gliotransmitter release. When extracellular glutamate and ATP levels are measured following CaMKII inhibition within our enriched astrocyte cultures, no alterations in glutamate levels are observed, whereas ATP levels in the extracellular environment significantly increase. Extracellular ATP accumulation associated with CaMKII inhibition contributes both to CHEMICAL oscillations within astrocytes and ultimately cortical neuron toxicity. Thus, a loss of CaMKII signaling within astrocytes dysregulates glutamate uptake and supports ATP release, two processes that would compromise neuronal survival following ischemic/excitotoxic insults. | REGULATOR |
| Loss of Calcium/Calmodulin-Dependent Protein Kinase II Activity in Cortical Astrocytes Decreases CHEMICAL Uptake and Induces Neurotoxic Release of ATP. The extent of calcium/calmodulin-dependent protein kinase II (CaMKII) inactivation in the brain following ischemia correlates with the extent of damage. We have previously shown that a loss of GENE activity in neurons is detrimental to neuronal viability by inducing excitotoxic CHEMICAL release. In the current study, we extend these findings to show that the ability of astrocytes to buffer extracellular CHEMICAL is reduced when GENE is inhibited. Furthermore, GENE inhibition in astrocytes is associated with the rapid onset of intracellular calcium oscillations. Surprisingly, this rapid calcium influx is blocked by the N-type calcium channel antagonist, omega-conotoxin. While the function of N-type calcium channels within astrocytes is controversial, these voltage-gated calcium channels have been linked to calcium-dependent vesicular gliotransmitter release. When extracellular CHEMICAL and ATP levels are measured following GENE inhibition within our enriched astrocyte cultures, no alterations in CHEMICAL levels are observed, whereas ATP levels in the extracellular environment significantly increase. Extracellular ATP accumulation associated with GENE inhibition contributes both to calcium oscillations within astrocytes and ultimately cortical neuron toxicity. Thus, a loss of GENE signaling within astrocytes dysregulates CHEMICAL uptake and supports ATP release, two processes that would compromise neuronal survival following ischemic/excitotoxic insults. | SUBSTRATE |
| 3-Hydroxypyridin-2-thione as Novel Zinc Binding Group for Selective Histone Deacetylase Inhibition. Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitors (HDACi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative nonhydroxamate ZBGs. We have identified 3-hydroxypyridin-2-thione (3-HPT) as a novel ZBG that is compatible with HDAC inhibition. CHEMICAL inhibits HDAC 6 and HDAC 8 with an IC50 of 681 and 3675 nM, respectively. Remarkably, CHEMICAL gives no inhibition of GENE. Subsequent optimization led to several novel 3HPT-based HDACi that are selective for HDAC 6 and HDAC 8. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines. | NO-RELATIONSHIP |
| 3-Hydroxypyridin-2-thione as Novel Zinc Binding Group for Selective Histone Deacetylase Inhibition. Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitors (HDACi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative nonhydroxamate ZBGs. We have identified CHEMICAL (3-HPT) as a novel ZBG that is compatible with GENE inhibition. 3-HPT inhibits GENE 6 and GENE 8 with an IC50 of 681 and 3675 nM, respectively. Remarkably, 3-HPT gives no inhibition of GENE 1. Subsequent optimization led to several novel 3HPT-based HDACi that are selective for GENE 6 and GENE 8. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines. | INHIBITOR |
| 3-Hydroxypyridin-2-thione as Novel Zinc Binding Group for Selective Histone Deacetylase Inhibition. Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitors (HDACi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative nonhydroxamate ZBGs. We have identified 3-hydroxypyridin-2-thione (CHEMICAL) as a novel ZBG that is compatible with GENE inhibition. CHEMICAL inhibits GENE 6 and GENE 8 with an IC50 of 681 and 3675 nM, respectively. Remarkably, CHEMICAL gives no inhibition of GENE 1. Subsequent optimization led to several novel 3HPT-based HDACi that are selective for GENE 6 and GENE 8. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines. | INHIBITOR |
| 3-Hydroxypyridin-2-thione as Novel Zinc Binding Group for Selective Histone Deacetylase Inhibition. Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitors (HDACi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative nonhydroxamate ZBGs. We have identified 3-hydroxypyridin-2-thione (3-HPT) as a novel ZBG that is compatible with HDAC inhibition. CHEMICAL inhibits GENE and HDAC 8 with an IC50 of 681 and 3675 nM, respectively. Remarkably, CHEMICAL gives no inhibition of HDAC 1. Subsequent optimization led to several novel 3HPT-based HDACi that are selective for GENE and HDAC 8. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines. | INHIBITOR |
| 3-Hydroxypyridin-2-thione as Novel Zinc Binding Group for Selective Histone Deacetylase Inhibition. Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitors (HDACi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative nonhydroxamate ZBGs. We have identified 3-hydroxypyridin-2-thione (3-HPT) as a novel ZBG that is compatible with HDAC inhibition. CHEMICAL inhibits HDAC 6 and GENE with an IC50 of 681 and 3675 nM, respectively. Remarkably, CHEMICAL gives no inhibition of HDAC 1. Subsequent optimization led to several novel 3HPT-based HDACi that are selective for HDAC 6 and GENE. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines. | INHIBITOR |
| 3-Hydroxypyridin-2-thione as Novel CHEMICAL Binding Group for Selective Histone Deacetylase Inhibition. Small molecules bearing hydroxamic acid as the CHEMICAL binding group (ZBG) have been the most effective GENE inhibitors (HDACi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative nonhydroxamate ZBGs. We have identified 3-hydroxypyridin-2-thione (3-HPT) as a novel ZBG that is compatible with HDAC inhibition. 3-HPT inhibits HDAC 6 and HDAC 8 with an IC50 of 681 and 3675 nM, respectively. Remarkably, 3-HPT gives no inhibition of HDAC 1. Subsequent optimization led to several novel 3HPT-based HDACi that are selective for HDAC 6 and HDAC 8. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines. | INHIBITOR |
| 3-Hydroxypyridin-2-thione as Novel CHEMICAL Binding Group for Selective Histone Deacetylase Inhibition. Small molecules bearing hydroxamic acid as the CHEMICAL binding group (ZBG) have been the most effective histone deacetylase inhibitors (GENEi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative nonhydroxamate ZBGs. We have identified 3-hydroxypyridin-2-thione (3-HPT) as a novel ZBG that is compatible with GENE inhibition. 3-HPT inhibits GENE 6 and GENE 8 with an IC50 of 681 and 3675 nM, respectively. Remarkably, 3-HPT gives no inhibition of GENE 1. Subsequent optimization led to several novel 3HPT-based HDACi that are selective for GENE 6 and GENE 8. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines. | DIRECT-REGULATOR |
| 3-Hydroxypyridin-2-thione as Novel Zinc Binding Group for Selective Histone Deacetylase Inhibition. Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitors (HDACi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative nonhydroxamate ZBGs. We have identified 3-hydroxypyridin-2-thione (3-HPT) as a novel ZBG that is compatible with GENE inhibition. 3-HPT inhibits GENE 6 and GENE 8 with an IC50 of 681 and 3675 nM, respectively. Remarkably, 3-HPT gives no inhibition of GENE 1. Subsequent optimization led to several novel CHEMICAL-based GENEi that are selective for GENE 6 and GENE 8. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines. | REGULATOR |
| 3-Hydroxypyridin-2-thione as Novel Zinc Binding Group for Selective Histone Deacetylase Inhibition. Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitors (HDACi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative nonhydroxamate ZBGs. We have identified 3-hydroxypyridin-2-thione (3-HPT) as a novel ZBG that is compatible with HDAC inhibition. 3-HPT inhibits GENE and HDAC 8 with an IC50 of 681 and 3675 nM, respectively. Remarkably, 3-HPT gives no inhibition of HDAC 1. Subsequent optimization led to several novel CHEMICAL-based HDACi that are selective for GENE and HDAC 8. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines. | INHIBITOR |
| 3-Hydroxypyridin-2-thione as Novel Zinc Binding Group for Selective Histone Deacetylase Inhibition. Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitors (HDACi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative nonhydroxamate ZBGs. We have identified 3-hydroxypyridin-2-thione (3-HPT) as a novel ZBG that is compatible with HDAC inhibition. 3-HPT inhibits HDAC 6 and GENE with an IC50 of 681 and 3675 nM, respectively. Remarkably, 3-HPT gives no inhibition of HDAC 1. Subsequent optimization led to several novel CHEMICAL-based HDACi that are selective for HDAC 6 and GENE. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines. | INHIBITOR |
| CHEMICAL as Novel Zinc Binding Group for Selective GENE Inhibition. Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitors (HDACi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative nonhydroxamate ZBGs. We have identified CHEMICAL (3-HPT) as a novel ZBG that is compatible with HDAC inhibition. 3-HPT inhibits HDAC 6 and HDAC 8 with an IC50 of 681 and 3675 nM, respectively. Remarkably, 3-HPT gives no inhibition of HDAC 1. Subsequent optimization led to several novel 3HPT-based HDACi that are selective for HDAC 6 and HDAC 8. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines. | INHIBITOR |
| Lixisenatide: first global approval. The selective once-daily prandial glucagon-like peptide-1 (GLP-1) receptor agonist lixisenatide (Lyxumia(®)) is under development with Sanofi for the treatment of type 2 diabetes mellitus. Lixisenatide belongs to a class of GLP-1 compounds designed to mimic the endogenous hormone GLP-1. Native GLP-1 stimulates GENE secretion in a CHEMICAL-dependent manner, as well as suppressing glucagon production and slowing gastric emptying. A once-daily subcutaneous formulation of lixisenatide has been approved in the EU, Iceland, Liechtenstein, Norway and Mexico for the treatment of type 2 diabetes, and is under regulatory review in the USA, Switzerland, Brazil, Canada, Ukraine, South Africa, Japan and Australia. This article summarizes the milestones in the development of lixisenatide, leading to this first approval for use in adults with type 2 diabetes. | GENE-CHEMICAL |
| Maqui berry (Aristotelia chilensis) and the constituent CHEMICAL inhibit GENE cell death induced by visible light. The protective effects of maqui berry (Aristotelia chilensis) extract (MBE) and its major anthocyanins [delphinidin 3,5-O-diglucoside (D3G5G) and delphinidin 3-O-sambubioside-5-O-glucoside (D3S5G)] against light-induced murine GENE cells (661W) death were evaluated. Viability of 661W after light treatment for 24h, assessed by the tetrazolium salt (WST-8) assay and Hoechst 33342 nuclear staining, was improved by addition of MBE, D3G5G, and D3S5G. Intracellular radical activation in 661W, evaluated using the reactive oxygen species (ROS)-sensitive probe 5-(and-6)-chloromethyl-2,7-dichlorodihydro fluorescein diacetate acetyl ester (CM-H2DCFDA), was reduced by MBE and its anthocyanins. The anti-apoptosis mechanism of MBE was evaluated by light-induced phosphorylation of p38. MBE significantly suppressed the light-induced phosphorylation of p38. These findings indicate that MBE and its anthocyanidins suppress the light-induced GENE cell death by inhibiting ROS production, suggesting that the inhibition of phosphorylated-p38 may be involved in the underlying mechanism. | INHIBITOR |
| Maqui berry (Aristotelia chilensis) and the constituent delphinidin glycoside inhibit photoreceptor cell death induced by visible light. The protective effects of maqui berry (Aristotelia chilensis) extract (MBE) and its major anthocyanins [delphinidin 3,5-O-diglucoside (D3G5G) and delphinidin 3-O-sambubioside-5-O-glucoside (D3S5G)] against light-induced murine photoreceptor cells (661W) death were evaluated. Viability of 661W after light treatment for 24h, assessed by the tetrazolium salt (WST-8) assay and Hoechst 33342 nuclear staining, was improved by addition of MBE, D3G5G, and D3S5G. Intracellular radical activation in 661W, evaluated using the reactive oxygen species (ROS)-sensitive probe 5-(and-6)-chloromethyl-2,7-dichlorodihydro fluorescein diacetate acetyl ester (CM-H2DCFDA), was reduced by MBE and its anthocyanins. The anti-apoptosis mechanism of MBE was evaluated by light-induced phosphorylation of p38. MBE significantly suppressed the light-induced phosphorylation of p38. These findings indicate that MBE and its CHEMICAL suppress the light-induced photoreceptor cell death by inhibiting ROS production, suggesting that the inhibition of GENE may be involved in the underlying mechanism. | INHIBITOR |
| CHEMICAL inhibits invasion and metastasis in K1 papillary thyroid cancer cells. CHEMICAL, the active constituent of dietary spice turmeric, possesses a strong potential for cancer prevention and treatment. However, there is no study to address the effects of CHEMICAL on invasion and metastasis of thyroid cancers. Thyroid cancer is the most common malignancy of endocrine organs, and its incidence rates have steadily increased over recent decades. Although most indolent tumours can be effectively managed, metastatic tumours at distant secondary sites behave aggressively and currently there is no effective form of treatment. Here, for the first time it has been reported that CHEMICAL inhibit multiple metastasis steps of K1 papillary thyroid cancer cells. CHEMICAL dose-dependently suppressed viability of K1 cells as well as its cell attachment, spreading, migration and invasion abilities. Moreover, CHEMICAL could also down-regulate the expression and activity of GENE (MMP-9). The findings showed that CHEMICAL might be an effective tumouristatic agent for the treatment of aggressive papillary thyroid carcinomas. | INDIRECT-DOWNREGULATOR |
| CHEMICAL inhibits invasion and metastasis in K1 papillary thyroid cancer cells. CHEMICAL, the active constituent of dietary spice turmeric, possesses a strong potential for cancer prevention and treatment. However, there is no study to address the effects of CHEMICAL on invasion and metastasis of thyroid cancers. Thyroid cancer is the most common malignancy of endocrine organs, and its incidence rates have steadily increased over recent decades. Although most indolent tumours can be effectively managed, metastatic tumours at distant secondary sites behave aggressively and currently there is no effective form of treatment. Here, for the first time it has been reported that CHEMICAL inhibit multiple metastasis steps of K1 papillary thyroid cancer cells. CHEMICAL dose-dependently suppressed viability of K1 cells as well as its cell attachment, spreading, migration and invasion abilities. Moreover, CHEMICAL could also down-regulate the expression and activity of matrix metalloproteinase-9 (GENE). The findings showed that CHEMICAL might be an effective tumouristatic agent for the treatment of aggressive papillary thyroid carcinomas. | INDIRECT-DOWNREGULATOR |
| Lignans extracted from Vitex negundo possess cytotoxic activity by G2/M phase cell cycle arrest and apoptosis induction. Evn-50 is a lignan compounds mixture extracted from Vitex negundo, a widely used herb in traditional Chinese medicine. This study is aimed to define the spectrum of cytotoxic activity of EVn-50, and also to investigate mechanisms underlying the anticancer actions via assessing the influence on cell cycle using EVn-50, and the lignan compound VB1 purified from EVn-50. The cytotoxic effect of EVn-50 and VB1 was determined with SRB assay using a panel of cancer cell lines. Breast cancer cell line MDA-MB-435 and liver cancer cell line SMMC-7721 were selected for further evaluating the effect of EVn-50 or VB1 on cell cycle by flow cytometric analysis. Apoptosis exerted by EVn-50 or VB1 was measured by TUNEL assay and DAPI staining, and Western blot analysis was utilized to assess the influence on expression and phosphorylation of proteins which are closely related to cell cycle and apoptosis. EVn-50 possessed a broad spectrum of in vitro anticancer activity for those tested cancer cells, especially sensitive to MDA-MB-435, SKOV-3, BXPC-3, SMMC-7721, MCF-7, HO-8910, SGC-7901, BEL-7402, HCT-116, and 786-O, with the respective IC50 below 10μg/ml. Treatment with EVn-50 or VB1 resulted in arresting the MDA-MB-435 and SMMC-7721 cells at G2/M phase, which was further supported by observations of increased phosphorylation of GENE at CHEMICAL10, phosphorylation of Cdk1 at Tyr15, expression of cyclin B1, and decreased expression of Cdc25c. Moreover, we found that exposure of MDA-MB-435 cells to EVn-50 or VB1 caused obvious apoptosis of MDA-MB-435 cells. Our data show that EVn-50, lignan compounds extracted from Vitex negundo, possesses a broad spectrum cytotoxic effect via arresting cancer cells at G2/M phase cell cycle and subsequently inducing apoptosis. | PART-OF |
| Lignans extracted from Vitex negundo possess cytotoxic activity by G2/M phase cell cycle arrest and apoptosis induction. Evn-50 is a lignan compounds mixture extracted from Vitex negundo, a widely used herb in traditional Chinese medicine. This study is aimed to define the spectrum of cytotoxic activity of EVn-50, and also to investigate mechanisms underlying the anticancer actions via assessing the influence on cell cycle using EVn-50, and the lignan compound VB1 purified from EVn-50. The cytotoxic effect of EVn-50 and VB1 was determined with SRB assay using a panel of cancer cell lines. Breast cancer cell line MDA-MB-435 and liver cancer cell line SMMC-7721 were selected for further evaluating the effect of EVn-50 or VB1 on cell cycle by flow cytometric analysis. Apoptosis exerted by EVn-50 or VB1 was measured by TUNEL assay and DAPI staining, and Western blot analysis was utilized to assess the influence on expression and phosphorylation of proteins which are closely related to cell cycle and apoptosis. EVn-50 possessed a broad spectrum of in vitro anticancer activity for those tested cancer cells, especially sensitive to MDA-MB-435, SKOV-3, BXPC-3, SMMC-7721, MCF-7, HO-8910, SGC-7901, BEL-7402, HCT-116, and 786-O, with the respective IC50 below 10μg/ml. Treatment with EVn-50 or VB1 resulted in arresting the MDA-MB-435 and SMMC-7721 cells at G2/M phase, which was further supported by observations of increased phosphorylation of Histone 3 at Ser10, phosphorylation of GENE at CHEMICAL15, expression of cyclin B1, and decreased expression of Cdc25c. Moreover, we found that exposure of MDA-MB-435 cells to EVn-50 or VB1 caused obvious apoptosis of MDA-MB-435 cells. Our data show that EVn-50, lignan compounds extracted from Vitex negundo, possesses a broad spectrum cytotoxic effect via arresting cancer cells at G2/M phase cell cycle and subsequently inducing apoptosis. | PART-OF |
| Lignans extracted from Vitex negundo possess cytotoxic activity by G2/M phase cell cycle arrest and apoptosis induction. CHEMICAL is a lignan compounds mixture extracted from Vitex negundo, a widely used herb in traditional Chinese medicine. This study is aimed to define the spectrum of cytotoxic activity of CHEMICAL, and also to investigate mechanisms underlying the anticancer actions via assessing the influence on cell cycle using CHEMICAL, and the lignan compound VB1 purified from CHEMICAL. The cytotoxic effect of CHEMICAL and VB1 was determined with SRB assay using a panel of cancer cell lines. Breast cancer cell line MDA-MB-435 and liver cancer cell line SMMC-7721 were selected for further evaluating the effect of CHEMICAL or VB1 on cell cycle by flow cytometric analysis. Apoptosis exerted by CHEMICAL or VB1 was measured by TUNEL assay and DAPI staining, and Western blot analysis was utilized to assess the influence on expression and phosphorylation of proteins which are closely related to cell cycle and apoptosis. CHEMICAL possessed a broad spectrum of in vitro anticancer activity for those tested cancer cells, especially sensitive to MDA-MB-435, SKOV-3, BXPC-3, SMMC-7721, MCF-7, HO-8910, SGC-7901, BEL-7402, HCT-116, and 786-O, with the respective IC50 below 10μg/ml. Treatment with CHEMICAL or VB1 resulted in arresting the MDA-MB-435 and SMMC-7721 cells at G2/M phase, which was further supported by observations of increased phosphorylation of GENE at Ser10, phosphorylation of Cdk1 at Tyr15, expression of cyclin B1, and decreased expression of Cdc25c. Moreover, we found that exposure of MDA-MB-435 cells to CHEMICAL or VB1 caused obvious apoptosis of MDA-MB-435 cells. Our data show that CHEMICAL, lignan compounds extracted from Vitex negundo, possesses a broad spectrum cytotoxic effect via arresting cancer cells at G2/M phase cell cycle and subsequently inducing apoptosis. | ACTIVATOR |
| Lignans extracted from Vitex negundo possess cytotoxic activity by G2/M phase cell cycle arrest and apoptosis induction. CHEMICAL is a lignan compounds mixture extracted from Vitex negundo, a widely used herb in traditional Chinese medicine. This study is aimed to define the spectrum of cytotoxic activity of CHEMICAL, and also to investigate mechanisms underlying the anticancer actions via assessing the influence on cell cycle using CHEMICAL, and the lignan compound VB1 purified from CHEMICAL. The cytotoxic effect of CHEMICAL and VB1 was determined with SRB assay using a panel of cancer cell lines. Breast cancer cell line MDA-MB-435 and liver cancer cell line SMMC-7721 were selected for further evaluating the effect of CHEMICAL or VB1 on cell cycle by flow cytometric analysis. Apoptosis exerted by CHEMICAL or VB1 was measured by TUNEL assay and DAPI staining, and Western blot analysis was utilized to assess the influence on expression and phosphorylation of proteins which are closely related to cell cycle and apoptosis. CHEMICAL possessed a broad spectrum of in vitro anticancer activity for those tested cancer cells, especially sensitive to MDA-MB-435, SKOV-3, BXPC-3, SMMC-7721, MCF-7, HO-8910, SGC-7901, BEL-7402, HCT-116, and 786-O, with the respective IC50 below 10μg/ml. Treatment with CHEMICAL or VB1 resulted in arresting the MDA-MB-435 and SMMC-7721 cells at G2/M phase, which was further supported by observations of increased phosphorylation of Histone 3 at Ser10, phosphorylation of GENE at Tyr15, expression of cyclin B1, and decreased expression of Cdc25c. Moreover, we found that exposure of MDA-MB-435 cells to CHEMICAL or VB1 caused obvious apoptosis of MDA-MB-435 cells. Our data show that CHEMICAL, lignan compounds extracted from Vitex negundo, possesses a broad spectrum cytotoxic effect via arresting cancer cells at G2/M phase cell cycle and subsequently inducing apoptosis. | ACTIVATOR |
| Lignans extracted from Vitex negundo possess cytotoxic activity by G2/M phase cell cycle arrest and apoptosis induction. Evn-50 is a lignan compounds mixture extracted from Vitex negundo, a widely used herb in traditional Chinese medicine. This study is aimed to define the spectrum of cytotoxic activity of EVn-50, and also to investigate mechanisms underlying the anticancer actions via assessing the influence on cell cycle using EVn-50, and the lignan compound CHEMICAL purified from EVn-50. The cytotoxic effect of EVn-50 and CHEMICAL was determined with SRB assay using a panel of cancer cell lines. Breast cancer cell line MDA-MB-435 and liver cancer cell line SMMC-7721 were selected for further evaluating the effect of EVn-50 or CHEMICAL on cell cycle by flow cytometric analysis. Apoptosis exerted by EVn-50 or CHEMICAL was measured by TUNEL assay and DAPI staining, and Western blot analysis was utilized to assess the influence on expression and phosphorylation of proteins which are closely related to cell cycle and apoptosis. EVn-50 possessed a broad spectrum of in vitro anticancer activity for those tested cancer cells, especially sensitive to MDA-MB-435, SKOV-3, BXPC-3, SMMC-7721, MCF-7, HO-8910, SGC-7901, BEL-7402, HCT-116, and 786-O, with the respective IC50 below 10μg/ml. Treatment with EVn-50 or CHEMICAL resulted in arresting the MDA-MB-435 and SMMC-7721 cells at G2/M phase, which was further supported by observations of increased phosphorylation of GENE at Ser10, phosphorylation of Cdk1 at Tyr15, expression of cyclin B1, and decreased expression of Cdc25c. Moreover, we found that exposure of MDA-MB-435 cells to EVn-50 or CHEMICAL caused obvious apoptosis of MDA-MB-435 cells. Our data show that EVn-50, lignan compounds extracted from Vitex negundo, possesses a broad spectrum cytotoxic effect via arresting cancer cells at G2/M phase cell cycle and subsequently inducing apoptosis. | INHIBITOR |
| Lignans extracted from Vitex negundo possess cytotoxic activity by G2/M phase cell cycle arrest and apoptosis induction. Evn-50 is a lignan compounds mixture extracted from Vitex negundo, a widely used herb in traditional Chinese medicine. This study is aimed to define the spectrum of cytotoxic activity of EVn-50, and also to investigate mechanisms underlying the anticancer actions via assessing the influence on cell cycle using EVn-50, and the lignan compound CHEMICAL purified from EVn-50. The cytotoxic effect of EVn-50 and CHEMICAL was determined with SRB assay using a panel of cancer cell lines. Breast cancer cell line MDA-MB-435 and liver cancer cell line SMMC-7721 were selected for further evaluating the effect of EVn-50 or CHEMICAL on cell cycle by flow cytometric analysis. Apoptosis exerted by EVn-50 or CHEMICAL was measured by TUNEL assay and DAPI staining, and Western blot analysis was utilized to assess the influence on expression and phosphorylation of proteins which are closely related to cell cycle and apoptosis. EVn-50 possessed a broad spectrum of in vitro anticancer activity for those tested cancer cells, especially sensitive to MDA-MB-435, SKOV-3, BXPC-3, SMMC-7721, MCF-7, HO-8910, SGC-7901, BEL-7402, HCT-116, and 786-O, with the respective IC50 below 10μg/ml. Treatment with EVn-50 or CHEMICAL resulted in arresting the MDA-MB-435 and SMMC-7721 cells at G2/M phase, which was further supported by observations of increased phosphorylation of Histone 3 at Ser10, phosphorylation of GENE at Tyr15, expression of cyclin B1, and decreased expression of Cdc25c. Moreover, we found that exposure of MDA-MB-435 cells to EVn-50 or CHEMICAL caused obvious apoptosis of MDA-MB-435 cells. Our data show that EVn-50, lignan compounds extracted from Vitex negundo, possesses a broad spectrum cytotoxic effect via arresting cancer cells at G2/M phase cell cycle and subsequently inducing apoptosis. | INHIBITOR |
| Lignans extracted from Vitex negundo possess cytotoxic activity by G2/M phase cell cycle arrest and apoptosis induction. CHEMICAL is a lignan compounds mixture extracted from Vitex negundo, a widely used herb in traditional Chinese medicine. This study is aimed to define the spectrum of cytotoxic activity of CHEMICAL, and also to investigate mechanisms underlying the anticancer actions via assessing the influence on cell cycle using CHEMICAL, and the lignan compound VB1 purified from CHEMICAL. The cytotoxic effect of CHEMICAL and VB1 was determined with SRB assay using a panel of cancer cell lines. Breast cancer cell line MDA-MB-435 and liver cancer cell line SMMC-7721 were selected for further evaluating the effect of CHEMICAL or VB1 on cell cycle by flow cytometric analysis. Apoptosis exerted by CHEMICAL or VB1 was measured by TUNEL assay and DAPI staining, and Western blot analysis was utilized to assess the influence on expression and phosphorylation of proteins which are closely related to cell cycle and apoptosis. CHEMICAL possessed a broad spectrum of in vitro anticancer activity for those tested cancer cells, especially sensitive to MDA-MB-435, SKOV-3, BXPC-3, SMMC-7721, MCF-7, HO-8910, SGC-7901, BEL-7402, HCT-116, and 786-O, with the respective IC50 below 10μg/ml. Treatment with CHEMICAL or VB1 resulted in arresting the MDA-MB-435 and SMMC-7721 cells at G2/M phase, which was further supported by observations of increased phosphorylation of Histone 3 at Ser10, phosphorylation of Cdk1 at Tyr15, expression of GENE, and decreased expression of Cdc25c. Moreover, we found that exposure of MDA-MB-435 cells to CHEMICAL or VB1 caused obvious apoptosis of MDA-MB-435 cells. Our data show that CHEMICAL, lignan compounds extracted from Vitex negundo, possesses a broad spectrum cytotoxic effect via arresting cancer cells at G2/M phase cell cycle and subsequently inducing apoptosis. | GENE-CHEMICAL |
| Lignans extracted from Vitex negundo possess cytotoxic activity by G2/M phase cell cycle arrest and apoptosis induction. Evn-50 is a lignan compounds mixture extracted from Vitex negundo, a widely used herb in traditional Chinese medicine. This study is aimed to define the spectrum of cytotoxic activity of EVn-50, and also to investigate mechanisms underlying the anticancer actions via assessing the influence on cell cycle using EVn-50, and the lignan compound CHEMICAL purified from EVn-50. The cytotoxic effect of EVn-50 and CHEMICAL was determined with SRB assay using a panel of cancer cell lines. Breast cancer cell line MDA-MB-435 and liver cancer cell line SMMC-7721 were selected for further evaluating the effect of EVn-50 or CHEMICAL on cell cycle by flow cytometric analysis. Apoptosis exerted by EVn-50 or CHEMICAL was measured by TUNEL assay and DAPI staining, and Western blot analysis was utilized to assess the influence on expression and phosphorylation of proteins which are closely related to cell cycle and apoptosis. EVn-50 possessed a broad spectrum of in vitro anticancer activity for those tested cancer cells, especially sensitive to MDA-MB-435, SKOV-3, BXPC-3, SMMC-7721, MCF-7, HO-8910, SGC-7901, BEL-7402, HCT-116, and 786-O, with the respective IC50 below 10μg/ml. Treatment with EVn-50 or CHEMICAL resulted in arresting the MDA-MB-435 and SMMC-7721 cells at G2/M phase, which was further supported by observations of increased phosphorylation of Histone 3 at Ser10, phosphorylation of Cdk1 at Tyr15, expression of GENE, and decreased expression of Cdc25c. Moreover, we found that exposure of MDA-MB-435 cells to EVn-50 or CHEMICAL caused obvious apoptosis of MDA-MB-435 cells. Our data show that EVn-50, lignan compounds extracted from Vitex negundo, possesses a broad spectrum cytotoxic effect via arresting cancer cells at G2/M phase cell cycle and subsequently inducing apoptosis. | INDIRECT-UPREGULATOR |
| Lignans extracted from Vitex negundo possess cytotoxic activity by G2/M phase cell cycle arrest and apoptosis induction. CHEMICAL is a lignan compounds mixture extracted from Vitex negundo, a widely used herb in traditional Chinese medicine. This study is aimed to define the spectrum of cytotoxic activity of CHEMICAL, and also to investigate mechanisms underlying the anticancer actions via assessing the influence on cell cycle using CHEMICAL, and the lignan compound VB1 purified from CHEMICAL. The cytotoxic effect of CHEMICAL and VB1 was determined with SRB assay using a panel of cancer cell lines. Breast cancer cell line MDA-MB-435 and liver cancer cell line SMMC-7721 were selected for further evaluating the effect of CHEMICAL or VB1 on cell cycle by flow cytometric analysis. Apoptosis exerted by CHEMICAL or VB1 was measured by TUNEL assay and DAPI staining, and Western blot analysis was utilized to assess the influence on expression and phosphorylation of proteins which are closely related to cell cycle and apoptosis. CHEMICAL possessed a broad spectrum of in vitro anticancer activity for those tested cancer cells, especially sensitive to MDA-MB-435, SKOV-3, BXPC-3, SMMC-7721, MCF-7, HO-8910, SGC-7901, BEL-7402, HCT-116, and 786-O, with the respective IC50 below 10μg/ml. Treatment with CHEMICAL or VB1 resulted in arresting the MDA-MB-435 and SMMC-7721 cells at G2/M phase, which was further supported by observations of increased phosphorylation of Histone 3 at Ser10, phosphorylation of Cdk1 at Tyr15, expression of cyclin B1, and decreased expression of GENE. Moreover, we found that exposure of MDA-MB-435 cells to CHEMICAL or VB1 caused obvious apoptosis of MDA-MB-435 cells. Our data show that CHEMICAL, lignan compounds extracted from Vitex negundo, possesses a broad spectrum cytotoxic effect via arresting cancer cells at G2/M phase cell cycle and subsequently inducing apoptosis. | INDIRECT-DOWNREGULATOR |
| Lignans extracted from Vitex negundo possess cytotoxic activity by G2/M phase cell cycle arrest and apoptosis induction. Evn-50 is a lignan compounds mixture extracted from Vitex negundo, a widely used herb in traditional Chinese medicine. This study is aimed to define the spectrum of cytotoxic activity of EVn-50, and also to investigate mechanisms underlying the anticancer actions via assessing the influence on cell cycle using EVn-50, and the lignan compound CHEMICAL purified from EVn-50. The cytotoxic effect of EVn-50 and CHEMICAL was determined with SRB assay using a panel of cancer cell lines. Breast cancer cell line MDA-MB-435 and liver cancer cell line SMMC-7721 were selected for further evaluating the effect of EVn-50 or CHEMICAL on cell cycle by flow cytometric analysis. Apoptosis exerted by EVn-50 or CHEMICAL was measured by TUNEL assay and DAPI staining, and Western blot analysis was utilized to assess the influence on expression and phosphorylation of proteins which are closely related to cell cycle and apoptosis. EVn-50 possessed a broad spectrum of in vitro anticancer activity for those tested cancer cells, especially sensitive to MDA-MB-435, SKOV-3, BXPC-3, SMMC-7721, MCF-7, HO-8910, SGC-7901, BEL-7402, HCT-116, and 786-O, with the respective IC50 below 10μg/ml. Treatment with EVn-50 or CHEMICAL resulted in arresting the MDA-MB-435 and SMMC-7721 cells at G2/M phase, which was further supported by observations of increased phosphorylation of Histone 3 at Ser10, phosphorylation of Cdk1 at Tyr15, expression of cyclin B1, and decreased expression of GENE. Moreover, we found that exposure of MDA-MB-435 cells to EVn-50 or CHEMICAL caused obvious apoptosis of MDA-MB-435 cells. Our data show that EVn-50, lignan compounds extracted from Vitex negundo, possesses a broad spectrum cytotoxic effect via arresting cancer cells at G2/M phase cell cycle and subsequently inducing apoptosis. | INDIRECT-DOWNREGULATOR |
| TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate. Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CHEMICAL. Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CHEMICAL and to determine the involvement of GENE, PKA, TRPV1, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. Results CHEMICAL was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4h after it was administered (200mg/kg). In the formalin test, two doses of CHEMICAL promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CHEMICAL. Pretreatment with CHEMICAL did not alter locomotor activity or motor coordination. In an investigation into the participation of TRP channels and ASICs in CAT's antinociceptive mechanism, we used capsaicin (2.2μg/paw), cinnamaldehyde (10mmol/paw), menthol (1.2mmol/paw) and acidified saline (2% acetic acid, pH 1.98). The results showed that TRPV1, TRPM8 and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of GENE and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CHEMICAL. Conclusion The results of this work contribute information regarding the antinociceptive properties of CHEMICAL on acute pain and show that, at least in part, TRPV1, TRPM8, ASIC, glutamate receptors, GENE and PKA participate in CAT's antinociceptive mechanism. | REGULATOR |
| TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate. Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CHEMICAL. Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CHEMICAL and to determine the involvement of PKC, GENE, TRPV1, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. Results CHEMICAL was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4h after it was administered (200mg/kg). In the formalin test, two doses of CHEMICAL promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CHEMICAL. Pretreatment with CHEMICAL did not alter locomotor activity or motor coordination. In an investigation into the participation of TRP channels and ASICs in CAT's antinociceptive mechanism, we used capsaicin (2.2μg/paw), cinnamaldehyde (10mmol/paw), menthol (1.2mmol/paw) and acidified saline (2% acetic acid, pH 1.98). The results showed that TRPV1, TRPM8 and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and GENE was also studied, and we showed that both play a role in the antinociceptive mechanism of CHEMICAL. Conclusion The results of this work contribute information regarding the antinociceptive properties of CHEMICAL on acute pain and show that, at least in part, TRPV1, TRPM8, ASIC, glutamate receptors, PKC and GENE participate in CAT's antinociceptive mechanism. | REGULATOR |
| TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate. Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CHEMICAL. Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CHEMICAL and to determine the involvement of PKC, PKA, GENE, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. Results CHEMICAL was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4h after it was administered (200mg/kg). In the formalin test, two doses of CHEMICAL promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CHEMICAL. Pretreatment with CHEMICAL did not alter locomotor activity or motor coordination. In an investigation into the participation of TRP channels and ASICs in CAT's antinociceptive mechanism, we used capsaicin (2.2μg/paw), cinnamaldehyde (10mmol/paw), menthol (1.2mmol/paw) and acidified saline (2% acetic acid, pH 1.98). The results showed that GENE, TRPM8 and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CHEMICAL. Conclusion The results of this work contribute information regarding the antinociceptive properties of CHEMICAL on acute pain and show that, at least in part, GENE, TRPM8, ASIC, glutamate receptors, PKC and PKA participate in CHEMICAL's antinociceptive mechanism. | REGULATOR |
| TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate. Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CHEMICAL. Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CHEMICAL and to determine the involvement of PKC, PKA, TRPV1, TRPA1, GENE and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. Results CHEMICAL was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4h after it was administered (200mg/kg). In the formalin test, two doses of CHEMICAL promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CHEMICAL. Pretreatment with CHEMICAL did not alter locomotor activity or motor coordination. In an investigation into the participation of TRP channels and ASICs in CAT's antinociceptive mechanism, we used capsaicin (2.2μg/paw), cinnamaldehyde (10mmol/paw), menthol (1.2mmol/paw) and acidified saline (2% acetic acid, pH 1.98). The results showed that TRPV1, GENE and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CHEMICAL. Conclusion The results of this work contribute information regarding the antinociceptive properties of CHEMICAL on acute pain and show that, at least in part, TRPV1, GENE, ASIC, glutamate receptors, PKC and PKA participate in CHEMICAL's antinociceptive mechanism. | REGULATOR |
| TRP and GENE channels mediate the antinociceptive effect of citronellyl acetate. Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CHEMICAL. Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CHEMICAL and to determine the involvement of PKC, PKA, TRPV1, TRPA1, TRPM8 and GENE in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. Results CHEMICAL was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4h after it was administered (200mg/kg). In the formalin test, two doses of CHEMICAL promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CHEMICAL. Pretreatment with CHEMICAL did not alter locomotor activity or motor coordination. In an investigation into the participation of TRP channels and ASICs in CAT's antinociceptive mechanism, we used capsaicin (2.2μg/paw), cinnamaldehyde (10mmol/paw), menthol (1.2mmol/paw) and acidified saline (2% acetic acid, pH 1.98). The results showed that TRPV1, TRPM8 and GENE, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CHEMICAL. Conclusion The results of this work contribute information regarding the antinociceptive properties of CHEMICAL on acute pain and show that, at least in part, TRPV1, TRPM8, GENE, glutamate receptors, PKC and PKA participate in CHEMICAL's antinociceptive mechanism. | REGULATOR |
| TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate. Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CHEMICAL. Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CHEMICAL and to determine the involvement of PKC, PKA, TRPV1, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. Results CHEMICAL was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4h after it was administered (200mg/kg). In the formalin test, two doses of CHEMICAL promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CHEMICAL. Pretreatment with CHEMICAL did not alter locomotor activity or motor coordination. In an investigation into the participation of TRP channels and ASICs in CAT's antinociceptive mechanism, we used capsaicin (2.2μg/paw), cinnamaldehyde (10mmol/paw), menthol (1.2mmol/paw) and acidified saline (2% acetic acid, pH 1.98). The results showed that TRPV1, TRPM8 and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CHEMICAL. Conclusion The results of this work contribute information regarding the antinociceptive properties of CHEMICAL on acute pain and show that, at least in part, TRPV1, TRPM8, ASIC, GENE, PKC and PKA participate in CHEMICAL's antinociceptive mechanism. | REGULATOR |
| TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate. Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CHEMICAL. Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CHEMICAL and to determine the involvement of PKC, PKA, TRPV1, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. Results CHEMICAL was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4h after it was administered (200mg/kg). In the formalin test, two doses of CHEMICAL promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CHEMICAL. Pretreatment with CHEMICAL did not alter locomotor activity or motor coordination. In an investigation into the participation of GENE and ASICs in CHEMICAL's antinociceptive mechanism, we used capsaicin (2.2μg/paw), cinnamaldehyde (10mmol/paw), menthol (1.2mmol/paw) and acidified saline (2% acetic acid, pH 1.98). The results showed that TRPV1, TRPM8 and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CHEMICAL. Conclusion The results of this work contribute information regarding the antinociceptive properties of CHEMICAL on acute pain and show that, at least in part, TRPV1, TRPM8, ASIC, glutamate receptors, PKC and PKA participate in CAT's antinociceptive mechanism. | REGULATOR |
| TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate. Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CHEMICAL. Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CHEMICAL and to determine the involvement of PKC, PKA, TRPV1, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. Results CHEMICAL was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4h after it was administered (200mg/kg). In the formalin test, two doses of CHEMICAL promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CHEMICAL. Pretreatment with CHEMICAL did not alter locomotor activity or motor coordination. In an investigation into the participation of TRP channels and GENE in CHEMICAL's antinociceptive mechanism, we used capsaicin (2.2μg/paw), cinnamaldehyde (10mmol/paw), menthol (1.2mmol/paw) and acidified saline (2% acetic acid, pH 1.98). The results showed that TRPV1, TRPM8 and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CHEMICAL. Conclusion The results of this work contribute information regarding the antinociceptive properties of CHEMICAL on acute pain and show that, at least in part, TRPV1, TRPM8, ASIC, glutamate receptors, PKC and PKA participate in CAT's antinociceptive mechanism. | REGULATOR |
| TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate. Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CAT. Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CAT and to determine the involvement of PKC, PKA, TRPV1, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. Results CAT was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4h after it was administered (200mg/kg). In the formalin test, two doses of CAT promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CAT. Pretreatment with CAT did not alter locomotor activity or motor coordination. In an investigation into the participation of GENE and ASICs in CAT's antinociceptive mechanism, we used CHEMICAL (2.2μg/paw), cinnamaldehyde (10mmol/paw), menthol (1.2mmol/paw) and acidified saline (2% acetic acid, pH 1.98). The results showed that TRPV1, TRPM8 and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CAT. Conclusion The results of this work contribute information regarding the antinociceptive properties of CAT on acute pain and show that, at least in part, TRPV1, TRPM8, ASIC, glutamate receptors, PKC and PKA participate in CAT's antinociceptive mechanism. | REGULATOR |
| TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate. Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CAT. Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CAT and to determine the involvement of PKC, PKA, TRPV1, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. Results CAT was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4h after it was administered (200mg/kg). In the formalin test, two doses of CAT promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CAT. Pretreatment with CAT did not alter locomotor activity or motor coordination. In an investigation into the participation of TRP channels and GENE in CAT's antinociceptive mechanism, we used CHEMICAL (2.2μg/paw), cinnamaldehyde (10mmol/paw), menthol (1.2mmol/paw) and acidified saline (2% acetic acid, pH 1.98). The results showed that TRPV1, TRPM8 and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CAT. Conclusion The results of this work contribute information regarding the antinociceptive properties of CAT on acute pain and show that, at least in part, TRPV1, TRPM8, ASIC, glutamate receptors, PKC and PKA participate in CAT's antinociceptive mechanism. | REGULATOR |
| TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate. Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CAT. Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CAT and to determine the involvement of PKC, PKA, TRPV1, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. Results CAT was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4h after it was administered (200mg/kg). In the formalin test, two doses of CAT promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CAT. Pretreatment with CAT did not alter locomotor activity or motor coordination. In an investigation into the participation of GENE and ASICs in CAT's antinociceptive mechanism, we used capsaicin (2.2μg/paw), CHEMICAL (10mmol/paw), menthol (1.2mmol/paw) and acidified saline (2% acetic acid, pH 1.98). The results showed that TRPV1, TRPM8 and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CAT. Conclusion The results of this work contribute information regarding the antinociceptive properties of CAT on acute pain and show that, at least in part, TRPV1, TRPM8, ASIC, glutamate receptors, PKC and PKA participate in CAT's antinociceptive mechanism. | REGULATOR |
| TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate. Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CAT. Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CAT and to determine the involvement of PKC, PKA, TRPV1, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. Results CAT was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4h after it was administered (200mg/kg). In the formalin test, two doses of CAT promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CAT. Pretreatment with CAT did not alter locomotor activity or motor coordination. In an investigation into the participation of TRP channels and GENE in CAT's antinociceptive mechanism, we used capsaicin (2.2μg/paw), CHEMICAL (10mmol/paw), menthol (1.2mmol/paw) and acidified saline (2% acetic acid, pH 1.98). The results showed that TRPV1, TRPM8 and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CAT. Conclusion The results of this work contribute information regarding the antinociceptive properties of CAT on acute pain and show that, at least in part, TRPV1, TRPM8, ASIC, glutamate receptors, PKC and PKA participate in CAT's antinociceptive mechanism. | REGULATOR |
| TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate. Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CAT. Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CAT and to determine the involvement of PKC, PKA, TRPV1, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. Results CAT was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4h after it was administered (200mg/kg). In the formalin test, two doses of CAT promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CAT. Pretreatment with CAT did not alter locomotor activity or motor coordination. In an investigation into the participation of GENE and ASICs in CAT's antinociceptive mechanism, we used capsaicin (2.2μg/paw), cinnamaldehyde (10mmol/paw), CHEMICAL (1.2mmol/paw) and acidified saline (2% acetic acid, pH 1.98). The results showed that TRPV1, TRPM8 and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CAT. Conclusion The results of this work contribute information regarding the antinociceptive properties of CAT on acute pain and show that, at least in part, TRPV1, TRPM8, ASIC, glutamate receptors, PKC and PKA participate in CAT's antinociceptive mechanism. | REGULATOR |
| TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate. Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CAT. Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CAT and to determine the involvement of PKC, PKA, TRPV1, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. Results CAT was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4h after it was administered (200mg/kg). In the formalin test, two doses of CAT promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CAT. Pretreatment with CAT did not alter locomotor activity or motor coordination. In an investigation into the participation of TRP channels and GENE in CAT's antinociceptive mechanism, we used capsaicin (2.2μg/paw), cinnamaldehyde (10mmol/paw), CHEMICAL (1.2mmol/paw) and acidified saline (2% acetic acid, pH 1.98). The results showed that TRPV1, TRPM8 and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CAT. Conclusion The results of this work contribute information regarding the antinociceptive properties of CAT on acute pain and show that, at least in part, TRPV1, TRPM8, ASIC, glutamate receptors, PKC and PKA participate in CAT's antinociceptive mechanism. | REGULATOR |
| TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate. Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CAT. Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CAT and to determine the involvement of PKC, PKA, TRPV1, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. Results CAT was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the CHEMICAL model; the highest dose reduced pain for 4h after it was administered (200mg/kg). In the formalin test, two doses of CAT promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CAT. Pretreatment with CAT did not alter locomotor activity or motor coordination. In an investigation into the participation of GENE and ASICs in CAT's antinociceptive mechanism, we used capsaicin (2.2μg/paw), cinnamaldehyde (10mmol/paw), menthol (1.2mmol/paw) and acidified saline (2% CHEMICAL, pH 1.98). The results showed that TRPV1, TRPM8 and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CAT. Conclusion The results of this work contribute information regarding the antinociceptive properties of CAT on acute pain and show that, at least in part, TRPV1, TRPM8, ASIC, glutamate receptors, PKC and PKA participate in CAT's antinociceptive mechanism. | REGULATOR |
| TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate. Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CAT. Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CAT and to determine the involvement of PKC, PKA, TRPV1, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. Results CAT was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the CHEMICAL model; the highest dose reduced pain for 4h after it was administered (200mg/kg). In the formalin test, two doses of CAT promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CAT. Pretreatment with CAT did not alter locomotor activity or motor coordination. In an investigation into the participation of TRP channels and GENE in CAT's antinociceptive mechanism, we used capsaicin (2.2μg/paw), cinnamaldehyde (10mmol/paw), menthol (1.2mmol/paw) and acidified saline (2% CHEMICAL, pH 1.98). The results showed that TRPV1, TRPM8 and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CAT. Conclusion The results of this work contribute information regarding the antinociceptive properties of CAT on acute pain and show that, at least in part, TRPV1, TRPM8, ASIC, glutamate receptors, PKC and PKA participate in CAT's antinociceptive mechanism. | REGULATOR |
| 2-Hydroxychalcone and xanthohumol inhibit invasion of triple negative breast cancer cells. Breast cancer is estimated as one of the most common causes of cancer death among women. In particular, triple negative breast cancers (TNBCs), which do not express the genes for estrogen/progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2), have been associated with poor prognosis and metastasis. Chalcones, the biosynthetic precursors of flavonoids present in edible plants, exert cytotoxic and chemopreventive activities. Although mounting evidence suggests the anticancer properties of chalcones, limited information is available regarding the inhibitory effects of chalcones on the aggressiveness of breast cancer cells. The present study aimed to investigate the effects of CHEMICAL and its derivatives on the growth and the invasiveness of TNBC cells. Here, we showed that treatment with CHEMICAL, 2-hydroxychalcone, and xanthohumol for 24h inhibited the growth of MDA-MB-231cells with IC50 values of 18.1, 4.6, and 6.7μM, respectively. Similarly, CHEMICAL, 2-hydroxychalcone, and xanthohumol also exerted cytotoxicity in another TNBC cell line, Hs578T. Neohesperidin dihydrochalcone, 4-methoxychalcone, and hesperidin methylchalcone did not show the cytotoxicity on the MDA-MB-231cells. Xanthohumol and 2-hydroxychalcone induced apoptosis by Bcl-2 downregulation. Importantly, 2-hydroxychalcone and xanthohumol exerted more potent inhibitory effects on the proliferation, GENE expression and invasive phenotype of MDA-MB-231 than CHEMICAL. These results suggest a potential application of these chalcones as anticancer agents that can alleviate malignant progression of TNBC. | INDIRECT-DOWNREGULATOR |
| 2-Hydroxychalcone and xanthohumol inhibit invasion of triple negative breast cancer cells. Breast cancer is estimated as one of the most common causes of cancer death among women. In particular, triple negative breast cancers (TNBCs), which do not express the genes for estrogen/progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2), have been associated with poor prognosis and metastasis. Chalcones, the biosynthetic precursors of flavonoids present in edible plants, exert cytotoxic and chemopreventive activities. Although mounting evidence suggests the anticancer properties of chalcones, limited information is available regarding the inhibitory effects of chalcones on the aggressiveness of breast cancer cells. The present study aimed to investigate the effects of chalcone and its derivatives on the growth and the invasiveness of TNBC cells. Here, we showed that treatment with chalcone, 2-hydroxychalcone, and xanthohumol for 24h inhibited the growth of MDA-MB-231cells with IC50 values of 18.1, 4.6, and 6.7μM, respectively. Similarly, Chalcone, 2-hydroxychalcone, and xanthohumol also exerted cytotoxicity in another TNBC cell line, Hs578T. Neohesperidin dihydrochalcone, 4-methoxychalcone, and hesperidin methylchalcone did not show the cytotoxicity on the MDA-MB-231cells. CHEMICAL and 2-hydroxychalcone induced apoptosis by GENE downregulation. Importantly, 2-hydroxychalcone and xanthohumol exerted more potent inhibitory effects on the proliferation, MMP-9 expression and invasive phenotype of MDA-MB-231 than chalcone. These results suggest a potential application of these chalcones as anticancer agents that can alleviate malignant progression of TNBC. | ACTIVATOR |
| 2-Hydroxychalcone and xanthohumol inhibit invasion of triple negative breast cancer cells. Breast cancer is estimated as one of the most common causes of cancer death among women. In particular, triple negative breast cancers (TNBCs), which do not express the genes for estrogen/progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2), have been associated with poor prognosis and metastasis. Chalcones, the biosynthetic precursors of flavonoids present in edible plants, exert cytotoxic and chemopreventive activities. Although mounting evidence suggests the anticancer properties of chalcones, limited information is available regarding the inhibitory effects of chalcones on the aggressiveness of breast cancer cells. The present study aimed to investigate the effects of chalcone and its derivatives on the growth and the invasiveness of TNBC cells. Here, we showed that treatment with chalcone, CHEMICAL, and xanthohumol for 24h inhibited the growth of MDA-MB-231cells with IC50 values of 18.1, 4.6, and 6.7μM, respectively. Similarly, Chalcone, CHEMICAL, and xanthohumol also exerted cytotoxicity in another TNBC cell line, Hs578T. Neohesperidin dihydrochalcone, 4-methoxychalcone, and hesperidin methylchalcone did not show the cytotoxicity on the MDA-MB-231cells. Xanthohumol and CHEMICAL induced apoptosis by GENE downregulation. Importantly, CHEMICAL and xanthohumol exerted more potent inhibitory effects on the proliferation, MMP-9 expression and invasive phenotype of MDA-MB-231 than chalcone. These results suggest a potential application of these chalcones as anticancer agents that can alleviate malignant progression of TNBC. | ACTIVATOR |
| 2-Hydroxychalcone and xanthohumol inhibit invasion of triple negative breast cancer cells. Breast cancer is estimated as one of the most common causes of cancer death among women. In particular, triple negative breast cancers (TNBCs), which do not express the genes for estrogen/progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2), have been associated with poor prognosis and metastasis. Chalcones, the biosynthetic precursors of flavonoids present in edible plants, exert cytotoxic and chemopreventive activities. Although mounting evidence suggests the anticancer properties of chalcones, limited information is available regarding the inhibitory effects of chalcones on the aggressiveness of breast cancer cells. The present study aimed to investigate the effects of chalcone and its derivatives on the growth and the invasiveness of TNBC cells. Here, we showed that treatment with chalcone, CHEMICAL, and xanthohumol for 24h inhibited the growth of MDA-MB-231cells with IC50 values of 18.1, 4.6, and 6.7μM, respectively. Similarly, Chalcone, CHEMICAL, and xanthohumol also exerted cytotoxicity in another TNBC cell line, Hs578T. Neohesperidin dihydrochalcone, 4-methoxychalcone, and hesperidin methylchalcone did not show the cytotoxicity on the MDA-MB-231cells. Xanthohumol and CHEMICAL induced apoptosis by Bcl-2 downregulation. Importantly, CHEMICAL and xanthohumol exerted more potent inhibitory effects on the proliferation, GENE expression and invasive phenotype of MDA-MB-231 than chalcone. These results suggest a potential application of these chalcones as anticancer agents that can alleviate malignant progression of TNBC. | INDIRECT-DOWNREGULATOR |
| 2-Hydroxychalcone and CHEMICAL inhibit invasion of triple negative breast cancer cells. Breast cancer is estimated as one of the most common causes of cancer death among women. In particular, triple negative breast cancers (TNBCs), which do not express the genes for estrogen/progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2), have been associated with poor prognosis and metastasis. Chalcones, the biosynthetic precursors of flavonoids present in edible plants, exert cytotoxic and chemopreventive activities. Although mounting evidence suggests the anticancer properties of chalcones, limited information is available regarding the inhibitory effects of chalcones on the aggressiveness of breast cancer cells. The present study aimed to investigate the effects of chalcone and its derivatives on the growth and the invasiveness of TNBC cells. Here, we showed that treatment with chalcone, 2-hydroxychalcone, and CHEMICAL for 24h inhibited the growth of MDA-MB-231cells with IC50 values of 18.1, 4.6, and 6.7μM, respectively. Similarly, Chalcone, 2-hydroxychalcone, and CHEMICAL also exerted cytotoxicity in another TNBC cell line, Hs578T. Neohesperidin dihydrochalcone, 4-methoxychalcone, and hesperidin methylchalcone did not show the cytotoxicity on the MDA-MB-231cells. CHEMICAL and 2-hydroxychalcone induced apoptosis by Bcl-2 downregulation. Importantly, 2-hydroxychalcone and CHEMICAL exerted more potent inhibitory effects on the proliferation, GENE expression and invasive phenotype of MDA-MB-231 than chalcone. These results suggest a potential application of these chalcones as anticancer agents that can alleviate malignant progression of TNBC. | INDIRECT-DOWNREGULATOR |
| 4-Hydroxypyridazin-3(2H)-one Derivatives as Novel d-Amino Acid Oxidase Inhibitors. d-Amino acid oxidase (DAAO) catalyzes the oxidation of d-amino acids including d-serine, a coagonist of the N-methyl-d-aspartate receptor. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel DAAO inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. CHEMICAL exhibited the predicted binding mode and demonstrated high inhibitory activity for GENE in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze. | INHIBITOR |
| CHEMICAL Derivatives as Novel GENE Inhibitors. d-Amino acid oxidase (DAAO) catalyzes the oxidation of d-amino acids including d-serine, a coagonist of the N-methyl-d-aspartate receptor. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel DAAO inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. 3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human DAAO in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze. | INHIBITOR |
| 4-Hydroxypyridazin-3(2H)-one Derivatives as Novel d-Amino Acid Oxidase Inhibitors. d-Amino acid oxidase (DAAO) catalyzes the oxidation of d-amino acids including d-serine, a coagonist of the N-methyl-d-aspartate receptor. We identified a series of CHEMICAL derivatives as novel GENE inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. 3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human GENE in enzyme- and cell-based assays. We further designed and synthesized CHEMICAL derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze. | INHIBITOR |
| 4-Hydroxypyridazin-3(2H)-one Derivatives as Novel d-Amino Acid Oxidase Inhibitors. d-Amino acid oxidase (DAAO) catalyzes the oxidation of d-amino acids including CHEMICAL, a coagonist of the GENE. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel DAAO inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. 3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human DAAO in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze. | SUBSTRATE |
| 4-Hydroxypyridazin-3(2H)-one Derivatives as Novel d-Amino Acid Oxidase Inhibitors. GENE (DAAO) catalyzes the oxidation of d-amino acids including CHEMICAL, a coagonist of the N-methyl-d-aspartate receptor. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel DAAO inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. 3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human DAAO in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze. | SUBSTRATE |
| 4-Hydroxypyridazin-3(2H)-one Derivatives as Novel d-Amino Acid Oxidase Inhibitors. d-Amino acid oxidase (GENE) catalyzes the oxidation of d-amino acids including CHEMICAL, a coagonist of the N-methyl-d-aspartate receptor. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel GENE inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. 3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human GENE in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze. | SUBSTRATE |
| 4-Hydroxypyridazin-3(2H)-one Derivatives as Novel d-Amino Acid Oxidase Inhibitors. GENE (DAAO) catalyzes the oxidation of CHEMICAL including d-serine, a coagonist of the N-methyl-d-aspartate receptor. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel DAAO inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. 3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human DAAO in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze. | SUBSTRATE |
| 4-Hydroxypyridazin-3(2H)-one Derivatives as Novel d-Amino Acid Oxidase Inhibitors. d-Amino acid oxidase (GENE) catalyzes the oxidation of CHEMICAL including d-serine, a coagonist of the N-methyl-d-aspartate receptor. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel GENE inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. 3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human GENE in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze. | SUBSTRATE |
| Comparative study on transcriptional activity of 17 CHEMICAL mediated by estrogen receptor α and β and androgen receptor. The structure-activity relationships of CHEMICAL which are widely used as preservatives for transcriptional activities mediated by human estrogen receptor α (hERα), hERβ and androgen receptor (hAR) were investigated. Fourteen of 17 CHEMICAL exhibited hERα and/or hERβ agonistic activity at concentrations of ⩽1×10(-5)M, whereas none of the 17 CHEMICAL showed GENE agonistic or antagonistic activity. Among 12 CHEMICAL with linear alkyl chains ranging in length from C1 to C12, heptylparaben (C7) and pentylparaben (C5) showed the most potent ERα and ERβ agonistic activity in the order of 10(-7)M and 10(-8)M, respectively, and the activities decreased in a stepwise manner as the alkyl chain was shortened to C1 or lengthened to C12. Most CHEMICAL showing estrogenic activity exhibited ERβ-agonistic activity at lower concentrations than those inducing ERα-agonistic activity. The estrogenic activity of butylparaben was markedly decreased by incubation with rat liver microsomes, and the decrease of activity was blocked by a carboxylesterase inhibitor. These results indicate that CHEMICAL are selective agonists for ERβ over ERα; their interactions with ERα/β are dependent on the size and bulkiness of the alkyl groups; and they are metabolized by carboxylesterases, leading to attenuation of their estrogenic activity. | NO-RELATIONSHIP |
| Comparative study on transcriptional activity of 17 CHEMICAL mediated by estrogen receptor α and β and GENE. The structure-activity relationships of CHEMICAL which are widely used as preservatives for transcriptional activities mediated by human estrogen receptor α (hERα), hERβ and GENE (hAR) were investigated. Fourteen of 17 CHEMICAL exhibited hERα and/or hERβ agonistic activity at concentrations of ⩽1×10(-5)M, whereas none of the 17 CHEMICAL showed AR agonistic or antagonistic activity. Among 12 CHEMICAL with linear alkyl chains ranging in length from C1 to C12, heptylparaben (C7) and pentylparaben (C5) showed the most potent ERα and ERβ agonistic activity in the order of 10(-7)M and 10(-8)M, respectively, and the activities decreased in a stepwise manner as the alkyl chain was shortened to C1 or lengthened to C12. Most CHEMICAL showing estrogenic activity exhibited ERβ-agonistic activity at lower concentrations than those inducing ERα-agonistic activity. The estrogenic activity of butylparaben was markedly decreased by incubation with rat liver microsomes, and the decrease of activity was blocked by a carboxylesterase inhibitor. These results indicate that CHEMICAL are selective agonists for ERβ over ERα; their interactions with ERα/β are dependent on the size and bulkiness of the alkyl groups; and they are metabolized by carboxylesterases, leading to attenuation of their estrogenic activity. | REGULATOR |
| Comparative study on transcriptional activity of 17 parabens mediated by estrogen receptor α and β and androgen receptor. The structure-activity relationships of parabens which are widely used as preservatives for transcriptional activities mediated by human estrogen receptor α (hERα), hERβ and androgen receptor (hAR) were investigated. Fourteen of 17 parabens exhibited hERα and/or hERβ agonistic activity at concentrations of ⩽1×10(-5)M, whereas none of the 17 parabens showed AR agonistic or antagonistic activity. Among 12 parabens with linear alkyl chains ranging in length from C1 to C12, CHEMICAL (C7) and pentylparaben (C5) showed the most potent GENE and ERβ agonistic activity in the order of 10(-7)M and 10(-8)M, respectively, and the activities decreased in a stepwise manner as the alkyl chain was shortened to C1 or lengthened to C12. Most parabens showing estrogenic activity exhibited ERβ-agonistic activity at lower concentrations than those inducing ERα-agonistic activity. The estrogenic activity of butylparaben was markedly decreased by incubation with rat liver microsomes, and the decrease of activity was blocked by a carboxylesterase inhibitor. These results indicate that parabens are selective agonists for ERβ over ERα; their interactions with ERα/β are dependent on the size and bulkiness of the alkyl groups; and they are metabolized by carboxylesterases, leading to attenuation of their estrogenic activity. | ACTIVATOR |
| Comparative study on transcriptional activity of 17 parabens mediated by estrogen receptor α and β and androgen receptor. The structure-activity relationships of parabens which are widely used as preservatives for transcriptional activities mediated by human estrogen receptor α (hERα), hERβ and androgen receptor (hAR) were investigated. Fourteen of 17 parabens exhibited hERα and/or hERβ agonistic activity at concentrations of ⩽1×10(-5)M, whereas none of the 17 parabens showed AR agonistic or antagonistic activity. Among 12 parabens with linear alkyl chains ranging in length from C1 to C12, CHEMICAL (C7) and pentylparaben (C5) showed the most potent ERα and GENE agonistic activity in the order of 10(-7)M and 10(-8)M, respectively, and the activities decreased in a stepwise manner as the alkyl chain was shortened to C1 or lengthened to C12. Most parabens showing estrogenic activity exhibited ERβ-agonistic activity at lower concentrations than those inducing ERα-agonistic activity. The estrogenic activity of butylparaben was markedly decreased by incubation with rat liver microsomes, and the decrease of activity was blocked by a carboxylesterase inhibitor. These results indicate that parabens are selective agonists for GENE over ERα; their interactions with ERα/β are dependent on the size and bulkiness of the alkyl groups; and they are metabolized by carboxylesterases, leading to attenuation of their estrogenic activity. | ACTIVATOR |
| Comparative study on transcriptional activity of 17 parabens mediated by estrogen receptor α and β and androgen receptor. The structure-activity relationships of parabens which are widely used as preservatives for transcriptional activities mediated by human estrogen receptor α (hERα), hERβ and androgen receptor (hAR) were investigated. Fourteen of 17 parabens exhibited hERα and/or hERβ agonistic activity at concentrations of ⩽1×10(-5)M, whereas none of the 17 parabens showed AR agonistic or antagonistic activity. Among 12 parabens with linear alkyl chains ranging in length from C1 to C12, heptylparaben (C7) and CHEMICAL (C5) showed the most potent GENE and ERβ agonistic activity in the order of 10(-7)M and 10(-8)M, respectively, and the activities decreased in a stepwise manner as the alkyl chain was shortened to C1 or lengthened to C12. Most parabens showing estrogenic activity exhibited ERβ-agonistic activity at lower concentrations than those inducing ERα-agonistic activity. The estrogenic activity of butylparaben was markedly decreased by incubation with rat liver microsomes, and the decrease of activity was blocked by a carboxylesterase inhibitor. These results indicate that parabens are selective agonists for ERβ over ERα; their interactions with ERα/β are dependent on the size and bulkiness of the alkyl groups; and they are metabolized by carboxylesterases, leading to attenuation of their estrogenic activity. | ACTIVATOR |
| Comparative study on transcriptional activity of 17 parabens mediated by estrogen receptor α and β and androgen receptor. The structure-activity relationships of parabens which are widely used as preservatives for transcriptional activities mediated by human estrogen receptor α (hERα), hERβ and androgen receptor (hAR) were investigated. Fourteen of 17 parabens exhibited hERα and/or hERβ agonistic activity at concentrations of ⩽1×10(-5)M, whereas none of the 17 parabens showed AR agonistic or antagonistic activity. Among 12 parabens with linear alkyl chains ranging in length from C1 to C12, heptylparaben (C7) and CHEMICAL (C5) showed the most potent ERα and GENE agonistic activity in the order of 10(-7)M and 10(-8)M, respectively, and the activities decreased in a stepwise manner as the alkyl chain was shortened to C1 or lengthened to C12. Most parabens showing estrogenic activity exhibited ERβ-agonistic activity at lower concentrations than those inducing ERα-agonistic activity. The estrogenic activity of butylparaben was markedly decreased by incubation with rat liver microsomes, and the decrease of activity was blocked by a carboxylesterase inhibitor. These results indicate that parabens are selective agonists for GENE over ERα; their interactions with ERα/β are dependent on the size and bulkiness of the alkyl groups; and they are metabolized by carboxylesterases, leading to attenuation of their estrogenic activity. | ACTIVATOR |
| Comparative study on transcriptional activity of 17 CHEMICAL mediated by estrogen receptor α and β and androgen receptor. The structure-activity relationships of CHEMICAL which are widely used as preservatives for transcriptional activities mediated by human estrogen receptor α (hERα), hERβ and androgen receptor (hAR) were investigated. Fourteen of 17 CHEMICAL exhibited hERα and/or hERβ agonistic activity at concentrations of ⩽1×10(-5)M, whereas none of the 17 CHEMICAL showed AR agonistic or antagonistic activity. Among 12 CHEMICAL with linear alkyl chains ranging in length from C1 to C12, heptylparaben (C7) and pentylparaben (C5) showed the most potent ERα and GENE agonistic activity in the order of 10(-7)M and 10(-8)M, respectively, and the activities decreased in a stepwise manner as the alkyl chain was shortened to C1 or lengthened to C12. Most CHEMICAL showing estrogenic activity exhibited GENE-agonistic activity at lower concentrations than those inducing ERα-agonistic activity. The estrogenic activity of butylparaben was markedly decreased by incubation with rat liver microsomes, and the decrease of activity was blocked by a carboxylesterase inhibitor. These results indicate that CHEMICAL are selective agonists for GENE over ERα; their interactions with ERα/β are dependent on the size and bulkiness of the alkyl groups; and they are metabolized by carboxylesterases, leading to attenuation of their estrogenic activity. | ACTIVATOR |
| Comparative study on transcriptional activity of 17 CHEMICAL mediated by estrogen receptor α and β and androgen receptor. The structure-activity relationships of CHEMICAL which are widely used as preservatives for transcriptional activities mediated by human estrogen receptor α (hERα), hERβ and androgen receptor (hAR) were investigated. Fourteen of 17 CHEMICAL exhibited hERα and/or hERβ agonistic activity at concentrations of ⩽1×10(-5)M, whereas none of the 17 CHEMICAL showed AR agonistic or antagonistic activity. Among 12 CHEMICAL with linear alkyl chains ranging in length from C1 to C12, heptylparaben (C7) and pentylparaben (C5) showed the most potent GENE and ERβ agonistic activity in the order of 10(-7)M and 10(-8)M, respectively, and the activities decreased in a stepwise manner as the alkyl chain was shortened to C1 or lengthened to C12. Most CHEMICAL showing estrogenic activity exhibited ERβ-agonistic activity at lower concentrations than those inducing GENE-agonistic activity. The estrogenic activity of butylparaben was markedly decreased by incubation with rat liver microsomes, and the decrease of activity was blocked by a carboxylesterase inhibitor. These results indicate that CHEMICAL are selective agonists for ERβ over ERα; their interactions with ERα/β are dependent on the size and bulkiness of the alkyl groups; and they are metabolized by carboxylesterases, leading to attenuation of their estrogenic activity. | ACTIVATOR |
| Comparative study on transcriptional activity of 17 CHEMICAL mediated by estrogen receptor α and β and androgen receptor. The structure-activity relationships of CHEMICAL which are widely used as preservatives for transcriptional activities mediated by human estrogen receptor α (hERα), hERβ and androgen receptor (hAR) were investigated. Fourteen of 17 CHEMICAL exhibited GENE and/or hERβ agonistic activity at concentrations of ⩽1×10(-5)M, whereas none of the 17 CHEMICAL showed AR agonistic or antagonistic activity. Among 12 CHEMICAL with linear alkyl chains ranging in length from C1 to C12, heptylparaben (C7) and pentylparaben (C5) showed the most potent ERα and ERβ agonistic activity in the order of 10(-7)M and 10(-8)M, respectively, and the activities decreased in a stepwise manner as the alkyl chain was shortened to C1 or lengthened to C12. Most CHEMICAL showing estrogenic activity exhibited ERβ-agonistic activity at lower concentrations than those inducing ERα-agonistic activity. The estrogenic activity of butylparaben was markedly decreased by incubation with rat liver microsomes, and the decrease of activity was blocked by a carboxylesterase inhibitor. These results indicate that CHEMICAL are selective agonists for ERβ over ERα; their interactions with ERα/β are dependent on the size and bulkiness of the alkyl groups; and they are metabolized by carboxylesterases, leading to attenuation of their estrogenic activity. | ACTIVATOR |
| Comparative study on transcriptional activity of 17 CHEMICAL mediated by estrogen receptor α and β and androgen receptor. The structure-activity relationships of CHEMICAL which are widely used as preservatives for transcriptional activities mediated by human estrogen receptor α (hERα), GENE and androgen receptor (hAR) were investigated. Fourteen of 17 CHEMICAL exhibited hERα and/or GENE agonistic activity at concentrations of ⩽1×10(-5)M, whereas none of the 17 CHEMICAL showed AR agonistic or antagonistic activity. Among 12 CHEMICAL with linear alkyl chains ranging in length from C1 to C12, heptylparaben (C7) and pentylparaben (C5) showed the most potent ERα and ERβ agonistic activity in the order of 10(-7)M and 10(-8)M, respectively, and the activities decreased in a stepwise manner as the alkyl chain was shortened to C1 or lengthened to C12. Most CHEMICAL showing estrogenic activity exhibited ERβ-agonistic activity at lower concentrations than those inducing ERα-agonistic activity. The estrogenic activity of butylparaben was markedly decreased by incubation with rat liver microsomes, and the decrease of activity was blocked by a carboxylesterase inhibitor. These results indicate that CHEMICAL are selective agonists for ERβ over ERα; their interactions with ERα/β are dependent on the size and bulkiness of the alkyl groups; and they are metabolized by carboxylesterases, leading to attenuation of their estrogenic activity. | ACTIVATOR |
| Comparative study on transcriptional activity of 17 parabens mediated by estrogen receptor α and β and androgen receptor. The structure-activity relationships of parabens which are widely used as preservatives for transcriptional activities mediated by human estrogen receptor α (hERα), hERβ and androgen receptor (hAR) were investigated. Fourteen of 17 parabens exhibited hERα and/or hERβ agonistic activity at concentrations of ⩽1×10(-5)M, whereas none of the 17 parabens showed AR agonistic or antagonistic activity. Among 12 parabens with linear CHEMICAL chains ranging in length from C1 to C12, heptylparaben (C7) and pentylparaben (C5) showed the most potent GENE and ERβ agonistic activity in the order of 10(-7)M and 10(-8)M, respectively, and the activities decreased in a stepwise manner as the CHEMICAL chain was shortened to C1 or lengthened to C12. Most parabens showing estrogenic activity exhibited ERβ-agonistic activity at lower concentrations than those inducing ERα-agonistic activity. The estrogenic activity of butylparaben was markedly decreased by incubation with rat liver microsomes, and the decrease of activity was blocked by a carboxylesterase inhibitor. These results indicate that parabens are selective agonists for ERβ over ERα; their interactions with ERα/β are dependent on the size and bulkiness of the CHEMICAL groups; and they are metabolized by carboxylesterases, leading to attenuation of their estrogenic activity. | ACTIVATOR |
| Comparative study on transcriptional activity of 17 parabens mediated by estrogen receptor α and β and androgen receptor. The structure-activity relationships of parabens which are widely used as preservatives for transcriptional activities mediated by human estrogen receptor α (hERα), hERβ and androgen receptor (hAR) were investigated. Fourteen of 17 parabens exhibited hERα and/or hERβ agonistic activity at concentrations of ⩽1×10(-5)M, whereas none of the 17 parabens showed AR agonistic or antagonistic activity. Among 12 parabens with linear CHEMICAL chains ranging in length from C1 to C12, heptylparaben (C7) and pentylparaben (C5) showed the most potent ERα and GENE agonistic activity in the order of 10(-7)M and 10(-8)M, respectively, and the activities decreased in a stepwise manner as the CHEMICAL chain was shortened to C1 or lengthened to C12. Most parabens showing estrogenic activity exhibited ERβ-agonistic activity at lower concentrations than those inducing ERα-agonistic activity. The estrogenic activity of butylparaben was markedly decreased by incubation with rat liver microsomes, and the decrease of activity was blocked by a carboxylesterase inhibitor. These results indicate that parabens are selective agonists for GENE over ERα; their interactions with ERα/β are dependent on the size and bulkiness of the CHEMICAL groups; and they are metabolized by carboxylesterases, leading to attenuation of their estrogenic activity. | ACTIVATOR |
| Comparative study on transcriptional activity of 17 CHEMICAL mediated by estrogen receptor α and β and androgen receptor. The structure-activity relationships of CHEMICAL which are widely used as preservatives for transcriptional activities mediated by human estrogen receptor α (hERα), hERβ and androgen receptor (hAR) were investigated. Fourteen of 17 CHEMICAL exhibited hERα and/or hERβ agonistic activity at concentrations of ⩽1×10(-5)M, whereas none of the 17 CHEMICAL showed AR agonistic or antagonistic activity. Among 12 CHEMICAL with linear alkyl chains ranging in length from C1 to C12, heptylparaben (C7) and pentylparaben (C5) showed the most potent ERα and ERβ agonistic activity in the order of 10(-7)M and 10(-8)M, respectively, and the activities decreased in a stepwise manner as the alkyl chain was shortened to C1 or lengthened to C12. Most CHEMICAL showing estrogenic activity exhibited ERβ-agonistic activity at lower concentrations than those inducing ERα-agonistic activity. The estrogenic activity of butylparaben was markedly decreased by incubation with rat liver microsomes, and the decrease of activity was blocked by a carboxylesterase inhibitor. These results indicate that CHEMICAL are selective agonists for ERβ over ERα; their interactions with ERα/β are dependent on the size and bulkiness of the alkyl groups; and they are metabolized by GENE, leading to attenuation of their estrogenic activity. | SUBSTRATE |
| In vivo and in vitro anti-inflammatory potential of pentahydroxy-pregn-14-ol, 20-one-β-d-thevetopyranoside in rats. Polyhydroxy pregnane glycoside (PPG), a CHEMICAL was isolated from Wattakaka volubilis Linn. (Stap.f.). PPG was evaluated for in vivo and in vitro anti-inflammatory activity using acute inflammation and chronic model of inflammation in rats and LPS-induced RAW 264.7 macrophage cells. PPG seemed to be responsible for the anti-inflammatory activity in the studied models. PPG at dose level of both 5 and 10mg/kg significantly reduced the edema induced by the carrageenan in acute model of inflammation. It also showed significant anti-proliferative effect (dry pellet weight basis) in chronic model of inflammation. Cellular content of granuloma was measured by assaying activity of N-acetyl glucosaminidase (NAG) and total nucleic acid content. PPG at 5 and 10mg/kg significantly suppressed the cellular infiltration measured by total nucleic acid content. In contrast, NAG activity decreased over a period of 10 days resulting in inhibition of granuloma weight gain. PPG had a more effective response than the reference drug diclofenac sodium in both the models of inflammation. Wattakaka volubilis CHEMICAL mixture (WVSM) and PPG (1-50μM) significantly inhibited the GENE and iNOS enzymes resulting in low levels of PGE2 and NO in LPS-induced RAW 264.7 macrophage cells. Hence the study supports the traditional use of Wattakaka volubilis and its constituent PPG in treatment of inflammatory disorders. | INDIRECT-DOWNREGULATOR |
| In vivo and in vitro anti-inflammatory potential of pentahydroxy-pregn-14-ol, 20-one-β-d-thevetopyranoside in rats. Polyhydroxy pregnane glycoside (PPG), a CHEMICAL was isolated from Wattakaka volubilis Linn. (Stap.f.). PPG was evaluated for in vivo and in vitro anti-inflammatory activity using acute inflammation and chronic model of inflammation in rats and LPS-induced RAW 264.7 macrophage cells. PPG seemed to be responsible for the anti-inflammatory activity in the studied models. PPG at dose level of both 5 and 10mg/kg significantly reduced the edema induced by the carrageenan in acute model of inflammation. It also showed significant anti-proliferative effect (dry pellet weight basis) in chronic model of inflammation. Cellular content of granuloma was measured by assaying activity of N-acetyl glucosaminidase (NAG) and total nucleic acid content. PPG at 5 and 10mg/kg significantly suppressed the cellular infiltration measured by total nucleic acid content. In contrast, NAG activity decreased over a period of 10 days resulting in inhibition of granuloma weight gain. PPG had a more effective response than the reference drug diclofenac sodium in both the models of inflammation. Wattakaka volubilis CHEMICAL mixture (WVSM) and PPG (1-50μM) significantly inhibited the COX-2 and GENE enzymes resulting in low levels of PGE2 and NO in LPS-induced RAW 264.7 macrophage cells. Hence the study supports the traditional use of Wattakaka volubilis and its constituent PPG in treatment of inflammatory disorders. | INHIBITOR |
| In vivo and in vitro anti-inflammatory potential of pentahydroxy-pregn-14-ol, 20-one-β-d-thevetopyranoside in rats. Polyhydroxy pregnane glycoside (PPG), a steroidal glycoside was isolated from Wattakaka volubilis Linn. (Stap.f.). CHEMICAL was evaluated for in vivo and in vitro anti-inflammatory activity using acute inflammation and chronic model of inflammation in rats and LPS-induced RAW 264.7 macrophage cells. CHEMICAL seemed to be responsible for the anti-inflammatory activity in the studied models. CHEMICAL at dose level of both 5 and 10mg/kg significantly reduced the edema induced by the carrageenan in acute model of inflammation. It also showed significant anti-proliferative effect (dry pellet weight basis) in chronic model of inflammation. Cellular content of granuloma was measured by assaying activity of N-acetyl glucosaminidase (NAG) and total nucleic acid content. CHEMICAL at 5 and 10mg/kg significantly suppressed the cellular infiltration measured by total nucleic acid content. In contrast, NAG activity decreased over a period of 10 days resulting in inhibition of granuloma weight gain. CHEMICAL had a more effective response than the reference drug diclofenac sodium in both the models of inflammation. Wattakaka volubilis steroidal glycoside mixture (WVSM) and CHEMICAL (1-50μM) significantly inhibited the GENE and iNOS enzymes resulting in low levels of PGE2 and NO in LPS-induced RAW 264.7 macrophage cells. Hence the study supports the traditional use of Wattakaka volubilis and its constituent CHEMICAL in treatment of inflammatory disorders. | INDIRECT-DOWNREGULATOR |
| In vivo and in vitro anti-inflammatory potential of pentahydroxy-pregn-14-ol, 20-one-β-d-thevetopyranoside in rats. Polyhydroxy pregnane glycoside (PPG), a steroidal glycoside was isolated from Wattakaka volubilis Linn. (Stap.f.). CHEMICAL was evaluated for in vivo and in vitro anti-inflammatory activity using acute inflammation and chronic model of inflammation in rats and LPS-induced RAW 264.7 macrophage cells. CHEMICAL seemed to be responsible for the anti-inflammatory activity in the studied models. CHEMICAL at dose level of both 5 and 10mg/kg significantly reduced the edema induced by the carrageenan in acute model of inflammation. It also showed significant anti-proliferative effect (dry pellet weight basis) in chronic model of inflammation. Cellular content of granuloma was measured by assaying activity of N-acetyl glucosaminidase (NAG) and total nucleic acid content. CHEMICAL at 5 and 10mg/kg significantly suppressed the cellular infiltration measured by total nucleic acid content. In contrast, NAG activity decreased over a period of 10 days resulting in inhibition of granuloma weight gain. CHEMICAL had a more effective response than the reference drug diclofenac sodium in both the models of inflammation. Wattakaka volubilis steroidal glycoside mixture (WVSM) and CHEMICAL (1-50μM) significantly inhibited the COX-2 and GENE enzymes resulting in low levels of PGE2 and NO in LPS-induced RAW 264.7 macrophage cells. Hence the study supports the traditional use of Wattakaka volubilis and its constituent CHEMICAL in treatment of inflammatory disorders. | INHIBITOR |
| Hypermethylation of P15, P16, and GENE genes in ovarian cancer. Both p16 and p15 proteins are inhibitors of cyclin-dependent kinases that prevent the cell going through the G1/S phase transaction. GENE is a transmembrane glycoprotein that mediates CHEMICAL-dependent interactions between adjacent epithelial cells. Two groups of patients were selected: the first group suffered from epithelial serous ovarian tumors and the second group suffered from benign ovarian lesions; ovarian tissue samples from all the subjects (benign and malignant) were subjected to methylation-specific polymerase chain reaction for methylated and unmethylated alleles of the genes (E-cadherin, p15, and p16). Results obtained showed that aberrant methylation of p15 and p16 genes were detected in 64.29 and 50% of ovarian cancer patients, while GENE hypermethylation was detected in 78.57% of ovarian cancer patients. Methylation of GENE was significantly correlated with different stage of disease (p < 0.05). It was found that the risk of GENE hypermethylation was 1.347-fold, while risk of p15 hypermethylation was 1.543-fold and p16 was 1.2-fold among patients with ovarian cancer than that among patients with benign ovarian lesions. In conclusion, Dysfunction of the cell cycle and/or the cell-cell adhesion molecule plays a role in the pathogenesis of ovarian cancer and that the analysis of the methylation of p15 and GENE genes can provide clinically important evidence on which to base the treatment. | REGULATOR |
| Quercetin suppressed CYP2E1-dependent CHEMICAL hepatotoxicity via depleting heme pool and releasing CO. Naturally occuring quercetin protects hepatocytes from ethanol-induced oxidative stress, and heme oxygenase-1 (HO-1) induction and carbon monoxide (CO) metabolite may be implicated in the beneficial effect. However, the precise mechanism by which quercetin counteracts GENE-mediated CHEMICAL hepatotoxicity through HO-1 system is still remained unclear. To explore the potential mechanism, herein, CHEMICAL (4.0g/kg.bw.) was administrated to rats for 90 days. Our data showed that chronic CHEMICAL over-activated GENE but suppressed HO-1 with concurrent hepatic oxidative damage, which was partially normalized by quercetin (100mg/kg.bw.). Quercetin (100μM) induced HO-1 and depleted heme pool when incubated to human hepatocytes. Ethanol-stimulated (100mM) GENE upregulation was suppressed by quercetin but further enhanced by HO-1 inhibition with resultant heme accumulation. CO scavenging blocked the suppression of quercetin only on GENE activity. CO donor dose-dependently inactivated GENE of ethanol-incubated microsome, which was mimicked by HO-1 substrate but abolished by CO scavenger. Thus, CYP2E1-mediated CHEMICAL hepatotoxicity was alleviated by quercetin through HO-1 induction. Depleted heme pool and CO releasing limited protein synthesis and inhibited enzymatic activity of GENE, respectively. | ACTIVATOR |
| CHEMICAL suppressed CYP2E1-dependent ethanol hepatotoxicity via depleting heme pool and releasing CO. Naturally occuring CHEMICAL protects hepatocytes from ethanol-induced oxidative stress, and heme oxygenase-1 (HO-1) induction and carbon monoxide (CO) metabolite may be implicated in the beneficial effect. However, the precise mechanism by which CHEMICAL counteracts CYP2E1-mediated ethanol hepatotoxicity through HO-1 system is still remained unclear. To explore the potential mechanism, herein, ethanol (4.0g/kg.bw.) was administrated to rats for 90 days. Our data showed that chronic ethanol over-activated GENE but suppressed HO-1 with concurrent hepatic oxidative damage, which was partially normalized by CHEMICAL (100mg/kg.bw.). CHEMICAL (100μM) induced HO-1 and depleted heme pool when incubated to human hepatocytes. Ethanol-stimulated (100mM) GENE upregulation was suppressed by CHEMICAL but further enhanced by HO-1 inhibition with resultant heme accumulation. CO scavenging blocked the suppression of CHEMICAL only on GENE activity. CO donor dose-dependently inactivated GENE of ethanol-incubated microsome, which was mimicked by HO-1 substrate but abolished by CO scavenger. Thus, CYP2E1-mediated ethanol hepatotoxicity was alleviated by CHEMICAL through HO-1 induction. Depleted heme pool and CO releasing limited protein synthesis and inhibited enzymatic activity of GENE, respectively. | INDIRECT-DOWNREGULATOR |
| CHEMICAL suppressed CYP2E1-dependent ethanol hepatotoxicity via depleting heme pool and releasing CO. Naturally occuring CHEMICAL protects hepatocytes from ethanol-induced oxidative stress, and heme oxygenase-1 (HO-1) induction and carbon monoxide (CO) metabolite may be implicated in the beneficial effect. However, the precise mechanism by which CHEMICAL counteracts CYP2E1-mediated ethanol hepatotoxicity through GENE system is still remained unclear. To explore the potential mechanism, herein, ethanol (4.0g/kg.bw.) was administrated to rats for 90 days. Our data showed that chronic ethanol over-activated CYP2E1 but suppressed GENE with concurrent hepatic oxidative damage, which was partially normalized by CHEMICAL (100mg/kg.bw.). CHEMICAL (100μM) induced GENE and depleted heme pool when incubated to human hepatocytes. Ethanol-stimulated (100mM) CYP2E1 upregulation was suppressed by CHEMICAL but further enhanced by GENE inhibition with resultant heme accumulation. CO scavenging blocked the suppression of CHEMICAL only on CYP2E1 activity. CO donor dose-dependently inactivated CYP2E1 of ethanol-incubated microsome, which was mimicked by GENE substrate but abolished by CO scavenger. Thus, CYP2E1-mediated ethanol hepatotoxicity was alleviated by CHEMICAL through GENE induction. Depleted heme pool and CO releasing limited protein synthesis and inhibited enzymatic activity of CYP2E1, respectively. | ACTIVATOR |
| Quercetin suppressed CYP2E1-dependent CHEMICAL hepatotoxicity via depleting heme pool and releasing CO. Naturally occuring quercetin protects hepatocytes from ethanol-induced oxidative stress, and heme oxygenase-1 (HO-1) induction and carbon monoxide (CO) metabolite may be implicated in the beneficial effect. However, the precise mechanism by which quercetin counteracts CYP2E1-mediated CHEMICAL hepatotoxicity through GENE system is still remained unclear. To explore the potential mechanism, herein, CHEMICAL (4.0g/kg.bw.) was administrated to rats for 90 days. Our data showed that chronic CHEMICAL over-activated CYP2E1 but suppressed GENE with concurrent hepatic oxidative damage, which was partially normalized by quercetin (100mg/kg.bw.). Quercetin (100μM) induced GENE and depleted heme pool when incubated to human hepatocytes. Ethanol-stimulated (100mM) CYP2E1 upregulation was suppressed by quercetin but further enhanced by GENE inhibition with resultant heme accumulation. CO scavenging blocked the suppression of quercetin only on CYP2E1 activity. CO donor dose-dependently inactivated CYP2E1 of ethanol-incubated microsome, which was mimicked by GENE substrate but abolished by CO scavenger. Thus, CYP2E1-mediated CHEMICAL hepatotoxicity was alleviated by quercetin through GENE induction. Depleted heme pool and CO releasing limited protein synthesis and inhibited enzymatic activity of CYP2E1, respectively. | INHIBITOR |
| Quercetin suppressed CYP2E1-dependent ethanol hepatotoxicity via depleting heme pool and releasing CHEMICAL. Naturally occuring quercetin protects hepatocytes from ethanol-induced oxidative stress, and heme oxygenase-1 (HO-1) induction and carbon monoxide (CO) metabolite may be implicated in the beneficial effect. However, the precise mechanism by which quercetin counteracts CYP2E1-mediated ethanol hepatotoxicity through HO-1 system is still remained unclear. To explore the potential mechanism, herein, ethanol (4.0g/kg.bw.) was administrated to rats for 90 days. Our data showed that chronic ethanol over-activated GENE but suppressed HO-1 with concurrent hepatic oxidative damage, which was partially normalized by quercetin (100mg/kg.bw.). Quercetin (100μM) induced HO-1 and depleted heme pool when incubated to human hepatocytes. Ethanol-stimulated (100mM) GENE upregulation was suppressed by quercetin but further enhanced by HO-1 inhibition with resultant heme accumulation. CHEMICAL scavenging blocked the suppression of quercetin only on GENE activity. CHEMICAL donor dose-dependently inactivated GENE of ethanol-incubated microsome, which was mimicked by HO-1 substrate but abolished by CHEMICAL scavenger. Thus, CYP2E1-mediated ethanol hepatotoxicity was alleviated by quercetin through HO-1 induction. Depleted heme pool and CHEMICAL releasing limited protein synthesis and inhibited enzymatic activity of GENE, respectively. | INHIBITOR |
| Quercetin suppressed CYP2E1-dependent ethanol hepatotoxicity via depleting heme pool and releasing CO. Naturally occuring quercetin protects hepatocytes from ethanol-induced oxidative stress, and heme oxygenase-1 (HO-1) induction and carbon monoxide (CO) metabolite may be implicated in the beneficial effect. However, the precise mechanism by which quercetin counteracts CYP2E1-mediated ethanol hepatotoxicity through GENE system is still remained unclear. To explore the potential mechanism, herein, ethanol (4.0g/kg.bw.) was administrated to rats for 90 days. Our data showed that chronic ethanol over-activated CYP2E1 but suppressed GENE with concurrent hepatic oxidative damage, which was partially normalized by quercetin (100mg/kg.bw.). Quercetin (100μM) induced GENE and depleted heme pool when incubated to human hepatocytes. CHEMICAL-stimulated (100mM) CYP2E1 upregulation was suppressed by quercetin but further enhanced by GENE inhibition with resultant heme accumulation. CO scavenging blocked the suppression of quercetin only on CYP2E1 activity. CO donor dose-dependently inactivated CYP2E1 of ethanol-incubated microsome, which was mimicked by GENE substrate but abolished by CO scavenger. Thus, CYP2E1-mediated ethanol hepatotoxicity was alleviated by quercetin through GENE induction. Depleted heme pool and CO releasing limited protein synthesis and inhibited enzymatic activity of CYP2E1, respectively. | ACTIVATOR |
| Quercetin suppressed CYP2E1-dependent ethanol hepatotoxicity via depleting CHEMICAL pool and releasing CO. Naturally occuring quercetin protects hepatocytes from ethanol-induced oxidative stress, and CHEMICAL oxygenase-1 (HO-1) induction and carbon monoxide (CO) metabolite may be implicated in the beneficial effect. However, the precise mechanism by which quercetin counteracts CYP2E1-mediated ethanol hepatotoxicity through GENE system is still remained unclear. To explore the potential mechanism, herein, ethanol (4.0g/kg.bw.) was administrated to rats for 90 days. Our data showed that chronic ethanol over-activated CYP2E1 but suppressed GENE with concurrent hepatic oxidative damage, which was partially normalized by quercetin (100mg/kg.bw.). Quercetin (100μM) induced GENE and depleted CHEMICAL pool when incubated to human hepatocytes. Ethanol-stimulated (100mM) CYP2E1 upregulation was suppressed by quercetin but further enhanced by GENE inhibition with resultant CHEMICAL accumulation. CO scavenging blocked the suppression of quercetin only on CYP2E1 activity. CO donor dose-dependently inactivated CYP2E1 of ethanol-incubated microsome, which was mimicked by GENE substrate but abolished by CO scavenger. Thus, CYP2E1-mediated ethanol hepatotoxicity was alleviated by quercetin through GENE induction. Depleted CHEMICAL pool and CO releasing limited protein synthesis and inhibited enzymatic activity of CYP2E1, respectively. | PRODUCT-OF |
| Novel racemic CHEMICAL analogues as potent GENE inhibitors. The synthesis of racemic tetrahydrocurcumin- (THC-), tetrahydrodemethoxycurcumin- (THDC-) and tetrahydrobisdemethoxycurcumin- (THBDC-) dihydropyrimidinone (DHPM) analogues was achieved by utilizing the multi-component Biginelli reaction in the presence of copper sulphate as a catalyst. The evaluation of GENE inhibitors for Alzheimer's disease of these compounds showed that they exhibited higher inhibitory activity than their parent analogues. THBDC-DHPM demonstrated the most potent inhibitory activity with an IC50 value of 1.34±0.03μM which was more active than the approved drug galanthamine (IC50=1.45±0.04μM). | INHIBITOR |
| Agonistic activity of CHEMICAL 182 780 on activation of GSK 3β/AKT pathway in the rat uterus during the estrous cycle. We examined the ability of CHEMICAL 182,780 (ICI) to block uterine cell proliferation via protein kinase b/AKT pathway in the uterus of the rat during the estrous cycle. Intact rats, with regular estrous cycles, received a subcutaneous (s.c.) injection of either vehicle or CHEMICAL at 08:00h on the day of proestrus or at 00:00h on the day of estrus and sacrificed at 13:00h of metaestrus. Estradiol (E2) and progesterone (P4) plasma levels were measured by radioimmunoassay. Both CHEMICAL treatments, induced a significant decrease (p<0.01) in uterine estrogen receptor alpha (ERα) content, had no effect on uterine GENE (PR) protein expression and caused marked nuclear localization of cyclin D1, in both luminal and glandular uterine epithelium, as compared to vehicle-treated animals. Furthermore, we detected that CHEMICAL treatment induced glycogen synthase kinase (Gsk3-β) Ser 9 phosphorylation, which correlates with cyclin D1 nuclear localization. However, some differences were observed between the two different time schedules of administration. We observed that the administration of CHEMICAL at 08:00h on proestrus day produced a 15% inhibition of luminal epithelial cell proliferation, reduced uterine wet weight by 21% and caused reduction of Akt phosphorylation at Ser 473 as compared to vehicle-treated animals, whereas CHEMICAL treatment at 00:00h on estrus day had no effect on these parameters. The overall results indicate that CHEMICAL may exert agonistic and antagonistic effects on uterine cell proliferation through differential activation of the Akt pathway depending on the administration period during the estrous cycle, and indicates that the mechanism of cell proliferation during the physiological conditions of the estrous cycle, is under a different and more complex regulation than in the ovariectomized +E2 animal model. | NO-RELATIONSHIP |
| Agonistic activity of CHEMICAL 182 780 on activation of GSK 3β/AKT pathway in the rat uterus during the estrous cycle. We examined the ability of CHEMICAL 182,780 (ICI) to block uterine cell proliferation via protein kinase b/AKT pathway in the uterus of the rat during the estrous cycle. Intact rats, with regular estrous cycles, received a subcutaneous (s.c.) injection of either vehicle or CHEMICAL at 08:00h on the day of proestrus or at 00:00h on the day of estrus and sacrificed at 13:00h of metaestrus. Estradiol (E2) and progesterone (P4) plasma levels were measured by radioimmunoassay. Both CHEMICAL treatments, induced a significant decrease (p<0.01) in uterine estrogen receptor alpha (ERα) content, had no effect on uterine progesterone receptor (GENE) protein expression and caused marked nuclear localization of cyclin D1, in both luminal and glandular uterine epithelium, as compared to vehicle-treated animals. Furthermore, we detected that CHEMICAL treatment induced glycogen synthase kinase (Gsk3-β) Ser 9 phosphorylation, which correlates with cyclin D1 nuclear localization. However, some differences were observed between the two different time schedules of administration. We observed that the administration of CHEMICAL at 08:00h on proestrus day produced a 15% inhibition of luminal epithelial cell proliferation, reduced uterine wet weight by 21% and caused reduction of Akt phosphorylation at Ser 473 as compared to vehicle-treated animals, whereas CHEMICAL treatment at 00:00h on estrus day had no effect on these parameters. The overall results indicate that CHEMICAL may exert agonistic and antagonistic effects on uterine cell proliferation through differential activation of the Akt pathway depending on the administration period during the estrous cycle, and indicates that the mechanism of cell proliferation during the physiological conditions of the estrous cycle, is under a different and more complex regulation than in the ovariectomized +E2 animal model. | NO-RELATIONSHIP |
| Agonistic activity of ICI 182 780 on activation of GSK 3β/AKT pathway in the rat uterus during the estrous cycle. We examined the ability of ICI 182,780 (ICI) to block uterine cell proliferation via protein kinase b/AKT pathway in the uterus of the rat during the estrous cycle. Intact rats, with regular estrous cycles, received a subcutaneous (s.c.) injection of either vehicle or ICI at 08:00h on the day of proestrus or at 00:00h on the day of estrus and sacrificed at 13:00h of metaestrus. Estradiol (E2) and progesterone (P4) plasma levels were measured by radioimmunoassay. Both ICI treatments, induced a significant decrease (p<0.01) in uterine estrogen receptor alpha (ERα) content, had no effect on uterine progesterone receptor (PR) protein expression and caused marked nuclear localization of cyclin D1, in both luminal and glandular uterine epithelium, as compared to vehicle-treated animals. Furthermore, we detected that ICI treatment induced glycogen synthase kinase (Gsk3-β) CHEMICAL 9 phosphorylation, which correlates with cyclin D1 nuclear localization. However, some differences were observed between the two different time schedules of administration. We observed that the administration of ICI at 08:00h on proestrus day produced a 15% inhibition of luminal epithelial cell proliferation, reduced uterine wet weight by 21% and caused reduction of GENE phosphorylation at CHEMICAL 473 as compared to vehicle-treated animals, whereas ICI treatment at 00:00h on estrus day had no effect on these parameters. The overall results indicate that ICI may exert agonistic and antagonistic effects on uterine cell proliferation through differential activation of the GENE pathway depending on the administration period during the estrous cycle, and indicates that the mechanism of cell proliferation during the physiological conditions of the estrous cycle, is under a different and more complex regulation than in the ovariectomized +E2 animal model. | PART-OF |
| Agonistic activity of CHEMICAL 182 780 on activation of GSK 3β/AKT pathway in the rat uterus during the estrous cycle. We examined the ability of CHEMICAL 182,780 (ICI) to block uterine cell proliferation via protein kinase b/AKT pathway in the uterus of the rat during the estrous cycle. Intact rats, with regular estrous cycles, received a subcutaneous (s.c.) injection of either vehicle or CHEMICAL at 08:00h on the day of proestrus or at 00:00h on the day of estrus and sacrificed at 13:00h of metaestrus. Estradiol (E2) and progesterone (P4) plasma levels were measured by radioimmunoassay. Both CHEMICAL treatments, induced a significant decrease (p<0.01) in uterine estrogen receptor alpha (ERα) content, had no effect on uterine progesterone receptor (PR) protein expression and caused marked nuclear localization of GENE, in both luminal and glandular uterine epithelium, as compared to vehicle-treated animals. Furthermore, we detected that CHEMICAL treatment induced glycogen synthase kinase (Gsk3-β) Ser 9 phosphorylation, which correlates with GENE nuclear localization. However, some differences were observed between the two different time schedules of administration. We observed that the administration of CHEMICAL at 08:00h on proestrus day produced a 15% inhibition of luminal epithelial cell proliferation, reduced uterine wet weight by 21% and caused reduction of Akt phosphorylation at Ser 473 as compared to vehicle-treated animals, whereas CHEMICAL treatment at 00:00h on estrus day had no effect on these parameters. The overall results indicate that CHEMICAL may exert agonistic and antagonistic effects on uterine cell proliferation through differential activation of the Akt pathway depending on the administration period during the estrous cycle, and indicates that the mechanism of cell proliferation during the physiological conditions of the estrous cycle, is under a different and more complex regulation than in the ovariectomized +E2 animal model. | GENE-CHEMICAL |
| Agonistic activity of CHEMICAL 182 780 on activation of GSK 3β/AKT pathway in the rat uterus during the estrous cycle. We examined the ability of CHEMICAL 182,780 (ICI) to block uterine cell proliferation via protein kinase b/AKT pathway in the uterus of the rat during the estrous cycle. Intact rats, with regular estrous cycles, received a subcutaneous (s.c.) injection of either vehicle or CHEMICAL at 08:00h on the day of proestrus or at 00:00h on the day of estrus and sacrificed at 13:00h of metaestrus. Estradiol (E2) and progesterone (P4) plasma levels were measured by radioimmunoassay. Both CHEMICAL treatments, induced a significant decrease (p<0.01) in uterine estrogen receptor alpha (ERα) content, had no effect on uterine progesterone receptor (PR) protein expression and caused marked nuclear localization of cyclin D1, in both luminal and glandular uterine epithelium, as compared to vehicle-treated animals. Furthermore, we detected that CHEMICAL treatment induced GENE (Gsk3-β) Ser 9 phosphorylation, which correlates with cyclin D1 nuclear localization. However, some differences were observed between the two different time schedules of administration. We observed that the administration of CHEMICAL at 08:00h on proestrus day produced a 15% inhibition of luminal epithelial cell proliferation, reduced uterine wet weight by 21% and caused reduction of Akt phosphorylation at Ser 473 as compared to vehicle-treated animals, whereas CHEMICAL treatment at 00:00h on estrus day had no effect on these parameters. The overall results indicate that CHEMICAL may exert agonistic and antagonistic effects on uterine cell proliferation through differential activation of the Akt pathway depending on the administration period during the estrous cycle, and indicates that the mechanism of cell proliferation during the physiological conditions of the estrous cycle, is under a different and more complex regulation than in the ovariectomized +E2 animal model. | ACTIVATOR |
| Agonistic activity of CHEMICAL 182 780 on activation of GSK 3β/AKT pathway in the rat uterus during the estrous cycle. We examined the ability of CHEMICAL 182,780 (ICI) to block uterine cell proliferation via protein kinase b/AKT pathway in the uterus of the rat during the estrous cycle. Intact rats, with regular estrous cycles, received a subcutaneous (s.c.) injection of either vehicle or CHEMICAL at 08:00h on the day of proestrus or at 00:00h on the day of estrus and sacrificed at 13:00h of metaestrus. Estradiol (E2) and progesterone (P4) plasma levels were measured by radioimmunoassay. Both CHEMICAL treatments, induced a significant decrease (p<0.01) in uterine estrogen receptor alpha (ERα) content, had no effect on uterine progesterone receptor (PR) protein expression and caused marked nuclear localization of cyclin D1, in both luminal and glandular uterine epithelium, as compared to vehicle-treated animals. Furthermore, we detected that CHEMICAL treatment induced glycogen synthase kinase (GENE) Ser 9 phosphorylation, which correlates with cyclin D1 nuclear localization. However, some differences were observed between the two different time schedules of administration. We observed that the administration of CHEMICAL at 08:00h on proestrus day produced a 15% inhibition of luminal epithelial cell proliferation, reduced uterine wet weight by 21% and caused reduction of Akt phosphorylation at Ser 473 as compared to vehicle-treated animals, whereas CHEMICAL treatment at 00:00h on estrus day had no effect on these parameters. The overall results indicate that CHEMICAL may exert agonistic and antagonistic effects on uterine cell proliferation through differential activation of the Akt pathway depending on the administration period during the estrous cycle, and indicates that the mechanism of cell proliferation during the physiological conditions of the estrous cycle, is under a different and more complex regulation than in the ovariectomized +E2 animal model. | ACTIVATOR |
| Agonistic activity of CHEMICAL on activation of GSK 3β/GENE pathway in the rat uterus during the estrous cycle. We examined the ability of ICI 182,780 (ICI) to block uterine cell proliferation via protein kinase b/AKT pathway in the uterus of the rat during the estrous cycle. Intact rats, with regular estrous cycles, received a subcutaneous (s.c.) injection of either vehicle or ICI at 08:00h on the day of proestrus or at 00:00h on the day of estrus and sacrificed at 13:00h of metaestrus. Estradiol (E2) and progesterone (P4) plasma levels were measured by radioimmunoassay. Both ICI treatments, induced a significant decrease (p<0.01) in uterine estrogen receptor alpha (ERα) content, had no effect on uterine progesterone receptor (PR) protein expression and caused marked nuclear localization of cyclin D1, in both luminal and glandular uterine epithelium, as compared to vehicle-treated animals. Furthermore, we detected that ICI treatment induced glycogen synthase kinase (Gsk3-β) Ser 9 phosphorylation, which correlates with cyclin D1 nuclear localization. However, some differences were observed between the two different time schedules of administration. We observed that the administration of ICI at 08:00h on proestrus day produced a 15% inhibition of luminal epithelial cell proliferation, reduced uterine wet weight by 21% and caused reduction of GENE phosphorylation at Ser 473 as compared to vehicle-treated animals, whereas ICI treatment at 00:00h on estrus day had no effect on these parameters. The overall results indicate that ICI may exert agonistic and antagonistic effects on uterine cell proliferation through differential activation of the GENE pathway depending on the administration period during the estrous cycle, and indicates that the mechanism of cell proliferation during the physiological conditions of the estrous cycle, is under a different and more complex regulation than in the ovariectomized +E2 animal model. | ACTIVATOR |
| Agonistic activity of CHEMICAL 182 780 on activation of GSK 3β/AKT pathway in the rat uterus during the estrous cycle. We examined the ability of CHEMICAL 182,780 (ICI) to block uterine cell proliferation via protein kinase b/AKT pathway in the uterus of the rat during the estrous cycle. Intact rats, with regular estrous cycles, received a subcutaneous (s.c.) injection of either vehicle or CHEMICAL at 08:00h on the day of proestrus or at 00:00h on the day of estrus and sacrificed at 13:00h of metaestrus. Estradiol (E2) and progesterone (P4) plasma levels were measured by radioimmunoassay. Both CHEMICAL treatments, induced a significant decrease (p<0.01) in uterine estrogen receptor alpha (ERα) content, had no effect on uterine progesterone receptor (PR) protein expression and caused marked nuclear localization of cyclin D1, in both luminal and glandular uterine epithelium, as compared to vehicle-treated animals. Furthermore, we detected that CHEMICAL treatment induced glycogen synthase kinase (Gsk3-β) Ser 9 phosphorylation, which correlates with cyclin D1 nuclear localization. However, some differences were observed between the two different time schedules of administration. We observed that the administration of CHEMICAL at 08:00h on proestrus day produced a 15% inhibition of luminal epithelial cell proliferation, reduced uterine wet weight by 21% and caused reduction of GENE phosphorylation at Ser 473 as compared to vehicle-treated animals, whereas CHEMICAL treatment at 00:00h on estrus day had no effect on these parameters. The overall results indicate that CHEMICAL may exert agonistic and antagonistic effects on uterine cell proliferation through differential activation of the GENE pathway depending on the administration period during the estrous cycle, and indicates that the mechanism of cell proliferation during the physiological conditions of the estrous cycle, is under a different and more complex regulation than in the ovariectomized +E2 animal model. | ACTIVATOR |
| Agonistic activity of CHEMICAL 182 780 on activation of GSK 3β/AKT pathway in the rat uterus during the estrous cycle. We examined the ability of CHEMICAL 182,780 (ICI) to block uterine cell proliferation via protein kinase b/AKT pathway in the uterus of the rat during the estrous cycle. Intact rats, with regular estrous cycles, received a subcutaneous (s.c.) injection of either vehicle or CHEMICAL at 08:00h on the day of proestrus or at 00:00h on the day of estrus and sacrificed at 13:00h of metaestrus. Estradiol (E2) and progesterone (P4) plasma levels were measured by radioimmunoassay. Both CHEMICAL treatments, induced a significant decrease (p<0.01) in uterine GENE (ERα) content, had no effect on uterine progesterone receptor (PR) protein expression and caused marked nuclear localization of cyclin D1, in both luminal and glandular uterine epithelium, as compared to vehicle-treated animals. Furthermore, we detected that CHEMICAL treatment induced glycogen synthase kinase (Gsk3-β) Ser 9 phosphorylation, which correlates with cyclin D1 nuclear localization. However, some differences were observed between the two different time schedules of administration. We observed that the administration of CHEMICAL at 08:00h on proestrus day produced a 15% inhibition of luminal epithelial cell proliferation, reduced uterine wet weight by 21% and caused reduction of Akt phosphorylation at Ser 473 as compared to vehicle-treated animals, whereas CHEMICAL treatment at 00:00h on estrus day had no effect on these parameters. The overall results indicate that CHEMICAL may exert agonistic and antagonistic effects on uterine cell proliferation through differential activation of the Akt pathway depending on the administration period during the estrous cycle, and indicates that the mechanism of cell proliferation during the physiological conditions of the estrous cycle, is under a different and more complex regulation than in the ovariectomized +E2 animal model. | INDIRECT-DOWNREGULATOR |
| Agonistic activity of CHEMICAL 182 780 on activation of GSK 3β/AKT pathway in the rat uterus during the estrous cycle. We examined the ability of CHEMICAL 182,780 (ICI) to block uterine cell proliferation via protein kinase b/AKT pathway in the uterus of the rat during the estrous cycle. Intact rats, with regular estrous cycles, received a subcutaneous (s.c.) injection of either vehicle or CHEMICAL at 08:00h on the day of proestrus or at 00:00h on the day of estrus and sacrificed at 13:00h of metaestrus. Estradiol (E2) and progesterone (P4) plasma levels were measured by radioimmunoassay. Both CHEMICAL treatments, induced a significant decrease (p<0.01) in uterine estrogen receptor alpha (GENE) content, had no effect on uterine progesterone receptor (PR) protein expression and caused marked nuclear localization of cyclin D1, in both luminal and glandular uterine epithelium, as compared to vehicle-treated animals. Furthermore, we detected that CHEMICAL treatment induced glycogen synthase kinase (Gsk3-β) Ser 9 phosphorylation, which correlates with cyclin D1 nuclear localization. However, some differences were observed between the two different time schedules of administration. We observed that the administration of CHEMICAL at 08:00h on proestrus day produced a 15% inhibition of luminal epithelial cell proliferation, reduced uterine wet weight by 21% and caused reduction of Akt phosphorylation at Ser 473 as compared to vehicle-treated animals, whereas CHEMICAL treatment at 00:00h on estrus day had no effect on these parameters. The overall results indicate that CHEMICAL may exert agonistic and antagonistic effects on uterine cell proliferation through differential activation of the Akt pathway depending on the administration period during the estrous cycle, and indicates that the mechanism of cell proliferation during the physiological conditions of the estrous cycle, is under a different and more complex regulation than in the ovariectomized +E2 animal model. | INDIRECT-DOWNREGULATOR |
| Agonistic activity of CHEMICAL on activation of GENE/AKT pathway in the rat uterus during the estrous cycle. We examined the ability of ICI 182,780 (ICI) to block uterine cell proliferation via protein kinase b/AKT pathway in the uterus of the rat during the estrous cycle. Intact rats, with regular estrous cycles, received a subcutaneous (s.c.) injection of either vehicle or ICI at 08:00h on the day of proestrus or at 00:00h on the day of estrus and sacrificed at 13:00h of metaestrus. Estradiol (E2) and progesterone (P4) plasma levels were measured by radioimmunoassay. Both ICI treatments, induced a significant decrease (p<0.01) in uterine estrogen receptor alpha (ERα) content, had no effect on uterine progesterone receptor (PR) protein expression and caused marked nuclear localization of cyclin D1, in both luminal and glandular uterine epithelium, as compared to vehicle-treated animals. Furthermore, we detected that ICI treatment induced glycogen synthase kinase (Gsk3-β) Ser 9 phosphorylation, which correlates with cyclin D1 nuclear localization. However, some differences were observed between the two different time schedules of administration. We observed that the administration of ICI at 08:00h on proestrus day produced a 15% inhibition of luminal epithelial cell proliferation, reduced uterine wet weight by 21% and caused reduction of Akt phosphorylation at Ser 473 as compared to vehicle-treated animals, whereas ICI treatment at 00:00h on estrus day had no effect on these parameters. The overall results indicate that ICI may exert agonistic and antagonistic effects on uterine cell proliferation through differential activation of the Akt pathway depending on the administration period during the estrous cycle, and indicates that the mechanism of cell proliferation during the physiological conditions of the estrous cycle, is under a different and more complex regulation than in the ovariectomized +E2 animal model. | ACTIVATOR |
| CHEMICAL derived from Grundmann's ketone as a novel chemotype of oxidosqualene cyclase inhibitors. A series of CHEMICAL, designed as mimics of a cationic high energy intermediate in the oxidosqualene cyclase(1) (GENE)-mediated cyclization of 2,3-oxidosqualen to lanosterol was prepared from Grundmann's ketone. Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds. A N,N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi GENE in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line. | INHIBITOR |
| CHEMICAL derived from Grundmann's ketone as a novel chemotype of oxidosqualene cyclase inhibitors. A series of CHEMICAL, designed as mimics of a cationic high energy intermediate in the GENE (OSC)-mediated cyclization of 2,3-oxidosqualen to lanosterol was prepared from Grundmann's ketone. Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds. A N,N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi OSC in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line. | INHIBITOR |
| Aminopropylindenes derived from Grundmann's ketone as a novel chemotype of oxidosqualene cyclase inhibitors. A series of aminopropylindenes, designed as mimics of a cationic high energy intermediate in the oxidosqualene cyclase(1) (OSC)-mediated cyclization of 2,3-oxidosqualen to lanosterol was prepared from Grundmann's ketone. Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds. A CHEMICAL derivative showed promising inhibition of GENE in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line. | INHIBITOR |
| CHEMICAL derived from Grundmann's ketone as a novel chemotype of GENE inhibitors. A series of aminopropylindenes, designed as mimics of a cationic high energy intermediate in the oxidosqualene cyclase(1) (OSC)-mediated cyclization of 2,3-oxidosqualen to lanosterol was prepared from Grundmann's ketone. Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds. A N,N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi OSC in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line. | INHIBITOR |
| Aminopropylindenes derived from CHEMICAL as a novel chemotype of GENE inhibitors. A series of aminopropylindenes, designed as mimics of a cationic high energy intermediate in the oxidosqualene cyclase(1) (OSC)-mediated cyclization of 2,3-oxidosqualen to lanosterol was prepared from CHEMICAL. Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds. A N,N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi OSC in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line. | INHIBITOR |
| Aminopropylindenes derived from Grundmann's ketone as a novel chemotype of oxidosqualene cyclase inhibitors. A series of aminopropylindenes, designed as mimics of a cationic high energy intermediate in the oxidosqualene cyclase(1) (GENE)-mediated cyclization of 2,3-oxidosqualen to CHEMICAL was prepared from Grundmann's ketone. Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds. A N,N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi GENE in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line. | SUBSTRATE |
| Aminopropylindenes derived from Grundmann's ketone as a novel chemotype of oxidosqualene cyclase inhibitors. A series of aminopropylindenes, designed as mimics of a cationic high energy intermediate in the GENE (OSC)-mediated cyclization of 2,3-oxidosqualen to CHEMICAL was prepared from Grundmann's ketone. Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds. A N,N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi OSC in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line. | SUBSTRATE |
| Aminopropylindenes derived from Grundmann's ketone as a novel chemotype of oxidosqualene cyclase inhibitors. A series of aminopropylindenes, designed as mimics of a cationic high energy intermediate in the oxidosqualene cyclase(1) (OSC)-mediated cyclization of 2,3-oxidosqualen to lanosterol was prepared from Grundmann's ketone. Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds. A N,N-dimethylaminopropyl derivative showed promising inhibition of GENE in combination with low cytotoxicity, and showed significant reduction of CHEMICAL biosynthesis in a human cell line. | PRODUCT-OF |
| Aminopropylindenes derived from Grundmann's ketone as a novel chemotype of oxidosqualene cyclase inhibitors. A series of aminopropylindenes, designed as mimics of a cationic high energy intermediate in the oxidosqualene cyclase(1) (GENE)-mediated cyclization of CHEMICAL to lanosterol was prepared from Grundmann's ketone. Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds. A N,N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi GENE in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line. | SUBSTRATE |
| Aminopropylindenes derived from Grundmann's ketone as a novel chemotype of oxidosqualene cyclase inhibitors. A series of aminopropylindenes, designed as mimics of a cationic high energy intermediate in the GENE (OSC)-mediated cyclization of CHEMICAL to lanosterol was prepared from Grundmann's ketone. Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds. A N,N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi OSC in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line. | SUBSTRATE |
| The CHEMICAL required for potentiation of skeletal muscle contraction is released via pannexin hemichannels. During repetitive stimulation of skeletal muscle, extracellular CHEMICAL levels raise, activating purinergic receptors, increasing Ca(2+) influx, and enhancing contractile force, a response called potentiation. We found that CHEMICAL appears to be released through pannexin1 hemichannels (Panx1 HCs). Immunocytochemical analyses and function were consistent with pannexin1 localization to T-tubules intercalated with dihydropyridine and ryanodine receptors in slow (soleus) and fast (extensor digitorum longus, EDL) muscles. Isolated myofibers took up ethidium (Etd(+)) and released small molecules (as ATP) during electrical stimulation. Consistent with two glucose uptake pathways, induced uptake of 2-NBDG, a fluorescent glucose derivative, was decreased by inhibition of HCs or glucose transporter (GLUT4), and blocked by dual blockade. Adult skeletal muscles apparently do not express connexins, making it unlikely that connexin hemichannels contribute to the uptake and release of small molecules. CHEMICAL release, Etd(+) uptake, and potentiation induced by repetitive electrical stimulation were blocked by HC blockers and did not occur in muscles of pannexin1 knockout mice. MRS2179, a P2Y1R blocker, prevented potentiation in EDL, but not soleus muscles, suggesting that in fast muscles CHEMICAL activates P2Y1 but not GENE. Phosphorylation on Ser and Thr residues of pannexin1 was increased during potentiation, possibly mediating HC opening. Opening of Panx1 HCs during repetitive activation allows efflux of CHEMICAL, influx of glucose and possibly Ca(2+) too, which are required for potentiation of contraction. This article is part of a Special Issue entitled 'Connexin based channels'. | NO-RELATIONSHIP |
| The ATP required for potentiation of skeletal muscle contraction is released via pannexin hemichannels. During repetitive stimulation of skeletal muscle, extracellular ATP levels raise, activating purinergic receptors, increasing Ca(2+) influx, and enhancing contractile force, a response called potentiation. We found that ATP appears to be released through GENE hemichannels (Panx1 HCs). Immunocytochemical analyses and function were consistent with GENE localization to T-tubules intercalated with dihydropyridine and ryanodine receptors in slow (soleus) and fast (extensor digitorum longus, EDL) muscles. Isolated myofibers took up ethidium (Etd(+)) and released small molecules (as ATP) during electrical stimulation. Consistent with two glucose uptake pathways, induced uptake of 2-NBDG, a fluorescent glucose derivative, was decreased by inhibition of HCs or glucose transporter (GLUT4), and blocked by dual blockade. Adult skeletal muscles apparently do not express connexins, making it unlikely that connexin hemichannels contribute to the uptake and release of small molecules. ATP release, Etd(+) uptake, and potentiation induced by repetitive electrical stimulation were blocked by HC blockers and did not occur in muscles of GENE knockout mice. MRS2179, a P2Y1R blocker, prevented potentiation in EDL, but not soleus muscles, suggesting that in fast muscles ATP activates P2Y1 but not P2X receptors. Phosphorylation on CHEMICAL and Thr residues of GENE was increased during potentiation, possibly mediating HC opening. Opening of Panx1 HCs during repetitive activation allows efflux of ATP, influx of glucose and possibly Ca(2+) too, which are required for potentiation of contraction. This article is part of a Special Issue entitled 'Connexin based channels'. | PART-OF |
| The ATP required for potentiation of skeletal muscle contraction is released via pannexin hemichannels. During repetitive stimulation of skeletal muscle, extracellular ATP levels raise, activating purinergic receptors, increasing Ca(2+) influx, and enhancing contractile force, a response called potentiation. We found that ATP appears to be released through GENE hemichannels (Panx1 HCs). Immunocytochemical analyses and function were consistent with GENE localization to T-tubules intercalated with dihydropyridine and ryanodine receptors in slow (soleus) and fast (extensor digitorum longus, EDL) muscles. Isolated myofibers took up ethidium (Etd(+)) and released small molecules (as ATP) during electrical stimulation. Consistent with two glucose uptake pathways, induced uptake of 2-NBDG, a fluorescent glucose derivative, was decreased by inhibition of HCs or glucose transporter (GLUT4), and blocked by dual blockade. Adult skeletal muscles apparently do not express connexins, making it unlikely that connexin hemichannels contribute to the uptake and release of small molecules. ATP release, Etd(+) uptake, and potentiation induced by repetitive electrical stimulation were blocked by HC blockers and did not occur in muscles of GENE knockout mice. MRS2179, a P2Y1R blocker, prevented potentiation in EDL, but not soleus muscles, suggesting that in fast muscles ATP activates P2Y1 but not P2X receptors. Phosphorylation on Ser and CHEMICAL residues of GENE was increased during potentiation, possibly mediating HC opening. Opening of Panx1 HCs during repetitive activation allows efflux of ATP, influx of glucose and possibly Ca(2+) too, which are required for potentiation of contraction. This article is part of a Special Issue entitled 'Connexin based channels'. | PART-OF |
| The ATP required for potentiation of skeletal muscle contraction is released via pannexin hemichannels. During repetitive stimulation of skeletal muscle, extracellular ATP levels raise, activating purinergic receptors, increasing Ca(2+) influx, and enhancing contractile force, a response called potentiation. We found that ATP appears to be released through GENE hemichannels (Panx1 HCs). Immunocytochemical analyses and function were consistent with GENE localization to T-tubules intercalated with CHEMICAL and ryanodine receptors in slow (soleus) and fast (extensor digitorum longus, EDL) muscles. Isolated myofibers took up ethidium (Etd(+)) and released small molecules (as ATP) during electrical stimulation. Consistent with two glucose uptake pathways, induced uptake of 2-NBDG, a fluorescent glucose derivative, was decreased by inhibition of HCs or glucose transporter (GLUT4), and blocked by dual blockade. Adult skeletal muscles apparently do not express connexins, making it unlikely that connexin hemichannels contribute to the uptake and release of small molecules. ATP release, Etd(+) uptake, and potentiation induced by repetitive electrical stimulation were blocked by HC blockers and did not occur in muscles of GENE knockout mice. MRS2179, a P2Y1R blocker, prevented potentiation in EDL, but not soleus muscles, suggesting that in fast muscles ATP activates P2Y1 but not P2X receptors. Phosphorylation on Ser and Thr residues of GENE was increased during potentiation, possibly mediating HC opening. Opening of Panx1 HCs during repetitive activation allows efflux of ATP, influx of glucose and possibly Ca(2+) too, which are required for potentiation of contraction. This article is part of a Special Issue entitled 'Connexin based channels'. | REGULATOR |
| The CHEMICAL required for potentiation of skeletal muscle contraction is released via pannexin hemichannels. During repetitive stimulation of skeletal muscle, extracellular CHEMICAL levels raise, activating GENE, increasing Ca(2+) influx, and enhancing contractile force, a response called potentiation. We found that CHEMICAL appears to be released through pannexin1 hemichannels (Panx1 HCs). Immunocytochemical analyses and function were consistent with pannexin1 localization to T-tubules intercalated with dihydropyridine and ryanodine receptors in slow (soleus) and fast (extensor digitorum longus, EDL) muscles. Isolated myofibers took up ethidium (Etd(+)) and released small molecules (as ATP) during electrical stimulation. Consistent with two glucose uptake pathways, induced uptake of 2-NBDG, a fluorescent glucose derivative, was decreased by inhibition of HCs or glucose transporter (GLUT4), and blocked by dual blockade. Adult skeletal muscles apparently do not express connexins, making it unlikely that connexin hemichannels contribute to the uptake and release of small molecules. CHEMICAL release, Etd(+) uptake, and potentiation induced by repetitive electrical stimulation were blocked by HC blockers and did not occur in muscles of pannexin1 knockout mice. MRS2179, a P2Y1R blocker, prevented potentiation in EDL, but not soleus muscles, suggesting that in fast muscles CHEMICAL activates P2Y1 but not P2X receptors. Phosphorylation on Ser and Thr residues of pannexin1 was increased during potentiation, possibly mediating HC opening. Opening of Panx1 HCs during repetitive activation allows efflux of CHEMICAL, influx of glucose and possibly Ca(2+) too, which are required for potentiation of contraction. This article is part of a Special Issue entitled 'Connexin based channels'. | ACTIVATOR |
| The CHEMICAL required for potentiation of skeletal muscle contraction is released via pannexin hemichannels. During repetitive stimulation of skeletal muscle, extracellular CHEMICAL levels raise, activating purinergic receptors, increasing Ca(2+) influx, and enhancing contractile force, a response called potentiation. We found that CHEMICAL appears to be released through pannexin1 hemichannels (Panx1 HCs). Immunocytochemical analyses and function were consistent with pannexin1 localization to T-tubules intercalated with dihydropyridine and ryanodine receptors in slow (soleus) and fast (extensor digitorum longus, EDL) muscles. Isolated myofibers took up ethidium (Etd(+)) and released small molecules (as ATP) during electrical stimulation. Consistent with two glucose uptake pathways, induced uptake of 2-NBDG, a fluorescent glucose derivative, was decreased by inhibition of HCs or glucose transporter (GLUT4), and blocked by dual blockade. Adult skeletal muscles apparently do not express connexins, making it unlikely that connexin hemichannels contribute to the uptake and release of small molecules. CHEMICAL release, Etd(+) uptake, and potentiation induced by repetitive electrical stimulation were blocked by HC blockers and did not occur in muscles of pannexin1 knockout mice. MRS2179, a P2Y1R blocker, prevented potentiation in EDL, but not soleus muscles, suggesting that in fast muscles CHEMICAL activates GENE but not P2X receptors. Phosphorylation on Ser and Thr residues of pannexin1 was increased during potentiation, possibly mediating HC opening. Opening of Panx1 HCs during repetitive activation allows efflux of CHEMICAL, influx of glucose and possibly Ca(2+) too, which are required for potentiation of contraction. This article is part of a Special Issue entitled 'Connexin based channels'. | ACTIVATOR |
| The ATP required for potentiation of skeletal muscle contraction is released via pannexin hemichannels. During repetitive stimulation of skeletal muscle, extracellular ATP levels raise, activating purinergic receptors, increasing Ca(2+) influx, and enhancing contractile force, a response called potentiation. We found that ATP appears to be released through pannexin1 hemichannels (Panx1 HCs). Immunocytochemical analyses and function were consistent with pannexin1 localization to T-tubules intercalated with dihydropyridine and ryanodine receptors in slow (soleus) and fast (extensor digitorum longus, EDL) muscles. Isolated myofibers took up ethidium (Etd(+)) and released small molecules (as ATP) during electrical stimulation. Consistent with two CHEMICAL uptake pathways, induced uptake of 2-NBDG, a fluorescent CHEMICAL derivative, was decreased by inhibition of HCs or GENE (GLUT4), and blocked by dual blockade. Adult skeletal muscles apparently do not express connexins, making it unlikely that connexin hemichannels contribute to the uptake and release of small molecules. ATP release, Etd(+) uptake, and potentiation induced by repetitive electrical stimulation were blocked by HC blockers and did not occur in muscles of pannexin1 knockout mice. MRS2179, a P2Y1R blocker, prevented potentiation in EDL, but not soleus muscles, suggesting that in fast muscles ATP activates P2Y1 but not P2X receptors. Phosphorylation on Ser and Thr residues of pannexin1 was increased during potentiation, possibly mediating HC opening. Opening of Panx1 HCs during repetitive activation allows efflux of ATP, influx of CHEMICAL and possibly Ca(2+) too, which are required for potentiation of contraction. This article is part of a Special Issue entitled 'Connexin based channels'. | SUBSTRATE |
| The ATP required for potentiation of skeletal muscle contraction is released via pannexin hemichannels. During repetitive stimulation of skeletal muscle, extracellular ATP levels raise, activating purinergic receptors, increasing Ca(2+) influx, and enhancing contractile force, a response called potentiation. We found that ATP appears to be released through pannexin1 hemichannels (Panx1 HCs). Immunocytochemical analyses and function were consistent with pannexin1 localization to T-tubules intercalated with dihydropyridine and ryanodine receptors in slow (soleus) and fast (extensor digitorum longus, EDL) muscles. Isolated myofibers took up ethidium (Etd(+)) and released small molecules (as ATP) during electrical stimulation. Consistent with two CHEMICAL uptake pathways, induced uptake of 2-NBDG, a fluorescent CHEMICAL derivative, was decreased by inhibition of HCs or CHEMICAL transporter (GENE), and blocked by dual blockade. Adult skeletal muscles apparently do not express connexins, making it unlikely that connexin hemichannels contribute to the uptake and release of small molecules. ATP release, Etd(+) uptake, and potentiation induced by repetitive electrical stimulation were blocked by HC blockers and did not occur in muscles of pannexin1 knockout mice. MRS2179, a P2Y1R blocker, prevented potentiation in EDL, but not soleus muscles, suggesting that in fast muscles ATP activates P2Y1 but not P2X receptors. Phosphorylation on Ser and Thr residues of pannexin1 was increased during potentiation, possibly mediating HC opening. Opening of Panx1 HCs during repetitive activation allows efflux of ATP, influx of CHEMICAL and possibly Ca(2+) too, which are required for potentiation of contraction. This article is part of a Special Issue entitled 'Connexin based channels'. | SUBSTRATE |
| The ATP required for potentiation of skeletal muscle contraction is released via pannexin hemichannels. During repetitive stimulation of skeletal muscle, extracellular ATP levels raise, activating purinergic receptors, increasing Ca(2+) influx, and enhancing contractile force, a response called potentiation. We found that ATP appears to be released through pannexin1 hemichannels (Panx1 HCs). Immunocytochemical analyses and function were consistent with pannexin1 localization to T-tubules intercalated with dihydropyridine and ryanodine receptors in slow (soleus) and fast (extensor digitorum longus, EDL) muscles. Isolated myofibers took up ethidium (Etd(+)) and released small molecules (as ATP) during electrical stimulation. Consistent with two glucose uptake pathways, induced uptake of CHEMICAL, a fluorescent glucose derivative, was decreased by inhibition of HCs or GENE (GLUT4), and blocked by dual blockade. Adult skeletal muscles apparently do not express connexins, making it unlikely that connexin hemichannels contribute to the uptake and release of small molecules. ATP release, Etd(+) uptake, and potentiation induced by repetitive electrical stimulation were blocked by HC blockers and did not occur in muscles of pannexin1 knockout mice. MRS2179, a P2Y1R blocker, prevented potentiation in EDL, but not soleus muscles, suggesting that in fast muscles ATP activates P2Y1 but not P2X receptors. Phosphorylation on Ser and Thr residues of pannexin1 was increased during potentiation, possibly mediating HC opening. Opening of Panx1 HCs during repetitive activation allows efflux of ATP, influx of glucose and possibly Ca(2+) too, which are required for potentiation of contraction. This article is part of a Special Issue entitled 'Connexin based channels'. | SUBSTRATE |
| The ATP required for potentiation of skeletal muscle contraction is released via pannexin hemichannels. During repetitive stimulation of skeletal muscle, extracellular ATP levels raise, activating purinergic receptors, increasing Ca(2+) influx, and enhancing contractile force, a response called potentiation. We found that ATP appears to be released through pannexin1 hemichannels (Panx1 HCs). Immunocytochemical analyses and function were consistent with pannexin1 localization to T-tubules intercalated with dihydropyridine and ryanodine receptors in slow (soleus) and fast (extensor digitorum longus, EDL) muscles. Isolated myofibers took up ethidium (Etd(+)) and released small molecules (as ATP) during electrical stimulation. Consistent with two glucose uptake pathways, induced uptake of CHEMICAL, a fluorescent glucose derivative, was decreased by inhibition of HCs or glucose transporter (GENE), and blocked by dual blockade. Adult skeletal muscles apparently do not express connexins, making it unlikely that connexin hemichannels contribute to the uptake and release of small molecules. ATP release, Etd(+) uptake, and potentiation induced by repetitive electrical stimulation were blocked by HC blockers and did not occur in muscles of pannexin1 knockout mice. MRS2179, a P2Y1R blocker, prevented potentiation in EDL, but not soleus muscles, suggesting that in fast muscles ATP activates P2Y1 but not P2X receptors. Phosphorylation on Ser and Thr residues of pannexin1 was increased during potentiation, possibly mediating HC opening. Opening of Panx1 HCs during repetitive activation allows efflux of ATP, influx of glucose and possibly Ca(2+) too, which are required for potentiation of contraction. This article is part of a Special Issue entitled 'Connexin based channels'. | SUBSTRATE |
| The CHEMICAL required for potentiation of skeletal muscle contraction is released via GENE hemichannels. During repetitive stimulation of skeletal muscle, extracellular CHEMICAL levels raise, activating purinergic receptors, increasing Ca(2+) influx, and enhancing contractile force, a response called potentiation. We found that CHEMICAL appears to be released through pannexin1 hemichannels (Panx1 HCs). Immunocytochemical analyses and function were consistent with pannexin1 localization to T-tubules intercalated with dihydropyridine and ryanodine receptors in slow (soleus) and fast (extensor digitorum longus, EDL) muscles. Isolated myofibers took up ethidium (Etd(+)) and released small molecules (as ATP) during electrical stimulation. Consistent with two glucose uptake pathways, induced uptake of 2-NBDG, a fluorescent glucose derivative, was decreased by inhibition of HCs or glucose transporter (GLUT4), and blocked by dual blockade. Adult skeletal muscles apparently do not express connexins, making it unlikely that connexin hemichannels contribute to the uptake and release of small molecules. CHEMICAL release, Etd(+) uptake, and potentiation induced by repetitive electrical stimulation were blocked by HC blockers and did not occur in muscles of pannexin1 knockout mice. MRS2179, a P2Y1R blocker, prevented potentiation in EDL, but not soleus muscles, suggesting that in fast muscles CHEMICAL activates P2Y1 but not P2X receptors. Phosphorylation on Ser and Thr residues of pannexin1 was increased during potentiation, possibly mediating HC opening. Opening of Panx1 HCs during repetitive activation allows efflux of CHEMICAL, influx of glucose and possibly Ca(2+) too, which are required for potentiation of contraction. This article is part of a Special Issue entitled 'Connexin based channels'. | GENE-CHEMICAL |
| The CHEMICAL required for potentiation of skeletal muscle contraction is released via pannexin hemichannels. During repetitive stimulation of skeletal muscle, extracellular CHEMICAL levels raise, activating purinergic receptors, increasing Ca(2+) influx, and enhancing contractile force, a response called potentiation. We found that CHEMICAL appears to be released through pannexin1 hemichannels (Panx1 HCs). Immunocytochemical analyses and function were consistent with pannexin1 localization to T-tubules intercalated with dihydropyridine and ryanodine receptors in slow (soleus) and fast (extensor digitorum longus, EDL) muscles. Isolated myofibers took up ethidium (Etd(+)) and released small molecules (as ATP) during electrical stimulation. Consistent with two glucose uptake pathways, induced uptake of 2-NBDG, a fluorescent glucose derivative, was decreased by inhibition of HCs or glucose transporter (GLUT4), and blocked by dual blockade. Adult skeletal muscles apparently do not express connexins, making it unlikely that connexin hemichannels contribute to the uptake and release of small molecules. CHEMICAL release, Etd(+) uptake, and potentiation induced by repetitive electrical stimulation were blocked by HC blockers and did not occur in muscles of pannexin1 knockout mice. MRS2179, a P2Y1R blocker, prevented potentiation in EDL, but not soleus muscles, suggesting that in fast muscles CHEMICAL activates P2Y1 but not P2X receptors. Phosphorylation on Ser and Thr residues of pannexin1 was increased during potentiation, possibly mediating HC opening. Opening of GENE HCs during repetitive activation allows efflux of CHEMICAL, influx of glucose and possibly Ca(2+) too, which are required for potentiation of contraction. This article is part of a Special Issue entitled 'Connexin based channels'. | SUBSTRATE |
| The ATP required for potentiation of skeletal muscle contraction is released via pannexin hemichannels. During repetitive stimulation of skeletal muscle, extracellular ATP levels raise, activating purinergic receptors, increasing Ca(2+) influx, and enhancing contractile force, a response called potentiation. We found that ATP appears to be released through pannexin1 hemichannels (Panx1 HCs). Immunocytochemical analyses and function were consistent with pannexin1 localization to T-tubules intercalated with dihydropyridine and ryanodine receptors in slow (soleus) and fast (extensor digitorum longus, EDL) muscles. Isolated myofibers took up ethidium (Etd(+)) and released small molecules (as ATP) during electrical stimulation. Consistent with two CHEMICAL uptake pathways, induced uptake of 2-NBDG, a fluorescent CHEMICAL derivative, was decreased by inhibition of HCs or CHEMICAL transporter (GLUT4), and blocked by dual blockade. Adult skeletal muscles apparently do not express connexins, making it unlikely that connexin hemichannels contribute to the uptake and release of small molecules. ATP release, Etd(+) uptake, and potentiation induced by repetitive electrical stimulation were blocked by HC blockers and did not occur in muscles of pannexin1 knockout mice. MRS2179, a P2Y1R blocker, prevented potentiation in EDL, but not soleus muscles, suggesting that in fast muscles ATP activates P2Y1 but not P2X receptors. Phosphorylation on Ser and Thr residues of pannexin1 was increased during potentiation, possibly mediating HC opening. Opening of GENE HCs during repetitive activation allows efflux of ATP, influx of CHEMICAL and possibly Ca(2+) too, which are required for potentiation of contraction. This article is part of a Special Issue entitled 'Connexin based channels'. | SUBSTRATE |
| The ATP required for potentiation of skeletal muscle contraction is released via pannexin hemichannels. During repetitive stimulation of skeletal muscle, extracellular ATP levels raise, activating purinergic receptors, increasing CHEMICAL influx, and enhancing contractile force, a response called potentiation. We found that ATP appears to be released through pannexin1 hemichannels (Panx1 HCs). Immunocytochemical analyses and function were consistent with pannexin1 localization to T-tubules intercalated with dihydropyridine and ryanodine receptors in slow (soleus) and fast (extensor digitorum longus, EDL) muscles. Isolated myofibers took up ethidium (Etd(+)) and released small molecules (as ATP) during electrical stimulation. Consistent with two glucose uptake pathways, induced uptake of 2-NBDG, a fluorescent glucose derivative, was decreased by inhibition of HCs or glucose transporter (GLUT4), and blocked by dual blockade. Adult skeletal muscles apparently do not express connexins, making it unlikely that connexin hemichannels contribute to the uptake and release of small molecules. ATP release, Etd(+) uptake, and potentiation induced by repetitive electrical stimulation were blocked by HC blockers and did not occur in muscles of pannexin1 knockout mice. MRS2179, a P2Y1R blocker, prevented potentiation in EDL, but not soleus muscles, suggesting that in fast muscles ATP activates P2Y1 but not P2X receptors. Phosphorylation on Ser and Thr residues of pannexin1 was increased during potentiation, possibly mediating HC opening. Opening of GENE HCs during repetitive activation allows efflux of ATP, influx of glucose and possibly CHEMICAL too, which are required for potentiation of contraction. This article is part of a Special Issue entitled 'Connexin based channels'. | SUBSTRATE |
| tert-Butylhydroquinone reduces lipid accumulation in C57BL/6 mice with lower body weight gain. tert-Butylhydroquinone (tBHQ) is a commonly used antioxidant additive that is approved for human use by both the Food and Agriculture Organization and the World Health Organization (FAO/WHO). In this study, we examined the effect of CHEMICAL on body weight gain and found that food supplementation with 0.001 % (w/w) CHEMICAL inhibited 61.4 % (P < 0.01) of body weight gain in high-fat diet (HFD)-induced C57BL/6 mice, and the oral administration of CHEMICAL (1.5 mg/kg) reduced 47.5 % (P < 0.05) of body weight gain in normal diet fed db/db mice. The HFD increased lipid deposit in adipocytes, but these were reduced significantly by CHEMICAL treatment in C57BL/6 mice. CHEMICAL supplementation significantly lowered the plasma triglyceride and total cholesterol, with reduced size of accumulated fat mass. The rate limiting enzyme of beta-oxidation (GENE) was significantly over-expressed in the liver with CHEMICAL treatment. These results indicate that CHEMICAL suppresses body weight gain in mice, possibly at least related to the up-regulation of GENE gene expression. | INDIRECT-UPREGULATOR |
| Dual Growth Factor Delivery Using Biocompatible Core-Shell Microcapsules for Angiogenesis. An optimized electrodropping system produces homogeneous core-shell microcapsules (C-S MCs) by using poly(L-lactic-co-glycolic acid) (PLGA) and alginate. Fluorescence imaging clearly shows the C-S domain in the MC. For release control, the use of high-molecular-weight CHEMICAL (HMW 270 000) restrains the initial burst release of protein compared to that of low-MW CHEMICAL (LMW 40 000). Layer-by-layer (LBL) assembly of chitosan and alginate on MCs is also useful in controlling the release profile of biomolecules. LBL (7-layer) treatment is effective in suppressing the initial burst release of protein compared to no LBL (0-layer). The difference of cumulative albumin release between HMW (7-layer LBL) and LMW (0-layer LBL) CHEMICAL is determined to be more than 40% on day 5. When dual angiogenic growth factors (GFs), such as platelet-derived GF (PDGF) and vascular endothelial GF (VEGF), are encapsulated separately in the core and shell domains, respectively, the GENE release rate is much greater than that of PDGF, and the difference of the cumulative release percentage between the two GFs is about 30% on day 7 with LMW core CHEMICAL and more than 45% with HMW core CHEMICAL. As for the angiogenic potential of MC GFs with human umbilical vein endothelial cells (HUVECs), the fluorescence signal of CD31+ suggests that the angiogenic sprout of ECs is more active in MC-mediated GF delivery than conventional GF delivery, and this difference is significant, based on the number of capillary branches in the unit area. This study demonstrates that the fabrication of biocompatible C-S MCs is possible, and that the release control of biomolecules is adjustable. Furthermore, MC-mediated GFs remain in an active form and can upregulate the angiogenic activity of ECs. | GENE-CHEMICAL |
| Dual Growth Factor Delivery Using Biocompatible Core-Shell Microcapsules for Angiogenesis. An optimized electrodropping system produces homogeneous core-shell microcapsules (C-S MCs) by using poly(L-lactic-co-glycolic acid) (PLGA) and alginate. Fluorescence imaging clearly shows the C-S domain in the MC. For release control, the use of high-molecular-weight CHEMICAL (HMW 270 000) restrains the initial burst release of protein compared to that of low-MW CHEMICAL (LMW 40 000). Layer-by-layer (LBL) assembly of chitosan and alginate on MCs is also useful in controlling the release profile of biomolecules. LBL (7-layer) treatment is effective in suppressing the initial burst release of protein compared to no LBL (0-layer). The difference of cumulative albumin release between HMW (7-layer LBL) and LMW (0-layer LBL) CHEMICAL is determined to be more than 40% on day 5. When dual angiogenic growth factors (GFs), such as platelet-derived GF (PDGF) and vascular endothelial GF (VEGF), are encapsulated separately in the core and shell domains, respectively, the VEGF release rate is much greater than that of GENE, and the difference of the cumulative release percentage between the two GFs is about 30% on day 7 with LMW core CHEMICAL and more than 45% with HMW core CHEMICAL. As for the angiogenic potential of MC GFs with human umbilical vein endothelial cells (HUVECs), the fluorescence signal of CD31+ suggests that the angiogenic sprout of ECs is more active in MC-mediated GF delivery than conventional GF delivery, and this difference is significant, based on the number of capillary branches in the unit area. This study demonstrates that the fabrication of biocompatible C-S MCs is possible, and that the release control of biomolecules is adjustable. Furthermore, MC-mediated GFs remain in an active form and can upregulate the angiogenic activity of ECs. | REGULATOR |
| Potency switch between CHK1 and GENE: Discovery of CHEMICAL- and imidazo[1,2-c]pyrimidine-based kinase inhibitors. Chemistry has been developed to access both imidazo[1,2-a]pyrazines and imidazo[1,2-c]pyrimidines. Small structural modifications in both series led to a switch of potency between two kinases involved in mediating cell cycle checkpoint control, CHK1 and GENE. | INHIBITOR |
| Potency switch between CHK1 and MK2: Discovery of CHEMICAL- and imidazo[1,2-c]pyrimidine-based GENE inhibitors. Chemistry has been developed to access both imidazo[1,2-a]pyrazines and imidazo[1,2-c]pyrimidines. Small structural modifications in both series led to a switch of potency between two kinases involved in mediating cell cycle checkpoint control, CHK1 and MK2. | INHIBITOR |
| Potency switch between GENE and MK2: Discovery of CHEMICAL- and imidazo[1,2-c]pyrimidine-based kinase inhibitors. Chemistry has been developed to access both imidazo[1,2-a]pyrazines and imidazo[1,2-c]pyrimidines. Small structural modifications in both series led to a switch of potency between two kinases involved in mediating cell cycle checkpoint control, GENE and MK2. | INHIBITOR |
| Potency switch between CHK1 and GENE: Discovery of imidazo[1,2-a]pyrazine- and CHEMICAL-based kinase inhibitors. Chemistry has been developed to access both imidazo[1,2-a]pyrazines and imidazo[1,2-c]pyrimidines. Small structural modifications in both series led to a switch of potency between two kinases involved in mediating cell cycle checkpoint control, CHK1 and GENE. | INHIBITOR |
| Potency switch between CHK1 and MK2: Discovery of imidazo[1,2-a]pyrazine- and CHEMICAL-based GENE inhibitors. Chemistry has been developed to access both imidazo[1,2-a]pyrazines and imidazo[1,2-c]pyrimidines. Small structural modifications in both series led to a switch of potency between two kinases involved in mediating cell cycle checkpoint control, CHK1 and MK2. | INHIBITOR |
| Potency switch between GENE and MK2: Discovery of imidazo[1,2-a]pyrazine- and CHEMICAL-based kinase inhibitors. Chemistry has been developed to access both imidazo[1,2-a]pyrazines and imidazo[1,2-c]pyrimidines. Small structural modifications in both series led to a switch of potency between two kinases involved in mediating cell cycle checkpoint control, GENE and MK2. | INHIBITOR |
| The Fer tyrosine kinase is important for platelet-derived growth factor-BB-induced Stat3 phosphorylation, colony formation in soft agar and tumor growth in vivo. Fer is a cytoplasmic tyrosine kinase that is activated in response to platelet-derived growth factor (PDGF) stimulation. In the present report, we show that Fer associates with the activated GENE (PDGFRbeta) through multiple autophosphorylation sites, i.e. CHEMICAL579, Tyr581, Tyr740 and Tyr1021. Using low molecular weight inhibitors, we found that PDGF-BB-induced Fer activation is dependent on PDGFRbeta kinase activity, but not on the enzymatic activity of Src or Jak kinases. In cells in which Fer was downregulated using siRNA, PDGF-BB was unable to induce phosphorylation of Stat3, whereas phosphorylations of Stat5, Erk1/2 and Akt were unaffected. PDGF-BB-induced activation of Stat3 occurred also in cells expressing kinase-dead Fer, suggesting a kinase-independent adaptor role of Fer. Expression of Fer was dispensable for PDGF-BB-induced proliferation and migration, but essential for colony formation in soft agar. Tumor growth in vivo was delayed in cells depleted of Fer expression. Our data suggests a critical role of Fer in PDGF-BB-induced Stat3 activation and cell transformation. | PART-OF |
| The Fer tyrosine kinase is important for platelet-derived growth factor-BB-induced Stat3 phosphorylation, colony formation in soft agar and tumor growth in vivo. Fer is a cytoplasmic tyrosine kinase that is activated in response to platelet-derived growth factor (PDGF) stimulation. In the present report, we show that Fer associates with the activated PDGFbeta receptor (GENE) through multiple autophosphorylation sites, i.e. CHEMICAL579, Tyr581, Tyr740 and Tyr1021. Using low molecular weight inhibitors, we found that PDGF-BB-induced Fer activation is dependent on GENE kinase activity, but not on the enzymatic activity of Src or Jak kinases. In cells in which Fer was downregulated using siRNA, PDGF-BB was unable to induce phosphorylation of Stat3, whereas phosphorylations of Stat5, Erk1/2 and Akt were unaffected. PDGF-BB-induced activation of Stat3 occurred also in cells expressing kinase-dead Fer, suggesting a kinase-independent adaptor role of Fer. Expression of Fer was dispensable for PDGF-BB-induced proliferation and migration, but essential for colony formation in soft agar. Tumor growth in vivo was delayed in cells depleted of Fer expression. Our data suggests a critical role of Fer in PDGF-BB-induced Stat3 activation and cell transformation. | PART-OF |
| Discovery of CHEMICAL and aryl amides as potent and selective GENE antagonists for the treatment of obesity (Part I). A series of structurally novel CHEMICAL was derived from optimization of the HTS lead as selective GENE (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays. | INHIBITOR |
| Discovery of CHEMICAL and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (Part I). A series of structurally novel CHEMICAL was derived from optimization of the HTS lead as selective histamine H3 receptor (GENE) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey GENE binding assays. | INHIBITOR |
| Discovery of aryl ureas and CHEMICAL as potent and selective GENE antagonists for the treatment of obesity (Part I). A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective GENE (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays. | INHIBITOR |
| Structure and energetics of gas phase halogen-bonding in mono-, bi-, and tri-dentate anion receptors as studied by BIRD. Complexes of mono-, bi- (RB), and tridentate (RT) receptors with a range of anions (Cl(-), Br(-), I(-), NO3(-), H2PO4(-), HSO4(-), and tosylate (TsO(-))) have been studied in the gas phase by both experimental and theoretical methods. Temperature dependent blackbody infrared radiative dissociation (BIRD) experiments were performed on complexes of C8F17I with Br(-) and I(-), RB with I(-), NO3(-), HSO4(-), H2PO4(-), and TsO(-), and RT with I(-), HSO4(-) and TsO(-) and the observed Arrhenius parameters are reported here. Master equation modeling of the BIRD kinetics data was carried out to determine threshold dissociation energies. Geometry optimizations and thermochemistry calculations were performed using the B3LYP/6-31+G(d,p) level of theory. Additional single point energies were calculated using MP2/6-311++G(2d,p). Results were examined in terms of the binding order of various anions as well as the added binding strength from additional CHEMICAL bonding (XB) interactions. The relative binding energies of ions were generally consistent with the ordering previously reported from solution phase experiments; however, the relatively strong binding of H2PO4(-) to the bidentate receptor contrasted the solution phase observation of oxoanions having weaker interactions when compared to halides. An increase in the energy required to remove the same anion from the GENE when compared to the bidentate and monodentate receptors is explained as being due to the increase in CHEMICAL bonding interactions. The possibility of mixed CHEMICAL and hydrogen bonded complexes were considered. | DIRECT-REGULATOR |
| CHEMICAL deficiency and heightened neuropathic pain in aged mice. Damaging of peripheral nerves may result in chronic neuropathic pain for which the likelihood is increased in the elderly. We assessed in mice if age-dependent alterations of endocannabinoids contributed to the heightened vulnerability to neuropathic pain at old age. We assessed nociception, endocannabinoids and the therapeutic efficacy of R-flurbiprofen in young and aged mice in the spared nerve injury model of neuropathic pain. R-flurbiprofen was used because it is able to reduce neuropathic pain in young mice in part by increasing CHEMICAL. Aged mice developed stronger nociceptive hypersensitivity after sciatic nerve injury than young mice. This was associated with low CHEMICAL levels in the dorsal root ganglia, spinal cord, thalamus and cortex, which further decreased after nerve injury. In aged mice, R-flurbiprofen had only weak antinociceptive efficacy and it failed to restore normal CHEMICAL levels after nerve injury. In terms of the mechanisms, we found that fatty acid amide hydrolase (GENE) which degrades CHEMICAL, was upregulated after nerve injury at both ages, so that this upregulation likely did not account for the age-dependent differences. However, enzymes contributing to oxidative metabolism of CHEMICAL, namely cyclooxygenase-1 and Cyp2D6, were increased in the brain of aged mice, possibly enhancing the oxidative breakdown of CHEMICAL. This may overwhelm the capacity of R-flurbiprofen to restore CHEMICAL homeostasis and may contribute to the heightened risk for neuropathic pain at old age. | SUBSTRATE |
| CHEMICAL deficiency and heightened neuropathic pain in aged mice. Damaging of peripheral nerves may result in chronic neuropathic pain for which the likelihood is increased in the elderly. We assessed in mice if age-dependent alterations of endocannabinoids contributed to the heightened vulnerability to neuropathic pain at old age. We assessed nociception, endocannabinoids and the therapeutic efficacy of R-flurbiprofen in young and aged mice in the spared nerve injury model of neuropathic pain. R-flurbiprofen was used because it is able to reduce neuropathic pain in young mice in part by increasing CHEMICAL. Aged mice developed stronger nociceptive hypersensitivity after sciatic nerve injury than young mice. This was associated with low CHEMICAL levels in the dorsal root ganglia, spinal cord, thalamus and cortex, which further decreased after nerve injury. In aged mice, R-flurbiprofen had only weak antinociceptive efficacy and it failed to restore normal CHEMICAL levels after nerve injury. In terms of the mechanisms, we found that GENE (FAAH) which degrades CHEMICAL, was upregulated after nerve injury at both ages, so that this upregulation likely did not account for the age-dependent differences. However, enzymes contributing to oxidative metabolism of CHEMICAL, namely cyclooxygenase-1 and Cyp2D6, were increased in the brain of aged mice, possibly enhancing the oxidative breakdown of CHEMICAL. This may overwhelm the capacity of R-flurbiprofen to restore CHEMICAL homeostasis and may contribute to the heightened risk for neuropathic pain at old age. | SUBSTRATE |
| CHEMICAL deficiency and heightened neuropathic pain in aged mice. Damaging of peripheral nerves may result in chronic neuropathic pain for which the likelihood is increased in the elderly. We assessed in mice if age-dependent alterations of endocannabinoids contributed to the heightened vulnerability to neuropathic pain at old age. We assessed nociception, endocannabinoids and the therapeutic efficacy of R-flurbiprofen in young and aged mice in the spared nerve injury model of neuropathic pain. R-flurbiprofen was used because it is able to reduce neuropathic pain in young mice in part by increasing CHEMICAL. Aged mice developed stronger nociceptive hypersensitivity after sciatic nerve injury than young mice. This was associated with low CHEMICAL levels in the dorsal root ganglia, spinal cord, thalamus and cortex, which further decreased after nerve injury. In aged mice, R-flurbiprofen had only weak antinociceptive efficacy and it failed to restore normal CHEMICAL levels after nerve injury. In terms of the mechanisms, we found that fatty acid amide hydrolase (FAAH) which degrades CHEMICAL, was upregulated after nerve injury at both ages, so that this upregulation likely did not account for the age-dependent differences. However, enzymes contributing to oxidative metabolism of CHEMICAL, namely GENE and Cyp2D6, were increased in the brain of aged mice, possibly enhancing the oxidative breakdown of CHEMICAL. This may overwhelm the capacity of R-flurbiprofen to restore CHEMICAL homeostasis and may contribute to the heightened risk for neuropathic pain at old age. | SUBSTRATE |
| CHEMICAL deficiency and heightened neuropathic pain in aged mice. Damaging of peripheral nerves may result in chronic neuropathic pain for which the likelihood is increased in the elderly. We assessed in mice if age-dependent alterations of endocannabinoids contributed to the heightened vulnerability to neuropathic pain at old age. We assessed nociception, endocannabinoids and the therapeutic efficacy of R-flurbiprofen in young and aged mice in the spared nerve injury model of neuropathic pain. R-flurbiprofen was used because it is able to reduce neuropathic pain in young mice in part by increasing CHEMICAL. Aged mice developed stronger nociceptive hypersensitivity after sciatic nerve injury than young mice. This was associated with low CHEMICAL levels in the dorsal root ganglia, spinal cord, thalamus and cortex, which further decreased after nerve injury. In aged mice, R-flurbiprofen had only weak antinociceptive efficacy and it failed to restore normal CHEMICAL levels after nerve injury. In terms of the mechanisms, we found that fatty acid amide hydrolase (FAAH) which degrades CHEMICAL, was upregulated after nerve injury at both ages, so that this upregulation likely did not account for the age-dependent differences. However, enzymes contributing to oxidative metabolism of CHEMICAL, namely cyclooxygenase-1 and GENE, were increased in the brain of aged mice, possibly enhancing the oxidative breakdown of CHEMICAL. This may overwhelm the capacity of R-flurbiprofen to restore CHEMICAL homeostasis and may contribute to the heightened risk for neuropathic pain at old age. | SUBSTRATE |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether CHEMICAL is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and ABCG1 was induced by CHEMICAL, as well as TO901317 and retinoic acid, which are ligands of the nuclear receptors LXR/RXR. When the expression of ABCA1 and ABCG1 was induced, CHEMICAL efflux was stimulated in the presence of high density lipoprotein (HDL), whereas GENE was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human ABCA1 or ABCG1; we clearly observed CHEMICAL efflux in the presence of HDL, whereas efflux in the presence of GENE was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of CHEMICAL. These results suggest that ABCA1 actively eliminates CHEMICAL in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | NO-RELATIONSHIP |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether 24-OHC is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and ABCG1 was induced by 24-OHC, as well as TO901317 and CHEMICAL, which are ligands of the GENE LXR/RXR. When the expression of ABCA1 and ABCG1 was induced, 24-OHC efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human ABCA1 or ABCG1; we clearly observed 24-OHC efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of 24-OHC. These results suggest that ABCA1 actively eliminates 24-OHC in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | DIRECT-REGULATOR |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether 24-OHC is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and ABCG1 was induced by 24-OHC, as well as TO901317 and CHEMICAL, which are ligands of the nuclear receptors GENE/RXR. When the expression of ABCA1 and ABCG1 was induced, 24-OHC efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human ABCA1 or ABCG1; we clearly observed 24-OHC efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of 24-OHC. These results suggest that ABCA1 actively eliminates 24-OHC in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | DIRECT-REGULATOR |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether 24-OHC is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and ABCG1 was induced by 24-OHC, as well as TO901317 and CHEMICAL, which are ligands of the nuclear receptors LXR/GENE. When the expression of ABCA1 and ABCG1 was induced, 24-OHC efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human ABCA1 or ABCG1; we clearly observed 24-OHC efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of 24-OHC. These results suggest that ABCA1 actively eliminates 24-OHC in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | DIRECT-REGULATOR |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether 24-OHC is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and ABCG1 was induced by 24-OHC, as well as CHEMICAL and retinoic acid, which are ligands of the GENE LXR/RXR. When the expression of ABCA1 and ABCG1 was induced, 24-OHC efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human ABCA1 or ABCG1; we clearly observed 24-OHC efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of 24-OHC. These results suggest that ABCA1 actively eliminates 24-OHC in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | DIRECT-REGULATOR |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether 24-OHC is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and ABCG1 was induced by 24-OHC, as well as CHEMICAL and retinoic acid, which are ligands of the nuclear receptors GENE/RXR. When the expression of ABCA1 and ABCG1 was induced, 24-OHC efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human ABCA1 or ABCG1; we clearly observed 24-OHC efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of 24-OHC. These results suggest that ABCA1 actively eliminates 24-OHC in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | DIRECT-REGULATOR |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether 24-OHC is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and ABCG1 was induced by 24-OHC, as well as CHEMICAL and retinoic acid, which are ligands of the nuclear receptors LXR/GENE. When the expression of ABCA1 and ABCG1 was induced, 24-OHC efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human ABCA1 or ABCG1; we clearly observed 24-OHC efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of 24-OHC. These results suggest that ABCA1 actively eliminates 24-OHC in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | DIRECT-REGULATOR |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether CHEMICAL is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and ABCG1 was induced by CHEMICAL, as well as TO901317 and retinoic acid, which are ligands of the nuclear receptors LXR/RXR. When the expression of ABCA1 and ABCG1 was induced, CHEMICAL efflux was stimulated in the presence of GENE (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human ABCA1 or ABCG1; we clearly observed CHEMICAL efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of CHEMICAL. These results suggest that ABCA1 actively eliminates CHEMICAL in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | GENE-CHEMICAL |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether CHEMICAL is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and ABCG1 was induced by CHEMICAL, as well as TO901317 and retinoic acid, which are ligands of the nuclear receptors LXR/RXR. When the expression of ABCA1 and ABCG1 was induced, CHEMICAL efflux was stimulated in the presence of high density lipoprotein (GENE), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human ABCA1 or ABCG1; we clearly observed CHEMICAL efflux in the presence of GENE, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of CHEMICAL. These results suggest that ABCA1 actively eliminates CHEMICAL in the presence of GENE as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | GENE-CHEMICAL |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by GENE. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether 24-OHC is actively eliminated via transporters induced by its accumulation. The expression of GENE and ABCG1 was induced by 24-OHC, as well as TO901317 and CHEMICAL, which are ligands of the nuclear receptors LXR/RXR. When the expression of GENE and ABCG1 was induced, 24-OHC efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against GENE, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human GENE or ABCG1; we clearly observed 24-OHC efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of 24-OHC. These results suggest that GENE actively eliminates 24-OHC in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | DIRECT-REGULATOR |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether 24-OHC is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and GENE was induced by 24-OHC, as well as TO901317 and CHEMICAL, which are ligands of the nuclear receptors LXR/RXR. When the expression of ABCA1 and GENE was induced, 24-OHC efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by GENE siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human ABCA1 or ABCG1; we clearly observed 24-OHC efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of 24-OHC. These results suggest that ABCA1 actively eliminates 24-OHC in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | INDIRECT-UPREGULATOR |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by GENE. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether CHEMICAL is actively eliminated via transporters induced by its accumulation. The expression of GENE and ABCG1 was induced by CHEMICAL, as well as TO901317 and retinoic acid, which are ligands of the nuclear receptors LXR/RXR. When the expression of GENE and ABCG1 was induced, CHEMICAL efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against GENE, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human GENE or ABCG1; we clearly observed CHEMICAL efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of CHEMICAL. These results suggest that GENE actively eliminates CHEMICAL in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | SUBSTRATE |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether CHEMICAL is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and GENE was induced by CHEMICAL, as well as TO901317 and retinoic acid, which are ligands of the nuclear receptors LXR/RXR. When the expression of ABCA1 and GENE was induced, CHEMICAL efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by GENE siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human ABCA1 or ABCG1; we clearly observed CHEMICAL efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of CHEMICAL. These results suggest that ABCA1 actively eliminates CHEMICAL in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | NO-RELATIONSHIP |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by GENE. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether 24-OHC is actively eliminated via transporters induced by its accumulation. The expression of GENE and ABCG1 was induced by 24-OHC, as well as CHEMICAL and retinoic acid, which are ligands of the nuclear receptors LXR/RXR. When the expression of GENE and ABCG1 was induced, 24-OHC efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against GENE, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human GENE or ABCG1; we clearly observed 24-OHC efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of 24-OHC. These results suggest that GENE actively eliminates 24-OHC in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | INDIRECT-UPREGULATOR |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether 24-OHC is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and GENE was induced by 24-OHC, as well as CHEMICAL and retinoic acid, which are ligands of the nuclear receptors LXR/RXR. When the expression of ABCA1 and GENE was induced, 24-OHC efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by GENE siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human ABCA1 or ABCG1; we clearly observed 24-OHC efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of 24-OHC. These results suggest that ABCA1 actively eliminates 24-OHC in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | INDIRECT-UPREGULATOR |
| CHEMICAL is actively eliminated from neuronal cells by ABCA1. High cholesterol turnover catalyzed by cholesterol GENE is essential for neural functions, especially learning. Because CHEMICAL (24-OHC), produced by GENE, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether 24-OHC is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and ABCG1 was induced by 24-OHC, as well as TO901317 and retinoic acid, which are ligands of the nuclear receptors LXR/RXR. When the expression of ABCA1 and ABCG1 was induced, 24-OHC efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human ABCA1 or ABCG1; we clearly observed 24-OHC efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of 24-OHC. These results suggest that ABCA1 actively eliminates 24-OHC in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | PRODUCT-OF |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. High cholesterol turnover catalyzed by cholesterol GENE is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (CHEMICAL), produced by GENE, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether CHEMICAL is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and ABCG1 was induced by CHEMICAL, as well as TO901317 and retinoic acid, which are ligands of the nuclear receptors LXR/RXR. When the expression of ABCA1 and ABCG1 was induced, CHEMICAL efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human ABCA1 or ABCG1; we clearly observed CHEMICAL efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of CHEMICAL. These results suggest that ABCA1 actively eliminates CHEMICAL in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | PRODUCT-OF |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether CHEMICAL is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and ABCG1 was induced by CHEMICAL, as well as TO901317 and retinoic acid, which are ligands of the nuclear receptors LXR/RXR. When the expression of ABCA1 and ABCG1 was induced, CHEMICAL efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing GENE or ABCG1; we clearly observed CHEMICAL efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of CHEMICAL. These results suggest that ABCA1 actively eliminates CHEMICAL in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | SUBSTRATE |
| CHEMICAL is actively eliminated from neuronal cells by GENE. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because CHEMICAL (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether 24-OHC is actively eliminated via transporters induced by its accumulation. The expression of GENE and ABCG1 was induced by 24-OHC, as well as TO901317 and retinoic acid, which are ligands of the nuclear receptors LXR/RXR. When the expression of GENE and ABCG1 was induced, 24-OHC efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against GENE, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human GENE or ABCG1; we clearly observed 24-OHC efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of 24-OHC. These results suggest that GENE actively eliminates 24-OHC in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | SUBSTRATE |
| 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. High CHEMICAL turnover catalyzed by GENE is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether 24-OHC is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and ABCG1 was induced by 24-OHC, as well as TO901317 and retinoic acid, which are ligands of the nuclear receptors LXR/RXR. When the expression of ABCA1 and ABCG1 was induced, 24-OHC efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human ABCA1 or ABCG1; we clearly observed 24-OHC efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of 24-OHC. These results suggest that ABCA1 actively eliminates 24-OHC in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. | SUBSTRATE |
| Design, Synthesis and biological evaluation of catecholamine vehicle for studying dopaminergic system. Catecholamine mimetic EDTA-bis(tyramide) was synthesized and characterized by various spectroscopic techniques (NMR, Mass spectroscopy) and λem 310 nm for the excitation at 270 nm. Molecular docking studies were performed with GENE (HSA: PDB 1E78), showing binding pattern with CHEMICAL residues Arg218, Arg222 and Lys444, identifies the ligand-HSA interaction for the transportation affinity of the ligand at the specific site of the target. Subsequently binding study with HSA at λex =350 nm found to be 5.847x10(4) M(-1) shows effective quenching effect. Additionally to go more insight AChE binding affinity was investigated, which shows 90% binding affinity for the 10 mM concentration. IC50 value was was found 18.60 μM for MAO-B inhibition. Finally, EDTA-bis(tyramide) labeled with (99m) Tc to investigate its in-vivo radiopharmaceutical efficiency, having 97% binding affinity with 98% radiochemical purity. In-vivo studies were carried out for (99m) Tc- EDTA-bis(tyramide) included blood kinetics showed a quick wash out from the circulation via renal route and biodistribution revealed that maximum%ID/g was found in kidney at 1h and its scintigraphy image shows 3.96% brain uptake with respect to whole body. This article is protected by copyright. All rights reserved. | PART-OF |
| Design, Synthesis and biological evaluation of catecholamine vehicle for studying dopaminergic system. Catecholamine mimetic EDTA-bis(tyramide) was synthesized and characterized by various spectroscopic techniques (NMR, Mass spectroscopy) and λem 310 nm for the excitation at 270 nm. Molecular docking studies were performed with Human Serum Albumin (GENE: PDB 1E78), showing binding pattern with CHEMICAL residues Arg218, Arg222 and Lys444, identifies the ligand-HSA interaction for the transportation affinity of the ligand at the specific site of the target. Subsequently binding study with GENE at λex =350 nm found to be 5.847x10(4) M(-1) shows effective quenching effect. Additionally to go more insight AChE binding affinity was investigated, which shows 90% binding affinity for the 10 mM concentration. IC50 value was was found 18.60 μM for MAO-B inhibition. Finally, EDTA-bis(tyramide) labeled with (99m) Tc to investigate its in-vivo radiopharmaceutical efficiency, having 97% binding affinity with 98% radiochemical purity. In-vivo studies were carried out for (99m) Tc- EDTA-bis(tyramide) included blood kinetics showed a quick wash out from the circulation via renal route and biodistribution revealed that maximum%ID/g was found in kidney at 1h and its scintigraphy image shows 3.96% brain uptake with respect to whole body. This article is protected by copyright. All rights reserved. | PART-OF |
| Design, Synthesis and biological evaluation of catecholamine vehicle for studying dopaminergic system. Catecholamine mimetic EDTA-bis(tyramide) was synthesized and characterized by various spectroscopic techniques (NMR, Mass spectroscopy) and λem 310 nm for the excitation at 270 nm. Molecular docking studies were performed with GENE (HSA: PDB 1E78), showing binding pattern with amino acid residues CHEMICAL218, Arg222 and Lys444, identifies the ligand-HSA interaction for the transportation affinity of the ligand at the specific site of the target. Subsequently binding study with HSA at λex =350 nm found to be 5.847x10(4) M(-1) shows effective quenching effect. Additionally to go more insight AChE binding affinity was investigated, which shows 90% binding affinity for the 10 mM concentration. IC50 value was was found 18.60 μM for MAO-B inhibition. Finally, EDTA-bis(tyramide) labeled with (99m) Tc to investigate its in-vivo radiopharmaceutical efficiency, having 97% binding affinity with 98% radiochemical purity. In-vivo studies were carried out for (99m) Tc- EDTA-bis(tyramide) included blood kinetics showed a quick wash out from the circulation via renal route and biodistribution revealed that maximum%ID/g was found in kidney at 1h and its scintigraphy image shows 3.96% brain uptake with respect to whole body. This article is protected by copyright. All rights reserved. | PART-OF |
| Design, Synthesis and biological evaluation of catecholamine vehicle for studying dopaminergic system. Catecholamine mimetic EDTA-bis(tyramide) was synthesized and characterized by various spectroscopic techniques (NMR, Mass spectroscopy) and λem 310 nm for the excitation at 270 nm. Molecular docking studies were performed with Human Serum Albumin (GENE: PDB 1E78), showing binding pattern with amino acid residues CHEMICAL218, Arg222 and Lys444, identifies the ligand-HSA interaction for the transportation affinity of the ligand at the specific site of the target. Subsequently binding study with GENE at λex =350 nm found to be 5.847x10(4) M(-1) shows effective quenching effect. Additionally to go more insight AChE binding affinity was investigated, which shows 90% binding affinity for the 10 mM concentration. IC50 value was was found 18.60 μM for MAO-B inhibition. Finally, EDTA-bis(tyramide) labeled with (99m) Tc to investigate its in-vivo radiopharmaceutical efficiency, having 97% binding affinity with 98% radiochemical purity. In-vivo studies were carried out for (99m) Tc- EDTA-bis(tyramide) included blood kinetics showed a quick wash out from the circulation via renal route and biodistribution revealed that maximum%ID/g was found in kidney at 1h and its scintigraphy image shows 3.96% brain uptake with respect to whole body. This article is protected by copyright. All rights reserved. | PART-OF |
| Design, Synthesis and biological evaluation of catecholamine vehicle for studying dopaminergic system. Catecholamine mimetic EDTA-bis(tyramide) was synthesized and characterized by various spectroscopic techniques (NMR, Mass spectroscopy) and λem 310 nm for the excitation at 270 nm. Molecular docking studies were performed with GENE (HSA: PDB 1E78), showing binding pattern with amino acid residues Arg218, Arg222 and CHEMICAL444, identifies the ligand-HSA interaction for the transportation affinity of the ligand at the specific site of the target. Subsequently binding study with HSA at λex =350 nm found to be 5.847x10(4) M(-1) shows effective quenching effect. Additionally to go more insight AChE binding affinity was investigated, which shows 90% binding affinity for the 10 mM concentration. IC50 value was was found 18.60 μM for MAO-B inhibition. Finally, EDTA-bis(tyramide) labeled with (99m) Tc to investigate its in-vivo radiopharmaceutical efficiency, having 97% binding affinity with 98% radiochemical purity. In-vivo studies were carried out for (99m) Tc- EDTA-bis(tyramide) included blood kinetics showed a quick wash out from the circulation via renal route and biodistribution revealed that maximum%ID/g was found in kidney at 1h and its scintigraphy image shows 3.96% brain uptake with respect to whole body. This article is protected by copyright. All rights reserved. | PART-OF |
| Design, Synthesis and biological evaluation of catecholamine vehicle for studying dopaminergic system. Catecholamine mimetic EDTA-bis(tyramide) was synthesized and characterized by various spectroscopic techniques (NMR, Mass spectroscopy) and λem 310 nm for the excitation at 270 nm. Molecular docking studies were performed with Human Serum Albumin (GENE: PDB 1E78), showing binding pattern with amino acid residues Arg218, Arg222 and CHEMICAL444, identifies the ligand-HSA interaction for the transportation affinity of the ligand at the specific site of the target. Subsequently binding study with GENE at λex =350 nm found to be 5.847x10(4) M(-1) shows effective quenching effect. Additionally to go more insight AChE binding affinity was investigated, which shows 90% binding affinity for the 10 mM concentration. IC50 value was was found 18.60 μM for MAO-B inhibition. Finally, EDTA-bis(tyramide) labeled with (99m) Tc to investigate its in-vivo radiopharmaceutical efficiency, having 97% binding affinity with 98% radiochemical purity. In-vivo studies were carried out for (99m) Tc- EDTA-bis(tyramide) included blood kinetics showed a quick wash out from the circulation via renal route and biodistribution revealed that maximum%ID/g was found in kidney at 1h and its scintigraphy image shows 3.96% brain uptake with respect to whole body. This article is protected by copyright. All rights reserved. | PART-OF |
| Presynaptic GENE modulates dopamine D3 receptor activation in striatonigral terminals of the rat brain in a CHEMICAL dependent manner. GENE is expressed at high density in the nucleus accumbens where it binds to postsynaptic D3 receptors inhibiting their effects. In striatonigral projections, activation of presynaptic D3 receptors potentiates D1 receptor-induced stimulation of cAMP production and GABA release. In this study we examined whether the presynaptic effects of D3 receptor stimulation in the substantia nigra reticulata (SNr) are modulated by CHEMICAL activation of GENE. In SNr synaptosomes two procedures that increase cytoplasmic CHEMICAL, ionomycin and K(+)-depolarization, blocked the additional stimulation of cAMP accumulation produced by coactivating D3 and D1 dopamine receptors. The selective GENE inhibitor KN-62 reversed the blockade produced by ionomycin and K(+)-depolarization. Incubation in either Ca(2) -free solutions or with the selective CHEMICAL blocker nifedipine, also reversed the blocking effects of K(+)-depolarization. Immunoblot studies showed that K(+)-depolarization increased GENE phosphorylation in a KN-62 sensitive manner and promoted GENE binding to D3 receptors. In K(+)-depolarized tissues, D3 receptors potentiated D1 receptor-induced stimulation of [(3)H]GABA release only when GENE was blocked with KN-62. In the presence of this inhibitor, the selective D3 agonist PD 128,907 reduced the ED50 for the D1 agonist SKF 38393 from 56 to 4 nM. KN-62 also enhanced the effects of dopamine on depolarization induced [(3)H]GABA release. KN-62 changed ED50 for dopamine from 584 to 56 nM. KN-62 did not affect D1 and D4 receptor responses. These experiments show that in striatonigral projections, GENE inhibits the action of D3 receptors in a CHEMICAL dependent manner blocking their modulatory effects on GABA release. These findings suggest a mechanism through which the frequency of action potential discharge in presynaptic terminals regulates dopamine effects. | REGULATOR |
| Presynaptic CaMKIIα modulates dopamine D3 receptor activation in striatonigral terminals of the rat brain in a CHEMICAL dependent manner. CaMKIIα is expressed at high density in the nucleus accumbens where it binds to postsynaptic GENE inhibiting their effects. In striatonigral projections, activation of presynaptic GENE potentiates D1 receptor-induced stimulation of cAMP production and GABA release. In this study we examined whether the presynaptic effects of D3 receptor stimulation in the substantia nigra reticulata (SNr) are modulated by CHEMICAL activation of CaMKIIα. In SNr synaptosomes two procedures that increase cytoplasmic CHEMICAL, ionomycin and K(+)-depolarization, blocked the additional stimulation of cAMP accumulation produced by coactivating D3 and D1 dopamine receptors. The selective CaMKIIα inhibitor KN-62 reversed the blockade produced by ionomycin and K(+)-depolarization. Incubation in either Ca(2) -free solutions or with the selective CHEMICAL blocker nifedipine, also reversed the blocking effects of K(+)-depolarization. Immunoblot studies showed that K(+)-depolarization increased CaMKIIα phosphorylation in a KN-62 sensitive manner and promoted CaMKIIα binding to GENE. In K(+)-depolarized tissues, GENE potentiated D1 receptor-induced stimulation of [(3)H]GABA release only when CaMKIIα was blocked with KN-62. In the presence of this inhibitor, the selective D3 agonist PD 128,907 reduced the ED50 for the D1 agonist SKF 38393 from 56 to 4 nM. KN-62 also enhanced the effects of dopamine on depolarization induced [(3)H]GABA release. KN-62 changed ED50 for dopamine from 584 to 56 nM. KN-62 did not affect D1 and D4 receptor responses. These experiments show that in striatonigral projections, CaMKIIα inhibits the action of GENE in a CHEMICAL dependent manner blocking their modulatory effects on GABA release. These findings suggest a mechanism through which the frequency of action potential discharge in presynaptic terminals regulates dopamine effects. | REGULATOR |
| Presynaptic GENE modulates dopamine D3 receptor activation in striatonigral terminals of the rat brain in a Ca(2+) dependent manner. GENE is expressed at high density in the nucleus accumbens where it binds to postsynaptic D3 receptors inhibiting their effects. In striatonigral projections, activation of presynaptic D3 receptors potentiates D1 receptor-induced stimulation of cAMP production and GABA release. In this study we examined whether the presynaptic effects of D3 receptor stimulation in the substantia nigra reticulata (SNr) are modulated by Ca(2+) activation of GENE. In SNr synaptosomes two procedures that increase cytoplasmic Ca(2+), ionomycin and K(+)-depolarization, blocked the additional stimulation of cAMP accumulation produced by coactivating D3 and D1 dopamine receptors. The selective GENE inhibitor CHEMICAL reversed the blockade produced by ionomycin and K(+)-depolarization. Incubation in either Ca(2) -free solutions or with the selective Ca(2+) blocker nifedipine, also reversed the blocking effects of K(+)-depolarization. Immunoblot studies showed that K(+)-depolarization increased GENE phosphorylation in a CHEMICAL sensitive manner and promoted GENE binding to D3 receptors. In K(+)-depolarized tissues, D3 receptors potentiated D1 receptor-induced stimulation of [(3)H]GABA release only when GENE was blocked with CHEMICAL. In the presence of this inhibitor, the selective D3 agonist PD 128,907 reduced the ED50 for the D1 agonist SKF 38393 from 56 to 4 nM. CHEMICAL also enhanced the effects of dopamine on depolarization induced [(3)H]GABA release. CHEMICAL changed ED50 for dopamine from 584 to 56 nM. CHEMICAL did not affect D1 and D4 receptor responses. These experiments show that in striatonigral projections, GENE inhibits the action of D3 receptors in a Ca(2+) dependent manner blocking their modulatory effects on GABA release. These findings suggest a mechanism through which the frequency of action potential discharge in presynaptic terminals regulates dopamine effects. | INHIBITOR |
| Presynaptic CaMKIIα modulates dopamine D3 receptor activation in striatonigral terminals of the rat brain in a Ca(2+) dependent manner. CaMKIIα is expressed at high density in the nucleus accumbens where it binds to postsynaptic GENE inhibiting their effects. In striatonigral projections, activation of presynaptic GENE potentiates D1 receptor-induced stimulation of cAMP production and GABA release. In this study we examined whether the presynaptic effects of D3 receptor stimulation in the substantia nigra reticulata (SNr) are modulated by Ca(2+) activation of CaMKIIα. In SNr synaptosomes two procedures that increase cytoplasmic Ca(2+), ionomycin and K(+)-depolarization, blocked the additional stimulation of cAMP accumulation produced by coactivating D3 and D1 dopamine receptors. The selective CaMKIIα inhibitor CHEMICAL reversed the blockade produced by ionomycin and K(+)-depolarization. Incubation in either Ca(2) -free solutions or with the selective Ca(2+) blocker nifedipine, also reversed the blocking effects of K(+)-depolarization. Immunoblot studies showed that K(+)-depolarization increased CaMKIIα phosphorylation in a CHEMICAL sensitive manner and promoted CaMKIIα binding to GENE. In K(+)-depolarized tissues, GENE potentiated D1 receptor-induced stimulation of [(3)H]GABA release only when CaMKIIα was blocked with CHEMICAL. In the presence of this inhibitor, the selective D3 agonist PD 128,907 reduced the ED50 for the D1 agonist SKF 38393 from 56 to 4 nM. CHEMICAL also enhanced the effects of dopamine on depolarization induced [(3)H]GABA release. CHEMICAL changed ED50 for dopamine from 584 to 56 nM. CHEMICAL did not affect D1 and D4 receptor responses. These experiments show that in striatonigral projections, CaMKIIα inhibits the action of GENE in a Ca(2+) dependent manner blocking their modulatory effects on GABA release. These findings suggest a mechanism through which the frequency of action potential discharge in presynaptic terminals regulates dopamine effects. | REGULATOR |
| Presynaptic GENE modulates dopamine D3 receptor activation in striatonigral terminals of the rat brain in a Ca(2+) dependent manner. GENE is expressed at high density in the nucleus accumbens where it binds to postsynaptic D3 receptors inhibiting their effects. In striatonigral projections, activation of presynaptic D3 receptors potentiates D1 receptor-induced stimulation of cAMP production and GABA release. In this study we examined whether the presynaptic effects of D3 receptor stimulation in the substantia nigra reticulata (SNr) are modulated by Ca(2+) activation of GENE. In SNr synaptosomes two procedures that increase cytoplasmic Ca(2+), ionomycin and K(+)-depolarization, blocked the additional stimulation of cAMP accumulation produced by coactivating D3 and D1 dopamine receptors. The selective GENE inhibitor KN-62 reversed the blockade produced by ionomycin and K(+)-depolarization. Incubation in either Ca(2) -free solutions or with the selective Ca(2+) blocker nifedipine, also reversed the blocking effects of K(+)-depolarization. Immunoblot studies showed that CHEMICAL-depolarization increased GENE phosphorylation in a KN-62 sensitive manner and promoted GENE binding to D3 receptors. In K(+)-depolarized tissues, D3 receptors potentiated D1 receptor-induced stimulation of [(3)H]GABA release only when GENE was blocked with KN-62. In the presence of this inhibitor, the selective D3 agonist PD 128,907 reduced the ED50 for the D1 agonist SKF 38393 from 56 to 4 nM. KN-62 also enhanced the effects of dopamine on depolarization induced [(3)H]GABA release. KN-62 changed ED50 for dopamine from 584 to 56 nM. KN-62 did not affect D1 and D4 receptor responses. These experiments show that in striatonigral projections, GENE inhibits the action of D3 receptors in a Ca(2+) dependent manner blocking their modulatory effects on GABA release. These findings suggest a mechanism through which the frequency of action potential discharge in presynaptic terminals regulates dopamine effects. | ACTIVATOR |
| Presynaptic CaMKIIα modulates GENE activation in striatonigral terminals of the rat brain in a CHEMICAL dependent manner. CaMKIIα is expressed at high density in the nucleus accumbens where it binds to postsynaptic D3 receptors inhibiting their effects. In striatonigral projections, activation of presynaptic D3 receptors potentiates D1 receptor-induced stimulation of cAMP production and GABA release. In this study we examined whether the presynaptic effects of D3 receptor stimulation in the substantia nigra reticulata (SNr) are modulated by CHEMICAL activation of CaMKIIα. In SNr synaptosomes two procedures that increase cytoplasmic CHEMICAL, ionomycin and K(+)-depolarization, blocked the additional stimulation of cAMP accumulation produced by coactivating D3 and D1 dopamine receptors. The selective CaMKIIα inhibitor KN-62 reversed the blockade produced by ionomycin and K(+)-depolarization. Incubation in either Ca(2) -free solutions or with the selective CHEMICAL blocker nifedipine, also reversed the blocking effects of K(+)-depolarization. Immunoblot studies showed that K(+)-depolarization increased CaMKIIα phosphorylation in a KN-62 sensitive manner and promoted CaMKIIα binding to D3 receptors. In K(+)-depolarized tissues, D3 receptors potentiated D1 receptor-induced stimulation of [(3)H]GABA release only when CaMKIIα was blocked with KN-62. In the presence of this inhibitor, the selective D3 agonist PD 128,907 reduced the ED50 for the D1 agonist SKF 38393 from 56 to 4 nM. KN-62 also enhanced the effects of dopamine on depolarization induced [(3)H]GABA release. KN-62 changed ED50 for dopamine from 584 to 56 nM. KN-62 did not affect D1 and D4 receptor responses. These experiments show that in striatonigral projections, CaMKIIα inhibits the action of D3 receptors in a CHEMICAL dependent manner blocking their modulatory effects on GABA release. These findings suggest a mechanism through which the frequency of action potential discharge in presynaptic terminals regulates dopamine effects. | ACTIVATOR |
| Presynaptic GENE modulates dopamine D3 receptor activation in striatonigral terminals of the rat brain in a Ca(2+) dependent manner. GENE is expressed at high density in the nucleus accumbens where it binds to postsynaptic D3 receptors inhibiting their effects. In striatonigral projections, activation of presynaptic D3 receptors potentiates D1 receptor-induced stimulation of cAMP production and GABA release. In this study we examined whether the presynaptic effects of D3 receptor stimulation in the substantia nigra reticulata (SNr) are modulated by Ca(2+) activation of GENE. In SNr synaptosomes two procedures that increase cytoplasmic Ca(2+), CHEMICAL and K(+)-depolarization, blocked the additional stimulation of cAMP accumulation produced by coactivating D3 and D1 dopamine receptors. The selective GENE inhibitor KN-62 reversed the blockade produced by CHEMICAL and K(+)-depolarization. Incubation in either Ca(2) -free solutions or with the selective Ca(2+) blocker nifedipine, also reversed the blocking effects of K(+)-depolarization. Immunoblot studies showed that K(+)-depolarization increased GENE phosphorylation in a KN-62 sensitive manner and promoted GENE binding to D3 receptors. In K(+)-depolarized tissues, D3 receptors potentiated D1 receptor-induced stimulation of [(3)H]GABA release only when GENE was blocked with KN-62. In the presence of this inhibitor, the selective D3 agonist PD 128,907 reduced the ED50 for the D1 agonist SKF 38393 from 56 to 4 nM. KN-62 also enhanced the effects of dopamine on depolarization induced [(3)H]GABA release. KN-62 changed ED50 for dopamine from 584 to 56 nM. KN-62 did not affect D1 and D4 receptor responses. These experiments show that in striatonigral projections, GENE inhibits the action of D3 receptors in a Ca(2+) dependent manner blocking their modulatory effects on GABA release. These findings suggest a mechanism through which the frequency of action potential discharge in presynaptic terminals regulates dopamine effects. | INHIBITOR |
| Presynaptic CaMKIIα modulates dopamine GENE receptor activation in striatonigral terminals of the rat brain in a Ca(2+) dependent manner. CaMKIIα is expressed at high density in the nucleus accumbens where it binds to postsynaptic GENE receptors inhibiting their effects. In striatonigral projections, activation of presynaptic GENE receptors potentiates D1 receptor-induced stimulation of cAMP production and GABA release. In this study we examined whether the presynaptic effects of GENE receptor stimulation in the substantia nigra reticulata (SNr) are modulated by Ca(2+) activation of CaMKIIα. In SNr synaptosomes two procedures that increase cytoplasmic Ca(2+), ionomycin and K(+)-depolarization, blocked the additional stimulation of cAMP accumulation produced by coactivating GENE and D1 dopamine receptors. The selective CaMKIIα inhibitor KN-62 reversed the blockade produced by ionomycin and K(+)-depolarization. Incubation in either Ca(2) -free solutions or with the selective Ca(2+) blocker nifedipine, also reversed the blocking effects of K(+)-depolarization. Immunoblot studies showed that K(+)-depolarization increased CaMKIIα phosphorylation in a KN-62 sensitive manner and promoted CaMKIIα binding to GENE receptors. In K(+)-depolarized tissues, GENE receptors potentiated D1 receptor-induced stimulation of [(3)H]GABA release only when CaMKIIα was blocked with KN-62. In the presence of this inhibitor, the selective GENE agonist CHEMICAL reduced the ED50 for the D1 agonist SKF 38393 from 56 to 4 nM. KN-62 also enhanced the effects of dopamine on depolarization induced [(3)H]GABA release. KN-62 changed ED50 for dopamine from 584 to 56 nM. KN-62 did not affect D1 and D4 receptor responses. These experiments show that in striatonigral projections, CaMKIIα inhibits the action of GENE receptors in a Ca(2+) dependent manner blocking their modulatory effects on GABA release. These findings suggest a mechanism through which the frequency of action potential discharge in presynaptic terminals regulates dopamine effects. | ACTIVATOR |
| Presynaptic CaMKIIα modulates dopamine D3 receptor activation in striatonigral terminals of the rat brain in a Ca(2+) dependent manner. CaMKIIα is expressed at high density in the nucleus accumbens where it binds to postsynaptic D3 receptors inhibiting their effects. In striatonigral projections, activation of presynaptic D3 receptors potentiates GENE receptor-induced stimulation of cAMP production and GABA release. In this study we examined whether the presynaptic effects of D3 receptor stimulation in the substantia nigra reticulata (SNr) are modulated by Ca(2+) activation of CaMKIIα. In SNr synaptosomes two procedures that increase cytoplasmic Ca(2+), ionomycin and K(+)-depolarization, blocked the additional stimulation of cAMP accumulation produced by coactivating D3 and GENE dopamine receptors. The selective CaMKIIα inhibitor KN-62 reversed the blockade produced by ionomycin and K(+)-depolarization. Incubation in either Ca(2) -free solutions or with the selective Ca(2+) blocker nifedipine, also reversed the blocking effects of K(+)-depolarization. Immunoblot studies showed that K(+)-depolarization increased CaMKIIα phosphorylation in a KN-62 sensitive manner and promoted CaMKIIα binding to D3 receptors. In K(+)-depolarized tissues, D3 receptors potentiated GENE receptor-induced stimulation of [(3)H]GABA release only when CaMKIIα was blocked with KN-62. In the presence of this inhibitor, the selective D3 agonist PD 128,907 reduced the ED50 for the GENE agonist CHEMICAL from 56 to 4 nM. KN-62 also enhanced the effects of dopamine on depolarization induced [(3)H]GABA release. KN-62 changed ED50 for dopamine from 584 to 56 nM. KN-62 did not affect GENE and D4 receptor responses. These experiments show that in striatonigral projections, CaMKIIα inhibits the action of D3 receptors in a Ca(2+) dependent manner blocking their modulatory effects on GABA release. These findings suggest a mechanism through which the frequency of action potential discharge in presynaptic terminals regulates dopamine effects. | ACTIVATOR |
| Effects of High Iron and CHEMICAL Concentrations over the Relative Expression of Bcl2, Bax, and Mfn2 in MIN6 Cells. Type 2 diabetes is characterized by hyperglycemia and oxidative stress. Hyperglycemia is linked to mitochondrial dysfunction and reduced β-cell mass due to the reduced expression of genes such as Mfn2 as well as the participation of the Bcl2 gene family, responsible for increased apoptosis. The purpose of this study was to describe the effect of different iron and/or CHEMICAL concentrations over Mfn2, Bax, and Bcl2 expressions in a β-pancreatic cell line (MIN6 cells). MIN6 cells were pre-incubated with different iron and/or CHEMICAL concentrations, and the relative mRNA abundance of the Bcl2/Bax ratio and of Mfn2 genes was measured by qRT-PCR. Heme oxygenase (HO) activity, iron uptake, superoxide dismutase activity, and glutathione content were also determined. The Bcl2/Bax ratio increased and Mfn2 expression decreased in MIN6 cells after CHEMICAL stimulation. These effects were higher when CHEMICAL and iron were incubated together. Additionally, treatment with CHEMICAL/iron showed a higher GENE activity. Our study revealed that high glucose/Fe concentrations in MIN6 cells induced an increase of the Bcl2/Bax ratio, an indicator of increased cell apoptosis. | ACTIVATOR |
| Effects of High CHEMICAL and Glucose Concentrations over the Relative Expression of Bcl2, Bax, and Mfn2 in MIN6 Cells. Type 2 diabetes is characterized by hyperglycemia and oxidative stress. Hyperglycemia is linked to mitochondrial dysfunction and reduced β-cell mass due to the reduced expression of genes such as Mfn2 as well as the participation of the Bcl2 gene family, responsible for increased apoptosis. The purpose of this study was to describe the effect of different CHEMICAL and/or glucose concentrations over Mfn2, Bax, and Bcl2 expressions in a β-pancreatic cell line (MIN6 cells). MIN6 cells were pre-incubated with different CHEMICAL and/or glucose concentrations, and the relative mRNA abundance of the Bcl2/Bax ratio and of Mfn2 genes was measured by qRT-PCR. Heme oxygenase (HO) activity, CHEMICAL uptake, superoxide dismutase activity, and glutathione content were also determined. The Bcl2/Bax ratio increased and Mfn2 expression decreased in MIN6 cells after glucose stimulation. These effects were higher when glucose and CHEMICAL were incubated together. Additionally, treatment with glucose/CHEMICAL showed a higher GENE activity. Our study revealed that high glucose/Fe concentrations in MIN6 cells induced an increase of the Bcl2/Bax ratio, an indicator of increased cell apoptosis. | ACTIVATOR |
| Effects of High Iron and CHEMICAL Concentrations over the Relative Expression of GENE, Bax, and Mfn2 in MIN6 Cells. Type 2 diabetes is characterized by hyperglycemia and oxidative stress. Hyperglycemia is linked to mitochondrial dysfunction and reduced β-cell mass due to the reduced expression of genes such as Mfn2 as well as the participation of the GENE gene family, responsible for increased apoptosis. The purpose of this study was to describe the effect of different iron and/or CHEMICAL concentrations over Mfn2, Bax, and GENE expressions in a β-pancreatic cell line (MIN6 cells). MIN6 cells were pre-incubated with different iron and/or CHEMICAL concentrations, and the relative mRNA abundance of the Bcl2/Bax ratio and of Mfn2 genes was measured by qRT-PCR. Heme oxygenase (HO) activity, iron uptake, superoxide dismutase activity, and glutathione content were also determined. The GENE/Bax ratio increased and Mfn2 expression decreased in MIN6 cells after CHEMICAL stimulation. These effects were higher when CHEMICAL and iron were incubated together. Additionally, treatment with glucose/iron showed a higher HO activity. Our study revealed that high glucose/Fe concentrations in MIN6 cells induced an increase of the Bcl2/Bax ratio, an indicator of increased cell apoptosis. | GENE-CHEMICAL |
| Effects of High Iron and CHEMICAL Concentrations over the Relative Expression of Bcl2, GENE, and Mfn2 in MIN6 Cells. Type 2 diabetes is characterized by hyperglycemia and oxidative stress. Hyperglycemia is linked to mitochondrial dysfunction and reduced β-cell mass due to the reduced expression of genes such as Mfn2 as well as the participation of the Bcl2 gene family, responsible for increased apoptosis. The purpose of this study was to describe the effect of different iron and/or CHEMICAL concentrations over Mfn2, GENE, and Bcl2 expressions in a β-pancreatic cell line (MIN6 cells). MIN6 cells were pre-incubated with different iron and/or CHEMICAL concentrations, and the relative mRNA abundance of the Bcl2/Bax ratio and of Mfn2 genes was measured by qRT-PCR. Heme oxygenase (HO) activity, iron uptake, superoxide dismutase activity, and glutathione content were also determined. The Bcl2/GENE ratio increased and Mfn2 expression decreased in MIN6 cells after CHEMICAL stimulation. These effects were higher when CHEMICAL and iron were incubated together. Additionally, treatment with glucose/iron showed a higher HO activity. Our study revealed that high glucose/Fe concentrations in MIN6 cells induced an increase of the Bcl2/Bax ratio, an indicator of increased cell apoptosis. | GENE-CHEMICAL |
| Effects of High Iron and Glucose Concentrations over the Relative Expression of GENE, Bax, and Mfn2 in MIN6 Cells. Type 2 diabetes is characterized by hyperglycemia and oxidative stress. Hyperglycemia is linked to mitochondrial dysfunction and reduced β-cell mass due to the reduced expression of genes such as Mfn2 as well as the participation of the GENE gene family, responsible for increased apoptosis. The purpose of this study was to describe the effect of different iron and/or glucose concentrations over Mfn2, Bax, and GENE expressions in a β-pancreatic cell line (MIN6 cells). MIN6 cells were pre-incubated with different iron and/or glucose concentrations, and the relative mRNA abundance of the Bcl2/Bax ratio and of Mfn2 genes was measured by qRT-PCR. Heme oxygenase (HO) activity, iron uptake, superoxide dismutase activity, and glutathione content were also determined. The Bcl2/Bax ratio increased and Mfn2 expression decreased in MIN6 cells after glucose stimulation. These effects were higher when glucose and iron were incubated together. Additionally, treatment with glucose/iron showed a higher HO activity. Our study revealed that high glucose/CHEMICAL concentrations in MIN6 cells induced an increase of the GENE/Bax ratio, an indicator of increased cell apoptosis. | INDIRECT-UPREGULATOR |
| Effects of High Iron and Glucose Concentrations over the Relative Expression of Bcl2, GENE, and Mfn2 in MIN6 Cells. Type 2 diabetes is characterized by hyperglycemia and oxidative stress. Hyperglycemia is linked to mitochondrial dysfunction and reduced β-cell mass due to the reduced expression of genes such as Mfn2 as well as the participation of the Bcl2 gene family, responsible for increased apoptosis. The purpose of this study was to describe the effect of different iron and/or glucose concentrations over Mfn2, GENE, and Bcl2 expressions in a β-pancreatic cell line (MIN6 cells). MIN6 cells were pre-incubated with different iron and/or glucose concentrations, and the relative mRNA abundance of the Bcl2/Bax ratio and of Mfn2 genes was measured by qRT-PCR. Heme oxygenase (HO) activity, iron uptake, superoxide dismutase activity, and glutathione content were also determined. The Bcl2/Bax ratio increased and Mfn2 expression decreased in MIN6 cells after glucose stimulation. These effects were higher when glucose and iron were incubated together. Additionally, treatment with glucose/iron showed a higher HO activity. Our study revealed that high glucose/CHEMICAL concentrations in MIN6 cells induced an increase of the Bcl2/GENE ratio, an indicator of increased cell apoptosis. | INDIRECT-UPREGULATOR |
| Effects of High Iron and CHEMICAL Concentrations over the Relative Expression of Bcl2, Bax, and GENE in MIN6 Cells. Type 2 diabetes is characterized by hyperglycemia and oxidative stress. Hyperglycemia is linked to mitochondrial dysfunction and reduced β-cell mass due to the reduced expression of genes such as GENE as well as the participation of the Bcl2 gene family, responsible for increased apoptosis. The purpose of this study was to describe the effect of different iron and/or CHEMICAL concentrations over GENE, Bax, and Bcl2 expressions in a β-pancreatic cell line (MIN6 cells). MIN6 cells were pre-incubated with different iron and/or CHEMICAL concentrations, and the relative mRNA abundance of the Bcl2/Bax ratio and of GENE genes was measured by qRT-PCR. Heme oxygenase (HO) activity, iron uptake, superoxide dismutase activity, and glutathione content were also determined. The Bcl2/Bax ratio increased and GENE expression decreased in MIN6 cells after CHEMICAL stimulation. These effects were higher when CHEMICAL and iron were incubated together. Additionally, treatment with glucose/iron showed a higher HO activity. Our study revealed that high glucose/Fe concentrations in MIN6 cells induced an increase of the Bcl2/Bax ratio, an indicator of increased cell apoptosis. | GENE-CHEMICAL |
| Genetic Insights into CHEMICAL Biosynthesis in Nonomuraea spiralis IMC A-0156. The biosynthetic gene cluster for the CHEMICAL antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156. The 41 kb gene cluster contains 27 ORFs predicted to encode all of the functions for CHEMICAL biosynthesis. This includes nonribosomal peptide synthetases (NRPS) and polyketide synthases (PKS) required for the formation of the benzopyranopyrrole core unit, as well as a suite of tailoring enzymes (e.g., four halogenases, an O-methyltransferase, and an N-glycosyltransferase) necessary for further modifications of the core structure. The GENE is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone. A gene cassette encoding C7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs. Targeted disruption of the gene encoding the GENE, prlH, abolished CHEMICAL production, and recombinant expression of PrlA confirms the activity of this enzyme as a sugar phosphate cyclase involved in the formation of the C7-cyclitol moiety. | NO-RELATIONSHIP |
| Genetic Insights into CHEMICAL Biosynthesis in Nonomuraea spiralis IMC A-0156. The biosynthetic gene cluster for the CHEMICAL antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156. The 41 kb gene cluster contains 27 ORFs predicted to encode all of the functions for CHEMICAL biosynthesis. This includes nonribosomal peptide synthetases (NRPS) and polyketide synthases (PKS) required for the formation of the benzopyranopyrrole core unit, as well as a suite of tailoring enzymes (e.g., four halogenases, an O-methyltransferase, and an N-glycosyltransferase) necessary for further modifications of the core structure. The N-glycosyltransferase is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone. A gene cassette encoding C7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs. Targeted disruption of the gene encoding the N-glycosyltransferase, GENE, abolished CHEMICAL production, and recombinant expression of PrlA confirms the activity of this enzyme as a sugar phosphate cyclase involved in the formation of the C7-cyclitol moiety. | PRODUCT-OF |
| Genetic Insights into Pyralomicin Biosynthesis in Nonomuraea spiralis IMC A-0156. The biosynthetic gene cluster for the pyralomicin antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156. The 41 kb gene cluster contains 27 ORFs predicted to encode all of the functions for pyralomicin biosynthesis. This includes nonribosomal peptide synthetases (NRPS) and polyketide synthases (PKS) required for the formation of the benzopyranopyrrole core unit, as well as a suite of tailoring enzymes (e.g., four halogenases, an O-methyltransferase, and an N-glycosyltransferase) necessary for further modifications of the core structure. The N-glycosyltransferase is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone. A gene cassette encoding C7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs. Targeted disruption of the gene encoding the N-glycosyltransferase, prlH, abolished pyralomicin production, and recombinant expression of GENE confirms the activity of this enzyme as a sugar phosphate cyclase involved in the formation of the CHEMICAL-cyclitol moiety. | PRODUCT-OF |
| Genetic Insights into Pyralomicin Biosynthesis in Nonomuraea spiralis IMC A-0156. The biosynthetic gene cluster for the pyralomicin antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156. The 41 kb gene cluster contains 27 ORFs predicted to encode all of the functions for pyralomicin biosynthesis. This includes nonribosomal peptide synthetases (NRPS) and polyketide synthases (PKS) required for the formation of the benzopyranopyrrole core unit, as well as a suite of tailoring enzymes (e.g., four halogenases, an O-methyltransferase, and an N-glycosyltransferase) necessary for further modifications of the core structure. The N-glycosyltransferase is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone. A gene cassette encoding C7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs. Targeted disruption of the gene encoding the N-glycosyltransferase, prlH, abolished pyralomicin production, and recombinant expression of PrlA confirms the activity of this enzyme as a GENE involved in the formation of the CHEMICAL-cyclitol moiety. | PRODUCT-OF |
| Genetic Insights into Pyralomicin Biosynthesis in Nonomuraea spiralis IMC A-0156. The biosynthetic gene cluster for the pyralomicin antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156. The 41 kb gene cluster contains 27 ORFs predicted to encode all of the functions for pyralomicin biosynthesis. This includes nonribosomal peptide synthetases (NRPS) and polyketide synthases (PKS) required for the formation of the benzopyranopyrrole core unit, as well as a suite of tailoring enzymes (e.g., four halogenases, an O-methyltransferase, and an N-glycosyltransferase) necessary for further modifications of the core structure. The N-glycosyltransferase is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone. A gene cassette encoding C7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs. Targeted disruption of the gene encoding the N-glycosyltransferase, prlH, abolished pyralomicin production, and recombinant expression of GENE confirms the activity of this enzyme as a sugar phosphate cyclase involved in the formation of the C7-CHEMICAL moiety. | PRODUCT-OF |
| Genetic Insights into Pyralomicin Biosynthesis in Nonomuraea spiralis IMC A-0156. The biosynthetic gene cluster for the pyralomicin antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156. The 41 kb gene cluster contains 27 ORFs predicted to encode all of the functions for pyralomicin biosynthesis. This includes nonribosomal peptide synthetases (NRPS) and polyketide synthases (PKS) required for the formation of the benzopyranopyrrole core unit, as well as a suite of tailoring enzymes (e.g., four halogenases, an O-methyltransferase, and an N-glycosyltransferase) necessary for further modifications of the core structure. The N-glycosyltransferase is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone. A gene cassette encoding C7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs. Targeted disruption of the gene encoding the N-glycosyltransferase, prlH, abolished pyralomicin production, and recombinant expression of PrlA confirms the activity of this enzyme as a GENE involved in the formation of the C7-CHEMICAL moiety. | PRODUCT-OF |
| Genetic Insights into Pyralomicin Biosynthesis in Nonomuraea spiralis IMC A-0156. The biosynthetic gene cluster for the pyralomicin antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156. The 41 kb gene cluster contains 27 ORFs predicted to encode all of the functions for pyralomicin biosynthesis. This includes GENE (NRPS) and polyketide synthases (PKS) required for the formation of the CHEMICAL core unit, as well as a suite of tailoring enzymes (e.g., four halogenases, an O-methyltransferase, and an N-glycosyltransferase) necessary for further modifications of the core structure. The N-glycosyltransferase is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone. A gene cassette encoding C7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs. Targeted disruption of the gene encoding the N-glycosyltransferase, prlH, abolished pyralomicin production, and recombinant expression of PrlA confirms the activity of this enzyme as a sugar phosphate cyclase involved in the formation of the C7-cyclitol moiety. | PRODUCT-OF |
| Genetic Insights into Pyralomicin Biosynthesis in Nonomuraea spiralis IMC A-0156. The biosynthetic gene cluster for the pyralomicin antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156. The 41 kb gene cluster contains 27 ORFs predicted to encode all of the functions for pyralomicin biosynthesis. This includes nonribosomal peptide synthetases (GENE) and polyketide synthases (PKS) required for the formation of the CHEMICAL core unit, as well as a suite of tailoring enzymes (e.g., four halogenases, an O-methyltransferase, and an N-glycosyltransferase) necessary for further modifications of the core structure. The N-glycosyltransferase is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone. A gene cassette encoding C7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs. Targeted disruption of the gene encoding the N-glycosyltransferase, prlH, abolished pyralomicin production, and recombinant expression of PrlA confirms the activity of this enzyme as a sugar phosphate cyclase involved in the formation of the C7-cyclitol moiety. | PRODUCT-OF |
| Genetic Insights into Pyralomicin Biosynthesis in Nonomuraea spiralis IMC A-0156. The biosynthetic gene cluster for the pyralomicin antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156. The 41 kb gene cluster contains 27 ORFs predicted to encode all of the functions for pyralomicin biosynthesis. This includes nonribosomal peptide synthetases (NRPS) and GENE (PKS) required for the formation of the CHEMICAL core unit, as well as a suite of tailoring enzymes (e.g., four halogenases, an O-methyltransferase, and an N-glycosyltransferase) necessary for further modifications of the core structure. The N-glycosyltransferase is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone. A gene cassette encoding C7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs. Targeted disruption of the gene encoding the N-glycosyltransferase, prlH, abolished pyralomicin production, and recombinant expression of PrlA confirms the activity of this enzyme as a sugar phosphate cyclase involved in the formation of the C7-cyclitol moiety. | PRODUCT-OF |
| Genetic Insights into Pyralomicin Biosynthesis in Nonomuraea spiralis IMC A-0156. The biosynthetic gene cluster for the pyralomicin antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156. The 41 kb gene cluster contains 27 ORFs predicted to encode all of the functions for pyralomicin biosynthesis. This includes nonribosomal peptide synthetases (NRPS) and polyketide synthases (GENE) required for the formation of the CHEMICAL core unit, as well as a suite of tailoring enzymes (e.g., four halogenases, an O-methyltransferase, and an N-glycosyltransferase) necessary for further modifications of the core structure. The N-glycosyltransferase is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone. A gene cassette encoding C7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs. Targeted disruption of the gene encoding the N-glycosyltransferase, prlH, abolished pyralomicin production, and recombinant expression of PrlA confirms the activity of this enzyme as a sugar phosphate cyclase involved in the formation of the C7-cyclitol moiety. | PRODUCT-OF |
| Genetic Insights into Pyralomicin Biosynthesis in Nonomuraea spiralis IMC A-0156. The biosynthetic gene cluster for the pyralomicin antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156. The 41 kb gene cluster contains 27 ORFs predicted to encode all of the functions for pyralomicin biosynthesis. This includes nonribosomal peptide synthetases (NRPS) and polyketide synthases (PKS) required for the formation of the CHEMICAL core unit, as well as a suite of tailoring enzymes (e.g., four GENE, an O-methyltransferase, and an N-glycosyltransferase) necessary for further modifications of the core structure. The N-glycosyltransferase is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone. A gene cassette encoding C7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs. Targeted disruption of the gene encoding the N-glycosyltransferase, prlH, abolished pyralomicin production, and recombinant expression of PrlA confirms the activity of this enzyme as a sugar phosphate cyclase involved in the formation of the C7-cyclitol moiety. | PRODUCT-OF |
| Genetic Insights into Pyralomicin Biosynthesis in Nonomuraea spiralis IMC A-0156. The biosynthetic gene cluster for the pyralomicin antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156. The 41 kb gene cluster contains 27 ORFs predicted to encode all of the functions for pyralomicin biosynthesis. This includes nonribosomal peptide synthetases (NRPS) and polyketide synthases (PKS) required for the formation of the CHEMICAL core unit, as well as a suite of tailoring enzymes (e.g., four halogenases, an GENE, and an N-glycosyltransferase) necessary for further modifications of the core structure. The N-glycosyltransferase is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone. A gene cassette encoding C7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs. Targeted disruption of the gene encoding the N-glycosyltransferase, prlH, abolished pyralomicin production, and recombinant expression of PrlA confirms the activity of this enzyme as a sugar phosphate cyclase involved in the formation of the C7-cyclitol moiety. | PRODUCT-OF |
| Genetic Insights into Pyralomicin Biosynthesis in Nonomuraea spiralis IMC A-0156. The biosynthetic gene cluster for the pyralomicin antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156. The 41 kb gene cluster contains 27 ORFs predicted to encode all of the functions for pyralomicin biosynthesis. This includes nonribosomal peptide synthetases (NRPS) and polyketide synthases (PKS) required for the formation of the CHEMICAL core unit, as well as a suite of tailoring enzymes (e.g., four halogenases, an O-methyltransferase, and an GENE) necessary for further modifications of the core structure. The GENE is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone. A gene cassette encoding C7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs. Targeted disruption of the gene encoding the GENE, prlH, abolished pyralomicin production, and recombinant expression of PrlA confirms the activity of this enzyme as a sugar phosphate cyclase involved in the formation of the C7-cyclitol moiety. | PRODUCT-OF |
| Synaptotagmin 1 is required for vesicular CHEMICAL /H(+) -antiport activity. A low-affinity CHEMICAL /H(+) -antiport was described in the membrane of mammalian brain synaptic vesicles. Electrophysiological studies showed that this antiport contributes to the extreme brevity of excitation-release coupling in rapid synapses. GENE, a vesicular protein interacting with membranes upon low-affinity CHEMICAL -binding, plays a major role in excitation-release coupling, by synchronizing calcium entry with fast neurotransmitter release. Here, we report that GENE is necessary for expression of the vesicular CHEMICAL /H(+) -antiport. We measured CHEMICAL /H(+) -antiport activity in vesicles and granules of pheochromocytoma PC12 cells by three methods: (1) CHEMICAL -induced dissipation of the vesicular H(+) -gradient; (2) bafilomycin-sensitive calcium accumulation and (3) pH-jump-induced calcium accumulation. The results were congruent and highly significant: CHEMICAL /H(+) -antiport activity is detectable only in acidic organelles expressing functional GENE. In contrast, synaptotagmin-1-deficient cells - and cells where transgenically encoded GENE was acutely photo-inactivated - were devoid of any CHEMICAL /H(+) -antiport activity. Therefore, in addition to its previously described functions, GENE is involved in a rapid vesicular CHEMICAL sequestration through a CHEMICAL /H(+) antiport. This article is protected by copyright. All rights reserved. | SUBSTRATE |
| Synaptotagmin 1 is required for vesicular Ca(2+) /H(+) -antiport activity. A low-affinity Ca(2+) /H(+) -antiport was described in the membrane of mammalian brain synaptic vesicles. Electrophysiological studies showed that this antiport contributes to the extreme brevity of excitation-release coupling in rapid synapses. GENE, a vesicular protein interacting with membranes upon low-affinity Ca(2+) -binding, plays a major role in excitation-release coupling, by synchronizing calcium entry with fast neurotransmitter release. Here, we report that GENE is necessary for expression of the vesicular Ca(2+) /CHEMICAL -antiport. We measured Ca(2+) /H(+) -antiport activity in vesicles and granules of pheochromocytoma PC12 cells by three methods: (1) Ca(2+) -induced dissipation of the vesicular CHEMICAL -gradient; (2) bafilomycin-sensitive calcium accumulation and (3) pH-jump-induced calcium accumulation. The results were congruent and highly significant: Ca(2+) /H(+) -antiport activity is detectable only in acidic organelles expressing functional GENE. In contrast, synaptotagmin-1-deficient cells - and cells where transgenically encoded GENE was acutely photo-inactivated - were devoid of any Ca(2+) /H(+) -antiport activity. Therefore, in addition to its previously described functions, GENE is involved in a rapid vesicular Ca(2+) sequestration through a Ca(2+) /H(+) antiport. This article is protected by copyright. All rights reserved. | SUBSTRATE |
| GENE is required for vesicular CHEMICAL /H(+) -antiport activity. A low-affinity CHEMICAL /H(+) -antiport was described in the membrane of mammalian brain synaptic vesicles. Electrophysiological studies showed that this antiport contributes to the extreme brevity of excitation-release coupling in rapid synapses. Synaptotagmin-1, a vesicular protein interacting with membranes upon low-affinity CHEMICAL -binding, plays a major role in excitation-release coupling, by synchronizing calcium entry with fast neurotransmitter release. Here, we report that synaptotagmin-1 is necessary for expression of the vesicular CHEMICAL /H(+) -antiport. We measured CHEMICAL /H(+) -antiport activity in vesicles and granules of pheochromocytoma PC12 cells by three methods: (1) CHEMICAL -induced dissipation of the vesicular H(+) -gradient; (2) bafilomycin-sensitive calcium accumulation and (3) pH-jump-induced calcium accumulation. The results were congruent and highly significant: CHEMICAL /H(+) -antiport activity is detectable only in acidic organelles expressing functional synaptotagmin-1. In contrast, synaptotagmin-1-deficient cells - and cells where transgenically encoded synaptotagmin-1 was acutely photo-inactivated - were devoid of any CHEMICAL /H(+) -antiport activity. Therefore, in addition to its previously described functions, synaptotagmin-1 is involved in a rapid vesicular CHEMICAL sequestration through a CHEMICAL /H(+) antiport. This article is protected by copyright. All rights reserved. | REGULATOR |
| GENE is required for vesicular Ca(2+) /CHEMICAL -antiport activity. A low-affinity Ca(2+) /H(+) -antiport was described in the membrane of mammalian brain synaptic vesicles. Electrophysiological studies showed that this antiport contributes to the extreme brevity of excitation-release coupling in rapid synapses. Synaptotagmin-1, a vesicular protein interacting with membranes upon low-affinity Ca(2+) -binding, plays a major role in excitation-release coupling, by synchronizing calcium entry with fast neurotransmitter release. Here, we report that synaptotagmin-1 is necessary for expression of the vesicular Ca(2+) /H(+) -antiport. We measured Ca(2+) /H(+) -antiport activity in vesicles and granules of pheochromocytoma PC12 cells by three methods: (1) Ca(2+) -induced dissipation of the vesicular CHEMICAL -gradient; (2) bafilomycin-sensitive calcium accumulation and (3) pH-jump-induced calcium accumulation. The results were congruent and highly significant: Ca(2+) /H(+) -antiport activity is detectable only in acidic organelles expressing functional synaptotagmin-1. In contrast, synaptotagmin-1-deficient cells - and cells where transgenically encoded synaptotagmin-1 was acutely photo-inactivated - were devoid of any Ca(2+) /H(+) -antiport activity. Therefore, in addition to its previously described functions, synaptotagmin-1 is involved in a rapid vesicular Ca(2+) sequestration through a Ca(2+) /H(+) antiport. This article is protected by copyright. All rights reserved. | SUBSTRATE |
| Synaptotagmin 1 is required for vesicular Ca(2+) /H(+) -antiport activity. A low-affinity Ca(2+) /H(+) -antiport was described in the membrane of mammalian brain synaptic vesicles. Electrophysiological studies showed that this antiport contributes to the extreme brevity of excitation-release coupling in rapid synapses. GENE, a vesicular protein interacting with membranes upon low-affinity Ca(2+) -binding, plays a major role in excitation-release coupling, by synchronizing CHEMICAL entry with fast neurotransmitter release. Here, we report that synaptotagmin-1 is necessary for expression of the vesicular Ca(2+) /H(+) -antiport. We measured Ca(2+) /H(+) -antiport activity in vesicles and granules of pheochromocytoma PC12 cells by three methods: (1) Ca(2+) -induced dissipation of the vesicular H(+) -gradient; (2) bafilomycin-sensitive CHEMICAL accumulation and (3) pH-jump-induced CHEMICAL accumulation. The results were congruent and highly significant: Ca(2+) /H(+) -antiport activity is detectable only in acidic organelles expressing functional synaptotagmin-1. In contrast, synaptotagmin-1-deficient cells - and cells where transgenically encoded synaptotagmin-1 was acutely photo-inactivated - were devoid of any Ca(2+) /H(+) -antiport activity. Therefore, in addition to its previously described functions, synaptotagmin-1 is involved in a rapid vesicular Ca(2+) sequestration through a Ca(2+) /H(+) antiport. This article is protected by copyright. All rights reserved. | SUBSTRATE |
| Estradiol replacement enhances CHEMICAL-stimulated locomotion in female C57BL/6 mice through GENE. Psychostimulant effects are enhanced by ovarian hormones in women and female rodents. Estradiol increases behavioral responses to psychostimulants in women and female rats, although the underlying mechanism is unknown. This study utilized mice to investigate the time frame and receptor mediation of estradiol's enhancement of cocaine-induced behavior as mice enable parallel use of genetic, surgical and pharmacological methods. The spontaneous behavior of Sham and Ovariectomized (Ovx) female wildtype (WT) mice was determined during habituation to a novel environment and after CHEMICAL administration. Ovx mice were replaced with vehicle (sesame oil) or 17β-estradiol (E2) for 2 days or 30 min prior to a CHEMICAL challenge to investigate the time course of E2's effects. To examine receptor mediation of estradiol effects, Ovx mice replaced for 2 days with either the ERα-selective agonist PPT or the ERβ-selective agonist DPN were compared to Sham mice, and mice lacking either ERα (αERKO) or ERβ (βERKO) were compared to WT littermates. Ovx mice exhibited fewer ambulations during habituation than Sham females. Cocaine-induced increases in behavioral ratings were greater in Sham than in Ovx mice. Two days but not 30 min of E2 replacement in Ovx mice increased CHEMICAL responses to Sham levels. PPT replacement also increased the CHEMICAL response relative to vehicle- or DPN- treated Ovx mice. αERKO mice displayed modestly attenuated behavioral responses to novelty and CHEMICAL compared to αWT littermates, but no behavioral differences were found between βERKO and βWT mice. These results suggest that E2 enhances cocaine-stimulated locomotion in mice predominantly through ERα. | REGULATOR |
| Estradiol replacement enhances cocaine-stimulated locomotion in female C57BL/6 mice through estrogen receptor alpha. Psychostimulant effects are enhanced by ovarian hormones in women and female rodents. Estradiol increases behavioral responses to psychostimulants in women and female rats, although the underlying mechanism is unknown. This study utilized mice to investigate the time frame and receptor mediation of estradiol's enhancement of cocaine-induced behavior as mice enable parallel use of genetic, surgical and pharmacological methods. The spontaneous behavior of Sham and Ovariectomized (Ovx) female wildtype (WT) mice was determined during habituation to a novel environment and after CHEMICAL administration. Ovx mice were replaced with vehicle (sesame oil) or 17β-estradiol (E2) for 2 days or 30 min prior to a CHEMICAL challenge to investigate the time course of E2's effects. To examine receptor mediation of estradiol effects, Ovx mice replaced for 2 days with either the ERα-selective agonist PPT or the ERβ-selective agonist DPN were compared to Sham mice, and mice lacking either GENE (αERKO) or ERβ (βERKO) were compared to WT littermates. Ovx mice exhibited fewer ambulations during habituation than Sham females. Cocaine-induced increases in behavioral ratings were greater in Sham than in Ovx mice. Two days but not 30 min of E2 replacement in Ovx mice increased CHEMICAL responses to Sham levels. PPT replacement also increased the CHEMICAL response relative to vehicle- or DPN- treated Ovx mice. αERKO mice displayed modestly attenuated behavioral responses to novelty and CHEMICAL compared to αWT littermates, but no behavioral differences were found between βERKO and βWT mice. These results suggest that E2 enhances CHEMICAL-stimulated locomotion in mice predominantly through GENE. | REGULATOR |
| Estradiol replacement enhances cocaine-stimulated locomotion in female C57BL/6 mice through estrogen receptor alpha. Psychostimulant effects are enhanced by ovarian hormones in women and female rodents. Estradiol increases behavioral responses to psychostimulants in women and female rats, although the underlying mechanism is unknown. This study utilized mice to investigate the time frame and receptor mediation of estradiol's enhancement of cocaine-induced behavior as mice enable parallel use of genetic, surgical and pharmacological methods. The spontaneous behavior of Sham and Ovariectomized (Ovx) female wildtype (WT) mice was determined during habituation to a novel environment and after cocaine administration. Ovx mice were replaced with vehicle (sesame oil) or 17β-estradiol (E2) for 2 days or 30 min prior to a cocaine challenge to investigate the time course of E2's effects. To examine receptor mediation of estradiol effects, Ovx mice replaced for 2 days with either the GENE-selective agonist CHEMICAL or the ERβ-selective agonist DPN were compared to Sham mice, and mice lacking either GENE (αERKO) or ERβ (βERKO) were compared to WT littermates. Ovx mice exhibited fewer ambulations during habituation than Sham females. Cocaine-induced increases in behavioral ratings were greater in Sham than in Ovx mice. Two days but not 30 min of E2 replacement in Ovx mice increased cocaine responses to Sham levels. CHEMICAL replacement also increased the cocaine response relative to vehicle- or DPN- treated Ovx mice. αERKO mice displayed modestly attenuated behavioral responses to novelty and cocaine compared to αWT littermates, but no behavioral differences were found between βERKO and βWT mice. These results suggest that E2 enhances cocaine-stimulated locomotion in mice predominantly through GENE. | ACTIVATOR |
| Estradiol replacement enhances cocaine-stimulated locomotion in female C57BL/6 mice through estrogen receptor alpha. Psychostimulant effects are enhanced by ovarian hormones in women and female rodents. Estradiol increases behavioral responses to psychostimulants in women and female rats, although the underlying mechanism is unknown. This study utilized mice to investigate the time frame and receptor mediation of estradiol's enhancement of cocaine-induced behavior as mice enable parallel use of genetic, surgical and pharmacological methods. The spontaneous behavior of Sham and Ovariectomized (Ovx) female wildtype (WT) mice was determined during habituation to a novel environment and after cocaine administration. Ovx mice were replaced with vehicle (sesame oil) or 17β-estradiol (E2) for 2 days or 30 min prior to a cocaine challenge to investigate the time course of E2's effects. To examine receptor mediation of estradiol effects, Ovx mice replaced for 2 days with either the ERα-selective agonist PPT or the GENE-selective agonist CHEMICAL were compared to Sham mice, and mice lacking either ERα (αERKO) or GENE (βERKO) were compared to WT littermates. Ovx mice exhibited fewer ambulations during habituation than Sham females. Cocaine-induced increases in behavioral ratings were greater in Sham than in Ovx mice. Two days but not 30 min of E2 replacement in Ovx mice increased cocaine responses to Sham levels. PPT replacement also increased the cocaine response relative to vehicle- or DPN- treated Ovx mice. αERKO mice displayed modestly attenuated behavioral responses to novelty and cocaine compared to αWT littermates, but no behavioral differences were found between βERKO and βWT mice. These results suggest that E2 enhances cocaine-stimulated locomotion in mice predominantly through ERα. | ACTIVATOR |
| The GENE Regulates Vascular Smooth Muscle Cell Proliferation via Controlling CHEMICAL-dependent Signaling. The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to a variety of cell activation processes in pathologies such as inflammation, carcinogenesis and vascular remodeling. We examined the electrophysiological and transcriptional mechanisms by which KCa3.1 regulates vascular smooth muscle cell (VSMC) proliferation. Platelet-derived growth factor-BB (PDGF)-induced proliferation of human coronary artery VSMCs was attenuated by lowering intracellular Ca(2+) concentration ([Ca(2+)]i) and was enhanced by elevating [Ca(2+)]i. KCa3.1 blockade or knockdown inhibited proliferation by suppressing the rise in [Ca(2+)]i and attenuating the expression of phosphorylated cAMP response element binding protein (CREB), c-fos and neuron-derived orphan receptor-1 (NOR-1). This anti-proliferative effect was abolished by elevating [Ca(2+)]i. KCa3.1 overexpression induced VSMC proliferation, and potentiated PDGF-induced proliferation, by inducing CREB phosphorylation, c-fos and NOR-1. Pharmacological stimulation of KCa3.1 unexpectedly suppressed proliferation by inhibiting the rise in [Ca(2+)]i and abolishing the expression and activity of KCa3.1 and PDGF β-receptors. The stimulation also attenuated the levels of phosphorylated CREB, c-fos and cyclins expression. After KCa3.1 blockade, the characteristic round shape of VSMCs expressing high l-caldesmon and low calponin-1 (dedifferentiation state) was maintained, whereas KCa3.1 stimulation induced a spindle-shape cellular appearance, with low l-caldesmon and high calponin-1. In conclusion, KCa3.1 plays an important role in VSMC proliferation via controlling Ca(2+)-dependent signaling pathways and its modulation may therefore constitute a new therapeutic target for cell proliferative diseases such as atherosclerosis. | REGULATOR |
| Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1-b]thiazole-based Inverse Agonists of the Ghrelin Receptor. The current study examined the bioactivation potential of GENE inverse agonists, 1-(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(imidazo[2,1-b]thiazol-6-yl)ethanone (1) and CHEMICAL (2), containing a fused imidazo[2,1-b]thiazole motif in the core structure. Both compounds underwent oxidative metabolism in NADPH- and glutathione-supplemented human liver microsomes to yield glutathione conjugates, which was consistent with their bioactivation to reactive species. Mass spectral fragmentation and NMR analysis indicated that the site of attachment of the glutathionyl moiety in the thiol conjugates was on the thiazole ring within the bicycle. Two glutathione conjugates were discerned with the imidazo[2,1-b]thiazole derivative 1. One adduct was derived from the Michael addition of glutathione to a putative S-oxide metabolite of 1, whereas, the second adduct was formed via the reaction of a second glutathione molecule with the initial glutathione-S-oxide adduct. In the case of the 2-methylimidazo[2,1-b]thiazole analog 2, glutathione conjugation occurred via an oxidative desulfation mechanism, possibly involving thiazole ring epoxidation as the rate-limiting step. Additional insights into the mechanism were obtained via 18O exchange and trapping studies with potassium cyanide. The mechanistic insights into the bioactivation pathways of 1 and 2 allowed the deployment of a rational chemical intervention strategy that involved replacement of the thiazole ring with a 1,2,4-thiadiazole group to yield -(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethanone (3). These structural changes not only abrogated the bioactivation liability but also retained the attractive pharmacological attributes of the prototype agents. | ACTIVATOR |
| Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1-b]thiazole-based Inverse Agonists of the Ghrelin Receptor. The current study examined the bioactivation potential of GENE inverse agonists, 1-(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(imidazo[2,1-b]thiazol-6-yl)ethanone (1) and 1-(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b]thiazol-6-yl)ethanone (2), containing a fused CHEMICAL motif in the core structure. Both compounds underwent oxidative metabolism in NADPH- and glutathione-supplemented human liver microsomes to yield glutathione conjugates, which was consistent with their bioactivation to reactive species. Mass spectral fragmentation and NMR analysis indicated that the site of attachment of the glutathionyl moiety in the thiol conjugates was on the thiazole ring within the bicycle. Two glutathione conjugates were discerned with the CHEMICAL derivative 1. One adduct was derived from the Michael addition of glutathione to a putative S-oxide metabolite of 1, whereas, the second adduct was formed via the reaction of a second glutathione molecule with the initial glutathione-S-oxide adduct. In the case of the 2-methylimidazo[2,1-b]thiazole analog 2, glutathione conjugation occurred via an oxidative desulfation mechanism, possibly involving thiazole ring epoxidation as the rate-limiting step. Additional insights into the mechanism were obtained via 18O exchange and trapping studies with potassium cyanide. The mechanistic insights into the bioactivation pathways of 1 and 2 allowed the deployment of a rational chemical intervention strategy that involved replacement of the thiazole ring with a 1,2,4-thiadiazole group to yield -(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethanone (3). These structural changes not only abrogated the bioactivation liability but also retained the attractive pharmacological attributes of the prototype agents. | ACTIVATOR |
| Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1-b]thiazole-based Inverse Agonists of the Ghrelin Receptor. The current study examined the bioactivation potential of GENE inverse agonists, CHEMICAL (1) and 1-(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b]thiazol-6-yl)ethanone (2), containing a fused imidazo[2,1-b]thiazole motif in the core structure. Both compounds underwent oxidative metabolism in NADPH- and glutathione-supplemented human liver microsomes to yield glutathione conjugates, which was consistent with their bioactivation to reactive species. Mass spectral fragmentation and NMR analysis indicated that the site of attachment of the glutathionyl moiety in the thiol conjugates was on the thiazole ring within the bicycle. Two glutathione conjugates were discerned with the imidazo[2,1-b]thiazole derivative 1. One adduct was derived from the Michael addition of glutathione to a putative S-oxide metabolite of 1, whereas, the second adduct was formed via the reaction of a second glutathione molecule with the initial glutathione-S-oxide adduct. In the case of the 2-methylimidazo[2,1-b]thiazole analog 2, glutathione conjugation occurred via an oxidative desulfation mechanism, possibly involving thiazole ring epoxidation as the rate-limiting step. Additional insights into the mechanism were obtained via 18O exchange and trapping studies with potassium cyanide. The mechanistic insights into the bioactivation pathways of 1 and 2 allowed the deployment of a rational chemical intervention strategy that involved replacement of the thiazole ring with a 1,2,4-thiadiazole group to yield -(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethanone (3). These structural changes not only abrogated the bioactivation liability but also retained the attractive pharmacological attributes of the prototype agents. | ACTIVATOR |
| Reactive Metabolite Trapping Studies on CHEMICAL-based Inverse Agonists of the GENE. The current study examined the bioactivation potential of ghrelin receptor inverse agonists, 1-(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(imidazo[2,1-b]thiazol-6-yl)ethanone (1) and 1-(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b]thiazol-6-yl)ethanone (2), containing a fused imidazo[2,1-b]thiazole motif in the core structure. Both compounds underwent oxidative metabolism in NADPH- and glutathione-supplemented human liver microsomes to yield glutathione conjugates, which was consistent with their bioactivation to reactive species. Mass spectral fragmentation and NMR analysis indicated that the site of attachment of the glutathionyl moiety in the thiol conjugates was on the thiazole ring within the bicycle. Two glutathione conjugates were discerned with the imidazo[2,1-b]thiazole derivative 1. One adduct was derived from the Michael addition of glutathione to a putative S-oxide metabolite of 1, whereas, the second adduct was formed via the reaction of a second glutathione molecule with the initial glutathione-S-oxide adduct. In the case of the 2-methylimidazo[2,1-b]thiazole analog 2, glutathione conjugation occurred via an oxidative desulfation mechanism, possibly involving thiazole ring epoxidation as the rate-limiting step. Additional insights into the mechanism were obtained via 18O exchange and trapping studies with potassium cyanide. The mechanistic insights into the bioactivation pathways of 1 and 2 allowed the deployment of a rational chemical intervention strategy that involved replacement of the thiazole ring with a 1,2,4-thiadiazole group to yield -(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethanone (3). These structural changes not only abrogated the bioactivation liability but also retained the attractive pharmacological attributes of the prototype agents. | ACTIVATOR |
| Probing the Role of the CHEMICAL E-Ring Aryl Chloride: Selective Divergent Synthesis and Evaluation of Alternatively Substituted E-Ring Analogues. The selective functionalization of a CHEMICAL aglycon derivative through direct conversion of the E-ring aryl chloride to a reactive boronic acid, and its use in the synthesis of a systematic series of CHEMICAL E-ring analogues are described. The series of analogues was used to examine the impact of the E-ring chloride in binding D-Ala-D-Ala and on antimicrobial activity. In contrast to the reduced activity of the unsubstituted E-ring derivatives, hydrophobic and relatively non-polar substituents approach or match the chloro substituted CHEMICAL and was insensitive to the electronic character of the substituent (e.g. Cl vs CN or OMe), whereas highly polar substituents fail to provide the enhancements. Moreover, the active permethylated CHEMICAL aglycon derivatives examined exhibit GENE VRE antimicrobial activity at levels that approach (typically within 2-fold) their activity against sensitive bacteria. The robust borylation reaction also enabled the selective functionalization of a minimally protected CHEMICAL aglycon (N-Boc CHEMICAL aglycon), and provides a direct method for the preparation of previously inaccessible analogues. | INHIBITOR |
| Exposure to CHEMICAL decreased four fatty acid levels in plasma of prepartum mice. Maternal exposure to di(2-ethylhexyl) phthalate (DEHP) decreased the plasma triglyceride in prepartum mice. To identify the fatty acid (FA) species involved and to understand the underlying mechanisms, pregnant Sv/129 wild-type (mPPARα), peroxisome proliferator-activated receptor α-null (Pparα-null) and humanized PPARα (hPPARα) mice were treated with diets containing 0%, 0.01%, 0.05% or 0.1% CHEMICAL. Dams were dissected on gestational day 18 together with fetuses, and on postnatal day 2 together with newborns. n-3/n-6 polyunsaturated, saturated, and monounsaturated FAs in maternal plasma and in liver of wild-type offspring, and representative enzymes for FA desaturation and elongation in maternal liver, were measured. The plasma levels of linoleic acid, α-linolenic acid, palmitic acid and oleic acid were higher in the pregnant control mPPARa mice than in Ppara-null and hPPARa mice. CHEMICAL exposure significantly decreased the levels of these four FAs only in pregnant GENE mice. Plasma levels of many FAs were higher in pregnant mice than in postpartum ones in a genotype-independent manner, while it was lower in the livers of fetuses than pups. CHEMICAL exposure slightly increased hepatic arachidonic acid, α-linolenic acid, palmitoleic acid and oleic acid in fetuses, but not in pups. However, CHEMICAL exposure did not clearly influence FA desaturase 1 and 2 nor elongase 2 and 5 expressions in the liver of all maternal mice. Taken together, the levels of plasma four FAs with shorter carbon chains were higher in pregnant GENE mice than in other genotypes, and CHEMICAL exposure decreased these specific FA concentrations only in GENE mice, similarly to triglyceride levels. | INDIRECT-DOWNREGULATOR |
| Soluble polysialylated NCAM: a novel player of the innate immune system in the lung. Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated GENE (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, CHEMICAL was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased CHEMICAL levels and processing of the GENE carrier were observed. Processing of polysialylated GENE was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, CHEMICAL chains of secreted GENE neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing "neutrophil extracellular traps", which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes. | PART-OF |
| Soluble polysialylated NCAM: a novel player of the innate immune system in the lung. Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated NCAM (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, CHEMICAL was exclusively attached to the transmembrane isoform GENE and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased CHEMICAL levels and processing of the NCAM carrier were observed. Processing of polysialylated NCAM was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, CHEMICAL chains of secreted NCAM neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing "neutrophil extracellular traps", which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes. | DIRECT-REGULATOR |
| Soluble polysialylated NCAM: a novel player of the innate immune system in the lung. Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated NCAM (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, CHEMICAL was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased CHEMICAL levels and processing of the NCAM carrier were observed. Processing of polysialylated NCAM was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, CHEMICAL chains of secreted NCAM neutralized the cytotoxic activity of extracellular GENE as well as DNA/histone-network-containing "neutrophil extracellular traps", which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes. | GENE-CHEMICAL |
| Soluble polysialylated NCAM: a novel player of the innate immune system in the lung. Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated NCAM (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, CHEMICAL was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased CHEMICAL levels and processing of the NCAM carrier were observed. Processing of polysialylated NCAM was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, CHEMICAL chains of secreted NCAM neutralized the cytotoxic activity of extracellular histones as well as DNA/GENE-network-containing "neutrophil extracellular traps", which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes. | PART-OF |
| Soluble polysialylated NCAM: a novel player of the innate immune system in the lung. Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of GENE (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, polySia was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased polySia levels and processing of the NCAM carrier were observed. Processing of GENE was reproduced in a mouse model by CHEMICAL administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, polySia chains of secreted NCAM neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing "neutrophil extracellular traps", which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes. | REGULATOR |
| Soluble polysialylated NCAM: a novel player of the innate immune system in the lung. Posttranslational modification of the GENE (NCAM) by polysialic acid (CHEMICAL) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated NCAM (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, CHEMICAL was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased CHEMICAL levels and processing of the NCAM carrier were observed. Processing of polysialylated NCAM was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, CHEMICAL chains of secreted NCAM neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing "neutrophil extracellular traps", which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes. | REGULATOR |
| Soluble polysialylated NCAM: a novel player of the innate immune system in the lung. Posttranslational modification of the GENE (NCAM) by CHEMICAL (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated NCAM (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, polySia was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased polySia levels and processing of the NCAM carrier were observed. Processing of polysialylated NCAM was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, polySia chains of secreted NCAM neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing "neutrophil extracellular traps", which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes. | REGULATOR |
| Soluble polysialylated NCAM: a novel player of the innate immune system in the lung. Posttranslational modification of the neural cell adhesion molecule (GENE) by CHEMICAL (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated GENE (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, polySia was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased polySia levels and processing of the GENE carrier were observed. Processing of polysialylated GENE was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, polySia chains of secreted GENE neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing "neutrophil extracellular traps", which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes. | REGULATOR |
| Soluble polysialylated NCAM: a novel player of the innate immune system in the lung. Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated NCAM (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, polySia was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased polySia levels and processing of the NCAM carrier were observed. Processing of polysialylated NCAM was reproduced in a mouse model by CHEMICAL administration leading to an activation of the inflammasome and secretion of GENE. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, polySia chains of secreted NCAM neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing "neutrophil extracellular traps", which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes. | GENE-CHEMICAL |
| Evaluation of the positive effects on insulin-resistance and β-cell measurements of vildagliptin in addition to metformin in type 2 diabetic patients. We evaluated the positive effects of vildagliptin in addition to metformin on glycemic control and β-cell function in type 2 diabetic patients. One hundred and seventy-one type 2 diabetic patients were instructed to add vildaglipin 50mg twice a day or placebo to metformin for 12 months. Body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, GENE, vaspin, visfatin, and omentin-1 were evaluated. Before, and after 12 months since the addition of vildagliptin, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. CHEMICAL+metformin were more effective than placebo+metformin in reducing body weight and BMI, glycemic control, HOMA-IR, GENE and insulin resistance measurements. Vildagliptin+metformin gave also a better increase of HOMA-β, and of all β-cell parameters after the clamp. We also recorded a significant correlation between M value increase and the decrease of vaspin, visfatin, and omentin-1 obtained with vildagliptin+metformin. CHEMICAL, in addition to metformin, proved to be effective in improving β-cell function and in reducing insulin resistance measurements. | INDIRECT-DOWNREGULATOR |
| Evaluation of the positive effects on insulin-resistance and β-cell measurements of vildagliptin in addition to metformin in type 2 diabetic patients. We evaluated the positive effects of vildagliptin in addition to metformin on glycemic control and β-cell function in type 2 diabetic patients. One hundred and seventy-one type 2 diabetic patients were instructed to add vildaglipin 50mg twice a day or placebo to metformin for 12 months. Body mass index (BMI), glycemic control, fasting plasma GENE (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma GENE ratio (Pr/FPI ratio), C-peptide, glucagon, vaspin, visfatin, and omentin-1 were evaluated. Before, and after 12 months since the addition of vildagliptin, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. CHEMICAL+metformin were more effective than placebo+metformin in reducing body weight and BMI, glycemic control, HOMA-IR, glucagon and GENE resistance measurements. Vildagliptin+metformin gave also a better increase of HOMA-β, and of all β-cell parameters after the clamp. We also recorded a significant correlation between M value increase and the decrease of vaspin, visfatin, and omentin-1 obtained with vildagliptin+metformin. CHEMICAL, in addition to metformin, proved to be effective in improving β-cell function and in reducing GENE resistance measurements. | INDIRECT-DOWNREGULATOR |
| Evaluation of the positive effects on insulin-resistance and β-cell measurements of vildagliptin in addition to CHEMICAL in type 2 diabetic patients. We evaluated the positive effects of vildagliptin in addition to CHEMICAL on glycemic control and β-cell function in type 2 diabetic patients. One hundred and seventy-one type 2 diabetic patients were instructed to add vildaglipin 50mg twice a day or placebo to CHEMICAL for 12 months. Body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, GENE, vaspin, visfatin, and omentin-1 were evaluated. Before, and after 12 months since the addition of vildagliptin, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. Vildagliptin+CHEMICAL were more effective than placebo+metformin in reducing body weight and BMI, glycemic control, HOMA-IR, GENE and insulin resistance measurements. Vildagliptin+metformin gave also a better increase of HOMA-β, and of all β-cell parameters after the clamp. We also recorded a significant correlation between M value increase and the decrease of vaspin, visfatin, and omentin-1 obtained with vildagliptin+metformin. Vildagliptin, in addition to CHEMICAL, proved to be effective in improving β-cell function and in reducing insulin resistance measurements. | INDIRECT-DOWNREGULATOR |
| Evaluation of the positive effects on insulin-resistance and β-cell measurements of vildagliptin in addition to CHEMICAL in type 2 diabetic patients. We evaluated the positive effects of vildagliptin in addition to CHEMICAL on glycemic control and β-cell function in type 2 diabetic patients. One hundred and seventy-one type 2 diabetic patients were instructed to add vildaglipin 50mg twice a day or placebo to CHEMICAL for 12 months. Body mass index (BMI), glycemic control, fasting plasma GENE (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma GENE ratio (Pr/FPI ratio), C-peptide, glucagon, vaspin, visfatin, and omentin-1 were evaluated. Before, and after 12 months since the addition of vildagliptin, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. Vildagliptin+CHEMICAL were more effective than placebo+metformin in reducing body weight and BMI, glycemic control, HOMA-IR, glucagon and GENE resistance measurements. Vildagliptin+metformin gave also a better increase of HOMA-β, and of all β-cell parameters after the clamp. We also recorded a significant correlation between M value increase and the decrease of vaspin, visfatin, and omentin-1 obtained with vildagliptin+metformin. Vildagliptin, in addition to CHEMICAL, proved to be effective in improving β-cell function and in reducing GENE resistance measurements. | GENE-CHEMICAL |
| Evaluation of the positive effects on insulin-resistance and β-cell measurements of CHEMICAL in addition to metformin in type 2 diabetic patients. We evaluated the positive effects of CHEMICAL in addition to metformin on glycemic control and β-cell function in type 2 diabetic patients. One hundred and seventy-one type 2 diabetic patients were instructed to add vildaglipin 50mg twice a day or placebo to metformin for 12 months. Body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, GENE, visfatin, and omentin-1 were evaluated. Before, and after 12 months since the addition of CHEMICAL, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. Vildagliptin+metformin were more effective than placebo+metformin in reducing body weight and BMI, glycemic control, HOMA-IR, glucagon and insulin resistance measurements. Vildagliptin+metformin gave also a better increase of HOMA-β, and of all β-cell parameters after the clamp. We also recorded a significant correlation between M value increase and the decrease of GENE, visfatin, and omentin-1 obtained with CHEMICAL+metformin. CHEMICAL, in addition to metformin, proved to be effective in improving β-cell function and in reducing insulin resistance measurements. | INDIRECT-DOWNREGULATOR |
| Evaluation of the positive effects on insulin-resistance and β-cell measurements of CHEMICAL in addition to metformin in type 2 diabetic patients. We evaluated the positive effects of CHEMICAL in addition to metformin on glycemic control and β-cell function in type 2 diabetic patients. One hundred and seventy-one type 2 diabetic patients were instructed to add vildaglipin 50mg twice a day or placebo to metformin for 12 months. Body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, vaspin, GENE, and omentin-1 were evaluated. Before, and after 12 months since the addition of CHEMICAL, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. Vildagliptin+metformin were more effective than placebo+metformin in reducing body weight and BMI, glycemic control, HOMA-IR, glucagon and insulin resistance measurements. Vildagliptin+metformin gave also a better increase of HOMA-β, and of all β-cell parameters after the clamp. We also recorded a significant correlation between M value increase and the decrease of vaspin, GENE, and omentin-1 obtained with CHEMICAL+metformin. CHEMICAL, in addition to metformin, proved to be effective in improving β-cell function and in reducing insulin resistance measurements. | INDIRECT-DOWNREGULATOR |
| Evaluation of the positive effects on insulin-resistance and β-cell measurements of CHEMICAL in addition to metformin in type 2 diabetic patients. We evaluated the positive effects of CHEMICAL in addition to metformin on glycemic control and β-cell function in type 2 diabetic patients. One hundred and seventy-one type 2 diabetic patients were instructed to add vildaglipin 50mg twice a day or placebo to metformin for 12 months. Body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, vaspin, visfatin, and GENE were evaluated. Before, and after 12 months since the addition of CHEMICAL, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. Vildagliptin+metformin were more effective than placebo+metformin in reducing body weight and BMI, glycemic control, HOMA-IR, glucagon and insulin resistance measurements. Vildagliptin+metformin gave also a better increase of HOMA-β, and of all β-cell parameters after the clamp. We also recorded a significant correlation between M value increase and the decrease of vaspin, visfatin, and GENE obtained with CHEMICAL+metformin. CHEMICAL, in addition to metformin, proved to be effective in improving β-cell function and in reducing insulin resistance measurements. | INDIRECT-DOWNREGULATOR |
| Evaluation of the positive effects on insulin-resistance and β-cell measurements of vildagliptin in addition to CHEMICAL in type 2 diabetic patients. We evaluated the positive effects of vildagliptin in addition to CHEMICAL on glycemic control and β-cell function in type 2 diabetic patients. One hundred and seventy-one type 2 diabetic patients were instructed to add vildaglipin 50mg twice a day or placebo to CHEMICAL for 12 months. Body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, GENE, visfatin, and omentin-1 were evaluated. Before, and after 12 months since the addition of vildagliptin, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. Vildagliptin+metformin were more effective than placebo+metformin in reducing body weight and BMI, glycemic control, HOMA-IR, glucagon and insulin resistance measurements. Vildagliptin+metformin gave also a better increase of HOMA-β, and of all β-cell parameters after the clamp. We also recorded a significant correlation between M value increase and the decrease of GENE, visfatin, and omentin-1 obtained with vildagliptin+CHEMICAL. Vildagliptin, in addition to CHEMICAL, proved to be effective in improving β-cell function and in reducing insulin resistance measurements. | INDIRECT-DOWNREGULATOR |
| Evaluation of the positive effects on insulin-resistance and β-cell measurements of vildagliptin in addition to CHEMICAL in type 2 diabetic patients. We evaluated the positive effects of vildagliptin in addition to CHEMICAL on glycemic control and β-cell function in type 2 diabetic patients. One hundred and seventy-one type 2 diabetic patients were instructed to add vildaglipin 50mg twice a day or placebo to CHEMICAL for 12 months. Body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, vaspin, GENE, and omentin-1 were evaluated. Before, and after 12 months since the addition of vildagliptin, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. Vildagliptin+metformin were more effective than placebo+metformin in reducing body weight and BMI, glycemic control, HOMA-IR, glucagon and insulin resistance measurements. Vildagliptin+metformin gave also a better increase of HOMA-β, and of all β-cell parameters after the clamp. We also recorded a significant correlation between M value increase and the decrease of vaspin, GENE, and omentin-1 obtained with vildagliptin+CHEMICAL. Vildagliptin, in addition to CHEMICAL, proved to be effective in improving β-cell function and in reducing insulin resistance measurements. | INDIRECT-DOWNREGULATOR |
| Evaluation of the positive effects on insulin-resistance and β-cell measurements of vildagliptin in addition to CHEMICAL in type 2 diabetic patients. We evaluated the positive effects of vildagliptin in addition to CHEMICAL on glycemic control and β-cell function in type 2 diabetic patients. One hundred and seventy-one type 2 diabetic patients were instructed to add vildaglipin 50mg twice a day or placebo to CHEMICAL for 12 months. Body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, vaspin, visfatin, and GENE were evaluated. Before, and after 12 months since the addition of vildagliptin, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. Vildagliptin+metformin were more effective than placebo+metformin in reducing body weight and BMI, glycemic control, HOMA-IR, glucagon and insulin resistance measurements. Vildagliptin+metformin gave also a better increase of HOMA-β, and of all β-cell parameters after the clamp. We also recorded a significant correlation between M value increase and the decrease of vaspin, visfatin, and GENE obtained with vildagliptin+CHEMICAL. Vildagliptin, in addition to CHEMICAL, proved to be effective in improving β-cell function and in reducing insulin resistance measurements. | INDIRECT-DOWNREGULATOR |
| 4-Hydroxytamoxifen-stimulated processing of GENE is mediated via G protein-coupled receptor 30 (GPR30) and accompanied by enhanced migration in MCF-7 breast cancer cells. Over-expression of cleaved GENE in breast tumors is closely associated with tumor progression and resistance to antiestrogens. 17β-Estradiol (E2) has been recently shown to induce GENE processing in breast cancer cells. Tamoxifen has been used in patients with estrogen-sensitive breast cancer, yet resistance to antiestrogens and recurrence will appear in some of the patients after its continued use. We therefore addressed possible effects of tamoxifen on the generation of cleaved GENE and its signal mechanism(s) in estrogen-responsive MCF-7 breast cancer cells that express both G protein-coupled protein (GPR) 30 and estrogen receptor α (ERα). CHEMICAL (OHT, tamoxifen's active form) failed to prevent E2-induced proteolysis of GENE and migration, but rather triggered GENE cleavage coincident with augmented migration. OHT-induced GENE truncation also occurred in SK-BR-3 cells that express GPR30 and lack ERα, but not in MDA-MB-231 cells that express neither GPR30 nor ERα. G1, a specific GPR 30 agonist, caused dramatic proteolysis of GENE and enhanced migration. Furthermore, OHT-stimulated cleavage of GENE and migration were tremendously attenuated by G15, a GPR30 antagonist, or siRNA against GPR30. In addition, inhibitors for EGFR or ERK1/2 remarkably suppressed OHT-induced truncation of GENE, suggesting involvement of EGFR signaling. Collectively, our data indicate that OHT contributes to the production of proteolyzed GENE via GPR30 with augmented migration in MCF-7 cells. | NO-RELATIONSHIP |
| 4-Hydroxytamoxifen-stimulated processing of GENE is mediated via G protein-coupled receptor 30 (GPR30) and accompanied by enhanced migration in MCF-7 breast cancer cells. Over-expression of cleaved GENE in breast tumors is closely associated with tumor progression and resistance to antiestrogens. 17β-Estradiol (E2) has been recently shown to induce GENE processing in breast cancer cells. Tamoxifen has been used in patients with estrogen-sensitive breast cancer, yet resistance to antiestrogens and recurrence will appear in some of the patients after its continued use. We therefore addressed possible effects of tamoxifen on the generation of cleaved GENE and its signal mechanism(s) in estrogen-responsive MCF-7 breast cancer cells that express both G protein-coupled protein (GPR) 30 and estrogen receptor α (ERα). 4-Hydroxytamoxifen (CHEMICAL, tamoxifen's active form) failed to prevent E2-induced proteolysis of GENE and migration, but rather triggered GENE cleavage coincident with augmented migration. OHT-induced GENE truncation also occurred in SK-BR-3 cells that express GPR30 and lack ERα, but not in MDA-MB-231 cells that express neither GPR30 nor ERα. G1, a specific GPR 30 agonist, caused dramatic proteolysis of GENE and enhanced migration. Furthermore, OHT-stimulated cleavage of GENE and migration were tremendously attenuated by G15, a GPR30 antagonist, or siRNA against GPR30. In addition, inhibitors for EGFR or ERK1/2 remarkably suppressed OHT-induced truncation of GENE, suggesting involvement of EGFR signaling. Collectively, our data indicate that CHEMICAL contributes to the production of proteolyzed GENE via GPR30 with augmented migration in MCF-7 cells. | NO-RELATIONSHIP |
| 4-Hydroxytamoxifen-stimulated processing of GENE is mediated via G protein-coupled receptor 30 (GPR30) and accompanied by enhanced migration in MCF-7 breast cancer cells. Over-expression of cleaved GENE in breast tumors is closely associated with tumor progression and resistance to antiestrogens. 17β-Estradiol (E2) has been recently shown to induce GENE processing in breast cancer cells. CHEMICAL has been used in patients with estrogen-sensitive breast cancer, yet resistance to antiestrogens and recurrence will appear in some of the patients after its continued use. We therefore addressed possible effects of CHEMICAL on the generation of cleaved GENE and its signal mechanism(s) in estrogen-responsive MCF-7 breast cancer cells that express both G protein-coupled protein (GPR) 30 and estrogen receptor α (ERα). 4-Hydroxytamoxifen (OHT, CHEMICAL's active form) failed to prevent E2-induced proteolysis of GENE and migration, but rather triggered GENE cleavage coincident with augmented migration. OHT-induced GENE truncation also occurred in SK-BR-3 cells that express GPR30 and lack ERα, but not in MDA-MB-231 cells that express neither GPR30 nor ERα. G1, a specific GPR 30 agonist, caused dramatic proteolysis of GENE and enhanced migration. Furthermore, OHT-stimulated cleavage of GENE and migration were tremendously attenuated by G15, a GPR30 antagonist, or siRNA against GPR30. In addition, inhibitors for EGFR or ERK1/2 remarkably suppressed OHT-induced truncation of GENE, suggesting involvement of EGFR signaling. Collectively, our data indicate that OHT contributes to the production of proteolyzed GENE via GPR30 with augmented migration in MCF-7 cells. | GENE-CHEMICAL |
| 4-Hydroxytamoxifen-stimulated processing of cyclin E is mediated via G protein-coupled receptor 30 (GPR30) and accompanied by enhanced migration in MCF-7 breast cancer cells. Over-expression of cleaved cyclin E in breast tumors is closely associated with tumor progression and resistance to antiestrogens. 17β-Estradiol (E2) has been recently shown to induce cyclin E processing in breast cancer cells. Tamoxifen has been used in patients with estrogen-sensitive breast cancer, yet resistance to antiestrogens and recurrence will appear in some of the patients after its continued use. We therefore addressed possible effects of tamoxifen on the generation of cleaved cyclin E and its signal mechanism(s) in estrogen-responsive MCF-7 breast cancer cells that express both G protein-coupled protein (GPR) 30 and estrogen receptor α (ERα). 4-Hydroxytamoxifen (OHT, tamoxifen's active form) failed to prevent E2-induced proteolysis of cyclin E and migration, but rather triggered cyclin E cleavage coincident with augmented migration. OHT-induced cyclin E truncation also occurred in SK-BR-3 cells that express GPR30 and lack ERα, but not in MDA-MB-231 cells that express neither GPR30 nor ERα. G1, a specific GPR 30 agonist, caused dramatic proteolysis of cyclin E and enhanced migration. Furthermore, OHT-stimulated cleavage of cyclin E and migration were tremendously attenuated by G15, a GPR30 antagonist, or siRNA against GPR30. In addition, inhibitors for GENE or ERK1/2 remarkably suppressed CHEMICAL-induced truncation of cyclin E, suggesting involvement of GENE signaling. Collectively, our data indicate that CHEMICAL contributes to the production of proteolyzed cyclin E via GPR30 with augmented migration in MCF-7 cells. | REGULATOR |
| 4-Hydroxytamoxifen-stimulated processing of cyclin E is mediated via G protein-coupled receptor 30 (GPR30) and accompanied by enhanced migration in MCF-7 breast cancer cells. Over-expression of cleaved cyclin E in breast tumors is closely associated with tumor progression and resistance to antiestrogens. 17β-Estradiol (E2) has been recently shown to induce cyclin E processing in breast cancer cells. Tamoxifen has been used in patients with estrogen-sensitive breast cancer, yet resistance to antiestrogens and recurrence will appear in some of the patients after its continued use. We therefore addressed possible effects of tamoxifen on the generation of cleaved cyclin E and its signal mechanism(s) in estrogen-responsive MCF-7 breast cancer cells that express both G protein-coupled protein (GPR) 30 and estrogen receptor α (ERα). 4-Hydroxytamoxifen (OHT, tamoxifen's active form) failed to prevent E2-induced proteolysis of cyclin E and migration, but rather triggered cyclin E cleavage coincident with augmented migration. CHEMICAL-induced cyclin E truncation also occurred in SK-BR-3 cells that express GENE and lack ERα, but not in MDA-MB-231 cells that express neither GENE nor ERα. G1, a specific GPR 30 agonist, caused dramatic proteolysis of cyclin E and enhanced migration. Furthermore, OHT-stimulated cleavage of cyclin E and migration were tremendously attenuated by G15, a GENE antagonist, or siRNA against GENE. In addition, inhibitors for EGFR or ERK1/2 remarkably suppressed OHT-induced truncation of cyclin E, suggesting involvement of EGFR signaling. Collectively, our data indicate that CHEMICAL contributes to the production of proteolyzed cyclin E via GENE with augmented migration in MCF-7 cells. | REGULATOR |
| CHEMICAL-stimulated processing of cyclin E is mediated via G protein-coupled receptor 30 (GENE and accompanied by enhanced migration in MCF-7 breast cancer cells. Over-expression of cleaved cyclin E in breast tumors is closely associated with tumor progression and resistance to antiestrogens. 17β-Estradiol (E2) has been recently shown to induce cyclin E processing in breast cancer cells. Tamoxifen has been used in patients with estrogen-sensitive breast cancer, yet resistance to antiestrogens and recurrence will appear in some of the patients after its continued use. We therefore addressed possible effects of tamoxifen on the generation of cleaved cyclin E and its signal mechanism(s) in estrogen-responsive MCF-7 breast cancer cells that express both G protein-coupled protein (GPR) 30 and estrogen receptor α (ERα). CHEMICAL (OHT, tamoxifen's active form) failed to prevent E2-induced proteolysis of cyclin E and migration, but rather triggered cyclin E cleavage coincident with augmented migration. OHT-induced cyclin E truncation also occurred in SK-BR-3 cells that express GPR30 and lack ERα, but not in MDA-MB-231 cells that express neither GPR30 nor ERα. G1, a specific GPR 30 agonist, caused dramatic proteolysis of cyclin E and enhanced migration. Furthermore, OHT-stimulated cleavage of cyclin E and migration were tremendously attenuated by G15, a GPR30 antagonist, or siRNA against GPR30. In addition, inhibitors for EGFR or ERK1/2 remarkably suppressed OHT-induced truncation of cyclin E, suggesting involvement of EGFR signaling. Collectively, our data indicate that OHT contributes to the production of proteolyzed cyclin E via GPR30 with augmented migration in MCF-7 cells. | REGULATOR |
| CHEMICAL-stimulated processing of cyclin E is mediated via GENE (GPR30) and accompanied by enhanced migration in MCF-7 breast cancer cells. Over-expression of cleaved cyclin E in breast tumors is closely associated with tumor progression and resistance to antiestrogens. 17β-Estradiol (E2) has been recently shown to induce cyclin E processing in breast cancer cells. Tamoxifen has been used in patients with estrogen-sensitive breast cancer, yet resistance to antiestrogens and recurrence will appear in some of the patients after its continued use. We therefore addressed possible effects of tamoxifen on the generation of cleaved cyclin E and its signal mechanism(s) in estrogen-responsive MCF-7 breast cancer cells that express both G protein-coupled protein (GPR) 30 and estrogen receptor α (ERα). CHEMICAL (OHT, tamoxifen's active form) failed to prevent E2-induced proteolysis of cyclin E and migration, but rather triggered cyclin E cleavage coincident with augmented migration. OHT-induced cyclin E truncation also occurred in SK-BR-3 cells that express GPR30 and lack ERα, but not in MDA-MB-231 cells that express neither GPR30 nor ERα. G1, a specific GPR 30 agonist, caused dramatic proteolysis of cyclin E and enhanced migration. Furthermore, OHT-stimulated cleavage of cyclin E and migration were tremendously attenuated by G15, a GPR30 antagonist, or siRNA against GPR30. In addition, inhibitors for EGFR or ERK1/2 remarkably suppressed OHT-induced truncation of cyclin E, suggesting involvement of EGFR signaling. Collectively, our data indicate that OHT contributes to the production of proteolyzed cyclin E via GPR30 with augmented migration in MCF-7 cells. | REGULATOR |
| 4-Hydroxytamoxifen-stimulated processing of GENE is mediated via G protein-coupled receptor 30 (GPR30) and accompanied by enhanced migration in MCF-7 breast cancer cells. Over-expression of cleaved GENE in breast tumors is closely associated with tumor progression and resistance to antiestrogens. CHEMICAL (E2) has been recently shown to induce GENE processing in breast cancer cells. Tamoxifen has been used in patients with estrogen-sensitive breast cancer, yet resistance to antiestrogens and recurrence will appear in some of the patients after its continued use. We therefore addressed possible effects of tamoxifen on the generation of cleaved GENE and its signal mechanism(s) in estrogen-responsive MCF-7 breast cancer cells that express both G protein-coupled protein (GPR) 30 and estrogen receptor α (ERα). 4-Hydroxytamoxifen (OHT, tamoxifen's active form) failed to prevent E2-induced proteolysis of GENE and migration, but rather triggered GENE cleavage coincident with augmented migration. OHT-induced GENE truncation also occurred in SK-BR-3 cells that express GPR30 and lack ERα, but not in MDA-MB-231 cells that express neither GPR30 nor ERα. G1, a specific GPR 30 agonist, caused dramatic proteolysis of GENE and enhanced migration. Furthermore, OHT-stimulated cleavage of GENE and migration were tremendously attenuated by G15, a GPR30 antagonist, or siRNA against GPR30. In addition, inhibitors for EGFR or ERK1/2 remarkably suppressed OHT-induced truncation of GENE, suggesting involvement of EGFR signaling. Collectively, our data indicate that OHT contributes to the production of proteolyzed GENE via GPR30 with augmented migration in MCF-7 cells. | REGULATOR |
| Mechanistic Aspects of GENE Maturation from the Solution Structure of Cu(I) -Loaded hCCS Domain 1 and Analysis of Disulfide-Free GENE Mutants. Superoxide dismutase 1 (SOD1) maturation within the cell is mainly accomplished with the SOD1-specific chaperone, CCS, a dimeric protein with three distinct domains in each monomer. We recently showed that the first domain of human CCS (hCCSD1) is responsible for copper transfer to its protein partner, human SOD1 (hSOD1). The NMR solution structure of the copper(I)-loaded form of hCCSD1 reported here contributes further to characterization of the copper-transfer mechanism to GENE. NMR spectroscopy was also used to examine the GENE mutants C57A, C146A, and C57A/C146A, which are unable to form the structurally conserved disulfide bond in SOD1, in order to investigate the role of these CHEMICAL during GENE copper acquisition. Together, the information on both hCCS and GENE, along with a sequence analysis of eukaryotic CCSD1, allows us to propose important mechanistic aspects regarding the copper-transfer process from hCCS to GENE. | REGULATOR |
| Mechanistic Aspects of hSOD1 Maturation from the Solution Structure of Cu(I) -Loaded hCCS Domain 1 and Analysis of Disulfide-Free hSOD1 Mutants. Superoxide dismutase 1 (SOD1) maturation within the cell is mainly accomplished with the SOD1-specific chaperone, CCS, a dimeric protein with three distinct domains in each monomer. We recently showed that the first domain of GENE (hCCSD1) is responsible for CHEMICAL transfer to its protein partner, human SOD1 (hSOD1). The NMR solution structure of the copper(I)-loaded form of hCCSD1 reported here contributes further to characterization of the copper-transfer mechanism to hSOD1. NMR spectroscopy was also used to examine the hSOD1 mutants C57A, C146A, and C57A/C146A, which are unable to form the structurally conserved disulfide bond in SOD1, in order to investigate the role of these cysteines during hSOD1 CHEMICAL acquisition. Together, the information on both hCCS and hSOD1, along with a sequence analysis of eukaryotic CCSD1, allows us to propose important mechanistic aspects regarding the copper-transfer process from hCCS to hSOD1. | SUBSTRATE |
| Mechanistic Aspects of hSOD1 Maturation from the Solution Structure of Cu(I) -Loaded hCCS Domain 1 and Analysis of Disulfide-Free hSOD1 Mutants. Superoxide dismutase 1 (SOD1) maturation within the cell is mainly accomplished with the SOD1-specific chaperone, CCS, a dimeric protein with three distinct domains in each monomer. We recently showed that the first domain of human CCS (GENE) is responsible for CHEMICAL transfer to its protein partner, human SOD1 (hSOD1). The NMR solution structure of the copper(I)-loaded form of GENE reported here contributes further to characterization of the copper-transfer mechanism to hSOD1. NMR spectroscopy was also used to examine the hSOD1 mutants C57A, C146A, and C57A/C146A, which are unable to form the structurally conserved disulfide bond in SOD1, in order to investigate the role of these cysteines during hSOD1 CHEMICAL acquisition. Together, the information on both hCCS and hSOD1, along with a sequence analysis of eukaryotic CCSD1, allows us to propose important mechanistic aspects regarding the copper-transfer process from hCCS to hSOD1. | SUBSTRATE |
| Mechanistic Aspects of hSOD1 Maturation from the Solution Structure of Cu(I) -Loaded hCCS Domain 1 and Analysis of Disulfide-Free hSOD1 Mutants. Superoxide dismutase 1 (SOD1) maturation within the cell is mainly accomplished with the SOD1-specific chaperone, CCS, a dimeric protein with three distinct domains in each monomer. We recently showed that the first domain of human CCS (hCCSD1) is responsible for CHEMICAL transfer to its protein partner, GENE (hSOD1). The NMR solution structure of the copper(I)-loaded form of hCCSD1 reported here contributes further to characterization of the copper-transfer mechanism to hSOD1. NMR spectroscopy was also used to examine the hSOD1 mutants C57A, C146A, and C57A/C146A, which are unable to form the structurally conserved disulfide bond in SOD1, in order to investigate the role of these cysteines during hSOD1 CHEMICAL acquisition. Together, the information on both hCCS and hSOD1, along with a sequence analysis of eukaryotic CCSD1, allows us to propose important mechanistic aspects regarding the copper-transfer process from hCCS to hSOD1. | SUBSTRATE |
| Mechanistic Aspects of GENE Maturation from the Solution Structure of Cu(I) -Loaded hCCS Domain 1 and Analysis of Disulfide-Free GENE Mutants. Superoxide dismutase 1 (SOD1) maturation within the cell is mainly accomplished with the SOD1-specific chaperone, CCS, a dimeric protein with three distinct domains in each monomer. We recently showed that the first domain of human CCS (hCCSD1) is responsible for CHEMICAL transfer to its protein partner, human SOD1 (GENE). The NMR solution structure of the copper(I)-loaded form of hCCSD1 reported here contributes further to characterization of the copper-transfer mechanism to GENE. NMR spectroscopy was also used to examine the GENE mutants C57A, C146A, and C57A/C146A, which are unable to form the structurally conserved disulfide bond in SOD1, in order to investigate the role of these cysteines during GENE CHEMICAL acquisition. Together, the information on both hCCS and GENE, along with a sequence analysis of eukaryotic CCSD1, allows us to propose important mechanistic aspects regarding the copper-transfer process from hCCS to GENE. | SUBSTRATE |
| Mechanistic Aspects of hSOD1 Maturation from the Solution Structure of Cu(I) -Loaded hCCS Domain 1 and Analysis of Disulfide-Free hSOD1 Mutants. Superoxide dismutase 1 (SOD1) maturation within the cell is mainly accomplished with the SOD1-specific chaperone, CCS, a dimeric protein with three distinct domains in each monomer. We recently showed that the first domain of human CCS (hCCSD1) is responsible for copper transfer to its protein partner, human SOD1 (hSOD1). The NMR solution structure of the CHEMICAL-loaded form of GENE reported here contributes further to characterization of the copper-transfer mechanism to hSOD1. NMR spectroscopy was also used to examine the hSOD1 mutants C57A, C146A, and C57A/C146A, which are unable to form the structurally conserved disulfide bond in SOD1, in order to investigate the role of these cysteines during hSOD1 copper acquisition. Together, the information on both hCCS and hSOD1, along with a sequence analysis of eukaryotic CCSD1, allows us to propose important mechanistic aspects regarding the copper-transfer process from hCCS to hSOD1. | PART-OF |
| Mechanistic Aspects of hSOD1 Maturation from the Solution Structure of Cu(I) -Loaded GENE Domain 1 and Analysis of Disulfide-Free hSOD1 Mutants. Superoxide dismutase 1 (SOD1) maturation within the cell is mainly accomplished with the SOD1-specific chaperone, CCS, a dimeric protein with three distinct domains in each monomer. We recently showed that the first domain of human CCS (hCCSD1) is responsible for CHEMICAL transfer to its protein partner, human SOD1 (hSOD1). The NMR solution structure of the copper(I)-loaded form of hCCSD1 reported here contributes further to characterization of the copper-transfer mechanism to hSOD1. NMR spectroscopy was also used to examine the hSOD1 mutants C57A, C146A, and C57A/C146A, which are unable to form the structurally conserved disulfide bond in SOD1, in order to investigate the role of these cysteines during hSOD1 CHEMICAL acquisition. Together, the information on both GENE and hSOD1, along with a sequence analysis of eukaryotic CCSD1, allows us to propose important mechanistic aspects regarding the CHEMICAL-transfer process from GENE to hSOD1. | SUBSTRATE |
| Mechanistic Aspects of GENE Maturation from the Solution Structure of CHEMICAL -Loaded hCCS Domain 1 and Analysis of Disulfide-Free GENE Mutants. Superoxide dismutase 1 (SOD1) maturation within the cell is mainly accomplished with the SOD1-specific chaperone, CCS, a dimeric protein with three distinct domains in each monomer. We recently showed that the first domain of human CCS (hCCSD1) is responsible for copper transfer to its protein partner, human SOD1 (hSOD1). The NMR solution structure of the copper(I)-loaded form of hCCSD1 reported here contributes further to characterization of the copper-transfer mechanism to GENE. NMR spectroscopy was also used to examine the GENE mutants C57A, C146A, and C57A/C146A, which are unable to form the structurally conserved disulfide bond in SOD1, in order to investigate the role of these cysteines during GENE copper acquisition. Together, the information on both hCCS and GENE, along with a sequence analysis of eukaryotic CCSD1, allows us to propose important mechanistic aspects regarding the copper-transfer process from hCCS to GENE. | DIRECT-REGULATOR |
| Mechanistic Aspects of hSOD1 Maturation from the Solution Structure of CHEMICAL -Loaded GENE and Analysis of Disulfide-Free hSOD1 Mutants. Superoxide dismutase 1 (SOD1) maturation within the cell is mainly accomplished with the SOD1-specific chaperone, CCS, a dimeric protein with three distinct domains in each monomer. We recently showed that the first domain of human CCS (hCCSD1) is responsible for copper transfer to its protein partner, human SOD1 (hSOD1). The NMR solution structure of the copper(I)-loaded form of hCCSD1 reported here contributes further to characterization of the copper-transfer mechanism to hSOD1. NMR spectroscopy was also used to examine the hSOD1 mutants C57A, C146A, and C57A/C146A, which are unable to form the structurally conserved disulfide bond in SOD1, in order to investigate the role of these cysteines during hSOD1 copper acquisition. Together, the information on both hCCS and hSOD1, along with a sequence analysis of eukaryotic CCSD1, allows us to propose important mechanistic aspects regarding the copper-transfer process from hCCS to hSOD1. | PART-OF |
| Design, Synthesis and Biological Evaluation of CHEMICAL Derivatives as GENE Ligands with Potential for Treatment of Alcohol Abuse. Attenuation of increased endocannabinoid signaling with a CB1R neutral antagonist might offer a new therapeutic direction for treatment of alcohol abuse. We have recently reported that a mono-hydroxylated metabolite of the synthetic aminoalkylindole cannabinoid JHW-073 (3) exhibits neutral antagonist activity at CB1Rs and thus may serve as a promising lead for the development of novel alcohol abuse therapies. In the current study, we show that systematic modification of an aminoalkylindole scaffold identifies two new compounds with dual CB1R antagonist/CB2R agonist activity. Similar to the CB1R antagonist/inverse agonist rimonabant, analogues 27 and 30 decrease oral alcohol self-administration, without affecting total fluid intake and block the development of alcohol-conditioned place preference. Collectively, these initial findings suggest that design and systematic modification of aminoalkylindoles such as 3 may lead to development of novel cannabinoid ligands with dual CB1R antagonist/CB2R agonist activity with potential for use as treatments of alcohol abuse. | DIRECT-REGULATOR |
| Design, Synthesis and Biological Evaluation of CHEMICAL Derivatives as Cannabinoid Receptor Ligands with Potential for Treatment of Alcohol Abuse. Attenuation of increased endocannabinoid signaling with a CB1R neutral antagonist might offer a new therapeutic direction for treatment of alcohol abuse. We have recently reported that a mono-hydroxylated metabolite of the synthetic CHEMICAL cannabinoid JHW-073 (3) exhibits neutral antagonist activity at CB1Rs and thus may serve as a promising lead for the development of novel alcohol abuse therapies. In the current study, we show that systematic modification of an CHEMICAL scaffold identifies two new compounds with dual CB1R antagonist/GENE agonist activity. Similar to the CB1R antagonist/inverse agonist rimonabant, analogues 27 and 30 decrease oral alcohol self-administration, without affecting total fluid intake and block the development of alcohol-conditioned place preference. Collectively, these initial findings suggest that design and systematic modification of aminoalkylindoles such as 3 may lead to development of novel cannabinoid ligands with dual CB1R antagonist/CB2R agonist activity with potential for use as treatments of alcohol abuse. | ACTIVATOR |
| Design, Synthesis and Biological Evaluation of Aminoalkylindole Derivatives as Cannabinoid Receptor Ligands with Potential for Treatment of Alcohol Abuse. Attenuation of increased endocannabinoid signaling with a CB1R neutral antagonist might offer a new therapeutic direction for treatment of alcohol abuse. We have recently reported that a mono-hydroxylated metabolite of the synthetic aminoalkylindole cannabinoid JHW-073 (3) exhibits neutral antagonist activity at CB1Rs and thus may serve as a promising lead for the development of novel alcohol abuse therapies. In the current study, we show that systematic modification of an aminoalkylindole scaffold identifies two new compounds with dual CB1R antagonist/CB2R agonist activity. Similar to the CB1R antagonist/inverse agonist rimonabant, analogues 27 and 30 decrease oral alcohol self-administration, without affecting total fluid intake and block the development of alcohol-conditioned place preference. Collectively, these initial findings suggest that design and systematic modification of CHEMICAL such as 3 may lead to development of novel cannabinoid ligands with dual CB1R antagonist/GENE agonist activity with potential for use as treatments of alcohol abuse. | ACTIVATOR |
| Design, Synthesis and Biological Evaluation of CHEMICAL Derivatives as Cannabinoid Receptor Ligands with Potential for Treatment of Alcohol Abuse. Attenuation of increased endocannabinoid signaling with a CB1R neutral antagonist might offer a new therapeutic direction for treatment of alcohol abuse. We have recently reported that a mono-hydroxylated metabolite of the synthetic CHEMICAL cannabinoid JHW-073 (3) exhibits neutral antagonist activity at GENE and thus may serve as a promising lead for the development of novel alcohol abuse therapies. In the current study, we show that systematic modification of an CHEMICAL scaffold identifies two new compounds with dual CB1R antagonist/CB2R agonist activity. Similar to the CB1R antagonist/inverse agonist rimonabant, analogues 27 and 30 decrease oral alcohol self-administration, without affecting total fluid intake and block the development of alcohol-conditioned place preference. Collectively, these initial findings suggest that design and systematic modification of aminoalkylindoles such as 3 may lead to development of novel cannabinoid ligands with dual CB1R antagonist/CB2R agonist activity with potential for use as treatments of alcohol abuse. | INHIBITOR |
| Design, Synthesis and Biological Evaluation of Aminoalkylindole Derivatives as Cannabinoid Receptor Ligands with Potential for Treatment of Alcohol Abuse. Attenuation of increased endocannabinoid signaling with a CB1R neutral antagonist might offer a new therapeutic direction for treatment of alcohol abuse. We have recently reported that a mono-hydroxylated metabolite of the synthetic aminoalkylindole cannabinoid CHEMICAL (3) exhibits neutral antagonist activity at GENE and thus may serve as a promising lead for the development of novel alcohol abuse therapies. In the current study, we show that systematic modification of an aminoalkylindole scaffold identifies two new compounds with dual CB1R antagonist/CB2R agonist activity. Similar to the CB1R antagonist/inverse agonist rimonabant, analogues 27 and 30 decrease oral alcohol self-administration, without affecting total fluid intake and block the development of alcohol-conditioned place preference. Collectively, these initial findings suggest that design and systematic modification of aminoalkylindoles such as 3 may lead to development of novel cannabinoid ligands with dual CB1R antagonist/CB2R agonist activity with potential for use as treatments of alcohol abuse. | INHIBITOR |
| Design, Synthesis and Biological Evaluation of CHEMICAL Derivatives as Cannabinoid Receptor Ligands with Potential for Treatment of Alcohol Abuse. Attenuation of increased endocannabinoid signaling with a GENE neutral antagonist might offer a new therapeutic direction for treatment of alcohol abuse. We have recently reported that a mono-hydroxylated metabolite of the synthetic CHEMICAL cannabinoid JHW-073 (3) exhibits neutral antagonist activity at CB1Rs and thus may serve as a promising lead for the development of novel alcohol abuse therapies. In the current study, we show that systematic modification of an CHEMICAL scaffold identifies two new compounds with dual GENE antagonist/CB2R agonist activity. Similar to the GENE antagonist/inverse agonist rimonabant, analogues 27 and 30 decrease oral alcohol self-administration, without affecting total fluid intake and block the development of alcohol-conditioned place preference. Collectively, these initial findings suggest that design and systematic modification of aminoalkylindoles such as 3 may lead to development of novel cannabinoid ligands with dual GENE antagonist/CB2R agonist activity with potential for use as treatments of alcohol abuse. | INHIBITOR |
| Design, Synthesis and Biological Evaluation of Aminoalkylindole Derivatives as Cannabinoid Receptor Ligands with Potential for Treatment of Alcohol Abuse. Attenuation of increased endocannabinoid signaling with a GENE neutral antagonist might offer a new therapeutic direction for treatment of alcohol abuse. We have recently reported that a mono-hydroxylated metabolite of the synthetic aminoalkylindole cannabinoid JHW-073 (3) exhibits neutral antagonist activity at CB1Rs and thus may serve as a promising lead for the development of novel alcohol abuse therapies. In the current study, we show that systematic modification of an aminoalkylindole scaffold identifies two new compounds with dual GENE antagonist/CB2R agonist activity. Similar to the GENE antagonist/inverse agonist rimonabant, analogues 27 and 30 decrease oral alcohol self-administration, without affecting total fluid intake and block the development of alcohol-conditioned place preference. Collectively, these initial findings suggest that design and systematic modification of CHEMICAL such as 3 may lead to development of novel cannabinoid ligands with dual GENE antagonist/CB2R agonist activity with potential for use as treatments of alcohol abuse. | INHIBITOR |
| Immunoregulatory effects of CHEMICAL exerts anti-asthmatic effects via modulation of Th1/Th2 cytokines and enhancement of CD4(+)CD25(+)Foxp3(+) regulatory T cells in GENE-sensitized mice. ETHNOPHARMACOLOGICAL RELEVANCE: CHEMICAL (GA) is the main bioactive ingredient of licorice (Glycyrrhiza glabra), and has been found to be associated with multiple therapeutic properties. AIM OF THE STUDY: In this study, we investigated immunoregulatory effects of glycyrrhizic acid on anti-asthmatic effects and underlying mechanisms. MATERIALS AND METHODS: Asthma model was established by ovalbumin-induced. A total of 60 mice were randomly assigned to six experimental groups: control, model, dexamethasone (2mg/kg) and GA (10mg/kg, 20mg/kg, 40mg/kg). Airway resistance (Raw) were measured by the forced oscillation technique, histological studies were evaluated by The hematoxylin and eosin (HE) staining, Th1/Th2 and Th17 cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA), and CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) was evaluated by Flow Cytometry (FCM), the forkhead/winged helix transcription factor (Foxp3) was evaluated by western blotting. RESULTS: Our study demonstrated that, compared with model group, GA inhibited OVA-induced increases in Raw and eosinophil count; interleukin (IL)-4, IL-5, IL-13 levels were recovered in bronchoalveolar lavage fluid compared; increased IFN-γlevel in bronchoalveolar lavage fluid; histological studies demonstrated that GA substantially inhibited OVA-induced eosinophilia in lung tissue and airway tissue compared with model group. Flow cytometry studies demonstrated that GA substantially enhanced Tregs compared with model group. CONCLUSION: These findings suggest that GA may effectively ameliorate the progression of asthma and could be used as a therapy for patients with allergic asthma. | ACTIVATOR |
| Immunoregulatory effects of CHEMICAL exerts anti-asthmatic effects via modulation of Th1/Th2 GENE and enhancement of CD4(+)CD25(+)Foxp3(+) regulatory T cells in ovalbumin-sensitized mice. ETHNOPHARMACOLOGICAL RELEVANCE: CHEMICAL (GA) is the main bioactive ingredient of licorice (Glycyrrhiza glabra), and has been found to be associated with multiple therapeutic properties. AIM OF THE STUDY: In this study, we investigated immunoregulatory effects of glycyrrhizic acid on anti-asthmatic effects and underlying mechanisms. MATERIALS AND METHODS: Asthma model was established by ovalbumin-induced. A total of 60 mice were randomly assigned to six experimental groups: control, model, dexamethasone (2mg/kg) and GA (10mg/kg, 20mg/kg, 40mg/kg). Airway resistance (Raw) were measured by the forced oscillation technique, histological studies were evaluated by The hematoxylin and eosin (HE) staining, Th1/Th2 and Th17 GENE were evaluated by enzyme-linked immunosorbent assay (ELISA), and CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) was evaluated by Flow Cytometry (FCM), the forkhead/winged helix transcription factor (Foxp3) was evaluated by western blotting. RESULTS: Our study demonstrated that, compared with model group, GA inhibited OVA-induced increases in Raw and eosinophil count; interleukin (IL)-4, IL-5, IL-13 levels were recovered in bronchoalveolar lavage fluid compared; increased IFN-γlevel in bronchoalveolar lavage fluid; histological studies demonstrated that GA substantially inhibited OVA-induced eosinophilia in lung tissue and airway tissue compared with model group. Flow cytometry studies demonstrated that GA substantially enhanced Tregs compared with model group. CONCLUSION: These findings suggest that GA may effectively ameliorate the progression of asthma and could be used as a therapy for patients with allergic asthma. | REGULATOR |
| Enhanced beta cell function and anti-inflammatory effect after chronic treatment with the dipeptidyl peptidase-4 inhibitor CHEMICAL in an advanced-aged diet-induced obesity mouse model. AIMS/HYPOTHESIS: Studies have shown that dipeptidyl peptidase-4 (DPP4) inhibitors stimulate insulin secretion and increase beta cell mass in rodents. However, in these models hyperglycaemia has been induced early on in life and the treatment periods have been short. To explore the long-term effects of GENE inhibition on insulin secretion and beta cell mass, we have generated a high-fat diet (HFD)-induced-obesity model in mice of advanced age (10 months old). METHODS: After 1 month of HFD alone, the mice were given the GENE inhibitor CHEMICAL for a further 11 months. At multiple time points throughout the study, OGTTs were performed and beta cell area and long-term survival were evaluated. RESULTS: Beta cell function and glucose tolerance were significantly improved by CHEMICAL with both diets. In contrast, in spite of the long treatment period, beta cell area was not significantly different between vildagliptin-treated mice and controls. Mice of advanced age chronically fed an HFD displayed clear and extensive pancreatic inflammation and peri-insulitis, mainly formed by CD3-positive T cells, which were completely prevented by CHEMICAL treatment. Chronic CHEMICAL treatment also improved survival rates for HFD-fed mice. CONCLUSIONS/INTERPRETATION: In a unique advanced-aged HFD-induced-obesity mouse model, insulin secretion was improved and the extensive peri-insulitis prevented by chronic GENE inhibition. The improved survival rates for obese mice chronically treated with CHEMICAL suggest that chronic GENE inhibition potentially results in additional quality-adjusted life-years for individuals with type 2 diabetes, which is the primary goal of any diabetes therapy. | INHIBITOR |
| Enhanced beta cell function and anti-inflammatory effect after chronic treatment with the GENE inhibitor CHEMICAL in an advanced-aged diet-induced obesity mouse model. AIMS/HYPOTHESIS: Studies have shown that GENE (DPP4) inhibitors stimulate insulin secretion and increase beta cell mass in rodents. However, in these models hyperglycaemia has been induced early on in life and the treatment periods have been short. To explore the long-term effects of DPP4 inhibition on insulin secretion and beta cell mass, we have generated a high-fat diet (HFD)-induced-obesity model in mice of advanced age (10 months old). METHODS: After 1 month of HFD alone, the mice were given the DPP4 inhibitor CHEMICAL for a further 11 months. At multiple time points throughout the study, OGTTs were performed and beta cell area and long-term survival were evaluated. RESULTS: Beta cell function and glucose tolerance were significantly improved by CHEMICAL with both diets. In contrast, in spite of the long treatment period, beta cell area was not significantly different between vildagliptin-treated mice and controls. Mice of advanced age chronically fed an HFD displayed clear and extensive pancreatic inflammation and peri-insulitis, mainly formed by CD3-positive T cells, which were completely prevented by CHEMICAL treatment. Chronic CHEMICAL treatment also improved survival rates for HFD-fed mice. CONCLUSIONS/INTERPRETATION: In a unique advanced-aged HFD-induced-obesity mouse model, insulin secretion was improved and the extensive peri-insulitis prevented by chronic DPP4 inhibition. The improved survival rates for obese mice chronically treated with CHEMICAL suggest that chronic DPP4 inhibition potentially results in additional quality-adjusted life-years for individuals with type 2 diabetes, which is the primary goal of any diabetes therapy. | INHIBITOR |
| Amelioration of palmitate-induced insulin resistance in C2C12 muscle cells by rooibos (Aspalathus linearis). Increased levels of free fatty acids (FFAs), specifically saturated free fatty acids such as palmitate are associated with insulin resistance of muscle, fat and liver. Skeletal muscle, responsible for up to 80% of the CHEMICAL disposal from the peripheral circulation, is particularly vulnerable to increased levels of saturated FFAs. Rooibos (Aspalathus linearis) and its unique dihydrochalcone C-glucoside, aspalathin, shown to reduce hyperglycemia in diabetic rats, could play a role in preventing or ameliorating the development of insulin resistance. This study aims to establish whether rooibos can ameliorate experimentally-induced insulin-resistance in C2C12 skeletal muscle cells. Palmitate-induced insulin resistant C2C12 cells were treated with an aspalathin-enriched green (unfermented) rooibos extract (GRE), previously shown for its blood CHEMICAL lowering effect in vitro and in vivo or an aqueous extract of fermented rooibos (FRE). CHEMICAL uptake and mitochondrial activity were measured using 2-deoxy-[(3)H]-d-glucose, MTT and ATP assays, respectively. Expression of proteins relevant to CHEMICAL metabolism was analysed by Western blot. GRE contained higher levels of all compounds, except the enolic phenylpyruvic acid-2-O-glucoside and luteolin-7-O-glucoside. Both rooibos extracts increased CHEMICAL uptake, mitochondrial activity and ATP production. Compared to FRE, GRE was more effective at increasing CHEMICAL uptake and ATP production. At a mechanistic level both extracts down-regulated PKC θ activation, which is associated with palmitate-induced insulin resistance. Furthermore, the extracts increased activation of key regulatory proteins (AKT and AMPK) involved in insulin-dependent and non-insulin regulated signalling pathways. Protein levels of the GENE (GLUT4) involved in CHEMICAL transport via these two pathways were also increased. This in vitro study therefore confirms that rooibos can ameliorate palmitate-induced insulin resistance in C2C12 skeletal muscle cells. Inhibition of PKC θ activation and increased activation of AMPK and AKT offer a plausible mechanistic explanation for this ameliorative effect. | SUBSTRATE |
| Amelioration of palmitate-induced insulin resistance in C2C12 muscle cells by rooibos (Aspalathus linearis). Increased levels of free fatty acids (FFAs), specifically saturated free fatty acids such as palmitate are associated with insulin resistance of muscle, fat and liver. Skeletal muscle, responsible for up to 80% of the CHEMICAL disposal from the peripheral circulation, is particularly vulnerable to increased levels of saturated FFAs. Rooibos (Aspalathus linearis) and its unique dihydrochalcone C-glucoside, aspalathin, shown to reduce hyperglycemia in diabetic rats, could play a role in preventing or ameliorating the development of insulin resistance. This study aims to establish whether rooibos can ameliorate experimentally-induced insulin-resistance in C2C12 skeletal muscle cells. Palmitate-induced insulin resistant C2C12 cells were treated with an aspalathin-enriched green (unfermented) rooibos extract (GRE), previously shown for its blood CHEMICAL lowering effect in vitro and in vivo or an aqueous extract of fermented rooibos (FRE). CHEMICAL uptake and mitochondrial activity were measured using 2-deoxy-[(3)H]-d-glucose, MTT and ATP assays, respectively. Expression of proteins relevant to CHEMICAL metabolism was analysed by Western blot. GRE contained higher levels of all compounds, except the enolic phenylpyruvic acid-2-O-glucoside and luteolin-7-O-glucoside. Both rooibos extracts increased CHEMICAL uptake, mitochondrial activity and ATP production. Compared to FRE, GRE was more effective at increasing CHEMICAL uptake and ATP production. At a mechanistic level both extracts down-regulated PKC θ activation, which is associated with palmitate-induced insulin resistance. Furthermore, the extracts increased activation of key regulatory proteins (AKT and AMPK) involved in insulin-dependent and non-insulin regulated signalling pathways. Protein levels of the CHEMICAL transporter (GENE) involved in CHEMICAL transport via these two pathways were also increased. This in vitro study therefore confirms that rooibos can ameliorate palmitate-induced insulin resistance in C2C12 skeletal muscle cells. Inhibition of PKC θ activation and increased activation of AMPK and AKT offer a plausible mechanistic explanation for this ameliorative effect. | SUBSTRATE |
| CHEMICAL stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/ERK and PI3K/Akt activation. CHEMICAL, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, has received increasing attention because of its possible role in the prevention of osteoporosis. Previously, we showed that CHEMICAL could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro. Further study confirmed that CHEMICAL stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that CHEMICAL increases proliferation and differentiation and opposes cisplatin-induced apoptosis in human osteoblastic MG-63 cells containing two estrogen receptor (ER) isoforms. CHEMICAL promotes proliferation by altering cell cycle distribution whereas puerarin-mediated survival may be associated with up-regulation of Bcl-xL expression. Treatment with the ER antagonist ICI 182,780 abolishes the above actions of CHEMICAL on osteoblast-derived cells. Using small interfering double-stranded RNA technology, we further demonstrate that the effects of CHEMICAL on proliferation, differentiation and survival are mediated by both GENE and ERβ. Moreover, we also demonstrate that CHEMICAL functions at least partially through activation of MEK/ERK and PI3K/Akt signaling. This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen. Therefore, CHEMICAL will be a promising agent that prevents or retards osteoporosis. | REGULATOR |
| CHEMICAL stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/ERK and PI3K/Akt activation. CHEMICAL, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, has received increasing attention because of its possible role in the prevention of osteoporosis. Previously, we showed that CHEMICAL could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro. Further study confirmed that CHEMICAL stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that CHEMICAL increases proliferation and differentiation and opposes cisplatin-induced apoptosis in human osteoblastic MG-63 cells containing two estrogen receptor (ER) isoforms. CHEMICAL promotes proliferation by altering cell cycle distribution whereas puerarin-mediated survival may be associated with up-regulation of Bcl-xL expression. Treatment with the ER antagonist ICI 182,780 abolishes the above actions of CHEMICAL on osteoblast-derived cells. Using small interfering double-stranded RNA technology, we further demonstrate that the effects of CHEMICAL on proliferation, differentiation and survival are mediated by both ERα and GENE. Moreover, we also demonstrate that CHEMICAL functions at least partially through activation of MEK/ERK and PI3K/Akt signaling. This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen. Therefore, CHEMICAL will be a promising agent that prevents or retards osteoporosis. | REGULATOR |
| Puerarin stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/ERK and PI3K/Akt activation. Puerarin, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, has received increasing attention because of its possible role in the prevention of osteoporosis. Previously, we showed that puerarin could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro. Further study confirmed that puerarin stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that puerarin increases proliferation and differentiation and opposes CHEMICAL-induced apoptosis in human osteoblastic MG-63 cells containing two GENE (ER) isoforms. Puerarin promotes proliferation by altering cell cycle distribution whereas puerarin-mediated survival may be associated with up-regulation of Bcl-xL expression. Treatment with the ER antagonist ICI 182,780 abolishes the above actions of puerarin on osteoblast-derived cells. Using small interfering double-stranded RNA technology, we further demonstrate that the effects of puerarin on proliferation, differentiation and survival are mediated by both ERα and ERβ. Moreover, we also demonstrate that puerarin functions at least partially through activation of MEK/ERK and PI3K/Akt signaling. This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen. Therefore, puerarin will be a promising agent that prevents or retards osteoporosis. | INHIBITOR |
| Puerarin stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/ERK and PI3K/Akt activation. Puerarin, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, has received increasing attention because of its possible role in the prevention of osteoporosis. Previously, we showed that puerarin could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro. Further study confirmed that puerarin stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that puerarin increases proliferation and differentiation and opposes CHEMICAL-induced apoptosis in human osteoblastic MG-63 cells containing two estrogen receptor (GENE) isoforms. Puerarin promotes proliferation by altering cell cycle distribution whereas puerarin-mediated survival may be associated with up-regulation of Bcl-xL expression. Treatment with the GENE antagonist ICI 182,780 abolishes the above actions of puerarin on osteoblast-derived cells. Using small interfering double-stranded RNA technology, we further demonstrate that the effects of puerarin on proliferation, differentiation and survival are mediated by both ERα and ERβ. Moreover, we also demonstrate that puerarin functions at least partially through activation of MEK/ERK and PI3K/Akt signaling. This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen. Therefore, puerarin will be a promising agent that prevents or retards osteoporosis. | INHIBITOR |
| CHEMICAL stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/ERK and PI3K/Akt activation. CHEMICAL, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, has received increasing attention because of its possible role in the prevention of osteoporosis. Previously, we showed that CHEMICAL could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro. Further study confirmed that CHEMICAL stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that CHEMICAL increases proliferation and differentiation and opposes cisplatin-induced apoptosis in human osteoblastic MG-63 cells containing two estrogen receptor (ER) isoforms. CHEMICAL promotes proliferation by altering cell cycle distribution whereas puerarin-mediated survival may be associated with up-regulation of Bcl-xL expression. Treatment with the GENE antagonist ICI 182,780 abolishes the above actions of CHEMICAL on osteoblast-derived cells. Using small interfering double-stranded RNA technology, we further demonstrate that the effects of CHEMICAL on proliferation, differentiation and survival are mediated by both ERα and ERβ. Moreover, we also demonstrate that CHEMICAL functions at least partially through activation of MEK/ERK and PI3K/Akt signaling. This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen. Therefore, CHEMICAL will be a promising agent that prevents or retards osteoporosis. | INHIBITOR |
| CHEMICAL stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/ERK and PI3K/Akt activation. CHEMICAL, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, has received increasing attention because of its possible role in the prevention of osteoporosis. Previously, we showed that CHEMICAL could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro. Further study confirmed that CHEMICAL stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that CHEMICAL increases proliferation and differentiation and opposes cisplatin-induced apoptosis in human osteoblastic MG-63 cells containing two GENE (ER) isoforms. CHEMICAL promotes proliferation by altering cell cycle distribution whereas puerarin-mediated survival may be associated with up-regulation of Bcl-xL expression. Treatment with the ER antagonist ICI 182,780 abolishes the above actions of CHEMICAL on osteoblast-derived cells. Using small interfering double-stranded RNA technology, we further demonstrate that the effects of CHEMICAL on proliferation, differentiation and survival are mediated by both ERα and ERβ. Moreover, we also demonstrate that CHEMICAL functions at least partially through activation of MEK/ERK and PI3K/Akt signaling. This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen. Therefore, CHEMICAL will be a promising agent that prevents or retards osteoporosis. | INHIBITOR |
| CHEMICAL stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent GENE/ERK and PI3K/Akt activation. CHEMICAL, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, has received increasing attention because of its possible role in the prevention of osteoporosis. Previously, we showed that puerarin could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro. Further study confirmed that puerarin stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that puerarin increases proliferation and differentiation and opposes cisplatin-induced apoptosis in human osteoblastic MG-63 cells containing two estrogen receptor (ER) isoforms. CHEMICAL promotes proliferation by altering cell cycle distribution whereas puerarin-mediated survival may be associated with up-regulation of Bcl-xL expression. Treatment with the ER antagonist ICI 182,780 abolishes the above actions of puerarin on osteoblast-derived cells. Using small interfering double-stranded RNA technology, we further demonstrate that the effects of puerarin on proliferation, differentiation and survival are mediated by both ERα and ERβ. Moreover, we also demonstrate that puerarin functions at least partially through activation of MEK/ERK and PI3K/Akt signaling. This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen. Therefore, puerarin will be a promising agent that prevents or retards osteoporosis. | ACTIVATOR |
| CHEMICAL stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/GENE and PI3K/Akt activation. CHEMICAL, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, has received increasing attention because of its possible role in the prevention of osteoporosis. Previously, we showed that puerarin could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro. Further study confirmed that puerarin stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that puerarin increases proliferation and differentiation and opposes cisplatin-induced apoptosis in human osteoblastic MG-63 cells containing two estrogen receptor (ER) isoforms. CHEMICAL promotes proliferation by altering cell cycle distribution whereas puerarin-mediated survival may be associated with up-regulation of Bcl-xL expression. Treatment with the ER antagonist ICI 182,780 abolishes the above actions of puerarin on osteoblast-derived cells. Using small interfering double-stranded RNA technology, we further demonstrate that the effects of puerarin on proliferation, differentiation and survival are mediated by both ERα and ERβ. Moreover, we also demonstrate that puerarin functions at least partially through activation of MEK/ERK and PI3K/Akt signaling. This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen. Therefore, puerarin will be a promising agent that prevents or retards osteoporosis. | ACTIVATOR |
| CHEMICAL stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/ERK and GENE/Akt activation. CHEMICAL, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, has received increasing attention because of its possible role in the prevention of osteoporosis. Previously, we showed that puerarin could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro. Further study confirmed that puerarin stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that puerarin increases proliferation and differentiation and opposes cisplatin-induced apoptosis in human osteoblastic MG-63 cells containing two estrogen receptor (ER) isoforms. CHEMICAL promotes proliferation by altering cell cycle distribution whereas puerarin-mediated survival may be associated with up-regulation of Bcl-xL expression. Treatment with the ER antagonist ICI 182,780 abolishes the above actions of puerarin on osteoblast-derived cells. Using small interfering double-stranded RNA technology, we further demonstrate that the effects of puerarin on proliferation, differentiation and survival are mediated by both ERα and ERβ. Moreover, we also demonstrate that puerarin functions at least partially through activation of MEK/ERK and PI3K/Akt signaling. This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen. Therefore, puerarin will be a promising agent that prevents or retards osteoporosis. | ACTIVATOR |
| CHEMICAL stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/ERK and PI3K/GENE activation. CHEMICAL, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, has received increasing attention because of its possible role in the prevention of osteoporosis. Previously, we showed that puerarin could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro. Further study confirmed that puerarin stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that puerarin increases proliferation and differentiation and opposes cisplatin-induced apoptosis in human osteoblastic MG-63 cells containing two estrogen receptor (ER) isoforms. CHEMICAL promotes proliferation by altering cell cycle distribution whereas puerarin-mediated survival may be associated with up-regulation of Bcl-xL expression. Treatment with the ER antagonist ICI 182,780 abolishes the above actions of puerarin on osteoblast-derived cells. Using small interfering double-stranded RNA technology, we further demonstrate that the effects of puerarin on proliferation, differentiation and survival are mediated by both ERα and ERβ. Moreover, we also demonstrate that puerarin functions at least partially through activation of MEK/ERK and PI3K/Akt signaling. This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen. Therefore, puerarin will be a promising agent that prevents or retards osteoporosis. | ACTIVATOR |
| CHEMICAL stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/ERK and PI3K/Akt activation. CHEMICAL, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, has received increasing attention because of its possible role in the prevention of osteoporosis. Previously, we showed that CHEMICAL could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro. Further study confirmed that CHEMICAL stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that CHEMICAL increases proliferation and differentiation and opposes cisplatin-induced apoptosis in human osteoblastic MG-63 cells containing two estrogen receptor (ER) isoforms. CHEMICAL promotes proliferation by altering cell cycle distribution whereas CHEMICAL-mediated survival may be associated with up-regulation of GENE expression. Treatment with the ER antagonist ICI 182,780 abolishes the above actions of CHEMICAL on osteoblast-derived cells. Using small interfering double-stranded RNA technology, we further demonstrate that the effects of CHEMICAL on proliferation, differentiation and survival are mediated by both ERα and ERβ. Moreover, we also demonstrate that CHEMICAL functions at least partially through activation of MEK/ERK and PI3K/Akt signaling. This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen. Therefore, CHEMICAL will be a promising agent that prevents or retards osteoporosis. | INDIRECT-UPREGULATOR |
| Puerarin stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/ERK and PI3K/Akt activation. Puerarin, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, has received increasing attention because of its possible role in the prevention of osteoporosis. Previously, we showed that puerarin could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro. Further study confirmed that puerarin stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that puerarin increases proliferation and differentiation and opposes cisplatin-induced apoptosis in human osteoblastic MG-63 cells containing two estrogen receptor (ER) isoforms. Puerarin promotes proliferation by altering cell cycle distribution whereas puerarin-mediated survival may be associated with up-regulation of Bcl-xL expression. Treatment with the GENE antagonist CHEMICAL abolishes the above actions of puerarin on osteoblast-derived cells. Using small interfering double-stranded RNA technology, we further demonstrate that the effects of puerarin on proliferation, differentiation and survival are mediated by both ERα and ERβ. Moreover, we also demonstrate that puerarin functions at least partially through activation of MEK/ERK and PI3K/Akt signaling. This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen. Therefore, puerarin will be a promising agent that prevents or retards osteoporosis. | INHIBITOR |
| The preventive effect of uncarboxylated osteocalcin against CHEMICAL-induced endothelial apoptosis through the activation of GENE/Akt signaling pathway: Uncarboxylated osteocalcin and endothelial apoptosis. OBJECTIVE: Increasing evidence suggests that osteocalcin (OC), one of the osteoblast-specific proteins, has been associated with atherosclerosis, but results are conflicting. The aim of this study was to elucidate the independent effect of uncarboxylated osteocalcin (ucOC), an active form of osteocalcin which has been suggested to have an insulin sensitizing effect, on vascular endothelial cells. MATERIALS AND METHODS: We used human aortic endothelial cells and treated them with ucOC. Linoleic acid (LA) was used as a representative CHEMICAL. Apoptosis was evaluated using various methods including a terminal deoxyribonucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling analysis kit and Western blotting for cleaved caspase 3, cleaved poly (ADP-ribose) polymerase and Bcl-xL. The phosphorylations of Akt and endothelial nitric oxide synthase (eNOS) as well as the level of NO were measured to confirm the effect of ucOC on insulin signaling pathway. RESULTS: Pretreatment of ucOC (30ng/ml) prevented LA-induced apoptosis in insulin-stimulated endothelial cells; effects were abolished by pretreatment with the GENE (PI3-kinase) inhibitor, wortmannin. Treatment of ucOC (ranged from 0.3 to 30ng/ml) significantly increased the phosphorylation of Akt and eNOS and nitric oxide secretion from endothelial cells in a PI3-kinase dependent manner. CONCLUSIONS: Our study is the first to demonstrate the independent effect of ucOC on vascular endothelial cells. Our results further suggest that ucOC could have beneficial effects on atherosclerosis. | ACTIVATOR |
| The preventive effect of uncarboxylated osteocalcin against CHEMICAL-induced endothelial apoptosis through the activation of phosphatidylinositol 3-kinase/GENE signaling pathway: Uncarboxylated osteocalcin and endothelial apoptosis. OBJECTIVE: Increasing evidence suggests that osteocalcin (OC), one of the osteoblast-specific proteins, has been associated with atherosclerosis, but results are conflicting. The aim of this study was to elucidate the independent effect of uncarboxylated osteocalcin (ucOC), an active form of osteocalcin which has been suggested to have an insulin sensitizing effect, on vascular endothelial cells. MATERIALS AND METHODS: We used human aortic endothelial cells and treated them with ucOC. Linoleic acid (LA) was used as a representative CHEMICAL. Apoptosis was evaluated using various methods including a terminal deoxyribonucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling analysis kit and Western blotting for cleaved caspase 3, cleaved poly (ADP-ribose) polymerase and Bcl-xL. The phosphorylations of GENE and endothelial nitric oxide synthase (eNOS) as well as the level of NO were measured to confirm the effect of ucOC on insulin signaling pathway. RESULTS: Pretreatment of ucOC (30ng/ml) prevented LA-induced apoptosis in insulin-stimulated endothelial cells; effects were abolished by pretreatment with the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, wortmannin. Treatment of ucOC (ranged from 0.3 to 30ng/ml) significantly increased the phosphorylation of GENE and eNOS and nitric oxide secretion from endothelial cells in a PI3-kinase dependent manner. CONCLUSIONS: Our study is the first to demonstrate the independent effect of ucOC on vascular endothelial cells. Our results further suggest that ucOC could have beneficial effects on atherosclerosis. | ACTIVATOR |
| The preventive effect of uncarboxylated osteocalcin against free fatty acid-induced endothelial apoptosis through the activation of phosphatidylinositol 3-kinase/Akt signaling pathway: Uncarboxylated osteocalcin and endothelial apoptosis. OBJECTIVE: Increasing evidence suggests that osteocalcin (OC), one of the osteoblast-specific proteins, has been associated with atherosclerosis, but results are conflicting. The aim of this study was to elucidate the independent effect of uncarboxylated osteocalcin (ucOC), an active form of osteocalcin which has been suggested to have an insulin sensitizing effect, on vascular endothelial cells. MATERIALS AND METHODS: We used human aortic endothelial cells and treated them with ucOC. Linoleic acid (LA) was used as a representative free fatty acid. Apoptosis was evaluated using various methods including a terminal deoxyribonucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling analysis kit and Western blotting for cleaved caspase 3, cleaved poly (ADP-ribose) polymerase and Bcl-xL. The phosphorylations of Akt and endothelial nitric oxide synthase (eNOS) as well as the level of NO were measured to confirm the effect of ucOC on insulin signaling pathway. RESULTS: Pretreatment of ucOC (30ng/ml) prevented LA-induced apoptosis in insulin-stimulated endothelial cells; effects were abolished by pretreatment with the GENE (PI3-kinase) inhibitor, CHEMICAL. Treatment of ucOC (ranged from 0.3 to 30ng/ml) significantly increased the phosphorylation of Akt and eNOS and nitric oxide secretion from endothelial cells in a PI3-kinase dependent manner. CONCLUSIONS: Our study is the first to demonstrate the independent effect of ucOC on vascular endothelial cells. Our results further suggest that ucOC could have beneficial effects on atherosclerosis. | INHIBITOR |
| The preventive effect of uncarboxylated osteocalcin against free fatty acid-induced endothelial apoptosis through the activation of phosphatidylinositol 3-kinase/Akt signaling pathway: Uncarboxylated osteocalcin and endothelial apoptosis. OBJECTIVE: Increasing evidence suggests that osteocalcin (OC), one of the osteoblast-specific proteins, has been associated with atherosclerosis, but results are conflicting. The aim of this study was to elucidate the independent effect of uncarboxylated osteocalcin (ucOC), an active form of osteocalcin which has been suggested to have an insulin sensitizing effect, on vascular endothelial cells. MATERIALS AND METHODS: We used human aortic endothelial cells and treated them with ucOC. Linoleic acid (LA) was used as a representative free fatty acid. Apoptosis was evaluated using various methods including a terminal deoxyribonucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling analysis kit and Western blotting for cleaved caspase 3, cleaved poly (ADP-ribose) polymerase and Bcl-xL. The phosphorylations of Akt and endothelial nitric oxide synthase (eNOS) as well as the level of NO were measured to confirm the effect of ucOC on insulin signaling pathway. RESULTS: Pretreatment of ucOC (30ng/ml) prevented LA-induced apoptosis in insulin-stimulated endothelial cells; effects were abolished by pretreatment with the phosphatidylinositol 3-kinase (GENE) inhibitor, CHEMICAL. Treatment of ucOC (ranged from 0.3 to 30ng/ml) significantly increased the phosphorylation of Akt and eNOS and nitric oxide secretion from endothelial cells in a GENE dependent manner. CONCLUSIONS: Our study is the first to demonstrate the independent effect of ucOC on vascular endothelial cells. Our results further suggest that ucOC could have beneficial effects on atherosclerosis. | INHIBITOR |
| The use of antioxidant enzymes in freshwater biofilms: Temporal variability vs. toxicological responses. This study aims to investigate the potential of antioxidant enzyme activities (AEA) as biomarkers of oxidative stress in freshwater biofilms. Therefore, biofilms were grown in channels for 38 days and then exposed to different concentrations (0-150μgL(-1)) of the herbicide CHEMICAL for 5 more weeks. Under control conditions, the AEA of biofilms were found to change throughout time with a significant increase in ascorbate peroxidase (APX) activity during the exponential growth and a more important role of catalase (CAT) and glutathione reductase (GR) activities during the slow growth phase. Chronic exposure to CHEMICAL led to slight variations in AEA, however, the ranges of variability of AEA in controls and exposed communities were similar, highlighting the difficulty of a direct interpretation of AEA values. After 5 weeks of exposure to CHEMICAL, no clear effects were observed on chl-a concentration or on the composition of other pigments suggesting that algal group composition was not affected. Eukaryotic communities were structured clearly by toxicant concentration and both eukaryotic and bacterial richness were reduced in communities exposed to the highest concentration. In addition, during acute exposure tests performed at the end of the chronic exposure, biofilms chronically exposed to 75 and 150μgL(-1) CHEMICAL showed a higher GENE activity than controls. Chronic exposure to CHEMICAL provoked then structural changes but also functional changes in the capacity of biofilm GENE activity to respond to a sudden increase in concentration, suggesting a selection of species with higher antioxidant capacity. This study highlighted the difficulty of interpretation of AEA values due to their temporal variation and to the absence of absolute threshold value indicative of oxidative stress induced by contaminants. Nevertheless, the determination of AEA pattern throughout acute exposure test is of high interest to compare oxidative stress levels undergone by different biofilm communities and thus determine their antioxidant capacity. | ACTIVATOR |
| Pharmacological and genetic evidence for pre- and postsynaptic D2 receptor involvement in motor responses to nociceptin/orphanin FQ receptor ligands. A combined pharmacological and genetic approach was undertaken to investigate the contribution of endogenous dopamine to the motor actions of nociceptin/orphanin FQ (N/OFQ) receptor (NOP receptor) ligands. Motor activity was evaluated by a battery of behavioural tests in mice. The involvement of the various DA receptor subtypes in the motor effects of N/OFQ and NOP receptor antagonists was evaluated pharmacologically, using GENE/D5 (CHEMICAL), D2/D3 (raclopride, amisulpride) and D3 (S33084) receptor antagonists, and by using D2 receptor knockout mice. Low doses of N/OFQ and NOP receptor antagonists promoted movement whereas higher doses inhibited it. Motor facilitation was selectively prevented by raclopride while motor inhibition was prevented by amisulpride. Amisulpride also attenuated the hypolocomotion induced by the D2/D3 receptor agonist pramipexole and dopamine precursor L-3,4-dihydroxyphenylalanine, whereas raclopride (and S33084) worsened it. To dissect out the contribution of pre- and postsynaptic D2 receptors, mice lacking the D2 receptor (D2R(-/-)) or its long isoform (D2L(-/-)) were used. Motor facilitation induced by N/OFQ and NOP receptor antagonists was lost in D2R(-/-) and D2L(-/-) mice whereas motor inhibition induced by NOP receptor antagonists (and pramipexole) was lost in D2R(-/-) but preserved in D2L(-/-) mice. N/OFQ-induced hypolocomotion was observed in both genotypes. We demonstrate that motor actions of NOP receptor ligands rely on the modulation of endogenous dopamine. Motor facilitation induced by NOP receptor antagonists as well as low dose N/OFQ is mediated through D2L postsynaptic receptors whereas motor inhibition observed with higher doses of N/OFQ occurs by direct inhibition of mesencephalic DA neurons. Motor inhibition seen with high doses of NOP receptor antagonists appears to be mediated through the D2 presynaptic autoreceptors. These data confirm that endogenous N/OFQ is a powerful modulator of dopamine transmission in vivo and that the effects of NOP receptor antagonists on motor function reflect the blockade of this endogenous N/OFQ tone. | INHIBITOR |
| Pharmacological and genetic evidence for pre- and postsynaptic D2 receptor involvement in motor responses to nociceptin/orphanin FQ receptor ligands. A combined pharmacological and genetic approach was undertaken to investigate the contribution of endogenous dopamine to the motor actions of nociceptin/orphanin FQ (N/OFQ) receptor (NOP receptor) ligands. Motor activity was evaluated by a battery of behavioural tests in mice. The involvement of the various DA receptor subtypes in the motor effects of N/OFQ and NOP receptor antagonists was evaluated pharmacologically, using D1/GENE (CHEMICAL), D2/D3 (raclopride, amisulpride) and D3 (S33084) receptor antagonists, and by using D2 receptor knockout mice. Low doses of N/OFQ and NOP receptor antagonists promoted movement whereas higher doses inhibited it. Motor facilitation was selectively prevented by raclopride while motor inhibition was prevented by amisulpride. Amisulpride also attenuated the hypolocomotion induced by the D2/D3 receptor agonist pramipexole and dopamine precursor L-3,4-dihydroxyphenylalanine, whereas raclopride (and S33084) worsened it. To dissect out the contribution of pre- and postsynaptic D2 receptors, mice lacking the D2 receptor (D2R(-/-)) or its long isoform (D2L(-/-)) were used. Motor facilitation induced by N/OFQ and NOP receptor antagonists was lost in D2R(-/-) and D2L(-/-) mice whereas motor inhibition induced by NOP receptor antagonists (and pramipexole) was lost in D2R(-/-) but preserved in D2L(-/-) mice. N/OFQ-induced hypolocomotion was observed in both genotypes. We demonstrate that motor actions of NOP receptor ligands rely on the modulation of endogenous dopamine. Motor facilitation induced by NOP receptor antagonists as well as low dose N/OFQ is mediated through D2L postsynaptic receptors whereas motor inhibition observed with higher doses of N/OFQ occurs by direct inhibition of mesencephalic DA neurons. Motor inhibition seen with high doses of NOP receptor antagonists appears to be mediated through the D2 presynaptic autoreceptors. These data confirm that endogenous N/OFQ is a powerful modulator of dopamine transmission in vivo and that the effects of NOP receptor antagonists on motor function reflect the blockade of this endogenous N/OFQ tone. | INHIBITOR |
| Pharmacological and genetic evidence for pre- and postsynaptic GENE receptor involvement in motor responses to nociceptin/orphanin FQ receptor ligands. A combined pharmacological and genetic approach was undertaken to investigate the contribution of endogenous dopamine to the motor actions of nociceptin/orphanin FQ (N/OFQ) receptor (NOP receptor) ligands. Motor activity was evaluated by a battery of behavioural tests in mice. The involvement of the various DA receptor subtypes in the motor effects of N/OFQ and NOP receptor antagonists was evaluated pharmacologically, using D1/D5 (SCH23390), GENE/D3 (CHEMICAL, amisulpride) and D3 (S33084) receptor antagonists, and by using GENE receptor knockout mice. Low doses of N/OFQ and NOP receptor antagonists promoted movement whereas higher doses inhibited it. Motor facilitation was selectively prevented by CHEMICAL while motor inhibition was prevented by amisulpride. Amisulpride also attenuated the hypolocomotion induced by the D2/D3 receptor agonist pramipexole and dopamine precursor L-3,4-dihydroxyphenylalanine, whereas CHEMICAL (and S33084) worsened it. To dissect out the contribution of pre- and postsynaptic GENE receptors, mice lacking the GENE receptor (D2R(-/-)) or its long isoform (D2L(-/-)) were used. Motor facilitation induced by N/OFQ and NOP receptor antagonists was lost in D2R(-/-) and D2L(-/-) mice whereas motor inhibition induced by NOP receptor antagonists (and pramipexole) was lost in D2R(-/-) but preserved in D2L(-/-) mice. N/OFQ-induced hypolocomotion was observed in both genotypes. We demonstrate that motor actions of NOP receptor ligands rely on the modulation of endogenous dopamine. Motor facilitation induced by NOP receptor antagonists as well as low dose N/OFQ is mediated through D2L postsynaptic receptors whereas motor inhibition observed with higher doses of N/OFQ occurs by direct inhibition of mesencephalic DA neurons. Motor inhibition seen with high doses of NOP receptor antagonists appears to be mediated through the GENE presynaptic autoreceptors. These data confirm that endogenous N/OFQ is a powerful modulator of dopamine transmission in vivo and that the effects of NOP receptor antagonists on motor function reflect the blockade of this endogenous N/OFQ tone. | INHIBITOR |
| Pharmacological and genetic evidence for pre- and postsynaptic D2 receptor involvement in motor responses to nociceptin/orphanin FQ receptor ligands. A combined pharmacological and genetic approach was undertaken to investigate the contribution of endogenous dopamine to the motor actions of nociceptin/orphanin FQ (N/OFQ) receptor (NOP receptor) ligands. Motor activity was evaluated by a battery of behavioural tests in mice. The involvement of the various DA receptor subtypes in the motor effects of N/OFQ and NOP receptor antagonists was evaluated pharmacologically, using D1/D5 (SCH23390), D2/GENE (CHEMICAL, amisulpride) and GENE (S33084) receptor antagonists, and by using D2 receptor knockout mice. Low doses of N/OFQ and NOP receptor antagonists promoted movement whereas higher doses inhibited it. Motor facilitation was selectively prevented by CHEMICAL while motor inhibition was prevented by amisulpride. Amisulpride also attenuated the hypolocomotion induced by the D2/D3 receptor agonist pramipexole and dopamine precursor L-3,4-dihydroxyphenylalanine, whereas CHEMICAL (and S33084) worsened it. To dissect out the contribution of pre- and postsynaptic D2 receptors, mice lacking the D2 receptor (D2R(-/-)) or its long isoform (D2L(-/-)) were used. Motor facilitation induced by N/OFQ and NOP receptor antagonists was lost in D2R(-/-) and D2L(-/-) mice whereas motor inhibition induced by NOP receptor antagonists (and pramipexole) was lost in D2R(-/-) but preserved in D2L(-/-) mice. N/OFQ-induced hypolocomotion was observed in both genotypes. We demonstrate that motor actions of NOP receptor ligands rely on the modulation of endogenous dopamine. Motor facilitation induced by NOP receptor antagonists as well as low dose N/OFQ is mediated through D2L postsynaptic receptors whereas motor inhibition observed with higher doses of N/OFQ occurs by direct inhibition of mesencephalic DA neurons. Motor inhibition seen with high doses of NOP receptor antagonists appears to be mediated through the D2 presynaptic autoreceptors. These data confirm that endogenous N/OFQ is a powerful modulator of dopamine transmission in vivo and that the effects of NOP receptor antagonists on motor function reflect the blockade of this endogenous N/OFQ tone. | INHIBITOR |
| Pharmacological and genetic evidence for pre- and postsynaptic GENE receptor involvement in motor responses to nociceptin/orphanin FQ receptor ligands. A combined pharmacological and genetic approach was undertaken to investigate the contribution of endogenous dopamine to the motor actions of nociceptin/orphanin FQ (N/OFQ) receptor (NOP receptor) ligands. Motor activity was evaluated by a battery of behavioural tests in mice. The involvement of the various DA receptor subtypes in the motor effects of N/OFQ and NOP receptor antagonists was evaluated pharmacologically, using D1/D5 (SCH23390), GENE/D3 (raclopride, CHEMICAL) and D3 (S33084) receptor antagonists, and by using GENE receptor knockout mice. Low doses of N/OFQ and NOP receptor antagonists promoted movement whereas higher doses inhibited it. Motor facilitation was selectively prevented by raclopride while motor inhibition was prevented by CHEMICAL. CHEMICAL also attenuated the hypolocomotion induced by the D2/D3 receptor agonist pramipexole and dopamine precursor L-3,4-dihydroxyphenylalanine, whereas raclopride (and S33084) worsened it. To dissect out the contribution of pre- and postsynaptic GENE receptors, mice lacking the GENE receptor (D2R(-/-)) or its long isoform (D2L(-/-)) were used. Motor facilitation induced by N/OFQ and NOP receptor antagonists was lost in D2R(-/-) and D2L(-/-) mice whereas motor inhibition induced by NOP receptor antagonists (and pramipexole) was lost in D2R(-/-) but preserved in D2L(-/-) mice. N/OFQ-induced hypolocomotion was observed in both genotypes. We demonstrate that motor actions of NOP receptor ligands rely on the modulation of endogenous dopamine. Motor facilitation induced by NOP receptor antagonists as well as low dose N/OFQ is mediated through D2L postsynaptic receptors whereas motor inhibition observed with higher doses of N/OFQ occurs by direct inhibition of mesencephalic DA neurons. Motor inhibition seen with high doses of NOP receptor antagonists appears to be mediated through the GENE presynaptic autoreceptors. These data confirm that endogenous N/OFQ is a powerful modulator of dopamine transmission in vivo and that the effects of NOP receptor antagonists on motor function reflect the blockade of this endogenous N/OFQ tone. | INHIBITOR |
| Pharmacological and genetic evidence for pre- and postsynaptic D2 receptor involvement in motor responses to nociceptin/orphanin FQ receptor ligands. A combined pharmacological and genetic approach was undertaken to investigate the contribution of endogenous dopamine to the motor actions of nociceptin/orphanin FQ (N/OFQ) receptor (NOP receptor) ligands. Motor activity was evaluated by a battery of behavioural tests in mice. The involvement of the various DA receptor subtypes in the motor effects of N/OFQ and NOP receptor antagonists was evaluated pharmacologically, using D1/D5 (SCH23390), D2/GENE (raclopride, CHEMICAL) and GENE (S33084) receptor antagonists, and by using D2 receptor knockout mice. Low doses of N/OFQ and NOP receptor antagonists promoted movement whereas higher doses inhibited it. Motor facilitation was selectively prevented by raclopride while motor inhibition was prevented by CHEMICAL. CHEMICAL also attenuated the hypolocomotion induced by the D2/D3 receptor agonist pramipexole and dopamine precursor L-3,4-dihydroxyphenylalanine, whereas raclopride (and S33084) worsened it. To dissect out the contribution of pre- and postsynaptic D2 receptors, mice lacking the D2 receptor (D2R(-/-)) or its long isoform (D2L(-/-)) were used. Motor facilitation induced by N/OFQ and NOP receptor antagonists was lost in D2R(-/-) and D2L(-/-) mice whereas motor inhibition induced by NOP receptor antagonists (and pramipexole) was lost in D2R(-/-) but preserved in D2L(-/-) mice. N/OFQ-induced hypolocomotion was observed in both genotypes. We demonstrate that motor actions of NOP receptor ligands rely on the modulation of endogenous dopamine. Motor facilitation induced by NOP receptor antagonists as well as low dose N/OFQ is mediated through D2L postsynaptic receptors whereas motor inhibition observed with higher doses of N/OFQ occurs by direct inhibition of mesencephalic DA neurons. Motor inhibition seen with high doses of NOP receptor antagonists appears to be mediated through the D2 presynaptic autoreceptors. These data confirm that endogenous N/OFQ is a powerful modulator of dopamine transmission in vivo and that the effects of NOP receptor antagonists on motor function reflect the blockade of this endogenous N/OFQ tone. | INHIBITOR |
| Pharmacological and genetic evidence for pre- and postsynaptic D2 receptor involvement in motor responses to nociceptin/orphanin FQ receptor ligands. A combined pharmacological and genetic approach was undertaken to investigate the contribution of endogenous dopamine to the motor actions of nociceptin/orphanin FQ (N/OFQ) receptor (NOP receptor) ligands. Motor activity was evaluated by a battery of behavioural tests in mice. The involvement of the various DA receptor subtypes in the motor effects of N/OFQ and NOP receptor antagonists was evaluated pharmacologically, using D1/D5 (SCH23390), D2/D3 (raclopride, amisulpride) and GENE (CHEMICAL) receptor antagonists, and by using D2 receptor knockout mice. Low doses of N/OFQ and NOP receptor antagonists promoted movement whereas higher doses inhibited it. Motor facilitation was selectively prevented by raclopride while motor inhibition was prevented by amisulpride. Amisulpride also attenuated the hypolocomotion induced by the D2/D3 receptor agonist pramipexole and dopamine precursor L-3,4-dihydroxyphenylalanine, whereas raclopride (and S33084) worsened it. To dissect out the contribution of pre- and postsynaptic D2 receptors, mice lacking the D2 receptor (D2R(-/-)) or its long isoform (D2L(-/-)) were used. Motor facilitation induced by N/OFQ and NOP receptor antagonists was lost in D2R(-/-) and D2L(-/-) mice whereas motor inhibition induced by NOP receptor antagonists (and pramipexole) was lost in D2R(-/-) but preserved in D2L(-/-) mice. N/OFQ-induced hypolocomotion was observed in both genotypes. We demonstrate that motor actions of NOP receptor ligands rely on the modulation of endogenous dopamine. Motor facilitation induced by NOP receptor antagonists as well as low dose N/OFQ is mediated through D2L postsynaptic receptors whereas motor inhibition observed with higher doses of N/OFQ occurs by direct inhibition of mesencephalic DA neurons. Motor inhibition seen with high doses of NOP receptor antagonists appears to be mediated through the D2 presynaptic autoreceptors. These data confirm that endogenous N/OFQ is a powerful modulator of dopamine transmission in vivo and that the effects of NOP receptor antagonists on motor function reflect the blockade of this endogenous N/OFQ tone. | INHIBITOR |
| Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of GENE at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. Administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express dopamine D2 receptors (D2Rs). This effect was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1). We also found that the effect of haloperidol on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation. These results show that haloperidol promotes mTORC1- and S6K1-dependent phosphorylation of GENE at CHEMICAL240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1. | PART-OF |
| CHEMICAL promotes GENE-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. Administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express dopamine D2 receptors (D2Rs). This effect was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1). We also found that the effect of haloperidol on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation. These results show that haloperidol promotes mTORC1- and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1. | ACTIVATOR |
| CHEMICAL promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via GENE and inhibition of protein phosphatase-1. The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. Administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express dopamine D2 receptors (D2Rs). This effect was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1). We also found that the effect of haloperidol on Ser240/244 phosphorylation was prevented by functional inactivation of GENE (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation. These results show that haloperidol promotes mTORC1- and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1. | INHIBITOR |
| CHEMICAL promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by CHEMICAL, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. Administration of CHEMICAL increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express dopamine D2 receptors (D2Rs). This effect was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1). We also found that the effect of CHEMICAL on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation. These results show that CHEMICAL promotes mTORC1- and GENE-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1. | REGULATOR |
| CHEMICAL promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by CHEMICAL, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. Administration of CHEMICAL increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express dopamine D2 receptors (D2Rs). This effect was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1). We also found that the effect of CHEMICAL on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation. These results show that CHEMICAL promotes mTORC1- and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing GENE. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1. | REGULATOR |
| CHEMICAL promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by CHEMICAL, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. Administration of CHEMICAL increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express GENE (D2Rs). This effect was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1). We also found that the effect of CHEMICAL on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation. These results show that CHEMICAL promotes mTORC1- and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1. | REGULATOR |
| CHEMICAL promotes mTORC1-dependent phosphorylation of GENE via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. The GENE (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. Administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express dopamine D2 receptors (D2Rs). This effect was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1). We also found that the effect of haloperidol on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation. These results show that haloperidol promotes mTORC1- and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1. | ACTIVATOR |
| CHEMICAL promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by CHEMICAL, a typical antipsychotic drug, on the phosphorylation of GENE at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. Administration of CHEMICAL increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express dopamine D2 receptors (D2Rs). This effect was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1). We also found that the effect of CHEMICAL on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation. These results show that CHEMICAL promotes mTORC1- and S6K1-dependent phosphorylation of GENE at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1. | REGULATOR |
| Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. Administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express dopamine D2 receptors (D2Rs). This effect was prevented by CHEMICAL, an inhibitor of the GENE (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1). We also found that the effect of haloperidol on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation. These results show that haloperidol promotes mTORC1- and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1. | INHIBITOR |
| Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. Administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express dopamine D2 receptors (D2Rs). This effect was prevented by CHEMICAL, an inhibitor of the mammalian target of CHEMICAL complex 1 (GENE), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1). We also found that the effect of haloperidol on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation. These results show that haloperidol promotes mTORC1- and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1. | INHIBITOR |
| Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. Administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express dopamine D2 receptors (D2Rs). This effect was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by CHEMICAL, a selective inhibitor of the GENE (S6K1). We also found that the effect of haloperidol on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation. These results show that haloperidol promotes mTORC1- and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1. | INHIBITOR |
| Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. Administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express dopamine D2 receptors (D2Rs). This effect was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by CHEMICAL, a selective inhibitor of the p70 ribosomal S6 kinase 1 (GENE). We also found that the effect of haloperidol on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation. These results show that haloperidol promotes mTORC1- and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1. | INHIBITOR |
| Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. Administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express dopamine D2 receptors (D2Rs). This effect was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1). We also found that the effect of haloperidol on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices with CHEMICAL and calyculin A, two inhibitors of GENE, increased Ser240/244 phosphorylation. These results show that haloperidol promotes mTORC1- and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of GENE. | INHIBITOR |
| CHEMICAL promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of GENE. The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. Administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express dopamine D2 receptors (D2Rs). This effect was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1). We also found that the effect of haloperidol on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of GENE (PP-1). In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation. These results show that haloperidol promotes mTORC1- and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1. | INHIBITOR |
| Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. Administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express dopamine D2 receptors (D2Rs). This effect was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1). We also found that the effect of haloperidol on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices with okadaic acid and CHEMICAL, two inhibitors of GENE, increased Ser240/244 phosphorylation. These results show that haloperidol promotes mTORC1- and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of GENE. | INHIBITOR |
| Low molecular weight dual inhibitors of factor Xa and GENE binding to GPIIb/IIIa with highly overlapped pharmacophores. Dual antithrombotic agents acting as anticoagulants and aggregation inhibitors could have substantial advantages over currently prescribed combinations of antithrombotic drugs. Herein, we report compounds with moderate inhibitory activity for factor Xa and GENE GPIIb/IIIa binding (both in the micromolar range). These compounds resulted from our efforts to merge the pharmacophores of selective factor Xa inhibitor rivaroxaban with a mimic of the CHEMICAL (RGD) sequence of GENE to obtain designed multiple ligands with potential antithrombotic activity. Resulting from this study, a structurally novel class of submicromolar GENE GPIIb/IIIa binding inhibitor bearing 1,2,4-oxadiazol-5(4H)-one moiety is also described. | PART-OF |
| Low molecular weight dual inhibitors of GENE and fibrinogen binding to GPIIb/IIIa with highly overlapped pharmacophores. Dual antithrombotic agents acting as anticoagulants and aggregation inhibitors could have substantial advantages over currently prescribed combinations of antithrombotic drugs. Herein, we report compounds with moderate inhibitory activity for GENE and fibrinogen GPIIb/IIIa binding (both in the micromolar range). These compounds resulted from our efforts to merge the pharmacophores of selective GENE inhibitor CHEMICAL with a mimic of the Arg-Gly-Asp (RGD) sequence of fibrinogen to obtain designed multiple ligands with potential antithrombotic activity. Resulting from this study, a structurally novel class of submicromolar fibrinogen GPIIb/IIIa binding inhibitor bearing 1,2,4-oxadiazol-5(4H)-one moiety is also described. | INHIBITOR |
| Low molecular weight dual inhibitors of factor Xa and fibrinogen binding to GENE with highly overlapped pharmacophores. Dual antithrombotic agents acting as anticoagulants and aggregation inhibitors could have substantial advantages over currently prescribed combinations of antithrombotic drugs. Herein, we report compounds with moderate inhibitory activity for factor Xa and fibrinogen GENE binding (both in the micromolar range). These compounds resulted from our efforts to merge the pharmacophores of selective factor Xa inhibitor rivaroxaban with a mimic of the Arg-Gly-Asp (RGD) sequence of fibrinogen to obtain designed multiple ligands with potential antithrombotic activity. Resulting from this study, a structurally novel class of submicromolar fibrinogen GENE binding inhibitor bearing CHEMICAL moiety is also described. | INHIBITOR |
| Role of quercetin in cadmium-induced oxidative stress, neuronal damage, and apoptosis in rats. The present study was carried out to evaluate the neuroprotective effect of quercetin (QE) in protecting the cadmium (Cd)-induced neuronal injury in frontal cortex of rats. A total of 30 adult male Sprague-Dawley rats were randomly divided into three groups of 10 animals each: control, CHEMICAL treated and CHEMICAL treated with QE. The Cd-treated group was injected subcutaneously with cadmium chloride (CdCl2) dissolved in saline at a dose of 2 ml/kg/day for 30 days, resulting in a dosage of 1 mg/kg CHEMICAL. The rats in QE-treated groups were given QE (15 mg/kg body weight) once a day intraperitoneally starting 2 days prior to CHEMICAL injection, during the study period. Rats were sacrificed at the end of the study and the frontal cortex tissues were removed for biochemical and histopathological investigation. To date, there is no available information on the effect of QE on neuronal injury after CHEMICAL exposure. Rats intoxicated with CHEMICAL for 30 days, significantly increased tissue malondialdehyde (MDA) levels and significantly decreased enzymatic antioxidants superoxide dismutase, glutathione peroxidase and catalase in the frontal cortex tissue. Administration of QE with CHEMICAL significantly diminished the levels of MDA and significantly elevated the levels of enzymatic antioxidants in the frontal cortex tissue. The histopathological studies in the brain of rats also supported that QE markedly reduced the Cd-induced histopathological changes and well preserved the normal histological architecture of the frontal cortex tissue. The GENE immunopositivity was increased in degenerating neurons of the CHEMICAL group. Treatment with QE markedly reduced the immunoreactivity of degenerating neurons. In conclusion, the results of the current study suggest that QE may be beneficial in combating the Cd-induced neurotoxicity in the brain of rats. We believe that further preclinical research into the utility of QE may indicate its usefulness as a potential treatment for neurodegeneration after CHEMICAL exposure in rats. | INDIRECT-UPREGULATOR |
| Role of quercetin in cadmium-induced oxidative stress, neuronal damage, and apoptosis in rats. The present study was carried out to evaluate the neuroprotective effect of quercetin (QE) in protecting the cadmium (Cd)-induced neuronal injury in frontal cortex of rats. A total of 30 adult male Sprague-Dawley rats were randomly divided into three groups of 10 animals each: control, CHEMICAL treated and CHEMICAL treated with QE. The Cd-treated group was injected subcutaneously with cadmium chloride (CdCl2) dissolved in saline at a dose of 2 ml/kg/day for 30 days, resulting in a dosage of 1 mg/kg CHEMICAL. The rats in QE-treated groups were given QE (15 mg/kg body weight) once a day intraperitoneally starting 2 days prior to CHEMICAL injection, during the study period. Rats were sacrificed at the end of the study and the frontal cortex tissues were removed for biochemical and histopathological investigation. To date, there is no available information on the effect of QE on neuronal injury after CHEMICAL exposure. Rats intoxicated with CHEMICAL for 30 days, significantly increased tissue malondialdehyde (MDA) levels and significantly decreased enzymatic antioxidants GENE, glutathione peroxidase and catalase in the frontal cortex tissue. Administration of QE with CHEMICAL significantly diminished the levels of MDA and significantly elevated the levels of enzymatic antioxidants in the frontal cortex tissue. The histopathological studies in the brain of rats also supported that QE markedly reduced the Cd-induced histopathological changes and well preserved the normal histological architecture of the frontal cortex tissue. The caspase-3 immunopositivity was increased in degenerating neurons of the CHEMICAL group. Treatment with QE markedly reduced the immunoreactivity of degenerating neurons. In conclusion, the results of the current study suggest that QE may be beneficial in combating the Cd-induced neurotoxicity in the brain of rats. We believe that further preclinical research into the utility of QE may indicate its usefulness as a potential treatment for neurodegeneration after CHEMICAL exposure in rats. | INDIRECT-DOWNREGULATOR |
| Role of quercetin in cadmium-induced oxidative stress, neuronal damage, and apoptosis in rats. The present study was carried out to evaluate the neuroprotective effect of quercetin (QE) in protecting the cadmium (Cd)-induced neuronal injury in frontal cortex of rats. A total of 30 adult male Sprague-Dawley rats were randomly divided into three groups of 10 animals each: control, CHEMICAL treated and CHEMICAL treated with QE. The Cd-treated group was injected subcutaneously with cadmium chloride (CdCl2) dissolved in saline at a dose of 2 ml/kg/day for 30 days, resulting in a dosage of 1 mg/kg CHEMICAL. The rats in QE-treated groups were given QE (15 mg/kg body weight) once a day intraperitoneally starting 2 days prior to CHEMICAL injection, during the study period. Rats were sacrificed at the end of the study and the frontal cortex tissues were removed for biochemical and histopathological investigation. To date, there is no available information on the effect of QE on neuronal injury after CHEMICAL exposure. Rats intoxicated with CHEMICAL for 30 days, significantly increased tissue malondialdehyde (MDA) levels and significantly decreased enzymatic antioxidants superoxide dismutase, GENE and catalase in the frontal cortex tissue. Administration of QE with CHEMICAL significantly diminished the levels of MDA and significantly elevated the levels of enzymatic antioxidants in the frontal cortex tissue. The histopathological studies in the brain of rats also supported that QE markedly reduced the Cd-induced histopathological changes and well preserved the normal histological architecture of the frontal cortex tissue. The caspase-3 immunopositivity was increased in degenerating neurons of the CHEMICAL group. Treatment with QE markedly reduced the immunoreactivity of degenerating neurons. In conclusion, the results of the current study suggest that QE may be beneficial in combating the Cd-induced neurotoxicity in the brain of rats. We believe that further preclinical research into the utility of QE may indicate its usefulness as a potential treatment for neurodegeneration after CHEMICAL exposure in rats. | INDIRECT-DOWNREGULATOR |
| Role of quercetin in cadmium-induced oxidative stress, neuronal damage, and apoptosis in rats. The present study was carried out to evaluate the neuroprotective effect of quercetin (QE) in protecting the cadmium (Cd)-induced neuronal injury in frontal cortex of rats. A total of 30 adult male Sprague-Dawley rats were randomly divided into three groups of 10 animals each: control, CHEMICAL treated and CHEMICAL treated with QE. The Cd-treated group was injected subcutaneously with cadmium chloride (CdCl2) dissolved in saline at a dose of 2 ml/kg/day for 30 days, resulting in a dosage of 1 mg/kg CHEMICAL. The rats in QE-treated groups were given QE (15 mg/kg body weight) once a day intraperitoneally starting 2 days prior to CHEMICAL injection, during the study period. Rats were sacrificed at the end of the study and the frontal cortex tissues were removed for biochemical and histopathological investigation. To date, there is no available information on the effect of QE on neuronal injury after CHEMICAL exposure. Rats intoxicated with CHEMICAL for 30 days, significantly increased tissue malondialdehyde (MDA) levels and significantly decreased enzymatic antioxidants superoxide dismutase, glutathione peroxidase and GENE in the frontal cortex tissue. Administration of QE with CHEMICAL significantly diminished the levels of MDA and significantly elevated the levels of enzymatic antioxidants in the frontal cortex tissue. The histopathological studies in the brain of rats also supported that QE markedly reduced the Cd-induced histopathological changes and well preserved the normal histological architecture of the frontal cortex tissue. The caspase-3 immunopositivity was increased in degenerating neurons of the CHEMICAL group. Treatment with QE markedly reduced the immunoreactivity of degenerating neurons. In conclusion, the results of the current study suggest that QE may be beneficial in combating the Cd-induced neurotoxicity in the brain of rats. We believe that further preclinical research into the utility of QE may indicate its usefulness as a potential treatment for neurodegeneration after CHEMICAL exposure in rats. | INDIRECT-DOWNREGULATOR |
| Oestrogen action on thyroid progenitor cells: relevant for the pathogenesis of thyroid nodules? Benign and malignant thyroid nodules are more prevalent in females than in men. Experimental data suggest that the proliferative effect of oestrogen rather than polymorphisms is responsible for this gender difference. This study analysed whether both differentiated thyroid cells and thyroid stem and progenitor cells are a target of oestrogen action. In thyroid stem/progenitor cells derived from nodular goitres the ability of CHEMICAL to induce thyrosphere formation, the expression of oestrogen receptors and the effect of CHEMICAL on growth, expression of marker of stem cells and thyroid differentiation (TSH receptor, thyroperoxidase, thyroglobulin, GENE expression) were analysed. CHEMICAL induced thyrosphere formation, albeit to lower extent than other growth factors. Thyroid stem and progenitor cells expressed oestrogen receptor alpha and beta with an 8 time higher expression level of oestrogen receptor alpha mRNA compared to differentiated thyrocytes. CHEMICAL was a potent stimulator of thyroid stem/ progenitor cell growth. In contrast, TSH-induced differentiation of progenitor cells, in particular the expression of the GENE, was significantly inhibited by CHEMICAL.In conclusion, oestrogen stimulated growth and simultaneously inhibited differentiation of thyroid nodules derived stem/progenitor cells. From these data and based on the concept of cellular heterogeneity, we hypothesize a supportive role of oestrogen in the propagation of thyroid stem/progenitor cells leading to a selection of a progeny of growth-prone cells with a decreased differentiation. These cells may be the origin of hypo- or non-functioning thyroid nodules in females. | GENE-CHEMICAL |
| Differential regulation of Arabidopsis plastid gene expression and RNA editing in non-photosynthetic tissues. RNA editing is one of the post-transcriptional processes that commonly occur in plant plastids and mitochondria. In Arabidopsis, 34 C-to-U RNA editing events, affecting transcripts of 18 plastid genes, have been identified. Here, we examined the editing and expression of these transcripts in different organs, and in green and non-green seedlings (etiolated, cia5-2, ispF and ispG albino mutants, lincomycin-, and norflurazon-treated). The editing efficiency of Arabidopsis plastid transcripts varies from site to site, and may be specifically regulated in different tissues. Steady state levels of plastid transcripts are low or undetectable in etiolated seedlings, but most editing sites are edited with efficiencies similar to those observed in green seedlings. By contrast, the editing of some sites is completely lost or significantly reduced in other non-green tissues; for instance, the editing of ndhB-149, ndhB-1255, and GENE is completely lost in roots and in lincomycin-treated seedlings. The editing of GENE is also completely lost in albino mutants and CHEMICAL-treated seedlings. However, matK-640 is completely edited, and accD-794, atpF-92, psbE-214, psbF-77, psbZ-50, and rps14-50 are completely or highly edited in both green and non-green tissues. In addition, the expression of nucleus-encoded RNA polymerase dependent transcripts is specifically induced by lincomycin, and the splicing of ndhB transcripts is significantly reduced in the albino mutants and inhibitor-treated seedlings. Our results indicate that plastid gene expression, and the splicing and editing of plastid transcripts are specifically and differentially regulated in various types of non-green tissues. | INHIBITOR |
| Differential regulation of Arabidopsis plastid gene expression and RNA editing in non-photosynthetic tissues. RNA editing is one of the post-transcriptional processes that commonly occur in plant plastids and mitochondria. In Arabidopsis, 34 C-to-U RNA editing events, affecting transcripts of 18 plastid genes, have been identified. Here, we examined the editing and expression of these transcripts in different organs, and in green and non-green seedlings (etiolated, cia5-2, ispF and ispG albino mutants, lincomycin-, and norflurazon-treated). The editing efficiency of Arabidopsis plastid transcripts varies from site to site, and may be specifically regulated in different tissues. Steady state levels of plastid transcripts are low or undetectable in etiolated seedlings, but most editing sites are edited with efficiencies similar to those observed in green seedlings. By contrast, the editing of some sites is completely lost or significantly reduced in other non-green tissues; for instance, the editing of ndhB-149, ndhB-1255, and ndhD-2 is completely lost in roots and in lincomycin-treated seedlings. The editing of ndhD-2 is also completely lost in albino mutants and norflurazon-treated seedlings. However, matK-640 is completely edited, and accD-794, atpF-92, psbE-214, psbF-77, psbZ-50, and rps14-50 are completely or highly edited in both green and non-green tissues. In addition, the expression of nucleus-encoded GENE dependent transcripts is specifically induced by CHEMICAL, and the splicing of ndhB transcripts is significantly reduced in the albino mutants and inhibitor-treated seedlings. Our results indicate that plastid gene expression, and the splicing and editing of plastid transcripts are specifically and differentially regulated in various types of non-green tissues. | ACTIVATOR |
| Differential regulation of Arabidopsis plastid gene expression and RNA editing in non-photosynthetic tissues. RNA editing is one of the post-transcriptional processes that commonly occur in plant plastids and mitochondria. In Arabidopsis, 34 C-to-U RNA editing events, affecting transcripts of 18 plastid genes, have been identified. Here, we examined the editing and expression of these transcripts in different organs, and in green and non-green seedlings (etiolated, cia5-2, ispF and ispG albino mutants, lincomycin-, and norflurazon-treated). The editing efficiency of Arabidopsis plastid transcripts varies from site to site, and may be specifically regulated in different tissues. Steady state levels of plastid transcripts are low or undetectable in etiolated seedlings, but most editing sites are edited with efficiencies similar to those observed in green seedlings. By contrast, the editing of some sites is completely lost or significantly reduced in other non-green tissues; for instance, the editing of ndhB-149, ndhB-1255, and ndhD-2 is completely lost in roots and in lincomycin-treated seedlings. The editing of ndhD-2 is also completely lost in albino mutants and norflurazon-treated seedlings. However, matK-640 is completely edited, and accD-794, atpF-92, psbE-214, psbF-77, psbZ-50, and rps14-50 are completely or highly edited in both green and non-green tissues. In addition, the expression of nucleus-encoded RNA polymerase dependent transcripts is specifically induced by CHEMICAL, and the splicing of GENE transcripts is significantly reduced in the albino mutants and inhibitor-treated seedlings. Our results indicate that plastid gene expression, and the splicing and editing of plastid transcripts are specifically and differentially regulated in various types of non-green tissues. | INDIRECT-UPREGULATOR |
| Differential regulation of Arabidopsis plastid gene expression and RNA editing in non-photosynthetic tissues. RNA editing is one of the post-transcriptional processes that commonly occur in plant plastids and mitochondria. In Arabidopsis, 34 C-to-U RNA editing events, affecting transcripts of 18 plastid genes, have been identified. Here, we examined the editing and expression of these transcripts in different organs, and in green and non-green seedlings (etiolated, cia5-2, ispF and ispG albino mutants, lincomycin-, and norflurazon-treated). The editing efficiency of Arabidopsis plastid transcripts varies from site to site, and may be specifically regulated in different tissues. Steady state levels of plastid transcripts are low or undetectable in etiolated seedlings, but most editing sites are edited with efficiencies similar to those observed in green seedlings. By contrast, the editing of some sites is completely lost or significantly reduced in other non-green tissues; for instance, the editing of GENE, ndhB-1255, and ndhD-2 is completely lost in roots and in CHEMICAL-treated seedlings. The editing of ndhD-2 is also completely lost in albino mutants and norflurazon-treated seedlings. However, matK-640 is completely edited, and accD-794, atpF-92, psbE-214, psbF-77, psbZ-50, and rps14-50 are completely or highly edited in both green and non-green tissues. In addition, the expression of nucleus-encoded RNA polymerase dependent transcripts is specifically induced by CHEMICAL, and the splicing of ndhB transcripts is significantly reduced in the albino mutants and inhibitor-treated seedlings. Our results indicate that plastid gene expression, and the splicing and editing of plastid transcripts are specifically and differentially regulated in various types of non-green tissues. | GENE-CHEMICAL |
| Differential regulation of Arabidopsis plastid gene expression and RNA editing in non-photosynthetic tissues. RNA editing is one of the post-transcriptional processes that commonly occur in plant plastids and mitochondria. In Arabidopsis, 34 C-to-U RNA editing events, affecting transcripts of 18 plastid genes, have been identified. Here, we examined the editing and expression of these transcripts in different organs, and in green and non-green seedlings (etiolated, cia5-2, ispF and ispG albino mutants, lincomycin-, and norflurazon-treated). The editing efficiency of Arabidopsis plastid transcripts varies from site to site, and may be specifically regulated in different tissues. Steady state levels of plastid transcripts are low or undetectable in etiolated seedlings, but most editing sites are edited with efficiencies similar to those observed in green seedlings. By contrast, the editing of some sites is completely lost or significantly reduced in other non-green tissues; for instance, the editing of ndhB-149, GENE, and ndhD-2 is completely lost in roots and in CHEMICAL-treated seedlings. The editing of ndhD-2 is also completely lost in albino mutants and norflurazon-treated seedlings. However, matK-640 is completely edited, and accD-794, atpF-92, psbE-214, psbF-77, psbZ-50, and rps14-50 are completely or highly edited in both green and non-green tissues. In addition, the expression of nucleus-encoded RNA polymerase dependent transcripts is specifically induced by CHEMICAL, and the splicing of ndhB transcripts is significantly reduced in the albino mutants and inhibitor-treated seedlings. Our results indicate that plastid gene expression, and the splicing and editing of plastid transcripts are specifically and differentially regulated in various types of non-green tissues. | GENE-CHEMICAL |
| Differential regulation of Arabidopsis plastid gene expression and RNA editing in non-photosynthetic tissues. RNA editing is one of the post-transcriptional processes that commonly occur in plant plastids and mitochondria. In Arabidopsis, 34 C-to-U RNA editing events, affecting transcripts of 18 plastid genes, have been identified. Here, we examined the editing and expression of these transcripts in different organs, and in green and non-green seedlings (etiolated, cia5-2, ispF and ispG albino mutants, lincomycin-, and norflurazon-treated). The editing efficiency of Arabidopsis plastid transcripts varies from site to site, and may be specifically regulated in different tissues. Steady state levels of plastid transcripts are low or undetectable in etiolated seedlings, but most editing sites are edited with efficiencies similar to those observed in green seedlings. By contrast, the editing of some sites is completely lost or significantly reduced in other non-green tissues; for instance, the editing of ndhB-149, ndhB-1255, and GENE is completely lost in roots and in CHEMICAL-treated seedlings. The editing of GENE is also completely lost in albino mutants and norflurazon-treated seedlings. However, matK-640 is completely edited, and accD-794, atpF-92, psbE-214, psbF-77, psbZ-50, and rps14-50 are completely or highly edited in both green and non-green tissues. In addition, the expression of nucleus-encoded RNA polymerase dependent transcripts is specifically induced by CHEMICAL, and the splicing of ndhB transcripts is significantly reduced in the albino mutants and inhibitor-treated seedlings. Our results indicate that plastid gene expression, and the splicing and editing of plastid transcripts are specifically and differentially regulated in various types of non-green tissues. | GENE-CHEMICAL |
| Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors. The HMG-CoA reductase inhibitors are a class of drugs also known as statins. These drugs are effective and widely prescribed for the treatment of hypercholesterolemia and prevention of cardiovascular morbidity and mortality. Seven statins are currently available: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Although these drugs are generally well tolerated, skeletal muscle abnormalities from myalgia to severe lethal rhabdomyolysis can occur. Factors that increase statin concentrations such as drug-drug interactions can increase the risk of these adverse events. Drug-drug interactions are dependent on statins' pharmacokinetic profile: simvastatin, lovastatin and atorvastatin are metabolized through cytochrome P450 (CYP) 3A, while the metabolism of the other statins is independent of this CYP. All statins are substrate of organic anion transporter polypeptide 1B1, an uptake transporter expressed in hepatocyte membrane that may also explain some drug-drug interactions. Many HIV-infected patients have dyslipidemia and comorbidities that may require statin treatment. HIV-protease inhibitors (HIV PIs) are part of recommended antiretroviral treatment in combination with two reverse transcriptase inhibitors. All HIV PIs except nelfinavir are coadministered with a low dose of ritonavir, a potent GENE inhibitor to improve their pharmacokinetic properties. Cobicistat is a new potent GENE inhibitor that is combined with elvitegravir and will be combined with HIV-PIs in the future. The HCV-PIs CHEMICAL and telaprevir are both, to different extents, inhibitors of GENE. This review summarizes the pharmacokinetic properties of statins and PIs with emphasis on their metabolic pathways explaining clinically important drug-drug interactions. Simvastatin and lovastatin metabolized through GENE have the highest potency for drug-drug interaction with potent GENE inhibitors such as ritonavir- or cobicistat-boosted HIV-PI or the hepatitis C virus (HCV) PI, telaprevir or CHEMICAL, and therefore their coadministration is contraindicated. Atorvastatin is also a GENE substrate, but less potent drug-drug interactions have been reported with GENE inhibitors. Non-CYP3A-dependent statin concentrations are also affected although to a lesser extent when coadministered with HIV or HCV PIs, mainly through interaction with OATP1B1, and treatment should start with the lowest available statin dose. Effectiveness and occurrence of adverse effects should be monitored at regular time intervals. | INHIBITOR |
| Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors. The HMG-CoA reductase inhibitors are a class of drugs also known as statins. These drugs are effective and widely prescribed for the treatment of hypercholesterolemia and prevention of cardiovascular morbidity and mortality. Seven statins are currently available: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Although these drugs are generally well tolerated, skeletal muscle abnormalities from myalgia to severe lethal rhabdomyolysis can occur. Factors that increase statin concentrations such as drug-drug interactions can increase the risk of these adverse events. Drug-drug interactions are dependent on statins' pharmacokinetic profile: simvastatin, lovastatin and atorvastatin are metabolized through cytochrome P450 (CYP) 3A, while the metabolism of the other statins is independent of this CYP. All statins are substrate of organic anion transporter polypeptide 1B1, an uptake transporter expressed in hepatocyte membrane that may also explain some drug-drug interactions. Many HIV-infected patients have dyslipidemia and comorbidities that may require statin treatment. HIV-protease inhibitors (HIV PIs) are part of recommended antiretroviral treatment in combination with two reverse transcriptase inhibitors. All HIV PIs except nelfinavir are coadministered with a low dose of CHEMICAL, a potent GENE inhibitor to improve their pharmacokinetic properties. Cobicistat is a new potent GENE inhibitor that is combined with elvitegravir and will be combined with HIV-PIs in the future. The HCV-PIs boceprevir and telaprevir are both, to different extents, inhibitors of GENE. This review summarizes the pharmacokinetic properties of statins and PIs with emphasis on their metabolic pathways explaining clinically important drug-drug interactions. Simvastatin and lovastatin metabolized through GENE have the highest potency for drug-drug interaction with potent GENE inhibitors such as ritonavir- or cobicistat-boosted HIV-PI or the hepatitis C virus (HCV) PI, telaprevir or boceprevir, and therefore their coadministration is contraindicated. Atorvastatin is also a GENE substrate, but less potent drug-drug interactions have been reported with GENE inhibitors. Non-CYP3A-dependent statin concentrations are also affected although to a lesser extent when coadministered with HIV or HCV PIs, mainly through interaction with OATP1B1, and treatment should start with the lowest available statin dose. Effectiveness and occurrence of adverse effects should be monitored at regular time intervals. | INHIBITOR |
| Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors. The HMG-CoA reductase inhibitors are a class of drugs also known as statins. These drugs are effective and widely prescribed for the treatment of hypercholesterolemia and prevention of cardiovascular morbidity and mortality. Seven statins are currently available: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Although these drugs are generally well tolerated, skeletal muscle abnormalities from myalgia to severe lethal rhabdomyolysis can occur. Factors that increase statin concentrations such as drug-drug interactions can increase the risk of these adverse events. Drug-drug interactions are dependent on statins' pharmacokinetic profile: simvastatin, lovastatin and atorvastatin are metabolized through cytochrome P450 (CYP) 3A, while the metabolism of the other statins is independent of this CYP. All statins are substrate of organic anion transporter polypeptide 1B1, an uptake transporter expressed in hepatocyte membrane that may also explain some drug-drug interactions. Many HIV-infected patients have dyslipidemia and comorbidities that may require statin treatment. HIV-protease inhibitors (HIV PIs) are part of recommended antiretroviral treatment in combination with two reverse transcriptase inhibitors. All HIV PIs except nelfinavir are coadministered with a low dose of ritonavir, a potent GENE inhibitor to improve their pharmacokinetic properties. Cobicistat is a new potent GENE inhibitor that is combined with elvitegravir and will be combined with HIV-PIs in the future. The HCV-PIs boceprevir and CHEMICAL are both, to different extents, inhibitors of GENE. This review summarizes the pharmacokinetic properties of statins and PIs with emphasis on their metabolic pathways explaining clinically important drug-drug interactions. Simvastatin and lovastatin metabolized through GENE have the highest potency for drug-drug interaction with potent GENE inhibitors such as ritonavir- or cobicistat-boosted HIV-PI or the hepatitis C virus (HCV) PI, CHEMICAL or boceprevir, and therefore their coadministration is contraindicated. Atorvastatin is also a GENE substrate, but less potent drug-drug interactions have been reported with GENE inhibitors. Non-CYP3A-dependent statin concentrations are also affected although to a lesser extent when coadministered with HIV or HCV PIs, mainly through interaction with OATP1B1, and treatment should start with the lowest available statin dose. Effectiveness and occurrence of adverse effects should be monitored at regular time intervals. | INHIBITOR |
| Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors. The HMG-CoA reductase inhibitors are a class of drugs also known as statins. These drugs are effective and widely prescribed for the treatment of hypercholesterolemia and prevention of cardiovascular morbidity and mortality. Seven statins are currently available: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Although these drugs are generally well tolerated, skeletal muscle abnormalities from myalgia to severe lethal rhabdomyolysis can occur. Factors that increase statin concentrations such as drug-drug interactions can increase the risk of these adverse events. Drug-drug interactions are dependent on statins' pharmacokinetic profile: simvastatin, lovastatin and atorvastatin are metabolized through cytochrome P450 (CYP) 3A, while the metabolism of the other statins is independent of this CYP. All statins are substrate of organic anion transporter polypeptide 1B1, an uptake transporter expressed in hepatocyte membrane that may also explain some drug-drug interactions. Many HIV-infected patients have dyslipidemia and comorbidities that may require statin treatment. HIV-protease inhibitors (HIV PIs) are part of recommended antiretroviral treatment in combination with two reverse transcriptase inhibitors. All HIV PIs except nelfinavir are coadministered with a low dose of ritonavir, a potent GENE inhibitor to improve their pharmacokinetic properties. CHEMICAL is a new potent GENE inhibitor that is combined with elvitegravir and will be combined with HIV-PIs in the future. The HCV-PIs boceprevir and telaprevir are both, to different extents, inhibitors of GENE. This review summarizes the pharmacokinetic properties of statins and PIs with emphasis on their metabolic pathways explaining clinically important drug-drug interactions. Simvastatin and lovastatin metabolized through GENE have the highest potency for drug-drug interaction with potent GENE inhibitors such as ritonavir- or CHEMICAL-boosted HIV-PI or the hepatitis C virus (HCV) PI, telaprevir or boceprevir, and therefore their coadministration is contraindicated. Atorvastatin is also a GENE substrate, but less potent drug-drug interactions have been reported with GENE inhibitors. Non-CYP3A-dependent statin concentrations are also affected although to a lesser extent when coadministered with HIV or HCV PIs, mainly through interaction with OATP1B1, and treatment should start with the lowest available statin dose. Effectiveness and occurrence of adverse effects should be monitored at regular time intervals. | INHIBITOR |
| Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors. The HMG-CoA reductase inhibitors are a class of drugs also known as statins. These drugs are effective and widely prescribed for the treatment of hypercholesterolemia and prevention of cardiovascular morbidity and mortality. Seven statins are currently available: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Although these drugs are generally well tolerated, skeletal muscle abnormalities from myalgia to severe lethal rhabdomyolysis can occur. Factors that increase statin concentrations such as drug-drug interactions can increase the risk of these adverse events. Drug-drug interactions are dependent on statins' pharmacokinetic profile: simvastatin, lovastatin and atorvastatin are metabolized through cytochrome P450 (CYP) 3A, while the metabolism of the other statins is independent of this CYP. All statins are substrate of organic anion transporter polypeptide 1B1, an uptake transporter expressed in hepatocyte membrane that may also explain some drug-drug interactions. Many HIV-infected patients have dyslipidemia and comorbidities that may require statin treatment. HIV-protease inhibitors (HIV PIs) are part of recommended antiretroviral treatment in combination with two reverse transcriptase inhibitors. All HIV PIs except nelfinavir are coadministered with a low dose of ritonavir, a potent GENE inhibitor to improve their pharmacokinetic properties. Cobicistat is a new potent GENE inhibitor that is combined with elvitegravir and will be combined with HIV-PIs in the future. The HCV-PIs boceprevir and telaprevir are both, to different extents, inhibitors of GENE. This review summarizes the pharmacokinetic properties of statins and PIs with emphasis on their metabolic pathways explaining clinically important drug-drug interactions. Simvastatin and lovastatin metabolized through GENE have the highest potency for drug-drug interaction with potent GENE inhibitors such as ritonavir- or cobicistat-boosted HIV-PI or the hepatitis C virus (HCV) PI, telaprevir or boceprevir, and therefore their coadministration is contraindicated. CHEMICAL is also a GENE substrate, but less potent drug-drug interactions have been reported with GENE inhibitors. Non-CYP3A-dependent statin concentrations are also affected although to a lesser extent when coadministered with HIV or HCV PIs, mainly through interaction with OATP1B1, and treatment should start with the lowest available statin dose. Effectiveness and occurrence of adverse effects should be monitored at regular time intervals. | SUBSTRATE |
| Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors. The HMG-CoA reductase inhibitors are a class of drugs also known as statins. These drugs are effective and widely prescribed for the treatment of hypercholesterolemia and prevention of cardiovascular morbidity and mortality. Seven statins are currently available: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and CHEMICAL. Although these drugs are generally well tolerated, skeletal muscle abnormalities from myalgia to severe lethal rhabdomyolysis can occur. Factors that increase statin concentrations such as drug-drug interactions can increase the risk of these adverse events. Drug-drug interactions are dependent on statins' pharmacokinetic profile: CHEMICAL, lovastatin and atorvastatin are metabolized through GENE, while the metabolism of the other statins is independent of this CYP. All statins are substrate of organic anion transporter polypeptide 1B1, an uptake transporter expressed in hepatocyte membrane that may also explain some drug-drug interactions. Many HIV-infected patients have dyslipidemia and comorbidities that may require statin treatment. HIV-protease inhibitors (HIV PIs) are part of recommended antiretroviral treatment in combination with two reverse transcriptase inhibitors. All HIV PIs except nelfinavir are coadministered with a low dose of ritonavir, a potent CYP3A inhibitor to improve their pharmacokinetic properties. Cobicistat is a new potent CYP3A inhibitor that is combined with elvitegravir and will be combined with HIV-PIs in the future. The HCV-PIs boceprevir and telaprevir are both, to different extents, inhibitors of CYP3A. This review summarizes the pharmacokinetic properties of statins and PIs with emphasis on their metabolic pathways explaining clinically important drug-drug interactions. CHEMICAL and lovastatin metabolized through CYP3A have the highest potency for drug-drug interaction with potent CYP3A inhibitors such as ritonavir- or cobicistat-boosted HIV-PI or the hepatitis C virus (HCV) PI, telaprevir or boceprevir, and therefore their coadministration is contraindicated. Atorvastatin is also a CYP3A substrate, but less potent drug-drug interactions have been reported with CYP3A inhibitors. Non-CYP3A-dependent statin concentrations are also affected although to a lesser extent when coadministered with HIV or HCV PIs, mainly through interaction with OATP1B1, and treatment should start with the lowest available statin dose. Effectiveness and occurrence of adverse effects should be monitored at regular time intervals. | SUBSTRATE |
| Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors. The HMG-CoA reductase inhibitors are a class of drugs also known as statins. These drugs are effective and widely prescribed for the treatment of hypercholesterolemia and prevention of cardiovascular morbidity and mortality. Seven statins are currently available: atorvastatin, fluvastatin, CHEMICAL, pitavastatin, pravastatin, rosuvastatin and simvastatin. Although these drugs are generally well tolerated, skeletal muscle abnormalities from myalgia to severe lethal rhabdomyolysis can occur. Factors that increase statin concentrations such as drug-drug interactions can increase the risk of these adverse events. Drug-drug interactions are dependent on statins' pharmacokinetic profile: simvastatin, CHEMICAL and atorvastatin are metabolized through GENE, while the metabolism of the other statins is independent of this CYP. All statins are substrate of organic anion transporter polypeptide 1B1, an uptake transporter expressed in hepatocyte membrane that may also explain some drug-drug interactions. Many HIV-infected patients have dyslipidemia and comorbidities that may require statin treatment. HIV-protease inhibitors (HIV PIs) are part of recommended antiretroviral treatment in combination with two reverse transcriptase inhibitors. All HIV PIs except nelfinavir are coadministered with a low dose of ritonavir, a potent CYP3A inhibitor to improve their pharmacokinetic properties. Cobicistat is a new potent CYP3A inhibitor that is combined with elvitegravir and will be combined with HIV-PIs in the future. The HCV-PIs boceprevir and telaprevir are both, to different extents, inhibitors of CYP3A. This review summarizes the pharmacokinetic properties of statins and PIs with emphasis on their metabolic pathways explaining clinically important drug-drug interactions. Simvastatin and CHEMICAL metabolized through CYP3A have the highest potency for drug-drug interaction with potent CYP3A inhibitors such as ritonavir- or cobicistat-boosted HIV-PI or the hepatitis C virus (HCV) PI, telaprevir or boceprevir, and therefore their coadministration is contraindicated. Atorvastatin is also a CYP3A substrate, but less potent drug-drug interactions have been reported with CYP3A inhibitors. Non-CYP3A-dependent statin concentrations are also affected although to a lesser extent when coadministered with HIV or HCV PIs, mainly through interaction with OATP1B1, and treatment should start with the lowest available statin dose. Effectiveness and occurrence of adverse effects should be monitored at regular time intervals. | SUBSTRATE |
| Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors. The HMG-CoA reductase inhibitors are a class of drugs also known as statins. These drugs are effective and widely prescribed for the treatment of hypercholesterolemia and prevention of cardiovascular morbidity and mortality. Seven statins are currently available: CHEMICAL, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Although these drugs are generally well tolerated, skeletal muscle abnormalities from myalgia to severe lethal rhabdomyolysis can occur. Factors that increase statin concentrations such as drug-drug interactions can increase the risk of these adverse events. Drug-drug interactions are dependent on statins' pharmacokinetic profile: simvastatin, lovastatin and CHEMICAL are metabolized through GENE, while the metabolism of the other statins is independent of this CYP. All statins are substrate of organic anion transporter polypeptide 1B1, an uptake transporter expressed in hepatocyte membrane that may also explain some drug-drug interactions. Many HIV-infected patients have dyslipidemia and comorbidities that may require statin treatment. HIV-protease inhibitors (HIV PIs) are part of recommended antiretroviral treatment in combination with two reverse transcriptase inhibitors. All HIV PIs except nelfinavir are coadministered with a low dose of ritonavir, a potent CYP3A inhibitor to improve their pharmacokinetic properties. Cobicistat is a new potent CYP3A inhibitor that is combined with elvitegravir and will be combined with HIV-PIs in the future. The HCV-PIs boceprevir and telaprevir are both, to different extents, inhibitors of CYP3A. This review summarizes the pharmacokinetic properties of statins and PIs with emphasis on their metabolic pathways explaining clinically important drug-drug interactions. Simvastatin and lovastatin metabolized through CYP3A have the highest potency for drug-drug interaction with potent CYP3A inhibitors such as ritonavir- or cobicistat-boosted HIV-PI or the hepatitis C virus (HCV) PI, telaprevir or boceprevir, and therefore their coadministration is contraindicated. CHEMICAL is also a CYP3A substrate, but less potent drug-drug interactions have been reported with CYP3A inhibitors. Non-CYP3A-dependent statin concentrations are also affected although to a lesser extent when coadministered with HIV or HCV PIs, mainly through interaction with OATP1B1, and treatment should start with the lowest available statin dose. Effectiveness and occurrence of adverse effects should be monitored at regular time intervals. | SUBSTRATE |
| Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors. The HMG-CoA reductase inhibitors are a class of drugs also known as statins. These drugs are effective and widely prescribed for the treatment of hypercholesterolemia and prevention of cardiovascular morbidity and mortality. Seven statins are currently available: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Although these drugs are generally well tolerated, skeletal muscle abnormalities from myalgia to severe lethal rhabdomyolysis can occur. Factors that increase statin concentrations such as drug-drug interactions can increase the risk of these adverse events. Drug-drug interactions are dependent on statins' pharmacokinetic profile: simvastatin, lovastatin and atorvastatin are metabolized through cytochrome P450 (CYP) 3A, while the metabolism of the other statins is independent of this CYP. All statins are substrate of organic anion transporter polypeptide 1B1, an uptake transporter expressed in hepatocyte membrane that may also explain some drug-drug interactions. Many HIV-infected patients have dyslipidemia and comorbidities that may require statin treatment. HIV-protease inhibitors (HIV PIs) are part of recommended antiretroviral treatment in combination with two reverse transcriptase inhibitors. All HIV PIs except nelfinavir are coadministered with a low dose of ritonavir, a potent GENE inhibitor to improve their pharmacokinetic properties. Cobicistat is a new potent GENE inhibitor that is combined with elvitegravir and will be combined with HIV-PIs in the future. The HCV-PIs boceprevir and telaprevir are both, to different extents, inhibitors of GENE. This review summarizes the pharmacokinetic properties of statins and PIs with emphasis on their metabolic pathways explaining clinically important drug-drug interactions. CHEMICAL and lovastatin metabolized through GENE have the highest potency for drug-drug interaction with potent GENE inhibitors such as ritonavir- or cobicistat-boosted HIV-PI or the hepatitis C virus (HCV) PI, telaprevir or boceprevir, and therefore their coadministration is contraindicated. Atorvastatin is also a GENE substrate, but less potent drug-drug interactions have been reported with GENE inhibitors. Non-CYP3A-dependent statin concentrations are also affected although to a lesser extent when coadministered with HIV or HCV PIs, mainly through interaction with OATP1B1, and treatment should start with the lowest available statin dose. Effectiveness and occurrence of adverse effects should be monitored at regular time intervals. | SUBSTRATE |
| Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors. The HMG-CoA reductase inhibitors are a class of drugs also known as statins. These drugs are effective and widely prescribed for the treatment of hypercholesterolemia and prevention of cardiovascular morbidity and mortality. Seven statins are currently available: atorvastatin, fluvastatin, CHEMICAL, pitavastatin, pravastatin, rosuvastatin and simvastatin. Although these drugs are generally well tolerated, skeletal muscle abnormalities from myalgia to severe lethal rhabdomyolysis can occur. Factors that increase statin concentrations such as drug-drug interactions can increase the risk of these adverse events. Drug-drug interactions are dependent on statins' pharmacokinetic profile: simvastatin, CHEMICAL and atorvastatin are metabolized through cytochrome P450 (CYP) 3A, while the metabolism of the other statins is independent of this CYP. All statins are substrate of organic anion transporter polypeptide 1B1, an uptake transporter expressed in hepatocyte membrane that may also explain some drug-drug interactions. Many HIV-infected patients have dyslipidemia and comorbidities that may require statin treatment. HIV-protease inhibitors (HIV PIs) are part of recommended antiretroviral treatment in combination with two reverse transcriptase inhibitors. All HIV PIs except nelfinavir are coadministered with a low dose of ritonavir, a potent GENE inhibitor to improve their pharmacokinetic properties. Cobicistat is a new potent GENE inhibitor that is combined with elvitegravir and will be combined with HIV-PIs in the future. The HCV-PIs boceprevir and telaprevir are both, to different extents, inhibitors of GENE. This review summarizes the pharmacokinetic properties of statins and PIs with emphasis on their metabolic pathways explaining clinically important drug-drug interactions. Simvastatin and CHEMICAL metabolized through GENE have the highest potency for drug-drug interaction with potent GENE inhibitors such as ritonavir- or cobicistat-boosted HIV-PI or the hepatitis C virus (HCV) PI, telaprevir or boceprevir, and therefore their coadministration is contraindicated. Atorvastatin is also a GENE substrate, but less potent drug-drug interactions have been reported with GENE inhibitors. Non-CYP3A-dependent statin concentrations are also affected although to a lesser extent when coadministered with HIV or HCV PIs, mainly through interaction with OATP1B1, and treatment should start with the lowest available statin dose. Effectiveness and occurrence of adverse effects should be monitored at regular time intervals. | SUBSTRATE |
| Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective GENE (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulf onyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective GENE inhibitor 15b (CHEMICAL) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients. | INHIBITOR |
| Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulf onyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation GENE inhibitor 4 (CHEMICAL). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients. | INHIBITOR |
| Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture. Effects of benzodiazepines (BDZs) and beta carbolines (beta CCs) on sustained repetitive firing at high frequency (SRF) of action potentials of mouse spinal cord neurons in cell culture were examined using intracellular recording techniques. In control medium neurons responded to depolarizing current pulses with SRF. Limitation of SRF was produced by the anticonvulsant BDZs (diazepam, clonazepam, nitrazepam and lorazepam) at low to mid nanomolar concentrations, by a convulsant CHEMICAL which does not bind to high affinity GENE (Ro 5-4864) at high nanomolar concentrations and by a CHEMICAL receptor weak partial agonist (Ro 15-1788) at micromolar concentrations. The limitation of SRF was accompanied by use- and voltage-dependent reduction of maximal rate of rise (Vmax) of sodium-dependent action potentials. Partial agonist and inverse agonist beta CCs did not limit SRF at concentrations up to 200 nM. The limitation of SRF by diazepam was not prevented by inverse or partial agonists at the CHEMICAL receptor, including Ro 15-1788 and the beta CCs. These findings suggest that limitation of SRF was produced by binding of BDZs, but not beta CCs, to voltage-dependent sodium channels and not to high affinity central CHEMICAL receptors, and that BDZs limit SRF by slowing recovery of sodium channels from inactivation. We propose that the limitation of SRF may contribute to the efficacy of BDZs against generalized tonic-clonic seizures and status epilepticus. | NO-RELATIONSHIP |
| Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture. Effects of benzodiazepines (BDZs) and beta carbolines (beta CCs) on sustained repetitive firing at high frequency (SRF) of action potentials of mouse spinal cord neurons in cell culture were examined using intracellular recording techniques. In control medium neurons responded to depolarizing current pulses with SRF. Limitation of SRF was produced by the anticonvulsant BDZs (diazepam, clonazepam, nitrazepam and lorazepam) at low to mid nanomolar concentrations, by a convulsant BDZ which does not bind to high affinity GENE (CHEMICAL) at high nanomolar concentrations and by a BDZ receptor weak partial agonist (Ro 15-1788) at micromolar concentrations. The limitation of SRF was accompanied by use- and voltage-dependent reduction of maximal rate of rise (Vmax) of sodium-dependent action potentials. Partial agonist and inverse agonist beta CCs did not limit SRF at concentrations up to 200 nM. The limitation of SRF by diazepam was not prevented by inverse or partial agonists at the BDZ receptor, including Ro 15-1788 and the beta CCs. These findings suggest that limitation of SRF was produced by binding of BDZs, but not beta CCs, to voltage-dependent sodium channels and not to high affinity central GENE, and that BDZs limit SRF by slowing recovery of sodium channels from inactivation. We propose that the limitation of SRF may contribute to the efficacy of BDZs against generalized tonic-clonic seizures and status epilepticus. | NO-RELATIONSHIP |
| Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture. Effects of benzodiazepines (BDZs) and beta carbolines (beta CCs) on sustained repetitive firing at high frequency (SRF) of action potentials of mouse spinal cord neurons in cell culture were examined using intracellular recording techniques. In control medium neurons responded to depolarizing current pulses with SRF. Limitation of SRF was produced by the anticonvulsant BDZs (diazepam, clonazepam, nitrazepam and lorazepam) at low to mid nanomolar concentrations, by a convulsant BDZ which does not bind to high affinity BDZ receptors (Ro 5-4864) at high nanomolar concentrations and by a BDZ receptor weak partial agonist (Ro 15-1788) at micromolar concentrations. The limitation of SRF was accompanied by use- and voltage-dependent reduction of maximal rate of rise (Vmax) of sodium-dependent action potentials. Partial agonist and inverse agonist CHEMICAL did not limit SRF at concentrations up to 200 nM. The limitation of SRF by diazepam was not prevented by inverse or partial agonists at the BDZ receptor, including Ro 15-1788 and the CHEMICAL. These findings suggest that limitation of SRF was produced by binding of BDZs, but not CHEMICAL, to GENE and not to high affinity central BDZ receptors, and that BDZs limit SRF by slowing recovery of sodium channels from inactivation. We propose that the limitation of SRF may contribute to the efficacy of BDZs against generalized tonic-clonic seizures and status epilepticus. | NO-RELATIONSHIP |
| Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture. Effects of benzodiazepines (BDZs) and beta carbolines (beta CCs) on sustained repetitive firing at high frequency (SRF) of action potentials of mouse spinal cord neurons in cell culture were examined using intracellular recording techniques. In control medium neurons responded to depolarizing current pulses with SRF. Limitation of SRF was produced by the anticonvulsant BDZs (diazepam, clonazepam, nitrazepam and lorazepam) at low to mid nanomolar concentrations, by a convulsant BDZ which does not bind to high affinity GENE (Ro 5-4864) at high nanomolar concentrations and by a BDZ receptor weak partial agonist (Ro 15-1788) at micromolar concentrations. The limitation of SRF was accompanied by use- and voltage-dependent reduction of maximal rate of rise (Vmax) of sodium-dependent action potentials. Partial agonist and inverse agonist CHEMICAL did not limit SRF at concentrations up to 200 nM. The limitation of SRF by diazepam was not prevented by inverse or partial agonists at the BDZ receptor, including Ro 15-1788 and the CHEMICAL. These findings suggest that limitation of SRF was produced by binding of BDZs, but not CHEMICAL, to voltage-dependent sodium channels and not to high affinity central GENE, and that BDZs limit SRF by slowing recovery of sodium channels from inactivation. We propose that the limitation of SRF may contribute to the efficacy of BDZs against generalized tonic-clonic seizures and status epilepticus. | NO-RELATIONSHIP |
| Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture. Effects of benzodiazepines (BDZs) and beta carbolines (beta CCs) on sustained repetitive firing at high frequency (SRF) of action potentials of mouse spinal cord neurons in cell culture were examined using intracellular recording techniques. In control medium neurons responded to depolarizing current pulses with SRF. Limitation of SRF was produced by the anticonvulsant CHEMICAL (diazepam, clonazepam, nitrazepam and lorazepam) at low to mid nanomolar concentrations, by a convulsant BDZ which does not bind to high affinity BDZ receptors (Ro 5-4864) at high nanomolar concentrations and by a BDZ receptor weak partial agonist (Ro 15-1788) at micromolar concentrations. The limitation of SRF was accompanied by use- and voltage-dependent reduction of maximal rate of rise (Vmax) of sodium-dependent action potentials. Partial agonist and inverse agonist beta CCs did not limit SRF at concentrations up to 200 nM. The limitation of SRF by diazepam was not prevented by inverse or partial agonists at the BDZ receptor, including Ro 15-1788 and the beta CCs. These findings suggest that limitation of SRF was produced by binding of CHEMICAL, but not beta CCs, to GENE and not to high affinity central BDZ receptors, and that CHEMICAL limit SRF by slowing recovery of sodium channels from inactivation. We propose that the limitation of SRF may contribute to the efficacy of CHEMICAL against generalized tonic-clonic seizures and status epilepticus. | DIRECT-REGULATOR |
| Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture. Effects of benzodiazepines (BDZs) and beta carbolines (beta CCs) on sustained repetitive firing at high frequency (SRF) of action potentials of mouse spinal cord neurons in cell culture were examined using intracellular recording techniques. In control medium neurons responded to depolarizing current pulses with SRF. Limitation of SRF was produced by the anticonvulsant CHEMICAL (diazepam, clonazepam, nitrazepam and lorazepam) at low to mid nanomolar concentrations, by a convulsant BDZ which does not bind to high affinity GENE (Ro 5-4864) at high nanomolar concentrations and by a BDZ receptor weak partial agonist (Ro 15-1788) at micromolar concentrations. The limitation of SRF was accompanied by use- and voltage-dependent reduction of maximal rate of rise (Vmax) of sodium-dependent action potentials. Partial agonist and inverse agonist beta CCs did not limit SRF at concentrations up to 200 nM. The limitation of SRF by diazepam was not prevented by inverse or partial agonists at the BDZ receptor, including Ro 15-1788 and the beta CCs. These findings suggest that limitation of SRF was produced by binding of CHEMICAL, but not beta CCs, to voltage-dependent sodium channels and not to high affinity central GENE, and that CHEMICAL limit SRF by slowing recovery of sodium channels from inactivation. We propose that the limitation of SRF may contribute to the efficacy of CHEMICAL against generalized tonic-clonic seizures and status epilepticus. | NO-RELATIONSHIP |
| Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture. Effects of benzodiazepines (BDZs) and beta carbolines (beta CCs) on sustained repetitive firing at high frequency (SRF) of action potentials of mouse spinal cord neurons in cell culture were examined using intracellular recording techniques. In control medium neurons responded to depolarizing current pulses with SRF. Limitation of SRF was produced by the anticonvulsant BDZs (diazepam, clonazepam, nitrazepam and lorazepam) at low to mid nanomolar concentrations, by a convulsant BDZ which does not bind to high affinity BDZ receptors (Ro 5-4864) at high nanomolar concentrations and by a GENE weak partial agonist (Ro 15-1788) at micromolar concentrations. The limitation of SRF was accompanied by use- and voltage-dependent reduction of maximal rate of rise (Vmax) of sodium-dependent action potentials. Partial agonist and inverse agonist beta CCs did not limit SRF at concentrations up to 200 nM. The limitation of SRF by CHEMICAL was not prevented by inverse or partial agonists at the GENE, including Ro 15-1788 and the beta CCs. These findings suggest that limitation of SRF was produced by binding of BDZs, but not beta CCs, to voltage-dependent sodium channels and not to high affinity central BDZ receptors, and that BDZs limit SRF by slowing recovery of sodium channels from inactivation. We propose that the limitation of SRF may contribute to the efficacy of BDZs against generalized tonic-clonic seizures and status epilepticus. | NO-RELATIONSHIP |
| Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture. Effects of benzodiazepines (BDZs) and beta carbolines (beta CCs) on sustained repetitive firing at high frequency (SRF) of action potentials of mouse spinal cord neurons in cell culture were examined using intracellular recording techniques. In control medium neurons responded to depolarizing current pulses with SRF. Limitation of SRF was produced by the anticonvulsant CHEMICAL (diazepam, clonazepam, nitrazepam and lorazepam) at low to mid nanomolar concentrations, by a convulsant BDZ which does not bind to high affinity BDZ receptors (Ro 5-4864) at high nanomolar concentrations and by a BDZ receptor weak partial agonist (Ro 15-1788) at micromolar concentrations. The limitation of SRF was accompanied by use- and voltage-dependent reduction of maximal rate of rise (Vmax) of sodium-dependent action potentials. Partial agonist and inverse agonist beta CCs did not limit SRF at concentrations up to 200 nM. The limitation of SRF by diazepam was not prevented by inverse or partial agonists at the BDZ receptor, including Ro 15-1788 and the beta CCs. These findings suggest that limitation of SRF was produced by binding of CHEMICAL, but not beta CCs, to voltage-dependent GENE and not to high affinity central BDZ receptors, and that CHEMICAL limit SRF by slowing recovery of GENE from inactivation. We propose that the limitation of SRF may contribute to the efficacy of CHEMICAL against generalized tonic-clonic seizures and status epilepticus. | DIRECT-REGULATOR |
| Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture. Effects of benzodiazepines (BDZs) and beta carbolines (beta CCs) on sustained repetitive firing at high frequency (SRF) of action potentials of mouse spinal cord neurons in cell culture were examined using intracellular recording techniques. In control medium neurons responded to depolarizing current pulses with SRF. Limitation of SRF was produced by the anticonvulsant BDZs (diazepam, clonazepam, nitrazepam and lorazepam) at low to mid nanomolar concentrations, by a convulsant BDZ which does not bind to high affinity BDZ receptors (Ro 5-4864) at high nanomolar concentrations and by a GENE weak partial agonist (CHEMICAL) at micromolar concentrations. The limitation of SRF was accompanied by use- and voltage-dependent reduction of maximal rate of rise (Vmax) of sodium-dependent action potentials. Partial agonist and inverse agonist beta CCs did not limit SRF at concentrations up to 200 nM. The limitation of SRF by diazepam was not prevented by inverse or partial agonists at the GENE, including CHEMICAL and the beta CCs. These findings suggest that limitation of SRF was produced by binding of BDZs, but not beta CCs, to voltage-dependent sodium channels and not to high affinity central BDZ receptors, and that BDZs limit SRF by slowing recovery of sodium channels from inactivation. We propose that the limitation of SRF may contribute to the efficacy of BDZs against generalized tonic-clonic seizures and status epilepticus. | ACTIVATOR |
| Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture. Effects of benzodiazepines (BDZs) and beta carbolines (beta CCs) on sustained repetitive firing at high frequency (SRF) of action potentials of mouse spinal cord neurons in cell culture were examined using intracellular recording techniques. In control medium neurons responded to depolarizing current pulses with SRF. Limitation of SRF was produced by the anticonvulsant BDZs (diazepam, clonazepam, nitrazepam and lorazepam) at low to mid nanomolar concentrations, by a convulsant BDZ which does not bind to high affinity BDZ receptors (Ro 5-4864) at high nanomolar concentrations and by a GENE weak partial agonist (Ro 15-1788) at micromolar concentrations. The limitation of SRF was accompanied by use- and voltage-dependent reduction of maximal rate of rise (Vmax) of sodium-dependent action potentials. Partial agonist and inverse agonist CHEMICAL did not limit SRF at concentrations up to 200 nM. The limitation of SRF by diazepam was not prevented by inverse or partial agonists at the GENE, including Ro 15-1788 and the CHEMICAL. These findings suggest that limitation of SRF was produced by binding of BDZs, but not CHEMICAL, to voltage-dependent sodium channels and not to high affinity central BDZ receptors, and that BDZs limit SRF by slowing recovery of sodium channels from inactivation. We propose that the limitation of SRF may contribute to the efficacy of BDZs against generalized tonic-clonic seizures and status epilepticus. | NO-RELATIONSHIP |
| Androgens directly stimulate proliferation of bone cells in vitro. This report describes the first observation of a direct mitogenic effect of androgens on isolated osteoblastic cells in serum-free culture. [3H]thymidine incorporation into DNA and cell counts were used as measures of cell proliferation. The percentage of cells that stained for alkaline phosphatase was used as a measure of differentiation. Dihydrotestosterone (DHT) enhanced mouse osteoblastic cell proliferation in a dose dependent manner over a wide range of doses (10(-8) to 10(-11) molar), and was maximally active at 10(-9) M. CHEMICAL also stimulated proliferation in human osteoblast cell cultures and in cultures of the human osteosarcoma cell line, TE89. Testosterone, fluoxymesterone (a synthetic androgenic steroid) and methenolone (an anabolic steroid) were also mitogenic in the mouse bone cell system. The mitogenic effect of CHEMICAL on bone cells was inhibited by antiandrogens (hydroxyflutamide and cyproterone acetate) which compete for binding to the GENE. In addition to effects on cell proliferation, CHEMICAL increased the percentage of alkaline phosphatase (ALP) positive cells in all three bone cell systems tested, and this effect was inhibited by antiandrogens. We conclude that androgens can stimulate human and murine osteoblastic cell proliferation in vitro, and induce expression of the osteoblast-line differentiation marker ALP, presumably by an GENE mediated mechanism. | REGULATOR |
| Androgens directly stimulate proliferation of bone cells in vitro. This report describes the first observation of a direct mitogenic effect of androgens on isolated osteoblastic cells in serum-free culture. [3H]thymidine incorporation into DNA and cell counts were used as measures of cell proliferation. The percentage of cells that stained for alkaline phosphatase was used as a measure of differentiation. Dihydrotestosterone (DHT) enhanced mouse osteoblastic cell proliferation in a dose dependent manner over a wide range of doses (10(-8) to 10(-11) molar), and was maximally active at 10(-9) M. DHT also stimulated proliferation in human osteoblast cell cultures and in cultures of the human osteosarcoma cell line, TE89. Testosterone, fluoxymesterone (a synthetic androgenic steroid) and methenolone (an anabolic steroid) were also mitogenic in the mouse bone cell system. The mitogenic effect of DHT on bone cells was inhibited by antiandrogens (CHEMICAL and cyproterone acetate) which compete for binding to the GENE. In addition to effects on cell proliferation, DHT increased the percentage of alkaline phosphatase (ALP) positive cells in all three bone cell systems tested, and this effect was inhibited by antiandrogens. We conclude that androgens can stimulate human and murine osteoblastic cell proliferation in vitro, and induce expression of the osteoblast-line differentiation marker ALP, presumably by an GENE mediated mechanism. | DIRECT-REGULATOR |
| Androgens directly stimulate proliferation of bone cells in vitro. This report describes the first observation of a direct mitogenic effect of androgens on isolated osteoblastic cells in serum-free culture. [3H]thymidine incorporation into DNA and cell counts were used as measures of cell proliferation. The percentage of cells that stained for alkaline phosphatase was used as a measure of differentiation. Dihydrotestosterone (DHT) enhanced mouse osteoblastic cell proliferation in a dose dependent manner over a wide range of doses (10(-8) to 10(-11) molar), and was maximally active at 10(-9) M. DHT also stimulated proliferation in human osteoblast cell cultures and in cultures of the human osteosarcoma cell line, TE89. Testosterone, fluoxymesterone (a synthetic androgenic steroid) and methenolone (an anabolic steroid) were also mitogenic in the mouse bone cell system. The mitogenic effect of DHT on bone cells was inhibited by antiandrogens (hydroxyflutamide and CHEMICAL) which compete for binding to the GENE. In addition to effects on cell proliferation, DHT increased the percentage of alkaline phosphatase (ALP) positive cells in all three bone cell systems tested, and this effect was inhibited by antiandrogens. We conclude that androgens can stimulate human and murine osteoblastic cell proliferation in vitro, and induce expression of the osteoblast-line differentiation marker ALP, presumably by an GENE mediated mechanism. | DIRECT-REGULATOR |
| CHEMICAL directly stimulate proliferation of bone cells in vitro. This report describes the first observation of a direct mitogenic effect of CHEMICAL on isolated osteoblastic cells in serum-free culture. [3H]thymidine incorporation into DNA and cell counts were used as measures of cell proliferation. The percentage of cells that stained for alkaline phosphatase was used as a measure of differentiation. Dihydrotestosterone (DHT) enhanced mouse osteoblastic cell proliferation in a dose dependent manner over a wide range of doses (10(-8) to 10(-11) molar), and was maximally active at 10(-9) M. DHT also stimulated proliferation in human osteoblast cell cultures and in cultures of the human osteosarcoma cell line, TE89. Testosterone, fluoxymesterone (a synthetic androgenic steroid) and methenolone (an anabolic steroid) were also mitogenic in the mouse bone cell system. The mitogenic effect of DHT on bone cells was inhibited by antiandrogens (hydroxyflutamide and cyproterone acetate) which compete for binding to the GENE. In addition to effects on cell proliferation, DHT increased the percentage of alkaline phosphatase (ALP) positive cells in all three bone cell systems tested, and this effect was inhibited by antiandrogens. We conclude that CHEMICAL can stimulate human and murine osteoblastic cell proliferation in vitro, and induce expression of the osteoblast-line differentiation marker ALP, presumably by an GENE mediated mechanism. | REGULATOR |
| Androgens directly stimulate proliferation of bone cells in vitro. This report describes the first observation of a direct mitogenic effect of androgens on isolated osteoblastic cells in serum-free culture. [3H]thymidine incorporation into DNA and cell counts were used as measures of cell proliferation. The percentage of cells that stained for GENE was used as a measure of differentiation. Dihydrotestosterone (DHT) enhanced mouse osteoblastic cell proliferation in a dose dependent manner over a wide range of doses (10(-8) to 10(-11) molar), and was maximally active at 10(-9) M. CHEMICAL also stimulated proliferation in human osteoblast cell cultures and in cultures of the human osteosarcoma cell line, TE89. Testosterone, fluoxymesterone (a synthetic androgenic steroid) and methenolone (an anabolic steroid) were also mitogenic in the mouse bone cell system. The mitogenic effect of CHEMICAL on bone cells was inhibited by antiandrogens (hydroxyflutamide and cyproterone acetate) which compete for binding to the androgen receptor. In addition to effects on cell proliferation, CHEMICAL increased the percentage of GENE (ALP) positive cells in all three bone cell systems tested, and this effect was inhibited by antiandrogens. We conclude that androgens can stimulate human and murine osteoblastic cell proliferation in vitro, and induce expression of the osteoblast-line differentiation marker ALP, presumably by an androgen receptor mediated mechanism. | INDIRECT-UPREGULATOR |
| Androgens directly stimulate proliferation of bone cells in vitro. This report describes the first observation of a direct mitogenic effect of androgens on isolated osteoblastic cells in serum-free culture. [3H]thymidine incorporation into DNA and cell counts were used as measures of cell proliferation. The percentage of cells that stained for alkaline phosphatase was used as a measure of differentiation. Dihydrotestosterone (DHT) enhanced mouse osteoblastic cell proliferation in a dose dependent manner over a wide range of doses (10(-8) to 10(-11) molar), and was maximally active at 10(-9) M. CHEMICAL also stimulated proliferation in human osteoblast cell cultures and in cultures of the human osteosarcoma cell line, TE89. Testosterone, fluoxymesterone (a synthetic androgenic steroid) and methenolone (an anabolic steroid) were also mitogenic in the mouse bone cell system. The mitogenic effect of CHEMICAL on bone cells was inhibited by antiandrogens (hydroxyflutamide and cyproterone acetate) which compete for binding to the androgen receptor. In addition to effects on cell proliferation, CHEMICAL increased the percentage of alkaline phosphatase (GENE) positive cells in all three bone cell systems tested, and this effect was inhibited by antiandrogens. We conclude that androgens can stimulate human and murine osteoblastic cell proliferation in vitro, and induce expression of the osteoblast-line differentiation marker GENE, presumably by an androgen receptor mediated mechanism. | INDIRECT-UPREGULATOR |
| CHEMICAL directly stimulate proliferation of bone cells in vitro. This report describes the first observation of a direct mitogenic effect of CHEMICAL on isolated osteoblastic cells in serum-free culture. [3H]thymidine incorporation into DNA and cell counts were used as measures of cell proliferation. The percentage of cells that stained for alkaline phosphatase was used as a measure of differentiation. Dihydrotestosterone (DHT) enhanced mouse osteoblastic cell proliferation in a dose dependent manner over a wide range of doses (10(-8) to 10(-11) molar), and was maximally active at 10(-9) M. DHT also stimulated proliferation in human osteoblast cell cultures and in cultures of the human osteosarcoma cell line, TE89. Testosterone, fluoxymesterone (a synthetic androgenic steroid) and methenolone (an anabolic steroid) were also mitogenic in the mouse bone cell system. The mitogenic effect of DHT on bone cells was inhibited by antiandrogens (hydroxyflutamide and cyproterone acetate) which compete for binding to the androgen receptor. In addition to effects on cell proliferation, DHT increased the percentage of alkaline phosphatase (ALP) positive cells in all three bone cell systems tested, and this effect was inhibited by antiandrogens. We conclude that CHEMICAL can stimulate human and murine osteoblastic cell proliferation in vitro, and induce expression of the GENE ALP, presumably by an androgen receptor mediated mechanism. | INDIRECT-UPREGULATOR |
| CHEMICAL directly stimulate proliferation of bone cells in vitro. This report describes the first observation of a direct mitogenic effect of CHEMICAL on isolated osteoblastic cells in serum-free culture. [3H]thymidine incorporation into DNA and cell counts were used as measures of cell proliferation. The percentage of cells that stained for alkaline phosphatase was used as a measure of differentiation. Dihydrotestosterone (DHT) enhanced mouse osteoblastic cell proliferation in a dose dependent manner over a wide range of doses (10(-8) to 10(-11) molar), and was maximally active at 10(-9) M. DHT also stimulated proliferation in human osteoblast cell cultures and in cultures of the human osteosarcoma cell line, TE89. Testosterone, fluoxymesterone (a synthetic androgenic steroid) and methenolone (an anabolic steroid) were also mitogenic in the mouse bone cell system. The mitogenic effect of DHT on bone cells was inhibited by antiandrogens (hydroxyflutamide and cyproterone acetate) which compete for binding to the androgen receptor. In addition to effects on cell proliferation, DHT increased the percentage of alkaline phosphatase (ALP) positive cells in all three bone cell systems tested, and this effect was inhibited by antiandrogens. We conclude that CHEMICAL can stimulate human and murine osteoblastic cell proliferation in vitro, and induce expression of the osteoblast-line differentiation marker GENE, presumably by an androgen receptor mediated mechanism. | INDIRECT-UPREGULATOR |
| The effect of GENE antagonism with CHEMICAL on concentration-related AMP-induced bronchoconstriction in asthma. Selective GENE antagonists inhibit adenosine 5'-monophosphate (AMP)-induced bronchoconstriction by greater than 80% when expressed as a percentage inhibition of the FEV1 time-response curve following inhalation of the provocation concentration of AMP required to produce a 20% decrease in FEV1 from baseline (PC20). To investigate this further we have determined that, in eight mild atopic asthmatic subjects, CHEMICAL (180 mg), administered 3 hr pre-challenge, increases the geometric mean PC20 for histamine from 0.4 (range 0.03-3) mg/ml after placebo, to 20.2 (range 0.6-64) mg/ml following active treatment (P less than 0.0001). For AMP, the PC20 increased from 9.3 (range 1.0-113.3) mg/ml after placebo, to 150.2 (range 32.1-1177.7) mg/ml with CHEMICAL (P less than 0.0001). This 16.2-fold (range, 5.5-47.9) displacement to the right of the AMP concentration-response curve by a selective GENE antagonist emphasizes the central role of histamine in the airways response to this nucleotide. | INHIBITOR |
| Ibrutinib: a review of its use in patients with mantle cell lymphoma or chronic lymphocytic leukaemia. CHEMICAL (Imbruvica(R)) is a first-in-class, potent, orally administered, covalent inhibitor of Bruton's tyrosine kinase (BTK) that inhibits B-cell antigen receptor signalling downstream of BTK. Oral CHEMICAL is indicated for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or GENE mutation. This article summarizes pharmacological, efficacy and tolerability data relevant to the use of CHEMICAL in these indications. In clinical studies, CHEMICAL induced a high overall response rate in patients with relapsed/refractory MCL (phase II study). In addition, CHEMICAL significantly prolonged progression-free survival and significantly improved the partial response rate and overall survival in patients with relapsed/refractory CLL (RESONATE study), including in those with del 17p, a subgroup with a poor prognosis. CHEMICAL had an acceptable tolerability profile in these studies with <10% of patients discontinuing treatment because of adverse events. Given its efficacy and tolerability, once-daily, oral CHEMICAL is an emerging treatment option for patients with relapsed/refractory MCL or CLL and CLL patients with del 17p or GENE mutation. | GENE-CHEMICAL |
| Ibrutinib: a review of its use in patients with mantle cell lymphoma or chronic lymphocytic leukaemia. CHEMICAL (Imbruvica(R)) is a first-in-class, potent, orally administered, covalent inhibitor of Bruton's tyrosine kinase (BTK) that inhibits GENE signalling downstream of BTK. Oral ibrutinib is indicated for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation. This article summarizes pharmacological, efficacy and tolerability data relevant to the use of ibrutinib in these indications. In clinical studies, ibrutinib induced a high overall response rate in patients with relapsed/refractory MCL (phase II study). In addition, ibrutinib significantly prolonged progression-free survival and significantly improved the partial response rate and overall survival in patients with relapsed/refractory CLL (RESONATE study), including in those with del 17p, a subgroup with a poor prognosis. CHEMICAL had an acceptable tolerability profile in these studies with <10% of patients discontinuing treatment because of adverse events. Given its efficacy and tolerability, once-daily, oral ibrutinib is an emerging treatment option for patients with relapsed/refractory MCL or CLL and CLL patients with del 17p or TP53 mutation. | INHIBITOR |
| Ibrutinib: a review of its use in patients with mantle cell lymphoma or chronic lymphocytic leukaemia. Ibrutinib (CHEMICAL) is a first-in-class, potent, orally administered, covalent inhibitor of Bruton's tyrosine kinase (BTK) that inhibits GENE signalling downstream of BTK. Oral ibrutinib is indicated for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation. This article summarizes pharmacological, efficacy and tolerability data relevant to the use of ibrutinib in these indications. In clinical studies, ibrutinib induced a high overall response rate in patients with relapsed/refractory MCL (phase II study). In addition, ibrutinib significantly prolonged progression-free survival and significantly improved the partial response rate and overall survival in patients with relapsed/refractory CLL (RESONATE study), including in those with del 17p, a subgroup with a poor prognosis. Ibrutinib had an acceptable tolerability profile in these studies with <10% of patients discontinuing treatment because of adverse events. Given its efficacy and tolerability, once-daily, oral ibrutinib is an emerging treatment option for patients with relapsed/refractory MCL or CLL and CLL patients with del 17p or TP53 mutation. | INHIBITOR |
| Ibrutinib: a review of its use in patients with mantle cell lymphoma or chronic lymphocytic leukaemia. CHEMICAL (Imbruvica(R)) is a first-in-class, potent, orally administered, covalent inhibitor of Bruton's tyrosine kinase (GENE) that inhibits B-cell antigen receptor signalling downstream of GENE. Oral ibrutinib is indicated for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation. This article summarizes pharmacological, efficacy and tolerability data relevant to the use of ibrutinib in these indications. In clinical studies, ibrutinib induced a high overall response rate in patients with relapsed/refractory MCL (phase II study). In addition, ibrutinib significantly prolonged progression-free survival and significantly improved the partial response rate and overall survival in patients with relapsed/refractory CLL (RESONATE study), including in those with del 17p, a subgroup with a poor prognosis. CHEMICAL had an acceptable tolerability profile in these studies with <10% of patients discontinuing treatment because of adverse events. Given its efficacy and tolerability, once-daily, oral ibrutinib is an emerging treatment option for patients with relapsed/refractory MCL or CLL and CLL patients with del 17p or TP53 mutation. | INHIBITOR |
| Ibrutinib: a review of its use in patients with mantle cell lymphoma or chronic lymphocytic leukaemia. CHEMICAL (Imbruvica(R)) is a first-in-class, potent, orally administered, covalent inhibitor of GENE (BTK) that inhibits B-cell antigen receptor signalling downstream of BTK. Oral ibrutinib is indicated for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation. This article summarizes pharmacological, efficacy and tolerability data relevant to the use of ibrutinib in these indications. In clinical studies, ibrutinib induced a high overall response rate in patients with relapsed/refractory MCL (phase II study). In addition, ibrutinib significantly prolonged progression-free survival and significantly improved the partial response rate and overall survival in patients with relapsed/refractory CLL (RESONATE study), including in those with del 17p, a subgroup with a poor prognosis. CHEMICAL had an acceptable tolerability profile in these studies with <10% of patients discontinuing treatment because of adverse events. Given its efficacy and tolerability, once-daily, oral ibrutinib is an emerging treatment option for patients with relapsed/refractory MCL or CLL and CLL patients with del 17p or TP53 mutation. | INHIBITOR |
| Ibrutinib: a review of its use in patients with mantle cell lymphoma or chronic lymphocytic leukaemia. Ibrutinib (CHEMICAL) is a first-in-class, potent, orally administered, covalent inhibitor of Bruton's tyrosine kinase (GENE) that inhibits B-cell antigen receptor signalling downstream of GENE. Oral ibrutinib is indicated for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation. This article summarizes pharmacological, efficacy and tolerability data relevant to the use of ibrutinib in these indications. In clinical studies, ibrutinib induced a high overall response rate in patients with relapsed/refractory MCL (phase II study). In addition, ibrutinib significantly prolonged progression-free survival and significantly improved the partial response rate and overall survival in patients with relapsed/refractory CLL (RESONATE study), including in those with del 17p, a subgroup with a poor prognosis. Ibrutinib had an acceptable tolerability profile in these studies with <10% of patients discontinuing treatment because of adverse events. Given its efficacy and tolerability, once-daily, oral ibrutinib is an emerging treatment option for patients with relapsed/refractory MCL or CLL and CLL patients with del 17p or TP53 mutation. | INHIBITOR |
| Ibrutinib: a review of its use in patients with mantle cell lymphoma or chronic lymphocytic leukaemia. Ibrutinib (CHEMICAL) is a first-in-class, potent, orally administered, covalent inhibitor of GENE (BTK) that inhibits B-cell antigen receptor signalling downstream of BTK. Oral ibrutinib is indicated for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) or chronic lymphocytic leukaemia (CLL) and for the treatment of patients with CLL and a chromosome 17 deletion (del 17p) or TP53 mutation. This article summarizes pharmacological, efficacy and tolerability data relevant to the use of ibrutinib in these indications. In clinical studies, ibrutinib induced a high overall response rate in patients with relapsed/refractory MCL (phase II study). In addition, ibrutinib significantly prolonged progression-free survival and significantly improved the partial response rate and overall survival in patients with relapsed/refractory CLL (RESONATE study), including in those with del 17p, a subgroup with a poor prognosis. Ibrutinib had an acceptable tolerability profile in these studies with <10% of patients discontinuing treatment because of adverse events. Given its efficacy and tolerability, once-daily, oral ibrutinib is an emerging treatment option for patients with relapsed/refractory MCL or CLL and CLL patients with del 17p or TP53 mutation. | INHIBITOR |
| Effects of beta-adrenoceptor antagonist administration on GENE density in human lymphocytes. The role of the "intrinsic sympathomimetic activity". Abrupt withdrawal of beta-adrenoceptor antagonists may lead to "rebound-effects". To study the mechanism underlying this phenomenon, the effects of the nonselective beta-adrenoceptor antagonists propranolol [no intrinsic sympathomimetic activity (ISA)], alprenolol (weak ISA) and mepindolol (strong ISA) on lymphocyte GENE density--assessed by (+/-)-[125I]-iodocyanopindolol (ICYP) binding--and plasma renin activity (PRA) were investigated in male healthy volunteers aged 23-35 years. Propranolol treatment (4 X 40 mg/day) increased the density of beta 2-adrenoceptors by 25% after 2 days; concomitantly PRA and heart rate were reduced. During treatment GENE density remained elevated. After withdrawal of propranolol PRA reached pre-drug levels rapidly, while heart rate was significantly enhanced. Beta 2-Adrenoceptor density, however, declined slowly being still significantly increased after 3 days, although propranolol was not detectable in plasma after 24 h. The affinity of ICYP to beta 2-adrenoceptors was not changed during or after treatment. Mepindolol treatment (2 X 5 mg/day) caused a 30% decrease of GENE density and PRA after 2 days; both parameters remained reduced during treatment. After withdrawal, PRA reached rapidly pre-drug levels, whereas GENE density was still after 4 days significantly diminished. The KD-values for ICYP, however, were not changed. During and after treatment heart rate was not affected. CHEMICAL treatment (4 X 100 mg/day) led to a rapid fall in PRA, but did not significantly affect GENE density. It is concluded, that the ISA may play an important role in modulating GENE density and hence tissue responsiveness to beta-adrenoceptor stimulation.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| Effects of beta-adrenoceptor antagonist administration on beta 2-adrenoceptor density in human lymphocytes. The role of the "intrinsic sympathomimetic activity". Abrupt withdrawal of beta-adrenoceptor antagonists may lead to "rebound-effects". To study the mechanism underlying this phenomenon, the effects of the nonselective beta-adrenoceptor antagonists propranolol [no intrinsic sympathomimetic activity (ISA)], alprenolol (weak ISA) and mepindolol (strong ISA) on lymphocyte beta 2-adrenoceptor density--assessed by (+/-)-[125I]-iodocyanopindolol (ICYP) binding--and plasma renin activity (PRA) were investigated in male healthy volunteers aged 23-35 years. Propranolol treatment (4 X 40 mg/day) increased the density of GENE by 25% after 2 days; concomitantly PRA and heart rate were reduced. During treatment beta 2-adrenoceptor density remained elevated. After withdrawal of propranolol PRA reached pre-drug levels rapidly, while heart rate was significantly enhanced. Beta 2-Adrenoceptor density, however, declined slowly being still significantly increased after 3 days, although propranolol was not detectable in plasma after 24 h. The affinity of CHEMICAL to GENE was not changed during or after treatment. Mepindolol treatment (2 X 5 mg/day) caused a 30% decrease of beta 2-adrenoceptor density and PRA after 2 days; both parameters remained reduced during treatment. After withdrawal, PRA reached rapidly pre-drug levels, whereas beta 2-adrenoceptor density was still after 4 days significantly diminished. The KD-values for CHEMICAL, however, were not changed. During and after treatment heart rate was not affected. Alprenolol treatment (4 X 100 mg/day) led to a rapid fall in PRA, but did not significantly affect beta 2-adrenoceptor density. It is concluded, that the ISA may play an important role in modulating beta 2-adrenoceptor density and hence tissue responsiveness to beta-adrenoceptor stimulation.(ABSTRACT TRUNCATED AT 250 WORDS) | DIRECT-REGULATOR |
| Effects of beta-adrenoceptor antagonist administration on beta 2-adrenoceptor density in human lymphocytes. The role of the "intrinsic sympathomimetic activity". Abrupt withdrawal of beta-adrenoceptor antagonists may lead to "rebound-effects". To study the mechanism underlying this phenomenon, the effects of the nonselective beta-adrenoceptor antagonists propranolol [no intrinsic sympathomimetic activity (ISA)], alprenolol (weak ISA) and mepindolol (strong ISA) on lymphocyte beta 2-adrenoceptor density--assessed by (+/-)-[125I]-iodocyanopindolol (ICYP) binding--and plasma renin activity (PRA) were investigated in male healthy volunteers aged 23-35 years. CHEMICAL treatment (4 X 40 mg/day) increased the density of GENE by 25% after 2 days; concomitantly PRA and heart rate were reduced. During treatment beta 2-adrenoceptor density remained elevated. After withdrawal of propranolol PRA reached pre-drug levels rapidly, while heart rate was significantly enhanced. Beta 2-Adrenoceptor density, however, declined slowly being still significantly increased after 3 days, although propranolol was not detectable in plasma after 24 h. The affinity of ICYP to GENE was not changed during or after treatment. Mepindolol treatment (2 X 5 mg/day) caused a 30% decrease of beta 2-adrenoceptor density and PRA after 2 days; both parameters remained reduced during treatment. After withdrawal, PRA reached rapidly pre-drug levels, whereas beta 2-adrenoceptor density was still after 4 days significantly diminished. The KD-values for ICYP, however, were not changed. During and after treatment heart rate was not affected. Alprenolol treatment (4 X 100 mg/day) led to a rapid fall in PRA, but did not significantly affect beta 2-adrenoceptor density. It is concluded, that the ISA may play an important role in modulating beta 2-adrenoceptor density and hence tissue responsiveness to beta-adrenoceptor stimulation.(ABSTRACT TRUNCATED AT 250 WORDS) | ACTIVATOR |
| Effects of beta-adrenoceptor antagonist administration on GENE density in human lymphocytes. The role of the "intrinsic sympathomimetic activity". Abrupt withdrawal of beta-adrenoceptor antagonists may lead to "rebound-effects". To study the mechanism underlying this phenomenon, the effects of the nonselective beta-adrenoceptor antagonists propranolol [no intrinsic sympathomimetic activity (ISA)], alprenolol (weak ISA) and mepindolol (strong ISA) on lymphocyte GENE density--assessed by (+/-)-[125I]-iodocyanopindolol (ICYP) binding--and plasma renin activity (PRA) were investigated in male healthy volunteers aged 23-35 years. Propranolol treatment (4 X 40 mg/day) increased the density of beta 2-adrenoceptors by 25% after 2 days; concomitantly PRA and heart rate were reduced. During treatment GENE density remained elevated. After withdrawal of propranolol PRA reached pre-drug levels rapidly, while heart rate was significantly enhanced. Beta 2-Adrenoceptor density, however, declined slowly being still significantly increased after 3 days, although propranolol was not detectable in plasma after 24 h. The affinity of ICYP to beta 2-adrenoceptors was not changed during or after treatment. CHEMICAL treatment (2 X 5 mg/day) caused a 30% decrease of GENE density and PRA after 2 days; both parameters remained reduced during treatment. After withdrawal, PRA reached rapidly pre-drug levels, whereas GENE density was still after 4 days significantly diminished. The KD-values for ICYP, however, were not changed. During and after treatment heart rate was not affected. Alprenolol treatment (4 X 100 mg/day) led to a rapid fall in PRA, but did not significantly affect GENE density. It is concluded, that the ISA may play an important role in modulating GENE density and hence tissue responsiveness to beta-adrenoceptor stimulation.(ABSTRACT TRUNCATED AT 250 WORDS) | GENE-CHEMICAL |
| Effects of GENE antagonist administration on beta 2-adrenoceptor density in human lymphocytes. The role of the "intrinsic sympathomimetic activity". Abrupt withdrawal of GENE antagonists may lead to "rebound-effects". To study the mechanism underlying this phenomenon, the effects of the nonselective GENE antagonists CHEMICAL [no intrinsic sympathomimetic activity (ISA)], alprenolol (weak ISA) and mepindolol (strong ISA) on lymphocyte beta 2-adrenoceptor density--assessed by (+/-)-[125I]-iodocyanopindolol (ICYP) binding--and plasma renin activity (PRA) were investigated in male healthy volunteers aged 23-35 years. CHEMICAL treatment (4 X 40 mg/day) increased the density of beta 2-adrenoceptors by 25% after 2 days; concomitantly PRA and heart rate were reduced. During treatment beta 2-adrenoceptor density remained elevated. After withdrawal of CHEMICAL PRA reached pre-drug levels rapidly, while heart rate was significantly enhanced. Beta 2-Adrenoceptor density, however, declined slowly being still significantly increased after 3 days, although CHEMICAL was not detectable in plasma after 24 h. The affinity of ICYP to beta 2-adrenoceptors was not changed during or after treatment. Mepindolol treatment (2 X 5 mg/day) caused a 30% decrease of beta 2-adrenoceptor density and PRA after 2 days; both parameters remained reduced during treatment. After withdrawal, PRA reached rapidly pre-drug levels, whereas beta 2-adrenoceptor density was still after 4 days significantly diminished. The KD-values for ICYP, however, were not changed. During and after treatment heart rate was not affected. Alprenolol treatment (4 X 100 mg/day) led to a rapid fall in PRA, but did not significantly affect beta 2-adrenoceptor density. It is concluded, that the ISA may play an important role in modulating beta 2-adrenoceptor density and hence tissue responsiveness to GENE stimulation.(ABSTRACT TRUNCATED AT 250 WORDS) | INHIBITOR |
| Effects of GENE antagonist administration on beta 2-adrenoceptor density in human lymphocytes. The role of the "intrinsic sympathomimetic activity". Abrupt withdrawal of GENE antagonists may lead to "rebound-effects". To study the mechanism underlying this phenomenon, the effects of the nonselective GENE antagonists propranolol [no intrinsic sympathomimetic activity (ISA)], CHEMICAL (weak ISA) and mepindolol (strong ISA) on lymphocyte beta 2-adrenoceptor density--assessed by (+/-)-[125I]-iodocyanopindolol (ICYP) binding--and plasma renin activity (PRA) were investigated in male healthy volunteers aged 23-35 years. Propranolol treatment (4 X 40 mg/day) increased the density of beta 2-adrenoceptors by 25% after 2 days; concomitantly PRA and heart rate were reduced. During treatment beta 2-adrenoceptor density remained elevated. After withdrawal of propranolol PRA reached pre-drug levels rapidly, while heart rate was significantly enhanced. Beta 2-Adrenoceptor density, however, declined slowly being still significantly increased after 3 days, although propranolol was not detectable in plasma after 24 h. The affinity of ICYP to beta 2-adrenoceptors was not changed during or after treatment. Mepindolol treatment (2 X 5 mg/day) caused a 30% decrease of beta 2-adrenoceptor density and PRA after 2 days; both parameters remained reduced during treatment. After withdrawal, PRA reached rapidly pre-drug levels, whereas beta 2-adrenoceptor density was still after 4 days significantly diminished. The KD-values for ICYP, however, were not changed. During and after treatment heart rate was not affected. CHEMICAL treatment (4 X 100 mg/day) led to a rapid fall in PRA, but did not significantly affect beta 2-adrenoceptor density. It is concluded, that the ISA may play an important role in modulating beta 2-adrenoceptor density and hence tissue responsiveness to GENE stimulation.(ABSTRACT TRUNCATED AT 250 WORDS) | INHIBITOR |
| Effects of GENE antagonist administration on beta 2-adrenoceptor density in human lymphocytes. The role of the "intrinsic sympathomimetic activity". Abrupt withdrawal of GENE antagonists may lead to "rebound-effects". To study the mechanism underlying this phenomenon, the effects of the nonselective GENE antagonists propranolol [no intrinsic sympathomimetic activity (ISA)], alprenolol (weak ISA) and CHEMICAL (strong ISA) on lymphocyte beta 2-adrenoceptor density--assessed by (+/-)-[125I]-iodocyanopindolol (ICYP) binding--and plasma renin activity (PRA) were investigated in male healthy volunteers aged 23-35 years. Propranolol treatment (4 X 40 mg/day) increased the density of beta 2-adrenoceptors by 25% after 2 days; concomitantly PRA and heart rate were reduced. During treatment beta 2-adrenoceptor density remained elevated. After withdrawal of propranolol PRA reached pre-drug levels rapidly, while heart rate was significantly enhanced. Beta 2-Adrenoceptor density, however, declined slowly being still significantly increased after 3 days, although propranolol was not detectable in plasma after 24 h. The affinity of ICYP to beta 2-adrenoceptors was not changed during or after treatment. CHEMICAL treatment (2 X 5 mg/day) caused a 30% decrease of beta 2-adrenoceptor density and PRA after 2 days; both parameters remained reduced during treatment. After withdrawal, PRA reached rapidly pre-drug levels, whereas beta 2-adrenoceptor density was still after 4 days significantly diminished. The KD-values for ICYP, however, were not changed. During and after treatment heart rate was not affected. Alprenolol treatment (4 X 100 mg/day) led to a rapid fall in PRA, but did not significantly affect beta 2-adrenoceptor density. It is concluded, that the ISA may play an important role in modulating beta 2-adrenoceptor density and hence tissue responsiveness to GENE stimulation.(ABSTRACT TRUNCATED AT 250 WORDS) | INHIBITOR |
| Inhibition of GENE pathway of arachidonic acid metabolism in human neutrophils by sulfasalazine and CHEMICAL. The possible effect of sulfasalazine, CHEMICAL, and acetyl-5-aminosalicylic acid on endogenous arachidonic acid release and metabolism was studied in human polymorphonuclear leukocytes (PMNs). A new in vitro assay was used by which [1-14C]arachidonic acid is incorporated by purified peripheral PMNs until steady state was obtained (5 hr). After preincubation with the test drugs prior to activation with calcium ionophore A23187, the released eicosanoids were isolated by extraction and thin-layer chromatography (TLC) and quantitated by autoradiography and laser densitometry. Median drug concentrations needed for 50% inhibition of leukotriene B4 and 5-hydroxyeicosatetraenoic acid (5-HETE) release was 4-5 mM (range 1-9 mM) for both sulfasalazine and CHEMICAL. The acetylated derivative of CHEMICAL was ineffective. The present data suggest that inhibition of arachidonic acid lipoxygenation may be an essential action of sulfasalazine and its active metabolite, CHEMICAL. Interference with lipoxygenase enzymes, rather than a steroid-like inhibition of arachidonic acid release from intracellular phospholipids, seems to be the mode of action. | INHIBITOR |
| Inhibition of GENE pathway of arachidonic acid metabolism in human neutrophils by CHEMICAL and 5-aminosalicylic acid. The possible effect of CHEMICAL, 5-aminosalicylic acid, and acetyl-5-aminosalicylic acid on endogenous arachidonic acid release and metabolism was studied in human polymorphonuclear leukocytes (PMNs). A new in vitro assay was used by which [1-14C]arachidonic acid is incorporated by purified peripheral PMNs until steady state was obtained (5 hr). After preincubation with the test drugs prior to activation with calcium ionophore A23187, the released eicosanoids were isolated by extraction and thin-layer chromatography (TLC) and quantitated by autoradiography and laser densitometry. Median drug concentrations needed for 50% inhibition of leukotriene B4 and 5-hydroxyeicosatetraenoic acid (5-HETE) release was 4-5 mM (range 1-9 mM) for both CHEMICAL and 5-aminosalicylic acid. The acetylated derivative of 5-aminosalicylic acid was ineffective. The present data suggest that inhibition of arachidonic acid lipoxygenation may be an essential action of CHEMICAL and its active metabolite, 5-aminosalicylic acid. Interference with lipoxygenase enzymes, rather than a steroid-like inhibition of arachidonic acid release from intracellular phospholipids, seems to be the mode of action. | INHIBITOR |
| Inhibition of 5-lipoxygenase pathway of arachidonic acid metabolism in human neutrophils by sulfasalazine and 5-aminosalicylic acid. The possible effect of sulfasalazine, 5-aminosalicylic acid, and acetyl-5-aminosalicylic acid on endogenous arachidonic acid release and metabolism was studied in human polymorphonuclear leukocytes (PMNs). A new in vitro assay was used by which [1-14C]arachidonic acid is incorporated by purified peripheral PMNs until steady state was obtained (5 hr). After preincubation with the test drugs prior to activation with calcium ionophore A23187, the released eicosanoids were isolated by extraction and thin-layer chromatography (TLC) and quantitated by autoradiography and laser densitometry. Median drug concentrations needed for 50% inhibition of leukotriene B4 and 5-hydroxyeicosatetraenoic acid (5-HETE) release was 4-5 mM (range 1-9 mM) for both sulfasalazine and 5-aminosalicylic acid. The acetylated derivative of 5-aminosalicylic acid was ineffective. The present data suggest that inhibition of arachidonic acid lipoxygenation may be an essential action of sulfasalazine and its active metabolite, 5-aminosalicylic acid. Interference with GENE enzymes, rather than a CHEMICAL-like inhibition of arachidonic acid release from intracellular phospholipids, seems to be the mode of action. | INHIBITOR |
| Inhibition of GENE pathway of CHEMICAL metabolism in human neutrophils by sulfasalazine and 5-aminosalicylic acid. The possible effect of sulfasalazine, 5-aminosalicylic acid, and acetyl-5-aminosalicylic acid on endogenous CHEMICAL release and metabolism was studied in human polymorphonuclear leukocytes (PMNs). A new in vitro assay was used by which [1-14C]arachidonic acid is incorporated by purified peripheral PMNs until steady state was obtained (5 hr). After preincubation with the test drugs prior to activation with calcium ionophore A23187, the released eicosanoids were isolated by extraction and thin-layer chromatography (TLC) and quantitated by autoradiography and laser densitometry. Median drug concentrations needed for 50% inhibition of leukotriene B4 and 5-hydroxyeicosatetraenoic acid (5-HETE) release was 4-5 mM (range 1-9 mM) for both sulfasalazine and 5-aminosalicylic acid. The acetylated derivative of 5-aminosalicylic acid was ineffective. The present data suggest that inhibition of CHEMICAL lipoxygenation may be an essential action of sulfasalazine and its active metabolite, 5-aminosalicylic acid. Interference with lipoxygenase enzymes, rather than a steroid-like inhibition of CHEMICAL release from intracellular phospholipids, seems to be the mode of action. | PRODUCT-OF |
| Inhibition of 5-lipoxygenase pathway of CHEMICAL metabolism in human neutrophils by sulfasalazine and 5-aminosalicylic acid. The possible effect of sulfasalazine, 5-aminosalicylic acid, and acetyl-5-aminosalicylic acid on endogenous CHEMICAL release and metabolism was studied in human polymorphonuclear leukocytes (PMNs). A new in vitro assay was used by which [1-14C]arachidonic acid is incorporated by purified peripheral PMNs until steady state was obtained (5 hr). After preincubation with the test drugs prior to activation with calcium ionophore A23187, the released eicosanoids were isolated by extraction and thin-layer chromatography (TLC) and quantitated by autoradiography and laser densitometry. Median drug concentrations needed for 50% inhibition of leukotriene B4 and 5-hydroxyeicosatetraenoic acid (5-HETE) release was 4-5 mM (range 1-9 mM) for both sulfasalazine and 5-aminosalicylic acid. The acetylated derivative of 5-aminosalicylic acid was ineffective. The present data suggest that inhibition of CHEMICAL lipoxygenation may be an essential action of sulfasalazine and its active metabolite, 5-aminosalicylic acid. Interference with GENE enzymes, rather than a steroid-like inhibition of CHEMICAL release from intracellular phospholipids, seems to be the mode of action. | PRODUCT-OF |
| Bevantolol: a beta-1 adrenoceptor antagonist with unique additional actions. UNLABELLED: CHEMICAL is a beta-1 adrenoceptor antagonist that has been shown to be as effective as other beta blockers for the treatment of angina pectoris and hypertension. Some interesting additional properties, such as the absence of the side effect of cold extremities, required investigation, and a great deal of new evidence has been accumulated during the last three years. This new data is consistent with the proposal put forward a couple of years ago that CHEMICAL interacts with GENE. All the available evidence, published and unpublished, has been reviewed and fits into a coherent pattern, here arranged into five sections. Chemistry: affinity for GENE. Animal experiments confirm both agonist and antagonist effects on alpha-receptors, in addition to antagonist activity at beta-1 receptors. In addition, CHEMICAL has electrophysiologic effects, including bradycardia by a direct action on the sinus node and a class 1 antiarrhythmic action. Investigations in humans have shown that although CHEMICAL has a short half-life, good control of hypertension can be achieved on once-a-day dosing. SAFETY: CHEMICAL has remarkably few side effects, does not cause cold extremities, and does not significantly affect glomerular filtration rate in patients with renal impairment. Evidence has been obtained in man for interaction with GENE in the brain; and in the peripheral circulation CHEMICAL does not, as do other beta blockers, increase peripheral vascular resistance, but reduces it. It is suggested that all the additional actions of CHEMICAL can be attributed to a partial agonist action on GENE. | DIRECT-REGULATOR |
| Bevantolol: a GENE antagonist with unique additional actions. UNLABELLED: CHEMICAL is a GENE antagonist that has been shown to be as effective as other beta blockers for the treatment of angina pectoris and hypertension. Some interesting additional properties, such as the absence of the side effect of cold extremities, required investigation, and a great deal of new evidence has been accumulated during the last three years. This new data is consistent with the proposal put forward a couple of years ago that bevantolol interacts with alpha-adrenoceptors. All the available evidence, published and unpublished, has been reviewed and fits into a coherent pattern, here arranged into five sections. Chemistry: affinity for alpha-adrenoceptors. Animal experiments confirm both agonist and antagonist effects on alpha-receptors, in addition to antagonist activity at beta-1 receptors. In addition, bevantolol has electrophysiologic effects, including bradycardia by a direct action on the sinus node and a class 1 antiarrhythmic action. Investigations in humans have shown that although bevantolol has a short half-life, good control of hypertension can be achieved on once-a-day dosing. SAFETY: bevantolol has remarkably few side effects, does not cause cold extremities, and does not significantly affect glomerular filtration rate in patients with renal impairment. Evidence has been obtained in man for interaction with alpha-adrenoceptors in the brain; and in the peripheral circulation bevantolol does not, as do other beta blockers, increase peripheral vascular resistance, but reduces it. It is suggested that all the additional actions of bevantolol can be attributed to a partial agonist action on alpha-adrenoceptors. | INHIBITOR |
| GENE binding of CHEMICAL in vivo: increased receptor number with low-dose alprazolam. CHEMICAL are in clinical use as hypnotics and anxiolytics. We analyzed in vivo receptor binding and brain concentrations of alprazolam, triazolam, and estazolam. Drug concentrations measured in the cerebral cortex 1 h after administration were directly proportional to dose for all three compounds. In vivo receptor binding, as defined by the specific uptake of [3H]Ro15-1788, decreased with increasing doses of estazolam and triazolam, a finding indicating dose-related increases in receptor occupancy due to these compounds. Triazolam was substantially more potent, with an IC50 value of 16 ng/g, compared with 117 ng/g for estazolam. At higher doses of alprazolam (greater than 0.2 mg/kg), receptor binding by [3H]Ro15-1788, likewise decreased with increasing dose of the former drug. However, at lower doses of alprazolam (0.02-0.05 mg/kg), which resulted in cortex concentrations of 2-7 ng/g, receptor binding was increased above control values in cortex, hypothalamus, and hippocampus but not in several other brain regions. Binding returned to control values at doses of greater than or equal to 0.01 mg/kg. Similar results were obtained in time course studies. At 8 and 10 h after a dose of 1 mg/kg i.p., corresponding to cortex concentrations of 2.7-7 ng/g, receptor binding was increased compared with controls. Similarly, at 1, 2, and 3 h after a single dose of 0.05 mg/kg, corresponding to cortex concentrations of 3.7-5.8 ng/g, receptor binding was also increased. The apparent affinity of benzodiazepine receptors for clonazepam in mice receiving alprazolam (0.05 mg/kg) was unchanged from that in untreated control mice, an observation suggesting that low doses of alprazolam increased receptor number.(ABSTRACT TRUNCATED AT 250 WORDS) | DIRECT-REGULATOR |
| Benzodiazepine receptor binding of triazolobenzodiazepines in vivo: increased receptor number with low-dose alprazolam. Triazolobenzodiazepines are in clinical use as hypnotics and anxiolytics. We analyzed in vivo receptor binding and brain concentrations of alprazolam, triazolam, and estazolam. Drug concentrations measured in the cerebral cortex 1 h after administration were directly proportional to dose for all three compounds. In vivo receptor binding, as defined by the specific uptake of [3H]Ro15-1788, decreased with increasing doses of estazolam and triazolam, a finding indicating dose-related increases in receptor occupancy due to these compounds. Triazolam was substantially more potent, with an IC50 value of 16 ng/g, compared with 117 ng/g for estazolam. At higher doses of alprazolam (greater than 0.2 mg/kg), receptor binding by [3H]Ro15-1788, likewise decreased with increasing dose of the former drug. However, at lower doses of alprazolam (0.02-0.05 mg/kg), which resulted in cortex concentrations of 2-7 ng/g, receptor binding was increased above control values in cortex, hypothalamus, and hippocampus but not in several other brain regions. Binding returned to control values at doses of greater than or equal to 0.01 mg/kg. Similar results were obtained in time course studies. At 8 and 10 h after a dose of 1 mg/kg i.p., corresponding to cortex concentrations of 2.7-7 ng/g, receptor binding was increased compared with controls. Similarly, at 1, 2, and 3 h after a single dose of 0.05 mg/kg, corresponding to cortex concentrations of 3.7-5.8 ng/g, receptor binding was also increased. The apparent affinity of GENE for CHEMICAL in mice receiving alprazolam (0.05 mg/kg) was unchanged from that in untreated control mice, an observation suggesting that low doses of alprazolam increased receptor number.(ABSTRACT TRUNCATED AT 250 WORDS) | DIRECT-REGULATOR |
| GENE binding of triazolobenzodiazepines in vivo: increased receptor number with low-dose CHEMICAL. Triazolobenzodiazepines are in clinical use as hypnotics and anxiolytics. We analyzed in vivo receptor binding and brain concentrations of CHEMICAL, triazolam, and estazolam. Drug concentrations measured in the cerebral cortex 1 h after administration were directly proportional to dose for all three compounds. In vivo receptor binding, as defined by the specific uptake of [3H]Ro15-1788, decreased with increasing doses of estazolam and triazolam, a finding indicating dose-related increases in receptor occupancy due to these compounds. Triazolam was substantially more potent, with an IC50 value of 16 ng/g, compared with 117 ng/g for estazolam. At higher doses of CHEMICAL (greater than 0.2 mg/kg), receptor binding by [3H]Ro15-1788, likewise decreased with increasing dose of the former drug. However, at lower doses of CHEMICAL (0.02-0.05 mg/kg), which resulted in cortex concentrations of 2-7 ng/g, receptor binding was increased above control values in cortex, hypothalamus, and hippocampus but not in several other brain regions. Binding returned to control values at doses of greater than or equal to 0.01 mg/kg. Similar results were obtained in time course studies. At 8 and 10 h after a dose of 1 mg/kg i.p., corresponding to cortex concentrations of 2.7-7 ng/g, receptor binding was increased compared with controls. Similarly, at 1, 2, and 3 h after a single dose of 0.05 mg/kg, corresponding to cortex concentrations of 3.7-5.8 ng/g, receptor binding was also increased. The apparent affinity of benzodiazepine receptors for clonazepam in mice receiving CHEMICAL (0.05 mg/kg) was unchanged from that in untreated control mice, an observation suggesting that low doses of CHEMICAL increased receptor number.(ABSTRACT TRUNCATED AT 250 WORDS) | DIRECT-REGULATOR |
| Benzodiazepine receptor binding of triazolobenzodiazepines in vivo: increased receptor number with low-dose CHEMICAL. Triazolobenzodiazepines are in clinical use as hypnotics and anxiolytics. We analyzed in vivo receptor binding and brain concentrations of CHEMICAL, triazolam, and estazolam. Drug concentrations measured in the cerebral cortex 1 h after administration were directly proportional to dose for all three compounds. In vivo receptor binding, as defined by the specific uptake of [3H]Ro15-1788, decreased with increasing doses of estazolam and triazolam, a finding indicating dose-related increases in receptor occupancy due to these compounds. Triazolam was substantially more potent, with an IC50 value of 16 ng/g, compared with 117 ng/g for estazolam. At higher doses of CHEMICAL (greater than 0.2 mg/kg), receptor binding by [3H]Ro15-1788, likewise decreased with increasing dose of the former drug. However, at lower doses of CHEMICAL (0.02-0.05 mg/kg), which resulted in cortex concentrations of 2-7 ng/g, receptor binding was increased above control values in cortex, hypothalamus, and hippocampus but not in several other brain regions. Binding returned to control values at doses of greater than or equal to 0.01 mg/kg. Similar results were obtained in time course studies. At 8 and 10 h after a dose of 1 mg/kg i.p., corresponding to cortex concentrations of 2.7-7 ng/g, receptor binding was increased compared with controls. Similarly, at 1, 2, and 3 h after a single dose of 0.05 mg/kg, corresponding to cortex concentrations of 3.7-5.8 ng/g, receptor binding was also increased. The apparent affinity of GENE for clonazepam in mice receiving CHEMICAL (0.05 mg/kg) was unchanged from that in untreated control mice, an observation suggesting that low doses of CHEMICAL increased receptor number.(ABSTRACT TRUNCATED AT 250 WORDS) | DIRECT-REGULATOR |
| Muscarinic cholinergic and histamine H1 receptor binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, CHEMICAL, levomepromazine, perphenazine and some of their metabolites for GENE, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for muscarinic cholinergic receptors and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. Chlorpromazine, levomepromazine, and their metabolites had 5-30 times higher binding affinities for muscarinic cholinergic receptors than CHEMICAL, perphenazine and their metabolites. Levomepromazine was the most potent and CHEMICAL the least potent of the four drugs in histamine H1 receptor binding. 7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and 7-hydroxy CHEMICAL had only 10% of the potency of the parent drug in histamine H1 receptor binding, while the 7-hydroxy-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system. Their histamine H1 receptor binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and histamine H1 receptor binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, fluphenazine, CHEMICAL, perphenazine and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for GENE and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. Chlorpromazine, CHEMICAL, and their metabolites had 5-30 times higher binding affinities for GENE than fluphenazine, perphenazine and their metabolites. CHEMICAL was the most potent and fluphenazine the least potent of the four drugs in histamine H1 receptor binding. 7-Hydroxy CHEMICAL, 3-hydroxy CHEMICAL and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in histamine H1 receptor binding, while the 7-hydroxy-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system. Their histamine H1 receptor binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and CHEMICAL. | DIRECT-REGULATOR |
| Muscarinic cholinergic and histamine H1 receptor binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, CHEMICAL, levomepromazine, perphenazine and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for GENE and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. Chlorpromazine, levomepromazine, and their metabolites had 5-30 times higher binding affinities for GENE than CHEMICAL, perphenazine and their metabolites. Levomepromazine was the most potent and CHEMICAL the least potent of the four drugs in histamine H1 receptor binding. 7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and 7-hydroxy CHEMICAL had only 10% of the potency of the parent drug in histamine H1 receptor binding, while the 7-hydroxy-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system. Their histamine H1 receptor binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and histamine H1 receptor binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, fluphenazine, CHEMICAL, perphenazine and some of their metabolites for GENE, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for muscarinic cholinergic receptors and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. Chlorpromazine, CHEMICAL, and their metabolites had 5-30 times higher binding affinities for muscarinic cholinergic receptors than fluphenazine, perphenazine and their metabolites. CHEMICAL was the most potent and fluphenazine the least potent of the four drugs in histamine H1 receptor binding. 7-Hydroxy CHEMICAL, 3-hydroxy CHEMICAL and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in histamine H1 receptor binding, while the 7-hydroxy-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system. Their histamine H1 receptor binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and CHEMICAL. | DIRECT-REGULATOR |
| Muscarinic cholinergic and histamine H1 receptor binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, fluphenazine, levomepromazine, CHEMICAL and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for GENE and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. Chlorpromazine, levomepromazine, and their metabolites had 5-30 times higher binding affinities for GENE than fluphenazine, CHEMICAL and their metabolites. Levomepromazine was the most potent and fluphenazine the least potent of the four drugs in histamine H1 receptor binding. 7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in histamine H1 receptor binding, while the 7-hydroxy-metabolites of chlorpromazine and CHEMICAL had about 75% of the potency of the parent drug in this binding system. Their histamine H1 receptor binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and GENE binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, fluphenazine, levomepromazine, perphenazine and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for muscarinic cholinergic receptors and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. Chlorpromazine, levomepromazine, and their metabolites had 5-30 times higher binding affinities for muscarinic cholinergic receptors than fluphenazine, perphenazine and their metabolites. CHEMICAL was the most potent and fluphenazine the least potent of the four drugs in GENE binding. 7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in GENE binding, while the 7-hydroxy-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system. Their GENE binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and GENE binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, CHEMICAL, levomepromazine, perphenazine and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for muscarinic cholinergic receptors and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. Chlorpromazine, levomepromazine, and their metabolites had 5-30 times higher binding affinities for muscarinic cholinergic receptors than CHEMICAL, perphenazine and their metabolites. Levomepromazine was the most potent and CHEMICAL the least potent of the four drugs in GENE binding. 7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and 7-hydroxy CHEMICAL had only 10% of the potency of the parent drug in GENE binding, while the 7-hydroxy-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system. Their GENE binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and GENE binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, fluphenazine, levomepromazine, perphenazine and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for muscarinic cholinergic receptors and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. Chlorpromazine, levomepromazine, and their metabolites had 5-30 times higher binding affinities for muscarinic cholinergic receptors than fluphenazine, perphenazine and their metabolites. Levomepromazine was the most potent and fluphenazine the least potent of the four drugs in GENE binding. CHEMICAL, 3-hydroxy levomepromazine and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in GENE binding, while the 7-hydroxy-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system. Their GENE binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and histamine H1 receptor binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, fluphenazine, levomepromazine, CHEMICAL and some of their metabolites for GENE, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for muscarinic cholinergic receptors and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. Chlorpromazine, levomepromazine, and their metabolites had 5-30 times higher binding affinities for muscarinic cholinergic receptors than fluphenazine, CHEMICAL and their metabolites. Levomepromazine was the most potent and fluphenazine the least potent of the four drugs in histamine H1 receptor binding. 7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in histamine H1 receptor binding, while the 7-hydroxy-metabolites of chlorpromazine and CHEMICAL had about 75% of the potency of the parent drug in this binding system. Their histamine H1 receptor binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and GENE binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, fluphenazine, levomepromazine, perphenazine and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for muscarinic cholinergic receptors and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. Chlorpromazine, levomepromazine, and their metabolites had 5-30 times higher binding affinities for muscarinic cholinergic receptors than fluphenazine, perphenazine and their metabolites. Levomepromazine was the most potent and fluphenazine the least potent of the four drugs in GENE binding. 7-Hydroxy levomepromazine, CHEMICAL and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in GENE binding, while the 7-hydroxy-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system. Their GENE binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and GENE binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, fluphenazine, levomepromazine, perphenazine and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for muscarinic cholinergic receptors and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. Chlorpromazine, levomepromazine, and their metabolites had 5-30 times higher binding affinities for muscarinic cholinergic receptors than fluphenazine, perphenazine and their metabolites. Levomepromazine was the most potent and fluphenazine the least potent of the four drugs in GENE binding. 7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and CHEMICAL had only 10% of the potency of the parent drug in GENE binding, while the 7-hydroxy-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system. Their GENE binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and GENE binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, fluphenazine, levomepromazine, perphenazine and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for muscarinic cholinergic receptors and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. Chlorpromazine, levomepromazine, and their metabolites had 5-30 times higher binding affinities for muscarinic cholinergic receptors than fluphenazine, perphenazine and their metabolites. Levomepromazine was the most potent and fluphenazine the least potent of the four drugs in GENE binding. 7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and CHEMICAL fluphenazine had only 10% of the potency of the parent drug in GENE binding, while the CHEMICAL-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system. Their GENE binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and GENE binding of phenothiazine drug metabolites. In vitro binding affinities of CHEMICAL, fluphenazine, levomepromazine, perphenazine and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for muscarinic cholinergic receptors and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. CHEMICAL, levomepromazine, and their metabolites had 5-30 times higher binding affinities for muscarinic cholinergic receptors than fluphenazine, perphenazine and their metabolites. Levomepromazine was the most potent and fluphenazine the least potent of the four drugs in GENE binding. 7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in GENE binding, while the 7-hydroxy-metabolites of CHEMICAL and perphenazine had about 75% of the potency of the parent drug in this binding system. Their GENE binding affinities indicate that metabolites may contribute to the sedative effects of CHEMICAL and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and GENE binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, fluphenazine, levomepromazine, CHEMICAL and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for muscarinic cholinergic receptors and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. Chlorpromazine, levomepromazine, and their metabolites had 5-30 times higher binding affinities for muscarinic cholinergic receptors than fluphenazine, CHEMICAL and their metabolites. Levomepromazine was the most potent and fluphenazine the least potent of the four drugs in GENE binding. 7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in GENE binding, while the 7-hydroxy-metabolites of chlorpromazine and CHEMICAL had about 75% of the potency of the parent drug in this binding system. Their GENE binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and GENE binding of CHEMICAL drug metabolites. In vitro binding affinities of chlorpromazine, fluphenazine, levomepromazine, perphenazine and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for muscarinic cholinergic receptors and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. Chlorpromazine, levomepromazine, and their metabolites had 5-30 times higher binding affinities for muscarinic cholinergic receptors than fluphenazine, perphenazine and their metabolites. Levomepromazine was the most potent and fluphenazine the least potent of the four drugs in GENE binding. 7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in GENE binding, while the 7-hydroxy-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system. Their GENE binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and GENE binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, fluphenazine, CHEMICAL, perphenazine and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for muscarinic cholinergic receptors and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. Chlorpromazine, CHEMICAL, and their metabolites had 5-30 times higher binding affinities for muscarinic cholinergic receptors than fluphenazine, perphenazine and their metabolites. CHEMICAL was the most potent and fluphenazine the least potent of the four drugs in GENE binding. 7-Hydroxy CHEMICAL, 3-hydroxy CHEMICAL and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in GENE binding, while the 7-hydroxy-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system. Their GENE binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and CHEMICAL. | DIRECT-REGULATOR |
| Muscarinic cholinergic and histamine H1 receptor binding of phenothiazine drug metabolites. In vitro binding affinities of CHEMICAL, fluphenazine, levomepromazine, perphenazine and some of their metabolites for GENE, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for muscarinic cholinergic receptors and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. CHEMICAL, levomepromazine, and their metabolites had 5-30 times higher binding affinities for muscarinic cholinergic receptors than fluphenazine, perphenazine and their metabolites. Levomepromazine was the most potent and fluphenazine the least potent of the four drugs in histamine H1 receptor binding. 7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in histamine H1 receptor binding, while the 7-hydroxy-metabolites of CHEMICAL and perphenazine had about 75% of the potency of the parent drug in this binding system. Their histamine H1 receptor binding affinities indicate that metabolites may contribute to the sedative effects of CHEMICAL and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and histamine H1 receptor binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, fluphenazine, levomepromazine, perphenazine and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for GENE and for histamine H1 receptors in rat brain, using CHEMICAL and 3H-mepyramine as radioligands. Chlorpromazine, levomepromazine, and their metabolites had 5-30 times higher binding affinities for GENE than fluphenazine, perphenazine and their metabolites. Levomepromazine was the most potent and fluphenazine the least potent of the four drugs in histamine H1 receptor binding. 7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in histamine H1 receptor binding, while the 7-hydroxy-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system. Their histamine H1 receptor binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and histamine H1 receptor binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, fluphenazine, levomepromazine, perphenazine and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for muscarinic cholinergic receptors and for GENE in rat brain, using CHEMICAL and 3H-mepyramine as radioligands. Chlorpromazine, levomepromazine, and their metabolites had 5-30 times higher binding affinities for muscarinic cholinergic receptors than fluphenazine, perphenazine and their metabolites. Levomepromazine was the most potent and fluphenazine the least potent of the four drugs in histamine H1 receptor binding. 7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in histamine H1 receptor binding, while the 7-hydroxy-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system. Their histamine H1 receptor binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and histamine H1 receptor binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, fluphenazine, levomepromazine, perphenazine and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for GENE and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and CHEMICAL as radioligands. Chlorpromazine, levomepromazine, and their metabolites had 5-30 times higher binding affinities for GENE than fluphenazine, perphenazine and their metabolites. Levomepromazine was the most potent and fluphenazine the least potent of the four drugs in histamine H1 receptor binding. 7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in histamine H1 receptor binding, while the 7-hydroxy-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system. Their histamine H1 receptor binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and histamine H1 receptor binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, fluphenazine, levomepromazine, perphenazine and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for muscarinic cholinergic receptors and for GENE in rat brain, using 3H-quinuclidinyl benzilate and CHEMICAL as radioligands. Chlorpromazine, levomepromazine, and their metabolites had 5-30 times higher binding affinities for muscarinic cholinergic receptors than fluphenazine, perphenazine and their metabolites. Levomepromazine was the most potent and fluphenazine the least potent of the four drugs in histamine H1 receptor binding. 7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in histamine H1 receptor binding, while the 7-hydroxy-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system. Their histamine H1 receptor binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine. | DIRECT-REGULATOR |
| Muscarinic cholinergic and histamine H1 receptor binding of phenothiazine drug metabolites. In vitro binding affinities of chlorpromazine, fluphenazine, levomepromazine, perphenazine and some of their metabolites for dopamine D2 receptors, alpha 1- and alpha 2 adrenoceptors in rat brain were previously reported from our laboratories. The present study reports the in vitro binding affinities of the same compounds for GENE and for histamine H1 receptors in rat brain, using 3H-quinuclidinyl benzilate and 3H-mepyramine as radioligands. CHEMICAL, levomepromazine, and their metabolites had 5-30 times higher binding affinities for GENE than fluphenazine, perphenazine and their metabolites. Levomepromazine was the most potent and fluphenazine the least potent of the four drugs in histamine H1 receptor binding. 7-Hydroxy levomepromazine, 3-hydroxy levomepromazine and 7-hydroxy fluphenazine had only 10% of the potency of the parent drug in histamine H1 receptor binding, while the 7-hydroxy-metabolites of chlorpromazine and perphenazine had about 75% of the potency of the parent drug in this binding system. Their histamine H1 receptor binding affinities indicate that metabolites may contribute to the sedative effects of chlorpromazine and levomepromazine. | DIRECT-REGULATOR |
| Retinoid-induced hemorrhaging and bone toxicity in rats fed diets deficient in vitamin K. The recent increase in the clinical use of synthetic vitamin A compounds has led to concern of possible side effects. Some of these effects are known to be influenced by dietary levels of vitamin K. We therefore compared the toxic effects of 13-cis-retinoic acid (13cisRA), retinyl acetate (ROAc), and N-(4-hydroxyphenyl)retinamide (4HPR) in male Sprague-Dawley rats maintained on diets containing different levels of vitamin K. Animals were fed either an NIH-07 diet supplemented with menadione (3.1 ppm vitamin K3), an NIH-07 diet not supplemented with menadione, or an AIN-076 purified diet devoid of vitamin K. The retinoids had no effect on prothrombin times of animals fed the supplemented diet. When menadione was omitted from the diet, however, 4HPR-dosed animals had elevated prothrombin times. This effect was observed as early as Day 7 and was accompanied by one confirmed hemorrhagic death. 13cisRA-dosed animals showed no change in prothrombin times. In the high-dose CHEMICAL group, there was a twofold increase in prothrombin times but only after prolonged dosing. In animals fed the NIH-07 diets, 13cisRA and CHEMICAL induced multiple bone fractures at all dose levels. In contrast, 4HPR administered at the highest dose induced only one fracture in one animal. Animals fed the purified diet lost weight faster and diet sooner than those maintained on the other diets. Bone fractures were not observed in these animals because of early deaths resulting from hemorrhaging. For all retinoid-dosed groups maintained on the purified diet, changes in prothrombin times occured as early as 1 week. The order of effect was 4HPR greater than CHEMICAL greater than 13cisRA, with increases in prothrombin times correlating with increases in hemorrhagic deaths. Hence, the degree of retinoid-induced hemorrhage, but not the incidence of bone fractures, was inversely related to vitamin K levels in the diet. 13cisRA and CHEMICAL, but not 4HPR, caused a dose-dependent reduction in plasma osteocalcin, an effect that correlated with retinoid-induced bone effects. In contrast, serum GENE was elevated in animals dosed with 13cisRA or 4HPR but not in those dose with CHEMICAL. For this enzyme, the electrophoretic pattern on agarose gel showed a decrease, compared to controls, in the major isozyme in serum of ROAc-dosed animals. Hence, plasma osteocalcin is a better predictor of retinoid-induced bone effects than serum GENE. | GENE-CHEMICAL |
| Retinoid-induced hemorrhaging and bone toxicity in rats fed diets deficient in vitamin K. The recent increase in the clinical use of synthetic vitamin A compounds has led to concern of possible side effects. Some of these effects are known to be influenced by dietary levels of vitamin K. We therefore compared the toxic effects of 13-cis-retinoic acid (13cisRA), retinyl acetate (ROAc), and N-(4-hydroxyphenyl)retinamide (4HPR) in male Sprague-Dawley rats maintained on diets containing different levels of vitamin K. Animals were fed either an NIH-07 diet supplemented with menadione (3.1 ppm vitamin K3), an NIH-07 diet not supplemented with menadione, or an AIN-076 purified diet devoid of vitamin K. The CHEMICAL had no effect on GENE times of animals fed the supplemented diet. When menadione was omitted from the diet, however, 4HPR-dosed animals had elevated GENE times. This effect was observed as early as Day 7 and was accompanied by one confirmed hemorrhagic death. 13cisRA-dosed animals showed no change in GENE times. In the high-dose ROAc group, there was a twofold increase in GENE times but only after prolonged dosing. In animals fed the NIH-07 diets, 13cisRA and ROAc induced multiple bone fractures at all dose levels. In contrast, 4HPR administered at the highest dose induced only one fracture in one animal. Animals fed the purified diet lost weight faster and diet sooner than those maintained on the other diets. Bone fractures were not observed in these animals because of early deaths resulting from hemorrhaging. For all retinoid-dosed groups maintained on the purified diet, changes in GENE times occured as early as 1 week. The order of effect was 4HPR greater than ROAc greater than 13cisRA, with increases in GENE times correlating with increases in hemorrhagic deaths. Hence, the degree of retinoid-induced hemorrhage, but not the incidence of bone fractures, was inversely related to vitamin K levels in the diet. 13cisRA and ROAc, but not 4HPR, caused a dose-dependent reduction in plasma osteocalcin, an effect that correlated with retinoid-induced bone effects. In contrast, serum alkaline phosphatase was elevated in animals dosed with 13cisRA or 4HPR but not in those dose with ROAc. For this enzyme, the electrophoretic pattern on agarose gel showed a decrease, compared to controls, in the major isozyme in serum of ROAc-dosed animals. Hence, plasma osteocalcin is a better predictor of retinoid-induced bone effects than serum alkaline phosphatase. | NO-RELATIONSHIP |
| Retinoid-induced hemorrhaging and bone toxicity in rats fed diets deficient in vitamin K. The recent increase in the clinical use of synthetic vitamin A compounds has led to concern of possible side effects. Some of these effects are known to be influenced by dietary levels of vitamin K. We therefore compared the toxic effects of 13-cis-retinoic acid (13cisRA), retinyl acetate (ROAc), and N-(4-hydroxyphenyl)retinamide (4HPR) in male Sprague-Dawley rats maintained on diets containing different levels of vitamin K. Animals were fed either an NIH-07 diet supplemented with menadione (3.1 ppm vitamin K3), an NIH-07 diet not supplemented with menadione, or an AIN-076 purified diet devoid of vitamin K. The retinoids had no effect on GENE times of animals fed the supplemented diet. When menadione was omitted from the diet, however, 4HPR-dosed animals had elevated GENE times. This effect was observed as early as Day 7 and was accompanied by one confirmed hemorrhagic death. CHEMICAL-dosed animals showed no change in GENE times. In the high-dose ROAc group, there was a twofold increase in GENE times but only after prolonged dosing. In animals fed the NIH-07 diets, CHEMICAL and ROAc induced multiple bone fractures at all dose levels. In contrast, 4HPR administered at the highest dose induced only one fracture in one animal. Animals fed the purified diet lost weight faster and diet sooner than those maintained on the other diets. Bone fractures were not observed in these animals because of early deaths resulting from hemorrhaging. For all retinoid-dosed groups maintained on the purified diet, changes in GENE times occured as early as 1 week. The order of effect was 4HPR greater than ROAc greater than CHEMICAL, with increases in GENE times correlating with increases in hemorrhagic deaths. Hence, the degree of retinoid-induced hemorrhage, but not the incidence of bone fractures, was inversely related to vitamin K levels in the diet. CHEMICAL and ROAc, but not 4HPR, caused a dose-dependent reduction in plasma osteocalcin, an effect that correlated with retinoid-induced bone effects. In contrast, serum alkaline phosphatase was elevated in animals dosed with CHEMICAL or 4HPR but not in those dose with ROAc. For this enzyme, the electrophoretic pattern on agarose gel showed a decrease, compared to controls, in the major isozyme in serum of ROAc-dosed animals. Hence, plasma osteocalcin is a better predictor of retinoid-induced bone effects than serum alkaline phosphatase. | NO-RELATIONSHIP |
| Retinoid-induced hemorrhaging and bone toxicity in rats fed diets deficient in vitamin K. The recent increase in the clinical use of synthetic vitamin A compounds has led to concern of possible side effects. Some of these effects are known to be influenced by dietary levels of vitamin K. We therefore compared the toxic effects of 13-cis-retinoic acid (13cisRA), retinyl acetate (ROAc), and N-(4-hydroxyphenyl)retinamide (4HPR) in male Sprague-Dawley rats maintained on diets containing different levels of vitamin K. Animals were fed either an NIH-07 diet supplemented with menadione (3.1 ppm vitamin K3), an NIH-07 diet not supplemented with menadione, or an AIN-076 purified diet devoid of vitamin K. The retinoids had no effect on prothrombin times of animals fed the supplemented diet. When menadione was omitted from the diet, however, 4HPR-dosed animals had elevated prothrombin times. This effect was observed as early as Day 7 and was accompanied by one confirmed hemorrhagic death. 13cisRA-dosed animals showed no change in prothrombin times. In the high-dose ROAc group, there was a twofold increase in prothrombin times but only after prolonged dosing. In animals fed the NIH-07 diets, 13cisRA and ROAc induced multiple bone fractures at all dose levels. In contrast, 4HPR administered at the highest dose induced only one fracture in one animal. Animals fed the purified diet lost weight faster and diet sooner than those maintained on the other diets. Bone fractures were not observed in these animals because of early deaths resulting from hemorrhaging. For all retinoid-dosed groups maintained on the purified diet, changes in prothrombin times occured as early as 1 week. The order of effect was 4HPR greater than ROAc greater than 13cisRA, with increases in prothrombin times correlating with increases in hemorrhagic deaths. Hence, the degree of retinoid-induced hemorrhage, but not the incidence of bone fractures, was inversely related to vitamin K levels in the diet. 13cisRA and ROAc, but not 4HPR, caused a dose-dependent reduction in plasma GENE, an effect that correlated with CHEMICAL-induced bone effects. In contrast, serum alkaline phosphatase was elevated in animals dosed with 13cisRA or 4HPR but not in those dose with ROAc. For this enzyme, the electrophoretic pattern on agarose gel showed a decrease, compared to controls, in the major isozyme in serum of ROAc-dosed animals. Hence, plasma GENE is a better predictor of retinoid-induced bone effects than serum alkaline phosphatase. | REGULATOR |
| Retinoid-induced hemorrhaging and bone toxicity in rats fed diets deficient in vitamin K. The recent increase in the clinical use of synthetic vitamin A compounds has led to concern of possible side effects. Some of these effects are known to be influenced by dietary levels of vitamin K. We therefore compared the toxic effects of 13-cis-retinoic acid (13cisRA), retinyl acetate (ROAc), and N-(4-hydroxyphenyl)retinamide (4HPR) in male Sprague-Dawley rats maintained on diets containing different levels of vitamin K. Animals were fed either an NIH-07 diet supplemented with menadione (3.1 ppm vitamin K3), an NIH-07 diet not supplemented with menadione, or an AIN-076 purified diet devoid of vitamin K. The retinoids had no effect on prothrombin times of animals fed the supplemented diet. When menadione was omitted from the diet, however, 4HPR-dosed animals had elevated prothrombin times. This effect was observed as early as Day 7 and was accompanied by one confirmed hemorrhagic death. 13cisRA-dosed animals showed no change in prothrombin times. In the high-dose ROAc group, there was a twofold increase in prothrombin times but only after prolonged dosing. In animals fed the NIH-07 diets, 13cisRA and ROAc induced multiple bone fractures at all dose levels. In contrast, 4HPR administered at the highest dose induced only one fracture in one animal. Animals fed the purified diet lost weight faster and diet sooner than those maintained on the other diets. Bone fractures were not observed in these animals because of early deaths resulting from hemorrhaging. For all retinoid-dosed groups maintained on the purified diet, changes in prothrombin times occured as early as 1 week. The order of effect was 4HPR greater than ROAc greater than 13cisRA, with increases in prothrombin times correlating with increases in hemorrhagic deaths. Hence, the degree of retinoid-induced hemorrhage, but not the incidence of bone fractures, was inversely related to vitamin K levels in the diet. 13cisRA and ROAc, but not 4HPR, caused a dose-dependent reduction in plasma osteocalcin, an effect that correlated with retinoid-induced bone effects. In contrast, serum GENE was elevated in animals dosed with 13cisRA or 4HPR but not in those dose with ROAc. For this enzyme, the electrophoretic pattern on agarose gel showed a decrease, compared to controls, in the major isozyme in serum of ROAc-dosed animals. Hence, plasma osteocalcin is a better predictor of CHEMICAL-induced bone effects than serum GENE. | NO-RELATIONSHIP |
| Retinoid-induced hemorrhaging and bone toxicity in rats fed diets deficient in vitamin K. The recent increase in the clinical use of synthetic vitamin A compounds has led to concern of possible side effects. Some of these effects are known to be influenced by dietary levels of vitamin K. We therefore compared the toxic effects of 13-cis-retinoic acid (13cisRA), retinyl acetate (ROAc), and N-(4-hydroxyphenyl)retinamide (4HPR) in male Sprague-Dawley rats maintained on diets containing different levels of vitamin K. Animals were fed either an NIH-07 diet supplemented with menadione (3.1 ppm vitamin K3), an NIH-07 diet not supplemented with menadione, or an AIN-076 purified diet devoid of vitamin K. The retinoids had no effect on GENE times of animals fed the supplemented diet. When menadione was omitted from the diet, however, 4HPR-dosed animals had elevated GENE times. This effect was observed as early as Day 7 and was accompanied by one confirmed hemorrhagic death. 13cisRA-dosed animals showed no change in GENE times. In the high-dose ROAc group, there was a twofold increase in GENE times but only after prolonged dosing. In animals fed the NIH-07 diets, 13cisRA and ROAc induced multiple bone fractures at all dose levels. In contrast, 4HPR administered at the highest dose induced only one fracture in one animal. Animals fed the purified diet lost weight faster and diet sooner than those maintained on the other diets. Bone fractures were not observed in these animals because of early deaths resulting from hemorrhaging. For all CHEMICAL-dosed groups maintained on the purified diet, changes in GENE times occured as early as 1 week. The order of effect was 4HPR greater than ROAc greater than 13cisRA, with increases in GENE times correlating with increases in hemorrhagic deaths. Hence, the degree of retinoid-induced hemorrhage, but not the incidence of bone fractures, was inversely related to vitamin K levels in the diet. 13cisRA and ROAc, but not 4HPR, caused a dose-dependent reduction in plasma osteocalcin, an effect that correlated with retinoid-induced bone effects. In contrast, serum alkaline phosphatase was elevated in animals dosed with 13cisRA or 4HPR but not in those dose with ROAc. For this enzyme, the electrophoretic pattern on agarose gel showed a decrease, compared to controls, in the major isozyme in serum of ROAc-dosed animals. Hence, plasma osteocalcin is a better predictor of retinoid-induced bone effects than serum alkaline phosphatase. | REGULATOR |
| Retinoid-induced hemorrhaging and bone toxicity in rats fed diets deficient in vitamin K. The recent increase in the clinical use of synthetic vitamin A compounds has led to concern of possible side effects. Some of these effects are known to be influenced by dietary levels of vitamin K. We therefore compared the toxic effects of 13-cis-retinoic acid (13cisRA), retinyl acetate (ROAc), and N-(4-hydroxyphenyl)retinamide (4HPR) in male Sprague-Dawley rats maintained on diets containing different levels of vitamin K. Animals were fed either an NIH-07 diet supplemented with menadione (3.1 ppm vitamin K3), an NIH-07 diet not supplemented with menadione, or an AIN-076 purified diet devoid of vitamin K. The retinoids had no effect on prothrombin times of animals fed the supplemented diet. When menadione was omitted from the diet, however, 4HPR-dosed animals had elevated prothrombin times. This effect was observed as early as Day 7 and was accompanied by one confirmed hemorrhagic death. 13cisRA-dosed animals showed no change in prothrombin times. In the high-dose ROAc group, there was a twofold increase in prothrombin times but only after prolonged dosing. In animals fed the NIH-07 diets, CHEMICAL and ROAc induced multiple bone fractures at all dose levels. In contrast, 4HPR administered at the highest dose induced only one fracture in one animal. Animals fed the purified diet lost weight faster and diet sooner than those maintained on the other diets. Bone fractures were not observed in these animals because of early deaths resulting from hemorrhaging. For all retinoid-dosed groups maintained on the purified diet, changes in prothrombin times occured as early as 1 week. The order of effect was 4HPR greater than ROAc greater than CHEMICAL, with increases in prothrombin times correlating with increases in hemorrhagic deaths. Hence, the degree of retinoid-induced hemorrhage, but not the incidence of bone fractures, was inversely related to vitamin K levels in the diet. CHEMICAL and ROAc, but not 4HPR, caused a dose-dependent reduction in plasma osteocalcin, an effect that correlated with retinoid-induced bone effects. In contrast, serum GENE was elevated in animals dosed with CHEMICAL or 4HPR but not in those dose with ROAc. For this enzyme, the electrophoretic pattern on agarose gel showed a decrease, compared to controls, in the major isozyme in serum of ROAc-dosed animals. Hence, plasma osteocalcin is a better predictor of retinoid-induced bone effects than serum GENE. | INDIRECT-UPREGULATOR |
| Retinoid-induced hemorrhaging and bone toxicity in rats fed diets deficient in vitamin K. The recent increase in the clinical use of synthetic vitamin A compounds has led to concern of possible side effects. Some of these effects are known to be influenced by dietary levels of vitamin K. We therefore compared the toxic effects of 13-cis-retinoic acid (13cisRA), retinyl acetate (ROAc), and N-(4-hydroxyphenyl)retinamide (4HPR) in male Sprague-Dawley rats maintained on diets containing different levels of vitamin K. Animals were fed either an NIH-07 diet supplemented with menadione (3.1 ppm vitamin K3), an NIH-07 diet not supplemented with menadione, or an AIN-076 purified diet devoid of vitamin K. The retinoids had no effect on prothrombin times of animals fed the supplemented diet. When menadione was omitted from the diet, however, 4HPR-dosed animals had elevated prothrombin times. This effect was observed as early as Day 7 and was accompanied by one confirmed hemorrhagic death. 13cisRA-dosed animals showed no change in prothrombin times. In the high-dose ROAc group, there was a twofold increase in prothrombin times but only after prolonged dosing. In animals fed the NIH-07 diets, 13cisRA and ROAc induced multiple bone fractures at all dose levels. In contrast, CHEMICAL administered at the highest dose induced only one fracture in one animal. Animals fed the purified diet lost weight faster and diet sooner than those maintained on the other diets. Bone fractures were not observed in these animals because of early deaths resulting from hemorrhaging. For all retinoid-dosed groups maintained on the purified diet, changes in prothrombin times occured as early as 1 week. The order of effect was CHEMICAL greater than ROAc greater than 13cisRA, with increases in prothrombin times correlating with increases in hemorrhagic deaths. Hence, the degree of retinoid-induced hemorrhage, but not the incidence of bone fractures, was inversely related to vitamin K levels in the diet. 13cisRA and ROAc, but not CHEMICAL, caused a dose-dependent reduction in plasma osteocalcin, an effect that correlated with retinoid-induced bone effects. In contrast, serum GENE was elevated in animals dosed with 13cisRA or CHEMICAL but not in those dose with ROAc. For this enzyme, the electrophoretic pattern on agarose gel showed a decrease, compared to controls, in the major isozyme in serum of ROAc-dosed animals. Hence, plasma osteocalcin is a better predictor of retinoid-induced bone effects than serum GENE. | INDIRECT-UPREGULATOR |
| Retinoid-induced hemorrhaging and bone toxicity in rats fed diets deficient in vitamin K. The recent increase in the clinical use of synthetic vitamin A compounds has led to concern of possible side effects. Some of these effects are known to be influenced by dietary levels of vitamin K. We therefore compared the toxic effects of 13-cis-retinoic acid (13cisRA), retinyl acetate (ROAc), and N-(4-hydroxyphenyl)retinamide (4HPR) in male Sprague-Dawley rats maintained on diets containing different levels of vitamin K. Animals were fed either an NIH-07 diet supplemented with menadione (3.1 ppm vitamin K3), an NIH-07 diet not supplemented with menadione, or an AIN-076 purified diet devoid of vitamin K. The retinoids had no effect on GENE times of animals fed the supplemented diet. When menadione was omitted from the diet, however, CHEMICAL-dosed animals had elevated GENE times. This effect was observed as early as Day 7 and was accompanied by one confirmed hemorrhagic death. 13cisRA-dosed animals showed no change in GENE times. In the high-dose ROAc group, there was a twofold increase in GENE times but only after prolonged dosing. In animals fed the NIH-07 diets, 13cisRA and ROAc induced multiple bone fractures at all dose levels. In contrast, CHEMICAL administered at the highest dose induced only one fracture in one animal. Animals fed the purified diet lost weight faster and diet sooner than those maintained on the other diets. Bone fractures were not observed in these animals because of early deaths resulting from hemorrhaging. For all retinoid-dosed groups maintained on the purified diet, changes in GENE times occured as early as 1 week. The order of effect was CHEMICAL greater than ROAc greater than 13cisRA, with increases in GENE times correlating with increases in hemorrhagic deaths. Hence, the degree of retinoid-induced hemorrhage, but not the incidence of bone fractures, was inversely related to vitamin K levels in the diet. 13cisRA and ROAc, but not CHEMICAL, caused a dose-dependent reduction in plasma osteocalcin, an effect that correlated with retinoid-induced bone effects. In contrast, serum alkaline phosphatase was elevated in animals dosed with 13cisRA or CHEMICAL but not in those dose with ROAc. For this enzyme, the electrophoretic pattern on agarose gel showed a decrease, compared to controls, in the major isozyme in serum of ROAc-dosed animals. Hence, plasma osteocalcin is a better predictor of retinoid-induced bone effects than serum alkaline phosphatase. | NO-RELATIONSHIP |
| Retinoid-induced hemorrhaging and bone toxicity in rats fed diets deficient in vitamin K. The recent increase in the clinical use of synthetic vitamin A compounds has led to concern of possible side effects. Some of these effects are known to be influenced by dietary levels of vitamin K. We therefore compared the toxic effects of 13-cis-retinoic acid (13cisRA), retinyl acetate (ROAc), and N-(4-hydroxyphenyl)retinamide (4HPR) in male Sprague-Dawley rats maintained on diets containing different levels of vitamin K. Animals were fed either an NIH-07 diet supplemented with menadione (3.1 ppm vitamin K3), an NIH-07 diet not supplemented with menadione, or an AIN-076 purified diet devoid of vitamin K. The retinoids had no effect on GENE times of animals fed the supplemented diet. When menadione was omitted from the diet, however, 4HPR-dosed animals had elevated GENE times. This effect was observed as early as Day 7 and was accompanied by one confirmed hemorrhagic death. 13cisRA-dosed animals showed no change in GENE times. In the high-dose CHEMICAL group, there was a twofold increase in GENE times but only after prolonged dosing. In animals fed the NIH-07 diets, 13cisRA and CHEMICAL induced multiple bone fractures at all dose levels. In contrast, 4HPR administered at the highest dose induced only one fracture in one animal. Animals fed the purified diet lost weight faster and diet sooner than those maintained on the other diets. Bone fractures were not observed in these animals because of early deaths resulting from hemorrhaging. For all retinoid-dosed groups maintained on the purified diet, changes in GENE times occured as early as 1 week. The order of effect was 4HPR greater than CHEMICAL greater than 13cisRA, with increases in GENE times correlating with increases in hemorrhagic deaths. Hence, the degree of retinoid-induced hemorrhage, but not the incidence of bone fractures, was inversely related to vitamin K levels in the diet. 13cisRA and CHEMICAL, but not 4HPR, caused a dose-dependent reduction in plasma osteocalcin, an effect that correlated with retinoid-induced bone effects. In contrast, serum alkaline phosphatase was elevated in animals dosed with 13cisRA or 4HPR but not in those dose with CHEMICAL. For this enzyme, the electrophoretic pattern on agarose gel showed a decrease, compared to controls, in the major isozyme in serum of ROAc-dosed animals. Hence, plasma osteocalcin is a better predictor of retinoid-induced bone effects than serum alkaline phosphatase. | NO-RELATIONSHIP |
| Retinoid-induced hemorrhaging and bone toxicity in rats fed diets deficient in vitamin K. The recent increase in the clinical use of synthetic vitamin A compounds has led to concern of possible side effects. Some of these effects are known to be influenced by dietary levels of vitamin K. We therefore compared the toxic effects of 13-cis-retinoic acid (13cisRA), retinyl acetate (ROAc), and N-(4-hydroxyphenyl)retinamide (4HPR) in male Sprague-Dawley rats maintained on diets containing different levels of vitamin K. Animals were fed either an NIH-07 diet supplemented with menadione (3.1 ppm vitamin K3), an NIH-07 diet not supplemented with menadione, or an AIN-076 purified diet devoid of vitamin K. The retinoids had no effect on prothrombin times of animals fed the supplemented diet. When menadione was omitted from the diet, however, 4HPR-dosed animals had elevated prothrombin times. This effect was observed as early as Day 7 and was accompanied by one confirmed hemorrhagic death. 13cisRA-dosed animals showed no change in prothrombin times. In the high-dose ROAc group, there was a twofold increase in prothrombin times but only after prolonged dosing. In animals fed the NIH-07 diets, CHEMICAL and ROAc induced multiple bone fractures at all dose levels. In contrast, 4HPR administered at the highest dose induced only one fracture in one animal. Animals fed the purified diet lost weight faster and diet sooner than those maintained on the other diets. Bone fractures were not observed in these animals because of early deaths resulting from hemorrhaging. For all retinoid-dosed groups maintained on the purified diet, changes in prothrombin times occured as early as 1 week. The order of effect was 4HPR greater than ROAc greater than CHEMICAL, with increases in prothrombin times correlating with increases in hemorrhagic deaths. Hence, the degree of retinoid-induced hemorrhage, but not the incidence of bone fractures, was inversely related to vitamin K levels in the diet. CHEMICAL and ROAc, but not 4HPR, caused a dose-dependent reduction in plasma GENE, an effect that correlated with retinoid-induced bone effects. In contrast, serum alkaline phosphatase was elevated in animals dosed with CHEMICAL or 4HPR but not in those dose with ROAc. For this enzyme, the electrophoretic pattern on agarose gel showed a decrease, compared to controls, in the major isozyme in serum of ROAc-dosed animals. Hence, plasma GENE is a better predictor of retinoid-induced bone effects than serum alkaline phosphatase. | INDIRECT-DOWNREGULATOR |
| Retinoid-induced hemorrhaging and bone toxicity in rats fed diets deficient in vitamin K. The recent increase in the clinical use of synthetic vitamin A compounds has led to concern of possible side effects. Some of these effects are known to be influenced by dietary levels of vitamin K. We therefore compared the toxic effects of 13-cis-retinoic acid (13cisRA), retinyl acetate (ROAc), and N-(4-hydroxyphenyl)retinamide (4HPR) in male Sprague-Dawley rats maintained on diets containing different levels of vitamin K. Animals were fed either an NIH-07 diet supplemented with menadione (3.1 ppm vitamin K3), an NIH-07 diet not supplemented with menadione, or an AIN-076 purified diet devoid of vitamin K. The retinoids had no effect on prothrombin times of animals fed the supplemented diet. When menadione was omitted from the diet, however, 4HPR-dosed animals had elevated prothrombin times. This effect was observed as early as Day 7 and was accompanied by one confirmed hemorrhagic death. 13cisRA-dosed animals showed no change in prothrombin times. In the high-dose CHEMICAL group, there was a twofold increase in prothrombin times but only after prolonged dosing. In animals fed the NIH-07 diets, 13cisRA and CHEMICAL induced multiple bone fractures at all dose levels. In contrast, 4HPR administered at the highest dose induced only one fracture in one animal. Animals fed the purified diet lost weight faster and diet sooner than those maintained on the other diets. Bone fractures were not observed in these animals because of early deaths resulting from hemorrhaging. For all retinoid-dosed groups maintained on the purified diet, changes in prothrombin times occured as early as 1 week. The order of effect was 4HPR greater than CHEMICAL greater than 13cisRA, with increases in prothrombin times correlating with increases in hemorrhagic deaths. Hence, the degree of retinoid-induced hemorrhage, but not the incidence of bone fractures, was inversely related to vitamin K levels in the diet. 13cisRA and CHEMICAL, but not 4HPR, caused a dose-dependent reduction in plasma GENE, an effect that correlated with retinoid-induced bone effects. In contrast, serum alkaline phosphatase was elevated in animals dosed with 13cisRA or 4HPR but not in those dose with CHEMICAL. For this enzyme, the electrophoretic pattern on agarose gel showed a decrease, compared to controls, in the major isozyme in serum of ROAc-dosed animals. Hence, plasma GENE is a better predictor of retinoid-induced bone effects than serum alkaline phosphatase. | INDIRECT-DOWNREGULATOR |
| Retinoid-induced hemorrhaging and bone toxicity in rats fed diets deficient in vitamin K. The recent increase in the clinical use of synthetic vitamin A compounds has led to concern of possible side effects. Some of these effects are known to be influenced by dietary levels of vitamin K. We therefore compared the toxic effects of 13-cis-retinoic acid (13cisRA), retinyl acetate (ROAc), and N-(4-hydroxyphenyl)retinamide (4HPR) in male Sprague-Dawley rats maintained on diets containing different levels of vitamin K. Animals were fed either an NIH-07 diet supplemented with menadione (3.1 ppm vitamin K3), an NIH-07 diet not supplemented with menadione, or an AIN-076 purified diet devoid of vitamin K. The retinoids had no effect on prothrombin times of animals fed the supplemented diet. When menadione was omitted from the diet, however, 4HPR-dosed animals had elevated prothrombin times. This effect was observed as early as Day 7 and was accompanied by one confirmed hemorrhagic death. 13cisRA-dosed animals showed no change in prothrombin times. In the high-dose ROAc group, there was a twofold increase in prothrombin times but only after prolonged dosing. In animals fed the NIH-07 diets, 13cisRA and ROAc induced multiple bone fractures at all dose levels. In contrast, CHEMICAL administered at the highest dose induced only one fracture in one animal. Animals fed the purified diet lost weight faster and diet sooner than those maintained on the other diets. Bone fractures were not observed in these animals because of early deaths resulting from hemorrhaging. For all retinoid-dosed groups maintained on the purified diet, changes in prothrombin times occured as early as 1 week. The order of effect was CHEMICAL greater than ROAc greater than 13cisRA, with increases in prothrombin times correlating with increases in hemorrhagic deaths. Hence, the degree of retinoid-induced hemorrhage, but not the incidence of bone fractures, was inversely related to vitamin K levels in the diet. 13cisRA and ROAc, but not CHEMICAL, caused a dose-dependent reduction in plasma GENE, an effect that correlated with retinoid-induced bone effects. In contrast, serum alkaline phosphatase was elevated in animals dosed with 13cisRA or CHEMICAL but not in those dose with ROAc. For this enzyme, the electrophoretic pattern on agarose gel showed a decrease, compared to controls, in the major isozyme in serum of ROAc-dosed animals. Hence, plasma GENE is a better predictor of retinoid-induced bone effects than serum alkaline phosphatase. | NO-RELATIONSHIP |
| Multiple affinity states of GENE in neuroblastoma x glioma NG108-15 hybrid cells. Opiate agonist association rate is a function of receptor occupancy. The existence of multiple affinity states for the GENE in neuroblastoma x glioma NG108-15 hybrid cells has been demonstrated by competition binding studies with tritiated diprenorphine and [D-Ala2, D-Leu5]enkephalin (DADLE). In the presence of 10 mM Mg2+, all receptors exist in a high affinity state with Kd = 1.88 +/- 0.16 nM. Addition of 10 microM guanyl-5'-yl imidodiphosphate (Gpp(NH)p) decreased the affinity of DADLE to Kd = 8.08 +/- 0.93 nM. However, in the presence of 100 mM Na+, which is required for opiate inhibition of adenylate cyclase activity, analysis of competition binding data revealed three sites: the first, consisting of 17.5% of total receptor population has a Kd = 0.38 +/- 0.18 nM; the second, 50.6% of the population, has a Kd = 6.8 +/- 2.2 nM; and the third, 31.9% of the population, has a Kd of 410 +/- 110 nM. Thus, in the presence of sodium, a high affinity complex between receptor (R), GTP binding component (Ni), and ligand (L) was formed which was different from that formed in the absence of sodium. These multiple affinity states of receptor in the hybrid cells are agonist-specific, and the percentage of total GENE in high affinity state is relatively constant in various concentrations of Na+. Multiple affinity states of GENE can be demonstrated further by Scatchard analysis of saturation binding studies with CHEMICAL. In the presence of Mg2+, or Gpp(NH)p, analysis of CHEMICAL binding demonstrates that GENE can exist in a single affinity state, with apparent Kd values of CHEMICAL in 10 mM Mg2+ = 1.75 +/- 0.28 nM and in 10 microM Gpp(NH)p = 0.85 +/- 0.12 nM. There is a reduction of Bmax value from 0.19 +/- 0.02 nM in the presence of Mg2+ to 0.14 +/- 0.03 nM in the presence of Gpp(NH)p. In the presence of 100 mM Na+, Scatchard analysis of saturation binding of CHEMICAL reveals nonlinear plots; two-site analysis of the curves yields Kd = 0.43 +/- 0.09 and 7.9 +/- 3.2 nM. These Kd values are analogous to that obtained with competition binding studies. Again, this conversion of single site binding Scatchard plots to multiple sites binding plots in the presence of Na+ is restricted to 3H-agonist binding only.(ABSTRACT TRUNCATED AT 400 WORDS) | DIRECT-REGULATOR |
| Multiple affinity states of GENE in neuroblastoma x glioma NG108-15 hybrid cells. Opiate agonist association rate is a function of receptor occupancy. The existence of multiple affinity states for the GENE in neuroblastoma x glioma NG108-15 hybrid cells has been demonstrated by competition binding studies with tritiated diprenorphine and [D-Ala2, D-Leu5]enkephalin (DADLE). In the presence of 10 mM Mg2+, all receptors exist in a high affinity state with Kd = 1.88 +/- 0.16 nM. Addition of 10 microM guanyl-5'-yl imidodiphosphate (Gpp(NH)p) decreased the affinity of DADLE to Kd = 8.08 +/- 0.93 nM. However, in the presence of 100 mM CHEMICAL, which is required for opiate inhibition of adenylate cyclase activity, analysis of competition binding data revealed three sites: the first, consisting of 17.5% of total receptor population has a Kd = 0.38 +/- 0.18 nM; the second, 50.6% of the population, has a Kd = 6.8 +/- 2.2 nM; and the third, 31.9% of the population, has a Kd of 410 +/- 110 nM. Thus, in the presence of sodium, a high affinity complex between receptor (R), GTP binding component (Ni), and ligand (L) was formed which was different from that formed in the absence of sodium. These multiple affinity states of receptor in the hybrid cells are agonist-specific, and the percentage of total GENE in high affinity state is relatively constant in various concentrations of CHEMICAL. Multiple affinity states of GENE can be demonstrated further by Scatchard analysis of saturation binding studies with [3H]DADLE. In the presence of Mg2+, or Gpp(NH)p, analysis of [3H]DADLE binding demonstrates that GENE can exist in a single affinity state, with apparent Kd values of [3H]DADLE in 10 mM Mg2+ = 1.75 +/- 0.28 nM and in 10 microM Gpp(NH)p = 0.85 +/- 0.12 nM. There is a reduction of Bmax value from 0.19 +/- 0.02 nM in the presence of Mg2+ to 0.14 +/- 0.03 nM in the presence of Gpp(NH)p. In the presence of 100 mM CHEMICAL, Scatchard analysis of saturation binding of [3H]DADLE reveals nonlinear plots; two-site analysis of the curves yields Kd = 0.43 +/- 0.09 and 7.9 +/- 3.2 nM. These Kd values are analogous to that obtained with competition binding studies. Again, this conversion of single site binding Scatchard plots to multiple sites binding plots in the presence of CHEMICAL is restricted to 3H-agonist binding only.(ABSTRACT TRUNCATED AT 400 WORDS) | DIRECT-REGULATOR |
| Multiple affinity states of opiate receptor in neuroblastoma x glioma NG108-15 hybrid cells. Opiate agonist association rate is a function of receptor occupancy. The existence of multiple affinity states for the opiate receptor in neuroblastoma x glioma NG108-15 hybrid cells has been demonstrated by competition binding studies with tritiated diprenorphine and [D-Ala2, D-Leu5]enkephalin (DADLE). In the presence of 10 mM Mg2+, all receptors exist in a high affinity state with Kd = 1.88 +/- 0.16 nM. Addition of 10 microM guanyl-5'-yl imidodiphosphate (Gpp(NH)p) decreased the affinity of DADLE to Kd = 8.08 +/- 0.93 nM. However, in the presence of 100 mM CHEMICAL, which is required for opiate inhibition of GENE activity, analysis of competition binding data revealed three sites: the first, consisting of 17.5% of total receptor population has a Kd = 0.38 +/- 0.18 nM; the second, 50.6% of the population, has a Kd = 6.8 +/- 2.2 nM; and the third, 31.9% of the population, has a Kd of 410 +/- 110 nM. Thus, in the presence of sodium, a high affinity complex between receptor (R), GTP binding component (Ni), and ligand (L) was formed which was different from that formed in the absence of sodium. These multiple affinity states of receptor in the hybrid cells are agonist-specific, and the percentage of total opiate receptor in high affinity state is relatively constant in various concentrations of CHEMICAL. Multiple affinity states of opiate receptor can be demonstrated further by Scatchard analysis of saturation binding studies with [3H]DADLE. In the presence of Mg2+, or Gpp(NH)p, analysis of [3H]DADLE binding demonstrates that opiate receptor can exist in a single affinity state, with apparent Kd values of [3H]DADLE in 10 mM Mg2+ = 1.75 +/- 0.28 nM and in 10 microM Gpp(NH)p = 0.85 +/- 0.12 nM. There is a reduction of Bmax value from 0.19 +/- 0.02 nM in the presence of Mg2+ to 0.14 +/- 0.03 nM in the presence of Gpp(NH)p. In the presence of 100 mM CHEMICAL, Scatchard analysis of saturation binding of [3H]DADLE reveals nonlinear plots; two-site analysis of the curves yields Kd = 0.43 +/- 0.09 and 7.9 +/- 3.2 nM. These Kd values are analogous to that obtained with competition binding studies. Again, this conversion of single site binding Scatchard plots to multiple sites binding plots in the presence of CHEMICAL is restricted to 3H-agonist binding only.(ABSTRACT TRUNCATED AT 400 WORDS) | INHIBITOR |
| Inhibition of the GENE of rat basophil leukemia cells by diethylcarbamazine, and synergism between diethylcarbamazine and CHEMICAL, a 5-lipoxygenase inhibitor. Diethylcarbamazine inhibited the formation of sulfidopeptide leukotrienes in rat basophil leukemia (RBL) cells (50% inhibitory concentration, EC50, 3 mM). Similar concentrations also inhibited the formation of leukotriene C4 (LTC4) by LTC synthetase, a detergent-solubilized cell free particulate enzyme from RBL cells which is capable of coupling LTA4 to glutathione. By contrast, the conversion of LTA4 to LTC4 using enzymes from rat liver was at least ten times less sensitive to this inhibitor. The EC50 for inhibition of the leukotriene C synthetase of RBL cells was directly proportional to the LTA4 concentration in the incubations, ranging from 1.5 mM at 10 microM LTA4 to over 40 mM at 500 microM LTA4. Kinetic analysis revealed that the inhibition of the leukotriene C synthetase reaction by diethylcarbamazine was competitive with respect to LTA4. In contrast to diethylcarbamazine, CHEMICAL (U-60,257; 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1), which inhibits the formation of sulfidopeptide leuktrienes in RBL cells at the 5-lipoxygenase step (EC50 5 microM), did not inhibit the GENE of these cells. On the other hand, low concentrations of CHEMICAL, which had no demonstrable inhibitory activity on leukotriene formation by themselves, markedly synergized the inhibitory activity of diethylcarbamazine. These results are consistent with the interpretation that both CHEMICAL and diethylcarbamazine inhibit leukotriene formation but that they act on sequential steps in the biosynthetic pathway in such a manner as to synergistically interfere with the availability or utilization of LTA4 in the leukotriene C synthetase reaction. | NO-RELATIONSHIP |
| Inhibition of the GENE of rat basophil leukemia cells by diethylcarbamazine, and synergism between diethylcarbamazine and piriprost, a 5-lipoxygenase inhibitor. Diethylcarbamazine inhibited the formation of sulfidopeptide leukotrienes in rat basophil leukemia (RBL) cells (50% inhibitory concentration, EC50, 3 mM). Similar concentrations also inhibited the formation of leukotriene C4 (LTC4) by LTC synthetase, a detergent-solubilized cell free particulate enzyme from RBL cells which is capable of coupling LTA4 to glutathione. By contrast, the conversion of LTA4 to LTC4 using enzymes from rat liver was at least ten times less sensitive to this inhibitor. The EC50 for inhibition of the leukotriene C synthetase of RBL cells was directly proportional to the LTA4 concentration in the incubations, ranging from 1.5 mM at 10 microM LTA4 to over 40 mM at 500 microM LTA4. Kinetic analysis revealed that the inhibition of the leukotriene C synthetase reaction by diethylcarbamazine was competitive with respect to LTA4. In contrast to diethylcarbamazine, piriprost (CHEMICAL; 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1), which inhibits the formation of sulfidopeptide leuktrienes in RBL cells at the 5-lipoxygenase step (EC50 5 microM), did not inhibit the GENE of these cells. On the other hand, low concentrations of piriprost, which had no demonstrable inhibitory activity on leukotriene formation by themselves, markedly synergized the inhibitory activity of diethylcarbamazine. These results are consistent with the interpretation that both piriprost and diethylcarbamazine inhibit leukotriene formation but that they act on sequential steps in the biosynthetic pathway in such a manner as to synergistically interfere with the availability or utilization of LTA4 in the leukotriene C synthetase reaction. | NO-RELATIONSHIP |
| Inhibition of the GENE of rat basophil leukemia cells by diethylcarbamazine, and synergism between diethylcarbamazine and piriprost, a 5-lipoxygenase inhibitor. Diethylcarbamazine inhibited the formation of sulfidopeptide leukotrienes in rat basophil leukemia (RBL) cells (50% inhibitory concentration, EC50, 3 mM). Similar concentrations also inhibited the formation of leukotriene C4 (LTC4) by LTC synthetase, a detergent-solubilized cell free particulate enzyme from RBL cells which is capable of coupling LTA4 to glutathione. By contrast, the conversion of LTA4 to LTC4 using enzymes from rat liver was at least ten times less sensitive to this inhibitor. The EC50 for inhibition of the leukotriene C synthetase of RBL cells was directly proportional to the LTA4 concentration in the incubations, ranging from 1.5 mM at 10 microM LTA4 to over 40 mM at 500 microM LTA4. Kinetic analysis revealed that the inhibition of the leukotriene C synthetase reaction by diethylcarbamazine was competitive with respect to LTA4. In contrast to diethylcarbamazine, piriprost (U-60,257; CHEMICAL), which inhibits the formation of sulfidopeptide leuktrienes in RBL cells at the 5-lipoxygenase step (EC50 5 microM), did not inhibit the GENE of these cells. On the other hand, low concentrations of piriprost, which had no demonstrable inhibitory activity on leukotriene formation by themselves, markedly synergized the inhibitory activity of diethylcarbamazine. These results are consistent with the interpretation that both piriprost and diethylcarbamazine inhibit leukotriene formation but that they act on sequential steps in the biosynthetic pathway in such a manner as to synergistically interfere with the availability or utilization of LTA4 in the leukotriene C synthetase reaction. | NO-RELATIONSHIP |
| Inhibition of the leukotriene synthetase of rat basophil leukemia cells by diethylcarbamazine, and synergism between diethylcarbamazine and piriprost, a 5-lipoxygenase inhibitor. Diethylcarbamazine inhibited the formation of sulfidopeptide leukotrienes in rat basophil leukemia (RBL) cells (50% inhibitory concentration, EC50, 3 mM). Similar concentrations also inhibited the formation of leukotriene C4 (LTC4) by LTC synthetase, a detergent-solubilized cell free particulate enzyme from RBL cells which is capable of coupling CHEMICAL to glutathione. By contrast, the conversion of CHEMICAL to LTC4 using enzymes from rat liver was at least ten times less sensitive to this inhibitor. The EC50 for inhibition of the GENE of RBL cells was directly proportional to the CHEMICAL concentration in the incubations, ranging from 1.5 mM at 10 microM CHEMICAL to over 40 mM at 500 microM CHEMICAL. Kinetic analysis revealed that the inhibition of the GENE reaction by diethylcarbamazine was competitive with respect to CHEMICAL. In contrast to diethylcarbamazine, piriprost (U-60,257; 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1), which inhibits the formation of sulfidopeptide leuktrienes in RBL cells at the 5-lipoxygenase step (EC50 5 microM), did not inhibit the leukotriene synthetase of these cells. On the other hand, low concentrations of piriprost, which had no demonstrable inhibitory activity on leukotriene formation by themselves, markedly synergized the inhibitory activity of diethylcarbamazine. These results are consistent with the interpretation that both piriprost and diethylcarbamazine inhibit leukotriene formation but that they act on sequential steps in the biosynthetic pathway in such a manner as to synergistically interfere with the availability or utilization of CHEMICAL in the GENE reaction. | GENE-CHEMICAL |
| Inhibition of the leukotriene synthetase of rat basophil leukemia cells by CHEMICAL, and synergism between CHEMICAL and piriprost, a 5-lipoxygenase inhibitor. CHEMICAL inhibited the formation of sulfidopeptide leukotrienes in rat basophil leukemia (RBL) cells (50% inhibitory concentration, EC50, 3 mM). Similar concentrations also inhibited the formation of leukotriene C4 (LTC4) by LTC synthetase, a detergent-solubilized cell free particulate enzyme from RBL cells which is capable of coupling LTA4 to glutathione. By contrast, the conversion of LTA4 to LTC4 using enzymes from rat liver was at least ten times less sensitive to this inhibitor. The EC50 for inhibition of the GENE of RBL cells was directly proportional to the LTA4 concentration in the incubations, ranging from 1.5 mM at 10 microM LTA4 to over 40 mM at 500 microM LTA4. Kinetic analysis revealed that the inhibition of the GENE reaction by CHEMICAL was competitive with respect to LTA4. In contrast to CHEMICAL, piriprost (U-60,257; 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1), which inhibits the formation of sulfidopeptide leuktrienes in RBL cells at the 5-lipoxygenase step (EC50 5 microM), did not inhibit the leukotriene synthetase of these cells. On the other hand, low concentrations of piriprost, which had no demonstrable inhibitory activity on leukotriene formation by themselves, markedly synergized the inhibitory activity of CHEMICAL. These results are consistent with the interpretation that both piriprost and CHEMICAL inhibit leukotriene formation but that they act on sequential steps in the biosynthetic pathway in such a manner as to synergistically interfere with the availability or utilization of LTA4 in the GENE reaction. | GENE-CHEMICAL |
| Inhibition of the leukotriene synthetase of rat basophil leukemia cells by CHEMICAL, and synergism between CHEMICAL and piriprost, a GENE inhibitor. CHEMICAL inhibited the formation of sulfidopeptide leukotrienes in rat basophil leukemia (RBL) cells (50% inhibitory concentration, EC50, 3 mM). Similar concentrations also inhibited the formation of leukotriene C4 (LTC4) by LTC synthetase, a detergent-solubilized cell free particulate enzyme from RBL cells which is capable of coupling LTA4 to glutathione. By contrast, the conversion of LTA4 to LTC4 using enzymes from rat liver was at least ten times less sensitive to this inhibitor. The EC50 for inhibition of the leukotriene C synthetase of RBL cells was directly proportional to the LTA4 concentration in the incubations, ranging from 1.5 mM at 10 microM LTA4 to over 40 mM at 500 microM LTA4. Kinetic analysis revealed that the inhibition of the leukotriene C synthetase reaction by CHEMICAL was competitive with respect to LTA4. In contrast to CHEMICAL, piriprost (U-60,257; 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1), which inhibits the formation of sulfidopeptide leuktrienes in RBL cells at the GENE step (EC50 5 microM), did not inhibit the leukotriene synthetase of these cells. On the other hand, low concentrations of piriprost, which had no demonstrable inhibitory activity on leukotriene formation by themselves, markedly synergized the inhibitory activity of CHEMICAL. These results are consistent with the interpretation that both piriprost and CHEMICAL inhibit leukotriene formation but that they act on sequential steps in the biosynthetic pathway in such a manner as to synergistically interfere with the availability or utilization of LTA4 in the leukotriene C synthetase reaction. | INHIBITOR |
| Inhibition of the GENE of rat basophil leukemia cells by CHEMICAL, and synergism between CHEMICAL and piriprost, a 5-lipoxygenase inhibitor. CHEMICAL inhibited the formation of sulfidopeptide leukotrienes in rat basophil leukemia (RBL) cells (50% inhibitory concentration, EC50, 3 mM). Similar concentrations also inhibited the formation of leukotriene C4 (LTC4) by LTC synthetase, a detergent-solubilized cell free particulate enzyme from RBL cells which is capable of coupling LTA4 to glutathione. By contrast, the conversion of LTA4 to LTC4 using enzymes from rat liver was at least ten times less sensitive to this inhibitor. The EC50 for inhibition of the leukotriene C synthetase of RBL cells was directly proportional to the LTA4 concentration in the incubations, ranging from 1.5 mM at 10 microM LTA4 to over 40 mM at 500 microM LTA4. Kinetic analysis revealed that the inhibition of the leukotriene C synthetase reaction by CHEMICAL was competitive with respect to LTA4. In contrast to CHEMICAL, piriprost (U-60,257; 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1), which inhibits the formation of sulfidopeptide leuktrienes in RBL cells at the 5-lipoxygenase step (EC50 5 microM), did not inhibit the GENE of these cells. On the other hand, low concentrations of piriprost, which had no demonstrable inhibitory activity on leukotriene formation by themselves, markedly synergized the inhibitory activity of CHEMICAL. These results are consistent with the interpretation that both piriprost and CHEMICAL inhibit leukotriene formation but that they act on sequential steps in the biosynthetic pathway in such a manner as to synergistically interfere with the availability or utilization of LTA4 in the leukotriene C synthetase reaction. | NO-RELATIONSHIP |
| Inhibition of the leukotriene synthetase of rat basophil leukemia cells by diethylcarbamazine, and synergism between diethylcarbamazine and CHEMICAL, a GENE inhibitor. Diethylcarbamazine inhibited the formation of sulfidopeptide leukotrienes in rat basophil leukemia (RBL) cells (50% inhibitory concentration, EC50, 3 mM). Similar concentrations also inhibited the formation of leukotriene C4 (LTC4) by LTC synthetase, a detergent-solubilized cell free particulate enzyme from RBL cells which is capable of coupling LTA4 to glutathione. By contrast, the conversion of LTA4 to LTC4 using enzymes from rat liver was at least ten times less sensitive to this inhibitor. The EC50 for inhibition of the leukotriene C synthetase of RBL cells was directly proportional to the LTA4 concentration in the incubations, ranging from 1.5 mM at 10 microM LTA4 to over 40 mM at 500 microM LTA4. Kinetic analysis revealed that the inhibition of the leukotriene C synthetase reaction by diethylcarbamazine was competitive with respect to LTA4. In contrast to diethylcarbamazine, CHEMICAL (U-60,257; 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1), which inhibits the formation of sulfidopeptide leuktrienes in RBL cells at the GENE step (EC50 5 microM), did not inhibit the leukotriene synthetase of these cells. On the other hand, low concentrations of CHEMICAL, which had no demonstrable inhibitory activity on leukotriene formation by themselves, markedly synergized the inhibitory activity of diethylcarbamazine. These results are consistent with the interpretation that both CHEMICAL and diethylcarbamazine inhibit leukotriene formation but that they act on sequential steps in the biosynthetic pathway in such a manner as to synergistically interfere with the availability or utilization of LTA4 in the leukotriene C synthetase reaction. | INHIBITOR |
| Inhibition of the leukotriene synthetase of rat basophil leukemia cells by diethylcarbamazine, and synergism between diethylcarbamazine and piriprost, a GENE inhibitor. Diethylcarbamazine inhibited the formation of sulfidopeptide leukotrienes in rat basophil leukemia (RBL) cells (50% inhibitory concentration, EC50, 3 mM). Similar concentrations also inhibited the formation of leukotriene C4 (LTC4) by LTC synthetase, a detergent-solubilized cell free particulate enzyme from RBL cells which is capable of coupling LTA4 to glutathione. By contrast, the conversion of LTA4 to LTC4 using enzymes from rat liver was at least ten times less sensitive to this inhibitor. The EC50 for inhibition of the leukotriene C synthetase of RBL cells was directly proportional to the LTA4 concentration in the incubations, ranging from 1.5 mM at 10 microM LTA4 to over 40 mM at 500 microM LTA4. Kinetic analysis revealed that the inhibition of the leukotriene C synthetase reaction by diethylcarbamazine was competitive with respect to LTA4. In contrast to diethylcarbamazine, piriprost (CHEMICAL; 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1), which inhibits the formation of sulfidopeptide leuktrienes in RBL cells at the GENE step (EC50 5 microM), did not inhibit the leukotriene synthetase of these cells. On the other hand, low concentrations of piriprost, which had no demonstrable inhibitory activity on leukotriene formation by themselves, markedly synergized the inhibitory activity of diethylcarbamazine. These results are consistent with the interpretation that both piriprost and diethylcarbamazine inhibit leukotriene formation but that they act on sequential steps in the biosynthetic pathway in such a manner as to synergistically interfere with the availability or utilization of LTA4 in the leukotriene C synthetase reaction. | INHIBITOR |
| Inhibition of the leukotriene synthetase of rat basophil leukemia cells by diethylcarbamazine, and synergism between diethylcarbamazine and piriprost, a GENE inhibitor. Diethylcarbamazine inhibited the formation of sulfidopeptide leukotrienes in rat basophil leukemia (RBL) cells (50% inhibitory concentration, EC50, 3 mM). Similar concentrations also inhibited the formation of leukotriene C4 (LTC4) by LTC synthetase, a detergent-solubilized cell free particulate enzyme from RBL cells which is capable of coupling LTA4 to glutathione. By contrast, the conversion of LTA4 to LTC4 using enzymes from rat liver was at least ten times less sensitive to this inhibitor. The EC50 for inhibition of the leukotriene C synthetase of RBL cells was directly proportional to the LTA4 concentration in the incubations, ranging from 1.5 mM at 10 microM LTA4 to over 40 mM at 500 microM LTA4. Kinetic analysis revealed that the inhibition of the leukotriene C synthetase reaction by diethylcarbamazine was competitive with respect to LTA4. In contrast to diethylcarbamazine, piriprost (U-60,257; CHEMICAL), which inhibits the formation of sulfidopeptide leuktrienes in RBL cells at the GENE step (EC50 5 microM), did not inhibit the leukotriene synthetase of these cells. On the other hand, low concentrations of piriprost, which had no demonstrable inhibitory activity on leukotriene formation by themselves, markedly synergized the inhibitory activity of diethylcarbamazine. These results are consistent with the interpretation that both piriprost and diethylcarbamazine inhibit leukotriene formation but that they act on sequential steps in the biosynthetic pathway in such a manner as to synergistically interfere with the availability or utilization of LTA4 in the leukotriene C synthetase reaction. | INHIBITOR |
| Inhibition of the leukotriene synthetase of rat basophil leukemia cells by diethylcarbamazine, and synergism between diethylcarbamazine and piriprost, a 5-lipoxygenase inhibitor. Diethylcarbamazine inhibited the formation of sulfidopeptide leukotrienes in rat basophil leukemia (RBL) cells (50% inhibitory concentration, EC50, 3 mM). Similar concentrations also inhibited the formation of CHEMICAL (LTC4) by GENE, a detergent-solubilized cell free particulate enzyme from RBL cells which is capable of coupling LTA4 to glutathione. By contrast, the conversion of LTA4 to LTC4 using enzymes from rat liver was at least ten times less sensitive to this inhibitor. The EC50 for inhibition of the leukotriene C synthetase of RBL cells was directly proportional to the LTA4 concentration in the incubations, ranging from 1.5 mM at 10 microM LTA4 to over 40 mM at 500 microM LTA4. Kinetic analysis revealed that the inhibition of the leukotriene C synthetase reaction by diethylcarbamazine was competitive with respect to LTA4. In contrast to diethylcarbamazine, piriprost (U-60,257; 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1), which inhibits the formation of sulfidopeptide leuktrienes in RBL cells at the 5-lipoxygenase step (EC50 5 microM), did not inhibit the leukotriene synthetase of these cells. On the other hand, low concentrations of piriprost, which had no demonstrable inhibitory activity on leukotriene formation by themselves, markedly synergized the inhibitory activity of diethylcarbamazine. These results are consistent with the interpretation that both piriprost and diethylcarbamazine inhibit leukotriene formation but that they act on sequential steps in the biosynthetic pathway in such a manner as to synergistically interfere with the availability or utilization of LTA4 in the leukotriene C synthetase reaction. | PRODUCT-OF |
| Inhibition of the leukotriene synthetase of rat basophil leukemia cells by diethylcarbamazine, and synergism between diethylcarbamazine and piriprost, a 5-lipoxygenase inhibitor. Diethylcarbamazine inhibited the formation of sulfidopeptide leukotrienes in rat basophil leukemia (RBL) cells (50% inhibitory concentration, EC50, 3 mM). Similar concentrations also inhibited the formation of leukotriene C4 (CHEMICAL) by GENE, a detergent-solubilized cell free particulate enzyme from RBL cells which is capable of coupling LTA4 to glutathione. By contrast, the conversion of LTA4 to CHEMICAL using enzymes from rat liver was at least ten times less sensitive to this inhibitor. The EC50 for inhibition of the leukotriene C synthetase of RBL cells was directly proportional to the LTA4 concentration in the incubations, ranging from 1.5 mM at 10 microM LTA4 to over 40 mM at 500 microM LTA4. Kinetic analysis revealed that the inhibition of the leukotriene C synthetase reaction by diethylcarbamazine was competitive with respect to LTA4. In contrast to diethylcarbamazine, piriprost (U-60,257; 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1), which inhibits the formation of sulfidopeptide leuktrienes in RBL cells at the 5-lipoxygenase step (EC50 5 microM), did not inhibit the leukotriene synthetase of these cells. On the other hand, low concentrations of piriprost, which had no demonstrable inhibitory activity on leukotriene formation by themselves, markedly synergized the inhibitory activity of diethylcarbamazine. These results are consistent with the interpretation that both piriprost and diethylcarbamazine inhibit leukotriene formation but that they act on sequential steps in the biosynthetic pathway in such a manner as to synergistically interfere with the availability or utilization of LTA4 in the leukotriene C synthetase reaction. | PRODUCT-OF |
| Inhibition of the leukotriene synthetase of rat basophil leukemia cells by diethylcarbamazine, and synergism between diethylcarbamazine and piriprost, a GENE inhibitor. Diethylcarbamazine inhibited the formation of sulfidopeptide leukotrienes in rat basophil leukemia (RBL) cells (50% inhibitory concentration, EC50, 3 mM). Similar concentrations also inhibited the formation of leukotriene C4 (LTC4) by LTC synthetase, a detergent-solubilized cell free particulate enzyme from RBL cells which is capable of coupling LTA4 to glutathione. By contrast, the conversion of LTA4 to LTC4 using enzymes from rat liver was at least ten times less sensitive to this inhibitor. The EC50 for inhibition of the leukotriene C synthetase of RBL cells was directly proportional to the LTA4 concentration in the incubations, ranging from 1.5 mM at 10 microM LTA4 to over 40 mM at 500 microM LTA4. Kinetic analysis revealed that the inhibition of the leukotriene C synthetase reaction by diethylcarbamazine was competitive with respect to LTA4. In contrast to diethylcarbamazine, piriprost (U-60,257; 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1), which inhibits the formation of CHEMICAL in RBL cells at the GENE step (EC50 5 microM), did not inhibit the leukotriene synthetase of these cells. On the other hand, low concentrations of piriprost, which had no demonstrable inhibitory activity on leukotriene formation by themselves, markedly synergized the inhibitory activity of diethylcarbamazine. These results are consistent with the interpretation that both piriprost and diethylcarbamazine inhibit leukotriene formation but that they act on sequential steps in the biosynthetic pathway in such a manner as to synergistically interfere with the availability or utilization of LTA4 in the leukotriene C synthetase reaction. | PRODUCT-OF |
| Inhibition of the leukotriene synthetase of rat basophil leukemia cells by diethylcarbamazine, and synergism between diethylcarbamazine and piriprost, a 5-lipoxygenase inhibitor. Diethylcarbamazine inhibited the formation of sulfidopeptide leukotrienes in rat basophil leukemia (RBL) cells (50% inhibitory concentration, EC50, 3 mM). Similar concentrations also inhibited the formation of leukotriene C4 (LTC4) by GENE, a detergent-solubilized cell free particulate enzyme from RBL cells which is capable of coupling CHEMICAL to glutathione. By contrast, the conversion of CHEMICAL to LTC4 using enzymes from rat liver was at least ten times less sensitive to this inhibitor. The EC50 for inhibition of the leukotriene C synthetase of RBL cells was directly proportional to the CHEMICAL concentration in the incubations, ranging from 1.5 mM at 10 microM CHEMICAL to over 40 mM at 500 microM CHEMICAL. Kinetic analysis revealed that the inhibition of the leukotriene C synthetase reaction by diethylcarbamazine was competitive with respect to CHEMICAL. In contrast to diethylcarbamazine, piriprost (U-60,257; 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1), which inhibits the formation of sulfidopeptide leuktrienes in RBL cells at the 5-lipoxygenase step (EC50 5 microM), did not inhibit the leukotriene synthetase of these cells. On the other hand, low concentrations of piriprost, which had no demonstrable inhibitory activity on leukotriene formation by themselves, markedly synergized the inhibitory activity of diethylcarbamazine. These results are consistent with the interpretation that both piriprost and diethylcarbamazine inhibit leukotriene formation but that they act on sequential steps in the biosynthetic pathway in such a manner as to synergistically interfere with the availability or utilization of CHEMICAL in the leukotriene C synthetase reaction. | INHIBITOR |
| Intestinal permeability and CHEMICAL hydrolysis in human rotaviral gastroenteritis assessed simultaneously by non-invasive differential sugar permeation. Changes in intestinal permeability and CHEMICAL hydrolysis have been investigated in three adults and fifteen infants with acute rotaviral gastroenteritis by differential sugar absorption. The method involves chromatographic measurement of urinary CHEMICAL, lactulose and L-rhamnose excretion following combined ingestion in an iso-osmolar test solution. All patients had abnormal intestinal permeability indicated by raised urine lactulose/L-rhamnose excretion, ratio of percentages recovered in 5 h, of 0.462 (0.100-1.227) mean and range, compared with 0.027 (0.008-0.052) for healthy controls (P less than 0.001). Ten patients also had urinary lactose/lactulose excretion ratios raised above the normal range (0.014-0.41, mean 0.258) during their acute illness, indicating impaired intestinal CHEMICAL hydrolysis. Both indices had become normal 4 weeks after the acute illness, serial investigation of five patients showing that improvement was complete much earlier. Except for the short duration these changes are similar to those associated with villous atrophy in coeliac disease. The test procedure was verified with respect to intestinal CHEMICAL hydrolysis by demonstrating a linear relationship between lactose/lactulose excretion and log jejunal mucosal GENE activity by in vitro assay (R2 = 0.95) in a further group of subjects. Differential lactose/lactulose/L-rhamnose absorption provides a non-invasive and sensitive index of small intestinal integrity of value for the interpretation of prolonged or otherwise complicated enteritis and the distinction of primary secondary intestinal GENE deficiency. | SUBSTRATE |
| Intestinal permeability and lactose hydrolysis in human rotaviral gastroenteritis assessed simultaneously by non-invasive differential sugar permeation. Changes in intestinal permeability and lactose hydrolysis have been investigated in three adults and fifteen infants with acute rotaviral gastroenteritis by differential sugar absorption. The method involves chromatographic measurement of urinary lactose, CHEMICAL and L-rhamnose excretion following combined ingestion in an iso-osmolar test solution. All patients had abnormal intestinal permeability indicated by raised urine lactulose/L-rhamnose excretion, ratio of percentages recovered in 5 h, of 0.462 (0.100-1.227) mean and range, compared with 0.027 (0.008-0.052) for healthy controls (P less than 0.001). Ten patients also had urinary lactose/lactulose excretion ratios raised above the normal range (0.014-0.41, mean 0.258) during their acute illness, indicating impaired intestinal lactose hydrolysis. Both indices had become normal 4 weeks after the acute illness, serial investigation of five patients showing that improvement was complete much earlier. Except for the short duration these changes are similar to those associated with villous atrophy in coeliac disease. The test procedure was verified with respect to intestinal lactose hydrolysis by demonstrating a linear relationship between lactose/CHEMICAL excretion and log jejunal mucosal GENE activity by in vitro assay (R2 = 0.95) in a further group of subjects. Differential lactose/lactulose/L-rhamnose absorption provides a non-invasive and sensitive index of small intestinal integrity of value for the interpretation of prolonged or otherwise complicated enteritis and the distinction of primary secondary intestinal GENE deficiency. | GENE-CHEMICAL |
| Intestinal permeability and lactose hydrolysis in human rotaviral gastroenteritis assessed simultaneously by non-invasive differential sugar permeation. Changes in intestinal permeability and lactose hydrolysis have been investigated in three adults and fifteen infants with acute rotaviral gastroenteritis by differential sugar absorption. The method involves chromatographic measurement of urinary lactose, lactulose and CHEMICAL excretion following combined ingestion in an iso-osmolar test solution. All patients had abnormal intestinal permeability indicated by raised urine lactulose/L-rhamnose excretion, ratio of percentages recovered in 5 h, of 0.462 (0.100-1.227) mean and range, compared with 0.027 (0.008-0.052) for healthy controls (P less than 0.001). Ten patients also had urinary lactose/lactulose excretion ratios raised above the normal range (0.014-0.41, mean 0.258) during their acute illness, indicating impaired intestinal lactose hydrolysis. Both indices had become normal 4 weeks after the acute illness, serial investigation of five patients showing that improvement was complete much earlier. Except for the short duration these changes are similar to those associated with villous atrophy in coeliac disease. The test procedure was verified with respect to intestinal lactose hydrolysis by demonstrating a linear relationship between lactose/lactulose excretion and log jejunal mucosal GENE activity by in vitro assay (R2 = 0.95) in a further group of subjects. Differential lactose/lactulose/CHEMICAL absorption provides a non-invasive and sensitive index of small intestinal integrity of value for the interpretation of prolonged or otherwise complicated enteritis and the distinction of primary secondary intestinal GENE deficiency. | SUBSTRATE |
| Characteristics of the binding of phenoxybenzamine to GENE. To determine the factors that influence the interaction between phenoxybenzamine and GENE, the binding of phenoxybenzamine to GENE was determined by equilibrium dialysis under a variety of experimental conditions. This interaction was found to be similar in some respects to the interaction between phenothiazines and GENE. It was saturable, with between 1 and 2 mol of phenoxybenzamine bound to 1 mol of GENE. It was also dependent upon temperature, the presence of a divalent cation such as calcium, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0. The site at which phenoxybenzamine bound to GENE appears to be similar to that at which certain antipsychotic agents bind, since several of them, including penfluridol, pimozide and spiroperidol, prevented the binding of phenoxybenzamine to GENE. However, in contrast to the reversible binding of most phenothiazines to GENE, phenoxybenzamine bound to GENE irreversibly. The binding of phenoxybenzamine to GENE was fairly selective in that other alpha-adrenergic agents such as CHEMICAL, yohimbine and clonidine failed to bind to GENE when examined under the same experimental conditions. In addition, phenoxybenzamine showed little or no calcium-dependent binding to the S-100 protein, bovine serum albumin or cytochrome c. The irreversible complex between phenoxybenzamine and GENE may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of GENE. | NO-RELATIONSHIP |
| Characteristics of the binding of phenoxybenzamine to GENE. To determine the factors that influence the interaction between phenoxybenzamine and GENE, the binding of phenoxybenzamine to GENE was determined by equilibrium dialysis under a variety of experimental conditions. This interaction was found to be similar in some respects to the interaction between phenothiazines and GENE. It was saturable, with between 1 and 2 mol of phenoxybenzamine bound to 1 mol of GENE. It was also dependent upon temperature, the presence of a divalent cation such as calcium, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0. The site at which phenoxybenzamine bound to GENE appears to be similar to that at which certain antipsychotic agents bind, since several of them, including penfluridol, pimozide and spiroperidol, prevented the binding of phenoxybenzamine to GENE. However, in contrast to the reversible binding of most phenothiazines to GENE, phenoxybenzamine bound to GENE irreversibly. The binding of phenoxybenzamine to GENE was fairly selective in that other alpha-adrenergic agents such as prazosin, CHEMICAL and clonidine failed to bind to GENE when examined under the same experimental conditions. In addition, phenoxybenzamine showed little or no calcium-dependent binding to the S-100 protein, bovine serum albumin or cytochrome c. The irreversible complex between phenoxybenzamine and GENE may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of GENE. | NO-RELATIONSHIP |
| Characteristics of the binding of phenoxybenzamine to GENE. To determine the factors that influence the interaction between phenoxybenzamine and GENE, the binding of phenoxybenzamine to GENE was determined by equilibrium dialysis under a variety of experimental conditions. This interaction was found to be similar in some respects to the interaction between phenothiazines and GENE. It was saturable, with between 1 and 2 mol of phenoxybenzamine bound to 1 mol of GENE. It was also dependent upon temperature, the presence of a divalent cation such as calcium, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0. The site at which phenoxybenzamine bound to GENE appears to be similar to that at which certain antipsychotic agents bind, since several of them, including penfluridol, pimozide and spiroperidol, prevented the binding of phenoxybenzamine to GENE. However, in contrast to the reversible binding of most phenothiazines to GENE, phenoxybenzamine bound to GENE irreversibly. The binding of phenoxybenzamine to GENE was fairly selective in that other alpha-adrenergic agents such as prazosin, yohimbine and CHEMICAL failed to bind to GENE when examined under the same experimental conditions. In addition, phenoxybenzamine showed little or no calcium-dependent binding to the S-100 protein, bovine serum albumin or cytochrome c. The irreversible complex between phenoxybenzamine and GENE may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of GENE. | NO-RELATIONSHIP |
| Characteristics of the binding of CHEMICAL to calmodulin. To determine the factors that influence the interaction between CHEMICAL and calmodulin, the binding of CHEMICAL to calmodulin was determined by equilibrium dialysis under a variety of experimental conditions. This interaction was found to be similar in some respects to the interaction between phenothiazines and calmodulin. It was saturable, with between 1 and 2 mol of CHEMICAL bound to 1 mol of calmodulin. It was also dependent upon temperature, the presence of a divalent cation such as calcium, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0. The site at which CHEMICAL bound to calmodulin appears to be similar to that at which certain antipsychotic agents bind, since several of them, including penfluridol, pimozide and spiroperidol, prevented the binding of CHEMICAL to calmodulin. However, in contrast to the reversible binding of most phenothiazines to calmodulin, CHEMICAL bound to calmodulin irreversibly. The binding of CHEMICAL to calmodulin was fairly selective in that other alpha-adrenergic agents such as prazosin, yohimbine and clonidine failed to bind to calmodulin when examined under the same experimental conditions. In addition, CHEMICAL showed little or no calcium-dependent binding to the GENE, bovine serum albumin or cytochrome c. The irreversible complex between CHEMICAL and calmodulin may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of calmodulin. | NO-RELATIONSHIP |
| Characteristics of the binding of CHEMICAL to calmodulin. To determine the factors that influence the interaction between CHEMICAL and calmodulin, the binding of CHEMICAL to calmodulin was determined by equilibrium dialysis under a variety of experimental conditions. This interaction was found to be similar in some respects to the interaction between phenothiazines and calmodulin. It was saturable, with between 1 and 2 mol of CHEMICAL bound to 1 mol of calmodulin. It was also dependent upon temperature, the presence of a divalent cation such as calcium, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0. The site at which CHEMICAL bound to calmodulin appears to be similar to that at which certain antipsychotic agents bind, since several of them, including penfluridol, pimozide and spiroperidol, prevented the binding of CHEMICAL to calmodulin. However, in contrast to the reversible binding of most phenothiazines to calmodulin, CHEMICAL bound to calmodulin irreversibly. The binding of CHEMICAL to calmodulin was fairly selective in that other alpha-adrenergic agents such as prazosin, yohimbine and clonidine failed to bind to calmodulin when examined under the same experimental conditions. In addition, CHEMICAL showed little or no calcium-dependent binding to the S-100 protein, GENE or cytochrome c. The irreversible complex between CHEMICAL and calmodulin may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of calmodulin. | NO-RELATIONSHIP |
| Characteristics of the binding of CHEMICAL to calmodulin. To determine the factors that influence the interaction between CHEMICAL and calmodulin, the binding of CHEMICAL to calmodulin was determined by equilibrium dialysis under a variety of experimental conditions. This interaction was found to be similar in some respects to the interaction between phenothiazines and calmodulin. It was saturable, with between 1 and 2 mol of CHEMICAL bound to 1 mol of calmodulin. It was also dependent upon temperature, the presence of a divalent cation such as calcium, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0. The site at which CHEMICAL bound to calmodulin appears to be similar to that at which certain antipsychotic agents bind, since several of them, including penfluridol, pimozide and spiroperidol, prevented the binding of CHEMICAL to calmodulin. However, in contrast to the reversible binding of most phenothiazines to calmodulin, CHEMICAL bound to calmodulin irreversibly. The binding of CHEMICAL to calmodulin was fairly selective in that other alpha-adrenergic agents such as prazosin, yohimbine and clonidine failed to bind to calmodulin when examined under the same experimental conditions. In addition, CHEMICAL showed little or no calcium-dependent binding to the S-100 protein, bovine serum albumin or GENE. The irreversible complex between CHEMICAL and calmodulin may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of calmodulin. | NO-RELATIONSHIP |
| Characteristics of the binding of CHEMICAL to GENE. To determine the factors that influence the interaction between CHEMICAL and GENE, the binding of CHEMICAL to GENE was determined by equilibrium dialysis under a variety of experimental conditions. This interaction was found to be similar in some respects to the interaction between phenothiazines and GENE. It was saturable, with between 1 and 2 mol of CHEMICAL bound to 1 mol of GENE. It was also dependent upon temperature, the presence of a divalent cation such as calcium, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0. The site at which CHEMICAL bound to GENE appears to be similar to that at which certain antipsychotic agents bind, since several of them, including penfluridol, pimozide and spiroperidol, prevented the binding of CHEMICAL to GENE. However, in contrast to the reversible binding of most phenothiazines to GENE, CHEMICAL bound to GENE irreversibly. The binding of CHEMICAL to GENE was fairly selective in that other alpha-adrenergic agents such as prazosin, yohimbine and clonidine failed to bind to GENE when examined under the same experimental conditions. In addition, CHEMICAL showed little or no calcium-dependent binding to the S-100 protein, bovine serum albumin or cytochrome c. The irreversible complex between CHEMICAL and GENE may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of GENE. | DIRECT-REGULATOR |
| Characteristics of the binding of phenoxybenzamine to GENE. To determine the factors that influence the interaction between phenoxybenzamine and GENE, the binding of phenoxybenzamine to GENE was determined by equilibrium dialysis under a variety of experimental conditions. This interaction was found to be similar in some respects to the interaction between phenothiazines and GENE. It was saturable, with between 1 and 2 mol of phenoxybenzamine bound to 1 mol of GENE. It was also dependent upon temperature, the presence of a divalent cation such as calcium, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0. The site at which phenoxybenzamine bound to GENE appears to be similar to that at which certain antipsychotic agents bind, since several of them, including CHEMICAL, pimozide and spiroperidol, prevented the binding of phenoxybenzamine to GENE. However, in contrast to the reversible binding of most phenothiazines to GENE, phenoxybenzamine bound to GENE irreversibly. The binding of phenoxybenzamine to GENE was fairly selective in that other alpha-adrenergic agents such as prazosin, yohimbine and clonidine failed to bind to GENE when examined under the same experimental conditions. In addition, phenoxybenzamine showed little or no calcium-dependent binding to the S-100 protein, bovine serum albumin or cytochrome c. The irreversible complex between phenoxybenzamine and GENE may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of GENE. | DIRECT-REGULATOR |
| Characteristics of the binding of phenoxybenzamine to GENE. To determine the factors that influence the interaction between phenoxybenzamine and GENE, the binding of phenoxybenzamine to GENE was determined by equilibrium dialysis under a variety of experimental conditions. This interaction was found to be similar in some respects to the interaction between phenothiazines and GENE. It was saturable, with between 1 and 2 mol of phenoxybenzamine bound to 1 mol of GENE. It was also dependent upon temperature, the presence of a divalent cation such as calcium, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0. The site at which phenoxybenzamine bound to GENE appears to be similar to that at which certain antipsychotic agents bind, since several of them, including penfluridol, CHEMICAL and spiroperidol, prevented the binding of phenoxybenzamine to GENE. However, in contrast to the reversible binding of most phenothiazines to GENE, phenoxybenzamine bound to GENE irreversibly. The binding of phenoxybenzamine to GENE was fairly selective in that other alpha-adrenergic agents such as prazosin, yohimbine and clonidine failed to bind to GENE when examined under the same experimental conditions. In addition, phenoxybenzamine showed little or no calcium-dependent binding to the S-100 protein, bovine serum albumin or cytochrome c. The irreversible complex between phenoxybenzamine and GENE may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of GENE. | DIRECT-REGULATOR |
| Characteristics of the binding of phenoxybenzamine to GENE. To determine the factors that influence the interaction between phenoxybenzamine and GENE, the binding of phenoxybenzamine to GENE was determined by equilibrium dialysis under a variety of experimental conditions. This interaction was found to be similar in some respects to the interaction between phenothiazines and GENE. It was saturable, with between 1 and 2 mol of phenoxybenzamine bound to 1 mol of GENE. It was also dependent upon temperature, the presence of a divalent cation such as calcium, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0. The site at which phenoxybenzamine bound to GENE appears to be similar to that at which certain antipsychotic agents bind, since several of them, including penfluridol, pimozide and CHEMICAL, prevented the binding of phenoxybenzamine to GENE. However, in contrast to the reversible binding of most phenothiazines to GENE, phenoxybenzamine bound to GENE irreversibly. The binding of phenoxybenzamine to GENE was fairly selective in that other alpha-adrenergic agents such as prazosin, yohimbine and clonidine failed to bind to GENE when examined under the same experimental conditions. In addition, phenoxybenzamine showed little or no calcium-dependent binding to the S-100 protein, bovine serum albumin or cytochrome c. The irreversible complex between phenoxybenzamine and GENE may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of GENE. | DIRECT-REGULATOR |
| Characteristics of the binding of phenoxybenzamine to GENE. To determine the factors that influence the interaction between phenoxybenzamine and GENE, the binding of phenoxybenzamine to GENE was determined by equilibrium dialysis under a variety of experimental conditions. This interaction was found to be similar in some respects to the interaction between CHEMICAL and GENE. It was saturable, with between 1 and 2 mol of phenoxybenzamine bound to 1 mol of GENE. It was also dependent upon temperature, the presence of a divalent cation such as calcium, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0. The site at which phenoxybenzamine bound to GENE appears to be similar to that at which certain antipsychotic agents bind, since several of them, including penfluridol, pimozide and spiroperidol, prevented the binding of phenoxybenzamine to GENE. However, in contrast to the reversible binding of most CHEMICAL to GENE, phenoxybenzamine bound to GENE irreversibly. The binding of phenoxybenzamine to GENE was fairly selective in that other alpha-adrenergic agents such as prazosin, yohimbine and clonidine failed to bind to GENE when examined under the same experimental conditions. In addition, phenoxybenzamine showed little or no calcium-dependent binding to the S-100 protein, bovine serum albumin or cytochrome c. The irreversible complex between phenoxybenzamine and GENE may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of GENE. | DIRECT-REGULATOR |
| Characteristics of the binding of phenoxybenzamine to calmodulin. To determine the factors that influence the interaction between phenoxybenzamine and calmodulin, the binding of phenoxybenzamine to calmodulin was determined by equilibrium dialysis under a variety of experimental conditions. This interaction was found to be similar in some respects to the interaction between phenothiazines and calmodulin. It was saturable, with between 1 and 2 mol of phenoxybenzamine bound to 1 mol of calmodulin. It was also dependent upon temperature, the presence of a divalent cation such as CHEMICAL, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0. The site at which phenoxybenzamine bound to calmodulin appears to be similar to that at which certain antipsychotic agents bind, since several of them, including penfluridol, pimozide and spiroperidol, prevented the binding of phenoxybenzamine to calmodulin. However, in contrast to the reversible binding of most phenothiazines to calmodulin, phenoxybenzamine bound to calmodulin irreversibly. The binding of phenoxybenzamine to calmodulin was fairly selective in that other alpha-adrenergic agents such as prazosin, yohimbine and clonidine failed to bind to calmodulin when examined under the same experimental conditions. In addition, phenoxybenzamine showed little or no CHEMICAL-dependent binding to the S-100 protein, bovine serum albumin or GENE. The irreversible complex between phenoxybenzamine and calmodulin may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of calmodulin. | DIRECT-REGULATOR |
| Characteristics of the binding of phenoxybenzamine to calmodulin. To determine the factors that influence the interaction between phenoxybenzamine and calmodulin, the binding of phenoxybenzamine to calmodulin was determined by equilibrium dialysis under a variety of experimental conditions. This interaction was found to be similar in some respects to the interaction between phenothiazines and calmodulin. It was saturable, with between 1 and 2 mol of phenoxybenzamine bound to 1 mol of calmodulin. It was also dependent upon temperature, the presence of a divalent cation such as calcium, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0. The site at which phenoxybenzamine bound to calmodulin appears to be similar to that at which certain antipsychotic agents bind, since several of them, including penfluridol, pimozide and spiroperidol, prevented the binding of phenoxybenzamine to calmodulin. However, in contrast to the reversible binding of most phenothiazines to calmodulin, phenoxybenzamine bound to calmodulin irreversibly. The binding of phenoxybenzamine to calmodulin was fairly selective in that other GENE agents such as CHEMICAL, yohimbine and clonidine failed to bind to calmodulin when examined under the same experimental conditions. In addition, phenoxybenzamine showed little or no calcium-dependent binding to the S-100 protein, bovine serum albumin or cytochrome c. The irreversible complex between phenoxybenzamine and calmodulin may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of calmodulin. | INHIBITOR |
| Characteristics of the binding of phenoxybenzamine to calmodulin. To determine the factors that influence the interaction between phenoxybenzamine and calmodulin, the binding of phenoxybenzamine to calmodulin was determined by equilibrium dialysis under a variety of experimental conditions. This interaction was found to be similar in some respects to the interaction between phenothiazines and calmodulin. It was saturable, with between 1 and 2 mol of phenoxybenzamine bound to 1 mol of calmodulin. It was also dependent upon temperature, the presence of a divalent cation such as calcium, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0. The site at which phenoxybenzamine bound to calmodulin appears to be similar to that at which certain antipsychotic agents bind, since several of them, including penfluridol, pimozide and spiroperidol, prevented the binding of phenoxybenzamine to calmodulin. However, in contrast to the reversible binding of most phenothiazines to calmodulin, phenoxybenzamine bound to calmodulin irreversibly. The binding of phenoxybenzamine to calmodulin was fairly selective in that other GENE agents such as prazosin, CHEMICAL and clonidine failed to bind to calmodulin when examined under the same experimental conditions. In addition, phenoxybenzamine showed little or no calcium-dependent binding to the S-100 protein, bovine serum albumin or cytochrome c. The irreversible complex between phenoxybenzamine and calmodulin may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of calmodulin. | DIRECT-REGULATOR |
| Characteristics of the binding of phenoxybenzamine to calmodulin. To determine the factors that influence the interaction between phenoxybenzamine and calmodulin, the binding of phenoxybenzamine to calmodulin was determined by equilibrium dialysis under a variety of experimental conditions. This interaction was found to be similar in some respects to the interaction between phenothiazines and calmodulin. It was saturable, with between 1 and 2 mol of phenoxybenzamine bound to 1 mol of calmodulin. It was also dependent upon temperature, the presence of a divalent cation such as calcium, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0. The site at which phenoxybenzamine bound to calmodulin appears to be similar to that at which certain antipsychotic agents bind, since several of them, including penfluridol, pimozide and spiroperidol, prevented the binding of phenoxybenzamine to calmodulin. However, in contrast to the reversible binding of most phenothiazines to calmodulin, phenoxybenzamine bound to calmodulin irreversibly. The binding of phenoxybenzamine to calmodulin was fairly selective in that other GENE agents such as prazosin, yohimbine and CHEMICAL failed to bind to calmodulin when examined under the same experimental conditions. In addition, phenoxybenzamine showed little or no calcium-dependent binding to the S-100 protein, bovine serum albumin or cytochrome c. The irreversible complex between phenoxybenzamine and calmodulin may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of calmodulin. | DIRECT-REGULATOR |
| Characteristics of the binding of phenoxybenzamine to calmodulin. To determine the factors that influence the interaction between phenoxybenzamine and calmodulin, the binding of phenoxybenzamine to calmodulin was determined by equilibrium dialysis under a variety of experimental conditions. This interaction was found to be similar in some respects to the interaction between phenothiazines and calmodulin. It was saturable, with between 1 and 2 mol of phenoxybenzamine bound to 1 mol of calmodulin. It was also dependent upon temperature, the presence of a divalent cation such as CHEMICAL, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0. The site at which phenoxybenzamine bound to calmodulin appears to be similar to that at which certain antipsychotic agents bind, since several of them, including penfluridol, pimozide and spiroperidol, prevented the binding of phenoxybenzamine to calmodulin. However, in contrast to the reversible binding of most phenothiazines to calmodulin, phenoxybenzamine bound to calmodulin irreversibly. The binding of phenoxybenzamine to calmodulin was fairly selective in that other alpha-adrenergic agents such as prazosin, yohimbine and clonidine failed to bind to calmodulin when examined under the same experimental conditions. In addition, phenoxybenzamine showed little or no CHEMICAL-dependent binding to the GENE, bovine serum albumin or cytochrome c. The irreversible complex between phenoxybenzamine and calmodulin may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of calmodulin. | DIRECT-REGULATOR |
| Characteristics of the binding of phenoxybenzamine to calmodulin. To determine the factors that influence the interaction between phenoxybenzamine and calmodulin, the binding of phenoxybenzamine to calmodulin was determined by equilibrium dialysis under a variety of experimental conditions. This interaction was found to be similar in some respects to the interaction between phenothiazines and calmodulin. It was saturable, with between 1 and 2 mol of phenoxybenzamine bound to 1 mol of calmodulin. It was also dependent upon temperature, the presence of a divalent cation such as CHEMICAL, and on pH, showing maximum binding at pH 6.5 with little binding at pH values below 4.2 or above 8.0. The site at which phenoxybenzamine bound to calmodulin appears to be similar to that at which certain antipsychotic agents bind, since several of them, including penfluridol, pimozide and spiroperidol, prevented the binding of phenoxybenzamine to calmodulin. However, in contrast to the reversible binding of most phenothiazines to calmodulin, phenoxybenzamine bound to calmodulin irreversibly. The binding of phenoxybenzamine to calmodulin was fairly selective in that other alpha-adrenergic agents such as prazosin, yohimbine and clonidine failed to bind to calmodulin when examined under the same experimental conditions. In addition, phenoxybenzamine showed little or no CHEMICAL-dependent binding to the S-100 protein, GENE or cytochrome c. The irreversible complex between phenoxybenzamine and calmodulin may be useful for inhibiting certain calmodulin-dependent reactions and for studying the various biological functions of calmodulin. | DIRECT-REGULATOR |
| Pharmacological and clinical studies of the antiandrogen CHEMICAL. This paper summarizes the animal and human studies with CHEMICAL available at the time of the meeting. The following was demonstrated in the rat and confirmed in man: interaction of CHEMICAL with the GENE, antiandrogen activity against testosterone (in particular against the early transient rise induced by LHRH analogs) and adrenal androgens. Thus, as shown in 4 different double blind studies performed in stage D2 prostrate cancer patients, the combination of CHEMICAL with surgical or chemical castration enhanced the beneficial effects of castration alone and thus seems a step forward in the hormonal treatment of prostatic carcinoma. | REGULATOR |
| Adenosine receptors: development of selective agonists and antagonists. Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while GENE mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the N6-substituted compounds are more potent at GENE than at A2 receptors. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for GENE. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 and A2 receptors. Replacement of the methyl groups of theophylline with CHEMICAL or larger alkyl groups yields xanthines with selectivity for GENE, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors. | REGULATOR |
| Adenosine receptors: development of selective agonists and antagonists. Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while GENE mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the N6-substituted compounds are more potent at GENE than at A2 receptors. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for GENE. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 and A2 receptors. Replacement of the methyl groups of theophylline with n-propyl or larger CHEMICAL groups yields xanthines with selectivity for GENE, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors. | PART-OF |
| Adenosine receptors: development of selective agonists and antagonists. Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while GENE mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the N6-substituted compounds are more potent at GENE than at A2 receptors. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for GENE. CHEMICAL are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 and A2 receptors. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields CHEMICAL with selectivity for GENE, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl CHEMICAL are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors. | REGULATOR |
| Adenosine receptors: development of selective agonists and antagonists. Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while GENE mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the N6-substituted compounds are more potent at GENE than at A2 receptors. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for GENE. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 and A2 receptors. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for GENE, particularly when combined with an CHEMICAL moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors. | REGULATOR |
| Adenosine receptors: development of selective agonists and antagonists. Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, GENE mediate vasodilation and reduction in blood pressure, while A1 receptors mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the N6-substituted compounds are more potent at A1 receptors than at GENE. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and GENE, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for A1 receptors. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. CHEMICAL and theophylline are virtually non-selective for A2 and GENE. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for A1 receptors, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of CHEMICAL in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for GENE. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors. | REGULATOR |
| Adenosine receptors: development of selective agonists and antagonists. Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, GENE mediate vasodilation and reduction in blood pressure, while A1 receptors mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the N6-substituted compounds are more potent at A1 receptors than at GENE. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and GENE, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for A1 receptors. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 and GENE. Replacement of the CHEMICAL groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for A1 receptors, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the CHEMICAL group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for GENE. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors. | REGULATOR |
| Adenosine receptors: development of selective agonists and antagonists. Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, GENE mediate vasodilation and reduction in blood pressure, while A1 receptors mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the N6-substituted compounds are more potent at A1 receptors than at GENE. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and GENE, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for A1 receptors. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 and GENE. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for A1 receptors, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or CHEMICAL group display selectivity for GENE. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors. | REGULATOR |
| CHEMICAL receptors: development of selective agonists and antagonists. CHEMICAL modulates a variety of physiological functions through interaction with A1 and A2 CHEMICAL receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while A1 receptors mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. CHEMICAL analogs in particular the N6-substituted compounds are more potent at A1 receptors than at A2 receptors. The subregion of the CHEMICAL receptor that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the CHEMICAL conjugates are highly selective for A1 receptors. Xanthines are classical antagonists for CHEMICAL receptors for many of their pharmacological actions may be due to blockade of CHEMICAL receptors. Caffeine and theophylline are virtually non-selective for A2 and A2 receptors. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for A1 receptors, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of CHEMICAL analogs or of xanthine antagonists can be used to define the nature of GENE. | REGULATOR |
| Adenosine receptors: development of selective agonists and antagonists. Adenosine modulates a variety of physiological functions through interaction with A1 and A2 GENE, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while A1 receptors mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the N6-substituted compounds are more potent at A1 receptors than at A2 receptors. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for A1 receptors. Xanthines are classical antagonists for GENE for many of their pharmacological actions may be due to blockade of GENE. Caffeine and theophylline are virtually non-selective for A2 and A2 receptors. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for A1 receptors, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of adenosine analogs or of CHEMICAL antagonists can be used to define the nature of GENE. | INHIBITOR |
| CHEMICAL receptors: development of selective agonists and antagonists. CHEMICAL modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while GENE mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. CHEMICAL analogs in particular the N6-substituted compounds are more potent at GENE than at A2 receptors. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for GENE. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 and A2 receptors. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for GENE, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors. | REGULATOR |
| CHEMICAL receptors: development of selective agonists and antagonists. CHEMICAL modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, GENE mediate vasodilation and reduction in blood pressure, while A1 receptors mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. CHEMICAL analogs in particular the N6-substituted compounds are more potent at A1 receptors than at GENE. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and GENE, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for A1 receptors. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 and GENE. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for A1 receptors, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for GENE. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors. | REGULATOR |
| Adenosine receptors: development of selective agonists and antagonists. Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while GENE mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the CHEMICAL-substituted compounds are more potent at GENE than at A2 receptors. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for GENE. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 and A2 receptors. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for GENE, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors. | REGULATOR |
| Adenosine receptors: development of selective agonists and antagonists. Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, GENE mediate vasodilation and reduction in blood pressure, while A1 receptors mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the CHEMICAL-substituted compounds are more potent at A1 receptors than at GENE. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and GENE, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for A1 receptors. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 and GENE. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for A1 receptors, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for GENE. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors. | REGULATOR |
| Adenosine receptors: development of selective agonists and antagonists. Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while A1 receptors mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the N6-substituted compounds are more potent at A1 receptors than at A2 receptors. The subregion of the GENE that interacts with the CHEMICAL-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for A1 receptors. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 and A2 receptors. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for A1 receptors, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors. | PART-OF |
| Adenosine receptors: development of selective agonists and antagonists. Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while A1 receptors mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the N6-substituted compounds are more potent at A1 receptors than at A2 receptors. The subregion of the GENE that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to CHEMICAL interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for A1 receptors. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 and A2 receptors. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for A1 receptors, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors. | DIRECT-REGULATOR |
| Adenosine receptors: development of selective agonists and antagonists. Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while GENE mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the N6-substituted compounds are more potent at GENE than at A2 receptors. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for GENE. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and theophylline are virtually non-selective for A2 and A2 receptors. Replacement of the CHEMICAL groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for GENE, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the CHEMICAL group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors. | REGULATOR |
| Adenosine receptors: development of selective agonists and antagonists. Adenosine modulates a variety of physiological functions through interaction with A1 and A2 adenosine receptors, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while GENE mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the N6-substituted compounds are more potent at GENE than at A2 receptors. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for GENE. Xanthines are classical antagonists for adenosine receptors for many of their pharmacological actions may be due to blockade of adenosine receptors. Caffeine and CHEMICAL are virtually non-selective for A2 and A2 receptors. Replacement of the methyl groups of CHEMICAL with n-propyl or larger alkyl groups yields xanthines with selectivity for GENE, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of adenosine receptors. | REGULATOR |
| Adenosine receptors: development of selective agonists and antagonists. Adenosine modulates a variety of physiological functions through interaction with A1 and A2 GENE, where agonists mediate inhibition and stimulation, respectively, of adenylate cyclase. In the cardiovascular system, A2 receptors mediate vasodilation and reduction in blood pressure, while A1 receptors mediate cardiac depression. The involvement of adenylate cyclase in these responses remains unresolved. Adenosine analogs in particular the N6-substituted compounds are more potent at A1 receptors than at A2 receptors. The subregion of the adenosine receptor that interacts with the N6-substituent is different for A1 and A2 receptors, particularly with respect to phenyl interactions, bulk tolerance and stereoselectivity. A series of para-substituted N6-phenyladenosines have been synthesized based on a "functionalized congener" approach in which a chemically reactive group, such as an amine or carboxylic acid, is introduced at the terminus of a chain. From the "functionalized congener" are synthesized a variety of conjugates each containing a common pharmacophore. Certain of the adenosine conjugates are highly selective for A1 receptors. CHEMICAL are classical antagonists for GENE for many of their pharmacological actions may be due to blockade of GENE. Caffeine and theophylline are virtually non-selective for A2 and A2 receptors. Replacement of the methyl groups of theophylline with n-propyl or larger alkyl groups yields xanthines with selectivity for A1 receptors, particularly when combined with an 8-phenyl moiety. Most 1,3-dialkyl-8-phenyl xanthines are very insoluble, but incorporation of polar aryl substituents, such as sulfo or carboxy to increase solubility, results in marked reduction in potency and selectivity. A new series of more hydrophilic 1,3-dipropyl-8-phenylxanthines has been synthesized using the "functionalized congener" approach. Certain conjugates of 8-[4-(carboxymethyloxy)phenyl 1]1,3-dipropylxanthine display A1 selectivity in biochemical and cardiovascular models. Certain analogs of caffeine in which the methyl group at the 1- or 7-position is replaced with a propargyl or propyl group display selectivity for A2 receptors. The profile of a series of adenosine analogs or of xanthine antagonists can be used to define the nature of GENE. | INHIBITOR |
| Inhibition of testicular LDH-X from laboratory animals and man by CHEMICAL and its isomers. The inhibitory effect of (+)-, (-)-, (+/-)-gossypol and (+/-)-gossypol acetic acid upon testicular cytosolic LDH-X was measured in vitro. CHEMICAL acetic acid (0-100 mumol/l) inhibited LDH-X prepared from the testes of the mouse greater than rabbit greater than human greater than rat greater than hamster. There was no relationship between inhibition and in-vivo antifertility activity. LDH activity measured in vitro in serum of men and hamsters was unaffected by CHEMICAL. CHEMICAL and its isomers were non-competitive inhibitors of GENE with respect to the coenzyme NADH, competitive inhibitors of human LDH-X and noncompetitive-competitive inhibitors of hamster LDH-X with respect to the substrate alpha-ketobutyrate. Co-incubation with human serum albumin or poly-L-lysine but not lysine protected GENE from CHEMICAL. | INHIBITOR |
| Inhibition of testicular LDH-X from laboratory animals and man by gossypol and its isomers. The inhibitory effect of (+)-, (-)-, (+/-)-gossypol and (+/-)-gossypol acetic acid upon testicular cytosolic LDH-X was measured in vitro. Gossypol acetic acid (0-100 mumol/l) inhibited LDH-X prepared from the testes of the mouse greater than rabbit greater than human greater than rat greater than hamster. There was no relationship between inhibition and in-vivo antifertility activity. LDH activity measured in vitro in serum of men and hamsters was unaffected by gossypol. Gossypol and its isomers were non-competitive inhibitors of GENE with respect to the coenzyme NADH, competitive inhibitors of human LDH-X and noncompetitive-competitive inhibitors of hamster LDH-X with respect to the substrate alpha-ketobutyrate. Co-incubation with human serum albumin or poly-L-lysine but not CHEMICAL protected GENE from gossypol. | NO-RELATIONSHIP |
| Inhibition of testicular LDH-X from laboratory animals and man by gossypol and its isomers. The inhibitory effect of (+)-, (-)-, (+/-)-gossypol and (+/-)-gossypol acetic acid upon testicular cytosolic LDH-X was measured in vitro. Gossypol acetic acid (0-100 mumol/l) inhibited LDH-X prepared from the testes of the mouse greater than rabbit greater than human greater than rat greater than hamster. There was no relationship between inhibition and in-vivo antifertility activity. LDH activity measured in vitro in serum of men and hamsters was unaffected by gossypol. Gossypol and its isomers were non-competitive inhibitors of GENE with respect to the coenzyme NADH, competitive inhibitors of human LDH-X and noncompetitive-competitive inhibitors of hamster LDH-X with respect to the substrate alpha-ketobutyrate. Co-incubation with human serum albumin or CHEMICAL but not lysine protected GENE from gossypol. | NO-RELATIONSHIP |
| Inhibition of testicular GENE from laboratory animals and man by CHEMICAL and its isomers. The inhibitory effect of (+)-, (-)-, (+/-)-gossypol and (+/-)-gossypol acetic acid upon testicular cytosolic GENE was measured in vitro. CHEMICAL acetic acid (0-100 mumol/l) inhibited GENE prepared from the testes of the mouse greater than rabbit greater than human greater than rat greater than hamster. There was no relationship between inhibition and in-vivo antifertility activity. LDH activity measured in vitro in serum of men and hamsters was unaffected by CHEMICAL. CHEMICAL and its isomers were non-competitive inhibitors of human and hamster GENE with respect to the coenzyme NADH, competitive inhibitors of human GENE and noncompetitive-competitive inhibitors of hamster GENE with respect to the substrate alpha-ketobutyrate. Co-incubation with human serum albumin or poly-L-lysine but not lysine protected human and hamster GENE from CHEMICAL. | INHIBITOR |
| Inhibition of testicular GENE from laboratory animals and man by gossypol and its isomers. The inhibitory effect of (+)-, (-)-, (+/-)-gossypol and (+/-)-gossypol acetic acid upon testicular cytosolic GENE was measured in vitro. CHEMICAL (0-100 mumol/l) inhibited GENE prepared from the testes of the mouse greater than rabbit greater than human greater than rat greater than hamster. There was no relationship between inhibition and in-vivo antifertility activity. LDH activity measured in vitro in serum of men and hamsters was unaffected by gossypol. Gossypol and its isomers were non-competitive inhibitors of human and hamster GENE with respect to the coenzyme NADH, competitive inhibitors of human GENE and noncompetitive-competitive inhibitors of hamster GENE with respect to the substrate alpha-ketobutyrate. Co-incubation with human serum albumin or poly-L-lysine but not lysine protected human and hamster GENE from gossypol. | INHIBITOR |
| Inhibition of testicular GENE from laboratory animals and man by gossypol and its isomers. The inhibitory effect of CHEMICAL and (+/-)-gossypol acetic acid upon testicular cytosolic GENE was measured in vitro. Gossypol acetic acid (0-100 mumol/l) inhibited GENE prepared from the testes of the mouse greater than rabbit greater than human greater than rat greater than hamster. There was no relationship between inhibition and in-vivo antifertility activity. LDH activity measured in vitro in serum of men and hamsters was unaffected by gossypol. Gossypol and its isomers were non-competitive inhibitors of human and hamster GENE with respect to the coenzyme NADH, competitive inhibitors of human GENE and noncompetitive-competitive inhibitors of hamster GENE with respect to the substrate alpha-ketobutyrate. Co-incubation with human serum albumin or poly-L-lysine but not lysine protected human and hamster GENE from gossypol. | INHIBITOR |
| Inhibition of testicular GENE from laboratory animals and man by gossypol and its isomers. The inhibitory effect of (+)-, (-)-, (+/-)-gossypol and CHEMICAL upon testicular cytosolic GENE was measured in vitro. Gossypol acetic acid (0-100 mumol/l) inhibited GENE prepared from the testes of the mouse greater than rabbit greater than human greater than rat greater than hamster. There was no relationship between inhibition and in-vivo antifertility activity. LDH activity measured in vitro in serum of men and hamsters was unaffected by gossypol. Gossypol and its isomers were non-competitive inhibitors of human and hamster GENE with respect to the coenzyme NADH, competitive inhibitors of human GENE and noncompetitive-competitive inhibitors of hamster GENE with respect to the substrate alpha-ketobutyrate. Co-incubation with human serum albumin or poly-L-lysine but not lysine protected human and hamster GENE from gossypol. | INHIBITOR |
| Inhibition of testicular LDH-X from laboratory animals and man by gossypol and its isomers. The inhibitory effect of (+)-, (-)-, (+/-)-gossypol and (+/-)-gossypol acetic acid upon testicular cytosolic LDH-X was measured in vitro. Gossypol acetic acid (0-100 mumol/l) inhibited LDH-X prepared from the testes of the mouse greater than rabbit greater than human greater than rat greater than hamster. There was no relationship between inhibition and in-vivo antifertility activity. LDH activity measured in vitro in serum of men and hamsters was unaffected by gossypol. Gossypol and its isomers were non-competitive inhibitors of human and hamster LDH-X with respect to the coenzyme CHEMICAL, competitive inhibitors of GENE and noncompetitive-competitive inhibitors of hamster LDH-X with respect to the substrate alpha-ketobutyrate. Co-incubation with human serum albumin or poly-L-lysine but not lysine protected human and hamster LDH-X from gossypol. | INHIBITOR |
| Inhibition of testicular LDH-X from laboratory animals and man by gossypol and its isomers. The inhibitory effect of (+)-, (-)-, (+/-)-gossypol and (+/-)-gossypol acetic acid upon testicular cytosolic LDH-X was measured in vitro. Gossypol acetic acid (0-100 mumol/l) inhibited LDH-X prepared from the testes of the mouse greater than rabbit greater than human greater than rat greater than hamster. There was no relationship between inhibition and in-vivo antifertility activity. LDH activity measured in vitro in serum of men and hamsters was unaffected by gossypol. Gossypol and its isomers were non-competitive inhibitors of human and GENE with respect to the coenzyme NADH, competitive inhibitors of human LDH-X and noncompetitive-competitive inhibitors of GENE with respect to the substrate CHEMICAL. Co-incubation with human serum albumin or poly-L-lysine but not lysine protected human and GENE from gossypol. | SUBSTRATE |
| Inactivation of prostaglandin H synthase and prostacyclin synthase by phenylbutazone. Requirement for peroxidative metabolism. Phenylbutazone (PB), a nonsteroidal anti-inflammatory drug, is an efficient reducing cofactor for the peroxidase activity of prostaglandin H synthase (PHS). Most reducing cofactors for the peroxidase protect GENE and prostacyclin synthase from inactivation by CHEMICAL. PB, however, does not protect these enzymes, but rather augments their hydroperoxide-dependent inactivation. Using ram seminal vesicle microsomes as a source of GENE and prostacyclin synthase, we have examined the interaction of PB and exogenous CHEMICAL. Chromatographic analysis of the metabolism of 14C-labeled arachidonic acid in this system revealed that PB-dependent inactivation of GENE is markedly increased in the presence of 100 microM H2O2. This inactivation is a linear function of PB concentration between 10 and 250 microM, with a half-maximal effect in this range at about 100 microM PB. Prostacyclin synthase is even more sensitive to inactivation by the combined PB and H2O2 treatment, with a corresponding half-maximal effect at PB concentrations near 25 microM. This PB- and H2O2-dependent inactivation is demonstrable whether PGH2 is generated in situ from arachidonic acid or is added exogenously, supporting a direct effect of the treatment on prostacyclin synthase. As PB undergoes peroxide-dependent co-oxygenation catalyzed by GENE, we propose that it is an oxygenated derivative of PB, rather than the parent compound, which is responsible for the inactivation of GENE and prostacyclin synthase. Nafazatrom, a competitive inhibitor of PB co-oxygenation, blocks the effects of the PB and H2O2 treatment, supporting our proposal. | INHIBITOR |
| Inactivation of prostaglandin H synthase and GENE by phenylbutazone. Requirement for peroxidative metabolism. Phenylbutazone (PB), a nonsteroidal anti-inflammatory drug, is an efficient reducing cofactor for the peroxidase activity of prostaglandin H synthase (PHS). Most reducing cofactors for the peroxidase protect PHS and GENE from inactivation by CHEMICAL. PB, however, does not protect these enzymes, but rather augments their hydroperoxide-dependent inactivation. Using ram seminal vesicle microsomes as a source of PHS and GENE, we have examined the interaction of PB and exogenous CHEMICAL. Chromatographic analysis of the metabolism of 14C-labeled arachidonic acid in this system revealed that PB-dependent inactivation of PHS is markedly increased in the presence of 100 microM H2O2. This inactivation is a linear function of PB concentration between 10 and 250 microM, with a half-maximal effect in this range at about 100 microM PB. GENE is even more sensitive to inactivation by the combined PB and H2O2 treatment, with a corresponding half-maximal effect at PB concentrations near 25 microM. This PB- and H2O2-dependent inactivation is demonstrable whether PGH2 is generated in situ from arachidonic acid or is added exogenously, supporting a direct effect of the treatment on GENE. As PB undergoes peroxide-dependent co-oxygenation catalyzed by PHS, we propose that it is an oxygenated derivative of PB, rather than the parent compound, which is responsible for the inactivation of PHS and GENE. Nafazatrom, a competitive inhibitor of PB co-oxygenation, blocks the effects of the PB and H2O2 treatment, supporting our proposal. | INHIBITOR |
| Inactivation of prostaglandin H synthase and prostacyclin synthase by phenylbutazone. Requirement for peroxidative metabolism. Phenylbutazone (PB), a nonsteroidal anti-inflammatory drug, is an efficient reducing cofactor for the peroxidase activity of prostaglandin H synthase (PHS). Most reducing cofactors for the peroxidase protect GENE and prostacyclin synthase from inactivation by hydroperoxides. PB, however, does not protect these enzymes, but rather augments their hydroperoxide-dependent inactivation. Using ram seminal vesicle microsomes as a source of GENE and prostacyclin synthase, we have examined the interaction of PB and exogenous hydroperoxides. Chromatographic analysis of the metabolism of 14C-labeled arachidonic acid in this system revealed that PB-dependent inactivation of GENE is markedly increased in the presence of 100 microM CHEMICAL. This inactivation is a linear function of PB concentration between 10 and 250 microM, with a half-maximal effect in this range at about 100 microM PB. Prostacyclin synthase is even more sensitive to inactivation by the combined PB and CHEMICAL treatment, with a corresponding half-maximal effect at PB concentrations near 25 microM. This PB- and H2O2-dependent inactivation is demonstrable whether PGH2 is generated in situ from arachidonic acid or is added exogenously, supporting a direct effect of the treatment on prostacyclin synthase. As PB undergoes peroxide-dependent co-oxygenation catalyzed by GENE, we propose that it is an oxygenated derivative of PB, rather than the parent compound, which is responsible for the inactivation of GENE and prostacyclin synthase. Nafazatrom, a competitive inhibitor of PB co-oxygenation, blocks the effects of the PB and CHEMICAL treatment, supporting our proposal. | INHIBITOR |
| Inactivation of GENE and prostacyclin synthase by CHEMICAL. Requirement for peroxidative metabolism. CHEMICAL (PB), a nonsteroidal anti-inflammatory drug, is an efficient reducing cofactor for the peroxidase activity of GENE (PHS). Most reducing cofactors for the peroxidase protect PHS and prostacyclin synthase from inactivation by hydroperoxides. PB, however, does not protect these enzymes, but rather augments their hydroperoxide-dependent inactivation. Using ram seminal vesicle microsomes as a source of PHS and prostacyclin synthase, we have examined the interaction of PB and exogenous hydroperoxides. Chromatographic analysis of the metabolism of 14C-labeled arachidonic acid in this system revealed that PB-dependent inactivation of PHS is markedly increased in the presence of 100 microM H2O2. This inactivation is a linear function of PB concentration between 10 and 250 microM, with a half-maximal effect in this range at about 100 microM PB. Prostacyclin synthase is even more sensitive to inactivation by the combined PB and H2O2 treatment, with a corresponding half-maximal effect at PB concentrations near 25 microM. This PB- and H2O2-dependent inactivation is demonstrable whether PGH2 is generated in situ from arachidonic acid or is added exogenously, supporting a direct effect of the treatment on prostacyclin synthase. As PB undergoes peroxide-dependent co-oxygenation catalyzed by PHS, we propose that it is an oxygenated derivative of PB, rather than the parent compound, which is responsible for the inactivation of PHS and prostacyclin synthase. Nafazatrom, a competitive inhibitor of PB co-oxygenation, blocks the effects of the PB and H2O2 treatment, supporting our proposal. | GENE-CHEMICAL |
| Inactivation of prostaglandin H synthase and GENE by CHEMICAL. Requirement for peroxidative metabolism. CHEMICAL (PB), a nonsteroidal anti-inflammatory drug, is an efficient reducing cofactor for the peroxidase activity of prostaglandin H synthase (PHS). Most reducing cofactors for the peroxidase protect PHS and GENE from inactivation by hydroperoxides. PB, however, does not protect these enzymes, but rather augments their hydroperoxide-dependent inactivation. Using ram seminal vesicle microsomes as a source of PHS and GENE, we have examined the interaction of PB and exogenous hydroperoxides. Chromatographic analysis of the metabolism of 14C-labeled arachidonic acid in this system revealed that PB-dependent inactivation of PHS is markedly increased in the presence of 100 microM H2O2. This inactivation is a linear function of PB concentration between 10 and 250 microM, with a half-maximal effect in this range at about 100 microM PB. GENE is even more sensitive to inactivation by the combined PB and H2O2 treatment, with a corresponding half-maximal effect at PB concentrations near 25 microM. This PB- and H2O2-dependent inactivation is demonstrable whether PGH2 is generated in situ from arachidonic acid or is added exogenously, supporting a direct effect of the treatment on GENE. As PB undergoes peroxide-dependent co-oxygenation catalyzed by PHS, we propose that it is an oxygenated derivative of PB, rather than the parent compound, which is responsible for the inactivation of PHS and GENE. Nafazatrom, a competitive inhibitor of PB co-oxygenation, blocks the effects of the PB and H2O2 treatment, supporting our proposal. | INHIBITOR |
| Inactivation of GENE and prostacyclin synthase by phenylbutazone. Requirement for peroxidative metabolism. Phenylbutazone (CHEMICAL), a nonsteroidal anti-inflammatory drug, is an efficient reducing cofactor for the peroxidase activity of GENE (PHS). Most reducing cofactors for the peroxidase protect PHS and prostacyclin synthase from inactivation by hydroperoxides. CHEMICAL, however, does not protect these enzymes, but rather augments their hydroperoxide-dependent inactivation. Using ram seminal vesicle microsomes as a source of PHS and prostacyclin synthase, we have examined the interaction of CHEMICAL and exogenous hydroperoxides. Chromatographic analysis of the metabolism of 14C-labeled arachidonic acid in this system revealed that PB-dependent inactivation of PHS is markedly increased in the presence of 100 microM H2O2. This inactivation is a linear function of CHEMICAL concentration between 10 and 250 microM, with a half-maximal effect in this range at about 100 microM CHEMICAL. Prostacyclin synthase is even more sensitive to inactivation by the combined CHEMICAL and H2O2 treatment, with a corresponding half-maximal effect at CHEMICAL concentrations near 25 microM. This PB- and H2O2-dependent inactivation is demonstrable whether PGH2 is generated in situ from arachidonic acid or is added exogenously, supporting a direct effect of the treatment on prostacyclin synthase. As CHEMICAL undergoes peroxide-dependent co-oxygenation catalyzed by PHS, we propose that it is an oxygenated derivative of CHEMICAL, rather than the parent compound, which is responsible for the inactivation of PHS and prostacyclin synthase. Nafazatrom, a competitive inhibitor of CHEMICAL co-oxygenation, blocks the effects of the CHEMICAL and H2O2 treatment, supporting our proposal. | GENE-CHEMICAL |
| Inactivation of prostaglandin H synthase and prostacyclin synthase by phenylbutazone. Requirement for peroxidative metabolism. Phenylbutazone (CHEMICAL), a nonsteroidal anti-inflammatory drug, is an efficient reducing cofactor for the peroxidase activity of prostaglandin H synthase (GENE). Most reducing cofactors for the peroxidase protect GENE and prostacyclin synthase from inactivation by hydroperoxides. CHEMICAL, however, does not protect these enzymes, but rather augments their hydroperoxide-dependent inactivation. Using ram seminal vesicle microsomes as a source of GENE and prostacyclin synthase, we have examined the interaction of CHEMICAL and exogenous hydroperoxides. Chromatographic analysis of the metabolism of 14C-labeled arachidonic acid in this system revealed that PB-dependent inactivation of GENE is markedly increased in the presence of 100 microM H2O2. This inactivation is a linear function of CHEMICAL concentration between 10 and 250 microM, with a half-maximal effect in this range at about 100 microM CHEMICAL. Prostacyclin synthase is even more sensitive to inactivation by the combined CHEMICAL and H2O2 treatment, with a corresponding half-maximal effect at CHEMICAL concentrations near 25 microM. This PB- and H2O2-dependent inactivation is demonstrable whether PGH2 is generated in situ from arachidonic acid or is added exogenously, supporting a direct effect of the treatment on prostacyclin synthase. As CHEMICAL undergoes peroxide-dependent co-oxygenation catalyzed by GENE, we propose that it is an oxygenated derivative of CHEMICAL, rather than the parent compound, which is responsible for the inactivation of GENE and prostacyclin synthase. Nafazatrom, a competitive inhibitor of CHEMICAL co-oxygenation, blocks the effects of the CHEMICAL and H2O2 treatment, supporting our proposal. | GENE-CHEMICAL |
| Inactivation of prostaglandin H synthase and prostacyclin synthase by phenylbutazone. Requirement for peroxidative metabolism. CHEMICAL (PB), a nonsteroidal anti-inflammatory drug, is an efficient reducing cofactor for the peroxidase activity of prostaglandin H synthase (GENE). Most reducing cofactors for the peroxidase protect GENE and prostacyclin synthase from inactivation by hydroperoxides. PB, however, does not protect these enzymes, but rather augments their hydroperoxide-dependent inactivation. Using ram seminal vesicle microsomes as a source of GENE and prostacyclin synthase, we have examined the interaction of PB and exogenous hydroperoxides. Chromatographic analysis of the metabolism of 14C-labeled arachidonic acid in this system revealed that PB-dependent inactivation of GENE is markedly increased in the presence of 100 microM H2O2. This inactivation is a linear function of PB concentration between 10 and 250 microM, with a half-maximal effect in this range at about 100 microM PB. Prostacyclin synthase is even more sensitive to inactivation by the combined PB and H2O2 treatment, with a corresponding half-maximal effect at PB concentrations near 25 microM. This PB- and H2O2-dependent inactivation is demonstrable whether PGH2 is generated in situ from arachidonic acid or is added exogenously, supporting a direct effect of the treatment on prostacyclin synthase. As PB undergoes peroxide-dependent co-oxygenation catalyzed by GENE, we propose that it is an oxygenated derivative of PB, rather than the parent compound, which is responsible for the inactivation of GENE and prostacyclin synthase. Nafazatrom, a competitive inhibitor of PB co-oxygenation, blocks the effects of the PB and H2O2 treatment, supporting our proposal. | GENE-CHEMICAL |
| Inactivation of prostaglandin H synthase and prostacyclin synthase by phenylbutazone. Requirement for peroxidative metabolism. Phenylbutazone (PB), a nonsteroidal anti-inflammatory drug, is an efficient reducing cofactor for the peroxidase activity of prostaglandin H synthase (PHS). Most reducing cofactors for the peroxidase protect GENE and prostacyclin synthase from inactivation by hydroperoxides. PB, however, does not protect these enzymes, but rather augments their hydroperoxide-dependent inactivation. Using ram seminal vesicle microsomes as a source of GENE and prostacyclin synthase, we have examined the interaction of PB and exogenous hydroperoxides. Chromatographic analysis of the metabolism of CHEMICAL in this system revealed that PB-dependent inactivation of GENE is markedly increased in the presence of 100 microM H2O2. This inactivation is a linear function of PB concentration between 10 and 250 microM, with a half-maximal effect in this range at about 100 microM PB. Prostacyclin synthase is even more sensitive to inactivation by the combined PB and H2O2 treatment, with a corresponding half-maximal effect at PB concentrations near 25 microM. This PB- and H2O2-dependent inactivation is demonstrable whether PGH2 is generated in situ from arachidonic acid or is added exogenously, supporting a direct effect of the treatment on prostacyclin synthase. As PB undergoes peroxide-dependent co-oxygenation catalyzed by GENE, we propose that it is an oxygenated derivative of PB, rather than the parent compound, which is responsible for the inactivation of GENE and prostacyclin synthase. Nafazatrom, a competitive inhibitor of PB co-oxygenation, blocks the effects of the PB and H2O2 treatment, supporting our proposal. | SUBSTRATE |
| Drug-protein interactions: isolation and characterization of covalent adducts of CHEMICAL and calmodulin. CHEMICAL, an alpha-adrenergic antagonist containing a (chloroethyl)amine group, labels calmodulin in the presence of calcium. The covalent interaction is inhibited by chlorpromazine in a concentration-dependent manner. Adducts of calmodulin and CHEMICAL were separated by high-performance liquid chromatography into four major fractions: two containing 0.6 and 1.2 mol of drug per mol of protein and two different fractions each containing 2.0 mol/mol. Each adduct had a reduced ability to activate cyclic nucleotide phosphodiesterase and myosin light chain kinase, and the chlorpromazine binding capacities of the phenoxybenzamine-calmodulin adducts were diminished to the extent of CHEMICAL incorporation into each adduct. Isolation and characterization of labeled peptides from CHEMICAL-modified GENE indicated that peptides encompassing residues 38-75, 107-126, and 127-148 contained CHEMICAL label. These studies directly demonstrate the relatedness between the binding activities of two structurally dissimilar calmodulin antagonists, demonstrate that covalent adducts of calmodulin and drugs with equal stoichiometries of labeling can have quantitative differences in activity and sites of modification, and provide direct evidence of distinct drug binding regions in calmodulin located in the amphipathic alpha-helical regions of the second and fourth domains. | DIRECT-REGULATOR |
| Drug-protein interactions: isolation and characterization of covalent adducts of CHEMICAL and GENE. CHEMICAL, an alpha-adrenergic antagonist containing a (chloroethyl)amine group, labels GENE in the presence of calcium. The covalent interaction is inhibited by chlorpromazine in a concentration-dependent manner. Adducts of GENE and CHEMICAL were separated by high-performance liquid chromatography into four major fractions: two containing 0.6 and 1.2 mol of drug per mol of protein and two different fractions each containing 2.0 mol/mol. Each adduct had a reduced ability to activate cyclic nucleotide phosphodiesterase and myosin light chain kinase, and the chlorpromazine binding capacities of the phenoxybenzamine-calmodulin adducts were diminished to the extent of CHEMICAL incorporation into each adduct. Isolation and characterization of labeled peptides from phenoxybenzamine-modified calmodulins indicated that peptides encompassing residues 38-75, 107-126, and 127-148 contained CHEMICAL label. These studies directly demonstrate the relatedness between the binding activities of two structurally dissimilar GENE antagonists, demonstrate that covalent adducts of GENE and drugs with equal stoichiometries of labeling can have quantitative differences in activity and sites of modification, and provide direct evidence of distinct drug binding regions in GENE located in the amphipathic alpha-helical regions of the second and fourth domains. | DIRECT-REGULATOR |
| Drug-protein interactions: isolation and characterization of covalent adducts of phenoxybenzamine and GENE. CHEMICAL, an alpha-adrenergic antagonist containing a (chloroethyl)amine group, labels GENE in the presence of calcium. The covalent interaction is inhibited by chlorpromazine in a concentration-dependent manner. Adducts of GENE and phenoxybenzamine were separated by high-performance liquid chromatography into four major fractions: two containing 0.6 and 1.2 mol of drug per mol of protein and two different fractions each containing 2.0 mol/mol. Each adduct had a reduced ability to activate cyclic nucleotide phosphodiesterase and myosin light chain kinase, and the chlorpromazine binding capacities of the phenoxybenzamine-calmodulin adducts were diminished to the extent of phenoxybenzamine incorporation into each adduct. Isolation and characterization of labeled peptides from phenoxybenzamine-modified calmodulins indicated that peptides encompassing residues 38-75, 107-126, and 127-148 contained phenoxybenzamine label. These studies directly demonstrate the relatedness between the binding activities of two structurally dissimilar GENE antagonists, demonstrate that covalent adducts of GENE and drugs with equal stoichiometries of labeling can have quantitative differences in activity and sites of modification, and provide direct evidence of distinct drug binding regions in GENE located in the amphipathic alpha-helical regions of the second and fourth domains. | DIRECT-REGULATOR |
| Drug-protein interactions: isolation and characterization of covalent adducts of phenoxybenzamine and GENE. Phenoxybenzamine, an alpha-adrenergic antagonist containing a (chloroethyl)amine group, labels GENE in the presence of calcium. The covalent interaction is inhibited by CHEMICAL in a concentration-dependent manner. Adducts of GENE and phenoxybenzamine were separated by high-performance liquid chromatography into four major fractions: two containing 0.6 and 1.2 mol of drug per mol of protein and two different fractions each containing 2.0 mol/mol. Each adduct had a reduced ability to activate cyclic nucleotide phosphodiesterase and myosin light chain kinase, and the CHEMICAL binding capacities of the phenoxybenzamine-GENE adducts were diminished to the extent of phenoxybenzamine incorporation into each adduct. Isolation and characterization of labeled peptides from phenoxybenzamine-modified calmodulins indicated that peptides encompassing residues 38-75, 107-126, and 127-148 contained phenoxybenzamine label. These studies directly demonstrate the relatedness between the binding activities of two structurally dissimilar GENE antagonists, demonstrate that covalent adducts of GENE and drugs with equal stoichiometries of labeling can have quantitative differences in activity and sites of modification, and provide direct evidence of distinct drug binding regions in GENE located in the amphipathic alpha-helical regions of the second and fourth domains. | DIRECT-REGULATOR |
| Drug-protein interactions: isolation and characterization of covalent adducts of phenoxybenzamine and GENE. Phenoxybenzamine, an alpha-adrenergic antagonist containing a CHEMICAL group, labels GENE in the presence of calcium. The covalent interaction is inhibited by chlorpromazine in a concentration-dependent manner. Adducts of GENE and phenoxybenzamine were separated by high-performance liquid chromatography into four major fractions: two containing 0.6 and 1.2 mol of drug per mol of protein and two different fractions each containing 2.0 mol/mol. Each adduct had a reduced ability to activate cyclic nucleotide phosphodiesterase and myosin light chain kinase, and the chlorpromazine binding capacities of the phenoxybenzamine-calmodulin adducts were diminished to the extent of phenoxybenzamine incorporation into each adduct. Isolation and characterization of labeled peptides from phenoxybenzamine-modified calmodulins indicated that peptides encompassing residues 38-75, 107-126, and 127-148 contained phenoxybenzamine label. These studies directly demonstrate the relatedness between the binding activities of two structurally dissimilar GENE antagonists, demonstrate that covalent adducts of GENE and drugs with equal stoichiometries of labeling can have quantitative differences in activity and sites of modification, and provide direct evidence of distinct drug binding regions in GENE located in the amphipathic alpha-helical regions of the second and fourth domains. | DIRECT-REGULATOR |
| Amine oxidase activities in brown adipose tissue of the rat: identification of semicarbazide-sensitive (clorgyline-resistant) activity at the fat cell membrane. Amine oxidase activity, previously described in homogenates of brown adipose tissue of the rat, has now been investigated in preparations of isolated fat cells. It was found that the specific activities of both monoamine oxidase A (MAO) and of the semicarbazide-sensitive clorgyline-resistant amine oxidase (SSAO) were higher in isolated fat cells than in the original whole tissue. Brown adipocytes therefore represent a major source of both these enzymes. In plasma membranes prepared from these isolated brown fat cells by CHEMICAL extraction there was a similar enrichment of activity of SSAO and of the plasma membrane marker enzyme, GENE. However in preparations of cell membranes made by binding the cells to polycation-coated beads, enrichment of GENE activity was much greater than that of SSAO. It is suggested that the disposition of the enzyme within the cell membrane may account for the discrepancy in these results, i.e. the sidedness of the membrane may be important. Histochemical visualization of enzyme activity in whole tissue at the ultrastructural level was undertaken. Positive staining of mitochondria was achieved in the presence of the MAO substrate, tryptamine. Staining around the edges of the brown fat cells was observed with the SSAO substrates, tyramine and benzylamine. Staining was largely absent when substrate was omitted or after pretreatment with the irreversible SSAO inhibitor, hydralazine and the slowly reversible inhibitor, semicarbazide. It is not definitely proven that this staining represents sites of enzyme activity but the results are consistent with evidence from other studies indicating that SSAO in brown adipose tissue of the rat may be found predominantly at the fat cell surface.(ABSTRACT TRUNCATED AT 250 WORDS) | GENE-CHEMICAL |
| GENE activities in brown adipose tissue of the rat: identification of semicarbazide-sensitive (CHEMICAL-resistant) activity at the fat cell membrane. GENE activity, previously described in homogenates of brown adipose tissue of the rat, has now been investigated in preparations of isolated fat cells. It was found that the specific activities of both monoamine oxidase A (MAO) and of the semicarbazide-sensitive clorgyline-resistant amine oxidase (SSAO) were higher in isolated fat cells than in the original whole tissue. Brown adipocytes therefore represent a major source of both these enzymes. In plasma membranes prepared from these isolated brown fat cells by borate extraction there was a similar enrichment of activity of SSAO and of the plasma membrane marker enzyme, phosphodiesterase I. However in preparations of cell membranes made by binding the cells to polycation-coated beads, enrichment of phosphodiesterase I activity was much greater than that of SSAO. It is suggested that the disposition of the enzyme within the cell membrane may account for the discrepancy in these results, i.e. the sidedness of the membrane may be important. Histochemical visualization of enzyme activity in whole tissue at the ultrastructural level was undertaken. Positive staining of mitochondria was achieved in the presence of the MAO substrate, tryptamine. Staining around the edges of the brown fat cells was observed with the SSAO substrates, tyramine and benzylamine. Staining was largely absent when substrate was omitted or after pretreatment with the irreversible SSAO inhibitor, hydralazine and the slowly reversible inhibitor, semicarbazide. It is not definitely proven that this staining represents sites of enzyme activity but the results are consistent with evidence from other studies indicating that SSAO in brown adipose tissue of the rat may be found predominantly at the fat cell surface.(ABSTRACT TRUNCATED AT 250 WORDS) | NO-RELATIONSHIP |
| GENE activities in brown adipose tissue of the rat: identification of CHEMICAL-sensitive (clorgyline-resistant) activity at the fat cell membrane. GENE activity, previously described in homogenates of brown adipose tissue of the rat, has now been investigated in preparations of isolated fat cells. It was found that the specific activities of both monoamine oxidase A (MAO) and of the semicarbazide-sensitive clorgyline-resistant amine oxidase (SSAO) were higher in isolated fat cells than in the original whole tissue. Brown adipocytes therefore represent a major source of both these enzymes. In plasma membranes prepared from these isolated brown fat cells by borate extraction there was a similar enrichment of activity of SSAO and of the plasma membrane marker enzyme, phosphodiesterase I. However in preparations of cell membranes made by binding the cells to polycation-coated beads, enrichment of phosphodiesterase I activity was much greater than that of SSAO. It is suggested that the disposition of the enzyme within the cell membrane may account for the discrepancy in these results, i.e. the sidedness of the membrane may be important. Histochemical visualization of enzyme activity in whole tissue at the ultrastructural level was undertaken. Positive staining of mitochondria was achieved in the presence of the MAO substrate, tryptamine. Staining around the edges of the brown fat cells was observed with the SSAO substrates, tyramine and benzylamine. Staining was largely absent when substrate was omitted or after pretreatment with the irreversible SSAO inhibitor, hydralazine and the slowly reversible inhibitor, CHEMICAL. It is not definitely proven that this staining represents sites of enzyme activity but the results are consistent with evidence from other studies indicating that SSAO in brown adipose tissue of the rat may be found predominantly at the fat cell surface.(ABSTRACT TRUNCATED AT 250 WORDS) | ACTIVATOR |
| Amine oxidase activities in brown adipose tissue of the rat: identification of semicarbazide-sensitive (clorgyline-resistant) activity at the fat cell membrane. Amine oxidase activity, previously described in homogenates of brown adipose tissue of the rat, has now been investigated in preparations of isolated fat cells. It was found that the specific activities of both monoamine oxidase A (MAO) and of the semicarbazide-sensitive clorgyline-resistant amine oxidase (SSAO) were higher in isolated fat cells than in the original whole tissue. Brown adipocytes therefore represent a major source of both these enzymes. In plasma membranes prepared from these isolated brown fat cells by CHEMICAL extraction there was a similar enrichment of activity of GENE and of the plasma membrane marker enzyme, phosphodiesterase I. However in preparations of cell membranes made by binding the cells to polycation-coated beads, enrichment of phosphodiesterase I activity was much greater than that of GENE. It is suggested that the disposition of the enzyme within the cell membrane may account for the discrepancy in these results, i.e. the sidedness of the membrane may be important. Histochemical visualization of enzyme activity in whole tissue at the ultrastructural level was undertaken. Positive staining of mitochondria was achieved in the presence of the MAO substrate, tryptamine. Staining around the edges of the brown fat cells was observed with the GENE substrates, tyramine and benzylamine. Staining was largely absent when substrate was omitted or after pretreatment with the irreversible GENE inhibitor, hydralazine and the slowly reversible inhibitor, semicarbazide. It is not definitely proven that this staining represents sites of enzyme activity but the results are consistent with evidence from other studies indicating that GENE in brown adipose tissue of the rat may be found predominantly at the fat cell surface.(ABSTRACT TRUNCATED AT 250 WORDS) | GENE-CHEMICAL |
| Amine oxidase activities in brown adipose tissue of the rat: identification of semicarbazide-sensitive (clorgyline-resistant) activity at the fat cell membrane. Amine oxidase activity, previously described in homogenates of brown adipose tissue of the rat, has now been investigated in preparations of isolated fat cells. It was found that the specific activities of both monoamine oxidase A (MAO) and of the semicarbazide-sensitive clorgyline-resistant amine oxidase (SSAO) were higher in isolated fat cells than in the original whole tissue. Brown adipocytes therefore represent a major source of both these enzymes. In plasma membranes prepared from these isolated brown fat cells by borate extraction there was a similar enrichment of activity of GENE and of the plasma membrane marker enzyme, phosphodiesterase I. However in preparations of cell membranes made by binding the cells to polycation-coated beads, enrichment of phosphodiesterase I activity was much greater than that of GENE. It is suggested that the disposition of the enzyme within the cell membrane may account for the discrepancy in these results, i.e. the sidedness of the membrane may be important. Histochemical visualization of enzyme activity in whole tissue at the ultrastructural level was undertaken. Positive staining of mitochondria was achieved in the presence of the MAO substrate, tryptamine. Staining around the edges of the brown fat cells was observed with the GENE substrates, tyramine and benzylamine. Staining was largely absent when substrate was omitted or after pretreatment with the irreversible GENE inhibitor, CHEMICAL and the slowly reversible inhibitor, semicarbazide. It is not definitely proven that this staining represents sites of enzyme activity but the results are consistent with evidence from other studies indicating that GENE in brown adipose tissue of the rat may be found predominantly at the fat cell surface.(ABSTRACT TRUNCATED AT 250 WORDS) | INHIBITOR |
| Amine oxidase activities in brown adipose tissue of the rat: identification of semicarbazide-sensitive (clorgyline-resistant) activity at the fat cell membrane. Amine oxidase activity, previously described in homogenates of brown adipose tissue of the rat, has now been investigated in preparations of isolated fat cells. It was found that the specific activities of both monoamine oxidase A (MAO) and of the semicarbazide-sensitive clorgyline-resistant amine oxidase (SSAO) were higher in isolated fat cells than in the original whole tissue. Brown adipocytes therefore represent a major source of both these enzymes. In plasma membranes prepared from these isolated brown fat cells by borate extraction there was a similar enrichment of activity of GENE and of the plasma membrane marker enzyme, phosphodiesterase I. However in preparations of cell membranes made by binding the cells to polycation-coated beads, enrichment of phosphodiesterase I activity was much greater than that of GENE. It is suggested that the disposition of the enzyme within the cell membrane may account for the discrepancy in these results, i.e. the sidedness of the membrane may be important. Histochemical visualization of enzyme activity in whole tissue at the ultrastructural level was undertaken. Positive staining of mitochondria was achieved in the presence of the MAO substrate, tryptamine. Staining around the edges of the brown fat cells was observed with the GENE substrates, tyramine and benzylamine. Staining was largely absent when substrate was omitted or after pretreatment with the irreversible GENE inhibitor, hydralazine and the slowly reversible inhibitor, CHEMICAL. It is not definitely proven that this staining represents sites of enzyme activity but the results are consistent with evidence from other studies indicating that GENE in brown adipose tissue of the rat may be found predominantly at the fat cell surface.(ABSTRACT TRUNCATED AT 250 WORDS) | INHIBITOR |
| Amine oxidase activities in brown adipose tissue of the rat: identification of semicarbazide-sensitive (clorgyline-resistant) activity at the fat cell membrane. Amine oxidase activity, previously described in homogenates of brown adipose tissue of the rat, has now been investigated in preparations of isolated fat cells. It was found that the specific activities of both monoamine oxidase A (MAO) and of the semicarbazide-sensitive clorgyline-resistant amine oxidase (SSAO) were higher in isolated fat cells than in the original whole tissue. Brown adipocytes therefore represent a major source of both these enzymes. In plasma membranes prepared from these isolated brown fat cells by borate extraction there was a similar enrichment of activity of SSAO and of the plasma membrane marker enzyme, phosphodiesterase I. However in preparations of cell membranes made by binding the cells to polycation-coated beads, enrichment of phosphodiesterase I activity was much greater than that of SSAO. It is suggested that the disposition of the enzyme within the cell membrane may account for the discrepancy in these results, i.e. the sidedness of the membrane may be important. Histochemical visualization of enzyme activity in whole tissue at the ultrastructural level was undertaken. Positive staining of mitochondria was achieved in the presence of the GENE substrate, CHEMICAL. Staining around the edges of the brown fat cells was observed with the SSAO substrates, tyramine and benzylamine. Staining was largely absent when substrate was omitted or after pretreatment with the irreversible SSAO inhibitor, hydralazine and the slowly reversible inhibitor, semicarbazide. It is not definitely proven that this staining represents sites of enzyme activity but the results are consistent with evidence from other studies indicating that SSAO in brown adipose tissue of the rat may be found predominantly at the fat cell surface.(ABSTRACT TRUNCATED AT 250 WORDS) | SUBSTRATE |
| Amine oxidase activities in brown adipose tissue of the rat: identification of semicarbazide-sensitive (clorgyline-resistant) activity at the fat cell membrane. Amine oxidase activity, previously described in homogenates of brown adipose tissue of the rat, has now been investigated in preparations of isolated fat cells. It was found that the specific activities of both monoamine oxidase A (MAO) and of the semicarbazide-sensitive clorgyline-resistant amine oxidase (SSAO) were higher in isolated fat cells than in the original whole tissue. Brown adipocytes therefore represent a major source of both these enzymes. In plasma membranes prepared from these isolated brown fat cells by borate extraction there was a similar enrichment of activity of GENE and of the plasma membrane marker enzyme, phosphodiesterase I. However in preparations of cell membranes made by binding the cells to polycation-coated beads, enrichment of phosphodiesterase I activity was much greater than that of GENE. It is suggested that the disposition of the enzyme within the cell membrane may account for the discrepancy in these results, i.e. the sidedness of the membrane may be important. Histochemical visualization of enzyme activity in whole tissue at the ultrastructural level was undertaken. Positive staining of mitochondria was achieved in the presence of the MAO substrate, tryptamine. Staining around the edges of the brown fat cells was observed with the GENE substrates, CHEMICAL and benzylamine. Staining was largely absent when substrate was omitted or after pretreatment with the irreversible GENE inhibitor, hydralazine and the slowly reversible inhibitor, semicarbazide. It is not definitely proven that this staining represents sites of enzyme activity but the results are consistent with evidence from other studies indicating that GENE in brown adipose tissue of the rat may be found predominantly at the fat cell surface.(ABSTRACT TRUNCATED AT 250 WORDS) | SUBSTRATE |
| Amine oxidase activities in brown adipose tissue of the rat: identification of semicarbazide-sensitive (clorgyline-resistant) activity at the fat cell membrane. Amine oxidase activity, previously described in homogenates of brown adipose tissue of the rat, has now been investigated in preparations of isolated fat cells. It was found that the specific activities of both monoamine oxidase A (MAO) and of the semicarbazide-sensitive clorgyline-resistant amine oxidase (SSAO) were higher in isolated fat cells than in the original whole tissue. Brown adipocytes therefore represent a major source of both these enzymes. In plasma membranes prepared from these isolated brown fat cells by borate extraction there was a similar enrichment of activity of GENE and of the plasma membrane marker enzyme, phosphodiesterase I. However in preparations of cell membranes made by binding the cells to polycation-coated beads, enrichment of phosphodiesterase I activity was much greater than that of GENE. It is suggested that the disposition of the enzyme within the cell membrane may account for the discrepancy in these results, i.e. the sidedness of the membrane may be important. Histochemical visualization of enzyme activity in whole tissue at the ultrastructural level was undertaken. Positive staining of mitochondria was achieved in the presence of the MAO substrate, tryptamine. Staining around the edges of the brown fat cells was observed with the GENE substrates, tyramine and CHEMICAL. Staining was largely absent when substrate was omitted or after pretreatment with the irreversible GENE inhibitor, hydralazine and the slowly reversible inhibitor, semicarbazide. It is not definitely proven that this staining represents sites of enzyme activity but the results are consistent with evidence from other studies indicating that GENE in brown adipose tissue of the rat may be found predominantly at the fat cell surface.(ABSTRACT TRUNCATED AT 250 WORDS) | SUBSTRATE |
| Penicillin-binding proteins and role of amdinocillin in causing bacterial cell death. The activity of CHEMICAL against bacteria is in large part related to binding to specific receptor proteins involved in cell wall biosynthesis. These proteins have been designated penicillin-binding proteins. They can be separated into distinct entities through the use of acrylamide gel electrophoresis and binding of radioactive 14C-labeled penicillin G. Six major proteins have been defined in the Enterobacteriaceae, penicillin-binding proteins 1 to 6. Selection of mutants has shown that there are three essential proteins: penicillin-binding protein 1, which is divided into penicillin-binding protein 1Bs, a peptidoglycan transpeptidase, and penicillin-binding protein 1A, which acts as a replacement for penicillin-binding protein 1Bs. GENE is a murein-elongation initiating enzyme and penicillin-binding protein 3 is a septal murein-synthesizing enzyme. Penicillin-binding proteins 4, 5, and 6 are not essential for bacterial survival. Binding of CHEMICAL to penicillin-binding protein 1Bs produces lysis, binding to GENE produces round cells, and binding to penicillin-binding protein 3 produces long filaments. Amdinocillin is a beta-amidino penicillanic acid derivative that binds specifically to GENE. The compound is more beta-lactamase stable than ampicillin and has no major delay in entry into the periplasmic space as do some CHEMICAL. Amdinocillin inhibits most of the Enterobacteriaceae, with the exception of some indole-positive Proteus species, but it does not inhibit gram-positive cocci or Pseudomonas aeruginosa. Amdinocillin produces spherical bacterial cells that eventually lyse. Its activity in vitro is markedly affected by ionic content of media. This agent acts synergistically with many CHEMICAL, such as ampicillin, carbenicillin, and the like, and with cephalosporins, cefazolin, cefamandole, or cefoxitin to inhibit gram-negative bacilli, probably on the basis of binding to different proteins needed for the production of the peptidoglycan of the bacterial cell wall. Amdinocillin possesses a number of the essentials for effective antimicrobial activity and, by virtue of its enhancement of the activity of other beta-lactams, may prove to be a useful agent in the chemotherapy of certain infections. | DIRECT-REGULATOR |
| Penicillin-binding proteins and role of amdinocillin in causing bacterial cell death. The activity of CHEMICAL against bacteria is in large part related to binding to specific receptor proteins involved in cell wall biosynthesis. These proteins have been designated penicillin-binding proteins. They can be separated into distinct entities through the use of acrylamide gel electrophoresis and binding of radioactive 14C-labeled penicillin G. Six major proteins have been defined in the Enterobacteriaceae, penicillin-binding proteins 1 to 6. Selection of mutants has shown that there are three essential proteins: penicillin-binding protein 1, which is divided into penicillin-binding protein 1Bs, a peptidoglycan transpeptidase, and penicillin-binding protein 1A, which acts as a replacement for penicillin-binding protein 1Bs. Penicillin-binding protein 2 is a murein-elongation initiating enzyme and GENE is a septal murein-synthesizing enzyme. Penicillin-binding proteins 4, 5, and 6 are not essential for bacterial survival. Binding of CHEMICAL to penicillin-binding protein 1Bs produces lysis, binding to penicillin-binding protein 2 produces round cells, and binding to GENE produces long filaments. Amdinocillin is a beta-amidino penicillanic acid derivative that binds specifically to penicillin-binding protein 2. The compound is more beta-lactamase stable than ampicillin and has no major delay in entry into the periplasmic space as do some CHEMICAL. Amdinocillin inhibits most of the Enterobacteriaceae, with the exception of some indole-positive Proteus species, but it does not inhibit gram-positive cocci or Pseudomonas aeruginosa. Amdinocillin produces spherical bacterial cells that eventually lyse. Its activity in vitro is markedly affected by ionic content of media. This agent acts synergistically with many CHEMICAL, such as ampicillin, carbenicillin, and the like, and with cephalosporins, cefazolin, cefamandole, or cefoxitin to inhibit gram-negative bacilli, probably on the basis of binding to different proteins needed for the production of the peptidoglycan of the bacterial cell wall. Amdinocillin possesses a number of the essentials for effective antimicrobial activity and, by virtue of its enhancement of the activity of other beta-lactams, may prove to be a useful agent in the chemotherapy of certain infections. | DIRECT-REGULATOR |
| Penicillin-binding proteins and role of amdinocillin in causing bacterial cell death. The activity of CHEMICAL against bacteria is in large part related to binding to specific receptor proteins involved in cell wall biosynthesis. These proteins have been designated penicillin-binding proteins. They can be separated into distinct entities through the use of acrylamide gel electrophoresis and binding of radioactive 14C-labeled penicillin G. Six major proteins have been defined in the Enterobacteriaceae, penicillin-binding proteins 1 to 6. Selection of mutants has shown that there are three essential proteins: penicillin-binding protein 1, which is divided into GENE, a peptidoglycan transpeptidase, and penicillin-binding protein 1A, which acts as a replacement for GENE. Penicillin-binding protein 2 is a murein-elongation initiating enzyme and penicillin-binding protein 3 is a septal murein-synthesizing enzyme. Penicillin-binding proteins 4, 5, and 6 are not essential for bacterial survival. Binding of CHEMICAL to GENE produces lysis, binding to penicillin-binding protein 2 produces round cells, and binding to penicillin-binding protein 3 produces long filaments. Amdinocillin is a beta-amidino penicillanic acid derivative that binds specifically to penicillin-binding protein 2. The compound is more beta-lactamase stable than ampicillin and has no major delay in entry into the periplasmic space as do some CHEMICAL. Amdinocillin inhibits most of the Enterobacteriaceae, with the exception of some indole-positive Proteus species, but it does not inhibit gram-positive cocci or Pseudomonas aeruginosa. Amdinocillin produces spherical bacterial cells that eventually lyse. Its activity in vitro is markedly affected by ionic content of media. This agent acts synergistically with many CHEMICAL, such as ampicillin, carbenicillin, and the like, and with cephalosporins, cefazolin, cefamandole, or cefoxitin to inhibit gram-negative bacilli, probably on the basis of binding to different proteins needed for the production of the peptidoglycan of the bacterial cell wall. Amdinocillin possesses a number of the essentials for effective antimicrobial activity and, by virtue of its enhancement of the activity of other beta-lactams, may prove to be a useful agent in the chemotherapy of certain infections. | DIRECT-REGULATOR |
| Penicillin-binding proteins and role of amdinocillin in causing bacterial cell death. The activity of penicillins against bacteria is in large part related to binding to specific receptor proteins involved in cell wall biosynthesis. These proteins have been designated penicillin-binding proteins. They can be separated into distinct entities through the use of acrylamide gel electrophoresis and binding of radioactive 14C-labeled penicillin G. Six major proteins have been defined in the Enterobacteriaceae, penicillin-binding proteins 1 to 6. Selection of mutants has shown that there are three essential proteins: penicillin-binding protein 1, which is divided into penicillin-binding protein 1Bs, a peptidoglycan transpeptidase, and penicillin-binding protein 1A, which acts as a replacement for penicillin-binding protein 1Bs. GENE is a murein-elongation initiating enzyme and penicillin-binding protein 3 is a septal murein-synthesizing enzyme. Penicillin-binding proteins 4, 5, and 6 are not essential for bacterial survival. Binding of penicillins to penicillin-binding protein 1Bs produces lysis, binding to GENE produces round cells, and binding to penicillin-binding protein 3 produces long filaments. CHEMICAL is a beta-amidino penicillanic acid derivative that binds specifically to GENE. The compound is more beta-lactamase stable than ampicillin and has no major delay in entry into the periplasmic space as do some penicillins. CHEMICAL inhibits most of the Enterobacteriaceae, with the exception of some indole-positive Proteus species, but it does not inhibit gram-positive cocci or Pseudomonas aeruginosa. CHEMICAL produces spherical bacterial cells that eventually lyse. Its activity in vitro is markedly affected by ionic content of media. This agent acts synergistically with many penicillins, such as ampicillin, carbenicillin, and the like, and with cephalosporins, cefazolin, cefamandole, or cefoxitin to inhibit gram-negative bacilli, probably on the basis of binding to different proteins needed for the production of the peptidoglycan of the bacterial cell wall. CHEMICAL possesses a number of the essentials for effective antimicrobial activity and, by virtue of its enhancement of the activity of other beta-lactams, may prove to be a useful agent in the chemotherapy of certain infections. | DIRECT-REGULATOR |
| Penicillin-binding proteins and role of amdinocillin in causing bacterial cell death. The activity of penicillins against bacteria is in large part related to binding to specific receptor proteins involved in cell wall biosynthesis. These proteins have been designated penicillin-binding proteins. They can be separated into distinct entities through the use of acrylamide gel electrophoresis and binding of radioactive 14C-labeled penicillin G. Six major proteins have been defined in the Enterobacteriaceae, penicillin-binding proteins 1 to 6. Selection of mutants has shown that there are three essential proteins: penicillin-binding protein 1, which is divided into penicillin-binding protein 1Bs, a peptidoglycan transpeptidase, and penicillin-binding protein 1A, which acts as a replacement for penicillin-binding protein 1Bs. GENE is a murein-elongation initiating enzyme and penicillin-binding protein 3 is a septal murein-synthesizing enzyme. Penicillin-binding proteins 4, 5, and 6 are not essential for bacterial survival. Binding of penicillins to penicillin-binding protein 1Bs produces lysis, binding to GENE produces round cells, and binding to penicillin-binding protein 3 produces long filaments. Amdinocillin is a CHEMICAL derivative that binds specifically to GENE. The compound is more beta-lactamase stable than ampicillin and has no major delay in entry into the periplasmic space as do some penicillins. Amdinocillin inhibits most of the Enterobacteriaceae, with the exception of some indole-positive Proteus species, but it does not inhibit gram-positive cocci or Pseudomonas aeruginosa. Amdinocillin produces spherical bacterial cells that eventually lyse. Its activity in vitro is markedly affected by ionic content of media. This agent acts synergistically with many penicillins, such as ampicillin, carbenicillin, and the like, and with cephalosporins, cefazolin, cefamandole, or cefoxitin to inhibit gram-negative bacilli, probably on the basis of binding to different proteins needed for the production of the peptidoglycan of the bacterial cell wall. Amdinocillin possesses a number of the essentials for effective antimicrobial activity and, by virtue of its enhancement of the activity of other beta-lactams, may prove to be a useful agent in the chemotherapy of certain infections. | DIRECT-REGULATOR |
| GENE and role of CHEMICAL in causing bacterial cell death. The activity of penicillins against bacteria is in large part related to binding to specific receptor proteins involved in cell wall biosynthesis. These proteins have been designated penicillin-binding proteins. They can be separated into distinct entities through the use of acrylamide gel electrophoresis and binding of radioactive 14C-labeled penicillin G. Six major proteins have been defined in the Enterobacteriaceae, penicillin-binding proteins 1 to 6. Selection of mutants has shown that there are three essential proteins: penicillin-binding protein 1, which is divided into penicillin-binding protein 1Bs, a peptidoglycan transpeptidase, and penicillin-binding protein 1A, which acts as a replacement for penicillin-binding protein 1Bs. Penicillin-binding protein 2 is a murein-elongation initiating enzyme and penicillin-binding protein 3 is a septal murein-synthesizing enzyme. GENE 4, 5, and 6 are not essential for bacterial survival. Binding of penicillins to penicillin-binding protein 1Bs produces lysis, binding to penicillin-binding protein 2 produces round cells, and binding to penicillin-binding protein 3 produces long filaments. CHEMICAL is a beta-amidino penicillanic acid derivative that binds specifically to penicillin-binding protein 2. The compound is more beta-lactamase stable than ampicillin and has no major delay in entry into the periplasmic space as do some penicillins. CHEMICAL inhibits most of the Enterobacteriaceae, with the exception of some indole-positive Proteus species, but it does not inhibit gram-positive cocci or Pseudomonas aeruginosa. CHEMICAL produces spherical bacterial cells that eventually lyse. Its activity in vitro is markedly affected by ionic content of media. This agent acts synergistically with many penicillins, such as ampicillin, carbenicillin, and the like, and with cephalosporins, cefazolin, cefamandole, or cefoxitin to inhibit gram-negative bacilli, probably on the basis of binding to different proteins needed for the production of the peptidoglycan of the bacterial cell wall. CHEMICAL possesses a number of the essentials for effective antimicrobial activity and, by virtue of its enhancement of the activity of other beta-lactams, may prove to be a useful agent in the chemotherapy of certain infections. | REGULATOR |
| Penicillin-binding proteins and role of amdinocillin in causing bacterial cell death. The activity of penicillins against bacteria is in large part related to binding to specific receptor proteins involved in cell wall biosynthesis. These proteins have been designated penicillin-binding proteins. They can be separated into distinct entities through the use of acrylamide gel electrophoresis and binding of radioactive 14C-labeled penicillin G. Six major proteins have been defined in the Enterobacteriaceae, penicillin-binding proteins 1 to 6. Selection of mutants has shown that there are three essential proteins: penicillin-binding protein 1, which is divided into penicillin-binding protein 1Bs, a peptidoglycan transpeptidase, and penicillin-binding protein 1A, which acts as a replacement for penicillin-binding protein 1Bs. Penicillin-binding protein 2 is a murein-elongation initiating enzyme and penicillin-binding protein 3 is a septal murein-synthesizing enzyme. Penicillin-binding proteins 4, 5, and 6 are not essential for bacterial survival. Binding of penicillins to penicillin-binding protein 1Bs produces lysis, binding to penicillin-binding protein 2 produces round cells, and binding to penicillin-binding protein 3 produces long filaments. Amdinocillin is a beta-amidino penicillanic acid derivative that binds specifically to penicillin-binding protein 2. The compound is more GENE stable than CHEMICAL and has no major delay in entry into the periplasmic space as do some penicillins. Amdinocillin inhibits most of the Enterobacteriaceae, with the exception of some indole-positive Proteus species, but it does not inhibit gram-positive cocci or Pseudomonas aeruginosa. Amdinocillin produces spherical bacterial cells that eventually lyse. Its activity in vitro is markedly affected by ionic content of media. This agent acts synergistically with many penicillins, such as CHEMICAL, carbenicillin, and the like, and with cephalosporins, cefazolin, cefamandole, or cefoxitin to inhibit gram-negative bacilli, probably on the basis of binding to different proteins needed for the production of the peptidoglycan of the bacterial cell wall. Amdinocillin possesses a number of the essentials for effective antimicrobial activity and, by virtue of its enhancement of the activity of other beta-lactams, may prove to be a useful agent in the chemotherapy of certain infections. | DIRECT-REGULATOR |
| Penicillin-binding proteins and role of amdinocillin in causing bacterial cell death. The activity of CHEMICAL against bacteria is in large part related to binding to specific receptor proteins involved in cell wall biosynthesis. These proteins have been designated penicillin-binding proteins. They can be separated into distinct entities through the use of acrylamide gel electrophoresis and binding of radioactive 14C-labeled penicillin G. Six major proteins have been defined in the Enterobacteriaceae, penicillin-binding proteins 1 to 6. Selection of mutants has shown that there are three essential proteins: penicillin-binding protein 1, which is divided into penicillin-binding protein 1Bs, a GENE transpeptidase, and penicillin-binding protein 1A, which acts as a replacement for penicillin-binding protein 1Bs. Penicillin-binding protein 2 is a murein-elongation initiating enzyme and penicillin-binding protein 3 is a septal murein-synthesizing enzyme. Penicillin-binding proteins 4, 5, and 6 are not essential for bacterial survival. Binding of CHEMICAL to penicillin-binding protein 1Bs produces lysis, binding to penicillin-binding protein 2 produces round cells, and binding to penicillin-binding protein 3 produces long filaments. Amdinocillin is a beta-amidino penicillanic acid derivative that binds specifically to penicillin-binding protein 2. The compound is more beta-lactamase stable than ampicillin and has no major delay in entry into the periplasmic space as do some CHEMICAL. Amdinocillin inhibits most of the Enterobacteriaceae, with the exception of some indole-positive Proteus species, but it does not inhibit gram-positive cocci or Pseudomonas aeruginosa. Amdinocillin produces spherical bacterial cells that eventually lyse. Its activity in vitro is markedly affected by ionic content of media. This agent acts synergistically with many CHEMICAL, such as ampicillin, carbenicillin, and the like, and with cephalosporins, cefazolin, cefamandole, or cefoxitin to inhibit gram-negative bacilli, probably on the basis of binding to different proteins needed for the production of the GENE of the bacterial cell wall. Amdinocillin possesses a number of the essentials for effective antimicrobial activity and, by virtue of its enhancement of the activity of other beta-lactams, may prove to be a useful agent in the chemotherapy of certain infections. | GENE-CHEMICAL |
| Penicillin-binding proteins and role of amdinocillin in causing bacterial cell death. The activity of penicillins against bacteria is in large part related to binding to specific receptor proteins involved in cell wall biosynthesis. These proteins have been designated penicillin-binding proteins. They can be separated into distinct entities through the use of acrylamide gel electrophoresis and binding of radioactive 14C-labeled penicillin G. Six major proteins have been defined in the Enterobacteriaceae, penicillin-binding proteins 1 to 6. Selection of mutants has shown that there are three essential proteins: penicillin-binding protein 1, which is divided into penicillin-binding protein 1Bs, a GENE transpeptidase, and penicillin-binding protein 1A, which acts as a replacement for penicillin-binding protein 1Bs. Penicillin-binding protein 2 is a murein-elongation initiating enzyme and penicillin-binding protein 3 is a septal murein-synthesizing enzyme. Penicillin-binding proteins 4, 5, and 6 are not essential for bacterial survival. Binding of penicillins to penicillin-binding protein 1Bs produces lysis, binding to penicillin-binding protein 2 produces round cells, and binding to penicillin-binding protein 3 produces long filaments. Amdinocillin is a beta-amidino penicillanic acid derivative that binds specifically to penicillin-binding protein 2. The compound is more beta-lactamase stable than CHEMICAL and has no major delay in entry into the periplasmic space as do some penicillins. Amdinocillin inhibits most of the Enterobacteriaceae, with the exception of some indole-positive Proteus species, but it does not inhibit gram-positive cocci or Pseudomonas aeruginosa. Amdinocillin produces spherical bacterial cells that eventually lyse. Its activity in vitro is markedly affected by ionic content of media. This agent acts synergistically with many penicillins, such as CHEMICAL, carbenicillin, and the like, and with cephalosporins, cefazolin, cefamandole, or cefoxitin to inhibit gram-negative bacilli, probably on the basis of binding to different proteins needed for the production of the GENE of the bacterial cell wall. Amdinocillin possesses a number of the essentials for effective antimicrobial activity and, by virtue of its enhancement of the activity of other beta-lactams, may prove to be a useful agent in the chemotherapy of certain infections. | GENE-CHEMICAL |
| Penicillin-binding proteins and role of amdinocillin in causing bacterial cell death. The activity of penicillins against bacteria is in large part related to binding to specific receptor proteins involved in cell wall biosynthesis. These proteins have been designated penicillin-binding proteins. They can be separated into distinct entities through the use of acrylamide gel electrophoresis and binding of radioactive 14C-labeled penicillin G. Six major proteins have been defined in the Enterobacteriaceae, penicillin-binding proteins 1 to 6. Selection of mutants has shown that there are three essential proteins: penicillin-binding protein 1, which is divided into penicillin-binding protein 1Bs, a GENE transpeptidase, and penicillin-binding protein 1A, which acts as a replacement for penicillin-binding protein 1Bs. Penicillin-binding protein 2 is a murein-elongation initiating enzyme and penicillin-binding protein 3 is a septal murein-synthesizing enzyme. Penicillin-binding proteins 4, 5, and 6 are not essential for bacterial survival. Binding of penicillins to penicillin-binding protein 1Bs produces lysis, binding to penicillin-binding protein 2 produces round cells, and binding to penicillin-binding protein 3 produces long filaments. Amdinocillin is a beta-amidino penicillanic acid derivative that binds specifically to penicillin-binding protein 2. The compound is more beta-lactamase stable than ampicillin and has no major delay in entry into the periplasmic space as do some penicillins. Amdinocillin inhibits most of the Enterobacteriaceae, with the exception of some indole-positive Proteus species, but it does not inhibit gram-positive cocci or Pseudomonas aeruginosa. Amdinocillin produces spherical bacterial cells that eventually lyse. Its activity in vitro is markedly affected by ionic content of media. This agent acts synergistically with many penicillins, such as ampicillin, CHEMICAL, and the like, and with cephalosporins, cefazolin, cefamandole, or cefoxitin to inhibit gram-negative bacilli, probably on the basis of binding to different proteins needed for the production of the GENE of the bacterial cell wall. Amdinocillin possesses a number of the essentials for effective antimicrobial activity and, by virtue of its enhancement of the activity of other beta-lactams, may prove to be a useful agent in the chemotherapy of certain infections. | INHIBITOR |
| Penicillin-binding proteins and role of amdinocillin in causing bacterial cell death. The activity of penicillins against bacteria is in large part related to binding to specific receptor proteins involved in cell wall biosynthesis. These proteins have been designated penicillin-binding proteins. They can be separated into distinct entities through the use of acrylamide gel electrophoresis and binding of radioactive 14C-labeled penicillin G. Six major proteins have been defined in the Enterobacteriaceae, penicillin-binding proteins 1 to 6. Selection of mutants has shown that there are three essential proteins: penicillin-binding protein 1, which is divided into penicillin-binding protein 1Bs, a GENE transpeptidase, and penicillin-binding protein 1A, which acts as a replacement for penicillin-binding protein 1Bs. Penicillin-binding protein 2 is a murein-elongation initiating enzyme and penicillin-binding protein 3 is a septal murein-synthesizing enzyme. Penicillin-binding proteins 4, 5, and 6 are not essential for bacterial survival. Binding of penicillins to penicillin-binding protein 1Bs produces lysis, binding to penicillin-binding protein 2 produces round cells, and binding to penicillin-binding protein 3 produces long filaments. Amdinocillin is a beta-amidino penicillanic acid derivative that binds specifically to penicillin-binding protein 2. The compound is more beta-lactamase stable than ampicillin and has no major delay in entry into the periplasmic space as do some penicillins. Amdinocillin inhibits most of the Enterobacteriaceae, with the exception of some indole-positive Proteus species, but it does not inhibit gram-positive cocci or Pseudomonas aeruginosa. Amdinocillin produces spherical bacterial cells that eventually lyse. Its activity in vitro is markedly affected by ionic content of media. This agent acts synergistically with many penicillins, such as ampicillin, carbenicillin, and the like, and with CHEMICAL, cefazolin, cefamandole, or cefoxitin to inhibit gram-negative bacilli, probably on the basis of binding to different proteins needed for the production of the GENE of the bacterial cell wall. Amdinocillin possesses a number of the essentials for effective antimicrobial activity and, by virtue of its enhancement of the activity of other beta-lactams, may prove to be a useful agent in the chemotherapy of certain infections. | GENE-CHEMICAL |
| Penicillin-binding proteins and role of amdinocillin in causing bacterial cell death. The activity of penicillins against bacteria is in large part related to binding to specific receptor proteins involved in cell wall biosynthesis. These proteins have been designated penicillin-binding proteins. They can be separated into distinct entities through the use of acrylamide gel electrophoresis and binding of radioactive 14C-labeled penicillin G. Six major proteins have been defined in the Enterobacteriaceae, penicillin-binding proteins 1 to 6. Selection of mutants has shown that there are three essential proteins: penicillin-binding protein 1, which is divided into penicillin-binding protein 1Bs, a GENE transpeptidase, and penicillin-binding protein 1A, which acts as a replacement for penicillin-binding protein 1Bs. Penicillin-binding protein 2 is a murein-elongation initiating enzyme and penicillin-binding protein 3 is a septal murein-synthesizing enzyme. Penicillin-binding proteins 4, 5, and 6 are not essential for bacterial survival. Binding of penicillins to penicillin-binding protein 1Bs produces lysis, binding to penicillin-binding protein 2 produces round cells, and binding to penicillin-binding protein 3 produces long filaments. Amdinocillin is a beta-amidino penicillanic acid derivative that binds specifically to penicillin-binding protein 2. The compound is more beta-lactamase stable than ampicillin and has no major delay in entry into the periplasmic space as do some penicillins. Amdinocillin inhibits most of the Enterobacteriaceae, with the exception of some indole-positive Proteus species, but it does not inhibit gram-positive cocci or Pseudomonas aeruginosa. Amdinocillin produces spherical bacterial cells that eventually lyse. Its activity in vitro is markedly affected by ionic content of media. This agent acts synergistically with many penicillins, such as ampicillin, carbenicillin, and the like, and with cephalosporins, CHEMICAL, cefamandole, or cefoxitin to inhibit gram-negative bacilli, probably on the basis of binding to different proteins needed for the production of the GENE of the bacterial cell wall. Amdinocillin possesses a number of the essentials for effective antimicrobial activity and, by virtue of its enhancement of the activity of other beta-lactams, may prove to be a useful agent in the chemotherapy of certain infections. | GENE-CHEMICAL |
| Penicillin-binding proteins and role of amdinocillin in causing bacterial cell death. The activity of penicillins against bacteria is in large part related to binding to specific receptor proteins involved in cell wall biosynthesis. These proteins have been designated penicillin-binding proteins. They can be separated into distinct entities through the use of acrylamide gel electrophoresis and binding of radioactive 14C-labeled penicillin G. Six major proteins have been defined in the Enterobacteriaceae, penicillin-binding proteins 1 to 6. Selection of mutants has shown that there are three essential proteins: penicillin-binding protein 1, which is divided into penicillin-binding protein 1Bs, a GENE transpeptidase, and penicillin-binding protein 1A, which acts as a replacement for penicillin-binding protein 1Bs. Penicillin-binding protein 2 is a murein-elongation initiating enzyme and penicillin-binding protein 3 is a septal murein-synthesizing enzyme. Penicillin-binding proteins 4, 5, and 6 are not essential for bacterial survival. Binding of penicillins to penicillin-binding protein 1Bs produces lysis, binding to penicillin-binding protein 2 produces round cells, and binding to penicillin-binding protein 3 produces long filaments. Amdinocillin is a beta-amidino penicillanic acid derivative that binds specifically to penicillin-binding protein 2. The compound is more beta-lactamase stable than ampicillin and has no major delay in entry into the periplasmic space as do some penicillins. Amdinocillin inhibits most of the Enterobacteriaceae, with the exception of some indole-positive Proteus species, but it does not inhibit gram-positive cocci or Pseudomonas aeruginosa. Amdinocillin produces spherical bacterial cells that eventually lyse. Its activity in vitro is markedly affected by ionic content of media. This agent acts synergistically with many penicillins, such as ampicillin, carbenicillin, and the like, and with cephalosporins, cefazolin, CHEMICAL, or cefoxitin to inhibit gram-negative bacilli, probably on the basis of binding to different proteins needed for the production of the GENE of the bacterial cell wall. Amdinocillin possesses a number of the essentials for effective antimicrobial activity and, by virtue of its enhancement of the activity of other beta-lactams, may prove to be a useful agent in the chemotherapy of certain infections. | GENE-CHEMICAL |
| Penicillin-binding proteins and role of amdinocillin in causing bacterial cell death. The activity of penicillins against bacteria is in large part related to binding to specific receptor proteins involved in cell wall biosynthesis. These proteins have been designated penicillin-binding proteins. They can be separated into distinct entities through the use of acrylamide gel electrophoresis and binding of radioactive 14C-labeled penicillin G. Six major proteins have been defined in the Enterobacteriaceae, penicillin-binding proteins 1 to 6. Selection of mutants has shown that there are three essential proteins: penicillin-binding protein 1, which is divided into penicillin-binding protein 1Bs, a GENE transpeptidase, and penicillin-binding protein 1A, which acts as a replacement for penicillin-binding protein 1Bs. Penicillin-binding protein 2 is a murein-elongation initiating enzyme and penicillin-binding protein 3 is a septal murein-synthesizing enzyme. Penicillin-binding proteins 4, 5, and 6 are not essential for bacterial survival. Binding of penicillins to penicillin-binding protein 1Bs produces lysis, binding to penicillin-binding protein 2 produces round cells, and binding to penicillin-binding protein 3 produces long filaments. Amdinocillin is a beta-amidino penicillanic acid derivative that binds specifically to penicillin-binding protein 2. The compound is more beta-lactamase stable than ampicillin and has no major delay in entry into the periplasmic space as do some penicillins. Amdinocillin inhibits most of the Enterobacteriaceae, with the exception of some indole-positive Proteus species, but it does not inhibit gram-positive cocci or Pseudomonas aeruginosa. Amdinocillin produces spherical bacterial cells that eventually lyse. Its activity in vitro is markedly affected by ionic content of media. This agent acts synergistically with many penicillins, such as ampicillin, carbenicillin, and the like, and with cephalosporins, cefazolin, cefamandole, or CHEMICAL to inhibit gram-negative bacilli, probably on the basis of binding to different proteins needed for the production of the GENE of the bacterial cell wall. Amdinocillin possesses a number of the essentials for effective antimicrobial activity and, by virtue of its enhancement of the activity of other beta-lactams, may prove to be a useful agent in the chemotherapy of certain infections. | DIRECT-REGULATOR |
| Loss of alpha 2-macroglobulin and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and epidermal growth factor (EGF) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for alpha 2-macroglobulin, and the EGF receptors do not reappear at the surface when CHEMICAL is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. CHEMICAL did not induce a loss of cell surface GENE, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of CHEMICAL was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and CHEMICAL are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the CHEMICAL induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | NO-RELATIONSHIP |
| Loss of GENE and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain CHEMICAL [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for GENE, and epidermal growth factor (EGF) in fibroblasts. The loss of GENE receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for GENE, and the EGF receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of GENE and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled GENE, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled GENE. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | GENE-CHEMICAL |
| Loss of alpha 2-macroglobulin and GENE surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain CHEMICAL [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and GENE (EGF) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for alpha 2-macroglobulin, and the EGF receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | REGULATOR |
| Loss of alpha 2-macroglobulin and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain CHEMICAL [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and epidermal growth factor (GENE) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of GENE receptor loss is less than for alpha 2-macroglobulin, and the GENE receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and GENE receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | GENE-CHEMICAL |
| Loss of alpha 2-macroglobulin and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and epidermal growth factor (EGF) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of GENE loss is less than for alpha 2-macroglobulin, and the EGF receptors do not reappear at the surface when CHEMICAL is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. CHEMICAL did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of CHEMICAL was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and CHEMICAL are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the CHEMICAL induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | GENE-CHEMICAL |
| Loss of GENE and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., CHEMICAL (W-7)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for GENE, and epidermal growth factor (EGF) in fibroblasts. The loss of GENE receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for GENE, and the EGF receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of GENE and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled GENE, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled GENE. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | INHIBITOR |
| Loss of alpha 2-macroglobulin and GENE surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., CHEMICAL (W-7)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and GENE (EGF) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for alpha 2-macroglobulin, and the EGF receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | INHIBITOR |
| Loss of alpha 2-macroglobulin and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., CHEMICAL (W-7)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and epidermal growth factor (GENE) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of GENE receptor loss is less than for alpha 2-macroglobulin, and the GENE receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and GENE receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | GENE-CHEMICAL |
| Loss of alpha 2-macroglobulin and GENE surface binding induced by phenothiazines and CHEMICAL. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and GENE (EGF) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for alpha 2-macroglobulin, and the EGF receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | ACTIVATOR |
| Loss of GENE and epidermal growth factor surface binding induced by phenothiazines and CHEMICAL. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for GENE, and epidermal growth factor (EGF) in fibroblasts. The loss of GENE receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for GENE, and the EGF receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of GENE and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled GENE, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled GENE. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | GENE-CHEMICAL |
| Loss of GENE and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (CHEMICAL)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for GENE, and epidermal growth factor (EGF) in fibroblasts. The loss of GENE receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for GENE, and the EGF receptors do not reappear at the surface when CHEMICAL is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. CHEMICAL did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of CHEMICAL was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of GENE and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and CHEMICAL are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled GENE, we saw that the CHEMICAL induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled GENE. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | INHIBITOR |
| Loss of alpha 2-macroglobulin and GENE surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (CHEMICAL)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and GENE (EGF) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for alpha 2-macroglobulin, and the EGF receptors do not reappear at the surface when CHEMICAL is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. CHEMICAL did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of CHEMICAL was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and CHEMICAL are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the CHEMICAL induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | INHIBITOR |
| Loss of alpha 2-macroglobulin and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (CHEMICAL)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and epidermal growth factor (GENE) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of GENE receptor loss is less than for alpha 2-macroglobulin, and the GENE receptors do not reappear at the surface when CHEMICAL is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. CHEMICAL did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of CHEMICAL was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and GENE receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and CHEMICAL are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the CHEMICAL induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | GENE-CHEMICAL |
| Loss of alpha 2-macroglobulin and GENE surface binding induced by CHEMICAL and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and CHEMICAL [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and GENE (EGF) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for alpha 2-macroglobulin, and the EGF receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | DIRECT-REGULATOR |
| Loss of GENE and epidermal growth factor surface binding induced by CHEMICAL and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and CHEMICAL [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for GENE, and epidermal growth factor (EGF) in fibroblasts. The loss of GENE receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for GENE, and the EGF receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of GENE and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled GENE, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled GENE. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | GENE-CHEMICAL |
| Loss of alpha 2-macroglobulin and epidermal growth factor surface binding induced by CHEMICAL and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and CHEMICAL [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and epidermal growth factor (GENE) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of GENE receptor loss is less than for alpha 2-macroglobulin, and the GENE receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and GENE receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | GENE-CHEMICAL |
| Loss of GENE and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., CHEMICAL (TFP)] induce a loss of cell-surface receptors for GENE, and epidermal growth factor (EGF) in fibroblasts. The loss of GENE receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for GENE, and the EGF receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of GENE and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled GENE, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled GENE. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | INHIBITOR |
| Loss of alpha 2-macroglobulin and GENE surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., CHEMICAL (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and GENE (EGF) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for alpha 2-macroglobulin, and the EGF receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | INHIBITOR |
| Loss of alpha 2-macroglobulin and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., CHEMICAL (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and epidermal growth factor (GENE) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of GENE receptor loss is less than for alpha 2-macroglobulin, and the GENE receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and GENE receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | INHIBITOR |
| Loss of GENE and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., trifluoperazine (CHEMICAL)] induce a loss of cell-surface receptors for GENE, and epidermal growth factor (EGF) in fibroblasts. The loss of GENE receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for GENE, and the EGF receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of GENE and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both CHEMICAL and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as CHEMICAL at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled GENE, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled GENE. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | INHIBITOR |
| Loss of alpha 2-macroglobulin and GENE surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., trifluoperazine (CHEMICAL)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and GENE (EGF) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for alpha 2-macroglobulin, and the EGF receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both CHEMICAL and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as CHEMICAL at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | INHIBITOR |
| Loss of alpha 2-macroglobulin and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., trifluoperazine (CHEMICAL)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and epidermal growth factor (GENE) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of GENE receptor loss is less than for alpha 2-macroglobulin, and the GENE receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and GENE receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both CHEMICAL and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as CHEMICAL at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | INHIBITOR |
| Loss of GENE and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for GENE, and epidermal growth factor (EGF) in fibroblasts. The loss of GENE receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for GENE, and the EGF receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of GENE and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of calmodulin, we investigated the possibility that inhibition of calmodulin was responsible for the loss of receptors. Three lines of evidence suggest that calmodulin inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of calmodulin, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several calmodulin functions, did not cause a loss of binding; 2) the microinjection of calmodulin into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of calmodulin over native levels into individual gerbil fibroma cells; using CHEMICAL-labeled GENE, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled GENE. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic calmodulin but that shares some drug sensitivities with calmodulin. | DIRECT-REGULATOR |
| Loss of alpha 2-macroglobulin and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and epidermal growth factor (EGF) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for alpha 2-macroglobulin, and the EGF receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both CHEMICAL and W-7 are potent inhibitors of GENE, we investigated the possibility that inhibition of GENE was responsible for the loss of receptors. Three lines of evidence suggest that GENE inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of GENE, is nearly as effective as CHEMICAL at inhibiting endocytosis; calmidazolium, a potent inhibitor of several GENE functions, did not cause a loss of binding; 2) the microinjection of GENE into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of GENE over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic GENE but that shares some drug sensitivities with GENE. | INHIBITOR |
| Loss of alpha 2-macroglobulin and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and epidermal growth factor (EGF) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for alpha 2-macroglobulin, and the EGF receptors do not reappear at the surface when CHEMICAL is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. CHEMICAL did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of CHEMICAL was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and CHEMICAL are potent inhibitors of GENE, we investigated the possibility that inhibition of GENE was responsible for the loss of receptors. Three lines of evidence suggest that GENE inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a phenothiazine that is a poor inhibitor of GENE, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several GENE functions, did not cause a loss of binding; 2) the microinjection of GENE into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of GENE over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the CHEMICAL induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic GENE but that shares some drug sensitivities with GENE. | INHIBITOR |
| Loss of alpha 2-macroglobulin and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and epidermal growth factor (EGF) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for alpha 2-macroglobulin, and the EGF receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of GENE, we investigated the possibility that inhibition of GENE was responsible for the loss of receptors. Three lines of evidence suggest that GENE inhibition is not responsible for the inhibition of binding and endocytosis: 1) CHEMICAL, a phenothiazine that is a poor inhibitor of GENE, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several GENE functions, did not cause a loss of binding; 2) the microinjection of GENE into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of GENE over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic GENE but that shares some drug sensitivities with GENE. | INHIBITOR |
| Loss of alpha 2-macroglobulin and epidermal growth factor surface binding induced by phenothiazines and naphthalene sulfonamides. We have found that certain naphthalenesulfonamides [e.g., N-6(-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7)] and phenothiazines [e.g., trifluoperazine (TFP)] induce a loss of cell-surface receptors for alpha 2-macroglobulin, and epidermal growth factor (EGF) in fibroblasts. The loss of alpha 2-macroglobulin receptors is independent of receptor occupancy and is rapidly reversed upon removal of these agents from the culture medium. The extent of EGF receptor loss is less than for alpha 2-macroglobulin, and the EGF receptors do not reappear at the surface when W-7 is removed. Receptor loss was measured as a change in the capacity for binding iodinated ligands; no change in affinity of binding was observed. This receptor loss could reflect inactivation of receptors or internalization. W-7 did not induce a loss of cell surface beta 2-microglobulin, a membrane protein which is excluded from coated pits and which is not internalized, indicating that the effect of W-7 was specific for membrane receptors and not a result of bulk depletion of plasma membrane. The loss of alpha 2-macroglobulin and EGF receptors occurs at concentrations which do not cause an increase in the pH of endocytic vesicles or the cytoplasm, indicating that these agents act by a mechanism distinct from the effect of other weak bases. Since both TFP and W-7 are potent inhibitors of GENE, we investigated the possibility that inhibition of GENE was responsible for the loss of receptors. Three lines of evidence suggest that GENE inhibition is not responsible for the inhibition of binding and endocytosis: 1) Promethazine, a CHEMICAL that is a poor inhibitor of GENE, is nearly as effective as TFP at inhibiting endocytosis; calmidazolium, a potent inhibitor of several GENE functions, did not cause a loss of binding; 2) the microinjection of GENE into cells did not reverse the effects of W-7; using pressure microinjection, we introduced up to a 100-fold excess of GENE over native levels into individual gerbil fibroma cells; using rhodamine-labeled alpha 2-macroglobulin, we saw that the W-7 induced inhibition of receptor-mediated endocytosis was the same in injected and uninjected cells; 3) we injected calcineurin, a calmodulin-binding protein, into cells (1-3 pg/cell) and observed no effect on the receptor-mediated endocytosis of rhodamine-labeled alpha 2-macroglobulin. These data indicated that cell surface receptor numbers can be regulated by a cellular component that is not cytoplasmic GENE but that shares some drug sensitivities with GENE. | INHIBITOR |
| The effect of various amino acids and drugs on the para- and meta-hydroxyphenylacetic acid concentrations in the mouse caudate nucleus. Injection of L-p-tyrosine (800 mg/kg, 2 h) increased the mouse striatal para-hydroxyphenylacetic acid (p-HPAA) concentrations. A smaller dose of D,L-m-tyrosine (20 mg/kg, 2 h) produced a larger increase in mouse striatal meta-hydroxyphenylacetic acid (m-HPAA) concentrations. The administration of L-phenylalanine to mice caused a slight increase in the CHEMICAL concentration in the corpus striatum after 2 h while a larger dose of L-phenylalanine (800 mg/kg) produced a greater increase. Eight hours following L-phenylalanine injection, CHEMICAL concentrations were still elevated. With D-phenylalanine a significant increase was observed at eight hours after drug administration. Two drugs which reduce dopamine synthesis, alpha-methyl-para-tyrosine and apomorphine, decreased m-HPAA striatal concentrations without affecting CHEMICAL concentrations. From these results, it is proposed that GENE activity determines CHEMICAL concentrations by regulating p-tyrosine availability. This enzyme may also synthesize m-tyrosine which is subsequently decarboxylated to form m-tyramine and then oxidatively deaminated to form m-HPAA. | PRODUCT-OF |
| The effect of various amino acids and drugs on the para- and meta-hydroxyphenylacetic acid concentrations in the mouse caudate nucleus. Injection of L-p-tyrosine (800 mg/kg, 2 h) increased the mouse striatal para-hydroxyphenylacetic acid (p-HPAA) concentrations. A smaller dose of D,L-m-tyrosine (20 mg/kg, 2 h) produced a larger increase in mouse striatal meta-hydroxyphenylacetic acid (m-HPAA) concentrations. The administration of L-phenylalanine to mice caused a slight increase in the p-HPAA concentration in the corpus striatum after 2 h while a larger dose of L-phenylalanine (800 mg/kg) produced a greater increase. Eight hours following L-phenylalanine injection, p-HPAA concentrations were still elevated. With D-phenylalanine a significant increase was observed at eight hours after drug administration. Two drugs which reduce dopamine synthesis, alpha-methyl-para-tyrosine and apomorphine, decreased m-HPAA striatal concentrations without affecting p-HPAA concentrations. From these results, it is proposed that GENE activity determines p-HPAA concentrations by regulating CHEMICAL availability. This enzyme may also synthesize m-tyrosine which is subsequently decarboxylated to form m-tyramine and then oxidatively deaminated to form m-HPAA. | SUBSTRATE |
| Demonstration of histamine receptors on human platelets by flow cytometry. Fluoresceinated human albumin conjugated with histamine (FHA-HIS) has been used for the demonstration of histamine receptors on human platelets. Such receptors were demonstrated on 40-63% of peripheral blood platelets in 4 healthy donors. The binding of GENE-HIS was inhibited on 35-79% of the platelets by the histamine H1 receptor antagonists CHEMICAL and clemastine. The histamine H2 receptor antagonist cimetidine blocked the FHA-HIS binding on 14-37% of the platelets. It is concluded that histamine H1 as well as H2 receptors occur on human platelets but the receptors are not equally distributed in the platelet population. | INHIBITOR |
| Demonstration of histamine receptors on human platelets by flow cytometry. Fluoresceinated human albumin conjugated with histamine (FHA-HIS) has been used for the demonstration of histamine receptors on human platelets. Such receptors were demonstrated on 40-63% of peripheral blood platelets in 4 healthy donors. The binding of GENE-HIS was inhibited on 35-79% of the platelets by the histamine H1 receptor antagonists diphenhydramine and CHEMICAL. The histamine H2 receptor antagonist cimetidine blocked the FHA-HIS binding on 14-37% of the platelets. It is concluded that histamine H1 as well as H2 receptors occur on human platelets but the receptors are not equally distributed in the platelet population. | INHIBITOR |
| Demonstration of histamine receptors on human platelets by flow cytometry. Fluoresceinated human albumin conjugated with histamine (FHA-HIS) has been used for the demonstration of histamine receptors on human platelets. Such receptors were demonstrated on 40-63% of peripheral blood platelets in 4 healthy donors. The binding of FHA-HIS was inhibited on 35-79% of the platelets by the histamine H1 receptor antagonists diphenhydramine and clemastine. The histamine H2 receptor antagonist CHEMICAL blocked the GENE-HIS binding on 14-37% of the platelets. It is concluded that histamine H1 as well as H2 receptors occur on human platelets but the receptors are not equally distributed in the platelet population. | INHIBITOR |
| Demonstration of histamine receptors on human platelets by flow cytometry. Fluoresceinated human albumin conjugated with histamine (FHA-HIS) has been used for the demonstration of histamine receptors on human platelets. Such receptors were demonstrated on 40-63% of peripheral blood platelets in 4 healthy donors. The binding of FHA-HIS was inhibited on 35-79% of the platelets by the GENE antagonists CHEMICAL and clemastine. The histamine H2 receptor antagonist cimetidine blocked the FHA-HIS binding on 14-37% of the platelets. It is concluded that histamine H1 as well as H2 receptors occur on human platelets but the receptors are not equally distributed in the platelet population. | INHIBITOR |
| Demonstration of histamine receptors on human platelets by flow cytometry. Fluoresceinated human albumin conjugated with histamine (FHA-HIS) has been used for the demonstration of histamine receptors on human platelets. Such receptors were demonstrated on 40-63% of peripheral blood platelets in 4 healthy donors. The binding of FHA-HIS was inhibited on 35-79% of the platelets by the GENE antagonists diphenhydramine and CHEMICAL. The histamine H2 receptor antagonist cimetidine blocked the FHA-HIS binding on 14-37% of the platelets. It is concluded that histamine H1 as well as H2 receptors occur on human platelets but the receptors are not equally distributed in the platelet population. | INHIBITOR |
| Demonstration of histamine receptors on human platelets by flow cytometry. Fluoresceinated human albumin conjugated with histamine (FHA-HIS) has been used for the demonstration of histamine receptors on human platelets. Such receptors were demonstrated on 40-63% of peripheral blood platelets in 4 healthy donors. The binding of FHA-HIS was inhibited on 35-79% of the platelets by the histamine H1 receptor antagonists diphenhydramine and clemastine. The GENE antagonist CHEMICAL blocked the FHA-HIS binding on 14-37% of the platelets. It is concluded that histamine H1 as well as H2 receptors occur on human platelets but the receptors are not equally distributed in the platelet population. | INHIBITOR |
| The effect of vitamin B6 deficiency on alanine: CHEMICAL aminotransferase isoenzymes in rat liver. Endogenous synthesis of oxalate has been reported to increase in vitamin B6 deficiency probably due to defective transamination of CHEMICAL, the direct source of oxalate, to glycine. GENE (AGT) in the liver catalyzes most of the CHEMICAL transamination in mammalian tissues (E. V. Rowsell, K. Snell, J. A. Carnie, and K. V. Rowsell (1972) Biochem. J. 127, 155-165). The effects of vitamin B6 deficiency on hepatic AGT isoenzymes, designated AGT 1 and AGT 2, respectively, were examined with male rats; AGT 1 is located both in the peroxisomes and in the mitochondria, and AGT 2 only in the mitochondria. The holo activity of combined peroxisomal and mitochondrial AGT 1 with a low Km for L-alanine rapidly decreased after a lag time of about 2 days during feeding of the vitamin B6-deficient diet (by 50% in 5 days, by 86% in 14 days). Peroxisomal AGT 1 activity was more affected than the mitochondrial. The holo activity of AGT 2 with a high Km for L-alanine decreased more slowly than AGT 1 (by 33% in 14 days, by 60% in 28 days). Urinary excretion of oxalate began to increase in 8-9 days, when AGT 2 remained intact but most of AGT 1 is depleted. When the defect in the CHEMICAL transamination in vivo in vitamin B6 deficiency is considered, these findings suggest that it is due to the deficiency of AGT 1. The importance of peroxisomal AGT 1 is discussed, since peroxisomes have been described to be probably the major site of CHEMICAL formation. | SUBSTRATE |
| The effect of vitamin B6 deficiency on alanine: CHEMICAL aminotransferase isoenzymes in rat liver. Endogenous synthesis of oxalate has been reported to increase in vitamin B6 deficiency probably due to defective transamination of CHEMICAL, the direct source of oxalate, to glycine. Alanine:glyoxylate aminotransferase (GENE) in the liver catalyzes most of the CHEMICAL transamination in mammalian tissues (E. V. Rowsell, K. Snell, J. A. Carnie, and K. V. Rowsell (1972) Biochem. J. 127, 155-165). The effects of vitamin B6 deficiency on hepatic GENE isoenzymes, designated GENE 1 and GENE 2, respectively, were examined with male rats; GENE 1 is located both in the peroxisomes and in the mitochondria, and GENE 2 only in the mitochondria. The holo activity of combined peroxisomal and mitochondrial GENE 1 with a low Km for L-alanine rapidly decreased after a lag time of about 2 days during feeding of the vitamin B6-deficient diet (by 50% in 5 days, by 86% in 14 days). Peroxisomal GENE 1 activity was more affected than the mitochondrial. The holo activity of GENE 2 with a high Km for L-alanine decreased more slowly than GENE 1 (by 33% in 14 days, by 60% in 28 days). Urinary excretion of oxalate began to increase in 8-9 days, when GENE 2 remained intact but most of GENE 1 is depleted. When the defect in the CHEMICAL transamination in vivo in vitamin B6 deficiency is considered, these findings suggest that it is due to the deficiency of GENE 1. The importance of peroxisomal GENE 1 is discussed, since peroxisomes have been described to be probably the major site of CHEMICAL formation. | SUBSTRATE |
| The effect of vitamin B6 deficiency on alanine: glyoxylate aminotransferase isoenzymes in rat liver. Endogenous synthesis of oxalate has been reported to increase in vitamin B6 deficiency probably due to defective transamination of glyoxylate, the direct source of oxalate, to glycine. Alanine:glyoxylate aminotransferase (AGT) in the liver catalyzes most of the glyoxylate transamination in mammalian tissues (E. V. Rowsell, K. Snell, J. A. Carnie, and K. V. Rowsell (1972) Biochem. J. 127, 155-165). The effects of vitamin B6 deficiency on hepatic AGT isoenzymes, designated GENE and AGT 2, respectively, were examined with male rats; GENE is located both in the peroxisomes and in the mitochondria, and AGT 2 only in the mitochondria. The holo activity of combined peroxisomal and mitochondrial GENE with a low Km for CHEMICAL rapidly decreased after a lag time of about 2 days during feeding of the vitamin B6-deficient diet (by 50% in 5 days, by 86% in 14 days). Peroxisomal GENE activity was more affected than the mitochondrial. The holo activity of AGT 2 with a high Km for CHEMICAL decreased more slowly than GENE (by 33% in 14 days, by 60% in 28 days). Urinary excretion of oxalate began to increase in 8-9 days, when AGT 2 remained intact but most of GENE is depleted. When the defect in the glyoxylate transamination in vivo in vitamin B6 deficiency is considered, these findings suggest that it is due to the deficiency of GENE. The importance of peroxisomal GENE is discussed, since peroxisomes have been described to be probably the major site of glyoxylate formation. | SUBSTRATE |
| The effect of vitamin B6 deficiency on alanine: glyoxylate aminotransferase isoenzymes in rat liver. Endogenous synthesis of oxalate has been reported to increase in vitamin B6 deficiency probably due to defective transamination of glyoxylate, the direct source of oxalate, to glycine. Alanine:glyoxylate aminotransferase (AGT) in the liver catalyzes most of the glyoxylate transamination in mammalian tissues (E. V. Rowsell, K. Snell, J. A. Carnie, and K. V. Rowsell (1972) Biochem. J. 127, 155-165). The effects of vitamin B6 deficiency on hepatic AGT isoenzymes, designated AGT 1 and GENE, respectively, were examined with male rats; AGT 1 is located both in the peroxisomes and in the mitochondria, and GENE only in the mitochondria. The holo activity of combined peroxisomal and mitochondrial AGT 1 with a low Km for CHEMICAL rapidly decreased after a lag time of about 2 days during feeding of the vitamin B6-deficient diet (by 50% in 5 days, by 86% in 14 days). Peroxisomal AGT 1 activity was more affected than the mitochondrial. The holo activity of GENE with a high Km for CHEMICAL decreased more slowly than AGT 1 (by 33% in 14 days, by 60% in 28 days). Urinary excretion of oxalate began to increase in 8-9 days, when GENE remained intact but most of AGT 1 is depleted. When the defect in the glyoxylate transamination in vivo in vitamin B6 deficiency is considered, these findings suggest that it is due to the deficiency of AGT 1. The importance of peroxisomal AGT 1 is discussed, since peroxisomes have been described to be probably the major site of glyoxylate formation. | SUBSTRATE |
| The effect of triclosan on mediators of gingival inflammation. CHEMICAL (2,4,4',-trichloro-2'-hydroxydiphenylether) is a well-known and widely used nonionic antibacterial agent which has recently been introduced in toothpastes and mouthrinses. The efficacy of triclosan-containing toothpaste and mouthrinse to reduce both plaque and gingivitis in long-term clinical trials has been well documented. Until recently, it was generally assumed that triclosan's effect on gingival inflammation was due to its antimicrobial and anti-plaque effect. It has now become apparent that triclosan may have a direct anti-inflammatory effect on the gingival tissues. Several in vitro studies were conducted to evaluate the effect of triclosan on 4 primary enzymes of the pathways of arachidonic acid metabolism, cyclo-oxygenase 1, cyclo-oxygenase 2, 5-lipoxygenase and 15-lipoxygenase. These pathways lead to the production of known mediators of inflammation such as the prostaglandins, leukotrienes and lipoxins. CHEMICAL inhibited both GENE and cyclo-oxygenase 2 with IC-50 values of 43 microM and 227 microM, respectively. CHEMICAL also inhibited 5-lipoxygenase with an IC-50 of 43 microM. The 15-lipoxygenase was similarly inhibited by triclosan with an IC-50 of 61 microM. Hence, triclosan has the ability to inhibit both the cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism with similar efficacy. In cell culture experiments, it was found that triclosan inhibited IL-1 beta induced prostaglandin E2 production by human gingival fibroblasts in a concentration dependent manner, and at relatively low concentrations. These data, taken together, indicate that triclosan can inhibit formation of several important mediators of gingival inflammation.(ABSTRACT TRUNCATED AT 250 WORDS) | INHIBITOR |
| The effect of triclosan on mediators of gingival inflammation. CHEMICAL (2,4,4',-trichloro-2'-hydroxydiphenylether) is a well-known and widely used nonionic antibacterial agent which has recently been introduced in toothpastes and mouthrinses. The efficacy of triclosan-containing toothpaste and mouthrinse to reduce both plaque and gingivitis in long-term clinical trials has been well documented. Until recently, it was generally assumed that triclosan's effect on gingival inflammation was due to its antimicrobial and anti-plaque effect. It has now become apparent that triclosan may have a direct anti-inflammatory effect on the gingival tissues. Several in vitro studies were conducted to evaluate the effect of triclosan on 4 primary enzymes of the pathways of arachidonic acid metabolism, cyclo-oxygenase 1, GENE, 5-lipoxygenase and 15-lipoxygenase. These pathways lead to the production of known mediators of inflammation such as the prostaglandins, leukotrienes and lipoxins. CHEMICAL inhibited both cyclooxygenase 1 and GENE with IC-50 values of 43 microM and 227 microM, respectively. CHEMICAL also inhibited 5-lipoxygenase with an IC-50 of 43 microM. The 15-lipoxygenase was similarly inhibited by triclosan with an IC-50 of 61 microM. Hence, triclosan has the ability to inhibit both the cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism with similar efficacy. In cell culture experiments, it was found that triclosan inhibited IL-1 beta induced prostaglandin E2 production by human gingival fibroblasts in a concentration dependent manner, and at relatively low concentrations. These data, taken together, indicate that triclosan can inhibit formation of several important mediators of gingival inflammation.(ABSTRACT TRUNCATED AT 250 WORDS) | INHIBITOR |
| The effect of triclosan on mediators of gingival inflammation. CHEMICAL (2,4,4',-trichloro-2'-hydroxydiphenylether) is a well-known and widely used nonionic antibacterial agent which has recently been introduced in toothpastes and mouthrinses. The efficacy of triclosan-containing toothpaste and mouthrinse to reduce both plaque and gingivitis in long-term clinical trials has been well documented. Until recently, it was generally assumed that triclosan's effect on gingival inflammation was due to its antimicrobial and anti-plaque effect. It has now become apparent that triclosan may have a direct anti-inflammatory effect on the gingival tissues. Several in vitro studies were conducted to evaluate the effect of triclosan on 4 primary enzymes of the pathways of arachidonic acid metabolism, cyclo-oxygenase 1, cyclo-oxygenase 2, GENE and 15-lipoxygenase. These pathways lead to the production of known mediators of inflammation such as the prostaglandins, leukotrienes and lipoxins. CHEMICAL inhibited both cyclooxygenase 1 and cyclo-oxygenase 2 with IC-50 values of 43 microM and 227 microM, respectively. CHEMICAL also inhibited GENE with an IC-50 of 43 microM. The 15-lipoxygenase was similarly inhibited by triclosan with an IC-50 of 61 microM. Hence, triclosan has the ability to inhibit both the cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism with similar efficacy. In cell culture experiments, it was found that triclosan inhibited IL-1 beta induced prostaglandin E2 production by human gingival fibroblasts in a concentration dependent manner, and at relatively low concentrations. These data, taken together, indicate that triclosan can inhibit formation of several important mediators of gingival inflammation.(ABSTRACT TRUNCATED AT 250 WORDS) | INHIBITOR |
| The effect of CHEMICAL on mediators of gingival inflammation. CHEMICAL (2,4,4',-trichloro-2'-hydroxydiphenylether) is a well-known and widely used nonionic antibacterial agent which has recently been introduced in toothpastes and mouthrinses. The efficacy of triclosan-containing toothpaste and mouthrinse to reduce both plaque and gingivitis in long-term clinical trials has been well documented. Until recently, it was generally assumed that triclosan's effect on gingival inflammation was due to its antimicrobial and anti-plaque effect. It has now become apparent that CHEMICAL may have a direct anti-inflammatory effect on the gingival tissues. Several in vitro studies were conducted to evaluate the effect of CHEMICAL on 4 primary enzymes of the pathways of arachidonic acid metabolism, cyclo-oxygenase 1, cyclo-oxygenase 2, 5-lipoxygenase and GENE. These pathways lead to the production of known mediators of inflammation such as the prostaglandins, leukotrienes and lipoxins. CHEMICAL inhibited both cyclooxygenase 1 and cyclo-oxygenase 2 with IC-50 values of 43 microM and 227 microM, respectively. CHEMICAL also inhibited 5-lipoxygenase with an IC-50 of 43 microM. The GENE was similarly inhibited by CHEMICAL with an IC-50 of 61 microM. Hence, CHEMICAL has the ability to inhibit both the cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism with similar efficacy. In cell culture experiments, it was found that CHEMICAL inhibited IL-1 beta induced prostaglandin E2 production by human gingival fibroblasts in a concentration dependent manner, and at relatively low concentrations. These data, taken together, indicate that CHEMICAL can inhibit formation of several important mediators of gingival inflammation.(ABSTRACT TRUNCATED AT 250 WORDS) | INHIBITOR |
| The effect of CHEMICAL on mediators of gingival inflammation. CHEMICAL (2,4,4',-trichloro-2'-hydroxydiphenylether) is a well-known and widely used nonionic antibacterial agent which has recently been introduced in toothpastes and mouthrinses. The efficacy of triclosan-containing toothpaste and mouthrinse to reduce both plaque and gingivitis in long-term clinical trials has been well documented. Until recently, it was generally assumed that triclosan's effect on gingival inflammation was due to its antimicrobial and anti-plaque effect. It has now become apparent that CHEMICAL may have a direct anti-inflammatory effect on the gingival tissues. Several in vitro studies were conducted to evaluate the effect of CHEMICAL on 4 primary enzymes of the pathways of arachidonic acid metabolism, GENE 1, GENE 2, 5-lipoxygenase and 15-lipoxygenase. These pathways lead to the production of known mediators of inflammation such as the prostaglandins, leukotrienes and lipoxins. CHEMICAL inhibited both cyclooxygenase 1 and GENE 2 with IC-50 values of 43 microM and 227 microM, respectively. CHEMICAL also inhibited 5-lipoxygenase with an IC-50 of 43 microM. The 15-lipoxygenase was similarly inhibited by CHEMICAL with an IC-50 of 61 microM. Hence, CHEMICAL has the ability to inhibit both the GENE and lipoxygenase pathways of arachidonic acid metabolism with similar efficacy. In cell culture experiments, it was found that CHEMICAL inhibited IL-1 beta induced prostaglandin E2 production by human gingival fibroblasts in a concentration dependent manner, and at relatively low concentrations. These data, taken together, indicate that CHEMICAL can inhibit formation of several important mediators of gingival inflammation.(ABSTRACT TRUNCATED AT 250 WORDS) | INHIBITOR |
| The effect of CHEMICAL on mediators of gingival inflammation. CHEMICAL (2,4,4',-trichloro-2'-hydroxydiphenylether) is a well-known and widely used nonionic antibacterial agent which has recently been introduced in toothpastes and mouthrinses. The efficacy of triclosan-containing toothpaste and mouthrinse to reduce both plaque and gingivitis in long-term clinical trials has been well documented. Until recently, it was generally assumed that triclosan's effect on gingival inflammation was due to its antimicrobial and anti-plaque effect. It has now become apparent that CHEMICAL may have a direct anti-inflammatory effect on the gingival tissues. Several in vitro studies were conducted to evaluate the effect of CHEMICAL on 4 primary enzymes of the pathways of arachidonic acid metabolism, cyclo-oxygenase 1, cyclo-oxygenase 2, 5-lipoxygenase and 15-lipoxygenase. These pathways lead to the production of known mediators of inflammation such as the prostaglandins, leukotrienes and lipoxins. CHEMICAL inhibited both cyclooxygenase 1 and cyclo-oxygenase 2 with IC-50 values of 43 microM and 227 microM, respectively. CHEMICAL also inhibited 5-lipoxygenase with an IC-50 of 43 microM. The 15-lipoxygenase was similarly inhibited by CHEMICAL with an IC-50 of 61 microM. Hence, CHEMICAL has the ability to inhibit both the cyclo-oxygenase and GENE pathways of arachidonic acid metabolism with similar efficacy. In cell culture experiments, it was found that CHEMICAL inhibited IL-1 beta induced prostaglandin E2 production by human gingival fibroblasts in a concentration dependent manner, and at relatively low concentrations. These data, taken together, indicate that CHEMICAL can inhibit formation of several important mediators of gingival inflammation.(ABSTRACT TRUNCATED AT 250 WORDS) | INHIBITOR |
| The effect of CHEMICAL on mediators of gingival inflammation. CHEMICAL (2,4,4',-trichloro-2'-hydroxydiphenylether) is a well-known and widely used nonionic antibacterial agent which has recently been introduced in toothpastes and mouthrinses. The efficacy of triclosan-containing toothpaste and mouthrinse to reduce both plaque and gingivitis in long-term clinical trials has been well documented. Until recently, it was generally assumed that triclosan's effect on gingival inflammation was due to its antimicrobial and anti-plaque effect. It has now become apparent that CHEMICAL may have a direct anti-inflammatory effect on the gingival tissues. Several in vitro studies were conducted to evaluate the effect of CHEMICAL on 4 primary enzymes of the pathways of arachidonic acid metabolism, cyclo-oxygenase 1, cyclo-oxygenase 2, 5-lipoxygenase and 15-lipoxygenase. These pathways lead to the production of known mediators of inflammation such as the prostaglandins, leukotrienes and lipoxins. CHEMICAL inhibited both cyclooxygenase 1 and cyclo-oxygenase 2 with IC-50 values of 43 microM and 227 microM, respectively. CHEMICAL also inhibited 5-lipoxygenase with an IC-50 of 43 microM. The 15-lipoxygenase was similarly inhibited by CHEMICAL with an IC-50 of 61 microM. Hence, CHEMICAL has the ability to inhibit both the cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism with similar efficacy. In cell culture experiments, it was found that CHEMICAL inhibited GENE induced prostaglandin E2 production by human gingival fibroblasts in a concentration dependent manner, and at relatively low concentrations. These data, taken together, indicate that CHEMICAL can inhibit formation of several important mediators of gingival inflammation.(ABSTRACT TRUNCATED AT 250 WORDS) | INHIBITOR |
| The effect of triclosan on mediators of gingival inflammation. Triclosan (2,4,4',-trichloro-2'-hydroxydiphenylether) is a well-known and widely used nonionic antibacterial agent which has recently been introduced in toothpastes and mouthrinses. The efficacy of triclosan-containing toothpaste and mouthrinse to reduce both plaque and gingivitis in long-term clinical trials has been well documented. Until recently, it was generally assumed that triclosan's effect on gingival inflammation was due to its antimicrobial and anti-plaque effect. It has now become apparent that triclosan may have a direct anti-inflammatory effect on the gingival tissues. Several in vitro studies were conducted to evaluate the effect of triclosan on 4 primary enzymes of the pathways of arachidonic acid metabolism, cyclo-oxygenase 1, cyclo-oxygenase 2, 5-lipoxygenase and 15-lipoxygenase. These pathways lead to the production of known mediators of inflammation such as the prostaglandins, leukotrienes and lipoxins. Triclosan inhibited both cyclooxygenase 1 and cyclo-oxygenase 2 with IC-50 values of 43 microM and 227 microM, respectively. Triclosan also inhibited 5-lipoxygenase with an IC-50 of 43 microM. The 15-lipoxygenase was similarly inhibited by triclosan with an IC-50 of 61 microM. Hence, triclosan has the ability to inhibit both the cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism with similar efficacy. In cell culture experiments, it was found that triclosan inhibited GENE induced CHEMICAL production by human gingival fibroblasts in a concentration dependent manner, and at relatively low concentrations. These data, taken together, indicate that triclosan can inhibit formation of several important mediators of gingival inflammation.(ABSTRACT TRUNCATED AT 250 WORDS) | PRODUCT-OF |
| The effect of triclosan on mediators of gingival inflammation. Triclosan (2,4,4',-trichloro-2'-hydroxydiphenylether) is a well-known and widely used nonionic antibacterial agent which has recently been introduced in toothpastes and mouthrinses. The efficacy of triclosan-containing toothpaste and mouthrinse to reduce both plaque and gingivitis in long-term clinical trials has been well documented. Until recently, it was generally assumed that triclosan's effect on gingival inflammation was due to its antimicrobial and anti-plaque effect. It has now become apparent that triclosan may have a direct anti-inflammatory effect on the gingival tissues. Several in vitro studies were conducted to evaluate the effect of triclosan on 4 primary enzymes of the pathways of CHEMICAL metabolism, GENE 1, GENE 2, 5-lipoxygenase and 15-lipoxygenase. These pathways lead to the production of known mediators of inflammation such as the prostaglandins, leukotrienes and lipoxins. Triclosan inhibited both cyclooxygenase 1 and GENE 2 with IC-50 values of 43 microM and 227 microM, respectively. Triclosan also inhibited 5-lipoxygenase with an IC-50 of 43 microM. The 15-lipoxygenase was similarly inhibited by triclosan with an IC-50 of 61 microM. Hence, triclosan has the ability to inhibit both the GENE and lipoxygenase pathways of CHEMICAL metabolism with similar efficacy. In cell culture experiments, it was found that triclosan inhibited IL-1 beta induced prostaglandin E2 production by human gingival fibroblasts in a concentration dependent manner, and at relatively low concentrations. These data, taken together, indicate that triclosan can inhibit formation of several important mediators of gingival inflammation.(ABSTRACT TRUNCATED AT 250 WORDS) | SUBSTRATE |
| The effect of triclosan on mediators of gingival inflammation. Triclosan (2,4,4',-trichloro-2'-hydroxydiphenylether) is a well-known and widely used nonionic antibacterial agent which has recently been introduced in toothpastes and mouthrinses. The efficacy of triclosan-containing toothpaste and mouthrinse to reduce both plaque and gingivitis in long-term clinical trials has been well documented. Until recently, it was generally assumed that triclosan's effect on gingival inflammation was due to its antimicrobial and anti-plaque effect. It has now become apparent that triclosan may have a direct anti-inflammatory effect on the gingival tissues. Several in vitro studies were conducted to evaluate the effect of triclosan on 4 primary enzymes of the pathways of CHEMICAL metabolism, cyclo-oxygenase 1, cyclo-oxygenase 2, 5-lipoxygenase and 15-lipoxygenase. These pathways lead to the production of known mediators of inflammation such as the prostaglandins, leukotrienes and lipoxins. Triclosan inhibited both cyclooxygenase 1 and cyclo-oxygenase 2 with IC-50 values of 43 microM and 227 microM, respectively. Triclosan also inhibited 5-lipoxygenase with an IC-50 of 43 microM. The 15-lipoxygenase was similarly inhibited by triclosan with an IC-50 of 61 microM. Hence, triclosan has the ability to inhibit both the cyclo-oxygenase and GENE pathways of CHEMICAL metabolism with similar efficacy. In cell culture experiments, it was found that triclosan inhibited IL-1 beta induced prostaglandin E2 production by human gingival fibroblasts in a concentration dependent manner, and at relatively low concentrations. These data, taken together, indicate that triclosan can inhibit formation of several important mediators of gingival inflammation.(ABSTRACT TRUNCATED AT 250 WORDS) | SUBSTRATE |
| The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism. The uptake and metabolism of cobalamin (Cbl) has been studied in L-1210 murine leukemia cells propagating in vitro. Extracellular Cbl (protein bound and free) and intracellular Cbl (protein bound and free) were determined after culturing L-1210 cells in the presence of [57Co]cyanocobalamin (CHEMICAL) bound to GENE (transcobalamin, TC). The intracellular pool of free [57Co]Cbl increased during the first 24 h of culture and a substantial fraction of this free pool was effluxed from the cell to the medium. Upon depletion of extracellular TC-[57Co]CN-Cbl, the intracellular concentration of free Cbl decreased as did the efflux of Cbl to the medium. Internalized [57Co]CN-Cbl was converted to hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl) and 5'-deoxyadenosylcobalamin. These Cbl forms were found in both soluble (cytoplasmic) and insoluble (membrane) fractions. Intracellular protein-bound [57Co]Cbl fractionated with methionine synthase (MS) and methylmalonyl-CoA mutase (MU) activity. The major form of Cbl associated with the two enzymes was OH-Cbl. Cells propagated in medium containing N5-methyltetrahydrofolate and homocysteine showed a substantial increase in MS activity which paralleled the increase in the intracellular concentration of Me-Cbl and the Cbl bound to the enzyme. | DIRECT-REGULATOR |
| The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism. The uptake and metabolism of cobalamin (Cbl) has been studied in L-1210 murine leukemia cells propagating in vitro. Extracellular Cbl (protein bound and free) and intracellular Cbl (protein bound and free) were determined after culturing L-1210 cells in the presence of [57Co]cyanocobalamin (CHEMICAL) bound to GENE II (GENE, TC). The intracellular pool of free [57Co]Cbl increased during the first 24 h of culture and a substantial fraction of this free pool was effluxed from the cell to the medium. Upon depletion of extracellular TC-[57Co]CN-Cbl, the intracellular concentration of free Cbl decreased as did the efflux of Cbl to the medium. Internalized [57Co]CN-Cbl was converted to hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl) and 5'-deoxyadenosylcobalamin. These Cbl forms were found in both soluble (cytoplasmic) and insoluble (membrane) fractions. Intracellular protein-bound [57Co]Cbl fractionated with methionine synthase (MS) and methylmalonyl-CoA mutase (MU) activity. The major form of Cbl associated with the two enzymes was OH-Cbl. Cells propagated in medium containing N5-methyltetrahydrofolate and homocysteine showed a substantial increase in MS activity which paralleled the increase in the intracellular concentration of Me-Cbl and the Cbl bound to the enzyme. | DIRECT-REGULATOR |
| The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism. The uptake and metabolism of cobalamin (Cbl) has been studied in L-1210 murine leukemia cells propagating in vitro. Extracellular Cbl (protein bound and free) and intracellular Cbl (protein bound and free) were determined after culturing L-1210 cells in the presence of [57Co]cyanocobalamin (CHEMICAL) bound to transcobalamin II (transcobalamin, GENE). The intracellular pool of free [57Co]Cbl increased during the first 24 h of culture and a substantial fraction of this free pool was effluxed from the cell to the medium. Upon depletion of extracellular TC-[57Co]CN-Cbl, the intracellular concentration of free Cbl decreased as did the efflux of Cbl to the medium. Internalized [57Co]CN-Cbl was converted to hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl) and 5'-deoxyadenosylcobalamin. These Cbl forms were found in both soluble (cytoplasmic) and insoluble (membrane) fractions. Intracellular protein-bound [57Co]Cbl fractionated with methionine synthase (MS) and methylmalonyl-CoA mutase (MU) activity. The major form of Cbl associated with the two enzymes was OH-Cbl. Cells propagated in medium containing N5-methyltetrahydrofolate and homocysteine showed a substantial increase in MS activity which paralleled the increase in the intracellular concentration of Me-Cbl and the Cbl bound to the enzyme. | DIRECT-REGULATOR |
| The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism. The uptake and metabolism of cobalamin (Cbl) has been studied in L-1210 murine leukemia cells propagating in vitro. Extracellular Cbl (protein bound and free) and intracellular Cbl (protein bound and free) were determined after culturing L-1210 cells in the presence of [57Co]cyanocobalamin (CN-Cbl) bound to transcobalamin II (transcobalamin, TC). The intracellular pool of free CHEMICAL increased during the first 24 h of culture and a substantial fraction of this free pool was effluxed from the cell to the medium. Upon depletion of extracellular TC-[57Co]CN-Cbl, the intracellular concentration of free Cbl decreased as did the efflux of Cbl to the medium. Internalized [57Co]CN-Cbl was converted to hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl) and 5'-deoxyadenosylcobalamin. These Cbl forms were found in both soluble (cytoplasmic) and insoluble (membrane) fractions. Intracellular protein-bound CHEMICAL fractionated with GENE (MS) and methylmalonyl-CoA mutase (MU) activity. The major form of Cbl associated with the two enzymes was OH-Cbl. Cells propagated in medium containing N5-methyltetrahydrofolate and homocysteine showed a substantial increase in MS activity which paralleled the increase in the intracellular concentration of Me-Cbl and the Cbl bound to the enzyme. | PART-OF |
| The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism. The uptake and metabolism of cobalamin (Cbl) has been studied in L-1210 murine leukemia cells propagating in vitro. Extracellular Cbl (protein bound and free) and intracellular Cbl (protein bound and free) were determined after culturing L-1210 cells in the presence of [57Co]cyanocobalamin (CN-Cbl) bound to transcobalamin II (transcobalamin, TC). The intracellular pool of free CHEMICAL increased during the first 24 h of culture and a substantial fraction of this free pool was effluxed from the cell to the medium. Upon depletion of extracellular TC-[57Co]CN-Cbl, the intracellular concentration of free Cbl decreased as did the efflux of Cbl to the medium. Internalized [57Co]CN-Cbl was converted to hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl) and 5'-deoxyadenosylcobalamin. These Cbl forms were found in both soluble (cytoplasmic) and insoluble (membrane) fractions. Intracellular protein-bound CHEMICAL fractionated with methionine synthase (GENE) and methylmalonyl-CoA mutase (MU) activity. The major form of Cbl associated with the two enzymes was OH-Cbl. Cells propagated in medium containing N5-methyltetrahydrofolate and homocysteine showed a substantial increase in GENE activity which paralleled the increase in the intracellular concentration of Me-Cbl and the Cbl bound to the enzyme. | SUBSTRATE |
| The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism. The uptake and metabolism of cobalamin (Cbl) has been studied in L-1210 murine leukemia cells propagating in vitro. Extracellular Cbl (protein bound and free) and intracellular Cbl (protein bound and free) were determined after culturing L-1210 cells in the presence of [57Co]cyanocobalamin (CN-Cbl) bound to transcobalamin II (transcobalamin, TC). The intracellular pool of free CHEMICAL increased during the first 24 h of culture and a substantial fraction of this free pool was effluxed from the cell to the medium. Upon depletion of extracellular TC-[57Co]CN-Cbl, the intracellular concentration of free Cbl decreased as did the efflux of Cbl to the medium. Internalized [57Co]CN-Cbl was converted to hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl) and 5'-deoxyadenosylcobalamin. These Cbl forms were found in both soluble (cytoplasmic) and insoluble (membrane) fractions. Intracellular protein-bound CHEMICAL fractionated with methionine synthase (MS) and GENE (MU) activity. The major form of Cbl associated with the two enzymes was OH-Cbl. Cells propagated in medium containing N5-methyltetrahydrofolate and homocysteine showed a substantial increase in MS activity which paralleled the increase in the intracellular concentration of Me-Cbl and the Cbl bound to the enzyme. | SUBSTRATE |
| The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism. The uptake and metabolism of cobalamin (Cbl) has been studied in L-1210 murine leukemia cells propagating in vitro. Extracellular Cbl (protein bound and free) and intracellular Cbl (protein bound and free) were determined after culturing L-1210 cells in the presence of [57Co]cyanocobalamin (CN-Cbl) bound to transcobalamin II (transcobalamin, TC). The intracellular pool of free CHEMICAL increased during the first 24 h of culture and a substantial fraction of this free pool was effluxed from the cell to the medium. Upon depletion of extracellular TC-[57Co]CN-Cbl, the intracellular concentration of free Cbl decreased as did the efflux of Cbl to the medium. Internalized [57Co]CN-Cbl was converted to hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl) and 5'-deoxyadenosylcobalamin. These Cbl forms were found in both soluble (cytoplasmic) and insoluble (membrane) fractions. Intracellular protein-bound CHEMICAL fractionated with methionine synthase (MS) and methylmalonyl-CoA mutase (GENE) activity. The major form of Cbl associated with the two enzymes was OH-Cbl. Cells propagated in medium containing N5-methyltetrahydrofolate and homocysteine showed a substantial increase in MS activity which paralleled the increase in the intracellular concentration of Me-Cbl and the Cbl bound to the enzyme. | SUBSTRATE |
| The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism. The uptake and metabolism of cobalamin (Cbl) has been studied in L-1210 murine leukemia cells propagating in vitro. Extracellular Cbl (protein bound and free) and intracellular Cbl (protein bound and free) were determined after culturing L-1210 cells in the presence of CHEMICAL (CN-Cbl) bound to GENE (transcobalamin, TC). The intracellular pool of free [57Co]Cbl increased during the first 24 h of culture and a substantial fraction of this free pool was effluxed from the cell to the medium. Upon depletion of extracellular TC-[57Co]CN-Cbl, the intracellular concentration of free Cbl decreased as did the efflux of Cbl to the medium. Internalized [57Co]CN-Cbl was converted to hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl) and 5'-deoxyadenosylcobalamin. These Cbl forms were found in both soluble (cytoplasmic) and insoluble (membrane) fractions. Intracellular protein-bound [57Co]Cbl fractionated with methionine synthase (MS) and methylmalonyl-CoA mutase (MU) activity. The major form of Cbl associated with the two enzymes was OH-Cbl. Cells propagated in medium containing N5-methyltetrahydrofolate and homocysteine showed a substantial increase in MS activity which paralleled the increase in the intracellular concentration of Me-Cbl and the Cbl bound to the enzyme. | DIRECT-REGULATOR |
| The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism. The uptake and metabolism of cobalamin (Cbl) has been studied in L-1210 murine leukemia cells propagating in vitro. Extracellular Cbl (protein bound and free) and intracellular Cbl (protein bound and free) were determined after culturing L-1210 cells in the presence of CHEMICAL (CN-Cbl) bound to GENE II (GENE, TC). The intracellular pool of free [57Co]Cbl increased during the first 24 h of culture and a substantial fraction of this free pool was effluxed from the cell to the medium. Upon depletion of extracellular TC-[57Co]CN-Cbl, the intracellular concentration of free Cbl decreased as did the efflux of Cbl to the medium. Internalized [57Co]CN-Cbl was converted to hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl) and 5'-deoxyadenosylcobalamin. These Cbl forms were found in both soluble (cytoplasmic) and insoluble (membrane) fractions. Intracellular protein-bound [57Co]Cbl fractionated with methionine synthase (MS) and methylmalonyl-CoA mutase (MU) activity. The major form of Cbl associated with the two enzymes was OH-Cbl. Cells propagated in medium containing N5-methyltetrahydrofolate and homocysteine showed a substantial increase in MS activity which paralleled the increase in the intracellular concentration of Me-Cbl and the Cbl bound to the enzyme. | DIRECT-REGULATOR |
| The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism. The uptake and metabolism of cobalamin (Cbl) has been studied in L-1210 murine leukemia cells propagating in vitro. Extracellular Cbl (protein bound and free) and intracellular Cbl (protein bound and free) were determined after culturing L-1210 cells in the presence of CHEMICAL (CN-Cbl) bound to transcobalamin II (transcobalamin, GENE). The intracellular pool of free [57Co]Cbl increased during the first 24 h of culture and a substantial fraction of this free pool was effluxed from the cell to the medium. Upon depletion of extracellular TC-[57Co]CN-Cbl, the intracellular concentration of free Cbl decreased as did the efflux of Cbl to the medium. Internalized [57Co]CN-Cbl was converted to hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl) and 5'-deoxyadenosylcobalamin. These Cbl forms were found in both soluble (cytoplasmic) and insoluble (membrane) fractions. Intracellular protein-bound [57Co]Cbl fractionated with methionine synthase (MS) and methylmalonyl-CoA mutase (MU) activity. The major form of Cbl associated with the two enzymes was OH-Cbl. Cells propagated in medium containing N5-methyltetrahydrofolate and homocysteine showed a substantial increase in MS activity which paralleled the increase in the intracellular concentration of Me-Cbl and the Cbl bound to the enzyme. | DIRECT-REGULATOR |
| The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism. The uptake and metabolism of cobalamin (Cbl) has been studied in L-1210 murine leukemia cells propagating in vitro. Extracellular Cbl (protein bound and free) and intracellular Cbl (protein bound and free) were determined after culturing L-1210 cells in the presence of [57Co]cyanocobalamin (CN-Cbl) bound to transcobalamin II (transcobalamin, TC). The intracellular pool of free [57Co]Cbl increased during the first 24 h of culture and a substantial fraction of this free pool was effluxed from the cell to the medium. Upon depletion of extracellular TC-[57Co]CN-Cbl, the intracellular concentration of free Cbl decreased as did the efflux of Cbl to the medium. Internalized [57Co]CN-Cbl was converted to hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl) and 5'-deoxyadenosylcobalamin. These Cbl forms were found in both soluble (cytoplasmic) and insoluble (membrane) fractions. Intracellular protein-bound [57Co]Cbl fractionated with methionine synthase (MS) and methylmalonyl-CoA mutase (MU) activity. The major form of Cbl associated with the two enzymes was OH-Cbl. Cells propagated in medium containing CHEMICAL and homocysteine showed a substantial increase in GENE activity which paralleled the increase in the intracellular concentration of Me-Cbl and the Cbl bound to the enzyme. | ACTIVATOR |
| The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism. The uptake and metabolism of cobalamin (Cbl) has been studied in L-1210 murine leukemia cells propagating in vitro. Extracellular Cbl (protein bound and free) and intracellular Cbl (protein bound and free) were determined after culturing L-1210 cells in the presence of [57Co]cyanocobalamin (CN-Cbl) bound to transcobalamin II (transcobalamin, TC). The intracellular pool of free [57Co]Cbl increased during the first 24 h of culture and a substantial fraction of this free pool was effluxed from the cell to the medium. Upon depletion of extracellular TC-[57Co]CN-Cbl, the intracellular concentration of free Cbl decreased as did the efflux of Cbl to the medium. Internalized [57Co]CN-Cbl was converted to hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl) and 5'-deoxyadenosylcobalamin. These Cbl forms were found in both soluble (cytoplasmic) and insoluble (membrane) fractions. Intracellular protein-bound [57Co]Cbl fractionated with methionine synthase (MS) and methylmalonyl-CoA mutase (MU) activity. The major form of Cbl associated with the two enzymes was OH-Cbl. Cells propagated in medium containing N5-methyltetrahydrofolate and CHEMICAL showed a substantial increase in GENE activity which paralleled the increase in the intracellular concentration of Me-Cbl and the Cbl bound to the enzyme. | ACTIVATOR |
| CHEMICAL binding and activation of D2 dopamine receptors in GH4ZR7 cells. CHEMICAL inhibition of radioligand binding to the GENE and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat GENE, were evaluated. CHEMICAL inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting VIP-stimulated cyclic AMP production, with EC50 values for ergovaline, ergonovine, alpha-ergocryptine, ergotamine, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by ergovaline was blocked by the dopamine receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to D2 dopamine receptors and elicit second messenger responses similar to that of dopamine. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to GENE activation. | DIRECT-REGULATOR |
| CHEMICAL binding and activation of GENE in GH4ZR7 cells. CHEMICAL inhibition of radioligand binding to the D2 dopamine receptor and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat D2 dopamine receptor, were evaluated. CHEMICAL inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting VIP-stimulated cyclic AMP production, with EC50 values for CHEMICAL, ergonovine, alpha-ergocryptine, ergotamine, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by CHEMICAL was blocked by the dopamine receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially CHEMICAL, bind to GENE and elicit second messenger responses similar to that of dopamine. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including CHEMICAL, may be due to D2 dopamine receptor activation. | ACTIVATOR |
| Ergovaline binding and activation of D2 CHEMICAL receptors in GH4ZR7 cells. Ergovaline inhibition of radioligand binding to the D2 CHEMICAL receptor and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat D2 CHEMICAL receptor, were evaluated. Ergovaline inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas CHEMICAL was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting VIP-stimulated cyclic AMP production, with EC50 values for ergovaline, ergonovine, alpha-ergocryptine, ergotamine, and CHEMICAL of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by ergovaline was blocked by the CHEMICAL receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to GENE and elicit second messenger responses similar to that of CHEMICAL. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to D2 CHEMICAL receptor activation. | DIRECT-REGULATOR |
| CHEMICAL binding and activation of GENE dopamine receptors in GH4ZR7 cells. CHEMICAL inhibition of radioligand binding to the GENE dopamine receptor and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat GENE dopamine receptor, were evaluated. CHEMICAL inhibition of the binding of the GENE-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting VIP-stimulated cyclic AMP production, with EC50 values for ergovaline, ergonovine, alpha-ergocryptine, ergotamine, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by ergovaline was blocked by the dopamine receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to GENE dopamine receptors and elicit second messenger responses similar to that of dopamine. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to GENE dopamine receptor activation. | INHIBITOR |
| Ergovaline binding and activation of GENE dopamine receptors in GH4ZR7 cells. Ergovaline inhibition of radioligand binding to the GENE dopamine receptor and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat GENE dopamine receptor, were evaluated. Ergovaline inhibition of the binding of the GENE-specific radioligand, CHEMICAL, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting VIP-stimulated cyclic AMP production, with EC50 values for ergovaline, ergonovine, alpha-ergocryptine, ergotamine, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by ergovaline was blocked by the dopamine receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to GENE dopamine receptors and elicit second messenger responses similar to that of dopamine. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to GENE dopamine receptor activation. | DIRECT-REGULATOR |
| Ergovaline binding and activation of GENE CHEMICAL receptors in GH4ZR7 cells. Ergovaline inhibition of radioligand binding to the GENE CHEMICAL receptor and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat GENE CHEMICAL receptor, were evaluated. Ergovaline inhibition of the binding of the GENE-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas CHEMICAL was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting VIP-stimulated cyclic AMP production, with EC50 values for ergovaline, ergonovine, alpha-ergocryptine, ergotamine, and CHEMICAL of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by ergovaline was blocked by the CHEMICAL receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to GENE CHEMICAL receptors and elicit second messenger responses similar to that of CHEMICAL. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to GENE CHEMICAL receptor activation. | DIRECT-REGULATOR |
| Ergovaline binding and activation of D2 dopamine receptors in GH4ZR7 cells. Ergovaline inhibition of radioligand binding to the GENE and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat GENE, were evaluated. Ergovaline inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM). CHEMICAL were also effective in inhibiting VIP-stimulated cyclic AMP production, with EC50 values for ergovaline, ergonovine, alpha-ergocryptine, ergotamine, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by ergovaline was blocked by the dopamine receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to D2 dopamine receptors and elicit second messenger responses similar to that of dopamine. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several CHEMICAL including ergovaline, may be due to GENE activation. | ACTIVATOR |
| Ergovaline binding and activation of D2 dopamine receptors in GH4ZR7 cells. Ergovaline inhibition of radioligand binding to the D2 dopamine receptor and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat D2 dopamine receptor, were evaluated. Ergovaline inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM). CHEMICAL were also effective in inhibiting GENE-stimulated cyclic AMP production, with EC50 values for ergovaline, ergonovine, alpha-ergocryptine, ergotamine, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by ergovaline was blocked by the dopamine receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to D2 dopamine receptors and elicit second messenger responses similar to that of dopamine. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to D2 dopamine receptor activation. | INHIBITOR |
| CHEMICAL binding and activation of D2 dopamine receptors in GH4ZR7 cells. CHEMICAL inhibition of radioligand binding to the D2 dopamine receptor and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat D2 dopamine receptor, were evaluated. CHEMICAL inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting GENE-stimulated cyclic AMP production, with EC50 values for CHEMICAL, ergonovine, alpha-ergocryptine, ergotamine, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by CHEMICAL was blocked by the dopamine receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially CHEMICAL, bind to D2 dopamine receptors and elicit second messenger responses similar to that of dopamine. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including CHEMICAL, may be due to D2 dopamine receptor activation. | INHIBITOR |
| Ergovaline binding and activation of D2 dopamine receptors in GH4ZR7 cells. Ergovaline inhibition of radioligand binding to the D2 dopamine receptor and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat D2 dopamine receptor, were evaluated. Ergovaline inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting GENE-stimulated cyclic AMP production, with EC50 values for ergovaline, CHEMICAL, alpha-ergocryptine, ergotamine, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by ergovaline was blocked by the dopamine receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to D2 dopamine receptors and elicit second messenger responses similar to that of dopamine. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to D2 dopamine receptor activation. | INHIBITOR |
| Ergovaline binding and activation of D2 dopamine receptors in GH4ZR7 cells. Ergovaline inhibition of radioligand binding to the D2 dopamine receptor and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat D2 dopamine receptor, were evaluated. Ergovaline inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting GENE-stimulated cyclic AMP production, with EC50 values for ergovaline, ergonovine, CHEMICAL, ergotamine, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by ergovaline was blocked by the dopamine receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to D2 dopamine receptors and elicit second messenger responses similar to that of dopamine. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to D2 dopamine receptor activation. | INHIBITOR |
| Ergovaline binding and activation of D2 dopamine receptors in GH4ZR7 cells. Ergovaline inhibition of radioligand binding to the D2 dopamine receptor and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat D2 dopamine receptor, were evaluated. Ergovaline inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting GENE-stimulated cyclic AMP production, with EC50 values for ergovaline, ergonovine, alpha-ergocryptine, CHEMICAL, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by ergovaline was blocked by the dopamine receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to D2 dopamine receptors and elicit second messenger responses similar to that of dopamine. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to D2 dopamine receptor activation. | INHIBITOR |
| Ergovaline binding and activation of D2 CHEMICAL receptors in GH4ZR7 cells. Ergovaline inhibition of radioligand binding to the D2 CHEMICAL receptor and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat D2 CHEMICAL receptor, were evaluated. Ergovaline inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas CHEMICAL was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting GENE-stimulated cyclic AMP production, with EC50 values for ergovaline, ergonovine, alpha-ergocryptine, ergotamine, and CHEMICAL of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by ergovaline was blocked by the CHEMICAL receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to D2 CHEMICAL receptors and elicit second messenger responses similar to that of CHEMICAL. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to D2 CHEMICAL receptor activation. | INHIBITOR |
| Ergovaline binding and activation of D2 dopamine receptors in GH4ZR7 cells. Ergovaline inhibition of radioligand binding to the D2 dopamine receptor and CHEMICAL inhibition of GENE (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat D2 dopamine receptor, were evaluated. Ergovaline inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting VIP-stimulated cyclic AMP production, with EC50 values for ergovaline, ergonovine, alpha-ergocryptine, ergotamine, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by ergovaline was blocked by the dopamine receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to D2 dopamine receptors and elicit second messenger responses similar to that of dopamine. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to D2 dopamine receptor activation. | INHIBITOR |
| Ergovaline binding and activation of D2 dopamine receptors in GH4ZR7 cells. Ergovaline inhibition of radioligand binding to the D2 dopamine receptor and CHEMICAL inhibition of vasoactive intestinal peptide (GENE)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat D2 dopamine receptor, were evaluated. Ergovaline inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting VIP-stimulated cyclic AMP production, with EC50 values for ergovaline, ergonovine, alpha-ergocryptine, ergotamine, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by ergovaline was blocked by the dopamine receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to D2 dopamine receptors and elicit second messenger responses similar to that of dopamine. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to D2 dopamine receptor activation. | INHIBITOR |
| Ergovaline binding and activation of D2 dopamine receptors in GH4ZR7 cells. Ergovaline inhibition of radioligand binding to the D2 GENE and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP production in GH4ZR7 cells, stably transfected with a rat D2 GENE, were evaluated. Ergovaline inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting VIP-stimulated cyclic AMP production, with EC50 values for ergovaline, ergonovine, alpha-ergocryptine, ergotamine, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of cyclic AMP production by ergovaline was blocked by the GENE antagonist, CHEMICAL (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to D2 dopamine receptors and elicit second messenger responses similar to that of dopamine. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to D2 GENE activation. | INHIBITOR |
| Ergovaline binding and activation of D2 dopamine receptors in GH4ZR7 cells. Ergovaline inhibition of radioligand binding to the D2 dopamine receptor and ergot alkaloid inhibition of vasoactive intestinal peptide (VIP)-stimulated CHEMICAL production in GH4ZR7 cells, stably transfected with a rat D2 dopamine receptor, were evaluated. Ergovaline inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting GENE-stimulated CHEMICAL production, with EC50 values for ergovaline, ergonovine, alpha-ergocryptine, ergotamine, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of CHEMICAL production by ergovaline was blocked by the dopamine receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to D2 dopamine receptors and elicit second messenger responses similar to that of dopamine. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to D2 dopamine receptor activation. | PRODUCT-OF |
| Ergovaline binding and activation of D2 dopamine receptors in GH4ZR7 cells. Ergovaline inhibition of radioligand binding to the D2 dopamine receptor and ergot alkaloid inhibition of GENE (VIP)-stimulated CHEMICAL production in GH4ZR7 cells, stably transfected with a rat D2 dopamine receptor, were evaluated. Ergovaline inhibition of the binding of the D2-specific radioligand, [3H]YM-09151-2, exhibited a KI (inhibition constant) of 6.9 +/- 2.6 nM, whereas dopamine was much less potent (370 +/- 160 nM). Ergot alkaloids were also effective in inhibiting VIP-stimulated CHEMICAL production, with EC50 values for ergovaline, ergonovine, alpha-ergocryptine, ergotamine, and dopamine of 8 +/- 2, 47 +/- 2, 28 +/- 2, 2 +/- 1, and 8 +/- 1 nM, respectively. Inhibition of CHEMICAL production by ergovaline was blocked by the dopamine receptor antagonist, (-)-sulpiride (IC50, 300 +/- 150 nM). Our results indicate that ergot compounds, especially ergovaline, bind to D2 dopamine receptors and elicit second messenger responses similar to that of dopamine. These findings suggest that some of the deleterious effects of consumption of endophyte-infected tall fescue, which contains several ergot alkaloids including ergovaline, may be due to D2 dopamine receptor activation. | PRODUCT-OF |
| Binding of antipsychotic drugs at alpha 1A- and alpha 1B-adrenoceptors: risperidone is selective for the alpha 1B-adrenoceptors. The binding of the antipsychotic drugs risperidone, (+)-butaclamol, clozapine, haloperidol, spiperone, thioridazine and YM-09151-2 was studied at the subtypes of the alpha 1-adrenoceptor. Saturation experiments showed that CHEMICAL labelled a single population of binding sites in the spleen (GENE) and hippocampus (alpha 1A and alpha 1B) (dissociation constants (KD): 0.26 nM and 0.14 nM respectively). Prazosin displaced the radioligand in a monophasic manner in both the spleen and hippocampus whereas 5-methyl-urapidil, phentolamine and WB 4101 displaced the radioligand in a monophasic manner in the spleen but in a biphasic manner in the hippocampus. The affinity of these three compounds for the low affinity site in the hippocampus was similar to that observed in the spleen, suggesting that all three were selective for the alpha 1A-adrenoceptor. Furthermore, the affinities for the alpha 1A- and alpha 1B-adrenoceptors calculated in this manner were in agreement with literature values. With the exception of risperidone, all the antipsychotic drugs tested failed to show selectivity for either of the alpha 1-adrenoceptor subtypes. Risperidone was 120-fold more selective for the alpha 1B-adrenoceptor with respect to the alpha 1A-adrenoceptor (Ki values: 2.3 +/- 1.2 nM and 283.6 +/- 174.1 nM respectively). | DIRECT-REGULATOR |
| Binding of antipsychotic drugs at alpha 1A- and alpha 1B-adrenoceptors: risperidone is selective for the alpha 1B-adrenoceptors. The binding of the antipsychotic drugs risperidone, (+)-butaclamol, clozapine, haloperidol, spiperone, thioridazine and YM-09151-2 was studied at the subtypes of the alpha 1-adrenoceptor. Saturation experiments showed that CHEMICAL labelled a single population of binding sites in the spleen (alpha 1B) and hippocampus (GENE and alpha 1B) (dissociation constants (KD): 0.26 nM and 0.14 nM respectively). Prazosin displaced the radioligand in a monophasic manner in both the spleen and hippocampus whereas 5-methyl-urapidil, phentolamine and WB 4101 displaced the radioligand in a monophasic manner in the spleen but in a biphasic manner in the hippocampus. The affinity of these three compounds for the low affinity site in the hippocampus was similar to that observed in the spleen, suggesting that all three were selective for the alpha 1A-adrenoceptor. Furthermore, the affinities for the alpha 1A- and alpha 1B-adrenoceptors calculated in this manner were in agreement with literature values. With the exception of risperidone, all the antipsychotic drugs tested failed to show selectivity for either of the alpha 1-adrenoceptor subtypes. Risperidone was 120-fold more selective for the alpha 1B-adrenoceptor with respect to the alpha 1A-adrenoceptor (Ki values: 2.3 +/- 1.2 nM and 283.6 +/- 174.1 nM respectively). | DIRECT-REGULATOR |
| Binding of antipsychotic drugs at alpha 1A- and alpha 1B-adrenoceptors: risperidone is selective for the alpha 1B-adrenoceptors. The binding of the antipsychotic drugs risperidone, (+)-butaclamol, CHEMICAL, haloperidol, spiperone, thioridazine and YM-09151-2 was studied at the subtypes of the GENE. Saturation experiments showed that [3H]prazosin labelled a single population of binding sites in the spleen (alpha 1B) and hippocampus (alpha 1A and alpha 1B) (dissociation constants (KD): 0.26 nM and 0.14 nM respectively). Prazosin displaced the radioligand in a monophasic manner in both the spleen and hippocampus whereas 5-methyl-urapidil, phentolamine and WB 4101 displaced the radioligand in a monophasic manner in the spleen but in a biphasic manner in the hippocampus. The affinity of these three compounds for the low affinity site in the hippocampus was similar to that observed in the spleen, suggesting that all three were selective for the alpha 1A-adrenoceptor. Furthermore, the affinities for the alpha 1A- and alpha 1B-adrenoceptors calculated in this manner were in agreement with literature values. With the exception of risperidone, all the antipsychotic drugs tested failed to show selectivity for either of the GENE subtypes. Risperidone was 120-fold more selective for the alpha 1B-adrenoceptor with respect to the alpha 1A-adrenoceptor (Ki values: 2.3 +/- 1.2 nM and 283.6 +/- 174.1 nM respectively). | DIRECT-REGULATOR |
| Binding of antipsychotic drugs at alpha 1A- and alpha 1B-adrenoceptors: risperidone is selective for the alpha 1B-adrenoceptors. The binding of the antipsychotic drugs risperidone, (+)-butaclamol, clozapine, CHEMICAL, spiperone, thioridazine and YM-09151-2 was studied at the subtypes of the GENE. Saturation experiments showed that [3H]prazosin labelled a single population of binding sites in the spleen (alpha 1B) and hippocampus (alpha 1A and alpha 1B) (dissociation constants (KD): 0.26 nM and 0.14 nM respectively). Prazosin displaced the radioligand in a monophasic manner in both the spleen and hippocampus whereas 5-methyl-urapidil, phentolamine and WB 4101 displaced the radioligand in a monophasic manner in the spleen but in a biphasic manner in the hippocampus. The affinity of these three compounds for the low affinity site in the hippocampus was similar to that observed in the spleen, suggesting that all three were selective for the alpha 1A-adrenoceptor. Furthermore, the affinities for the alpha 1A- and alpha 1B-adrenoceptors calculated in this manner were in agreement with literature values. With the exception of risperidone, all the antipsychotic drugs tested failed to show selectivity for either of the GENE subtypes. Risperidone was 120-fold more selective for the alpha 1B-adrenoceptor with respect to the alpha 1A-adrenoceptor (Ki values: 2.3 +/- 1.2 nM and 283.6 +/- 174.1 nM respectively). | DIRECT-REGULATOR |
| Binding of antipsychotic drugs at alpha 1A- and alpha 1B-adrenoceptors: risperidone is selective for the alpha 1B-adrenoceptors. The binding of the antipsychotic drugs risperidone, (+)-butaclamol, clozapine, haloperidol, CHEMICAL, thioridazine and YM-09151-2 was studied at the subtypes of the GENE. Saturation experiments showed that [3H]prazosin labelled a single population of binding sites in the spleen (alpha 1B) and hippocampus (alpha 1A and alpha 1B) (dissociation constants (KD): 0.26 nM and 0.14 nM respectively). Prazosin displaced the radioligand in a monophasic manner in both the spleen and hippocampus whereas 5-methyl-urapidil, phentolamine and WB 4101 displaced the radioligand in a monophasic manner in the spleen but in a biphasic manner in the hippocampus. The affinity of these three compounds for the low affinity site in the hippocampus was similar to that observed in the spleen, suggesting that all three were selective for the alpha 1A-adrenoceptor. Furthermore, the affinities for the alpha 1A- and alpha 1B-adrenoceptors calculated in this manner were in agreement with literature values. With the exception of risperidone, all the antipsychotic drugs tested failed to show selectivity for either of the GENE subtypes. Risperidone was 120-fold more selective for the alpha 1B-adrenoceptor with respect to the alpha 1A-adrenoceptor (Ki values: 2.3 +/- 1.2 nM and 283.6 +/- 174.1 nM respectively). | DIRECT-REGULATOR |
| Binding of antipsychotic drugs at alpha 1A- and alpha 1B-adrenoceptors: CHEMICAL is selective for the GENE. The binding of the antipsychotic drugs CHEMICAL, (+)-butaclamol, clozapine, haloperidol, spiperone, thioridazine and YM-09151-2 was studied at the subtypes of the alpha 1-adrenoceptor. Saturation experiments showed that [3H]prazosin labelled a single population of binding sites in the spleen (alpha 1B) and hippocampus (alpha 1A and alpha 1B) (dissociation constants (KD): 0.26 nM and 0.14 nM respectively). Prazosin displaced the radioligand in a monophasic manner in both the spleen and hippocampus whereas 5-methyl-urapidil, phentolamine and WB 4101 displaced the radioligand in a monophasic manner in the spleen but in a biphasic manner in the hippocampus. The affinity of these three compounds for the low affinity site in the hippocampus was similar to that observed in the spleen, suggesting that all three were selective for the alpha 1A-adrenoceptor. Furthermore, the affinities for the alpha 1A- and GENE calculated in this manner were in agreement with literature values. With the exception of CHEMICAL, all the antipsychotic drugs tested failed to show selectivity for either of the alpha 1-adrenoceptor subtypes. CHEMICAL was 120-fold more selective for the alpha 1B-adrenoceptor with respect to the alpha 1A-adrenoceptor (Ki values: 2.3 +/- 1.2 nM and 283.6 +/- 174.1 nM respectively). | DIRECT-REGULATOR |
| Binding of antipsychotic drugs at alpha 1A- and alpha 1B-adrenoceptors: CHEMICAL is selective for the alpha 1B-adrenoceptors. The binding of the antipsychotic drugs CHEMICAL, (+)-butaclamol, clozapine, haloperidol, spiperone, thioridazine and YM-09151-2 was studied at the subtypes of the GENE. Saturation experiments showed that [3H]prazosin labelled a single population of binding sites in the spleen (alpha 1B) and hippocampus (alpha 1A and alpha 1B) (dissociation constants (KD): 0.26 nM and 0.14 nM respectively). Prazosin displaced the radioligand in a monophasic manner in both the spleen and hippocampus whereas 5-methyl-urapidil, phentolamine and WB 4101 displaced the radioligand in a monophasic manner in the spleen but in a biphasic manner in the hippocampus. The affinity of these three compounds for the low affinity site in the hippocampus was similar to that observed in the spleen, suggesting that all three were selective for the alpha 1A-adrenoceptor. Furthermore, the affinities for the alpha 1A- and alpha 1B-adrenoceptors calculated in this manner were in agreement with literature values. With the exception of CHEMICAL, all the antipsychotic drugs tested failed to show selectivity for either of the GENE subtypes. CHEMICAL was 120-fold more selective for the alpha 1B-adrenoceptor with respect to the alpha 1A-adrenoceptor (Ki values: 2.3 +/- 1.2 nM and 283.6 +/- 174.1 nM respectively). | DIRECT-REGULATOR |
| Binding of antipsychotic drugs at alpha 1A- and alpha 1B-adrenoceptors: risperidone is selective for the alpha 1B-adrenoceptors. The binding of the antipsychotic drugs risperidone, (+)-butaclamol, clozapine, haloperidol, spiperone, CHEMICAL and YM-09151-2 was studied at the subtypes of the GENE. Saturation experiments showed that [3H]prazosin labelled a single population of binding sites in the spleen (alpha 1B) and hippocampus (alpha 1A and alpha 1B) (dissociation constants (KD): 0.26 nM and 0.14 nM respectively). Prazosin displaced the radioligand in a monophasic manner in both the spleen and hippocampus whereas 5-methyl-urapidil, phentolamine and WB 4101 displaced the radioligand in a monophasic manner in the spleen but in a biphasic manner in the hippocampus. The affinity of these three compounds for the low affinity site in the hippocampus was similar to that observed in the spleen, suggesting that all three were selective for the alpha 1A-adrenoceptor. Furthermore, the affinities for the alpha 1A- and alpha 1B-adrenoceptors calculated in this manner were in agreement with literature values. With the exception of risperidone, all the antipsychotic drugs tested failed to show selectivity for either of the GENE subtypes. Risperidone was 120-fold more selective for the alpha 1B-adrenoceptor with respect to the alpha 1A-adrenoceptor (Ki values: 2.3 +/- 1.2 nM and 283.6 +/- 174.1 nM respectively). | DIRECT-REGULATOR |
| Binding of antipsychotic drugs at alpha 1A- and alpha 1B-adrenoceptors: risperidone is selective for the alpha 1B-adrenoceptors. The binding of the antipsychotic drugs risperidone, (+)-butaclamol, clozapine, haloperidol, spiperone, thioridazine and YM-09151-2 was studied at the subtypes of the alpha 1-adrenoceptor. Saturation experiments showed that [3H]prazosin labelled a single population of binding sites in the spleen (alpha 1B) and hippocampus (alpha 1A and alpha 1B) (dissociation constants (KD): 0.26 nM and 0.14 nM respectively). Prazosin displaced the radioligand in a monophasic manner in both the spleen and hippocampus whereas 5-methyl-urapidil, phentolamine and WB 4101 displaced the radioligand in a monophasic manner in the spleen but in a biphasic manner in the hippocampus. The affinity of these three compounds for the low affinity site in the hippocampus was similar to that observed in the spleen, suggesting that all three were selective for the alpha 1A-adrenoceptor. Furthermore, the affinities for the alpha 1A- and alpha 1B-adrenoceptors calculated in this manner were in agreement with literature values. With the exception of risperidone, all the antipsychotic drugs tested failed to show selectivity for either of the alpha 1-adrenoceptor subtypes. CHEMICAL was 120-fold more selective for the GENE with respect to the alpha 1A-adrenoceptor (Ki values: 2.3 +/- 1.2 nM and 283.6 +/- 174.1 nM respectively). | DIRECT-REGULATOR |
| Binding of antipsychotic drugs at alpha 1A- and alpha 1B-adrenoceptors: risperidone is selective for the alpha 1B-adrenoceptors. The binding of the antipsychotic drugs risperidone, (+)-butaclamol, clozapine, haloperidol, spiperone, thioridazine and YM-09151-2 was studied at the subtypes of the alpha 1-adrenoceptor. Saturation experiments showed that [3H]prazosin labelled a single population of binding sites in the spleen (alpha 1B) and hippocampus (alpha 1A and alpha 1B) (dissociation constants (KD): 0.26 nM and 0.14 nM respectively). Prazosin displaced the radioligand in a monophasic manner in both the spleen and hippocampus whereas 5-methyl-urapidil, phentolamine and WB 4101 displaced the radioligand in a monophasic manner in the spleen but in a biphasic manner in the hippocampus. The affinity of these three compounds for the low affinity site in the hippocampus was similar to that observed in the spleen, suggesting that all three were selective for the GENE. Furthermore, the affinities for the alpha 1A- and alpha 1B-adrenoceptors calculated in this manner were in agreement with literature values. With the exception of risperidone, all the antipsychotic drugs tested failed to show selectivity for either of the alpha 1-adrenoceptor subtypes. CHEMICAL was 120-fold more selective for the alpha 1B-adrenoceptor with respect to the GENE (Ki values: 2.3 +/- 1.2 nM and 283.6 +/- 174.1 nM respectively). | DIRECT-REGULATOR |
| Binding of antipsychotic drugs at alpha 1A- and alpha 1B-adrenoceptors: risperidone is selective for the alpha 1B-adrenoceptors. The binding of the antipsychotic drugs risperidone, (+)-butaclamol, clozapine, haloperidol, spiperone, thioridazine and CHEMICAL was studied at the subtypes of the GENE. Saturation experiments showed that [3H]prazosin labelled a single population of binding sites in the spleen (alpha 1B) and hippocampus (alpha 1A and alpha 1B) (dissociation constants (KD): 0.26 nM and 0.14 nM respectively). Prazosin displaced the radioligand in a monophasic manner in both the spleen and hippocampus whereas 5-methyl-urapidil, phentolamine and WB 4101 displaced the radioligand in a monophasic manner in the spleen but in a biphasic manner in the hippocampus. The affinity of these three compounds for the low affinity site in the hippocampus was similar to that observed in the spleen, suggesting that all three were selective for the alpha 1A-adrenoceptor. Furthermore, the affinities for the alpha 1A- and alpha 1B-adrenoceptors calculated in this manner were in agreement with literature values. With the exception of risperidone, all the antipsychotic drugs tested failed to show selectivity for either of the GENE subtypes. Risperidone was 120-fold more selective for the alpha 1B-adrenoceptor with respect to the alpha 1A-adrenoceptor (Ki values: 2.3 +/- 1.2 nM and 283.6 +/- 174.1 nM respectively). | DIRECT-REGULATOR |
| Binding of antipsychotic drugs at alpha 1A- and alpha 1B-adrenoceptors: risperidone is selective for the alpha 1B-adrenoceptors. The binding of the antipsychotic drugs risperidone, CHEMICAL, clozapine, haloperidol, spiperone, thioridazine and YM-09151-2 was studied at the subtypes of the GENE. Saturation experiments showed that [3H]prazosin labelled a single population of binding sites in the spleen (alpha 1B) and hippocampus (alpha 1A and alpha 1B) (dissociation constants (KD): 0.26 nM and 0.14 nM respectively). Prazosin displaced the radioligand in a monophasic manner in both the spleen and hippocampus whereas 5-methyl-urapidil, phentolamine and WB 4101 displaced the radioligand in a monophasic manner in the spleen but in a biphasic manner in the hippocampus. The affinity of these three compounds for the low affinity site in the hippocampus was similar to that observed in the spleen, suggesting that all three were selective for the alpha 1A-adrenoceptor. Furthermore, the affinities for the alpha 1A- and alpha 1B-adrenoceptors calculated in this manner were in agreement with literature values. With the exception of risperidone, all the antipsychotic drugs tested failed to show selectivity for either of the GENE subtypes. Risperidone was 120-fold more selective for the alpha 1B-adrenoceptor with respect to the alpha 1A-adrenoceptor (Ki values: 2.3 +/- 1.2 nM and 283.6 +/- 174.1 nM respectively). | DIRECT-REGULATOR |
| Mediation of noradrenaline-induced contractions of rat aorta by the GENE subtype. 1. The subtypes of alpha 1-adrenoceptor mediating contractions to exogenous noradrenaline (NA) in rat aorta have been examined in both biochemical and functional studies. 2. Incubation of rat aortic membranes with the irreversible GENE antagonist, chloroethylclonidine (CEC: 10 microM) did not change the KD of CHEMICAL binding in comparison to untreated membranes, but reduced by 88% the total number of binding sites (Bmax). 3. Contractions of rat aortic strips to NA after CEC (50 microM for 30 min) incubation followed by repetitive washing, showed a marked shift in the potency of NA and a partial reduction in the maximum response. The residual contractions to NA after CEC incubation were not affected by prazosin (10 nM). 4. The competitive antagonists prazosin, terazosin, (R)-YM-12617, phentolamine, 5-methylurapidil and spiperone inhibited contractions to NA with estimated pA2 values of 9.85, 8.54, 9.34, 7.71, 7.64 and 8.41, respectively. 5. The affinity of the same antagonists for the alpha 1A- and alpha 1B- adrenoceptors was evaluated by utilizing membranes from rat hippocampus pretreated with CEC, and rat liver, respectively. 5-Methylurapidil and phentolamine were confirmed as selective for the alpha 1A-adrenoceptors, whereas spiperone was alpha 1B-selective. 6. A significant correlation was found between the pA2 values of the alpha 1-adrenoceptor antagonists tested and their affinity for the GENE subtype, but not for the alpha 1A-subtype. 7. In conclusion, these findings indicate that in rat aorta most of the contraction is mediated by alpha 1B-adrenoceptors, and that the potency (pA2) of an antagonist in this tissue should be related to its antagonistic effect on this subtype of the alpha 1-adrenoceptor population. | DIRECT-REGULATOR |
| Mediation of noradrenaline-induced contractions of rat aorta by the alpha 1B-adrenoceptor subtype. 1. The subtypes of GENE mediating contractions to exogenous CHEMICAL (NA) in rat aorta have been examined in both biochemical and functional studies. 2. Incubation of rat aortic membranes with the irreversible alpha 1B-adrenoceptor antagonist, chloroethylclonidine (CEC: 10 microM) did not change the KD of [3H]-prazosin binding in comparison to untreated membranes, but reduced by 88% the total number of binding sites (Bmax). 3. Contractions of rat aortic strips to NA after CEC (50 microM for 30 min) incubation followed by repetitive washing, showed a marked shift in the potency of NA and a partial reduction in the maximum response. The residual contractions to NA after CEC incubation were not affected by prazosin (10 nM). 4. The competitive antagonists prazosin, terazosin, (R)-YM-12617, phentolamine, 5-methylurapidil and spiperone inhibited contractions to NA with estimated pA2 values of 9.85, 8.54, 9.34, 7.71, 7.64 and 8.41, respectively. 5. The affinity of the same antagonists for the alpha 1A- and alpha 1B- adrenoceptors was evaluated by utilizing membranes from rat hippocampus pretreated with CEC, and rat liver, respectively. 5-Methylurapidil and phentolamine were confirmed as selective for the alpha 1A-adrenoceptors, whereas spiperone was alpha 1B-selective. 6. A significant correlation was found between the pA2 values of the GENE antagonists tested and their affinity for the alpha 1B-adrenoceptor subtype, but not for the alpha 1A-subtype. 7. In conclusion, these findings indicate that in rat aorta most of the contraction is mediated by alpha 1B-adrenoceptors, and that the potency (pA2) of an antagonist in this tissue should be related to its antagonistic effect on this subtype of the GENE population. | ACTIVATOR |
| Mediation of noradrenaline-induced contractions of rat aorta by the alpha 1B-adrenoceptor subtype. 1. The subtypes of GENE mediating contractions to exogenous noradrenaline (CHEMICAL) in rat aorta have been examined in both biochemical and functional studies. 2. Incubation of rat aortic membranes with the irreversible alpha 1B-adrenoceptor antagonist, chloroethylclonidine (CEC: 10 microM) did not change the KD of [3H]-prazosin binding in comparison to untreated membranes, but reduced by 88% the total number of binding sites (Bmax). 3. Contractions of rat aortic strips to CHEMICAL after CEC (50 microM for 30 min) incubation followed by repetitive washing, showed a marked shift in the potency of CHEMICAL and a partial reduction in the maximum response. The residual contractions to CHEMICAL after CEC incubation were not affected by prazosin (10 nM). 4. The competitive antagonists prazosin, terazosin, (R)-YM-12617, phentolamine, 5-methylurapidil and spiperone inhibited contractions to CHEMICAL with estimated pA2 values of 9.85, 8.54, 9.34, 7.71, 7.64 and 8.41, respectively. 5. The affinity of the same antagonists for the alpha 1A- and alpha 1B- adrenoceptors was evaluated by utilizing membranes from rat hippocampus pretreated with CEC, and rat liver, respectively. 5-Methylurapidil and phentolamine were confirmed as selective for the alpha 1A-adrenoceptors, whereas spiperone was alpha 1B-selective. 6. A significant correlation was found between the pA2 values of the GENE antagonists tested and their affinity for the alpha 1B-adrenoceptor subtype, but not for the alpha 1A-subtype. 7. In conclusion, these findings indicate that in rat aorta most of the contraction is mediated by alpha 1B-adrenoceptors, and that the potency (pA2) of an antagonist in this tissue should be related to its antagonistic effect on this subtype of the GENE population. | ACTIVATOR |
| Mediation of CHEMICAL-induced contractions of rat aorta by the GENE subtype. 1. The subtypes of alpha 1-adrenoceptor mediating contractions to exogenous CHEMICAL (NA) in rat aorta have been examined in both biochemical and functional studies. 2. Incubation of rat aortic membranes with the irreversible GENE antagonist, chloroethylclonidine (CEC: 10 microM) did not change the KD of [3H]-prazosin binding in comparison to untreated membranes, but reduced by 88% the total number of binding sites (Bmax). 3. Contractions of rat aortic strips to NA after CEC (50 microM for 30 min) incubation followed by repetitive washing, showed a marked shift in the potency of NA and a partial reduction in the maximum response. The residual contractions to NA after CEC incubation were not affected by prazosin (10 nM). 4. The competitive antagonists prazosin, terazosin, (R)-YM-12617, phentolamine, 5-methylurapidil and spiperone inhibited contractions to NA with estimated pA2 values of 9.85, 8.54, 9.34, 7.71, 7.64 and 8.41, respectively. 5. The affinity of the same antagonists for the alpha 1A- and alpha 1B- adrenoceptors was evaluated by utilizing membranes from rat hippocampus pretreated with CEC, and rat liver, respectively. 5-Methylurapidil and phentolamine were confirmed as selective for the alpha 1A-adrenoceptors, whereas spiperone was alpha 1B-selective. 6. A significant correlation was found between the pA2 values of the alpha 1-adrenoceptor antagonists tested and their affinity for the GENE subtype, but not for the alpha 1A-subtype. 7. In conclusion, these findings indicate that in rat aorta most of the contraction is mediated by alpha 1B-adrenoceptors, and that the potency (pA2) of an antagonist in this tissue should be related to its antagonistic effect on this subtype of the alpha 1-adrenoceptor population. | REGULATOR |
| Mediation of noradrenaline-induced contractions of rat aorta by the alpha 1B-adrenoceptor subtype. 1. The subtypes of alpha 1-adrenoceptor mediating contractions to exogenous noradrenaline (NA) in rat aorta have been examined in both biochemical and functional studies. 2. Incubation of rat aortic membranes with the irreversible alpha 1B-adrenoceptor antagonist, chloroethylclonidine (CEC: 10 microM) did not change the KD of [3H]-prazosin binding in comparison to untreated membranes, but reduced by 88% the total number of binding sites (Bmax). 3. Contractions of rat aortic strips to NA after CEC (50 microM for 30 min) incubation followed by repetitive washing, showed a marked shift in the potency of NA and a partial reduction in the maximum response. The residual contractions to NA after CEC incubation were not affected by prazosin (10 nM). 4. The competitive antagonists prazosin, terazosin, (R)-YM-12617, phentolamine, CHEMICAL and spiperone inhibited contractions to NA with estimated pA2 values of 9.85, 8.54, 9.34, 7.71, 7.64 and 8.41, respectively. 5. The affinity of the same antagonists for the alpha 1A- and alpha 1B- adrenoceptors was evaluated by utilizing membranes from rat hippocampus pretreated with CEC, and rat liver, respectively. CHEMICAL and phentolamine were confirmed as selective for the GENE, whereas spiperone was alpha 1B-selective. 6. A significant correlation was found between the pA2 values of the alpha 1-adrenoceptor antagonists tested and their affinity for the alpha 1B-adrenoceptor subtype, but not for the alpha 1A-subtype. 7. In conclusion, these findings indicate that in rat aorta most of the contraction is mediated by alpha 1B-adrenoceptors, and that the potency (pA2) of an antagonist in this tissue should be related to its antagonistic effect on this subtype of the alpha 1-adrenoceptor population. | DIRECT-REGULATOR |
| Mediation of noradrenaline-induced contractions of rat aorta by the alpha 1B-adrenoceptor subtype. 1. The subtypes of alpha 1-adrenoceptor mediating contractions to exogenous noradrenaline (NA) in rat aorta have been examined in both biochemical and functional studies. 2. Incubation of rat aortic membranes with the irreversible alpha 1B-adrenoceptor antagonist, chloroethylclonidine (CEC: 10 microM) did not change the KD of [3H]-prazosin binding in comparison to untreated membranes, but reduced by 88% the total number of binding sites (Bmax). 3. Contractions of rat aortic strips to NA after CEC (50 microM for 30 min) incubation followed by repetitive washing, showed a marked shift in the potency of NA and a partial reduction in the maximum response. The residual contractions to NA after CEC incubation were not affected by prazosin (10 nM). 4. The competitive antagonists prazosin, terazosin, (R)-YM-12617, CHEMICAL, 5-methylurapidil and spiperone inhibited contractions to NA with estimated pA2 values of 9.85, 8.54, 9.34, 7.71, 7.64 and 8.41, respectively. 5. The affinity of the same antagonists for the alpha 1A- and alpha 1B- adrenoceptors was evaluated by utilizing membranes from rat hippocampus pretreated with CEC, and rat liver, respectively. 5-Methylurapidil and CHEMICAL were confirmed as selective for the GENE, whereas spiperone was alpha 1B-selective. 6. A significant correlation was found between the pA2 values of the alpha 1-adrenoceptor antagonists tested and their affinity for the alpha 1B-adrenoceptor subtype, but not for the alpha 1A-subtype. 7. In conclusion, these findings indicate that in rat aorta most of the contraction is mediated by alpha 1B-adrenoceptors, and that the potency (pA2) of an antagonist in this tissue should be related to its antagonistic effect on this subtype of the alpha 1-adrenoceptor population. | DIRECT-REGULATOR |
| Mediation of noradrenaline-induced contractions of rat aorta by the GENE subtype. 1. The subtypes of alpha 1-adrenoceptor mediating contractions to exogenous noradrenaline (NA) in rat aorta have been examined in both biochemical and functional studies. 2. Incubation of rat aortic membranes with the irreversible GENE antagonist, CHEMICAL (CEC: 10 microM) did not change the KD of [3H]-prazosin binding in comparison to untreated membranes, but reduced by 88% the total number of binding sites (Bmax). 3. Contractions of rat aortic strips to NA after CEC (50 microM for 30 min) incubation followed by repetitive washing, showed a marked shift in the potency of NA and a partial reduction in the maximum response. The residual contractions to NA after CEC incubation were not affected by prazosin (10 nM). 4. The competitive antagonists prazosin, terazosin, (R)-YM-12617, phentolamine, 5-methylurapidil and spiperone inhibited contractions to NA with estimated pA2 values of 9.85, 8.54, 9.34, 7.71, 7.64 and 8.41, respectively. 5. The affinity of the same antagonists for the alpha 1A- and alpha 1B- adrenoceptors was evaluated by utilizing membranes from rat hippocampus pretreated with CEC, and rat liver, respectively. 5-Methylurapidil and phentolamine were confirmed as selective for the alpha 1A-adrenoceptors, whereas spiperone was alpha 1B-selective. 6. A significant correlation was found between the pA2 values of the alpha 1-adrenoceptor antagonists tested and their affinity for the GENE subtype, but not for the alpha 1A-subtype. 7. In conclusion, these findings indicate that in rat aorta most of the contraction is mediated by alpha 1B-adrenoceptors, and that the potency (pA2) of an antagonist in this tissue should be related to its antagonistic effect on this subtype of the alpha 1-adrenoceptor population. | INHIBITOR |
| Mediation of noradrenaline-induced contractions of rat aorta by the GENE subtype. 1. The subtypes of alpha 1-adrenoceptor mediating contractions to exogenous noradrenaline (NA) in rat aorta have been examined in both biochemical and functional studies. 2. Incubation of rat aortic membranes with the irreversible GENE antagonist, chloroethylclonidine (CHEMICAL: 10 microM) did not change the KD of [3H]-prazosin binding in comparison to untreated membranes, but reduced by 88% the total number of binding sites (Bmax). 3. Contractions of rat aortic strips to NA after CHEMICAL (50 microM for 30 min) incubation followed by repetitive washing, showed a marked shift in the potency of NA and a partial reduction in the maximum response. The residual contractions to NA after CHEMICAL incubation were not affected by prazosin (10 nM). 4. The competitive antagonists prazosin, terazosin, (R)-YM-12617, phentolamine, 5-methylurapidil and spiperone inhibited contractions to NA with estimated pA2 values of 9.85, 8.54, 9.34, 7.71, 7.64 and 8.41, respectively. 5. The affinity of the same antagonists for the alpha 1A- and alpha 1B- adrenoceptors was evaluated by utilizing membranes from rat hippocampus pretreated with CHEMICAL, and rat liver, respectively. 5-Methylurapidil and phentolamine were confirmed as selective for the alpha 1A-adrenoceptors, whereas spiperone was alpha 1B-selective. 6. A significant correlation was found between the pA2 values of the alpha 1-adrenoceptor antagonists tested and their affinity for the GENE subtype, but not for the alpha 1A-subtype. 7. In conclusion, these findings indicate that in rat aorta most of the contraction is mediated by alpha 1B-adrenoceptors, and that the potency (pA2) of an antagonist in this tissue should be related to its antagonistic effect on this subtype of the alpha 1-adrenoceptor population. | INHIBITOR |
| Beta 2- but not GENE are involved in CHEMICAL enhancement of aggressive behavior in long-term isolated mice. The effects of several beta-adrenoceptor antagonists on the desipramine-induced increase in aggressive behavior in long-term isolated mice were examined. CHEMICAL HCl (10 mg/kg, IP) significantly increased the duration of aggressive behavior in isolated mice but did not significantly change the latency to the first attack consistent with our previous reports. Intraperitoneal administration of (+/- )propranolol HCl (2.5-10 mg/kg), a nonselective beta-adrenoceptor antagonist, dose dependently attenuated the desipramine-induced enhancement of aggressive behavior without significantly affecting the basal aggressive responses. ICI118,551 HCl (1.25-5 mg/kg, IP), a selective beta 2-adrenoceptor antagonist, also blocked the desipramine-induced enhancement of aggressive behavior in a dose-dependent manner, whereas metoprolol tartrate (5-20 mg/kg, IP), a selective beta 1-adrenoceptor antagonist, did not affect it. Moreover, clenbuterol HCl (0.1-0.5 mg/kg, IP), a lipophilic beta 2-adrenoceptor agonist, significantly increased the duration of basal aggressive behavior. Taken together with our previous finding that the desipramine-induced enhancement of aggressive behavior can be blocked by yohimbine, an alpha 2-adrenoceptor antagonist, the present results indicate that not only alpha 2- but also beta 2-adrenoceptor stimulation plays important roles in modulation of aggressive behavior in long-term isolated mice. | NO-RELATIONSHIP |
| Beta 2- but not beta 1-adrenoceptors are involved in CHEMICAL enhancement of aggressive behavior in long-term isolated mice. The effects of several beta-adrenoceptor antagonists on the desipramine-induced increase in aggressive behavior in long-term isolated mice were examined. CHEMICAL HCl (10 mg/kg, IP) significantly increased the duration of aggressive behavior in isolated mice but did not significantly change the latency to the first attack consistent with our previous reports. Intraperitoneal administration of (+/- )propranolol HCl (2.5-10 mg/kg), a nonselective beta-adrenoceptor antagonist, dose dependently attenuated the desipramine-induced enhancement of aggressive behavior without significantly affecting the basal aggressive responses. ICI118,551 HCl (1.25-5 mg/kg, IP), a selective GENE antagonist, also blocked the desipramine-induced enhancement of aggressive behavior in a dose-dependent manner, whereas metoprolol tartrate (5-20 mg/kg, IP), a selective beta 1-adrenoceptor antagonist, did not affect it. Moreover, clenbuterol HCl (0.1-0.5 mg/kg, IP), a lipophilic GENE agonist, significantly increased the duration of basal aggressive behavior. Taken together with our previous finding that the CHEMICAL-induced enhancement of aggressive behavior can be blocked by yohimbine, an alpha 2-adrenoceptor antagonist, the present results indicate that not only alpha 2- but also GENE stimulation plays important roles in modulation of aggressive behavior in long-term isolated mice. | ACTIVATOR |
| Beta 2- but not beta 1-adrenoceptors are involved in desipramine enhancement of aggressive behavior in long-term isolated mice. The effects of several beta-adrenoceptor antagonists on the desipramine-induced increase in aggressive behavior in long-term isolated mice were examined. Desipramine HCl (10 mg/kg, IP) significantly increased the duration of aggressive behavior in isolated mice but did not significantly change the latency to the first attack consistent with our previous reports. Intraperitoneal administration of (+/- )propranolol HCl (2.5-10 mg/kg), a nonselective beta-adrenoceptor antagonist, dose dependently attenuated the desipramine-induced enhancement of aggressive behavior without significantly affecting the basal aggressive responses. ICI118,551 HCl (1.25-5 mg/kg, IP), a selective GENE antagonist, also blocked the desipramine-induced enhancement of aggressive behavior in a dose-dependent manner, whereas metoprolol tartrate (5-20 mg/kg, IP), a selective beta 1-adrenoceptor antagonist, did not affect it. Moreover, CHEMICAL (0.1-0.5 mg/kg, IP), a lipophilic GENE agonist, significantly increased the duration of basal aggressive behavior. Taken together with our previous finding that the desipramine-induced enhancement of aggressive behavior can be blocked by yohimbine, an alpha 2-adrenoceptor antagonist, the present results indicate that not only alpha 2- but also GENE stimulation plays important roles in modulation of aggressive behavior in long-term isolated mice. | ACTIVATOR |
| Beta 2- but not beta 1-adrenoceptors are involved in desipramine enhancement of aggressive behavior in long-term isolated mice. The effects of several beta-adrenoceptor antagonists on the desipramine-induced increase in aggressive behavior in long-term isolated mice were examined. Desipramine HCl (10 mg/kg, IP) significantly increased the duration of aggressive behavior in isolated mice but did not significantly change the latency to the first attack consistent with our previous reports. Intraperitoneal administration of (+/- )propranolol HCl (2.5-10 mg/kg), a nonselective beta-adrenoceptor antagonist, dose dependently attenuated the desipramine-induced enhancement of aggressive behavior without significantly affecting the basal aggressive responses. ICI118,551 HCl (1.25-5 mg/kg, IP), a selective beta 2-adrenoceptor antagonist, also blocked the desipramine-induced enhancement of aggressive behavior in a dose-dependent manner, whereas metoprolol tartrate (5-20 mg/kg, IP), a selective beta 1-adrenoceptor antagonist, did not affect it. Moreover, clenbuterol HCl (0.1-0.5 mg/kg, IP), a lipophilic beta 2-adrenoceptor agonist, significantly increased the duration of basal aggressive behavior. Taken together with our previous finding that the desipramine-induced enhancement of aggressive behavior can be blocked by CHEMICAL, an GENE antagonist, the present results indicate that not only alpha 2- but also beta 2-adrenoceptor stimulation plays important roles in modulation of aggressive behavior in long-term isolated mice. | INHIBITOR |
| Beta 2- but not beta 1-adrenoceptors are involved in desipramine enhancement of aggressive behavior in long-term isolated mice. The effects of several GENE antagonists on the desipramine-induced increase in aggressive behavior in long-term isolated mice were examined. Desipramine HCl (10 mg/kg, IP) significantly increased the duration of aggressive behavior in isolated mice but did not significantly change the latency to the first attack consistent with our previous reports. Intraperitoneal administration of CHEMICAL (2.5-10 mg/kg), a nonselective GENE antagonist, dose dependently attenuated the desipramine-induced enhancement of aggressive behavior without significantly affecting the basal aggressive responses. ICI118,551 HCl (1.25-5 mg/kg, IP), a selective beta 2-adrenoceptor antagonist, also blocked the desipramine-induced enhancement of aggressive behavior in a dose-dependent manner, whereas metoprolol tartrate (5-20 mg/kg, IP), a selective beta 1-adrenoceptor antagonist, did not affect it. Moreover, clenbuterol HCl (0.1-0.5 mg/kg, IP), a lipophilic beta 2-adrenoceptor agonist, significantly increased the duration of basal aggressive behavior. Taken together with our previous finding that the desipramine-induced enhancement of aggressive behavior can be blocked by yohimbine, an alpha 2-adrenoceptor antagonist, the present results indicate that not only alpha 2- but also beta 2-adrenoceptor stimulation plays important roles in modulation of aggressive behavior in long-term isolated mice. | INHIBITOR |
| Beta 2- but not beta 1-adrenoceptors are involved in desipramine enhancement of aggressive behavior in long-term isolated mice. The effects of several beta-adrenoceptor antagonists on the desipramine-induced increase in aggressive behavior in long-term isolated mice were examined. Desipramine HCl (10 mg/kg, IP) significantly increased the duration of aggressive behavior in isolated mice but did not significantly change the latency to the first attack consistent with our previous reports. Intraperitoneal administration of (+/- )propranolol HCl (2.5-10 mg/kg), a nonselective beta-adrenoceptor antagonist, dose dependently attenuated the desipramine-induced enhancement of aggressive behavior without significantly affecting the basal aggressive responses. CHEMICAL (1.25-5 mg/kg, IP), a selective GENE antagonist, also blocked the desipramine-induced enhancement of aggressive behavior in a dose-dependent manner, whereas metoprolol tartrate (5-20 mg/kg, IP), a selective beta 1-adrenoceptor antagonist, did not affect it. Moreover, clenbuterol HCl (0.1-0.5 mg/kg, IP), a lipophilic GENE agonist, significantly increased the duration of basal aggressive behavior. Taken together with our previous finding that the desipramine-induced enhancement of aggressive behavior can be blocked by yohimbine, an alpha 2-adrenoceptor antagonist, the present results indicate that not only alpha 2- but also GENE stimulation plays important roles in modulation of aggressive behavior in long-term isolated mice. | INHIBITOR |
| Beta 2- but not beta 1-adrenoceptors are involved in desipramine enhancement of aggressive behavior in long-term isolated mice. The effects of several beta-adrenoceptor antagonists on the desipramine-induced increase in aggressive behavior in long-term isolated mice were examined. Desipramine HCl (10 mg/kg, IP) significantly increased the duration of aggressive behavior in isolated mice but did not significantly change the latency to the first attack consistent with our previous reports. Intraperitoneal administration of (+/- )propranolol HCl (2.5-10 mg/kg), a nonselective beta-adrenoceptor antagonist, dose dependently attenuated the desipramine-induced enhancement of aggressive behavior without significantly affecting the basal aggressive responses. ICI118,551 HCl (1.25-5 mg/kg, IP), a selective beta 2-adrenoceptor antagonist, also blocked the desipramine-induced enhancement of aggressive behavior in a dose-dependent manner, whereas CHEMICAL (5-20 mg/kg, IP), a selective GENE antagonist, did not affect it. Moreover, clenbuterol HCl (0.1-0.5 mg/kg, IP), a lipophilic beta 2-adrenoceptor agonist, significantly increased the duration of basal aggressive behavior. Taken together with our previous finding that the desipramine-induced enhancement of aggressive behavior can be blocked by yohimbine, an alpha 2-adrenoceptor antagonist, the present results indicate that not only alpha 2- but also beta 2-adrenoceptor stimulation plays important roles in modulation of aggressive behavior in long-term isolated mice. | INHIBITOR |
| Alpha 1-adrenoceptor subtypes mediating the regulation and modulation of Ca2+ sensitization in rabbit thoracic aorta. CHEMICAL (10 microM), methoxamine (100 microM) and clonidine (100 microM) with guanosine 5'-triphosphate (GTP, 50 microM) or guanosine 5'-O-(3-thiotriphosphate) (GTP gamma-S, 10 microM) all significantly enhanced the contraction induced by 0.3 microM Ca2+ (pCa6.5) in beta-escin-skinned smooth muscle of rabbit thoracic aorta. The enhancement of Ca2+ contraction produced by CHEMICAL was greater than that produced by methoxamine or clonidine. In beta-escin-skinned strips of chloroethylclonidine-pretreated smooth muscle, the enhancement of Ca2+ contraction produced by CHEMICAL was significantly decreased, whereas the amplitude was the same as that produced by methoxamine or clonidine; this enhancement was inhibited by the selective alpha 1A-adrenoceptor antagonist WB 4101 (100 nM). The enhancement of Ca2+ contraction produced by methoxamine and clonidine was not affected by chloroethylclonidine pretreatment. The effects of methoxamine, clonidine and CHEMICAL in the chloroethylclonidine-pretreated tissue were all inhibited by guanosine 5'-O-(2-thiodiphosphate) (GDP beta-S, 1 mM) and 1-(5-isoquinolinylsulfonyl)-methylpiperazine (H-7, 20 microM). Furthermore, the phosphorylation of GENE produced by CHEMICAL was greater than that produced by clonidine. These results suggest that both alpha 1-adrenoceptor subtypes (alpha 1A and alpha 1B) increase the Ca2+ sensitivity of contractile elements, and that the Ca2+ sensitization produced by alpha 1A-subtype receptors is mediated through G-protein and protein kinase C, and plays an important role in contraction of smooth muscle of rabbit thoracic aorta. | ACTIVATOR |
| Alpha 1-adrenoceptor subtypes mediating the regulation and modulation of Ca2+ sensitization in rabbit thoracic aorta. Norepinephrine (10 microM), methoxamine (100 microM) and CHEMICAL (100 microM) with guanosine 5'-triphosphate (GTP, 50 microM) or guanosine 5'-O-(3-thiotriphosphate) (GTP gamma-S, 10 microM) all significantly enhanced the contraction induced by 0.3 microM Ca2+ (pCa6.5) in beta-escin-skinned smooth muscle of rabbit thoracic aorta. The enhancement of Ca2+ contraction produced by norepinephrine was greater than that produced by methoxamine or CHEMICAL. In beta-escin-skinned strips of chloroethylclonidine-pretreated smooth muscle, the enhancement of Ca2+ contraction produced by norepinephrine was significantly decreased, whereas the amplitude was the same as that produced by methoxamine or clonidine; this enhancement was inhibited by the selective alpha 1A-adrenoceptor antagonist WB 4101 (100 nM). The enhancement of Ca2+ contraction produced by methoxamine and CHEMICAL was not affected by chloroethylclonidine pretreatment. The effects of methoxamine, CHEMICAL and norepinephrine in the chloroethylclonidine-pretreated tissue were all inhibited by guanosine 5'-O-(2-thiodiphosphate) (GDP beta-S, 1 mM) and 1-(5-isoquinolinylsulfonyl)-methylpiperazine (H-7, 20 microM). Furthermore, the phosphorylation of GENE produced by norepinephrine was greater than that produced by CHEMICAL. These results suggest that both alpha 1-adrenoceptor subtypes (alpha 1A and alpha 1B) increase the Ca2+ sensitivity of contractile elements, and that the Ca2+ sensitization produced by alpha 1A-subtype receptors is mediated through G-protein and protein kinase C, and plays an important role in contraction of smooth muscle of rabbit thoracic aorta. | ACTIVATOR |
| Alpha 1-adrenoceptor subtypes mediating the regulation and modulation of Ca2+ sensitization in rabbit thoracic aorta. Norepinephrine (10 microM), methoxamine (100 microM) and clonidine (100 microM) with guanosine 5'-triphosphate (GTP, 50 microM) or guanosine 5'-O-(3-thiotriphosphate) (GTP gamma-S, 10 microM) all significantly enhanced the contraction induced by 0.3 microM Ca2+ (pCa6.5) in beta-escin-skinned smooth muscle of rabbit thoracic aorta. The enhancement of Ca2+ contraction produced by norepinephrine was greater than that produced by methoxamine or clonidine. In beta-escin-skinned strips of chloroethylclonidine-pretreated smooth muscle, the enhancement of Ca2+ contraction produced by norepinephrine was significantly decreased, whereas the amplitude was the same as that produced by methoxamine or clonidine; this enhancement was inhibited by the selective GENE antagonist CHEMICAL (100 nM). The enhancement of Ca2+ contraction produced by methoxamine and clonidine was not affected by chloroethylclonidine pretreatment. The effects of methoxamine, clonidine and norepinephrine in the chloroethylclonidine-pretreated tissue were all inhibited by guanosine 5'-O-(2-thiodiphosphate) (GDP beta-S, 1 mM) and 1-(5-isoquinolinylsulfonyl)-methylpiperazine (H-7, 20 microM). Furthermore, the phosphorylation of myosin light chain produced by norepinephrine was greater than that produced by clonidine. These results suggest that both alpha 1-adrenoceptor subtypes (alpha 1A and alpha 1B) increase the Ca2+ sensitivity of contractile elements, and that the Ca2+ sensitization produced by alpha 1A-subtype receptors is mediated through G-protein and protein kinase C, and plays an important role in contraction of smooth muscle of rabbit thoracic aorta. | INHIBITOR |
| CHEMICAL transport and cytotoxicity. Specific enhancement in GLUT2-expressing cells. The glucose analog streptozotocin (STZ) has long been used as a tool for creating experimental diabetes because of its relatively specific beta-cell cytotoxic effect, but the mechanism by which systemic injection of CHEMICAL causes beta-cell destruction is not well understood. In the current study, we have used insulinoma (RIN) and AtT-20ins cell lines engineered for overexpression of GLUT2 or GENE to investigate the role of glucose transporter isoforms in mediating CHEMICAL cytotoxicity. The in vivo effects of CHEMICAL were evaluated by implantation of RIN cells expressing or lacking GLUT2 into athymic nude rats. The drug had a potent cytotoxic effect on RIN cells expressing GLUT2, but had no effect on cells lacking GLUT2 expression, as indicated by histological analysis and measurement of the blood glucose levels of treated animals. The preferential cytotoxic effect of CHEMICAL on GLUT2-expressing cell lines was confirmed by in vitro analysis of GLUT2-expressing and untransfected RIN cells, as well as GLUT2- and GLUT1-overexpressing AtT-20ins cells. Consistent with these data, only GLUT2-expressing RIN or AtT-20ins cells transported CHEMICAL efficiently. We conclude that expression of GLUT2 is required for efficient killing of neuroendocrine cells by CHEMICAL, and this effect is related to specific recognition of the drug as a transported substrate by GLUT2 but not GENE. | NO-RELATIONSHIP |
| STZ transport and cytotoxicity. Specific enhancement in GLUT2-expressing cells. The CHEMICAL analog streptozotocin (STZ) has long been used as a tool for creating experimental diabetes because of its relatively specific beta-cell cytotoxic effect, but the mechanism by which systemic injection of STZ causes beta-cell destruction is not well understood. In the current study, we have used insulinoma (RIN) and AtT-20ins cell lines engineered for overexpression of GENE or GLUT1 to investigate the role of CHEMICAL transporter isoforms in mediating STZ cytotoxicity. The in vivo effects of STZ were evaluated by implantation of RIN cells expressing or lacking GENE into athymic nude rats. The drug had a potent cytotoxic effect on RIN cells expressing GENE, but had no effect on cells lacking GENE expression, as indicated by histological analysis and measurement of the blood CHEMICAL levels of treated animals. The preferential cytotoxic effect of STZ on GLUT2-expressing cell lines was confirmed by in vitro analysis of GLUT2-expressing and untransfected RIN cells, as well as GLUT2- and GLUT1-overexpressing AtT-20ins cells. Consistent with these data, only GLUT2-expressing RIN or AtT-20ins cells transported STZ efficiently. We conclude that expression of GENE is required for efficient killing of neuroendocrine cells by STZ, and this effect is related to specific recognition of the drug as a transported substrate by GENE but not GLUT1. | SUBSTRATE |
| CHEMICAL transport and cytotoxicity. Specific enhancement in GLUT2-expressing cells. The glucose analog streptozotocin (STZ) has long been used as a tool for creating experimental diabetes because of its relatively specific beta-cell cytotoxic effect, but the mechanism by which systemic injection of CHEMICAL causes beta-cell destruction is not well understood. In the current study, we have used insulinoma (RIN) and AtT-20ins cell lines engineered for overexpression of GENE or GLUT1 to investigate the role of glucose transporter isoforms in mediating CHEMICAL cytotoxicity. The in vivo effects of CHEMICAL were evaluated by implantation of RIN cells expressing or lacking GENE into athymic nude rats. The drug had a potent cytotoxic effect on RIN cells expressing GENE, but had no effect on cells lacking GENE expression, as indicated by histological analysis and measurement of the blood glucose levels of treated animals. The preferential cytotoxic effect of CHEMICAL on GLUT2-expressing cell lines was confirmed by in vitro analysis of GLUT2-expressing and untransfected RIN cells, as well as GLUT2- and GLUT1-overexpressing AtT-20ins cells. Consistent with these data, only GENE-expressing RIN or AtT-20ins cells transported CHEMICAL efficiently. We conclude that expression of GENE is required for efficient killing of neuroendocrine cells by CHEMICAL, and this effect is related to specific recognition of the drug as a transported substrate by GENE but not GLUT1. | SUBSTRATE |
| Inhibitory effects of lysine analogues on t-PA induced whole blood clot lysis. The lysine analogues epsilon-aminocaproic acid (EACA) and trans-4-amino-methyl cyclohexane carboxylic acid (AMCA) are used to prevent excessive bleeding in patients with coagulopathies, such as hemophilia and thrombocytopenia, or in those who have received tissue plasminogen activator (t-PA). However, their relative efficacy in inhibiting lysis of clots that have been formed in the presence of exogenous t-PA or that have been formed and then exposed to exogenous t-PA has not been well characterized. The present study utilized blood from normal volunteers and CHEMICAL-GENE in a dilute whole blood clot assay to determine the relative concentrations of lysine analogues required for inhibition of clot lysis induced by exogenous t-PA. AMCA (0.06 mM) and EACA (0.6 mM) were effective in prolonging clot lysis if (1) whole blood clots were formed and then exposed to a lysine analogue and exogenous t-PA or if (2) whole blood clots were formed in the presence of exogenous t-PA and a lysine analogue. However, their inhibitory effect was markedly reduced if clots were formed in the presence of t-PA and then exposed to either of the lysine analogues. The analogues did not inhibit the initial binding of t-PA to fibrin. They did inhibit binding of plasminogen to fibrin as well as the activation of plasminogen by t-PA in the absence of fibrin. The data suggest that lysine analogues, even at low concentrations, reduce the rate of t-PA induced whole blood clot lysis by several mechanisms. | REGULATOR |
| Inhibitory effects of CHEMICAL analogues on GENE induced whole blood clot lysis. The CHEMICAL analogues epsilon-aminocaproic acid (EACA) and trans-4-amino-methyl cyclohexane carboxylic acid (AMCA) are used to prevent excessive bleeding in patients with coagulopathies, such as hemophilia and thrombocytopenia, or in those who have received tissue plasminogen activator (t-PA). However, their relative efficacy in inhibiting lysis of clots that have been formed in the presence of exogenous GENE or that have been formed and then exposed to exogenous GENE has not been well characterized. The present study utilized blood from normal volunteers and 125I-fibrinogen in a dilute whole blood clot assay to determine the relative concentrations of CHEMICAL analogues required for inhibition of clot lysis induced by exogenous GENE. AMCA (0.06 mM) and EACA (0.6 mM) were effective in prolonging clot lysis if (1) whole blood clots were formed and then exposed to a CHEMICAL analogue and exogenous GENE or if (2) whole blood clots were formed in the presence of exogenous GENE and a CHEMICAL analogue. However, their inhibitory effect was markedly reduced if clots were formed in the presence of GENE and then exposed to either of the CHEMICAL analogues. The analogues did not inhibit the initial binding of GENE to fibrin. They did inhibit binding of plasminogen to fibrin as well as the activation of plasminogen by GENE in the absence of fibrin. The data suggest that CHEMICAL analogues, even at low concentrations, reduce the rate of GENE induced whole blood clot lysis by several mechanisms. | INHIBITOR |
| Inhibitory effects of lysine analogues on GENE induced whole blood clot lysis. The lysine analogues epsilon-aminocaproic acid (EACA) and trans-4-amino-methyl cyclohexane carboxylic acid (AMCA) are used to prevent excessive bleeding in patients with coagulopathies, such as hemophilia and thrombocytopenia, or in those who have received tissue plasminogen activator (t-PA). However, their relative efficacy in inhibiting lysis of clots that have been formed in the presence of exogenous GENE or that have been formed and then exposed to exogenous GENE has not been well characterized. The present study utilized blood from normal volunteers and 125I-fibrinogen in a dilute whole blood clot assay to determine the relative concentrations of lysine analogues required for inhibition of clot lysis induced by exogenous GENE. CHEMICAL (0.06 mM) and EACA (0.6 mM) were effective in prolonging clot lysis if (1) whole blood clots were formed and then exposed to a lysine analogue and exogenous GENE or if (2) whole blood clots were formed in the presence of exogenous GENE and a lysine analogue. However, their inhibitory effect was markedly reduced if clots were formed in the presence of GENE and then exposed to either of the lysine analogues. The analogues did not inhibit the initial binding of GENE to fibrin. They did inhibit binding of plasminogen to fibrin as well as the activation of plasminogen by GENE in the absence of fibrin. The data suggest that lysine analogues, even at low concentrations, reduce the rate of GENE induced whole blood clot lysis by several mechanisms. | REGULATOR |
| Inhibitory effects of lysine analogues on GENE induced whole blood clot lysis. The lysine analogues epsilon-aminocaproic acid (EACA) and trans-4-amino-methyl cyclohexane carboxylic acid (AMCA) are used to prevent excessive bleeding in patients with coagulopathies, such as hemophilia and thrombocytopenia, or in those who have received tissue plasminogen activator (t-PA). However, their relative efficacy in inhibiting lysis of clots that have been formed in the presence of exogenous GENE or that have been formed and then exposed to exogenous GENE has not been well characterized. The present study utilized blood from normal volunteers and 125I-fibrinogen in a dilute whole blood clot assay to determine the relative concentrations of lysine analogues required for inhibition of clot lysis induced by exogenous GENE. AMCA (0.06 mM) and CHEMICAL (0.6 mM) were effective in prolonging clot lysis if (1) whole blood clots were formed and then exposed to a lysine analogue and exogenous GENE or if (2) whole blood clots were formed in the presence of exogenous GENE and a lysine analogue. However, their inhibitory effect was markedly reduced if clots were formed in the presence of GENE and then exposed to either of the lysine analogues. The analogues did not inhibit the initial binding of GENE to fibrin. They did inhibit binding of plasminogen to fibrin as well as the activation of plasminogen by GENE in the absence of fibrin. The data suggest that lysine analogues, even at low concentrations, reduce the rate of GENE induced whole blood clot lysis by several mechanisms. | INHIBITOR |
| CHEMICAL enhances the depolarizing afterpotential of immunohistochemically identified vasopressin neurons in the rat supraoptic nucleus via GENE activation. Previous studies have demonstrated that histamine primarily excites unidentified neurons in the rat supraoptic nucleus. We investigated the neuromodulatory effects of histamine on immunohistochemically identified vasopressin neurons in the rat supraoptic nucleus using intracellular recording techniques from the hypothalamo-neurohypophysial explant. Exogenous application of histamine (0.1-100 microM) to vasopressinergic neurons produced a small membrane depolarization accompanied by an increase of up to 100% in the amplitude of the depolarizing afterpotential that follows current-evoked trains of action potentials. The enhancement of the depolarizing afterpotential by histamine did not depend upon the depolarization. Further, histamine enhanced the amplitude of the depolarizing afterpotential when blocking the afterhyperpolarizing potential with d-tubocurarine or apamin, and in the presence of tetrodotoxin and d-tubocurarine or apamin, indicating a postsynaptic action of histamine on the depolarizing afterpotential that is not simply a reflection of a decrease in the afterhyperpolarizing potential. These toxins also had no effect on the histamine-induced depolarization. The enhancement of the depolarizing afterpotential by histamine was mimicked by the histamine GENE agonist 2-thiazolylethylamine and was reduced or blocked by the GENE antagonist promethazine, but was not blocked or reduced in the presence of the histamine H2-receptor antagonist, cimetidine. In summary, these results show that the excitatory effect of histamine on immunohistochemically identified vasopressin neurons in the supraoptic nucleus is due in part to the H1-receptor-mediated enhancement of the depolarizing afterpotential independent of any change in the afterhyperpolarizing potential or membrane potential. | ACTIVATOR |
| Histamine enhances the depolarizing afterpotential of immunohistochemically identified vasopressin neurons in the rat supraoptic nucleus via H1-receptor activation. Previous studies have demonstrated that histamine primarily excites unidentified neurons in the rat supraoptic nucleus. We investigated the neuromodulatory effects of histamine on immunohistochemically identified vasopressin neurons in the rat supraoptic nucleus using intracellular recording techniques from the hypothalamo-neurohypophysial explant. Exogenous application of histamine (0.1-100 microM) to vasopressinergic neurons produced a small membrane depolarization accompanied by an increase of up to 100% in the amplitude of the depolarizing afterpotential that follows current-evoked trains of action potentials. The enhancement of the depolarizing afterpotential by histamine did not depend upon the depolarization. Further, histamine enhanced the amplitude of the depolarizing afterpotential when blocking the afterhyperpolarizing potential with d-tubocurarine or apamin, and in the presence of tetrodotoxin and d-tubocurarine or apamin, indicating a postsynaptic action of histamine on the depolarizing afterpotential that is not simply a reflection of a decrease in the afterhyperpolarizing potential. These toxins also had no effect on the histamine-induced depolarization. The enhancement of the depolarizing afterpotential by histamine was mimicked by the GENE agonist CHEMICAL and was reduced or blocked by the H1-receptor antagonist promethazine, but was not blocked or reduced in the presence of the histamine H2-receptor antagonist, cimetidine. In summary, these results show that the excitatory effect of histamine on immunohistochemically identified vasopressin neurons in the supraoptic nucleus is due in part to the H1-receptor-mediated enhancement of the depolarizing afterpotential independent of any change in the afterhyperpolarizing potential or membrane potential. | ACTIVATOR |
| Histamine enhances the depolarizing afterpotential of immunohistochemically identified vasopressin neurons in the rat supraoptic nucleus via GENE activation. Previous studies have demonstrated that histamine primarily excites unidentified neurons in the rat supraoptic nucleus. We investigated the neuromodulatory effects of histamine on immunohistochemically identified vasopressin neurons in the rat supraoptic nucleus using intracellular recording techniques from the hypothalamo-neurohypophysial explant. Exogenous application of histamine (0.1-100 microM) to vasopressinergic neurons produced a small membrane depolarization accompanied by an increase of up to 100% in the amplitude of the depolarizing afterpotential that follows current-evoked trains of action potentials. The enhancement of the depolarizing afterpotential by histamine did not depend upon the depolarization. Further, histamine enhanced the amplitude of the depolarizing afterpotential when blocking the afterhyperpolarizing potential with d-tubocurarine or apamin, and in the presence of tetrodotoxin and d-tubocurarine or apamin, indicating a postsynaptic action of histamine on the depolarizing afterpotential that is not simply a reflection of a decrease in the afterhyperpolarizing potential. These toxins also had no effect on the histamine-induced depolarization. The enhancement of the depolarizing afterpotential by histamine was mimicked by the histamine GENE agonist 2-thiazolylethylamine and was reduced or blocked by the GENE antagonist CHEMICAL, but was not blocked or reduced in the presence of the histamine H2-receptor antagonist, cimetidine. In summary, these results show that the excitatory effect of histamine on immunohistochemically identified vasopressin neurons in the supraoptic nucleus is due in part to the H1-receptor-mediated enhancement of the depolarizing afterpotential independent of any change in the afterhyperpolarizing potential or membrane potential. | INHIBITOR |
| Histamine enhances the depolarizing afterpotential of immunohistochemically identified vasopressin neurons in the rat supraoptic nucleus via H1-receptor activation. Previous studies have demonstrated that histamine primarily excites unidentified neurons in the rat supraoptic nucleus. We investigated the neuromodulatory effects of histamine on immunohistochemically identified vasopressin neurons in the rat supraoptic nucleus using intracellular recording techniques from the hypothalamo-neurohypophysial explant. Exogenous application of histamine (0.1-100 microM) to vasopressinergic neurons produced a small membrane depolarization accompanied by an increase of up to 100% in the amplitude of the depolarizing afterpotential that follows current-evoked trains of action potentials. The enhancement of the depolarizing afterpotential by histamine did not depend upon the depolarization. Further, histamine enhanced the amplitude of the depolarizing afterpotential when blocking the afterhyperpolarizing potential with d-tubocurarine or apamin, and in the presence of tetrodotoxin and d-tubocurarine or apamin, indicating a postsynaptic action of histamine on the depolarizing afterpotential that is not simply a reflection of a decrease in the afterhyperpolarizing potential. These toxins also had no effect on the histamine-induced depolarization. The enhancement of the depolarizing afterpotential by histamine was mimicked by the histamine H1-receptor agonist 2-thiazolylethylamine and was reduced or blocked by the H1-receptor antagonist promethazine, but was not blocked or reduced in the presence of the GENE antagonist, CHEMICAL. In summary, these results show that the excitatory effect of histamine on immunohistochemically identified vasopressin neurons in the supraoptic nucleus is due in part to the H1-receptor-mediated enhancement of the depolarizing afterpotential independent of any change in the afterhyperpolarizing potential or membrane potential. | INHIBITOR |
| CHEMICAL, a new chemical entity with retinoid activity. CHEMICAL is a novel chemical entity which, in terms of pharmacology, behaves similar to tretinoin, but is chemically and photochemically stable. It has a particular selectivity profile for the known nuclear retinoic acid receptors with low affinity for RAR alpha and no transactivating potential for RXR alpha. This receptor profile could imply that CHEMICAL, in contrast to tretinoin, affects the terminal differentiation pathway of epidermal cells rather than their proliferation. Furthermore, CHEMICAL does not bind to members of the cellular GENE family. CHEMICAL has comedolytic activity in the topical rhino mouse model. It exerts a moderate-to-potent anti-inflammatory effect in a series of in vitro and in vivo models. In comparative clinical studies involving 72 acne patients, the efficacy of CHEMICAL was comparable, if not superior, to tretinoin, but CHEMICAL was better tolerated. The data reviewed in this paper indicate that CHEMICAL should be particularly beneficial in the treatment of acne. | NO-RELATIONSHIP |
| Comparative effects of three different potent renin inhibitors in primates. The goal of the present study was to compare the effects of three potent reference renin inhibitors (remikiren, CGP 38560A, and enalkiren) in sodium-depleted normotensive squirrel monkeys. In these monkeys, arterial pressure was measured in the conscious state with a telemetry system. Oral and intravenous maximal effective doses of the three renin inhibitors were compared in parallel groups of monkeys. In additional experiments, remikiren was given on top of either CGP 38560A or enalkiren in the same animals. Finally, the three drugs were compared with the GENE inhibitor CHEMICAL. The effects of the three drugs on the plasma components of the renin-angiotensin system (plasma renin activity, immunoreactive renin, and immunoreactive angiotensin II concentrations) were also measured. Our results show that remikiren was as effective as CHEMICAL and markedly more effective than CGP 38560A or enalkiren in reducing arterial pressure in our monkey model. Interestingly, these differences in arterial pressure could not be explained by differences of in vitro potency or different biochemical changes of the plasma components of the renin-angiotensin system, because the inhibitors all reduced immunoreactive angiotensin II to similarly low levels. One possible explanation is that, in our model, remikiren in contrast to CGP 38560A and enalkiren is able to inhibit renin in a functionally important extraplasmatic compartment. | INHIBITOR |
| Comparative effects of three different potent GENE inhibitors in primates. The goal of the present study was to compare the effects of three potent reference GENE inhibitors (CHEMICAL, CGP 38560A, and enalkiren) in sodium-depleted normotensive squirrel monkeys. In these monkeys, arterial pressure was measured in the conscious state with a telemetry system. Oral and intravenous maximal effective doses of the three GENE inhibitors were compared in parallel groups of monkeys. In additional experiments, CHEMICAL was given on top of either CGP 38560A or enalkiren in the same animals. Finally, the three drugs were compared with the angiotensin converting enzyme inhibitor cilazapril. The effects of the three drugs on the plasma components of the renin-angiotensin system (plasma GENE activity, immunoreactive GENE, and immunoreactive angiotensin II concentrations) were also measured. Our results show that CHEMICAL was as effective as cilazapril and markedly more effective than CGP 38560A or enalkiren in reducing arterial pressure in our monkey model. Interestingly, these differences in arterial pressure could not be explained by differences of in vitro potency or different biochemical changes of the plasma components of the renin-angiotensin system, because the inhibitors all reduced immunoreactive angiotensin II to similarly low levels. One possible explanation is that, in our model, CHEMICAL in contrast to CGP 38560A and enalkiren is able to inhibit GENE in a functionally important extraplasmatic compartment. | INHIBITOR |
| Comparative effects of three different potent GENE inhibitors in primates. The goal of the present study was to compare the effects of three potent reference GENE inhibitors (remikiren, CHEMICAL, and enalkiren) in sodium-depleted normotensive squirrel monkeys. In these monkeys, arterial pressure was measured in the conscious state with a telemetry system. Oral and intravenous maximal effective doses of the three GENE inhibitors were compared in parallel groups of monkeys. In additional experiments, remikiren was given on top of either CHEMICAL or enalkiren in the same animals. Finally, the three drugs were compared with the angiotensin converting enzyme inhibitor cilazapril. The effects of the three drugs on the plasma components of the renin-angiotensin system (plasma GENE activity, immunoreactive GENE, and immunoreactive angiotensin II concentrations) were also measured. Our results show that remikiren was as effective as cilazapril and markedly more effective than CHEMICAL or enalkiren in reducing arterial pressure in our monkey model. Interestingly, these differences in arterial pressure could not be explained by differences of in vitro potency or different biochemical changes of the plasma components of the renin-angiotensin system, because the inhibitors all reduced immunoreactive angiotensin II to similarly low levels. One possible explanation is that, in our model, remikiren in contrast to CHEMICAL and enalkiren is able to inhibit GENE in a functionally important extraplasmatic compartment. | INHIBITOR |
| Comparative effects of three different potent GENE inhibitors in primates. The goal of the present study was to compare the effects of three potent reference GENE inhibitors (remikiren, CGP 38560A, and CHEMICAL) in sodium-depleted normotensive squirrel monkeys. In these monkeys, arterial pressure was measured in the conscious state with a telemetry system. Oral and intravenous maximal effective doses of the three GENE inhibitors were compared in parallel groups of monkeys. In additional experiments, remikiren was given on top of either CGP 38560A or CHEMICAL in the same animals. Finally, the three drugs were compared with the angiotensin converting enzyme inhibitor cilazapril. The effects of the three drugs on the plasma components of the renin-angiotensin system (plasma GENE activity, immunoreactive GENE, and immunoreactive angiotensin II concentrations) were also measured. Our results show that remikiren was as effective as cilazapril and markedly more effective than CGP 38560A or CHEMICAL in reducing arterial pressure in our monkey model. Interestingly, these differences in arterial pressure could not be explained by differences of in vitro potency or different biochemical changes of the plasma components of the renin-angiotensin system, because the inhibitors all reduced immunoreactive angiotensin II to similarly low levels. One possible explanation is that, in our model, remikiren in contrast to CGP 38560A and CHEMICAL is able to inhibit GENE in a functionally important extraplasmatic compartment. | INHIBITOR |
| Inhibition of cytokine-primed eosinophil chemotaxis by nedocromil sodium. BACKGROUND: Eosinophil influx into the lung tissue is considered to be relevant for the pathogenesis of asthma. Various chemotactic factors may be responsible for this influx. Recently it has been demonstrated that the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5) are present in the circulation of individuals with allergic asthma. These cytokines have the capacity to modulate chemotactic responses of eosinophils toward platelet-activating factor, formyl-methionyl-leucyl-phenylalanine, (FMLP) and neutrophil-activating factor (NAF)/IL-8, but not toward complement fragment C5a (C5a). Here the effect of nedocromil sodium on the chemotactic response of eosinophils from allergic asthmatic individuals and from normal donors preincubated with GENE or IL-3 toward FMLP, NAF/IL-8 was evaluated. RESULTS: CHEMICAL inhibited the chemotactic response toward FMLP and NAF/IL-8 of GENE primed eosinophils approximately 60% (inhibitory concentration of 50% [IC50] approximately 1 to 10 nmol/L), whereas these responses of IL-3 primed eosinophils was completely inhibited (IC50 approximately 1 nmol/L). CONCLUSIONS: The chemotactic responses toward C5a were inhibited by nedocromil sodium at higher concentrations than were required in the priming studies (IC50 approximately 10 to 100 nmol/L). CHEMICAL (0.1 mumol/L) was also effective in inhibiting the chemotactic response toward FMLP (10 nmol/L) of eosinophils isolated from the circulation of patients with allergic asthma 3 hours after allergen challenge. These findings might explain in part the antiinflammatory action of nedocromil sodium. | INHIBITOR |
| Inhibition of GENE-primed eosinophil chemotaxis by CHEMICAL. BACKGROUND: Eosinophil influx into the lung tissue is considered to be relevant for the pathogenesis of asthma. Various chemotactic factors may be responsible for this influx. Recently it has been demonstrated that the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5) are present in the circulation of individuals with allergic asthma. These cytokines have the capacity to modulate chemotactic responses of eosinophils toward platelet-activating factor, formyl-methionyl-leucyl-phenylalanine, (FMLP) and neutrophil-activating factor (NAF)/IL-8, but not toward complement fragment C5a (C5a). Here the effect of CHEMICAL on the chemotactic response of eosinophils from allergic asthmatic individuals and from normal donors preincubated with GM-CSF or IL-3 toward FMLP, NAF/IL-8 was evaluated. RESULTS: CHEMICAL inhibited the chemotactic response toward FMLP and NAF/IL-8 of GM-CSF primed eosinophils approximately 60% (inhibitory concentration of 50% [IC50] approximately 1 to 10 nmol/L), whereas these responses of IL-3 primed eosinophils was completely inhibited (IC50 approximately 1 nmol/L). CONCLUSIONS: The chemotactic responses toward C5a were inhibited by CHEMICAL at higher concentrations than were required in the priming studies (IC50 approximately 10 to 100 nmol/L). CHEMICAL (0.1 mumol/L) was also effective in inhibiting the chemotactic response toward FMLP (10 nmol/L) of eosinophils isolated from the circulation of patients with allergic asthma 3 hours after allergen challenge. These findings might explain in part the antiinflammatory action of CHEMICAL. | INHIBITOR |
| Inhibition of cytokine-primed eosinophil chemotaxis by CHEMICAL. BACKGROUND: Eosinophil influx into the lung tissue is considered to be relevant for the pathogenesis of asthma. Various chemotactic factors may be responsible for this influx. Recently it has been demonstrated that the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5) are present in the circulation of individuals with allergic asthma. These cytokines have the capacity to modulate chemotactic responses of eosinophils toward platelet-activating factor, formyl-methionyl-leucyl-phenylalanine, (FMLP) and neutrophil-activating factor (NAF)/IL-8, but not toward complement fragment GENE (C5a). Here the effect of CHEMICAL on the chemotactic response of eosinophils from allergic asthmatic individuals and from normal donors preincubated with GM-CSF or IL-3 toward FMLP, NAF/IL-8 was evaluated. RESULTS: CHEMICAL inhibited the chemotactic response toward FMLP and NAF/IL-8 of GM-CSF primed eosinophils approximately 60% (inhibitory concentration of 50% [IC50] approximately 1 to 10 nmol/L), whereas these responses of IL-3 primed eosinophils was completely inhibited (IC50 approximately 1 nmol/L). CONCLUSIONS: The chemotactic responses toward GENE were inhibited by CHEMICAL at higher concentrations than were required in the priming studies (IC50 approximately 10 to 100 nmol/L). CHEMICAL (0.1 mumol/L) was also effective in inhibiting the chemotactic response toward FMLP (10 nmol/L) of eosinophils isolated from the circulation of patients with allergic asthma 3 hours after allergen challenge. These findings might explain in part the antiinflammatory action of CHEMICAL. | INHIBITOR |
| Inhibition of cytokine-primed eosinophil chemotaxis by nedocromil sodium. BACKGROUND: Eosinophil influx into the lung tissue is considered to be relevant for the pathogenesis of asthma. Various chemotactic factors may be responsible for this influx. Recently it has been demonstrated that the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5) are present in the circulation of individuals with allergic asthma. These cytokines have the capacity to modulate chemotactic responses of eosinophils toward platelet-activating factor, formyl-methionyl-leucyl-phenylalanine, (FMLP) and neutrophil-activating factor (NAF)/IL-8, but not toward complement fragment C5a (C5a). Here the effect of nedocromil sodium on the chemotactic response of eosinophils from allergic asthmatic individuals and from normal donors preincubated with GM-CSF or GENE toward FMLP, NAF/IL-8 was evaluated. RESULTS: CHEMICAL inhibited the chemotactic response toward FMLP and NAF/IL-8 of GM-CSF primed eosinophils approximately 60% (inhibitory concentration of 50% [IC50] approximately 1 to 10 nmol/L), whereas these responses of GENE primed eosinophils was completely inhibited (IC50 approximately 1 nmol/L). CONCLUSIONS: The chemotactic responses toward C5a were inhibited by nedocromil sodium at higher concentrations than were required in the priming studies (IC50 approximately 10 to 100 nmol/L). CHEMICAL (0.1 mumol/L) was also effective in inhibiting the chemotactic response toward FMLP (10 nmol/L) of eosinophils isolated from the circulation of patients with allergic asthma 3 hours after allergen challenge. These findings might explain in part the antiinflammatory action of nedocromil sodium. | INHIBITOR |
| Inhibition of cytokine-primed eosinophil chemotaxis by nedocromil sodium. BACKGROUND: Eosinophil influx into the lung tissue is considered to be relevant for the pathogenesis of asthma. Various chemotactic factors may be responsible for this influx. Recently it has been demonstrated that the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5) are present in the circulation of individuals with allergic asthma. These cytokines have the capacity to modulate chemotactic responses of eosinophils toward platelet-activating factor, formyl-methionyl-leucyl-phenylalanine, (FMLP) and neutrophil-activating factor (NAF)/IL-8, but not toward complement fragment C5a (C5a). Here the effect of nedocromil sodium on the chemotactic response of eosinophils from allergic asthmatic individuals and from normal donors preincubated with GM-CSF or IL-3 toward FMLP, NAF/IL-8 was evaluated. RESULTS: CHEMICAL inhibited the chemotactic response toward FMLP and GENE/IL-8 of GM-CSF primed eosinophils approximately 60% (inhibitory concentration of 50% [IC50] approximately 1 to 10 nmol/L), whereas these responses of IL-3 primed eosinophils was completely inhibited (IC50 approximately 1 nmol/L). CONCLUSIONS: The chemotactic responses toward C5a were inhibited by nedocromil sodium at higher concentrations than were required in the priming studies (IC50 approximately 10 to 100 nmol/L). CHEMICAL (0.1 mumol/L) was also effective in inhibiting the chemotactic response toward FMLP (10 nmol/L) of eosinophils isolated from the circulation of patients with allergic asthma 3 hours after allergen challenge. These findings might explain in part the antiinflammatory action of nedocromil sodium. | INHIBITOR |
| Inhibition of cytokine-primed eosinophil chemotaxis by nedocromil sodium. BACKGROUND: Eosinophil influx into the lung tissue is considered to be relevant for the pathogenesis of asthma. Various chemotactic factors may be responsible for this influx. Recently it has been demonstrated that the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5) are present in the circulation of individuals with allergic asthma. These cytokines have the capacity to modulate chemotactic responses of eosinophils toward platelet-activating factor, formyl-methionyl-leucyl-phenylalanine, (FMLP) and neutrophil-activating factor (NAF)/IL-8, but not toward complement fragment C5a (C5a). Here the effect of nedocromil sodium on the chemotactic response of eosinophils from allergic asthmatic individuals and from normal donors preincubated with GM-CSF or IL-3 toward FMLP, NAF/IL-8 was evaluated. RESULTS: CHEMICAL inhibited the chemotactic response toward FMLP and NAF/GENE of GM-CSF primed eosinophils approximately 60% (inhibitory concentration of 50% [IC50] approximately 1 to 10 nmol/L), whereas these responses of IL-3 primed eosinophils was completely inhibited (IC50 approximately 1 nmol/L). CONCLUSIONS: The chemotactic responses toward C5a were inhibited by nedocromil sodium at higher concentrations than were required in the priming studies (IC50 approximately 10 to 100 nmol/L). CHEMICAL (0.1 mumol/L) was also effective in inhibiting the chemotactic response toward FMLP (10 nmol/L) of eosinophils isolated from the circulation of patients with allergic asthma 3 hours after allergen challenge. These findings might explain in part the antiinflammatory action of nedocromil sodium. | INHIBITOR |
| Dominant expression of mRNA for prostaglandin D synthase in leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. CHEMICAL-independent prostaglandin D synthase [GENE; (5Z,13E)-(15S)-9 alpha,11 alpha-epidioxy-15-hydroxyprosta-5,13-dienoate D-isomerase, EC 5.3.99.2] is an enzyme responsible for biosynthesis of prostaglandin D2 in the central nervous system. In situ hybridization with antisense RNA for the enzyme indicated that mRNA for the enzyme was predominantly expressed in the leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. The findings agree with those obtained by immunohistochemical staining with antibodies against the enzyme. It was further revealed that prostaglandin D synthase activity was considerably greater in the isolated leptomeninges (14.2 nmol per min per mg of protein) and choroid plexus (7.0 nmol per min per mg of protein) than the activity in the whole brain (2.0 nmol per min per mg of protein). These results, taken together, indicate that the enzyme is mainly synthesized and located in the leptomeninges, choroid plexus, and oligodendrocytes in the brain. | NO-RELATIONSHIP |
| Dominant expression of mRNA for prostaglandin D synthase in leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. CHEMICAL-independent prostaglandin D synthase [prostaglandin-H2 D-isomerase; GENE, EC 5.3.99.2] is an enzyme responsible for biosynthesis of prostaglandin D2 in the central nervous system. In situ hybridization with antisense RNA for the enzyme indicated that mRNA for the enzyme was predominantly expressed in the leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. The findings agree with those obtained by immunohistochemical staining with antibodies against the enzyme. It was further revealed that prostaglandin D synthase activity was considerably greater in the isolated leptomeninges (14.2 nmol per min per mg of protein) and choroid plexus (7.0 nmol per min per mg of protein) than the activity in the whole brain (2.0 nmol per min per mg of protein). These results, taken together, indicate that the enzyme is mainly synthesized and located in the leptomeninges, choroid plexus, and oligodendrocytes in the brain. | NO-RELATIONSHIP |
| Dominant expression of mRNA for prostaglandin D synthase in leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. CHEMICAL-independent prostaglandin D synthase [prostaglandin-H2 D-isomerase; (5Z,13E)-(15S)-9 alpha,11 alpha-epidioxy-15-hydroxyprosta-5,13-dienoate D-isomerase, GENE] is an enzyme responsible for biosynthesis of prostaglandin D2 in the central nervous system. In situ hybridization with antisense RNA for the enzyme indicated that mRNA for the enzyme was predominantly expressed in the leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. The findings agree with those obtained by immunohistochemical staining with antibodies against the enzyme. It was further revealed that prostaglandin D synthase activity was considerably greater in the isolated leptomeninges (14.2 nmol per min per mg of protein) and choroid plexus (7.0 nmol per min per mg of protein) than the activity in the whole brain (2.0 nmol per min per mg of protein). These results, taken together, indicate that the enzyme is mainly synthesized and located in the leptomeninges, choroid plexus, and oligodendrocytes in the brain. | NO-RELATIONSHIP |
| Dominant expression of mRNA for GENE in leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. CHEMICAL-independent GENE [prostaglandin-H2 D-isomerase; (5Z,13E)-(15S)-9 alpha,11 alpha-epidioxy-15-hydroxyprosta-5,13-dienoate D-isomerase, EC 5.3.99.2] is an enzyme responsible for biosynthesis of prostaglandin D2 in the central nervous system. In situ hybridization with antisense RNA for the enzyme indicated that mRNA for the enzyme was predominantly expressed in the leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. The findings agree with those obtained by immunohistochemical staining with antibodies against the enzyme. It was further revealed that GENE activity was considerably greater in the isolated leptomeninges (14.2 nmol per min per mg of protein) and choroid plexus (7.0 nmol per min per mg of protein) than the activity in the whole brain (2.0 nmol per min per mg of protein). These results, taken together, indicate that the enzyme is mainly synthesized and located in the leptomeninges, choroid plexus, and oligodendrocytes in the brain. | NO-RELATIONSHIP |
| Dominant expression of mRNA for prostaglandin D synthase in leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. Glutathione-independent prostaglandin D synthase [GENE; (5Z,13E)-(15S)-9 alpha,11 alpha-epidioxy-15-hydroxyprosta-5,13-dienoate D-isomerase, EC 5.3.99.2] is an enzyme responsible for biosynthesis of CHEMICAL in the central nervous system. In situ hybridization with antisense RNA for the enzyme indicated that mRNA for the enzyme was predominantly expressed in the leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. The findings agree with those obtained by immunohistochemical staining with antibodies against the enzyme. It was further revealed that prostaglandin D synthase activity was considerably greater in the isolated leptomeninges (14.2 nmol per min per mg of protein) and choroid plexus (7.0 nmol per min per mg of protein) than the activity in the whole brain (2.0 nmol per min per mg of protein). These results, taken together, indicate that the enzyme is mainly synthesized and located in the leptomeninges, choroid plexus, and oligodendrocytes in the brain. | PRODUCT-OF |
| Dominant expression of mRNA for prostaglandin D synthase in leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. Glutathione-independent prostaglandin D synthase [prostaglandin-H2 D-isomerase; GENE, EC 5.3.99.2] is an enzyme responsible for biosynthesis of CHEMICAL in the central nervous system. In situ hybridization with antisense RNA for the enzyme indicated that mRNA for the enzyme was predominantly expressed in the leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. The findings agree with those obtained by immunohistochemical staining with antibodies against the enzyme. It was further revealed that prostaglandin D synthase activity was considerably greater in the isolated leptomeninges (14.2 nmol per min per mg of protein) and choroid plexus (7.0 nmol per min per mg of protein) than the activity in the whole brain (2.0 nmol per min per mg of protein). These results, taken together, indicate that the enzyme is mainly synthesized and located in the leptomeninges, choroid plexus, and oligodendrocytes in the brain. | PRODUCT-OF |
| Dominant expression of mRNA for prostaglandin D synthase in leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. Glutathione-independent prostaglandin D synthase [prostaglandin-H2 D-isomerase; (5Z,13E)-(15S)-9 alpha,11 alpha-epidioxy-15-hydroxyprosta-5,13-dienoate D-isomerase, GENE] is an enzyme responsible for biosynthesis of CHEMICAL in the central nervous system. In situ hybridization with antisense RNA for the enzyme indicated that mRNA for the enzyme was predominantly expressed in the leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. The findings agree with those obtained by immunohistochemical staining with antibodies against the enzyme. It was further revealed that prostaglandin D synthase activity was considerably greater in the isolated leptomeninges (14.2 nmol per min per mg of protein) and choroid plexus (7.0 nmol per min per mg of protein) than the activity in the whole brain (2.0 nmol per min per mg of protein). These results, taken together, indicate that the enzyme is mainly synthesized and located in the leptomeninges, choroid plexus, and oligodendrocytes in the brain. | PRODUCT-OF |
| Dominant expression of mRNA for GENE in leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. Glutathione-independent GENE [prostaglandin-H2 D-isomerase; (5Z,13E)-(15S)-9 alpha,11 alpha-epidioxy-15-hydroxyprosta-5,13-dienoate D-isomerase, EC 5.3.99.2] is an enzyme responsible for biosynthesis of CHEMICAL in the central nervous system. In situ hybridization with antisense RNA for the enzyme indicated that mRNA for the enzyme was predominantly expressed in the leptomeninges, choroid plexus, and oligodendrocytes of the adult rat brain. The findings agree with those obtained by immunohistochemical staining with antibodies against the enzyme. It was further revealed that GENE activity was considerably greater in the isolated leptomeninges (14.2 nmol per min per mg of protein) and choroid plexus (7.0 nmol per min per mg of protein) than the activity in the whole brain (2.0 nmol per min per mg of protein). These results, taken together, indicate that the enzyme is mainly synthesized and located in the leptomeninges, choroid plexus, and oligodendrocytes in the brain. | PRODUCT-OF |
| cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration. We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated GENE, shares a 90% CHEMICAL identity with the previously reported rat GluR5-2b cDNA splice variant and differed from human GluR5-1d in the amino and carboxy terminal regions. Cell lines stably expressing GENE protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, L-glutamate and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (AMPA). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-N-methyl-D-aspartate (NMDA) receptor antagonist CNQX (6-cyano-7-nitro-quinoxalinedione). Coexpression of GENE and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. Kainate and AMPA activated the heteromeric channel with significantly higher affinities than observed for GENE alone. Ligand binding studies with the recombinant GENE receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing [3H]-kainate binding to GENE receptor was: domoate > kainate > L-glutamate = quisqualate > 6,7-dinitroquinoxaline-2,3-dione (DNQX) = CNQX > AMPA > dihydrokainate > NMDA. | PART-OF |
| cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration. We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated EAA3a, shares a 90% CHEMICAL identity with the previously reported GENE cDNA splice variant and differed from human GluR5-1d in the amino and carboxy terminal regions. Cell lines stably expressing EAA3a protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, L-glutamate and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (AMPA). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-N-methyl-D-aspartate (NMDA) receptor antagonist CNQX (6-cyano-7-nitro-quinoxalinedione). Coexpression of EAA3a and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. Kainate and AMPA activated the heteromeric channel with significantly higher affinities than observed for EAA3a alone. Ligand binding studies with the recombinant EAA3a receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing [3H]-kainate binding to EAA3a receptor was: domoate > kainate > L-glutamate = quisqualate > 6,7-dinitroquinoxaline-2,3-dione (DNQX) = CNQX > AMPA > dihydrokainate > NMDA. | PART-OF |
| cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration. We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated EAA3a, shares a 90% nucleotide identity with the previously reported rat GluR5-2b cDNA splice variant and differed from GENE in the CHEMICAL and carboxy terminal regions. Cell lines stably expressing EAA3a protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, L-glutamate and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (AMPA). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-N-methyl-D-aspartate (NMDA) receptor antagonist CNQX (6-cyano-7-nitro-quinoxalinedione). Coexpression of EAA3a and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. Kainate and AMPA activated the heteromeric channel with significantly higher affinities than observed for EAA3a alone. Ligand binding studies with the recombinant EAA3a receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing [3H]-kainate binding to EAA3a receptor was: domoate > kainate > L-glutamate = quisqualate > 6,7-dinitroquinoxaline-2,3-dione (DNQX) = CNQX > AMPA > dihydrokainate > NMDA. | PART-OF |
| cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration. We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated EAA3a, shares a 90% nucleotide identity with the previously reported rat GluR5-2b cDNA splice variant and differed from GENE in the amino and CHEMICAL terminal regions. Cell lines stably expressing EAA3a protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, L-glutamate and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (AMPA). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-N-methyl-D-aspartate (NMDA) receptor antagonist CNQX (6-cyano-7-nitro-quinoxalinedione). Coexpression of EAA3a and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. Kainate and AMPA activated the heteromeric channel with significantly higher affinities than observed for EAA3a alone. Ligand binding studies with the recombinant EAA3a receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing [3H]-kainate binding to EAA3a receptor was: domoate > kainate > L-glutamate = quisqualate > 6,7-dinitroquinoxaline-2,3-dione (DNQX) = CNQX > AMPA > dihydrokainate > NMDA. | PART-OF |
| cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration. We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated GENE, shares a 90% nucleotide identity with the previously reported rat GluR5-2b cDNA splice variant and differed from human GluR5-1d in the amino and carboxy terminal regions. Cell lines stably expressing GENE protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, L-glutamate and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (AMPA). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-N-methyl-D-aspartate (NMDA) receptor antagonist CNQX (6-cyano-7-nitro-quinoxalinedione). Coexpression of GENE and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. Kainate and AMPA activated the heteromeric channel with significantly higher affinities than observed for GENE alone. Ligand binding studies with the recombinant GENE receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing [3H]-kainate binding to GENE receptor was: domoate > kainate > L-glutamate = quisqualate > 6,7-dinitroquinoxaline-2,3-dione (DNQX) = CNQX > AMPA > CHEMICAL > NMDA. | REGULATOR |
| cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration. We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated GENE, shares a 90% nucleotide identity with the previously reported rat GluR5-2b cDNA splice variant and differed from human GluR5-1d in the amino and carboxy terminal regions. Cell lines stably expressing GENE protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, L-glutamate and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (AMPA). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-N-methyl-D-aspartate (NMDA) receptor antagonist CNQX (6-cyano-7-nitro-quinoxalinedione). Coexpression of GENE and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. Kainate and AMPA activated the heteromeric channel with significantly higher affinities than observed for GENE alone. Ligand binding studies with the recombinant GENE receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing [3H]-kainate binding to GENE receptor was: domoate > kainate > L-glutamate = quisqualate > 6,7-dinitroquinoxaline-2,3-dione (DNQX) = CNQX > AMPA > dihydrokainate > CHEMICAL. | DIRECT-REGULATOR |
| cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration. We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated GENE, shares a 90% nucleotide identity with the previously reported rat GluR5-2b cDNA splice variant and differed from human GluR5-1d in the amino and carboxy terminal regions. Cell lines stably expressing GENE protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, CHEMICAL, L-glutamate and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (AMPA). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-N-methyl-D-aspartate (NMDA) receptor antagonist CNQX (6-cyano-7-nitro-quinoxalinedione). Coexpression of GENE and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. CHEMICAL and AMPA activated the heteromeric channel with significantly higher affinities than observed for GENE alone. Ligand binding studies with the recombinant GENE receptor expressed in mammalian cells indicated a high affinity CHEMICAL binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing [3H]-kainate binding to GENE receptor was: domoate > CHEMICAL > L-glutamate = quisqualate > 6,7-dinitroquinoxaline-2,3-dione (DNQX) = CNQX > AMPA > dihydrokainate > NMDA. | DIRECT-REGULATOR |
| cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration. We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated GENE, shares a 90% nucleotide identity with the previously reported rat GluR5-2b cDNA splice variant and differed from human GluR5-1d in the amino and carboxy terminal regions. Cell lines stably expressing GENE protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, CHEMICAL and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (AMPA). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-N-methyl-D-aspartate (NMDA) receptor antagonist CNQX (6-cyano-7-nitro-quinoxalinedione). Coexpression of GENE and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. Kainate and AMPA activated the heteromeric channel with significantly higher affinities than observed for GENE alone. Ligand binding studies with the recombinant GENE receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing [3H]-kainate binding to GENE receptor was: domoate > kainate > CHEMICAL = quisqualate > 6,7-dinitroquinoxaline-2,3-dione (DNQX) = CNQX > AMPA > dihydrokainate > NMDA. | DIRECT-REGULATOR |
| cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration. We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated GENE, shares a 90% nucleotide identity with the previously reported rat GluR5-2b cDNA splice variant and differed from human GluR5-1d in the amino and carboxy terminal regions. Cell lines stably expressing GENE protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, L-glutamate and CHEMICAL (AMPA). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-N-methyl-D-aspartate (NMDA) receptor antagonist CNQX (6-cyano-7-nitro-quinoxalinedione). Coexpression of GENE and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. Kainate and AMPA activated the heteromeric channel with significantly higher affinities than observed for GENE alone. Ligand binding studies with the recombinant GENE receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing [3H]-kainate binding to GENE receptor was: domoate > kainate > L-glutamate = quisqualate > 6,7-dinitroquinoxaline-2,3-dione (DNQX) = CNQX > AMPA > dihydrokainate > NMDA. | DIRECT-REGULATOR |
| cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration. We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated GENE, shares a 90% nucleotide identity with the previously reported rat GluR5-2b cDNA splice variant and differed from human GluR5-1d in the amino and carboxy terminal regions. Cell lines stably expressing GENE protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, L-glutamate and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (CHEMICAL). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-N-methyl-D-aspartate (NMDA) receptor antagonist CNQX (6-cyano-7-nitro-quinoxalinedione). Coexpression of GENE and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. Kainate and CHEMICAL activated the heteromeric channel with significantly higher affinities than observed for GENE alone. Ligand binding studies with the recombinant GENE receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing [3H]-kainate binding to GENE receptor was: domoate > kainate > L-glutamate = quisqualate > 6,7-dinitroquinoxaline-2,3-dione (DNQX) = CNQX > CHEMICAL > dihydrokainate > NMDA. | DIRECT-REGULATOR |
| cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration. We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated GENE, shares a 90% nucleotide identity with the previously reported rat GluR5-2b cDNA splice variant and differed from human GluR5-1d in the amino and carboxy terminal regions. Cell lines stably expressing GENE protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, L-glutamate and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (AMPA). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-N-methyl-D-aspartate (NMDA) receptor antagonist CNQX (6-cyano-7-nitro-quinoxalinedione). Coexpression of GENE and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. Kainate and AMPA activated the heteromeric channel with significantly higher affinities than observed for GENE alone. Ligand binding studies with the recombinant GENE receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing CHEMICAL binding to GENE receptor was: domoate > kainate > L-glutamate = quisqualate > 6,7-dinitroquinoxaline-2,3-dione (DNQX) = CNQX > AMPA > dihydrokainate > NMDA. | DIRECT-REGULATOR |
| cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration. We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated GENE, shares a 90% nucleotide identity with the previously reported rat GluR5-2b cDNA splice variant and differed from human GluR5-1d in the amino and carboxy terminal regions. Cell lines stably expressing GENE protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, L-glutamate and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (AMPA). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-N-methyl-D-aspartate (NMDA) receptor antagonist CNQX (6-cyano-7-nitro-quinoxalinedione). Coexpression of GENE and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. Kainate and AMPA activated the heteromeric channel with significantly higher affinities than observed for GENE alone. Ligand binding studies with the recombinant GENE receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing [3H]-kainate binding to GENE receptor was: domoate > kainate > L-glutamate = CHEMICAL > 6,7-dinitroquinoxaline-2,3-dione (DNQX) = CNQX > AMPA > dihydrokainate > NMDA. | DIRECT-REGULATOR |
| cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration. We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated GENE, shares a 90% nucleotide identity with the previously reported rat GluR5-2b cDNA splice variant and differed from human GluR5-1d in the amino and carboxy terminal regions. Cell lines stably expressing GENE protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, L-glutamate and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (AMPA). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-N-methyl-D-aspartate (NMDA) receptor antagonist CNQX (6-cyano-7-nitro-quinoxalinedione). Coexpression of GENE and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. Kainate and AMPA activated the heteromeric channel with significantly higher affinities than observed for GENE alone. Ligand binding studies with the recombinant GENE receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing [3H]-kainate binding to GENE receptor was: domoate > kainate > L-glutamate = quisqualate > CHEMICAL (DNQX) = CNQX > AMPA > dihydrokainate > NMDA. | DIRECT-REGULATOR |
| cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration. We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated GENE, shares a 90% nucleotide identity with the previously reported rat GluR5-2b cDNA splice variant and differed from human GluR5-1d in the amino and carboxy terminal regions. Cell lines stably expressing GENE protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, L-glutamate and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (AMPA). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-N-methyl-D-aspartate (NMDA) receptor antagonist CNQX (6-cyano-7-nitro-quinoxalinedione). Coexpression of GENE and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. Kainate and AMPA activated the heteromeric channel with significantly higher affinities than observed for GENE alone. Ligand binding studies with the recombinant GENE receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing [3H]-kainate binding to GENE receptor was: domoate > kainate > L-glutamate = quisqualate > 6,7-dinitroquinoxaline-2,3-dione (CHEMICAL) = CNQX > AMPA > dihydrokainate > NMDA. | DIRECT-REGULATOR |
| cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration. We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated GENE, shares a 90% nucleotide identity with the previously reported rat GluR5-2b cDNA splice variant and differed from human GluR5-1d in the amino and carboxy terminal regions. Cell lines stably expressing GENE protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, L-glutamate and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (AMPA). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-N-methyl-D-aspartate (NMDA) receptor antagonist CHEMICAL (6-cyano-7-nitro-quinoxalinedione). Coexpression of GENE and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. Kainate and AMPA activated the heteromeric channel with significantly higher affinities than observed for GENE alone. Ligand binding studies with the recombinant GENE receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing [3H]-kainate binding to GENE receptor was: domoate > kainate > L-glutamate = quisqualate > 6,7-dinitroquinoxaline-2,3-dione (DNQX) = CHEMICAL > AMPA > dihydrokainate > NMDA. | INHIBITOR |
| cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration. We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated EAA3a, shares a 90% nucleotide identity with the previously reported rat GluR5-2b cDNA splice variant and differed from human GluR5-1d in the amino and carboxy terminal regions. Cell lines stably expressing EAA3a protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, L-glutamate and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (AMPA). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-GENE antagonist CHEMICAL (6-cyano-7-nitro-quinoxalinedione). Coexpression of EAA3a and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. Kainate and AMPA activated the heteromeric channel with significantly higher affinities than observed for EAA3a alone. Ligand binding studies with the recombinant EAA3a receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing [3H]-kainate binding to EAA3a receptor was: domoate > kainate > L-glutamate = quisqualate > 6,7-dinitroquinoxaline-2,3-dione (DNQX) = CHEMICAL > AMPA > dihydrokainate > NMDA. | INHIBITOR |
| cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration. We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated EAA3a, shares a 90% nucleotide identity with the previously reported rat GluR5-2b cDNA splice variant and differed from human GluR5-1d in the amino and carboxy terminal regions. Cell lines stably expressing EAA3a protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, L-glutamate and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (AMPA). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-GENE antagonist CNQX (CHEMICAL). Coexpression of EAA3a and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. Kainate and AMPA activated the heteromeric channel with significantly higher affinities than observed for EAA3a alone. Ligand binding studies with the recombinant EAA3a receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing [3H]-kainate binding to EAA3a receptor was: domoate > kainate > L-glutamate = quisqualate > 6,7-dinitroquinoxaline-2,3-dione (DNQX) = CNQX > AMPA > dihydrokainate > NMDA. | INHIBITOR |
| Leukotrienes in the pathogenesis of pulmonary blast injury. Our previous studies demonstrate a significant increase of sulfidopeptide leukotriene concentrations in animals exposed to a free air blast. The aim of this study was to analyze the role of leukotrienes in the local response of lung tissue as well as in the general response of organisms to blast overpressure. The study was conducted on adult rabbits exposed to moderate blast overpressure (four pulmonary contusions characterized as confluent ecchymoses involving 30 to 60% of the lungs), generated in laboratory conditions. One group of experimental animals was treated with 5-lipoxygenase (5-LO) inhibitor, diethylcarbamazine (DEC, Sigma, St. Louis, Missouri) (50 mg/kg, i.v.), immediately before blast. The early posttraumatic period was observed (30 minutes after blast). Hemodynamic parameters (mean arterial pressure, heart rate, blood gases) as well as arterial plasma levels of conjugated dienes were observed. The myeloperoxidase activity, lipid peroxidation products levels, and water contents were measured in the lung tissue of injured rabbits. We observed that GENE inhibition reduced edema formation, accumulation of neutrophils, and generation of lipid peroxidation products in injured lungs. In this study, we demonstrated that treatment with CHEMICAL inhibits the increased systemic generation of conjugated dienes after blast injury. Although CHEMICAL exerts local antioxidant activity with beneficial effects on lung tissue, this GENE inhibitor intensifies the blast overpressure caused hemodynamic insufficiency. | INHIBITOR |
| Leukotrienes in the pathogenesis of pulmonary blast injury. Our previous studies demonstrate a significant increase of sulfidopeptide leukotriene concentrations in animals exposed to a free air blast. The aim of this study was to analyze the role of leukotrienes in the local response of lung tissue as well as in the general response of organisms to blast overpressure. The study was conducted on adult rabbits exposed to moderate blast overpressure (four pulmonary contusions characterized as confluent ecchymoses involving 30 to 60% of the lungs), generated in laboratory conditions. One group of experimental animals was treated with GENE (5-LO) inhibitor, CHEMICAL (DEC, Sigma, St. Louis, Missouri) (50 mg/kg, i.v.), immediately before blast. The early posttraumatic period was observed (30 minutes after blast). Hemodynamic parameters (mean arterial pressure, heart rate, blood gases) as well as arterial plasma levels of conjugated dienes were observed. The myeloperoxidase activity, lipid peroxidation products levels, and water contents were measured in the lung tissue of injured rabbits. We observed that 5-LO inhibition reduced edema formation, accumulation of neutrophils, and generation of lipid peroxidation products in injured lungs. In this study, we demonstrated that treatment with DEC inhibits the increased systemic generation of conjugated dienes after blast injury. Although DEC exerts local antioxidant activity with beneficial effects on lung tissue, this 5-LO inhibitor intensifies the blast overpressure caused hemodynamic insufficiency. | INHIBITOR |
| Leukotrienes in the pathogenesis of pulmonary blast injury. Our previous studies demonstrate a significant increase of sulfidopeptide leukotriene concentrations in animals exposed to a free air blast. The aim of this study was to analyze the role of leukotrienes in the local response of lung tissue as well as in the general response of organisms to blast overpressure. The study was conducted on adult rabbits exposed to moderate blast overpressure (four pulmonary contusions characterized as confluent ecchymoses involving 30 to 60% of the lungs), generated in laboratory conditions. One group of experimental animals was treated with 5-lipoxygenase (GENE) inhibitor, CHEMICAL (DEC, Sigma, St. Louis, Missouri) (50 mg/kg, i.v.), immediately before blast. The early posttraumatic period was observed (30 minutes after blast). Hemodynamic parameters (mean arterial pressure, heart rate, blood gases) as well as arterial plasma levels of conjugated dienes were observed. The myeloperoxidase activity, lipid peroxidation products levels, and water contents were measured in the lung tissue of injured rabbits. We observed that GENE inhibition reduced edema formation, accumulation of neutrophils, and generation of lipid peroxidation products in injured lungs. In this study, we demonstrated that treatment with DEC inhibits the increased systemic generation of conjugated dienes after blast injury. Although DEC exerts local antioxidant activity with beneficial effects on lung tissue, this GENE inhibitor intensifies the blast overpressure caused hemodynamic insufficiency. | INHIBITOR |
| Leukotrienes in the pathogenesis of pulmonary blast injury. Our previous studies demonstrate a significant increase of sulfidopeptide leukotriene concentrations in animals exposed to a free air blast. The aim of this study was to analyze the role of leukotrienes in the local response of lung tissue as well as in the general response of organisms to blast overpressure. The study was conducted on adult rabbits exposed to moderate blast overpressure (four pulmonary contusions characterized as confluent ecchymoses involving 30 to 60% of the lungs), generated in laboratory conditions. One group of experimental animals was treated with GENE (5-LO) inhibitor, diethylcarbamazine (CHEMICAL, Sigma, St. Louis, Missouri) (50 mg/kg, i.v.), immediately before blast. The early posttraumatic period was observed (30 minutes after blast). Hemodynamic parameters (mean arterial pressure, heart rate, blood gases) as well as arterial plasma levels of conjugated dienes were observed. The myeloperoxidase activity, lipid peroxidation products levels, and water contents were measured in the lung tissue of injured rabbits. We observed that 5-LO inhibition reduced edema formation, accumulation of neutrophils, and generation of lipid peroxidation products in injured lungs. In this study, we demonstrated that treatment with CHEMICAL inhibits the increased systemic generation of conjugated dienes after blast injury. Although CHEMICAL exerts local antioxidant activity with beneficial effects on lung tissue, this 5-LO inhibitor intensifies the blast overpressure caused hemodynamic insufficiency. | INHIBITOR |
| CHEMICAL, the first prostate-selective GENE antagonist. A meta-analysis of two randomized, placebo-controlled, multicentre studies in patients with benign prostatic obstruction (symptomatic BPH). European CHEMICAL Study Group. OBJECTIVE: This meta-analysis of two European studies evaluated the efficacy and safety of modified-release tamsulosin 0.4 mg once daily compared with placebo in patients with benign prostatic enlargement, lower urinary tract symptoms and prostatic obstruction (symptomatic BPH). METHODS: Patients entered a 2-week placebo run-in period, followed by randomization to treatment with tamsulosin (382 patients) or placebo (193 patients) once daily for 12 weeks. RESULTS: Maximum urinary flow rate improved to a greater extent in the tamsulosin group (1.6 ml/s, 16%) than the placebo group (0.6 ml/s, 6%) (p = 0.002). Total Boyarsky symptom score also improved to a greater extent in the tamsulosin group (3.3 points, 35.1% reduction) than the placebo group (2.4 points, 25.5% reduction) (p = 0.002). Significantly more tamsulosin patients (66%) than placebo patients (49%) had a > or = 25% decrease in total symptom score at endpoint (p < 0.001). Twelve weeks of treatment with tamsulosin also produced significant improvements in average urinary flow rate (p = 0.005) and voiding or "obstructive" (p = 0.008) and storage or "irritative' (p = 0.017) symptom scores. The incidence of drug-related adverse events was comparable for the tamsulosin and placebo groups (13 and 12% respectively, p = 0.802). The same applies to the incidence of adverse events commonly attributed to alpha 1-adrenoceptor antagonists, such as dizziness, headache, postural hypotension, syncope, asthenia, somnolence and rhinitis. There were no clinically significant changes in blood pressure or pulse rate in tamsulosin patients compared with placebo patients both in hypertensive and normotensive BPH patients. CONCLUSION: CHEMICAL 0.4 mg once daily is safe, well-tolerated and improves both the symptoms and urinary flow rate in patients with benign prostatic obstruction (symptomatic BPH). | INHIBITOR |
| Human prohormone convertase 3 gene: exon-intron organization and molecular scanning for mutations in Japanese subjects with NIDDM. Proinsulin is converted to insulin by the concerted action of two sequence-specific subtilisin-like proteases termed prohormone convertase 2 (PC2) and prohormone convertase 3 (PC3). PC3 is a type I proinsulin-processing enzyme that initiates the sequential processing of proinsulin to insulin by cleaving the proinsulin molecule on the COOH-terminal side of the dibasic peptide, Arg31-Arg32, joining the B-chain and C-peptide. Thus, PC3 plays a key role in regulating insulin biosynthesis. Expressions of insulin and PC3, but not GENE, are coordinately regulated by CHEMICAL, consistent with the important role of PC3 in regulating proinsulin processing. NIDDM is associated with increased secretion of proinsulin and proinsulin-like molecules, suggesting that mutations in the PC3 gene may be involved in the development of this disorder. To examine this hypothesis, we have isolated and characterized the human PC3 gene and screened it for mutations in a group of Japanese subjects with NIDDM. The PC3 gene consists of 14 exons spanning more than 35 kb. The exon-intron organization of GENE and PC3 genes are conserved, consistent with a common evolutionary origin for the prohormone convertase gene family. Single-strand conformational analysis and nucleotide sequencing of the entire coding region of the PC3 gene in 102 Japanese subjects with NIDDM revealed missense mutations in exons 2 (Arg/Gln53) and 14 (Gln/Glu638), neither of which was associated with NIDDM in this population. These data suggest that genetic variation in the PC3 gene is unlikely to be a major contributor to NIDDM susceptibility in Japanese. | NO-RELATIONSHIP |
| Human prohormone convertase 3 gene: exon-intron organization and molecular scanning for mutations in Japanese subjects with NIDDM. Proinsulin is converted to insulin by the concerted action of two sequence-specific subtilisin-like proteases termed prohormone convertase 2 (PC2) and prohormone convertase 3 (PC3). GENE is a type I proinsulin-processing enzyme that initiates the sequential processing of proinsulin to insulin by cleaving the proinsulin molecule on the COOH-terminal side of the dibasic peptide, Arg31-Arg32, joining the B-chain and C-peptide. Thus, GENE plays a key role in regulating insulin biosynthesis. Expressions of insulin and GENE, but not PC2, are coordinately regulated by glucose, consistent with the important role of GENE in regulating proinsulin processing. NIDDM is associated with increased secretion of proinsulin and proinsulin-like molecules, suggesting that mutations in the GENE gene may be involved in the development of this disorder. To examine this hypothesis, we have isolated and characterized the human GENE gene and screened it for mutations in a group of Japanese subjects with NIDDM. The GENE gene consists of 14 exons spanning more than 35 kb. The exon-intron organization of PC2 and GENE genes are conserved, consistent with a common evolutionary origin for the prohormone convertase gene family. Single-strand conformational analysis and CHEMICAL sequencing of the entire coding region of the GENE gene in 102 Japanese subjects with NIDDM revealed missense mutations in exons 2 (Arg/Gln53) and 14 (Gln/Glu638), neither of which was associated with NIDDM in this population. These data suggest that genetic variation in the GENE gene is unlikely to be a major contributor to NIDDM susceptibility in Japanese. | PART-OF |
| Human prohormone convertase 3 gene: exon-intron organization and molecular scanning for mutations in Japanese subjects with NIDDM. Proinsulin is converted to insulin by the concerted action of two sequence-specific subtilisin-like proteases termed prohormone convertase 2 (PC2) and prohormone convertase 3 (PC3). PC3 is a type I proinsulin-processing enzyme that initiates the sequential processing of proinsulin to insulin by cleaving the proinsulin molecule on the COOH-terminal side of the dibasic peptide, Arg31-Arg32, joining the B-chain and C-peptide. Thus, PC3 plays a key role in regulating insulin biosynthesis. Expressions of insulin and PC3, but not PC2, are coordinately regulated by glucose, consistent with the important role of PC3 in regulating proinsulin processing. NIDDM is associated with increased secretion of proinsulin and proinsulin-like molecules, suggesting that mutations in the PC3 gene may be involved in the development of this disorder. To examine this hypothesis, we have isolated and characterized the human PC3 gene and screened it for mutations in a group of Japanese subjects with NIDDM. The PC3 gene consists of 14 exons spanning more than 35 kb. The exon-intron organization of PC2 and PC3 genes are conserved, consistent with a common evolutionary origin for the prohormone convertase gene family. Single-strand conformational analysis and CHEMICAL sequencing of the entire coding region of the PC3 gene in 102 Japanese subjects with NIDDM revealed missense mutations in exons 2 (GENE) and 14 (Gln/Glu638), neither of which was associated with NIDDM in this population. These data suggest that genetic variation in the PC3 gene is unlikely to be a major contributor to NIDDM susceptibility in Japanese. | PART-OF |
| Human prohormone convertase 3 gene: exon-intron organization and molecular scanning for mutations in Japanese subjects with NIDDM. Proinsulin is converted to insulin by the concerted action of two sequence-specific subtilisin-like proteases termed prohormone convertase 2 (PC2) and prohormone convertase 3 (PC3). PC3 is a type I proinsulin-processing enzyme that initiates the sequential processing of proinsulin to insulin by cleaving the proinsulin molecule on the COOH-terminal side of the dibasic peptide, Arg31-Arg32, joining the B-chain and C-peptide. Thus, PC3 plays a key role in regulating insulin biosynthesis. Expressions of insulin and PC3, but not PC2, are coordinately regulated by glucose, consistent with the important role of PC3 in regulating proinsulin processing. NIDDM is associated with increased secretion of proinsulin and proinsulin-like molecules, suggesting that mutations in the PC3 gene may be involved in the development of this disorder. To examine this hypothesis, we have isolated and characterized the human PC3 gene and screened it for mutations in a group of Japanese subjects with NIDDM. The PC3 gene consists of 14 exons spanning more than 35 kb. The exon-intron organization of PC2 and PC3 genes are conserved, consistent with a common evolutionary origin for the prohormone convertase gene family. Single-strand conformational analysis and CHEMICAL sequencing of the entire coding region of the PC3 gene in 102 Japanese subjects with NIDDM revealed missense mutations in exons 2 (Arg/Gln53) and 14 (GENE), neither of which was associated with NIDDM in this population. These data suggest that genetic variation in the PC3 gene is unlikely to be a major contributor to NIDDM susceptibility in Japanese. | PART-OF |
| Human prohormone convertase 3 gene: exon-intron organization and molecular scanning for mutations in Japanese subjects with NIDDM. GENE is converted to insulin by the concerted action of two sequence-specific subtilisin-like proteases termed prohormone convertase 2 (PC2) and prohormone convertase 3 (PC3). PC3 is a type I proinsulin-processing enzyme that initiates the sequential processing of GENE to insulin by cleaving the GENE molecule on the CHEMICAL-terminal side of the dibasic peptide, Arg31-Arg32, joining the B-chain and C-peptide. Thus, PC3 plays a key role in regulating insulin biosynthesis. Expressions of insulin and PC3, but not PC2, are coordinately regulated by glucose, consistent with the important role of PC3 in regulating GENE processing. NIDDM is associated with increased secretion of GENE and proinsulin-like molecules, suggesting that mutations in the PC3 gene may be involved in the development of this disorder. To examine this hypothesis, we have isolated and characterized the human PC3 gene and screened it for mutations in a group of Japanese subjects with NIDDM. The PC3 gene consists of 14 exons spanning more than 35 kb. The exon-intron organization of PC2 and PC3 genes are conserved, consistent with a common evolutionary origin for the prohormone convertase gene family. Single-strand conformational analysis and nucleotide sequencing of the entire coding region of the PC3 gene in 102 Japanese subjects with NIDDM revealed missense mutations in exons 2 (Arg/Gln53) and 14 (Gln/Glu638), neither of which was associated with NIDDM in this population. These data suggest that genetic variation in the PC3 gene is unlikely to be a major contributor to NIDDM susceptibility in Japanese. | PART-OF |
| Human prohormone convertase 3 gene: exon-intron organization and molecular scanning for mutations in Japanese subjects with NIDDM. GENE is converted to insulin by the concerted action of two sequence-specific subtilisin-like proteases termed prohormone convertase 2 (PC2) and prohormone convertase 3 (PC3). PC3 is a type I proinsulin-processing enzyme that initiates the sequential processing of GENE to insulin by cleaving the GENE molecule on the COOH-terminal side of the dibasic peptide, Arg31-Arg32, joining the B-chain and CHEMICAL-peptide. Thus, PC3 plays a key role in regulating insulin biosynthesis. Expressions of insulin and PC3, but not PC2, are coordinately regulated by glucose, consistent with the important role of PC3 in regulating GENE processing. NIDDM is associated with increased secretion of GENE and proinsulin-like molecules, suggesting that mutations in the PC3 gene may be involved in the development of this disorder. To examine this hypothesis, we have isolated and characterized the human PC3 gene and screened it for mutations in a group of Japanese subjects with NIDDM. The PC3 gene consists of 14 exons spanning more than 35 kb. The exon-intron organization of PC2 and PC3 genes are conserved, consistent with a common evolutionary origin for the prohormone convertase gene family. Single-strand conformational analysis and nucleotide sequencing of the entire coding region of the PC3 gene in 102 Japanese subjects with NIDDM revealed missense mutations in exons 2 (Arg/Gln53) and 14 (Gln/Glu638), neither of which was associated with NIDDM in this population. These data suggest that genetic variation in the PC3 gene is unlikely to be a major contributor to NIDDM susceptibility in Japanese. | PART-OF |
| Human prohormone convertase 3 gene: exon-intron organization and molecular scanning for mutations in Japanese subjects with NIDDM. Proinsulin is converted to GENE by the concerted action of two sequence-specific subtilisin-like proteases termed prohormone convertase 2 (PC2) and prohormone convertase 3 (PC3). PC3 is a type I proinsulin-processing enzyme that initiates the sequential processing of proinsulin to GENE by cleaving the proinsulin molecule on the COOH-terminal side of the dibasic peptide, Arg31-Arg32, joining the B-chain and C-peptide. Thus, PC3 plays a key role in regulating GENE biosynthesis. Expressions of GENE and PC3, but not PC2, are coordinately regulated by CHEMICAL, consistent with the important role of PC3 in regulating proinsulin processing. NIDDM is associated with increased secretion of proinsulin and proinsulin-like molecules, suggesting that mutations in the PC3 gene may be involved in the development of this disorder. To examine this hypothesis, we have isolated and characterized the human PC3 gene and screened it for mutations in a group of Japanese subjects with NIDDM. The PC3 gene consists of 14 exons spanning more than 35 kb. The exon-intron organization of PC2 and PC3 genes are conserved, consistent with a common evolutionary origin for the prohormone convertase gene family. Single-strand conformational analysis and nucleotide sequencing of the entire coding region of the PC3 gene in 102 Japanese subjects with NIDDM revealed missense mutations in exons 2 (Arg/Gln53) and 14 (Gln/Glu638), neither of which was associated with NIDDM in this population. These data suggest that genetic variation in the PC3 gene is unlikely to be a major contributor to NIDDM susceptibility in Japanese. | GENE-CHEMICAL |
| Human prohormone convertase 3 gene: exon-intron organization and molecular scanning for mutations in Japanese subjects with NIDDM. Proinsulin is converted to insulin by the concerted action of two sequence-specific subtilisin-like proteases termed prohormone convertase 2 (PC2) and prohormone convertase 3 (PC3). GENE is a type I proinsulin-processing enzyme that initiates the sequential processing of proinsulin to insulin by cleaving the proinsulin molecule on the COOH-terminal side of the dibasic peptide, Arg31-Arg32, joining the B-chain and C-peptide. Thus, GENE plays a key role in regulating insulin biosynthesis. Expressions of insulin and GENE, but not PC2, are coordinately regulated by CHEMICAL, consistent with the important role of GENE in regulating proinsulin processing. NIDDM is associated with increased secretion of proinsulin and proinsulin-like molecules, suggesting that mutations in the GENE gene may be involved in the development of this disorder. To examine this hypothesis, we have isolated and characterized the human GENE gene and screened it for mutations in a group of Japanese subjects with NIDDM. The GENE gene consists of 14 exons spanning more than 35 kb. The exon-intron organization of PC2 and GENE genes are conserved, consistent with a common evolutionary origin for the prohormone convertase gene family. Single-strand conformational analysis and nucleotide sequencing of the entire coding region of the GENE gene in 102 Japanese subjects with NIDDM revealed missense mutations in exons 2 (Arg/Gln53) and 14 (Gln/Glu638), neither of which was associated with NIDDM in this population. These data suggest that genetic variation in the GENE gene is unlikely to be a major contributor to NIDDM susceptibility in Japanese. | REGULATOR |
| Desipramine administration in the olfactory bulbectomized rat: changes in brain beta-adrenoceptor and 5-HT2A binding sites and their relationship to behaviour. 1. The effects of repeated administration of the tricyclic antidepressant drug, desipramine (DMI), on behaviour (locomotor activity and rearing) and the number and affinity of brain beta-adrenoceptor and 5-HT2A receptor binding sites were examined in olfactory bulbectomized (OB) and sham-operated control rats. 2. Locomotor activity and rearing were increased in OB rats compared to sham-operated controls. The effect of various doses of CHEMICAL (administered orally twice daily for 21 days) on these behavioural measures was examined. A dose of 7.5 mg kg-1 provided optimal reversal of hyperlocomotion and increased rearing in OB rats, without changing these measures in sham-operated controls. 3. The time course of CHEMICAL (7.5 mg kg-1) on behavioural and neurochemical measures was examined. locomotion and rearing in OB rats were not significantly altered after 7 days, were significantly attenuated after 14 days and were normalized after 21 days. 4. After 7 days of CHEMICAL administration the number of GENE was lower in frontal and occipital cortex and hippocampus. This reduction was largely restricted to the beta 1-adrenoceptor subtype. Administration of CHEMICAL for 14 or 21 days did not further reduce the number of GENE. The CHEMICAL induced reduction in GENE did not differ in OB and sham-operated control rats. 5. CHEMICAL administration for up to 21 days produced a progressive reduction in the number of 5-HT2A receptors in frontal cortex, without significant alterations in occipital cortex. 6. The time course of the reduction in the number of 5-HT2A receptors was similar to that of the DMI-induced behavioural changes whereas that for the reduction in GENE was clearly different. 7. The present results suggest that the action of CHEMICAL in this animal model is unlikely to be directly related to a reduction in GENE but may be related to a reduction in frontal cortical 5-HT2A receptors. | NO-RELATIONSHIP |
| CHEMICAL administration in the olfactory bulbectomized rat: changes in brain beta-adrenoceptor and GENE binding sites and their relationship to behaviour. 1. The effects of repeated administration of the tricyclic antidepressant drug, desipramine (DMI), on behaviour (locomotor activity and rearing) and the number and affinity of brain beta-adrenoceptor and GENE receptor binding sites were examined in olfactory bulbectomized (OB) and sham-operated control rats. 2. Locomotor activity and rearing were increased in OB rats compared to sham-operated controls. The effect of various doses of DMI (administered orally twice daily for 21 days) on these behavioural measures was examined. A dose of 7.5 mg kg-1 provided optimal reversal of hyperlocomotion and increased rearing in OB rats, without changing these measures in sham-operated controls. 3. The time course of DMI (7.5 mg kg-1) on behavioural and neurochemical measures was examined. locomotion and rearing in OB rats were not significantly altered after 7 days, were significantly attenuated after 14 days and were normalized after 21 days. 4. After 7 days of DMI administration the number of beta-adrenoceptors was lower in frontal and occipital cortex and hippocampus. This reduction was largely restricted to the beta 1-adrenoceptor subtype. Administration of DMI for 14 or 21 days did not further reduce the number of beta-adrenoceptors. The DMI induced reduction in beta-adrenoceptors did not differ in OB and sham-operated control rats. 5. DMI administration for up to 21 days produced a progressive reduction in the number of GENE receptors in frontal cortex, without significant alterations in occipital cortex. 6. The time course of the reduction in the number of GENE receptors was similar to that of the DMI-induced behavioural changes whereas that for the reduction in beta-adrenoceptors was clearly different. 7. The present results suggest that the action of DMI in this animal model is unlikely to be directly related to a reduction in beta-adrenoceptors but may be related to a reduction in frontal cortical GENE receptors. | DIRECT-REGULATOR |
| CHEMICAL administration in the olfactory bulbectomized rat: changes in brain GENE and 5-HT2A binding sites and their relationship to behaviour. 1. The effects of repeated administration of the tricyclic antidepressant drug, desipramine (DMI), on behaviour (locomotor activity and rearing) and the number and affinity of brain GENE and 5-HT2A receptor binding sites were examined in olfactory bulbectomized (OB) and sham-operated control rats. 2. Locomotor activity and rearing were increased in OB rats compared to sham-operated controls. The effect of various doses of DMI (administered orally twice daily for 21 days) on these behavioural measures was examined. A dose of 7.5 mg kg-1 provided optimal reversal of hyperlocomotion and increased rearing in OB rats, without changing these measures in sham-operated controls. 3. The time course of DMI (7.5 mg kg-1) on behavioural and neurochemical measures was examined. locomotion and rearing in OB rats were not significantly altered after 7 days, were significantly attenuated after 14 days and were normalized after 21 days. 4. After 7 days of DMI administration the number of beta-adrenoceptors was lower in frontal and occipital cortex and hippocampus. This reduction was largely restricted to the beta 1-adrenoceptor subtype. Administration of DMI for 14 or 21 days did not further reduce the number of beta-adrenoceptors. The DMI induced reduction in beta-adrenoceptors did not differ in OB and sham-operated control rats. 5. DMI administration for up to 21 days produced a progressive reduction in the number of 5-HT2A receptors in frontal cortex, without significant alterations in occipital cortex. 6. The time course of the reduction in the number of 5-HT2A receptors was similar to that of the DMI-induced behavioural changes whereas that for the reduction in beta-adrenoceptors was clearly different. 7. The present results suggest that the action of DMI in this animal model is unlikely to be directly related to a reduction in beta-adrenoceptors but may be related to a reduction in frontal cortical 5-HT2A receptors. | DIRECT-REGULATOR |
| Desipramine administration in the olfactory bulbectomized rat: changes in brain beta-adrenoceptor and GENE binding sites and their relationship to behaviour. 1. The effects of repeated administration of the tricyclic antidepressant drug, desipramine (DMI), on behaviour (locomotor activity and rearing) and the number and affinity of brain beta-adrenoceptor and GENE receptor binding sites were examined in olfactory bulbectomized (OB) and sham-operated control rats. 2. Locomotor activity and rearing were increased in OB rats compared to sham-operated controls. The effect of various doses of CHEMICAL (administered orally twice daily for 21 days) on these behavioural measures was examined. A dose of 7.5 mg kg-1 provided optimal reversal of hyperlocomotion and increased rearing in OB rats, without changing these measures in sham-operated controls. 3. The time course of CHEMICAL (7.5 mg kg-1) on behavioural and neurochemical measures was examined. locomotion and rearing in OB rats were not significantly altered after 7 days, were significantly attenuated after 14 days and were normalized after 21 days. 4. After 7 days of CHEMICAL administration the number of beta-adrenoceptors was lower in frontal and occipital cortex and hippocampus. This reduction was largely restricted to the beta 1-adrenoceptor subtype. Administration of CHEMICAL for 14 or 21 days did not further reduce the number of beta-adrenoceptors. The CHEMICAL induced reduction in beta-adrenoceptors did not differ in OB and sham-operated control rats. 5. CHEMICAL administration for up to 21 days produced a progressive reduction in the number of GENE receptors in frontal cortex, without significant alterations in occipital cortex. 6. The time course of the reduction in the number of GENE receptors was similar to that of the DMI-induced behavioural changes whereas that for the reduction in beta-adrenoceptors was clearly different. 7. The present results suggest that the action of CHEMICAL in this animal model is unlikely to be directly related to a reduction in beta-adrenoceptors but may be related to a reduction in frontal cortical GENE receptors. | INDIRECT-DOWNREGULATOR |
| Binding of CHEMICAL to alpha1-acid glycoprotein may be involved in its inhibition of tumor necrosis factor alpha production. In addition to its well known sedative and teratogenic effects, CHEMICAL also possesses potent immunomodulatory and antiinflammatory activities, being most effective against leprosy and chronic graft-versus-host disease. The immunomodulatory activity of CHEMICAL has been ascribed to the selective inhibition of tumor necrosis factor alpha from monocytes. The molecular mechanism for the immunomodulatory effect of CHEMICAL remains unknown. To elucidate this mechanism, we synthesized an active photoaffinity label of CHEMICAL as a probe to identify the molecular target of the drug. Using the probe, we specifically labeled a pair of proteins of 43-45 kDa with high acidity from bovine thymus extract. Purification of these proteins and partial peptide sequence determination revealed them to be alpha1-acid glycoprotein (AGP). We show that the binding of CHEMICAL photoaffinity label to authentic GENE is competed with both CHEMICAL and the nonradioactive photoaffinity label at concentrations comparable to those required for inhibition of production of tumor necrosis factor alpha from human monocytes, suggesting that AGP may be involved in the immunomodulatory activity of CHEMICAL. | DIRECT-REGULATOR |
| Binding of CHEMICAL to GENE may be involved in its inhibition of tumor necrosis factor alpha production. In addition to its well known sedative and teratogenic effects, CHEMICAL also possesses potent immunomodulatory and antiinflammatory activities, being most effective against leprosy and chronic graft-versus-host disease. The immunomodulatory activity of CHEMICAL has been ascribed to the selective inhibition of tumor necrosis factor alpha from monocytes. The molecular mechanism for the immunomodulatory effect of CHEMICAL remains unknown. To elucidate this mechanism, we synthesized an active photoaffinity label of CHEMICAL as a probe to identify the molecular target of the drug. Using the probe, we specifically labeled a pair of proteins of 43-45 kDa with high acidity from bovine thymus extract. Purification of these proteins and partial peptide sequence determination revealed them to be GENE (AGP). We show that the binding of CHEMICAL photoaffinity label to authentic human AGP is competed with both CHEMICAL and the nonradioactive photoaffinity label at concentrations comparable to those required for inhibition of production of tumor necrosis factor alpha from human monocytes, suggesting that AGP may be involved in the immunomodulatory activity of CHEMICAL. | DIRECT-REGULATOR |
| Binding of CHEMICAL to alpha1-acid glycoprotein may be involved in its inhibition of tumor necrosis factor alpha production. In addition to its well known sedative and teratogenic effects, CHEMICAL also possesses potent immunomodulatory and antiinflammatory activities, being most effective against leprosy and chronic graft-versus-host disease. The immunomodulatory activity of CHEMICAL has been ascribed to the selective inhibition of tumor necrosis factor alpha from monocytes. The molecular mechanism for the immunomodulatory effect of CHEMICAL remains unknown. To elucidate this mechanism, we synthesized an active photoaffinity label of CHEMICAL as a probe to identify the molecular target of the drug. Using the probe, we specifically labeled a pair of proteins of 43-45 kDa with high acidity from bovine thymus extract. Purification of these proteins and partial peptide sequence determination revealed them to be alpha1-acid glycoprotein (AGP). We show that the binding of CHEMICAL photoaffinity label to authentic human GENE is competed with both CHEMICAL and the nonradioactive photoaffinity label at concentrations comparable to those required for inhibition of production of tumor necrosis factor alpha from human monocytes, suggesting that GENE may be involved in the immunomodulatory activity of CHEMICAL. | DIRECT-REGULATOR |
| Binding of CHEMICAL to alpha1-acid glycoprotein may be involved in its inhibition of GENE production. In addition to its well known sedative and teratogenic effects, CHEMICAL also possesses potent immunomodulatory and antiinflammatory activities, being most effective against leprosy and chronic graft-versus-host disease. The immunomodulatory activity of CHEMICAL has been ascribed to the selective inhibition of GENE from monocytes. The molecular mechanism for the immunomodulatory effect of CHEMICAL remains unknown. To elucidate this mechanism, we synthesized an active photoaffinity label of CHEMICAL as a probe to identify the molecular target of the drug. Using the probe, we specifically labeled a pair of proteins of 43-45 kDa with high acidity from bovine thymus extract. Purification of these proteins and partial peptide sequence determination revealed them to be alpha1-acid glycoprotein (AGP). We show that the binding of CHEMICAL photoaffinity label to authentic human AGP is competed with both CHEMICAL and the nonradioactive photoaffinity label at concentrations comparable to those required for inhibition of production of GENE from human monocytes, suggesting that AGP may be involved in the immunomodulatory activity of CHEMICAL. | DIRECT-REGULATOR |
| AMPA receptor heterogeneity in rat hippocampal neurons revealed by differential sensitivity to CHEMICAL. 1. The kinetics of onset of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization by glutamate, and the extent of attenuation of AMPA receptor desensitization by CHEMICAL, showed pronounced cell-to-cell variation in cultures of rat hippocampal neurons. Cultures prepared from area CA1 stratum radiatum tended to show weaker modulation by CHEMICAL than cultures prepared from the whole hippocampus. 2. Kinetic analysis of concentration jump responses to glutamate revealed multiple populations of receptors with fast (approximately 400 ms), intermediate (approximately 2-4 s), and slow (> 20 s) time constants for recovery from modulation by CHEMICAL. The amplitudes of these components varied widely between cells, suggesting the existence of at least three populations of AMPA receptor subtypes, the relative density of which varied from cell to cell. 3. The complex patterns of sensitivity to CHEMICAL seen in hippocampal neurons could be reconstituted by assembly of recombinant AMPA receptor subunits generated from cDNAs encoding the flip (i) and flop (o) splice variants of the GENE and GluR-B subunits. Recovery from modulation by CHEMICAL was slower for GluR-AiBi and GluR-AoBi than for GluR-AiBo and GluR-AoBo. 4. Coexpression of the flip and flop splice variants of GENE, in the absence of GluR-B, revealed that heteromeric AMPA receptors with intermediate sensitivity to CHEMICAL, similar to responses observed for the combinations GluR-AoBi or GluR-AiBo, could be generated independently of the presence of the GluR-B subunit. However, recovery from modulation by CHEMICAL was twofold slower for GluR-AiBi than for homomeric GluR-Ai, indicating that the GENE and GluR-B subunits are not functionally equivalent in controlling sensitivity to CHEMICAL. 5. These results demonstrate that AMPA receptors expressed in hippocampal neurons are assembled in a variety of subunit and splice variant combinations that might serve as a mechanism to fine-tune the kinetics of synaptic transmission. | NO-RELATIONSHIP |
| AMPA receptor heterogeneity in rat hippocampal neurons revealed by differential sensitivity to CHEMICAL. 1. The kinetics of onset of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization by glutamate, and the extent of attenuation of AMPA receptor desensitization by CHEMICAL, showed pronounced cell-to-cell variation in cultures of rat hippocampal neurons. Cultures prepared from area CA1 stratum radiatum tended to show weaker modulation by CHEMICAL than cultures prepared from the whole hippocampus. 2. Kinetic analysis of concentration jump responses to glutamate revealed multiple populations of receptors with fast (approximately 400 ms), intermediate (approximately 2-4 s), and slow (> 20 s) time constants for recovery from modulation by CHEMICAL. The amplitudes of these components varied widely between cells, suggesting the existence of at least three populations of AMPA receptor subtypes, the relative density of which varied from cell to cell. 3. The complex patterns of sensitivity to CHEMICAL seen in hippocampal neurons could be reconstituted by assembly of recombinant AMPA receptor subunits generated from cDNAs encoding the flip (i) and flop (o) splice variants of the GluR-A and GluR-B subunits. Recovery from modulation by CHEMICAL was slower for GluR-AiBi and GENE than for GluR-AiBo and GluR-AoBo. 4. Coexpression of the flip and flop splice variants of GluR-A, in the absence of GluR-B, revealed that heteromeric AMPA receptors with intermediate sensitivity to CHEMICAL, similar to responses observed for the combinations GENE or GluR-AiBo, could be generated independently of the presence of the GluR-B subunit. However, recovery from modulation by CHEMICAL was twofold slower for GluR-AiBi than for homomeric GluR-Ai, indicating that the GluR-A and GluR-B subunits are not functionally equivalent in controlling sensitivity to CHEMICAL. 5. These results demonstrate that AMPA receptors expressed in hippocampal neurons are assembled in a variety of subunit and splice variant combinations that might serve as a mechanism to fine-tune the kinetics of synaptic transmission. | REGULATOR |
| AMPA receptor heterogeneity in rat hippocampal neurons revealed by differential sensitivity to CHEMICAL. 1. The kinetics of onset of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization by glutamate, and the extent of attenuation of AMPA receptor desensitization by CHEMICAL, showed pronounced cell-to-cell variation in cultures of rat hippocampal neurons. Cultures prepared from area CA1 stratum radiatum tended to show weaker modulation by CHEMICAL than cultures prepared from the whole hippocampus. 2. Kinetic analysis of concentration jump responses to glutamate revealed multiple populations of receptors with fast (approximately 400 ms), intermediate (approximately 2-4 s), and slow (> 20 s) time constants for recovery from modulation by CHEMICAL. The amplitudes of these components varied widely between cells, suggesting the existence of at least three populations of AMPA receptor subtypes, the relative density of which varied from cell to cell. 3. The complex patterns of sensitivity to CHEMICAL seen in hippocampal neurons could be reconstituted by assembly of recombinant AMPA receptor subunits generated from cDNAs encoding the flip (i) and flop (o) splice variants of the GluR-A and GluR-B subunits. Recovery from modulation by CHEMICAL was slower for GluR-AiBi and GluR-AoBi than for GENE and GluR-AoBo. 4. Coexpression of the flip and flop splice variants of GluR-A, in the absence of GluR-B, revealed that heteromeric AMPA receptors with intermediate sensitivity to CHEMICAL, similar to responses observed for the combinations GluR-AoBi or GENE, could be generated independently of the presence of the GluR-B subunit. However, recovery from modulation by CHEMICAL was twofold slower for GluR-AiBi than for homomeric GluR-Ai, indicating that the GluR-A and GluR-B subunits are not functionally equivalent in controlling sensitivity to CHEMICAL. 5. These results demonstrate that AMPA receptors expressed in hippocampal neurons are assembled in a variety of subunit and splice variant combinations that might serve as a mechanism to fine-tune the kinetics of synaptic transmission. | REGULATOR |
| AMPA receptor heterogeneity in rat hippocampal neurons revealed by differential sensitivity to CHEMICAL. 1. The kinetics of onset of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization by glutamate, and the extent of attenuation of AMPA receptor desensitization by CHEMICAL, showed pronounced cell-to-cell variation in cultures of rat hippocampal neurons. Cultures prepared from area CA1 stratum radiatum tended to show weaker modulation by CHEMICAL than cultures prepared from the whole hippocampus. 2. Kinetic analysis of concentration jump responses to glutamate revealed multiple populations of receptors with fast (approximately 400 ms), intermediate (approximately 2-4 s), and slow (> 20 s) time constants for recovery from modulation by CHEMICAL. The amplitudes of these components varied widely between cells, suggesting the existence of at least three populations of AMPA receptor subtypes, the relative density of which varied from cell to cell. 3. The complex patterns of sensitivity to CHEMICAL seen in hippocampal neurons could be reconstituted by assembly of recombinant AMPA receptor subunits generated from cDNAs encoding the flip (i) and flop (o) splice variants of the GluR-A and GENE subunits. Recovery from modulation by CHEMICAL was slower for GluR-AiBi and GluR-AoBi than for GluR-AiBo and GluR-AoBo. 4. Coexpression of the flip and flop splice variants of GluR-A, in the absence of GENE, revealed that heteromeric AMPA receptors with intermediate sensitivity to CHEMICAL, similar to responses observed for the combinations GluR-AoBi or GluR-AiBo, could be generated independently of the presence of the GENE subunit. However, recovery from modulation by CHEMICAL was twofold slower for GluR-AiBi than for homomeric GluR-Ai, indicating that the GluR-A and GENE subunits are not functionally equivalent in controlling sensitivity to CHEMICAL. 5. These results demonstrate that AMPA receptors expressed in hippocampal neurons are assembled in a variety of subunit and splice variant combinations that might serve as a mechanism to fine-tune the kinetics of synaptic transmission. | NO-RELATIONSHIP |
| AMPA receptor heterogeneity in rat hippocampal neurons revealed by differential sensitivity to CHEMICAL. 1. The kinetics of onset of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization by glutamate, and the extent of attenuation of AMPA receptor desensitization by CHEMICAL, showed pronounced cell-to-cell variation in cultures of rat hippocampal neurons. Cultures prepared from area CA1 stratum radiatum tended to show weaker modulation by CHEMICAL than cultures prepared from the whole hippocampus. 2. Kinetic analysis of concentration jump responses to glutamate revealed multiple populations of receptors with fast (approximately 400 ms), intermediate (approximately 2-4 s), and slow (> 20 s) time constants for recovery from modulation by CHEMICAL. The amplitudes of these components varied widely between cells, suggesting the existence of at least three populations of AMPA receptor subtypes, the relative density of which varied from cell to cell. 3. The complex patterns of sensitivity to CHEMICAL seen in hippocampal neurons could be reconstituted by assembly of recombinant AMPA receptor subunits generated from cDNAs encoding the flip (i) and flop (o) splice variants of the GluR-A and GluR-B subunits. Recovery from modulation by CHEMICAL was slower for GENE and GluR-AoBi than for GluR-AiBo and GluR-AoBo. 4. Coexpression of the flip and flop splice variants of GluR-A, in the absence of GluR-B, revealed that heteromeric AMPA receptors with intermediate sensitivity to CHEMICAL, similar to responses observed for the combinations GluR-AoBi or GluR-AiBo, could be generated independently of the presence of the GluR-B subunit. However, recovery from modulation by CHEMICAL was twofold slower for GENE than for homomeric GluR-Ai, indicating that the GluR-A and GluR-B subunits are not functionally equivalent in controlling sensitivity to CHEMICAL. 5. These results demonstrate that AMPA receptors expressed in hippocampal neurons are assembled in a variety of subunit and splice variant combinations that might serve as a mechanism to fine-tune the kinetics of synaptic transmission. | REGULATOR |
| AMPA receptor heterogeneity in rat hippocampal neurons revealed by differential sensitivity to CHEMICAL. 1. The kinetics of onset of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization by glutamate, and the extent of attenuation of AMPA receptor desensitization by CHEMICAL, showed pronounced cell-to-cell variation in cultures of rat hippocampal neurons. Cultures prepared from area CA1 stratum radiatum tended to show weaker modulation by CHEMICAL than cultures prepared from the whole hippocampus. 2. Kinetic analysis of concentration jump responses to glutamate revealed multiple populations of receptors with fast (approximately 400 ms), intermediate (approximately 2-4 s), and slow (> 20 s) time constants for recovery from modulation by CHEMICAL. The amplitudes of these components varied widely between cells, suggesting the existence of at least three populations of AMPA receptor subtypes, the relative density of which varied from cell to cell. 3. The complex patterns of sensitivity to CHEMICAL seen in hippocampal neurons could be reconstituted by assembly of recombinant AMPA receptor subunits generated from cDNAs encoding the flip (i) and flop (o) splice variants of the GluR-A and GluR-B subunits. Recovery from modulation by CHEMICAL was slower for GluR-AiBi and GluR-AoBi than for GluR-AiBo and GluR-AoBo. 4. Coexpression of the flip and flop splice variants of GluR-A, in the absence of GluR-B, revealed that heteromeric AMPA receptors with intermediate sensitivity to CHEMICAL, similar to responses observed for the combinations GluR-AoBi or GluR-AiBo, could be generated independently of the presence of the GluR-B subunit. However, recovery from modulation by CHEMICAL was twofold slower for GluR-AiBi than for homomeric GENE, indicating that the GluR-A and GluR-B subunits are not functionally equivalent in controlling sensitivity to CHEMICAL. 5. These results demonstrate that AMPA receptors expressed in hippocampal neurons are assembled in a variety of subunit and splice variant combinations that might serve as a mechanism to fine-tune the kinetics of synaptic transmission. | REGULATOR |
| GENE heterogeneity in rat hippocampal neurons revealed by differential sensitivity to CHEMICAL. 1. The kinetics of onset of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization by glutamate, and the extent of attenuation of GENE desensitization by CHEMICAL, showed pronounced cell-to-cell variation in cultures of rat hippocampal neurons. Cultures prepared from area CA1 stratum radiatum tended to show weaker modulation by CHEMICAL than cultures prepared from the whole hippocampus. 2. Kinetic analysis of concentration jump responses to glutamate revealed multiple populations of receptors with fast (approximately 400 ms), intermediate (approximately 2-4 s), and slow (> 20 s) time constants for recovery from modulation by CHEMICAL. The amplitudes of these components varied widely between cells, suggesting the existence of at least three populations of GENE subtypes, the relative density of which varied from cell to cell. 3. The complex patterns of sensitivity to CHEMICAL seen in hippocampal neurons could be reconstituted by assembly of recombinant GENE subunits generated from cDNAs encoding the flip (i) and flop (o) splice variants of the GluR-A and GluR-B subunits. Recovery from modulation by CHEMICAL was slower for GluR-AiBi and GluR-AoBi than for GluR-AiBo and GluR-AoBo. 4. Coexpression of the flip and flop splice variants of GluR-A, in the absence of GluR-B, revealed that heteromeric AMPA receptors with intermediate sensitivity to CHEMICAL, similar to responses observed for the combinations GluR-AoBi or GluR-AiBo, could be generated independently of the presence of the GluR-B subunit. However, recovery from modulation by CHEMICAL was twofold slower for GluR-AiBi than for homomeric GluR-Ai, indicating that the GluR-A and GluR-B subunits are not functionally equivalent in controlling sensitivity to CHEMICAL. 5. These results demonstrate that AMPA receptors expressed in hippocampal neurons are assembled in a variety of subunit and splice variant combinations that might serve as a mechanism to fine-tune the kinetics of synaptic transmission. | REGULATOR |
| AMPA receptor heterogeneity in rat hippocampal neurons revealed by differential sensitivity to CHEMICAL. 1. The kinetics of onset of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization by glutamate, and the extent of attenuation of AMPA receptor desensitization by CHEMICAL, showed pronounced cell-to-cell variation in cultures of rat hippocampal neurons. Cultures prepared from area CA1 stratum radiatum tended to show weaker modulation by CHEMICAL than cultures prepared from the whole hippocampus. 2. Kinetic analysis of concentration jump responses to glutamate revealed multiple populations of receptors with fast (approximately 400 ms), intermediate (approximately 2-4 s), and slow (> 20 s) time constants for recovery from modulation by CHEMICAL. The amplitudes of these components varied widely between cells, suggesting the existence of at least three populations of AMPA receptor subtypes, the relative density of which varied from cell to cell. 3. The complex patterns of sensitivity to CHEMICAL seen in hippocampal neurons could be reconstituted by assembly of recombinant AMPA receptor subunits generated from cDNAs encoding the flip (i) and flop (o) splice variants of the GluR-A and GluR-B subunits. Recovery from modulation by CHEMICAL was slower for GluR-AiBi and GluR-AoBi than for GluR-AiBo and GENE. 4. Coexpression of the flip and flop splice variants of GluR-A, in the absence of GluR-B, revealed that heteromeric AMPA receptors with intermediate sensitivity to CHEMICAL, similar to responses observed for the combinations GluR-AoBi or GluR-AiBo, could be generated independently of the presence of the GluR-B subunit. However, recovery from modulation by CHEMICAL was twofold slower for GluR-AiBi than for homomeric GluR-Ai, indicating that the GluR-A and GluR-B subunits are not functionally equivalent in controlling sensitivity to CHEMICAL. 5. These results demonstrate that AMPA receptors expressed in hippocampal neurons are assembled in a variety of subunit and splice variant combinations that might serve as a mechanism to fine-tune the kinetics of synaptic transmission. | REGULATOR |
| AMPA receptor heterogeneity in rat hippocampal neurons revealed by differential sensitivity to cyclothiazide. 1. The kinetics of onset of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid GENE desensitization by CHEMICAL, and the extent of attenuation of AMPA receptor desensitization by cyclothiazide, showed pronounced cell-to-cell variation in cultures of rat hippocampal neurons. Cultures prepared from area CA1 stratum radiatum tended to show weaker modulation by cyclothiazide than cultures prepared from the whole hippocampus. 2. Kinetic analysis of concentration jump responses to CHEMICAL revealed multiple populations of receptors with fast (approximately 400 ms), intermediate (approximately 2-4 s), and slow (> 20 s) time constants for recovery from modulation by cyclothiazide. The amplitudes of these components varied widely between cells, suggesting the existence of at least three populations of AMPA receptor subtypes, the relative density of which varied from cell to cell. 3. The complex patterns of sensitivity to cyclothiazide seen in hippocampal neurons could be reconstituted by assembly of recombinant AMPA receptor subunits generated from cDNAs encoding the flip (i) and flop (o) splice variants of the GluR-A and GluR-B subunits. Recovery from modulation by cyclothiazide was slower for GluR-AiBi and GluR-AoBi than for GluR-AiBo and GluR-AoBo. 4. Coexpression of the flip and flop splice variants of GluR-A, in the absence of GluR-B, revealed that heteromeric AMPA receptors with intermediate sensitivity to cyclothiazide, similar to responses observed for the combinations GluR-AoBi or GluR-AiBo, could be generated independently of the presence of the GluR-B subunit. However, recovery from modulation by cyclothiazide was twofold slower for GluR-AiBi than for homomeric GluR-Ai, indicating that the GluR-A and GluR-B subunits are not functionally equivalent in controlling sensitivity to cyclothiazide. 5. These results demonstrate that AMPA receptors expressed in hippocampal neurons are assembled in a variety of subunit and splice variant combinations that might serve as a mechanism to fine-tune the kinetics of synaptic transmission. | REGULATOR |
| AMPA receptor heterogeneity in rat hippocampal neurons revealed by differential sensitivity to CHEMICAL. 1. The kinetics of onset of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization by glutamate, and the extent of attenuation of AMPA receptor desensitization by CHEMICAL, showed pronounced cell-to-cell variation in cultures of rat hippocampal neurons. Cultures prepared from area CA1 stratum radiatum tended to show weaker modulation by CHEMICAL than cultures prepared from the whole hippocampus. 2. Kinetic analysis of concentration jump responses to glutamate revealed multiple populations of receptors with fast (approximately 400 ms), intermediate (approximately 2-4 s), and slow (> 20 s) time constants for recovery from modulation by CHEMICAL. The amplitudes of these components varied widely between cells, suggesting the existence of at least three populations of AMPA receptor subtypes, the relative density of which varied from cell to cell. 3. The complex patterns of sensitivity to CHEMICAL seen in hippocampal neurons could be reconstituted by assembly of recombinant AMPA receptor subunits generated from cDNAs encoding the flip (i) and flop (o) splice variants of the GluR-A and GluR-B subunits. Recovery from modulation by CHEMICAL was slower for GluR-AiBi and GluR-AoBi than for GluR-AiBo and GluR-AoBo. 4. Coexpression of the flip and flop splice variants of GluR-A, in the absence of GluR-B, revealed that heteromeric GENE with intermediate sensitivity to CHEMICAL, similar to responses observed for the combinations GluR-AoBi or GluR-AiBo, could be generated independently of the presence of the GluR-B subunit. However, recovery from modulation by CHEMICAL was twofold slower for GluR-AiBi than for homomeric GluR-Ai, indicating that the GluR-A and GluR-B subunits are not functionally equivalent in controlling sensitivity to CHEMICAL. 5. These results demonstrate that GENE expressed in hippocampal neurons are assembled in a variety of subunit and splice variant combinations that might serve as a mechanism to fine-tune the kinetics of synaptic transmission. | REGULATOR |
| Striatal dopamine, dopamine transporter, and vesicular monoamine transporter in chronic cocaine users. Depletion of striatal dopamine (DA) has been hypothesized to explain some of the neurological and psychiatric complications of chronic use of cocaine, including increased risk for neuroleptic-precipitated movement disorders. We measured levels of DA, as well as two DA nerve terminal indices, namely, the DA transporter (DAT) and the vesicular monoamine transporter (VMAT2) in autopsied brain of 12 chronic cocaine users. Mean DA levels were normal in the putamen, the motor component of the striatum; however 4 of the 12 subjects had DA values below the lower limit of the control range. DA concentrations were significantly reduced in the caudate head (head, -33%; tail, -39%) with a trend for reduction in nucleus accumbens (-27%). Striatal GENE protein (-25 to -46%) and VMAT2 (-17 to -22%) were reduced, whereas GENE determined by CHEMICAL binding was normal. In conclusion, our data suggest that chronic cocaine use is associated with modestly reduced levels of striatal DA and the DA transporter in some subjects and that these changes might contribute to the neurological and psychiatric effects of the drug. | DIRECT-REGULATOR |
| Striatal dopamine, dopamine transporter, and vesicular monoamine transporter in chronic CHEMICAL users. Depletion of striatal dopamine (DA) has been hypothesized to explain some of the neurological and psychiatric complications of chronic use of CHEMICAL, including increased risk for neuroleptic-precipitated movement disorders. We measured levels of DA, as well as two DA nerve terminal indices, namely, the GENE (DAT) and the vesicular monoamine transporter (VMAT2) in autopsied brain of 12 chronic CHEMICAL users. Mean DA levels were normal in the putamen, the motor component of the striatum; however 4 of the 12 subjects had DA values below the lower limit of the control range. DA concentrations were significantly reduced in the caudate head (head, -33%; tail, -39%) with a trend for reduction in nucleus accumbens (-27%). Striatal DAT protein (-25 to -46%) and VMAT2 (-17 to -22%) were reduced, whereas DAT determined by [3H]WIN 35,428 binding was normal. In conclusion, our data suggest that chronic CHEMICAL use is associated with modestly reduced levels of striatal DA and the GENE in some subjects and that these changes might contribute to the neurological and psychiatric effects of the drug. | GENE-CHEMICAL |
| Purification and characterization of a novel hyaluronan-binding protein (PHBP) from human plasma: it has three EGF, a kringle and a serine protease domain, similar to hepatocyte growth factor activator. A novel hyaluronan-binding protein (PHBP) was purified from human plasma by affinity chromatography on hyaluronan-conjugated Sepharose. The contaminating IgM and albumin in the partially purified preparation were removed with anti-IgG antibody-conjugated Sepharose and anti-albumin antibody-conjugated Sepharose, respectively, and no other contaminant was observed. Finally, 800 micrograms of GENE was isolated from 500 ml of human plasma. GENE gave a single 70-kDa band on SDS-PAGE under non-reducing conditions, and 50-kDa and 17-kDa bands under reducing conditions. Thus, GENE was a heterodimer composed of 50-kDa and 17-kDa subunits, bridged by a disulfide linkage. Both subunits had novel N-terminal amino acid sequences, indicating that GENE was a novel hyaluronan-binding protein in human plasma. The amino acid sequence deduced from the nucleotide sequence of the cloned GENE cDNA exhibited significant homology to that of hepatocyte growth factor activator (HGFA). The results of Northern blot analysis indicated that liver, kidney, and pancreas expressed GENE mRNA. The predicted structure of GENE showed three epidermal growth factor (EGF) domains, a kringle domain and a serine protease domain, from its CHEMICAL-terminus, although HGFA has a fibronectin type II domain, an EGF domain, a fibronectin type I domain, an EGF domain, a kringle domain, and a serine protease domain, from its N-terminus. | PART-OF |
| Purification and characterization of a novel hyaluronan-binding protein (PHBP) from human plasma: it has three EGF, a kringle and a serine protease domain, similar to hepatocyte growth factor activator. A novel hyaluronan-binding protein (PHBP) was purified from human plasma by affinity chromatography on hyaluronan-conjugated Sepharose. The contaminating IgM and albumin in the partially purified preparation were removed with anti-IgG antibody-conjugated Sepharose and anti-albumin antibody-conjugated Sepharose, respectively, and no other contaminant was observed. Finally, 800 micrograms of PHBP was isolated from 500 ml of human plasma. PHBP gave a single 70-kDa band on SDS-PAGE under non-reducing conditions, and 50-kDa and 17-kDa bands under reducing conditions. Thus, PHBP was a heterodimer composed of 50-kDa and 17-kDa subunits, bridged by a disulfide linkage. Both subunits had novel N-terminal amino acid sequences, indicating that PHBP was a novel hyaluronan-binding protein in human plasma. The amino acid sequence deduced from the nucleotide sequence of the cloned PHBP cDNA exhibited significant homology to that of hepatocyte growth factor activator (HGFA). The results of Northern blot analysis indicated that liver, kidney, and pancreas expressed PHBP mRNA. The predicted structure of PHBP showed three GENE, a kringle domain and a serine protease domain, from its CHEMICAL-terminus, although HGFA has a fibronectin type II domain, an EGF domain, a fibronectin type I domain, an EGF domain, a kringle domain, and a serine protease domain, from its N-terminus. | PART-OF |
| Purification and characterization of a novel hyaluronan-binding protein (PHBP) from human plasma: it has three EGF, a kringle and a serine protease domain, similar to hepatocyte growth factor activator. A novel hyaluronan-binding protein (PHBP) was purified from human plasma by affinity chromatography on hyaluronan-conjugated Sepharose. The contaminating IgM and albumin in the partially purified preparation were removed with anti-IgG antibody-conjugated Sepharose and anti-albumin antibody-conjugated Sepharose, respectively, and no other contaminant was observed. Finally, 800 micrograms of PHBP was isolated from 500 ml of human plasma. PHBP gave a single 70-kDa band on SDS-PAGE under non-reducing conditions, and 50-kDa and 17-kDa bands under reducing conditions. Thus, PHBP was a heterodimer composed of 50-kDa and 17-kDa subunits, bridged by a disulfide linkage. Both subunits had novel N-terminal amino acid sequences, indicating that PHBP was a novel hyaluronan-binding protein in human plasma. The amino acid sequence deduced from the nucleotide sequence of the cloned PHBP cDNA exhibited significant homology to that of hepatocyte growth factor activator (HGFA). The results of Northern blot analysis indicated that liver, kidney, and pancreas expressed PHBP mRNA. The predicted structure of PHBP showed three epidermal growth factor (EGF) domains, a GENE and a serine protease domain, from its CHEMICAL-terminus, although HGFA has a fibronectin type II domain, an EGF domain, a fibronectin type I domain, an EGF domain, a GENE, and a serine protease domain, from its N-terminus. | PART-OF |
| Purification and characterization of a novel hyaluronan-binding protein (PHBP) from human plasma: it has three EGF, a kringle and a GENE, similar to hepatocyte growth factor activator. A novel hyaluronan-binding protein (PHBP) was purified from human plasma by affinity chromatography on hyaluronan-conjugated Sepharose. The contaminating IgM and albumin in the partially purified preparation were removed with anti-IgG antibody-conjugated Sepharose and anti-albumin antibody-conjugated Sepharose, respectively, and no other contaminant was observed. Finally, 800 micrograms of PHBP was isolated from 500 ml of human plasma. PHBP gave a single 70-kDa band on SDS-PAGE under non-reducing conditions, and 50-kDa and 17-kDa bands under reducing conditions. Thus, PHBP was a heterodimer composed of 50-kDa and 17-kDa subunits, bridged by a disulfide linkage. Both subunits had novel N-terminal amino acid sequences, indicating that PHBP was a novel hyaluronan-binding protein in human plasma. The amino acid sequence deduced from the nucleotide sequence of the cloned PHBP cDNA exhibited significant homology to that of hepatocyte growth factor activator (HGFA). The results of Northern blot analysis indicated that liver, kidney, and pancreas expressed PHBP mRNA. The predicted structure of PHBP showed three epidermal growth factor (EGF) domains, a kringle domain and a GENE, from its CHEMICAL-terminus, although HGFA has a fibronectin type II domain, an EGF domain, a fibronectin type I domain, an EGF domain, a kringle domain, and a GENE, from its N-terminus. | PART-OF |
| Purification and characterization of a novel hyaluronan-binding protein (PHBP) from human plasma: it has three EGF, a kringle and a serine protease domain, similar to hepatocyte growth factor activator. A novel hyaluronan-binding protein (PHBP) was purified from human plasma by affinity chromatography on hyaluronan-conjugated Sepharose. The contaminating IgM and albumin in the partially purified preparation were removed with anti-IgG antibody-conjugated Sepharose and anti-albumin antibody-conjugated Sepharose, respectively, and no other contaminant was observed. Finally, 800 micrograms of PHBP was isolated from 500 ml of human plasma. PHBP gave a single 70-kDa band on SDS-PAGE under non-reducing conditions, and 50-kDa and 17-kDa bands under reducing conditions. Thus, PHBP was a heterodimer composed of 50-kDa and 17-kDa subunits, bridged by a disulfide linkage. Both subunits had novel N-terminal amino acid sequences, indicating that PHBP was a novel hyaluronan-binding protein in human plasma. The amino acid sequence deduced from the nucleotide sequence of the cloned PHBP cDNA exhibited significant homology to that of hepatocyte growth factor activator (HGFA). The results of Northern blot analysis indicated that liver, kidney, and pancreas expressed PHBP mRNA. The predicted structure of PHBP showed three epidermal growth factor (EGF) domains, a kringle domain and a serine protease domain, from its N-terminus, although GENE has a fibronectin type II domain, an EGF domain, a fibronectin type I domain, an EGF domain, a kringle domain, and a serine protease domain, from its CHEMICAL-terminus. | PART-OF |
| Purification and characterization of a novel hyaluronan-binding protein (PHBP) from human plasma: it has three EGF, a kringle and a serine protease domain, similar to hepatocyte growth factor activator. A novel hyaluronan-binding protein (PHBP) was purified from human plasma by affinity chromatography on hyaluronan-conjugated Sepharose. The contaminating IgM and albumin in the partially purified preparation were removed with anti-IgG antibody-conjugated Sepharose and anti-albumin antibody-conjugated Sepharose, respectively, and no other contaminant was observed. Finally, 800 micrograms of PHBP was isolated from 500 ml of human plasma. PHBP gave a single 70-kDa band on SDS-PAGE under non-reducing conditions, and 50-kDa and 17-kDa bands under reducing conditions. Thus, PHBP was a heterodimer composed of 50-kDa and 17-kDa subunits, bridged by a disulfide linkage. Both subunits had novel N-terminal amino acid sequences, indicating that PHBP was a novel hyaluronan-binding protein in human plasma. The amino acid sequence deduced from the nucleotide sequence of the cloned PHBP cDNA exhibited significant homology to that of hepatocyte growth factor activator (HGFA). The results of Northern blot analysis indicated that liver, kidney, and pancreas expressed PHBP mRNA. The predicted structure of PHBP showed three epidermal growth factor (EGF) domains, a kringle domain and a serine protease domain, from its N-terminus, although HGFA has a GENE, an EGF domain, a fibronectin type I domain, an EGF domain, a kringle domain, and a serine protease domain, from its CHEMICAL-terminus. | PART-OF |
| Purification and characterization of a novel hyaluronan-binding protein (PHBP) from human plasma: it has three EGF, a kringle and a serine protease domain, similar to hepatocyte growth factor activator. A novel hyaluronan-binding protein (PHBP) was purified from human plasma by affinity chromatography on hyaluronan-conjugated Sepharose. The contaminating IgM and albumin in the partially purified preparation were removed with anti-IgG antibody-conjugated Sepharose and anti-albumin antibody-conjugated Sepharose, respectively, and no other contaminant was observed. Finally, 800 micrograms of PHBP was isolated from 500 ml of human plasma. PHBP gave a single 70-kDa band on SDS-PAGE under non-reducing conditions, and 50-kDa and 17-kDa bands under reducing conditions. Thus, PHBP was a heterodimer composed of 50-kDa and 17-kDa subunits, bridged by a disulfide linkage. Both subunits had novel N-terminal amino acid sequences, indicating that PHBP was a novel hyaluronan-binding protein in human plasma. The amino acid sequence deduced from the nucleotide sequence of the cloned PHBP cDNA exhibited significant homology to that of hepatocyte growth factor activator (HGFA). The results of Northern blot analysis indicated that liver, kidney, and pancreas expressed PHBP mRNA. The predicted structure of PHBP showed three epidermal growth factor (EGF) domains, a kringle domain and a serine protease domain, from its N-terminus, although HGFA has a fibronectin type II domain, an GENE, a fibronectin type I domain, an GENE, a kringle domain, and a serine protease domain, from its CHEMICAL-terminus. | PART-OF |
| Purification and characterization of a novel hyaluronan-binding protein (PHBP) from human plasma: it has three EGF, a kringle and a serine protease domain, similar to hepatocyte growth factor activator. A novel hyaluronan-binding protein (PHBP) was purified from human plasma by affinity chromatography on hyaluronan-conjugated Sepharose. The contaminating IgM and albumin in the partially purified preparation were removed with anti-IgG antibody-conjugated Sepharose and anti-albumin antibody-conjugated Sepharose, respectively, and no other contaminant was observed. Finally, 800 micrograms of PHBP was isolated from 500 ml of human plasma. PHBP gave a single 70-kDa band on SDS-PAGE under non-reducing conditions, and 50-kDa and 17-kDa bands under reducing conditions. Thus, PHBP was a heterodimer composed of 50-kDa and 17-kDa subunits, bridged by a disulfide linkage. Both subunits had novel N-terminal amino acid sequences, indicating that PHBP was a novel hyaluronan-binding protein in human plasma. The amino acid sequence deduced from the nucleotide sequence of the cloned PHBP cDNA exhibited significant homology to that of hepatocyte growth factor activator (HGFA). The results of Northern blot analysis indicated that liver, kidney, and pancreas expressed PHBP mRNA. The predicted structure of PHBP showed three epidermal growth factor (EGF) domains, a kringle domain and a serine protease domain, from its N-terminus, although HGFA has a fibronectin type II domain, an EGF domain, a GENE, an EGF domain, a kringle domain, and a serine protease domain, from its CHEMICAL-terminus. | PART-OF |
| Purification and characterization of a novel hyaluronan-binding protein (PHBP) from human plasma: it has three EGF, a kringle and a serine protease domain, similar to hepatocyte growth factor activator. A novel hyaluronan-binding protein (PHBP) was purified from human plasma by affinity chromatography on hyaluronan-conjugated Sepharose. The contaminating IgM and albumin in the partially purified preparation were removed with anti-IgG antibody-conjugated Sepharose and anti-albumin antibody-conjugated Sepharose, respectively, and no other contaminant was observed. Finally, 800 micrograms of GENE was isolated from 500 ml of human plasma. GENE gave a single 70-kDa band on SDS-PAGE under non-reducing conditions, and 50-kDa and 17-kDa bands under reducing conditions. Thus, GENE was a heterodimer composed of 50-kDa and 17-kDa subunits, bridged by a CHEMICAL linkage. Both subunits had novel N-terminal amino acid sequences, indicating that GENE was a novel hyaluronan-binding protein in human plasma. The amino acid sequence deduced from the nucleotide sequence of the cloned GENE cDNA exhibited significant homology to that of hepatocyte growth factor activator (HGFA). The results of Northern blot analysis indicated that liver, kidney, and pancreas expressed GENE mRNA. The predicted structure of GENE showed three epidermal growth factor (EGF) domains, a kringle domain and a serine protease domain, from its N-terminus, although HGFA has a fibronectin type II domain, an EGF domain, a fibronectin type I domain, an EGF domain, a kringle domain, and a serine protease domain, from its N-terminus. | PART-OF |
| Purification and characterization of a novel hyaluronan-binding protein (PHBP) from human plasma: it has three EGF, a kringle and a serine protease domain, similar to hepatocyte growth factor activator. A novel hyaluronan-binding protein (PHBP) was purified from human plasma by affinity chromatography on hyaluronan-conjugated Sepharose. The contaminating IgM and albumin in the partially purified preparation were removed with anti-IgG antibody-conjugated Sepharose and anti-albumin antibody-conjugated Sepharose, respectively, and no other contaminant was observed. Finally, 800 micrograms of GENE was isolated from 500 ml of human plasma. GENE gave a single 70-kDa band on SDS-PAGE under non-reducing conditions, and 50-kDa and 17-kDa bands under reducing conditions. Thus, GENE was a heterodimer composed of 50-kDa and 17-kDa subunits, bridged by a disulfide linkage. Both subunits had novel N-terminal CHEMICAL sequences, indicating that GENE was a novel hyaluronan-binding protein in human plasma. The CHEMICAL sequence deduced from the nucleotide sequence of the cloned GENE cDNA exhibited significant homology to that of hepatocyte growth factor activator (HGFA). The results of Northern blot analysis indicated that liver, kidney, and pancreas expressed GENE mRNA. The predicted structure of GENE showed three epidermal growth factor (EGF) domains, a kringle domain and a serine protease domain, from its N-terminus, although HGFA has a fibronectin type II domain, an EGF domain, a fibronectin type I domain, an EGF domain, a kringle domain, and a serine protease domain, from its N-terminus. | PART-OF |
| Purification and characterization of a novel hyaluronan-binding protein (PHBP) from human plasma: it has three EGF, a kringle and a serine protease domain, similar to hepatocyte growth factor activator. A novel hyaluronan-binding protein (PHBP) was purified from human plasma by affinity chromatography on hyaluronan-conjugated Sepharose. The contaminating IgM and albumin in the partially purified preparation were removed with anti-IgG antibody-conjugated Sepharose and anti-albumin antibody-conjugated Sepharose, respectively, and no other contaminant was observed. Finally, 800 micrograms of GENE was isolated from 500 ml of human plasma. GENE gave a single 70-kDa band on SDS-PAGE under non-reducing conditions, and 50-kDa and 17-kDa bands under reducing conditions. Thus, GENE was a heterodimer composed of 50-kDa and 17-kDa subunits, bridged by a disulfide linkage. Both subunits had novel N-terminal amino acid sequences, indicating that GENE was a novel hyaluronan-binding protein in human plasma. The amino acid sequence deduced from the CHEMICAL sequence of the cloned GENE cDNA exhibited significant homology to that of hepatocyte growth factor activator (HGFA). The results of Northern blot analysis indicated that liver, kidney, and pancreas expressed GENE mRNA. The predicted structure of GENE showed three epidermal growth factor (EGF) domains, a kringle domain and a serine protease domain, from its N-terminus, although HGFA has a fibronectin type II domain, an EGF domain, a fibronectin type I domain, an EGF domain, a kringle domain, and a serine protease domain, from its N-terminus. | PART-OF |
| Hypoxemia associated with cimetidine therapy in a newborn infant. Cimetidine therapy used for the treatment of gastric bleeding due to CHEMICAL therapy in a newborn infant was temporally associated with episodes of severe hypoxemia. It appears likely that the GENE blocked by cimetidine obviated the pulmonary vasodilator effect of CHEMICAL therapy. | NO-RELATIONSHIP |
| Hypoxemia associated with CHEMICAL therapy in a newborn infant. CHEMICAL therapy used for the treatment of gastric bleeding due to tolazoline therapy in a newborn infant was temporally associated with episodes of severe hypoxemia. It appears likely that the GENE blocked by CHEMICAL obviated the pulmonary vasodilator effect of tolazoline therapy. | INHIBITOR |
| Interactions of 2,3-benzodiazepines and CHEMICAL at AMPA receptors: patch clamp recordings in cultured neurones and area CA1 in hippocampal slices. 1. The 2,3-benzodiazepines GYKI 52466, GYKI 53405 and GYKI 53655 antagonized AMPA-induced currents in cultured superior colliculus neurones in a non use-dependent manner (steady state IC50s: GYKI 52466 9.8 +/- 0.6 microM; GYKI 53405 3.1 +/- 0.6 microM; GYKI 53655 0.8 +/- 0.1 microM). 2. Higher concentrations of all three antagonists slowed the onset kinetics and quickened the offset kinetics of AMPA-induced currents indicative of an allosteric interaction with the AMPA recognition site. 3. CHEMICAL (3-300 microM) dramatically slowed desensitization of AMPA-induced currents and potentiated steady state currents (EC50 10.0 +/- 2.5 microM) to a much greater degree than peak currents. Both tau on and tau off were also increased by CHEMICAL in a concentration-dependent manner (EC50: tau on 42.1 +/- 4.5 microM; tau off 31.6 +/- 6.6 microM). 4. CHEMICAL (10-100 microM) shifted the concentration-response curves of the 2,3-benzodiazepines to the right. For example, with 10 microM CHEMICAL the IC50s of GYKI 52466 and GYKI 53405 on steady-state AMPA-induced currents were 57.9 +/- 9.5 and 41.6 +/- 1.5 microM, respectively. 5. GYKI 53405 and GYKI 52466 concentration-dependently reversed the effects of CHEMICAL (100 microM) on offset kinetics (GYKI 53405 IC50 16.6 +/- 4.2 microM). However, the 2,3-benzodiazepines were unable to reintroduce desensitization in the presence of CHEMICAL and even concentration-dependently slowed the onset kinetics of AMPA responses further (GYKI 53405 EC50 8.0 +/- 2.8 microM). 6. GYKI 52466 decreased the peak amplitude of hippocampal area CA1 AMPA receptor-mediated excitatory postsynaptic currents (e.p.s.cs) (IC50 10.8 +/- 0.8 microM) with no apparent effect on response kinetics. CHEMICAL prolonged the decay time constant of AMPA receptor-mediated e.p.s.cs (EC50 35.7 +/- 6.5 microM) with less pronounced effects in slowing e.p.s.c. onset kinetics and increasing e.p.s.c. amplitude. 7. CHEMICAL (330 microM) shifted the concentration-response curve for the effects of GYKI 52466 on AMPA receptor-mediated e.p.s.c. peak amplitude to the right (GYKI 52466 IC50 26.9 +/- 9.4 microM). Likewise, GYKI 52466 (30-100 microM)) shifted the concentration-response curve for the effects of CHEMICAL on AMPA receptor-mediated e.p.s.c. decay time constants to the right. 8. In conclusion, CHEMICAL and the 2,3-benzodiazepines seem to bind to different sites on GENE but exert strong allosteric interactions with one another and with other domains such as the agonist recognition site. The interactions of GYKI 52466 and CHEMICAL on AMPA receptor-mediated e.p.s.cs in area CA1 of hippocampal slices provide evidence that the decay time constant of these synaptic events are not governed by desensitization. | REGULATOR |
| Interactions of CHEMICAL and cyclothiazide at AMPA receptors: patch clamp recordings in cultured neurones and area CA1 in hippocampal slices. 1. The CHEMICAL GYKI 52466, GYKI 53405 and GYKI 53655 antagonized AMPA-induced currents in cultured superior colliculus neurones in a non use-dependent manner (steady state IC50s: GYKI 52466 9.8 +/- 0.6 microM; GYKI 53405 3.1 +/- 0.6 microM; GYKI 53655 0.8 +/- 0.1 microM). 2. Higher concentrations of all three antagonists slowed the onset kinetics and quickened the offset kinetics of AMPA-induced currents indicative of an allosteric interaction with the AMPA recognition site. 3. Cyclothiazide (3-300 microM) dramatically slowed desensitization of AMPA-induced currents and potentiated steady state currents (EC50 10.0 +/- 2.5 microM) to a much greater degree than peak currents. Both tau on and tau off were also increased by cyclothiazide in a concentration-dependent manner (EC50: tau on 42.1 +/- 4.5 microM; tau off 31.6 +/- 6.6 microM). 4. Cyclothiazide (10-100 microM) shifted the concentration-response curves of the CHEMICAL to the right. For example, with 10 microM cyclothiazide the IC50s of GYKI 52466 and GYKI 53405 on steady-state AMPA-induced currents were 57.9 +/- 9.5 and 41.6 +/- 1.5 microM, respectively. 5. GYKI 53405 and GYKI 52466 concentration-dependently reversed the effects of cyclothiazide (100 microM) on offset kinetics (GYKI 53405 IC50 16.6 +/- 4.2 microM). However, the CHEMICAL were unable to reintroduce desensitization in the presence of cyclothiazide and even concentration-dependently slowed the onset kinetics of AMPA responses further (GYKI 53405 EC50 8.0 +/- 2.8 microM). 6. GYKI 52466 decreased the peak amplitude of hippocampal area CA1 AMPA receptor-mediated excitatory postsynaptic currents (e.p.s.cs) (IC50 10.8 +/- 0.8 microM) with no apparent effect on response kinetics. Cyclothiazide prolonged the decay time constant of AMPA receptor-mediated e.p.s.cs (EC50 35.7 +/- 6.5 microM) with less pronounced effects in slowing e.p.s.c. onset kinetics and increasing e.p.s.c. amplitude. 7. Cyclothiazide (330 microM) shifted the concentration-response curve for the effects of GYKI 52466 on AMPA receptor-mediated e.p.s.c. peak amplitude to the right (GYKI 52466 IC50 26.9 +/- 9.4 microM). Likewise, GYKI 52466 (30-100 microM)) shifted the concentration-response curve for the effects of cyclothiazide on AMPA receptor-mediated e.p.s.c. decay time constants to the right. 8. In conclusion, cyclothiazide and the CHEMICAL seem to bind to different sites on GENE but exert strong allosteric interactions with one another and with other domains such as the agonist recognition site. The interactions of GYKI 52466 and cyclothiazide on AMPA receptor-mediated e.p.s.cs in area CA1 of hippocampal slices provide evidence that the decay time constant of these synaptic events are not governed by desensitization. | REGULATOR |
| Interactions of 2,3-benzodiazepines and cyclothiazide at AMPA receptors: patch clamp recordings in cultured neurones and area CA1 in hippocampal slices. 1. The 2,3-benzodiazepines CHEMICAL, GYKI 53405 and GYKI 53655 antagonized AMPA-induced currents in cultured superior colliculus neurones in a non use-dependent manner (steady state IC50s: CHEMICAL 9.8 +/- 0.6 microM; GYKI 53405 3.1 +/- 0.6 microM; GYKI 53655 0.8 +/- 0.1 microM). 2. Higher concentrations of all three antagonists slowed the onset kinetics and quickened the offset kinetics of AMPA-induced currents indicative of an allosteric interaction with the AMPA recognition site. 3. Cyclothiazide (3-300 microM) dramatically slowed desensitization of AMPA-induced currents and potentiated steady state currents (EC50 10.0 +/- 2.5 microM) to a much greater degree than peak currents. Both tau on and tau off were also increased by cyclothiazide in a concentration-dependent manner (EC50: tau on 42.1 +/- 4.5 microM; tau off 31.6 +/- 6.6 microM). 4. Cyclothiazide (10-100 microM) shifted the concentration-response curves of the 2,3-benzodiazepines to the right. For example, with 10 microM cyclothiazide the IC50s of CHEMICAL and GYKI 53405 on steady-state AMPA-induced currents were 57.9 +/- 9.5 and 41.6 +/- 1.5 microM, respectively. 5. GYKI 53405 and CHEMICAL concentration-dependently reversed the effects of cyclothiazide (100 microM) on offset kinetics (GYKI 53405 IC50 16.6 +/- 4.2 microM). However, the 2,3-benzodiazepines were unable to reintroduce desensitization in the presence of cyclothiazide and even concentration-dependently slowed the onset kinetics of AMPA responses further (GYKI 53405 EC50 8.0 +/- 2.8 microM). 6. CHEMICAL decreased the peak amplitude of hippocampal area CA1 AMPA receptor-mediated excitatory postsynaptic currents (e.p.s.cs) (IC50 10.8 +/- 0.8 microM) with no apparent effect on response kinetics. Cyclothiazide prolonged the decay time constant of AMPA receptor-mediated e.p.s.cs (EC50 35.7 +/- 6.5 microM) with less pronounced effects in slowing e.p.s.c. onset kinetics and increasing e.p.s.c. amplitude. 7. Cyclothiazide (330 microM) shifted the concentration-response curve for the effects of CHEMICAL on AMPA receptor-mediated e.p.s.c. peak amplitude to the right (GYKI 52466 IC50 26.9 +/- 9.4 microM). Likewise, CHEMICAL (30-100 microM)) shifted the concentration-response curve for the effects of cyclothiazide on AMPA receptor-mediated e.p.s.c. decay time constants to the right. 8. In conclusion, cyclothiazide and the 2,3-benzodiazepines seem to bind to different sites on AMPA receptors but exert strong allosteric interactions with one another and with other domains such as the agonist recognition site. The interactions of CHEMICAL and cyclothiazide on GENE-mediated e.p.s.cs in area CA1 of hippocampal slices provide evidence that the decay time constant of these synaptic events are not governed by desensitization. | INHIBITOR |
| Interactions of 2,3-benzodiazepines and CHEMICAL at AMPA receptors: patch clamp recordings in cultured neurones and area CA1 in hippocampal slices. 1. The 2,3-benzodiazepines GYKI 52466, GYKI 53405 and GYKI 53655 antagonized AMPA-induced currents in cultured superior colliculus neurones in a non use-dependent manner (steady state IC50s: GYKI 52466 9.8 +/- 0.6 microM; GYKI 53405 3.1 +/- 0.6 microM; GYKI 53655 0.8 +/- 0.1 microM). 2. Higher concentrations of all three antagonists slowed the onset kinetics and quickened the offset kinetics of AMPA-induced currents indicative of an allosteric interaction with the AMPA recognition site. 3. CHEMICAL (3-300 microM) dramatically slowed desensitization of AMPA-induced currents and potentiated steady state currents (EC50 10.0 +/- 2.5 microM) to a much greater degree than peak currents. Both tau on and tau off were also increased by CHEMICAL in a concentration-dependent manner (EC50: tau on 42.1 +/- 4.5 microM; tau off 31.6 +/- 6.6 microM). 4. CHEMICAL (10-100 microM) shifted the concentration-response curves of the 2,3-benzodiazepines to the right. For example, with 10 microM CHEMICAL the IC50s of GYKI 52466 and GYKI 53405 on steady-state AMPA-induced currents were 57.9 +/- 9.5 and 41.6 +/- 1.5 microM, respectively. 5. GYKI 53405 and GYKI 52466 concentration-dependently reversed the effects of CHEMICAL (100 microM) on offset kinetics (GYKI 53405 IC50 16.6 +/- 4.2 microM). However, the 2,3-benzodiazepines were unable to reintroduce desensitization in the presence of CHEMICAL and even concentration-dependently slowed the onset kinetics of AMPA responses further (GYKI 53405 EC50 8.0 +/- 2.8 microM). 6. GYKI 52466 decreased the peak amplitude of hippocampal area CA1 AMPA receptor-mediated excitatory postsynaptic currents (e.p.s.cs) (IC50 10.8 +/- 0.8 microM) with no apparent effect on response kinetics. CHEMICAL prolonged the decay time constant of AMPA receptor-mediated e.p.s.cs (EC50 35.7 +/- 6.5 microM) with less pronounced effects in slowing e.p.s.c. onset kinetics and increasing e.p.s.c. amplitude. 7. CHEMICAL (330 microM) shifted the concentration-response curve for the effects of GYKI 52466 on AMPA receptor-mediated e.p.s.c. peak amplitude to the right (GYKI 52466 IC50 26.9 +/- 9.4 microM). Likewise, GYKI 52466 (30-100 microM)) shifted the concentration-response curve for the effects of CHEMICAL on AMPA receptor-mediated e.p.s.c. decay time constants to the right. 8. In conclusion, CHEMICAL and the 2,3-benzodiazepines seem to bind to different sites on AMPA receptors but exert strong allosteric interactions with one another and with other domains such as the agonist recognition site. The interactions of GYKI 52466 and CHEMICAL on GENE-mediated e.p.s.cs in area CA1 of hippocampal slices provide evidence that the decay time constant of these synaptic events are not governed by desensitization. | REGULATOR |
| Comparison of ligand binding affinities at human I1-imidazoline binding sites and the high affinity state of alpha-2 adrenoceptor subtypes. To identify selective compounds for nonadrenergic I1-imidazoline receptors (I1), the affinities of 22 ligands for [125I]p-iodoclonidine binding have been compared at human platelet I1-imidazoline binding sites (analyzed under norepinephrine mask of alpha-2 AR) and at human alpha-2A, alpha-2B and alpha-2C adrenoceptors stably expressed on transfected Chinese hamster ovary cells. Competition curves at the platelet I1-imidazoline binding site were biphasic for most compounds. Only tizanidine and BDF,6143 displayed monophasic I1 competition curves. Agmatine, an endogenous neurotransmitter candidate for the I1-imidazoline receptor, was identified as the most selective agent for a subcomponent of platelet I1 sites. The affinity of agmatine at the high affinity component of platelet I1 sites was 1400-fold selective over alpha-2A adrenoceptors, 5000-fold selective over alpha-2B adrenoceptors and 800-fold selective over alpha-2C adrenoceptors. Moxonidine and tizanidine also displayed selectivities for a high affinity component of the platelet I1 binding sites over alpha-2 adrenoceptors. CHEMICAL was the most selective compound for the high affinity state of the GENE, displaying 7-, 23- and 9-fold higher affinity than alpha-2B, alpha-2C and platelet I1-midazoline binding sites, respectively. No single selective compound was identified for the alpha-2B adrenoceptor. Norepinephrine displayed, respectively, 18- and 31-fold selectivity for the high affinity state of the alpha-2C adrenoceptor as compared to alpha-2A- or alpha-2B adrenoceptors, and was > 100,000- fold selective over platelet I1-imidazoline sites. Thus, human alpha-2 adrenoceptors and the platelet I1-imidazoline binding site can be clearly discriminated based on their affinities for certain compounds. | DIRECT-REGULATOR |
| Comparison of ligand binding affinities at human I1-imidazoline binding sites and the high affinity state of alpha-2 adrenoceptor subtypes. To identify selective compounds for nonadrenergic I1-imidazoline receptors (I1), the affinities of 22 ligands for CHEMICAL binding have been compared at GENE (analyzed under norepinephrine mask of alpha-2 AR) and at human alpha-2A, alpha-2B and alpha-2C adrenoceptors stably expressed on transfected Chinese hamster ovary cells. Competition curves at the platelet I1-imidazoline binding site were biphasic for most compounds. Only tizanidine and BDF,6143 displayed monophasic I1 competition curves. Agmatine, an endogenous neurotransmitter candidate for the I1-imidazoline receptor, was identified as the most selective agent for a subcomponent of platelet I1 sites. The affinity of agmatine at the high affinity component of platelet I1 sites was 1400-fold selective over alpha-2A adrenoceptors, 5000-fold selective over alpha-2B adrenoceptors and 800-fold selective over alpha-2C adrenoceptors. Moxonidine and tizanidine also displayed selectivities for a high affinity component of the platelet I1 binding sites over alpha-2 adrenoceptors. Naphazoline was the most selective compound for the high affinity state of the alpha-2A adrenoceptor, displaying 7-, 23- and 9-fold higher affinity than alpha-2B, alpha-2C and platelet I1-midazoline binding sites, respectively. No single selective compound was identified for the alpha-2B adrenoceptor. Norepinephrine displayed, respectively, 18- and 31-fold selectivity for the high affinity state of the alpha-2C adrenoceptor as compared to alpha-2A- or alpha-2B adrenoceptors, and was > 100,000- fold selective over platelet I1-imidazoline sites. Thus, human alpha-2 adrenoceptors and the platelet I1-imidazoline binding site can be clearly discriminated based on their affinities for certain compounds. | DIRECT-REGULATOR |
| Activation of cytoprotective GENE by CHEMICAL as a possible explanation for its hair growth-stimulating effect. Data from the literature indicate that nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, naproxen, piroxicam, or ibuprofen, induce hair loss in vivo. These NSAIDs are well-known inhibitors of both the cytoprotective isoform of prostaglandin endoperoxide synthase-1 (PGHS-1) and of the inducible form (PGHS-2). By immunohistochemical staining, we found that PGHS-1 is the main isoform present in the dermal papilla from normal human hair follicle (either anagen or catagen), whereas PGHS-2 was only faintly and exclusively expressed in anagen dermal papilla. Thus, PGHS-1 might be the primary target of the hair growth-inhibitory effects of NSAIDs. We thus speculated that activation of PGHS-1 might be a mechanism by which CHEMICAL (2,4-diamino-6-piperidinopyrimidine-3-oxyde) stimulates hair growth in vivo. We demonstrate here that CHEMICAL is a potent activator of purified PGHS-1 (AC50 = 80 microM), as assayed by oxygen consumption and PGE2 production. This activation was also evidenced by increased PGE2 production by BALB/c 3T3 fibroblasts and by human dermal papilla fibroblasts in culture. Our findings suggest that CHEMICAL and its derivatives may have a cytoprotective activity in vivo and that more potent second-generation hair growth-promoting drugs might be designed, based on this mechanism. | ACTIVATOR |
| Activation of cytoprotective prostaglandin synthase-1 by CHEMICAL as a possible explanation for its hair growth-stimulating effect. Data from the literature indicate that nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, naproxen, piroxicam, or ibuprofen, induce hair loss in vivo. These NSAIDs are well-known inhibitors of both the cytoprotective isoform of prostaglandin endoperoxide synthase-1 (PGHS-1) and of the inducible form (PGHS-2). By immunohistochemical staining, we found that GENE is the main isoform present in the dermal papilla from normal human hair follicle (either anagen or catagen), whereas PGHS-2 was only faintly and exclusively expressed in anagen dermal papilla. Thus, GENE might be the primary target of the hair growth-inhibitory effects of NSAIDs. We thus speculated that activation of GENE might be a mechanism by which CHEMICAL (2,4-diamino-6-piperidinopyrimidine-3-oxyde) stimulates hair growth in vivo. We demonstrate here that CHEMICAL is a potent activator of purified GENE (AC50 = 80 microM), as assayed by oxygen consumption and PGE2 production. This activation was also evidenced by increased PGE2 production by BALB/c 3T3 fibroblasts and by human dermal papilla fibroblasts in culture. Our findings suggest that CHEMICAL and its derivatives may have a cytoprotective activity in vivo and that more potent second-generation hair growth-promoting drugs might be designed, based on this mechanism. | ACTIVATOR |
| Activation of cytoprotective prostaglandin synthase-1 by minoxidil as a possible explanation for its hair growth-stimulating effect. Data from the literature indicate that nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, naproxen, piroxicam, or ibuprofen, induce hair loss in vivo. These NSAIDs are well-known inhibitors of both the cytoprotective isoform of prostaglandin endoperoxide synthase-1 (PGHS-1) and of the inducible form (PGHS-2). By immunohistochemical staining, we found that GENE is the main isoform present in the dermal papilla from normal human hair follicle (either anagen or catagen), whereas PGHS-2 was only faintly and exclusively expressed in anagen dermal papilla. Thus, GENE might be the primary target of the hair growth-inhibitory effects of NSAIDs. We thus speculated that activation of GENE might be a mechanism by which minoxidil (CHEMICAL) stimulates hair growth in vivo. We demonstrate here that minoxidil is a potent activator of purified GENE (AC50 = 80 microM), as assayed by oxygen consumption and PGE2 production. This activation was also evidenced by increased PGE2 production by BALB/c 3T3 fibroblasts and by human dermal papilla fibroblasts in culture. Our findings suggest that minoxidil and its derivatives may have a cytoprotective activity in vivo and that more potent second-generation hair growth-promoting drugs might be designed, based on this mechanism. | ACTIVATOR |
| Evolution of the aminoacyl-tRNA synthetase family and the organization of the Drosophila GENE gene. Intron/exon structure of the gene, control of expression of the two mRNAs, selective advantage of the multienzyme complex. In Drosophila, GENE is a multifunctional synthetase encoded by a unique gene and composed of three domains: the CHEMICAL- and carboxy-terminal domains catalyze the aminoacylation of glutamic acid and proline tRNA species, respectively, and the central domain is made of 75 CHEMICAL acids repeated six times amongst which 46 are highly conserved and constitute the repeated motifs [Cerini, C., Kerjan, P., Astier, M., Gratecos, D., Mirande, M. & Semeriva, M. (1991) EMBO J. 10, 4267-4277]. The intron/exon organization of the Drosophila gene reveals the presence of six exons among which four are in the 5'-end encoding glutamic acid activity. Only one exon encodes the repeated motifs. A comparison of introns positions, intron classes and intron/exon boundaries in the Drosophila gene and in its human counterpart is compatible with the intron-early hypothesis presiding, at least in part, to the evolution of the synthetases. The full-length fly protein is encoded by a 6.1-kb mRNA which is expressed throughout development. In addition, a shorter transcript encompasses the 3'-end of the cDNA and it is especially abundant in 5-10-h embryos until the first larval stage. Expression of these two mRNAs seems to be controlled by two independent promoters. The 6.1-kb mRNA promoter is probably localized in the 5'-end of the gene. The small mRNA promoter resides in the 4th intron and evidence is provided that the mRNA encodes only the domain corresponding to prolyl-tRNA synthetase and is functional in vivo. Finally, transgenic flies have been established by using constructs corresponding to the three domains of the protein. Overexpression of the repeated motifs leads to a sterility of the flies that suggests a role of these motifs in linking the multienzyme complex to an, as yet, unknown structure of the protein synthesis apparatus. | PART-OF |
| Evolution of the aminoacyl-tRNA synthetase family and the organization of the Drosophila GENE gene. Intron/exon structure of the gene, control of expression of the two mRNAs, selective advantage of the multienzyme complex. In Drosophila, GENE is a multifunctional synthetase encoded by a unique gene and composed of three domains: the amino- and CHEMICAL-terminal domains catalyze the aminoacylation of glutamic acid and proline tRNA species, respectively, and the central domain is made of 75 amino acids repeated six times amongst which 46 are highly conserved and constitute the repeated motifs [Cerini, C., Kerjan, P., Astier, M., Gratecos, D., Mirande, M. & Semeriva, M. (1991) EMBO J. 10, 4267-4277]. The intron/exon organization of the Drosophila gene reveals the presence of six exons among which four are in the 5'-end encoding glutamic acid activity. Only one exon encodes the repeated motifs. A comparison of introns positions, intron classes and intron/exon boundaries in the Drosophila gene and in its human counterpart is compatible with the intron-early hypothesis presiding, at least in part, to the evolution of the synthetases. The full-length fly protein is encoded by a 6.1-kb mRNA which is expressed throughout development. In addition, a shorter transcript encompasses the 3'-end of the cDNA and it is especially abundant in 5-10-h embryos until the first larval stage. Expression of these two mRNAs seems to be controlled by two independent promoters. The 6.1-kb mRNA promoter is probably localized in the 5'-end of the gene. The small mRNA promoter resides in the 4th intron and evidence is provided that the mRNA encodes only the domain corresponding to prolyl-tRNA synthetase and is functional in vivo. Finally, transgenic flies have been established by using constructs corresponding to the three domains of the protein. Overexpression of the repeated motifs leads to a sterility of the flies that suggests a role of these motifs in linking the multienzyme complex to an, as yet, unknown structure of the protein synthesis apparatus. | PART-OF |
| Evolution of the aminoacyl-tRNA synthetase family and the organization of the Drosophila GENE gene. Intron/exon structure of the gene, control of expression of the two mRNAs, selective advantage of the multienzyme complex. In Drosophila, GENE is a multifunctional synthetase encoded by a unique gene and composed of three domains: the amino- and carboxy-terminal domains catalyze the aminoacylation of CHEMICAL and proline tRNA species, respectively, and the central domain is made of 75 amino acids repeated six times amongst which 46 are highly conserved and constitute the repeated motifs [Cerini, C., Kerjan, P., Astier, M., Gratecos, D., Mirande, M. & Semeriva, M. (1991) EMBO J. 10, 4267-4277]. The intron/exon organization of the Drosophila gene reveals the presence of six exons among which four are in the 5'-end encoding CHEMICAL activity. Only one exon encodes the repeated motifs. A comparison of introns positions, intron classes and intron/exon boundaries in the Drosophila gene and in its human counterpart is compatible with the intron-early hypothesis presiding, at least in part, to the evolution of the synthetases. The full-length fly protein is encoded by a 6.1-kb mRNA which is expressed throughout development. In addition, a shorter transcript encompasses the 3'-end of the cDNA and it is especially abundant in 5-10-h embryos until the first larval stage. Expression of these two mRNAs seems to be controlled by two independent promoters. The 6.1-kb mRNA promoter is probably localized in the 5'-end of the gene. The small mRNA promoter resides in the 4th intron and evidence is provided that the mRNA encodes only the domain corresponding to prolyl-tRNA synthetase and is functional in vivo. Finally, transgenic flies have been established by using constructs corresponding to the three domains of the protein. Overexpression of the repeated motifs leads to a sterility of the flies that suggests a role of these motifs in linking the multienzyme complex to an, as yet, unknown structure of the protein synthesis apparatus. | SUBSTRATE |
| Evolution of the aminoacyl-tRNA synthetase family and the organization of the Drosophila GENE gene. Intron/exon structure of the gene, control of expression of the two mRNAs, selective advantage of the multienzyme complex. In Drosophila, GENE is a multifunctional synthetase encoded by a unique gene and composed of three domains: the amino- and carboxy-terminal domains catalyze the aminoacylation of glutamic acid and proline tRNA species, respectively, and the central domain is made of 75 CHEMICAL repeated six times amongst which 46 are highly conserved and constitute the repeated motifs [Cerini, C., Kerjan, P., Astier, M., Gratecos, D., Mirande, M. & Semeriva, M. (1991) EMBO J. 10, 4267-4277]. The intron/exon organization of the Drosophila gene reveals the presence of six exons among which four are in the 5'-end encoding glutamic acid activity. Only one exon encodes the repeated motifs. A comparison of introns positions, intron classes and intron/exon boundaries in the Drosophila gene and in its human counterpart is compatible with the intron-early hypothesis presiding, at least in part, to the evolution of the synthetases. The full-length fly protein is encoded by a 6.1-kb mRNA which is expressed throughout development. In addition, a shorter transcript encompasses the 3'-end of the cDNA and it is especially abundant in 5-10-h embryos until the first larval stage. Expression of these two mRNAs seems to be controlled by two independent promoters. The 6.1-kb mRNA promoter is probably localized in the 5'-end of the gene. The small mRNA promoter resides in the 4th intron and evidence is provided that the mRNA encodes only the domain corresponding to prolyl-tRNA synthetase and is functional in vivo. Finally, transgenic flies have been established by using constructs corresponding to the three domains of the protein. Overexpression of the repeated motifs leads to a sterility of the flies that suggests a role of these motifs in linking the multienzyme complex to an, as yet, unknown structure of the protein synthesis apparatus. | PART-OF |
| Pharmacology and chemistry of adapalene. BACKGROUND: Retinoid research in the field of dermatology has been influenced by the clinical success of topical CHEMICAL and oral isotretinoin in the treatment of acne, and by the discovery of high-affinity binding proteins for retinoic acid mediating its action and interaction with other vitamins and hormones. OBJECTIVE: We sought molecules with an optimal balance between stability, efficacy, and local tolerance for topical acne therapy. METHODS: In vitro and in vivo bioassay systems were used to test the ability of retinoids to modulate cell proliferation and differentiation. In addition, antiinflammatory properties were assessed. Binding and transactivation assays were used to compare affinities and transcriptional activities of adapalene and CHEMICAL for the GENE, retinoic acid receptors (RARs). RESULTS AND CONCLUSION: Adapalene is a stable naphthoic acid derivative with potent retinoid pharmacology, controlling cell proliferation and differentiation. In addition it has significant antiinflammatory action. The nuclear gene transcription factors RAR beta and RAR gamma mediate the retinoid activity of adapalene. | DIRECT-REGULATOR |
| Pharmacology and chemistry of adapalene. BACKGROUND: Retinoid research in the field of dermatology has been influenced by the clinical success of topical CHEMICAL and oral isotretinoin in the treatment of acne, and by the discovery of high-affinity binding proteins for retinoic acid mediating its action and interaction with other vitamins and hormones. OBJECTIVE: We sought molecules with an optimal balance between stability, efficacy, and local tolerance for topical acne therapy. METHODS: In vitro and in vivo bioassay systems were used to test the ability of retinoids to modulate cell proliferation and differentiation. In addition, antiinflammatory properties were assessed. Binding and transactivation assays were used to compare affinities and transcriptional activities of adapalene and CHEMICAL for the nuclear transcription factors, GENE (RARs). RESULTS AND CONCLUSION: Adapalene is a stable naphthoic acid derivative with potent retinoid pharmacology, controlling cell proliferation and differentiation. In addition it has significant antiinflammatory action. The nuclear gene transcription factors RAR beta and RAR gamma mediate the retinoid activity of adapalene. | DIRECT-REGULATOR |
| Pharmacology and chemistry of adapalene. BACKGROUND: Retinoid research in the field of dermatology has been influenced by the clinical success of topical CHEMICAL and oral isotretinoin in the treatment of acne, and by the discovery of high-affinity binding proteins for retinoic acid mediating its action and interaction with other vitamins and hormones. OBJECTIVE: We sought molecules with an optimal balance between stability, efficacy, and local tolerance for topical acne therapy. METHODS: In vitro and in vivo bioassay systems were used to test the ability of retinoids to modulate cell proliferation and differentiation. In addition, antiinflammatory properties were assessed. Binding and transactivation assays were used to compare affinities and transcriptional activities of adapalene and CHEMICAL for the nuclear transcription factors, retinoic acid receptors (GENE). RESULTS AND CONCLUSION: Adapalene is a stable naphthoic acid derivative with potent retinoid pharmacology, controlling cell proliferation and differentiation. In addition it has significant antiinflammatory action. The nuclear gene transcription factors RAR beta and RAR gamma mediate the retinoid activity of adapalene. | DIRECT-REGULATOR |
| Pharmacology and chemistry of CHEMICAL. BACKGROUND: Retinoid research in the field of dermatology has been influenced by the clinical success of topical tretinoin and oral isotretinoin in the treatment of acne, and by the discovery of high-affinity binding proteins for retinoic acid mediating its action and interaction with other vitamins and hormones. OBJECTIVE: We sought molecules with an optimal balance between stability, efficacy, and local tolerance for topical acne therapy. METHODS: In vitro and in vivo bioassay systems were used to test the ability of retinoids to modulate cell proliferation and differentiation. In addition, antiinflammatory properties were assessed. Binding and transactivation assays were used to compare affinities and transcriptional activities of CHEMICAL and tretinoin for the GENE, retinoic acid receptors (RARs). RESULTS AND CONCLUSION: CHEMICAL is a stable naphthoic acid derivative with potent retinoid pharmacology, controlling cell proliferation and differentiation. In addition it has significant antiinflammatory action. The nuclear gene transcription factors RAR beta and RAR gamma mediate the retinoid activity of CHEMICAL. | DIRECT-REGULATOR |
| Pharmacology and chemistry of CHEMICAL. BACKGROUND: Retinoid research in the field of dermatology has been influenced by the clinical success of topical tretinoin and oral isotretinoin in the treatment of acne, and by the discovery of high-affinity binding proteins for retinoic acid mediating its action and interaction with other vitamins and hormones. OBJECTIVE: We sought molecules with an optimal balance between stability, efficacy, and local tolerance for topical acne therapy. METHODS: In vitro and in vivo bioassay systems were used to test the ability of retinoids to modulate cell proliferation and differentiation. In addition, antiinflammatory properties were assessed. Binding and transactivation assays were used to compare affinities and transcriptional activities of CHEMICAL and tretinoin for the nuclear transcription factors, GENE (RARs). RESULTS AND CONCLUSION: CHEMICAL is a stable naphthoic acid derivative with potent retinoid pharmacology, controlling cell proliferation and differentiation. In addition it has significant antiinflammatory action. The nuclear gene transcription factors RAR beta and RAR gamma mediate the retinoid activity of CHEMICAL. | DIRECT-REGULATOR |
| Pharmacology and chemistry of CHEMICAL. BACKGROUND: Retinoid research in the field of dermatology has been influenced by the clinical success of topical tretinoin and oral isotretinoin in the treatment of acne, and by the discovery of high-affinity binding proteins for retinoic acid mediating its action and interaction with other vitamins and hormones. OBJECTIVE: We sought molecules with an optimal balance between stability, efficacy, and local tolerance for topical acne therapy. METHODS: In vitro and in vivo bioassay systems were used to test the ability of retinoids to modulate cell proliferation and differentiation. In addition, antiinflammatory properties were assessed. Binding and transactivation assays were used to compare affinities and transcriptional activities of CHEMICAL and tretinoin for the nuclear transcription factors, retinoic acid receptors (GENE). RESULTS AND CONCLUSION: CHEMICAL is a stable naphthoic acid derivative with potent retinoid pharmacology, controlling cell proliferation and differentiation. In addition it has significant antiinflammatory action. The nuclear gene transcription factors RAR beta and RAR gamma mediate the retinoid activity of CHEMICAL. | DIRECT-REGULATOR |
| Pharmacology and chemistry of CHEMICAL. BACKGROUND: Retinoid research in the field of dermatology has been influenced by the clinical success of topical tretinoin and oral isotretinoin in the treatment of acne, and by the discovery of high-affinity binding proteins for retinoic acid mediating its action and interaction with other vitamins and hormones. OBJECTIVE: We sought molecules with an optimal balance between stability, efficacy, and local tolerance for topical acne therapy. METHODS: In vitro and in vivo bioassay systems were used to test the ability of retinoids to modulate cell proliferation and differentiation. In addition, antiinflammatory properties were assessed. Binding and transactivation assays were used to compare affinities and transcriptional activities of CHEMICAL and tretinoin for the nuclear transcription factors, retinoic acid receptors (RARs). RESULTS AND CONCLUSION: CHEMICAL is a stable naphthoic acid derivative with potent retinoid pharmacology, controlling cell proliferation and differentiation. In addition it has significant antiinflammatory action. The GENE RAR beta and RAR gamma mediate the retinoid activity of CHEMICAL. | REGULATOR |
| Pharmacology and chemistry of CHEMICAL. BACKGROUND: Retinoid research in the field of dermatology has been influenced by the clinical success of topical tretinoin and oral isotretinoin in the treatment of acne, and by the discovery of high-affinity binding proteins for retinoic acid mediating its action and interaction with other vitamins and hormones. OBJECTIVE: We sought molecules with an optimal balance between stability, efficacy, and local tolerance for topical acne therapy. METHODS: In vitro and in vivo bioassay systems were used to test the ability of retinoids to modulate cell proliferation and differentiation. In addition, antiinflammatory properties were assessed. Binding and transactivation assays were used to compare affinities and transcriptional activities of CHEMICAL and tretinoin for the nuclear transcription factors, retinoic acid receptors (RARs). RESULTS AND CONCLUSION: CHEMICAL is a stable naphthoic acid derivative with potent retinoid pharmacology, controlling cell proliferation and differentiation. In addition it has significant antiinflammatory action. The nuclear gene transcription factors GENE and RAR gamma mediate the retinoid activity of CHEMICAL. | REGULATOR |
| Pharmacology and chemistry of CHEMICAL. BACKGROUND: Retinoid research in the field of dermatology has been influenced by the clinical success of topical tretinoin and oral isotretinoin in the treatment of acne, and by the discovery of high-affinity binding proteins for retinoic acid mediating its action and interaction with other vitamins and hormones. OBJECTIVE: We sought molecules with an optimal balance between stability, efficacy, and local tolerance for topical acne therapy. METHODS: In vitro and in vivo bioassay systems were used to test the ability of retinoids to modulate cell proliferation and differentiation. In addition, antiinflammatory properties were assessed. Binding and transactivation assays were used to compare affinities and transcriptional activities of CHEMICAL and tretinoin for the nuclear transcription factors, retinoic acid receptors (RARs). RESULTS AND CONCLUSION: CHEMICAL is a stable naphthoic acid derivative with potent retinoid pharmacology, controlling cell proliferation and differentiation. In addition it has significant antiinflammatory action. The nuclear gene transcription factors RAR beta and GENE mediate the retinoid activity of CHEMICAL. | REGULATOR |
| Cinitapride protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds. This study was designed to determine the gastroprotective properties of cinitapride (CNT), a novel prokinetic benzamide derivative agonist of 5-HT4 and 5-HT1 receptors and 5-HT2 antagonist, on mucosal injury produced by 50% (v/v) ethanol. Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1). The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CNT were also examined. Intraperitoneal administration of CNT (0.50 and 1 mg kg-1), 30 min before ethanol, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus. CNT (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values. On the contrary, pretreatment with CHEMICAL worsened ethanol-induced erosions, however, did not affect gastric mucus secretion, GENE content or PGE2 levels, although the non-protein SH fraction was significantly decreased. The present results demonstrate that the gastroprotective effects of CNT could be partly explained by a complex PG dependent mechanism. We suggest that CHEMICAL dependent mechanisms through 5-HT2 receptor blockade and 5-HT1 receptor activation could be also involved. | NO-RELATIONSHIP |
| Cinitapride protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds. This study was designed to determine the gastroprotective properties of cinitapride (CNT), a novel prokinetic benzamide derivative agonist of 5-HT4 and 5-HT1 receptors and 5-HT2 antagonist, on mucosal injury produced by 50% (v/v) CHEMICAL. Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1). The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CNT were also examined. Intraperitoneal administration of CNT (0.50 and 1 mg kg-1), 30 min before CHEMICAL, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus. CNT (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values. On the contrary, pretreatment with 5-HT worsened CHEMICAL-induced erosions, however, did not affect gastric mucus secretion, GENE content or PGE2 levels, although the non-protein SH fraction was significantly decreased. The present results demonstrate that the gastroprotective effects of CNT could be partly explained by a complex PG dependent mechanism. We suggest that 5-HT dependent mechanisms through 5-HT2 receptor blockade and 5-HT1 receptor activation could be also involved. | NO-RELATIONSHIP |
| Cinitapride protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds. This study was designed to determine the gastroprotective properties of cinitapride (CNT), a novel prokinetic benzamide derivative agonist of 5-HT4 and 5-HT1 receptors and GENE antagonist, on mucosal injury produced by 50% (v/v) ethanol. Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1). The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CNT were also examined. Intraperitoneal administration of CNT (0.50 and 1 mg kg-1), 30 min before ethanol, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus. CNT (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values. On the contrary, pretreatment with CHEMICAL worsened ethanol-induced erosions, however, did not affect gastric mucus secretion, glycoprotein content or PGE2 levels, although the non-protein SH fraction was significantly decreased. The present results demonstrate that the gastroprotective effects of CNT could be partly explained by a complex PG dependent mechanism. We suggest that CHEMICAL dependent mechanisms through GENE receptor blockade and 5-HT1 receptor activation could be also involved. | REGULATOR |
| Cinitapride protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds. This study was designed to determine the gastroprotective properties of cinitapride (CNT), a novel prokinetic benzamide derivative agonist of 5-HT4 and GENE receptors and 5-HT2 antagonist, on mucosal injury produced by 50% (v/v) ethanol. Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1). The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CNT were also examined. Intraperitoneal administration of CNT (0.50 and 1 mg kg-1), 30 min before ethanol, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus. CNT (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values. On the contrary, pretreatment with CHEMICAL worsened ethanol-induced erosions, however, did not affect gastric mucus secretion, glycoprotein content or PGE2 levels, although the non-protein SH fraction was significantly decreased. The present results demonstrate that the gastroprotective effects of CNT could be partly explained by a complex PG dependent mechanism. We suggest that CHEMICAL dependent mechanisms through 5-HT2 receptor blockade and GENE receptor activation could be also involved. | REGULATOR |
| CHEMICAL protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds. This study was designed to determine the gastroprotective properties of CHEMICAL (CNT), a novel prokinetic benzamide derivative agonist of GENE and 5-HT1 receptors and 5-HT2 antagonist, on mucosal injury produced by 50% (v/v) ethanol. Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1). The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CNT were also examined. Intraperitoneal administration of CNT (0.50 and 1 mg kg-1), 30 min before ethanol, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus. CNT (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values. On the contrary, pretreatment with 5-HT worsened ethanol-induced erosions, however, did not affect gastric mucus secretion, glycoprotein content or PGE2 levels, although the non-protein SH fraction was significantly decreased. The present results demonstrate that the gastroprotective effects of CNT could be partly explained by a complex PG dependent mechanism. We suggest that 5-HT dependent mechanisms through 5-HT2 receptor blockade and 5-HT1 receptor activation could be also involved. | ACTIVATOR |
| CHEMICAL protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds. This study was designed to determine the gastroprotective properties of CHEMICAL (CNT), a novel prokinetic benzamide derivative agonist of 5-HT4 and GENE receptors and 5-HT2 antagonist, on mucosal injury produced by 50% (v/v) ethanol. Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1). The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CNT were also examined. Intraperitoneal administration of CNT (0.50 and 1 mg kg-1), 30 min before ethanol, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus. CNT (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values. On the contrary, pretreatment with 5-HT worsened ethanol-induced erosions, however, did not affect gastric mucus secretion, glycoprotein content or PGE2 levels, although the non-protein SH fraction was significantly decreased. The present results demonstrate that the gastroprotective effects of CNT could be partly explained by a complex PG dependent mechanism. We suggest that 5-HT dependent mechanisms through 5-HT2 receptor blockade and GENE receptor activation could be also involved. | ACTIVATOR |
| Cinitapride protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds. This study was designed to determine the gastroprotective properties of cinitapride (CNT), a novel prokinetic CHEMICAL derivative agonist of GENE and 5-HT1 receptors and 5-HT2 antagonist, on mucosal injury produced by 50% (v/v) ethanol. Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1). The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CNT were also examined. Intraperitoneal administration of CNT (0.50 and 1 mg kg-1), 30 min before ethanol, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus. CNT (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values. On the contrary, pretreatment with 5-HT worsened ethanol-induced erosions, however, did not affect gastric mucus secretion, glycoprotein content or PGE2 levels, although the non-protein SH fraction was significantly decreased. The present results demonstrate that the gastroprotective effects of CNT could be partly explained by a complex PG dependent mechanism. We suggest that 5-HT dependent mechanisms through 5-HT2 receptor blockade and 5-HT1 receptor activation could be also involved. | ACTIVATOR |
| Cinitapride protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds. This study was designed to determine the gastroprotective properties of cinitapride (CNT), a novel prokinetic CHEMICAL derivative agonist of 5-HT4 and GENE receptors and 5-HT2 antagonist, on mucosal injury produced by 50% (v/v) ethanol. Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1). The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CNT were also examined. Intraperitoneal administration of CNT (0.50 and 1 mg kg-1), 30 min before ethanol, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus. CNT (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values. On the contrary, pretreatment with 5-HT worsened ethanol-induced erosions, however, did not affect gastric mucus secretion, glycoprotein content or PGE2 levels, although the non-protein SH fraction was significantly decreased. The present results demonstrate that the gastroprotective effects of CNT could be partly explained by a complex PG dependent mechanism. We suggest that 5-HT dependent mechanisms through 5-HT2 receptor blockade and GENE receptor activation could be also involved. | ACTIVATOR |
| Cinitapride protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds. This study was designed to determine the gastroprotective properties of cinitapride (CHEMICAL), a novel prokinetic benzamide derivative agonist of GENE and 5-HT1 receptors and 5-HT2 antagonist, on mucosal injury produced by 50% (v/v) ethanol. Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1). The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CHEMICAL were also examined. Intraperitoneal administration of CHEMICAL (0.50 and 1 mg kg-1), 30 min before ethanol, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus. CHEMICAL (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values. On the contrary, pretreatment with 5-HT worsened ethanol-induced erosions, however, did not affect gastric mucus secretion, glycoprotein content or PGE2 levels, although the non-protein SH fraction was significantly decreased. The present results demonstrate that the gastroprotective effects of CHEMICAL could be partly explained by a complex PG dependent mechanism. We suggest that 5-HT dependent mechanisms through 5-HT2 receptor blockade and 5-HT1 receptor activation could be also involved. | ACTIVATOR |
| Cinitapride protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds. This study was designed to determine the gastroprotective properties of cinitapride (CHEMICAL), a novel prokinetic benzamide derivative agonist of 5-HT4 and GENE receptors and 5-HT2 antagonist, on mucosal injury produced by 50% (v/v) ethanol. Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1). The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CHEMICAL were also examined. Intraperitoneal administration of CHEMICAL (0.50 and 1 mg kg-1), 30 min before ethanol, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus. CHEMICAL (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values. On the contrary, pretreatment with 5-HT worsened ethanol-induced erosions, however, did not affect gastric mucus secretion, glycoprotein content or PGE2 levels, although the non-protein SH fraction was significantly decreased. The present results demonstrate that the gastroprotective effects of CHEMICAL could be partly explained by a complex PG dependent mechanism. We suggest that 5-HT dependent mechanisms through 5-HT2 receptor blockade and GENE receptor activation could be also involved. | ACTIVATOR |
| CHEMICAL protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds. This study was designed to determine the gastroprotective properties of CHEMICAL (CNT), a novel prokinetic benzamide derivative agonist of 5-HT4 and 5-HT1 receptors and GENE antagonist, on mucosal injury produced by 50% (v/v) ethanol. Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1). The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CNT were also examined. Intraperitoneal administration of CNT (0.50 and 1 mg kg-1), 30 min before ethanol, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus. CNT (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values. On the contrary, pretreatment with 5-HT worsened ethanol-induced erosions, however, did not affect gastric mucus secretion, glycoprotein content or PGE2 levels, although the non-protein SH fraction was significantly decreased. The present results demonstrate that the gastroprotective effects of CNT could be partly explained by a complex PG dependent mechanism. We suggest that 5-HT dependent mechanisms through GENE receptor blockade and 5-HT1 receptor activation could be also involved. | INHIBITOR |
| Cinitapride protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds. This study was designed to determine the gastroprotective properties of cinitapride (CNT), a novel prokinetic CHEMICAL derivative agonist of 5-HT4 and 5-HT1 receptors and GENE antagonist, on mucosal injury produced by 50% (v/v) ethanol. Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1). The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CNT were also examined. Intraperitoneal administration of CNT (0.50 and 1 mg kg-1), 30 min before ethanol, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus. CNT (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values. On the contrary, pretreatment with 5-HT worsened ethanol-induced erosions, however, did not affect gastric mucus secretion, glycoprotein content or PGE2 levels, although the non-protein SH fraction was significantly decreased. The present results demonstrate that the gastroprotective effects of CNT could be partly explained by a complex PG dependent mechanism. We suggest that 5-HT dependent mechanisms through GENE receptor blockade and 5-HT1 receptor activation could be also involved. | INHIBITOR |
| Cinitapride protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds. This study was designed to determine the gastroprotective properties of cinitapride (CHEMICAL), a novel prokinetic benzamide derivative agonist of 5-HT4 and 5-HT1 receptors and GENE antagonist, on mucosal injury produced by 50% (v/v) ethanol. Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1). The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CHEMICAL were also examined. Intraperitoneal administration of CHEMICAL (0.50 and 1 mg kg-1), 30 min before ethanol, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus. CHEMICAL (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values. On the contrary, pretreatment with 5-HT worsened ethanol-induced erosions, however, did not affect gastric mucus secretion, glycoprotein content or PGE2 levels, although the non-protein SH fraction was significantly decreased. The present results demonstrate that the gastroprotective effects of CHEMICAL could be partly explained by a complex PG dependent mechanism. We suggest that 5-HT dependent mechanisms through GENE receptor blockade and 5-HT1 receptor activation could be also involved. | INHIBITOR |
| GENE is a specific partner for the Grb2 isoform Grb3-3. Grb3-3 is an isoform of Grb2, thought to arise by alternative splicing, that lacks a functional SH2 domain but retains functional SH3 domains, which allow interaction with other proteins through binding to prolinerich sequences. Several evidences suggest that besides common partners for Grb2 and Grb3-3, specific targets could exist. In order to find specific partners for Grb3-3, we have screened a human cDNA library by the yeast two-hybrid system with Grb3-3 as a bait. We have identified GENE, an enzyme involved in CHEMICAL metabolism whose deficiency is associated with severe combined immunodeficiency, as a Grb3-3 binding protein that is not able to bind to Grb2. This interaction has been confirmed in vitro with GST fusion proteins and in vivo by coimmunoprecipitation experiments in NIH3T3 cells stably transfected with Grb3-3. The functional significance of this finding is discussed. | SUBSTRATE |
| CHEMICAL inhibition of protein-tyrosine-phosphatase-meg1. CHEMICAL (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis. Its molecular mechanism of action, however, has not been defined precisely. Here we report that alendronate is a potent inhibitor of the protein-tyrosine-phosphatase-meg1 (PTPmeg1). Two substrates were employed in this study: fluorescein diphosphate and the phosphotyrosyl peptide src-pY527. With either substrate, alendronate was a slow binding inhibitor of PTPmeg1. Among the other bisphosphonates studied, alendronate was more potent and selective for PTPmeg1. The hydrolysis of fluorescein diphosphate by GENE and PTPmeg1 was sensitive to alendronate, with IC50 values of less than 1 microM; PTPsigma, however, under the same conditions, was inhibited by only 50% with 141 microM alendronate. Similarly, with the src-pY527 substrate, alendronate inhibition was also PTP dependent. CHEMICAL inhibited PTPmeg1 with an IC50 value of 23 microM, PTPsigma with an IC50 value of 2 microM, and did not inhibit GENE at concentrations up to 1 mM. The alendronate inhibition of these three PTPs and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor. PTP inhibition by hisphosphonates or vanadate was diminished by the metal chelating agent EDTA, or by the reducing agent dithiothreitol, suggesting that a metal ion and the oxidation of a cysteine residue are required for full inhibition. These observations show substrate- and enzyme-specific PTP inhibition by alendronate and support the possibility that a certain PTP(s) may be the molecular target for alendronate action. | NO-RELATIONSHIP |
| Alendronate inhibition of protein-tyrosine-phosphatase-meg1. Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis. Its molecular mechanism of action, however, has not been defined precisely. Here we report that alendronate is a potent inhibitor of the protein-tyrosine-phosphatase-meg1 (PTPmeg1). Two substrates were employed in this study: fluorescein diphosphate and the phosphotyrosyl peptide src-pY527. With either substrate, alendronate was a slow binding inhibitor of PTPmeg1. Among the other bisphosphonates studied, alendronate was more potent and selective for PTPmeg1. The hydrolysis of fluorescein diphosphate by GENE epsilon and PTPmeg1 was sensitive to alendronate, with IC50 values of less than 1 microM; PTPsigma, however, under the same conditions, was inhibited by only 50% with 141 microM alendronate. Similarly, with the src-pY527 substrate, alendronate inhibition was also GENE dependent. Alendronate inhibited PTPmeg1 with an IC50 value of 23 microM, PTPsigma with an IC50 value of 2 microM, and did not inhibit GENE epsilon at concentrations up to 1 mM. The alendronate inhibition of these three PTPs and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor. GENE inhibition by hisphosphonates or vanadate was diminished by the metal chelating agent EDTA, or by the reducing agent dithiothreitol, suggesting that a metal ion and the oxidation of a CHEMICAL residue are required for full inhibition. These observations show substrate- and enzyme-specific GENE inhibition by alendronate and support the possibility that a certain PTP(s) may be the molecular target for alendronate action. | PART-OF |
| CHEMICAL inhibition of protein-tyrosine-phosphatase-meg1. CHEMICAL (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis. Its molecular mechanism of action, however, has not been defined precisely. Here we report that CHEMICAL is a potent inhibitor of the protein-tyrosine-phosphatase-meg1 (PTPmeg1). Two substrates were employed in this study: fluorescein diphosphate and the phosphotyrosyl peptide src-pY527. With either substrate, CHEMICAL was a slow binding inhibitor of PTPmeg1. Among the other bisphosphonates studied, CHEMICAL was more potent and selective for PTPmeg1. The hydrolysis of fluorescein diphosphate by GENE epsilon and PTPmeg1 was sensitive to CHEMICAL, with IC50 values of less than 1 microM; PTPsigma, however, under the same conditions, was inhibited by only 50% with 141 microM CHEMICAL. Similarly, with the src-pY527 substrate, CHEMICAL inhibition was also GENE dependent. CHEMICAL inhibited PTPmeg1 with an IC50 value of 23 microM, PTPsigma with an IC50 value of 2 microM, and did not inhibit GENE epsilon at concentrations up to 1 mM. The CHEMICAL inhibition of these three PTPs and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor. GENE inhibition by hisphosphonates or vanadate was diminished by the metal chelating agent EDTA, or by the reducing agent dithiothreitol, suggesting that a metal ion and the oxidation of a cysteine residue are required for full inhibition. These observations show substrate- and enzyme-specific GENE inhibition by CHEMICAL and support the possibility that a certain GENE(s) may be the molecular target for CHEMICAL action. | REGULATOR |
| CHEMICAL inhibition of protein-tyrosine-phosphatase-meg1. CHEMICAL (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis. Its molecular mechanism of action, however, has not been defined precisely. Here we report that CHEMICAL is a potent inhibitor of the protein-tyrosine-phosphatase-meg1 (PTPmeg1). Two substrates were employed in this study: fluorescein diphosphate and the phosphotyrosyl peptide src-pY527. With either substrate, CHEMICAL was a slow binding inhibitor of PTPmeg1. Among the other bisphosphonates studied, CHEMICAL was more potent and selective for PTPmeg1. The hydrolysis of fluorescein diphosphate by GENE and PTPmeg1 was sensitive to CHEMICAL, with IC50 values of less than 1 microM; PTPsigma, however, under the same conditions, was inhibited by only 50% with 141 microM CHEMICAL. Similarly, with the src-pY527 substrate, CHEMICAL inhibition was also PTP dependent. CHEMICAL inhibited PTPmeg1 with an IC50 value of 23 microM, PTPsigma with an IC50 value of 2 microM, and did not inhibit GENE at concentrations up to 1 mM. The CHEMICAL inhibition of these three PTPs and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor. PTP inhibition by hisphosphonates or vanadate was diminished by the metal chelating agent EDTA, or by the reducing agent dithiothreitol, suggesting that a metal ion and the oxidation of a cysteine residue are required for full inhibition. These observations show substrate- and enzyme-specific PTP inhibition by CHEMICAL and support the possibility that a certain PTP(s) may be the molecular target for CHEMICAL action. | NO-RELATIONSHIP |
| CHEMICAL inhibition of protein-tyrosine-phosphatase-meg1. CHEMICAL (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis. Its molecular mechanism of action, however, has not been defined precisely. Here we report that CHEMICAL is a potent inhibitor of the protein-tyrosine-phosphatase-meg1 (PTPmeg1). Two substrates were employed in this study: fluorescein diphosphate and the phosphotyrosyl peptide src-pY527. With either substrate, CHEMICAL was a slow binding inhibitor of GENE. Among the other bisphosphonates studied, CHEMICAL was more potent and selective for GENE. The hydrolysis of fluorescein diphosphate by PTP epsilon and GENE was sensitive to CHEMICAL, with IC50 values of less than 1 microM; PTPsigma, however, under the same conditions, was inhibited by only 50% with 141 microM CHEMICAL. Similarly, with the src-pY527 substrate, CHEMICAL inhibition was also PTP dependent. CHEMICAL inhibited GENE with an IC50 value of 23 microM, PTPsigma with an IC50 value of 2 microM, and did not inhibit PTP epsilon at concentrations up to 1 mM. The CHEMICAL inhibition of these three PTPs and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor. PTP inhibition by hisphosphonates or vanadate was diminished by the metal chelating agent EDTA, or by the reducing agent dithiothreitol, suggesting that a metal ion and the oxidation of a cysteine residue are required for full inhibition. These observations show substrate- and enzyme-specific PTP inhibition by CHEMICAL and support the possibility that a certain PTP(s) may be the molecular target for CHEMICAL action. | REGULATOR |
| Alendronate inhibition of protein-tyrosine-phosphatase-meg1. Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis. Its molecular mechanism of action, however, has not been defined precisely. Here we report that alendronate is a potent inhibitor of the protein-tyrosine-phosphatase-meg1 (PTPmeg1). Two substrates were employed in this study: fluorescein diphosphate and the phosphotyrosyl peptide src-pY527. With either substrate, alendronate was a slow binding inhibitor of PTPmeg1. Among the other bisphosphonates studied, alendronate was more potent and selective for PTPmeg1. The hydrolysis of fluorescein diphosphate by GENE epsilon and PTPmeg1 was sensitive to alendronate, with IC50 values of less than 1 microM; PTPsigma, however, under the same conditions, was inhibited by only 50% with 141 microM alendronate. Similarly, with the src-pY527 substrate, alendronate inhibition was also GENE dependent. Alendronate inhibited PTPmeg1 with an IC50 value of 23 microM, PTPsigma with an IC50 value of 2 microM, and did not inhibit GENE epsilon at concentrations up to 1 mM. The alendronate inhibition of these three PTPs and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor. GENE inhibition by hisphosphonates or vanadate was diminished by the metal chelating agent CHEMICAL, or by the reducing agent dithiothreitol, suggesting that a metal ion and the oxidation of a cysteine residue are required for full inhibition. These observations show substrate- and enzyme-specific GENE inhibition by alendronate and support the possibility that a certain PTP(s) may be the molecular target for alendronate action. | INHIBITOR |
| Alendronate inhibition of protein-tyrosine-phosphatase-meg1. Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis. Its molecular mechanism of action, however, has not been defined precisely. Here we report that alendronate is a potent inhibitor of the protein-tyrosine-phosphatase-meg1 (PTPmeg1). Two substrates were employed in this study: fluorescein diphosphate and the phosphotyrosyl peptide src-pY527. With either substrate, alendronate was a slow binding inhibitor of PTPmeg1. Among the other bisphosphonates studied, alendronate was more potent and selective for PTPmeg1. The hydrolysis of fluorescein diphosphate by GENE epsilon and PTPmeg1 was sensitive to alendronate, with IC50 values of less than 1 microM; PTPsigma, however, under the same conditions, was inhibited by only 50% with 141 microM alendronate. Similarly, with the src-pY527 substrate, alendronate inhibition was also GENE dependent. Alendronate inhibited PTPmeg1 with an IC50 value of 23 microM, PTPsigma with an IC50 value of 2 microM, and did not inhibit GENE epsilon at concentrations up to 1 mM. The alendronate inhibition of these three PTPs and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor. GENE inhibition by hisphosphonates or vanadate was diminished by the metal chelating agent EDTA, or by the reducing agent CHEMICAL, suggesting that a metal ion and the oxidation of a cysteine residue are required for full inhibition. These observations show substrate- and enzyme-specific GENE inhibition by alendronate and support the possibility that a certain PTP(s) may be the molecular target for alendronate action. | INHIBITOR |
| CHEMICAL inhibition of GENE. CHEMICAL (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis. Its molecular mechanism of action, however, has not been defined precisely. Here we report that CHEMICAL is a potent inhibitor of the GENE (PTPmeg1). Two substrates were employed in this study: fluorescein diphosphate and the phosphotyrosyl peptide src-pY527. With either substrate, CHEMICAL was a slow binding inhibitor of PTPmeg1. Among the other bisphosphonates studied, CHEMICAL was more potent and selective for PTPmeg1. The hydrolysis of fluorescein diphosphate by PTP epsilon and PTPmeg1 was sensitive to CHEMICAL, with IC50 values of less than 1 microM; PTPsigma, however, under the same conditions, was inhibited by only 50% with 141 microM CHEMICAL. Similarly, with the src-pY527 substrate, CHEMICAL inhibition was also PTP dependent. CHEMICAL inhibited PTPmeg1 with an IC50 value of 23 microM, PTPsigma with an IC50 value of 2 microM, and did not inhibit PTP epsilon at concentrations up to 1 mM. The CHEMICAL inhibition of these three PTPs and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor. PTP inhibition by hisphosphonates or vanadate was diminished by the metal chelating agent EDTA, or by the reducing agent dithiothreitol, suggesting that a metal ion and the oxidation of a cysteine residue are required for full inhibition. These observations show substrate- and enzyme-specific PTP inhibition by CHEMICAL and support the possibility that a certain PTP(s) may be the molecular target for CHEMICAL action. | INHIBITOR |
| Alendronate inhibition of protein-tyrosine-phosphatase-meg1. Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis. Its molecular mechanism of action, however, has not been defined precisely. Here we report that alendronate is a potent inhibitor of the protein-tyrosine-phosphatase-meg1 (PTPmeg1). Two substrates were employed in this study: fluorescein diphosphate and the phosphotyrosyl peptide src-pY527. With either substrate, alendronate was a slow binding inhibitor of GENE. Among the other CHEMICAL studied, alendronate was more potent and selective for GENE. The hydrolysis of fluorescein diphosphate by PTP epsilon and GENE was sensitive to alendronate, with IC50 values of less than 1 microM; PTPsigma, however, under the same conditions, was inhibited by only 50% with 141 microM alendronate. Similarly, with the src-pY527 substrate, alendronate inhibition was also PTP dependent. Alendronate inhibited GENE with an IC50 value of 23 microM, PTPsigma with an IC50 value of 2 microM, and did not inhibit PTP epsilon at concentrations up to 1 mM. The alendronate inhibition of these three PTPs and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor. PTP inhibition by hisphosphonates or vanadate was diminished by the metal chelating agent EDTA, or by the reducing agent dithiothreitol, suggesting that a metal ion and the oxidation of a cysteine residue are required for full inhibition. These observations show substrate- and enzyme-specific PTP inhibition by alendronate and support the possibility that a certain PTP(s) may be the molecular target for alendronate action. | REGULATOR |
| CHEMICAL inhibition of protein-tyrosine-phosphatase-meg1. CHEMICAL (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis. Its molecular mechanism of action, however, has not been defined precisely. Here we report that CHEMICAL is a potent inhibitor of the protein-tyrosine-phosphatase-meg1 (PTPmeg1). Two substrates were employed in this study: fluorescein diphosphate and the phosphotyrosyl peptide src-pY527. With either substrate, CHEMICAL was a slow binding inhibitor of PTPmeg1. Among the other bisphosphonates studied, CHEMICAL was more potent and selective for PTPmeg1. The hydrolysis of fluorescein diphosphate by PTP epsilon and PTPmeg1 was sensitive to CHEMICAL, with IC50 values of less than 1 microM; GENE, however, under the same conditions, was inhibited by only 50% with 141 microM CHEMICAL. Similarly, with the src-pY527 substrate, CHEMICAL inhibition was also PTP dependent. CHEMICAL inhibited PTPmeg1 with an IC50 value of 23 microM, GENE with an IC50 value of 2 microM, and did not inhibit PTP epsilon at concentrations up to 1 mM. The CHEMICAL inhibition of these three PTPs and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor. PTP inhibition by hisphosphonates or vanadate was diminished by the metal chelating agent EDTA, or by the reducing agent dithiothreitol, suggesting that a metal ion and the oxidation of a cysteine residue are required for full inhibition. These observations show substrate- and enzyme-specific PTP inhibition by CHEMICAL and support the possibility that a certain PTP(s) may be the molecular target for CHEMICAL action. | INHIBITOR |
| CHEMICAL inhibition of protein-tyrosine-phosphatase-meg1. CHEMICAL (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis. Its molecular mechanism of action, however, has not been defined precisely. Here we report that alendronate is a potent inhibitor of the protein-tyrosine-phosphatase-meg1 (PTPmeg1). Two substrates were employed in this study: fluorescein diphosphate and the phosphotyrosyl peptide src-pY527. With either substrate, alendronate was a slow binding inhibitor of GENE. Among the other bisphosphonates studied, alendronate was more potent and selective for GENE. The hydrolysis of fluorescein diphosphate by PTP epsilon and GENE was sensitive to alendronate, with IC50 values of less than 1 microM; PTPsigma, however, under the same conditions, was inhibited by only 50% with 141 microM alendronate. Similarly, with the src-pY527 substrate, alendronate inhibition was also PTP dependent. CHEMICAL inhibited GENE with an IC50 value of 23 microM, PTPsigma with an IC50 value of 2 microM, and did not inhibit PTP epsilon at concentrations up to 1 mM. The alendronate inhibition of these three PTPs and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor. PTP inhibition by hisphosphonates or vanadate was diminished by the metal chelating agent EDTA, or by the reducing agent dithiothreitol, suggesting that a metal ion and the oxidation of a cysteine residue are required for full inhibition. These observations show substrate- and enzyme-specific PTP inhibition by alendronate and support the possibility that a certain PTP(s) may be the molecular target for alendronate action. | INHIBITOR |
| CHEMICAL inhibition of protein-tyrosine-phosphatase-meg1. CHEMICAL (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis. Its molecular mechanism of action, however, has not been defined precisely. Here we report that alendronate is a potent inhibitor of the protein-tyrosine-phosphatase-meg1 (PTPmeg1). Two substrates were employed in this study: fluorescein diphosphate and the phosphotyrosyl peptide src-pY527. With either substrate, alendronate was a slow binding inhibitor of PTPmeg1. Among the other bisphosphonates studied, alendronate was more potent and selective for PTPmeg1. The hydrolysis of fluorescein diphosphate by PTP epsilon and PTPmeg1 was sensitive to alendronate, with IC50 values of less than 1 microM; GENE, however, under the same conditions, was inhibited by only 50% with 141 microM alendronate. Similarly, with the src-pY527 substrate, alendronate inhibition was also PTP dependent. CHEMICAL inhibited PTPmeg1 with an IC50 value of 23 microM, GENE with an IC50 value of 2 microM, and did not inhibit PTP epsilon at concentrations up to 1 mM. The alendronate inhibition of these three PTPs and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor. PTP inhibition by hisphosphonates or vanadate was diminished by the metal chelating agent EDTA, or by the reducing agent dithiothreitol, suggesting that a metal ion and the oxidation of a cysteine residue are required for full inhibition. These observations show substrate- and enzyme-specific PTP inhibition by alendronate and support the possibility that a certain PTP(s) may be the molecular target for alendronate action. | INHIBITOR |
| CHEMICAL inhibition of protein-tyrosine-phosphatase-meg1. CHEMICAL (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis. Its molecular mechanism of action, however, has not been defined precisely. Here we report that CHEMICAL is a potent inhibitor of the protein-tyrosine-phosphatase-meg1 (PTPmeg1). Two substrates were employed in this study: fluorescein diphosphate and the phosphotyrosyl peptide src-pY527. With either substrate, CHEMICAL was a slow binding inhibitor of PTPmeg1. Among the other bisphosphonates studied, CHEMICAL was more potent and selective for PTPmeg1. The hydrolysis of fluorescein diphosphate by PTP epsilon and PTPmeg1 was sensitive to CHEMICAL, with IC50 values of less than 1 microM; PTPsigma, however, under the same conditions, was inhibited by only 50% with 141 microM CHEMICAL. Similarly, with the src-pY527 substrate, CHEMICAL inhibition was also PTP dependent. CHEMICAL inhibited PTPmeg1 with an IC50 value of 23 microM, PTPsigma with an IC50 value of 2 microM, and did not inhibit PTP epsilon at concentrations up to 1 mM. The CHEMICAL inhibition of these three GENE and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor. PTP inhibition by hisphosphonates or vanadate was diminished by the metal chelating agent EDTA, or by the reducing agent dithiothreitol, suggesting that a metal ion and the oxidation of a cysteine residue are required for full inhibition. These observations show substrate- and enzyme-specific PTP inhibition by CHEMICAL and support the possibility that a certain PTP(s) may be the molecular target for CHEMICAL action. | INHIBITOR |
| Alendronate inhibition of protein-tyrosine-phosphatase-meg1. Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis. Its molecular mechanism of action, however, has not been defined precisely. Here we report that alendronate is a potent inhibitor of the protein-tyrosine-phosphatase-meg1 (PTPmeg1). Two substrates were employed in this study: fluorescein diphosphate and the phosphotyrosyl peptide src-pY527. With either substrate, alendronate was a slow binding inhibitor of PTPmeg1. Among the other bisphosphonates studied, alendronate was more potent and selective for PTPmeg1. The hydrolysis of fluorescein diphosphate by GENE epsilon and PTPmeg1 was sensitive to alendronate, with IC50 values of less than 1 microM; PTPsigma, however, under the same conditions, was inhibited by only 50% with 141 microM alendronate. Similarly, with the src-pY527 substrate, alendronate inhibition was also GENE dependent. Alendronate inhibited PTPmeg1 with an IC50 value of 23 microM, PTPsigma with an IC50 value of 2 microM, and did not inhibit GENE epsilon at concentrations up to 1 mM. The alendronate inhibition of these three PTPs and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor. GENE inhibition by CHEMICAL or vanadate was diminished by the metal chelating agent EDTA, or by the reducing agent dithiothreitol, suggesting that a metal ion and the oxidation of a cysteine residue are required for full inhibition. These observations show substrate- and enzyme-specific GENE inhibition by alendronate and support the possibility that a certain PTP(s) may be the molecular target for alendronate action. | INHIBITOR |
| Alendronate inhibition of protein-tyrosine-phosphatase-meg1. Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis. Its molecular mechanism of action, however, has not been defined precisely. Here we report that alendronate is a potent inhibitor of the protein-tyrosine-phosphatase-meg1 (PTPmeg1). Two substrates were employed in this study: fluorescein diphosphate and the phosphotyrosyl peptide src-pY527. With either substrate, alendronate was a slow binding inhibitor of PTPmeg1. Among the other bisphosphonates studied, alendronate was more potent and selective for PTPmeg1. The hydrolysis of fluorescein diphosphate by GENE epsilon and PTPmeg1 was sensitive to alendronate, with IC50 values of less than 1 microM; PTPsigma, however, under the same conditions, was inhibited by only 50% with 141 microM alendronate. Similarly, with the src-pY527 substrate, alendronate inhibition was also GENE dependent. Alendronate inhibited PTPmeg1 with an IC50 value of 23 microM, PTPsigma with an IC50 value of 2 microM, and did not inhibit GENE epsilon at concentrations up to 1 mM. The alendronate inhibition of these three PTPs and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor. GENE inhibition by hisphosphonates or CHEMICAL was diminished by the metal chelating agent EDTA, or by the reducing agent dithiothreitol, suggesting that a metal ion and the oxidation of a cysteine residue are required for full inhibition. These observations show substrate- and enzyme-specific GENE inhibition by alendronate and support the possibility that a certain PTP(s) may be the molecular target for alendronate action. | INHIBITOR |
| Alendronate inhibition of protein-tyrosine-phosphatase-meg1. Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis. Its molecular mechanism of action, however, has not been defined precisely. Here we report that alendronate is a potent inhibitor of the protein-tyrosine-phosphatase-meg1 (PTPmeg1). Two substrates were employed in this study: fluorescein CHEMICAL and the phosphotyrosyl peptide src-pY527. With either substrate, alendronate was a slow binding inhibitor of PTPmeg1. Among the other bisphosphonates studied, alendronate was more potent and selective for PTPmeg1. The hydrolysis of fluorescein CHEMICAL by GENE and PTPmeg1 was sensitive to alendronate, with IC50 values of less than 1 microM; PTPsigma, however, under the same conditions, was inhibited by only 50% with 141 microM alendronate. Similarly, with the src-pY527 substrate, alendronate inhibition was also PTP dependent. Alendronate inhibited PTPmeg1 with an IC50 value of 23 microM, PTPsigma with an IC50 value of 2 microM, and did not inhibit GENE at concentrations up to 1 mM. The alendronate inhibition of these three PTPs and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor. PTP inhibition by hisphosphonates or vanadate was diminished by the metal chelating agent EDTA, or by the reducing agent dithiothreitol, suggesting that a metal ion and the oxidation of a cysteine residue are required for full inhibition. These observations show substrate- and enzyme-specific PTP inhibition by alendronate and support the possibility that a certain PTP(s) may be the molecular target for alendronate action. | SUBSTRATE |
| Alendronate inhibition of protein-tyrosine-phosphatase-meg1. Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is a potent bisphosphonate that inhibits osteoclastic bone resorption and has proven effective for the treatment of osteoporosis. Its molecular mechanism of action, however, has not been defined precisely. Here we report that alendronate is a potent inhibitor of the protein-tyrosine-phosphatase-meg1 (PTPmeg1). Two substrates were employed in this study: fluorescein CHEMICAL and the phosphotyrosyl peptide src-pY527. With either substrate, alendronate was a slow binding inhibitor of GENE. Among the other bisphosphonates studied, alendronate was more potent and selective for GENE. The hydrolysis of fluorescein CHEMICAL by PTP epsilon and GENE was sensitive to alendronate, with IC50 values of less than 1 microM; PTPsigma, however, under the same conditions, was inhibited by only 50% with 141 microM alendronate. Similarly, with the src-pY527 substrate, alendronate inhibition was also PTP dependent. Alendronate inhibited GENE with an IC50 value of 23 microM, PTPsigma with an IC50 value of 2 microM, and did not inhibit PTP epsilon at concentrations up to 1 mM. The alendronate inhibition of these three PTPs and two substrates is consistent with the formation of a ternary complex comprised of enzyme, substrate, and inhibitor. PTP inhibition by hisphosphonates or vanadate was diminished by the metal chelating agent EDTA, or by the reducing agent dithiothreitol, suggesting that a metal ion and the oxidation of a cysteine residue are required for full inhibition. These observations show substrate- and enzyme-specific PTP inhibition by alendronate and support the possibility that a certain PTP(s) may be the molecular target for alendronate action. | SUBSTRATE |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and GENE subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and GENE receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by CHEMICAL, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the GENE receptor, and by 1-OH-PGE1 that bound to the GENE but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | NO-RELATIONSHIP |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and GENE subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and GENE receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, CHEMICAL and AH-6809 that bound to the EP2 receptor but not to the GENE receptor, and by 1-OH-PGE1 that bound to the GENE but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | NO-RELATIONSHIP |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and GENE subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and GENE receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and CHEMICAL that bound to the EP2 receptor but not to the GENE receptor, and by 1-OH-PGE1 that bound to the GENE but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | NO-RELATIONSHIP |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, GENE, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The GENE and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the GENE receptor but not to the EP4 receptor, and by CHEMICAL that bound to the EP4 but not to the GENE receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, GENE and EP3 receptor at 10 microM concentration. | NO-RELATIONSHIP |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the GENE, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The GENE receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. CHEMICAL and two putative GENE antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, CHEMICAL and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | INHIBITOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the GENE, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The GENE receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative GENE antagonists, CHEMICAL and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | INHIBITOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the GENE, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The GENE receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative GENE antagonists, AH6809 and CHEMICAL, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | INHIBITOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, GENE, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The GENE and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by CHEMICAL, AH-13205 and AH-6809 that bound to the GENE receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the GENE receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, GENE and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, GENE, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The GENE and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, CHEMICAL and AH-6809 that bound to the GENE receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the GENE receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, GENE and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, GENE, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The GENE and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and CHEMICAL that bound to the GENE receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the GENE receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, GENE and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and GENE subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and GENE receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the GENE receptor, and by CHEMICAL that bound to the GENE but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, GENE and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, CHEMICAL and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative GENE agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The GENE receptor showed the broadest binding profile, and bound CHEMICAL, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and GENE receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, GENE and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and CHEMICAL bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. CHEMICAL, a putative GENE agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The GENE receptor showed the broadest binding profile, and bound sulprostone, CHEMICAL, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and GENE receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, GENE and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative GENE agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The GENE receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, CHEMICAL, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and GENE receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, GENE and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative GENE agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and CHEMICAL in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The GENE receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, CHEMICAL, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and GENE receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, GENE and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. CHEMICAL and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative GENE agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The GENE receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, CHEMICAL and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and GENE receptor at 10 microM concentration. | NO-RELATIONSHIP |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, GENE and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, CHEMICAL, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound CHEMICAL, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative GENE agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The GENE receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and CHEMICAL, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and GENE receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the GENE, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, CHEMICAL, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The GENE receptor bound CHEMICAL, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative GENE antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and CHEMICAL, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, GENE and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, CHEMICAL and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to CHEMICAL and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative GENE agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl CHEMICAL and 11-deoxy-PGE1 in addition to CHEMICAL and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The GENE receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to CHEMICAL and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and GENE receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, GENE and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and CHEMICAL, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative GENE agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and CHEMICAL. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The GENE receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and CHEMICAL, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and GENE receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, GENE and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, CHEMICAL and isocabacyclin for GENE, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and CHEMICAL in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three GENE ligands, CHEMICAL, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the GENE and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the GENE, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, GENE and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for GENE, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three GENE ligands, iloprost, CHEMICAL and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the GENE and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the GENE, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, GENE and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for GENE, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three GENE ligands, iloprost, carbacyclin and CHEMICAL, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the GENE and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the GENE, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and GENE receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for GENE. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, CHEMICAL, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one GENE ligand, CHEMICAL, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and GENE receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, GENE, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the GENE, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The GENE receptor bound 17-phenyl-PGE2, CHEMICAL and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative GENE antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound CHEMICAL, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, GENE and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative GENE agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The GENE receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. CHEMICAL alpha showed only weak binding to the IP, TP, FP, EP2 and GENE receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, GENE and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for GENE, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three GENE ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the GENE and TP receptors, respectively. CHEMICAL alpha showed only weak binding to the GENE, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and GENE receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for GENE. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one GENE ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and GENE receptors, respectively. CHEMICAL alpha showed only weak binding to the IP, GENE, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The GENE receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. CHEMICAL alpha showed only weak binding to the IP, TP, GENE, EP2 and EP3 receptor at 10 microM concentration. | SUBSTRATE |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, GENE, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The GENE and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the GENE receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the GENE receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. CHEMICAL alpha showed only weak binding to the IP, TP, FP, GENE and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the GENE, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, CHEMICAL and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The GENE receptor bound 17-phenyl-PGE2, sulprostone and CHEMICAL in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative GENE antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, CHEMICAL, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The GENE, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as CHEMICAL, BW245C and BW868C for GENE, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, CHEMICAL, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The GENE, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, CHEMICAL and BW868C for GENE, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The GENE, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and CHEMICAL for GENE, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, GENE and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, CHEMICAL, iloprost and isocabacyclin for GENE, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three GENE ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the GENE and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the GENE, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, GENE and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and CHEMICAL for GENE, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three GENE ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the GENE and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the GENE, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the GENE, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, CHEMICAL and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The GENE receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to CHEMICAL and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative GENE antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl CHEMICAL and 11-deoxy-PGE1 in addition to CHEMICAL and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to CHEMICAL and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and GENE receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and CHEMICAL, I-BOP and GR 32191 for GENE. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one GENE ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and GENE receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, GENE, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and GENE receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, CHEMICAL and GR 32191 for GENE. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, CHEMICAL, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one GENE ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and GENE receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, GENE, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and GENE receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and CHEMICAL for GENE. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one GENE ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and GENE receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, GENE, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The GENE bound CHEMICAL alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The GENE bound PGF2 alpha and CHEMICAL with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the GENE, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The GENE receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and CHEMICAL, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative GENE antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and CHEMICAL. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and CHEMICAL, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 microM concentration. | DIRECT-REGULATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, GENE, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative EP3 agonist, and CHEMICAL, a putative GENE/EP3 agonist, also bound to this receptor with Ki values of 120 nM. 5. The GENE and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the GENE receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the GENE receptor. 6. The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, GENE and EP3 receptor at 10 microM concentration. | ACTIVATOR |
| Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. 1. Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, GENE and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors. 2. The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S-145, I-BOP and GR 32191 for TP. 3. The FP receptor bound PGF2 alpha and fluprostenol with Ki values of 3-4 nM. In addition, PGD2, 17-phenyl-PGE2, STA2, I-BOP, PGE2 and M&B-28767 bound to this receptor with Ki values less than 100 nM. 4. The EP1 receptor bound 17-phenyl-PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14-36 nM. 16,16-dimethyl-PGE2 and two putative EP1 antagonists, AH6809 and SC-19220, did not show any significant binding to this receptor. M&B-28767, a putative GENE agonist, and CHEMICAL, a putative EP2/GENE agonist, also bound to this receptor with Ki values of 120 nM. 5. The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16-dimethyl PGE2 and 11-deoxy-PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH-13205 and AH-6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1-OH-PGE1 that bound to the EP4 but not to the EP2 receptor. 6. The GENE receptor showed the broadest binding profile, and bound sulprostone, M&B-28767, GR63799X, 11-deoxy-PGE1, 16,16-dimethyl-PGE2 and 17-phenyl-PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6-3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively. 7. 8-Epi-PGF2 alpha showed only weak binding to the IP, TP, FP, EP2 and GENE receptor at 10 microM concentration. | ACTIVATOR |
| The structures of thymidine kinase from herpes simplex virus type 1 in complex with substrates and a substrate analogue. Thymidine kinase from Herpes simplex virus type 1 (GENE) was crystallized in an CHEMICAL-terminally truncated but fully active form. The structures of GENE complexed with ADP at the ATP-site and deoxythymidine-5'-monophosphate (dTMP), deoxythymidine (dT), or idoxuridine-5'-phosphate (5-iodo-dUMP) at the substrate-site were refined to 2.75 A, 2.8 A, and 3.0 A resolution, respectively. GENE catalyzes the phosphorylation of dT resulting in an ester, and the phosphorylation of dTMP giving rise to an anhydride. The presented GENE structures indicate that there are only small differences between these two modes of action. Glu83 serves as a general base in the ester reaction. Arg163 parks at an internal aspartate during ester formation and binds the alpha-phosphate of dTMP during anhydride formation. The bound deoxythymidine leaves a 35 A3 cavity at position 5 of the base and two sequestered water molecules at position 2. Cavity and water molecules reduce the substrate specificity to such an extent that GENE can phosphorylate various substrate analogues useful in pharmaceutical applications. GENE is structurally homologous to the well-known nucleoside monophosphate kinases but contains large additional peptide segments. | PART-OF |
| The structures of thymidine kinase from herpes simplex virus type 1 in complex with substrates and a substrate analogue. Thymidine kinase from Herpes simplex virus type 1 (TK) was crystallized in an N-terminally truncated but fully active form. The structures of GENE complexed with CHEMICAL at the ATP-site and deoxythymidine-5'-monophosphate (dTMP), deoxythymidine (dT), or idoxuridine-5'-phosphate (5-iodo-dUMP) at the substrate-site were refined to 2.75 A, 2.8 A, and 3.0 A resolution, respectively. GENE catalyzes the phosphorylation of dT resulting in an ester, and the phosphorylation of dTMP giving rise to an anhydride. The presented GENE structures indicate that there are only small differences between these two modes of action. Glu83 serves as a general base in the ester reaction. Arg163 parks at an internal aspartate during ester formation and binds the alpha-phosphate of dTMP during anhydride formation. The bound deoxythymidine leaves a 35 A3 cavity at position 5 of the base and two sequestered water molecules at position 2. Cavity and water molecules reduce the substrate specificity to such an extent that GENE can phosphorylate various substrate analogues useful in pharmaceutical applications. GENE is structurally homologous to the well-known nucleoside monophosphate kinases but contains large additional peptide segments. | DIRECT-REGULATOR |
| The structures of thymidine kinase from herpes simplex virus type 1 in complex with substrates and a substrate analogue. GENE from Herpes simplex virus type 1 (TK) was crystallized in an CHEMICAL-terminally truncated but fully active form. The structures of TK complexed with ADP at the ATP-site and deoxythymidine-5'-monophosphate (dTMP), deoxythymidine (dT), or idoxuridine-5'-phosphate (5-iodo-dUMP) at the substrate-site were refined to 2.75 A, 2.8 A, and 3.0 A resolution, respectively. TK catalyzes the phosphorylation of dT resulting in an ester, and the phosphorylation of dTMP giving rise to an anhydride. The presented TK structures indicate that there are only small differences between these two modes of action. Glu83 serves as a general base in the ester reaction. Arg163 parks at an internal aspartate during ester formation and binds the alpha-phosphate of dTMP during anhydride formation. The bound deoxythymidine leaves a 35 A3 cavity at position 5 of the base and two sequestered water molecules at position 2. Cavity and water molecules reduce the substrate specificity to such an extent that TK can phosphorylate various substrate analogues useful in pharmaceutical applications. TK is structurally homologous to the well-known nucleoside monophosphate kinases but contains large additional peptide segments. | PART-OF |
| Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent CHEMICAL. CHEMICAL, a gastrointestinal prokinetic agent, is known to cause long Q-T syndrome and ventricular arrhythmias. The cellular mechanism is not known. The GENE (HERG), which encodes the rapidly activating delayed rectifier K+ current and is important in cardiac repolarization, may serve as a target for the action of CHEMICAL. We tested the hypothesis that CHEMICAL blocks HERG. The whole cell patch-clamp recording technique was used to study HERG channels stably expressed heterologously in HEK293 cells. Under voltage-clamp conditions, CHEMICAL block of HERG is dose dependent with a half-maximal inhibitory concentration of 6.5 nM at 22 degrees C (n = 25 cells). Currents rapidly recovered with drug washout. The onset of block by CHEMICAL required channel activation indicative of open or inactivated state blockage. Block of HERG with CHEMICAL after channel activation was voltage dependent. At -20 mV, 10 nM CHEMICAL reduced HERG tail-current amplitude by 5%, whereas, at + 20 mV, the tail-current amplitude was reduced by 45% (n = 4 cells). At -20 and + 20 mV, 100 nM CHEMICAL reduced tail-current amplitude by 66 and 90%, respectively. We conclude that CHEMICAL is a potent blocker of HERG channels expressed in HEK293 cells. This effect may account for the clinical occurrence of Q-T prolongation and ventricular arrhythmias observed with CHEMICAL. | REGULATOR |
| Blockage of the GENE human cardiac K+ channel by the gastrointestinal prokinetic agent CHEMICAL. CHEMICAL, a gastrointestinal prokinetic agent, is known to cause long Q-T syndrome and ventricular arrhythmias. The cellular mechanism is not known. The human ether-a-go-go-related gene (GENE), which encodes the rapidly activating delayed rectifier K+ current and is important in cardiac repolarization, may serve as a target for the action of CHEMICAL. We tested the hypothesis that CHEMICAL blocks GENE. The whole cell patch-clamp recording technique was used to study GENE channels stably expressed heterologously in HEK293 cells. Under voltage-clamp conditions, CHEMICAL block of GENE is dose dependent with a half-maximal inhibitory concentration of 6.5 nM at 22 degrees C (n = 25 cells). Currents rapidly recovered with drug washout. The onset of block by CHEMICAL required channel activation indicative of open or inactivated state blockage. Block of GENE with CHEMICAL after channel activation was voltage dependent. At -20 mV, 10 nM CHEMICAL reduced GENE tail-current amplitude by 5%, whereas, at + 20 mV, the tail-current amplitude was reduced by 45% (n = 4 cells). At -20 and + 20 mV, 100 nM CHEMICAL reduced tail-current amplitude by 66 and 90%, respectively. We conclude that CHEMICAL is a potent blocker of GENE channels expressed in HEK293 cells. This effect may account for the clinical occurrence of Q-T prolongation and ventricular arrhythmias observed with CHEMICAL. | REGULATOR |
| Blockage of the GENE by the gastrointestinal prokinetic agent CHEMICAL. CHEMICAL, a gastrointestinal prokinetic agent, is known to cause long Q-T syndrome and ventricular arrhythmias. The cellular mechanism is not known. The human ether-a-go-go-related gene (HERG), which encodes the rapidly activating delayed rectifier K+ current and is important in cardiac repolarization, may serve as a target for the action of CHEMICAL. We tested the hypothesis that CHEMICAL blocks HERG. The whole cell patch-clamp recording technique was used to study HERG channels stably expressed heterologously in HEK293 cells. Under voltage-clamp conditions, CHEMICAL block of HERG is dose dependent with a half-maximal inhibitory concentration of 6.5 nM at 22 degrees C (n = 25 cells). Currents rapidly recovered with drug washout. The onset of block by CHEMICAL required channel activation indicative of open or inactivated state blockage. Block of HERG with CHEMICAL after channel activation was voltage dependent. At -20 mV, 10 nM CHEMICAL reduced HERG tail-current amplitude by 5%, whereas, at + 20 mV, the tail-current amplitude was reduced by 45% (n = 4 cells). At -20 and + 20 mV, 100 nM CHEMICAL reduced tail-current amplitude by 66 and 90%, respectively. We conclude that CHEMICAL is a potent blocker of HERG channels expressed in HEK293 cells. This effect may account for the clinical occurrence of Q-T prolongation and ventricular arrhythmias observed with CHEMICAL. | INHIBITOR |
| Analysis of GENE in the human spinal cord. GENE in postmortem human spinal cord were analyzed using CHEMICAL ligand binding and immunoblotting with NMDA receptor subunit-specific antibodies. The average KD for CHEMICAL binding was 1.77 nM with a Bmax of 0.103 pmol/mg. The EC50 for stimulation of -3H-MK-801 binding with L-glutamate was 0.34 microM. None of these parameters were affected by postmortem intervals up to 72 h. Immunoblotting of native GENE showed that NR1, NR2A, NR2C, and NR2D subunits could all be found in the human spinal cord of which NR1 was preferentially located to the dorsal half. Immunoprecipitation of solubilized receptors revealed that NR1, NR2C, and NR2D subunits coprecipitated with the NR2A subunit, indicating that native human spinal cord GENE are heteroligimeric receptors assembled by at least three different receptor subunits. These results provide a basis for the development of drugs selectively aimed at spinal cord GENE for the future treatment of spinal cord disorders. | DIRECT-REGULATOR |
| GENE and sodium channel mechanisms in the rapid pressor response to CHEMICAL. Intravenous (I.V.) CHEMICAL (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390. Monoamine uptake inhibitors structurally analogous to CHEMICAL (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse monoamine transporter selectivities (BTCP, indatraline, GBR 12935, mazindol, nomifensine, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the sodium channel blockers acetylprocainamide, dibucaine, dyclonine, prilocaine, proparacaine, quinidine, and tetracaine produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, CHEMICAL and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both CHEMICAL and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to CHEMICAL. The sodium channel-blocking action of CHEMICAL per se does not appear to be involved in the rapid pressor response to CHEMICAL. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by CHEMICAL. | REGULATOR |
| Monoamine transporter and GENE mechanisms in the rapid pressor response to CHEMICAL. Intravenous (I.V.) CHEMICAL (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390. Monoamine uptake inhibitors structurally analogous to CHEMICAL (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse monoamine transporter selectivities (BTCP, indatraline, GBR 12935, mazindol, nomifensine, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the GENE blockers acetylprocainamide, dibucaine, dyclonine, prilocaine, proparacaine, quinidine, and tetracaine produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, CHEMICAL and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both CHEMICAL and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to CHEMICAL. The sodium channel-blocking action of CHEMICAL per se does not appear to be involved in the rapid pressor response to CHEMICAL. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by CHEMICAL. | REGULATOR |
| GENE and sodium channel mechanisms in the rapid pressor response to cocaine. Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390. Monoamine uptake inhibitors structurally analogous to cocaine (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse GENE selectivities (CHEMICAL, indatraline, GBR 12935, mazindol, nomifensine, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the sodium channel blockers acetylprocainamide, dibucaine, dyclonine, prilocaine, proparacaine, quinidine, and tetracaine produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, cocaine and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both cocaine and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to cocaine. The sodium channel-blocking action of cocaine per se does not appear to be involved in the rapid pressor response to cocaine. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by cocaine. | INHIBITOR |
| GENE and sodium channel mechanisms in the rapid pressor response to cocaine. Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390. Monoamine uptake inhibitors structurally analogous to cocaine (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse GENE selectivities (BTCP, CHEMICAL, GBR 12935, mazindol, nomifensine, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the sodium channel blockers acetylprocainamide, dibucaine, dyclonine, prilocaine, proparacaine, quinidine, and tetracaine produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, cocaine and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both cocaine and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to cocaine. The sodium channel-blocking action of cocaine per se does not appear to be involved in the rapid pressor response to cocaine. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by cocaine. | INHIBITOR |
| GENE and sodium channel mechanisms in the rapid pressor response to cocaine. Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390. Monoamine uptake inhibitors structurally analogous to cocaine (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse GENE selectivities (BTCP, indatraline, CHEMICAL, mazindol, nomifensine, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the sodium channel blockers acetylprocainamide, dibucaine, dyclonine, prilocaine, proparacaine, quinidine, and tetracaine produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, cocaine and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both cocaine and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to cocaine. The sodium channel-blocking action of cocaine per se does not appear to be involved in the rapid pressor response to cocaine. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by cocaine. | INHIBITOR |
| GENE and sodium channel mechanisms in the rapid pressor response to cocaine. Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390. Monoamine uptake inhibitors structurally analogous to cocaine (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse GENE selectivities (BTCP, indatraline, GBR 12935, CHEMICAL, nomifensine, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the sodium channel blockers acetylprocainamide, dibucaine, dyclonine, prilocaine, proparacaine, quinidine, and tetracaine produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, cocaine and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both cocaine and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to cocaine. The sodium channel-blocking action of cocaine per se does not appear to be involved in the rapid pressor response to cocaine. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by cocaine. | INHIBITOR |
| GENE and sodium channel mechanisms in the rapid pressor response to cocaine. Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390. Monoamine uptake inhibitors structurally analogous to cocaine (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse GENE selectivities (BTCP, indatraline, GBR 12935, mazindol, CHEMICAL, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the sodium channel blockers acetylprocainamide, dibucaine, dyclonine, prilocaine, proparacaine, quinidine, and tetracaine produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, cocaine and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both cocaine and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to cocaine. The sodium channel-blocking action of cocaine per se does not appear to be involved in the rapid pressor response to cocaine. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by cocaine. | INHIBITOR |
| GENE and sodium channel mechanisms in the rapid pressor response to cocaine. Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390. Monoamine uptake inhibitors structurally analogous to cocaine (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse GENE selectivities (BTCP, indatraline, GBR 12935, mazindol, nomifensine, and CHEMICAL) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the sodium channel blockers acetylprocainamide, dibucaine, dyclonine, prilocaine, proparacaine, quinidine, and tetracaine produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, cocaine and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both cocaine and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to cocaine. The sodium channel-blocking action of cocaine per se does not appear to be involved in the rapid pressor response to cocaine. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by cocaine. | INHIBITOR |
| Monoamine transporter and GENE mechanisms in the rapid pressor response to cocaine. Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390. Monoamine uptake inhibitors structurally analogous to cocaine (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse monoamine transporter selectivities (BTCP, indatraline, GBR 12935, mazindol, nomifensine, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the GENE blockers CHEMICAL, dibucaine, dyclonine, prilocaine, proparacaine, quinidine, and tetracaine produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, cocaine and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both cocaine and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to cocaine. The sodium channel-blocking action of cocaine per se does not appear to be involved in the rapid pressor response to cocaine. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by cocaine. | INHIBITOR |
| Monoamine transporter and GENE mechanisms in the rapid pressor response to cocaine. Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390. Monoamine uptake inhibitors structurally analogous to cocaine (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse monoamine transporter selectivities (BTCP, indatraline, GBR 12935, mazindol, nomifensine, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the GENE blockers acetylprocainamide, CHEMICAL, dyclonine, prilocaine, proparacaine, quinidine, and tetracaine produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, cocaine and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both cocaine and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to cocaine. The sodium channel-blocking action of cocaine per se does not appear to be involved in the rapid pressor response to cocaine. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by cocaine. | INHIBITOR |
| Monoamine transporter and GENE mechanisms in the rapid pressor response to cocaine. Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390. Monoamine uptake inhibitors structurally analogous to cocaine (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse monoamine transporter selectivities (BTCP, indatraline, GBR 12935, mazindol, nomifensine, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the GENE blockers acetylprocainamide, dibucaine, CHEMICAL, prilocaine, proparacaine, quinidine, and tetracaine produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, cocaine and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both cocaine and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to cocaine. The sodium channel-blocking action of cocaine per se does not appear to be involved in the rapid pressor response to cocaine. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by cocaine. | INHIBITOR |
| Monoamine transporter and GENE mechanisms in the rapid pressor response to cocaine. Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390. Monoamine uptake inhibitors structurally analogous to cocaine (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse monoamine transporter selectivities (BTCP, indatraline, GBR 12935, mazindol, nomifensine, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the GENE blockers acetylprocainamide, dibucaine, dyclonine, CHEMICAL, proparacaine, quinidine, and tetracaine produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, cocaine and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both cocaine and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to cocaine. The sodium channel-blocking action of cocaine per se does not appear to be involved in the rapid pressor response to cocaine. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by cocaine. | INHIBITOR |
| Monoamine transporter and GENE mechanisms in the rapid pressor response to cocaine. Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390. Monoamine uptake inhibitors structurally analogous to cocaine (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse monoamine transporter selectivities (BTCP, indatraline, GBR 12935, mazindol, nomifensine, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the GENE blockers acetylprocainamide, dibucaine, dyclonine, prilocaine, CHEMICAL, quinidine, and tetracaine produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, cocaine and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both cocaine and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to cocaine. The sodium channel-blocking action of cocaine per se does not appear to be involved in the rapid pressor response to cocaine. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by cocaine. | INHIBITOR |
| Monoamine transporter and GENE mechanisms in the rapid pressor response to cocaine. Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390. Monoamine uptake inhibitors structurally analogous to cocaine (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse monoamine transporter selectivities (BTCP, indatraline, GBR 12935, mazindol, nomifensine, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the GENE blockers acetylprocainamide, dibucaine, dyclonine, prilocaine, proparacaine, CHEMICAL, and tetracaine produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, cocaine and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both cocaine and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to cocaine. The sodium channel-blocking action of cocaine per se does not appear to be involved in the rapid pressor response to cocaine. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by cocaine. | INHIBITOR |
| Monoamine transporter and GENE mechanisms in the rapid pressor response to cocaine. Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the dopamine receptor antagonist, SCH 23390. Monoamine uptake inhibitors structurally analogous to cocaine (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse monoamine transporter selectivities (BTCP, indatraline, GBR 12935, mazindol, nomifensine, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the GENE blockers acetylprocainamide, dibucaine, dyclonine, prilocaine, proparacaine, quinidine, and CHEMICAL produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, cocaine and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with SCH 23390 prevented the prolonged but not the initial rapid and brief pressor and activity responses to both cocaine and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to cocaine. The sodium channel-blocking action of cocaine per se does not appear to be involved in the rapid pressor response to cocaine. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by cocaine. | INHIBITOR |
| Monoamine transporter and sodium channel mechanisms in the rapid pressor response to cocaine. Intravenous (I.V.) cocaine (0.03-3 mg/kg) produced dose-dependent, rapid, and brief increases in blood pressure (BP) in conscious rats pretreated with the GENE antagonist, CHEMICAL. Monoamine uptake inhibitors structurally analogous to cocaine (cocaethylene, CFT, betaCIT, CPT, (+)-cocaine, norcocaine, and benztropine) also produced this rapid pressor response, whereas structurally unrelated uptake inhibitors with diverse monoamine transporter selectivities (BTCP, indatraline, GBR 12935, mazindol, nomifensine, and zimeldine) either did not produce a rapid pressor response or produced only a small pressor response. At nonconvulsant doses, the sodium channel blockers acetylprocainamide, dibucaine, dyclonine, prilocaine, proparacaine, quinidine, and tetracaine produced a small pressor response or no increase in BP. In rats implanted with telemetric devices, cocaine and its analog, CFT, produced a biphasic pharmacological response that consisted of an initial brief and abrupt behavioral arousal associated with a rapid, large increase in BP followed by prolonged, parallel increases in BP and locomotor activity. Pretreatment with CHEMICAL prevented the prolonged but not the initial rapid and brief pressor and activity responses to both cocaine and CFT administration. The present data suggest that the inhibition of dopamine, norepinephrine, or serotonin transporter functions, either alone or in combination, does not mediate the rapid pressor response to cocaine. The sodium channel-blocking action of cocaine per se does not appear to be involved in the rapid pressor response to cocaine. Finally, the present results confirm previous findings that dopaminergic mechanisms mediate the prolonged increases in BP and locomotor activity produced by cocaine. | INHIBITOR |
| Characterization of binding sites of a new neurotensin receptor antagonist, [3H]SR 142948A, in the rat brain. The present study describes the characterization of the binding properties and autoradiographic distribution of a new nonpeptide antagonist of neurotensin receptors, [3H]SR 142948A (2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methyl carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]-amino]-ad amantane-2-carboxylic acid, hydrochloride), in the rat brain. The binding of [3H]SR 142948A in brain membrane homogenates was specific, time-dependent, reversible and saturable. [3H]SR 142948A bound to an apparently homogeneous population of sites, with a Kd of 3.5 nM and a Bmax value of 508 fmol/mg of protein, which was 80% higher than that observed in saturation experiments with [3H]neurotensin. [3H]SR 142948A binding was inhibited by SR 142948A, the related nonpeptide receptor antagonist, SR 48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]-adamantane-2-carboxylic acid) and neurotensin. Saturation and competition studies in the presence or absence of the histamine H1 receptor antagonist, CHEMICAL, revealed that [3H]SR 142948A bound with similar affinities to both the CHEMICAL-insensitive GENE (20% of the total binding population) and the recently cloned levocabastine-sensitive neurotensin NT2 receptors (80% of the receptors) (Kd = 6.8 and 4.8 nM, respectively). The regional distribution of [3H]SR 142948A binding in the rat brain closely matched the distribution of [125I]neurotensin binding. In conclusion, these findings indicate that [3H]SR 142948A is a new potent antagonist radioligand which recognizes with high affinity both neurotensin NT1 and NT2 receptors and represents thus an excellent tool to study neurotensin receptors in the rat brain. | NO-RELATIONSHIP |
| Characterization of binding sites of a new neurotensin receptor antagonist, CHEMICAL, in the rat brain. The present study describes the characterization of the binding properties and autoradiographic distribution of a new nonpeptide antagonist of neurotensin receptors, CHEMICAL (2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methyl carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]-amino]-ad amantane-2-carboxylic acid, hydrochloride), in the rat brain. The binding of CHEMICAL in brain membrane homogenates was specific, time-dependent, reversible and saturable. CHEMICAL bound to an apparently homogeneous population of sites, with a Kd of 3.5 nM and a Bmax value of 508 fmol/mg of protein, which was 80% higher than that observed in saturation experiments with [3H]neurotensin. CHEMICAL binding was inhibited by SR 142948A, the related nonpeptide receptor antagonist, SR 48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]-adamantane-2-carboxylic acid) and neurotensin. Saturation and competition studies in the presence or absence of the histamine H1 receptor antagonist, levocabastine, revealed that CHEMICAL bound with similar affinities to both the levocabastine-insensitive GENE receptors (20% of the total binding population) and the recently cloned levocabastine-sensitive neurotensin NT2 receptors (80% of the receptors) (Kd = 6.8 and 4.8 nM, respectively). The regional distribution of CHEMICAL binding in the rat brain closely matched the distribution of [125I]neurotensin binding. In conclusion, these findings indicate that CHEMICAL is a new potent antagonist radioligand which recognizes with high affinity both GENE and NT2 receptors and represents thus an excellent tool to study neurotensin receptors in the rat brain. | DIRECT-REGULATOR |
| Characterization of binding sites of a new neurotensin receptor antagonist, CHEMICAL, in the rat brain. The present study describes the characterization of the binding properties and autoradiographic distribution of a new nonpeptide antagonist of neurotensin receptors, CHEMICAL (2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methyl carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]-amino]-ad amantane-2-carboxylic acid, hydrochloride), in the rat brain. The binding of CHEMICAL in brain membrane homogenates was specific, time-dependent, reversible and saturable. CHEMICAL bound to an apparently homogeneous population of sites, with a Kd of 3.5 nM and a Bmax value of 508 fmol/mg of protein, which was 80% higher than that observed in saturation experiments with [3H]neurotensin. CHEMICAL binding was inhibited by SR 142948A, the related nonpeptide receptor antagonist, SR 48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]-adamantane-2-carboxylic acid) and neurotensin. Saturation and competition studies in the presence or absence of the histamine H1 receptor antagonist, levocabastine, revealed that CHEMICAL bound with similar affinities to both the levocabastine-insensitive neurotensin NT1 receptors (20% of the total binding population) and the recently cloned levocabastine-sensitive neurotensin GENE (80% of the receptors) (Kd = 6.8 and 4.8 nM, respectively). The regional distribution of CHEMICAL binding in the rat brain closely matched the distribution of [125I]neurotensin binding. In conclusion, these findings indicate that CHEMICAL is a new potent antagonist radioligand which recognizes with high affinity both neurotensin NT1 and GENE and represents thus an excellent tool to study neurotensin receptors in the rat brain. | DIRECT-REGULATOR |
| Characterization of binding sites of a new neurotensin receptor antagonist, CHEMICAL, in the rat brain. The present study describes the characterization of the binding properties and autoradiographic distribution of a new nonpeptide antagonist of neurotensin receptors, CHEMICAL (2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methyl carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]-amino]-ad amantane-2-carboxylic acid, hydrochloride), in the rat brain. The binding of CHEMICAL in brain membrane homogenates was specific, time-dependent, reversible and saturable. CHEMICAL bound to an apparently homogeneous population of sites, with a Kd of 3.5 nM and a Bmax value of 508 fmol/mg of protein, which was 80% higher than that observed in saturation experiments with [3H]neurotensin. CHEMICAL binding was inhibited by SR 142948A, the related nonpeptide receptor antagonist, SR 48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]-adamantane-2-carboxylic acid) and neurotensin. Saturation and competition studies in the presence or absence of the histamine H1 receptor antagonist, levocabastine, revealed that CHEMICAL bound with similar affinities to both the levocabastine-insensitive GENE (20% of the total binding population) and the recently cloned levocabastine-sensitive neurotensin NT2 receptors (80% of the receptors) (Kd = 6.8 and 4.8 nM, respectively). The regional distribution of CHEMICAL binding in the rat brain closely matched the distribution of [125I]neurotensin binding. In conclusion, these findings indicate that CHEMICAL is a new potent antagonist radioligand which recognizes with high affinity both neurotensin NT1 and NT2 receptors and represents thus an excellent tool to study neurotensin receptors in the rat brain. | DIRECT-REGULATOR |
| Characterization of binding sites of a new neurotensin receptor antagonist, CHEMICAL, in the rat brain. The present study describes the characterization of the binding properties and autoradiographic distribution of a new nonpeptide antagonist of neurotensin receptors, CHEMICAL (2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methyl carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]-amino]-ad amantane-2-carboxylic acid, hydrochloride), in the rat brain. The binding of CHEMICAL in brain membrane homogenates was specific, time-dependent, reversible and saturable. CHEMICAL bound to an apparently homogeneous population of sites, with a Kd of 3.5 nM and a Bmax value of 508 fmol/mg of protein, which was 80% higher than that observed in saturation experiments with [3H]neurotensin. CHEMICAL binding was inhibited by SR 142948A, the related nonpeptide receptor antagonist, SR 48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]-adamantane-2-carboxylic acid) and neurotensin. Saturation and competition studies in the presence or absence of the histamine H1 receptor antagonist, levocabastine, revealed that CHEMICAL bound with similar affinities to both the levocabastine-insensitive neurotensin NT1 receptors (20% of the total binding population) and the recently cloned levocabastine-sensitive GENE (80% of the receptors) (Kd = 6.8 and 4.8 nM, respectively). The regional distribution of CHEMICAL binding in the rat brain closely matched the distribution of [125I]neurotensin binding. In conclusion, these findings indicate that CHEMICAL is a new potent antagonist radioligand which recognizes with high affinity both neurotensin NT1 and NT2 receptors and represents thus an excellent tool to study neurotensin receptors in the rat brain. | DIRECT-REGULATOR |
| Characterization of binding sites of a new neurotensin receptor antagonist, CHEMICAL, in the rat brain. The present study describes the characterization of the binding properties and autoradiographic distribution of a new nonpeptide antagonist of GENE, CHEMICAL (2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methyl carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]-amino]-ad amantane-2-carboxylic acid, hydrochloride), in the rat brain. The binding of CHEMICAL in brain membrane homogenates was specific, time-dependent, reversible and saturable. CHEMICAL bound to an apparently homogeneous population of sites, with a Kd of 3.5 nM and a Bmax value of 508 fmol/mg of protein, which was 80% higher than that observed in saturation experiments with [3H]neurotensin. CHEMICAL binding was inhibited by SR 142948A, the related nonpeptide receptor antagonist, SR 48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]-adamantane-2-carboxylic acid) and neurotensin. Saturation and competition studies in the presence or absence of the histamine H1 receptor antagonist, levocabastine, revealed that CHEMICAL bound with similar affinities to both the levocabastine-insensitive neurotensin NT1 receptors (20% of the total binding population) and the recently cloned levocabastine-sensitive neurotensin NT2 receptors (80% of the receptors) (Kd = 6.8 and 4.8 nM, respectively). The regional distribution of CHEMICAL binding in the rat brain closely matched the distribution of [125I]neurotensin binding. In conclusion, these findings indicate that CHEMICAL is a new potent antagonist radioligand which recognizes with high affinity both neurotensin NT1 and NT2 receptors and represents thus an excellent tool to study GENE in the rat brain. | INHIBITOR |
| Characterization of binding sites of a new neurotensin receptor antagonist, [3H]SR 142948A, in the rat brain. The present study describes the characterization of the binding properties and autoradiographic distribution of a new nonpeptide antagonist of neurotensin receptors, [3H]SR 142948A (2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methyl carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]-amino]-ad amantane-2-carboxylic acid, hydrochloride), in the rat brain. The binding of [3H]SR 142948A in brain membrane homogenates was specific, time-dependent, reversible and saturable. [3H]SR 142948A bound to an apparently homogeneous population of sites, with a Kd of 3.5 nM and a Bmax value of 508 fmol/mg of protein, which was 80% higher than that observed in saturation experiments with [3H]neurotensin. [3H]SR 142948A binding was inhibited by SR 142948A, the related nonpeptide receptor antagonist, SR 48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]-adamantane-2-carboxylic acid) and neurotensin. Saturation and competition studies in the presence or absence of the histamine H1 receptor antagonist, CHEMICAL, revealed that [3H]SR 142948A bound with similar affinities to both the levocabastine-insensitive neurotensin NT1 receptors (20% of the total binding population) and the recently cloned CHEMICAL-sensitive GENE (80% of the receptors) (Kd = 6.8 and 4.8 nM, respectively). The regional distribution of [3H]SR 142948A binding in the rat brain closely matched the distribution of [125I]neurotensin binding. In conclusion, these findings indicate that [3H]SR 142948A is a new potent antagonist radioligand which recognizes with high affinity both neurotensin NT1 and NT2 receptors and represents thus an excellent tool to study neurotensin receptors in the rat brain. | ACTIVATOR |
| Characterization of binding sites of a new neurotensin receptor antagonist, [3H]SR 142948A, in the rat brain. The present study describes the characterization of the binding properties and autoradiographic distribution of a new nonpeptide antagonist of GENE, [3H]SR 142948A (CHEMICAL), in the rat brain. The binding of [3H]SR 142948A in brain membrane homogenates was specific, time-dependent, reversible and saturable. [3H]SR 142948A bound to an apparently homogeneous population of sites, with a Kd of 3.5 nM and a Bmax value of 508 fmol/mg of protein, which was 80% higher than that observed in saturation experiments with [3H]neurotensin. [3H]SR 142948A binding was inhibited by SR 142948A, the related nonpeptide receptor antagonist, SR 48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]-adamantane-2-carboxylic acid) and neurotensin. Saturation and competition studies in the presence or absence of the histamine H1 receptor antagonist, levocabastine, revealed that [3H]SR 142948A bound with similar affinities to both the levocabastine-insensitive neurotensin NT1 receptors (20% of the total binding population) and the recently cloned levocabastine-sensitive neurotensin NT2 receptors (80% of the receptors) (Kd = 6.8 and 4.8 nM, respectively). The regional distribution of [3H]SR 142948A binding in the rat brain closely matched the distribution of [125I]neurotensin binding. In conclusion, these findings indicate that [3H]SR 142948A is a new potent antagonist radioligand which recognizes with high affinity both neurotensin NT1 and NT2 receptors and represents thus an excellent tool to study GENE in the rat brain. | INHIBITOR |
| Characterization of binding sites of a new GENE antagonist, CHEMICAL, in the rat brain. The present study describes the characterization of the binding properties and autoradiographic distribution of a new nonpeptide antagonist of neurotensin receptors, CHEMICAL (2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methyl carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]-amino]-ad amantane-2-carboxylic acid, hydrochloride), in the rat brain. The binding of CHEMICAL in brain membrane homogenates was specific, time-dependent, reversible and saturable. CHEMICAL bound to an apparently homogeneous population of sites, with a Kd of 3.5 nM and a Bmax value of 508 fmol/mg of protein, which was 80% higher than that observed in saturation experiments with [3H]neurotensin. CHEMICAL binding was inhibited by SR 142948A, the related nonpeptide receptor antagonist, SR 48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]-adamantane-2-carboxylic acid) and neurotensin. Saturation and competition studies in the presence or absence of the histamine H1 receptor antagonist, levocabastine, revealed that CHEMICAL bound with similar affinities to both the levocabastine-insensitive neurotensin NT1 receptors (20% of the total binding population) and the recently cloned levocabastine-sensitive neurotensin NT2 receptors (80% of the receptors) (Kd = 6.8 and 4.8 nM, respectively). The regional distribution of CHEMICAL binding in the rat brain closely matched the distribution of [125I]neurotensin binding. In conclusion, these findings indicate that CHEMICAL is a new potent antagonist radioligand which recognizes with high affinity both neurotensin NT1 and NT2 receptors and represents thus an excellent tool to study neurotensin receptors in the rat brain. | INHIBITOR |
| Characterization of binding sites of a new neurotensin receptor antagonist, [3H]SR 142948A, in the rat brain. The present study describes the characterization of the binding properties and autoradiographic distribution of a new nonpeptide antagonist of neurotensin receptors, [3H]SR 142948A (2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methyl carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]-amino]-ad amantane-2-carboxylic acid, hydrochloride), in the rat brain. The binding of [3H]SR 142948A in brain membrane homogenates was specific, time-dependent, reversible and saturable. [3H]SR 142948A bound to an apparently homogeneous population of sites, with a Kd of 3.5 nM and a Bmax value of 508 fmol/mg of protein, which was 80% higher than that observed in saturation experiments with [3H]neurotensin. [3H]SR 142948A binding was inhibited by SR 142948A, the related nonpeptide receptor antagonist, SR 48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]-adamantane-2-carboxylic acid) and neurotensin. Saturation and competition studies in the presence or absence of the GENE antagonist, CHEMICAL, revealed that [3H]SR 142948A bound with similar affinities to both the levocabastine-insensitive neurotensin NT1 receptors (20% of the total binding population) and the recently cloned levocabastine-sensitive neurotensin NT2 receptors (80% of the receptors) (Kd = 6.8 and 4.8 nM, respectively). The regional distribution of [3H]SR 142948A binding in the rat brain closely matched the distribution of [125I]neurotensin binding. In conclusion, these findings indicate that [3H]SR 142948A is a new potent antagonist radioligand which recognizes with high affinity both neurotensin NT1 and NT2 receptors and represents thus an excellent tool to study neurotensin receptors in the rat brain. | INHIBITOR |
| A new concept of drug delivery for acne. Adapalene is a stable naphthoic acid derivative that displays a strong CHEMICAL agonist pharmacology. This drug controls cell proliferation and differentiation, and possesses significant anti-inflammatory action. The CHEMICAL action of adapalene are mediated by the ligand-activated gene transcription factors retinoic acid receptors GENE and RAR gamma. We describe here how an aqueous gel containing adapalene was selected for the topical treatment of acne. | REGULATOR |
| A new concept of drug delivery for acne. Adapalene is a stable naphthoic acid derivative that displays a strong CHEMICAL agonist pharmacology. This drug controls cell proliferation and differentiation, and possesses significant anti-inflammatory action. The CHEMICAL action of adapalene are mediated by the ligand-activated gene transcription factors retinoic acid receptors RAR beta and GENE. We describe here how an aqueous gel containing adapalene was selected for the topical treatment of acne. | ACTIVATOR |
| A new concept of drug delivery for acne. Adapalene is a stable naphthoic acid derivative that displays a strong CHEMICAL agonist pharmacology. This drug controls cell proliferation and differentiation, and possesses significant anti-inflammatory action. The CHEMICAL action of adapalene are mediated by the GENE retinoic acid receptors RAR beta and RAR gamma. We describe here how an aqueous gel containing adapalene was selected for the topical treatment of acne. | REGULATOR |
| A new concept of drug delivery for acne. CHEMICAL is a stable naphthoic acid derivative that displays a strong retinoid agonist pharmacology. This drug controls cell proliferation and differentiation, and possesses significant anti-inflammatory action. The retinoid action of CHEMICAL are mediated by the ligand-activated gene transcription factors retinoic acid receptors GENE and RAR gamma. We describe here how an aqueous gel containing CHEMICAL was selected for the topical treatment of acne. | REGULATOR |
| A new concept of drug delivery for acne. CHEMICAL is a stable naphthoic acid derivative that displays a strong retinoid agonist pharmacology. This drug controls cell proliferation and differentiation, and possesses significant anti-inflammatory action. The retinoid action of CHEMICAL are mediated by the ligand-activated gene transcription factors retinoic acid receptors RAR beta and GENE. We describe here how an aqueous gel containing CHEMICAL was selected for the topical treatment of acne. | REGULATOR |
| A new concept of drug delivery for acne. CHEMICAL is a stable naphthoic acid derivative that displays a strong retinoid agonist pharmacology. This drug controls cell proliferation and differentiation, and possesses significant anti-inflammatory action. The retinoid action of CHEMICAL are mediated by the GENE retinoic acid receptors RAR beta and RAR gamma. We describe here how an aqueous gel containing CHEMICAL was selected for the topical treatment of acne. | REGULATOR |
| Isoform-specific inhibition of L-type calcium channels by dihydropyridines is independent of isoform-specific gating properties. Dihydropyridines (DHPs) block L-type Ca2+ channels more potently at depolarized membrane potentials, consistent with high affinity binding to the inactivated state. Nisoldipine (a CHEMICAL antagonist) blocks the smooth muscle channel more potently than the cardiac one, a phenomenon observed not only in native channels but also in expressed channels. We examined whether this tissue specificity was attributable to differences of inactivation in the two channel types. We expressed cardiac or smooth muscle alpha1C subunits in combination with beta2a and alpha2/delta subunits in human embryonic kidney cells, and used 2 mM Ca2+ as the permeant ion. This system thus reproduces the in vivo topology and charge carrier of the channels while facilitating comparison of the two alpha1C splice variants. Both voltage-dependent and isoform-specific sensitivity of 10 nM nisoldipine inhibition of the channel were demonstrated, with the use of -100 mV as the holding potential for fully reprimed channels and -65 mV to populate the inactivated state. Under drug-free conditions, we characterized fast inactivation (1-sec prepulses) and slow inactivation (3 min prepulses) in the two isoforms. Inactivation parameters were not statistically different in the two channel isoforms; if anything, cardiac channels tended to inactivate more than the smooth muscle channels at relevant voltages. Likewise, the voltage-dependent activation was identical in the two isoforms. We thus conclude that the more potent nisoldipine inhibition of smooth muscle versus cardiac L-type Ca2+ channels is not attributable to differences in channel inactivation or activation. Intrinsic, gating-independent GENE binding affinity differences must be invoked to explain the isoform-specific sensitivity of the CHEMICAL block. | DIRECT-REGULATOR |
| Isoform-specific inhibition of L-type calcium channels by dihydropyridines is independent of isoform-specific gating properties. Dihydropyridines (DHPs) block L-type CHEMICAL channels more potently at depolarized membrane potentials, consistent with high affinity binding to the inactivated state. Nisoldipine (a DHP antagonist) blocks the smooth muscle channel more potently than the cardiac one, a phenomenon observed not only in native channels but also in expressed channels. We examined whether this tissue specificity was attributable to differences of inactivation in the two channel types. We expressed cardiac or GENE subunits in combination with beta2a and alpha2/delta subunits in human embryonic kidney cells, and used 2 mM CHEMICAL as the permeant ion. This system thus reproduces the in vivo topology and charge carrier of the channels while facilitating comparison of the two alpha1C splice variants. Both voltage-dependent and isoform-specific sensitivity of 10 nM nisoldipine inhibition of the channel were demonstrated, with the use of -100 mV as the holding potential for fully reprimed channels and -65 mV to populate the inactivated state. Under drug-free conditions, we characterized fast inactivation (1-sec prepulses) and slow inactivation (3 min prepulses) in the two isoforms. Inactivation parameters were not statistically different in the two channel isoforms; if anything, cardiac channels tended to inactivate more than the smooth muscle channels at relevant voltages. Likewise, the voltage-dependent activation was identical in the two isoforms. We thus conclude that the more potent nisoldipine inhibition of smooth muscle versus cardiac L-type CHEMICAL channels is not attributable to differences in channel inactivation or activation. Intrinsic, gating-independent DHP receptor binding affinity differences must be invoked to explain the isoform-specific sensitivity of the DHP block. | SUBSTRATE |
| Isoform-specific inhibition of GENE by CHEMICAL is independent of isoform-specific gating properties. CHEMICAL (DHPs) block L-type Ca2+ channels more potently at depolarized membrane potentials, consistent with high affinity binding to the inactivated state. Nisoldipine (a DHP antagonist) blocks the smooth muscle channel more potently than the cardiac one, a phenomenon observed not only in native channels but also in expressed channels. We examined whether this tissue specificity was attributable to differences of inactivation in the two channel types. We expressed cardiac or smooth muscle alpha1C subunits in combination with beta2a and alpha2/delta subunits in human embryonic kidney cells, and used 2 mM Ca2+ as the permeant ion. This system thus reproduces the in vivo topology and charge carrier of the channels while facilitating comparison of the two alpha1C splice variants. Both voltage-dependent and isoform-specific sensitivity of 10 nM nisoldipine inhibition of the channel were demonstrated, with the use of -100 mV as the holding potential for fully reprimed channels and -65 mV to populate the inactivated state. Under drug-free conditions, we characterized fast inactivation (1-sec prepulses) and slow inactivation (3 min prepulses) in the two isoforms. Inactivation parameters were not statistically different in the two channel isoforms; if anything, cardiac channels tended to inactivate more than the smooth muscle channels at relevant voltages. Likewise, the voltage-dependent activation was identical in the two isoforms. We thus conclude that the more potent nisoldipine inhibition of smooth muscle versus cardiac L-type Ca2+ channels is not attributable to differences in channel inactivation or activation. Intrinsic, gating-independent DHP receptor binding affinity differences must be invoked to explain the isoform-specific sensitivity of the DHP block. | INHIBITOR |
| Isoform-specific inhibition of L-type calcium channels by dihydropyridines is independent of isoform-specific gating properties. CHEMICAL (DHPs) block GENE more potently at depolarized membrane potentials, consistent with high affinity binding to the inactivated state. Nisoldipine (a DHP antagonist) blocks the smooth muscle channel more potently than the cardiac one, a phenomenon observed not only in native channels but also in expressed channels. We examined whether this tissue specificity was attributable to differences of inactivation in the two channel types. We expressed cardiac or smooth muscle alpha1C subunits in combination with beta2a and alpha2/delta subunits in human embryonic kidney cells, and used 2 mM Ca2+ as the permeant ion. This system thus reproduces the in vivo topology and charge carrier of the channels while facilitating comparison of the two alpha1C splice variants. Both voltage-dependent and isoform-specific sensitivity of 10 nM nisoldipine inhibition of the channel were demonstrated, with the use of -100 mV as the holding potential for fully reprimed channels and -65 mV to populate the inactivated state. Under drug-free conditions, we characterized fast inactivation (1-sec prepulses) and slow inactivation (3 min prepulses) in the two isoforms. Inactivation parameters were not statistically different in the two channel isoforms; if anything, cardiac channels tended to inactivate more than the smooth muscle channels at relevant voltages. Likewise, the voltage-dependent activation was identical in the two isoforms. We thus conclude that the more potent nisoldipine inhibition of smooth muscle versus cardiac GENE is not attributable to differences in channel inactivation or activation. Intrinsic, gating-independent DHP receptor binding affinity differences must be invoked to explain the isoform-specific sensitivity of the DHP block. | INHIBITOR |
| Isoform-specific inhibition of L-type calcium channels by dihydropyridines is independent of isoform-specific gating properties. Dihydropyridines (DHPs) block L-type Ca2+ channels more potently at depolarized membrane potentials, consistent with high affinity binding to the inactivated state. CHEMICAL (a DHP antagonist) blocks the smooth muscle channel more potently than the cardiac one, a phenomenon observed not only in native channels but also in expressed channels. We examined whether this tissue specificity was attributable to differences of inactivation in the two channel types. We expressed cardiac or smooth muscle alpha1C subunits in combination with beta2a and alpha2/delta subunits in human embryonic kidney cells, and used 2 mM Ca2+ as the permeant ion. This system thus reproduces the in vivo topology and charge carrier of the channels while facilitating comparison of the two alpha1C splice variants. Both voltage-dependent and isoform-specific sensitivity of 10 nM CHEMICAL inhibition of the channel were demonstrated, with the use of -100 mV as the holding potential for fully reprimed channels and -65 mV to populate the inactivated state. Under drug-free conditions, we characterized fast inactivation (1-sec prepulses) and slow inactivation (3 min prepulses) in the two isoforms. Inactivation parameters were not statistically different in the two channel isoforms; if anything, cardiac channels tended to inactivate more than the smooth muscle channels at relevant voltages. Likewise, the voltage-dependent activation was identical in the two isoforms. We thus conclude that the more potent CHEMICAL inhibition of smooth muscle versus GENE is not attributable to differences in channel inactivation or activation. Intrinsic, gating-independent DHP receptor binding affinity differences must be invoked to explain the isoform-specific sensitivity of the DHP block. | INHIBITOR |
| Isoform-specific inhibition of L-type calcium channels by dihydropyridines is independent of isoform-specific gating properties. Dihydropyridines (DHPs) block L-type Ca2+ channels more potently at depolarized membrane potentials, consistent with high affinity binding to the inactivated state. CHEMICAL (a DHP antagonist) blocks the GENE more potently than the cardiac one, a phenomenon observed not only in native channels but also in expressed channels. We examined whether this tissue specificity was attributable to differences of inactivation in the two channel types. We expressed cardiac or smooth muscle alpha1C subunits in combination with beta2a and alpha2/delta subunits in human embryonic kidney cells, and used 2 mM Ca2+ as the permeant ion. This system thus reproduces the in vivo topology and charge carrier of the channels while facilitating comparison of the two alpha1C splice variants. Both voltage-dependent and isoform-specific sensitivity of 10 nM nisoldipine inhibition of the channel were demonstrated, with the use of -100 mV as the holding potential for fully reprimed channels and -65 mV to populate the inactivated state. Under drug-free conditions, we characterized fast inactivation (1-sec prepulses) and slow inactivation (3 min prepulses) in the two isoforms. Inactivation parameters were not statistically different in the two channel isoforms; if anything, cardiac channels tended to inactivate more than the smooth muscle channels at relevant voltages. Likewise, the voltage-dependent activation was identical in the two isoforms. We thus conclude that the more potent nisoldipine inhibition of smooth muscle versus cardiac L-type Ca2+ channels is not attributable to differences in channel inactivation or activation. Intrinsic, gating-independent DHP receptor binding affinity differences must be invoked to explain the isoform-specific sensitivity of the DHP block. | INHIBITOR |
| Isoform-specific inhibition of L-type calcium channels by dihydropyridines is independent of isoform-specific gating properties. Dihydropyridines (DHPs) block L-type Ca2+ channels more potently at depolarized membrane potentials, consistent with high affinity binding to the inactivated state. Nisoldipine (a CHEMICAL antagonist) blocks the GENE more potently than the cardiac one, a phenomenon observed not only in native channels but also in expressed channels. We examined whether this tissue specificity was attributable to differences of inactivation in the two channel types. We expressed cardiac or smooth muscle alpha1C subunits in combination with beta2a and alpha2/delta subunits in human embryonic kidney cells, and used 2 mM Ca2+ as the permeant ion. This system thus reproduces the in vivo topology and charge carrier of the channels while facilitating comparison of the two alpha1C splice variants. Both voltage-dependent and isoform-specific sensitivity of 10 nM nisoldipine inhibition of the channel were demonstrated, with the use of -100 mV as the holding potential for fully reprimed channels and -65 mV to populate the inactivated state. Under drug-free conditions, we characterized fast inactivation (1-sec prepulses) and slow inactivation (3 min prepulses) in the two isoforms. Inactivation parameters were not statistically different in the two channel isoforms; if anything, cardiac channels tended to inactivate more than the smooth muscle channels at relevant voltages. Likewise, the voltage-dependent activation was identical in the two isoforms. We thus conclude that the more potent nisoldipine inhibition of smooth muscle versus cardiac L-type Ca2+ channels is not attributable to differences in channel inactivation or activation. Intrinsic, gating-independent CHEMICAL receptor binding affinity differences must be invoked to explain the isoform-specific sensitivity of the CHEMICAL block. | INHIBITOR |
| Isoform-specific inhibition of L-type calcium channels by dihydropyridines is independent of isoform-specific gating properties. Dihydropyridines (CHEMICAL) block GENE more potently at depolarized membrane potentials, consistent with high affinity binding to the inactivated state. Nisoldipine (a DHP antagonist) blocks the smooth muscle channel more potently than the cardiac one, a phenomenon observed not only in native channels but also in expressed channels. We examined whether this tissue specificity was attributable to differences of inactivation in the two channel types. We expressed cardiac or smooth muscle alpha1C subunits in combination with beta2a and alpha2/delta subunits in human embryonic kidney cells, and used 2 mM Ca2+ as the permeant ion. This system thus reproduces the in vivo topology and charge carrier of the channels while facilitating comparison of the two alpha1C splice variants. Both voltage-dependent and isoform-specific sensitivity of 10 nM nisoldipine inhibition of the channel were demonstrated, with the use of -100 mV as the holding potential for fully reprimed channels and -65 mV to populate the inactivated state. Under drug-free conditions, we characterized fast inactivation (1-sec prepulses) and slow inactivation (3 min prepulses) in the two isoforms. Inactivation parameters were not statistically different in the two channel isoforms; if anything, cardiac channels tended to inactivate more than the smooth muscle channels at relevant voltages. Likewise, the voltage-dependent activation was identical in the two isoforms. We thus conclude that the more potent nisoldipine inhibition of smooth muscle versus cardiac GENE is not attributable to differences in channel inactivation or activation. Intrinsic, gating-independent DHP receptor binding affinity differences must be invoked to explain the isoform-specific sensitivity of the DHP block. | INHIBITOR |
| Remethylation defects: guidelines for clinical diagnosis and treatment. The main remethylation defects include disorders which all have defective methionine synthesis in common. GENE deficiency impairs CHEMICAL synthesis, defects in cytosolic reduction of hydroxocobalamin (CblC/D) impair the synthesis of both methyl- and adenosyl cobalamin and deficiencies of methionine synthase (CblE/G) are associated with defective methyl cobalamin synthesis. The clinical presentation is characterized by acute neurological distress in early infancy. In childhood, patients present with progressive encephalopathy with an end-stage which has many signs in common with the adult onset form. In fact, both have more or less severe signs of subacute degeneration of the cord. Cobalamin defective patients must be treated with parenteral supplementation of hydroxocobalamin (1-2 mg per dose). Some methylenetetrahydrofolate patients could be folate responsive and must have a high-dosage folate trial. In addition, oral betaine supplementation (2-9 g per day depending on age) appears an effective means to prevent further neurological deterioration. | PRODUCT-OF |
| Remethylation defects: guidelines for clinical diagnosis and treatment. The main remethylation defects include disorders which all have defective methionine synthesis in common. Methylenetetrahydrofolate reductase deficiency impairs methyltetrahydrofolate synthesis, defects in cytosolic reduction of hydroxocobalamin (CblC/D) impair the synthesis of both methyl- and adenosyl cobalamin and deficiencies of GENE (CblE/G) are associated with defective CHEMICAL synthesis. The clinical presentation is characterized by acute neurological distress in early infancy. In childhood, patients present with progressive encephalopathy with an end-stage which has many signs in common with the adult onset form. In fact, both have more or less severe signs of subacute degeneration of the cord. Cobalamin defective patients must be treated with parenteral supplementation of hydroxocobalamin (1-2 mg per dose). Some methylenetetrahydrofolate patients could be folate responsive and must have a high-dosage folate trial. In addition, oral betaine supplementation (2-9 g per day depending on age) appears an effective means to prevent further neurological deterioration. | PRODUCT-OF |
| Increased Cat3-mediated cationic amino acid transport functionally compensates in Cat1 knockout cell lines. CHEMICAL transport is important for a number of biological processes in vertebrates, and its transport may be rate-limiting for the production of nitric oxide. The majority of L-Arg transport is mediated by System y+, although several other carriers have been kinetically defined. System y+ cationic amino acid transport is mediated by proteins encoded by a family of genes, Cat1, Cat2, and GENE. High affinity L-arginine transport was investigated in embryonic fibroblast cells derived from Cat1 knockout mice that lack functional Cat1. Both wild type and knockout cells transport CHEMICAL with comparable Km and Vmax. However, the apparent affinity for lysine transport was 2.4 times lower in Cat1(-/-) cells when compared with wild type cells, a property characteristic of Cat3-mediated transport. Northern analysis-documented Cat2 mRNA increased 2-fold, whereas GENE mRNA levels increased 11-fold in Cat1(-/-) relative to Cat1(+/+) cells. The low affinity Cat2a mRNA was not detectably expressed in these cells. Even though GENE expression is normally limited to adult brain, there was a large increase in the amount of GENE protein present at the plasma membrane of Cat1(-/-) embryonic fibroblast cells. These results suggest that GENE compensates for the loss of functional Cat1 in cells derived from Cat1 knockout mice and mediates the majority of high affinity CHEMICAL transport. | SUBSTRATE |
| Increased Cat3-mediated cationic amino acid transport functionally compensates in Cat1 knockout cell lines. Arginine transport is important for a number of biological processes in vertebrates, and its transport may be rate-limiting for the production of nitric oxide. The majority of CHEMICAL transport is mediated by GENE, although several other carriers have been kinetically defined. GENE cationic amino acid transport is mediated by proteins encoded by a family of genes, Cat1, Cat2, and Cat3. High affinity L-arginine transport was investigated in embryonic fibroblast cells derived from Cat1 knockout mice that lack functional Cat1. Both wild type and knockout cells transport arginine with comparable Km and Vmax. However, the apparent affinity for lysine transport was 2.4 times lower in Cat1(-/-) cells when compared with wild type cells, a property characteristic of Cat3-mediated transport. Northern analysis-documented Cat2 mRNA increased 2-fold, whereas Cat3 mRNA levels increased 11-fold in Cat1(-/-) relative to Cat1(+/+) cells. The low affinity Cat2a mRNA was not detectably expressed in these cells. Even though Cat3 expression is normally limited to adult brain, there was a large increase in the amount of Cat3 protein present at the plasma membrane of Cat1(-/-) embryonic fibroblast cells. These results suggest that Cat3 compensates for the loss of functional Cat1 in cells derived from Cat1 knockout mice and mediates the majority of high affinity arginine transport. | SUBSTRATE |
| Increased Cat3-mediated cationic CHEMICAL transport functionally compensates in Cat1 knockout cell lines. Arginine transport is important for a number of biological processes in vertebrates, and its transport may be rate-limiting for the production of nitric oxide. The majority of L-Arg transport is mediated by GENE, although several other carriers have been kinetically defined. GENE cationic CHEMICAL transport is mediated by proteins encoded by a family of genes, Cat1, Cat2, and Cat3. High affinity L-arginine transport was investigated in embryonic fibroblast cells derived from Cat1 knockout mice that lack functional Cat1. Both wild type and knockout cells transport arginine with comparable Km and Vmax. However, the apparent affinity for lysine transport was 2.4 times lower in Cat1(-/-) cells when compared with wild type cells, a property characteristic of Cat3-mediated transport. Northern analysis-documented Cat2 mRNA increased 2-fold, whereas Cat3 mRNA levels increased 11-fold in Cat1(-/-) relative to Cat1(+/+) cells. The low affinity Cat2a mRNA was not detectably expressed in these cells. Even though Cat3 expression is normally limited to adult brain, there was a large increase in the amount of Cat3 protein present at the plasma membrane of Cat1(-/-) embryonic fibroblast cells. These results suggest that Cat3 compensates for the loss of functional Cat1 in cells derived from Cat1 knockout mice and mediates the majority of high affinity arginine transport. | SUBSTRATE |
| Increased Cat3-mediated cationic CHEMICAL transport functionally compensates in GENE knockout cell lines. Arginine transport is important for a number of biological processes in vertebrates, and its transport may be rate-limiting for the production of nitric oxide. The majority of L-Arg transport is mediated by System y+, although several other carriers have been kinetically defined. System y+ cationic CHEMICAL transport is mediated by proteins encoded by a family of genes, GENE, Cat2, and Cat3. High affinity L-arginine transport was investigated in embryonic fibroblast cells derived from GENE knockout mice that lack functional GENE. Both wild type and knockout cells transport arginine with comparable Km and Vmax. However, the apparent affinity for lysine transport was 2.4 times lower in Cat1(-/-) cells when compared with wild type cells, a property characteristic of Cat3-mediated transport. Northern analysis-documented Cat2 mRNA increased 2-fold, whereas Cat3 mRNA levels increased 11-fold in Cat1(-/-) relative to Cat1(+/+) cells. The low affinity Cat2a mRNA was not detectably expressed in these cells. Even though Cat3 expression is normally limited to adult brain, there was a large increase in the amount of Cat3 protein present at the plasma membrane of Cat1(-/-) embryonic fibroblast cells. These results suggest that Cat3 compensates for the loss of functional GENE in cells derived from GENE knockout mice and mediates the majority of high affinity arginine transport. | SUBSTRATE |
| Increased Cat3-mediated cationic CHEMICAL transport functionally compensates in Cat1 knockout cell lines. Arginine transport is important for a number of biological processes in vertebrates, and its transport may be rate-limiting for the production of nitric oxide. The majority of L-Arg transport is mediated by System y+, although several other carriers have been kinetically defined. System y+ cationic CHEMICAL transport is mediated by proteins encoded by a family of genes, Cat1, GENE, and Cat3. High affinity L-arginine transport was investigated in embryonic fibroblast cells derived from Cat1 knockout mice that lack functional Cat1. Both wild type and knockout cells transport arginine with comparable Km and Vmax. However, the apparent affinity for lysine transport was 2.4 times lower in Cat1(-/-) cells when compared with wild type cells, a property characteristic of Cat3-mediated transport. Northern analysis-documented GENE mRNA increased 2-fold, whereas Cat3 mRNA levels increased 11-fold in Cat1(-/-) relative to Cat1(+/+) cells. The low affinity Cat2a mRNA was not detectably expressed in these cells. Even though Cat3 expression is normally limited to adult brain, there was a large increase in the amount of Cat3 protein present at the plasma membrane of Cat1(-/-) embryonic fibroblast cells. These results suggest that Cat3 compensates for the loss of functional Cat1 in cells derived from Cat1 knockout mice and mediates the majority of high affinity arginine transport. | SUBSTRATE |
| Increased Cat3-mediated cationic CHEMICAL transport functionally compensates in Cat1 knockout cell lines. Arginine transport is important for a number of biological processes in vertebrates, and its transport may be rate-limiting for the production of nitric oxide. The majority of L-Arg transport is mediated by System y+, although several other carriers have been kinetically defined. System y+ cationic CHEMICAL transport is mediated by proteins encoded by a family of genes, Cat1, Cat2, and GENE. High affinity L-arginine transport was investigated in embryonic fibroblast cells derived from Cat1 knockout mice that lack functional Cat1. Both wild type and knockout cells transport arginine with comparable Km and Vmax. However, the apparent affinity for lysine transport was 2.4 times lower in Cat1(-/-) cells when compared with wild type cells, a property characteristic of Cat3-mediated transport. Northern analysis-documented Cat2 mRNA increased 2-fold, whereas GENE mRNA levels increased 11-fold in Cat1(-/-) relative to Cat1(+/+) cells. The low affinity Cat2a mRNA was not detectably expressed in these cells. Even though GENE expression is normally limited to adult brain, there was a large increase in the amount of GENE protein present at the plasma membrane of Cat1(-/-) embryonic fibroblast cells. These results suggest that GENE compensates for the loss of functional Cat1 in cells derived from Cat1 knockout mice and mediates the majority of high affinity arginine transport. | SUBSTRATE |
| Increased Cat3-mediated cationic amino acid transport functionally compensates in Cat1 knockout cell lines. Arginine transport is important for a number of biological processes in vertebrates, and its transport may be rate-limiting for the production of nitric oxide. The majority of L-Arg transport is mediated by System y+, although several other carriers have been kinetically defined. System y+ cationic amino acid transport is mediated by proteins encoded by a family of genes, Cat1, Cat2, and GENE. High affinity L-arginine transport was investigated in embryonic fibroblast cells derived from Cat1 knockout mice that lack functional Cat1. Both wild type and knockout cells transport arginine with comparable Km and Vmax. However, the apparent affinity for CHEMICAL transport was 2.4 times lower in Cat1(-/-) cells when compared with wild type cells, a property characteristic of GENE-mediated transport. Northern analysis-documented Cat2 mRNA increased 2-fold, whereas GENE mRNA levels increased 11-fold in Cat1(-/-) relative to Cat1(+/+) cells. The low affinity Cat2a mRNA was not detectably expressed in these cells. Even though GENE expression is normally limited to adult brain, there was a large increase in the amount of GENE protein present at the plasma membrane of Cat1(-/-) embryonic fibroblast cells. These results suggest that GENE compensates for the loss of functional Cat1 in cells derived from Cat1 knockout mice and mediates the majority of high affinity arginine transport. | DIRECT-REGULATOR |
| Effect of lintitript, a new CCK-A receptor antagonist, on gastric emptying of a solid-liquid meal in humans. The role of cholecystokinin (CCK) in the regulation of gastric emptying of physiological meals containing solids and liquids in humans remains controversial. We studied the role of endogenous GENE in the emptying of a solid/liquid meal administering the new, highly specific and potent CCK-A receptor antagonist lintitript. Gastric emptying was assessed in nine healthy male volunteers using a randomized, double blind, two-period crossover design with oral lintitript (15 mg 1 h prior to meal intake) or placebo on two different days. After ingestion of a pancake (570 kcal) labelled with 500 microCi of 99mTc-sulfur colloid and 500 ml 10% dextrose containing 80 microCi. 111In-DTPA, subjects were studied in a sitting position, using a dual-headed gamma camera. Plasma GENE and pancreatic polypeptide (PP) were measured by a specific RIA. CHEMICAL distinctly accelerated gastric emptying of solids, while gastric emptying of liquids was not significantly altered. The lag period was shortened by 20% (P<0.05), AUC and half emptying time of solid emptying were lowered by 12% and 13%, respectively (P<0.03). CHEMICAL markedly increased postprandial plasma GENE release (P<0.001) while distinctly reducing postprandial PP levels (P<0.01) as compared to placebo. These data provide further evidence for a significant role of GENE in the regulation of gastric emptying of solids. The study demonstrates for the first time the marked gastrokinetic properties of the new CCK-A receptor antagonist lintitript in humans. | INDIRECT-UPREGULATOR |
| Effect of lintitript, a new CCK-A receptor antagonist, on gastric emptying of a solid-liquid meal in humans. The role of cholecystokinin (CCK) in the regulation of gastric emptying of physiological meals containing solids and liquids in humans remains controversial. We studied the role of endogenous CCK in the emptying of a solid/liquid meal administering the new, highly specific and potent CCK-A receptor antagonist lintitript. Gastric emptying was assessed in nine healthy male volunteers using a randomized, double blind, two-period crossover design with oral lintitript (15 mg 1 h prior to meal intake) or placebo on two different days. After ingestion of a pancake (570 kcal) labelled with 500 microCi of 99mTc-sulfur colloid and 500 ml 10% dextrose containing 80 microCi. 111In-DTPA, subjects were studied in a sitting position, using a dual-headed gamma camera. Plasma CCK and pancreatic polypeptide (PP) were measured by a specific RIA. CHEMICAL distinctly accelerated gastric emptying of solids, while gastric emptying of liquids was not significantly altered. The lag period was shortened by 20% (P<0.05), AUC and half emptying time of solid emptying were lowered by 12% and 13%, respectively (P<0.03). CHEMICAL markedly increased postprandial plasma CCK release (P<0.001) while distinctly reducing postprandial GENE levels (P<0.01) as compared to placebo. These data provide further evidence for a significant role of CCK in the regulation of gastric emptying of solids. The study demonstrates for the first time the marked gastrokinetic properties of the new CCK-A receptor antagonist lintitript in humans. | INDIRECT-DOWNREGULATOR |
| Effect of CHEMICAL, a new GENE antagonist, on gastric emptying of a solid-liquid meal in humans. The role of cholecystokinin (CCK) in the regulation of gastric emptying of physiological meals containing solids and liquids in humans remains controversial. We studied the role of endogenous CCK in the emptying of a solid/liquid meal administering the new, highly specific and potent GENE antagonist CHEMICAL. Gastric emptying was assessed in nine healthy male volunteers using a randomized, double blind, two-period crossover design with oral CHEMICAL (15 mg 1 h prior to meal intake) or placebo on two different days. After ingestion of a pancake (570 kcal) labelled with 500 microCi of 99mTc-sulfur colloid and 500 ml 10% dextrose containing 80 microCi. 111In-DTPA, subjects were studied in a sitting position, using a dual-headed gamma camera. Plasma CCK and pancreatic polypeptide (PP) were measured by a specific RIA. CHEMICAL distinctly accelerated gastric emptying of solids, while gastric emptying of liquids was not significantly altered. The lag period was shortened by 20% (P<0.05), AUC and half emptying time of solid emptying were lowered by 12% and 13%, respectively (P<0.03). CHEMICAL markedly increased postprandial plasma CCK release (P<0.001) while distinctly reducing postprandial PP levels (P<0.01) as compared to placebo. These data provide further evidence for a significant role of CCK in the regulation of gastric emptying of solids. The study demonstrates for the first time the marked gastrokinetic properties of the new GENE antagonist CHEMICAL in humans. | INHIBITOR |
| Beta-adrenoceptor-mediated inhibition of GENE, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced GENE, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on GENE, GM-CSF, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of GENE, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular CHEMICAL (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of GENE, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | PRODUCT-OF |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GENE mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GENE, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GENE, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GENE protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GENE mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GENE, and IL-3 mRNA accumulation and GENE protein secretion were related to the accumulation of intracellular CHEMICAL (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GENE, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | PRODUCT-OF |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, GENE, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GM-CSF, and GENE mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GM-CSF, and GENE mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and GENE mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular CHEMICAL (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and GENE mRNA accumulation is solely mediated by beta2-adrenoceptors. | PRODUCT-OF |
| Beta-adrenoceptor-mediated inhibition of GENE, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced GENE, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on GENE, GM-CSF, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of GENE, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (CHEMICAL) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular CHEMICAL levels. These data demonstrate that beta-agonist-induced inhibition of GENE, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | PRODUCT-OF |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GENE mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GENE, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GENE, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GENE protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GENE mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GENE, and IL-3 mRNA accumulation and GENE protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (CHEMICAL) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular CHEMICAL levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GENE, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | PRODUCT-OF |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, GENE, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GM-CSF, and GENE mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GM-CSF, and GENE mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and GENE mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (CHEMICAL) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular CHEMICAL levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and GENE mRNA accumulation is solely mediated by beta2-adrenoceptors. | PRODUCT-OF |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of GENE subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various GENE agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective GENE agonist isoproterenol and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to GENE stimulation. The observed inhibition on IFN-gamma, GM-CSF, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the GENE-mediated inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular CHEMICAL (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | PRODUCT-OF |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of GENE subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various GENE agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective GENE agonist isoproterenol and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to GENE stimulation. The observed inhibition on IFN-gamma, GM-CSF, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the GENE-mediated inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (CHEMICAL) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular CHEMICAL levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | PRODUCT-OF |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. GENE (Con A)-induced IFN-gamma, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist CHEMICAL and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GM-CSF, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of CHEMICAL followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | INHIBITOR |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (GENE)-induced IFN-gamma, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist CHEMICAL and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GM-CSF, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of CHEMICAL followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | INHIBITOR |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. GENE (Con A)-induced IFN-gamma, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist CHEMICAL. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GM-CSF, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | INHIBITOR |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (GENE)-induced IFN-gamma, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist CHEMICAL. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GM-CSF, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | INHIBITOR |
| Beta-adrenoceptor-mediated inhibition of GENE, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced GENE, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on GENE, GM-CSF, and IL-3 mRNA was blocked by the selective beta2AR antagonist CHEMICAL (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of GENE, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of GENE, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | INHIBITOR |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GENE mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GENE, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GENE, and IL-3 mRNA was blocked by the selective beta2AR antagonist CHEMICAL (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GENE protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GENE mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GENE, and IL-3 mRNA accumulation and GENE protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GENE, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | INHIBITOR |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, GENE, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GM-CSF, and GENE mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GM-CSF, and GENE mRNA was blocked by the selective beta2AR antagonist CHEMICAL (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and GENE mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and GENE mRNA accumulation is solely mediated by beta2-adrenoceptors. | INHIBITOR |
| Beta-adrenoceptor-mediated inhibition of GENE, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced GENE, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on GENE, GM-CSF, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by CHEMICAL (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of GENE, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of GENE, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | INHIBITOR |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GENE mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GENE, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GENE, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by CHEMICAL (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GENE protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GENE mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GENE, and IL-3 mRNA accumulation and GENE protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GENE, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | INHIBITOR |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, GENE, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GM-CSF, and GENE mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GM-CSF, and GENE mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by CHEMICAL (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and GENE mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and GENE mRNA accumulation is solely mediated by beta2-adrenoceptors. | INHIBITOR |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GENE mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GENE, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist CHEMICAL and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GENE, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GENE protein in the presence of increasing concentrations of CHEMICAL followed a similar pattern as observed for GENE mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GENE, and IL-3 mRNA accumulation and GENE protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GENE, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | GENE-CHEMICAL |
| Beta-adrenoceptor-mediated inhibition of GENE, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced GENE, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist CHEMICAL and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on GENE, GM-CSF, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of CHEMICAL followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of GENE, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of GENE, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | INHIBITOR |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, GENE, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GM-CSF, and GENE mRNAs are dose-dependently inhibited by the nonselective betaAR agonist CHEMICAL and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GM-CSF, and GENE mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of CHEMICAL followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and GENE mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and GENE mRNA accumulation is solely mediated by beta2-adrenoceptors. | INDIRECT-DOWNREGULATOR |
| Beta-adrenoceptor-mediated inhibition of GENE, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced GENE, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist CHEMICAL. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on GENE, GM-CSF, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of GENE, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of GENE, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | INHIBITOR |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GENE mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GENE, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist CHEMICAL. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GENE, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GENE protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GENE mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GENE, and IL-3 mRNA accumulation and GENE protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GENE, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | INDIRECT-DOWNREGULATOR |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, GENE, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GM-CSF, and GENE mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist CHEMICAL. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GM-CSF, and GENE mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and GENE mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and GENE mRNA accumulation is solely mediated by beta2-adrenoceptors. | INDIRECT-DOWNREGULATOR |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GM-CSF, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although GENE mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the GENE agonist CHEMICAL had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | ACTIVATOR |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of GENE subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various GENE agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective GENE agonist CHEMICAL and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to GENE stimulation. The observed inhibition on IFN-gamma, GM-CSF, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of CHEMICAL followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | ACTIVATOR |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective GENE agonist CHEMICAL. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GM-CSF, and IL-3 mRNA was blocked by the selective GENE antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | ACTIVATOR |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective GENE agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GM-CSF, and IL-3 mRNA was blocked by the selective GENE antagonist CHEMICAL (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | INHIBITOR |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective GENE agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GM-CSF, and IL-3 mRNA was blocked by the selective GENE antagonist ICI 118,551 (10(-6) M) and by CHEMICAL (10(-6) M), a nonselective antagonist. The selective beta1AR antagonist atenolol (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | INHIBITOR |
| Beta-adrenoceptor-mediated inhibition of IFN-gamma, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Cytokine gene expression in T lymphocytes is a strictly regulated process, involving both stimulatory and inhibitory signals. beta-Adrenoceptor (betaAR) agonists are widely used in the treatment of asthma and are able to induce an inhibitory signal on immunological responses after binding to their specific receptors. In this study, the characterization of betaAR subtype(s) (beta1, beta2, and beta3) involved in the regulation of interleukin (IL)-3, IL-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma) mRNA accumulation was studied by using various betaAR agonists and antagonists. Concanavalin A (Con A)-induced IFN-gamma, GM-CSF, and IL-3 mRNAs are dose-dependently inhibited by the nonselective betaAR agonist isoproterenol and by the selective beta2AR agonist fenoterol. IL-4 mRNA accumulation was not susceptible to betaAR stimulation. The observed inhibition on IFN-gamma, GM-CSF, and IL-3 mRNA was blocked by the selective beta2AR antagonist ICI 118,551 (10(-6) M) and by timolol (10(-6) M), a nonselective antagonist. The selective GENE antagonist CHEMICAL (0.3 x 10(-6) M) did not have any effect. Secretion of GM-CSF protein in the presence of increasing concentrations of isoproterenol followed a similar pattern as observed for GM-CSF mRNA. In addition, the betaAR-mediated inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation and GM-CSF protein secretion were related to the accumulation of intracellular cyclic adenosine monophosphate (cAMP) levels. Although beta3AR mRNA was detectable in Con A-activated T lymphocytes, we could not demonstrate a functional activity in the regulation of cytokine expression: the beta3AR agonist BRL 37344 had no effect on the accumulation of the studied cytokine mRNAs, and did not significantly affect cellular cAMP levels. These data demonstrate that beta-agonist-induced inhibition of IFN-gamma, GM-CSF, and IL-3 mRNA accumulation is solely mediated by beta2-adrenoceptors. | INHIBITOR |
| Oxytocin receptor binding and uterotonic activity of CHEMICAL and its metabolites following enzymatic degradation. Metabolites of the analogue 1-deamino-1-carba-2-tyrosine(O-methyl)-oxytocin (carbetocin) following incubation with a rat kidney homogenate were isolated and their pharmacodynamic properties investigated. Apart from the parent compound two metabolites were identified namely desGlyNH2-carbetocin (carbetocin metabolite I) and desLeuGlyNH2-carbetocin (carbetocin metabolite II). Both CHEMICAL, CHEMICAL metabolite I and CHEMICAL metabolite II displayed binding affinities to the myometrial oxytocin receptor of a similar magnitude as oxytocin. CHEMICAL was found to have agonistic properties on isolated myometrial strips and it was found to exert this effect through generation of inositol phosphates, as is the case for oxytocin. However, maximal contractile effect of CHEMICAL was approximately 50% lower than that of oxytocin (2.70 +/- 0.12 g compared to 5.22 +/- 0.26 g) and EC50 was approximately ten times higher (48.0 +/- 8.20 nM compared to 5.62 +/- 1.22 nM). Neither CHEMICAL metabolite I nor CHEMICAL metabolite II were able to contract isolated myometrial tissue. All three compounds displayed antagonistic properties against oxytocin in vitro, with CHEMICAL being the strongest inhibitor (pA2 = 8.21) and CHEMICAL metabolite II (pA2 = 8.01) being stronger than CHEMICAL metabolite I (pA2 = 7.81). These results indicate that CHEMICAL is a partial agonist/antagonist to the oxytocin receptor while the two metabolites CHEMICAL metabolite I and CHEMICAL metabolite II are pure antagonists. All three analogues bound to the myometrial vasopressin V1 receptor, albeit with much lower affinities than to the oxytocin receptor. CHEMICAL metabolite II showed the weakest binding affinity of 33.7 +/- 7.34 nM compared to 7.24 +/- 0.29 nM for CHEMICAL and 9.89 + 2.80 nM for CHEMICAL metabolite I. Only CHEMICAL bound to the renal GENE though the binding affinity was very low (61.3 +/- 14.6 nM). | DIRECT-REGULATOR |
| GENE binding and uterotonic activity of CHEMICAL and its metabolites following enzymatic degradation. Metabolites of the analogue 1-deamino-1-carba-2-tyrosine(O-methyl)-oxytocin (carbetocin) following incubation with a rat kidney homogenate were isolated and their pharmacodynamic properties investigated. Apart from the parent compound two metabolites were identified namely desGlyNH2-carbetocin (carbetocin metabolite I) and desLeuGlyNH2-carbetocin (carbetocin metabolite II). Both CHEMICAL, CHEMICAL metabolite I and CHEMICAL metabolite II displayed binding affinities to the myometrial GENE of a similar magnitude as oxytocin. CHEMICAL was found to have agonistic properties on isolated myometrial strips and it was found to exert this effect through generation of inositol phosphates, as is the case for oxytocin. However, maximal contractile effect of CHEMICAL was approximately 50% lower than that of oxytocin (2.70 +/- 0.12 g compared to 5.22 +/- 0.26 g) and EC50 was approximately ten times higher (48.0 +/- 8.20 nM compared to 5.62 +/- 1.22 nM). Neither CHEMICAL metabolite I nor CHEMICAL metabolite II were able to contract isolated myometrial tissue. All three compounds displayed antagonistic properties against oxytocin in vitro, with CHEMICAL being the strongest inhibitor (pA2 = 8.21) and CHEMICAL metabolite II (pA2 = 8.01) being stronger than CHEMICAL metabolite I (pA2 = 7.81). These results indicate that CHEMICAL is a partial agonist/antagonist to the GENE while the two metabolites CHEMICAL metabolite I and CHEMICAL metabolite II are pure antagonists. All three analogues bound to the myometrial vasopressin V1 receptor, albeit with much lower affinities than to the GENE. CHEMICAL metabolite II showed the weakest binding affinity of 33.7 +/- 7.34 nM compared to 7.24 +/- 0.29 nM for CHEMICAL and 9.89 + 2.80 nM for CHEMICAL metabolite I. Only CHEMICAL bound to the renal vasopressin V2 receptor though the binding affinity was very low (61.3 +/- 14.6 nM). | DIRECT-REGULATOR |
| CHEMICAL receptor binding and uterotonic activity of carbetocin and its metabolites following enzymatic degradation. Metabolites of the analogue 1-deamino-1-carba-2-tyrosine(O-methyl)-oxytocin (carbetocin) following incubation with a rat kidney homogenate were isolated and their pharmacodynamic properties investigated. Apart from the parent compound two metabolites were identified namely desGlyNH2-carbetocin (carbetocin metabolite I) and desLeuGlyNH2-carbetocin (carbetocin metabolite II). Both carbetocin, carbetocin metabolite I and carbetocin metabolite II displayed binding affinities to the myometrial GENE of a similar magnitude as CHEMICAL. Carbetocin was found to have agonistic properties on isolated myometrial strips and it was found to exert this effect through generation of inositol phosphates, as is the case for CHEMICAL. However, maximal contractile effect of carbetocin was approximately 50% lower than that of CHEMICAL (2.70 +/- 0.12 g compared to 5.22 +/- 0.26 g) and EC50 was approximately ten times higher (48.0 +/- 8.20 nM compared to 5.62 +/- 1.22 nM). Neither carbetocin metabolite I nor carbetocin metabolite II were able to contract isolated myometrial tissue. All three compounds displayed antagonistic properties against CHEMICAL in vitro, with carbetocin being the strongest inhibitor (pA2 = 8.21) and carbetocin metabolite II (pA2 = 8.01) being stronger than carbetocin metabolite I (pA2 = 7.81). These results indicate that carbetocin is a partial agonist/antagonist to the CHEMICAL receptor while the two metabolites carbetocin metabolite I and carbetocin metabolite II are pure antagonists. All three analogues bound to the myometrial vasopressin V1 receptor, albeit with much lower affinities than to the CHEMICAL receptor. Carbetocin metabolite II showed the weakest binding affinity of 33.7 +/- 7.34 nM compared to 7.24 +/- 0.29 nM for carbetocin and 9.89 + 2.80 nM for carbetocin metabolite I. Only carbetocin bound to the renal vasopressin V2 receptor though the binding affinity was very low (61.3 +/- 14.6 nM). | DIRECT-REGULATOR |
| GENE binding and uterotonic activity of CHEMICAL and its metabolites following enzymatic degradation. Metabolites of the analogue 1-deamino-1-carba-2-tyrosine(O-methyl)-oxytocin (carbetocin) following incubation with a rat kidney homogenate were isolated and their pharmacodynamic properties investigated. Apart from the parent compound two metabolites were identified namely desGlyNH2-carbetocin (carbetocin metabolite I) and desLeuGlyNH2-carbetocin (carbetocin metabolite II). Both CHEMICAL, CHEMICAL metabolite I and CHEMICAL metabolite II displayed binding affinities to the myometrial oxytocin receptor of a similar magnitude as oxytocin. CHEMICAL was found to have agonistic properties on isolated myometrial strips and it was found to exert this effect through generation of inositol phosphates, as is the case for oxytocin. However, maximal contractile effect of CHEMICAL was approximately 50% lower than that of oxytocin (2.70 +/- 0.12 g compared to 5.22 +/- 0.26 g) and EC50 was approximately ten times higher (48.0 +/- 8.20 nM compared to 5.62 +/- 1.22 nM). Neither CHEMICAL metabolite I nor CHEMICAL metabolite II were able to contract isolated myometrial tissue. All three compounds displayed antagonistic properties against oxytocin in vitro, with CHEMICAL being the strongest inhibitor (pA2 = 8.21) and CHEMICAL metabolite II (pA2 = 8.01) being stronger than CHEMICAL metabolite I (pA2 = 7.81). These results indicate that CHEMICAL is a partial agonist/antagonist to the oxytocin receptor while the two metabolites CHEMICAL metabolite I and CHEMICAL metabolite II are pure antagonists. All three analogues bound to the myometrial vasopressin V1 receptor, albeit with much lower affinities than to the oxytocin receptor. CHEMICAL metabolite II showed the weakest binding affinity of 33.7 +/- 7.34 nM compared to 7.24 +/- 0.29 nM for CHEMICAL and 9.89 + 2.80 nM for CHEMICAL metabolite I. Only CHEMICAL bound to the renal vasopressin V2 receptor though the binding affinity was very low (61.3 +/- 14.6 nM). | DIRECT-REGULATOR |
| GENE receptor binding and uterotonic activity of CHEMICAL and its metabolites following enzymatic degradation. Metabolites of the analogue 1-deamino-1-carba-2-tyrosine(O-methyl)-oxytocin (carbetocin) following incubation with a rat kidney homogenate were isolated and their pharmacodynamic properties investigated. Apart from the parent compound two metabolites were identified namely desGlyNH2-carbetocin (carbetocin metabolite I) and desLeuGlyNH2-carbetocin (carbetocin metabolite II). Both CHEMICAL, CHEMICAL metabolite I and CHEMICAL metabolite II displayed binding affinities to the myometrial GENE receptor of a similar magnitude as GENE. CHEMICAL was found to have agonistic properties on isolated myometrial strips and it was found to exert this effect through generation of inositol phosphates, as is the case for GENE. However, maximal contractile effect of CHEMICAL was approximately 50% lower than that of GENE (2.70 +/- 0.12 g compared to 5.22 +/- 0.26 g) and EC50 was approximately ten times higher (48.0 +/- 8.20 nM compared to 5.62 +/- 1.22 nM). Neither CHEMICAL metabolite I nor CHEMICAL metabolite II were able to contract isolated myometrial tissue. All three compounds displayed antagonistic properties against GENE in vitro, with CHEMICAL being the strongest inhibitor (pA2 = 8.21) and CHEMICAL metabolite II (pA2 = 8.01) being stronger than CHEMICAL metabolite I (pA2 = 7.81). These results indicate that CHEMICAL is a partial agonist/antagonist to the GENE receptor while the two metabolites CHEMICAL metabolite I and CHEMICAL metabolite II are pure antagonists. All three analogues bound to the myometrial vasopressin V1 receptor, albeit with much lower affinities than to the GENE receptor. CHEMICAL metabolite II showed the weakest binding affinity of 33.7 +/- 7.34 nM compared to 7.24 +/- 0.29 nM for CHEMICAL and 9.89 + 2.80 nM for CHEMICAL metabolite I. Only CHEMICAL bound to the renal vasopressin V2 receptor though the binding affinity was very low (61.3 +/- 14.6 nM). | DIRECT-REGULATOR |
| Crystallographic analysis of the human phenylalanine hydroxylase catalytic domain with bound catechol inhibitors at 2.0 A resolution. The aromatic amino acid hydroxylases represent a superfamily of structurally and functionally closely related enzymes, one of those functions being reversible inhibition by catechol derivatives. Here we present the crystal structure of the dimeric catalytic domain (residues 117-424) of human phenylalanine hydroxylase (hPheOH), cocrystallized with various potent and well-known catechol inhibitors and refined at a resolution of 2.0 A. The catechols bind by bidentate coordination to each iron in both subunits of the dimer through the catechol hydroxyl groups, forming a blue-green colored ligand-to-metal charge-transfer complex. In addition, Glu330 and Tyr325 are identified as determinant residues in the recognition of the inhibitors. In particular, the interaction with Glu330 conforms to the structural explanation for the pH dependence of catecholamine binding to PheOH, with a pKa value of 5.1 (20 degreesC). The overall structure of the catechol-bound enzyme is very similar to that of the uncomplexed enzyme (rms difference of 0.2 A for the Calpha atoms). Most striking is the replacement of two iron-bound water molecules with catechol hydroxyl groups. This change is consistent with a change in the ligand field symmetry of the high-spin (S = 5/2) Fe(III) from a rhombic to a nearly axial ligand field symmetry as seen upon noradrenaline binding using EPR spectroscopy [Martinez, A., Andersson, K. K., Haavik, J., and Flatmark, T. (1991) Eur. J. Biochem. 198, 675-682]. Crystallographic comparison with the structurally related GENE binary complex with the oxidized cofactor CHEMICAL revealed overlapping binding sites for the catechols and the cofactor, compatible with a competitive type of inhibition of the catechols versus BH4. The comparison demonstrates some structural differences at the active site as the potential basis for the different substrate specificity of the two enzymes. | DIRECT-REGULATOR |
| Crystallographic analysis of the human phenylalanine hydroxylase catalytic domain with bound catechol inhibitors at 2.0 A resolution. The aromatic amino acid hydroxylases represent a superfamily of structurally and functionally closely related enzymes, one of those functions being reversible inhibition by catechol derivatives. Here we present the crystal structure of the dimeric catalytic domain (residues 117-424) of human phenylalanine hydroxylase (hPheOH), cocrystallized with various potent and well-known catechol inhibitors and refined at a resolution of 2.0 A. The CHEMICAL bind by bidentate coordination to each iron in both subunits of the dimer through the catechol hydroxyl groups, forming a blue-green colored ligand-to-metal charge-transfer complex. In addition, Glu330 and Tyr325 are identified as determinant residues in the recognition of the inhibitors. In particular, the interaction with Glu330 conforms to the structural explanation for the pH dependence of catecholamine binding to PheOH, with a pKa value of 5.1 (20 degreesC). The overall structure of the catechol-bound enzyme is very similar to that of the uncomplexed enzyme (rms difference of 0.2 A for the Calpha atoms). Most striking is the replacement of two iron-bound water molecules with catechol hydroxyl groups. This change is consistent with a change in the ligand field symmetry of the high-spin (S = 5/2) Fe(III) from a rhombic to a nearly axial ligand field symmetry as seen upon noradrenaline binding using EPR spectroscopy [Martinez, A., Andersson, K. K., Haavik, J., and Flatmark, T. (1991) Eur. J. Biochem. 198, 675-682]. Crystallographic comparison with the structurally related GENE binary complex with the oxidized cofactor 7,8-dihydrobiopterin revealed overlapping binding sites for the CHEMICAL and the cofactor, compatible with a competitive type of inhibition of the CHEMICAL versus BH4. The comparison demonstrates some structural differences at the active site as the potential basis for the different substrate specificity of the two enzymes. | DIRECT-REGULATOR |
| Crystallographic analysis of the GENE with bound CHEMICAL inhibitors at 2.0 A resolution. The aromatic amino acid hydroxylases represent a superfamily of structurally and functionally closely related enzymes, one of those functions being reversible inhibition by CHEMICAL derivatives. Here we present the crystal structure of the dimeric catalytic domain (residues 117-424) of human phenylalanine hydroxylase (hPheOH), cocrystallized with various potent and well-known CHEMICAL inhibitors and refined at a resolution of 2.0 A. The catechols bind by bidentate coordination to each iron in both subunits of the dimer through the CHEMICAL hydroxyl groups, forming a blue-green colored ligand-to-metal charge-transfer complex. In addition, Glu330 and Tyr325 are identified as determinant residues in the recognition of the inhibitors. In particular, the interaction with Glu330 conforms to the structural explanation for the pH dependence of catecholamine binding to PheOH, with a pKa value of 5.1 (20 degreesC). The overall structure of the catechol-bound enzyme is very similar to that of the uncomplexed enzyme (rms difference of 0.2 A for the Calpha atoms). Most striking is the replacement of two iron-bound water molecules with CHEMICAL hydroxyl groups. This change is consistent with a change in the ligand field symmetry of the high-spin (S = 5/2) Fe(III) from a rhombic to a nearly axial ligand field symmetry as seen upon noradrenaline binding using EPR spectroscopy [Martinez, A., Andersson, K. K., Haavik, J., and Flatmark, T. (1991) Eur. J. Biochem. 198, 675-682]. Crystallographic comparison with the structurally related rat tyrosine hydroxylase binary complex with the oxidized cofactor 7,8-dihydrobiopterin revealed overlapping binding sites for the catechols and the cofactor, compatible with a competitive type of inhibition of the catechols versus BH4. The comparison demonstrates some structural differences at the active site as the potential basis for the different substrate specificity of the two enzymes. | DIRECT-REGULATOR |
| Crystallographic analysis of the human phenylalanine hydroxylase catalytic domain with bound CHEMICAL inhibitors at 2.0 A resolution. The GENE represent a superfamily of structurally and functionally closely related enzymes, one of those functions being reversible inhibition by CHEMICAL derivatives. Here we present the crystal structure of the dimeric catalytic domain (residues 117-424) of human phenylalanine hydroxylase (hPheOH), cocrystallized with various potent and well-known CHEMICAL inhibitors and refined at a resolution of 2.0 A. The catechols bind by bidentate coordination to each iron in both subunits of the dimer through the CHEMICAL hydroxyl groups, forming a blue-green colored ligand-to-metal charge-transfer complex. In addition, Glu330 and Tyr325 are identified as determinant residues in the recognition of the inhibitors. In particular, the interaction with Glu330 conforms to the structural explanation for the pH dependence of catecholamine binding to PheOH, with a pKa value of 5.1 (20 degreesC). The overall structure of the catechol-bound enzyme is very similar to that of the uncomplexed enzyme (rms difference of 0.2 A for the Calpha atoms). Most striking is the replacement of two iron-bound water molecules with CHEMICAL hydroxyl groups. This change is consistent with a change in the ligand field symmetry of the high-spin (S = 5/2) Fe(III) from a rhombic to a nearly axial ligand field symmetry as seen upon noradrenaline binding using EPR spectroscopy [Martinez, A., Andersson, K. K., Haavik, J., and Flatmark, T. (1991) Eur. J. Biochem. 198, 675-682]. Crystallographic comparison with the structurally related rat tyrosine hydroxylase binary complex with the oxidized cofactor 7,8-dihydrobiopterin revealed overlapping binding sites for the catechols and the cofactor, compatible with a competitive type of inhibition of the catechols versus BH4. The comparison demonstrates some structural differences at the active site as the potential basis for the different substrate specificity of the two enzymes. | INHIBITOR |
| Crystallographic analysis of the GENE catalytic domain with bound CHEMICAL inhibitors at 2.0 A resolution. The aromatic amino acid hydroxylases represent a superfamily of structurally and functionally closely related enzymes, one of those functions being reversible inhibition by CHEMICAL derivatives. Here we present the crystal structure of the dimeric catalytic domain (residues 117-424) of GENE (hPheOH), cocrystallized with various potent and well-known CHEMICAL inhibitors and refined at a resolution of 2.0 A. The catechols bind by bidentate coordination to each iron in both subunits of the dimer through the CHEMICAL hydroxyl groups, forming a blue-green colored ligand-to-metal charge-transfer complex. In addition, Glu330 and Tyr325 are identified as determinant residues in the recognition of the inhibitors. In particular, the interaction with Glu330 conforms to the structural explanation for the pH dependence of catecholamine binding to PheOH, with a pKa value of 5.1 (20 degreesC). The overall structure of the catechol-bound enzyme is very similar to that of the uncomplexed enzyme (rms difference of 0.2 A for the Calpha atoms). Most striking is the replacement of two iron-bound water molecules with CHEMICAL hydroxyl groups. This change is consistent with a change in the ligand field symmetry of the high-spin (S = 5/2) Fe(III) from a rhombic to a nearly axial ligand field symmetry as seen upon noradrenaline binding using EPR spectroscopy [Martinez, A., Andersson, K. K., Haavik, J., and Flatmark, T. (1991) Eur. J. Biochem. 198, 675-682]. Crystallographic comparison with the structurally related rat tyrosine hydroxylase binary complex with the oxidized cofactor 7,8-dihydrobiopterin revealed overlapping binding sites for the catechols and the cofactor, compatible with a competitive type of inhibition of the catechols versus BH4. The comparison demonstrates some structural differences at the active site as the potential basis for the different substrate specificity of the two enzymes. | INHIBITOR |
| Crystallographic analysis of the human phenylalanine hydroxylase catalytic domain with bound CHEMICAL inhibitors at 2.0 A resolution. The aromatic amino acid hydroxylases represent a superfamily of structurally and functionally closely related enzymes, one of those functions being reversible inhibition by CHEMICAL derivatives. Here we present the crystal structure of the dimeric catalytic domain (residues 117-424) of human phenylalanine hydroxylase (GENE), cocrystallized with various potent and well-known CHEMICAL inhibitors and refined at a resolution of 2.0 A. The catechols bind by bidentate coordination to each iron in both subunits of the dimer through the CHEMICAL hydroxyl groups, forming a blue-green colored ligand-to-metal charge-transfer complex. In addition, Glu330 and Tyr325 are identified as determinant residues in the recognition of the inhibitors. In particular, the interaction with Glu330 conforms to the structural explanation for the pH dependence of catecholamine binding to PheOH, with a pKa value of 5.1 (20 degreesC). The overall structure of the catechol-bound enzyme is very similar to that of the uncomplexed enzyme (rms difference of 0.2 A for the Calpha atoms). Most striking is the replacement of two iron-bound water molecules with CHEMICAL hydroxyl groups. This change is consistent with a change in the ligand field symmetry of the high-spin (S = 5/2) Fe(III) from a rhombic to a nearly axial ligand field symmetry as seen upon noradrenaline binding using EPR spectroscopy [Martinez, A., Andersson, K. K., Haavik, J., and Flatmark, T. (1991) Eur. J. Biochem. 198, 675-682]. Crystallographic comparison with the structurally related rat tyrosine hydroxylase binary complex with the oxidized cofactor 7,8-dihydrobiopterin revealed overlapping binding sites for the catechols and the cofactor, compatible with a competitive type of inhibition of the catechols versus BH4. The comparison demonstrates some structural differences at the active site as the potential basis for the different substrate specificity of the two enzymes. | INHIBITOR |
| Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-kappaB-dependent transcription. Glucocorticoids (GCs) influence a great variety of cellular functions by at least three important modes of action: the activation (or repression) of genes controlled by binding sites for the glucocorticoid receptor (GR), the induction of apoptosis in lymphocytes and the recently discovered cross-talk to other transcription factors such as NF-kappaB. In this study we systematically compared various natural and synthetic steroid hormones frequently used as therapeutic agents on their ability to mediate these three modes of action. Betamethasone, triamcinolone, dexamethasone and clobetasol turned out to be the best inducers of gene expression and apoptosis. All GCs including the antagonistic compound CHEMICAL efficiently reduced NF-kappaB-mediated transactivation to comparable extents, suggesting that ligand-induced nuclear localization of the GENE is sufficient for transrepression. Glucocorticoid treatment of cells did not result in elevated IkappaB-alpha expression, but impaired the tumor necrosis factor (TNF)-alpha-induced degradation of IkappaB-alpha without affecting DNA binding of NF-kappaB. The structural requirements for the various functions of glucocorticoids are discussed. | INHIBITOR |
| Various glucocorticoids differ in their ability to induce gene expression, apoptosis and to repress NF-kappaB-dependent transcription. Glucocorticoids (GCs) influence a great variety of cellular functions by at least three important modes of action: the activation (or repression) of genes controlled by binding sites for the glucocorticoid receptor (GR), the induction of apoptosis in lymphocytes and the recently discovered cross-talk to other transcription factors such as GENE. In this study we systematically compared various natural and synthetic steroid hormones frequently used as therapeutic agents on their ability to mediate these three modes of action. Betamethasone, triamcinolone, dexamethasone and clobetasol turned out to be the best inducers of gene expression and apoptosis. All GCs including the antagonistic compound CHEMICAL efficiently reduced GENE-mediated transactivation to comparable extents, suggesting that ligand-induced nuclear localization of the GR is sufficient for transrepression. Glucocorticoid treatment of cells did not result in elevated IkappaB-alpha expression, but impaired the tumor necrosis factor (TNF)-alpha-induced degradation of IkappaB-alpha without affecting DNA binding of GENE. The structural requirements for the various functions of glucocorticoids are discussed. | INHIBITOR |
| Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of GENE subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and MgADP, but not the CHEMICAL salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to GENE. Mutation in the Walker A and B motifs of NBF2 of GENE abolished this stabilizing effect of MgADP. These results suggest that GENE binds 8-azido-ATP strongly at NBF1 and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from GENE in the presence of MgADP or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of GENE suggests that glibenclamide both blocks this cooperative binding of ATP and MgADP and, in cooperation with the MgADP bound at NBF2, causes ATP to be released from NBF1. | NO-RELATIONSHIP |
| Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of GENE subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and MgADP, but not the Mg salt of CHEMICAL, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to GENE. Mutation in the Walker A and B motifs of NBF2 of GENE abolished this stabilizing effect of MgADP. These results suggest that GENE binds 8-azido-ATP strongly at NBF1 and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from GENE in the presence of MgADP or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of GENE suggests that glibenclamide both blocks this cooperative binding of ATP and MgADP and, in cooperation with the MgADP bound at NBF2, causes ATP to be released from NBF1. | NO-RELATIONSHIP |
| Cooperative binding of ATP and CHEMICAL in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, CHEMICAL, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of SUR1 subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and CHEMICAL, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1. Mutation in the GENE of NBF2 of SUR1 abolished this stabilizing effect of CHEMICAL. These results suggest that SUR1 binds 8-azido-ATP strongly at NBF1 and that CHEMICAL, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of CHEMICAL or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of SUR1 suggests that glibenclamide both blocks this cooperative binding of ATP and CHEMICAL and, in cooperation with the CHEMICAL bound at NBF2, causes ATP to be released from NBF1. | REGULATOR |
| Cooperative binding of ATP and CHEMICAL in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, CHEMICAL, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of SUR1 subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and CHEMICAL, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1. Mutation in the Walker A and B motifs of GENE of SUR1 abolished this stabilizing effect of CHEMICAL. These results suggest that SUR1 binds 8-azido-ATP strongly at NBF1 and that CHEMICAL, either by direct binding to GENE or by hydrolysis of bound MgATP at GENE, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of CHEMICAL or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of SUR1 suggests that glibenclamide both blocks this cooperative binding of ATP and CHEMICAL and, in cooperation with the CHEMICAL bound at GENE, causes ATP to be released from NBF1. | DIRECT-REGULATOR |
| Cooperative binding of ATP and CHEMICAL in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, CHEMICAL, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of GENE subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and CHEMICAL, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to GENE. Mutation in the Walker A and B motifs of NBF2 of GENE abolished this stabilizing effect of CHEMICAL. These results suggest that GENE binds 8-azido-ATP strongly at NBF1 and that CHEMICAL, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from GENE in the presence of CHEMICAL or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of GENE suggests that glibenclamide both blocks this cooperative binding of ATP and CHEMICAL and, in cooperation with the CHEMICAL bound at NBF2, causes ATP to be released from NBF1. | DIRECT-REGULATOR |
| Cooperative binding of CHEMICAL and MgADP in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by CHEMICAL, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of SUR1 subunits of the CHEMICAL-binding-cassette superfamily with two GENE (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1. Mutation in the Walker A and B motifs of NBF2 of SUR1 abolished this stabilizing effect of MgADP. These results suggest that SUR1 binds 8-azido-ATP strongly at NBF1 and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of MgADP or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of SUR1 suggests that glibenclamide both blocks this cooperative binding of CHEMICAL and MgADP and, in cooperation with the MgADP bound at NBF2, causes CHEMICAL to be released from NBF1. | DIRECT-REGULATOR |
| Cooperative binding of CHEMICAL and MgADP in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by CHEMICAL, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of SUR1 subunits of the CHEMICAL-binding-cassette superfamily with two nucleotide-binding folds (GENE and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1. Mutation in the Walker A and B motifs of NBF2 of SUR1 abolished this stabilizing effect of MgADP. These results suggest that SUR1 binds 8-azido-ATP strongly at GENE and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at GENE. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of MgADP or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of SUR1 suggests that glibenclamide both blocks this cooperative binding of CHEMICAL and MgADP and, in cooperation with the MgADP bound at NBF2, causes CHEMICAL to be released from GENE. | DIRECT-REGULATOR |
| Cooperative binding of CHEMICAL and MgADP in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by CHEMICAL, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of SUR1 subunits of the CHEMICAL-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and GENE) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1. Mutation in the Walker A and B motifs of GENE of SUR1 abolished this stabilizing effect of MgADP. These results suggest that SUR1 binds 8-azido-ATP strongly at NBF1 and that MgADP, either by direct binding to GENE or by hydrolysis of bound MgATP at GENE, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of MgADP or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of SUR1 suggests that glibenclamide both blocks this cooperative binding of CHEMICAL and MgADP and, in cooperation with the MgADP bound at GENE, causes CHEMICAL to be released from NBF1. | DIRECT-REGULATOR |
| Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of GENE subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound CHEMICAL to GENE. Mutation in the Walker A and B motifs of NBF2 of GENE abolished this stabilizing effect of MgADP. These results suggest that GENE binds 8-azido-ATP strongly at NBF1 and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea glibenclamide caused release of prebound CHEMICAL from GENE in the presence of MgADP or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of GENE suggests that glibenclamide both blocks this cooperative binding of ATP and MgADP and, in cooperation with the MgADP bound at NBF2, causes ATP to be released from NBF1. | DIRECT-REGULATOR |
| Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of GENE subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to GENE. Mutation in the Walker A and B motifs of NBF2 of GENE abolished this stabilizing effect of MgADP. These results suggest that GENE binds CHEMICAL strongly at NBF1 and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound CHEMICAL binding at NBF1. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from GENE in the presence of MgADP or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of GENE suggests that glibenclamide both blocks this cooperative binding of ATP and MgADP and, in cooperation with the MgADP bound at NBF2, causes ATP to be released from NBF1. | DIRECT-REGULATOR |
| Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of SUR1 subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1. Mutation in the Walker A and B motifs of NBF2 of SUR1 abolished this stabilizing effect of MgADP. These results suggest that SUR1 binds CHEMICAL strongly at GENE and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound CHEMICAL binding at GENE. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of MgADP or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of SUR1 suggests that glibenclamide both blocks this cooperative binding of ATP and MgADP and, in cooperation with the MgADP bound at NBF2, causes ATP to be released from GENE. | DIRECT-REGULATOR |
| Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of GENE subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to GENE. Mutation in the Walker A and B motifs of NBF2 of GENE abolished this stabilizing effect of MgADP. These results suggest that GENE binds 8-azido-ATP strongly at NBF1 and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at NBF1. The CHEMICAL caused release of prebound 8-azido-[alpha-32P]ATP from GENE in the presence of MgADP or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of GENE suggests that glibenclamide both blocks this cooperative binding of ATP and MgADP and, in cooperation with the MgADP bound at NBF2, causes ATP to be released from NBF1. | REGULATOR |
| Cooperative binding of CHEMICAL and MgADP in the GENE is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by CHEMICAL, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of SUR1 subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1. Mutation in the Walker A and B motifs of NBF2 of SUR1 abolished this stabilizing effect of MgADP. These results suggest that SUR1 binds 8-azido-ATP strongly at NBF1 and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of MgADP or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of SUR1 suggests that glibenclamide both blocks this cooperative binding of CHEMICAL and MgADP and, in cooperation with the MgADP bound at NBF2, causes CHEMICAL to be released from NBF1. | REGULATOR |
| Cooperative binding of ATP and CHEMICAL in the GENE is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, CHEMICAL, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of SUR1 subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and CHEMICAL, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1. Mutation in the Walker A and B motifs of NBF2 of SUR1 abolished this stabilizing effect of CHEMICAL. These results suggest that SUR1 binds 8-azido-ATP strongly at NBF1 and that CHEMICAL, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of CHEMICAL or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of SUR1 suggests that glibenclamide both blocks this cooperative binding of ATP and CHEMICAL and, in cooperation with the CHEMICAL bound at NBF2, causes ATP to be released from NBF1. | REGULATOR |
| Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of SUR1 subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1. Mutation in the Walker A and B motifs of NBF2 of SUR1 abolished this stabilizing effect of MgADP. These results suggest that SUR1 binds 8-azido-ATP strongly at NBF1 and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of MgADP or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in CHEMICAL binding of the two GENE of SUR1 suggests that glibenclamide both blocks this cooperative binding of ATP and MgADP and, in cooperation with the MgADP bound at NBF2, causes ATP to be released from NBF1. | DIRECT-REGULATOR |
| Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of GENE subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to GENE. Mutation in the Walker A and B motifs of NBF2 of GENE abolished this stabilizing effect of MgADP. These results suggest that GENE binds 8-azido-ATP strongly at NBF1 and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from GENE in the presence of MgADP or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in CHEMICAL binding of the two NBFs of GENE suggests that glibenclamide both blocks this cooperative binding of ATP and MgADP and, in cooperation with the MgADP bound at NBF2, causes ATP to be released from NBF1. | DIRECT-REGULATOR |
| Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by CHEMICAL. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of SUR1 subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1. Mutation in the Walker A and B motifs of GENE of SUR1 abolished this stabilizing effect of MgADP. These results suggest that SUR1 binds 8-azido-ATP strongly at NBF1 and that MgADP, either by direct binding to GENE or by hydrolysis of bound MgATP at GENE, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea CHEMICAL caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of MgADP or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of SUR1 suggests that CHEMICAL both blocks this cooperative binding of ATP and MgADP and, in cooperation with the MgADP bound at GENE, causes ATP to be released from NBF1. | DIRECT-REGULATOR |
| Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by CHEMICAL. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of SUR1 subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1. Mutation in the Walker A and B motifs of NBF2 of SUR1 abolished this stabilizing effect of MgADP. These results suggest that SUR1 binds 8-azido-ATP strongly at GENE and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at GENE. The sulfonylurea CHEMICAL caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of MgADP or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of SUR1 suggests that CHEMICAL both blocks this cooperative binding of ATP and MgADP and, in cooperation with the MgADP bound at NBF2, causes ATP to be released from GENE. | REGULATOR |
| Cooperative binding of CHEMICAL and MgADP in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of GENE by CHEMICAL, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of SUR1 subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1. Mutation in the Walker A and B motifs of NBF2 of SUR1 abolished this stabilizing effect of MgADP. These results suggest that SUR1 binds 8-azido-ATP strongly at NBF1 and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of MgADP or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of SUR1 suggests that glibenclamide both blocks this cooperative binding of CHEMICAL and MgADP and, in cooperation with the MgADP bound at NBF2, causes CHEMICAL to be released from NBF1. | REGULATOR |
| Cooperative binding of ATP and CHEMICAL in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of GENE by ATP, CHEMICAL, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of SUR1 subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and CHEMICAL, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1. Mutation in the Walker A and B motifs of NBF2 of SUR1 abolished this stabilizing effect of CHEMICAL. These results suggest that SUR1 binds 8-azido-ATP strongly at NBF1 and that CHEMICAL, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of CHEMICAL or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of SUR1 suggests that glibenclamide both blocks this cooperative binding of ATP and CHEMICAL and, in cooperation with the CHEMICAL bound at NBF2, causes ATP to be released from NBF1. | REGULATOR |
| Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of GENE subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that CHEMICAL and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to GENE. Mutation in the Walker A and B motifs of NBF2 of GENE abolished this stabilizing effect of MgADP. These results suggest that GENE binds 8-azido-ATP strongly at NBF1 and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound CHEMICAL at NBF2, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from GENE in the presence of MgADP or CHEMICAL in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of GENE suggests that glibenclamide both blocks this cooperative binding of ATP and MgADP and, in cooperation with the MgADP bound at NBF2, causes ATP to be released from NBF1. | DIRECT-REGULATOR |
| Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of SUR1 subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that CHEMICAL and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1. Mutation in the Walker A and B motifs of NBF2 of SUR1 abolished this stabilizing effect of MgADP. These results suggest that SUR1 binds 8-azido-ATP strongly at GENE and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound CHEMICAL at NBF2, stabilizes prebound 8-azido-ATP binding at GENE. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of MgADP or CHEMICAL in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of SUR1 suggests that glibenclamide both blocks this cooperative binding of ATP and MgADP and, in cooperation with the MgADP bound at NBF2, causes ATP to be released from GENE. | REGULATOR |
| Cooperative binding of ATP and MgADP in the GENE is modulated by CHEMICAL. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of SUR1 subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1. Mutation in the Walker A and B motifs of NBF2 of SUR1 abolished this stabilizing effect of MgADP. These results suggest that SUR1 binds 8-azido-ATP strongly at NBF1 and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea CHEMICAL caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of MgADP or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of SUR1 suggests that CHEMICAL both blocks this cooperative binding of ATP and MgADP and, in cooperation with the MgADP bound at NBF2, causes ATP to be released from NBF1. | REGULATOR |
| Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of CHEMICAL-induced GENE secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of SUR1 subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that MgATP and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1. Mutation in the Walker A and B motifs of NBF2 of SUR1 abolished this stabilizing effect of MgADP. These results suggest that SUR1 binds 8-azido-ATP strongly at NBF1 and that MgADP, either by direct binding to NBF2 or by hydrolysis of bound MgATP at NBF2, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of MgADP or MgATP in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of SUR1 suggests that glibenclamide both blocks this cooperative binding of ATP and MgADP and, in cooperation with the MgADP bound at NBF2, causes ATP to be released from NBF1. | INDIRECT-UPREGULATOR |
| Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by glibenclamide. The ATP-sensitive potassium (KATP) channels in pancreatic beta cells are critical in the regulation of glucose-induced insulin secretion. Although electrophysiological studies provide clues to the complex control of KATP channels by ATP, MgADP, and pharmacological agents, the molecular mechanism of KATP-channel regulation remains unclear. The KATP channel is a heterooligomeric complex of SUR1 subunits of the ATP-binding-cassette superfamily with two nucleotide-binding folds (NBF1 and NBF2) and the pore-forming Kir6.2 subunits. Here, we report that CHEMICAL and MgADP, but not the Mg salt of gamma-thio-ATP, stabilize the binding of prebound 8-azido-[alpha-32P]ATP to SUR1. Mutation in the Walker A and B motifs of GENE of SUR1 abolished this stabilizing effect of MgADP. These results suggest that SUR1 binds 8-azido-ATP strongly at NBF1 and that MgADP, either by direct binding to GENE or by hydrolysis of bound CHEMICAL at GENE, stabilizes prebound 8-azido-ATP binding at NBF1. The sulfonylurea glibenclamide caused release of prebound 8-azido-[alpha-32P]ATP from SUR1 in the presence of MgADP or CHEMICAL in a concentration-dependent manner. This direct biochemical evidence of cooperative interaction in nucleotide binding of the two NBFs of SUR1 suggests that glibenclamide both blocks this cooperative binding of ATP and MgADP and, in cooperation with the MgADP bound at GENE, causes ATP to be released from NBF1. | DIRECT-REGULATOR |
| Determinants of sensitivity to DZNep induced apoptosis in multiple myeloma cells. The CHEMICAL (CHEMICAL), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in DZNep insensitive cells, and cotreatment with DZNep and ABT-737, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of DZNep insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, DZNep insensitivity might be associated with overexpression of Bcl-2, and the combination of ABT-737 and DZNep could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM. | NO-RELATIONSHIP |
| Determinants of sensitivity to DZNep induced apoptosis in multiple myeloma cells. The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in CHEMICAL insensitive cells, and cotreatment with CHEMICAL and ABT-737, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of DZNep insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, DZNep insensitivity might be associated with overexpression of Bcl-2, and the combination of ABT-737 and DZNep could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM. | NO-RELATIONSHIP |
| Determinants of sensitivity to DZNep induced apoptosis in multiple myeloma cells. The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in CHEMICAL insensitive cells, and cotreatment with DZNep and CHEMICAL, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of DZNep insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, DZNep insensitivity might be associated with overexpression of Bcl-2, and the combination of ABT-737 and DZNep could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM. | NO-RELATIONSHIP |
| Determinants of sensitivity to DZNep induced apoptosis in multiple myeloma cells. The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in CHEMICAL insensitive cells, and cotreatment with DZNep and ABT-737, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of CHEMICAL insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, DZNep insensitivity might be associated with overexpression of Bcl-2, and the combination of ABT-737 and DZNep could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM. | NO-RELATIONSHIP |
| Determinants of sensitivity to DZNep induced apoptosis in multiple myeloma cells. The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in DZNep insensitive cells, and cotreatment with CHEMICAL and CHEMICAL, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of DZNep insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, DZNep insensitivity might be associated with overexpression of Bcl-2, and the combination of ABT-737 and DZNep could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM. | CHEMICALS-INTERACTION |
| Determinants of sensitivity to DZNep induced apoptosis in multiple myeloma cells. The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in DZNep insensitive cells, and cotreatment with CHEMICAL and ABT-737, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of CHEMICAL insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, DZNep insensitivity might be associated with overexpression of Bcl-2, and the combination of ABT-737 and DZNep could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM. | NO-RELATIONSHIP |
| Determinants of sensitivity to DZNep induced apoptosis in multiple myeloma cells. The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in DZNep insensitive cells, and cotreatment with DZNep and CHEMICAL, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of CHEMICAL insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, DZNep insensitivity might be associated with overexpression of Bcl-2, and the combination of ABT-737 and DZNep could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM. | NO-RELATIONSHIP |
| Determinants of sensitivity to DZNep induced apoptosis in multiple myeloma cells. The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in DZNep insensitive cells, and cotreatment with DZNep and ABT-737, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of DZNep insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, CHEMICAL insensitivity might be associated with overexpression of Bcl-2, and the combination of CHEMICAL and DZNep could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM. | REGULATOR |
| Determinants of sensitivity to DZNep induced apoptosis in multiple myeloma cells. The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in DZNep insensitive cells, and cotreatment with DZNep and ABT-737, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of DZNep insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, CHEMICAL insensitivity might be associated with overexpression of Bcl-2, and the combination of ABT-737 and CHEMICAL could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM. | CHEMICALS-INTERACTION |
| Determinants of sensitivity to DZNep induced apoptosis in multiple myeloma cells. The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down-regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in DZNep insensitive cells, and cotreatment with DZNep and ABT-737, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of DZNep insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down-regulate the ALOX5 levels. In addition, DZNep insensitivity might be associated with overexpression of Bcl-2, and the combination of CHEMICAL and CHEMICAL could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM. | CHEMICALS-INTERACTION |
| CHEMICAL enhances the antinociceptive effect of CHEMICAL in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, ephedrine (10 mg/kg) + saline, saline + dexmedetomidine (15 g/kg) and ephedrine (10 mg/kg) + dexmedetomidine (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg dexmedetomidine with 10 mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. We concluded that the combined administration of dexmedetomidine with ephedrine may have beneficial effects in the treatment of pain without causing sedation, which limits the use of dexmedetomidine as an analgesic in humans. | CHEMICALS-INTERACTION |
| Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug CHEMICAL has any effect on CHEMICAL-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, ephedrine (10 mg/kg) + saline, saline + dexmedetomidine (15 g/kg) and ephedrine (10 mg/kg) + dexmedetomidine (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg dexmedetomidine with 10 mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. We concluded that the combined administration of dexmedetomidine with ephedrine may have beneficial effects in the treatment of pain without causing sedation, which limits the use of dexmedetomidine as an analgesic in humans. | NO-RELATIONSHIP |
| Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, CHEMICAL (10 mg/kg) + saline, saline + CHEMICAL (15 g/kg) and ephedrine (10 mg/kg) + dexmedetomidine (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg dexmedetomidine with 10 mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. We concluded that the combined administration of dexmedetomidine with ephedrine may have beneficial effects in the treatment of pain without causing sedation, which limits the use of dexmedetomidine as an analgesic in humans. | NO-RELATIONSHIP |
| Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, CHEMICAL (10 mg/kg) + saline, saline + dexmedetomidine (15 g/kg) and CHEMICAL (10 mg/kg) + dexmedetomidine (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg dexmedetomidine with 10 mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. We concluded that the combined administration of dexmedetomidine with ephedrine may have beneficial effects in the treatment of pain without causing sedation, which limits the use of dexmedetomidine as an analgesic in humans. | NO-RELATIONSHIP |
| Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, CHEMICAL (10 mg/kg) + saline, saline + dexmedetomidine (15 g/kg) and ephedrine (10 mg/kg) + CHEMICAL (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg dexmedetomidine with 10 mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. We concluded that the combined administration of dexmedetomidine with ephedrine may have beneficial effects in the treatment of pain without causing sedation, which limits the use of dexmedetomidine as an analgesic in humans. | NO-RELATIONSHIP |
| Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, ephedrine (10 mg/kg) + saline, saline + CHEMICAL (15 g/kg) and CHEMICAL (10 mg/kg) + dexmedetomidine (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg dexmedetomidine with 10 mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. We concluded that the combined administration of dexmedetomidine with ephedrine may have beneficial effects in the treatment of pain without causing sedation, which limits the use of dexmedetomidine as an analgesic in humans. | NO-RELATIONSHIP |
| Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, ephedrine (10 mg/kg) + saline, saline + CHEMICAL (15 g/kg) and ephedrine (10 mg/kg) + CHEMICAL (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg dexmedetomidine with 10 mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. We concluded that the combined administration of dexmedetomidine with ephedrine may have beneficial effects in the treatment of pain without causing sedation, which limits the use of dexmedetomidine as an analgesic in humans. | NO-RELATIONSHIP |
| Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, ephedrine (10 mg/kg) + saline, saline + dexmedetomidine (15 g/kg) and CHEMICAL (10 mg/kg) + CHEMICAL (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg dexmedetomidine with 10 mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. We concluded that the combined administration of dexmedetomidine with ephedrine may have beneficial effects in the treatment of pain without causing sedation, which limits the use of dexmedetomidine as an analgesic in humans. | NO-RELATIONSHIP |
| Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, ephedrine (10 mg/kg) + saline, saline + dexmedetomidine (15 g/kg) and ephedrine (10 mg/kg) + dexmedetomidine (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg CHEMICAL with 10 mg/kg CHEMICAL intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. We concluded that the combined administration of dexmedetomidine with ephedrine may have beneficial effects in the treatment of pain without causing sedation, which limits the use of dexmedetomidine as an analgesic in humans. | CHEMICALS-INTERACTION |
| Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, ephedrine (10 mg/kg) + saline, saline + dexmedetomidine (15 g/kg) and ephedrine (10 mg/kg) + dexmedetomidine (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg CHEMICAL with 10 mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by CHEMICAL. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. We concluded that the combined administration of dexmedetomidine with ephedrine may have beneficial effects in the treatment of pain without causing sedation, which limits the use of dexmedetomidine as an analgesic in humans. | NO-RELATIONSHIP |
| Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, ephedrine (10 mg/kg) + saline, saline + dexmedetomidine (15 g/kg) and ephedrine (10 mg/kg) + dexmedetomidine (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg dexmedetomidine with 10 mg/kg CHEMICAL intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by CHEMICAL. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. We concluded that the combined administration of dexmedetomidine with ephedrine may have beneficial effects in the treatment of pain without causing sedation, which limits the use of dexmedetomidine as an analgesic in humans. | NO-RELATIONSHIP |
| Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, ephedrine (10 mg/kg) + saline, saline + dexmedetomidine (15 g/kg) and ephedrine (10 mg/kg) + dexmedetomidine (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg dexmedetomidine with 10 mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of CHEMICAL was counteracted by CHEMICAL. We concluded that the combined administration of dexmedetomidine with ephedrine may have beneficial effects in the treatment of pain without causing sedation, which limits the use of dexmedetomidine as an analgesic in humans. | CHEMICALS-INTERACTION |
| Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, ephedrine (10 mg/kg) + saline, saline + dexmedetomidine (15 g/kg) and ephedrine (10 mg/kg) + dexmedetomidine (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg dexmedetomidine with 10 mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. We concluded that the combined administration of CHEMICAL with CHEMICAL may have beneficial effects in the treatment of pain without causing sedation, which limits the use of dexmedetomidine as an analgesic in humans. | CHEMICALS-INTERACTION |
| Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, ephedrine (10 mg/kg) + saline, saline + dexmedetomidine (15 g/kg) and ephedrine (10 mg/kg) + dexmedetomidine (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg dexmedetomidine with 10 mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. We concluded that the combined administration of CHEMICAL with ephedrine may have beneficial effects in the treatment of pain without causing sedation, which limits the use of CHEMICAL as an analgesic in humans. | NO-RELATIONSHIP |
| Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, ephedrine (10 mg/kg) + saline, saline + dexmedetomidine (15 g/kg) and ephedrine (10 mg/kg) + dexmedetomidine (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg dexmedetomidine with 10 mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. We concluded that the combined administration of CHEMICAL with ephedrine may have beneficial effects in the treatment of pain without causing sedation, which limits the use of dexmedetomidine as an CHEMICAL in humans. | NO-RELATIONSHIP |
| Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, ephedrine (10 mg/kg) + saline, saline + dexmedetomidine (15 g/kg) and ephedrine (10 mg/kg) + dexmedetomidine (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg dexmedetomidine with 10 mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. We concluded that the combined administration of dexmedetomidine with CHEMICAL may have beneficial effects in the treatment of pain without causing sedation, which limits the use of CHEMICAL as an analgesic in humans. | NO-RELATIONSHIP |
| Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, ephedrine (10 mg/kg) + saline, saline + dexmedetomidine (15 g/kg) and ephedrine (10 mg/kg) + dexmedetomidine (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg dexmedetomidine with 10 mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. We concluded that the combined administration of dexmedetomidine with CHEMICAL may have beneficial effects in the treatment of pain without causing sedation, which limits the use of dexmedetomidine as an CHEMICAL in humans. | NO-RELATIONSHIP |
| Ephedrine enhances the antinociceptive effect of dexmedetomidine in mice. Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application. In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, ephedrine (10 mg/kg) + saline, saline + dexmedetomidine (15 g/kg) and ephedrine (10 mg/kg) + dexmedetomidine (15 g/kg), intraperitoneally, 30 min before hot plate or holed open field tests. In the hot plate test in mice, co-administration of 15 g/kg dexmedetomidine with 10 mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine. We concluded that the combined administration of dexmedetomidine with ephedrine may have beneficial effects in the treatment of pain without causing sedation, which limits the use of CHEMICAL as an CHEMICAL in humans. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: CHEMICAL, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of CHEMICAL when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving CHEMICAL or other potent CYP3A4 inhibitors such as other CHEMICAL (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving CHEMICAL or other potent CYP3A4 inhibitors such as other azole antifungals (eg, CHEMICAL, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving CHEMICAL or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, CHEMICAL) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving CHEMICAL or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or CHEMICAL (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving CHEMICAL or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, CHEMICAL, clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving CHEMICAL or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, CHEMICAL) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving CHEMICAL or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or CHEMICAL or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving CHEMICAL or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or CHEMICAL, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving CHEMICAL or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of CHEMICAL is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other CHEMICAL (eg, CHEMICAL, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other CHEMICAL (eg, itraconazole, CHEMICAL) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other CHEMICAL (eg, itraconazole, miconazole) or CHEMICAL (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other CHEMICAL (eg, itraconazole, miconazole) or macrolide antibiotics (eg, CHEMICAL, clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other CHEMICAL (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, CHEMICAL) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other CHEMICAL (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or CHEMICAL or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other CHEMICAL (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or CHEMICAL, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other CHEMICAL (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of CHEMICAL is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, CHEMICAL, CHEMICAL) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, CHEMICAL, miconazole) or CHEMICAL (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, CHEMICAL, miconazole) or macrolide antibiotics (eg, CHEMICAL, clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, CHEMICAL, miconazole) or macrolide antibiotics (eg, erythromycin, CHEMICAL) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, CHEMICAL, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or CHEMICAL or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, CHEMICAL, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or CHEMICAL, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, CHEMICAL, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of CHEMICAL is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, CHEMICAL) or CHEMICAL (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, CHEMICAL) or macrolide antibiotics (eg, CHEMICAL, clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, CHEMICAL) or macrolide antibiotics (eg, erythromycin, CHEMICAL) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, CHEMICAL) or macrolide antibiotics (eg, erythromycin, clarithromycin) or CHEMICAL or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, CHEMICAL) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or CHEMICAL, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, CHEMICAL) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of CHEMICAL is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or CHEMICAL (eg, CHEMICAL, clarithromycin) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or CHEMICAL (eg, erythromycin, CHEMICAL) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or CHEMICAL (eg, erythromycin, clarithromycin) or CHEMICAL or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or CHEMICAL (eg, erythromycin, clarithromycin) or cyclosporine or CHEMICAL, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or CHEMICAL (eg, erythromycin, clarithromycin) or cyclosporine or vinblastine, the recommended dose of CHEMICAL is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, CHEMICAL, CHEMICAL) or cyclosporine or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, CHEMICAL, clarithromycin) or CHEMICAL or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, CHEMICAL, clarithromycin) or cyclosporine or CHEMICAL, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, CHEMICAL, clarithromycin) or cyclosporine or vinblastine, the recommended dose of CHEMICAL is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, CHEMICAL) or CHEMICAL or vinblastine, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, CHEMICAL) or cyclosporine or CHEMICAL, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, CHEMICAL) or cyclosporine or vinblastine, the recommended dose of CHEMICAL is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or CHEMICAL or CHEMICAL, the recommended dose of DETROL LA is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | NO-RELATIONSHIP |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or CHEMICAL or vinblastine, the recommended dose of CHEMICAL is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| CYP3A4 Inhibitors: Ketoconazole, an inhibitor of the drug metabolizing enzyme CYP3A4, significantly increased plasma concentrations of tolterodine when coadministered to subjects who were poor metabolizers (see CLINICAL PHARMACOLOGY, Variability in Metabolism and Drug-Drug Interactions). For patients receiving ketoconazole or other potent CYP3A4 inhibitors such as other azole antifungals (eg, itraconazole, miconazole) or macrolide antibiotics (eg, erythromycin, clarithromycin) or cyclosporine or CHEMICAL, the recommended dose of CHEMICAL is 2 mg daily. Drug-Laboratory-Test Interactions Interactions between tolterodine and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| Potential for CHEMICAL to Affect Other Drugs CHEMICAL is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. At therapeutic concentrations, paliperidone did not inhibit P-glycoprotein. Paliperidone is therefore not expected to inhibit P-glycoprotein-mediated transport of other drugs in a clinically relevant manner. Given the primary CNS effects of paliperidone, INVEGA should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when INVEGA is administered with other therapeutic agents that have this potential. Potential for Other Drugs to Affect INVEGA Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. | NO-RELATIONSHIP |
| Potential for INVEGA to Affect Other Drugs Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. At therapeutic concentrations, paliperidone did not inhibit P-glycoprotein. Paliperidone is therefore not expected to inhibit P-glycoprotein-mediated transport of other drugs in a clinically relevant manner. Given the primary CNS effects of CHEMICAL, CHEMICAL should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when INVEGA is administered with other therapeutic agents that have this potential. Potential for Other Drugs to Affect INVEGA Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. | NO-RELATIONSHIP |
| Potential for INVEGA to Affect Other Drugs Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. At therapeutic concentrations, paliperidone did not inhibit P-glycoprotein. Paliperidone is therefore not expected to inhibit P-glycoprotein-mediated transport of other drugs in a clinically relevant manner. Given the primary CNS effects of CHEMICAL, INVEGA should be used with caution in combination with other CHEMICAL and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when INVEGA is administered with other therapeutic agents that have this potential. Potential for Other Drugs to Affect INVEGA Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. | NO-RELATIONSHIP |
| Potential for INVEGA to Affect Other Drugs Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. At therapeutic concentrations, paliperidone did not inhibit P-glycoprotein. Paliperidone is therefore not expected to inhibit P-glycoprotein-mediated transport of other drugs in a clinically relevant manner. Given the primary CNS effects of CHEMICAL, INVEGA should be used with caution in combination with other centrally acting drugs and CHEMICAL. Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when INVEGA is administered with other therapeutic agents that have this potential. Potential for Other Drugs to Affect INVEGA Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. | NO-RELATIONSHIP |
| Potential for INVEGA to Affect Other Drugs Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. At therapeutic concentrations, paliperidone did not inhibit P-glycoprotein. Paliperidone is therefore not expected to inhibit P-glycoprotein-mediated transport of other drugs in a clinically relevant manner. Given the primary CNS effects of paliperidone, CHEMICAL should be used with caution in combination with other CHEMICAL and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when INVEGA is administered with other therapeutic agents that have this potential. Potential for Other Drugs to Affect INVEGA Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. | CHEMICALS-INTERACTION |
| Potential for INVEGA to Affect Other Drugs Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. At therapeutic concentrations, paliperidone did not inhibit P-glycoprotein. Paliperidone is therefore not expected to inhibit P-glycoprotein-mediated transport of other drugs in a clinically relevant manner. Given the primary CNS effects of paliperidone, CHEMICAL should be used with caution in combination with other centrally acting drugs and CHEMICAL. Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when INVEGA is administered with other therapeutic agents that have this potential. Potential for Other Drugs to Affect INVEGA Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. | CHEMICALS-INTERACTION |
| Potential for INVEGA to Affect Other Drugs Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. At therapeutic concentrations, paliperidone did not inhibit P-glycoprotein. Paliperidone is therefore not expected to inhibit P-glycoprotein-mediated transport of other drugs in a clinically relevant manner. Given the primary CNS effects of paliperidone, INVEGA should be used with caution in combination with other CHEMICAL and CHEMICAL. Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when INVEGA is administered with other therapeutic agents that have this potential. Potential for Other Drugs to Affect INVEGA Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. | NO-RELATIONSHIP |
| Potential for INVEGA to Affect Other Drugs Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. At therapeutic concentrations, paliperidone did not inhibit P-glycoprotein. Paliperidone is therefore not expected to inhibit P-glycoprotein-mediated transport of other drugs in a clinically relevant manner. Given the primary CNS effects of paliperidone, INVEGA should be used with caution in combination with other centrally acting drugs and alcohol. CHEMICAL may antagonize the effect of CHEMICAL and other dopamine agonists. Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when INVEGA is administered with other therapeutic agents that have this potential. Potential for Other Drugs to Affect INVEGA Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. | CHEMICALS-INTERACTION |
| Potential for INVEGA to Affect Other Drugs Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. At therapeutic concentrations, paliperidone did not inhibit P-glycoprotein. Paliperidone is therefore not expected to inhibit P-glycoprotein-mediated transport of other drugs in a clinically relevant manner. Given the primary CNS effects of paliperidone, INVEGA should be used with caution in combination with other centrally acting drugs and alcohol. CHEMICAL may antagonize the effect of levodopa and other CHEMICAL. Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when INVEGA is administered with other therapeutic agents that have this potential. Potential for Other Drugs to Affect INVEGA Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. | CHEMICALS-INTERACTION |
| Potential for INVEGA to Affect Other Drugs Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. At therapeutic concentrations, paliperidone did not inhibit P-glycoprotein. Paliperidone is therefore not expected to inhibit P-glycoprotein-mediated transport of other drugs in a clinically relevant manner. Given the primary CNS effects of paliperidone, INVEGA should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of CHEMICAL and other CHEMICAL. Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when INVEGA is administered with other therapeutic agents that have this potential. Potential for Other Drugs to Affect INVEGA Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. | NO-RELATIONSHIP |
| Potential for INVEGA to Affect Other Drugs Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties. At therapeutic concentrations, paliperidone did not inhibit P-glycoprotein. Paliperidone is therefore not expected to inhibit P-glycoprotein-mediated transport of other drugs in a clinically relevant manner. Given the primary CNS effects of paliperidone, INVEGA should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when INVEGA is administered with other therapeutic agents that have this potential. Potential for Other Drugs to Affect CHEMICAL CHEMICAL is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. | NO-RELATIONSHIP |
| The concomitant use of CHEMICAL with other CHEMICAL or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | CHEMICALS-INTERACTION |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean CHEMICAL plasma concentrations were approximately 2 fold higher when CHEMICAL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean CHEMICAL plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with CHEMICAL, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when CHEMICAL was administered with CHEMICAL, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | CHEMICALS-INTERACTION |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as CHEMICAL (e.g., CHEMICAL and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as CHEMICAL (e.g., itraconazole and CHEMICAL) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as CHEMICAL (e.g., itraconazole and miconazole) or CHEMICAL (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as CHEMICAL (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., CHEMICAL and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as CHEMICAL (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and CHEMICAL), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as CHEMICAL (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter CHEMICAL mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | CHEMICALS-INTERACTION |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., CHEMICAL and CHEMICAL) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., CHEMICAL and miconazole) or CHEMICAL (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., CHEMICAL and miconazole) or macrolide antibiotics (e.g., CHEMICAL and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., CHEMICAL and miconazole) or macrolide antibiotics (e.g., erythromycin and CHEMICAL), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., CHEMICAL and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter CHEMICAL mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | CHEMICALS-INTERACTION |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and CHEMICAL) or CHEMICAL (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and CHEMICAL) or macrolide antibiotics (e.g., CHEMICAL and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and CHEMICAL) or macrolide antibiotics (e.g., erythromycin and CHEMICAL), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and CHEMICAL) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter CHEMICAL mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | CHEMICALS-INTERACTION |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or CHEMICAL (e.g., CHEMICAL and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or CHEMICAL (e.g., erythromycin and CHEMICAL), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or CHEMICAL (e.g., erythromycin and clarithromycin), may alter CHEMICAL mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | CHEMICALS-INTERACTION |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., CHEMICAL and CHEMICAL), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., CHEMICAL and clarithromycin), may alter CHEMICAL mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | CHEMICALS-INTERACTION |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and CHEMICAL), may alter CHEMICAL mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | CHEMICALS-INTERACTION |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of CHEMICAL (20 mL of CHEMICAL containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of CHEMICAL (20 mL of antacid containing CHEMICAL, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of CHEMICAL (20 mL of antacid containing aluminum hydroxide, CHEMICAL, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of CHEMICAL (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and CHEMICAL) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of CHEMICAL (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of CHEMICAL or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of CHEMICAL (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or CHEMICAL. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of CHEMICAL containing CHEMICAL, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of CHEMICAL containing aluminum hydroxide, CHEMICAL, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of CHEMICAL containing aluminum hydroxide, magnesium hydroxide, and CHEMICAL) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of CHEMICAL containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of CHEMICAL or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of CHEMICAL containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or CHEMICAL. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing CHEMICAL, CHEMICAL, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing CHEMICAL, magnesium hydroxide, and CHEMICAL) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing CHEMICAL, magnesium hydroxide, and simethicone) did not significantly affect the exposure of CHEMICAL or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing CHEMICAL, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or CHEMICAL. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, CHEMICAL, and CHEMICAL) did not significantly affect the exposure of oxybutynin or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, CHEMICAL, and simethicone) did not significantly affect the exposure of CHEMICAL or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, CHEMICAL, and simethicone) did not significantly affect the exposure of oxybutynin or CHEMICAL. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and CHEMICAL) did not significantly affect the exposure of CHEMICAL or desethyloxybutynin. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and CHEMICAL) did not significantly affect the exposure of oxybutynin or CHEMICAL. | NO-RELATIONSHIP |
| The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. This may be of concern for drugs with a narrow therapeutic index. Mean oxybutynin chloride plasma concentrations were approximately 2 fold higher when DITROPAN XL was administered with ketoconazole, a potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of CHEMICAL or CHEMICAL. | NO-RELATIONSHIP |
| CHEMICAL has been reported to accelerate the metabolism of CHEMICAL by the mechanism of hepatic microsomal enzyme induction, leading to an increase in dosage requirements for warfarin. Therefore, physicians should closely monitor patients for a change in anticoagulant dosage requirements when administering Mitotane to patients on coumarin-type anticoagulants. In addition, Mitotane should be given with caution to patients receiving other drugs susceptible to the influence of hepatic enzyme induction. | CHEMICALS-INTERACTION |
| CHEMICAL has been reported to accelerate the metabolism of warfarin by the mechanism of hepatic microsomal enzyme induction, leading to an increase in dosage requirements for CHEMICAL. Therefore, physicians should closely monitor patients for a change in anticoagulant dosage requirements when administering Mitotane to patients on coumarin-type anticoagulants. In addition, Mitotane should be given with caution to patients receiving other drugs susceptible to the influence of hepatic enzyme induction. | NO-RELATIONSHIP |
| Mitotane has been reported to accelerate the metabolism of CHEMICAL by the mechanism of hepatic microsomal enzyme induction, leading to an increase in dosage requirements for CHEMICAL. Therefore, physicians should closely monitor patients for a change in anticoagulant dosage requirements when administering Mitotane to patients on coumarin-type anticoagulants. In addition, Mitotane should be given with caution to patients receiving other drugs susceptible to the influence of hepatic enzyme induction. | NO-RELATIONSHIP |
| Mitotane has been reported to accelerate the metabolism of warfarin by the mechanism of hepatic microsomal enzyme induction, leading to an increase in dosage requirements for warfarin. Therefore, physicians should closely monitor patients for a change in CHEMICAL dosage requirements when administering CHEMICAL to patients on coumarin-type anticoagulants. In addition, Mitotane should be given with caution to patients receiving other drugs susceptible to the influence of hepatic enzyme induction. | CHEMICALS-INTERACTION |
| Mitotane has been reported to accelerate the metabolism of warfarin by the mechanism of hepatic microsomal enzyme induction, leading to an increase in dosage requirements for warfarin. Therefore, physicians should closely monitor patients for a change in CHEMICAL dosage requirements when administering Mitotane to patients on CHEMICAL. In addition, Mitotane should be given with caution to patients receiving other drugs susceptible to the influence of hepatic enzyme induction. | NO-RELATIONSHIP |
| Mitotane has been reported to accelerate the metabolism of warfarin by the mechanism of hepatic microsomal enzyme induction, leading to an increase in dosage requirements for warfarin. Therefore, physicians should closely monitor patients for a change in anticoagulant dosage requirements when administering CHEMICAL to patients on CHEMICAL. In addition, Mitotane should be given with caution to patients receiving other drugs susceptible to the influence of hepatic enzyme induction. | CHEMICALS-INTERACTION |
| Concomitant administration of CHEMICAL and CHEMICAL has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as amphotericin B, aminoglycosides, bacitracin, polymyxin B, colistin, viomycin, or cisplatin, when indicated, requires careful monitoring. | CHEMICALS-INTERACTION |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as CHEMICAL, CHEMICAL, bacitracin, polymyxin B, colistin, viomycin, or cisplatin, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as CHEMICAL, aminoglycosides, CHEMICAL, polymyxin B, colistin, viomycin, or cisplatin, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as CHEMICAL, aminoglycosides, bacitracin, CHEMICAL, colistin, viomycin, or cisplatin, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as CHEMICAL, aminoglycosides, bacitracin, polymyxin B, CHEMICAL, viomycin, or cisplatin, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as CHEMICAL, aminoglycosides, bacitracin, polymyxin B, colistin, CHEMICAL, or cisplatin, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as CHEMICAL, aminoglycosides, bacitracin, polymyxin B, colistin, viomycin, or CHEMICAL, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as amphotericin B, CHEMICAL, CHEMICAL, polymyxin B, colistin, viomycin, or cisplatin, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as amphotericin B, CHEMICAL, bacitracin, CHEMICAL, colistin, viomycin, or cisplatin, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as amphotericin B, CHEMICAL, bacitracin, polymyxin B, CHEMICAL, viomycin, or cisplatin, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as amphotericin B, CHEMICAL, bacitracin, polymyxin B, colistin, CHEMICAL, or cisplatin, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as amphotericin B, CHEMICAL, bacitracin, polymyxin B, colistin, viomycin, or CHEMICAL, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as amphotericin B, aminoglycosides, CHEMICAL, CHEMICAL, colistin, viomycin, or cisplatin, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as amphotericin B, aminoglycosides, CHEMICAL, polymyxin B, CHEMICAL, viomycin, or cisplatin, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as amphotericin B, aminoglycosides, CHEMICAL, polymyxin B, colistin, CHEMICAL, or cisplatin, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as amphotericin B, aminoglycosides, CHEMICAL, polymyxin B, colistin, viomycin, or CHEMICAL, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as amphotericin B, aminoglycosides, bacitracin, CHEMICAL, CHEMICAL, viomycin, or cisplatin, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as amphotericin B, aminoglycosides, bacitracin, CHEMICAL, colistin, CHEMICAL, or cisplatin, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as amphotericin B, aminoglycosides, bacitracin, CHEMICAL, colistin, viomycin, or CHEMICAL, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as amphotericin B, aminoglycosides, bacitracin, polymyxin B, CHEMICAL, CHEMICAL, or cisplatin, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as amphotericin B, aminoglycosides, bacitracin, polymyxin B, CHEMICAL, viomycin, or CHEMICAL, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Concomitant administration of vancomycin and anesthetic agents has been associated with erythema and histamine-like flushing and anaphylactoid reactions. Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as amphotericin B, aminoglycosides, bacitracin, polymyxin B, colistin, CHEMICAL, or CHEMICAL, when indicated, requires careful monitoring. | NO-RELATIONSHIP |
| Protective effect of CHEMICAL and CHEMICAL against the acute toxicity of diepoxybutane to human lymphocytes. The biotransformation and oxidative stress may contribute to 1,2:3,4-diepoxybutane (DEB)-induced toxicity to human lymphocytes of Fanconi Anemia (FA) patients. Thus, the identification of putative inhibitors of bioactivation, as well as the determination of the protective role of oxidant defenses, on DEB-induced toxicity, can help to understand what is failing in FA cells. In the present work we studied the contribution of several biochemical pathways for DEB-induced acute toxicity in human lymphocyte suspensions, by using inhibitors of epoxide hydrolases, inhibitors of protective enzymes as glutathione S-transferase and catalase, the depletion of glutathione (GSH), and the inhibition of protein synthesis; and a variety of putative protective compounds, including antioxidants, and mitochondrial protective agents. The present study reports two novel findings: (i) it was clearly evidenced, for the first time, that the acute exposure of freshly isolated human lymphocytes to DEB results in severe GSH depletion and loss of ATP, followed by cell death; (ii) acetyl-l-carnitine elicits a significant protective effect on DEB induced toxicity, which was potentiated by alpha-lipoic acid. Collectively, these findings contribute to increase our knowledge of DEB-induce toxicity and will be very useful when applied in studies with lymphocytes from FA patients, in order to find out a protective agent against spontaneous and DEB-induced chromosome instability. | NO-RELATIONSHIP |
| Protective effect of acetyl-l-carnitine and alpha lipoic acid against the acute toxicity of diepoxybutane to human lymphocytes. The biotransformation and oxidative stress may contribute to 1,2:3,4-diepoxybutane (DEB)-induced toxicity to human lymphocytes of Fanconi Anemia (FA) patients. Thus, the identification of putative inhibitors of bioactivation, as well as the determination of the protective role of oxidant defenses, on DEB-induced toxicity, can help to understand what is failing in FA cells. In the present work we studied the contribution of several biochemical pathways for DEB-induced acute toxicity in human lymphocyte suspensions, by using inhibitors of epoxide hydrolases, inhibitors of protective enzymes as glutathione S-transferase and catalase, the depletion of glutathione (GSH), and the inhibition of protein synthesis; and a variety of putative protective compounds, including antioxidants, and mitochondrial protective agents. The present study reports two novel findings: (i) it was clearly evidenced, for the first time, that the acute exposure of freshly isolated human lymphocytes to DEB results in severe GSH depletion and loss of ATP, followed by cell death; (ii) CHEMICAL elicits a significant protective effect on DEB induced toxicity, which was potentiated by CHEMICAL. Collectively, these findings contribute to increase our knowledge of DEB-induce toxicity and will be very useful when applied in studies with lymphocytes from FA patients, in order to find out a protective agent against spontaneous and DEB-induced chromosome instability. | CHEMICALS-INTERACTION |
| Coadministration of CHEMICAL with CHEMICAL resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14- hydroxy- clarithromycin plasma concentrations (31%). Coadministration with aspirin results in a slight decrease in the rate of salicylate absorption that is clinically unimportant. Coadministration with a high dose of antacid (170 mEq) results in a 28% decrease in plasma concentrations of ranitidine and may decrease plasma concentrations of bismuth from TRITEC. These effects are clinically insignificant. For information on drug interactions associated with ranitidine, refer to the ZANTAC package insert. | CHEMICALS-INTERACTION |
| Coadministration of CHEMICAL with clarithromycin resulted in increased plasma CHEMICAL concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14- hydroxy- clarithromycin plasma concentrations (31%). Coadministration with aspirin results in a slight decrease in the rate of salicylate absorption that is clinically unimportant. Coadministration with a high dose of antacid (170 mEq) results in a 28% decrease in plasma concentrations of ranitidine and may decrease plasma concentrations of bismuth from TRITEC. These effects are clinically insignificant. For information on drug interactions associated with ranitidine, refer to the ZANTAC package insert. | NO-RELATIONSHIP |
| Coadministration of CHEMICAL with clarithromycin resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased CHEMICAL plasma concentrations (31%). Coadministration with aspirin results in a slight decrease in the rate of salicylate absorption that is clinically unimportant. Coadministration with a high dose of antacid (170 mEq) results in a 28% decrease in plasma concentrations of ranitidine and may decrease plasma concentrations of bismuth from TRITEC. These effects are clinically insignificant. For information on drug interactions associated with ranitidine, refer to the ZANTAC package insert. | NO-RELATIONSHIP |
| Coadministration of TRITEC with CHEMICAL resulted in increased plasma CHEMICAL concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14- hydroxy- clarithromycin plasma concentrations (31%). Coadministration with aspirin results in a slight decrease in the rate of salicylate absorption that is clinically unimportant. Coadministration with a high dose of antacid (170 mEq) results in a 28% decrease in plasma concentrations of ranitidine and may decrease plasma concentrations of bismuth from TRITEC. These effects are clinically insignificant. For information on drug interactions associated with ranitidine, refer to the ZANTAC package insert. | NO-RELATIONSHIP |
| Coadministration of TRITEC with CHEMICAL resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased CHEMICAL plasma concentrations (31%). Coadministration with aspirin results in a slight decrease in the rate of salicylate absorption that is clinically unimportant. Coadministration with a high dose of antacid (170 mEq) results in a 28% decrease in plasma concentrations of ranitidine and may decrease plasma concentrations of bismuth from TRITEC. These effects are clinically insignificant. For information on drug interactions associated with ranitidine, refer to the ZANTAC package insert. | NO-RELATIONSHIP |
| Coadministration of TRITEC with clarithromycin resulted in increased plasma CHEMICAL concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased CHEMICAL plasma concentrations (31%). Coadministration with aspirin results in a slight decrease in the rate of salicylate absorption that is clinically unimportant. Coadministration with a high dose of antacid (170 mEq) results in a 28% decrease in plasma concentrations of ranitidine and may decrease plasma concentrations of bismuth from TRITEC. These effects are clinically insignificant. For information on drug interactions associated with ranitidine, refer to the ZANTAC package insert. | NO-RELATIONSHIP |
| Coadministration of TRITEC with clarithromycin resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14- hydroxy- clarithromycin plasma concentrations (31%). Coadministration with CHEMICAL results in a slight decrease in the rate of CHEMICAL absorption that is clinically unimportant. Coadministration with a high dose of antacid (170 mEq) results in a 28% decrease in plasma concentrations of ranitidine and may decrease plasma concentrations of bismuth from TRITEC. These effects are clinically insignificant. For information on drug interactions associated with ranitidine, refer to the ZANTAC package insert. | CHEMICALS-INTERACTION |
| Coadministration of TRITEC with clarithromycin resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14- hydroxy- clarithromycin plasma concentrations (31%). Coadministration with aspirin results in a slight decrease in the rate of salicylate absorption that is clinically unimportant. Coadministration with a high dose of CHEMICAL (170 mEq) results in a 28% decrease in plasma concentrations of CHEMICAL and may decrease plasma concentrations of bismuth from TRITEC. These effects are clinically insignificant. For information on drug interactions associated with ranitidine, refer to the ZANTAC package insert. | NO-RELATIONSHIP |
| Coadministration of TRITEC with clarithromycin resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14- hydroxy- clarithromycin plasma concentrations (31%). Coadministration with aspirin results in a slight decrease in the rate of salicylate absorption that is clinically unimportant. Coadministration with a high dose of CHEMICAL (170 mEq) results in a 28% decrease in plasma concentrations of ranitidine and may decrease plasma concentrations of bismuth from CHEMICAL. These effects are clinically insignificant. For information on drug interactions associated with ranitidine, refer to the ZANTAC package insert. | CHEMICALS-INTERACTION |
| Coadministration of TRITEC with clarithromycin resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14- hydroxy- clarithromycin plasma concentrations (31%). Coadministration with aspirin results in a slight decrease in the rate of salicylate absorption that is clinically unimportant. Coadministration with a high dose of antacid (170 mEq) results in a 28% decrease in plasma concentrations of CHEMICAL and may decrease plasma concentrations of bismuth from CHEMICAL. These effects are clinically insignificant. For information on drug interactions associated with ranitidine, refer to the ZANTAC package insert. | NO-RELATIONSHIP |
| Coadministration of TRITEC with clarithromycin resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14- hydroxy- clarithromycin plasma concentrations (31%). Coadministration with aspirin results in a slight decrease in the rate of salicylate absorption that is clinically unimportant. Coadministration with a high dose of antacid (170 mEq) results in a 28% decrease in plasma concentrations of ranitidine and may decrease plasma concentrations of bismuth from TRITEC. These effects are clinically insignificant. For information on drug interactions associated with CHEMICAL, refer to the CHEMICAL package insert. | NO-RELATIONSHIP |
| SPIRIVA has been used concomitantly with other drugs commonly used in COPD without increases in adverse drug reactions. These include CHEMICAL, CHEMICAL, and oral and inhaled steroids. However, the co administration of SPIRIVA with other anticholinergic containing drugs (e.g., ipratropium) has not been studied and is therefore not recommended. | NO-RELATIONSHIP |
| SPIRIVA has been used concomitantly with other drugs commonly used in COPD without increases in adverse drug reactions. These include CHEMICAL, methylxanthines, and oral and inhaled CHEMICAL. However, the co administration of SPIRIVA with other anticholinergic containing drugs (e.g., ipratropium) has not been studied and is therefore not recommended. | NO-RELATIONSHIP |
| SPIRIVA has been used concomitantly with other drugs commonly used in COPD without increases in adverse drug reactions. These include sympathomimetic bronchodilators, CHEMICAL, and oral and inhaled CHEMICAL. However, the co administration of SPIRIVA with other anticholinergic containing drugs (e.g., ipratropium) has not been studied and is therefore not recommended. | NO-RELATIONSHIP |
| SPIRIVA has been used concomitantly with other drugs commonly used in COPD without increases in adverse drug reactions. These include sympathomimetic bronchodilators, methylxanthines, and oral and inhaled steroids. However, the co administration of CHEMICAL with other CHEMICAL containing drugs (e.g., ipratropium) has not been studied and is therefore not recommended. | CHEMICALS-INTERACTION |
| SPIRIVA has been used concomitantly with other drugs commonly used in COPD without increases in adverse drug reactions. These include sympathomimetic bronchodilators, methylxanthines, and oral and inhaled steroids. However, the co administration of CHEMICAL with other anticholinergic containing drugs (e.g., CHEMICAL) has not been studied and is therefore not recommended. | CHEMICALS-INTERACTION |
| SPIRIVA has been used concomitantly with other drugs commonly used in COPD without increases in adverse drug reactions. These include sympathomimetic bronchodilators, methylxanthines, and oral and inhaled steroids. However, the co administration of SPIRIVA with other CHEMICAL containing drugs (e.g., CHEMICAL) has not been studied and is therefore not recommended. | NO-RELATIONSHIP |
| Prothrombin time or other suitable anticoagulation test should be monitored if CHEMICAL is administered with CHEMICAL. Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective. Drug/Laboratory Test Interactions There are no reported drug-laboratory test interactions. | CHEMICALS-INTERACTION |
| Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin. Concurrent use of CHEMICAL with oral CHEMICAL may render oral contraceptives less effective. Drug/Laboratory Test Interactions There are no reported drug-laboratory test interactions. | CHEMICALS-INTERACTION |
| Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin. Concurrent use of CHEMICAL with oral contraceptives may render oral CHEMICAL less effective. Drug/Laboratory Test Interactions There are no reported drug-laboratory test interactions. | NO-RELATIONSHIP |
| Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin. Concurrent use of antibacterial drugs with oral CHEMICAL may render oral CHEMICAL less effective. Drug/Laboratory Test Interactions There are no reported drug-laboratory test interactions. | NO-RELATIONSHIP |
| The role of p27(Kip1) in CHEMICAL-enhanced CHEMICAL cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | CHEMICALS-INTERACTION |
| The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of CHEMICAL, an inhibitor of Src and Abl kinases, on CHEMICAL sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | REGULATOR |
| The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by CHEMICAL and CHEMICAL were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | NO-RELATIONSHIP |
| The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with CHEMICAL plus CHEMICAL formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | CHEMICALS-INTERACTION |
| The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with CHEMICAL plus CHEMICAL inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | CHEMICALS-INTERACTION |
| The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with CHEMICAL plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, CHEMICAL + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | NO-RELATIONSHIP |
| The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with CHEMICAL plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + CHEMICAL vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | NO-RELATIONSHIP |
| The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with CHEMICAL plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs CHEMICAL: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | NO-RELATIONSHIP |
| The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus CHEMICAL inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, CHEMICAL + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | NO-RELATIONSHIP |
| The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus CHEMICAL inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + CHEMICAL vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | NO-RELATIONSHIP |
| The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus CHEMICAL inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs CHEMICAL: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | NO-RELATIONSHIP |
| The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, CHEMICAL + CHEMICAL vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | NO-RELATIONSHIP |
| The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, CHEMICAL + paclitaxel vs CHEMICAL: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | NO-RELATIONSHIP |
| The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + CHEMICAL vs CHEMICAL: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | NO-RELATIONSHIP |
| The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); CHEMICAL + CHEMICAL vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | NO-RELATIONSHIP |
| The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased CHEMICAL- and CHEMICAL-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | NO-RELATIONSHIP |
| The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that CHEMICAL-mediated induction of p27(Kip1) enhanced CHEMICAL-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | CHEMICALS-INTERACTION |
| The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. Inhibition of Src family and Abl kinases with either siRNAs or CHEMICAL enhances CHEMICAL sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. | NO-RELATIONSHIP |
| CHEMICAL may enhance the sedative effects of CHEMICAL including alcohol, barbiturates, hypnotics, narcotic analgesics, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | CHEMICALS-INTERACTION |
| CHEMICAL may enhance the sedative effects of central nervous system depressants including CHEMICAL, barbiturates, hypnotics, narcotic analgesics, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | CHEMICALS-INTERACTION |
| CHEMICAL may enhance the sedative effects of central nervous system depressants including alcohol, CHEMICAL, hypnotics, narcotic analgesics, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | CHEMICALS-INTERACTION |
| CHEMICAL may enhance the sedative effects of central nervous system depressants including alcohol, barbiturates, CHEMICAL, narcotic analgesics, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | CHEMICALS-INTERACTION |
| CHEMICAL may enhance the sedative effects of central nervous system depressants including alcohol, barbiturates, hypnotics, CHEMICAL, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | CHEMICALS-INTERACTION |
| CHEMICAL may enhance the sedative effects of central nervous system depressants including alcohol, barbiturates, hypnotics, narcotic analgesics, CHEMICAL, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | CHEMICALS-INTERACTION |
| CHEMICAL may enhance the sedative effects of central nervous system depressants including alcohol, barbiturates, hypnotics, narcotic analgesics, sedatives, and CHEMICAL. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | CHEMICALS-INTERACTION |
| Triprolidine may enhance the sedative effects of CHEMICAL including CHEMICAL, barbiturates, hypnotics, narcotic analgesics, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of CHEMICAL including alcohol, CHEMICAL, hypnotics, narcotic analgesics, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of CHEMICAL including alcohol, barbiturates, CHEMICAL, narcotic analgesics, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of CHEMICAL including alcohol, barbiturates, hypnotics, CHEMICAL, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of CHEMICAL including alcohol, barbiturates, hypnotics, narcotic analgesics, CHEMICAL, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of CHEMICAL including alcohol, barbiturates, hypnotics, narcotic analgesics, sedatives, and CHEMICAL. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including CHEMICAL, CHEMICAL, hypnotics, narcotic analgesics, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including CHEMICAL, barbiturates, CHEMICAL, narcotic analgesics, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including CHEMICAL, barbiturates, hypnotics, CHEMICAL, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including CHEMICAL, barbiturates, hypnotics, narcotic analgesics, CHEMICAL, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including CHEMICAL, barbiturates, hypnotics, narcotic analgesics, sedatives, and CHEMICAL. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including alcohol, CHEMICAL, CHEMICAL, narcotic analgesics, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including alcohol, CHEMICAL, hypnotics, CHEMICAL, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including alcohol, CHEMICAL, hypnotics, narcotic analgesics, CHEMICAL, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including alcohol, CHEMICAL, hypnotics, narcotic analgesics, sedatives, and CHEMICAL. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including alcohol, barbiturates, CHEMICAL, CHEMICAL, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including alcohol, barbiturates, CHEMICAL, narcotic analgesics, CHEMICAL, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including alcohol, barbiturates, CHEMICAL, narcotic analgesics, sedatives, and CHEMICAL. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including alcohol, barbiturates, hypnotics, CHEMICAL, CHEMICAL, and tranquillisers. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including alcohol, barbiturates, hypnotics, CHEMICAL, sedatives, and CHEMICAL. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including alcohol, barbiturates, hypnotics, narcotic analgesics, CHEMICAL, and CHEMICAL. The effects of anticholinergic drugs, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including alcohol, barbiturates, hypnotics, narcotic analgesics, sedatives, and tranquillisers. The effects of CHEMICAL, such as CHEMICAL and tricyclic antidepressants may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including alcohol, barbiturates, hypnotics, narcotic analgesics, sedatives, and tranquillisers. The effects of CHEMICAL, such as atropine and CHEMICAL may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including alcohol, barbiturates, hypnotics, narcotic analgesics, sedatives, and tranquillisers. The effects of CHEMICAL, such as atropine and tricyclic antidepressants may be enhanced by the concomitant administration of CHEMICAL. Triprolidine may effect the metabolism of drugs in the liver. | CHEMICALS-INTERACTION |
| Triprolidine may enhance the sedative effects of central nervous system depressants including alcohol, barbiturates, hypnotics, narcotic analgesics, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as CHEMICAL and CHEMICAL may be enhanced by the concomitant administration of triprolidine. Triprolidine may effect the metabolism of drugs in the liver. | NO-RELATIONSHIP |
| Triprolidine may enhance the sedative effects of central nervous system depressants including alcohol, barbiturates, hypnotics, narcotic analgesics, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as CHEMICAL and tricyclic antidepressants may be enhanced by the concomitant administration of CHEMICAL. Triprolidine may effect the metabolism of drugs in the liver. | CHEMICALS-INTERACTION |
| Triprolidine may enhance the sedative effects of central nervous system depressants including alcohol, barbiturates, hypnotics, narcotic analgesics, sedatives, and tranquillisers. The effects of anticholinergic drugs, such as atropine and CHEMICAL may be enhanced by the concomitant administration of CHEMICAL. Triprolidine may effect the metabolism of drugs in the liver. | CHEMICALS-INTERACTION |
| Interaction of CHEMICAL with different CHEMICAL is antagonistic in breast but not in other cancer cells. Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, cisplatin, doxorubicin and etoposide celecoxib following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. | CHEMICALS-INTERACTION |
| Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells. Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of CHEMICAL to sensitize cells from different origins to several CHEMICAL. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, cisplatin, doxorubicin and etoposide celecoxib following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. | REGULATOR |
| Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells. Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to CHEMICAL, CHEMICAL, doxorubicin and etoposide celecoxib following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. | NO-RELATIONSHIP |
| Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells. Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to CHEMICAL, cisplatin, CHEMICAL and etoposide celecoxib following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. | NO-RELATIONSHIP |
| Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells. Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to CHEMICAL, cisplatin, doxorubicin and CHEMICAL celecoxib following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. | NO-RELATIONSHIP |
| Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells. Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to CHEMICAL, cisplatin, doxorubicin and etoposide CHEMICAL following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. | NO-RELATIONSHIP |
| Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells. Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, CHEMICAL, CHEMICAL and etoposide celecoxib following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. | NO-RELATIONSHIP |
| Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells. Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, CHEMICAL, doxorubicin and CHEMICAL celecoxib following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. | NO-RELATIONSHIP |
| Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells. Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, CHEMICAL, doxorubicin and etoposide CHEMICAL following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. | NO-RELATIONSHIP |
| Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells. Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, cisplatin, CHEMICAL and CHEMICAL celecoxib following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. | NO-RELATIONSHIP |
| Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells. Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, cisplatin, CHEMICAL and etoposide CHEMICAL following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. | NO-RELATIONSHIP |
| Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells. Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, cisplatin, doxorubicin and CHEMICAL CHEMICAL following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. | NO-RELATIONSHIP |
| Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells. Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, cisplatin, doxorubicin and etoposide celecoxib following different incubation schedules were analyzed. We found antagonism between CHEMICAL and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between CHEMICAL and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. | INHIBITOR |
| Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells. Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, cisplatin, doxorubicin and etoposide celecoxib following different incubation schedules were analyzed. We found antagonism between CHEMICAL and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and CHEMICAL in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. | INHIBITOR |
| Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells. Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, cisplatin, doxorubicin and etoposide celecoxib following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between CHEMICAL and CHEMICAL in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. | NO-RELATIONSHIP |
| Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells. Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, cisplatin, doxorubicin and etoposide celecoxib following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that CHEMICAL is not a suitable chemosensitizer for breast cancer or with CHEMICAL for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. CHEMICAL and CHEMICAL) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. CHEMICAL and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain CHEMICAL (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. CHEMICAL and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. CHEMICAL and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | CHEMICALS-INTERACTION |
| CYP 3A4 Inhibitors (e.g. CHEMICAL and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and CHEMICAL) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and CHEMICAL) There have been rare reports of serious adverse events in connection with the coadministration of certain CHEMICAL (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and CHEMICAL) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. CHEMICAL and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and CHEMICAL) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and CHEMICAL) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain CHEMICAL (e.g. CHEMICAL and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain CHEMICAL (e.g. dihydroergotamine and CHEMICAL) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. CHEMICAL and CHEMICAL) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include CHEMICAL (e.g., CHEMICAL, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include CHEMICAL (e.g., erythromycin, CHEMICAL, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include CHEMICAL (e.g., erythromycin, troleandomycin, CHEMICAL), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include CHEMICAL (e.g., erythromycin, troleandomycin, clarithromycin), CHEMICAL or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include CHEMICAL (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or CHEMICAL (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include CHEMICAL (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., CHEMICAL, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include CHEMICAL (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, CHEMICAL, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include CHEMICAL (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, CHEMICAL, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include CHEMICAL (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, CHEMICAL) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include CHEMICAL (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or CHEMICAL (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include CHEMICAL (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., CHEMICAL, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include CHEMICAL (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, CHEMICAL, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include CHEMICAL (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, CHEMICAL). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., CHEMICAL, CHEMICAL, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., CHEMICAL, troleandomycin, CHEMICAL), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., CHEMICAL, troleandomycin, clarithromycin), CHEMICAL or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., CHEMICAL, troleandomycin, clarithromycin), HIV protease inhibitors or CHEMICAL (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., CHEMICAL, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., CHEMICAL, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., CHEMICAL, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, CHEMICAL, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., CHEMICAL, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, CHEMICAL, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., CHEMICAL, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, CHEMICAL) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., CHEMICAL, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or CHEMICAL (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., CHEMICAL, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., CHEMICAL, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., CHEMICAL, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, CHEMICAL, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., CHEMICAL, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, CHEMICAL). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, CHEMICAL, CHEMICAL), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, CHEMICAL, clarithromycin), CHEMICAL or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, CHEMICAL, clarithromycin), HIV protease inhibitors or CHEMICAL (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, CHEMICAL, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., CHEMICAL, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, CHEMICAL, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, CHEMICAL, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, CHEMICAL, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, CHEMICAL, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, CHEMICAL, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, CHEMICAL) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, CHEMICAL, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or CHEMICAL (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, CHEMICAL, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., CHEMICAL, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, CHEMICAL, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, CHEMICAL, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, CHEMICAL, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, CHEMICAL). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, CHEMICAL), CHEMICAL or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, CHEMICAL), HIV protease inhibitors or CHEMICAL (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, CHEMICAL), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., CHEMICAL, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, CHEMICAL), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, CHEMICAL, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, CHEMICAL), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, CHEMICAL, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, CHEMICAL), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, CHEMICAL) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, CHEMICAL), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or CHEMICAL (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, CHEMICAL), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., CHEMICAL, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, CHEMICAL), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, CHEMICAL, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, CHEMICAL), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, CHEMICAL). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), CHEMICAL or CHEMICAL (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), CHEMICAL or reverse transcriptase inhibitors (e.g., CHEMICAL, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), CHEMICAL or reverse transcriptase inhibitors (e.g., ritonavir, CHEMICAL, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), CHEMICAL or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, CHEMICAL, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), CHEMICAL or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, CHEMICAL) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), CHEMICAL or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or CHEMICAL (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), CHEMICAL or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., CHEMICAL, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), CHEMICAL or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, CHEMICAL, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), CHEMICAL or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, CHEMICAL). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or CHEMICAL (e.g., CHEMICAL, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or CHEMICAL (e.g., ritonavir, CHEMICAL, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or CHEMICAL (e.g., ritonavir, indinavir, CHEMICAL, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or CHEMICAL (e.g., ritonavir, indinavir, nelfinavir, CHEMICAL) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or CHEMICAL (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or CHEMICAL (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or CHEMICAL (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., CHEMICAL, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or CHEMICAL (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, CHEMICAL, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or CHEMICAL (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, CHEMICAL). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., CHEMICAL, CHEMICAL, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., CHEMICAL, indinavir, CHEMICAL, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., CHEMICAL, indinavir, nelfinavir, CHEMICAL) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., CHEMICAL, indinavir, nelfinavir, delavirdine) or CHEMICAL (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., CHEMICAL, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., CHEMICAL, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., CHEMICAL, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, CHEMICAL, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., CHEMICAL, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, CHEMICAL). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, CHEMICAL, CHEMICAL, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, CHEMICAL, nelfinavir, CHEMICAL) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, CHEMICAL, nelfinavir, delavirdine) or CHEMICAL (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, CHEMICAL, nelfinavir, delavirdine) or azole antifungals (e.g., CHEMICAL, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, CHEMICAL, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, CHEMICAL, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, CHEMICAL, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, CHEMICAL). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, CHEMICAL, CHEMICAL) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, CHEMICAL, delavirdine) or CHEMICAL (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, CHEMICAL, delavirdine) or azole antifungals (e.g., CHEMICAL, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, CHEMICAL, delavirdine) or azole antifungals (e.g., ketoconazole, CHEMICAL, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, CHEMICAL, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, CHEMICAL). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, CHEMICAL) or CHEMICAL (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, CHEMICAL) or azole antifungals (e.g., CHEMICAL, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, CHEMICAL) or azole antifungals (e.g., ketoconazole, CHEMICAL, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, CHEMICAL) or azole antifungals (e.g., ketoconazole, itraconazole, CHEMICAL). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or CHEMICAL (e.g., CHEMICAL, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or CHEMICAL (e.g., ketoconazole, CHEMICAL, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or CHEMICAL (e.g., ketoconazole, itraconazole, CHEMICAL). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., CHEMICAL, CHEMICAL, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., CHEMICAL, itraconazole, CHEMICAL). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, CHEMICAL, CHEMICAL). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include CHEMICAL, CHEMICAL, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include CHEMICAL, nefazodone, CHEMICAL, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include CHEMICAL, nefazodone, fluconazole, grapefruit juice, CHEMICAL, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include CHEMICAL, nefazodone, fluconazole, grapefruit juice, fluoxetine, CHEMICAL, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include CHEMICAL, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, CHEMICAL, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include CHEMICAL, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and CHEMICAL. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, CHEMICAL, CHEMICAL, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, CHEMICAL, fluconazole, grapefruit juice, CHEMICAL, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, CHEMICAL, fluconazole, grapefruit juice, fluoxetine, CHEMICAL, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, CHEMICAL, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, CHEMICAL, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, CHEMICAL, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and CHEMICAL. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, CHEMICAL, grapefruit juice, CHEMICAL, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, CHEMICAL, grapefruit juice, fluoxetine, CHEMICAL, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, CHEMICAL, grapefruit juice, fluoxetine, fluvoxamine, CHEMICAL, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, CHEMICAL, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and CHEMICAL. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, CHEMICAL, CHEMICAL, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, CHEMICAL, fluvoxamine, CHEMICAL, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, CHEMICAL, fluvoxamine, zileuton, and CHEMICAL. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, CHEMICAL, CHEMICAL, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, CHEMICAL, zileuton, and CHEMICAL. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, CHEMICAL, and CHEMICAL. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when CHEMICAL (CHEMICAL) is used concurrently with other vasoconstrictors or ergot alkaloids. | NO-RELATIONSHIP |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when CHEMICAL (methylergonovine maleate) is used concurrently with other CHEMICAL or ergot alkaloids. | CHEMICALS-INTERACTION |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when CHEMICAL (methylergonovine maleate) is used concurrently with other vasoconstrictors or CHEMICAL. | CHEMICALS-INTERACTION |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (CHEMICAL) is used concurrently with other CHEMICAL or ergot alkaloids. | CHEMICALS-INTERACTION |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (CHEMICAL) is used concurrently with other vasoconstrictors or CHEMICAL. | CHEMICALS-INTERACTION |
| CYP 3A4 Inhibitors (e.g. Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g. dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, potent CYP 3A4 inhibitors should not be coadministered with methylergonovine. Examples of some of the more potent CYP 3A4 inhibitors include macrolide antibiotics (e.g., erythromycin, troleandomycin, clarithromycin), HIV protease inhibitors or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir, delavirdine) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Less potent CYP 3A4 inhibitors should be administered with caution. Less potent inhibitors include saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, and clotrimazole. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methergine (methylergonovine maleate) is used concurrently with other CHEMICAL or CHEMICAL. | NO-RELATIONSHIP |
| Since CHEMICAL is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter CHEMICAL plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with CHEMICAL in AIDS patients for other indications that could elicit this activity include CHEMICAL, rifampin, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | CHEMICALS-INTERACTION |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with CHEMICAL in AIDS patients for other indications that could elicit this activity include erythromycin, CHEMICAL, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | CHEMICALS-INTERACTION |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with CHEMICAL in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, CHEMICAL, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | CHEMICALS-INTERACTION |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with CHEMICAL in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, CHEMICAL, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | CHEMICALS-INTERACTION |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with CHEMICAL in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and CHEMICAL. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | CHEMICALS-INTERACTION |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include CHEMICAL, CHEMICAL, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include CHEMICAL, rifampin, CHEMICAL, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include CHEMICAL, rifampin, rifabutin, CHEMICAL, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include CHEMICAL, rifampin, rifabutin, ketoconazole, and CHEMICAL. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, CHEMICAL, CHEMICAL, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, CHEMICAL, rifabutin, CHEMICAL, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, CHEMICAL, rifabutin, ketoconazole, and CHEMICAL. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, CHEMICAL, CHEMICAL, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, CHEMICAL, ketoconazole, and CHEMICAL. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, CHEMICAL, and CHEMICAL. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that CHEMICAL caused a significant reduction in CHEMICAL metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | CHEMICALS-INTERACTION |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that CHEMICAL caused a significant reduction in trimetrexate metabolism and that CHEMICAL altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in CHEMICAL metabolism and that CHEMICAL altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted CHEMICAL (CHEMICAL, ketoconazole, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted CHEMICAL (clotrimazole, CHEMICAL, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted CHEMICAL (clotrimazole, ketoconazole, CHEMICAL) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted CHEMICAL (clotrimazole, ketoconazole, miconazole) were potent, non-competitive inhibitors of CHEMICAL metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | CHEMICALS-INTERACTION |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (CHEMICAL, CHEMICAL, miconazole) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (CHEMICAL, ketoconazole, CHEMICAL) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (CHEMICAL, ketoconazole, miconazole) were potent, non-competitive inhibitors of CHEMICAL metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | CHEMICALS-INTERACTION |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, CHEMICAL, CHEMICAL) were potent, non-competitive inhibitors of trimetrexate metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | NO-RELATIONSHIP |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, CHEMICAL, miconazole) were potent, non-competitive inhibitors of CHEMICAL metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | INHIBITOR |
| Since trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug-drug interactions that may alter trimetrexate plasma concentrations. Agents that might be coadministered with trimetrexate in AIDS patients for other indications that could elicit this activity include erythromycin, rifampin, rifabutin, ketoconazole, and fluconazole. In vitro perfusion of isolated rat liver has shown that cimetidine caused a significant reduction in trimetrexate metabolism and that acetaminophen altered the relative concentration of trimetrexate metabolites possibly by competing for sulfate metabolites. Based on an in vitro rat liver model, nitrogen substituted imidazole drugs (clotrimazole, ketoconazole, CHEMICAL) were potent, non-competitive inhibitors of CHEMICAL metabolism. Patients medicated with these drugs and trimetrexate should be carefully monitored. | INHIBITOR |
| CHEMICAL has been studied on a background of CHEMICAL and heparin. The use of AGGRASTAT, in combination with heparin and aspirin, has been associated with an increase in bleeding compared to heparin and aspirin alone (see | NO-RELATIONSHIP |
| CHEMICAL has been studied on a background of aspirin and CHEMICAL. The use of AGGRASTAT, in combination with heparin and aspirin, has been associated with an increase in bleeding compared to heparin and aspirin alone (see | NO-RELATIONSHIP |
| AGGRASTAT has been studied on a background of CHEMICAL and CHEMICAL. The use of AGGRASTAT, in combination with heparin and aspirin, has been associated with an increase in bleeding compared to heparin and aspirin alone (see | NO-RELATIONSHIP |
| AGGRASTAT has been studied on a background of aspirin and heparin. The use of CHEMICAL, in combination with CHEMICAL and aspirin, has been associated with an increase in bleeding compared to heparin and aspirin alone (see | CHEMICALS-INTERACTION |
| AGGRASTAT has been studied on a background of aspirin and heparin. The use of CHEMICAL, in combination with heparin and CHEMICAL, has been associated with an increase in bleeding compared to heparin and aspirin alone (see | CHEMICALS-INTERACTION |
| AGGRASTAT has been studied on a background of aspirin and heparin. The use of CHEMICAL, in combination with heparin and aspirin, has been associated with an increase in bleeding compared to CHEMICAL and aspirin alone (see | NO-RELATIONSHIP |
| AGGRASTAT has been studied on a background of aspirin and heparin. The use of CHEMICAL, in combination with heparin and aspirin, has been associated with an increase in bleeding compared to heparin and CHEMICAL alone (see | NO-RELATIONSHIP |
| AGGRASTAT has been studied on a background of aspirin and heparin. The use of AGGRASTAT, in combination with CHEMICAL and CHEMICAL, has been associated with an increase in bleeding compared to heparin and aspirin alone (see | NO-RELATIONSHIP |
| AGGRASTAT has been studied on a background of aspirin and heparin. The use of AGGRASTAT, in combination with CHEMICAL and aspirin, has been associated with an increase in bleeding compared to CHEMICAL and aspirin alone (see | NO-RELATIONSHIP |
| AGGRASTAT has been studied on a background of aspirin and heparin. The use of AGGRASTAT, in combination with CHEMICAL and aspirin, has been associated with an increase in bleeding compared to heparin and CHEMICAL alone (see | NO-RELATIONSHIP |
| AGGRASTAT has been studied on a background of aspirin and heparin. The use of AGGRASTAT, in combination with heparin and CHEMICAL, has been associated with an increase in bleeding compared to CHEMICAL and aspirin alone (see | NO-RELATIONSHIP |
| AGGRASTAT has been studied on a background of aspirin and heparin. The use of AGGRASTAT, in combination with heparin and CHEMICAL, has been associated with an increase in bleeding compared to heparin and CHEMICAL alone (see | NO-RELATIONSHIP |
| AGGRASTAT has been studied on a background of aspirin and heparin. The use of AGGRASTAT, in combination with heparin and aspirin, has been associated with an increase in bleeding compared to CHEMICAL and CHEMICAL alone (see | NO-RELATIONSHIP |
| Nasal Spray: Formal studies designed to evaluate drug interactions with Calcitonin (salmon) have not been done. No drug interaction studies have been performed with Calcitonin (salmon) nasal spray ingredients. Currently, no drug interactions with Calcitonin (salmon) have been observed. The effects of prior use of diphosphonates in postmenopausal osteoporosis patients have not been assessed; however, in patients with Paget's Disease prior CHEMICAL use appears to reduce the anti-resorptive response to CHEMICAL nasal spray. | CHEMICALS-INTERACTION |
| To minimize CNS depression and possible potentiation, CHEMICAL, CHEMICAL, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., amitriptyline HCl, imipramine HCl) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, CHEMICAL, antihistamines, CHEMICAL, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., amitriptyline HCl, imipramine HCl) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, CHEMICAL, antihistamines, narcotics, CHEMICAL or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., amitriptyline HCl, imipramine HCl) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, CHEMICAL, antihistamines, narcotics, hypotensive agents or CHEMICAL should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., amitriptyline HCl, imipramine HCl) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, CHEMICAL, CHEMICAL, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., amitriptyline HCl, imipramine HCl) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, CHEMICAL, narcotics, CHEMICAL or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., amitriptyline HCl, imipramine HCl) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, CHEMICAL, narcotics, hypotensive agents or CHEMICAL should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., amitriptyline HCl, imipramine HCl) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, CHEMICAL, CHEMICAL or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., amitriptyline HCl, imipramine HCl) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, CHEMICAL, hypotensive agents or CHEMICAL should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., amitriptyline HCl, imipramine HCl) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, CHEMICAL or CHEMICAL should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., amitriptyline HCl, imipramine HCl) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because CHEMICAL exhibits some monoamine oxidase inhibitory activity, CHEMICAL, tricyclic antidepressant drugs (e.g., amitriptyline HCl, imipramine HCl) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because CHEMICAL exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, CHEMICAL drugs (e.g., amitriptyline HCl, imipramine HCl) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because CHEMICAL exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., CHEMICAL, imipramine HCl) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | CHEMICALS-INTERACTION |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because CHEMICAL exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., amitriptyline HCl, CHEMICAL) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because CHEMICAL exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., amitriptyline HCl, imipramine HCl) and other drugs and foods with known high CHEMICAL content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, CHEMICAL, CHEMICAL drugs (e.g., amitriptyline HCl, imipramine HCl) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, CHEMICAL, tricyclic antidepressant drugs (e.g., CHEMICAL, imipramine HCl) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, CHEMICAL, tricyclic antidepressant drugs (e.g., amitriptyline HCl, CHEMICAL) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, CHEMICAL, tricyclic antidepressant drugs (e.g., amitriptyline HCl, imipramine HCl) and other drugs and foods with known high CHEMICAL content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, CHEMICAL drugs (e.g., CHEMICAL, imipramine HCl) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, CHEMICAL drugs (e.g., amitriptyline HCl, CHEMICAL) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, CHEMICAL drugs (e.g., amitriptyline HCl, imipramine HCl) and other drugs and foods with known high CHEMICAL content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., CHEMICAL, CHEMICAL) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., CHEMICAL, imipramine HCl) and other drugs and foods with known high CHEMICAL content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., amitriptyline HCl, CHEMICAL) and other drugs and foods with known high CHEMICAL content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated. | NO-RELATIONSHIP |
| To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (e.g., amitriptyline HCl, imipramine HCl) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes. No cross-resistance with other CHEMICAL, radiotherapy or CHEMICAL has been demonstrated. | NO-RELATIONSHIP |
| No formal drug interaction studies between Neulasta and other drugs have been performed. Drugs such as lithium may potentiate the release of neutrophils; patients receiving CHEMICAL and CHEMICAL should have more frequent monitoring of neutrophil counts. | CHEMICALS-INTERACTION |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between CHEMICAL and CHEMICAL, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | CHEMICALS-INTERACTION |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between CHEMICAL and mycophenolate mofetil, CHEMICAL, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | CHEMICALS-INTERACTION |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between CHEMICAL and mycophenolate mofetil, cyclosporine, CHEMICAL, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | CHEMICALS-INTERACTION |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between CHEMICAL and mycophenolate mofetil, cyclosporine, tacrolimus, CHEMICAL, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | CHEMICALS-INTERACTION |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between CHEMICAL and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, CHEMICAL, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | CHEMICALS-INTERACTION |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between CHEMICAL and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, CHEMICAL, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | CHEMICALS-INTERACTION |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between CHEMICAL and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, CHEMICAL, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | CHEMICALS-INTERACTION |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between CHEMICAL and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, CHEMICAL, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | CHEMICALS-INTERACTION |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between CHEMICAL and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and CHEMICAL. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | CHEMICALS-INTERACTION |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and CHEMICAL, CHEMICAL, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and CHEMICAL, cyclosporine, CHEMICAL, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and CHEMICAL, cyclosporine, tacrolimus, CHEMICAL, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and CHEMICAL, cyclosporine, tacrolimus, prednisolone, CHEMICAL, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and CHEMICAL, cyclosporine, tacrolimus, prednisolone, sirolimus, CHEMICAL, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and CHEMICAL, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, CHEMICAL, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and CHEMICAL, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, CHEMICAL, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and CHEMICAL, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and CHEMICAL. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, CHEMICAL, CHEMICAL, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, CHEMICAL, tacrolimus, CHEMICAL, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, CHEMICAL, tacrolimus, prednisolone, CHEMICAL, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, CHEMICAL, tacrolimus, prednisolone, sirolimus, CHEMICAL, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, CHEMICAL, tacrolimus, prednisolone, sirolimus, nifedipine, CHEMICAL, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, CHEMICAL, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, CHEMICAL, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, CHEMICAL, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and CHEMICAL. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, CHEMICAL, CHEMICAL, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, CHEMICAL, prednisolone, CHEMICAL, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, CHEMICAL, prednisolone, sirolimus, CHEMICAL, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, CHEMICAL, prednisolone, sirolimus, nifedipine, CHEMICAL, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, CHEMICAL, prednisolone, sirolimus, nifedipine, fluconazole, CHEMICAL, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, CHEMICAL, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and CHEMICAL. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, CHEMICAL, CHEMICAL, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, CHEMICAL, sirolimus, CHEMICAL, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, CHEMICAL, sirolimus, nifedipine, CHEMICAL, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, CHEMICAL, sirolimus, nifedipine, fluconazole, CHEMICAL, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, CHEMICAL, sirolimus, nifedipine, fluconazole, ritonavir, and CHEMICAL. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, CHEMICAL, CHEMICAL, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, CHEMICAL, nifedipine, CHEMICAL, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, CHEMICAL, nifedipine, fluconazole, CHEMICAL, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, CHEMICAL, nifedipine, fluconazole, ritonavir, and CHEMICAL. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, CHEMICAL, CHEMICAL, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, CHEMICAL, fluconazole, CHEMICAL, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, CHEMICAL, fluconazole, ritonavir, and CHEMICAL. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, CHEMICAL, CHEMICAL, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, CHEMICAL, ritonavir, and CHEMICAL. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, CHEMICAL, and CHEMICAL. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of CHEMICAL on CHEMICAL, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of CHEMICAL on mycophenolate mofetil, CHEMICAL, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of CHEMICAL on mycophenolate mofetil, cyclosporine, CHEMICAL, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of CHEMICAL on mycophenolate mofetil, cyclosporine, tacrolimus, CHEMICAL, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of CHEMICAL on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and CHEMICAL pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on CHEMICAL, CHEMICAL, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on CHEMICAL, cyclosporine, CHEMICAL, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on CHEMICAL, cyclosporine, tacrolimus, CHEMICAL, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on CHEMICAL, cyclosporine, tacrolimus, prednisolone, and CHEMICAL pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, CHEMICAL, CHEMICAL, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, CHEMICAL, tacrolimus, CHEMICAL, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, CHEMICAL, tacrolimus, prednisolone, and CHEMICAL pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, CHEMICAL, CHEMICAL, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, CHEMICAL, prednisolone, and CHEMICAL pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, CHEMICAL, and CHEMICAL pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. CHEMICAL AUC was increased by 21% with no effect on Cmax in the presence of steady-state CHEMICAL compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. CHEMICAL AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with CHEMICAL alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state CHEMICAL compared with CHEMICAL alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. CHEMICAL AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state CHEMICAL compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | CHEMICALS-INTERACTION |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. CHEMICAL AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with CHEMICAL alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state CHEMICAL compared with CHEMICAL alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving CHEMICAL or CHEMICAL in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving CHEMICAL or nifedipine in combination with CHEMICAL should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | CHEMICALS-INTERACTION |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving CHEMICAL or nifedipine in combination with MYCAMINE should be monitored for CHEMICAL or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving CHEMICAL or nifedipine in combination with MYCAMINE should be monitored for sirolimus or CHEMICAL toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving CHEMICAL or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and CHEMICAL or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | CHEMICALS-INTERACTION |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving CHEMICAL or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or CHEMICAL dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or CHEMICAL in combination with CHEMICAL should be monitored for sirolimus or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | CHEMICALS-INTERACTION |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or CHEMICAL in combination with MYCAMINE should be monitored for CHEMICAL or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or CHEMICAL in combination with MYCAMINE should be monitored for sirolimus or CHEMICAL toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or CHEMICAL in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and CHEMICAL or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or CHEMICAL in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and sirolimus or CHEMICAL dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with CHEMICAL should be monitored for CHEMICAL or nifedipine toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with CHEMICAL should be monitored for sirolimus or CHEMICAL toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with CHEMICAL should be monitored for sirolimus or nifedipine toxicity and CHEMICAL or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with CHEMICAL should be monitored for sirolimus or nifedipine toxicity and sirolimus or CHEMICAL dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for CHEMICAL or CHEMICAL toxicity and sirolimus or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for CHEMICAL or nifedipine toxicity and CHEMICAL or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for CHEMICAL or nifedipine toxicity and sirolimus or CHEMICAL dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or CHEMICAL toxicity and CHEMICAL or nifedipine dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or CHEMICAL toxicity and sirolimus or CHEMICAL dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| A total of 11 clinical drug-drug interaction studies were conducted in healthy volunteers to evaluate the potential for interaction between MYCAMINE and mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, sirolimus, nifedipine, fluconazole, ritonavir, and rifampin. In these studies, no interaction that altered the pharmacokinetics of micafungin was observed. There was no effect of a single dose or multiple doses of MYCAMINE on mycophenolate mofetil, cyclosporine, tacrolimus, prednisolone, and fluconazole pharmacokinetics. Sirolimus AUC was increased by 21% with no effect on Cmax in the presence of steady-state MYCAMINE compared with sirolimus alone. Nifedipine AUC and Cmax were increased by 18% and 42%, respectively, in the presence of steady-state MYCAMINE compared with nifedipine alone. Patients receiving sirolimus or nifedipine in combination with MYCAMINE should be monitored for sirolimus or nifedipine toxicity and CHEMICAL or CHEMICAL dosage should be reduced if necessary. Micafungin is not an inhibitor of P-glycoprotein and, therefore, would not be expected to alter P-glycoprotein-mediated drug transport activity. | NO-RELATIONSHIP |
| Dosages of concomitantly administered CHEMICAL should be reduced by approximately half, because CHEMICAL amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if levomepromazine is given with benzodiazepines or barbiturates. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining levomepromazine with other anticholinergic drugs (tricyclic antidepressants and antiparkinsonian-agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. Caffeine and/or stimulantes of the ephedrine/amphetamine type may counteract the specific actions of levomepromazine. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | CHEMICALS-INTERACTION |
| Dosages of concomitantly administered CHEMICAL should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of CHEMICAL. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if levomepromazine is given with benzodiazepines or barbiturates. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining levomepromazine with other anticholinergic drugs (tricyclic antidepressants and antiparkinsonian-agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. Caffeine and/or stimulantes of the ephedrine/amphetamine type may counteract the specific actions of levomepromazine. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | NO-RELATIONSHIP |
| Dosages of concomitantly administered opioids should be reduced by approximately half, because CHEMICAL amplifies the therapeutic actions and side-effects of CHEMICAL. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if levomepromazine is given with benzodiazepines or barbiturates. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining levomepromazine with other anticholinergic drugs (tricyclic antidepressants and antiparkinsonian-agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. Caffeine and/or stimulantes of the ephedrine/amphetamine type may counteract the specific actions of levomepromazine. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | CHEMICALS-INTERACTION |
| Dosages of concomitantly administered opioids should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with CHEMICAL (CHEMICAL) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if levomepromazine is given with benzodiazepines or barbiturates. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining levomepromazine with other anticholinergic drugs (tricyclic antidepressants and antiparkinsonian-agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. Caffeine and/or stimulantes of the ephedrine/amphetamine type may counteract the specific actions of levomepromazine. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | NO-RELATIONSHIP |
| Dosages of concomitantly administered opioids should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if CHEMICAL is given with CHEMICAL or barbiturates. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining levomepromazine with other anticholinergic drugs (tricyclic antidepressants and antiparkinsonian-agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. Caffeine and/or stimulantes of the ephedrine/amphetamine type may counteract the specific actions of levomepromazine. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | CHEMICALS-INTERACTION |
| Dosages of concomitantly administered opioids should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if CHEMICAL is given with benzodiazepines or CHEMICAL. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining levomepromazine with other anticholinergic drugs (tricyclic antidepressants and antiparkinsonian-agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. Caffeine and/or stimulantes of the ephedrine/amphetamine type may counteract the specific actions of levomepromazine. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | CHEMICALS-INTERACTION |
| Dosages of concomitantly administered opioids should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if levomepromazine is given with CHEMICAL or CHEMICAL. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining levomepromazine with other anticholinergic drugs (tricyclic antidepressants and antiparkinsonian-agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. Caffeine and/or stimulantes of the ephedrine/amphetamine type may counteract the specific actions of levomepromazine. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | NO-RELATIONSHIP |
| Dosages of concomitantly administered opioids should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if levomepromazine is given with benzodiazepines or barbiturates. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining CHEMICAL with other CHEMICAL (tricyclic antidepressants and antiparkinsonian-agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. Caffeine and/or stimulantes of the ephedrine/amphetamine type may counteract the specific actions of levomepromazine. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | CHEMICALS-INTERACTION |
| Dosages of concomitantly administered opioids should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if levomepromazine is given with benzodiazepines or barbiturates. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining CHEMICAL with other anticholinergic drugs (CHEMICAL and antiparkinsonian-agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. Caffeine and/or stimulantes of the ephedrine/amphetamine type may counteract the specific actions of levomepromazine. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | CHEMICALS-INTERACTION |
| Dosages of concomitantly administered opioids should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if levomepromazine is given with benzodiazepines or barbiturates. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining CHEMICAL with other anticholinergic drugs (tricyclic antidepressants and CHEMICAL): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. Caffeine and/or stimulantes of the ephedrine/amphetamine type may counteract the specific actions of levomepromazine. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | CHEMICALS-INTERACTION |
| Dosages of concomitantly administered opioids should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if levomepromazine is given with benzodiazepines or barbiturates. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining levomepromazine with other CHEMICAL (CHEMICAL and antiparkinsonian-agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. Caffeine and/or stimulantes of the ephedrine/amphetamine type may counteract the specific actions of levomepromazine. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | NO-RELATIONSHIP |
| Dosages of concomitantly administered opioids should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if levomepromazine is given with benzodiazepines or barbiturates. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining levomepromazine with other CHEMICAL (tricyclic antidepressants and CHEMICAL): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. Caffeine and/or stimulantes of the ephedrine/amphetamine type may counteract the specific actions of levomepromazine. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | NO-RELATIONSHIP |
| Dosages of concomitantly administered opioids should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if levomepromazine is given with benzodiazepines or barbiturates. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining levomepromazine with other anticholinergic drugs (CHEMICAL and CHEMICAL): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. Caffeine and/or stimulantes of the ephedrine/amphetamine type may counteract the specific actions of levomepromazine. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | NO-RELATIONSHIP |
| Dosages of concomitantly administered opioids should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if levomepromazine is given with benzodiazepines or barbiturates. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining levomepromazine with other anticholinergic drugs (tricyclic antidepressants and antiparkinsonian-agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. CHEMICAL and/or stimulantes of the CHEMICAL/amphetamine type may counteract the specific actions of levomepromazine. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | NO-RELATIONSHIP |
| Dosages of concomitantly administered opioids should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if levomepromazine is given with benzodiazepines or barbiturates. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining levomepromazine with other anticholinergic drugs (tricyclic antidepressants and antiparkinsonian-agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. CHEMICAL and/or stimulantes of the ephedrine/CHEMICAL type may counteract the specific actions of levomepromazine. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | NO-RELATIONSHIP |
| Dosages of concomitantly administered opioids should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if levomepromazine is given with benzodiazepines or barbiturates. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining levomepromazine with other anticholinergic drugs (tricyclic antidepressants and antiparkinsonian-agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. CHEMICAL and/or stimulantes of the ephedrine/amphetamine type may counteract the specific actions of CHEMICAL. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | CHEMICALS-INTERACTION |
| Dosages of concomitantly administered opioids should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if levomepromazine is given with benzodiazepines or barbiturates. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining levomepromazine with other anticholinergic drugs (tricyclic antidepressants and antiparkinsonian-agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. Caffeine and/or stimulantes of the CHEMICAL/CHEMICAL type may counteract the specific actions of levomepromazine. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | NO-RELATIONSHIP |
| Dosages of concomitantly administered opioids should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if levomepromazine is given with benzodiazepines or barbiturates. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining levomepromazine with other anticholinergic drugs (tricyclic antidepressants and antiparkinsonian-agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. Caffeine and/or stimulantes of the CHEMICAL/amphetamine type may counteract the specific actions of CHEMICAL. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | CHEMICALS-INTERACTION |
| Dosages of concomitantly administered opioids should be reduced by approximately half, because levomepromazine amplifies the therapeutic actions and side-effects of opioids. Combination with tramadol (Ultram) is associated with increased risk of seizures. Additive sedative effects and confusional states may emerge if levomepromazine is given with benzodiazepines or barbiturates. This may be avoided by using the lowest dose possible with the substances in question. Exert particular caution in combining levomepromazine with other anticholinergic drugs (tricyclic antidepressants and antiparkinsonian-agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma. Reduce both the dose of levomepromazine and the dose of the other drug. If possible, avoid such combinations. Caffeine and/or stimulantes of the ephedrine/CHEMICAL type may counteract the specific actions of CHEMICAL. Concomitant use of these substances should be avoided. Coffee and black tea should be avoided because they decrease the absorption of levomepromazine considerably. The same is true for antacids; these should be given 1 to 2 hours before or after oral administration of leveomepromazine. | CHEMICALS-INTERACTION |
| Although CHEMICAL (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between CHEMICAL and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although CHEMICAL (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and CHEMICAL has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between CHEMICAL and CHEMICAL has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of CHEMICAL can potentiate the neuromuscular blocking effects of CHEMICAL. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from CHEMICAL should be observed before the administration of CHEMICAL. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of CHEMICAL before CHEMICAL to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of CHEMICAL before succinylcholine to attenuate some of the side effects of CHEMICAL has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before CHEMICAL to attenuate some of the side effects of CHEMICAL has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of CHEMICAL with other CHEMICAL. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. CHEMICAL and CHEMICAL (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. CHEMICAL and enflurane (administered with CHEMICAL/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. CHEMICAL and enflurane (administered with nitrous oxide/CHEMICAL to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and CHEMICAL (administered with CHEMICAL/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and CHEMICAL (administered with nitrous oxide/CHEMICAL to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with CHEMICAL/CHEMICAL to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of CHEMICAL may be expected with higher concentrations of CHEMICAL or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of CHEMICAL may be expected with higher concentrations of enflurane or CHEMICAL. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of CHEMICAL or CHEMICAL. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of CHEMICAL such as CHEMICAL include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of CHEMICAL such as MIVACRON include certain CHEMICAL (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of CHEMICAL such as MIVACRON include certain antibiotics (e.g., CHEMICAL, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of CHEMICAL such as MIVACRON include certain antibiotics (e.g., aminoglycosides, CHEMICAL, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of CHEMICAL such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, CHEMICAL, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of CHEMICAL such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, CHEMICAL, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of CHEMICAL such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, CHEMICAL, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of CHEMICAL such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, CHEMICAL, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of CHEMICAL such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, CHEMICAL, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of CHEMICAL such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and CHEMICAL), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of CHEMICAL such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), CHEMICAL salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of CHEMICAL such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, CHEMICAL, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of CHEMICAL such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local CHEMICAL, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of CHEMICAL such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, CHEMICAL, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of CHEMICAL such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and CHEMICAL. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as CHEMICAL include certain CHEMICAL (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as CHEMICAL include certain antibiotics (e.g., CHEMICAL, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as CHEMICAL include certain antibiotics (e.g., aminoglycosides, CHEMICAL, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as CHEMICAL include certain antibiotics (e.g., aminoglycosides, tetracyclines, CHEMICAL, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as CHEMICAL include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, CHEMICAL, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as CHEMICAL include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, CHEMICAL, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as CHEMICAL include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, CHEMICAL, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as CHEMICAL include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, CHEMICAL, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as CHEMICAL include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and CHEMICAL), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as CHEMICAL include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), CHEMICAL salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as CHEMICAL include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, CHEMICAL, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as CHEMICAL include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local CHEMICAL, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as CHEMICAL include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, CHEMICAL, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as CHEMICAL include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and CHEMICAL. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain CHEMICAL (e.g., CHEMICAL, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain CHEMICAL (e.g., aminoglycosides, CHEMICAL, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain CHEMICAL (e.g., aminoglycosides, tetracyclines, CHEMICAL, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain CHEMICAL (e.g., aminoglycosides, tetracyclines, bacitracin, CHEMICAL, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain CHEMICAL (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, CHEMICAL, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain CHEMICAL (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, CHEMICAL, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain CHEMICAL (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, CHEMICAL, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain CHEMICAL (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and CHEMICAL), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain CHEMICAL (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), CHEMICAL salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain CHEMICAL (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, CHEMICAL, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain CHEMICAL (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local CHEMICAL, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain CHEMICAL (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, CHEMICAL, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain CHEMICAL (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and CHEMICAL. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., CHEMICAL, CHEMICAL, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., CHEMICAL, tetracyclines, CHEMICAL, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., CHEMICAL, tetracyclines, bacitracin, CHEMICAL, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., CHEMICAL, tetracyclines, bacitracin, polymyxins, CHEMICAL, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., CHEMICAL, tetracyclines, bacitracin, polymyxins, lincomycin, CHEMICAL, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., CHEMICAL, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, CHEMICAL, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., CHEMICAL, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and CHEMICAL), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., CHEMICAL, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), CHEMICAL salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., CHEMICAL, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, CHEMICAL, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., CHEMICAL, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local CHEMICAL, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., CHEMICAL, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, CHEMICAL, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., CHEMICAL, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and CHEMICAL. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, CHEMICAL, CHEMICAL, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, CHEMICAL, bacitracin, CHEMICAL, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, CHEMICAL, bacitracin, polymyxins, CHEMICAL, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, CHEMICAL, bacitracin, polymyxins, lincomycin, CHEMICAL, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, CHEMICAL, bacitracin, polymyxins, lincomycin, clindamycin, CHEMICAL, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, CHEMICAL, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and CHEMICAL), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, CHEMICAL, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), CHEMICAL salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, CHEMICAL, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, CHEMICAL, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, CHEMICAL, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local CHEMICAL, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, CHEMICAL, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, CHEMICAL, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, CHEMICAL, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and CHEMICAL. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, CHEMICAL, CHEMICAL, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, CHEMICAL, polymyxins, CHEMICAL, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, CHEMICAL, polymyxins, lincomycin, CHEMICAL, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, CHEMICAL, polymyxins, lincomycin, clindamycin, CHEMICAL, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, CHEMICAL, polymyxins, lincomycin, clindamycin, colistin, and CHEMICAL), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, CHEMICAL, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), CHEMICAL salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, CHEMICAL, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, CHEMICAL, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, CHEMICAL, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local CHEMICAL, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, CHEMICAL, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, CHEMICAL, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, CHEMICAL, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and CHEMICAL. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, CHEMICAL, CHEMICAL, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, CHEMICAL, lincomycin, CHEMICAL, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, CHEMICAL, lincomycin, clindamycin, CHEMICAL, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, CHEMICAL, lincomycin, clindamycin, colistin, and CHEMICAL), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, CHEMICAL, lincomycin, clindamycin, colistin, and sodium colistimethate), CHEMICAL salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, CHEMICAL, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, CHEMICAL, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, CHEMICAL, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local CHEMICAL, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, CHEMICAL, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, CHEMICAL, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, CHEMICAL, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and CHEMICAL. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, CHEMICAL, CHEMICAL, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, CHEMICAL, clindamycin, CHEMICAL, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, CHEMICAL, clindamycin, colistin, and CHEMICAL), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, CHEMICAL, clindamycin, colistin, and sodium colistimethate), CHEMICAL salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, CHEMICAL, clindamycin, colistin, and sodium colistimethate), magnesium salts, CHEMICAL, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, CHEMICAL, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local CHEMICAL, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, CHEMICAL, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, CHEMICAL, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, CHEMICAL, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and CHEMICAL. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, CHEMICAL, CHEMICAL, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, CHEMICAL, colistin, and CHEMICAL), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, CHEMICAL, colistin, and sodium colistimethate), CHEMICAL salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, CHEMICAL, colistin, and sodium colistimethate), magnesium salts, CHEMICAL, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, CHEMICAL, colistin, and sodium colistimethate), magnesium salts, lithium, local CHEMICAL, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, CHEMICAL, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, CHEMICAL, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, CHEMICAL, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and CHEMICAL. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, CHEMICAL, and CHEMICAL), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, CHEMICAL, and sodium colistimethate), CHEMICAL salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, CHEMICAL, and sodium colistimethate), magnesium salts, CHEMICAL, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, CHEMICAL, and sodium colistimethate), magnesium salts, lithium, local CHEMICAL, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, CHEMICAL, and sodium colistimethate), magnesium salts, lithium, local anesthetics, CHEMICAL, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, CHEMICAL, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and CHEMICAL. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and CHEMICAL), CHEMICAL salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and CHEMICAL), magnesium salts, CHEMICAL, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and CHEMICAL), magnesium salts, lithium, local CHEMICAL, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and CHEMICAL), magnesium salts, lithium, local anesthetics, CHEMICAL, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and CHEMICAL), magnesium salts, lithium, local anesthetics, procainamide, and CHEMICAL. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), CHEMICAL salts, CHEMICAL, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), CHEMICAL salts, lithium, local CHEMICAL, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), CHEMICAL salts, lithium, local anesthetics, CHEMICAL, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), CHEMICAL salts, lithium, local anesthetics, procainamide, and CHEMICAL. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, CHEMICAL, local CHEMICAL, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, CHEMICAL, local anesthetics, CHEMICAL, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, CHEMICAL, local anesthetics, procainamide, and CHEMICAL. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local CHEMICAL, CHEMICAL, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local CHEMICAL, procainamide, and CHEMICAL. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, CHEMICAL, and CHEMICAL. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of CHEMICAL may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral CHEMICAL, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of CHEMICAL may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, CHEMICAL, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of CHEMICAL may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain CHEMICAL) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of CHEMICAL may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing CHEMICAL has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of CHEMICAL may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered CHEMICAL or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of CHEMICAL may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or CHEMICAL. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral CHEMICAL, CHEMICAL, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral CHEMICAL, glucocorticoids, or certain CHEMICAL) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral CHEMICAL, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing CHEMICAL has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral CHEMICAL, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered CHEMICAL or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral CHEMICAL, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or CHEMICAL. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, CHEMICAL, or certain CHEMICAL) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, CHEMICAL, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing CHEMICAL has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, CHEMICAL, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered CHEMICAL or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, CHEMICAL, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or CHEMICAL. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain CHEMICAL) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing CHEMICAL has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain CHEMICAL) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered CHEMICAL or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain CHEMICAL) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or CHEMICAL. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing CHEMICAL has been demonstrated in patients chronically administered CHEMICAL or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing CHEMICAL has been demonstrated in patients chronically administered phenytoin or CHEMICAL. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | CHEMICALS-INTERACTION |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered CHEMICAL or CHEMICAL. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic CHEMICAL or CHEMICAL therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic CHEMICAL or carbamazepine therapy on the action of CHEMICAL are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or CHEMICAL therapy on the action of CHEMICAL are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - CHEMICAL - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as CHEMICAL or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - CHEMICAL - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or CHEMICAL - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - CHEMICAL - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain CHEMICAL given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - CHEMICAL - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - CHEMICAL - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - CHEMICAL - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - CHEMICAL - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - CHEMICAL - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - CHEMICAL - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - CHEMICAL - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - CHEMICAL or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - CHEMICAL - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or CHEMICAL - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - CHEMICAL - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local CHEMICAL such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - CHEMICAL - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as CHEMICAL - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - CHEMICAL - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general CHEMICAL - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - CHEMICAL - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - CHEMICAL or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - CHEMICAL - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other CHEMICAL | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as CHEMICAL or CHEMICAL - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as CHEMICAL or carbamazepine - certain CHEMICAL given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as CHEMICAL or carbamazepine - certain antibiotics given by injection - CHEMICAL - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as CHEMICAL or carbamazepine - certain antibiotics given by injection - cisplatin - CHEMICAL - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as CHEMICAL or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - CHEMICAL - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as CHEMICAL or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - CHEMICAL or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as CHEMICAL or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or CHEMICAL - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as CHEMICAL or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local CHEMICAL such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as CHEMICAL or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as CHEMICAL - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as CHEMICAL or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general CHEMICAL - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as CHEMICAL or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - CHEMICAL or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as CHEMICAL or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other CHEMICAL | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or CHEMICAL - certain CHEMICAL given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or CHEMICAL - certain antibiotics given by injection - CHEMICAL - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or CHEMICAL - certain antibiotics given by injection - cisplatin - CHEMICAL - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or CHEMICAL - certain antibiotics given by injection - cisplatin - edrophonium - CHEMICAL - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or CHEMICAL - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - CHEMICAL or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or CHEMICAL - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or CHEMICAL - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or CHEMICAL - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local CHEMICAL such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or CHEMICAL - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as CHEMICAL - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or CHEMICAL - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general CHEMICAL - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or CHEMICAL - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - CHEMICAL or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or CHEMICAL - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other CHEMICAL | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain CHEMICAL given by injection - CHEMICAL - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain CHEMICAL given by injection - cisplatin - CHEMICAL - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain CHEMICAL given by injection - cisplatin - edrophonium - CHEMICAL - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain CHEMICAL given by injection - cisplatin - edrophonium - neostigmine - CHEMICAL or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain CHEMICAL given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or CHEMICAL - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain CHEMICAL given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local CHEMICAL such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain CHEMICAL given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as CHEMICAL - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain CHEMICAL given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general CHEMICAL - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain CHEMICAL given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - CHEMICAL or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain CHEMICAL given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other CHEMICAL | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - CHEMICAL - CHEMICAL - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - CHEMICAL - edrophonium - CHEMICAL - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - CHEMICAL - edrophonium - neostigmine - CHEMICAL or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - CHEMICAL - edrophonium - neostigmine - polymyxin B or CHEMICAL - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - CHEMICAL - edrophonium - neostigmine - polymyxin B or bacitracin - local CHEMICAL such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - CHEMICAL - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as CHEMICAL - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - CHEMICAL - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general CHEMICAL - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - CHEMICAL - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - CHEMICAL or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - CHEMICAL - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other CHEMICAL | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - CHEMICAL - CHEMICAL - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - CHEMICAL - neostigmine - CHEMICAL or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - CHEMICAL - neostigmine - polymyxin B or CHEMICAL - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - CHEMICAL - neostigmine - polymyxin B or bacitracin - local CHEMICAL such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - CHEMICAL - neostigmine - polymyxin B or bacitracin - local anesthetics such as CHEMICAL - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - CHEMICAL - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general CHEMICAL - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - CHEMICAL - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - CHEMICAL or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - CHEMICAL - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other CHEMICAL | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - CHEMICAL - CHEMICAL or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - CHEMICAL - polymyxin B or CHEMICAL - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - CHEMICAL - polymyxin B or bacitracin - local CHEMICAL such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - CHEMICAL - polymyxin B or bacitracin - local anesthetics such as CHEMICAL - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - CHEMICAL - polymyxin B or bacitracin - local anesthetics such as procaine - general CHEMICAL - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - CHEMICAL - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - CHEMICAL or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - CHEMICAL - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other CHEMICAL | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - CHEMICAL or CHEMICAL - local anesthetics such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - CHEMICAL or bacitracin - local CHEMICAL such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - CHEMICAL or bacitracin - local anesthetics such as CHEMICAL - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - CHEMICAL or bacitracin - local anesthetics such as procaine - general CHEMICAL - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - CHEMICAL or bacitracin - local anesthetics such as procaine - general anesthetics - CHEMICAL or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - CHEMICAL or bacitracin - local anesthetics such as procaine - general anesthetics - succinylcholine or other CHEMICAL | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or CHEMICAL - local CHEMICAL such as procaine - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or CHEMICAL - local anesthetics such as CHEMICAL - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or CHEMICAL - local anesthetics such as procaine - general CHEMICAL - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or CHEMICAL - local anesthetics such as procaine - general anesthetics - CHEMICAL or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or CHEMICAL - local anesthetics such as procaine - general anesthetics - succinylcholine or other CHEMICAL | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local CHEMICAL such as CHEMICAL - general anesthetics - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local CHEMICAL such as procaine - general CHEMICAL - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local CHEMICAL such as procaine - general anesthetics - CHEMICAL or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local CHEMICAL such as procaine - general anesthetics - succinylcholine or other CHEMICAL | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as CHEMICAL - general CHEMICAL - succinylcholine or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as CHEMICAL - general anesthetics - CHEMICAL or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as CHEMICAL - general anesthetics - succinylcholine or other CHEMICAL | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general CHEMICAL - CHEMICAL or other muscle relaxants | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general CHEMICAL - succinylcholine or other CHEMICAL | NO-RELATIONSHIP |
| Although MIVACRON (a mixture of three stereoisomers) has been administered safely following succinylcholine-facilitated tracheal intubation, the interaction between MIVACRON and succinylcholine has not been systematically studied. Prior administration of succinylcholine can potentiate the neuromuscular blocking effects of nondepolarizing agents. Evidence of spontaneous recovery from succinylcholine should be observed before the administration of MIVACRON. The use of MIVACRON before succinylcholine to attenuate some of the side effects of succinylcholine has not been studied. There are no clinical data on the use of MIVACRON with other nondepolarizing neuromuscular blocking agents. Isoflurane and enflurane (administered with nitrous oxide/oxygen to achieve 1.25 M.C. decrease the ED50 of MIVACRON by as much as 25% (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Individualization of Dosages). These agents may also prolong the clinically effective duration of action and decrease the average infusion requirement of MIVACRON by as much as 35% to 40%. A greater potentiation of the neuromuscular blocking effects of MIVACRON may be expected with higher concentrations of enflurane or isoflurane. Halothane has little or no effect on the ED50 , but may prolong the duration of action and decrease the average infusion requirement by as much as 20%. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as MIVACRON include certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistimethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine. The neuromuscular blocking effect of MIVACRON may be enhanced by drugs that reduce plasma cholinesterase activity (e.g., chronically administered oral contraceptives, glucocorticoids, or certain monoamine oxidase inhibitors) or by drugs that irreversibly inhibit plasma cholinesterase . Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic phenytoin or carbamazepine therapy on the action of MIVACRON are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some drug interactions are: - birth control pills - corticosteroids - medicines for angina or high blood pressure - medicines for pain - medicines to control seizures such as phenytoin or carbamazepine - certain antibiotics given by injection - cisplatin - edrophonium - neostigmine - polymyxin B or bacitracin - local anesthetics such as procaine - general anesthetics - CHEMICAL or other CHEMICAL | NO-RELATIONSHIP |
| Drug interaction of levothyroxine with infant colic drops. Infacol (Forest Laboratories UK, Kent, UK) is a widely available over-the-counter preparation used to relieve colic symptoms in neonates and infants. The active ingredient is simeticone. No drug interactions with simeticone are documented in the current summary of product characteristics. The authors report the case of an infant with confirmed congenital hypothyroidism on CHEMICAL who experienced a possible drug interaction with CHEMICAL. Despite adequate levothyroxine dosage, thyroid stimulating hormone (TSH) was high, suggesting undertreatment. Questioning revealed the child was taking Infacol drops before feeds while on levothyroxine. The colic drops were immediately discontinued and TSH promptly normalised with a reduction in thyroxine requirement to an age appropriate dosage. Drug interaction of thyroxine with simeticone has not been reported previously and is not listed in the British National Formulary for Children. Clinicians and parents need to be aware of this interaction to avoid unnecessary undertreatment and prevent potential long-term neurological sequelae. | CHEMICALS-INTERACTION |
| Drug interaction of levothyroxine with infant colic drops. Infacol (Forest Laboratories UK, Kent, UK) is a widely available over-the-counter preparation used to relieve colic symptoms in neonates and infants. The active ingredient is simeticone. No drug interactions with simeticone are documented in the current summary of product characteristics. The authors report the case of an infant with confirmed congenital hypothyroidism on levothyroxine who experienced a possible drug interaction with simeticone. Despite adequate levothyroxine dosage, thyroid stimulating hormone (TSH) was high, suggesting undertreatment. Questioning revealed the child was taking CHEMICAL drops before feeds while on CHEMICAL. The colic drops were immediately discontinued and TSH promptly normalised with a reduction in thyroxine requirement to an age appropriate dosage. Drug interaction of thyroxine with simeticone has not been reported previously and is not listed in the British National Formulary for Children. Clinicians and parents need to be aware of this interaction to avoid unnecessary undertreatment and prevent potential long-term neurological sequelae. | CHEMICALS-INTERACTION |
| Drug interaction of levothyroxine with infant colic drops. Infacol (Forest Laboratories UK, Kent, UK) is a widely available over-the-counter preparation used to relieve colic symptoms in neonates and infants. The active ingredient is simeticone. No drug interactions with simeticone are documented in the current summary of product characteristics. The authors report the case of an infant with confirmed congenital hypothyroidism on levothyroxine who experienced a possible drug interaction with simeticone. Despite adequate levothyroxine dosage, thyroid stimulating hormone (TSH) was high, suggesting undertreatment. Questioning revealed the child was taking Infacol drops before feeds while on levothyroxine. The colic drops were immediately discontinued and TSH promptly normalised with a reduction in thyroxine requirement to an age appropriate dosage. Drug interaction of CHEMICAL with CHEMICAL has not been reported previously and is not listed in the British National Formulary for Children. Clinicians and parents need to be aware of this interaction to avoid unnecessary undertreatment and prevent potential long-term neurological sequelae. | NO-RELATIONSHIP |
| Do not exceed a 5 mg daily dose of CHEMICAL when administered with therapeutic doses of CHEMICAL or other potent CYP3A4 inhibitors. Patients with Congenital or Acquired QT Prolongation In a study of the effect of solifenacin on the QT interval in 76 healthy women, the QT prolonging effect appeared less with solifenacin 10 mg than with 30 mg (three times the maximum recommended dose), and the effect of solifenacin 30 mg did not appear as large as that of the positive control moxifloxacin at its therapeutic dose. This observation should be considered in clinical decisions to prescribe VESIcare for patients with a known history of QT prolongation or patients who are taking medications known to prolong the QT interval. | CHEMICALS-INTERACTION |
| Do not exceed a 5 mg daily dose of VESIcare when administered with therapeutic doses of ketoconazole or other potent CYP3A4 inhibitors. Patients with Congenital or Acquired QT Prolongation In a study of the effect of CHEMICAL on the QT interval in 76 healthy women, the QT prolonging effect appeared less with CHEMICAL 10 mg than with 30 mg (three times the maximum recommended dose), and the effect of solifenacin 30 mg did not appear as large as that of the positive control moxifloxacin at its therapeutic dose. This observation should be considered in clinical decisions to prescribe VESIcare for patients with a known history of QT prolongation or patients who are taking medications known to prolong the QT interval. | NO-RELATIONSHIP |
| Do not exceed a 5 mg daily dose of VESIcare when administered with therapeutic doses of ketoconazole or other potent CYP3A4 inhibitors. Patients with Congenital or Acquired QT Prolongation In a study of the effect of CHEMICAL on the QT interval in 76 healthy women, the QT prolonging effect appeared less with solifenacin 10 mg than with 30 mg (three times the maximum recommended dose), and the effect of CHEMICAL 30 mg did not appear as large as that of the positive control moxifloxacin at its therapeutic dose. This observation should be considered in clinical decisions to prescribe VESIcare for patients with a known history of QT prolongation or patients who are taking medications known to prolong the QT interval. | NO-RELATIONSHIP |
| Do not exceed a 5 mg daily dose of VESIcare when administered with therapeutic doses of ketoconazole or other potent CYP3A4 inhibitors. Patients with Congenital or Acquired QT Prolongation In a study of the effect of CHEMICAL on the QT interval in 76 healthy women, the QT prolonging effect appeared less with solifenacin 10 mg than with 30 mg (three times the maximum recommended dose), and the effect of solifenacin 30 mg did not appear as large as that of the positive control CHEMICAL at its therapeutic dose. This observation should be considered in clinical decisions to prescribe VESIcare for patients with a known history of QT prolongation or patients who are taking medications known to prolong the QT interval. | NO-RELATIONSHIP |
| Do not exceed a 5 mg daily dose of VESIcare when administered with therapeutic doses of ketoconazole or other potent CYP3A4 inhibitors. Patients with Congenital or Acquired QT Prolongation In a study of the effect of solifenacin on the QT interval in 76 healthy women, the QT prolonging effect appeared less with CHEMICAL 10 mg than with 30 mg (three times the maximum recommended dose), and the effect of CHEMICAL 30 mg did not appear as large as that of the positive control moxifloxacin at its therapeutic dose. This observation should be considered in clinical decisions to prescribe VESIcare for patients with a known history of QT prolongation or patients who are taking medications known to prolong the QT interval. | NO-RELATIONSHIP |
| Do not exceed a 5 mg daily dose of VESIcare when administered with therapeutic doses of ketoconazole or other potent CYP3A4 inhibitors. Patients with Congenital or Acquired QT Prolongation In a study of the effect of solifenacin on the QT interval in 76 healthy women, the QT prolonging effect appeared less with CHEMICAL 10 mg than with 30 mg (three times the maximum recommended dose), and the effect of solifenacin 30 mg did not appear as large as that of the positive control CHEMICAL at its therapeutic dose. This observation should be considered in clinical decisions to prescribe VESIcare for patients with a known history of QT prolongation or patients who are taking medications known to prolong the QT interval. | NO-RELATIONSHIP |
| Do not exceed a 5 mg daily dose of VESIcare when administered with therapeutic doses of ketoconazole or other potent CYP3A4 inhibitors. Patients with Congenital or Acquired QT Prolongation In a study of the effect of solifenacin on the QT interval in 76 healthy women, the QT prolonging effect appeared less with solifenacin 10 mg than with 30 mg (three times the maximum recommended dose), and the effect of CHEMICAL 30 mg did not appear as large as that of the positive control CHEMICAL at its therapeutic dose. This observation should be considered in clinical decisions to prescribe VESIcare for patients with a known history of QT prolongation or patients who are taking medications known to prolong the QT interval. | NO-RELATIONSHIP |
| Interaction with CHEMICAL: Although CHEMICAL does not itself cause orthostatic hypotension, its administration to patients already receiving guanethidine can result in profound orthostatic effects. If at all possible guanethidine should be discontinued well before minoxidil is begun. Where this is not possible, minoxidil therapy should be started in the hospital and the patient should remain institutionalized until severe orthostatic effects are no longer present or the patient has learned to avoid activities that provoke them. | NO-RELATIONSHIP |
| Interaction with CHEMICAL: Although minoxidil does not itself cause orthostatic hypotension, its administration to patients already receiving CHEMICAL can result in profound orthostatic effects. If at all possible guanethidine should be discontinued well before minoxidil is begun. Where this is not possible, minoxidil therapy should be started in the hospital and the patient should remain institutionalized until severe orthostatic effects are no longer present or the patient has learned to avoid activities that provoke them. | NO-RELATIONSHIP |
| Interaction with Guanethidine: Although CHEMICAL does not itself cause orthostatic hypotension, its administration to patients already receiving CHEMICAL can result in profound orthostatic effects. If at all possible guanethidine should be discontinued well before minoxidil is begun. Where this is not possible, minoxidil therapy should be started in the hospital and the patient should remain institutionalized until severe orthostatic effects are no longer present or the patient has learned to avoid activities that provoke them. | CHEMICALS-INTERACTION |
| Interaction with Guanethidine: Although minoxidil does not itself cause orthostatic hypotension, its administration to patients already receiving guanethidine can result in profound orthostatic effects. If at all possible CHEMICAL should be discontinued well before CHEMICAL is begun. Where this is not possible, minoxidil therapy should be started in the hospital and the patient should remain institutionalized until severe orthostatic effects are no longer present or the patient has learned to avoid activities that provoke them. | CHEMICALS-INTERACTION |
| While co-administration of CHEMICAL appeared to increase the clearance of CHEMICAL by 70%, these results are not conclusive because of the small number of subjects studied and because patients took variable doses of Cerezyme. Combination therapy with Cerezyme (imiglucerase) and ZAVESCA is not indicated. | CHEMICALS-INTERACTION |
| While co-administration of CHEMICAL appeared to increase the clearance of Cerezyme by 70%, these results are not conclusive because of the small number of subjects studied and because patients took variable doses of CHEMICAL. Combination therapy with Cerezyme (imiglucerase) and ZAVESCA is not indicated. | CHEMICALS-INTERACTION |
| While co-administration of ZAVESCA appeared to increase the clearance of CHEMICAL by 70%, these results are not conclusive because of the small number of subjects studied and because patients took variable doses of CHEMICAL. Combination therapy with Cerezyme (imiglucerase) and ZAVESCA is not indicated. | NO-RELATIONSHIP |
| While co-administration of ZAVESCA appeared to increase the clearance of Cerezyme by 70%, these results are not conclusive because of the small number of subjects studied and because patients took variable doses of Cerezyme. Combination therapy with CHEMICAL (CHEMICAL) and ZAVESCA is not indicated. | NO-RELATIONSHIP |
| While co-administration of ZAVESCA appeared to increase the clearance of Cerezyme by 70%, these results are not conclusive because of the small number of subjects studied and because patients took variable doses of Cerezyme. Combination therapy with CHEMICAL (imiglucerase) and CHEMICAL is not indicated. | CHEMICALS-INTERACTION |
| While co-administration of ZAVESCA appeared to increase the clearance of Cerezyme by 70%, these results are not conclusive because of the small number of subjects studied and because patients took variable doses of Cerezyme. Combination therapy with Cerezyme (CHEMICAL) and CHEMICAL is not indicated. | NO-RELATIONSHIP |
| No drug-drug interaction studies have been conducted with depo-subQ provera 104. CHEMICAL administered concomitantly with CHEMICAL may significantly decrease the serum concentrations of MPA. Laboratory Tests The pathologist should be advised of progestin therapy when relevant specimens are submitted. The physician should be informed that certain endocrine and liver function tests, and blood components may be affected by progestin therapy: (a) Plasma and urinary steroid levels are decreased (e.g., progesterone, estradiol, pregnanediol, testosterone, cortisol). (b) Plasma and urinary gonadotropin levels are decreased (e.g., LH, FSH). (c) SHBG concentrations are decreased. (d) T3-uptake values may decrease. (e) There may be small changes in coagulation factors. (f) Sulfobromophthalein and other liver function test values may be increased slightly. (g) There may be small changes in lipid profiles. | CHEMICALS-INTERACTION |
| No drug-drug interaction studies have been conducted with depo-subQ provera 104. CHEMICAL administered concomitantly with depo-subQ provera 104 may significantly decrease the serum concentrations of CHEMICAL. Laboratory Tests The pathologist should be advised of progestin therapy when relevant specimens are submitted. The physician should be informed that certain endocrine and liver function tests, and blood components may be affected by progestin therapy: (a) Plasma and urinary steroid levels are decreased (e.g., progesterone, estradiol, pregnanediol, testosterone, cortisol). (b) Plasma and urinary gonadotropin levels are decreased (e.g., LH, FSH). (c) SHBG concentrations are decreased. (d) T3-uptake values may decrease. (e) There may be small changes in coagulation factors. (f) Sulfobromophthalein and other liver function test values may be increased slightly. (g) There may be small changes in lipid profiles. | NO-RELATIONSHIP |
| No drug-drug interaction studies have been conducted with depo-subQ provera 104. Aminoglutethimide administered concomitantly with CHEMICAL may significantly decrease the serum concentrations of CHEMICAL. Laboratory Tests The pathologist should be advised of progestin therapy when relevant specimens are submitted. The physician should be informed that certain endocrine and liver function tests, and blood components may be affected by progestin therapy: (a) Plasma and urinary steroid levels are decreased (e.g., progesterone, estradiol, pregnanediol, testosterone, cortisol). (b) Plasma and urinary gonadotropin levels are decreased (e.g., LH, FSH). (c) SHBG concentrations are decreased. (d) T3-uptake values may decrease. (e) There may be small changes in coagulation factors. (f) Sulfobromophthalein and other liver function test values may be increased slightly. (g) There may be small changes in lipid profiles. | NO-RELATIONSHIP |
| Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may develop during concomitant use of CHEMICAL or CHEMICAL. Insulin requirements in diabetic patients may be increased, decreased, or unchanged. Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Thiazide drugs may increase the responsiveness of tubocurarine. Lithium renal clearance is reduced by thiazides, increasing the risk of lithium toxicity. Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic adrenergic blocking drugs or peripheral adrenergic blocking drugs. | NO-RELATIONSHIP |
| Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may develop during concomitant use of steroids or ACTH. Insulin requirements in diabetic patients may be increased, decreased, or unchanged. CHEMICAL may decrease arterial responsiveness to CHEMICAL. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Thiazide drugs may increase the responsiveness of tubocurarine. Lithium renal clearance is reduced by thiazides, increasing the risk of lithium toxicity. Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic adrenergic blocking drugs or peripheral adrenergic blocking drugs. | CHEMICALS-INTERACTION |
| Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may develop during concomitant use of steroids or ACTH. Insulin requirements in diabetic patients may be increased, decreased, or unchanged. Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. CHEMICAL may increase the responsiveness of CHEMICAL. Lithium renal clearance is reduced by thiazides, increasing the risk of lithium toxicity. Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic adrenergic blocking drugs or peripheral adrenergic blocking drugs. | CHEMICALS-INTERACTION |
| Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may develop during concomitant use of steroids or ACTH. Insulin requirements in diabetic patients may be increased, decreased, or unchanged. Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Thiazide drugs may increase the responsiveness of tubocurarine. CHEMICAL renal clearance is reduced by CHEMICAL, increasing the risk of lithium toxicity. Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic adrenergic blocking drugs or peripheral adrenergic blocking drugs. | CHEMICALS-INTERACTION |
| Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may develop during concomitant use of steroids or ACTH. Insulin requirements in diabetic patients may be increased, decreased, or unchanged. Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Thiazide drugs may increase the responsiveness of tubocurarine. CHEMICAL renal clearance is reduced by thiazides, increasing the risk of CHEMICAL toxicity. Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic adrenergic blocking drugs or peripheral adrenergic blocking drugs. | NO-RELATIONSHIP |
| Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may develop during concomitant use of steroids or ACTH. Insulin requirements in diabetic patients may be increased, decreased, or unchanged. Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Thiazide drugs may increase the responsiveness of tubocurarine. Lithium renal clearance is reduced by CHEMICAL, increasing the risk of CHEMICAL toxicity. Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic adrenergic blocking drugs or peripheral adrenergic blocking drugs. | NO-RELATIONSHIP |
| Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may develop during concomitant use of steroids or ACTH. Insulin requirements in diabetic patients may be increased, decreased, or unchanged. Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Thiazide drugs may increase the responsiveness of tubocurarine. Lithium renal clearance is reduced by thiazides, increasing the risk of lithium toxicity. CHEMICAL may add to or potentiate the action of other CHEMICAL. Potentiation occurs with ganglionic adrenergic blocking drugs or peripheral adrenergic blocking drugs. | CHEMICALS-INTERACTION |
| Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may develop during concomitant use of steroids or ACTH. Insulin requirements in diabetic patients may be increased, decreased, or unchanged. Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Thiazide drugs may increase the responsiveness of tubocurarine. Lithium renal clearance is reduced by thiazides, increasing the risk of lithium toxicity. Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with CHEMICAL or CHEMICAL. | NO-RELATIONSHIP |
| CHEMICAL: Patients on CHEMICAL, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| CHEMICAL: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of CHEMICAL Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on CHEMICAL, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of CHEMICAL Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | CHEMICALS-INTERACTION |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the CHEMICAL or increasing the salt intake prior to initiation of treatment with CHEMICAL. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | CHEMICALS-INTERACTION |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If CHEMICAL cannot be interrupted, close medical supervision should be provided with the first dose of CHEMICAL Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | CHEMICALS-INTERACTION |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of CHEMICAL absorption and elimination are not affected by concomitant CHEMICAL. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of CHEMICAL was reduced by CHEMICAL, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | CHEMICALS-INTERACTION |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. CHEMICAL Supplements and CHEMICAL: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. CHEMICAL Supplements and Potassium-Sparing Diuretics: CHEMICAL Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and CHEMICAL: CHEMICAL Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of CHEMICAL (CHEMICAL, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of CHEMICAL (spironolactone, CHEMICAL, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of CHEMICAL (spironolactone, amiloride, CHEMICAL and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of CHEMICAL (spironolactone, amiloride, triamterene and others), CHEMICAL supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of CHEMICAL (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (CHEMICAL, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of CHEMICAL (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, CHEMICAL, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of CHEMICAL (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, CHEMICAL and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (CHEMICAL, CHEMICAL, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (CHEMICAL, amiloride, CHEMICAL and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (CHEMICAL, amiloride, triamterene and others), CHEMICAL supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (CHEMICAL, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (CHEMICAL, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (CHEMICAL, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, CHEMICAL, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (CHEMICAL, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, CHEMICAL and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, CHEMICAL, CHEMICAL and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, CHEMICAL, triamterene and others), CHEMICAL supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, CHEMICAL, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (CHEMICAL, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, CHEMICAL, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, CHEMICAL, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, CHEMICAL, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, CHEMICAL and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, CHEMICAL and others), CHEMICAL supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, CHEMICAL and others), potassium supplements or other drugs capable of increasing serum potassium (CHEMICAL, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, CHEMICAL and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, CHEMICAL, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, CHEMICAL and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, CHEMICAL and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), CHEMICAL supplements or other drugs capable of increasing serum potassium (CHEMICAL, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), CHEMICAL supplements or other drugs capable of increasing serum potassium (indomethacin, CHEMICAL, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), CHEMICAL supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, CHEMICAL and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (CHEMICAL, CHEMICAL, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (CHEMICAL, heparin, CHEMICAL and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, CHEMICAL, CHEMICAL and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. CHEMICAL: Increased serum CHEMICAL and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. CHEMICAL: Increased serum lithium and symptoms of CHEMICAL toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. CHEMICAL: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant CHEMICAL and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum CHEMICAL and symptoms of CHEMICAL toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum CHEMICAL and symptoms of lithium toxicity have been reported in patients receiving concomitant CHEMICAL and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of CHEMICAL toxicity have been reported in patients receiving concomitant CHEMICAL and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a CHEMICAL may further increase the risk of CHEMICAL toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | CHEMICALS-INTERACTION |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. CHEMICAL: A controlled pharmacokinetic study has shown no effect on plasma CHEMICAL concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. CHEMICAL: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with CHEMICAL Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. CHEMICAL: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of CHEMICAL on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. CHEMICAL: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of CHEMICAL/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. CHEMICAL: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/CHEMICAL has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma CHEMICAL concentrations when coadministered with CHEMICAL Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma CHEMICAL concentrations when coadministered with ACEON Tablets, but an effect of CHEMICAL on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma CHEMICAL concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of CHEMICAL/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma CHEMICAL concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/CHEMICAL has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with CHEMICAL Tablets, but an effect of CHEMICAL on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with CHEMICAL Tablets, but an effect of digoxin on the plasma concentration of CHEMICAL/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with CHEMICAL Tablets, but an effect of digoxin on the plasma concentration of perindopril/CHEMICAL has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of CHEMICAL on the plasma concentration of CHEMICAL/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of CHEMICAL on the plasma concentration of perindopril/CHEMICAL has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of CHEMICAL/CHEMICAL has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. CHEMICAL: Animal data have suggested the possibility of interaction between CHEMICAL and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. CHEMICAL: Animal data have suggested the possibility of interaction between perindopril and CHEMICAL. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between CHEMICAL and CHEMICAL. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of CHEMICAL Tablets with food does not significantly lower the rate or extent of CHEMICAL absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | NO-RELATIONSHIP |
| Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of ACEON Tablets therapy. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of ACEON Tablets, for at least two hours and until blood pressure has stabilized for another hour. The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: ACEON Tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON Tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Coadministration of both drugs should proceed with caution. Food Interaction: Oral administration of ACEON Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of CHEMICAL to the active metabolite, CHEMICAL, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state. | CHEMICALS-INTERACTION |
| Methyprylon may interact with other addictive medications, in that it may increase the likelyhood of addiction and abuse. Concurrent use of CHEMICAL and other CHEMICAL may increase the CNS depressant effects of methyprylon or these other medications. | CHEMICALS-INTERACTION |
| Methyprylon may interact with other addictive medications, in that it may increase the likelyhood of addiction and abuse. Concurrent use of CHEMICAL and other CNS depression-producing drugs may increase the CNS depressant effects of CHEMICAL or these other medications. | NO-RELATIONSHIP |
| Methyprylon may interact with other addictive medications, in that it may increase the likelyhood of addiction and abuse. Concurrent use of alcohol and other CHEMICAL may increase the CNS depressant effects of CHEMICAL or these other medications. | CHEMICALS-INTERACTION |
| Administration of CHEMICAL decreases oral clearance of CHEMICAL by about 5%. The clinical implication of this effect is not known. Patients with Severe Hepatic or Renal Impairment Caution should be exercised when TEMODAR Capsules are administered to patients with severe hepatic or renal impairment. | CHEMICALS-INTERACTION |
| In a study in which 34 different drugs were tested, therapeutically relevant concentrations of CHEMICAL, CHEMICAL and sulfamethizole displaced protein-bound teniposide in fresh human serum to a small but significant extent. Because of the extremely high binding of teniposide to plasma proteins, these small decreases in binding could cause substantial increases in free drug levels in plasma which could result in potentiation of drug toxicity. Therefore, caution should be used in administering VUMON (teniposide injection) to patients receiving these other agents. There was no change in the plasma kinetics of teniposide when coadministered with methotrexate. However, the plasma clearance of methotrexate was slightly increased. An increase in intracellular levels of methotrexate was observed in vitro in the presence of teniposide. | NO-RELATIONSHIP |
| In a study in which 34 different drugs were tested, therapeutically relevant concentrations of CHEMICAL, sodium salicylate and CHEMICAL displaced protein-bound teniposide in fresh human serum to a small but significant extent. Because of the extremely high binding of teniposide to plasma proteins, these small decreases in binding could cause substantial increases in free drug levels in plasma which could result in potentiation of drug toxicity. Therefore, caution should be used in administering VUMON (teniposide injection) to patients receiving these other agents. There was no change in the plasma kinetics of teniposide when coadministered with methotrexate. However, the plasma clearance of methotrexate was slightly increased. An increase in intracellular levels of methotrexate was observed in vitro in the presence of teniposide. | NO-RELATIONSHIP |
| In a study in which 34 different drugs were tested, therapeutically relevant concentrations of CHEMICAL, sodium salicylate and sulfamethizole displaced protein-bound CHEMICAL in fresh human serum to a small but significant extent. Because of the extremely high binding of teniposide to plasma proteins, these small decreases in binding could cause substantial increases in free drug levels in plasma which could result in potentiation of drug toxicity. Therefore, caution should be used in administering VUMON (teniposide injection) to patients receiving these other agents. There was no change in the plasma kinetics of teniposide when coadministered with methotrexate. However, the plasma clearance of methotrexate was slightly increased. An increase in intracellular levels of methotrexate was observed in vitro in the presence of teniposide. | CHEMICALS-INTERACTION |
| In a study in which 34 different drugs were tested, therapeutically relevant concentrations of tolbutamide, CHEMICAL and CHEMICAL displaced protein-bound teniposide in fresh human serum to a small but significant extent. Because of the extremely high binding of teniposide to plasma proteins, these small decreases in binding could cause substantial increases in free drug levels in plasma which could result in potentiation of drug toxicity. Therefore, caution should be used in administering VUMON (teniposide injection) to patients receiving these other agents. There was no change in the plasma kinetics of teniposide when coadministered with methotrexate. However, the plasma clearance of methotrexate was slightly increased. An increase in intracellular levels of methotrexate was observed in vitro in the presence of teniposide. | NO-RELATIONSHIP |
| In a study in which 34 different drugs were tested, therapeutically relevant concentrations of tolbutamide, CHEMICAL and sulfamethizole displaced protein-bound CHEMICAL in fresh human serum to a small but significant extent. Because of the extremely high binding of teniposide to plasma proteins, these small decreases in binding could cause substantial increases in free drug levels in plasma which could result in potentiation of drug toxicity. Therefore, caution should be used in administering VUMON (teniposide injection) to patients receiving these other agents. There was no change in the plasma kinetics of teniposide when coadministered with methotrexate. However, the plasma clearance of methotrexate was slightly increased. An increase in intracellular levels of methotrexate was observed in vitro in the presence of teniposide. | CHEMICALS-INTERACTION |
| In a study in which 34 different drugs were tested, therapeutically relevant concentrations of tolbutamide, sodium salicylate and CHEMICAL displaced protein-bound CHEMICAL in fresh human serum to a small but significant extent. Because of the extremely high binding of teniposide to plasma proteins, these small decreases in binding could cause substantial increases in free drug levels in plasma which could result in potentiation of drug toxicity. Therefore, caution should be used in administering VUMON (teniposide injection) to patients receiving these other agents. There was no change in the plasma kinetics of teniposide when coadministered with methotrexate. However, the plasma clearance of methotrexate was slightly increased. An increase in intracellular levels of methotrexate was observed in vitro in the presence of teniposide. | CHEMICALS-INTERACTION |
| In a study in which 34 different drugs were tested, therapeutically relevant concentrations of tolbutamide, sodium salicylate and sulfamethizole displaced protein-bound teniposide in fresh human serum to a small but significant extent. Because of the extremely high binding of teniposide to plasma proteins, these small decreases in binding could cause substantial increases in free drug levels in plasma which could result in potentiation of drug toxicity. Therefore, caution should be used in administering CHEMICAL (CHEMICAL injection) to patients receiving these other agents. There was no change in the plasma kinetics of teniposide when coadministered with methotrexate. However, the plasma clearance of methotrexate was slightly increased. An increase in intracellular levels of methotrexate was observed in vitro in the presence of teniposide. | NO-RELATIONSHIP |
| In a study in which 34 different drugs were tested, therapeutically relevant concentrations of tolbutamide, sodium salicylate and sulfamethizole displaced protein-bound teniposide in fresh human serum to a small but significant extent. Because of the extremely high binding of teniposide to plasma proteins, these small decreases in binding could cause substantial increases in free drug levels in plasma which could result in potentiation of drug toxicity. Therefore, caution should be used in administering VUMON (teniposide injection) to patients receiving these other agents. There was no change in the plasma kinetics of CHEMICAL when coadministered with CHEMICAL. However, the plasma clearance of methotrexate was slightly increased. An increase in intracellular levels of methotrexate was observed in vitro in the presence of teniposide. | NO-RELATIONSHIP |
| In a study in which 34 different drugs were tested, therapeutically relevant concentrations of tolbutamide, sodium salicylate and sulfamethizole displaced protein-bound teniposide in fresh human serum to a small but significant extent. Because of the extremely high binding of teniposide to plasma proteins, these small decreases in binding could cause substantial increases in free drug levels in plasma which could result in potentiation of drug toxicity. Therefore, caution should be used in administering VUMON (teniposide injection) to patients receiving these other agents. There was no change in the plasma kinetics of teniposide when coadministered with methotrexate. However, the plasma clearance of methotrexate was slightly increased. An increase in intracellular levels of CHEMICAL was observed in vitro in the presence of CHEMICAL. | CHEMICALS-INTERACTION |
| CHEMICAL (oral): The activity of oral CHEMICAL may be potentiated by anti-vitamin-K activity attributed to methimazole. -adrenergic blocking agents: Hyperthyroidism may cause an increased clearance of beta ratio. A dose reduction of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid. Digitalis glycosides: Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; reduced dosage of digitalis glycosides may be required. Theophylline: Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed. | NO-RELATIONSHIP |
| CHEMICAL (oral): The activity of oral anticoagulants may be potentiated by anti-vitamin-K activity attributed to CHEMICAL. -adrenergic blocking agents: Hyperthyroidism may cause an increased clearance of beta ratio. A dose reduction of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid. Digitalis glycosides: Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; reduced dosage of digitalis glycosides may be required. Theophylline: Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed. | NO-RELATIONSHIP |
| Anticoagulants (oral): The activity of oral CHEMICAL may be potentiated by anti-vitamin-K activity attributed to CHEMICAL. -adrenergic blocking agents: Hyperthyroidism may cause an increased clearance of beta ratio. A dose reduction of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid. Digitalis glycosides: Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; reduced dosage of digitalis glycosides may be required. Theophylline: Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed. | CHEMICALS-INTERACTION |
| Anticoagulants (oral): The activity of oral anticoagulants may be potentiated by anti-vitamin-K activity attributed to methimazole. -adrenergic blocking agents: Hyperthyroidism may cause an increased clearance of beta ratio. A dose reduction of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid. CHEMICAL: Serum digitalis levels may be increased when hyperthyroid patients on a stable CHEMICAL regimen become euthyroid; reduced dosage of digitalis glycosides may be required. Theophylline: Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed. | NO-RELATIONSHIP |
| Anticoagulants (oral): The activity of oral anticoagulants may be potentiated by anti-vitamin-K activity attributed to methimazole. -adrenergic blocking agents: Hyperthyroidism may cause an increased clearance of beta ratio. A dose reduction of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid. Digitalis glycosides: Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; reduced dosage of digitalis glycosides may be required. CHEMICAL: CHEMICAL clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed. | NO-RELATIONSHIP |
| Anticoagulants (oral): The activity of oral anticoagulants may be potentiated by anti-vitamin-K activity attributed to methimazole. -adrenergic blocking agents: Hyperthyroidism may cause an increased clearance of beta ratio. A dose reduction of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid. Digitalis glycosides: Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; reduced dosage of digitalis glycosides may be required. CHEMICAL: Theophylline clearance may decrease when hyperthyroid patients on a stable CHEMICAL regimen become euthyroid; a reduced dose of theophylline may be needed. | NO-RELATIONSHIP |
| Anticoagulants (oral): The activity of oral anticoagulants may be potentiated by anti-vitamin-K activity attributed to methimazole. -adrenergic blocking agents: Hyperthyroidism may cause an increased clearance of beta ratio. A dose reduction of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid. Digitalis glycosides: Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; reduced dosage of digitalis glycosides may be required. Theophylline: CHEMICAL clearance may decrease when hyperthyroid patients on a stable CHEMICAL regimen become euthyroid; a reduced dose of theophylline may be needed. | NO-RELATIONSHIP |
| In vivo CYP3A activity is significantly lower in CHEMICAL-treated as compared with CHEMICAL-treated renal allograft recipients. In vitro studies have identified cyclosporine and tacrolimus as CYP3A inhibitors. In the current study in renal allograft recipients, we used intravenously and orally administered midazolam as a drug probe to assess whether the study drugs at doses that are generally used in clinical practice have differential effects on in vivo hepatic and first-pass CYP3A activities. Systemic and apparent oral midazolam clearance were 24% (269 73 vs. 354 102 ml/min, P = 0.022) and 31% (479 190 vs. 688 265 ml/min, P = 0.013), respectively, lower in cyclosporine-treated patients (n = 20) than in matched tacrolimus-treated patients (n = 20). The latter displayed midazolam clearances similar to those in two larger cohorts of nonmatched tacrolimus-treated patients (n = 58 and n = 80) and to those receiving a calcineurin inhibitor-free regimen (n = 6). This implies that in vivo hepatic and first-pass CYP3A activities are significantly lower in patients receiving cyclosporine than in those receiving tacrolimus, indicating that, at the doses generally used in clinical practice, cyclosporine is the stronger of the two with respect to CYP3A inhibition. This observation has important implications in the context of drug-drug interactions in transplant recipients. | NO-RELATIONSHIP |
| In vivo CYP3A activity is significantly lower in cyclosporine-treated as compared with tacrolimus-treated renal allograft recipients. In vitro studies have identified CHEMICAL and CHEMICAL as CYP3A inhibitors. In the current study in renal allograft recipients, we used intravenously and orally administered midazolam as a drug probe to assess whether the study drugs at doses that are generally used in clinical practice have differential effects on in vivo hepatic and first-pass CYP3A activities. Systemic and apparent oral midazolam clearance were 24% (269 73 vs. 354 102 ml/min, P = 0.022) and 31% (479 190 vs. 688 265 ml/min, P = 0.013), respectively, lower in cyclosporine-treated patients (n = 20) than in matched tacrolimus-treated patients (n = 20). The latter displayed midazolam clearances similar to those in two larger cohorts of nonmatched tacrolimus-treated patients (n = 58 and n = 80) and to those receiving a calcineurin inhibitor-free regimen (n = 6). This implies that in vivo hepatic and first-pass CYP3A activities are significantly lower in patients receiving cyclosporine than in those receiving tacrolimus, indicating that, at the doses generally used in clinical practice, cyclosporine is the stronger of the two with respect to CYP3A inhibition. This observation has important implications in the context of drug-drug interactions in transplant recipients. | INHIBITOR |
| In vivo CYP3A activity is significantly lower in cyclosporine-treated as compared with tacrolimus-treated renal allograft recipients. In vitro studies have identified cyclosporine and tacrolimus as CYP3A inhibitors. In the current study in renal allograft recipients, we used intravenously and orally administered midazolam as a drug probe to assess whether the study drugs at doses that are generally used in clinical practice have differential effects on in vivo hepatic and first-pass CYP3A activities. Systemic and apparent oral CHEMICAL clearance were 24% (269 73 vs. 354 102 ml/min, P = 0.022) and 31% (479 190 vs. 688 265 ml/min, P = 0.013), respectively, lower in CHEMICAL-treated patients (n = 20) than in matched tacrolimus-treated patients (n = 20). The latter displayed midazolam clearances similar to those in two larger cohorts of nonmatched tacrolimus-treated patients (n = 58 and n = 80) and to those receiving a calcineurin inhibitor-free regimen (n = 6). This implies that in vivo hepatic and first-pass CYP3A activities are significantly lower in patients receiving cyclosporine than in those receiving tacrolimus, indicating that, at the doses generally used in clinical practice, cyclosporine is the stronger of the two with respect to CYP3A inhibition. This observation has important implications in the context of drug-drug interactions in transplant recipients. | CHEMICALS-INTERACTION |
| In vivo CYP3A activity is significantly lower in cyclosporine-treated as compared with tacrolimus-treated renal allograft recipients. In vitro studies have identified cyclosporine and tacrolimus as CYP3A inhibitors. In the current study in renal allograft recipients, we used intravenously and orally administered midazolam as a drug probe to assess whether the study drugs at doses that are generally used in clinical practice have differential effects on in vivo hepatic and first-pass CYP3A activities. Systemic and apparent oral CHEMICAL clearance were 24% (269 73 vs. 354 102 ml/min, P = 0.022) and 31% (479 190 vs. 688 265 ml/min, P = 0.013), respectively, lower in cyclosporine-treated patients (n = 20) than in matched CHEMICAL-treated patients (n = 20). The latter displayed midazolam clearances similar to those in two larger cohorts of nonmatched tacrolimus-treated patients (n = 58 and n = 80) and to those receiving a calcineurin inhibitor-free regimen (n = 6). This implies that in vivo hepatic and first-pass CYP3A activities are significantly lower in patients receiving cyclosporine than in those receiving tacrolimus, indicating that, at the doses generally used in clinical practice, cyclosporine is the stronger of the two with respect to CYP3A inhibition. This observation has important implications in the context of drug-drug interactions in transplant recipients. | NO-RELATIONSHIP |
| In vivo CYP3A activity is significantly lower in cyclosporine-treated as compared with tacrolimus-treated renal allograft recipients. In vitro studies have identified cyclosporine and tacrolimus as CYP3A inhibitors. In the current study in renal allograft recipients, we used intravenously and orally administered midazolam as a drug probe to assess whether the study drugs at doses that are generally used in clinical practice have differential effects on in vivo hepatic and first-pass CYP3A activities. Systemic and apparent oral midazolam clearance were 24% (269 73 vs. 354 102 ml/min, P = 0.022) and 31% (479 190 vs. 688 265 ml/min, P = 0.013), respectively, lower in CHEMICAL-treated patients (n = 20) than in matched CHEMICAL-treated patients (n = 20). The latter displayed midazolam clearances similar to those in two larger cohorts of nonmatched tacrolimus-treated patients (n = 58 and n = 80) and to those receiving a calcineurin inhibitor-free regimen (n = 6). This implies that in vivo hepatic and first-pass CYP3A activities are significantly lower in patients receiving cyclosporine than in those receiving tacrolimus, indicating that, at the doses generally used in clinical practice, cyclosporine is the stronger of the two with respect to CYP3A inhibition. This observation has important implications in the context of drug-drug interactions in transplant recipients. | NO-RELATIONSHIP |
| In vivo CYP3A activity is significantly lower in cyclosporine-treated as compared with tacrolimus-treated renal allograft recipients. In vitro studies have identified cyclosporine and tacrolimus as CYP3A inhibitors. In the current study in renal allograft recipients, we used intravenously and orally administered midazolam as a drug probe to assess whether the study drugs at doses that are generally used in clinical practice have differential effects on in vivo hepatic and first-pass CYP3A activities. Systemic and apparent oral midazolam clearance were 24% (269 73 vs. 354 102 ml/min, P = 0.022) and 31% (479 190 vs. 688 265 ml/min, P = 0.013), respectively, lower in cyclosporine-treated patients (n = 20) than in matched tacrolimus-treated patients (n = 20). The latter displayed CHEMICAL clearances similar to those in two larger cohorts of nonmatched CHEMICAL-treated patients (n = 58 and n = 80) and to those receiving a calcineurin inhibitor-free regimen (n = 6). This implies that in vivo hepatic and first-pass CYP3A activities are significantly lower in patients receiving cyclosporine than in those receiving tacrolimus, indicating that, at the doses generally used in clinical practice, cyclosporine is the stronger of the two with respect to CYP3A inhibition. This observation has important implications in the context of drug-drug interactions in transplant recipients. | NO-RELATIONSHIP |
| In vivo CYP3A activity is significantly lower in cyclosporine-treated as compared with tacrolimus-treated renal allograft recipients. In vitro studies have identified cyclosporine and tacrolimus as CYP3A inhibitors. In the current study in renal allograft recipients, we used intravenously and orally administered midazolam as a drug probe to assess whether the study drugs at doses that are generally used in clinical practice have differential effects on in vivo hepatic and first-pass CYP3A activities. Systemic and apparent oral midazolam clearance were 24% (269 73 vs. 354 102 ml/min, P = 0.022) and 31% (479 190 vs. 688 265 ml/min, P = 0.013), respectively, lower in cyclosporine-treated patients (n = 20) than in matched tacrolimus-treated patients (n = 20). The latter displayed CHEMICAL clearances similar to those in two larger cohorts of nonmatched tacrolimus-treated patients (n = 58 and n = 80) and to those receiving a CHEMICAL-free regimen (n = 6). This implies that in vivo hepatic and first-pass CYP3A activities are significantly lower in patients receiving cyclosporine than in those receiving tacrolimus, indicating that, at the doses generally used in clinical practice, cyclosporine is the stronger of the two with respect to CYP3A inhibition. This observation has important implications in the context of drug-drug interactions in transplant recipients. | NO-RELATIONSHIP |
| In vivo CYP3A activity is significantly lower in cyclosporine-treated as compared with tacrolimus-treated renal allograft recipients. In vitro studies have identified cyclosporine and tacrolimus as CYP3A inhibitors. In the current study in renal allograft recipients, we used intravenously and orally administered midazolam as a drug probe to assess whether the study drugs at doses that are generally used in clinical practice have differential effects on in vivo hepatic and first-pass CYP3A activities. Systemic and apparent oral midazolam clearance were 24% (269 73 vs. 354 102 ml/min, P = 0.022) and 31% (479 190 vs. 688 265 ml/min, P = 0.013), respectively, lower in cyclosporine-treated patients (n = 20) than in matched tacrolimus-treated patients (n = 20). The latter displayed midazolam clearances similar to those in two larger cohorts of nonmatched CHEMICAL-treated patients (n = 58 and n = 80) and to those receiving a CHEMICAL-free regimen (n = 6). This implies that in vivo hepatic and first-pass CYP3A activities are significantly lower in patients receiving cyclosporine than in those receiving tacrolimus, indicating that, at the doses generally used in clinical practice, cyclosporine is the stronger of the two with respect to CYP3A inhibition. This observation has important implications in the context of drug-drug interactions in transplant recipients. | NO-RELATIONSHIP |
| In vivo CYP3A activity is significantly lower in cyclosporine-treated as compared with tacrolimus-treated renal allograft recipients. In vitro studies have identified cyclosporine and tacrolimus as CYP3A inhibitors. In the current study in renal allograft recipients, we used intravenously and orally administered midazolam as a drug probe to assess whether the study drugs at doses that are generally used in clinical practice have differential effects on in vivo hepatic and first-pass CYP3A activities. Systemic and apparent oral midazolam clearance were 24% (269 73 vs. 354 102 ml/min, P = 0.022) and 31% (479 190 vs. 688 265 ml/min, P = 0.013), respectively, lower in cyclosporine-treated patients (n = 20) than in matched tacrolimus-treated patients (n = 20). The latter displayed midazolam clearances similar to those in two larger cohorts of nonmatched tacrolimus-treated patients (n = 58 and n = 80) and to those receiving a calcineurin inhibitor-free regimen (n = 6). This implies that in vivo hepatic and first-pass CYP3A activities are significantly lower in patients receiving CHEMICAL than in those receiving CHEMICAL, indicating that, at the doses generally used in clinical practice, cyclosporine is the stronger of the two with respect to CYP3A inhibition. This observation has important implications in the context of drug-drug interactions in transplant recipients. | NO-RELATIONSHIP |
| In vivo CYP3A activity is significantly lower in cyclosporine-treated as compared with tacrolimus-treated renal allograft recipients. In vitro studies have identified cyclosporine and tacrolimus as CYP3A inhibitors. In the current study in renal allograft recipients, we used intravenously and orally administered midazolam as a drug probe to assess whether the study drugs at doses that are generally used in clinical practice have differential effects on in vivo hepatic and first-pass CYP3A activities. Systemic and apparent oral midazolam clearance were 24% (269 73 vs. 354 102 ml/min, P = 0.022) and 31% (479 190 vs. 688 265 ml/min, P = 0.013), respectively, lower in cyclosporine-treated patients (n = 20) than in matched tacrolimus-treated patients (n = 20). The latter displayed midazolam clearances similar to those in two larger cohorts of nonmatched tacrolimus-treated patients (n = 58 and n = 80) and to those receiving a calcineurin inhibitor-free regimen (n = 6). This implies that in vivo hepatic and first-pass CYP3A activities are significantly lower in patients receiving CHEMICAL than in those receiving tacrolimus, indicating that, at the doses generally used in clinical practice, CHEMICAL is the stronger of the two with respect to CYP3A inhibition. This observation has important implications in the context of drug-drug interactions in transplant recipients. | CHEMICALS-INTERACTION |
| In vivo CYP3A activity is significantly lower in cyclosporine-treated as compared with tacrolimus-treated renal allograft recipients. In vitro studies have identified cyclosporine and tacrolimus as CYP3A inhibitors. In the current study in renal allograft recipients, we used intravenously and orally administered midazolam as a drug probe to assess whether the study drugs at doses that are generally used in clinical practice have differential effects on in vivo hepatic and first-pass CYP3A activities. Systemic and apparent oral midazolam clearance were 24% (269 73 vs. 354 102 ml/min, P = 0.022) and 31% (479 190 vs. 688 265 ml/min, P = 0.013), respectively, lower in cyclosporine-treated patients (n = 20) than in matched tacrolimus-treated patients (n = 20). The latter displayed midazolam clearances similar to those in two larger cohorts of nonmatched tacrolimus-treated patients (n = 58 and n = 80) and to those receiving a calcineurin inhibitor-free regimen (n = 6). This implies that in vivo hepatic and first-pass CYP3A activities are significantly lower in patients receiving cyclosporine than in those receiving CHEMICAL, indicating that, at the doses generally used in clinical practice, CHEMICAL is the stronger of the two with respect to CYP3A inhibition. This observation has important implications in the context of drug-drug interactions in transplant recipients. | CHEMICALS-INTERACTION |
| The interaction of CHEMICAL (CHEMICAL) with other drugs has not been studied in humans. Patients who are receiving CYLERT concurrently with other drugs, especially drugs with CNS activity, should be monitored carefully. Decreased seizure threshold has been reported in patients receiving CYLERT concomitantly with antiepileptic medications. | NO-RELATIONSHIP |
| The interaction of CYLERT (pemoline) with other drugs has not been studied in humans. Patients who are receiving CYLERT concurrently with other drugs, especially drugs with CNS activity, should be monitored carefully. Decreased seizure threshold has been reported in patients receiving CHEMICAL concomitantly with CHEMICAL. | CHEMICALS-INTERACTION |
| CHEMICAL failure in an HIV-positive woman on CHEMICAL therapy resulting in two ectopic pregnancies. Since its introduction in 1999, Implanon remains one of the preferred contraceptive choices for many women as it offers a highly effective means of long-term contraception for three years that does not rely on adherence. Like all hormonal contraceptives, certain hepatic enzyme-inducing drugs may reduce its efficacy. We present an interesting case of an HIV-positive woman on antiretroviral therapy having tubal pregnancies on two separate occasions with Implanon in place. | NO-RELATIONSHIP |
| Implanon failure in an HIV-positive woman on antiretroviral therapy resulting in two ectopic pregnancies. Since its introduction in 1999, Implanon remains one of the preferred contraceptive choices for many women as it offers a highly effective means of long-term contraception for three years that does not rely on adherence. Like all hormonal contraceptives, certain hepatic enzyme-inducing drugs may reduce its efficacy. We present an interesting case of an HIV-positive woman on CHEMICAL therapy having tubal pregnancies on two separate occasions with CHEMICAL in place. | NO-RELATIONSHIP |
| CHEMICAL: CHEMICAL and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| CHEMICAL: Furosemide and probably other CHEMICAL given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| CHEMICAL: Furosemide and probably other loop diuretics given concomitantly with CHEMICAL can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: CHEMICAL and probably other CHEMICAL given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: CHEMICAL and probably other loop diuretics given concomitantly with CHEMICAL can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | CHEMICALS-INTERACTION |
| Diuretics: Furosemide and probably other CHEMICAL given concomitantly with CHEMICAL can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | CHEMICALS-INTERACTION |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other CHEMICAL: When CHEMICAL Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other CHEMICAL: When MYKROX Tablets are used with other CHEMICAL, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When CHEMICAL Tablets are used with other CHEMICAL, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | CHEMICALS-INTERACTION |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. CHEMICAL, CHEMICAL, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. CHEMICAL, Barbiturates, and CHEMICAL: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. CHEMICAL, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with CHEMICAL therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, CHEMICAL, and CHEMICAL: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, CHEMICAL, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with CHEMICAL therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and CHEMICAL: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with CHEMICAL therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. CHEMICAL: CHEMICAL-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. CHEMICAL: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to CHEMICAL. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: CHEMICAL-induced hypokalemia can increase the sensitivity of the myocardium to CHEMICAL. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. CHEMICAL or CHEMICAL: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. CHEMICAL: Serum CHEMICAL levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. CHEMICAL: CHEMICAL-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. CHEMICAL: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of CHEMICAL (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. CHEMICAL: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as CHEMICAL) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: CHEMICAL-induced hypokalemia may enhance neuromuscular blocking effects of CHEMICAL (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | CHEMICALS-INTERACTION |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: CHEMICAL-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as CHEMICAL) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | CHEMICALS-INTERACTION |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of CHEMICAL (such as CHEMICAL) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. CHEMICAL and Other CHEMICAL: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. CHEMICAL and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of CHEMICAL Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | CHEMICALS-INTERACTION |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other CHEMICAL: May decrease the antihypertensive effects of CHEMICAL Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | CHEMICALS-INTERACTION |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. CHEMICAL: CHEMICAL may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. CHEMICAL: Metolazone may decrease arterial responsiveness to CHEMICAL, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: CHEMICAL may decrease arterial responsiveness to CHEMICAL, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | CHEMICALS-INTERACTION |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. CHEMICAL: Efficacy may be decreased due to urinary alkalizing effect of CHEMICAL. Anticoagulants: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. CHEMICAL: CHEMICAL, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. CHEMICAL: Metolazone, as well as other CHEMICAL, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. CHEMICAL: Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to CHEMICAL; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: CHEMICAL, as well as other CHEMICAL, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary. | NO-RELATIONSHIP |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: CHEMICAL, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to CHEMICAL; dosage adjustments may be necessary. | CHEMICALS-INTERACTION |
| Diuretics: Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes. Other Antihypertensives: When MYKROX Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, and Narcotics: The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides: Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids or ACTH: May increase the risk of hypokalemia and increase salt and water retention. Lithium: Serum lithium levels may increase. Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue MYKROX Tablets three days before elective surgery. Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs: May decrease the antihypertensive effects of MYKROX Tablets. Sympathomimetics: Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants: Metolazone, as well as other CHEMICAL, may affect the hypoprothrombinemic response to CHEMICAL; dosage adjustments may be necessary. | CHEMICALS-INTERACTION |
| The following agents may increase certain actions or side effects of CHEMICAL: CHEMICAL, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | CHEMICALS-INTERACTION |
| The following agents may increase certain actions or side effects of CHEMICAL: amantadine, CHEMICAL (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | CHEMICALS-INTERACTION |
| The following agents may increase certain actions or side effects of CHEMICAL: amantadine, antiarrhythmic agents of class I (e.g., CHEMICAL), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of CHEMICAL: amantadine, antiarrhythmic agents of class I (e.g., quinidine), CHEMICAL, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | CHEMICALS-INTERACTION |
| The following agents may increase certain actions or side effects of CHEMICAL: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, CHEMICAL (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of CHEMICAL: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., CHEMICAL), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | CHEMICALS-INTERACTION |
| The following agents may increase certain actions or side effects of CHEMICAL: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), CHEMICAL, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | CHEMICALS-INTERACTION |
| The following agents may increase certain actions or side effects of CHEMICAL: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, CHEMICAL, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | CHEMICALS-INTERACTION |
| The following agents may increase certain actions or side effects of CHEMICAL: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, CHEMICAL (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | CHEMICALS-INTERACTION |
| The following agents may increase certain actions or side effects of CHEMICAL: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., CHEMICAL), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of CHEMICAL: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), CHEMICAL and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of CHEMICAL: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and CHEMICAL, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of CHEMICAL: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, CHEMICAL, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of CHEMICAL: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, CHEMICAL, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | CHEMICALS-INTERACTION |
| The following agents may increase certain actions or side effects of anticholinergic drugs: CHEMICAL, CHEMICAL (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: CHEMICAL, antiarrhythmic agents of class I (e.g., CHEMICAL), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: CHEMICAL, antiarrhythmic agents of class I (e.g., quinidine), CHEMICAL, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: CHEMICAL, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, CHEMICAL (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: CHEMICAL, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., CHEMICAL), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: CHEMICAL, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), CHEMICAL, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: CHEMICAL, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, CHEMICAL, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: CHEMICAL, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, CHEMICAL (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: CHEMICAL, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., CHEMICAL), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: CHEMICAL, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), CHEMICAL and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: CHEMICAL, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and CHEMICAL, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: CHEMICAL, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, CHEMICAL, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: CHEMICAL, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, CHEMICAL, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, CHEMICAL (e.g., CHEMICAL), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, CHEMICAL (e.g., quinidine), CHEMICAL, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, CHEMICAL (e.g., quinidine), antihistamines, CHEMICAL (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, CHEMICAL (e.g., quinidine), antihistamines, antipsychotic agents (e.g., CHEMICAL), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, CHEMICAL (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), CHEMICAL, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, CHEMICAL (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, CHEMICAL, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, CHEMICAL (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, CHEMICAL (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, CHEMICAL (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., CHEMICAL), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, CHEMICAL (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), CHEMICAL and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, CHEMICAL (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and CHEMICAL, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, CHEMICAL (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, CHEMICAL, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, CHEMICAL (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, CHEMICAL, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., CHEMICAL), CHEMICAL, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., CHEMICAL), antihistamines, CHEMICAL (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., CHEMICAL), antihistamines, antipsychotic agents (e.g., CHEMICAL), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., CHEMICAL), antihistamines, antipsychotic agents (e.g., phenothiazines), CHEMICAL, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., CHEMICAL), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, CHEMICAL, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., CHEMICAL), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, CHEMICAL (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., CHEMICAL), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., CHEMICAL), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., CHEMICAL), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), CHEMICAL and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., CHEMICAL), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and CHEMICAL, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., CHEMICAL), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, CHEMICAL, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., CHEMICAL), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, CHEMICAL, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), CHEMICAL, CHEMICAL (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), CHEMICAL, antipsychotic agents (e.g., CHEMICAL), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), CHEMICAL, antipsychotic agents (e.g., phenothiazines), CHEMICAL, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), CHEMICAL, antipsychotic agents (e.g., phenothiazines), benzodiazepines, CHEMICAL, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), CHEMICAL, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, CHEMICAL (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), CHEMICAL, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., CHEMICAL), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), CHEMICAL, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), CHEMICAL and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), CHEMICAL, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and CHEMICAL, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), CHEMICAL, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, CHEMICAL, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), CHEMICAL, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, CHEMICAL, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, CHEMICAL (e.g., CHEMICAL), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, CHEMICAL (e.g., phenothiazines), CHEMICAL, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, CHEMICAL (e.g., phenothiazines), benzodiazepines, CHEMICAL, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, CHEMICAL (e.g., phenothiazines), benzodiazepines, MAO inhibitors, CHEMICAL (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, CHEMICAL (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., CHEMICAL), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, CHEMICAL (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), CHEMICAL and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, CHEMICAL (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and CHEMICAL, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, CHEMICAL (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, CHEMICAL, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, CHEMICAL (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, CHEMICAL, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., CHEMICAL), CHEMICAL, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., CHEMICAL), benzodiazepines, CHEMICAL, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., CHEMICAL), benzodiazepines, MAO inhibitors, CHEMICAL (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., CHEMICAL), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., CHEMICAL), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., CHEMICAL), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), CHEMICAL and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., CHEMICAL), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and CHEMICAL, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., CHEMICAL), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, CHEMICAL, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., CHEMICAL), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, CHEMICAL, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), CHEMICAL, CHEMICAL, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), CHEMICAL, MAO inhibitors, CHEMICAL (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), CHEMICAL, MAO inhibitors, narcotic analgesics (e.g., CHEMICAL), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), CHEMICAL, MAO inhibitors, narcotic analgesics (e.g., meperidine), CHEMICAL and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), CHEMICAL, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and CHEMICAL, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), CHEMICAL, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, CHEMICAL, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), CHEMICAL, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, CHEMICAL, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, CHEMICAL, CHEMICAL (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, CHEMICAL, narcotic analgesics (e.g., CHEMICAL), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, CHEMICAL, narcotic analgesics (e.g., meperidine), CHEMICAL and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, CHEMICAL, narcotic analgesics (e.g., meperidine), nitrates and CHEMICAL, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, CHEMICAL, narcotic analgesics (e.g., meperidine), nitrates and nitrites, CHEMICAL, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, CHEMICAL, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, CHEMICAL, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, CHEMICAL (e.g., CHEMICAL), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, CHEMICAL (e.g., meperidine), CHEMICAL and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, CHEMICAL (e.g., meperidine), nitrates and CHEMICAL, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, CHEMICAL (e.g., meperidine), nitrates and nitrites, CHEMICAL, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, CHEMICAL (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, CHEMICAL, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., CHEMICAL), CHEMICAL and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., CHEMICAL), nitrates and CHEMICAL, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., CHEMICAL), nitrates and nitrites, CHEMICAL, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., CHEMICAL), nitrates and nitrites, sympathomimetic agents, CHEMICAL, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), CHEMICAL and CHEMICAL, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), CHEMICAL and nitrites, CHEMICAL, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), CHEMICAL and nitrites, sympathomimetic agents, CHEMICAL, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and CHEMICAL, CHEMICAL, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and CHEMICAL, sympathomimetic agents, CHEMICAL, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, CHEMICAL, CHEMICAL, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | NO-RELATIONSHIP |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. CHEMICAL antagonize the effects of CHEMICAL. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | CHEMICALS-INTERACTION |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. CHEMICAL in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as CHEMICAL. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | CHEMICALS-INTERACTION |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. CHEMICAL may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of CHEMICAL; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | CHEMICALS-INTERACTION |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. CHEMICAL may antagonize the effects of drugs that alter gastrointestinal motility, such as CHEMICAL. Because antacids may interfere with the absorption of anticholinergic agents, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | CHEMICALS-INTERACTION |
| The following agents may increase certain actions or side effects of anticholinergic drugs: amantadine, antiarrhythmic agents of class I (e.g., quinidine), antihistamines, antipsychotic agents (e.g., phenothiazines), benzodiazepines, MAO inhibitors, narcotic analgesics (e.g., meperidine), nitrates and nitrites, sympathomimetic agents, tricyclic antidepressants, and other drugs having anticholinergic activity. Anticholinergics antagonize the effects of antiglaucoma agents. Anticholinergic drugs in the presence of increased intraocular pressure may be hazardous when taken concurrently with agents such as corticosteroids. Anticholinergic agents may affect gastrointestinal absorption of various drugs, such as slowly dissolving dosage forms of digoxin; increased serum digoxin concentrations may result. Anticholinergic drugs may antagonize the effects of drugs that alter gastrointestinal motility, such as metoclopramide. Because CHEMICAL may interfere with the absorption of CHEMICAL, simultaneous use of these drugs should be avoided. The inhibiting effects of anticholinergic drugs on gastric hydrochloric acid secretion are antagonized by agents used to treat achlorhydria and those used to test gastric secretion. | CHEMICALS-INTERACTION |
| CHEMICAL should be used with caution in patients receiving other local CHEMICAL or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of Ropivacaine, can interact with Ropivacaine leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in-vivo plasma clearance of ropivacaine. | CHEMICALS-INTERACTION |
| CHEMICAL should be used with caution in patients receiving other local anesthetics or agents structurally related to CHEMICAL, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of Ropivacaine, can interact with Ropivacaine leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in-vivo plasma clearance of ropivacaine. | CHEMICALS-INTERACTION |
| Ropivacaine should be used with caution in patients receiving other local CHEMICAL or agents structurally related to CHEMICAL, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of Ropivacaine, can interact with Ropivacaine leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in-vivo plasma clearance of ropivacaine. | NO-RELATIONSHIP |
| Ropivacaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of CHEMICAL was reduced by 70% during coadministration of CHEMICAL (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of Ropivacaine, can interact with Ropivacaine leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in-vivo plasma clearance of ropivacaine. | CHEMICALS-INTERACTION |
| Ropivacaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as CHEMICAL, given concomitantly during administration of CHEMICAL, can interact with Ropivacaine leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in-vivo plasma clearance of ropivacaine. | CHEMICALS-INTERACTION |
| Ropivacaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as CHEMICAL, given concomitantly during administration of Ropivacaine, can interact with CHEMICAL leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in-vivo plasma clearance of ropivacaine. | CHEMICALS-INTERACTION |
| Ropivacaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as CHEMICAL, given concomitantly during administration of Ropivacaine, can interact with Ropivacaine leading to increased CHEMICAL plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in-vivo plasma clearance of ropivacaine. | NO-RELATIONSHIP |
| Ropivacaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of CHEMICAL, can interact with CHEMICAL leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in-vivo plasma clearance of ropivacaine. | CHEMICALS-INTERACTION |
| Ropivacaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of CHEMICAL, can interact with Ropivacaine leading to increased CHEMICAL plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in-vivo plasma clearance of ropivacaine. | NO-RELATIONSHIP |
| Ropivacaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of Ropivacaine, can interact with CHEMICAL leading to increased CHEMICAL plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in-vivo plasma clearance of ropivacaine. | NO-RELATIONSHIP |
| Ropivacaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of Ropivacaine, can interact with Ropivacaine leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as CHEMICAL and CHEMICAL may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in-vivo plasma clearance of ropivacaine. | NO-RELATIONSHIP |
| Ropivacaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of Ropivacaine, can interact with Ropivacaine leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, CHEMICAL (100 mg bid for 2 days with CHEMICAL infusion administered 1 hour after ketoconazole) caused a 15% reduction in in-vivo plasma clearance of ropivacaine. | CHEMICALS-INTERACTION |
| Ropivacaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of Ropivacaine, can interact with Ropivacaine leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, CHEMICAL (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after CHEMICAL) caused a 15% reduction in in-vivo plasma clearance of ropivacaine. | NO-RELATIONSHIP |
| Ropivacaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of Ropivacaine, can interact with Ropivacaine leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, CHEMICAL (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in-vivo plasma clearance of CHEMICAL. | NO-RELATIONSHIP |
| Ropivacaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of Ropivacaine, can interact with Ropivacaine leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with CHEMICAL infusion administered 1 hour after CHEMICAL) caused a 15% reduction in in-vivo plasma clearance of ropivacaine. | NO-RELATIONSHIP |
| Ropivacaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of Ropivacaine, can interact with Ropivacaine leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with CHEMICAL infusion administered 1 hour after ketoconazole) caused a 15% reduction in in-vivo plasma clearance of CHEMICAL. | NO-RELATIONSHIP |
| Ropivacaine should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of Ropivacaine, can interact with Ropivacaine leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after CHEMICAL) caused a 15% reduction in in-vivo plasma clearance of CHEMICAL. | NO-RELATIONSHIP |
| In elderly patients concurrently receiving certain CHEMICAL, primarily CHEMICAL, an increased incidence of thrombopenia with purpura has been reported. It has been reported that sulfamethoxazole may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin. This interaction should be kept in mind when Gantanol is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. Sulfamethoxazole may inhibit the hepatic metabolism of phenytoin. At a 1.6-g dose, sulfamethoxazole produced a slight but significant increase in the half-life of phenytoin but did not produce a corresponding decrease in the metabolic clearance rate. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. Sulfonamides can also displace methotrexate from plasma protein-binding sites, thus increasing free methotrexate concentrations. The presence of sulfamethoxazole may interfere with the Jaff alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values. | NO-RELATIONSHIP |
| In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombopenia with purpura has been reported. It has been reported that CHEMICAL may prolong the prothrombin time in patients who are receiving the CHEMICAL warfarin. This interaction should be kept in mind when Gantanol is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. Sulfamethoxazole may inhibit the hepatic metabolism of phenytoin. At a 1.6-g dose, sulfamethoxazole produced a slight but significant increase in the half-life of phenytoin but did not produce a corresponding decrease in the metabolic clearance rate. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. Sulfonamides can also displace methotrexate from plasma protein-binding sites, thus increasing free methotrexate concentrations. The presence of sulfamethoxazole may interfere with the Jaff alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values. | CHEMICALS-INTERACTION |
| In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombopenia with purpura has been reported. It has been reported that CHEMICAL may prolong the prothrombin time in patients who are receiving the anticoagulant CHEMICAL. This interaction should be kept in mind when Gantanol is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. Sulfamethoxazole may inhibit the hepatic metabolism of phenytoin. At a 1.6-g dose, sulfamethoxazole produced a slight but significant increase in the half-life of phenytoin but did not produce a corresponding decrease in the metabolic clearance rate. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. Sulfonamides can also displace methotrexate from plasma protein-binding sites, thus increasing free methotrexate concentrations. The presence of sulfamethoxazole may interfere with the Jaff alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values. | CHEMICALS-INTERACTION |
| In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombopenia with purpura has been reported. It has been reported that sulfamethoxazole may prolong the prothrombin time in patients who are receiving the CHEMICAL CHEMICAL. This interaction should be kept in mind when Gantanol is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. Sulfamethoxazole may inhibit the hepatic metabolism of phenytoin. At a 1.6-g dose, sulfamethoxazole produced a slight but significant increase in the half-life of phenytoin but did not produce a corresponding decrease in the metabolic clearance rate. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. Sulfonamides can also displace methotrexate from plasma protein-binding sites, thus increasing free methotrexate concentrations. The presence of sulfamethoxazole may interfere with the Jaff alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values. | NO-RELATIONSHIP |
| In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombopenia with purpura has been reported. It has been reported that sulfamethoxazole may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin. This interaction should be kept in mind when Gantanol is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. CHEMICAL may inhibit the hepatic metabolism of CHEMICAL. At a 1.6-g dose, sulfamethoxazole produced a slight but significant increase in the half-life of phenytoin but did not produce a corresponding decrease in the metabolic clearance rate. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. Sulfonamides can also displace methotrexate from plasma protein-binding sites, thus increasing free methotrexate concentrations. The presence of sulfamethoxazole may interfere with the Jaff alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values. | CHEMICALS-INTERACTION |
| In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombopenia with purpura has been reported. It has been reported that sulfamethoxazole may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin. This interaction should be kept in mind when Gantanol is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. Sulfamethoxazole may inhibit the hepatic metabolism of phenytoin. At a 1.6-g dose, CHEMICAL produced a slight but significant increase in the half-life of CHEMICAL but did not produce a corresponding decrease in the metabolic clearance rate. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. Sulfonamides can also displace methotrexate from plasma protein-binding sites, thus increasing free methotrexate concentrations. The presence of sulfamethoxazole may interfere with the Jaff alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values. | CHEMICALS-INTERACTION |
| In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombopenia with purpura has been reported. It has been reported that sulfamethoxazole may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin. This interaction should be kept in mind when Gantanol is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. Sulfamethoxazole may inhibit the hepatic metabolism of phenytoin. At a 1.6-g dose, sulfamethoxazole produced a slight but significant increase in the half-life of phenytoin but did not produce a corresponding decrease in the metabolic clearance rate. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. CHEMICAL can also displace CHEMICAL from plasma protein-binding sites, thus increasing free methotrexate concentrations. The presence of sulfamethoxazole may interfere with the Jaff alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values. | CHEMICALS-INTERACTION |
| In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombopenia with purpura has been reported. It has been reported that sulfamethoxazole may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin. This interaction should be kept in mind when Gantanol is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. Sulfamethoxazole may inhibit the hepatic metabolism of phenytoin. At a 1.6-g dose, sulfamethoxazole produced a slight but significant increase in the half-life of phenytoin but did not produce a corresponding decrease in the metabolic clearance rate. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. CHEMICAL can also displace methotrexate from plasma protein-binding sites, thus increasing free CHEMICAL concentrations. The presence of sulfamethoxazole may interfere with the Jaff alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values. | NO-RELATIONSHIP |
| In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombopenia with purpura has been reported. It has been reported that sulfamethoxazole may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin. This interaction should be kept in mind when Gantanol is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. Sulfamethoxazole may inhibit the hepatic metabolism of phenytoin. At a 1.6-g dose, sulfamethoxazole produced a slight but significant increase in the half-life of phenytoin but did not produce a corresponding decrease in the metabolic clearance rate. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. Sulfonamides can also displace CHEMICAL from plasma protein-binding sites, thus increasing free CHEMICAL concentrations. The presence of sulfamethoxazole may interfere with the Jaff alkaline picrate reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values. | NO-RELATIONSHIP |
| There is usually complete cross-resistance between CHEMICAL (CHEMICAL) and TABLOID brand Thioguanine. As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy. | NO-RELATIONSHIP |
| There is usually complete cross-resistance between CHEMICAL (mercaptopurine) and CHEMICAL brand Thioguanine. As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy. | CHEMICALS-INTERACTION |
| There is usually complete cross-resistance between CHEMICAL (mercaptopurine) and TABLOID brand CHEMICAL. As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy. | CHEMICALS-INTERACTION |
| There is usually complete cross-resistance between PURINETHOL (CHEMICAL) and CHEMICAL brand Thioguanine. As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy. | NO-RELATIONSHIP |
| There is usually complete cross-resistance between PURINETHOL (CHEMICAL) and TABLOID brand CHEMICAL. As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy. | CHEMICALS-INTERACTION |
| There is usually complete cross-resistance between PURINETHOL (mercaptopurine) and CHEMICAL brand CHEMICAL. As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy. | NO-RELATIONSHIP |
| There is usually complete cross-resistance between PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine. As there is in vitro evidence that CHEMICAL (e.g., CHEMICAL, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy. | NO-RELATIONSHIP |
| There is usually complete cross-resistance between PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine. As there is in vitro evidence that CHEMICAL (e.g., olsalazine, CHEMICAL, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy. | NO-RELATIONSHIP |
| There is usually complete cross-resistance between PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine. As there is in vitro evidence that CHEMICAL (e.g., olsalazine, mesalazine, or CHEMICAL) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy. | NO-RELATIONSHIP |
| There is usually complete cross-resistance between PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine. As there is in vitro evidence that CHEMICAL (e.g., olsalazine, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent CHEMICAL therapy. | CHEMICALS-INTERACTION |
| There is usually complete cross-resistance between PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine. As there is in vitro evidence that aminosalicylate derivatives (e.g., CHEMICAL, CHEMICAL, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy. | NO-RELATIONSHIP |
| There is usually complete cross-resistance between PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine. As there is in vitro evidence that aminosalicylate derivatives (e.g., CHEMICAL, mesalazine, or CHEMICAL) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy. | NO-RELATIONSHIP |
| There is usually complete cross-resistance between PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine. As there is in vitro evidence that aminosalicylate derivatives (e.g., CHEMICAL, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent CHEMICAL therapy. | CHEMICALS-INTERACTION |
| There is usually complete cross-resistance between PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine. As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, CHEMICAL, or CHEMICAL) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy. | NO-RELATIONSHIP |
| There is usually complete cross-resistance between PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine. As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, CHEMICAL, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent CHEMICAL therapy. | CHEMICALS-INTERACTION |
| There is usually complete cross-resistance between PURINETHOL (mercaptopurine) and TABLOID brand Thioguanine. As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or CHEMICAL) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent CHEMICAL therapy. | CHEMICALS-INTERACTION |
| CHEMICAL has been reported to enhance the sedative activity of CHEMICAL, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | CHEMICALS-INTERACTION |
| CHEMICAL has been reported to enhance the sedative activity of barbiturates, CHEMICAL, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | CHEMICALS-INTERACTION |
| CHEMICAL has been reported to enhance the sedative activity of barbiturates, alcohol, CHEMICAL, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | CHEMICALS-INTERACTION |
| CHEMICAL has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and CHEMICAL. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | CHEMICALS-INTERACTION |
| Thalidomide has been reported to enhance the sedative activity of CHEMICAL, CHEMICAL, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of CHEMICAL, alcohol, CHEMICAL, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of CHEMICAL, alcohol, chlorpromazine, and CHEMICAL. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, CHEMICAL, CHEMICAL, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, CHEMICAL, chlorpromazine, and CHEMICAL. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, CHEMICAL, and CHEMICAL. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral CHEMICAL: In 10 healthy women, the pharmacokinetic profiles of CHEMICAL and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral CHEMICAL: In 10 healthy women, the pharmacokinetic profiles of norethindrone and CHEMICAL following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral CHEMICAL: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of CHEMICAL and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral CHEMICAL: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of CHEMICAL were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of CHEMICAL and CHEMICAL following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of CHEMICAL and ethinyl estradiol following administration of a single dose containing 1.0 mg of CHEMICAL and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of CHEMICAL and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of CHEMICAL were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and CHEMICAL following administration of a single dose containing 1.0 mg of CHEMICAL and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and CHEMICAL following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of CHEMICAL were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of CHEMICAL and 75 g of CHEMICAL were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-CHEMICAL Drug Interactions Drugs That Interfere with CHEMICAL: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-CHEMICAL Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of CHEMICAL, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-CHEMICAL Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, CHEMICAL, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-CHEMICAL Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, CHEMICAL, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-CHEMICAL Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, CHEMICAL, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-CHEMICAL Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, CHEMICAL, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-CHEMICAL Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, CHEMICAL, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-CHEMICAL Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, CHEMICAL, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-CHEMICAL Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, CHEMICAL, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with CHEMICAL: Concomitant use of CHEMICAL, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with CHEMICAL: Concomitant use of HIV-protease inhibitors, CHEMICAL, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with CHEMICAL: Concomitant use of HIV-protease inhibitors, griseofulvin, CHEMICAL, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with CHEMICAL: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, CHEMICAL, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with CHEMICAL: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, CHEMICAL, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with CHEMICAL: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, CHEMICAL, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with CHEMICAL: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, CHEMICAL, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with CHEMICAL: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, CHEMICAL, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of CHEMICAL, CHEMICAL, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of CHEMICAL, griseofulvin, CHEMICAL, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of CHEMICAL, griseofulvin, modafinil, CHEMICAL, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of CHEMICAL, griseofulvin, modafinil, penicillins, CHEMICAL, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of CHEMICAL, griseofulvin, modafinil, penicillins, rifampin, CHEMICAL, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of CHEMICAL, griseofulvin, modafinil, penicillins, rifampin, rifabutin, CHEMICAL, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of CHEMICAL, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, CHEMICAL, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, CHEMICAL, CHEMICAL, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, CHEMICAL, modafinil, CHEMICAL, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, CHEMICAL, modafinil, penicillins, CHEMICAL, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, CHEMICAL, modafinil, penicillins, rifampin, CHEMICAL, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, CHEMICAL, modafinil, penicillins, rifampin, rifabutin, CHEMICAL, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, CHEMICAL, modafinil, penicillins, rifampin, rifabutin, phenytoin, CHEMICAL, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, CHEMICAL, CHEMICAL, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, CHEMICAL, penicillins, CHEMICAL, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, CHEMICAL, penicillins, rifampin, CHEMICAL, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, CHEMICAL, penicillins, rifampin, rifabutin, CHEMICAL, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, CHEMICAL, penicillins, rifampin, rifabutin, phenytoin, CHEMICAL, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, CHEMICAL, CHEMICAL, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, CHEMICAL, rifampin, CHEMICAL, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, CHEMICAL, rifampin, rifabutin, CHEMICAL, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, CHEMICAL, rifampin, rifabutin, phenytoin, CHEMICAL, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, CHEMICAL, CHEMICAL, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, CHEMICAL, rifabutin, CHEMICAL, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, CHEMICAL, rifabutin, phenytoin, CHEMICAL, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, CHEMICAL, CHEMICAL, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, CHEMICAL, phenytoin, CHEMICAL, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, CHEMICAL, CHEMICAL, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | NO-RELATIONSHIP |
| Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine. Peripheral Neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. Oral Contraceptives: In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 g of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels. Important Non-Thalidomide Drug Interactions Drugs That Interfere with Hormonal Contraceptives: Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. CHEMICAL with CHEMICAL may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide. | CHEMICALS-INTERACTION |
| Catecholamine-depleting drugs (e.g., CHEMICAL) may have an additive effect when given with CHEMICAL. Patients treated with extended release metoprolol succinate plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. | CHEMICALS-INTERACTION |
| The CNS-depressant effect of CHEMICAL is additive with that of other CHEMICAL, including alcohol. As is the case with many medicinal agents, propoxyphene may slow the metabolism of a concomitantly administered drug. Should this occur, the higher serum concentrations of that drug may result in increased pharmacologic or adverse effects of that drug. Such occurrences have been reported when propoxyphene was administered to patients on antidepressants, anticonvulsants, or warfarin-like drugs. Sever neurologic signs, including coma, have occurred with concurrent use of carbamazepine. | CHEMICALS-INTERACTION |
| The CNS-depressant effect of CHEMICAL is additive with that of other CNS depressants, including CHEMICAL. As is the case with many medicinal agents, propoxyphene may slow the metabolism of a concomitantly administered drug. Should this occur, the higher serum concentrations of that drug may result in increased pharmacologic or adverse effects of that drug. Such occurrences have been reported when propoxyphene was administered to patients on antidepressants, anticonvulsants, or warfarin-like drugs. Sever neurologic signs, including coma, have occurred with concurrent use of carbamazepine. | CHEMICALS-INTERACTION |
| The CNS-depressant effect of propoxyphene is additive with that of other CHEMICAL, including CHEMICAL. As is the case with many medicinal agents, propoxyphene may slow the metabolism of a concomitantly administered drug. Should this occur, the higher serum concentrations of that drug may result in increased pharmacologic or adverse effects of that drug. Such occurrences have been reported when propoxyphene was administered to patients on antidepressants, anticonvulsants, or warfarin-like drugs. Sever neurologic signs, including coma, have occurred with concurrent use of carbamazepine. | NO-RELATIONSHIP |
| The CNS-depressant effect of propoxyphene is additive with that of other CNS depressants, including alcohol. As is the case with many medicinal agents, propoxyphene may slow the metabolism of a concomitantly administered drug. Should this occur, the higher serum concentrations of that drug may result in increased pharmacologic or adverse effects of that drug. Such occurrences have been reported when CHEMICAL was administered to patients on CHEMICAL, anticonvulsants, or warfarin-like drugs. Sever neurologic signs, including coma, have occurred with concurrent use of carbamazepine. | CHEMICALS-INTERACTION |
| The CNS-depressant effect of propoxyphene is additive with that of other CNS depressants, including alcohol. As is the case with many medicinal agents, propoxyphene may slow the metabolism of a concomitantly administered drug. Should this occur, the higher serum concentrations of that drug may result in increased pharmacologic or adverse effects of that drug. Such occurrences have been reported when CHEMICAL was administered to patients on antidepressants, CHEMICAL, or warfarin-like drugs. Sever neurologic signs, including coma, have occurred with concurrent use of carbamazepine. | CHEMICALS-INTERACTION |
| The CNS-depressant effect of propoxyphene is additive with that of other CNS depressants, including alcohol. As is the case with many medicinal agents, propoxyphene may slow the metabolism of a concomitantly administered drug. Should this occur, the higher serum concentrations of that drug may result in increased pharmacologic or adverse effects of that drug. Such occurrences have been reported when CHEMICAL was administered to patients on antidepressants, anticonvulsants, or CHEMICAL-like drugs. Sever neurologic signs, including coma, have occurred with concurrent use of carbamazepine. | CHEMICALS-INTERACTION |
| The CNS-depressant effect of propoxyphene is additive with that of other CNS depressants, including alcohol. As is the case with many medicinal agents, propoxyphene may slow the metabolism of a concomitantly administered drug. Should this occur, the higher serum concentrations of that drug may result in increased pharmacologic or adverse effects of that drug. Such occurrences have been reported when propoxyphene was administered to patients on CHEMICAL, CHEMICAL, or warfarin-like drugs. Sever neurologic signs, including coma, have occurred with concurrent use of carbamazepine. | NO-RELATIONSHIP |
| The CNS-depressant effect of propoxyphene is additive with that of other CNS depressants, including alcohol. As is the case with many medicinal agents, propoxyphene may slow the metabolism of a concomitantly administered drug. Should this occur, the higher serum concentrations of that drug may result in increased pharmacologic or adverse effects of that drug. Such occurrences have been reported when propoxyphene was administered to patients on CHEMICAL, anticonvulsants, or CHEMICAL-like drugs. Sever neurologic signs, including coma, have occurred with concurrent use of carbamazepine. | NO-RELATIONSHIP |
| The CNS-depressant effect of propoxyphene is additive with that of other CNS depressants, including alcohol. As is the case with many medicinal agents, propoxyphene may slow the metabolism of a concomitantly administered drug. Should this occur, the higher serum concentrations of that drug may result in increased pharmacologic or adverse effects of that drug. Such occurrences have been reported when propoxyphene was administered to patients on antidepressants, CHEMICAL, or CHEMICAL-like drugs. Sever neurologic signs, including coma, have occurred with concurrent use of carbamazepine. | NO-RELATIONSHIP |
| CHEMICAL at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of CHEMICAL (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of CHEMICAL (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of CHEMICAL on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of CHEMICAL (a substrate of cytochrome P450 3A4) or CHEMICAL, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of CHEMICAL (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with CHEMICAL 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or CHEMICAL, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with CHEMICAL 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. CHEMICAL at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral CHEMICAL containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. CHEMICAL at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing CHEMICAL 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. CHEMICAL at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl CHEMICAL 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral CHEMICAL containing CHEMICAL 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral CHEMICAL containing norethindrone 1 mg/ethinyl CHEMICAL 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing CHEMICAL 1 mg/ethinyl CHEMICAL 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of CHEMICAL or CHEMICAL following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of CHEMICAL or prednisolone following administration of either oral CHEMICAL or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of CHEMICAL or prednisolone following administration of either oral prednisone or intravenous CHEMICAL. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or CHEMICAL following administration of either oral CHEMICAL or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or CHEMICAL following administration of either oral prednisone or intravenous CHEMICAL. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral CHEMICAL or intravenous CHEMICAL. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. CHEMICAL, which induces hepatic metabolism, decreased the AUC of CHEMICAL approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | CHEMICALS-INTERACTION |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. CHEMICAL, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of CHEMICAL. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | CHEMICALS-INTERACTION |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of CHEMICAL approximately 40% following a single 10-mg dose of CHEMICAL. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as CHEMICAL or CHEMICAL, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as CHEMICAL or rifampin, are co-administered with CHEMICAL. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | CHEMICALS-INTERACTION |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or CHEMICAL, are co-administered with CHEMICAL. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | CHEMICALS-INTERACTION |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of CHEMICAL did not have clinically important effects on the pharmacokinetics of the following drugs: CHEMICAL, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of CHEMICAL did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, CHEMICAL, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of CHEMICAL did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, CHEMICAL, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of CHEMICAL did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral CHEMICAL (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of CHEMICAL did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (CHEMICAL 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of CHEMICAL did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/CHEMICAL 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of CHEMICAL did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), CHEMICAL, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of CHEMICAL did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, CHEMICAL, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of CHEMICAL did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and CHEMICAL. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: CHEMICAL, CHEMICAL, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: CHEMICAL, prednisone, CHEMICAL, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: CHEMICAL, prednisone, prednisolone, oral CHEMICAL (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: CHEMICAL, prednisone, prednisolone, oral contraceptives (CHEMICAL 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: CHEMICAL, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/CHEMICAL 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: CHEMICAL, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), CHEMICAL, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: CHEMICAL, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, CHEMICAL, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: CHEMICAL, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and CHEMICAL. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, CHEMICAL, CHEMICAL, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, CHEMICAL, prednisolone, oral CHEMICAL (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, CHEMICAL, prednisolone, oral contraceptives (CHEMICAL 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, CHEMICAL, prednisolone, oral contraceptives (norethindrone 1 mg/CHEMICAL 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, CHEMICAL, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), CHEMICAL, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, CHEMICAL, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, CHEMICAL, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, CHEMICAL, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and CHEMICAL. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, CHEMICAL, oral CHEMICAL (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, CHEMICAL, oral contraceptives (CHEMICAL 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, CHEMICAL, oral contraceptives (norethindrone 1 mg/CHEMICAL 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, CHEMICAL, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), CHEMICAL, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, CHEMICAL, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, CHEMICAL, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, CHEMICAL, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and CHEMICAL. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral CHEMICAL (CHEMICAL 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral CHEMICAL (norethindrone 1 mg/CHEMICAL 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral CHEMICAL (norethindrone 1 mg/ethinyl estradiol 35 mcg), CHEMICAL, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral CHEMICAL (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, CHEMICAL, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral CHEMICAL (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and CHEMICAL. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (CHEMICAL 1 mg/CHEMICAL 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (CHEMICAL 1 mg/ethinyl estradiol 35 mcg), CHEMICAL, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (CHEMICAL 1 mg/ethinyl estradiol 35 mcg), terfenadine, CHEMICAL, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (CHEMICAL 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and CHEMICAL. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/CHEMICAL 35 mcg), CHEMICAL, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/CHEMICAL 35 mcg), terfenadine, CHEMICAL, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/CHEMICAL 35 mcg), terfenadine, digoxin, and CHEMICAL. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), CHEMICAL, CHEMICAL, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), CHEMICAL, digoxin, and CHEMICAL. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, CHEMICAL, and CHEMICAL. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included CHEMICAL, CHEMICAL, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included CHEMICAL, sedative hypnotics, CHEMICAL, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included CHEMICAL, sedative hypnotics, non-steroidal anti-inflammatory agents, CHEMICAL, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included CHEMICAL, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and CHEMICAL. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, CHEMICAL, CHEMICAL, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, CHEMICAL, non-steroidal anti-inflammatory agents, CHEMICAL, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, CHEMICAL, non-steroidal anti-inflammatory agents, benzodiazepines, and CHEMICAL. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, CHEMICAL, CHEMICAL, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, CHEMICAL, benzodiazepines, and CHEMICAL. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, CHEMICAL, and CHEMICAL. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. CHEMICAL, which induces hepatic metabolism, decreased the AUC of CHEMICAL approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | CHEMICALS-INTERACTION |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. CHEMICAL, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of CHEMICAL. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of CHEMICAL approximately 40% following a single 10-mg dose of CHEMICAL. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as CHEMICAL or CHEMICAL, are co-administered with montelukast. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as CHEMICAL or rifampin, are co-administered with CHEMICAL. | NO-RELATIONSHIP |
| Montelukast at a Dose of 10 mg Once Daily Dosed to Pharmacokinetic Steady State - did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline (predominantly a cytochrome P450 1A2 substrate). - did not change the pharmacokinetic profile of warfarin (a substrate of cytochromes P450 2A6 and 2C9) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the INR (International Normalized Ratio). - did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin. - did not change the plasma concentration profile of terfenadine (a substrate of cytochrome P450 3A4) or fexofenadine, its carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily. Montelukast at Doses of 100 mg Daily Dosed to Pharmacokinetic Steady State: - did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ethinyl estradiol 35 mcg. - did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast. Montelukast has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, prednisolone, oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants. Phenobarbital, which induces hepatic metabolism, decreased the AUC of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast is recommended. It is reasonable to employ appropriate clinical monitoring when potent cytochrome P450 enzyme inducers, such as phenobarbital or CHEMICAL, are co-administered with CHEMICAL. | NO-RELATIONSHIP |
| CHEMICAL/CHEMICAL: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| CHEMICAL/Levodopa: CHEMICAL/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| CHEMICAL/Levodopa: Carbidopa/CHEMICAL does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| CHEMICAL/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of CHEMICAL in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/CHEMICAL: CHEMICAL/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/CHEMICAL: Carbidopa/CHEMICAL does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/CHEMICAL: Carbidopa/Levodopa does not influence the pharmacokinetics of CHEMICAL in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: CHEMICAL/CHEMICAL does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: CHEMICAL/Levodopa does not influence the pharmacokinetics of CHEMICAL in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/CHEMICAL does not influence the pharmacokinetics of CHEMICAL in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. CHEMICAL: In healthy volunteers (N= 11), CHEMICAL did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. CHEMICAL: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of CHEMICAL. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), CHEMICAL did not influence the pharmacokinetics of CHEMICAL. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. CHEMICAL: Population pharmacokinetic analysis suggests that CHEMICAL is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. CHEMICAL: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of CHEMICAL (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that CHEMICAL is unlikely to alter the oral clearance of CHEMICAL (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). CHEMICAL: CHEMICAL, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). CHEMICAL: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in CHEMICAL AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: CHEMICAL, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in CHEMICAL AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | CHEMICALS-INTERACTION |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). CHEMICAL: CHEMICAL, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). CHEMICAL: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence CHEMICAL pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: CHEMICAL, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence CHEMICAL pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., CHEMICAL, CHEMICAL, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., CHEMICAL, ranitidine, CHEMICAL, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., CHEMICAL, ranitidine, diltiazem, CHEMICAL, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., CHEMICAL, ranitidine, diltiazem, triamterene, CHEMICAL, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., CHEMICAL, ranitidine, diltiazem, triamterene, verapamil, CHEMICAL, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., CHEMICAL, ranitidine, diltiazem, triamterene, verapamil, quinidine, and CHEMICAL) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., CHEMICAL, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of CHEMICAL by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | CHEMICALS-INTERACTION |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., CHEMICAL, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., CHEMICAL, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., CHEMICAL, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, CHEMICAL, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., CHEMICAL, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, CHEMICAL, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., CHEMICAL, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, CHEMICAL, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., CHEMICAL, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and CHEMICAL) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., CHEMICAL, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of CHEMICAL. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, CHEMICAL, CHEMICAL, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, CHEMICAL, diltiazem, CHEMICAL, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, CHEMICAL, diltiazem, triamterene, CHEMICAL, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, CHEMICAL, diltiazem, triamterene, verapamil, CHEMICAL, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, CHEMICAL, diltiazem, triamterene, verapamil, quinidine, and CHEMICAL) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, CHEMICAL, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of CHEMICAL by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | CHEMICALS-INTERACTION |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, CHEMICAL, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., CHEMICAL, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, CHEMICAL, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, CHEMICAL, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, CHEMICAL, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, CHEMICAL, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, CHEMICAL, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, CHEMICAL, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, CHEMICAL, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and CHEMICAL) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, CHEMICAL, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of CHEMICAL. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, CHEMICAL, CHEMICAL, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, CHEMICAL, triamterene, CHEMICAL, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, CHEMICAL, triamterene, verapamil, CHEMICAL, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, CHEMICAL, triamterene, verapamil, quinidine, and CHEMICAL) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, CHEMICAL, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of CHEMICAL by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | CHEMICALS-INTERACTION |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, CHEMICAL, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., CHEMICAL, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, CHEMICAL, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, CHEMICAL, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, CHEMICAL, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, CHEMICAL, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, CHEMICAL, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, CHEMICAL, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, CHEMICAL, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and CHEMICAL) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, CHEMICAL, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of CHEMICAL. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, CHEMICAL, CHEMICAL, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, CHEMICAL, verapamil, CHEMICAL, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, CHEMICAL, verapamil, quinidine, and CHEMICAL) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, CHEMICAL, verapamil, quinidine, and quinine) decreases the oral clearance of CHEMICAL by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | CHEMICALS-INTERACTION |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, CHEMICAL, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., CHEMICAL, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, CHEMICAL, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, CHEMICAL, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, CHEMICAL, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, CHEMICAL, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, CHEMICAL, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, CHEMICAL, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, CHEMICAL, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and CHEMICAL) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, CHEMICAL, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of CHEMICAL. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, CHEMICAL, CHEMICAL, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, CHEMICAL, quinidine, and CHEMICAL) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, CHEMICAL, quinidine, and quinine) decreases the oral clearance of CHEMICAL by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | CHEMICALS-INTERACTION |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, CHEMICAL, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., CHEMICAL, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, CHEMICAL, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, CHEMICAL, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, CHEMICAL, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, CHEMICAL, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, CHEMICAL, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, CHEMICAL, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, CHEMICAL, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and CHEMICAL) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, CHEMICAL, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of CHEMICAL. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, CHEMICAL, and CHEMICAL) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, CHEMICAL, and quinine) decreases the oral clearance of CHEMICAL by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | CHEMICALS-INTERACTION |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, CHEMICAL, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., CHEMICAL, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, CHEMICAL, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, CHEMICAL, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, CHEMICAL, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, CHEMICAL, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, CHEMICAL, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, CHEMICAL, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, CHEMICAL, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and CHEMICAL) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, CHEMICAL, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of CHEMICAL. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and CHEMICAL) decreases the oral clearance of CHEMICAL by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | CHEMICALS-INTERACTION |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and CHEMICAL) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., CHEMICAL, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and CHEMICAL) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, CHEMICAL, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and CHEMICAL) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, CHEMICAL, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and CHEMICAL) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, CHEMICAL, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and CHEMICAL) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and CHEMICAL) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and CHEMICAL) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of CHEMICAL. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of CHEMICAL by about 20%, while those secreted by the anionic transport system (e.g., CHEMICAL, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of CHEMICAL by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, CHEMICAL, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of CHEMICAL by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, CHEMICAL, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of CHEMICAL by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, CHEMICAL, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of CHEMICAL by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and CHEMICAL) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of CHEMICAL by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of CHEMICAL. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., CHEMICAL, CHEMICAL, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., CHEMICAL, penicillins, CHEMICAL, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., CHEMICAL, penicillins, indomethacin, CHEMICAL, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., CHEMICAL, penicillins, indomethacin, hydrochlorothiazide, and CHEMICAL) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., CHEMICAL, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of CHEMICAL. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | GENE-DISEASE |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, CHEMICAL, CHEMICAL, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, CHEMICAL, indomethacin, CHEMICAL, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, CHEMICAL, indomethacin, hydrochlorothiazide, and CHEMICAL) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, CHEMICAL, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of CHEMICAL. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, CHEMICAL, CHEMICAL, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, CHEMICAL, hydrochlorothiazide, and CHEMICAL) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, CHEMICAL, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of CHEMICAL. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, CHEMICAL, and CHEMICAL) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, CHEMICAL, and chlorpropamide) are likely to have little effect on the oral clearance of CHEMICAL. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and CHEMICAL) are likely to have little effect on the oral clearance of CHEMICAL. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | GENE-DISEASE |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect CHEMICAL elimination because CHEMICAL is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). CHEMICAL: Since CHEMICAL is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). CHEMICAL: Since pramipexole is a CHEMICAL, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). CHEMICAL: Since pramipexole is a dopamine agonist, it is possible that CHEMICAL, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). CHEMICAL: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the CHEMICAL (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). CHEMICAL: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (CHEMICAL, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). CHEMICAL: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, CHEMICAL, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). CHEMICAL: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, CHEMICAL) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). CHEMICAL: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or CHEMICAL, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). CHEMICAL: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of CHEMICAL. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since CHEMICAL is a CHEMICAL, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since CHEMICAL is a dopamine agonist, it is possible that CHEMICAL, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since CHEMICAL is a dopamine agonist, it is possible that dopamine antagonists, such as the CHEMICAL (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since CHEMICAL is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (CHEMICAL, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since CHEMICAL is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, CHEMICAL, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | CHEMICALS-INTERACTION |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since CHEMICAL is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, CHEMICAL) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since CHEMICAL is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or CHEMICAL, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | CHEMICALS-INTERACTION |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since CHEMICAL is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of CHEMICAL. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a CHEMICAL, it is possible that CHEMICAL, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a CHEMICAL, it is possible that dopamine antagonists, such as the CHEMICAL (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a CHEMICAL, it is possible that dopamine antagonists, such as the neuroleptics (CHEMICAL, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a CHEMICAL, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, CHEMICAL, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a CHEMICAL, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, CHEMICAL) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a CHEMICAL, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or CHEMICAL, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a CHEMICAL, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of CHEMICAL. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that CHEMICAL, such as the CHEMICAL (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that CHEMICAL, such as the neuroleptics (CHEMICAL, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that CHEMICAL, such as the neuroleptics (phenothiazines, CHEMICAL, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that CHEMICAL, such as the neuroleptics (phenothiazines, butyrophenones, CHEMICAL) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that CHEMICAL, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or CHEMICAL, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | CHEMICALS-INTERACTION |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that CHEMICAL, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of CHEMICAL. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | CHEMICALS-INTERACTION |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the CHEMICAL (CHEMICAL, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the CHEMICAL (phenothiazines, CHEMICAL, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the CHEMICAL (phenothiazines, butyrophenones, CHEMICAL) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the CHEMICAL (phenothiazines, butyrophenones, thioxanthenes) or CHEMICAL, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the CHEMICAL (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of CHEMICAL. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | CHEMICALS-INTERACTION |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (CHEMICAL, CHEMICAL, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (CHEMICAL, butyrophenones, CHEMICAL) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (CHEMICAL, butyrophenones, thioxanthenes) or CHEMICAL, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (CHEMICAL, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of CHEMICAL. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | CHEMICALS-INTERACTION |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, CHEMICAL, CHEMICAL) or metoclopramide, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, CHEMICAL, thioxanthenes) or CHEMICAL, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, CHEMICAL, thioxanthenes) or metoclopramide, may diminish the effectiveness of CHEMICAL. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | CHEMICALS-INTERACTION |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, CHEMICAL) or CHEMICAL, may diminish the effectiveness of MIRAPEX. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | NO-RELATIONSHIP |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, CHEMICAL) or metoclopramide, may diminish the effectiveness of CHEMICAL. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | CHEMICALS-INTERACTION |
| Carbidopa/Levodopa: Carbidopa/Levodopa does not influence the pharmacokinetics of pramipexole in healthy volunteers (N= 10). 5 hours. Selegiline: In healthy volunteers (N= 11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analysis suggests that amantadine is unlikely to alter the oral clearance of pramipexole (N= 54). Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N= 12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the aruonic transporter, did not noticeably influence pramipexole pharmacokinetics (N= 12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid). Dopamine antagonists: Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or CHEMICAL, may diminish the effectiveness of CHEMICAL. Drug/ Laboratory Test Interactions There are no known interactions between MIRAPEX and laboratory tests. | CHEMICALS-INTERACTION |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of CHEMICAL with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: CHEMICAL, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, CHEMICAL, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, CHEMICAL, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, CHEMICAL, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, CHEMICAL, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, CHEMICAL (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, CHEMICAL), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), CHEMICAL, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, CHEMICAL, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, CHEMICAL, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, CHEMICAL, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, CHEMICAL, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, CHEMICAL, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral CHEMICAL (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (CHEMICAL/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/CHEMICAL), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), CHEMICAL, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, CHEMICAL, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, CHEMICAL, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, CHEMICAL, warfarin, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, CHEMICAL, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, CHEMICAL, midazolam, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, CHEMICAL, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, CHEMICAL, clarithromycin, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, CHEMICAL, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, CHEMICAL, metronidazole, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, CHEMICAL, or CHEMICAL. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with CHEMICAL, adjustment of the dosage of CHEMICAL or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving CHEMICAL, including CHEMICAL, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving CHEMICAL, including pantoprazole, and CHEMICAL concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including CHEMICAL, and CHEMICAL concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with CHEMICAL and CHEMICAL concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | CHEMICALS-INTERACTION |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, CHEMICAL may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, CHEMICAL, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | CHEMICALS-INTERACTION |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, CHEMICAL may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, CHEMICAL esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | CHEMICALS-INTERACTION |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, CHEMICAL may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and CHEMICAL salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | CHEMICALS-INTERACTION |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, CHEMICAL, CHEMICAL esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, CHEMICAL, ampicillin esters, and CHEMICAL salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, CHEMICAL esters, and CHEMICAL salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for CHEMICAL (CHEMICAL) in patients receiving most proton pump inhibitors, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | NO-RELATIONSHIP |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for CHEMICAL (THC) in patients receiving most CHEMICAL, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | CHEMICALS-INTERACTION |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for CHEMICAL (THC) in patients receiving most proton pump inhibitors, including CHEMICAL. An alternative confirmatory method should be considered to verify positive results. | CHEMICALS-INTERACTION |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (CHEMICAL) in patients receiving most CHEMICAL, including pantoprazole. An alternative confirmatory method should be considered to verify positive results. | CHEMICALS-INTERACTION |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (CHEMICAL) in patients receiving most proton pump inhibitors, including CHEMICAL. An alternative confirmatory method should be considered to verify positive results. | CHEMICALS-INTERACTION |
| Pantoprazole is metabolized through the cytochrome P450 system, primarily the CYP2C19 and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation. Based on studies evaluating possible interactions of pantoprazole with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin. Clinically relevant interactions of pantoprazole with other drugs with the same metabolic pathways are not expected. Therefore, when coadministered with pantoprazole, adjustment of the dosage of pantoprazole or of such drugs may not be necessary. There was also no interaction with concomitantly administered antacids. There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including pantoprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly should be monitored for increases in INR and prothrombin time. Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may interfere with absorption of drugs where gastric pH is an important determinant of their bioavailability (eg, ketoconazole, ampicillin esters, and iron salts). Laboratory Tests There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving most CHEMICAL, including CHEMICAL. An alternative confirmatory method should be considered to verify positive results. | CHEMICALS-INTERACTION |
| Other eye drops or medications such as CHEMICAL (CHEMICAL) and carbachol (Carboptic, Isopto Carbachol) may decrease the effects of suprofen ophthalmic. | NO-RELATIONSHIP |
| Other eye drops or medications such as CHEMICAL (Miochol) and CHEMICAL (Carboptic, Isopto Carbachol) may decrease the effects of suprofen ophthalmic. | NO-RELATIONSHIP |
| Other eye drops or medications such as CHEMICAL (Miochol) and carbachol (CHEMICAL, Isopto Carbachol) may decrease the effects of suprofen ophthalmic. | NO-RELATIONSHIP |
| Other eye drops or medications such as CHEMICAL (Miochol) and carbachol (Carboptic, CHEMICAL) may decrease the effects of suprofen ophthalmic. | NO-RELATIONSHIP |
| Other eye drops or medications such as CHEMICAL (Miochol) and carbachol (Carboptic, Isopto Carbachol) may decrease the effects of CHEMICAL ophthalmic. | CHEMICALS-INTERACTION |
| Other eye drops or medications such as acetylcholine chloride (CHEMICAL) and CHEMICAL (Carboptic, Isopto Carbachol) may decrease the effects of suprofen ophthalmic. | NO-RELATIONSHIP |
| Other eye drops or medications such as acetylcholine chloride (CHEMICAL) and carbachol (CHEMICAL, Isopto Carbachol) may decrease the effects of suprofen ophthalmic. | NO-RELATIONSHIP |
| Other eye drops or medications such as acetylcholine chloride (CHEMICAL) and carbachol (Carboptic, CHEMICAL) may decrease the effects of suprofen ophthalmic. | NO-RELATIONSHIP |
| Other eye drops or medications such as acetylcholine chloride (CHEMICAL) and carbachol (Carboptic, Isopto Carbachol) may decrease the effects of CHEMICAL ophthalmic. | CHEMICALS-INTERACTION |
| Other eye drops or medications such as acetylcholine chloride (Miochol) and CHEMICAL (CHEMICAL, Isopto Carbachol) may decrease the effects of suprofen ophthalmic. | NO-RELATIONSHIP |
| Other eye drops or medications such as acetylcholine chloride (Miochol) and CHEMICAL (Carboptic, CHEMICAL) may decrease the effects of suprofen ophthalmic. | NO-RELATIONSHIP |
| Other eye drops or medications such as acetylcholine chloride (Miochol) and CHEMICAL (Carboptic, Isopto Carbachol) may decrease the effects of CHEMICAL ophthalmic. | CHEMICALS-INTERACTION |
| Other eye drops or medications such as acetylcholine chloride (Miochol) and carbachol (CHEMICAL, CHEMICAL) may decrease the effects of suprofen ophthalmic. | NO-RELATIONSHIP |
| Other eye drops or medications such as acetylcholine chloride (Miochol) and carbachol (CHEMICAL, Isopto Carbachol) may decrease the effects of CHEMICAL ophthalmic. | CHEMICALS-INTERACTION |
| Other eye drops or medications such as acetylcholine chloride (Miochol) and carbachol (Carboptic, CHEMICAL) may decrease the effects of CHEMICAL ophthalmic. | CHEMICALS-INTERACTION |
| You cannot take CHEMICAL if you have taken a CHEMICAL (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | CHEMICALS-INTERACTION |
| You cannot take CHEMICAL if you have taken a monoamine oxidase inhibitor (CHEMICAL) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | CHEMICALS-INTERACTION |
| You cannot take CHEMICAL if you have taken a monoamine oxidase inhibitor (MAOI) such as CHEMICAL (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | CHEMICALS-INTERACTION |
| You cannot take CHEMICAL if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (CHEMICAL), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | CHEMICALS-INTERACTION |
| You cannot take CHEMICAL if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), CHEMICAL (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | CHEMICALS-INTERACTION |
| You cannot take CHEMICAL if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (CHEMICAL), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | CHEMICALS-INTERACTION |
| You cannot take CHEMICAL if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or CHEMICAL (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | CHEMICALS-INTERACTION |
| You cannot take CHEMICAL if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (CHEMICAL) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | CHEMICALS-INTERACTION |
| You cannot take mazindol if you have taken a CHEMICAL (CHEMICAL) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a CHEMICAL (MAOI) such as CHEMICAL (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a CHEMICAL (MAOI) such as isocarboxazid (CHEMICAL), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a CHEMICAL (MAOI) such as isocarboxazid (Marplan), CHEMICAL (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a CHEMICAL (MAOI) such as isocarboxazid (Marplan), tranylcypromine (CHEMICAL), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a CHEMICAL (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or CHEMICAL (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a CHEMICAL (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (CHEMICAL) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (CHEMICAL) such as CHEMICAL (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (CHEMICAL) such as isocarboxazid (CHEMICAL), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (CHEMICAL) such as isocarboxazid (Marplan), CHEMICAL (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (CHEMICAL) such as isocarboxazid (Marplan), tranylcypromine (CHEMICAL), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (CHEMICAL) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or CHEMICAL (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (CHEMICAL) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (CHEMICAL) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as CHEMICAL (CHEMICAL), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as CHEMICAL (Marplan), CHEMICAL (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as CHEMICAL (Marplan), tranylcypromine (CHEMICAL), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as CHEMICAL (Marplan), tranylcypromine (Parnate), or CHEMICAL (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as CHEMICAL (Marplan), tranylcypromine (Parnate), or phenelzine (CHEMICAL) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (CHEMICAL), CHEMICAL (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (CHEMICAL), tranylcypromine (CHEMICAL), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (CHEMICAL), tranylcypromine (Parnate), or CHEMICAL (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (CHEMICAL), tranylcypromine (Parnate), or phenelzine (CHEMICAL) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), CHEMICAL (CHEMICAL), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), CHEMICAL (Parnate), or CHEMICAL (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), CHEMICAL (Parnate), or phenelzine (CHEMICAL) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (CHEMICAL), or CHEMICAL (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (CHEMICAL), or phenelzine (CHEMICAL) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or CHEMICAL (CHEMICAL) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in CHEMICAL and other diabetes drug therapies may be necessary during treatment with CHEMICAL. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | CHEMICALS-INTERACTION |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. CHEMICAL may reduce the effects of CHEMICAL (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | CHEMICALS-INTERACTION |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. CHEMICAL may reduce the effects of guanethidine (CHEMICAL). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | CHEMICALS-INTERACTION |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of CHEMICAL (CHEMICAL). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a CHEMICAL such as CHEMICAL (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a CHEMICAL such as amitriptyline (CHEMICAL), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a CHEMICAL such as amitriptyline (Elavil), CHEMICAL (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a CHEMICAL such as amitriptyline (Elavil), amoxapine (CHEMICAL), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a CHEMICAL such as amitriptyline (Elavil), amoxapine (Asendin), CHEMICAL (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a CHEMICAL such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (CHEMICAL), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a CHEMICAL such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), CHEMICAL (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a CHEMICAL such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (CHEMICAL), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a CHEMICAL such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), CHEMICAL (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a CHEMICAL such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (CHEMICAL), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a CHEMICAL such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), CHEMICAL (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a CHEMICAL such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (CHEMICAL), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a CHEMICAL such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), CHEMICAL (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a CHEMICAL such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (CHEMICAL), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a CHEMICAL such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or CHEMICAL (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a CHEMICAL such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (CHEMICAL). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as CHEMICAL (CHEMICAL), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as CHEMICAL (Elavil), CHEMICAL (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as CHEMICAL (Elavil), amoxapine (CHEMICAL), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as CHEMICAL (Elavil), amoxapine (Asendin), CHEMICAL (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as CHEMICAL (Elavil), amoxapine (Asendin), doxepin (CHEMICAL), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as CHEMICAL (Elavil), amoxapine (Asendin), doxepin (Sinequan), CHEMICAL (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as CHEMICAL (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (CHEMICAL), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as CHEMICAL (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), CHEMICAL (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as CHEMICAL (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (CHEMICAL), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as CHEMICAL (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), CHEMICAL (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as CHEMICAL (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (CHEMICAL), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as CHEMICAL (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), CHEMICAL (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as CHEMICAL (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (CHEMICAL), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as CHEMICAL (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or CHEMICAL (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as CHEMICAL (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (CHEMICAL). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (CHEMICAL), CHEMICAL (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (CHEMICAL), amoxapine (CHEMICAL), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (CHEMICAL), amoxapine (Asendin), CHEMICAL (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (CHEMICAL), amoxapine (Asendin), doxepin (CHEMICAL), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (CHEMICAL), amoxapine (Asendin), doxepin (Sinequan), CHEMICAL (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (CHEMICAL), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (CHEMICAL), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (CHEMICAL), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), CHEMICAL (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (CHEMICAL), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (CHEMICAL), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (CHEMICAL), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), CHEMICAL (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (CHEMICAL), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (CHEMICAL), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (CHEMICAL), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), CHEMICAL (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (CHEMICAL), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (CHEMICAL), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (CHEMICAL), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or CHEMICAL (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (CHEMICAL), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (CHEMICAL). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), CHEMICAL (CHEMICAL), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), CHEMICAL (Asendin), CHEMICAL (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), CHEMICAL (Asendin), doxepin (CHEMICAL), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), CHEMICAL (Asendin), doxepin (Sinequan), CHEMICAL (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), CHEMICAL (Asendin), doxepin (Sinequan), nortriptyline (CHEMICAL), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), CHEMICAL (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), CHEMICAL (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), CHEMICAL (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (CHEMICAL), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), CHEMICAL (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), CHEMICAL (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), CHEMICAL (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (CHEMICAL), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), CHEMICAL (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), CHEMICAL (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), CHEMICAL (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (CHEMICAL), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), CHEMICAL (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or CHEMICAL (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), CHEMICAL (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (CHEMICAL). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (CHEMICAL), CHEMICAL (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (CHEMICAL), doxepin (CHEMICAL), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (CHEMICAL), doxepin (Sinequan), CHEMICAL (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (CHEMICAL), doxepin (Sinequan), nortriptyline (CHEMICAL), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (CHEMICAL), doxepin (Sinequan), nortriptyline (Pamelor), CHEMICAL (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (CHEMICAL), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (CHEMICAL), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (CHEMICAL), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), CHEMICAL (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (CHEMICAL), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (CHEMICAL), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (CHEMICAL), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), CHEMICAL (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (CHEMICAL), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (CHEMICAL), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (CHEMICAL), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or CHEMICAL (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (CHEMICAL), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (CHEMICAL). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), CHEMICAL (CHEMICAL), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), CHEMICAL (Sinequan), CHEMICAL (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), CHEMICAL (Sinequan), nortriptyline (CHEMICAL), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), CHEMICAL (Sinequan), nortriptyline (Pamelor), CHEMICAL (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), CHEMICAL (Sinequan), nortriptyline (Pamelor), imipramine (CHEMICAL), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), CHEMICAL (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), CHEMICAL (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), CHEMICAL (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (CHEMICAL), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), CHEMICAL (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), CHEMICAL (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), CHEMICAL (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (CHEMICAL), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), CHEMICAL (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or CHEMICAL (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), CHEMICAL (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (CHEMICAL). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (CHEMICAL), CHEMICAL (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (CHEMICAL), nortriptyline (CHEMICAL), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (CHEMICAL), nortriptyline (Pamelor), CHEMICAL (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (CHEMICAL), nortriptyline (Pamelor), imipramine (CHEMICAL), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (CHEMICAL), nortriptyline (Pamelor), imipramine (Tofranil), CHEMICAL (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (CHEMICAL), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (CHEMICAL), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (CHEMICAL), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), CHEMICAL (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (CHEMICAL), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (CHEMICAL), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (CHEMICAL), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or CHEMICAL (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (CHEMICAL), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (CHEMICAL). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), CHEMICAL (CHEMICAL), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), CHEMICAL (Pamelor), CHEMICAL (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), CHEMICAL (Pamelor), imipramine (CHEMICAL), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), CHEMICAL (Pamelor), imipramine (Tofranil), CHEMICAL (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), CHEMICAL (Pamelor), imipramine (Tofranil), clomipramine (CHEMICAL), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), CHEMICAL (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), CHEMICAL (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), CHEMICAL (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (CHEMICAL), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), CHEMICAL (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or CHEMICAL (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), CHEMICAL (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (CHEMICAL). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (CHEMICAL), CHEMICAL (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (CHEMICAL), imipramine (CHEMICAL), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (CHEMICAL), imipramine (Tofranil), CHEMICAL (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (CHEMICAL), imipramine (Tofranil), clomipramine (CHEMICAL), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (CHEMICAL), imipramine (Tofranil), clomipramine (Anafranil), CHEMICAL (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (CHEMICAL), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (CHEMICAL), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (CHEMICAL), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or CHEMICAL (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (CHEMICAL), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (CHEMICAL). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), CHEMICAL (CHEMICAL), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), CHEMICAL (Tofranil), CHEMICAL (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), CHEMICAL (Tofranil), clomipramine (CHEMICAL), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), CHEMICAL (Tofranil), clomipramine (Anafranil), CHEMICAL (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), CHEMICAL (Tofranil), clomipramine (Anafranil), protriptyline (CHEMICAL), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), CHEMICAL (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or CHEMICAL (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), CHEMICAL (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (CHEMICAL). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (CHEMICAL), CHEMICAL (Anafranil), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (CHEMICAL), clomipramine (CHEMICAL), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (CHEMICAL), clomipramine (Anafranil), CHEMICAL (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (CHEMICAL), clomipramine (Anafranil), protriptyline (CHEMICAL), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (CHEMICAL), clomipramine (Anafranil), protriptyline (Vivactil), or CHEMICAL (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (CHEMICAL), clomipramine (Anafranil), protriptyline (Vivactil), or desipramine (CHEMICAL). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), CHEMICAL (CHEMICAL), protriptyline (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), CHEMICAL (Anafranil), CHEMICAL (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), CHEMICAL (Anafranil), protriptyline (CHEMICAL), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), CHEMICAL (Anafranil), protriptyline (Vivactil), or CHEMICAL (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), CHEMICAL (Anafranil), protriptyline (Vivactil), or desipramine (CHEMICAL). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (CHEMICAL), CHEMICAL (Vivactil), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (CHEMICAL), protriptyline (CHEMICAL), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (CHEMICAL), protriptyline (Vivactil), or CHEMICAL (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (CHEMICAL), protriptyline (Vivactil), or desipramine (CHEMICAL). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), CHEMICAL (CHEMICAL), or desipramine (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), CHEMICAL (Vivactil), or CHEMICAL (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), CHEMICAL (Vivactil), or desipramine (CHEMICAL). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (CHEMICAL), or CHEMICAL (Norpramin). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (CHEMICAL), or desipramine (CHEMICAL). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| You cannot take mazindol if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days. Changes in insulin and other diabetes drug therapies may be necessary during treatment with mazindol. Mazindol may reduce the effects of guanethidine (Ismelin). This could lead to an increase in blood pressure. Tell your doctor if you are taking guanethidine. Before taking this medication, tell your doctor if you are taking a tricyclic antidepressant such as amitriptyline (Elavil), amoxapine (Asendin), doxepin (Sinequan), nortriptyline (Pamelor), imipramine (Tofranil), clomipramine (Anafranil), protriptyline (Vivactil), or CHEMICAL (CHEMICAL). These drugs may decrease the effects of mazindol. | NO-RELATIONSHIP |
| Synergistic interaction between CHEMICAL and CHEMICAL is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by sunitinib is superior to sunitinib followed by docetaxel and concurrent administration. | CHEMICALS-INTERACTION |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of CHEMICAL and that of concurrent or sequential administration of CHEMICAL and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by sunitinib is superior to sunitinib followed by docetaxel and concurrent administration. | NO-RELATIONSHIP |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of CHEMICAL and that of concurrent or sequential administration of sunitinib and CHEMICAL in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by sunitinib is superior to sunitinib followed by docetaxel and concurrent administration. | NO-RELATIONSHIP |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of CHEMICAL and CHEMICAL in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by sunitinib is superior to sunitinib followed by docetaxel and concurrent administration. | NO-RELATIONSHIP |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either CHEMICAL or CHEMICAL or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by sunitinib is superior to sunitinib followed by docetaxel and concurrent administration. | NO-RELATIONSHIP |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. CHEMICAL exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas CHEMICAL arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by sunitinib is superior to sunitinib followed by docetaxel and concurrent administration. | INHIBITOR |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of CHEMICAL and CHEMICAL has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by sunitinib is superior to sunitinib followed by docetaxel and concurrent administration. | CHEMICALS-INTERACTION |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to CHEMICAL followed by CHEMICAL, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by sunitinib is superior to sunitinib followed by docetaxel and concurrent administration. | CHEMICALS-INTERACTION |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by CHEMICAL exposure were efficiently suppressed by the subsequent exposure to CHEMICAL. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by sunitinib is superior to sunitinib followed by docetaxel and concurrent administration. | CHEMICALS-INTERACTION |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. CHEMICAL as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of CHEMICAL followed by sunitinib is superior to sunitinib followed by docetaxel and concurrent administration. | NO-RELATIONSHIP |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. CHEMICAL as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by CHEMICAL is superior to sunitinib followed by docetaxel and concurrent administration. | NO-RELATIONSHIP |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. CHEMICAL as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by sunitinib is superior to CHEMICAL followed by docetaxel and concurrent administration. | NO-RELATIONSHIP |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. CHEMICAL as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by sunitinib is superior to sunitinib followed by CHEMICAL and concurrent administration. | NO-RELATIONSHIP |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of CHEMICAL followed by CHEMICAL is superior to sunitinib followed by docetaxel and concurrent administration. | NO-RELATIONSHIP |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of CHEMICAL followed by sunitinib is superior to CHEMICAL followed by docetaxel and concurrent administration. | NO-RELATIONSHIP |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of CHEMICAL followed by sunitinib is superior to sunitinib followed by CHEMICAL and concurrent administration. | NO-RELATIONSHIP |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by CHEMICAL is superior to CHEMICAL followed by docetaxel and concurrent administration. | NO-RELATIONSHIP |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by CHEMICAL is superior to sunitinib followed by CHEMICAL and concurrent administration. | NO-RELATIONSHIP |
| Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non-small lung cancer with EGFR TKIs-resistant mutation. Previous studies have demonstrated that sunitinib has the anti-tumor activity in human non-small cell lung cancer (NSCLC). This study was aimed to investigate the efficacy of single use of sunitinib and that of concurrent or sequential administration of sunitinib and docetaxel in NSCLC cell lines that are resistant to EGFR TKIs. NSCLC cell lines with EGFR T790M mutation and K-ras mutation were exposed to either sunitinib or docetaxel or both based on various sequential administrations. After exposure, the cell viability was measured by MTT assay, cell cycle distribution was analyzed by flow cytometry, and alterations in signaling pathway were determined by immunoblotting. Sunitinib exhibited dose-dependent growth inhibition in NSCLC cell lines and arrested cell cycle at G1 phase, whereas docetaxel arrested at S phase. Although single or concurrent use of sunitinib and docetaxel has some anti-proliferative effects, the sequential administrations of both drugs remarkably enhanced anti-tumor activity. When cells were exposed to docetaxel followed by sunitinib, synergism was observed. The molecular basis of this synergism is that the signaling pathways that were initially activated by docetaxel exposure were efficiently suppressed by the subsequent exposure to sunitinib. In contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. Sunitinib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR T790M and K-ras mutations but the sequential administration of docetaxel followed by sunitinib is superior to CHEMICAL followed by CHEMICAL and concurrent administration. | NO-RELATIONSHIP |
| Pharmacokinetic properties of CHEMICAL were not altered by the addition of either CHEMICAL or zidovudine or the combination of lamivudine and zidovudine. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of CHEMICAL were not altered by the addition of either lamivudine or CHEMICAL or the combination of lamivudine and zidovudine. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of CHEMICAL were not altered by the addition of either lamivudine or zidovudine or the combination of CHEMICAL and zidovudine. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of CHEMICAL were not altered by the addition of either lamivudine or zidovudine or the combination of lamivudine and CHEMICAL. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of abacavir were not altered by the addition of either CHEMICAL or CHEMICAL or the combination of lamivudine and zidovudine. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of abacavir were not altered by the addition of either CHEMICAL or zidovudine or the combination of CHEMICAL and zidovudine. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of abacavir were not altered by the addition of either CHEMICAL or zidovudine or the combination of lamivudine and CHEMICAL. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of abacavir were not altered by the addition of either lamivudine or CHEMICAL or the combination of CHEMICAL and zidovudine. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of abacavir were not altered by the addition of either lamivudine or CHEMICAL or the combination of lamivudine and CHEMICAL. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of abacavir were not altered by the addition of either lamivudine or zidovudine or the combination of CHEMICAL and CHEMICAL. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of abacavir were not altered by the addition of either lamivudine or zidovudine or the combination of lamivudine and zidovudine. No clinically significant changes to CHEMICAL or CHEMICAL pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of abacavir were not altered by the addition of either lamivudine or zidovudine or the combination of lamivudine and zidovudine. No clinically significant changes to CHEMICAL or zidovudine pharmacokinetics were observed following concomitant administration of CHEMICAL. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of abacavir were not altered by the addition of either lamivudine or zidovudine or the combination of lamivudine and zidovudine. No clinically significant changes to lamivudine or CHEMICAL pharmacokinetics were observed following concomitant administration of CHEMICAL. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of abacavir were not altered by the addition of either lamivudine or zidovudine or the combination of lamivudine and zidovudine. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. CHEMICAL has no effect on the pharmacokinetic properties of CHEMICAL. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of abacavir were not altered by the addition of either lamivudine or zidovudine or the combination of lamivudine and zidovudine. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. CHEMICAL decreases the elimination of CHEMICAL causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | CHEMICALS-INTERACTION |
| Pharmacokinetic properties of abacavir were not altered by the addition of either lamivudine or zidovudine or the combination of lamivudine and zidovudine. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. CHEMICAL decreases the elimination of abacavir causing an increase in overall exposure . The addition of CHEMICAL has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of abacavir were not altered by the addition of either lamivudine or zidovudine or the combination of lamivudine and zidovudine. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. CHEMICAL decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of CHEMICAL. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of abacavir were not altered by the addition of either lamivudine or zidovudine or the combination of lamivudine and zidovudine. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of CHEMICAL causing an increase in overall exposure . The addition of CHEMICAL has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of abacavir were not altered by the addition of either lamivudine or zidovudine or the combination of lamivudine and zidovudine. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of CHEMICAL causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of CHEMICAL. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of abacavir were not altered by the addition of either lamivudine or zidovudine or the combination of lamivudine and zidovudine. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of CHEMICAL has no clinically significant effect on the pharmacokinetic properties of CHEMICAL. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of abacavir were not altered by the addition of either lamivudine or zidovudine or the combination of lamivudine and zidovudine. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving CHEMICAL-maintenance therapy (40 mg and 90 mg daily) with 600 mg of CHEMICAL twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | CHEMICALS-INTERACTION |
| Pharmacokinetic properties of abacavir were not altered by the addition of either lamivudine or zidovudine or the combination of lamivudine and zidovudine. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving CHEMICAL-maintenance therapy (40 mg and 90 mg daily) with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral CHEMICAL clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| Pharmacokinetic properties of abacavir were not altered by the addition of either lamivudine or zidovudine or the combination of lamivudine and zidovudine. No clinically significant changes to lamivudine or zidovudine pharmacokinetics were observed following concomitant administration of abacavir. Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure . The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. In a study of 11 HIV-infected patients receiving methadone-maintenance therapy (40 mg and 90 mg daily) with 600 mg of CHEMICAL twice daily (twice the currently recommended dose), oral CHEMICAL clearance increased 22% (90% CI 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. | NO-RELATIONSHIP |
| CHEMICAL may increase the effects of CHEMICAL, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | CHEMICALS-INTERACTION |
| CHEMICAL may increase the effects of barbiturates, CHEMICAL, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | CHEMICALS-INTERACTION |
| CHEMICAL may increase the effects of barbiturates, tolbutamide, and CHEMICAL. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | CHEMICALS-INTERACTION |
| Sulfoxone may increase the effects of CHEMICAL, CHEMICAL, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of CHEMICAL, tolbutamide, and CHEMICAL. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, CHEMICAL, and CHEMICAL. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with CHEMICAL (increased thrombocytopenia), CHEMICAL (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with CHEMICAL (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), CHEMICAL (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with CHEMICAL (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), CHEMICAL (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with CHEMICAL (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), CHEMICAL (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with CHEMICAL (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of CHEMICAL), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with CHEMICAL (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), CHEMICAL (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with CHEMICAL (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of CHEMICAL). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), CHEMICAL (increased nephrotoxicity), CHEMICAL (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), CHEMICAL (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), CHEMICAL (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), CHEMICAL (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), CHEMICAL (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), CHEMICAL (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of CHEMICAL), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), CHEMICAL (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), CHEMICAL (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), CHEMICAL (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of CHEMICAL). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), CHEMICAL (increased hypoglycemic response), CHEMICAL (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), CHEMICAL (increased hypoglycemic response), warfarin (increased anticoagulant effect), CHEMICAL (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), CHEMICAL (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of CHEMICAL), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), CHEMICAL (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), CHEMICAL (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), CHEMICAL (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of CHEMICAL). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), CHEMICAL (increased anticoagulant effect), CHEMICAL (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), CHEMICAL (increased anticoagulant effect), methotrexate (decreased renal excretion of CHEMICAL), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), CHEMICAL (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), CHEMICAL (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), CHEMICAL (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of CHEMICAL). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), CHEMICAL (decreased renal excretion of CHEMICAL), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), CHEMICAL (decreased renal excretion of methotrexate), CHEMICAL (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), CHEMICAL (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of CHEMICAL). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of CHEMICAL), CHEMICAL (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of CHEMICAL), phenytoin (decreased hepatic clearance of CHEMICAL). | NO-RELATIONSHIP |
| Sulfoxone may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), CHEMICAL (decreased hepatic clearance of CHEMICAL). | NO-RELATIONSHIP |
| CHEMICAL are capable of potentiating CHEMICAL (e.g., barbiturates, anesthetics, opiates, alcohol, etc.) as well as atropine and phosphorous insecticides. | CHEMICALS-INTERACTION |
| CHEMICAL are capable of potentiating CNS depressants (e.g., CHEMICAL, anesthetics, opiates, alcohol, etc.) as well as atropine and phosphorous insecticides. | CHEMICALS-INTERACTION |
| CHEMICAL are capable of potentiating CNS depressants (e.g., barbiturates, CHEMICAL, opiates, alcohol, etc.) as well as atropine and phosphorous insecticides. | CHEMICALS-INTERACTION |
| CHEMICAL are capable of potentiating CNS depressants (e.g., barbiturates, anesthetics, CHEMICAL, alcohol, etc.) as well as atropine and phosphorous insecticides. | CHEMICALS-INTERACTION |
| CHEMICAL are capable of potentiating CNS depressants (e.g., barbiturates, anesthetics, opiates, CHEMICAL, etc.) as well as atropine and phosphorous insecticides. | CHEMICALS-INTERACTION |
| Phenothiazines are capable of potentiating CHEMICAL (e.g., CHEMICAL, anesthetics, opiates, alcohol, etc.) as well as atropine and phosphorous insecticides. | NO-RELATIONSHIP |
| Phenothiazines are capable of potentiating CHEMICAL (e.g., barbiturates, CHEMICAL, opiates, alcohol, etc.) as well as atropine and phosphorous insecticides. | NO-RELATIONSHIP |
| Phenothiazines are capable of potentiating CHEMICAL (e.g., barbiturates, anesthetics, CHEMICAL, alcohol, etc.) as well as atropine and phosphorous insecticides. | NO-RELATIONSHIP |
| Phenothiazines are capable of potentiating CHEMICAL (e.g., barbiturates, anesthetics, opiates, CHEMICAL, etc.) as well as atropine and phosphorous insecticides. | NO-RELATIONSHIP |
| Phenothiazines are capable of potentiating CNS depressants (e.g., CHEMICAL, CHEMICAL, opiates, alcohol, etc.) as well as atropine and phosphorous insecticides. | NO-RELATIONSHIP |
| Phenothiazines are capable of potentiating CNS depressants (e.g., CHEMICAL, anesthetics, CHEMICAL, alcohol, etc.) as well as atropine and phosphorous insecticides. | NO-RELATIONSHIP |
| Phenothiazines are capable of potentiating CNS depressants (e.g., CHEMICAL, anesthetics, opiates, CHEMICAL, etc.) as well as atropine and phosphorous insecticides. | NO-RELATIONSHIP |
| Phenothiazines are capable of potentiating CNS depressants (e.g., barbiturates, CHEMICAL, CHEMICAL, alcohol, etc.) as well as atropine and phosphorous insecticides. | NO-RELATIONSHIP |
| Phenothiazines are capable of potentiating CNS depressants (e.g., barbiturates, CHEMICAL, opiates, CHEMICAL, etc.) as well as atropine and phosphorous insecticides. | NO-RELATIONSHIP |
| Phenothiazines are capable of potentiating CNS depressants (e.g., barbiturates, anesthetics, CHEMICAL, CHEMICAL, etc.) as well as atropine and phosphorous insecticides. | NO-RELATIONSHIP |
| Phenothiazines are capable of potentiating CNS depressants (e.g., barbiturates, anesthetics, opiates, alcohol, etc.) as well as CHEMICAL and CHEMICAL. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, CHEMICAL, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of CHEMICAL. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | INHIBITOR |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular CHEMICAL injections (0.2-0.5 mg/kg body weight), in combination with daily administration of CHEMICAL or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular CHEMICAL injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (CHEMICAL/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular CHEMICAL injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/CHEMICAL versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular CHEMICAL injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus CHEMICAL/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of CHEMICAL or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (CHEMICAL/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of CHEMICAL or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/CHEMICAL versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of CHEMICAL or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus CHEMICAL/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (CHEMICAL/CHEMICAL versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (CHEMICAL/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus CHEMICAL/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/CHEMICAL versus CHEMICAL/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of CHEMICAL treatment, all CHEMICAL/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of CHEMICAL treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the CHEMICAL/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of CHEMICAL treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/CHEMICAL-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all CHEMICAL/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the CHEMICAL/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all CHEMICAL/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/CHEMICAL-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the CHEMICAL/CHEMICAL-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in CHEMICAL/CHEMICAL-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | NO-RELATIONSHIP |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in CHEMICAL/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in CHEMICAL/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | REGULATOR |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/CHEMICAL-treated animals than in CHEMICAL/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | REGULATOR |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The CHEMICAL treatment also had a significant effect on the CHEMICAL-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | INHIBITOR |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In CHEMICAL/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in CHEMICAL/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | INHIBITOR |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In CHEMICAL/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/CHEMICAL-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | INHIBITOR |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in CHEMICAL/CHEMICAL-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | INHIBITOR |
| Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Degeneration of the dopaminergic nigrostriatal system and of noradrenergic neurons in the locus coeruleus are important pathological features of Parkinson's disease. There is an urgent need to develop therapies that slow down the progression of neurodegeneration in Parkinson's disease. In the present study, we tested whether the highly specific metabotropic glutamate receptor 5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine, reduces dopaminergic and noradrenergic neuronal loss in monkeys rendered parkinsonian by chronic treatment with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Weekly intramuscular 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections (0.2-0.5 mg/kg body weight), in combination with daily administration of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine or vehicle, were performed until the development of parkinsonian motor symptoms in either of the two experimental groups (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine versus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle). After 21 weeks of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment, all 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals displayed parkinsonian symptoms, whereas none of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys were significantly affected. These behavioural observations were consistent with in vivo positron emission tomography dopamine transporter imaging data, and with post-mortem stereological counts of midbrain dopaminergic neurons, as well as striatal intensity measurements of dopamine transporter and tyrosine hydroxylase immunoreactivity, which were all significantly higher in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated animals than in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated monkeys. The 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine treatment also had a significant effect on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced loss of norepinephrine neurons in the locus coeruleus and adjoining A5 and A7 noradrenaline cell groups. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/vehicle-treated animals, almost 40% loss of tyrosine hydroxylase-positive norepinephrine neurons was found in locus coeruleus/A5/A7 noradrenaline cell groups, whereas the extent of neuronal loss was lower than 15% of control values in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/3-[(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine-treated monkeys. Our data demonstrate that chronic treatment with the metabotropic glutamate receptor 5 antagonist, CHEMICAL, significantly reduces CHEMICAL toxicity towards dopaminergic and noradrenergic cell groups in non-human primates. This suggests that the use of metabotropic glutamate receptor 5 antagonists may be a useful strategy to reduce degeneration of catecholaminergic neurons in Parkinson's disease. | INHIBITOR |
| Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of CHEMICAL or CHEMICAL to warrant dosage adjustment when megestrol acetate is administered with these drugs. A pharmacokinetic study demonstrated that coadministration of megestrol acetate and indinavir results in a significant decrease in the pharmacokinetic parameters (~36% for Cmax and ~28% for AUC) of indinavir. Administration of a higher dose of indinavir should be considered when coadministering with megestrol acetate. The effects of indinavir, zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied. | NO-RELATIONSHIP |
| Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of CHEMICAL or rifabutin to warrant dosage adjustment when CHEMICAL is administered with these drugs. A pharmacokinetic study demonstrated that coadministration of megestrol acetate and indinavir results in a significant decrease in the pharmacokinetic parameters (~36% for Cmax and ~28% for AUC) of indinavir. Administration of a higher dose of indinavir should be considered when coadministering with megestrol acetate. The effects of indinavir, zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied. | NO-RELATIONSHIP |
| Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or CHEMICAL to warrant dosage adjustment when CHEMICAL is administered with these drugs. A pharmacokinetic study demonstrated that coadministration of megestrol acetate and indinavir results in a significant decrease in the pharmacokinetic parameters (~36% for Cmax and ~28% for AUC) of indinavir. Administration of a higher dose of indinavir should be considered when coadministering with megestrol acetate. The effects of indinavir, zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied. | NO-RELATIONSHIP |
| Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs. A pharmacokinetic study demonstrated that coadministration of CHEMICAL and CHEMICAL results in a significant decrease in the pharmacokinetic parameters (~36% for Cmax and ~28% for AUC) of indinavir. Administration of a higher dose of indinavir should be considered when coadministering with megestrol acetate. The effects of indinavir, zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied. | CHEMICALS-INTERACTION |
| Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs. A pharmacokinetic study demonstrated that coadministration of CHEMICAL and indinavir results in a significant decrease in the pharmacokinetic parameters (~36% for Cmax and ~28% for AUC) of CHEMICAL. Administration of a higher dose of indinavir should be considered when coadministering with megestrol acetate. The effects of indinavir, zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied. | NO-RELATIONSHIP |
| Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs. A pharmacokinetic study demonstrated that coadministration of megestrol acetate and CHEMICAL results in a significant decrease in the pharmacokinetic parameters (~36% for Cmax and ~28% for AUC) of CHEMICAL. Administration of a higher dose of indinavir should be considered when coadministering with megestrol acetate. The effects of indinavir, zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied. | NO-RELATIONSHIP |
| Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs. A pharmacokinetic study demonstrated that coadministration of megestrol acetate and indinavir results in a significant decrease in the pharmacokinetic parameters (~36% for Cmax and ~28% for AUC) of indinavir. Administration of a higher dose of CHEMICAL should be considered when coadministering with CHEMICAL. The effects of indinavir, zidovudine or rifabutin on the pharmacokinetics of megestrol acetate were not studied. | CHEMICALS-INTERACTION |
| Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs. A pharmacokinetic study demonstrated that coadministration of megestrol acetate and indinavir results in a significant decrease in the pharmacokinetic parameters (~36% for Cmax and ~28% for AUC) of indinavir. Administration of a higher dose of indinavir should be considered when coadministering with megestrol acetate. The effects of CHEMICAL, CHEMICAL or rifabutin on the pharmacokinetics of megestrol acetate were not studied. | NO-RELATIONSHIP |
| Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs. A pharmacokinetic study demonstrated that coadministration of megestrol acetate and indinavir results in a significant decrease in the pharmacokinetic parameters (~36% for Cmax and ~28% for AUC) of indinavir. Administration of a higher dose of indinavir should be considered when coadministering with megestrol acetate. The effects of CHEMICAL, zidovudine or CHEMICAL on the pharmacokinetics of megestrol acetate were not studied. | NO-RELATIONSHIP |
| Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs. A pharmacokinetic study demonstrated that coadministration of megestrol acetate and indinavir results in a significant decrease in the pharmacokinetic parameters (~36% for Cmax and ~28% for AUC) of indinavir. Administration of a higher dose of indinavir should be considered when coadministering with megestrol acetate. The effects of CHEMICAL, zidovudine or rifabutin on the pharmacokinetics of CHEMICAL were not studied. | NO-RELATIONSHIP |
| Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs. A pharmacokinetic study demonstrated that coadministration of megestrol acetate and indinavir results in a significant decrease in the pharmacokinetic parameters (~36% for Cmax and ~28% for AUC) of indinavir. Administration of a higher dose of indinavir should be considered when coadministering with megestrol acetate. The effects of indinavir, CHEMICAL or CHEMICAL on the pharmacokinetics of megestrol acetate were not studied. | NO-RELATIONSHIP |
| Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs. A pharmacokinetic study demonstrated that coadministration of megestrol acetate and indinavir results in a significant decrease in the pharmacokinetic parameters (~36% for Cmax and ~28% for AUC) of indinavir. Administration of a higher dose of indinavir should be considered when coadministering with megestrol acetate. The effects of indinavir, CHEMICAL or rifabutin on the pharmacokinetics of CHEMICAL were not studied. | NO-RELATIONSHIP |
| Pharmacokinetic studies show that there are no significant alterations in pharmacokinetic parameters of zidovudine or rifabutin to warrant dosage adjustment when megestrol acetate is administered with these drugs. A pharmacokinetic study demonstrated that coadministration of megestrol acetate and indinavir results in a significant decrease in the pharmacokinetic parameters (~36% for Cmax and ~28% for AUC) of indinavir. Administration of a higher dose of indinavir should be considered when coadministering with megestrol acetate. The effects of indinavir, zidovudine or CHEMICAL on the pharmacokinetics of CHEMICAL were not studied. | NO-RELATIONSHIP |
| ZANOSAR may demonstrate additive toxicity when used in combination with other cytotoxic drugs. CHEMICAL has been reported to prolong the elimination half-life of CHEMICAL and may lead to severe bone marrow suppression; a reduction of the doxorubicin dosage should be considered in patients receiving ZANOSAR concurrently. The concurrent use of streptozocin and phenytoin has been reported in one case to result in reduced streptozocin cytotoxicity. | CHEMICALS-INTERACTION |
| ZANOSAR may demonstrate additive toxicity when used in combination with other cytotoxic drugs. Streptozocin has been reported to prolong the elimination half-life of doxorubicin and may lead to severe bone marrow suppression; a reduction of the CHEMICAL dosage should be considered in patients receiving CHEMICAL concurrently. The concurrent use of streptozocin and phenytoin has been reported in one case to result in reduced streptozocin cytotoxicity. | CHEMICALS-INTERACTION |
| ZANOSAR may demonstrate additive toxicity when used in combination with other cytotoxic drugs. Streptozocin has been reported to prolong the elimination half-life of doxorubicin and may lead to severe bone marrow suppression; a reduction of the doxorubicin dosage should be considered in patients receiving ZANOSAR concurrently. The concurrent use of CHEMICAL and CHEMICAL has been reported in one case to result in reduced streptozocin cytotoxicity. | CHEMICALS-INTERACTION |
| ZANOSAR may demonstrate additive toxicity when used in combination with other cytotoxic drugs. Streptozocin has been reported to prolong the elimination half-life of doxorubicin and may lead to severe bone marrow suppression; a reduction of the doxorubicin dosage should be considered in patients receiving ZANOSAR concurrently. The concurrent use of CHEMICAL and phenytoin has been reported in one case to result in reduced CHEMICAL cytotoxicity. | NO-RELATIONSHIP |
| ZANOSAR may demonstrate additive toxicity when used in combination with other cytotoxic drugs. Streptozocin has been reported to prolong the elimination half-life of doxorubicin and may lead to severe bone marrow suppression; a reduction of the doxorubicin dosage should be considered in patients receiving ZANOSAR concurrently. The concurrent use of streptozocin and CHEMICAL has been reported in one case to result in reduced CHEMICAL cytotoxicity. | NO-RELATIONSHIP |
| CHEMICAL should be used with caution in digitalized patients, since the combination of CHEMICAL and sympathomimetic amines may cause ectopic arrhythmias. Monoamine oxidase inhibitors or tricyclic antidepressants may potentiate the action of sympathomimetic amines. Therefore, when initiating pressor therapy in patients receiving these drugs, the initial dose should be small and given with caution. | NO-RELATIONSHIP |
| CHEMICAL should be used with caution in digitalized patients, since the combination of digitalis and CHEMICAL may cause ectopic arrhythmias. Monoamine oxidase inhibitors or tricyclic antidepressants may potentiate the action of sympathomimetic amines. Therefore, when initiating pressor therapy in patients receiving these drugs, the initial dose should be small and given with caution. | NO-RELATIONSHIP |
| ARAMINE should be used with caution in digitalized patients, since the combination of CHEMICAL and CHEMICAL may cause ectopic arrhythmias. Monoamine oxidase inhibitors or tricyclic antidepressants may potentiate the action of sympathomimetic amines. Therefore, when initiating pressor therapy in patients receiving these drugs, the initial dose should be small and given with caution. | CHEMICALS-INTERACTION |
| ARAMINE should be used with caution in digitalized patients, since the combination of digitalis and sympathomimetic amines may cause ectopic arrhythmias. CHEMICAL or CHEMICAL may potentiate the action of sympathomimetic amines. Therefore, when initiating pressor therapy in patients receiving these drugs, the initial dose should be small and given with caution. | NO-RELATIONSHIP |
| ARAMINE should be used with caution in digitalized patients, since the combination of digitalis and sympathomimetic amines may cause ectopic arrhythmias. CHEMICAL or tricyclic antidepressants may potentiate the action of CHEMICAL. Therefore, when initiating pressor therapy in patients receiving these drugs, the initial dose should be small and given with caution. | CHEMICALS-INTERACTION |
| ARAMINE should be used with caution in digitalized patients, since the combination of digitalis and sympathomimetic amines may cause ectopic arrhythmias. Monoamine oxidase inhibitors or CHEMICAL may potentiate the action of CHEMICAL. Therefore, when initiating pressor therapy in patients receiving these drugs, the initial dose should be small and given with caution. | CHEMICALS-INTERACTION |
| CHEMICAL can interact with CHEMICAL, antichlolinergic, TCA, MAOIs, and alcohol. | CHEMICALS-INTERACTION |
| CHEMICAL can interact with CNS depressant, CHEMICAL, TCA, MAOIs, and alcohol. | CHEMICALS-INTERACTION |
| CHEMICAL can interact with CNS depressant, antichlolinergic, CHEMICAL, MAOIs, and alcohol. | CHEMICALS-INTERACTION |
| CHEMICAL can interact with CNS depressant, antichlolinergic, TCA, CHEMICAL, and alcohol. | CHEMICALS-INTERACTION |
| CHEMICAL can interact with CNS depressant, antichlolinergic, TCA, MAOIs, and CHEMICAL. | CHEMICALS-INTERACTION |
| Mequitazine can interact with CHEMICAL, CHEMICAL, TCA, MAOIs, and alcohol. | NO-RELATIONSHIP |
| Mequitazine can interact with CHEMICAL, antichlolinergic, CHEMICAL, MAOIs, and alcohol. | NO-RELATIONSHIP |
| Mequitazine can interact with CHEMICAL, antichlolinergic, TCA, CHEMICAL, and alcohol. | NO-RELATIONSHIP |
| Mequitazine can interact with CHEMICAL, antichlolinergic, TCA, MAOIs, and CHEMICAL. | NO-RELATIONSHIP |
| Mequitazine can interact with CNS depressant, CHEMICAL, CHEMICAL, MAOIs, and alcohol. | NO-RELATIONSHIP |
| Mequitazine can interact with CNS depressant, CHEMICAL, TCA, CHEMICAL, and alcohol. | NO-RELATIONSHIP |
| Mequitazine can interact with CNS depressant, CHEMICAL, TCA, MAOIs, and CHEMICAL. | NO-RELATIONSHIP |
| Mequitazine can interact with CNS depressant, antichlolinergic, CHEMICAL, CHEMICAL, and alcohol. | NO-RELATIONSHIP |
| Mequitazine can interact with CNS depressant, antichlolinergic, CHEMICAL, MAOIs, and CHEMICAL. | NO-RELATIONSHIP |
| Mequitazine can interact with CNS depressant, antichlolinergic, TCA, CHEMICAL, and CHEMICAL. | NO-RELATIONSHIP |
| CHEMICAL may decrease the effectiveness of oral CHEMICAL, certain antibiotics, quinidine, theophylline, corticosteroids, anticoagulants, and beta blockers. | CHEMICALS-INTERACTION |
| CHEMICAL may decrease the effectiveness of oral contraceptives, certain CHEMICAL, quinidine, theophylline, corticosteroids, anticoagulants, and beta blockers. | CHEMICALS-INTERACTION |
| CHEMICAL may decrease the effectiveness of oral contraceptives, certain antibiotics, CHEMICAL, theophylline, corticosteroids, anticoagulants, and beta blockers. | CHEMICALS-INTERACTION |
| CHEMICAL may decrease the effectiveness of oral contraceptives, certain antibiotics, quinidine, CHEMICAL, corticosteroids, anticoagulants, and beta blockers. | CHEMICALS-INTERACTION |
| CHEMICAL may decrease the effectiveness of oral contraceptives, certain antibiotics, quinidine, theophylline, CHEMICAL, anticoagulants, and beta blockers. | CHEMICALS-INTERACTION |
| CHEMICAL may decrease the effectiveness of oral contraceptives, certain antibiotics, quinidine, theophylline, corticosteroids, CHEMICAL, and beta blockers. | CHEMICALS-INTERACTION |
| CHEMICAL may decrease the effectiveness of oral contraceptives, certain antibiotics, quinidine, theophylline, corticosteroids, anticoagulants, and CHEMICAL. | CHEMICALS-INTERACTION |
| Barbiturates may decrease the effectiveness of oral CHEMICAL, certain CHEMICAL, quinidine, theophylline, corticosteroids, anticoagulants, and beta blockers. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral CHEMICAL, certain antibiotics, CHEMICAL, theophylline, corticosteroids, anticoagulants, and beta blockers. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral CHEMICAL, certain antibiotics, quinidine, CHEMICAL, corticosteroids, anticoagulants, and beta blockers. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral CHEMICAL, certain antibiotics, quinidine, theophylline, CHEMICAL, anticoagulants, and beta blockers. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral CHEMICAL, certain antibiotics, quinidine, theophylline, corticosteroids, CHEMICAL, and beta blockers. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral CHEMICAL, certain antibiotics, quinidine, theophylline, corticosteroids, anticoagulants, and CHEMICAL. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral contraceptives, certain CHEMICAL, CHEMICAL, theophylline, corticosteroids, anticoagulants, and beta blockers. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral contraceptives, certain CHEMICAL, quinidine, CHEMICAL, corticosteroids, anticoagulants, and beta blockers. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral contraceptives, certain CHEMICAL, quinidine, theophylline, CHEMICAL, anticoagulants, and beta blockers. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral contraceptives, certain CHEMICAL, quinidine, theophylline, corticosteroids, CHEMICAL, and beta blockers. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral contraceptives, certain CHEMICAL, quinidine, theophylline, corticosteroids, anticoagulants, and CHEMICAL. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral contraceptives, certain antibiotics, CHEMICAL, CHEMICAL, corticosteroids, anticoagulants, and beta blockers. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral contraceptives, certain antibiotics, CHEMICAL, theophylline, CHEMICAL, anticoagulants, and beta blockers. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral contraceptives, certain antibiotics, CHEMICAL, theophylline, corticosteroids, CHEMICAL, and beta blockers. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral contraceptives, certain antibiotics, CHEMICAL, theophylline, corticosteroids, anticoagulants, and CHEMICAL. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral contraceptives, certain antibiotics, quinidine, CHEMICAL, CHEMICAL, anticoagulants, and beta blockers. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral contraceptives, certain antibiotics, quinidine, CHEMICAL, corticosteroids, CHEMICAL, and beta blockers. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral contraceptives, certain antibiotics, quinidine, CHEMICAL, corticosteroids, anticoagulants, and CHEMICAL. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral contraceptives, certain antibiotics, quinidine, theophylline, CHEMICAL, CHEMICAL, and beta blockers. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral contraceptives, certain antibiotics, quinidine, theophylline, CHEMICAL, anticoagulants, and CHEMICAL. | NO-RELATIONSHIP |
| Barbiturates may decrease the effectiveness of oral contraceptives, certain antibiotics, quinidine, theophylline, corticosteroids, CHEMICAL, and CHEMICAL. | NO-RELATIONSHIP |
| CHEMICAL may increase the effects of CHEMICAL, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | CHEMICALS-INTERACTION |
| CHEMICAL may increase the effects of barbiturates, CHEMICAL, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | CHEMICALS-INTERACTION |
| CHEMICAL may increase the effects of barbiturates, tolbutamide, and CHEMICAL. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | CHEMICALS-INTERACTION |
| Sulfamethizole may increase the effects of CHEMICAL, CHEMICAL, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of CHEMICAL, tolbutamide, and CHEMICAL. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, CHEMICAL, and CHEMICAL. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with CHEMICAL (increased thrombocytopenia), CHEMICAL (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with CHEMICAL (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), CHEMICAL (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with CHEMICAL (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), CHEMICAL (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with CHEMICAL (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), CHEMICAL (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with CHEMICAL (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of CHEMICAL), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with CHEMICAL (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), CHEMICAL (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with CHEMICAL (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of CHEMICAL). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), CHEMICAL (increased nephrotoxicity), CHEMICAL (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), CHEMICAL (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), CHEMICAL (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), CHEMICAL (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), CHEMICAL (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), CHEMICAL (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of CHEMICAL), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), CHEMICAL (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), CHEMICAL (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), CHEMICAL (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of CHEMICAL). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), CHEMICAL (increased hypoglycemic response), CHEMICAL (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), CHEMICAL (increased hypoglycemic response), warfarin (increased anticoagulant effect), CHEMICAL (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), CHEMICAL (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of CHEMICAL), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), CHEMICAL (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), CHEMICAL (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), CHEMICAL (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of CHEMICAL). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), CHEMICAL (increased anticoagulant effect), CHEMICAL (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), CHEMICAL (increased anticoagulant effect), methotrexate (decreased renal excretion of CHEMICAL), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), CHEMICAL (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), CHEMICAL (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), CHEMICAL (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of CHEMICAL). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), CHEMICAL (decreased renal excretion of CHEMICAL), phenytoin (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), CHEMICAL (decreased renal excretion of methotrexate), CHEMICAL (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), CHEMICAL (decreased renal excretion of methotrexate), phenytoin (decreased hepatic clearance of CHEMICAL). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of CHEMICAL), CHEMICAL (decreased hepatic clearance of phenytoin). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of CHEMICAL), phenytoin (decreased hepatic clearance of CHEMICAL). | NO-RELATIONSHIP |
| Sulfamethizole may increase the effects of barbiturates, tolbutamide, and uricosurics. It may also interact with thiazides (increased thrombocytopenia), cyclosporine (increased nephrotoxicity), sulfonylurea agents (increased hypoglycemic response), warfarin (increased anticoagulant effect), methotrexate (decreased renal excretion of methotrexate), CHEMICAL (decreased hepatic clearance of CHEMICAL). | NO-RELATIONSHIP |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of CHEMICAL were routinely treated with CHEMICAL and aspirin. Anticoagulants (such as heparin and vitamin K antagonists) and drugs that alter platelet function (such as acetylsalicylic acid, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after TNKase therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | NO-RELATIONSHIP |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of CHEMICAL were routinely treated with heparin and CHEMICAL. Anticoagulants (such as heparin and vitamin K antagonists) and drugs that alter platelet function (such as acetylsalicylic acid, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after TNKase therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | NO-RELATIONSHIP |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of TNKase were routinely treated with CHEMICAL and CHEMICAL. Anticoagulants (such as heparin and vitamin K antagonists) and drugs that alter platelet function (such as acetylsalicylic acid, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after TNKase therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | NO-RELATIONSHIP |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of TNKase were routinely treated with heparin and aspirin. CHEMICAL (such as CHEMICAL and vitamin K antagonists) and drugs that alter platelet function (such as acetylsalicylic acid, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after TNKase therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | NO-RELATIONSHIP |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of TNKase were routinely treated with heparin and aspirin. CHEMICAL (such as heparin and CHEMICAL) and drugs that alter platelet function (such as acetylsalicylic acid, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after TNKase therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | NO-RELATIONSHIP |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of TNKase were routinely treated with heparin and aspirin. CHEMICAL (such as heparin and vitamin K antagonists) and drugs that alter platelet function (such as CHEMICAL, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after TNKase therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | NO-RELATIONSHIP |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of TNKase were routinely treated with heparin and aspirin. CHEMICAL (such as heparin and vitamin K antagonists) and drugs that alter platelet function (such as acetylsalicylic acid, CHEMICAL, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after TNKase therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | NO-RELATIONSHIP |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of TNKase were routinely treated with heparin and aspirin. CHEMICAL (such as heparin and vitamin K antagonists) and drugs that alter platelet function (such as acetylsalicylic acid, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after CHEMICAL therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | CHEMICALS-INTERACTION |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of TNKase were routinely treated with heparin and aspirin. Anticoagulants (such as CHEMICAL and CHEMICAL) and drugs that alter platelet function (such as acetylsalicylic acid, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after TNKase therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | NO-RELATIONSHIP |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of TNKase were routinely treated with heparin and aspirin. Anticoagulants (such as CHEMICAL and vitamin K antagonists) and drugs that alter platelet function (such as CHEMICAL, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after TNKase therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | NO-RELATIONSHIP |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of TNKase were routinely treated with heparin and aspirin. Anticoagulants (such as CHEMICAL and vitamin K antagonists) and drugs that alter platelet function (such as acetylsalicylic acid, CHEMICAL, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after TNKase therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | NO-RELATIONSHIP |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of TNKase were routinely treated with heparin and aspirin. Anticoagulants (such as CHEMICAL and vitamin K antagonists) and drugs that alter platelet function (such as acetylsalicylic acid, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after CHEMICAL therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | CHEMICALS-INTERACTION |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of TNKase were routinely treated with heparin and aspirin. Anticoagulants (such as heparin and CHEMICAL) and drugs that alter platelet function (such as CHEMICAL, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after TNKase therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | NO-RELATIONSHIP |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of TNKase were routinely treated with heparin and aspirin. Anticoagulants (such as heparin and CHEMICAL) and drugs that alter platelet function (such as acetylsalicylic acid, CHEMICAL, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after TNKase therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | NO-RELATIONSHIP |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of TNKase were routinely treated with heparin and aspirin. Anticoagulants (such as heparin and CHEMICAL) and drugs that alter platelet function (such as acetylsalicylic acid, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after CHEMICAL therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | CHEMICALS-INTERACTION |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of TNKase were routinely treated with heparin and aspirin. Anticoagulants (such as heparin and vitamin K antagonists) and drugs that alter platelet function (such as CHEMICAL, CHEMICAL, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after TNKase therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | NO-RELATIONSHIP |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of TNKase were routinely treated with heparin and aspirin. Anticoagulants (such as heparin and vitamin K antagonists) and drugs that alter platelet function (such as CHEMICAL, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after CHEMICAL therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | CHEMICALS-INTERACTION |
| Formal interaction studies of TNKase with other drugs have not been performed. Patients studied in clinical trials of TNKase were routinely treated with heparin and aspirin. Anticoagulants (such as heparin and vitamin K antagonists) and drugs that alter platelet function (such as acetylsalicylic acid, CHEMICAL, and GP IIb/IIIa inhibitors) may increase the risk of bleeding if administered prior to, during, or after CHEMICAL therapy. Drug/Laboratory Test Interactions During TNKase therapy, results of coagulation tests and/or measures of fibrinolytic activity may be unreliable unless specific precautions are taken to prevent in vitro artifacts. Tenecteplase is an enzyme that, when present in blood in pharmacologic concentrations, remains active under in vitro conditions. This can lead to degradation of fibrinogen in blood samples removed for analysis. | CHEMICALS-INTERACTION |
| CHEMICAL: The effects of chronic CHEMICAL use on the metabolism of rimantadine are not known. When a single 100 mg dose of rimantadine HCl was administered one hour after the initiation of Cimetidine (300 mg four times a day), the apparent total rimantadine clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total rimantadine clearance in the same subjects in the absence of cimetidine). Acetaminophen: Rimantadine HCl, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Rimantadine HCl, 100 mg, was given twice daily fro 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. | NO-RELATIONSHIP |
| CHEMICAL: The effects of chronic cimetidine use on the metabolism of CHEMICAL are not known. When a single 100 mg dose of rimantadine HCl was administered one hour after the initiation of Cimetidine (300 mg four times a day), the apparent total rimantadine clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total rimantadine clearance in the same subjects in the absence of cimetidine). Acetaminophen: Rimantadine HCl, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Rimantadine HCl, 100 mg, was given twice daily fro 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. | NO-RELATIONSHIP |
| Cimetidine: The effects of chronic CHEMICAL use on the metabolism of CHEMICAL are not known. When a single 100 mg dose of rimantadine HCl was administered one hour after the initiation of Cimetidine (300 mg four times a day), the apparent total rimantadine clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total rimantadine clearance in the same subjects in the absence of cimetidine). Acetaminophen: Rimantadine HCl, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Rimantadine HCl, 100 mg, was given twice daily fro 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. | NO-RELATIONSHIP |
| Cimetidine: The effects of chronic cimetidine use on the metabolism of rimantadine are not known. When a single 100 mg dose of CHEMICAL was administered one hour after the initiation of CHEMICAL (300 mg four times a day), the apparent total rimantadine clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total rimantadine clearance in the same subjects in the absence of cimetidine). Acetaminophen: Rimantadine HCl, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Rimantadine HCl, 100 mg, was given twice daily fro 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. | CHEMICALS-INTERACTION |
| Cimetidine: The effects of chronic cimetidine use on the metabolism of rimantadine are not known. When a single 100 mg dose of CHEMICAL was administered one hour after the initiation of Cimetidine (300 mg four times a day), the apparent total CHEMICAL clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total rimantadine clearance in the same subjects in the absence of cimetidine). Acetaminophen: Rimantadine HCl, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Rimantadine HCl, 100 mg, was given twice daily fro 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. | NO-RELATIONSHIP |
| Cimetidine: The effects of chronic cimetidine use on the metabolism of rimantadine are not known. When a single 100 mg dose of CHEMICAL was administered one hour after the initiation of Cimetidine (300 mg four times a day), the apparent total rimantadine clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total CHEMICAL clearance in the same subjects in the absence of cimetidine). Acetaminophen: Rimantadine HCl, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Rimantadine HCl, 100 mg, was given twice daily fro 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. | NO-RELATIONSHIP |
| Cimetidine: The effects of chronic cimetidine use on the metabolism of rimantadine are not known. When a single 100 mg dose of CHEMICAL was administered one hour after the initiation of Cimetidine (300 mg four times a day), the apparent total rimantadine clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total rimantadine clearance in the same subjects in the absence of CHEMICAL). Acetaminophen: Rimantadine HCl, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Rimantadine HCl, 100 mg, was given twice daily fro 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. | NO-RELATIONSHIP |
| Cimetidine: The effects of chronic cimetidine use on the metabolism of rimantadine are not known. When a single 100 mg dose of rimantadine HCl was administered one hour after the initiation of CHEMICAL (300 mg four times a day), the apparent total CHEMICAL clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total rimantadine clearance in the same subjects in the absence of cimetidine). Acetaminophen: Rimantadine HCl, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Rimantadine HCl, 100 mg, was given twice daily fro 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. | NO-RELATIONSHIP |
| Cimetidine: The effects of chronic cimetidine use on the metabolism of rimantadine are not known. When a single 100 mg dose of rimantadine HCl was administered one hour after the initiation of CHEMICAL (300 mg four times a day), the apparent total rimantadine clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total CHEMICAL clearance in the same subjects in the absence of cimetidine). Acetaminophen: Rimantadine HCl, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Rimantadine HCl, 100 mg, was given twice daily fro 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. | NO-RELATIONSHIP |
| Cimetidine: The effects of chronic cimetidine use on the metabolism of rimantadine are not known. When a single 100 mg dose of rimantadine HCl was administered one hour after the initiation of CHEMICAL (300 mg four times a day), the apparent total rimantadine clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total rimantadine clearance in the same subjects in the absence of CHEMICAL). Acetaminophen: Rimantadine HCl, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Rimantadine HCl, 100 mg, was given twice daily fro 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. | NO-RELATIONSHIP |
| Cimetidine: The effects of chronic cimetidine use on the metabolism of rimantadine are not known. When a single 100 mg dose of rimantadine HCl was administered one hour after the initiation of Cimetidine (300 mg four times a day), the apparent total CHEMICAL clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total CHEMICAL clearance in the same subjects in the absence of cimetidine). Acetaminophen: Rimantadine HCl, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Rimantadine HCl, 100 mg, was given twice daily fro 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. | NO-RELATIONSHIP |
| Cimetidine: The effects of chronic cimetidine use on the metabolism of rimantadine are not known. When a single 100 mg dose of rimantadine HCl was administered one hour after the initiation of Cimetidine (300 mg four times a day), the apparent total CHEMICAL clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total rimantadine clearance in the same subjects in the absence of CHEMICAL). Acetaminophen: Rimantadine HCl, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Rimantadine HCl, 100 mg, was given twice daily fro 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. | NO-RELATIONSHIP |
| Cimetidine: The effects of chronic cimetidine use on the metabolism of rimantadine are not known. When a single 100 mg dose of rimantadine HCl was administered one hour after the initiation of Cimetidine (300 mg four times a day), the apparent total rimantadine clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total CHEMICAL clearance in the same subjects in the absence of CHEMICAL). Acetaminophen: Rimantadine HCl, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Rimantadine HCl, 100 mg, was given twice daily fro 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. | NO-RELATIONSHIP |
| Cimetidine: The effects of chronic cimetidine use on the metabolism of rimantadine are not known. When a single 100 mg dose of rimantadine HCl was administered one hour after the initiation of Cimetidine (300 mg four times a day), the apparent total rimantadine clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total rimantadine clearance in the same subjects in the absence of cimetidine). CHEMICAL: CHEMICAL, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Rimantadine HCl, 100 mg, was given twice daily fro 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. | NO-RELATIONSHIP |
| Cimetidine: The effects of chronic cimetidine use on the metabolism of rimantadine are not known. When a single 100 mg dose of rimantadine HCl was administered one hour after the initiation of Cimetidine (300 mg four times a day), the apparent total rimantadine clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total rimantadine clearance in the same subjects in the absence of cimetidine). Acetaminophen: Rimantadine HCl, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with CHEMICAL reduced the peak concentration and AUC values for CHEMICAL by approximately 11%. Aspirin: Rimantadine HCl, 100 mg, was given twice daily fro 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. | CHEMICALS-INTERACTION |
| Cimetidine: The effects of chronic cimetidine use on the metabolism of rimantadine are not known. When a single 100 mg dose of rimantadine HCl was administered one hour after the initiation of Cimetidine (300 mg four times a day), the apparent total rimantadine clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total rimantadine clearance in the same subjects in the absence of cimetidine). Acetaminophen: Rimantadine HCl, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. CHEMICAL: CHEMICAL, 100 mg, was given twice daily fro 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of rimantadine were reduced approximately 10% in the presence of aspirin. | NO-RELATIONSHIP |
| Cimetidine: The effects of chronic cimetidine use on the metabolism of rimantadine are not known. When a single 100 mg dose of rimantadine HCl was administered one hour after the initiation of Cimetidine (300 mg four times a day), the apparent total rimantadine clearance of this single dose in normal healthy adults was reduced by 18% (compared to the apparent total rimantadine clearance in the same subjects in the absence of cimetidine). Acetaminophen: Rimantadine HCl, 100 mg, was given twice daily for 13 days to 12 healthy volunteers. On day 11, acetaminophen (650 mg four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Coadministration with acetaminophen reduced the peak concentration and AUC values for rimantadine by approximately 11%. Aspirin: Rimantadine HCl, 100 mg, was given twice daily fro 13 days to 12 healthy volunteers. On day 11, aspirin (650 mg, four times daily) was started and continued for 8 days. The pharmacokinetics of rimantadine were assessed on days 11 and 13. Peak plasma concentrations and AUC of CHEMICAL were reduced approximately 10% in the presence of CHEMICAL. | CHEMICALS-INTERACTION |
| CHEMICAL may inhibit the hepatic metabolism of CHEMICAL. Trimethoprim, given at a common clinical dosage, increased the phenytoin half-life by 51% and decreased the phenytoin metabolic clearance rate by 30%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. | CHEMICALS-INTERACTION |
| Trimethoprim may inhibit the hepatic metabolism of phenytoin. CHEMICAL, given at a common clinical dosage, increased the CHEMICAL half-life by 51% and decreased the phenytoin metabolic clearance rate by 30%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. | CHEMICALS-INTERACTION |
| Trimethoprim may inhibit the hepatic metabolism of phenytoin. CHEMICAL, given at a common clinical dosage, increased the phenytoin half-life by 51% and decreased the CHEMICAL metabolic clearance rate by 30%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. | CHEMICALS-INTERACTION |
| Trimethoprim may inhibit the hepatic metabolism of phenytoin. Trimethoprim, given at a common clinical dosage, increased the CHEMICAL half-life by 51% and decreased the CHEMICAL metabolic clearance rate by 30%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. | NO-RELATIONSHIP |
| CHEMICAL should be administered with caution to patients taking CHEMICAL because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | CHEMICALS-INTERACTION |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., CHEMICAL, inhaled CHEMICAL). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: CHEMICAL, artificial tears, CHEMICAL, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: CHEMICAL, artificial tears, calcium, CHEMICAL, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: CHEMICAL, artificial tears, calcium, conjugated estrogens, CHEMICAL, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: CHEMICAL, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, CHEMICAL, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: CHEMICAL, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, CHEMICAL, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: CHEMICAL, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, CHEMICAL, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: CHEMICAL, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, CHEMICAL, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: CHEMICAL, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, CHEMICAL, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: CHEMICAL, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, CHEMICAL, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: CHEMICAL, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, CHEMICAL, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: CHEMICAL, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, CHEMICAL, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: CHEMICAL, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and CHEMICAL. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, CHEMICAL, CHEMICAL, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, CHEMICAL, conjugated estrogens, CHEMICAL, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, CHEMICAL, conjugated estrogens, hydroxychloroquine sulfate, CHEMICAL, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, CHEMICAL, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, CHEMICAL, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, CHEMICAL, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, CHEMICAL, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, CHEMICAL, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, CHEMICAL, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, CHEMICAL, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, CHEMICAL, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, CHEMICAL, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, CHEMICAL, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, CHEMICAL, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, CHEMICAL, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, CHEMICAL, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, CHEMICAL, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, CHEMICAL, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and CHEMICAL. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, CHEMICAL, CHEMICAL, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, CHEMICAL, hydroxychloroquine sulfate, CHEMICAL, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, CHEMICAL, hydroxychloroquine sulfate, ibuprofen, CHEMICAL, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, CHEMICAL, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, CHEMICAL, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, CHEMICAL, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, CHEMICAL, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, CHEMICAL, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, CHEMICAL, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, CHEMICAL, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, CHEMICAL, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, CHEMICAL, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, CHEMICAL, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, CHEMICAL, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, CHEMICAL, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, CHEMICAL, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and CHEMICAL. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, CHEMICAL, CHEMICAL, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, CHEMICAL, ibuprofen, CHEMICAL, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, CHEMICAL, ibuprofen, levothyroxine sodium, CHEMICAL, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, CHEMICAL, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, CHEMICAL, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, CHEMICAL, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, CHEMICAL, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, CHEMICAL, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, CHEMICAL, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, CHEMICAL, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, CHEMICAL, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, CHEMICAL, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, CHEMICAL, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, CHEMICAL, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and CHEMICAL. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, CHEMICAL, CHEMICAL, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, CHEMICAL, levothyroxine sodium, CHEMICAL, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, CHEMICAL, levothyroxine sodium, medroxyprogesterone acetate, CHEMICAL, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, CHEMICAL, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, CHEMICAL, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, CHEMICAL, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, CHEMICAL, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, CHEMICAL, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, CHEMICAL, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, CHEMICAL, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, CHEMICAL, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, CHEMICAL, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and CHEMICAL. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, CHEMICAL, CHEMICAL, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, CHEMICAL, medroxyprogesterone acetate, CHEMICAL, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, CHEMICAL, medroxyprogesterone acetate, methotrexate, CHEMICAL, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, CHEMICAL, medroxyprogesterone acetate, methotrexate, multivitamins, CHEMICAL, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, CHEMICAL, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, CHEMICAL, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, CHEMICAL, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, CHEMICAL, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, CHEMICAL, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and CHEMICAL. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, CHEMICAL, CHEMICAL, multivitamins, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, CHEMICAL, methotrexate, CHEMICAL, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, CHEMICAL, methotrexate, multivitamins, CHEMICAL, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, CHEMICAL, methotrexate, multivitamins, naproxen, CHEMICAL, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, CHEMICAL, methotrexate, multivitamins, naproxen, omeprazole, CHEMICAL, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, CHEMICAL, methotrexate, multivitamins, naproxen, omeprazole, paracetamol, and CHEMICAL. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, CHEMICAL, CHEMICAL, naproxen, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, CHEMICAL, multivitamins, CHEMICAL, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, CHEMICAL, multivitamins, naproxen, CHEMICAL, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, CHEMICAL, multivitamins, naproxen, omeprazole, CHEMICAL, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, CHEMICAL, multivitamins, naproxen, omeprazole, paracetamol, and CHEMICAL. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, CHEMICAL, CHEMICAL, omeprazole, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, CHEMICAL, naproxen, CHEMICAL, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, CHEMICAL, naproxen, omeprazole, CHEMICAL, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, CHEMICAL, naproxen, omeprazole, paracetamol, and CHEMICAL. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, CHEMICAL, CHEMICAL, paracetamol, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, CHEMICAL, omeprazole, CHEMICAL, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, CHEMICAL, omeprazole, paracetamol, and CHEMICAL. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, CHEMICAL, CHEMICAL, and prednisone. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, CHEMICAL, paracetamol, and CHEMICAL. | NO-RELATIONSHIP |
| Pilocarpine should be administered with caution to patients taking beta adrenergic antagonists because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with pilocarpine would be expected to result in additive pharmacologic effects. Pilocarpine might antagonize the anticholinergic effects of drugs used concomitantly. These effects should be considered when anticholinergic properties may be contributing to the therapeutic effect of concomitant medication (e.g., atropine, inhaled ipratropium). While no formal drug interaction studies have been performed, the following concomitant drugs were used in at least 10% of patients in either or both Sj grens efficacy studies: acetylsalicylic acid, artificial tears, calcium, conjugated estrogens, hydroxychloroquine sulfate, ibuprofen, levothyroxine sodium, medroxyprogesterone acetate, methotrexate, multivitamins, naproxen, omeprazole, CHEMICAL, and CHEMICAL. | NO-RELATIONSHIP |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of CHEMICAL and CHEMICAL; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin, and rifampin may increase the clearance of methylprednisolone and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of CHEMICAL and CHEMICAL. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin, and rifampin may increase the clearance of methylprednisolone and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as CHEMICAL, CHEMICAL, and rifampin may increase the clearance of methylprednisolone and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | NO-RELATIONSHIP |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as CHEMICAL, phenytoin, and CHEMICAL may increase the clearance of methylprednisolone and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | NO-RELATIONSHIP |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as CHEMICAL, phenytoin, and rifampin may increase the clearance of CHEMICAL and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as CHEMICAL, phenytoin, and rifampin may increase the clearance of methylprednisolone and may require increased in CHEMICAL dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, CHEMICAL, and CHEMICAL may increase the clearance of methylprednisolone and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | NO-RELATIONSHIP |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, CHEMICAL, and rifampin may increase the clearance of CHEMICAL and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, CHEMICAL, and rifampin may increase the clearance of methylprednisolone and may require increased in CHEMICAL dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin, and CHEMICAL may increase the clearance of CHEMICAL and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin, and CHEMICAL may increase the clearance of methylprednisolone and may require increased in CHEMICAL dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin, and rifampin may increase the clearance of CHEMICAL and may require increased in CHEMICAL dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | NO-RELATIONSHIP |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin, and rifampin may increase the clearance of methylprednisolone and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as CHEMICAL and CHEMICAL may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | NO-RELATIONSHIP |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin, and rifampin may increase the clearance of methylprednisolone and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as CHEMICAL and ketoconazole may inhibit the metabolism of CHEMICAL and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin, and rifampin may increase the clearance of methylprednisolone and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and CHEMICAL may inhibit the metabolism of CHEMICAL and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin, and rifampin may increase the clearance of methylprednisolone and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. CHEMICAL may increase the clearance of chronic high dose CHEMICAL. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin, and rifampin may increase the clearance of methylprednisolone and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased CHEMICAL serum levels or increase the risk of CHEMICAL toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | NO-RELATIONSHIP |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin, and rifampin may increase the clearance of methylprednisolone and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased CHEMICAL serum levels or increase the risk of salicylate toxicity when CHEMICAL is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | NO-RELATIONSHIP |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin, and rifampin may increase the clearance of methylprednisolone and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of CHEMICAL toxicity when CHEMICAL is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin, and rifampin may increase the clearance of methylprednisolone and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. CHEMICAL should be used cautiously in conjunction with CHEMICAL in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin, and rifampin may increase the clearance of methylprednisolone and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of CHEMICAL on oral CHEMICAL is variable. There are reports of enhanced as well as diminished effects of anticoagulant when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. convulsions have been reported with concurrent use of methylprednisolone and cyclosporin. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin, and rifampin may increase the clearance of methylprednisolone and may require increased in methylprednisolone dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of methylprednisolone and thus decrease its clearance. Therefore, the dose of methylprednisolone should be titrated to avoid steroid toxicity. Methylprednisolone may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when methylprednisolone is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of methylprednisolone on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of CHEMICAL when given concurrently with CHEMICAL. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The effects of CHEMICAL on gastrointestinal motility are antagonized by CHEMICAL and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | CHEMICALS-INTERACTION |
| The effects of CHEMICAL on gastrointestinal motility are antagonized by anticholinergic drugs and CHEMICAL. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | CHEMICALS-INTERACTION |
| The effects of metoclopramide on gastrointestinal motility are antagonized by CHEMICAL and CHEMICAL. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when CHEMICAL is given with CHEMICAL, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | CHEMICALS-INTERACTION |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when CHEMICAL is given with alcohol, CHEMICAL, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | CHEMICALS-INTERACTION |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when CHEMICAL is given with alcohol, sedatives, CHEMICAL, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | CHEMICALS-INTERACTION |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when CHEMICAL is given with alcohol, sedatives, hypnotics, CHEMICAL, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | CHEMICALS-INTERACTION |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when CHEMICAL is given with alcohol, sedatives, hypnotics, narcotics, or CHEMICAL. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | CHEMICALS-INTERACTION |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with CHEMICAL, CHEMICAL, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with CHEMICAL, sedatives, CHEMICAL, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with CHEMICAL, sedatives, hypnotics, CHEMICAL, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with CHEMICAL, sedatives, hypnotics, narcotics, or CHEMICAL. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, CHEMICAL, CHEMICAL, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, CHEMICAL, hypnotics, CHEMICAL, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, CHEMICAL, hypnotics, narcotics, or CHEMICAL. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, CHEMICAL, CHEMICAL, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, CHEMICAL, narcotics, or CHEMICAL. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, CHEMICAL, or CHEMICAL. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that CHEMICAL releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving CHEMICAL. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | CHEMICALS-INTERACTION |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., CHEMICAL) by CHEMICAL, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | CHEMICALS-INTERACTION |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., CHEMICAL) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., CHEMICAL, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., CHEMICAL) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, CHEMICAL, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., CHEMICAL) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, CHEMICAL, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., CHEMICAL) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, CHEMICAL, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., CHEMICAL) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, CHEMICAL). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by CHEMICAL, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., CHEMICAL, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by CHEMICAL, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, CHEMICAL, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by CHEMICAL, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, CHEMICAL, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by CHEMICAL, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, CHEMICAL, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by CHEMICAL, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, CHEMICAL). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., CHEMICAL, CHEMICAL, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., CHEMICAL, tetracycline, CHEMICAL, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., CHEMICAL, tetracycline, levodopa, CHEMICAL, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., CHEMICAL, tetracycline, levodopa, ethanol, CHEMICAL). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, CHEMICAL, CHEMICAL, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, CHEMICAL, levodopa, CHEMICAL, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, CHEMICAL, levodopa, ethanol, CHEMICAL). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, CHEMICAL, CHEMICAL, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, CHEMICAL, ethanol, CHEMICAL). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, CHEMICAL, CHEMICAL). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of metoclopramide will influence the delivery of food to the intestines and thus the rate of absorption, insulin dosage or timing of dosage may require adjustment. | NO-RELATIONSHIP |
| The effects of metoclopramide on gastrointestinal motility are antagonized by anticholinergic drugs and narcotic analgesics. Additive sedative effects can occur when metoclopramide is given with alcohol, sedatives, hypnotics, narcotics, or tranquilizers. The finding that metoclopramide releases catecholamines in patients with essential hypertension suggests that it should be used cautiously, if at all, in patients receiving monoamine oxi-dase inhibitors. Absorption of drugs from the stomach may be diminished (e.g., digoxin) by metoclopramide, whereas the rate and/or extent of absorption of drugs from the small bowel may be increased (e.g., acetaminophen, tetracycline, levodopa, ethanol, cyclosporine). Gastroparesis (gastric stasis) may be responsible for poor diabetic control in some patients. Exogenously administered insulin may begin to act before food has left the stomach and lead to hypoglycemia. Because the action of CHEMICAL will influence the delivery of food to the intestines and thus the rate of absorption, CHEMICAL dosage or timing of dosage may require adjustment. | CHEMICALS-INTERACTION |
| CHEMICAL, particularly CHEMICAL, may cause serious cardiac arrhythmias during halothane anesthesia and therefore should be used only with great caution or not at all. MAO Inhibitors: The pressor effect of sympathomimetic pressor amines is markedly potentiated in patients receiving monoamine oxidase inhibitors (MAOI). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | NO-RELATIONSHIP |
| CHEMICAL, particularly metaraminol, may cause serious cardiac arrhythmias during CHEMICAL anesthesia and therefore should be used only with great caution or not at all. MAO Inhibitors: The pressor effect of sympathomimetic pressor amines is markedly potentiated in patients receiving monoamine oxidase inhibitors (MAOI). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | CHEMICALS-INTERACTION |
| Vasopressors, particularly CHEMICAL, may cause serious cardiac arrhythmias during CHEMICAL anesthesia and therefore should be used only with great caution or not at all. MAO Inhibitors: The pressor effect of sympathomimetic pressor amines is markedly potentiated in patients receiving monoamine oxidase inhibitors (MAOI). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | CHEMICALS-INTERACTION |
| Vasopressors, particularly metaraminol, may cause serious cardiac arrhythmias during halothane anesthesia and therefore should be used only with great caution or not at all. CHEMICAL: The pressor effect of CHEMICAL is markedly potentiated in patients receiving monoamine oxidase inhibitors (MAOI). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | NO-RELATIONSHIP |
| Vasopressors, particularly metaraminol, may cause serious cardiac arrhythmias during halothane anesthesia and therefore should be used only with great caution or not at all. CHEMICAL: The pressor effect of sympathomimetic pressor amines is markedly potentiated in patients receiving CHEMICAL (MAOI). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | NO-RELATIONSHIP |
| Vasopressors, particularly metaraminol, may cause serious cardiac arrhythmias during halothane anesthesia and therefore should be used only with great caution or not at all. CHEMICAL: The pressor effect of sympathomimetic pressor amines is markedly potentiated in patients receiving monoamine oxidase inhibitors (CHEMICAL). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | NO-RELATIONSHIP |
| Vasopressors, particularly metaraminol, may cause serious cardiac arrhythmias during halothane anesthesia and therefore should be used only with great caution or not at all. MAO Inhibitors: The pressor effect of CHEMICAL is markedly potentiated in patients receiving CHEMICAL (MAOI). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | CHEMICALS-INTERACTION |
| Vasopressors, particularly metaraminol, may cause serious cardiac arrhythmias during halothane anesthesia and therefore should be used only with great caution or not at all. MAO Inhibitors: The pressor effect of CHEMICAL is markedly potentiated in patients receiving monoamine oxidase inhibitors (CHEMICAL). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | CHEMICALS-INTERACTION |
| Vasopressors, particularly metaraminol, may cause serious cardiac arrhythmias during halothane anesthesia and therefore should be used only with great caution or not at all. MAO Inhibitors: The pressor effect of sympathomimetic pressor amines is markedly potentiated in patients receiving CHEMICAL (CHEMICAL). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | NO-RELATIONSHIP |
| Vasopressors, particularly metaraminol, may cause serious cardiac arrhythmias during halothane anesthesia and therefore should be used only with great caution or not at all. MAO Inhibitors: The pressor effect of sympathomimetic pressor amines is markedly potentiated in patients receiving monoamine oxidase inhibitors (MAOI). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of CHEMICAL may also be potentiated by CHEMICAL. | CHEMICALS-INTERACTION |
| [Interaction between CHEMICAL and CHEMICAL]. The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in literature. Concomitant use of omeprazole and clopidogrel was found to decrease the exposure (AUC) to clopidogrel's active metabolite by 50% and to sharply increase platelet reactivity, as a result of inhibition by omeprazole of CYP2C19, a cytochrome P450 (CYP) enzyme. Pantoprazole has a much weaker effect on clopidogrel's pharmacokinetics and on platelet reactivity during concomitant use. The influence of the other proton pump inhibitors when used simultaneously with clopidogrel has not yet been investigated in adequately randomized studies. Regulatory agencies state that the combination of clopidogrel and the CYP2C19 inhibitors omeprazole and esomeprazole should be avoided. To date, there is no conclusive evidence of a clinically-relevant interaction between any of the proton pump inhibitors and clopidogrel. | NO-RELATIONSHIP |
| [Interaction between clopidogrel and proton pump inhibitors]. The drug interaction between CHEMICAL and CHEMICAL has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in literature. Concomitant use of omeprazole and clopidogrel was found to decrease the exposure (AUC) to clopidogrel's active metabolite by 50% and to sharply increase platelet reactivity, as a result of inhibition by omeprazole of CYP2C19, a cytochrome P450 (CYP) enzyme. Pantoprazole has a much weaker effect on clopidogrel's pharmacokinetics and on platelet reactivity during concomitant use. The influence of the other proton pump inhibitors when used simultaneously with clopidogrel has not yet been investigated in adequately randomized studies. Regulatory agencies state that the combination of clopidogrel and the CYP2C19 inhibitors omeprazole and esomeprazole should be avoided. To date, there is no conclusive evidence of a clinically-relevant interaction between any of the proton pump inhibitors and clopidogrel. | NO-RELATIONSHIP |
| [Interaction between clopidogrel and proton pump inhibitors]. The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of CHEMICAL on platelet reactivity and on clinical outcome in CHEMICAL-treated patients have been reported in literature. Concomitant use of omeprazole and clopidogrel was found to decrease the exposure (AUC) to clopidogrel's active metabolite by 50% and to sharply increase platelet reactivity, as a result of inhibition by omeprazole of CYP2C19, a cytochrome P450 (CYP) enzyme. Pantoprazole has a much weaker effect on clopidogrel's pharmacokinetics and on platelet reactivity during concomitant use. The influence of the other proton pump inhibitors when used simultaneously with clopidogrel has not yet been investigated in adequately randomized studies. Regulatory agencies state that the combination of clopidogrel and the CYP2C19 inhibitors omeprazole and esomeprazole should be avoided. To date, there is no conclusive evidence of a clinically-relevant interaction between any of the proton pump inhibitors and clopidogrel. | NO-RELATIONSHIP |
| [Interaction between clopidogrel and proton pump inhibitors]. The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in literature. Concomitant use of CHEMICAL and CHEMICAL was found to decrease the exposure (AUC) to clopidogrel's active metabolite by 50% and to sharply increase platelet reactivity, as a result of inhibition by omeprazole of CYP2C19, a cytochrome P450 (CYP) enzyme. Pantoprazole has a much weaker effect on clopidogrel's pharmacokinetics and on platelet reactivity during concomitant use. The influence of the other proton pump inhibitors when used simultaneously with clopidogrel has not yet been investigated in adequately randomized studies. Regulatory agencies state that the combination of clopidogrel and the CYP2C19 inhibitors omeprazole and esomeprazole should be avoided. To date, there is no conclusive evidence of a clinically-relevant interaction between any of the proton pump inhibitors and clopidogrel. | CHEMICALS-INTERACTION |
| [Interaction between clopidogrel and proton pump inhibitors]. The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in literature. Concomitant use of CHEMICAL and clopidogrel was found to decrease the exposure (AUC) to clopidogrel's active metabolite by 50% and to sharply increase platelet reactivity, as a result of inhibition by CHEMICAL of CYP2C19, a cytochrome P450 (CYP) enzyme. Pantoprazole has a much weaker effect on clopidogrel's pharmacokinetics and on platelet reactivity during concomitant use. The influence of the other proton pump inhibitors when used simultaneously with clopidogrel has not yet been investigated in adequately randomized studies. Regulatory agencies state that the combination of clopidogrel and the CYP2C19 inhibitors omeprazole and esomeprazole should be avoided. To date, there is no conclusive evidence of a clinically-relevant interaction between any of the proton pump inhibitors and clopidogrel. | INHIBITOR |
| [Interaction between clopidogrel and proton pump inhibitors]. The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in literature. Concomitant use of omeprazole and CHEMICAL was found to decrease the exposure (AUC) to clopidogrel's active metabolite by 50% and to sharply increase platelet reactivity, as a result of inhibition by CHEMICAL of CYP2C19, a cytochrome P450 (CYP) enzyme. Pantoprazole has a much weaker effect on clopidogrel's pharmacokinetics and on platelet reactivity during concomitant use. The influence of the other proton pump inhibitors when used simultaneously with clopidogrel has not yet been investigated in adequately randomized studies. Regulatory agencies state that the combination of clopidogrel and the CYP2C19 inhibitors omeprazole and esomeprazole should be avoided. To date, there is no conclusive evidence of a clinically-relevant interaction between any of the proton pump inhibitors and clopidogrel. | NO-RELATIONSHIP |
| [Interaction between clopidogrel and proton pump inhibitors]. The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in literature. Concomitant use of omeprazole and clopidogrel was found to decrease the exposure (AUC) to clopidogrel's active metabolite by 50% and to sharply increase platelet reactivity, as a result of inhibition by omeprazole of CYP2C19, a cytochrome P450 (CYP) enzyme. CHEMICAL has a much weaker effect on CHEMICAL's pharmacokinetics and on platelet reactivity during concomitant use. The influence of the other proton pump inhibitors when used simultaneously with clopidogrel has not yet been investigated in adequately randomized studies. Regulatory agencies state that the combination of clopidogrel and the CYP2C19 inhibitors omeprazole and esomeprazole should be avoided. To date, there is no conclusive evidence of a clinically-relevant interaction between any of the proton pump inhibitors and clopidogrel. | CHEMICALS-INTERACTION |
| [Interaction between clopidogrel and proton pump inhibitors]. The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in literature. Concomitant use of omeprazole and clopidogrel was found to decrease the exposure (AUC) to clopidogrel's active metabolite by 50% and to sharply increase platelet reactivity, as a result of inhibition by omeprazole of CYP2C19, a cytochrome P450 (CYP) enzyme. Pantoprazole has a much weaker effect on clopidogrel's pharmacokinetics and on platelet reactivity during concomitant use. The influence of the other CHEMICAL when used simultaneously with CHEMICAL has not yet been investigated in adequately randomized studies. Regulatory agencies state that the combination of clopidogrel and the CYP2C19 inhibitors omeprazole and esomeprazole should be avoided. To date, there is no conclusive evidence of a clinically-relevant interaction between any of the proton pump inhibitors and clopidogrel. | NO-RELATIONSHIP |
| [Interaction between clopidogrel and proton pump inhibitors]. The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in literature. Concomitant use of omeprazole and clopidogrel was found to decrease the exposure (AUC) to clopidogrel's active metabolite by 50% and to sharply increase platelet reactivity, as a result of inhibition by omeprazole of CYP2C19, a cytochrome P450 (CYP) enzyme. Pantoprazole has a much weaker effect on clopidogrel's pharmacokinetics and on platelet reactivity during concomitant use. The influence of the other proton pump inhibitors when used simultaneously with clopidogrel has not yet been investigated in adequately randomized studies. Regulatory agencies state that the combination of CHEMICAL and the CYP2C19 inhibitors CHEMICAL and esomeprazole should be avoided. To date, there is no conclusive evidence of a clinically-relevant interaction between any of the proton pump inhibitors and clopidogrel. | CHEMICALS-INTERACTION |
| [Interaction between clopidogrel and proton pump inhibitors]. The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in literature. Concomitant use of omeprazole and clopidogrel was found to decrease the exposure (AUC) to clopidogrel's active metabolite by 50% and to sharply increase platelet reactivity, as a result of inhibition by omeprazole of CYP2C19, a cytochrome P450 (CYP) enzyme. Pantoprazole has a much weaker effect on clopidogrel's pharmacokinetics and on platelet reactivity during concomitant use. The influence of the other proton pump inhibitors when used simultaneously with clopidogrel has not yet been investigated in adequately randomized studies. Regulatory agencies state that the combination of CHEMICAL and the CYP2C19 inhibitors omeprazole and CHEMICAL should be avoided. To date, there is no conclusive evidence of a clinically-relevant interaction between any of the proton pump inhibitors and clopidogrel. | CHEMICALS-INTERACTION |
| [Interaction between clopidogrel and proton pump inhibitors]. The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in literature. Concomitant use of omeprazole and clopidogrel was found to decrease the exposure (AUC) to clopidogrel's active metabolite by 50% and to sharply increase platelet reactivity, as a result of inhibition by omeprazole of CYP2C19, a cytochrome P450 (CYP) enzyme. Pantoprazole has a much weaker effect on clopidogrel's pharmacokinetics and on platelet reactivity during concomitant use. The influence of the other proton pump inhibitors when used simultaneously with clopidogrel has not yet been investigated in adequately randomized studies. Regulatory agencies state that the combination of clopidogrel and the CYP2C19 inhibitors CHEMICAL and CHEMICAL should be avoided. To date, there is no conclusive evidence of a clinically-relevant interaction between any of the proton pump inhibitors and clopidogrel. | NO-RELATIONSHIP |
| [Interaction between clopidogrel and proton pump inhibitors]. The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in literature. Concomitant use of omeprazole and clopidogrel was found to decrease the exposure (AUC) to clopidogrel's active metabolite by 50% and to sharply increase platelet reactivity, as a result of inhibition by omeprazole of CYP2C19, a cytochrome P450 (CYP) enzyme. Pantoprazole has a much weaker effect on clopidogrel's pharmacokinetics and on platelet reactivity during concomitant use. The influence of the other proton pump inhibitors when used simultaneously with clopidogrel has not yet been investigated in adequately randomized studies. Regulatory agencies state that the combination of clopidogrel and the CYP2C19 inhibitors omeprazole and esomeprazole should be avoided. To date, there is no conclusive evidence of a clinically-relevant interaction between any of the CHEMICAL and CHEMICAL. | NO-RELATIONSHIP |
| CHEMICAL may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | CHEMICALS-INTERACTION |
| Methscopolamine may interact with CHEMICAL (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with CHEMICAL (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (CHEMICAL type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), CHEMICAL (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., CHEMICAL, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, CHEMICAL, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, CHEMICAL, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, CHEMICAL, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, CHEMICAL, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, CHEMICAL), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), CHEMICAL, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, CHEMICAL, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, CHEMICAL (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., CHEMICAL), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other CHEMICAL, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, CHEMICAL supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, CHEMICAL, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, CHEMICAL (e.g., kaolin-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-CHEMICAL), phenothiazines (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., CHEMICAL-pectin), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), CHEMICAL (e.g., chlorpromazine, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-CHEMICAL), phenothiazines (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., CHEMICAL, promethazine). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), CHEMICAL (e.g., chlorpromazine, CHEMICAL). | NO-RELATIONSHIP |
| Methscopolamine may interact with antidepressants (tricyclic type), MAO inhibitors (e.g., phenelzine, linezolid, tranylcypromine, isocarboxazid, selegiline, furazolidone), quinidine, amantadine, antihistamines (e.g., diphenhydramine), other anticholinergics, potassium chloride supplements, antacids, absorbent-type anti-diarrhea medicines (e.g., kaolin-pectin), phenothiazines (e.g., CHEMICAL, CHEMICAL). | NO-RELATIONSHIP |
| Effect of CHEMICAL-mediated CYP3A4 inhibition on clinical pharmacokinetics of CHEMICAL (LBH589), an orally active histone deacetylase inhibitor. Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in C (max) and AUC of panobinostat, respectively. No substantial change in T (max) or half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary. | REGULATOR |
| Effect of CHEMICAL-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (CHEMICAL), an orally active histone deacetylase inhibitor. Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in C (max) and AUC of panobinostat, respectively. No substantial change in T (max) or half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary. | REGULATOR |
| Effect of CHEMICAL-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active CHEMICAL. Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in C (max) and AUC of panobinostat, respectively. No substantial change in T (max) or half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary. | REGULATOR |
| Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of CHEMICAL (CHEMICAL), an orally active histone deacetylase inhibitor. Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in C (max) and AUC of panobinostat, respectively. No substantial change in T (max) or half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary. | NO-RELATIONSHIP |
| Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of CHEMICAL (LBH589), an orally active CHEMICAL. Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in C (max) and AUC of panobinostat, respectively. No substantial change in T (max) or half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary. | NO-RELATIONSHIP |
| Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (CHEMICAL), an orally active CHEMICAL. Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in C (max) and AUC of panobinostat, respectively. No substantial change in T (max) or half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary. | NO-RELATIONSHIP |
| Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor. Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, CHEMICAL, on the pharmacokinetics and safety of CHEMICAL. Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in C (max) and AUC of panobinostat, respectively. No substantial change in T (max) or half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary. | NO-RELATIONSHIP |
| Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor. Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single CHEMICAL dose was co-administered with CHEMICAL. Panobinostat was administered as single agent three times a week on day 15 and onward. In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in C (max) and AUC of panobinostat, respectively. No substantial change in T (max) or half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary. | NO-RELATIONSHIP |
| Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor. Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. In the presence of CHEMICAL, there was 1.6- and 1.8-fold increase in C (max) and AUC of CHEMICAL, respectively. No substantial change in T (max) or half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary. | CHEMICALS-INTERACTION |
| Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor. Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in C (max) and AUC of panobinostat, respectively. No substantial change in T (max) or half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. Co-administration of CHEMICAL with CYP3A inhibitors is feasible as the observed increase in CHEMICAL PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary. | NO-RELATIONSHIP |
| Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor. Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in C (max) and AUC of panobinostat, respectively. No substantial change in T (max) or half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of CHEMICAL was not studied with CYP3A inhibitors, close monitoring of CHEMICAL-related adverse events is necessary. | REGULATOR |
| Phase I trial of CHEMICAL and CHEMICAL in patients with relapsed multiple myeloma: evidence for lenalidomide-CCI-779 interaction via P-glycoprotein. Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM. | NO-RELATIONSHIP |
| Phase I trial of CHEMICAL and CCI-779 in patients with relapsed multiple myeloma: evidence for CHEMICAL-CCI-779 interaction via P-glycoprotein. Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM. | NO-RELATIONSHIP |
| Phase I trial of CHEMICAL and CCI-779 in patients with relapsed multiple myeloma: evidence for lenalidomide-CHEMICAL interaction via P-glycoprotein. Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM. | NO-RELATIONSHIP |
| Phase I trial of lenalidomide and CHEMICAL in patients with relapsed multiple myeloma: evidence for CHEMICAL-CCI-779 interaction via P-glycoprotein. Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM. | NO-RELATIONSHIP |
| Phase I trial of lenalidomide and CHEMICAL in patients with relapsed multiple myeloma: evidence for lenalidomide-CHEMICAL interaction via P-glycoprotein. Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM. | NO-RELATIONSHIP |
| Phase I trial of lenalidomide and CCI-779 in patients with relapsed multiple myeloma: evidence for CHEMICAL-CHEMICAL interaction via P-glycoprotein. Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM. | CHEMICALS-INTERACTION |
| Phase I trial of lenalidomide and CCI-779 in patients with relapsed multiple myeloma: evidence for lenalidomide-CCI-779 interaction via P-glycoprotein. Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of CHEMICAL with the mTOR inhibitor CHEMICAL has displayed synergy in vitro and represents a novel combination in MM. | CHEMICALS-INTERACTION |
| Due to its effects on gastric emptying, CHEMICAL therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., CHEMICAL such as atropine) and agents that slow the intestinal absorption of nutrients (e.g., alpha glucosidase inhibitors). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at least 1 hour prior to or 2 hours after SYMLIN injection. In clinical trials, the concomitant use of sulfonylureas or biguanides did not alter the adverse event profile of SYMLIN. No formal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing SYMLIN and Insulin The pharmacokinetic parameters of SYMLIN were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant human insulin immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. | CHEMICALS-INTERACTION |
| Due to its effects on gastric emptying, CHEMICAL therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., anticholinergic agents such as CHEMICAL) and agents that slow the intestinal absorption of nutrients (e.g., alpha glucosidase inhibitors). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at least 1 hour prior to or 2 hours after SYMLIN injection. In clinical trials, the concomitant use of sulfonylureas or biguanides did not alter the adverse event profile of SYMLIN. No formal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing SYMLIN and Insulin The pharmacokinetic parameters of SYMLIN were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant human insulin immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. | CHEMICALS-INTERACTION |
| Due to its effects on gastric emptying, CHEMICAL therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) and agents that slow the intestinal absorption of nutrients (e.g., CHEMICAL). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at least 1 hour prior to or 2 hours after SYMLIN injection. In clinical trials, the concomitant use of sulfonylureas or biguanides did not alter the adverse event profile of SYMLIN. No formal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing SYMLIN and Insulin The pharmacokinetic parameters of SYMLIN were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant human insulin immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. | CHEMICALS-INTERACTION |
| Due to its effects on gastric emptying, SYMLIN therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., CHEMICAL such as CHEMICAL) and agents that slow the intestinal absorption of nutrients (e.g., alpha glucosidase inhibitors). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at least 1 hour prior to or 2 hours after SYMLIN injection. In clinical trials, the concomitant use of sulfonylureas or biguanides did not alter the adverse event profile of SYMLIN. No formal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing SYMLIN and Insulin The pharmacokinetic parameters of SYMLIN were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant human insulin immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. | NO-RELATIONSHIP |
| Due to its effects on gastric emptying, SYMLIN therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., CHEMICAL such as atropine) and agents that slow the intestinal absorption of nutrients (e.g., CHEMICAL). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at least 1 hour prior to or 2 hours after SYMLIN injection. In clinical trials, the concomitant use of sulfonylureas or biguanides did not alter the adverse event profile of SYMLIN. No formal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing SYMLIN and Insulin The pharmacokinetic parameters of SYMLIN were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant human insulin immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. | NO-RELATIONSHIP |
| Due to its effects on gastric emptying, SYMLIN therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., anticholinergic agents such as CHEMICAL) and agents that slow the intestinal absorption of nutrients (e.g., CHEMICAL). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at least 1 hour prior to or 2 hours after SYMLIN injection. In clinical trials, the concomitant use of sulfonylureas or biguanides did not alter the adverse event profile of SYMLIN. No formal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing SYMLIN and Insulin The pharmacokinetic parameters of SYMLIN were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant human insulin immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. | NO-RELATIONSHIP |
| Due to its effects on gastric emptying, SYMLIN therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) and agents that slow the intestinal absorption of nutrients (e.g., alpha glucosidase inhibitors). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as CHEMICAL), the agent should be administered at least 1 hour prior to or 2 hours after CHEMICAL injection. In clinical trials, the concomitant use of sulfonylureas or biguanides did not alter the adverse event profile of SYMLIN. No formal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing SYMLIN and Insulin The pharmacokinetic parameters of SYMLIN were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant human insulin immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. | CHEMICALS-INTERACTION |
| Due to its effects on gastric emptying, SYMLIN therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) and agents that slow the intestinal absorption of nutrients (e.g., alpha glucosidase inhibitors). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at least 1 hour prior to or 2 hours after SYMLIN injection. In clinical trials, the concomitant use of CHEMICAL or CHEMICAL did not alter the adverse event profile of SYMLIN. No formal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing SYMLIN and Insulin The pharmacokinetic parameters of SYMLIN were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant human insulin immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. | NO-RELATIONSHIP |
| Due to its effects on gastric emptying, SYMLIN therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) and agents that slow the intestinal absorption of nutrients (e.g., alpha glucosidase inhibitors). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at least 1 hour prior to or 2 hours after SYMLIN injection. In clinical trials, the concomitant use of CHEMICAL or biguanides did not alter the adverse event profile of CHEMICAL. No formal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing SYMLIN and Insulin The pharmacokinetic parameters of SYMLIN were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant human insulin immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. | NO-RELATIONSHIP |
| Due to its effects on gastric emptying, SYMLIN therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) and agents that slow the intestinal absorption of nutrients (e.g., alpha glucosidase inhibitors). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at least 1 hour prior to or 2 hours after SYMLIN injection. In clinical trials, the concomitant use of sulfonylureas or CHEMICAL did not alter the adverse event profile of CHEMICAL. No formal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing SYMLIN and Insulin The pharmacokinetic parameters of SYMLIN were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant human insulin immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. | NO-RELATIONSHIP |
| Due to its effects on gastric emptying, SYMLIN therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) and agents that slow the intestinal absorption of nutrients (e.g., alpha glucosidase inhibitors). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at least 1 hour prior to or 2 hours after SYMLIN injection. In clinical trials, the concomitant use of sulfonylureas or biguanides did not alter the adverse event profile of SYMLIN. No formal interaction studies have been performed to assess the effect of CHEMICAL on the kinetics of oral CHEMICAL. Mixing SYMLIN and Insulin The pharmacokinetic parameters of SYMLIN were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant human insulin immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. | NO-RELATIONSHIP |
| Due to its effects on gastric emptying, SYMLIN therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) and agents that slow the intestinal absorption of nutrients (e.g., alpha glucosidase inhibitors). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at least 1 hour prior to or 2 hours after SYMLIN injection. In clinical trials, the concomitant use of sulfonylureas or biguanides did not alter the adverse event profile of SYMLIN. No formal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing CHEMICAL and CHEMICAL The pharmacokinetic parameters of SYMLIN were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant human insulin immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. | NO-RELATIONSHIP |
| Due to its effects on gastric emptying, SYMLIN therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) and agents that slow the intestinal absorption of nutrients (e.g., alpha glucosidase inhibitors). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at least 1 hour prior to or 2 hours after SYMLIN injection. In clinical trials, the concomitant use of sulfonylureas or biguanides did not alter the adverse event profile of SYMLIN. No formal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing CHEMICAL and Insulin The pharmacokinetic parameters of CHEMICAL were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant human insulin immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. | NO-RELATIONSHIP |
| Due to its effects on gastric emptying, SYMLIN therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) and agents that slow the intestinal absorption of nutrients (e.g., alpha glucosidase inhibitors). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at least 1 hour prior to or 2 hours after SYMLIN injection. In clinical trials, the concomitant use of sulfonylureas or biguanides did not alter the adverse event profile of SYMLIN. No formal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing CHEMICAL and Insulin The pharmacokinetic parameters of SYMLIN were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant CHEMICAL immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. | NO-RELATIONSHIP |
| Due to its effects on gastric emptying, SYMLIN therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) and agents that slow the intestinal absorption of nutrients (e.g., alpha glucosidase inhibitors). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at least 1 hour prior to or 2 hours after SYMLIN injection. In clinical trials, the concomitant use of sulfonylureas or biguanides did not alter the adverse event profile of SYMLIN. No formal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing SYMLIN and CHEMICAL The pharmacokinetic parameters of CHEMICAL were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant human insulin immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. | NO-RELATIONSHIP |
| Due to its effects on gastric emptying, SYMLIN therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) and agents that slow the intestinal absorption of nutrients (e.g., alpha glucosidase inhibitors). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at least 1 hour prior to or 2 hours after SYMLIN injection. In clinical trials, the concomitant use of sulfonylureas or biguanides did not alter the adverse event profile of SYMLIN. No formal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing SYMLIN and CHEMICAL The pharmacokinetic parameters of SYMLIN were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant CHEMICAL immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. | NO-RELATIONSHIP |
| Due to its effects on gastric emptying, SYMLIN therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) and agents that slow the intestinal absorption of nutrients (e.g., alpha glucosidase inhibitors). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at least 1 hour prior to or 2 hours after SYMLIN injection. In clinical trials, the concomitant use of sulfonylureas or biguanides did not alter the adverse event profile of SYMLIN. No formal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing SYMLIN and Insulin The pharmacokinetic parameters of CHEMICAL were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant CHEMICAL immediately prior to injection. Thus, SYMLIN and insulin should not be mixed and must be administered separately. | NO-RELATIONSHIP |
| Due to its effects on gastric emptying, SYMLIN therapy should not be considered for patients taking drugs that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) and agents that slow the intestinal absorption of nutrients (e.g., alpha glucosidase inhibitors). Patients using these drugs have not been studied in clinical trials. SYMLIN has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset of a concomitant orally administered agent is a critical determinant of effectiveness (such as analgesics), the agent should be administered at least 1 hour prior to or 2 hours after SYMLIN injection. In clinical trials, the concomitant use of sulfonylureas or biguanides did not alter the adverse event profile of SYMLIN. No formal interaction studies have been performed to assess the effect of SYMLIN on the kinetics of oral antidiabetic agents. Mixing SYMLIN and Insulin The pharmacokinetic parameters of SYMLIN were altered when mixed with regular, NPH, and 70/30 premixed formulations of recombinant human insulin immediately prior to injection. Thus, CHEMICAL and CHEMICAL should not be mixed and must be administered separately. | CHEMICALS-INTERACTION |
| CHEMICAL (CHEMICAL)--better than clopidogrel (Plavix) The FDA has approved ticagrelor (Brilinta-AstraZeneca), an oral antiplatelet drug, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (Plavix) and prasugrel (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | NO-RELATIONSHIP |
| CHEMICAL (Brilinta)--better than CHEMICAL (Plavix) The FDA has approved ticagrelor (Brilinta-AstraZeneca), an oral antiplatelet drug, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (Plavix) and prasugrel (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | NO-RELATIONSHIP |
| CHEMICAL (Brilinta)--better than clopidogrel (CHEMICAL) The FDA has approved ticagrelor (Brilinta-AstraZeneca), an oral antiplatelet drug, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (Plavix) and prasugrel (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | NO-RELATIONSHIP |
| Ticagrelor (CHEMICAL)--better than CHEMICAL (Plavix) The FDA has approved ticagrelor (Brilinta-AstraZeneca), an oral antiplatelet drug, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (Plavix) and prasugrel (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | NO-RELATIONSHIP |
| Ticagrelor (CHEMICAL)--better than clopidogrel (CHEMICAL) The FDA has approved ticagrelor (Brilinta-AstraZeneca), an oral antiplatelet drug, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (Plavix) and prasugrel (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | NO-RELATIONSHIP |
| Ticagrelor (Brilinta)--better than CHEMICAL (CHEMICAL) The FDA has approved ticagrelor (Brilinta-AstraZeneca), an oral antiplatelet drug, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (Plavix) and prasugrel (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | NO-RELATIONSHIP |
| Ticagrelor (Brilinta)--better than clopidogrel (Plavix) The FDA has approved CHEMICAL (CHEMICAL-AstraZeneca), an oral antiplatelet drug, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (Plavix) and prasugrel (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | NO-RELATIONSHIP |
| Ticagrelor (Brilinta)--better than clopidogrel (Plavix) The FDA has approved CHEMICAL (Brilinta-AstraZeneca), an oral CHEMICAL, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (Plavix) and prasugrel (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | NO-RELATIONSHIP |
| Ticagrelor (Brilinta)--better than clopidogrel (Plavix) The FDA has approved CHEMICAL (Brilinta-AstraZeneca), an oral antiplatelet drug, for use with low-dose CHEMICAL to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (Plavix) and prasugrel (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | CHEMICALS-INTERACTION |
| Ticagrelor (Brilinta)--better than clopidogrel (Plavix) The FDA has approved ticagrelor (CHEMICAL-AstraZeneca), an oral CHEMICAL, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (Plavix) and prasugrel (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | NO-RELATIONSHIP |
| Ticagrelor (Brilinta)--better than clopidogrel (Plavix) The FDA has approved ticagrelor (CHEMICAL-AstraZeneca), an oral antiplatelet drug, for use with low-dose CHEMICAL to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (Plavix) and prasugrel (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | NO-RELATIONSHIP |
| Ticagrelor (Brilinta)--better than clopidogrel (Plavix) The FDA has approved ticagrelor (Brilinta-AstraZeneca), an oral CHEMICAL, for use with low-dose CHEMICAL to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (Plavix) and prasugrel (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | CHEMICALS-INTERACTION |
| Ticagrelor (Brilinta)--better than clopidogrel (Plavix) The FDA has approved ticagrelor (Brilinta-AstraZeneca), an oral antiplatelet drug, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with CHEMICAL (CHEMICAL) and prasugrel (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | NO-RELATIONSHIP |
| Ticagrelor (Brilinta)--better than clopidogrel (Plavix) The FDA has approved ticagrelor (Brilinta-AstraZeneca), an oral antiplatelet drug, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with CHEMICAL (Plavix) and CHEMICAL (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | NO-RELATIONSHIP |
| Ticagrelor (Brilinta)--better than clopidogrel (Plavix) The FDA has approved ticagrelor (Brilinta-AstraZeneca), an oral antiplatelet drug, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with CHEMICAL (Plavix) and prasugrel (CHEMICAL) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | NO-RELATIONSHIP |
| Ticagrelor (Brilinta)--better than clopidogrel (Plavix) The FDA has approved ticagrelor (Brilinta-AstraZeneca), an oral antiplatelet drug, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (CHEMICAL) and CHEMICAL (Effient) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | NO-RELATIONSHIP |
| Ticagrelor (Brilinta)--better than clopidogrel (Plavix) The FDA has approved ticagrelor (Brilinta-AstraZeneca), an oral antiplatelet drug, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (CHEMICAL) and prasugrel (CHEMICAL) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | NO-RELATIONSHIP |
| Ticagrelor (Brilinta)--better than clopidogrel (Plavix) The FDA has approved ticagrelor (Brilinta-AstraZeneca), an oral antiplatelet drug, for use with low-dose aspirin to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS). It will compete with clopidogrel (Plavix) and CHEMICAL (CHEMICAL) for such use. Clopidogrel is expected to become available generically in the US within the next few months. | NO-RELATIONSHIP |
| Exposure to oral CHEMICAL is unaffected by CHEMICAL but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | NO-RELATIONSHIP |
| Exposure to oral CHEMICAL is unaffected by itraconazole but greatly increased by CHEMICAL. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | CHEMICALS-INTERACTION |
| Exposure to oral S-ketamine is unaffected by CHEMICAL but greatly increased by CHEMICAL. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | NO-RELATIONSHIP |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral CHEMICAL with the cytochrome P450 (CYP) 2B6 inhibitor CHEMICAL and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | REGULATOR |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral CHEMICAL with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor CHEMICAL. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | REGULATOR |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor CHEMICAL and the CYP3A inhibitor CHEMICAL. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | NO-RELATIONSHIP |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg CHEMICAL after pretreatments with oral CHEMICAL (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | NO-RELATIONSHIP |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg CHEMICAL after pretreatments with oral ticlopidine (250 mg twice daily), CHEMICAL (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | NO-RELATIONSHIP |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral CHEMICAL (250 mg twice daily), CHEMICAL (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | NO-RELATIONSHIP |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. CHEMICAL treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral CHEMICAL by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | CHEMICALS-INTERACTION |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. CHEMICAL treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas CHEMICAL treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | NO-RELATIONSHIP |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. CHEMICAL treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to CHEMICAL. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | NO-RELATIONSHIP |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral CHEMICAL by 2.4-fold, whereas CHEMICAL treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | NO-RELATIONSHIP |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral CHEMICAL by 2.4-fold, whereas itraconazole treatment did not increase the exposure to CHEMICAL. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | NO-RELATIONSHIP |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas CHEMICAL treatment did not increase the exposure to CHEMICAL. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | NO-RELATIONSHIP |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of CHEMICAL AUC(0- ) to CHEMICAL AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | NO-RELATIONSHIP |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of CHEMICAL AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the CHEMICAL (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | CHEMICALS-INTERACTION |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of CHEMICAL AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and CHEMICAL phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | NO-RELATIONSHIP |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0- ) to CHEMICAL AUC(0- ) was significantly decreased in the CHEMICAL (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | NO-RELATIONSHIP |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0- ) to CHEMICAL AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and CHEMICAL phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | NO-RELATIONSHIP |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the CHEMICAL (P < 0.001) and CHEMICAL phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | NO-RELATIONSHIP |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the CHEMICAL and CHEMICAL phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine. | NO-RELATIONSHIP |
| Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine. This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0- )) of oral ketamine by 2.4-fold, whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0- ) to ketamine AUC(0- ) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of CHEMICAL should be reduced in patients receiving CHEMICAL. | CHEMICALS-INTERACTION |
| Patients receiving CHEMICAL and CHEMICAL generally should not be treated with ganglion blockers. The action of Mecamylamine may be potentiated by anesthesia, other antihypertensive drugs and alcohol. | NO-RELATIONSHIP |
| Patients receiving CHEMICAL and sulfonamides generally should not be treated with CHEMICAL. The action of Mecamylamine may be potentiated by anesthesia, other antihypertensive drugs and alcohol. | CHEMICALS-INTERACTION |
| Patients receiving antibiotics and CHEMICAL generally should not be treated with CHEMICAL. The action of Mecamylamine may be potentiated by anesthesia, other antihypertensive drugs and alcohol. | CHEMICALS-INTERACTION |
| Patients receiving antibiotics and sulfonamides generally should not be treated with ganglion blockers. The action of CHEMICAL may be potentiated by anesthesia, other CHEMICAL and alcohol. | CHEMICALS-INTERACTION |
| Patients receiving antibiotics and sulfonamides generally should not be treated with ganglion blockers. The action of CHEMICAL may be potentiated by anesthesia, other antihypertensive drugs and CHEMICAL. | CHEMICALS-INTERACTION |
| Patients receiving antibiotics and sulfonamides generally should not be treated with ganglion blockers. The action of Mecamylamine may be potentiated by anesthesia, other CHEMICAL and CHEMICAL. | NO-RELATIONSHIP |
| Oral CHEMICAL has been reported to potentiate the anticoagulant effect of CHEMICAL and warfarin, resulting in a prolongation of prothrombin time. Drug interactions should be kept in mind when METROGEL (metronidazole gel), 1% is prescribed for patients who are receiving anticoagulant treatment, although they are less likely to occur with topical metronidazole administration because of low absorption. | CHEMICALS-INTERACTION |
| Oral CHEMICAL has been reported to potentiate the anticoagulant effect of coumarin and CHEMICAL, resulting in a prolongation of prothrombin time. Drug interactions should be kept in mind when METROGEL (metronidazole gel), 1% is prescribed for patients who are receiving anticoagulant treatment, although they are less likely to occur with topical metronidazole administration because of low absorption. | CHEMICALS-INTERACTION |
| Oral metronidazole has been reported to potentiate the anticoagulant effect of CHEMICAL and CHEMICAL, resulting in a prolongation of prothrombin time. Drug interactions should be kept in mind when METROGEL (metronidazole gel), 1% is prescribed for patients who are receiving anticoagulant treatment, although they are less likely to occur with topical metronidazole administration because of low absorption. | NO-RELATIONSHIP |
| Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin, resulting in a prolongation of prothrombin time. Drug interactions should be kept in mind when CHEMICAL (CHEMICAL gel), 1% is prescribed for patients who are receiving anticoagulant treatment, although they are less likely to occur with topical metronidazole administration because of low absorption. | NO-RELATIONSHIP |
| Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin, resulting in a prolongation of prothrombin time. Drug interactions should be kept in mind when CHEMICAL (metronidazole gel), 1% is prescribed for patients who are receiving anticoagulant treatment, although they are less likely to occur with topical CHEMICAL administration because of low absorption. | NO-RELATIONSHIP |
| Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin, resulting in a prolongation of prothrombin time. Drug interactions should be kept in mind when METROGEL (CHEMICAL gel), 1% is prescribed for patients who are receiving anticoagulant treatment, although they are less likely to occur with topical CHEMICAL administration because of low absorption. | NO-RELATIONSHIP |
| Concomitant use of CHEMICAL with CHEMICAL may result in an adverse drug interaction. | CHEMICALS-INTERACTION |
| Other CHEMICAL should not be used concomitantly with CHEMICAL because they may have additive effects. | CHEMICALS-INTERACTION |
| A study published in 2002 found that CHEMICAL causes a statistically significant increase in plasma clearance of CHEMICAL. In 1984, Drs Rimmer and Richens at the University of Wales reported that administering vigabatrin with phenytoin lowered the serum phenytoin concentration in patients with treatment-resistant epilepsy. The concentration of phenytoin falls to 23% within five weeks, according to an experiment published in 1989 by the same two scientists that tried and failed to elucidate the mechanism behind this interaction. | CHEMICALS-INTERACTION |
| A study published in 2002 found that vigabatrin causes a statistically significant increase in plasma clearance of carbamazepine. In 1984, Drs Rimmer and Richens at the University of Wales reported that administering CHEMICAL with CHEMICAL lowered the serum phenytoin concentration in patients with treatment-resistant epilepsy. The concentration of phenytoin falls to 23% within five weeks, according to an experiment published in 1989 by the same two scientists that tried and failed to elucidate the mechanism behind this interaction. | CHEMICALS-INTERACTION |
| A study published in 2002 found that vigabatrin causes a statistically significant increase in plasma clearance of carbamazepine. In 1984, Drs Rimmer and Richens at the University of Wales reported that administering CHEMICAL with phenytoin lowered the serum CHEMICAL concentration in patients with treatment-resistant epilepsy. The concentration of phenytoin falls to 23% within five weeks, according to an experiment published in 1989 by the same two scientists that tried and failed to elucidate the mechanism behind this interaction. | NO-RELATIONSHIP |
| A study published in 2002 found that vigabatrin causes a statistically significant increase in plasma clearance of carbamazepine. In 1984, Drs Rimmer and Richens at the University of Wales reported that administering vigabatrin with CHEMICAL lowered the serum CHEMICAL concentration in patients with treatment-resistant epilepsy. The concentration of phenytoin falls to 23% within five weeks, according to an experiment published in 1989 by the same two scientists that tried and failed to elucidate the mechanism behind this interaction. | NO-RELATIONSHIP |
| CHEMICAL: Concurrent use of CHEMICAL and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| CHEMICAL: Concurrent use of procaine hydrochloride and CHEMICAL may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| CHEMICAL: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since CHEMICAL inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| CHEMICAL: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of CHEMICAL. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of CHEMICAL and CHEMICAL may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | CHEMICALS-INTERACTION |
| Anticholinesterases: Concurrent use of CHEMICAL and anticholinesterase agents may result in increased systemic toxicity since CHEMICAL inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of CHEMICAL and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of CHEMICAL. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and CHEMICAL may result in increased systemic toxicity since CHEMICAL inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and CHEMICAL may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of CHEMICAL. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since CHEMICAL inhibit the breakdown of CHEMICAL. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | CHEMICALS-INTERACTION |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CHEMICAL medications: Concurrent use of CHEMICAL and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CHEMICAL medications: Concurrent use of procaine hydrochloride and CHEMICAL may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of CHEMICAL and CHEMICAL may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | CHEMICALS-INTERACTION |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. CHEMICAL: CHEMICAL may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. CHEMICAL: Hyaluronidase may increase the diffusion rate of CHEMICAL, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: CHEMICAL may increase the diffusion rate of CHEMICAL, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | CHEMICALS-INTERACTION |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. CHEMICAL (such as CHEMICAL): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. CHEMICAL (such as suxamethonium chloride): Concurrent use of CHEMICAL and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. CHEMICAL (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and CHEMICAL may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as CHEMICAL): Concurrent use of CHEMICAL and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as CHEMICAL): Concurrent use of procaine hydrochloride and CHEMICAL may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of CHEMICAL and CHEMICAL may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | CHEMICALS-INTERACTION |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. CHEMICAL: Concurrent use of CHEMICAL and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. CHEMICAL: Concurrent use of procaine hydrochloride and CHEMICAL may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. CHEMICAL: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the CHEMICAL. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of CHEMICAL and CHEMICAL may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | CHEMICALS-INTERACTION |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of CHEMICAL and sulfonamides may result in a reduction of the antibacterial action of the CHEMICAL. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and CHEMICAL may result in a reduction of the antibacterial action of the CHEMICAL. Acetazolamide: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. CHEMICAL: Concurrent use of CHEMICAL and procaine hydrochloride may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. CHEMICAL: Concurrent use of acetazolamide and CHEMICAL may extend the plasma half-life of procaine. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. CHEMICAL: Concurrent use of acetazolamide and procaine hydrochloride may extend the plasma half-life of CHEMICAL. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of CHEMICAL and CHEMICAL may extend the plasma half-life of procaine. | CHEMICALS-INTERACTION |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of CHEMICAL and procaine hydrochloride may extend the plasma half-life of CHEMICAL. | NO-RELATIONSHIP |
| Anticholinesterases: Concurrent use of procaine hydrochloride and anticholinesterase agents may result in increased systemic toxicity since anticholinesterases inhibit the breakdown of procaine hydrochloride. Antimyasthenics Concurrent use of procaine hydrochloride and antimyasthenics may result in loss of control of symptoms of myasthenia gravis due to antagonism of the effects of antimyasthenics on skeletal muscle. Temporary dosage adjustment of antimyasthenics may be required. Also antimyasthenics may have anticholinesterase activity. CNS depressant medications: Concurrent use of procaine hydrochloride and CNS depressant medications may result in additive depressant effects. Hyaluronidase: Hyaluronidase may increase the diffusion rate of procaine hydrochloride, resulting in a decreased time of onset, but an increase in systemic toxicity. Neuromuscular blocking agents (such as suxamethonium chloride): Concurrent use of procaine hydrochloride and neuromuscular blocking agents may result in prolongation or enhancement of the neuromuscular blockade. Sulfonamides: Concurrent use of procaine hydrochloride and sulfonamides may result in a reduction of the antibacterial action of the sulfonamide. Acetazolamide: Concurrent use of acetazolamide and CHEMICAL may extend the plasma half-life of CHEMICAL. | NO-RELATIONSHIP |
| Co-administration of CHEMICAL with strong inhibitors of the CYP3A4 family (e.g., CHEMICAL, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of CHEMICAL with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, CHEMICAL, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of CHEMICAL with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, CHEMICAL, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of CHEMICAL with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, CHEMICAL, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of CHEMICAL with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of CHEMICAL with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of CHEMICAL with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of CHEMICAL with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of CHEMICAL with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of CHEMICAL with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of CHEMICAL with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, CHEMICAL) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of CHEMICAL with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases CHEMICAL concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., CHEMICAL, CHEMICAL, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., CHEMICAL, itraconazole, CHEMICAL, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., CHEMICAL, itraconazole, clarithromycin, CHEMICAL, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., CHEMICAL, itraconazole, clarithromycin, atazanavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., CHEMICAL, itraconazole, clarithromycin, atazanavir, indinavir, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., CHEMICAL, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., CHEMICAL, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., CHEMICAL, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., CHEMICAL, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., CHEMICAL, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, CHEMICAL) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., CHEMICAL, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases CHEMICAL concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, CHEMICAL, CHEMICAL, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, CHEMICAL, clarithromycin, CHEMICAL, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, CHEMICAL, clarithromycin, atazanavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, CHEMICAL, clarithromycin, atazanavir, indinavir, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, CHEMICAL, clarithromycin, atazanavir, indinavir, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, CHEMICAL, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, CHEMICAL, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, CHEMICAL, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, CHEMICAL, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, CHEMICAL) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, CHEMICAL, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases CHEMICAL concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, CHEMICAL, CHEMICAL, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, CHEMICAL, atazanavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, CHEMICAL, atazanavir, indinavir, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, CHEMICAL, atazanavir, indinavir, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, CHEMICAL, atazanavir, indinavir, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, CHEMICAL, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, CHEMICAL, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, CHEMICAL, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, CHEMICAL) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, CHEMICAL, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases CHEMICAL concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, CHEMICAL, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, CHEMICAL, indinavir, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, CHEMICAL, indinavir, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, CHEMICAL, indinavir, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, CHEMICAL, indinavir, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, CHEMICAL, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, CHEMICAL, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, CHEMICAL) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, CHEMICAL, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases CHEMICAL concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, CHEMICAL, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, CHEMICAL, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, CHEMICAL, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, CHEMICAL) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases CHEMICAL concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, CHEMICAL, CHEMICAL, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, CHEMICAL, nelfinavir, CHEMICAL, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, CHEMICAL, nelfinavir, ritonavir, CHEMICAL, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, CHEMICAL, nelfinavir, ritonavir, saquinavir, CHEMICAL, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin, CHEMICAL) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases CHEMICAL concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, CHEMICAL, CHEMICAL, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, CHEMICAL, ritonavir, CHEMICAL, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, CHEMICAL, ritonavir, saquinavir, CHEMICAL, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin, CHEMICAL) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin, voriconizole) may increases CHEMICAL concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, CHEMICAL, CHEMICAL, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, CHEMICAL, saquinavir, CHEMICAL, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin, CHEMICAL) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin, voriconizole) may increases CHEMICAL concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, CHEMICAL, CHEMICAL, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin, CHEMICAL) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin, voriconizole) may increases CHEMICAL concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL, CHEMICAL) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL, voriconizole) may increases CHEMICAL concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, CHEMICAL) may increases CHEMICAL concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of CHEMICAL with inducers of the CYP3A4 family (e.g., CHEMICAL, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of CHEMICAL with inducers of the CYP3A4 family (e.g., dexamethasone, CHEMICAL, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of CHEMICAL with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, CHEMICAL, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of CHEMICAL with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, CHEMICAL, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of CHEMICAL with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, CHEMICAL, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of CHEMICAL with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, CHEMICAL, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of CHEMICAL with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, CHEMICAL, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of CHEMICAL with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease CHEMICAL concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., CHEMICAL, CHEMICAL, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., CHEMICAL, phenytoin, CHEMICAL, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., CHEMICAL, phenytoin, carbamazepine, CHEMICAL, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., CHEMICAL, phenytoin, carbamazepine, rifampin, CHEMICAL, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., CHEMICAL, phenytoin, carbamazepine, rifampin, rifabutin, CHEMICAL, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., CHEMICAL, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, CHEMICAL, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., CHEMICAL, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease CHEMICAL concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, CHEMICAL, CHEMICAL, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, CHEMICAL, carbamazepine, CHEMICAL, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, CHEMICAL, carbamazepine, rifampin, CHEMICAL, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, CHEMICAL, carbamazepine, rifampin, rifabutin, CHEMICAL, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, CHEMICAL, carbamazepine, rifampin, rifabutin, rifapentin, CHEMICAL, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, CHEMICAL, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease CHEMICAL concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, CHEMICAL, CHEMICAL, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, CHEMICAL, rifampin, CHEMICAL, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, CHEMICAL, rifampin, rifabutin, CHEMICAL, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, CHEMICAL, rifampin, rifabutin, rifapentin, CHEMICAL, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, CHEMICAL, rifampin, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease CHEMICAL concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, CHEMICAL, CHEMICAL, rifapentin, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, CHEMICAL, rifabutin, CHEMICAL, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, CHEMICAL, rifabutin, rifapentin, CHEMICAL, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, CHEMICAL, rifabutin, rifapentin, phenobarbital, St. Johns Wort) may decrease CHEMICAL concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | CHEMICALS-INTERACTION |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, CHEMICAL, CHEMICAL, phenobarbital, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, CHEMICAL, rifapentin, CHEMICAL, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, CHEMICAL, rifapentin, phenobarbital, St. Johns Wort) may decrease CHEMICAL concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, CHEMICAL, CHEMICAL, St. Johns Wort) may decrease sunitinib concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, CHEMICAL, phenobarbital, St. Johns Wort) may decrease CHEMICAL concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increases sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, CHEMICAL, St. Johns Wort) may decrease CHEMICAL concentrations. St. Johns Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. Johns Wort concomitantly. SUTENT dose modification is recommended in patients using concomitant CYP3A4 inhibitors or inducers. | NO-RELATIONSHIP |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as CHEMICAL, CHEMICAL and rifampin may increase the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | NO-RELATIONSHIP |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as CHEMICAL, phenytoin and CHEMICAL may increase the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | NO-RELATIONSHIP |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as CHEMICAL, phenytoin and rifampin may increase the clearance of CHEMICAL and may require increases in corticosteroid dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as CHEMICAL, phenytoin and rifampin may increase the clearance of corticosteroids and may require increases in CHEMICAL dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, CHEMICAL and CHEMICAL may increase the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | NO-RELATIONSHIP |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, CHEMICAL and rifampin may increase the clearance of CHEMICAL and may require increases in corticosteroid dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, CHEMICAL and rifampin may increase the clearance of corticosteroids and may require increases in CHEMICAL dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and CHEMICAL may increase the clearance of CHEMICAL and may require increases in corticosteroid dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and CHEMICAL may increase the clearance of corticosteroids and may require increases in CHEMICAL dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the clearance of CHEMICAL and may require increases in CHEMICAL dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | NO-RELATIONSHIP |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response. Drugs such as CHEMICAL and CHEMICAL may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | NO-RELATIONSHIP |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response. Drugs such as CHEMICAL and ketoconazole may inhibit the metabolism of CHEMICAL and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response. Drugs such as troleandomycin and CHEMICAL may inhibit the metabolism of CHEMICAL and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. CHEMICAL may increase the clearance of chronic high dose CHEMICAL. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased CHEMICAL serum levels or increase the risk of CHEMICAL toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | NO-RELATIONSHIP |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased CHEMICAL serum levels or increase the risk of salicylate toxicity when CHEMICAL is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | NO-RELATIONSHIP |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of CHEMICAL toxicity when CHEMICAL is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. CHEMICAL should be used cautiously in conjunction with CHEMICAL in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of CHEMICAL on oral CHEMICAL is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| The pharmacokinetic interactions listed below are potentially clinically important. Drugs that induce hepatic enzymes such as phenobarbital, phenytoin and rifampin may increase the clearance of corticosteroids and may require increases in corticosteroid dose to achieve the desired response. Drugs such as troleandomycin and ketoconazole may inhibit the metabolism of corticosteroids and thus decrease their clearance. Therefore, the dose of corticosteroid should be titrated to avoid steroid toxicity. Corticosteroids may increase the clearance of chronic high dose aspirin. This could lead to decreased salicylate serum levels or increase the risk of salicylate toxicity when corticosteroid is withdrawn. Aspirin should be used cautiously in conjunction with corticosteroids in patients suffering from hypoprothrombinemia. The effect of corticosteroids on oral anticoagulants is variable. There are reports of enhanced as well as diminished effects of CHEMICAL when given concurrently with CHEMICAL. Therefore, coagulation indices should be monitored to maintain the desired anticoagulant effect. | CHEMICALS-INTERACTION |
| Interactions for CHEMICAL (CHEMICAL): Loop Diuretics, Oral Contraceptives, Stavudine, Tricyclic Antidepressants | NO-RELATIONSHIP |
| Interactions for CHEMICAL (Thiamine): CHEMICAL, Oral Contraceptives, Stavudine, Tricyclic Antidepressants | NO-RELATIONSHIP |
| Interactions for CHEMICAL (Thiamine): Loop Diuretics, Oral CHEMICAL, Stavudine, Tricyclic Antidepressants | NO-RELATIONSHIP |
| Interactions for CHEMICAL (Thiamine): Loop Diuretics, Oral Contraceptives, CHEMICAL, Tricyclic Antidepressants | NO-RELATIONSHIP |
| Interactions for CHEMICAL (Thiamine): Loop Diuretics, Oral Contraceptives, Stavudine, CHEMICAL | NO-RELATIONSHIP |
| Interactions for Vitamin B1 (CHEMICAL): CHEMICAL, Oral Contraceptives, Stavudine, Tricyclic Antidepressants | NO-RELATIONSHIP |
| Interactions for Vitamin B1 (CHEMICAL): Loop Diuretics, Oral CHEMICAL, Stavudine, Tricyclic Antidepressants | NO-RELATIONSHIP |
| Interactions for Vitamin B1 (CHEMICAL): Loop Diuretics, Oral Contraceptives, CHEMICAL, Tricyclic Antidepressants | NO-RELATIONSHIP |
| Interactions for Vitamin B1 (CHEMICAL): Loop Diuretics, Oral Contraceptives, Stavudine, CHEMICAL | NO-RELATIONSHIP |
| Interactions for Vitamin B1 (Thiamine): CHEMICAL, Oral CHEMICAL, Stavudine, Tricyclic Antidepressants | NO-RELATIONSHIP |
| Interactions for Vitamin B1 (Thiamine): CHEMICAL, Oral Contraceptives, CHEMICAL, Tricyclic Antidepressants | NO-RELATIONSHIP |
| Interactions for Vitamin B1 (Thiamine): CHEMICAL, Oral Contraceptives, Stavudine, CHEMICAL | NO-RELATIONSHIP |
| Interactions for Vitamin B1 (Thiamine): Loop Diuretics, Oral CHEMICAL, CHEMICAL, Tricyclic Antidepressants | NO-RELATIONSHIP |
| Interactions for Vitamin B1 (Thiamine): Loop Diuretics, Oral CHEMICAL, Stavudine, CHEMICAL | NO-RELATIONSHIP |
| Interactions for Vitamin B1 (Thiamine): Loop Diuretics, Oral Contraceptives, CHEMICAL, CHEMICAL | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of CHEMICAL (CHEMICAL) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of CHEMICAL (rivastigmine tartrate) on the Metabolism of Other Drugs: CHEMICAL is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (CHEMICAL) on the Metabolism of Other Drugs: CHEMICAL is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between CHEMICAL and CHEMICAL, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between CHEMICAL and digoxin, CHEMICAL, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between CHEMICAL and digoxin, warfarin, CHEMICAL, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between CHEMICAL and digoxin, warfarin, diazepam, or CHEMICAL in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and CHEMICAL, CHEMICAL, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and CHEMICAL, warfarin, CHEMICAL, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and CHEMICAL, warfarin, diazepam, or CHEMICAL in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, CHEMICAL, CHEMICAL, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, CHEMICAL, diazepam, or CHEMICAL in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, CHEMICAL, or CHEMICAL in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by CHEMICAL is not affected by administration of CHEMICAL. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of CHEMICAL: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of CHEMICAL. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of CHEMICAL is not significantly affected by concurrent administration of CHEMICAL, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of CHEMICAL is not significantly affected by concurrent administration of digoxin, CHEMICAL, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of CHEMICAL is not significantly affected by concurrent administration of digoxin, warfarin, CHEMICAL, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of CHEMICAL is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or CHEMICAL. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of CHEMICAL, CHEMICAL, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of CHEMICAL, warfarin, CHEMICAL, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of CHEMICAL, warfarin, diazepam, or CHEMICAL. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, CHEMICAL, CHEMICAL, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, CHEMICAL, diazepam, or CHEMICAL. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, CHEMICAL, or CHEMICAL. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of CHEMICAL were not influenced by commonly prescribed medications such as CHEMICAL (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of CHEMICAL were not influenced by commonly prescribed medications such as antacids (n=77), CHEMICAL (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of CHEMICAL were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), CHEMICAL (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of CHEMICAL were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), CHEMICAL (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of CHEMICAL were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), CHEMICAL (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of CHEMICAL were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), CHEMICAL (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of CHEMICAL were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), CHEMICAL (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of CHEMICAL were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), CHEMICAL (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of CHEMICAL were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and CHEMICAL (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as CHEMICAL (n=77), CHEMICAL (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as CHEMICAL (n=77), antihypertensives (n=72), CHEMICAL (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as CHEMICAL (n=77), antihypertensives (n=72), calcium channel blockers (n=75), CHEMICAL (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as CHEMICAL (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), CHEMICAL (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as CHEMICAL (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), CHEMICAL (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as CHEMICAL (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), CHEMICAL (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as CHEMICAL (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), CHEMICAL (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as CHEMICAL (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and CHEMICAL (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), CHEMICAL (n=72), CHEMICAL (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), CHEMICAL (n=72), calcium channel blockers (n=75), CHEMICAL (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), CHEMICAL (n=72), calcium channel blockers (n=75), antidiabetics (n=21), CHEMICAL (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), CHEMICAL (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), CHEMICAL (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), CHEMICAL (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), CHEMICAL (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), CHEMICAL (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), CHEMICAL (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), CHEMICAL (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and CHEMICAL (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), CHEMICAL (n=75), CHEMICAL (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), CHEMICAL (n=75), antidiabetics (n=21), CHEMICAL (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), CHEMICAL (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), CHEMICAL (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), CHEMICAL (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), CHEMICAL (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), CHEMICAL (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), CHEMICAL (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), CHEMICAL (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and CHEMICAL (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), CHEMICAL (n=21), CHEMICAL (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), CHEMICAL (n=21), nonsteroidal anti-inflammatory drugs (n=79), CHEMICAL (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), CHEMICAL (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), CHEMICAL (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), CHEMICAL (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), CHEMICAL (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), CHEMICAL (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and CHEMICAL (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), CHEMICAL (n=79), CHEMICAL (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), CHEMICAL (n=79), estrogens (n=70), CHEMICAL (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), CHEMICAL (n=79), estrogens (n=70), salicylate analgesics (n=177), CHEMICAL (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), CHEMICAL (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and CHEMICAL (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), CHEMICAL (n=70), CHEMICAL (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), CHEMICAL (n=70), salicylate analgesics (n=177), CHEMICAL (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), CHEMICAL (n=70), salicylate analgesics (n=177), antianginals (n=35), and CHEMICAL (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), CHEMICAL (n=177), CHEMICAL (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), CHEMICAL (n=177), antianginals (n=35), and CHEMICAL (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), CHEMICAL (n=35), and CHEMICAL (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with CHEMICAL: Because of their mechanism of action, CHEMICAL have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with CHEMICAL: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of CHEMICAL. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, CHEMICAL have the potential to interfere with the activity of CHEMICAL. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | CHEMICALS-INTERACTION |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with CHEMICAL and Other CHEMICAL: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with CHEMICAL and Other Cholinesterase Inhibitors: A synergistic effect may be expected when CHEMICAL are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with CHEMICAL and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with CHEMICAL, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with CHEMICAL and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar CHEMICAL or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with CHEMICAL and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or CHEMICAL such as bethanechol. | CHEMICALS-INTERACTION |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with CHEMICAL and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as CHEMICAL. | CHEMICALS-INTERACTION |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other CHEMICAL: A synergistic effect may be expected when CHEMICAL are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other CHEMICAL: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with CHEMICAL, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other CHEMICAL: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar CHEMICAL or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other CHEMICAL: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or CHEMICAL such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other CHEMICAL: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as CHEMICAL. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when CHEMICAL are given concurrently with CHEMICAL, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. | CHEMICALS-INTERACTION |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when CHEMICAL are given concurrently with succinylcholine, similar CHEMICAL or cholinergic agonists such as bethanechol. | CHEMICALS-INTERACTION |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when CHEMICAL are given concurrently with succinylcholine, similar neuromuscular blocking agents or CHEMICAL such as bethanechol. | CHEMICALS-INTERACTION |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when CHEMICAL are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as CHEMICAL. | CHEMICALS-INTERACTION |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with CHEMICAL, similar CHEMICAL or cholinergic agonists such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with CHEMICAL, similar neuromuscular blocking agents or CHEMICAL such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with CHEMICAL, similar neuromuscular blocking agents or cholinergic agonists such as CHEMICAL. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar CHEMICAL or CHEMICAL such as bethanechol. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar CHEMICAL or cholinergic agonists such as CHEMICAL. | NO-RELATIONSHIP |
| Drug-Drug Interactions Effect of Exelon (rivastigmine tartrate) on the Metabolism of Other Drugs: Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, or CYP2C19. No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The elevation of prothrombin time induced by warfarin is not affected by administration of Exelon. Effect of Other Drugs on the Metabolism of Exelon: Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Single dose pharmacokinetic studies demonstrated that the metabolism of rivastigmine is not significantly affected by concurrent administration of digoxin, warfarin, diazepam, or fluoxetine. Population PK analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15). Use with Anticholinergics: Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. Use with Cholinomimetics and Other Cholinesterase Inhibitors: A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or CHEMICAL such as CHEMICAL. | NO-RELATIONSHIP |
| CHEMICAL: Spontaneous adverse reaction reports of patients taking concomitant CHEMICAL with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| CHEMICAL: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of CHEMICAL demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant CHEMICAL with recommended doses of CHEMICAL demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that CHEMICAL markedly inhibits the metabolism of CHEMICAL, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that CHEMICAL markedly inhibits the metabolism of terfenadine, resulting in elevated plasma CHEMICAL levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of CHEMICAL, resulting in elevated plasma CHEMICAL levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of CHEMICAL and CHEMICAL is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. CHEMICAL: Torsades de pointes and elevated parent CHEMICAL levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. CHEMICAL: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of CHEMICAL and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. CHEMICAL: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and CHEMICAL in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. CHEMICAL: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of CHEMICAL and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent CHEMICAL levels have been reported during concomitant use of CHEMICAL and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent CHEMICAL levels have been reported during concomitant use of terfenadine and CHEMICAL in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent CHEMICAL levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of CHEMICAL and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of CHEMICAL and CHEMICAL in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of CHEMICAL and itraconazole in clinical trials of CHEMICAL and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and CHEMICAL in clinical trials of CHEMICAL and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of CHEMICAL and CHEMICAL is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other CHEMICAL (including CHEMICAL, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other CHEMICAL (including fluconazole, CHEMICAL, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other CHEMICAL (including fluconazole, metronidazole, and CHEMICAL) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other CHEMICAL (including fluconazole, metronidazole, and miconazole) to CHEMICAL, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other CHEMICAL (including fluconazole, metronidazole, and miconazole) to ketoconazole, and CHEMICAL, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other CHEMICAL (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with CHEMICAL is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including CHEMICAL, CHEMICAL, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including CHEMICAL, metronidazole, and CHEMICAL) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including CHEMICAL, metronidazole, and miconazole) to CHEMICAL, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including CHEMICAL, metronidazole, and miconazole) to ketoconazole, and CHEMICAL, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including CHEMICAL, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with CHEMICAL is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, CHEMICAL, and CHEMICAL) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, CHEMICAL, and miconazole) to CHEMICAL, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, CHEMICAL, and miconazole) to ketoconazole, and CHEMICAL, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, CHEMICAL, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with CHEMICAL is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and CHEMICAL) to CHEMICAL, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and CHEMICAL) to ketoconazole, and CHEMICAL, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and CHEMICAL) to ketoconazole, and itraconazole, concomitant use of these products with CHEMICAL is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to CHEMICAL, and CHEMICAL, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to CHEMICAL, and itraconazole, concomitant use of these products with CHEMICAL is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and CHEMICAL, concomitant use of these products with CHEMICAL is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. CHEMICAL: Clinical drug interaction studies indicate that CHEMICAL and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. CHEMICAL: Clinical drug interaction studies indicate that erythromycin and CHEMICAL can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. CHEMICAL: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on CHEMICAL metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. CHEMICAL: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of CHEMICAL, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that CHEMICAL and CHEMICAL can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that CHEMICAL and clarithromycin can exert an effect on CHEMICAL metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that CHEMICAL and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of CHEMICAL, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and CHEMICAL can exert an effect on CHEMICAL metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and CHEMICAL can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of CHEMICAL, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on CHEMICAL metabolism by a mechanism which may be similar to that of CHEMICAL, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving CHEMICAL or CHEMICAL. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of CHEMICAL with CHEMICAL, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of CHEMICAL with clarithromycin, CHEMICAL, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of CHEMICAL with clarithromycin, erythromycin, or CHEMICAL is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of CHEMICAL with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of CHEMICAL with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of CHEMICAL with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other CHEMICAL, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of CHEMICAL with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including CHEMICAL, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with CHEMICAL, CHEMICAL, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with CHEMICAL, erythromycin, or CHEMICAL is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with CHEMICAL, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of CHEMICAL with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with CHEMICAL, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other CHEMICAL, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with CHEMICAL, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including CHEMICAL, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, CHEMICAL, or CHEMICAL is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, CHEMICAL, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of CHEMICAL with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, CHEMICAL, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other CHEMICAL, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, CHEMICAL, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including CHEMICAL, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or CHEMICAL is contraindicated: Pending full characterization of potential interactions, concomitant administration of CHEMICAL with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or CHEMICAL is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other CHEMICAL, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or CHEMICAL is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including CHEMICAL, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of CHEMICAL with other CHEMICAL, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of CHEMICAL with other macrolide antibiotics, including CHEMICAL, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | CHEMICALS-INTERACTION |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other CHEMICAL, including CHEMICAL, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress. | NO-RELATIONSHIP |
| Ketoconazole: Spontaneous adverse reaction reports of patients taking concomitant ketoconazole with recommended doses of terfenadine demonstrate QT interval prolongation and rare serious cardiac events, e.g. death, cardiac arrest, and ventricular arrhythmia including torsades de pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine is associated with statistically significant prolongation of the QT and QTc intervals. Concomitant administration of ketoconazole and terfenadine is contraindicated. Itraconazole: Torsades de pointes and elevated parent terfenadine levels have been reported during concomitant use of terfenadine and itraconazole in clinical trials of itraconazole and from foreign post-marketing sources. One death has also been reported from foreign post- marketing sources. Concomitant administration of itraconazole and terfenadine is contraindicated. Due to the chemical similarity of other azole-type antifungal agents (including fluconazole, metronidazole, and miconazole) to ketoconazole, and itraconazole, concomitant use of these products with terfenadine is not recommended pending full examination of potential interactions. Macrolides: Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine acid metabolite, its influence on terfenadine plasma levels is still under investigation. A few spontaneous accounts of QT interval prolongation with ventricular arrhythmia including torsades de pointes, have been reported in patients receiving erythromycin or troleandomycin. Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin is contraindicated: Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of CHEMICAL with CHEMICAL are in progress. | CHEMICALS-INTERACTION |
| Caution is recommended when administering CHEMICAL with compounds that are metabolized/eliminated predominantly by the UGT1A1 pathway (e.g. CHEMICAL). Concomitant treatment with NEXAVAR resulted in a 21% increase in the AUC of doxorubicin. Caution is recommended when administering doxorubicin with NEXAVAR. Sorafenib inhibits CYP2B6 and CYP2C8 in vitro with Ki values of 6 and 1-2 ?M, respectively. Systemic exposure to substrates of CYP2B6 and CYP2C8 is expected to increase when co-administered with NEXAVAR. Caution is recommended when administering substrates of CYP2B6 and CYP2C8 with NEXAVAR. | CHEMICALS-INTERACTION |
| Caution is recommended when administering NEXAVAR with compounds that are metabolized/eliminated predominantly by the UGT1A1 pathway (e.g. irinotecan). Concomitant treatment with CHEMICAL resulted in a 21% increase in the AUC of CHEMICAL. Caution is recommended when administering doxorubicin with NEXAVAR. Sorafenib inhibits CYP2B6 and CYP2C8 in vitro with Ki values of 6 and 1-2 ?M, respectively. Systemic exposure to substrates of CYP2B6 and CYP2C8 is expected to increase when co-administered with NEXAVAR. Caution is recommended when administering substrates of CYP2B6 and CYP2C8 with NEXAVAR. | CHEMICALS-INTERACTION |
| Caution is recommended when administering NEXAVAR with compounds that are metabolized/eliminated predominantly by the UGT1A1 pathway (e.g. irinotecan). Concomitant treatment with NEXAVAR resulted in a 21% increase in the AUC of doxorubicin. Caution is recommended when administering CHEMICAL with CHEMICAL. Sorafenib inhibits CYP2B6 and CYP2C8 in vitro with Ki values of 6 and 1-2 ?M, respectively. Systemic exposure to substrates of CYP2B6 and CYP2C8 is expected to increase when co-administered with NEXAVAR. Caution is recommended when administering substrates of CYP2B6 and CYP2C8 with NEXAVAR. | CHEMICALS-INTERACTION |
| In a pharmacokinetic study of 18 chronic hepatitis C patients concomitantly receiving CHEMICAL, treatment with CHEMICAL once weekly for 4 weeks was associated with a mean increase of 16% in methadone AUC; in 2 out of 18 patients, methadone AUC doubled. The clinical significance of this finding is unknown; however, patients should be monitored for the signs and symptoms of increased narcotic effect. | CHEMICALS-INTERACTION |
| In a pharmacokinetic study of 18 chronic hepatitis C patients concomitantly receiving CHEMICAL, treatment with PEG-Intron once weekly for 4 weeks was associated with a mean increase of 16% in CHEMICAL AUC; in 2 out of 18 patients, methadone AUC doubled. The clinical significance of this finding is unknown; however, patients should be monitored for the signs and symptoms of increased narcotic effect. | NO-RELATIONSHIP |
| In a pharmacokinetic study of 18 chronic hepatitis C patients concomitantly receiving methadone, treatment with CHEMICAL once weekly for 4 weeks was associated with a mean increase of 16% in CHEMICAL AUC; in 2 out of 18 patients, methadone AUC doubled. The clinical significance of this finding is unknown; however, patients should be monitored for the signs and symptoms of increased narcotic effect. | NO-RELATIONSHIP |
| Since CHEMICAL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter CHEMICAL plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of CHEMICAL was decreased by 38% following the coadministration of CHEMICAL, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of CHEMICAL did not alter the kinetics of CHEMICAL in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of CHEMICAL were unaffected in either phenotype by the coadministration of CHEMICAL. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of CHEMICAL to CHEMICAL did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of CHEMICAL to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than CHEMICAL alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to CHEMICAL did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than CHEMICAL alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with CHEMICAL is initiated, the dose of CHEMICAL should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program CHEMICAL has been used concurrently with commonly employed antianginal, CHEMICAL, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program CHEMICAL has been used concurrently with commonly employed antianginal, antihypertensive, and CHEMICAL without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, CHEMICAL, and CHEMICAL without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of CHEMICAL such as CHEMICAL or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of CHEMICAL such as quinidine or CHEMICAL were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as CHEMICAL or CHEMICAL were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When CHEMICAL or other hepatic enzyme inducers such as CHEMICAL and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When CHEMICAL or other hepatic enzyme inducers such as rifampin and CHEMICAL have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When CHEMICAL or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with CHEMICAL , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When CHEMICAL or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered CHEMICAL plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as CHEMICAL and CHEMICAL have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as CHEMICAL and phenobarbital have been taken concurrently with CHEMICAL , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as CHEMICAL and phenobarbital have been taken concurrently with Mexitil , lowered CHEMICAL plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and CHEMICAL have been taken concurrently with CHEMICAL , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and CHEMICAL have been taken concurrently with Mexitil , lowered CHEMICAL plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with CHEMICAL , lowered CHEMICAL plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, CHEMICAL were shown not to affect CHEMICAL plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent CHEMICAL and CHEMICAL, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent CHEMICAL and digoxin, CHEMICAL, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent CHEMICAL and digoxin, diuretics, or CHEMICAL. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and CHEMICAL, CHEMICAL, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and CHEMICAL, diuretics, or CHEMICAL. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, CHEMICAL, or CHEMICAL. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of CHEMICAL and CHEMICAL has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of CHEMICAL and Mexitil has been reported to increase, decrease, or leave unchanged CHEMICAL plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and CHEMICAL has been reported to increase, decrease, or leave unchanged CHEMICAL plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. CHEMICAL does not alter serum CHEMICAL levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. CHEMICAL does not alter serum digoxin levels but CHEMICAL, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. CHEMICAL does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to CHEMICAL , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. CHEMICAL does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum CHEMICAL levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum CHEMICAL levels but CHEMICAL, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum CHEMICAL levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to CHEMICAL , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum CHEMICAL levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum CHEMICAL levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but CHEMICAL, when used to treat gastrointestinal symptoms due to CHEMICAL , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but CHEMICAL, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum CHEMICAL levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to CHEMICAL , has been reported to lower serum CHEMICAL levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | NO-RELATIONSHIP |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of CHEMICAL and CHEMICAL may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of CHEMICAL and theophylline may lead to increased plasma CHEMICAL levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and CHEMICAL may lead to increased plasma CHEMICAL levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting CHEMICAL . CHEMICAL plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting CHEMICAL . Theophylline plasma levels returned to pre-CHEMICAL values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting CHEMICAL . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing CHEMICAL . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting CHEMICAL . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If CHEMICAL and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting CHEMICAL . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and CHEMICAL are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting CHEMICAL . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, CHEMICAL blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting CHEMICAL . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the CHEMICAL dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . CHEMICAL plasma levels returned to pre-CHEMICAL values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . CHEMICAL plasma levels returned to pre-Mexitil values within 48 hours after discontinuing CHEMICAL . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . CHEMICAL plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If CHEMICAL and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . CHEMICAL plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and CHEMICAL are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . CHEMICAL plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, CHEMICAL blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . CHEMICAL plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the CHEMICAL dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-CHEMICAL values within 48 hours after discontinuing CHEMICAL . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-CHEMICAL values within 48 hours after discontinuing Mexitil . If CHEMICAL and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-CHEMICAL values within 48 hours after discontinuing Mexitil . If Mexitil and CHEMICAL are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-CHEMICAL values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, CHEMICAL blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-CHEMICAL values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the CHEMICAL dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing CHEMICAL . If CHEMICAL and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing CHEMICAL . If Mexitil and CHEMICAL are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing CHEMICAL . If Mexitil and theophylline are to be used concurrently, CHEMICAL blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing CHEMICAL . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the CHEMICAL dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If CHEMICAL and CHEMICAL are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If CHEMICAL and theophylline are to be used concurrently, CHEMICAL blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If CHEMICAL and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the CHEMICAL dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and CHEMICAL are to be used concurrently, CHEMICAL blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and CHEMICAL are to be used concurrently, theophylline blood levels should be monitored, particularly when the CHEMICAL dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, CHEMICAL blood levels should be monitored, particularly when the CHEMICAL dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of caffeine was decreased 50% following the administration of Mexitil . | CHEMICALS-INTERACTION |
| Since MEXITIL is a substrate for the metabolic pathways involving CYP2D6 and CYP1A2 enzymes, inhibition or induction of either of these enzymes would be expected to alter mexiletine plasma concentrations. In a formal, single-dose interaction study (n = 6 males) the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2. In another formal study (n = 8 extensive and n = 7 poor metabolizers of CYP2D6), coadministration of propafenone did not alter the kinetics of mexiletine in the poor CYP2D6 metabolizer group. However, the metabolic clearance of mexiletine in the extensive metabolizer phenotype decreased by about 70% making the poor and extensive metabolizer groups indistinguishable. In this crossover steady state study, the pharmacokinetics of propafenone were unaffected in either phenotype by the coadministration of mexiletine. Addition of mexiletine to propafenone did not lead to further electrocardiographic parameters changes of QRS, QTc, RR, and PR intervals than propafenone alone. When concomitant administration of either of these two drugs with mexiletine is initiated, the dose of mexiletine should be slowly titrated to desired effect. In a large compassionate use program Mexitil has been used concurrently with commonly employed antianginal, antihypertensive, and anticoagulant drugs without observed interactions. A variety of antiarrhythmics such as quinidine or propranolol were also added, sometimes with improved control of ventricular ectopy. When phenytoin or other hepatic enzyme inducers such as rifampin and phenobarbital have been taken concurrently with Mexitil , lowered Mexitil plasma levels have been reported. Monitoring of Mexitil plasma levels is recommended during such concurrent use to avoid ineffective therapy. In a formal study, benzodiazepines were shown not to affect Mexitil plasma concentrations. ECG intervals (PR, QRS, and QT) were not affected by concurrent Mexitil and digoxin, diuretics, or propranolol. Concurrent administration of cimetidine and Mexitil has been reported to increase, decrease, or leave unchanged Mexitil plasma levels; therefore patients should be followed carefully during concurrent therapy. Mexitil does not alter serum digoxin levels but magnesium-aluminum hydroxide, when used to treat gastrointestinal symptoms due to Mexitil , has been reported to lower serum digoxin levels. Concurrent use of Mexitil and theophylline may lead to increased plasma theophylline levels. One controlled study in eight normal subjects showed a 72% mean increase (range 35-136%) in plasma theophylline levels. This increase was observed at the first test point which was the second day after starting Mexitil . Theophylline plasma levels returned to pre-Mexitil values within 48 hours after discontinuing Mexitil . If Mexitil and theophylline are to be used concurrently, theophylline blood levels should be monitored, particularly when the Mexitil dose is changed. An appropriate adjustment in theophylline dose should be considered. Additionally, in one controlled study in five normal subjects and seven patients, the clearance of CHEMICAL was decreased 50% following the administration of CHEMICAL . | CHEMICALS-INTERACTION |
| Usage with CHEMICAL: Due to the potential for increased CNS depressants effects, CHEMICAL should be used with caution in patients who are currently receiving pentazocine. | NO-RELATIONSHIP |
| Usage with CHEMICAL: Due to the potential for increased CNS depressants effects, alcohol should be used with caution in patients who are currently receiving CHEMICAL. | NO-RELATIONSHIP |
| Usage with Alcohol: Due to the potential for increased CNS depressants effects, CHEMICAL should be used with caution in patients who are currently receiving CHEMICAL. | CHEMICALS-INTERACTION |
| Improved parathyroid hormone control by CHEMICAL is associated with reduction in CHEMICAL requirement in patients with end-stage renal disease. Uncontrolled hy-per-parathyroidism causes bone marrow fibrosis, leading to erythropoietin (EPO) resistance. Medical treatment with cinacalcet is effective in reducing plasma parathyroid hormone (PTH) levels, but its effect on darbepoetin dosing is unknown. METHODS AND AIMS: We conducted a retrospective cohort study of 40 end-stage renal disease (ESRD) patients (age: 55 14; mean SD; 21:male) who had at least 12 months of cinacalcet therapy. The distribution of renal replacement therapies were: 14 peritoneal dialysis, 18 conventional hemodialysis and 8 nocturnal hemodialysis. Standard dialysis related biochemical indices and medications used were recorded. The primary objective of the study was to ascertain the difference in darbepoetin responsiveness before and after 12 months of cinacalcet therapy. Our secondary objective was to determine if there was a relationship between the changes in PTH and darbepoetin requirement. Overall, PTH levels decreased from 197.5 (151.8; 249.2) to 66.1 (41.2; 136.5) (median (25th;75th percentile)) pmol/l; p < 0.001. Cinacalcet dose increased from 30.0 6 to 63 25 mg/day, p < 0.05. Hemoglobin remained unchanged (116 13 to 116 13 g/l), while darbepoetin requirement decreased from 40 (20; 60) to 24 (19; 59) g/week, p = 0.02. The remainder of the dialysis-related biochemistry (electrolytes, calcium, phosphate, iron status) and vitamin D use remained unchanged. A reduction in PTH level of greater than 30% was experienced by 82.5% (33/40) of our cohort. Among the responders, the fall in PTH and reduction darbepoetin requirement were related (R = -0.48, p = 0.004). Reduction of PTH by cinacalcet is associated with a decrease in darbepoetin requirement. The interface between bone and bone marrow in uremia represents a critical step in red blood cell production which merits further investigation. | CHEMICALS-INTERACTION |
| Improved parathyroid hormone control by cinacalcet is associated with reduction in darbepoetin requirement in patients with end-stage renal disease. Uncontrolled hy-per-parathyroidism causes bone marrow fibrosis, leading to CHEMICAL (CHEMICAL) resistance. Medical treatment with cinacalcet is effective in reducing plasma parathyroid hormone (PTH) levels, but its effect on darbepoetin dosing is unknown. METHODS AND AIMS: We conducted a retrospective cohort study of 40 end-stage renal disease (ESRD) patients (age: 55 14; mean SD; 21:male) who had at least 12 months of cinacalcet therapy. The distribution of renal replacement therapies were: 14 peritoneal dialysis, 18 conventional hemodialysis and 8 nocturnal hemodialysis. Standard dialysis related biochemical indices and medications used were recorded. The primary objective of the study was to ascertain the difference in darbepoetin responsiveness before and after 12 months of cinacalcet therapy. Our secondary objective was to determine if there was a relationship between the changes in PTH and darbepoetin requirement. Overall, PTH levels decreased from 197.5 (151.8; 249.2) to 66.1 (41.2; 136.5) (median (25th;75th percentile)) pmol/l; p < 0.001. Cinacalcet dose increased from 30.0 6 to 63 25 mg/day, p < 0.05. Hemoglobin remained unchanged (116 13 to 116 13 g/l), while darbepoetin requirement decreased from 40 (20; 60) to 24 (19; 59) g/week, p = 0.02. The remainder of the dialysis-related biochemistry (electrolytes, calcium, phosphate, iron status) and vitamin D use remained unchanged. A reduction in PTH level of greater than 30% was experienced by 82.5% (33/40) of our cohort. Among the responders, the fall in PTH and reduction darbepoetin requirement were related (R = -0.48, p = 0.004). Reduction of PTH by cinacalcet is associated with a decrease in darbepoetin requirement. The interface between bone and bone marrow in uremia represents a critical step in red blood cell production which merits further investigation. | NO-RELATIONSHIP |
| Improved parathyroid hormone control by cinacalcet is associated with reduction in darbepoetin requirement in patients with end-stage renal disease. Uncontrolled hy-per-parathyroidism causes bone marrow fibrosis, leading to erythropoietin (EPO) resistance. Medical treatment with CHEMICAL is effective in reducing plasma parathyroid hormone (PTH) levels, but its effect on CHEMICAL dosing is unknown. METHODS AND AIMS: We conducted a retrospective cohort study of 40 end-stage renal disease (ESRD) patients (age: 55 14; mean SD; 21:male) who had at least 12 months of cinacalcet therapy. The distribution of renal replacement therapies were: 14 peritoneal dialysis, 18 conventional hemodialysis and 8 nocturnal hemodialysis. Standard dialysis related biochemical indices and medications used were recorded. The primary objective of the study was to ascertain the difference in darbepoetin responsiveness before and after 12 months of cinacalcet therapy. Our secondary objective was to determine if there was a relationship between the changes in PTH and darbepoetin requirement. Overall, PTH levels decreased from 197.5 (151.8; 249.2) to 66.1 (41.2; 136.5) (median (25th;75th percentile)) pmol/l; p < 0.001. Cinacalcet dose increased from 30.0 6 to 63 25 mg/day, p < 0.05. Hemoglobin remained unchanged (116 13 to 116 13 g/l), while darbepoetin requirement decreased from 40 (20; 60) to 24 (19; 59) g/week, p = 0.02. The remainder of the dialysis-related biochemistry (electrolytes, calcium, phosphate, iron status) and vitamin D use remained unchanged. A reduction in PTH level of greater than 30% was experienced by 82.5% (33/40) of our cohort. Among the responders, the fall in PTH and reduction darbepoetin requirement were related (R = -0.48, p = 0.004). Reduction of PTH by cinacalcet is associated with a decrease in darbepoetin requirement. The interface between bone and bone marrow in uremia represents a critical step in red blood cell production which merits further investigation. | NO-RELATIONSHIP |
| Improved parathyroid hormone control by cinacalcet is associated with reduction in darbepoetin requirement in patients with end-stage renal disease. Uncontrolled hy-per-parathyroidism causes bone marrow fibrosis, leading to erythropoietin (EPO) resistance. Medical treatment with cinacalcet is effective in reducing plasma parathyroid hormone (PTH) levels, but its effect on darbepoetin dosing is unknown. METHODS AND AIMS: We conducted a retrospective cohort study of 40 end-stage renal disease (ESRD) patients (age: 55 14; mean SD; 21:male) who had at least 12 months of cinacalcet therapy. The distribution of renal replacement therapies were: 14 peritoneal dialysis, 18 conventional hemodialysis and 8 nocturnal hemodialysis. Standard dialysis related biochemical indices and medications used were recorded. The primary objective of the study was to ascertain the difference in CHEMICAL responsiveness before and after 12 months of CHEMICAL therapy. Our secondary objective was to determine if there was a relationship between the changes in PTH and darbepoetin requirement. Overall, PTH levels decreased from 197.5 (151.8; 249.2) to 66.1 (41.2; 136.5) (median (25th;75th percentile)) pmol/l; p < 0.001. Cinacalcet dose increased from 30.0 6 to 63 25 mg/day, p < 0.05. Hemoglobin remained unchanged (116 13 to 116 13 g/l), while darbepoetin requirement decreased from 40 (20; 60) to 24 (19; 59) g/week, p = 0.02. The remainder of the dialysis-related biochemistry (electrolytes, calcium, phosphate, iron status) and vitamin D use remained unchanged. A reduction in PTH level of greater than 30% was experienced by 82.5% (33/40) of our cohort. Among the responders, the fall in PTH and reduction darbepoetin requirement were related (R = -0.48, p = 0.004). Reduction of PTH by cinacalcet is associated with a decrease in darbepoetin requirement. The interface between bone and bone marrow in uremia represents a critical step in red blood cell production which merits further investigation. | NO-RELATIONSHIP |
| Improved parathyroid hormone control by cinacalcet is associated with reduction in darbepoetin requirement in patients with end-stage renal disease. Uncontrolled hy-per-parathyroidism causes bone marrow fibrosis, leading to erythropoietin (EPO) resistance. Medical treatment with cinacalcet is effective in reducing plasma parathyroid hormone (PTH) levels, but its effect on darbepoetin dosing is unknown. METHODS AND AIMS: We conducted a retrospective cohort study of 40 end-stage renal disease (ESRD) patients (age: 55 14; mean SD; 21:male) who had at least 12 months of cinacalcet therapy. The distribution of renal replacement therapies were: 14 peritoneal dialysis, 18 conventional hemodialysis and 8 nocturnal hemodialysis. Standard dialysis related biochemical indices and medications used were recorded. The primary objective of the study was to ascertain the difference in darbepoetin responsiveness before and after 12 months of cinacalcet therapy. Our secondary objective was to determine if there was a relationship between the changes in PTH and darbepoetin requirement. Overall, PTH levels decreased from 197.5 (151.8; 249.2) to 66.1 (41.2; 136.5) (median (25th;75th percentile)) pmol/l; p < 0.001. Cinacalcet dose increased from 30.0 6 to 63 25 mg/day, p < 0.05. Hemoglobin remained unchanged (116 13 to 116 13 g/l), while darbepoetin requirement decreased from 40 (20; 60) to 24 (19; 59) g/week, p = 0.02. The remainder of the dialysis-related biochemistry (electrolytes, calcium, phosphate, iron status) and vitamin D use remained unchanged. A reduction in PTH level of greater than 30% was experienced by 82.5% (33/40) of our cohort. Among the responders, the fall in PTH and reduction darbepoetin requirement were related (R = -0.48, p = 0.004). Reduction of PTH by CHEMICAL is associated with a decrease in CHEMICAL requirement. The interface between bone and bone marrow in uremia represents a critical step in red blood cell production which merits further investigation. | CHEMICALS-INTERACTION |
| CHEMICAL may compete with other drugs, such as CHEMICAL, for sites of metabolism in the liver, thus elevating the serum levels of such compounds to potentially toxic levels. Therefore, when concomitant use of thiabendazole and xanthine derivatives is anticipated, it may be necessary to monitor blood levels and/or reduce the dosage of such compounds. Such concomitant use should be administered under careful medical supervision. | CHEMICALS-INTERACTION |
| Thiabendazole may compete with other drugs, such as theophylline, for sites of metabolism in the liver, thus elevating the serum levels of such compounds to potentially toxic levels. Therefore, when concomitant use of CHEMICAL and CHEMICAL is anticipated, it may be necessary to monitor blood levels and/or reduce the dosage of such compounds. Such concomitant use should be administered under careful medical supervision. | CHEMICALS-INTERACTION |
| CHEMICAL may be used with CHEMICAL, quinine and other antimalarials, and with other antibiotics. If signs of folate deficiency develop, pyrimethamine should be discontinued. Folinic acid (leucovorin) should be administered until normal hematopoiesis is restored. Mild hepatotoxicity has been reported in some patients when lorazepam and pyrimethamine were administered concomitantly. | CHEMICALS-INTERACTION |
| CHEMICAL may be used with sulfonamides, CHEMICAL and other antimalarials, and with other antibiotics. If signs of folate deficiency develop, pyrimethamine should be discontinued. Folinic acid (leucovorin) should be administered until normal hematopoiesis is restored. Mild hepatotoxicity has been reported in some patients when lorazepam and pyrimethamine were administered concomitantly. | CHEMICALS-INTERACTION |
| CHEMICAL may be used with sulfonamides, quinine and other CHEMICAL, and with other antibiotics. If signs of folate deficiency develop, pyrimethamine should be discontinued. Folinic acid (leucovorin) should be administered until normal hematopoiesis is restored. Mild hepatotoxicity has been reported in some patients when lorazepam and pyrimethamine were administered concomitantly. | CHEMICALS-INTERACTION |
| CHEMICAL may be used with sulfonamides, quinine and other antimalarials, and with other CHEMICAL. If signs of folate deficiency develop, pyrimethamine should be discontinued. Folinic acid (leucovorin) should be administered until normal hematopoiesis is restored. Mild hepatotoxicity has been reported in some patients when lorazepam and pyrimethamine were administered concomitantly. | CHEMICALS-INTERACTION |
| Pyrimethamine may be used with CHEMICAL, CHEMICAL and other antimalarials, and with other antibiotics. If signs of folate deficiency develop, pyrimethamine should be discontinued. Folinic acid (leucovorin) should be administered until normal hematopoiesis is restored. Mild hepatotoxicity has been reported in some patients when lorazepam and pyrimethamine were administered concomitantly. | NO-RELATIONSHIP |
| Pyrimethamine may be used with CHEMICAL, quinine and other CHEMICAL, and with other antibiotics. If signs of folate deficiency develop, pyrimethamine should be discontinued. Folinic acid (leucovorin) should be administered until normal hematopoiesis is restored. Mild hepatotoxicity has been reported in some patients when lorazepam and pyrimethamine were administered concomitantly. | NO-RELATIONSHIP |
| Pyrimethamine may be used with CHEMICAL, quinine and other antimalarials, and with other CHEMICAL. If signs of folate deficiency develop, pyrimethamine should be discontinued. Folinic acid (leucovorin) should be administered until normal hematopoiesis is restored. Mild hepatotoxicity has been reported in some patients when lorazepam and pyrimethamine were administered concomitantly. | NO-RELATIONSHIP |
| Pyrimethamine may be used with sulfonamides, CHEMICAL and other CHEMICAL, and with other antibiotics. If signs of folate deficiency develop, pyrimethamine should be discontinued. Folinic acid (leucovorin) should be administered until normal hematopoiesis is restored. Mild hepatotoxicity has been reported in some patients when lorazepam and pyrimethamine were administered concomitantly. | NO-RELATIONSHIP |
| Pyrimethamine may be used with sulfonamides, CHEMICAL and other antimalarials, and with other CHEMICAL. If signs of folate deficiency develop, pyrimethamine should be discontinued. Folinic acid (leucovorin) should be administered until normal hematopoiesis is restored. Mild hepatotoxicity has been reported in some patients when lorazepam and pyrimethamine were administered concomitantly. | NO-RELATIONSHIP |
| Pyrimethamine may be used with sulfonamides, quinine and other CHEMICAL, and with other CHEMICAL. If signs of folate deficiency develop, pyrimethamine should be discontinued. Folinic acid (leucovorin) should be administered until normal hematopoiesis is restored. Mild hepatotoxicity has been reported in some patients when lorazepam and pyrimethamine were administered concomitantly. | NO-RELATIONSHIP |
| Pyrimethamine may be used with sulfonamides, quinine and other antimalarials, and with other antibiotics. If signs of folate deficiency develop, pyrimethamine should be discontinued. CHEMICAL (CHEMICAL) should be administered until normal hematopoiesis is restored. Mild hepatotoxicity has been reported in some patients when lorazepam and pyrimethamine were administered concomitantly. | NO-RELATIONSHIP |
| Pyrimethamine may be used with sulfonamides, quinine and other antimalarials, and with other antibiotics. If signs of folate deficiency develop, pyrimethamine should be discontinued. Folinic acid (leucovorin) should be administered until normal hematopoiesis is restored. Mild hepatotoxicity has been reported in some patients when CHEMICAL and CHEMICAL were administered concomitantly. | CHEMICALS-INTERACTION |
| CHEMICAL-CHEMICAL interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | CHEMICALS-INTERACTION |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an CHEMICAL increases the risk of hospitalization for gastrointestinal bleeding in CHEMICAL users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | CHEMICAL-INDUCED-DISEASE |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 CHEMICAL users contributed 407,370 person-years of CHEMICAL use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. CHEMICAL users had an increased odds ratio of gastrointestinal bleeding upon initiation of CHEMICAL (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | CHEMICALS-INTERACTION |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. CHEMICAL users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), CHEMICAL (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. CHEMICAL users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), CHEMICAL (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | CHEMICALS-INTERACTION |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. CHEMICAL users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), CHEMICAL (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | CHEMICAL-INDUCED-DISEASE |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of CHEMICAL (OR = 1.73 [95% CI, 1.25-2.38]), CHEMICAL (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of CHEMICAL (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), CHEMICAL (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of CHEMICAL (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), CHEMICAL (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), CHEMICAL (OR = 1.63 [95% CI, 1.11-2.38]), CHEMICAL (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), CHEMICAL (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), CHEMICAL (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), CHEMICAL (OR = 1.64 [95% CI, 1.27-2.12]), CHEMICAL (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also CHEMICAL, which is not believed to interact with CHEMICAL, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). CHEMICAL users who initiated CHEMICAL, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | CHEMICALS-INTERACTION |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). CHEMICAL users who initiated citalopram, CHEMICAL, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | CHEMICALS-INTERACTION |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). CHEMICAL users who initiated citalopram, fluoxetine, CHEMICAL, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | CHEMICALS-INTERACTION |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). CHEMICAL users who initiated citalopram, fluoxetine, paroxetine, CHEMICAL, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | CHEMICALS-INTERACTION |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). CHEMICAL users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or CHEMICAL had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | CHEMICALS-INTERACTION |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated CHEMICAL, CHEMICAL, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated CHEMICAL, fluoxetine, CHEMICAL, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated CHEMICAL, fluoxetine, paroxetine, CHEMICAL, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated CHEMICAL, fluoxetine, paroxetine, amitriptyline, or CHEMICAL had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, CHEMICAL, CHEMICAL, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, CHEMICAL, paroxetine, CHEMICAL, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, CHEMICAL, paroxetine, amitriptyline, or CHEMICAL had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, CHEMICAL, CHEMICAL, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, CHEMICAL, amitriptyline, or CHEMICAL had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those 18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). Warfarin users who initiated citalopram, fluoxetine, paroxetine, CHEMICAL, or CHEMICAL had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk. | NO-RELATIONSHIP |
| CHEMICAL inhibits some of the liver's ability to metabolize some other drugs - CHEMICAL, astemizole, cisapride, cyclosporine, and tricyclic antidepressants. Thus the concentrations of these drugs would increase meaning side effects may be seen. A dose adjustment may be required. | CHEMICALS-INTERACTION |
| CHEMICAL inhibits some of the liver's ability to metabolize some other drugs - terfenadine, CHEMICAL, cisapride, cyclosporine, and tricyclic antidepressants. Thus the concentrations of these drugs would increase meaning side effects may be seen. A dose adjustment may be required. | CHEMICALS-INTERACTION |
| CHEMICAL inhibits some of the liver's ability to metabolize some other drugs - terfenadine, astemizole, CHEMICAL, cyclosporine, and tricyclic antidepressants. Thus the concentrations of these drugs would increase meaning side effects may be seen. A dose adjustment may be required. | CHEMICALS-INTERACTION |
| CHEMICAL inhibits some of the liver's ability to metabolize some other drugs - terfenadine, astemizole, cisapride, CHEMICAL, and tricyclic antidepressants. Thus the concentrations of these drugs would increase meaning side effects may be seen. A dose adjustment may be required. | CHEMICALS-INTERACTION |
| CHEMICAL inhibits some of the liver's ability to metabolize some other drugs - terfenadine, astemizole, cisapride, cyclosporine, and CHEMICAL. Thus the concentrations of these drugs would increase meaning side effects may be seen. A dose adjustment may be required. | CHEMICALS-INTERACTION |
| Posicor inhibits some of the liver's ability to metabolize some other drugs - CHEMICAL, CHEMICAL, cisapride, cyclosporine, and tricyclic antidepressants. Thus the concentrations of these drugs would increase meaning side effects may be seen. A dose adjustment may be required. | NO-RELATIONSHIP |
| Posicor inhibits some of the liver's ability to metabolize some other drugs - CHEMICAL, astemizole, CHEMICAL, cyclosporine, and tricyclic antidepressants. Thus the concentrations of these drugs would increase meaning side effects may be seen. A dose adjustment may be required. | NO-RELATIONSHIP |
| Posicor inhibits some of the liver's ability to metabolize some other drugs - CHEMICAL, astemizole, cisapride, CHEMICAL, and tricyclic antidepressants. Thus the concentrations of these drugs would increase meaning side effects may be seen. A dose adjustment may be required. | NO-RELATIONSHIP |
| Posicor inhibits some of the liver's ability to metabolize some other drugs - CHEMICAL, astemizole, cisapride, cyclosporine, and CHEMICAL. Thus the concentrations of these drugs would increase meaning side effects may be seen. A dose adjustment may be required. | NO-RELATIONSHIP |
| Posicor inhibits some of the liver's ability to metabolize some other drugs - terfenadine, CHEMICAL, CHEMICAL, cyclosporine, and tricyclic antidepressants. Thus the concentrations of these drugs would increase meaning side effects may be seen. A dose adjustment may be required. | NO-RELATIONSHIP |
| Posicor inhibits some of the liver's ability to metabolize some other drugs - terfenadine, CHEMICAL, cisapride, CHEMICAL, and tricyclic antidepressants. Thus the concentrations of these drugs would increase meaning side effects may be seen. A dose adjustment may be required. | NO-RELATIONSHIP |
| Posicor inhibits some of the liver's ability to metabolize some other drugs - terfenadine, CHEMICAL, cisapride, cyclosporine, and CHEMICAL. Thus the concentrations of these drugs would increase meaning side effects may be seen. A dose adjustment may be required. | NO-RELATIONSHIP |
| Posicor inhibits some of the liver's ability to metabolize some other drugs - terfenadine, astemizole, CHEMICAL, CHEMICAL, and tricyclic antidepressants. Thus the concentrations of these drugs would increase meaning side effects may be seen. A dose adjustment may be required. | NO-RELATIONSHIP |
| Posicor inhibits some of the liver's ability to metabolize some other drugs - terfenadine, astemizole, CHEMICAL, cyclosporine, and CHEMICAL. Thus the concentrations of these drugs would increase meaning side effects may be seen. A dose adjustment may be required. | NO-RELATIONSHIP |
| Posicor inhibits some of the liver's ability to metabolize some other drugs - terfenadine, astemizole, cisapride, CHEMICAL, and CHEMICAL. Thus the concentrations of these drugs would increase meaning side effects may be seen. A dose adjustment may be required. | NO-RELATIONSHIP |
| Enhancement of humoral immune responses to inactivated Newcastle disease and CHEMICAL by oral administration of CHEMICAL in chickens. Newcastle disease (ND) and avian influenza (AI) are common in the poultry industry. The objective of this study was to evaluate the effect of oral administration of ginseng stem-and-leaf saponins (GSLS) on the humoral immune responses of chickens to inactivated ND vaccines and AI vaccines. In experiment 1, oral administration of GSLS at a dose of 5 mg/kg of BW for 7 d on the immune response in chickens intramuscularly injected with inactivated ND vaccine was evaluated. Results showed that GSLS significantly increased the antibody level against ND in the serum of chickens. In experiment 2, the same regimen of GSLS was administered to chickens inoculated with inactivated AI vaccines, and an enhanced serum antibody response to AI vaccination was also observed. Considering the safety of GSLS, because no adverse effect was found throughout the experiments, GSLS may be a promising oral adjuvant to improve immunization in poultry. | NO-RELATIONSHIP |
| Enhancement of humoral immune responses to inactivated Newcastle disease and avian influenza vaccines by oral administration of ginseng stem-and-leaf saponins in chickens. Newcastle disease (ND) and avian influenza (AI) are common in the poultry industry. The objective of this study was to evaluate the effect of oral administration of CHEMICAL (CHEMICAL) on the humoral immune responses of chickens to inactivated ND vaccines and AI vaccines. In experiment 1, oral administration of GSLS at a dose of 5 mg/kg of BW for 7 d on the immune response in chickens intramuscularly injected with inactivated ND vaccine was evaluated. Results showed that GSLS significantly increased the antibody level against ND in the serum of chickens. In experiment 2, the same regimen of GSLS was administered to chickens inoculated with inactivated AI vaccines, and an enhanced serum antibody response to AI vaccination was also observed. Considering the safety of GSLS, because no adverse effect was found throughout the experiments, GSLS may be a promising oral adjuvant to improve immunization in poultry. | NO-RELATIONSHIP |
| Enhancement of humoral immune responses to inactivated Newcastle disease and avian influenza vaccines by oral administration of ginseng stem-and-leaf saponins in chickens. Newcastle disease (ND) and avian influenza (AI) are common in the poultry industry. The objective of this study was to evaluate the effect of oral administration of CHEMICAL (GSLS) on the humoral immune responses of chickens to CHEMICAL and AI vaccines. In experiment 1, oral administration of GSLS at a dose of 5 mg/kg of BW for 7 d on the immune response in chickens intramuscularly injected with inactivated ND vaccine was evaluated. Results showed that GSLS significantly increased the antibody level against ND in the serum of chickens. In experiment 2, the same regimen of GSLS was administered to chickens inoculated with inactivated AI vaccines, and an enhanced serum antibody response to AI vaccination was also observed. Considering the safety of GSLS, because no adverse effect was found throughout the experiments, GSLS may be a promising oral adjuvant to improve immunization in poultry. | NO-RELATIONSHIP |
| Enhancement of humoral immune responses to inactivated Newcastle disease and avian influenza vaccines by oral administration of ginseng stem-and-leaf saponins in chickens. Newcastle disease (ND) and avian influenza (AI) are common in the poultry industry. The objective of this study was to evaluate the effect of oral administration of ginseng stem-and-leaf saponins (CHEMICAL) on the humoral immune responses of chickens to CHEMICAL and AI vaccines. In experiment 1, oral administration of GSLS at a dose of 5 mg/kg of BW for 7 d on the immune response in chickens intramuscularly injected with inactivated ND vaccine was evaluated. Results showed that GSLS significantly increased the antibody level against ND in the serum of chickens. In experiment 2, the same regimen of GSLS was administered to chickens inoculated with inactivated AI vaccines, and an enhanced serum antibody response to AI vaccination was also observed. Considering the safety of GSLS, because no adverse effect was found throughout the experiments, GSLS may be a promising oral adjuvant to improve immunization in poultry. | NO-RELATIONSHIP |
| CHEMICAL may interact with CHEMICAL or mitotane (causing too great a decrease in adrenal function). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with aminoglutethimide or CHEMICAL (causing too great a decrease in adrenal function). | CHEMICALS-INTERACTION |
| Trilostane may interact with CHEMICAL or CHEMICAL (causing too great a decrease in adrenal function). | NO-RELATIONSHIP |
| ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., CHEMICAL) could potentially result in delayed clearance of CHEMICAL. Although ibuprofen (400 mg qid) can be administered with ALIMTA in patients with normal renal function (creatinine clearance 80 mL/min), caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. Drug/Laboratory Test Interactions None known. | CHEMICALS-INTERACTION |
| ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. Although CHEMICAL (400 mg qid) can be administered with CHEMICAL in patients with normal renal function (creatinine clearance 80 mL/min), caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. Drug/Laboratory Test Interactions None known. | CHEMICALS-INTERACTION |
| ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. Although CHEMICAL (400 mg qid) can be administered with ALIMTA in patients with normal renal function (creatinine clearance 80 mL/min), caution should be used when administering CHEMICAL concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. Drug/Laboratory Test Interactions None known. | NO-RELATIONSHIP |
| ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. Although CHEMICAL (400 mg qid) can be administered with ALIMTA in patients with normal renal function (creatinine clearance 80 mL/min), caution should be used when administering ibuprofen concurrently with CHEMICAL to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. Drug/Laboratory Test Interactions None known. | NO-RELATIONSHIP |
| ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. Although ibuprofen (400 mg qid) can be administered with CHEMICAL in patients with normal renal function (creatinine clearance 80 mL/min), caution should be used when administering CHEMICAL concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. Drug/Laboratory Test Interactions None known. | NO-RELATIONSHIP |
| ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. Although ibuprofen (400 mg qid) can be administered with CHEMICAL in patients with normal renal function (creatinine clearance 80 mL/min), caution should be used when administering ibuprofen concurrently with CHEMICAL to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. Drug/Laboratory Test Interactions None known. | NO-RELATIONSHIP |
| ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. Although ibuprofen (400 mg qid) can be administered with ALIMTA in patients with normal renal function (creatinine clearance 80 mL/min), caution should be used when administering CHEMICAL concurrently with CHEMICAL to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. Drug/Laboratory Test Interactions None known. | CHEMICALS-INTERACTION |
| ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. Although ibuprofen (400 mg qid) can be administered with ALIMTA in patients with normal renal function (creatinine clearance 80 mL/min), caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking CHEMICAL with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of CHEMICAL. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. Drug/Laboratory Test Interactions None known. | CHEMICALS-INTERACTION |
| ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. Although ibuprofen (400 mg qid) can be administered with ALIMTA in patients with normal renal function (creatinine clearance 80 mL/min), caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between CHEMICAL and CHEMICAL with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. Drug/Laboratory Test Interactions None known. | NO-RELATIONSHIP |
| ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. Although ibuprofen (400 mg qid) can be administered with ALIMTA in patients with normal renal function (creatinine clearance 80 mL/min), caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between CHEMICAL and NSAIDs with longer half-lives, all patients taking these CHEMICAL should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. Drug/Laboratory Test Interactions None known. | NO-RELATIONSHIP |
| ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. Although ibuprofen (400 mg qid) can be administered with ALIMTA in patients with normal renal function (creatinine clearance 80 mL/min), caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between CHEMICAL and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following CHEMICAL administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. Drug/Laboratory Test Interactions None known. | NO-RELATIONSHIP |
| ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. Although ibuprofen (400 mg qid) can be administered with ALIMTA in patients with normal renal function (creatinine clearance 80 mL/min), caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and CHEMICAL with longer half-lives, all patients taking these CHEMICAL should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. Drug/Laboratory Test Interactions None known. | NO-RELATIONSHIP |
| ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. Although ibuprofen (400 mg qid) can be administered with ALIMTA in patients with normal renal function (creatinine clearance 80 mL/min), caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and CHEMICAL with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following CHEMICAL administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. Drug/Laboratory Test Interactions None known. | NO-RELATIONSHIP |
| ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. Although ibuprofen (400 mg qid) can be administered with ALIMTA in patients with normal renal function (creatinine clearance 80 mL/min), caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these CHEMICAL should interrupt dosing for at least 5 days before, the day of, and 2 days following CHEMICAL administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. Drug/Laboratory Test Interactions None known. | CHEMICALS-INTERACTION |
| CHEMICAL does not inhibit the absorption of 5 milligrams of CHEMICAL or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| CHEMICAL does not inhibit the absorption of 5 milligrams of nonheme iron or CHEMICAL at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| Calcium does not inhibit the absorption of 5 milligrams of CHEMICAL or CHEMICAL at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. CHEMICAL is the only known component in the diet that may affect absorption of both CHEMICAL and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | CHEMICALS-INTERACTION |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. CHEMICAL is the only known component in the diet that may affect absorption of both nonheme iron and CHEMICAL. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | CHEMICALS-INTERACTION |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both CHEMICAL and CHEMICAL. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a CHEMICAL effect on CHEMICAL absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a CHEMICAL effect on iron absorption mainly comes from studies that did not isolate the effect of CHEMICAL from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on CHEMICAL absorption mainly comes from studies that did not isolate the effect of CHEMICAL from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of CHEMICAL on absorption of CHEMICAL and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of CHEMICAL on absorption of nonheme iron and CHEMICAL and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of CHEMICAL and CHEMICAL and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of CHEMICAL doses between 200 and 1500 mg on absorption of 5 mg CHEMICAL (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of CHEMICAL doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as CHEMICAL). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg CHEMICAL (as CHEMICAL). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of CHEMICAL doses between 200 and 800 mg on absorption of 5 mg CHEMICAL [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. CHEMICAL was administered as CHEMICAL in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. CHEMICAL was administered as calcium chloride in all studies and CHEMICAL were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as CHEMICAL in all studies and CHEMICAL were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. CHEMICAL doses 1000 mg diminished CHEMICAL absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | CHEMICALS-INTERACTION |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A CHEMICAL dose of 800 mg diminished absorption of 5 mg CHEMICAL by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | CHEMICALS-INTERACTION |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of CHEMICAL (as chloride) on absorption of 5 mg of iron provided as CHEMICAL (as sulfate) and heme iron (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | CHEMICALS-INTERACTION |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of CHEMICAL (as chloride) on absorption of 5 mg of iron provided as nonheme iron (as sulfate) and CHEMICAL (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | CHEMICALS-INTERACTION |
| Calcium does not inhibit the absorption of 5 milligrams of nonheme iron or heme iron at doses less than 800 milligrams in nonpregnant women. Calcium is the only known component in the diet that may affect absorption of both nonheme iron and heme iron. However, the evidence for a calcium effect on iron absorption mainly comes from studies that did not isolate the effect of calcium from that of other dietary components, because it was detected in single-meal studies. Our objective was to establish potential effects of calcium on absorption of nonheme iron and heme iron and the dose response for this effect in the absence of a meal. Fifty-four healthy, nonpregnant women were selected to participate in 4 iron absorption studies using iron radioactive tracers. We evaluated the effects of calcium doses between 200 and 1500 mg on absorption of 5 mg nonheme iron (as ferrous sulfate). We also evaluated the effects of calcium doses between 200 and 800 mg on absorption of 5 mg heme iron [as concentrated RBC (CRBC)]. Calcium was administered as calcium chloride in all studies and minerals were ingested on an empty stomach. Calcium doses 1000 mg diminished nonheme iron absorption by an average of 49.6%. A calcium dose of 800 mg diminished absorption of 5 mg heme iron by 37.7%. In conclusion, we demonstrated an isolated effect of calcium (as chloride) on absorption of 5 mg of iron provided as CHEMICAL (as sulfate) and CHEMICAL (as CRBC) iron. This effect was observed at doses higher than previously reported from single-meal studies, starting at ~800 mg of calcium. | NO-RELATIONSHIP |
| CHEMICAL may decrease the hypotensive effect of CHEMICAL. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | CHEMICALS-INTERACTION |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that CHEMICAL may inhibit the metabolism of CHEMICAL, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | CHEMICALS-INTERACTION |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that CHEMICAL may inhibit the metabolism of coumarin anticoagulants, CHEMICAL (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | CHEMICALS-INTERACTION |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that CHEMICAL may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (CHEMICAL, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | CHEMICALS-INTERACTION |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that CHEMICAL may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, CHEMICAL, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | CHEMICALS-INTERACTION |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that CHEMICAL may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, CHEMICAL), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | CHEMICALS-INTERACTION |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that CHEMICAL may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), CHEMICAL, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | CHEMICALS-INTERACTION |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that CHEMICAL may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and CHEMICAL (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | CHEMICALS-INTERACTION |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that CHEMICAL may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (CHEMICAL, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | CHEMICALS-INTERACTION |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that CHEMICAL may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, CHEMICAL, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | CHEMICALS-INTERACTION |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that CHEMICAL may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, CHEMICAL). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | CHEMICALS-INTERACTION |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of CHEMICAL, CHEMICAL (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of CHEMICAL, anticonvulsants (CHEMICAL, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of CHEMICAL, anticonvulsants (phenobarbital, CHEMICAL, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of CHEMICAL, anticonvulsants (phenobarbital, diphenylhydantoin, CHEMICAL), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of CHEMICAL, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), CHEMICAL, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of CHEMICAL, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and CHEMICAL (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of CHEMICAL, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (CHEMICAL, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of CHEMICAL, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, CHEMICAL, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of CHEMICAL, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, CHEMICAL). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, CHEMICAL (CHEMICAL, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, CHEMICAL (phenobarbital, CHEMICAL, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, CHEMICAL (phenobarbital, diphenylhydantoin, CHEMICAL), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, CHEMICAL (phenobarbital, diphenylhydantoin, primidone), CHEMICAL, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, CHEMICAL (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and CHEMICAL (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, CHEMICAL (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (CHEMICAL, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, CHEMICAL (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, CHEMICAL, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, CHEMICAL (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, CHEMICAL). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (CHEMICAL, CHEMICAL, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (CHEMICAL, diphenylhydantoin, CHEMICAL), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (CHEMICAL, diphenylhydantoin, primidone), CHEMICAL, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (CHEMICAL, diphenylhydantoin, primidone), phenylbutazone, and CHEMICAL (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (CHEMICAL, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (CHEMICAL, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (CHEMICAL, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, CHEMICAL, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (CHEMICAL, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, CHEMICAL). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, CHEMICAL, CHEMICAL), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, CHEMICAL, primidone), CHEMICAL, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, CHEMICAL, primidone), phenylbutazone, and CHEMICAL (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, CHEMICAL, primidone), phenylbutazone, and tricyclic drugs (CHEMICAL, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, CHEMICAL, primidone), phenylbutazone, and tricyclic drugs (imipramine, CHEMICAL, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, CHEMICAL, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, CHEMICAL). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, CHEMICAL), CHEMICAL, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, CHEMICAL), phenylbutazone, and CHEMICAL (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, CHEMICAL), phenylbutazone, and tricyclic drugs (CHEMICAL, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, CHEMICAL), phenylbutazone, and tricyclic drugs (imipramine, CHEMICAL, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, CHEMICAL), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, CHEMICAL). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), CHEMICAL, and CHEMICAL (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), CHEMICAL, and tricyclic drugs (CHEMICAL, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), CHEMICAL, and tricyclic drugs (imipramine, CHEMICAL, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), CHEMICAL, and tricyclic drugs (imipramine, clomipramine, CHEMICAL). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and CHEMICAL (CHEMICAL, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and CHEMICAL (imipramine, CHEMICAL, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and CHEMICAL (imipramine, clomipramine, CHEMICAL). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (CHEMICAL, CHEMICAL, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (CHEMICAL, clomipramine, CHEMICAL). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, CHEMICAL, CHEMICAL). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using CHEMICAL in combination with CHEMICAL or other centrally acting alpha-2 agonists has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using CHEMICAL in combination with clonidine or other centrally acting CHEMICAL has not been systemically evaluated. | NO-RELATIONSHIP |
| Ritalin may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents. Human pharmacologic studies have shown that Ritalin may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and tricyclic drugs (imipramine, clomipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with Ritalin. Serious adverse events have been reported in concomitant use with clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with CHEMICAL or other centrally acting CHEMICAL has not been systemically evaluated. | NO-RELATIONSHIP |
| CHEMICAL: Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving CHEMICAL concomitantly with coumarin-derivative anticoagulants. Physicians should carefully monitor PT and INR in patients concurrently administered ZOLINZA and coumarin derivatives. Other HDAC Inhibitors Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of ZOLINZA and other HDAC inhibitors (e.g., valproic acid). Monitor platelet count every 2 weeks for the first 2 months. | NO-RELATIONSHIP |
| CHEMICAL: Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving ZOLINZA concomitantly with CHEMICAL. Physicians should carefully monitor PT and INR in patients concurrently administered ZOLINZA and coumarin derivatives. Other HDAC Inhibitors Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of ZOLINZA and other HDAC inhibitors (e.g., valproic acid). Monitor platelet count every 2 weeks for the first 2 months. | NO-RELATIONSHIP |
| Coumarin-Derivative Anticoagulants: Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving CHEMICAL concomitantly with CHEMICAL. Physicians should carefully monitor PT and INR in patients concurrently administered ZOLINZA and coumarin derivatives. Other HDAC Inhibitors Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of ZOLINZA and other HDAC inhibitors (e.g., valproic acid). Monitor platelet count every 2 weeks for the first 2 months. | CHEMICALS-INTERACTION |
| Coumarin-Derivative Anticoagulants: Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving ZOLINZA concomitantly with coumarin-derivative anticoagulants. Physicians should carefully monitor PT and INR in patients concurrently administered CHEMICAL and CHEMICAL. Other HDAC Inhibitors Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of ZOLINZA and other HDAC inhibitors (e.g., valproic acid). Monitor platelet count every 2 weeks for the first 2 months. | CHEMICALS-INTERACTION |
| Coumarin-Derivative Anticoagulants: Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving ZOLINZA concomitantly with coumarin-derivative anticoagulants. Physicians should carefully monitor PT and INR in patients concurrently administered ZOLINZA and coumarin derivatives. Other CHEMICAL Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of CHEMICAL and other HDAC inhibitors (e.g., valproic acid). Monitor platelet count every 2 weeks for the first 2 months. | NO-RELATIONSHIP |
| Coumarin-Derivative Anticoagulants: Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving ZOLINZA concomitantly with coumarin-derivative anticoagulants. Physicians should carefully monitor PT and INR in patients concurrently administered ZOLINZA and coumarin derivatives. Other CHEMICAL Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of ZOLINZA and other CHEMICAL (e.g., valproic acid). Monitor platelet count every 2 weeks for the first 2 months. | NO-RELATIONSHIP |
| Coumarin-Derivative Anticoagulants: Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving ZOLINZA concomitantly with coumarin-derivative anticoagulants. Physicians should carefully monitor PT and INR in patients concurrently administered ZOLINZA and coumarin derivatives. Other CHEMICAL Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of ZOLINZA and other HDAC inhibitors (e.g., CHEMICAL). Monitor platelet count every 2 weeks for the first 2 months. | NO-RELATIONSHIP |
| Coumarin-Derivative Anticoagulants: Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving ZOLINZA concomitantly with coumarin-derivative anticoagulants. Physicians should carefully monitor PT and INR in patients concurrently administered ZOLINZA and coumarin derivatives. Other HDAC Inhibitors Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of CHEMICAL and other CHEMICAL (e.g., valproic acid). Monitor platelet count every 2 weeks for the first 2 months. | CHEMICALS-INTERACTION |
| Coumarin-Derivative Anticoagulants: Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving ZOLINZA concomitantly with coumarin-derivative anticoagulants. Physicians should carefully monitor PT and INR in patients concurrently administered ZOLINZA and coumarin derivatives. Other HDAC Inhibitors Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of CHEMICAL and other HDAC inhibitors (e.g., CHEMICAL). Monitor platelet count every 2 weeks for the first 2 months. | CHEMICALS-INTERACTION |
| Coumarin-Derivative Anticoagulants: Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving ZOLINZA concomitantly with coumarin-derivative anticoagulants. Physicians should carefully monitor PT and INR in patients concurrently administered ZOLINZA and coumarin derivatives. Other HDAC Inhibitors Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of ZOLINZA and other CHEMICAL (e.g., CHEMICAL). Monitor platelet count every 2 weeks for the first 2 months. | NO-RELATIONSHIP |
| No specific cytochrome P450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m2 CHEMICAL and infusional CHEMICAL has been observed in patients treated every 2 weeks. Increases of 5-FU plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 ELOXATIN dosed every 3 weeks. Since platinum containing species are eliminated primarily through the kidney, clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds; although, this has not been specifically studied. | NO-RELATIONSHIP |
| No specific cytochrome P450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m2 ELOXATIN and infusional 5-FU has been observed in patients treated every 2 weeks. Increases of CHEMICAL plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 CHEMICAL dosed every 3 weeks. Since platinum containing species are eliminated primarily through the kidney, clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds; although, this has not been specifically studied. | NO-RELATIONSHIP |
| CHEMICAL: In a multiple-dose study in 30 normal weight subjects, coadministration of CHEMICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| CHEMICAL: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of CHEMICAL (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| CHEMICAL: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of CHEMICAL pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| CHEMICAL: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, CHEMICAL pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| CHEMICAL: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to CHEMICAL. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of CHEMICAL and 40 grams of CHEMICAL (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of CHEMICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of CHEMICAL pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of CHEMICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, CHEMICAL pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of CHEMICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to CHEMICAL. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of CHEMICAL (e.g., approximately 3 glasses of wine) did not result in alteration of CHEMICAL pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of CHEMICAL (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, CHEMICAL pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of CHEMICAL (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to CHEMICAL. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of CHEMICAL pharmacokinetics, CHEMICAL pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of CHEMICAL pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to CHEMICAL. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, CHEMICAL pharmacodynamics (fecal fat excretion), or systemic exposure to CHEMICAL. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. CHEMICAL: Preliminary data from a CHEMICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. CHEMICAL: Preliminary data from a XENICAL and CHEMICAL drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. CHEMICAL: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in CHEMICAL plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. CHEMICAL: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when CHEMICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. CHEMICAL: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with CHEMICAL. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a CHEMICAL and CHEMICAL drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a CHEMICAL and cyclosporine drug interaction study indicate a reduction in CHEMICAL plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a CHEMICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when CHEMICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a CHEMICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with CHEMICAL. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and CHEMICAL drug interaction study indicate a reduction in CHEMICAL plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and CHEMICAL drug interaction study indicate a reduction in cyclosporine plasma levels when CHEMICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and CHEMICAL drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with CHEMICAL. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in CHEMICAL plasma levels when CHEMICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in CHEMICAL plasma levels when XENICAL was coadministered with CHEMICAL. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when CHEMICAL was coadministered with CHEMICAL. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | CHEMICALS-INTERACTION |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. CHEMICAL: In 12 normal-weight subjects receiving CHEMICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. CHEMICAL: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, CHEMICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. CHEMICAL: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of CHEMICAL. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving CHEMICAL 120 mg three times a day for 6 days, CHEMICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving CHEMICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of CHEMICAL. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, CHEMICAL did not alter the pharmacokinetics of a single dose of CHEMICAL. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. CHEMICAL and Analogues: A pharmacokinetic interaction study showed a 30% reduction in CHEMICAL supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. CHEMICAL and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with CHEMICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in CHEMICAL supplement absorption when concomitantly administered with CHEMICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | CHEMICALS-INTERACTION |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. CHEMICAL inhibited absorption of a CHEMICAL supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | CHEMICALS-INTERACTION |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of CHEMICAL on the absorption of supplemental CHEMICAL, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of CHEMICAL on the absorption of supplemental vitamin D, CHEMICAL, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of CHEMICAL on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived CHEMICAL is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental CHEMICAL, CHEMICAL, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental CHEMICAL, vitamin A, and nutritionally-derived CHEMICAL is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, CHEMICAL, and nutritionally-derived CHEMICAL is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. CHEMICAL: In 12 normal-weight subjects receiving CHEMICAL 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. CHEMICAL: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, CHEMICAL did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. CHEMICAL: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of CHEMICAL. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving CHEMICAL 80 mg three times a day for 5 days, CHEMICAL did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving CHEMICAL 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of CHEMICAL. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, CHEMICAL did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of CHEMICAL. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. CHEMICAL (extended-release tablets): In 17 normal-weight subjects receiving CHEMICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. CHEMICAL (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, CHEMICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. CHEMICAL (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of CHEMICAL (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving CHEMICAL 120 mg three times a day for 6 days, CHEMICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving CHEMICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of CHEMICAL (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, CHEMICAL did not alter the bioavailability of CHEMICAL (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral CHEMICAL: In 20 normal-weight female subjects, the treatment of CHEMICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral CHEMICAL: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral CHEMICAL. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of CHEMICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral CHEMICAL. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. CHEMICAL: In 12 normal-weight subjects receiving CHEMICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. CHEMICAL: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, CHEMICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. CHEMICAL: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of CHEMICAL. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving CHEMICAL 120 mg three times a day for 7 days, CHEMICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving CHEMICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of CHEMICAL. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, CHEMICAL did not alter the pharmacokinetics of a single 300-mg dose of CHEMICAL. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. CHEMICAL: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving CHEMICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. CHEMICAL: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, CHEMICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. CHEMICAL: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of CHEMICAL. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving CHEMICAL 120 mg three times a day for 6 days, CHEMICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving CHEMICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of CHEMICAL. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, CHEMICAL did not affect the pharmacokinetics of CHEMICAL. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. CHEMICAL: In 12 normal-weight subjects, administration of CHEMICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. CHEMICAL: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either CHEMICAL pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of CHEMICAL 120 mg three times a day for 16 days did not result in any change in either CHEMICAL pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | NO-RELATIONSHIP |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with CHEMICAL administration, vitamin K levels tended to decline in subjects taking CHEMICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | CHEMICALS-INTERACTION |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as CHEMICAL absorption may be decreased with CHEMICAL, patients on chronic stable doses of warfarin who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | CHEMICALS-INTERACTION |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as CHEMICAL absorption may be decreased with XENICAL, patients on chronic stable doses of CHEMICAL who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | CHEMICALS-INTERACTION |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as CHEMICAL absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who are prescribed CHEMICAL should be monitored closely for changes in coagulation parameters. | CHEMICALS-INTERACTION |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with CHEMICAL, patients on chronic stable doses of CHEMICAL who are prescribed XENICAL should be monitored closely for changes in coagulation parameters. | CHEMICALS-INTERACTION |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with CHEMICAL, patients on chronic stable doses of warfarin who are prescribed CHEMICAL should be monitored closely for changes in coagulation parameters. | CHEMICALS-INTERACTION |
| Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40 grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat. Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine. Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the pharmacokinetics of a single dose of digoxin. Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time. Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide. Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets). Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives. Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days, XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin. Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of pravastatin. Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16 days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics (prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL. Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of CHEMICAL who are prescribed CHEMICAL should be monitored closely for changes in coagulation parameters. | CHEMICALS-INTERACTION |
| In vitro studies with human liver microsomes showed that CHEMICAL does not inhibit the metabolism of CHEMICAL, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that CHEMICAL does not inhibit the metabolism of tolbutamide, CHEMICAL, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that CHEMICAL does not inhibit the metabolism of tolbutamide, ethinylestradiol, CHEMICAL, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that CHEMICAL does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and CHEMICAL. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of CHEMICAL, CHEMICAL, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of CHEMICAL, ethinylestradiol, CHEMICAL, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of CHEMICAL, ethinylestradiol, ethoxycoumarin, and CHEMICAL. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, CHEMICAL, CHEMICAL, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, CHEMICAL, ethoxycoumarin, and CHEMICAL. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, CHEMICAL, and CHEMICAL. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as CHEMICAL, -blockers, CHEMICAL (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as CHEMICAL, -blockers, selective serotonin reuptake inhibitors (CHEMICAL), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as CHEMICAL, -blockers, selective serotonin reuptake inhibitors (SSRIs), and CHEMICAL, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, CHEMICAL (CHEMICAL), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, CHEMICAL (SSRIs), and CHEMICAL, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (CHEMICAL), and CHEMICAL, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that CHEMICAL does not affect the clearance of CHEMICAL or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that CHEMICAL does not affect the clearance of antipyrine or CHEMICAL. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of CHEMICAL or CHEMICAL. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. CHEMICAL decreases the clearance of CHEMICAL by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | CHEMICALS-INTERACTION |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. CHEMICAL increases the clearance of CHEMICAL by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | CHEMICALS-INTERACTION |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral CHEMICAL and CHEMICAL, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | CHEMICALS-INTERACTION |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral CHEMICAL and warfarin, however, a causal relationship between CHEMICAL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and CHEMICAL, however, a causal relationship between CHEMICAL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. CHEMICAL clearance is increased 100% by CHEMICAL, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | CHEMICALS-INTERACTION |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. CHEMICAL clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by CHEMICAL, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | CHEMICALS-INTERACTION |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by CHEMICAL, a CyP450 enzyme inducer, and decreased 33% by CHEMICAL, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. CHEMICAL clearance is unaffected by CHEMICAL. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral CHEMICAL, hormone replacement therapies, CHEMICAL, theophyllines, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral CHEMICAL, hormone replacement therapies, hypoglycemics, CHEMICAL, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral CHEMICAL, hormone replacement therapies, hypoglycemics, theophyllines, CHEMICAL, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral CHEMICAL, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, CHEMICAL, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral CHEMICAL, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, CHEMICAL, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral CHEMICAL, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, beta blockers, and CHEMICAL. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, CHEMICAL, CHEMICAL, phenytoins, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, CHEMICAL, theophyllines, CHEMICAL, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, CHEMICAL, theophyllines, phenytoins, CHEMICAL, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, CHEMICAL, theophyllines, phenytoins, thiazide diuretics, CHEMICAL, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, CHEMICAL, theophyllines, phenytoins, thiazide diuretics, beta blockers, and CHEMICAL. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, CHEMICAL, CHEMICAL, thiazide diuretics, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, CHEMICAL, phenytoins, CHEMICAL, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, CHEMICAL, phenytoins, thiazide diuretics, CHEMICAL, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, CHEMICAL, phenytoins, thiazide diuretics, beta blockers, and CHEMICAL. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, CHEMICAL, CHEMICAL, beta blockers, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, CHEMICAL, thiazide diuretics, CHEMICAL, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, CHEMICAL, thiazide diuretics, beta blockers, and CHEMICAL. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, CHEMICAL, CHEMICAL, and calcium channel blockers. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, CHEMICAL, beta blockers, and CHEMICAL. | NO-RELATIONSHIP |
| In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, and cyclosporine. In vitro studies have also shown that terbinafine inhibits CYP2D6-mediated metabolism. This may be of clinical relevance for compounds predominantly metabolized by this enzyme, such as tricyclic antidepressants, -blockers, selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAO-Is) Type B, if they have a narrow therapeutic window. In vivo drug-drug interaction studies conducted in normal volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between LAMISIL Tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CyP450 enzyme inducer, and decreased 33% by cimetidine, a CyP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, CHEMICAL, and CHEMICAL. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. CHEMICAL AND OTHER CHEMICAL WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. CHEMICAL AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO CHEMICAL AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | CHEMICALS-INTERACTION |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. CHEMICAL AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF CHEMICAL TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | CHEMICALS-INTERACTION |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER CHEMICAL WILL BE ADDITIVE TO CHEMICAL AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | CHEMICALS-INTERACTION |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER CHEMICAL WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF CHEMICAL TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | CHEMICALS-INTERACTION |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO CHEMICAL AND MAY INCREASE PLASMA CONCENTRATIONS OF CHEMICAL TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. CHEMICAL given concomitantly with CHEMICAL may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | CHEMICALS-INTERACTION |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. CHEMICAL may enhance the hypoglycemic effect of oral CHEMICAL of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | CHEMICALS-INTERACTION |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. CHEMICAL competes with a number of drugs for protein binding sites, notably CHEMICAL, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | CHEMICALS-INTERACTION |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. CHEMICAL competes with a number of drugs for protein binding sites, notably penicillin, CHEMICAL, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | CHEMICALS-INTERACTION |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. CHEMICAL competes with a number of drugs for protein binding sites, notably penicillin, thiopental, CHEMICAL, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | CHEMICALS-INTERACTION |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. CHEMICAL competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, CHEMICAL, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | CHEMICALS-INTERACTION |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. CHEMICAL competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, CHEMICAL, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | CHEMICALS-INTERACTION |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. CHEMICAL competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, CHEMICAL, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | CHEMICALS-INTERACTION |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. CHEMICAL competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, CHEMICAL, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | CHEMICALS-INTERACTION |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. CHEMICAL competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, CHEMICAL, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | CHEMICALS-INTERACTION |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. CHEMICAL competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, CHEMICAL, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | CHEMICALS-INTERACTION |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. CHEMICAL competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly CHEMICAL. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | CHEMICALS-INTERACTION |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably CHEMICAL, CHEMICAL, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably CHEMICAL, thiopental, CHEMICAL, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably CHEMICAL, thiopental, thyroxine, CHEMICAL, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably CHEMICAL, thiopental, thyroxine, triiodothyronine, CHEMICAL, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably CHEMICAL, thiopental, thyroxine, triiodothyronine, phenytoin, CHEMICAL, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably CHEMICAL, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, CHEMICAL, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably CHEMICAL, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, CHEMICAL, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably CHEMICAL, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, CHEMICAL, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably CHEMICAL, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly CHEMICAL. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, CHEMICAL, CHEMICAL, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, CHEMICAL, thyroxine, CHEMICAL, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, CHEMICAL, thyroxine, triiodothyronine, CHEMICAL, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, CHEMICAL, thyroxine, triiodothyronine, phenytoin, CHEMICAL, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, CHEMICAL, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, CHEMICAL, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, CHEMICAL, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, CHEMICAL, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, CHEMICAL, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, CHEMICAL, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, CHEMICAL, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly CHEMICAL. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, CHEMICAL, CHEMICAL, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, CHEMICAL, triiodothyronine, CHEMICAL, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, CHEMICAL, triiodothyronine, phenytoin, CHEMICAL, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, CHEMICAL, triiodothyronine, phenytoin, sulfinpyrazone, CHEMICAL, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, CHEMICAL, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, CHEMICAL, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, CHEMICAL, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, CHEMICAL, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, CHEMICAL, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly CHEMICAL. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, CHEMICAL, CHEMICAL, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, CHEMICAL, phenytoin, CHEMICAL, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, CHEMICAL, phenytoin, sulfinpyrazone, CHEMICAL, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, CHEMICAL, phenytoin, sulfinpyrazone, naproxen, CHEMICAL, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, CHEMICAL, phenytoin, sulfinpyrazone, naproxen, warfarin, CHEMICAL, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, CHEMICAL, phenytoin, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly CHEMICAL. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, CHEMICAL, CHEMICAL, naproxen, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, CHEMICAL, sulfinpyrazone, CHEMICAL, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, CHEMICAL, sulfinpyrazone, naproxen, CHEMICAL, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, CHEMICAL, sulfinpyrazone, naproxen, warfarin, CHEMICAL, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, CHEMICAL, sulfinpyrazone, naproxen, warfarin, methotrexate, and possibly CHEMICAL. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, CHEMICAL, CHEMICAL, warfarin, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, CHEMICAL, naproxen, CHEMICAL, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, CHEMICAL, naproxen, warfarin, CHEMICAL, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, CHEMICAL, naproxen, warfarin, methotrexate, and possibly CHEMICAL. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, CHEMICAL, CHEMICAL, methotrexate, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, CHEMICAL, warfarin, CHEMICAL, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, CHEMICAL, warfarin, methotrexate, and possibly CHEMICAL. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, CHEMICAL, CHEMICAL, and possibly corticosteroids. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, CHEMICAL, methotrexate, and possibly CHEMICAL. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Salicylates antagonize the uricosuric action of . drugs used to treat gout. ASPIRIN AND OTHER SALICYLATE DRUGS WILL BE ADDITIVE TO DISALCID AND MAY INCREASE PLASMA CONCENTRATIONS OF SALICYLIC ACID TO TOXIC LEVELS. Drugs and foods that raise urine pH will increase renal clearance and urinary excretion of salicylic acid, thus lowering plasma levels; acidifying drugs or foods will decrease urinary excretion and increase plasma levels. Salicylates given concomitantly with anticoagulant drugs may predispose to systemic bleeding. Salicylates may enhance the hypoglycemic effect of oral antidiabetic drugs of the sulfonylurea class. Salicylate competes with a number of drugs for protein binding sites, notably penicillin, thiopental, thyroxine, triiodothyronine, phenytoin, sulfinpyrazone, naproxen, warfarin, CHEMICAL, and possibly CHEMICAL. Drug/ Laboratory Test Interactions Salicylate competes with thyroid hormone for binding to plasma proteins, which may be reflected in a depressed plasma T4 value in some patients; thyroid function and basal metabolism are unaffected. | NO-RELATIONSHIP |
| Catecholamine-depleting drugs (e.g., CHEMICAL) may have an additive effect when given with CHEMICAL. Patients receiving pindolol plus a catecholamine-depleting agent should, therefore, be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or postural hypotension. Pindolol has been used with a variety of antihypertensive agents, including hydrochlorothiazide, hydralazine, and guanethidine without unexpected adverse interactions. Pindolol has been shown to increase serum thioridazine levels when both drugs are co-administered. Pindolol levels may also be increased with this combination. Risk of anaphylactic reaction: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. | CHEMICALS-INTERACTION |
| Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients receiving pindolol plus a catecholamine-depleting agent should, therefore, be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or postural hypotension. CHEMICAL has been used with a variety of CHEMICAL, including hydrochlorothiazide, hydralazine, and guanethidine without unexpected adverse interactions. Pindolol has been shown to increase serum thioridazine levels when both drugs are co-administered. Pindolol levels may also be increased with this combination. Risk of anaphylactic reaction: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. | NO-RELATIONSHIP |
| Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients receiving pindolol plus a catecholamine-depleting agent should, therefore, be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or postural hypotension. CHEMICAL has been used with a variety of antihypertensive agents, including CHEMICAL, hydralazine, and guanethidine without unexpected adverse interactions. Pindolol has been shown to increase serum thioridazine levels when both drugs are co-administered. Pindolol levels may also be increased with this combination. Risk of anaphylactic reaction: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. | NO-RELATIONSHIP |
| Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients receiving pindolol plus a catecholamine-depleting agent should, therefore, be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or postural hypotension. CHEMICAL has been used with a variety of antihypertensive agents, including hydrochlorothiazide, CHEMICAL, and guanethidine without unexpected adverse interactions. Pindolol has been shown to increase serum thioridazine levels when both drugs are co-administered. Pindolol levels may also be increased with this combination. Risk of anaphylactic reaction: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. | NO-RELATIONSHIP |
| Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients receiving pindolol plus a catecholamine-depleting agent should, therefore, be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or postural hypotension. CHEMICAL has been used with a variety of antihypertensive agents, including hydrochlorothiazide, hydralazine, and CHEMICAL without unexpected adverse interactions. Pindolol has been shown to increase serum thioridazine levels when both drugs are co-administered. Pindolol levels may also be increased with this combination. Risk of anaphylactic reaction: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. | NO-RELATIONSHIP |
| Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients receiving pindolol plus a catecholamine-depleting agent should, therefore, be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or postural hypotension. Pindolol has been used with a variety of CHEMICAL, including CHEMICAL, hydralazine, and guanethidine without unexpected adverse interactions. Pindolol has been shown to increase serum thioridazine levels when both drugs are co-administered. Pindolol levels may also be increased with this combination. Risk of anaphylactic reaction: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. | NO-RELATIONSHIP |
| Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients receiving pindolol plus a catecholamine-depleting agent should, therefore, be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or postural hypotension. Pindolol has been used with a variety of CHEMICAL, including hydrochlorothiazide, CHEMICAL, and guanethidine without unexpected adverse interactions. Pindolol has been shown to increase serum thioridazine levels when both drugs are co-administered. Pindolol levels may also be increased with this combination. Risk of anaphylactic reaction: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. | NO-RELATIONSHIP |
| Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients receiving pindolol plus a catecholamine-depleting agent should, therefore, be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or postural hypotension. Pindolol has been used with a variety of CHEMICAL, including hydrochlorothiazide, hydralazine, and CHEMICAL without unexpected adverse interactions. Pindolol has been shown to increase serum thioridazine levels when both drugs are co-administered. Pindolol levels may also be increased with this combination. Risk of anaphylactic reaction: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. | NO-RELATIONSHIP |
| Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients receiving pindolol plus a catecholamine-depleting agent should, therefore, be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or postural hypotension. Pindolol has been used with a variety of antihypertensive agents, including CHEMICAL, CHEMICAL, and guanethidine without unexpected adverse interactions. Pindolol has been shown to increase serum thioridazine levels when both drugs are co-administered. Pindolol levels may also be increased with this combination. Risk of anaphylactic reaction: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. | NO-RELATIONSHIP |
| Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients receiving pindolol plus a catecholamine-depleting agent should, therefore, be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or postural hypotension. Pindolol has been used with a variety of antihypertensive agents, including CHEMICAL, hydralazine, and CHEMICAL without unexpected adverse interactions. Pindolol has been shown to increase serum thioridazine levels when both drugs are co-administered. Pindolol levels may also be increased with this combination. Risk of anaphylactic reaction: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. | NO-RELATIONSHIP |
| Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients receiving pindolol plus a catecholamine-depleting agent should, therefore, be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or postural hypotension. Pindolol has been used with a variety of antihypertensive agents, including hydrochlorothiazide, CHEMICAL, and CHEMICAL without unexpected adverse interactions. Pindolol has been shown to increase serum thioridazine levels when both drugs are co-administered. Pindolol levels may also be increased with this combination. Risk of anaphylactic reaction: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. | NO-RELATIONSHIP |
| Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients receiving pindolol plus a catecholamine-depleting agent should, therefore, be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or postural hypotension. Pindolol has been used with a variety of antihypertensive agents, including hydrochlorothiazide, hydralazine, and guanethidine without unexpected adverse interactions. CHEMICAL has been shown to increase serum CHEMICAL levels when both drugs are co-administered. Pindolol levels may also be increased with this combination. Risk of anaphylactic reaction: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. | CHEMICALS-INTERACTION |
| Although specific drug or food interactions with CHEMICAL have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that CHEMICAL, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with CHEMICAL have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, CHEMICAL, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with CHEMICAL have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, CHEMICAL, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with CHEMICAL have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of CHEMICAL). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that CHEMICAL, CHEMICAL, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that CHEMICAL, itraconazole, CHEMICAL, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that CHEMICAL, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of CHEMICAL). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | CHEMICALS-INTERACTION |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, CHEMICAL, CHEMICAL, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, CHEMICAL, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of CHEMICAL). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | CHEMICALS-INTERACTION |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, CHEMICAL, and grapefruit juice may inhibit its metabolism (increasing serum levels of CHEMICAL). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | CHEMICALS-INTERACTION |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, CHEMICAL, CHEMICAL, St. John s Wort, and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain CHEMICAL (CHEMICAL, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain CHEMICAL (phenytoin, CHEMICAL, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain CHEMICAL (phenytoin, phenobarbital, CHEMICAL) may induce mifepristone metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain CHEMICAL (phenytoin, phenobarbital, carbamazepine) may induce CHEMICAL metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | CHEMICALS-INTERACTION |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain CHEMICAL (phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of CHEMICAL). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (CHEMICAL, CHEMICAL, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (CHEMICAL, phenobarbital, CHEMICAL) may induce mifepristone metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (CHEMICAL, phenobarbital, carbamazepine) may induce CHEMICAL metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | CHEMICALS-INTERACTION |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (CHEMICAL, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of CHEMICAL). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (phenytoin, CHEMICAL, CHEMICAL) may induce mifepristone metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (phenytoin, CHEMICAL, carbamazepine) may induce CHEMICAL metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | CHEMICALS-INTERACTION |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (phenytoin, CHEMICAL, carbamazepine) may induce mifepristone metabolism (lowering serum levels of CHEMICAL). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (phenytoin, phenobarbital, CHEMICAL) may induce CHEMICAL metabolism (lowering serum levels of mifepristone). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | CHEMICALS-INTERACTION |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (phenytoin, phenobarbital, CHEMICAL) may induce mifepristone metabolism (lowering serum levels of CHEMICAL). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug s metabolism by CYP 3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampin, dexamethasone, St. John s Wort, and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce CHEMICAL metabolism (lowering serum levels of CHEMICAL). Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia. | NO-RELATIONSHIP |
| The interaction of Retavase with other cardioactive drugs has not been studied. In addition to bleeding associated with CHEMICAL and CHEMICAL, drugs that alter platelet function (such as aspirin, dipyridamole, and abciximab) may increase the risk of bleeding if administered prior to or after Retavase therapy. | NO-RELATIONSHIP |
| The interaction of Retavase with other cardioactive drugs has not been studied. In addition to bleeding associated with CHEMICAL and vitamin K antagonists, drugs that alter platelet function (such as CHEMICAL, dipyridamole, and abciximab) may increase the risk of bleeding if administered prior to or after Retavase therapy. | CHEMICALS-INTERACTION |
| The interaction of Retavase with other cardioactive drugs has not been studied. In addition to bleeding associated with CHEMICAL and vitamin K antagonists, drugs that alter platelet function (such as aspirin, CHEMICAL, and abciximab) may increase the risk of bleeding if administered prior to or after Retavase therapy. | NO-RELATIONSHIP |
| The interaction of Retavase with other cardioactive drugs has not been studied. In addition to bleeding associated with CHEMICAL and vitamin K antagonists, drugs that alter platelet function (such as aspirin, dipyridamole, and CHEMICAL) may increase the risk of bleeding if administered prior to or after Retavase therapy. | NO-RELATIONSHIP |
| The interaction of Retavase with other cardioactive drugs has not been studied. In addition to bleeding associated with CHEMICAL and vitamin K antagonists, drugs that alter platelet function (such as aspirin, dipyridamole, and abciximab) may increase the risk of bleeding if administered prior to or after CHEMICAL therapy. | CHEMICALS-INTERACTION |
| The interaction of Retavase with other cardioactive drugs has not been studied. In addition to bleeding associated with heparin and CHEMICAL, drugs that alter platelet function (such as CHEMICAL, dipyridamole, and abciximab) may increase the risk of bleeding if administered prior to or after Retavase therapy. | NO-RELATIONSHIP |
| The interaction of Retavase with other cardioactive drugs has not been studied. In addition to bleeding associated with heparin and CHEMICAL, drugs that alter platelet function (such as aspirin, CHEMICAL, and abciximab) may increase the risk of bleeding if administered prior to or after Retavase therapy. | NO-RELATIONSHIP |
| The interaction of Retavase with other cardioactive drugs has not been studied. In addition to bleeding associated with heparin and CHEMICAL, drugs that alter platelet function (such as aspirin, dipyridamole, and CHEMICAL) may increase the risk of bleeding if administered prior to or after Retavase therapy. | NO-RELATIONSHIP |
| The interaction of Retavase with other cardioactive drugs has not been studied. In addition to bleeding associated with heparin and CHEMICAL, drugs that alter platelet function (such as aspirin, dipyridamole, and abciximab) may increase the risk of bleeding if administered prior to or after CHEMICAL therapy. | CHEMICALS-INTERACTION |
| The interaction of Retavase with other cardioactive drugs has not been studied. In addition to bleeding associated with heparin and vitamin K antagonists, drugs that alter platelet function (such as CHEMICAL, CHEMICAL, and abciximab) may increase the risk of bleeding if administered prior to or after Retavase therapy. | NO-RELATIONSHIP |
| The interaction of Retavase with other cardioactive drugs has not been studied. In addition to bleeding associated with heparin and vitamin K antagonists, drugs that alter platelet function (such as CHEMICAL, dipyridamole, and CHEMICAL) may increase the risk of bleeding if administered prior to or after Retavase therapy. | NO-RELATIONSHIP |
| The interaction of Retavase with other cardioactive drugs has not been studied. In addition to bleeding associated with heparin and vitamin K antagonists, drugs that alter platelet function (such as CHEMICAL, dipyridamole, and abciximab) may increase the risk of bleeding if administered prior to or after CHEMICAL therapy. | CHEMICALS-INTERACTION |
| The interaction of Retavase with other cardioactive drugs has not been studied. In addition to bleeding associated with heparin and vitamin K antagonists, drugs that alter platelet function (such as aspirin, CHEMICAL, and CHEMICAL) may increase the risk of bleeding if administered prior to or after Retavase therapy. | NO-RELATIONSHIP |
| The interaction of Retavase with other cardioactive drugs has not been studied. In addition to bleeding associated with heparin and vitamin K antagonists, drugs that alter platelet function (such as aspirin, CHEMICAL, and abciximab) may increase the risk of bleeding if administered prior to or after CHEMICAL therapy. | CHEMICALS-INTERACTION |
| The interaction of Retavase with other cardioactive drugs has not been studied. In addition to bleeding associated with heparin and vitamin K antagonists, drugs that alter platelet function (such as aspirin, dipyridamole, and CHEMICAL) may increase the risk of bleeding if administered prior to or after CHEMICAL therapy. | CHEMICALS-INTERACTION |
| The occurrence of stupor, muscular rigidity, severe agitation, and elevated temperature has been reported in some patients receiving the combination of CHEMICAL and CHEMICAL. Symptoms usually resolve over days when the combination is discontinued. This is typical of the interaction of meperidine and MAOIs. Other serious reactions (including severe agitation, hallucinations, and death) have been reported in patients receiving this combination. Severe toxicity has also been reported in patients receiving the combination of tricyclic antidepressants and ELDEPRYL and selective serotonin reuptake inhibitors and ELDEPRYL. One case of hypertensive crisis has been reported in a patient taking the recommended doses of selegiline and a sympathomimetic medication (ephedrine). | CHEMICALS-INTERACTION |
| The occurrence of stupor, muscular rigidity, severe agitation, and elevated temperature has been reported in some patients receiving the combination of selegiline and meperidine. Symptoms usually resolve over days when the combination is discontinued. This is typical of the interaction of CHEMICAL and CHEMICAL. Other serious reactions (including severe agitation, hallucinations, and death) have been reported in patients receiving this combination. Severe toxicity has also been reported in patients receiving the combination of tricyclic antidepressants and ELDEPRYL and selective serotonin reuptake inhibitors and ELDEPRYL. One case of hypertensive crisis has been reported in a patient taking the recommended doses of selegiline and a sympathomimetic medication (ephedrine). | CHEMICALS-INTERACTION |
| The occurrence of stupor, muscular rigidity, severe agitation, and elevated temperature has been reported in some patients receiving the combination of selegiline and meperidine. Symptoms usually resolve over days when the combination is discontinued. This is typical of the interaction of meperidine and MAOIs. Other serious reactions (including severe agitation, hallucinations, and death) have been reported in patients receiving this combination. Severe toxicity has also been reported in patients receiving the combination of CHEMICAL and CHEMICAL and selective serotonin reuptake inhibitors and ELDEPRYL. One case of hypertensive crisis has been reported in a patient taking the recommended doses of selegiline and a sympathomimetic medication (ephedrine). | CHEMICALS-INTERACTION |
| The occurrence of stupor, muscular rigidity, severe agitation, and elevated temperature has been reported in some patients receiving the combination of selegiline and meperidine. Symptoms usually resolve over days when the combination is discontinued. This is typical of the interaction of meperidine and MAOIs. Other serious reactions (including severe agitation, hallucinations, and death) have been reported in patients receiving this combination. Severe toxicity has also been reported in patients receiving the combination of CHEMICAL and ELDEPRYL and CHEMICAL and ELDEPRYL. One case of hypertensive crisis has been reported in a patient taking the recommended doses of selegiline and a sympathomimetic medication (ephedrine). | CHEMICALS-INTERACTION |
| The occurrence of stupor, muscular rigidity, severe agitation, and elevated temperature has been reported in some patients receiving the combination of selegiline and meperidine. Symptoms usually resolve over days when the combination is discontinued. This is typical of the interaction of meperidine and MAOIs. Other serious reactions (including severe agitation, hallucinations, and death) have been reported in patients receiving this combination. Severe toxicity has also been reported in patients receiving the combination of CHEMICAL and ELDEPRYL and selective serotonin reuptake inhibitors and CHEMICAL. One case of hypertensive crisis has been reported in a patient taking the recommended doses of selegiline and a sympathomimetic medication (ephedrine). | CHEMICALS-INTERACTION |
| The occurrence of stupor, muscular rigidity, severe agitation, and elevated temperature has been reported in some patients receiving the combination of selegiline and meperidine. Symptoms usually resolve over days when the combination is discontinued. This is typical of the interaction of meperidine and MAOIs. Other serious reactions (including severe agitation, hallucinations, and death) have been reported in patients receiving this combination. Severe toxicity has also been reported in patients receiving the combination of tricyclic antidepressants and CHEMICAL and CHEMICAL and ELDEPRYL. One case of hypertensive crisis has been reported in a patient taking the recommended doses of selegiline and a sympathomimetic medication (ephedrine). | NO-RELATIONSHIP |
| The occurrence of stupor, muscular rigidity, severe agitation, and elevated temperature has been reported in some patients receiving the combination of selegiline and meperidine. Symptoms usually resolve over days when the combination is discontinued. This is typical of the interaction of meperidine and MAOIs. Other serious reactions (including severe agitation, hallucinations, and death) have been reported in patients receiving this combination. Severe toxicity has also been reported in patients receiving the combination of tricyclic antidepressants and CHEMICAL and selective serotonin reuptake inhibitors and CHEMICAL. One case of hypertensive crisis has been reported in a patient taking the recommended doses of selegiline and a sympathomimetic medication (ephedrine). | NO-RELATIONSHIP |
| The occurrence of stupor, muscular rigidity, severe agitation, and elevated temperature has been reported in some patients receiving the combination of selegiline and meperidine. Symptoms usually resolve over days when the combination is discontinued. This is typical of the interaction of meperidine and MAOIs. Other serious reactions (including severe agitation, hallucinations, and death) have been reported in patients receiving this combination. Severe toxicity has also been reported in patients receiving the combination of tricyclic antidepressants and ELDEPRYL and CHEMICAL and CHEMICAL. One case of hypertensive crisis has been reported in a patient taking the recommended doses of selegiline and a sympathomimetic medication (ephedrine). | NO-RELATIONSHIP |
| The occurrence of stupor, muscular rigidity, severe agitation, and elevated temperature has been reported in some patients receiving the combination of selegiline and meperidine. Symptoms usually resolve over days when the combination is discontinued. This is typical of the interaction of meperidine and MAOIs. Other serious reactions (including severe agitation, hallucinations, and death) have been reported in patients receiving this combination. Severe toxicity has also been reported in patients receiving the combination of tricyclic antidepressants and ELDEPRYL and selective serotonin reuptake inhibitors and ELDEPRYL. One case of hypertensive crisis has been reported in a patient taking the recommended doses of CHEMICAL and a CHEMICAL (ephedrine). | CHEMICALS-INTERACTION |
| The occurrence of stupor, muscular rigidity, severe agitation, and elevated temperature has been reported in some patients receiving the combination of selegiline and meperidine. Symptoms usually resolve over days when the combination is discontinued. This is typical of the interaction of meperidine and MAOIs. Other serious reactions (including severe agitation, hallucinations, and death) have been reported in patients receiving this combination. Severe toxicity has also been reported in patients receiving the combination of tricyclic antidepressants and ELDEPRYL and selective serotonin reuptake inhibitors and ELDEPRYL. One case of hypertensive crisis has been reported in a patient taking the recommended doses of CHEMICAL and a sympathomimetic medication (CHEMICAL). | CHEMICALS-INTERACTION |
| The occurrence of stupor, muscular rigidity, severe agitation, and elevated temperature has been reported in some patients receiving the combination of selegiline and meperidine. Symptoms usually resolve over days when the combination is discontinued. This is typical of the interaction of meperidine and MAOIs. Other serious reactions (including severe agitation, hallucinations, and death) have been reported in patients receiving this combination. Severe toxicity has also been reported in patients receiving the combination of tricyclic antidepressants and ELDEPRYL and selective serotonin reuptake inhibitors and ELDEPRYL. One case of hypertensive crisis has been reported in a patient taking the recommended doses of selegiline and a CHEMICAL (CHEMICAL). | NO-RELATIONSHIP |
| CHEMICAL locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with CHEMICAL. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the amphetamine-paired context compared with quinpirole-free controls conditioned with amphetamine, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | NO-RELATIONSHIP |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal CHEMICAL treatment on effects of CHEMICAL in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the amphetamine-paired context compared with quinpirole-free controls conditioned with amphetamine, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | NO-RELATIONSHIP |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal CHEMICAL treatment enhanced CHEMICAL locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the amphetamine-paired context compared with quinpirole-free controls conditioned with amphetamine, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | CHEMICALS-INTERACTION |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal CHEMICAL treatment enhanced amphetamine locomotor sensitization compared with CHEMICAL-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the amphetamine-paired context compared with quinpirole-free controls conditioned with amphetamine, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | NO-RELATIONSHIP |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal CHEMICAL treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to CHEMICAL. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the amphetamine-paired context compared with quinpirole-free controls conditioned with amphetamine, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | NO-RELATIONSHIP |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced CHEMICAL locomotor sensitization compared with CHEMICAL-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the amphetamine-paired context compared with quinpirole-free controls conditioned with amphetamine, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | NO-RELATIONSHIP |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced CHEMICAL locomotor sensitization compared with quinpirole-free controls sensitized to CHEMICAL. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the amphetamine-paired context compared with quinpirole-free controls conditioned with amphetamine, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | NO-RELATIONSHIP |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with CHEMICAL-free controls sensitized to CHEMICAL. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the amphetamine-paired context compared with quinpirole-free controls conditioned with amphetamine, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | NO-RELATIONSHIP |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to CHEMICAL, although this was muted compared with female rats, and were unaffected by neonatal CHEMICAL. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the amphetamine-paired context compared with quinpirole-free controls conditioned with amphetamine, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | NO-RELATIONSHIP |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal CHEMICAL enhanced time spent in the CHEMICAL-paired context compared with quinpirole-free controls conditioned with amphetamine, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | CHEMICALS-INTERACTION |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal CHEMICAL enhanced time spent in the amphetamine-paired context compared with CHEMICAL-free controls conditioned with amphetamine, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | NO-RELATIONSHIP |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal CHEMICAL enhanced time spent in the amphetamine-paired context compared with quinpirole-free controls conditioned with CHEMICAL, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | NO-RELATIONSHIP |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal CHEMICAL enhanced time spent in the amphetamine-paired context compared with quinpirole-free controls conditioned with amphetamine, but only female controls conditioned with CHEMICAL spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | NO-RELATIONSHIP |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the CHEMICAL-paired context compared with CHEMICAL-free controls conditioned with amphetamine, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | NO-RELATIONSHIP |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the CHEMICAL-paired context compared with quinpirole-free controls conditioned with CHEMICAL, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | NO-RELATIONSHIP |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the CHEMICAL-paired context compared with quinpirole-free controls conditioned with amphetamine, but only female controls conditioned with CHEMICAL spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | NO-RELATIONSHIP |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the amphetamine-paired context compared with CHEMICAL-free controls conditioned with CHEMICAL, but only female controls conditioned with amphetamine spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | NO-RELATIONSHIP |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the amphetamine-paired context compared with CHEMICAL-free controls conditioned with amphetamine, but only female controls conditioned with CHEMICAL spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | NO-RELATIONSHIP |
| Amphetamine locomotor sensitization and conditioned place preference in adolescent male and female rats neonatally treated with quinpirole. Neonatal quinpirole treatment has been shown to produce an increase in dopamine D2-like receptor sensitivity that persists throughout the subject's lifetime. The objective was to analyze the effects of neonatal quinpirole treatment on effects of amphetamine in adolescent rats using locomotor sensitization and conditioned place preference procedures. Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1 to P11 and raised to adolescence. For locomotor sensitization, subjects were given amphetamine (1 mg/kg) or saline every second day from P35 to P47 and were placed into a locomotor arena. In female rats, neonatal quinpirole treatment enhanced amphetamine locomotor sensitization compared with quinpirole-free controls sensitized to amphetamine. Male rats demonstrated sensitization to amphetamine, although this was muted compared with female rats, and were unaffected by neonatal quinpirole. For conditioned place preference, subjects were conditioned for 8 consecutive days (P32-39) with amphetamine (1 mg/kg) or saline and a drug-free preference test was conducted at P40. Rats treated with neonatal quinpirole enhanced time spent in the amphetamine-paired context compared with quinpirole-free controls conditioned with CHEMICAL, but only female controls conditioned with CHEMICAL spent more time in the drug-paired context compared with saline-treated controls. Increased D -like receptor sensitivity appears to have enhanced the behavioral effects of amphetamine, but these effects were more prevalent in adolescent female rats compared with male rats. | NO-RELATIONSHIP |
| Interactions between ZADAXIN and other drugs have not been fully evaluated. Caution should be exercised when administering CHEMICAL therapy in combination with other CHEMICAL. ZADAXIN should not be mixed with any other drug. | CHEMICALS-INTERACTION |
| Caution should be observed in administering CHEMICAL to patients receiving CHEMICAL or haloperidol because the extrapyramidal effects of these drugs can be expected to be potentiated by inhibition of catecholamine synthesis. Concurrent use of DEMSER with alcohol or other CNS depressants can increase their sedative effects. | CHEMICALS-INTERACTION |
| Caution should be observed in administering CHEMICAL to patients receiving phenothiazines or CHEMICAL because the extrapyramidal effects of these drugs can be expected to be potentiated by inhibition of catecholamine synthesis. Concurrent use of DEMSER with alcohol or other CNS depressants can increase their sedative effects. | CHEMICALS-INTERACTION |
| Caution should be observed in administering DEMSER to patients receiving CHEMICAL or CHEMICAL because the extrapyramidal effects of these drugs can be expected to be potentiated by inhibition of catecholamine synthesis. Concurrent use of DEMSER with alcohol or other CNS depressants can increase their sedative effects. | NO-RELATIONSHIP |
| Caution should be observed in administering DEMSER to patients receiving phenothiazines or haloperidol because the extrapyramidal effects of these drugs can be expected to be potentiated by inhibition of catecholamine synthesis. Concurrent use of CHEMICAL with CHEMICAL or other CNS depressants can increase their sedative effects. | CHEMICALS-INTERACTION |
| Caution should be observed in administering DEMSER to patients receiving phenothiazines or haloperidol because the extrapyramidal effects of these drugs can be expected to be potentiated by inhibition of catecholamine synthesis. Concurrent use of CHEMICAL with alcohol or other CHEMICAL can increase their sedative effects. | CHEMICALS-INTERACTION |
| Caution should be observed in administering DEMSER to patients receiving phenothiazines or haloperidol because the extrapyramidal effects of these drugs can be expected to be potentiated by inhibition of catecholamine synthesis. Concurrent use of DEMSER with CHEMICAL or other CHEMICAL can increase their sedative effects. | NO-RELATIONSHIP |
| Drugs affecting pituitary or adrenocortical function, including all corticosteroid therapy, must be discontinued prior to and during testing with Metopirone. The metabolism of CHEMICAL is accelerated by CHEMICAL; therefore, results of the test may be inaccurate in patients taking phenytoin within two weeks before. Asubnormal response may occur in patients on estrogen therapy. Metopirone inhibits the glucuronidation of acetaminophen and could possibly potentiate acetaminophen toxicity. | CHEMICALS-INTERACTION |
| Drugs affecting pituitary or adrenocortical function, including all corticosteroid therapy, must be discontinued prior to and during testing with Metopirone. The metabolism of Metopirone is accelerated by phenytoin; therefore, results of the test may be inaccurate in patients taking phenytoin within two weeks before. Asubnormal response may occur in patients on estrogen therapy. CHEMICAL inhibits the glucuronidation of CHEMICAL and could possibly potentiate acetaminophen toxicity. | CHEMICALS-INTERACTION |
| Drugs affecting pituitary or adrenocortical function, including all corticosteroid therapy, must be discontinued prior to and during testing with Metopirone. The metabolism of Metopirone is accelerated by phenytoin; therefore, results of the test may be inaccurate in patients taking phenytoin within two weeks before. Asubnormal response may occur in patients on estrogen therapy. CHEMICAL inhibits the glucuronidation of acetaminophen and could possibly potentiate CHEMICAL toxicity. | CHEMICALS-INTERACTION |
| Drugs affecting pituitary or adrenocortical function, including all corticosteroid therapy, must be discontinued prior to and during testing with Metopirone. The metabolism of Metopirone is accelerated by phenytoin; therefore, results of the test may be inaccurate in patients taking phenytoin within two weeks before. Asubnormal response may occur in patients on estrogen therapy. Metopirone inhibits the glucuronidation of CHEMICAL and could possibly potentiate CHEMICAL toxicity. | NO-RELATIONSHIP |
| CHEMICAL, such as the CHEMICAL (phenothiazines, butyrophenones, thioxanthines ) or metoclopramide, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| CHEMICAL, such as the neuroleptics (CHEMICAL, butyrophenones, thioxanthines ) or metoclopramide, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| CHEMICAL, such as the neuroleptics (phenothiazines, CHEMICAL, thioxanthines ) or metoclopramide, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| CHEMICAL, such as the neuroleptics (phenothiazines, butyrophenones, CHEMICAL ) or metoclopramide, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| CHEMICAL, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthines ) or CHEMICAL, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| CHEMICAL, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthines ) or metoclopramide, ordinarily should not be administered concurrently with CHEMICAL (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | CHEMICALS-INTERACTION |
| CHEMICAL, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthines ) or metoclopramide, ordinarily should not be administered concurrently with Permax (a CHEMICAL); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| Dopamine antagonists, such as the CHEMICAL (CHEMICAL, butyrophenones, thioxanthines ) or metoclopramide, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| Dopamine antagonists, such as the CHEMICAL (phenothiazines, CHEMICAL, thioxanthines ) or metoclopramide, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| Dopamine antagonists, such as the CHEMICAL (phenothiazines, butyrophenones, CHEMICAL ) or metoclopramide, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| Dopamine antagonists, such as the CHEMICAL (phenothiazines, butyrophenones, thioxanthines ) or CHEMICAL, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| Dopamine antagonists, such as the CHEMICAL (phenothiazines, butyrophenones, thioxanthines ) or metoclopramide, ordinarily should not be administered concurrently with CHEMICAL (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | CHEMICALS-INTERACTION |
| Dopamine antagonists, such as the CHEMICAL (phenothiazines, butyrophenones, thioxanthines ) or metoclopramide, ordinarily should not be administered concurrently with Permax (a CHEMICAL); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | CHEMICALS-INTERACTION |
| Dopamine antagonists, such as the neuroleptics (CHEMICAL, CHEMICAL, thioxanthines ) or metoclopramide, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| Dopamine antagonists, such as the neuroleptics (CHEMICAL, butyrophenones, CHEMICAL ) or metoclopramide, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| Dopamine antagonists, such as the neuroleptics (CHEMICAL, butyrophenones, thioxanthines ) or CHEMICAL, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| Dopamine antagonists, such as the neuroleptics (CHEMICAL, butyrophenones, thioxanthines ) or metoclopramide, ordinarily should not be administered concurrently with CHEMICAL (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | CHEMICALS-INTERACTION |
| Dopamine antagonists, such as the neuroleptics (CHEMICAL, butyrophenones, thioxanthines ) or metoclopramide, ordinarily should not be administered concurrently with Permax (a CHEMICAL); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | CHEMICALS-INTERACTION |
| Dopamine antagonists, such as the neuroleptics (phenothiazines, CHEMICAL, CHEMICAL ) or metoclopramide, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| Dopamine antagonists, such as the neuroleptics (phenothiazines, CHEMICAL, thioxanthines ) or CHEMICAL, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| Dopamine antagonists, such as the neuroleptics (phenothiazines, CHEMICAL, thioxanthines ) or metoclopramide, ordinarily should not be administered concurrently with CHEMICAL (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | CHEMICALS-INTERACTION |
| Dopamine antagonists, such as the neuroleptics (phenothiazines, CHEMICAL, thioxanthines ) or metoclopramide, ordinarily should not be administered concurrently with Permax (a CHEMICAL); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| Dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, CHEMICAL ) or CHEMICAL, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| Dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, CHEMICAL ) or metoclopramide, ordinarily should not be administered concurrently with CHEMICAL (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | CHEMICALS-INTERACTION |
| Dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, CHEMICAL ) or metoclopramide, ordinarily should not be administered concurrently with Permax (a CHEMICAL); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | CHEMICALS-INTERACTION |
| Dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthines ) or CHEMICAL, ordinarily should not be administered concurrently with CHEMICAL (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | CHEMICALS-INTERACTION |
| Dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthines ) or CHEMICAL, ordinarily should not be administered concurrently with Permax (a CHEMICAL); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | CHEMICALS-INTERACTION |
| Dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthines ) or metoclopramide, ordinarily should not be administered concurrently with CHEMICAL (a CHEMICAL); these agents may diminish the effectiveness of Permax. Because pergolide mesylate is approximately 90% bound to plasma proteins, caution should be exercised if pergolide mesylate is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| Dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthines ) or metoclopramide, ordinarily should not be administered concurrently with Permax (a dopamine agonist); these agents may diminish the effectiveness of Permax. Because CHEMICAL is approximately 90% bound to plasma proteins, caution should be exercised if CHEMICAL is coadministered with other drugs known to affect protein binding. | NO-RELATIONSHIP |
| Co-administration of oral CHEMICAL 200 mg twice daily increased CHEMICAL geometric mean AUC(0-24) and Cmax by 81% after topical application of retapamulin ointment, 1% on the abraded skin of healthy adult males. Due to low systemic exposure to retapamulin following topical application in patients, dosage adjustments for retapamulin are unnecessary when co-administered with CYP3A4 inhibitors, such as ketoconazole. Based on in vitro P450 inhibition studies and the low systemic exposure observed following topical application of ALTABAX, retapamulin is unlikely to affect the metabolism of other P450 substrates. The effect of concurrent application of ALTABAX and other topical products to the same area of skin has not been studied. | CHEMICALS-INTERACTION |
| Co-administration of oral CHEMICAL 200 mg twice daily increased retapamulin geometric mean AUC(0-24) and Cmax by 81% after topical application of CHEMICAL ointment, 1% on the abraded skin of healthy adult males. Due to low systemic exposure to retapamulin following topical application in patients, dosage adjustments for retapamulin are unnecessary when co-administered with CYP3A4 inhibitors, such as ketoconazole. Based on in vitro P450 inhibition studies and the low systemic exposure observed following topical application of ALTABAX, retapamulin is unlikely to affect the metabolism of other P450 substrates. The effect of concurrent application of ALTABAX and other topical products to the same area of skin has not been studied. | CHEMICALS-INTERACTION |
| Co-administration of oral ketoconazole 200 mg twice daily increased CHEMICAL geometric mean AUC(0-24) and Cmax by 81% after topical application of CHEMICAL ointment, 1% on the abraded skin of healthy adult males. Due to low systemic exposure to retapamulin following topical application in patients, dosage adjustments for retapamulin are unnecessary when co-administered with CYP3A4 inhibitors, such as ketoconazole. Based on in vitro P450 inhibition studies and the low systemic exposure observed following topical application of ALTABAX, retapamulin is unlikely to affect the metabolism of other P450 substrates. The effect of concurrent application of ALTABAX and other topical products to the same area of skin has not been studied. | NO-RELATIONSHIP |
| Co-administration of oral ketoconazole 200 mg twice daily increased retapamulin geometric mean AUC(0-24) and Cmax by 81% after topical application of retapamulin ointment, 1% on the abraded skin of healthy adult males. Due to low systemic exposure to CHEMICAL following topical application in patients, dosage adjustments for CHEMICAL are unnecessary when co-administered with CYP3A4 inhibitors, such as ketoconazole. Based on in vitro P450 inhibition studies and the low systemic exposure observed following topical application of ALTABAX, retapamulin is unlikely to affect the metabolism of other P450 substrates. The effect of concurrent application of ALTABAX and other topical products to the same area of skin has not been studied. | NO-RELATIONSHIP |
| Co-administration of oral ketoconazole 200 mg twice daily increased retapamulin geometric mean AUC(0-24) and Cmax by 81% after topical application of retapamulin ointment, 1% on the abraded skin of healthy adult males. Due to low systemic exposure to CHEMICAL following topical application in patients, dosage adjustments for retapamulin are unnecessary when co-administered with CYP3A4 inhibitors, such as CHEMICAL. Based on in vitro P450 inhibition studies and the low systemic exposure observed following topical application of ALTABAX, retapamulin is unlikely to affect the metabolism of other P450 substrates. The effect of concurrent application of ALTABAX and other topical products to the same area of skin has not been studied. | NO-RELATIONSHIP |
| Co-administration of oral ketoconazole 200 mg twice daily increased retapamulin geometric mean AUC(0-24) and Cmax by 81% after topical application of retapamulin ointment, 1% on the abraded skin of healthy adult males. Due to low systemic exposure to retapamulin following topical application in patients, dosage adjustments for CHEMICAL are unnecessary when co-administered with CYP3A4 inhibitors, such as CHEMICAL. Based on in vitro P450 inhibition studies and the low systemic exposure observed following topical application of ALTABAX, retapamulin is unlikely to affect the metabolism of other P450 substrates. The effect of concurrent application of ALTABAX and other topical products to the same area of skin has not been studied. | CHEMICALS-INTERACTION |
| Co-administration of oral ketoconazole 200 mg twice daily increased retapamulin geometric mean AUC(0-24) and Cmax by 81% after topical application of retapamulin ointment, 1% on the abraded skin of healthy adult males. Due to low systemic exposure to retapamulin following topical application in patients, dosage adjustments for retapamulin are unnecessary when co-administered with CYP3A4 inhibitors, such as ketoconazole. Based on in vitro P450 inhibition studies and the low systemic exposure observed following topical application of CHEMICAL, CHEMICAL is unlikely to affect the metabolism of other P450 substrates. The effect of concurrent application of ALTABAX and other topical products to the same area of skin has not been studied. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that CHEMICAL approximately doubled CHEMICAL AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | CHEMICALS-INTERACTION |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that CHEMICAL approximately doubled paricalcitol AUC0- . Since CHEMICAL is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that CHEMICAL approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and CHEMICAL le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that CHEMICAL approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing CHEMICAL with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that CHEMICAL approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with CHEMICAL and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that CHEMICAL approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including CHEMICAL, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that CHEMICAL approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, CHEMICAL, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that CHEMICAL approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, CHEMICAL, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that CHEMICAL approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that CHEMICAL approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that CHEMICAL approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that CHEMICAL approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that CHEMICAL approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that CHEMICAL approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that CHEMICAL approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or CHEMICAL. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled CHEMICAL AUC0- . Since CHEMICAL is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled CHEMICAL AUC0- . Since paricalcitol is partially metabolized by CYP3A and CHEMICAL le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled CHEMICAL AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing CHEMICAL with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled CHEMICAL AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with CHEMICAL and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled CHEMICAL AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including CHEMICAL, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled CHEMICAL AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, CHEMICAL, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled CHEMICAL AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, CHEMICAL, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled CHEMICAL AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled CHEMICAL AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled CHEMICAL AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled CHEMICAL AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled CHEMICAL AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled CHEMICAL AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled CHEMICAL AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or CHEMICAL. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since CHEMICAL is partially metabolized by CYP3A and CHEMICAL le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since CHEMICAL is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing CHEMICAL with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since CHEMICAL is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with CHEMICAL and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since CHEMICAL is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including CHEMICAL, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | CHEMICALS-INTERACTION |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since CHEMICAL is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, CHEMICAL, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since CHEMICAL is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, CHEMICAL, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since CHEMICAL is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since CHEMICAL is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | CHEMICALS-INTERACTION |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since CHEMICAL is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since CHEMICAL is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since CHEMICAL is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since CHEMICAL is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since CHEMICAL is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or CHEMICAL. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and CHEMICAL le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing CHEMICAL with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and CHEMICAL le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with CHEMICAL and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and CHEMICAL le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including CHEMICAL, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and CHEMICAL le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, CHEMICAL, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and CHEMICAL le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, CHEMICAL, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and CHEMICAL le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and CHEMICAL le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and CHEMICAL le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and CHEMICAL le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and CHEMICAL le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and CHEMICAL le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and CHEMICAL le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or CHEMICAL. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing CHEMICAL with CHEMICAL and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | CHEMICALS-INTERACTION |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing CHEMICAL with ketoconazole and other strong P450 3A inhibitors including CHEMICAL, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | CHEMICALS-INTERACTION |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing CHEMICAL with ketoconazole and other strong P450 3A inhibitors including atazanavir, CHEMICAL, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | CHEMICALS-INTERACTION |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing CHEMICAL with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, CHEMICAL, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | CHEMICALS-INTERACTION |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing CHEMICAL with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | CHEMICALS-INTERACTION |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing CHEMICAL with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | CHEMICALS-INTERACTION |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing CHEMICAL with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | CHEMICALS-INTERACTION |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing CHEMICAL with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | CHEMICALS-INTERACTION |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing CHEMICAL with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | CHEMICALS-INTERACTION |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing CHEMICAL with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | CHEMICALS-INTERACTION |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing CHEMICAL with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or CHEMICAL. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | CHEMICALS-INTERACTION |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with CHEMICAL and other strong P450 3A inhibitors including CHEMICAL, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with CHEMICAL and other strong P450 3A inhibitors including atazanavir, CHEMICAL, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with CHEMICAL and other strong P450 3A inhibitors including atazanavir, clarithromycin, CHEMICAL, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with CHEMICAL and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with CHEMICAL and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with CHEMICAL and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with CHEMICAL and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with CHEMICAL and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with CHEMICAL and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with CHEMICAL and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or CHEMICAL. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including CHEMICAL, CHEMICAL, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including CHEMICAL, clarithromycin, CHEMICAL, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including CHEMICAL, clarithromycin, indinavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including CHEMICAL, clarithromycin, indinavir, itraconazole, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including CHEMICAL, clarithromycin, indinavir, itraconazole, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including CHEMICAL, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including CHEMICAL, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including CHEMICAL, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including CHEMICAL, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or CHEMICAL. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, CHEMICAL, CHEMICAL, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, CHEMICAL, indinavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, CHEMICAL, indinavir, itraconazole, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, CHEMICAL, indinavir, itraconazole, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, CHEMICAL, indinavir, itraconazole, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, CHEMICAL, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, CHEMICAL, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, CHEMICAL, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or CHEMICAL. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, CHEMICAL, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, CHEMICAL, itraconazole, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, CHEMICAL, itraconazole, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, CHEMICAL, itraconazole, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, CHEMICAL, itraconazole, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, CHEMICAL, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, CHEMICAL, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or CHEMICAL. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, CHEMICAL, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, CHEMICAL, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, CHEMICAL, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, CHEMICAL, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or CHEMICAL. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, CHEMICAL, CHEMICAL, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, CHEMICAL, nelfinavir, CHEMICAL, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, CHEMICAL, nelfinavir, ritonavir, CHEMICAL, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, CHEMICAL, nelfinavir, ritonavir, saquinavir, CHEMICAL or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, CHEMICAL, nelfinavir, ritonavir, saquinavir, telithromycin or CHEMICAL. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, CHEMICAL, CHEMICAL, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, CHEMICAL, ritonavir, CHEMICAL, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, CHEMICAL, ritonavir, saquinavir, CHEMICAL or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, CHEMICAL, ritonavir, saquinavir, telithromycin or CHEMICAL. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, CHEMICAL, CHEMICAL, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, CHEMICAL, saquinavir, CHEMICAL or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, CHEMICAL, saquinavir, telithromycin or CHEMICAL. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, CHEMICAL, CHEMICAL or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, CHEMICAL, telithromycin or CHEMICAL. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, CHEMICAL or CHEMICAL. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | NO-RELATIONSHIP |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of CHEMICAL Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as CHEMICAL. Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules. | CHEMICALS-INTERACTION |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of CHEMICAL, such as CHEMICAL, may interfere with the absorption of Zemplar Capsules. | CHEMICALS-INTERACTION |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of CHEMICAL, such as cholestyramine, may interfere with the absorption of CHEMICAL Capsules. | CHEMICALS-INTERACTION |
| Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A. A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC0- . Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole. Drugs that impair intestinal absorption of fat-soluble vitamins, such as CHEMICAL, may interfere with the absorption of CHEMICAL Capsules. | CHEMICALS-INTERACTION |
| In vitro activity of CHEMICAL combined with CHEMICAL against clinical isolates of methicillin-resistant Staphylococcus aureus. This study aimed to evaluate the in vitro activity of minocycline combined with fosfomycin against isolates of methicillin-resistant Staphylococcus aureus (MRSA). A total of 87 clinical isolates of MRSA collected from three Chinese hospitals were included in the study. The checkerboard method with determination of the fractional IC index (FICI) was used to determine whether antibiotic combinations act synergistically against these isolates. The susceptibility results for minocycline and fosfomycin were interpreted according to the most relevant criteria. The results demonstrated the following interactions: 76 isolates (87.4%) showed synergistic interactions (FICI 0.5) and 11 isolates (12.6%) showed indifferent interactions (0.5<FICI<4). No antagonistic interactions (FICI 4) were observed. The combination of minocycline and fosfomycin can be synergistic against MRSA. Further studies are required to determine the potential clinical role of this combination regimen as a therapeutic alternative for certain types of MRSA infections. | NO-RELATIONSHIP |
| In vitro activity of CHEMICAL combined with fosfomycin against clinical isolates of CHEMICAL-resistant Staphylococcus aureus. This study aimed to evaluate the in vitro activity of minocycline combined with fosfomycin against isolates of methicillin-resistant Staphylococcus aureus (MRSA). A total of 87 clinical isolates of MRSA collected from three Chinese hospitals were included in the study. The checkerboard method with determination of the fractional IC index (FICI) was used to determine whether antibiotic combinations act synergistically against these isolates. The susceptibility results for minocycline and fosfomycin were interpreted according to the most relevant criteria. The results demonstrated the following interactions: 76 isolates (87.4%) showed synergistic interactions (FICI 0.5) and 11 isolates (12.6%) showed indifferent interactions (0.5<FICI<4). No antagonistic interactions (FICI 4) were observed. The combination of minocycline and fosfomycin can be synergistic against MRSA. Further studies are required to determine the potential clinical role of this combination regimen as a therapeutic alternative for certain types of MRSA infections. | NO-RELATIONSHIP |
| In vitro activity of minocycline combined with CHEMICAL against clinical isolates of CHEMICAL-resistant Staphylococcus aureus. This study aimed to evaluate the in vitro activity of minocycline combined with fosfomycin against isolates of methicillin-resistant Staphylococcus aureus (MRSA). A total of 87 clinical isolates of MRSA collected from three Chinese hospitals were included in the study. The checkerboard method with determination of the fractional IC index (FICI) was used to determine whether antibiotic combinations act synergistically against these isolates. The susceptibility results for minocycline and fosfomycin were interpreted according to the most relevant criteria. The results demonstrated the following interactions: 76 isolates (87.4%) showed synergistic interactions (FICI 0.5) and 11 isolates (12.6%) showed indifferent interactions (0.5<FICI<4). No antagonistic interactions (FICI 4) were observed. The combination of minocycline and fosfomycin can be synergistic against MRSA. Further studies are required to determine the potential clinical role of this combination regimen as a therapeutic alternative for certain types of MRSA infections. | NO-RELATIONSHIP |
| In vitro activity of minocycline combined with fosfomycin against clinical isolates of methicillin-resistant Staphylococcus aureus. This study aimed to evaluate the in vitro activity of CHEMICAL combined with CHEMICAL against isolates of methicillin-resistant Staphylococcus aureus (MRSA). A total of 87 clinical isolates of MRSA collected from three Chinese hospitals were included in the study. The checkerboard method with determination of the fractional IC index (FICI) was used to determine whether antibiotic combinations act synergistically against these isolates. The susceptibility results for minocycline and fosfomycin were interpreted according to the most relevant criteria. The results demonstrated the following interactions: 76 isolates (87.4%) showed synergistic interactions (FICI 0.5) and 11 isolates (12.6%) showed indifferent interactions (0.5<FICI<4). No antagonistic interactions (FICI 4) were observed. The combination of minocycline and fosfomycin can be synergistic against MRSA. Further studies are required to determine the potential clinical role of this combination regimen as a therapeutic alternative for certain types of MRSA infections. | NO-RELATIONSHIP |
| In vitro activity of minocycline combined with fosfomycin against clinical isolates of methicillin-resistant Staphylococcus aureus. This study aimed to evaluate the in vitro activity of CHEMICAL combined with fosfomycin against isolates of CHEMICAL-resistant Staphylococcus aureus (MRSA). A total of 87 clinical isolates of MRSA collected from three Chinese hospitals were included in the study. The checkerboard method with determination of the fractional IC index (FICI) was used to determine whether antibiotic combinations act synergistically against these isolates. The susceptibility results for minocycline and fosfomycin were interpreted according to the most relevant criteria. The results demonstrated the following interactions: 76 isolates (87.4%) showed synergistic interactions (FICI 0.5) and 11 isolates (12.6%) showed indifferent interactions (0.5<FICI<4). No antagonistic interactions (FICI 4) were observed. The combination of minocycline and fosfomycin can be synergistic against MRSA. Further studies are required to determine the potential clinical role of this combination regimen as a therapeutic alternative for certain types of MRSA infections. | NO-RELATIONSHIP |
| In vitro activity of minocycline combined with fosfomycin against clinical isolates of methicillin-resistant Staphylococcus aureus. This study aimed to evaluate the in vitro activity of minocycline combined with CHEMICAL against isolates of CHEMICAL-resistant Staphylococcus aureus (MRSA). A total of 87 clinical isolates of MRSA collected from three Chinese hospitals were included in the study. The checkerboard method with determination of the fractional IC index (FICI) was used to determine whether antibiotic combinations act synergistically against these isolates. The susceptibility results for minocycline and fosfomycin were interpreted according to the most relevant criteria. The results demonstrated the following interactions: 76 isolates (87.4%) showed synergistic interactions (FICI 0.5) and 11 isolates (12.6%) showed indifferent interactions (0.5<FICI<4). No antagonistic interactions (FICI 4) were observed. The combination of minocycline and fosfomycin can be synergistic against MRSA. Further studies are required to determine the potential clinical role of this combination regimen as a therapeutic alternative for certain types of MRSA infections. | NO-RELATIONSHIP |
| In vitro activity of minocycline combined with fosfomycin against clinical isolates of methicillin-resistant Staphylococcus aureus. This study aimed to evaluate the in vitro activity of minocycline combined with fosfomycin against isolates of methicillin-resistant Staphylococcus aureus (MRSA). A total of 87 clinical isolates of MRSA collected from three Chinese hospitals were included in the study. The checkerboard method with determination of the fractional IC index (FICI) was used to determine whether antibiotic combinations act synergistically against these isolates. The susceptibility results for CHEMICAL and CHEMICAL were interpreted according to the most relevant criteria. The results demonstrated the following interactions: 76 isolates (87.4%) showed synergistic interactions (FICI 0.5) and 11 isolates (12.6%) showed indifferent interactions (0.5<FICI<4). No antagonistic interactions (FICI 4) were observed. The combination of minocycline and fosfomycin can be synergistic against MRSA. Further studies are required to determine the potential clinical role of this combination regimen as a therapeutic alternative for certain types of MRSA infections. | NO-RELATIONSHIP |
| In vitro activity of minocycline combined with fosfomycin against clinical isolates of methicillin-resistant Staphylococcus aureus. This study aimed to evaluate the in vitro activity of minocycline combined with fosfomycin against isolates of methicillin-resistant Staphylococcus aureus (MRSA). A total of 87 clinical isolates of MRSA collected from three Chinese hospitals were included in the study. The checkerboard method with determination of the fractional IC index (FICI) was used to determine whether antibiotic combinations act synergistically against these isolates. The susceptibility results for minocycline and fosfomycin were interpreted according to the most relevant criteria. The results demonstrated the following interactions: 76 isolates (87.4%) showed synergistic interactions (FICI 0.5) and 11 isolates (12.6%) showed indifferent interactions (0.5<FICI<4). No antagonistic interactions (FICI 4) were observed. The combination of CHEMICAL and CHEMICAL can be synergistic against MRSA. Further studies are required to determine the potential clinical role of this combination regimen as a therapeutic alternative for certain types of MRSA infections. | CHEMICALS-INTERACTION |
| Methazolamide should be used with caution in patients on steroid therapy because of the potential for developing hypokalemia. Caution is advised for patients receiving high-dose CHEMICAL and CHEMICAL concomitantly, as anorexia, tachypnea, lethargy, coma and death have been reported with concomitant use of high-dose aspirin and carbonic anhydrase inhibitors. | CHEMICALS-INTERACTION |
| Methazolamide should be used with caution in patients on steroid therapy because of the potential for developing hypokalemia. Caution is advised for patients receiving high-dose CHEMICAL and methazolamide concomitantly, as anorexia, tachypnea, lethargy, coma and death have been reported with concomitant use of high-dose CHEMICAL and carbonic anhydrase inhibitors. | NO-RELATIONSHIP |
| Methazolamide should be used with caution in patients on steroid therapy because of the potential for developing hypokalemia. Caution is advised for patients receiving high-dose CHEMICAL and methazolamide concomitantly, as anorexia, tachypnea, lethargy, coma and death have been reported with concomitant use of high-dose aspirin and CHEMICAL. | NO-RELATIONSHIP |
| Methazolamide should be used with caution in patients on steroid therapy because of the potential for developing hypokalemia. Caution is advised for patients receiving high-dose aspirin and CHEMICAL concomitantly, as anorexia, tachypnea, lethargy, coma and death have been reported with concomitant use of high-dose CHEMICAL and carbonic anhydrase inhibitors. | NO-RELATIONSHIP |
| Methazolamide should be used with caution in patients on steroid therapy because of the potential for developing hypokalemia. Caution is advised for patients receiving high-dose aspirin and CHEMICAL concomitantly, as anorexia, tachypnea, lethargy, coma and death have been reported with concomitant use of high-dose aspirin and CHEMICAL. | NO-RELATIONSHIP |
| Methazolamide should be used with caution in patients on steroid therapy because of the potential for developing hypokalemia. Caution is advised for patients receiving high-dose aspirin and methazolamide concomitantly, as anorexia, tachypnea, lethargy, coma and death have been reported with concomitant use of high-dose CHEMICAL and CHEMICAL. | CHEMICALS-INTERACTION |
| CHEMICAL enhances CHEMICAL-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. Although it was previously reported that lapatinib combined with Herceptin improved the progression-free survival rate compared with lapatinib alone for patients with Herceptin-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. We evaluated how lapatinib interacts with Herceptin in HER2-positive breast cancer, with a particular focus on Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC). In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. Lapatinib may have the potential to convert Herceptin-refractory to Herceptin-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2. | CHEMICALS-INTERACTION |
| Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. Although it was previously reported that CHEMICAL combined with CHEMICAL improved the progression-free survival rate compared with lapatinib alone for patients with Herceptin-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. We evaluated how lapatinib interacts with Herceptin in HER2-positive breast cancer, with a particular focus on Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC). In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. Lapatinib may have the potential to convert Herceptin-refractory to Herceptin-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2. | CHEMICALS-INTERACTION |
| Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. Although it was previously reported that CHEMICAL combined with Herceptin improved the progression-free survival rate compared with CHEMICAL alone for patients with Herceptin-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. We evaluated how lapatinib interacts with Herceptin in HER2-positive breast cancer, with a particular focus on Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC). In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. Lapatinib may have the potential to convert Herceptin-refractory to Herceptin-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2. | NO-RELATIONSHIP |
| Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. Although it was previously reported that CHEMICAL combined with Herceptin improved the progression-free survival rate compared with lapatinib alone for patients with CHEMICAL-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. We evaluated how lapatinib interacts with Herceptin in HER2-positive breast cancer, with a particular focus on Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC). In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. Lapatinib may have the potential to convert Herceptin-refractory to Herceptin-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2. | NO-RELATIONSHIP |
| Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. Although it was previously reported that lapatinib combined with CHEMICAL improved the progression-free survival rate compared with CHEMICAL alone for patients with Herceptin-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. We evaluated how lapatinib interacts with Herceptin in HER2-positive breast cancer, with a particular focus on Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC). In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. Lapatinib may have the potential to convert Herceptin-refractory to Herceptin-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2. | NO-RELATIONSHIP |
| Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. Although it was previously reported that lapatinib combined with CHEMICAL improved the progression-free survival rate compared with lapatinib alone for patients with CHEMICAL-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. We evaluated how lapatinib interacts with Herceptin in HER2-positive breast cancer, with a particular focus on Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC). In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. Lapatinib may have the potential to convert Herceptin-refractory to Herceptin-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2. | NO-RELATIONSHIP |
| Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. Although it was previously reported that lapatinib combined with Herceptin improved the progression-free survival rate compared with CHEMICAL alone for patients with CHEMICAL-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. We evaluated how lapatinib interacts with Herceptin in HER2-positive breast cancer, with a particular focus on Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC). In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. Lapatinib may have the potential to convert Herceptin-refractory to Herceptin-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2. | NO-RELATIONSHIP |
| Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. Although it was previously reported that lapatinib combined with Herceptin improved the progression-free survival rate compared with lapatinib alone for patients with Herceptin-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. We evaluated how CHEMICAL interacts with CHEMICAL in HER2-positive breast cancer, with a particular focus on Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC). In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. Lapatinib may have the potential to convert Herceptin-refractory to Herceptin-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2. | DIRECT-REGULATOR |
| Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. Although it was previously reported that lapatinib combined with Herceptin improved the progression-free survival rate compared with lapatinib alone for patients with Herceptin-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. We evaluated how CHEMICAL interacts with Herceptin in HER2-positive breast cancer, with a particular focus on CHEMICAL-mediated antibody-dependent cellular cytotoxicity (ADCC). In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. Lapatinib may have the potential to convert Herceptin-refractory to Herceptin-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2. | REGULATOR |
| Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. Although it was previously reported that lapatinib combined with Herceptin improved the progression-free survival rate compared with lapatinib alone for patients with Herceptin-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. We evaluated how lapatinib interacts with CHEMICAL in HER2-positive breast cancer, with a particular focus on CHEMICAL-mediated antibody-dependent cellular cytotoxicity (ADCC). In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. Lapatinib may have the potential to convert Herceptin-refractory to Herceptin-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2. | REGULATOR |
| Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. Although it was previously reported that lapatinib combined with Herceptin improved the progression-free survival rate compared with lapatinib alone for patients with Herceptin-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. We evaluated how lapatinib interacts with Herceptin in HER2-positive breast cancer, with a particular focus on Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC). In an in vitro assay, CHEMICAL induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of CHEMICAL-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. Lapatinib may have the potential to convert Herceptin-refractory to Herceptin-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2. | REGULATOR |
| Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. Although it was previously reported that lapatinib combined with Herceptin improved the progression-free survival rate compared with lapatinib alone for patients with Herceptin-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. We evaluated how lapatinib interacts with Herceptin in HER2-positive breast cancer, with a particular focus on Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC). In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second CHEMICAL treatment following CHEMICAL resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. Lapatinib may have the potential to convert Herceptin-refractory to Herceptin-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2. | CHEMICALS-INTERACTION |
| Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. Although it was previously reported that lapatinib combined with Herceptin improved the progression-free survival rate compared with lapatinib alone for patients with Herceptin-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. We evaluated how lapatinib interacts with Herceptin in HER2-positive breast cancer, with a particular focus on Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC). In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. CHEMICAL may have the potential to convert CHEMICAL-refractory to Herceptin-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2. | CHEMICALS-INTERACTION |
| Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. Although it was previously reported that lapatinib combined with Herceptin improved the progression-free survival rate compared with lapatinib alone for patients with Herceptin-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. We evaluated how lapatinib interacts with Herceptin in HER2-positive breast cancer, with a particular focus on Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC). In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. CHEMICAL may have the potential to convert Herceptin-refractory to CHEMICAL-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2. | NO-RELATIONSHIP |
| Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression. Although it was previously reported that lapatinib combined with Herceptin improved the progression-free survival rate compared with lapatinib alone for patients with Herceptin-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. We evaluated how lapatinib interacts with Herceptin in HER2-positive breast cancer, with a particular focus on Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC). In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. Lapatinib may have the potential to convert CHEMICAL-refractory to CHEMICAL-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2. | NO-RELATIONSHIP |
| Influence of CHEMICAL on CHEMICAL induced antinociception and its pharmacokinetics. Piperine (CAS 94-62-2), an alkaloid obtained from Piper nigrum and P. longum, is a known inhibitor of various enzymes (CYP isozymes) responsible for biotransformation of drugs. By inhibiting the metabolism of drugs, piperine improves the bioavailability of drugs. In the present study piperine (10 mg/kg) significantly increased the dose-dependent antinociceptive activity of ibuprofen evaluated by both acetic acid writhing and formalin test, when it was administered with ibuprofen. Ibuprofen plasma concentration was also increased when it was administered with piperine. The synergistic antinociception activity of ibuprofen when administered with piperine can be attributed to increased plasma concentration of ibuprofen. From this study it can be concluded that piperine can be used as a bioenhancer along with ibuprofen. | NO-RELATIONSHIP |
| Influence of piperine on ibuprofen induced antinociception and its pharmacokinetics. Piperine (CAS 94-62-2), an alkaloid obtained from Piper nigrum and P. longum, is a known inhibitor of various enzymes (CYP isozymes) responsible for biotransformation of drugs. By inhibiting the metabolism of drugs, piperine improves the bioavailability of drugs. In the present study CHEMICAL (10 mg/kg) significantly increased the dose-dependent antinociceptive activity of CHEMICAL evaluated by both acetic acid writhing and formalin test, when it was administered with ibuprofen. Ibuprofen plasma concentration was also increased when it was administered with piperine. The synergistic antinociception activity of ibuprofen when administered with piperine can be attributed to increased plasma concentration of ibuprofen. From this study it can be concluded that piperine can be used as a bioenhancer along with ibuprofen. | CHEMICALS-INTERACTION |
| Influence of piperine on ibuprofen induced antinociception and its pharmacokinetics. Piperine (CAS 94-62-2), an alkaloid obtained from Piper nigrum and P. longum, is a known inhibitor of various enzymes (CYP isozymes) responsible for biotransformation of drugs. By inhibiting the metabolism of drugs, piperine improves the bioavailability of drugs. In the present study CHEMICAL (10 mg/kg) significantly increased the dose-dependent antinociceptive activity of ibuprofen evaluated by both CHEMICAL writhing and formalin test, when it was administered with ibuprofen. Ibuprofen plasma concentration was also increased when it was administered with piperine. The synergistic antinociception activity of ibuprofen when administered with piperine can be attributed to increased plasma concentration of ibuprofen. From this study it can be concluded that piperine can be used as a bioenhancer along with ibuprofen. | NO-RELATIONSHIP |
| Influence of piperine on ibuprofen induced antinociception and its pharmacokinetics. Piperine (CAS 94-62-2), an alkaloid obtained from Piper nigrum and P. longum, is a known inhibitor of various enzymes (CYP isozymes) responsible for biotransformation of drugs. By inhibiting the metabolism of drugs, piperine improves the bioavailability of drugs. In the present study CHEMICAL (10 mg/kg) significantly increased the dose-dependent antinociceptive activity of ibuprofen evaluated by both acetic acid writhing and formalin test, when it was administered with CHEMICAL. Ibuprofen plasma concentration was also increased when it was administered with piperine. The synergistic antinociception activity of ibuprofen when administered with piperine can be attributed to increased plasma concentration of ibuprofen. From this study it can be concluded that piperine can be used as a bioenhancer along with ibuprofen. | NO-RELATIONSHIP |
| Influence of piperine on ibuprofen induced antinociception and its pharmacokinetics. Piperine (CAS 94-62-2), an alkaloid obtained from Piper nigrum and P. longum, is a known inhibitor of various enzymes (CYP isozymes) responsible for biotransformation of drugs. By inhibiting the metabolism of drugs, piperine improves the bioavailability of drugs. In the present study piperine (10 mg/kg) significantly increased the dose-dependent antinociceptive activity of CHEMICAL evaluated by both CHEMICAL writhing and formalin test, when it was administered with ibuprofen. Ibuprofen plasma concentration was also increased when it was administered with piperine. The synergistic antinociception activity of ibuprofen when administered with piperine can be attributed to increased plasma concentration of ibuprofen. From this study it can be concluded that piperine can be used as a bioenhancer along with ibuprofen. | NO-RELATIONSHIP |
| Influence of piperine on ibuprofen induced antinociception and its pharmacokinetics. Piperine (CAS 94-62-2), an alkaloid obtained from Piper nigrum and P. longum, is a known inhibitor of various enzymes (CYP isozymes) responsible for biotransformation of drugs. By inhibiting the metabolism of drugs, piperine improves the bioavailability of drugs. In the present study piperine (10 mg/kg) significantly increased the dose-dependent antinociceptive activity of CHEMICAL evaluated by both acetic acid writhing and formalin test, when it was administered with CHEMICAL. Ibuprofen plasma concentration was also increased when it was administered with piperine. The synergistic antinociception activity of ibuprofen when administered with piperine can be attributed to increased plasma concentration of ibuprofen. From this study it can be concluded that piperine can be used as a bioenhancer along with ibuprofen. | NO-RELATIONSHIP |
| Influence of piperine on ibuprofen induced antinociception and its pharmacokinetics. Piperine (CAS 94-62-2), an alkaloid obtained from Piper nigrum and P. longum, is a known inhibitor of various enzymes (CYP isozymes) responsible for biotransformation of drugs. By inhibiting the metabolism of drugs, piperine improves the bioavailability of drugs. In the present study piperine (10 mg/kg) significantly increased the dose-dependent antinociceptive activity of ibuprofen evaluated by both CHEMICAL writhing and formalin test, when it was administered with CHEMICAL. Ibuprofen plasma concentration was also increased when it was administered with piperine. The synergistic antinociception activity of ibuprofen when administered with piperine can be attributed to increased plasma concentration of ibuprofen. From this study it can be concluded that piperine can be used as a bioenhancer along with ibuprofen. | NO-RELATIONSHIP |
| Influence of piperine on ibuprofen induced antinociception and its pharmacokinetics. Piperine (CAS 94-62-2), an alkaloid obtained from Piper nigrum and P. longum, is a known inhibitor of various enzymes (CYP isozymes) responsible for biotransformation of drugs. By inhibiting the metabolism of drugs, piperine improves the bioavailability of drugs. In the present study piperine (10 mg/kg) significantly increased the dose-dependent antinociceptive activity of ibuprofen evaluated by both acetic acid writhing and formalin test, when it was administered with ibuprofen. CHEMICAL plasma concentration was also increased when it was administered with CHEMICAL. The synergistic antinociception activity of ibuprofen when administered with piperine can be attributed to increased plasma concentration of ibuprofen. From this study it can be concluded that piperine can be used as a bioenhancer along with ibuprofen. | CHEMICALS-INTERACTION |
| Influence of piperine on ibuprofen induced antinociception and its pharmacokinetics. Piperine (CAS 94-62-2), an alkaloid obtained from Piper nigrum and P. longum, is a known inhibitor of various enzymes (CYP isozymes) responsible for biotransformation of drugs. By inhibiting the metabolism of drugs, piperine improves the bioavailability of drugs. In the present study piperine (10 mg/kg) significantly increased the dose-dependent antinociceptive activity of ibuprofen evaluated by both acetic acid writhing and formalin test, when it was administered with ibuprofen. Ibuprofen plasma concentration was also increased when it was administered with piperine. The synergistic antinociception activity of CHEMICAL when administered with CHEMICAL can be attributed to increased plasma concentration of ibuprofen. From this study it can be concluded that piperine can be used as a bioenhancer along with ibuprofen. | CHEMICALS-INTERACTION |
| Influence of piperine on ibuprofen induced antinociception and its pharmacokinetics. Piperine (CAS 94-62-2), an alkaloid obtained from Piper nigrum and P. longum, is a known inhibitor of various enzymes (CYP isozymes) responsible for biotransformation of drugs. By inhibiting the metabolism of drugs, piperine improves the bioavailability of drugs. In the present study piperine (10 mg/kg) significantly increased the dose-dependent antinociceptive activity of ibuprofen evaluated by both acetic acid writhing and formalin test, when it was administered with ibuprofen. Ibuprofen plasma concentration was also increased when it was administered with piperine. The synergistic antinociception activity of CHEMICAL when administered with piperine can be attributed to increased plasma concentration of CHEMICAL. From this study it can be concluded that piperine can be used as a bioenhancer along with ibuprofen. | NO-RELATIONSHIP |
| Influence of piperine on ibuprofen induced antinociception and its pharmacokinetics. Piperine (CAS 94-62-2), an alkaloid obtained from Piper nigrum and P. longum, is a known inhibitor of various enzymes (CYP isozymes) responsible for biotransformation of drugs. By inhibiting the metabolism of drugs, piperine improves the bioavailability of drugs. In the present study piperine (10 mg/kg) significantly increased the dose-dependent antinociceptive activity of ibuprofen evaluated by both acetic acid writhing and formalin test, when it was administered with ibuprofen. Ibuprofen plasma concentration was also increased when it was administered with piperine. The synergistic antinociception activity of ibuprofen when administered with CHEMICAL can be attributed to increased plasma concentration of CHEMICAL. From this study it can be concluded that piperine can be used as a bioenhancer along with ibuprofen. | NO-RELATIONSHIP |
| Influence of piperine on ibuprofen induced antinociception and its pharmacokinetics. Piperine (CAS 94-62-2), an alkaloid obtained from Piper nigrum and P. longum, is a known inhibitor of various enzymes (CYP isozymes) responsible for biotransformation of drugs. By inhibiting the metabolism of drugs, piperine improves the bioavailability of drugs. In the present study piperine (10 mg/kg) significantly increased the dose-dependent antinociceptive activity of ibuprofen evaluated by both acetic acid writhing and formalin test, when it was administered with ibuprofen. Ibuprofen plasma concentration was also increased when it was administered with piperine. The synergistic antinociception activity of ibuprofen when administered with piperine can be attributed to increased plasma concentration of ibuprofen. From this study it can be concluded that CHEMICAL can be used as a bioenhancer along with CHEMICAL. | CHEMICALS-INTERACTION |
| Drug-Drug Interactions: The pharmacokinetic and pharmacodynamic interactions between CHEMICAL capsules and other CHEMICAL have not been determined. However, interactions may be expected and FLOMAX capsules should NOT be used in combination with other alpha-adrenergic blocking agents. The pharmacokinetic interaction between cimetidine and FLOMAX capsules was investigated. The results indicate significant changes in tamsulosin HCI clearance (26% decrease) and AUC (44% increase). Therefore, FLOMAX capsules should be used with caution in combination with cimetidine, particularly at doses higher than 0.4 mg. Results from limited in vitro and in vivo drug-drug interaction studies between tamsulosin HCI and warfarin are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and FLOMAX capsules. | NO-RELATIONSHIP |
| Drug-Drug Interactions: The pharmacokinetic and pharmacodynamic interactions between FLOMAX capsules and other alpha-adrenergic blocking agents have not been determined. However, interactions may be expected and CHEMICAL capsules should NOT be used in combination with other CHEMICAL. The pharmacokinetic interaction between cimetidine and FLOMAX capsules was investigated. The results indicate significant changes in tamsulosin HCI clearance (26% decrease) and AUC (44% increase). Therefore, FLOMAX capsules should be used with caution in combination with cimetidine, particularly at doses higher than 0.4 mg. Results from limited in vitro and in vivo drug-drug interaction studies between tamsulosin HCI and warfarin are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and FLOMAX capsules. | CHEMICALS-INTERACTION |
| Drug-Drug Interactions: The pharmacokinetic and pharmacodynamic interactions between FLOMAX capsules and other alpha-adrenergic blocking agents have not been determined. However, interactions may be expected and FLOMAX capsules should NOT be used in combination with other alpha-adrenergic blocking agents. The pharmacokinetic interaction between CHEMICAL and CHEMICAL capsules was investigated. The results indicate significant changes in tamsulosin HCI clearance (26% decrease) and AUC (44% increase). Therefore, FLOMAX capsules should be used with caution in combination with cimetidine, particularly at doses higher than 0.4 mg. Results from limited in vitro and in vivo drug-drug interaction studies between tamsulosin HCI and warfarin are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and FLOMAX capsules. | NO-RELATIONSHIP |
| Drug-Drug Interactions: The pharmacokinetic and pharmacodynamic interactions between FLOMAX capsules and other alpha-adrenergic blocking agents have not been determined. However, interactions may be expected and FLOMAX capsules should NOT be used in combination with other alpha-adrenergic blocking agents. The pharmacokinetic interaction between cimetidine and FLOMAX capsules was investigated. The results indicate significant changes in tamsulosin HCI clearance (26% decrease) and AUC (44% increase). Therefore, CHEMICAL capsules should be used with caution in combination with CHEMICAL, particularly at doses higher than 0.4 mg. Results from limited in vitro and in vivo drug-drug interaction studies between tamsulosin HCI and warfarin are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and FLOMAX capsules. | CHEMICALS-INTERACTION |
| Drug-Drug Interactions: The pharmacokinetic and pharmacodynamic interactions between FLOMAX capsules and other alpha-adrenergic blocking agents have not been determined. However, interactions may be expected and FLOMAX capsules should NOT be used in combination with other alpha-adrenergic blocking agents. The pharmacokinetic interaction between cimetidine and FLOMAX capsules was investigated. The results indicate significant changes in tamsulosin HCI clearance (26% decrease) and AUC (44% increase). Therefore, FLOMAX capsules should be used with caution in combination with cimetidine, particularly at doses higher than 0.4 mg. Results from limited in vitro and in vivo drug-drug interaction studies between CHEMICAL and CHEMICAL are inconclusive. Therefore, caution should be exercised with concomitant administration of warfarin and FLOMAX capsules. | NO-RELATIONSHIP |
| Drug-Drug Interactions: The pharmacokinetic and pharmacodynamic interactions between FLOMAX capsules and other alpha-adrenergic blocking agents have not been determined. However, interactions may be expected and FLOMAX capsules should NOT be used in combination with other alpha-adrenergic blocking agents. The pharmacokinetic interaction between cimetidine and FLOMAX capsules was investigated. The results indicate significant changes in tamsulosin HCI clearance (26% decrease) and AUC (44% increase). Therefore, FLOMAX capsules should be used with caution in combination with cimetidine, particularly at doses higher than 0.4 mg. Results from limited in vitro and in vivo drug-drug interaction studies between tamsulosin HCI and warfarin are inconclusive. Therefore, caution should be exercised with concomitant administration of CHEMICAL and CHEMICAL capsules. | CHEMICALS-INTERACTION |
| Excessive glucocorticoid therapy will inhibit the growth-promoting effect of human GH. Patients with ACTH deficiency should have their glucocorticoid-replacement dose carefully adjusted to avoid an inhibitory effect on growth. The use of Nutropin in patients with chronic renal insufficiency receiving glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth-promoting effect of Nutropin. If CHEMICAL replacement is required, the CHEMICAL dose should be carefully adjusted. There was no evidence in the controlled studies of Nutropin s interaction with drugs commonly used in chronic renal insufficiency patients. Limited published data indicate that GH treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that GH administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporin). Careful monitoring is advisable when GH is administered in combination with other drugs known to be metabolized by CP450 liver enzymes. | NO-RELATIONSHIP |
| Excessive glucocorticoid therapy will inhibit the growth-promoting effect of human GH. Patients with ACTH deficiency should have their glucocorticoid-replacement dose carefully adjusted to avoid an inhibitory effect on growth. The use of Nutropin in patients with chronic renal insufficiency receiving glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth-promoting effect of Nutropin. If glucocorticoid replacement is required, the glucocorticoid dose should be carefully adjusted. There was no evidence in the controlled studies of Nutropin s interaction with drugs commonly used in chronic renal insufficiency patients. Limited published data indicate that CHEMICAL treatment increases cytochrome P450 (CP450) mediated CHEMICAL clearance in man. These data suggest that GH administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporin). Careful monitoring is advisable when GH is administered in combination with other drugs known to be metabolized by CP450 liver enzymes. | CHEMICALS-INTERACTION |
| Excessive glucocorticoid therapy will inhibit the growth-promoting effect of human GH. Patients with ACTH deficiency should have their glucocorticoid-replacement dose carefully adjusted to avoid an inhibitory effect on growth. The use of Nutropin in patients with chronic renal insufficiency receiving glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth-promoting effect of Nutropin. If glucocorticoid replacement is required, the glucocorticoid dose should be carefully adjusted. There was no evidence in the controlled studies of Nutropin s interaction with drugs commonly used in chronic renal insufficiency patients. Limited published data indicate that GH treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that CHEMICAL administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g., CHEMICAL, sex steroids, anticonvulsants, cyclosporin). Careful monitoring is advisable when GH is administered in combination with other drugs known to be metabolized by CP450 liver enzymes. | CHEMICALS-INTERACTION |
| Excessive glucocorticoid therapy will inhibit the growth-promoting effect of human GH. Patients with ACTH deficiency should have their glucocorticoid-replacement dose carefully adjusted to avoid an inhibitory effect on growth. The use of Nutropin in patients with chronic renal insufficiency receiving glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth-promoting effect of Nutropin. If glucocorticoid replacement is required, the glucocorticoid dose should be carefully adjusted. There was no evidence in the controlled studies of Nutropin s interaction with drugs commonly used in chronic renal insufficiency patients. Limited published data indicate that GH treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that CHEMICAL administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g., corticosteroids, CHEMICAL, anticonvulsants, cyclosporin). Careful monitoring is advisable when GH is administered in combination with other drugs known to be metabolized by CP450 liver enzymes. | CHEMICALS-INTERACTION |
| Excessive glucocorticoid therapy will inhibit the growth-promoting effect of human GH. Patients with ACTH deficiency should have their glucocorticoid-replacement dose carefully adjusted to avoid an inhibitory effect on growth. The use of Nutropin in patients with chronic renal insufficiency receiving glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth-promoting effect of Nutropin. If glucocorticoid replacement is required, the glucocorticoid dose should be carefully adjusted. There was no evidence in the controlled studies of Nutropin s interaction with drugs commonly used in chronic renal insufficiency patients. Limited published data indicate that GH treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that CHEMICAL administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g., corticosteroids, sex steroids, CHEMICAL, cyclosporin). Careful monitoring is advisable when GH is administered in combination with other drugs known to be metabolized by CP450 liver enzymes. | CHEMICALS-INTERACTION |
| Excessive glucocorticoid therapy will inhibit the growth-promoting effect of human GH. Patients with ACTH deficiency should have their glucocorticoid-replacement dose carefully adjusted to avoid an inhibitory effect on growth. The use of Nutropin in patients with chronic renal insufficiency receiving glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth-promoting effect of Nutropin. If glucocorticoid replacement is required, the glucocorticoid dose should be carefully adjusted. There was no evidence in the controlled studies of Nutropin s interaction with drugs commonly used in chronic renal insufficiency patients. Limited published data indicate that GH treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that CHEMICAL administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, CHEMICAL). Careful monitoring is advisable when GH is administered in combination with other drugs known to be metabolized by CP450 liver enzymes. | CHEMICALS-INTERACTION |
| Excessive glucocorticoid therapy will inhibit the growth-promoting effect of human GH. Patients with ACTH deficiency should have their glucocorticoid-replacement dose carefully adjusted to avoid an inhibitory effect on growth. The use of Nutropin in patients with chronic renal insufficiency receiving glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth-promoting effect of Nutropin. If glucocorticoid replacement is required, the glucocorticoid dose should be carefully adjusted. There was no evidence in the controlled studies of Nutropin s interaction with drugs commonly used in chronic renal insufficiency patients. Limited published data indicate that GH treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that GH administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g., CHEMICAL, CHEMICAL, anticonvulsants, cyclosporin). Careful monitoring is advisable when GH is administered in combination with other drugs known to be metabolized by CP450 liver enzymes. | NO-RELATIONSHIP |
| Excessive glucocorticoid therapy will inhibit the growth-promoting effect of human GH. Patients with ACTH deficiency should have their glucocorticoid-replacement dose carefully adjusted to avoid an inhibitory effect on growth. The use of Nutropin in patients with chronic renal insufficiency receiving glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth-promoting effect of Nutropin. If glucocorticoid replacement is required, the glucocorticoid dose should be carefully adjusted. There was no evidence in the controlled studies of Nutropin s interaction with drugs commonly used in chronic renal insufficiency patients. Limited published data indicate that GH treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that GH administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g., CHEMICAL, sex steroids, CHEMICAL, cyclosporin). Careful monitoring is advisable when GH is administered in combination with other drugs known to be metabolized by CP450 liver enzymes. | NO-RELATIONSHIP |
| Excessive glucocorticoid therapy will inhibit the growth-promoting effect of human GH. Patients with ACTH deficiency should have their glucocorticoid-replacement dose carefully adjusted to avoid an inhibitory effect on growth. The use of Nutropin in patients with chronic renal insufficiency receiving glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth-promoting effect of Nutropin. If glucocorticoid replacement is required, the glucocorticoid dose should be carefully adjusted. There was no evidence in the controlled studies of Nutropin s interaction with drugs commonly used in chronic renal insufficiency patients. Limited published data indicate that GH treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that GH administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g., CHEMICAL, sex steroids, anticonvulsants, CHEMICAL). Careful monitoring is advisable when GH is administered in combination with other drugs known to be metabolized by CP450 liver enzymes. | NO-RELATIONSHIP |
| Excessive glucocorticoid therapy will inhibit the growth-promoting effect of human GH. Patients with ACTH deficiency should have their glucocorticoid-replacement dose carefully adjusted to avoid an inhibitory effect on growth. The use of Nutropin in patients with chronic renal insufficiency receiving glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth-promoting effect of Nutropin. If glucocorticoid replacement is required, the glucocorticoid dose should be carefully adjusted. There was no evidence in the controlled studies of Nutropin s interaction with drugs commonly used in chronic renal insufficiency patients. Limited published data indicate that GH treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that GH administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g., corticosteroids, CHEMICAL, CHEMICAL, cyclosporin). Careful monitoring is advisable when GH is administered in combination with other drugs known to be metabolized by CP450 liver enzymes. | NO-RELATIONSHIP |
| Excessive glucocorticoid therapy will inhibit the growth-promoting effect of human GH. Patients with ACTH deficiency should have their glucocorticoid-replacement dose carefully adjusted to avoid an inhibitory effect on growth. The use of Nutropin in patients with chronic renal insufficiency receiving glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth-promoting effect of Nutropin. If glucocorticoid replacement is required, the glucocorticoid dose should be carefully adjusted. There was no evidence in the controlled studies of Nutropin s interaction with drugs commonly used in chronic renal insufficiency patients. Limited published data indicate that GH treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that GH administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g., corticosteroids, CHEMICAL, anticonvulsants, CHEMICAL). Careful monitoring is advisable when GH is administered in combination with other drugs known to be metabolized by CP450 liver enzymes. | NO-RELATIONSHIP |
| Excessive glucocorticoid therapy will inhibit the growth-promoting effect of human GH. Patients with ACTH deficiency should have their glucocorticoid-replacement dose carefully adjusted to avoid an inhibitory effect on growth. The use of Nutropin in patients with chronic renal insufficiency receiving glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth-promoting effect of Nutropin. If glucocorticoid replacement is required, the glucocorticoid dose should be carefully adjusted. There was no evidence in the controlled studies of Nutropin s interaction with drugs commonly used in chronic renal insufficiency patients. Limited published data indicate that GH treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that GH administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g., corticosteroids, sex steroids, CHEMICAL, CHEMICAL). Careful monitoring is advisable when GH is administered in combination with other drugs known to be metabolized by CP450 liver enzymes. | NO-RELATIONSHIP |
| The CNS depressant effects of CHEMICAL may be additive with that of other CHEMICAL.. | CHEMICALS-INTERACTION |
| Use with Other CHEMICAL: The depressant effects of CHEMICAL are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other CHEMICAL: The depressant effects of morphine are potentiated by the presence of other CHEMICAL such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other CHEMICAL: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as CHEMICAL, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other CHEMICAL: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, CHEMICAL, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other CHEMICAL: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, CHEMICAL, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other CHEMICAL: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or CHEMICAL. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of CHEMICAL are potentiated by the presence of other CHEMICAL such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | CHEMICALS-INTERACTION |
| Use with Other Central Nervous System Depressants: The depressant effects of CHEMICAL are potentiated by the presence of other CNS depressants such as CHEMICAL, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | CHEMICALS-INTERACTION |
| Use with Other Central Nervous System Depressants: The depressant effects of CHEMICAL are potentiated by the presence of other CNS depressants such as alcohol, CHEMICAL, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | CHEMICALS-INTERACTION |
| Use with Other Central Nervous System Depressants: The depressant effects of CHEMICAL are potentiated by the presence of other CNS depressants such as alcohol, sedatives, CHEMICAL, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | CHEMICALS-INTERACTION |
| Use with Other Central Nervous System Depressants: The depressant effects of CHEMICAL are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or CHEMICAL. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | CHEMICALS-INTERACTION |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CHEMICAL such as CHEMICAL, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CHEMICAL such as alcohol, CHEMICAL, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CHEMICAL such as alcohol, sedatives, CHEMICAL, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CHEMICAL such as alcohol, sedatives, antihistaminics, or CHEMICAL. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as CHEMICAL, CHEMICAL, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as CHEMICAL, sedatives, CHEMICAL, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as CHEMICAL, sedatives, antihistaminics, or CHEMICAL. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, CHEMICAL, CHEMICAL, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, CHEMICAL, antihistaminics, or CHEMICAL. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, CHEMICAL, or CHEMICAL. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of CHEMICAL in conjunction with oral CHEMICAL may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | CHEMICALS-INTERACTION |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with CHEMICAL: CHEMICAL (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with CHEMICAL: Agonist/antagonist analgesics (i.e., CHEMICAL, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with CHEMICAL: Agonist/antagonist analgesics (i.e., pentazocine, CHEMICAL, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with CHEMICAL: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, CHEMICAL, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with CHEMICAL: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or CHEMICAL) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with CHEMICAL: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof CHEMICAL. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: CHEMICAL (i.e., CHEMICAL, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: CHEMICAL (i.e., pentazocine, CHEMICAL, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: CHEMICAL (i.e., pentazocine, nalbuphine, CHEMICAL, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: CHEMICAL (i.e., pentazocine, nalbuphine, butorphanol, or CHEMICAL) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: CHEMICAL (i.e., pentazocine, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof CHEMICAL. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | CHEMICALS-INTERACTION |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., CHEMICAL, CHEMICAL, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., CHEMICAL, nalbuphine, CHEMICAL, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., CHEMICAL, nalbuphine, butorphanol, or CHEMICAL) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., CHEMICAL, nalbuphine, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof CHEMICAL. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | CHEMICALS-INTERACTION |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, CHEMICAL, CHEMICAL, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, CHEMICAL, butorphanol, or CHEMICAL) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, CHEMICAL, butorphanol, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof CHEMICAL. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | CHEMICALS-INTERACTION |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, CHEMICAL, or CHEMICAL) should NOT be administered to patients who have received or are receiving a course of therapy with a proof opioid agonist analgesic. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | NO-RELATIONSHIP |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, CHEMICAL, or buprenorphine) should NOT be administered to patients who have received or are receiving a course of therapy with a proof CHEMICAL. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | CHEMICALS-INTERACTION |
| Use with Other Central Nervous System Depressants: The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistaminics, or psychotropic drugs. Use of neuroleptics in conjunction with oral morphine may increase the risk of respiratory depression, hypotension and profound sedation or coma. Interaction with Mixed Agonist/Antagonist Opioid Analgesics: Agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, butorphanol, or CHEMICAL) should NOT be administered to patients who have received or are receiving a course of therapy with a proof CHEMICAL. In these patients, the mixed agonist/antagonist may alter the analgesic effect or may precipitate withdrawal symptoms. | CHEMICALS-INTERACTION |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of CHEMICAL-containing or CHEMICAL (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of CHEMICAL-containing or ergot-type medications (like CHEMICAL or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of CHEMICAL-containing or ergot-type medications (like dihydroergotamine or CHEMICAL) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of CHEMICAL-containing or ergot-type medications (like dihydroergotamine or methysergide) and CHEMICAL within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | CHEMICALS-INTERACTION |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or CHEMICAL (like CHEMICAL or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or CHEMICAL (like dihydroergotamine or CHEMICAL) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or CHEMICAL (like dihydroergotamine or methysergide) and CHEMICAL within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | CHEMICALS-INTERACTION |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like CHEMICAL or CHEMICAL) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like CHEMICAL or methysergide) and CHEMICAL within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | CHEMICALS-INTERACTION |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or CHEMICAL) and CHEMICAL within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | CHEMICALS-INTERACTION |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. CHEMICAL reduce CHEMICAL clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | CHEMICALS-INTERACTION |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of CHEMICAL tablets in patients receiving CHEMICAL is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | CHEMICALS-INTERACTION |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of CHEMICAL tablets in patients receiving MAO-A inhibitors is contraindicated . CHEMICAL (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of CHEMICAL tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (CHEMICAL) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of CHEMICAL tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., CHEMICAL, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of CHEMICAL tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, CHEMICAL, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of CHEMICAL tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, CHEMICAL, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of CHEMICAL tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, CHEMICAL) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of CHEMICAL tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with CHEMICAL. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving CHEMICAL is contraindicated . CHEMICAL (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving CHEMICAL is contraindicated . Selective serotonin reuptake inhibitors (CHEMICAL) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving CHEMICAL is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., CHEMICAL, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving CHEMICAL is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, CHEMICAL, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving CHEMICAL is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, CHEMICAL, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving CHEMICAL is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, CHEMICAL) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving CHEMICAL is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with CHEMICAL. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . CHEMICAL (CHEMICAL) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . CHEMICAL (SSRIs) (e.g., CHEMICAL, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . CHEMICAL (SSRIs) (e.g., fluoxetine, CHEMICAL, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . CHEMICAL (SSRIs) (e.g., fluoxetine, fluvoxamine, CHEMICAL, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . CHEMICAL (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, CHEMICAL) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . CHEMICAL (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with CHEMICAL. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | CHEMICALS-INTERACTION |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (CHEMICAL) (e.g., CHEMICAL, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (CHEMICAL) (e.g., fluoxetine, CHEMICAL, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (CHEMICAL) (e.g., fluoxetine, fluvoxamine, CHEMICAL, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (CHEMICAL) (e.g., fluoxetine, fluvoxamine, paroxetine, CHEMICAL) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (CHEMICAL) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with CHEMICAL. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | CHEMICALS-INTERACTION |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., CHEMICAL, CHEMICAL, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., CHEMICAL, fluvoxamine, CHEMICAL, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., CHEMICAL, fluvoxamine, paroxetine, CHEMICAL) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., CHEMICAL, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with CHEMICAL. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | CHEMICALS-INTERACTION |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, CHEMICAL, CHEMICAL, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, CHEMICAL, paroxetine, CHEMICAL) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, CHEMICAL, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with CHEMICAL. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | CHEMICALS-INTERACTION |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, CHEMICAL, CHEMICAL) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | NO-RELATIONSHIP |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, CHEMICAL, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with CHEMICAL. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | CHEMICALS-INTERACTION |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, CHEMICAL) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with CHEMICAL. If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised. | CHEMICALS-INTERACTION |
| Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because there is a theoretical basis that these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and sumatriptan within 24 hours of each other should be avoided. MAO-A inhibitors reduce sumatriptan clearance, significantly increasing systemic exposure. Therefore, the use of sumatriptan succinate tablets in patients receiving MAO-A inhibitors is contraindicated . Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) have been reported, rarely, to cause weakness, hyperreflexia, and incoordination when coadministered with sumatriptan. If concomitant treatment with CHEMICAL and an CHEMICAL is clinically warranted, appropriate observation of the patient is advised. | CHEMICALS-INTERACTION |
| CHEMICAL: Absorption of a single dose of CHEMICAL was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| CHEMICAL: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking CHEMICAL-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| CHEMICAL: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-CHEMICAL containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| CHEMICAL: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing CHEMICAL (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| CHEMICAL: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when CHEMICAL was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of CHEMICAL was decreased when administered to 12 stable renal transplant patients also taking CHEMICAL-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | CHEMICALS-INTERACTION |
| Antacids: Absorption of a single dose of CHEMICAL was decreased when administered to 12 stable renal transplant patients also taking magnesium-CHEMICAL containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | CHEMICALS-INTERACTION |
| Antacids: Absorption of a single dose of CHEMICAL was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing CHEMICAL (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | CHEMICALS-INTERACTION |
| Antacids: Absorption of a single dose of CHEMICAL was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when CHEMICAL was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking CHEMICAL-CHEMICAL containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking CHEMICAL-aluminum containing CHEMICAL (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking CHEMICAL-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when CHEMICAL was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-CHEMICAL containing CHEMICAL (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-CHEMICAL containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when CHEMICAL was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing CHEMICAL (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when CHEMICAL was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that CHEMICAL and CHEMICAL not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | CHEMICALS-INTERACTION |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. CHEMICAL: When studied in stable renal transplant patients, CHEMICAL, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. CHEMICAL: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of CHEMICAL. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, CHEMICAL, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of CHEMICAL. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. CHEMICAL/CHEMICAL: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. CHEMICAL/Ganciclovir: may be taken with CHEMICAL; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | CHEMICALS-INTERACTION |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/CHEMICAL: may be taken with CHEMICAL; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | CHEMICALS-INTERACTION |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both CHEMICAL/CHEMICAL and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both CHEMICAL/ganciclovir and CHEMICAL concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/CHEMICAL and CHEMICAL concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. CHEMICAL/CHEMICAL: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. CHEMICAL/Mycophenolate Mofetil: Given that CHEMICAL and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. CHEMICAL/Mycophenolate Mofetil: Given that azathioprine and CHEMICAL inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. CHEMICAL/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that CHEMICAL not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. CHEMICAL/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with CHEMICAL or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. CHEMICAL/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or CHEMICAL. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/CHEMICAL: Given that CHEMICAL and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/CHEMICAL: Given that azathioprine and CHEMICAL inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/CHEMICAL: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that CHEMICAL not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/CHEMICAL: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with CHEMICAL or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/CHEMICAL: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or CHEMICAL. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that CHEMICAL and CHEMICAL inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that CHEMICAL and mycophenolate mofetil inhibit purine metabolism, it is recommended that CHEMICAL not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that CHEMICAL and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with CHEMICAL or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that CHEMICAL and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or CHEMICAL. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and CHEMICAL inhibit purine metabolism, it is recommended that CHEMICAL not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and CHEMICAL inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with CHEMICAL or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and CHEMICAL inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or CHEMICAL. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that CHEMICAL not be administered concomitantly with CHEMICAL or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | CHEMICALS-INTERACTION |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that CHEMICAL not be administered concomitantly with azathioprine or CHEMICAL. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | CHEMICALS-INTERACTION |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with CHEMICAL or CHEMICAL. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. CHEMICAL and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce CHEMICAL exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. CHEMICAL and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with CHEMICAL. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce CHEMICAL exposure when coadministered with CHEMICAL. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | CHEMICALS-INTERACTION |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer CHEMICAL with CHEMICAL or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer CHEMICAL with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral CHEMICAL, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer CHEMICAL with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of CHEMICAL. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with CHEMICAL or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral CHEMICAL, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with CHEMICAL or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of CHEMICAL. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral CHEMICAL, because of the potential to reduce the efficacy of CHEMICAL. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | CHEMICALS-INTERACTION |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral CHEMICAL: Given the different metabolism of CHEMICAL and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral CHEMICAL: Given the different metabolism of Myfortic and oral CHEMICAL, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of CHEMICAL and oral CHEMICAL, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean CHEMICAL AUC was decreased by 15% when coadministered with CHEMICAL. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | CHEMICALS-INTERACTION |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral CHEMICAL are co- administered with CHEMICAL with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | CHEMICALS-INTERACTION |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. CHEMICAL: During treatment with CHEMICAL, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. CHEMICAL: During treatment with Myfortic, the use of CHEMICAL should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | NO-RELATIONSHIP |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with CHEMICAL, the use of CHEMICAL should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of MPAG hydrolysis may lead to less MPA available for absorption. | CHEMICALS-INTERACTION |
| Antacids: Absorption of a single dose of Myfortic was decreased when administered to 12 stable renal transplant patients also taking magnesium-aluminum containing antacids (30 mL): the mean Cmax and AUC(0-t) values for MPA were 25% and 37% lower, respectively, than when Myfortic was administered alone under fasting conditions. It is recommended that Myfortic and antacids not be administered simultaneously. Cyclosporine: When studied in stable renal transplant patients, cyclosporine, USP (MODIFIED) pharmacokinetics were unaffected by steady state dosing of Myfortic. Acyclovir/Ganciclovir: may be taken with Myfortic; however, during the period of treatment, physicians should monitor blood cell counts. Both acyclovir/ganciclovir and MPAG concentrations are increased in the presence of renal impairment, their coexistence may compete for tubular secretion and further increase in the concentrations of the two. Azathioprine/Mycophenolate Mofetil: Given that azathioprine and mycophenolate mofetil inhibit purine metabolism, it is recommended that Myfortic not be administered concomitantly with azathioprine or mycophenolate mofetil. Cholestyramine and Drugs that Bind Bile Acids: These drugs interrupt enterohepatic recirculation and reduce MPA exposure when coadministered with mycophenolate mofetil. Therefore, do not administer Myfortic with cholestyramine or other agents that may interfere with enterohepatic recirculation or drugs that may bind bile acids, for example bile acid sequestrates or oral activated charcoal, because of the potential to reduce the efficacy of Myfortic. Oral Contraceptives: Given the different metabolism of Myfortic and oral contraceptives, no drug interaction between these two classes of drug is expected. However, in a drug-drug interaction study, mean levonorgesterol AUC was decreased by 15% when coadministered with mycophenolate mofetil. Therefore, it is recommended that oral contraceptives are co- administered with Myfortic with caution and additional birth control methods be considered. Live Vaccines: During treatment with Myfortic, the use of live attenuated vaccines should be avoided and patients should be advised that vaccinations may be less effective. Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination. Drugs that alter the gastrointestinal flora may interact with Myfortic by disrupting enterohepatic recirculation. Interference of CHEMICAL hydrolysis may lead to less CHEMICAL available for absorption. | CHEMICALS-INTERACTION |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with CHEMICAL, interactions with CHEMICAL have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with CHEMICAL, interactions with coumarin-type anticoagulants have been reported with CHEMICAL since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with CHEMICAL, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering CHEMICAL to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with CHEMICAL, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on CHEMICAL and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with CHEMICAL have been reported with CHEMICAL since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | CHEMICALS-INTERACTION |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with CHEMICAL have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering CHEMICAL to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with CHEMICAL have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on CHEMICAL and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with CHEMICAL since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering CHEMICAL to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with CHEMICAL since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on CHEMICAL and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering CHEMICAL to patients on CHEMICAL and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | CHEMICALS-INTERACTION |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of CHEMICAL are depressed to approximately 80% of their normal values when CHEMICAL is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of CHEMICAL are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with CHEMICAL (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of CHEMICAL are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of CHEMICAL has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of CHEMICAL are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on CHEMICAL plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of CHEMICAL are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . CHEMICAL, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of CHEMICAL are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including CHEMICAL, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of CHEMICAL are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma CHEMICAL levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when CHEMICAL is administered in conjunction with CHEMICAL (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | CHEMICALS-INTERACTION |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when CHEMICAL is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of CHEMICAL has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when CHEMICAL is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on CHEMICAL plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when CHEMICAL is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . CHEMICAL, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when CHEMICAL is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including CHEMICAL, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when CHEMICAL is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma CHEMICAL levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with CHEMICAL (3900 mg/day), but concomitant administration of CHEMICAL has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with CHEMICAL (3900 mg/day), but concomitant administration of antacids has no effect on CHEMICAL plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with CHEMICAL (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . CHEMICAL, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with CHEMICAL (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including CHEMICAL, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with CHEMICAL (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma CHEMICAL levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of CHEMICAL has no effect on CHEMICAL plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of CHEMICAL has no effect on piroxicam plasma levels . CHEMICAL, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of CHEMICAL has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including CHEMICAL, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of CHEMICAL has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma CHEMICAL levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on CHEMICAL plasma levels . CHEMICAL, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on CHEMICAL plasma levels . Nonsteroidal anti-inflammatory agents, including CHEMICAL, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on CHEMICAL plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma CHEMICAL levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . CHEMICAL, including CHEMICAL, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | NO-RELATIONSHIP |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . CHEMICAL, including FELDENE, have been reported to increase steady state plasma CHEMICAL levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | CHEMICALS-INTERACTION |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including CHEMICAL, have been reported to increase steady state plasma CHEMICAL levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. | CHEMICALS-INTERACTION |
| FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels . Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma CHEMICAL levels be monitored when initiating, adjusting and discontinuing CHEMICAL. | CHEMICALS-INTERACTION |
| CHEMICAL, particularly CHEMICAL, may cause serious cardiac arrhythmias during halothane anesthesia and therefore should be used only with great caution or not at all. MAO Inhibitors - The pressor effect of sympathomimetic pressor amines is markedly potentiated in patients receiving monoamine oxidase inhibitors (MAOI). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | NO-RELATIONSHIP |
| CHEMICAL, particularly metaraminol, may cause serious cardiac arrhythmias during CHEMICAL anesthesia and therefore should be used only with great caution or not at all. MAO Inhibitors - The pressor effect of sympathomimetic pressor amines is markedly potentiated in patients receiving monoamine oxidase inhibitors (MAOI). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | CHEMICALS-INTERACTION |
| Vasopressors, particularly CHEMICAL, may cause serious cardiac arrhythmias during CHEMICAL anesthesia and therefore should be used only with great caution or not at all. MAO Inhibitors - The pressor effect of sympathomimetic pressor amines is markedly potentiated in patients receiving monoamine oxidase inhibitors (MAOI). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | CHEMICALS-INTERACTION |
| Vasopressors, particularly metaraminol, may cause serious cardiac arrhythmias during halothane anesthesia and therefore should be used only with great caution or not at all. CHEMICAL - The pressor effect of CHEMICAL is markedly potentiated in patients receiving monoamine oxidase inhibitors (MAOI). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | NO-RELATIONSHIP |
| Vasopressors, particularly metaraminol, may cause serious cardiac arrhythmias during halothane anesthesia and therefore should be used only with great caution or not at all. CHEMICAL - The pressor effect of sympathomimetic pressor amines is markedly potentiated in patients receiving CHEMICAL (MAOI). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | NO-RELATIONSHIP |
| Vasopressors, particularly metaraminol, may cause serious cardiac arrhythmias during halothane anesthesia and therefore should be used only with great caution or not at all. CHEMICAL - The pressor effect of sympathomimetic pressor amines is markedly potentiated in patients receiving monoamine oxidase inhibitors (CHEMICAL). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | NO-RELATIONSHIP |
| Vasopressors, particularly metaraminol, may cause serious cardiac arrhythmias during halothane anesthesia and therefore should be used only with great caution or not at all. MAO Inhibitors - The pressor effect of CHEMICAL is markedly potentiated in patients receiving CHEMICAL (MAOI). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | CHEMICALS-INTERACTION |
| Vasopressors, particularly metaraminol, may cause serious cardiac arrhythmias during halothane anesthesia and therefore should be used only with great caution or not at all. MAO Inhibitors - The pressor effect of CHEMICAL is markedly potentiated in patients receiving monoamine oxidase inhibitors (CHEMICAL). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | CHEMICALS-INTERACTION |
| Vasopressors, particularly metaraminol, may cause serious cardiac arrhythmias during halothane anesthesia and therefore should be used only with great caution or not at all. MAO Inhibitors - The pressor effect of sympathomimetic pressor amines is markedly potentiated in patients receiving CHEMICAL (CHEMICAL). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of adrenergic agents may also be potentiated by tricyclic antidepressants. | NO-RELATIONSHIP |
| Vasopressors, particularly metaraminol, may cause serious cardiac arrhythmias during halothane anesthesia and therefore should be used only with great caution or not at all. MAO Inhibitors - The pressor effect of sympathomimetic pressor amines is markedly potentiated in patients receiving monoamine oxidase inhibitors (MAOI). Therefore, when initiating pressor therapy in these patients, the initial dose should be small and used with due caution. The pressor response of CHEMICAL may also be potentiated by CHEMICAL. | CHEMICALS-INTERACTION |
| Acromegalic patients with diabetes mellitus being treated with CHEMICAL and/or oral CHEMICAL agents may require dose reductions of these therapeutic agents after the initiation of therapy with SOMAVERT. In clinical studies, patients on opioids often needed higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opioids. The mechanism of this interaction is not known. | NO-RELATIONSHIP |
| Acromegalic patients with diabetes mellitus being treated with CHEMICAL and/or oral hypoglycemic agents may require dose reductions of these therapeutic agents after the initiation of therapy with CHEMICAL. In clinical studies, patients on opioids often needed higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opioids. The mechanism of this interaction is not known. | CHEMICALS-INTERACTION |
| Acromegalic patients with diabetes mellitus being treated with insulin and/or oral CHEMICAL agents may require dose reductions of these therapeutic agents after the initiation of therapy with CHEMICAL. In clinical studies, patients on opioids often needed higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opioids. The mechanism of this interaction is not known. | CHEMICALS-INTERACTION |
| Acromegalic patients with diabetes mellitus being treated with insulin and/or oral hypoglycemic agents may require dose reductions of these therapeutic agents after the initiation of therapy with SOMAVERT. In clinical studies, patients on CHEMICAL often needed higher serum CHEMICAL concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opioids. The mechanism of this interaction is not known. | CHEMICALS-INTERACTION |
| Acromegalic patients with diabetes mellitus being treated with insulin and/or oral hypoglycemic agents may require dose reductions of these therapeutic agents after the initiation of therapy with SOMAVERT. In clinical studies, patients on CHEMICAL often needed higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving CHEMICAL. The mechanism of this interaction is not known. | NO-RELATIONSHIP |
| Acromegalic patients with diabetes mellitus being treated with insulin and/or oral hypoglycemic agents may require dose reductions of these therapeutic agents after the initiation of therapy with SOMAVERT. In clinical studies, patients on opioids often needed higher serum CHEMICAL concentrations to achieve appropriate IGF-I suppression compared with patients not receiving CHEMICAL. The mechanism of this interaction is not known. | NO-RELATIONSHIP |
| CHEMICAL: There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of CHEMICAL with the co-administration of 100 mg sitagliptin for 10 days. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or JANUVIA is recommended. | NO-RELATIONSHIP |
| CHEMICAL: There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of digoxin with the co-administration of 100 mg CHEMICAL for 10 days. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or JANUVIA is recommended. | NO-RELATIONSHIP |
| Digoxin: There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of CHEMICAL with the co-administration of 100 mg CHEMICAL for 10 days. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or JANUVIA is recommended. | CHEMICALS-INTERACTION |
| Digoxin: There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of digoxin with the co-administration of 100 mg sitagliptin for 10 days. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of CHEMICAL or CHEMICAL is recommended. | NO-RELATIONSHIP |
| Limited evidence suggests that CHEMICAL may influence the intensity and duration of action of CHEMICAL. | CHEMICALS-INTERACTION |
| CHEMICAL can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - CHEMICAL: can increase seizure activity - Live virus vaccines: may potentiate the replication of the vaccine virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - Mitomycin-C: may cause shortness of breath and bronchospasm - Killed virus vaccines: may decrease patient's response to the vaccine | CHEMICALS-INTERACTION |
| CHEMICAL can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - Phenytoin: can increase seizure activity - CHEMICAL: may potentiate the replication of the vaccine virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - Mitomycin-C: may cause shortness of breath and bronchospasm - Killed virus vaccines: may decrease patient's response to the vaccine | CHEMICALS-INTERACTION |
| CHEMICAL can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - Phenytoin: can increase seizure activity - Live virus vaccines: may potentiate the replication of the CHEMICAL virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - Mitomycin-C: may cause shortness of breath and bronchospasm - Killed virus vaccines: may decrease patient's response to the vaccine | CHEMICALS-INTERACTION |
| CHEMICAL can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - Phenytoin: can increase seizure activity - Live virus vaccines: may potentiate the replication of the vaccine virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - CHEMICAL: may cause shortness of breath and bronchospasm - Killed virus vaccines: may decrease patient's response to the vaccine | CHEMICALS-INTERACTION |
| CHEMICAL can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - Phenytoin: can increase seizure activity - Live virus vaccines: may potentiate the replication of the vaccine virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - Mitomycin-C: may cause shortness of breath and bronchospasm - CHEMICAL: may decrease patient's response to the vaccine | CHEMICALS-INTERACTION |
| CHEMICAL can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - Phenytoin: can increase seizure activity - Live virus vaccines: may potentiate the replication of the vaccine virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - Mitomycin-C: may cause shortness of breath and bronchospasm - Killed virus vaccines: may decrease patient's response to the CHEMICAL | CHEMICALS-INTERACTION |
| Vindesine can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - CHEMICAL: can increase seizure activity - CHEMICAL: may potentiate the replication of the vaccine virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - Mitomycin-C: may cause shortness of breath and bronchospasm - Killed virus vaccines: may decrease patient's response to the vaccine | NO-RELATIONSHIP |
| Vindesine can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - CHEMICAL: can increase seizure activity - Live virus vaccines: may potentiate the replication of the CHEMICAL virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - Mitomycin-C: may cause shortness of breath and bronchospasm - Killed virus vaccines: may decrease patient's response to the vaccine | NO-RELATIONSHIP |
| Vindesine can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - CHEMICAL: can increase seizure activity - Live virus vaccines: may potentiate the replication of the vaccine virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - CHEMICAL: may cause shortness of breath and bronchospasm - Killed virus vaccines: may decrease patient's response to the vaccine | NO-RELATIONSHIP |
| Vindesine can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - CHEMICAL: can increase seizure activity - Live virus vaccines: may potentiate the replication of the vaccine virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - Mitomycin-C: may cause shortness of breath and bronchospasm - CHEMICAL: may decrease patient's response to the vaccine | NO-RELATIONSHIP |
| Vindesine can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - CHEMICAL: can increase seizure activity - Live virus vaccines: may potentiate the replication of the vaccine virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - Mitomycin-C: may cause shortness of breath and bronchospasm - Killed virus vaccines: may decrease patient's response to the CHEMICAL | NO-RELATIONSHIP |
| Vindesine can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - Phenytoin: can increase seizure activity - CHEMICAL: may potentiate the replication of the CHEMICAL virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - Mitomycin-C: may cause shortness of breath and bronchospasm - Killed virus vaccines: may decrease patient's response to the vaccine | CHEMICALS-INTERACTION |
| Vindesine can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - Phenytoin: can increase seizure activity - CHEMICAL: may potentiate the replication of the vaccine virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - CHEMICAL: may cause shortness of breath and bronchospasm - Killed virus vaccines: may decrease patient's response to the vaccine | NO-RELATIONSHIP |
| Vindesine can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - Phenytoin: can increase seizure activity - CHEMICAL: may potentiate the replication of the vaccine virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - Mitomycin-C: may cause shortness of breath and bronchospasm - CHEMICAL: may decrease patient's response to the vaccine | NO-RELATIONSHIP |
| Vindesine can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - Phenytoin: can increase seizure activity - CHEMICAL: may potentiate the replication of the vaccine virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - Mitomycin-C: may cause shortness of breath and bronchospasm - Killed virus vaccines: may decrease patient's response to the CHEMICAL | NO-RELATIONSHIP |
| Vindesine can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - Phenytoin: can increase seizure activity - Live virus vaccines: may potentiate the replication of the CHEMICAL virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - CHEMICAL: may cause shortness of breath and bronchospasm - Killed virus vaccines: may decrease patient's response to the vaccine | NO-RELATIONSHIP |
| Vindesine can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - Phenytoin: can increase seizure activity - Live virus vaccines: may potentiate the replication of the CHEMICAL virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - Mitomycin-C: may cause shortness of breath and bronchospasm - CHEMICAL: may decrease patient's response to the vaccine | NO-RELATIONSHIP |
| Vindesine can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - Phenytoin: can increase seizure activity - Live virus vaccines: may potentiate the replication of the CHEMICAL virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - Mitomycin-C: may cause shortness of breath and bronchospasm - Killed virus vaccines: may decrease patient's response to the CHEMICAL | NO-RELATIONSHIP |
| Vindesine can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - Phenytoin: can increase seizure activity - Live virus vaccines: may potentiate the replication of the vaccine virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - CHEMICAL: may cause shortness of breath and bronchospasm - CHEMICAL: may decrease patient's response to the vaccine | NO-RELATIONSHIP |
| Vindesine can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - Phenytoin: can increase seizure activity - Live virus vaccines: may potentiate the replication of the vaccine virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - CHEMICAL: may cause shortness of breath and bronchospasm - Killed virus vaccines: may decrease patient's response to the CHEMICAL | NO-RELATIONSHIP |
| Vindesine can interact with the drugs of the following categories: - Blood dyscrasia: can cause unpredictable myelotoxicity - Bone marrow depressants: can cause a predictable dose-related myelotoxicity - Radiation therapy: may cause marrow depression - Neurotoxic medications: can cause neurologic toxicity - Phenytoin: can increase seizure activity - Live virus vaccines: may potentiate the replication of the vaccine virus, may increase the side effects of the vaccination, and decrease patient's response to the vaccine - Mitomycin-C: may cause shortness of breath and bronchospasm - CHEMICAL: may decrease patient's response to the CHEMICAL | CHEMICALS-INTERACTION |
| CHEMICAL: Excessive reductions in blood pressure may occur in patients on diuretic therapy when CHEMICAL are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with CHEMICAL can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with CHEMICAL . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with CHEMICAL can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of CHEMICAL should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with CHEMICAL . If this is not possible, the starting dose of CHEMICAL should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. CHEMICAL Supplements and CHEMICAL: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. CHEMICAL Supplements and Potassium-Sparing Diuretics: CHEMICAL can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and CHEMICAL: CHEMICAL can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of CHEMICAL (CHEMICAL, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of CHEMICAL (spironolactone, CHEMICAL, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of CHEMICAL (spironolactone, triamterene, CHEMICAL) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of CHEMICAL (spironolactone, triamterene, amiloride) or CHEMICAL supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of CHEMICAL (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with CHEMICAL can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | CHEMICALS-INTERACTION |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (CHEMICAL, CHEMICAL, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (CHEMICAL, triamterene, CHEMICAL) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (CHEMICAL, triamterene, amiloride) or CHEMICAL supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (CHEMICAL, triamterene, amiloride) or potassium supplements concomitantly with CHEMICAL can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | CHEMICALS-INTERACTION |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, CHEMICAL, CHEMICAL) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, CHEMICAL, amiloride) or CHEMICAL supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, CHEMICAL, amiloride) or potassium supplements concomitantly with CHEMICAL can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | CHEMICALS-INTERACTION |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, CHEMICAL) or CHEMICAL supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, CHEMICAL) or potassium supplements concomitantly with CHEMICAL can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | CHEMICALS-INTERACTION |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or CHEMICAL supplements concomitantly with CHEMICAL can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | CHEMICALS-INTERACTION |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral CHEMICAL: Interaction studies with CHEMICAL failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral CHEMICAL: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the CHEMICAL or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with CHEMICAL failed to identify any clinically important effect on the serum concentrations of the CHEMICAL or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. CHEMICAL: Increased serum CHEMICAL levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. CHEMICAL: Increased serum lithium levels and symptoms of CHEMICAL toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. CHEMICAL: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving CHEMICAL during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. CHEMICAL: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with CHEMICAL. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum CHEMICAL levels and symptoms of CHEMICAL toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum CHEMICAL levels and symptoms of lithium toxicity have been reported in patients receiving CHEMICAL during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum CHEMICAL levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with CHEMICAL. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of CHEMICAL toxicity have been reported in patients receiving CHEMICAL during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of CHEMICAL toxicity have been reported in patients receiving ACE inhibitors during therapy with CHEMICAL. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving CHEMICAL during therapy with CHEMICAL. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | CHEMICALS-INTERACTION |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a CHEMICAL is also used, the risk of CHEMICAL toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | CHEMICALS-INTERACTION |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when CHEMICAL was administered concomitantly with CHEMICAL, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when CHEMICAL was administered concomitantly with hydrochlorothiazide, CHEMICAL, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when CHEMICAL was administered concomitantly with hydrochlorothiazide, digoxin, or CHEMICAL. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with CHEMICAL, CHEMICAL, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with CHEMICAL, digoxin, or CHEMICAL. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, CHEMICAL, or CHEMICAL. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. CHEMICAL has been used in clinical trials concomitantly with CHEMICAL, diuretics, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. CHEMICAL has been used in clinical trials concomitantly with calcium-channel-blocking agents, CHEMICAL, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. CHEMICAL has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, CHEMICAL, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. CHEMICAL has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, CHEMICAL, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. CHEMICAL has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, digoxin, oral CHEMICAL, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with CHEMICAL, CHEMICAL, H2 blockers, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with CHEMICAL, diuretics, CHEMICAL, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with CHEMICAL, diuretics, H2 blockers, CHEMICAL, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with CHEMICAL, diuretics, H2 blockers, digoxin, oral CHEMICAL, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, CHEMICAL, CHEMICAL, digoxin, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, CHEMICAL, H2 blockers, CHEMICAL, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, CHEMICAL, H2 blockers, digoxin, oral CHEMICAL, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, CHEMICAL, CHEMICAL, oral hypoglycemic agents, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, CHEMICAL, digoxin, oral CHEMICAL, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| Diuretics: Excessive reductions in blood pressure may occur in patients on diuretic therapy when ACE inhibitors are started. The possibility of hypotensive effects with UNIVASC can be minimized by discontinuing diuretic therapy for several days or cautiously increasing salt intake before initiation of treatment with UNIVASC . If this is not possible, the starting dose of moexpril should be reduced.. Potassium Supplements and Potassium-Sparing Diuretics: UNIVASC can increase serum potassium because it decreases aldosterone secretion. Use of potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements concomitantly with ACE inhibitors can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored. Oral Anticoagulants: Interaction studies with warfarin failed to identify any clinically important effect on the serum concentrations of the anticoagulant or on its anticoagulant effect. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other Agents: No clinically important pharmacokinetic interactions occurred when UNIVASC was administered concomitantly with hydrochlorothiazide, digoxin, or cimetidine. UNIVASC has been used in clinical trials concomitantly with calcium-channel-blocking agents, diuretics, H2 blockers, CHEMICAL, oral CHEMICAL, and cholesterol-lowering agents. There was no evidence of clinically important adverse interactions. | NO-RELATIONSHIP |
| CHEMICAL may interact with the following drugs: CHEMICAL and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with the following drugs: aspirin and other CHEMICAL (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with the following drugs: aspirin and other NSAIDs (may lower CHEMICAL levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| CHEMICAL may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), CHEMICAL (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral CHEMICAL is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), CHEMICAL (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease CHEMICAL levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| CHEMICAL may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), CHEMICAL (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), CHEMICAL (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of CHEMICAL with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with CHEMICAL can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| CHEMICAL may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), CHEMICAL and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and CHEMICAL (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of CHEMICAL and corticosteroids may interfere with the efficacy of the corticosteroids). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and CHEMICAL may interfere with the efficacy of the corticosteroids). | CHEMICALS-INTERACTION |
| CHEMICAL may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the CHEMICAL). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: CHEMICAL and other CHEMICAL (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: CHEMICAL and other NSAIDs (may lower CHEMICAL levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | CHEMICALS-INTERACTION |
| Melatonin may interact with the following drugs: CHEMICAL and other NSAIDs (may lower melatonin levels), CHEMICAL (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: CHEMICAL and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral CHEMICAL is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: CHEMICAL and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), CHEMICAL (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: CHEMICAL and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease CHEMICAL levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: CHEMICAL and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), CHEMICAL (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: CHEMICAL and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), CHEMICAL (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: CHEMICAL and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of CHEMICAL with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: CHEMICAL and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with CHEMICAL can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: CHEMICAL and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), CHEMICAL and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: CHEMICAL and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and CHEMICAL (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: CHEMICAL and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of CHEMICAL and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: CHEMICAL and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and CHEMICAL may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: CHEMICAL and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the CHEMICAL). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other CHEMICAL (may lower CHEMICAL levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | CHEMICALS-INTERACTION |
| Melatonin may interact with the following drugs: aspirin and other CHEMICAL (may lower melatonin levels), CHEMICAL (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other CHEMICAL (may lower melatonin levels), fluvoxamine (bioavailability of oral CHEMICAL is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other CHEMICAL (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), CHEMICAL (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other CHEMICAL (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease CHEMICAL levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other CHEMICAL (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), CHEMICAL (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other CHEMICAL (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), CHEMICAL (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other CHEMICAL (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of CHEMICAL with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other CHEMICAL (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with CHEMICAL can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other CHEMICAL (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), CHEMICAL and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other CHEMICAL (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and CHEMICAL (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other CHEMICAL (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of CHEMICAL and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other CHEMICAL (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and CHEMICAL may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other CHEMICAL (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the CHEMICAL). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower CHEMICAL levels), CHEMICAL (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower CHEMICAL levels), fluvoxamine (bioavailability of oral CHEMICAL is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower CHEMICAL levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), CHEMICAL (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower CHEMICAL levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease CHEMICAL levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower CHEMICAL levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), CHEMICAL (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower CHEMICAL levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), CHEMICAL (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower CHEMICAL levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of CHEMICAL with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower CHEMICAL levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with CHEMICAL can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower CHEMICAL levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), CHEMICAL and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower CHEMICAL levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and CHEMICAL (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower CHEMICAL levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of CHEMICAL and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower CHEMICAL levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and CHEMICAL may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower CHEMICAL levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the CHEMICAL). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), CHEMICAL (bioavailability of oral CHEMICAL is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), CHEMICAL (bioavailability of oral melatonin is increased with coadministration), CHEMICAL (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), CHEMICAL (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease CHEMICAL levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), CHEMICAL (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), CHEMICAL (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), CHEMICAL (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), CHEMICAL (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), CHEMICAL (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of CHEMICAL with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), CHEMICAL (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with CHEMICAL can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), CHEMICAL (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), CHEMICAL and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), CHEMICAL (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and CHEMICAL (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), CHEMICAL (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of CHEMICAL and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), CHEMICAL (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and CHEMICAL may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), CHEMICAL (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the CHEMICAL). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral CHEMICAL is increased with coadministration), CHEMICAL (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral CHEMICAL is increased with coadministration), beta blockers (may decrease CHEMICAL levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral CHEMICAL is increased with coadministration), beta blockers (may decrease melatonin levels), CHEMICAL (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral CHEMICAL is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), CHEMICAL (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral CHEMICAL is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of CHEMICAL with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral CHEMICAL is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with CHEMICAL can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral CHEMICAL is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), CHEMICAL and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral CHEMICAL is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and CHEMICAL (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral CHEMICAL is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of CHEMICAL and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral CHEMICAL is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and CHEMICAL may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral CHEMICAL is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the CHEMICAL). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), CHEMICAL (may decrease CHEMICAL levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | CHEMICALS-INTERACTION |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), CHEMICAL (may decrease melatonin levels), CHEMICAL (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), CHEMICAL (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), CHEMICAL (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), CHEMICAL (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of CHEMICAL with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), CHEMICAL (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with CHEMICAL can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), CHEMICAL (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), CHEMICAL and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), CHEMICAL (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and CHEMICAL (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), CHEMICAL (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of CHEMICAL and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), CHEMICAL (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and CHEMICAL may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), CHEMICAL (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the CHEMICAL). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease CHEMICAL levels), CHEMICAL (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease CHEMICAL levels), fluoxetine (reports of psychotic episodes when coadministered), CHEMICAL (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease CHEMICAL levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of CHEMICAL with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease CHEMICAL levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with CHEMICAL can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease CHEMICAL levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), CHEMICAL and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease CHEMICAL levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and CHEMICAL (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease CHEMICAL levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of CHEMICAL and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease CHEMICAL levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and CHEMICAL may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease CHEMICAL levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the CHEMICAL). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), CHEMICAL (reports of psychotic episodes when coadministered), CHEMICAL (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), CHEMICAL (reports of psychotic episodes when coadministered), progestin (coadministration of CHEMICAL with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), CHEMICAL (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with CHEMICAL can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), CHEMICAL (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), CHEMICAL and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), CHEMICAL (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and CHEMICAL (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), CHEMICAL (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of CHEMICAL and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), CHEMICAL (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and CHEMICAL may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), CHEMICAL (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the CHEMICAL). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), CHEMICAL (coadministration of CHEMICAL with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), CHEMICAL (coadministration of melatonin with CHEMICAL can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), CHEMICAL (coadministration of melatonin with progestin can inhibit ovarian function in women), CHEMICAL and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), CHEMICAL (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and CHEMICAL (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), CHEMICAL (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of CHEMICAL and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), CHEMICAL (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and CHEMICAL may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), CHEMICAL (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the CHEMICAL). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of CHEMICAL with CHEMICAL can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | CHEMICALS-INTERACTION |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of CHEMICAL with progestin can inhibit ovarian function in women), CHEMICAL and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of CHEMICAL with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and CHEMICAL (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of CHEMICAL with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of CHEMICAL and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of CHEMICAL with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and CHEMICAL may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of CHEMICAL with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the CHEMICAL). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with CHEMICAL can inhibit ovarian function in women), CHEMICAL and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with CHEMICAL can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and CHEMICAL (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with CHEMICAL can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of CHEMICAL and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with CHEMICAL can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and CHEMICAL may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with CHEMICAL can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the CHEMICAL). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), CHEMICAL and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and CHEMICAL (coadministration of melatonin and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), CHEMICAL and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of CHEMICAL and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), CHEMICAL and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and CHEMICAL may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), CHEMICAL and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and corticosteroids may interfere with the efficacy of the CHEMICAL). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and CHEMICAL (coadministration of CHEMICAL and corticosteroids may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and CHEMICAL (coadministration of melatonin and CHEMICAL may interfere with the efficacy of the corticosteroids). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and CHEMICAL (coadministration of melatonin and corticosteroids may interfere with the efficacy of the CHEMICAL). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of CHEMICAL and CHEMICAL may interfere with the efficacy of the corticosteroids). | CHEMICALS-INTERACTION |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of CHEMICAL and corticosteroids may interfere with the efficacy of the CHEMICAL). | NO-RELATIONSHIP |
| Melatonin may interact with the following drugs: aspirin and other NSAIDs (may lower melatonin levels), fluvoxamine (bioavailability of oral melatonin is increased with coadministration), beta blockers (may decrease melatonin levels), fluoxetine (reports of psychotic episodes when coadministered), progestin (coadministration of melatonin with progestin can inhibit ovarian function in women), benzodiazepenes and other sedating drugs (may result in additive sedation and an increased incidence of adverse effects), and corticosteroids (coadministration of melatonin and CHEMICAL may interfere with the efficacy of the CHEMICAL). | NO-RELATIONSHIP |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of CHEMICAL (CHEMICAL) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERON SolTab. Diazepam: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | NO-RELATIONSHIP |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that CHEMICAL is not a potent inhibitor of any of these enzymes, an indication that CHEMICAL is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERON SolTab. Diazepam: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | NO-RELATIONSHIP |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that CHEMICAL is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of CHEMICAL with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERON SolTab. Diazepam: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | NO-RELATIONSHIP |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that CHEMICAL is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of CHEMICAL with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERON SolTab. Diazepam: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | NO-RELATIONSHIP |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. CHEMICAL: Concomitant administration of CHEMICAL (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERON SolTab. Diazepam: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | NO-RELATIONSHIP |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. CHEMICAL: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of CHEMICAL (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERON SolTab. Diazepam: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | NO-RELATIONSHIP |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of CHEMICAL (equivalent to 60 g) had a minimal effect on plasma levels of CHEMICAL (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERON SolTab. Diazepam: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | NO-RELATIONSHIP |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by CHEMICAL were shown to be additive with those produced by CHEMICAL. Accordingly, patients should be advised to avoid alcohol while taking REMERON SolTab. Diazepam: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | CHEMICALS-INTERACTION |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid CHEMICAL while taking CHEMICAL. Diazepam: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | CHEMICALS-INTERACTION |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid CHEMICAL while taking REMERON SolTab. CHEMICAL: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | NO-RELATIONSHIP |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid CHEMICAL while taking REMERON SolTab. Diazepam: Concomitant administration of CHEMICAL (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | NO-RELATIONSHIP |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid CHEMICAL while taking REMERON SolTab. Diazepam: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of CHEMICAL (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | NO-RELATIONSHIP |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking CHEMICAL. CHEMICAL: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | NO-RELATIONSHIP |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking CHEMICAL. Diazepam: Concomitant administration of CHEMICAL (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | NO-RELATIONSHIP |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking CHEMICAL. Diazepam: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of CHEMICAL (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | NO-RELATIONSHIP |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERON SolTab. CHEMICAL: Concomitant administration of CHEMICAL (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | NO-RELATIONSHIP |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERON SolTab. CHEMICAL: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of CHEMICAL (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | NO-RELATIONSHIP |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERON SolTab. Diazepam: Concomitant administration of CHEMICAL (15 mg) had a minimal effect on plasma levels of CHEMICAL (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | NO-RELATIONSHIP |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERON SolTab. Diazepam: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by CHEMICAL has been shown to be additive with those caused by CHEMICAL. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON SolTab. | CHEMICALS-INTERACTION |
| As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility. Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of REMERON SolTab (mirtazapine) Orally Disintegrating Tablets may be affected by the induction or inhibition of drug-metab-olizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON SolTab with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON SolTab with such drugs. Alcohol: Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by REMERON were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERON SolTab. Diazepam: Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by REMERON has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid CHEMICAL and other similar drugs while taking CHEMICAL. | CHEMICALS-INTERACTION |
| Interaction with Other CHEMICAL: CHEMICAL SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other CHEMICAL: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER CHEMICAL, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other CHEMICAL: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL CHEMICAL, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other CHEMICAL: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, CHEMICAL, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other CHEMICAL: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER CHEMICAL, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other CHEMICAL: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, CHEMICAL (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other CHEMICAL: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING CHEMICAL), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other CHEMICAL: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), CHEMICAL AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other CHEMICAL: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CHEMICAL (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other CHEMICAL: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING CHEMICAL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: CHEMICAL SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER CHEMICAL, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | CHEMICALS-INTERACTION |
| Interaction with Other Central Nervous System Depressants: CHEMICAL SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL CHEMICAL, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | CHEMICALS-INTERACTION |
| Interaction with Other Central Nervous System Depressants: CHEMICAL SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, CHEMICAL, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | CHEMICALS-INTERACTION |
| Interaction with Other Central Nervous System Depressants: CHEMICAL SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER CHEMICAL, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | CHEMICALS-INTERACTION |
| Interaction with Other Central Nervous System Depressants: CHEMICAL SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, CHEMICAL (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | CHEMICALS-INTERACTION |
| Interaction with Other Central Nervous System Depressants: CHEMICAL SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING CHEMICAL), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | CHEMICALS-INTERACTION |
| Interaction with Other Central Nervous System Depressants: CHEMICAL SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), CHEMICAL AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | CHEMICALS-INTERACTION |
| Interaction with Other Central Nervous System Depressants: CHEMICAL SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CHEMICAL (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | CHEMICALS-INTERACTION |
| Interaction with Other Central Nervous System Depressants: CHEMICAL SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING CHEMICAL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | CHEMICALS-INTERACTION |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER CHEMICAL, GENERAL CHEMICAL, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER CHEMICAL, GENERAL ANESTHETICS, CHEMICAL, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER CHEMICAL, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER CHEMICAL, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER CHEMICAL, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, CHEMICAL (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER CHEMICAL, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING CHEMICAL), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER CHEMICAL, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), CHEMICAL AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER CHEMICAL, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CHEMICAL (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER CHEMICAL, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING CHEMICAL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL CHEMICAL, CHEMICAL, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL CHEMICAL, PHENOTHIAZINES, OTHER CHEMICAL, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL CHEMICAL, PHENOTHIAZINES, OTHER TRANQUILIZERS, CHEMICAL (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL CHEMICAL, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING CHEMICAL), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL CHEMICAL, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), CHEMICAL AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL CHEMICAL, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CHEMICAL (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL CHEMICAL, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING CHEMICAL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, CHEMICAL, OTHER CHEMICAL, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, CHEMICAL, OTHER TRANQUILIZERS, CHEMICAL (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, CHEMICAL, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING CHEMICAL), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, CHEMICAL, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), CHEMICAL AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, CHEMICAL, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CHEMICAL (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, CHEMICAL, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING CHEMICAL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER CHEMICAL, CHEMICAL (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER CHEMICAL, SEDATIVE-HYPNOTICS (INCLUDING CHEMICAL), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER CHEMICAL, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), CHEMICAL AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER CHEMICAL, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CHEMICAL (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER CHEMICAL, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING CHEMICAL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, CHEMICAL (INCLUDING CHEMICAL), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, CHEMICAL (INCLUDING BARBITURATES), CHEMICAL AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, CHEMICAL (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CHEMICAL (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, CHEMICAL (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING CHEMICAL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING CHEMICAL), CHEMICAL AND OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING CHEMICAL), TRICYCLIC ANTIDEPRESSANTS AND OTHER CHEMICAL (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING CHEMICAL), TRICYCLIC ANTIDEPRESSANTS AND OTHER CNS DEPRESSANTS (INCLUDING CHEMICAL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), CHEMICAL AND OTHER CHEMICAL (INCLUDING ALCOHOL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), CHEMICAL AND OTHER CNS DEPRESSANTS (INCLUDING CHEMICAL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Interaction with Other Central Nervous System Depressants: MEPERIDINE SHOULD BE USED WITH GREAT CAUTION AND IN REDUCED DOSAGE IN PATIENTS WHO ARE CONCURRENTLY RECEIVING OTHER NARCOTIC ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES, OTHER TRANQUILIZERS, SEDATIVE-HYPNOTICS (INCLUDING BARBITURATES), TRICYCLIC ANTIDEPRESSANTS AND OTHER CHEMICAL (INCLUDING CHEMICAL). RESPIRATORY DEPRESSION, HYPOTENSION, AND PROFOUND SEDATION OR COMA MAY RESULT. | NO-RELATIONSHIP |
| Concurrent administration of CHEMICAL (e.g., CHEMICAL, tetracycline) may diminish the bactericidal effects of penicillins by slowing the rate of bacterial growth. Bactericidal agents work most effectively against the immature cell wall of rapidly proliferating microorganisms. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented. There are few clinical situations in which the concurrent use of ''static'' and ''cidal '' antibiotics are indicated. However, in selected circumstances in which such therapy is appropriate, using adequate doses of antibacterial agents and beginning penicillin therapy first, should minimize the potential for interaction. Penicillin blood levels may be prolonged by concurrent administration of probenecid which blocks the renal tubular secretion of penicillins. Displacement of penicillin from plasma protein binding sites will elevate the level of free penicillin in the serum. | NO-RELATIONSHIP |
| Concurrent administration of CHEMICAL (e.g., erythromycin, CHEMICAL) may diminish the bactericidal effects of penicillins by slowing the rate of bacterial growth. Bactericidal agents work most effectively against the immature cell wall of rapidly proliferating microorganisms. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented. There are few clinical situations in which the concurrent use of ''static'' and ''cidal '' antibiotics are indicated. However, in selected circumstances in which such therapy is appropriate, using adequate doses of antibacterial agents and beginning penicillin therapy first, should minimize the potential for interaction. Penicillin blood levels may be prolonged by concurrent administration of probenecid which blocks the renal tubular secretion of penicillins. Displacement of penicillin from plasma protein binding sites will elevate the level of free penicillin in the serum. | NO-RELATIONSHIP |
| Concurrent administration of CHEMICAL (e.g., erythromycin, tetracycline) may diminish the bactericidal effects of CHEMICAL by slowing the rate of bacterial growth. Bactericidal agents work most effectively against the immature cell wall of rapidly proliferating microorganisms. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented. There are few clinical situations in which the concurrent use of ''static'' and ''cidal '' antibiotics are indicated. However, in selected circumstances in which such therapy is appropriate, using adequate doses of antibacterial agents and beginning penicillin therapy first, should minimize the potential for interaction. Penicillin blood levels may be prolonged by concurrent administration of probenecid which blocks the renal tubular secretion of penicillins. Displacement of penicillin from plasma protein binding sites will elevate the level of free penicillin in the serum. | CHEMICALS-INTERACTION |
| Concurrent administration of bacteriostatic antibiotics (e.g., CHEMICAL, CHEMICAL) may diminish the bactericidal effects of penicillins by slowing the rate of bacterial growth. Bactericidal agents work most effectively against the immature cell wall of rapidly proliferating microorganisms. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented. There are few clinical situations in which the concurrent use of ''static'' and ''cidal '' antibiotics are indicated. However, in selected circumstances in which such therapy is appropriate, using adequate doses of antibacterial agents and beginning penicillin therapy first, should minimize the potential for interaction. Penicillin blood levels may be prolonged by concurrent administration of probenecid which blocks the renal tubular secretion of penicillins. Displacement of penicillin from plasma protein binding sites will elevate the level of free penicillin in the serum. | NO-RELATIONSHIP |
| Concurrent administration of bacteriostatic antibiotics (e.g., CHEMICAL, tetracycline) may diminish the bactericidal effects of CHEMICAL by slowing the rate of bacterial growth. Bactericidal agents work most effectively against the immature cell wall of rapidly proliferating microorganisms. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented. There are few clinical situations in which the concurrent use of ''static'' and ''cidal '' antibiotics are indicated. However, in selected circumstances in which such therapy is appropriate, using adequate doses of antibacterial agents and beginning penicillin therapy first, should minimize the potential for interaction. Penicillin blood levels may be prolonged by concurrent administration of probenecid which blocks the renal tubular secretion of penicillins. Displacement of penicillin from plasma protein binding sites will elevate the level of free penicillin in the serum. | CHEMICALS-INTERACTION |
| Concurrent administration of bacteriostatic antibiotics (e.g., erythromycin, CHEMICAL) may diminish the bactericidal effects of CHEMICAL by slowing the rate of bacterial growth. Bactericidal agents work most effectively against the immature cell wall of rapidly proliferating microorganisms. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented. There are few clinical situations in which the concurrent use of ''static'' and ''cidal '' antibiotics are indicated. However, in selected circumstances in which such therapy is appropriate, using adequate doses of antibacterial agents and beginning penicillin therapy first, should minimize the potential for interaction. Penicillin blood levels may be prolonged by concurrent administration of probenecid which blocks the renal tubular secretion of penicillins. Displacement of penicillin from plasma protein binding sites will elevate the level of free penicillin in the serum. | CHEMICALS-INTERACTION |
| Concurrent administration of bacteriostatic antibiotics (e.g., erythromycin, tetracycline) may diminish the bactericidal effects of penicillins by slowing the rate of bacterial growth. Bactericidal agents work most effectively against the immature cell wall of rapidly proliferating microorganisms. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented. There are few clinical situations in which the concurrent use of ''static'' and ''cidal '' antibiotics are indicated. However, in selected circumstances in which such therapy is appropriate, using adequate doses of antibacterial agents and beginning penicillin therapy first, should minimize the potential for interaction. CHEMICAL blood levels may be prolonged by concurrent administration of CHEMICAL which blocks the renal tubular secretion of penicillins. Displacement of penicillin from plasma protein binding sites will elevate the level of free penicillin in the serum. | CHEMICALS-INTERACTION |
| Concurrent administration of bacteriostatic antibiotics (e.g., erythromycin, tetracycline) may diminish the bactericidal effects of penicillins by slowing the rate of bacterial growth. Bactericidal agents work most effectively against the immature cell wall of rapidly proliferating microorganisms. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented. There are few clinical situations in which the concurrent use of ''static'' and ''cidal '' antibiotics are indicated. However, in selected circumstances in which such therapy is appropriate, using adequate doses of antibacterial agents and beginning penicillin therapy first, should minimize the potential for interaction. CHEMICAL blood levels may be prolonged by concurrent administration of probenecid which blocks the renal tubular secretion of CHEMICAL. Displacement of penicillin from plasma protein binding sites will elevate the level of free penicillin in the serum. | NO-RELATIONSHIP |
| Concurrent administration of bacteriostatic antibiotics (e.g., erythromycin, tetracycline) may diminish the bactericidal effects of penicillins by slowing the rate of bacterial growth. Bactericidal agents work most effectively against the immature cell wall of rapidly proliferating microorganisms. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented. There are few clinical situations in which the concurrent use of ''static'' and ''cidal '' antibiotics are indicated. However, in selected circumstances in which such therapy is appropriate, using adequate doses of antibacterial agents and beginning penicillin therapy first, should minimize the potential for interaction. Penicillin blood levels may be prolonged by concurrent administration of CHEMICAL which blocks the renal tubular secretion of CHEMICAL. Displacement of penicillin from plasma protein binding sites will elevate the level of free penicillin in the serum. | CHEMICALS-INTERACTION |
| Concurrent administration of bacteriostatic antibiotics (e.g., erythromycin, tetracycline) may diminish the bactericidal effects of penicillins by slowing the rate of bacterial growth. Bactericidal agents work most effectively against the immature cell wall of rapidly proliferating microorganisms. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented. There are few clinical situations in which the concurrent use of ''static'' and ''cidal '' antibiotics are indicated. However, in selected circumstances in which such therapy is appropriate, using adequate doses of antibacterial agents and beginning penicillin therapy first, should minimize the potential for interaction. Penicillin blood levels may be prolonged by concurrent administration of probenecid which blocks the renal tubular secretion of penicillins. Displacement of CHEMICAL from plasma protein binding sites will elevate the level of free CHEMICAL in the serum. | CHEMICALS-INTERACTION |
| Drug Interactions: Women on oral CHEMICAL have shown a significant increase in plasma CHEMICAL levels. | CHEMICALS-INTERACTION |
| CHEMICAL is not known to interact with other drugs including CHEMICAL supplements; interactions have not been systematically studied. Concomitant administration of CHEMET with other chelation therapy, such as CaNa 2 EDTA is not recommended. Drug/Laboratory Tests Interaction: Succimer may interfere with serum and urinary laboratory tests. In vitro studies have shown succimer to cause false positive results for ketones in urine using nitroprusside reagents such as Ketostix and falsely decreased measurements of serum uric acid and CPK. | NO-RELATIONSHIP |
| CHEMET is not known to interact with other drugs including iron supplements; interactions have not been systematically studied. Concomitant administration of CHEMICAL with other chelation therapy, such as CHEMICAL is not recommended. Drug/Laboratory Tests Interaction: Succimer may interfere with serum and urinary laboratory tests. In vitro studies have shown succimer to cause false positive results for ketones in urine using nitroprusside reagents such as Ketostix and falsely decreased measurements of serum uric acid and CPK. | CHEMICALS-INTERACTION |
| Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of CHEMICAL (CHEMICAL). AAV2 containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken -actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including collagenase, hyaluronan lyase, heparinase III, or chondroitin ABC lyase. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of heparinase III or chondroitin ABC lyase greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. Hyaluronan lyase had a limited effect and collagenase was ineffective. Electroretinograms survived with higher concentrations of heparinase III and chondroitin ABC lyase than were required for optimal retinal transduction. AAV2-mediated retinal transduction is improved by co-injection of heparinase III or chondroitin ABC lyase. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina. | NO-RELATIONSHIP |
| Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of adeno-associated virus-2 (AAV2). CHEMICAL containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken -actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including CHEMICAL, hyaluronan lyase, heparinase III, or chondroitin ABC lyase. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of heparinase III or chondroitin ABC lyase greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. Hyaluronan lyase had a limited effect and collagenase was ineffective. Electroretinograms survived with higher concentrations of heparinase III and chondroitin ABC lyase than were required for optimal retinal transduction. AAV2-mediated retinal transduction is improved by co-injection of heparinase III or chondroitin ABC lyase. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina. | REGULATOR |
| Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of adeno-associated virus-2 (AAV2). CHEMICAL containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken -actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including collagenase, CHEMICAL, heparinase III, or chondroitin ABC lyase. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of heparinase III or chondroitin ABC lyase greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. Hyaluronan lyase had a limited effect and collagenase was ineffective. Electroretinograms survived with higher concentrations of heparinase III and chondroitin ABC lyase than were required for optimal retinal transduction. AAV2-mediated retinal transduction is improved by co-injection of heparinase III or chondroitin ABC lyase. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina. | REGULATOR |
| Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of adeno-associated virus-2 (AAV2). CHEMICAL containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken -actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including collagenase, hyaluronan lyase, CHEMICAL, or chondroitin ABC lyase. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of heparinase III or chondroitin ABC lyase greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. Hyaluronan lyase had a limited effect and collagenase was ineffective. Electroretinograms survived with higher concentrations of heparinase III and chondroitin ABC lyase than were required for optimal retinal transduction. AAV2-mediated retinal transduction is improved by co-injection of heparinase III or chondroitin ABC lyase. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina. | SUBSTRATE |
| Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of adeno-associated virus-2 (AAV2). CHEMICAL containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken -actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including collagenase, hyaluronan lyase, heparinase III, or CHEMICAL. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of heparinase III or chondroitin ABC lyase greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. Hyaluronan lyase had a limited effect and collagenase was ineffective. Electroretinograms survived with higher concentrations of heparinase III and chondroitin ABC lyase than were required for optimal retinal transduction. AAV2-mediated retinal transduction is improved by co-injection of heparinase III or chondroitin ABC lyase. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina. | SUBSTRATE |
| Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of adeno-associated virus-2 (AAV2). AAV2 containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken -actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including CHEMICAL, CHEMICAL, heparinase III, or chondroitin ABC lyase. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of heparinase III or chondroitin ABC lyase greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. Hyaluronan lyase had a limited effect and collagenase was ineffective. Electroretinograms survived with higher concentrations of heparinase III and chondroitin ABC lyase than were required for optimal retinal transduction. AAV2-mediated retinal transduction is improved by co-injection of heparinase III or chondroitin ABC lyase. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina. | NO-RELATIONSHIP |
| Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of adeno-associated virus-2 (AAV2). AAV2 containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken -actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including CHEMICAL, hyaluronan lyase, CHEMICAL, or chondroitin ABC lyase. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of heparinase III or chondroitin ABC lyase greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. Hyaluronan lyase had a limited effect and collagenase was ineffective. Electroretinograms survived with higher concentrations of heparinase III and chondroitin ABC lyase than were required for optimal retinal transduction. AAV2-mediated retinal transduction is improved by co-injection of heparinase III or chondroitin ABC lyase. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina. | NO-RELATIONSHIP |
| Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of adeno-associated virus-2 (AAV2). AAV2 containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken -actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including CHEMICAL, hyaluronan lyase, heparinase III, or CHEMICAL. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of heparinase III or chondroitin ABC lyase greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. Hyaluronan lyase had a limited effect and collagenase was ineffective. Electroretinograms survived with higher concentrations of heparinase III and chondroitin ABC lyase than were required for optimal retinal transduction. AAV2-mediated retinal transduction is improved by co-injection of heparinase III or chondroitin ABC lyase. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina. | NO-RELATIONSHIP |
| Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of adeno-associated virus-2 (AAV2). AAV2 containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken -actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including collagenase, CHEMICAL, CHEMICAL, or chondroitin ABC lyase. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of heparinase III or chondroitin ABC lyase greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. Hyaluronan lyase had a limited effect and collagenase was ineffective. Electroretinograms survived with higher concentrations of heparinase III and chondroitin ABC lyase than were required for optimal retinal transduction. AAV2-mediated retinal transduction is improved by co-injection of heparinase III or chondroitin ABC lyase. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina. | NO-RELATIONSHIP |
| Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of adeno-associated virus-2 (AAV2). AAV2 containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken -actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including collagenase, CHEMICAL, heparinase III, or CHEMICAL. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of heparinase III or chondroitin ABC lyase greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. Hyaluronan lyase had a limited effect and collagenase was ineffective. Electroretinograms survived with higher concentrations of heparinase III and chondroitin ABC lyase than were required for optimal retinal transduction. AAV2-mediated retinal transduction is improved by co-injection of heparinase III or chondroitin ABC lyase. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina. | NO-RELATIONSHIP |
| Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of adeno-associated virus-2 (AAV2). AAV2 containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken -actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including collagenase, hyaluronan lyase, CHEMICAL, or CHEMICAL. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of heparinase III or chondroitin ABC lyase greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. Hyaluronan lyase had a limited effect and collagenase was ineffective. Electroretinograms survived with higher concentrations of heparinase III and chondroitin ABC lyase than were required for optimal retinal transduction. AAV2-mediated retinal transduction is improved by co-injection of heparinase III or chondroitin ABC lyase. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina. | NO-RELATIONSHIP |
| Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of adeno-associated virus-2 (AAV2). AAV2 containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken -actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including collagenase, hyaluronan lyase, heparinase III, or chondroitin ABC lyase. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of CHEMICAL or CHEMICAL greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. Hyaluronan lyase had a limited effect and collagenase was ineffective. Electroretinograms survived with higher concentrations of heparinase III and chondroitin ABC lyase than were required for optimal retinal transduction. AAV2-mediated retinal transduction is improved by co-injection of heparinase III or chondroitin ABC lyase. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina. | NO-RELATIONSHIP |
| Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of adeno-associated virus-2 (AAV2). AAV2 containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken -actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including collagenase, hyaluronan lyase, heparinase III, or chondroitin ABC lyase. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of heparinase III or chondroitin ABC lyase greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. CHEMICAL had a limited effect and CHEMICAL was ineffective. Electroretinograms survived with higher concentrations of heparinase III and chondroitin ABC lyase than were required for optimal retinal transduction. AAV2-mediated retinal transduction is improved by co-injection of heparinase III or chondroitin ABC lyase. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina. | NO-RELATIONSHIP |
| Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of adeno-associated virus-2 (AAV2). AAV2 containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken -actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including collagenase, hyaluronan lyase, heparinase III, or chondroitin ABC lyase. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of heparinase III or chondroitin ABC lyase greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. Hyaluronan lyase had a limited effect and collagenase was ineffective. Electroretinograms survived with higher concentrations of CHEMICAL and CHEMICAL than were required for optimal retinal transduction. AAV2-mediated retinal transduction is improved by co-injection of heparinase III or chondroitin ABC lyase. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina. | GENE-CHEMICAL |
| Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of adeno-associated virus-2 (AAV2). AAV2 containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken -actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including collagenase, hyaluronan lyase, heparinase III, or chondroitin ABC lyase. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of heparinase III or chondroitin ABC lyase greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. Hyaluronan lyase had a limited effect and collagenase was ineffective. Electroretinograms survived with higher concentrations of heparinase III and chondroitin ABC lyase than were required for optimal retinal transduction. CHEMICAL-mediated retinal transduction is improved by co-injection of CHEMICAL or chondroitin ABC lyase. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina. | REGULATOR |
| Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of adeno-associated virus-2 (AAV2). AAV2 containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken -actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including collagenase, hyaluronan lyase, heparinase III, or chondroitin ABC lyase. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of heparinase III or chondroitin ABC lyase greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. Hyaluronan lyase had a limited effect and collagenase was ineffective. Electroretinograms survived with higher concentrations of heparinase III and chondroitin ABC lyase than were required for optimal retinal transduction. CHEMICAL-mediated retinal transduction is improved by co-injection of heparinase III or CHEMICAL. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina. | REGULATOR |
| Glycosidic enzymes enhance retinal transduction following intravitreal delivery of AAV2. To determine whether the co-injection of extracellular matrix degrading enzymes improves retinal transduction following intravitreal delivery of adeno-associated virus-2 (AAV2). AAV2 containing cDNA encoding enhanced green fluorescent protein (GFP), under the control of a chicken -actin promoter, was delivered by intravitreal injection to adult mice in conjunction with enzymes including collagenase, hyaluronan lyase, heparinase III, or chondroitin ABC lyase. Two weeks later, retinal flatmounts were examined for GFP expression using confocal microscopy. Without the addition of enzymes, transduction was limited to occasional cells in the retinal ganglion cell layer. The addition of heparinase III or chondroitin ABC lyase greatly enhanced transduction of the retinal ganglion cell layer and increased the depth of transduction into the outer retina. Hyaluronan lyase had a limited effect and collagenase was ineffective. Electroretinograms survived with higher concentrations of heparinase III and chondroitin ABC lyase than were required for optimal retinal transduction. AAV2-mediated retinal transduction is improved by co-injection of CHEMICAL or CHEMICAL. Improved transduction efficiency may allow intravitreal injection to become the preferred route for delivering gene therapy to both the inner and outer retina. | NO-RELATIONSHIP |
| When CHEMICAL is used with other CHEMICAL, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | CHEMICALS-INTERACTION |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of CHEMICAL when on CHEMICAL. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | CHEMICALS-INTERACTION |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When CHEMICAL and CHEMICAL are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | CHEMICALS-INTERACTION |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When CHEMICAL and lithium are given concomitantly the patient should be carefully monitored for symptoms of CHEMICAL toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | NO-RELATIONSHIP |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and CHEMICAL are given concomitantly the patient should be carefully monitored for symptoms of CHEMICAL toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | NO-RELATIONSHIP |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of CHEMICAL when it is ingested with CHEMICAL or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | CHEMICALS-INTERACTION |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of CHEMICAL when it is ingested with ferrous sulfate or CHEMICAL. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | CHEMICALS-INTERACTION |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with CHEMICAL or CHEMICAL. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | NO-RELATIONSHIP |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of CHEMICAL with CHEMICAL or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | CHEMICALS-INTERACTION |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of CHEMICAL with ferrous sulfate or CHEMICAL is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | CHEMICALS-INTERACTION |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with CHEMICAL or CHEMICAL is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | NO-RELATIONSHIP |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. CHEMICAL does not interfere with measurement of CHEMICAL (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | NO-RELATIONSHIP |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. CHEMICAL does not interfere with measurement of VMA (CHEMICAL), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | NO-RELATIONSHIP |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. CHEMICAL does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert CHEMICAL to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | NO-RELATIONSHIP |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. CHEMICAL does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to CHEMICAL. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | NO-RELATIONSHIP |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of CHEMICAL (CHEMICAL), a test for pheochromocytoma, by those methods which convert VMA to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | NO-RELATIONSHIP |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of CHEMICAL (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert CHEMICAL to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | NO-RELATIONSHIP |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of CHEMICAL (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert VMA to CHEMICAL. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | NO-RELATIONSHIP |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (CHEMICAL), a test for pheochromocytoma, by those methods which convert CHEMICAL to vanillin. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | NO-RELATIONSHIP |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (CHEMICAL), a test for pheochromocytoma, by those methods which convert VMA to CHEMICAL. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | NO-RELATIONSHIP |
| When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive effect may occur. Patients should be followed carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on methyldopa. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. When methyldopa and lithium are given concomitantly the patient should be carefully monitored for symptoms of lithium toxicity. Read the circular for lithium preparations. Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulfate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa. Coadministration of methyldopa with ferrous sulfate or ferrous gluconate is not recommended. Monoamine oxidase (MAO) inhibitors: See CONTRAINDICATIONS. Drug/Laboratory Test Interactions Methyldopa may interfere with measurement of: urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and SGOT by colorimetric methods. Interference with spectrophotometric methods for SGOT analysis has not been reported. Since methyldopa causes fluorescence in urine samples at the same wave lengths as catecholamines, falsely high levels of urinary catecholamines may be reported. This will interfere with the diagnosis of pheochromocytoma. It is important to recognize this phenomenon before a patient with a possible pheochromocytoma is subjected to surgery. Methyldopa does not interfere with measurement of VMA (vanillylmandelic acid), a test for pheochromocytoma, by those methods which convert CHEMICAL to CHEMICAL. Methyldopa is not recommended for the treatment of patients with pheochromocytoma. Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites. | NO-RELATIONSHIP |
| Additives may be incompatible; CHEMICAL and CHEMICAL are incompatible with sodium bicarbonate solution. The addition of sodium bicarbonate to parenteral solutions containing calcium should be avoided, except where compatibility has been previously established. Precipitation or haze may result from sodium bicarbonate-calcium admixtures. NOTE: Do not use the injection if it contains precipitate. Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix thoroughly and do not store. | NO-RELATIONSHIP |
| Additives may be incompatible; CHEMICAL and dobutamine are incompatible with CHEMICAL solution. The addition of sodium bicarbonate to parenteral solutions containing calcium should be avoided, except where compatibility has been previously established. Precipitation or haze may result from sodium bicarbonate-calcium admixtures. NOTE: Do not use the injection if it contains precipitate. Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix thoroughly and do not store. | CHEMICALS-INTERACTION |
| Additives may be incompatible; norepinephrine and CHEMICAL are incompatible with CHEMICAL solution. The addition of sodium bicarbonate to parenteral solutions containing calcium should be avoided, except where compatibility has been previously established. Precipitation or haze may result from sodium bicarbonate-calcium admixtures. NOTE: Do not use the injection if it contains precipitate. Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix thoroughly and do not store. | CHEMICALS-INTERACTION |
| Additives may be incompatible; norepinephrine and dobutamine are incompatible with sodium bicarbonate solution. The addition of CHEMICAL to parenteral solutions containing CHEMICAL should be avoided, except where compatibility has been previously established. Precipitation or haze may result from sodium bicarbonate-calcium admixtures. NOTE: Do not use the injection if it contains precipitate. Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix thoroughly and do not store. | CHEMICALS-INTERACTION |
| Antitumor effects of CRM197, a specific inhibitor of HB-EGF, in T-cell acute lymphoblastic leukemia. The therapeutic outcome for T-cell acute lymphoblastic leukemia (T-ALL) remains poor; thus, novel, targeted therapies are urgently needed. Recently, we showed that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGF family, is a promising target for the treatment of various types of cancer. The aim of the present study was to investigate whether HB-EGF is a therapeutic target for T-ALL, and to further elucidate the antitumor effects of a specific inhibitor of HB-EGF, CHEMICAL (CHEMICAL). We elucidated the expression of HB-EGF in T-ALL cell lines, and evaluated the effect of CRM197 on these cells alone or in combination with anticancer agent. The expression of EGFR and EGFR ligands was determined by flow cytometry, RT-PCR and real-time quantitative PCR. Induction of apoptosis was assessed by TUNEL assay. HB-EGF was strongly expressed by T-ALL cell lines, and the expression of both HB-EGF and EGFR was enhanced by doxorubicin. CRM197 induced apoptosis, and furthermore, the combination of CRM197 plus doxorubicin enhanced cytotoxicity in a T-ALL cell line. These results suggest that HB-EGF is a promising therapeutic target for T-ALL. | NO-RELATIONSHIP |
| Antitumor effects of CRM197, a specific inhibitor of HB-EGF, in T-cell acute lymphoblastic leukemia. The therapeutic outcome for T-cell acute lymphoblastic leukemia (T-ALL) remains poor; thus, novel, targeted therapies are urgently needed. Recently, we showed that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGF family, is a promising target for the treatment of various types of cancer. The aim of the present study was to investigate whether HB-EGF is a therapeutic target for T-ALL, and to further elucidate the antitumor effects of a specific inhibitor of HB-EGF, cross-reacting material 197 (CRM197). We elucidated the expression of HB-EGF in T-ALL cell lines, and evaluated the effect of CHEMICAL on these cells alone or in combination with CHEMICAL. The expression of EGFR and EGFR ligands was determined by flow cytometry, RT-PCR and real-time quantitative PCR. Induction of apoptosis was assessed by TUNEL assay. HB-EGF was strongly expressed by T-ALL cell lines, and the expression of both HB-EGF and EGFR was enhanced by doxorubicin. CRM197 induced apoptosis, and furthermore, the combination of CRM197 plus doxorubicin enhanced cytotoxicity in a T-ALL cell line. These results suggest that HB-EGF is a promising therapeutic target for T-ALL. | NO-RELATIONSHIP |
| Antitumor effects of CRM197, a specific inhibitor of HB-EGF, in T-cell acute lymphoblastic leukemia. The therapeutic outcome for T-cell acute lymphoblastic leukemia (T-ALL) remains poor; thus, novel, targeted therapies are urgently needed. Recently, we showed that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGF family, is a promising target for the treatment of various types of cancer. The aim of the present study was to investigate whether HB-EGF is a therapeutic target for T-ALL, and to further elucidate the antitumor effects of a specific inhibitor of HB-EGF, cross-reacting material 197 (CRM197). We elucidated the expression of HB-EGF in T-ALL cell lines, and evaluated the effect of CRM197 on these cells alone or in combination with anticancer agent. The expression of EGFR and EGFR ligands was determined by flow cytometry, RT-PCR and real-time quantitative PCR. Induction of apoptosis was assessed by TUNEL assay. HB-EGF was strongly expressed by T-ALL cell lines, and the expression of both HB-EGF and EGFR was enhanced by doxorubicin. CHEMICAL induced apoptosis, and furthermore, the combination of CHEMICAL plus doxorubicin enhanced cytotoxicity in a T-ALL cell line. These results suggest that HB-EGF is a promising therapeutic target for T-ALL. | NO-RELATIONSHIP |
| Antitumor effects of CRM197, a specific inhibitor of HB-EGF, in T-cell acute lymphoblastic leukemia. The therapeutic outcome for T-cell acute lymphoblastic leukemia (T-ALL) remains poor; thus, novel, targeted therapies are urgently needed. Recently, we showed that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGF family, is a promising target for the treatment of various types of cancer. The aim of the present study was to investigate whether HB-EGF is a therapeutic target for T-ALL, and to further elucidate the antitumor effects of a specific inhibitor of HB-EGF, cross-reacting material 197 (CRM197). We elucidated the expression of HB-EGF in T-ALL cell lines, and evaluated the effect of CRM197 on these cells alone or in combination with anticancer agent. The expression of EGFR and EGFR ligands was determined by flow cytometry, RT-PCR and real-time quantitative PCR. Induction of apoptosis was assessed by TUNEL assay. HB-EGF was strongly expressed by T-ALL cell lines, and the expression of both HB-EGF and EGFR was enhanced by doxorubicin. CHEMICAL induced apoptosis, and furthermore, the combination of CRM197 plus CHEMICAL enhanced cytotoxicity in a T-ALL cell line. These results suggest that HB-EGF is a promising therapeutic target for T-ALL. | NO-RELATIONSHIP |
| Antitumor effects of CRM197, a specific inhibitor of HB-EGF, in T-cell acute lymphoblastic leukemia. The therapeutic outcome for T-cell acute lymphoblastic leukemia (T-ALL) remains poor; thus, novel, targeted therapies are urgently needed. Recently, we showed that heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGF family, is a promising target for the treatment of various types of cancer. The aim of the present study was to investigate whether HB-EGF is a therapeutic target for T-ALL, and to further elucidate the antitumor effects of a specific inhibitor of HB-EGF, cross-reacting material 197 (CRM197). We elucidated the expression of HB-EGF in T-ALL cell lines, and evaluated the effect of CRM197 on these cells alone or in combination with anticancer agent. The expression of EGFR and EGFR ligands was determined by flow cytometry, RT-PCR and real-time quantitative PCR. Induction of apoptosis was assessed by TUNEL assay. HB-EGF was strongly expressed by T-ALL cell lines, and the expression of both HB-EGF and EGFR was enhanced by doxorubicin. CRM197 induced apoptosis, and furthermore, the combination of CHEMICAL plus CHEMICAL enhanced cytotoxicity in a T-ALL cell line. These results suggest that HB-EGF is a promising therapeutic target for T-ALL. | CHEMICALS-INTERACTION |
| The bioavailability of CHEMICAL is decreased 80% by CHEMICAL, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | CHEMICALS-INTERACTION |
| The bioavailability of CHEMICAL is decreased 80% by calcium, when CHEMICAL and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of CHEMICAL is decreased 80% by calcium, when calcium and CHEMICAL are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of CHEMICAL is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some CHEMICAL- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of CHEMICAL is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or CHEMICAL-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of CHEMICAL is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing CHEMICAL, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of CHEMICAL is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before CHEMICAL. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by CHEMICAL, when CHEMICAL and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by CHEMICAL, when calcium and CHEMICAL are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by CHEMICAL, when calcium and SKELID are administered at the same time, and 60% by some CHEMICAL- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by CHEMICAL, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or CHEMICAL-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by CHEMICAL, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing CHEMICAL, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by CHEMICAL, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before CHEMICAL. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by calcium, when CHEMICAL and CHEMICAL are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | CHEMICALS-INTERACTION |
| The bioavailability of SKELID is decreased 80% by calcium, when CHEMICAL and SKELID are administered at the same time, and 60% by some CHEMICAL- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by calcium, when CHEMICAL and SKELID are administered at the same time, and 60% by some aluminum- or CHEMICAL-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by calcium, when CHEMICAL and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing CHEMICAL, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by calcium, when CHEMICAL and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before CHEMICAL. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and CHEMICAL are administered at the same time, and 60% by some CHEMICAL- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and CHEMICAL are administered at the same time, and 60% by some aluminum- or CHEMICAL-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and CHEMICAL are administered at the same time, and 60% by some aluminum- or magnesium-containing CHEMICAL, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and CHEMICAL are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before CHEMICAL. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some CHEMICAL- or CHEMICAL-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some CHEMICAL- or magnesium-containing CHEMICAL, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some CHEMICAL- or magnesium-containing antacids, when administered 1 hour before CHEMICAL. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | CHEMICALS-INTERACTION |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or CHEMICAL-containing CHEMICAL, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or CHEMICAL-containing antacids, when administered 1 hour before CHEMICAL. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | CHEMICALS-INTERACTION |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing CHEMICAL, when administered 1 hour before CHEMICAL. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | CHEMICALS-INTERACTION |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before SKELID. CHEMICAL may decrease bioavailability of CHEMICAL by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | CHEMICALS-INTERACTION |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before SKELID. CHEMICAL may decrease bioavailability of SKELID by up to 50% when taken 2 hours after CHEMICAL. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | CHEMICALS-INTERACTION |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of CHEMICAL by up to 50% when taken 2 hours after CHEMICAL. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | CHEMICALS-INTERACTION |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of CHEMICAL is increased 2-4 fold by CHEMICAL but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | CHEMICALS-INTERACTION |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of CHEMICAL is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of CHEMICAL. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by CHEMICAL but is not significantly altered by coadministration of CHEMICAL. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of CHEMICAL are not significantly modified by CHEMICAL coadministration. In vitro studies show that tiludronate does not displace warfarin from its binding site on protein. | NO-RELATIONSHIP |
| The bioavailability of SKELID is decreased 80% by calcium, when calcium and SKELID are administered at the same time, and 60% by some aluminum- or magnesium-containing antacids, when administered 1 hour before SKELID. Aspirin may decrease bioavailability of SKELID by up to 50% when taken 2 hours after SKELID. The bioavailability of SKELID is increased 2-4 fold by indomethacin but is not significantly altered by coadministration of diclofenac. The pharmacokinetic parameters of digoxin are not significantly modified by SKELID coadministration. In vitro studies show that CHEMICAL does not displace CHEMICAL from its binding site on protein. | NO-RELATIONSHIP |
| CHEMICAL, a bacteriostatic CHEMICAL, may antagonize the bactericidal effect of penicillin and concurrent use of these drugs should be avoided. | NO-RELATIONSHIP |
| CHEMICAL, a bacteriostatic antibiotic, may antagonize the bactericidal effect of CHEMICAL and concurrent use of these drugs should be avoided. | CHEMICALS-INTERACTION |
| Tetracycline, a bacteriostatic CHEMICAL, may antagonize the bactericidal effect of CHEMICAL and concurrent use of these drugs should be avoided. | NO-RELATIONSHIP |
| The absorption of oral medications may be decreased during the concurrent use of scopolamine because of decreased gastric motility and delayed gastric emptying. CHEMICAL should be used with care in patients taking other drugs that are capable of causing CNS effects such as CHEMICAL, tranquilizers, or alcohol. Special attention should be paid to potential interactions with drugs having anticholinergic properties; e.g., other belladonna alkaloids, antihistamines (including meclizine), tricyclic antidepressants, and muscle relaxants. Laboratory Test Interactions Scopolamine will interfere with the gastric secretion test. | CHEMICALS-INTERACTION |
| The absorption of oral medications may be decreased during the concurrent use of scopolamine because of decreased gastric motility and delayed gastric emptying. CHEMICAL should be used with care in patients taking other drugs that are capable of causing CNS effects such as sedatives, CHEMICAL, or alcohol. Special attention should be paid to potential interactions with drugs having anticholinergic properties; e.g., other belladonna alkaloids, antihistamines (including meclizine), tricyclic antidepressants, and muscle relaxants. Laboratory Test Interactions Scopolamine will interfere with the gastric secretion test. | CHEMICALS-INTERACTION |
| The absorption of oral medications may be decreased during the concurrent use of scopolamine because of decreased gastric motility and delayed gastric emptying. CHEMICAL should be used with care in patients taking other drugs that are capable of causing CNS effects such as sedatives, tranquilizers, or CHEMICAL. Special attention should be paid to potential interactions with drugs having anticholinergic properties; e.g., other belladonna alkaloids, antihistamines (including meclizine), tricyclic antidepressants, and muscle relaxants. Laboratory Test Interactions Scopolamine will interfere with the gastric secretion test. | CHEMICALS-INTERACTION |
| The absorption of oral medications may be decreased during the concurrent use of scopolamine because of decreased gastric motility and delayed gastric emptying. Scopolamine should be used with care in patients taking other drugs that are capable of causing CNS effects such as CHEMICAL, CHEMICAL, or alcohol. Special attention should be paid to potential interactions with drugs having anticholinergic properties; e.g., other belladonna alkaloids, antihistamines (including meclizine), tricyclic antidepressants, and muscle relaxants. Laboratory Test Interactions Scopolamine will interfere with the gastric secretion test. | NO-RELATIONSHIP |
| The absorption of oral medications may be decreased during the concurrent use of scopolamine because of decreased gastric motility and delayed gastric emptying. Scopolamine should be used with care in patients taking other drugs that are capable of causing CNS effects such as CHEMICAL, tranquilizers, or CHEMICAL. Special attention should be paid to potential interactions with drugs having anticholinergic properties; e.g., other belladonna alkaloids, antihistamines (including meclizine), tricyclic antidepressants, and muscle relaxants. Laboratory Test Interactions Scopolamine will interfere with the gastric secretion test. | NO-RELATIONSHIP |
| The absorption of oral medications may be decreased during the concurrent use of scopolamine because of decreased gastric motility and delayed gastric emptying. Scopolamine should be used with care in patients taking other drugs that are capable of causing CNS effects such as sedatives, CHEMICAL, or CHEMICAL. Special attention should be paid to potential interactions with drugs having anticholinergic properties; e.g., other belladonna alkaloids, antihistamines (including meclizine), tricyclic antidepressants, and muscle relaxants. Laboratory Test Interactions Scopolamine will interfere with the gastric secretion test. | NO-RELATIONSHIP |
| The absorption of oral medications may be decreased during the concurrent use of scopolamine because of decreased gastric motility and delayed gastric emptying. Scopolamine should be used with care in patients taking other drugs that are capable of causing CNS effects such as sedatives, tranquilizers, or alcohol. Special attention should be paid to potential interactions with drugs having anticholinergic properties; e.g., other CHEMICAL, CHEMICAL (including meclizine), tricyclic antidepressants, and muscle relaxants. Laboratory Test Interactions Scopolamine will interfere with the gastric secretion test. | NO-RELATIONSHIP |
| The absorption of oral medications may be decreased during the concurrent use of scopolamine because of decreased gastric motility and delayed gastric emptying. Scopolamine should be used with care in patients taking other drugs that are capable of causing CNS effects such as sedatives, tranquilizers, or alcohol. Special attention should be paid to potential interactions with drugs having anticholinergic properties; e.g., other CHEMICAL, antihistamines (including CHEMICAL), tricyclic antidepressants, and muscle relaxants. Laboratory Test Interactions Scopolamine will interfere with the gastric secretion test. | NO-RELATIONSHIP |
| The absorption of oral medications may be decreased during the concurrent use of scopolamine because of decreased gastric motility and delayed gastric emptying. Scopolamine should be used with care in patients taking other drugs that are capable of causing CNS effects such as sedatives, tranquilizers, or alcohol. Special attention should be paid to potential interactions with drugs having anticholinergic properties; e.g., other CHEMICAL, antihistamines (including meclizine), CHEMICAL, and muscle relaxants. Laboratory Test Interactions Scopolamine will interfere with the gastric secretion test. | NO-RELATIONSHIP |
| The absorption of oral medications may be decreased during the concurrent use of scopolamine because of decreased gastric motility and delayed gastric emptying. Scopolamine should be used with care in patients taking other drugs that are capable of causing CNS effects such as sedatives, tranquilizers, or alcohol. Special attention should be paid to potential interactions with drugs having anticholinergic properties; e.g., other CHEMICAL, antihistamines (including meclizine), tricyclic antidepressants, and CHEMICAL. Laboratory Test Interactions Scopolamine will interfere with the gastric secretion test. | NO-RELATIONSHIP |
| The absorption of oral medications may be decreased during the concurrent use of scopolamine because of decreased gastric motility and delayed gastric emptying. Scopolamine should be used with care in patients taking other drugs that are capable of causing CNS effects such as sedatives, tranquilizers, or alcohol. Special attention should be paid to potential interactions with drugs having anticholinergic properties; e.g., other belladonna alkaloids, CHEMICAL (including CHEMICAL), tricyclic antidepressants, and muscle relaxants. Laboratory Test Interactions Scopolamine will interfere with the gastric secretion test. | NO-RELATIONSHIP |
| The absorption of oral medications may be decreased during the concurrent use of scopolamine because of decreased gastric motility and delayed gastric emptying. Scopolamine should be used with care in patients taking other drugs that are capable of causing CNS effects such as sedatives, tranquilizers, or alcohol. Special attention should be paid to potential interactions with drugs having anticholinergic properties; e.g., other belladonna alkaloids, CHEMICAL (including meclizine), CHEMICAL, and muscle relaxants. Laboratory Test Interactions Scopolamine will interfere with the gastric secretion test. | NO-RELATIONSHIP |
| The absorption of oral medications may be decreased during the concurrent use of scopolamine because of decreased gastric motility and delayed gastric emptying. Scopolamine should be used with care in patients taking other drugs that are capable of causing CNS effects such as sedatives, tranquilizers, or alcohol. Special attention should be paid to potential interactions with drugs having anticholinergic properties; e.g., other belladonna alkaloids, CHEMICAL (including meclizine), tricyclic antidepressants, and CHEMICAL. Laboratory Test Interactions Scopolamine will interfere with the gastric secretion test. | NO-RELATIONSHIP |
| The absorption of oral medications may be decreased during the concurrent use of scopolamine because of decreased gastric motility and delayed gastric emptying. Scopolamine should be used with care in patients taking other drugs that are capable of causing CNS effects such as sedatives, tranquilizers, or alcohol. Special attention should be paid to potential interactions with drugs having anticholinergic properties; e.g., other belladonna alkaloids, antihistamines (including CHEMICAL), CHEMICAL, and muscle relaxants. Laboratory Test Interactions Scopolamine will interfere with the gastric secretion test. | NO-RELATIONSHIP |
| The absorption of oral medications may be decreased during the concurrent use of scopolamine because of decreased gastric motility and delayed gastric emptying. Scopolamine should be used with care in patients taking other drugs that are capable of causing CNS effects such as sedatives, tranquilizers, or alcohol. Special attention should be paid to potential interactions with drugs having anticholinergic properties; e.g., other belladonna alkaloids, antihistamines (including CHEMICAL), tricyclic antidepressants, and CHEMICAL. Laboratory Test Interactions Scopolamine will interfere with the gastric secretion test. | NO-RELATIONSHIP |
| The absorption of oral medications may be decreased during the concurrent use of scopolamine because of decreased gastric motility and delayed gastric emptying. Scopolamine should be used with care in patients taking other drugs that are capable of causing CNS effects such as sedatives, tranquilizers, or alcohol. Special attention should be paid to potential interactions with drugs having anticholinergic properties; e.g., other belladonna alkaloids, antihistamines (including meclizine), CHEMICAL, and CHEMICAL. Laboratory Test Interactions Scopolamine will interfere with the gastric secretion test. | NO-RELATIONSHIP |
| The induction dose requirements of CHEMICAL Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with CHEMICAL (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | CHEMICALS-INTERACTION |
| The induction dose requirements of CHEMICAL Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, CHEMICAL, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | CHEMICALS-INTERACTION |
| The induction dose requirements of CHEMICAL Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, CHEMICAL, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | CHEMICALS-INTERACTION |
| The induction dose requirements of CHEMICAL Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and CHEMICAL, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | CHEMICALS-INTERACTION |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with CHEMICAL (eg, CHEMICAL, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with CHEMICAL (eg, morphine, CHEMICAL, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with CHEMICAL (eg, morphine, meperidine, and CHEMICAL, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, CHEMICAL, CHEMICAL, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, CHEMICAL, meperidine, and CHEMICAL, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, CHEMICAL, and CHEMICAL, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of CHEMICAL and CHEMICAL (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of CHEMICAL and sedatives (eg, CHEMICAL, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of CHEMICAL and sedatives (eg, benzodiazepines, CHEMICAL, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of CHEMICAL and sedatives (eg, benzodiazepines, barbiturates, CHEMICAL, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of CHEMICAL and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, CHEMICAL, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and CHEMICAL (eg, CHEMICAL, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and CHEMICAL (eg, benzodiazepines, CHEMICAL, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and CHEMICAL (eg, benzodiazepines, barbiturates, CHEMICAL, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and CHEMICAL (eg, benzodiazepines, barbiturates, chloral hydrate, CHEMICAL, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, CHEMICAL, CHEMICAL, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, CHEMICAL, barbiturates, CHEMICAL, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, CHEMICAL, barbiturates, chloral hydrate, CHEMICAL, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, CHEMICAL, CHEMICAL, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, CHEMICAL, chloral hydrate, CHEMICAL, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, CHEMICAL, CHEMICAL, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of CHEMICAL Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental CHEMICAL (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | CHEMICALS-INTERACTION |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of CHEMICAL Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, CHEMICAL or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | CHEMICALS-INTERACTION |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of CHEMICAL Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or CHEMICAL). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | CHEMICALS-INTERACTION |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental CHEMICAL (eg, CHEMICAL or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental CHEMICAL (eg, nitrous oxide or CHEMICAL). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, CHEMICAL or CHEMICAL). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, CHEMICAL, CHEMICAL, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, CHEMICAL, enflurane, and CHEMICAL) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, CHEMICAL, enflurane, and halothane) during maintenance with CHEMICAL Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, CHEMICAL, and CHEMICAL) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, CHEMICAL, and halothane) during maintenance with CHEMICAL Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and CHEMICAL) during maintenance with CHEMICAL Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. CHEMICAL Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used CHEMICAL (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. CHEMICAL Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, CHEMICAL and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. CHEMICAL Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and CHEMICAL). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used CHEMICAL (eg, CHEMICAL and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used CHEMICAL (eg, succinylcholine and CHEMICAL). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, CHEMICAL and CHEMICAL). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, analgesic agents, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of CHEMICAL, inhalational agents, CHEMICAL, and local anesthetic agents) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of CHEMICAL, inhalational agents, analgesic agents, and local CHEMICAL) have been observed. | NO-RELATIONSHIP |
| The induction dose requirements of DIPRIVAN Injectable Emulsion may be reduced in patients with intramuscular or intravenous premedication, particularly with narcotics (eg, morphine, meperidine, and fentanyl, etc.) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, chloral hydrate, droperidol, etc.). These agents may increase the anesthetic or sedative effects of DIPRIVAN Injectable Emulsion and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. During maintenance of anesthesia or sedation, the rate of DIPRIVAN Injectable Emulsion administration should be adjusted according to the desired level of anesthesia or sedation and may be reduced in the presence of supplemental analgesic agents (eg, nitrous oxide or opioids). The concurrent administration of potent inhalational agents (eg, isoflurane, enflurane, and halothane) during maintenance with DIPRIVAN Injectable Emulsion has not been extensively evaluated. These inhalational agents can also be expected to increase the anesthetic or sedative and cardiorespiratory effects of DIPRIVAN Injectable Emulsion. DIPRIVAN Injectable Emulsion does not cause a clinically significant change in onset, intensity, or duration of action of the commonly used neuromuscular blocking agents (eg, succinylcholine and nondepolarizing muscle relaxants). No significant adverse interactions with commonly used premedications or drugs used during anesthesia or sedation (including a range of muscle relaxants, inhalational agents, CHEMICAL, and local CHEMICAL) have been observed. | NO-RELATIONSHIP |
| Prevention of emergence agitation in seven children receiving low-dose CHEMICAL and CHEMICAL total intravenous anesthesia. Emergence agitation (EA) can be a distressing side effect of pediatric anesthesia. We retrospectively reviewed the records of 7 pediatric oncology patients who received low-dose ketamine in conjunction with propofol for total intravenous anesthesia (TIVA) repeatedly for radiation therapy. EA signs were observed in all 7 patients in association with propofol TIVA but did not recur in any of 123 subsequent anesthetics sessions during which low-dose ketamine was added to propofol. Based on this experience, we suggest that low-dose ketamine added to propofol may be associated with prevention of EA in children with a history of EA with propofol TIVA. | CHEMICALS-INTERACTION |
| Prevention of emergence agitation in seven children receiving low-dose ketamine and propofol total intravenous anesthesia. Emergence agitation (EA) can be a distressing side effect of pediatric anesthesia. We retrospectively reviewed the records of 7 pediatric oncology patients who received low-dose CHEMICAL in conjunction with CHEMICAL for total intravenous anesthesia (TIVA) repeatedly for radiation therapy. EA signs were observed in all 7 patients in association with propofol TIVA but did not recur in any of 123 subsequent anesthetics sessions during which low-dose ketamine was added to propofol. Based on this experience, we suggest that low-dose ketamine added to propofol may be associated with prevention of EA in children with a history of EA with propofol TIVA. | NO-RELATIONSHIP |
| Prevention of emergence agitation in seven children receiving low-dose ketamine and propofol total intravenous anesthesia. Emergence agitation (EA) can be a distressing side effect of pediatric anesthesia. We retrospectively reviewed the records of 7 pediatric oncology patients who received low-dose ketamine in conjunction with propofol for total intravenous anesthesia (TIVA) repeatedly for radiation therapy. EA signs were observed in all 7 patients in association with CHEMICAL TIVA but did not recur in any of 123 subsequent anesthetics sessions during which low-dose CHEMICAL was added to propofol. Based on this experience, we suggest that low-dose ketamine added to propofol may be associated with prevention of EA in children with a history of EA with propofol TIVA. | NO-RELATIONSHIP |
| Prevention of emergence agitation in seven children receiving low-dose ketamine and propofol total intravenous anesthesia. Emergence agitation (EA) can be a distressing side effect of pediatric anesthesia. We retrospectively reviewed the records of 7 pediatric oncology patients who received low-dose ketamine in conjunction with propofol for total intravenous anesthesia (TIVA) repeatedly for radiation therapy. EA signs were observed in all 7 patients in association with CHEMICAL TIVA but did not recur in any of 123 subsequent anesthetics sessions during which low-dose ketamine was added to CHEMICAL. Based on this experience, we suggest that low-dose ketamine added to propofol may be associated with prevention of EA in children with a history of EA with propofol TIVA. | NO-RELATIONSHIP |
| Prevention of emergence agitation in seven children receiving low-dose ketamine and propofol total intravenous anesthesia. Emergence agitation (EA) can be a distressing side effect of pediatric anesthesia. We retrospectively reviewed the records of 7 pediatric oncology patients who received low-dose ketamine in conjunction with propofol for total intravenous anesthesia (TIVA) repeatedly for radiation therapy. EA signs were observed in all 7 patients in association with propofol TIVA but did not recur in any of 123 subsequent anesthetics sessions during which low-dose CHEMICAL was added to CHEMICAL. Based on this experience, we suggest that low-dose ketamine added to propofol may be associated with prevention of EA in children with a history of EA with propofol TIVA. | NO-RELATIONSHIP |
| Prevention of emergence agitation in seven children receiving low-dose ketamine and propofol total intravenous anesthesia. Emergence agitation (EA) can be a distressing side effect of pediatric anesthesia. We retrospectively reviewed the records of 7 pediatric oncology patients who received low-dose ketamine in conjunction with propofol for total intravenous anesthesia (TIVA) repeatedly for radiation therapy. EA signs were observed in all 7 patients in association with propofol TIVA but did not recur in any of 123 subsequent anesthetics sessions during which low-dose ketamine was added to propofol. Based on this experience, we suggest that low-dose CHEMICAL added to CHEMICAL may be associated with prevention of EA in children with a history of EA with propofol TIVA. | CHEMICALS-INTERACTION |
| Prevention of emergence agitation in seven children receiving low-dose ketamine and propofol total intravenous anesthesia. Emergence agitation (EA) can be a distressing side effect of pediatric anesthesia. We retrospectively reviewed the records of 7 pediatric oncology patients who received low-dose ketamine in conjunction with propofol for total intravenous anesthesia (TIVA) repeatedly for radiation therapy. EA signs were observed in all 7 patients in association with propofol TIVA but did not recur in any of 123 subsequent anesthetics sessions during which low-dose ketamine was added to propofol. Based on this experience, we suggest that low-dose CHEMICAL added to propofol may be associated with prevention of EA in children with a history of EA with CHEMICAL TIVA. | NO-RELATIONSHIP |
| Prevention of emergence agitation in seven children receiving low-dose ketamine and propofol total intravenous anesthesia. Emergence agitation (EA) can be a distressing side effect of pediatric anesthesia. We retrospectively reviewed the records of 7 pediatric oncology patients who received low-dose ketamine in conjunction with propofol for total intravenous anesthesia (TIVA) repeatedly for radiation therapy. EA signs were observed in all 7 patients in association with propofol TIVA but did not recur in any of 123 subsequent anesthetics sessions during which low-dose ketamine was added to propofol. Based on this experience, we suggest that low-dose ketamine added to CHEMICAL may be associated with prevention of EA in children with a history of EA with CHEMICAL TIVA. | NO-RELATIONSHIP |
| The in vitro binding of CHEMICAL to human plasma proteins is unaffected by CHEMICAL, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants. In adult diabetic patients under treatment with either sulfonylureas or insulin there is no change in the clinical effects of either TOLECTIN or the hypoglycemic agents. Caution should be used if TOLECTIN is administered concomitantly with methotrexate. TOLECTIN and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly enhancing the toxicity of methotrexate. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | NO-RELATIONSHIP |
| The in vitro binding of CHEMICAL to human plasma proteins is unaffected by tolmetin, and CHEMICAL does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants. In adult diabetic patients under treatment with either sulfonylureas or insulin there is no change in the clinical effects of either TOLECTIN or the hypoglycemic agents. Caution should be used if TOLECTIN is administered concomitantly with methotrexate. TOLECTIN and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly enhancing the toxicity of methotrexate. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | NO-RELATIONSHIP |
| The in vitro binding of warfarin to human plasma proteins is unaffected by CHEMICAL, and CHEMICAL does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants. In adult diabetic patients under treatment with either sulfonylureas or insulin there is no change in the clinical effects of either TOLECTIN or the hypoglycemic agents. Caution should be used if TOLECTIN is administered concomitantly with methotrexate. TOLECTIN and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly enhancing the toxicity of methotrexate. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | NO-RELATIONSHIP |
| The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant CHEMICAL and CHEMICAL therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants. In adult diabetic patients under treatment with either sulfonylureas or insulin there is no change in the clinical effects of either TOLECTIN or the hypoglycemic agents. Caution should be used if TOLECTIN is administered concomitantly with methotrexate. TOLECTIN and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly enhancing the toxicity of methotrexate. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | CHEMICALS-INTERACTION |
| The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering CHEMICAL to patients on CHEMICAL. In adult diabetic patients under treatment with either sulfonylureas or insulin there is no change in the clinical effects of either TOLECTIN or the hypoglycemic agents. Caution should be used if TOLECTIN is administered concomitantly with methotrexate. TOLECTIN and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly enhancing the toxicity of methotrexate. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | CHEMICALS-INTERACTION |
| The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants. In adult diabetic patients under treatment with either CHEMICAL or CHEMICAL there is no change in the clinical effects of either TOLECTIN or the hypoglycemic agents. Caution should be used if TOLECTIN is administered concomitantly with methotrexate. TOLECTIN and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly enhancing the toxicity of methotrexate. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | NO-RELATIONSHIP |
| The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants. In adult diabetic patients under treatment with either CHEMICAL or insulin there is no change in the clinical effects of either CHEMICAL or the hypoglycemic agents. Caution should be used if TOLECTIN is administered concomitantly with methotrexate. TOLECTIN and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly enhancing the toxicity of methotrexate. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | NO-RELATIONSHIP |
| The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants. In adult diabetic patients under treatment with either CHEMICAL or insulin there is no change in the clinical effects of either TOLECTIN or the CHEMICAL. Caution should be used if TOLECTIN is administered concomitantly with methotrexate. TOLECTIN and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly enhancing the toxicity of methotrexate. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | NO-RELATIONSHIP |
| The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants. In adult diabetic patients under treatment with either sulfonylureas or CHEMICAL there is no change in the clinical effects of either CHEMICAL or the hypoglycemic agents. Caution should be used if TOLECTIN is administered concomitantly with methotrexate. TOLECTIN and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly enhancing the toxicity of methotrexate. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | NO-RELATIONSHIP |
| The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants. In adult diabetic patients under treatment with either sulfonylureas or CHEMICAL there is no change in the clinical effects of either TOLECTIN or the CHEMICAL. Caution should be used if TOLECTIN is administered concomitantly with methotrexate. TOLECTIN and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly enhancing the toxicity of methotrexate. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | NO-RELATIONSHIP |
| The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants. In adult diabetic patients under treatment with either sulfonylureas or insulin there is no change in the clinical effects of either CHEMICAL or the CHEMICAL. Caution should be used if TOLECTIN is administered concomitantly with methotrexate. TOLECTIN and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly enhancing the toxicity of methotrexate. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | NO-RELATIONSHIP |
| The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants. In adult diabetic patients under treatment with either sulfonylureas or insulin there is no change in the clinical effects of either TOLECTIN or the hypoglycemic agents. Caution should be used if CHEMICAL is administered concomitantly with CHEMICAL. TOLECTIN and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly enhancing the toxicity of methotrexate. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | CHEMICALS-INTERACTION |
| The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants. In adult diabetic patients under treatment with either sulfonylureas or insulin there is no change in the clinical effects of either TOLECTIN or the hypoglycemic agents. Caution should be used if TOLECTIN is administered concomitantly with methotrexate. CHEMICAL and other CHEMICAL have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly enhancing the toxicity of methotrexate. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | NO-RELATIONSHIP |
| The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants. In adult diabetic patients under treatment with either sulfonylureas or insulin there is no change in the clinical effects of either TOLECTIN or the hypoglycemic agents. Caution should be used if TOLECTIN is administered concomitantly with methotrexate. CHEMICAL and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of CHEMICAL in an animal model, possibly enhancing the toxicity of methotrexate. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | CHEMICALS-INTERACTION |
| The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants. In adult diabetic patients under treatment with either sulfonylureas or insulin there is no change in the clinical effects of either TOLECTIN or the hypoglycemic agents. Caution should be used if TOLECTIN is administered concomitantly with methotrexate. CHEMICAL and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly enhancing the toxicity of CHEMICAL. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | CHEMICALS-INTERACTION |
| The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants. In adult diabetic patients under treatment with either sulfonylureas or insulin there is no change in the clinical effects of either TOLECTIN or the hypoglycemic agents. Caution should be used if TOLECTIN is administered concomitantly with methotrexate. TOLECTIN and other CHEMICAL have been reported to reduce the tubular secretion of CHEMICAL in an animal model, possibly enhancing the toxicity of methotrexate. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | CHEMICALS-INTERACTION |
| The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants. In adult diabetic patients under treatment with either sulfonylureas or insulin there is no change in the clinical effects of either TOLECTIN or the hypoglycemic agents. Caution should be used if TOLECTIN is administered concomitantly with methotrexate. TOLECTIN and other CHEMICAL have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly enhancing the toxicity of CHEMICAL. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | NO-RELATIONSHIP |
| The in vitro binding of warfarin to human plasma proteins is unaffected by tolmetin, and tolmetin does not alter the prothrombin time of normal volunteers. However, increased prothrombin time and bleeding have been reported in patients on concomitant TOLECTIN and warfarin therapy. Therefore, caution should be exercised when administering TOLECTIN to patients on anticoagulants. In adult diabetic patients under treatment with either sulfonylureas or insulin there is no change in the clinical effects of either TOLECTIN or the hypoglycemic agents. Caution should be used if TOLECTIN is administered concomitantly with methotrexate. TOLECTIN and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of CHEMICAL in an animal model, possibly enhancing the toxicity of CHEMICAL. Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up. | NO-RELATIONSHIP |
| CHEMICAL may accentuate the orthostatic hypotension that may occur with CHEMICAL. Antihypertensive effects of guanethidine and related compounds may be counteracted when phenothiazines are used concomitantly. Concomitant administration of propranolol with phenothiazines results in increased plasma levels of both drugs. | CHEMICALS-INTERACTION |
| Thiazide diuretics may accentuate the orthostatic hypotension that may occur with phenothiazines. Antihypertensive effects of CHEMICAL and related compounds may be counteracted when CHEMICAL are used concomitantly. Concomitant administration of propranolol with phenothiazines results in increased plasma levels of both drugs. | CHEMICALS-INTERACTION |
| Thiazide diuretics may accentuate the orthostatic hypotension that may occur with phenothiazines. Antihypertensive effects of guanethidine and related compounds may be counteracted when phenothiazines are used concomitantly. Concomitant administration of CHEMICAL with CHEMICAL results in increased plasma levels of both drugs. | CHEMICALS-INTERACTION |
| In clinical studies of CHEMICAL, patients taking CHEMICAL concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | INHIBITOR |
| In clinical studies of CHEMICAL, patients taking TOBI concomitantly with CHEMICAL (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | ACTIVATOR |
| In clinical studies of CHEMICAL, patients taking TOBI concomitantly with dornase alfa (CHEMICAL , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | ACTIVATOR |
| In clinical studies of CHEMICAL, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), CHEMICAL, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of CHEMICAL, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled CHEMICAL, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | GENE-CHEMICAL |
| In clinical studies of CHEMICAL, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other CHEMICAL, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | REGULATOR |
| In clinical studies of CHEMICAL, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral CHEMICAL demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | REGULATOR |
| In clinical studies of TOBI, patients taking CHEMICAL concomitantly with CHEMICAL (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | CHEMICALS-INTERACTION |
| In clinical studies of TOBI, patients taking CHEMICAL concomitantly with dornase alfa (CHEMICAL , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | ACTIVATOR |
| In clinical studies of TOBI, patients taking CHEMICAL concomitantly with dornase alfa (PULMOZYME , Genentech), CHEMICAL, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | CHEMICALS-INTERACTION |
| In clinical studies of TOBI, patients taking CHEMICAL concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled CHEMICAL, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | ACTIVATOR |
| In clinical studies of TOBI, patients taking CHEMICAL concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other CHEMICAL, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | CHEMICALS-INTERACTION |
| In clinical studies of TOBI, patients taking CHEMICAL concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral CHEMICAL demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | CHEMICALS-INTERACTION |
| In clinical studies of TOBI, patients taking TOBI concomitantly with CHEMICAL (CHEMICAL , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with CHEMICAL (PULMOZYME , Genentech), CHEMICAL, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with CHEMICAL (PULMOZYME , Genentech), (beta)-agonists, inhaled CHEMICAL, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with CHEMICAL (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other CHEMICAL, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with CHEMICAL (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral CHEMICAL demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (CHEMICAL , Genentech), CHEMICAL, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (CHEMICAL , Genentech), (beta)-agonists, inhaled CHEMICAL, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (CHEMICAL , Genentech), (beta)-agonists, inhaled corticosteroids, other CHEMICAL, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (CHEMICAL , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral CHEMICAL demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), CHEMICAL, inhaled CHEMICAL, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), CHEMICAL, inhaled corticosteroids, other CHEMICAL, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), CHEMICAL, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral CHEMICAL demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled CHEMICAL, other CHEMICAL, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled CHEMICAL, other anti-pseudomonal antibiotics, or parenteral CHEMICAL demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other CHEMICAL, or parenteral CHEMICAL demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some CHEMICAL can enhance CHEMICAL toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | CHEMICALS-INTERACTION |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some CHEMICAL can enhance aminoglycoside toxicity by altering CHEMICAL concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance CHEMICAL toxicity by altering CHEMICAL concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. CHEMICAL should not be administered concomitantly with CHEMICAL, furosemide, urea, or mannitol. | CHEMICALS-INTERACTION |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. CHEMICAL should not be administered concomitantly with ethacrynic acid, CHEMICAL, urea, or mannitol. | CHEMICALS-INTERACTION |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. CHEMICAL should not be administered concomitantly with ethacrynic acid, furosemide, CHEMICAL, or mannitol. | CHEMICALS-INTERACTION |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. CHEMICAL should not be administered concomitantly with ethacrynic acid, furosemide, urea, or CHEMICAL. | CHEMICALS-INTERACTION |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with CHEMICAL, CHEMICAL, urea, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with CHEMICAL, furosemide, CHEMICAL, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with CHEMICAL, furosemide, urea, or CHEMICAL. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, CHEMICAL, CHEMICAL, or mannitol. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, CHEMICAL, urea, or CHEMICAL. | NO-RELATIONSHIP |
| In clinical studies of TOBI, patients taking TOBI concomitantly with dornase alfa (PULMOZYME , Genentech), (beta)-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, CHEMICAL, or CHEMICAL. | NO-RELATIONSHIP |
| An inhibitor of CYP2C8 (such as CHEMICAL) may increase the AUC of CHEMICAL and an inducer of CYP2C8 (such as rifampin) may decrease the AUC of rosiglitazone. Therefore, if an inhibitor or an inducer of CYP2C8 is started or stopped during treatment with rosiglitazone, changes in diabetes treatment may be needed based upon clinical response. | CHEMICALS-INTERACTION |
| An inhibitor of CYP2C8 (such as CHEMICAL) may increase the AUC of rosiglitazone and an inducer of CYP2C8 (such as CHEMICAL) may decrease the AUC of rosiglitazone. Therefore, if an inhibitor or an inducer of CYP2C8 is started or stopped during treatment with rosiglitazone, changes in diabetes treatment may be needed based upon clinical response. | CHEMICALS-INTERACTION |
| An inhibitor of CYP2C8 (such as CHEMICAL) may increase the AUC of rosiglitazone and an inducer of CYP2C8 (such as rifampin) may decrease the AUC of CHEMICAL. Therefore, if an inhibitor or an inducer of CYP2C8 is started or stopped during treatment with rosiglitazone, changes in diabetes treatment may be needed based upon clinical response. | NO-RELATIONSHIP |
| An inhibitor of CYP2C8 (such as gemfibrozil) may increase the AUC of CHEMICAL and an inducer of CYP2C8 (such as CHEMICAL) may decrease the AUC of rosiglitazone. Therefore, if an inhibitor or an inducer of CYP2C8 is started or stopped during treatment with rosiglitazone, changes in diabetes treatment may be needed based upon clinical response. | NO-RELATIONSHIP |
| An inhibitor of CYP2C8 (such as gemfibrozil) may increase the AUC of CHEMICAL and an inducer of CYP2C8 (such as rifampin) may decrease the AUC of CHEMICAL. Therefore, if an inhibitor or an inducer of CYP2C8 is started or stopped during treatment with rosiglitazone, changes in diabetes treatment may be needed based upon clinical response. | NO-RELATIONSHIP |
| An inhibitor of CYP2C8 (such as gemfibrozil) may increase the AUC of rosiglitazone and an inducer of CYP2C8 (such as CHEMICAL) may decrease the AUC of CHEMICAL. Therefore, if an inhibitor or an inducer of CYP2C8 is started or stopped during treatment with rosiglitazone, changes in diabetes treatment may be needed based upon clinical response. | CHEMICALS-INTERACTION |
| CHEMICAL: CHEMICAL causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| CHEMICAL: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of CHEMICAL and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| CHEMICAL: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with CHEMICAL. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: CHEMICAL causes a 60% reduction in the absorption and enterohepatic cycling of CHEMICAL and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | CHEMICALS-INTERACTION |
| Cholestyramine: CHEMICAL causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with CHEMICAL. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | CHEMICALS-INTERACTION |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of CHEMICAL and should not be coadministered with CHEMICAL. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | CHEMICALS-INTERACTION |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. CHEMICAL: The coadministration of CHEMICAL and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. CHEMICAL: The coadministration of EVISTA and CHEMICAL has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of CHEMICAL and CHEMICAL has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If CHEMICAL is given concurrently with CHEMICAL, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | CHEMICALS-INTERACTION |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, CHEMICAL did not affect the binding of CHEMICAL, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, CHEMICAL did not affect the binding of warfarin, CHEMICAL, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, CHEMICAL did not affect the binding of warfarin, phenytoin, or CHEMICAL. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of CHEMICAL, CHEMICAL, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of CHEMICAL, phenytoin, or CHEMICAL. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, CHEMICAL, or CHEMICAL. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when CHEMICAL is coadministered with other highly protein-bound drugs, such as CHEMICAL, indomethacin, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | CHEMICALS-INTERACTION |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when CHEMICAL is coadministered with other highly protein-bound drugs, such as clofibrate, CHEMICAL, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | CHEMICALS-INTERACTION |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when CHEMICAL is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, CHEMICAL, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | CHEMICALS-INTERACTION |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when CHEMICAL is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, CHEMICAL, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | CHEMICALS-INTERACTION |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when CHEMICAL is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, CHEMICAL, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | CHEMICALS-INTERACTION |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when CHEMICAL is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, diazepam, and CHEMICAL. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | CHEMICALS-INTERACTION |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as CHEMICAL, CHEMICAL, naproxen, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as CHEMICAL, indomethacin, CHEMICAL, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as CHEMICAL, indomethacin, naproxen, CHEMICAL, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as CHEMICAL, indomethacin, naproxen, ibuprofen, CHEMICAL, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as CHEMICAL, indomethacin, naproxen, ibuprofen, diazepam, and CHEMICAL. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, CHEMICAL, CHEMICAL, ibuprofen, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, CHEMICAL, naproxen, CHEMICAL, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, CHEMICAL, naproxen, ibuprofen, CHEMICAL, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, CHEMICAL, naproxen, ibuprofen, diazepam, and CHEMICAL. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, CHEMICAL, CHEMICAL, diazepam, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, CHEMICAL, ibuprofen, CHEMICAL, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, CHEMICAL, ibuprofen, diazepam, and CHEMICAL. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, CHEMICAL, CHEMICAL, and diazoxide. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, CHEMICAL, diazepam, and CHEMICAL. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| Cholestyramine: Cholestyramine causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene and should not be coadministered with EVISTA. Warfarin: The coadministration of EVISTA and warfarin has not been assessed under chronic conditions. However, 10% decreases in prothrombin time have been observed in single-dose studies. If EVISTA is given concurrently with warfarin, prothrombin time should be monitored. Other Highly Protein-Bound Drugs: Raloxifene is more than 95% bound to plasma proteins. In vitro, raloxifene did not affect the binding of warfarin, phenytoin, or tamoxifen. Caution should be used when EVISTA is coadministered with other highly protein-bound drugs, such as clofibrate, indomethacin, naproxen, ibuprofen, CHEMICAL, and CHEMICAL. See also CLINICAL PHARMACOLOGY, Drug-Drug Interactions | NO-RELATIONSHIP |
| CHEMICAL competes with CHEMICAL for active tubular secretion and thus inhibits the renal excretion of meropenem. This led to statistically significant increases in the elimination half-life (38%) and in the extent of systemic exposure (56%). Therefore, the coadministration of probenecid with meropenem is not recommended. There is evidence that meropenem may reduce serum levels of valproic acid to subtherapeutic levels (therapeutic range considered to be 50 to 100 g/mL total valproate). | CHEMICALS-INTERACTION |
| CHEMICAL competes with meropenem for active tubular secretion and thus inhibits the renal excretion of CHEMICAL. This led to statistically significant increases in the elimination half-life (38%) and in the extent of systemic exposure (56%). Therefore, the coadministration of probenecid with meropenem is not recommended. There is evidence that meropenem may reduce serum levels of valproic acid to subtherapeutic levels (therapeutic range considered to be 50 to 100 g/mL total valproate). | CHEMICALS-INTERACTION |
| Probenecid competes with CHEMICAL for active tubular secretion and thus inhibits the renal excretion of CHEMICAL. This led to statistically significant increases in the elimination half-life (38%) and in the extent of systemic exposure (56%). Therefore, the coadministration of probenecid with meropenem is not recommended. There is evidence that meropenem may reduce serum levels of valproic acid to subtherapeutic levels (therapeutic range considered to be 50 to 100 g/mL total valproate). | NO-RELATIONSHIP |
| Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. This led to statistically significant increases in the elimination half-life (38%) and in the extent of systemic exposure (56%). Therefore, the coadministration of CHEMICAL with CHEMICAL is not recommended. There is evidence that meropenem may reduce serum levels of valproic acid to subtherapeutic levels (therapeutic range considered to be 50 to 100 g/mL total valproate). | CHEMICALS-INTERACTION |
| Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. This led to statistically significant increases in the elimination half-life (38%) and in the extent of systemic exposure (56%). Therefore, the coadministration of probenecid with meropenem is not recommended. There is evidence that CHEMICAL may reduce serum levels of CHEMICAL to subtherapeutic levels (therapeutic range considered to be 50 to 100 g/mL total valproate). | CHEMICALS-INTERACTION |
| Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. This led to statistically significant increases in the elimination half-life (38%) and in the extent of systemic exposure (56%). Therefore, the coadministration of probenecid with meropenem is not recommended. There is evidence that CHEMICAL may reduce serum levels of valproic acid to subtherapeutic levels (therapeutic range considered to be 50 to 100 g/mL total CHEMICAL). | NO-RELATIONSHIP |
| Probenecid competes with meropenem for active tubular secretion and thus inhibits the renal excretion of meropenem. This led to statistically significant increases in the elimination half-life (38%) and in the extent of systemic exposure (56%). Therefore, the coadministration of probenecid with meropenem is not recommended. There is evidence that meropenem may reduce serum levels of CHEMICAL to subtherapeutic levels (therapeutic range considered to be 50 to 100 g/mL total CHEMICAL). | NO-RELATIONSHIP |
| Other CHEMICAL should not be used concomitantly with CHEMICAL (metaproterenol sulfate USP) because they may have additive effects. Beta adrenergic agonists should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, since the action of beta adrenergic agonists on the vascular system may be potentiated. | CHEMICALS-INTERACTION |
| Other CHEMICAL should not be used concomitantly with Alupent (CHEMICAL USP) because they may have additive effects. Beta adrenergic agonists should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, since the action of beta adrenergic agonists on the vascular system may be potentiated. | CHEMICALS-INTERACTION |
| Other beta adrenergic aerosol bronchodilators should not be used concomitantly with CHEMICAL (CHEMICAL USP) because they may have additive effects. Beta adrenergic agonists should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, since the action of beta adrenergic agonists on the vascular system may be potentiated. | NO-RELATIONSHIP |
| Other beta adrenergic aerosol bronchodilators should not be used concomitantly with Alupent (metaproterenol sulfate USP) because they may have additive effects. CHEMICAL should be administered with caution to patients being treated with CHEMICAL or tricyclic antidepressants, since the action of beta adrenergic agonists on the vascular system may be potentiated. | CHEMICALS-INTERACTION |
| Other beta adrenergic aerosol bronchodilators should not be used concomitantly with Alupent (metaproterenol sulfate USP) because they may have additive effects. CHEMICAL should be administered with caution to patients being treated with monoamine oxidase inhibitors or CHEMICAL, since the action of beta adrenergic agonists on the vascular system may be potentiated. | CHEMICALS-INTERACTION |
| Other beta adrenergic aerosol bronchodilators should not be used concomitantly with Alupent (metaproterenol sulfate USP) because they may have additive effects. CHEMICAL should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, since the action of CHEMICAL on the vascular system may be potentiated. | NO-RELATIONSHIP |
| Other beta adrenergic aerosol bronchodilators should not be used concomitantly with Alupent (metaproterenol sulfate USP) because they may have additive effects. Beta adrenergic agonists should be administered with caution to patients being treated with CHEMICAL or CHEMICAL, since the action of beta adrenergic agonists on the vascular system may be potentiated. | NO-RELATIONSHIP |
| Other beta adrenergic aerosol bronchodilators should not be used concomitantly with Alupent (metaproterenol sulfate USP) because they may have additive effects. Beta adrenergic agonists should be administered with caution to patients being treated with CHEMICAL or tricyclic antidepressants, since the action of CHEMICAL on the vascular system may be potentiated. | NO-RELATIONSHIP |
| Other beta adrenergic aerosol bronchodilators should not be used concomitantly with Alupent (metaproterenol sulfate USP) because they may have additive effects. Beta adrenergic agonists should be administered with caution to patients being treated with monoamine oxidase inhibitors or CHEMICAL, since the action of CHEMICAL on the vascular system may be potentiated. | NO-RELATIONSHIP |
| Drug Interactions: The use of CHEMICAL (CHEMICAL) Injection before succinylcholine, for the purpose of attenuating some of the side effects of succinylcholine, has not been studied. If ZEMURON is administered following administration of succinylcholine, it should not be given until recovery from succinylcholine has been observed. The median duration of action of ZEMURON 0.6 mg/kg administered after a 1 mg/kg dose of succinylcholine when T 1 returned to 75% of control was 36 minutes (range 14-57, n=12) vs. 28 minutes (17-51, n=12) without succinylcholine. There are no controlled studies documenting the use of ZEMURON before or after other nondepolarizing muscle relaxants. Interactions have been observed when other nondepolarizing muscle relaxants have been administered in succession. Drug/Laboratory Test Interactions: None known. | NO-RELATIONSHIP |
| Drug Interactions: The use of CHEMICAL (rocuronium bromide) Injection before CHEMICAL, for the purpose of attenuating some of the side effects of succinylcholine, has not been studied. If ZEMURON is administered following administration of succinylcholine, it should not be given until recovery from succinylcholine has been observed. The median duration of action of ZEMURON 0.6 mg/kg administered after a 1 mg/kg dose of succinylcholine when T 1 returned to 75% of control was 36 minutes (range 14-57, n=12) vs. 28 minutes (17-51, n=12) without succinylcholine. There are no controlled studies documenting the use of ZEMURON before or after other nondepolarizing muscle relaxants. Interactions have been observed when other nondepolarizing muscle relaxants have been administered in succession. Drug/Laboratory Test Interactions: None known. | NO-RELATIONSHIP |
| Drug Interactions: The use of CHEMICAL (rocuronium bromide) Injection before succinylcholine, for the purpose of attenuating some of the side effects of CHEMICAL, has not been studied. If ZEMURON is administered following administration of succinylcholine, it should not be given until recovery from succinylcholine has been observed. The median duration of action of ZEMURON 0.6 mg/kg administered after a 1 mg/kg dose of succinylcholine when T 1 returned to 75% of control was 36 minutes (range 14-57, n=12) vs. 28 minutes (17-51, n=12) without succinylcholine. There are no controlled studies documenting the use of ZEMURON before or after other nondepolarizing muscle relaxants. Interactions have been observed when other nondepolarizing muscle relaxants have been administered in succession. Drug/Laboratory Test Interactions: None known. | NO-RELATIONSHIP |
| Drug Interactions: The use of ZEMURON (CHEMICAL) Injection before CHEMICAL, for the purpose of attenuating some of the side effects of succinylcholine, has not been studied. If ZEMURON is administered following administration of succinylcholine, it should not be given until recovery from succinylcholine has been observed. The median duration of action of ZEMURON 0.6 mg/kg administered after a 1 mg/kg dose of succinylcholine when T 1 returned to 75% of control was 36 minutes (range 14-57, n=12) vs. 28 minutes (17-51, n=12) without succinylcholine. There are no controlled studies documenting the use of ZEMURON before or after other nondepolarizing muscle relaxants. Interactions have been observed when other nondepolarizing muscle relaxants have been administered in succession. Drug/Laboratory Test Interactions: None known. | NO-RELATIONSHIP |
| Drug Interactions: The use of ZEMURON (CHEMICAL) Injection before succinylcholine, for the purpose of attenuating some of the side effects of CHEMICAL, has not been studied. If ZEMURON is administered following administration of succinylcholine, it should not be given until recovery from succinylcholine has been observed. The median duration of action of ZEMURON 0.6 mg/kg administered after a 1 mg/kg dose of succinylcholine when T 1 returned to 75% of control was 36 minutes (range 14-57, n=12) vs. 28 minutes (17-51, n=12) without succinylcholine. There are no controlled studies documenting the use of ZEMURON before or after other nondepolarizing muscle relaxants. Interactions have been observed when other nondepolarizing muscle relaxants have been administered in succession. Drug/Laboratory Test Interactions: None known. | NO-RELATIONSHIP |
| Drug Interactions: The use of ZEMURON (rocuronium bromide) Injection before CHEMICAL, for the purpose of attenuating some of the side effects of CHEMICAL, has not been studied. If ZEMURON is administered following administration of succinylcholine, it should not be given until recovery from succinylcholine has been observed. The median duration of action of ZEMURON 0.6 mg/kg administered after a 1 mg/kg dose of succinylcholine when T 1 returned to 75% of control was 36 minutes (range 14-57, n=12) vs. 28 minutes (17-51, n=12) without succinylcholine. There are no controlled studies documenting the use of ZEMURON before or after other nondepolarizing muscle relaxants. Interactions have been observed when other nondepolarizing muscle relaxants have been administered in succession. Drug/Laboratory Test Interactions: None known. | NO-RELATIONSHIP |
| Drug Interactions: The use of ZEMURON (rocuronium bromide) Injection before succinylcholine, for the purpose of attenuating some of the side effects of succinylcholine, has not been studied. If CHEMICAL is administered following administration of CHEMICAL, it should not be given until recovery from succinylcholine has been observed. The median duration of action of ZEMURON 0.6 mg/kg administered after a 1 mg/kg dose of succinylcholine when T 1 returned to 75% of control was 36 minutes (range 14-57, n=12) vs. 28 minutes (17-51, n=12) without succinylcholine. There are no controlled studies documenting the use of ZEMURON before or after other nondepolarizing muscle relaxants. Interactions have been observed when other nondepolarizing muscle relaxants have been administered in succession. Drug/Laboratory Test Interactions: None known. | CHEMICALS-INTERACTION |
| Drug Interactions: The use of ZEMURON (rocuronium bromide) Injection before succinylcholine, for the purpose of attenuating some of the side effects of succinylcholine, has not been studied. If CHEMICAL is administered following administration of succinylcholine, it should not be given until recovery from CHEMICAL has been observed. The median duration of action of ZEMURON 0.6 mg/kg administered after a 1 mg/kg dose of succinylcholine when T 1 returned to 75% of control was 36 minutes (range 14-57, n=12) vs. 28 minutes (17-51, n=12) without succinylcholine. There are no controlled studies documenting the use of ZEMURON before or after other nondepolarizing muscle relaxants. Interactions have been observed when other nondepolarizing muscle relaxants have been administered in succession. Drug/Laboratory Test Interactions: None known. | NO-RELATIONSHIP |
| Drug Interactions: The use of ZEMURON (rocuronium bromide) Injection before succinylcholine, for the purpose of attenuating some of the side effects of succinylcholine, has not been studied. If ZEMURON is administered following administration of CHEMICAL, it should not be given until recovery from CHEMICAL has been observed. The median duration of action of ZEMURON 0.6 mg/kg administered after a 1 mg/kg dose of succinylcholine when T 1 returned to 75% of control was 36 minutes (range 14-57, n=12) vs. 28 minutes (17-51, n=12) without succinylcholine. There are no controlled studies documenting the use of ZEMURON before or after other nondepolarizing muscle relaxants. Interactions have been observed when other nondepolarizing muscle relaxants have been administered in succession. Drug/Laboratory Test Interactions: None known. | NO-RELATIONSHIP |
| Drug Interactions: The use of ZEMURON (rocuronium bromide) Injection before succinylcholine, for the purpose of attenuating some of the side effects of succinylcholine, has not been studied. If ZEMURON is administered following administration of succinylcholine, it should not be given until recovery from succinylcholine has been observed. The median duration of action of CHEMICAL 0.6 mg/kg administered after a 1 mg/kg dose of CHEMICAL when T 1 returned to 75% of control was 36 minutes (range 14-57, n=12) vs. 28 minutes (17-51, n=12) without succinylcholine. There are no controlled studies documenting the use of ZEMURON before or after other nondepolarizing muscle relaxants. Interactions have been observed when other nondepolarizing muscle relaxants have been administered in succession. Drug/Laboratory Test Interactions: None known. | CHEMICALS-INTERACTION |
| Drug Interactions: The use of ZEMURON (rocuronium bromide) Injection before succinylcholine, for the purpose of attenuating some of the side effects of succinylcholine, has not been studied. If ZEMURON is administered following administration of succinylcholine, it should not be given until recovery from succinylcholine has been observed. The median duration of action of ZEMURON 0.6 mg/kg administered after a 1 mg/kg dose of succinylcholine when T 1 returned to 75% of control was 36 minutes (range 14-57, n=12) vs. 28 minutes (17-51, n=12) without succinylcholine. There are no controlled studies documenting the use of CHEMICAL before or after other CHEMICAL. Interactions have been observed when other nondepolarizing muscle relaxants have been administered in succession. Drug/Laboratory Test Interactions: None known. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because CHEMICAL is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of CHEMICAL. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. CHEMICAL, CHEMICAL, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. CHEMICAL, Carbamazepine, and CHEMICAL: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. CHEMICAL, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., CHEMICAL, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. CHEMICAL, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, CHEMICAL, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. CHEMICAL, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and CHEMICAL), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. CHEMICAL, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of CHEMICAL was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. CHEMICAL, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and CHEMICAL blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, CHEMICAL, and CHEMICAL: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, CHEMICAL, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., CHEMICAL, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, CHEMICAL, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, CHEMICAL, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, CHEMICAL, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and CHEMICAL), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, CHEMICAL, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of CHEMICAL was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, CHEMICAL, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and CHEMICAL blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and CHEMICAL: In patients treated with potent inducers of CYP3A4 (i.e., CHEMICAL, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and CHEMICAL: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, CHEMICAL, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and CHEMICAL: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and CHEMICAL), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and CHEMICAL: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of CHEMICAL was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and CHEMICAL: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and CHEMICAL blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., CHEMICAL, CHEMICAL, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., CHEMICAL, carbamazepine, and CHEMICAL), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., CHEMICAL, carbamazepine, and rifampicin), the clearance of CHEMICAL was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | CHEMICALS-INTERACTION |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., CHEMICAL, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and CHEMICAL blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, CHEMICAL, and CHEMICAL), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, CHEMICAL, and rifampicin), the clearance of CHEMICAL was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | CHEMICALS-INTERACTION |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, CHEMICAL, and rifampicin), the clearance of ondansetron was significantly increased and CHEMICAL blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and CHEMICAL), the clearance of CHEMICAL was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | CHEMICALS-INTERACTION |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and CHEMICAL), the clearance of ondansetron was significantly increased and CHEMICAL blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of CHEMICAL was significantly increased and CHEMICAL blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for CHEMICAL is recommended for patients on these drugs.1,3 CHEMICAL: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for CHEMICAL is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between CHEMICAL and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for CHEMICAL is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and CHEMICAL has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for CHEMICAL is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that CHEMICAL may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for CHEMICAL is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of CHEMICAL.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for CHEMICAL is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by CHEMICAL. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 CHEMICAL: Although no pharmacokinetic drug interaction between CHEMICAL and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 CHEMICAL: Although no pharmacokinetic drug interaction between ondansetron and CHEMICAL has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 CHEMICAL: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that CHEMICAL may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 CHEMICAL: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of CHEMICAL.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 CHEMICAL: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by CHEMICAL. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between CHEMICAL and CHEMICAL has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between CHEMICAL and tramadol has been observed, data from 2 small studies indicate that CHEMICAL may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between CHEMICAL and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of CHEMICAL.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between CHEMICAL and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by CHEMICAL. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and CHEMICAL has been observed, data from 2 small studies indicate that CHEMICAL may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and CHEMICAL has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of CHEMICAL.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and CHEMICAL has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by CHEMICAL. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that CHEMICAL may be associated with an increase in patient controlled administration of CHEMICAL.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | CHEMICALS-INTERACTION |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that CHEMICAL may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by CHEMICAL. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of CHEMICAL.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by CHEMICAL. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, CHEMICAL, CHEMICAL, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, CHEMICAL, etoposide, and CHEMICAL do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, CHEMICAL, etoposide, and cisplatin do not affect the pharmacokinetics of CHEMICAL. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, CHEMICAL, and CHEMICAL do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, CHEMICAL, and cisplatin do not affect the pharmacokinetics of CHEMICAL. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and CHEMICAL do not affect the pharmacokinetics of CHEMICAL. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate. | NO-RELATIONSHIP |
| Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver. Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of limited available data, no dosage adjustment is recommended for patients on these drugs. Phenytoin, Carbamazepine, and Rifampicin: In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1,3 Tramadol: Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4,5 Chemotherapy: Tumor response to chemotherapy in the P 388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. CHEMICAL did not increase blood levels of high-dose CHEMICAL. | NO-RELATIONSHIP |
| There have been no formal drug interaction studies performed with HERCEPTIN in humans. Administration of CHEMICAL in combination with CHEMICAL resulted in a two-fold decrease in HERCEPTIN clearance in a non-human primate study and in a 1.5-fold increase in HERCEPTIN serum levels in clinical studies. | CHEMICALS-INTERACTION |
| There have been no formal drug interaction studies performed with HERCEPTIN in humans. Administration of CHEMICAL in combination with HERCEPTIN resulted in a two-fold decrease in CHEMICAL clearance in a non-human primate study and in a 1.5-fold increase in HERCEPTIN serum levels in clinical studies. | NO-RELATIONSHIP |
| There have been no formal drug interaction studies performed with HERCEPTIN in humans. Administration of CHEMICAL in combination with HERCEPTIN resulted in a two-fold decrease in HERCEPTIN clearance in a non-human primate study and in a 1.5-fold increase in CHEMICAL serum levels in clinical studies. | NO-RELATIONSHIP |
| There have been no formal drug interaction studies performed with HERCEPTIN in humans. Administration of paclitaxel in combination with CHEMICAL resulted in a two-fold decrease in CHEMICAL clearance in a non-human primate study and in a 1.5-fold increase in HERCEPTIN serum levels in clinical studies. | NO-RELATIONSHIP |
| There have been no formal drug interaction studies performed with HERCEPTIN in humans. Administration of paclitaxel in combination with CHEMICAL resulted in a two-fold decrease in HERCEPTIN clearance in a non-human primate study and in a 1.5-fold increase in CHEMICAL serum levels in clinical studies. | NO-RELATIONSHIP |
| There have been no formal drug interaction studies performed with HERCEPTIN in humans. Administration of paclitaxel in combination with HERCEPTIN resulted in a two-fold decrease in CHEMICAL clearance in a non-human primate study and in a 1.5-fold increase in CHEMICAL serum levels in clinical studies. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - CHEMICAL and CHEMICAL: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - CHEMICAL and astemizole: Certain CHEMICAL interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - CHEMICAL and astemizole: Certain macrolides interact with CHEMICAL and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - CHEMICAL and astemizole: Certain macrolides interact with terfenadine and CHEMICAL leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and CHEMICAL: Certain CHEMICAL interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and CHEMICAL: Certain macrolides interact with CHEMICAL and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and CHEMICAL: Certain macrolides interact with terfenadine and CHEMICAL leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain CHEMICAL interact with CHEMICAL and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | CHEMICALS-INTERACTION |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain CHEMICAL interact with terfenadine and CHEMICAL leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | CHEMICALS-INTERACTION |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with CHEMICAL and CHEMICAL leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with CHEMICAL, concomitant administration of CHEMICAL with terfenadine or astemizole is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with CHEMICAL, concomitant administration of roxithromycin with CHEMICAL or astemizole is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with CHEMICAL, concomitant administration of roxithromycin with terfenadine or CHEMICAL is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of CHEMICAL with CHEMICAL or astemizole is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | CHEMICALS-INTERACTION |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of CHEMICAL with terfenadine or CHEMICAL is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | CHEMICALS-INTERACTION |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with CHEMICAL or CHEMICAL is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - CHEMICAL, CHEMICAL: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - CHEMICAL, pimozide: Other drugs such as CHEMICAL or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - CHEMICAL, pimozide: Other drugs such as cisapride or CHEMICAL, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - CHEMICAL, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some CHEMICAL. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - Cisapride, CHEMICAL: Other drugs such as CHEMICAL or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - Cisapride, CHEMICAL: Other drugs such as cisapride or CHEMICAL, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - Cisapride, CHEMICAL: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some CHEMICAL. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - Cisapride, pimozide: Other drugs such as CHEMICAL or CHEMICAL, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | NO-RELATIONSHIP |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - Cisapride, pimozide: Other drugs such as CHEMICAL or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some CHEMICAL. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | CHEMICALS-INTERACTION |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or CHEMICAL, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some CHEMICAL. Although such a risk is not verified for roxithromycin, combination of roxithromycin with such drugs is not recommended. | CHEMICALS-INTERACTION |
| Concomitant administration contra-indicated: - Vasoconstrictive ergot alkaloids. Concomitant administrations not recommended: - Terfenadine and astemizole: Certain macrolides interact with terfenadine and astemizole leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointe. Although such a reaction has not been demonstrated with roxithromycin, concomitant administration of roxithromycin with terfenadine or astemizole is not recommended. - Cisapride, pimozide: Other drugs such as cisapride or pimozide, which are metabolised by hepatic CYP3A isozymes have been associated with QT interval prolongation and/or cardiac arrythmias (typically torsades de pointe) as a result of increase in their serum level subsequent to interaction with significant inhibitors of the isozyme, including some macrolide antibacterials. Although such a risk is not verified for CHEMICAL, combination of CHEMICAL with such drugs is not recommended. | NO-RELATIONSHIP |
| Some CHEMICAL may interact with CHEMICAL. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some steroid medications, warfarin, certain heart medicines, birth control pills, anti-infective medicines, furosemide and theophylline Please note that Mephenytoin may interact with other drugs that are not listed here. | CHEMICALS-INTERACTION |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those CHEMICAL include CHEMICAL, valproic acid, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some steroid medications, warfarin, certain heart medicines, birth control pills, anti-infective medicines, furosemide and theophylline Please note that Mephenytoin may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those CHEMICAL include divalproex sodium, CHEMICAL, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some steroid medications, warfarin, certain heart medicines, birth control pills, anti-infective medicines, furosemide and theophylline Please note that Mephenytoin may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those CHEMICAL include divalproex sodium, valproic acid, and CHEMICAL. Mephenytoin may also affect the effects of other drugs, which include some steroid medications, warfarin, certain heart medicines, birth control pills, anti-infective medicines, furosemide and theophylline Please note that Mephenytoin may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include CHEMICAL, CHEMICAL, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some steroid medications, warfarin, certain heart medicines, birth control pills, anti-infective medicines, furosemide and theophylline Please note that Mephenytoin may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include CHEMICAL, valproic acid, and CHEMICAL. Mephenytoin may also affect the effects of other drugs, which include some steroid medications, warfarin, certain heart medicines, birth control pills, anti-infective medicines, furosemide and theophylline Please note that Mephenytoin may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, CHEMICAL, and CHEMICAL. Mephenytoin may also affect the effects of other drugs, which include some steroid medications, warfarin, certain heart medicines, birth control pills, anti-infective medicines, furosemide and theophylline Please note that Mephenytoin may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. CHEMICAL may also affect the effects of other drugs, which include some CHEMICAL, warfarin, certain heart medicines, birth control pills, anti-infective medicines, furosemide and theophylline Please note that Mephenytoin may interact with other drugs that are not listed here. | CHEMICALS-INTERACTION |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. CHEMICAL may also affect the effects of other drugs, which include some steroid medications, CHEMICAL, certain heart medicines, birth control pills, anti-infective medicines, furosemide and theophylline Please note that Mephenytoin may interact with other drugs that are not listed here. | CHEMICALS-INTERACTION |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. CHEMICAL may also affect the effects of other drugs, which include some steroid medications, warfarin, certain heart medicines, birth control pills, CHEMICAL, furosemide and theophylline Please note that Mephenytoin may interact with other drugs that are not listed here. | CHEMICALS-INTERACTION |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. CHEMICAL may also affect the effects of other drugs, which include some steroid medications, warfarin, certain heart medicines, birth control pills, anti-infective medicines, CHEMICAL and theophylline Please note that Mephenytoin may interact with other drugs that are not listed here. | CHEMICALS-INTERACTION |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. CHEMICAL may also affect the effects of other drugs, which include some steroid medications, warfarin, certain heart medicines, birth control pills, anti-infective medicines, furosemide and CHEMICAL Please note that Mephenytoin may interact with other drugs that are not listed here. | CHEMICALS-INTERACTION |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. CHEMICAL may also affect the effects of other drugs, which include some steroid medications, warfarin, certain heart medicines, birth control pills, anti-infective medicines, furosemide and theophylline Please note that CHEMICAL may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some CHEMICAL, CHEMICAL, certain heart medicines, birth control pills, anti-infective medicines, furosemide and theophylline Please note that Mephenytoin may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some CHEMICAL, warfarin, certain heart medicines, birth control pills, CHEMICAL, furosemide and theophylline Please note that Mephenytoin may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some CHEMICAL, warfarin, certain heart medicines, birth control pills, anti-infective medicines, CHEMICAL and theophylline Please note that Mephenytoin may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some CHEMICAL, warfarin, certain heart medicines, birth control pills, anti-infective medicines, furosemide and CHEMICAL Please note that Mephenytoin may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some CHEMICAL, warfarin, certain heart medicines, birth control pills, anti-infective medicines, furosemide and theophylline Please note that CHEMICAL may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some steroid medications, CHEMICAL, certain heart medicines, birth control pills, CHEMICAL, furosemide and theophylline Please note that Mephenytoin may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some steroid medications, CHEMICAL, certain heart medicines, birth control pills, anti-infective medicines, CHEMICAL and theophylline Please note that Mephenytoin may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some steroid medications, CHEMICAL, certain heart medicines, birth control pills, anti-infective medicines, furosemide and CHEMICAL Please note that Mephenytoin may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some steroid medications, CHEMICAL, certain heart medicines, birth control pills, anti-infective medicines, furosemide and theophylline Please note that CHEMICAL may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some steroid medications, warfarin, certain heart medicines, birth control pills, CHEMICAL, CHEMICAL and theophylline Please note that Mephenytoin may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some steroid medications, warfarin, certain heart medicines, birth control pills, CHEMICAL, furosemide and CHEMICAL Please note that Mephenytoin may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some steroid medications, warfarin, certain heart medicines, birth control pills, CHEMICAL, furosemide and theophylline Please note that CHEMICAL may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some steroid medications, warfarin, certain heart medicines, birth control pills, anti-infective medicines, CHEMICAL and CHEMICAL Please note that Mephenytoin may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some steroid medications, warfarin, certain heart medicines, birth control pills, anti-infective medicines, CHEMICAL and theophylline Please note that CHEMICAL may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| Some anticonvulsants may interact with Mephenytoin. They can either increase or decrease the effect of Mephenytoin. Those anticonvulsants include divalproex sodium, valproic acid, and phenobarbital. Mephenytoin may also affect the effects of other drugs, which include some steroid medications, warfarin, certain heart medicines, birth control pills, anti-infective medicines, furosemide and CHEMICAL Please note that CHEMICAL may interact with other drugs that are not listed here. | NO-RELATIONSHIP |
| The interaction of CHEMICAL, CHEMICAL, with other drugs has not been well studied. Use of Anticoagulants and Antiplatelet Agents -- Streptase, Streptokinase, alone or in combination with antiplatelet agents and anticoagulants, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | NO-RELATIONSHIP |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of CHEMICAL and CHEMICAL -- Streptase, Streptokinase, alone or in combination with antiplatelet agents and anticoagulants, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | NO-RELATIONSHIP |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of CHEMICAL and Antiplatelet Agents -- CHEMICAL, Streptokinase, alone or in combination with antiplatelet agents and anticoagulants, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | NO-RELATIONSHIP |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of CHEMICAL and Antiplatelet Agents -- Streptase, CHEMICAL, alone or in combination with antiplatelet agents and anticoagulants, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | NO-RELATIONSHIP |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of CHEMICAL and Antiplatelet Agents -- Streptase, Streptokinase, alone or in combination with CHEMICAL and anticoagulants, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | NO-RELATIONSHIP |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of CHEMICAL and Antiplatelet Agents -- Streptase, Streptokinase, alone or in combination with antiplatelet agents and CHEMICAL, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | NO-RELATIONSHIP |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of Anticoagulants and CHEMICAL -- CHEMICAL, Streptokinase, alone or in combination with antiplatelet agents and anticoagulants, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | NO-RELATIONSHIP |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of Anticoagulants and CHEMICAL -- Streptase, CHEMICAL, alone or in combination with antiplatelet agents and anticoagulants, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | NO-RELATIONSHIP |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of Anticoagulants and CHEMICAL -- Streptase, Streptokinase, alone or in combination with CHEMICAL and anticoagulants, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | NO-RELATIONSHIP |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of Anticoagulants and CHEMICAL -- Streptase, Streptokinase, alone or in combination with antiplatelet agents and CHEMICAL, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | NO-RELATIONSHIP |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of Anticoagulants and Antiplatelet Agents -- CHEMICAL, CHEMICAL, alone or in combination with antiplatelet agents and anticoagulants, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | NO-RELATIONSHIP |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of Anticoagulants and Antiplatelet Agents -- CHEMICAL, Streptokinase, alone or in combination with CHEMICAL and anticoagulants, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | NO-RELATIONSHIP |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of Anticoagulants and Antiplatelet Agents -- CHEMICAL, Streptokinase, alone or in combination with antiplatelet agents and CHEMICAL, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | NO-RELATIONSHIP |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of Anticoagulants and Antiplatelet Agents -- Streptase, CHEMICAL, alone or in combination with CHEMICAL and anticoagulants, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | NO-RELATIONSHIP |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of Anticoagulants and Antiplatelet Agents -- Streptase, CHEMICAL, alone or in combination with antiplatelet agents and CHEMICAL, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | NO-RELATIONSHIP |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of Anticoagulants and Antiplatelet Agents -- Streptase, Streptokinase, alone or in combination with CHEMICAL and CHEMICAL, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | NO-RELATIONSHIP |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of Anticoagulants and Antiplatelet Agents -- Streptase, Streptokinase, alone or in combination with antiplatelet agents and anticoagulants, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, CHEMICAL, when not otherwise contraindicated, should be administered with CHEMICAL ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | CHEMICALS-INTERACTION |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of Anticoagulants and Antiplatelet Agents -- Streptase, Streptokinase, alone or in combination with antiplatelet agents and anticoagulants, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and CHEMICAL After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of CHEMICAL has been shown to reduce the incidence of reinfarction and stroke. The addition of aspirin to Streptokinase causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | NO-RELATIONSHIP |
| The interaction of Streptase, Streptokinase, with other drugs has not been well studied. Use of Anticoagulants and Antiplatelet Agents -- Streptase, Streptokinase, alone or in combination with antiplatelet agents and anticoagulants, may cause bleeding complications. Therefore, careful monitoring is advised. In the treatment of acute MI, aspirin, when not otherwise contraindicated, should be administered with Streptokinase ( see below ). Anticoagulation and Antiplatelets After Treatment for Myocardial Infarction -- In the treatment of acute myocardial infarction, the use of aspirin has been shown to reduce the incidence of reinfarction and stroke. The addition of CHEMICAL to CHEMICAL causes a minimal increase in the risk of minor bleeding (3.9% vs. 3.1%), but does not appear to increase the incidence of major bleeding (see | CHEMICALS-INTERACTION |
| CHEMICAL and CHEMICAL increase the effects of pseudoephedrine. Sympathomimetics may reduce the antihypertensive effects of methyldopa, mecamylamine, reserpine and veratrum alkaloids. | NO-RELATIONSHIP |
| CHEMICAL and beta adrenergic blockers increase the effects of CHEMICAL. Sympathomimetics may reduce the antihypertensive effects of methyldopa, mecamylamine, reserpine and veratrum alkaloids. | CHEMICALS-INTERACTION |
| MAO inhibitors and CHEMICAL increase the effects of CHEMICAL. Sympathomimetics may reduce the antihypertensive effects of methyldopa, mecamylamine, reserpine and veratrum alkaloids. | CHEMICALS-INTERACTION |
| MAO inhibitors and beta adrenergic blockers increase the effects of pseudoephedrine. CHEMICAL may reduce the antihypertensive effects of CHEMICAL, mecamylamine, reserpine and veratrum alkaloids. | CHEMICALS-INTERACTION |
| MAO inhibitors and beta adrenergic blockers increase the effects of pseudoephedrine. CHEMICAL may reduce the antihypertensive effects of methyldopa, CHEMICAL, reserpine and veratrum alkaloids. | CHEMICALS-INTERACTION |
| MAO inhibitors and beta adrenergic blockers increase the effects of pseudoephedrine. CHEMICAL may reduce the antihypertensive effects of methyldopa, mecamylamine, CHEMICAL and veratrum alkaloids. | CHEMICALS-INTERACTION |
| MAO inhibitors and beta adrenergic blockers increase the effects of pseudoephedrine. CHEMICAL may reduce the antihypertensive effects of methyldopa, mecamylamine, reserpine and CHEMICAL. | CHEMICALS-INTERACTION |
| MAO inhibitors and beta adrenergic blockers increase the effects of pseudoephedrine. Sympathomimetics may reduce the antihypertensive effects of CHEMICAL, CHEMICAL, reserpine and veratrum alkaloids. | NO-RELATIONSHIP |
| MAO inhibitors and beta adrenergic blockers increase the effects of pseudoephedrine. Sympathomimetics may reduce the antihypertensive effects of CHEMICAL, mecamylamine, CHEMICAL and veratrum alkaloids. | NO-RELATIONSHIP |
| MAO inhibitors and beta adrenergic blockers increase the effects of pseudoephedrine. Sympathomimetics may reduce the antihypertensive effects of CHEMICAL, mecamylamine, reserpine and CHEMICAL. | NO-RELATIONSHIP |
| MAO inhibitors and beta adrenergic blockers increase the effects of pseudoephedrine. Sympathomimetics may reduce the antihypertensive effects of methyldopa, CHEMICAL, CHEMICAL and veratrum alkaloids. | NO-RELATIONSHIP |
| MAO inhibitors and beta adrenergic blockers increase the effects of pseudoephedrine. Sympathomimetics may reduce the antihypertensive effects of methyldopa, CHEMICAL, reserpine and CHEMICAL. | NO-RELATIONSHIP |
| MAO inhibitors and beta adrenergic blockers increase the effects of pseudoephedrine. Sympathomimetics may reduce the antihypertensive effects of methyldopa, mecamylamine, CHEMICAL and CHEMICAL. | NO-RELATIONSHIP |
| Distinct synergistic action of CHEMICAL and CHEMICAL against Pseudomonas aeruginosa. The dicarbonyl compound methylglyoxal is a natural constituent of Manuka honey produced from Manuka flowers in New Zealand. It is known to possess both anticancer and antibacterial activity. Such observations prompted to investigate the ability of methylglyoxal as a potent drug against multidrug resistant Pseudomonas aeruginosa. A total of 12 test P. aeruginosa strains isolated from various hospitals were tested for their resistances against many antibiotics, most of which are applied in the treatment of P. aeruginosa infections. Results revealed that the strains were resistant to many drugs at high levels, only piperacillin, carbenicillin, amikacin and ciprofloxacin showed resistances at comparatively lower levels. Following multiple experimentations it was observed that methylglyoxal was also antimicrobic against all the strains at comparable levels. Distinct and statistically significant synergism was observed between methylglyoxal and piperacillin by disc diffusion tests when compared with their individual effects. The fractional inhibitory concentration index of this combination evaluated by checkerboard analysis, was 0.5, which confirmed synergism between the pair. Synergism was also noted when methylglyoxal was combined with carbenicillin and amikacin. | CHEMICALS-INTERACTION |
| Distinct synergistic action of piperacillin and methylglyoxal against Pseudomonas aeruginosa. The dicarbonyl compound methylglyoxal is a natural constituent of Manuka honey produced from Manuka flowers in New Zealand. It is known to possess both anticancer and antibacterial activity. Such observations prompted to investigate the ability of methylglyoxal as a potent drug against multidrug resistant Pseudomonas aeruginosa. A total of 12 test P. aeruginosa strains isolated from various hospitals were tested for their resistances against many antibiotics, most of which are applied in the treatment of P. aeruginosa infections. Results revealed that the strains were resistant to many drugs at high levels, only CHEMICAL, CHEMICAL, amikacin and ciprofloxacin showed resistances at comparatively lower levels. Following multiple experimentations it was observed that methylglyoxal was also antimicrobic against all the strains at comparable levels. Distinct and statistically significant synergism was observed between methylglyoxal and piperacillin by disc diffusion tests when compared with their individual effects. The fractional inhibitory concentration index of this combination evaluated by checkerboard analysis, was 0.5, which confirmed synergism between the pair. Synergism was also noted when methylglyoxal was combined with carbenicillin and amikacin. | NO-RELATIONSHIP |
| Distinct synergistic action of piperacillin and methylglyoxal against Pseudomonas aeruginosa. The dicarbonyl compound methylglyoxal is a natural constituent of Manuka honey produced from Manuka flowers in New Zealand. It is known to possess both anticancer and antibacterial activity. Such observations prompted to investigate the ability of methylglyoxal as a potent drug against multidrug resistant Pseudomonas aeruginosa. A total of 12 test P. aeruginosa strains isolated from various hospitals were tested for their resistances against many antibiotics, most of which are applied in the treatment of P. aeruginosa infections. Results revealed that the strains were resistant to many drugs at high levels, only CHEMICAL, carbenicillin, CHEMICAL and ciprofloxacin showed resistances at comparatively lower levels. Following multiple experimentations it was observed that methylglyoxal was also antimicrobic against all the strains at comparable levels. Distinct and statistically significant synergism was observed between methylglyoxal and piperacillin by disc diffusion tests when compared with their individual effects. The fractional inhibitory concentration index of this combination evaluated by checkerboard analysis, was 0.5, which confirmed synergism between the pair. Synergism was also noted when methylglyoxal was combined with carbenicillin and amikacin. | NO-RELATIONSHIP |
| Distinct synergistic action of piperacillin and methylglyoxal against Pseudomonas aeruginosa. The dicarbonyl compound methylglyoxal is a natural constituent of Manuka honey produced from Manuka flowers in New Zealand. It is known to possess both anticancer and antibacterial activity. Such observations prompted to investigate the ability of methylglyoxal as a potent drug against multidrug resistant Pseudomonas aeruginosa. A total of 12 test P. aeruginosa strains isolated from various hospitals were tested for their resistances against many antibiotics, most of which are applied in the treatment of P. aeruginosa infections. Results revealed that the strains were resistant to many drugs at high levels, only CHEMICAL, carbenicillin, amikacin and CHEMICAL showed resistances at comparatively lower levels. Following multiple experimentations it was observed that methylglyoxal was also antimicrobic against all the strains at comparable levels. Distinct and statistically significant synergism was observed between methylglyoxal and piperacillin by disc diffusion tests when compared with their individual effects. The fractional inhibitory concentration index of this combination evaluated by checkerboard analysis, was 0.5, which confirmed synergism between the pair. Synergism was also noted when methylglyoxal was combined with carbenicillin and amikacin. | NO-RELATIONSHIP |
| Distinct synergistic action of piperacillin and methylglyoxal against Pseudomonas aeruginosa. The dicarbonyl compound methylglyoxal is a natural constituent of Manuka honey produced from Manuka flowers in New Zealand. It is known to possess both anticancer and antibacterial activity. Such observations prompted to investigate the ability of methylglyoxal as a potent drug against multidrug resistant Pseudomonas aeruginosa. A total of 12 test P. aeruginosa strains isolated from various hospitals were tested for their resistances against many antibiotics, most of which are applied in the treatment of P. aeruginosa infections. Results revealed that the strains were resistant to many drugs at high levels, only piperacillin, CHEMICAL, CHEMICAL and ciprofloxacin showed resistances at comparatively lower levels. Following multiple experimentations it was observed that methylglyoxal was also antimicrobic against all the strains at comparable levels. Distinct and statistically significant synergism was observed between methylglyoxal and piperacillin by disc diffusion tests when compared with their individual effects. The fractional inhibitory concentration index of this combination evaluated by checkerboard analysis, was 0.5, which confirmed synergism between the pair. Synergism was also noted when methylglyoxal was combined with carbenicillin and amikacin. | NO-RELATIONSHIP |
| Distinct synergistic action of piperacillin and methylglyoxal against Pseudomonas aeruginosa. The dicarbonyl compound methylglyoxal is a natural constituent of Manuka honey produced from Manuka flowers in New Zealand. It is known to possess both anticancer and antibacterial activity. Such observations prompted to investigate the ability of methylglyoxal as a potent drug against multidrug resistant Pseudomonas aeruginosa. A total of 12 test P. aeruginosa strains isolated from various hospitals were tested for their resistances against many antibiotics, most of which are applied in the treatment of P. aeruginosa infections. Results revealed that the strains were resistant to many drugs at high levels, only piperacillin, CHEMICAL, amikacin and CHEMICAL showed resistances at comparatively lower levels. Following multiple experimentations it was observed that methylglyoxal was also antimicrobic against all the strains at comparable levels. Distinct and statistically significant synergism was observed between methylglyoxal and piperacillin by disc diffusion tests when compared with their individual effects. The fractional inhibitory concentration index of this combination evaluated by checkerboard analysis, was 0.5, which confirmed synergism between the pair. Synergism was also noted when methylglyoxal was combined with carbenicillin and amikacin. | NO-RELATIONSHIP |
| Distinct synergistic action of piperacillin and methylglyoxal against Pseudomonas aeruginosa. The dicarbonyl compound methylglyoxal is a natural constituent of Manuka honey produced from Manuka flowers in New Zealand. It is known to possess both anticancer and antibacterial activity. Such observations prompted to investigate the ability of methylglyoxal as a potent drug against multidrug resistant Pseudomonas aeruginosa. A total of 12 test P. aeruginosa strains isolated from various hospitals were tested for their resistances against many antibiotics, most of which are applied in the treatment of P. aeruginosa infections. Results revealed that the strains were resistant to many drugs at high levels, only piperacillin, carbenicillin, CHEMICAL and CHEMICAL showed resistances at comparatively lower levels. Following multiple experimentations it was observed that methylglyoxal was also antimicrobic against all the strains at comparable levels. Distinct and statistically significant synergism was observed between methylglyoxal and piperacillin by disc diffusion tests when compared with their individual effects. The fractional inhibitory concentration index of this combination evaluated by checkerboard analysis, was 0.5, which confirmed synergism between the pair. Synergism was also noted when methylglyoxal was combined with carbenicillin and amikacin. | NO-RELATIONSHIP |
| Distinct synergistic action of piperacillin and methylglyoxal against Pseudomonas aeruginosa. The dicarbonyl compound methylglyoxal is a natural constituent of Manuka honey produced from Manuka flowers in New Zealand. It is known to possess both anticancer and antibacterial activity. Such observations prompted to investigate the ability of methylglyoxal as a potent drug against multidrug resistant Pseudomonas aeruginosa. A total of 12 test P. aeruginosa strains isolated from various hospitals were tested for their resistances against many antibiotics, most of which are applied in the treatment of P. aeruginosa infections. Results revealed that the strains were resistant to many drugs at high levels, only piperacillin, carbenicillin, amikacin and ciprofloxacin showed resistances at comparatively lower levels. Following multiple experimentations it was observed that methylglyoxal was also antimicrobic against all the strains at comparable levels. Distinct and statistically significant synergism was observed between CHEMICAL and CHEMICAL by disc diffusion tests when compared with their individual effects. The fractional inhibitory concentration index of this combination evaluated by checkerboard analysis, was 0.5, which confirmed synergism between the pair. Synergism was also noted when methylglyoxal was combined with carbenicillin and amikacin. | CHEMICALS-INTERACTION |
| Distinct synergistic action of piperacillin and methylglyoxal against Pseudomonas aeruginosa. The dicarbonyl compound methylglyoxal is a natural constituent of Manuka honey produced from Manuka flowers in New Zealand. It is known to possess both anticancer and antibacterial activity. Such observations prompted to investigate the ability of methylglyoxal as a potent drug against multidrug resistant Pseudomonas aeruginosa. A total of 12 test P. aeruginosa strains isolated from various hospitals were tested for their resistances against many antibiotics, most of which are applied in the treatment of P. aeruginosa infections. Results revealed that the strains were resistant to many drugs at high levels, only piperacillin, carbenicillin, amikacin and ciprofloxacin showed resistances at comparatively lower levels. Following multiple experimentations it was observed that methylglyoxal was also antimicrobic against all the strains at comparable levels. Distinct and statistically significant synergism was observed between methylglyoxal and piperacillin by disc diffusion tests when compared with their individual effects. The fractional inhibitory concentration index of this combination evaluated by checkerboard analysis, was 0.5, which confirmed synergism between the pair. Synergism was also noted when CHEMICAL was combined with CHEMICAL and amikacin. | CHEMICALS-INTERACTION |
| Distinct synergistic action of piperacillin and methylglyoxal against Pseudomonas aeruginosa. The dicarbonyl compound methylglyoxal is a natural constituent of Manuka honey produced from Manuka flowers in New Zealand. It is known to possess both anticancer and antibacterial activity. Such observations prompted to investigate the ability of methylglyoxal as a potent drug against multidrug resistant Pseudomonas aeruginosa. A total of 12 test P. aeruginosa strains isolated from various hospitals were tested for their resistances against many antibiotics, most of which are applied in the treatment of P. aeruginosa infections. Results revealed that the strains were resistant to many drugs at high levels, only piperacillin, carbenicillin, amikacin and ciprofloxacin showed resistances at comparatively lower levels. Following multiple experimentations it was observed that methylglyoxal was also antimicrobic against all the strains at comparable levels. Distinct and statistically significant synergism was observed between methylglyoxal and piperacillin by disc diffusion tests when compared with their individual effects. The fractional inhibitory concentration index of this combination evaluated by checkerboard analysis, was 0.5, which confirmed synergism between the pair. Synergism was also noted when CHEMICAL was combined with carbenicillin and CHEMICAL. | CHEMICALS-INTERACTION |
| Distinct synergistic action of piperacillin and methylglyoxal against Pseudomonas aeruginosa. The dicarbonyl compound methylglyoxal is a natural constituent of Manuka honey produced from Manuka flowers in New Zealand. It is known to possess both anticancer and antibacterial activity. Such observations prompted to investigate the ability of methylglyoxal as a potent drug against multidrug resistant Pseudomonas aeruginosa. A total of 12 test P. aeruginosa strains isolated from various hospitals were tested for their resistances against many antibiotics, most of which are applied in the treatment of P. aeruginosa infections. Results revealed that the strains were resistant to many drugs at high levels, only piperacillin, carbenicillin, amikacin and ciprofloxacin showed resistances at comparatively lower levels. Following multiple experimentations it was observed that methylglyoxal was also antimicrobic against all the strains at comparable levels. Distinct and statistically significant synergism was observed between methylglyoxal and piperacillin by disc diffusion tests when compared with their individual effects. The fractional inhibitory concentration index of this combination evaluated by checkerboard analysis, was 0.5, which confirmed synergism between the pair. Synergism was also noted when methylglyoxal was combined with CHEMICAL and CHEMICAL. | NO-RELATIONSHIP |
| Because CHEMICAL have been shown to depress plasma prothrombin activity, patients who are on CHEMICAL therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | CHEMICALS-INTERACTION |
| Because CHEMICAL have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their CHEMICAL dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | NO-RELATIONSHIP |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on CHEMICAL therapy may require downward adjustment of their CHEMICAL dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | NO-RELATIONSHIP |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of CHEMICAL, it is advisable to avoid giving CHEMICAL in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | NO-RELATIONSHIP |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of CHEMICAL, it is advisable to avoid giving tetracycline class drugs in conjunction with CHEMICAL. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | NO-RELATIONSHIP |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving CHEMICAL in conjunction with CHEMICAL. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | CHEMICALS-INTERACTION |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of CHEMICAL is impaired by CHEMICAL containing aluminum, calcium or magnesium, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | CHEMICALS-INTERACTION |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of CHEMICAL is impaired by antacids containing CHEMICAL, calcium or magnesium, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | CHEMICALS-INTERACTION |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of CHEMICAL is impaired by antacids containing aluminum, CHEMICAL or magnesium, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | CHEMICALS-INTERACTION |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of CHEMICAL is impaired by antacids containing aluminum, calcium or CHEMICAL, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | CHEMICALS-INTERACTION |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of CHEMICAL is impaired by antacids containing aluminum, calcium or magnesium, and CHEMICAL-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | CHEMICALS-INTERACTION |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by CHEMICAL containing CHEMICAL, calcium or magnesium, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | NO-RELATIONSHIP |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by CHEMICAL containing aluminum, CHEMICAL or magnesium, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | NO-RELATIONSHIP |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by CHEMICAL containing aluminum, calcium or CHEMICAL, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | NO-RELATIONSHIP |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by CHEMICAL containing aluminum, calcium or magnesium, and CHEMICAL-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | NO-RELATIONSHIP |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing CHEMICAL, CHEMICAL or magnesium, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | NO-RELATIONSHIP |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing CHEMICAL, calcium or CHEMICAL, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | NO-RELATIONSHIP |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing CHEMICAL, calcium or magnesium, and CHEMICAL-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | NO-RELATIONSHIP |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, CHEMICAL or CHEMICAL, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | NO-RELATIONSHIP |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, CHEMICAL or magnesium, and CHEMICAL-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | NO-RELATIONSHIP |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or CHEMICAL, and CHEMICAL-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | NO-RELATIONSHIP |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium, and iron-containing preparations. The concurrent use of CHEMICAL and CHEMICAL has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective. | CHEMICALS-INTERACTION |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of CHEMICAL with oral CHEMICAL may render oral contraceptives less effective. | CHEMICALS-INTERACTION |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of CHEMICAL with oral contraceptives may render oral CHEMICAL less effective. | NO-RELATIONSHIP |
| Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline class drugs in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium, and iron-containing preparations. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracyclines with oral CHEMICAL may render oral CHEMICAL less effective. | NO-RELATIONSHIP |
| The concomitant use of CHEMICAL with other CHEMICAL that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, pancuronium, morphine, vancomycin, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with CHEMICAL have not been conducted, CHEMICAL has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, pancuronium, morphine, vancomycin, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with CHEMICAL have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. CHEMICAL, procainamide, pancuronium, morphine, vancomycin, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with CHEMICAL have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, CHEMICAL, pancuronium, morphine, vancomycin, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with CHEMICAL have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, CHEMICAL, morphine, vancomycin, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with CHEMICAL have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, pancuronium, CHEMICAL, vancomycin, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with CHEMICAL have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, pancuronium, morphine, CHEMICAL, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with CHEMICAL have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, pancuronium, morphine, vancomycin, CHEMICAL and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with CHEMICAL have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, pancuronium, morphine, vancomycin, metformin and CHEMICAL). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, CHEMICAL has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. CHEMICAL, procainamide, pancuronium, morphine, vancomycin, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, CHEMICAL has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, CHEMICAL, pancuronium, morphine, vancomycin, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, CHEMICAL has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, CHEMICAL, morphine, vancomycin, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, CHEMICAL has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, pancuronium, CHEMICAL, vancomycin, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, CHEMICAL has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, pancuronium, morphine, CHEMICAL, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, CHEMICAL has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, pancuronium, morphine, vancomycin, CHEMICAL and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, CHEMICAL has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, pancuronium, morphine, vancomycin, metformin and CHEMICAL). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | CHEMICALS-INTERACTION |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. CHEMICAL, CHEMICAL, pancuronium, morphine, vancomycin, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. CHEMICAL, procainamide, CHEMICAL, morphine, vancomycin, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. CHEMICAL, procainamide, pancuronium, CHEMICAL, vancomycin, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. CHEMICAL, procainamide, pancuronium, morphine, CHEMICAL, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. CHEMICAL, procainamide, pancuronium, morphine, vancomycin, CHEMICAL and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. CHEMICAL, procainamide, pancuronium, morphine, vancomycin, metformin and CHEMICAL). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, CHEMICAL, CHEMICAL, morphine, vancomycin, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, CHEMICAL, pancuronium, CHEMICAL, vancomycin, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, CHEMICAL, pancuronium, morphine, CHEMICAL, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, CHEMICAL, pancuronium, morphine, vancomycin, CHEMICAL and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, CHEMICAL, pancuronium, morphine, vancomycin, metformin and CHEMICAL). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, CHEMICAL, CHEMICAL, vancomycin, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, CHEMICAL, morphine, CHEMICAL, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, CHEMICAL, morphine, vancomycin, CHEMICAL and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, CHEMICAL, morphine, vancomycin, metformin and CHEMICAL). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, pancuronium, CHEMICAL, CHEMICAL, metformin and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, pancuronium, CHEMICAL, vancomycin, CHEMICAL and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, pancuronium, CHEMICAL, vancomycin, metformin and CHEMICAL). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, pancuronium, morphine, CHEMICAL, CHEMICAL and tenofovir). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, pancuronium, morphine, CHEMICAL, metformin and CHEMICAL). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, pancuronium, morphine, vancomycin, CHEMICAL and CHEMICAL). Coadministration of Sanctura with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of Sanctura and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| The concomitant use of Sanctura with other anticholinergic agents that produce dry mouth, constipation, and other anticholinergic pharmacological effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility. Drugs Eliminated by Active Tubular Secretion: Although studies to assess drug-drug interactions with Sanctura have not been conducted, Sanctura has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion (e.g. digoxin, procainamide, pancuronium, morphine, vancomycin, metformin and tenofovir). Coadministration of CHEMICAL with drugs that are eliminated by active renal tubular secretion may increase the serum concentration of CHEMICAL and/or the coadministered drug due to competition for this elimination pathway. Careful patient monitoring is recommended in patients receiving such drugs. Drug-Laboratory-Test Interactions Interactions between Sanctura and laboratory tests have not been studied. | NO-RELATIONSHIP |
| DRUG INTERACTIONS There are no known drug/drug interactions with oral CHEMICAL Vaccinations with CHEMICAL are not recommended in immunocompromised individuals Nalidixic acid together with high-dose intravenous melphalan has caused deaths in children due to haemorrhagic enterocolitis. Impaired renal function has been described in bone marrow transplant patients who were conditioned with high-dose intravenous melphalan and who subsequently received cyclosporin to prevent graft-versus-host disease | NO-RELATIONSHIP |
| DRUG INTERACTIONS There are no known drug/drug interactions with oral CHEMICAL Vaccinations with live organism vaccines are not recommended in immunocompromised individuals CHEMICAL together with high-dose intravenous melphalan has caused deaths in children due to haemorrhagic enterocolitis. Impaired renal function has been described in bone marrow transplant patients who were conditioned with high-dose intravenous melphalan and who subsequently received cyclosporin to prevent graft-versus-host disease | NO-RELATIONSHIP |
| DRUG INTERACTIONS There are no known drug/drug interactions with oral CHEMICAL Vaccinations with live organism vaccines are not recommended in immunocompromised individuals Nalidixic acid together with high-dose intravenous CHEMICAL has caused deaths in children due to haemorrhagic enterocolitis. Impaired renal function has been described in bone marrow transplant patients who were conditioned with high-dose intravenous melphalan and who subsequently received cyclosporin to prevent graft-versus-host disease | NO-RELATIONSHIP |
| DRUG INTERACTIONS There are no known drug/drug interactions with oral ALKERAN Vaccinations with CHEMICAL are not recommended in immunocompromised individuals CHEMICAL together with high-dose intravenous melphalan has caused deaths in children due to haemorrhagic enterocolitis. Impaired renal function has been described in bone marrow transplant patients who were conditioned with high-dose intravenous melphalan and who subsequently received cyclosporin to prevent graft-versus-host disease | NO-RELATIONSHIP |
| DRUG INTERACTIONS There are no known drug/drug interactions with oral ALKERAN Vaccinations with CHEMICAL are not recommended in immunocompromised individuals Nalidixic acid together with high-dose intravenous CHEMICAL has caused deaths in children due to haemorrhagic enterocolitis. Impaired renal function has been described in bone marrow transplant patients who were conditioned with high-dose intravenous melphalan and who subsequently received cyclosporin to prevent graft-versus-host disease | NO-RELATIONSHIP |
| DRUG INTERACTIONS There are no known drug/drug interactions with oral ALKERAN Vaccinations with live organism vaccines are not recommended in immunocompromised individuals CHEMICAL together with high-dose intravenous CHEMICAL has caused deaths in children due to haemorrhagic enterocolitis. Impaired renal function has been described in bone marrow transplant patients who were conditioned with high-dose intravenous melphalan and who subsequently received cyclosporin to prevent graft-versus-host disease | CHEMICALS-INTERACTION |
| DRUG INTERACTIONS There are no known drug/drug interactions with oral ALKERAN Vaccinations with live organism vaccines are not recommended in immunocompromised individuals Nalidixic acid together with high-dose intravenous melphalan has caused deaths in children due to haemorrhagic enterocolitis. Impaired renal function has been described in bone marrow transplant patients who were conditioned with high-dose intravenous CHEMICAL and who subsequently received CHEMICAL to prevent graft-versus-host disease | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when CHEMICAL is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of CHEMICAL, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when CHEMICAL is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, CHEMICAL, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when CHEMICAL is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, CHEMICAL, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when CHEMICAL is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and CHEMICAL). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of CHEMICAL, CHEMICAL, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of CHEMICAL, protease inhibitors, CHEMICAL, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of CHEMICAL, protease inhibitors, calcium channel antagonists, and CHEMICAL). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, CHEMICAL, CHEMICAL, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, CHEMICAL, calcium channel antagonists, and CHEMICAL). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, CHEMICAL, and CHEMICAL). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as CHEMICAL, CHEMICAL, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as CHEMICAL, diltiazem, CHEMICAL, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as CHEMICAL, diltiazem, verapamil, CHEMICAL, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as CHEMICAL, diltiazem, verapamil, ketoconazole, CHEMICAL and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as CHEMICAL, diltiazem, verapamil, ketoconazole, fluconazole and CHEMICAL were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as CHEMICAL, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered CHEMICAL. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, CHEMICAL, CHEMICAL, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, CHEMICAL, verapamil, CHEMICAL, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, CHEMICAL, verapamil, ketoconazole, CHEMICAL and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, CHEMICAL, verapamil, ketoconazole, fluconazole and CHEMICAL were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, CHEMICAL, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered CHEMICAL. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, CHEMICAL, CHEMICAL, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, CHEMICAL, ketoconazole, CHEMICAL and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, CHEMICAL, ketoconazole, fluconazole and CHEMICAL were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, CHEMICAL, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered CHEMICAL. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, CHEMICAL, CHEMICAL and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, CHEMICAL, fluconazole and CHEMICAL were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, CHEMICAL, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered CHEMICAL. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, CHEMICAL and CHEMICAL were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, CHEMICAL and itraconazole were shown to significantly increase the C max and AUC of orally administered CHEMICAL. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and CHEMICAL were shown to significantly increase the C max and AUC of orally administered CHEMICAL. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors CHEMICAL and CHEMICAL may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors CHEMICAL and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of CHEMICAL. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and CHEMICAL may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of CHEMICAL. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as CHEMICAL, CHEMICAL, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as CHEMICAL, carbamazepine, and CHEMICAL, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as CHEMICAL, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral CHEMICAL in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, CHEMICAL, and CHEMICAL, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, CHEMICAL, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral CHEMICAL in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and CHEMICAL, induce metabolism and caused a markedly decreased C max and AUC of oral CHEMICAL in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the CHEMICAL due to both the gastrointestinal effects and stimulant effects of CHEMICAL. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of CHEMICAL is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly CHEMICAL (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of CHEMICAL is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, CHEMICAL, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of CHEMICAL is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, CHEMICAL and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of CHEMICAL is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and CHEMICAL), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of CHEMICAL is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), CHEMICAL, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of CHEMICAL is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, CHEMICAL, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of CHEMICAL is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, CHEMICAL, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of CHEMICAL is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, CHEMICAL and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of CHEMICAL is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and CHEMICAL. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | CHEMICALS-INTERACTION |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly CHEMICAL (eg, CHEMICAL, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly CHEMICAL (eg, morphine, CHEMICAL and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly CHEMICAL (eg, morphine, meperidine and CHEMICAL), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly CHEMICAL (eg, morphine, meperidine and fentanyl), CHEMICAL, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly CHEMICAL (eg, morphine, meperidine and fentanyl), propofol, CHEMICAL, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly CHEMICAL (eg, morphine, meperidine and fentanyl), propofol, ketamine, CHEMICAL, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly CHEMICAL (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, CHEMICAL and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly CHEMICAL (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and CHEMICAL. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, CHEMICAL, CHEMICAL and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, CHEMICAL, meperidine and CHEMICAL), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, CHEMICAL, meperidine and fentanyl), CHEMICAL, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, CHEMICAL, meperidine and fentanyl), propofol, CHEMICAL, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, CHEMICAL, meperidine and fentanyl), propofol, ketamine, CHEMICAL, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, CHEMICAL, meperidine and fentanyl), propofol, ketamine, nitrous oxide, CHEMICAL and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, CHEMICAL, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and CHEMICAL. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, CHEMICAL and CHEMICAL), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, CHEMICAL and fentanyl), CHEMICAL, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, CHEMICAL and fentanyl), propofol, CHEMICAL, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, CHEMICAL and fentanyl), propofol, ketamine, CHEMICAL, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, CHEMICAL and fentanyl), propofol, ketamine, nitrous oxide, CHEMICAL and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, CHEMICAL and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and CHEMICAL. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and CHEMICAL), CHEMICAL, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and CHEMICAL), propofol, CHEMICAL, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and CHEMICAL), propofol, ketamine, CHEMICAL, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and CHEMICAL), propofol, ketamine, nitrous oxide, CHEMICAL and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and CHEMICAL), propofol, ketamine, nitrous oxide, secobarbital and CHEMICAL. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), CHEMICAL, CHEMICAL, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), CHEMICAL, ketamine, CHEMICAL, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), CHEMICAL, ketamine, nitrous oxide, CHEMICAL and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), CHEMICAL, ketamine, nitrous oxide, secobarbital and CHEMICAL. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, CHEMICAL, CHEMICAL, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, CHEMICAL, nitrous oxide, CHEMICAL and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, CHEMICAL, nitrous oxide, secobarbital and CHEMICAL. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, CHEMICAL, CHEMICAL and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, CHEMICAL, secobarbital and CHEMICAL. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, CHEMICAL and CHEMICAL. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as CHEMICAL, CHEMICAL, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as CHEMICAL, scopolamine, CHEMICAL, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as CHEMICAL, scopolamine, glycopyrrolate, CHEMICAL, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as CHEMICAL, scopolamine, glycopyrrolate, diazepam, CHEMICAL, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as CHEMICAL, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other CHEMICAL) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as CHEMICAL, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local CHEMICAL have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, CHEMICAL, CHEMICAL, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, CHEMICAL, glycopyrrolate, CHEMICAL, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, CHEMICAL, glycopyrrolate, diazepam, CHEMICAL, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, CHEMICAL, glycopyrrolate, diazepam, hydroxyzine, and other CHEMICAL) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, CHEMICAL, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local CHEMICAL have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, CHEMICAL, CHEMICAL, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, CHEMICAL, diazepam, CHEMICAL, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, CHEMICAL, diazepam, hydroxyzine, and other CHEMICAL) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, CHEMICAL, diazepam, hydroxyzine, and other muscle relaxants) or local CHEMICAL have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, CHEMICAL, CHEMICAL, and other muscle relaxants) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, CHEMICAL, hydroxyzine, and other CHEMICAL) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, CHEMICAL, hydroxyzine, and other muscle relaxants) or local CHEMICAL have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, CHEMICAL, and other CHEMICAL) or local anesthetics have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, CHEMICAL, and other muscle relaxants) or local CHEMICAL have been observed. | NO-RELATIONSHIP |
| Drug Interactions: Inhibitors of CYP3A4 Isozymes: Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as erythromycin, diltiazem, verapamil, ketoconazole, fluconazole and itraconazole were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam. Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when VERSED Syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated. Inducers of CYP3A4 Isozymes: Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and caused a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering VERSED Syrup to patients receiving these medications and if necessary dose adjustments should be considered. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate. The sedative effect of VERSED Syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (eg, morphine, meperidine and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of VERSED Syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response. No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other CHEMICAL) or local CHEMICAL have been observed. | NO-RELATIONSHIP |
| Interactions between Leukine and other drugs have not been fully evaluated. Drugs which may potentiate the myeloproliferative effects of CHEMICAL, such as CHEMICAL and corticosteroids, should be used with caution. | CHEMICALS-INTERACTION |
| Interactions between Leukine and other drugs have not been fully evaluated. Drugs which may potentiate the myeloproliferative effects of CHEMICAL, such as lithium and CHEMICAL, should be used with caution. | CHEMICALS-INTERACTION |
| Interactions between Leukine and other drugs have not been fully evaluated. Drugs which may potentiate the myeloproliferative effects of Leukine, such as CHEMICAL and CHEMICAL, should be used with caution. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with CHEMICAL with and without CHEMICAL or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | CHEMICALS-INTERACTION |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with CHEMICAL with and without anticoagulants or CHEMICAL. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without CHEMICAL or CHEMICAL. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of CHEMICAL and CHEMICAL-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | CHEMICALS-INTERACTION |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of CHEMICAL and theophylline-containing drugs leads to increased CHEMICAL levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of CHEMICAL and theophylline-containing drugs leads to increased theophylline levels and CHEMICAL toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and CHEMICAL-containing drugs leads to increased CHEMICAL levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and CHEMICAL-containing drugs leads to increased theophylline levels and CHEMICAL toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased CHEMICAL levels and CHEMICAL toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. CHEMICAL has been used concurrently with CHEMICAL, beta blockers, digitalis, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. CHEMICAL has been used concurrently with antihypertensive drugs, CHEMICAL, digitalis, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. CHEMICAL has been used concurrently with antihypertensive drugs, beta blockers, CHEMICAL, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. CHEMICAL has been used concurrently with antihypertensive drugs, beta blockers, digitalis, CHEMICAL, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. CHEMICAL has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, CHEMICAL, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. CHEMICAL has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, antidiabetic agents, and CHEMICAL, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with CHEMICAL, CHEMICAL, digitalis, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with CHEMICAL, beta blockers, CHEMICAL, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with CHEMICAL, beta blockers, digitalis, CHEMICAL, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with CHEMICAL, beta blockers, digitalis, diuretics, CHEMICAL, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with CHEMICAL, beta blockers, digitalis, diuretics, antidiabetic agents, and CHEMICAL, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, CHEMICAL, CHEMICAL, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, CHEMICAL, digitalis, CHEMICAL, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, CHEMICAL, digitalis, diuretics, CHEMICAL, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, CHEMICAL, digitalis, diuretics, antidiabetic agents, and CHEMICAL, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, beta blockers, CHEMICAL, CHEMICAL, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, beta blockers, CHEMICAL, diuretics, CHEMICAL, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, beta blockers, CHEMICAL, diuretics, antidiabetic agents, and CHEMICAL, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, beta blockers, digitalis, CHEMICAL, CHEMICAL, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, beta blockers, digitalis, CHEMICAL, antidiabetic agents, and CHEMICAL, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| Although a causal relationship has not been established, there have been reports of bleeding and/or prolonged prothrombin time in patients treated with TRENTAL with and without anticoagulants or platelet aggregation inhibitors. Patients on Warfarin should have more frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of TRENTAL and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. TRENTAL has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, CHEMICAL, and CHEMICAL, without observed problems. Small decreases in blood pressure have been observed in some patients treated with TRENTAL; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced. | NO-RELATIONSHIP |
| CHEMICAL Reports suggest that CHEMICAL may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| CHEMICAL Reports suggest that NSAIDs may diminish the antihypertensive effect of CHEMICAL. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that CHEMICAL may diminish the antihypertensive effect of CHEMICAL. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking CHEMICAL concomitantly with CHEMICAL. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. CHEMICAL: Concomitant administration of CHEMICAL (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. CHEMICAL: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of CHEMICAL. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of CHEMICAL (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of CHEMICAL. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other CHEMICAL, concomitant administration of CHEMICAL and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other CHEMICAL, concomitant administration of meloxicam and CHEMICAL is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of CHEMICAL and CHEMICAL is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose CHEMICAL with CHEMICAL may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose CHEMICAL with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of CHEMICAL alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with CHEMICAL may result in an increased rate of GI ulceration or other complications, compared to use of CHEMICAL alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. CHEMICAL is not a substitute for CHEMICAL for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. CHEMICAL: Pretreatment for four days with CHEMICAL significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. CHEMICAL: Pretreatment for four days with cholestyramine significantly increased the clearance of CHEMICAL by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with CHEMICAL significantly increased the clearance of CHEMICAL by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. CHEMICAL: Concomitant administration of 200 mg CHEMICAL QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. CHEMICAL: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg CHEMICAL. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg CHEMICAL QID did not alter the single-dose pharmacokinetics of 30 mg CHEMICAL. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. CHEMICAL: CHEMICAL 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. CHEMICAL: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of CHEMICAL after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: CHEMICAL 15 mg once daily for 7 days did not alter the plasma concentration profile of CHEMICAL after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between CHEMICAL and CHEMICAL. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. CHEMICAL: Clinical studies, as well as post-marketing observations, have shown that CHEMICAL can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. CHEMICAL: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of CHEMICAL and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. CHEMICAL: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and CHEMICAL in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that CHEMICAL can reduce the natriuretic effect of CHEMICAL and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that CHEMICAL can reduce the natriuretic effect of furosemide and CHEMICAL in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of CHEMICAL and CHEMICAL in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with CHEMICAL agents and CHEMICAL have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. CHEMICAL: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of CHEMICAL. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with CHEMICAL and CHEMICAL, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. CHEMICAL: In clinical trials, CHEMICAL have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. CHEMICAL: In clinical trials, NSAIDs have produced an elevation of plasma CHEMICAL levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. CHEMICAL: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal CHEMICAL clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, CHEMICAL have produced an elevation of plasma CHEMICAL levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, CHEMICAL have produced an elevation of plasma lithium levels and a reduction in renal CHEMICAL clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma CHEMICAL levels and a reduction in renal CHEMICAL clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose CHEMICAL concentration and AUC were increased by 21% in subjects receiving CHEMICAL doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose CHEMICAL concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with CHEMICAL 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose CHEMICAL concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving CHEMICAL alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | NO-RELATIONSHIP |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving CHEMICAL doses ranging from 804 to 1072 mg BID with CHEMICAL 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving CHEMICAL doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving CHEMICAL alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with CHEMICAL 15 mg QD as compared to subjects receiving CHEMICAL alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on CHEMICAL treatment should be closely monitored when CHEMICAL is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. CHEMICAL: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of CHEMICAL on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. CHEMICAL: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of CHEMICAL taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of CHEMICAL on the pharmacokinetics of CHEMICAL taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. CHEMICAL did not have a significant effect on the pharmacokinetics of single doses of CHEMICAL. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, CHEMICAL did not displace CHEMICAL from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. CHEMICAL: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing CHEMICAL therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. CHEMICAL: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving CHEMICAL or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing CHEMICAL therapy in patients receiving CHEMICAL or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of CHEMICAL on the anticoagulant effect of CHEMICAL was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of CHEMICAL on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of CHEMICAL that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of CHEMICAL was studied in a group of healthy subjects receiving daily doses of CHEMICAL that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, CHEMICAL did not alter CHEMICAL pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, CHEMICAL did not alter warfarin pharmacokinetics and the average anticoagulant effect of CHEMICAL as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter CHEMICAL pharmacokinetics and the average anticoagulant effect of CHEMICAL as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering CHEMICAL with CHEMICAL since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering CHEMICAL with warfarin since patients on CHEMICAL may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| ACE inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors. Aspirin: Concomitant administration of aspirin (1000 mg TID) to healthy volunteers tended to increase the AUC (10%) and Cmax (24%) of meloxicam. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with MOBIC may result in an increased rate of GI ulceration or other complications, compared to use of MOBIC alone. MOBIC is not a substitute for aspirin for cardiovascular prophylaxis. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine QID did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after b-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Furosemide: Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. This effect has been attributed to inhibition of renal prostaglandin synthesis. Studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide: single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with furosemide and MOBIC, patients should be observed closely for signs of declining renal function, as well as to assure diuretic efficacy. Lithium: In clinical trials, NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg BID with meloxicam 15 mg QD as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by MOBIC. Patients on lithium treatment should be closely monitored when MOBIC is introduced or withdrawn. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites. Warfarin: Anticoagulant activity should be monitored, particularly in the first few days after initiating or changing MOBIC therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding. The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering MOBIC with CHEMICAL since patients on CHEMICAL may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced. | CHEMICALS-INTERACTION |
| When administered concomitantly with CHEMICAL , CHEMICAL may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., CHEMICAL, CHEMICAL, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., CHEMICAL, pseudoephedrine, CHEMICAL, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., CHEMICAL, pseudoephedrine, ephedrine, CHEMICAL or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., CHEMICAL, pseudoephedrine, ephedrine, phenylpropanolamine or CHEMICAL) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., CHEMICAL, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of CHEMICAL . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., CHEMICAL, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when CHEMICAL is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, CHEMICAL, CHEMICAL, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, CHEMICAL, ephedrine, CHEMICAL or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, CHEMICAL, ephedrine, phenylpropanolamine or CHEMICAL) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, CHEMICAL, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of CHEMICAL . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, CHEMICAL, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when CHEMICAL is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, CHEMICAL, CHEMICAL or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, CHEMICAL, phenylpropanolamine or CHEMICAL) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, CHEMICAL, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of CHEMICAL . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, CHEMICAL, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when CHEMICAL is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, CHEMICAL or CHEMICAL) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, CHEMICAL or dihydroergotamine) may enhance or potentiate the pressor effects of CHEMICAL . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, CHEMICAL or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when CHEMICAL is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or CHEMICAL) may enhance or potentiate the pressor effects of CHEMICAL . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or CHEMICAL) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when CHEMICAL is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of CHEMICAL . Therefore, caution should be used when CHEMICAL is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. CHEMICAL has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., CHEMICAL), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. CHEMICAL. CHEMICAL, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. CHEMICAL. Alpha-adrenergic blocking agents, such as CHEMICAL, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. CHEMICAL. Alpha-adrenergic blocking agents, such as prazosin, CHEMICAL, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. CHEMICAL. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and CHEMICAL, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. CHEMICAL. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of CHEMICAL. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. CHEMICAL. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of CHEMICAL (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. CHEMICAL. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as CHEMICAL, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. CHEMICAL. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, CHEMICAL, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. CHEMICAL. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, CHEMICAL, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. CHEMICAL. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, CHEMICAL, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. CHEMICAL. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, CHEMICAL, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. CHEMICAL. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, CHEMICAL, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. CHEMICAL. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and CHEMICAL. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. CHEMICAL, such as CHEMICAL, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. CHEMICAL, such as prazosin, CHEMICAL, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. CHEMICAL, such as prazosin, terazosin, and CHEMICAL, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. CHEMICAL, such as prazosin, terazosin, and doxazosin, can antagonize the effects of CHEMICAL. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. CHEMICAL, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of CHEMICAL (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. CHEMICAL, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as CHEMICAL, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. CHEMICAL, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, CHEMICAL, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. CHEMICAL, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, CHEMICAL, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. CHEMICAL, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, CHEMICAL, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. CHEMICAL, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, CHEMICAL, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. CHEMICAL, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, CHEMICAL, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. CHEMICAL, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and CHEMICAL. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as CHEMICAL, CHEMICAL, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as CHEMICAL, terazosin, and CHEMICAL, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as CHEMICAL, terazosin, and doxazosin, can antagonize the effects of CHEMICAL. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as CHEMICAL, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of CHEMICAL (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as CHEMICAL, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as CHEMICAL, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as CHEMICAL, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, CHEMICAL, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as CHEMICAL, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, CHEMICAL, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as CHEMICAL, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, CHEMICAL, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as CHEMICAL, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, CHEMICAL, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as CHEMICAL, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, CHEMICAL, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as CHEMICAL, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and CHEMICAL. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, CHEMICAL, and CHEMICAL, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, CHEMICAL, and doxazosin, can antagonize the effects of CHEMICAL. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, CHEMICAL, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of CHEMICAL (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, CHEMICAL, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as CHEMICAL, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, CHEMICAL, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, CHEMICAL, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, CHEMICAL, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, CHEMICAL, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, CHEMICAL, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, CHEMICAL, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, CHEMICAL, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, CHEMICAL, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, CHEMICAL, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, CHEMICAL, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, CHEMICAL, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and CHEMICAL. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and CHEMICAL, can antagonize the effects of CHEMICAL. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and CHEMICAL, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of CHEMICAL (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and CHEMICAL, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as CHEMICAL, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and CHEMICAL, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, CHEMICAL, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and CHEMICAL, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, CHEMICAL, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and CHEMICAL, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, CHEMICAL, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and CHEMICAL, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, CHEMICAL, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and CHEMICAL, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, CHEMICAL, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and CHEMICAL, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and CHEMICAL. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of CHEMICAL. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of CHEMICAL (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of CHEMICAL. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as CHEMICAL, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of CHEMICAL. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, CHEMICAL, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of CHEMICAL. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, CHEMICAL, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of CHEMICAL. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, CHEMICAL, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of CHEMICAL. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, CHEMICAL, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of CHEMICAL. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, CHEMICAL, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of CHEMICAL. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and CHEMICAL. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of CHEMICAL (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as CHEMICAL, cimetidine, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of CHEMICAL (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, CHEMICAL, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of CHEMICAL (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, CHEMICAL, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of CHEMICAL (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, CHEMICAL, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of CHEMICAL (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, CHEMICAL, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of CHEMICAL (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, CHEMICAL, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | CHEMICALS-INTERACTION |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of CHEMICAL (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide, and CHEMICAL. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as CHEMICAL, CHEMICAL, ranitidine, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as CHEMICAL, cimetidine, CHEMICAL, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as CHEMICAL, cimetidine, ranitidine, CHEMICAL, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as CHEMICAL, cimetidine, ranitidine, procainamide, CHEMICAL, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as CHEMICAL, cimetidine, ranitidine, procainamide, triamterene, CHEMICAL, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as CHEMICAL, cimetidine, ranitidine, procainamide, triamterene, flecainide, and CHEMICAL. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, CHEMICAL, CHEMICAL, procainamide, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, CHEMICAL, ranitidine, CHEMICAL, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, CHEMICAL, ranitidine, procainamide, CHEMICAL, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, CHEMICAL, ranitidine, procainamide, triamterene, CHEMICAL, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, CHEMICAL, ranitidine, procainamide, triamterene, flecainide, and CHEMICAL. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, CHEMICAL, CHEMICAL, triamterene, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, CHEMICAL, procainamide, CHEMICAL, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, CHEMICAL, procainamide, triamterene, CHEMICAL, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, CHEMICAL, procainamide, triamterene, flecainide, and CHEMICAL. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, CHEMICAL, CHEMICAL, flecainide, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, CHEMICAL, triamterene, CHEMICAL, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, CHEMICAL, triamterene, flecainide, and CHEMICAL. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, CHEMICAL, CHEMICAL, and quinidine. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, CHEMICAL, flecainide, and CHEMICAL. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| When administered concomitantly with ProAmatine , cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia. The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of ProAmatine . Therefore, caution should be used when ProAmatine is administered concomitantly with agents that cause vasoconstriction. ProAmatine has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with. ProAmatine. Alpha-adrenergic blocking agents, such as prazosin, terazosin, and doxazosin, can antagonize the effects of ProAmatine. Potential for Drug Interactions: It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, CHEMICAL, and CHEMICAL. Thus there may be a potential for drug-drug interactions with these drugs. | NO-RELATIONSHIP |
| Preliminary evidence suggests that CHEMICAL inhibits CHEMICAL metabolism and may result in an increase in plasma concentrations of mebendazole. | CHEMICALS-INTERACTION |
| Preliminary evidence suggests that CHEMICAL inhibits mebendazole metabolism and may result in an increase in plasma concentrations of CHEMICAL. | CHEMICALS-INTERACTION |
| Preliminary evidence suggests that cimetidine inhibits CHEMICAL metabolism and may result in an increase in plasma concentrations of CHEMICAL. | NO-RELATIONSHIP |
| Interactions for CHEMICAL (CHEMICAL): Alcohol - impairs the intestinal absorption of riboflavin Probenecid - concurrent use decreases gastrointestinal absorption of riboflavin; requirements for riboflavin may be increased in patients receiving probenecid. | NO-RELATIONSHIP |
| Interactions for CHEMICAL (Riboflavin): CHEMICAL - impairs the intestinal absorption of riboflavin Probenecid - concurrent use decreases gastrointestinal absorption of riboflavin; requirements for riboflavin may be increased in patients receiving probenecid. | NO-RELATIONSHIP |
| Interactions for CHEMICAL (Riboflavin): Alcohol - impairs the intestinal absorption of CHEMICAL Probenecid - concurrent use decreases gastrointestinal absorption of riboflavin; requirements for riboflavin may be increased in patients receiving probenecid. | NO-RELATIONSHIP |
| Interactions for Vitamin B2 (CHEMICAL): CHEMICAL - impairs the intestinal absorption of riboflavin Probenecid - concurrent use decreases gastrointestinal absorption of riboflavin; requirements for riboflavin may be increased in patients receiving probenecid. | NO-RELATIONSHIP |
| Interactions for Vitamin B2 (CHEMICAL): Alcohol - impairs the intestinal absorption of CHEMICAL Probenecid - concurrent use decreases gastrointestinal absorption of riboflavin; requirements for riboflavin may be increased in patients receiving probenecid. | NO-RELATIONSHIP |
| Interactions for Vitamin B2 (Riboflavin): CHEMICAL - impairs the intestinal absorption of CHEMICAL Probenecid - concurrent use decreases gastrointestinal absorption of riboflavin; requirements for riboflavin may be increased in patients receiving probenecid. | CHEMICALS-INTERACTION |
| Interactions for Vitamin B2 (Riboflavin): Alcohol - impairs the intestinal absorption of riboflavin CHEMICAL - concurrent use decreases gastrointestinal absorption of CHEMICAL; requirements for riboflavin may be increased in patients receiving probenecid. | NO-RELATIONSHIP |
| Interactions for Vitamin B2 (Riboflavin): Alcohol - impairs the intestinal absorption of riboflavin Probenecid - concurrent use decreases gastrointestinal absorption of riboflavin; requirements for CHEMICAL may be increased in patients receiving CHEMICAL. | CHEMICALS-INTERACTION |
| The concomitant use of other CHEMICAL including CHEMICAL, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CHEMICAL including sedatives, CHEMICAL, tranquilizers, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CHEMICAL including sedatives, hypnotics, CHEMICAL, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CHEMICAL including sedatives, hypnotics, tranquilizers, general CHEMICAL, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CHEMICAL including sedatives, hypnotics, tranquilizers, general anesthetics, CHEMICAL, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CHEMICAL including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other CHEMICAL, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CHEMICAL including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, CHEMICAL, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CHEMICAL including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, CHEMICAL, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CHEMICAL including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and CHEMICAL may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | CHEMICALS-INTERACTION |
| The concomitant use of other CNS depressants including CHEMICAL, CHEMICAL, tranquilizers, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including CHEMICAL, hypnotics, CHEMICAL, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including CHEMICAL, hypnotics, tranquilizers, general CHEMICAL, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including CHEMICAL, hypnotics, tranquilizers, general anesthetics, CHEMICAL, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including CHEMICAL, hypnotics, tranquilizers, general anesthetics, phenothiazines, other CHEMICAL, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including CHEMICAL, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, CHEMICAL, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including CHEMICAL, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, CHEMICAL, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including CHEMICAL, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and CHEMICAL may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, CHEMICAL, CHEMICAL, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, CHEMICAL, tranquilizers, general CHEMICAL, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, CHEMICAL, tranquilizers, general anesthetics, CHEMICAL, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, CHEMICAL, tranquilizers, general anesthetics, phenothiazines, other CHEMICAL, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, CHEMICAL, tranquilizers, general anesthetics, phenothiazines, other opioids, CHEMICAL, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, CHEMICAL, tranquilizers, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, CHEMICAL, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, CHEMICAL, tranquilizers, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and CHEMICAL may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, CHEMICAL, general CHEMICAL, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, CHEMICAL, general anesthetics, CHEMICAL, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, CHEMICAL, general anesthetics, phenothiazines, other CHEMICAL, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, CHEMICAL, general anesthetics, phenothiazines, other opioids, CHEMICAL, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, CHEMICAL, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, CHEMICAL, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, CHEMICAL, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and CHEMICAL may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general CHEMICAL, CHEMICAL, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general CHEMICAL, phenothiazines, other CHEMICAL, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general CHEMICAL, phenothiazines, other opioids, CHEMICAL, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general CHEMICAL, phenothiazines, other opioids, tricyclic antidepressants, CHEMICAL, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general CHEMICAL, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and CHEMICAL may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, CHEMICAL, other CHEMICAL, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, CHEMICAL, other opioids, CHEMICAL, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, CHEMICAL, other opioids, tricyclic antidepressants, CHEMICAL, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, CHEMICAL, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and CHEMICAL may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other CHEMICAL, CHEMICAL, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other CHEMICAL, tricyclic antidepressants, CHEMICAL, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other CHEMICAL, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and CHEMICAL may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, CHEMICAL, CHEMICAL, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, CHEMICAL, monoamine oxidase (MAO) inhibitors, and CHEMICAL may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, CHEMICAL, and CHEMICAL may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. CHEMICAL or other medications with anticholinergic activity when used concurrently with CHEMICAL may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | CHEMICALS-INTERACTION |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when CHEMICAL was combined with CHEMICAL for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of cimetidine with opioid analgesics; no clear-cut cause and effect relationship was established. | CHEMICALS-INTERACTION |
| The concomitant use of other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol may produce additive CNS depressant effects. When such combined therapy is contemplated, the dose of one or both agents should be reduced. Anticholinergics or other medications with anticholinergic activity when used concurrently with opioid analgesics may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. It has been reported that the incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia. In addition, CNS toxicity has been reported (confusion, disorientation, respiratory depression, apnea, seizures) following coadministration of CHEMICAL with CHEMICAL; no clear-cut cause and effect relationship was established. | NO-RELATIONSHIP |
| Since CHEMICAL (CHEMICAL) may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (eg methsuximide may increase the plasma concentrations of phenytoin and phenobarbital). | NO-RELATIONSHIP |
| Since CHEMICAL (methsuximide) may interact with concurrently administered CHEMICAL, periodic serum level determinations of these drugs may be necessary (eg methsuximide may increase the plasma concentrations of phenytoin and phenobarbital). | CHEMICALS-INTERACTION |
| Since CHEMICAL (methsuximide) may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (eg CHEMICAL may increase the plasma concentrations of phenytoin and phenobarbital). | NO-RELATIONSHIP |
| Since CHEMICAL (methsuximide) may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (eg methsuximide may increase the plasma concentrations of CHEMICAL and phenobarbital). | NO-RELATIONSHIP |
| Since CHEMICAL (methsuximide) may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (eg methsuximide may increase the plasma concentrations of phenytoin and CHEMICAL). | NO-RELATIONSHIP |
| Since Celontin (CHEMICAL) may interact with concurrently administered CHEMICAL, periodic serum level determinations of these drugs may be necessary (eg methsuximide may increase the plasma concentrations of phenytoin and phenobarbital). | CHEMICALS-INTERACTION |
| Since Celontin (CHEMICAL) may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (eg CHEMICAL may increase the plasma concentrations of phenytoin and phenobarbital). | NO-RELATIONSHIP |
| Since Celontin (CHEMICAL) may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (eg methsuximide may increase the plasma concentrations of CHEMICAL and phenobarbital). | NO-RELATIONSHIP |
| Since Celontin (CHEMICAL) may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (eg methsuximide may increase the plasma concentrations of phenytoin and CHEMICAL). | NO-RELATIONSHIP |
| Since Celontin (methsuximide) may interact with concurrently administered CHEMICAL, periodic serum level determinations of these drugs may be necessary (eg CHEMICAL may increase the plasma concentrations of phenytoin and phenobarbital). | NO-RELATIONSHIP |
| Since Celontin (methsuximide) may interact with concurrently administered CHEMICAL, periodic serum level determinations of these drugs may be necessary (eg methsuximide may increase the plasma concentrations of CHEMICAL and phenobarbital). | NO-RELATIONSHIP |
| Since Celontin (methsuximide) may interact with concurrently administered CHEMICAL, periodic serum level determinations of these drugs may be necessary (eg methsuximide may increase the plasma concentrations of phenytoin and CHEMICAL). | NO-RELATIONSHIP |
| Since Celontin (methsuximide) may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (eg CHEMICAL may increase the plasma concentrations of CHEMICAL and phenobarbital). | CHEMICALS-INTERACTION |
| Since Celontin (methsuximide) may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (eg CHEMICAL may increase the plasma concentrations of phenytoin and CHEMICAL). | CHEMICALS-INTERACTION |
| Since Celontin (methsuximide) may interact with concurrently administered antiepileptic drugs, periodic serum level determinations of these drugs may be necessary (eg methsuximide may increase the plasma concentrations of CHEMICAL and CHEMICAL). | NO-RELATIONSHIP |
| When CHEMICAL and CHEMICAL are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, succinylcholine, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. | CHEMICALS-INTERACTION |
| When CHEMICAL and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when CHEMICAL is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, succinylcholine, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and CHEMICAL are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when CHEMICAL is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, succinylcholine, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of CHEMICAL has been large and the administration of CHEMICAL has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, succinylcholine, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. | CHEMICALS-INTERACTION |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of CHEMICAL: since CHEMICAL are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, succinylcholine, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of CHEMICAL: since barbiturates are potentiated by the CHEMICAL, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, succinylcholine, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since CHEMICAL are potentiated by the CHEMICAL, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, succinylcholine, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. | CHEMICALS-INTERACTION |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; CHEMICAL, CHEMICAL, aminophylline, succinylcholine, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; CHEMICAL, theophylline, CHEMICAL, succinylcholine, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; CHEMICAL, theophylline, aminophylline, CHEMICAL, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; CHEMICAL, theophylline, aminophylline, succinylcholine, CHEMICAL, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; CHEMICAL, theophylline, aminophylline, succinylcholine, reserpine, and CHEMICAL should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, CHEMICAL, CHEMICAL, succinylcholine, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, CHEMICAL, aminophylline, CHEMICAL, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, CHEMICAL, aminophylline, succinylcholine, CHEMICAL, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, CHEMICAL, aminophylline, succinylcholine, reserpine, and CHEMICAL should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, CHEMICAL, CHEMICAL, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, CHEMICAL, succinylcholine, CHEMICAL, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, CHEMICAL, succinylcholine, reserpine, and CHEMICAL should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, CHEMICAL, CHEMICAL, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, CHEMICAL, reserpine, and CHEMICAL should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. 2 - 4 The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, succinylcholine, CHEMICAL, and CHEMICAL should be avoided in patients with organophosphate poisoning. | NO-RELATIONSHIP |
| Reduced absorption of CHEMICAL and CHEMICAL have been reported when those agents were administered concomitantly with sulfasalazine. When daily doses of sulfasalazine 2 g and weekly doses of methotrexate 7.5 mg were coadministered to 15 rheumatoid arthritis patients in a drug-drug interaction study, the pharmacokinetic disposition of the drugs was not altered. Daily doses of sulfasalazine 2 g (maximum 3 g) and weekly doses of methotrexate 7.5 mg (maximum 15 mg) were administered alone or in combination to 310 rheumatoid arthritis patients in two controlled 52-week clinical studies. The overall toxicity profile of the combination revealed an increased incidence of gastrointestinal adverse events, especially nausea, when compared to the incidence associated with either drug administered alone. Drug/Laboratory Test Interactions: The presence of sulfasalazine or its metabolites in body fluids has not been reported to interfere with laboratory test procedures. REFERENCES 7.Farr M, et al. Immunodeficiencies associated with sulphasalazine therapy in inflammatory arthritis. British Jnl Rheum 1991;30:413-417. | NO-RELATIONSHIP |
| Reduced absorption of CHEMICAL and digoxin have been reported when those agents were administered concomitantly with CHEMICAL. When daily doses of sulfasalazine 2 g and weekly doses of methotrexate 7.5 mg were coadministered to 15 rheumatoid arthritis patients in a drug-drug interaction study, the pharmacokinetic disposition of the drugs was not altered. Daily doses of sulfasalazine 2 g (maximum 3 g) and weekly doses of methotrexate 7.5 mg (maximum 15 mg) were administered alone or in combination to 310 rheumatoid arthritis patients in two controlled 52-week clinical studies. The overall toxicity profile of the combination revealed an increased incidence of gastrointestinal adverse events, especially nausea, when compared to the incidence associated with either drug administered alone. Drug/Laboratory Test Interactions: The presence of sulfasalazine or its metabolites in body fluids has not been reported to interfere with laboratory test procedures. REFERENCES 7.Farr M, et al. Immunodeficiencies associated with sulphasalazine therapy in inflammatory arthritis. British Jnl Rheum 1991;30:413-417. | CHEMICALS-INTERACTION |
| Reduced absorption of folic acid and CHEMICAL have been reported when those agents were administered concomitantly with CHEMICAL. When daily doses of sulfasalazine 2 g and weekly doses of methotrexate 7.5 mg were coadministered to 15 rheumatoid arthritis patients in a drug-drug interaction study, the pharmacokinetic disposition of the drugs was not altered. Daily doses of sulfasalazine 2 g (maximum 3 g) and weekly doses of methotrexate 7.5 mg (maximum 15 mg) were administered alone or in combination to 310 rheumatoid arthritis patients in two controlled 52-week clinical studies. The overall toxicity profile of the combination revealed an increased incidence of gastrointestinal adverse events, especially nausea, when compared to the incidence associated with either drug administered alone. Drug/Laboratory Test Interactions: The presence of sulfasalazine or its metabolites in body fluids has not been reported to interfere with laboratory test procedures. REFERENCES 7.Farr M, et al. Immunodeficiencies associated with sulphasalazine therapy in inflammatory arthritis. British Jnl Rheum 1991;30:413-417. | NO-RELATIONSHIP |
| Reduced absorption of folic acid and digoxin have been reported when those agents were administered concomitantly with sulfasalazine. When daily doses of CHEMICAL 2 g and weekly doses of CHEMICAL 7.5 mg were coadministered to 15 rheumatoid arthritis patients in a drug-drug interaction study, the pharmacokinetic disposition of the drugs was not altered. Daily doses of sulfasalazine 2 g (maximum 3 g) and weekly doses of methotrexate 7.5 mg (maximum 15 mg) were administered alone or in combination to 310 rheumatoid arthritis patients in two controlled 52-week clinical studies. The overall toxicity profile of the combination revealed an increased incidence of gastrointestinal adverse events, especially nausea, when compared to the incidence associated with either drug administered alone. Drug/Laboratory Test Interactions: The presence of sulfasalazine or its metabolites in body fluids has not been reported to interfere with laboratory test procedures. REFERENCES 7.Farr M, et al. Immunodeficiencies associated with sulphasalazine therapy in inflammatory arthritis. British Jnl Rheum 1991;30:413-417. | NO-RELATIONSHIP |
| Reduced absorption of folic acid and digoxin have been reported when those agents were administered concomitantly with sulfasalazine. When daily doses of sulfasalazine 2 g and weekly doses of methotrexate 7.5 mg were coadministered to 15 rheumatoid arthritis patients in a drug-drug interaction study, the pharmacokinetic disposition of the drugs was not altered. Daily doses of CHEMICAL 2 g (maximum 3 g) and weekly doses of CHEMICAL 7.5 mg (maximum 15 mg) were administered alone or in combination to 310 rheumatoid arthritis patients in two controlled 52-week clinical studies. The overall toxicity profile of the combination revealed an increased incidence of gastrointestinal adverse events, especially nausea, when compared to the incidence associated with either drug administered alone. Drug/Laboratory Test Interactions: The presence of sulfasalazine or its metabolites in body fluids has not been reported to interfere with laboratory test procedures. REFERENCES 7.Farr M, et al. Immunodeficiencies associated with sulphasalazine therapy in inflammatory arthritis. British Jnl Rheum 1991;30:413-417. | NO-RELATIONSHIP |
| CHEMICAL CHEMICAL may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| CHEMICAL Anabolic steroids may increase sensitivity to oral CHEMICAL. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| Anticoagulants CHEMICAL may increase sensitivity to oral CHEMICAL. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | CHEMICALS-INTERACTION |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. CHEMICAL: A multidose study of CHEMICAL, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. CHEMICAL: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with CHEMICAL, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. CHEMICAL: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in CHEMICAL half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. CHEMICAL: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in CHEMICAL half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of CHEMICAL, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with CHEMICAL, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | CHEMICALS-INTERACTION |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of CHEMICAL, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in CHEMICAL half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of CHEMICAL, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in CHEMICAL half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with CHEMICAL, resulted in a mean increase in CHEMICAL half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with CHEMICAL, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in CHEMICAL half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in CHEMICAL half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in CHEMICAL half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean CHEMICAL dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of CHEMICAL dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When CHEMICAL therapy is initiated in a patient already receiving treatment with CHEMICAL, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | CHEMICALS-INTERACTION |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When CHEMICAL therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of CHEMICAL adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with CHEMICAL, the INR or prothrombin time (PT) should be monitored closely and the dose of CHEMICAL adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the CHEMICAL dosage if indicated are recommended when the CHEMICAL dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | CHEMICALS-INTERACTION |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral CHEMICAL CHEMICAL may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral CHEMICAL Oxandrolone may inhibit the metabolism of oral CHEMICAL. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents CHEMICAL may inhibit the metabolism of oral CHEMICAL. Adrenal steroids or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | CHEMICALS-INTERACTION |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. CHEMICAL or CHEMICAL In patients with edema, concomitant administration with adrenal cortical steroids or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. CHEMICAL or ACTH In patients with edema, concomitant administration with CHEMICAL or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | CHEMICALS-INTERACTION |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. CHEMICAL or ACTH In patients with edema, concomitant administration with adrenal cortical steroids or CHEMICAL may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | CHEMICALS-INTERACTION |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or CHEMICAL In patients with edema, concomitant administration with CHEMICAL or ACTH may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | CHEMICALS-INTERACTION |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or CHEMICAL In patients with edema, concomitant administration with adrenal cortical steroids or CHEMICAL may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | CHEMICALS-INTERACTION |
| Anticoagulants Anabolic steroids may increase sensitivity to oral anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain desired prothrombin time. Patients receiving oral anticoagulant therapy require close monitoring, especially when anabolic steroids are started or stopped. Warfarin: A multidose study of oxandrolone, given as 5 or 10 mg BID in 15 healthy subjects concurrently treated with warfarin, resulted in a mean increase in S-warfarin half-life from 26 to 48 hours and AUC from 4.55 to 12.08 ng*hr/mL: similar increases in R-warfarin half-life and AUC were also detected. Microscopic hematuria (9/15) and gingival bleeding (1/15) were also observed. A 5.5-fold decrease in the mean warfarin dose from 6.13 mg/day to 1.13 mg/day (approximately 80-85% reduction of warfarin dose), was necessary to maintain a target INR of 1.5. When oxandrolone therapy is initiated in a patient already receiving treatment with warfarin, the INR or prothrombin time (PT) should be monitored closely and the dose of warfarin adjusted as necessary until a stable target INR or PT has been achieved. Furthermore, in patients receiving both drugs, careful monitoring of the INR or PT, and adjustment of the warfarin dosage if indicated are recommended when the oxandrolone dose is changed or discontinued. Patients should be closely monitored for signs and symptoms of occult bleeding. Oral hypoglycemic agents Oxandrolone may inhibit the metabolism of oral hypoglycemic agents. Adrenal steroids or ACTH In patients with edema, concomitant administration with CHEMICAL or CHEMICAL may increase the edema. Drug/Laboratory test interactions Anabolic steroids may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged. In addition, a decrease in PBI and radioactive iodine uptake may occur. | NO-RELATIONSHIP |
| Interaction study of CHEMICAL and CHEMICAL with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. CHEMICAL and CHEMICAL are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. CHEMICAL and lomefloxacin are CHEMICAL used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and CHEMICAL are CHEMICAL used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being CHEMICAL and lomefloxacin CHEMICAL the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being CHEMICAL and lomefloxacin fluoroquinolones the interaction study of was carried out with CHEMICAL, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being CHEMICAL and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, CHEMICAL, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being CHEMICAL and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, CHEMICAL and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being CHEMICAL and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and CHEMICAL. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin CHEMICAL the interaction study of was carried out with CHEMICAL, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin CHEMICAL the interaction study of was carried out with sucralfate, CHEMICAL, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin CHEMICAL the interaction study of was carried out with sucralfate, gelusil, CHEMICAL and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin CHEMICAL the interaction study of was carried out with sucralfate, gelusil, erythromycin and CHEMICAL. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with CHEMICAL, CHEMICAL, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with CHEMICAL, gelusil, CHEMICAL and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with CHEMICAL, gelusil, erythromycin and CHEMICAL. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, CHEMICAL, CHEMICAL and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, CHEMICAL, erythromycin and CHEMICAL. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, CHEMICAL and CHEMICAL. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of CHEMICAL and CHEMICAL after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. CHEMICAL and CHEMICAL reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. CHEMICAL and Lomefloxacin reacts faster with CHEMICAL and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | CHEMICALS-INTERACTION |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. CHEMICAL and Lomefloxacin reacts faster with sucralfate and CHEMICAL in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | CHEMICALS-INTERACTION |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. CHEMICAL and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with CHEMICAL in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. CHEMICAL and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and CHEMICAL in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and CHEMICAL reacts faster with CHEMICAL and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | CHEMICALS-INTERACTION |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and CHEMICAL reacts faster with sucralfate and CHEMICAL in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | CHEMICALS-INTERACTION |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and CHEMICAL reacts faster with sucralfate and gelusil in acidic media whereas with CHEMICAL in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | CHEMICALS-INTERACTION |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and CHEMICAL reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and CHEMICAL in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with CHEMICAL and CHEMICAL in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with CHEMICAL and gelusil in acidic media whereas with CHEMICAL in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with CHEMICAL and gelusil in acidic media whereas with erythromycin in basic media and CHEMICAL in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and CHEMICAL in acidic media whereas with CHEMICAL in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and CHEMICAL in acidic media whereas with erythromycin in basic media and CHEMICAL in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| Interaction study of moxifloxacin and lomefloxacin with co-administered drugs. Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37 C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37 C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with CHEMICAL in basic media and CHEMICAL in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential. | NO-RELATIONSHIP |
| CHEMICAL may reverse the analgesic activity of CHEMICAL. Concurrent use with vasoconstrictor agents including ergot alkaloids, sumatriptan, and nicotine (e.g. smoking) may result in enhanced vasoconstriction. | CHEMICALS-INTERACTION |
| Methysergide may reverse the analgesic activity of narcotic analgesics. Concurrent use with CHEMICAL including CHEMICAL, sumatriptan, and nicotine (e.g. smoking) may result in enhanced vasoconstriction. | NO-RELATIONSHIP |
| Methysergide may reverse the analgesic activity of narcotic analgesics. Concurrent use with CHEMICAL including ergot alkaloids, CHEMICAL, and nicotine (e.g. smoking) may result in enhanced vasoconstriction. | NO-RELATIONSHIP |
| Methysergide may reverse the analgesic activity of narcotic analgesics. Concurrent use with CHEMICAL including ergot alkaloids, sumatriptan, and CHEMICAL (e.g. smoking) may result in enhanced vasoconstriction. | NO-RELATIONSHIP |
| Methysergide may reverse the analgesic activity of narcotic analgesics. Concurrent use with vasoconstrictor agents including CHEMICAL, CHEMICAL, and nicotine (e.g. smoking) may result in enhanced vasoconstriction. | NO-RELATIONSHIP |
| Methysergide may reverse the analgesic activity of narcotic analgesics. Concurrent use with vasoconstrictor agents including CHEMICAL, sumatriptan, and CHEMICAL (e.g. smoking) may result in enhanced vasoconstriction. | NO-RELATIONSHIP |
| Methysergide may reverse the analgesic activity of narcotic analgesics. Concurrent use with vasoconstrictor agents including ergot alkaloids, CHEMICAL, and CHEMICAL (e.g. smoking) may result in enhanced vasoconstriction. | NO-RELATIONSHIP |
| CHEMICAL competitively inhibits the intracellular phosphorylation of CHEMICAL. Therefore, use of zidovudine in combination with ZERIT should be avoided. In vitro data indicate that the phosphorylation of stavudine is also inhibited at relevant concentrations by doxorubicin and ribavirin. The clinical significance of these in vitro interactions is unknown; therefore, concomitant use of stavudine with either of these drugs should be undertaken with caution. | CHEMICALS-INTERACTION |
| Zidovudine competitively inhibits the intracellular phosphorylation of stavudine. Therefore, use of CHEMICAL in combination with CHEMICAL should be avoided. In vitro data indicate that the phosphorylation of stavudine is also inhibited at relevant concentrations by doxorubicin and ribavirin. The clinical significance of these in vitro interactions is unknown; therefore, concomitant use of stavudine with either of these drugs should be undertaken with caution. | CHEMICALS-INTERACTION |
| Zidovudine competitively inhibits the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with ZERIT should be avoided. In vitro data indicate that the phosphorylation of CHEMICAL is also inhibited at relevant concentrations by CHEMICAL and ribavirin. The clinical significance of these in vitro interactions is unknown; therefore, concomitant use of stavudine with either of these drugs should be undertaken with caution. | CHEMICALS-INTERACTION |
| Zidovudine competitively inhibits the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with ZERIT should be avoided. In vitro data indicate that the phosphorylation of CHEMICAL is also inhibited at relevant concentrations by doxorubicin and CHEMICAL. The clinical significance of these in vitro interactions is unknown; therefore, concomitant use of stavudine with either of these drugs should be undertaken with caution. | CHEMICALS-INTERACTION |
| Zidovudine competitively inhibits the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with ZERIT should be avoided. In vitro data indicate that the phosphorylation of stavudine is also inhibited at relevant concentrations by CHEMICAL and CHEMICAL. The clinical significance of these in vitro interactions is unknown; therefore, concomitant use of stavudine with either of these drugs should be undertaken with caution. | NO-RELATIONSHIP |
| When administered concurrently, CHEMICAL may increase the effects of oral CHEMICAL; monitor and adjust anticoagulant dosage accordingly. Drug/Laboratory Test Interactions: Physiologic effects of testolactone may result in decreased estradiol concentrations with radioimmunoassays for estradiol, increased plasma calcium concentrations, and increased 24-hour urinary excretion of creatine and 17-ketosteroids. | CHEMICALS-INTERACTION |
| Tamoxifen and CYP 2D6 inhibitors: caution. CHEMICAL, an CHEMICAL, is the standard hormone treatment for breast cancer. It is extensively transformed into its active metabolites by the cytochrome P450 enzyme system, especially into endoxifen by isoenzyme CYP 2D6. Co-administration of tamoxifen with isoenzyme CYP 2D6 inhibitors reduces this metabolism. Selective serotonin reuptake inhibitor (SSRI) antidepressants inhibit isoenzyme CYP 2D6. Paroxetine and fluoxetine reduce the plasma concentration of endoxifen by about 50%. Two epidemiological studies involving about 3700 women have shown a link between the use of SSRI antidepressants and an increased frequency of breast cancer recurrence. Other studies, with a lower level of evidence, were less convincing. Studies of other isoenzyme CYP 2D6 inhibitors showed no increase in the risk of breast cancer recurrence, but they lacked statistical power. It is better to avoid prescribing isoenzyme CYP 2D6 inhibitors to women treated with tamoxifen for breast cancer, especially SSRI antidepressants such as paroxetine and fluoxetine. Depression does not always require antidepressant drug therapy, and antidepressants have no proven preventive impact on hot flushes linked to the menopause. If in certain cases, an antidepressant is considered necessary, it may be advisable to replace tamoxifen with anastrozole. | NO-RELATIONSHIP |
| Tamoxifen and CYP 2D6 inhibitors: caution. Tamoxifen, an estrogen antagonist, is the standard hormone treatment for breast cancer. It is extensively transformed into its active metabolites by the cytochrome P450 enzyme system, especially into endoxifen by isoenzyme CYP 2D6. Co-administration of tamoxifen with isoenzyme CYP 2D6 inhibitors reduces this metabolism. Selective serotonin reuptake inhibitor (SSRI) antidepressants inhibit isoenzyme CYP 2D6. CHEMICAL and CHEMICAL reduce the plasma concentration of endoxifen by about 50%. Two epidemiological studies involving about 3700 women have shown a link between the use of SSRI antidepressants and an increased frequency of breast cancer recurrence. Other studies, with a lower level of evidence, were less convincing. Studies of other isoenzyme CYP 2D6 inhibitors showed no increase in the risk of breast cancer recurrence, but they lacked statistical power. It is better to avoid prescribing isoenzyme CYP 2D6 inhibitors to women treated with tamoxifen for breast cancer, especially SSRI antidepressants such as paroxetine and fluoxetine. Depression does not always require antidepressant drug therapy, and antidepressants have no proven preventive impact on hot flushes linked to the menopause. If in certain cases, an antidepressant is considered necessary, it may be advisable to replace tamoxifen with anastrozole. | NO-RELATIONSHIP |
| Tamoxifen and CYP 2D6 inhibitors: caution. Tamoxifen, an estrogen antagonist, is the standard hormone treatment for breast cancer. It is extensively transformed into its active metabolites by the cytochrome P450 enzyme system, especially into endoxifen by isoenzyme CYP 2D6. Co-administration of tamoxifen with isoenzyme CYP 2D6 inhibitors reduces this metabolism. Selective serotonin reuptake inhibitor (SSRI) antidepressants inhibit isoenzyme CYP 2D6. CHEMICAL and fluoxetine reduce the plasma concentration of CHEMICAL by about 50%. Two epidemiological studies involving about 3700 women have shown a link between the use of SSRI antidepressants and an increased frequency of breast cancer recurrence. Other studies, with a lower level of evidence, were less convincing. Studies of other isoenzyme CYP 2D6 inhibitors showed no increase in the risk of breast cancer recurrence, but they lacked statistical power. It is better to avoid prescribing isoenzyme CYP 2D6 inhibitors to women treated with tamoxifen for breast cancer, especially SSRI antidepressants such as paroxetine and fluoxetine. Depression does not always require antidepressant drug therapy, and antidepressants have no proven preventive impact on hot flushes linked to the menopause. If in certain cases, an antidepressant is considered necessary, it may be advisable to replace tamoxifen with anastrozole. | CHEMICALS-INTERACTION |
| Tamoxifen and CYP 2D6 inhibitors: caution. Tamoxifen, an estrogen antagonist, is the standard hormone treatment for breast cancer. It is extensively transformed into its active metabolites by the cytochrome P450 enzyme system, especially into endoxifen by isoenzyme CYP 2D6. Co-administration of tamoxifen with isoenzyme CYP 2D6 inhibitors reduces this metabolism. Selective serotonin reuptake inhibitor (SSRI) antidepressants inhibit isoenzyme CYP 2D6. Paroxetine and CHEMICAL reduce the plasma concentration of CHEMICAL by about 50%. Two epidemiological studies involving about 3700 women have shown a link between the use of SSRI antidepressants and an increased frequency of breast cancer recurrence. Other studies, with a lower level of evidence, were less convincing. Studies of other isoenzyme CYP 2D6 inhibitors showed no increase in the risk of breast cancer recurrence, but they lacked statistical power. It is better to avoid prescribing isoenzyme CYP 2D6 inhibitors to women treated with tamoxifen for breast cancer, especially SSRI antidepressants such as paroxetine and fluoxetine. Depression does not always require antidepressant drug therapy, and antidepressants have no proven preventive impact on hot flushes linked to the menopause. If in certain cases, an antidepressant is considered necessary, it may be advisable to replace tamoxifen with anastrozole. | CHEMICALS-INTERACTION |
| Tamoxifen and CYP 2D6 inhibitors: caution. Tamoxifen, an estrogen antagonist, is the standard hormone treatment for breast cancer. It is extensively transformed into its active metabolites by the cytochrome P450 enzyme system, especially into endoxifen by isoenzyme CYP 2D6. Co-administration of tamoxifen with isoenzyme CYP 2D6 inhibitors reduces this metabolism. Selective serotonin reuptake inhibitor (SSRI) antidepressants inhibit isoenzyme CYP 2D6. Paroxetine and fluoxetine reduce the plasma concentration of endoxifen by about 50%. Two epidemiological studies involving about 3700 women have shown a link between the use of SSRI antidepressants and an increased frequency of breast cancer recurrence. Other studies, with a lower level of evidence, were less convincing. Studies of other isoenzyme CYP 2D6 inhibitors showed no increase in the risk of breast cancer recurrence, but they lacked statistical power. It is better to avoid prescribing isoenzyme CYP 2D6 inhibitors to women treated with CHEMICAL for breast cancer, especially CHEMICAL such as paroxetine and fluoxetine. Depression does not always require antidepressant drug therapy, and antidepressants have no proven preventive impact on hot flushes linked to the menopause. If in certain cases, an antidepressant is considered necessary, it may be advisable to replace tamoxifen with anastrozole. | NO-RELATIONSHIP |
| Tamoxifen and CYP 2D6 inhibitors: caution. Tamoxifen, an estrogen antagonist, is the standard hormone treatment for breast cancer. It is extensively transformed into its active metabolites by the cytochrome P450 enzyme system, especially into endoxifen by isoenzyme CYP 2D6. Co-administration of tamoxifen with isoenzyme CYP 2D6 inhibitors reduces this metabolism. Selective serotonin reuptake inhibitor (SSRI) antidepressants inhibit isoenzyme CYP 2D6. Paroxetine and fluoxetine reduce the plasma concentration of endoxifen by about 50%. Two epidemiological studies involving about 3700 women have shown a link between the use of SSRI antidepressants and an increased frequency of breast cancer recurrence. Other studies, with a lower level of evidence, were less convincing. Studies of other isoenzyme CYP 2D6 inhibitors showed no increase in the risk of breast cancer recurrence, but they lacked statistical power. It is better to avoid prescribing isoenzyme CYP 2D6 inhibitors to women treated with CHEMICAL for breast cancer, especially SSRI antidepressants such as CHEMICAL and fluoxetine. Depression does not always require antidepressant drug therapy, and antidepressants have no proven preventive impact on hot flushes linked to the menopause. If in certain cases, an antidepressant is considered necessary, it may be advisable to replace tamoxifen with anastrozole. | CHEMICALS-INTERACTION |
| Tamoxifen and CYP 2D6 inhibitors: caution. Tamoxifen, an estrogen antagonist, is the standard hormone treatment for breast cancer. It is extensively transformed into its active metabolites by the cytochrome P450 enzyme system, especially into endoxifen by isoenzyme CYP 2D6. Co-administration of tamoxifen with isoenzyme CYP 2D6 inhibitors reduces this metabolism. Selective serotonin reuptake inhibitor (SSRI) antidepressants inhibit isoenzyme CYP 2D6. Paroxetine and fluoxetine reduce the plasma concentration of endoxifen by about 50%. Two epidemiological studies involving about 3700 women have shown a link between the use of SSRI antidepressants and an increased frequency of breast cancer recurrence. Other studies, with a lower level of evidence, were less convincing. Studies of other isoenzyme CYP 2D6 inhibitors showed no increase in the risk of breast cancer recurrence, but they lacked statistical power. It is better to avoid prescribing isoenzyme CYP 2D6 inhibitors to women treated with CHEMICAL for breast cancer, especially SSRI antidepressants such as paroxetine and CHEMICAL. Depression does not always require antidepressant drug therapy, and antidepressants have no proven preventive impact on hot flushes linked to the menopause. If in certain cases, an antidepressant is considered necessary, it may be advisable to replace tamoxifen with anastrozole. | CHEMICALS-INTERACTION |
| Tamoxifen and CYP 2D6 inhibitors: caution. Tamoxifen, an estrogen antagonist, is the standard hormone treatment for breast cancer. It is extensively transformed into its active metabolites by the cytochrome P450 enzyme system, especially into endoxifen by isoenzyme CYP 2D6. Co-administration of tamoxifen with isoenzyme CYP 2D6 inhibitors reduces this metabolism. Selective serotonin reuptake inhibitor (SSRI) antidepressants inhibit isoenzyme CYP 2D6. Paroxetine and fluoxetine reduce the plasma concentration of endoxifen by about 50%. Two epidemiological studies involving about 3700 women have shown a link between the use of SSRI antidepressants and an increased frequency of breast cancer recurrence. Other studies, with a lower level of evidence, were less convincing. Studies of other isoenzyme CYP 2D6 inhibitors showed no increase in the risk of breast cancer recurrence, but they lacked statistical power. It is better to avoid prescribing isoenzyme CYP 2D6 inhibitors to women treated with tamoxifen for breast cancer, especially CHEMICAL such as CHEMICAL and fluoxetine. Depression does not always require antidepressant drug therapy, and antidepressants have no proven preventive impact on hot flushes linked to the menopause. If in certain cases, an antidepressant is considered necessary, it may be advisable to replace tamoxifen with anastrozole. | NO-RELATIONSHIP |
| Tamoxifen and CYP 2D6 inhibitors: caution. Tamoxifen, an estrogen antagonist, is the standard hormone treatment for breast cancer. It is extensively transformed into its active metabolites by the cytochrome P450 enzyme system, especially into endoxifen by isoenzyme CYP 2D6. Co-administration of tamoxifen with isoenzyme CYP 2D6 inhibitors reduces this metabolism. Selective serotonin reuptake inhibitor (SSRI) antidepressants inhibit isoenzyme CYP 2D6. Paroxetine and fluoxetine reduce the plasma concentration of endoxifen by about 50%. Two epidemiological studies involving about 3700 women have shown a link between the use of SSRI antidepressants and an increased frequency of breast cancer recurrence. Other studies, with a lower level of evidence, were less convincing. Studies of other isoenzyme CYP 2D6 inhibitors showed no increase in the risk of breast cancer recurrence, but they lacked statistical power. It is better to avoid prescribing isoenzyme CYP 2D6 inhibitors to women treated with tamoxifen for breast cancer, especially CHEMICAL such as paroxetine and CHEMICAL. Depression does not always require antidepressant drug therapy, and antidepressants have no proven preventive impact on hot flushes linked to the menopause. If in certain cases, an antidepressant is considered necessary, it may be advisable to replace tamoxifen with anastrozole. | NO-RELATIONSHIP |
| Tamoxifen and CYP 2D6 inhibitors: caution. Tamoxifen, an estrogen antagonist, is the standard hormone treatment for breast cancer. It is extensively transformed into its active metabolites by the cytochrome P450 enzyme system, especially into endoxifen by isoenzyme CYP 2D6. Co-administration of tamoxifen with isoenzyme CYP 2D6 inhibitors reduces this metabolism. Selective serotonin reuptake inhibitor (SSRI) antidepressants inhibit isoenzyme CYP 2D6. Paroxetine and fluoxetine reduce the plasma concentration of endoxifen by about 50%. Two epidemiological studies involving about 3700 women have shown a link between the use of SSRI antidepressants and an increased frequency of breast cancer recurrence. Other studies, with a lower level of evidence, were less convincing. Studies of other isoenzyme CYP 2D6 inhibitors showed no increase in the risk of breast cancer recurrence, but they lacked statistical power. It is better to avoid prescribing isoenzyme CYP 2D6 inhibitors to women treated with tamoxifen for breast cancer, especially SSRI antidepressants such as CHEMICAL and CHEMICAL. Depression does not always require antidepressant drug therapy, and antidepressants have no proven preventive impact on hot flushes linked to the menopause. If in certain cases, an antidepressant is considered necessary, it may be advisable to replace tamoxifen with anastrozole. | NO-RELATIONSHIP |
| Tamoxifen and CYP 2D6 inhibitors: caution. Tamoxifen, an estrogen antagonist, is the standard hormone treatment for breast cancer. It is extensively transformed into its active metabolites by the cytochrome P450 enzyme system, especially into endoxifen by isoenzyme CYP 2D6. Co-administration of tamoxifen with isoenzyme CYP 2D6 inhibitors reduces this metabolism. Selective serotonin reuptake inhibitor (SSRI) antidepressants inhibit isoenzyme CYP 2D6. Paroxetine and fluoxetine reduce the plasma concentration of endoxifen by about 50%. Two epidemiological studies involving about 3700 women have shown a link between the use of SSRI antidepressants and an increased frequency of breast cancer recurrence. Other studies, with a lower level of evidence, were less convincing. Studies of other isoenzyme CYP 2D6 inhibitors showed no increase in the risk of breast cancer recurrence, but they lacked statistical power. It is better to avoid prescribing isoenzyme CYP 2D6 inhibitors to women treated with tamoxifen for breast cancer, especially SSRI antidepressants such as paroxetine and fluoxetine. Depression does not always require CHEMICAL therapy, and CHEMICAL have no proven preventive impact on hot flushes linked to the menopause. If in certain cases, an antidepressant is considered necessary, it may be advisable to replace tamoxifen with anastrozole. | NO-RELATIONSHIP |
| Tamoxifen and CYP 2D6 inhibitors: caution. Tamoxifen, an estrogen antagonist, is the standard hormone treatment for breast cancer. It is extensively transformed into its active metabolites by the cytochrome P450 enzyme system, especially into endoxifen by isoenzyme CYP 2D6. Co-administration of tamoxifen with isoenzyme CYP 2D6 inhibitors reduces this metabolism. Selective serotonin reuptake inhibitor (SSRI) antidepressants inhibit isoenzyme CYP 2D6. Paroxetine and fluoxetine reduce the plasma concentration of endoxifen by about 50%. Two epidemiological studies involving about 3700 women have shown a link between the use of SSRI antidepressants and an increased frequency of breast cancer recurrence. Other studies, with a lower level of evidence, were less convincing. Studies of other isoenzyme CYP 2D6 inhibitors showed no increase in the risk of breast cancer recurrence, but they lacked statistical power. It is better to avoid prescribing isoenzyme CYP 2D6 inhibitors to women treated with tamoxifen for breast cancer, especially SSRI antidepressants such as paroxetine and fluoxetine. Depression does not always require antidepressant drug therapy, and antidepressants have no proven preventive impact on hot flushes linked to the menopause. If in certain cases, an CHEMICAL is considered necessary, it may be advisable to replace CHEMICAL with anastrozole. | NO-RELATIONSHIP |
| Tamoxifen and CYP 2D6 inhibitors: caution. Tamoxifen, an estrogen antagonist, is the standard hormone treatment for breast cancer. It is extensively transformed into its active metabolites by the cytochrome P450 enzyme system, especially into endoxifen by isoenzyme CYP 2D6. Co-administration of tamoxifen with isoenzyme CYP 2D6 inhibitors reduces this metabolism. Selective serotonin reuptake inhibitor (SSRI) antidepressants inhibit isoenzyme CYP 2D6. Paroxetine and fluoxetine reduce the plasma concentration of endoxifen by about 50%. Two epidemiological studies involving about 3700 women have shown a link between the use of SSRI antidepressants and an increased frequency of breast cancer recurrence. Other studies, with a lower level of evidence, were less convincing. Studies of other isoenzyme CYP 2D6 inhibitors showed no increase in the risk of breast cancer recurrence, but they lacked statistical power. It is better to avoid prescribing isoenzyme CYP 2D6 inhibitors to women treated with tamoxifen for breast cancer, especially SSRI antidepressants such as paroxetine and fluoxetine. Depression does not always require antidepressant drug therapy, and antidepressants have no proven preventive impact on hot flushes linked to the menopause. If in certain cases, an CHEMICAL is considered necessary, it may be advisable to replace tamoxifen with CHEMICAL. | NO-RELATIONSHIP |
| Tamoxifen and CYP 2D6 inhibitors: caution. Tamoxifen, an estrogen antagonist, is the standard hormone treatment for breast cancer. It is extensively transformed into its active metabolites by the cytochrome P450 enzyme system, especially into endoxifen by isoenzyme CYP 2D6. Co-administration of tamoxifen with isoenzyme CYP 2D6 inhibitors reduces this metabolism. Selective serotonin reuptake inhibitor (SSRI) antidepressants inhibit isoenzyme CYP 2D6. Paroxetine and fluoxetine reduce the plasma concentration of endoxifen by about 50%. Two epidemiological studies involving about 3700 women have shown a link between the use of SSRI antidepressants and an increased frequency of breast cancer recurrence. Other studies, with a lower level of evidence, were less convincing. Studies of other isoenzyme CYP 2D6 inhibitors showed no increase in the risk of breast cancer recurrence, but they lacked statistical power. It is better to avoid prescribing isoenzyme CYP 2D6 inhibitors to women treated with tamoxifen for breast cancer, especially SSRI antidepressants such as paroxetine and fluoxetine. Depression does not always require antidepressant drug therapy, and antidepressants have no proven preventive impact on hot flushes linked to the menopause. If in certain cases, an antidepressant is considered necessary, it may be advisable to replace CHEMICAL with CHEMICAL. | CHEMICALS-INTERACTION |
| [Efficacy of fixed combination CHEMICAL/CHEMICAL in hospitalized patients with hypertensive disease] Efficacy and tolerability of fixed amlodipine/valsartan combination was studied in 86 patients with hypertensive disease hospitalized in departments of general internal medicine or cardiology. All patients had indications for antihypertensive therapy and were randomized either to fixed combination amlodipine/valsartan (n=43) or to therapy which corresponded to the hospital formulary (n=43). Correction of antihypertensive therapy was performed by treating physician at daily rounds. Self-control of blood pressure (BP) was performed by patients with the use of UA767PC apparatus. Results of BP self-control were compared with clinical measurements in order to detect concealed inefficacy of treatment. Results. Rate of achievement of target BP with fixed combination amlodipine/valsartan (93%) was comparable with that on traditional therapy (90%). But the use of fixed combination amlodipine/valsartan compared with traditional therapy was associated with lower clinical and self measured BP, quicker achievement of target BP (5.8+/-2.3 and 9.2+/-1.8 days, respectively, 0.05), lesser number of antihypertensive drugs (2.5+/-0.6 and 3.0+/-0.9 days, respectively), lower rate of concealed inefficacy of treatment (12 and 31%, respectively, 0.05). Conclusions. We have demonstrated appropriateness of inhospital administration of fixed amlodipine/valsartan combination as an approach allowing to achieve target BP in shorter time, with the use of fewer antihypertensive drugs, and diminishing concealed inefficacy of treatment. | NO-RELATIONSHIP |
| [Efficacy of fixed combination amlodipine/valsartan in hospitalized patients with hypertensive disease] Efficacy and tolerability of fixed CHEMICAL/CHEMICAL combination was studied in 86 patients with hypertensive disease hospitalized in departments of general internal medicine or cardiology. All patients had indications for antihypertensive therapy and were randomized either to fixed combination amlodipine/valsartan (n=43) or to therapy which corresponded to the hospital formulary (n=43). Correction of antihypertensive therapy was performed by treating physician at daily rounds. Self-control of blood pressure (BP) was performed by patients with the use of UA767PC apparatus. Results of BP self-control were compared with clinical measurements in order to detect concealed inefficacy of treatment. Results. Rate of achievement of target BP with fixed combination amlodipine/valsartan (93%) was comparable with that on traditional therapy (90%). But the use of fixed combination amlodipine/valsartan compared with traditional therapy was associated with lower clinical and self measured BP, quicker achievement of target BP (5.8+/-2.3 and 9.2+/-1.8 days, respectively, 0.05), lesser number of antihypertensive drugs (2.5+/-0.6 and 3.0+/-0.9 days, respectively), lower rate of concealed inefficacy of treatment (12 and 31%, respectively, 0.05). Conclusions. We have demonstrated appropriateness of inhospital administration of fixed amlodipine/valsartan combination as an approach allowing to achieve target BP in shorter time, with the use of fewer antihypertensive drugs, and diminishing concealed inefficacy of treatment. | REGULATOR |
| [Efficacy of fixed combination amlodipine/valsartan in hospitalized patients with hypertensive disease] Efficacy and tolerability of fixed amlodipine/valsartan combination was studied in 86 patients with hypertensive disease hospitalized in departments of general internal medicine or cardiology. All patients had indications for antihypertensive therapy and were randomized either to fixed combination CHEMICAL/CHEMICAL (n=43) or to therapy which corresponded to the hospital formulary (n=43). Correction of antihypertensive therapy was performed by treating physician at daily rounds. Self-control of blood pressure (BP) was performed by patients with the use of UA767PC apparatus. Results of BP self-control were compared with clinical measurements in order to detect concealed inefficacy of treatment. Results. Rate of achievement of target BP with fixed combination amlodipine/valsartan (93%) was comparable with that on traditional therapy (90%). But the use of fixed combination amlodipine/valsartan compared with traditional therapy was associated with lower clinical and self measured BP, quicker achievement of target BP (5.8+/-2.3 and 9.2+/-1.8 days, respectively, 0.05), lesser number of antihypertensive drugs (2.5+/-0.6 and 3.0+/-0.9 days, respectively), lower rate of concealed inefficacy of treatment (12 and 31%, respectively, 0.05). Conclusions. We have demonstrated appropriateness of inhospital administration of fixed amlodipine/valsartan combination as an approach allowing to achieve target BP in shorter time, with the use of fewer antihypertensive drugs, and diminishing concealed inefficacy of treatment. | NO-RELATIONSHIP |
| [Efficacy of fixed combination amlodipine/valsartan in hospitalized patients with hypertensive disease] Efficacy and tolerability of fixed amlodipine/valsartan combination was studied in 86 patients with hypertensive disease hospitalized in departments of general internal medicine or cardiology. All patients had indications for antihypertensive therapy and were randomized either to fixed combination amlodipine/valsartan (n=43) or to therapy which corresponded to the hospital formulary (n=43). Correction of antihypertensive therapy was performed by treating physician at daily rounds. Self-control of blood pressure (BP) was performed by patients with the use of UA767PC apparatus. Results of BP self-control were compared with clinical measurements in order to detect concealed inefficacy of treatment. Results. Rate of achievement of target BP with fixed combination CHEMICAL/CHEMICAL (93%) was comparable with that on traditional therapy (90%). But the use of fixed combination amlodipine/valsartan compared with traditional therapy was associated with lower clinical and self measured BP, quicker achievement of target BP (5.8+/-2.3 and 9.2+/-1.8 days, respectively, 0.05), lesser number of antihypertensive drugs (2.5+/-0.6 and 3.0+/-0.9 days, respectively), lower rate of concealed inefficacy of treatment (12 and 31%, respectively, 0.05). Conclusions. We have demonstrated appropriateness of inhospital administration of fixed amlodipine/valsartan combination as an approach allowing to achieve target BP in shorter time, with the use of fewer antihypertensive drugs, and diminishing concealed inefficacy of treatment. | NO-RELATIONSHIP |
| [Efficacy of fixed combination amlodipine/valsartan in hospitalized patients with hypertensive disease] Efficacy and tolerability of fixed amlodipine/valsartan combination was studied in 86 patients with hypertensive disease hospitalized in departments of general internal medicine or cardiology. All patients had indications for antihypertensive therapy and were randomized either to fixed combination amlodipine/valsartan (n=43) or to therapy which corresponded to the hospital formulary (n=43). Correction of antihypertensive therapy was performed by treating physician at daily rounds. Self-control of blood pressure (BP) was performed by patients with the use of UA767PC apparatus. Results of BP self-control were compared with clinical measurements in order to detect concealed inefficacy of treatment. Results. Rate of achievement of target BP with fixed combination amlodipine/valsartan (93%) was comparable with that on traditional therapy (90%). But the use of fixed combination CHEMICAL/CHEMICAL compared with traditional therapy was associated with lower clinical and self measured BP, quicker achievement of target BP (5.8+/-2.3 and 9.2+/-1.8 days, respectively, 0.05), lesser number of antihypertensive drugs (2.5+/-0.6 and 3.0+/-0.9 days, respectively), lower rate of concealed inefficacy of treatment (12 and 31%, respectively, 0.05). Conclusions. We have demonstrated appropriateness of inhospital administration of fixed amlodipine/valsartan combination as an approach allowing to achieve target BP in shorter time, with the use of fewer antihypertensive drugs, and diminishing concealed inefficacy of treatment. | NO-RELATIONSHIP |
| [Efficacy of fixed combination amlodipine/valsartan in hospitalized patients with hypertensive disease] Efficacy and tolerability of fixed amlodipine/valsartan combination was studied in 86 patients with hypertensive disease hospitalized in departments of general internal medicine or cardiology. All patients had indications for antihypertensive therapy and were randomized either to fixed combination amlodipine/valsartan (n=43) or to therapy which corresponded to the hospital formulary (n=43). Correction of antihypertensive therapy was performed by treating physician at daily rounds. Self-control of blood pressure (BP) was performed by patients with the use of UA767PC apparatus. Results of BP self-control were compared with clinical measurements in order to detect concealed inefficacy of treatment. Results. Rate of achievement of target BP with fixed combination amlodipine/valsartan (93%) was comparable with that on traditional therapy (90%). But the use of fixed combination CHEMICAL/valsartan compared with traditional therapy was associated with lower clinical and self measured BP, quicker achievement of target BP (5.8+/-2.3 and 9.2+/-1.8 days, respectively, 0.05), lesser number of CHEMICAL (2.5+/-0.6 and 3.0+/-0.9 days, respectively), lower rate of concealed inefficacy of treatment (12 and 31%, respectively, 0.05). Conclusions. We have demonstrated appropriateness of inhospital administration of fixed amlodipine/valsartan combination as an approach allowing to achieve target BP in shorter time, with the use of fewer antihypertensive drugs, and diminishing concealed inefficacy of treatment. | NO-RELATIONSHIP |
| [Efficacy of fixed combination amlodipine/valsartan in hospitalized patients with hypertensive disease] Efficacy and tolerability of fixed amlodipine/valsartan combination was studied in 86 patients with hypertensive disease hospitalized in departments of general internal medicine or cardiology. All patients had indications for antihypertensive therapy and were randomized either to fixed combination amlodipine/valsartan (n=43) or to therapy which corresponded to the hospital formulary (n=43). Correction of antihypertensive therapy was performed by treating physician at daily rounds. Self-control of blood pressure (BP) was performed by patients with the use of UA767PC apparatus. Results of BP self-control were compared with clinical measurements in order to detect concealed inefficacy of treatment. Results. Rate of achievement of target BP with fixed combination amlodipine/valsartan (93%) was comparable with that on traditional therapy (90%). But the use of fixed combination amlodipine/CHEMICAL compared with traditional therapy was associated with lower clinical and self measured BP, quicker achievement of target BP (5.8+/-2.3 and 9.2+/-1.8 days, respectively, 0.05), lesser number of CHEMICAL (2.5+/-0.6 and 3.0+/-0.9 days, respectively), lower rate of concealed inefficacy of treatment (12 and 31%, respectively, 0.05). Conclusions. We have demonstrated appropriateness of inhospital administration of fixed amlodipine/valsartan combination as an approach allowing to achieve target BP in shorter time, with the use of fewer antihypertensive drugs, and diminishing concealed inefficacy of treatment. | NO-RELATIONSHIP |
| [Efficacy of fixed combination amlodipine/valsartan in hospitalized patients with hypertensive disease] Efficacy and tolerability of fixed amlodipine/valsartan combination was studied in 86 patients with hypertensive disease hospitalized in departments of general internal medicine or cardiology. All patients had indications for antihypertensive therapy and were randomized either to fixed combination amlodipine/valsartan (n=43) or to therapy which corresponded to the hospital formulary (n=43). Correction of antihypertensive therapy was performed by treating physician at daily rounds. Self-control of blood pressure (BP) was performed by patients with the use of UA767PC apparatus. Results of BP self-control were compared with clinical measurements in order to detect concealed inefficacy of treatment. Results. Rate of achievement of target BP with fixed combination amlodipine/valsartan (93%) was comparable with that on traditional therapy (90%). But the use of fixed combination amlodipine/valsartan compared with traditional therapy was associated with lower clinical and self measured BP, quicker achievement of target BP (5.8+/-2.3 and 9.2+/-1.8 days, respectively, 0.05), lesser number of antihypertensive drugs (2.5+/-0.6 and 3.0+/-0.9 days, respectively), lower rate of concealed inefficacy of treatment (12 and 31%, respectively, 0.05). Conclusions. We have demonstrated appropriateness of inhospital administration of fixed CHEMICAL/CHEMICAL combination as an approach allowing to achieve target BP in shorter time, with the use of fewer antihypertensive drugs, and diminishing concealed inefficacy of treatment. | NO-RELATIONSHIP |
| [Efficacy of fixed combination amlodipine/valsartan in hospitalized patients with hypertensive disease] Efficacy and tolerability of fixed amlodipine/valsartan combination was studied in 86 patients with hypertensive disease hospitalized in departments of general internal medicine or cardiology. All patients had indications for antihypertensive therapy and were randomized either to fixed combination amlodipine/valsartan (n=43) or to therapy which corresponded to the hospital formulary (n=43). Correction of antihypertensive therapy was performed by treating physician at daily rounds. Self-control of blood pressure (BP) was performed by patients with the use of UA767PC apparatus. Results of BP self-control were compared with clinical measurements in order to detect concealed inefficacy of treatment. Results. Rate of achievement of target BP with fixed combination amlodipine/valsartan (93%) was comparable with that on traditional therapy (90%). But the use of fixed combination amlodipine/valsartan compared with traditional therapy was associated with lower clinical and self measured BP, quicker achievement of target BP (5.8+/-2.3 and 9.2+/-1.8 days, respectively, 0.05), lesser number of antihypertensive drugs (2.5+/-0.6 and 3.0+/-0.9 days, respectively), lower rate of concealed inefficacy of treatment (12 and 31%, respectively, 0.05). Conclusions. We have demonstrated appropriateness of inhospital administration of fixed CHEMICAL/valsartan combination as an approach allowing to achieve target BP in shorter time, with the use of fewer CHEMICAL, and diminishing concealed inefficacy of treatment. | NO-RELATIONSHIP |
| [Efficacy of fixed combination amlodipine/valsartan in hospitalized patients with hypertensive disease] Efficacy and tolerability of fixed amlodipine/valsartan combination was studied in 86 patients with hypertensive disease hospitalized in departments of general internal medicine or cardiology. All patients had indications for antihypertensive therapy and were randomized either to fixed combination amlodipine/valsartan (n=43) or to therapy which corresponded to the hospital formulary (n=43). Correction of antihypertensive therapy was performed by treating physician at daily rounds. Self-control of blood pressure (BP) was performed by patients with the use of UA767PC apparatus. Results of BP self-control were compared with clinical measurements in order to detect concealed inefficacy of treatment. Results. Rate of achievement of target BP with fixed combination amlodipine/valsartan (93%) was comparable with that on traditional therapy (90%). But the use of fixed combination amlodipine/valsartan compared with traditional therapy was associated with lower clinical and self measured BP, quicker achievement of target BP (5.8+/-2.3 and 9.2+/-1.8 days, respectively, 0.05), lesser number of antihypertensive drugs (2.5+/-0.6 and 3.0+/-0.9 days, respectively), lower rate of concealed inefficacy of treatment (12 and 31%, respectively, 0.05). Conclusions. We have demonstrated appropriateness of inhospital administration of fixed amlodipine/CHEMICAL combination as an approach allowing to achieve target BP in shorter time, with the use of fewer CHEMICAL, and diminishing concealed inefficacy of treatment. | NO-RELATIONSHIP |
| CHEMICAL: Concomitant CHEMICAL administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| CHEMICAL: Concomitant cholestyramine administration decreased the mean AUC of total CHEMICAL approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant CHEMICAL administration decreased the mean AUC of total CHEMICAL approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | CHEMICALS-INTERACTION |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding CHEMICAL to CHEMICAL may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | CHEMICALS-INTERACTION |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. CHEMICAL: The safety and effectiveness of CHEMICAL administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. CHEMICAL: The safety and effectiveness of ezetimibe administered with CHEMICAL have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of CHEMICAL administered with CHEMICAL have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of CHEMICAL with CHEMICAL is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | CHEMICALS-INTERACTION |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. CHEMICAL: In a pharmacokinetic study, concomitant CHEMICAL administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. CHEMICAL: In a pharmacokinetic study, concomitant fenofibrate administration increased total CHEMICAL concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant CHEMICAL administration increased total CHEMICAL concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | CHEMICALS-INTERACTION |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. CHEMICAL: In a pharmacokinetic study, concomitant CHEMICAL administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. CHEMICAL: In a pharmacokinetic study, concomitant gemfibrozil administration increased total CHEMICAL concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant CHEMICAL administration increased total CHEMICAL concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | CHEMICALS-INTERACTION |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. CHEMICAL: No clinically significant pharmacokinetic interactions were seen when CHEMICAL was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. CHEMICAL: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with CHEMICAL, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. CHEMICAL: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, CHEMICAL, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. CHEMICAL: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, CHEMICAL, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. CHEMICAL: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, CHEMICAL, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. CHEMICAL: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or CHEMICAL. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when CHEMICAL was co-administered with CHEMICAL, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when CHEMICAL was co-administered with atorvastatin, CHEMICAL, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when CHEMICAL was co-administered with atorvastatin, simvastatin, CHEMICAL, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when CHEMICAL was co-administered with atorvastatin, simvastatin, pravastatin, CHEMICAL, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when CHEMICAL was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or CHEMICAL. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with CHEMICAL, CHEMICAL, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with CHEMICAL, simvastatin, CHEMICAL, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with CHEMICAL, simvastatin, pravastatin, CHEMICAL, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with CHEMICAL, simvastatin, pravastatin, lovastatin, or CHEMICAL. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, CHEMICAL, CHEMICAL, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, CHEMICAL, pravastatin, CHEMICAL, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, CHEMICAL, pravastatin, lovastatin, or CHEMICAL. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, CHEMICAL, CHEMICAL, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, CHEMICAL, lovastatin, or CHEMICAL. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, CHEMICAL, or CHEMICAL. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. CHEMICAL: The total CHEMICAL level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. CHEMICAL: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including CHEMICAL. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total CHEMICAL level increased 12-fold in one renal transplant patient receiving multiple medications, including CHEMICAL. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | CHEMICALS-INTERACTION |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both CHEMICAL and CHEMICAL should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | CHEMICALS-INTERACTION |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with CHEMICAL was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total CHEMICAL). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with CHEMICAL was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total CHEMICAL). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of CHEMICAL conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total CHEMICAL). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with CHEMICAL, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total CHEMICAL). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of CHEMICAL given in combination with CHEMICAL (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of CHEMICAL given in combination with HMG-CoA reductase inhibitors (CHEMICAL) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of CHEMICAL given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher CHEMICAL and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with CHEMICAL (CHEMICAL) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with CHEMICAL (statins) in rats and rabbits during organogenesis result in higher CHEMICAL and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (CHEMICAL) in rats and rabbits during organogenesis result in higher CHEMICAL and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When CHEMICAL is administered with an CHEMICAL in a woman of childbearing potential, refer to the pregnancy category and package labeling for the HMG-CoA reductase inhibitor. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When CHEMICAL is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and package labeling for the CHEMICAL. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Cholestyramine: Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction. Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA with fibrates is not recommended until use in patients is studied. Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold. Gemfibrozil: In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold. HMG-CoA reductase inhibitors: No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin. Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully monitored. Carcinogenesis, Mutagenesis, Impairment of Fertility A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice. No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test. In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Pregnancy Pregnancy Category: C There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple dose studies of ezetimibe given in combination with HMG-CoA reductase inhibitors (statins) in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an CHEMICAL in a woman of childbearing potential, refer to the pregnancy category and package labeling for the CHEMICAL. Labor and Delivery The effects of ZETIA on labor and delivery in pregnant women are unknown. Nursing Mothers In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. Pediatric Use The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. Geriatric Use Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. | NO-RELATIONSHIP |
| Interaction of CHEMICAL and CHEMICAL, in vitro and in vivo, in human A375 melanoma cells. We evaluated mechanisms of interaction between the alkyating agent dacarbazine (DTIC) and the pro-oxidant, imexon, in the human A375 melanoma cell line. The effect of DTIC and imexon, alone and in combination, was evaluated for growth inhibition (MTT), radiolabeled drug uptake, cellular thiol content (HPLC), and DNA strand breaks (Comet assay). Pharmacokinetic and antitumor effects were evaluated in mice. Growth inhibition in vitro was additive with the two drugs. There was no effect on drug uptake or on the number of DNA strand breaks. There was a >75% reduction in cellular glutathione and cysteine with imexon but not DTIC. Co-administration of the two drugs in mice caused an increase in the area under the curve of both drugs, but the combination was not effective in reducing human A375 melanoma tumors in vivo. Imexon and dacarbazine show additive effects in vitro but not in vivo in human A375 melanoma cells. | CHEMICALS-INTERACTION |
| Interaction of dacarbazine and imexon, in vitro and in vivo, in human A375 melanoma cells. We evaluated mechanisms of interaction between the alkyating agent CHEMICAL (CHEMICAL) and the pro-oxidant, imexon, in the human A375 melanoma cell line. The effect of DTIC and imexon, alone and in combination, was evaluated for growth inhibition (MTT), radiolabeled drug uptake, cellular thiol content (HPLC), and DNA strand breaks (Comet assay). Pharmacokinetic and antitumor effects were evaluated in mice. Growth inhibition in vitro was additive with the two drugs. There was no effect on drug uptake or on the number of DNA strand breaks. There was a >75% reduction in cellular glutathione and cysteine with imexon but not DTIC. Co-administration of the two drugs in mice caused an increase in the area under the curve of both drugs, but the combination was not effective in reducing human A375 melanoma tumors in vivo. Imexon and dacarbazine show additive effects in vitro but not in vivo in human A375 melanoma cells. | NO-RELATIONSHIP |
| Interaction of dacarbazine and imexon, in vitro and in vivo, in human A375 melanoma cells. We evaluated mechanisms of interaction between the alkyating agent CHEMICAL (DTIC) and the pro-oxidant, CHEMICAL, in the human A375 melanoma cell line. The effect of DTIC and imexon, alone and in combination, was evaluated for growth inhibition (MTT), radiolabeled drug uptake, cellular thiol content (HPLC), and DNA strand breaks (Comet assay). Pharmacokinetic and antitumor effects were evaluated in mice. Growth inhibition in vitro was additive with the two drugs. There was no effect on drug uptake or on the number of DNA strand breaks. There was a >75% reduction in cellular glutathione and cysteine with imexon but not DTIC. Co-administration of the two drugs in mice caused an increase in the area under the curve of both drugs, but the combination was not effective in reducing human A375 melanoma tumors in vivo. Imexon and dacarbazine show additive effects in vitro but not in vivo in human A375 melanoma cells. | NO-RELATIONSHIP |
| Interaction of dacarbazine and imexon, in vitro and in vivo, in human A375 melanoma cells. We evaluated mechanisms of interaction between the alkyating agent dacarbazine (CHEMICAL) and the pro-oxidant, CHEMICAL, in the human A375 melanoma cell line. The effect of DTIC and imexon, alone and in combination, was evaluated for growth inhibition (MTT), radiolabeled drug uptake, cellular thiol content (HPLC), and DNA strand breaks (Comet assay). Pharmacokinetic and antitumor effects were evaluated in mice. Growth inhibition in vitro was additive with the two drugs. There was no effect on drug uptake or on the number of DNA strand breaks. There was a >75% reduction in cellular glutathione and cysteine with imexon but not DTIC. Co-administration of the two drugs in mice caused an increase in the area under the curve of both drugs, but the combination was not effective in reducing human A375 melanoma tumors in vivo. Imexon and dacarbazine show additive effects in vitro but not in vivo in human A375 melanoma cells. | CHEMICALS-INTERACTION |
| Interaction of dacarbazine and imexon, in vitro and in vivo, in human A375 melanoma cells. We evaluated mechanisms of interaction between the alkyating agent dacarbazine (DTIC) and the pro-oxidant, imexon, in the human A375 melanoma cell line. The effect of CHEMICAL and CHEMICAL, alone and in combination, was evaluated for growth inhibition (MTT), radiolabeled drug uptake, cellular thiol content (HPLC), and DNA strand breaks (Comet assay). Pharmacokinetic and antitumor effects were evaluated in mice. Growth inhibition in vitro was additive with the two drugs. There was no effect on drug uptake or on the number of DNA strand breaks. There was a >75% reduction in cellular glutathione and cysteine with imexon but not DTIC. Co-administration of the two drugs in mice caused an increase in the area under the curve of both drugs, but the combination was not effective in reducing human A375 melanoma tumors in vivo. Imexon and dacarbazine show additive effects in vitro but not in vivo in human A375 melanoma cells. | NO-RELATIONSHIP |
| Interaction of dacarbazine and imexon, in vitro and in vivo, in human A375 melanoma cells. We evaluated mechanisms of interaction between the alkyating agent dacarbazine (DTIC) and the pro-oxidant, imexon, in the human A375 melanoma cell line. The effect of DTIC and imexon, alone and in combination, was evaluated for growth inhibition (MTT), radiolabeled drug uptake, cellular thiol content (HPLC), and DNA strand breaks (Comet assay). Pharmacokinetic and antitumor effects were evaluated in mice. Growth inhibition in vitro was additive with the two drugs. There was no effect on drug uptake or on the number of DNA strand breaks. There was a >75% reduction in cellular glutathione and cysteine with CHEMICAL but not CHEMICAL. Co-administration of the two drugs in mice caused an increase in the area under the curve of both drugs, but the combination was not effective in reducing human A375 melanoma tumors in vivo. Imexon and dacarbazine show additive effects in vitro but not in vivo in human A375 melanoma cells. | NO-RELATIONSHIP |
| Interaction of dacarbazine and imexon, in vitro and in vivo, in human A375 melanoma cells. We evaluated mechanisms of interaction between the alkyating agent dacarbazine (DTIC) and the pro-oxidant, imexon, in the human A375 melanoma cell line. The effect of DTIC and imexon, alone and in combination, was evaluated for growth inhibition (MTT), radiolabeled drug uptake, cellular thiol content (HPLC), and DNA strand breaks (Comet assay). Pharmacokinetic and antitumor effects were evaluated in mice. Growth inhibition in vitro was additive with the two drugs. There was no effect on drug uptake or on the number of DNA strand breaks. There was a >75% reduction in cellular glutathione and cysteine with imexon but not DTIC. Co-administration of the two drugs in mice caused an increase in the area under the curve of both drugs, but the combination was not effective in reducing human A375 melanoma tumors in vivo. CHEMICAL and CHEMICAL show additive effects in vitro but not in vivo in human A375 melanoma cells. | CHEMICALS-INTERACTION |
| [Influence of CHEMICAL and CHEMICAL on MPTP-evoked behavior violations in C57BL/6 mice]. The effects of anti-parkinsonian drug hemantane [(2-adamantyl)hexamethylenimine] (10 mg/kg, p. o.) and/or antibiotic drug doxycycline (100 mg/kg, p. o.), as well as that of neurotoxin 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP) (4 x 20 mg/kg, i. p.) were studied in elevated plus maze test on C57BL/6 mice. On second day after injection, MPTP decreased the locomot or activity in comparison to saline. Acute administration of hemantane or doxycycline failed to influence locomotion in mice, while their combination normalized motor activity. The results obtained confirm the role of inflammatory processes in parkinsonism and suggest expediency of combined pharmacotherapy of neurodegenerative diseases. | NO-RELATIONSHIP |
| [Influence of hemantane and doxycycline on MPTP-evoked behavior violations in C57BL/6 mice]. The effects of CHEMICAL CHEMICAL [(2-adamantyl)hexamethylenimine] (10 mg/kg, p. o.) and/or antibiotic drug doxycycline (100 mg/kg, p. o.), as well as that of neurotoxin 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP) (4 x 20 mg/kg, i. p.) were studied in elevated plus maze test on C57BL/6 mice. On second day after injection, MPTP decreased the locomot or activity in comparison to saline. Acute administration of hemantane or doxycycline failed to influence locomotion in mice, while their combination normalized motor activity. The results obtained confirm the role of inflammatory processes in parkinsonism and suggest expediency of combined pharmacotherapy of neurodegenerative diseases. | NO-RELATIONSHIP |
| [Influence of hemantane and doxycycline on MPTP-evoked behavior violations in C57BL/6 mice]. The effects of CHEMICAL hemantane [CHEMICAL] (10 mg/kg, p. o.) and/or antibiotic drug doxycycline (100 mg/kg, p. o.), as well as that of neurotoxin 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP) (4 x 20 mg/kg, i. p.) were studied in elevated plus maze test on C57BL/6 mice. On second day after injection, MPTP decreased the locomot or activity in comparison to saline. Acute administration of hemantane or doxycycline failed to influence locomotion in mice, while their combination normalized motor activity. The results obtained confirm the role of inflammatory processes in parkinsonism and suggest expediency of combined pharmacotherapy of neurodegenerative diseases. | NO-RELATIONSHIP |
| [Influence of hemantane and doxycycline on MPTP-evoked behavior violations in C57BL/6 mice]. The effects of anti-parkinsonian drug CHEMICAL [CHEMICAL] (10 mg/kg, p. o.) and/or antibiotic drug doxycycline (100 mg/kg, p. o.), as well as that of neurotoxin 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP) (4 x 20 mg/kg, i. p.) were studied in elevated plus maze test on C57BL/6 mice. On second day after injection, MPTP decreased the locomot or activity in comparison to saline. Acute administration of hemantane or doxycycline failed to influence locomotion in mice, while their combination normalized motor activity. The results obtained confirm the role of inflammatory processes in parkinsonism and suggest expediency of combined pharmacotherapy of neurodegenerative diseases. | NO-RELATIONSHIP |
| [Influence of hemantane and doxycycline on MPTP-evoked behavior violations in C57BL/6 mice]. The effects of anti-parkinsonian drug hemantane [(2-adamantyl)hexamethylenimine] (10 mg/kg, p. o.) and/or CHEMICAL CHEMICAL (100 mg/kg, p. o.), as well as that of neurotoxin 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP) (4 x 20 mg/kg, i. p.) were studied in elevated plus maze test on C57BL/6 mice. On second day after injection, MPTP decreased the locomot or activity in comparison to saline. Acute administration of hemantane or doxycycline failed to influence locomotion in mice, while their combination normalized motor activity. The results obtained confirm the role of inflammatory processes in parkinsonism and suggest expediency of combined pharmacotherapy of neurodegenerative diseases. | NO-RELATIONSHIP |
| [Influence of hemantane and doxycycline on MPTP-evoked behavior violations in C57BL/6 mice]. The effects of anti-parkinsonian drug hemantane [(2-adamantyl)hexamethylenimine] (10 mg/kg, p. o.) and/or CHEMICAL doxycycline (100 mg/kg, p. o.), as well as that of neurotoxin CHEMICAL (MPTP) (4 x 20 mg/kg, i. p.) were studied in elevated plus maze test on C57BL/6 mice. On second day after injection, MPTP decreased the locomot or activity in comparison to saline. Acute administration of hemantane or doxycycline failed to influence locomotion in mice, while their combination normalized motor activity. The results obtained confirm the role of inflammatory processes in parkinsonism and suggest expediency of combined pharmacotherapy of neurodegenerative diseases. | NO-RELATIONSHIP |
| [Influence of hemantane and doxycycline on MPTP-evoked behavior violations in C57BL/6 mice]. The effects of anti-parkinsonian drug hemantane [(2-adamantyl)hexamethylenimine] (10 mg/kg, p. o.) and/or CHEMICAL doxycycline (100 mg/kg, p. o.), as well as that of neurotoxin 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (CHEMICAL) (4 x 20 mg/kg, i. p.) were studied in elevated plus maze test on C57BL/6 mice. On second day after injection, MPTP decreased the locomot or activity in comparison to saline. Acute administration of hemantane or doxycycline failed to influence locomotion in mice, while their combination normalized motor activity. The results obtained confirm the role of inflammatory processes in parkinsonism and suggest expediency of combined pharmacotherapy of neurodegenerative diseases. | NO-RELATIONSHIP |
| [Influence of hemantane and doxycycline on MPTP-evoked behavior violations in C57BL/6 mice]. The effects of anti-parkinsonian drug hemantane [(2-adamantyl)hexamethylenimine] (10 mg/kg, p. o.) and/or antibiotic drug CHEMICAL (100 mg/kg, p. o.), as well as that of neurotoxin CHEMICAL (MPTP) (4 x 20 mg/kg, i. p.) were studied in elevated plus maze test on C57BL/6 mice. On second day after injection, MPTP decreased the locomot or activity in comparison to saline. Acute administration of hemantane or doxycycline failed to influence locomotion in mice, while their combination normalized motor activity. The results obtained confirm the role of inflammatory processes in parkinsonism and suggest expediency of combined pharmacotherapy of neurodegenerative diseases. | NO-RELATIONSHIP |
| [Influence of hemantane and doxycycline on MPTP-evoked behavior violations in C57BL/6 mice]. The effects of anti-parkinsonian drug hemantane [(2-adamantyl)hexamethylenimine] (10 mg/kg, p. o.) and/or antibiotic drug CHEMICAL (100 mg/kg, p. o.), as well as that of neurotoxin 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (CHEMICAL) (4 x 20 mg/kg, i. p.) were studied in elevated plus maze test on C57BL/6 mice. On second day after injection, MPTP decreased the locomot or activity in comparison to saline. Acute administration of hemantane or doxycycline failed to influence locomotion in mice, while their combination normalized motor activity. The results obtained confirm the role of inflammatory processes in parkinsonism and suggest expediency of combined pharmacotherapy of neurodegenerative diseases. | NO-RELATIONSHIP |
| [Influence of hemantane and doxycycline on MPTP-evoked behavior violations in C57BL/6 mice]. The effects of anti-parkinsonian drug hemantane [(2-adamantyl)hexamethylenimine] (10 mg/kg, p. o.) and/or antibiotic drug doxycycline (100 mg/kg, p. o.), as well as that of neurotoxin CHEMICAL (CHEMICAL) (4 x 20 mg/kg, i. p.) were studied in elevated plus maze test on C57BL/6 mice. On second day after injection, MPTP decreased the locomot or activity in comparison to saline. Acute administration of hemantane or doxycycline failed to influence locomotion in mice, while their combination normalized motor activity. The results obtained confirm the role of inflammatory processes in parkinsonism and suggest expediency of combined pharmacotherapy of neurodegenerative diseases. | NO-RELATIONSHIP |
| [Influence of hemantane and doxycycline on MPTP-evoked behavior violations in C57BL/6 mice]. The effects of anti-parkinsonian drug hemantane [(2-adamantyl)hexamethylenimine] (10 mg/kg, p. o.) and/or antibiotic drug doxycycline (100 mg/kg, p. o.), as well as that of neurotoxin 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP) (4 x 20 mg/kg, i. p.) were studied in elevated plus maze test on C57BL/6 mice. On second day after injection, MPTP decreased the locomot or activity in comparison to saline. Acute administration of CHEMICAL or CHEMICAL failed to influence locomotion in mice, while their combination normalized motor activity. The results obtained confirm the role of inflammatory processes in parkinsonism and suggest expediency of combined pharmacotherapy of neurodegenerative diseases. | NO-RELATIONSHIP |
| In clinical studies, the concurrent administration of the ASMANEX TWISTHALER inhaler and other drugs commonly used in the treatment of asthma was not associated with any unusual adverse events. However, CHEMICAL, a potent inhibitor of cytochrome P450 3A4, may increase plasma levels of CHEMICAL during concomitant dosing. | CHEMICALS-INTERACTION |
| Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. We present a comprehensive in vitro approach to assessing metabolism-mediated hepatotoxicity using male Sprague-Dawley rat liver slices incubated with the well characterized hepatotoxicant, precocene I, and inhibitors of cytochrome P450 (CYP) enzymes. This approach combines liquid chromatography mass spectrometry (LC MS) detection methods with multiple toxicity endpoints to enable identification of critical metabolic pathways for hepatotoxicity. The incubations were performed in the absence and presence of the non-specific CYP inhibitor, CHEMICAL (CHEMICAL) and isoform-specific inhibitors. The metabolite profile of precocene I in rat liver slices shares some features of the in vivo profile, but also had a major difference in that epoxide dihydrodiol hydrolysis products were not observed to a measurable extent. As examples of our liver slice metabolite identification procedure, a minor glutathione adduct and previously unreported 7-O-desmethyl and glucuronidated metabolites of precocene I are reported. Precocene I induced hepatocellular necrosis in a dose- and time-dependent manner. ABT decreased the toxicity of precocene I, increased exposure to parent compound, and decreased metabolite levels in a dose-dependent manner. Of the isoform-specific CYP inhibitors tested for an effect on the precocene I metabolite profile, only tranylcypromine was noticeably effective, indicating a role of CYPs 2A6, 2C9, 2Cl9, and 2E1. With respect to toxicity, the order of CYP inhibitor effectiveness was ABT>diethyldithiocarbamate~tranylcypromine>ketoconazole. Furafylline and sulfaphenazole had no effect, while quinidine appeared to augment precocene I toxicity. These results suggest that rat liver slices do not reproduce the reported in vivo biotransformation of precocene I and therefore may not be an appropriate model for precocene I metabolism. However, these results provide an example of how small molecule manipulation of CYP activity in an in vitro model can be used to confirm metabolism-mediated toxicity. | NO-RELATIONSHIP |
| Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. We present a comprehensive in vitro approach to assessing metabolism-mediated hepatotoxicity using male Sprague-Dawley rat liver slices incubated with the well characterized hepatotoxicant, precocene I, and inhibitors of cytochrome P450 (CYP) enzymes. This approach combines liquid chromatography mass spectrometry (LC MS) detection methods with multiple toxicity endpoints to enable identification of critical metabolic pathways for hepatotoxicity. The incubations were performed in the absence and presence of the non-specific CYP inhibitor, 1-aminobenzotriazole (ABT) and isoform-specific inhibitors. The metabolite profile of precocene I in rat liver slices shares some features of the in vivo profile, but also had a major difference in that epoxide dihydrodiol hydrolysis products were not observed to a measurable extent. As examples of our liver slice metabolite identification procedure, a minor glutathione adduct and previously unreported 7-O-desmethyl and glucuronidated metabolites of precocene I are reported. Precocene I induced hepatocellular necrosis in a dose- and time-dependent manner. CHEMICAL decreased the toxicity of CHEMICAL, increased exposure to parent compound, and decreased metabolite levels in a dose-dependent manner. Of the isoform-specific CYP inhibitors tested for an effect on the precocene I metabolite profile, only tranylcypromine was noticeably effective, indicating a role of CYPs 2A6, 2C9, 2Cl9, and 2E1. With respect to toxicity, the order of CYP inhibitor effectiveness was ABT>diethyldithiocarbamate~tranylcypromine>ketoconazole. Furafylline and sulfaphenazole had no effect, while quinidine appeared to augment precocene I toxicity. These results suggest that rat liver slices do not reproduce the reported in vivo biotransformation of precocene I and therefore may not be an appropriate model for precocene I metabolism. However, these results provide an example of how small molecule manipulation of CYP activity in an in vitro model can be used to confirm metabolism-mediated toxicity. | CHEMICALS-INTERACTION |
| Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. We present a comprehensive in vitro approach to assessing metabolism-mediated hepatotoxicity using male Sprague-Dawley rat liver slices incubated with the well characterized hepatotoxicant, precocene I, and inhibitors of cytochrome P450 (CYP) enzymes. This approach combines liquid chromatography mass spectrometry (LC MS) detection methods with multiple toxicity endpoints to enable identification of critical metabolic pathways for hepatotoxicity. The incubations were performed in the absence and presence of the non-specific CYP inhibitor, 1-aminobenzotriazole (ABT) and isoform-specific inhibitors. The metabolite profile of precocene I in rat liver slices shares some features of the in vivo profile, but also had a major difference in that epoxide dihydrodiol hydrolysis products were not observed to a measurable extent. As examples of our liver slice metabolite identification procedure, a minor glutathione adduct and previously unreported 7-O-desmethyl and glucuronidated metabolites of precocene I are reported. Precocene I induced hepatocellular necrosis in a dose- and time-dependent manner. ABT decreased the toxicity of precocene I, increased exposure to parent compound, and decreased metabolite levels in a dose-dependent manner. Of the isoform-specific CYP inhibitors tested for an effect on the CHEMICAL metabolite profile, only CHEMICAL was noticeably effective, indicating a role of CYPs 2A6, 2C9, 2Cl9, and 2E1. With respect to toxicity, the order of CYP inhibitor effectiveness was ABT>diethyldithiocarbamate~tranylcypromine>ketoconazole. Furafylline and sulfaphenazole had no effect, while quinidine appeared to augment precocene I toxicity. These results suggest that rat liver slices do not reproduce the reported in vivo biotransformation of precocene I and therefore may not be an appropriate model for precocene I metabolism. However, these results provide an example of how small molecule manipulation of CYP activity in an in vitro model can be used to confirm metabolism-mediated toxicity. | REGULATOR |
| Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. We present a comprehensive in vitro approach to assessing metabolism-mediated hepatotoxicity using male Sprague-Dawley rat liver slices incubated with the well characterized hepatotoxicant, precocene I, and inhibitors of cytochrome P450 (CYP) enzymes. This approach combines liquid chromatography mass spectrometry (LC MS) detection methods with multiple toxicity endpoints to enable identification of critical metabolic pathways for hepatotoxicity. The incubations were performed in the absence and presence of the non-specific CYP inhibitor, 1-aminobenzotriazole (ABT) and isoform-specific inhibitors. The metabolite profile of precocene I in rat liver slices shares some features of the in vivo profile, but also had a major difference in that epoxide dihydrodiol hydrolysis products were not observed to a measurable extent. As examples of our liver slice metabolite identification procedure, a minor glutathione adduct and previously unreported 7-O-desmethyl and glucuronidated metabolites of precocene I are reported. Precocene I induced hepatocellular necrosis in a dose- and time-dependent manner. ABT decreased the toxicity of precocene I, increased exposure to parent compound, and decreased metabolite levels in a dose-dependent manner. Of the isoform-specific CYP inhibitors tested for an effect on the precocene I metabolite profile, only tranylcypromine was noticeably effective, indicating a role of CYPs 2A6, 2C9, 2Cl9, and 2E1. With respect to toxicity, the order of CYP inhibitor effectiveness was CHEMICAL>CHEMICAL~tranylcypromine>ketoconazole. Furafylline and sulfaphenazole had no effect, while quinidine appeared to augment precocene I toxicity. These results suggest that rat liver slices do not reproduce the reported in vivo biotransformation of precocene I and therefore may not be an appropriate model for precocene I metabolism. However, these results provide an example of how small molecule manipulation of CYP activity in an in vitro model can be used to confirm metabolism-mediated toxicity. | INHIBITOR |
| Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. We present a comprehensive in vitro approach to assessing metabolism-mediated hepatotoxicity using male Sprague-Dawley rat liver slices incubated with the well characterized hepatotoxicant, precocene I, and inhibitors of cytochrome P450 (CYP) enzymes. This approach combines liquid chromatography mass spectrometry (LC MS) detection methods with multiple toxicity endpoints to enable identification of critical metabolic pathways for hepatotoxicity. The incubations were performed in the absence and presence of the non-specific CYP inhibitor, 1-aminobenzotriazole (ABT) and isoform-specific inhibitors. The metabolite profile of precocene I in rat liver slices shares some features of the in vivo profile, but also had a major difference in that epoxide dihydrodiol hydrolysis products were not observed to a measurable extent. As examples of our liver slice metabolite identification procedure, a minor glutathione adduct and previously unreported 7-O-desmethyl and glucuronidated metabolites of precocene I are reported. Precocene I induced hepatocellular necrosis in a dose- and time-dependent manner. ABT decreased the toxicity of precocene I, increased exposure to parent compound, and decreased metabolite levels in a dose-dependent manner. Of the isoform-specific CYP inhibitors tested for an effect on the precocene I metabolite profile, only tranylcypromine was noticeably effective, indicating a role of CYPs 2A6, 2C9, 2Cl9, and 2E1. With respect to toxicity, the order of CYP inhibitor effectiveness was CHEMICAL>diethyldithiocarbamate~CHEMICAL>ketoconazole. Furafylline and sulfaphenazole had no effect, while quinidine appeared to augment precocene I toxicity. These results suggest that rat liver slices do not reproduce the reported in vivo biotransformation of precocene I and therefore may not be an appropriate model for precocene I metabolism. However, these results provide an example of how small molecule manipulation of CYP activity in an in vitro model can be used to confirm metabolism-mediated toxicity. | INHIBITOR |
| Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. We present a comprehensive in vitro approach to assessing metabolism-mediated hepatotoxicity using male Sprague-Dawley rat liver slices incubated with the well characterized hepatotoxicant, precocene I, and inhibitors of cytochrome P450 (CYP) enzymes. This approach combines liquid chromatography mass spectrometry (LC MS) detection methods with multiple toxicity endpoints to enable identification of critical metabolic pathways for hepatotoxicity. The incubations were performed in the absence and presence of the non-specific CYP inhibitor, 1-aminobenzotriazole (ABT) and isoform-specific inhibitors. The metabolite profile of precocene I in rat liver slices shares some features of the in vivo profile, but also had a major difference in that epoxide dihydrodiol hydrolysis products were not observed to a measurable extent. As examples of our liver slice metabolite identification procedure, a minor glutathione adduct and previously unreported 7-O-desmethyl and glucuronidated metabolites of precocene I are reported. Precocene I induced hepatocellular necrosis in a dose- and time-dependent manner. ABT decreased the toxicity of precocene I, increased exposure to parent compound, and decreased metabolite levels in a dose-dependent manner. Of the isoform-specific CYP inhibitors tested for an effect on the precocene I metabolite profile, only tranylcypromine was noticeably effective, indicating a role of CYPs 2A6, 2C9, 2Cl9, and 2E1. With respect to toxicity, the order of CYP inhibitor effectiveness was CHEMICAL>diethyldithiocarbamate~tranylcypromine>CHEMICAL. Furafylline and sulfaphenazole had no effect, while quinidine appeared to augment precocene I toxicity. These results suggest that rat liver slices do not reproduce the reported in vivo biotransformation of precocene I and therefore may not be an appropriate model for precocene I metabolism. However, these results provide an example of how small molecule manipulation of CYP activity in an in vitro model can be used to confirm metabolism-mediated toxicity. | INHIBITOR |
| Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. We present a comprehensive in vitro approach to assessing metabolism-mediated hepatotoxicity using male Sprague-Dawley rat liver slices incubated with the well characterized hepatotoxicant, precocene I, and inhibitors of cytochrome P450 (CYP) enzymes. This approach combines liquid chromatography mass spectrometry (LC MS) detection methods with multiple toxicity endpoints to enable identification of critical metabolic pathways for hepatotoxicity. The incubations were performed in the absence and presence of the non-specific CYP inhibitor, 1-aminobenzotriazole (ABT) and isoform-specific inhibitors. The metabolite profile of precocene I in rat liver slices shares some features of the in vivo profile, but also had a major difference in that epoxide dihydrodiol hydrolysis products were not observed to a measurable extent. As examples of our liver slice metabolite identification procedure, a minor glutathione adduct and previously unreported 7-O-desmethyl and glucuronidated metabolites of precocene I are reported. Precocene I induced hepatocellular necrosis in a dose- and time-dependent manner. ABT decreased the toxicity of precocene I, increased exposure to parent compound, and decreased metabolite levels in a dose-dependent manner. Of the isoform-specific CYP inhibitors tested for an effect on the precocene I metabolite profile, only tranylcypromine was noticeably effective, indicating a role of CYPs 2A6, 2C9, 2Cl9, and 2E1. With respect to toxicity, the order of CYP inhibitor effectiveness was ABT>CHEMICAL~CHEMICAL>ketoconazole. Furafylline and sulfaphenazole had no effect, while quinidine appeared to augment precocene I toxicity. These results suggest that rat liver slices do not reproduce the reported in vivo biotransformation of precocene I and therefore may not be an appropriate model for precocene I metabolism. However, these results provide an example of how small molecule manipulation of CYP activity in an in vitro model can be used to confirm metabolism-mediated toxicity. | INHIBITOR |
| Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. We present a comprehensive in vitro approach to assessing metabolism-mediated hepatotoxicity using male Sprague-Dawley rat liver slices incubated with the well characterized hepatotoxicant, precocene I, and inhibitors of cytochrome P450 (CYP) enzymes. This approach combines liquid chromatography mass spectrometry (LC MS) detection methods with multiple toxicity endpoints to enable identification of critical metabolic pathways for hepatotoxicity. The incubations were performed in the absence and presence of the non-specific CYP inhibitor, 1-aminobenzotriazole (ABT) and isoform-specific inhibitors. The metabolite profile of precocene I in rat liver slices shares some features of the in vivo profile, but also had a major difference in that epoxide dihydrodiol hydrolysis products were not observed to a measurable extent. As examples of our liver slice metabolite identification procedure, a minor glutathione adduct and previously unreported 7-O-desmethyl and glucuronidated metabolites of precocene I are reported. Precocene I induced hepatocellular necrosis in a dose- and time-dependent manner. ABT decreased the toxicity of precocene I, increased exposure to parent compound, and decreased metabolite levels in a dose-dependent manner. Of the isoform-specific CYP inhibitors tested for an effect on the precocene I metabolite profile, only tranylcypromine was noticeably effective, indicating a role of CYPs 2A6, 2C9, 2Cl9, and 2E1. With respect to toxicity, the order of CYP inhibitor effectiveness was ABT>CHEMICAL~tranylcypromine>CHEMICAL. Furafylline and sulfaphenazole had no effect, while quinidine appeared to augment precocene I toxicity. These results suggest that rat liver slices do not reproduce the reported in vivo biotransformation of precocene I and therefore may not be an appropriate model for precocene I metabolism. However, these results provide an example of how small molecule manipulation of CYP activity in an in vitro model can be used to confirm metabolism-mediated toxicity. | INHIBITOR |
| Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. We present a comprehensive in vitro approach to assessing metabolism-mediated hepatotoxicity using male Sprague-Dawley rat liver slices incubated with the well characterized hepatotoxicant, precocene I, and inhibitors of cytochrome P450 (CYP) enzymes. This approach combines liquid chromatography mass spectrometry (LC MS) detection methods with multiple toxicity endpoints to enable identification of critical metabolic pathways for hepatotoxicity. The incubations were performed in the absence and presence of the non-specific CYP inhibitor, 1-aminobenzotriazole (ABT) and isoform-specific inhibitors. The metabolite profile of precocene I in rat liver slices shares some features of the in vivo profile, but also had a major difference in that epoxide dihydrodiol hydrolysis products were not observed to a measurable extent. As examples of our liver slice metabolite identification procedure, a minor glutathione adduct and previously unreported 7-O-desmethyl and glucuronidated metabolites of precocene I are reported. Precocene I induced hepatocellular necrosis in a dose- and time-dependent manner. ABT decreased the toxicity of precocene I, increased exposure to parent compound, and decreased metabolite levels in a dose-dependent manner. Of the isoform-specific CYP inhibitors tested for an effect on the precocene I metabolite profile, only tranylcypromine was noticeably effective, indicating a role of CYPs 2A6, 2C9, 2Cl9, and 2E1. With respect to toxicity, the order of CYP inhibitor effectiveness was ABT>diethyldithiocarbamate~CHEMICAL>CHEMICAL. Furafylline and sulfaphenazole had no effect, while quinidine appeared to augment precocene I toxicity. These results suggest that rat liver slices do not reproduce the reported in vivo biotransformation of precocene I and therefore may not be an appropriate model for precocene I metabolism. However, these results provide an example of how small molecule manipulation of CYP activity in an in vitro model can be used to confirm metabolism-mediated toxicity. | INHIBITOR |
| Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. We present a comprehensive in vitro approach to assessing metabolism-mediated hepatotoxicity using male Sprague-Dawley rat liver slices incubated with the well characterized hepatotoxicant, precocene I, and inhibitors of cytochrome P450 (CYP) enzymes. This approach combines liquid chromatography mass spectrometry (LC MS) detection methods with multiple toxicity endpoints to enable identification of critical metabolic pathways for hepatotoxicity. The incubations were performed in the absence and presence of the non-specific CYP inhibitor, 1-aminobenzotriazole (ABT) and isoform-specific inhibitors. The metabolite profile of precocene I in rat liver slices shares some features of the in vivo profile, but also had a major difference in that epoxide dihydrodiol hydrolysis products were not observed to a measurable extent. As examples of our liver slice metabolite identification procedure, a minor glutathione adduct and previously unreported 7-O-desmethyl and glucuronidated metabolites of precocene I are reported. Precocene I induced hepatocellular necrosis in a dose- and time-dependent manner. ABT decreased the toxicity of precocene I, increased exposure to parent compound, and decreased metabolite levels in a dose-dependent manner. Of the isoform-specific CYP inhibitors tested for an effect on the precocene I metabolite profile, only tranylcypromine was noticeably effective, indicating a role of CYPs 2A6, 2C9, 2Cl9, and 2E1. With respect to toxicity, the order of CYP inhibitor effectiveness was ABT>diethyldithiocarbamate~tranylcypromine>ketoconazole. CHEMICAL and CHEMICAL had no effect, while quinidine appeared to augment precocene I toxicity. These results suggest that rat liver slices do not reproduce the reported in vivo biotransformation of precocene I and therefore may not be an appropriate model for precocene I metabolism. However, these results provide an example of how small molecule manipulation of CYP activity in an in vitro model can be used to confirm metabolism-mediated toxicity. | NO-RELATIONSHIP |
| Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. We present a comprehensive in vitro approach to assessing metabolism-mediated hepatotoxicity using male Sprague-Dawley rat liver slices incubated with the well characterized hepatotoxicant, precocene I, and inhibitors of cytochrome P450 (CYP) enzymes. This approach combines liquid chromatography mass spectrometry (LC MS) detection methods with multiple toxicity endpoints to enable identification of critical metabolic pathways for hepatotoxicity. The incubations were performed in the absence and presence of the non-specific CYP inhibitor, 1-aminobenzotriazole (ABT) and isoform-specific inhibitors. The metabolite profile of precocene I in rat liver slices shares some features of the in vivo profile, but also had a major difference in that epoxide dihydrodiol hydrolysis products were not observed to a measurable extent. As examples of our liver slice metabolite identification procedure, a minor glutathione adduct and previously unreported 7-O-desmethyl and glucuronidated metabolites of precocene I are reported. Precocene I induced hepatocellular necrosis in a dose- and time-dependent manner. ABT decreased the toxicity of precocene I, increased exposure to parent compound, and decreased metabolite levels in a dose-dependent manner. Of the isoform-specific CYP inhibitors tested for an effect on the precocene I metabolite profile, only tranylcypromine was noticeably effective, indicating a role of CYPs 2A6, 2C9, 2Cl9, and 2E1. With respect to toxicity, the order of CYP inhibitor effectiveness was ABT>diethyldithiocarbamate~tranylcypromine>ketoconazole. CHEMICAL and sulfaphenazole had no effect, while CHEMICAL appeared to augment precocene I toxicity. These results suggest that rat liver slices do not reproduce the reported in vivo biotransformation of precocene I and therefore may not be an appropriate model for precocene I metabolism. However, these results provide an example of how small molecule manipulation of CYP activity in an in vitro model can be used to confirm metabolism-mediated toxicity. | NO-RELATIONSHIP |
| Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. We present a comprehensive in vitro approach to assessing metabolism-mediated hepatotoxicity using male Sprague-Dawley rat liver slices incubated with the well characterized hepatotoxicant, precocene I, and inhibitors of cytochrome P450 (CYP) enzymes. This approach combines liquid chromatography mass spectrometry (LC MS) detection methods with multiple toxicity endpoints to enable identification of critical metabolic pathways for hepatotoxicity. The incubations were performed in the absence and presence of the non-specific CYP inhibitor, 1-aminobenzotriazole (ABT) and isoform-specific inhibitors. The metabolite profile of precocene I in rat liver slices shares some features of the in vivo profile, but also had a major difference in that epoxide dihydrodiol hydrolysis products were not observed to a measurable extent. As examples of our liver slice metabolite identification procedure, a minor glutathione adduct and previously unreported 7-O-desmethyl and glucuronidated metabolites of precocene I are reported. Precocene I induced hepatocellular necrosis in a dose- and time-dependent manner. ABT decreased the toxicity of precocene I, increased exposure to parent compound, and decreased metabolite levels in a dose-dependent manner. Of the isoform-specific CYP inhibitors tested for an effect on the precocene I metabolite profile, only tranylcypromine was noticeably effective, indicating a role of CYPs 2A6, 2C9, 2Cl9, and 2E1. With respect to toxicity, the order of CYP inhibitor effectiveness was ABT>diethyldithiocarbamate~tranylcypromine>ketoconazole. CHEMICAL and sulfaphenazole had no effect, while quinidine appeared to augment CHEMICAL toxicity. These results suggest that rat liver slices do not reproduce the reported in vivo biotransformation of precocene I and therefore may not be an appropriate model for precocene I metabolism. However, these results provide an example of how small molecule manipulation of CYP activity in an in vitro model can be used to confirm metabolism-mediated toxicity. | NO-RELATIONSHIP |
| Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. We present a comprehensive in vitro approach to assessing metabolism-mediated hepatotoxicity using male Sprague-Dawley rat liver slices incubated with the well characterized hepatotoxicant, precocene I, and inhibitors of cytochrome P450 (CYP) enzymes. This approach combines liquid chromatography mass spectrometry (LC MS) detection methods with multiple toxicity endpoints to enable identification of critical metabolic pathways for hepatotoxicity. The incubations were performed in the absence and presence of the non-specific CYP inhibitor, 1-aminobenzotriazole (ABT) and isoform-specific inhibitors. The metabolite profile of precocene I in rat liver slices shares some features of the in vivo profile, but also had a major difference in that epoxide dihydrodiol hydrolysis products were not observed to a measurable extent. As examples of our liver slice metabolite identification procedure, a minor glutathione adduct and previously unreported 7-O-desmethyl and glucuronidated metabolites of precocene I are reported. Precocene I induced hepatocellular necrosis in a dose- and time-dependent manner. ABT decreased the toxicity of precocene I, increased exposure to parent compound, and decreased metabolite levels in a dose-dependent manner. Of the isoform-specific CYP inhibitors tested for an effect on the precocene I metabolite profile, only tranylcypromine was noticeably effective, indicating a role of CYPs 2A6, 2C9, 2Cl9, and 2E1. With respect to toxicity, the order of CYP inhibitor effectiveness was ABT>diethyldithiocarbamate~tranylcypromine>ketoconazole. Furafylline and CHEMICAL had no effect, while CHEMICAL appeared to augment precocene I toxicity. These results suggest that rat liver slices do not reproduce the reported in vivo biotransformation of precocene I and therefore may not be an appropriate model for precocene I metabolism. However, these results provide an example of how small molecule manipulation of CYP activity in an in vitro model can be used to confirm metabolism-mediated toxicity. | NO-RELATIONSHIP |
| Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. We present a comprehensive in vitro approach to assessing metabolism-mediated hepatotoxicity using male Sprague-Dawley rat liver slices incubated with the well characterized hepatotoxicant, precocene I, and inhibitors of cytochrome P450 (CYP) enzymes. This approach combines liquid chromatography mass spectrometry (LC MS) detection methods with multiple toxicity endpoints to enable identification of critical metabolic pathways for hepatotoxicity. The incubations were performed in the absence and presence of the non-specific CYP inhibitor, 1-aminobenzotriazole (ABT) and isoform-specific inhibitors. The metabolite profile of precocene I in rat liver slices shares some features of the in vivo profile, but also had a major difference in that epoxide dihydrodiol hydrolysis products were not observed to a measurable extent. As examples of our liver slice metabolite identification procedure, a minor glutathione adduct and previously unreported 7-O-desmethyl and glucuronidated metabolites of precocene I are reported. Precocene I induced hepatocellular necrosis in a dose- and time-dependent manner. ABT decreased the toxicity of precocene I, increased exposure to parent compound, and decreased metabolite levels in a dose-dependent manner. Of the isoform-specific CYP inhibitors tested for an effect on the precocene I metabolite profile, only tranylcypromine was noticeably effective, indicating a role of CYPs 2A6, 2C9, 2Cl9, and 2E1. With respect to toxicity, the order of CYP inhibitor effectiveness was ABT>diethyldithiocarbamate~tranylcypromine>ketoconazole. Furafylline and CHEMICAL had no effect, while quinidine appeared to augment CHEMICAL toxicity. These results suggest that rat liver slices do not reproduce the reported in vivo biotransformation of precocene I and therefore may not be an appropriate model for precocene I metabolism. However, these results provide an example of how small molecule manipulation of CYP activity in an in vitro model can be used to confirm metabolism-mediated toxicity. | NO-RELATIONSHIP |
| Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. We present a comprehensive in vitro approach to assessing metabolism-mediated hepatotoxicity using male Sprague-Dawley rat liver slices incubated with the well characterized hepatotoxicant, precocene I, and inhibitors of cytochrome P450 (CYP) enzymes. This approach combines liquid chromatography mass spectrometry (LC MS) detection methods with multiple toxicity endpoints to enable identification of critical metabolic pathways for hepatotoxicity. The incubations were performed in the absence and presence of the non-specific CYP inhibitor, 1-aminobenzotriazole (ABT) and isoform-specific inhibitors. The metabolite profile of precocene I in rat liver slices shares some features of the in vivo profile, but also had a major difference in that epoxide dihydrodiol hydrolysis products were not observed to a measurable extent. As examples of our liver slice metabolite identification procedure, a minor glutathione adduct and previously unreported 7-O-desmethyl and glucuronidated metabolites of precocene I are reported. Precocene I induced hepatocellular necrosis in a dose- and time-dependent manner. ABT decreased the toxicity of precocene I, increased exposure to parent compound, and decreased metabolite levels in a dose-dependent manner. Of the isoform-specific CYP inhibitors tested for an effect on the precocene I metabolite profile, only tranylcypromine was noticeably effective, indicating a role of CYPs 2A6, 2C9, 2Cl9, and 2E1. With respect to toxicity, the order of CYP inhibitor effectiveness was ABT>diethyldithiocarbamate~tranylcypromine>ketoconazole. Furafylline and sulfaphenazole had no effect, while CHEMICAL appeared to augment CHEMICAL toxicity. These results suggest that rat liver slices do not reproduce the reported in vivo biotransformation of precocene I and therefore may not be an appropriate model for precocene I metabolism. However, these results provide an example of how small molecule manipulation of CYP activity in an in vitro model can be used to confirm metabolism-mediated toxicity. | CHEMICALS-INTERACTION |
| Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. We present a comprehensive in vitro approach to assessing metabolism-mediated hepatotoxicity using male Sprague-Dawley rat liver slices incubated with the well characterized hepatotoxicant, precocene I, and inhibitors of cytochrome P450 (CYP) enzymes. This approach combines liquid chromatography mass spectrometry (LC MS) detection methods with multiple toxicity endpoints to enable identification of critical metabolic pathways for hepatotoxicity. The incubations were performed in the absence and presence of the non-specific CYP inhibitor, 1-aminobenzotriazole (ABT) and isoform-specific inhibitors. The metabolite profile of precocene I in rat liver slices shares some features of the in vivo profile, but also had a major difference in that epoxide dihydrodiol hydrolysis products were not observed to a measurable extent. As examples of our liver slice metabolite identification procedure, a minor glutathione adduct and previously unreported 7-O-desmethyl and glucuronidated metabolites of precocene I are reported. Precocene I induced hepatocellular necrosis in a dose- and time-dependent manner. ABT decreased the toxicity of precocene I, increased exposure to parent compound, and decreased metabolite levels in a dose-dependent manner. Of the isoform-specific CYP inhibitors tested for an effect on the precocene I metabolite profile, only tranylcypromine was noticeably effective, indicating a role of CYPs 2A6, 2C9, 2Cl9, and 2E1. With respect to toxicity, the order of CYP inhibitor effectiveness was ABT>diethyldithiocarbamate~tranylcypromine>ketoconazole. Furafylline and sulfaphenazole had no effect, while quinidine appeared to augment precocene I toxicity. These results suggest that rat liver slices do not reproduce the reported in vivo biotransformation of CHEMICAL and therefore may not be an appropriate model for CHEMICAL metabolism. However, these results provide an example of how small molecule manipulation of CYP activity in an in vitro model can be used to confirm metabolism-mediated toxicity. | SUBSTRATE |
| CHEMICAL may enhance the effects of CHEMICAL, barbiturates and other CNS depressants. | CHEMICALS-INTERACTION |
| CHEMICAL may enhance the effects of alcohol, CHEMICAL and other CNS depressants. | CHEMICALS-INTERACTION |
| CHEMICAL may enhance the effects of alcohol, barbiturates and other CHEMICAL. | CHEMICALS-INTERACTION |
| SKELAXIN may enhance the effects of CHEMICAL, CHEMICAL and other CNS depressants. | NO-RELATIONSHIP |
| SKELAXIN may enhance the effects of CHEMICAL, barbiturates and other CHEMICAL. | NO-RELATIONSHIP |
| SKELAXIN may enhance the effects of alcohol, CHEMICAL and other CHEMICAL. | NO-RELATIONSHIP |
| Our work supported GENE genetic variants as possible susceptibility factors for DISEASE and fractures in humans. | NO-RELATIONSHIP |
| Especially, the SNP GENE and its strongly associated SNPs (e.g., rs1784235) could be important to human DISEASE phenotypes. | NO-RELATIONSHIP |
| Especially, the SNP rs491347 and its strongly associated SNPs (e.g., GENE) could be important to human DISEASE phenotypes. | GENE-DISEASE |
| The HBS1L-MYB intergenic region on chromosome 6q23 is a quantitative trait locus controlling GENE level in carriers of DISEASE. | GENE-DISEASE |
| Fetal haemoglobin (GENE) level modifies the clinical severity of DISEASE. | GENE-DISEASE |
| GENE (HbF) level modifies the clinical severity of DISEASE. | GENE-DISEASE |
| The GENE intergenic region on chromosome 6q23 is a quantitative trait locus controlling fetal haemoglobin level in carriers of DISEASE. | GENE-DISEASE |
| The HBS1L-MYB intergenic region on chromosome GENE is a quantitative trait locus controlling fetal haemoglobin level in carriers of DISEASE. | NO-RELATIONSHIP |
| Functional studies to unravel the biological significance of this region in regulating GENE production is clearly indicated, which may lead to new strategies to modify the disease course of severe DISEASE. | NO-RELATIONSHIP |
| IL-1, IL-1R and GENE in Iranian patients with DISEASE. | NO-RELATIONSHIP |
| On the other hand the frequency of GENE genotype (p=0.028), IL-1R C pst1 1970 allele (p=0.0001) and CC genotype (p=0.00006), TNFalpha G -308 allele (p=0.0002) and GG genotype (p=0.000001) decreased significantly in the patients versus normal subjects.These results suggest that polymorphic variations of these pro-inflammatory cytokines may play an important role in susceptibility of Iranian DISEASE patients. | GENE-DISEASE |
| On the other hand the frequency of IL-1alpha TT -889 genotype (p=0.028), IL-1R C pst1 1970 allele (p=0.0001) and CC genotype (p=0.00006), GENE (p=0.0002) and GG genotype (p=0.000001) decreased significantly in the patients versus normal subjects.These results suggest that polymorphic variations of these pro-inflammatory cytokines may play an important role in susceptibility of Iranian DISEASE patients. | GENE-DISEASE |
| GENE, IL-1R and TNFalpha gene polymorphisms in Iranian patients with DISEASE. | GENE-DISEASE |
| Overall and relapse-free survival in DISEASE and hypopharyngeal squamous cell carcinoma are associated with genotypes of GENE gene. | GENE-DISEASE |
| Overall and relapse-free survival in oropharyngeal and DISEASE are associated with genotypes of GENE gene. | GENE-DISEASE |
| The GENE SNP could be considered as a genetic marker to predict the clinical course of patients suffering from oropharyngeal and DISEASE. | NO-RELATIONSHIP |
| The GENE SNP could be considered as a genetic marker to predict the clinical course of patients suffering from DISEASE and hypopharyngeal cancer. | NO-RELATIONSHIP |
| The prognostic value of the GENE SNP was evaluated in an unselected series of patients treated with curative intent for DISEASE and hypopharyngeal squamous cell carcinomas, including all tumor stages with different therapeutic regimens. | NO-RELATIONSHIP |
| However, the majority of DISEASE cells have deregulation of the GENE/beta-catenin pathway. | GENE-DISEASE |
| Lysophosphatidic acid facilitates proliferation of DISEASE cells via induction of GENE. | GENE-DISEASE |
| A recent study showed that LPA-mediated proliferation of DISEASE cells requires activation of GENE. | GENE-DISEASE |
| On multivariate analysis the GENE (OR 8.205, 95% CI 1.616-41.667, p = 0.011) and smaller number of treatment cycles (OR 0.156, 95% CI 0.037-0.659, p = 0.011) were independent factors for DISEASE (grade 3 or greater) throughout the period of chemotherapy. | GENE-DISEASE |
| The GENE, which is involved in the metabolism of vinblastine and doxorubicin, might be a genetic predictor of the severity of DISEASE induced by chemotherapy with methotrexate, vinblastine, doxorubicin and cisplatin. | NO-RELATIONSHIP |
| GENE genotyping might make tailor chemotherapy possible for DISEASE patients treated with oxaliplatin-based chemotherapy. | NO-RELATIONSHIP |
| GENE predicts overall survival of DISEASE patients receiving oxaliplatin-based chemotherapy in Chinese population. | GENE-DISEASE |
| This study assessed associations between the GENE gene and DISEASE (MI), using a haplotype-based case-control study of 234 MI patients and 248 controls genotyped for 5 single-nucleotide polymorphisms (rs3093105, rs3093135, rs1558139, rs2108622, rs3093200). | GENE-DISEASE |
| A haplotype of the GENE gene associated with DISEASE in Japanese men. | GENE-DISEASE |
| For men, G allele frequency of GENE and frequency of the T-C-G haplotype were significantly higher, and frequency of the T-C-A haplotype was significantly lower for DISEASE patients than for controls (P=0.006, P=0.001 and P=0.002, respectively). | GENE-DISEASE |
| This study assessed associations between the GENE gene and myocardial infarction (MI), using a haplotype-based case-control study of 234 DISEASE patients and 248 controls genotyped for 5 single-nucleotide polymorphisms (rs3093105, rs3093135, rs1558139, rs2108622, rs3093200). | GENE-DISEASE |
| When stratified by GENE polymorphism, alcohol-related increases in DISEASE risk were restricted to individuals with the AG/GG genotypes, with a more than 2-fold risk among daily drinkers (OR=2.63, 95% CI=1.00-6.88) and 3-fold risk (OR=3.66, 95% CI=1.19-11.24) among those with 40 or more drink-years. | GENE-DISEASE |
| The GENE gene at 7q22.1 has been shown to be associated with familial intracranial aneurysms (DISEASE) in the Japanese population. | GENE-DISEASE |
| The GENE gene at 7q22.1 has been shown to be associated with familial DISEASE (IAs) in the Japanese population. | GENE-DISEASE |
| The GENE polymorphism of COL1A2 could be a genetic risk factor for sporadic DISEASE among individuals of Chinese Han ethnicity. | GENE-DISEASE |
| This study is the first to confirm the association between GENE and DISEASE. | NO-RELATIONSHIP |
| Cutting edge: A common polymorphism impairs cell surface trafficking and functional responses of GENE but protects against DISEASE. | GENE-DISEASE |
| Surprisingly, the GENE allele is associated with a decreased incidence of DISEASE, suggesting that Mycobacterium leprae subverts the TLR system as a mechanism of immune evasion. | NO-RELATIONSHIP |
| These results suggest that combination of HDACi with adenoviral GENE gene therapy may be a new therapeutic approach for the treatment of DISEASE that warrants further investigation. | GENE-DISEASE |
| These results suggest that the C1772T polymorphism in GENE is not involved in progression or metastasis of DISEASE. | GENE-DISEASE |
| In our setting, DISEASE among alcoholic individuals seems to be independent of the presence of mutations C282Y, H63D and S65C in the GENE gene. | GENE-DISEASE |
| MPO genotype GG is associated with DISEASE in patients with hereditary GENE. | NO-RELATIONSHIP |
| These three studies do not provide consistent evidence supporting the hypothesis that GENE mutations are associated with an increased risk of DISEASE and with the development of arteriosclerosis. | NO-RELATIONSHIP |
| Our prospective findings suggest that individuals carrying the GENE C282Y mutation may be at increased risk of DISEASE. | GENE-DISEASE |
| We conclude that homozygosity for the G1514-->A mutation is exclusively responsible for the adult form of DISEASE in this family, and that the A619-->G substitution is not a deleterious mutation but rather a common GENE polymorphism. | GENE-DISEASE |
| The data suggest that the GENE gene or a linked locus significantly modulates the risk for DISEASE. | GENE-DISEASE |
| The novel gene GENE may be related with the infiltration and proliferation of DISEASE. | GENE-DISEASE |
| Our findings suggest that the genetic variants of the GENE but not the TIM-3 gene contribute to DISEASE susceptibility in this African-American population. | NO-RELATIONSHIP |
| In conclusion, the M416V polymorphism of GENE gene is not associated with insulin resistance in DISEASE. | GENE-DISEASE |
| We found no evidence that mutation in GENE,GNGT1,or RGS9 gene is a cause of DISEASE. | GENE-DISEASE |
| These results suggest that the GENE null genotype may be associated with increased risk of DISEASE. | GENE-DISEASE |
| These findings suggest that the GSTA1 and GENE polymorphisms are associated with DISEASE susceptibility, especially among smokers. | GENE-DISEASE |
| These findings suggest that individual susceptibility to DISEASE may be modulated by GSTM1, GENE and NAT2 polymorphisms. | GENE-DISEASE |
| These results suggest that the GENE null-genotype is associated with an increased risk of DISEASE, especially in younger individuals. | GENE-DISEASE |
| These results support previous reports that the GSTM1 null genotype is associated with a modest increase in risk for DISEASE, particularly among heavy smokers, suggest no role for GENE and the need for further study of GSTP1. | GENE-DISEASE |
| We conclude that the two polymorphisms, GENE null and PON1 BB, are common genetic traits that pose low individual risk but may be important determinants of overall population DISEASE risk, particularly among groups exposed to NHL-related carcinogens. | GENE-DISEASE |
| We conclude that the two polymorphisms, GENE null and PON1 BB, are common genetic traits that pose low individual risk but may be important determinants of overall population NHL risk, particularly among groups exposed to DISEASE-related carcinogens. | GENE-DISEASE |
| Polymorphisms in the oxidative stress-related genes (CYP1A1, GSTM1, GENE, MPO, MnSOD) do not seem to be risk factors for DISEASE. | GENE-DISEASE |
| The GENE-null genotype may increase the risk for DISEASE and is associated with favorable prognostic factors, and the presence of at least one GST deletion indicates an improved disease-free survival. | GENE-DISEASE |
| This study suggests that certain null GSTM1 and GENE genotypes may be associated with an elevated risk of DISEASE which may be modified by interaction of the two genetic polymorphisms and cigarette smoking. | GENE-DISEASE |
| Individuals who bear GENE 0/0 genotype or GSTT1 0/0-GSTM1 0/0 combined genotypes are more susceptible to DISEASE, especially for male and younger carriers. | GENE-DISEASE |
| Individuals who bear GSTT1 0/0 genotype or GENE 0/0-GSTM1 0/0 combined genotypes are more susceptible to DISEASE, especially for male and younger carriers. | GENE-DISEASE |
| The gene polymorphism for GENE was not associated with susceptibility to DISEASE in the Chinese population. | GENE-DISEASE |
| The genetic polymorphism in GENE gene exon5 was not associated with the susceptibility to DISEASE in northern Chinese population of Han nationality. | GENE-DISEASE |
| Polymorphisms in the oxidative stress-related genes (CYP1A1, GENE, GSTT1, MPO, MnSOD) do not seem to be risk factors for DISEASE. | GENE-DISEASE |
| There is a synergy of susceptible genotypes GENE 0/0 and CYP1A1 Val/Val or CYP1A1 Ile/Val to enhance the individual susceptibility to DISEASE. | NO-RELATIONSHIP |
| These data suggest that polymorphisms in CYP1A1 and GENE contribute to the increased risk of females for DISEASE. | GENE-DISEASE |
| The combination of GENE genotype 0/0 and matrix metalloproteinase 9 mutant allele (-15621) is a risk factor for DISEASE (OR-7.7). | GENE-DISEASE |
| These results support previous reports that the GENE null genotype is associated with a modest increase in risk for DISEASE, particularly among heavy smokers, suggest no role for GSTT1 and the need for further study of GSTP1. | GENE-DISEASE |
| The present study suggests that the GENE polymorphism may be associated with increased risk of development of DISEASE. | GENE-DISEASE |
| The results suggest that the GENE null genotype is a risk factor for development of DISEASE among Indian tobacco habitues. | GENE-DISEASE |
| Individuals who bear GSTT1 0/0 genotype or GSTT1 0/0-GENE 0/0 combined genotypes are more susceptible to DISEASE, especially for male and younger carriers. | NO-RELATIONSHIP |
| Our results through Meta-analysis did not support the association between GENE null genotype and DISEASE, but the smokers carring the GSTM1 null genotype might be associated with the increased risk of esophageal cancer. | GENE-DISEASE |
| Our results through Meta-analysis did not support the association between GENE null genotype and esophageal cancer, but the smokers carring the GSTM1 null genotype might be associated with the increased risk of DISEASE. | GENE-DISEASE |
| Our results through Meta-analysis did not support the association between GSTM1 null genotype and DISEASE, but the smokers carring the GENE null genotype might be associated with the increased risk of esophageal cancer. | GENE-DISEASE |
| Our results through Meta-analysis did not support the association between GSTM1 null genotype and esophageal cancer, but the smokers carring the GENE null genotype might be associated with the increased risk of DISEASE. | GENE-DISEASE |
| No associations between the GENE alleles, including the null allele, and DISEASE were detected in this study. | GENE-DISEASE |
| These findings suggest that the GENE and GSTT1 polymorphisms are associated with DISEASE susceptibility, especially among smokers. | GENE-DISEASE |
| Because our samples provided quite high power, these results indicate that GENE may not play a major role in Japanese DISEASE. | GENE-DISEASE |
| We conclude that at least one susceptibility locus for DISEASE is located within the GENE region in Japanese. | GENE-DISEASE |
| Our results partially support the previous studies in other ethnic groups and indicate that the GENE gene may play an important role in the etiology of DISEASE in the Han Chinese. | GENE-DISEASE |
| These data suggest that polymorphisms in the GENE gene may be useful as predictors of negative symptom improvement in persons with DISEASE treated with olanzapine. | NO-RELATIONSHIP |
| Our data indicate that at least one susceptibility locus for DISEASE is situated within or very close to the GENE region in the Japanese patients. | GENE-DISEASE |
| Examination of our own data and those of other groups leads us to conclude that at present, GENE should not be viewed as a gene for which there is replicated evidence for association with DISEASE. | GENE-DISEASE |
| These findings suggest that the combined effects of the polymorphisms in the GRIN1 and GENE genes might be involved in the etiology of DISEASE. | GENE-DISEASE |
| These findings suggest that the combined effects of the polymorphisms in the GENE and GRIN2B genes might be involved in the etiology of DISEASE. | GENE-DISEASE |
| The association reported in this study suggests that the GENE gene is a good candidate for the susceptibility to DISEASE. | GENE-DISEASE |
| Results indicate that genomic variations of the GENE gene are not likely to be involved substantially in the etiology of DISEASE. | GENE-DISEASE |
| revealed no significant association between DISEASE and the SNPs in the upstream region of GENE, these SNPs apparently do not play a critical role in the pathogenesis of schizophrenia in the Japanese population. | GENE-DISEASE |
| revealed no significant association between schizophrenia and the SNPs in the upstream region of GENE, these SNPs apparently do not play a critical role in the pathogenesis of DISEASE in the Japanese population. | GENE-DISEASE |
| The association reported in this study suggests that the GENE gene is a good candidate for the susceptibility to DISEASE. | GENE-DISEASE |
| We conclude that GENE does not play a major role in the pathogenesis of DISEASE in the Japanese population. | GENE-DISEASE |
| We conclude that GENE does not play a major role in the pathogenesis of DISEASE in the Japanese population. | GENE-DISEASE |
| We conclude that GENE does not play a major role in DISEASE pathogenesis in the Japanese population. | GENE-DISEASE |
| We conclude that GENE does not play a major role in DISEASE pathogenesis in the Japanese population. | GENE-DISEASE |
| Our results suggest that the three SNPs of GENE are unlikely to play a major role in the susceptibility to DISEASE in the Chinese population. | GENE-DISEASE |
| These results suggest that at least one susceptibility locus for DISEASE is located within or very close to the GENE region in Japanese. | GENE-DISEASE |
| The result of this study suggests that the GENE genotype is unlikely to be associated with the risk of developing DISEASE. | GENE-DISEASE |
| The result of this study suggests that the GENE genotype is unlikely to be associated with the risk of developing DISEASE. | GENE-DISEASE |
| Determination of VNTR of the GENE gene may prove useful for identifying high-risk individuals for DISEASE. | GENE-DISEASE |
| The molecular abnormality demonstrated in this family provides evidence that defective synthesis of GENE alters the membrane expression of the GP Ib-IX complex and may be responsible for DISEASE. | GENE-DISEASE |
| We found no evidence that mutation in GUCA1B,GENE,or RGS9 gene is a cause of DISEASE. | GENE-DISEASE |
| Our study indicated that a loss of GENE function contributes to a major pathogenesis of X-linked DISEASE. | GENE-DISEASE |
| This study provides strong evidence linking GENE polymorphisms to enhanced atrial vulnerability and increased risk of DISEASE. | GENE-DISEASE |
| The human T1663A GENE gene polymorphism, which may confer lower levels of GH and IGF-I, appears to be associated with a decreased risk of DISEASE. | GENE-DISEASE |
| The human T1663A GH1 gene polymorphism, which may confer lower levels of GENE and IGF-I, appears to be associated with a decreased risk of DISEASE. | NO-RELATIONSHIP |
| The results of the current study suggest that genetic polymorphisms in the proximal promoter region and in the fourth intron of the GENE gene are unrelated to DISEASE risk in Chinese women. | GENE-DISEASE |
| Overall, we obtained no solid evidence for the involvement of the GENE gene in the pathogenesis of DISEASE, although further studies in larger numbers of subjects will be required to conclude whether the trinucleotide repeat polymorphism is associated with the development of schizophrenia. | GENE-DISEASE |
| Overall, we obtained no solid evidence for the involvement of the GENE gene in the pathogenesis of schizophrenia, although further studies in larger numbers of subjects will be required to conclude whether the trinucleotide repeat polymorphism is associated with the development of DISEASE. | GENE-DISEASE |
| Overall, we obtained no solid evidence for the involvement of the GENE gene in the pathogenesis of DISEASE, although further studies in larger numbers of subjects will be required to conclude whether the trinucleotide repeat polymorphism is associated with the development of schizophrenia. | GENE-DISEASE |
| Overall, we obtained no solid evidence for the involvement of the GENE gene in the pathogenesis of schizophrenia, although further studies in larger numbers of subjects will be required to conclude whether the trinucleotide repeat polymorphism is associated with the development of DISEASE. | GENE-DISEASE |
| These findings suggest that the -588T polymorphism of the GENE gene may suppress GCLM gene induction in response to oxidants and that it is a genetic risk factor for DISEASE. | GENE-DISEASE |
| These findings suggest that the -588T polymorphism of the GCLM gene may suppress GENE gene induction in response to oxidants and that it is a genetic risk factor for DISEASE. | GENE-DISEASE |
| Mutations that affect the properties of GENE are found in the French population, but they do not seem to account for the linkage between the 2p23 locus and quantitative markers of DISEASE. | NO-RELATIONSHIP |
| Our results suggest that GENE gene was associated with Chinese DISEASE, and haplotype of GCK1/GCK2 B/2 was a protective factor for GDM. | GENE-DISEASE |
| Our results suggest that GENE gene was associated with Chinese GDM, and haplotype of GCK1/GCK2 B/2 was a protective factor for DISEASE. | NO-RELATIONSHIP |
| Taken together, these results demonstrate that the GENE*1F and GC*2 alleles are associated with sputum hypersecretion in individuals who are at increased risk of developing DISEASE. | GENE-DISEASE |
| Our results suggest that heterozygosity for a GENE mutation may predispose Ashkenazi Jews to DISEASE. | GENE-DISEASE |
| The experiments reported herein provide no evidence supporting involvement of the GENE locus in the development of DISEASE. | GENE-DISEASE |
| The experiments reported herein provide no evidence supporting involvement of the GENE locus in the development of DISEASE. | GENE-DISEASE |
| Our results suggest that GENE does not play a major role in DISEASE in these two European populations. | GENE-DISEASE |
| Although our results are negative, this was the first study to investigate GENE genes in DISEASE, and further studies of these genes, particularly with schizophrenia subtypes, may prove valuable. | GENE-DISEASE |
| Although our results are negative, this was the first study to investigate GENE genes in schizophrenia, and further studies of these genes, particularly with DISEASE subtypes, may prove valuable. | GENE-DISEASE |
| In conclusion, the present study indicates that in a population of DISEASE patients, heterozygosity of the GENE major (G1) allele confers higher levels of somatic symptoms, anxiety/insomnia, social dysfunction and depression than found in homozygosity. | GENE-DISEASE |
| The results of our study indicate that GENE gene might also be involved in the genetic pathophysiology of unipolar DISEASE (at least in female patients), even if the findings do not support a predominant role of GABRA 3. | GENE-DISEASE |
| The results of our study indicate that GABRA 3 gene might also be involved in the genetic pathophysiology of unipolar DISEASE (at least in female patients), even if the findings do not support a predominant role of GENE. | GENE-DISEASE |
| These results suggest the GENE gene may be a risk factor for DISEASE. As with the DRD2 gene, the effect may be mediated through its regulation of prolactin release. | GENE-DISEASE |
| These findings replicate and extend recently reported findings, which together underscore the potential contribution of polymorphic variation at the GENE locus to the risk for DISEASE. | GENE-DISEASE |
| The very strong association of GENE with both DISEASE and the beta frequency of the electroencephalogram, combined with biological evidence for a role of this gene in both phenotypes, suggest that GABRA2 might influence susceptibility to alcohol dependence by modulating the level of neural excitation. | NO-RELATIONSHIP |
| The very strong association of GENE with both alcohol dependence and the beta frequency of the electroencephalogram, combined with biological evidence for a role of this gene in both phenotypes, suggest that GABRA2 might influence susceptibility to DISEASE by modulating the level of neural excitation. | GENE-DISEASE |
| The very strong association of GABRA2 with both DISEASE and the beta frequency of the electroencephalogram, combined with biological evidence for a role of this gene in both phenotypes, suggest that GENE might influence susceptibility to alcohol dependence by modulating the level of neural excitation. | NO-RELATIONSHIP |
| The very strong association of GABRA2 with both alcohol dependence and the beta frequency of the electroencephalogram, combined with biological evidence for a role of this gene in both phenotypes, suggest that GENE might influence susceptibility to DISEASE by modulating the level of neural excitation. | GENE-DISEASE |
| We identified no sequence variations in the GENE core promoter or in the 5' UTR of these G6PD-deficient individuals, which indicates that DISEASE is not associated with promoter mutations in the G6PD locus. | NO-RELATIONSHIP |
| We identified no sequence variations in the G6PD core promoter or in the 5' UTR of these GENE-deficient individuals, which indicates that DISEASE is not associated with promoter mutations in the G6PD locus. | NO-RELATIONSHIP |
| We identified no sequence variations in the G6PD core promoter or in the 5' UTR of these G6PD-deficient individuals, which indicates that DISEASE is not associated with promoter mutations in the GENE locus. | GENE-DISEASE |
| We conclude that GENE A- heterozygous females are protected against all forms of P. falciparum malaria, and that the TNFalpha(-238A) allele confers protection against clinical DISEASE. | NO-RELATIONSHIP |
| Although two prior studies have reported associations using limited numbers of SNPs on GENE, our intensive study failed to support any major contribution of FZD3 to DISEASE susceptibility. | GENE-DISEASE |
| Although two prior studies have reported associations using limited numbers of SNPs on FZD3, our intensive study failed to support any major contribution of GENE to DISEASE susceptibility. | GENE-DISEASE |
| These results suggested that the GENE gene might be involved in the predisposition to DISEASE. | GENE-DISEASE |
| Our data indicate that allelic variation in or near the coding regions of the GENE gene does not have a major role in the inherited susceptibility to the common form of DISEASE. | GENE-DISEASE |
| In conclusion, the GENE/Scurfin gene appears to confer a significant susceptibility to DISEASE in the Japanese population. | NO-RELATIONSHIP |
| In conclusion, the FOXP3/GENE gene appears to confer a significant susceptibility to DISEASE in the Japanese population. | NO-RELATIONSHIP |
| In conclusion, the GENE/Scurfin gene appears to confer a significant susceptibility to DISEASE in the Japanese population. | NO-RELATIONSHIP |
| In conclusion, the FOXP3/GENE gene appears to confer a significant susceptibility to DISEASE in the Japanese population. | NO-RELATIONSHIP |
| Our results may suggest a relationship between DISEASE and the GENE gene or a gene located nearby. | GENE-DISEASE |
| The analysis did not reveal any mutation in the 240 analysed chromosomes, indicating that mutations in the GENE coding region are rarely associated with non-syndromic DISEASE. | GENE-DISEASE |
| Thus, the SNPs identified in the GENE gene are unlikely to have major effects on susceptibility to Japanese DISEASE. | GENE-DISEASE |
| Thus, the SNPs identified in the GENE gene are unlikely to have major effects on susceptibility to Japanese DISEASE. | GENE-DISEASE |
| These data did not provide evidence for a contribution of the GENE gene to susceptibility to DISEASE. | GENE-DISEASE |
| These data did not provide evidence for a contribution of the GENE gene to susceptibility to DISEASE. | GENE-DISEASE |
| Although uncommon, point mutations in the GENE gene may be a cause of DISEASE and mental retardation in Japanese patients. | NO-RELATIONSHIP |
| The GENE Arg388 allele is associated with both an increased incidence and clinical aggressiveness of DISEASE and results in changes in cellular motility and invasiveness in immortalized prostate epithelial cells consistent with the promotion of metastasis. | GENE-DISEASE |
| We conclude that the spectrum of GENE mutations causing DISEASE is wider than previously recognized but that, nevertheless, the IgIIIa/IIIc region represents a genuine mutation hotspot. | GENE-DISEASE |
| The results showed that the GENE gene is associated with autopsy-confirmed DISEASE. | GENE-DISEASE |
| Our data suggest that the fibrinogen-elevating GENE G-455A gene polymorphism is not linked to an increased risk for DISEASE. | GENE-DISEASE |
| A modest association between GENE and DISEASE suggests that this gene and the DISC1-mediated molecular pathway might play roles in the development of schizophrenia, with FEZ1 affecting only a small subset of Japanese schizophrenia patients. | GENE-DISEASE |
| A modest association between GENE and schizophrenia suggests that this gene and the DISC1-mediated molecular pathway might play roles in the development of DISEASE, with FEZ1 affecting only a small subset of Japanese schizophrenia patients. | GENE-DISEASE |
| A modest association between GENE and schizophrenia suggests that this gene and the DISC1-mediated molecular pathway might play roles in the development of schizophrenia, with FEZ1 affecting only a small subset of Japanese DISEASE patients. | GENE-DISEASE |
| A modest association between FEZ1 and DISEASE suggests that this gene and the DISC1-mediated molecular pathway might play roles in the development of schizophrenia, with GENE affecting only a small subset of Japanese schizophrenia patients. | GENE-DISEASE |
| A modest association between FEZ1 and schizophrenia suggests that this gene and the DISC1-mediated molecular pathway might play roles in the development of DISEASE, with GENE affecting only a small subset of Japanese schizophrenia patients. | GENE-DISEASE |
| A modest association between FEZ1 and schizophrenia suggests that this gene and the DISC1-mediated molecular pathway might play roles in the development of schizophrenia, with GENE affecting only a small subset of Japanese DISEASE patients. | GENE-DISEASE |
| This study provides the first evidence that the infant GENE His/His131 genotype is associated with susceptibility to perinatal DISEASE-1 transmission and further suggests that there is a dose-response relationship for the effect of the Fc gamma RIIa His131 gene on transmission. | NO-RELATIONSHIP |
| This study provides the first evidence that the infant Fc gamma RIIa His/His131 genotype is associated with susceptibility to perinatal DISEASE-1 transmission and further suggests that there is a dose-response relationship for the effect of the GENE His131 gene on transmission. | NO-RELATIONSHIP |
| Patients with DISEASE have higher frequencies of GENE exon 15 TT and exon 27 GG genotypes, which supports a role of the FBN1 exon 15 and 27 polymorphisms in determining the risk of MVP among the Chinese population in Taiwan. | GENE-DISEASE |
| Patients with MVP have higher frequencies of GENE exon 15 TT and exon 27 GG genotypes, which supports a role of the FBN1 exon 15 and 27 polymorphisms in determining the risk of DISEASE among the Chinese population in Taiwan. | GENE-DISEASE |
| Patients with DISEASE have higher frequencies of FBN1 exon 15 TT and exon 27 GG genotypes, which supports a role of the GENE exon 15 and 27 polymorphisms in determining the risk of MVP among the Chinese population in Taiwan. | GENE-DISEASE |
| Patients with MVP have higher frequencies of FBN1 exon 15 TT and exon 27 GG genotypes, which supports a role of the GENE exon 15 and 27 polymorphisms in determining the risk of DISEASE among the Chinese population in Taiwan. | GENE-DISEASE |
| Patients with DISEASE have higher frequencies of GENE exon 15 TT and exon 27 GG genotypes, which supports a role of the FBN1 exon 15 and 27 polymorphisms in determining the risk of MVP among the Chinese population in Taiwan. | GENE-DISEASE |
| Patients with MVP have higher frequencies of GENE exon 15 TT and exon 27 GG genotypes, which supports a role of the FBN1 exon 15 and 27 polymorphisms in determining the risk of DISEASE among the Chinese population in Taiwan. | GENE-DISEASE |
| Patients with DISEASE have higher frequencies of FBN1 exon 15 TT and exon 27 GG genotypes, which supports a role of the GENE exon 15 and 27 polymorphisms in determining the risk of MVP among the Chinese population in Taiwan. | GENE-DISEASE |
| Patients with MVP have higher frequencies of FBN1 exon 15 TT and exon 27 GG genotypes, which supports a role of the GENE exon 15 and 27 polymorphisms in determining the risk of DISEASE among the Chinese population in Taiwan. | GENE-DISEASE |
| In conclusion, our data do not suggest common genetic GENE variants to significantly contribute to the pathogenesis of either Hashimoto's thyroiditis or DISEASE. | GENE-DISEASE |
| We conclude that the GENE/FASL promoter haplotypes are functional and that polymorphisms in FAS may contribute to DISEASE in SLE. | NO-RELATIONSHIP |
| We conclude that the FAS/FASL promoter haplotypes are functional and that polymorphisms in GENE may contribute to DISEASE in SLE. | NO-RELATIONSHIP |
| Our results agree with the previously published studies and highlight that the association of the polymorphisms is restricted to women with DISEASE. We did not find an association between CD95L and susceptibility to MS nor GENE or CD95L and age of onset, disease course and disease severity. | NO-RELATIONSHIP |
| Our results agree with the previously published studies and highlight that the association of the polymorphisms is restricted to women with MS. We did not find an association between CD95L and susceptibility to DISEASE nor GENE or CD95L and age of onset, disease course and disease severity. | NO-RELATIONSHIP |
| Taken together these data support the assertion that inherited mutations in GENE can predispose to DISEASE. | GENE-DISEASE |
| It was concluded that GENE genotype influences DISEASE independent of body composition, habitual physical activity levels, and HRT status in postmenopausal white women | GENE-DISEASE |
| The Ala54Thr polymorphism of the GENE gene is not associated with DISEASE, markers of the metabolic syndrome, or the fatty acid profile of serum lipids in Finnish CHD patients. | NO-RELATIONSHIP |
| The Ala54Thr polymorphism of the GENE gene is not associated with CHD, markers of the metabolic syndrome, or the fatty acid profile of serum lipids in Finnish DISEASE patients. | GENE-DISEASE |
| In conclusion, Thr54 allele of GENE has associations with lower adjusted resting metabolic rate, resistance in reducing visceral white adipose tissue (WAT) and early onset of DISEASE in Japanese obese women. | GENE-DISEASE |
| In conclusion, Thr54 allele of GENE has associations with lower adjusted resting metabolic rate, resistance in reducing visceral white adipose tissue (WAT) and early onset of obesity in Japanese DISEASE women. | GENE-DISEASE |
| The A54T polymorphism at the GENE locus is a risk factor for DISEASE in a Caucasian population. | GENE-DISEASE |
| Our data suggested that Ala54Thr polymorphism of the GENE gene is not a major contributing factor for obesity and obesity with DISEASE in Japanese children. | GENE-DISEASE |
| These results suggest a role for the GENE 385 A/A missense polymorphism as an endocannabinoid risk factor in overweight/DISEASE and may provide indirect evidence to support cannabinoid antagonist treatment strategies in overweight disorders. | GENE-DISEASE |
| In conclusion, we provide evidence for a joint effect on DISEASE risk between G1691A factor V point mutation and GENE Arg/Gln(353) gene polymorphism as well as between factor V point mutation and metabolic risk factors. | GENE-DISEASE |
| The G-455A polymorphism of the fibrinogen gene promoter and the decamer insertion or deletion polymorphism of the GENE gene promoter are unlikely to be major genetic predisposing factors for DISEASE in subjects from eastern Finland. | GENE-DISEASE |
| In conclusion, there was no association between the beta-fibrinogen -455 G/A, GP IIIa PlA1/A2, PAI-1 4G/5G, GENE 1691 G/A, TNFalpha -238 G/A, TNFalpha -308 G/A, IL-1alpha -889 C/T, the IL-1beta -511 C/T, MTHFR 677 C/T and eNOS 4 b/a gene polymorphisms and the risk of DISEASE after PTCA as well as recurrent restenosis after repeated PTCA. | GENE-DISEASE |
| In conclusion, there was no association between the beta-fibrinogen -455 G/A, GP IIIa PlA1/A2, PAI-1 4G/5G, GENE 1691 G/A, TNFalpha -238 G/A, TNFalpha -308 G/A, IL-1alpha -889 C/T, the IL-1beta -511 C/T, MTHFR 677 C/T and eNOS 4 b/a gene polymorphisms and the risk of restenosis after PTCA as well as recurrent DISEASE after repeated PTCA. | GENE-DISEASE |
| We conclude that the 20210 G/A GENE gene mutation is not a major risk factor for premature DISEASE in our predominantly Caucasian Australian population. | GENE-DISEASE |
| We found a 6-fold higher risk of acute DISEASE associated with the homozygosity of the T allele of the GENE, 46C-->T polymorphism in the Spanish population. | GENE-DISEASE |
| Our results are consistent with the hypothesis of a joint effect of GENE sequence variants and endogenous estrogen exposure on DISEASE risk. | GENE-DISEASE |
| Our results indicate that GENE polymorphisms may not be associated with DISEASE risk. | GENE-DISEASE |
| GENE and VDR genes may contribute to DISEASE in a distinct manner: estrogen sensitivity influences the severity in the early phase after menopause while vitamin D plays an important role at older ages when the contribution of estrogen loss is weaker. | GENE-DISEASE |
| GENE alpha polymorphisms, but not beta3-adrenergic receptor gene, may be associated with a risk of DISEASE. | GENE-DISEASE |
| We provide evidence that variants of XRCC1, XRCC3, and GENE/XPF genes, particularly in combination, contribute to DISEASE susceptibility. | GENE-DISEASE |
| We provide evidence that variants of XRCC1, XRCC3, and ERCC4/GENE genes, particularly in combination, contribute to DISEASE susceptibility. | GENE-DISEASE |
| Our findings suggest that Ki-ras and GENE SNPs are possible markers for DISEASE formation, whereas cyclin D1 and p16 SNPs may be markers of genes that have an inverse effect on the risk to develop meningioma in irradiated and nonirradiated populations. | GENE-DISEASE |
| Our findings suggest that Ki-ras and GENE SNPs are possible markers for meningioma formation, whereas cyclin D1 and p16 SNPs may be markers of genes that have an inverse effect on the risk to develop DISEASE in irradiated and nonirradiated populations. | GENE-DISEASE |
| In our population, common GENE polymorphisms are not involved in predisposition to DISEASE. | GENE-DISEASE |
| In conclusion, our results support the view that both the ER codon 594 and GENE codon 655 polymorphisms are not associated with increased risk of DISEASE. | GENE-DISEASE |
| Common polymorphisms within GENE and EPHX2 do not appear to be important risk factors for DISEASE. | GENE-DISEASE |
| Our data show that the K1019X mutation in the GENE gene differs in frequency between AA and EA, is associated with increased risk for PC in AA men with a positive family history, and may be an important genetic risk factor for DISEASE in AA. | NO-RELATIONSHIP |
| Although further replication studies are necessary to test the validity of the described genotype-phenotype relationship, our study supports the hypothesis that GENE 121Q predicts genetic susceptibility to DISEASE in both South Asians and Caucasians. | GENE-DISEASE |
| We conclude that the interaction between the K121Q polymorphism of the GENE gene and birth length affects insulin sensitivity and increases susceptibility to DISEASE and hypertension in adulthood. | NO-RELATIONSHIP |
| The authors failed to find an association between the intronic insertion polymorphism of the GENE gene and aneurysmal DISEASE in a Polish population. | GENE-DISEASE |
| In summary, the GENE gene variants Leu217 and Thr541 were associated with an increased risk for DISEASE and for PIN in males undergoing radical prostatectomies in the Calgary region. | NO-RELATIONSHIP |
| The absence of GENE mutations and lack of association between polymorphisms in ELAC2 and DISEASE in cases and controls leads us to conclude that ELAC2 does not contribute significantly to the elevated prevalence of prostate cancer in Afro-Caribbean males of Tobago. | GENE-DISEASE |
| The absence of GENE mutations and lack of association between polymorphisms in ELAC2 and prostate cancer in cases and controls leads us to conclude that ELAC2 does not contribute significantly to the elevated prevalence of DISEASE in Afro-Caribbean males of Tobago. | GENE-DISEASE |
| The absence of ELAC2 mutations and lack of association between polymorphisms in GENE and DISEASE in cases and controls leads us to conclude that ELAC2 does not contribute significantly to the elevated prevalence of prostate cancer in Afro-Caribbean males of Tobago. | GENE-DISEASE |
| The absence of ELAC2 mutations and lack of association between polymorphisms in GENE and prostate cancer in cases and controls leads us to conclude that ELAC2 does not contribute significantly to the elevated prevalence of DISEASE in Afro-Caribbean males of Tobago. | GENE-DISEASE |
| The absence of ELAC2 mutations and lack of association between polymorphisms in ELAC2 and DISEASE in cases and controls leads us to conclude that GENE does not contribute significantly to the elevated prevalence of prostate cancer in Afro-Caribbean males of Tobago. | GENE-DISEASE |
| The absence of ELAC2 mutations and lack of association between polymorphisms in ELAC2 and prostate cancer in cases and controls leads us to conclude that GENE does not contribute significantly to the elevated prevalence of DISEASE in Afro-Caribbean males of Tobago. | GENE-DISEASE |
| There is no evidence that either GENE polymorphism is associated with DISEASE or PSA level. | NO-RELATIONSHIP |
| The present study suggested that the common variants in the GENE/ELAC2 gene play a limited role in the risk of DISEASE in the Japanese population. | GENE-DISEASE |
| The present study suggested that the common variants in the HPC2/GENE gene play a limited role in the risk of DISEASE in the Japanese population. | GENE-DISEASE |
| The present study suggested that the common variants in the GENE/ELAC2 gene play a limited role in the risk of DISEASE in the Japanese population. | GENE-DISEASE |
| The present study suggested that the common variants in the HPC2/GENE gene play a limited role in the risk of DISEASE in the Japanese population. | GENE-DISEASE |
| In conclusion, our findings support an etiological role of GENE in DISEASE development. | GENE-DISEASE |
| This is the second study to find no association between GENE +61 and DISEASE susceptibility. | GENE-DISEASE |
| Our results suggest that the polymorphism in GENE gene might not confer increased susceptibility for DISEASE in a Japanese population. | GENE-DISEASE |
| Our findings suggest that the A-G polymorphism of GENE is involved not only in the occurrence but also in the malignant progression of DISEASE. | GENE-DISEASE |
| This study suggests that high GENE production might be important in the development of DISEASE. | NO-RELATIONSHIP |
| This study suggests that high GENE production might be important in the development of DISEASE. | NO-RELATIONSHIP |
| All our results indicate that the presence of the GENE genotype (++) in patients with structural heart disease, severe left ventricular dysfunction and malignant ventricular DISEASE increases the risk for these patients of hemodynamic collapse during these arrhythmias. | NO-RELATIONSHIP |
| All our results indicate that the presence of the GENE genotype (++) in patients with structural heart disease, severe left ventricular dysfunction and malignant ventricular arrhythmias increases the risk for these patients of hemodynamic collapse during these DISEASE. | NO-RELATIONSHIP |
| The GENE gene polymorphism in this study did not seem to be associated with the incidence of DISEASE among the Japanese workers. | GENE-DISEASE |
| It follows that the examined polymorphisms in the genes for ACE, angiotensinogen, and GENE could participate in the etiopathogenesis of DISEASE diseases. | GENE-DISEASE |
| Thus, in contrast to prior studies reporting positive association of the GENE gene with DISEASE in both Irish and German population, our data indicate that the human DTNBP1 is unlikely a major susceptible gene for schizophrenia in Chinese Han patients from Taiwan. | GENE-DISEASE |
| Thus, in contrast to prior studies reporting positive association of the GENE gene with schizophrenia in both Irish and German population, our data indicate that the human DTNBP1 is unlikely a major susceptible gene for DISEASE in Chinese Han patients from Taiwan. | GENE-DISEASE |
| Thus, in contrast to prior studies reporting positive association of the DTNBP1 gene with DISEASE in both Irish and German population, our data indicate that the human GENE is unlikely a major susceptible gene for schizophrenia in Chinese Han patients from Taiwan. | GENE-DISEASE |
| Thus, in contrast to prior studies reporting positive association of the DTNBP1 gene with schizophrenia in both Irish and German population, our data indicate that the human GENE is unlikely a major susceptible gene for DISEASE in Chinese Han patients from Taiwan. | GENE-DISEASE |
| Our study provides further evidence for a role of the GENE gene in the genetic etiology of DISEASE. | GENE-DISEASE |
| We conclude that the GENE *2236 C allele may mark another polymorphism in DRP-2, or in a nearby gene, that may influence susceptibility to DISEASE. | GENE-DISEASE |
| We conclude that the DRP-2 *2236 C allele may mark another polymorphism in GENE, or in a nearby gene, that may influence susceptibility to DISEASE. | GENE-DISEASE |
| Our results suggest that the *2236C allele in the 3'UTR of the GENE gene, or an unknown mutation in linkage disequilibrium with this allele, may reduce the susceptibility to DISEASE, especially the paranoid subtype. | GENE-DISEASE |
| These results suggest that the *2236C allele in the 3'UTR of the GENE gene, or an unknown mutation in linkage disequilibrium with this allele, may reduce the susceptibility to DISEASE, especially the paranoid subtype. | GENE-DISEASE |
| These results provide further evidence of an association between GENE and DISEASE, supporting the involvement of the dopamine pathway in the pathogenesis of CD. | GENE-DISEASE |
| The present results do not support a major role for GENE in the etiology of DISEASE among Caucasians from Sweden. | GENE-DISEASE |
| In children with DISEASE, possession of the GENE 7-repeat allele appears to be associated with an inaccurate, impulsive response style on neuropsychological tasks that is not explained by ADHD symptom severity. | GENE-DISEASE |
| In children with ADHD, possession of the GENE 7-repeat allele appears to be associated with an inaccurate, impulsive response style on neuropsychological tasks that is not explained by DISEASE symptom severity. | GENE-DISEASE |
| In children with DISEASE, possession of the GENE 7-repeat allele appears to be associated with an inaccurate, impulsive response style on neuropsychological tasks that is not explained by ADHD symptom severity. | GENE-DISEASE |
| In children with ADHD, possession of the GENE 7-repeat allele appears to be associated with an inaccurate, impulsive response style on neuropsychological tasks that is not explained by DISEASE symptom severity. | GENE-DISEASE |
| Our results suggest that MAO-A, COMT, 5-HT2A, DRD2, and GENE gene variants are not involved in susceptibility toward different time courses in DISEASE. | GENE-DISEASE |
| The present results do not support a major role for GENE in the etiology of DISEASE among Caucasians from Sweden. | GENE-DISEASE |
| Overall our results indicates that the HTR2A, 5-HTT, GENE and GABA(A)gamma2 genes are not likely to be a major genetic risk factor for DISEASE in this population, with the exception of possible association between nasal inhalation and DRD2 promoter - 141DeltaC polymorphism. | GENE-DISEASE |
| There is good evidence that gene coding for the GENE does not play a major role in the genetic vulnerability to DISEASE. | GENE-DISEASE |
| These results suggest that the S/S genotype of the GENE is associated with worse therapeutic response and more severe executive dysfunctions in patients with DISEASE. | GENE-DISEASE |
| We suggest that the GENE Ser9Gly polymorphism may be a contributing factor to the performance of eye movements used as a phenotypic marker of DISEASE. | GENE-DISEASE |
| Although there remains a possibility that the GENE TaqI A polymorphism plays some role in modifying the phenotype of the disease, these results suggest that neither the A1 allele nor the homozygous A1 genotype is associated with DISEASE. | GENE-DISEASE |
| The results suggest that both the GENE promoter region and the DAT gene do not play a significant role in conferring vulnerability to DISEASE. | GENE-DISEASE |
| Our findings indicate that the GENE -141C Ins allele and the 5-HTTLPR S allele are genetic risk factors for DISEASE in Mexican-Americans, and that smoking modulates the association between genetic risk factors and alcoholism. | GENE-DISEASE |
| Our findings indicate that the GENE -141C Ins allele and the 5-HTTLPR S allele are genetic risk factors for alcoholism in Mexican-Americans, and that smoking modulates the association between genetic risk factors and DISEASE. | GENE-DISEASE |
| These findings suggest that the TaqI A GENE) polymorphism is associated with the predisposition to DISEASE. | GENE-DISEASE |
| We conclude that our data do not support an allelic association between the A1 allele at GENE and DISEASE. | NO-RELATIONSHIP |
| Our results suggest that MAO-A, COMT, 5-HT2A, GENE, and DRD4 gene variants are not involved in susceptibility toward different time courses in DISEASE. | GENE-DISEASE |
| Examination of specific GENE gene polymorphism in 247 Japanese DISEASE patients, 53 alcoholic WKS patients, and 368 nondemented Japanese control subjects revealed no significant differences in DLST genotypes and failed to replicate the findings of earlier studies indicating an association between DLST gene polymorphism and AD. | NO-RELATIONSHIP |
| Examination of specific GENE gene polymorphism in 247 Japanese AD patients, 53 alcoholic WKS patients, and 368 nondemented Japanese control subjects revealed no significant differences in DLST genotypes and failed to replicate the findings of earlier studies indicating an association between DLST gene polymorphism and DISEASE. | NO-RELATIONSHIP |
| Examination of specific DLST gene polymorphism in 247 Japanese DISEASE patients, 53 alcoholic WKS patients, and 368 nondemented Japanese control subjects revealed no significant differences in GENE genotypes and failed to replicate the findings of earlier studies indicating an association between DLST gene polymorphism and AD. | NO-RELATIONSHIP |
| Examination of specific DLST gene polymorphism in 247 Japanese AD patients, 53 alcoholic WKS patients, and 368 nondemented Japanese control subjects revealed no significant differences in GENE genotypes and failed to replicate the findings of earlier studies indicating an association between DLST gene polymorphism and DISEASE. | GENE-DISEASE |
| Examination of specific DLST gene polymorphism in 247 Japanese DISEASE patients, 53 alcoholic WKS patients, and 368 nondemented Japanese control subjects revealed no significant differences in DLST genotypes and failed to replicate the findings of earlier studies indicating an association between GENE gene polymorphism and AD. | NO-RELATIONSHIP |
| Examination of specific DLST gene polymorphism in 247 Japanese AD patients, 53 alcoholic WKS patients, and 368 nondemented Japanese control subjects revealed no significant differences in DLST genotypes and failed to replicate the findings of earlier studies indicating an association between GENE gene polymorphism and DISEASE. | GENE-DISEASE |
| This study provides support for the hypothesis that GENE constitutes a true DISEASE risk factor of modest effect. | GENE-DISEASE |
| The GENE genotype appears to operate independently of APOE in conferring DISEASE risk. | GENE-DISEASE |
| These results suggest that GENE is unlikely to play an important role in DISEASE susceptibility. | GENE-DISEASE |
| These results suggest that GENE is unlikely to play an important role in DISEASE susceptibility. | GENE-DISEASE |
| These results suggest that the genomic interval of GENE probably involved in transcriptional regulation does not display major genetic relevance in Japanese DISEASE patients. | GENE-DISEASE |
| Although the T79C SNP of the GENE gene was studied in several groups of white subjects, the association between this SNP and DISEASE-related phenotypes, previously described, was not confirmed in our population. | GENE-DISEASE |
| Variation in GENE contributes to DISEASE diagnosis, with apparent gender-specific effects. | GENE-DISEASE |
| Genetic variations in GENE may define a high-risk subgroup of DISEASE where the component of chronic bronchitis is predominant. | GENE-DISEASE |
| Genetic variations in GENE may define a high-risk subgroup of DISEASE where the component of chronic bronchitis is predominant. | GENE-DISEASE |
| Genetic variations in GENE may define a high-risk subgroup of DISEASE where the component of chronic bronchitis is predominant. | GENE-DISEASE |
| Genetic variations in GENE may define a high-risk subgroup of DISEASE where the component of chronic bronchitis is predominant. | GENE-DISEASE |
| The observed haplotypic association provides the first evidence of the importance of GENE polymorphisms in DISEASE susceptibility. | GENE-DISEASE |
| No association was observed between the Arg201Gly polymorphism of GENE and DISEASE risk. | GENE-DISEASE |
| These results suggest that GENE does not contribute to the development of DISEASE in Japanese. | GENE-DISEASE |
| In a selected Caucasian population, the GENE SNP 386 is completely absent and SNP 260 is not associated with spermatogenic failure and therefore does not represent a molecular marker for genetic diagnosis of DISEASE. | GENE-DISEASE |
| In the haplotype analysis based on the information of linkage-disequilibrium block across this gene locus, we demonstrated a highly significant association between DISEASE and a GENE haplotype (P = 2.0173 x 10(-21)), which therefore provides an independent statistical support for association of the DAAO gene with schizophrenia and indicates that the DAAO gene may play a significant role in the etiology of schizophrenia in the Han Chinese. | GENE-DISEASE |
| In the haplotype analysis based on the information of linkage-disequilibrium block across this gene locus, we demonstrated a highly significant association between schizophrenia and a GENE haplotype (P = 2.0173 x 10(-21)), which therefore provides an independent statistical support for association of the DAAO gene with DISEASE and indicates that the DAAO gene may play a significant role in the etiology of schizophrenia in the Han Chinese. | GENE-DISEASE |
| In the haplotype analysis based on the information of linkage-disequilibrium block across this gene locus, we demonstrated a highly significant association between schizophrenia and a GENE haplotype (P = 2.0173 x 10(-21)), which therefore provides an independent statistical support for association of the DAAO gene with schizophrenia and indicates that the DAAO gene may play a significant role in the etiology of DISEASE in the Han Chinese. | GENE-DISEASE |
| In the haplotype analysis based on the information of linkage-disequilibrium block across this gene locus, we demonstrated a highly significant association between DISEASE and a DAAO haplotype (P = 2.0173 x 10(-21)), which therefore provides an independent statistical support for association of the GENE gene with schizophrenia and indicates that the DAAO gene may play a significant role in the etiology of schizophrenia in the Han Chinese. | NO-RELATIONSHIP |
| In the haplotype analysis based on the information of linkage-disequilibrium block across this gene locus, we demonstrated a highly significant association between schizophrenia and a DAAO haplotype (P = 2.0173 x 10(-21)), which therefore provides an independent statistical support for association of the GENE gene with DISEASE and indicates that the DAAO gene may play a significant role in the etiology of schizophrenia in the Han Chinese. | GENE-DISEASE |
| In the haplotype analysis based on the information of linkage-disequilibrium block across this gene locus, we demonstrated a highly significant association between schizophrenia and a DAAO haplotype (P = 2.0173 x 10(-21)), which therefore provides an independent statistical support for association of the GENE gene with schizophrenia and indicates that the DAAO gene may play a significant role in the etiology of DISEASE in the Han Chinese. | GENE-DISEASE |
| In the haplotype analysis based on the information of linkage-disequilibrium block across this gene locus, we demonstrated a highly significant association between DISEASE and a DAAO haplotype (P = 2.0173 x 10(-21)), which therefore provides an independent statistical support for association of the DAAO gene with schizophrenia and indicates that the GENE gene may play a significant role in the etiology of schizophrenia in the Han Chinese. | NO-RELATIONSHIP |
| In the haplotype analysis based on the information of linkage-disequilibrium block across this gene locus, we demonstrated a highly significant association between schizophrenia and a DAAO haplotype (P = 2.0173 x 10(-21)), which therefore provides an independent statistical support for association of the DAAO gene with DISEASE and indicates that the GENE gene may play a significant role in the etiology of schizophrenia in the Han Chinese. | GENE-DISEASE |
| In the haplotype analysis based on the information of linkage-disequilibrium block across this gene locus, we demonstrated a highly significant association between schizophrenia and a DAAO haplotype (P = 2.0173 x 10(-21)), which therefore provides an independent statistical support for association of the DAAO gene with schizophrenia and indicates that the GENE gene may play a significant role in the etiology of DISEASE in the Han Chinese. | GENE-DISEASE |
| Our findings could not demonstrate any involvement of POF1B, but suggest that rare mutations in the GENE gene may have a role in the DISEASE phenotype. | GENE-DISEASE |
| Here we report that polymorphisms within the APOE promoter, ACE1 and GENE gene are not risk factors for DISEASE and are not associated with parenchymal or vascular accumulation of Abeta. | GENE-DISEASE |
| Our results indicate that the intron 2 GENE C/C genotype may predispose to DISEASE, and this association is independent of the apolipoprotein E genotype. | GENE-DISEASE |
| These findings provide direct evidence that GENE and ApoE polymorphisms synergically increase the risk for DISEASE development, and influence on the rate of cognitive decline. | GENE-DISEASE |
| Our data indicate that the Intron 2 polymorphism of GENE does not affect the risk of DISEASE in our sample. | GENE-DISEASE |
| Our results indicate that the GENE gene locus may predispose to DISEASE by increasing the 24S-hydroxycholesterol/cholesterol ratio in the brain. | GENE-DISEASE |
| GENE influences brain beta-amyloid load, cerebrospinal fluid levels of beta-amyloid peptides and phosphorylated tau, and the genetic risk of late-onset sporadic DISEASE. | GENE-DISEASE |
| The observation that CYP3A4 and GENE were associated with DISEASE, are not in linkage equilibrium, and are both involved in testosterone metabolism, suggest that both CYP3A4*1B and CYP3A43*3 may influence the probability of having prostate cancer and disease severity. | GENE-DISEASE |
| The observation that CYP3A4 and GENE were associated with prostate cancer, are not in linkage equilibrium, and are both involved in testosterone metabolism, suggest that both CYP3A4*1B and CYP3A43*3 may influence the probability of having DISEASE and disease severity. | GENE-DISEASE |
| The observation that CYP3A4 and CYP3A43 were associated with DISEASE, are not in linkage equilibrium, and are both involved in testosterone metabolism, suggest that both CYP3A4*1B and GENE*3 may influence the probability of having prostate cancer and disease severity. | GENE-DISEASE |
| The observation that CYP3A4 and CYP3A43 were associated with prostate cancer, are not in linkage equilibrium, and are both involved in testosterone metabolism, suggest that both CYP3A4*1B and GENE*3 may influence the probability of having DISEASE and disease severity. | GENE-DISEASE |
| GENE influences brain beta-amyloid load, cerebrospinal fluid levels of beta-amyloid peptides and phosphorylated tau, and the genetic risk of late-onset sporadic DISEASE. | GENE-DISEASE |
| Our results suggest that the GENE-Pro(340)Ala polymorphism contributes to DISEASE risk. | GENE-DISEASE |
| A functionally relevant polymorphism of the GENE gene is independently associated with an increased risk of DISEASE. | GENE-DISEASE |
| The GENE C2 allele is a susceptibility factor for DISEASE, especially for colon cancer, and there is an apparent gene-environment interaction between the susceptible genotype and salted food. | GENE-DISEASE |
| The GENE c1/c1 genotype is a susceptibility factor for development of DISEASE in Chinese and there is an apparent gene-environment interaction between the susceptible genotype and cigarette smoking. | GENE-DISEASE |
| These data establish a whole-gene, high-resolution haplotype structure for GENE in a European American patient population and suggest that genetic variation in exons, rather than the promoter or other regulatory regions, is largely responsible for DISEASE associated with CYP2C9 variants in this population. | NO-RELATIONSHIP |
| These data establish a whole-gene, high-resolution haplotype structure for CYP2C9 in a European American patient population and suggest that genetic variation in exons, rather than the promoter or other regulatory regions, is largely responsible for DISEASE associated with GENE variants in this population. | GENE-DISEASE |
| The results suggest that GENE genetic polymorphism may be related to a DISEASE due to an alteration in endogenous metabolism, although a linkage between CYP2C9 and some other gene related to depression cannot be ruled out. | NO-RELATIONSHIP |
| The results suggest that CYP2C9 genetic polymorphism may be related to a DISEASE due to an alteration in endogenous metabolism, although a linkage between GENE and some other gene related to depression cannot be ruled out. | NO-RELATIONSHIP |
| Association between GENE polymorphism and DISEASE risk was not identified in this study. | GENE-DISEASE |
| These results do not support the hypothesis that DISEASE resulting from NSAID usage is linked to the poor metabolizing genotypes of GENE. | NO-RELATIONSHIP |
| The effect of GENE polymorphisms on nateglinide kinetics may cause a slightly increased risk for DISEASE, which may become relevant in diabetic patients. | NO-RELATIONSHIP |
| Our results suggest that rate of gastric emptying, but not GENE polymorphism, is likely to be an important factor in the delayed healing of patients with PPI-resistant DISEASE. | GENE-DISEASE |
| Our data suggest that deficient GENE activity due to genetic polymorphism reduces DISEASE risk in betel quid chewers. | NO-RELATIONSHIP |
| In this Caucasian population, we found neither a relation between genetically impaired nicotine metabolism and cigarette consumption, nor any modification of DISEASE risk related to the presence of defective GENE alleles (odds ratio = 1.1, 95% confidence interval = 0.7-1.9). | GENE-DISEASE |
| This study suggests that the GENE gene does not play a major role as a DISEASE susceptibility gene. | GENE-DISEASE |
| The results suggest that the CYP19 Arg(264)Cys polymorphism modifies DISEASE risk (OR=1.5, 95% CI=1.1-2.2), especially in association with alcohol consumption (P for interaction=0.04), whereas the GENE Leu(432)Val polymorphism appears to play no role here. | GENE-DISEASE |
| Our data shows no association between DISEASE and the Leu432Val polymorphism of the GENE gene or the tetranucleotide repeats of the CYP19 gene. | GENE-DISEASE |
| Our study showed that gene polymorphisms of GENE and SULT1A1 induce an individual susceptibility to DISEASE among current smokers. | GENE-DISEASE |
| We conclude that the GENE* 3 allele appears to be a factor for susceptibility to DISEASE in Turkish women especially those with a BMI greater than 24 kg/m(2). | GENE-DISEASE |
| Our results suggested that the Val GENE allele increases the susceptibility to DISEASE in women exposed to waste incinerator or agricultural pollutants. | GENE-DISEASE |
| These results do not support a favoring role of GENE*3 in DISEASE development in our population. | GENE-DISEASE |
| We found no evidence for an overall association between GENE genotype and DISEASE risk, nor was there any clear indication of gene-environment interaction. | GENE-DISEASE |
| These results suggest that HLA class I antigens and GENE A-308G are not associated with susceptibility or resistance to the development of TDI-induced DISEASE. | GENE-DISEASE |
| These results suggest that the C1772T polymorphism in GENE is not involved in DISEASE or metastasis of colorectal carcinoma. | NO-RELATIONSHIP |
| These results provide substantial evidence that genetic variation within or extremely close to GENE impacts both DISEASE risk and traits related to the severity of AD. | GENE-DISEASE |
| This study provides the first evidence that GENE may be a candidate susceptibility loci that affects the DISEASE of atherosclerosis in Japanese subjects. | NO-RELATIONSHIP |
| Since only eight out GENE iron-overloaded HbH patients carry a DISEASE in the TFR2 or HFE gene in the heterozygote state and their iron loading status was comparable to the matched controls without such defects, it would appear that the accumulation of excess iron in HbH disease is more likely a result of increase dietary absorption secondary to ineffective erythropoiesis. | NO-RELATIONSHIP |
| The H63D DISEASE of the GENE gene has a moderate but significant influence on sTfR concentration in the general population, the presence of one or two mutated alleles being associated with an average of 0.27 mg/L less sTfR than nonmutated homozygotes. | NO-RELATIONSHIP |
| In Mediterranean populations from Southern Italy the C282Y DISEASE occurs sporadically and GENE polymorphisms seem to have little diagnostic relevance. | NO-RELATIONSHIP |
| GENE genotype GG is associated with cirrhosis in patients with DISEASE. | GENE-DISEASE |
| C282Y and H63D mutations do not appear to be associated with an increased risk of GENE in patients with DISEASE. | NO-RELATIONSHIP |
| The clinical DISEASE and laboratory findings of the patient and his relatives are consistent with the conclusion that the E168Q mutation by itself is unlikely to result in GENE. | NO-RELATIONSHIP |
| Our prospective findings suggest that individuals carrying the GENE C282Y DISEASE may be at increased risk of CHD. | NO-RELATIONSHIP |
| We conclude that homozygosity for the G1514-->A DISEASE is exclusively responsible for the adult form of Sandhoff disease in this family, and that the A619-->G substitution is not a deleterious mutation but rather a common GENE polymorphism. | NO-RELATIONSHIP |
| The results further support the evidence that the repeat expansion at the chromosome 16q24.3 locus is the direct cause of GENE and provide preliminary guidelines for the genetic testing of patients with an DISEASE-like phenotype. | GENE-DISEASE |
| These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the DISEASE among GENE affected persons with large expanded CAG repeats. | NO-RELATIONSHIP |
| The novel gene GENE may be related with the DISEASE and proliferation of liver cancer. | NO-RELATIONSHIP |
| DISEASE mutations of GENE/42, CD17, CD71/72, IVS-II-654 had no influence on Hb F levels, but (G)Gamma-158(C-->T) had a strong association with moderately increased Hb F levels in beta-thalassemia heterozygotes in the Guangxi area of China. | NO-RELATIONSHIP |
| Our findings suggest that the genetic variants of the TIM-1 but not the GENE gene contribute to DISEASE susceptibility in this African-American population. | GENE-DISEASE |
| Our results suggest that the GENE 168His variant is associated with reduced susceptibility to DISEASE. | GENE-DISEASE |
| We found no evidence that DISEASE in GENE,GNGT1,or RGS9 gene is a cause of retinitis pigmentosa. | NO-RELATIONSHIP |
| Statistical analysis indicates that there is no association of the GENE variant and hence the gene does not appear to play a significant role in the development of DISEASE. | GENE-DISEASE |
| Our findings indicate that the polymorphisms of the GENE, CYP2E1, and GSTT1 genes probably play a substantial part in susceptibility to severe airway and lung injury in cases of children with DISEASE and relapsing pneumonia. | NO-RELATIONSHIP |
| Our findings support the view that GENE genotypes contribute to the individual DISEASE risk, especially in certain combinations. | GENE-DISEASE |
| We conclude that genetic alterations in the GENE, GSTM3, GSTT1, and GSTM1 genes do not play a dominant role in DISEASE. | GENE-DISEASE |
| These results support previous reports that the GSTM1 null genotype is associated with a modest increase in risk for DISEASE, particularly among heavy smokers, suggest no role for GSTT1 and the need for further study of GENE. | GENE-DISEASE |
| We conclude that the two polymorphisms, GSTT1 null and PON1 BB, are common genetic GENE that pose low individual risk but may be important determinants of overall population DISEASE risk, particularly among groups exposed to NHL-related carcinogens. | GENE-DISEASE |
| Polymorphisms in the DISEASE-related genes (GENE, GSTM1, GSTT1, MPO, MnSOD) do not seem to be risk factors for preeclampsia. | GENE-DISEASE |
| The GENE-null genotype may increase the risk for HL and is associated with favorable prognostic factors, and the presence of at least one GST DISEASE indicates an improved disease-free survival. | NO-RELATIONSHIP |
| Genetic DISEASE of the GENE enzyme is an independent and powerful predictor of premature vascular morbidity and death in individuals with type 2 diabetes. | NO-RELATIONSHIP |
| In conclusion, GENE, GSTM1, and GSTP1 genotyping seems to be a risk predictor of BPDE-DISEASE in leukocytes. | NO-RELATIONSHIP |
| The results suggest for the first time that in addition to GENE, the NATs play an important role in inception of DISEASE reactions related to occupational exposure to diisocyanates. | NO-RELATIONSHIP |
| Our findings suggest that the polymorphism (Ile105Val) on exon 5 of the GENE gene may contribute to a vulnerability to DISEASE associated with MAP abuse in Japanese population. | NO-RELATIONSHIP |
| Our findings suggest that genetic variability in members of the GENE gene family may be associated with an increased susceptibility to DISEASE. | GENE-DISEASE |
| The GENE Ile(105)Val polymorphism is associated in a dose-dependent fashion with increased survival of patients with advanced DISEASE receiving 5-FU/oxaliplatin chemotherapy. | NO-RELATIONSHIP |
| Our findings suggest that interactions of polymorphic genotypes within the GENE gene cluster affect individual susceptibility to colorectal DISEASE, the GSTM3*B variant presence being a risk factor especially in combination with the GSTM1-null genotype. | NO-RELATIONSHIP |
| Significant associations between genetic polymorphisms in GENE, NQO1 and mEH gene and risk for chromosomal damage were found among occupational PAH-exposed workers, which related to the mechanism of PAH DISEASE. | NO-RELATIONSHIP |
| This study suggests that the GENE polymorphism and its combination with GSTM1 may be associated with DISEASE susceptibility in the Japanese population. | GENE-DISEASE |
| These data suggest that polymorphisms in GENE and GSTM1 contribute to the increased risk of females for DISEASE. | GENE-DISEASE |
| These findings suggest that the cause of GENE gene DISEASE in smokers with lung adenocarcinoma may be in part an accumulation of BP diol epoxide which is not well detoxified in individuals with the GSTM1 null genotype. | NO-RELATIONSHIP |
| The combination of GENE genotype 0/0 and matrix metalloproteinase 9 DISEASE allele (-15621) is a risk factor for chronic obstructive pulmonary disease (OR-7.7). | NO-RELATIONSHIP |
| Our data suggested that the DISEASE of 29-bp nucleotides in the promoter region of the GENE gene associates with the development of PD | NO-RELATIONSHIP |
| These results suggest that the association between urinary 1-OHPG and GENE DISEASE might be modulated by the GSTM1 genotype. | NO-RELATIONSHIP |
| The GENE-null genotype may be associated with an increased risk of HCC, but not of DISEASE and LC. | NO-RELATIONSHIP |
| Individuals with homozygous DISEASE of the GENE gene and a NAT2 slow-acetylator genotype who are exposed to high levels of asbestos appear to have enhanced susceptibility to asbestos-related pulmonary disorders. | NO-RELATIONSHIP |
| No associations between the GENE alleles, including the DISEASE, and cataracts were detected in this study. | NO-RELATIONSHIP |
| Results warrant interest for the variants of genes pertaining to the molecular GENE as possible endophenotypes of DISEASE, but caution ought to be taken in interpreting these preliminary results and future replication studies must be awaited. | GENE-CHEMICAL |
| These data suggest that polymorphisms in the GENE gene may be useful as predictors of negative DISEASE improvement in persons with schizophrenia treated with olanzapine. | NO-RELATIONSHIP |
| These results suggest that variants in NMDAR genes are associated with DISEASE and related GENE. | NO-RELATIONSHIP |
| revealed no significant association between schizophrenia and the SNPs in the upstream region of GENE, these SNPs apparently do not play a critical role in the DISEASE of schizophrenia in the Japanese population. | NO-RELATIONSHIP |
| We conclude that GENE does not play a major role in the DISEASE of schizophrenia in the Japanese population. | NO-RELATIONSHIP |
| We conclude that GENE does not play a major role in schizophrenia DISEASE in the Japanese population. | NO-RELATIONSHIP |
| These results suggest that functional variants in the GENE gene are associated with increased IMT of carotid arteries and risk of cardiovascular and DISEASE in type 2 diabetic patients. | NO-RELATIONSHIP |
| the DISEASE is responsible for a GENE phenotype observed in the patient. | NO-RELATIONSHIP |
| Our results suggest that the GENE Met/VNTR B haplotype of the platelet DISEASE factor and thrombin receptor protein GP Ib-V-IX may be considered to be a major risk factor of coronary thrombosis, fatal MI, and SCD in early middle age. | NO-RELATIONSHIP |
| In conclusion, platelet GENE Ia C807T and GP Ib C3550T polymorphisms in our population are less common compared with Caucasians, and GP IIIa Pl(A1/A2) genetic DISEASE is not found, and all of them are not associated with ischemic stroke in young Taiwanese. | NO-RELATIONSHIP |
| It was concluded that the Kozak T/C polymorphism, which is associated with an increase in platelet GENE Ibalpha surface expression, is an independent risk factor for first-ever DISEASE. | GENE-DISEASE |
| In an unstable coronary DISEASE population the T-5C polymorphism in GPIb(alpha) influences risk of subsequent GENE. | NO-RELATIONSHIP |
| The DISEASE identified in the family studied, responsible for the deficiency of the GENE Ib/IX/V complex, suggests that the cysteine at amino acid position 209 may be involved in disulphide bonding. | NO-RELATIONSHIP |
| The DISEASE demonstrated in this family provides evidence that defective synthesis of GENE alters the membrane expression of the GP Ib-IX complex and may be responsible for Bernard-Soulier syndrome. | NO-RELATIONSHIP |
| Polymorphic markers of GENE and GNB3 candidate genes influence clinical diversity of pathological signs in DM2 patients through modification of AH and DISEASE severity and the level of proinflammatory cytokines. | NO-RELATIONSHIP |
| Although the effect of the gene on each phenotype appears to be DISEASE, considering the combined GENE of the effects of the C825T polymorphism on risk factors, the GNB3 gene may be an important gene for human health. | NO-RELATIONSHIP |
| In conclusion, our results suggest an association between DISEASE and the C825T allele of the G-protein GENE subunit gene. | NO-RELATIONSHIP |
| The current findings of the study suggest that increased body fatness along with low cardiorespiratory fitness may magnify the genetic susceptibility of the GENE 825T allele to elevated DISEASE pressure in this study population. | NO-RELATIONSHIP |
| These results indicate that the GENE C825T polymorphism has no major influence on the pressor response to salt in DISEASE and therefore do not support its usefulness as an early genetic marker of salt sensitivity in this disease. | NO-RELATIONSHIP |
| The T825 allele of GENE is associated with increased serum potassium and total cholesterol levels but not with DISEASE pressure in a Japanese population. | NO-RELATIONSHIP |
| We conclude that the C825T polymorphism of the G-protein GENE subunit gene does not notably contribute to the development of DISEASE or obesity, and is not a significant determinant for blood pressure and body mass index in white men. | NO-RELATIONSHIP |
| In summary, our results demonstrate that the GENE 825T allele is associated with reduced DISEASE in men with abdominal fat distribution and with more advanced carotid atherosclerosis in middle-aged white men and women. | GENE-DISEASE |
| These results suggested that alterations in GENE (or a closely linked gene) were associated with the development and DISEASE of oligodendroglioma. | NO-RELATIONSHIP |
| Our data suggest that GENE alterations are common but have no or a low genetic relevance in the Austrian hearing DISEASE population with or without Cx26 alterations. | NO-RELATIONSHIP |
| None of these patients was carrying the DISEASE in GENE indicating that the occurrence of this deletion is restricted to certain populations. | NO-RELATIONSHIP |
| Screening for GENE mutations in DNA recovered from buccal smears of individuals with inherited hearing DISEASE offers an easy, non-invasive method for early diagnosis and a basis of genetic counselling. | NO-RELATIONSHIP |
| The identification of GENE as the DFNB1 gene should provide a better understanding of the biology of normal and abnormal hearing, help form the basis for diagnosis and may facilitate development of strategies for treatment of this common DISEASE. | NO-RELATIONSHIP |
| Our study indicated that a loss of GENE function contributes to a major DISEASE of X-linked Charcot-Marie-Tooth disease. | NO-RELATIONSHIP |
| In conclusion, we did not obtain conclusive evidence for an involvement of the GENE gene in DISEASE regulation or SNS in our study groups. | NO-RELATIONSHIP |
| The human T1663A GH1 gene polymorphism, which may confer lower levels of GH and GENE, appears to be associated with a decreased risk of DISEASE. | NO-RELATIONSHIP |
| Overall, we obtained no solid evidence for the involvement of the GENE gene in the DISEASE of schizophrenia, although further studies in larger numbers of subjects will be required to conclude whether the trinucleotide repeat polymorphism is associated with the development of schizophrenia. | NO-RELATIONSHIP |
| Genetic variation in GENE is thus unlikely to have a major impact on susceptibility to DISEASE. | GENE-DISEASE |
| Our results suggest that GCK gene was associated with Chinese DISEASE, and haplotype of GCK1/GCK2 GENE was a protective factor for GDM. | NO-RELATIONSHIP |
| These findings support a role for genetic variants within the GABA receptor gene complex in 15q11-GENE in DISEASE. | GENE-DISEASE |
| We conclude that the -30 beta-GENE GCK gene promoter variant is associated with reduced beta-cell function in middle-aged Japanese-American men and may contribute to the high risk of abnormal glucose DISEASE in this population. | NO-RELATIONSHIP |
| These results indicate that the variant (-30) of the islet promoter region of the GENE gene does not have a significant effect on insulin secretion in Finnish subjects with NGT, IGT, or DISEASE. | NO-RELATIONSHIP |
| The Gly40Ser polymorphism of the GENE-R gene is associated with central DISEASE independently from total body mass in men. | GENE-DISEASE |
| Taken together, these results demonstrate that the GC*1F and GENE alleles are associated with sputum hypersecretion in individuals who are at increased risk of developing DISEASE. | GENE-DISEASE |
| Our results suggest that heterozygosity for a GENE DISEASE may predispose Ashkenazi Jews to Parkinson's disease. | NO-RELATIONSHIP |
| We conclude that the nature of the amino acid substitution at position 218 of the Nf of GENE is of crucial importance in determining the severity of the phenotype in DISEASE patients and possibly also in inducing skewed X inactivation. | GENE-DISEASE |
| It is unlikely that either maternal or fetal GENE enzyme activity could affect paramesonephric duct development, because neither galactosaemic subjects nor their children have an increased incidence of DISEASE. | GENE-DISEASE |
| We conclude that the GENE N314D allele does not predispose to DISEASE. | GENE-DISEASE |
| We conclude that the N314D DISEASE is a common allele that probably causes the Duarte GENE biochemical phenotype and occurs in a predominantly Caucasian, nongalactosemic population, with a prevalence of 5.9%. | NO-RELATIONSHIP |
| Our data suggest that GENE is involved in the DISEASE of NSCLP in the Japanese population. | NO-RELATIONSHIP |
| In conclusion, the present study indicates that in a population of PTSD patients, heterozygosity of the GENE major (G1) allele confers higher levels of somatic DISEASE, anxiety/insomnia, social dysfunction and depression than found in homozygosity. | NO-RELATIONSHIP |
| Results with GENE and DRD4 genes indicate that these two genes may not play major roles in the development of DISEASE. | NO-RELATIONSHIP |
| These findings support a role for the serotonin transporter and GABA(A) alpha6 subunit in DISEASE-related GENE. | NO-RELATIONSHIP |
| These results suggest that the T1521C polymorphism in the GENE gene is associated with specific DISEASE characteristics as well as a marked attenuation in hormonal and blood pressure responses to psychological stress. | GENE-DISEASE |
| These results suggest that the GENE gene may confer susceptibility to DISEASE. | GENE-DISEASE |
| The presence or DISEASE of the 282-bp allele in the genotype of GENE patients was not shown to influence the age of onset and the overall clinical severity, but was found to be associated with a preponderance of manic over depressive episodes in the course of the illness. | NO-RELATIONSHIP |
| This study can rule out even small size effects in the total sample and suggests a lack of association between GENE polymorphism and DISEASE, in the Spanish population. | GENE-DISEASE |
| The results of our study indicate that GENE gene might also be involved in the genetic DISEASE of unipolar major depressive disorder (at least in female patients), even if the findings do not support a predominant role of GABRA 3. | NO-RELATIONSHIP |
| These findings suggest that genetic variants of GENE increase risk for DISEASE in the Russian population and provide additional support to the hypothesis that polymorphic variation at the GABRA2 locus plays an important role in predisposing to AD at least in European-ancestry populations. | NO-RELATIONSHIP |
| These data did not support our hypothesis that polymorphisms of the GENE gene may confer vulnerability for DISEASE. | GENE-DISEASE |
| We postulate that the GENE gene might not be a susceptibility gene for DISEASE at least in the Chinese population. | GENE-DISEASE |
| We identified no sequence variations in the G6PD core promoter or in the 5' GENE of these G6PD-deficient individuals, which indicates that DISEASE is not associated with promoter mutations in the G6PD locus. | NO-RELATIONSHIP |
| We conclude that GENE A- heterozygous females are protected against all forms of DISEASE malaria, and that the TNFalpha(-238A) allele confers protection against clinical malaria. | NO-RELATIONSHIP |
| Our results indicate a possible association of DISEASE with a genotype of the SNP T137346C of the GENE fyn, with C being the risk allele. | NO-RELATIONSHIP |
| The results showed that none of them had the DISEASE, indicating that genetic defects in the GENE gene are unlikely to be a common cause of typical PD, at least in a North America population. | NO-RELATIONSHIP |
| The GENE Ser680/Ser680 genotype is associated with higher ovarian threshold to FSH, decreased negative feedback of luteal secretion to the pituitary during the intercycle DISEASE, and longer menstrual cycles. | NO-RELATIONSHIP |
| The analysis did not reveal any DISEASE in the 240 analysed chromosomes, indicating that mutations in the GENE coding region are rarely associated with non-syndromic POF. | NO-RELATIONSHIP |
| Our data indicate that variation in GENE may have a DISEASE role in body weight control and seems to be involved in the regulation of basal glucose turnover and plasma triglyceride levels in women, but this gene does not significantly contribute to the etiology of type 2 diabetes in Pima Indians. | NO-RELATIONSHIP |
| We conclude that GENE is associated with DISEASE and metabolic deterioration but does not contribute to an increased risk for type 2 diabetes. | NO-RELATIONSHIP |
| Our data suggest that GENE is a DISEASE but consistent candidate gene for obesity and dyslipidemia. | NO-RELATIONSHIP |
| These data suggest that the presence of the H475Y GENE allele impairs the intestinal absorption of dietary folates, resulting in relatively low DISEASE folate levels and consequent hyperhomocysteinemia. | NO-RELATIONSHIP |
| We conclude that genotypes of the GENE gene are useful prognostic factors in SSc, helping to predict individuals likely to develop DISEASE. | GENE-DISEASE |
| These findings support a central role of genes regulating the GENE axis in the causality of DISEASE and the mechanism of action of antidepressant drugs. | GENE-DISEASE |
| Our results support the conclusion that the GENE Arg(388) allele represents a determinant that is innocuous in healthy individuals but predisposes DISEASE patients for significantly accelerated disease progression. | GENE-DISEASE |
| The GENE Arg388 allele is associated with both an increased incidence and clinical DISEASE of prostate cancer and results in changes in cellular motility and invasiveness in immortalized prostate epithelial cells consistent with the promotion of metastasis. | NO-RELATIONSHIP |
| We conclude that the spectrum of GENE mutations causing craniosynostosis is wider than previously recognized but that, nevertheless, the IgIIIa/IIIc region represents a genuine DISEASE hotspot. | GENE-DISEASE |
| The G-455A polymorphism of the fibrinogen gene promoter and the decamer insertion or DISEASE polymorphism of the GENE gene promoter are unlikely to be major genetic predisposing factors for preeclampsia in subjects from eastern Finland. | NO-RELATIONSHIP |
| In conclusion, there was no association between the beta-fibrinogen -455 G/A, GENE IIIa PlA1/A2, PAI-1 4G/5G, factor V Leiden 1691 G/A, TNFalpha -238 G/A, TNFalpha -308 G/A, IL-1alpha -889 C/T, the IL-1beta -511 C/T, MTHFR 677 C/T and eNOS 4 b/a gene polymorphisms and the risk of DISEASE after PTCA as well as recurrent restenosis after repeated PTCA. | GENE-DISEASE |
| While the results should be interpreted with caution as the frequency of the -455A allele is rare, the -455A allele of the beta-fibrinogen gene does not appear to be associated with an increased risk of GENE or DISEASE. | NO-RELATIONSHIP |
| beta fibrinogen gene -455G/A polymorphism is associated with increased plasma fibrinogen levels and may be an important risk factor in the DISEASE of GENE. | NO-RELATIONSHIP |
| The present study demonstrates that neither the Bgl GENE gene polymorphism nor -455G/A polymorphism in the beta fibrinogen gene is a genetic marker for DISEASE in Slovene population (Caucasians) with type 2 diabetes. | NO-RELATIONSHIP |
| Plasma fibrinogen expression is affected by the beta-fibrinogen gene -455A/G polymorphism, and the GENE allele may be a risk factor for DISEASE in Chinese males. | GENE-DISEASE |
| A modest association between GENE and schizophrenia suggests that this gene and the DISC1-mediated molecular pathway might DISEASE in the development of schizophrenia, with FEZ1 affecting only a small subset of Japanese schizophrenia patients. | NO-RELATIONSHIP |
| The observation that GENE patients carrying the R allele of FcgammaRIIA are at higher risk of acquiring chronic P. aeruginosa DISEASE suggests that the FcgammaRII loci genetic variation is contributing to this infection susceptibility. | NO-RELATIONSHIP |
| This study suggests that FcgammaR GENE a-131 is a major factor predisposing to the development of DISEASE in southern Chinese Han population. | NO-RELATIONSHIP |
| We conclude that Fcgamma receptor polymorphisms influence neither susceptibility nor clinical DISEASE of GENE. | NO-RELATIONSHIP |
| Thus, we concluded that the association of GENE-131H/R and Fc gamma RIIIB-NA1/NA2 polymorphisms with DISEASE in Thailand is not due to the LD caused by Fc gamma RIIIA-176F/V. | NO-RELATIONSHIP |
| We conclude that polymorphisms of the low-affinity Fcgamma receptors are not associated with DISEASE in GENE disease. | NO-RELATIONSHIP |
| The GENE-R/R131 genotype may be one of the contributors for the increased susceptibility to severe DISEASE in Chinese Han nationality. | NO-RELATIONSHIP |
| The present study suggests that the IgG2-binding GENE-His/His131 genotype is associated with enhanced susceptibility to PM in DISEASE-positive women but not in HIV-negative women. | NO-RELATIONSHIP |
| This study provides the first evidence that the infant GENE His/His131 genotype is associated with susceptibility to perinatal HIV-1 DISEASE and further suggests that there is a dose-response relationship for the effect of the Fc gamma RIIa His131 gene on transmission. | NO-RELATIONSHIP |
| This is the first evidence for an association between GENE polymorphism and severe DISEASE and provides an example of balancing selective pressures from different infectious diseases operating at the same genetic locus. | NO-RELATIONSHIP |
| Although a causative link has not been shown, these data are consistent with an important role for GENE genotype in cardiovascular risk associated with large-artery stiffening and pulse pressure elevation in individuals with DISEASE. | GENE-DISEASE |
| We did not find any statistically significant association of DISEASE and GENE polymorphisms and haplotypes with AIDS progression. | NO-RELATIONSHIP |
| These results are consistent with our initial findings in DISEASE and further support the hypothesis that the GENE and FASL triggered apoptosis pathway plays an important role in human carcinogenesis. | GENE-DISEASE |
| On the whole, our data suggest that DISEASE and GENE polymorphisms, as well as their haplotypes, are unlikely to be associated with successful human longevity. | NO-RELATIONSHIP |
| In conclusion, our data do not suggest common genetic GENE variants to significantly contribute to the DISEASE of either Hashimoto's thyroiditis or Graves' disease. | NO-RELATIONSHIP |
| DISEASE-670 polymorphism is not associated with GENE in Chinese patients. | NO-RELATIONSHIP |
| A genetic variant in the DISEASE gene is associated with an increased rate of GENE in multifetal pregnancies. | NO-RELATIONSHIP |
| Our results do not confirm the hypothesis that GENE genotype in DISEASE gene promoter may be engaged in the development of cervical neoplasia. | NO-RELATIONSHIP |
| Our data suggest that the DISEASE promoter -670 polymorphism is associated with development of anti-GENE antibodies in SLE. | NO-RELATIONSHIP |
| These findings provide evidence that GENE and PPARgamma work together to influence a biologic pathway affecting DISEASE and body composition, illustrating the importance of investigating the joint effect of genes in determining susceptibility for complex disease. | GENE-DISEASE |
| The GENE A54T missense DISEASE may contribute to the TG enrichment of HDL in the postprandial state that, in turn, may alter the risk of atherosclerotic vascular disease. | NO-RELATIONSHIP |
| These results therefore suggested that the effects of the GENE polymorphism on TG, LDL-C and body mass index were associated with gender difference and DISEASE amongst non-diabetic Japanese-American subjects. | NO-RELATIONSHIP |
| These results suggest that the GENE Thr54 allele may have a DISEASE contribution to the insulin resistance syndrome in a white general population. | NO-RELATIONSHIP |
| These results suggest a role for the GENE 385 A/A missense polymorphism as an endocannabinoid risk factor in DISEASE/obesity and may provide indirect evidence to support cannabinoid antagonist treatment strategies in overweight disorders. | NO-RELATIONSHIP |
| Because the Pro129Thr polymorphism reduces enzyme instability, it is unlikely that DISEASE of GENE and enhanced endocannabinoid system induce susceptibility to either methamphetamine dependence/psychosis or schizophrenia. | NO-RELATIONSHIP |
| In conclusion, the GENE of FXIII Val34Leu on the venous thromboembolic risk is modest, suggesting that screening for this DISEASE in factor V Leiden carriers is not justified. | NO-RELATIONSHIP |
| The 4G/4G-GENE genotype might be a protective factor against ACI, whereas the factor V point DISEASE (1691G-A) and the factor VII Arg/Gln353 gene polymorphism have not proved to be risk factors for ACI. | NO-RELATIONSHIP |
| The results suggested that possible association existed between the use of COC and the onset of DISEASE, however the mutations of G1691-->A in factor V gene, G20210-->A in GENE gene and I/D polymorphism of ACE gene did not seem to contribute to this association. | GENE-DISEASE |
| We conclude that GENE and the PT-20210A are risk factors for DISEASE as well as Hcy levels, but the MTHFR and PAI-1 polymorphisms do not appear to be associated with VT in our country. | NO-RELATIONSHIP |
| These data suggest that GENE is associated with an increased risk of obstetric DISEASE, but that the -455A allele of beta-fibrinogen, PGM and MTHFR do not appear to be implicated. | CHEMICAL-INDUCED-DISEASE |
| Present data indicate that testing for heritable DISEASE would be important to identify aPL subjects with an increased risk of developing GENE. | NO-RELATIONSHIP |
| Factor GENE gene 3'-UT G20210A DISEASE allele is absent in Chinese patients with ischemic stroke and normal subjects; its mutation may not be a major risk factor for thrombogenesis in Chinese people. | NO-RELATIONSHIP |
| The single-nucleotide polymorphism of GENE C807T seems to play a role as a prognostic factor in recovery from sudden DISEASE. | GENE-DISEASE |
| Homozygosity for GENE 4G or FXIII 34Leu polymorphisms as well as compound carrier status is associated with DISEASE loss. | NO-RELATIONSHIP |
| The GENE allele of the amino acid polymorphism of the FXIII gene is associated with a decreased risk of DISEASE, and this protecting association seems to be more pronounced in smokers. | NO-RELATIONSHIP |
| Our results showed that the FXIII Leu allele has no protective effect in the development of DISEASE in GENE. | NO-RELATIONSHIP |
| We found GENE-fold higher risk of acute DISEASE associated with the homozygosity of the T allele of the F12, 46C-->T polymorphism in the Spanish population. | GENE-DISEASE |
| The AluI polymorphism in the ERbeta gene is associated with an increased risk of stage GENE DISEASE in a Japanese population. | NO-RELATIONSHIP |
| Polymorphisms in the genes encoding for ERalpha, ERbeta and GENE did not correlate with the occurrence of uterine DISEASE in our Caucasian population. | GENE-DISEASE |
| These data thus indicate that the GENE genotype may modulate the relationship between BMD or rates of DISEASE and estrogen levels in men and that bone mass in men with the X or P alleles may be more susceptible to the consequences of estrogen deficiency (and conversely, benefit most from estrogen sufficiency) than in men with the xx or pp genotypes. | NO-RELATIONSHIP |
| ER and GENE genes may contribute to DISEASE in a distinct manner: estrogen sensitivity influences the severity in the early phase after menopause while vitamin D plays an important role at older ages when the contribution of estrogen loss is weaker. | GENE-DISEASE |
| The results suggest that the studied dinucleotide repeat polymorphism of the GENE gene may contribute to specific components of DISEASE. | GENE-DISEASE |
| GENE gene RFLPs is related to TCM DISEASE Differentiation typing. | NO-RELATIONSHIP |
| Estrogen receptor alpha polymorphisms, but not GENE-adrenergic receptor gene, may be associated with a risk of DISEASE. | NO-RELATIONSHIP |
| Our findings suggest that GENE and ERCC2 SNPs are possible markers for DISEASE formation, whereas cyclin D1 and p16 SNPs may be markers of genes that have an inverse effect on the risk to develop meningioma in irradiated and nonirradiated populations. | GENE-DISEASE |
| These results suggest that individuals who smoke and have the GENE codon 312 Asp/Asp genotype may be at a greater risk of p53 mutations, especially if combined with other polymorphisms that may result in DISEASE. | NO-RELATIONSHIP |
| Adjusting for performance status and GENE of treatment regimen, carrying at least one ERCC1 8092A allele is associated with a >2-fold increase in grade 3 or 4 gastrointestinal toxicity among platinum-treated DISEASE patients. | NO-RELATIONSHIP |
| In conclusion, the GENE C8092A polymorphism may be a useful predictor of OS in advanced DISEASE patients treated with platinum-based chemotherapy. | NO-RELATIONSHIP |
| Therefore, we suggest that the GENE genotype in codon 118 of ERCC1 is a surrogate marker for predicting better survival in DISEASE patients treated with cisplatin combination chemotherapy. | NO-RELATIONSHIP |
| In conclusion, our results support the view that both the GENE codon 594 and HER2 codon 655 polymorphisms are not associated with increased risk of DISEASE. | GENE-DISEASE |
| These results suggest that sEH and EDHF play some important role in the DISEASE of GENE resistance found in type 2 diabetes. | NO-RELATIONSHIP |
| In conclusion, GENE variants at codon 113 and 139 associated with high predicted enzymatic activity appear to increase risk for DISEASE, particularly among recent and current smokers. | GENE-DISEASE |
| Our data show that the K1019X DISEASE in the GENE gene differs in frequency between AA and EA, is associated with increased risk for PC in AA men with a positive family history, and may be an important genetic risk factor for prostate cancer in AA. | NO-RELATIONSHIP |
| In healthy normoglycemic Finnish subjects, the K121Q polymorphism of the GENE gene is associated with DISEASE but not with impaired insulin secretion or dyslipidemia. | NO-RELATIONSHIP |
| The results showed that the K121Q GENE polymorphism in the Spanish population has no significant impact on DISEASE. | GENE-DISEASE |
| We conclude that carriers of the Q variant of GENE are at increased risk for developing DISEASE early in the course of type 1 diabetes. | GENE-DISEASE |
| We conclude that the interaction between the K121Q polymorphism of the GENE gene and birth length affects DISEASE and increases susceptibility to type 2 diabetes and hypertension in adulthood. | NO-RELATIONSHIP |
| In conclusion, we have identified a possible molecular mechanism for GENE overexpression that confers an increased risk for DISEASE-related abnormalities. | NO-RELATIONSHIP |
| In summary, the HPC2 gene variants Leu217 and Thr541 were associated with an increased risk for DISEASE and for GENE in males undergoing radical prostatectomies in the Calgary region. | NO-RELATIONSHIP |
| The DISEASE of GENE mutations and lack of association between polymorphisms in ELAC2 and prostate cancer in cases and controls leads us to conclude that ELAC2 does not contribute significantly to the elevated prevalence of prostate cancer in Afro-Caribbean males of Tobago. | NO-RELATIONSHIP |
| Therefore, GENE and RNASEL may play a role in prostate DISEASE and severity. | NO-RELATIONSHIP |
| There is no evidence that either GENE polymorphism is associated with prostate cancer or DISEASE level. | NO-RELATIONSHIP |
| This study suggests that epithelium-specific GENE and ETS-3 genes are unlikely to contain polymorphic loci that have a major impact on DISEASE susceptibility in our population. | GENE-DISEASE |
| GENE DISEASE and EGFR amplification are important prognostic factors in patients with anaplastic astrocytoma and in older patients with glioblastoma multiforme, respectively. | NO-RELATIONSHIP |
| These results indicate that DISEASE is not associated with AluI polymorphism of GENE gene and EGF gene polymorphism is different between schizophrenia and lung cancer patients. | GENE-DISEASE |
| Our findings suggest that the A-G polymorphism of GENE is involved not only in the occurrence but also in the malignant DISEASE of gastric cancer. | NO-RELATIONSHIP |
| In summary, in our group, the GENE +61 polymorphism was not a risk factor for CMM susceptibility, but this polymorphism may play a role in DISEASE. | NO-RELATIONSHIP |
| Our study thus suggests possible involvement of GENE in essential DISEASE. | NO-RELATIONSHIP |
| Although a functional relevance of the GENE G-N haplotype itself remains unclear, the data demonstrate that genetic variation at the EDN1 locus has a significant effect on DISEASE filtration but not on UAE in the general | NO-RELATIONSHIP |
| Our DISEASE suggests a gender-specific relationship between the G5665T GENE polymorphism and change in SBP in response to antihypertensive treatment with irbesartan or atenolol, suggesting the endothelin pathway to be a common mechanism included in the hypertensive action of the drugs. | NO-RELATIONSHIP |
| All our results indicate that the presence of the GENE genotype (++) in patients with structural DISEASE, severe left ventricular dysfunction and malignant ventricular arrhythmias increases the risk for these patients of hemodynamic collapse during these arrhythmias. | NO-RELATIONSHIP |
| It follows that the examined polymorphisms in the genes for GENE, angiotensinogen, and ET-1 could participate in the etiopathogenesis of DISEASE diseases. | NO-RELATIONSHIP |
| All our results suggested that the presence of the (++)GENE genotype in patients with structural DISEASE, severe left ventricular dysfunction, and malignant ventricular arrhythmia put these patients at a higher risk of hemodynamic collapse during arrhythmic episodes. | NO-RELATIONSHIP |
| Herewith, we report, based on a case-control analysis, that the same GENE polymorphism participates in susceptibility to the endemic form of PF seen in Tunisia and, thus, show that common genetic factors govern the breakage of DISEASE to desmoglein 1 in different epidemiological and environmental situations. | NO-RELATIONSHIP |
| We conclude that the DRP-2 *2236 C allele may GENE another polymorphism in DRP-2, or in a nearby gene, that may influence susceptibility to DISEASE. | NO-RELATIONSHIP |
| Our results suggest that the *2236C allele in the 3'GENE of the DRP-2 gene, or an unknown DISEASE in linkage disequilibrium with this allele, may reduce the susceptibility to schizophrenia, especially the paranoid subtype. | NO-RELATIONSHIP |
| The present study did not provide any evidence for a contribution of the GENE gene to susceptibility to DISEASE. | GENE-DISEASE |
| These results suggest that the *2236C allele in the 3'GENE of the DRP-2 gene, or an unknown DISEASE in linkage disequilibrium with this allele, may reduce the susceptibility to schizophrenia, especially the paranoid subtype. | NO-RELATIONSHIP |
| These results provide further evidence of an association between GENE and cervical dystonia, supporting the involvement of the dopamine pathway in the DISEASE of CD. | NO-RELATIONSHIP |
| No evidence for an involvement of GENE, DRD5, HLA-DRB, or polymorphisms in the homocysteine pathway in the DISEASE of F-ITD was found. | NO-RELATIONSHIP |
| No significant difference was demonstrated for genotype or allele frequency when comparing GENE-dependent and control cases for the DRD2 TaqI and the DRD4 gene exon III VNTR polymorphisms, suggesting that these two polymorphisms do not play major roles in MAP DISEASE for our sample of Chinese males. | NO-RELATIONSHIP |
| Thus, an interaction between GENE and 5-HTTLPR genes constitutes susceptibility to DISEASE, thereby yielding apparent relationships between the major psychiatric symptomatology scores and genotype combinations in samples that are obtained by pooling schizophrenia with other diagnostic categories. | GENE-DISEASE |
| Using these methods, no association was found between the -616 C/G SNP and DISEASE factors of Cloninger's temperament and character inventory (GENE) in our population. | NO-RELATIONSHIP |
| In children with ADHD, possession of the GENE 7-repeat allele appears to be associated with an inaccurate, impulsive response style on neuropsychological tasks that is not explained by ADHD DISEASE severity. | NO-RELATIONSHIP |
| Results suggested that GENE L participants demonstrated significantly higher craving after DISEASE of alcohol as compared with the control beverage. | NO-RELATIONSHIP |
| The GENE gene is probably not of importance to the different DISEASE dimensions as measured by the Karolinska Scales of Personality. | NO-RELATIONSHIP |
| Overall our results indicates that the HTR2A, GENE, DRD3 and GABA(A)gamma2 genes are not likely to be a major genetic risk factor for DISEASE in this population, with the exception of possible association between nasal inhalation and DRD2 promoter - 141DeltaC polymorphism. | GENE-DISEASE |
| We conclude that the investigated GENE polymorphism does not have a major impact on DISEASE in the investigated population. | GENE-DISEASE |
| We found no evidence that the GENE gene is likely to confer susceptibility to the development of DISEASE in Chinese patients with schizophrenia. | NO-RELATIONSHIP |
| Our results possibly indicate an association of DISEASE with GENE homozygosity (P=0.056). | GENE-DISEASE |
| These data suggest that the GENE Ser9Gly polymorphism or, alternatively, another genetic variation that is in linkage disequilibrium, may influence response to risperidone in negative DISEASE and social functioning. | NO-RELATIONSHIP |
| These results do not provide evidence for an involvement of the GENE gene in DISEASE pressure levels or in the pathogenesis of diabetic nephropathy in type 1 diabetic patients. | NO-RELATIONSHIP |
| The results of our study suggest that variations of the GENE gene are likely involved in the regulation of impulsivity and some psychopathological aspects of DISEASE related to violent behavior. | NO-RELATIONSHIP |
| These results are consistent with no role for genetic variation of the GENE dopamine receptor in susceptibility to DISEASE. | GENE-DISEASE |
| In conclusion, we suggest that Gly/Gly homozygotes in the MscI polymorphic site of the GENE gene may cause some change in the function of the dopamine D3 receptor and may be involved the DISEASE of TD. | NO-RELATIONSHIP |
| We conclude that this GENE polymorphism is not a risk factor for DISEASE in our sample. | GENE-DISEASE |
| Although there remains a possibility that the GENE TaqI A polymorphism plays some role in modifying the phenotype of the DISEASE, these results suggest that neither the A1 allele nor the homozygous A1 genotype is associated with alcoholism. | GENE-DISEASE |
| Our results provide evidence for a possible developmental link between GENE and DISEASE via early sustained attention and information processing. | GENE-DISEASE |
| Our findings indicate that the GENE -141C DISEASE allele and the 5-HTTLPR S allele are genetic risk factors for alcoholism in Mexican-Americans, and that smoking modulates the association between genetic risk factors and alcoholism. | NO-RELATIONSHIP |
| These findings suggest that GENE TaqIA polymorphism may be associated with an increased risk for developing motor DISEASE in PD. | NO-RELATIONSHIP |
| No association was found between TaqI A GENE polymorphism and DISEASE in the Russians and the Tatars. | GENE-DISEASE |
| In the GENE of this DISEASE, A2A2 DRD2 genotype appears to be related to chronicity of schizophrenia. | NO-RELATIONSHIP |
| We conclude that GENE alleles are not associated with DISEASE in this sample, and that genetic variation at the DRD2 locus is not likely to be an important contributor to risk for this disorder. | GENE-DISEASE |
| We conclude that our data do not support an allelic association between the GENE allele at DRD2 and DISEASE. | GENE-DISEASE |
| This result indicates that germline mutations in GENE are unlikely to cause an inherited predisposition to DISEASE. | GENE-DISEASE |
| The markedly increased bone density in individuals having the GENE, 4 bp DEL,NT3198 DISEASE shows that this alteration affects both endochondral and intramembranous bone formation and suggests that the DLX3 gene is important in bone formation and/or homeostasis of the appendicular skeleton. | NO-RELATIONSHIP |
| The AT/GENE genotype of DLST gene is associated with an increased risk for DISEASE. | NO-RELATIONSHIP |
| The DLD genotype appears to operate independently of GENE in conferring DISEASE risk. | GENE-DISEASE |
| These data support the idea that these apparently distinct DISEASE have at least a partially convergent etiology and that variation at the GENE locus predisposes individuals to a variety of psychiatric disorders. | NO-RELATIONSHIP |
| The DII-ORFa-Gly3Asp and DII-Thr92Ala polymorphisms do not explain differences in well-being, neurocognitive functioning, or appreciation of T4/GENE combination therapy in patients treated for DISEASE. | NO-RELATIONSHIP |
| These results indicate that genetic variations in the GENE gene encoding hBD-1 may have a major role in mediating and/or contributing to susceptibility to DISEASE. | NO-RELATIONSHIP |
| The GENE SNPs examined are not involved in susceptibility to juvenile DISEASE. | GENE-DISEASE |
| Thus, our results do not support an involvement of the 1-bp or 4-bp DISEASE within the GENE gene in the etiology of affective disorders. | NO-RELATIONSHIP |
| The 179 allele variant of the GENE gene is related to a slower DISEASE of DN in type 1 diabetic patients with albuminuria and receiving antihypertensive therapy. | NO-RELATIONSHIP |
| In a selected Caucasian population, the DAZL SNP 386 is completely absent and SNP 260 is not associated with GENE and therefore does not represent a molecular marker for genetic diagnosis of DISEASE. | GENE-DISEASE |
| These results indicated that specific variants of the GENE gene might be associated with the mechanisms responsible for adult BA and contribute to airway DISEASE and remodeling. | NO-RELATIONSHIP |
| In the haplotype analysis based on the information of linkage-disequilibrium DISEASE across this gene locus, we demonstrated a highly significant association between schizophrenia and a GENE haplotype (P = 2.0173 x 10(-21)), which therefore provides an independent statistical support for association of the DAAO gene with schizophrenia and indicates that the DAAO gene may play a significant role in the etiology of schizophrenia in the Han Chinese. | NO-RELATIONSHIP |
| In conclusion, we present evidence that the CC variant of the A-278C polymorphism in the rate-limiting enzyme in the catabolism of cholesterol, GENE, increases the DISEASE of atherosclerosis and possibly the risk of a new clinical event. | NO-RELATIONSHIP |
| A decreased risk of proximal DISEASE in relation to the CC genotype of GENE A-203C, which probably renders less activity of the enzyme converting cholesterol to bile acids, is new evidence for the role of bile acids in colorectal carcinogenesis. | GENE-DISEASE |
| Here we report that polymorphisms within the APOE promoter, ACE1 and CYP46 gene are not risk factors for DISEASE and are not associated with parenchymal or vascular accumulation of GENE. | GENE-DISEASE |
| Our results provide an important independent replication of previous findings, supporting the existence of GENE sequence variants that contribute to variability in beta-DISEASE metabolism. | NO-RELATIONSHIP |
| Our results indicate that the intron 2 CYP46 GENE genotype may predispose to DISEASE, and this association is independent of the apolipoprotein E genotype. | GENE-DISEASE |
| These findings provide direct evidence that GENE and ApoE polymorphisms synergically increase the risk for AD development, and influence on the rate of DISEASE. | NO-RELATIONSHIP |
| GENE influences brain beta-DISEASE load, cerebrospinal fluid levels of beta-amyloid peptides and phosphorylated tau, and the genetic risk of late-onset sporadic AD. | NO-RELATIONSHIP |
| Despite growing evidence implicating cholesterol metabolism in DISEASE risk and GENE generation, our data does not support a robust genetic relationship between the CYP46 intron 2 polymorphism and AD risk or neuropathology. | NO-RELATIONSHIP |
| The observation that GENE and CYP3A43 were associated with prostate cancer, are not in linkage equilibrium, and are both involved in testosterone metabolism, suggest that both CYP3A4*1B and CYP3A43*3 may influence the probability of having prostate cancer and DISEASE severity. | GENE-DISEASE |
| The GENE*6 allele is rare in the Caucasian population, and no association is inferred between this allelic variant and DISEASE. | NO-RELATIONSHIP |
| Polymorphic variants of GENE genes may contribute to the DISEASE of liver disease and HCC risk in HCV-infected subjects. | NO-RELATIONSHIP |
| In conclusion, genetic polymorphisms of GENE 2D6 and 2E1, PXR, and MDR1 do not appear to play a role in the onset of DISEASE. | GENE-DISEASE |
| Therefore, no significant association between GENE RsaI, CYP2E1 DraI, ADH1C, NQO1 polymorphisms and alcohol DISEASE was observed in healthy controls. | NO-RELATIONSHIP |
| The GENE C2 allele is a susceptibility factor for colorectal cancer, especially for DISEASE, and there is an apparent gene-environment interaction between the susceptible genotype and salted food. | GENE-DISEASE |
| The CYP2E1 GENE/c1 genotype is a susceptibility factor for development of DISEASE in Chinese and there is an apparent gene-environment interaction between the susceptible genotype and cigarette smoking. | NO-RELATIONSHIP |
| This result suggests that susceptibility to DISEASE may be associated with the RsaI and GENE polymorphism of the P450IIE1 gene. | NO-RELATIONSHIP |